U.S. patent application number 13/321262 was filed with the patent office on 2012-05-31 for processes for the preparation of substituted tetrahydro beta-carbolines.
Invention is credited to Neil Almstead, Peter Seongwoo Hwang, Young-Choon Moon, Hongyan Qi, Arasu Tamil.
Application Number | 20120136154 13/321262 |
Document ID | / |
Family ID | 43223058 |
Filed Date | 2012-05-31 |
United States Patent
Application |
20120136154 |
Kind Code |
A1 |
Hwang; Peter Seongwoo ; et
al. |
May 31, 2012 |
PROCESSES FOR THE PREPARATION OF SUBSTITUTED TETRAHYDRO
BETA-CARBOLINES
Abstract
Provided herein are improved processes for the synthesis of
substituted tetrahydro beta-carboline derivatives. In particular,
provided herein are improved processes useful for the preparation
of (S)-4-chlorophenyl
6-chloro-1-(4-methoxyphenyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-car-
boxylate. Formula (I) ##STR00001##
Inventors: |
Hwang; Peter Seongwoo;
(Edison, NJ) ; Moon; Young-Choon; (Belle Mead,
NJ) ; Tamil; Arasu; (Edison, NJ) ; Qi;
Hongyan; (Plainsboro, NJ) ; Almstead; Neil;
(Princeton, NJ) |
Family ID: |
43223058 |
Appl. No.: |
13/321262 |
Filed: |
May 27, 2010 |
PCT Filed: |
May 27, 2010 |
PCT NO: |
PCT/US2010/036273 |
371 Date: |
February 6, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61181652 |
May 27, 2009 |
|
|
|
Current U.S.
Class: |
546/85 |
Current CPC
Class: |
C07D 471/04
20130101 |
Class at
Publication: |
546/85 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Claims
1. A process for preparing a compound of Formula (II): ##STR00025##
comprising the steps of: i) reacting a compound of Formula (IV)
with a mixture of a chiral acid in a first solvent mixture:
##STR00026## and ii) recrystallizing the reaction product in a
second solvent mixture to provide the compound of Formula (II),
wherein X is halogen; and R is substituted or unsubstituted C.sub.1
to C.sub.8 alkyl.
2. The process of claim 1, wherein X is chloro.
3. The process of claim 1, wherein R is C.sub.1 to C.sub.8 alkyl
substituted with one or more substituents selected from halogen,
hydroxyl or C.sub.1 to C.sub.8alkoxy.
4. The process of claim 1, wherein R is methyl.
5. The process of claim 1, wherein X is chloro and R is methyl.
6. The process of claim 1, wherein the first solvent mixture is a
mixture of water and a solvent in a ratio in a range of from about
1 to about 5% volume/volume water:solvent.
7. The process of claim 6, wherein the ratio of the first solvent
mixture is in a range of from about 2 to about 5% volume/volume
water:solvent.
8. The process of claim 7, wherein the solvent in the first solvent
mixture is methanol, ethanol, 1-propanol, 1-butanol or a mixture
thereof.
9. The process of claim 8, wherein the solvent in the first solvent
mixture is methanol, ethanol or a mixture thereof.
10. The process of claim 9, wherein the solvent in the first
solvent mixture is ethanol.
11. The process of claim 1, wherein the solvent in the second
solvent mixture is a mixture of water and a solvent, wherein the
solvent is iPrOAc, EtOAc, MTBE, MEK, DCM, DCE, toluene, DMA or a
mixture thereof.
12. The process of claim 11, wherein the solvent in the second
solvent mixture is EtOAc or MEK or a mixture thereof.
13. The process of claim 12, wherein the solvent in the second
solvent mixture is MEK.
14. A process for preparing a compound of Formula (II):
##STR00027## comprising the step of reacting about one equivalent
of a compound of Formula (IV) with a chiral acid in a range of from
about 0.1 to about 0.5 equivalents in a first solvent mixture
comprising a mixture of ethanol and water in a ratio in a range of
from about 1 to about 5% volume/volume water:ethanol: ##STR00028##
to provide the compound of Formula (II), wherein X is halogen; and
R is substituted or unsubstituted C.sub.1 to C.sub.8 alkyl.
15. The process of claim 14, wherein the chiral acid is about 0.5
equivalents.
16. The process of claim 14, wherein the ratio of the first solvent
mixture is in a range of from about 2 to about 5% volume/volume
water:ethanol.
17. A process for preparing a compound of Formula (I) or a
pharmaceutically acceptable salt, hydrate or solvate thereof:
##STR00029## comprising the steps of: i) reacting a compound of
Formula (IV), with a chiral acid in a first solvent mixture:
##STR00030## to provide a compound of Formula (II), wherein X is
halogen; and R is substituted or unsubstituted C.sub.1 to C.sub.8
alkyl; and ii) reacting the compound of Formula (II) with a
compound of Formula (III) in the presence of a base and a second
solvent mixture comprising water and a solvent: ##STR00031## to
provide a compound of Formula (I), wherein X is at each occurrence
independently halogen; and R is substituted or unsubstituted
C.sub.1 to C.sub.8 alkyl.
18. The process of claim 17, wherein the first solvent mixture is a
mixture of water and a solvent in a ratio in a range of from about
1 to about 5% volume/volume water:solvent.
19. The process of claim 18, wherein the ratio of the first solvent
mixture is in a range of from about 2 to about 5% volume/volume
water:solvent.
20. The process of claim 18, wherein the solvent in the first
solvent mixture is methanol, ethanol, 1-propanol, 1-butanol or a
mixture thereof.
21. The process of claim 20, wherein the solvent in the first
solvent mixture is methanol, ethanol or a mixture thereof.
22. The process of claim 21, wherein the solvent in the first
solvent mixture is ethanol.
23. The process of claim 17, wherein the solvent in the second
solvent mixture is iPrOAc, EtOAc, MTBE, MEK, DCM, DCE, toluene, DMA
or a mixture thereof.
24. The process of claim 23, wherein the solvent in the second
solvent mixture is EtOAc or MEK or a mixture thereof.
25. The process of claim 24, wherein the solvent in the second
solvent mixture is MEK.
26. The process of claim 1, wherein a compound of Formula (I) is a
compound of Formula (X): ##STR00032##
27. The process of claim 1, wherein the compound of Formula (II) is
##STR00033##
28. The process of any of claim 1, 15 or 18, wherein the chiral
acid is N-acetyl-L-phenylalanine,
(S)-2-(methoxycarbonylamino)-3-phenylpropanoic acid,
(S)-2-(isopropoxycarbonylamino)-3-phenylpropanoic acid,
(S)-2-benzamido-3-phenylpropanoic acid,
(S)-2-(4-chlorobenzamido)-3-phenylpropanoic acid,
(S)-2-(4-methoxybenzamido)-3-phenylpropanoic acid,
(S)-3-phenyl-2-(4-(trifluoromethyl)benzamido)propanoic acid,
(S)-2-isobutyramido-3-phenylpropanoic acid,
(S)-3-phenyl-2-(phenylsulfonamido)propanoic acid,
(S)-3-phenyl-2-(4-(trifluoromethyl)phenylsulfonamido)propanoic
acid, (S)-2-(4-methoxyphenylsulfonamido)-3-phenylpropanoic acid or
(S)-2-(4-methylphenylsulfonamido)-3-phenylpropanoic acid.
29. The process of any of claim 1, 15 or 18, wherein the chiral
acid is N-acetyl-L-phenylalanine.
30. The process of claim 1, further comprising the step of
preparing a compound of Formula (IV) by reacting a compound of
Formula (V): ##STR00034## with a solvated base, wherein X is
halogen, R is substituted or unsubstituted C.sub.1 to C.sub.8
alkyl, and HB is an acid suitable to form a salt with a compound of
Formula (V).
31. The process of claim 30, wherein HB is an acid suitable to form
a salt with a compound of Formula (V), such as hydrochloric acid or
acetic acid and the solvated base is aqueous ammonium hydroxide in
a mixture with ethyl acetate or isopropyl acetate.
32. The process of claim 30, further comprising the step of
preparing a compound of Formula (V) by reacting a compound of
Formula (VII): ##STR00035## with a compound of Formula (VI):
##STR00036## in the presence of a suitable acid in a suitable
solvent, wherein X is halogen, R is substituted or unsubstituted
C.sub.1 to C.sub.8 alkyl, and HB' is an acid suitable to form a
salt with the amino group of a compound of Formula (VII).
33. The process of claim 32, wherein the suitable acid is
hydrochloric acid, the solvent is water or EtOAc and HB' is
hydrochloric acid or acetic acid.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S.
Provisional Patent Application 61/181,652, filed May 27, 2009,
incorporated herein by reference in its entirety and for all
purposes.
1. FIELD
[0002] Provided herein are processes for the synthesis of
substituted tetrahydro beta-carboline derivatives. In particular,
provided herein are processes useful for the preparation of
(S)-4-chlorophenyl
6-chloro-1-(4-methoxyphenyl)-3,4-dihydro-1H-pyrido[3,4-b)]indole-2(9H)-ca-
rboxylate. 2. BACKGROUND
[0003] Substituted tetrahydro beta-carboline derivatives have been
shown to have biological activity. See International Publication
Nos. WO2005/089764, WO2006/113703, WO2008/127715 and WO2008/127714,
each incorporated by reference herein in their entirety.
