U.S. patent application number 15/786195 was filed with the patent office on 2018-02-08 for process for the preparation of (3r,4r)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine.
The applicant listed for this patent is UNICHEM LABORATORIES LIMITED. Invention is credited to Nilesh L. Bonde, Arijit Das, Ankush Sampat Kekan, Yogesh Subhash Patil, Dhananjay G. Sathe.
Application Number | 20180037551 15/786195 |
Document ID | / |
Family ID | 53370688 |
Filed Date | 2018-02-08 |
United States Patent
Application |
20180037551 |
Kind Code |
A1 |
Sathe; Dhananjay G. ; et
al. |
February 8, 2018 |
Process for the Preparation of
(3R,4R)-(1-BENZYL-4-METHYLPIPERIDIN-3-YL)-METHYLAMINE
Abstract
The present disclosure is related to an improved and efficient
process for preparation of
(3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine which
comprises: (a) N-acylation of 3-Amino-4-methyl pyridine; (b)
Quarternization of 3-Acetylamino-4-methyl pyridine using benzyl
halide; (c) Partial reduction of quarternized
3-Acetylamino-4-methyl pyridine by Sodium borohydride in Methanol
or water; (d) Hydrolysis of partially reduced product to
1-Benzyl-4-methylpiperidin-3-one in presence of acid; (e) Reductive
amination of 1-Benzyl-4-methylpiperidin-3-one using Methanolic
methylamine in presence of Titanium(IV) isopropoxide in Methanol;
(f) Resolution of 1-Benzyl-4-methylpiperidin-3-yl)-methylamine
using Ditoluoyl (L) tartaric acid to get
(3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine. The
disclosure is also related to novel intermediates: ##STR00001##
wherein R, R' and X are as described in the specification.
Inventors: |
Sathe; Dhananjay G.; (Thane,
IN) ; Das; Arijit; (Kolkata, IN) ; Patil;
Yogesh Subhash; (Aurangabad, IN) ; Bonde; Nilesh
L.; (Baroda, IN) ; Kekan; Ankush Sampat;
(Pune, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UNICHEM LABORATORIES LIMITED |
Mumbai |
|
IN |
|
|
Family ID: |
53370688 |
Appl. No.: |
15/786195 |
Filed: |
October 17, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15590408 |
May 9, 2017 |
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15786195 |
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14891028 |
Nov 13, 2015 |
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PCT/IB2014/066510 |
Dec 2, 2014 |
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15590408 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 211/72 20130101;
C07D 211/02 20130101; C07D 213/74 20130101; C07D 211/98 20130101;
C07D 213/75 20130101; C07D 211/56 20130101 |
International
Class: |
C07D 213/75 20060101
C07D213/75; C07D 213/74 20060101 C07D213/74; C07D 211/56 20060101
C07D211/56; C07D 211/98 20060101 C07D211/98 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 9, 2013 |
IN |
3843/MUM/2013 |
Claims
1. The compound of the formula (IVa) and salts thereof,
##STR00012## wherein R represents C3-C10 alkyl, aryl or substituted
aryl, but not including iso-propyl, t-butyl and phenyl.
2. A compound of formula (Va). ##STR00013## wherein R represents
alkyl, aryl or substituted aryl; R' represents aryl or substituted
aryl group; and X represents halides groups selected from chloro,
bromo, iodo or any leaving group selected from tosyloxy or
mesyloxy.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional of U.S. patent
application Ser. No. 15/590,408 filed May 9, 2017, which is a
divisional of U.S. patent application Ser. No. 14/891,028, filed on
Nov. 13, 2015, which is U.S. National Phase filing of International
Application No. PCT/IB2014/066510, filed on Dec. 2, 2014,
designating the United States of America and claiming priority to
Indian Patent Application No. 3843/MUM/2013, filed Dec. 9, 2013,
and this application claims priority to and the benefit of the
above-identified applications, which are all incorporated by
reference herein in their entireties.
TECHNICAL FIELD
[0002] The present invention provides an efficient and improved
process for the preparation of
(3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine; a key
starting material for the synthesis of
3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piper-
idin-1-yl}-3-oxo-propanenitrile.
BACKGROUND OF THE INVENTION
[0003]
3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
]piperidin-1-yl}-3-oxo-propanenitrile,2-hydroxypropane-1,2,3-tricarboxylat-
e described as FORMULA I below and as disclosed in WO 02/096909,
U.S. Pat. No. 7,301,023. US FDA approved it for rheumatoid
arthritis.
##STR00002##
[0004] The key step for the preparation of
3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piper-
idin-1-yl}-3-oxo-propanenitrile as depicted in (Scheme-1) WO
02/096909 includes: [0005] (i) resolution of racemic
(1-Benzyl-4-methylpiperidin-3-yl)-methylamine to
(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine using
Di-p-toluoyl-L-tartarate; [0006] (ii) condensation of
4-Chlropyrrolo[2,3-d]pyrimidine with
(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine to get
(3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimid-
in-4-yl)-amine; and (iii) debenzylation of
(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimid-
in-4-yl)-amine followed by condensation with cyano acetic acid
derivative to get
3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amin-
o]piperidin-1-yl}-3-oxo-propanenitrile (FORMULA I), (Scheme-1).
