DESC:Field of the invention
The present invention relates to an industrially viable and inherently safer process for manufacturing of (R)-3-chloro-2-hydroxypropanoic acid of formula (I) by using CSTRs technology.

This formula (I) is used as an intermediate in the synthesis of Lacosamide.

The present invention is also relates to a process for the preparation of (R)-3-chloro-2-hydroxypropanoic acid of formula (I) with high yield and purity.

Background of the invention
(R)-3-chloro-2-hydroxypropanoic acid is also known as (+)-3-chloro lactic acid.

(R)-3-chloro-2-hydroxypropanoic acid and its method of preparation is disclosed in Journal of American Chemical Society Vol (104) (16), (1982), P.No. 4458-4460. This reference provides lab scale synthesis for the preparation of (+)-3-chloro lactic acid through enantio selective enzymatic/chemical synthesis of chloro pyruvic acid. The above process is shown in the Scheme - 1 given below:

Scheme-1

The major drawback of above synthesis is that the substrate chloro pyruvic acid is reactive towards the enzyme.
The method of preparation for (R)-3-chloro-2-hydroxypropanoic acid is also reported in a patent JPS6262154, which involves the reaction of 3-halo-1,2-propanediol with a microorganism belonging to a Geotrichum group. The above process is shown in the Scheme -2 given below:

Scheme-2

The major drawback of above synthesis is use of microorganism which is expensive and not feasible in commercial scale.

The method of preparation for (R)-3-chloro-2-hydroxypropanoic acid is also reported in Organic Process Research Development volume 16, issue 4, pages 687-696, 2012, which involves oxidation of a-chlorohydrin with nitric acid and the obtained product purified by recrystallization. The above process is shown in the Scheme - 3 given below:


Scheme-3

The main drawback of the above process is that, the process is not suitable for commercial, highly exothermic in nature and difficult to control the strong gas (NOx) evolution (Heat of reaction is about 183 KJ/mol and adiabatic temperature rise ?Tad is about 111°C) which makes the reaction fall in high severe hazardous category.

The method of preparation for (R)-3-chloro-2-hydroxypropanoic acid is also reported in IN 4228/CHE/2014, which involves hydrolysis of (R)-epichlorohydrin to obtain diol intermediate and oxidation of diol intermediate with nitric acid to obtain (R)-3-chloro-2-hydroxypropanoic acid, The above process is shown in the Scheme - 4 given below:


Scheme-4

The main drawbacks of the above process are:
a. Oxidation reaction initiates suddenly after 20% addition of 65% nitric acid which results in liberation of huge energy and NOx at a time which is difficult to control.
b. Accumulation of liberated NOx inside the mass results in poor quality and low yield.
c. Yield is < 75% and purity is < 85%.
d. Time of addition of reagent increases proportionally with batch size. Hence cycle time increases which effects batch frequency, thereby productivity decreases.
In order to overcome the above said problems it is necessary to develop a yield improving and safer process, and maintain temperature conditions to avoid vigorous gas evolution.

Objects of the invention
The primary object of present invention is to provide a process for the preparation of (R)-3-chloro-2-hydroxypropanoic acid, which is used as an intermediate in the synthesis of Lacosamide by using CSTRs technology.

Another object of the present invention is to provide industrially viable and inherently safer process for the preparation of (R)-3-chloro-2-hydroxypropanoic acid of formula (I) with high yield and purity.

Brief description of the drawings
Figure-I illustrates an experimental set-up of a continuous stirring tank reactors (CSTRs) in series.

Summary of the invention
In one aspect, the present invention relates to an improved process for the preparation of (R)-3-chloro-2-hydroxypropanoic acid by using CSTRs technology, which comprises:
(i) hydrolysis of Epichlorohydrin to obtain 3-chloro-1,2-propanediol;

(ii) cool the oxidizing agent and diol reaction mass obtained from step (i) individually to below 5°C in two separate beakers;
(iii) mix the diol reaction mass and oxidizing agent;
(iv) slowly add sodium nitrite solution to the resulting mixture obtained in step (iii);
(v) pre heat the CSTRs set up in series at about 35 ° C to 110 ° C by circulation of hot oil in the jackets;
(vi) feed the reaction mass obtained in step (iv) continuously into CSTR-1 at calculated flow rate;
(vii) overflow from CSTR-1 is transferred into CSTR-2, followed by CSTR-3 to convert unreacted diol into formula (I);
(viii) collect the samples from the sampling points of each reactor.

In another aspect, the present invention provides (R)-3-chloro-2-hydroxypropanoic acid of formula (I) with high yield and purity.

