U.S. patent application number 12/580855 was filed with the patent office on 2010-02-11 for synthesis of ccr5 receptor antagonists.
This patent application is currently assigned to Schering Corporation. Invention is credited to Bosco D'Sa, Vilas Dahanukar, Hong-Chang Lee, William Leong, Feng Liang, Yi Liu, Hoa N. Nguyen, Cecilia Proietti, Xiongwei Shi, Loc Thanh Tran, Wenxue Wu, Ilia A. Zavialov, Shannon Zhao, Man Zhu.
Application Number | 20100036125 12/580855 |
Document ID | / |
Family ID | 36571985 |
Filed Date | 2010-02-11 |
United States Patent
Application |
20100036125 |
Kind Code |
A1 |
Shi; Xiongwei ; et
al. |
February 11, 2010 |
SYNTHESIS OF CCR5 RECEPTOR ANTAGONISTS
Abstract
The present invention is directed to the synthesis of
4-[4-[(R)-[1-[cyclopropylsulfonyl)-4-piperidinyl](3-fluorophenyl)methyl]--
3(S)-methyl-1-piperazinyl]-1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-meth-
ylpiperidine], and intermediates therefor from readily available
starting materials by a novel route.
Inventors: |
Shi; Xiongwei; (Edison,
NJ) ; Zhu; Man; (Clark, NJ) ; Leong;
William; (Westfield, NJ) ; Dahanukar; Vilas;
(Hyderabad, IN) ; Zavialov; Ilia A.; (Princeton,
NJ) ; Proietti; Cecilia; (Westfield, NJ) ;
Zhao; Shannon; (Littleton, MA) ; Lee; Hong-Chang;
(Livingston, NJ) ; Liu; Yi; (Iselin, NJ) ;
Nguyen; Hoa N.; (Dayton, NJ) ; Wu; Wenxue;
(Princeton Junction, NJ) ; D'Sa; Bosco; (Edison,
NJ) ; Liang; Feng; (Monmouth Junction, NJ) ;
Tran; Loc Thanh; (Piscataway, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation
|
Family ID: |
36571985 |
Appl. No.: |
12/580855 |
Filed: |
October 16, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11326154 |
Jan 5, 2006 |
|
|
|
12580855 |
|
|
|
|
60641900 |
Jan 6, 2005 |
|
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Current U.S.
Class: |
544/360 ;
546/248 |
Current CPC
Class: |
A61P 1/04 20180101; A61P
17/02 20180101; A61P 37/08 20180101; A61P 19/02 20180101; A61P
37/06 20180101; A61P 25/00 20180101; C07D 211/96 20130101; C07D
401/14 20130101; A61P 17/06 20180101; A61P 31/18 20180101; A61P
11/06 20180101; A61P 29/00 20180101; C07D 211/26 20130101; A61P
43/00 20180101 |
Class at
Publication: |
544/360 ;
546/248 |
International
Class: |
C07D 401/06 20060101
C07D401/06; C07D 211/30 20060101 C07D211/30 |
Claims
1. A process for preparing a compound of formula (V) ##STR00028##
where PMB is p-methoxybenzyl and Cbz is carbobenzyloxy from a
compound of formula (IV): ##STR00029## said process comprising
reacting said compound of formula IV with a reagent selected from
(i) benzotriazole, a nitrites, a halogen, an alkylsulfonate or a
haloalkyl ester (ii) 3-fluorophenylmagnesium bromide; and (iii) the
compound: ##STR00030## in a suitable solvent to yield a compound of
formula V.
2. A process for preparing a compound of formula VI: ##STR00031##
from a compound of formula V: ##STR00032## where PMB is
p-methoxybenzyl and Cbz is carbobenzyloxy, said process comprising
removing the PMB protecting group of the compound of formula V to
produce a compound of formula VI.
3. A process for preparing a compound of formula VII ##STR00033##
where Cbz is carbobenzyloxy, from a compound of formula VI:
##STR00034## said process comprising sulfonylating the compound of
formula VI with cyclopropyl sulfonyl chloride to form the compound
of formula VIII.
4. The process for preparing a compound of formula VIII:
##STR00035## from a compound of formula VIII: ##STR00036## where
Cbz is carbobenzyloxy, said process comprising removing the Cbz
protecting group from the compound of formula VII and reacting with
hydrogen bromide to produce the di-hydrobromide salt formula
VIII.
5. The process of claim 1 wherein said solvent is selected from the
group consisting of hydrocarbon, ether, and mixtures thereof.
6. The process of claim 1 wherein said reagent is
benzotriazole.
7. The process of claim 2 wherein removal of said PMB protecting
group is accomplished with trifluoroacetic anhydride.
8. The process of claim 3 wherein said sulfonylating step is
performed in toluene and utilizing triethyl amine as the base.
9. The process of claim 4 wherein removal of said Cbz is
accomplished using methanesulfonic acid.
10. A compound of the formula: ##STR00037## where PMB is
p-methoxybenzyl and Cbz is carbobenzyloxy, including isomers of
said compound.
11. A compound of the formula: ##STR00038## where Cbz is
carbobenzyloxy, including isomers of said compound.
12. A compound of the formula: ##STR00039## where Cbz is
carbobenzyloxy, including isomers of said compound.
13. A compound of the formula: ##STR00040## including isomers of
said compound.
14. A compound of the formula: ##STR00041## including isomers of
said compound.
15. A compound of the formula: ##STR00042## including isomers of
said compound.
16. A compound of the formula: ##STR00043## including isomers of
said compound.
Description
CROSS REFERENCE TO PRIORITY APPLICATION
[0001] This application claims the benefit of priority to U.S.
provisional application Ser. No. 60/641,900 filed Jan. 6, 2005.
FIELD OF THE INVENTION
[0002] This application concerns the synthesis of the CCR5 receptor
antagonist
4-[4-[(R)-[1-[cyclopropylsulfonyl)-4-piperidinyl](3-fluorophenyl)methyl]--
3(S)-methyl-1-piperazinyl]-1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-meth-
ylpiperidine.
