WO2022168122A1 - Processes for the preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile - Google Patents

Processes for the preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile Download PDF

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WO2022168122A1
WO2022168122A1 PCT/IN2022/050100 IN2022050100W WO2022168122A1 WO 2022168122 A1 WO2022168122 A1 WO 2022168122A1 IN 2022050100 W IN2022050100 W IN 2022050100W WO 2022168122 A1 WO2022168122 A1 WO 2022168122A1
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formula
compound
process according
optionally
conversion
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PCT/IN2022/050100
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French (fr)
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Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Venkat Reddy Ghojala
Vijayavitthal T MATHAD
Markandeya BEKKAM
Ganapathi Chary NAGUNURI
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Msn Laboratories Private Limited, R&D Center
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention provides various processes for the preparation of 6-(2-hydroxy-
  • 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diaza bicyclo[3.1.1 ]heptan-3-yl)pyridin-3-yl)pyrazolo[l ,5-a]pyridine-3-carbonitrile is commonly known as Selpercatinib.
  • Selpercatinib is designed and developed by Loxo Oncology Inc.,. It is indicated for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC). Selpercatinib is approved by USFDA on May 08, 2020 and is being marketed under the brand name RETEVMOTM.
  • US10112942B2 describes Selpercatinib, its intermediates and processes for preparation thereof. Still, there is a significant need in the art for the development of novel processes for the preparation of Selpercatinib.
  • the first embodiment of the present invention is to provide a process for the preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)- 3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile compound of formula- 1.
  • the second embodiment of the present invention provides another process for the preparation of compound of formula- 1.
  • the third embodiment of the present invention provides another process for the preparation of compound of formula- 1.
  • solvent wherever necessary in the present invention can be selected from but not limited to "hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethyls
  • the “base” wherever necessary in the present invention can be selected from but not limited to “inorganic bases” selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide and the like; ammonia; "organic bases” like “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium
  • the “deprotecting agent” in the present invention can be selected based on the protecting group employed.
  • the “deprotecting agent” can be selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates, ammonia, aqueous ammonia, ammonium cerium(IV) nitrate (CAN); and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; hydrogenating agents such as Pd/C, Pd(OH)2/C (Pearlman’s catalyst), palladium acetate, platinum oxide, platinum black, Rh/C,
  • the “dehydrating agent” in the present invention can be selected from but not limited to acetic anhydride, trifluoroacetic anhydride (TFAA), trifluoromethanesulfonic anhydride, phthalic anhydride, trifluoroacetic acid, oxalyl chloride, thionyl chloride, P2O5, phosphoric acid, polyphosphoric acid, POCI3 optionally in presence of imidazole, cyunaric chloride, sulfuric acid, dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, formic acid, acetyl chloride, trichloroacetyl chloride, phosgene, diphosgene, triphosgene and the like.
  • the “demethylating agent” in the present invention can be selected from Lewis acids such as lithium chloride, lithium bromide, lithium iodide, AICI3, AlBr3, BBr3, 1 -dodecanethiol, methanesulfonic acid, pyridine hydrochloride, HBr optionally in combination with carboxylic acid such as formic acid, acetic acid and the like.
  • Lewis acids such as lithium chloride, lithium bromide, lithium iodide, AICI3, AlBr3, BBr3, 1 -dodecanethiol, methanesulfonic acid, pyridine hydrochloride, HBr optionally in combination with carboxylic acid such as formic acid, acetic acid and the like.
  • the “reducing agent” in the present invention can be selected from diisobutylaluminum hydride (DIBAL-H), sodium triacetoxyborohydride, lithium trialkoxyaluminium hydrides such as lithium triethoxyaluminium hydride (Li(EtO)3AlH), lithium tri tert, butoxyaluminium hydride (Li(OtBu)3AlH), sodium borohydride, sodium cyanoborohydride, triethylsilane, lithium aluminum hydride, tetramethylammonium triacetoxyborohydride, sodium bis(2-methoxyethoxy)aluminium hydride (Vitride), boranes such as borane-tetrahydrofuran complex, borane-DMS and the like.
  • DIBAL-H diisobutylaluminum hydride
  • Li(EtO)3AlH lithium triethoxyaluminium hydride
  • the “triflating agent” in the present invention can be selected from trifluoromethanesulfonic acid, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride (Tf2O), N-phenylbis(trifhioromethanesufonimide) (1,1,1-trifluoro-N-phenyl-N- [(trifluoromethyl)sulfonyl] methanesulfonamide; TF2NPI1), 4-nitrophenyltriflate, trifluoroacetyl triflate and the like.
  • the “hydroxylating agent” in the present invention can be selected from hydrogen peroxide (H2O2) and water.
  • the “Palladium catalyst” in the present invention can be selected from PdCl 2 (dppf)DCM, Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , PdCl 2 (dppf)C12, Pd(dba) 2 , [(n 3 -C 4 H 7 )PdCl] 2 , palladium(II)chloride, palladium(II)bromide, palladium(II)acetate, palladium(II) acetylacetonate, dichlorobis(benzonitrile)palladium(II), dichloro bis
  • This compound up on treatment with dehydrating agent provides compound of formula- 1.
  • Vilsmeier-Haack reaction (Vilsmeier-Haack formylation) can be carried out by using N,N-dimethylformamide (DMF), an acid chloride (for example POCI3, SOCI2, COCI2) optionally in presence of a base followed by aqueous work-up of the reaction mixture.
  • DMF N,N-dimethylformamide
  • an acid chloride for example POCI3, SOCI2, COCI2
  • step-h is carried out as per the process described above for the conversion of formula- 1 lb to compound of formula- 1.
  • step-h is carried out as per the process described above for the conversion of formula- 1 le to compound of formula- 1.
  • compound of formula-7 can also be prepared by reacting compound of formula- 12 with compound of formula-6 in presence of a Palladium catalyst optionally in presence of a base.
  • a Palladium catalyst optionally in presence of a base.
  • the second embodiment of the present invention provides another process for the preparation of compound of formula- 1, comprising; a) reacting compound of formula-8 with compound of formula- 10 optionally in presence of a base to provide compound of formula- 13, b) reacting compound of formula- 13 with 2,2-dimethyloxirane optionally in presence of a base to provide compound of formula-11, c) converting compound of formula- 11 to compound of formula- 1 as described above.
  • the third embodiment of the present invention provides another process for the preparation of compound of formula- 1, comprising; a) reacting compound of formula- 12 with compound of formula- 14, wherein, ‘PG’ represents amine protecting group and ‘R3’, ‘R4’ are as defined above; in presence of a palladium catalyst optionally in presence of a base to provide compound of formula- 15, b) treating compound of formula- 15 with a boron compound of formula wherein, ‘R3’, ‘R4’, ‘R5’, ‘R6’ and ‘R7’ are same as defined above; in presence of a palladium catalyst optionally in presence of a base followed by treating the obtained compound with a hydroxylating agent optionally in presence of a base to provide compound of formula- 16, c) reacting compound of formula- 16 with 2,2-dimethyloxirane optionally in presence of a base to provide compound of formula- 17, d) treating compound of formula- 17 with a deprotecting agent to provide compound of formula- 18, e) reacting compound of formula- 18 with 6-
  • compound of formula- 17 can be prepared by reacting compound of formula-9 with compound of formula- 19 optionally in presence of a base.
