Novel Process For The Preparation Of R Phenylacetylcarbinol And ß

Novel Process For The Preparation Of R Phenylacetylcarbinol And ß Aminoalcohols

Abstract: Novel process for the preparation of R-Phenylacetylcarbinol and P- aminoalcohols Disclosed herein is a process for the manufacture of (R)-phenylacetylcarbinol ((R)-PAC), (1R,2S)-Ephedrine and its salts, (lR,2S)-norephedrine and its salts and l-(Phenyl/Substituted phenyl)-2-(amino/alkylamino/dialklyamino) propan-1-ol and its salts, by enzymatic reduction of a-isonitrosopropiophenone (INP) and substituted a-isonitrosopropiophenone (substituted INP). The P-amino alcohols, produced by the process of present invention gives their corresponding diastereomers on Walden inversion. The present preparation process of (R)-PAC with (R)-PAC oxime as an intermediate has the advantage, that propiophenone as a key raw material which is easily available and has a low-price, operationally simple with high yield and a single process leading to the synthesis of several 1,2-aminoalcohol/ P- aminoalcohols active pharmaceutical ingredients. The design approach of the process is to reduce environmental impact of the product by comparing to the present manufacturing process.

Patent Information

Application #

Filing Date

22 December 2018

Publication Number

26/2020

Publication Type

INA

Invention Field

CHEMICAL

Status

Email

ipr@puthrans.com

Parent Application

Patent Number

Legal Status

Grant Date

2024-03-30

Renewal Date

Applicants

Malladi Drugs and Pharmaceuticals Ltd

No.9, G.S.T Road, St. Thomas Mount Chennai – 16, Tamil Nadu, India.

Inventors

1. V.N. Gopalkrishnan

c/o Malladi Drugs and Pharmaceuticals Ltd, No.9, G.S.T Road, St. Thomas Mount, Chennai – 600016.

2. S. Shreya

Malladi Drugs and Pharmaceuticals Ltd, No.9, G.S.T Road, St. Thomas Mount Chennai – 600016

3. Dr. R. Saravanan

c/o Malladi Drugs and Pharmaceuticals Ltd, No.9, G.S.T Road, St. Thomas Mount Chennai – 600016

4. S. Perumal

c/o Malladi Drugs and Pharmaceuticals Ltd No.9, G.S.T Road, St. Thomas Mount Chennai – 600016

5. Dr. K.Balamurugan

c/o Malladi Drugs and Pharmaceuticals Ltd, No.9, G.S.T Road, St. Thomas Mount Chennai – 600016