BACKGROUND OF THE INVENTION
[0003]
4-[4-[(R)-[1-[cyclopropylsulfonyl)-4-piperidinyl](3-fluorophenyl)me-
thyl]-3(S)-methyl-1-piperazinyl]-1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]--
4-methylpiperidine] has the structure shown below (Formula I):
##STR00001##
[0004] The compound of Formula I is an antagonist of the CCR5
receptor and is useful for the treatment of AIDS and related HIV
infections. CCR5 receptors have also been reported to mediate cell
transfer in inflammatory diseases such as arthritis, rheumatoid
arthritis, atopic dermatitis, psoriasis, asthma and allergies, and
inhibitors of such receptors are expected to be useful in the
treatment of such diseases, and in the treatment of other
inflammatory diseases or conditions such as inflammatory bowel
disease, multiple sclerosis, solid organ transplant rejection and
graft v. host disease. This compound is described and claimed in
U.S. Pat. No. 6,720,325, the disclosure of which is incorporated
herein by reference.
[0005] Reference is also made to patent application Ser. No. ______
(Attorney Docket # CD06221L01), filed concurrently herewith which
relates to certain rotamer salts.
[0006] In view of the importance of antagonists of the CCR5
receptor, new, novel methods of making such antagonists are always
of interest.
SUMMARY OF THE INVENTION
[0007] In one embodiment, the present application teaches a novel
process of making a compound of formula I. The compound of formula
I is prepared from a compound of formula V:
##STR00002##
[0008] where X is selected from the group consisting of:
p-methoxybenzyl (PMB), allyl, methoxymethyl, benzyloxymethyl,
trityl, pivaloyloxymethyl, tetrahydranyl, benzyl,
di(p-methoxyphenyl)methyl, triphenylmethyl,
(p-methoxyphenyl)diphenylmethyl, and t-butyl carbamate ("t-Boc");
and Y is selected from the group consisting of: carbobenzyloxy
(Cbz), CZ.sub.3CO (where Z is a halogen), 2-trimethylsilylethyl
carbamate, 1-methyl-1-phenylethyl carbamate, t-butyl carbamate,
cyclobutyl carbamate, 1-methylcyclobutyl carbamate, adamantyl
carbamate, vinyl carbamate, allyl carbamate, cinnamyl carbamate,
8-quinolyl carbamate, 4,5-diphenyl-3-oxazolin-2-one, benzyl
carbamate, 9-anthrylmethyl carbamate, diphenylmethyl carbamate,
S-benzylcarbamate, methyl carbamate, ethyl carbamate,
diphenylphosphinyl, benzenesulfenyl, RCO (where R is
C.sub.1-6alkyl), benzoyl, and other common acyl groups, with the
proviso that X and Y are not the same group (e.g., both X and Y are
not t-Boc simultaneously) since the inventive process utilizes the
differentiation of X and Y under the reaction conditions employed
in the invention, e.g., X can be selectively removed without
affecting Y.
[0009] The inventive process comprises the sequential steps of:
[0010] (a) selectively removing the X protecting group of the
compound of formula V to produce a compound of formula VI:
##STR00003##
[0011] (b) sulfonylating the compound of formula VI with
##STR00004##
where W=a halide or triflate, to form the compound of formula
VII:
##STR00005##
[0012] (c) removing the Y protecting group from the compound of
formula VII and then reacting with hydrogen bromide to produce the
di-hydrobromide salt formula VIII:
##STR00006##
[0013] (d) reacting the compound of formula VIII with (i) an agent
containing a leaving group G, where G is a leaving group selected
from the group consisting of CN, Z, OSO.sub.2R.sup.1, OCOCZ.sub.3
and benzotriazolyl, with R.sup.1 being an alkyl or aryl group and Z
is a halogen, and (ii) the compound:
##STR00007##
to form the compound of formula IX:
##STR00008##
and
[0014] (e) reacting the compound of formula IX with a Grignard
reagent in a suitable solvent, followed by a workup, to yield the
compound of formula I.
[0015] The inventive process to make the compound of formula I has
numerous advantages including it is economical and can be easily
scaled-up.
DESCRIPTION OF THE INVENTION
[0016] Except where stated otherwise, the following definitions
apply throughout the present specification and claims. These
definitions apply regardless of whether a term is used by itself or
in combination with other terms.
[0017] "Acyl" means an H--C(O)--, alkyl-C(O)--, cycloalkyl-C(O)--,
or aryl-C(O)-- and the like. The bond to the parent moiety is
through the carbonyl.
[0018] "Alkyl" means an aliphatic hydrocarbon group which may be
straight or branched and comprising about 1 to about 20 carbon
atoms in the chain. Preferred alkyl groups contain about 1 to about
12 carbon atoms in the chain. More preferred alkyl groups contain
about 1 to about 6 carbon atoms in the chain. Branched means that
one or more lower alkyl groups such as methyl, ethyl or propyl, are
attached to a linear alkyl chain. "Lower alkyl" means a group
having about 1 to about 6 carbon atoms in the chain which may be
straight or branched. The term "substituted alkyl" means that the
alkyl group may be substituted by one or more substituents which
may be the same or different, each substituent being independently
selected from the group consisting of halo, alkyl, aryl,
cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, carboxy and --C(O)O-alkyl.
Non-limiting examples of suitable alkyl groups include methyl,
ethyl, n-propyl, isopropyl and t-butyl.
[0019] "Alkylsulfonate" means an alkyl-S(O.sub.2)--O-- group in
which the alkyl group is as previously described. Preferred groups
are those in which the alkyl group is lower alkyl. The bond to the
parent moiety is through the oxygen.
[0020] "Aryl" means an aromatic monocyclic or multicyclic ring
system comprising about 6 to about 14 carbon atoms, preferably
about 6 to about 10 carbon atoms. The aryl group can be optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined herein. Non-limiting
examples of suitable aryl groups include phenyl and naphthyl.