[0004] Methods for synthesizing substituted tetrahydro
beta-carboline derivatives are described in International Patent
Applications Nos. WO2005/089764 and WO2006/113703. While these
methods disclose various methods for preparing substituted
tetrahydro beta-carboline derivatives, alternative or improved
methods for their preparation, particularly for large scale,
environmentally-friendly manufacturing, are still needed.
[0005] Citation of any reference in this application is not to be
construed as an admission that such reference is prior art to the
present application.
3. SUMMARY OF THE INVENTION
[0006] Provided herein are processes for the synthesis of
substituted tetrahydro beta-carboline derivatives. Substituted
tetrahydro beta-carboline derivatives have demonstrated certain
therapeutic value in the inhibition of VEGF production. See
International Patent Applications Nos. WO2005/089764,
WO2006/113703, WO2008/127715 and WO2008/127714.
[0007] Provided herein is a process for preparing a compound of
Formula (II):
##STR00002##
[0008] comprising the steps of [0009] i) reacting a compound of
Formula (IV) with a mixture of a chiral acid in a first solvent
mixture:
##STR00003##
[0009] and [0010] ii) recrystallizing the reaction product in a
second solvent mixture to provide the compound of Formula (II),
wherein [0011] X is halogen; and [0012] R is substituted or
unsubstituted C.sub.1 to C.sub.8 alkyl.
[0013] Further provided herein is a process for preparing a
compound of Formula (II):
##STR00004## [0014] comprising the step of reacting about one
equivalent of a compound of Formula (IV) with about 0.5 equivalents
of a chiral acid in a first solvent mixture comprising water and a
solvent in a ratio in a range of from about 1 to about 5%
volume/volume water:solvent:
##STR00005##
[0015] to provide the compound of Formula (II), wherein [0016] X is
halogen; and [0017] R is substituted or unsubstituted C.sub.1 to
C.sub.8 alkyl.
[0018] Further provided herein is a process for preparing a
compound of Formula (I) or a pharmaceutically acceptable salt,
hydrate or solvate thereof:
##STR00006##
[0019] comprising the steps of: [0020] i) reacting a compound of
Formula (IV) with a chiral acid in a first solvent mixture:
[0020] ##STR00007## [0021] to provide a compound of Formula (II),
wherein [0022] X is halogen; and [0023] R is substituted or
unsubstituted C.sub.1 to C.sub.8 alkyl; and [0024] ii) reacting the
compound of Formula (II) with a compound of Formula (III) in the
presence of a base and a second solvent mixture comprising water
and a solvent:
[0024] ##STR00008## [0025] to provide a compound of Formula (I),
wherein [0026] X is at each occurrence independently halogen; and
[0027] R is substituted or unsubstituted C.sub.1 to C.sub.8
alkyl.
[0028] In one embodiment, the first solvent mixture is a mixture of
water and a solvent in a ratio in a range of from about 1 to about
5% volume/volume water:solvent.
[0029] In one embodiment, the ratio of the first solvent mixture is
in a range of from about 2 to about 5% volume/volume
water:solvent.
[0030] In another embodiment, the solvent in the first solvent
mixture is a C.sub.1-C.sub.8 saturated alcohol or a mixture
thereof.
[0031] In another embodiment, the solvent in the first solvent
mixture is methanol, ethanol, 1-propanol, 1-butanol or a mixture
thereof.
[0032] In another embodiment, the solvent in the first solvent
mixture is methanol, ethanol or a mixture thereof.
[0033] In another embodiment, the solvent in the first solvent
mixture is ethanol.
[0034] In one embodiment, the solvent in the second solvent mixture
is iPrOAc, EtOAc, MTBE, MEK, DCM, DCE, toluene, DMA or a mixture
thereof.
[0035] In another embodiment, the solvent in the second solvent
mixture is EtOAc or MEK or a mixture thereof.
[0036] In another embodiment, the solvent in the second solvent
mixture is MEK.
[0037] In one embodiment the compound of Formula (I) is a compound
of Formula (X):
##STR00009##
4. DETAILED DESCRIPTION OF THE INVENTION
[0038] 4.1 Terminology
[0039] As used herein the terms "halogen", and "halo" refer to
substituents independently selected from fluorine, chlorine,
bromine, and iodine.
[0040] As used herein, the term "alkyl" generally refers to
saturated hydrocarbyl radicals of straight or branched chain
configuration including, but not limited to methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, n-hexyl, n-heptyl, octyl, n-octyl, and the like. In some
embodiments, the term "alkyl" includes C.sub.1 to C.sub.8, C.sub.1
to C.sub.6, or C.sub.1 to C.sub.4 alkyl.
[0041] Examples of suitable alkyl substituents include, hydrogen;
or one or more substituents selected from halogen, hydroxyl,
C.sub.1 to C.sub.8alkoxy, C.sub.2 to C.sub.9 alkylene;
--C(O)--R.sub.n; --C(O)O--R.sub.b; --C(O)--NH--R.sub.b;
C.sub.3-C.sub.14cycloalkyl; aryl; heteroaryl; heterocyclyl; C.sub.1
to C.sub.9 alkyl optionally substituted with one or more
substituents independently selected from hydroxyl, halogen, C.sub.1
to C.sub.4 alkoxy, amino, alkylamino, acetamide, --C(O)--R.sub.b,
--C(O)O--R.sub.b, aryl, 3 to 12 membered heterocycle, or 5 to 12
membered heteroaryl, further wherein the alkylamino is optionally
substituted with hydroxyl, C.sub.1 to C.sub.4 alkoxy, or 5 to 12
membered heteroaryl optionally substituted with C.sub.1 to C.sub.4
alkyl, further wherein the acetamide is optionally substituted with
C.sub.1 to C.sub.4 alkoxy, sulfonyl, or alkylsulfonyl, further
wherein the 3 to 12 membered heterocycle is optionally substituted
with C.sub.1 to C.sub.4 alkyl optionally substituted with hydroxyl,
--C(O)--R.sub.n, --C(O)O--R.sub.n, or oxo, further wherein the
amino is optionally substituted with C.sub.1 to C.sub.4
alkoxycarbonyl, imidazole, isothiazole, pyrazole, pyridine,
pyrazine, pyrimidine, pyrrole, thiazole or sulfonyl substituted
with C.sub.1 to C.sub.6 alkyl, wherein pyridine and thiazole are
each optionally substituted with C.sub.1 to C.sub.4 alkyl; [0042]
wherein, R.sub.b is hydroxyl; amino; alkylamino optionally
substituted with hydroxyl, amino, alkylamino, C.sub.1 to C.sub.4
alkoxy, 3 to 12 membered heterocycle optionally substituted with
one or more independently selected C.sub.1 to C.sub.6 alkyl, oxo,
--C(O)O--R.sub.n, or 5 to 12 membered heteroaryl optionally
substituted with C.sub.1 to C.sub.4 alkyl; C.sub.1 to C.sub.4
alkoxy; C.sub.2 to C.sub.9 alkenyl; C.sub.2 to C.sub.8 alkynyl;
aryl, wherein the aryl is optionally substituted with one or more
substituents independently selected from halogen or C.sub.1 to
C.sub.4 alkoxy; 5 to 12 membered heteroaryl; 3 to 12 membered
heterocycle optionally substituted with one or more substituents
independently selected from acetamide, --C(O)O--R.sub.n, 5 to 6
membered heterocycle, or C.sub.1 to C.sub.6 alkyl optionally
substituted with hydroxyl, C.sub.1 to C.sub.4 alkoxy, amino, or
alkylamino; or C.sub.1 to C.sub.8 alkyl optionally substituted with
one or more substituents independently selected from C.sub.1 to
C.sub.4 alkoxy, aryl, amino, or 3 to 12 membered heterocycle,
wherein the amino and 3 to 12 membered heterocycle are optionally
substituted with one or more substituents independently selected
from C.sub.1 to C.sub.6 alkyl, oxo, or --C(O)O--R.sub.n; and
wherein, R.sub.n is hydroxyl, C.sub.1 to C.sub.4 alkoxy, amino, or
C.sub.1 to C.sub.6 alkyl.
[0043] As used herein and unless otherwise indicated, the term
"process(es) of preparing" or "process(es) for the preparation"
refers to the methods disclosed herein which are useful for
preparing a compound disclosed herein. Modifications to the methods
disclosed herein (e.g., starting materials, reagents, protecting
groups, solvents, temperatures, reaction times, purification) are
also encompassed by the methods and processes provided herein.
[0044] As used herein and unless otherwise indicated, the term
"adding", "reacting" or "in the presence of" and the like means
contacting one reactant, reagent, solvent, catalyst, reactive group
or the like with another reactant, reagent, solvent, catalyst,
reactive group or the like. Reactants, reagents, solvents,
catalysts, reactive group or the like can be added individually,
simultaneously or separately and can be added in any order, unless
otherwise specified. They can be added in the presence or absence
of heat and can optionally be added under an inert atmosphere.
