Description:DESCRIPTION

A CONTINUOUS PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE 2-AMINO BUTYRAMIDE AND ITS SALTS

FIELD OF INVENTION
The present invention relates to a continuous process for production of optically active 2-aminobutyramide and its salts.

BACKGROUND OF INVENTION
Optically active 2-aminobutyramide, particularly (S)-2-aminobutyramide (V) or its hydrochloride salt (VI) is a key intermediate (see Scheme 1) in the synthesis of pharmaceutical drug molecule, Levetiracetam (A), which is a known anticonvulsant and used in the field of treating epilepsy.

V VI

Scheme 1

Levetiracetam (A)
The growing demand (said to be ~6% annually) for Levetiracetam may be met by efficient manufacturing in terms of low cost and quick turnaround time to enable ready availability of the drug molecule and its intermediates particularly, (S)-2-aminobutyramide (V). Though the literature is replete with various routes of synthesis for V through batch processing, a continuous process for conversion of V or VI appears not known. The present disclosure aims at providing a continuous process for the synthesis of V or VI.
The preparation of the intermediate V or VI from (S)-2-amino butyric acid, I, (also known as (L-amino butyric acid) has been known and a review of processes which are all done in batch mode is presented below. The well-known route for synthesis of V or its salt VI is presented in Scheme 2. The route typically has two steps, the first step being an esterification step and the second step being an amidation step. The starting material for the first step is I or its hydrochloride salt.
The first step of esterification is carried out with thionyl chloride and methanol. Thionyl chloride is an esterification agent. Methanol is both solvent and reactant.
The subsequent amidation reaction using ammonia as presented in Scheme 2 has been adopted by many players.

-Patent publication, CN101130504A discloses a procedure for effecting an esterification and an amidation in batch mode as given in Scheme 2. The time of esterification of (S)-aminobutyric acid was 3h at methanol reflux condition. The amidation of the ester was conducted with aqueous ammonia for a lengthy period of 24 h.

