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Process For The Preparation Disodium Salt Of Pyrroloquinoline Quinone

Abstract: The present invention relates to a process tor the preparation of disodium salt of pyrroloquinoline quinone. Also relates to novel polymorphic form of pyrroloquinoline quinone disodium salt and process for its preparation.

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Patent Information

Application #
Filing Date
10 January 2017
Publication Number
28/2018
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2021-12-31
Renewal Date

Applicants

Laurus Labs Ltd
Plot No. DS1 IKP Knowledge Park, Genome Valley, Turkapally Shameerpet, Hyderabad. Telangana India 500 078

Inventors

1. Munisekharreddy SANNAREDDY
Plot No. DS1 IKP Knowledge Park, Genome Valley, Turkapally Shameerpet, Hyderabad. Telangana, India 500 078.
2. Gangadhar MANDHAPURAM
Plot No. DS1 IKP Knowledge Park, Genome Valley, Turkapally Shameerpet, Hyderabad. Telangana India 500 078.
3. Sravana Kumar CHENNUPATI
Plot No. DS1 IKP Knowledge Park, Genome Valley, Turkapally Shameerpet, Hyderabad. Telangana, India 500 078.
4. Ravinder APPANI
Plot No. DS1 IKP Knowledge Park, Genome Valley, Turkapally Shameerpet, Hyderabad. Telangana, India 500 078.
5. Sreenivasa Rao DAMARLA
Plot No. DS1 IKP Knowledge Park, Genome Valley, Turkapally Shameerpet, Hyderabad. Telangana, India 500 078.

