U.S. patent application number 09/969681 was filed with the patent office on 2002-04-04 for substituted oxygen alicyclic compounds, including methods for synthesis thereof.
Invention is credited to Adhikari, Susanta Sekhar, Chorghade, Mukund Shankar, Gurjar, Mukund Keshao, Islam, Aminul, Krishna, Levadala Murali, Krishna, Palakodety Radha, Lalitha, Sista Venkata Sai, Lanka, Hymavathi, Mhaskar, Sunil Vyankatesh, Murugaiah, Andappan Murugaiah Subbaiah, Prasad, Chittineni Hari, Prasad, Tangallapally Rajendra, Rao, Alla Venkata Rama, Rao, Batchu Venkateswara, Reddy, Bethi Sridhar, Reddy, Vavilala Goverdhan, Sadalapure, Kashinath, Sharma, Gangavaram Vasantha Madhava, Sreenivas, Punna.
Application Number | 20020040154 09/969681 |
Document ID | / |
Family ID | 22229180 |
Filed Date | 2002-04-04 |
United States Patent
Application |
20020040154 |
Kind Code |
A1 |
Chorghade, Mukund Shankar ;
et al. |
April 4, 2002 |
Substituted oxygen alicyclic compounds, including methods for
synthesis thereof
Abstract
The invention provides new methods for preparation of cyclic
oxygen compounds, including 2,5-disubstituted tetrahydrofurans,
2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and
2,8-oxocanes. The invention also provides new cyclic oxygen
compounds and pharmaceutical compositions and therapeutic methods
that comprise such compounds.
Inventors: |
Chorghade, Mukund Shankar;
(Natick, MA) ; Gurjar, Mukund Keshao; (Pune,
IN) ; Krishna, Palakodety Radha; (Hyderabad, IN)
; Lalitha, Sista Venkata Sai; (Sunnyvale, CA) ;
Sadalapure, Kashinath; (Dt. Gulbarga, IN) ; Adhikari,
Susanta Sekhar; (West Bengal, IN) ; Murugaiah,
Andappan Murugaiah Subbaiah; (Tamilnadu, IN) ; Rao,
Batchu Venkateswara; (Nellore, IN) ; Krishna,
Levadala Murali; (Hyderbad, IN) ; Mhaskar, Sunil
Vyankatesh; (Natick, MA) ; Sharma, Gangavaram
Vasantha Madhava; (Hyderabad, IN) ; Prasad,
Tangallapally Rajendra; (Warangal, IN) ; Sreenivas,
Punna; (Nalgonda, IN) ; Reddy, Vavilala
Goverdhan; (Mahabubnagar, IN) ; Islam, Aminul;
(Hyderabad, IN) ; Rao, Alla Venkata Rama;
(Hyderabad, IN) ; Lanka, Hymavathi; (Hyderabad,
IN) ; Reddy, Bethi Sridhar; (Hyderabad, IN) ;
Prasad, Chittineni Hari; (Hyderabad, IN) |
Correspondence
Address: |
DIKE, BRONSTEIN, ROBERTS AND CUSHMAN,
INTELLECTUAL PROPERTY PRACTICE GROUP
EDWARDS & ANGELL, LLP.
P.O. BOX 9169
BOSTON
MA
02209
US
|
Family ID: |
22229180 |
Appl. No.: |
09/969681 |
Filed: |
October 2, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09969681 |
Oct 2, 2001 |
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09347113 |
Jul 2, 1999 |
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6306895 |
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60091694 |
Jul 3, 1998 |
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Current U.S.
Class: |
549/475 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 307/33 20130101; A61P 9/00 20180101; C07D 313/04 20130101;
C07D 307/12 20130101; C07D 309/06 20130101; A61P 37/08 20180101;
A61P 37/02 20180101 |
Class at
Publication: |
549/475 |
International
Class: |
C07D 307/02 |
Claims
What is claimed is:
1. A method for preparing a hydroxy-substituted tetrahydrofuran,
comprising: a) reacting an arylhydroxy compound and an epoxy
compound to form an epoxy-aryl ether; b) reacting the epoxy-aryl
ether with an active methylene compound to form a lactone; and c)
reducing the lactone to provide a hydroxy-substituted
tetrahydrofuran.
2. The method of claim 1 wherein the arylhydroxy compound is a
hydroxy-substituted carbocyclic aryl compound.
3. The method of claim 1 wherein the arylhydroxy compound is a
hydroxy-substituted heteroaryl compound.
4. The method of claim 1 wherein the epoxy compound is a glycidyl
compound substituted with an electron-withdrawing group.
5. The method of claim 1 wherein the epoxy compound is an
epihalohydrin or a glycidyl sulfonyl ester compound.
6. The method of claim 1 wherein the epoxy compound is optically
active.
7. The method of claim 1 wherein the epoxy compound is racemic.
8. The method of claim 1 or 7 wherein the arylhydroxy compound and
the epoxide are reacted in the presence of an optically active
compound.
9. The method of claim 1 wherein the epoxide is racemic and the
arylhydroxide and epoxide are reacted in the presence of an
optically active compound to form an optically active epoxy-aryl
ether.
10. The method of claim 1 wherein the active methylene compound is
a diester or a half-ester thereof.
11. The method of claim 1 wherein the active methylene compound is
a dialkyl malonate.
12. The method of claim 1 further comprising activating the hydroxy
group of the hydroxy-substituted tetrahydrofuran and substituting
the activated tetrahydrofuran position.
13. The method of claim 12 wherein the tetrahydrofuran position is
substituted with a nucleophilic compound.
14. The method of claim 12 wherein the tetrahydrofuran position is
substituted with a 1-alkynyl compound.
15. The method of any one of claims 12-14 wherein the substitution
produces an enantiomeric excess of a stereoisomer.
16. The method of claim 15 wherein the substitution produces a
steroisomer that is present in at least about 60 percent relative
to the other steroisomer.
17. The method of claim 15 wherein the substitution produces a
steroisomer that is present in at least about 70 percent relative
to the other steroisomer.
18. The method of claim 15 wherein the substitution produces a
trans steroisomer that is present in at least about 60 percent
relative to the cis steroisomer.
19. The method of claim 15 wherein the substitution produces a
trans steroisomer that is present in at least 70 percent relative
to the cis steroisomer.
20. The method of claim 15 wherein the substitution produces a cis
steroisomer that is present in at least about 60 percent relative
to the trans steroisomer.
21. The method of claim 15 wherein the substitution produces a cis
steroisomer that is present in at least about 70 percent relative
to the trans steroisomer.
22. The method of claim of claim 1 wherein the hydroxy-substituted
tetrahydrofuran is represented by the following formula: 33 wherein
Ar is optionally substituted carbocyclic aryl or optionally
substituted heteroaryl.
23. The method of claim 22 wherein Ar is optionally substituted
carbocyclic aryl.
24. The method of claim 22 wherein Ar is optionally substituted
phenyl.
25. A method for preparing a substituted .gamma.-butyrolactone,
comprising: a) reacting mannitol with an alkanoyl compound to form
a trialkylene mannitol; b) hydrolyzing the trialkylene mannitol to
provide a 2,5-O-alkylene-mannitol; and c) functionalizing secondary
hydroxy groups of the 2,5-O-alkylene-mannitol to provide a fused
ring cyclic ether comprising a first cyclic ether fused to a second
cyclic ether; d) reacting the fused ring cyclic ether with an
optionally substituted arylhydroxy or arylakyhdroxy compound to
form a bis-arylether or bis-arylakylether and e) cleaving the
bis-arylether or bis-arylalkylether to form a substituted
.gamma.-butyrolactone.
26. The method of claim 25 wherein primary hydroxy-substituted
carbons of the fused ring cyclic ether are activated prior to
reaction with an optionally substituted arylhydroxy or
arylalkylhydroxy compound.
27. The method of claim 25 or 26 wherein the fused ring cyclic
ether is reacted with an optionally substituted phenol.
28. The method of claim 25 or 26 wherein the fused ring cyclic
ether is cleaved to an acyclic ether prior to forming the
substituted .gamma.-butyrolactone.
29. The method of claim 25 or 26 wherein an acyclic ether of the
following formula is cleaved to form the substituted
.gamma.-butyrolactone: 34wherein each Ar is a carbocyclic aryl or
optionally substituted heteroaryl group; each W is a chemical bond
or an optionally substituted alkylene linkage; and each X is an
.alpha.,.beta.-unsaturated electron-withdrawing group.
30. The method of claim 25 wherein in step e) a compound of the
following formula is formed: 35wherein Ar is optionally substituted
carbocyclic aryl or optionally substituted heteroaryl.
31. The method of claim 30 wherein an enantiomeric excess of a
stereoisomer of the .gamma.-butyrolactone moiety is formed.
32. The method of claim 25 wherein cleavage of the bis-arylether or
bis-arylalkylether produces two molar equivalents of the
substituted .gamma.-butyrolactone.
33. A method for preparing an alkynyl-substituted tetrahydrofuran,
tetrahydropyran or oxepane, comprising: treating with base a
compound comprising a substituted alkyl group to form an
alkynyl-substituted tetrahydrofuran, alkynyl-substituted
tetrahydropyran or alkynyl-substituted oxepane, wherein the
substituted alkyl group has 6, 7, 8 or more carbon atoms, the
2,3-positions of alkyl group forming an epoxide ring, the
1-position of the alkyl group substituted with a first leaving
group, and the 6-, 7- or 8-position of the alkyl group substituted
with a second leaving group.
34. The method of claim 33 wherein the substituted alkyl compound
is treated with a molar excess of base.
35. The method of claim 33 wherein the substituted alkyl compound
is treated with about a three molar excess of base.
36. The method of claim 33 wherein the base is an alkyllithium
reagent, an amide salt or a hydride.
37. The method of claim 33 wherein the first and second leaving
groups are each independently a halogen, a sulfonic alkyl ester, a
sulfonic aryl ester or a sulfonic arylalkyl ester.
38. The method of claim 33 wherein one or both of the epoxide
carbons are optically active.
39. The method of claim 33 wherein the formed tetrahydrofuran,
tetrahydropyran or oxepane is optically active.
40. The method of claim 33 wherein both of the epoxide carbons are
optically active.
41. The method of claim 40 wherein the two carbons adjacent to the
ring oxygen of the formed tetrahydrofuran, tetrahydropyran or
oxepane are each optically active.
42. The method of claim 33 wherein the tetrahydrofuran,
tetrahydropyran or oxepane is formed from the substituted alkyl
compound without isolation of intermediate compounds.
43. The method of claim 42 wherein the tetrahydrofuran,
tetrahydropyran or oxepane is formed from the substituted alkyl
compound in a single reaction step.
44. The method of claim 33 wherein the substituted alkyl compound
is substituted at the 7, 8 or 9 carbons by an alkoxy, arylalkoxy or
aryloxy group.
45. The method of claim 33 where the alkyl-substituted compound is
substituted at the 6-position with the second leaving group, and
treatment with base provides an alkynyl-substituted
tetrahydrofuran.
46. The method of claim 33 wherein the a tetrahydrofuran of the
following formula is provided: 36wherein Ar is optionally
substituted carbocyclic aryl or optionally substituted
heteroaryl.
47. The method of claim 33 wherein the alkyl-substituted compound
is substituted at the 6-position with the second leaving group, and
treatment with base provides an alkynyl-substituted
tetrahydropyran.
48. The method of claim 47 where the tetrahydropyran is represented
by the following formula: 37wherein Ar is optionally substituted
carbocyclic aryl or optionally substituted heteroaryl; Z is a
chemical bond, optionally substituted alkylene, optionally
substituted alkenylene, optionally substituted alkynylene,
optionally substituted heteroalkylene, optionally substituted
heteroalkenylene, optionally substituted heteroalkynylene, or a
hetero atom; each R.sup.1 is independently hydrogen or a
non-hydrogen substituent; q is an integer of from 0 to 9.
49. The method of claim 33 where the alkyl-substituted compound is
substituted at the 7-position with the second leaving group, and
treatment with base provides an alkynyl-substituted oxepane.
50. The method of claim 49 where the oxepane is represented by the
following formula: 38wherein Ar is optionally substituted
carbocyclic aryl or optionally substituted heteroaryl; Z is a
chemical bond, optionally substituted alkylene, optionally
substituted alkenylene, optionally substituted alkynylene,
optionally substituted heteroalkylene, optionally substituted
heteroalkenylene, optionally substituted heteroalkynylene, or a
hetero atom; each R.sup.1 is independently hydrogen or a
non-hydrogen substituent; r is an integer of from 0 to 11.
51. The method of claim 33 where the alkyl-substituted compound is
substituted at the 8-position with the second leaving group, and
treatment with base provides an alkynyl-substituted oxocane.
52. The method of claim 51 where the oxocane is represented by the
following formula: 39wherein Ar is optionally substituted
carbocyclic aryl or optionally heteroaryl; Z is a chemical bond,
optionally substituted alkylene, optionally substituted alkenylene,
optionally substituted alkynylene, optionally substituted
heteroalkylene, optionally substituted heteroalkenylene, optionally
substituted heteroalkynylene, or a hetero atom; each R.sup.1 is
independently hydrogen or a non-hydrogen substituent; s is an
integer of from 0 to 9.
53. A method of preparing an oxygen alicyclic compound, comprising:
subjecting a keto-substituted dioxolane compound to at least one
Wittig-type reaction; forming an epoxide moiety from a
carbon-carbon double bond produced by the Wittig-type reaction;
ring-opening the dioxolane group to form an acyclic compound and
cyclizing the acyclic compound to provide an alicyclic compound
having an oxygen ring member.
54. The method of claim 53 wherein the alicyclic compound is a
tetrahydrofuran, tetrahydropyran or oxepane.
55. The method of claim 53 wherein the epoxide undergoes an
elimination reaction to form a propargyl alcohol substituent of the
dioxalone group.
56. A method for preparing an alkynyl-substituted oxygen alicyclic
compound, comprising: reacting a compound having a terminal alkynyl
moiety with an unsaturated anhydride compound to form a keto
alkynyl compound having a terminal alkene group; epoxidizing the
alkene group of the compound and then cyclizing the compound to
provide a alkynyl-substituted alicyclic compound having an oxygen
ring member.
57. The method of claim 56 wherein the alicyclic compound is a
tetrahydrofuran, tetrahydropyran or oxepane.
58. The method of claim 56 wherein the compound is cyclized in the
presences of borane methyl sulfide.
59. A compound of the following Formula I: 40wherein Ar is
optionally substituted aryl or optionally substituted heteroaryl;
each R.sup.1, X and Y is independently hydrogen or a non-hydrogen
substituent such as halogen, hydroxyl, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted alkoxy, optionally substituted
alkylthio, optionally substituted alkylsulfinyl, optionally
substituted alkylsulfonyl, optionally substituted aminoalkyl,
optionally substituted alkanoyl, optionally substituted carbocyclic
aryl having at least about 6 ring carbons, or substituted or
unsubstituted aralkyl having at least about 6 ring carbons; Z is a
chemical bond, optionally substituted alkylene, optionally
substituted alkenylene, optionally substituted alkynylene,
optionally substituted heteroalkylene, optionally substituted
heteroalkenylene, optionally substituted heteroalkynylene, or a
hetero atom; n is an integer from 1 to 11; p is an integer from 0
to 4; and pharmaceutically acceptable salts thereof.
60. A compound of the following Formula III: 41wherein Ar is
optionally substituted carbocyclic aryl or optionally substituted
heteroaryl; Z is a chemical bond, optionally substituted alkylene,
optionally substituted alkenylene, optionally substituted
alkynylene, optionally substituted heteroalkylene, optionally
substituted heteroalkenylene, optionally substituted
heteroalkynylene, or a hetero atom; each R.sup.1 is independently
hydrogen or a non-hydrogen substituent; q is an integer of from 0
to 9; and pharmaceutically salts thereof.
61. A compound of the following Formula IV: 42wherein Ar is
optionally substituted carbocyclic aryl or optionally substituted
heteroaryl; Z is a chemical bond, optionally substituted alkylene,
optionally substituted alkenylene, optionally substituted
alkynylene, optionally substituted heteroalkylene, optionally
substituted heteroalkenylene, optionally substituted
heteroalkynylene, or a hetero atom; each R.sup.1 is independently
hydrogen or a non-hydrogen substituent; r is an integer of from 0
to 11; and pharmaceutically acceptable salts thereof.
62. A compound of the following Formula V: 43 wherein Ar is
optionally substituted carbocyclic aryl or optionally substituted
heteroaryl; Z is a chemical bond, optionally substituted alkylene,
optionally substituted alkenylene, optionally substituted
alkynylene, optionally substituted heteroalkylene, optionally
substituted heteroalkenylene, optionally substituted
heteroalkynylene, or a hetero atom; each R.sup.1 is independently
hydrogen or a non-hydrogen substituent; s is an integer of from 0
to 9; and pharmaceutically salts thereof.
63. A compound of any one claims 59-62 wherein at least one R.sup.1
group is hydroxy or alkoxy and p is greater than 0.
64. A compound of any one claims 59-62 wherein at least two R.sup.1
groups is hydroxy or alkoxy and p is greater than 1.
65. A compound of any one claims 59-62 wherein two R.sup.1 are
present as hydroxy groups on adjacent ring positions.
66. A compound of any one claims 59-62 wherein two R.sup.1 are
present as alkoxy groups on adjacent ring positions.
67. A pharmaceutical composition comprising a compound of any one
of claims 59-66 and a pharmaceutically acceptable carrier.
68. A method of treating a disorder or disease associated with
5-lipoxygenase, comprising administering to a subject suffering
from or susceptible to such a disease or disorder an effective
amount of a compound or composition of any one of claims 59-67.
69. A method of treating a immune, allergic or cardiovascular
disorder or disease, comprising administering to a subject
suffering from or susceptible to such a disease or disorder an
effective amount of a compound or composition of any one of claims
59-67.
Description
[0001] The present application claims the benefit of U.S.
provisional application No. 60/091,694, filed Jul. 3, 1998, which
is incorporated herein by reference in its entirety.
BACKGROUND
[0002] 1. Field of the Invention
[0003] The present invention provides new methods for preparation
of various oxygen ring compounds (oxygen as an alicyclic ring
member) including 2,5-disubstituted tetrahydrofurans,
2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and
2,8-oxocanes. The invention further provides novel compounds and
pharmaceutical compositions and therapeutic methods that comprise
such compounds.
[0004] 2. Background
[0005] Leukotrienes are recognized potent local mediators, playing
a significant role in inflammatory and allegeric responses,
including arthritis, asthma, psoriasis and thrombotic disease.
Leukotrienes are produced by the oxidation of arachidonic acid by
lipoxygenase. More particularly, arachidonic acid is oxidized by
5-lipooxygenase to the hydroperoxide 5-hydroperoxy-eicosatetraenoic
acid (5-HPETE), that is converted to leukotriene A.sub.4, that in
turn can be converted to leukotriene B.sub.4, C.sub.4, or D.sub.4.
The slow-reacting substance of anaphylaxis is now known to be a
mixture of leukotrienes C.sub.4, D.sub.4 and E.sub.4, all of which
are potent bronchoconstrictors.
[0006] Efforts have been made to identify receptor antagonists or
inhibitors of leukotriene biosynthesis, to prevent or minimize
pathogenic inflammatory responses mediated by leukotrienes.
[0007] For example, European Patent Application Nos. 901171171.0
and 901170171.0 report indole, benzofuran, and benzothiophene
lipoxygenase inhibiting compounds.
[0008] Various 2,5-disubstituted tetrahydrofurans have exhibited
significant biological activity, including as lipoxygenase
inhibitors. See U.S. Pat. Nos. 5,703,093; 5,681,966; 5,648,486;
5,434,151; and 5,358,938.
[0009] While such compounds are highly useful therapeutic agents,
current methods for synthesis of least some of the compounds
require lengthy routes, and reagents and protocols that are less
preferred in larger scale operations, such as to produce kilogram
quantities.
[0010] It thus would be desirable to have improved methods to
substituted tetrahydrofurans and other cyclic oxygen compounds,
particularly new syntheses that facilitate larger scale production
of such compounds.
SUMMARY OF THE INVENTION
[0011] We have now found new methods for preparation of cyclic
oxygen compounds, including 2,5-disubstituted tetrahydrofurans,
2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and
2,8-oxocanes. These methods utilize reagents and synthetic
protocols that facilitate large scale manufacture, and provide
increased yields relative to prior approaches.
[0012] The methods of the invention are suitable for preparation of
a variety of cyclic oxygen-containing compounds (i.e., alicyclic
compounds having an oxygen ring member), including compounds of the
following Formula I: 1
[0013] wherein Ar is optionally substituted carbocyclic aryl or
optionally substituted heteroaryl;
[0014] each R.sup.1, X and Y is independently hydrogen or a
non-hydrogen substituent such as halogen, hydroxyl, optionally
substituted alkyl preferably having from 1 to about 20 carbon
atoms, optionally substituted alkenyl preferably having from 2 to
about 20 carbon atoms, optionally substituted alkynyl preferably
having from 2 to about 20 carbon atoms, optionally substituted
alkoxy preferably having from 1 to about 20 carbon atoms,
optionally substituted alkylthio preferably having from 1 to about
20 carbon atoms, optionally substituted alkylsulfinyl preferably
having from 1 to about 20 carbon atoms, optionally substituted
alkylsulfonyl preferably having from 1 to about 20 carbon atoms,
optionally substituted aminoalkyl preferably having from 1 to about
20 carbon atoms, optionally substituted alkanoyl preferably having
from 1 to about 20 carbon atoms, optionally substituted carbocyclic
aryl having at least about 6 ring carbons,, or substituted or
unsubstituted aralkyl having at least about 6 ring carbons, and the
like;
[0015] Z is a chemical bond, optionally substituted alkylene,
optionally substituted alkenylene, optionally substituted
alkynylene, optionally substituted heteroalkylene, optionally
substituted heteroalkenylene, optionally substituted
heteroalkynylene, or a hetero atom such as O, S, S(O), S(O).sub.2,
or NR.sup.1 wherein R.sup.1 is the same as defined immediately
above;
[0016] n is an integer from 1 to 11, and preferably is 1 to 9, more
preferably 1 to 7;
[0017] p is an integer from 0 (where the a and , ring positions are
fully hydrogen-substituted) to 4; and pharmaceutically acceptable
salts thereof.
[0018] The methods of the invention are particularly suitable for
synthesis of substituted tetrahydrofurans, including compounds of
the following Formula II: 2
[0019] wherein Ar is optionally substituted aryl or heteroaryl;
[0020] m is 0 or 1; n is 1-6;
[0021] W is --AN(OM)C(O)N(R.sup.3)R.sup.4,
--N(OM)C(O)N(R.sup.3)R.sup.4, --AN(R.sup.3)C(O)N(OM)R.sup.4,
--N(R.sup.3)C(O)N(OM)R.sup.4, --AN(OM)C(O)R.sup.4,
--N(OM)C(O)R.sup.4, --AC(O)N(OM)R.sup.4, --C(O)N(OM)R.sup.4, or
--C(O)NHA; and A is lower alkyl, lower alkenyl, lower alkynyl,
alkylaryl or arylalkyl, wherein one or more carbons optionally can
be replaced by N, O or S, however --Y--A--, --A--, or --AW-- should
not include two adjacent heteroatoms;
[0022] M is hydrogen, a pharmaceutically acceptable cation or a
metabolically cleavable leaving group;
[0023] X and Y are each independently O, S, S(O), S(O).sub.2,
NR.sup.3 or CHR.sup.5;
[0024] Z is O, S, S(O), S(O).sub.2, or NR.sup.3;
[0025] R.sup.1 and R.sup.2 are each independently hydrogen, lower
alkyl, C.sub.3-8 cycloalkyl, halolower alkyl, halo or --COOH;
[0026] R.sup.3 and R.sup.4 are independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, arylalkyl,
C.sub.1-6alkoxy--C.sub.1-10alkyl,
C.sub.1-6alkylthio--C.sub.1-10alkyl, heteroaryl, or
heteroarylalkyl;
[0027] R.sup.5 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, arylalkyl, alkaryl, --AN(OM)C(O)N(R.sup.3)R.sup.3,
--AN(R.sup.3)C(O)N(OM)R.sup.4, --AN(OM)C(O)R.sup.4,
--AC(O)N(OM)R.sup.4, --AS(O).sub.xR.sup.3,
--AS(O).sub.xCH.sub.2C(O)R.sup.3,
--AS(O).sub.xCH.sub.2CH(OH)R.sup.3, or --AC(O)NHR.sup.3, wherein x
is 0-2; and pharmaceutically acceptable of such compounds.
[0028] Compounds of Formula II have been disclosed in U.S. Pat.
5,703,093. As disclosed in that patent, preferred compounds of
Formula II include compounds where Ar is substituted by halo
(including but not limited to fluoro), lower alkoxy (including
methoxy), lower aryloxy (including phenoxy), W (as defined above in
Formula II), cyano, or R.sup.3 (as defined above in Formula II).
Those substituents are also preferred Ar group substituents for
compounds of other formulae disclosed herein. Specifically suitable
Ar groups for the above Formula II as well as the other formulae
disclosed herein include phenyl, trimethoxyphenyl, dimethoxyphenyl,
fluorophenyl (specifically 4-fluorophenyl), difluorophenyl,
pyridyl, dimethoxypyridyl, quinolinyl, furyl, imidazolyl, and
thienyl. Additionally, in Formula II as well as other formulae
disclosed herein, W suitably is lower alkyl, such as a branched
alkyl group, e.g. --(CH2).sub.nC(alkyl)H--, wherein n is 1-5, and
specifically --(CH.sub.2).sub.2C(CH.sub.3)H--, or lower alkynyl
such as of the formula --C.ident.C--CH(alkyl)--, including
--C.ident.C--CH(CH.sub.3)--.
[0029] In particularly preferred aspect, methods of the invention
are employed to synthesis the following compound 1,
2S,5S-trans-2-(4-fluoroph-
enoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran:
3
[0030] It has been found that biological activity, particularly
5-lipoxygenase activity, can vary among optically active isomers of
compounds of the invention, and therefore a single optical isomer
of a compound may be preferred. Accordingly, the synthetic methods
of the invention include preparation of enantiomerically enriched
compounds of the invention.