-Patent publication, JP2002253294 discloses the esterification of racemic form of 1 with sulfuric acid as the catalyst and amidation using methanolic ammonia followed by enzyme catalyzed stereoselective hydrolysis of (R)-amino acid amide, leaving behind the (S) isomer. The reaction details such as time of esterification or amidation are not present in this reference.
-In the journal publication, Organic & Biomolecular Chem., 17(6), 1552-1557; 2019, data on the reaction times for both esterification and amidation were not found. For the amidation step, methanolic ammonia was the reagent.
-Patent publication, CN105646265A discloses esterification of aminobutyric acid in the presence of chiral acids to obtain optical active ester isomer, followed by a) hydrolysis to produce the optically active aminobutyric acid isomer, b) conversion of the acid into acid chloride and c) amidation of the optically active (S) isomer of acid chloride to prepare compound V. For the amidation of acid chloride, methanolic ammonia was used. The reaction time for the amidation was not found in the reference.
-The journal publication, Journal of Labelled Compounds and Radiopharmaceuticals 55(1), 48-51, 2012 carries the procedure for both esterification using thionyl chloride in methanol solvent and amidation using methanolic ammonia. The reaction times were not found in the reference.
-Patent publication, CN101624362A discloses esterification of (S)-2-aminobutyric acid I, using thionyl chloride and methanol solvent with reaction time of 5h at room temperature and amidation using methanolic ammonia with reaction time of 18h at room temperature.
- Patent publication CN105646265A discloses esterification of (S)-2-aminobutyric acid I, using thionyl chloride and methanol solvent with reaction time of 4h at 80 deg C and amidation using methanolic ammonia with reaction time 8h at 50 deg C at a pressure of 0.4-0.5MPa.
- Patent publication, CN110698379A discloses esterification of (S)-2-aminobutyric acid I, using thionyl chloride and methanol solvent with reaction time of 4h at 40 deg C and amidation using aqueous ammonia with a total reaction time of 9 h including 4h at 0 deg C and 5h at 20 deg C. It further discloses preparation of hydrochloride salt of V using HCl in methanol.
- Patent publication, IN20009CH00267 discloses esterification of (S)-2-aminobutyric acid I, using thionyl chloride and methanol solvent with reaction time of 4h at 40 deg C and amidation using methanolic ammonia at 40-45 deg C with a reaction time of 32h. It further discloses preparation of hydrochloride salt of V using HCl in methanol.
-In a journal publication, Indian Journal of Chemistry, Section B: Organic Chemistry including Medicinal Chemistry, 533(9), 1218-1221, 2014, the esterification of (S)-2-aminobutyric acid, I, using thionyl chloride and methanol at 40-45 deg C with a reaction time of 4h and amidation to form (S)-2-aminobutyramide using methanolic ammonia for 24h, at 50 deg C, and at a pressure of 50-55 psi are disclosed.
-Patent publication, CN104030942 discloses esterification of (S)-2-aminobutyric acid I, using the reagent, 2,2-dimethoxypropane at room temperature for 18h followed by amidation for 24h, in ethanol, at 70-80 deg C and a pressure of 5 atm. It further discloses preparation of hydrochloride salt of V with HCl and methanol.
-Patent publication, US20050182262A1 discloses esterification of (S)-2-aminobutyric acid, I, using thionyl chloride and methanol followed by amidation using ammonia/isopropanol under pressure. Reaction times have not been disclosed in this prior art.
-Patent publication, CN109134341 discloses esterification of (S)-2-aminobutyric acid, I, using thionyl chloride and methanol with a total esterification reaction time of 3h including 1h at 25 deg C and 2h at 40 deg C followed by amidation using aqueous ammonia at 5 deg C with a reaction time of 36h.
-Patent publication, CN103045667 discloses esterification of (S)-2-aminobutyric acid, I, using thionyl chloride and methanol with a total esterification reaction time of 18h including 3h at 40 deg C and 15h at 20 deg C, followed by amidation with aqueous ammonia with a reaction time of 18h.
-Patent publication, WO2010019469 discloses esterification of (S)-2-aminobutyric acid, I, using thionyl chloride and methanol at 55 deg C overnight, followed by amidation with aqueous ammonia with a reaction of time of 18h.
Thionyl chloride/methanol system for esterification is the most preferred route from literature reports. All the cited prior art references are concerned with reactions conducted in batch mode and they report reaction times of esterification ranging from 3h to 18 h, and reaction times of amidation ranging from 4h to 36 h. For the amidation reaction, aqueous ammonia or methanolic ammonia have been the reagents of choice by many players as seen in the prior art references above. There is a need to decrease the reaction times for both esterification and amidation steps and make the process for (S)-2-aminobutyramide, V a continuous process to meet the increasing demand of Levetiracetam or its intermediate V or VI. The inventors of the present invention have addressed these challenges innovatively in the present disclosure and have provided a new process as disclosed below.
SUMMARY OF THE INVENTION
The present invention discloses an integrated continuous process for optically active 2-Amino butyramide, V and its hydrochloride salt, VI. It comprises a continuous esterification step (A), a continuous amidation step (B), step (C) for continuous separation of ammonium chloride and step (D) for continuous formation of hydrochloride salt of 2-amino butyramide.
The step (A) comprises
(a.i) continuously pumping a slurry of an optically active 2-amino butyric acid, I suspended in a monohydric solvent-A and an esterification agent into a reactor-A which is provided with a heat exchanger
(a.ii) allowing the slurry to react for a residence period of at least 15 min and not exceeding 2 h, at a reaction temperature ranging from 40 to 55 deg C under a pressure of 1-10 bar
(a.iii) continuously pumping the contents of the reactor-A into a second continuous flow reactor -B kept at a temperature ≤ 60 deg C and
(a.iv) continuously sending the contents of the second reactor to a continuous evaporator to recover the solvent and strip dissolved gases such as HCl and SO2 to form an ester. hydrochloride solution II;
the step (B) comprises:
(b.i) continuously pumping the ester.hydrochloride solution II and aqueous ammonia reagent into a tubular reactor-C equipped with efficient inter phase mixing to form a reaction mixture, III.
(b.ii) maintaining the reactor-C at 45-55 deg C for a residence time of at least 20 min and not exceeding 60 min under a pressure of 2 to 10 bar
(b.iii) continuously collecting the reaction mixture III in a collection vessel
(b.iv) continuously removing unreacted ammonia from the mixture in the collection vessel in a degassing unit and
(b.v) continuously removing the solvent and water by evaporation in a continuous evaporator-drier to provide mixture IV;
the step (C) comprises:
(c.i) continuously making a slurry VII from the mixture IV with a monohydric solvent-B selected from a group consisting of isopropyl alcohol, butyl alcohol, isobutyl alcohol, amyl alcohol and a combination thereof.
(c.ii) continuously removing the residual water from the slurry, VII as an azeotrope to obtain a slurry VIII
(c.iii) continuously rendering the slurry VIII ammoniacal by passing ammonia gas
(c.iv) continuously filtering off ammonium chloride to provide a filtrate containing an ammoniacal solution of the amide, V
(c.v) continuously evaporating the solvent or solvents present in the solution of the amide, V in suitable continuous evaporator to provide a wet cake of the amide, V and
(c.vi) continuously drying the wet cake of the amide, V to provide a dry powder of the amide, V and
the step (D) comprises:
(d.i) continuously reacting the dry powder of the amide, V with a solution of HCl dissolved in solvent-C selected from a group consisting of methanol, isopropyl alcohol, and a combination thereof for 30 min to 90 min to precipitate the salt, VI
(d.ii) continuously collecting the salt, VI by filtration followed by drying and
(d.iii) continuously recovering and recycling the solvents.

