U.S. patent application number 17/149170 was filed with the patent office on 2021-05-06 for prodrugs of gamma-hydroxybutyric acid, compositions and uses thereof.
The applicant listed for this patent is XWPHARMA LTD.. Invention is credited to JIA-NING XIANG, XUESONG XU, XUAN ZHANG.
Application Number | 20210130281 17/149170 |
Document ID | / |
Family ID | 1000005341067 |
Filed Date | 2021-05-06 |
United States Patent
Application |
20210130281 |
Kind Code |
A1 |
XIANG; JIA-NING ; et
al. |
May 6, 2021 |
PRODRUGS OF GAMMA-HYDROXYBUTYRIC ACID, COMPOSITIONS AND USES
THEREOF
Abstract
Provided are prodrugs of gamma-hydroxybutyric acid as well as
compositions and uses thereof.
Inventors: |
XIANG; JIA-NING; (WUHAN,
CN) ; XU; XUESONG; (WUHAN, CN) ; ZHANG;
XUAN; (WUHAN, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
XWPHARMA LTD. |
GRAND CAYMAN |
|
KY |
|
|
Family ID: |
1000005341067 |
Appl. No.: |
17/149170 |
Filed: |
January 14, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16988200 |
Aug 7, 2020 |
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17149170 |
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16831086 |
Mar 26, 2020 |
10774031 |
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16988200 |
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16601908 |
Oct 15, 2019 |
10640451 |
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16831086 |
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16275165 |
Feb 13, 2019 |
10501401 |
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16601908 |
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15762559 |
Mar 23, 2018 |
10457627 |
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PCT/CN2016/099763 |
Sep 22, 2016 |
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16275165 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 277/30 20130101;
C07D 207/16 20130101; C07D 309/12 20130101; C07C 229/34 20130101;
C07C 69/34 20130101; C07D 333/38 20130101; C07C 69/738 20130101;
C07C 255/57 20130101; C07C 69/74 20130101; C07C 69/618 20130101;
C07D 211/46 20130101; C07D 207/12 20130101; C07C 69/612 20130101;
C07C 271/34 20130101; C07C 69/608 20130101; C07C 317/14 20130101;
C07C 2601/06 20170501; C07C 69/78 20130101; C07C 69/76 20130101;
C07D 211/44 20130101; C07C 69/22 20130101; C07D 213/79 20130101;
C07C 69/24 20130101; C07D 277/56 20130101; C07C 69/28 20130101;
C07C 69/96 20130101; C07D 213/80 20130101; C07C 233/47 20130101;
C07C 2601/16 20170501; C07C 229/36 20130101; C07C 317/44 20130101;
C07D 317/64 20130101; C07C 271/22 20130101; C07D 307/68 20130101;
C07C 229/08 20130101; C07B 59/001 20130101; C07C 2601/08 20170501;
C07C 2601/14 20170501 |
International
Class: |
C07C 69/78 20060101
C07C069/78; C07C 255/57 20060101 C07C255/57; C07D 213/79 20060101
C07D213/79; C07D 213/80 20060101 C07D213/80; C07D 309/12 20060101
C07D309/12; C07C 271/22 20060101 C07C271/22; C07C 271/34 20060101
C07C271/34; C07C 69/612 20060101 C07C069/612; C07D 317/64 20060101
C07D317/64; C07D 333/38 20060101 C07D333/38; C07C 229/08 20060101
C07C229/08; C07C 233/47 20060101 C07C233/47; C07D 207/16 20060101
C07D207/16; C07D 307/68 20060101 C07D307/68; C07B 59/00 20060101
C07B059/00; C07C 69/76 20060101 C07C069/76; C07C 69/24 20060101
C07C069/24; C07C 229/36 20060101 C07C229/36; C07C 69/608 20060101
C07C069/608; C07C 317/44 20060101 C07C317/44; C07D 277/56 20060101
C07D277/56; C07D 211/46 20060101 C07D211/46; C07C 69/738 20060101
C07C069/738; C07C 69/28 20060101 C07C069/28; C07C 69/22 20060101
C07C069/22; C07C 69/34 20060101 C07C069/34; C07C 69/618 20060101
C07C069/618; C07C 69/74 20060101 C07C069/74; C07C 69/96 20060101
C07C069/96; C07C 229/34 20060101 C07C229/34; C07C 317/14 20060101
C07C317/14; C07D 207/12 20060101 C07D207/12; C07D 211/44 20060101
C07D211/44; C07D 277/30 20060101 C07D277/30 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 23, 2015 |
CN |
PCT/CN2015/090326 |
Aug 31, 2016 |
CN |
201610782104.1 |
Claims
1-34. (canceled)
35. The compound (S)-4-(2-amino-3-methybutanoyloxy)butanoic acid:
##STR00344## or a pharmaceutically acceptable salt thereof.
Description
FIELD OF THE INVENTION
[0001] The present disclosure generally relates to prodrugs of
gamma-hydroxybutyric acid (GHB), as well as compositions and uses
thereof.
BACKGROUND OF THE INVENTION
[0002] Narcolepsy is a chronic neurological disorder characterized
by excessive daytime sleepiness (EDS), cataplexy, sleep paralysis,
hypnagogic hallucinations, and disturbed nocturnal sleep. EDS is
usually present and appears first. Cataplexy occurs in
approximately 70% of patients with narcolepsy while the other
symptoms feature less frequently and in various combinations. The
prevalence of narcolepsy in the United States and Europe ranges
from 20 to 67 per 100,000.
[0003] GHB is a naturally-occurring central nervous system (CNS)
transmitter. The GHB sodium salt also called sodium oxybate,
currently being marketed by Jazz Pharmaceuticals plc as Xyrem, is
the first and only drug approved by the U.S. Food and Drug
Administration (FDA) to treat cataplexy associated with narcolepsy.
Sodium oxybate has been shown to be highly efficacious with a 70%
reduction of the total number of cataplexy episodes. In Europe,
sodium oxybate is used medicinally for various purposes including
narcolepsy, alcohol dependence, and opiate dependence. In November
2005, the FDA approved an expanded indication for sodium oxybate as
a treatment for excessive daytime sleepiness (EDS). In addition,
sodium oxybate has also been conducted in the clinical trial in the
U.S. for fibromyalgia syndrome, a pain of fibromyalgia that is
notoriously difficult to treat. Sodium oxybate also has potential
to treat other CNS disorders such as insomnia, hallucinogenic
dreams and sleep paralysis.
[0004] Despite its efficacious effect and advantageous position in
treating EDS and cataplexy associated with narcolepsy, sodium
oxybate displays a sub-optimal pharmacokinetics profile that makes
it difficult to provide optimal therapeutic benefits. The
deficiencies of sodium oxybate include: 1) variable oral
bioavailability and unpredictable drug plasma concentrations
resulting from its erratic absorption in patients; 2) short plasma
half-life (t.sub.1/2<1 hr); 3) significant food effect (high fat
meal may significantly delay and decrease absorption of sodium
oxybate); 4) high bolus oral dosing caused unpleasant GI
disturbance; 5) poor patient compliance and inconvenient drug
administration (due to the twice per night dosage regimen); 6) risk
of hypernatremia (due to intake of large amount of sodium salt form
compounds). Consequently, these deficiencies prevent sodium oxybate
from providing the maximum therapeutic benefit that it can possibly
achieve. Therefore, there remains a continuing need for compounds
derived from GHB to overcome some or all of the above described
deficiencies.
SUMMARY OF THE INVENTION
[0005] The present disclosure provides, inter alia, a compound of
Formula I:
##STR00001##
or a pharmaceutically acceptable salt, ester, hydrate, or solvate
thereof, wherein the variables are defined below.
[0006] The present disclosure further provides a pharmaceutical
composition comprising one or more compounds of the present
disclosure.
[0007] The present disclosure also provides use of one or more
compounds in the manufacture of a medicament for treating a
disease, wherein the disease is narcolepsy, excessive daytime
sleepiness, cataplexy, neurodegenerative disease, sleep disturbance
syndrome, fibromyalgia, chronic fatigue, schizophrenia, binge
eating disorder, Parkinson disease, tardive dyskinesia, or
Alzheimer's disease.
[0008] The present disclosure further provides a method of treating
a disease, comprising administering to a subject an effective
amount of one or more compounds of the present disclosure, wherein
the disease is narcolepsy, excessive daytime sleepiness, cataplexy,
neurodegenerative disease, sleep disturbance syndrome,
fibromyalgia, chronic fatigue, schizophrenia, Binge eating
disorder, Parkinson disease, tardive dyskinesia, or Alzheimer's
disease.
[0009] The present disclosure also provides a compound of the
present disclosure for use in any of the methods described
herein.
DETAILED DESCRIPTION OF THE INVENTION
Compound
[0010] In one aspect, the present disclosure provides a compound of
Formula I:
##STR00002##
or a pharmaceutically acceptable salt, ester, hydrate, or solvate
thereof, wherein,
[0011] B is
##STR00003##
--(O)R.sup.1, --R.sup.2(OCO)R.sup.3, substituted or unsubstituted
C.sub.5-10 aryl, C.sub.1-12 alkyl, C.sub.5-12 aralkyl, C.sub.2-12
alkenyl, C.sub.6-12 aralkenyl, C.sub.2-12 alkynyl, C.sub.3-8
cycloalkyl, 3-10 membered heterocyclic alkyl, or 5-10 membered
heterocyclic aryl, wherein the one or more substituents are
selected from the group consisting of C.sub.1-12 alkyl, amino,
substituted amino, amino protecting group, --R.sup.4--S--R.sup.5,
halogen, hydroxyl, cyano, mono-, di- or tri-halo-C.sub.1-6 alkyl,
C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.1-12 alkoxy,
C.sub.5-10 aryl, C.sub.5-10 alkylaryl, C.sub.3-8 cycloalkyl,
C.sub.1-12 alkylsulfonyl, 3-8 membered heterocyclic alkyl, 3-10
membered heterocyclic aryl, C.sub.5-10 aryloxyl, C.sub.5-10
arylcarbonyl, C.sub.1-6 alkylcarbonyloxyl or C.sub.1-4
alkyloxycarbonyl;
[0012] wherein
[0013] R.sup.1 and R.sup.3 are independently C.sub.1-12 alkyl,
C.sub.2-12 alkenyl, C.sub.5-12 aralkyl, C.sub.6-12 aralkenyl,
C.sub.2-12 alkynyl, C.sub.5-10 aryl, C.sub.3-8 cycloalkyl, 3-10
membered heterocyclic alkyl, 5-10 membered heterocyclic aryl,
or
##STR00004##
any of which can be optionally mono- or independently
multi-substituted by --R.sup.4--S--R.sup.5, halogen, hydroxyl,
cyano, amino, substituted amino, C.sub.1-12 alkyl, C.sub.2-12
alkenyl, C.sub.2-12 alkynyl, C.sub.5-10 aryl, C.sub.1-12 alkoxy,
C.sub.3-8 cycloalkyl, 3-8 membered heterocyclic alkyl, or 3-10
membered heterocyclic aryl, C.sub.1-4 alkylsulfonyl, C.sub.5-10
aryloxyl, C.sub.5-10arylcarbonyl, C.sub.1-4 alkyloxycarbonyl, or
C.sub.1-12 alkylcarbonylamino;
[0014] R.sup.2 is C.sub.1-6 alkylene or C.sub.1-6 alkyleneoxyl, any
of which is optionally further substituted with C.sub.1-6
alkyl;
[0015] R.sup.4 is a bond, C.sub.1-6 alkylene, C.sub.5-10 arylene,
or C.sub.5-12 arylenealkylene, any of which is optionally further
substituted with C.sub.1-3 alkyl, and R.sup.5 is hydrogen or
C.sub.1-12 alkyl, [0016] R.sub.g is hydrogen, C.sub.1-6 alkyl,
phenyl, or phenylmethyl, any of which is optionally mono- or
independently multi-substituted by halogen, hydroxyl, methylthio,
C.sub.1-4 alkyl, or C.sub.5-8 aryl; and R.sub.h and R.sub.f are
independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl,
C.sub.1-5alkoxylcarbonyl, C.sub.3-6 cycloalkoxylcarbonyl, or an
amino protecting group; [0017] or [0018] R.sub.f and R.sub.g
together with C, O, N or S atom form a 4-8 membered heterocyclic
alkyl or
##STR00005##
[0018] any of which is optionally mono- or independently
multi-substituted by halogen, hydroxyl or C.sub.1-4 alkyl, and
R.sub.h is hydrogen, C.sub.1-6 alkyl or an amino protecting
group.
[0019] In some embodiments, B is C.sub.1-8 alkyl substituted with
C.sub.2-6 alkyl, aryl or amino group and B is not linear alkyl. In
some embodiments, B is C.sub.2-6 alkenyl substituted with C.sub.1-6
alkyl, aryl or amino group. In some embodiments, B is substituted
or unsubstituted C.sub.3-8 cycloalkyl, wherein the substituent is
selected from the group consisting of halogen, hydroxyl and
C.sub.1-6 alkyl. In some embodiments, B is substituted or
unsubstituted 3-8 membered heterocyclic alkyl, wherein the
substituent is selected from the group consisting of halogen,
hydroxyl and C.sub.1-6 alkyl. In some embodiments, B is substituted
or unsubstituted 5-8 membered heterocyclic aryl, wherein the
substituent is selected from the group consisting of halogen,
hydroxyl and C.sub.1-6 alkyl.
[0020] In some embodiments, B is --CHR.sup.13R.sup.14, wherein
R.sup.13 and R.sup.14 are independently selected from the group
consisting of hydrogen, C.sub.1-6 alkyl, C.sub.5-10 aryl and amino
group, wherein R.sup.13 and R.sup.14 cannot be methyl at the same
time. In some embodiments, R.sup.13 and R.sup.14 can be cyclized to
form a C.sub.3-8 cycloalkyl. In some embodiments, R.sup.13 and
R.sup.14 together with a 0, N or S atom form a 3-8 membered
heterocyclic alkyl.
[0021] The present disclosure also provides a compound having the
chemical structure shown in Formula (IA):
##STR00006##
or a pharmaceutically acceptable salt, ester, hydrate, or solvate
thereof, wherein,
[0022] R.sub.g is hydrogen, C.sub.1-6 alkyl, phenyl, or
phenylmethyl, any of which is optionally mono- or independently
multi-substituted by halogen, hydroxyl, methylthio, C.sub.1-4
alkyl, or C.sub.5-8 aryl; and R.sub.h and R.sub.f are independently
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, C.sub.1-6
alkoxylcarbonyl, C.sub.3-6 cycloalkoxylcarbonyl or an amino
protecting group.
[0023] In some embodiments, R.sub.g is hydrogen or C.sub.1-3 alkyl.
In some embodiments, at least one of R.sub.h and R.sub.f is
hydrogen or C.sub.1-3 alkyl. In some embodiments, both R.sub.h and
R.sub.f are hydrogen or C.sub.1-3 alkyl. In some embodiments,
R.sub.h is hydrogen or C.sub.1-3 alkyl and R.sub.f is --COR.sup.5,
and R.sup.5 is C.sub.1-3 alkyl, C.sub.1-3 alkoxyl, or C.sub.56
cycloalkyloxyl. In some embodiments, when R.sub.f or R.sub.h is an
amino protecting group, R.sub.g is not isopropyl or benzyl.
[0024] The present disclosure also provides a compound having the
chemical structure shown in Formula (IA):
##STR00007##
or a pharmaceutically acceptable salt, ester, hydrate, or solvate
thereof, wherein,
[0025] R.sub.f and R.sub.g together with C, O, or N atom form a 4-6
membered heterocyclic alkyl or
##STR00008##
any of which is optionally mono- or independently multi-substituted
by halogen, hydroxyl, C.sub.1-4 alkyl or an amino protecting
group;
[0026] R.sub.h is hydrogen, C.sub.1-3 alkyl or an amino protecting
group.
[0027] The present disclosure also provides a compound having the
chemical structure shown in Formula (IA-1):
##STR00009## [0028] or a pharmaceutically acceptable salt, ester,
hydrate, or solvate thereof, wherein, R.sub.h is hydrogen,
C.sub.1-3 alkyl or an amino protecting group.
[0029] The present disclosure also provides a compound having the
chemical structure shown in Formula (IA-2):
##STR00010## [0030] or a pharmaceutically acceptable salt, ester,
hydrate, or solvate thereof, wherein, R.sub.i is hydrogen,
C.sub.1-4 alkyl or an amino protecting group.
[0031] The present disclosure also provides a compound having the
chemical structure shown in Formula (IB):
##STR00011##
or a pharmaceutically acceptable salt, ester, hydrate, or solvate
thereof, wherein,
[0032] R.sup.1 is C.sub.1-8 alkyl, C.sub.5-12 aryl, C.sub.5-12
aralkyl, 3-10 membered heterocyclic alkyl or
##STR00012##
any of which is optionally mono- or independently multi-substituted
by halogen, cyano, hydroxyl, C.sub.1-12 alkyl or C.sub.1-4
alkoxy.
[0033] In some embodiments, R.sup.1 is
##STR00013##
and wherein R.sub.1a and R.sub.1b are independently hydrogen,
C.sub.1-12 alkyl, C.sub.1-4 alkoxy or halogen. In some embodiments,
R.sup.1 is
##STR00014##
and R.sub.1c is hydrogen, C.sub.1-12 alkyl or halogen.
[0034] The present disclosure also provides a compound having the
chemical structure shown in Formula (IC):
##STR00015##
or a pharmaceutically acceptable salt, ester, hydrate, or solvate
thereof, wherein,
[0035] R.sub.a, R.sub.b, R.sub.cd, R.sub.d and R.sub.e are
independently hydrogen, halogen, C.sub.1-12 alkyl, C.sub.1-12
alkoxy, cyano, C.sub.1-12 alkylsulfonyl, C.sub.1-6
alkylcarbonyloxyl, C.sub.1-4 alkyloxycarbonyl, mono-, di- or
tri-halo-C.sub.1-6 alkyl, C.sub.5-10 aryloxyl or C.sub.5-10
arylcarbonyl; and
[0036] when R.sub.a, R.sub.b, R.sub.c, R.sub.d and R.sub.e are all
hydrogen, at least one of R.sub.a, R.sub.b, R.sub.c, R.sub.d and
R.sub.e is not protium.
[0037] In some embodiments, R.sub.b, R.sub.c, R.sub.d are all
hydrogen, and R.sub.e and R.sub.a are independently hydrogen,
halogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, cyano, C.sub.1-3
alkylsulfonyl, C.sub.1-3 alkylcarbonyloxyl, C.sub.1-3
alkyloxycarbonyl, or mono-, di- or tri-halo-C.sub.1-3 alkyl. In
some embodiments, one of R.sub.e and R.sub.a is hydrogen. In some
embodiments, not all of R.sub.a, R.sub.b, R.sub.c, R.sub.d and
R.sub.e are hydrogen at the same time.
[0038] The present disclosure also provides a compound having the
chemical structure shown in Formula (ID):
##STR00016##
or a pharmaceutically acceptable salt, ester, hydrate, or solvate
thereof, wherein,
[0039] R.sup.2 is --(CR.sup.6R.sup.7).sub.m--, wherein m=1-6 and
R.sup.6 and R.sup.7 are independently hydrogen or C.sub.1-3
alkyl;
[0040] R.sup.3 is C.sub.1-12 alkyl, C.sub.5-8 aryl, 3-8 membered
heterocyclic alkyl, or 5-8 membered heterocyclic aryl, which are
each optionally mono- or independently multi-substituted by
halogen, unsubstituted or substituted amino, C.sub.1-6 alkyl or
C.sub.1-6 alkoxy; wherein when the amino is substituted it can be
optionally mono- or independently multi-substituted by C.sub.1-6
alkyl, or C.sub.1-6 alkylcarbonyl.
[0041] In some embodiment, R.sup.2 is --CH.sub.2--. In some
embodiment, R.sup.3 is methyl, ethyl, phenyl, which are each
optionally mono- or independently multi-substituted by methoxyl,
methyl or ethyl.
[0042] The present disclosure also provides a compound having the
chemical structure shown in Formula (ID-1):
##STR00017##
or a pharmaceutically acceptable salt, ester, hydrate, or solvate
thereof, wherein,
[0043] R.sub.3a, R.sub.3b, R.sub.3c, R.sub.3d and R.sub.3c are
independently hydrogen, halogen, C.sub.1-6 alkyl, or C.sub.1-6
alkoxy.
[0044] The present disclosure also provides a compound having the
chemical structure shown in Formula (ID-2):
##STR00018##
or a pharmaceutically acceptable salt, ester, hydrate, or solvate
thereof, wherein,
[0045] R.sup.9 and R.sup.10 are independently hydrogen, C.sub.1-6
alkyl or C.sub.1-6 alkylcarbonyl; and R.sup.8 is hydrogen or
C.sub.1-6 alkyl.
[0046] The present disclosure also provides a compound having the
chemical structure shown in Formula (IE):
##STR00019##
or a pharmaceutically acceptable salt, ester, hydrate, or solvate
thereof, wherein,
[0047] R.sup.11 is C.sub.1-8 alkyl or C.sub.5-8 aryl, any of which
is optionally mono- or independently multi-substituted by halogen,
hydroxyl, C.sub.1-6 alkyl or C.sub.1-4 alkoxy;
[0048] R.sup.12 is hydrogen or C.sub.1-6 alkyl.
[0049] In some embodiments, the molecular weight of each of the
compounds disclosed herein is no more than 450 Da. In some
embodiments, the molecular weight of each of the compounds
disclosed herein is 150-450 Da, 150-300 Da, or 200-300 Da.
[0050] In some embodiments, the compound is selected from:
TABLE-US-00001 ##STR00020## ##STR00021## ##STR00022## ##STR00023##
##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028##
##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033##
##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038##
##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043##
##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048##
##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053##
##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058##
##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063##
##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068##
##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073##
##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078##
##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083##
##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088##
##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093##
##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098##
##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103##
##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108##
##STR00109##
[0051] Various features of the present disclosure that are, for
brevity, described in the context of a single embodiment, can also
be provided separately or in any suitable subcombination.
[0052] As used herein, the term "substituted", when refers to a
chemical group, means the chemical group has one or more hydrogen
atoms that is/are removed and replaced by substituents. As used
herein, the term "substituent" has the ordinary meaning known in
the art and refers to a chemical moiety that is covalently attached
to, or if appropriate fused to, a parent group. As used herein, the
term "optionally substituted" means that the chemical group may
have no substituents (i.e. unsubstituted) or may have one or more
substituents (i.e. substituted). It is to be understood that
substitution at a given atom is limited by valency.
[0053] As used herein, the term "C.sub.n-m" indicates a range of
the carbon atoms numbers, wherein n and m are integers and the
range of the carbon atoms numbers includes the endpoints (i.e. n
and m) and each integer point in between. For examples, C.sub.1-6
indicates a range of one to six carbon atoms, including one carbon
atom, two carbon atoms, three carbon atoms, four carbon atoms, five
carbon atoms and six carbon atoms.
[0054] As used herein, the term "alkyl", whether as part of another
term or used independently, refers to a saturated hydrocarbon group
that may be straight-chain or branched-chain. The term "C.sub.n-m
alkyl" refers to an alkyl having n to m carbon atoms. In some
embodiments, the alkyl group contains 1 to 12, 1 to 8, 1 to 6, 1 to
4, 1 to 3, or 1 to 2 carbon atoms. Examples of alkyl group include,
but are not limited to, chemical groups such as methyl, ethyl,
n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl;
higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl,
n-hexyl, 1,2,2-trimethylpropyl, and the like.
[0055] As used herein, the term "alkenyl", whether as part of
another term or used independently, refers to an unsaturated
hydrocarbon group that may be straight-chain or branched-chain
having at least one carbon-carbon double bond. The term "C.sub.n-m
alkenyl" refers to an alkenyl having n to m carbon atoms. In some
embodiments, the alkenyl group contains 2 to 12, 2 to 10, 2 to 8, 2
to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. In some embodiments,
the alkenyl group contains 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2,
or 1 carbon-carbon double bond. Examples of alkenyl groups include,
but are not limited to, chemical groups such as ethenyl,
n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.
[0056] As used herein, the term "alkynyl", whether as part of
another term or used independently, refers to an unsaturated
hydrocarbon group that may be straight-chain or branched-chain
having at least one carbon-carbon triple bonds. The term "C.sub.n-m
alkynyl" refers to an alkynyl having n to m carbon atoms. In some
embodiments, the alkynyl group contains 2 to 12, 2 to 10, 2 to 8, 2
to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. In some embodiments,
the alkynyl group contains 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2,
or 1 carbon-carbon triple bond. Examples of alkynyl groups include,
but are not limited to, chemical groups such as ethynyl,
propyn-1-yl, propyn-2-yl, and the like.
[0057] As used herein, the term "alkylene", whether as part of
another term or used independently, refers to a bivalent saturated
hydrocarbon moieties which is linear, or branched, and which
connects two other parts of a molecule. The term "C.sub.n-m
alkylene" refers to an alkylene having n to m carbon atoms. In some
embodiments, the alkylene group contains 1 to 12, 1 to 10, 1 to 8,
1 to 6, 1 to 5, 1 to 4, or 1 to 3 carbon atoms. Examples of
alkylene groups include, but are not limited to, chemical groups
such as methylene, ethylene, 1-methyl-methylene, propylidene,
butylidene and the like.
[0058] As used herein, the term "aryl" or "aromatic", whether as
part of another term or used independently, refers to a mono- or
polycyclic carbocyclic ring system radicals with alternating double
and single bonds between carbon atoms forming the rings. In some
embodiments, the aryl ring systems have 5 to 10, 5 to 8, or 5 to 6
carbon atoms in one or more rings. In some embodiment, the aryl
ring system have 2 or more rings fused together. Examples of aryl
groups include, but are not limited to, chemical groups such as
phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the
like.
[0059] As used herein, the term "arylene", whether as part of
another term or used independently, refers to a divalent aryl ring
or ring system which connects two other parts of a molecule, i.e.
the two parts are bonded to the ring in two distinct ring
positions. When the aryl ring of the arylene is a monocyclic ring
system, the two parts are bonded to the same ring in two distinct
ring positions. When the aryl ring of the arylene is a polycyclic
ring system, the two parts can be bonded to the same ring or
different rings in two distinct ring positions. Arylene may be
substituted or unsubstituted. Unsubstituted arylene has no
substituents other than the two parts of the molecule it connects.
Substituted arylene has substituents in addition to the two parts
of the molecule it connects.
[0060] As used herein, the term "aralkyl", whether as part of
another term or used independently, refers to a group of formula
-alkyl-aryl. The term "C.sub.n-m aralkyl" refers to aralkyl with a
total carbon number between n to m. In some embodiments, the alkyl
moiety has 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. In some
embodiments, the aralkyl group has 5-12, 5-10, 5-8, or 6-7 carbon
atoms. Examples of aralkyl groups include, but are not limited to,
various alkyl benzenes and alkyl naphthalenes.
[0061] As used herein, the term "arylenealkylene", whether as part
of another term or used independently, refers to a group of formula
-alkylene-arylene, wherein the arylene and alkylene groups are as
previously described, wherein the term "C.sub.n-m arylenealkylene"
refers to an arylenealkylene group with a total carbon number
between n to m. In some embodiments, the alkylene portion of the
arylenealkylene moiety has 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon
atoms. In some embodiments, the arylene portion of the
arylenealkylene moiety has 6 to 12, 6 to 11, 6 to 10, 6 to 9, or 6
to 8 ring forming carbon atoms. In some embodiments, the
arylenealkylene moiety has 7-12, 7-10, 7-9, or 7-8 carbon
atoms.
[0062] As used herein, the term "aralkenyl", whether as part of
another term or used independently, refers to a group of formula
-alkenyl-aryl, wherein the term "C.sub.n-m aralkenyl" refers to an
aralkenyl group with a total carbon number between n to m. In some
embodiments, the alkenyl moiety contains 2 to 12, 2 to 10, 2 to 8,
2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. In some
embodiments, the aralkenyl group has 6-18, 6-12, 6-10, 6-8, or 6-7
carbon atoms. Examples of aralkenyl groups include, but are not
limited to, chemical groups such as styryl, 3-(benzyl) prop-2-enyl,
and 6-napthylhex-2-enyl.
[0063] As used herein, the term "cycloalkyl", whether as part of
another term or used independently, refers to non-aromatic cyclic
hydrocarbons including cyclized alkyl and/or alkenyl groups.
Cycloalkyl groups can include mono- or polycyclic (e.g., having 2,
3 or 4 fused rings) groups and spirocycles. In some embodiments,
the cycloalkyl is saturated cycloalkyl. Cycloalkyl groups can have
3, 4, 5, 6, 7, 8 ring-forming carbons (C.sub.3-8). Examples of
cycloalkyl groups include, but are not limited to, chemical groups
such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,
cycloheptatrienyl, and the like. In some embodiments, a cycloalkyl
used herein may be fused (i.e., having a bond in common with) with
one or more aromatic rings, for example, benzo or thienyl
derivatives of cyclopentane, cyclohexane, and the like. In some
embodiments, a cycloalkyl group containing a fused aromatic ring
can be attached through any ring-forming atom including a
ring-forming atom of the fused aromatic ring.
[0064] As used herein, the term "cycloalkylene", whether as part of
another term or used independently, refers to a bivalent saturated
or partially saturated non-aromatic cyclic hydrocarbons group, and
which connects two other parts of a molecule. The term "C.sub.n-m
cycloalkylene" refers to a cycloalkylene having n to m carbon
atoms. In some embodiments, the cycloalkylene group contains 3 to
12, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4 carbon
atoms. Examples of cycloalkylene groups include, but are not
limited to, chemical groups such as cyclopropylidene,
cyclobutalidene and the like.
[0065] As used herein, the term "alkoxy", whether as part of
another term or used independently, refers to a group of formula
--O-alkyl. The term "C.sub.n-m alkoxy" means that the alkyl moiety
of the alkoxy group has n to m carbon atoms. In some embodiments,
the alkyl moiety has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
Examples of alkoxy groups include, but are not limited to, chemical
groups such as methoxy, ethoxy, propoxy (e.g., n-propoxy and
isopropoxy), t-butoxy, and the like.
[0066] As used herein, the term "aryloxyl" refers to a group of
formula --O-aryl, wherein the aryl group is as previously
described. "C.sub.n-m aryloxyl" means that the aryl moiety of the
aryloxyl group has n to m carbon atoms. In some embodiments, the
aryl moiety has 5 to 10, 5 to 8, or 5 to 6 carbon atoms.
[0067] As used herein, the term "alkylamino", whether as part of
another term or used independently, refers to a group of formula
--NH-alkyl. The term "C-m alkylamino" means that the alkyl moiety
of the alkylamino group has n to m carbon atoms. In some
embodiments, the alkyl moiety has 1 to 6, 1 to 4, or 1 to 3 carbon
atoms.
[0068] As used herein, the term "arylcarbonyl", whether as part of
another term or used independently, refers to a group of formula
--C(.dbd.O)-aryl, wherein the aryl group is as previously
described. "C.sub.n-m arylcarbonyl" means that the aryl moiety of
the arylcarbonyl group has n to m carbon atoms. In some
embodiments, the aryl moiety has 5 to 10, 5 to 8, or 5 to 6 carbon
atoms.
[0069] As used herein, the term "alkylcarbonyl", whether as part of
another term or used independently, refers to a group of formula
--C(.dbd.O)-alkyl. The term "C-m alkylcarbonyl" means that the
alkyl moiety of the alkylcarbonyl group has n to m carbon atoms. In
some embodiments, the alkyl moiety has 1 to 6, 1 to 4, 1 to 3 or 1
to 2 carbon atoms.
[0070] As used herein, the term "alkoxycarbonyl", whether as part
of another term or used independently, refers to a group of formula
--C(.dbd.O)--O-alkyl. The term "C.sub.n-m alkoxycarbonyl" means
that the alkyl moiety of the alkoxycarbonyl group has n to m carbon
atoms. In some embodiments, the alkyl moiety has 1 to 6, 1 to 4, 1
to 3 or 1 to 2 carbon atoms.