[0021] "Cbz" means carbobenzyloxy.
[0022] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms. Preferred cycloalkyl rings
contain about 5 to about 7 ring atoms.
[0023] "Halide" means fluoro, chloro, bromo or iodo.
[0024] "Halogen" means fluoro, chloro, bromo or iodo.
[0025] "Heterocyclic" means a non-aromatic saturated monocyclic or
multicyclic ring system comprising about 3 to about 10 ring atoms,
preferably about 4 to about 7 ring atoms, in which one or more of
the atoms in the ring system is an element other than carbon, for
Preparative Example nitrogen, oxygen or sulfur, alone or in
combination. There are no adjacent oxygen and/or sulfur atoms
present in the ring system. Preferred heterocyclyls contain about 5
to about 6 ring atoms. The prefix aza, oxa or thia before the
heterocyclyl root name means that at least a nitrogen, oxygen or
sulfur atom respectively is present as a ring atom. Any --NH in a
heterocyclyl ring may exist protected such as, for example, as an
--N(Boc), --N(cbz), --N(Tos) group and the like; such protections
are also considered part of this invention.
[0026] "PMB" means p-methoxybenzyl.
[0027] "Triflate" means trifluoromethanesulfonyl.
[0028] In one embodiment, the present invention discloses a novel,
easy-to-use process for preparing the compound of formula I. The
process comprises:
[0029] (a) converting the compound of formula II:
##STR00009##
to a compound of formula III by reaction with a reagent that
introduces a group X:
##STR00010##
where X is selected from the group consisting of: p-methoxybenzyl
(PMB), allyl, methoxymethyl, benzyloxymethyl, trityl,
pivaloyloxymethyl, tetrahydranyl, benzyl,
di(p-methoxyphenyl)methyl, triphenylmethyl,
(p-methoxyphenyl)diphenylmethyl and t-Boc, and is preferably
p-methoxybenzyl (PMB);
[0030] (b) reacting the compound of formula III with a suitable
reducing reagent, followed by purification through formation of a
bisulfite salt and subsequent treatment with a base, to yield a
compound of formula IV:
##STR00011##
[0031] (c) reacting the compound of formula IV with (i) the
compound of formula:
##STR00012##
and (ii) a compound selected from the group consisting of
benzotriazole, a nitrile, a halide, an alkylsulfonate, a haloalkyl
sulfonate and a haloalkyl acid, preferably benzotriazole, and (iii)
3-fluorophenylmagnesium bromide, to yield a compound of formula
V:
##STR00013##
where Y is selected from the group consisting of: carbobenzyloxy
(Cbz), CZ.sub.3CO (where Z is a halogen), 2-trimethylsilylethyl
carbamate, 1-methyl-1-phenylethyl carbamate, t-butyl carbamate,
cyclobutyl carbamate, 1-methylcyclobutyl carbamate, adamantyl
carbamate, vinyl carbamate, allyl carbamate, cinnamyl carbamate,
8-quinolyl carbamate, 4,5-diphenyl-3-oxazolin-2-one, benzyl
carbamate, 9-anthrylmethyl carbamate, diphenylmethyl carbamate,
S-benzylcarbamate, methyl carbamate, ethyl carbamate,
diphenylphosphinyl, benzenesulfenyl, RCO (where R is
C.sub.1-6alkyl), benzoyl and other common acyl groups, and is
preferably carbobenzyloxy (Cbz), with the proviso that X and Y are
different such that X may be selectively removed;
[0032] (d) removing the X protecting group of the compound of
formula V to produce a compound of formula VI:
##STR00014##
[0033] (e) sulfonylating the compound of formula VI with a
cyclopropyl
##STR00015##
sulfonyl moiety, where W is a halide or triflate, to form the
compound of formula VII:
##STR00016##
[0034] (f) removing the Y protecting group from the compound of
formula VII and reacting with hydrogen bromide to produce the
di-hydrobromide salt formula VIII:
##STR00017##
[0035] (g) reacting the compound of formula VIII with an agent
containing a leaving group G where G is a leaving group preferably
selected from the group consisting of CN, Z, OSO.sub.2R.sup.1,
OCOCZ.sub.3 and benzotriazolyl, with R.sup.1 being an alkyl or aryl
group and Z is a halogen; and the compound of Formula VIIIa:
##STR00018##
to form the compound of formula IX:
##STR00019##
and
[0036] (h) reacting the compound of formula IX with a Grignard
reagent in a suitable solvent to yield the compound of formula
I.
[0037] As stated above, X and Y are not the same moiety since X and
Y are to be differentiated under the reaction conditions
employed.
[0038] The preferred protecting group for X is p-methoxybenzyl
(PMB):
##STR00020##
[0039] The preferred protecting group for Y is carbobenzyloxy
(Cbz):
##STR00021##
[0040] Protecting groups are sometimes named as carbamates herein
for convenience; for example Cbz could be referred to as benzyl
carbamate and so forth.
[0041] The deprotection in step (d) is performed using
2,3-dichoro-5,6-dicyano-1,4-benzoquinone or trifluoroacetic
anhydride. Preferably, the deprotection is performed using
trifluoroacetic anhydride.
[0042] The preferred W in step (e) is Cl.
[0043] The deprotection in step (f) is performed using strong acids
such as sulfuric acid, hydrochloric acid, hydrobromic acid,
methanesulfonic acid and the like. Preferably, the protection is
accomplished using methanesulfonic acid.
[0044] The reaction in step (g) comprises (1) converting compound
of formula VIII to a free base by use of a basic compound and (2)
reacting free base with an agent containing a leaving group G and
the compound of Formula VIIIa:
##STR00022##
where G is a leaving group preferably selected from the group
consisting of CN, Z, OSO.sub.2R.sub.2, OCOCZ.sub.3 and
benzotriazolyl, with R.sub.2 being an alkyl or aryl group and Z is
a halogen.
