WO2013024383A1 - An improved process for the preparation of lacosamide - Google Patents
An improved process for the preparation of lacosamide Download PDFInfo
- Publication number
- WO2013024383A1 WO2013024383A1 PCT/IB2012/053875 IB2012053875W WO2013024383A1 WO 2013024383 A1 WO2013024383 A1 WO 2013024383A1 IB 2012053875 W IB2012053875 W IB 2012053875W WO 2013024383 A1 WO2013024383 A1 WO 2013024383A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- benzyl
- lacosamide
- butoxy
- preparation
- methoxypropionamide
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
Definitions
- the present invention relates to an improved process for the preparation of Lacosamide having formula (I).
- Lacosamide (R)-2-acetamido-N-benzyl-3 methoxypropionamide has the following formula:
- Lacosamide is marketed under the trade name Vimpat(R) by UCB. It was approved by the FDA as an adjunctive therapy for partial-onset seizures in October 2008.
- U.S. Patent No. 5,654,301 discloses certain compounds which are amino acid derivatives and includes lacosamide. Various synthetic schemes for the preparation of these derivatives are disclosed.
- Lacosamide and its methods of preparation are disclosed in U.S. Reissue Patent No. RE 38,551.
- the patent provides three general methods for the preparation of lacosamide. The first two methods do not involve the protection of active groups in intermediate compounds (such as amino, hydroxy and carboxylic acid groups).
- the other method disclosed in this patent involves protection of an amino group present in D-serine with carbobenzoxy chloride (Cbz-Cl), subsequent O-methylation at the hydroxy group followed by amidation at carboxylic (-COOH) acid with benzylamine and finally removal of the 'Cbz' group followed by acetylation, to produce lacosamide.
- US 20090143472 disclose certain intermediates and methods of preparation of lacosamide using the intermediates.
- the process of preparation of lacosamide involves O- methylation of the intermediate, benzyl amine amidation, detritylation and finally acetylation to yield lacosamide.
- Another method disclosed involves first benzyl amine amidation of the intermediate, and then O-methylation, subsequently followed by detritylation and finally acetylation.
- WO2010052011 discloses the resolution of 2-acetamido-N-benzyl-3- methoxypropionamide using chiral chromatography.
- an object of the present invention is to provide an improved process for the preparation Lacosamide.
- Another object of the present invention is to provide an improved process for the preparation of Lacosamide which is operationally simple, easy to handle and applicable at an industrial scale.
- Yet another object of the present invention is to provide process for the preparation of Lacosamide comprising steps of:
- Another object of the present invention is to provide an improved process for the preparation of Lacosamide comprising a step of:
- Another aspect of the present invention is to provide an improved process for the preparation of Lacosamide comprising a step of:
- Fig. I shows the X-ray powder diffraction pattern of crystalline Form I prepared by prior art process.
- Fig. II shows the X-ray powder diffraction pattern of crystalline Form I of Lacosamide obtained by the present invention.
- the present embodiment provides an improved process for the preparation of Lacosamide comprising steps of:
- Another embodiment of the present invention is to provide an improved process for the preparation of Lacosamide comprising a step of:
- 'treating' refers to suspending, dissolving or mixing and contacting or reacting of product with solvent or reagents followed by isolating product by removal of reagents and solvents.
- Suitable phase transfer catalysts are tetraethylammonium p- toluenesulfonate, tetrapropylammonium trifluoromethanesulfonate, tetraphenylphosphonium hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenylphosponium chloride, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltriphenylphosphonium chloride, benzytributylammonium chloride, butyltriethylammonium bromide, butyltriphenylphosphonium bromide, cetyltri methyl ammonium bromide, cetyltri methyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammoni
- Suitable methylation agents are e.g. dimethyl sulphate, trimethyl phosphate or methyl iodide with dimethyl sulphate being particularly preferred.
- Base is selected from the group comprising like alkali or alkaline earth metal hydroxide, alkali or alkaline carbonate, alkali or alkaline bicarbonate, organolithium, organomagnesium compounds, organic base and the like or mixtures thereof.