[0071] As used herein, the term "cycloalkoxylcarbonyl", whether as
part of another term or used independently, refers to a group of
formula --C(.dbd.O)--O-cycloalkyl, wherein the cycloalkyl group is
as previously described. The term "C.sub.n-m
cycloalkyloxylcarbonyl" means that the cycloalkyl moiety of the
cycloalkoxylcarbonyl group has n to m carbon atoms. In some
embodiments, the cycloalkyl moiety has 3 to 8, 3 to 6, 3 to 5 or 3
to 4 carbon atoms.
[0072] As used herein, the term "alkylcarbonyloxyl", whether as
part of another term or used independently, refers to a group of
formula --O--C(.dbd.O)-alkyl. The term "C.sub.n-m
alkylcarbonyloxyl" means that the alkyl moiety of the
alkylcarbonyloxyl group has n to m carbon atoms. In some
embodiments, the alkyl moiety has 1 to 6, 1 to 4, 1 to 3 or 1 to 2
carbon atoms.
[0073] As used herein, the term "n membered", wherein n is an
integer typically employed in combination with a ring system to
describe the number of ring-forming atoms in the ring system. For
example, piperidinyl is an example of a 6 membered heterocycloalkyl
ring, pyrazolyl is an example of a 5 membered heteroaryl ring,
pyridyl is an example of a 6 membered heteroaryl ring, and
1,2,3,4-tetrahydro-naphthalene is an example of a 10 membered
cycloalkyl group.
[0074] As used herein, the term "heterocyclic aryl" refers to aryl
group wherein at least one ring atom in the aromatic ring is a
heteroatom, and the remainder of the ring atoms being carbon atoms.
The term "n-m membered heterocyclic aryl" refers to heterocyclic
aryl having n to m ring-forming members. Example heteroatoms
include, but are not limited to, oxygen, sulfur, nitrogen,
phosphorus, and the like. In some embodiments, heterocyclic aryl
can have 5 to 10, 5 to 8, or 5 to 6 ring-forming members. In some
embodiments, heterocyclic aryl is 5 membered or 6 membered
heterocyclic aryl. Examples of heterocyclic aryl include, but are
not limited to, furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl
pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl,
indolyl and the like.
[0075] A 5 membered heterocyclic aryl is a heterocyclic aryl with a
ring having five ring atoms, wherein one or more (e.g., 1, 2, or 3)
ring atoms can be independently selected from N, O, P, and S.
Exemplary 5 membered heterocyclic aryl are thienyl, furyl,
pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,
isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and
1,3,4-oxadiazolyl.
[0076] A 6 membered heterocyclic aryl is a heterocyclic aryl with a
ring having six ring atoms, wherein one or more (e.g., 1, 2, or 3)
ring atoms can be independently selected from N, O, P, and S.
Exemplary 6 membered heterocyclic aryl are pyridyl, pyrazinyl,
pyrimidinyl, triazinyl and pyridazinyl.
[0077] As used herein, the term "heterocyclic alkyl" refers to
cycloalkyl group wherein at least one ring atom in the ring systems
is a heteroatom, and the remainder of the ring atoms being carbon
atoms. The term "n-m membered heterocyclic alkyl" refers to
heterocyclic alkyl having n to m ring-forming members. In addition,
the ring may also have one or more double bonds, but not have a
completely conjugated system. In some embodiments, the heterocyclic
alkyl is saturated heterocyclic alkyl. Examples of heteroatoms
include, but are not limited to, oxygen, sulfur, nitrogen,
phosphorus, and the like. In some embodiments, heterocyclic alkyl
has 3 to 8, 3 to 6, or 4 to 6 ring-forming carbons. Examples of
heterocyclic alkyl include, but are not limited to, azetidine,
aziridine, pyrrolidyl, piperidyl, piperazinyl, morpholinyl,
thiomorpholinyl, homopiperazinyl, and the like.
[0078] As used herein the terms "halo" and "halogen" refer to an
atom selected from fluorine, chlorine, bromine and iodine.
[0079] As used herein, "mono-, di- or tri-halo-C.sub.n-m alkyl"
refers to an alkyl group that is substituted by one, two or three
halo, wherein the alkyl group has n to m carbon atoms and the halo
as substituent may be same or different. Examples of mono-, di- or
tri-halo-C.sub.n-m alkyl include without limitation,
trichloromethyl, chloromethyl, bischloromethyl,
chlorobromomethyl.
[0080] As used herein the terms "cyano" refer to a group of formula
--CN.
[0081] As used herein, the term "hydroxyl" refers to a group of
formula --OH.
[0082] As used herein, the term "methylthio" refers to a group of
formula --S--CH.sub.3.
[0083] As used herein, the term "alkylsulfonyl" refers to a group
of formula -sulfonyl-alkyl. The term "C.sub.n-m alkylsulfonyl"
refers to alkylsulfonyl wherein the alkyl moiety has n to m carbon
atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or
1 to 3 carbon atoms. Examples of alkylsulfonyl groups include
without limitation, methanesulfonyl, ethanesulfonyl,
tert-butanesulfonyl, and the like.
[0084] As used herein, the term "amino" refers to a group of
formula --NH.sub.2.
[0085] As used herein, the term "substituted amino" refers to an
amino that is mono- or independently substituted by one or more
substituents. Examples of substituents include, but are not limited
to, halogen, hydroxyl, C.sub.1-4 alkyl, C.sub.5-8 aryl, C.sub.1-6
alkoxyl, C.sub.3-8 cycloalkyl, 3-8 membered heterocyclic alkyl, or
3-8 membered heterocyclic aryl, C.sub.1-4 alkylsulfonyl, C.sub.5-10
aryloxyl, C.sub.5-10 arylcarbonyl or C.sub.1-6 alkyloxycarbonyl,
amino protecting group, and the like.
[0086] As used herein, the term "amino protecting group" refers to
a substituent that protects an amino functionality against
undesirable reactions during synthetic procedures. Examples of
amino protecting groups include, but are not limited to,
carbamate-protecting groups, such as
2-trimethyl-silylethoxycarbonyl (Teoc),
1-methyl-1-(4-bi-phenyl-yl)-ethoxy-carbonyl (Bpoc),
t-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc),
9-fluorenyl-methyloxycarbonyl (Fmoc), and benzyl-oxycarbonyl (Cbz);
amide-protecting groups, such as formyl, acetyl, trihaloacetyl,
benzoyl, and nitrophenylacetyl; sulfona-mide-protecting groups,
such as 2-nitrobenzenesulfonyl; and imine- and cyclic
imide-protecting groups, such as phthalimido and
dithiasuccinoyl.
[0087] As used herein, the term "compound" is meant to include all
stereoisomers (eg. enantiomers and diastereomers), geometric
iosomers, tautomers, and isotopes of the structures depicted.
Compounds herein identified by name or structure as one particular
tautomeric form are intended to include other tautomeric forms
unless otherwise specified.
[0088] The compounds described herein can be asymmetric (e.g.,
having one or more stereocenters). All stereoisomers, such as
enantiomers and diastereomers, are intended unless otherwise
indicated. Compounds of the present disclosure that contain
asymmetrically substituted carbon atoms can be isolated in
optically active or racemic forms. Methods on how to prepare
optically active forms from optically inactive starting materials
are known in the art, such as by resolution of racemic mixtures or
by stereoselective synthesis. Many geometric isomers of olefins,
carbon-carbon double bonds, and the like can also be present in the
compounds described herein, and all such stable isomers are
contemplated in the present disclosure. Cis and trans geometric
isomers of the compounds of the present disclosure are described
and may be isolated as a mixture of isomers or as separated
isomeric forms.
[0089] In some embodiments, the compounds described herein have the
(R)-configuration. In some embodiments, the compounds described
herein have the (S)-configuration.
[0090] Resolution of racemic mixtures of compounds can be carried
out by any of numerous methods known in the art. An example method
includes fractional recrystallizaion using a chiral resolving acid,
which is an optically active, salt-forming organic acid. Suitable
resolving agents for fractional recrystallization methods are, for
example, optically active acids, such as the D and L forms of
tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,
mandelic acid, malic acid, lactic acid or the various optically
active camphorsulfonic acids such as .beta.-camphorsulfonic acid.
Other resolving agents suitable for fractional crystallization
methods include stereoisomerically pure forms of
.alpha.-methylbenzylamine (e.g., S and R forms, or
diastereomerically pure forms), 2-phenylglycinol, norephedrine,
ephedrine, N-methylephedrine, cyclohexylethylamine,
1,2-diaminocyclohexane, and the like.
[0091] Resolution of racemic mixtures can also be carried out by
elution on a column packed with an optically active resolving agent
(e.g., dinitrobenzoylphenylglycine). Suitable elution solvent
composition can be determined by one skilled in the art.
[0092] Compounds of the present disclosure also include tautomeric
forms. Tautomeric forms result from the swapping of a single bond
with an adjacent double bond together with the concomitant
migration of a proton. Tautomeric forms include prototropic
tautomers which are isomeric protonation states having the same
empirical formula and total charge. Example prototropic tautomers
include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim
pairs, enamine-imine pairs, and annular forms where a proton can
occupy two or more positions of a heterocyclic system, for example,
1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and
2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in
equilibrium or sterically locked into one form by appropriate
substitution.
[0093] Compounds of the present disclosure can also include all
isotopes of atoms occurring in the intermediates or final
compounds. Isotopes include those atoms having the same atomic
number but different mass numbers. For example, isotopes of
hydrogen include protium, deuterium and tritium. In some
embodiments, the isotope of hydrogen is protium and deuterium. In
some embodiments, the hydrogens on the aromatic ring of the
compounds include at least one deuterium. In some embodiments, the
hydrogens on the aromatic ring of the compounds are all
deuteriums.
[0094] In some embodiments, the compounds of the present disclosure
can convert to GHB after oral administration. In some embodiments,
the compounds of the present disclosure can enter into human
circulatory system through a biological process after oral
administration. In some embodiment, the compounds of the present
disclosure convert to GHB in liver. In some embodiment, the
compounds of the present disclosure convert to GHB in blood. In
some embodiment, the GHB releasing efficiency of the compounds
within 1 hour after contacting blood or liver is no less than 90%,
80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. In some embodiment, the
GHB releasing efficiency of the compounds within 2 hours after
contacting blood or liver is no less than 90%, 80%, 70%, 60%, 50%,
40%, 30%, or 20%.
[0095] In some embodiments, the compounds of the present disclosure
have higher oral bioavailability than the oral bioavailablity of
GHB sodium salt. In some embodiments, the oral bioavailability of
the compounds of the present disclosure is 1.1, 1.2, 1.3, 1.4, 1.5,
1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, or 4 times higher than the oral
bioavailability of GHB sodium salt. In some embodiments, the
compounds of the present disclosure have higher colonic absorption
than the colonic absorption of GHB. In some embodiments, the
colonic absorption of the compounds of the present disclosure is
1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5. 3, 4, 5, 6, 8,
or 10 times higher than the colonic absorption of GHB. In some
embodiment, the oral bioavailability of the compounds of the
present disclosure is no less than 20%, 30%, 40%, 50%, 60%, 70%,
80%, or 90%.
[0096] Not to be limited by the theory, the nature of compounds of
the present disclosure enables the compounds to be formulated to a
stable solid formulation, especially the sustained or
controlled-release formulation. For example, some compounds of the
present disclosure can be formulated into a drug with controlled
absorption in GI tract. In some embodiment, the oral absorption of
the compounds in the colon is no less than 40%, 50%, 60%, 70%, 80%,
90% or more of the total oral absorption.
Synthesis Method
[0097] Compounds of the present disclosure, including salts,
esters, hydrates, or solvates thereof, can be prepared using any
known organic synthesis techniques and can be synthesized according
to any of numerous possible synthetic routes.
[0098] The reactions for preparing compounds of the present
disclosure can be carried out in suitable solvents, which can be
readily selected by one skilled in the art of organic synthesis.
Suitable solvents can be substantially non-reactive with the
starting materials (reactants), the intermediates, or products at
the temperatures at which the reactions are carried out, e.g.,
temperatures that can range from the solvent's freezing temperature
to the solvent's boiling temperature. A given reaction can be
carried out in one solvent or a mixture of more than one solvent.
Depending on the particular reaction step, suitable solvents for a
particular reaction step can be selected by a skilled artisan.
[0099] Preparation of compounds of the present disclosure can
involve the protection and deprotection of various chemical groups.
The need for protection and deprotection, and the selection of
appropriate protecting groups, can be readily determined by one
skilled in the art. The chemistry of protecting groups can be
found, for example, in T. W. Greene and P. G. M. Wuts, Protective
Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New
York (1999), which is incorporated herein by reference in its
entirety.
[0100] Reactions can be monitored according to any suitable method
known in the art. For example, product formation can be monitored
by spectroscopic means, such as nuclear magnetic resonance
spectroscopy (e.g., .sup.1H or .sup.13C), infrared spectroscopy,
spectrophotometry (e.g., UV-visible), mass spectrometry, or by
chromatographic methods such as high performance liquid
chromatography (HPLC), liquid chromatography-mass spectroscopy
(LCMS), or thin layer chromatography (TLC). Compounds can be
purified by those skilled in the art by a variety of methods,
including high performance liquid chromatography (HPLC)
("Preparative LC-MS Purification: Improved Compound Specific Method
Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P.
Combs J. Combi. Chem. 2004, 6(6), 874-883, which is incorporated
herein by reference in its entirety) and normal phase silica
chromatography. Exemplary synthetic schemes are listed below, the
abbreviations for the reactants or for the chemical groups of the
reactants included in the synthetic schemes are defined in the
Examples.
[0101] For example, compounds of Formula I can be formed as shown
in Scheme 1.
##STR00110##
[0102] Alternatively, compounds of Formula I can be formed as shown
in Scheme 2.
##STR00111##
[0103] For example, compounds of Formula IA can be formed as shown
in Scheme 3 (X in the scheme refers to any substituent group).
##STR00112##
[0104] A representative compound of Formula IA can be formed as
shown in Scheme 4.
##STR00113##
[0105] A representative compound of Formula IA can be formed as
shown in Scheme 5.
##STR00114##
[0106] Alternatively, the compounds of Formula IA can be formed as
shown in Scheme 6 (wherein X in the scheme refers to any
substituent group).
##STR00115##
[0107] A representative compound of Formula IA can be formed as
shown in Scheme 7.
##STR00116##
[0108] A representative compound of Formula IA can be formed as
shown in Scheme 8.
##STR00117##
[0109] A representative compound of Formula IA-2 can be formed as
shown in Scheme 9.
##STR00118##
[0110] For example, compounds of Formula IB can be formed as shown
in Scheme 10.
##STR00119##
[0111] A representative compound of Formula IB can be formed as
shown in Scheme 11.
##STR00120##
[0112] A representative compound of Formula IB can be formed as
shown in Scheme 12.
##STR00121##
[0113] For example, compounds of Formula ID can be formed as shown
in Scheme 13.
##STR00122##
[0114] A representative compound of Formula ID-2 can be formed as
shown in Scheme 14.
##STR00123##
[0115] A representative compound of Formula ID-2 can be formed as
shown in Scheme 15.
##STR00124##
[0116] A representative compound of Formula ID-2 can be formed as
shown in Scheme 16.
##STR00125##
[0117] For example, compounds of Formula IE can be formed as shown
in Scheme 17.
##STR00126##
Pharmaceutical Composition
[0118] The present disclosure provides pharmaceutical composition
comprising one or more compounds of the present disclosure, and a
pharmaceutically acceptable carrier.
[0119] These pharmaceutical compositions can be prepared in a
manner well known in the pharmaceutical art. In some embodiments,
the compounds of the present disclosure may be admixed with
pharmaceutically acceptable carrier for the preparation of
pharmaceutical composition.
[0120] As used herein, the phrase "pharmaceutically acceptable"
refers to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio. In some embodiments, compounds, materials,
compositions, and/or dosage forms that are pharmaceutically
acceptable refer to those approved by a regulatory agency (such as
U.S. Food and Drug Administration, China Food and Drug
Administration or European Medicines Agency) or listed in generally
recognized pharmacopoeia (such as U.S. Pharmacopoeia, China
Pharmacopoeia or European Pharmacopoeia) for use in animals, and
more particularly in humans.
[0121] As used herein, the term "pharmaceutically acceptable
carrier" refers to any and all solvents, excipients, coatings,
antibacterial and antifungal agents, flavoring agents, isotonic and
absorption delaying agents, and the like that are pharmaceutically
acceptable and can facilitate storage and administration of the
compounds of the present disclosure to a subject. Pharmaceutically
acceptable carrier that can be employed in present disclosure
includes those generally known in the art, such as those described
in "Remington Pharmaceutical Sciences" Mack Pub. Co., New Jersey
(1991), which is incorporated herein by reference.
[0122] Examples of pharmaceutically acceptable carriers include,
but are not limited to, solvents, liposomes, polymeric excipients
and the like.
[0123] In certain embodiments, the pharmaceutically acceptable
carrier is a solvent that can dissolve or disperse the compounds of
the present disclosure. Illustrative examples of solvent include,
without limitation, buffer saline, normal saline, phosphate buffer,
citrate buffer, acetate buffer, bicarbonate buffer, sucrose
solution, polysorbate solution, oil, ester, and alcohol.
[0124] In certain embodiments, the pharmaceutically acceptable
carriers are liposomes, and the compounds of the present disclosure
can be encapsulated within the aqueous portion or lipid portion of
the liposomes. Illustrative examples of liposomes include, without
limitation, liposomes based on 3[N--(N',N'-dimethylaminoethane)
carbamoyl] cholesterol (DC-Chlo), liposomes based on
N-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammonium chloride (DOTMA),
and liposomes based on 1,2-dioleoyloxy-3-trimethylammonium propane
(DOTAP).
[0125] In certain embodiments, the pharmaceutically acceptable
carriers are polymeric excipients such as, without limitation,
microspheres, microcapsules, polymeric micelles and dendrimers. The
compounds of the present disclosure may be encapsulated, adhered
to, or coated on the polymer-based components by methods known in
the art.
[0126] The form of pharmaceutical compositions depends on a number
of criteria, including, but not limited to, route of
administration, extent of disease, or dose to be administered. The
pharmaceutical compositions can be formulated for oral, nasal,
rectal, percutaneous, intravenous, or intramuscular administration.
In accordance to the desired route of administration, the
pharmaceutical compositions can be formulated in the form of
tablets, pills, powders, lozenges, sachets, cachets, suspensions,
emulsions, solutions, syrups, aerosols (as a solid or in a liquid
medium) or ointments.
[0127] For oral administration, powders, granules, pills, tablets,
caplets, capsules, and gelcaps are acceptable as solid dosage
forms. These can be prepared, for example, by mixing one or more
compounds of the present disclosure with at least one carrier such
as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran,
sorbitol, starch, agar, alginates, chitins, chitosans, pectins,
tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,
synthetic or semi-synthetic polymers or glycerides, methyl
cellulose, hydroxypropylmethyl-cellulose, and/or
polyvinylpyrrolidone. In some embodiments, solid dosage forms for
oral administration can further comprise other carrier ingredients
to aid in manufacture or administration with lubricants such as
magnesium stearate, or preservatives such as paraben or sorbic
acid, or anti-oxidants such as ascorbic acid, tocopherol or
cysteine, a disintegrating agents, or chelating agents such as
EDTA, binders, thickeners, flavoring agents or perfuming agents. In
certain embodiments, solid dosage forms for oral administration may
additionally comprise dyestuffs or pigments for identification.
Tablets and pills may be further treated with suitable coating
materials known in the art, such as moisture protective, enteric,
or sustained release coatings.
[0128] For oral administration, emulsions, syrups, elixirs,
suspensions, slurries and solutions are acceptable as liquid dosage
forms. These can be prepared, for example, by mixing one or more
compounds of the present disclosure with sterile inactive solvent,
such as but not limited to, water, alcohol, oil and a combination
thereof. In some embodiments, the inactive diluent used in the
liquid dosage form for oral administration comprise oil, such as
but not limited to, peanut oil, sesame oil, cottonseed oil, corn
oil and olive oil. In some embodiments, the inactive diluent used
in the liquid dosage form for oral administration comprise esters
of fatty acids, such as but not limited to, ethyl oleate, isopropyl
myristate, fatty acid glycerides and acetylated fatty acid
glycerides. In some embodiments, the inactive diluent used in the
liquid dosage form for oral administration comprise alcohols, such
as but not limited to, ethanol, isopropyl alcohol, hexadecyl
alcohol, glycerol and propylene glycol. In some embodiment, liquid
dosage forms for oral administration can further comprise
surfactants, suspending agents, emulsifying agents, stabilizers,
flavoring agents, chelating agents, preservatives, antioxidants,
solubilizers (such as propylene glycol, glycerin, or sorbitol),
dyes, or thickeners. In some embodiments, the liquid dosage form
for oral administration can further comprise pH adjusting agent,
such as but not limited to, sodium hydroxide, hydrochloric acid, or
malic acid.
[0129] The pharmaceutical composition of the present disclosure can
be formulated so as to provide quick, sustained or delayed release
of the active ingredient after administration to the patient by
employing procedures known in the art. In some embodiments, the
composition is formulated in a sustained released form. As used
herein, the term "sustained released form" refers to release of the
active agent from the pharmaceutical composition so that it becomes
available for bio-absorption in the subject, primarily in the
gastrointestinal tract of the subject, over a prolonged period of
time (extended release), or at a certain location (controlled
release). In some embodiments, the prolonged period of time can be
about 1 hour to 24 hours, 2 hours to 12 hours, 3 hours to 8 hours,
4 hours to 6 hours, 1 to 2 days or more. In certain embodiments,
the prolonged period of time is at least about 4 hours, at least
about 8 hours, at least about 12 hours, or at least about 24
hours.
[0130] In some embodiments, the sustained release form of
pharmaceutical compositions are tablets or pills, and the tablets
or pills are coated or otherwise formulated to provide a dosage
form affording the advantage of prolonged action. Factors affecting
drug release are well known to the skilled artisan and have been
described in the art (Bamba et al., Int. J. Pharm., 1979, 2, 307),
which is incorporated herein by reference in its entirety. For
example, release rate of the active agent can not only be
controlled by dissolution of the active agent in gastrointestinal
fluid and subsequent diffusion out of the tablet or pills
independent of pH, but can also be influenced by physical processes
of disintegration and erosion of the tablet. In some embodiments,
polymeric materials as described in "Medical Applications of
Controlled Release," Langer and Wise (eds.), CRC Pres., Boca Raton,
Fla. (1974); "Controlled Drug Bioavailability," Drug Product Design
and Performance, Smolen and Ball (eds.), Wiley, New York (1984);
Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem.
23:61; see also Levy et al., 1985, Science 228:190; During et al.,
1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg.
71:105 can be used for sustained release. The above references are
incorporated herein by reference in its entirety.
[0131] In some embodiments, polymeric materials are used for oral
sustained release delivery. Examples of the polymeric materials
include sodium carboxymethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose and hydroxyethylcellulose. Other
cellulose ethers have been described in Alderman, Int. J. Pharm.
Tech. & Prod. Mfr., 1984, 5(3) 1-9, which is incorporated
herein by reference in its entirety. In some embodiments,
enteric-coated preparations can be used for oral sustained release
administration. Examples of the coating materials include polymers
with a pH-dependent solubility (i.e., pH-controlled release),
polymers with a slow pH-dependent rate of swelling, dissolution or
erosion (i.e., time-controlled release), polymers that are degraded
by enzymes (i.e., enzyme-controlled release) and polymers that form
firm layers that are destroyed by an increase in pressure (i.e.,
pressure-controlled release). In some embodiments, osmotic delivery
systems are used for oral sustained release administration as
described in Verma et al., Drug Dev. Ind. Pharm., 2000, 26:695-708,
which is incorporated herein by reference in its entirety. In a
preferred embodiment, OROS.TM. osmotic devices are used for oral
sustained release delivery devices as described in Theeuwes et al.,
U.S. Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No. 3,916,899,
which are incorporated herein by reference in its entirety. In some
embodiments, a controlled-release system can be placed in proximity
of the target of the compounds and/or composition of the present
disclosure, thus requiring only a fraction of the systemic dose,
see, e.g., Goodson, in "Medical Applications of Controlled
Release," supra, vol. 2, pp. 115-138 (1984), which is incorporated
herein by reference in its entirety. Other controlled-release
systems as described in Langer, 1990, Science 249:1527-1533 may
also be used, which is incorporated herein by reference in its
entirety.
[0132] The compositions can be formulated in a unit dosage form,
each dosage containing from about 0.5 to about 30 g, about 1 to
about 20 g, about 2 to about 20 g, about 3 to about 20 g, about 4
to about 20 g, about 5 to about 20 g, about 6 to about 20 g, about
7 to about 20 g, about 8 to about 20 g, about 9 to about 20 g,
about 10 to about 20 g, about 11 to about 20 g, about 12 to about
20 g, about 13 to about 20 g, about 14 to about 20 g, about 15 to
about 20 g, about 16 to about 20 g, about 17 to about 20 g, about
18 to about 20 g, 2 to about 18 g, about 2 to about 16 g, about 2
to about 14 g, about 2 to about 12 g, about 2 to about 10 g, about
2 to about 9 g, about 2 to about 8 g, about 2 to about 6 g of the
active ingredient. The term "unit dosage forms" refers to
physically discrete units suitable as unitary dosages for human
subjects and other mammals, each unit containing a predetermined
quantity of active material calculated to produce the desired
therapeutic effect, in association with a suitable pharmaceutical
carrier.
Method for Treatment
[0133] The present disclosure provides, a method of treating a
disease, comprising administering to a subject an effective amount
of one or more compounds of the present disclosure.
[0134] In some embodiments, the disease is narcolepsy, excessive
daytime sleepiness, cataplexy, neurodegenerative disease, sleep
disturbance syndrome, fibromyalgia, chronic fatigue, schizophenia,
binge eating disorder, Parkinson disease, tardive dyskinesia, or
Alzheimer's disease. In some embodiments, the disease is excessive
daytime sleepiness or cataplexy associated with narcolepsy.
[0135] Administration may be via oral, nasal, intravenous,
subcutaneous, sublingual, or intramuscular administration.
[0136] The frequency of administration of the compounds will vary
depending upon what is being administered, the amount of the
therapeutic agent, the purpose of the administration, the state of
the patient, the manner of administration, and the like.
Determination of frequency of administration is well within the
capability of those skilled in the art. In some embodiments, the
administration is conducted no more than two time per day, no more
than one time per day, no more than two times per three days, no
more than one time per two days, no more than one time per three
days, no more than one time per five days, no more than one time
per one week, or no more than one time per two weeks.
[0137] As used herein, the term "effective amount" means an amount
of the therapeutic agent that is effective to provide a desired
outcome. Determination of a therapeutically effective amount is
well within the capability of those skilled in the art. Generally,
a therapeutically effective amount can vary with the subject's
history, age, condition, sex, as well as the severity and type of
the medical condition in the subject, and administration of other
agents that inhibit pathological processes in neurodegenerative
disorders. In some embodiments, the effective amount of the
therapeutic agent is from about 0.5 to about 30 g, about 1 to about
15 g, about 2 to about 15 g, about 3 to about 10 g, about 4 to
about 10 g.
[0138] As used herein, the term "treating" or "treatment" of any
disease or disorder refers to delaying onset of the disease or
disorder; ameliorating at least one of the clinical symptoms
relating to the disease or disorder; or both.
Pharmaceutical Use
[0139] The present disclosure also provides use of one or more
compounds of the present disclosure in the manufacture of a
medicament for treating a disease. In some embodiments, the disease
is narcolepsy, excessive daytime sleepiness, cataplexy,
neurodegenerative disease, sleep disturbance syndrome,
fibromyalgia, chronic fatigue, schizophenia, binge eating disorder,
Parkinson disease, tardive dyskinesia, or Alzheimer's disease. In
some embodiments, the disease is excessive daytime sleepiness or
cataplexy associated with narcolepsy.
[0140] The present disclosure also provides the compounds of the
present disclosure for treating a disease. In some embodiments, the
disease is narcolepsy, excessive daytime sleepiness, cataplexy,
neurodegenerative disease, sleep disturbance syndrome,
fibromyalgia, chronic fatigue, schizophenia, binge eating disorder,
Parkinson disease, tardive dyskinesia, or Alzheimer's disease. In
some embodiments, the disease is excessive daytime sleepiness or
cataplexy associated with narcolepsy.
EXAMPLES
[0141] The following examples are presented to illustrate the
present disclosure. They are not intended to be limiting in any
manner.
Example 1: Preparation and Characterization of Exemplary
Compounds
[0142] Compounds encompassed in the present disclosure may be
prepared via different schemes. Detailed preparation processes of
90 exemplary compounds via various schemes are described below and
the characterization results are listed for each compound as
well.
[0143] Unless stated otherwise, all reagents were purchased from
commercial suppliers without further purification. Solvent drying
by standard methods was employed when necessary. The plates used
for thin-layer chromatography (TLC) were E. Merck silica gel 60F254
(0.24 nm thickness) precoated on aluminum plates, and then
visualized under UV light (365 nm and 254 nm) or through staining
with a 5% of dodecamolybdophosphoric acid in ethanol and subsequent
heating. Column chromatography was performed using silica gel
(200-400 mesh) from commercial suppliers. .sup.1H NMR spectra were
recorded on an Agilent 400-MR NMR spectrometer (400.00 MHz for 1H)
at room temperature. Solvent signal was used as reference for
.sup.1H NMR (CDCl.sub.3, 7.26 ppm; CD.sub.3OD, 3.31 ppm;
d.sub.6-DMSO, 2.50 ppm; D.sub.2O, 4.79 ppm). The following
abbreviations were used to explain the multiplicities: s=singlet,
d=doublet, t=triplet, q=quartet, br.s.=broad singlet, dd=double
doublet, td=triple doublet, dt=double triplet, dq=double quartet,
m=multiplet. Other abbreviations used in the experimental details
are as follows: Ar=aryl, Boc=tert-butyloxy carbonyl, Bn=Benzyl,
6=chemical shift in parts per million downfield from
tetramethylsilane, DCC=dicyclohexylcarbodiimide,
DCM=dichloromethane, DIPEA=diisopropylethylamine,
DMAP=4-(dimethylamino)pyridine, DMF=N,N'-dimethylformamide,
EA=ethyl acetate, Et=ethyl,
HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate, Hex.=hexanes, Hz=hertz, J=coupling
constant (in NMR), Me=methyl, min=minute (s), NMR=nuclear magnetic
resonance, Ph=phenyl, ppm=parts per million, iPr=isopropyl,
TBAF=tetrabutylammonium fluoride, tert=tertiary,
TFA=trifluoroacetic acid, THF=tetrahydrofuran, TLC=thin-layer
chromatography.
##STR00127##
Example 1-1
Intermediate Compound 1': 4-hydroxybutyl 2-methylbenzoate
##STR00128##
[0145] A solution of 2-methylbenzoyl chloride (770 mg, 5 mmol) in
DCM (2 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (8 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was then washed with saturated
brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated.
The residue was purified by a silica gel flash column with
Hex/EA=10:1-3:1 to yield the titled compound (470 mg, 45%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.91 (d, J=8.0 Hz, 1H), 7.40 (t, J=7.4 Hz, 1H),
7.26-7.22 (m, 2H), 4.34 (t, J=6.8 Hz, 2H), 3.73 (t, J=6.4 Hz, 2H),
2.60 (s, 3H), 1.90-1.83 (m, 2H), 1.77-1.70 (m, 2H).
Compound 1: 4-(2-methylbenzoyloxy)butanoic acid
##STR00129##
[0147] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2-methylbenzoate (400 mg, 1.92 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (5 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
then dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The
residue was purified by a silica gel flash column with Hex/EA=3:1
to yield the titled compound (380 mg, 89%) as crystalline solids.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.91 (d, J=8.0 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.28-7.22
(m, 2H), 4.36 (t, J=6.2 Hz, 2H), 2.61 (s, 3H), 2.55 (t, J=7.4 Hz,
2H), 2.15-2.08 (m, 2H).
Example 1-2
Intermediate Compound 2': 4-hydroxybutyl 3-methylbenzoate
##STR00130##
[0149] A solution of 3-methylbenzoyl chloride (616 mg, 4 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was then washed with saturated
brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated.
The residue was purified by a silica gel flash column with
Hex/EA=10:1-3:1 to yield the titled compound (410 mg, 49%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.83-7.81 (m, 2H), 7.35-7.28 (m, 2H), 4.33 (t,
J=6.6 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H), 2.38 (s, 3H), 2.07 (s, 1H),
1.89-1.82 (m, 2H), 1.75-1.68 (m, 2H).