The amide product is an optically active amide viz., an (S) isomer or (R) isomer. The monohydric solvent for esterification is selected from a group consisting of methanol, ethanol, propanol, isopropyl alcohol (IPA), n-butanol, isobutanol and a combination thereof. The esterification agent is selected from a group consisting of thionyl chloride, sulfuryl chloride, acetyl chloride, trimethyl silyl chloride, sodium bisulphate, hydrogen chloride, sulfuric acid, an ion-exchange resin, and a combination thereof. The reactors A, B and C are single reactors or series of multiple reactors. They are selected from a group consisting of continuous stirred tank reactors (CSTRs) and tubular reactors (TRs). The aqueous ammonia reagent is selected from a group consisting of aqueous ammonia liquor saturated with ammonia gas, aqueous ammonia liquor, methanol containing ammonia liquor, aqueous solutions of ammonium formate, ammonium acetate and ammonium carbonate and a combination thereof. The residence time for the esterification ranges from 15 min to 120 min. The residence time for the amidation ranges from 15 min to 90 min.

DETAILED DESCRIPTION OF THE INVENTION
Definitions
Esterification agent: It is a compound or a combination of selected compounds which facilitates the reaction to form esters from a carboxylic acid and an alcohol. Known examples are thionyl chloride, sulfuryl chloride, acetyl chloride, trimethyl silyl chloride, sodium bisulphate, hydrogen chloride, sulfuric acid, an ion-exchange resin, and a combination thereof.
Amidation: It is a reaction between an ester and ammonia or an amine to form an amide.
Salt: In the present invention, the expression “salt” corresponds to the product resulting from a neutralization reaction between a mineral acid such as dry or aqueous hydrochloric acid and a compound containing at least one primary amino group,
Monohydric solvent: An organic solvent which contains one hydroxyl group. Examples include methanol, ethanol, propanol, isopropanol, butanol, isobutyl alcohol and tert-butanol.
Residence time: Average time the molecules of the reaction mixture remain in the reactor or combination of reactors. Typically, during the residence time, the reaction occurs to form the product/s.
Batch reactor: Vessel used for chemical reaction that has no feed or effluent streams. The reactor is well stirred and usually run either isothermally or adiabatically. The main design variable is how much time the reactants are allowed to remain in the reactor to achieve the desired level of conversion.
Integrated continuous process: It is a continuous process wherein there is continuous input of starting materials and reagents and continuous output of the product or product mixture in the process. An Integrated continuous process integrates one or more continuous process steps to make the desired product.
Continuous stirred tank reactor (CSTR): Sometimes called a continuous-flow stirred-tank reactor, with continuous input and output of material. The outlet concentration is assumed to be the same as the concentration at any point in the reactor.
Tubular reactor: It consists of a long pipe or tube. Optionally, mixing elements are provided in the tube to cause interphase mixing and turbulence. The tubular reactors are also jacketed to provide heat transfer ability to/from an external fluid to maintain the process side fluid in the desired temperature range for the reaction. The reacting mixture moves down the tube resulting in a change in concentration down the length of the reactor.
Conversion: Fraction or percentage that describes the extent of a chemical reaction. Conversion is calculated by dividing the number of moles of a reactant that reacted by the initial moles of reactant. Conversion is defined only in terms of a limiting reactant.
Yield: Expressed as a percentage, it is the ratio of moles of a desired product to moles of a limiting reactant used.
(L)-ABA: The abbreviation ABA stands for 2-aminobutyric acid. (L)-ABA is interchangeably used to mean (S)-2-aminobutyric acid.
SABAM: This abbreviation refers to (S)-2-aminobutyramide, V
SABAM.HCl: This abbreviation refers to the HCl salt, VI
Optically Active: The expression, ‘optically active’ refers to the optically active (R) or (S) isomers of chiral compounds in this disclosure.
Productivity: In this disclosure, productivity means the ability to make a product at a high quality and quick speed.
Ester.HCl: It refers to the hydrochloride salt of the ester, alkyl (S)-2-aminobutyrate. It is also expressed as ester.hydrochloride or ester.HCl or ester.Hydrochloride. The preferred alkyl group is methyl.

The present invention discloses an integrated continuous process for optically active 2-Amino butyramide, V and its hydrochloride salt, VI.

