WO2024022475A1 - A pyridinyl substituted thiohydantoin pharmaceutical intermediate and its preparation method and use - Google Patents
A pyridinyl substituted thiohydantoin pharmaceutical intermediate and its preparation method and use Download PDFInfo
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- WO2024022475A1 WO2024022475A1 PCT/CN2023/109790 CN2023109790W WO2024022475A1 WO 2024022475 A1 WO2024022475 A1 WO 2024022475A1 CN 2023109790 W CN2023109790 W CN 2023109790W WO 2024022475 A1 WO2024022475 A1 WO 2024022475A1
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- Prior art keywords
- formula
- compound
- preparation
- alkyl
- alkoxy
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- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- UGWULZWUXSCWPX-UHFFFAOYSA-N 2-sulfanylideneimidazolidin-4-one Chemical class O=C1CNC(=S)N1 UGWULZWUXSCWPX-UHFFFAOYSA-N 0.000 title description 15
- 125000004076 pyridyl group Chemical group 0.000 title description 9
- 239000012450 pharmaceutical intermediate Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 191
- 238000000034 method Methods 0.000 claims abstract description 66
- -1 aryl isothiocyanate Chemical class 0.000 claims abstract description 24
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 48
- 150000002367 halogens Chemical class 0.000 claims description 48
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 46
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 29
- 239000003513 alkali Substances 0.000 claims description 27
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims description 19
- 229960004926 chlorobutanol Drugs 0.000 claims description 16
- 239000002994 raw material Substances 0.000 claims description 13
- 238000006467 substitution reaction Methods 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 238000005886 esterification reaction Methods 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 6
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 238000005580 one pot reaction Methods 0.000 claims description 6
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 238000004458 analytical method Methods 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 239000003814 drug Substances 0.000 abstract description 8
- 239000000543 intermediate Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 150000001735 carboxylic acids Chemical class 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract description 2
- 238000011144 upstream manufacturing Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 238000006243 chemical reaction Methods 0.000 description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 230000014759 maintenance of location Effects 0.000 description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000012071 phase Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 229960000630 chlorobutanol hemihydrate Drugs 0.000 description 12
- 238000010828 elution Methods 0.000 description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000010998 test method Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000010606 normalization Methods 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000000010 aprotic solvent Substances 0.000 description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 6
- 150000007522 mineralic acids Chemical class 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- XXSPGBOGLXKMDU-UHFFFAOYSA-N 2-bromo-2-methylpropanoic acid Chemical compound CC(C)(Br)C(O)=O XXSPGBOGLXKMDU-UHFFFAOYSA-N 0.000 description 5
- XAEBTCPOZVEMHR-UHFFFAOYSA-N 2-methylpropan-2-ol;potassium Chemical compound [K].CC(C)(C)O XAEBTCPOZVEMHR-UHFFFAOYSA-N 0.000 description 5
- UENBBJXGCWILBM-UHFFFAOYSA-N 6-methylpyridin-3-amine Chemical compound CC1=CC=C(N)C=N1 UENBBJXGCWILBM-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 5
- 150000008041 alkali metal carbonates Chemical class 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 5
- 229940011051 isopropyl acetate Drugs 0.000 description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 5
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 5
- FTPYTOBWBIDLKS-UHFFFAOYSA-N 3-fluoro-4-isothiocyanato-2-methoxybenzonitrile Chemical compound COC1=C(F)C(N=C=S)=CC=C1C#N FTPYTOBWBIDLKS-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 4
- 230000002152 alkylating effect Effects 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 102000001307 androgen receptors Human genes 0.000 description 4
- 108010080146 androgen receptors Proteins 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000005191 phase separation Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
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- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
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- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
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- 229940123407 Androgen receptor antagonist Drugs 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical group ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 2