[0031] In a first preferred aspect, substituted tetahydrofuran
compounds are provided by reacting a hydroxy substituted aryl
compound with an epoxide having a reactive carbon, e.g. a glycidyl
compound substituted at the C3 position with an
electron-withdrawing group such as halo (e.g. epichlorohydrin,
epibromohydrin), mesyl or tosyl (glycidyl mesylate and glycidyl
tosylate), etc., to form an epoxyarylether or epoxyoarylether in
the presence of base and preferably at or above about 0.degree. C.
(As used herein, the term "aryl" refers to both carbocyclic aryl
and heteroaromatic or heteroaryl groups, which terms are further
discussed below). That epoxyether is then reacted with an active
methylene compound to form a lactone, preferably a .gamma.-lactone.
The active methylene compound can be a variety of agents. Diethyl
and dimethyl malonate are generally preferred, which provide an
ethyl or methyl ester as a lactone ring substituent. That ester
group is then removed (e.g. via hydrolysis and decarboxylation),
and the lactone suitably reduced to a hydroxy-substituted
tetrahydrofuran, particularly a hydroxytetrahydrofuran-aryl
ether.
[0032] The hydroxy tetrahydrofuran can be further functionalized as
desired, particularly by activating the hydroxyl substituent of the
hydroxytetrahydrofuran-aryl ether followed by substitution of the
corresponding position of the tetrahydrofuran ring such as by a
1-alkyne reagent. Also, rather than directly activating the
hydroxyl moiety, that group can be replaced with a halide, and the
halide-substituted tetrahydrofuran reacted with a benzylsulfonic
acid reagent.
[0033] It also has been found that methods of the invention enable
such substitution of the tetrahydrofuran to proceed with extremely
high stereoselectivity, e.g. at least greater than about 60 mole
percent of one stereoisomer than the other, more typcially greater
than about 70 or 75 mole percent of one stereoisomer than the other
isomer. Recrystallization of such an enantiomerically enriched
mixture has provided very high optical purities, e.g. about 95 mole
%, 97 mole % or even 99 mole % or more of the single
stereoisomer.
[0034] In another aspect, methods are provided that involve
cleavage of a bis-compound to provide high yields of
tetrahydrofuran compounds, including compounds of Formula II above.
These methods preferably involve condensation of mannitol with an
alkanoyl compound such as formaldehyde to form a trialkylene
mannitol such as a tri(C1-10alkylene) mannitol such as trimethylene
mannitol where formaldehyde is employed, which is then cleaved to
form 2,5,--O--methylene-mannitol, which has two primary hydroxyl
groups and two secondary hydroxyl groups. The primary hydroxyl
groups are protected (e.g. as esters) and the secondary hydroxyl
groups then are suitably cyclized, e.g. with a trialkylorthoformate
reagent, to provide a cyclic ether. The protected primary alcohols
are then converted to aryl ethers, followed by cleavage of the
cyclic ether to provide again the secondary hydroxyl groups. The
mannitol compound then undergoes oxidative cleavage to provide the
corresponding alicyclic dialdehyde, which aldehyde groups are
functionalized to bis-.alpha.,.beta.-unsaturate- d esters. The
carbon-carbon double bonds of that compound are suitably saturated,
and the bis-compound cleaved and the cleavage products cyclized to
provide an aryltetrahydrofuran ether which can be further
functionalized as described above.
[0035] In yet another aspect of the invention, preparative methods
are provided that include multiple reactions that surprisingly
proceed as a single step without isolation of intermediates to
provide oxygen ring compounds that have varying ring size as
desired. These methods are suitable for preparation of oxygen ring
compounds having from 5 to 12 or more ring members, and are
particularly useful for synthesis of oxygen ring compounds having
from 5 to 8 or 9 ring members.
[0036] Moreover, it has been surprisingly found that the one step
procedure is enantioselective. Hence, if the starting reagent (a
2,3-epoxide) is optically active, the resulting substituted oxygen
ring compound also will be optically active. Moreover, the reaction
proceeds with stereoselectivity, i.e. full rentention of
configuration.
[0037] More particularly, in this aspect of the invention the
methods include formation, in a single step, of an
alkynyl-substituted oxygen ring compound. For preparation of an
alkynyl-tetrahydrofuran, a compound is reacted that has at least a
six-carbon alkyl or alklyene chain that is activated at the 1- and
6-carbon positions such as by substitution by suitable leaving
groups, and 2- and 3-carbon positions of the chain form an epoxide
ring. The leaving groups of the 1- and 6-positions may be e.g.
halo, such as chloro or bromo, or an ester, such as an alkyl or
aryl sulfonic ester. Preferably, the 1-position is
halo-substituted, particularly bromo-, iodo- or chloro-substituted,
and the 6-position is substituted by an ester such as by a
benzylsulfonyl group. That compound is reacted with a molar excess
of a strong base such as an alkyllithium reagent that affords an
alkynyl-substituted tetrahydrofuran in a single step.
[0038] Larger ring alkynyl-substituted compounds are readily
provided through corresponding chain homologation of the epoxy
reagent, i.e. by interposing additional "spacing" or alkylene chain
members between the reagent's activated positions.
[0039] Thus, for example, to prepare an alkynyl-substituted
tetrahydopyran, a reagent is employed that has at least a
seven-carbon alkyl or alkylene chain that is activated at the 1-
and 7- carbon positions e.g. by substitution by suitable leaving
groups (such as those mentioned above), and the 2- and 3- positions
of the chain form an epoxide ring. That compound is reacted with
base to provide an alkynyl-substituted tetrahydropyran.
[0040] Similarly, to prepare an alkynyl-substituted oxepane, a
reagent is employed that has at least a seven-carbon alkyl or
alkylene chain activated (particularly by leaving groups) at the 1-
and 8-carbon positions, and the 2- and 3-postion of the chain form
an epoxide ring. To prepare an alkynyl-substituted oxocane
compound, a reagent is employed that has at least eight-carbon
alkyl of alkylene chain activated at the 1- and 9-carbon positions,
with the 2- and 3-positions of the chain forming an epoxide ring.
Treatment of those respective reagents with appropriate base
provides alkynyl-substituted oxepane and oxocane compounds.
[0041] In another aspect of the invention, a chiral synthon is
preferably employed such as glyceraldehyde, mannitol, ascorbic
acid, and the like, that can provide stereoselective routes to
desired compounds of the invention. This approach includes
formation of a substituted dioxolane, typically a 1,3-dioxolane
(particularly (2,2-dimethyl)- 1,3-dioxolane), which preferably is
optically active. A side chain of the dioxolane, preferably at the
4-position, is suitably extended e.g. by one or more Wittig
reactions, typically one, two or more Wittig reactions that provide
.alpha.,.beta.-unsaturated moieties such as an
.alpha.,.beta.-unsaturated C.sub.1-6alkyl ester. Such an
.alpha.,.beta.-unsaturated provided then can be epoxidized,
preferably by asymmetric oxidation of the conjugated alkene to
provide an optically active epoxide, which then participates in an
elimination reaction to yield a propargyl alcohol as the dioxolane
ring substituent. The dioxolane ring then can be opened, typically
in the presence of acid and the acyclic intermediate cyclized to
provide an optically active oxygen alicyclic compound. See Scheme
XV below and the discussion related thereto below. The substituted
alicyclic compound can be further functionalized as desired. For
instance, the primary hydroxy of the alkylhydroxy substituent of
the cyclic compound can be esterified (e.g., sulfonate such as a
tosylate) and the activated methyl reacted to provide an aryl
substituent, e.g. optionally substituted phenyl substituent. The
alkynyl substituent can be extended to provided the hydroxy urea as
discussed herein.
[0042] In yet a further aspect of the invention, an
alkyne-substituted tetrahydrofuran is prepared directly (e.g.,
without a dioxolane intermediate) from an acyclic keto alkyne
compound. More specifically, a keto alkynyl reagent with terminal
alkenyl group is suitably employed, e.g.
--CH.sub.2.dbd.CH(CH.sub.2).sub.nC(.dbd.O)C.ident.CR where n is an
integer of 2 to 6, preferably 2 to 5, and R is suitably C.sub.1-6
alkyl and the like. The terminal alkene is then epoxidized, e.g. by
ozonolysis or other suitable oxidant. The epoxidized keto alkyne
then can be cyclized, e.g. in the presence of boron methyl sulfide
and the resulting oxygen alicyclic compound functionalized as
desired.
[0043] Further provided are new routes to substituted hydroxy
ureas. In preferred aspects, these routes include reaction of a
protected hydroxyurea (e.g., a compound of the formula
NH.sub.2C(O)NHOR, where R is a hydroxy protecting group such as
para-methoxybenzyl-) with a substituted alcohol in the presence of
suitable dehydrating agent(s) to provide an amino ester, which is
treated with ammonia and a Lewis acid to provide a hydroxy
urea.
[0044] As mentioned above, compounds produced by the methods of the
invention are useful as pharmaceutical agents, particularly to
treat disorders or diseases mediated by 5-lipoxygenase such as
immune, allegeric and cardiovascular disorders and diseases, e.g.
general inflammation, hypertension, skeletal-muscular disorders,
osteoarthritis, gout, asthma, lung edema, adult respiratory
distress syndrome, pain, aggregation of platelets, shock, shock,
rheumatoid arthritis, psoriatic arthritis, psoriasis, autoimmune
uveitis, allergic encephalomyelitis, systemic lupus erythematosis,
acute necrotizing hemmorrhagic encephalopathy, idiopathic
thrombocytopenia, polychondritis, chronic active hepatitis,
idiopathic sprue, Crohn's disease, Graves ophthalmopathy, primary
biliary cirrhosis, uveitis posterior, interstitial lung fibrosis,
allergic asthma and inappropriate allergic responses to
environmental stimuli.
[0045] In other aspects, the invention provides new compounds as
well as pharmaceutical compositions that comprise one or more of
such compounds preferably with a pharmaceutically acceptable
carrier. More particularly, the invention in a composition aspect
includes compounds of Formula I above, where n is 2 or greater
(i.e. compounds with alicyclic oxygen rings that have 6 or more
ring members), which includes compounds of Formulae III, IIIa, IV,
IVa, V, Va, as those formulae are defined below. The invention
further provides methods for treatment and/or prophylaxis of
various disorders and diseases including those disclosed above such
as immune, allegeric and cardiovascular disorders and diseases, the
methods in general comprising administering an effective amount of
one or more compounds of Formula I above, where n is 2 or greater,
to a subject, such as a mammal particularly a primate such as a
human, that is suffering from or susceptible to such a disorder or
disease.
[0046] Compounds produced by the methods of the invention are
useful as synthetic intermediates to prepare other compounds that
will be useful for therapeutic applications. Other aspects of the
invention are disclosed infra.
DETAILED DESCRIPTION OF THE INVENTION
[0047] As discussed above, the invention provides methods that are
particularly suitable for synthesis of compounds of the following
Formula I: 4
[0048] wherein Ar, Z, X, Y, R.sup.1, n and p are as defined
above.
[0049] As discussed above, in addition to the above-discussed
substituted tetrahydrofurans, methods of the invention also provide
oxygen ring compounds having 6 or more ring members.
[0050] More particularly, preferred compounds produced by the
methods of the invention include substituted tetrahydropyrans,
including substituted tetrahydropyrans of the following Formula
III: 5
[0051] wherein Ar, Z and R.sup.1 are each the same as defined above
for Formula I, and q is an integer of from 0 to 9, and preferably q
is 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
[0052] Generally preferred are 2,6-disubstituted tetrahydropyrans,
such as compounds of the following Formula IIIa: 6
[0053] wherein Ar, Z, Y, W, R.sup.1 and m are each the same as
defined for Formula II above, and q' is an integer of from 0 to 6,
and preferably q' is 0, 1, 2, 3 or 4; and pharmaceutically
acceptable salts thereof.
[0054] The methods are also particularly useful for preparations of
substituted oxepanes including compounds of the following Formula
IV: 7
[0055] wherein Ar, Z and R.sup.1 are each the same as defined above
for Formula I, and r is an integer of from 0 to 11, and preferably
r is 1, 2, 3 or 4; and pharmaceutically acceptable salts
thereof.
[0056] Generally preferred are 2,7-disubstituted oxepanes, such as
compounds of the following Formula IVa: 8
[0057] wherein Ar, Z, Y, W, R.sup.1 and m are each the same as
defined for Formula II above, and r' is an integer of from 0 to 10,
and preferably r' is 0, 1, 2, 3 or 4; and pharmaceutically
acceptable salts thereof.
[0058] Still further, methods of the invention can be especially
useful for synthesis of substituted oxocanes, such as compounds of
the following Formula V: 9
[0059] wherein Ar, Z and R.sup.1 are each the same as defined above
for Formula I, and s is an integer of from 0 to 13,and preferably s
is 1, 2, 3 or 4; and pharmaceutically acceptable salts thereof.
[0060] Generally preferred are 2,8-disubstituted oxocanes, such as
compounds of the following Formula Va: 10
[0061] wherein Ar, Z, Y, W, R.sup.1 and m are each the same as
defined for Formula II above, and s' is an integer of from 0 to 10,
and preferably s' is 0, 1, 2, 3 or 4; and pharmaceutically
acceptable salts thereof.
[0062] Preferred compounds of the invention include those having
one or more hydroxy and/or alkoxy substituents on the alicyclic
ring, typically one, two or three hydroxy and/or alkoxy ring
substituents. Hence, in the above formulae I, III, IIIa, IV, IVa,
V, IVa, each R.sup.1 is independently hydroxy or alkoxy and p is
one or greater. Typical alkoxy alicyclic ring substituents include
C.sub.1-8alkoxy, more typically C.sub.1-6alkoxy, still more
typically C.sub.1-3alkoxy compounds. Particularly preferred
compounds include those where at least two hydroxy and/or alkoxy
groups are substituents on adjacent carbons of the alicyclic ring,
e.g. vicinal di-hydroxy compounds and vicinal di-alkoxy
compounds.
[0063] The term alkyl, as used herein, unless otherwise specified,
refers to a saturated straight, branched, or cyclic hydrocarbon and
unless otherwise specified is C.sub.1 to C.sub.10, and specifically
includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl,
isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and
2,3-dimethylbutyl. The alkyl group can be optionally substituted
with any appropriate group, including but not limited to R.sup.3 or
one or more moieties selected from the group consisting of halo,
hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro,
cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or
phosphonate, either unprotected, or protected as necessary, as
known to those skilled in the art, for example, as disclosed in
Greene et al., "Protective Groups in Organic Synthesis", John Wiley
and Sons, Second Edition, 1991.
[0064] The term halo, as used herein, refers to chloro, fluoro,
iodo, or bromo.
[0065] The term lower alkyl, as used herein, and unless otherwise
specified, refers to a C.sub.1 to C.sub.6 saturated straight,
branched, or cyclic (in the case of C.sub.5-.sub.6) hydrocarbon,
and specifically includes methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl,
hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and
2,3-dimethylbutyl, optionally substituted as described above for
the alkyl groups.
[0066] The term alkenyl, as referred to herein, and unless
otherwise specified, refers to a straight, branched, or cyclic (in
the case of C.sub.5-6) hydrocarbon of C.sub.2 to C.sub.10 with at
least one double bond, optionally substituted as described
above.
[0067] The term lower alkenyl, as referred to herein, and unless
otherwise specified, refers to an alkenyl group of C.sub.2 to
C.sub.6, and specifically includes vinyl and allyl.
[0068] The term lower alkylamino refers to an amino group that has
one or two lower alkyl substituents.
[0069] The term alkynyl, as referred to herein, and unless
otherwise specified, refers to a C.sub.2 to C.sub.10 straight or
branched hydrocarbon with at least one triple bond, optionally
substituted as described above. The term lower alkynyl, as referred
to herein, and unless otherwise specified, refers to a C.sub.2 to
C.sub.6 alkynyl group, specifically including acetylenyl, propynyl,
and --C.ident.C--CH(alkyl)--- , including
--C.ident.C--CH(CH.sub.3)--.
[0070] The term carbocyclic aryl, as used herein, and unless
otherwise specified, refers to non-hetero aromatic groups that have
1 to 3 separate or fused rings and 6 to about 18 carbon rings
members and may include e.g. phenyl, naphthyl, biphenyl,
phenanthracyl, and the like. The carbocyclic aryl group can be
optionally substituted with any suitable group, including but not
limited to one or moieties selected from the group consisting of
halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy,
nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate,
or phosphonate, either unprotected, or protected as necessary, as
known to those skilled in the art, for example, as taught in Greene
et al., "Protective Groups in Organic Synthesis", John Wiley and
Sons, Second Edition, 1991, and preferably with halo (including but
not limited to fluoro), lower alkoxy (including methoxy), lower
aryloxy (including phenoxy), W, cyano, or R.sup.3.
[0071] The term haloalkyl, haloalkenyl, or haloalkynyl refers to
alkyl, alkenyl, or alkynyl group in which at least one of the
hydrogens in the group has been replaced with a halogen atom.
[0072] The term heteroaryl, heterocycle or heteroaromatic, as used
herein, refers to an aromatic moiety that includes at least one
sulfur, oxygen, or nitrogen in the aromatic ring, which can
optionally be substituted as described above for the aryl groups.
Non-limiting examples are pyrryl, furyl, pyridyl,
1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl,
tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, benzofuran,
isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,
purinyl, carbazolyl, benzimidazolyl, and isoxazolyl. Suitable
heteroaromatic or heteroaryl groups will have 1 to 3 rings, 3 to 8
ring members in each ring and from 1 to 3 heteroatoms (N, O or
S).
[0073] The term arylalkyl refers to a carbocyclic aryl group with
an alkyl substituent.
[0074] The term alkylaryl refers to an alkyl group that has a
carbocyclic aryl substituent.
[0075] The term organic or inorganic anion refers to an organic or
inorganic moiety that carries a negative charge and can be used as
the negative portion of a salt.
[0076] The term "pharmaceutically acceptable cation" refers to an
organic or inorganic moiety that carries a positive charge and that
can be administered in association with a pharmaceutical agent, for
example, as a counter cation in a salt. Pharmaceutically acceptable
cations are known to those of skill in the art, and include but are
not limited to sodium, potassium, and quaternary amine.
[0077] The term "metabolically cleavable leaving group" refers to a
moiety that can be cleaved in vivo from the molecule to which it is
attached, and includes but it not limited to an organic or
inorganic anion, a pharmaceutically acceptable cation, acryl (for
example (alkyl)C(O), including acetyl, propionyl, and butyryl),
alkyl, phosphate, sulfate and sulfonate.
[0078] Alkylene and heteroalkylene groups typically will have about
1 to about 8 atoms in the chain, more typically 1 to about 6 atoms
in the linkage. Alkenylene, heteroalkenylene, alkynylene and
heteroalkynylene groups typically will have about 2 to about 8
atoms in the chain, more typically 2 to about 6 atoms in the
linkage, and one ore more unsaturated carbon-carbon bonds,
typically one or two unsaturated carbon-carbon bonds. A
heteroalkylene, heteroalkenylene or heteroalkynylene group will
have at least one hetero atom (N, O or S) as a divalent chain
member.
[0079] The term alkanoyl refers to groups that in general formulae
generally will have from 1 to about 16 carbon atoms and at least
one carbonyl (C.dbd.O) moiety, more typically from 1 to about 8
carbon atoms, still more typically 1 to about 4-6 carbon atoms. The
term alkylthio generally refers to moieties having one or more
thioether linkages and preferably from 1 to about 12 carbon atoms,
more preferably from 1 to about 6 carbon atoms. The term
alkylsulfinyl generally refers to moieties having one or more
sulfinyl (S(O)) linkages and preferably from 1 to about 12 carbon
atoms, more preferably from 1 to about 6 carbon atoms. The term
alkylsulfonyl generally refers to moieties having one or more
sulfonyl (S(O).sub.2) linkages and preferably from 1 to about 12
carbon atoms, more preferably from 1 to about 6 carbon atoms. The
term aminoalkyl generally refers to groups having one or more N
atoms and from 1 to about 12 carbon atoms, preferably from 1 to
about 6 carbon atoms.
[0080] As discussed above, various substituent groups of the above
formulae may be optionally substituted. Suitable groups that may be
present on such a "substituted" group include e.g. halogen such as
fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido;
sulfhydryl; alkanoyl e.g. C.sub.1-6 alkanoyl group such as acetyl
and the like; carboxamido; alkyl groups including those groups
having 1 to about 12 carbon atoms, preferably from 1 to about 6
carbon atoms; alkenyl and alkynyl groups including groups having
one or more unsaturated linkages and from 2 to about 12 carbon
atoms, preferably from 2 to about 6 carbon atoms; alkoxy groups
having one or more oxygen linkages and from 1 to about 12 carbon
atoms, preferably 1 to about 6 carbon atoms; aryloxy such as
phenoxy; alkylthio groups including those moieties having one or
more thioether linkages and from 1 to about 12 carbon atoms,
preferably from 1 to about 6 carbon atoms; alkylsulfinyl groups
including those moieties having one or more sulfinyl linkages and
from 1 to about 12 carbon atoms, preferably from 1 to about 6
carbon atoms; alkylsulfonyl groups including those moieties having
one or more sulfonyl linkages and from 1 to about 12 carbon atoms,
preferably from 1 to about 6 carbon atoms; aminoalkyl groups such
as groups having one or more N atoms and from 1 to about 12 carbon
atoms, preferably from 1 to about 6 carbon atoms; carbocyclic aryl
having 6 or more carbons, particularly phenyl; aryloxy such as
phenoxy; aralkyl having 1 to 3 separate or fused rings and from 6
to about 18 carbon ring atoms, with benzyl being a preferred group;
aralkoxy having 1 to 3 separate or fused rings and from 6 to about
18 carbon ring atoms, with O-benzyl being a preferred group; or a
heteroaromatic or heteroalicyclic group having 1 to 3 separate or
fused rings with 3 to about 8 members per ring and one or more N, O
or S atoms, e.g. coumarinyl, quinolinyl, pyridyl, pyrazinyl,
pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl,
imidazolyl, indolyl, benzofuranyl, benzothiazolyl,
tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and
pyrrolidinyl. A "substituted" group of a compound of the invention
prepared by a method of the invention may be substituted at one or
more available positions, typically 1 to about 3 positions, by one
or more suitable groups such as those listed immediately above.
[0081] Particularly preferred preparative methods of the invention
are exemplified in the following Schemes I through XVI. For
purposes of exemplification only, particularly preferred compounds
and substituents are depicted in the Schemes, and it will be
understood that a variety of other compounds can be employed in
similar manner as described below with respect to the exemplified
compounds. For instance, the carbocyclic aryl group of
4-fluorophenol is depicted throughout the Schemes, although a wide
variety of other aryl group could be employed in the same or
similar manner as fluorophenyl. It should also be understood that
references to "aryl" with respect to the Schemes and as otherwise
specified herein includes those groups specified for the
substituent Ar in Formula I above and thus encompasses carbocyclic
aryl such as phenyl and the like as well as heteroaryl groups.
Additionally, while compounds in the below Schemes generally depict
substitution only at the ring carbons a to the ring oxygen, other
ring positions can be readily substituted, e.g. by using
appropriately substituted starting reagents. 11
[0082] Scheme I exemplifies a preferred preparative method of the
invention wherein arylhydroxide 2 is reacted with epoxide 3 having
a reactive C3 carbon. Preferred epoxides are those that are
enantiomerically enriched, such as the glycidyl tosylate 3 shown
above that is condensed with phenol 2 for a time and temperature
sufficient for reaction completion to provide epoxyaryl ether 4.
See Example 1, Part 1 below for exemplary reaction conditions. The
reagents 2 and 3 are typically reacted in a suitable solvent, e.g.
dimethyl formamide, N-methyl pyrrolidinone and the like.
Enantiomerically enriched epoxides suitable for condensation with
an arylhydroxide are commercially available or can be readily
prepared by known procedures. See, for instance, U.S. Pat. Nos.
4,946,974 and 5,332,843 to Sharpless et al. for preparation of
optically active derivatives of glycidol.
[0083] The epoxyaryl ether 4 then is reacted with an active
methylene group, such a diethyl or dimethyl malonate to provide
butyrolactone 5. The exocyclic ester of 5 is then suitably cleaved,
e.g. with reaction with magnesium chloride hexahydrate, to provide
the aryllactone ether 6. See Example 1, Part 3 which follows for an
exemplary reaction conditions. That lactone 6 is then reduced to
the hydroxy-tetrahydrofuran 7. Suitable reducing agents include
e.g. DIBAL-H and the like. See Example 1, Part 4, which follows. 12
13
[0084] Schemes II and III exemplify further preferred methods of
the invention for synthesis of alkynyl-substituted
tetrahydrofuranaryl ethers. More specifically, the hydroxy
substituent of tetrahydrofuran 7 is preferably protected, e.g. as
an ether or ester. Thus, as depicted in Schemes II and III, the
hydroxy moiety of 7 can be reacted with a suitable silyl reagent,
e.g. to form the t-butyldimethylsilyl ether 8 or with reagent for
esterification, e.g. an anhydride such as acetic anhydride to
acetyl ester 11. See Example 1, Part 5 and Example 2, Part 1 for
suitable reaction conditions for exemplary conditions.
[0085] The protected aryltetrahydrofuran ether 8 or 11 then can
reacted to provide the alkynyl-substituted tetrahydrofuran 9 by
treatment with a 1-alkyne in the presence of a strong base such an
alkyllithium. Preferably the alkyne reagent contains a protected
hydroxy moiety such as a silyl ether, e.g. a tetrahydropyranyl
ether as depicted in the above Schemes. The hydroxy group can be
readily deprotected after coupling of the alkynyl reagent to the
tetrahydrofuran ring, e.g. by treatment with dilute acid.
Typically, the alkyne reagent will contain a primary or secondary
hydroxy moiety. 14
[0086] Schemes IV and V above exemplify further convenient routes
that can provide alkynyl-substituted tetrahydrofurans of Formula 1.
Thus, in Scheme IV, halo-substituted compound 12 can be reacted
with an alkyne reagent as generally described above with respect to
Schemes II and III to provide 9, which can be readily deprotected
to provide the primary alcohol of compound 10. See generally
Example 3 which follows for exemplary reaction conditions.
[0087] In Scheme V, hydroxytetrahydrofuran 7 (depicted as the
lactol) is condensed with a sulfonic acid reagent to provide the
sulfonic ester 8 which can be reacted with an alkyne reagent as
generally described above to provide 9. Compound 10 is readily
provided by treatment of the protected alcohol 9 with treatment
with dilute acid. See Example 4 below.