- Alkali or alkaline earth metal hydroxide, alkali or alkaline carbonate, alkali or alkaline bicarbonate used herein above are selected from NaOH, KOH, LiOH, NaHCO 3 , KHCO 3 , LiHCO 3 , Na 2 CO 3 , K 2 CO 3 , Li 2 CO 3 , Mg(OH) 2 , Ca(OH) 2 , CaCO 3 , MgCO 3 , Ba(OH) 2 , Be(OH) 2 , BaCO 3 , SrCO 3 , (CH 3 ) 3 COK and the like or mixtures thereof.
- Organolithium used herein above are selected from n-BuLi, sec-BuLi, t-BuLi, MeLi, PhLi.
- Organomagnesium used herein above are selected from phenylmagnesium bromide, ethylmagnesium bromide.
- Organic base used herein above are selected from nitrogen containing base such as pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
- Suitable solvent is selected from a group comprising ketones, nitriles, acetates, aromatic hydrocarbons, alcohol, ether, alkanes and the like or mixtures thereof.
- Ketones used herein above are selected from methyl ethyl ketone, acetone, methyl isobutyl ketone, 3-heptanone.
- Acetates used herein above are selected from isopropyl acetate, ethyl acetate, methyl acetate, n-butyl acetate, t-butyl acetate.
- Nitriles used herein above are selected from acetonitrile, benzonitrile.
- Aromatic hydrocarbons used herein above are selected from toluene, xylene.
- Alcohols used herein above are selected from C1-C4 linear or nonlinear.
- Ethers used herein above are selected from diethyl ether, dimethyl ether, THF & dioxane.
- Alkanes used herein above are selected form any of the C1-C10 compounds.
- the XRD's characterizing of the lacosamide polymorphs as described herein were obtained using the X-pert-PRO RDAD-1044.
- Reaction mass of Stage II 190 g
- toluene 950 ml
- NaOH 71 g in 380ml of process water
- tetrabutyl ammonium bromide 35.36 g
- dimethyl sulfate (162.8 g) was added at 2 ⁇ 3°C followed by stirring for 5-10 min. at 2 ⁇ 3°C.
- Raised the temperature of reaction mass to 27 ⁇ 3°C and then it was stirred for 90 min. at the same temperature. The layers were separated. The organic layer was collected.
- Step II reaction mass (145 gm), dichloromethane (725 ml) and HCl (217.5 ml) were added at 27 ⁇ 3°C and stirred the reaction mass for 80-90 min. at 27 ⁇ 3°C.
- DM water was added 27 ⁇ 3°C and stirred for 5-10 min. at 27 ⁇ 3°C.
- the layers were separated. The organic layer was collected. The organic layer was washed with 10% v/v HCl solution (29ml con HCl make 290 ml using DM water), stirred at 27 ⁇ 3°C for 5-10 min and allowed to settle.
- the combined aqueous layer was cooled to 0-5°C. Adjust pH 9-10 using 20%w/v Sodium hydroxide solution at 0-15°C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to an improved process for the preparation of Lacosamide having formula (I).
Description
The present invention relates to an improved process
for the preparation of Lacosamide having formula (I).
Lacosamide (R)-2-acetamido-N-benzyl-3
methoxypropionamide , has the following formula:
It is a drug that has been used in the treatment of
epilepsy. Lacosamide is marketed under the trade name Vimpat(R) by UCB. It was
approved by the FDA as an adjunctive therapy for partial-onset seizures in
October 2008.
U.S. Patent No. 5,654,301 discloses certain compounds
which are amino acid derivatives and includes lacosamide. Various synthetic
schemes for the preparation of these derivatives are disclosed.
Lacosamide and its methods of preparation are
disclosed in U.S. Reissue Patent No. RE 38,551. The patent provides three
general methods for the preparation of lacosamide. The first two methods do not
involve the protection of active groups in intermediate compounds (such as
amino, hydroxy and carboxylic acid groups). The other method disclosed in this
patent involves protection of an amino group present in D-serine with
carbobenzoxy chloride (Cbz-Cl), subsequent O-methylation at the hydroxy group
followed by amidation at carboxylic (-COOH) acid with benzylamine and finally
removal of the 'Cbz' group followed by acetylation, to produce lacosamide.
An alternative method for the preparation of
lacosamide is disclosed in International (PCT) Publication No. WO 2006/037574
that involves O-methylation of N- Boc-protected-D-serine ('Boc' refers to
t-butoxycarbonyl) directly in one step by avoiding simultaneous formation of
the methyl ester moiety.