##STR00003##
[0007] The most important part for the preparation of FORMULA I is
the synthesis of
(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine as it is very
tedious synthesis and also requires very expensive reagent. There
are several processes reported in literature for the synthesis and
resolution of racemic (1-Benzyl-4-methylpiperidin-3-yl)-methylamine
to (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine.
[0008] WO 2007/012953 discloses preparation of
1-Benzyl-3-methoxycarbonylamino-4-methyl-pyridinium bromide and
it's asymmetric reduction using mixture of Ruthenium and Iridium
based chiral catalysts under hydrogenation condition to provide
(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine with 84% cis
isomer, having 68% ee.
[0009] The patent further discloses the preparation of same
intermediate by applying partial reduction followed by asymmetric
reduction approach to obtain highly enriched Piperidine derivative
as depicted in Scheme-2.
##STR00004##
Both the approaches make use of very high chiral catalyst loading
and render their commercial use expensive and difficult. Further,
the process requires very high pressure which makes it risky,
costlier and unfavorable for scale up.
[0010] WO 2010/123919 provides an additional process for
preparation of (1-Benzyl-4-methylpiperidin-3-yl)-methylamine, which
includes: [0011] (i) protection of amino group of 3-Amino-4-methyl
pyridine with Dimethyl carbonate in presence of Potassium
tert-butoxide in Tetrahydrofuran; [0012] (ii) quaternization of
Nitrogen of Pyridine system using Benzyl bromide in Toluene; [0013]
(iii) partial reduction of the quaternized Pyridine system to
produce 1,2,5,6-Tetrahydropyridine in presence of Sodium
borohydride in Methanol; [0014] (iv) reduction with Platinum oxide
in Methanol provides Piperidine derivative. Followed by the
purification by column chromatography; and [0015] (v) further
reaction with Lithium aluminium hydride and purification by column
chromatography to get
(1-Benzyl-4-methyl-piperidin-3-yl)-methylamine.
[0016] The process has several drawbacks. Overall process yield is
very poor i.e. approximately 40%. The process uses column
chromatography at two stages. Lithium aluminum hydride, a known
pyrophoric reagent, account for the safety risk during its
manufacturing. Lastly Platinum oxide is very explosive in presence
of hydrogen. It is very costly reagent which discourages its use on
plant scale. Overall the process is costlier, not so safe to work
on commercial scale and demands stringent skill of art.
[0017] WO 2010/123919 further reveals an additional procedure for
the preparation of (1-Benzyl-4-methylpiperidin-3-yl)-methylamine
and the synthetic procedure is summarized in Scheme-3.
##STR00005##
[0018] Process involves debenzylation and quaternization of ethyl
1-Benzyl-3-oxopiperidine-4-carboxylate followed by protection of
the resulted Ethyl 3-oxopiperidine-4-carboxylate derivative using
di-tert-butyl dicarbonate. Protected Piperidine derivative was
methylated by abstracting the Methylenic proton using Sodium
hydride and further reaction with Iodomethane. In the next stage
deprotection of N-tert-butoxycarbonyl group was carried out in
acidic media, and the resulting 4-Methylpiperidin-3-one was
benzylated followed by reductive amination with Methylamine and
Sodium triacetoxyborohydride provide the desired product
(1-Benzyl-4-methylpiperidin-3-yl)-methylamine.
[0019] The overall conversion involves five stages from quite a
complex starting material. The process involves protection and
deprotection in different stages. Use of costly, non safe reagents
such as Sodium hydride and lacrimatic Benzyl bromide and Sodium
triacetoxyborohydride limit its commercial scale production. The
process has major draw back with respect to the use of column
chromatography at three stages. Moreover disclosure of process is
silent about the purity of intermediates and of the target molecule
produced. The overall yield mentioned for the process is also very
low i.e. 13.6 molar percent.
[0020] U.S. Pat. No. 6,627,754 provides a similar reductive
amination route as discussed in WO 2010/123919 for the synthesis of
(1-Benzyl-4-methyl piperidin-3-yl)-methylamine from
1-Benzyl-4-methylpiperidin-3-one in a sealed tube using Sodium
triacetoxyborohydride as a reducing agent. Sodium
triacetoxyborohydride is extremely moisture sensitive pyrophoric
reagent. Sealed tube reaction is difficult to execute on large
scale.
[0021] The processes taught by prior art have several drawbacks
namely expensive, not suitable for scale up at plant level, energy
intensive, difficult, giving lower yields, forcing use of corrosive
acids, longer duration of corrosive reactions and less user
friendly. Considering the drawbacks of prior art and very complex
methodologies applied, for the preparation of the
(1-Benzyl-4-methyl piperidin-3-yl)-methylamine, there is a urgent
and pressing need for simple, energy economical, financially
cheaper plant friendly process, environment friendly process for
the preparation of
(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine to synthesize
FORMULA I that does not use hygroscopic and pyrophoric chemicals
and yet provides better yields.
