WO2018096550A1 - Process for the preparation of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate and its polymorphs thereof - Google Patents
Process for the preparation of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate and its polymorphs thereof Download PDFInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- the present invention relates to an improved process for the preparation of methyl 4,6- diamino-2-[l-(2-fluorobenzyl)-l H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula- 1 , represented by the following structural formula:
- the present invention also relates to novel crystalline form of methyl 4,6-diamino-2-
- Riociguat also known as methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- l H-pyrazolo[3, 4- b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1.
- Riociguat is the first of a new class of guanylatecyclase (sGC) agonist, directly activates sGC and increases low levels of NO sensitivity, for treating pulmonary hypertension and chronic obstructive pulmonary hypertension.
- sGC guanylatecyclase
- WO 03/095451 describes the preparation of the compound of the formula- 1.
- disadvantages associated with the process disclosed in WO 03/095451.
- the prior known described methods for the preparation of methyl 4,6-diamino-2-[l- (2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1 involve long reaction time, usage of hazardous reagents which leads to the formation of higher impurities and not suitable for commercial level process.
- CN 104530044 discloses the- process for the preparation of 4,6-diamino-2-[l-(2- fluorobenzyO-l H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyI)carbamate compound of formula- 1 by reacting 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine- 4,5,6-triamine, compound of formula-2 with formic acid in presence of acetic anhydride followed by reducing using sodium borohydride/ BF 3 -etherate to provide compound of formula-3 with low yield and purity, which was further reacts with methyl chloroformate to provide compound of formula- 1 with low yield and purity.
- WO2015/055124 A 1 claims crystalline Form 1, Form II, Form III and Form IV and amorphous forms of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1.
- WO2016/113415 Al claims crystalline forms of methyl acetate solvate, hemi-ethyl acetate solvate and 2-butanone solvate of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1.
- WO2017/025981 Al claims Form-M, Form-M-I, Form-R-I, Form-R-II and Form-S of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula- 1.
- the crystalline form of a drug compound may have different chemical and physical properties, including appearances, melting point, chemical reactivity, apparent solubility, dissolution rate, stability, optical and mechanical properties, vapor pressure and density. These properties may have a direct effect on the ability to process and/or manufacture the drug compound and the drug product, as well as on drug product stability, dissolution, and bioavailability.
- the crystalline forms of the compound of formula- 1 may affect the quality, safety, and efficacy of a drug product comprising the compound of formula- 1.
- the first aspect of the present invention is to provide an improved process for the preparation of methyl 4 > 6-diamino-2-[l-(2-fluoroben2yl)-1H-pyra2olo[3,4-b]pyridin-3-yl]-5- ' pyrimidinyl(methyl)carbamate compound of formula- 1.
- the second aspect of the present invention is to provide a process for the preparation of 2-(l -(2-fluorobenzyI)- 1 H-pyrazolo[3,4-b]pyridin-3-yl)-N5-methylpyrimidine-4,5,6- triamine compound of formula-3.
- the third aspect of the present invention relates to solid state form of 2-(l-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-NS-methylpyrimidine-4,S,6-triamine compound of formula-3.
- the fourth aspect of the present invention is to provide a novel crystalline form of methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl (methyl)carbamate compound of formula- 1, herein after designated as form-M-Il and process for its preparation.
- the fifth aspect of the present invention is to provide an improved process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1.
- Figure 1 Illustrates the PXRD pattern of crystalline form-M-11 of methyl 4,6-diamino-2-[l-
- suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like; "ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl, ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents” such as methyl
- suitable base used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as potassium hydride, lithium hydride and the like; ammonia; and organic bases such "alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert- butoxide and the like; Iriethyl amine, methyl amine, ethyl amine; 1 ,8-diazabicyclo [S.4.0]undec-7-ene (DBU), l,5-di
- the first aspect of the present invention provides an improved process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1, comprising,
- the suitable methylating agent is selected from bromo methane, chloro methane, diazo methane, dimethyl carbonate, dimethyl sulfate, dimethyl zinc, methyl iodide, trimethyl oxonium tetrafluoroborate, tetramethyl ammonium chloride, methyl fluorosulfonate; methyl p-toluene sulfonate, trimethyl aluminum, methyl bromide, methyl chloride, dimethyl oxalate and trimethyl phosphate;
- the suitable base is selected from organic or inorganic bases
- the suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
- the preferred embodiment of the present invention provides an improved process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- yl]-S-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising,
- CN 104530044 discloses process for the preparation of 4,6-diamino-2-[l-(2-fluoro benzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, by reacting 2-(l -(2-fluorobenzyl)- i H-pyrazolo[3, 4-b]pyridin-3-yl)pyrimidine- 4,5,6-triaminc compound of formula-2 ' with formic acid and acetic anhydride to provide N- formyl transition intermediate, which is further reacted with sodium borohydride and BF3- etherate to provide compound of formula-3 with low yield and purity.
- the inventors of the present invention has been developed simple, economical, eco-friendly, commercially viable process for the preparation of compound of formula- 1, by reacting compound of formula-2 with methylating agent such as dimethyl sulfate, which is low cost and highly reactive to provide compound of formula-3 with high yield and purity. Further, the compound of formula-3 reacts with methyl chloroformate to provide compound of formula- 1 with high yield and purity.
- methylating agent such as dimethyl sulfate
- the starting material 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl) pyrimidine-4,S,6-triamine compound of formula-2 used in the present invention can be prepared according to any one of the processes known in the art.
- the second aspect of the present invention provides a process for the preparation of 2- (l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin ⁇
- the. suitable methylating agent is same as defined in step-a) of the first aspect of the present invention and the suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
- the preferred embodiment of the present invention provides an improved process for the preparation of 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N5-methyl pyrimidine-4,5,6-triamine compound of formula-3, comprising reacting the 2-(l-(2-fluoro benzyl)-! H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine compound of formula-2 with dimethyl sulfate in acetone to provide 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin- 3-yl)-NS-methylpyrimidine-4,5,6-triamine compound of formula-3.