Compound 2: 4-(3-methylbenzoyloxy)butanoic acid
##STR00131##
[0151] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 3-methylbenzoate (350 mg, 1.68 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (5 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=3:1 to yield
the titled compound (333 mg, 89%) as a colorless oil. .sup.1H NMR
was performed at 400 MHz with CDCl.sub.3 as solvent to characterize
the titled compound, results are as follows: .delta.=7.83-7.81 (m,
2H), 7.36-7.28 (m, 2H), 4.36 (t, J=6.2 Hz, 2H), 2.53 (t, J=7.2 Hz,
2H), 2.38 (s, 3H), 2.14-2.07 (m, 2H).
Example 1-3
Intermediate Compound 3': 4-hydroxybutyl 4-methylbenzoate
##STR00132##
[0153] A solution of 4-methylbenzoyl chloride (616 mg, 4 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-3:1 to yield the titled compound (470 mg, 56%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.91 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H),
4.32 (t, J=6.6 Hz, 2H), 3.69 (t, J=6.6 Hz, 2H), 2.38 (s, 3H), 2.19
(br. s., 1H), 1.87-1.80 (m, 2H), 1.74-1.67 (m, 2H).
Compound 3: 4-(4-methylbenzoyloxy)butanoic acid
##STR00133##
[0155] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 4-methylbenzoate (400 mg, 1.92 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (5 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=3:1 to yield
the titled compound (364 mg, 85%) as crystalline solids. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.91 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 4.36 (t,
J=6.2 Hz, 2H), 2.54 (t, J=7.4 Hz, 2H), 2.40 (s, 3H), 2.14-2.08 (m,
2H).
Example 1-4
Intermediate Compound 4': 4-hydroxybutyl 4-fluorobenzoate
##STR00134##
[0157] A solution of 4-fluorobenzoyl chloride (632 mg, 4 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-3:1 to yield the titled compound (540 mg, 64%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=8.07-8.04 (m, 2H), 7.11 (t, J=8.6 Hz, 2H), 4.36
(t, J=6.4 Hz, 2H), 3.73 (t, J=6.4 Hz, 2H), 1.90-1.83 (m, 2H),
1.76-1.69 (m, 2H), 1.41 (br. s., 1H).
Compound 4: 4-(4-fluorobenzoyloxy)butanoic acid
##STR00135##
[0159] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 4-fluorobenzoate (500 mg, 2.36 mmol) and
Celite.COPYRGT.(diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (356 mg, 67%) as
crystalline solids. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=8.06-8.03 (m, 2H), 7.11 (t, J=8.6 Hz, 2H),
4.38 (t, J=6.4 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 2.15-2.07 (m,
2H).
Example 1-5
Intermediate Compound 5': 4-hydroxybutyl
2,4,6-trimethylbenzoate
##STR00136##
[0161] A solution of 2,4,6-trimethylbenzoyl chloride (728 mg, 4
mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg,
5 mmol) in DCM (5 mL) at 0.degree. C. was added a solution of
2,4,6-trimethylbenzoyl chloride (728 mg, 4 mmol) in DCM (5 mL)
dropwise during 10 min. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-3:1 to yield the titled compound (600 mg, 64%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=6.85 (s, 2H), 4.34 (t, J=6.6 Hz, 2H), 3.69 (t,
J=6.6 Hz, 2H), 2.29 (s, 6H), 2.28 (s, 3H), 1.88-1.80 (m, 2H),
1.73-1.66 (m, 2H), 1.49 (br. s., 1H).
Compound 5: 4-(2,4,6-trimethylbenzoyloxy)butanoic acid
##STR00137##
[0163] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2,4,6-trimethylbenzoate (500 mg, 2.12 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=5:1-3:1 to yield the titled compound (450 mg, 85%) as a
white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=6.85 (s, 2H), 4.36 (t, J=6.4 Hz, 2H), 2.51 (t,
J=7.2 Hz, 2H), 2.29 (s, 6H), 2.28 (s, 3H), 2.12-2.05 (m, 2H).
Example 1-6
Intermediate Compound 6': 4-hydroxybutyl 2-methoxybenzoate
##STR00138##
[0165] A solution of 2-methoxybenzoyl chloride (680 mg, 4 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-5:1 to yield the titled compound (370 mg, 41%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.79 (dd, J=1.6, 7.6 Hz, 1H), 7.49-7.45 (m, 1H),
7.00-6.97 (m, 2H), 4.35 (t, J=6.2 Hz, 2H), 3.90 (s, 3H), 3.77-3.68
(m, 2H), 1.91-1.83 (m, 2H), 1.77-1.69 (m, 2H), 1.56 (br. s.,
1H).
Compound 6: 4-(2-methoxybenzoyloxy)butanoic acid
##STR00139##
[0167] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2-methoxybenzoate (300 mg, 1.34 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-3:1 to yield the titled compound (244 mg, 76%) as
crystalline solids. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.78 (dd, J=1.8, 7.8 Hz, 1H), 7.49-7.45 (m,
1H), 7.00-6.96 (m, 2H), 4.36 (t, J=6.0 Hz, 2H), 3.90 (s, 3H), 2.57
(t, J=7.4 Hz, 2H), 2.13-2.07 (m, 2H).
Example 1-7
Intermediate Compound 7': 4-hydroxybutyl 3-methoxybenzoate
##STR00140##
[0169] A solution of 3-methoxybenzoyl chloride (680 mg, 4 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-3:1 to yield the titled compound (420 mg, 47%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.63 (d, J=7.6 Hz, 1H), 7.56 (s, 1H), 7.34 (t,
J=8.0 Hz, 1H), 7.10 (dd, J=2.4, 8.0 Hz, 1H), 4.36 (t, J=6.4 Hz,
2H), 3.85 (s, 3H), 3.73 (t, J=6.2 Hz, 2H), 1.91-1.84 (m, 2H),
1.76-1.69 (m, 2H).
Compound 7: 4-(3-methoxybenzoyloxy)butanoic acid
##STR00141##
[0171] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 3-methoxybenzoate (350 mg, 1.56 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=8:1-3:1 to yield the titled compound (287 mg, 77%) as
crystalline solids. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.63 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.35
(t, J=7.8 Hz, 1H), 7.10 (dd, J=2.4, 8.0 Hz, 1H), 4.39 (t, J=6.4 Hz,
2H), 3.86 (s, 3H), 2.54 (t, J=7.2 Hz, 2H), 2.16-2.08 (m, 2H).
Example 1-8
Intermediate Compound 8': 4-hydroxybutyl 4-methoxybenzoate
##STR00142##
[0173] A solution of 4-methoxybenzoyl chloride (680 mg, 4 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-5:1 to yield the titled compound (500 mg, 56%) as a
colorless oil. H NMR was performed at 400 MHz with CDCl.sub.3 as
solvent to characterize the titled compound, results are as
follows: .delta.=7.99 (d, J=9.2 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H),
4.33 (t, J=6.6 Hz, 2H), 3.86 (s, 3H), 3.73 (s, 2H), 1.89-1.82 (m,
2H), 1.76-1.69 (m, 2H), 1.44 (br. s., 1H).
Compound 8: 4-(4-methoxybenzoyloxy)butanoic acid
##STR00143##
[0175] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 4-methoxybenzoate (400 mg, 1.79 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-3:1 to yield the titled compound (370 mg, 87%) as
a white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.99 (d, J=9.2 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H),
4.35 (t, J=6.2 Hz, 2H), 3.86 (s, 3H), 2.54 (t, J=7.2 Hz, 2H),
2.13-2.08 (m, 2H).
Example 1-9
Intermediate Compound 9': 4-hydroxybutyl 2-chlorobenzoate
##STR00144##
[0177] A solution of 2-chlorobenzoyl chloride (2 g, 11.43 mmol) in
DCM (10 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (3085 mg, 34.28 mmol) and Et.sub.3N (2308 mg,
22.85 mmol) in DCM (50 mL) at 0.degree. C. The reaction was allowed
to warm up gradually and stirred at 0 25.degree. C. over 16 h.
After that, the reaction mixture was diluted with H.sub.2O (30 mL)
and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (10 mL). The combined organic phase was washed
with brine (20 mL), dried over Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with Hex/EA=8:1
to yield the titled compound (1.8 g, 69%) as colorless oil. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.81 (dd, J=1.4, 7.8 Hz, 1H), 7.45-7.38 (m, 2H), 7.34-7.28
(m, 1H), 4.38 (t, J=6.4 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H), 1.91-1.84
(m, 2H), 1.77-1.70 (m, 2H).
Compound 9: 4-(2-chlorobenzoyloxy)butanoic acid
##STR00145##
[0179] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2-chlorobenzoate (1.6 g, 7.02 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (10 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (20 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with brine (3 mL.times.2), dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by a
silica gel flash column with Hex/EA=3:1 to yield the titled
compound (1 g, 59%) as crystalline solids. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.82 (dd, J=1.2,
8.0 Hz, 1H), 7.49-7.38 (m, 2H), 7.34-7.29 (m, 1H), 4.41 (t, J=6.2
Hz, 2H), 2.57 (t, J=7.2 Hz, 2H), 2.16-2.09 (m, 2H).
Example 1-10
Intermediate Compound 10': 4-hydroxybutyl 3-chlorobenzoate
##STR00146##
[0181] A solution of 3-chlorobenzoyl chloride (696 mg, 4 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-5:1 to yield the titled compound (550 mg, 60%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=8.00 (s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.52 (dd,
J=0.8, 8.4 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 4.36 (t, J=6.4 Hz, 2H),
3.73 (dd, J=6.2, 10.6 Hz, 2H), 1.91-1.84 (m, 2H), 1.76-1.69 (m,
3H).
Compound 10: 4-(3-chlorobenzoyloxy)butanoic acid
##STR00147##
[0183] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 3-chlorobenzoate (500 mg, 2.19 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (5 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=10:1-3:1 to
yield the titled compound (420 mg, 79%) as a colorless oil. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=8.00 (s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.55-7.52 (m, 1H),
7.39 (t, J=7.8 Hz, 1H), 4.39 (t, J=6.2 Hz, 2H), 2.55 (t, J=7.2 Hz,
2H), 2.16-2.09 (m, 2H).
Example 1-11
Intermediate Compound 11': 4-hydroxybutyl 4-chlorobenzoate
##STR00148##
[0185] A solution of 4-chlorobenzoyl chloride (2 g, 11.43 mmol) in
DCM (10 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (3085 mg, 34.28 mmol) and Et.sub.3N (2308 mg,
22.85 mmol) in DCM (50 mL) at 0.degree. C. The reaction was allowed
to warm up gradually and stirred at 0-25.degree. C. over 1 h. After
that, the reaction mixture was diluted with H.sub.2O (30 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (10 mL). The combined organic phase was washed with brine
(20 mL), dried over Na.sub.2SO.sub.4 and evaporated. The residue
was purified by a silica gel flash column with Hex/EA=7:1 to yield
the titled compound (1.6 g, 62%) as crystalline solids. .sup.1H NMR
was performed at 400 MHz with CDCl.sub.3 as solvent to characterize
the titled compound, results are as follows: .delta.=7.97 (d, J=8.4
Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 4.36 (t, J=6.6 Hz, 2H), 3.73 (t,
J=6.4 Hz, 2H), 1.90-1.84 (m, 2H), 1.75-1.69 (m, 2H).
Compound 11: 4-(4-chlorobenzoyloxy)butanoic acid
##STR00149##
[0187] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 4-chlorobenzoate (1.5 g, 6.58 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (10 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. over 16 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (20 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with brine (3 mL.times.2), dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by a
silica gel flash column with Hex/EA=3:1 to afford the title
compound (600 mg, 38%) as crystalline solids. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.96 (d, J=8.0 Hz,
2H), 7.41 (d, J=8.0 Hz, 2H), 4.39 (t, J=6.2 Hz, 2H), 2.54 (t, J=7.2
Hz, 2H), 2.15-2.07 (m, 2H).
Example 1-12
Intermediate Compound 12': 4-hydroxybutyl 3-cyanobenzoate
##STR00150##
[0189] A solution of 3-cyanobenzoyl chloride (660 mg, 4 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-5:1 to yield the titled compound (450 mg, 51%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=8.31 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.83 (d,
J=7.6 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 4.39 (t, J=6.4 Hz, 2H), 3.73
(t, J=6.4 Hz, 2H), 1.92-1.85 (m, 2H), 1.76-1.69 (m, 2H).
Compound 12: 4-(3-cyanobenzoyloxy)butanoic acid
##STR00151##
[0191] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 3-cyanobenzoate (400 mg, 1.83 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (5 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=10:1-3:1 to
yield the titled compound (330 mg, 77%) as a white solid. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=8.31 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.85 (d, J=7.6 Hz,
1H), 7.59 (t, J=7.8 Hz, 1H), 4.43 (t, J=6.4 Hz, 2H), 2.56 (t, J=7.2
Hz, 2H), 2.18-2.11 (m, 2H).
Example 1-13
Intermediate Compound 13': 4-hydroxybutyl 4-tert-butylbenzoate
##STR00152##
[0193] A solution of 4-tert-butylbenzoyl chloride (784 mg, 4 mmol)
in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg,
5 mmol) in DCM (5 mL) at 0.degree. C. The reaction was allowed to
warm up gradually and stirred at 0-25.degree. C. for over 1 h.
After that, the reaction mixture was diluted with H.sub.2O (5 mL)
and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=10:1-5:1 to yield the titled compound (530 mg,
53%) as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.97 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.8 Hz,
2H), 4.35 (t, J=6.4 Hz, 2H), 3.73 (t, J=6.2 Hz, 2H), 1.91-1.83 (m,
2H), 1.76-1.71 (m, 2H), 1.34 (s, 9H).
Compound 13: 4-(4-tert-butylbenzoyloxy)butanoic acid
##STR00153##
[0195] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 4-tert-butylbenzoate (450 mg, 1.8 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-3:1 to yield the titled compound (370 mg, 79%) as
a white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.96 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.8 Hz, 2H),
4.37 (t, J=6.2 Hz, 2H), 2.55 (t, J=7.4 Hz, 2H), 2.15-2.06 (m, 2H),
1.34 (s, 9H).
Example 1-14
Intermediate Compound 14': 4-hydroxybutyl
3-(trifluoromethyl)benzoate
##STR00154##
[0197] A solution of 3-(trifluoromethyl)benzoyl chloride (832 mg, 4
mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg,
5 mmol) in DCM (5 mL) at 0.degree. C. The reaction was allowed to
warm up gradually and stirred at 0-25.degree. C. over 12 h. After
that, the reaction mixture was diluted with H.sub.2O (5 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (5 mL). The combined organic phase was washed with
saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (670 mg, 64%) as
a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=8.29 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.82
(d, J=8.0 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 4.40 (t, J=6.4 Hz, 2H),
3.74 (t, J=6.6 Hz, 2H), 1.93-1.86 (m, 2H), 1.77-1.70 (m, 2H), 1.42
(br. s., 1H).
Compound 14: 4-(3-(trifluoromethyl)benzoyloxy)butanoic acid
##STR00155##
[0199] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 3-(trifluoromethyl)benzoate (600 mg, 2.29 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-3:1 to yield the titled compound (400 mg, 63%) as
a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=8.29 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.82
(d, J=7.6 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 4.43 (t, J=6.4 Hz, 2H),
2.55 (t, J=7.4 Hz, 2H), 2.18-2.12 (m, 2H).
Example 1-15
Intermediate Compound 15': 4-hydroxybutyl
3,4,5-trimethoxybenzoate
##STR00156##
[0201] A solution of 3,4,5-trimethoxybenzoyl chloride (920 mg, 4
mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg,
5 mmol) in DCM (5 mL) at 0.degree. C. The reaction was allowed to
warm up gradually and stirred at 0-25.degree. C. over 12 h. After
that, the reaction mixture was diluted with H.sub.2O (5 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (5 mL). The combined organic phase was washed with
saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-4:1 to yield the titled compound (700 mg, 62%) as
a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.29 (s, 2H), 4.35 (t, J=6.6 Hz, 2H), 3.90
(s, 9H), 3.77-3.69 (m, 2H), 1.92-1.84 (m, 2H), 1.75-1.68 (m, 2H),
1.48 (br. s., 1H).
Compound 15: 4-(3,4,5-trimethoxybenzoyloxy)butanoic acid
##STR00157##
[0203] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 3,4,5-trimethoxybenzoate (600 mg, 2.11 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=8:1-3:1 to yield the titled compound (440 mg, 70%) as
crystalline solids. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.28 (s, 2H), 4.37 (t, J=6.4 Hz, 2H), 3.90
(s, 9H), 2.52 (t, J=7.2 Hz, 2H), 2.15-2.08 (m, 2H).
Example 1-16
Intermediate Compound 16': 4-hydroxybutyl 4-ethylbenzoate
##STR00158##
[0205] A solution of 4-ethylbenzoyl chloride (500 mg, 2.98 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (534 mg, 5.93 mmol) and Et.sub.3N (599 mg, 5.93
mmol) in DCM (10 mL) at 0.degree. C. The reaction was allowed to
warm up gradually and stirred at 0-25.degree. C. for over 1 h.
After that, the reaction mixture was diluted with H.sub.2O (5 mL)
and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=10:1-6:1 to yield the titled compound (450 mg,
68%) as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.97 (s, 1H), 7.94 (s, 1H), 7.27 (s, 1H),
7.25 (s, 1H), 4.35 (t, J=6.4 Hz, 2H), 3.73 (t, J=6.2 Hz, 2H), 2.70
(q, J=7.6 Hz, 2H), 1.90-1.83 (m, 2H), 1.77-1.70 (m, 2H), 1.34 (br.
s., 1H), 1.25 (t, J=7.6 Hz, 3H).
Compound 16: 4-(4-ethylbenzoyloxy)butanoic acid
##STR00159##
[0207] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 4-ethylbenzoate (450 mg, 2.03 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (10 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=10:1-5:1 to
yield the titled compound (270 mg, 56%) as a colorless oil. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.96 (s, 1H), 7.94 (s, 1H), 7.27 (s, 1H), 7.25 (s, 1H),
4.37 (t, J=6.2 Hz, 2H), 2.70 (q, J=7.6 Hz, 2H), 2.55 (t, J=7.4 Hz,
2H), 2.15-2.09 (m, 2H), 1.25 (t, J=7.6 Hz, 3H).
Example 1-17
Intermediate Compound 17': 4-hydroxybutyl 2,3-dimethylbenzoate
##STR00160##
[0209] A solution of 2,3-dimethylbenzoyl chloride (500 mg, 2.97
mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (534 mg, 5.93 mmol) and Et.sub.3N (599
mg, 5.93 mmol) in DCM (10 mL) at 0.degree. C. The reaction was
allowed to warm up gradually and stirred at 0-25.degree. C. over 3
h. After that, the reaction mixture was diluted with H.sub.2O (5
mL) and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=7:1 to yield the titled compound (390 mg, 59%)
as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.61 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.6 Hz,
1H), 7.13 (t, J=7.8 Hz, 1H), 4.34 (t, J=6.6 Hz, 2H), 3.73 (t, J=6.0
Hz, 2H), 2.45 (s, 3H), 2.32 (s, 3H), 1.90-1.83 (m, 2H), 1.78-1.69
(m, 2H), 1.36 (br. s., 1H).
Compound 17: 4-(2,3-dimethylbenzoyloxy)butanoic acid
##STR00161##
[0211] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2,3-dimethylbenzoate (350 mg, 1.58 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-6:1 to yield the titled compound (230 mg, 62%) as
a white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.61 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H),
7.13 (t, J=7.6 Hz, 1H), 4.35 (t, J=6.2 Hz, 2H), 2.54 (t, J=7.2 Hz,
2H), 2.45 (s, 3H), 2.32 (s, 3H), 2.15-2.08 (m, 2H).
Example 1-18
Intermediate Compound 18': 4-hydroxybutyl 3,5-dimethoxybenzoate
##STR00162##
[0213] A solution of 3,5-dimethoxybenzoyl chloride (500 mg, 2.49
mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg,
5 mmol) in DCM (10 mL) at 0.degree. C. The reaction was allowed to
warm up gradually and stirred at 0-25.degree. C. over 3 h. After
that, the reaction mixture was diluted with H.sub.2O (5 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (5 mL). The combined organic phase was washed with
saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue was purified by a silica gel flash column
with Hex/EA=7:1 to yield the titled compound (430 mg, 68%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.18 (d, J=2.4 Hz, 2H), 6.65 (t, J=2.0 Hz, 1H),
4.36 (t, J=6.4 Hz, 2H), 3.83 (s, 6H), 3.73 (t, J=6.2 Hz, 2H),
1.90-1.83 (m, 2H), 1.76-1.69 (m, 2H).
Compound 18: 4-(3,5-dimethoxybenzoyloxy)butanoic acid
##STR00163##
[0215] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 3,5-dimethoxybenzoate (400 mg, 1.57 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (200 mg, 47%) as
a white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.16 (d, J=2.4 Hz, 2H), 6.64 (t, J=2.0 Hz, 1H),
4.37 (t, J=6.2 Hz, 2H), 3.82 (s, 6H), 2.52 (t, J=7.2 Hz, 2H),
2.14-2.07 (m, 2H).
Example 1-19
Intermediate Compound 19': 4-hydroxybutyl 3,5-dimethylbenzoate
##STR00164##
[0217] A solution of 3,5-dimethylbenzoyl chloride (500 mg, 2.96
mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (534 mg, 5.93 mmol) and Et.sub.3N (599
mg, 5.93 mmol) in DCM (10 mL) at 0.degree. C. The reaction was
allowed to warm up gradually and stirred at 0-25.degree. C. over 16
h. After that, the reaction mixture was diluted with H.sub.2O (5
mL) and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=7:1 to yield the titled compound (400 mg, 61%)
as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.65 (s, 2H), 7.19 (s, 1H), 4.35 (t, J=6.4
Hz, 2H), 3.73 (s, 2H), 2.36 (s, 6H), 1.90-1.83 (m, 2H), 1.77-1.70
(m, 2H).
Compound 19: 4-(3,5-dimethylbenzoyloxy)butanoic acid
##STR00165##
[0219] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 3,5-dimethylbenzoate (400 mg, 1.8 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (300 mg, 70%) as
a white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.64 (s, 2H), 7.19 (s, 1H), 4.36 (t, J=6.0 Hz,
2H), 2.55 (t, J=7.4 Hz, 2H), 2.36 (s, 6H), 2.15-2.08 (m, 2H).
Example 1-20
Intermediate Compound 20': 4-hydroxybutyl cinnamate
##STR00166##
[0221] A solution of cinnamoyl chloride (664 mg, 4 mmol) in DCM (5
mL) was added dropwise during 10 min to a stirred solution of
butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol) in
DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-3:1 to yield the titled compound (455 mg, 52%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.69 (d, J=16.0 Hz, 1H), 7.54-7.52 (m, 2H), 7.39
(t, J=3.2 Hz, 3H), 6.44 (d, J=16.0 Hz, 1H), 4.25 (t, J=6.4 Hz, 2H),
3.72 (t, J=6.2 Hz, 2H), 1.85-1.78 (m, 2H), 1.73-1.66 (m, 2H), 1.44
(br. s., 1H).
Compound 20: (E)-4-(cinnamoyloxy)butanoic acid
##STR00167##
[0223] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl cinnamate (400 mg, 1.81 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (5 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=3:1 to yield
the titled compound (370 mg, 87%) as colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: 6=7.68 (d, J=16.0 Hz, 1H),
7.54-7.52 (m, 2H), 7.40-7.38 (m, 3H), 6.43 (d, J=16.0 Hz, 1H), 4.26
(t, J=6.2 Hz, 2H), 2.48 (t, J=7.2 Hz, 2H), 2.07-2.01 (m, 2H).
Example 1-21
Intermediate Compound 21': 4-hydroxybutyl 3-phenylpropanoate
##STR00168##
[0225] A solution of 3-phenylpropanoyl chloride (672 mg, 4 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-3:1 to yield the titled compound (370 mg, 42%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.31-7.27 (m, 2H), 7.21-7.19 (m, 3H), 4.10 (t,
J=6.6 Hz, 2H), 3.65 (t, J=6.4 Hz, 2H), 2.95 (t, J=7.8 Hz, 2H), 2.63
(t, J=7.6 Hz, 2H), 1.73-1.66 (m, 2H), 1.60-1.54 (m, 2H), 1.33 (br.
s., 1H).
Compound 21: 4-(3-phenylpropanoyloxy)butanoic acid
##STR00169##
[0227] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 3-phenylpropanoate (300 mg, 1.35 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=3:1 to yield the titled compound (277 mg, 87%) as
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: 6=7.31-7.27 (m, 2H), 7.22-7.19 (m, 3H), 4.12 (t, J=6.2 Hz,
2H), 2.95 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.37 (t, J=7.4
Hz, 2H), 1.96-1.90 (m, 2H).
Example 1-22
Intermediate Compound 22': 4-hydroxybutyl pivalate
##STR00170##
[0229] A solution of pivaloyl chloride (1.2 g, 10 mmol) was added
dropwise during 10 min to a stirred solution of butane-1,4-diol
(2.7 g, 30 mmol) and Et.sub.3N (2.02 g, 20 mmol) in DCM (30 mL) at
0.degree. C. The reaction was allowed to warm up gradually and
stirred at 0 25.degree. C. over 1 h. After that, the reaction
mixture was diluted with H.sub.2O (10 mL) and stirred for 5 min.
The aqueous phase was separated and extracted with DCM (15 mL). The
combined organic phase was washed with brine (15 mL), dried over
Na.sub.2SO.sub.4 and evaporated. The residue was purified by a
silica gel flash column with Hex/EA=20:1-5:1 to yield the titled
compound (1.5 g, 86%) as a colorless oil. .sup.1H NMR was performed
at 400 MHz with CDCl.sub.3 as solvent to characterize the titled
compound, results are as follows: .delta.=4.09 (t, J=6.0 Hz, 2H),
3.68 (t, J=6.4 Hz, 2H), 1.74-1.70 (m, 2H), 1.65-1.61 (m, 2H), 1.19
(s, 9H).
Compound 22: 4-(pivaloyloxy)butanoic acid
##STR00171##
[0231] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl pivalate (1.0 g, 5.75 mmol) and Celite.COPYRGT.
(diatomaceous earth, 2 g) in acetone (20 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (20 mL) and then
filtered. The filtered cake was washed with EA (10 mL) and the
combined filtrate was washed with brine (5 mL.times.2), dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by a
silica gel flash column with Hex/EA=5:1 to yield the titled
compound (700 mg, 65%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=4.11 (t, J=6.4 Hz,
2H), 2.46 (t, J=7.4 Hz, 2H), 2.02-1.95 (m, 2H), 1.19 (s, 9H).
Example 1-23
Intermediate Compound 23': 4-hydroxybutyl 2-ethylbutanoate
##STR00172##
[0233] A solution of 2-ethylbutanoyl chloride (500 mg, 3.7 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (669 mg, 7.43 mmol) and Et.sub.3N (750 mg, 7.43
mmol) in DCM (10 mL) at 0.degree. C. The reaction was allowed to
warm up gradually and stirred at 0-25.degree. C. over 3 h. After
that, the reaction mixture was diluted with H.sub.2O (5 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (5 mL). The combined organic phase was washed with
saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue was purified by a silica gel flash column
with Hex/EA=6:1 to yield the titled compound (450 mg, 65%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=4.13 (t, J=6.4 Hz, 2H), 3.73-3.64 (m, 2H),
2.23-2.16 (m, 1H), 1.77-1.70 (m, 2H), 1.68-1.58 (m, 4H), 1.55-1.46
(m, 2H), 0.89 (t, J=7.4 Hz, 6H).
Compound 23: 4-(2-ethylbutanoyloxy)butanoic acid
##STR00173##
[0235] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2-ethylbutanoate (450 mg, 2.39 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (10 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=10:1-5:1 to
yield the titled compound (300 mg, 62%) as a colorless oil. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=4.14 (t, J=6.2 Hz, 2H), 2.46 (t, J=7.6 Hz, 2H), 2.24-2.17
(m, 1H), 2.02-1.95 (m, 2H), 1.66-1.46 (m, 4H), 0.89 (t, J=7.4 Hz,
6H).
Example 1-24
Intermediate Compound 24': 4-hydroxybutyl 2-propylpentanoate
##STR00174##
[0237] A solution of 2-propylpentanoyl chloride (1 g, 6.13 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (1107 mg, 12.3 mmol) and Et.sub.3N (1242 mg,
12.3 mmol) in DCM (10 mL) at 0.degree. C. The reaction was allowed
to warm up gradually and stirred at 0-25.degree. C. over 16 h.
After that, the reaction mixture was diluted with H.sub.2O (5 mL)
and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=5:1 to yield the titled compound (700 mg, 53%)
as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=4.11 (t, J=6.6 Hz, 2H), 3.69 (q, J=5.8 Hz,
2H), 2.39-2.32 (m, 1H), 1.77-1.69 (m, 2H), 1.68-1.60 (m, 3H),
1.58-1.53 (m, 1H), 1.45-1.36 (m, 3H), 1.33-1.24 (m, 4H), 0.89 (t,
J=7.2 Hz, 6H).
Compound 24: 4-(2-propylpentanoyloxy)butanoic acid
##STR00175##
[0239] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2-propylpentanoate (500 mg, 2.31 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (160 mg, 30%) as
a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=4.12 (t, J=6.0 Hz, 2H), 2.46 (t, J=7.6 Hz,
2H), 2.41-2.31 (m, 1H), 2.01-1.95 (m, 2H), 1.63-1.54 (m, 2H),
1.45-1.37 (m, 2H), 1.33-1.24 (m, 4H), 0.89 (t, J=7.2 Hz, 6H).
Example 1-25
Intermediate Compound 25': 4-hydroxybutyl
cyclopentanecarboxylate
##STR00176##
[0241] A solution of cyclopentanecarbonyl chloride (528 mg, 4 mmol)
in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg,
5 mmol) in DCM (5 mL) at 0.degree. C. The reaction was allowed to
warm up gradually and stirred at 0-25.degree. C. for over 1 h.
After that, the reaction mixture was diluted with H.sub.2O (5 mL)
and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=10:1-3:1 to yield the titled compound (520 mg,
70%) as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=4.10 (t, J=6.4 Hz, 2H), 3.68 (t, J=6.0 Hz,
2H), 2.76-2.68 (m, 1H), 1.92-1.62 (m, 10H), 1.60-1.53 (m, 2H), 1.41
(br. s., 1H).
Compound 25: 4-(cyclopentanecarbonyloxy)butanoic acid
##STR00177##
[0243] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl cyclopentanecarboxylate (450 mg, 2.42 mmol) and
Celite.COPYRGT. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=3:1 to yield the titled compound (373 mg, 77%) as
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=4.12 (t, J=6.2 Hz, 2H), 2.76-2.68 (m, 1H), 2.45
(t, J=7.2 Hz, 2H), 2.01-1.94 (m, 2H), 1.92-1.84 (m, 2H), 1.82-1.65
(m, 4H), 1.61-1.50 (m, 2H).
Example 1-26
Intermediate Compound 26': 4-hydroxybutyl
cyclohexanecarboxylate
##STR00178##
[0245] A solution of cyclohexanecarbonyl chloride (584 mg, 4 mmol)
in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg,
5 mmol) in DCM (5 mL) at 0.degree. C. The reaction was allowed to
warm up gradually and stirred at 0-25.degree. C. for over 1 h.
After that, the reaction mixture was diluted with H.sub.2O (5 mL)
and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=10:1-3:1 to yield the titled compound (440 mg,
55%) as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=4.08 (t, J=6.2 Hz, 2H), 3.66 (t, J=6.2 Hz,
2H), 2.32-2.24 (m, 1H), 1.88 (d, J=13.2 Hz, 2H), 1.76-1.58 (m, 8H),
1.48-1.37 (m, 2H), 1.31-1.15 (m, 3H).
Compound 26: 4-(cyclohexanecarbonyloxy)butanoic acid
##STR00179##
[0247] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl cyclohexanecarboxylate (400 mg, 2 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=3:1 to yield the titled compound (350 mg, 82%) as
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=4.11 (t, J=6.4 Hz, 2H), 2.45 (t, J=7.4 Hz, 2H),
2.29 (tt, J=3.6, 11.3 Hz, 1H), 2.01-1.94 (m, 2H), 1.91-1.87 (m,
2H), 1.76-1.69 (m, 2H), 1.65-1.62 (m, 1H), 1.48-1.38 (m, 2H),
1.33-1.19 (m, 3H).