  • the fourth embodiment of the present invention provides a process for the preparation of Selpercatinib of formula- 1, comprising converting compound of formula- 11 (‘R’ is selected from H, CHO, COOH, COOR 1 CONH 2 , -CON(CH 3 )(OCH 3 ) [Weinribb amide] and CORg; Ri and Rg are as defined above) to compound of formula- 1.
  • R is selected from H, CHO, COOH, COOR 1 CONH 2 , -CON(CH 3 )(OCH 3 ) [Weinribb amide] and CORg; Ri and Rg are as defined above
  • the fifth embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising reacting compound of formula- 18 with 6-methoxynicotinaldehyde in presence of a reducing agent optionally in presence of a base or with a compound of formula-20 optionally in presence of a base to provide compound of formula- 11 and converting compound of formula- 11 to compound of formula- 1.
  • the sixth embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising treating compound of formula- 17 with a deprotecting agent optionally in presence of a solvent to provide compound of formula- 18 and converting compound of formula- 18 to compound of formula- 1.
  • the seventh embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising reacting compound of formula-9 with compound of formula- 19 optionally in presence of a base and/or a solvent to provide compound of formula- 17 and converting compound of formula- 17 to compound of formula- 1.
  • the eighth embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising one or more conversions in accordance with the following scheme.
  • ‘X1’ ‘R’, ‘R3’, ‘R4’, ‘R5’, ‘R6’, ‘R7’, ‘PG’ are same as defined in the present invention.
  • ‘R’ is CONH2.
  • Suitable reagents/bases/solvents/catalysts etc as required for carrying out various conversions of the present invention are selected from those defined in the present invention.
  • a preferred aspect of the eighth embodiment provides a process for the preparation of compound of formula- 1 , comprising one or more conversions in accordance with scheme- A.
  • Scheme-A The ninth embodiment of the present invention provides novel intermediate compounds which are useful for the preparation of compound of formula- 1.
  • the said novel intermediate compounds are represented by the following structural formulae; wherein, ‘PG’ and ‘R’ are as defined above.
  • ‘R’ is preferably CONH2.
  • One aspect of the ninth embodiment of the present invention provides use of above novel intermediates for the preparation of compound of formula- 1.
  • the compound of formula-2, compound of formula-6, compound of formula- 10, compound of formula- 12, compound of formula- 14, compound of formula- 19 and 6-methoxynicotinaldehyde as used in the present invention can be prepared by any of the processes known in the art or they can be obtained from any sources available.
  • the compound of formula- 1 obtained according to various processes of the present invention are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used.
  • the compound of formula- 1 produced by the processes of the present invention may have particle size distribution of D90 less than about 400 pm, preferably less than about 300 pm, more preferably less than about 200 pm.
  • the compound of formula- 1 may have particle size distribution of D90 less than about 100 pm, preferably less than about 50 pm.
  • the compound of formula- 1 produced by the processes of the present invention can be further micronized or milled to get 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 includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product.
  • the present invention is schematically represented as follows:
  • ‘X1’, ‘X2’ are same or different and can be independently selected from halogens such as F, Cl, Br and I;
  • R is selected from H, CHO, COOH, COOR 1 CONH 2 , -CON(CH 3 )(OCH 3 ) [Weinribb amide] and COR8;
  • Ci is selected from Ci-Ce straight chain or branched chain alkyl, aryl or aralkyl groups
  • ‘R 3 ’, ‘R4’, ‘R6’, ‘R7’ are the same or different and can be independently selected from H, straight chain or branched chain C1-C6 alkyl or ‘R 3 ’, ‘R4’ together with the oxygen atoms to which they are attached can form an optionally substituted five or six membered ring and ‘Re’, ‘R7’ together with the oxygen atoms to which they are attached can form an optionally substituted five or six membered ring;
  • R5 can be selected from H, straight chain or branched chain Ci-Ce alkoxy
  • PG represents “N-protecting group” or “amine protecting group” selected from but not limited to alkoxycarbonyl such methoxycarbonyl (Moc), ethoxycarbonyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxy carbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA), trichloroethoxycarbonyl (Troc), pivaloyl (Piv), triphenylmethyl (trityl or Trt) and the like.
  • a mixture of compound of formula-3a (0.5 gm) and dimethylformamide (5 ml) was stirred for 10 min at 25-30°C and then cooled to 0-5°C.
  • Aqueous NaOH solution (0.148 gm of NaOH in 0.296 ml of water) followed by 1 -dodecanethiol (0.74 gm) were slowly added to the reaction mixture at 0-5°C. Heated the reaction mixture to 45-50°C and stirred for 4 hr at the same temperature. Cooled the reaction mixture to 25-30°C.
  • Aqueous potassium carbonate solution (4.77 gm of potassium carbonate in 25 ml of water) was slowly added to the reaction mixture at 25-30°C and stirred for 22 hr at the same temperature.
  • Step-a A mixture of compound of formula-7a (2.5 gm) and toluene (50 ml) was stirred for 15 min at 25-30°C. Potassium acetate (2.92 gm) was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Heated the reaction mixture to 110-115°C and stirred for 90 min at the same temperature.
  • Step-b A mixture of borolan compound obtained in step-a (0.1 gm) and tetrahydrofuran (10 ml) was stirred for 10 min at 25-30°C. Cooled the reaction mixture to 0-5°C. Aqueous sodium hydroxide solution was slowly added to the reaction mixture at 0-5°C and stirred for 15 min at the same temperature. 50% Aqueous hydrogen peroxide solution (0.088 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 1 hr at the same temperature. 50% Aqueous sodium thiosulfate solution followed by water were slowly added to the reaction mixture at 0-5°C and stirred for 10 min at the same temperature.
  • Example-6 Preparation of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy) pyrazolo[l,5-a]pyridine-3-carboxamide (Formula-9a)
  • Example-7 Preparation of tert-butyl 3-(5-(3-carbamoyl-6-(2-hydroxy-2-methyl propoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (Formula-17a)
  • Example-8 Preparation of 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[l,5-a]pyridine-3-carboxamide (Formula-18a)
  • Step-a A mixture of compound of formula-7a (210 gm) and toluene (2100 ml) was stirred for 10 min at 25-30°C. Potassium acetate (246 gm) was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Heated the reaction mixture to 110-115°C and stirred for 2 hr 30 min at the same temperature.
  • Step-b A mixture of compound obtained in step-a (30 gm) and tetrahydrofuran (450 ml) was stirred for 10 min at 25-30°C. Cooled the reaction mixture to 0-5°C.
  • Aqueous sodium hydroxide solution (9.41 gm of NaOH in 150 ml of water) followed by 50% aqueous hydrogen peroxide solution (32.02 ml) were slowly added to the reaction mixture at 0-5°C and stirred for 2 hr at the same temperature.
  • Aqueous sodium hydroxide solution (1.983 gm of sodium hydroxide in 18 ml of water) followed by isobutylene oxide (29.35 ml) were slowly added to a pre-cooled mixture of compound of formula-8a (9 gm) and dimethylformamide (36 ml) at 0-5°C and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 10 hr at the same temperature. Cooled the reaction mixture to 25-30°C, water was added and stirred for 15 min at the same temperature. Acidified the reaction mixture by using aqueous citric acid solution at 25-30°C and stirred for 90 min at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 7 gm.