- the third aspect of the present invention relates to solid state form of 2-(l-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-NS-methylpyrimidine-4,S,6-triamine compound of formula-3.
- the fourth aspect of the present invention relates to crystalline form M-II of methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl(methyl) carbamate compound of formula- 1 characterized by its X-ray powder diffractogram having peaks at 5.4, 7.8, 8.7, 11.1, 12.2, 13.6, 14.1, 16.0, 17.5, 18.0, 19.2, 19.7, 20.3, 21.0, 21.7, 22.8, 24.1, 26.3, 27.6, 28.9, 30.3, 31.4, 36.0, 38.7 and 42.8 ⁇ 0.2 degrees two-theta as illustrated in figure- 1.
- the another embodiment of the present invention provides a process for the preparation of crystalline form M-II of methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1 H- pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising the following steps:
- step-c) adding the obtained filtrate in step-c) to a pre-cooled suitable solvent at a suitable temperature
- the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof; in step-b) the temperature is ranging from 25°C to reflux temperature of the solvent used in the reaction; in step-d) the suitable solvent is polar solvent like water; the suitable temperature is ranging from -20°C to 20°C.
- the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M-II of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-pvrimidinyl(methyl)carbamate compound of formula- 1, comprising the following steps:
- step-c) adding the filtrate obtained in step-c) to a pre-cooled water at 0-5°C,
- the fifth aspect of the present invention provides an improved process for the preparation of methyl 4,6-diamino-2-[l-(2-fluoroben2yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1, comprising: a) reacting 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride compound of formula-4 with 2-(phenyldiazenyl)malononitrile compound of formula- 5 in the presence of sodium formate in a suitable solvent to provide (E)-2-( 1 -(2-lluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl)-5-(pheny 1 diazenyl)pyrimidine-4,6-diamine compound of formula-6,
- the suitable reducing agent is selected from metal catalyst such as nickel, palladium, platinum, iridium, ruthenium and the like, in combination with hydrogen;
- the alkyl halo formate is a methyl derivative of a chloro or brorno formate and suitable base is selected from organic or inorganic bases;
- the suitable methylating agent is selected from methyl iodide, methyl bromide, dimethyl sulfate, methyl p- toluenesulfonate, and methanesulfonate and the suitable base is selected from organic or inorganic bases;
- the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, nitrile solvents, ether solvents, polar aprotic solvents, hydrocarbon solvents and polar solvents like water or mixture thereof.
- the preferred embodiment of the present invention provides an improved process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3.4-b]pyridin-3- yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising:
- step-e) purifying the methyl 4,6-diamino-2-(l -(2-fluorobenzyl)- 1H- pyrazolo[3,4-b] pyridin-3-yl)pyrimidin-S-ylcarbamate compound of formula-7 of the present invention comprising:
- step-g) purifying the methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl(methyl)carbamate compound of formula- 1 of the present invention comprising:
- step-d e) adding dimethyl formamide and ethyl acetate to the obtained compound in step-d), f) heating the reaction mixture to 90-95°C,
- the methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1 obtained according to the present invention is having purity greater than 99.6 % by HPLC.
- Methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1 produced by the present invention can be further micronized or milled in a conventional techniques to gel the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
- compositions comprising compound of formula- 1 or salts thereof of the present invention.
- pharmaceutical compositions or “pharmaceutical formulations” include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
- Example-1 Preparation of 2-(l-(2-fluorobenzyl)-1H-pyrazolo
- Example-5 Preparation of methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-1H-pyrazolo
- Tetrahydrofuran 60 Its was added to methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate (6.0 kgs) at 25-30°C. Cooled the reaction mixture to -5°C to 5°C. Lithium hexamethyl disilazide (10.5 kgs) was added to the reaction mixture at -5°C to 5°C under nitrogen atmosphere.
- a mixture of tetrahydrofuran (3.0 Its) and methyl iodide (2.5 kgs) was added to the reaction mixture at -5°C to 5°C under nitrogen atmosphere and stirred form 4 hours at the same temperature.
- a mixture of tetrahydrofuran (1.0 It) and methyl iodide (0.6 kgs) was added to the reaction mixture at -5°C to 5°C under nitrogen atmosphere and stirred for 4 hours at the same temperature.
- Aqueous ammonium chloride solution was added to the reaction mixture at -5°C to 5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature.
- Both the organic and aqueous layers were separated and extracted the aqueous layer using a mixture of tetrahydrofuran and ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Carbon (0.6 kgs) was added to the organic layer at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through silica bed and washed the bed with tetrahydrofuran. Distilled off the solvent completely from the filtrate under reduced pressure. Tetrahydrofuran (18.0 Its) was added to the obtained compound at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the solid.
- Tetrahydrofuran (1S.0 Its) and dimethyl sulfoxide (1.0 It) were added to the obtained compound at 25-30°C. Heated the reaction mixture to S0-S5°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with tetrahydrofuran and dried at 60-65°C. A mixture of dimethyl formamide (18.0 Its) and ethyl acetate (18.0 Its) was added to the obtained compound. Heated the reaction mixture to 90-95°C and stirred for IS minutes at the same temperature.
- Example-7 Preparation of crystalline form-M-II of methyl 4,6-diamino-2-[l-(2-fluoro benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate: (Formula- 1)
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Abstract
The present invention relates to an improved process for the preparation of methyl 4,6-diamino-2-[ 1-(2-fluorobenzyl)-1 H -pyrazolo[3,4-b )pyridin-3 -yl]-5-pyrimidinyl(methyl)carbamatecompound of formula-1 and its polymorphs thereof, represented by the following structure:
Description
Process for the preparation of methvj 4.6-diamino-2-ll-(2-fluorobenzvn-1H-Pvrazolo
[3.4-blpvridin-3-vll-5-nvrimidinvl(mcthvhcarbamate and its polymorphs thereof
Related Applications:
This application claims the benefit of priority of our Indian patent application numbers 201641040564 filed on 28,h November 2016 and 201741027578 filed on 3rd August 2017 which are incorporated herein by reference.