Example 1-27
Intermediate Compound 27': 4-hydroxybutyl 2-acetoxyacetate
##STR00180##
[0249] A solution of 2-chloro-2-oxoethyl acetate (544 mg, 4 mmol)
in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg,
5 mmol) in DCM (5 mL) at 0.degree. C. The reaction was allowed to
warm up gradually and stirred at 0-25.degree. C. for over 1 h.
After that, the reaction mixture was diluted with H.sub.2O (5 mL)
and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=8:1-5:1 to yield the titled compound (500 mg,
66%) as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=4.60 (s, 2H), 4.22 (t, J=6.4 Hz, 2H), 3.68
(dd, J=5.8, 10.6 Hz, 2H), 2.16 (s, 3H), 1.81-1.72 (m, 2H),
1.68-1.60 (m, 2H), 1.39 (br. s., 1H).
Compound 27: 4-(2-acetoxyacetoxy)butanoic acid
##STR00181##
[0251] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2-acetoxyacetate (400 mg, 2.11 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (5 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=8:1-3:1 to
yield the titled compound (370 mg, 86%) as a colorless oil. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=4.60 (s, 2H), 4.24 (t, J=6.2 Hz, 2H), 2.46 (t, J=7.4 Hz,
2H), 2.16 (s, 3H), 2.04-1.97 (m, 2H).
Example 1-28
Intermediate Compound 28': ethyl (4-hydroxybutyl) carbonate
##STR00182##
[0253] A solution of ethyl carbonochloridate (1 g, 9.17 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (1659 mg, 18.43 mmol) and Et.sub.3N (1861 mg,
18.43 mmol) in DCM (10 mL) at 0.degree. C. The reaction was allowed
to warm up gradually and stirred at 0-25.degree. C. over 16 h.
After that, the reaction mixture was diluted with H.sub.2O (5 mL)
and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=5:1 to yield the titled compound (700 mg, 47%)
as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=4.22-4.16 (m, 4H), 3.68 (q, J=5.8 Hz, 2H),
1.81-1.74 (m, 2H), 1.69-1.62 (m, 2H), 1.38 (t, J=5.0 Hz, 1H), 1.31
(t, J=7.0 Hz, 3H).
Compound 28: 4-(ethoxycarbonyloxy)butanoic acid
##STR00183##
[0255] Jones reagent was added in portions to a stirred mixture of
ethyl (4-hydroxybutyl) carbonate (500 mg, 3.09 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (70 mg, 13%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=4.22-4.17 (m, 4H), 2.50 (t, J=7.2 Hz, 2H),
2.05-1.98 (m, 2H), 1.31 (t, J=7.2 Hz, 3H).
Example 1-29
Intermediate Compound 29': 4-hydroxybutyl isopropyl carbonate
##STR00184##
[0257] A solution of isopropyl carbonochloridate (10 ml, 1.0 M/L,
10 mmol) in DCM (10 mL) was added dropwise during 10 min to a
stirred solution of butane-1,4-diol (1800 mg, 20 mmol) and
Et.sub.3N (2020 mg, 20 mmol) in DCM (20 mL) at 0.degree. C. The
reaction was allowed to warm up gradually and stirred at
0-25.degree. C. over 16 h. After that, the reaction mixture was
diluted with H.sub.2O (5 mL) and stirred for 5 min. The aqueous
phase was separated and extracted with DCM (5 mL). The combined
organic phase was washed with saturated brine (5 mL), dried over
anhydrous Na.sub.2SO.sub.4 and evaporated. The residue was purified
by a silica gel flash column with Hex/EA=5:1 to yield the titled
compound (1.58 g, 90%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=4.90-4.84 (m, 1H),
4.16 (t, J=6.6 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 1.80-1.73 (m, 2H),
1.69-1.62 (m, 2H), 1.29 (d, J=5.6 Hz, 6H).
Compound 29: 4-(isopropoxycarbonyloxy)butanoic acid
##STR00185##
[0259] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl isopropyl carbonate (800 mg, 4.55 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (260 mg, 30%) as
a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=4.90-4.84 (m, 1H), 4.18 (t, J=6.2 Hz, 2H),
2.50 (t, J=7.2 Hz, 2H), 2.05-1.97 (m, 2H), 1.30 (d, J=6.0 Hz,
6H).
Example 1-30
Intermediate Compound 30': 4-hydroxybutyl isobutyl carbonate
##STR00186##
[0261] A solution of isobutyl carbonochloridate (544 mg, 4 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-6:1 to yield the titled compound (250 mg, 33%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=4.18 (t, J=6.4 Hz, 2H), 3.91 (d, J=6.8 Hz, 2H),
3.69 (dd, J=5.4, 11.0 Hz, 2H), 1.81-1.75 (m, 3H), 1.70-1.62 (m,
2H), 0.96 (s, 3H), 0.94 (s, 3H).
Compound 30: 4-(isobutoxycarbonyloxy)butanoic acid
##STR00187##
[0263] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl isobutyl carbonate (200 mg, 1.1 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=8:1-3:1 to yield the titled compound (110 mg, 51%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=4.20 (t, J=6.4 Hz, 2H), 3.92 (d, J=6.8 Hz, 2H),
2.49 (t, J=7.2 Hz, 2H), 2.06-1.93 (m, 3H), 0.96 (s, 3H), 0.94 (s,
3H).
Example 1-31
Intermediate Compound 31': benzyl (4-hydroxybutyl) carbonate
##STR00188##
[0265] A solution of benzyl carbonochloridate (1 g, 5.86 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (1055 mg, 11.72 mmol) and Et.sub.3N (1184 mg,
11.72 mmol) in DCM (10 mL) at 0.degree. C. The reaction was allowed
to warm up gradually and stirred at 0-25.degree. C. over 3 h. After
that, the reaction mixture was diluted with H.sub.2O (5 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (5 mL). The combined organic phase was washed with
saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue was purified by a silica gel flash column
with Hex/EA=7:1 to yield the titled compound (292 mg, 22%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.40-7.32 (m, 5H), 5.16 (s, 2H), 4.20 (t, J=6.6
Hz, 2H), 3.68 (q, J=6.0 Hz, 2H), 1.81-1.74 (m, 2H), 1.68-1.62 (m,
2H), 1.29 (t, J=5.4 Hz, 1H).
Compound 31: 4-(benzyloxycarbonyloxy)butanoic acid
##STR00189##
[0267] Jones reagent was added in portions to a stirred mixture of
benzyl (4-hydroxybutyl) carbonate (290 mg, 1.29 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (188 mg, 61%) as
a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.38-7.33 (m, 5H), 5.16 (s, 2H), 4.21 (t,
J=6.2 Hz, 2H), 2.47 (t, J=7.2 Hz, 2H), 2.03-1.97 (m, 2H).
Example 1-32
Intermediate Compound 32': 4-hydroxybutyl phenyl carbonate
##STR00190##
[0269] A solution of phenyl carbonochloridate (624 mg, 4 mmol) in
DCM (5 mL) was added dropwise during 10 min to a stirred solution
of butane-1,4-diol (450 mg, 5 mmol) and Et.sub.3N (505 mg, 5 mmol)
in DCM (5 mL) at 0.degree. C. The reaction was allowed to warm up
gradually and stirred at 0-25.degree. C. for over 1 h. After that,
the reaction mixture was diluted with H.sub.2O (5 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(5 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
Hex/EA=10:1-5:1 to yield the titled compound (333 mg, 40%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.39 (t, J=7.8 Hz, 2H), 7.26-7.23 (m, 1H), 7.18
(d, J=8.0 Hz, 2H), 4.30 (t, J=6.6 Hz, 2H), 3.72 (dd, J=6.2, 11.2
Hz, 2H), 1.89-1.82 (m, 2H), 1.75-1.68 (m, 2H), 1.35 (t, J=5.2 Hz,
1H).
Compound 32: 4-(phenoxycarbonyloxy)butanoic acid
##STR00191##
[0271] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl phenyl carbonate (300 mg, 1.55 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (5 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=10:1-2:1 to
yield the titled compound (210 mg, 65%) as a white solid. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.39 (t, J=8.0 Hz, 2H), 7.25 (t, J=7.2 Hz, 1H), 7.18 (d,
J=8.0 Hz, 2H), 4.32 (t, J=6.2 Hz, 2H), 2.55 (t, J=7.4 Hz, 2H),
2.13-2.06 (m, 2H).
Example 1-33
Intermediate Compound 33': 4-chlorophenyl (4-hydroxybutyl)
carbonate
##STR00192##
[0273] A solution of 4-chlorophenyl carbonochloridate (500 mg, 2.62
mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (707 mg, 7.86 mmol) and Et.sub.3N (529
mg, 5.24 mmol) in DCM (10 mL) at 0.degree. C. The reaction was
allowed to warm up gradually and stirred at 0-25.degree. C. over 16
h. After that, the reaction mixture was diluted with H.sub.2O (5
mL) and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=6:1 to yield the titled compound (420 mg, 66%)
as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.35 (d, J=9.2 Hz, 2H), 7.13 (d, J=9.2 Hz,
2H), 4.30 (t, J=6.4 Hz, 2H), 3.72 (t, J=6.2 Hz, 2H), 1.89-1.82 (m,
2H), 1.74-1.67 (m, 2H).
Compound 33: 4-((4-chlorophenoxy)carbonyloxy)butanoic acid
##STR00193##
[0275] Jones reagent was added in portions to a stirred mixture of
4-chlorophenyl (4-hydroxybutyl) carbonate (400 mg, 1.64 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (220 mg, 52%) as
a white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.35 (d, J=9.2 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H),
4.32 (t, J=6.2 Hz, 2H), 2.55 (t, J=7.4 Hz, 2H), 2.13-2.06 (m,
2H).
Example 1-34
Intermediate Compound 34': 4-hydroxybutyl p-tolyl carbonate
##STR00194##
[0277] A solution of p-tolyl carbonochloridate (500 mg, 2.94 mmol)
in DCM (5 mL) was added dropwise during 10 min to a stirred
solution of butane-1,4-diol (794 mg, 8.82 mmol) and Et.sub.3N (594
mg, 5.88 mmol) in DCM (10 mL) at 0.degree. C. The reaction was
allowed to warm up gradually and stirred at 0-25.degree. C. over 16
h. After that, the reaction mixture was diluted with H.sub.2O (5
mL) and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=6:1 to yield the titled compound (600 mg, 91%)
as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.17 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz,
2H), 4.29 (t, J=6.8 Hz, 2H), 3.72 (t, J=6.2 Hz, 2H), 2.34 (s, 3H),
1.89-1.82 (m, 2H), 1.74-1.67 (m, 2H).
Compound 34: 4-(p-tolyloxycarbonyloxy)butanoic acid
##STR00195##
[0279] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl p-tolyl carbonate (500 mg, 2.23 mmol) and
Celite.COPYRGT. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (170 mg, 32%) as a
white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.17 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H),
4.31 (t, J=6.2 Hz, 2H), 2.55 (t, J=7.2 Hz, 2H), 2.34 (s, 3H),
2.12-2.07 (m, 2H).
##STR00196##
Example 1-35
Intermediate Compound 35': 4-hydroxybutyl 4-butoxybenzoate
##STR00197##
[0281] 4-butoxybenzoic acid (882 mg, 4.55 mmol), DCC (1030 mg, 5
mmol) and DMAP (50 mg) was added to a stirred solution of
butane-1,4-diol (450 mg, 5 mmol) in DCM (15 mL). The reaction was
stirred at 25.degree. C. for 3 h. After that, the reaction mixture
was diluted with saturated aqueous NH.sub.4Cl (10 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(10 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with Hex/EA=5:1
to yield the titled compound (500 mg, 41%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.97 (d, J=8.4 Hz, 2H), 6.90 (d, J=9.2 Hz, 2H), 4.33 (t,
J=6.2 Hz, 2H), 4.01 (t, J=6.6 Hz, 2H), 3.73 (t, J=6.4 Hz, 2H),
1.89-1.71 (m, 6H), 1.61 (br. s., 1H), 1.54-1.45 (m, 2H), 0.98 (t,
J=7.2 Hz, 3H).
Compound 35: 4-(4-butoxybenzoyloxy)butanoic acid
##STR00198##
[0283] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 4-butoxybenzoate (450 mg, 1.69 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (10 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=5:1 to yield
the titled compound (200 mg, 42%) as crystalline solids. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.97 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.35 (t,
J=6.2 Hz, 2H), 4.01 (t, J=6.4 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H),
2.14-2.07 (m, 2H), 1.82-1.75 (m, 2H), 1.53-1.46 (m, 2H), 0.98 (t,
J=7.4 Hz, 3H).
Example 1-36
Intermediate Compound 36': 4-hydroxybutyl 4-isopropylbenzoate
##STR00199##
[0285] 4-isopropylbenzoic acid (745 mg, 4.54 mmol), DCC (1030 mg, 5
mmol) and DMAP (50 mg) was added to a stirred solution of
butane-1,4-diol (450 mg, 5 mmol) in DCM (15 mL). The reaction was
stirred at 25.degree. C. for 3 h. After that, the reaction mixture
was diluted with saturated aqueous NH.sub.4Cl (10 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(10 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with Hex/EA=5:1
to yield the titled compound (400 mg, 37%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.96 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 4.35 (t,
J=6.4 Hz, 2H), 3.76-3.69 (m, 2H), 2.99-2.93 (m, 1H), 1.90-1.83 (m,
2H), 1.76-1.69 (m, 2H), 1.40 (br. s., 1H), 1.27 (s, 3H), 1.26 (s,
3H).
Compound 36: 4-(4-isopropylbenzoyloxy) butanoic acid
##STR00200##
[0287] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 4-isopropylbenzoate (350 mg, 1.48 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (200 mg, 54%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.95 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H),
4.37 (t, J=6.2 Hz, 2H), 2.99-2.92 (m, 1H), 2.54 (t, J=7.4 Hz, 2H),
2.15-2.08 (m, 2H), 1.27 (s, 3H), 1.25 (s, 3H).
Example 1-37
Intermediate Compound 37': 4-hydroxybutyl
3-(methylsulfonyl)benzoate
##STR00201##
[0289] 3-(methylsulfonyl) benzoic acid (505 mg, 2.53 mmol), DCC
(572 mg, 2.78 mmol) and DMAP (50 mg) was added to a stirred
solution of butane-1,4-diol (250 mg, 2.78 mmol) in DCM (15 mL). The
reaction was stirred at 25.degree. C. for 3 h. After that, the
reaction mixture was diluted with saturated aqueous NH.sub.4Cl (10
mL) and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (5 mL). The combined organic phase was washed
with saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=2:1 to yield the titled compound (150 mg, 22%)
as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=8.60 (s, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.15
(d, J=8.0 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 4.42 (t, J=6.6 Hz, 2H),
3.74 (q, J=6.0 Hz, 2H), 3.10 (s, 3H), 1.94-1.87 (m, 2H), 1.76-1.70
(m, 2H), 1.36 (t, J=5.0 Hz, 1H).
Compound 37: 4-(3-(methylsulfonyl)benzoyloxy)butanoic acid
##STR00202##
[0291] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 3-(methylsulfonyl)benzoate (150 mg, 0.55 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=2:1 to yield the titled compound (70 mg, 44%) as
crystalline solids. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=8.59 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.15
(d, J=8.0 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 4.44 (t, J=6.2 Hz, 2H),
3.11 (s, 3H), 2.55 (t, J=7.0 Hz, 2H), 2.20-2.14 (m, 2H).
Example 1-38
Intermediate Compound 38': 4-hydroxybutyl nicotinate
##STR00203##
[0293] Nicotinic acid (615 mg, 5 mmol), DCC (1133 mg, 5.5 mmol) and
DMAP (50 mg) was added to a stirred solution of butane-1,4-diol
(900 mg, 10 mmol) in DCM (15 mL). The reaction was stirred at
25.degree. C. for 16 h. After that, the reaction mixture was
diluted with saturated aqueous NH.sub.4Cl (10 mL) and stirred for 5
min. The aqueous phase was separated and extracted with DCM (5 mL).
The combined organic phase was washed with saturated brine (10 mL),
dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The residue
was purified by a silica gel flash column with Hex/EA=1:1 to yield
the titled compound (450 mg, 46%) as a colorless oil. .sup.1H NMR
was performed at 400 MHz with CDCl.sub.3 as solvent to characterize
the titled compound, results are as follows: .delta.=9.22 (d, J=1.6
Hz, 1H), 8.78 (dd, J=1.6, 4.8 Hz, 1H), 8.30 (td, J=1.6, 8.0 Hz,
1H), 7.40 (dd, J=5.0, 7.8 Hz, 1H), 4.41 (t, J=6.6 Hz, 2H), 3.74 (t,
J=6.2 Hz, 2H), 1.93-1.86 (m, 2H), 1.77-1.70 (m, 2H), 1.46 (br. s.,
1H).
Compound 38: 4-(nicotinoyloxy)butanoic acid
##STR00204##
[0295] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl nicotinate (450 mg, 2.31 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (10 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=1:1 to yield
the titled compound (50 mg, 10%) as crystalline solids. .sup.1H NMR
was performed at 400 MHz with CDCl.sub.3 as solvent to characterize
the titled compound, results are as follows: .delta.=9.21 (d, J=1.6
Hz, 1H), 8.72 (dd, J=1.2, 4.8 Hz, 1H), 8.33 (td, J=1.6, 7.6 Hz,
1H), 7.40 (dd, J=5.0, 7.8 Hz, 1H), 4.45 (t, J=6.2 Hz, 2H), 2.56 (t,
J=7.0 Hz, 2H), 2.21-2.15 (m, 2H).
Example 1-39
Intermediate Compound 39': 4-hydroxybutyl isonicotinate
##STR00205##
[0297] Isonicotinic acid (1.23 g, 10 mmol), DCC (2.27 g, 11 mmol)
and DMAP (122 mg) was added to a stirred solution of
butane-1,4-diol (2.7 g, 30 mmol) in DCM (30 mL). The reaction was
stirred at 25.degree. C. for 8 h. After that, the reaction mixture
was diluted with saturated aqueous NH.sub.4Cl (10 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(15 mL). The combined organic phase was washed with brine (10 mL),
dried over Na.sub.2SO.sub.4 and evaporated. The residue was
purified by a silica gel flash column with Hex/EA=10:1-2:1 to yield
the titled compound (1 g, 51%) as a pale yellow oil. H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=8.76 (d, J=8.4 Hz,
2H), 7.84 (d, J=5.6 Hz, 2H), 4.39 (t, J=6.4 Hz, 2H), 3.72 (t, J=6.2
Hz, 2H), 1.92-1.85 (m, 2H), 1.75-1.70 (m, 2H).
Compound 39: 4-(isonicotinoyloxy)butanoic acid
##STR00206##
[0299] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl isonicotinate (900 mg, 4.62 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (30 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (50 mL) and then
filtered. The filtered cake was washed with EA (50 mL) and the
combined filtrate was washed with brine (5 mL.times.2), dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by a
silica gel flash column with Hex/EA=2:1 to yield the titled
compound (70 mg, 7%) as a white solid. .sup.1H NMR was performed at
400 MHz with CDCl.sub.3 as solvent to characterize the titled
compound, results are as follows: .delta.=8.55 (d, J=6.0 Hz, 2H),
7.86 (d, J=6.4 Hz, 2H), 4.49 (t, J=5.8 Hz, 2H), 2.53 (t, J=6.6 Hz,
2H), 2.23-2.17 (m, 2H).
Example 1-40
Intermediate Compound 40': 4-hydroxybutyl
3-methoxy-4-methylbenzoate
##STR00207##
[0301] 3-methoxy-4-methylbenzoic acid (500 mg, 3 mmol), DCC (683
mg, 3.32 mmol) and DMAP (50 mg) was added to a stirred solution of
butane-1,4-diol (542 mg, 6 mmol) in DCM (15 mL). The reaction was
stirred at 25.degree. C. for 3 h. After that, the reaction mixture
was diluted with saturated aqueous NH.sub.4Cl (10 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with saturated brine
(10 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with Hex/EA=5:1
to yield the titled compound (450 mg, 63%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.55 (d, J=7.6 Hz, 1H), 7.48 (s, 1H), 7.18 (d, J=8.0 Hz,
1H), 4.36 (t, J=6.4 Hz, 2H), 3.88 (s, 3H), 3.73 (t, J=6.2 Hz, 2H),
2.26 (s, 3H), 1.91-1.84 (m, 2H), 1.76-1.70 (m, 2H).
Compound 40: 4-(3-methoxy-4-methylbenzoyloxy)butanoic acid
##STR00208##
[0303] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 3-methoxy-4-methylbenzoate (450 mg, 1.89 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=4:1 to yield the titled compound (280 mg, 59%) as
crystalline solids. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.54 (d, J=7.6 Hz, 1H), 7.47 (s, 1H), 7.18
(d, J=7.6 Hz, 1H), 4.37 (t, J=6.2 Hz, 2H), 3.88 (s, 3H), 2.54 (t,
J=7.4 Hz, 2H), 2.26 (s, 3H), 2.15-2.09 (m, 2H).
Example 1-41
Intermediate Compound 41': 4-hydroxybutyl 2,6-dimethylbenzoate
##STR00209##
[0305] 2,6-dimethylbenzoic acid (500 mg, 3.33 mmol), DCC (755 mg,
3.67 mmol) and DMAP (50 mg) was added to a stirred solution of
butane-1,4-diol (600 mg, 6.67 mmol) in DCM (15 mL). The reaction
was stirred at 25.degree. C. for 3 h. After that, the reaction
mixture was diluted with saturated aqueous NH.sub.4Cl (10 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (5 mL). The combined organic phase was washed with
saturated brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (100 mg, 14%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.18 (t, J=7.6 Hz, 1H), 7.03 (d, J=8.0 Hz, 2H),
4.37 (t, J=6.6 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H), 2.32 (s, 6H),
1.89-1.82 (m, 2H), 1.74-1.67 (m, 2H).
Compound 41: 4-(2,6-dimethylbenzoyloxy)butanoic acid
##STR00210##
[0307] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2,6-dimethylbenzoate (100 mg, 0.45 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (50 mg, 47%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.19 (t, J=7.4 Hz, 1H), 7.03 (d, J=7.6 Hz, 2H),
4.39 (t, J=6.4 Hz, 2H), 2.52 (t, J=7.4 Hz, 2H), 2.32 (s, 6H),
2.13-2.07 (m, 2H).
Example 1-42
Intermediate Compound 42': 4-hydroxybutyl 2-phenoxybenzoate
##STR00211##
[0309] 2-phenoxybenzoic acid (1070 mg, 5 mmol), DCC (1133 mg, 5.5
mmol) and DMAP (50 mg) was added to a stirred solution of
butane-1,4-diol (900 mg, 10 mmol) in DCM (30 mL). The reaction was
stirred at 25.degree. C. for 16 h. After that, the reaction mixture
was diluted with saturated aqueous NH.sub.4Cl (10 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(10 mL). The combined organic phase was washed with saturated brine
(15 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with Hex/EA=8:1
to yield the titled compound (700 mg, 49%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.93 (dd, J=1.6, 8.0 Hz, 1H), 7.50-7.45 (m, 1H), 7.32 (t,
J=7.8 Hz, 2H), 7.21 (t, J=7.6 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 7.00
(d, J=8.0 Hz, 1H), 6.94 (d, J=7.6 Hz, 2H), 4.26 (t, J=6.2 Hz, 2H),
3.58 (s, 2H), 1.72-1.65 (m, 2H), 1.58-1.51 (m, 2H).
Compound 42: 4-(2-phenoxybenzoyloxy)butanoic acid
##STR00212##
[0311] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2-phenoxybenzoate (700 mg, 2.45 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (400 mg, 54%) as a
white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.92 (dd, J=1.6, 7.6 Hz, 1H), 7.50-7.46 (m, 1H),
7.31 (d, J=8.0 Hz, 2H), 7.20 (t, J=7.6 Hz, 1H), 7.07 (t, J=7.4 Hz,
1H), 7.00 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.0 Hz, 2H), 4.27 (t, J=6.2
Hz, 2H), 2.36 (t, J=7.2 Hz, 2H), 1.96-1.90 (m, 2H).
Example 1-43
Intermediate Compound 43': 4-hydroxybutyl 2,4-dimethylbenzoate
##STR00213##
[0313] 2,4-dimethylbenzoic acid (750 mg, 5 mmol), DCC (1133 mg, 5.5
mmol) and DMAP (50 mg) was added to a stirred solution of
butane-1,4-diol (900 mg, 10 mmol) in DCM (30 mL). The reaction was
stirred at 25.degree. C. for 16 h. After that, the reaction mixture
was diluted with saturated aqueous NH.sub.4Cl (10 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(10 mL). The combined organic phase was washed with saturated brine
(15 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with Hex/EA=8:1
to yield the titled compound (700 mg, 63%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.82 (d, J=7.6 Hz, 1H), 7.05-7.03 (m, 2H), 4.32 (t, J=6.6
Hz, 2H), 3.73 (s, 2H), 2.57 (s, 3H), 2.35 (s, 3H), 1.89-1.82 (m,
2H), 1.76-1.69 (m, 2H).
Compound 43: 4-(2,4-dimethylbenzoyloxy)butanoic acid
##STR00214##
[0315] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2,4-dimethylbenzoate (700 mg, 3.15 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (550 mg, 74%) as a
white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.82 (d, J=7.6 Hz, 1H), 7.05-7.03 (m, 2H), 4.34
(t, J=6.2 Hz, 2H), 2.57 (s, 3H), 2.54 (t, J=7.4 Hz, 2H), 2.35 (s,
3H), 2.14-2.08 (m, 2H).
Example 1-44
Intermediate Compound 44': 4-hydroxybutyl 2,3-dimethoxybenzoate
##STR00215##
[0317] 2,3-dimethoxybenzoic acid (910 mg, 5 mmol), DCC (1133 mg,
5.5 mmol) and DMAP (50 mg) was added to a stirred solution of
butane-1,4-diol (900 mg, 10 mmol) in DCM (30 mL). The reaction was
stirred at 25.degree. C. for 16 h. After that, the reaction mixture
was diluted with saturated aqueous NH.sub.4Cl (10 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(10 mL). The combined organic phase was washed with saturated brine
(15 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with Hex/EA=8:1
to yield the titled compound (600 mg, 47%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.32 (dd, J=1.6, 7.2 Hz, 1H), 7.11-7.04 (m, 2H), 4.36 (t,
J=6.4 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.74-3.70 (m, 2H),
1.90-1.84 (m, 2H), 1.77-1.70 (m, 2H), 1.40 (t, J=4.8 Hz, 1H).
Compound 44: 4-(2,3-dimethoxybenzoyloxy)butanoic acid
##STR00216##
[0319] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2,3-dimethoxybenzoate (600 mg, 2.36 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (250 mg, 39%) as a
white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.31 (dd, J=2.0, 7.2 Hz, 1H), 7.11-7.05 (m, 2H),
4.38 (t, J=6.2 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 2.57 (t, J=7.4
Hz, 2H), 2.15-2.08 (m, 2H).
Example 1-45
Intermediate Compound 45': 4-hydroxybutyl 4-isopropoxybenzoate
##STR00217##
[0321] 4-isopropoxybenzoic acid (900 mg, 5 mmol), DCC (1133 mg, 5.5
mmol) and DMAP (50 mg) was added to a stirred solution of
butane-1,4-diol (900 mg, 10 mmol) in DCM (30 mL). The reaction was
stirred at 25.degree. C. for 16 h. After that, the reaction mixture
was diluted with saturated aqueous NH.sub.4Cl (10 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(10 mL). The combined organic phase was washed with saturated brine
(15 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with Hex/EA=6:1
to yield the titled compound (800 mg, 63%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.97 (d, J=8.8 Hz, 2H), 6.88 (d, J=9.2 Hz, 2H), 4.66-4.60
(m, 1H), 4.33 (t, J=6.4 Hz, 2H), 3.73 (q, J=6.0 Hz, 2H), 1.89-1.82
(m, 2H), 1.76-1.69 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H).
Compound 45: 4-(4-isopropoxybenzoyloxy)butanoic acid
##STR00218##
[0323] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 4-isopropoxybenzoate (800 mg, 3.17 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (380 mg, 45%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.96 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H),
4.66-4.60 (m, 1H), 4.35 (t, J=6.2 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H),
2.15-2.08 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H).
Example 1-46
Intermediate Compound 46': 4-hydroxybutyl 2-ethylbenzoate
##STR00219##
[0325] 2,6-dimethylbenzoic acid (500 mg, 3.33 mmol), DCC (755 mg,
3.67 mmol) and DMAP (50 mg) was added to a stirred solution of
butane-1,4-diol (600 mg, 6.67 mmol) in DCM (30 mL). The reaction
was stirred at 25.degree. C. for 3 h. After that, the reaction
mixture was diluted with saturated aqueous NH.sub.4Cl (10 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (10 mL). The combined organic phase was washed with
saturated brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue was purified by a silica gel flash column
with Hex/EA=8:1 to yield the titled compound (480 mg, 65%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.84 (d, J=8.0 Hz, 1H), 7.43 (t, J=7.4 Hz, 1H),
7.28-7.22 (m, 2H), 4.34 (t, J=6.6 Hz, 2H), 3.73 (t, J=6.0 Hz, 2H),
2.98 (q, J=7.6 Hz, 2H), 1.91-1.84 (m, 2H), 1.77-1.70 (m, 2H), 1.24
(t, J=7.4 Hz, 3H).
Compound 46: 4-(2-ethylbenzoyloxy)butanoic acid
##STR00220##
[0327] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2-ethylbenzoate (480 mg, 2.16 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (10 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. for over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (5 mL) and the
combined filtrate was washed with saturated brine (2 mL.times.2),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified by a silica gel flash column with Hex/EA=6:1 to yield
the titled compound (290 mg, 57%) as a white solid. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.84 (d, J=8.0 Hz,
1H), 7.43 (d, J=7.2 Hz, 1H), 7.29-7.22 (m, 2H), 4.36 (t, J=6.2 Hz,
2H), 2.98 (q, J=7.6 Hz, 2H), 2.55 (t, J=7.2 Hz, 2H), 2.15-2.08 (m,
2H), 1.24 (t, J=7.6 Hz, 3H).
Example 1-47
Intermediate Compound 47': 4-hydroxybutyl 4-benzoylbenzoate
##STR00221##
[0329] 4-benzoylbenzoic acid (500 mg, 2.21 mmol), DCC (501 mg, 2.44
mmol) and DMAP (5 mg) was added to a stirred solution of
butane-1,4-diol (398 mg, 4.42 mmol) in DCM (30 mL). The reaction
was stirred at 25.degree. C. for 3 h. After that, the reaction
mixture was diluted with saturated aqueous NH.sub.4Cl (10 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (10 mL). The combined organic phase was washed with
saturated brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue was purified by a silica gel flash column
with Hex/EA=6:1 to yield the titled compound (400 mg, 61%) as a
white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=8.15 (d, J=8.4 Hz, 2H), 7.85-7.80 (m, 4H), 7.62
(t, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 2H), 4.41 (t, J=6.4 Hz, 2H),
3.75 (t, J=6.4 Hz, 2H), 1.94-1.87 (m, 2H), 1.79-1.72 (m, 2H).
Compound 47: 4-(4-benzoylbenzoyloxy)butanoic acid
##STR00222##
[0331] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 4-benzoylbenzoate (400 mg, 1.34 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (280 mg, 67%) as a
white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=8.14 (d, J=8.4 Hz, 2H), 7.85-7.80 (m, 4H), 7.62
(t, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 2H), 4.44 (t, J=6.2 Hz, 2H),
2.57 (t, J=7.2 Hz, 2H), 2.19-2.12 (m, 2H).