SUMMARY OF THE INVENTION
[0022] An object of the present invention is to provide an improved
and efficient process for the preparation of
(1-Benzyl-4-methylpiperidin-3-yl)-methylamine which has better over
all yield.
[0023] Another object of the invention is to provide a cost
effective, environment friendly and energy economic process to
prepare (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine
[0024] Yet another object of the invention is to provide a process
for the synthesis of
(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine to prepare
3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)ami-
no]piperidin-1-yl}-3-oxo-propanenitrile,2-hydroxypropane-1,2,3-tricarboxyl-
ate (FORMULA I).
[0025] According to a first aspect of the present invention an
improved and efficient process for the preparation of
(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine, of the
Formula II is provided.
[0026] Another aspect of the present invention is to provide a
process for the preparation of a compound of Formula IIa, as
depicted in Scheme-4, comprising: [0027] (i) N-acylation of
3-Amino-4-methyl pyridine (Formula III) with alkyl, aryl or
substituted aryl acid anhydride or acid chloride to get Formula
IVa; [0028] (ii) quaternization of Nitrogen of Pyridine system
having Formula IVa, using Benzyl or substituted Benzyl halide in an
organic solvent or aqueous solvent or mixture(s) thereof to get
Formula Va; [0029] (iii) partial reduction of the optionally
isolated quarternized pyridine system having Formula Va to produce
1,2,5,6-Tetrahydropyridine system of Formula VIa in the presence of
a reducing agent or any Borohydride agent in an organic solvent or
aqueous solvent or mixture(s) thereof, at an ambient temperature;
[0030] (iv) hydrolysis of 1,2,5,6-Tetrahydropyridine system of
Formula VIa in presence of an acid or mixture of acids to get
Formula VIIa, at an ambient temperature; [0031] (v) reductive
amination of Formula VIIa using Methylamine in presence of any
Lewis acids in an organic solvent or aqueous solvent or mixture(s)
thereof followed by reduction using any reducing agent or any
alkali metal Borohydride derivatives produce compound of Formula
VIIIa, at an ambient temperature; and [0032] (vi) further
resolution of compound VIIIa in presence of any resoluting agent in
an organic solvent or aqueous solvent or mixture(s) thereof produce
compound of Formula IIa.
##STR00006##
[0032] wherein R represents hydrogen, alkyl, aryl, substituted aryl
and R' represents aryl or substituted aryl group.
[0033] Prior art WO 2010/123919 uses reactants of different class
of compounds. The two routes of synthesis (ROS) are dissimilar. WO
2010/123919 does not envisage use of anhydride in the first step.
The intermediate formed in the reaction of the present invention
has a Methyl in the side chain which is not the case with prior
art. Initial use of different class of reactants produces different
classes of intermediates. Hydrolysis and reductive amination steps
and the intermediates formed are unique to the ROS of the present
invention. These are absent in the prior art. Lithium Aluminium
Hydride is essential in WO 2010/123919 but is absent in present
invention. Inventive step of the present invention also resides in
surprisingly reduced durations of various reaction steps as
compared to those in WO 2010/123919. Preparation of
1,2,5,6-Tetrahydropyridine system of Formula VIa can be completed
30% of time required by WO 2010/123919.
[0034] Yet another aspect of the present invention is to provide a
process for the preparation of
(3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine of Formula
(II), as depicted in Scheme 5, comprising: [0035] (i) N-acylation
of 3-amino-4-methyl pyridine with Acetyl chloride or Acetic
anhydride to get Formula IV; [0036] (ii) quaternization of Nitrogen
of pyridine system having Formula IV, using Benzyl chloride in
presence of toluene to get Formula V; [0037] (iii) partial
reduction of the optionally isolated quaternized Pyridine system of
Formula V to produce 1,2,5,6-Tetrahydropyridine system of Formula
VI in presence of Sodium borohydride in Methanol or water to get
Formula VI, at an ambient temperature; [0038] (iv) hydrolysis of
1,2,5,6-Tetrahydropyridine system of Formula V in presence of
mixture of Hydrochloric acid and Acetic acid to get Formula VII, at
an ambient temperature; [0039] (v) reductive amination of Formula
VII in presence of Titanium(IV) tetraisopropoxide in Methylamine
followed by reduction with Sodium borohydride to get
1-Benzyl-4-methylpiperidin-3-yl)-methylamine of Formula VIII, at an
ambient temperature; and [0040] (vi) further resolution of compound
of Formula VIII in presence of a resoluting agent such as
Dibenzoyl-L-tartaric acid or Ditoluoyl-L-tartaric acid in the
mixture of methanol and/or water to produce
(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine of the
Formula II.