US 20090143472 disclose certain intermediates and
methods of preparation of lacosamide using the intermediates. The process of
preparation of lacosamide involves O- methylation of the intermediate, benzyl
amine amidation, detritylation and finally acetylation to yield lacosamide.
Another method disclosed involves first benzyl amine amidation of the
intermediate, and then O-methylation, subsequently followed by detritylation
and finally acetylation.
WO2010052011 discloses the resolution of
2-acetamido-N-benzyl-3- methoxypropionamide using chiral chromatography.
In view of the preparation methods available for
lacosamide, there is a need for simple and cost effective processes for the
preparation of lacosamide that provides improved efficiency per reaction volume
in terms of yield and purity, including both chemically and chirally.
It is therefore an object of the present invention is
to provide an improved process for the preparation Lacosamide.
Another object of the present invention is to provide
an improved process for the preparation of Lacosamide which is operationally
simple, easy to handle and applicable at an industrial scale.
Yet another object of the present invention is to
provide process for the preparation of Lacosamide comprising steps of:
- condensing N-Boc-D-serine with benzyl amine to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide
- treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide with phase transfer catalyst in presence of base & methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide
- deprotecting (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide in presence of conc. HCl & MDC to obtain (R)-2- amino-N-benzyl-3- methoxypropionamide
- treating (R)-2- amino-N-benzyl-3- methoxypropionamide with acetic anhydride in presence of MDC to obtain crude Lacosamide
- treating crude Lacosamide in presence of solvent to obtain pure Lacosamide
Another object of the present invention is to provide
an improved process for the preparation of Lacosamide comprising a step of:
treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3-
hydroxypropionamide with phase transfer catalyst in presence of base &
methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3-
methoxypropionamide.
In the present aspect of the invention, it provides an
improved process for the preparation of Lacosamide comprising steps of:
- condensing N-Boc-D-serine with benzyl amine to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide;
- treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide with phase transfer catalyst in presence of base & methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide;
- deprotecting (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide in presence of conc. HCl & MDC to obtain (R)-2- amino-N-benzyl-3- methoxypropionamide;
- treating (R)-2- amino-N-benzyl-3- methoxypropionamide with acetic anhydride in presence of MDC to obtain crude Lacosamide;
- treating crude Lacosamide in presence of solvent to obtain pure Lacosamide.
Another aspect of the present invention is to provide
an improved process for the preparation of Lacosamide comprising a step of:
treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3-
hydroxypropionamide with phase transfer catalyst in presence of base &
methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3-
methoxypropionamide.
Fig. I shows the X-ray powder diffraction pattern of
crystalline Form I prepared by prior art process.
Fig. II shows the X-ray powder diffraction pattern of
crystalline Form I of Lacosamide obtained by the present invention.
The present embodiment provides an improved process
for the preparation of Lacosamide comprising steps of:
- condensing N-Boc-D-serine with benzyl amine to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide;
- treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide with phase transfer catalyst in presence of base & methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide;
- deprotecting (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide in presence of conc. HCl & MDC to obtain (R)-2- amino-N-benzyl-3- methoxypropionamide;
- treating (R)-2- amino-N-benzyl-3- methoxypropionamide with acetic anhydride in presence of MDC to obtain crude Lacosamide;
- treating crude Lacosamide in presence of solvent to obtain pure Lacosamide.
Another embodiment of the present invention is to
provide an improved process for the preparation of Lacosamide comprising a step
of:
treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3-
hydroxypropionamide with phase transfer catalyst in presence of base &
methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3-
methoxypropionamide.
The term 'treating' as used hereinabove refers to
suspending, dissolving or mixing and contacting or reacting of product with
solvent or reagents followed by isolating product by removal of reagents and
solvents.
