WO2018108130A1 - Procédé de préparation d'un nouvel antagoniste du récepteur des androgènes - Google Patents

Procédé de préparation d'un nouvel antagoniste du récepteur des androgènes Download PDF

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WO2018108130A1
WO2018108130A1 PCT/CN2017/116226 CN2017116226W WO2018108130A1 WO 2018108130 A1 WO2018108130 A1 WO 2018108130A1 CN 2017116226 W CN2017116226 W CN 2017116226W WO 2018108130 A1 WO2018108130 A1 WO 2018108130A1
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compound
formula
group
reaction
preparation
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PCT/CN2017/116226
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Tingting Pan
Chunguang Xia
Yulei Yang
Aiming Zhang
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Lianyungang Runzhong Pharamceutcial Co., Ltd.
Shanghai Institute Of Pharmaceutical Industry
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Publication of WO2018108130A1 publication Critical patent/WO2018108130A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to the field of pharmaceutical synthesis, in particular to an improved process for the preparation of a novel androgen receptor antagonist, specifically ODM-201 and its key intermediates.
  • Androgen receptor is a member of the nuclear receptor superfamily.
  • the superfamily has several members, but there are only 5 existing in vertebrates, which are progesterone receptors, estrogen receptors, androgen receptors (AR) , glucocorticoid receptors and mineralocorticoid receptors.
  • AR contains 918 amino acid residues, which constitutes three important domains, namely DNA binding domain (DBD) , ligand binding domain (LBD) , N-terminal domain (NTD) .
  • AR exists in cytoplasm and is combined with heat shock proteins (Hsp90) .
  • Hsp90 heat shock proteins
  • AR will release Hsp90, and combine with androgen in LBD zone at the same time. This combination will induce the structural transformation in the LBD zone, coupled with phosphorylation of receptors, and then activate AR.
  • the AR-androgen complex formed after activation will further initiate related genetic transcription and then exert its subsequent biological effect.
  • AR antagonists can inhibit the proliferation of prostatic cells and promote their apoptosis.
  • the patients in the early stages of prostate cancer will show the decreasing in the level of prostate specific antigen after treatment of AR antagonist, which accompanies reduction in prostate volume and symptoms in different degree, extension of survival. So far, there are 4 AR antagonists in the market, all belong to non-steroidal small molecule drug. Therefore, it is necessary to develop new non-steroidal AR antagonists for the treatment of prostatic cancer.
  • ODM-201 is a new type of androgen receptor antagonist, co-developed by Bayer AG and Orion Corp.
  • ODM-201 is structurally distinct from any known antiandrogens. Unlike other anti-androgen drugs, ODM-201 does not enter into the brain in a nonclinical model and can inhibit androgen receptor by blocking the nuclear ectopia. Phase I and Phase II clinical studies have shown ODM-201 has significant anti-tumor activity and good tolerance and safety. Its structure is as follow:
  • ODM-201 N- ( (S) -1- (3- (3-chloro-4-cyanophenyl) -1H-pyrazol-1-yl) -propan-2-yl) -5- (1-hydroxyethyl) -1H-pyrazole-3-carboxamide.
  • the carbon at position 1 of hydroxyethyl on the pyrazole ring has two configurations.
  • ODM-201 is a mixture of two diastereomers, namely the compounds of formula Ia and formula Ib as shown below.
  • the chemical name of the compound of formula Ia is N- ( (S) -1- (3- (3-chloro-4-cyanophenyl) -1H-pyrazol-1-yl) -propan-2-yl) -5- ( (R) -1-hydroxyethyl) -1H-pyrazole-3-carboxamide
  • the compound of formula Ib is N- ( (S) -1- (3- (3-chloro-4-cyanophenyl) -1H-pyrazol-1-yl) -propan-2-yl) -5- ( (S) -1-hydroxyethyl) -1H-pyrazole-3-carboxamide.
  • both the compounds of formula Ia and formula Ib are potent androgen receptor antagonists that could be used for the treatment of prostatic cancer.
  • ODM-201 could be synthesized by the method described in WO2011051540 as in route 1.
  • Route 1 the synthetic route of ODM-201.
  • compound 7 can be prepared according to the method disclosed in WO2012139930: compound 9 is cyclized with compound 10 under the catalysis of indium trichloride to form pyrazole compound 11; and compound 11 is hydrolyzed to give compound 7.