[0088] Scheme VI below exemplifies a further preferred method of
the invention that provides compounds of Formula I and involves
cleavage of a bis-compound to provide high yields of compounds of
Formula I. 15
[0089] More specifically, as depicted above, trimethylene mannitol
16 is suitably prepared by condensation of mannitol 15 with
formaldehyde in the presence of acid. The labile rings are cleaved
and the resulting esters of 17 reduced to the primary and secondary
alcohols of 18. The primary alcohols are protected, e.g. as an
allyl or aryl sulfonic ester, to provide intermediate 19. The
secondary hydroxyl groups of 19 then are functionalized by reaction
with a trialkylorthoformate, e.g. a
tri(C.sub.1-10alkyl)orthoformate such as triethylorthoformate, to
provide 20. The protected primary alcohols of 20 are then converted
to aryl ethers, preferably under basic conditions by reaction with
an arylhydroxide compound such as a phenol to provide di-aryl ether
21. That aryl ether is then reacted in the presence of acid to
cleave the methylene ethers to provide secondary hydroxyl groups of
compound 22.
[0090] Compound 22 then undergoes oxidative cleavage by treatment
with a suitable reagent such as Pb(OAc).sub.4, and the resulting
dialdehyde is functionalized to the acyclic
.alpha.,.beta.-unsaturated ester 23 such as by reaction with
carboethoxymethylenetriphenyl phosphorane. Other
.alpha.,.beta.-unsaturated groups will for suitable for the
alicyclic compound, e.g. .alpha.,.beta.-unsaturated esters have 1
to about 12 carbon atoms, .alpha.,.beta.-unsaturated acids, and
other Michael-type acceptors. The carbon-carbon double bonds of 23
then are saturated, preferably by hydrogenation, and the resulting
compound is cleaved and cyclized in the presence of acid to form
the aryl ether 6. In one system, the saturated compound is refluxed
in a suitable solvent such as an alcohol, ethanol, for a time
sufficient to provide 6. See Example 5 which follows for exemplary
reagents and reaction conditions. Compound 6 then can be further
functionalized, e.g. as discussed above with respect to Schemes II
and III. 16
[0091] Scheme VII above exemplifies a further preferred method of
the invention that provides compounds of Formula I and features
multiple reactions that proceed as a single step without isolation
of intermediates.
[0092] More specifically, as shown above aryl compound 2 is reacted
with epoxide 24 that has a reactive C3 carbon to provide the
arylepoxy ether 25. If the epoxide 24 is not enantiomerically
enriched such as 3, the arylepoxy ether 25 may be resolved if
desired such as by procedures generally depicted in Scheme VI above
to provide optically active epoxide ethers 27 and 4. See Example 6,
Parts 2-4 below for exemplary reagents and reaction conditions.
That procedure generally entails formation of optically active
aryldiol ether and arylepoxide ether 26 and 27 from the racemic
arylepoxide 25 with an optically active reagent, preferably an
optically active catalyst such as Jacobsen's catalyst. See E.
Jacobsen, Science, 277:936-938 (1997). The optically active diol 26
can be readily cyclized to the epoxide 4, for example by
esterification (e.g. a sulfonic ester as shown exemplified by 28
above) of the primary hydroxyl group of the diol followed by
epoxide formation under basic conditions (e.g. NaH).
[0093] An allyl halide is suitably reacted with the arylepoxide
ether, suitably in the presence of Mg, catalytic amount of iodine
and cuprous cyanide to provide aryl/alkene ether 29. The secondary
hydroxy is suitably protected, e.g. as an ester, preferably as a
sulfonic ester, to provide 30. An ester group is then suitably
grafted to terminal carbon-carbon double bond to the
.alpha.,.beta.-unsaturated ester 31, and the ester reduced to the
alcohol, typically by treatment with strong base such as
DIBAL-H.
[0094] The alkene is then suitably oxidized to provide epoxy group
of 33. The oxidation may be conducted to provide optically active
epoxy carbons as generally shown in Scheme VI (compound 33) and
conducted using suitable optically active reagent(s) such as an
optically catalyst or other reagent. See Example 6, Part 9 for an
exemplary procedure. The racemic epoxides also may be resolved,
e.g. by chromatography using an optically active packing material.
The glycidyl compound 33 is then converted to the epihalohydrin
34.
[0095] The epihalohydrin 34, in a single step, is converted to the
alkynyltetrahydrofuran ether 35 upon treatment with a molar excess,
preferably at least about a three molar excess of a strong base
such as an alkyllithium reagent or sodium amide. BuLi is generally
preferred, particularly n-BuLi.
[0096] While not being bound by theory, it is believed the single
step reaction proceeds through the mechanism shown immediately
below, where Ar is the same as defined for Formula I and Ms is
mesyl (--S(O).sub.2CH.sub.3): 17
[0097] The alkynyl group of compound 35 can be further
functionalized as desired, e.g. by reaction with ethylene oxide in
the presence of base to afford the single enantiomer 10.
[0098] Compound 10 also can be further functionalized as desired.
For example, to produce compound 1 as shown above, compound 10 can
be reacted with N,O-bisphenoxycarbonyl hydroxylamine and
triphenylphosphine and duisopropylazo-dicarboxylate, followed by
treatment of resulting intermediate with NH.sub.3.
[0099] However, in a preferred aspect and as discussed above, the
invention provides new routes to substituted hydroxy ureas. More
particularly, a protected hydroxynrea (e.g., a compound of the
formula NH.sub.2C(O)NHOR, where R is a hydroxy protecting group
such as an alkyl, aryl or preferably aryalkyl ether such as an
ether of an optionally substituted (phenyl)OCH.sub.2--) is reacted
with a substituted alcohol compound such as 10 of Scheme II,
preferably in the presence of suitable dehydrating agent(s) such as
triphenyl phosphine and diethylazodicarboxylate (DEAD) to provide
an amino ester, i.e. a moiety of the formula --NRC(O)OR.sup.1R
where R is as defined immediately above and R.sup.1 is a
non-hydrogen group such as aryl, particularly phenyl, alkyl, e.g.
C.sub.1-10alkyl, etc. That amino ester is then treated with ammonia
and a Lewis acid such as boron trifluoride etherate and the like to
provide a hydroxy urea.
[0100] Schemes VIII, IX and X exemplify preferred methods for
synthesis of substituted oxepanes in accordance with the invention.
18
[0101] Thus, as generally shown in Scheme VIII above, the halo
benzyloxyalkane 41 is condensed with an arylether oxirane in the
presence of an appropriate metal for a time and temperature
sufficient for reaction completion to provide the arylbenzylether
hydroalkane 42. The hydroxyl functionality of the arylether 42 is
suitably protected especially as an ether such as
methoxyethoxymethyl ether, methoxymethyl ether or tetrahydropyranyl
ether and the like to provide the intermediate 43. The benzyl
protection group of arylether 43 is removed under appropriate
conditions such as hydrogenation using palladium on activated
carbon. The resulting primary alcohol 44 is then oxidized to the
corresponding aldehyde 45 using an appropriate oxidizing agent such
as oxalyl chlorine with dimethyl sulfoxide in an appropriate
solvent such as methylene chloride or chloroform, or a buffered
solution of pyridinium dichromate in dry methylene chloride. 19
20
[0102] The hydroxy group of 49 can be readily deprotected after
coupling of the alkynyl reagent to the oxepane ring, e.g. by
treatment with dilute acid such as a 1% HCl methanol solution to
provide the alkynylhydroxy substituted oxepane 50 as shown in
Scheme X. The arylether alkynylhydroxy oxepane 50 can be further
functionalized as desired e.g. by amidation using a N,O-substituted
hydroxylamine, preferably in the presence of dehydrating reagents
such as triphenyiphosphine and diisopropylazodicarboylate, followed
by treatment of the resulting intermediate 51 with ammonia to yield
the hydroxylamine oxepane 52. See the above discussion and Example
7, Parts 9 and 10 which follow for exemplary reaction
conditions.
[0103] Synthetic methods of the invention also include preparation
of compounds useful as intermediates to prepare
2,7-disubstituted-tetrahydro- pyran compounds of the above Formula
I. 21
[0104] Schemes XI, XII and XIII exemplify some preferred
preparative methods of the invention for synthesis of
alkynyl-substituted tetrahydropyrans.
[0105] Generally as shown is Scheme XI, the epoxy aryl ether 4, is
reacted with a 1-alkyne reagent in the presence of a strong base
such as butyl lithium and boron trifluoroetherate in THF to yield
the alkyne 56. Preferably the alkyne reactant contains an ester
moiety such as a methyl ester. The alkynyl functionality of
arylether 56 is reduced under appropriate conditions such as
hydrogenation using palladium on activated carbon as catalyst in an
appropriate solvent such as methanol or ethanol to yield the alkane
57. Rearrangement with cyclization of the arylether methyl ester 57
is done by treatment with toluenesulfonic acid preferably in an
appropriate solvent such as toluene to yield the
tetrahydropyrrolinone 58. 22
[0106] The aldehyde 58 is reduced, e.g. by reaction with
diisobutylaluminum hydride to yield the corresponding alcohol 58 as
shown in Scheme XII. The arylether alcohol 59 and benzylsulfonic
acid react in an appropriate solvent such as methylene chloride or
chloroform in the presence of a drying agent such as calcium
chloride to afford the cyclized arylether benzylsulfinic
tetrahydropyran 60. The benzylsulfinic tetrahydropyran 60 can then
react with a 1-alkyne in the presence of magnesium and isopropyl
bromide to provide the alkynyl-substituted tetrahydropyran 61.
Preferably the alkyne reactant contains a protected hydroxyl moiety
such as tetrahydropyranyl ether or t-butyldimethylsilyl ether. It
has been surprisingly found that reaction of the alkyne reagent
with a mixture of a stereoisomers of 60 (i.e. racemic at
phenylsulfinic-substituted ring carbon) proceeds stereoselectively
to produce the trans compound 61. In fact, it has been found that
the trans 61 compound can be the exclusive reaction product. The
hydroxy group of 61 can be readily deprotected after coupling of
the alkynyl reagent to the oxepane ring, e.g. by treatment with
dilute acid such as a 1% HCl methanol solution to provide the
alkynylhydroxy substituted tetrahydropyran 62. 23
[0107] The arylether alkynylhydroxy tetrahydropyran 62 can be
purified to yield the enantiomerically enriched disubstituted
tetrahydropyran 63. The arylether alkynylhydroxy tetrahydropyran 63
further functionalized as desired by amidation using a
N,O-substituted hydroxylamine, preferably in the presence of
dehydrating reagents such as, triphenylphosphine and
diisopropylazodicarboylate, followed by treatment of the resulting
intermediate 64 with ammonia to yield the hydroxylamine
tetrahydropyran 65.
[0108] Synthetic methods of the invention also include preparation
of compounds useful as intermediates to prepare 2,7-disubstituted
oxepane compounds of the above Formula II.
[0109] Scheme XIV below another preferred preparative method of the
invention that employs a polyol (polyhydroxy) reagent. As depicted
in the below Scheme, the entire reaction is stereoselective (i.e.
no separate resolution step or procedure required), beginning with
the optically active glyceraldehyde 1, which is commercially
available. Other glyceraldehyde stereoisomers can be employed in
the same manner as depicted in Scheme VIII to provide the
corresponding distinct stereoisomer as the reaction scheme
product.
[0110] In the following Schemes XIV through XVI, the compound
numerals in the discussions of those Schemes are made in reference
to the compound depicted in the particular Scheme, with the
exception of compound 1, i.e.
2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofura-
n.
[0111] As generally exemplified in Scheme XIV below, the chiral
synthon (glyceraldehyde) is cyclized in the presence of base to the
bis-dioxolane compound 2 which is then oxidized to the keto
(aldehyde) dioxolane 3 and reacted with an appropriate Wittig
reagent to provide the .alpha.,.beta.-unsaturated ester 4. As
referred to herein, unless specified otherwise, the term "Wittig
reaction" or "Wittig-type reaction" designates any of the broad
classes of alkene-formation reactions, typically involving ylide
intermediates such as may be provided by phosphonate and
phosphorane reagents. Additionally, as referred to herein, unless
otherwise specified, to "keto", "carbonyl", or "carboxy" or like
term designate any functional group that includes a carbon-oxygen
double bond (C.dbd.O).
[0112] The carbon-carbon double bond produced by the Wittig
reaction then can be saturated, e.g. hydrogenated in the presence
of a suitable catalyst such as PtO.sub.2, and the ester reduced and
then oxidized to provide aldehyde 7. Wittig reaction of the
aldehyde moiety provides the .alpha.,.beta.-unsaturated compound 9
which can be reduced to alcohol 9, and converted to the propargyl
compound, e.g. via an epoxidized intermediate. More specifically,
unsaturated alcohol 9 can be epoxidized to compound 10, suitably
with an optically active oxidant and then elimination of the
epihalohydrin derivative 11 in the presence of a suitable base e.g.
LDA or other suitable agent to provide the propargyl compound 12.
Additional, successive Wittig-type reactions with intervening
carbon-carbon double bond saturation and aldehyde formation can be
employed to prepare larger oxygen ring compounds. Thus, to prepare
six-member oxygen alicyclic compounds of the invention, the
sequence of steps shown in Scheme XIV below in the transformation
of compound 3 to 7 would be repeated to compound 9a (which is
compound 9 oxidized to the corresponding aldehyde). Similarly, to
prepare seven member oxygen alicyclic compounds of the invention,
the sequence of steps shown in Scheme XIV below in the
transformation of compound 3 to 7 would be repeated two more times;
to prepare eight member oxygen alicyclic compounds of the
invention, the sequence of steps shown in Scheme XIV below in the
transformation of compound 3 to 7 would be repeated three more
times beyond that shown in the Scheme. Alternatively, or in
combination with successive Wittig reactions, other Wittig reagents
can be employed that provide for greater chain extension in a
single step, e.g. Ph.sub.3P.dbd.CHCH.sub.2CO.sub.2Et,
Ph.sub.3P.dbd.CHCH.sub.2CH.sub.2- CO2Et, and the like, or
corresponding Wadsworth-Emmons reagents.
[0113] Acidic opening of the dioxolane ring provides diol 14 and
esterification (e.g. sulfonate ester such as a tosylate) provides
the substituted tetrahydrofuran 16. The resulting hydroxy
tetrahydrofuran can be functionalized as desired, e.g.
esterification of the hydroxy followed by aryl substitution and
functionalization of the alkynyl group provides compound 1,
particularly 2S,5S-trans-(4-fluorophenoxymethyl)-5-(4-N-hydro-
xyureidyl-1-butynyl)-tetrahydrofuran. See, generally, Example 11
which follows for exemplary preferred reaction procedures. 24
[0114] Scheme XV depicts a related approach to provide another
stereoisomer of a substituted oxygen alicyclic compound. As shown
in Scheme XV, L-ascorbic acid can be employed as a starting reagent
to provide hydroxy dioxolane compound 19, which is oxidized;
subjected to multiple Witting reactions; epoxidized; and an
epihalohydrin intermediate reacted in the presence of base to form
a propargyl alcohol intermediate, which is converted to the
optically active aryl-substituted alkyne tetrahydrofuran compounds
33 and 34. To produce larger ring compounds, additional, successive
Wittig reactions can be carried out, as discussed above with
respect to Scheme XIV. 25
[0115] It should be appreciated that the unsubstituted alkyne
produced through the routes of Schemes XIV and XV above is a
versatile intermediate that can be further reacted to provide a
wide range of moieties, including groups that can be detected,
either upon in vitro or in vivo applications. For instance, the
unsubstituted alkyne can be reacted with a group to provide
radiolabeled and stable isotopic moieties, e.g. .sup.125I, .sup.3H,
.sup.32P, .sup.99Tc, .sup.14C, .sup.13C, .sup.15N or the like,
which may be useful inter alia for mechanistic studies.
[0116] Scheme XVI below depicts highly efficient routes to oxygen
alicyclic compounds of the invention. As shown in the Scheme,
butynyl reagent 52 is treated with base, preferably a strong base
such as an alkyl lithium e.g. butyl lithium, and then reacted with
an unsaturated anhydride 53 to provide the keto alkynyl compound 54
with terminal alkene group. The alkene group is oxidized, e.g. via
ozonolysis, and the keto-epoxide compound 55 reduced and cyclized
in the presence of a suitable reducing agent, e.g. borane dimethyl
sulfide. The resulting hydroxy tetrahydrofuran can be
functionalized as desired, e.g. esterification of the hydroxy
moiety followed by aryl substitution and functionalization of the
alkynyl group provides 2-(4-fluorophenoxymethyl)-
-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran. See Example 12
which follows for exemplary preferred reaction conditions.
[0117] Larger ring compounds also can be prepared by this general
route, e.g. by reaction of corresponding ring-extended compounds
corresponding to compound 53 below. That is, to prepare oxygen
alicyclic compounds having six ring members, the compound
CH.sub.2.dbd.CH(CH.sub.2).sub.3C(.d- bd.O)OCOOEt can be employed in
place of compound 53 in the below Scheme; to prepare oxygen
alicyclic compounds having seven ring members, the compound
CH.sub.2.dbd.CH(CH.sub.2).sub.4C(.dbd.O)OCOOEt can be employed in
place of compound 53 in the below Scheme; and to prepare oxygen
alicyclic compounds having eight ring members, the compound
CH.sub.2.dbd.CH(CH.sub.2).sub.4C(.dbd.O)OCOOEt can be employed in
place of compound 53 in the below Scheme. 26
[0118] Schemes XVII and XVIII below depict routes to alicyclic
compounds of the invention having one or preferably more hydroxy or
alkoxy (e.g. C.sub.1-12 alkoxy, more preferably C.sub.1-8 or
C.sub.1-6alkoxy) substituents, preferably two hydroxy or alkoxy
substituents on adjacent (vicinal) ring positions of the alicyclic
compound. Thus, as shown in Scheme XVII below, mannose diacetonide
70 is converted to sulfide 72 followed by hydrolysis to provide 73.
The alkylhydroxy ring substituent of 73 can be functionalized as
desired, e.g. activation of a carbon such as by esterification
(e.g. sulfonate, such as tosylate, mesylate, etc.) and nucleophilic
substitution of the activated carbon, e.g. by an aryl nucleophile,
particularly a carbocyclic aryl nucleophile such as a optionally
substituted phenol. Other ring positions can be functionalized as
desired, e.g. as shown in Scheme XVII, the sulfide group can be
oxidized to the sulfone 74 to activate the ring carbon and that
position substituted by a suitable reagent, e.g. a terminal alkyne,
to provide compound 75. The vicinal alkoxy groups of compounds 75
and 76 can be readily converted to the corresponding vicinal
di-hydroxy groups by acidic hydrolysis. Scheme XVIII shows
alternate functionalization of the alicyclic compound. The
di-alkoxy compounds 85 and 86 can be converted to the corresponding
vicinal di-hydroxy compounds by acidic hydrolysis. 27 28
[0119] Often, it will be preferable to use an optically active or
enantiomerically enriched mixture of a chiral compound of the
invention for a given therapeutic application. As used herein, the
term "enantiomerically enriched" refers to a compound mixture that
is at least approximately 85% or 90%, and preferably a mixture of
approximately at least about 95%, 97%, 98%, 99%, or 100% of a
single enantiomer of the compound.
[0120] As discussed above, compounds of the invention are useful
for numerous therapeutic applications. The compounds can be
administered to a subject, particularly a mammal such as a human,
in need of treatment, by a variety of routes. For example, the
compound can be administered orally, parenterally, intravenously,
intradermally, subcutaneously, or topically. For example, for
parenteral application, particularly suitable are solutions,
preferably oily or aqueous solutions as well as suspensions,
emulsions, or implants, including suppositories. Ampules are
convenient unit dosages. For enteral application, particularly
suitable are tablets, dragees or capsules e.g. having talc and/or
carbohydrate carrier binder or the like, the carrier suitably being
lactose and/or corn starch and/or potato starch.
[0121] The active compound may be administered to a subject as a
pharmaceutically active salt, e.g. salts formed by addition of an
inorganic acid such as hydrochloric acid, hydrobromic acid,
phosphoric acid, etc., or an organic acid such as acetic acid,
oxalic acid, tartaric acid, succinic acid, etc. Base addition salts
also can be formulated if an appropriate acidic group is present on
the compound. For example, suitable base addition salts include
those formed by addition of metal cations such as zinc, calcium,
etc., or salts formed by addition of ammonium, tetraethylammonium,
etc. Suitable dosages for a given therapy can be readily determined
by the medical practitioner based on standard dosing protocols. See
also U.S. Pat. No. 5,703,093.
[0122] All documents mentioned herein are incorporated herein by
reference. The following non-limiting examples are illustrative of
the invention.
EXAMPLE 1
[0123] Preparation of
(2S)(5R)-2-(4-fluorophenoxymethyl)-5-(4-hydroxybutyn-
-1-yl)-tetrahydrofuran (Scheme II; 10)
[0124] Part 1: (S)-Glycidyl-4-fluorophenyl ether (Scheme I; 4)
[0125] In a 100 ml two-necked round bottom flask equipped with
magnetic stir bar, nitrogen inlet and a septum, was taken sodium
hydride (60% dispersion in oil, 0.742 g, 0.0185 mol) and 10 mL of
dry dimethyl formamide (DMF). The reaction mixture was cooled to
0.degree. C. and 4-fluorophenol 2 (1.9 g, 0.017 mol) in dry DMF (20
mL) was introduced. The reaction mixture was stirred at room
temperature for 1 hour and cooled to 0.degree. C. (S)-Glycidyl
tosylate 3 (3.52 g, 0.015 mol) in DMF (10 mL) was added, and the
reaction mixture was stirred at room temperature and monitored by
TLC (EtOAc-light petroleum ether 1:4, Rf=0.5). After 4 hours, the
reaction mixture was quenched by addition of ice-water (1 mL) and
extracted with (2.times.25 mL) ethyl ether. The ether layer was
washed with water, brine, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to afford
(S)-glycidyl-4-fluorophenyl ether 4, crude yield 3.6 g. The crude
compound was purified by distillation at 160.degree.-170.degree.
C./9 mm, to yield 1.98 g (76%) of purified product 4,
[.alpha.].sub.D+4.96.degree. (c 2.335, CHCl.sub.3). .sup.1H NMR
(200 MHz, CDCl.sub.3): .delta.2.68 (dd, J=4.5, 2.2 Hz, 1 H), 2.85
(t, J=4.5 Hz, 1 H), 3.27 (m, 1 H), 3.89 (dd, J=15.7, 6.7 Hz, 1 H),
4.11 (dd, J=15.7, 4.5 Hz, 1 H), 6.74-7.02 (m, 4 H).
[0126] Part 2:
(4S)-2-carboethoxy-(4-fluoro-phenoxy-methyl)-.gamma.-butyro-
lactone (Scheme I; 5)
[0127] In a 50 ml two-necked round bottom flask equipped with
magnetic stir bar, nitrogen inlet septum, sodium salt of diethyl
malonate (prepared from 1.8 mL/0.0118 mol of diethyl malonate and
0.245 g/0.0106 mol of sodium) in dry TBF (10 mL) was taken. The
reaction mixture was cooled to 0.degree. C. and
(S)-glycidyl-4-fluorophenyl ether 4 (1.788 g, 0.0106 mol) in
tetrahydrofuran (THF) (10 mL) was added. The reaction mixture was
stirred at room temperature and monitored by TLC, (EtOAc-light
petroleum 1:3, Rf=0.30). After 12 hours, THF was removed on
rotavapor. The residue was dissolved in ethyl acetate (25 mL) and
washed with water, brine, dried over Na.sub.2SO.sub.4 and
concentrated on rotavapor to afford
(4S)-2-carboethoxy-(4-fluoro-phenoxy-methyl)-.gamma.--
butyrolactone 5 with a crude yield of 2.816 g. That crude product
was purified on silica gel column chromatography using EtOAc-light
petroleum ether (1:8) to provide 2.10 g (70%) of purified product
5, m.p.69.degree.-71.degree. C., [.alpha.].sub.D+16.95.degree. (c
1.51, CHCl.sub.3). .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.1.3
(m, 3 H), 2.37-2.9 (m, 2 H), 3.52-3.8 (m, 1 H), 3.95 4.32 (m, 4 H),
4.68-4.82 (m, 1/3 H), 4.82-4.98 (m, 2/3 H), 6.72-7.01 (m, 4 H). It
is also noted that the crude product can be suitably employed
directly in the decarboxylative elimination of Part 3 below.
[0128] Part 3: (4S)-4-fluorophenoxy-methyl)-.gamma.-butyrolactone
(Scheme I; 6)
[0129]
(4S)-2-carboethoxy-(4-fluoro-phenoxy-methyl)-.gamma.-butyrolactone
5 (2.1 g, 0.0074 mol) and N,N-dimethylacetamide (10 mL) were taken
in a 25 mL round bottom flask equipped with a stir bar and reflux
condenser. MgCl.sub.26H.sub.2O (1.51 g, 0.0074 mol) was added, and
the reaction mixture was heated under reflux for 4 hours and
monitored by TLC (EtOAc-light petroleum 1:2, Rf=0.2). The reaction
mixture then was partitioned between ethyl ether and water (50 mL
each). The ether layer was separated, washed twice with water,
brine, dried over Na.sub.2SO.sub.4 and concentrated on rotavapor to
afford (4S)-4-fluorophenoxy-methyl)-.gamma.-butyrolactone 6, yield
1.40 g (90%), m.p. 58.degree.-59.degree. C.,
[.alpha.].sub.D+23.degree. (c 1.99, CHCl.sub.3), e.e. 92%. .sup.1H
NMR (200 MHz, CDCl.sub.3): .delta.2.13-2.80 (m, 4 H), 4.02 (dd, 1
H,J=4.5, 9.0 Hz), 4.11 (dd, 1 H,J=4.5, 9.0 Hz), 4.80 (m, 1 H),
6.75=7.02 (m, 4 H).
[0130] Part 4:
(2S)-(4-Fluorophenoxymethyl)-5-hydroxytetrahydrofuran (Scheme I;
7)
[0131] A flame dried 100 mL two neck round bottom flask equipped
with a magnetic stir bar and nitrogen inlet was charged with a
solution of 3.5 g (0.0167 mol) of
(4S)-4-fluorophenoxy-methyl)-.gamma.-butyrolactone 6 in 30 mL of
CH.sub.2Cl.sub.2. That solution was cooled to -78.degree. C. and
7.34 mL (0.018 mol) diisobutylaluminum hydride (DIBAL-H; 2.5 M
solution in hexane) was added dropwise. The reaction mixture was
stirred at -78.degree. C. for 3 hours. The reaction mixture was
quenched with methanol (5 mL) and saturated aqueous solution of
potassium sodium tartrate. The organic layer was separated, dried
over Na.sub.2SO.sub.4 and concentrated on rotavapor to provide
(2S)-(4-fluorophenoxymethyl)-5-h- ydroxytetrahydrofuran 7 as a
solid (3.47 g). This crude lactol was used in the next reaction
(Part 5) without further purification.