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- 238000012544 monitoring process Methods 0.000 description 2
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- 206010028980 Neoplasm Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FIULGFJIHJJXMT-UHFFFAOYSA-N [C]1[N]C=CC=C1 Chemical group [C]1[N]C=CC=C1 FIULGFJIHJJXMT-UHFFFAOYSA-N 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 150000008431 aliphatic amides Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- HJBWBFZLDZWPHF-UHFFFAOYSA-N apalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C2(CCC2)C(=O)N(C=2C=C(C(C#N)=NC=2)C(F)(F)F)C1=S HJBWBFZLDZWPHF-UHFFFAOYSA-N 0.000 description 1
- 229950007511 apalutamide Drugs 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- ZRXHYHZENMJKMG-UHFFFAOYSA-N bis(benzotriazol-1-yl)methanethione Chemical compound N1=NC2=CC=CC=C2N1C(=S)N1C2=CC=CC=C2N=N1 ZRXHYHZENMJKMG-UHFFFAOYSA-N 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 150000003950 cyclic amides Chemical class 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 1
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- LRDFRRGEGBBSRN-UHFFFAOYSA-N isobutyronitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 1
- 229940102253 isopropanolamine Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- OHZZTXYKLXZFSZ-UHFFFAOYSA-I manganese(3+) 5,10,15-tris(1-methylpyridin-1-ium-4-yl)-20-(1-methylpyridin-4-ylidene)porphyrin-22-ide pentachloride Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Mn+3].C1=CN(C)C=CC1=C1C(C=C2)=NC2=C(C=2C=C[N+](C)=CC=2)C([N-]2)=CC=C2C(C=2C=C[N+](C)=CC=2)=C(C=C2)N=C2C(C=2C=C[N+](C)=CC=2)=C2N=C1C=C2 OHZZTXYKLXZFSZ-UHFFFAOYSA-I 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- KERBAAIBDHEFDD-UHFFFAOYSA-N n-ethylformamide Chemical compound CCNC=O KERBAAIBDHEFDD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- MWPOEMYVTCIOPT-UHFFFAOYSA-N pyridin-2-yloxymethanethioic s-acid Chemical compound SC(=O)OC1=CC=CC=N1 MWPOEMYVTCIOPT-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- HBEFYGYBMKPNSZ-UHFFFAOYSA-N s-phenyl chloromethanethioate Chemical compound ClC(=O)SC1=CC=CC=C1 HBEFYGYBMKPNSZ-UHFFFAOYSA-N 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- ZKLZYKQXBZQOKL-UHFFFAOYSA-M sodium;2-[4-[2-(dimethylamino)ethoxy]anilino]-2-methylpropanoate Chemical compound [Na+].CN(C)CCOC1=CC=C(NC(C)(C)C([O-])=O)C=C1 ZKLZYKQXBZQOKL-UHFFFAOYSA-M 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- RYXNTTXRPACDJA-UHFFFAOYSA-N sulfanyl carbonochloridate Chemical compound SOC(Cl)=O RYXNTTXRPACDJA-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Definitions
- the present invention belongs to the technical field of pharmaceutical synthesis and relates to a pyridinyl substituted thiohydantoin pharmaceutical intermediate and its preparation method and use.
- Androgen receptor antagonist therapy is currently one of the main clinical treatments for prostate cancer.
- AR androgen receptor
- drugs have been successfully marketed, such as Enzalutamide and Apalutamide.
- Enzalutamide and Apalutamide drugs that have been successfully marketed, such as Enzalutamide and Apalutamide.
- the efficacy of these antagonist drugs as monotherapy or combination therapy against resistant prostate cancer is limited. Therefore, there is a need for better AR small molecule antagonists which should have potent antagonistic effects without any agonistic effects, and there is also a need to reduce the observed side effects.
- CN102757389B discloses an AR small molecule antagonist of a pyridinyl substituted thiohydantoin pharmaceutical compound.
- the patent also discloses a preparation method of the pyridinyl substituted thiohydantoin pharmaceutical compound (Example 20) as follows.
- Example 9 in paragraph [0124] discloses a method for preparing 2- [4- (2-dimethylamino ethoxy) -phenylamino] -2-methylpropionic acid sodium salt by the reaction of aromatic amine and chlorobutanol under sodium hydroxide alkaline condition (the yield is 63.06%) .
- the yield of thiohydantoin is low (the total yield of two steps is only 10.73%) by first generating sodium amino acid salt, and then using the sodium salt and aryl isothiocyanate to produce the thiohydantoin, which cannot meet the needs of industrial production.
- the purpose of the invention is to provide an intermediate for pyridinyl substituted thiohydantoin pharmaceuticals, and to be used for the preparation of pyridinyl substituted thiohydantoin pharmaceuticals (in particular, compounds of formula (VII) ) which solves the defects of the prior art for the preparation of pyridinyl substituted thiohydantoin pharmaceuticals, such as high toxicity of raw materials, unstable nature of the intermediates, low reaction yields, and inapplicability for large scale production.
- R is selected from C 1 -C 6 alkyl
- A is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy.
- R is selected from C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably R is methyl, ethyl or tert-butyl, more preferably R is methyl.