Detailed description of the invention
The main embodiment of present invention is to provide a process for the preparation of (R)-3-chloro-2-hydroxypropanoic acid by,
i) hydrolysis of (R)-Epichlorohydrin to obtain diol intermediate;
ii) obtained diol intermediate in step (i) which in in-situ further undergoes oxidation with suitable oxidizing agent by using CSTRs in series.

Another embodiment of present invention is to provide industrially viable and inherently safer process for the preparation of (R)-3-chloro-2-hydroxypropanoic acid of formula (I) with high yield and purity.

Suitable oxidizing agents used in step (ii) are nitric acid or (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO). More preferably, 65% nitric acid is used.

Procedure for Continuous Stirred Tank Reactors (CSTRs) in series.
Take two separate beakers; charge diol reaction mass and oxidizing agent in two separate beakers. Cool both beakers to below 5°C. Mix both the reaction mixture at below 5°C. Add sodium nitrate solution to above reaction mixture and select the total residence time and there by calculate required flow rate. Pre heat the CSTR in series to about 35 °C to 110 °C by circulation of hot oil inside jackets. Feed the reaction mixture to CSTR-1 at calculated flow rate. Overflow from CSTR-1 is transferred into CSTR-2, followed by CSTR-3 to convert unreacted diol into formula (I). Samples are collected from the sampling points of each reactor.

The invention is further illustrated with examples:

Example: Preparation of (R)-3-chloro-2-hydroxypropanoic acid (formula I)
Step (i): Preparation of 3-chloro-1,2-propanediol
To the round bottom flask having 100 mL of demineralized water (DM water) is charged epichlorohydrin (100 grams) at room temperature (RT) and subsequently reaction temperature is raised to 90 °C, reaction mixture is allowed to stir at same temperature with vigorous stirring for 6 hours. Check TLC, if complies proceed to step (ii).

Step (ii): Preparation of formula (I)
Three CSTRs are modified in such a way that CSTR-I holds (720 mL) and CSTR-II (600 mL) at constant tip speed of 1.0 m/s; Initially total residence time (?=?1+?2+ ?3) is arbitrarily chosen to be 469 minutes approximately; Required flow rate is calculated accordingly whose value turned out to be 2.817 mL/minutes; Meanwhile hot oil at 35 °C to 110 °C is circulated in the jacket of both CSTRs for preheating; 2.0 kg diol reaction mass (Equivalent to 1.0 Kg R(-) epichlorohydrin is taken in a 5 L Beaker; Sodium nitrite solution (1gram in 10 mL) is added to the diol mass; The mixture is cooled to below 5°C; 2.0 L oxidizing agent cooled to below 5°C is added to the above mixture at below 5°C; The above mixture is continuously fed into CSTR-I at calculated flow rate i.e 2.817 mL/minutes; The reaction mass passed through CSTR-I and CSTR-II followed by about 370 mL mass was collected in CSTR-III. It is called Lot-I; the above procedure was repeated for different values of total residence time; Finally after completing the five lots, hold up volume in CSTR-I (720 mL) and CSTR-II (600 mL) were withdrawn; Lot-II, Lot-III and Lot-IV were stirred for 100 minutes, 60 minutes and 60 minutes respectively at 35 °C to 110 °C in CSTR-III. All the collected lots worked up and isolated compound of formula (I).

Advantages of the invention:
1. As the reaction was performed in flow reactors the rate of liberation of NOx and energy were much lower therefore the process is inherently safer;
2. Higher yield and purity;
4. No accumulation of liberated NOx;
5. Productivity increases with increase of reactor capacity since higher flow rate is required. ,CLAIMS:1. An improved process for the preparation of (R)-3-chloro-2-hydroxypropanoic acid which comprises:
(i) hydrolysis of Epichlorohydrin to obtain 3-chloro-1,2-propanediol;

(ii) cool the oxidizing agent and diol reaction mass obtained from step (i) individually to below 5°C in two separate beakers;
(iii) mix the diol reaction mass and oxidizing agent;
(iv) slowly add aqueous sodium nitrite solution to the resulting mixture obtained in step (iii);
(v) pre heat the CSTRs set up in series at about 35 °C to 110 °C by circulation of hot oil in the jackets;
(vi) feed the reaction mass obtained in step (iv) continuously into CSTR-1 at calculated flow rate;
(vii) overflow from CSTR-1 is transferred into CSTR-2, followed by CSTR-3 to convert unreacted diol into formula (I);
(viii) collect the samples from the sampling points of each reactor.

2. The process as claimed in claim 1, wherein the oxidizing agent used in step (ii) is nitric acid or TEMPO.

3. The process as claimed in claim 2, wherein nitric acid used in step (ii) is 65% nitric acid.

4. The process as claimed in claim 1, wherein the reaction of step (v) takes place at a temperature of 85 °C.