[0132] Part 5: (2S)
(4-fluoophenoxymethyl)-5-(tert-butyldimethylsiloxy)-te-
trahydrofuran) (Scheme II; 8)
[0133] A solution of 3.47 g of
(2S)-(4-fluorophenoxymethyl)-5-hydroxytetra- hydrofuran 7 in 30 mL
of CH.sub.2Cl.sub.2 was taken in an 100 mL round bottom flask
equipped with a magnetic stir bar and nitrogen inlet. That solution
was cooled in an ice-water bath and 2.18 g (0.032 mol) of imidazole
was added, followed by a solution of 3.6 g (0.024 mol) of
tert-butyldimethylsilylchloride (TBDMSCl) in 30 mL of
CH.sub.2Cl.sub.2. The reaction mixture then was stirred at room
temperature for 3 hours, and the reaction then quenched with ice
water, the organic layer separated, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was purified by
column chromatography using light petroleum ether:ethyl acetate
(9:1) to yield (2S) (4-fluoophenoxymethyl)--
5-(tert-butyldimethylsiloxy)-tetrahydrofuran) 8 as an oil (5.1 g,
95%). .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.0.09 (s, 6 H), 0.88
(s, 9 H), 1.72-2.34 (m, 4 H), 3.76=4.08 (m, 2 H), 4.28-4.54 (m, 1
H), 5.47 (s, 1/3 H), 5.54 (d, J=4.5 Hz, 2/3 H), 6.75-7.0 (m, 4
H).
[0134] Part 6: (2S) (5SR)
(4-fluoophenoxymethyl)-5-(1-butynyl-4-tert-butyl-
dimethylsiloxy)-tetrahydrofuran (Scheme II; 9)
[0135] To a flame dried 100 mL two neck round bottom flack equipped
with a magnetic stir bar and nitrogen inlet and septum was added a
solution of 5 g (0.0154 mol) of (2S)
(4-fluoophenoxymethyl)-5-(tert-butyldimethylsiloxy-
)-tetrahydrofuran) 8 in 25 mL of CH.sub.2Cl.sub.2. That solution
was cooled to -78.degree. C. and 2.82 mL (0.0184 mol) of
trimethylsilylbromide (TMSBr) was added dropwise. The reaction
mixture was then stirred at -78.degree. C. for 3 hours.
[0136] In a separate flame dried 50 mL two neck round bottom flask
equipped with a magnetic stir bar, nitrogen inlet and septum was
added a solution of 3.4 g (0.0184 mol) of
4-tert-butyl-dimethylsiloxy-1-butyne in 30 mL of THF. That solution
was cooled to -78.degree. C. and 15.4 mL (1.5M solution in hexane;
0.023 mol) of n-BuLi was added dropwise. That reaction mixture was
stirred at -78.degree. C. for 1 hour, and then transferred via
syringe to the TMSBr solution. The combined solutions were stirred
at -78.degree. C. for 2 hours, and then the reaction quenched with
saturated ammonium chloride solution (20 mL) and the organic layer
separated. The aqueous layer was extracted with CH.sub.2Cl.sub.2
and the combined organic layers were dried over Na.sub.2SO.sub.4
and then concentrated under reduced pressure to afford (2S) (5SR)
(4-fluoophenoxymethyl)-5-(1-butynyl-4-tert-butyldimethylsiloxy-
)-tetrahydrofuran 9 as a thick syrup (6.0 g; 97%).
[0137] Part 7: (2S)
(5RS)-2-(4-Fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl-
)-tetrahydrofuran (Scheme II; 10)
[0138] Without further purification, (2S) (5SR)
(4-fluoophenoxymethyl)-5-(- 1-butynyl-4-
tert-butyldimethylsiloxy)-tetrahydrofuran 9 as prepared in Part 6
above was dissolved in 25 mL of methanol in a 50 mL single neck
round bottom flask. That methanol solution was cooled in an
ice-water bath and 3 mL of 1% HCl solution in methanol was added.
The reaction mixture was then stirred at room temperature for 3
hours, followed by neutralization with saturated aqueous sodium
bicarbonate solution. After removal of methanol under reduced
pressure, the resulting residue was dissolved in 100 mL of ethyl
acetate. The organic layer was washed with water and brine, dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by column chromatography using light petroleum
ether:ethyl acetate (1:1) to provide (2S)
(5RS)-2-(4-fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran
10 as a thick syrup (4.0 g, 96%). .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta.1.76-2.32 (m, 4 H), 2.46 (dt, 2 H, J -2.2, 6.7
Hz), 3.69 (t, 2 H, J=6.7 Hz), 3.89 (d, 2 H, J=4.5 Hz), 4.41 (m, 1
H), 4.70 (m, 1 H), 6.73-6.98 (m, 4 H).
EXAMPLE 2
[0139] Alternate preparation of (2S)
(5RS)-2-(4-fluorophenoxymethyl)-5-(4--
hydroxybutyn-1-yl)-tetrahydrofuran (Scheme III; 10)
[0140] Part 1: (2S) (5RS)-5-0-acetyl-2-(4-fluoro-phenoxymethyl)
tetrahydrofuran (Scheme III; 11).
[0141] To a 25 ml round bottom flask with magnetic stir bar, (2S)
(5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy tetrahydrofuran 7 (1.0 g,
0.0047 mol) in CH.sub.2CI.sub.2 (5 mL) was added. The solution was
cooled in an ice-bath, pyridine (0.8 mL), acetic anhydride (0.9 mL)
and DMAP (catalytic amount) were added in succession. The reaction
was monitored by TLC (EtOAc-light petroleum ether 1:3, Rf=0.5). The
reaction mixture was diluted with CH.sub.2Cl.sub.2 (10 mL) washed
with 5% HCI, brine and dried over Na.sub.2SO.sub.4. The solvent was
removed on rotavapor to give (2S)
(5RS)-5-O-acetyl-2-(4-fluoro-phenoxymethyl) tetrahydrofuran 11
(1.05 g, 88%). .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.1.98, 2.05
(2s, 3 H), 1.89-2.3 (m, 4 H), 3.85-4.09 (m, 2 H), 4.36-4.61 (m, 1
H), 6.26 (s, 1/2 H), 6.33 (d,J=4.5 Hz, 1/2 H), 6.75-7.01 (m, 4
H).
[0142] Part 2: (2 S) (5SR)
(4-fluorophenoxymethyl)-5-(1-butynyl-4-tert-but-
yldimethylsiloxy)-tetrahydrofuran (Scheme III; 9).
[0143] To a flame dried 25 ml two-necked round bottom flask
equipped with magnetic stir bar, nitrogen inlet and a septum, was
added a solution of (2S)
(5RS)-2-(4-fluorophenoxy-methyl)-5-O-acetyl tetrahydrofuran 11
(1.05 g, 0.004 mol) in CH.sub.2Cl.sub.2 (12 mL). The solution was
cooled to 78.degree. C. and TMS-Br (0.65 ml, 0.0049 mol) was added
dropwise. The reaction mixture was stirred at -78.degree. C. for 3
hours (monitored by TLC, EtOAc-light petroleum 1:4, Rf=0.4). In a
separate flame dried 50 mL two-necked round bottom flask equipped
with magnetic stir bar, nitrogen inlet and a septum, a solution of
4-tert-butyldimethylsiloxy-1-butyne (0.913 g, 0.0049 mol) in THF
(15 mL) was taken. The solution was cooled to -78.degree. C. and
n-BuLi in hexane (1.5M, 4.13 mL, 0.0062 mol) was added dropwise.
The reaction mixture was stirred at -78.degree. C. for 1 hour. This
solution was transferred via cannula to the reaction mixture of
step 3 at -78.degree. C. The reaction was monitored by TLC
(EtOAc-light petroleum 1:4, Rf=0.7) and completed in 2 hours. The
reaction mixture was quenched with saturated ammonium chloride
solution (10 mL). THF was removed under reduced pressure and
extracted with CH.sub.2Cl.sub.2 (2.times.10 mL) dried over
Na.sub.2SO.sub.4 and concentrated, to provide a crude yield of 1.7
g of (2S) (5SR)
(4-fluoophenoxymethyl)-5-(1-butynyl-4-tert-butyldimethylsiloxy)-tetrahydr-
ofuran 9.
[0144] Part 3: (2S)
(5RS)-2-(4-Fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl-
)-tetrahydrofuran (Scheme III; 10)
[0145] The crude product 9 (1.7 g) as prepared in Part 2 above was
dissolved in methanol (10 mL), and 1% HCI solution in methanol (5
mL) was added. After 3 h the reaction mixture was neutralized with
saturated aqueous sodium bicarbonate. After removal of methanol on
rotavapor, the residue was dissolved in ethyl acetate (15 mL). The
EtOAc fraction was washed with water, brine, dried over
Na.sub.2SO.sub.4 and concentrated on rotavapor. The residue
afforded (2S) (5Rs)-2-(4-fluorophenoxymethyl)-5-(4-
-hydroxybutyn-1-yl)-tetrahydrofuran 10 as a thick syrup (0.957 g,
88%).
EXAMPLE 3
[0146] Further alternate preparation of (2S)
(5RS)-2-(4-fluorophenoxymethy-
l)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran (Scheme IV; 10)
[0147] Part 1: (2S)
(5RS)-5-bromo-2-(4-fluorophenoxymethyl)tetrahydrofuran (Scheme IV;
12)
[0148] (2S) (5RS)-5-bromo-2-(4-fluorophenoxymethyl)tetrahydrofuran
was prepared from (2S)
(5RS)-5-O-acetyl-2-(4-fluorophenoxymethyl)tetrahydrofu- ran 11
(1.06 g, 0.00417 mol) and TMS-Br (0.65 mL, 0.0049 mol).
[0149] Part 2: (2S)
(5RS)-2-(4-fluorophenoxymethyl)-5-(4-tetrahydropyranoy-
loxybutyn-1-yl)-tetrahydrofuran (Scheme IV; 13)
[0150] In a flame dried 50 mL two-necked RB flask equipped with a
magnetic stir bar, nitrogen inlet and a septum
4-tetrahydropyranoyl-1-butyne (0.774 g, 0.005 mol) in THF (10 mL)
was taken and cooled to -78.degree. C. A solution of n-BuLi in
hexane (1.5 M, 4.2 mL, 0.0063 mol) was added dropwise, and the
reaction mixture was stirred at -78.degree. C. for 1 hour. This
solution was transferred via cannula to the reaction mixture of art
1 of this example at -78.degree. C. That reaction mixture was
stirred at -78.degree. C. for 2h and monitored by TLC (EtOAc-light
petroleum 1:4, Rf=0.7). The reaction mixture was quenched with
saturated ammonium chloride solution and THF was removed on
rotavapor. The residue was partitioned between CH.sub.2Cl.sub.2 (20
mL) and water, and the organic layer was separated, washed with
water, brine dried over Na.sub.2SO.sub.4 and concentrated on
rotavapor to provide a crude yield of 1.73 g.
[0151] Part 3: (2S)
(5RS)-2-(4-fluorophenoxymethyl)-5-(4-hydroxybutyn-1-yl-
)-tetrahydrofuran (Scheme IV; 10) That crude product 13 (1.73 g)
was dissolved in MeOH (10 mL) and 1% HCI in methanol (5 mL) was
added. After 2.5 h, the reaction mixture was quenched by saturated
aqueous NaHCO.sub.3, and concentrated under reduced pressure. The
residue was dissolved in EtOAc (20 mL), washed with water, brine,
dried over Na.sub.2SO.sub.4 and concentrated to give (2S)
(5RS)-2-(4-fluorophenoxyme-
thyl)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran 10 (1.03 g, 93%).
HPLC analysis: Column ODS; flowrate: 1.0 mL/min.; UV: 225 nm.
Mobile phase 60% methanol in water. Trans:cis ratio (65:35).
EXAMPLE 4
[0152] Further alternate preparation of
(2S)(5RS)-2-(4-fluorophenoxymethyl-
)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran (Scheme V: 10)
[0153] Part 1: (2S)
(5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetra- hydrofuran
(Scheme V; 14)
[0154] To benzenesulfonic acid sodium salt (10.0 g, 0.061 mol), 25%
HCl was added dropwise with stirring until the solid dissolved. The
reaction mixture was extracted (100 mL each, 3 times) with EtOAc,
dried over Na.sub.2SO.sub.4 and concentrated to give
benzenesulfonic acid (7.8 g, 90%). To a 100 mL round bottom with a
magnetic stir bar, benzenesulfonic acid (4.61 g, 0.0324 mol),
CaCl.sub.2(3.6 g, 0.0324 mol) and dry dichloromethane (30 mL) were
added. The reaction mixture was cooled to 0.degree. C. and (2S)
(5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy-tetrahydr- ofuran (4.6 g,
0.0216 mol) in dry CH.sub.2CI.sub.2 (20 mL) was added. The reaction
mixture was stirred for 3 h and monitored by TLC (EtOAc-light
petroleum ether 1:4, Rf=0.25). The reaction mixture was filtered
through celite and washed with CH.sub.2Cl.sub.2 (3 times). The
combined organic layer was washed with saturated aqueous
Na.sub.2CO.sub.3, water brine and dried over Na.sub.2SO.sub.4.
Solvent was removed under reduced pressure to afford the crude (2S)
(5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl- )tetrahydrofuran
14 which was crystallized from chloroform-hexane to give pure white
solid, yield 6.8 g (93%), m.p. 102.degree. C.-104.degree. C.
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta.1.90-3.0 (m, 4 H),
3.85-5.0 (m, 4 H), 6.70-7.05 (m, 4 H), 7.45-7.72 (m, 3 H), 7.77-8.0
(m, 2 H).
[0155] Part 2: (2S)
(5RS)-2-(4-fluorophenoxymethyl)-5-(4-tetrahydropyranoy-
l-1-butyne)-tetrahydrofuran (Scheme V; 9)
[0156] To a 250 ml two-necked RB flask equipped with magnetic stir
bar, nitrogen inlet and a septum, Grignard grade magnesium (2.0 g,
0.0833 mol) was taken and the flask flame dried along with
magnesium. The flask was cooled to room temperature and dry THF (5
mL) was added followed by 1,2-dibromoethane (catalytic amount) to
activate the magnesium. Isopropylbromide (8.78 g, 0.0714 mol) in
THF (140 mL) as added dropwise over 15 min. The reaction mixture
was stirred for 1 hour. The isopropyl magnesium bromide was
cannulated in a 1000 mL flame dried two-necked round bottom flask
with spin-bar, nitrogen inlet and septum.
4-Tetrahydropyranoyl-1-butyne (11.0 g, 0.0714 mol) in THF (140 mL)
was added. The reaction mixture was stirred for 30 min. and cooled
at 0.degree. C. Freshly prepared ZnBr.sub.2 solution (1M, 43 mL,
0.0428 mol) in THF was introduced. After 45 min. at room
temperature (2S)
(5RS)-5-benzenesulfonyl-2-(4-fluorophenoxy-methyl)tetrahydrofuran
(12.0 g, 0.0357 mol) in THF (70 mL) was added at room temperature
and stirred for 3h. (TLC, EtOAc-light petroleum 1:4, Rf=0.7).
Saturated aqueous NH.sub.4Cl solution was added at 0.degree. C. to
quench the reaction. THF was removed on rotavapor and the reaction
mixture was partitioned between water and EtOAc. The EtOAc layer
was washed with water, brine, dried over Na.sub.2SO.sub.4 and
concentrated to provide (2S) (5RS)-2-(4-fluorophenox-
ymethyl)-5-(4-tetrahydropyranoyl-1-butyne)-tetrahydrofuran 9, crude
yield 18.9 g.
[0157] Part 3: (2S)
(5RS)-2-(4-fluorophenoxy-methyl)-5-(4-hydroxybutyn-1-y-
l)tetrahydrofuran (Scheme V; 10)
[0158] That crude product 9 (18.9 g) was dissolved in methanol (60
mL) in 100 mL round bottom flask fitted with magnetic stirring
arrangement. 1% HCI in methanol (25 mL) was introduced, and the
reaction mixture was stirred at room temperature for 2 hours (TLC,
EtOAc-light petroleum ether 1:1, Rf=0.4). The reaction mixture was
neutralized by saturated aqueous Na.sub.2CO.sub.3 solution and then
concentrated under reduced pressure. The residue was extracted with
ethyl acetate, washed with water, brine, dried over
Na.sub.2SO.sub.4 and concentrated on rotavapor. The residue was
dried under vacuum on hot water bath to give (2S)
(5RS)-2-(4-fluorophenoxy-methyl)-5-(4-hydroxybutyn-1-yl)tetrahydrofuran
10, yield 10.9 g. HPLC analysis: Column ODS; flowrate: 1.0 mL/min.;
UV: 225 nm. Mobile phase 60% methanol in water. Trans:cis ratio
(69:31). That crude product of 10 was crystallized (2 times) from
ether-light petroleum ether by seeding to yield the pure product
(3.3 g, 35%), m.p. 76.degree. C. [.alpha.].sub.D-34.26.degree. (c
1.36, CHCl.sub.3). HPLC purity above 95%.
EXAMPLE 5
[0159] Further preparation of
(4S)-4-fluorophenoxy-methyl)-.gamma.-butyrol- actone (Scheme VI;
6)
[0160] Part 1: Trimethylene D-mannitol (Scheme VI; 16)
[0161] D-mannitol (2.0 kg, 10.98 mol) (Scheme VII; 15) formaldehyde
solution (35% by weight, 4.4 lit, 51.2 mmol) and conc. HCl (4.0
lit.) were taken in a 10 lit. flask with mechanical stirring
arrangement. The reaction mixture was kept at room temperature for
72 hours. The solid was filtered, washed with water and dried to
provide 2.2 kg (91.9%) of trimethylene D-mannitol 16, m.p.
228.degree.-230.degree., [.alpha.].sub.D-108.degree. (c 2.0,
CHCl.sub.3), TLC (silica gel), 1:2, ethyl acetate: hexane, Rf=0.4.
.sup.1H NMR (CDCl.sub.3): .delta.3.4-3.75 (m, 6H), 4.18 (dd, J=4.0,
8.0 Hz), 4.59 (d, 2H, J-4.0 Hz), 4.76 (s, 2H), 5.05 (d, 2H, J=4.0
Hz).
[0162] Part 2: 1,3,4,6-Tetra-O-acetyl-2,5-O-methylene-D-mannitol
(Scheme VI; 17)
[0163] Ice cold acetylating mixture (10.1 lit.) prepared from 7.0
liters of acetic anhydride, 3.0 liters of acetic acid and 0.1
liters of concentrated H.sub.2SO.sub.4 was taken in 20 lit. round
bottom flask with mechanical stirring arrangement. Trimethylene
D-mannitol 16 (2.2 kg, 10.1 mol) was slowly added in portions (45
min.-1 hour). After 3 h the reaction mixture was poured over
ice-water with vigorous stirring (50-60 lit.). The solid was
filtered, washed with water and dried to provide 2.8 kg (78%) of
17, m.p. 126.degree.-128.degree., [.alpha.].sub.D+57.8.degree- . (c
3.6, CHCl.sub.3); TLC (silica gel), 2:1, ethyl acetate: hexane,
Rf=0.5.
[0164] Part 3: 2,5-O-methylene-D-mannitol (Scheme VI; 18)
[0165] 1,3,4,6-Tetra-0-acetyl-2,5-0-methylene-D-mannitol 17 (2.8
kg, 7.73 mol) was added to chloroform (14 lit.) in 25 lit. round
bottom flask with mechanical stirring. The reaction mixture was
cooled to 0.degree. C., and 0.5% NaOMe solution (6.5 lit.) was
added slowly. The reaction mixture was stirred for 3 hours. The
solid was filtered and dried to provide 1.0 kg (67%) of
2,5-O-methylene-D-mannitol 18, m.p. 172.degree.-173.degree. C.,
[.alpha.].sub.D -52.degree. (c 1.18, CHCl.sub.3), TLC (silica gel),
1:4, methanol: chloroform, Rf =0.8. 'H NMR (D.sub.20): 5 3.42 (m,
2H), 3.72 (m, 4 H), 3.97 (m, 2 H), 4.91 (s, 2 H).
[0166] Part 4: 1,6-Di-O-tosyl-2,5-O-methylene-D-mannitol (Scheme
VI; 19)
[0167] 2,5-O-methylene-D-mannitol 18 (200 g, 1.03 mol) was
dissolved in pyridine (1.2 lit.) in 3 liter two neck R B flask
fitted with an addition funnel and mechanical stirring arrangement.
The reaction mixture was cooled to 0.degree. C., tosyl chloride
(430.9 g, 2.26 mol) dissolved in pyridine (0.8 lit.) was added
slowly, and the reaction mixture was stirred at room temperature
for 12 h. Pyridine then was removed on rotavapour under vacuo. The
thick slurry was poured over ice-water (10 lit.) with mechanical
stirring. After 2 hours the solid was filtered, washed with water,
dried (yield, 400 g crude) and crystallized from methanol to
provide 260 g of product 19, m.p. 142.degree. C.,
[.alpha.].sub.D-23.39.degree. (c 1.7, MeCOMe), TLC (silica gel),
4:1, ethyl acetate: hexane, Rf=0.4. .sup.1H NMR
(CD.sub.3COCD.sub.3): .delta.2.45 (s, 6H), 2.85 (s, 2 H), 3.27 (m,
2 H), 3.65 (m, 2 H), 4.12 (dd, 2 H, J-6.2, 10.0 Hz), 4.45 (m, 2 H),
4.46 (s, 2 H), 7.38, 7.63 (Abq, 8 H, J=8.0 Hz).
[0168] Part 5:
3,4-O-Ethoxymethylene-2,5-O-methylene-1-6-di-O-tosyl-D-mann- itol
(Scheme VI, 20)
[0169] 2,5-O-methylene-1,6-di-O-tosyl-D-mannitol 19, (185 g, 0.368
mol) triethylorthoformate (613 mL) and PTSA (100 mg) were stirred
in a 1 lit. round bottom flask fitted with mechanical stirring
arrangement at room temperature. After 3 hours of stirring
potassium carbonate was added to neutralize PTSA. Solid was
filtered and filtrate concentrated under reduced pressure and dried
under vacuo to provide 206 g (100%) of product 20, m.p.
87.degree.-88.degree. C., [.alpha.].sub.D+46.02.degree. (c 0.93,
CHCl.sub.3), TLC (silica gel) 7:3 hexane: EtOAc, Rf=0.4 .sup.1H NMR
(CDCl.sub.3: .delta.1.21 t, 3 H, J=7.6 Hz), 2.45 (s, 6 H), 3.55 (q,
2 H, J=7.6 Hz), 3.7-3.85 (m, 2 H), 3.97 (t, 1 H, J=8.5 Hz),
4.08-4.31 (m, 5 H). 4.74 (s, 2 H), 5.76 (s, 1 H), 7.34, 7.77 (ABq,
8 H, J=8.5 Hz).
[0170] Part 6:
3,4-O-ethoxymethylene-1,6-di-O-p-fluorophenyl-2,5-O-methyle-
ne-D-mannitol (Scheme VI: 21)
[0171] 4-Fluorophenol 2 (124 g, 1107 mol) was dissolved in
CH.sub.3CN (250 ml) and then KOH solution (62 g, in 45 mL,
H.sub.2O, 1.107 mol) was added. The reaction mixture was stirred
for 15 minutes.
3,4-O-Ethoxymethylene-2,5-O-methylene-1,6-di-O-tosyl-D-mannitol 20
(206 g, 0.369 mol) (used as prepared in Part 5 above without
further purification) in CH.sub.3CN (400 mL) was separately taken
in 1 liter two neck round bottom flask fitted with reflux
condenser, guard tube and mechanical stirring arrangement. To this
solution the potassium salt of 4-fluorophenol was added at room
temperature. The reaction mixture was heated under reflux for 6
hours and monitored by TLC (silica gel, 3:7, ethyl acetate:hexane,
Rf=0.7). The reaction mixture was cooled in ice-water and solid was
filtered washed with ethyl acetate (100 mL), and the combined
filtrate was concentrated under reduced pressure. The resulting
residue was dissolved in ethyl acetate (800 mL) and the organic
layer was washed with 2M NaOH (4.times.100 mL), water and brine
dried over Na.sub.2SO.sub.4. Concentration under reduced pressure
afforded
3,4-O-ethoxymethylene-1,6-di-O-p-fluorophenyl-2,5-O-methylene-D-mannitol
21 (147 g, 90.9). .sup.1H NMR (CDCl.sub.3): .delta.1.3 (t, 3 H,
J=6.25 Hz), 3.70 (q, 2 H,J=6.25 Hz) 4.0-4.45 (m, 7 H), 4.56 (t, 1
H,J=9.6 Hz), 5.19 (s, 2 H), 5.97 (s, 1 H), 6.89-7.10 (m, 8 H).
[0172] Part 7: 1,6-Di-O-p-fluorophenyl-2,5-O-methylene-D-mannitol
(Scheme VI: 22)
[0173]
3,4-O-Ethoxymethylene-1,6-di-O-p-fluorophenyl-2,5-O-methylene-D-man-
nitol 21 (145 g 0.331 mol), tetrahydrofuran (350 mL) and 0.1%
aqueous HCl (40 mL) were mixed in a 1 lit two neck round bottom
flask fitted with mechanical stirring arrangement at 0.degree. C.
The reaction mixture was allowed to attain room temperature and
further stirred for 6 hours and monitored by TLC (silica gel, 1:1,
ethyl acetate: hexane, Rf=0.3). The reaction mixture was basified
to pH 8 by saturated NaHCO.sub.3 solution, and the solid was
filtered and the filtrate concentrated to dryness to provide 125 kg
(99%) of product 22, m.p. 126.degree.-127.degree. C.,
[.alpha.].sub.D-34.49.degree. (c 1.148, MeCOMe). .sup.1H NMR
(CDCl.sub.3): .delta.2.7 s, 2 H), 3.72 (m, 2 H) 3.90 (m, 2 H), 4.12
(m, 4 H), 4.87 (s, 2 H), 6.77-7.0 (m, 8 H).