Suitable phase transfer catalysts are
tetraethylammonium p- toluenesulfonate, tetrapropylammonium
trifluoromethanesulfonate, tetraphenylphosphonium hexafluoroantimonate,
cetylpyridinium bromide, triphenylmethyl triphenylphosponium chloride,
benzyltriethylammonium chloride, benzyltrimethylammonium chloride,
benzyltriphenylphosphonium chloride, benzytributylammonium chloride,
butyltriethylammonium bromide, butyltriphenylphosphonium bromide, cetyltri
methyl ammonium bromide, cetyltri methyl ammonium chloride,
ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide,
methyltrioctylammonium bromide, methyltriphenylphosphonium bromide,
methyltriphenylphosphonium iodide, phenyltrimethylammonium chloride,
tetrabutylammonium hydroxide, tetrabutylammonium perchlorate,
tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate,
tetrabutylammonium iodide, tetrabutylammonium tetrafluoroborate,
tetrabutylammonium thiocyanate, tetraethylammonium hydroxide,
tetraethylammonium iodide, tetraethylammonium bromide, tetramethylammonium
chloride, tetramethylammonium iodide, tetramethylammonium chloride,
tetraoctylammonium bromide, tetraphenylphosphonium bromide, tetrapropylammonium
hydroxide, tetrapropylammonium bromide and tributylmethylammonium chloride,
wherein tetrabutylammonium salts and particularly tetrabutylammonium halides,
e.g. the bromide are especially preferred.
Suitable methylation agents are e.g. dimethyl
sulphate, trimethyl phosphate or methyl iodide with dimethyl sulphate being
particularly preferred.
Base is selected from the group comprising like
alkali or alkaline earth metal hydroxide, alkali or alkaline carbonate, alkali
or alkaline bicarbonate, organolithium, organomagnesium compounds, organic base
and the like or mixtures thereof. Alkali or alkaline earth metal hydroxide,
alkali or alkaline carbonate, alkali or alkaline bicarbonate used herein above
are selected from NaOH, KOH, LiOH, NaHCO3, KHCO3,
LiHCO3, Na2CO3, K2CO3,
Li2CO3, Mg(OH)2, Ca(OH)2,
CaCO3, MgCO3, Ba(OH)2, Be(OH)2,
BaCO3, SrCO3, (CH3)3COK and the
like or mixtures thereof. Organolithium used herein above are selected from
n-BuLi, sec-BuLi, t-BuLi, MeLi, PhLi. Organomagnesium used herein above are
selected from phenylmagnesium bromide, ethylmagnesium bromide. Organic base
used herein above are selected from nitrogen containing base such as pyridine,
piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine,
triethyl amine and the like or mixtures thereof.
Suitable solvent is selected from a group comprising
ketones, nitriles, acetates, aromatic hydrocarbons, alcohol, ether, alkanes and
the like or mixtures thereof. Ketones used herein above are selected from
methyl ethyl ketone, acetone, methyl isobutyl ketone, 3-heptanone. Acetates
used herein above are selected from isopropyl acetate, ethyl acetate, methyl
acetate, n-butyl acetate, t-butyl acetate. Nitriles used herein above are
selected from acetonitrile, benzonitrile. Aromatic hydrocarbons used herein
above are selected from toluene, xylene. Alcohols used herein above are
selected from C1-C4 linear or nonlinear. Ethers used herein above are selected
from diethyl ether, dimethyl ether, THF & dioxane. Alkanes used herein
above are selected form any of the C1-C10 compounds.
The general reaction scheme is as follow:
It is an applicants observation that when Lacosamide
is prepared according to WO2006037574A1 (Example 4) it produces crystalline
Form I. This Form I is characterized by XRD reflections (peak) at about 6.8,
8.5, 10.7, 13.3, 15.8, 16.9, 17.8, 21.7, 25.2, 25.6 & 27.3 ±0.2 degrees 2θ.
In summary Form I is resulted by preparing the prior art process as disclosed
in WO2006037574A1 (Example 4).
Applicants has also obtained the same crystalline
form I of Lacosamide by following the present improved process of Lacosamide.
This form I is characterized by XRD reflections (peaks) at about 6.6, 8.4,
10.5, 13.1, 15.7, 16.7, 17.7, 21.5, 25.1, 25.4 & 27.3 ±0.2 degrees 2θ.
The XRD's characterizing of the lacosamide polymorphs
as described herein were obtained using the X-pert-PRO RDAD-1044.
In the following section, aspects are described by
way of examples to illustrate the process of the invention & product
thereof. However, the examples mentioned below are not intended in any way to
limit the scope of the present invention. Several variants of these examples
would be evident to persons ordinarily skilled in the art.