Specification

This application claims the benefit under Indian Provisional Application No. [N201741000952 filed on Jan 10, 2017, the content of which is incorporated by reference herein. FIELD OF THE INVENTION: The present invention relates to a process for the preparation of disodium salt of pyrroloquinoline quinone. The present invention also relates to novel polymorphic form of pyrroloquinoline quinone disodium salt, process for its preparation and use thereof. BACKGROUND OF THE INVENTION: Pyrroloquinoline quinone (herein after referred as "PQQ") is a natural product and is categorized as an essential 20 micronutrient and dietary supplement as it plays a critical role in the mitochondrial biogenesis. PQQ is also known as methoxatin and chemically known as 2,7,9-tricarboxylH-pyrrolo(2s3-f)quinolone-4,5-dione or 4,5-dioxo-4,52 in 35 ml of DM water) was slowly added to the above, reaction mass at -25 to -35°C and stirred for 15 mins. Ethanol (100 ml) was added to the-reaction mass at -25 to -35°C. The reaction mass temperature was raised to -8 to -10°C and stirred for 30 mins. The reaction mass was then cooled to -25°C to -15°C, 45% aqueous fluoro boric acid (58.6 ml) followed by ethanol (100 ml) was added to it at below -5°C and stirred for 30 mins at -5 to 0°C. The reaction mass was filtered, washed with cold ethanol and the obtained solid was washed with di-isopropylether. The solid obtained followed by ethyl 2-methylacetoacetate (43.4 g) was added to pre-cooled ethanol (275 ml) at -25 to -15°C. Sodium acetate solution (obtained by dissolving 81.5 g of sodium acetate in 250 ml of DM water) was added to the reaction mass at below -10° C for about lhr. The reaction mass temperature was raised to 25-35°C and stirred for 12 hrs under nitrogen atm. The solid obtained was filtered off, washed with 10% aqueous ethanol and dried the solid under vacuum at 55-65°C for 6 hrs to get the title compound. Yield: 55 g, Purity by HPLC: 98.2% ■ Example-5: Preparation of ethyl-6-formylamino-5-methoxy-lH-indole-2- To a 1.0 L 4 neck RB flask fixed with a mechanical stirrer, thermo-well and" condenser and heating mantle with guard tube, formic acid (300 ml) and ethyl 2-[(3-formylamino-4-methoxyphenyl)hydrazono]propionate (75 g) was added at 25-35°C. The reaction mass was heated to 75-85°C and stirred for 5 hrs. After reaction completion, the reaction mass was. cooled to 25-35°C, isopropanol (300 ml) was added and stirred for an hour at 25-35°C. The solid obtained was filtered, washed with isopropanol, suck dried and finally dried under vacuum at 55-65° C for 6 hrs to get the title compound. Yield: 36 g, Purity by HPLC: 99.4% Example-6: Preparation of ethyl 6-amino-5-methoxy-lH-indole-2-carboxylate: To a 2.0 L 4 neck RB flask fixed with a mechanical stirrer, thermo-well and condenser and heating mantle with guard tube, acetone (1.0 L), dilute hydrochloric acid solution (160 ml, obtained by addition of 52 ml of con.HCl in to 108 ml of DM water) was added at 25-35°C and stirred for 15 mins. Ethyl-6-formylamino-5-methoxy-lH-indole-2-carboxylate (40 g) was added to the reaction mass at 25-35°C. The reaction mass was heated to 50-60°C and stirred for 3 hrs at 50-60°C. After reaction completion, the reaction mass was cooled to 25-35°C and stirred for ■30 mins. The reaction mass was filtered and the solid obtained was suck dried for 30 mins. DCM (400 ml) was added to the obtained solid and stirred for 5 mins. 8% sodium bicarbonate solution (240 ml, obtained by dissolving 19.2 g of NaHCC>3 in 240 ml of DM water) was added to the reaction mass' and stirred for 5 mins. Organic and aqueous layers were separated, and the solvent from organic layer was distilled out at 35-40°C under vacuum. Diisopropylethylether (40 ml) was added to the obtained crude at 25-35°C and stirred for 30 mins. The solid obtained was filtered, washed with diisopropylethylether, suck dried for 30 mins under vacuum and finally dried under vacuum at 55-65° C for 6 hrs to get the title compound. Yield: 30 g, Purity by HPLC: 97.93% Example-7: Preparation of 5-methoxy-lH-pyrrolo[2,3-f|quinolone-2,7,9-tricarboxylic acid-2-ethyl ester-7,9-dimethyl ester: To a 0.5 L RB flask fixed with a mechanical stirrer, thermo-well and condenser with guard tube, methylenechloride (180 ml), ethyl 6-amino-5-methoxy-lH-indole- 120 ml of methylene chloride) was added at 25-30°C and stirred for 3 hrs at 25-35°C. After reaction completion, the reaction mass was distilled under vacuum at 35-45°C. The reaction mass was then cooled to 25-35°C, methanol (150 ml) was added to it and stirred for an hour at 25-35°C. The reaction mass was filtered, washed with methanol, suck dried for 30 min under vacuum. Formic acid (135 ml) was added to the suck dried material at 25-35°C and stirred for 10 mins at 25-35°C. Copper (II) acetate (13.98 g) was added to the reaction mass and stirred for 16 hrs at 25-35°C. After reaction completion, the reaction mass was added to methylenchloride (750 ml) at 25-35°C and stirred for 10 mins at 25-35°C. DM water (300 ml) was added to the reaction mass and stirred for 10 mins at 25-35°C. Organic and aqueous layers were separated. Organic layer was washed with DM water, filtered through celite bed and washed with methylene chloride. Organic layers were combined and distilled off under vacuum at below 35°C. Ethyl acetate (240 ml) was added to the obtained crude and stirred for 30 mins at 25-35°C. The solid obtained was filtered, washed with ethyl acetate, suck dried and finally dried under vacuum at 60-65°C for 6 hrs to get the title compound. Yield: 30g, Purity by HPLC: 98.86% Example-8: Preparation of 4,5-Dioxo-4,5-dihydro-lH-pyrrolo[2,3-i]quinoIone-2,7,9-tri carboxylic acid-2-ethyl ester 7,9-dimethyl ester: To a 2.0 L RBF fixed with a mechanical stirrer, thermo-well and condenser and heating mantle with guard tube, 5-methoxy-lH-pyrrolo[2,3.