[0174] Part 8: 4,4'-methylenedioxy-bis[(R)ethyl,
(E)-2-ene-5-p-fluoropheno- xy-pentanoate] (Scheme VI: 23)
[0175] In a 250 ml two neck round bottom flask equipped with
magnetic stirring arrangement and fitted with a guard tube was
taken a solution of
1,6-di-O-p-fluorophenyl-2,5-O-methylene-D-mannitol 22 (10.0 g,
0.026 mol) in CH.sub.2Cl.sub.2 (100 ml). The solution was cooled to
0.degree. C. and Pb(OAc).sub.4 (12.8 g, 0.0288 mol) was added in
portions. After 3 hours, ethylene glycol (1 ml) was added to quench
excess Pb(OAc).sub.4. The reaction mixture was filtered over
celite, and the filtrate was washed successively with water and
brine. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to afford the di-aldehyde as
thick syrup. That crude dialdehyde was taken in CH.sub.2Cl.sub.2
(100 ml) in 250 ml two necked round bottom flask with magnetic
stirring arrangement and fitted with a nitrogen inlet.
Carboethoxymethylenetriphenyl phosphorane (27.3 g, 0.0785 mol) was
added in portions. The reaction mixture then was stirred for 3
hours, concentrated and purified on silica gel chromatography with
85:15 hexane:ethyl acetate as the eluent. The isolated fractions on
concentration under reduced pressure yielded
4,4'-methylenedioxy-bis[ethy- l,
(E)-2-ene-5-p-fluorophenoxypentanoate] 23 (100 g, 74%) as an oil.
.sup.1H NMR (CDCl.sub.3): .delta.1.24-1.40 m, 6 H), 3.86-4.30 (m, 8
H), 4.70 (m, 1 H), 4.84 (s, 2 H), 5.70 (brs, 1 H), 5.9-6.32 (m, 4
H), 6.76-7.02 (m, 8 H).
[0176] Part 9: 4S-(4-Fluorophenoxymethyl)-.gamma.-butyrolactone
(Scheme VI: 6)
[0177] A solution of 4,4'-methylenedioxy-bis[(R)ethyl,
(E)-2-ene-5-p-fluorophenoxypentanoate] 23 (10.0 g, 0.0192 mol) in
methanol (10 ml) was taken in a 200 ml parr hydrogenation flask.
Pd/C (500 mg) was added to that solution and the mixture shaken in
a parr apparatus at 40-50 psi for 6 hour and monitored by TLC. The
reaction mixture was filtered over celite and the filtrate
concentrated to afford 4,4'-methylenedioxy-bis[(R) ethyl,
5-p-fluorophenoxypentanoate] as an oil (10.0 g, 100%).
[0178] A 250 ml round bottom flask equipped with magnetic stirring
arrangement and fitted with a reflux condenser was then charged
with 4,4'-methylenedioxy-bis [.RTM.ethyl,
5-p-fluorophenoxypentanoate] (10.0 g, 0.019 mol) in ethanol (60
ml). To that solution 10% aqueous solution H.sub.2SO.sub.4 (15 ml)
was added. The mixture was heated under reflux for 10-12 hours and
monitored by TLC, silica gel, 1:1, ethyl acetate: hexane, Rf=0.25.
The reaction was cooled to 0.degree. C. and neutralized with
saturated sodium bicarbonate solution. The reaction mixture was
concentrated on a rotavapour to dryness and redissolved in ethyl
acetate (100 ml). The organic layer was washed with water and brine
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
purified by column chromatography to afford off white crystalline
solid of 4S-(4-fluorophenoxymethyl)-.gamma.-butyrolactone 6 (7.0 g,
87%), .m.p 60.degree.-61.degree. C., [.alpha.].sub.D+25.degree. (c
2.18, CHCl.sub.3). .sup.1H NMR (CDCl.sub.3): .delta.2.13-2.80 (m, 4
H), 4.02 (dd, 1 H, J=4.5, 9.0 Hz), 4.11 (dd, 1 H, J=4.5, 9.0 Hz),
4.80 (m, 1 H), 6.75-7.02 (m, 4 H).
EXAMPLE 6
[0179] Further alternate preparation of (2S)
(5RS)-2-(4-Fluorophenoxymethy-
l)-5-(4-hydroxybutyn-1-yl)-tetrahydrofuran (Scheme VII; 10)
[0180] Part 1: (.+-.)-1,2-Epoxy-(4-fluoro)phenoxy propane (Scheme
VII; 25)
[0181] p-Fluorophenol 2 (5 g, 4.6 mmol) and epichlorohydrin 24
(16.5 g, 178.4 mmol 13) were admixed in anhydrous acetone (100 ml).
Anhydrous K.sub.2CO.sub.3 (24.0 g, 178.4 mmol) was added in 10
minutes and the reaction mixture was heated at reflux for 18 hours
until the complete consumption of p-fluorophenol as monitored by
TLC (4:1 hexane:ether). The reaction mixture then was filtered off,
the filtrate was concentrated under vacuo to afford a light yellow
oil, excess epichlorohydrin was distilled off, the residue was
subjected to column chromatography on silica gel (2:8, ethyl
acetate-hexane) to afford (.+-.)-1,2-epoxy-(fluoro- )phenoxy
propane 25 in quantitative yield (8.5 g).
[0182] Part 2: (2R)-3-(4-fluoro)phenoxy-propane-1,2-diol (Scheme
VII; 26)
[0183] (2R)-3-(4-fluoro)phenoxy-propane-1,2-diol 26 was prepared
using Jacobsen's catalyst as generally described in E. Jacobsen,
Science, 277:936-938 (1997). More specifically
(.+-.)-1,2-epoxy-3-(4-fluoro)phenox- y propane 25 (10 g, 59.5 mmol)
and (R,R)-Jacobsen's catalyst (215 mg, 0.29 mmol) were taken in a
50 ml round bottom flask and cooled to 0.degree. C. Water (0.6 ml,
32.7 mmol) was then added dropwise for 1 hour and stirred for 5
hours at room temperature, monitored by TLC (1:1 ethyl
acetate:hexane). Ethyl acetate (50 ml) was added, followed by
anhydrous Na.sub.2SO.sub.4 (200 mg), stirred for 10 minutes
filtered, concentrated to afford dark colored residue of a mixture
of 26 and 27, which on column chromatography gave isolated epoxide
27 (4.36 g, 43%, 1:9 ethyl acetate-hexane) and
(2R)-3-(4-fluoro)phenoxy-propane-1,2-diol 26 (5.06 g, 46% 1:1 ethyl
acetate-hexane).
[0184] Part 3: (2S)-3-(4-fluoro)phenoxy-1-tosyloxy-propane-2-ol
(Scheme VII; 28)
[0185] A mixture of (2R)-3-(4-fluoro)phenoxy-propan-1,2-diol 26
(5.0 g, 26.8 mmol) and pyridine (4.5 ml) in CH.sub.2Cl.sub.2 (60
ml) were cooled to 0.degree. C., and then p-toluenesulphonyl
chloride (5.0 g, 26.8 mmol) was added portionwise to the cooled
mixture. The mixture was stirred at room temperature overnight (TLC
2:3, ethyl acetate-hexane). The solvent was then removed by
codistillation with toluene, and the resulting residue purified by
silica gel column chromatography (2:3, ethyl acetate-hexane) to
afford the product 28 (7.7 g, 855).
[0186] Part 4: (2R)-1,2-epoxy-3-(4-fluoro)phenoxypropane (Scheme
VII; 4)
[0187] (2R)-(4-Fluoro)phenoxy-1-tosyloxy-propan-2-ol 28 (5.0 g,
14.7 mmol) in a solvent mixture of THF and DMF (100 ml, 4:1) was
cooled to 0.degree. C. and NaH (0.75 g, 19.2 mmol) was added
portionwise, followed by stirring of the reaction mixture for 1
hour at room temperature with monitoring of the reaction by TLC
(20% ethyl acetate in hexane). The THF was removed and the residue
was taken in ethyl ether (50 ml). That ether solution was washed
successively with water (3.times.50 ml), brine (1.times.50 ml)
dried (Na.sub.2SO.sub.4) and concentrated to afford
(2R)-1,2-epoxy-3-(4-fluoro)phenoxypropane 4 as a colorless oil
(2.53 g, 95%).
[0188] Part 5: (2R)-1-(4-fluoro)phenoxyhex-5-en-2-ol (Scheme VII;
29)
[0189] Magnesium (0.89 g, 36.6 mmol) and iodine (catalytic amount)
were taken in a 50 ml 2-neck round bottom flask provided with a
reflux condenser and a septum, under N.sub.2 atmosphere. A solution
of allyl bromide (3.0 g, 24.4 mmol) in 10 ml of ethyl ether was
slowly added and stirred for 30 minutes at room temperature.
Cuprous cyanide (22 mg) then was added, and the color of the
reaction mixture became dark brown. The reaction mixture was cooled
to -22.degree. C. (CCl.sub.4/dry ice bath), and
(2R)-1,2-epoxy-3-(4-fluoro)phenoxypropane 4 (2.05 g, 12.2 mmol) in
25 ml of ethyl ether was added. The reaction was completed within
30 minutes, as determined by TLC (benzene). Saturated aqueous
ammonium chloride (4 ml) then was added ant the mixture stirred for
30 minutes. Inorganic material was filtered and washed with ethyl
ether (25 ml). The ether layer was dried (sodium sulphate)
concentrated to give a colorless oil of
(2R)-1-(4-fluoro)phenoxyhex-5-en-2-ol 29 (2.3 g, 90%).
[0190] Part 6:
(2R)-2-benzenesulfonyloxy-1-(4-fluoro)-phenoxy-5-hexane (Scheme
VII; 30)
[0191] (2R)-(4 Fluoro)phenoxyhex-5-en-2-ol, 29 (7.4 g, 35.2 mmol),
triethylamine (10 ml) and 4-N,N'-dimethylaminopyridine (DMAP, 0.43
g, catalytic) were dissolved in 50 ml of dry CH.sub.2Cl.sub.2 and
cooled in ice bath while stirring. Benzenesulfonyl chloride (5 ml,
38.7 mmol) in CH.sub.2Cl.sub.2 (10 ml) was then added dropwise to
the mixture. The reaction mixture was stirred at room temperature
for 6 hours and monitored by TLC (benzene)]. Solvent then was
removed and the residue was poured onto a short silica gel column
and eluted with 1:4 ethyl acetate-hexane to afford
(2R)-2-benzenesulfonyloxy-1-(4-fluoro)-phenoxy-5- -hexane 30 as a
colorless oil (11.3 g, 92%).
[0192] Part 7:
(6R,2E)-ethyl-6-benzenesulfonyloxy-7-(4-fluoro)-phenoxy-hep-
t-2-en-1-oate (Scheme VII; 31)
[0193] (2R)-2-Benzenesulfonyloxy-1-(4-fluoro)-phenoxy-5-hexane 30
(11.3 g, 32.5 mmol 19) in 30 ml of dry CH.sub.2Cl.sub.2 was cooled
to -78.degree. C. O.sub.3 then was bubbled through the mixture
until the blue color persisted (30 minutes). A stream of N.sub.2
then was purged for 5 minutes through the mixture to remove excess
of ozone. Dimethylsulfide (13.9 ml 325 mmol) was added and stirred
for 2 hours. The reaction mixture was washed with water (2.times.25
ml), brine (1.times.30 ml) and concentrated to afford the crude
product (10.8 g, 95%). (2R)-Benzenesulfonyloxy-1-(4-f-
luoro)-phenoxy-5-pentanel (10.5 g, 30 mmol) was added and heated at
reflux for 5 hours. Ethoxycarbonylmethylene triphenylphosphorane
(11.5 g, 33 mmol) was added and heated at reflux for 5 hours.
Completion of the reaction was checked by TLC (1:10, EtOAc-benzene)
and the solvent was removed, the residue was purified by column
chromatography on silica gel (1:3, ethyl acetate-hexane) to afford
(6R,2E)-ethyl-6-benzenesulfonyloxy--
7-(4-fluoro)-phenoxy-hept-2-en-1-oate 31 (8.8 g, 70%) as a
colorless oil.
[0194] Part 8:
(6R,2E)-ethyl-6-benzenesulfonyloxy-7-(4-fluoro)-phenoxy-hep-
t-2-en-1-ol (Scheme VII; 32)
[0195]
(6R,2E)-Ethyl-6-benzenesulfonyloxy-7-(4-fluoro)-phenoxy-hept-2-en-1-
-oate 3 g, 7.1 mmol) 31 was dissolved in 30 ml of CH.sub.2Cl.sub.2
under N.sub.2 atmosphere and cooled to -78.degree. C. DIBAL-H (14.2
ml, 14.2 mmol, 1M solution in toluene) was added dropwise over 5
minutes and the solution was stirred at -78.degree. C. for 45
minutes. At reaction completion as monitored by TLC (2:5, ethyl
acetate-hexane), saturated aqueous ammonium chloride solution (3
ml) was added and the mixture stirred for another 30 minutes. The
reaction mixture then was filtered through a celite pad the
filtrate was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated, the residue was filtered through a short silica gel
pad and concentrated to obtain (6R,2E)-ethyl-6-benzenesu-
lfonyloxy-7-(4-fluoro)-phenoxy-hept-2-en-1-ol 32 as a solid (2.2 g,
82% yield).
[0196] Part 9:
(2S,3S,6R)-6-benzenesulfonyloxy-2,3-epoxy-7-(4-fluoro)-phen-
oxy-7-heptan-1-ol (Scheme VII; 33)
[0197] Powdered molecular sieves 4.ANG. (3 g) were activated under
N.sub.2 atmosphere in a 25 ml 2 necked round bottom flask.
CH.sub.2Cl.sub.2 (15 ml) was added followed by titanium
tetraisopropoxide (1.62 ml, 5.47 mmol), (+)-diisopropyltartrate
(1.07 ml, 6.56 mmol) and the mixture was cooled to -20.degree. C.
with stirring. After 5 minutes cumene-hydroperoxide (2.1 ml, 10.94
mmol, 80% solution in cumene) was added dropwise. The mixture was
stirred for 15 minutes at -20.degree. C.
(6R,2E)-benzenesulfonyloxy-7-(4-fluoro)-phenoxy-hept-2-en-1-ol 32
(2.0 g, 5.47 mmol) in 10 ml of CH.sub.2Cl.sub.2 was then added and
the reaction mixture was stirred for 2.5 hours at -20.degree. C.
The reaction mixture was checked for the completion by TLC (1:1,
ethyl acetate-hexane), 1 ml of 10% aqueous tartaric acid solution
was added at -20.degree. C. and the reaction mixture was warmed to
room temperature in 30 minutes. The reaction mixture was filtered
through a celite pad dried over Na.sub.2SO.sub.4, concentrated and
the residue was subjected to column chromatography on silica gel
(1:1, ethyl acetate-hexane) to afford
(2S,3S,6R)-6-benzenesulfonyloxy-2,3-epoxy-7-(4-fluoro)-phenoxy-7-heptan-1-
-ol 33 (2.4 g, 98% yield) as a solid.
[0198] Part 10:
(2S,3S,6R)-6-benzenesulfonyloxy-1-chloro-2,3-epoxy-7-(4-fl-
uoro)-phenoxy-heptane (Scheme VII; 34)
[0199]
(2S,3S,6R)-6-Benzenesulfonyloxy-2,3-epoxy-7-(4-fluoro)-phenoxy-7-he-
ptan-1-ol (2.25 g, 5.7 mmol) 33 and triphenylphosphine (1.5 g, 5.7
mmol) were dissolved in solvent mixture of CHCl.sub.3 and CCl.sub.4
(40 ml, 1:1) and NaHCO.sub.3 (0.3 g) was added. The reaction
mixture was refluxed for 3 hours and monitored by TLC (2:5, ethyl
acetate-hexane). Solvent was removed, the residue was purified by
column chromatography on silica gel (1:4, ethyl acetate-hexane) to
afford (2S,3S,6R)-6-benzenesulfonyloxy-1-c-
hloro-2,3-epoxy-7-(4-fluoro)-phenoxy-heptane 34 (1.5 g, 64% yield)
as a solid.
[0200] Part 11:
(2S,5S)-5-ethynyl-2-(4-fluoro)-phenoxymethyl-tetrahydrofur- an
(Scheme VII; 35)
[0201] n-BuLi (7.2 ml, 7.2 mmol) was added to a solution of freshly
distilled diisopropylamine (1.12 ml, 8.6 mmol) in 6 ml of dry THF
at -40.degree. C. and stirred for 15 minutes. A solution of
(2S,3S,6R)-6-benzenesulfonyloxy-1-chloro-2,3-epoxy-7-(4-fluoro)-phenoxy-h-
eptane 34 (1.0 g, 2.42 mmol) was added in 8 ml of dry THF. The
reaction mixture was stirred at -40.degree. C. for 1 hour and then
at room temperature for 1 hour. When TLC showed complete
consumption of starting material the reaction was quenched at
40.degree. C. with aqueous ammonium chloride (1 ml), THF was
removed under vacuo, the residue was taken in ethyl acetate,
filtered, dried over Na.sub.2SO.sub.4 and concentrated. Crude
product was subjected to column chromatography on silica gel (1:9,
ethyl acetate-hexane) to afford
(2S,5S)-5-ethynyl-2-(4-fluoro)-phenoxymet- hyl-tetrahydrofuran 35
(0.32 g, 60% yield).
[0202] Part 12: Preparation of
(2S,5S)-5-(2'-hydroxyethyl)-ethynyl-2-(4-fl-
uoro)-phenoxymethyltetrahydrofuran (Scheme VII; 10)
[0203] To a solution of
(2S,5S)-5-ethynyl-2-(4-fluoro)-phenoxymethyl-tetra- hydrofuran 35
(0.8 g, 3.6 mmol) in 15 ml of dry THF at -78.degree. C., n-BuLi (5
ml, 1M solution in hexane), stirred for 15 minutes. Freshly
distilled BF.sub.3Et.sub.2O (1.4 ml, 11 mmol) was added followed by
ethyleneoxide (excess, THF solution). The reaction mixture was
continued to stir at -78.degree. C. until completion (30 minutes).
Saturated aqueous ammonium chloride solution (1 ml) was added at
-78.degree. C. stirred for 5 minutes, warmed to room temperature,
THF was removed, residue was extracted with ether (2.times.20 ml),
combined organic layer was dried over Na.sub.2SO.sub.4,
concentrated to afford a residue. That residue was purified by
column chromatography on silica gel (2:5, ethyl acetate-hexane) to
afford (2S,5S)-5-(2'-hydroxyethyl)-ethynyl-2-(4-fluoro-
)-phenoxymethyltetrahydrofuran 10 (0.87 g, 90% yield) as a white
solid. That product 10 was found to be identical (NMR, optical
rotation, TLC) with samples prepared by Example 1 above.
EXAMPLE 7
[0204] Preparation of
(.+-.)-2-(4-fluorophenoxymethyl)-7-(4-N-hydroxy-urei-
dyl-1-butynyl)-oxepane (Scheme VIII; 42)
[0205] Part 1: (.+-.)-7-Benzyloxy-1-(fluorophenoxy)-heptane-2-ol
(Scheme VIII; 42)
[0206] Magnesium (2.4 g, 98 mmol) was added to a 250 ml flask and
flame dried. Dry THF, 25 ml, and 1 ml of dibromoethane were then
added. 1-Bromo-4-benzyloxy-butane 41 (12g, 49.4 mmol) dissolved in
50 ml of dry THF was added dropwise and the reaction mixture was
stirred at room temperature. After 1 hour, the reaction mixture is
cooled in an ice-water bath and 90 mg of copper cyanide is added.
After 10 minutes in an ice-bath, 4-fluorophenyl-glycidyl ether (5
g, 29.6 mmol) dissolved in 30 ml of dry THF is added slowly. The
reaction is monitored by TLC (ethyl acetate:hexane 3:7). After 15
minutes, the reaction is quenched with saturated aqueous ammonium
chloride, concentrated and partitioned between water-ethyl acetate.
The ethyl acetate layer is then washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated to give the desired
benzyloxy-heptane 42. The structure was confirmed by
.sup.1H-NMR.
[0207] Part 2:
(.+-.)-7-(4-Fluorophenoxy)-6-(2-methoxyethoxymethoxy)-hepta-
ne-1-ol (Scheme VIII, 43)
[0208] (.+-.)-7-Benzyloxy-1-(fluorophenoxy)-heptane-2-ol 42 (9.8 g,
29.5 mmol) in 30 ml of chloroform is added to a 100 ml round bottom
flask. Diisopropylethylamine 7.6 ml, 44.3 mmol) and
methoxyethoxymethyl chloride (3.7 ml, 32.5 mmol) are added and the
reaction mixture is stirred for 3 hours. The mixture is then washed
with water, brine, dried (Na.sub.2SO.sub.4) and concentrated. The
residue was purified on silica gel (ethyl acetate:hexane 1:9) to
give (.+-.)-7-benzyloxy-1-(4-fluorophen-
oxy)-2-(2-methoxyethoxy-methoxy)heptane 7-3 (11 g, 89%).
[0209] Part 3:
(.+-.)-7-(4-Fluorophenoxy)-6-(2-methoxyethoxymethoxy)heptan- -1-ol
(Scheme VIII; 44)
[0210]
(.+-.)-7-benzyloxy-1-(4-fluorophenoxy)-2-(2-methoxyethoxy-methoxy)--
heptane 43 (11 g, 26.3 mmol) in 30 ml of ethanol is added to 50 ml
round bottom flask. Palladium on activated carbon (10% Pd/C, 150
mg) is added and the reaction mixture is stirred under an
atmosphere of hydrogen. After 3 hours, the reaction mixture was
filtered through celite, washed with ethanol and concentrated. The
crude product was purified on silica gel (ethyl acetate:hexane 1:1)
to give (.+-.)-7-(4-fluorophenoxy)-6-(2-me-
thoxyethoxymethoxy)heptan-1-ol 44 (7.9 g, 91%). The structure was
confirmed by .sup.1H-NMR.
[0211] Part 4:
(.+-.)-7-(4-Fluorophenoxy)-6-(2-methoxyethoxymethoxy)-hepta- n-1-al
(Scheme VIII; 45)
[0212] Oxalyl chloride (2.9 ml, 33.6 mmol) is added to 25 ml of
methylene chloride and cooled to -78.degree. C. Dry dimethyl
sulfoxide (4.7 ml, 67.2 mmol) is then added and the reaction is
stirred at -78.degree. C. After 45 minutes,
(.+-.)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)-h- eptan-1-ol
44 (3.7 g, 11.2 mmol) dissolved in CH.sub.2Cl.sub.2 is added and
the reaction is stirred at -78.degree. C. After 1 hour, the
reaction is quenched with 15.7 ml of triethylamine and diluted with
CH.sub.2Cl.sub.2. The reaction mixture is then washed with water,
brine dried (Na.sub.2SO.sub.4) and concentrated. The crude product
is purified on silica gel (ethyl acetate:hexane 1:9) to give
(.+-.)-7-(4-fluorophenox- y)-6-(2-methoxyethoxymethoxy)-heptan-1-al
45, 3.3 g, 89%.
[0213] Part 5: (.+-.)-7-(4-fluorophenoxy)-6-(hydroxy)-heptan-al
(Scheme IX; 47)
(.+-.)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)heptan-1-al 45
(2 g, 6.1 mmol) and 2 ml of trifluoroacetic acid are added to 10 ml
of chloroform. The reaction mixture is stirred for 24 hours and
then is neutralized with 1% aqueous NaOH. The organic layer is
washed with water, brine, dried (Na.sub.2SO.sub.4), concentrated.
The crude trifluoroacetyl-aldehyde 46 is then dissolved in
MeOH:H.sub.2O (1:1) and solid K.sub.2CO.sub.3 is added to maintain
pH 8. The reaction is complete is approximately 15 minutes, as
monitored by TLC (ethyl acetate:hexane 3:7). Methanol is removed in
vacuo and remaining solution is extracted with ethyl acetate to
give (.+-.)-7-(4-fluorophenoxy)-6-(hydroxy)-heptan-- al 47 (1.2 g,
82%).
[0214] Part 6:
(.+-.)-7-(Benzylsulfonyl)-4-fluorophenopxymethyl)-oxepane (Scheme
IX; 48)
[0215] Benzene sulfinic acid (0.79 g, 5.62 mmol) and CaCl.sub.2
(0.62 g, 5.62 mmol) are added to 15 ml of CH.sub.2Cl.sub.2 and
cooled in an ice-water bath.
(.+-.)-7-(4-Fluorophenoxy)-6-(hydroxy)heptan-1-al 47 (0.90 g, 3.75
mmol), dissolved in 5 ml of CH.sub.2Cl.sub.2, is added to the
reaction mixture and stirred at room temperature. After 3 hours the
reaction mixture is filtered through celite and washed with
CH.sub.2Cl.sub.2. The filtrate is washed with saturated aqueous
Na.sub.2CO.sub.3, water, brine, dried (Na.sub.2SO.sub.4) and
concentrated. The crude product is then purified on silica gel
(ethyl acetate:hexane 1:6) to give
(.+-.)-7-(benzylsulfonyl)-(4-fluorophenopxyme- thyl)-oxepane 48 in
80% yield (1.1 g). The structure was confirmed by .sup.1H-NMR.
[0216] Part 7:
(.+-.)-2-(4-Fluorophenoxymethyl)-7-(tetrahyropyranloxybutyn-
-1-yl)-oxepane (Scheme IX; 49)
[0217] Magnesium (0.1 g, 4.3 mmol) was added to a 50 ml round
bottom flask and flame dried. Dry THF (10 ml) and a few drips of
1,2-dibromoethane were then added followed by isopropyl bromide
(0.34 g, 2.7 mmol). The reaction was stirred for 1 hour and the
resulting isopropyl magnesium bromide solution was cannulated into
a 100 ml flame dried flask. 4-Tetrahydropyranoyl-1-butyne (0.34 g,
2.18 mmol) dissolved in THF was added to the reaction mixture and
it was stirred. After 30 minutes, the reaction mixture was cooled
in an ice-water bath and ZnBr.sub.2 (1.3 ml, 1 M in THF) was added
at room temperature. After 45 minutes,
(.+-.)-7-benzensulfonyl)-2-(4-fluorophenoxymethyl)-oxepane (0.4 g,
1.1 mmol) dissolved in 2 ml of THF was added. The reaction was
stirred at room temperature for 30 minutes, then cooled in an
ice-water bath and the reaction was quenched with saturated aqueous
NH.sub.4Cl. THF was removed in vacuo and the reaction mixture was
partitioned between water and ethyl acetate. The ethyl acetate
layer was washed with water, brine, dried (Na.sub.2SO.sub.4) and
concentrated to get (.+-.)-2-(4-fluorophenoxymethy-
l)-7-(4-teterahydropyranyloxybutyn-1-yl)-oxepane 49 which was used
with out further purification.