V VI
It comprises a continuous esterification step (A), a continuous amidation step (B), step (C) for continuous separation of ammonium chloride and step (D) for continuous formation of hydrochloride salt of 2-amino butyramide.
The continuous esterification step (A) comprises the following sub-steps:
(a.i) continuously pumping a slurry of an optically active 2-amino butyric acid, I suspended in a monohydric solvent-A and an esterification agent into a reactor-A which is provided with a heat exchanger
(a.ii) allowing the slurry to react for a residence period of at least 15 min and not exceeding 2 h, at a reaction temperature ranging from 40 to 55 deg C under a pressure of 1-10 bar
(a.iii) continuously pumping the contents of the reactor-A into a second continuous flow reactor -B kept at a temperature ≤ 60 deg C and
(a.iv) continuously sending the contents of the second reactor to a continuous evaporator to recover the solvent and strip dissolved gases such as HCl and SO2 to form an ester. hydrochloride solution II;
the continuous amidation step (B) comprises the following sub-steps:
(b.i) continuously pumping the ester.hydrochloride solution II and aqueous ammonia reagent into a tubular reactor-C equipped with efficient inter phase mixing to form a reaction mixture, III.
(b.ii) maintaining a reactor-C at 45-55 deg C for a residence time of at least 20 min and not exceeding 60 min under a pressure of 2 to 10 bar
(b.iii) continuously collecting the reaction mixture III in a collection vessel
(b.iv) continuously removing unreacted ammonia from the mixture in the collection vessel in a degassing unit and
(b.v) continuously removing the solvent and water by evaporation in a continuous evaporator-drier to provide mixture IV;
the step (C) comprises the following sub-steps:
(c.i) continuously making a slurry VII from the mixture IV with a monohydric solvent-B selected from a group consisting of isopropyl alcohol, butyl alcohol, isobutyl alcohol, amyl alcohol and a combination thereof.
(c.ii) continuously removing the residual water from the slurry, VII as an azeotrope to obtain a slurry VIII
(c.iii) continuously rendering the slurry VIII ammoniacal by passing ammonia gas
(c.iv) continuously filtering off ammonium chloride to provide a filtrate containing an ammoniacal solution of the amide, V
(c.v) continuously evaporating the solvent or solvents present in the solution of the amide, V in suitable continuous evaporator to provide a wet cake of the amide, V and
(c.vi) continuously drying the wet cake of the amide, V to provide a dry powder of the amide, V and
the step (D) comprises the following sub-steps.
(d.i) continuously reacting the dry powder of the amide, V with a solution of HCl dissolved in solvent-C selected from a group consisting of methanol, isopropyl alcohol, and a combination thereof for 30 min to 90 min to precipitate the salt, VI
(d.ii) continuously collecting the salt, VI by filtration followed by drying and
(d.iii) continuously recovering and recycling the solvents.
.
In an embodiment, the starting material is optically active 2-amino butyric acid, I or its HCl salt.

In another embodiment, the compound I, can be an (S)-isomer of 2-aminobutyric acid.

In yet another embodiment, the compound I, can be an (R)-isomer of 2-aminobutyric acid.

In an embodiment, the amide product is an optically active amide viz., an (S)-isomer or an (R)-isomer.

In an embodiment, the monohydric solvent for esterification is selected from a group consisting of methanol, ethanol, propanol, isopropyl alcohol, n-butanol, isobutanol and a combination thereof.

In a preferred embodiment, the monohydric alcohol for esterification is methanol.

In one embodiment, the esterification agent is selected from a group consisting of thionyl chloride, sulfuryl chloride, acetyl chloride, trimethyl silyl chloride, sodium bisulphate, hydrogen chloride, sulfuric acid, an ion-exchange resin, p-toluene sulfonic acid, methane sulfonic acid, dodecylbenzene sulfonic acid and a combination thereof.

In a preferred embodiment, the esterification agent is thionyl chloride.

In one embodiment, the molar ratio of amounts of carboxylic acid substrate, thionyl chloride and methanol taken for esterification ranges from 1.0 :1.0 :5 to 1.0: 1.5: 10.

In a preferred embodiment, the ratio of amounts of carboxylic acid substrate, thionyl chloride and methanol taken for esterification ranges from 1.0: 1.05: 5 to 1.0: 1.4: 7.

In one embodiment, the pressure in the reactor during esterification ranges from 1.5 to 10 bar.

In a preferred embodiment, the pressure in the reactor during esterification ranges from 2 to 6 bar.

The reactors A, B and C, are single reactors or series of multiple reactors.

In one embodiment, the reactors A, B and C, are continuous stirred reactors (CSTRs).

In another embodiment, the reactors A, B and RC, are tubular reactors (TRs).

In yet another embodiment, the reactors A, B and C, are selected from a combination of continuous stirred tank reactors (CSTRs) and tubular reactors (TRs).

The aqueous ammonia reagent used for amidation is selected from a group consisting of ammonia liquor saturated with ammonia gas, aqueous ammonia liquor, methanol containing ammonia liquor, aqueous solutions of ammonium formate, ammonium acetate and ammonium carbonate and a combination thereof. Ammonia liquor saturated with ammonia gas is prepared by passing ammonia gas into water.

In one embodiment, the amidation reaction is conducted in the presence of ammonia gas at pressure ranging from 2 to 10 bar

In one embodiment, the total residence time for the esterification ranges from 15 min to 120 min.

In a preferred embodiment, the total residence time for the esterification ranges from 30 min to 75 min.

In one embodiment, the total residence time for the amidation ranges from 15 min to 90 min.
In a preferred embodiment, the residence time for the amidation ranges from 30 min to 60 min.

In one embodiment, the amidation is conducted with the ester to ammonia molar ratio ranging from 1:5 to 1:15. In a preferred embodiment, the amidation is carried out with the ester to ammonia molar ratio ranging from 1:5 to 1:12.

In one embodiment, the amidation is conducted in the presence of ammonia gas while maintaining a pressure ranging from 2 to 10 bar. In a preferred embodiment, the amidation is carried out in the presence of ammonia gas at a pressure ranging from 3 to 8 bar.

