Claims:1. A process for preparation of (R)-3-aminobutan-1-ol (Formula I) employing methyl-3-amino crotonate as the starting material, wherein the process comprises:
(i) reducing methyl-3-amino crotonate (Formula II) in presence of sodium borohydride and acetic acid to obtain a crude reaction mixture comprising (±)-methyl-3-aminobutanoate (Formula III);


(ii) reacting methyl-3-aminobutanoate with a resolving agent in presence of a solvent to obtain a salt of tartaric acid of Formula IV, wherein the salt is neutralized in presence of a neutralizing agent to obtain (R)-methyl-3-aminobutanoate (Formula V), wherein the resolving agent is selected from D-tartaric acid, dibenzoyl tartrate, mandelic acid, camphorsulphonic acid; and

(iii) reducing (R)-methyl-3-aminobutanoate with lithium aluminium hydride in presence of a solvent to obtain (R)-3-aminobutan-1-ol (Formula I);
.

2. The process as claimed in claim 1, wherein in step (ii) the resolving agent is D-tartaric acid.

3. The process as claimed in claim 1, wherein in step (i) the crude reaction mixture is neutralized with sodium bicarbonate followed by separation of the aqueous layer from the organic layer using an organic solvent to obtain (±)-methyl-3-aminobutanoate, wherein the organic solvent is selected from the group consisting of dichloromethane, ethyl acetate, isopropylacetate, chloroform, and 2-methyl tetrahydrofuran.

4. The process as claimed in claim 1, wherein in step (i) methyl-3-amino crotonate is reacted with sodium borohydride at -5? to 5? to obtain the crude reaction mixture followed by stirring of the crude reaction mixture for 10-18 hours to obtain (±)-methyl-3-aminobutanoate (Formula III).

5. The process as claimed in claim 1, wherein the solvent in step (ii) is selected from the group consisting of methanol, ethanol, and isopropanol.

6. The process as claimed in claim 1, wherein in step (ii) a solution of methyl-3-aminobutanoate is refluxed with D-tartaric acid at room temperature for 16-24 hours.

7. The process as claimed in claim 1, wherein in step (ii) the neutralizing agent is selected from alkaline bases, wherein the neutralizing agent is sodium hydroxide.

8. The process as claimed in claim 1, wherein the solvent in step (iii) is selected from the group consisting of tetrahydrofuran, 2-methyl tetrahydrofuran, and methyl tertiary butyl ether.

9. The process as claimed in claim 1, wherein in step (iii) (R)-methyl-3-aminobutanoate is reacted with lithium aluminium hydride at -5? to 5? to obtain a reaction mixture followed by stirring of the reaction mixture for 5-8 hours at room temperature and quenching with a saturated solution of sodium sulfate at -5? to 5? to obtain (R)-3-aminobutan-1-ol.

10. The process as claimed in claim 1, wherein (R)-3-aminobutan-1-ol as and when employed as a key starting material for synthesis of anti-retroviral agents.
, Description:FIELD OF THE INVENTION

The present invention relates to a process for the preparation of (R)-3-aminobutan-1-ol. More particularly, the present invention relates to an improved process for one pot synthesis of (R)-3-aminobutan-1-ol employing methyl-3-amino crotonate as the starting material, wherein the process is cost effective and prevents formation of any unwanted impurities.

BACKGROUND OF THE INVENTION

(R)-3-amino-1-butanol is the most important building block for the synthesis of pharmaceuticals, especially anti-retroviral agents like Dolutegravir, including penicillium antibiotics and anti-tumor drugs like 4-methylcyclophosphamide. Particularly, (R)-3-amino-1-butanol is the key starting material for synthesis of Dolutegravir which is a new-generation integrase inhibitor for the treatment of HIV infection. Compared with other traditional anti-HIV/AIDS drugs, Dolutegravir exhibits conjoint therapeutic effect combining several anti-HIV/AIDS drugs with different therapy mechanisms, which can be used independent of drug enhancers. In addition, use of Dolutegravir shows excellent efficacy with low risk of treatment-limiting toxicities. The fixed dose combination therapy of tenofovir, lamivudine and dolutegravir is becoming firstline therapy for HIV patients in more than 50 low- to middle-income countries. Thus, reducing the production costs associated with this suite of medicines will increase the number of patients who have access to these medicines. Dolutegravir is a newer medicine and has received less attention from a synthetic standpoint relative to tenofovir and lamivudine. Dolutegravir (DTG), is a second-generation INSTI (integrase inhibitor) and an FDA-approved drug for the treatment of HIV infection, marketed as Tivicay by GlaxoSmithKline (GSK). It has shown remarkable antiviral value based on randomized controlled trials when compared to other first-line regimens, acclaimed by the HIV treatment guidelines for adults and adolescents. However, the use of Dolutegravir has been significantly limited due to its very high cost of production. The four carbon (R)-3-aminobutan-1-ol is the key starting material in the process of synthesis of this anti-retroviral drug and is a major cost driver for dolutegravir production, nearly 30% of the overall cost. The synthesis of small chiral alcohols is challenging for many reasons including purification complications because of their low boiling points. A market price of (R)-3- aminobutan-1-ol is difficult to establish, as only low volume transactions with a wide range of prices are available. As a result, production of (R)-3-amino-1-butanol through a simple synthetic procedure has attracted a great deal of attention, so as to obtain (R)-3-amino-1-butanol by a cost effective and simple process with minimum formation of unwanted impurities and minimum purification requirements.