[0218] Part 8:
(.+-.)-2-(4-Fluorophenoxymethyl)-7-(4-hydroxybutyn-1-yl)-ox- epane
(Scheme X; 50)
[0219]
(.+-.)-2-(4-Fluorophenoxymethyl)-7-(4-teterahydropyranloxybutyn-1-y-
l)-oxepane 49 from the above reaction was dissolved in 5 ml of
methanol and 2 ml of 1% HCl in methanol was added. Hydrolysis of
the THP group was complete in 2 hours as detected by TLC (ethyl
acetate:hexane 4:6). The reaction mixture was neutralized by
addition of solid Na.sub.2CO.sub.3 and solvent was evaporated. The
residue was dissolved in ethyl acetate, washed with water, brine,
dried (Na.sub.2So.sub.4) and concentrated. The crude product was
purified on silica gel (ethyl acetate:hexane 3:7) to give
(.+-.)-2-(4-fluorophenoxymetyl)-7-(4-hydroxybutyn-1-yl)-oxepane 50
(0.24 g, 75%). The product was confirmed by .sup.1H-NMR.
[0220] Part 9:
(.+-.)-2-(4-Fluorophenoxymethyl)-7-[4-(N,O-biscarbo-henoxy)-
-1-butynyl]-oxepane (Scheme X; 51)
[0221] A solution of
(.+-.)-2-(4-fluorophenoxymetyl)-7-(4-hydroxybutyn-1-y- l)-oxepane
50 (0.12 g, 0.41 mmol) and 5 ml of dry THF was cooled in an
ice-water bath. Triphenylphosphine (0.13 g, 0.49 mmol),
N,O-biscarbophenoxy-hydroxylamine (0.135 g, 0.49 mmol) and diethyl
azodicarboxylate (0.85 g, 0.49 mmol) were then added sequentially.
The reaction mixture was stirred at room temperature. After 4
hours, solvent was in vacuo and the residue was dissolved in ethyl
acetate, washed with water, brine, dried (Na.sub.2SO.sub.4) and
concentrated. The residue was purified on silica gel (ethyl
acetate:hexane 6:1) to give
(.+-.)-2-(4-fluorophenoxymethyl)-7-[4-N,O-biscarbo-henoxy)-butynyl]-oxepa-
ne 51 in 92% yield (0.195 g). The structure was confirmed by
.sup.1H-NMR.
[0222] Part 10:
(.+-.)-2-(4-Fluorophenoxymethyl)-7-(4-N-hydroxy-ureidyl-1--
butynyl)-oxepane (Scheme X; 52)
[0223]
(.+-.)-2-(4-Fluorophenoxymethyl)-7-[4-N,O-biscarbo-henoxy)-butynyl]-
-oxepane 51 was dissolved in 10 ml of methanol and 2 ml of a
saturated solution of ammonia in methanol was added. The reaction
mixture was stirred at room temperature. After 12 hours the solvent
was removed and the crude product was purified on silica gel (ethyl
acetate:hexane 1:1) to give
(.+-.)-2-(4-fluorophenoxymethyl)-7-(4-N-hydroxy-ureidyl-1-butynyl-
)-oxepane 52 in 82% yield (55 mg). The structure was confirmed by
.sup.1H-NMR.
EXAMPLE 8
[0224] Preparation of
(2RS,6S)-2-Benzenesulfonyl-6-(4-fluorophenoxymethyl)-
-tetrahydropyran.
[0225] References in this Example 8 to compound numerals (generally
underlined) designate the compounds depicted structurally in the
following Scheme XIX; 29
[0226] Part 1: (S)-Glycidyl-4-fluorophenyl ether (Scheme XIX;
3):
[0227] To a solution of 4-fluorophenol (40 g, 0.35 mol) in acetone
(350 ml) was added dry K.sub.2CO.sub.3 (148 g, 1.05 mol) and
epichlorohydrin (95 ml, 1.05 ml). The reaction was heated at
60.degree. C. for 12h, then filtered and the filtrate distilled
under reduced pressure (b.p. 160.degree.-170.degree. C./9 mm) to
afford pure (R,S)-glycidyl-4-fluoroph- enyl ether (52 g, 85%) as a
colourless liquid. Co-salen acetate (RR-catalyst) (1.03 g, 1.54
mmol) was added to (R, S)-glycidyl-4-fluorophenyl ether (52 g, 0.31
mol), followed by drop wise addition of water (3.06 ml, 0.17 mol)
over 1h at 0.degree. C. The reaction mixture was allowed to come to
room temperature and stirred for 18h. The catalyst was filtered off
and the filtrate distilled under reduced pressure to afford
(S)-glycidyl-4-fluorophenyl ether (22 g, 85%) as a colourless
liquid. TLC: ethyl acetate-light petroleum (1:4), Rf=0.5. Boiling
point: 160.degree.-170.degree. C./9 mm. Optical rotation
[.alpha.].sub.D: +5.degree. (c 2.3, CHCl.sub.3). .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta.2.68 (dd, J=4.5, 2.2 Hz, 1H), 2.85 (t,
J=4.5 Hz, 1H), 3.27 (m, 1H), 3.89 (dd, J=15.7, 6.7 Hz, 1H), 4.11
(dd, J=15.7, 4.5 Hz, 1H), 6.74-7.02 (m, 4H).
[0228] Part 2: Methyl
(S)-6-(4-fluorophenoxy)-5-hydroxy-hex-2-ynoate (Scheme XIX; 4):
[0229] A solution of n-BuLi in hexane (11.4 ml, 26.8 mmol) was
added at -78.degree. C. to a solution of methyl propiolate (2.25 g,
26.8 mmol) in THF (15 ml) under N.sub.2 atmosphere and the mixture
was stirred for 20 min. Borontrifluoride etherate (3.4 ml, 26.8
mmol) was then added to the solution, stirring was continued for a
further 20 min at -78.degree. C. A solution of
(S)-glycidyl-4-fluorophenyl ether (3 g, 17.8 mmol) in THF (10 ml
was then added and after stirring for 1h at -78.degree. C., the
reaction was quenched by the addition of aqueous NH.sub.4Cl. The
reaction mixture was extracted with ethylacetate, dried
(Na.sub.2So.sub.4), and concentrated. The crude product was
purified on a silica gel (EtOAc-light petroleum (1:4) as eluent) to
afford methyl (S)-6-(4-fluorophenoxy)-5-hyd- roxy hex-2-ynoate (2.5
g, 60%) as a yellow color liquid. TLC: ethyl acetate-light
petroleum (1:3), Rf=0.4. Optical rotation [.alpha.].sub.D:
+15.5.degree. (c 1.2, CHCl.sub.3). .sup.1H NMR (CDCl.sub.3, 200
MHz): .delta.2.62 (d, J=5 Hz, 1 H), 2.71 (d, J=5.6 Hz, 2H), 3.76
(s, 3H), 3.92-4.02 (m, 2H), 4.2 (m, 1H), 6.8-7.02 (m, 4H).
[0230] Part 3: Methyl (S)-6-(4-fluorophenoxy)-5-hydroxy-hexanoate
(Scheme XIX; 5):
[0231] To a solution of methyl (S)-6-(4-fluorophenoxy)-5-hydroxy
hex-2-ynoate (2.5 g, 9.9 mmol) in methanol (20 ml), 10% Pd/C (250
mg) was added and the mixture stirred under H.sub.2 at room
temperature for 3h. The reaction mixture was filtered through
celite, washed with methanol and concentrated in vacuum. The
residue was purified on silica gel column using EtOAc-light
petroleum (1:4) to give methyl (S)-6-(4-fluorophenoxy)--
5-hydroxy-hexanoate (2.15 g, 85%) as a colourless liquid. TLC:
ethyl acetate-light petroleum (1:3), Rf=0.4. Optical rotation
[.alpha.].sub.D:+8.degree. (c 1.1, CHCl.sub.3). .sup.1H NMR
(CDCl.sub.3, 200 MHz): .delta.1.55-1.9 (m, 4H), 2.3-2.43 (t,J=6.5
Hz, 2H), 2.5 (s, 1H), 3.68 (s, 3H), 3.76-4.02 (m, 3H), 6.76-7.02
(m, 4H).
[0232] Part 4: (6S)-6-(4-Fluorophenoxymethyl)-tetrahydropyran-2-one
(Scheme XIX; 6):
[0233] To a solution of methyl
(S)-6-(4-fluorophenoxy)-5-hydroxy-hexanoate (0.8 g 3.12 mmol) in
CH.sub.2Cl.sub.2 (20 ml), a catalytic amount of PTSA (10 mg) was
added and the reaction mixture was stirred at 40.degree. C. for
12h. The reaction was then neutralised with sodium bicarbonate and
the product extracted with dichloromethane. The organic layer was
dried (Na.sub.2SO.sub.4) and concentrated. The crude product on
purification on a silica gel (EtOAc-light petroleum (1:3) as
eluent) gave (6S)-6-(4-fluorophenoxymethyl)-tetrahydropyran-2-one
(0.5 g, 70%) as a colourless liquid. TLC: ethyl acetate-light
petroleum (1:4), Rf=0.3 Optical rotation [.alpha.].sub.D:
+19.degree. (c 0.9, CHCl.sub.3). .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.1.7-2.15 (m, 4H), 2.48-2.7 (m, 2H), 3.95-4.15 (m, 2H),
4.55-4.7 (m, 1H), 6.77-7.0 (m, 4H).
[0234] Part 5: (2RS,
6S)-2-Benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetra- hydropyran
(Scheme XIX; 8):
[0235] To solution of
(6S)-6-(4-fluorophenoxymethyl)-tetrahydropyran-2-one (0.5 g, 2.23
mmol) in dry CH.sub.2Cl.sub.2 was added DIBAL-H (1 ml, 2M solution
in toluene, 2.4 mmol) dropwise at -78.degree. C. The reaction
mixture was stirred at -78.degree. C. for 3h. It was then quenched
with potassium sodium tartrate, extracted with dichloromethane,
dried (Na.sub.2SO.sub.4), and concentrated to afford the crude
product (0.42 g, 85%).
[0236] 25% HCl was added dropwise to benzenesulfinic acid sodium
salt (0.6 g), until the solid dissolved. This mixture was extracted
with ethyl acetate (15 ml) dried (Na.sub.2SO.sub.4) and
concentrated to give benzenesulfinic acid (0.4 g). To an ice-cooled
mixture of benzenesulfinic acid (0.32 g, 2.23 mmol) and calcium
chloride (0.25 g, 2.23 mmol) in dry CH.sub.2Cl.sub.2 a solution of
(2RS, 6S)-6-(4-fluorophenoxymethyl)-2-hydr- oxy-tetrahydropyran
(0.42 g, 1.86 mmol) in dry CH.sub.2Cl.sub.2 (5 ml) was added. The
reaction mixture was stirred for 4h, filtered through celite and
washed with CH.sub.2Cl.sub.2. The combined organic layers were
washed with saturated aqueous Na.sub.2CO.sub.3, water, brine and
dried (Na.sub.2SO.sub.4). The solvent was removed under vacuum and
the residue was purified on a silica gel column using light
petroleum-ethyl acetate (4:1) as eluent to afford pure (2RS,
6S)-2-benzenesulfonyl-6-(4-fluorophe- noxymethyl)-tetrahydropyran
(0.5 g, 70%) as a viscous liquid. TLC: ethyl acetate-light
petroleum (1:3), Rf=0.4. .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.1.5 (m, 2H), 1.75-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m,
1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H), 4.85-5.0 (m, 1H), 6.7-7.0 (m,
4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz, 2H).
EXAMPLE 9
[0237] Preparation of (2S,
6S)-6-(4-Fluorophenoxymethyl)-2-(4-N-hydroxyure-
idyl-1-butynyl)-tetrahydropyran (Scheme XX; 17):
[0238] Reference in this Example 9 to compound numerals (generally
underlined) designate the compounds depicted structurally in the
following Scheme XX: 30
[0239] Part 1: (2S)-6-Benzyloxy-1-(4-fluorophenoxy)-hex-4-un-2-ol
(Scheme XX; 9):
[0240] To a solution of benzyloxy prop-2-yne (2.3 g, 16 mmol) in
dry THF (25 ml) at -78.degree. C. was added n-BuLi in hexane (10.7
ml, 16 mmol) and the mixture stirred for 20 min. Borontrifluoride
etherate (2 ml, 16 mmol) was then added to the solution and
stirring continued for 20 min. at -78.degree. C. A THF solution of
(S)-glycidol-4-fluorophenyl ether (1.8 g, 10.7 mmol) was added and
after stirring for 1h at -78.degree. C., the reaction was quenched
by adding aqueous NH.sub.4Cl. The organic materials were extracted
with ethyl acetate, dried (Na.sub.2SO.sub.4) and concentrated under
vacuum. The crude product was purified on a silica gel column using
EtOAc-light petroleum (1:4) as eluent to give
(2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 65%) as a
yellow colour liquid. TLC: ethyl acetate-light petroleum (1:3),
Rf=0.4. .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.2.65 (m, 2H),
3.95-4.10 (m, 2H), 4.13-4.21 (m, 3H), 4.6 (s, 2H), 6.8-7.02 (m,
4H), 7.30-7.38 (m, 5H).
[0241] Part 2:
(2S)-6-Benzyloxy-1-(4-fluorophenoxy)-2-(methoxyethoxymethyl-
oxy)-hex-4-yne (Scheme XX; 10):
[0242] To an ice cooled solution of
(2S)-6-benzyloxy-1-(4-fluorophenoxy)-h- ex-4-yn-2-ol (2 g, 6.4
mmol) in dry CH.sub.2Cl.sub.2 (8 ml) was added
N-ethyldiisopropylamine (1.7 ml, 9.5 mmol) and stirred for 10
minutes MEM-chloride (1.1 ml, 9.5 mmol) was added to the solution
at 0.degree. C. and stirred for 3h at room temperature. The solvent
was concentrated and the residue purified on a silica gel column
using EtOAc-light petroleum (1:4) as eluent to yield
(2S)-6-benzyloxy-1-(4-fluorophenoxy)-2-(methoxye-
thoxymethyloxy)-hex-4-yne (2.2 g, 85%) as a yellow colour liquid.
TLC: ethyl acetate-light petroleum (1:3), Rf=0.5 .sup.1 H NMR
(CDCl.sub.3, 200 MHz): .delta.2.65-2.75 (m, 2H), 3.39 (s, 3H), 3.55
(t, J=4.8 Hz, 2H), 3.78 (t, J=4.8 Hz, 2H), 4.11 (s, 2H), 4.16 (m,
3H), 4.56 (s, 2H), 4.89 (s, 2H), 6.8-7.02 m, 4H), 7.3-7.35 (m,
5H).
[0243] Part 3:
(2S)-1-(4-Fluorophenoxy)-2-(methoxyethoxymethyloxy)-hexan-6- -ol
(Scheme XX; 11):
[0244] To a solution of
(2S)-6-benzyloxy-1-(4-fluorophenoxy)-2-(methoxyeth-
oxymethyloxy)-hex-4-yne (2.2 g, 5.4 mmol) in dry methanol (20 ml)
was added 10% Pd/C (250 mg) and the mixture stirred under H.sub.2
at room temperature for 4h. The reaction mixture was filtered
through celite, washed with excess methanol. Evaporation of the
solvent afforded a crude product which was purified by silica gel
column using ethyl acetate-light petroleum (2:3) as eluent to give
(2S)-1-(4-fluorophenoxy)-2-(methoxyetho- xymethyloxy)-hexan-6-ol
(1.3 g, 76%) as a colourless liquid. TLC: ethyl acetate-light
petroleum (2.3), Rf=0.3. .sup.1H NMR (CDCl.sub.3, 200 MHz)
.delta.1.5-1.7 (m, 6H), 3.35 (s, 3H), 3.5 (t, J=4.8 Hz, 2H), 3.65
(t, J=4.8 Hz, 2H), 3.7-3.8 (m, 2H), 3.85-3.95 (s, 3H), 4.75-4.95
(dd, J=12.6, 6.0 Hz, 2H), 6.75-7.0 (m, 4H).
[0245] Part 4: (2Rs,
6S)-6-(4-Fluorophenoxymethyl)-2-methoxy-tetrahydropyr- an (Scheme
XX; 13):
[0246] To a solution of
(2S)-1-(4-fluorophenoxy)-2-(methoxyethoxymethyloxy- )-hexan-6-ol
(1.25 g, 3.9 mmol) and oxalyl chloride (0.7 ml, 7.9 mmol) in dry
CH.sub.2Cl.sub.2 was added dry DMSO (1.12 ml, 15.8 mmol) slowly at
-78.degree. C. The stirring was continued for a further 30 min. at
-78.degree. C. and quenched with dry Et.sub.3N (3.15 ml, 23.7
mmol). The reaction mixture was extracted with CH.sub.2Cl.sub.2 and
dried (Na.sub.2SO.sub.4) to afford the crude aldehyde (1.1 g, 85%).
A 20% methanolic HCl solution was added to the aldehyde and stirred
for 5h. at room temperature. The reaction mixture was neutralised
with aqueous NaHCO.sub.3, extracted with ethyl acetate, dried
(Na.sub.2SO.sub.4) and concentrated under vacuum. The crude product
was purified by silica gel column chromatography to give a
cis-trans mixture (2RS,
6S)-6-(4-fluorophenoxymethyl)-2-methoxytetrahydropyran (0.6 g, 80%)
as a yellow syrup. TLC: ethyl acetate-light petroleum (1:3),
Rf=0.8. .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.1.6-2.0 (m, 6H),
3.45 (s, 3H), 3.9-3.96 (m, 2H), 4.0-4.15 (m, 1H), 4.8 (s, 1H),
6.8-7.01 (m, 4H).
[0247] Part 5: (2RS,
6S)-2-Benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetra- hydropyran
(Scheme XX; 8):
[0248] 25% HCl was added dropwise to benzenesulfinic acid sodium
salt (2.0 g), till the solid dissolved. This mixture was extracted
with ethyl acetate (30 ml), dried (Na.sub.2SO.sub.4) and
concentrated to give benzenesulfinic acid (1.5 g). To an ice-cooled
mixture of benzenesulfinic acid (1.48 g, 10.5 mmol) and calcium
chloride (1.15 g, 10.5 mmol) in dry CH.sub.2Cl.sub.2 a solution of
(2RS, 6S)-6-(4-fluorophenoxymethyl)-2-meth- oxytetrahydropyran (0.5
g, 2.1 mmol) in dry CH.sub.2Cl.sub.2 (5 ml) was added. The reaction
mixture was stirred for 4h, filtered through celite and washed with
CH.sub.2Cl.sub.2. The combined organic layer was washed with
saturated aqueous Na.sub.2CO.sub.3, water, brine and dried
(Na.sub.2SO.sub.4). The solvent was removed under vacuum and the
residue was purified on a silica gel column using light
petroleum-ethyl acetate (4:1) as eluent to afford pure (2RS,
6S)-6-benzenesulfonyl-2-(4-fluorophe- noxymethyl)-tetrahydropyran
(0.5 g, 70%) as a viscous liquid. TLC: ethyl acetate-light
petroleum (1:3), Rf=0.4. .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.1.5 (m, 2H), 1.75-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m,
1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H), 4.85-5.0 (m, 1H), 6.7-7.0 (m,
4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz, 2H).
[0249] Part 6: (2S,
6S)-6-(4-Fluorophenoxymethyl)-2-(4-hydroxybutyn-1-yl)--
tetrahydropyran (Scheme XX; 15).
[0250] To a suspension of magnesium (0.14 g, 5.7 mmol) in dry THF
(5 ml) catalytic 1,2-dibromoethane was added followed by dropwise
addition of a solution of isopropylbromide (0.3 ml, 2.86 mmol) in
THF. The reaction mixture was stirred for 1h and the
isopropylmagnesiumbromide was cannulated into a two necked flask. A
solution 4-tetrahydropyranoyl-1-but- yne (0.44 g, 2.86 mmol) in THF
(2 ml) was added and the mixture was stirred for 30 min. and cooled
to 0.degree. C. Freshly prepared ZnBr.sub.2 solution (2 ml, 1.7
mmol) in THF was introduced dropwise. After 45 min. at room
temperature (2RS,6S)-2-benzenesulfonyl-6-(4-fluorop-
henoxymethyl)-tetrahydropyran (0.5 g, 1.43 mmol) in THF (4 ml) was
added and the mixture stirred for 3h. The reaction was quenched
with saturated aqueous NH.sub.4Cl solution at 0.degree. C. THF was
removed under vacuum and the residue was extracted with ethyl
acetate, dried (Na.sub.2SO.sub.4) and concentrated to give 2S,
6S)-6-(4-fluorophenoxymet-
hyl)-2-(4-tetrahydropyranoyl-1-butyne)-tetrahydropyran. The crude
product was dissolved in methanol (5 ml) and 5% HCl in methanol (10
ml) was added. The reaction mixture was stirred at room temperature
for 2h and neutralised with saturated aqueous Na.sub.2CO.sub.3
solution and concentrated. The residue was extracted with ethyl
acetate, dried (Na.sub.2SO.sub.4) and concentrated. The crude
product was purified on a silica gel column to give (2S,
6S)-6-(4-fluorophenoxymethyl)-2-(4-hydroxy-
butyn-1-yl)-tetrahydropyran (0.24 g, 70%) as a colourless liquid
and as a single isomer (by HPLC). TLC: ethyl acetate-light
petroleum (1:3), Rf=0.3. Optical rotation [.alpha.].sub.D:
-32.degree. (c 1.1, CHCl.sub.3). .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.1.6-2.0 (m, 6H), 2.55 (m, 2H), 3.73 (t, J=6.35 Hz, 2H),
3.8-4.0 (m, 2H), 4.15-4.3 (m, 1H), 4.8 (s, 1H), 6.80-7.0 (m,
4H).
[0251] Part 7: N,O-bis-phenoxycarbonylhydroxylamine:
[0252] To a solution of sodium bicarbonate (21.5 g, 0.256 mol) in
water (150 ml) at 0.degree. C. was added hydroxylamine
hydrochloride (8.8 g, 0.127 mol). The reaction mixture was stirred
for 30 min. and phenylchloroformate (60 g, 0.383 mol) was
introduced directly into the vigorously stirred mixture. Sodium
bicarbonate (32.3 g, 3.85 mol) in water (300 ml) was added to the
mixture. The mixture was stirred for 30 min., the ice-bath removed
and stirring continued for an additional 2h at room temperature.
The resultant suspension was filtered and the filter cake washed
with water. The wet filter cake was collected, suspended in hexane,
filtered and again washed with hexane. The solid was kept at
0.degree. C. overnight to afford
N,O-bis-phenoxycarbonylhydroxylamine (23.5 g, 68%) as a solid.
Melting point: 80.degree.-82.degree. C. .sup.1H NMR (CDCl.sub.3,
200 MHz): .delta.7.26 (m, 5H), 7.42 (m, 5H) and 8.54 (s, 1H).
[0253] Part 8: (2S,
6S)-6-(4-Fluorophenoxymethyl)-2-(4-N,O-bis-phenoxycarb-
onylhydroxylamino-1-butynyl)-tetrahydropyran (Scheme XX; 16):
[0254] To an ice cooled solution of (2S,
6S)-6-(4-fluorophenoxymethyl)-2-(-
4-hydroxybutyn-1-yl)-tetrahydropyran (0.23 g, 0.83 mmol) in dry THF
(10 ml), triphenylphosphine (0.26 g, 0.99 mmol) and
N,O-bis-phenoxycarbonyl hydroxylamine (0.26 g, 0.95 mmol) were
added. After 15 min., diethylazodicarboxylate (0.173 g, 0.99 mmol)
was added dropwise. The mixture was then allowed to warm to room
temperature and stirred for 3h. The solvent was evaporated under
reduced pressure and the residue purified on a silica gel column to
yield (2S, 6S)-6-(4-fluorophenoxymethy-
l)-2-(4-N,O-bis-phenoxycarbonylhydroxylamino-1-butynyl-tetrahydropyran
(0.3 g, 70%) as a yellow colour liquid. TLC: ethyl acetate-light
petroleum (1:3), Rf=0.6 .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.1.45-1.8 (m, 6H), 2.75 (t,J=6.8 Hz, 2H), 3.75-3.9 (m,2H),
4.0-4.1 (t,J=7.32 Hz, 2H)4.15-4.3 (m, 1H), 6.7-6.95 (m, 4H),
7.1-7.45 (m, 10H).