Specification

FIELD OF THE INVENTION; The present invention generally relates to phenylacetylcarbinol synthesis and more particularly, it relates to a novel process for the preparation of (i?)-phenylacetylcarbinoland (R)-1 -hydroxy-1-phenylpropan-2-one oxime, an intermediate P-amino alcohol more specifically for ephedrine, norephedrine & other drug substances. BACKGROUND; (i?)-phenylacetylcarbinol (hereinafter referred to as (RJ-PAC) is a typical precursor for the chemical synthesis of (li?,2Isomer: 0.1% Specific optical rotation: 142.8° (2%, ethanol): *H NMR (CDC13,400MHZ): 5H: 1.75 (3H, s, C=N-CH3), 5.32 (1H, s, CH-OH), 7.29 - 7.38 (5H, m, C6H5). 13C NMR (CDC13,100MHz): 5C: 10.15 (C=N-CH3), 75.04 (CH-OH), 126.52 - 139.48 (aromatic carbons), 159.67 (C=N-CH3). Example 1C: I Preparation of (i?)-pheylacetylcarbinol (I) from(R)-l-hydroxy-l-phenylpropan-2-one oxime (II) The (i?)-PAC oxime II obtained in the example IB is dissolved in 500 mL of toluene and then cooled to 10 °C. 250 mL of Hydrochloric acid diluted with 350 mL of water is added to it for about 3 to 4 hours at 10 °C to 15 °C. The resulting reaction mass was agitated for about 2 hours at 10 °C ' to 15 °C. The completion of hydrolysis reaction of oxime is monitored by GC. The organic layer was separated and product in aqueous layer was extracted twice with 200 mL of toluene. The toluene layers were combined and washed with 200 mL of water and concentrated completely under reduced pressure at below 40 °C to yield (i?)-PAC (85 g) as golden yellow oil with 88% yield. The analytical details are as below. I Purity: 96.7 % (GC) (R)-Phenylacetylcarbinol: 99.2% (GC) S-Phenylacetylcarbinol: 0.8% Example 2: Repetition of example IB by replacing 2-propanol with 2-butanol ' 100 g of 0.613 mole of a-isonitrosopropiophenone HI was suspended in 170 mL of 2-butanol at 20 to 25 °C and agitated for about 20 min. To the suspension of 7.5 g of oxidoreductase IEPOxl62 and 5.0 g of IEPOxl52 in 120 mL of phosphate (pH 8.0) buffer solution added 0.1 g of charged P-nicotinamide adenine dinucleotide (P-NAD) is also suspended inlO mL of phosphate (pH 8.0) buffer solution under vigorous stirring I at 20 °C to 25 °C. The contents are agitated vigorously at 25 °C to 30 °C to get uniform suspension of enzymes. The suspension of enzymes are transferred into the suspension of a-isonitrosopropiophenone III in 2-butanol at 25 °C to 30 °C. The resulting reaction mass was agitated for about 24 - 48 hours at 25 °C to 30 °C The progress of the reaction was monitored by HPLC. After complete conversion, 300 mL of toluene was charged and the resulting mass was ' filtered through celite and the celite bed was washed with 100 mL of toluene. The organic layer is further concentrated in reduced pressure by keeping the temperature less than 50 °C. The concentrated syrup was stirred with hexane to facilitate the precipitation. The precipitated product was filtered and dried to give 96 g (95%) of (i?)-PAC-oxime showing purity > 99% (GC) and > 99 % ee (GC). Example 3: Repetition of example IB except isolating (i?)-PAC oxime followed by hydrolysis 100 g of 0.613 mole of a-isonitrosopropiophenone III was suspended in 170 mL of 2-propanol at 20 to 25 °C and agitated for about 20 min. To the suspension of 7.5 g of oxidoreductase IEPOxl62 and 5.0 g of IEPOxl52 in 120 mL of phosphate (pH 8.0) buffer solution added 0.1 g of charged P-nicotinamide adenine dinucleotide (P-NAD) is also suspended inlO mL of phosphate (pH 8.0) buffer solution under vigorous stirring at 20 °C to 25 °C. The contents are agitated vigorously at 25 °C to 30 °C to get uniform suspension of enzymes. The suspension of enzymes are transferred in to the suspension of a-isonitrosopropiophenone HI in 2-propanol at 25 °C to 30 °C. The resulting reaction mass was agitated for about 24 - 48 hours at 25 °C to 30 °C. The progress of the reaction was monitored by HPLC. After complete conversion 800 mL of toluene was charged and the resulting mass was filtered through celite and the celite bed was washed with 100 mL of toluene. The total filtrate along with the aqueous phase was cooled to 10 °C. Hydrochloric acid (30%) 250 mL diluted with 350 mL of water was added for about 3 to 4 hours at 10 °C to 15 °C. The resulting reaction mass was agitated for about 2 hours at 15 °C to 10 °C. The complete hydrolysis reaction of (i?)-PAC oxime was monitored by GC. The organic layer was separated and the product in aqueous layer was extracted twice with 200 mL of toluene. The combined toluene layers are combined and washed with water 200 mL and concentrated till residual volume of 600 mL volume under reduced pressure at below 40 °C to yield (i?)-PAC in toluene as golden yellow oil of in toluene layer estimated as 82 g (89%) having purity 94.8% with > 99% ee. Example 4 Hydrolysis of the (i?)-PAC oxime (Il)with organic acid The (R)-PAC oxime II 10 g obtained in the example IB was dissolved in 60 mL of toluene and i then cooled to 10 °C. 50 mL of acetic acid diluted with 100 mL of water was added to it for about 3 to 4 hours at 10 °C to 15 °C. The resulting reaction mass was agitated for about 2 hours at 35 °C to 40 °C. The completion of hydrolysis reaction of oxime was monitored by GC. The organic layer was separated and the product in aqueous layer was extracted twice with 200 mL of toluene. The toluene layers are combined and washed with water 50 mL and concentrated completely under I reduced pressure at below 40 °C to yield (i?)