Example 1-48
Intermediate Compound 48': 4-hydroxybutyl methyl phthalate
##STR00223##
[0333] 2-(methoxycarbonyl)benzoic acid (900 mg, 5 mmol), DCC (1.13
g, 5.5 mmol) and DMAP (60 mg) was added to a stirred solution of
butane-1,4-diol (1.35 g, 15 mmol) in DCM (30 mL). The reaction was
stirred at 25.degree. C. for 3 h. After that, the reaction mixture
was diluted with saturated aqueous NH.sub.4Cl (10 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(15 mL). The combined organic phase was washed with brine (10 mL),
dried over Na.sub.2SO.sub.4 and evaporated. The residue was
purified by a silica gel flash column with Hex/EA=10:1-2:1 to yield
the titled compound (1 g, 79%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.72-7.68 (m, 2H),
7.55-7.51 (m, 2H), 4.34 (t, J=6.6 Hz, 2H), 3.89 (s, 3H), 3.68 (t,
J=6.4 Hz, 2H), 1.83-1.77 (m, 3H), 1.70-1.65 (m, 2H).
Compound 48: 4-(2-(methoxycarbonyl)benzoyloxy)butanoic acid
##STR00224##
[0335] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl methyl phthalate (900 mg, 3.57 mmol) and Celite.RTM.
(diatomaceous earth, 2 g) in acetone (20 mL) at 0.degree. C. The
reaction proceeded at 0.degree. C. over 1 h and the reaction
progress was monitored by TLC. After completion, the reaction was
quenched with drops of iPrOH, diluted with EA (10 mL) and then
filtered. The filtered cake was washed with EA (10 mL) and the
combined filtrate was washed with brine (3 mL.times.2), dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by a
silica gel flash column with Hex/EA=10:1-1:1 to yield the titled
compound (800 mg, 84%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.74-7.70 (m, 2H),
7.55-7.53 (m, 2H), 4.37 (t, J=6.2 Hz, 2H), 3.91 (s, 3H), 2.51 (t,
J=7.2 Hz, 2H), 2.10-2.03 (m, 2H).
Example 1-49
Intermediate Compound 49': 4-hydroxybutyl methyl terephthalate
##STR00225##
[0337] 4-(methoxycarbonyl)benzoic acid (1 g, 5.56 mmol), DCC (1258
mg, 6.11 mmol) and DMAP (10 mg) was added to a stirred solution of
butane-1,4-diol (1.5 g, 16.67 mmol) in DCM (20 mL). The reaction
was stirred at 25.degree. C. for 16 h. After that, the reaction
mixture was diluted with saturated aqueous NH.sub.4Cl (10 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (5 mL). The combined organic phase was washed with brine
(10 mL), dried over Na.sub.2SO.sub.4 and evaporated. The residue
was purified by a silica gel flash column with Hex/EA=7:1 to yield
the titled compound (750 mg, 54%) as crystalline solids. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=8.10 (s, 4H), 4.39 (t, J=6.6 Hz, 2H), 3.95 (s, 3H), 3.74
(t, J=6.4 Hz, 2H), 1.92-1.87 (m, 2H), 1.77-1.72 (m, 2H).
Compound 49: 4-(4-(methoxycarbonyl)benzoyloxy)butanoic acid
##STR00226##
[0339] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl methyl terephthalate (700 mg, 2.78 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. over 1 h and
the reaction progress was monitored by TLC. After completion, the
reaction was quenched with drops of iPrOH, diluted with EA (10 mL)
and then filtered. The filtered cake was washed with EA (5 mL) and
the combined filtrate was washed with brine (2 mL.times.2), dried
over Na.sub.2SO.sub.4 and concentrated. The residue was purified by
a silica gel flash column with Hex/EA=7:1 to yield the titled
compound (400 mg, 54%) as crystalline solids. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=8.09 (s, 4H), 4.41
(t, J=6.2 Hz, 2H), 3.95 (s, 3H), 2.55 (t, J=7.2 Hz, 2H), 2.18-2.11
(m, 2H).
Example 1-50
Intermediate Compound 50': 4-hydroxybutyl
(.sup.2H.sub.5)benzoate
##STR00227##
[0341] (.sup.2H.sub.5) benzoic acid (300 mg, 2.36 mmol), DCC (535
mg, 2.6 mmol) and DMAP (10 mg) was added to a stirred solution of
butane-1,4-diol (425 mg, 4.72 mmol) in DCM (20 mL). The reaction
was stirred at 25.degree. C. for 16 h. After that, the reaction
mixture was diluted with saturated aqueous NH.sub.4Cl (10 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (10 mL). The combined organic phase was washed with
saturated brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (320 mg, 68%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=4.37 (t, J=6.4 Hz, 2H), 3.74 (t, J=6.4 Hz, 2H),
1.91-1.84 (m, 2H), 1.78-1.71 (m, 2H).
Compound 50: 4-((.sup.2H.sub.5)phenylcarbonyloxy)butanoic acid
##STR00228##
[0343] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl (.sup.2H.sub.5)benzoate (300 mg, 1.51 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (220 mg, 69%) as
a white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=4.39 (t, J=6.2 Hz, 2H), 2.56 (t, J=7.4 Hz, 2H),
2.17-2.10 (m, 2H).
Example 1-51
Intermediate Compound 51': 4-hydroxybutyl
thiazole-2-carboxylate
##STR00229##
[0345] Thiazole-2-carboxylic acid (500 mg, 3.88 mmol), DCC (879 mg,
4.27 mmol) and DMAP (50 mg) was added to a stirred solution of
butane-1,4-diol (1.05 g, 11.66 mmol) in DCM (10 mL). The reaction
was stirred at 25.degree. C. for 8 h. After that, the reaction
mixture was diluted with saturated aqueous NH.sub.4Cl (10 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (5 mL). The combined organic phase was washed with brine
(10 mL), dried over Na.sub.2SO.sub.4 and evaporated. The residue
was purified by a silica gel flash column with Hex/EA=10:1-2:1 to
yield the titled compound (300 mg, 38%) as a pale yellow oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=8.03 (d, J=2.8 Hz, 1H), 7.64 (d, J=3.2 Hz, 1H), 4.47 (t,
J=6.6 Hz, 2H), 3.73 (t, J=6.2 Hz, 2H), 1.97-1.90 (m, 2H), 1.77-1.70
(m, 2H).
Compound 51: 4-(thiazole-2-carbonyloxy)butanoic acid
##STR00230##
[0347] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl thiazole-2-carboxylate (300 mg, 1.49 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. over 1 h and
the reaction progress was monitored by TLC. After completion, the
reaction was quenched with drops of iPrOH, diluted with EA (10 mL)
and then filtered. The filtered cake was washed with EA (5 mL) and
the combined filtrate was washed with brine (2 mL.times.2), dried
over Na.sub.2SO.sub.4 and concentrated. The residue was purified by
a silica gel flash column with Hex/EA=10:1-1:1 to yield the titled
compound (200 mg, 62%) as crystalline solids. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=8.06 (d, J=2.8 Hz,
1H), 7.67 (d, J=3.2 Hz, 1H), 4.49 (t, J=6.2 Hz, 2H), 2.58 (t, J=7.2
Hz, 2H), 2.19-2.12 (m, 2H).
Example 1-52
Intermediate Compound 52': 4-hydroxybutyl furan-3-carboxylate
##STR00231##
[0349] Furan-3-carboxylic acid (224 mg, 2 mmol), DCC (453 mg, 2.2
mmol) and DMAP (24 mg) was added to a stirred solution of
butane-1,4-diol (540 mg, 6 mmol) in DCM (10 mL). The reaction was
stirred at 25.degree. C. for 12 h. After that, the reaction mixture
was diluted with saturated aqueous NH.sub.4Cl (10 mL) and stirred
for 5 min. The aqueous phase was separated and extracted with DCM
(5 mL). The combined organic phase was washed with brine (10 mL),
dried over Na.sub.2SO.sub.4 and evaporated. The residue was
purified by a silica gel flash column with Hex/EA=10:1-5:1 to yield
the titled compound (270 mg, 73%) as a pale yellow oil. .sup.1H NMR
was performed at 400 MHz with CDCl.sub.3 as solvent to characterize
the titled compound, results are as follows: .delta.=8.00 (s, 1H),
7.42 (s, 1H), 6.73 (s, 1H), 4.28 (t, J=6.4 Hz, 2H), 3.70 (t, J=6.4
Hz, 2H), 1.83-1.67 (m, 4H).
Compound 52: 4-(furan-3-carbonyloxy)butanoic acid
##STR00232##
[0351] Jones reagent in portions was added to a stirred mixture of
4-hydroxybutyl furan-3-carboxylate (750 mg, 4.09 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. over 1 h and
the reaction progress was monitored by TLC. After completion, the
reaction was quenched with drops of iPrOH, diluted with EA (10 mL)
and then filtered. The filtered cake was washed with EA (5 mL) and
the combined filtrate was washed with brine (2 mL.times.2), dried
over Na.sub.2SO.sub.4 and concentrated. The residue was purified by
a silica gel flash column with Hex/EA=3:1 to yield the titled
compound (600 mg, 74%) as crystalline solids. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=8.01 (s, 1H), 7.42
(s, 1H), 6.73 (s, 1H), 4.31 (t, J=6.2 Hz, 2H), 2.51 (t, J=7.4 Hz,
2H), 2.12-2.05 (m, 2H).
Example 1-53
Intermediate Compound 53': 4-hydroxybutyl
thiophene-3-carboxylate
##STR00233##
[0353] Thiophene-3-carboxylic acid (1 g, 7.81 mmol), DCC (1.77 g,
8.59 mmol) and DMAP (10 mg) was added to a stirred solution of
butane-1,4-diol (2.1 g, 23.33 mmol) in DCM (50 mL). The reaction
was stirred at 25.degree. C. for 16 h. After that, the reaction
mixture was diluted with saturated aqueous NH.sub.4Cl (10 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (5 mL). The combined organic phase was washed with brine
(10 mL), dried over Na.sub.2SO.sub.4 and evaporated. The residue
was purified by a silica gel flash column with Hex/EA=7:1 to afford
the crude product, which was further purified by prep-TLC with
Hex/EA=1:1 to yield the pure titled compound (600 mg, 38%) as
crystalline solids. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=8.10 (d, J=2.0 Hz, 1H), 7.53 (d, J=5.2 Hz,
1H), 7.31 (dd, J=3.2, 5.2 Hz, 1H), 4.32 (t, J=6.4 Hz, 2H), 3.73 (t,
J=6.4 Hz, 2H), 1.90-1.80 (m, 2H), 1.76-1.68 (m, 2H).
Compound 53: 4-(thiophene-3-carbonyloxy)butanoic acid
##STR00234##
[0355] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl thiophene-3-carboxylate (400 mg, 2 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. over 1 h and
the reaction progress was monitored by TLC. After completion, the
reaction was quenched with drops of iPrOH, diluted with EA (10 mL)
and then filtered. The filtered cake was washed with EA (5 mL) and
the combined filtrate was washed with brine (2 mL.times.2), dried
over Na.sub.2SO.sub.4 and concentrated. The residue was purified by
prep-HPLC to yield the titled compound (100 mg, 23%) as crystalline
solids. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as
solvent to characterize the titled compound, results are as
follows: .delta.=8.10 (d, J=2.0 Hz, 1H), 7.52 (d, J=5.2 Hz, 1H),
7.31 (dd, J=3.0, 5.0 Hz, 1H), 4.34 (t, J=6.2 Hz, 2H), 2.53 (t,
J=7.2 Hz, 2H), 2.13-2.07 (m, 2H).
Example 1-54
Intermediate Compound 54': (S)-1-tert-butyl 2-(4-hydroxybutyl)
pyrrolidine-1,2-dicarboxylate
##STR00235##
[0357] (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2
g, 9.3 mmol), DCC (2108 mg, 10.23 mmol) and DMAP (50 mg) was added
to a stirred solution of butane-1,4-diol (1674 mg, 18.6 mmol) in
DCM (30 mL). The reaction was stirred at 25.degree. C. for 3 h.
After that, the reaction mixture was diluted with saturated aqueous
NH.sub.4Cl (10 mL) and stirred for 5 min. The aqueous phase was
separated and extracted with DCM (10 mL). The combined organic
phase was washed with saturated brine (15 mL), dried over anhydrous
Na.sub.2SO.sub.4 and evaporated. The residue was purified by a
silica gel flash column with Hex/EA=5:1 to yield the titled
compound (1.4 g, 52%) as a colorless oil. .sup.1H NMR was performed
at 400 MHz with CDCl.sub.3 as solvent to characterize the titled
compound, results are as follows: .delta.=4.32-4.12 (m, 3H),
3.71-3.62 (m, 2H), 3.58-3.35 (m, 2H), 2.27-2.16 (m, 1H), 2.02-1.60
(m, 8H), 1.46 (s, 4H), 1.41 (s, 5H).
Compound 54
(S)-4-(1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyloxy)butanoic
acid
##STR00236##
[0359] Jones reagent was added in portions to a stirred mixture of
(S)-1-tert-butyl 2-(4-hydroxybutyl) pyrrolidine-1,2-dicarboxylate
(400 mg, 1.39 mmol) and Celite.RTM. (diatomaceous earth, 2 g) in
acetone (10 mL) at 0.degree. C. The reaction proceeded at 0.degree.
C. for over 1 h and the reaction progress was monitored by TLC.
After completion, the reaction was quenched with drops of iPrOH,
diluted with EA (10 mL) and then filtered. The filtered cake was
washed with EA (5 mL) and the combined filtrate was washed with
saturated brine (2 mL.times.2), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The residue was purified by a
silica gel flash column with DCM/MeOH=120:1 to yield the titled
compound (200 mg, 48%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=4.40-4.32 (m, 1H),
4.26-4.07 (m, 2H), 3.58-3.35 (m, 2H), 2.45 (t, J=7.0 Hz, 2H),
2.33-2.12 (m, 2H), 2.01-1.83 (m, 4H), 1.46 (s, 5H), 1.41 (s,
4H).
Example 1-55
Intermediate Compound 55': 4-hydroxybutyl
2-(tert-butoxycarbonylamino)acetate
##STR00237##
[0361] 2-(tert-butoxycarbonylamino)acetic acid (340 mg, 1.94 mmol),
DCC (440 mg, 2.14 mmol) and DMAP (5 mg) was added to a stirred
solution of butane-1,4-diol (350 mg, 3.89 mmol) in DCM (30 mL). The
reaction was stirred at 25.degree. C. for 16 h. After that, the
reaction mixture was diluted with saturated aqueous NH.sub.4Cl (10
mL) and stirred for 5 min. The aqueous phase was separated and
extracted with DCM (10 mL). The combined organic phase was washed
with saturated brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4
and evaporated. The residue was purified by a silica gel flash
column with Hex/EA=5:1 to yield the titled compound (200 mg, 42%)
as a white solid. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=5.00 (br. s., 1H), 4.20 (t, J=6.6 Hz, 2H),
3.90 (d, J=5.2 Hz, 2H), 3.68 (q, J=6.0 Hz, 2H), 1.79-1.72 (m, 2H),
1.67-1.62 (m, 2H), 1.45 (s, 9H), 1.37-1.34 (m, 1H).
Compound 55: 4-(2-(tert-butoxycarbonylamino)acetoxy)butanoic
acid
##STR00238##
[0363] Jones reagent was added in portions to a stirred mixture of
4-hydroxybutyl 2-(tert-butoxycarbonylamino)acetate (200 mg, 0.81
mmol) and Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL)
at 0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a flash column (silica
gel, DCM/MeOH=100:1 to yield the titled compound (150 mg, 71%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=5.03 (br. s., 1H), 4.23 (t, J=6.2 Hz, 2H), 3.90
(d, J=5.2 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H), 2.05-1.98 (m, 2H), 1.45
(s, 9H).
Example 1-56
Compound 56: 4-(2-aminoacetoxy)butanoic acid
##STR00239##
[0365] A solution of
4-(2-(tert-butoxycarbonylamino)acetoxy)butanoic acid (150 mg, 0.57
mmol) in HC/EA (.about.2 M, 1.5 mL) was stirred at 25.degree. C.
for 24 h. After that, the reaction mixture was filtered and the
resulting precipitate was collected, washed with Et.sub.2O (0.5
mL), dried in vacuo to yield the titled compound (82 mg, 89%) as a
white solid in HCl salt form. .sup.1H NMR was performed at 400 MHz
with CD.sub.3OD as solvent to characterize the titled compound,
results are as follows: .delta.=4.30 (t, J=6.4 Hz, 2H), 3.84 (s,
2H), 2.42 (t, J=7.2 Hz, 2H), 2.03-1.94 (m, 2H).
Example 1-57
Intermediate Compound 57': (S)-4-hydroxybutyl
2-(tert-butoxycarbonylamino)-3-phenylpropanoate
##STR00240##
[0367] (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (1
g, 3.37 mmol), DCC (855 mg, 4.15 mmol) and DMAP (10 mg) was added
to a stirred solution of butane-1,4-diol (679 mg, 7.54 mmol) in DCM
(20 mL). The reaction was stirred at 25.degree. C. for 16 h. After
that, the reaction mixture was diluted with saturated aqueous
NH.sub.4Cl (10 mL) and stirred for 5 min. The aqueous phase was
separated and extracted with DCM (10 mL). The combined organic
phase was washed with saturated brine (15 mL), dried over anhydrous
Na.sub.2SO.sub.4 and evaporated. The residue was purified by a
silica gel flash column with Hex/EA=5:1 to yield the titled
compound (700 mg, 55%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.32-7.27 (m, 2H),
7.26-7.21 (m, 1H), 7.14 (d, J=6.8 Hz, 2H), 4.97 (d, J=8.0 Hz, 1H),
4.58-4.53 (m, 1H), 4.19-4.08 (m, 2H), 3.64 (q, J=5.6 Hz, 2H), 3.07
(t, J=4.8 Hz, 2H), 1.72-1.65 (m, 2H), 1.56-1.51 (m, 2H), 1.42 (s,
9H).
Intermediate Compound 57'':
(S)-4-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)butanoic
acid
##STR00241##
[0369] Jones reagent was added in portions to a stirred mixture of
(S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-phenylpropanoate
(600 mg, 1.78 mmol) and Celite.COPYRGT.(diatomaceous earth, 2 g) in
acetone (10 mL) at 0.degree. C. The reaction proceeded at 0.degree.
C. for over 1 h and the reaction progress was monitored by TLC.
After completion, the reaction was quenched with drops of iPrOH,
diluted with EA (10 mL) and then filtered. The filtered cake was
washed with EA (5 mL) and the combined filtrate was washed with
saturated brine (2 mL.times.2), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The residue was purified by a
silica gel flash column with Hex/EA=10:1-5:1 to yield the titled
compound (220 mg, 35%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.34-7.27 (m, 2H),
7.26-7.20 (m, 1H), 7.14 (d, J=6.8 Hz, 2H), 4.99 (d, J=8.0 Hz, 1H),
4.61-4.51 (m, 1H), 4.22-4.09 (m, 2H), 3.06 (d, J=6.0 Hz, 2H), 2.34
(t, J=7.2 Hz, 2H), 1.97-1.89 (m, 2H), 1.42 (s, 9H).
Compound 57: (S)-4-(2-amino-3-phenylpropanoyloxy)butanoic acid
##STR00242##
[0371] A solution of
(S)-4-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy) butanoic
acid (180 mg, 0.51 mmol) in HCl/EA (2 M, 2 mL) stirred at
25.degree. C. for 24 h. After that, the reaction mixture was
filtered and the resulting precipitate was collected, washed with
Et.sub.2O (0.5 mL), dried in vacuo to yield the titled compound
(100 mg, 78%) as a white solid in HCl salt form. .sup.1H NMR was
performed at 400 MHz with CD.sub.3OD as solvent to characterize the
titled compound, results are as follows: .delta.=7.41-7.31 (m, 3H),
7.27-7.25 (m, 2H), 4.30 (t, J=7.0 Hz, 1H), 4.26-4.19 (m, 2H),
3.25-3.15 (m, 2H), 2.28 (t, J=7.2 Hz, 2H), 1.92-1.86 (m, 2H).
Example 1-58
Intermediate Compound 58': (S)-4-hydroxybutyl
2-(tert-butoxycarbonylamino)-3-methylbutanoate
##STR00243##
[0373] (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (1 g,
4.61 mmol), DCC (1044 mg, 5.07 mmol) and DMAP (10 mg) was added to
a stirred solution of butane-1,4-diol (829 mg, 9.21 mmol) in DCM
(20 mL). The reaction was stirred at 25.degree. C. for 16 h. After
that, the reaction mixture was diluted with saturated aqueous
NH.sub.4Cl (10 mL) and stirred for 5 min. The aqueous phase was
separated and extracted with DCM (10 mL). The combined organic
phase was washed with saturated brine (15 mL), dried over anhydrous
Na.sub.2SO.sub.4 and evaporated. The residue was purified by a
silica gel flash column with Hex/EA=5:1 to yield the titled
compound (700 mg, 53%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=5.07 (d, J=8.8 Hz,
1H), 4.16-4.11 (m, 3H), 3.62 (t, J=6.2 Hz, 2H), 2.32 (br. s., 1H),
2.12-2.04 (m, 1H), 1.75-1.68 (m, 2H), 1.62-1.56 (m, 2H), 1.40 (s,
9H), 0.92 (d, J=7.2 Hz, 3H), 0.85 (d, J=7.2 Hz, 3H).
Intermediate Compound 58'':
(S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic
acid
##STR00244##
[0375] Jones reagent was added in portions to a stirred mixture of
(S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate
(500 mg, 1.73 mmol) and Celite.RTM. (diatomaceous earth, 2 g) in
acetone (10 mL) at 0.degree. C. The reaction proceeded at 0.degree.
C. for over 1 h and the reaction progress was monitored by TLC.
After completion, the reaction was quenched with drops of iPrOH,
diluted with EA (10 mL) and then filtered. The filtered cake was
washed with EA (5 mL) and the combined filtrate was washed with
saturated brine (2 mL.times.2), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The residue was purified by a
silica gel flash column with Hex/EA=10:1-5:1 to yield the titled
compound (170 mg, 32%) as a white solid. .sup.1H NMR was performed
at 400 MHz with CDCl.sub.3 as solvent to characterize the titled
compound, results are as follows: .delta.=5.03 (d, J=9.2 Hz, 1H),
4.30-4.24 (m, 1H), 4.22-4.13 (m, 2H), 2.46 (t, J=7.4 Hz, 2H),
2.16-2.08 (m, 1H), 2.06-1.96 (m, 2H), 1.45 (s, 9H), 0.96 (d, J=6.8
Hz, 3H), 0.89 (d, J=6.4 Hz, 3H).
Compound 58: (S)-4-(2-amino-3-methylbutanoyloxy)butanoic acid
##STR00245##
[0377] A solution of
(S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic
acid (104 mg, 0.34 mmol) in HC/EA (2 M, 1.5 mL) stirred at
25.degree. C. for 24 h. After that, the reaction mixture was
filtered and the resulting precipitate was collected, washed with
Et.sub.2O (0.5 mL), dried in vacuo to yield the titled compound (50
mg, 71%) as a white solid in HCl salt form. .sup.1H NMR was
performed at 400 MHz with CD.sub.3OD as solvent to characterize the
titled compound, results are as follows: .delta.=4.33-4.26 (m, 2H),
3.92 (d, J=4.8 Hz, 1H), 2.42 (t, J=7.2 Hz, 2H), 2.34-2.25 (m, 1H),
2.05-1.94 (m, 2H), 1.06 (d, J=6.8 Hz, 6H).
[0378] A suspension of the above white solid (800 mg, 3.3 mmol) in
ethanol (4 mL) was stirred at 80.degree. C. for around 30 min and a
clear solution was formed. Then the solution was gradually cooled
to 25.degree. C., propylene oxide (580 mg, 10 mmol) was added
dropwise. The reaction was stirred at 25.degree. C. for 16 h and
then the resultant suspension was filtered. The white solid was
collected, washed with cold ethanol, dried in vacuo to afford the
titled compound (510 mg, 75%) in free salt form. .sup.1H NMR was
performed at 400 MHz with d.sub.6-DMSO as solvent to characterize
the titled compound, results are as follows: .delta.=4.10-3.99 (m,
2H), 3.11 (d, J=5.2 Hz, 1H), 2.29 (t, J=7.4 Hz, 2H), 1.90-1.74 (m,
3H), 0.87 (d, J=6.8 Hz, 3H), 0.82 (d, J=6.4 Hz, 3H).
Example 1-59
Intermediate Compound 59': 4-hydroxybutyl 2-(p-tolyl)acetate
##STR00246##
[0380] 2-(p-tolyl)acetic acid (1 g, 6.67 mmol), DCC (1.5 g, 7.33
mmol) and DMAP (10 mg) was added to a stirred solution of
butane-1,4-diol (3 g, 33.33 mmol) in DCM (50 mL). The reaction was
stirred at 25.degree. C. for 16 h. After that, the reaction mixture
was filtered and the filtrate was washed with saturated aqueous
NH.sub.4Cl (20 mL). The resultant organic phase was washed with
brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by a silica gel flash column with Hex/EA=3:1
to afford the titled compound (1.1 g, 74%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.18-7.12 (m, 4H), 4.12 (t, J=6.6 Hz, 2H), 3.64 (t, J=6.4
Hz, 2H), 3.58 (s, 2H), 2.33 (s, 3H), 1.75-1.68 (m, 2H), 1.62-1.55
(m, 2H).
Compound 59: 4-(2-(p-tolyl)acetoxy)butanoic acid
##STR00247##
[0382] Jones reagent was added dropwise to a stirred mixture of
4-hydroxybutyl 2-(p-tolyl)acetate (800 mg, 3.60 mmol) and
Celite.RTM. (diatomaceous earth, 1.6 g) in acetone (15 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. over 1 h and
the reaction progress was monitored by TLC. After completion, the
reaction was quenched with drops of isopropanol, diluted with EA
(30 mL), and then filtered. The filtered cake was washed with EA
(10 mL) and the combined filtrate was washed with brine (10
mL.times.2), dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by a silica gel flash column with Hex/EA=2:1
to afford the titled compound (500 mg, 59%) as crystalline solids.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
6=7.17-7.12 (m, 4H), 4.14 (t, J=6.2 Hz, 2H), 3.57 (s, 2H), 2.41 (t,
J=7.2 Hz, 2H), 2.33 (s, 3H), 1.99-1.93 (m, 2H).
Example 1-60
Intermediate Compound 60': (R)-4-hydroxybutyl
2-(tert-butoxycarbonylamino)-3-methylbutanoate
##STR00248##
[0384] DCC (3.1 g, 15.21 mmol) and DMAP (17 mg, 0.14 mmol) was
added to a stirred suspension of
(R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (3.0 g,
13.82 mmol) and butane-1,4-diol (3.7 g, 41.47 mmol) in DCM (40 mL)
at 0.degree. C. The reaction was allowed to warm up gradually and
stirred at 25.degree. C. for 16 h. After that, the reaction mixture
was filtered and the filtered cake was washed with DCM (10 mL). The
combined filtrate was washed with saturated aqueous NH.sub.4Cl (10
mL.times.2), dried over Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with DCM/EA=20:1
to afford the titled compound (2.5 g, 63%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=5.02 (d, J=8.4 Hz, 1H), 4.20-4.16 (m, 2H), 3.68 (q, J=6.0
Hz, 2H), 2.16-2.08 (m, 1H), 1.79-1.70 (m, 2H), 1.69-1.64 (m, 2H),
1.44 (s, 9H), 0.96 (d, J=6.8 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H).
Intermediate Compound 60'':
(R)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic
acid
##STR00249##
[0386] Jones reagent was dropwise added to a stirred mixture of
(R)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate
(2.5 g, 8.65 mmol) and Celite.RTM. (diatomaceous earth, 5.0 g) in
acetone (25 mL) at 0.degree. C. The reaction proceeded at 0.degree.
C. over 1 h and the reaction progress was monitored by TLC. After
completion, the reaction was quenched with drops of isopropanol,
diluted with EA (25 mL), and then filtered. The filtered cake was
washed with EA (25 mL) and the combined filtrate was washed with
brine (20 mL.times.2), dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with DCM/EA=20:1-3:1 to afford the titled compound (1.1 g, 42%) as
a white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=5.03 (d, J=8.8 Hz, 1H), 4.26-4.18 (m, 2H), 2.45
(t, J=7.4 Hz, 2H), 2.14-2.10 (m, 1H), 2.03-2.00 (m, 2H), 1.45 (s,
9H), 0.96 (d, J=6.8 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H).
Compound 60: (R)-4-(2-amino-3-methylbutanoyloxy)butanoic acid
##STR00250##
[0387]
(R)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic
acid
[0388] (400.0 mg, 1.32 mmol) was added to a stirred solution of
HCl/EA (2 M, 2 mL) at 0.degree. C. The reaction was allowed to warm
up gradually and stirred at 25.degree. C. for 16 h. After that, the
resulting suspension was filtered. The white precipitate was
collected, washed with EA (2 mL) and dried in vacuo to afford the
titled compound (184.0 mg, 58%) as a white solid in HCl salt form.
.sup.1H NMR was performed at 400 MHz with D.sub.2O as solvent to
characterize the titled compound, results are as follows:
.delta.=4.32 (t, J=5.6 Hz, 2H), 4.03 (d, J=4.4 Hz, 1H), 2.51 (t,
J=7.2 Hz, 2H), 2.39-2.35 (m, 1H), 2.03 (t, J=6.6 Hz, 2H), 1.04 (t,
J=7.2 Hz, 6H).
Example 1-61
Intermediate Compound 61': (S)-4-hydroxybutyl
2-(tert-butoxycarbonylamino)propanoate
##STR00251##
[0390] A solution of (Boc).sub.2O (13.5 g, 61.80 mmol) in
1,4-dioxane (56 mL) was added to a stirred solution
(S)-2-aminopropanoic acid (5.0 g, 56.18 mmol) in water (56 mL) and
aqueous NaOH (56.2 mL, 1 M) at 0.degree. C. The reaction was
allowed to warm up gradually and stirred at 25.degree. C. for 16 h.
After that, the reaction mixture was cooled to 0.degree. C., then
acidified with HCl (2 M) until pH=2-3. The mixture was diluted with
EA (56 mL), the aqueous phase was separated and extracted with EA
(56 mL.times.3). The combined organic phase was washed with brine
(56 mL), dried over Na.sub.2SO.sub.4 and evaporated to afford the
crude (S)-2-(tert-butoxycarbonylamino)propanoic acid (9.0 g) as a
white solid, which was used directly for the next step without
further purification.
[0391] DCC (4.4 g, 21.16 mmol) and DMAP (25 mg) was added to a
stirred suspension of the above crude
(S)-2-(tert-butoxycarbonylamino)propanoic acid (4.0 g) and
butane-1,4-diol (5.7 g, 63.49 mmol) in DCM (50 mL) at 0.degree. C.
The reaction was allowed to warm up gradually and stirred at
25.degree. C. for 16 h. After that, the reaction mixture was
filtered, the filtered cake was washed with DCM (10 mL). The
combined filtrate was washed with saturated aqueous NH.sub.4Cl (15
mL.times.2), dried over Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with
PE/EA=4:1-1:1 to afford the titled compound (3.0 g, 55%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=5.02 (br. s., 1H), 4.29 (t, J=6.8 Hz, 1H), 4.18
(t, J=6.4 Hz, 2H), 3.68 (q, J=6.0 Hz, 2H), 1.79-1.72 (m, 2H),
1.68-1.60 (m, 2H), 1.44 (s, 9H), 1.38 (d, J=7.2 Hz, 3H).
Intermediate Compound 61'':
(S)-4-(2-(tert-butoxycarbonylamino)propanoyloxy)butanoic acid
##STR00252##
[0393] Jones reagent was dropwise added to a stirred mixture of
(S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)propanoate (3.0 g,
11.49 mmol) and Celite.RTM. (diatomaceous earth, 6.0 g) in acetone
(30 mL) at 0.degree. C. The reaction proceeded at 0.degree. C. over
1 h and the reaction progress was monitored by TLC. After
completion, the reaction was quenched with drops of isopropanol,
diluted with EA (100 mL), and then filtered. The filtered cake was
washed with EA (20 mL) and the combined filtrate was washed with
brine (30 mL.times.2), dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with DCM/EA=20:1 to afford the titled compound (1.8 g, 57%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=5.06 (br. s., 1H), 4.31-4.16 (m, 3H), 2.45 (t,
J=7.2 Hz, 2H), 2.02-1.97 (m, 2H), 1.44 (s, 9H), 1.38 (d, J=7.2 Hz,
3H).