"Reacting" can refer to in situ formation or intramolecular
reaction where the reactive groups are in the same molecule.
[0045] As used herein, the term "pharmaceutically acceptable
salt(s)" refers to a salt prepared from a pharmaceutically
acceptable non-toxic acid or base including an inorganic acid and
base and an organic acid and base. Suitable pharmaceutically
acceptable base addition salts of the Compounds provided herein
include, but are not limited to metallic salts made from aluminum,
calcium, lithium, magnesium, potassium, sodium and zinc or organic
salts made from lysine, N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procaine. Suitable non-toxic acids include,
but are not limited to, inorganic and organic acids such as acetic,
alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic,
citric, ethenesulfonic, formic, fumaric, furoic, galacturonic,
gluconic, glucuronic, glutamic, glycolic, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic,
phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,
sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific
non-toxic acids include hydrochloric, hydrobromic, phosphoric,
sulfuric, and methanesulfonic acids. Others are well-known in the
art, see for example, Remington's Pharmaceutical Sciences, 18th
eds., Mack Publishing, Easton Pa. (1990) or Remington: The Science
and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton Pa.
(1995).
[0046] As used herein, "about" means a range around a given value
wherein the resulting process is substantially the same as a
process with the recited value. In one embodiment, "about" means
within 25% of a given value or range. For example, "70% by weight"
of a compound present in a composition comprises at least all
compositions in which the component is present from 52% to 88% by
weight. In another embodiment "about" means within 10% of a given
value or range. For example, 70% by weight of a component present
in a composition comprises at least all compositions in which the
component is present from 63% to 77% by weight.
[0047] Acronyms or symbols for groups or reagents have the
following definitions: AUC=area under the curve;
DCE=dichloroethene, DCM=dichloromethane, DMA=dimethylacetamide
EtOAc=ethyl acetate; HPLC=high performance liquid chromatography;
IPC=In-process control/check; iPrOAc=isopropyl acetate, MEK=methyl
ethyl ketone, MTBE=methyl tert-butyl ether, VEGF=vascular
endothelial growth factor.
[0048] 4.2 Processes
[0049] In one embodiment provided herein is a process for the
preparation of substituted tetrahydro beta-carboline derivatives of
Formula (I):
##STR00010##
or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein X is at each occurrence independently halogen; and R is
substituted or unsubstituted C.sub.1 to C.sub.8 alkyl.
[0050] In one embodiment, the tetrahydro beta-carboline is a
compound of Formula (Ia):
##STR00011##
or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein X is at each occurrence independently halogen; and R is
substituted or unsubstituted C.sub.1 to C.sub.8 alkyl.
[0051] In one embodiment, the tetrahydro beta-carboline is a
compound of Formula (I) or (Ia) or a pharmaceutically acceptable
salt, hydrate or solvate thereof, wherein X is Cl.
[0052] In another embodiment the tetrahydro beta-carboline is a
compound of Formula (I) or (Ia) or a pharmaceutically acceptable
salt, hydrate or solvate thereof, wherein R is methyl.
[0053] In a specific embodiment the tetrahydro beta-carboline is a
compound of Formula (I) or (Ia) or a pharmaceutically acceptable
salt, hydrate or solvate thereof, wherein X is Cl and R is
methyl.
[0054] In one embodiment the tetrahydro beta-carboline is
(S)-4-chlorophenyl
6-chloro-1-(4-methoxyphenyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-car-
boxylate, having the structure of
##STR00012##
[0055] In one embodiment provided herein is a process for preparing
a compound of Formula (I) or a pharmaceutically acceptable salt,
hydrate or solvate thereof, wherein X is at each occurrence
independently halogen; and R is substituted or unsubstituted
C.sub.1 to C.sub.8 alkyl, comprising the step of reacting a
compound of Formula (II) with a compound of Formula (III) as shown
in Scheme A.
##STR00013##
[0056] In a first step (i), a compound of Formula (II), such as
(S)-6-chloro-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
e (S)-2-acetamido-3-phenylpropanoate, is converted to the free base
by dissolving a compound of Formula (II) in a second solvent
mixture comprising water and a suitable organic solvent, such as
iPrOAc, EtOAc, MTBE, MEK, DCM, DCE, toluene, DMA or a mixture
thereof, and adding a first portion of a suitable base, such as an
aqueous potassium carbonate solution. The biphasic mixture is
stirred at a suitable temperature, such as a range of from about 20
to about 40.degree. C. for a suitable time, such as a range of from
about 1 to about 4 h, then the aqueous phase is removed, and the
organic layer is washed with water until a suitable pH, such as
less than about pH 7.5 is reached. The solvent volume is reduced,
e.g., to about 50% of the original solvent volume, by a suitable
method, such as by distillation with or without vacuum at a
suitable temperature, such as less than about 30.degree. C.
[0057] In an embodiment of the first step (i), the suitable solvent
is EtOAc or MEK or a mixture thereof.
[0058] In an embodiment of the first step (i), the suitable solvent
is MEK.
[0059] In a second step (ii), a second portion of a suitable base
is added, such as an aqueous potassium carbonate solution, and the
mixture is reacted with a compound of Formula (III), such as
4-chlorophenyl chloroformate, for a suitable time, such as a range
of from about 1 to about 4 h, at a suitable temperature, such as a
range of less than from about 35 to about 45.degree. C.
[0060] In an embodiment of the second step (ii), the suitable
temperature for the reaction is less than about 40.+-.2.degree.
C.
[0061] The reaction mixture from the second step (ii) is cooled to
a suitable temperature, such as a range of from about 20 to about
30.degree. C., then the aqueous phase is removed. The organic layer
is washed with water until a suitable pH, such as less than about
pH 7.5 is reached. The organic solution is filtered via an in-line
filter such as PE or PP filter. The volume of the second solvent
mixture is reduced, e.g., to about 20% of the original solvent
volume, by a suitable method, such as by distillation with or
without vacuum at a suitable temperature, such as less than about
50.degree. C. The remaining mixture is cooled to a suitable
temperature, such as a range of from about 20 to about 30.degree.
C. for a suitable time, such as a range of from about 1 to about 4
h, then heptanes are added over a suitable time, such as a range of
from about 1 to about 4 h. The mixture is stirred for a suitable
time, such as a range of from about 1 to about 4 h at a suitable
temperature, such as a range of from about 20 to about 30.degree.
C.
[0062] In an embodiment of the second step (ii), the suitable
temperature to which the reaction mixture is cooled is about
25.+-.3.degree. C., the suitable temperature to which the
distillation mixture is cooled is about 25.+-.3.degree. C. and the
suitable temperature at which the heptane mixture is stirred is
about 25.+-.3.degree. C.
[0063] The heptane mixture is filtered, washed with water and a
third solvent mixture comprising a suitable solvent in a mixture
with heptanes, such as a mixture of EtOAc and heptanes or a mixture
of MEK and heptanes, and dried at a suitable temperature, such as a
range of from about 45 to about 55.degree. C., for a suitable time,
such as about 1-3 days to give a target compound of Formula (I).
The resulting material of Formula (I) can optionally be further
purified. For example, a compound of Formula (I) can be taken up in
a suitable solvent, such as EtOAc or MEK, in a suitable amount,
such as up to about 9.times., and warmed to a suitable temperature,
such as a range of from about 85 to about 90.degree. C., and
stirred for a suitable time, such as a range of from about 1 to
about 3 h. The mixture is then cooled to a suitable temperature,
such as a range of from about 20 to about 30.degree. C. for a
suitable time, such as a range of from about 1 to about 4 h, and
heptanes are added over a suitable time, such as a range of from
about 1 to about 4 h. The mixture can then be filtered, washed with
the third solvent mixture, and dried to give a purified compound of
Formula (I).
[0064] In one embodiment of the second step (ii), the suitable
temperature to which the Formula (I) mixture is cooled is about
25.+-.3.degree. C.
[0065] In another embodiment, the third solvent mixture is a
mixture of MEK and heptanes.
[0066] In another embodiment, the solvent in the Formula (I)
mixture is MEK.
[0067] In one embodiment provided herein is a process for preparing
a compound of Formula (II), wherein X is halogen; and R is
substituted or unsubstituted C.sub.1 to C.sub.8 alkyl, comprising
the step of reacting a compound of Formula (IV) with a chiral acid
as shown in Scheme B.
##STR00014##
[0068] In a first step (i), the chiral resolution step, a compound
of Formula (IV) is reacted with a suitable chiral acid, in a first
solvent mixture comprising water and a suitable solvent, at a
suitable temperature, such as about 64.degree. C. or about
78.degree. C., for a suitable time, such as about 15-45 min. The
reaction mixture is then cooled to a suitable temperature, such as
about 20-30.degree. C. over a suitable time, such as 2-4-h, then
stirred for a suitable time, such as about 10-20 h, at a suitable
temperature, such as about 20-30.degree. C.