  • the drawbacks of synthetic route 1 are: (1) .
  • the starting material but-3-yn-2-one (compound 10) for synthesis of compound 7 is not commercially available in large quantities, and a small amount of customization of this compound is expensive which is not suitable for industrial production.
  • the preparation of compound 11 requires the use of indium trichloride as a catalyst. Indium trichloride is a transition metal. The post-treatment wastewater seriously pollutes the environment when indium trichloride is used in the industrial production.
  • Compound 11 is selectively reduced under the catalysis of ketoreductase (KRED enzyme) to give compound 12a; the hydroxyl group of compound 12a is protected by tert-butyldiphenylsilyl group to give compound 13a; compound 13a is hydrolyzed to give compound 14a; compound 14a undergoes an amidation reaction with compound 6 to give compound 15a; compound 15a is deprotected to give the compound of formula Ia.
  • compound 12a can also be prepared from compound 9 and compound 16a under the action of a catalyst.
  • Compound 11 is selectively reduced under the catalysis of ketoreductase (KRED enzyme) to give compound 12b; the hydroxyl group of compound 12b is protected by tert-butyldiphenylsilyl group to give compound 13b; compound 13b is hydrolyzed to give compound 14b; compound 14b undergoes an amidation reaction with compound 6 to give compound 15b; compound 15b is deprotected to give the compound of formula Ib.
  • compound 12b can also be prepared from compound 9 and compound 16b under the action of a catalyst.
  • the drawbacks of synthetic routes 2 and 3 are: (1) The preparation of starting material, namely compound 11 is difficult; (2) KRED enzyme is not suitable for industrial production as a biological enzyme; (3) Synthesis yield of compound 12a or compound 12b from compound 9 and compound 16a or compound 16b is very low, only 0.026%.
  • the published synthetic routes of ODM-201, the compounds of formula Ia and formula Ib are not suitable for industrial production.
  • This invention aims to provide a new process for preparing ODM-201 and its optical isomers (the compounds of formula Ia and formula Ib) which is suitable for industrial production.
  • the present invention provides a process for the preparation of a compound of formula VI, comprising: the compound of formula VI is synthesized from a compound of formula V through cyclization reaction.
  • R 1 is hydroxyl-protective group
  • R 2 is C 1-6 alkyl group.
  • the “hydroxyl-protective group” is selected from pivaloyl group, benzoyl group, acetyl group, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triisopropylsilyl group, benzyl group, p-methoxybenzyl group, triphenylmethyl group, methoxymethyl group, 2-ethoxyethyl group, 2- (trimethylsilyl) ethoxymethyl group or allyl group, preferably t-butyldimethylsilyl group, t-butyldiphenylsilyl group, more preferably t-butyldimethylsilyl group.
  • R 2 is selected from methyl, ethyl, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group or t-butyl group.
  • R 2 is ethyl group.
  • the “cyclization reaction” is carried out in a solvent.
  • the “solvent” includes but is not limited to tetrachloromethane, chloroform, dichloromethane, n-hexane, n-heptane, n-octane, isooctane or mixtures of two or more thereof, preferably n-octane or isooctane, more preferably n-octane.
  • the cyclization reaction may be carried out at the reflux temperature of the reaction solvent, and may also be carried out at 100-200°C, specifically 120-130°C.
  • the invention provides a process for the preparation of a compound of formula V, comprising: (1) a compound of formula VII is synthesized from condensation reaction of a compound of formula VIII and a compound of formula IX; and (2) the compound of formula V is synthesized from dehydration reaction of the compound of formula VII.
  • R 1 and R 2 are as defined above.
  • the “condensation reaction” in step (1) is carried out in the presence of a base and a solvent.
  • the base used in step (1) includes but is not limited to potassium hydride, sodium hydride, n-butyllithium, t-butyllithium, isopropyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, or mixtures of two or more thereof, preferably lithium diisopropylamide or lithium bis (trimethylsilyl) amide, more preferably lithium bis (trimethylsilyl) amide.
  • the solvent used in step (1) includes but is not limited to acetonitrile, methyl tertiary butyl ether, isopropyl ether, dioxane, toluene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol diethyl ether, or mixtures of two or more thereof, preferably tetrahydrofuran or methyltetrahydrofuran, more preferably tetrahydrofuran.