Compound 61: (S)-4-(2-aminopropanoyloxy)butanoic acid
##STR00253##
[0395] (S)-4-(2-(tert-butoxycarbonylamino)propanoyloxy)butanoic
acid (200.0 mg, 0.73 mmol) was added to a stirred solution of HC/EA
(1.0 mL, .about.2 M) at 0.degree. C. The reaction was allowed to
warm up gradually and stirred at 25.degree. C. for 16 h. After
that, the reaction mixture was evaporated, the residue was purified
by prep-HPLC to afford the titled compound (80.0 mg, 52%) as a
colorless oil in HCl salt form. .sup.1H NMR was performed at 400
MHz with CD.sub.3OD as solvent to characterize the titled compound,
results are as follows: .delta.=4.31-4.27 (m, 2H), 4.11 (q, J=7.2
Hz, 1H), 2.48-2.41 (m, 2H), 2.04-1.97 (m, 2H), 1.55 (dd, J=1.6, 7.2
Hz, 3H).
Example 1-62
Intermediate Compound 62': (S)-4-hydroxybutyl
2-acetamidopropanoate
##STR00254##
[0397] Ac.sub.2O (6.8 g, 66.67 mmol) was added to a stirred
suspension of (S)-2-aminopropanoic acid (5.0 g, 56.18 mmol) in HOAc
(25 mL). The reaction was stirred at 25.degree. C. for 16 h. After
that, the reaction mixture was evaporated to yield the crude
(S)-2-acetamidopropanoic acid as a white solid (8.0 g), which was
used directly for next step without further purification.
[0398] DCC (3.1 g, 15.28 mmol) and DMAP (20 mg) was added to a
stirred suspension of the above (S)-2-acetamidopropanoic acid (2.0
g, 15.28 mmol) and butane-1,4-diol (4.1 g, 45.80 mmol) in DCM (50
mL). The reaction was stirred at 25.degree. C. for 16 h. After
that, the reaction mixture was filtered and the filtrate was
concentrated. The residue was purified by prep-HPLC to afford the
titled compound (2.0 g, 67%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=6.12 (br. s., 1H),
4.59-4.52 (m, 1H), 4.24-4.13 (m, 2H), 3.67 (t, J=6.4 Hz, 2H), 2.01
(s, 3H), 1.77-1.72 (m, 2H), 1.66-1.59 (m, 2H), 1.40 (d, J=7.6 Hz,
3H).
Compound 62: (S)-4-(2-acetamidopropanoyloxy)butanoic acid
##STR00255##
[0400] Jones reagent was dropwise added to a stirred mixture of
(S)-4-hydroxybutyl 2-acetamidopropanoate (660 mg, 3.25 mmol) and
Celite.RTM. (diatomaceous earth, 1.2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. over 1 h and
the reaction progress was monitored by TLC. After completion, the
reaction was quenched with drops of isopropanol, diluted with EA
(10 mL), and then filtered. The filtered cake was washed with EA
(10 mL) and the combined filtrate was washed with brine (10
mL.times.2), dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by prep-HPLC to afford the titled compound
(300 mg, 42%) as a colorless oil. .sup.1H NMR was performed at 400
MHz with CDCl.sub.3 as solvent to characterize the titled compound,
results are as follows: .delta.=6.25 (d, J=6.4 Hz, 1H), 4.61-4.54
(m, 1H), 4.28-4.15 (m, 2H), 2.44 (t, J=7.0 Hz, 2H), 2.03 (s, 3H),
2.07-1.97 (m, 2H), 1.40 (d, J=7.2 Hz, 3H).
##STR00256##
Example 1-63
Intermediate Compound 63': benzyl
4-(2-(tert-butoxycarbonyl)aminoacetoxy)butanoate
##STR00257##
[0402] A mixture of N-Boc glycine (2.0 g, 11.4 mmol), benzyl
4-hydroxybutanoate (2.7 g, 13.7 mmol), DCC (3.1 g, 14.8 mmol) and
DMAP (5 mg) in DCM (20 mL) was stirred at 25.degree. C. for 16 h.
The reaction mixture was filtered and the filtrate was washed with
aqueous saturated NH.sub.4Cl (2.times.20 mL). The organic layer was
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified by a silica gel flash column with PE/EA=10:1-1:1 to
afford the titled compound (2.0 g, 50%) as a colorless oil. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.45-7.27 (m, 5H), 5.13 (s, 2H), 4.99 (br. s., 1H), 4.20
(t, J=6.2 Hz, 2H), 3.88 (d, J=4.4 Hz, 2H), 2.46 (t, J=7.4 Hz, 2H),
2.04-1.97 (m, 2H), 1.45 (s, 9H).
Intermediate Compound 63'': benzyl 4-(2-aminoacetoxy)butanoate
##STR00258##
[0404] TFA (3.0 mL) was added to a solution of benzyl
4-(2-(tert-butoxycarbonyl)aminoacetoxy)butanoate (1.60 g, 4.56
mmol) in DCM (15 mL) at 0.degree. C., and the reaction was stirred
at the same temperature for 2 h. After that, solvent was evaporated
to afford the titled compound (1.2 g), which was used directly for
the next step without further purification.
Intermediate Compound 63''': benzyl
4-(2-propionamidoacetoxy)butanoate
##STR00259##
[0406] Propionyl chloride (162 mg, 1.75 mmol) was dropwise added to
a solution of benzyl 4-(2-aminoacetoxy)butanoate (400 mg, 1.59
mmol) and Et.sub.3N (0.66 mL, 4.78 mmol) in DCM (10 mL) at
0.degree. C. The reaction was allowed to warm up and stirred at
25.degree. C. for 16 h. After that, the reaction was quenched by
water (10 mL) with stirring for 5 min. The aqueous phase was
extracted with DCM (10 mL.times.3), the combined organic phase was
washed with brine (20 mL), dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by silica gel flash column
with PE/EA=1:1 to afford the titled compound (440 mg, 90%) as
colorless oil.
Compound 63: 4-(2-propionamidoacetoxy)butanoic acid
##STR00260##
[0408] Pd/C (50 mg) was added to a solution of benzyl
4-(2-propionamidoacetoxy)butanoate (400 mg, 1.3 mmol) in MeOH (10
mL), and the mixture was stirred at 25.degree. C. for 16 h under
H.sub.2 atmosphere. After that, the reaction mixture was filtered
and the filtrate was concentrated. The residue was purified by a
silica gel flash column with PE/EA=1:50 to afford the titled
compound (170 mg, 60%) as a white solid. .sup.1H NMR was performed
at 400 MHz with CD.sub.3OD as solvent to characterize the titled
compound, results are as follows: .delta.=4.18 (t, J=6.2 Hz, 2H),
3.92 (s, 2H), 2.39 (t, J=7.4 Hz, 2H), 2.27 (q, J=7.6 Hz, 2H),
1.98-1.91 (m, 2H), 1.14 (t, J=7.6 Hz, 3H).
Example 1-64
Intermediate Compound 64': benzyl
4-(2-isobutyramidoacetoxy)butanoate
##STR00261##
[0410] Isobutyryl chloride (0.8 g, 7.5 mmol) was added dropwise to
a solution of benzyl 4-(2-aminoacetoxy)butanoate (1.57 g, 6.26
mmol) and Et.sub.3N (1.58 mL, 15.7 mmol) in DCM (20 mL) at
0.degree. C. The reaction was stirred at 25.degree. C. for 16 h and
then washed with brine (2.times.10 mL). The organic layer was dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by prep-HPLC to afford the titled compound (0.8 g, 40%) as
a colorless oil. .sup.1H NMR was performed at 600 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.45-7.27 (m, 5H), 5.93 (br. s., 1H), 5.12
(s, 2H), 4.20 (t, J=6.3 Hz, 2H), 4.00 (d, J=4.8 Hz, 2H), 2.50-2.37
(m, 3H), 2.04-1.99 (m, 2H), 1.18 (d, J=7.2 Hz, 6H).
Compound 64: 4-(2-isobutyramidoacetoxy)butanoic acid
##STR00262##
[0412] Pd/C (75 mg) was added to a solution of benzyl
4-(2-isobutyramidoacetoxy)butanoate (0.75 g, 2.3 mmol) in EA (10
mL). The reaction was stirred under H.sub.2 atmosphere for 16 h at
25.degree. C. The reaction was filtered and the filtrate was
concentrated. The residue was purified by a silica gel flash column
with PE/EA=5:1-3:1 to afford the titled compound (270 mg, 50%) as a
white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=6.04 (br. s., 1H), 4.24 (t, J=6.2 Hz, 2H), 4.03
(d, J=5.2 Hz, 2H), 2.57-2.36 (m, 3H), 2.06-1.99 (m, 2H), 1.18 (d,
J=7.2 Hz, 6H).
Example 1-65
Intermediate Compound 65'; benzyl
4-(2-(tert-butoxycarbonyl)methylaminoacetoxy)butanoate
##STR00263##
[0414] A mixture of 2-((tert-butoxycarbonyl)methylamino)acetic acid
(5.0 g, 26.45 mmol), benzyl 4-hydroxybutanoate (4.6 g, 23.71 mmol),
DCC (6.0 g, 29.07 mmol) and DMAP (cat.) in DCM (100 mL) was stirred
at 25.degree. C. for 16 h. After that, the reaction mixture was
filtered and the filtrate was concentrated. The residue was
purified by a silica gel flash column with PE/EA=10:1 to afford the
titled compound (8.0 g, 83%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.35-7.26 (m, 5H),
5.12 (s, 2H), 4.17 (q, J=5.6 Hz, 2H), 3.94 (s, 1H), 3.86 (s, 1H),
2.90 (d, J=6.8 Hz, 3H), 2.45 (t, J=7.4 Hz, 2H), 2.02-1.97 (m, 2H),
1.43 (d, J=19.6 Hz, 9H).
Intermediate Compound 65''; benzyl
4-(2-(N-methylacetamido)acetoxy)butanoate
##STR00264##
[0416] TFA (8.0 mL) was added to a solution of benzyl
4-(2-(tert-butoxycarbonyl)methylaminoacetoxy)butanoate (8.0 g,
21.89 mmol) in DCM (80 mL) at 0.degree. C., the reaction was
stirred at the same temperature for 2 h. After that, solvent was
evaporated, the residue (5.8 g) was used directly for next
step.
[0417] The above residue (5.8 g) was dissolved in DCM (60 mL), to
which Et.sub.3N (9.2 mL, 65.58 mmol) was added, followed by
addition of acetyl chloride (3.4 g, 43.72 mmol) at 0.degree. C. The
reaction was allowed to warm up and stirred at 25.degree. C. for 16
h. After that, solvent was evaporated, and the residue was purified
by prep-HPLC to afford the titled compound (4.0 g, 59%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.35-7.31 (m, 5H), 5.10 (s, 2H), 4.14 (t, J=6.2
Hz, 2H), 4.06 (s, 2H), 3.03 (s, 3H), 2.43 (t, J=7.4 Hz, 2H), 2.10
(s, 2H), 2.11-1.96 (m, 3H).
Compound 65: 4-(2-(N-methylacetamido)acetoxy)butanoic acid
##STR00265##
[0419] Pd/C (400 mg) was added to a solution of benzyl
4-(2-(N-methylacetamido)acetoxy)butanoate (4.0 g, 13.01 mmol) in
MeOH (40 mL), and the reaction was stirred at 25.degree. C. for 16
h under H.sub.2 atmosphere. After that, the reaction mixture was
filtered. The filtrate was concentrated and the residue was
purified by a silica gel flash column with PE/EA=1:10 to afford the
titled compound (1.2 g, 42%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=5.92 (br. s., 1H),
4.20 (t, J=6.2 Hz, 2H), 4.11 (s, 2H), 3.09 (s, 3H), 2.42 (t, J=7.2
Hz, 2H), 2.16 (s, 3H), 2.02-1.95 (m, 2H).
##STR00266##
Example 1-66
Intermediate Compound 66': benzyl
4-(2-acetamidoacetoxy)butanoate
##STR00267##
[0421] 2-acetamidoacetic acid (362 mg, 3.09 mmol), DCC (584 mg,
2.83 mmol) and DMAP (5 mg) was added to a stirred solution of
benzyl 4-hydroxybutanoate (500 mg, 2.58 mmol) in DCM (20 mL). The
reaction was stirred at 25.degree. C. for 16 h. After that, the
reaction mixture was filtered. The filtrate was washed with
saturated aqueous NH.sub.4Cl (15 mL), the organic phase was
separated, washed with brine (10 mL), dried over Na.sub.2SO.sub.4
and concentrated. The residue was purified by prep-HPLC to afford
the titled compound (320 mg, 42%) as crystalline solids. .sup.1H
NMR was performed at 400 MHz with CD.sub.3OD as solvent to
characterize the titled compound, results are as follows:
.delta.=7.36-7.31 (m, 5H), 5.13 (s, 2H), 4.17 (t, J=6.2 Hz, 2H),
3.88 (s, 2H), 2.48 (t, J=7.4H, 2H), 2.01-1.94 (m, 5H).
Compound 66: 4-(2-acetamidoacetoxy)butanoic acid
##STR00268##
[0423] Pd/C (30 mg) was added to a solution of benzyl
4-(2-acetamidoacetoxy)butanoate (280 mg, 0.96 mmol) in methanol (10
mL), the reaction was stirred at 25.degree. C. under H.sub.2
atmosphere for 16 h. After completion, the reaction mixture was
filtered through Celite.RTM. (diatomaceous earth) and the filtrate
was concentrated. The residue was purified by prep-HPLC to afford
the titled compound (110 mg, 57%) as crystalline solids. H NMR was
performed at 400 MHz with CD.sub.3OD as solvent to characterize the
titled compound, results are as follows: .delta.=4.18 (t, J=6.4 Hz,
2H), 3.92 (s, 2H), 2.39 (t, J=7.4 Hz, 2H), 2.00 (s, 3H), 1.98-1.91
(m, 2H).
Example 1-67
##STR00269##
[0424] Intermediate Compound 67': (S)-4-hydroxybutyl
2-acetamido-3-methylbutanoate
##STR00270##
[0426] HATU (5258 mg, 13.84 mmol) and DIPEA (3245 mg, 25.16 mmol)
was added to a stirred solution of (S)-2-acetamido-3-methylbutanoic
acid (2 g, 12.58 mmol) and butane-1,4-diol (3396 mg, 37.74 mmol) in
DCM (50 mL). The reaction was stirred at 25.degree. C. for 16 h.
After that, the mixture was concentrated and the residue was
purified by prep-HPLC to afford the titled compound (600 mg, 21%)
as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=5.96 (d, J=8.0 Hz, 1H), 4.54 (dd, J=5.0,
8.6 Hz, 1H), 4.26-4.11 (m, 2H), 3.69 (t, J=6.4 Hz, 2H), 2.18-2.11
(m, 1H), 2.05 (s, 3H), 1.79-1.72 (m, 2H), 1.69-1.65 (m, 2H), 0.95
(d, J=6.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H).
Compound 67: (S)-4-(2-acetamido-3-methylbutanoyloxy)butanoic
acid
##STR00271##
[0428] Jones reagent was added dropwise to a stirred mixture of
(S)-4-hydroxybutyl 2-acetamido-3-methylbutanoate (500 mg, 2.16
mmol) and Celite.RTM. (diatomaceous earth, 1 g) in acetone (10 mL)
at 0.degree. C. The reaction proceeded at 0.degree. C. over 1 h and
the reaction progress was monitored by TLC. After completion, the
reaction mixture was quenched by drops of isopropanol, diluted with
EA (10 mL) and then filtered. The filtered cake was washed with EA
(10 mL), the combined filtrate was washed with brine (5
mL.times.2), dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by prep-HPLC to afford the titled compound
(190 mg, 36%) as crystalline solids. .sup.1H NMR was performed at
400 MHz with CDCl.sub.3 as solvent to characterize the titled
compound, results are as follows: .delta.=6.18 (d, J=7.2 Hz, 1H),
4.55 (dd, J=4.8, 8.4 Hz, 1H), 4.30-4.24 (m, 1H), 4.20-4.14 (m, 1H),
2.47 (t, J=7.0 Hz, 2H), 2.20-2.12 (m, 1H), 2.09 (s, 3H), 2.06-1.98
(m, 2H), 0.95 (d, J=6.8 Hz, 3H), 0.91 (d, J=6.8 Hz, 3H).
##STR00272##
Example 1-68
Intermediate Compound 68': 2-(ethoxycarbonylamino)acetic acid
##STR00273##
[0430] Ethyl carbonochloridate (3.8 g, 34.6 mmol) was dropwise
added to solution of glycine (2.0 g, 26.6 mmol) and K.sub.2CO.sub.3
(9.6 g, 96.3 mmol) in water (40 mL) at 0.degree. C. The reaction
was warmed up to 25.degree. C. and stirred for 16 h. After that,
the reaction mixture was extracted with EA (2.times.20 mL). The
aqueous phase was separated and acidified with cold conc. HCl until
pH=2, which was extracted with EA (2.times.40 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated to afford the titled compound (3.5 g, 89%) as a white
solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as
solvent to characterize the titled compound, results are as
follows: .delta.=5.16 (br. s., 1H), 4.24-4.08 (m, 2H), 4.07-3.93
(m, 2H), 1.41-1.14 (m, 3H).
Intermediate Compound 68'': 4-hydroxybutyl
2-(ethoxycarbonylamino)acetate
##STR00274##
[0432] A mixture of 2-(ethoxycarbonylamino)acetic acid (1.0 g, 6.8
mmol), butane-1,4-diol (3.1 g, 34.0 mmol), DCC (1.7 g, 8.2 mmol)
and DMAP (10 mg) in DCM (30 mL) was stirred at 25.degree. C. for 16
h. After that, the reaction mixture was filtered and the filtrate
was washed with water (2.times.20 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated. The
residue was purified by a silica gel flash column with
PE/EA=5:1-2:1 to afford the titled compound (630 mg, 42%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=5.16 (br. s., 1H), 4.20 (t, J=6.6 Hz, 2H), 4.14
(t, J=7.2 Hz, 2H), 3.95 (d, J=5.2 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H),
1.83-1.69 (m, 2H), 1.69-1.52 (m, 2H), 1.25 (t, J=7.2 Hz, 3H).
Compound 68: 4-(2-(ethoxycarbonyl)aminoacetoxy)butanoic acid
##STR00275##
[0434] Jones reagent was added in portions to a mixture of
4-hydroxybutyl 2-(ethoxycarbonylamino)acetate (500 mg, 2.3 mmol)
and Celite.RTM. (diatomaceous earth, 1.5 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. over 30 min and
the reaction progress was monitored by TLC. After completion, the
reaction mixture was quenched by drops of isopropanol, diluted with
EA (20 mL) and filtered. The filtered cake was washed with EA (10
mL), the combined filtrate was washed with brine (5 mL.times.2),
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
purified by a silica gel flash column with DCM/EA=20:1-5:1 to
afford the titled compound (190 mg, 36%) as a white solid. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=5.20 (br. s., 1H), 4.23 (t, J=6.4 Hz, 2H), 4.14 (q, J=7.2
Hz, 2H), 3.96 (d, J=5.6 Hz, 2H), 2.46 (t, J=7.2 Hz, 2H), 2.04-1.97
(m, 2H), 1.25 (t, J=7.0 Hz, 3H).
Example 1-69
Intermediate Compound 69': 2-(isopropoxycarbonylamino)acetic
acid
##STR00276##
[0436] Isopropyl carbonochloridate (2.1 g, 17.3 mmol) was dropwise
added to solution of glycine (1.0 g, 13.3 mmol) and K.sub.2CO.sub.3
(4.8 g, 34.6 mmol) in water (30 mL) at 0.degree. C. The reaction
was warmed up to 25.degree. C. and stirred for 16 h. After that,
the reaction mixture was extracted with EA (2.times.20 mL). The
aqueous phase was separated and acidified with cold conc. HCl until
pH=2, which was extracted with EA (2.times.30 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated to afford the titled compound (2.0 g, 93%) as a white
solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as
solvent to characterize the titled compound, results are as
follows: .delta.=5.21 (br. s., 1H), 4.98-4.89 (m, 1H), 4.02-3.96
(m, 2H), 1.26-1.23 (m, 6H).
Intermediate Compound 69'': 4-hydroxybutyl
2-(isopropoxycarbonylamino)acetate
##STR00277##
[0438] A mixture of 2-(isopropoxycarbonylamino)acetic acid (500 mg,
3.1 mmol), butane-1,4-diol (839 mg, 9.3 mmol), DCC (768 mg, 3.7
mmol) and DMAP (10 mg) in DCM (10 mL) was stirred at 25.degree. C.
for 16 h. After that, the reaction mixture was filtered and the
filtrate was washed with water (2.times.20 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by a silica gel flash column
with PE/EA=10:1-1:1 to afford the titled compound (500 mg, 69%) as
a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=5.10 (br. s., 1H), 4.95-4.88 (m, 1H), 4.20
(t, J=6.4 Hz, 2H), 3.95 (d, J=5.6 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H),
1.79-1.72 (m, 2H), 1.67-1.57 (m, 2H), 1.24 (d, J=6.4 Hz, 6H).
Compound 69: 4-(2-(isopropoxycarbonyl)aminoacetoxy)butanoic
acid
##STR00278##
[0440] Jones reagent was added in portions to a mixture of
4-hydroxybutyl 2-(isopropoxycarbonylamino)acetate (500 mg, 2.1
mmol) and Celite.RTM. (diatomaceous earth, 1.5 g) in acetone (10
mL) at 0.degree. C. The reaction proceeded at 0.degree. C. over 30
min and the reaction progress was monitored by TLC. After
completion, the reaction mixture was quenched by drops of
isopropanol, diluted with EA (20 mL) and filtered. The filtered
cake was washed with EA (10 mL), the combined filtrate was washed
with brine (5 mL.times.2), dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by prep-HPLC to afford the
titled compound (220 mg, 42%) as a white solid. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=5.13 (br. s., 1H),
4.95-4.89 (m, 1H), 4.22 (t, J=6.2 Hz, 2H), 3.95 (d, J=5.6 Hz, 2H),
2.46 (t, J=7.2 Hz, 2H), 2.04-1.97 (m, 2H), 1.24 (d, J=6.4 Hz,
6H).
##STR00279##
Example 1-70
Intermediate Compound 70': 2-((cyclohexyloxy)carbonylamino)acetic
acid
##STR00280##
[0442] Pyridine (1.2 g, 15.0 mmol) was added dropwise to a solution
of triphosgene (3.6 g, 12.0 mmol) in toluene (20 mL) at 0.degree.
C., and the formed yellow slurry was stirred for 0.5 h. After that,
a solution of cyclohexanol (1.0 g, 10.0 mmol) in toluene (10 mL)
was added dropwise at 0.degree. C. The reaction was allowed to warm
up and stirred at 25.degree. C. for additional 1 h, then was
quenched by the addition of water (30 mL). The resulting aqueous
phase was extracted with EA (2.times.20 mL). The combined organic
layer was dried over MgSO.sub.4, filtered and concentrated. The
residue was used directly for the next step without
purification.
[0443] The above crude cyclohexyl carbonochloridate was added
dropwise to solution of glycine (675 mg, 9.0 mmol) and
K.sub.2CO.sub.3 (3.5 g, 25.0 mmol) in water (20 mL) at 0.degree. C.
The reaction was allowed to warm up and stirred at 25.degree. C.
for 16 h. After that, the reaction mixture was extracted with EA
(2.times.30 mL). The aqueous phase was separated and acidified with
cold conc. HCl until pH=2, which was extracted with EA (2.times.30
mL). The combined organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated to afford the titled compound (0.9 g,
45%) as a white solid. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=5.14 (br. s., 1H), 4.79-4.59 (m, 1H),
4.07-3.92 (m, 2H), 1.95-1.80 (m, 2H), 1.73-1.70 (m, 2H), 1.61-1.14
(m, 6H).
Intermediate Compound 70'': benzyl
4-(2-((cyclohexyloxy)carbonylamino)acetoxy)butanoate
##STR00281##
[0445] A solution of 2-((cyclohexyloxy)carbonylamino)acetic acid
(850 mg, 4.2 mmol), benzyl 4-hydroxybutanoate (985 mg, 6.3 mmol),
HATU (1.9 g, 5.1 mmol) and DIPEA (819 mg, 6.3 mmol) in DCM (20 mL)
was stirred at 25.degree. C. for 16 h. After that, the reaction
mixture was diluted with DCM (10 mL) and washed with water
(2.times.20 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by a silica gel column with PE/EA=100:1-5:1 to afford the
titled compound (0.9 g, 56%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.42-7.29 (m, 5H),
5.12 (s, 2H), 5.08 (br. s., 1H), 4.77-4.55 (m, 1H), 4.20 (t, J=6.4
Hz, 2H), 3.93 (d, J=5.6 Hz, 2H), 2.45 (t, J=7.6 Hz, 2H), 2.04-1.97
(m, 2H), 1.87-1.85 (m, 2H), 1.78-1.64 (m, 2H), 1.58-1.46 (m, 1H),
1.46-1.14 (m, 5H).
Compound 70: 4-(2-(cyclohexyloxy)carbonylaminoacetoxy)butanoic
acid
##STR00282##
[0447] Pd/C (90 mg) was added to a solution of benzyl
4-(2-((cyclohexyloxy)carbonylamino)acetoxy)butanoate (900 mg, 2.4
mmol) in EA (10 mL). The reaction was stirred under H.sub.2
atmosphere at 25.degree. C. for 16 h. After that, the reaction
mixture was filtered and the filtrate was concentrated. The residue
was purified by a silica gel flash column with PE/EA=10:1-1:1 to
afford the titled compound (220 mg, 32%) as a white solid. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=5.13 (br. s., 1H), 4.67-4.62 (m, 1H), 4.23 (t, J=6.2 Hz,
2H), 3.95 (d, J=6.0 Hz, 2H), 2.46 (t, J=7.2 Hz, 2H), 2.05-1.98 (m,
2H), 1.88-1.86 (m, 2H), 1.72-1.70 (m, 2H), 1.59-1.47 (m, 1H),
1.46-1.12 (m, 5H).
##STR00283##
Example 1-71
Intermediate Compound 71':
(S)-2-(ethoxycarbonylamino)-3-methylbutanoic acid
##STR00284##
[0449] Ethyl carbonochloridate (1.9 g, 17.3 mmol) was added
dropwise to a solution of L-valine (1.0 g, 8.5 mmol) and
K.sub.2CO.sub.3 (4.8 g, 34.6 mmol) in water (30 mL) at 0.degree. C.
The reaction was allowed to warm up and stirred at 25.degree. C.
for 16 h. After that, the reaction mixture was extracted with EA
(2.times.20 mL). The aqueous phase was separated and acidified with
cold conc. HCl until pH=2, which was extracted with EA (2.times.30
mL). The combined organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated to afford the titled compound (1.5 g,
60%) as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=5.12 (d, J=9.2 Hz, 1H), 4.33 (dd, J=4.6,
9.0 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 2.32-2.11 (m, 1H), 1.26 (t,
J=7.2 Hz, 3H), 1.01 (d, J=6.4 Hz, 3H), 0.94 (d, J=7.2 Hz, 3H).
Intermediate Compound 71'': (S)-4-(benzyloxy)-4-oxobutyl
2-(ethoxycarbonylamino)-3-methylbutanoate
##STR00285##
[0451] A solution of (S)-2-(ethoxycarbonylamino)-3-methylbutanoic
acid (536 mg, 2.8 mmol), benzyl 4-hydroxybutanoate (500 mg, 2.6
mmol), HATU (1.2 g, 3.1 mmol) and DIPEA (499 mg, 3.9 mmol) in DCM
(20 mL) was stirred at 25.degree. C. for 16 h. After that, the
reaction mixture was diluted with DCM (10 mL) and washed with water
(2.times.20 mL). The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by silica gel
flash column with PE/EA=20:1-5:1 to afford the titled compound (370
mg, 39%) as a colorless oil. .sup.1H NMR was performed at 400 MHz
with CDCl.sub.3 as solvent to characterize the titled compound,
results are as follows: .delta.=7.45-7.46 (m, 5H), 5.13 (s, 2H),
4.26 (dd, J=4.8, 8.8 Hz, 1H), 4.17 (t, J=6.4 Hz, 2H), 4.11 (q,
J=7.2 Hz, 2H), 2.46 (t, J=7.6 Hz, 2H), 2.21-2.07 (m, 1H), 2.04-1.97
(m, 2H), 1.24 (t, J=7.0 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H), 0.87 (d,
J=6.8 Hz, 3H).
Compound 71
(S)-4-(2-((ethoxycarbonyl)amino)-3-methylbutanoyloxy)butanoic
acid
##STR00286##
[0453] Pd/C (40 mg) was added to a solution of
(S)-4-(benzyoxy)-4-oxobutyl
2-(ethoxycarbonylamino)-3-methylbutanoate (350 mg, 1.0 mmol) in EA
(10 mL). The reaction was stirred under H.sub.2 atmosphere at
25.degree. C. for 16 h. The reaction was filtered and the filtrate
was concentrated to afford the titled compound (240 mg, 91%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=5.16 (d, J=8.8 Hz, 1H), 4.28-4.10 (m, 5H), 2.46
(t, J=7.2 Hz, 2H), 2.25-2.08 (m, 1H), 2.05-1.96 (m, 2H), 1.25 (t,
J=7.0 Hz, 3H), 0.93 (dd, J=7.0, 31.4 Hz, 6H).
##STR00287##
Example 1-72
Intermediate Compound 72': benzyl 4-hydroxybutanoate
##STR00288##
[0455] A mixture of dihydrofuran-2(3H)-one (5.1 g, 59.2 mmol) and
NaOH (2.37 g, 59.2 mmol) in H.sub.2O (60 mL) was heated under
100.degree. C. for 1 h. The clear solution was then cooled and
concentrated. The resultant solid was suspended in toluene and
concentrated to remove H.sub.2O. The resultant solid was suspended
in acetone (60 mL), to which TBAF (772 mg, 2.96 mmol) and
(bromomethyl)benzene (12.2 g, 71.1 mmol) was added. The reaction
was heated under reflux for 3 h. After that, the reaction mixture
was partitioned between EA (150 mL) and H.sub.2O (100 mL). The
organic layer was separated, dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=2:1-1:2 to afford the titled compound (8.5 g, 74%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.37-7.34 (m, 5H), 5.13 (s, 2H), 3.68 (t, J=6.2
Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 1.94-1.87 (m, 2H).
Intermediate Compound 72'': (S)-4-(benzyloxy)-4-oxobutyl
5-oxopyrrolidine-2-carboxylate
##STR00289##
[0457] HATU (2.9 g, 7.7 mmol) and DIPEA (998 mg, 7.7 mmol) was
added to a solution of L-pyroglutamic acid (731 mg, 5.7 mmol) and
benzyl 4-hydroxybutanoate (1.0 g, 5.1 mmol) in DMF (20 mL). The
mixture was stirred at 25.degree. C. for 16 h. The reaction was
concentrated and the residue was purified by prep-HPLC to afford
the titled compound (0.9 g, 57%) as a colorless oil. .sup.1H NMR
was performed at 400 MHz with CDCl.sub.3 as solvent to characterize
the titled compound, results are as follows: .delta.=7.39-7.33 (m,
5H), 6.34 (br. s., 1H), 5.13 (s, 2H), 4.21 (t, J=6.0 Hz, 3H),
2.53-2.28 (m, 5H), 2.27-2.13 (m, 1H), 2.09-1.96 (m, 2H).
Compound 72: (S)-4-(5-oxopyrrolidine-2-carbonyloxy)butanoic
acid
##STR00290##
[0459] Pd/C (90 mg) was added to a solution of
(S)-4-(benzyloxy)-4-oxobutyl 5-oxopyrrolidine-2-carboxylate (900
mg, 3.0 mmol) in EA (20 mL). The reaction was stirred under H.sub.2
atmosphere at 25.degree. C. for 16 h. After that, the reaction
mixture was filtered and the filtrate was concentrated to afford
the titled compound (580 mg, 91%) as a white solid. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.98 (br. s., 1H),
4.31-4.16 (m, 3H), 2.52-2.39 (m, 5H), 2.35-2.19 (m, 1H), 2.06-1.94
(m, 2H).