Process for the preparation of
Lacosamide
Step-1 Preparation of (R)-N-benzyl-2((t-butoxy)
carbonyl amino)-3- hydroxypropionamide
Charged the N-Boc-D-serine (200 gm) with MDC (600ml)
followed by cooling the reaction mass at R.T. Add N-methyl morpholine (108.44
g) at-35±5°C in the obtained reaction mass followed by addition of methyl
chloroformate (101.31 g) at-35±5°C.in minimum 25-30min. Stirred the reaction
mass for approximate 30 min. Add prechilled solution of benzyl amine in MDC
(5-10°C) in to the obtained reaction mass in minimum 25-30min at R.T. Stirred
the reaction mass for 25-30 min followed by addition of process water (600 ml)
at 27±3°C and layers formed were separated. The organic layer was washed with
de-ionized water. Layers were separated and solvent was recovered from the
organic layer to obtain crude material. Charged cyclohexane (1400 ml) at below
60°C. Cool the reaction mass at R.T followed by stirring the reaction mass for
2-3 hrs at same temperature. Filter the solid and wash it with cyclohexane (200
ml) at 27±3°C. Drying under vacuum at 47±3°C gave title compound.
Step-2 Preparation of tert-butyl
[(2R)-1-(benzylamino)-3-methoxy-1-oxopropan-2-
yl] carbamate
Reaction mass of Stage II (190 g), toluene (950 ml),
NaOH (71 g in 380ml of process water) (~415ml) and tetrabutyl ammonium bromide
(35.36 g) were added at 27±3°C. Cooled the reaction mass to 2±3°C and the
solution was stirred for 5-10 min. at 2±3°C and dimethyl sulfate (162.8 g) was
added at 2±3°C followed by stirring for 5-10 min. at 2±3°C. Raised the
temperature of reaction mass to 27±3°C and then it was stirred for 90 min. at
the same temperature. The layers were separated. The organic layer was
collected. The aqueous layer was extracted with toluene (190 ml), stirred and
allowed to settle. The combined organic layers were washed with 5% w/v sodium
bicarbonate solution (47.5 g in 950 ml). The organic layer was collected and
distilled out toluene completely under vacuum at below 56°C to obtained
residue. Cyclohexane (190 ml) was added to residue at below 56°C and distilled
out cyclohexane completely under vacuum at below 56°C. Degas the residue for
1-2 hr under vacuum (720 mm/Hg) at below 56°C. Cyclohexane (380 ml) was added
to residue at below 56°C. Cooled the reaction mass to 27±3°C and then it was
stirred for 2-3 hr. at the same temperature. Solid was filtered and washed with
cyclohexane (190 ml) at 27±3°C. The solid was dried under vacuum at 47±3°C.
Step-3 Preparation of
(2R)-2-amino-N-benzyl-3-methoxypropanamide
Step II reaction mass (145 gm), dichloromethane (725
ml) and HCl (217.5 ml) were added at 27±3°C and stirred the reaction mass for
80-90 min. at 27±3°C. DM water was added 27±3°C and stirred for 5-10 min. at
27±3°C. The layers were separated. The organic layer was collected. The organic
layer was washed with 10% v/v HCl solution (29ml con HCl make 290 ml using DM
water), stirred at 27±3°C for 5-10 min and allowed to settle. The combined
aqueous layer was cooled to 0-5°C. Adjust pH 9-10 using 20%w/v Sodium hydroxide
solution at 0-15°C. Dichloromethane (725 ml) was added at 10-25°C and stirred
for 5-10 min. at 27±3°C. The layers were separated. The organic layer was
collected. The aqueous layer was extracted with dichloromethane (2×290 ml),
stirred at 27±3°C and allowed to settle and layers were separated. Combined
organic layers and sodium chloride solution (65.25g in 435ml DM water) was
added at 27±3°C and stirred for 10-15 min. at 27±3°C. The layers were
separated. The organic layer (Product is in organic layer) was collected.