  • 6-Methoxynicotinaldehyde (1.03 gm) was added to a mixture of compound of formula- 18a (4 gm) and dichloromethane (40 ml) at 25-30°C.
  • Triethylamine (3.35 gm) followed by sodium triacetoxyborohydride (4.01 gm) were slowly added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Heated the reaction mixture to 30-35°C and stirred for 11 hr at the same temperature.
  • Sodium triacetoxyborohydride (2 gm) was added to the reaction mixture at 30-35°C and stirred for 2 hr 30 min at the same temperature.

Abstract

The present invention relates to various processes for the preparation of 6-(2-hydroxy-2-methylpropoxy)-4­(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)pyridin-3­yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, commonly known as Selpercatinib which is represented by the following structural formula-1. The present invention further relates to novel intermediate compounds and process for the preparation of compound of formula-1 by using said novel intermediate compounds.

Description

Processes for the preparation of 6-(2-hvdroxy-2-methylpropoxy)-4- (6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicvclor3.1.11heptan-3-yl) pyridin- 3-yl)pyrazolori,5-alpyridine-3-carbonitrile
Related Application:
This application claims the benefit of priority of our Indian patent application 202141005169 filed on February 06, 2021 which is incorporated herein by reference.
Field of the Invention:
The present invention provides various processes for the preparation of 6-(2-hydroxy-
2-methylpropoxy) -4-(6-(6-((6-methoxypyridin-3 -yl)methyl)-3 ,6-diazabicyclo [3.1.1] heptan-
3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile represented by the following structural formula- 1.
Figure imgf000002_0001
Background of the Invention:
6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diaza bicyclo[3.1.1 ]heptan-3-yl)pyridin-3-yl)pyrazolo[l ,5-a]pyridine-3-carbonitrile is commonly known as Selpercatinib.
Selpercatinib is designed and developed by Loxo Oncology Inc.,. It is indicated for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC). Selpercatinib is approved by USFDA on May 08, 2020 and is being marketed under the brand name RETEVMO™.
US10112942B2 describes Selpercatinib, its intermediates and processes for preparation thereof. Still, there is a significant need in the art for the development of novel processes for the preparation of Selpercatinib.
Brief description of the invention:
The first embodiment of the present invention is to provide a process for the preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)- 3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile compound of formula- 1.
The second embodiment of the present invention provides another process for the preparation of compound of formula- 1.
The third embodiment of the present invention provides another process for the preparation of compound of formula- 1.
Detailed description of the Invention:
The "solvent" wherever necessary in the present invention can be selected from but not limited to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, 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 isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tertbutanol, ethane- 1 ,2-diol, propane- 1 ,2-diol and the like; "polar solvents" such as water; formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents. V arious conversions/steps in the processes of the present invention can be carried out in presence or absence of a solvent or mixture of solvents. The said solvent(s) can be selected from those as described above.
The "base" wherever necessary in the present invention can be selected from but not limited to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; ammonia; "organic bases" like "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; dimethylamine, diethylamine, diisopropyl mine, diisopropylethylamine (DIPEA), diisobutylamine, trimethylamine, triethylamine, triisopropylamine, tributylamine, tert.butyl amine, pyridine, piperidine, 4-dimethylamino pyridine (DMAP), quinoline, imidazole, N-methylimidazole, l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), dimethylaniline, N-methylmorpholine (NMM), l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; "organolithium bases" such as methyl lithium, n-butyl lithium, lithium diisopropylamide (LDA) and the like; "organosilicon bases" such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or mixtures thereof.
The “deprotecting agent” in the present invention can be selected based on the protecting group employed. The “deprotecting agent” can be selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates, ammonia, aqueous ammonia, ammonium cerium(IV) nitrate (CAN); and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; hydrogenating agents such as Pd/C, Pd(OH)2/C (Pearlman’s catalyst), palladium acetate, platinum oxide, platinum black, Rh/C, Ru, sodium borohydride, Na-liquid ammonia, Raney-Ni, Zn-acetic acid, tri(Ci-C6)alkylsilanes, tri(Ci-Ce) alkylsilyl halides and the like.
The “dehydrating agent” in the present invention can be selected from but not limited to acetic anhydride, trifluoroacetic anhydride (TFAA), trifluoromethanesulfonic anhydride, phthalic anhydride, trifluoroacetic acid, oxalyl chloride, thionyl chloride, P2O5, phosphoric acid, polyphosphoric acid, POCI3 optionally in presence of imidazole, cyunaric chloride, sulfuric acid, dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, formic acid, acetyl chloride, trichloroacetyl chloride, phosgene, diphosgene, triphosgene and the like.
The “demethylating agent” in the present invention can be selected from Lewis acids such as lithium chloride, lithium bromide, lithium iodide, AICI3, AlBr3, BBr3, 1 -dodecanethiol, methanesulfonic acid, pyridine hydrochloride, HBr optionally in combination with carboxylic acid such as formic acid, acetic acid and the like.
The “reducing agent” in the present invention can be selected from diisobutylaluminum hydride (DIBAL-H), sodium triacetoxyborohydride, lithium trialkoxyaluminium hydrides such as lithium triethoxyaluminium hydride (Li(EtO)3AlH), lithium tri tert, butoxyaluminium hydride (Li(OtBu)3AlH), sodium borohydride, sodium cyanoborohydride, triethylsilane, lithium aluminum hydride, tetramethylammonium triacetoxyborohydride, sodium bis(2-methoxyethoxy)aluminium hydride (Vitride), boranes such as borane-tetrahydrofuran complex, borane-DMS and the like.
The “triflating agent” in the present invention can be selected from trifluoromethanesulfonic acid, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride (Tf2O), N-phenylbis(trifhioromethanesufonimide) (1,1,1-trifluoro-N-phenyl-N- [(trifluoromethyl)sulfonyl] methanesulfonamide; TF2NPI1), 4-nitrophenyltriflate, trifluoroacetyl triflate and the like. The “hydroxylating agent” in the present invention can be selected from hydrogen peroxide (H2O2) and water.
The “Palladium catalyst” in the present invention can be selected from PdCl2(dppf)DCM, Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf)C12, Pd(dba)2, [(n3-C4H7)PdCl]2, palladium(II)chloride, palladium(II)bromide, palladium(II)acetate, palladium(II) acetylacetonate, dichlorobis(benzonitrile)palladium(II), dichloro bis
(acetonitrile )palladium(II), dichloro tetraamminepalladium(II), dichloro(cycloocta-l,5- diene)palladium(II), palladium(II) trifluoroacetate, tris(dibenzylideneacetone)dipalladium (0), tris(dibenzylideneacetone)dipalladium (0) chloroform complex and the like.