[0255] Part 9: (2S,
6S)-6-(4-Fluorophenoxymethyl)-2-(4-N-hydroxyureidyl-1--
butynyl)-tetrahydropyran (Scheme XX; 17):
[0256] A solution of (2S,
6S)-6-(4-fluorophenoxymethyl)-2-(4-N,O-bis-pheno- xycarbonyl
hydroxylamino-1-butynyl)-tetrahydropyran (0.3 g, 0.56 mmol) and
aqueous NH.sub.4OH in methanol (10 ml) were stirred at room
temperature for 12h. Methanol was evaporated and the residue was
purified on a silica gel column using light petroleum-ethyl acetate
(2:3) as eluent to give (2S,
6S)-6-(4-fluorophenoxymethyl)-2-(4-N-hydroxyureidyl-1-butynyl)-tetra-
hydropyran (0.12 g, 65%) as a yellow viscous liquid. TLC: ethyl
acetate-light petroleum (4:1), Rf=0.3. Optical rotation
[.alpha.].sub.D:-28.degree. (c 1.2, CHCl.sub.3). .sup.1H NMR
(CDCl.sub.3, 200 MHz): .delta.1.5-2.0 (m, 6H), 2.45-2.6 (t, J=6.35
Hz, 2H), 3.65 (t, J=7.32 Hz, 2H), 3.75-3.9 (m, 2H), 4.1-4.3 (m,
1H), 4.75
EXAMPLE 10
[0257] Preparation of (2S,
6S)-6-(4-Fluorophenoxymethyl)-2-(4-N-hydroxyure-
idyl-1-butynyl)-tetrahydropyran (Scheme XXI; 9):
[0258] References in this Example 10 to compound numerals
(generally underlined) designate the compounds depicted
structurally in the following Scheme XXI. 31
[0259] Reagents: a) (a), 0.55 eq. H.sub.2O b) Mg,
1,2-dibromoethane, CuCN, THF c) Pd/C, H.sub.2, EtOH d) IBX, THF,
DMSO e) PhSO.sub.2H, CaCl.sub.2, CH.sub.2Cl.sub.2 f) (i) isopropyl
magnesiumbromide, CH.ident.CCH.sub.2CH.sub.2OTHP, ZnBr.sub.2, THF
(ii) 1%HCl-MeOH g) TPP. PhO.sub.2CONHCO.sub.2Ph, DEAD, THF h)
NH.sub.3-MeOH
[0260] Part 1: (2S)-7-Benzyloxy-1-(4-fluorophenoxy)-heptane-2-ol
(Scheme XXI; 3)
[0261] To a suspension of magnesium (1.4 g, 57.6 mmol) in dry THF
(25 ml) was added 1,2-dibromoethane (1 ml) dropwise followed by
addition of a solution of 1-bromo-4-benzloxy-butane (7 g, 28.8
mmol) in dry THF (25 ml) slowly at room temperature. The reaction
mixture was stirred for 1 hour, cooled in ice-salt bath and then
CuCN (50.0 mg, 0.57 mmol) was added followed by a solution of
(S)-4-fluorophenyl-glycidyl ether (2.9 g, 17.3 mmol) in dry THF (30
ml) was introduced slowly. The reaction was stirred for 15 min and
quenched with saturated aqueous ammonium chloride solution at
0.degree. C. THF was removed under vacuum and the residue
partitioned between EtOAc and water. The organic layer was
successively washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated. The crude product was purified
on silica gel chromatography using EtOAc-hexane (1:6) as eluent to
give (2S)-7-benzyloxy-1-(4-fluorophenoxy)-heptane-2-ol (5.8 g,
73%), [.alpha.].sub.D+12 (c 2.2, CHCl.sub.3), .sup.1H-NMR
(CDCl.sub.3, 200 Hz): .delta.1.35-1.69 (m, 8H), 3.45 (t, J=6.25
Hz,2H), 3.71-3.95 (m, 2H), 4.48 (s, 2H), 6.77-7.00 (m, 4H),
7.27-7.35 (m, 5H); HRMS (FAB); calcd. for C.sub.20H.sub.25O.sub.3F
(M+) 332.178773 found 332.180309.
[0262] Part 2: (6S)-7-(4-fluorophenoxy)-heptane-1,6-diol (Scheme
XXI; 4):
[0263] To a solution of
(2S)-7-Benzyloxy-1-(4-fluorophenoxy)-heptane-2-ol (5.8 g, 17.5
mmol) in ethanol (30 ml), 10% of Pd/C (100 mg) was added and
stirred under H.sub.2 atmosphere at normal temperature and pressure
for 3 hours. The reaction mixture was filtered through celite,
washed with ethanol and concentrated. The residue was purified by
silica gel chromatography using EtOAc-hexane (1:1) to give
(6S)-7-(4-fluorophenoxy)-- heptane-1,6-diol (3.92 g, 93%);
[.alpha.].sub.D+12 (c 3.1, CHCl.sub.3), .sup.1H-NMR CDCl.sub.3, 200
Hz): .delta.1.29-1.69 (m, 8H), 3.65 (t, J=6.8 Hz, 2H), 3.82-4.01
(m, 2H), 6.75-7.0 (m, 4H); HRMS (EI): calcd. for
C.sub.13H.sub.19O.sub.3F (M+) 242.131823 found 242.131900.
[0264] Part 3: (6S)-7-(4-fluorophenoxy)-6-hydroxy-heptanal (Scheme
XXI; 5)
[0265] To a solution of (6S)-7-(4-fluorophenoxy)-heptane-1,6-diol
(3.6 g, 14.8 mmol) in dry THF (60 ml) was added dropwise a solution
of 2-iodobenzoic acid (5 g, 17.8 mmol) in dry DMSO (4 ml) over a
period of 25 minutes at room temperature. After 15 minutes the
reaction mixture was decomposed with crushed ice, filtered through
celite and concentrated. The residue was extracted with ethylether,
washed with brine, dried over Na.sub.2SO.sub.4 and the organic
solvent was removed under reduced pressure. The residue was
purified by silica gel chromatography using EtOAc-hexane (1:9) to
give (6S)-7-(4-fluorophenoxy)-6-hydroxy-heptanal (2.2 g, 61.6%);
[.alpha.].sub.D+12 (c 3.8, CHCl.sub.3), .sup.1H-NMR (CDCl.sub.3,
200 Hz): .delta.1.4-1.8 (m, 6H), 2.49 (dt, 2H), 3.71-4.05 (m, 4H),
6.782-7.02 (m, 4H), 9.8 (s, 1H); HRMS (FAB): calcd. for
C.sub.13H.sub.17O.sub.3F (M+) 2.40.116173 found 240.116465.
[0266] Part 4:
(2RS,7S)-2-(Benzenesulfonyl)-7-(4-fluorophenoxymethyl)oxepa- ne
(Scheme XXI; 6)
[0267] 25% HCl was added dropwise to sodium salt of benzenesulfinic
acid (5 g, 30.5 mmol) until the solid dissolved. The reaction
mixture was extracted with ETOAc, dried over Na.sub.2SO.sub.4 and
concentrated to give benzenesulfinic acid (3.9 g, 90%). To an
ice-cold mixture of benzene sulfinic acid (1.8 g, 12.4 mmol) and
CaCl.sub.2 (1.4 g, 12.5 mmol) in dry methylene chloride (50 ml) was
added dropwise a solution of
(6S)-7-(4-fluorophenoxy)-6-hydroxy-heptanal (2 g, 8.3 mmol) in
methylene chloride (10 ml). The reaction mixture was stirred for 3
hours and filtered through celite, and washed with methylene
chloride. The combined organic layer was washed with saturated
aqueous Na.sub.2CO.sub.3, water, brine and dried over
Na.sub.2SO.sub.4. Solvent was removed under reduced pressure and
the residue was purified by silica gel chromatography using
EtOAC-hexane (1:6) as eluent to give
(2RS,7S)-2-(benzenesulfonyl)-7-(4-fl- uorophenoxymethyl)oxepane
(2.45 g, 80.8%); .sup.1H-NMR (CDCl.sub.3, 200 Hz): .delta.1.39-2.20
(m, 7H), 2.5 (m, 1H), 3.57-3.90 (m, 2H), 4.45 (m, 1H), 4.72 (dd,
J=6.6, 12.0 Hz, 1H), 6.57-7.00 (m, 4H), 7.36-7.96 (m, 5H).
[0268] Part 5:
(2s,7S)-7-(4-Fluorophenoxymethyl-2-(4-hydroxybutynyl)oxepan- e
(Scheme XXI; 7)
[0269] To a suspension of magnesium (0.58 g, 24.2 mmol) in dry THF
(10 ml) was added catalytic 1,2-dibromoethane followed by dropwise
addition of a solution of isopropyl bromide (1.85 g, 15.1 mmol) in
THF (5 ml). The reaction mixture was stirred for 1 hour and
isoprpylmagnesiumbromide was cannulated into a 50 ml two-necked
flask. A solution of 4-tetrahydropyranoyl-1-butyne (1.86 g, 12.0
mmol) in THF (5 ml) was added and the mixture was stirred for 30
minutes followed by addition of freshly prepared ZnBr.sub.2
solution (1 M, 7.25 ml, 7.2 mmol) in THF at 0.degree. C. After 45
minutes (2RS,7S)-2-(benzenesulfonyl)-7-(4-fluorophe-
noxymethyl)oxepane (2.2 g, 6.0 mmol) in THF (10 ml) was added and
the mixture stirred for 30 hours. The reaction was quenched with
saturated aqueous NH.sub.4Cl solution at 0.degree. C. THF was
removed under reduced preesure and the residue was portioned
between EtOAc and water. The organic layer was washed with brine,
dried over Na.sub.2SO.sub.4 and concentrated to give
(2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-tetrahydropyr-
anoyl-1-butynyl)oxepane. The crude product was dissolved in MeOH
(25 ml) and 1% HCl in MeOH (5 ml) was added. The hydrolysis of the
THP group was completed in 2 hours and neutralized with saturated
Na.sub.2CO.sub.3 solution and concentrated. The crude product was
purified by silica gel chromotography using EtOAc-hexane (1:8) to
give (2S,7S)-7-(4-fluorophenox-
ymethyl)-2-(4-hydroxybutynyl)oxepane (1.32 g, 75%);
[.alpha.].sub.D-74 (c 3.63, CHCl.sub.3), .sup.1H-NMR (CDCl.sub.3,
200 Hz): .delta.1.4-2.0 (m, 7H), 2.12 (m, 1H), 2.3 (s, 1H), 2.46
(dt, 2H), 3.65 (t, J=3.6 Hz, 2H), 3.74-3.97 (m, 2H), 4.51 (q, 1H),
6.8-7.0 (m, 4H); HRMS (EI): calcd. for C.sub.17H.sub.21O.sub.3F
(M+) 292.147756 found 292.147473. Also,
(2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane by
similar procedure: [.alpha.].sub.D+26.9 (c 2.2, CHCl.sub.3),
.sup.1H-NMR (CDCl.sub.3, 200 Hz): .delta.1.48-2.03 (m, 8H), 2.2 (s,
1H), 2.47 (dt, 2H), 3.69 (t, J=6.9Hz, 2H), 3.74-4.02 (m, 3H), 4.34
(dt, 2H), 6.78-7.0 (m, 4H).
[0270] Part 6:
(2S,7S)-7-(4-Fluorophenoxymethyl)-2-[4-(N,O-biscarbophenoxy-
)-1-butynyl]oxepane (Scheme XXI; 8)
[0271] A mixture of
(2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)- oxepane
(0.9 g, 3.1 mmol), TTP (1.0 g, 3.7 mmol), N,O-biscarbophenoxy-hydr-
oxylamine (1 g, 3.7 mmol) in dry THF (20 ml) was cooled to
0.degree. C. Diethylazacarboxylate (0.64 g, 3.7 mmol) was added
dropwise and the reaction mixture stirred at room temperature for 4
hours. Solvent was removed on rotovapor. The residue was
partitioned between EtOAc and ater, washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated. The product was purified by
silica gel chromatography using EtOAc-hexane (1:9) to give pure
(2S,7S)-7-(4-fluorophenoxymethyl)-2-[4-(N,O-biscarboph-
enoxy)-1-butynyl]oxepane (1.55 g, 92%); [.alpha.].sub.D-46.0 (c
2.42, CHCl.sub.3), .sup.1H-NMR (CDCl.sub.3, 200 Hz):
.delta.1.39-22.0 (m, 8H), 2.73 (t, J=6.9Hz, 2H), 3.72-4.07 (m, 4H),
4.15 (m, 1H), 4.51 (dt, 1H), 6.76-7.46 (m, 4H). Also,
(2R,7S)-7-(4-Fluorophenoxymethyl)-2-[4-(N,O-bisc-
arbophenoxy)-1-butynyl]oxepane by similar procedure:
[.alpha.].sub.D+11 (c 4.3, CHCl.sub.3), .sup.1H-NMR (CDCl.sub.3,
200 Hz): .delta.1.48-2.03 (m, 8H), 3.76 (dt, 2H), 3.68-4.08 (m,
5H), 6.75-7.47 (m, 14H).
[0272] Part 7:
(2S,7S)-7-(4-fluorophenoxymethyl)-2-(4N-hydroxy-ureidyl-1-b-
utynyl)oxepane (Scheme XXI; 9)
[0273] A solution of
(2S,7S)-7-(4-Fluorophenoxymethyl)-2-[4-(N,O-biscarbop-
henoxy)-1-butynyl]oxepane (1.4 g, 2.6 mmol) in MeOH (25 ml) was
cooled to 0.degree. C. Saturated methanolic ammonia solution (10
ml) was added and the reaction was stirred for 12 hours at room
temperature. Solvent was removed and the residue was purified by
silica gel chromatography using EtOAc-hexane (1:1) to give
(2S,7S)-7-(4-fluorophenoxymethyl)-2-(4N-hydrox-
y-ureidyl-1-butynyl)oxepane (820 mg, 92.5%); [.alpha.].sub.D-56.0
(c 2.15, CHCl.sub.3), .sup.1HMR (CDCl.sub.3, 200 Hz):
.delta.1.43-2.20 (m, 8H), 2.51 (dt, 2H), 3.7 (t, J=7.1 Hz, 1H),
3.8-3.96 (m, 2H), 4.13 (m, 1H), 4.51 (q, 1H), 5.25 (s, 2H),
7.83-8.02 (m, 4H), 7.70 (s, 1H); HRMS (FAB): calcd. for
C.sub.18H.sub.24O.sub.4N.sub.4F (M+) 351.172011 found 351.173621.
13C: 17.187, 24.589, 27452, 32.032, 37.125, 48.887, 67.114, 72.029,
72.312, 81.857, 82.414, 115.506, 115.658, 115.814, 115.965,
154.903, 159.661, 161.788. Also,
(2R,7S)-7-(4-fluorophenoxymethyl)-2-(4-h- ydroxybutynyl)oxepane by
similar procedure: [.alpha.].sub.D+32 (c 0.5, CHCl.sub.3),
.sup.1H-NMR (CDCl.sub.3, 200 Hz): .delta.1.42-1.94 (m, 8H), 2.44
(s, 1H), 3.57 (t, J=7.1Hz, 2H), 3.69-3.92 (m, 3H), 5.44 (s, 2H),
6.72-6.97 (m, 4H), 8.1 (s, 1H).
EXAMPLE 11
[0274] Synthesis of
(2R,5R)-5-Ethynyl-2-(hydroxymethyl)-tetrahydrofuran from
L-Glyceraldehyde
[0275] References in this Example 11 to compound numerals
(generally underlined) designate the compounds depicted
structurally in Scheme XV above.
[0276] Part 1: Ethyl (2E,4R)-4,5-isopropylidenedioxy-2-pentenoate
(Scheme XV; 20):
[0277] A solution of
(2S,3R)-1,2-O-isopropylidene-butane-1,2,3,4-tetrol 19 (11.0 g, 68.1
mmol) in CH.sub.2Cl.sub.2 (120 mL) containing saturated NaHCO.sub.3
solution (4.5 mL) was cooled to 0.degree. C., treated with
NaIO.sub.4 (29.1 g, 136.3 mmol) and allowed to stir at 0.degree. C.
to 20.degree. C. After 2 to 3 h (TLC analysis), solid
Na.sub.2SO.sub.4 (6 g) was added and the reaction mixture was
stirred further for 15 min. The reaction mixture was filtered and
solvent evaporated (below 25.degree. C. bath temperature) to give
(S)-glyceraldehyde 19a (8.7 g) in 98% yield as a colorless liquid.
Compound 19 was prepared by procedures described in J. Am. Chem.
Soc., 102, 6304 (1980); and J. Org. Chem., 53, 2598 (1988).
[0278] A solution of (S)-glyceraldehyde 19a (15 g, 115.4 mmol) in
MeOH (200 mL) was cooled to 0.degree.-10.degree. C. (ice-salt bath)
and treated with (carbethoxymethylene) triphenyl phosphorane (48.1
g,138.4 mmol) in portions. After stirring at room temperature for 9
h, the solvent was evaporated, the residue obtained on purification
by column chromatography (Si-gel, 10% EtOAc-Hexane) gave ethyl
(2E,4R)-4,5-isopropylidenedioxy-2-pentenoate 20 (23 g) in 99% yield
as a pale yellow liquid. [.alpha.].sub.D-116.3 (c 0.71,
CHCl.sub.3); .sup.1HNMR (CDCl.sub.3, 200 MHz): .delta.1.2 (t, 3H, J
6.8 Hz, CH.sub.3), 1.3, 1.35 (2s, 6H, CH.sub.3), 3.5 (dd, 1H), J
5.9 Hz, H-5), 4.07 (q, 2H, J 6.8 Hz, --OCH.sub.2), 4.27 (dd, 1H, J
5.9 Hz, H-5a), 5.32-5.43 (m, 1H, H-4), 5.72 (dd, 1H, J 2.2, 11.3
Hz, H-2), 6.27 (dd, 1H, J 5.4, 11.3 Hz, H-3); .sup.13CNMR
(CDCl.sub.3, 50 MHz): .delta.25.2, 26.3, 60.1, 69.21, 73.3, 109.4,
120.5, 149.1, 165.3; EIMS m/z (relative intensity): 185
(M.sup.+-15, 15), 173 (6), 149 (23), 125 (20), 97 (45), 43 (100);
HRMS: Calculated for C.sub.9H.sub.13O.sub.4 (M.sup.+-15):
145.09649; Observed: 145.087162.
[0279] Part 2: Ethyl (4R)-4,5-isopropylidenedioxy-1-pentanoate
(Scheme XV; 21):
[0280] A solution of ethyl
(2E,4R)-4,5-isopropylidenedioxy-2-pentenoate 20 (23 g, 115 mmol) in
EtOAc (50 mL) was treated with PtO.sub.2 (0.100 g mmol) and
hydrogenated till there was no additional consumption of hydrogen
(3-4 h). At the end of reaction, the reaction mixture was filtered
and concentrated to afford ethyl (4R)-4,5-isopropylidenedioxy-1--
pentanoate 21 (23 g) in 99% yield as a colorless liquid.
[.alpha.].sub.D-4.0 (c 2.0, CHCl.sub.3); .sup.1HNMR (CDCl.sub.3,
200 MHz): .delta.1.25 (t, 3H), J6.8 Hz, CH.sub.3), 1.29, 1.32 (2s,
6H, CH.sub.3), 1.75-1.89 (m, 2H, H-3), 2.3-2.45 (m, 2H, H-2), 3.5
(t, 1H, J 6.5 Hz, H-5), 3.92-4.15 (m, 4H, H-4,5a, --OCH.sub.2);
.sup.13CNMR (CDCl.sub.3, 50 MHz): .delta.14.0, 25.4, 26.8, 28.6,
30.2, 60.1, 68.8, 74.7, 108.7, 172.6. EIMS m/z (relative
intensity): 203 (M.sup.++1,23), 173 (16.4), 143 (13.4), 101 (100),
43 (97); HRMS: Calculated for C.sub.8H.sub.13O.sub.4 (M.sup.+-29):
173.081384; Observed: 1173.091619.
[0281] Part 3: (2R)-1,2-Isopropylidenedioxy-5-pentanol (Scheme XV;
22):
[0282] A suspension of LAH (4.93 g, 130.4 mmol) in THF (50 mL) was
cooled to 0.degree. C. and treated drop wise with a solution of
ethyl (4R)-4,5-isopropylidenedioxy-1-pentanoate 21 (22 g, 108.9
mmol) in THF (75 mL). The reaction mixture was warmed to room
temperature, then allowed to stir for 3 h and treated with a
saturated solution of Na.sub.2SO.sub.4 (15 mL). After stirring for
additional 30 min., it was filtered through celite and washed with
EtOAc (3.times.75 mL). The combined organic layers were washed with
NaCl solution and evaporated to provide the
(2R)-1,2-isopropylidenedioxy-5-pentanol 22 (17 g) in 97% yield as a
colorless liquid. [.alpha.].sub.D-10.3 (c 0.75, CHCl.sub.3);
.sup.1HNMR (CDCl.sub.3, 200 MHz): .delta.1.35, 1.4 (2s, 6H),
1.6-1.75 (m, 4H, H-3,4), 1.92 (br.s, 1H, OH), 3.5 (t, 1H, J 6.1 Hz,
H-1), 3.6-3.72 (m, 2H, H-5), 3.98-4.16 (m, 2H, H-1a,2); .sup.13CNMR
(CDCl.sub.3, 50 MHz): .delta.25.6, 26.8, 29.0, 30.1, 62.4, 69.4,
75.9, 108.8; EIMS m/z (relative intensity): 145 (M.sup.+-15, 13.4),
85 (32), 72 (18), 57 (13.4), 43 (100); HRMS: Calculated for
C.sub.7H.sub.13O.sub.3 (M.sup.+-15): 145.086468; Observed:
145.087162.
[0283] Part 4: (4R)-4,5-Isopropylidenedioxy-1-pentanal (Scheme XV;
23):
[0284] Method A: A stirred solution of
(2R)-1,2-isopropylidenedioxy-5-pent- anol 22 (17 g, 106.3 mmol) in
CH.sub.2Cl.sub.2 (200 mL) was treated with PDC (59.9 g, 159.3 mmol)
in portions and allowed stir at 40.degree. C. for 5 h. The reaction
mixture was diluted with ether (4.times.300 mL) and decanted
through a small pad of silica gel. Evaporation of solvent afforded
(4R)-4,5-isopropylidenedioxy-1-pentanal 23 (15 g) in 89% yield as a
pale yellow liquid.
[0285] Method B: a stirred solution of
(2R)-1,2-isopropylidenedioxy-5-pent- anol 22 (0.800 g, 5.0 mmol) in
DMSO (5 mL) was cooled to 0.degree. C., treated with IBX (1.47 g,
5.26 mmol) in portions while maintaining the temperature below
0.degree. C. and stirred at room temperature for 4 h. The reaction
mixture was treated with saturated NaHCO.sub.3 solution, filtered
through celite and washed with EtOAc (3.times.30 mL). Two layers
were separated and organic layer was washed with water, brine and
dried (Na.sub.2SO.sub.4). Evaporation of solvent gave
(4R)-4,5-isopropylidenedi- oxy-1-pentanal 23 (16.2 g) in 78% yield
as a yellow liquid. [.alpha.].sub.D+0.3 (c 2.0, CHCl.sub.3).
[0286] Part 5: Ethyl (2E,6R)-6.7-isopropylidenedioxy hept-2-enoate
(Scheme XV; 24):
[0287] A solution of (4R)-4,5-isopropylidenedioxy-1-pentanal 23 (15
g, 94.9 mmol) in benzene (200 mL) was treated with
(carbethoxymethylene) triphenyl phosphorane (39.6 g, 113.8 mmol)
and heated at reflux for 6h. Solvent was evaporated and the residue
purified by column chromatography (Si-gel, 10% EtOAc-hexane) to
afford ethyl (2E,6R)-6,7-isopropylidenediox- y hept-2-enoate 24 (14
g) in 65% yield as a pale yellow liquid. [.alpha.].sub.D-5.4 (c
1.2, CHCl.sub.3); .sup.1HNMR (CDCl.sub.3, 200 MHz): .delta.1.3 (t,
3H, J 6.8 Hz, CH.sub.3), 1.34, 1.4 (2s, 6H), 1.61-1.7 (m, 2H, H-6),
2.2-2.42 (m, 2H, H-4), 3.5 (t, 1H, J 6.8Hz, H-7a), 3.99-4.26 (m,
4H, H-6,7,--OCH.sub.2), 5.82 (td,1H, J 2.25, 15.75 Hz, H-2), 6.94
(dt, 1H, J 6.8, 15.75 Hz, H-3); .sup.13CNMR (CDCl.sub.3, 50 MHz):
.delta.14.0, 25.4, 26.7, 28.2, 31.9, 60.0, 69.0, 74.9, 108.7,
121.7, 147.7, 166.3; EIMS m/z (relative intensity): 213
(M.sup.+-15, 9), 95 (40.2), 67 (25.3), 55 (53.7), 41 (100); HRMS:
Calculated for C.sub.11H.sub.17O.sub.4 (M.sup.+-15): 213.112684;
observed: 213.112732.
[0288] Part 6: (2E,6R)-6,7-Isopropylidenedioxy hept-2-ene-1-ol
(Scheme XV; 25):
[0289] A stirred solution of ethyl (2E,6R)-6,7-isopropylidenedioxy
hept-2-enoate 24 (13.87 g, 60.8 mmol) in dry CH.sub.2Cl.sub.2 (60
mL) was cooled to -20.degree. C. (CCl.sub.4+dry ice bath) and
treated with a solution of DIBAL-H (17.27 g, 121.6 g, mmol; 2.5M
solution in hexane) drop wise. After stirring for 2h, the reaction
mixture was warmed to 0.degree. C., treated drop wise with MeOH (10
mL) to obtain a gelatin cake. The mixture was diluted with
CH.sub.2Cl.sub.2 (100 mL) and stirred for 15 min. A solution of
Na-K tartarate (90 mL) was added drop wise and stirred for an
additional 45 min. Reaction mixture was filtered through celite and
washed with CH.sub.2Cl.sub.2 (2.times.50 mL). the organic layer was
washed with water (2.times.100 mL), brine (50 mL), dried
(Na.sub.2SO.sub.4) and evaporated to give
(2E,6R)-6,7-isopropylidenedioxy hept-2-ene-1-ol 25 (11 g) in 98.2%
yield as a colorless liquid. [.alpha.].sub.D-13.2 (c 2.5,
CHCl.sub.3); .sup.1HNMR (CDCl.sub.3, 200 MHz): .delta.1.16, 1.2
(2s, 6H, CH.sub.3), 1.46-1.74 (m, 2H, H-5), 1.79-198 (m, 1H, --OH),
2.02-2.19 (m, 2H, H-4), 3.36-3.78 (m, 3H, H-6,7), 4.02-4.12 (m, 2H,
H-1), 5.61-5.71 (m, 2H, H-2,3); .sup.13CNMR (CDCl.sub.3, 50 MHz):
.delta.25.3, 26.5, 28.0, 32.7, 62.8, 68.9, 75.1, 108.3, 129.8 (2C);
EIMS m/z (relative intensity): 171 (M.sup.+-15, 35.8), 93 (22.3),
67 (37.3), 55 (26.8), 43 (100); HRMS: Calculated for C9H15O3
(M+-15): 171.102120; observed: 171.102195.
[0290] Part 7: (2R,3R,6R)-2,3-Epoxy-6,7-isopropylidenedioxy
heptan-1-ol (Scheme XV; 26):
[0291] To a stirred and cooled (-20.degree. C.) suspension of
molecular sieves (4 A, 1.25 g) in CH.sub.2Cl.sub.2 (10 mL) under
N.sub.2 atmosphere, (-)-diisopropyl D-tartarate (7.6 g, 32.4 mmol),
titanium (IV) isopropoxide (7.68 g, 27.02 mmol) and cumene
hydroperoxide (8.22 g, 54 mmol) were added sequentially. After 20
min., the resulting mixture was treated drop wise addition of a
solution of (2E,6R)-6,7-isopropylidenedio- xy hept-2-ene-1-ol 25 (5
g, 26.88 mmol) in CH.sub.2Cl.sub.2 (15 mL) and stirred for
additional 3h. The reaction mixture was quenched with 10% NaOH
solution saturated with NaCl (15 mL) and filtered through celite.