Esterification
Esterification in a continuous process using flow reactors does not involve long addition time for adding reagents such as thionyl chloride as exothermicity of the reaction is managed by efficient heat removal with external coolant. The esterification reaction can also be conducted at higher temperatures i.e., >45 deg C to enable faster reaction completion.

On the other hand, esterification in a batch process where, L-2-Amino butyric acid is converted to its methyl ester hydrochloride salt, takes 3-4 hrs for slow addition of thionyl chloride at low temperatures, viz., less than 20oC to cope with the exothermicity of the reaction. The batch processes are generally conducted at ambient pressure conditions. If the methyl ester hydrochloride salt thus prepared is subjected to purification procedures, considerable loss in yield and lowered purity are encountered.

This reaction is overly sensitive to temperature as the substrate and the product are chiral molecules and any harsher conditions will lead to racemization to form unwanted isomer and reduces chiral purity of the product.
Amidation
In the second step, the ester·HCl in methanol (ester. Hydrochloride solution II) is reacted under pressure and at temperature of 45 to 55 °C with aqueous ammonia. Optionally additional ammonia gas is added to maintain desired ammonia to ester.HCL mole ratio. Pressure is maintained above 2 bar. Residence time needs to be around 30 to 60 min. The main product is the optically active (2-aminobutanamide), V and by-product is ammonium chloride. The reactor of choice would be Tubular reactor with provision for maintaining reaction temperature within the range through the jacket and efficient multi-phase mixing. The reaction mixture is freed from ammonia in a degassing unit and all the methanol and water is evaporated to dryness in continuous evaporator-driers like thin film evaporators or an agitated thin-film evaporator and combinations thereof to yield a mixture IV.

Product Isolation and Purification
In step (C), another monohydric solvent B is added to this mixture IV. The solvent-B is selected from a group consisting of ethanol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, amyl alcohol and a combination thereof. The resultant mixture is a slurry, VII containing ammonium chloride, residual water, and the product amide. The preferred solvent-B is isopropyl alcohol (IPA). The residual water from the slurry, VII is removed as an azeotrope to obtain a slurry VIII, which is then rendered ammoniacal by passing ammonia gas. Ammonium chloride is precipitated and filtered. The filtrate containing V is preheated and solvent IPA or any other solvent present is evaporated in a continuous evaporator. The resulting wet cake of the amide V is then dried to provide a dry powder of the amide, V and can be packed for use in the manufacture of Levetiracetam, in-house.

In step (D), for the preparation of the amide.HCl salt (VI), dry powder of V is introduced in a stirred reactor, where it is reacted with HCl pre-dissolved in a solvent-C selected from a group consisting of methanol, IPA, and a combination thereof. After an appropriate residence time (~1h), the HCl salt VI precipitates. It is then filtered, dried, and packaged. Acidic solvent is sent to solvent recovery and any solvent collected overhead is recycled.

All the above operations in steps (C) and (D) can be conducted in batch, semi-continuous or continuous mode.

All the fugitive gases, like HCl and ammonia from various steps of reaction are scrubbed in basic and acidic medium as appropriate.

EXAMPLES AND COMPARATIVE EXAMPLES
General procedure for Esterification in continuous mode
(For Examples E.1 to E.3, see Table 1; for Comparative Examples C1 to C8 see Table 2)
Esterification
In step (A), a slurry containing monohydric alcohol (solvent-A), preferably, methanol and (S)-amino butyric acid, 1 in a feed tank is continuously pumped into continuous reactor-A. Simultaneously thionyl chloride is continuously pumped from another feed tank into the reactor-A in equimolar amounts (1:1.05) with respect to (S)-2-amino butyric acid, 1. This reaction mixture is continuously pumped from reactor-A at a monitored flow rate into a continuous flow reactor-B with provision to remove heat of reaction through jacket or external heat exchanger. The contents of the reactor-B are kept at a temperature ≤ 60 deg C or the reaction can be conducted in a series of (and/or combinations of) flow reactors kept at ≤ 60 deg C resulting in total cumulative residence time of 45 to 90 min. The reaction temperature is maintained at and below 60 °C. Since the reaction is exothermic, constant removal of heat is necessary to prevent the reaction from heating up. A pressure of 2 bar is applied to the reaction mixture.

The by-products of this reaction include HCl and SO2. The ester product forms a salt with co-produced HCl. The contents of the reactor B are continuously pumped to a continuous evaporator to recover methanol and strip dissolved gases such as HCl and SO2. The resulting solution is referred to as ester.HCl solution II which contains the HCl salt of the product ester and residual solvent. This ester.HCl solution is then taken as the input for the subsequent step, step (B) of amidation.