The first embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising; a) converting compound of formula-2 to compound of formula-3,
Figure imgf000006_0001
wherein, ‘R’ is selected from H, CHO, COOH, COOR1, CONH2, CON(CH3)(OCH3) [Weinreb amide], CORg (Rg= morpholine); and ‘X1’ is a halogen selected from F, Cl, Br and I; ‘R1' is selected from C1-C6 straight chain or branched chain alkyl, aryl or aralkyl groups; b) treating compound of formula-3 with a demethylating agent optionally in presence of a base to provide compound of formula-4,
Figure imgf000006_0002
c) treating compound of formula-4 with a triflating agent optionally in presence of a base to provide compound of formula-5,
Figure imgf000007_0001
d) reacting compound of formula-5 with compound of formula-6
Figure imgf000007_0002
wherein, ‘R3’, ‘R4’ are as defined below; in presence of a Palladium catalyst optionally in presence of a base to provide compound of formula-7,
Figure imgf000007_0003
e) treating compound of formula-7 with a boron compound of formula
Figure imgf000007_0004
wherein, ‘R3’, ‘R4’, ‘R6’, ‘R7’are the same or different and can be independently selected from H, straight chain or branched chain C1-C6 alkyl or ‘R3’, ‘R4’ together with the oxygen atoms to which they are attached can form an optionally substituted five or six membered ring and ‘Re’, ‘R7’ together with the oxygen atoms to which they are attached can form an optionally substituted five or six membered ring; and ‘R5’ can be selected from H, straight chain or branched chain Ci-Ce alkoxy; in presence of a Palladium catalyst optionally in presence of a base followed by hydroxylating the obtained compound with a hydroxylating agent optionally in presence of a base to provide compound of formula-8,
Figure imgf000008_0001
f) reacting compound of formula-8 with 2,2-dimethyloxirane (isobutylene oxide) optionally in presence of a base to provide compound of formula-9,
Figure imgf000008_0002
g) reacting compound of formula-9 with compound of formula- 10
Figure imgf000008_0003
optionally in presence of a base to provide compound of formula- 11
Figure imgf000008_0004
h) converting compound of formula- 11 to compound of formula- 1.
In the above described process, when 'R' is H, step-h can be carried out under Vilsmeier-Haack reaction conditions to provide compound formula- 11b (Formua-11, R= CHO), which is treated with hydroxylamine or its hydrochloride salt to provide compound formula-11c (Formula-11, R is CH=NOH). This compound up on treatment with dehydrating agent provides compound of formula- 1.
Figure imgf000009_0001
Vilsmeier-Haack reaction (Vilsmeier-Haack formylation) can be carried out by using N,N-dimethylformamide (DMF), an acid chloride (for example POCI3, SOCI2, COCI2) optionally in presence of a base followed by aqueous work-up of the reaction mixture.
When 'R' is CHO, step-h is carried out as per the process described above for the conversion of formula- 1 lb to compound of formula- 1.
When 'R' is COOH, step-h is carried out by treating compound of formula- l id (Formula- 11, R= COOH) with ammonia to provide compound of formula- He (Formula-11, R=CONH2) which up on treatment with dehydrating agent optionally in presence of a base provides compound of formula- 1.
Figure imgf000009_0002
When 'R' is COORi, step-h is carried out by treating compound of formula- I lf (Formula- 11, R= COORi) with ammonia to provide compound of formula- l ie (Formula-11, R=CONH2) which up on treatment with dehydrating agent optionally in presence of a base provides compound of formula- 1.
When 'R' is CONH2, step-h is carried out as per the process described above for the conversion of formula- 1 le to compound of formula- 1.
When 'R' is CON(CH3)(OCH3) [Weinreb amide], step-h is carried out by treating compound of formula-11g (Formula-11, R= CON(CH3)(OCH3)) with reducing agent to provide compound of formula- 11b which can be converted to compound of formula- 1 as described below.
Figure imgf000010_0001
When 'R' is CORg, step-h is carried out by treating compound of formula- l lh (Formula- 11, R= CORg) with reducing agent to provide compound of formula- 1 lb which can be converted to compound of formula- 1 as described above.
In an aspect of the present invention, compound of formula-7 can also be prepared by reacting compound of formula- 12 with compound of formula-6 in presence of a Palladium catalyst optionally in presence of a base.
Figure imgf000010_0002
wherein, ‘X1’ , ‘X2’ are same or different and independently selected from halogens such as F, Cl, Br, I; and R, R3, R4 are same as defined above.
The second embodiment of the present invention provides another process for the preparation of compound of formula- 1, comprising; a) reacting compound of formula-8 with compound of formula- 10 optionally in presence of a base to provide compound of formula- 13,
Figure imgf000011_0001
b) reacting compound of formula- 13 with 2,2-dimethyloxirane optionally in presence of a base to provide compound of formula-11, c) converting compound of formula- 11 to compound of formula- 1 as described above.
The third embodiment of the present invention provides another process for the preparation of compound of formula- 1, comprising; a) reacting compound of formula- 12 with compound of formula- 14,
Figure imgf000011_0002
wherein, ‘PG’ represents amine protecting group and ‘R3’, ‘R4’ are as defined above; in presence of a palladium catalyst optionally in presence of a base to provide compound of formula- 15,
Figure imgf000011_0003
b) treating compound of formula- 15 with a boron compound of formula
Figure imgf000012_0001
wherein, ‘R3’, ‘R4’, ‘R5’, ‘R6’ and ‘R7’ are same as defined above; in presence of a palladium catalyst optionally in presence of a base followed by treating the obtained compound with a hydroxylating agent optionally in presence of a base to provide compound of formula- 16,
Figure imgf000012_0002
c) reacting compound of formula- 16 with 2,2-dimethyloxirane optionally in presence of a base to provide compound of formula- 17,
Figure imgf000012_0003
d) treating compound of formula- 17 with a deprotecting agent to provide compound of formula- 18,
Figure imgf000012_0004
e) reacting compound of formula- 18 with 6-methoxynicotinaldehyde in presence of a reducing agent optionally in presence of a base or with a compound of formula-20 optionally in presence of a base
Figure imgf000013_0001
wherein, ‘R2’ represents OH, halogens such as F, Cl, Br, I and substituted or unsubstituted alkyl/aryl sulfonyloxy such as methanesulfonyloxy (OMs), benzenesulfonyloxy, p-toluenesulfonyloxy (OTs) and the like; to provide compound of formula-11, f) converting compound of formula- 11 to compound of formula- 1 as per the process described above.
Few examples of boron compounds that can be used in the present invention include but not limited to;
Figure imgf000013_0002
In an aspect of third embodiment of the present invention, compound of formula- 17 can be prepared by reacting compound of formula-9 with compound of formula- 19 optionally in presence of a base.
Figure imgf000014_0001
The fourth embodiment of the present invention provides a process for the preparation of Selpercatinib of formula- 1, comprising converting compound of formula- 11 (‘R’ is selected from H, CHO, COOH, COOR 1 CONH2, -CON(CH3)(OCH3) [Weinribb amide] and CORg; Ri and Rg are as defined above) to compound of formula- 1.
Wherein the said conversion is carried out by using the methods as described above based on the ‘R’ group employed.
The fifth embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising reacting compound of formula- 18 with 6-methoxynicotinaldehyde in presence of a reducing agent optionally in presence of a base or with a compound of formula-20 optionally in presence of a base to provide compound of formula- 11 and converting compound of formula- 11 to compound of formula- 1.