  • the molar ratio of the compound of formula VIII to the compound of formula IX to be used in step (1) is 1: 1-2, preferably 1: 1.2-1.8, more preferably 1: 1.5-1.6.
  • the molar ratio of the compound of formula VIII to the base to be used in step (1) is 1: 1-2, preferably 1: 1.2-1.6, more preferably 1: 1.4-1.6.
  • the condensation reaction of step (1) may be carried out at -70 to -90°C, preferably at -75 to -80°C.
  • the “dehydration reaction” in step (2) is carried out in the presence of a dehydrant, a base and a solvent.
  • the dehydrant used in step (2) includes but is not limited to phosphorus oxychloride, cyanuric chloride, phosphorus pentoxide, thionyl chloride, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride, oxyalyl chloride, or mixtures of two or more thereof, preferably trifluoroacetic anhydride or phosphorus oxychloride, more preferably trifluoroacetic anhydride.
  • the base used in step (2) includes but is not limited to triethylamine, N, N-diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, tetramethyl guanidine, 4-dimethyl pyridine, or mixtures of two or more thereof, preferably triethylamine or N, N-diisopropylethylamine, more preferably triethylamine.
  • the solvent used in step (2) includes but is not limited to chloroform, dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, acetonitrile, or mixtures of two or more thereof, preferably dichloromethane or tetrahydrofuran, more preferably dichloromethane.
  • the molar ratio of the compound of formula VII to the dehydrant to be used in step (2) is 1: 1-3, preferably 1: 1.5-2.5, more preferably 1: 1.5-2.
  • the molar ratio of the compound of formula VII to the base to be used in step (2) is 1: 1-10, preferably 1: 1-8, more preferably 1: 2-6.
  • the dehydration reaction of step (2) may be carried out at 15-30°C, preferably 25-30°C.
  • the invention provides a process for the preparation of a compound of formula VIII, comprising: (1) a compound of formula XI is synthesized from hydroxyl-protection reaction of a compound of formula X; and (2) the compound of formula VIII is synthesized from reduction reaction of the compound of formula XI.
  • R 1 is as defined above.
  • the “hydroxyl-protection reaction” in step (1) is carried out in the presence of a protective agent of hydroxyl group, a base and a solvent.
  • the protective agent of hydroxyl group used in step (1) includes but is not limited to pivaloyl chloride, benzoyl chloride, acetyl chloride, trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triisopropylsilyl chloride, benzyl chloride, p-methoxybenzyl chloride, triphenylmethyl chloride, chloromethyl methyl ether, 2-chloroethyl ethyl ether, 2- (trimethylsilyl) ethoxymethyl chloride or allyl chloride, preferably t-butyldimethylsilyl chloride or t-butyldiphenylsilyl chloride, more
  • the base used in step (1) includes but is not limited to triethylamine, imidazole, N, N-diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, tetramethyl guanidine, 4-dimethylpyridine, or mixtures of two or more thereof, preferably triethylamine, imidazole or N, N-diisopropylethylamine, more preferably imidazole.
  • the solvent used in step (1) includes but is not limited to chloroform, dichloromethane, N, N-dimethylformamide, tetrahydrofuran, 1, 2-dichloroethane, acetonitrile, or mixtures of two or more thereof, preferably dichloromethane or N, N-dimethylformamide, more preferably dichloromethane.
  • the molar ratio of the compound of formula X to the hydroxyl protective agent to be used in step (1) is 1: 1-2, preferably 1: 1-1.5, more preferably 1: 1-1.2.
  • the molar ratio of the compound of formula X to the base to be used in step (1) is 1: 1-10, preferably 1: 1-4, more preferably 1: 1.5-2.
  • the hydroxyl protection reaction of step (1) may be carried out at 15-30°C, preferably 25-30°C.
  • the “reduction reaction” in step (2) is carried out in the presence of a reductant and a solvent.
  • the reductant used in step (2) includes but is not limited to lithium diethoxyaluminium hydride, lithium triethoxyaluminium hydride, lithium aluminium hydride or diisobutyl aluminium hydride, preferably lithium aluminium hydride or diisobutyl aluminium hydride, more preferably diisobutyl aluminium hydride;
  • the solvent used in step (2) includes but is not limited to chloroform, dichloromethane, N, N-dimethylformamide, tetrahydrofuran, 1, 2-dichloroethane, acetonitrile, or mixtures of two or more thereof, preferably dichloromethane or tetrahydrofuran, more preferably dichloromethane.