##STR00007##
[0040] DETAILED DESCRIPTION OF THE INVENTION
[0041] The present invention relates to an improved and efficient
process for the preparation of compound of formula (IIa)
comprising: [0042] (i) N-acylation of 3-amino-4-methyl pyridine
(Formula III) with alkyl, aryl or substituted aryl acid anhydride
or acid chloride to get Formula IVa; [0043] (ii) quarternization of
Nitrogen of Pyridine system having Formula IVa, using Benzyl or
substituted Benzyl halide in an organic solvent to get Formula Va;
[0044] (iii) partial reduction of the quarternized pyridine system
having Formula Va to produce 1,2,5,6-Tetrahydropyridine system of
Formula VIa in presence of a reducing agent or any Borohydride
agent in an organic solvent, at an ambient temperature; [0045] (iv)
hydrolysis of 1,2,5,6-Tetrahydropyridine system of Formula VIa in
presence of acid or mixture of acids to get Formula VIIa, at an
ambient temperature; [0046] (v) reductive amination of Formula VIIa
using Methylamine in presence of any Lewis acids in an organic
solvent or aqueous solvent or mixture(s) thereof followed by
reduction using any reducing agent or any alkali metal borohydride
derivatives produce compound of Formula VIIIa, at an ambient
temperature; and [0047] (vi) further resolution of compound VIIIa
in presence of any resoluting agent in an organic solvent or
aqueous solvent or mixture(s) thereof produce compound of Formula
IIa
[0048] C1 acid anhydride is an anhydride of Acetic acid i.e. Acetic
anhydride. C2 acid anhydride is an anhydride of Propanoic acid. In
the present invention one may use anhydrides of C1-10 acids. C1-10
Acid chloride is to be construed as Acid chloride of Formic acid to
Decanoic acid, aryl acid chlorides or substituted acid chlorides
having up to 10 carbon atoms. C1-05 alcohols are to be construed as
Methanol, Ethanol, Propanol, Butanol and Pentanol. Better overall
yield is to be interpreted as overall yield more than 50% for the
synthesis of 1-Benzyl-4-methylpiperidine-3-yl)-methylamine an
intermediate before resolution.
[0049] Terms quarternization and quaternization are used
interchangeably and have the same meaning with respect to
attachments to tertiary Nitrogen. Terms improved and efficient are
to be construed in view of better yields, less energy intensive,
reactions of shorter durations besides reduced costs of inputs and
simplicity of the procedures involved, better scalability to plant
level. Pyridine system means pyridine ring portion in the molecular
structure with or without substituents. Ambient temperature is to
be interpreted as temperature between 0.degree. C. to 30.degree. C.
RT is room temperature. Terms Methylene chloride and Methylene
dichloride i.e. MDC are used interchangeably. The inventive step of
the present invention resides in (Scheme-6): [0050] (i) N-acylation
of 3-Amino-4-methyl pyridine (Formula III) with alkyl, aryl or
substituted aryl acid anhydride or acid chloride to get Formula
IVa. Prior art is devoid of acetylation reaction at this stage.
Prior art teaches use of Dimethyl carbonate and due to difference
in reactants of this initial stage, structurally different
intermediates are formed belonging to different classes of chemical
compounds exhibiting different properties; [0051] (ii)
quarternization of Nitrogen of Pyridine system having Formula IVa,
using Benzyl or substituted Benzyl halide in an organic solvent to
get Formula Va; [0052] (iii) partial reduction of the optionally
isolating quarternized Pyridine system having Formula Va to produce
1,2,5,6-Tetrahydropyridine system of Formula VIa in presence of a
reducing agent or any borohydride agent in an organic solvent at an
ambient temperature; [0053] (iv) hydrolysis of
1,2,5,6-Tetrahydropyridine system of Formula VIa in presence of
acid or mixture of acids to get Formula VIIa at an ambient
temperature; and [0054] (v) reductive amination of Formula VIIa
using Methylamine in presence of any Lewis acids in an organic
solvent or aqueous solvent or mixture(s) thereof followed by
reduction using any reducing agent or any alkali metal borohydride
derivatives produce compound of Formula VIIIa at an ambient
temperature.
##STR00008##
[0054] wherein R represents hydrogen, alkyl, aryl, substituted aryl
and R' represents aryl or substituted aryl group.
[0055] N-acylation of 3-Amino-4-methyl pyridine (Formula III) with
alkyl, aryl or substituted aryl acid anhydride includes C1-10
anhydride, acetic anhydride, and more preferably acetic
anhydride.
[0056] N-acylation of 3-Amino-4-methyl pyridine (Formula III) with
alkyl, aryl or substituted aryl acid chloride includes C1-10 acid
chloride, acetyl chlorides, benzoyl chloride etc. more preferably
acetyl chloride. N acylation leads to formation of the compound of
the formula (IVa) and salts thereof,
##STR00009##
wherein R represents C1-C10 alkyl, aryl or substituted aryl, but
not including iso-propyl, t-butyl and phenyl. When R represents
C3-C10 alkyl, aryl or substituted aryl, but not including
iso-propyl, t-butyl and phenyl, novel compounds are formed.
[0057] Quarternization of Nitrogen of Pyridine system having
Formula IVa, using benzyl or substituted benzyl halide includes
Benzyl chloride, Benzyl bromides etc. more preferably benzyl
chloride.
[0058] Quarternization of Nitrogen of Pyridine system having
Formula IVa, to get Formula Va is carried out using Benzyl halide
or substituted benzyl halide in presence of an organic or
aqueous-organic solvent which includes Toluene, Xylenes, alcoholic
solvents, ethereal solvents more preferably Toluene and Xylenes
most preferably Toluene. Polar, protic, aprotic solvents are to be
interpreted as per prevailing definitions.