Evaporation of solvent and purification of residue by column
chromatography (Si-gel, 1:1 EtOAc-hexane) gave
(2R,3R,6R)-2,3-epoxy-6,7-i- sopropylidenedioxy heptan-1-ol 26 (4.15
g) in 76.4% yield as a colorless liquid. [.alpha.].sub.D+24.3 (c
0.3, CHCl.sub.3); .sup.1HNMR (CDCl.sub.3, 200 MHz): .delta.1.32,
1.38 (2s, 6H, CH.sub.3), 1.58-1.78 (m, 4H, H-4,5), 2.84-3.01 (m,
2H, H-2,3), 3.5 (t, 1H, J 6.1 Hz, H-7), 3.6 (dd, 1H, J 4.7, 11.75
Hz, H-1), 3.85 (dd, 1H, J 3.29, 11.75, H-1a), 3.98-4.2 (m, 2H,
H-6,7'); .sup.13CNMR (CDCl.sub.3, 50 MHz): .delta.25.5, 26.8, 27.6,
29.6, 55.3, 58.3, 61.6, 69.1, 75.1, 108.8; EIMS M/Z (relative
intensity): 188 (M.sup.+-15, 14.9), 144 (85), 101 (47.7), 83 (95),
43 (100); HRMS: Calculated for C.sub.9H.sub.15O.sub.4 (M-15):
187.097034; Observed: 187.096634.
[0292] Part 8:
(2R,3R,6R)-1-Chloro-2,3-epoxy-6,7-isopropylidenedioxy heptane
(Scheme XV; 27):
[0293] A stirred mixture of
(2R,3R,6R)-2,3-epoxy-6,7-isopropylidenedioxy heptan-1-ol 26 (3.8 g,
18.8 mmol), Ph.sub.3P (7.4 g, 28.3 mmol) and NaHCO.sub.3 (0.6 g) in
CCl.sub.4 (50 mL) was heated at reflux for 3 h. The solvent was
evaporated and residue obtained purified by column chromatography
(Si-gel, 20% EtOAc-hexane) to give (2R,3R,6R)-1-chloro-2,3-
-epoxy-6,7-isopropylidenedioxy heptane 27 (2.8 g) in 67.8% yield as
a colorless liquid. [.alpha.].sub.D+8.16 (c 0.7, CHCl.sub.3);
.sup.1HNMR (CDCl.sub.3, 200 MHz): .delta.1.31, 1.36 (2s, 6H,
CH.sub.3), 1.63-1.72 (m, 4H, H-4,5), 2.8-2.9 (m, 1H, H-2),
2.91-3.02 (m, 1H, H-3), 3.32-3.68 (m, 3H, H-1,7), 3,95-4.19 (m, 2H,
H-6,7a); .sup.13CNMR (CDCl.sub.3, 50 MHz): .delta.25.6, 26.9, 27.6,
29.6, 44.5, 57.0, 58.3, 69.2, 75.1, 108.9; EIMS m/z (relative
intensity): 205 (M.sup.+-15, 35.8), 145 (23), 83 (61), 72 (98), 43
(100); HRMS: Calculated for C.sub.9H.sub.14ClO.sub.3 (M.sup.+-15):
205.063147; Observed: 205.062719.
[0294] Part 9: (3R,6R)-3-Hydroxy-6,7-isopropylidenedioxy-hept-1-yne
(Scheme XV; 28):
[0295] To freshly prepared LDA [prepared from diisopropyl amine
(4.6 g, 45.5 mmol) and n-BuLi (2.91 g, 45.54 mmol; 1.4N hexane
solution)] in THF (10 mL), a solution of
(2R,3R,6R)-1-chloro-2,3-epoxy-6,7-isopropylidenedi- oxy heptane 27
(2.5 g, 11.36 mmol) in THF (20 mL) was added at -40.degree. C.
(CH.sub.3CN+dry ice bath). After 3h, the reaction was quenched with
aq. NH.sub.4Cl solution and diluted with CH.sub.2Cl.sub.2 (50 mL).
The organic layer was separated, washed with water (3.times.20 mL),
brine (200 mL) and dried (Na.sub.2SO.sub.4), evaporated and residue
purified by column chromatography (Si-gel, 15% EtOAc-hexane) to
furnish (3R,6R)-3-hydroxy-6,7-isopropylidenedioxy-hept-1-yne 28
(2.0 g) in 95% yield as a pale yellow liquid. [.alpha.].sub.D-3.02
(c 2.2, CHCl.sub.3); .sup.1HNMR (CDCl.sub.3, 200 MHz): .delta.1.32,
1.39 (2s, 6H, CH.sub.3), 1.64-1.94 (m, 4H, H-4,5), 2.19-2.21 (br.s,
1H, OH), 2.39 (d, 1H J 2.3Hz, H-1), 3.5 (t, 1H, J 5.7 Hz, H-7),
3.96-4.16 (m, 2H, H-6,7a), 4.34-4.45 (m, 1H, H-3); .sup.13CNMR
(CDCl.sub.3, 50 MHz): .delta.25.4, 26.6, 28.8, 33.5, 61.3, 69.0,
72.7, 75.3, 84.7, 108.7; EIMS m/z (relative intensity): 169
(M.sup.+-15, 22.3), 109 (20.8), 81 (37.3), 55 (35.8), 43 (100);
HRMS: Calculated for C.sub.9H.sub.13O.sub.3 (M-15): 169.086469;
Observed: 169.086140.
[0296] Part 10:
(3R,6R)-3-Acetoxy-6,7-isopropylidenedioxy-hept-1-yne (Scheme XV;
29):
[0297] A solution of hydroxy-6,7-isopropylidenedioxy-hept-1-yne 28
(1.8 g, 9.8 mmol) and pyridine (3.1 g, 39.2 mmol) in
CH.sub.2Cl.sub.2 (15 mL) containing DMAP (catalytic) at 0.degree.
C. was treated with Ac.sub.2O (1.2 g, 11.7 mmol) and stirred at
room temperature for 30 min. After completion, the reaction was
diluted with CH.sub.2Cl.sub.2 (50 mL), sequentially washed with
CuSO.sub.4 solution (3.times.30 mL), saturated aq. NaHCO.sub.3
solution (20 mL), water (20 mL), brine (20 mL) and dried.
Evaporation of solvent and purification of residue by column
chromatography (Si-gel, 10% EtOAc-hexane) gave
(3R,6R)-3-acetoxy-6,7-isop- ropylidenedioxy-hept-1-yne 29 (2.15 g)
in 97.2% yield as a yellow liquid. [.alpha.].sub.D+37.5 (c 2.1,
CHCl.sub.3); .sup.1HNMR (CDCl.sub.3, 200 MHz): .delta.1.3, 1.39
(2s, 6H, CH.sub.3), 1.64-2.0 (m, 2H, H-4,5), 2.06 (sm 3H,
CH.sub.3), 2.4 (d, 1H, J 2.0 Hz, H-1), 3.5 (t, 1H, J 5.7 Hz, H-7),
3.95-4.13 (m, 2H, H-6,7a), 5.31-5.41 (m, 1H, H-3); .sup.13CNMR
(CDCl.sub.3, 50 MHz): .delta.20.8, 25.5, 26.8, 28.8, 30.7, 63.3,
69.1, 73.7, 75.1, 80.7, 108.9, 169.6; EIMS m/z (relative
intensity): 211 (M.sup.+-15, 29.8), 169 (11.9), 91 (22.3), 72 (23),
43 (100); HRMS: Calculated for C.sub.11H.sub.15O.sub.4
(M.sup.+-15): 211.097034; Observed; 211.095947.
[0298] Part 11: (3R,6R)-3-Acetoxy-6,7-dihydroxy-hept-1-yne (Scheme
XV; 30):
[0299] A solution of
(3R,6R)-3-acetoxy-6,7-isopropylidenedioxy-hept-1-yne 29 (2 g, 8.8
mmol) in MeOH (150 mL) containing catalytic amount of PTSA was
stirred at 0.degree. C. for 8 h. The reaction mixture was
neutralised with saturated sat. NaHCO.sub.3 solution, evaporated to
remove MeOH and extracted with EtOAc (3.times.50 mL). Organic layer
were evaporated and the residue filtered through a small pad of
silica gel with 1:1 EtOAc-hexane to afford
(3R,6R)-3-acetoxy-6,7-dihydroxy-hept-1-yne 30 (1.2 g) in 72.9%
yield as a colorless syrup. [.alpha.].sub.D+83.2 (c 1.2,
CHCl.sub.3); .sup.1HNMR (CDCl.sub.3, 200 MHz): .delta.1.5-1.7 (m,
2H, H-4), 1.75-2.05 (m, 2H, H-5), 2.14 (s, 3H, --OAc), 2.45 (d, 2H,
H-1), 2.57 (br.s, 1H, OH), 3.35-3.5 (m, H, H-7), 3.57-3.8 (m, 2H,
H-6,7a), 5.32-5.47 (m, 1H, H-3); CIMS m/z (relative intensity): 187
(M+1, 74.6), 127 (5.97), 109 (35.8), 81 (56.7), 43 (100); HRMS
Calculated for C.sub.9H.sub.15O.sub.4 (M+1): 187.097034; Observed:
187.096547.
[0300] Part 12: (3R,6R)-3-Acetoxy-6-hydroxy-7-p-toluene
sulfonyloxy-hept-1-yne (Scheme XV; 31);
[0301] A solution of (3R,6R)-3-acetoxy-6,7-dihydroxy-hept-1-yne 30
(1.1 g, 5.9 mmol) in CH.sub.2Cl.sub.2 (20 ml) containing pyridine
(0.934 g, 11.82 mmol) was cooled to 0.degree. C., treated with
p-TsCl (1.12 g, 5.91 mmol) and stirred at room temperature for 8 h.
The reaction mixture was diluted with CH.sub.2Cl.sub.2 and washed
sequentially with water (20 mL), CuSO.sub.4 solution (3.times.20
mL) and water (20 mL). Organic layer was dried (Na.sub.2SO.sub.4),
evaporated and residue obtained was purified by column
chromatography (Si-gel, 10% EtOAc-Hexane); first eluted was (3R,
6R)-3-acetoxy-6,7-di-p-toluene sulfonyloxy-hept-1-yne 31a (0.23 g)
in 8% yield as a yellow syrup. .sup.1HNMR (CDCl.sub.3, 200 MHz):
.delta.1.5-1.85 (m, 4H, H-3,4), 2.05 (s, 3H, OAc), 2.41-2.52 (m,
7H, H-7, Ar--CH.sub.3), 4.0 (d, 2H, J4.8 Hz, H-1), 4.58-4.62 (m,
1H, H-2), 5.12-5.26 (m, 1H, H-5), 7.28-7.44, 7.64-7.81 (m, 4H each,
Ar--H).
[0302] Second eluted was (3R,6R)-3-acetoxy-6-hydroxy-7-p-toluene
sulfonyloxy-hept-1-yne 31 (1.1 g) in 55% yield as a yellow syrup.
[.alpha.].sub.D+28.1 (c 1.0, CHCl.sub.3); .sup.1HNMR (CDCl.sub.3,
200 MHz): .delta.1.35-1.68 (m, 3H, H-4, --OH), 1.68-2.0 (m, 2H,
H-5), 2.08 (s, 3H, CH.sub.3), 2.4 (d, 1H, J 2.4 Hz, H-1), 2.46 (s,
3H, Ar--CH.sub.3), 3.79-4.06 (m, 3H, H-6,7), 5.35 (td, 1H, J 4.8,
7.2 Hz, H-3), 7.36 (d, 2H, J 7.2 Hz, Ar--H), 7.8 (d, 2H, J 7.2 Hz,
Ar--H). FABMS m/z (relative intensity): 341 (M+1, 13.8), 281 (50),
155 (54.1), 133 (52.7), 109 (100). HRMS: Calculated for
C.sub.16H.sub.21O.sub.6S (M+1): 341.105885; Observed:
341.104916.
[0303] Part 13: (2R,5R)-5-Ethynyl-2-(hydroxymethyl)-tetrahydrofuran
(Scheme XV; 32):
[0304] To a solution of (3R,6R)-3-acetoxy-6-hydroxy-7-p-toluene
sulfonyloxy-hept-1-yne 31 (0.6 g, 1.76 mmol) in MeOH (10 mL) at
room temperature, K.sub.2CO.sub.3 (0.536 g, 3.88 mmol) was added
and the mixture was stirred for 2h. It was treated with NH.sub.4Cl
solution, evaporated MeOH and the residue extracted with EtOAc
(3.times.20 mL). Organic layer was washed with water (10 mL), brine
(10 mL), dried (Na.sub.2SO.sub.4) evaporated. The residue obtained
was purified by column chromatography (Si-gel, 20% EtOAc-hexane) to
furnish (2R,5R)-5-ethynyl-2-(hydroxymethyl)-tetrahydrofuran 32
(0.22 g) in 99% yield as a colorless liquid. [.alpha.].sub.D+20.0
(c 1.0, CHCl.sub.3); .sup.1HNMR (CDCl.sub.3, 200 MHz):
.delta.1.89-2.38 (m, 4H, H-3,4), 2.4 (br.s, 1H, OH), 2.46 (d, 1H, J
2.2 Hz, H-7), 3.55 (dd, 1H, J 4.5, 11.25 Hz, H-1), 3.72 (dd, 1H, J
4.0, 11.25 Hz, H-1a), 4.0-4.15 (m, 1H, H-2), 4.52-4.66 (m, 1H,
H-5); .sup.13CNMR (CDCl.sub.3, 50 MHz): .delta.26.6, 29.6, 33.6,
64.6, 68.3, 73.0, 80.7; EIMS m/z (relative intensity): 125
(M.sup.+-1, 8), 95 (74.6) 67 (100), 53 (40), 41 (80); HRMS:
Calculated for C.sub.7H.sub.9O.sub.2 (M-1): 125.060255; Observed:
125.060322.
[0305] Part 14: (2R,5R)-5-Ethynyl-2-(p-toluene
sulfonyloxymethyl)-tetrahyd- rofuran (Scheme XV; 33):
[0306] A solution of alcohol
(2R,5R)-5-ethynyl-2-(hydroxymethyl)-tetrahydr- ofuran 32 (0.22 g,
1.75 mmol) in pyridine (0.6 mL) was treated with p-TsCl (0.354 g,
1.86 mmol) and the mixture stirred at room temperature for 3 h. The
reaction mixture was diluted with CH.sub.2Cl.sub.2 (20 mL) and
washed sequentially with water (10 mL), CuSO.sub.4 solution
(2.times.10 mL), brine (10 mL) and dried (Na.sub.2SO.sub.4).
Evaporation of solvent and purification of residue by column
chromatography (Si-gel, 15% EtOAc-hexane) gave
(2R,5R)-5-ethynyl-2-(p-toluene sulfonyloxymethyl-(tetr- ahydrofuran
33 (0.33 g) in 63.9% yield as a yellow syrup. [.alpha.].sub.D+10.0
(c 0.54, CHCl.sub.3); .sup.1HNMR (CDCl.sub.3, 200 MHz);
.delta.1.84-2.11 (m, 4H, H-3,4) 2.32 (d, 1H, J 2.1 Hz, H-7), 2.45
(s, 3H, CH.sub.3), 3.92-4.2 (m, 3H, H-2,1,1a), 4.48-4.58 (m, 1H,
H-5), 7.34 (dm 2H, J 7.6 Hz, Ar--H), 7.8 (d, 2H, J 7.6 Hz, Ar--H);
CIMS m/z (relative intensity): 281 (M+1, 100), 109 (49.2), 117
(31.3), 81 (7.0), 43 (100); HRMS: Calculated for
C.sub.14H.sub.17O.sub.4S (M+1): 281.084756; Observed:
281.083610.
[0307] Part 15: (2R,5R)-5-Ethynyl-2-(4-fluoro
phenoxymethyl)-tetrahydrofur- an (Scheme XV; 34):
[0308] To a stirred suspension of NaH (0.032 g, 1.33 mmol) in DMF
(3 mL), a solution of (2R,5R)-5-ethynyl-2-(p-toluene sulfonyloxy
methyl)-tetrahydrofuran 33 (0.33 g, 1.1 mmol) in DMF (3 mL) was
added and heated at 80.degree. C. for 5h. The reaction mixture was
cooled to room temperature and treated with NH.sub.4Cl solution. It
was extracted with ether (2.times.10 mL) and the organic layer was
washed with water (2.times.10 mL), brine (10 mL) and dried
(Na.sub.2SO.sub.4). Evaporation of solvent and purification of
residue by column chromatography (Si-gel, 7% EtOAc-hexane) afforded
(2R,5R)-5-ethynyl-2-(4-fluoro phenoxy methyl)-tetrahydrofuran 34
(0.21 g) in 85.7% yield as a colorless liquid, whose spectral data
is accordance with the reported reference values.
[.alpha.].sub.D+16.0 (c 1.0, CHCl.sub.3); .sup.1HNMR (CDCl.sub.3,
200 MHz): .delta.1.88-2.32 (m, 4H, H-3,4), 2.41 (d, 1H, J 2.3 Hz,
H-7), 3.9 (dd, 1H, J 4.6, 9.1 Hz, H-1), 4.06 (dd, 1H, J 5.9, 9.1
Hz, H-1a), 4.22-4.36 (m, 1H, H-2), 4.58-4.69 (m, 1H, H-5),
6.75-7.02 (m, 4H, Ar--H); .sup.13CNMR (CDCl.sub.3, 50 MHz);
.delta.28.2, 33.1, 68.5, 71.2, 72.9, 76.3, 83.7, 115.4, 115.6,
115.8, 115.9, 154.9, 159.6; EIMS m/z (relative intensity):
(M.sup.+, 10.4), 125 (14.9), 95 (94), 67 (100), 41 (59.7); HRMS:
Calculated for C.sub.13H.sub.13O.sub.2F (M.sup.+): 220.089958;
Observed: 220.089497.
EXAMPLE 12
[0309] Keto-epoxide Cyclisation
[0310] References in this Example 12 to compound numerals
(generally underlined) designate the compounds depicted
structurally in Scheme XVI above.
[0311] Part 1: Non-8-ene-1-p-methoxy phenyl methyl-5-oxo-3-yn-1-ol
(Scheme XVI; 54):
[0312] A. Mixed anhydride (Scheme XVI; 53): A stirred and cooled
(-10.degree. C. to 0.degree. C.) solution of pent-4-enoic acid (0.5
g, 5 mmol) and freshly distilled Et.sub.3N (0.505 g, 5 mmol) in dry
ether (5 mL), was treated with ethyl chloro formate (0.542 g, 5
mmol). The reaction mixture was allowed to reach room temperature
and stirred for 3 h. The reaction mixture was filtered and washed
with ether. Organic layer was washed with saturated NaHCO.sub.3
solution (25 mL), water (25 mL), brine (20 mL), and dried
(Na.sub.2SO.sub.4). Evaporation of solvent under vacuum at room
temperature afforded mixed anhydride 53 (0.79 g) in 91.8% yield as
a colorless syrup.
[0313] B. Non-8-ene-1-p-methoxy phenyl methyl-5-oxo-3-yn-1-ol
(Scheme XVI; 54): A stirred solution of 1-p-methoxy phenyl
methyl-but-3-yn-1-ol (52: 1.12 g, 5.91 mmol) in dry THF (5 mL) was
cooled to -78.degree. C. and treated with n-BuLi (4 mL, 5.91 mmol;
1.5 N hexane solution) dropwise. After 30 min., a solution of
anhydride 53 (0.78 g, 4.54 mmol) in THF (5 mL) was added and
stirred at the same temperature for 2 hours. The reaction mixture
was quenched with aq. NH.sub.4Cl solution (10 mL) and extracted
with EtOAc (2.times.25 mL). Organic layer was washed with brine (25
mL), dried (Na.sub.2SO.sub.4), evaporated and purified the residue
by column chromatography (Si-gel, 8:1 Hexane-EtOAc) to afford
non-8-ene-1-p-methoxy phenyl methyl-5-oxo-3-yn-1-ol (54; 0.35 g) in
27% yield as a colorless syrup. .sup.1HNMR (CDCl.sub.3, 200 MHz):
.delta.2.32-2.46 (m, 2H, H-7), 2.56-2.69 (m, 4H, H-6,2), 3.59 (t,
2H, J 8.37 Hz, H-1), 3.8 (s, 3H, --OMe), 4.47 (s, 2H, --OCH.sub.2),
4.95-5.11 (m, 2H, H-9), 5.67-5.9 (m, 1H, H-8), 6.84, 7.22 (2d, 2H
each, J9.3 Hz, Ar--H).
[0314] Part 2: 1,2-Epoxy-9-p-methoxy phenyl
methyl-5-oxo-non-6-yn-9-ol (Scheme XVI; 55):
[0315] A solution of non-8-ene-1-p-methoxy phenyl
methyl-5-oxo-3-yn-1-ol 54 (0.2 g, 0.73 mmol) in acetone (5 mL) was
sequentially treated with solid NaHCO.sub.3 (0.306 g, 3.65 mmol),
water (5 mL) followed by a solution of oxone (0.448 g, 073 mmol) in
aqueous. 4.times.10.sup.-4 M EDTA disodium solution (10 mL)
dropwise at 0.degree. C. and stirred at room temperature for 4h.
The reaction mixture was filtered and washed with EtOAc (10 mL).
The aqueous layer was extracted with EtOAc (2.times.10 mL) and
combined organic layers were washed with brine (20 mL) and dried
(Na.sub.2SO.sub.4). Evaporation of solvent and purification of
residue by column chromatography (Si-gel, 15% EtOAc in hexane) gave
1,2-epoxy-9-p-methoxy phenyl methyl-5-oxo-non-6-yn-9-ol 55 (0.1 g)
in 48% yield as a colorless syrup. .sup.1HNMR (CDCl.sub.3, 200
MHz): .delta.1.62-1.82 (m, 1H, H-3), 1.9-2.1 (m, 1H, H-3'),
2.41-2.57 (m, 1H, H-1), 2.57-2.74 (m, 5H, H-1',4,8), 2.85-2.96 (m,
1H, H-2), 3.58 (t, 2H, J 8.13 Hz, H-9), 3.8 (s, 3H, --OMe), 4.45
(s, 2H, --OCH.sub.2), 6.84, 7.22 (2d, 2H each, J 9.3 Hz, Ar-H).
[0316] Part 3:
(2S,5RS)-2-(Hydroxymethyl)-5-(1-p-methoxyphenylmethylenoxy--
but-3-yn-4-yl)-tetrahydrofuran (Scheme XVI; 56):
[0317] To a stirred and cooled -78.degree. C. solution of
1,2-epoxy-9-p-methoxy phenyl methyl-5-oxo-non-6-yn-9-ol 55 (0.075
g. 0.26 mmol) in CH.sub.2Cl.sub.2 (52 mL; 0.005M solution), a
solution of BH.sub.3-DMS (0.25 mL, 0.26 mmol; 1 M solution in
CH.sub.2Cl.sub.2) was added dropwise. After 3 hours, the reaction
mixture was quenched with aq. NH.sub.4Cl solution (10 mL) at
0.degree. C. and extracted with EtOAc (2.times.10 mL). Organic
layer was washed with water (2.times.10 mL), brine (10 mL) and
dried (Na.sub.2SO.sub.4). Evaporation of solvent and purification
of residue by column chromatography (Si-gel, 25% EtOAc in hexane)
gave racemic 2-(Hydroxymethyl)-5-(1-p-methoxyphenylmethylenoxy-bu-
t-3-yn-4-yl)-tetrahydrofuran 56 (0.025 g) in 34% yield as a
colorless syrup. The compound 56 thus obtained by this approach is
comparable to compound 39 (Scheme IX) by TLC analysis as well as
.sup.1HNMR data.
EXAMPLE 13
[0318] Di-hydroxy compound
[0319] References in this Example 13 to compound numerals
(generally underlined) designate the compounds depicted
structurally in Scheme XVII above.
[0320] Mannose diacetonide 70 is converted to the corresponding
sulfide 72 on reaction with diphenyl sulfide and tributyl phosphone
in dichloromethane. The 5,6-acetonide group of the reaction product
is hydrolyzed with 60% aqueous acetic acid to afford the diol,
which on cleavage with sodium periodate gives the aldehyde.
Reaction of the aldehyde with sodium borohydride gives the alcohol
73, which on reaction with tosyl chloride gives the tosylate.
Reaction of the tosylate with the sodium salt of p-fluorophenol in
dimethyl formamide gives the aryl ether 74. The sulfide is oxidized
with oxone to sulfone. The resulting sulfone on further reaction
with magneium acetylide of 4-OPM-but-1-yn-4-ol (prepared from ethyl
magnesium bromide and homoproargyl alcohol MPM ether) in the
presence of zinc bromide gives the acetylene 75. The acetylene
compound is reacted with DDQ to give the alcohol, which in turn on
reaction with N-hydroxy urea derivative and further reaction with
ammonia provides compound 76.
EXAMPLE 14
[0321] Human whole blood assay
[0322] The following compound of the invention was tested for
Leukotriene B.sub.4 inhibition in the human whole blood assay
detailed below. 32
[0323] Heparinized human whole blood was pre-incubated with
selected concentrations of the test compound for 15 minutes at
37.degree. C. and stimulated with 50 .mu.M calcium ionphor for 30
minutes at 37.degree. C. The reaction was stopped by placing
samples on ice and cold centrifugation at 4.degree. C. for 10
minutes at 1100.times.g. Test sample plasma was diluted in buffer
and assayed for LTB.sub.4 content. Test compound activity was
determined as per Cayman LTD EIA and evaluated as IC.sub.50 [nM].
The compound had an IC.sub.50 of 148 nM. Other tested stereoisomers
of the above compound exhibited differing IC.sub.50 values.
[0324] The invention has been described in detail including
preferred embodiments thereof. However, it will be understood that
those skilled in the art, upon consideration of this disclosure,
may make modifications and improvements thereon without departing
from the spirit and scope of the invention as set forth in the
following claims.
* * * * *