- A is selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl and C 1 -C 4 haloalkoxy, preferably A is selected from C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tertiary-butyl, preferably A is methyl, ethyl or tertiary-butyl, more preferably A is methyl.
- R and A are not both methyl.
- the present invention provides a preparation method of a compound of formula (I) (Method A) which comprises esterification reaction of a compound of formula (II) or its pharmaceutically acceptable salt thereof reacting with ROH to obtain a compound of formula (I) ;
- R and A are as defined in formula (I) .
- the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol.
- the ROH is a solvent used in the reaction for dispersing the dissolved solid reactants.
- the esterification reaction is carried out in the presence of a catalyst;
- the catalyst is a chlorinated reagent, an alkylating reagent or an inorganic acid;
- the chlorinated reagent is thionyl chloride (SOCl 2 ) , phosphorus trichloride (POCl 3 ) , phosphorus pentachloride (PCl 5 ) , or phosgene (COCl 2 ) , etc.
- the alkylating reagent is methylene iodide, dimethyl sulphate, or dimethyl carbonate, etc.;
- the inorganic acid is sulfuric, phosphoric, or hydrochloric acid, etc., preferably a chlorination reagent.
- the compound of formula (II) or a pharmaceutically acceptable salt thereof reacts with methanol in the presence of thionyl chloride by esterification reaction; furthermore, calculated as the prototype compound, the molar ratio of the thionyl chloride to the compound of formula (II) is 1.5-5.0: 1, for example 2.0: 1, 2.5: 1, 3.0: 1 or 5.0: 1.
- the method A further which comprises a compound of formula (III) or its pharmaceutically acceptable salt thereof reacting with chlorobutanol or its hydrate thereof to obtain a compound of formula (II) ;
- n 0, 0.5 or 1;
- A is as defined in formula (I) ;
- chlorobutanol is chlorobutanol hemihydrate.
- the molar ratio of the compound of formula (III) to the chlorobutanol is 1: 1.1-3.0, for example 1: 1.5, 1: 2, 1: 2.5, or 1: 3.0.
- the reaction is carried out in the presence of a solvent and alkali, and after the reaction is completed, acid is used for post-treatment.
- the solvent is any one or more of a aprotic solvent or a protonic solvent
- the aprotic solvent comprises a chained or cyclic C 1 -C 6 aliphatic ketone (for example acetone, butanone) , a chained or cyclic C 1 -C 6 aliphatic ether (for example tetrahydrofuran, dimethyl ether) , etc.
- the protonic solvent comprises a chained or cyclic C 1 -C 6 aliphatic alcohol (for example methanol, ethanol, isopropanol, tert-butanol) , preferably the solvent is any one or more of acetone, tetrahydrofuran and tert-butanol.
- the alkali is an alkali metal hydroxide, preferably sodium hydroxide.
- the molar ratio of the alkali to the compound of formula (III) is 2-10: 1, for example 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, or 8: 1.
- the acid is an inorganic acid or organic acid, preferably an inorganic acid such as hydrochloric acid, phosphoric acid, or sulfuric acid.
- the compound of formula (III) or a pharmaceutically acceptable salt thereof reacts with chlorobutanol hemihydrate
- the reaction is carried out in the presence of acetone, tetrahydrofuran and sodium hydroxide, and at the end of the reaction, post-treatment is carried out using hydrochloric acid;
- the molar ratio of the compound of formula (III) to the chlorobutanol hemihydrate is 1 : 1.1-3.0, such as 1: 1.5, 1: 2 or 1: 2.5; and the molar ratio of the sodium hydroxide to the compound of formula (III) is 2-10: 1, such as 3: 1, 4: 1, 5: 1.
- the method A further comprises a substitution reaction of a compound of formula (III) or a pharmaceutically acceptable salt thereof with a compound of formula (IV) to obtain a compound of formula (II) ;
- X is Cl, Br or I, preferably Cl or Br, further preferably Br;
- A are as defined in formula (I) .
- the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1.1-2.0: 1, for example 1.1: 1, 1.35: 1, 1.5: 1, or 1.8: 1.
- the substitution reaction is carried out in the presence of a solvent.
- the solvent is any one or more of an aprotic solvent or a protonic solvent, wherein the aprotic solvent comprises an aromatic hydrocarbon (for example benzene, toluene, dimethylbenzene, etc. ) , and the protonic solvent comprises a chain or cyclic C 1 -C 6 aliphatic alcohol (for example methanol, ethanol, isopropanol, tertiary butyl alcohol, etc. ) .