  • the molar ratio of the compound of formula XI to the reductant to be used in step (2) is 1: 1-3, preferably 1: 1-1.5, more preferably 1: 1-1.1.
  • the reduction reaction of step (2) is carried out at -90 to -70°C, preferably -80 to -75°C.
  • the invention provides a process for the preparation of a compound of III, comprising: the compound of formula III is synthesized from hydrolysis reaction of a compound of formula VI.
  • R 1 and R 2 are as defined above.
  • the “hydrolysis reaction” is carried out in the presence of a base and a solvent.
  • the base includes but is not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, or mixtures of two or more thereof, preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide.
  • the solvent includes but is not limited to ethanol, methanol, isopropanol, tetrahydrofuran, or mixtures of two or more thereof, preferably ethanol or tetrahydrofuran.
  • the molar ratio of the compound of formula VI to the base to be used in hydrolysis reaction is 1: 1-5, preferably 1: 1-3, more preferably 1: 1.5-2.
  • the hydrolysis reaction may be carried out at the reflux temperature of the reaction solvent, specifically 40-70°C, more specifically 40-50°C.
  • the invention provides a process for the preparation of a compound of formula III, comprising: the compound of formula III is synthesized from cyclization reaction of a compound of formula V, and then the resulting product is hydrolyzed sequentially without separation.
  • R 1 and R 2 are as defined above.
  • the “cyclization reaction” may be carried out in the presence of a solvent.
  • the solvent includes but is not limited to tetrachloromethane, chloroform, dichloromethane, n-hexane, n-heptane, n-octane, isooctane, or mixtures of two or more thereof, preferably n-octane or isooctane, more preferably n-octane.
  • the “cyclization reaction” may be carried out at the reflux temperature of the reaction solvent, specifically 100-200°C, more specifically 120-130°C.
  • the hydrolysis reaction is carried out after the cyclization reaction, which is to add the base and solvent directly to the system without separation of the products from the cyclization reaction.
  • the solvent used in the hydrolysis reaction is a mixed solvent, including original solvent from the cyclization reaction and the added solvent for the hydrolysis reaction.
  • Original solvent and added solvent can be the same or different.
  • the hydrolysis reaction requires further addition of a base and a solvent.
  • the base used in the hydrolysis reaction includes but is not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, or mixtures of two or more thereof, preferably sodium hydroxide or potassium hydroxide, more preferably sodium hydroxide.
  • the solvent includes but is not limited to ethanol, methanol, isopropanol, tetrahydrofuran, or mixtures of two or more thereof, preferably ethanol or tetrahydrofuran.
  • the molar ratio of the compound of formula VI to the base to be used in the hydrolysis reaction is 1: 1-5, preferably 1: 1-3, more preferably 1: 1.5-2.
  • the base is used as its aqueous solution preferably.
  • the hydrolysis reaction is carried out at the reflux temperature of the reaction solvent, specifically 40-70°C, more specifically 40-50°C.
  • the invention provides a process for the preparation of a compound of formula I, comprising: (1) the compound of formula II is synthesized from amidation reaction of a compound of formula III and a compound of formula IV; and (2) the compound of formula I is synthesized from deprotection reaction of the compound of formula II.
  • R 1 and R 2 are as defined above.
  • the “amidation reaction” in step (1) is carried out in the presence of an activator of carboxylic acid, a condensation agent, a base and a solvent.
  • the activator of carboxylic acid used in step (1) includes but is not limited to 4-dimethylaminopyridine (DMAP) , 1-hydroxy-7-azabenzotriazole (HOAT) or 1-hydroxybenzotriazole (HOBT) , preferably HOBT.
  • the condensation agent used in step (1) includes but is not limited to N, N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) , preferably EDCI.
  • the base used in step (1) includes but is not limited to triethylamine, N, N-diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, tetramethyl guanidine, 4-dimethylaminopyridine, or mixtures of two or more thereof, preferably N, N-diisopropylethylamine or triethylamine, more preferably N, N-diisopropylethylamine.