Field of the Invention:
The present invention relates to an improved process for the preparation of methyl 4,6- diamino-2-[l-(2-fluorobenzyl)-l H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula- 1 , represented by the following structural formula:
Formula- 1
The present invention also relates to novel crystalline form of methyl 4,6-diamino-2-
[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidiny l(methyl)carbamate compound of formula- 1.
Background of the Invention:
Riociguat, also known as methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- l H-pyrazolo[3, 4- b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1. Riociguat is the first of a new class of guanylatecyclase (sGC) agonist, directly activates sGC and increases low levels of NO sensitivity, for treating pulmonary hypertension and chronic obstructive pulmonary hypertension.
WO 03/095451 describes the preparation of the compound of the formula- 1. However, there are number of disadvantages associated with the process disclosed in WO 03/095451.
The prior known described methods for the preparation of methyl 4,6-diamino-2-[l- (2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1 involve long reaction time, usage of hazardous reagents which leads to the formation of higher impurities and not suitable for commercial level process.
CN 104530044 discloses the- process for the preparation of 4,6-diamino-2-[l-(2- fluorobenzyO-l H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyI)carbamate compound of formula- 1 by reacting 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine- 4,5,6-triamine, compound of formula-2 with formic acid in presence of acetic anhydride followed by reducing using sodium borohydride/ BF3-etherate to provide compound of formula-3 with low yield and purity, which was further reacts with methyl chloroformate to provide compound of formula- 1 with low yield and purity.
Hence, there is an unmet need to develop an improved process which is cost-effective, environment friendly, commercially viable process which provide final compound of formula- 1 with high yield and purity.
WO2014/128109 Al claims crystalline modification 1, modification II, mono-DMSO solvate, scsqui-DMSO solvate, ¼ ethyl acetate solvate and amorphous forms of methyl 4,6- diamino-2-[l -(2-fluoTobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(melhyl) carbamate compound of formula- 1.
WO2015/055124 A 1 claims crystalline Form 1, Form II, Form III and Form IV and amorphous forms of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1.
WO2016/113415 Al claims crystalline forms of methyl acetate solvate, hemi-ethyl acetate solvate and 2-butanone solvate of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1.
WO2017/025981 Al claims Form-M, Form-M-I, Form-R-I, Form-R-II and Form-S of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula- 1.
It has been the endeavor of pharmaceutical scientists to provide novel and stable forms of drug substances, which would have the strengths of thermodynamic stability, enhanced solubility, rapid onset of action and an enhanced bioavailability.
The crystalline form of a drug compound may have different chemical and physical properties, including appearances, melting point, chemical reactivity, apparent solubility, dissolution rate, stability, optical and mechanical properties, vapor pressure and density. These properties may have a direct effect on the ability to process and/or manufacture the drug compound and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus the crystalline forms of the compound of formula- 1 may affect the quality, safety, and efficacy of a drug product comprising the compound of formula- 1.
Brief description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of methyl 4>6-diamino-2-[l-(2-fluoroben2yl)-1H-pyra2olo[3,4-b]pyridin-3-yl]-5- ' pyrimidinyl(methyl)carbamate compound of formula- 1.
The second aspect of the present invention is to provide a process for the preparation of 2-(l -(2-fluorobenzyI)- 1 H-pyrazolo[3,4-b]pyridin-3-yl)-N5-methylpyrimidine-4,5,6- triamine compound of formula-3.
The third aspect of the present invention relates to solid state form of 2-(l-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-NS-methylpyrimidine-4,S,6-triamine compound of formula-3.
The fourth aspect of the present invention is to provide a novel crystalline form of methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl (methyl)carbamate compound of formula- 1, herein after designated as form-M-Il and process for its preparation.
The fifth aspect of the present invention is to provide an improved process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1.
Brief description of the Drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-M-11 of methyl 4,6-diamino-2-[l-
(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl(methyl)carbamate compound of formula- 1.
Detailed description of the Invention:
As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like; "ether solvents" such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl, ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylfbrmamide (DMF), dimethyl sulfoxide (DMSO), N- methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, propylene glycol, 2-methoxyethanol, I, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, anisole, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
The term "suitable base" used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydrides" such as potassium hydride, lithium hydride and the like; ammonia; and organic bases such "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert- butoxide and the like; Iriethyl amine, methyl amine, ethyl amine; 1 ,8-diazabicyclo [S.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium dioisopropyl amide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropyl amine, diiso propylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylamino
pyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methyl imidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
The first aspect of the present invention provides an improved process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1, comprising,
a) reacting 2-(l-(2-fluorobenzyl)-l H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6- triamine compound of formula-2 with a suitable methylating agent in a suitable solvent to provide 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-NS-methyl pyrimidine-4,S,6-triamine compound of formula-3,
b) reacting the compound of formula-3 with methyl chloroformate (or) dimethyl dicarbonate in presence of a suitable base in a suitable solvent to provide methyl 4,6- diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl (methyl)carbamate compound of formula- 1.
Wherein, in step-a) the suitable methylating agent is selected from bromo methane, chloro methane, diazo methane, dimethyl carbonate, dimethyl sulfate, dimethyl zinc, methyl iodide, trimethyl oxonium tetrafluoroborate, tetramethyl ammonium chloride, methyl fluorosulfonate; methyl p-toluene sulfonate, trimethyl aluminum, methyl bromide, methyl chloride, dimethyl oxalate and trimethyl phosphate;
in step-b) the suitable base is selected from organic or inorganic bases;
in step-a) and b) the suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
The preferred embodiment of the present invention provides an improved process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- yl]-S-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising,
a) reacting 2-(l-(2-fluorobenzyl)-l H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6- triamine compound of formula-2 with dimethyl sulfate in acetone to provide 2-(l-(2-
fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N5-me%
compound of formula-3,
b) reacting the compound of formula-3 with methyl chloroformate (or) dimethyl dicarbonate in presence of aqueous sodium carbonate in letrahydrofuran to provide methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1.