Among the conventional methods available for synthesis of (R)-3-amino-1-butanol, the common ones include chemoenzymatic approaches, asymmetric catalysis, chiral resolutions, and chiral auxiliaries/chiral pool. Enzymatic transformations although facilitated by readily available materials (D-glucose, NADH/NADPH, etc.), inexpensive first-row transition metals, if a metal is required at all, without relying on the use of expensive chiral ligands; but suffers from the disadvantage of involving multiple unit operations (up to 3 synthetic steps) making these strategies expensive. Further, use of asymmetric methodologies involving Noyori hydrogenation of methyl acetoacetate using a ruthenium-BINAP catalytic system suffer from several drawbacks like use of stoichiometric reagents that are shock and temperature sensitive, use of expensive ligands or organocatalysts, multistep synthetic processes and others.

US 8,288,575 discloses a process for the preparation of (R)-3-amino-1-butanol, wherein methyl (R)-3-aminobutanoate is hydrogenated using ruthenium complex in a solvent. The major disadvantage with the said process is that the sensitivity and the use of expensive catalyst such as ruthenium complex, which are not easy to handle on commercial scale, and this process is not suitable for commercial scale production of (R)-3-amino-1-butanol.

Tang et al. (Tang et al., Efficient biosynthesis of (R)-3-amino-1-butanol by a novel (R)-selective transaminase from Actinobacteria sp., Journal of Biotechnology 2019, 295, 49-54) refers to efficient biosynthesis of (R)-3-amino-1-butanol by a novel (R)-selective transaminase from Actinobacteria sp. (As-TA), whereby transaminase serves as biocatalyst for the synthesis of chiral amines. The authors demonstrated the biosynthesis of (R)-3-amino-1-butanol with transaminase as biocatalyst and the obtained As-TA enriched the enzyme pool of transaminase with (R)-specificity. However, the process is complex and involves construction of recombinant E. coli harboring transaminases.

Yatcherla et al. (Yatcherla et al., a simple and convenient route for the synthesis of (R)-3-aminobutanol, an intermediate for the synthesis of Dolutegravir, Heterocyclic letters 2015, 5, 241-244) provided a simple route for the synthesis of (R)-3-aminobutanol involving ethyl acetoacetate as starting material, whereby ethylacetoacetate was converted to the corresponding oxime by reacting with hydroxylamine hydrochloride in presence of NaOH, followed by reduction of the oxime with Lithium Aluminum Hydride (LAH) and resolving with D-(-)-tartaric acid to obtain (R)-3-aminobutanol tartarate salt. Subsequently, the (R)-3-aminobutanol tartarate salt was neutralized using potassium carbonate in acetonitrile medium to obtain (R)-3-aminobutanol. However, the process involves the use of acetonitrile reagent and rigorous purification is required to remove the said reagent to avoid any health hazard that might be caused even from minute residues of the said reagent.

The Indian patent application 725/CHE/2013 provides a process for the preparation of (R)-3- amino-1-butanol which comprises hydrogenating 4-hydroxy-2-butanone oxime to obtain (R,S)-3-amino-1-butanol, followed by treatment with an optically active carboxylic acid to produce an optically active salt of the R-isomer and subsequently converting the same to obtain of (R)-3- amino-1-butanol. However, the hydrogenation step in this process refers to the involvement of expensive hydrogenation catalyst that comprises palladium in the form of Pd-C, Pd(OH)2/C; platinum in the form of PtO2; nickel in the form Ra-Ni, Urushibara nickel; rhodium complex; ruthenium complex.

Thus, although a large number of methods are available for the synthesis of (R)-3-aminobutanol, the key starting material for synthesis of life saving anti-retroviral drugs, most of the conventional methods involve time consuming expensive procedures of synthesis along with poor commercial scale production of (R)-3-aminobutanol. Further, even if some of the processes exhibit improved yield, the processes suffer from the use of harmful reagents that may cause serious health issues if not removed completely through rigorous purification processes. This necessitates for an advanced process of synthesis of (R)-3-aminobutanol whereby the yield of the desired product is improved even upon employing the process on industrial scale and the process ensures yield of pure starting material for subsequent synthesis of anti-retroviral agents.