##STR00291##
Example 1-73
Intermediate Compound 73': 4-hydroxybutyl
(2-methoxyphenyl)carbonate
##STR00292##
[0461] A solution of 2-methoxyphenol (1 g, 8.06 mmol) and Et.sub.3N
(977 mg, 9.68 mmol) in DCM (10 mL) was added dropwise to a stirred
solution of triphosgene (788 mg, 2.66 mmol) in DCM (10 mL) at
0.degree. C. during 10 min. After that, the reaction was allowed to
warm up gradually and stirred at 25.degree. C. for 2 h. The above
reaction solution was added dropwise to a stirred solution of
butane-1,4-diol (2.18 g, 24.19 mmol) in DCM (10 mL) at 0.degree. C.
during 10 min, and then the reaction mixture was stirred at
25.degree. C. for 14 h. After that, the reaction mixture was
diluted with water (10 mL), separated and the organic phase was
washed with brine (10 mL), dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with DCM/EA=10:1 to afford the titled compound (350 mg, 27%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.22 (t, J=8.0 Hz, 1H), 7.13 (d, J=6.8 Hz, 1H),
6.99-6.93 (m, 2H), 4.30 (t, J=6.4 Hz, 2H), 3.86 (s, 3H), 3.72 (t,
J=6.2 Hz, 2H), 1.89-1.82 (m, 2H), 1.75-1.68 (m, 2H).
Compound 73: 4-((2-methoxyphenoxy)carbonyloxy)butanoic acid
##STR00293##
[0463] Jones reagent was added dropwise to a stirred mixture of
4-hydroxybutyl (2-methoxyphenyl) carbonate (350 mg, 1.46 mmol) and
Celite.RTM. (diatomaceous earth, 700 mg) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. over 1 h and
the reaction progress was monitored by TLC. After completion, the
reaction was quenched with drops of isopropanol, diluted with EA
(15 mL), and then filtered. The filtered cake was washed with EA (5
mL) and the combined filtrate was washed with brine (5 mL.times.2),
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
purified by a silica gel flash column with DCM/EA=10:1 to afford
the titled compound (180 mg, 49%) as crystalline solids. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.22 (t, J=8.0 Hz, 1H), 7.13 (d, J=6.8 Hz, 1H), 6.99-6.93
(m, 2H), 4.33 (t, J=6.2 Hz, 2H), 3.86 (s, 3H), 2.55 (t, J=7.4 Hz,
2H), 2.12-2.05 (m, 2H).
Example 1-74
Intermediate Compound 74': 4-hydroxybutyl
(2-isopropyl-5-methylphenyl) carbonate
##STR00294##
[0465] A solution of 2-isopropyl-5-methylphenol (1 g, 6.67 mmol)
and Et.sub.3N (741 mg, 7.33 mmol) in DCM (10 mL) was added dropwise
to a stirred solution of triphosgene (651 mg, 2.20 mmol) in DCM (10
mL) at 0.degree. C. during 10 min. After that, the reaction was
allowed to warm up gradually and stirred at 0-25.degree. C. for 2
h. The above reaction solution was dropwise added to a stirred
solution of butane-1,4-diol (1.8 g, 20 mmol) in DCM (10 mL) at
0.degree. C. during 10 min, and then the reaction mixture was
stirred at 0-25.degree. C. for 14 h. After that, the reaction
mixture was diluted with water (10 mL), separated and the organic
phase was washed with brine (10 mL), dried over Na.sub.2SO.sub.4
and concentrated. The residue was purified by a silica gel flash
column with Hex/EA=3:1 to afford the titled compound (900 mg, 51%)
as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.19 (d, J=8.0 Hz, 1H), 7.04 (d, J=7.8 Hz,
1H), 6.90 (s, 1H), 4.30 (t, J=6.4 Hz, 2H), 3.72 (t, J=6.2 Hz, 2H),
3.10-3.03 (m, 1H), 2.32 (s, 3H), 1.89-1.82 (m, 2H), 1.75-1.68 (m,
2H), 1.20 (d, J=7.2 Hz, 6H).
Compound 74: 4-((2-isopropyl-5-methylphenoxy)carbonyloxy)butanoic
acid
##STR00295##
[0467] Jones reagent was added dropwise to a stirred mixture of
4-hydroxybutyl (2-isopropyl-5-methylphenyl) carbonate (900 mg, 3.38
mmol) and Celite.RTM. (diatomaceous earth, 1.8 g) in acetone (10
mL) at 0.degree. C. The reaction proceeded at 0.degree. C. over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of isopropanol, diluted with
EA (30 mL), and then filtered. The filtered cake was washed with EA
(10 mL) and the combined filtrate was washed with brine (10
mL.times.2), dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by a silica gel flash column with DCM/EA=8:1
to afford the titled compound (500 mg, 53%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.19 (d, J=8.0 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 6.90 (s,
1H), 4.32 (t, J=6.2 Hz, 2H), 3.09-3.02 (m, 1H), 2.55 (t, J=7.2 Hz,
2H), 2.32 (s, 3H), 2.13-2.06 (m, 2H), 1.20 (d, J=6.8 Hz, 6H).
Example 1-75
Intermediate Compound 75':
benzo[d][1,3]dioxo-5-yl(4-hydroxybutyl)carbonate
##STR00296##
[0469] A solution of benzo[d][1,3]dioxol-5-ol (1 g, 7.25 mmol) and
Et.sub.3N (878 mg, 8.70 mmol) in DCM (10 mL) was added dropwise to
a stirred solution of triphosgene (708 mg, 2.39 mmol) in DCM (10
mL) at 0.degree. C. during 10 min. After that, the reaction was
allowed to warm up gradually and stirred at 0-25.degree. C. for 2
h. The above reaction solution was dropwise added to a stirred
solution of butane-1,4-diol (1.96 g, 21.74 mmol) in DCM (10 mL) at
0.degree. C. during 10 min, and then the reaction mixture was
stirred at 0-25.degree. C. for 14 h. After that, the reaction
mixture was diluted with water (10 mL), separated and the organic
phase was washed with brine (10 mL), dried over Na.sub.2SO.sub.4
and concentrated, the residue was purified by a silica gel flash
column with DCM/EA=10:1 to afford the titled compound (500 mg, 27%)
as a yellow oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=6.75 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.0 Hz,
1H), 6.60 (dd, J=2.0, 8.4 Hz, 1H), 5.97 (s, 2H), 4.26 (t, J=6.6 Hz,
2H), 3.68 (t, J=6.2 Hz, 2H), 1.85-1.78 (m, 2H), 1.71-1.64 (m,
2H).
Compound 75: 4-((benzo[d][1,3]dioxol-5-yloxy)carbonyloxy)butanoic
acid
##STR00297##
[0471] Jones reagent was added dropwise to a stirred mixture of
benzo[d][1,3]dioxol-5-yl (4-hydroxybutyl) carbonate (500 mg, 1.97
mmol) and Celite.RTM. (diatomaceous earth, 1 g) in acetone (10 mL)
at 0.degree. C. The reaction proceeded at 0.degree. C. over 1 h and
the reaction progress was monitored by TLC. After completion, the
reaction was quenched with drops of isopropanol, diluted with EA
(30 mL), and then filtered. The filtered cake was washed with EA
(10 mL) and the combined filtrate was washed with brine (10
mL.times.2), dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by a silica gel flash column with DCM/EA=8:1
to afford the titled compound (300 mg, 57%) as brown solid. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=6.77 (d, J=8.4 Hz, 1H), 6.69 (d, J=1.6 Hz, 1H), 6.62 (dd,
J=2.0, 8.4 Hz, 1H), 5.99 (s, 2H), 4.30 (t, J=6.2 Hz, 2H), 2.54 (t,
J=7.2 Hz, 2H), 2.11-2.05 (m, 2H).
Example 1-76
Intermediate Compound 76': 4-methylbenzyl carbonochloridate
##STR00298##
[0473] Pyridine (4.86 g, 61.48 mmol) was added to a stirred
solution of triphosgene (14.5 g, 49.18 mmol) in toluene (100 mL) at
0.degree. C. and the mixture was stirred for 30 min. After that, a
solution of p-tolylmethanol (5 g, 40.98 mmol) in toluene (50 mL)
was dropwise added during 30 min, and then the reaction proceeded
at 0.degree. C. for additional 1 h. The reaction mixture was
partitioned between water (50 mL) and EA (100 mL), the organic
phase was separated and dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by a silica gel flash column
with PE/EA=10:1 to afford the titled compound (6 g, 79%) as a
colorless oil.
Intermediate Compound 76'': 4-hydroxybutyl 4-methylbenzyl
carbonate
##STR00299##
[0474] 4-methylbenzyl carbonochloridate
[0475] (3 g, 16.30 mmol) in DCM (20 mL) was dropwise added to a
stirred solution of Et.sub.3N (5 g, 49.50 mmol) and butane-1,4-diol
(4.4 g, 48.89 mmol) in DCM (40 mL) at 0.degree. C. during 15 min.
The reaction was stirred at 25.degree. C. for 16 h. After that, the
reaction mixture was diluted with water (30 mL) and the aqueous
phase was separated. The resulting organic phase was washed with
brine (15 mL), dried over Na.sub.2SO.sub.4 and concentrated, the
residue was purified by a silica gel flash column with PE/EA=3:1 to
afford the titled compound (700 mg, 18%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.28 (d, J=8.0 Hz, 2H), 7.17 (d, J=7.6 Hz, 2H), 5.11 (s,
2H), 4.18 (t, J=6.4 Hz, 2H), 3.67 (t, J=6.4 Hz, 2H), 2.35 (s, 3H),
1.80-1.73 (m, 2H), 1.68-1.61 (m, 2H).
Compound 76: 4-((4-methylbenzyl)oxycarbonyloxy)butanoic acid
##STR00300##
[0477] Jones reagent was added dropwise to a stirred mixture of
4-hydroxybutyl 4-methylbenzyl carbonate (700 mg, 2.94 mmol) and
Celite.RTM. (diatomaceous earth, 1.4 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. over 1 h and
the reaction progress was monitored by TLC. After completion, the
reaction was quenched with drops of isopropanol, diluted with EA
(20 mL), and then filtered. The filtered cake was washed with EA
(10 mL) and the combined filtrate was washed with brine (10
mL.times.2), dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by a silica gel flash column with PE/EA=2:1 to
afford the titled compound (400 mg, 54%) as crystalline solids.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.28 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.11 (s,
2H), 4.20 (t, J=6.4 Hz, 2H), 2.47 (t, J=7.2 Hz, 2H), 2.35 (s, 3H),
2.03-1.96 (m, 2H).
Example 1-77
Intermediate Compound 77': 4-hydroxybutyl
(tetrahydro-2H-pyran-4-yl) carbonate
##STR00301##
[0479] A solution of tetrahydro-2H-pyran-4-ol (1.0 g, 9.8 mmol) and
Et.sub.3N (1.2 g, 11.8 mmol) in DCM (10 mL) was added dropwise to
solution of triphosgene (1.0 g, 3.2 mmol) in DCM (10 mL) at
0.degree. C. After the addition is complete, the reaction was
stirred at 0.degree. C. for 1 h. After that, the above slurry was
added dropwise to the suspension of butane-1,4-diol (2.7 g, 29.4
mmol) in DCM (10 mL) at 0.degree. C. The resulting mixture was
warmed up gradually to 25.degree. C. and stirred for 16 h. The
reaction was quenched by water (10 mL) and separated. The organic
phase was dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by a silica gel flash column with
PE/EA=10:1-1:1 to afford the titled compound (380 mg, 18%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=4.82-4.78 (m, 1H), 4.18 (t, J=6.4 Hz, 2H),
3.97-3.92 (m, 2H), 3.69 (t, J=6.2 Hz, 2H), 3.70-3.53 (m, 2H),
2.06-1.93 (m, 2H), 1.87-1.59 (m, 6H).
Compound 77: 4-((tetrahydro-2H-pyran-4-yl)oxycarbonyloxy)butanoic
acid
##STR00302##
[0481] Jones reagent was added dropwise to a stirred mixture of
4-hydroxybutyl (tetrahydro-2H-pyran-4-yl) carbonate (300 mg, 1.4
mmol) and Celite.RTM. (diatomaceous earth, 0.6 g) in acetone (6
mL). The reaction proceeded at 0.degree. C. over 1 h and the
reaction progress was monitored by TLC. After completion, the
reaction was quenched with drops of isopropanol, diluted with EA
(20 mL), and then filtered. The filtered cake was washed with EA
(20 mL) and the combined filtrate was washed with brine (10
mL.times.2), dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by a silica gel flash column with
PE/EA=50:1-5:1 to afford the titled compound (110 mg, 34%) as
crystalline solids. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=4.84-4.77 (m, 1H), 4.20 (t, J=6.4 Hz, 2H),
4.03-3.86 (m, 2H), 3.64-3.44 (m, 2H), 2.50 (t, J=7.6 Hz, 2H),
2.05-1.88 (m, 4H), 1.79-1.70 (m, 2H).
##STR00303##
Example 1-78
Intermediate Compound 78': tert-butyl (4-hydroxybutyl)
carbonate
##STR00304##
[0483] (Boc).sub.2O (2.05 g, 9.4 mmol) and DMAP (100 mg) was added
to a stirred solution of butane-1,4-diol (10 g, 111.11 mmol) in DCM
(100 mL). The reaction was stirred at 25.degree. C. for 16 h. After
that, the reaction mixture was diluted with saturated aqueous
NH.sub.4Cl (20 mL) and stirred for 5 min. The aqueous phase was
separated and extracted with DCM (20 mL). The combined organic
phase was washed with saturated brine (30 mL), dried over anhydrous
Na.sub.2SO.sub.4 and evaporated. The residue was purified by a
silica gel flash column with Hex/EA=10:1 to yield the titled
compound (1 g, 56%) as a colorless oil. .sup.1H NMR was performed
at 400 MHz with CDCl.sub.3 as solvent to characterize the titled
compound, results are as follows: .delta.=4.10 (t, J=6.6 Hz, 2H),
3.68 (q, J=6.0 Hz, 2H), 1.79-1.72 (m, 2H), 1.69-1.62 (m, 2H), 1.48
(s, 9H), 1.34 (t, J=5.2 Hz, 1H).
Compound 78: 4-(tert-butoxycarbonyloxy)butanoic acid
##STR00305##
[0485] Jones reagent was added in portions to a stirred mixture of
tert-butyl (4-hydroxybutyl) carbonate (800 mg, 4.21 mmol) and
Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-6:1 to yield the titled compound (500 mg, 58%) as
a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=4.12 (t, J=6.2 Hz, 2H), 2.49 (t, J=7.4 Hz,
2H), 2.03-1.96 (m, 2H), 1.48 (s, 9H).
##STR00306##
Example 1-79
Intermediate Compound 79': benzyl
4-(chlorocarbonyloxy)butanoate
##STR00307##
[0487] Pyridine (305 mg, 3.9 mmol) was slowly added to a solution
of triphosgene (976 mg, 3.4 mmol) in toluene (10 mL) at 0.degree.
C. and stirred for 0.5 h. A solution of benzyl 4-hydroxybutanoate
(500 mg, 2.6 mmol) in toluene (5 mL) was added to the above formed
slurry at 0.degree. C. The reaction was allowed to warm up and
stirred at 25.degree. C. for 1.5 h. After that, the reaction
mixture was partitioned between water (15 mL) and EA (15 mL). The
organic layer was separated, washed with brine (10 mL), dried over
Na.sub.2SO.sub.4 and filtered. The filtrated was concentrated to
yield a light yellow oil, which was purified by a silica gel flash
column with PE/EA=20:1-5:1 to afford the titled compound (490 mg,
74%) as colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.43-7.27 (m, 5H), 5.14 (s, 2H), 4.37 (t,
J=6.2 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.12-2.05 (m, 2H).
Intermediate Compound 79'': benzyl
4-((1-methylpiperidin-4-yl)oxycarbonyl oxy) butanoate
##STR00308##
[0489] A solution of benzyl 4-(chlorocarbonyloxy)butanoate (500 mg,
1.95 mmol) and Et.sub.3N (395 mg, 3.91 mmol) in DCM (5 mL) was
added dropwise to a stirred solution of 1-methylpiperidin-4-ol (225
mg, 1.96 mmol) in DCM (5 mL) at 0.degree. C. during 10 min. After
that, the reaction mixture was diluted with water (5 mL), the
resulting aqueous phase was separated and extracted with DCM (5
mL). The combined organic phase was washed with brine (5 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by prep-HPLC to afford the titled compound (240 mg, 37%)
as a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.43-7.29 (m, 5H), 5.12 (s, 2H), 4.77 (br.
s., 1H), 4.18 (t, J=6.2 Hz, 2H), 2.84-2.65 (m, 4H), 2.51-2.47 (m,
5H), 2.18-1.99 (m, 4H), 1.98-1.83 (m, 2H).
Compound 79: 4-((1-methylpiperidin-4-yl)oxycarbonyloxy)butanoic
acid
##STR00309##
[0491] Pd/C (40 mg) was added to a solution of benzyl
4-((1-methylpiperidin-4-yl)oxycarbonyoxy)butanoate (200 mg, 0.6
mmol) in methanol (3 mL). The mixture was stirred at 25.degree. C.
under H.sub.2 atmosphere for 16 h. After that, the mixture was
filtered through Celite.RTM. (diatomaceous earth) and the filtered
cake was washed with methanol (3 mL). The combined filtrate was
concentrated, the residue was purified by prep-HPLC to afford the
titled compound (15 mg, 10%) as crystalline solids. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=4.92 (br. s., 1H),
4.22 (t, J=6.4 Hz, 2H), 3.19 (br. s., 4H), 2.77 (s, 3H), 2.44 (t,
J=7.2 Hz, 2H), 2.35-2.20 (m, 2H), 2.13-2.08 (m, 2H), 2.05-1.98 (m,
2H).
##STR00310##
Example 1-80
Intermediate Compound 80': 4-hydroxybutyl 2-chloroacetate
##STR00311##
[0493] A solution of 2-chloroacetyl chloride (5 g, 44.25 mmol) in
DCM (10 mL) dropwise during 10 min was added to a stirred solution
of butane-1,4-diol (19.9 g, 221.11 mmol) and Et.sub.3N (8.9 g, 88.5
mmol) in DCM (40 mL) at 0.degree. C. The reaction was allowed to
warm up gradually and stirred at 0-25.degree. C. over 16 h. After
that, the reaction mixture was diluted with H.sub.2O (20 mL) and
stirred for 5 min. The aqueous phase was separated and extracted
with DCM (20 mL). The combined organic phase was washed with
saturated brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and
evaporated. The residue was purified by a silica gel flash column
with Hex/EA=5:1 to yield the titled compound (3.2 g, 44%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=4.24 (t, J=6.6 Hz, 2H), 4.07 (s, 2H), 3.69 (t,
J=6.4 Hz, 2H), 1.82-1.75 (m, 2H), 1.68-1.61 (m, 2H).
Intermediate Compound 80'': 2-(4-hydroxybutoxy)-2-oxoethyl
2-ethylbenzoate
##STR00312##
[0495] Et.sub.3N (365 mg, 3.61 mmol) and 4-hydroxybutyl
2-chloroacetate (300 mg, 1.81 mmol) was added to a stirred solution
of 2-ethylbenzoic acid (542 mg, 3.61 mmol) in acetone (10 mL). The
reaction was stirred at 50.degree. C. for 5 h. After that, the
reaction mixture was partitioned between DCM (20 mL) and H.sub.2O
(10 mL). The aqueous phase was separated and extracted with DCM (10
mL). The combined organic phase was washed with saturated brine (20
mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with Hex/EA=6:1
to yield the titled compound (175 mg, 35%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=8.02-7.95 (m, 1H), 7.49-7.44 (m, 1H), 7.32-7.24 (m, 2H),
4.83 (s, 2H), 4.25 (t, J=6.4 Hz, 2H), 3.67 (t, J=6.4 Hz, 2H),
3.08-2.97 (m, 2H), 1.81-1.74 (m, 2H), 1.67-1.60 (m, 2H), 1.28-1.22
(m, 3H).
Compound 80: 4-(2-(2-ethylbenzoyloxy)acetoxy)utanoic acid
##STR00313##
[0497] Jones reagent was added in portions to a stirred mixture of
2-(4-hydroxybutoxy)-2-oxoethyl 2-ethylbenzoate (170 mg, 0.61 mmol)
and Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (90 mg, 51%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.96 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.0 Hz, 1H),
7.31-7.25 (m, 2H), 4.83 (s, 2H), 4.28 (t, J=6.2 Hz, 2H), 3.00 (q,
J=7.6 Hz, 2H), 2.47 (t, J=7.4 Hz, 2H), 2.06-1.99 (m, 2H), 1.24 (t,
J=7.4 Hz, 3H).
Example 1-81
Intermediate Compound 81': 2-(4-hydroxybutoxy)-2-oxoethyl
2,4-dimethylbenzoate
##STR00314##
[0499] Et.sub.3N (364 mg, 3.6 mmol) and 4-hydroxybutyl
2-chloroacetate (300 mg, 1.81 mmol) to a stirred solution of
2,4-dimethylbenzoic acid (405 mg, 2.7 mmol) in acetone (10 mL). The
reaction was stirred at 50.degree. C. for 5 h. After that, the
reaction mixture was partitioned between DCM (20 mL) and H.sub.2O
(10 mL). The aqueous phase was separated and extracted with DCM (10
mL). The combined organic phase was washed with saturated brine (20
mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with Hex/EA=6:1
to yield the titled compound (350 mg, 69%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.92 (d, J=8.0 Hz, 1H), 7.08-7.06 (m, 2H), 4.81 (s, 2H),
4.24 (t, J=6.6 Hz, 2H), 3.67 (t, J=6.2 Hz, 2H), 2.59 (s, 3H), 2.36
(s, 3H), 1.80-1.73 (m, 2H), 1.66-1.60 (m, 2H), 1.44 (br. s.,
1H).
Compound 81: 4-(2-(2,4-dimethylbenzoyloxy)acetoxy)butanoic acid
##STR00315##
[0501] Jones reagent was added in portions to a stirred mixture of
2-(4-hydroxybutoxy)-2-oxoethyl 2,4-dimethylbenzoate (300 mg, 1.07
mmol) and Celite.RTM. (diatomaceous earth, 2 g) in acetone (10 mL)
at 0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (150 mg, 48%) as
a colorless oil. .sup.1H NMR was performed at 400 MHz with
CDCl.sub.3 as solvent to characterize the titled compound, results
are as follows: .delta.=7.92 (d, J=8.4 Hz, 1H), 7.18-7.06 (m, 2H),
4.81 (s, 2H), 4.27 (t, J=6.2 Hz, 2H), 2.58 (s, 3H), 2.47 (t, J=7.4
Hz, 2H), 2.36 (s, 3H), 2.06-2.00 (m, 2H).
Example 1-82
Intermediate Compound 82': 2-(4-hydroxybutoxy)-2-oxoethyl
2,3-dimethoxybenzoate
##STR00316##
[0503] Et.sub.3N (364 mg, 3.6 mmol) and 4-hydroxybutyl
2-chloroacetate (300 mg, 1.81 mmol) was added to a stirred solution
of 2,3-dimethoxybenzoic acid (655 mg, 3.6 mmol) in acetone (10 mL).
The reaction was stirred at 50.degree. C. for 5 h. After that, the
reaction mixture was partitioned between DCM (20 mL) and H.sub.2O
(10 mL). The aqueous phase was separated and extracted with DCM (10
mL). The combined organic phase was washed with saturated brine (20
mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The
residue was purified by a silica gel flash column with Hex/EA=2:1
to yield the titled compound (200 mg, 35%) as a colorless oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.43 (dd, J=2.4, 6.8 Hz, 1H), 7.14-7.08 (m, 2H), 4.84 (s,
2H), 4.25 (t, J=6.5 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.67 (t,
J=6.2 Hz, 2H), 1.81-1.74 (m, 2H), 1.67-1.60 (m, 2H).
Compound 82: 4-(2-(2,3-dimethoxybenzoyloxy)acetoxy)butanoic
acid
##STR00317##
[0505] Jones reagent was added in portions to a stirred mixture of
2-(4-hydroxybutoxy)-2-oxoethyl 2,3-dimethoxybenzoate (200 mg, 0.64
mmol) and Celite.RTM. (diatomaceous earth, 2 g) in acetone (5 mL)
at 0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=5:1-2:1 to yield the titled compound (100 mg, 48%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=7.43 (dd, J=2.6, 7.0 Hz, 1H), 7.14-7.09 (m, 2H),
4.84 (s, 2H), 4.27 (t, J=6.0 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H),
2.47 (t, J=7.2 Hz, 2H), 2.06-1.99 (m, 2H).
Example 1-83
Intermediate Compound 83': 2-(4-hydroxybutoxy)-2-oxoethyl
benzoate
##STR00318##
[0507] Et.sub.3N (364 mg, 3.6 mmol) and 4-hydroxybutyl
2-chloroacetate (300 mg, 1.81 mmol) was added to a stirred solution
of benzoic acid (439 mg, 3.6 mmol) in acetone (10 mL). The reaction
was stirred at 50.degree. C. for 5 h. After that, the reaction
mixture was partitioned between DCM (20 mL) and H.sub.2O (10 mL).
The aqueous phase was separated and extracted with DCM (10 mL). The
combined organic phase was washed with saturated brine (20 mL),
dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The residue
was purified by a silica gel flash column with Hex/EA=6:1 to yield
the titled compound (260 mg, 57%) as a colorless oil. .sup.1H NMR
was performed at 400 MHz with CDCl.sub.3 as solvent to characterize
the titled compound, results are as follows: .delta.=8.10 (d, J=7.2
Hz, 2H), 7.60 (t, J=7.4 Hz, 1H), 7.47 (t, J=7.8 Hz, 2H), 4.85 (s,
2H), 4.25 (t, J=6.6 Hz, 2H), 3.67 (t, J=6.2 Hz, 2H), 1.80-1.73 (m,
2H), 1.66-1.59 (m, 2H).
Compound 83: 4-(2-(benzoyloxy)acetoxy)butanoic acid
##STR00319##
[0509] Jones reagent was added in portions to a stirred mixture of
2-(4-hydroxybutoxy)-2-oxoethyl benzoate (250 mg, 0.99 mmol) and
Celite.COPYRGT. (diatomaceous earth, 2 g) in acetone (5 mL) at
0.degree. C. The reaction proceeded at 0.degree. C. for over 1 h
and the reaction progress was monitored by TLC. After completion,
the reaction was quenched with drops of iPrOH, diluted with EA (10
mL) and then filtered. The filtered cake was washed with EA (5 mL)
and the combined filtrate was washed with saturated brine (2
mL.times.2), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by a silica gel flash column
with Hex/EA=10:1-5:1 to yield the titled compound (140 mg, 53%) as
a white solid. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=8.10 (d, J=7.2 Hz, 2H), 7.60 (t, J=7.4 Hz, 1H),
7.47 (t, J=7.8 Hz, 2H), 4.85 (s, 2H), 4.27 (t, J=6.2 Hz, 2H), 2.46
(t, J=7.4 Hz, 2H), 2.05-1.98 (m, 2H).
##STR00320##
Example 1-84
Intermediate Compound 84': benzyl 4-(2-chloroacetoxy)butanoate
##STR00321##
[0511] A solution of 2-chloroacetyl chloride (865 mg, 7.65 mmol) in
DCM (10 mL) was added to a stirred solution of benzyl
4-hydroxybutanoate (1350 mg, 6.96 mmol) and Et.sub.3N (1406 mg,
13.92 mmol) in DCM (10 mL) at 0.degree. C. during 10 min. The
reaction was stirred at 25.degree. C. for 16 h. After completion,
the reaction mixture was diluted with water (10 mL). The organic
phase was collected, washed with brine (5 mL), dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by a
silica gel flash column with PE/EA=8:1 to afford the titled
compound (977 mg, 52%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.41-7.30 (m, 5H),
5.13 (s, 2H), 4.24 (t, J=6.4 Hz, 2H), 4.02 (s, 2H), 2.47 (t, J=7.4
Hz, 2H), 2.07-2.00 (m, 2H).
Intermediate Compound 84': benzyl
4-(2-2-(tert-butoxycarbonyl)aminoacetoxyacetoxy)butanoate
##STR00322##
[0513] A solution of 2-(tert-butoxycarbonylamino)acetic acid (654
mg, 3.74 mmol), Et.sub.3N (686 mg, 6.79 mmol) and benzyl
4-(2-chloroacetoxy)butanoate (917 mg, 3.40 mmol) in acetone (10 mL)
was stirred at 50.degree. C. for 16 h. After that, the mixture was
diluted with EA (30 mL) and water (10 mL), the aqueous phase was
separated and the organic phase was washed with brine (10 mL),
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
purified by a silica gel flash column with PE/EA=5:1 to afford the
titled compound (1.16 g, 84%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.41-7.32 (m, 5H),
5.13 (s, 2H), 5.01 (br. s., 1H), 4.64 (s, 2H), 4.22 (t, J=6.4 Hz,
2H), 4.04 (d, J=5.6 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H), 2.05-1.98 (t,
J=6.8 Hz, 2H), 1.45 (s, 9H).
Intermediate Compound 84''':
2,2-dimethyl-4,7,10-trioxo-3,8,11-trioxa-5-azapentadecan-15-oic
acid
##STR00323##
[0515] Pd/C (100 mg) was added to a stirred solution of benzyl
4-(2-2-(tert-butoxycarbonyl)aminoacetoxyacetoxy)butanoate (1 g,
2.44 mmol) in THF (10 mL), the mixture was stirred at 25.degree. C.
under H.sub.2 atmosphere for 16 h. After that, the reaction mixture
was filtered through Celite.RTM. (diatomaceous earth). The filtered
cake was washed with EA (5 mL), the combined filtrate was
concentrated. The residue was purified by prep-HPLC to afford the
titled compound (600 mg, 77%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=5.11 (br. s., 1H),
4.70 (s, 2H), 4.24 (t, J=5.8 Hz, 2H), 4.11 (d, J=6.0 Hz, 2H), 2.46
(t, J=6.8 Hz, 2H), 2.10-2.02 (m, 2H), 1.46 (s, 9H).
Compound 84: 4-(2-(2-aminoacetoxy)acetoxy)butanoic acid
##STR00324##
[0516]
2,2-dimethyl-4,7,10-trioxo-3,8,11-trioxa-5-azapentadecan-15-oic
acid
[0517] (600 mg, 1.88 mmol) was dissolved in HCl/EA (6 mL, .about.2
M) and the solution was stirred at 25.degree. C. for 16 h. After
that, the reaction mixture was filtered, the collected solid was
washed with Et.sub.2O (5 mL) to afford the titled compound (450 mg,
94%) as crystalline solids in HCl salt form. .sup.1H NMR was
performed at 400 MHz with D.sub.2O as solvent to characterize the
titled compound, results are as follows: .delta.=4.84 (s, 2H), 4.23
(t, J=6.0 Hz, 2H), 4.03 (s, 2H), 2.43 (t, J=7.2 Hz, 2H), 1.98-1.91
(m, 2H).
##STR00325##
Example 1-85
Intermediate Compound 85': benzyl
4-(2-chloropropanoyloxy)butanoate
##STR00326##
[0519] A solution of 2-chloropropanoyl chloride (1080 mg, 8.50
mmol) in DCM (10 mL) was dropwise added to a stirred solution of
benzyl 4-hydroxybutanoate (1.5 g, 7.73 mmol) Et.sub.3N (1562 mg,
15.47 mmol) in DCM (10 mL) at 0.degree. C., the reaction was
stirred at 25.degree. C. for 16 h. After that, the reaction mixture
was diluted with water (10 mL), the aqueous phase was separated and
the organic phase was washed with brine (10 mL), dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by a
silica gel flash column with PE/EA=8:1 to afford the titled
compound (1.38 g, 63%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.41-7.30 (m, 5H),
5.13 (s, 2H), 4.36 (q, J=7.0 Hz, 1H), 4.22 (t, J=6.0 Hz, 2H), 2.48
(t, J=7.4 Hz, 2H), 2.07-2.00 (m, 2H), 1.67 (d, J=6.8 Hz, 3H).