Step-4 Preparation of
(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide (crystalline Form I)
To the organic layer (dichloromethane layer)
obtained as above, acetic anhydride (57.55 g) was added at 27±3°C and stirred
for 30 min. at 27±3°C. DM water (290 ml) was added 27±3°C and stirred for 5-10
min. at same temperature. The layers were separated. The organic layer was
collected. The organic layer was washed with 5% w/v sodium bicarbonate solution
(14.5g in 290 ml DM water), stirred at 27±3°C and allowed to settle. The
organic layer was collected. The organic layer was washed with DM water,
stirred at 27±3°C and allowed to settle. The organic layer was collected.
Activated carbon was added 27±3°C and stirred for 30 min. at 27±3°C. Filtered
the reaction mass through hyflow bed and washed the bed with dichloromethane
(145 ml). Filtrate was collected. Distilled out dichloromethane at below 50°C
atmospherically, Isopropyl alcohol was added at 47±3°C and stirred for 5-10
min. Distilled out Isopropyl alcohol under vacuum at 47±3°C. Isopropyl alcohol
(290 ml) was added at 47±3°C and the reaction was heated at 81±3°C followed by
addition of n-heptane (1450 ml) at same temperature. Stir the reaction mass for
15-20 min. at the same temperature. Cooled the reaction mass to 40±3°C and
stirred for 8 hr. at the same temperature. Cooled the reaction mass to 3±3°C
and stirred for 30 min. at the same temperature. Solid was filtered at 3±3°C
and washed with n-heptane (145 ml) at 27±3°C. The solid was dried in vaccum at
42±3°C for 6-8 hr.
Claims (2)
- An improved process for the preparation of Lacosamide comprising steps of :i) condensing N-Boc-D-serine with benzyl amine to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide;ii) treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide with TBAB as a phase transfer catalyst in presence of NaOH & DMS as a methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide;iii) deprotecting (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide in presence of conc. HCl & MDC to obtain (R)-2- amino-N-benzyl-3- methoxypropionamide;iv) treating (R)-2- amino-N-benzyl-3- methoxypropionamide with acetic anhydride in presence of MDC to obtain crude Lacosamide;v) treating crude Lacosamide in presence of mix. of isopropyl alcohol and n-heptane to obtain pure Lacosamide.
- An improved process for the preparation of Lacosamide comprising a step of :treating (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- hydroxypropionamide with TBAB as a phase transfer catalyst in presence of NaOH & DMS as a methylating agent to obtain (R)-N-benzyl-2((t-butoxy) carbonyl amino)-3- methoxypropionamide.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN2293/MUM/2011 | 2011-08-12 | ||
IN2293MU2011 | 2011-08-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013024383A1 true WO2013024383A1 (en) | 2013-02-21 |
Family
ID=47714821
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2012/053875 WO2013024383A1 (en) | 2011-08-12 | 2012-07-30 | An improved process for the preparation of lacosamide |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2013024383A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104326944A (en) * | 2014-11-04 | 2015-02-04 | 崇州合瑞科技有限公司 | Method for preparing Boc-L-threonine |
WO2016030911A3 (en) * | 2014-08-28 | 2016-04-21 | RAO, Davuluri Ramamohan | Improved process for the preparation of lacosamide and its novel intermediate |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101591300A (en) * | 2009-02-19 | 2009-12-02 | 成都伊诺达博医药科技有限公司 | The novel method of synthesizing lacosamide |
CN101928230A (en) * | 2004-10-02 | 2010-12-29 | Ucb医药有限公司 | The synthetic method of improved scheme for lacosamide |
US20110034731A1 (en) * | 2009-08-06 | 2011-02-10 | Medichem, S.A. | Solid Forms Of An N-(Phenylmethyl)Propanamide Derivative And Processes Of Preparation |
CN102020589A (en) * | 2009-09-19 | 2011-04-20 | 浙江九洲药业股份有限公司 | Tert-butyl carbamate derivative and preparation method and application thereof |
EP2399901A1 (en) * | 2010-06-23 | 2011-12-28 | Archimica GmbH | Intermediate for producing lacosamide and a process for its preparation and conversion to lacosamide |
WO2012001710A1 (en) * | 2010-07-02 | 2012-01-05 | Sun Pharmaceutical Industries Ltd | An improved process for the preparation of lacosamide |