The sixth embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising treating compound of formula- 17 with a deprotecting agent optionally in presence of a solvent to provide compound of formula- 18 and converting compound of formula- 18 to compound of formula- 1.
The seventh embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising reacting compound of formula-9 with compound of formula- 19 optionally in presence of a base and/or a solvent to provide compound of formula- 17 and converting compound of formula- 17 to compound of formula- 1. The eighth embodiment of the present invention provides a process for the preparation of compound of formula- 1, comprising one or more conversions in accordance with the following scheme.
Figure imgf000015_0001
Wherein, ‘X1’ ‘R’, ‘R3’, ‘R4’, ‘R5’, ‘R6’, ‘R7’, ‘PG’ are same as defined in the present invention.
In one aspect of the eighth embodiment of the present invention, ‘R’ is CONH2.
Suitable reagents/bases/solvents/catalysts etc as required for carrying out various conversions of the present invention are selected from those defined in the present invention. A preferred aspect of the eighth embodiment provides a process for the preparation of compound of formula- 1 , comprising one or more conversions in accordance with scheme- A. Scheme-A:
Figure imgf000016_0001
The ninth embodiment of the present invention provides novel intermediate compounds which are useful for the preparation of compound of formula- 1. The said novel intermediate compounds are represented by the following structural formulae;
Figure imgf000017_0001
wherein, ‘PG’ and ‘R’ are as defined above.
In an aspect of the ninth embodiment, ‘R’ is preferably CONH2.
Figure imgf000017_0002
Figure imgf000018_0001
One aspect of the ninth embodiment of the present invention provides use of above novel intermediates for the preparation of compound of formula- 1.
The compound of formula-2, compound of formula-6, compound of formula- 10, compound of formula- 12, compound of formula- 14, compound of formula- 19 and 6-methoxynicotinaldehyde as used in the present invention can be prepared by any of the processes known in the art or they can be obtained from any sources available.
The compound of formula- 1 obtained according to various processes of the present invention are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used.
The compound of formula- 1 produced by the processes of the present invention may have particle size distribution of D90 less than about 400 pm, preferably less than about 300 pm, more preferably less than about 200 pm.
In one aspect of the present invention, the compound of formula- 1 may have particle size distribution of D90 less than about 100 pm, preferably less than about 50 pm.
The compound of formula- 1 produced by the processes of the present invention can be further micronized or milled to get 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 includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling/micronization may be performed before drying or after drying of the product. The present invention is schematically represented as follows:
Scheme-I:
Figure imgf000019_0001
Scheme-II:
Figure imgf000020_0001
Scheme-Ill:
Figure imgf000020_0002
In the above schemes-I, II and III,
‘X1’, ‘X2’ are same or different and can be independently selected from halogens such as F, Cl, Br and I;
‘R’ is selected from H, CHO, COOH, COOR 1 CONH2, -CON(CH3)(OCH3) [Weinribb amide] and COR8;
‘Ri’ is selected from Ci-Ce straight chain or branched chain alkyl, aryl or aralkyl groups;
‘R3’, ‘R4’, ‘R6’, ‘R7’are the same or different and can be independently selected from H, straight chain or branched chain C1-C6 alkyl or ‘R3’, ‘R4’ together with the oxygen atoms to which they are attached can form an optionally substituted five or six membered ring and ‘Re’, ‘R7’ together with the oxygen atoms to which they are attached can form an optionally substituted five or six membered ring;
‘R5’ can be selected from H, straight chain or branched chain Ci-Ce alkoxy;
‘Rs’ represents morpholine;
‘PG’ represents “N-protecting group” or “amine protecting group” selected from but not limited to alkoxycarbonyl such methoxycarbonyl (Moc), ethoxycarbonyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxy carbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA), trichloroethoxycarbonyl (Troc), pivaloyl (Piv), triphenylmethyl (trityl or Trt) and the like.
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples:
Example-1: Preparation of 6-bromo-4-methoxypyrazolo[l,5-a]pyridine-3-carboxamide
(Formula-3a)
Dimethylsulfoxide (10 ml) was added to a mixture of 6-bromo-4-methoxy pyrazolo[l,5-a]pyridine-3-carbonitrile compound of formua-2a (10 gm) and methanol (160 ml) at 25-30°C. IM Sodium hydroxide solution (60 ml) followed by 35% aqueous hydrogen peroxide solution (20 ml) were slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 2 hr 30 min at the same temperature. Cooled the reaction mixture to 25-30°C, water (50 ml) was slowly added to it and stirred for 20 min at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 10.5 gm.
Example-2: Preparation of 6-bromo-4-hydroxypyrazolo[l,5-a]pyridine-3-carboxamide (Formula-4a)
A mixture of compound of formula-3a (0.5 gm) and dimethylformamide (5 ml) was stirred for 10 min at 25-30°C and then cooled to 0-5°C. Aqueous NaOH solution (0.148 gm of NaOH in 0.296 ml of water) followed by 1 -dodecanethiol (0.74 gm) were slowly added to the reaction mixture at 0-5°C. Heated the reaction mixture to 45-50°C and stirred for 4 hr at the same temperature. Cooled the reaction mixture to 25-30°C. Slowly added the reaction mixture to pre-cooled water (10 ml) at 0-5°C. Acidified the reaction mixture with 10% aqueous citric acid solution at 10-15°C. Filtered the solid, washed with water and dried to get the title compound. Yield: 0.5 gm.
Example-3: Preparation of 6-bromo-3-carbamoylpyrazolo[l,5-a]pyridin-4-yl trifluoro methanesulfonate (Formula-5a)
A mixture of compound of formula-4a (1 gm) and tetrahydrofuran (10 ml) was stirred for 10 min at 25-30°C and then cooled to 0-5°C. N,N-Diisopropylethylamine (2.02 gm) followed by 1,1,1 -trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.115 gm) were slowly added to the reaction mixture at 0-5°C and stirred for 3 hr at 15-20°C. Water was slowly added to the reaction mixture at 25-30°C and stirred for 45 min at the same temperature. Ethyl acetate was added to the reaction mixture and stirred for 5 min. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with 5% aqueous NaCl solution. Distilled off solvent completely from the organic layer to get title compound. Yield: 0.3 gm.
Example-4: Preparation of 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[l,5-a]pyridine-3- carboxamide (Formula-7a)
A solution of compound of formula-5a (5 gm) in 1,4-dioxane (10 ml) was slowly added to a mixture of 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine compound of formula-6a (2.873 gm), tetrakis(triphenylphosphine)palladium(O) (0.595 gm) and 1,4-dioxane (50 ml) under nitrogen atmosphere at 25-30°C. Aqueous potassium carbonate solution (4.77 gm of potassium carbonate in 25 ml of water) was slowly added to the reaction mixture at 25-30°C and stirred for 22 hr at the same temperature. Water (25 ml) was slowly added to the reaction mixture at 25-30°C. Filtered the unwanted solid and washed with water. Ethyl acetate was added to the filtrate at 25-30°C and stirred for 10 min. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with water. Distilled off the solvent from the organic layer under reduced pressure. The obtained compound was purified by column chromatography by using cyclohexane: ethyl acetate (1:1). Distilled off the solvent from the wanted fractions. Isopropyl alcohol (10 ml) was added to the obtained compound at 25-30°C and stirred the mixture for 1 hr at the same temperature. Filtered the solid, washed with isopropyl alcohol and dried to get title compound. Yield: 80 mg.