OBJECTIVES OF THE INVENTION

An object of the present invention is to provide an improved process for the preparation of (R)-3-aminobutanol, the key starting material for synthesis of anti-retroviral drugs.

Another objective of the present invention is to provide an improved process for the synthesis of (R)-3-aminobutanol without involving any expensive reagent and ensuring complete synthesis of the desired product employing minimum number of reaction steps.

A preferred object of the present invention is to provide an improved process for the synthesis of (R)-3-aminobutanol with less impurities and high yield.

Yet another objective of the present invention is to provide a process with less reaction time and to obtain the desired product at very competitive market price.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a process for the preparation of (R)-3-aminobutanol starting from methyl-3-amino crotonate. The reagents employed in the process are cheap and the process involved is simple without involving formation of any harmful impurities.

Thus, the present invention provides a process for preparation of (R)-3-aminobutan-1-ol (Formula I) employing methyl-3-amino crotonate as the starting material, wherein the process comprises:
(i) reducing methyl-3-amino crotonate (Formula II) in presence of sodium borohydride and acetic acid to obtain a crude reaction mixture comprising (±)-methyl-3-aminobutanoate (Formula III);


(ii) reacting methyl-3-aminobutanoate with a resolving agent in presence of a solvent to obtain a salt of tartaric acid of Formula IV, wherein the salt is neutralized in presence of a neutralizing agent to obtain (R)-methyl-3-aminobutanoate (Formula V), wherein the resolving agent is selected from D-tartaric acid, dibenzoyl tartrate, mandelic acid, camphorsulphonic acid; and

(iii) reducing (R)-methyl-3-aminobutanoate with lithium aluminium hydride in presence of a solvent to obtain (R)-3-aminobutan-1-ol (Formula I);
.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1: Schematic representation of the process of synthesis of (R)-3-aminobutan-1-ol (Formula I)
Figure 2: 1H NMR spectra for identification of (±)-Methyl 3-aminobutanoate (Formula III)
Figure 3: 1H NMR spectra for identification of (R)-3-aminobutan-1-ol (Formula I)

DESCRIPTION OF THE INVENTION
For the purpose of promoting an understanding of the principles of the present disclosure, reference will now be made to the specific embodiments of the present invention further illustrated in the drawings and specific language will be used to describe the same. The foregoing general description and the following detailed description are explanatory of the present disclosure and are not intended to be restrictive thereof.

The present invention relates to a process for the preparation of (R)-3-aminobutan-1-ol. The present invention advantageously provides an improved process with less number of impurities and higher yield. The present invention thus provides a process for the synthesis of (R)-3-aminobutan-1-ol employing methyl-3-amino crotonate as the starting material, whereby the process provides better yield of the end product at competitive market price thereby reducing cost of production of the anti-retroviral drugs that employ (R)-3-aminobutan-1-ol as the key starting material. More particularly, the present invention relates to an improved process for one pot synthesis of (R)-3-aminobutan-1-ol employing methyl-3-amino crotonate as the starting material, wherein the process is cost effective and prevents formation of any unwanted impurities.

The present invention provides a process for preparation of (R)-3-aminobutan-1-ol (Formula I) employing methyl-3-amino crotonate as the starting material, wherein the process (Figure 1) comprises:
(i) reducing methyl-3-amino crotonate (Formula II) in presence of sodium borohydride (NaBH4) and acetic acid (AcOH) to obtain a crude reaction mixture comprising (±)-methyl-3-aminobutanoate (Formula III);


(ii) reacting methyl-3-aminobutanoate with a resolving agent in presence of a solvent to obtain a salt of tartaric acid of Formula IV, wherein the salt is neutralized in presence of a neutralizing agent to obtain (R)-methyl-3-aminobutanoate (Formula V), wherein the resolving agent is selected from D-tartaric acid, dibenzoyl tartrate, mandelic acid, camphorsulphonic acid; and

(iii) reducing (R)-methyl-3-aminobutanoate with lithium aluminium hydride (LAH) in presence of a solvent to obtain (R)-3-aminobutan-1-ol (Formula I);
.
In a preferred embodiment, the resolving agent in step (ii) of the disclosed process is D-tartaric acid.

In an embodiment, in step (i) of the disclosed process, the crude reaction mixture is neutralized with sodium bicarbonate followed by separation of the aqueous layer from the organic layer using an organic solvent to obtain (±)-methyl-3-aminobutanoate. The organic solvent is selected from but not limited to dichloromethane, ethyl acetate, isopropylacetate, chloroform, 2-methyl tetrahydrofuran, and like.

In a preferred embodiment, in step (i) of the disclosed process, methyl-3-amino crotonate is reacted with sodium borohydride at -5? to 5? to obtain the crude reaction mixture followed by stirring the crude reaction mixture for 10-18 hours to obtain (±)-methyl-3-aminobutanoate (Formula III).