CN 104530044 discloses process for the preparation of 4,6-diamino-2-[l-(2-fluoro benzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, by reacting 2-(l -(2-fluorobenzyl)- i H-pyrazolo[3, 4-b]pyridin-3-yl)pyrimidine- 4,5,6-triaminc compound of formula-2' with formic acid and acetic anhydride to provide N- formyl transition intermediate, which is further reacted with sodium borohydride and BF3- etherate to provide compound of formula-3 with low yield and purity.
Inventors of the present invention when repeated the same reaction, i.e. reacting compound of formula-2 with formic acid and acetic anhydride provided N-formyl intermediate, which is further reacted with sodium borohydride and BFa-etherate provided compound of formula-3 and N-formyl intermediate is retained as an impurity. This compound of formula-3 reacted with methyl chloroformate provided compound of formula- 1 with low yield and purity. In order to get the pure compound, multiple purifications are required which leads to decrease in the yield and generation of lot of spent solvents and solid waste which are difficult to dispose and which may lead to the pollution of the environment. Moreover the said reaction requires longer hours and also involves usage of sodium borohydride.
Considering the several drawbacks associated in the above process for the preparation of compound of formula- 1, the inventors of the present invention has been developed simple, economical, eco-friendly, commercially viable process for the preparation of compound of formula- 1, by reacting compound of formula-2 with methylating agent such as dimethyl sulfate, which is low cost and highly reactive to provide compound of formula-3 with high yield and purity. Further, the compound of formula-3 reacts with methyl chloroformate to provide compound of formula- 1 with high yield and purity.
2-(l-(2-Fluorobenzyl)-1H-pyrazolo[3)4-b]pyridin-3-yl)-N-methylpyrimidine-4,5]6- triamine compound of formula-3 of the present invention having purity of greater than 99.9%, preferably a purity of greater than 99.95% as determined by HPLC area percentage.
The starting material 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl) pyrimidine-4,S,6-triamine compound of formula-2 used in the present invention can be prepared according to any one of the processes known in the art.
The second aspect of the present invention provides a process for the preparation of 2- (l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin^
compound of formula-3, comprising reacting the 2-(l-(2-fiuorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl)pyrimidine-4,5,6-triamine compound of formula-2 with a suitable methylating agent in the presence of a suitable solvent.
Wherein,' the. suitable methylating agent is same as defined in step-a) of the first aspect of the present invention and the suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
The preferred embodiment of the present invention provides an improved process for the preparation of 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N5-methyl pyrimidine-4,5,6-triamine compound of formula-3, comprising reacting the 2-(l-(2-fluoro benzyl)-! H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine compound of formula-2 with dimethyl sulfate in acetone to provide 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin- 3-yl)-NS-methylpyrimidine-4,5,6-triamine compound of formula-3.
The third aspect of the present invention relates to solid state form of 2-(l-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-NS-methylpyrimidine-4,S,6-triamine compound of formula-3.
Use of solid state form of 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N5- methylpyrimidine-4,S,6-triamine compound of formula-3 in the preparation of pure compound of formula- 1.
The process of the present invention can be represented schematically as follows:
The fourth aspect of the present invention relates to crystalline form M-II of methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl(methyl) carbamate compound of formula- 1 characterized by its X-ray powder diffractogram having peaks at 5.4, 7.8, 8.7, 11.1, 12.2, 13.6, 14.1, 16.0, 17.5, 18.0, 19.2, 19.7, 20.3, 21.0, 21.7, 22.8, 24.1, 26.3, 27.6, 28.9, 30.3, 31.4, 36.0, 38.7 and 42.8 ± 0.2 degrees two-theta as illustrated in figure- 1.
The another embodiment of the present invention provides a process for the preparation of crystalline form M-II of methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1 H- pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising the following steps:
a) adding a suitable solvent to methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1 H-pyrazolo
[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate,
b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture and filtering the reaction mixture,
d) adding the obtained filtrate in step-c) to a pre-cooled suitable solvent at a suitable temperature,
e) stirring the reaction mixture, filtering the precipitated solid to get crystalline form M- II of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-S- pyrimidinyl(methyl)carbamate compound of formula- 1.
Wherein, in step-a), the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof; in step-b) the temperature is ranging from 25°C to reflux temperature of the solvent used in the reaction; in step-d) the suitable solvent is polar solvent like water; the suitable temperature is ranging from -20°C to 20°C.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M-II of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-pvrimidinyl(methyl)carbamate compound of formula- 1, comprising the following steps:
a) adding methanol to methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate,
b) heating the reaction mixture to 6S-70°C,
c) stirring the reaction mixture and filtering the reaction mixture,
d) adding the filtrate obtained in step-c) to a pre-cooled water at 0-5°C,
e) stirring the reaction mixture, filtering the precipitated solid and drying to get crystalline form-M-II of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4- b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1.
The fifth aspect of the present invention provides an improved process for the preparation of methyl 4,6-diamino-2-[l-(2-fluoroben2yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1, comprising:
a) reacting 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride compound of formula-4 with 2-(phenyldiazenyl)malononitrile compound of formula- 5 in the presence of sodium formate in a suitable solvent to provide (E)-2-( 1 -(2-lluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl)-5-(pheny 1 diazenyl)pyrimidine-4,6-diamine compound of formula-6,
b) optionally purifying the compound of formula-6 using a suitable solvent,
c) reduction of compound of formula-6 using a suitable reducing agent in a suitable solvent to provide 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine- 4,5,6-triamine compound of formula-2,
d) reacting the compound of formula-2 with alkyl halo formate in presence of a suitable base in a suitable solvent to provide methyl 4,6-diamino-2-(l -(2-fluorobenzyl)- 1H- pyrazolo[3.4-b]pyridin-3-yl)pyrimidin-S-ylcarbamate compound of formula-7, e) optionally purifying the compound of formula-7 using a suitable solvent,
f) reacting the compound of formula-7 with a suitable methylating agent in presence of a suitable base in a suitable solvent to provide methyl 4,6-diamino-2-[1 -(2-fluoro benzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl(methyl)carbamate compound of formula- 1,
g) purifying the compound of formula- 1 using a suitable solvent to provide pure methyl 4,6-diamino-2-[1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1.