  • the solvent used in step (1) includes but is not limited to chloroform, dichloromethane, N, N-dimethylformamide, tetrahydrofuran, 1, 2-dichloroethane, acetonitrile, or mixtures of two or more thereof, preferably dichloromethane, tetrahydrofuran, or mixtures of two or more thereof, more preferably dichloromethane.
  • the molar ratio of the compound of formula III to the compound of formula IV to be used in step (1) is 1: 0.5-2, preferably 1: 0.7-1.2, more preferably 1: 0.8-1.
  • the molar ratio of the compound of formula III to the activator to be used in step (1) is 1: 1-2, preferably 1: 1-1.5, more preferably 1: 1-1.2.
  • the molar ratio of the compound of formula III to the condensation agent to be used in step (1) is 1: 1-2, preferably 1: 1-1.5, more preferably 1: 1-1.2.
  • the molar ratio of the compound of formula III to the base to be used in step (1) is 1: 1-5, preferably 1: 1-2, more preferably 1: 1-1.2.
  • reaction of step (1) may be carried out at 15-30°C, preferably 25-30°C.
  • the “deprotection reaction” in step (2) is carried out in the presence of a deprotective agent and a solvent.
  • the deprotective agent includes but is not limited to hydrofluoric acid, 2-iodoxybenzoic acid, sodium periodate, zinc bromide, zirconium tetrachloride or tetrabutylammonium fluoride, preferably tetrabutylammonium fluoride or hydrofluoric acid, more preferably tetrabutylammonium fluoride.
  • the solvent includes but is not limited to acetonitrile, methyl tertiary butyl ether, isopropyl ether, dioxane, toluene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol diethyl ether, or mixtures of two or more thereof, preferably tetrahydrofuran or toluene, more preferably tetrahydrofuran.
  • the molar ratio of the compound of formula II to the deprotective agent in step (2) is 1: 1-5, preferably 1: 1-3, more preferably 1: 1-2.
  • the reaction in step (2) may be carried out at 15-30°C, preferably 25-30°C.
  • the compound with carbon atom marked with * means a mixture of R and S configurations at any ratio, a single enantiomer with R configuration at the carbon atom marked with *, or a single enantiomer with S configuration at the carbon atom marked with *.
  • any ratio means the ratio of R configuration to S configuration is, more than 1, equal to 1, less than 1, can be about 50: 50 to 40: 60, or 50: 50 to 60: 40 etc, preferably racemate.
  • configuration transformation rarely occurs at the marked *carbon atom.
  • the invention provides a process for the preparation of ODM-201, comprising: (1) a compound of formula (XI’) is synthesized from hydroxyl-protective reaction of a compound of formula (X’) ; (2) a compound of formula (VIII’) is synthesized from reduction reaction of the compound of formula (XI’) ; (3) a compound of formula (VII’) is synthesized from condensation reaction of the compounds of formula (VIII’) and formula IX; (4) a compound of formula (V’) is synthesized from dehydration reaction of the compound of formula (VII’) ; (5) a compound of formula (VI’) is synthesized from cyclization reaction of the compound of formula (V’) ; (6) a compound of formula (III’) is synthesized from hydrolysis reaction of the compound of formula (VI’) ; (7) a compound of formula (II’) is synthesized from amidation reaction of the compounds of formula (III’) and formula IV; (8) ODM-201 is synthesized from
  • R 1 and R 2 are as defined above.
  • R 1 is selected from t-butyldimethylsilyl group
  • R 2 is selected from ethyl group.
  • the compound of formula (VI’) from step (5) can be directly used in step (6) without separation.
  • the reaction condition is also as defined above.
  • the invention provides specific compounds as follow:
  • the invention also provides the use of above specific compounds in the preparation of ODM-201.
  • the invention provides a process for the preparation of the compound of formula Ia, comprising: (1) a compound of formula (XIa) is synthesized from hydroxyl-protective reaction of a compound of formula (Xa) ; (2) a compound of formula (VIIIa) is synthesized from reduction reaction of the compound of formula (XIa) ; (3) a compound of formula (VIIa) is synthesized from condensation reaction of the compounds of formula (VIIIa) and formula IX; (4) a compound of formula (Va) is synthesized from dehydration reaction of the compound of formula (VIIa) ; (5) a compound of formula (VIa) is synthesized from cyclization reaction of the compound of formula (Va) ; (6) a compound of formula (IIIa) is synthesized from hydrolysis reaction of the compound of formula (VIa) ; (7) a compound of formula (IIa) is synthesized from amidation reaction of the compounds of formula (IIIa) and formula IV; (8) the compound of formula
  • R 1 and R 2 are as defined above.