[0069] The reaction mixture is filtered and in a second step (ii),
the recrystallization step, a suitable solvent, such as ethanol, is
added and the recrystallization mixture is heated to a suitable
temperature, such as about 78.degree. C. for a suitable time. The
recrystallization mixture is then cooled to a suitable temperature,
such as about 20-30.degree. C., over a suitable time, such as
2-4-h, stirred for a suitable time, such as about 10-20 h, at a
suitable temperature, such as about 20-30.degree. C., filtered and
dried at a suitable temperature, such as about 45-55.degree. C. for
a suitable time, such as about 1-3 days to give a compound of
Formula (II).
[0070] In one embodiment, the first solvent mixture comprising
water and a solvent are in a ratio in a range of from about 1 to
about 5% volume/volume water:solvent.
[0071] In another embodiment, the ratio of the first solvent
mixture is in a range of from about 2 to about 5% volume/volume
water:solvent.
[0072] In another embodiment, the solvent in the first solvent
mixture is methanol, ethanol, 1-propanol, 1-butanol or a mixture
thereof.
[0073] In another embodiment, the solvent in the first solvent
mixture is methanol, ethanol or a mixture thereof.
[0074] In another embodiment, the solvent in the first solvent
mixture is ethanol.
[0075] In an alternative embodiment, the process shown in Scheme B
is carried out as a seeded chiral resolution process.
[0076] In a first step (i) of the seeded chiral resolution process,
the chiral resolution step, about one equivalent of a compound of
Formula (IV) is reacted with a suitable chiral acid in a range of
from about 0.1 to about 0.5 equivalents, in a first solvent mixture
comprising water and a suitable solvent, such as methanol, ethanol,
1-propanol, or 1-butanol or a mixture thereof in a ratio in a range
of from about 1 to about 5% v/v (volume/volume) of water:solvent.
The resolution mixture was treated with a suitable seed of Formula
(IV), such as an amount in a range of from about 1 to about 2% by
weight of Formula (IV) at a suitable temperature, such as about a
range of from about 50 to about 60.degree. C. The mixture is then
cooled to a suitable temperature, such as a range of from about 10
to about 20.degree. C. over a suitable time, such as a range of
from about 1 to about 2 h, then stirred for a suitable time, such
as a range of from about 1 to about 2 h, at a suitable temperature,
such as a range of from about 10 to about 20.degree. C.
[0077] In one embodiment, the ratio of the first solvent mixture is
in a range of from about 2 to about 5% volume/volume
water:solvent.
[0078] In another embodiment, the solvent in the first solvent
mixture is methanol, ethanol or a mixture thereof.
[0079] In another embodiment, the solvent in the first solvent
mixture is ethanol.
[0080] In another embodiment, the solvent in the first solvent
mixture is ethanol.
[0081] In an embodiment of the first step (i), the suitable seeding
temperature is about 55.+-.3.degree. C., the suitable temperature
to which the seeded mixture is cooled is about 15.+-.2.degree. C.
and the suitable temperature at which the cooled mixture is stirred
is about 15.+-.2.degree. C.
[0082] The cooled mixture is then filtered and in a second step
(ii), the slurry wash step, the first solvent mixture is added and
the mixture is stirred to a suitable temperature, such as a range
of from about 20 to about 25.degree. C. for a suitable time. The
suspension is then cooled to a suitable temperature, such as a
range of from about 10 to about 20.degree. C., over a suitable
time, filtered and dried at a suitable temperature, such as a range
of from about 45 to about 55.degree. C. for a suitable time, such
as about 1-3 days to give a compound of Formula (II).
[0083] In an embodiment of the second slurry wash step (i), the
suitable temperature at which the mixture is stirred is about
22.+-.2.degree. C. and the suitable temperature to which the
suspension is cooled is about 15.+-.2.degree. C.
[0084] In a certain embodiment, the process shown in Scheme B1 is
carried out as a one step procedure for preparing a compound of
Formula (II), without the recrystallization step.
##STR00015##
[0085] A compound of Formula (IV) (1 eq.) is reacted with a
suitable chiral acid (in an amount of about 0.51 equivalents), in a
first solvent mixture, for a suitable time, such as about 16-20 h.
Upon cooling, filtration and drying, a compound of Formula (II) is
obtained. In one embodiment, the first solvent mixture is a mixture
of ethanol and water in a ratio in a range of from about 1 to about
5% v/v (volume/volume) of water:ethanol. In another embodiment, the
first solvent mixture is a mixture of ethanol and water in a ratio
in a range of from about 2 to about 5% v/v (volume/volume) of
water:ethanol. In certain embodiments the enantiomeric excess is
greater than about 90% e.e. In certain embodiments, the
enantiomeric excess is greater than about 95% e.e. In certain
embodiments, the enantiomeric excess is greater than about 98% e.e.
In certain embodiments, the enantiomeric excess is greater than
about 99% e.e. In certain embodiments, the enantiomeric excess is
greater than about 99.5% e.e. In certain embodiments, the
enantiomeric excess is about 100% e.e.
[0086] In another embodiment, one equivalent of a compound of
Formula (IV) is reacted with about 0.5, about 0.8, or about 0.5 to
about 1.0 equivalents of a suitable chiral acid. Embodiments of the
chiral acid include, and are not limited to,
N-acetyl-L-phenylalanine (also referred to as
(S)-2-acetamido-3-phenylpropanoic acid),
(S)-2-(methoxycarbonylamino)-3-phenylpropanoic acid,
(S)-2-(isopropoxycarbonylamino)-3-phenylpropanoic acid,
(S)-2-benzamido-3-phenylpropanoic acid,
(S)-2-(4-chlorobenzamido)-3-phenylpropanoic acid,
(S)-2-(4-methoxybenzamido)-3-phenylpropanoic acid,
(S)-3-phenyl-2-(4-(trifluoromethyl)benzamido)propanoic acid,
(S)-2-isobutyramido-3-phenylpropanoic acid,
(S)-3-phenyl-2-(phenylsulfonamido)propanoic acid,
(S)-3-phenyl-2-(4-(trifluoromethyl)phenylsulfonamido)propanoic
acid, (S)-2-(4-methoxyphenylsulfonamido)-3-phenylpropanoic acid,
(S)-2-(4-methylphenylsulfonamido)-3-phenylpropanoic acid,
(1,1'-binaphtalene)-2,2'-dicarboxylic acid,
3-bromo-8-camphorsulfonic acid, camphor-8-sulfonic acid,
camphor-10-sulfonic acid,
2,3:4,6-di-O-isopropylidene-xylo-hexylosonic acid,
4-hydroxydinaphtho[2,1-d:1',2'-f]-1,3,2-dioxaphoshpepin 4-oxide,
4-hydroxy-3-phenylbutanoic acid lactone, Mosher's acid, lactic acid
and its derivatives, mandelic acid and its derivatives,
3-menthoxyacetic acid, 3-menthylglycine,
2-methyl-2-phenylbutanedioic acid, naproxen,
5-oxo-2-pyrrolidinescarboxylic acids,
2-[((phenylamino)carbonyl)oxy]propanoic acid,
1-phenylethanesulfonic acid, tartaric acid and its derivatives,
1,2,3,4-tetrahydro-3-isoquinoline sulfonic acid
(2,4,5,7-tetranitro-9-fuorenylideneaminoxy)-propionic acid,
4-thiazolidenecarboxylic acid and further reagents disclosed in CRC
Handbook of Optical Resolutions via Diastereomeric Salt Formation,
D. Kozma (Editor), CRC Press 2002, pages 51-61 and Appendix 2
(pages 579-625), herewith incorporated by reference in its
entirety.
[0087] In another embodiment, the chiral acid is
N-acetyl-L-phenylalanine,
(S)-2-(methoxycarbonylamino)-3-phenylpropanoic acid,
(S)-2-(isopropoxycarbonylamino)-3-phenylpropanoic acid,
(S)-2-benzamido-3-phenylpropanoic acid,
(S)-2-(4-chlorobenzamido)-3-phenylpropanoic acid,
(S)-2-(4-methoxybenzamido)-3-phenylpropanoic acid,
(S)-3-phenyl-2-(4-(trifluoromethyl)benzamido)propanoic acid,
(S)-2-isobutyramido-3-phenylpropanoic acid,
(S)-3-phenyl-2-(phenylsulfonamido)propanoic acid,
(S)-3-phenyl-2-(4-(trifluoromethyl)phenylsulfonamido)propanoic
acid, (S)-2-(4-methoxyphenylsulfonamido)-3-phenylpropanoic acid or
(S)-2-(4-methylphenylsulfonamido)-3-phenylpropanoic acid.
[0088] In another embodiment, the chiral acid is
N-acetyl-L-phenylalanine.
[0089] In one embodiment provided herein is a process for preparing
a compound of Formula (IV), wherein X is halogen; and R is
substituted or unsubstituted C.sub.1 to C.sub.8 alkyl, comprising
the step of reacting a compound of Formula (V), wherein HB is an
acid suitable to form a salt with a compound of Formula (V), such
as hydrochloric acid or acetic acid, with a solvated base as shown
in Scheme C.