[0045] The term "an agent containing a leaving group G" refers to a
compound that upon reaction as shown herein, leaves a moiety G
described above on the compound being reacted. Thus, the
above-noted phrase "where G is a leaving group preferably selected
from the group consisting of CN, Z, OSO.sub.2R.sub.2, OCOCZ.sub.3
and benzotriazolyl" means that the compound (agent) contains in it
as bonded moiety CN, Z, OSO.sub.2R.sub.2, OCOCZ.sub.3 or
benzotriazolyl, and then leaves the CN, Z, OSO.sub.2R.sub.2,
OCOCZ.sub.3 or benzotriazolyl upon being reacted with the compound
of Formula VIII to form the compound of Formula IX as a result of
said reaction. The more preferred agent containing a leaving group
is a cyanating agent and is selected from the group consisting of:
HCN, acetone cyanohydrin; cyclohexanone cyanohydrin; a mixture of
(C.sub.2H.sub.5).sub.2AlCN and Ti(OPr).sub.4, a mixture of acetic
acid, H.sub.2SO.sub.4; NaHSO.sub.4, KHSO.sub.3 or
Na.sub.2S.sub.2O.sub.5 and a cyanide source such as NaCN or KCN;
trimethylsilylcyanide; glycolonitrile; mandelonitrile;
glycinonitrile; acetone amino nitrile; and
dimethylaminoacetonitrile. Most preferably, the cyanating agent is
acetone cyanohydrin.
[0046] The acetone cyanohydrin is used in about 1-5 molar
equivalents with respect to the compound of formula VIII.
##STR00023##
The compound of Formula VIIIa is used in about 1-4 molar
equivalents with respect to the compound of formula VIII.
[0047] The basic compound in step (g) is selected from the group
consisting of a metal hydroxide, oxide, carbonate and a
bicarbonate, wherein the metal is selected from the group
consisting of lithium, sodium, potassium, rubidium, cesium,
beryllium, magnesium, calcium, strontium, barium, aluminum, indium,
thallium, titanium, zirconium, cobalt, copper, silver, zinc,
cadmium, mercury and cerium; a metal salt of a C.sub.1-C.sub.12
alkanol, a C.sub.3-C.sub.12 cycloalkanol, a (C.sub.3-C.sub.8
cycloalkyl)C.sub.1-C.sub.6 alkanol; ammonia, a C.sub.1-C.sub.12
alkylamine, a di(C.sub.1-C.sub.12 alkyl)amine, a C.sub.3-C.sub.8
cycloalkylamine, a N--(C.sub.3-C.sub.8
cycloalkyl)-N--(C.sub.1-C.sub.12 alkyl)amine. a di(C.sub.3-C.sub.8
cycloalkyl)amine, a (C.sub.3-C.sub.8 cycloalkyl)C.sub.1-C.sub.6
alkylamine, a
N--(C.sub.3-C.sub.8-cycloalkyl)C.sub.1-C.sub.6-alkyl-N--(C.sub.1-C.sub.12
alkyl)amine, a N--(C.sub.3-C.sub.8 cycloalkyl)C.sub.1-C.sub.6
alkyl-N--(C.sub.3-C.sub.8 cycloalkyl)amine, a di[(C.sub.1-C.sub.6
cycloalkyl)C.sub.1-C.sub.6 alkyl[amine; and a heterocyclic amine
selected from the group consisting of imidazole, triazole,
pyrrolidine, piperidine, heptamethyleneimine, morpholine,
thiomorpholine and a 1-(C.sub.1-C.sub.4 alkyl)piperazine.
[0048] Preferably, the basic compound is selected from the group
consisting of KOH, NaOH, Na.sub.2CO.sub.3, K.sub.2CO.sub.3,
NaHCO.sub.3, KHCO.sub.3, tetramethylguanidine, DBU,
diisopropylethylamine and mixtures thereof. More preferably, the
basic compound is Na.sub.2CO.sub.3 or K.sub.2CO.sub.3. Most
preferably, the basic compound is K.sub.2CO.sub.3.
[0049] The Grignard reagent in step (h) is selected from the group
consisting of MeMgCl, MeMgBr and MeMgI and is most preferably
MeMgCl.
[0050] The MeMgCl is used in about 1-4 molar equivalents with
respect to the compound of formula IX.
[0051] The solvent in step (h) is selected from the group
consisting of toluene, xylene, chlorobenzene, or dichlorobenzene
alone or in admixture with a solvent selected from the group
consisting of a C.sub.5-C.sub.12 alkyl ether, 1,2-dimethoxyethane,
1.2-diethoxyethane, diglyme, 1,4-dioxane and tetrahydrofuran. The
preferred solvent is a mixture of toluene and tetrahydrofuran.
[0052] The work-up in step (h) is treatment with an acid such as
sulfuric acid, hydrochloric acid, phosphoric acid, and the like, in
an aqueous phase and is preferably hydrochloric acid.
[0053] In another embodiment, the application teaches a method for
the preparation of a compound of formula V from a compound of
formula IV:
##STR00024##
wherein the process comprises reacting the compound of formula IV
with (i) benzotriazole, nitriles, halogens, alkylsulfonates or
haloalkyl esters, preferably benzotriazole; (ii)
3-fluorophenylmagnesium bromide, and (ii) the compound:
##STR00025##
in a suitable solvent to yield a compound of formula V.
[0054] The solvent is selected from the group consisting of
hydrocarbons, halogenated hydrocarbons, ethers, and mixtures
thereof, and is preferably a mixture of toluene and
tetrahydrofuran.