[0059] Quarternization of Nitrogen of Pyridine system having
Formula IVa, using benzyl or substituted benzyl halide in presence
of an organic solvent to get Formula Va was carried out at
temperature between 40.degree. C. to 110.degree. C. more preferably
between 75.degree. C. to 85.degree. C. A compound of the formula
(Va)
##STR00010##
wherein R represents alkyl, aryl or substituted aryl more
preferably methyl; R' represents aryl or substituted aryl group
more preferably phenyl; and X represents halides group such as
chloro, bromo, iodo, or any leaving group such as tosyloxy or
mesyloxy.
[0060] Partial reduction of the quarternized pyridine system of
Formula Va produces 1,2,5,6-Tetrahydropyridine system of Formula
Via, in presence of a reducing agent such as borohydride agent
including Sodium borohydride, Sodium cyanoborohydride, Sodium
triacetoxyborohydride more preferably Sodium borohydride and the
organic solvent selected from the group consisting of alcoholic
solvents such as Methanol, Ethanol ethereal solvents such as
Di-isopropyl ether (DIPE), Methyl tertiary butyl ether (MTB) or
Toluene, Xylenes or aqueous mixture thereof more preferably
Methanol, water most preferably water. The reduction using the
borohydride reagent was carried out between 0.degree. C. to
10.degree. C. more preferably between 0.degree. C. to 5.degree.
C.
[0061] 1,2,5,6-Tetrahydropyridine system of Formula VIa can be
obtained from Pyridine system having Formula IVa optionally
isolating quarternized Pyridine system having Formula Va. A
compound of the formula (VIa) and salts thereof
##STR00011##
wherein R represents alkyl, aryl or substituted aryl more
preferably methyl; R' represents aryl or substituted aryl group
more preferably phenyl.
[0062] Hydrolysis of 1,2,5,6-Tetrahydropyridine system of Formula
VIa in presence of an acid or mixture of acids which includes
Hydrochloric acid, Sulfuric acid, Phosphoric acid, Trifluoroacetic
acid, Trichloroacetic acid, acetic acid or aqueous solutions
thereof or mixture(s) thereof more preferably Hydrochloric acid and
Acetic acid most preferably mixture of Hydrochloric acid and Acetic
acid.
[0063] Hydrolysis of 1,2,5,6-Tetrahydropyridine system of Formula
VIa in presence of an acid or mixture of acids was carried out at
temperature between 40.degree. C. to 110.degree. C. more preferably
between 75.degree. C. to 90.degree. C. most preferably between
85.degree. C. to 90.degree. C.
[0064] Reductive amination of Formula VIIa can be carried out by
using Methylamine in presence of any Lewis acids such as
AlCl.sub.3, InCl.sub.3, Titanium(IV) tetraisopropoxide, FeCl.sub.3
etc. more preferably Titanium(IV) tetraisopropoxide. Reductive
amination of Formula VIIa can be carried out by using Methylamine
in presence of any Lewis acids in an organic solvent such as
alcoholic solvent like Methanol, Ethanol or ethereal solvents like
Di-isopropyl ether (DIPE), Methyl tertiary butyl ether (MTB) or
Toluene, Xylenes or aqueous mixture(s) thereof more preferably
Methanol or water most preferably water.
[0065] Reductive amination of Formula VIIa using Methylamine in
presence of any Lewis acids in an organic solvent followed by
reduction using any reducing agent such as alkali metal borohydride
derivatives which includes Sodium borohydride, Sodium
cyanoborohydride, Sodium triacetoxyborohydride more preferably
Sodium borohydride to produce compound of Formula VIIIa.
[0066] Reductive amination of Formula VIIa using Methylamine in
presence of any Lewis acids in an organic solvent followed by
reduction using any reducing agent or any alkali metal borohydride
derivatives to get compound of Formula VIIIa was carried out at
temperature between 0.degree. C. to 10.degree. C. more preferably
between 0.degree. C. to 5.degree. C.
[0067] Resolution of Formula VIIIa in presence of resoluting agent
which includes Tartaric acid, Dibenzoyl tartaric acid (DBTA),
Ditoluoyl tartaric acid (DTTA), Mandalic acid, Camphor sulphonic
acid etc. more preferably Dibenzoyl tartaric acid (DBTA), Ditoluoyl
tartaric acid (DTTA) most preferably Ditoluoyl tartaric acid (DTTA)
to get compound of Formula IIa
[0068] Resolution of compound VIIIa in presence of any resoluting
agent in an organic solvent includes alcoholic solvent such as
Methanol, Ethanol, ethereal solvents, Toluene, Xylenes or aqueous
mixture(s) thereof, more preferably methanol to get compound of
Formula IIa. Ethereal solvents include Di-isopropyl ether (DIPE),
Methyl tertiary butyl ether (MTB) but not limited only to these two
solvents. The invention is further illustrated by way of the
following examples.