Characterisation of ester.HCl salt:
The ester.HCl is analytically characterized by High performance Liquid Chromatography (HPLC) and reaction details are tabulated in Tables 1 and 2.
Table 1: Esterification - Continuous Process
Example Reactants Quantity Molar equivalents Temperature Yield Reaction time / total residence time Comment on racemization (Refer to Table 6 for details)
E.1 L-ABA
MeOH
SOCl2 5g
15mL
3.5mL 1
7.6
1 80 deg C 90.0% 22 min Significant racemization
E.2 L-ABA
MeOH
SOCl2 5g
15mL
3.5mL 1
7.6
1 60 deg C 90.0% 30 min No racemization
E.3 L-ABA
MeOH
SOCl2 5g
15mL
3.5mL 1
7.6
1 55 deg C 91.0% 45 min No racemization

Table 2: Esterification – Comparative Examples C.1 to C.8
Example Reactants Qty Mol. Eq Tempe(°C) P
(bar) Reaction conditions Purity Remarks
C.1. L-ABA
MeOH
SOCl2 5g
15mL
3.5mL 1
7.6
1 T:45-55 1 Procedure: Batch
T=1h
T=2h
T=3h
T=4h

91.4%
90.5%
88.2%
91.2% Examples C.1 to C.4 show the effect of Thionyl chloride concentration on the esterification reaction.

Conclusion: Minimum of one molar equivalent of Thionyl chloride is required for complete conversion of L-ABA to Ester in 1h.
C.2. L-ABA
MeOH
SOCl2 5g
15mL
3.9mL 1
7.6
1.1 T:45-60 1 Procedure: Batch
T=1h
T=2h
T=3h
T=4h

90.9%
91.5%
91.8%
91.0%

C.3 L-ABA
MeOH
SOCl2 5g
15mL
3.2mL 1
7.6
0.9 T:45-60 1 Procedure: Batch
T=1h
T=3h

75.5%
86.1%
C.4 L-ABA
MeOH
SOCl2 50g
150mL
42.2mL 1
7.6
1.2 T:35-45 1 Procedure: Batch
T=1h
T=2h
T=3h

92.4%
88.5%
91.4%
C.5 L-ABA
MeOH
SOCl2 5g
15mL
4.22mL 1
7.6
1.2 T:45-55 1 Procedure: Batch
T=3h
Moisture Content in MeOH (Anhydrous): 1.8%
90.2% Examples C.5 to C.7 show the effect of moisture content on esterification reaction.

Conclusion: The max tolerance to moisture content in esterification reaction is <4%
C.6 L-ABA
MeOH
SOCl2 5g
15mL
4.22mL 1
7.6
1.2 T:45-55 1 Procedure: Batch
T=3h
Moisture Content in MeOH: 3.8%
91.7%
C.7 L-ABA
MeOH
SOCl2 5g
15mL
4.22mL 1
7.6
1.2 T:45-55 1 Procedure: Batch
T=3h
Moisture Content in MeOH: 7%
78.0%
E.1. L-ABA
MeOH
SOCl2 5g
15mL
3.5mL 1
7.6
1 T:75-80 1 Procedure: flow
T=23min. 87.7% Examples, E.1 and C.8 were conducted to check the effect of temperature in the racemization of esterification reaction. See Table 6.

Conclusion: Temperature> 60°C is leading to racemization.
C.8.

L-ABA
MeOH
SOCl2 5g
15mL
3.9mL 1
7.6
1.1 T:45-60 1 Procedure: Batch
T= 2h 92.0%

Table 3: Esterification – A comparison of Batch Vs. Continuous
Parameters Continuous Process Batch process
Reaction (Rxn) time (mins) 30 mins – 90min 3 hrs
Temperature /Pressure 50 to 60 °C @ 2 to 5 bar 40-45°C
Yield /Purity
Corrected Yield 100%(w/w) / 90%
90% 100%(w/w) / 90%
90%
Key Points Flow reactor with continuous operation to maintain temperature and shorter residence time
Jacketed Stirred vessel

General Experimental procedure for Amidation in continuous mode
Amidation of the ester of 2-aminobutyric acid is carried out in step (B) of the disclosed process which involves reacting the ester.HCl solution with ammonia as given in sub-steps b(i) to b(v) as follows:
(b.i) continuously pumping the ester.hydrochloride solution II and aqueous ammonia reagent into a tubular reactor-C equipped with efficient inter phase mixing to form a reaction mixture, III.
(b.ii) maintaining the reactor-C at 45-55 deg C for a residence time of at least 20 min and not exceeding 60 min under a pressure of 2 to 10 bar- Note the pressure is maintained above 2 bar.
(b.iii) continuously collecting the reaction mixture III in a collection vessel
(b.iv) continuously removing unreacted ammonia from the mixture in the collection vessel in a degassing unit and
(b.v) continuously removing the solvent and water by evaporation in a continuous evaporator-drier to provide mixture IV.

Steps (C) and (D) are carried out as given in the section titled Isolation and purification given in page 12.

Table 4: Amidation: EXAMPLES E.4 to E.7 AND COMPARATIVE EXAMPLES C.9 to C.13
Example Reactants Amounts Molar Equivalents (ester to ammonia) Temp
(°C) P (BPR)
(bar) Reaction Condition Purity Remarks
C.9 Ester.HCl (solid)
NH4OH (aq.Ammonia) & NH3 dry 11g

55mL 1

12
85
7-10 Direct Addition of reactants
ꞇ (85°C): 5min
ꞇ (total):12min 84.1% Examples C9 to C11 show the effect of temperature on amidation reaction and extent of Racemization.
Amidation at 85°C leads to racemization of upto 2.8%. See Table 6.