-PAC I 8.0 g (88 %) as golden yellow oil with purity 93.5% and 98.8% ee. Comparative Example 1: Preparation of (li?,25)-l-ephedrine HC1 To the 600 mL of concentrated mass of toluene containing (R)-phenylacetylcarbinol I, 40% ' solution of aqueous monomethylamine 62 g was added. The resulting mass was hydrogenated at 30 °C to 55 °C at 2 kg/cm2 to 4 kg/cm2 of hydrogen pressure in the presence of 5% platinum on carbon (8 g) till hydrogen consumption ceases. The mass was maintained at 40 °C to 55 °C in 2 kg/cm2 to 4 kg/cm2 of hydrogen gas pressure. The progress of the reaction mass was monitored by GC and mass was cooled to 30 °C to 35 °C. The platinum catalyst was filtered off and to the filtrate i water of 150 mL was added. The pH of the reaction mass was adjusted to about 2.0 with hydrochloric acid and the aqueous layer was separated. The separated aqueous layer was concentrated under reduced pressure and the precipitated product was isolated using acetone 160 mL at 20 °C to 25 °C. The isolated ephedrine hydrochloride was washed with acetone 100 mL to yield crude ephedrine hydrochloride. The crude ephedrine hydrochloride on re-crystallisation with ' water yields (80 g, 74 %), (li?,2S)-Ephedrine hydrochloride as white crystalline solid. Purity by HPLC > 99.5 % with 99.5 % ee, Specific optical rotation: (-) 32.4 °. Comparative Example 2: I Preparation of (li?,2iS)-phenylpropanolamine (Norephedrine) In a hydrogenation flask taken (R)-phenylacetylcarbinol oxime II prepared in example IB, methanol700 mL followed by Nickel-L(+)-tartaric acid complex prepared by conventional method. The mass charged with aqueous ammonia solution and hydrogenated at 30 °C to 40 °C at 3 kg/cm2 to 4 kg/cm2 of hydrogen pressure till hydrogen consumption ceases. The mass was maintained at 30 °C to 40 °C in 3 kg/cm2 to 4 kg/cm2 of hydrogen gas pressure. The progress of the reaction mass was monitored by HPLC and mass was cooled to 30 °C to 35 °C. The Nickel-Tartaric acid was filtered off and the filtrate was concentrated under reduced pressure. The above mass was diluted with 2-propanol and pH adjusted was adjusted 2.0 - 3.0 with IPA. HC1 and the precipitated product was filtered and washed with 2-propanol (with ee 99.3% and de 97%). The crude (li?,2 99.5 %, Enantiomericpurity> 99 %, Diasteromeric impurity: < 0.2%, Specific optical rotation: (-) 34.2 °. TABLE 1: Input and output data of the major compounds used in the present invention with their respective yields. The advantages of process of the present invention including, but not limited to, are: high enantioselectivity process leading chiral purity > 99%, high purity of about > 95%, decreased effluent load and increased in productivity due to lesser cycle time, much lower energy consumption and a single process leading to the synthesis of two API. Thus, the present invention provides an efficient process to yield (i?)-phenylacetylcarbinol ((i?)-PAC) and (i?)-l-hydroxy-l-phenylpropan-2-one oxime ((i?)-PAC oxime), an intermediate for ephedrine, norephedrine & other drug substances. While the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The invention should therefore not be limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention as claimed. 5 We Claim; 1. A process for preparing (R)-1 -hydroxy-1 -phenylpropan-2-one, of chemical formula I: the process comprises of converting propiophenone(IV) in presence of methanol and sodium nitrite in acidic medium to form a-isonitrosopropiophenone (III): subjecting the a-isonitrosopropiophenone (III) to biotransformation reaction with oxidoreductase in the presence of regeneration enzyme and cofactor nicotinamide adenine dinucleotide (NAD) in aliphatic alcohols solvent system at a temperature ranging from 20°C to 50 °C and pH ranging from 7 to 9 to produce (R)-l-hydroxy-l-phenylpropan-2-one oxime of formula (II) with high chiral purity and hydrolyzing the(i?)-l -hydroxy-1-phenylpropan-2-one oxime (II) in acidic medium at temperature ranging from 5°C to 60 °C to obtain the formula I with optical purity greater than 99%. 2. The process as claimed in claim 1, wherein the solvent used in the biotransformation reduction is selected from carbon chain C-3 to C-8. 3. The process as claimed in claim 1 or 2, wherein the solvent is an isopropylalcohol. 4. The process as claimed in claim 1, wherein the co factor P-NAD acts as hydrogen donor. 5. The process as claimed in claim 1, wherein the temperature selected for the enzymatic reduction is 30° C to 35° C. 6. The process as claimed in claim 1, wherein an optimized pH for the enzymatic reduction is 8.0. 7. The process as claimed in claim 1, wherein the hydrolysis is performed using inorganic and organic acids having carbon chain C-l to C-4 at temperature ranging from 5°C to 60 °C. 8. The process as claimed in claim 7, wherein the acid is hydrochloric acid. 9. The process as claimed in 1 or 7, wherein the temperature range is fromlO°C to 15 °C. 10. The process as claimed in claim 1, wherein comprising utilizing the (R)-1 -hydroxy-1-phenylpropan-2-one oxime as a precursor for production of norephedrine. 11. The process as claimed in claim 1, wherein comprising utilizing synthesis of optically active ephedrine hydrochloride from propiophenone without involving fermentation process. 12. The process as claimed in claim 1, wherein comprising utilizing the (R)-1 -hydroxy-1-phenylpropan-2-one for synthesis of P-aminoalcohols.