EXAMPLES
Example-1: Preparation of N-(4-methylpyridin-3-yl)-acetamide from
3-Amino-4-methyl pyridine
[0069] 3-Amino-4-methyl pyridine (200 gm) and Acetic acid (600 mL)
were charged in a 2 L 4-neck round bottom flask with an overhead
stirrer and stirred for 15 minutes at RT. Acetic anhydride (284
gm/263 mL) or Acetyl chloride (174 gm) was added drop wise within
1-2 h at that temperature. The reaction mass was then stirred at RT
for 8-10 h. After the completion of the reaction as monitored by
TLC, HPLC; acetic acid was distilled out under vacuum. Methanol (1
L) was then added to the reaction mixture and the pH of the
reaction mixture was maintained around 10-12 by liq. Ammonia.
Methanol was distilled out completely under vacuum at 50.degree. C.
to 55.degree. C. The product was then extracted with MDC (1 L) to
get the pure product. Yield: 98% w/w; HPLC Purity: 98%.
Example-2: Preparation of N-(4-methylpyridin-3-yl)-acetamide from
3-Amino-4-methyl pyridine
[0070] 3-Amino-4-methyl pyridine (200 gm) and Acetic anhydride (284
gm/263 mL) in a 2 L 4-neck round bottom flask with an overhead
stirrer were stirred for 15 minutes at RT. The stirring was
continued at RT for 1-3 h. After the completion of the reaction as
monitored by TLC, Methanol (1 L) was added to the reaction mixture
and the pH of the reaction mixture was maintained around 10-12 by
liq. Ammonia. Methanol was distilled out completely under vacuum at
50.degree. C. to 55.degree. C. Extraction with MDC (1 L) gave pure
product. Yield: 98% w/w; HPLC Purity: 98%.
Example-3: Preparation of N-(4-methylpyridinium-3-yl)-acetamide
acetate from 3-amino-4-methyl pyridine
[0071] 3-Amino-4-methyl pyridine (200 gm), Acetic anhydride (284
gm/263 mL) or Acetyl chloride (174 gm) and MDC (1 L) in a 2 L
4-neck round bottom flask with an overhead stirrer were stirred for
15 minuets at RT. The reaction mass was stirred at RT for 8-10 h.
Completion of the reaction was monitored by TLC, HPLC. Extraction
with MDC (1 L) gave pure product. Yield: 98% w/w; HPLC Purity:
98%.
Example-4: Preparation of N-(4-methylpyridin-3-yl)-acetamide from
3-Amino-4-methyl pyridine
[0072] 3-Amino-4-methyl pyridine (200 gm), Acetic anhydride (284
gm/263 mL) or Acetyl chloride (174 gm) and MDC (1 L) in a 2 L
4-neck round bottom flask with an overhead stirrer were stirred for
15 minutes at RT. The reaction mass then stirred at RT for 8-10 h.
Completion of the reaction as monitored by TLC. pH of the reaction
mixture was maintained around 10-12 by liq. Ammonia. Extraction
with MDC (1 L) gave pure product. Yield: 98% w/w; HPLC Purity:
98%.
Example-5: Preparation of
1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridine-3-yl-acetyl amine from
N-(4-methylpyridin-3-yl)-acetamide
[0073] Toluene (1 L) and N-(4-methylpyridin-3-yl)-acetamide (200
gm) were charged in a 2 L 4-neck round bottom flask with an
overhead stirrer and stirred for 15 minutes at RT. Benzyl chloride
(202 gm) or Benzyl bromide (273 gm) was added to the insoluble
reaction mass and stirred for 15 minutes at RT. The temperature of
the reaction mass was raised to 80.degree. C. to 85.degree. C. and
stirred until the completion of the reaction (monitored by TLC,
HPLC). The reaction mass was then cooled to 25.degree. C. to
30.degree. C. and decanted out the toluene layer. Methanol (1 L)
was charged to the reaction mixture, stirred to get clear solution
and was cooled to 0.degree. C. to 5.degree. C. Sodium borohydride
solution (60 gm in 0.1 N Sodium hydroxide) was added drop wise at
0.degree. C. to 5.degree. C. The reaction mixture was then stirred
for 10-12 h as required to complete the reaction (monitored by TLC,
HPLC). Water (600 mL) was added to the reaction mass and stirred to
get clear solution. Distilled out Methanol under vacuum. Solid
precipitation observed was filtered by Buckner funnel to get the
pure product. (Yield=84-87%; HPLC: 90%).
Example-6: Preparation of
1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridine-3-yl-acetyl amine from
N-(4-methylpyridin-3-yl)-acetamide
[0074] Toluene (1 L), N-acetyl-3-amino-4-methyl pyridine (200 gm)
were charged in a 2 L 4-neck round bottom flask with an overhead
stirrer and stirred for 15 minutes at RT. Benzyl chloride (202 gm)
or Benzyl bromide (273 gm) was added to the insoluble reaction mass
and stirred for 15 minutes at that temperature. The temperature of
the reaction mass was then raised to 80.degree. C. to 85.degree. C.
and stirred the reaction mixture at that temperature for 8-10 h as
required to complete the reaction (monitored by TLC, HPLC). The
reaction mass was cooled to 25.degree. C. to 30.degree. C. Water (1
L) was charged to the reaction mixture and stirred for 15 minutes.