-f]quinolone-2,7,9-tricarboxylic acid-2-ethyl ester-7,9-dimethyl ester (30 g) followed by acetonitrile (900 ml) was added at 25-35°C. The reaction mass was cooled to -25 to -15°C. Ceric ammonium nitrate solution (obtained by dissolving 219.3 g of eerie ammonium nitrate in 330 ml of DM water) was added to the reaction mass at -25 to -15°C for 30 mins and stirred for 2 hrs at -25 to -15°C. After reaction completion, organic and aqueous layers were separated; organic layer was filtered through celite bed and washed with acetonitrile. Organic layers were combined and distilled off at below 35°C. Then, water present in the reaction mass was removed by filtration and the solid was washed with water, suck dried for 30 mins under vacuum. Methanol (150 ml) was added to the suck dried solid at 25-35°C and stirred.for 30, mins. The finally dried under vacuum at 55-65°C for 6 hrs to get the title compound. Yield: 15 g, Purity by HPLC: 95.95% Example-9: Preparation of dimethyl 2-oxoglutaconate: Step 1: Dimethyl 2-oxoglutarate: To a 10.0 L 4 neck RB flask fixed with a mechanical stirrer, thermo-well and guard tube, methanol (8 L) and 2-oxo-glutaric acid (500 g) was added at 25-35°C and stirred for 15 mins. Sulfuric acid (49.5 g) was added to the above reaction mass at 25-35°C and slowly heated to reflux temperature, then the reaction mass was stirred for 3 hrs at 60-65°C. After reaction completion, the reaction mass was cooled to 30-40°C and distilled off methanol under vacuum at below 40°C. Methylene chloride (2.5 L) followed by DM water (500 ml) was added to the reaction mass at 30-35°C and stirred for 15 mins. Organic and aqueous layers were separated. Organic layer washed with 3% sodium bicarbonate solution, followed by DM water. Then organic layer was dried over sodium sulphate and distilled under vacuum at 25-35°C. The final compound was collected by fractional distillation at 150-160°C under vacuum. Yield: 502 g. Step-2: Dimethyl 2-oxoglutaconate To a' 5.0 L 4 neck RB flask fixed with a mechanical stirrer, thermo-well and addition funneland heating mantle with guard tube, methylene chloride (2.5L) and dimethyi-2-oxo-glutarate (500 g) was added at 25-35°C. The reaction mass was heated to 35-45°C. Bromine solution (440 g,. prepared by mixing 142 ml of bromine with 1 L of methylene chloride) was added to the reaction mass at 35-45°C for an hour and stirred for 3 hrs at same temperature. After reaction completion, methylene chloride was distilled off completely at below 40°C under vacuum. Co-distilled the crude with di-isopropyl ether (500 ml) at 35-45°C under vacuum. Di-isopropyl ether (5 L) was added to the reaction mass and stirred for 15 mins. Triethylamine (255.6"g) was added to the reaction mass at below 35°C and stirred for an hour. The reaction mass was filtered, washed with washed with di-isopropyl ether and nitrogen was bubbled through the filtrate for an hour; then filtered through silica gel. The diisopropyl ether from filtrate was distilled off completely at below 40°C 30°C and stirred for 30 mins at 0-5°C. The product obtained was filtered, washed with chilled di-isopropyl ether and dried at 25-35°C under air dryer for 2 hrs. Yield: 201.5 g. We Claim: Claim 1: A process for the preparation of disodium salt of PQQ, which comprise of: a) reacting trialkyl ester compound having the following structural formula (II) wherein R|, R2, R3 is same or different and selected from straight or branched chain d-g alkyl; with a base in presence a solvent, b) adjusting step a) reaction mass pH to less than 1 with a suitable acid, c) optionally heating the reaction mass, d) filtering the reaction mass to obtain PQQ. e) reacting the PQQ obtained in step d) with sodium acetate in a suitable solvent; and f) isolating the disodium salt of PQQ. Claim 2: The process as claimed in cllaim 1, wherein R|, R?. or R3 is either methyl or ethyl. Claim 3: The process as claimed in claim 1, wherein the solvent in step a) and step e) is selected from the group comprising methanol, ethanol, isopropanol, butanol, tetrahydrofuran, 2-methyl tetrflhvHmfnran, methyltert-butyiether, 1,4-dioxane, water and mixtures thereof. Claim 4: The process as claimed in claim 1, wherein the base in step a) is selected from the group comprising sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and mixtures thereof. Claim 5: The process as claimed in claim 1. wherein the acid in step b) is hydrochloric acid or sulphuric acid. Claim 6: • The process as claimed in claim 1, wnerein in the temperature of step c) for heating the reaction mass is about 40°C|to reflux temperature. Claim 7: The process as claimed in claim 1, wherein the step e) reaction is carried out at a temperature of about 15°C tn Ahnnt 45°C. Claim 8: The process as claimed in claim 1, wherein the solvent in step a) and step e) is water; the base in step a) is sodium hvdroxide; and the acid in step b) is hydrochloric acid. Claim 9: The process as claimed in claim 1, wherein the disodium salt of PQQ is free of mono and tri sodium salts. 'Claim 10: The disodium salt of PQQ obtained according to the process as claimed in claim 1 is characterized by a powder X-ray diffraction pattern having one or more peaks at about 8.2, 13.6, 15.1, io.:>, 17.3, 21.4, 22.3, 24.8, 25.7, 27.2, 29.8, 33.5, 34.3, 38.8 and 42.0 ± 0.2° 20.