In yet another embodiment, the solvent in step (ii) is selected from the group consisting of C1 to C4 alcohols, preferably methanol, ethanol, and isopropanol. More preferably, the solvent is methanol.

In a preferred embodiment, in step (ii) of the disclosed process, a solution of methyl-3-aminobutanoate is refluxed with D-tartaric acid at room temperature for 16-28 hours, preferably 16-24 hours.

In an embodiment, in step (ii) of the disclosed process, the neutralizing agent is selected from alkaline bases, preferably the neutralizing agent is sodium hydroxide.

In another embodiment, the solvent in step (iii) is selected from the group consisting of tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tertiary butyl ether, and like. Preferably, the solvent is tetrahydrofuran.

In a preferred embodiment, in step (iii) of the disclosed process (R)-methyl-3-aminobutanoate is reacted with lithium aluminium hydride at -5? to 5? to obtain a reaction mixture followed by stirring of the reaction mixture for 5-8 hours at room temperature and quenching with a saturated solution of sodium sulfate at -5? to 5? to obtain (R)-3-aminobutan-1-ol.

In an embodiment, the (R)-3-aminobutan-1-ol end product serves as the key starting material for synthesis of anti-retroviral agent.

Some illustrative non-limiting examples of the present invention are described below.

EXAMPLE

STAGE-I: Preparation of (±)-Methyl 3-aminobutanoate (Formula III)
To a stirred solution of methyl-3-amino crotonate (Formula II) (25 g, 0.21 mol) in acetic acid (250 mL), sodium borohydride (20.83 g, 0.55 mol) was charged portion wise for 30 minutes at 0oC. The resulting reaction mass was stirred further for 16 hours. After completion of stirring, the reaction mass was distilled under reduced pressure (using 10% methanol in dichloromethane) to obtain a crude reaction mixture. The resulting crude reaction mixture was diluted with water and neutralized with sodium bicarbonate (100ml). The aqueous layer was extracted with dichloromethane (2×200 ml). The combined organic layer was concentrated to obtain 18.75 g of (±)-Methyl-3-aminobutanoate as yellow oil (yield: 70%). 1H NMR (DMSO-D6, 400 MHz): d 3.6 (S, 3H), 3.02 (quintet, 1H, J=6.8 Hz), 2.42-2.14 (m, 2H), 0.97 (dd, 3H, J= 6.4, 11.6 Hz)

STAGE-II: Preparation of (R)-methyl 3-aminobutanoate (Formula V)
To a solution of (±)-Methyl-3-amino butanoate (10 g, 0.085 mol) in methanol, D-tartaric acid (12.82 g, 0.85) was added and the resulting solution was heated to reflux for 1 hour and cooled to room temperature. The reaction mass was allowed to stand at room temperature for 24hours to obtain a precipitate of a salt of tartaric acid (Formula IV). The resulting precipitate was filtered and washed with methanol. The tartrate salt was dissolved in 1 N aq. sodium hydroxide (100 ml) for neutralization and was extracted with chloroform (3 x 50 mL). The combined organic layer was dried with anhydrous sodium sulfate and concentrated to give 4.0 g of (R)-methyl 3-aminobutanoate as colourless oil (yield: 80%). [a]25D = - 30.5? (c=1; Ethanol).

Stage-III: Preparation of (R)-3-aminobutan-1-ol (Formula I)
To a stirred solution of (R)-methyl-3-aminobutanoate (4.0 g, 0.034) in tetrahydrofuran, lithium aluminium hydride (2.57 g, 0.068 mol) was charged portion wise for 15 minutes at 0oC. The resulting reaction mass was stirred further for 6hours at room temperature. After completion of stirring, the reaction mass was quenched with saturated sodium sulfate solution at 0oC slowly. The resulting mixture was filtered to remove solids. The filtrate was concentrated to obtain 2.80 g of (R)-3-aminobutanol as yellow oil (yield: 93%). 1H NMR (DMSO-D6, 400 MHz): d 3.53-3.43 (m, 2H), 2.82-2.73 (m, 1H), 1.55-1.30 (m, 2H), 0.98-0.92 (m, 3H). [a]25D = - 8.0o (c=0.5; Ethanol)

Table 1: Comparison of (R)-3-aminobutan-1-ol obtained from different processes
Parameters Conventional process Present invention
% yield (wt %) 27 45
Chiral purity 99.2% ee* 99.1% ee*
*ee: enantiomeric excess

From Table 1, it can be inferred that the yield of the product synthesized based on the presently disclosed process is about 45 wt% that is much higher than the yield of 27 wt% as obtained from the conventional processes. Moreover, the (R)-3-aminobutan-1-ol thus prepared has purity of more than 99% ee.