  • R 1 is selected from t-butyldimethylsilyl group; R 2 is ethyl group.
  • the compound of formula (VIa) from step (5) can be directly used in step (6) without separation.
  • the reaction condition is also as defined above.
  • the invention provides specific compounds as follow:
  • the invention provides a process of the preparation of a compound of formula Ib, comprising: (1) a compound of formula (XIb) is synthesized from hydroxyl-protective reaction of a compound of formula (Xb) ; (2) a compound of formula (VIIIb) is synthesized from reduction reaction of the compound of formula (XIb) ; (3) a compound of formula (VIIb) is synthesized from condensation reaction of the compounds of formula (VIIIb) and formula IX; (4) a compound of formula (Vb) is synthesized from dehydration reaction of the compound of formula (VIIb) ; (5) a compound of formula (VIb) is synthesized from cyclization reaction of the compound of formula (Vb) ; (6) compound of formula (IIIb) is synthesized from hydrolysis reaction of the compound of formula (VIb) ; (7) a compound of formula (IIb) is synthesized from amidation reaction of the compounds of formula (IIIb) and formula IV; (8) the compound of formula I
  • R 1 and R 2 are as defined above.
  • R 1 is selected from t-butyldimethylsilyl group; R 2 is ethyl group.
  • the compound of formula (VIb) from step (5) can be directly used in step (6) without separation.
  • the reaction condition is also as defined above.
  • the invention provides specific compounds as follow:
  • the said hydroxyl protective group in this invention includes but is not limited to the hydroxyl protective groups described in ⁇ Protective Groups in Organic Synthesis> (4 th edition, John Wiley &Sons: New Jersey) .
  • This literature is incorporated into this invention as reference.
  • a person having ordinary skill in the art could take well known methods to get connect with or rid of the compounds.
  • the hydroxyl protective group described in this invention is selected from pivaloyl group, benzoyl group, acetyl group, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triisopropylsilyl group, benzyl group, p-methoxybenzyl group, triphenylmethyl group, methoxymethyl group, 2-ethoxyethyl group, 2- (trimethylsilyl) ethoxymethyl group and allyl group.
  • the compound of formula IV can be synthesized according the method published in CN201280019463.1
  • the compound of formula IX is commercially available or can be prepared according to methods known in the art.
  • TBSCl refers to t-butyldimethylsilyl chloride.
  • DIBAL-H diisobutylaluminium hydride
  • LIHMDS lithium bis (trimethylsilyl) amide
  • DIPEA N, N-diisopropylethylamine
  • HOBt refers to1-hydroxybenzotriazole.
  • EDCI refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimidehydrochloride.
  • THF tetrahydrofuran
  • dehydrant refers to the reagent that could help dehydration under heating or catalyst.
  • condensation reaction refers to a reaction that one big molecule is formed by covalent bond after interaction between two or more organic molecules or intramolecular reaction within one molecule, and often accompanied by the lost of small molecular (such as water, hydrogen chloride and alcohol etc. ) .
  • activator of carboxylic acid refers to the reagent that reacts with carboxylic acid, removes one water molecule, and forms a new compound which could increase the reactivity of carboxylic group.
  • condensation agent refers to a reagent added in the condensation reaction.
  • a reagent capable of forming an active intermediate with a carbonyl-containing compound is a condensing agent, and the resulting active intermediate is further reacted with an amine to obtain an amide.
  • the term of “deprotective agent” refers to the reagent that can remove the hydroxyl protective agent, amino protective agent and the like under heating or catalyst.
  • the chiral compound is in enantiomeric excess.
  • enantiomeric excess is the content of a chiral isomer is equal or over about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%or about 99.99%.
  • compounds can have specific geometrical or steric isomers.
  • the invention assumes all these compounds, including cis-and trans-isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereoisomers, (D) -isomers, (L) -isomers and racemic mixtures or other mixtures thereof.
  • mixtures with stereomeric or diastereomeric excess are both belonging to the range of this invention.
  • Alkyl substituent and the like may contain other asymmetric carbon atoms. All these isomers or their mixtures are belonging to the range of this invention.