##STR00016##
[0090] A compound of Formula (V), in a suitable solvent, such as
water, is mixed with a suitable base, such as aqueous ammonium
hydroxide, and a suitable solvent, such as EtOAc or iPrOAc. The
resulting mixture is heated to a suitable temperature, such as
about 25-35.degree. C., for a suitable time, such as about 15-45
min, and then cooled to a suitable temperature, such as about
20-30.degree. C., and agitated for a suitable time, such as about
30-90 min. The aqueous phase is removed and the organic layer is
washed with water. The volume of the organic layer is reduced under
vacuum to a suitable extent, such as about 20% of the original
organic solvent volume, by heating to a suitable temperature, such
as not more than about 50.degree. C. The remaining volume is
charged with a suitable solvent, such as heptane or heptanes,
stirred for a suitable time, such as about 1-3 h, at a suitable
temperature, such as about 20-30.degree. C., and the compound of
Formula (IV) is isolated by filtration and dried at a suitable
temperature, such as about 45-55.degree. C., for a suitable time,
such as 1-3 days.
[0091] In one embodiment provided herein is a process of preparing
a compound of Formula (V), wherein X is halogen; R is substituted
or unsubstituted C.sub.1 to C.sub.8 alkyl; wherein HB is an acid
suitable to form a salt with a compound of Formula (V), comprising
the step of reacting a compound of Formula (VII) in the presence of
an acid HB and a solvent, wherein HB' is an acid suitable to form a
salt with the amino group of a compound of Formula (VII), with a
compound of Formula (VI) as shown in Scheme D.
##STR00017##
[0092] A compound of Formula (VII), such as a substituted
5-chlorotryptamine hydrochloride salt is reacted with a compound of
Formula (VI), such as an alkyl substituted aldehyde compound of
Formula (VI), in the presence of a first suitable acid, such as
hydrochloric acid, in a suitable solvent, such as water or EtOAc,
at a suitable concentration, such as about 0.3-0.7M, at a suitable
temperature, such as about 100.degree. C., for a suitable time,
such as about 10-20 h. The mixture is cooled to a suitable
temperature, such as about 20-30.degree. C., and filtered. The
obtained crude solid is stirred with a second suitable acid, such
as acetic acid for a suitable time, such as about 30-90 min, at a
suitable temperature, such as about 20-30.degree. C., then filtered
and washed with a suitable acid, such as acetic acid. The crude
product is stirred in the suitable solvent, such as water or EtOAc,
for a suitable time, such as about 0.5-2 h, at a suitable
temperature, such as about 20-30.degree. C., then filtered and
washed with the suitable solvent, such as water or EtOAc to provide
a target compound of Formula (V). The compound of Formula (V) is
dried for a suitable time, such as a range of from about 1 to about
6 days under vacuum at a suitable temperature, such as about
45-55.degree. C.
[0093] In certain embodiments, the first suitable solvent is
water.
[0094] In certain embodiments, the processes provided herein
comprise multiple steps, as described above.
[0095] In one embodiment provided herein is a process for the
preparation of substituted tetrahydro beta-carboline derivatives of
Formula (I):
##STR00018##
[0096] or a pharmaceutically acceptable salt, hydrate or solvate
thereof, wherein X is at each occurrence independently halogen; and
R is substituted or unsubstituted C.sub.1 to C.sub.8 alkyl;
[0097] comprising the step of reacting a compound of Formula (VII),
wherein HB' is an acid suitable to form a salt with the amino group
of a compound of Formula (VII) such as hydrochloric acid or acetic
acid, with an aldehyde compound of Formula (VI) in the presence of
a suitable acid, such as hydrochloric acid, and a solvent, such as
water or EtOAc, to provide a compound of Formula (V):
##STR00019##
[0098] further comprising the step of reacting a compound of
Formula (V), wherein HB is an acid suitable to form a salt with a
compound of Formula (V) such as hydrochloric acid or acetic acid,
with a base, such as NH.sub.4OH in the presence of a solvent to
provide a compound of Formula (IV):
##STR00020##
[0099] further comprising the step of reacting a compound of
Formula (IV) with a chiral acid, in a first solvent mixture
comprising a ratio of water:solvent, wherein the solvent is
methanol, ethanol or a mixture thereof, then optionally
recrystallizing the reaction product in a second solvent mixture
comprising water and a solvent, wherein the solvent is ethanol to
provide a compound of Formula (II):
##STR00021##
[0100] further comprising the step of reacting a compound of
Formula (II) with a compound of Formula (III) to provide the
compound of Formula (I):
##STR00022##
[0101] further comprising the step of optionally purifying a
compound of Formula (I), by taking up a compound of Formula (I) in
a suitable solvent, such as MEK or EtOAc, in a suitable amount,
such as up to about 9.times., then warming, stirring, filtering,
and washing with a suitable solvent mixture, such as a mixture of
EtOAc and heptanes or a mixture of MEK and heptanes, and drying;
wherein, in one embodiment, the suitable solvent mixture is a
mixture of MEK and heptanes;
[0102] wherein, for a compound of Formula (I), each occurrence of X
is independently halogen, in one embodiment chloro, and R is
substituted or unsubstituted C.sub.1 to C.sub.8 alkyl; and,
wherein, in one embodiment, alkyl is methyl.
[0103] The embodiments described herein are further illustrated by
the examples set forth in Section 5 below, which are not to be
construed as limiting the scope of the embodiments described
herein.
[0104] Starting materials and reagents useful in the processes
described herein can be obtained from commercial sources or
prepared using methods known to one skilled in the art.
5. EXAMPLES
5.1 Synthesis of (5)-4-chlorophenol
6-chloro-1-(4-methoxyphenyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-car-
boxylate, compound of Formula (X)
##STR00023## ##STR00024##
[0105] 5.1.1 Synthesis of
6-chloro-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
hydrochloride, Compound of Formula (Va)
[0106] General information. The reaction depicted in Scheme E was
performed in a 300-gallon glass-lined reactor. A
5-Chlorotryptamine*HCl compound of Formula (VIIa) was purchased
from ABChem Technologies (99% AUC) and a p-anisaldehyde compound of
Formula (VIa) was purchased from Alfa Aesar (99.7% AUC). Reagent
grades of 37% HCl, acetic acid and ethyl acetate were used.
[0107] Procedure. A solution of 0.5M HCl was prepared by diluting
37% HCl (16.9 Kg) in purified water (329.0 Kg). 5-Chlorotryptamine
hydrochloride salt compound of Formula (VIIa) (40.0 Kg, 173.1 mol,
1.0 eq) was charged into the reactor followed by the 0.5M HCl
(340.6 Kg, 8.5.times.) and p-anisaldehyde compound of Formula (VIa)
(28.5 Kg, 209.3 mol, 1.2 eq). The resulting slurry was warmed to
100.+-.2.degree. C. and refluxed for 14 hours. The slurry was
cooled to <45.degree. C. and sampled by HPLC analysis for IPC
(Limit: .ltoreq.1.0% of the 5-chlorotryptamine hydrochloride salt
compound of Formula (VIIa) relative to target compound of Formula
(Va)) and found to pass. The slurry was cooled to 25.+-.2.degree.
C. and filtered on a Nutsche filter. A sample of the wet cake was
taken for information purposes. The wet cake (150.1 Kg) was
recharged to the vessel followed by acetic acid (181.6 Kg,
4.5.times.) and the slurry stirred at 25.+-.2.degree. C. for 1
hour. The slurry was filtered on the Nutsche filter and the cake
washed with acetic acid (45.4 Kg, 1.1.times.). A sample of the wet
cake was taken for information purposes. The wet cake (149.8 Kg)
was recharged to the vessel followed by ethyl acetate (155.7 Kg,
3.9.times.) and the slurry stirred at 25.+-.2.degree. C. for 1
hour. The slurry was filtered on the Nutsche filter and the cake
washed with ethyl acetate (38.9 Kg, 1.0.times.). Additional ethyl
acetate (20 Kg, 0.5.times.) was used to remove residual compound of
Formula (Va) from the vessel. The wet cake (113.3 Kg) was dried at
a set-point of 50.degree. C. for 4 days under vacuum. A total of
55.1 Kg compound of Formula (Va) was obtained as an off-white
solid. Mp=302.degree. C. (dec.); IR: 3168, 2906, 2767, 1612, 1513,
1421, 1248, 1174, 1032 cm.sup.-1; HPLC (std): 7.89 min;
ES-MS=313.33 (M.sup.+H); .sup.1H NMR (300 MHz, DMSO-d6) .delta.
11.06 (s, 1H), 7.58 (s, 1H), 7.29 (dd, 3H), 6.99-7.10 (m, 3H), 5.87
(s, 1H), 3.76 (s, 3H), 3.33 (m, br, 2H), 2.94-3.13 (m, 2H).
5.1.2 Synthesis of
6-chloro-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
Compound of Formula (IVa)
[0108] General information. The reaction depicted in Scheme E was
performed in a 300-gallon glass-lined reactor. Reagent grade
ammonium hydroxide, 37% hydrochloric acid and ethyl acetate were
used along with technical grade heptane. For the HCl scrubber (100
gallon reactor), potable water was used and purified water from the
house system for all other processing purposes.