Conclusion: Temperature for amidation reaction should be less than 60 deg C.
C.10 Ester.HCl (solid)
NH4OH (25% aq.Ammonia) 52g

250mL 1

12
50
10 Direct Addition of reactants (Batch)
ꞇ :1.5h 82.8%
C.11 Ester.HCl (solid)
NH4OH (aq.Ammonia) 5g

25mL 1

12
30-35
1 Direct Addition of reactants (Batch)
ꞇ :17h 92.4%
C.12 Ester.HCl (solid)
Methanolic NH3(7M) +
NH3 gas (under pressure) 25g

100mL

2.55g 1

4.38

1
40-50
7.5 Direct Addition of reactants (Batch)
Followed by further NH3 gas purge
ꞇ :17h 65.4% Examples C11 to C13 show the effect of solvent on amidation reaction. Lowering of the purity of amide resulted with Methanol and IPA.

Conclusion: Aqueous ammonia was found to be the most suitable solvent for amidation for a shorter residence time
C.13 Ester.HCl (solid)
IPA
NH3 gas (atmospheric pressure) 25g

125mL
1

Purging at 0°C
Overnight at RT
1 Direct Addition of reactants (Batch)
Followed by NH3 gas purge to achieve pH 11-12
ꞇ :6h
ꞇ :17h

42.1%
55.6%
E.4 Ester. HCl +MeOH (liq)

Water
NH3 100mL
(62g Ester.HCl)
186mL
50g
1

25.5
6.77

49

6 Continuous flow of reactants
Run time (Reactants):82 min
ꞇ :25min

68.1%
E.5 Ester. HCl +MeOH(liq)

Water
NH3 100mL
(62g Ester.HCl)
186mL
70g
1

25.5
10.16

49

6 Continuous flow of reactants
Run time (Reactants):82 min
ꞇ :25min

92.8%
E.6 Ester. HCl +MeOH (liq)

Water
NH3 210mL
(145g Ester.HCl)
436mL
161-165g 1

25.5
10

49

5 Continuous flow of reactants
Run time (Reactants):225 min
ꞇ :38min 91.1% Expts E.5, 6 & 7 are steady state runs conducted under optimised conditions.
E.7 Ester. HCl +MeOH (liq)

Water
NH3 538mL (290g Ester. HCl)
870mL
325g 1

25.5
10.09

49

5 Continuous flow of reactants
Run time (Reactants):7h.40 min
ꞇ :~35 min 88.5%

Table 5: Amidation: A comparison of Batch Vs. Continuous
Parameters Continuous Process A typical batch Process
Reaction time 30 mins 18 hrs
Temperature /Pressure 50 °C @ 5-7bar 40-45°C @ 2 bar
Yield (by assay) /Purity
Isolated Yield (amide V) 84-86% / 95%
75-80% 60-75%
Key Points 1. Solvent: Water + methanol
2. high ratio of ammonia to substrate without dilution
3. Removal of NH4Cl using IPA under basic condition (Cl content<5%) • Solvent: Methanol/ IPA
• Use of Methanol retains NH4Cl (Cl content >10%).

Table 6: Effect of temperature on racemization during esterification and amidation starting from (S)-2-aminobutyric acid

Temperature for Esterification Temperature for Amidation Extent of R isomer in Levetiracetam prepared Extent of S isomer in Levetiracetam prepared
80°C 30°C 2.8% 97.2%
80°C 80°C 5.5% 94.5%
60°C 50°C 0.6% 99.4%

The Table 6 suggests racemization of Levetiracetam by 2.78% on carrying out esterification at 80°C and additional 2.75 % racemization on carrying out amidation at 80°C. Racemization occurred to much less extent at lower temperatures. To prevent racemization, the maximum temperature was set at 60°C for esterification and 50°C for amidation. The chiral purity was determined by using a chiral HPLC column and conducting HPLC with samples prepared from Levetiracetam which in turn was prepared by a standard procedure from the amide samples generated.
Method of Chiral purity determination
Chiral purity was analysed by Chiral HPLC. Enantiomeric separation of Levetiracetam was achieved by Chiralpak AD column (250mm 4.6mm; 10μm particle size), using a mixture of hexane and ethanol (4:1) as a mobile phase, at a flow rate of 1mL/min. Samples were prepared by dissolution of 10mg/ml in ethanol. UV spectrophotometry was used for detection at 210 nm. Under optimized conditions, the (R)- and (S)-enantiomers were highly resolved. Linearity of the quantification of the (R)- and (S)-enantiomers was established, and the limits of detection and quantification were established. The robustness and repeatability of the method were demonstrated, and the precision and accuracy of the assay were shown to be high.
The inventors of the present invention have observed that a continuous process for preparation of SABAM or its salt is enabled by selecting a key combination of parameters for process intensification, particularly a) choice of pressure parameters for the continuous esterification and b) choice of ammonia concentration parameters by application of ammonia pressure in aqueous solvent for the continuous amidation.

