WO2022168122A1 - Procédés de préparation de 6-(2-hydroxy-2-méthylpropoxy)-4-(6-(6-((6-méthoxypyridin-3-yl)méthyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile - Google Patents

Procédés de préparation de 6-(2-hydroxy-2-méthylpropoxy)-4-(6-(6-((6-méthoxypyridin-3-yl)méthyl)-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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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.

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne divers procédés pour la préparation de 6-(2-hydroxy-2-méthylpropoxy)-4­(6-(6-((6-méthoxypyridin-3-yl)méthyl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)pyridin-3­yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, communément appelé Selpercatinib qui est représenté par la formule développée 1 suivante. La présente invention concerne en outre de nouveaux composés intermédiaires et un procédé de préparation du composé de formule 1 à l'aide desdits nouveaux composés intermédiaires.
PCT/IN2022/050100 2021-02-06 2022-02-07 Procédés de préparation de 6-(2-hydroxy-2-méthylpropoxy)-4-(6-(6-((6-méthoxypyridin-3-yl)méthyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile WO2022168122A1 (fr)

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IN202141005169 2021-02-06

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019075114A1 (fr) * 2017-10-10 2019-04-18 Mark Reynolds Formulations comprenant du 6-(2-hydroxy-2-méthylpropoxy)-4-(6-(6-((6-méthoxypyridin-3-yl)méthyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
WO2019075092A1 (fr) * 2017-10-10 2019-04-18 Charles Todd Eary Procédé de préparation de 6-(2-hydroxy-2-méthylpropoxy)-4-(6-(6-((6-méthoxypyridin-3-yl)méthyl)-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 (fr) * 2017-10-10 2019-04-18 Mark Reynolds Formulations comprenant du 6-(2-hydroxy-2-méthylpropoxy)-4-(6-(6-((6-méthoxypyridin-3-yl)méthyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
WO2019075092A1 (fr) * 2017-10-10 2019-04-18 Charles Todd Eary Procédé de préparation de 6-(2-hydroxy-2-méthylpropoxy)-4-(6-(6-((6-méthoxypyridin-3-yl)méthyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

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