Documents

Application Documents

#	Name	Date
1	201841048764-STATEMENT OF UNDERTAKING (FORM 3) [22-12-2018(online)].pdf	2018-12-22
2	201841048764-FORM 1 [22-12-2018(online)].pdf	2018-12-22
3	201841048764-DECLARATION OF INVENTORSHIP (FORM 5) [22-12-2018(online)].pdf	2018-12-22
4	201841048764-COMPLETE SPECIFICATION [22-12-2018(online)].pdf	2018-12-22
5	Correspondence by Agent_F3, F5, Power of Attorney_04-01-2019.pdf	2019-01-04
6	201841048764-Information under section 8(2) (MANDATORY) [04-01-2019(online)].pdf	2019-01-04
7	201841048764-Information under section 8(2) (MANDATORY) [04-01-2019(online)]-1.pdf	2019-01-04
8	201841048764-Proof of Right (MANDATORY) [29-01-2019(online)].pdf	2019-01-29
9	Correspondence by Agent_Form 1_30-01-2019.pdf	2019-01-30
10	201841048764-Request Letter-Correspondence [30-12-2019(online)].pdf	2019-12-30
11	201841048764-Power of Attorney [30-12-2019(online)].pdf	2019-12-30
12	201841048764-Form 1 (Submitted on date of filing) [30-12-2019(online)].pdf	2019-12-30
13	201841048764-CERTIFIED COPIES TRANSMISSION TO IB [30-12-2019(online)].pdf	2019-12-30
14	201841048764-FORM 3 [06-01-2020(online)].pdf	2020-01-06
15	201841048764-FORM 3 [30-09-2020(online)].pdf	2020-09-30
16	201841048764-RELEVANT DOCUMENTS [11-10-2021(online)].pdf	2021-10-11
17	201841048764-FORM 13 [11-10-2021(online)].pdf	2021-10-11
18	201841048764-AMENDED DOCUMENTS [11-10-2021(online)].pdf	2021-10-11
19	201841048764-FORM 18 [06-12-2022(online)].pdf	2022-12-06
20	201841048764-FER.pdf	2022-12-22
21	201841048764-Information under section 8(2) [23-06-2023(online)].pdf	2023-06-23
22	201841048764-FORM 3 [23-06-2023(online)].pdf	2023-06-23
23	201841048764-FER_SER_REPLY [23-06-2023(online)].pdf	2023-06-23
24	201841048764-US(14)-HearingNotice-(HearingDate-28-02-2024).pdf	2024-02-07
25	201841048764-Correspondence to notify the Controller [26-02-2024(online)].pdf	2024-02-26
26	201841048764-FORM-26 [27-02-2024(online)].pdf	2024-02-27
27	201841048764-Written submissions and relevant documents [12-03-2024(online)].pdf	2024-03-12
28	201841048764-FORM 3 [12-03-2024(online)].pdf	2024-03-12
29	201841048764-PatentCertificate30-03-2024.pdf	2024-03-30
30	201841048764-IntimationOfGrant30-03-2024.pdf	2024-03-30

Search Strategy

1	_c-kPJh1nCd3k_Br1YipLOCge1HcOy3egYB-PNFrBGnajzFrQ1kamP_oXouWusy-J8eeh4VROVDGq-0PR1kBiB7w2VuK1sT3byTR1B95wOLl6rxiJjOMoByDhSiqyUrcE_22-12-2022.pdf