[0055] The inventive process is schematically described in Scheme
I:
##STR00026## ##STR00027##
[0056] The term "alkyl" refers to a monovalent group derived from a
straight or branched chain saturated hydrocarbon by the removal of
a single atom having from 1 to 8 carbon atoms, preferably from 1 to
6. The term "aryl" represents a carbocyclic group having from 6 to
14 carbon atoms and having at least one benzenoid ring, with all
available substitutable aromatic carbon atoms of the carbocyclic
group being intended as possible points of attachment. Preferred
aryl groups include phenyl, 1-naphthyl and 2-naphthyl, and
especially phenyl. The term "halogen" represents fluorine,
chlorine, bromine and iodine.
[0057] If desired, the compound of formula I may be further
converted to the CCR5 antagonist of formula X by suitable
procedures known to those skilled in the art.
[0058] The products of the various steps in the reaction schemes
described herein may be isolated and purified by conventional
techniques such as, for example, filtration, recrystallization,
solvent extraction, distillation, precipitation, sublimation and
the like, well known to those skilled in the art. The products may
be analyzed and/or checked for purity by conventional methods well
known to those skilled in the art such as, for example, thin layer
chromatography, NMR, HPLC, melting point, mass spectral analysis,
elemental analysis and the like.
[0059] The following nonlimiting EXAMPLES are provided in order to
further illustrate the present invention. It will be apparent to
those skilled in the art that many modifications, variations and
alterations to the present disclosure, both to materials, methods
and reaction conditions, may be practiced. All such modifications,
variations and alterations are intended to be within the spirit and
scope of the present invention.
EXAMPLES
[0060] Unless otherwise stated, the following abbreviations have
the stated meanings in the Examples below:
CDCl.sub.3=Deuterochloroform
[0061] Cbz=carbobenzyloxy
DSC=Differential Scanning Calorimetry
[0062] DMSO=dimethylsulfoxide EtOH=ethanol g=grams HCl=hydrochloric
acid
HPLC=High Performance Liquid Chromatography
[0063] M.pt: melting point MHz=megahertz mL=milliliters
MS=Mass Spectrum
[0064] MTBE=methyl t-butyl ether NaOH=sodium hydroxide NMR=nuclear
magnetic resonance spectroscopy PMB=p-methoxybenzyl
THF=tetrahydrofuran
Example 1
[0065] Preparation of Compound of formula III from a compound of
formula II: Compound III is prepared from compound II and
p-anisaldehyde via reductive amination. Compound II (50 g, 318
mmol) is added to a stirred slurry of sodium triacetoxyborohydride
(101.1 g, 1.5 equiv) in anhydrous tetrahydrofuran (500 mL).
p-Anisaldehyde (45.5 g, 1.05 equiv) is next added to the batch
slowly at a batch temperature below 25.degree. C. The mixture is
stirred for about 16 hours at room temperature. Upon completion the
reaction is quenched with the addition of water (150 mL), and THF
is removed via vacuum distillation. MTBE and water are added to the
batch followed by pH adjustment to 1.5-2.5 with hydrochloric acid.
The batch is filtered to remove boric acid before splitting the
layers. The product containing aqueous layer is washed with MTBE.
After splitting, fresh MTBE is charged to aqueous layer followed by
pH adjustment to 9-11 with sodium hydroxide. After splitting, the
aqueous layer is charged with MTBE, the mixture is filtered and the
phases are separated. The combined organic layers are concentrated
and diluted with toluene. The batch is concentrated under vacuum to
a final volume of 150 mL. This solvent displacement provides III in
about 90-95% yield as an approximately 50% solution in toluene. The
product solution is filtered to remove residual solids and is used
directly in the next step. For oxalate salt of compound III:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.41 (m, 2H), 6.92 (m,
2H), 4.11 (br, 4H), 3.80 (s, 3H), 3.20 (br, 2H), 2.82 (br, 2H),
2.61 (s, 1H), 2.05 (d, J=6.5 Hz), 1.85 (br, 2H), 1.21 (t, J=7.1 Hz,
3H); .sup.13C NMR (100.6 MHz, DMSO-d.sub.6) .delta. 173.5, 164.6,
160.1, 132.7, 123.2, 114.4, 60.6, 59.1, 55.5, 50.4, 39.2, 38.2,
25.5, 14.4; MS (ESI) for M+H calcd. 278, found 278.
Example 2
[0066] Preparation of Compound of formula IV from a compound of
formula III: Literature reference: Abe, T.; Haga, T.; Negi, S.;
Morita, Y.; Takayanagi, K.; Hamamura, K. Tetrahedron, 2001, 57,
2701.
[0067] The modified Red-Al reagent is prepared according to the
above literature reference: Red-Al solution (150 mL, 70 wt % in
toluene) is charged to a clean reaction vessel under nitrogen. MTBE
(180 mL) is added to dilute the reagent and the batch is cooled to
-25.degree. C. Pyrrolidine (52 mL) is slowly charged to the batch
maintaining the temperature below -5.degree. C. The batch is warmed
to 25.degree. C. and agitated for 10 hours. A slurry of potassium
t-butoxide (4.3 g) in THF (12 mL) is added and the mixture is
agitated for 1 hour to give the modified Red-Al reagent.
[0068] To a solution of III in toluene (containing 100 g active,
360 mmole) diluted with MTBE (100 mL) is slowly charged the above
modified Red-Al reagent at a temperature below 10.degree. C. Batch
is agitated at 5-10.degree. C. until the reaction completion is
indicated by GC analysis. Batch is cooled to -5.degree. C. and
quenched first with a solution of sodium citrate dihydrate (120 g)
in water (400 mL), followed by addition of an aqueous solution of
citric acid to adjust pH to 8-9 range. The product containing
organic layer is washed with water. The crude product aldehyde IV
is extracted from organic layer with two washes of aqueous sodium
bisulfite. The pH of combined bisulfite extracts is adjusted to
9-10 using potassium carbonate (approx. 120 g) in water (250 mL).
The precipitated bisulfite salt IVa is collected by filtration and
washed with MTBE. A sample of the bisulfite salt was dried to give
a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.14 (d,
J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 4.82 (d, J=5.3 Hz, 1H), 3.68
(s, 3H), 3.57 (t, J=5.2 Hz, 1H), 3.27 (s, 2H), 2.71 (br d, J=10.9
Hz, 2H), 1.62 (m, 5H), 1.25 (m, 2H).