Example-5: Preparation of 4-(6-fluoropyridin-3-yl)-6-hydroxypyrazolo[l,5-a]pyridine- 3-carboxamide (Formula-8a)
Step-a: A mixture of compound of formula-7a (2.5 gm) and toluene (50 ml) was stirred for 15 min at 25-30°C. Potassium acetate (2.92 gm) was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Heated the reaction mixture to 110-115°C and stirred for 90 min at the same temperature. Bis(Pinacolato)diboron (3.78 gm) and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane [Pd(dppf)C12.CH2C12; 0.181 gm) were added lot wise to the reaction mixture at 110-115°C and stirred for 6 hr at the same temperature. Reduced the temperature of the reaction mixture to 50-55°C. Charcoal (0.25 gm) was added to the reaction mixture at 50-55°C and stirred for 10 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with ethyl acetate. Water was added to the filtrate at 25-30°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with 5% aq.NaCl solution. Distilled off the solvent completely from the organic layer under reduced pressure. Methanol (5 ml) was added to the obtained compound at 25-30°C and stirred the mixture for 30 min at the same temperature. Cooled the mixture to 10-15°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with methanol and dried to get 4-(6-fluoropyridin-3- yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine-3-carboxamide. Yield: 0.5 gm.
Step-b: A mixture of borolan compound obtained in step-a (0.1 gm) and tetrahydrofuran (10 ml) was stirred for 10 min at 25-30°C. Cooled the reaction mixture to 0-5°C. Aqueous sodium hydroxide solution was slowly added to the reaction mixture at 0-5°C and stirred for 15 min at the same temperature. 50% Aqueous hydrogen peroxide solution (0.088 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 1 hr at the same temperature. 50% Aqueous sodium thiosulfate solution followed by water were slowly added to the reaction mixture at 0-5°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with methyl tert.butyl ether. Acidified the aqueous layer with 10% aqueous citric acid solution at 20-25°C and stirred the reaction mixture for 15 min at the same temperature. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with 5% aq. NaCl solution. Distilled off solvent completely from organic layer under reduced pressure to get title compound. Yield: 30 mg.
Example-6: Preparation of 4-(6-fluoropyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy) pyrazolo[l,5-a]pyridine-3-carboxamide (Formula-9a)
A mixture of compound of formula-8a (0.1 gm) and dimethylformamide (10 ml) was stirred for 10 min at 25-30°C. Cooled the reaction mixture to 0-5°C, aqueous sodium hydroxide solution (0.0146 gm of sodium hydroxide in 0.2 ml of water) followed by isobutylene oxide (0.264 gm) were slowly added to it at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 12 hr at the same temperature. Cooled the reaction mixture to 25-30°C, water followed by ethyl acetate were added to it and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with 5% aqueous NaCl solution followed by with chilled water. Distilled off solvent completely from organic layer under reduced pressure to get the title compound. Yield: 80 mg.
Example-7: Preparation of tert-butyl 3-(5-(3-carbamoyl-6-(2-hydroxy-2-methyl propoxy)pyrazolo[l,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (Formula-17a)
Tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate compound of formula-19a (1.7 gm) followed by potassium acetate (1.7 gm) were added to a mixture of compound of formula-9a (2 gm) and dimethylsulfoxide (10 ml) at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 4 hr at the same temperature. Cooled the reaction mixture to 25-30°C. Water and ethyl acetate were added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Adjusted the aqueous layer pH to 7 with 10% aqueous citric acid solution and extracted the aqueous layer with ethyl acetate. Distilled off the solvent from total organic layer under reduced pressure to get title compound. Yield: 1 gm.
Example-8: Preparation of 4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[l,5-a]pyridine-3-carboxamide (Formula-18a)
A mixture of compound of formula- 17a (1 gm) and 5% aqueous isopropyl alcohol solution (4 ml) was stirred for 10 min at 25-30°C. Sulfuric acid (0.41 ml) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 4 hr at the same temperature. Cooled the reaction mixture to 25-30°C. Water and ethyl acetate were added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with 5% aqueous NaCl solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 0.112 gm. Example-9: Preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin- 3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3- carboxamide (Formula-lie)
A mixture of compound of formula- 18a (0.1 gm) and dichloromethane (1 ml) was stirred for 15 min at 25-30°C. 6-Methoxyni cotinaldehyde (0.025 gm), triethylamine (0.083 gm) followed by sodium triacetoxyborohydride (0.1 gm) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 30-35°C and stirred for 14 hr at the same temperature. Dichloromethane and water were added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with 5% aqueous NaCl solution. Distilled off solvent completely from the organic layer to get title compound. Yield: 50 mg. Example-10: Preparation of Selpercatinib (Formula-1)
A mixture of compound of formula- l ie (0.5 gm) and dichloromethane (20 ml) was stirred for 5 min at 25-30°C under nitrogen atmosphere. Cooled the mixture to 0-5°C. Triethylamine (0.258 ml) followed by trifluoroacetic anhydride (0.127 ml) were slowly added to the reaction mixture at 0-5°C and stirred for 2 hr at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 5 hr at the same temperature. Cooled the reaction mixture to 0-5°C, water followed by dichloromethane were added to it. Raised the temperature of the reaction mixture to 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with 5% aqueous sodium bicarbonate solution followed by with 5% aqueous NaCl solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 0.41 gm.
Example-11: Preparation of compound of formula-5a
A mixture of compound of formula-4a (550 gm) and tetrahydrofuran (2750 ml) was stirred for 10 min at 25-30°C and then cooled to 10-15°C. N,N-Diisopropylethylamine (1112.2 gm) followed by l,l,l-trifhioro-N-phenyl-N-((trifhioromethyl)sulfonyl)methane sulfonamide (613.7 gm) were slowly added to the reaction mixture at 10-15°C and stirred for 6 hr at the same temperature. Cooled the reaction mixture to 0-5°C, water (5500 ml) was slowly added to it and stirred for 2 hr at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 563 gm.
Example-12: Preparation of compound of formula-7a
Compound of formula-6a (28.73 gm) was added to a mixture of tetrakis(triphenylphosphine)palladium(O) (8.92 gm) and 1,4-dioxane (2500 ml) under nitrogen atmosphere at 25-30°C. Aqueous potassium carbonate solution (53.41 gm of potassium carbonate in 250 ml of water) was slowly added to the reaction mixture at 25-30°C. Compound of formula-5a (50 gm) was added to the reaction mixture at 25-30°C and stirred for 19 hr at the same temperature. Water (1000 ml) was slowly added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hr at the same temperature. Filtered the unwanted compound and aqueous sodium chloride solution was added to the filtrate at 25-30°C.Both the layers were separated and extracted the aqueous layer with ethyl acetate. Distilled off the solvent from the organic layer and co-distiller with methyl tert. butyl ether. Methyl tert.butyl ether (100 ml) was added to the obtained compound at 25-30°C and stirred for 90 min at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and dried to get the title compound. Yield: 40 gm.