ADVANTAGES OF THE PRESENT INVENTION
The continuous process of the invention comprising an esterification step and amidation step is highly productive as indicated by the residence times in both the steps. The continuous process affords products with good purity and high yield without compromising optical purity. Hence the innovative and intensified process disclosed in the present invention improves process productivity significantly when compared to existing batch processes which have long reaction times.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the disclosure. Other aspects of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.”
, Claims:We Claim:
1. An integrated continuous process for optically active 2-Amino butyramide, V and its hydrochloride salt, VI comprises a continuous esterification step (A), a continuous amidation step (B), step (C) for continuous separation of ammonium chloride and step (D) for continuous formation of hydrochloride salt of the 2-amino butyramide, wherein,
the step (A) comprises
(a.i) continuously pumping a slurry of an optically active 2-amino butyric acid, I suspended in a monohydric solvent-A and an esterification agent into a reactor-A which is provided with a heat exchanger
(a.ii) allowing the slurry to react for a residence period of at least 15 min and not exceeding 2 h, at a reaction temperature ranging from 40 to 55 deg C under a pressure of 1-10 bar
(a.iii) continuously pumping the contents of the reactor-A into a second continuous flow reactor -B kept at a temperature ≤ 60 deg C and
(a.iv) continuously sending the contents of the second reactor to a continuous evaporator to recover the solvent and strip dissolved gases such as HCl and SO2 to form an ester. Hydrochloride solution II;
the step (B) comprises:
(b.i) continuously pumping the ester.hydrochloride solution II and aqueous ammonia reagent into a tubular reactor-C equipped with efficient inter phase mixing to form a reaction mixture, III.
(b.ii) maintaining a reactor-C at 45-55 deg C for a residence time of at least 20 min and not exceeding 60 min under a pressure of 2 to 10 bar
(b.iii) continuously collecting the reaction mixture III in a collection vessel
(b.iv) continuously removing unreacted ammonia from the mixture in the collection vessel in a degassing unit and
(b.v) continuously removing the solvent and water by evaporation in a continuous evaporator-drier to provide mixture IV,
the step (C) comprises:
(c.i) continuously making a slurry VII from the mixture IV with a monohydric solvent-B selected from a group consisting of isopropyl alcohol, butyl alcohol, isobutyl alcohol, amyl alcohol and a combination thereof.
(c.ii) continuously removing the residual water from the slurry, VII as an azeotrope to obtain a slurry VIII
(c.iii) continuously rendering the slurry VIII ammoniacal by passing ammonia gas
(c.iv) continuously filtering off ammonium chloride to provide a filtrate containing an ammoniacal solution of the amide, V
(c.v) continuously evaporating the solvent or solvents present in the solution of the amide, V in suitable continuous evaporator to provide a wet cake of the amide, V and
(c.vi) continuously drying the wet cake of the amide, V to provide a dry powder of the amide, V and
the step (D) comprises:
(d.i) continuously reacting the dry powder of the amide, V with a solution of HCl dissolved in solvent-C selected from a group consisting of methanol, isopropyl alcohol, and a combination thereof for 30 min to 90 min to precipitate the salt, VI
(d.ii) continuously collecting the salt, VI by filtration followed by drying and
(d.iii) continuously recovering and recycling the solvents.

2. The process as claimed in 1, wherein the optically active amide is an (S) isomer or (R) isomer.
3. The process as claimed in claim 1, wherein the monohydric solvent-A is selected from a group consisting of methanol, ethanol, propanol, isopropyl alcohol, n-butanol, isobutanol and a combination thereof.
4. The process as claimed in Claim 1, wherein the esterification agent is selected from a group consisting of thionyl chloride, sulfuryl chloride, acetyl chloride, trimethyl silyl chloride, sodium bisulphate, hydrogen chloride, sulfuric acid, an ion-exchange resin, p-toluene sulfonic acid, methane sulfonic acid, dodecylbenzene sulfonic acid and a combination thereof.

5. The process as claimed in Claim 1, wherein the second reactor is reactor-B.

6. The process as claimed in Claim 1, wherein the reactors-A, reaction-B and reactor-C are single reactors or series of multiple reactors.
7. The process as claimed in Claim 6, wherein the reactor-A, reactor-B and reactor-C are selected from a group consisting of continuous stirred tank reactors (CSTRs) and Tubular flow reactors (TRs).
8. The process as claimed in Claim 1, wherein the aqueous ammonia reagent is selected from a group consisting of ammonia liquor saturated with ammonia gas, aqueous ammonia liquor, methanol containing ammonia liquor, aqueous solutions of ammonium formate, ammonium acetate and ammonium carbonate and a combination thereof.
9. The process as claimed in Claim 1, wherein the residence time for the esterification ranges from 15 min to 120 min.
10. The process as claimed in Claim 1, wherein the residence time for the amidation ranges from 15 min to 90 min.
11. The process as claimed in Claim 1, wherein the optical purity of V, or VI is greater than >99.0%.