  • the reaction is optionally carried out in a solvent. All the solvents are commercially available and can be used without any further purification. Normally, the reaction is conducted under inert nitrogen and in anhydrous solvents.
  • the compounds are named by a person or software Commercially available compounds use the inventory from suppliers.
  • room temperature refers to 25-30°C.
  • reaction time unit of “h” refers to hour (s) .
  • This invention provides a preparation method of a compound of formula I, which has the advantages of easily obtainable starting material, high atomic utilization rate, mild reaction condition, easy post-treatment.
  • single isomers of formula Ia and formula Ib and ODM-201 can be synthesized directionally by controlling the stereochemistry of starting material, i.e., the compound of XI, with the advantages of simple and controllable process and suitability for industrial production.
  • Example 13 5- ( (S) -1- ( (tert-butyldimethylsilyl) oxy) ethyl) -N- ( (S) -1- (3- (3-chloro-4-cyanophenyl) -1H-pyrazol-1-yl) propan-2-yl) -1H-pyrazole-3-carboxamide
  • reaction mixture was poured onto a saturated aqueous solution of sodium potassium tartrate (300mL) and extracted with ether (300mL ⁇ 3) .
  • the combined organic layer was washed with water (three times) and brine (three times) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound. Yield 15.6 g (89.6%) .
  • Example 20 5- (-1- ( (tert-butyldimethylsilyl) oxy) ethyl) -N- ( (S) -1- (3- (3-chloro-4-cyanophenyl) -1H-pyrazol-1-yl) propan-2-yl) -1H-pyrazole-3-carboxamide
  • Example 21 N- ( (S) -1- (3- (3-chloro-4-cyanophenyl) -1H-pyrazol-1-yl) -propan-2-yl) -5- (1-hydroxyethyl) -1H-pyrazole-3-carboxamide (ODM-201)

Abstract

L'invention concerne un procédé de préparation d'un nouvel antagoniste du récepteur des androgènes, comprenant essentiellement la mise en oeuvre d'une réaction de cyclisation d'un composé de formule V pour obtenir un composé de formule VI. Le procédé présente les avantages d'un matériau de départ facilement obtenu, d'un taux d'utilisation atomique élevé, de conditions de réaction modérées et d'un post-traitement simple. En plus, l'ODM-201 et ses isomères uniques peuvent être synthétisés de manière directionnelle par la commande de la stéréochimie du matériau de départ, avec les avantages d'un procédé simple et contrôlable et d'une aptitude pour une production industrielle.
PCT/CN2017/116226 2016-12-15 2017-12-14 Procédé de préparation d'un nouvel antagoniste du récepteur des androgènes WO2018108130A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012143599A1 (fr) * 2011-04-21 2012-10-26 Orion Corporation Carboxamides modulant les récepteurs d'androgènes
WO2016120530A1 (fr) * 2015-01-30 2016-08-04 Orion Corporation Dérivé de carboxamide et ses diastéréomères sous une forme cristalline stable

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012143599A1 (fr) * 2011-04-21 2012-10-26 Orion Corporation Carboxamides modulant les récepteurs d'androgènes
WO2016120530A1 (fr) * 2015-01-30 2016-08-04 Orion Corporation Dérivé de carboxamide et ses diastéréomères sous une forme cristalline stable

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HE, SHENG ET AL.: "1, 3-Dipolar cycloaddition of diazoacetate compounds to terminal alkyne: promoted by Zn(OTf)2: an efficient way to the preparation of pyrazoles", TETRAHEDRON LETTERS, vol. 50, no. 20, 11 March 2009 (2009-03-11), pages 2443 - 2445, XP026063218 *
PADWA, ALBERT ET AL.: "Reaction of Carbonyl Compounds with Ethyl Lithiodiazoacetate. Studies Dealing with the Rhodium (It) -Catalyzed Behavior of the Resulting Adducts", J.ORG.CHEM., vol. 55, no. 13, 31 December 1990 (1990-12-31) *
PAN, TINGTING ET AL.: "Chemical synthesis of the ODM-201's Diastereomers through an Efficient Intramolecular 1, 3-Dipolar Cycloaddition", CHEM.PHARM.BULL., vol. 65, no. 6, 5 April 2017 (2017-04-05), pages 582 - 585, XP055509635 *

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