[0109] Procedure. An HCl scrubber was prepared in a 100 gallon
reactor by diluting 37% hydrochloric acid (182.9 Kg) with potable
water (240 L). Compound of Formula (Va) (55.1 Kg, 157.8 mol) was
charged into the 300-gallon reactor followed by purified water (225
L, 4.1.times.), 28-30% ammonium hydroxide (124.5 Kg, 138 L, 1031.6
mol, 2.5.times.), then ethyl acetate (497 Kg, 552 L, 10.times.).
The mixture was heated to 30.+-.2.degree. C. for 30 minutes and
then cooled to 25.+-.2.degree. C. and agitated for a further hour.
The biphasic mixture was sampled for solids and pH analysis (IPC
Limit: Free of visible solids, pH of aqueous phase >9.0) and
found to pass. The aqueous phase was removed and the organic phase
washed twice with water (2.times.367 L, 2.times.6.7.times.) to
achieve an aqueous phase pH of <7.5. The batch was distilled
under vacuum to a volume of .about.2.times. (.about.110 L; maximum
batch temperature: 30.degree. C.). Heptane (376.9 Kg, 551 L,
10.times.) was charged over about 2 hours and agitated at
25.+-.2.degree. C. for a further 2 hours. The product compound of
Formula (IVa) was isolated on the Nutsche filter and washed with a
mixture of heptane (125.6 Kg, 183 L, 3.3.times.) and ethyl acetate
(16.5 Kg, 18 L, 0.3.times.). The wet cake (67.6 Kg) was dried at a
set-point of 50.degree. C. for 2 days under vacuum. A total of 46.3
Kg compound of Formula (IVa) was obtained as an off-white solid.
Mp=161.degree. C.; IR: 2903, 2836, 1610, 1511, 1439, 1243, 1173,
1029 cm.sup.-1; HPLC (std): 7.89 min; HPLC (chiralPAK AD-H, 20% IPA
in hexane): 13.3, 18.3 min; ES-MS=313.33 (M.sup.+H); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.61 (s, br, 1H), 7.49 (s, 1H),
7.05-7.26 (m, 4H), 6.85-6.90 (m, 2H), 5.09 (s, 1H), 3.80 (s, 3H),
3.15-3.40 (m, 1H), 3.07-3.14 (m, 1H), 2.72-2.91 (m, 2H), 1.75 (s,
1H).
5.1.3 Alternative Synthesis of
6-chloro-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
Compound of Formula (IVa)
[0110] Procedure. To deionized water (8 L), concentrated
hydrochloric acid (0.36 L) was added slowly while maintaining the
temperature between 23.degree. C. and 17.degree. C. The
5-Chlorotryptamine hydrochloride salt compound of Formula (VIIa) (1
kg) was charged into the reaction vessel and then the
p-anisaldehyde compound of Formula (VIa) (0.60 L) was added while
maintaining the temperature between 23.degree. C. and 17.degree. C.
The suspension was heated to reflux and kept under reflux until
completion of the reaction. The reaction is complete after 8-18
hours, when the content of 5-chlorotryptamine hydrochloride is NMT
1.0% as determined by percent HPLC area. The suspension was cooled
to a temperature of between about 27.degree. C. and 23.degree. C.
The suspension was then filtered to provide a crude, wet
(.+-.)-piperidinoindole hydrochloride product.
[0111] To pure acetic acid (4 L), the crude, wet
(.+-.)-piperidinoindole hydrochloride was added. The suspension was
stirred at a temperature of between about 27.degree. C. and
23.degree. C. for a period of at least 1 hour. The suspension was
then filtered to provide a wet product that was then washed with
pure acetic acid (0.5 L). The wash was repeated with pure acetic
acid (0.5 L) added to the wet product. The wet
(.+-.)-piperidinoindole hydrochloride product was added to ethyl
acetate (4 L) and the suspension was stirred at a temperature of
between about 27.degree. C. and 23.degree. C. for a period of at
least 1 hour. The suspension was then filtered to provide a wet
(.+-.)-piperidinoindole hydrochloride product. The wet product was
washed twice with ethyl acetate (0.8 L). and then weighed to obtain
the wet weight (Wwet). A sample of the wet product was also used to
determine LOD for the content of residual solvents.
[0112] Calculate the weight (W) (kg) of the wet
(.+-.)-piperidinoindole hydrochloride product using the formula
W=Wwet-(Wwet.times.LOD/100) kg.
[0113] To deionized water (4.times.W)L add the wet
(.+-.)-piperidinoindole hydrochloride (Wwet)kg isolated above while
maintaining the temperature between 25.degree. C. and 15.degree. C.
Add ethyl acetate (10.times.W)L to the solution while maintaining
the temperature between 25.degree. C. and 15.degree. C. Over a
period of 30 minutes, add 25% ammonium hydroxide (2.8.times.W)L
while maintaining the temperature between 30.degree. C. and
15.degree. C. Heat the temperature of the reaction mixture to a
temperature of between about 27.degree. C. and 33.degree. C. and
stir for at least 30 minutes at a temperature of between about
27.degree. C. and 33.degree. C. Cool down the reaction mixture to
temperature of between about 28.degree. C. and 22.degree. C. and
stir the reaction mixture at a temperature of between about
28.degree. C. and 22.degree. C. for a period of at least 60
minutes. Take a sample of the reaction mixture for pH measurement
of the aqueous phase. Stop stirring and allow the phases to
separate for a period of at least 30 minutes. Discharge the aqueous
phase, then add ethyl acetate (5.times.W)L to the organic phase
while maintaining the temperature between 15.degree. C. and
30.degree. C. Stabilize the temperature between 28.degree. C. and
23.degree. C. Add deionized water (7.times.W)L while maintaining
the temperature between about 28.degree. C. and 22.degree. C. Stir
the two phase mixture for a period of about 10 to 20 minutes while
maintaining the temperature between about 28.degree. C. and
22.degree. C. Stop stirring and allow the phases to separate for a
period of at least 30 minutes, then discharge the aqueous
phase.
[0114] Add to the organic phase deionized water (7.times.W)L while
maintaining the temperature between about 28.degree. C. and
22.degree. C. Stir the two phase mixture for a time period of 10 to
20 minutes while maintaining the temperature between about
28.degree. C. and 22.degree. C., then allow the phases to separate
for a time period of at least 30 minutes. Discharge the aqueous
phase. Add to the organic phase deionized water (7.times.W)L while
maintaining the temperature between about 28.degree. C. and
22.degree. C. Stir the two phase mixture for a time period of 10 to
20 minutes while maintaining the temperature between about
28.degree. C. and 22.degree. C., then allow the phases to separate
for a time period of at least 30 minutes. Discharge the aqueous
phase. Sample the aqueous phase and measure the pH. If pH is
>7.5, repeat the water wash above. If the pH is <7.5, add
n-heptane (5.times.W)L over a time period of 20 to 30 minutes while
maintaining the temperature .ltoreq.30.degree. C. Distill the
mixture under an approximate pressure of -0.85 bar while
maintaining the temperature at .ltoreq.50.degree. C. until
(4.4.times.W)kg of the solvent has been distilled. Add n-heptane
(6.times.W)L over a time period of 20 to 30 minutes while
maintaining the temperature at .ltoreq.50.degree. C. Distill the
mixture under an approximate pressure of -0.85 bar while
maintaining the temperature at .ltoreq.50.degree. C. until
(4.4.times.W)kg of the solvent has been distilled. Add n-heptane
(6.times.W)L over a time period of 20 to 30 minutes while
maintaining the temperature at .ltoreq.50.degree. C. Sample the
mixture and determine the ratio of ethyl acetate:n-heptane by GC
analysis. Cool the mixture to a temperature of between about
28.degree. C. and 22.degree. C. under nitrogen atmosphere, then
stir the mixture for a time period of at least 2 hours while
maintaining the temperature between about 28.degree. C. and
22.degree. C. Filter the product to obtain a wet cake. Wash the wet
cake with a mixture of n-heptane (2.8.times.W)L and ethyl acetate
(0.3.times.W)L. Dry the wet product under vacuum at a temperature
of .ltoreq.50.degree. C. until LOD <2.0%.
5.1.4 Synthesis of
(S)-6-chloro-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
e (S)-2-acetamido-3-phenylpropanoate Compound of Formula (IIa)
[0115] General information. The reaction depicted in Scheme E was
performed in a 300-gallon glass-lined reactor. The chiral acid
N-Acetyl-L-phenylalanine was purchased from Paragon (99.5% AUC).
Methanol (reagent grade) and ethanol (ethanol, absolute, 200 proof,
reagent grade) were used.