Wherein, in step-c) the suitable reducing agent is selected from metal catalyst such as nickel, palladium, platinum, iridium, ruthenium and the like, in combination with hydrogen; in step-d) the alkyl halo formate is a methyl derivative of a chloro or brorno formate and suitable base is selected from organic or inorganic bases; in step-f) the suitable methylating agent is selected from methyl iodide, methyl bromide, dimethyl sulfate, methyl p- toluenesulfonate, and methanesulfonate and the suitable base is selected from organic or inorganic bases; in step-a) to step-g) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, nitrile solvents, ether solvents, polar aprotic solvents, hydrocarbon solvents and polar solvents like water or mixture thereof.
The preferred embodiment of the present invention provides an improved process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3.4-b]pyridin-3- yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising:
a) reacting the l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride compound of formu)a-4 with 2-(phenyldiazenyl)malononitrile compound of formula-5 in presence of sodium formate in toluene to provide (E)-2-(l- (2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6- diamine compound of formula-6,
b) purifying the compound of formula-6 using isopropanol,
c) reduction of- compound of formula-6 using Pd/C in presence of dimethyl formamide to provide 2-(l-(2-fluorobenzyl)-l H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5.6- triamine compound of formula-2,
d) reacting the compound of formula-2 with methyl chloroformate in presence of triethyl amine in a mixture of methanol and isopropanol to provide methyl 4,6- diamino-2-(l -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3 -yl)pyrimidin-5-yl carbamate compound of formula-7,
e) purifying the compound of formula-7 using a suitable solvent,
f) reacting the compound of formula-7 with methyl iodide in presence of lithium hexamethyldisilazide in tetrahydrofuran to provide methyl 4,6-diamino-2-[l-(2-fluoro benzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl(methyl)carbamate compound of formula- 1,
g) purifying the compound of formula- 1 using a suitable solvent to get pure methyl 4,6- diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula- 1.
Wherein, in step-e) purifying the methyl 4,6-diamino-2-(l -(2-fluorobenzyl)- 1H- pyrazolo[3,4-b] pyridin-3-yl)pyrimidin-S-ylcarbamate compound of formula-7 of the present invention comprising:
a) dissolving the compound of formula-7 in a mixture of methanol and dichloromethane,
b) adding silica gel and carbon to the reaction mixture and stirring the reaction mixture at 25-30°C,
c) filtering the reaction mixture through hyflow bed,
d) distilling off the solvent from the filtrate obtained in step-c),
e) adding dimethyl formamide to the obtained compound,
0 heating the reaction mixture to 70-75°C and stirring the reaction mixture,
g) adding ethyl acetate to the reaction mixture and stirring the reaction mixture at 70- 75°C,
h) cooling the reaction mixture to 25-30°C and stirring the reaction mixture,
i) filtering the precipitated solid,
j) adding water to the obtained compound at 25-30°C and stirring the reaction mixture, k) filtering the solid, washing with water and drying to provide methyl 4,6-diamino-2-
(l-(2-fluorobenzyl)-1H-pyraz01o[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate compound offormula-7.
Wherein, in step-g) purifying the methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl(methyl)carbamate compound of formula- 1 of the present invention comprising:
a) adding tetrahydrofuran and dimethyl sulfoxide to compound of formula- 1 , b) heating the reaction mixture to 50-55°C and stirring the reaction mixture,
c) cooling the reaction mixture and stirring the reaction mixture,
d) filtering the precipitated solid,
e) adding dimethyl formamide and ethyl acetate to the obtained compound in step-d), f) heating the reaction mixture to 90-95°C,
g) adding carbon to the reaction mixture,
h) filtering the reaction mixture,
i) adding ethyl acetate to the filtrate at 25-30°C and stirring the reaction mixture, j) filtering the precipitated solid,
k) adding water to the obtained solid,
1) heating the reaction mixture to 50-55°C and stirring the reaction mixture,
m) cooling the reaction mixture and filtering the solid and drying to provide pure methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)-1 H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula- 1.
The process of the present invention is represented schematically as below:
The methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1 obtained according to the present invention is having purity greater than 99.6 % by HPLC.
Methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1 produced by the present invention can be further micronized or milled in a conventional techniques to gel the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The invention also encompasses pharmaceutical compositions comprising compound of formula- 1 or salts thereof of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
P-XRD Method of Analysis:
PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/ AXS X-Ray diffracto meter using Cu Ka radiation of wavelength 1.S406 A° and continuous scan speed of 0.03°/min.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention
Examples:
Example-1: Preparation of 2-(l-(2-fluorobenzyl)-1H-pyrazolo|3,4-b]pyridin-3-yl)-N- methylpyrimidinc-4,5,6-triamine (Formula-3)
Acetone (SO ml) was added to 2-(l-(2-fluorobenzyl)-1H-pyrazo]o[3,4-b]pyridin-3-yl) pyrimidine-4,S,6-triamine (10 gms) compound of formula-2 at 25-30°C and stirred for 10 minutes at the same temperature. Dimethyl sulfate (10.79 gms) was slowly added to the reaction mixture at 25-30°C and stirred for 40 hours at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 8 gms. ExampIe-2: Preparation of methyl 4,6-diamino-2-[l-(2-fluorobcnzyl)-1H-pyrazolo|3,4-b] pyridin-3-yl]-5-pyrimidinyI(methyl)carbamate (Formula-l)
A mixture of 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N-methyl pyrimidine-4,5,6-triamine (8 gms) compound of formula-3, tetrahydrofuran (56 ml), aqueous sodium carbonate solution were stirred for 20 minutes at 0-5°C. Methyl chloroformate (2.48 gms) was slowly added to the reaction mixture at 0-5°C. Raised the reaction mixture temperature to 10-15°C and stirred for 4 hours at the same temperature. Water (40 ml) and ethyl acetate (40 ml) were added to the reaction mixture at 10-15°C. Raised the reaction mixture temperature to 2S-30°C and stirred for 40 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure. Methanol (40 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 5 gms.