Intermediate Compound 85'': benzyl
4-(2-(2-(tert-butoxycarbonyl)aminoacetoxy)propanoyloxy)butanoate
##STR00327##
[0521] Et.sub.3N (782 mg, 7.75 mmol) and NaI (20 mg) was added to a
stirred solution of 2-(tert-butoxycarbonylamino)acetic acid (746
mg, 4.26 mmol) and benzyl 4-(2-chloropropanoyloxy)butanoate (1.1 g,
3.87 mmol) in DMF (15 mL), the reaction mixture was stirred at
70.degree. C. for 16 h. After that, the mixture was concentrated,
the residue was partitioned between EA (20 mL) and water (10 mL).
The aqueous phase was separated, the organic phase was washed with
brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by a silica gel flash column with PE/EA=5:1 to
afford the titled compound (1.1 g, 69%) as a colorless oil. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.43-7.29 (m, 5H), 5.15-5.09 (m, 3H), 5.00 (br. s., 1H),
4.19 (t, J=6.2 Hz, 2H), 4.06 (dd, J=6.0, 18.4 Hz, 1H), 3.93 (dd,
J=5.0, 14.2 Hz, 1H), 2.44 (t, J=7.2 Hz, 2H), 2.03-1.97 (m, 2H),
1.49 (d, J=6.8 Hz, 3H), 1.45 (s, 9H).
Intermediate Compound 85''':
2,2,9-trimethyl-4,7,10-trioxo-3,8,11-trioxa-5-azapentadecan-15-oic
acid
##STR00328##
[0523] Pd/C (100 mg) was added to a stirred solution of benzyl
4-(2-(2-(tert-butoxycarbonyl)aminoacetoxy)propanoyloxy)butanoate
(1.1 g, 2.60 mmol) in THF (10 mL), the reaction mixture was stirred
at 25.degree. C. under H.sub.2 atmosphere for 16 h. After that, the
reaction mixture was filtered through Celite.RTM. (diatomaceous
earth) and the filtered cake was washed with EA (5 mL). The
combined filtrate was concentrated, the residue was purified by
prep-HPLC to afford the titled compound (800 mg, 92%) as a
colorless oil. .sup.1H NMR was performed at 400 MHz with CDCl.sub.3
as solvent to characterize the titled compound, results are as
follows: .delta.=5.21 (q, J=6.8 Hz, 1H), 5.12 (br. s., 1H),
4.29-4.09 (m, 3H), 3.94 (dd, J=4.6, 18.8 Hz, 1H), 2.45 (t, J=6.8
Hz, 2H), 2.09-1.98 (m, 2H), 1.50 (d, J=7.2 Hz, 3H), 1.46 (s,
9H).
Compound 85: 4-(2-(2-aminoacetoxy)propanoyloxy)butanoic acid
##STR00329##
[0525]
2,2,9-trimethyl-4,7,10-trioxo-3,8,11-trioxa-5-azapentadecan-15-oic
acid (770 mg, 2.31 mmol) was dissolved in HCl/EA (10 mL, .about.2
M) at 0.degree. C. and the solution was stirred at 25.degree. C.
for 16 h. After that, the reaction mixture was concentrated, the
residue was purified by prep-HPLC to afford the titled compound (48
mg, 9%) as a colorless oil in HCl salt form. .sup.1H NMR was
performed at 400 MHz with D.sub.2O as solvent to characterize the
titled compound, results are as follows: .delta.=5.26 (d, J=7.2 Hz,
1H), 4.23 (dt, J=2.8, 6.0 Hz, 2H), 4.00 (d, J=1.6 Hz, 2H), 2.45 (t,
J=7.0 Hz, 2H), 2.01-1.91 (m, 2H), 1.50 (d, J=7.2 Hz, 3H).
##STR00330##
Example 1-86
Intermediate Compound 86': benzyl
4-(2-(2-acetamidoacetoxy)propanoyloxy)butanoate
##STR00331##
[0527] A mixture of benzyl 4-(2-chloropropanoyloxy)butanoate (500
mg, 1.76 mmol), 2-acetamidoacetic acid (260 mg, 2.22 mmol), NaI
(138 mg, 0.92 mmol) and Et.sub.3N (0.52 mL, 3.69 mmol) in DMF (5
mL) was stirred at 80.degree. C. for 16 h. The reaction mixture was
filtered and the filtrate was concentrated. The residue was
purified by silica gel flash column with PE/EA=5:1 to afford the
titled compound (500 mg, 78%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.39-7.31 (m, 5H),
6.01 (br. s., 1H), 5.13 (s, 2H), 5.10 (t, J=3.2 Hz, 1H), 4.25-4.18
(m, 3H), 4.03 (dd, J=4.8, 18.8 Hz, 1H), 2.44 (t, J=7.4 Hz, 2H),
2.04-1.97 (m, 5H), 1.50 (d, J=7.2 Hz, 3H).
Compound 86: 4-(2-(2-acetamidoacetoxy)propanoyloxy)butanoic
acid
##STR00332##
[0529] Pd/C (150 mg) was added to a stirred solution of benzyl
4-(2-(2-acetamidoacetoxy)propanoyloxy)butanoate (500 mg, 1.37 mmol)
in THF (10 mL), the reaction was stirred at 25.degree. C. for 16 h
under H.sub.2 atmosphere. After that, the reaction mixture was
filtered and the filtrate was concentrated. The residue was
purified by a silica gel flash column with PE/EA=1:50 to afford the
titled compound (280 mg, 74%) as a white solid. .sup.1H NMR was
performed at 400 MHz with d.sub.6-DMSO as solvent to characterize
the titled compound, results are as follows: .delta.=12.15 (s, 1H),
8.34 (t, J=5.6 Hz, 1H), 5.02 (q, J=6.8 Hz, 1H), 4.12-4.06 (m, 2H),
3.93 (dd, J=6.2, 17.8 Hz, 1H), 3.84 (dd, J=6.0, 17.6 Hz, 1H), 2.28
(t, J=7.2 Hz, 2H), 1.85 (s, 3H), 1.84-1.77 (m, 2H), 1.41 (d, J=7.2
Hz, 3H).
##STR00333##
Example 1-87
Intermediate Compound 87': benzyl
4-((1-chloroethoxy)carbonyloxy)butanoate
##STR00334##
[0531] 1-chloroethyl carbonochloridate (1.0 g, 7.2 mmol) was added
dropwise to a solution of benzyl 4-hydroxybutanoate (1.0 g, 5.2
mmol) and Et.sub.3N (1.1 mL, 1.7 mmol) in DCM (10 mL) over 5 min at
-5-0.degree. C. After that, the reaction was quenched by water (5
mL). The organic layer was separated, dried over Na.sub.2SO.sub.4
and filtered. The filtrate was concentrated and the residue was
purified by silica gel flash column with PE/EA=20:1-5:1 to afford
titled compound (680 mg, 44%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.39-7.33 (m, 5H),
6.41 (q, J=5.6 Hz, 1H), 5.13 (s, 2H), 4.26 (t, J=6.4 Hz, 2H), 2.49
(t, J=7.4 Hz, 2H), 2.09-2.02 (m, 2H), 1.82 (d, J=6.0 Hz, 3H).
Intermediate Compound 87'': benzyl
4-((1-acetoxyethoxy)carbonyloxy)butanoate
##STR00335##
[0533] A solution of benzyl
4-((1-chloroethoxy)carbonyloxy)butanoate (180 mg, 598 .mu.mol),
acetic acid (720 mg, 12.0 mmol) and Et.sub.3N (151 mg, 1.5 mmol) in
acetone (4 mL) was heated under reflux for 2 days. The reaction was
diluted with EA (20 mL) and washed with water (10 mL). The organic
layer was separated, dried over Na.sub.2SO.sub.4 and filtered. The
filtrate was concentrated and the residue was purified by a silica
gel flash column with PE/EA=10:1-3:1 to afford the titled compound
(120 mg, 64%) as a colorless oil. .sup.1H NMR was performed at 400
MHz with CDCl.sub.3 as solvent to characterize the titled compound,
results are as follows: .delta.=7.38-7.33 (m, 5H), 6.74 (q, J=3.6
Hz, 1H), 5.13 (s, 2H), 4.21 (t, J=6.2 Hz, 2H), 2.48 (t, J=4.8 Hz,
2H), 2.08 (s, 3H), 2.06-2.01 (m, 2H), 1.51 (d, J=3.6 Hz, 3H).
Compound 87: 4-((1-acetoxyethoxy)carbonyloxy)butanoic acid
##STR00336##
[0535] Pd/C (10 mg) was added to a mixture of benzyl
4-((1-acetoxyethoxy)carbonyloxy)butanoate (110 mg, 339 .mu.mol) in
EA (2 mL). The reaction was stirred under H.sub.2 atmosphere for 16
h at 25.degree. C. After that, the reaction mixture was filtered
and the filtrate was concentrated to afford the titled compound (70
mg, 88%) as a colorless oil. .sup.1H NMR was performed at 400 MHz
with CDCl.sub.3 as solvent to characterize the titled compound,
results are as follows: .delta.=6.75 (q, J=5.2 Hz, 1H), 4.23 (t,
J=6.2 Hz, 2H), 2.49 (t, J=7.2 Hz, 2H), 2.09 (s, 3H), 2.06-1.99 (m,
2H), 1.52 (d, J=5.2 Hz, 3H).
Example 1-88
Intermediate Compound 88': benzyl
4-(1-(isobutyryloxy)ethoxycarbonyloxy)butanoate
##STR00337##
[0537] A solution of benzyl
4-((1-chloroethoxy)carbonyloxy)butanoate (300 mg, 998 .mu.mol),
isobutyric acid (879 mg, 10.0 mmol), NaI (179 mg, 1.2 mmol) and
Et.sub.3N (121 mg, 1.2 mmol) in acetone (6 mL) was heated under
reflux for 2 days. After that, the reaction mixture was diluted
with EA (20 mL) and washed with saturated NaHCO.sub.3 (10 mL). The
organic layer was separated, dried over Na.sub.2SO.sub.4 and
filtered. The filtrate was concentrated and the residue was
purified by a silica gel column with PE/EA=50:1-5:1 to afford the
titled compound (300 mg, 85%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=7.42-7.29 (m, 5H),
6.74 (q, J=5.2 Hz, 1H), 5.12 (s, 2H), 4.21 (t, J=6.2 Hz, 2H),
2.58-2.51 (m, 1H), 2.48 (t, J=7.2 Hz, 2H), 2.06-2.00 (m, 2H), 1.51
(d, J=5.6 Hz, 3H), 1.17 (d, J=7.2 Hz, 6H).
Compound 88: 4-(1-(isobutyryloxy)ethoxycarbonyloxy)butanoic
acid
##STR00338##
[0539] Pd/C (28 mg) was added to a mixture of benzyl
4-(1-(isobutyryloxy)ethoxycarbonyloxy)butanoate (280 mg, 795 mol)
in EA (6 mL). The reaction was stirred under H.sub.2 atmosphere for
16 h at 25.degree. C. After that, the reaction mixture was filtered
and the filtrate was concentrated to afford the titled compound
(200 mg, 96%) as a colorless oil. .sup.1H NMR was performed at 400
MHz with CDCl.sub.3 as solvent to characterize the titled compound,
results are as follows: .delta.=6.74 (q, J=5.6 Hz, 1H), 4.23 (t,
J=6.0 Hz, 2H), 2.60-2.53 (m, 1H), 2.49 (t, J=7.2 Hz, 2H), 2.06-1.99
(m, 2H), 1.52 (d, J=5.2 Hz, 3H), 1.18 (d, J=6.8 Hz, 6H).
Example 1-89
Intermediate Compound 89':
1-((4-benzyloxy-4-oxobutoxy)carbonyloxy)ethyl benzoate
##STR00339##
[0541] A solution of benzyl
4-((1-chloroethoxy)carbonyloxy)butanoate (300 mg, 998 .mu.mol),
benzoic acid (244 mg, 2.0 mmol), NaI (179 mg, 1.2 mmol) and
Et.sub.3N (121 mg, 1.2 mmol) in acetone (6 mL) was heated under
reflux for 3 days. After that, the reaction was diluted with EA (20
mL) and washed with saturated NaHCO.sub.3 (10 mL). The organic
layer was separated, dried over Na.sub.2SO.sub.4 and filtered. The
filtrate was concentrated and the residue was purified by a silica
gel flash column with PE/EA=100:1-10:1 to afford the titled
compound (240 mg, 62%) as a colorless oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=8.05 (d, J=7.2 Hz,
2H), 7.58 (t, J=7.4 Hz, 1H), 7.44 (t, J=7.6 Hz, 2H), 7.39-7.28 (m,
5H), 7.02 (q, J=5.6 Hz, 1H), 5.11 (s, 2H), 4.32-4.12 (m, 2H), 2.48
(t, J=7.6 Hz, 2H), 2.07-1.97 (m, 2H), 1.65 (d, J=5.6 Hz, 3H).
Compound 89: 4-(1-(benzoyloxy)ethoxycarbonyloxy)butanoic acid
##STR00340##
[0543] Pd/C (20 mg) was added to a mixture of
1-((4-benzyloxy-4-oxobutoxy)carbonyloxy)ethyl benzoate (200 mg, 518
.mu.mol) in EA (4 mL). The reaction was stirred under H.sub.2
atmosphere for 16 h at 25.degree. C. After that, the reaction
mixture was filtered and the filtrate was concentrated to afford
the titled compound (120 mg, 78%) as a sticky oil. .sup.1H NMR was
performed at 400 MHz with CDCl.sub.3 as solvent to characterize the
titled compound, results are as follows: .delta.=8.06 (d, J=7.2 Hz,
2H), 7.59 (t, J=7.4 Hz, 1H), 7.45 (t, J=7.6 Hz, 2H), 7.03 (q, J=5.6
Hz, 1H), 4.24 (t, J=6.4 Hz, 2H), 2.49 (t, J=7.2 Hz, 2H), 2.06-1.99
(m, 2H), 1.66 (d, J=5.6 Hz, 3H).
Example 1-90
Intermediate Compound 90': benzyl
4-(3,10,10-trimethyl-5,8-dioxo-2,4,9-trioxa-7-azaundecan-1-oyloxy)butanoa-
te
##STR00341##
[0545] A solution of benzyl
4-((1-chloroethoxy)carbonyloxy)butanoate (450 mg, 1.5 mmol),
2-(tert-butoxycarbonylamino)acetic acid (524 mg, 3.0 mmol), NaI
(449 mg, 3.0 mmol) and Et.sub.3N (182 mg, 1.8 mmol) in acetone (10
mL) was heated under reflux for 3 days. The reaction mixture was
filtered and the filtrate was concentrated. The residue was
purified by a silica gel flash column with PE/EA=10:1-1:1 to afford
the titled compound (390 mg, 59%) as a colorless sticky oil.
.sup.1H NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=7.39-7.31 (m, 5H), 6.80 (q, J=5.6 Hz, 1H), 5.12 (s, 2H),
4.97 (br. s., 1H), 4.21 (t, J=6.2 Hz, 2H), 4.03-3.84 (m, 2H), 2.48
(t, J=7.4 Hz, 2H), 2.06-2.00 (m, 2H), 1.53 (d, J=5.2 Hz, 3H), 1.44
(s, 9H).
Intermediate Compound 90'':
2,2,9-trimethyl-4,7,11-trioxo-3,8,10,12-tetraoxa-5-azahexadecan-16-oic
acid
##STR00342##
[0547] Pd/C (38 mg) was added to a mixture of benzyl
4-(3,10,10-trimethyl-5,8-dioxo-2,4,9-trioxa-7-azaundecan-1-oyloxy)butanoa-
te (380 mg, 865 .mu.mol) in EA (8 mL). The reaction was stirred
under H.sub.2 atmosphere for 16 h at 25.degree. C. After that, the
reaction mixture was filtered and the filtrate was concentrated to
afford the titled compound (280 mg, 93%) as a sticky oil. .sup.1H
NMR was performed at 400 MHz with CDCl.sub.3 as solvent to
characterize the titled compound, results are as follows:
.delta.=6.82 (q, J=5.2 Hz, 1H), 5.03 (br. s., 1H), 4.34-4.15 (m,
2H), 3.96 (d, J=6.0 Hz, 2H), 2.49 (t, J=7.0 Hz, 2H), 2.13-1.96 (m,
2H), 1.54 (d, J=5.6 Hz, 3H), 1.45 (s, 9H).
Compound 90
4-(1-(2-aminoacetoxy)ethoxycarbonyloxy)butanoic acid
##STR00343##
[0549] A solution of
2,2,9-trimethyl-4,7,11-trioxo-3,8,10,12-tetraoxa-5-azahexadecan-16-oic
acid (280 mg, 802 .mu.mol) in HCl/EA (5 mL, .about.2 M) was stirred
for 16 h at 25.degree. C. The precipitate was formed and filtered.
The filtered cake was washed with EA (10 mL) and then dried in
vacuo to afford the titled compound (168 mg, 84%) as a white solid
in HCl salt form. .sup.1H NMR was performed at 400 MHz with
D.sub.2O as solvent to characterize the titled compound, results
are as follows: .delta.=6.81 (q, J=5.6 Hz, 1H), 4.22 (t, J=6.0 Hz,
2H), 3.94 (s, 2H), 2.44 (t, J=7.2 Hz, 2H), 1.98-1.92 (m, 2H), 1.52
(d, J=5.2 Hz, 3H).
Example 2: Metabolic stability assay of the test compounds
Rat/Human Liver S9 Fractions Metabolic Stability Assay
[0550] The protocol for rat/human liver S9 fractions metabolic
stability assay is employed to determine the half-life (T.sub.1/2)
of the compounds of the present disclosure and their releasing
efficiency of converting from the prodrugs to GHB in vitro.
[0551] The following is the study outline for S9 assay: 1) For GHB
releasing efficiency assay, pooled liver S9 fractions (human or
rat) in mixed gender were obtained from commercial vendors (e.g.,
Xenotech) and stored at -80.degree. C. prior to use. 2) A master
solution in the incubation plate containing phosphate buffer,
ultra-pure H.sub.2O, MgCl.sub.2 solution and liver S9 fraction was
made to keep S9 fractions at 1 mg/mL final concentration. The
mixture was pre-warmed at 37.degree. C. water bath for 5 minutes.
3) Add 4 .mu.L of 500 .mu.M test compound solution to the master
solution plate at the final concentration of 5 M test compound. The
reaction was started with the addition of 40 .mu.L of 10 mM NADPH
and carried out at 37.degree. C. 4) 50 .mu.L aliquots of the
reaction solution were taken out and put into new plates at
different time points including 0, 15, 30, 45 and 60 minutes, and
incubated at 37.degree. C. water bath with shaking at 60 rpm. The
reaction was stopped by adding 200 .mu.L of cold quench solution
(methanol containing internal standards) at the appointed time
points. The plates were centrifuged at 3220 g at 4.degree. C. for
40 minutes to precipitate protein. 5) 100 .mu.L of the supernatant
was transferred to a new plate. The supernatant was diluted with
water according to the LC/MS signal response and peak shape, mixed
well and analyzed using LC/MS/MS for measurement of test compounds
and GHB. The measurement results were then used for calculation of
half-life (T.sub.1/2) of the test compounds and their conversion
efficiency into GHB in S9 fractions. GHB releasing efficiency is
calculated by dividing the detected amount of GHB by the total
amount of GHB that can be released by the test compound. Data are
shown as below in Table 1.
TABLE-US-00002 TABLE 1 Metabolic Stability of Test Compounds in
Human and Rat Liver S9 Fractions GHB releasing efficiency T.sub.1/2
(%) at 60 Test Compounds Species (min) min point Compound 32 Human
40.43 47 4-(phenoxycarbonyloxy)butanoic acid Rat 8.50 74
hydrochloride salt of Compound 57 Human 2.15 61
(S)-4-(2-amino-3-phenylpropanoyloxy) Rat 2.48 69 butanoic acid
hydrochloride Compound 66 Human 9.21 78
4-(2-acetamidoacetoxy)butanoic acid Rat 8.00 71 Compound 67 Human
83.17 35 (S)-4-(2-acetamido-3-methylbutanoyloxy) Rat 74.22 32
butanoic acid Compound 64 Human 58.01 42
4-(2-isobutyramidoacetoxy)butanoic acid Rat 62.66 30 Compound 89
Human 10.54 42 4-(1-(benzoyloxy)ethoxycarbonyloxy) Rat 17.48 51
butanoic acid
[0552] The in vitro GHB releasing efficiency assay employing
rat/human liver S9 fractions had shown that the prodrug compounds
could be converted to GHB with variable releasing efficiencies,
which suggested that they would be converted into GHB in the
systemic circulation after being administered to rat/human.
[0553] Rat/Human Hepatocytes Metabolic Stability Assay
[0554] The protocol for rat/human hepatocytes metabolic stability
assay is employed to determine the half-life (T.sub.1/2) of the
compounds of the present disclosure and their releasing efficiency
of converting from the prodrugs to GHB in vitro.
[0555] The following is the study outline for hepatocytes assay: 1)
For GHB releasing efficiency assay, rat hepatocytes in male gender
and human hepatocytes in mixed gender were obtained from commercial
vendors (e.g., BioreclamationlVT) and stored at -150.degree. C.
prior to use. 2) 30 mM stock solutions of test compounds were
prepared in DMSO. Thawing medium and supplement incubation medium
(serum-free) were placed in a 37.degree. C. water bath for at least
15 minutes prior to use. Stock solutions were diluted to 500 M by
combining 295 L acetonitrile and 5 .mu.L of 30 mM stock solution.
3) Vials of cryopreserved hepatocytes were removed from storage,
ensured that vials remain at cryogenic temperatures. The pressure
was removed by loosening and re-tightening the cap. The vials were
thawed in a 37.degree. C. water bath with gently shaking. Vials
were kept in water bath until all ice crystals had dissolved and
were no longer visible. Vials were sprayed with 70% ethanol before
being transferred to a biosafety cabinet. And then the contents
were poured into the 50 mL thawing medium conical tube. Vials were
centrifuged at 100 g for 10 minutes at room temperature. Thawing
medium was aspirated and hepatocytes were resuspended with
serum-free incubation medium to yield .about.1.5.times.10.sup.6
cells/mL. 4) Cell viability and density were counted using a Trypan
Blue exclusion, and then cells were diluted with serum-free
incubation medium to a working cell density of 1.times.10.sup.6
viable cells/ml. 5) A portion of the hepatocytes at
1.times.10.sup.6 viable cells/mL was boiled for 10 min prior to
adding to the plate as negative control to eliminate the enzymatic
activity so that little or no substrate turnover should be
observed. The inactivated hepatocytes were used to prepare negative
samples, which were used to exclude the misleading factor that
resulted from instability of chemical itself. 6) Aliquots of 247.5
.mu.L hepatocytes were dispensed into each well of a 96-well
non-coated plate. The plate was placed in the incubator on an
orbital shaker at 500 rpm for approximately 10 minutes. 7) Aliquots
of 2.5 .mu.L of the 500 M test compounds were added into respective
wells of the non-coated 96-well plate to start the reaction. This
assay was performed in duplicate. The plate was incubated in the
incubator on an orbital shaker at 500 rpm for the designed time
points. 8) 25 .mu.L of contents were transferred and mixed with 6
volumes (150 L) of cold acetonitrile with internal standard to
terminate the reaction at time points of 0, 5, 15, 30, 60, 90 and
120 minutes. Samples were centrifuges for 25 minutes at 3220 g and
aliquots of 100 L of the supernatants were used for LC-MS/MS
analysis for measurement of test compounds and GHB. The measurement
results were then used for calculation of half-life (T.sub.1/2) of
the test compounds and their conversion efficiency into GHB in
hepatocytes. Data are shown as below in Table 2.
TABLE-US-00003 TABLE 2 Metabolic Stability of Test Compounds in
Human and Rat Hepatocytes GHB releasing efficiency T.sub.1/2 (%) at
120 Test Compounds Species (min) min point Compound 58 Human 159.97
73 (S)-4-(2-amino-3-methylbutanoyloxy) Rat 46.66 46 butanoic acid
Compound 66 Human 24.95 46 4-(2-acetamidoacetoxy)butanoic acid Rat
16.68 35 Compound 67 Human 219.89 22
(S)-4-(2-acetamido-3-methylbutanoyloxy) Rat 130.66 21 butanoic
acid
[0556] The in vitro GHB releasing efficiency assay employing
rat/human hepatocytes had shown that prodrug compounds could be
converted to GHB with variable releasing efficiencies, which
suggested that they would be converted into GHB in the systemic
circulation after being administered to rat/human.
Rat/Human Whole Blood Metabolic Stability Assay
[0557] The protocol for rat/human whole blood metabolic stability
assay is employed to determine the releasing efficiency of the
compounds of the present disclosure converting from the prodrugs to
GHB in vitro.
[0558] The following is the study outline for whole blood assay: 1)
For GHB releasing efficiency assay, rat whole blood in mixed gender
was obtained from commercial vendors (e.g., SiBeiFu (Beijing)
Laboratory Animal Science and Technology Co Ltd) and human whole
blood was obtained from healthy volunteers in mixed gender, stored
at 4.degree. C. prior to use. 2) The stock solution of test
compounds was prepared in DMSO and diluted at the final
concentration of 500 .mu.M. 3) 5 .mu.L of 500 .mu.M working
solution was spiked to 495 .mu.L whole blood to reach a final
concentration of 5 .mu.M. The final concentration of organic
solvents was 1%. The assay was performed in duplicate. The reaction
samples were incubated at 37.degree. C. at approximately 60 rpm in
a water bath. 4) Aliquots of 50 .mu.L were taken from the reaction
samples at 0, 15, 30, 45, 60 and 120 minutes. The reaction was
stopped by the addition of 7 volumes of cold methanol containing
internal standards. 5) All samples were vortexed for 10 minutes,
followed by centrifugation at 3220 g for 30 minutes to precipitate
proteins. 100 .mu.L of the supernatant was transferred to a new
plate. The supernatant was diluted with ultra pure water according
to the LC-MS signal response and peak shape. Samples were analyzed
using LC/MS/MS for measurement of test compounds and GHB. The
measurement results were then used for calculation of conversion
efficiency the test compounds into GHB in whole blood. Data are
shown as below in Table 3.
TABLE-US-00004 TABLE 3 Metabolic Stability of Test Compounds in
Human and Rat Whole Blood GHB releasing efficiency (%) at 120 Test
Compounds Species min point Compound 58 Human 42
(S)-4-(2-amino-3-methylbutanoyloxy) Rat 85 butanoic acid Compound
66 Human 76 4-(2-acetamidoacetoxy)butanoic acid Rat 100 Compound 67
Human 45 (S)-4-(2-acetamido-3-methylbutanoyloxy) Rat 83 butanoic
acid
[0559] The in vitro GHB releasing efficiency assay employing
rat/human whole blood had shown that prodrug compounds could be
converted to GHB with variable releasing efficiencies, which
suggested that they would be converted into GHB in the systemic
circulation after being administered to rat/human.
Example 3: Pharmacokinetic Studies
[0560] For rat pharmacokinetic studies, male Sprague-Dawley rats
were housed individually and fasted overnight before use. The
animal dosing experiments were carried out in accordance to the
National Institutes of Health Guide to the Care and Use of
Laboratory Animals and the Animal Welfare Act. For GHB sodium salt,
a single dose of 50 mg/kg was administered to each rat in two
groups (n=3/group) via intravenous (IV) and oral (PO)
administration, respectively. The vehicle used for GHB sodium salt
is saline. For other test compounds, a single dose of each test
compound was administered to each rat orally (n=3/group). The
dosage of each test compound is listed in the Table 4. The vehicle
used for dosing test compounds was 0.5% (w/v) Sodium Carboxyl
Methyl Cellulose (CMC-Na) in saline. Blood samples were collected
at specified time-points (pre-dose, 10 minutes, 0.5 hour, 1 hour, 2
hours, 4 hours, 6 hours) following administration to individual
rats within IV and PO group. Blood samples were clotted on ice
immediately, plasma samples were then isolated by centrifugation
and stored frozen (-80.degree. C.) until further analysis. The
concentrations of GHB and all other test compounds were
individually determined by LC/MS/MS assay. Various pharmacokinetic
parameters were calculated using Phoenix.TM. WinNonlin.RTM.
software. To quantify the bioconversion efficiency of the test
compounds in the circulation system, the relative bioavailability
of GHB sodium salt after PO administration was calculated. The
values of relative bioavailability were expressed as the ratio of
the AUC of GHB converted from the test compounds versus the AUC of
GHB sodium salt administrated via IV alone adjusted by dose. Data
are shown as below in Table 4.
TABLE-US-00005 TABLE 4 Rat pharmacokinetic parameters of GHB sodium
salt and representative compounds AUC.sub.last T.sub.max C.sub.max
Bioavailability (h*.mu.g/mL) (min) (.mu.g/mL) F (%) GHB sodium salt
IV 25.9 100 @50 mg/kg PO 6.7 17 7.6 26 Compound 32
4-(phenoxycarbonyloxy)butanoic acid PO* 12.4 10 22.4 48** @ 89
mg/kg Compound 58 PO* 14.3 17 18.5 55**
(S)-4-(2-amino-3-methylbutanoyloxy)butanoic acid @ 81 mg/kg
Compound 67 PO* 7.4 10 11.1 29**
(S)-4-(2-acetamido-3-methylbutanoyloxy)butanoic acid @ 97 mg/kg
Compound 64 PO* 11.8 30 8.6 45** 4-(2-isobutyramidoacetoxy)butanoic
acid @ 92 mg/kg Note: *measured and calculated based on GHB,
**relative bioavailability
[0561] For dog pharmacokinetic studies, male Beagle dogs were
housed individually. Dogs in oral administration groups were fasted
overnight before use but with free access to water supply. Dogs in
IV groups have free access to food and water. The animal dosing
experiments were carried out in accordance with the National
Institutes of Health Guide to the Care and Use of Laboratory
Animals and the Animal Welfare Act. For GHB sodium salt, a single
dose of 20 mg/kg was administered to each dog in two groups
(n=3/group) via intravenous (IV) administration. The vehicle used
for GHB sodium salt is saline. For other test compounds, a single
dose of each test compound was administered to each dog orally
(n=3/group). The dosage of each test compound is listed in the
Table 5. The vehicle used for dosing test compounds was 0.5% (w/v)
Sodium Carboxyl Methyl Cellulose (CMC-Na) in saline. Blood samples
were collected at specified time-points (pre-dose, 5 min, 10 min,
20 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, post-dose) following
administration to individual dogs within IV and PO group. Blood
samples were clotted on ice immediately, plasma samples were then
isolated by centrifugation and stored frozen (-80.degree. C.) until
further analysis. The concentrations of GHB and all other test
compounds were individually determined by LC/MS/MS assay. Various
pharmacokinetic parameters were calculated using Phoenix.TM.
WinNonlin.RTM. software. To quantify the bioconversion efficiency
of the test compounds in the circulation system, the
bioavailability of GHB sodium salt after PO administration was
calculated. Data are shown as below in Table 5.
TABLE-US-00006 TABLE 5 Dog pharmacokinetic parameters of GHB sodium
salt and representative compound AUC.sub.last T.sub.max C.sub.max
Bioavailability (h*.mu.g/mL) (min) (.mu.g/mL) F (%) GHB sodium salt
@ 20 mg/kg IV 35.652 100 Compound 58 PO* 17.866 13 32.4 51**
(S)-4-(2-amino-3-methylbutanoyloxy)butanoic acid @32 mg/kg Note:
*measured and calculated based on GHB, **relative
bioavailability
Example 4: Colonic Absorption in Rat
[0562] The purpose of the colonic absorption trial is to evaluate
the effect of the improved transport properties of prodrugs on the
resulting pharmacokinetics and distribution of GHB. The study is to
be conducted by the following general procedures: GHB and the
compounds of the present invention are each administered to groups
of three to seven male rats through a bolus injection directly into
the colon via the indwelling cannula. Following dosing, blood
samples are obtained at intervals over 24 hours and are immediately
processed to obtain the plasma at 4.degree. C. The concentrations
of GHB and all other test compounds are individually determined by
HPLC-MS/MS assay. The compounds of the present disclosure
demonstrate more effective colonic absorption than GHB.
[0563] While the present disclosure has been particularly shown and
described with reference to specific embodiments (some of which are
preferred embodiments), it should be understood by those skilled in
the art that various changes in form and detail may be made therein
without departing from the spirit and scope of the present
disclosure as disclosed herein.
* * * * *