[0116] Procedure. Compound of Formula (IVa) (23.1 Kg, 73.8 mol, lot
04-PVC-001X, 1.0 eq) was charged into the 300-gallon reactor
followed by chiral acid N-Acetyl-L-phenylalanine (12.2 Kg, 58.9
mol, 0.80 eq) and methanol (547.5 Kg, 693 L, 30.times.). The
mixture was heated to 64.+-.2.degree. C. held for 30 minutes,
dissolution confirmed and the solution then cooled on a ramp to
25.+-.2.degree. C. over 3 hours. The slurry was stirred at
25.+-.2.degree. C. for a further 16 hours. The slurry was filtered
and the wet cake recharged to the vessel. Ethanol (584.5 Kg, 740 L,
32.times.) was charged to the vessel and the slurry heated to
78.+-.2.degree. C. Dissolution was confirmed and the solution then
cooled on a ramp to 25.+-.2.degree. C. over 3 hours. The slurry was
stirred at 25.+-.2.degree. C. for a further 16 hours. The slurry
was filtered and the wet cake washed with ethanol (45.5 Kg, 58 L,
2.5.times.). The wet cake (37.1 Kg) was dried at a set-point of
50.degree. C. for 2 days under vacuum. A total of 15.5 Kg target
compound of Formula (IIa) was obtained as an off-white solid. HPLC:
94.6% e.e., (ChiralPak AD-R.sup.H column, 150.times.4.6 mm, 5
.mu.m; hexanes, isopropanol, diethylamine); Mp=214.degree. C., IR:
3271, 1634, 1541, 1400, 1251, 1179 cm.sup.-1; .sup.1H NMR (300 MHz,
DMSO-d6) .delta. 10.68 (s, 1H), 7.99-8.08 (d, 1H), 7.44-7.45 (d,
1H), 7.13-7.26 (m, 8H), 6.69-7.01 (dd, 1H), 6.88-6.93 (m, 2H), 5.19
(s, 1H), 4.28-4.35 (m, 2H), 3.72 (s, 3H), 2.94-3.15 (m, 3H),
2.66-2.84 (m, 2H), 1.75 (s, 3H). The percent enantiomeric excess (%
e.e.) for the compound of Formula (IIa) was calculated using the
following formula (wherein the term "(R)-Formula (IIa)" refers to
the (R) isomer of the compound of Formula (IIa)):
e.e.
Formula(IIa)=[(AUC.sub.Formula(IIa)-AUC.sub.(R)-Formula(IIa))/(AUC.-
sub.Formula(IIa)+AUC.sub.(R)-Formula(IIa)].times.100
5.1.5 Seeded Synthesis of
(5)-6-chloro-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
e (5)-2-acetamido-3-phenylpropanoate Compound of Formula (IIa)
[0117] Procedure. To absolute ethanol (2.9 L), add deionized water
(0.058 L)., then add N-acetyl-(L)-phenylalanine (0.36 kg) while
maintaining the temperature between about 28.degree. C. and
22.degree. C. Heat the mixture to reflux over a time period of
about 30 to 60 minutes. Cool the mixture to a temperature of
between about 58.degree. C. and 52.degree. C. and sample for
in-process control (IPC).
[0118] To absolute ethanol (19.6 L), add deionized water (0.4 L),
then add (.+-.)piperidinoindole (1 kg) while maintaining the
temperature between about 28.degree. C. and 22.degree. C. Heat the
mixture to reflux and maintain at reflux temperature for a time
period of about 50 minutes to 70 minutes and sample for in-process
control (IPC).
[0119] To the solution of (.+-.)-piperidinoindole, add over a time
period of about 10 to 15 minutes 25% of the solution of
N-acetyl-(L)-phenylalanine while maintaining the temperature
between about 58.degree. C. and 52.degree. C. Seed the reaction
mixture with the (S)-piperidinoindole Form B (0.01 kg). Stir for a
time period of about 5 minutes at a temperature of between about
58.degree. C. and 52.degree. C. and sample for in-process control
(IPC).
[0120] Add over a time period of about 2 hours the remaining 75% of
the solution N-acetyl-(L)-phenylalanine while maintaining the
temperature between about 58.degree. C. and 52.degree. C. Stir the
suspension over a time period of about 1 hour while maintaining the
temperature between about 58.degree. C. and 52.degree. C. Cool the
suspension over a time period of about 2 hours at an approximately
linear rate to a temperature of between about 17.degree. C. and
13.degree. C. Then stir the suspension for a time period of about 1
hour while maintaining the temperature between about 17.degree. C.
and 13.degree. C. Filter the suspension and wash the product with a
mixture of absolute ethanol (5.4 L) and deionized water (0.11 L)
previously cooled to a temperature of between about 17.degree. C.
and 13.degree. C. to provide a wet product. Add the wet product to
a mixture of absolute ethanol (13.5 L) and deionized water (0.28 L)
previously cooled to a temperature of between about 24.degree. C.
and 20.degree. C. Stir the suspension for a time period of about 2
hours while maintaining the temperature between about 24.degree. C.
and 20.degree. C., then cool the suspension to a temperature of
between about 17.degree. C. and 13.degree. C. Filter the suspension
and wash the product with a mixture of absolute ethanol (5.4 L) and
deionized water (0.08 L) previously cooled to a temperature of
between about 17.degree. C. and 13.degree. C. Sample the wet
product for chiral HPLC analysis.
[0121] To a mixture of absolute ethanol (36.3 L) and deionized
water (0.7 L) previously adjusted to a temperature of between about
25.degree. C. and 15.degree. C. add the crude, wet
(S)-piperidinoindole Ac-Phe product while maintaining the
temperature between about 25.degree. C. and 15.degree. C. Heat the
mixture to reflux and stir at reflux temperature for a time period
of about 50 minutes to 70 minutes, then sample for in-process
control (IPC). Cool the suspension over a time period of about 4
hours at an approximately constant rate to a temperature of between
about 17.degree. C. and 13.degree. C. Filter the suspension and
wash the product with a mixture of absolute ethanol (3.9 L) and
deionized water (0.08 L) previously cooled to a temperature of
between about 17.degree. C. and 13.degree. C. Sample the wet
product for chiral HPLC analysis. Dry the wet product under vacuum
at temperature .ltoreq.50.degree. C. until LOD .ltoreq.10.0 wt %
(preferentially with an LOD of between about 8.0 wt % and 10.0 wt
%).
5.1.6 Synthesis of (S)-4-chlorophenol
6-chloro-1-(4-methoxyphenyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-car-
boxylate Compound of Formula (X)
[0122] General information. The reaction depicted in Scheme E was
performed in a 300-gallon glass-lined reactor. Potassium carbonate,
anhydrous (reagent grade), ethyl acetate (reagent grade) and
heptane (technical grade) were used. 4-chlorophenyl chloroformate
(>98%) was purchased from Aldrich. Purified water from the house
system was employed for all processing purposes.
[0123] Procedure. A 4.2 wt % solution of potassium carbonate (27.0
Kg, 195 mol, 3.3 eq) in water (592 L) was prepared in a 300 gallon
reactor before processing and drummed. To the reactor was charged
the compound of Formula (IIa) (30.8 Kg, 59.2 mol, 1.0 eq), ethyl
acetate (266.4 Kg, 296 L, 9.6.times.) and a 4.2 wt % potassium
carbonate solution (322.6 Kg, 10.5.times.). The biphasic slurry was
stirred at 25.+-.2.degree. C. for 3 hours and sampled for IPC
(Limit: Free of visible solids; pH of aqueous phase <9.0). Once
complete the lower aqueous phase was removed and the organic phase
washed with water (237 L, 7.7.times.) to achieve an aqueous phase
pH of <7.5. The organic layer was discharged to drums and the
vessel rinsed with ethyl acetate (30 Kg, 1.times.). The batch
solution was recharged to the vessel via a 1 micron filter. The
batch was distilled under vacuum to .about.148 L (4.8.times.),
maximum batch temperature: 30.degree. C. To the reactor was charged
4.2 wt % potassium carbonate solution (322.6 Kg, 10.5.times.). A
4-Chlorophenyl chloroformate compound of Formula (Ma) (13.5 Kg,
71.1 mol, 1.2 eq) was charged over 30 minutes while maintaining the
batch temperature below 30.degree. C. The slurry was stirred at
25.+-.2.degree. C. for 1 hour and a sample submitted for an
in-process check (.ltoreq.1.0% PV-4 free base relative to PV-5,
passed). Once complete, the slurry was filtered and the wet cake
washed with water (119 L, 3.9.times.), followed by ethyl acetate
(53.3 Kg, 59 L, 1.9.times.). The wet cake was sampled for an IPC
(Limit: ROI .ltoreq.0.5%) and passed. The wet cake (39.1 Kg) was
dried at a set-point of 50.degree. C. for 2 days under vacuum. A
total of 21.9 Kg the target compound of Formula (X) was obtained as
an off-white solid (HPLC purity: 98.7% (ChiralPak AD-RH column,
150.times.4.6 mm, 5 .mu.m; 20:80 Mobile Phase B (1 mL
diethylamine+1000 mL isopropanol for each liter)/Mobile Phase A (1
mL diethylamine+1000 mL hexanes for each liter); 104 injection
volume; 1.0 mL/min; 40.degree. C.; detection at 230 nm);
Mp=222-223.degree. C.; IR: 3168, 2906, 2767, 1612, 1513, 1421,
1248, 1174, 1032 cm.sup.-1; HPLC (std): 14.5 min; HPLC (chiralPAK
AD-H, 30% IPA in hexane): 22 min; ES-MS=467.29 (M+H). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.96 (s, 1H), 7.53 (s, 1H), 7.33 (d,
2H), 7.25 (d, 2H), 7.14 (s, 2H), 7.06 (dd, 2H), 6.84 (d, 2H), 6.46
(s, 1H), 4.46 (dd, 1H), 3.79 (s, 3H), 3.32 (m, broad, 1H), 2.99 (m,
broad, 1H), 2.82-2.89 (dd, 1H).