Example-3: Preparation of (E)-2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5- (phenyldiazenyI)pyrimidine-4,6-diamine (Formula-6)
A mixture of toluene (63 Its), l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3- carboximidamide hydrochloride (9.0 kgs), 2-(phenyldiazenyl)malononitrile (5.5 kgs), and sodium formate (2.4 kgs) were heated to 105-110°C and stirred for 8 hours at the same temperature. Cooled the reaction mixture to 50-55°C. Water (36.0 Its) was added to the reaction mixture at 50-55°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and washed with toluene. To the obtained compound, isopropanol (45 Its)
was added at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 12.47 kgs.
Examplc-4: Preparation of 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl) pyrimidine-4,5,6-triamine (Formula-2)
Dimethyl formamide (46 Us) was added to (E)-2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4- b]pyridin-3-yl)-5-(phenyldiazenyl)pyritnidine-4,6-diamine (10 kgs), at 25-30°C. 50% Pd/C (1.0. kgs) was added to the reaction mixture at 25-30°C under nitrogen atmosphere. The reaction mixture was hydrogcnated for 8 hours under a hydrogen gas pressure 3.0-5.0 kg/cm2 at 60-65°C. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed the bed with dimethyl formamide. Distilled off the solvent completely from the filtrate under reduced pressure. Aqueous hydrochloric acid solution was slowly added to the obtained compound at 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Filtered the solid and washed with water. To the obtained compound, aqueous sodium carbonate solution was added at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with water and dried to get the title compound.
Yield: 7.62 kgs.
Example-5: Preparation of methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-1H-pyrazolo|3,4-b] pyridin-3-yl)pyrimidin-5-ylcarbainate (Formula- 7)
Isopropanol (75 Its) was added to 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)pyrimidine-4,5,6-triamine (7.5 kgs) at 25-30°C and stirred for 10 minutes at the same temperature. Methyl chloroformate (2.4 kgs) was slowly added to the reaction mixture at 25- 30°C and stirred for 90 minutes at the same temperature. Heated the reaction mixture to 50- 55°C. Triethyl amine (4.5 Its) and methanol (1.5 Its) were added to the reaction mixture at 50- 55°C and stirred for 90 minutes at the same temperature. Cooled the reaction mixture to 25- 30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and washed with a mixture of isopropanol and methanol. To the obtained compound, dichloromethane (112.5 Its) and methanol (1 12.5 Its) were added at 25-30°C and stirred for 15 minutes at the same temperature. Silica gel was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Carbon (3.0 kgs) was added to the reaction mixture at 25- 30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through
hyflow bed and washed the bed with a mixture of methanol and dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure. Dimethyl formamide (15.0 Its) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 70-75X and stirred for 15 minutes at the same temperature. Ethyl acetate (37.5 Its) was slowly added to the reaction mixture at 70-75°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with ethyl acetate. To the obtained compound, water (22.5 Its) was added at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the solid, washed with water and dried to get the title compound.
Yield: 6.40 kgs.
ExampIe-6: Preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo|3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (Formula-1)
Tetrahydrofuran (60 Its) was added to methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate (6.0 kgs) at 25-30°C. Cooled the reaction mixture to -5°C to 5°C. Lithium hexamethyl disilazide (10.5 kgs) was added to the reaction mixture at -5°C to 5°C under nitrogen atmosphere. A mixture of tetrahydrofuran (3.0 Its) and methyl iodide (2.5 kgs) was added to the reaction mixture at -5°C to 5°C under nitrogen atmosphere and stirred form 4 hours at the same temperature. A mixture of tetrahydrofuran (1.0 It) and methyl iodide (0.6 kgs) was added to the reaction mixture at -5°C to 5°C under nitrogen atmosphere and stirred for 4 hours at the same temperature. Aqueous ammonium chloride solution was added to the reaction mixture at -5°C to 5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer using a mixture of tetrahydrofuran and ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Carbon (0.6 kgs) was added to the organic layer at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through silica bed and washed the bed with tetrahydrofuran. Distilled off the solvent completely from the filtrate under reduced pressure. Tetrahydrofuran (18.0 Its) was added to the obtained compound at 25-30°C and stirred for 45 minutes at the same temperature.
Filtered the solid. Tetrahydrofuran (1S.0 Its) and dimethyl sulfoxide (1.0 It) were added to the obtained compound at 25-30°C. Heated the reaction mixture to S0-S5°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with tetrahydrofuran and dried at 60-65°C. A mixture of dimethyl formamide (18.0 Its) and ethyl acetate (18.0 Its) was added to the obtained compound. Heated the reaction mixture to 90-95°C and stirred for IS minutes at the same temperature. Carbon (0.9 kgs) was added to the reaction mixture at 90- 95°C and stirred for 10 minutes at the same temperature. Filtered the reaction mixture through silica bed and washed the bed with hot ethyl acetate. Ethyl acetate (36.0 Its) was added to the obtained filtrate at 25-30°C and stirred for 16 hours at the same temperature. Filtered the precipitated solid and washed with ethyl acetate. Water (24.0 Its) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for IS minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 1.98 kgs.
Example-7: Preparation of crystalline form-M-II of methyl 4,6-diamino-2-[l-(2-fluoro benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate: (Formula- 1)
Methanol (400 ml) was added to methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl(methyl)carbamate (4 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 65-70°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed. The obtained filtrate was slowly added to pre-cooled water (1200 nil) at 0°C and stirred for 40 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 3.0 gms.
The P-XRD pattern of the obtained compound was depicted in figure- 1.
Claims
1. A process for the preparation of methyl 4,6-diamino-2-[l-(2-fiuorobenzyl)-1H-pyrazolo
[3,4-b]pyridin-3-yl]-5-pyrimidinyl(inethyl)carbamate compound of formula- 1, comprising, a) reacting 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6- triamine compound of formula-2 with a suitable methylating agent in a suitable solvent to provide 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-NS-methyl pyrimidine-4,5,6-triamine compound of formula-3,
b) reacting compound of formula-3 with methyl chloroformate (or) dimethyl dicarbonate in presence of a suitable base in a suitable solvent to provide methyl 4,6- diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-S-pyrimidinyl (methyl)carbamate compound of formula- 1.