- aromatic hydrocarbon for example benzene, toluene, dimethylbenzene, etc.
- the protonic solvent comprises a chain or cyclic C 1 -C 6 aliphatic alcohol (for example methanol, ethanol, isopropanol, tertiary butyl alcohol, etc. ) .
- the substitution reaction is carried out in the presence of an alkali.
- the alkali is an alkali metal alkyd, an alkali metal carbonate, an alkali metal hydroxide or a nitrogenous organic alkali, wherein the alkali metal alkyd comprises sodium methanol, sodium ethanol, sodium tert-butanol, potassium tert-butanol, etc., preferably potassium tert-butanol; the alkali metal carbonate comprises sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, etc., preferably cesium carbonate; the alkali metal hydroxide comprises sodium hydroxide, potassium hydroxide, lithium hydroxide etc., preferably sodium hydroxide or potassium hydroxide; the nitrogenous organic alkalis include triethylamine (TEA) , N, N-diisopropylethylamine (DIPEA) , 4-dimethylaminopyridine (DMAP) etc.; the alkali is preferably nitrogenous organic alkalis, and more preferably N, N-diiso
- the compound of formula (III) or a pharmaceutically acceptable salt thereof reacts with 2-bromo-2-methylpropionic acid in the presence of isopropanol and triethylamine by a substitution reaction; furthermore, calculated as the prototype compound, the molar ratio of the 2-bromo-2-methylpropionic acid to the compound of formula (III) is 1.1-2.0: 1, for example 1.1: 1, 1.35: 1, 1.5: 1 or 1.8.1; the molar ratio of the triethylamine to the compound of formula (III) is 1-6: 1, for example 1.5: 1, 2: 1, 3: 1, 4: 1 or 5: 1.
- the present invention provides a preparation method of a compound of formula (I) (Method B) which comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof reacting with a compound of formula (V) by substitution reaction to obtain a compound of formula (I) ;
- X is Cl, Br or I, preferably Cl or Br, further preferably Br; R and A are as defined in formula (I) .
- the molar ratio of the compound of formula (V) to the compound of formula (III) is 1.1-2.0: 1, for example 1.1: 1, 1.35: 1, 1.5: 1 or 2.0: 1.
- the substitution reaction is carried out in the presence of a solvent.
- the solvent is a chain or cyclic C 1 -C 6 aliphatic amide (for example N, N-dimethylformamide, N, N-dimethylacetamide, etc. ) .
- the substitution reaction is carried out in the presence of an alkali.
- the alkali is an alkali metal carbonate or a nitrogenous organic alkali, wherein the alkali metal carbonate comprises sodium carbonate, potassium carbonate etc., and the nitrogenous organic alkali comprises N, N-diisopropylethylamine (DIPEA) , 4-dimethylaminopyridine (DMAP) etc.; preferably, the alkali is an alkali metal carbonate, preferably potassium carbonate; even more preferably, calculated as the prototype compound, the molar ratio of the alkali to the formula (III) compound in a molar ratio of 1-6: 1, for example 1.5: 1, 2: 1, 3: 1, 4: 1 or 5: 1.
- DIPEA N-diisopropylethylamine
- DMAP 4-dimethylaminopyridine
- the compound of formula (III) or a pharmaceutically acceptable salt thereof reacts with 2-bromo-2-methylpropionic acid by substitution reaction in the presence of N, N-dimethylformamide and potassium carbonate; further, calculated as the prototype compound, the molar ratio of the methyl 2-bromo-2-methylpropionate to the compound of formula (III) is 1.1-2.0: 1, for example 1.1: 1, 1.35: 1, 1.5: 1 or 2.0: 1, preferably 2.0: 1; the molar ratio of the potassium carbonate to the compound of formula (III) is 1-6: 1, for example 1.5: 1, 2: 1, 3: 1, 4: 1 or 5: 1.
- the present invention provides a preparation method of a compound of formula (I) (Method C) which comprises a compound of formula (III) or its pharmaceutically acceptable salt thereof reacting with a chlorobutanol or its hydrate in the presence of an alkali to obtain a compound of formula (II) -M, and then reacts with ROH by esterification reaction to obtain a compound of formula (I) ;
- the hydrate of chlorobutanol is chlorobutanol hemihydrate.
- the molar ratio of the compound of formula (III) to the chlorobutanol is 1: 1.1-3.0, for example 1: 1.5, 1: 2, 1: 2.5 or 1: 3.0.
- the reaction is carried out in the presence of a solvent.