5.1.7 Alternate Synthesis of (S)-4-chlorophenol
6-chloro-1-(4-methoxyphenyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-car-
boxylate Compound of Formula (X)
[0124] Procedure. To a vigorously stirred suspension of Formula
(IIa) (200 g corrected from 220.32 g, after correction of ethanol
(9%) with KF (0.23%)) in MEK (4 L) at 30.+-.3.degree. C. was added
8.4% aqueous potassium carbonate (1048 g). The suspension was
stirred at 30.+-.3.degree. C. for a time period of at least 60
minutes. The biphasic mixture was IPC sampled for solids and pH
analysis (Limit: free of visible solids, pH of aqueous phase
>9.0). The layers were allowed to separate and the organic phase
was washed with 8.4% aqueous solution of potassium carbonate (1048
g). The organic phase was then recharged to the vessel via a
1-micron filter. The vessel was charged with 8.4% aqueous potassium
carbonate (1048 g). Then 4-chlorophenyl chloroformate (77.13 g,
1.05 eq) was charged over a time period of 30 minutes while
maintaining the bath temperature at 40.+-.2.degree. C. The batch
was stirred at about 40.+-.2.degree. C. for an additional 2 hours,
then sampled IPC (Limit: NMT 0.1% Formula (IIa) relative to Formula
(X)). The layers were allowed to separate and the organic phase was
washed twice with purified water (2.times.720 g). The organic layer
was distilled under atmospheric conditions at about 85-90.degree.
C. to a volume of about 4.times. (about 800 mL MEK) and sampled for
KF. The batch was diluted with MEK (3.2 L), redistilled under
atmospheric conditions at about 85.degree. C.-90.degree. C. to a
volume of about 4.times. (about 800 mL MEK) and sampled for KF.
These steps were repeated until a proper KF (below 0.5%) for the
residual organic layer was achieved. The organic layer was then
cooled to RT (25.+-.2.degree. C.) and diluted with heptanes (1.35
Kg) over a time period of about 1 hour.
[0125] The slurry was stirred at 25.+-.2.degree. C. over a time
period of about 1 hour. The product was isolated by filtration to
provide a wet cake. The wet cake was washed with a mixture of
heptane (130 g) and ethyl acetate (260 g), dried under suction for
30 min, then dried at 50.+-.3.degree. C. under vacuum for 13 h to
yield 146.5 g of pure Formula (X) (yield: 90%; LCAP: 99.8%; chiral
purity: 100%).
5.1.7.1 Removal of Entrained Compound of Formula (IIa)
[0126] The example demonstrates methods to remove entrained
compound of Formula (IIa) from the reaction product obtained in the
procedure described for the synthesis of the compound of Formula
(X) in Section 5.1.5.
[0127] Evaluation on small scale. A series of experiments were
conducted to provide a suitable rework procedure to remove
entrained compound of Formula (IIa). A representative list of
experiments is given in Table 1. Solvent, batch temperature, time,
and solvent volume were all found to be critical to the
effectiveness of the rework procedure. The experiment in which the
compound of Formula (X), obtained by the procedure described
hereinabove, was refluxed in 8 volumes of ethyl acetate for 3 hours
provided consistent yield and purity, and was used as the basis for
the pilot plant rework procedure.
TABLE-US-00001 TABLE 1 Development of Rework Procedure for the
Compound of Formula (X) Solvent system Time Impurity RRT-0.48 Yield
(Volumes) Temperature (h) (area %) (%) EtOAc (4) ambient 1 1.05
88.3 EtOAc (4) reflux 1 0.48 90.0 EtOAc (8) reflux 1 0.38 83.3
EtOAc (16) reflux 1 0.31 74.8 EtOAc (8) reflux 3 0.16 88.2 EtOH
(15) reflux 1 0.47 93.0 MeOH (4) reflux 1 1.02 91.3 DCM (4) reflux
1 0.43 79.4 Acetone (4) reflux 1 0.25 84.5 Water (4) reflux 1 1.10
96.7 1M HCl (4) ambient 1 1.10 88.0
[0128] Plant Scale Experiment.
[0129] General information. Ethyl acetate (reagent grade) was
used.
[0130] Procedure. To a 100 gallon reactor was charged the compound
of Formula (X) (21.6 Kg, 46.2 mol) followed by ethyl acetate (157.3
Kg, 175 L, 8.1.times.). The slurry was warmed to 77.+-.2.degree. C.
and stirred for 3 hours. The slurry was cooled to 20-23.degree. C.
over about 1.5 hours. The slurry was stirred at 20-23.degree. C.
for about 4 hours. The slurry was filtered and the wet cake washed
with ethyl acetate (19.7 Kg, 21.9 L, 1.times.). The wet cake was
sampled for IPC (Limit: ROI .ltoreq.0.5%). The wet cake was dried
at ambient for 2 hours, 30.+-.2.degree. C. for 2 hours,
40.+-.2.degree. C. for 2 hours and 50.degree. C. until dry (2 days)
under vacuum. A total of 17.7 Kg of the compound of Formula (X) was
obtained as an off-white solid (HPLC; purity 99.5%, >99.9%
e.e.).
[0131] The chiral purity was calculated as % enantiomeric excess
following HPLC analysis (column: ChiralPak AD-RH, 150.times.4.6 mm,
5 .mu.m; mobile phase: hexanes (0.1% v/v diethylamine) and
isopropanol (0.1% v/v diethylamine) (80:20); column temperature:
40.degree. C.; flow rate: 1.0 mL/min; Detection: UV, 230 nm). The
retention times of (R)--Formula (IVa) and (S)--Formula (IVa) are
11.3 min and 22.2 min, respectively. The percent enantiomeric
excess (% e.e.) for the compound of Formula (X) was calculated
using the following formula (wherein the term "(R)-Formula (X)"
refers to the (R) isomer of the compound of Formula (X)):
% e.e.
Formula(X)=[(AUC.sub.Formula(X)-AUC.sub.(R)-Formula(X))/(AUC.sub.-
Formula(X)+AUC.sub.(R)-Formula(X)PV-5)].times.100
5.2 Chiral Resolution of
6-chloro-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
Compound of Formula (IVa)
[0132] This example demonstrates that ethanol with a 2-5% v/v water
content delivers
(S)-6-chloro-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
e (S)-2-acetamido-3-phenylpropanoate compound of Formula (IIa) with
an optical purity of greater than about 98%.
[0133] Procedure.
6-chloro-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
compound of Formula (IVa) (1 eq) and N-acetyl-L-phenylalamine (0.51
eq) were dissolved in a various mixtures of 260 ml of ethanol and
water (as shown in Table 2) content and heated under reflux for 18
h. The mixture was then cooled, and filtrated to obtain
(S)-6-chloro-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
e (S)-2-acetamido-3-phenylpropanoate compound of Formula (IIa) in
the yields and enantiomeric purity reported in Table 2. The chiral
purity is calculated as % enantiomeric excess following HPLC
analysis (column: ChiralPak AD-H, 150.times.4.6 mm, 5 .mu.m; mobile
phase: isopropanol:hexanes:diethylamine=20:80:1; column
temperature: 25.degree. C.; flow rate: 1.0 mL/min; Detection: UV,
230 nm). The retention times of (R)-Formula (IIa) and compound of
Formula (IIa) are 0.71 min and 1.00 min, respectively. The percent
enantiomeric excess (% e.e.) for the compound of Formula (IIa) was
calculated using the following formula (wherein the term
"(R)-Formula (IIa)" refers to the (R) isomer of the compound of
Formula (IIa)):
% e.e.
Formula(IIa)=[(AUC.sub.Formula(IIa)-AUC.sub.(R)-Formula(IIa))/(AU-
C.sub.(Formula(IIa)+AUC.sub.(R)-Formula(IIa))].times.100
TABLE-US-00002 TABLE 2 N--Ac--L- Amount of Chiral Scale
Phenylalanine EtOH water Purity Exp. # (g) (eq.) (mL) (v/v) Yield
(%) (e.e. %) 1 20 0.51 260 None 45.8 97.9 2 20 0.51 260 1% H.sub.2O
45.5 97.8 3 50 0.51 260 2% H.sub.2O 45.0 99.4 4 110 0.51 260 2%
H.sub.2O 45.7 99.4 5 20 0.51 260 3% H.sub.2O 45.5 99.1 6 20 0.51
260 4% H.sub.2O 45.2 99.0 7 20 0.51 260 5% H.sub.2O 44.0 98.6
[0134] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments described herein. Such
equivalents are intended to be encompassed by the following claims.
All publications, patents and patent applications mentioned in this
specification are herein incorporated by reference into the
specification to the same extent as if each individual publication,
patent or patent application was specifically and individually
indicated to be incorporated herein by reference.
* * * * *