-
2012
- 2012-07-30 WO PCT/IB2012/053875 patent/WO2013024383A1/en active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101928230A (en) * | 2004-10-02 | 2010-12-29 | Ucb医药有限公司 | The synthetic method of improved scheme for lacosamide |
CN101591300A (en) * | 2009-02-19 | 2009-12-02 | 成都伊诺达博医药科技有限公司 | The novel method of synthesizing lacosamide |
US20110034731A1 (en) * | 2009-08-06 | 2011-02-10 | Medichem, S.A. | Solid Forms Of An N-(Phenylmethyl)Propanamide Derivative And Processes Of Preparation |
CN102020589A (en) * | 2009-09-19 | 2011-04-20 | 浙江九洲药业股份有限公司 | Tert-butyl carbamate derivative and preparation method and application thereof |
EP2399901A1 (en) * | 2010-06-23 | 2011-12-28 | Archimica GmbH | Intermediate for producing lacosamide and a process for its preparation and conversion to lacosamide |
WO2012001710A1 (en) * | 2010-07-02 | 2012-01-05 | Sun Pharmaceutical Industries Ltd | An improved process for the preparation of lacosamide |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016030911A3 (en) * | 2014-08-28 | 2016-04-21 | RAO, Davuluri Ramamohan | Improved process for the preparation of lacosamide and its novel intermediate |
AU2015308035B2 (en) * | 2014-08-28 | 2019-04-04 | RAO, Davuluri Ramamohan | Improved process for the preparation of Lacosamide and its novel intermediate |
CN104326944A (en) * | 2014-11-04 | 2015-02-04 | 崇州合瑞科技有限公司 | Method for preparing Boc-L-threonine |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2019043724A1 (en) | Processes for the preparation of (s)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid and polymorphs thereof | |
US20030216593A1 (en) | Method of preparing salicylamides | |
CN107382997A (en) | For preparing the method and intermediate of drug agents | |
US20130041180A1 (en) | Process for preparing (r)-2-acetamido-n-benzyl-3-methoxy-propionamide | |
WO2016024284A2 (en) | A process for the preparation of mirabegron and its intermediates | |
US8598386B2 (en) | Process for producing lacosamide | |
WO2013024383A1 (en) | An improved process for the preparation of lacosamide | |
US20210163410A1 (en) | An improved process for the preparation of (2s)-2-[(4r)-2-oxo-4-propyltetrahydro-1h-pyrrol-1-yl] butanamide and its intermediates thereof | |
JPWO2002032853A1 (en) | Method for producing acylphenylalanine | |
EP2970195A2 (en) | Novel processes for producing sovaprevir | |
KR102255357B1 (en) | A process for the preparation of 2-amino-1,3-propane diol compounds and salts thereof | |
WO2012117410A1 (en) | A process for the preparation of n-[2-[(acetylthio) methyl]-1-oxo-3-phenylpropyl] glycine phenyl methyl ester and intermediates thereof | |
WO2014145507A1 (en) | A process for making a 4-amino-4-oxobutanoyl peptide cyclic analogue, an inhibitor of viral replication, and intermediates thereof | |
US20110319649A1 (en) | Intermediate for producing lacosamide and a process for its preparation and conversion to lacosamide | |
EP2448916B1 (en) | Production of trans-4-aminocyclopent-2-ene-1-carboxylic acid derivatives | |
US9416105B2 (en) | Process for preparation of saxagliptin and its hydrochloride salt | |
WO2014083575A2 (en) | Improved process for the preparation of boceprevir intermediate | |
CN111247127B (en) | Process for the production of intermediate compounds for the synthesis of medicaments | |
KR20190127681A (en) | Improved Preparation of Boric Acid Ester | |
US8664443B2 (en) | Process for the preparation of (1S, 3S, 5S)-2-[2(S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile | |
US9067868B2 (en) | Chemical process for opening ring compounds | |
Rajan et al. | Process for the preparation of (S)-2-(2-(benzofuran-6-carbonyl)-5, 7-dichloro-1, 2, 3, 4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl) phenyl) propanoic acid and polymorphs thereof | |
US20240262805A1 (en) | Method for producing compound or pharmaceutically acceptable salt thereof | |
US7122696B2 (en) | Processes for preparation of N-protected-β-amino alcohols and N-protected-β-amino epoxides | |
EP3330260A1 (en) | Process for the preparation of an intermediate for the synthesis of i.a. carfilzomib |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12823289 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 12823289 Country of ref document: EP Kind code of ref document: A1 |