Separated out aqueous layer and cooled it to 0.degree. C. to
5.degree. C. Sodium borohydride solution (60 gm in 0.1 N Sodium
hydroxide) was then added into the aqueous layer drop wise at
0.degree. C. to 5.degree. C. The reaction mixture was then stirred
for 10-12 h to complete the reaction (monitored by TLC, HPLC).
After the completion of the reaction solid precipitation observed
was filtered by Buckner funnel to get the pure product.
(Yield=84-87%; HPLC: 90%)
Example-7: Preparation of benzyl quarternized salt of
N-(4-methylpyridin-3-yl)-acetamide
[0075] Toluene (1 L), N-(4-methylpyridin-3-yl)-acetamide (200 gm)
were charged in a 2 L 4-neck round bottom flask with an overhead
stirrer and stirred for 15 minutes at RT. Benzyl chloride (202 gm)
or Benzyl bromide (273 gm) was added into the insoluble reaction
mass and stirred for 15 minutes at that temperature. The
temperature of the reaction mass was then raised to 80.degree. C.
to 85.degree. C. and stirred for 8-10 h to complete the reaction
(monitored by TLC, HPLC). The reaction mass was then cooled to
25.degree. C. to 30.degree. C. and filtered off the Toluene layer
to get pure benzyl quarternized salt of
N-(4-methylpyridin-3-yl)-acetamide (Yield=98%; HPLC: 95%)
Example-8: Preparation of
1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine from
benzyl quarternized salt of N-(4-methylpyridin-3-yl)-acetamide
[0076] Methanol (1 L), benzyl quarternized salt of
N-(4-methylpyridin-3-yl)-acetamide (200 gm) were charged in a 2 L
4-neck round bottom flask with an overhead stirrer and stirred for
15 minutes at RT. Cooled the reaction mixture to 0.degree. C. to
5.degree. C. and added Sodium borohydride solution (60 gm in 0.1 N
Sodium hydroxide) drop wise at that temperature. Stirred for 10-12
h to complete the reaction (monitored by TLC, HPLC). After the
completion of the reaction, water (600 mL) was added and stirred to
get clear solution. Distilled out methanol under vacuum. Solid
precipitation observed was filtered to get the pure product.
(Yield=75%; HPLC: 98%).
Example-9: Preparation of
1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine from
3-amino-4-methyl pyridine
[0077] 3-Amino-4-methyl pyridine (200 gm) and Acetic anhydride (284
gm/263 mL) were charged in a 2 L 4-neck round bottom flask with an
overhead stirrer and stirred at 25.degree. C. to 30.degree. C. for
1-3 h. After the completion of the reaction as monitored by TLC,
methanol (1 L) was added to the reaction mixture and the pH
maintained around 10-12 by liq. Ammonia. Methanol was distilled out
completely under vacuum at 50.degree. C. to 55.degree. C. The
product was then extracted with MDC (1 L) and distilled out the
organic layer to get crude N-(4-methylpyridin-3-yl)-acetamide.
[0078] Toluene (1 L) was charged to the reaction mixture and
stirred for 15 minutes at RT. Benzyl chloride (202 gm) or Benzyl
bromide (273 gm) was added into the insoluble reaction mass and
stirred for 15 minutes at that temperature The temperature was then
raised to 80.degree. C. to 85.degree. C. and stirred the reaction
mixture at that temperature for 8-10 h as required to complete the
reaction (monitored by TLC, HPLC). The reaction mass was cooled to
25.degree. C. to 30.degree. C. Water (1 L) was then charged to the
reaction mixture and stirred for 15 minutes. Separated out aqueous
layer and cooled it to 0.degree. C. to 5.degree. C. Sodium
borohydride solution (60 gm in 0.1N Sodium hydroxide) was added
into the aqueous layer drop wise at 0.degree. C. to 5.degree. C.
The reaction mixture was then stirred for 10-12 h as required to
complete the reaction (monitored by TLC, HPLC). After the
completion of the reaction solid precipitation observed was
filtered by Buckner funnel to get the pure product. (Yield=84-87%;
HPLC: 90%).
Example-10: Preparation of N-Benzyl-4-methylpiperidin-3-one from
1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine
[0079] Acetic acid (50 mL), Conc. HCl 35% (100 mL) were charged in
a 2 L 4-neck round bottom flask with an overhead stirrer and
stirred for 10 minutes at RT.
1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine (100
gm) was then added into the reaction mass at that temperature.
Temperature of the reaction mixture was raised slowly to 85.degree.
C. to 90.degree. C. and stirred for 3-4 h at that temperature as
required to complete the reaction (monitored by TLC, HPLC). The
reaction mixture was cooled to 25.degree. C. to 30.degree. C. and
extracted with Toluene (500 mL) to get the pure product. Yield:
95%; HPLC: 95%
Example-11: Preparation of N-Benzyl-4-methylpiperidin-3-one from
1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine
[0080] Conc. HCl 35% (150 mL) and
1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine (100
gm) were charged in a 2 L 4-neck round bottom flask with an
over-head stirrer and stirred for 10 minutes at RT. Temperature of
the reaction mixture was raised slowly to 85.degree. C. to
90.degree. C. and stirred for 3-4 h to complete the reaction
(monitored by TLC, HPLC). The reaction mixture was then cooled to
25.degree. C. to 30.degree. C. and extracted with Toluene (500 mL)
to get the pure product. Yield: 95%; HPLC: 90%.