Documents

Application Documents

# Name Date
1 Form2 Title Page_Provisional_10-01-2017.pdf 2017-01-10
2 Form1_As Filed_10-01-2017.pdf 2017-01-10
3 Drawings_As Filed_10-01-2017.pdf 2017-01-10
4 Description Provisional_As Filed_10-01-2017.pdf 2017-01-10
5 Correspondence by Agent_Provisional Specificational_10-01-2017.pdf 2017-01-10
6 Correspondence by Applicant_Change Email Address_18-09-2017.pdf 2017-09-18
7 Form 5_Complete After Provisional_08-01-2018.pdf 2018-01-08
8 Form 2(Title Page)_Complete After Provisional_08-01-2018.pdf 2018-01-08
9 Drawing_Complete After Provisional_08-01-2018.pdf 2018-01-08
10 Description (Complete)_Complete After Provisional_08-01-2018.pdf 2018-01-08
11 Correspondence by Applicant_Complete After Provisional_08-01-2018.pdf 2018-01-08
12 Claims_Complete After Provisional_08-01-2018.pdf 2018-01-08
13 Abstract_Complete After Provisional_08-01-2018.pdf 2018-01-08
14 201741000952-RELEVANT DOCUMENTS [31-12-2020(online)].pdf 2020-12-31
15 201741000952-FORM 18 [31-12-2020(online)].pdf 2020-12-31
16 201741000952-FORM 13 [31-12-2020(online)].pdf 2020-12-31
17 201741000952-AMENDED DOCUMENTS [31-12-2020(online)].pdf 2020-12-31
18 201741000952-FORM 4(ii) [07-09-2021(online)].pdf 2021-09-07
19 201741000952-OTHERS [05-10-2021(online)].pdf 2021-10-05
20 201741000952-FER_SER_REPLY [05-10-2021(online)].pdf 2021-10-05
21 201741000952-COMPLETE SPECIFICATION [05-10-2021(online)].pdf 2021-10-05
22 201741000952-CLAIMS [05-10-2021(online)].pdf 2021-10-05
23 201741000952-ABSTRACT [05-10-2021(online)].pdf 2021-10-05
24 201741000952-US(14)-HearingNotice-(HearingDate-09-11-2021).pdf 2021-10-17
25 201741000952-FER.pdf 2021-10-17
26 201741000952-Correspondence to notify the Controller [23-10-2021(online)].pdf 2021-10-23
27 201741000952-Written submissions and relevant documents [24-11-2021(online)].pdf 2021-11-24
28 201741000952-PETITION UNDER RULE 137 [24-11-2021(online)].pdf 2021-11-24
29 201741000952-Correspondence_Affidavit, Verification_02-12-2021.pdf 2021-12-02
30 201741000952-PatentCertificate31-12-2021.pdf 2021-12-31
31 201741000952-IntimationOfGrant31-12-2021.pdf 2021-12-31
32 201741000952-RELEVANT DOCUMENTS [12-09-2022(online)].pdf 2022-09-12
33 201741000952-RELEVANT DOCUMENTS [15-09-2023(online)].pdf 2023-09-15

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