[0069] The wet bisulfite salt IVa is suspended in MTBE (300 mL) at
25.degree. C. and treated with 25% NaOH (250 mL) for 1 hour. After
split, product containing organic layer is concentrated and the
solvent is exchanged to toluene to a final volume of 300 mL. The
solution of III in toluene is used directly in the next step. A
purified sample of IV gives the following spectral data: .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. 9.65 (s, 1H), 7.25 (m, 2H), 6.82
(m, 2H), 3.82 (s, 3H), 3.41 (s, 2H), 2.82 (m, 2H), 2.25 (m, 1H),
2.15 (m, 2H), 1.91 (m, 2H), 1.70 (m, 2H). MS (ESI) for M+H calcd.
234, found 234.
Example 3
[0070] Preparation of Compound of formula V from compounds of
formula IV and A: Benzotriazole (57.0 g), toluene (1 L) and
solution of A (105.5 g active) in toluene are charged to vessel
equipped with a Dean-Stark collection apparatus under nitrogen. A
solution of IV (100.0 g active, 429 mmol) in toluene is charged
keeping the batch temperature below 30.degree. C. The batch is
heated to reflux (110-120.degree. C.) and agitated until water
collection in the Dean-Stark trap is complete. The batch is
atmospherically concentrated and a sample is taken to check for
reaction completion by NMR and batch KF. The batch is further
concentrated under vacuum to 300 mL. Anhydrous THF (1800 mL) is
added at 50-60.degree. C. and the batch is cooled to 15.degree. C.
A solution of 3-fluorophenylmagnesium bromide in THF (643 mL of 1.0
M solution) is slowly charged to the batch keeping the batch
temperature below 25.degree. C. Upon reaction completion by HPLC,
the batch is quenched at 0.degree. C. by adding a solution of
sodium citrate in water (100 mL, 22 wt %) and the organic layer is
concentrated to 800 mL by atmospheric distillation. The batch is
cooled to 25.degree. C. and MTBE (800 mL) is added followed by a
solution of sodium citrate in water (500 mL, 22 wt %) are added.
The batch is warmed up to 35.degree. C. and agitated for 15 min.
The aqueous layer is extracted with fresh MTBE (500 mL). Organic
layers are combined, washed with sodium hydroxide (400 mL, 2.0 N)
to remove benzotriazole and finally concentrated to 400 mL. The
prepared solution of V is kept warm at 50-60.degree. C. to avoid
solidification and used directly in the next step. A purified
sample of V gives the following spectral data: .sup.1H NMR (400
MHz, CDCl.sub.3) of a purified sample of V: .delta. 7.20 (m, 9H),
6.75 (m, 4H), 5.01 (m, 2H), 3.65 (s, 3H), 3.51 (d, J=8.1 Hz, 1H),
3.36 (s, 2H), 2.81 (br, 2H), 2.58 (br, 1H), 1.85 (m, 5H), 1.20 (m,
2H), 1.05 (br, 4H). MS (ESI) for M+H calcd. 546, found 546.
Example 4
[0071] Preparation of Compound of formula VI from compound of
formula V: A solution of V (109 g, 199 mmol) is cooled to 0.degree.
C. and triethylamine (56 mL) is added. Trifluoroacetic anhydride
(56 mL) is added slowly to the batch keeping the temperature below
10.degree. C. The batch is warmed to 20.degree. C. and agitated for
1 hour. A sample is taken to check for reaction completion by HPLC.
Batch is cooled to 0.degree. C. and water (300 mL) is charged
keeping the temperature below 10.degree. C. Batch is agitated for
30 min, settled, and aqueous layer is split to waste. The organic
layer is a solution of compound Va. A purified sample of Va gives
the following spectral data: .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.32 (m, 6H), 6.85 (m, 3H), 5.05 (br, 2H), 4.69 (m, 1H),
4.45 (m, 1H), 4.05 (br, 3H), 3.75 (m, 1H), 3.20 (m, 3H), 2.74 (m,
2H), 2.25 (br, 2H), 1.75 (s, 2H), 1.45 (m, 2H), 1.20 (m, 3H). MS
(ES!) for M+H calcd. 522.2, found 522.2.
[0072] The above solution of Va is charged with benzyl
triethylammonium chloride (15 g) and 25% sodium hydroxide solution
(200 g). The batch is heated to 55.degree. C. and agitated for 3
hours. A sample is taken to check for reaction completion by HPLC.
The batch is cooled to 20.degree. C., settled and aqueous layer is
split to waste. The pH is adjusted to 0-1 with hydrochloric acid.
Batch is agitated at 25.degree. C. for 1 hour, settled, and the
product containing aqueous layer was split and washed twice with
isopropyl acetate to remove non-basic impurities. THF (250 mL) and
MTBE (250 mL) were charged to the batch, followed by pH adjustment
to 11-12 with sodium hydroxide. Product containing organic layer
was washed with 20% sodium chloride solution (300 mL). The solvent
is exchanged to toluene, the batch is azeotropically dried and
concentrated to 500 mL. The prepared solution of VI in toluene was
used directly in the next step. A purified sample of VI gives the
following spectral data: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.35 (m, 5H), 7.25 (m, 1H), 6.96 (m, 1H), 6.90 (m, 1H), 6.85 (m,
1H), 5.10 (br, 2H), 3.90 (br, 2H), 3.67 (m, 1H), 3.15 (m, 1H), 3.01
(m, 2H), 2.70 (br, 4H), 2.20 (m, 5H), 1.32 (m, 1H), 1.21 (m, 4H),
1.05 (m, 1H). MS (ESI) for M+H calcd. 426, found 426.