2. The process as .claimed in claim 1, wherein, in step-a) the suitable methylating agent is selected from bromo methane, chloro methane, diazomethane, dimethyl carbonate, dimethyl sulfate, dimethyl zinc, methyl iodide, trimethyl oxonium tetrafluoroborate, tetramethyl ammonium chloride, methyl fluorosulfonate, methyl p-toluene sulfonate, trimethyl aluminum, methyl bromide, methyl chloride, dimethyl oxalate and trimethyl phosphate;
in step-b) the suitable base is selected from organic or inorganic bases;
in step-a) and b) the suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
3. A process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo
[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising, a) reacting 2-( 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6- triamine compound of formula-2 with dimethyl sulfate in acetone to provide 2-(l-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N5-methylpyrimidine-4,S,6-triamine compound of formula-3,
b) reacting compound of formula-3 with methyl chloroformate (or) dimethyl dicarbonate in the presence of aqueous sodium carbonate in tetrahydrofuran to
provide methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3J4-b]pyridin-3-yl]- 5-pyrimidinyl(methyl)carbamate compound of formula- 1.
4. A process for the preparation of 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- N5-memylpyrimidine-4,5,6-niamine compound of formula-3, comprising reacting the 2- (1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,S,6-triamine compound of formula-2 with methylating agent in the presence of a suitable solvent.
5. The process as claimed in claim 4, wherein, the suitable methylating agent is selected from bromo methane, chloro methane, diazomethane, dimethyl carbonate, dimethyl sulfate, dimethyl zinc, methyl iodide, trimethyl oxonium tetrafluoroborate, tetramethyl ammonium chloride, methyl fluorosulfonate, methyl p-toluene sulfonate, trimethyl aluminum, methyl bromide, methyl chloride, dimethyl oxalate and trimethyl phosphate and the suitable solvent is selected from chloro solvents, alcohol solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
6. A process for the preparation of 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)- N5-methyl pyrimidine-4,5,6-triamine compound of formula-3, comprising reacting the 2- (l-(2-fluoro benzyl)-! H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine compound of formula-2 with dimethyl sulfate in acetone to provide 2-(l -(2-fluorobenzyl)- 1H- pyrazolo [3,4-b]pyridin-3-yl)-NS-methylpyrimidine-4,5,6-triamine compound of formula- 3.
7. Solid state form of 2-(l -(2-fluorobenzyl)- 1H-pyrazolo[3,4-b]pyridin-3-yl)-N5-methyl pyrimidinc-4,5 ,6-triamine.
8. Use of solid state form of 2-(l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N5- methylpyrimidine-4,S,6-triamine compound of fo.rmula-3 in the preparation of pure compound of formula- 1.
9. Crystalline form M-II of methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1H-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1 is characterized by
its X-ray powder diffractogram having peaks at 5.4, 7.8, 8.7, 12.2, 13.6, 14.1, 16.0, 17.5, 18.0, 19.2, 19.7, 20.3, 21.0, 21.7, 22.8, 24.1, 26.3, 27.6, 28.9, 30.3 and 31.4 ± 0.2 degrees two-theta.
10. Crystalline form M-II of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazoIo[3,4-b] pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate is characterized by P-XRD pattern as depicted in figure- 1.
11. A process for the preparation of crystalline form M-II of methyl 4,6-diamino-2-[l-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising the following steps:
a) adding a suitable solvent to methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo
[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate,
b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture and filtering the reaction mixture,
d) adding the obtained filtrate in step-c) to a pre-cooled suitable solvent at a suitable temperature,
e) stirring the reaction mixture, filtering the precipitated solid and drying to get crystalline form M-II of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4- b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1.
12. The process as claimed in claim 11, wherein, in step-a), the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof;
in step-b) the temperature is ranging from 25°C to reflux temperature of the solvent used in the reaction; in step-d) the suitable solvent is polar solvent like water and the suitable temperature is ranging from -20°C to 20°C
13. A process for the preparation of crystalline form M-II of methyl 4,6-diamino-2-[l-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising the following steps:
a) adding methanol to methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1H-pyrazolo[3,4-b] pyridin-3-yl]-S-pyrimidinyl(methyl)carbamate,
b) heating the reaction mixture to 6S-70°C,
c) stirring the reaction mixture and filtering the reaction mixture,
d) adding the filtrate obtained in step-c) to a pre-cooled water at 0-5°C,
e) stirring the reaction mixture, filtering the precipitated solid and drying to get crystalline form M-II of methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1H-pyrazolo[3,4- b]pyridin-3-yl]-S-pyrimidinyl(methyl)carbamate compound of formula- 1.
14. A process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo
[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising:
a) reacting l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride compound of formula-4 with 2-(phenyldiazenyl)malononitrile compound of formula-5 in the presence of sodium formate in a suitable solvent to provide (E)-2-( 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl)-5-(pheny 1 diazenyl)pyrimidine-4,6-diamine compound of formula-6,
b) optionally purifying the compound of formula-6 using a suitable solvent,
c) reducing the compound of formula-6 using a suitable reducing agent in a suitable solvent to provide 2-(l-(2-f1uorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine- 4,5,6-triamine compound of formula-2,
d) reacting compound of formula-2 with alkyl halo formate in presence of a suitable base in a suitable solvent to provide methyl 4,6-diamino-2-(l -(2-fluorobenzyl)- 1H- pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-S-ylcarbamate compound of formula-7, e) optionally purifying the compound of formula-7 using a suitable solvent,
f) reacting the compound of formula-7 with a suitable methylating agent in presence of a suitable base in a suitable solvent to provide methyl 4,6-diamino-2-[l-(2-fluoro benzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-y l]-5-pyrimidinyl(methy l)carbamate compound of formula- 1,
g) purifying the compound of formula- 1 using a suitable solvent to provide pure methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1.