Example-12: Preparation of N-Benzyl-4-methylpiperidin-3-one from
1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine
[0081] Acetic acid (100 mL) and
1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridine-3-yl-acetylamine (100
gm) were charged in a 2 L 4-neck round bottom flask with an
overhead stirrer and stirred for 15 minutes at RT. Temperature of
the reaction mixture was raised slowly to 85.degree. C. to
90.degree. C. and stirred for 3-4 h to complete the reaction
(monitored by TLC, HPLC). The reaction mixture was then cooled to
25.degree. C. to 30.degree. C. and extracted with toluene (500 mL)
to get the pure product. Yield: 95%; HPLC: 90%.
Example-13: Preparation of
(1-Benzyl-4-methylpiperidin-3-yl)-methylamine from
N-Benzyl-4-methylpiperidin-3-one
[0082] Methanol (500 mL) and N-Benzyl-4-methylpiperid-3-one (100
gm) were charged in a 2 L 4-neck round bottom flask with an
overhead stirrer and stirred for 15 minutes at RT. The reaction
mass was cooled to 0.degree. C. to 5.degree. C. and Titanium(IV)
tetraisopropoxide solution (175 mL) was added drop wise within
30-45 minutes. The reaction mass was stirred at 0.degree. C. to
5.degree. C. for 30 minutes and Methanolic methylamine solution
(30%) (100 mL) was added drop wise at 0.degree. C. to 5.degree. C.
within 30-45 minutes. The reaction mass was stirred for 2-3 h at
0.degree. C. to 5.degree. C. Sodium borohydride (22 gm) was then
added to the reaction mass within 30-45 minutes at 0.degree. C. to
5.degree. C. and stirred for 2-3 h. After the completion of the
reaction as monitored by TLC, HPLC; water (500 mL) was added to the
reaction mixture and stirred for 30-45 minutes at RT. The product
was extracted using MDC (500 mL) to get the pure product. Yield:
90%; HPLC: 90%.
Example-14: Preparation of
(1-Benzyl-4-methylpiperidin-3-yl)-methylamine from
N-Benzyl-4-methyl-3-piperidone
[0083] Methanol (500 mL) and N-Benzyl-4-methylpiperid-3-one (100
gm) were charged in a 2 L 4-neck round bottom flask with an
overhead stirrer. Stirred for 15 minutes at RT. The reaction mass
was cooled to 0.degree. C. to 5.degree. C. and Titanium(IV)
tetraisopropoxide solution (175 mL) was added drop wise within
30-45 minutes. The reaction mass was stirred at 0.degree. C. to
5.degree. C. for 30 minutes and Methylamine hydrochloride (66 gm)
was added at 0.degree. C. to 5.degree. C. within 30-45 minutes. The
reaction mass was stirred for 2-3 h at 0.degree. C. to 5.degree. C.
Sodium borohydride (22 gm) was added to the reaction mass within
30-45 minutes at 0.degree. C. to 5.degree. C. and stirred for 2-3
h. After the completion of the reaction as monitored by TLC, HPLC;
water (500 mL) was added to the reaction mass and stirred for 30-45
minutes at RT. The product was extracted by using MDC (500 mL) to
get the pure product. Yield: 95%; HPLC: 90%.
Example-15: Resolution of
(1-Benzyl-4-methylpiperidin-3-yl)-methylamine to get
(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine
[0084] Methanol (500 mL) and
(1-Benzyl-4-methylpiperidin-3-yl)-methylamine (100 gm) were charged
in a 2 L 4-neck round bottom flask with an overhead stirrer and
stirred for 15 minutes at RT. Ditoluoyl-L-tartaric acid (DTTA) (106
gm) or Dibenzoyl-L-tartaric acid (DBTA) (98 gm) was added to the
reaction mixture and stirred for 15 minutes to get clear solution.
Water (500 mL) was added to the reaction mass and the temperature
was raised to 65.degree. C. to 70.degree. C. and stirred for 1 h.
The reaction mass was cooled to 10.degree. C. to 15.degree. C. and
maintained for 3 h. The solid precipitated was filtered off to get
pure Ditoluoyl-L-tartaric acid (DTTA) or Dibenzoyl-L-tartaric acid
(DBTA) salt of
(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine.
Yield=80-82%; HPLC: 98%.
[0085] Although the present invention recites various specific
embodiments, it is not meant to be construed in a limiting sense.
Various modifications of the disclosed embodiments and alternate
embodiments will become apparent to persons skilled in the art upon
reference to the present invention. It is therefore contemplated
that such modifications can be made without departing from the true
spirit or scope of the present invention as exemplified and claimed
herein below.
* * * * *