Example 5
[0073] Optional Purification of Compound of formula V via compound
of formula Vb: A warm solution of V (80 g active, 147 mmol) is
diluted with EtOH (1000 mL) and concentrated atmospherically to a
final volume of 700 mL. Batch is cooled to 25.degree. C. and
aqueous solution of NaOH (170 mL, 50 wt %) is charged keeping the
batch temperature below 40.degree. C. The batch is heated to reflux
and agitated at reflux for about 6 hours until the conversion is
complete by HPLC. The batch is cooled to 25.degree. C. and
concentrated under vacuum to a volume of about 300 mL. Water (600
mL) and MTBE (500 mL) are added to the batch, temperature is
adjusted to 30-40.degree. C. After agitation, settling and split,
the aqueous layer is extracted with fresh MTBE (200 mL), and
organic layers are combined. The product is back-extracted with
dilute hydrochloric acid at pH-5-6. The aqueous layer is washed
with fresh MTBE, diluted with MTBE (500 mL), and the batch pH is
adjusted to 12-14 with sodium hydroxide. Aqueous layer is split,
extracted with fresh MTBE (500 mL). The combined organic layers are
washed with water and concentrated by atmospheric distillation to
400 mL volume and cooled to 40.degree. C. Isopropyl alcohol is
charged (1600 mL) and the batch is concentrated by atmospheric
distillation to 1200 mL volume. Batch is cooled to 25.degree. C.
and treated with activated carbon (10 g, DARCO.RTM.) at reflux for
2 hours. The batch is cooled to 25.degree. C., filtered through
celite pad, followed by wash of celite cake with isopropyl alcohol
(200 mL). The filtrate is concentrated by atmospheric distillation
to 500 mL volume and diluted with fresh isopropyl alcohol (700 mL).
Solution of oxalic acid (40 g) in isopropyl alcohol (200 mL) is
added keeping the batch temperature below 30.degree. C. MTBE (1500
mL) is added and the batch is heated to reflux and agitated for 4
hours. The batch is cooled to 20.degree. C. and precipitated
product is filtered. The cake is washed with isopropyl alcohol/MTBE
mixture (400 mL, 1:1 v/v) and dried under vacuum with nitrogen
purge at 70-80.degree. C. to give 140.0 g of Vb as an off-white
solid. m.p.: 194.degree. C. by DSC. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.31 (m, 2H), 6.93 (m, 1H), 6.82 (m, 4H), 6.65
(m, 1H), 3.52 (d, J=10.1 Hz, 1H), 3.41 (s, 2H), 3.33 (s, 3H), 2.97
(m, 1H), 2.71 (m, 1H), 2.55 (m, 2H), 2.35 (m, 2H), 2.10 (m, 1H),
1.95 (m, 1H), 1.79 (m, 2H), 1.70 (m, 1H), 1.4 (m, 1H), 1.2 (m, 2H).
MS (ESI) for M+H calcd. 412, found 412.
[0074] Solid compound Vb (100 g, 199 mmol) and
N-(benzyloxycarbonyloxy) succinimide (53 g) are charged to a
reaction vessel under nitrogen atmosphere. THF (300 mL) and water
(300 mL) are added and batch is agitated at 25.degree. C. for 30
min. Batch is then warmed to 35.degree. C. and agitated for an
additional 3 hours. A sample is taken to check for reaction
completion by HPLC. Toluene (500 mL) is charged to the batch. A
solution of potassium carbonate (200 g) in water (200 mL) is
charged slowly maintaining batch temperature below 20.degree. C.
Batch pH is adjusted to a range of 9-11. The lower aqueous layer is
split and extracted with toluene (300 mL). Organic layers are
combined, washed with water and concentrated by atmospheric
distillation to 450 mL volume to give a solution of V.
Example 6
[0075] Preparation of Compound of formula VIII from compound of
formula VI: To a solution of compound VI (100 g active, 235 mmol)
is charged toluene (500 mL) and triethylamine (28 g) and the batch
is cooled to 0.degree. C. Cyclopropyl sulfonyl chloride (36.5 g) is
added keeping the batch temperature below 10.degree. C. The batch
is agitated at 0.degree. C. for 2 hours and sampled for reaction
completion. Batch is washed with a solution of 10% acetic acid in
water (200 mL) to give a solution of VII in toluene. A purified
sample of VII gives the following spectral data: .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 7.28 (m, 6H), 6.95 (m, 1H), 6.87 (m, 1H),
6.78 (m, 1H), 5.05 (br, 2H), 3.85 (d, J=112 Hz, 2H), 3.65 (m, 2H),
2.80 (m, 5H), 2.25 (m, 3H), 1.15 (m, 6H), 0.95 (m, 3H); .sup.13C
NMR (100.6 MHz, DMSO-d.sub.6) .delta. 171.1, 163.9, 161.4, 154.8,
138.0, 136.6, 129.6, 128.5, 128.0, 124.8, 114.4, 67.0, 60.3, 51.5,
46.5, 46.3, 35.2, 29.7, 25.6, 21.0, 14.1, 4.2. MS (ESI) for M+H
calcd. 530, found 530.
[0076] To the above solution is added a solution of methanesulfonic
acid (250 mL) in water (250 mL) keeping the temperature below
30.degree. C. The batch is warmed to 50.degree. C., agitated for 30
min, settled and product containing aqueous layer is split. The
organic layer is washed with methanesulfonic acid (250 mL) in water
(250 mL). The combined aqueous layers are heated at 10.degree. C.
for 15-20 hours. A sample is taken to check for reaction completion
by HPLC. Batch is cooled to 25.degree. C. and toluene (500 mL) is
added, followed by slow addition of 50% sodium hydroxide (100 mL).