Example-13: Preparation of compound of formula-8a
Step-a: A mixture of compound of formula-7a (210 gm) and toluene (2100 ml) was stirred for 10 min at 25-30°C. Potassium acetate (246 gm) was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Heated the reaction mixture to 110-115°C and stirred for 2 hr 30 min at the same temperature. Bis(Pinacolato)diboron (238.7 gm) followed by [ 1, 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane [Pd(dppf)C12.CH2C12; 5.11 gm) were slowly added to the reaction mixture at 110-115°C and stirred for 30 min at the same temperature. Reduced the temperature of the reaction mixture to 50-55°C and charcoal (21 gm) was added to it. Cooled the reaction mixture to 25-30°C, filtered through hyflow bed and washed the hyflow bed with ethyl acetate. The above hyflow bed and ethyl acetate were taken in a RBF at 25-30°C and stirred for 30 min at the same temperature. Filtered the mixture through hyflow bed and washed with ethyl acetate. Water was added to the filtrate at 25-30°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure. n-Heptane (420 ml) was added to the obtained compound at 25-30°C and stirred the mixture for 1 hr at the same temperature. Filtered the solid, washed with n-heptane and dried to get 4-(6-fluoropyridin-3-yl)-6-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine-3-carboxamide. Yield: 150 gm. Step-b: A mixture of compound obtained in step-a (30 gm) and tetrahydrofuran (450 ml) was stirred for 10 min at 25-30°C. Cooled the reaction mixture to 0-5°C. Aqueous sodium hydroxide solution (9.41 gm of NaOH in 150 ml of water) followed by 50% aqueous hydrogen peroxide solution (32.02 ml) were slowly added to the reaction mixture at 0-5°C and stirred for 2 hr at the same temperature. 50% Aqueous sodium thiosulfate solution, water followed by methyl tert.butyl ether were slowly added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and acidified the aqueous layer with 10% aqueous citric acid solution at 25-30°C. Filtered the solid, washed with water and dried to get the title compound. Yield: 8 gm.
Example-14: Preparation of compound of formula-9a
Aqueous sodium hydroxide solution (1.983 gm of sodium hydroxide in 18 ml of water) followed by isobutylene oxide (29.35 ml) were slowly added to a pre-cooled mixture of compound of formula-8a (9 gm) and dimethylformamide (36 ml) at 0-5°C and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 10 hr at the same temperature. Cooled the reaction mixture to 25-30°C, water was added and stirred for 15 min at the same temperature. Acidified the reaction mixture by using aqueous citric acid solution at 25-30°C and stirred for 90 min at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 7 gm.
Example-15: Preparation of compound of formula-17a
Compound of formula- 19a (5.46 gm) followed by potassium acetate (5.41 gm) were added to a mixture of compound of formula-9a (6 gm) and dimethylsulfoxide (24 ml) at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 10 hr at the same temperature. Compound of formula- 19a (1.68 gm) was added to the reaction mixture at 70-75°C and stirred for 4 hr at the same temperature. Cooled the reaction mixture to 25-30°C. Water (12 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid and washed with dimethyl sulfoxide and water mixture followed by with acetone and dried to get the title compound. Yield: 7 gm.
Example-16: Preparation of compound of formula-18a
Sulfuric acid (2.03 ml) was slowly added to a mixture of compound of formula- 17a (5 gm) and 5% aqueous isopropyl alcohol solution (20 ml) at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Heated the reaction mixture to 40-45°C and stirred for 12 hr at the same temperature. Cooled the reaction mixture to 25-30°C, isopropyl alcohol (50 ml) was added to it and stirred for 90 min at the same temperature. Filtered the solid, washed with isopropyl alcohol followed by with a mixture of isopropyl alcohol and methyl tert.butyl ether. Methyl tert.butyl ether (25 ml) was added to the obtained compound at 25-30°C and stirred for 90 min at the same temperature. Filtered the solid, washed with methyl tert.butyl ether and dried the material to get the title compound. Yield: 4 gm. Example-17: Preparation of compound of formula-lie
6-Methoxynicotinaldehyde (1.03 gm) was added to a mixture of compound of formula- 18a (4 gm) and dichloromethane (40 ml) at 25-30°C. Triethylamine (3.35 gm) followed by sodium triacetoxyborohydride (4.01 gm) were slowly added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Heated the reaction mixture to 30-35°C and stirred for 11 hr at the same temperature. Sodium triacetoxyborohydride (2 gm) was added to the reaction mixture at 30-35°C and stirred for 2 hr 30 min at the same temperature. Dichloromethane and water were added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with 5% aqueous NaCl solution. Distilled off the solvent completely from the organic layer under reduced pressure. Isopropyl alcohol (8 ml) was added to the obtained compound at 25-30°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with isopropyl alcohol and dried the material to get the title compound. Yield: 2 gm.

Claims

We Claim:
1. A process for the preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6- methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl) pyrazolo[l,5-a]pyridine-3-carbonitrile compound of formula- 1, comprising one or more conversions in accordance with the below scheme
Figure imgf000030_0001
wherein, ‘X1' is selected from halogens such as F, Cl, Br and I;
‘R’ is selected from H, CHO, COOH, COOR 1 CONH2, -CON(CH3)(OCH3) [Weinribb amide] and CORg;
‘R1’ is selected from C1-C6 straight chain or branched chain alkyl, aryl or aralkyl groups; ‘R3’, ‘R4’, ‘R6’, ‘R7’are the same or different and can be independently selected from H, straight chain or branched chain C1-C6 alkyl or ‘R3’, ‘R4’ together with the oxygen atoms to which they are attached can form an optionally substituted five or six membered ring and ‘R6’, ‘R7’ together with the oxygen atoms to which they are attached can form an optionally substituted five or six membered ring;
‘R5’ is selected from H, straight chain or branched chain C1-C6 alkoxy;
‘R8’ represents morpholine;
‘PG’ represents “N-protecting group” or “amine protecting group” selected from alkoxycarbonyl such methoxycarbonyl (Moc), ethoxycarbonyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxy carbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA), trichloroethoxycarbonyl (Troc), pivaloyl (Piv), triphenylmethyl (trityl or Trt). The process according to claim 1 , wherein R is CONH2. The process according to claim 1, wherein conversion of compound of formula-3 to compound of formula-4 is carried out by using a demethylating agent optionally in presence of a base. The process according to claim 3, wherein the demethylating agent is selected from Lewis acids such as lithium chloride, lithium bromide, lithium iodide, AICI3, AlBr3, BBr3, 1 -dodecanethiol, methanesulfonic acid, pyridine hydrochloride, HBr optionally in combination with carboxylic acid such as formic acid, acetic acid. The process according to claim 1, wherein conversion of compound of formula-4 to compound of formula-5 is carried out by using a triflating agent optionally in presence of a base. The process according to claim 5, wherein the triflating agent is selected from trifluoromethanesulfonic acid, trifluoromethanesulfonyl chloride, trifluoromethane sulfonic anhydride (Tf2O), N-phenylbis(trifhroromethanesufonimide) ( 1,1,1 -trifluoro-N- phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide; TF2NPI1), 4-nitrophenyl triflate, trifluoroacetyl triflate. The process according to claim 1, wherein conversion of compound of formula-5 to compound of formula-7 is carried out by reacting compound of formula-5 with compound of formula-6 in presence of a Palladium catalyst optionally in presence of a base. The process according to claim 1, wherein the conversion of compound of formula-7 to compound of formula-8 is carried out by reacting compound of formula-7 with a boron compound of formula