15. The process as claimed in claim 14, wherein, in step-c) the suitable reducing agent is selected from metal catalyst such as nickel, palladium, platinum, iridium, ruthenium and the like, in combination with hydrogen;
in step-d) the alkyl halo formate is a methyl derivative of a chloro or brorno formate and suitable base is selected from organic or inorganic bases;
in step-f) the suitable methylating agents is selected from methyl iodide, methyl bromide, dimethyl sulfate, methyl p-toluenesulfonate, and methanesulfonate and the suitable base is selected from organic or inorganic bases;
in step-a) to step-g) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, nitrile solvents, ether solvents, polar aprotic solvents, hydrocarbon solvents and polar solvents like water or mixture thereof.
16. A process for the preparation of methyl 4,6-diamino-2-[1 -(2-fluorobenzyl)- 1H-pyrazolo
[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising:
a) reacting 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride compound, of formula-4 with 2-(phenyldiazenyl)malononitrile compound of formula- 5 in presence of sodium formate in toluene to provide (E)-2-(l - (2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6- diamine compound of formula-6,
b) purifying the compound of formula-6 using isopropanol,
c) reducing the compound of formula-6 using Pd/C in presence of dimethyl formamide to provide 2-(l -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6- triamine compound of formula-2,
d) reacting compound of formula-2 with methyl chloroformate in presence of triethyl amine in a mixture of methanol and isopropanol to provide methyl 4,6-diamino-2-(l-
(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-S-ylcarbamate compound of formula-7,
e) purifying the compound of formula-7 using a suitable solvent,
f) reacting the compound of formula-7 with methyl iodide in presence of lithium hexa methyldisilazide in tetrahydrofuran to provide methyl 4,6-diamino-2-[l-(2-fluoro benzyl)- 1 H-pyrazolo[3.4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1,
g) purifying the compound of formula- 1 using a suitable solvent to get pure methyl 4,6- diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3 -yl]-5-pyrimidinyl (methyl)carbamate compound of formula- 1.
17. A process for the purification of methyl 4,6-diamino-2-(l -(2-fluorobenzyl)- 1H-pyrazolo
[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula-7 obtained in step-e) of claims 16, comprising:
a) dissolving the compound of formula-7 in a mixture of methanol and dichloromethane,
b) adding silica gel and carbon to the reaction mixture and stirring the reaction mixture at 25-30°C,
c) filtering the reaction mixture through hyflow bed,
d) distilling off the solvent from the filtrate obtained in step-c),
e) adding dimethyl formamide to the obtained compound,
f) heating the reaction mixture to 70-75°C and stirring the reaction mixture,
g) adding ethyl acetate to the reaction mixture and stirring the reaction mixture at 70- 75°C,
h) cooling the reaction mixture to 25-30°C and stirring the reaction mixture,
i) filtering the precipitated solid,
j) adding water to the obtained compound at 2S-30°C and stirring the reaction mixture, k) filtering the solid, washing with water to provide methyl 4,6-diamino-2'-(l-(2-fluoro benzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula-7.
18. A process for the purification of methyl 4,6-diamino-2-[l-(2-fIuorobenzyI)-1H-pyrazolo [3,4-b]ron:idin-3-yl]-S-pyrimidinyl(rnethyl)carbainate compound of formula- 1 obtained according to claims 1, 3, 14 and 16, comprising:
a) adding tetrahydrofuran and dimethyl sulfoxide to compound of formula- 1 , b) heating the reaction mixture to 50-55°C and stirring the reaction mixture,'
c) cooling the reaction mixture and stirring the reaction mixture,
d) filtering the precipitated solid,
e) adding dimethyl formamide and ethyl acetate to the obtained solid in step-d), f) heating the reaction mixture to 90-95°C,
g) adding carbon to the reaction mixture,
h) filtering the reaction mixture,
i) adding ethyl acetate to the filtrate at 2S-30°C and stirring the reaction mixture, j) filtering the precipitated solid,
k) adding water to the obtained solid,
1) heating the reaction mixture to 50-55°C and stirring the reaction mixture,
m) cooling the reaction mixture and filtering the solid to provide pure methyl 4,6- diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl
(methyl)carbamate compound of formula- 1.
19. Methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimi dinyl(methyl)carbarnale compound of formula-] obtained according to the present invention is having purity greater than 99.6 % by HPLC.
20. 2-(l-(2-fluorobenzyl)-1H-pyra-∞lo[3>4-b]pyridin-3-yl)-N-memylpyrimidine-4,5
diamine compound of formula-3 according to claim 1 and 4 having purity of greater than 99.9%, preferably a purity of greater than 99.95% by HPLC.
21. Use of crystalline form M-1I of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-1H-pyrazolo
[3,4-b]pyridin-3-yl]-5-pyrimi dinyl(methyl)carbamate compound of formula- 1 in the preparation of pharmaceutical composition.
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| US20110130410A1 (en) * | 2009-11-27 | 2011-06-02 | Bayer Schering Pharma Aktiengesellschaft | Process for preparing methyl methylcarbamate and its purification for use as pharmaceutically active compound |
| CN104530044A (en) * | 2014-12-31 | 2015-04-22 | 安徽联创生物医药股份有限公司 | Method for synthesizing riociguat |
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| CN104530044A (en) * | 2014-12-31 | 2015-04-22 | 安徽联创生物医药股份有限公司 | Method for synthesizing riociguat |
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| WO2023213525A1 (en) * | 2022-05-03 | 2023-11-09 | Moehs Iberica, S.L. | 2-(5-FLUORO-1-(2-FLUOROBENZYL)-1H-PYRAZOLO[3,4-b]PYRIDIN-3-YL)-5-NITROSOPYRIMIDIN-4,6-DIAMINE OR A SALT THEREOF, METHOD FOR THE PREPARATION THEREOF, AND USE THEREOF IN THE SYNTHESIS OF VERICIGUAT |
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