Batch is agitated for 15 min and a sample is taken to ensure pH
<2.0. The batch is settled for at least 1 hour and then the
product containing aqueous layer split. THF is added to the aqueous
layer and the batch is cooled to 0.degree. C. Batch pH is carefully
adjusted to 8-10 range using 50 wt % sodium hydroxide keeping the
temperature below 30.degree. C. The aqueous layer is split to
waste, and organic layer is concentrated solvent-exchanged to
isopropyl alcohol. The batch is passed twice through CUNO.RTM.
cartridges containing DARCO.RTM.-G60. The batch is heated to
75.degree. C. and 48% hydrobromic acid solution (98 g) is added
slowly. The batch is heated to reflux (80-85.degree. C.) and
agitated for 3-5 hours until the start of product crystallization.
The batch was slowly cooled to 15.degree. C. over 4 hours, held at
15.degree. C. for 1 hour and then filtered. Isolated cake was
washed twice with isopropyl alcohol (170 mL total) and dried under
vacuum at 60.degree. C. Obtained 100.4 g of compound VIII as an
off-white solid. m.p.: 176.degree. C. by DSC. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.31 (m, 1H), 7.05 (m, 1H), 6.91 (m, 1H), 6.82
(m, 1H), 3.86 (br d, J=12.0 Hz, 1H), 3.67 (m, 1H), 3.63 (d, J=10.5
Hz, 1H), 2.75 (br m, 5H), 2.50 (m, 2H), 2.25 (m, 2H), 2.15 (m, 1H),
2.02 (s, 2H), 1.30 (m, 3H), 1.10 (m, 6H), 0.95 (m, 2H). MS (ESI)
for M+H calcd. 396, found 396.
Example 7
[0077] Preparation of Compound of formula IX from compound of
formula VIII and compound of formula B: Compound VIII (100 g, 179
mmol) is suspended in ethyl acetate (1000 mL) and treated with a
solution of aqueous potassium carbonate (52 g, 2.1 eq, in 500 mL
water). The aqueous layer is split off at 35-45.degree. C. and the
organic layer is washed with water at 35-45.degree. C. The organic
layer is azetropically dried and mixed with compound B (42 g, 1 eq)
and acetone cyanohydrin (18 g, 1.2 eq). The resulting mixture is
concentrated atmospherically to 300 mL over 8-10 hours. The
concentrate is diluted with ethyl acetate (900 mL) and filtered
through a bed of Celite (10 g). The filtrate is atmospherically
concentrated to 400 mL and heptane (150 mL) containing compound IX
seeds is added at reflux. After heated at reflux for 1 hour,
additional heptane (150 mL) is added at reflux. The resulting
slurry is heated at reflux for 1 hour and cooled over 1 hour to
room temperature. After stirring at room temperature for 1 hour,
the slurry is filtered and washed with 1:1 ethyl acetate/heptane
(200 mL). The wet cake is dried at 45.degree. C. under vacuum
overnight to give a white solid (96 g, 84% yield). m.p.:
185.degree. C. by DSC. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
8.98 (s, 1H), 7.29 (dt, J.sub.1=7.8 Hz, J.sub.2=6.1 Hz, 1H), 6.97
(dt, J.sub.1=8.4 Hz, J.sub.2=2.1 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H),
6.80 (br d, J=9.7 Hz, 1H), 4.53 (br d, J=14.2 Hz, 1H), 3.87 (br d,
J=12.0 Hz, 1H), 3.66 (m, 2H), 3.32 (m, 2H), 3.22 (m, 1H), 2.60-2.95
(m, 5H), 2.41 (s, 3H), 2.37 (s, 3H), 2.35 (m, 1H), 2.22 (m, 4H),
2.05 (m, 4H), 1.65 (m, 1H), 1.55 (m, 1H), 1.30 (m, 2H), 1.15 (m,
6H), 0.95 (m, 2H), MS (ESI) for M+H calcd. 638, found 638.
Example 8
[0078] Preparation of Compound of formula I from compound of
formula IX: To a solution of compound IX (250.0 g, 393 mmol) in
tetrahydrofuran (1250 mL) cooled to 15-25.degree. C. was added
.about.20 wt % of trimethyl aluminum in toluene (500 mL, 530 mmol).
To the resulting homogeneous solution was slowly added 3.0M methyl
magnesium chloride in tetrahydrofuran (325 mL, 510 mmol) at
15-25.degree. C. The reaction mixture was stirred for 4 hours and
then quenched in 10% aqueous sodium citrate solution (1575 mL)
maintained at 35-45.degree. C. The organic layer was washed with
10% aqueous sodium citrate solution (550 mL). The organic layer was
washed with 1.5M aqueous HCl (442 ml). The aqueous acidic layer was
digested at 35-45.degree. C. for 4 hours and then cooled to
15-25.degree. C. The aqueous layer was neutralized with 25% aqueous
NaOH (119 mL) and then extracted into isopropyl acetate (1250 mL).
The organic layer was washed with water (500 mL) and then
evaporated under vacuum to give a foam. The yield was 96%. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta.8.6 (s, 1H); 7.3 (t, J=6.2 Hz,
1H); 7.0 (t, J=7.2 Hz, 1H); 6.9 (d, J=7.5 Hz, 1H); 6.8 (d, J=8.6
Hz, 1H); 4.0 (br, 1H); 3.8 (br, 1H); 3.6 (br m, 2H); 3.3 (t, J=11.0
Hz, 1H); 3.2 (t, J=11.0 Hz, 1H); 2.7 (br m, 5H); 2.5 (br, 1H); 2.4
(s, 3H); 2.3 (s, 3H); 2.2 (br m, 5H); 1.9 (br m, 3H); 1.7 (br, 1H);
1.4 (br m, 3H); 1.1 and 1.0 (br m, 7H); 0.93 (m, 2H), 0.88 (s, 3H).
MS (ESI) for M+H calcd. 627, found 627.
[0079] While the EXAMPLES are described herein as the preparation
of the compounds indicated, it will be apparent to those skilled in
the art that many modifications, variations and alterations to the
present disclosure, both to materials, methods and reaction
conditions, may be practiced. All such modifications, variations
and alterations are intended to be within the spirit and scope of
the present invention.
* * * * *