Figure imgf000032_0001
wherein, ‘R3’, ‘R4’, ‘R5’, ‘R6’, ‘R7’are same as defined above; in presence of a Palladium catalyst optionally in presence of a base followed by hydroxylating the obtained compound with a hydroxylating agent optionally in presence of a base. The process according to claims 7 and 8, wherein the Palladium catalyst is selected from PdCl2(dppf)DCM, Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf)C12, Pd(dba)2, [(n3-C4H7)PdCl]2, palladium(II)chloride, palladium(II)bromide, palladium(II)acetate, palladium(II) acetylacetonate, dichlorobis(benzonitrile)palladium(II), dichloro bis (acetonitrile) palladium(II), dichloro tetraamminepalladium(II), dichloro(cycloocta-l,5-diene) palladium(II), palladium(II) trifluoroacetate, tris(dibenzylideneacetone)dipalladium (0), tris(dibenzylideneacetone)dipalladium (0) chloroform complex; and the hydroxylating agent is selected from hydrogen peroxide (H2O2) and water. The process according to claim 1, wherein the conversion of compound of formula-8 to compound of formula-9 is carried out by reacting compound of formula-8 with 2,2- dimethyloxirane optionally in presence of a base. The process according to claim 1 , wherein the conversion of compound of formula-9 to compound of formula- 17 is carried out by reacting compound of formula-9 with compound of formula- 19 optionally in presence of a base. The process according to claim 1, wherein the conversion of compound of formula- 17 to compound of formula- 18 is carried out by treating compound of formula- 17 with a deprotecting agent. The process according to claim 12, wherein the deprotecting agent is selected based on the protecting group employed and it is selected from acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates, ammonia, aqueous ammonia, ammonium cerium(IV) nitrate (CAN); and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; hydrogenating agents such as Pd/C, Pd(OH)2/C (Pearlman’s catalyst), palladium acetate, platinum oxide, platinum black, Rh/C, Ru, sodium borohydride, Na-liquid ammonia, Raney-Ni, Zn-acetic acid, tri(Ci- C6)alkylsilanes, tri(Ci-Ce) alkylsilyl halides. The process according to claim 13, wherein the conversion of compound of formula- 18 to compound of formula- 11 is carried out by reacting compound of formula- 18 with 6- methoxynicotinaldehyde in presence of a reducing agent optionally in presence of a base or with a compound of formula-20 optionally in presence of a base
Figure imgf000033_0001
wherein, ‘R2’ represents OH, halogens such as F, Cl, Br, I and substituted or unsubstituted alkyl/aryl sulfonyloxy such as methanesulfonyloxy (OMs), benzenesulfonyloxy, p-toluenesulfonyloxy (OTs). The process according to claim 14, herein the reducing agent is selected from diisobutylaluminum hydride (DIBAL-H), sodium triacetoxyborohydride, lithium trialkoxyaluminium hydrides such as lithium triethoxyaluminium hydride (Li(EtO)3AlH), lithium tri tert. butoxyaluminium hydride (Li(OtBu)3AlH), sodium borohydride, sodium cyanoborohydride, triethylsilane, lithium aluminum hydride, tetramethylammonium triacetoxyborohydride, sodium bis(2-methoxyethoxy)aluminium hydride (Vitride), boranes such as borane-tetrahydrofuran complex, borane-DMS. The process according to claim 1, when 'R' is H, the conversion of compound of formula- 11 to compound of formula- 1 is carried out under Vilsmeier-Haack reaction conditions to provide compound formula- 11b (Formua-11, R= CHO), which is treated with hydroxylamine or its hydrochloride salt to provide compound formula- 11c (Formula-11, R is CH=NOH) which up on treatment with a dehydrating agent provides compound of formula- 1.
Figure imgf000034_0001
wherein, Vilsmeier-Haack reaction (Vilsmeier-Haack formylation) is carried out by using N,N-dimethylformamide (DMF), an acid chloride (POCI3, SOCI2, COCI2) optionally in presence of a base followed by aqueous work-up of the reaction mixture. The process according to claim 1, when 'R' is CHO, the conversion of compound of formula- 11 to compound of formula- 1 is carried out as per the process described above in claim 16 for the conversion of formula- 1 lb to compound of formula- 1. The process according to claim 1, when 'R' is COOH, the conversion of compound of formula- 11 to compound of formula- 1 is carried out by treating compound of formula- l id (Formula-11, R= COOH) with ammonia to provide compound of formulal ie (Formula-11, R=CONH2) which up on treatment with a dehydrating agent optionally in presence of a base provides compound of formula- 1.
Figure imgf000035_0001
The process according to claim 1, when 'R' is COORi, the conversion of compound of formula- 11 to compound of formula- 1 is carried out by treating compound of formula- I lf (Formula-11, R= COORi) with ammonia to provide compound of formula- l ie (Formula-11, R=CONH2) which up on treatment with a dehydrating agent optionally in presence of a base provides compound of formula- 1. The process according to claim 1, when 'R' is CONH2, the conversion of compound of formula- 11 to compound of formula- 1 is carried out by treating it with a dehydrating agent optionally in presence of a base. The process according to claim 1, when 'R' is CON(CH3)(OCH3) [Weinreb amide], the conversion of compound of formula- 11 to compound of formula- 1 is carried out by treating compound of formula- 11g (Formula-11, R= CON(CH3)(OCH3)) with a reducing agent to provide compound of formula- 11b which can be converted to compound of formula- 1 as per the process described in claim 16. The process according to claim 1, when 'R' is CORg, the conversion of compound of formula- 11 to compound of formula- 1 is carried out by treating it with a reducing agent to provide compound of formula- 1 lb which can be converted to compound of formula- 1 as per the process described in claim 16. Compounds represented by the following structural formulae;
Figure imgf000036_0001
wherein, ‘R’ is selected from H, CHO, COOH, COOR1 CONH2, -CON(CH3)(OCH3) [Weinribb amide] and CORg;
‘Ri’ is selected from C1-C6 straight chain or branched chain alkyl, aryl or aralkyl groups; ‘Rg’ represents morpholine;
‘PG’ represents “amine protecting group” selected from alkoxycarbonyl such methoxycarbonyl (Moc), ethoxycarbonyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxy carbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA), trichloroethoxycarbonyl (Troc), pivaloyl (Piv), triphenylmethyl (trityl or Trt). Compounds according to claim 24, wherein ‘R’ is CONH2. Compounds represented by the following structural formulae;
Figure imgf000037_0001
PCT/IN2022/050100 2021-02-06 2022-02-07 Processes for the preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile WO2022168122A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019075114A1 (en) * 2017-10-10 2019-04-18 Mark Reynolds Formulations comprising 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazab icyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
WO2019075092A1 (en) * 2017-10-10 2019-04-18 Charles Todd Eary Process for the preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019075114A1 (en) * 2017-10-10 2019-04-18 Mark Reynolds Formulations comprising 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazab icyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
WO2019075092A1 (en) * 2017-10-10 2019-04-18 Charles Todd Eary Process for the preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

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