- the solvent is any one or more of aprotic solvents, wherein the aprotic solvents include chained or cyclic C 1 -C 6 aliphatic ketones (for example acetone, butanone) , chained or cyclic C 1 -C 6 aliphatic ethers (for example tetrahydrofuran, dimethyl ether) , etc., preferably the solvent is any one or more of acetone, tetrahydrofuran.
- the aprotic solvents include chained or cyclic C 1 -C 6 aliphatic ketones (for example acetone, butanone) , chained or cyclic C 1 -C 6 aliphatic ethers (for example tetrahydrofuran, dimethyl ether) , etc., preferably the solvent is any one or more of acetone, tetrahydrofuran.
- the alkali is an alkali metal hydroxide or alkaline earth metal hydroxide, preferably sodium hydroxide, potassium hydroxide or calcium hydroxide, more preferably sodium hydroxide.
- the compound of formula (II) -M is a sodium, potassium or calcium salt corresponding to the compound of formula (II) .
- the molar ratio of the alkali to the compound of formula (III) is 2-10: 1, for example 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, or 8: 1.
- the compound of formula (III) or a pharmaceutically acceptable salt thereof reacts with chlorobutanol hemihydrate
- the reaction is carried out in the presence of acetone and sodium hydroxide; furthermore, calculated as the prototype compound, the molar ratio of the compound of formula (III) to the chlorobutanol hemihydrate is 1: 1.1-3.0, for example 1: 1.5, 1: 2 or 1: 2.5; the molar ratio of the sodium hydroxide to the compound of formula (III) is 2-10: 1, for example 3: 1, 4: 1, 5: 1.
- the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol.
- the ROH is a solvent used in the reaction to disperse the dissolved solid reactants.
- the esterification reaction is carried out in the presence of a catalyst;
- the catalyst is a chlorinated reagent, an alkylating reagent or an inorganic acid;
- the chlorinated reagent is SOCl 2 , POCl 3 or COCl 2 , etc.;
- the alkylating reagent is methylene iodide, dimethyl sulphate or dimethyl carbonate, etc.;
- the inorganic acid is sulphuric acid, phosphoric acid or hydrochloric acid, etc., more preferably a chlorinated reagent, and even more preferably SOCl 2 .
- the compound of formula (II) or a pharmaceutically acceptable salt thereof reacts with methanol by an esterification reaction in the presence of a sulfoxide chloride; furthermore, the molar ratio of the sulfoxide chloride to the compound of formula (II) , calculated as the prototype compound, is 1.5-5.0: 1, for example, 2.0: 1, 2.5: 1, 3.0: 1 or 5.0: 1.
- the present invention provides a preparation method of a compound of formula (I) (Method D) which comprises a one-pot reaction of the compound of formula (III) or its pharmaceutically acceptable salt thereof reacting with a 2-trichloromethyl-2-propanol or its hydrate thereof in the presence of an alkali and ROH to obtain a compound of formula (I) .
- the hydrate of chlorobutanol is chlorobutanol hemihydrate.
- the molar ratio of the compound of formula (III) to the chlorobutanol is 1: 1.1-3.0, for example 1: 1.5, 1: 2, 1: 2.5 or 1: 3.0.
- the alkali is an alkali metal alcohol, preferably sodium methanol, sodium ethanol, sodium tert-butanol or potassium tert-butanol.
- the molar ratio of the alkali to the compound of formula (III) is 2-10: 1, for example 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, or 8: 1.
- the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol.
- the ROH is a solvent used in the reaction for dispersing the dissolved solid reactants.
- the compound of formula (III) or a pharmaceutically acceptable salt thereof reacts with chlorobutanol hemihydrate that the reaction is carried out in the presence of sodium methanol and methanol; furthermore, the molar ratio of the compound of formula (III) to the chlorobutanol hemihydrate, calculated as the prototype compound, is 1: 1.1-3.0, for example 1: 1.5, 1: 2, or 1 : 2.5; the molar ratio of the sodium methanolate to the compound of formula (III) is 2-10: 1, for example 3: 1, 4: 1, 5: 1.
- the present invention provides a preparation method for a compound of formula (VII) which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof reacting with a compound of formula (VI) by a ring closing reaction to obtain a compound of formula (VII) ;
- Z is selected from hydrogen, halogen, cyano, C 1 -C 4 alkyl optionally substituted by one or more halogens and C 1 -C 4 alkoxy optionally substituted by one or more halogens, preferably C 1 -C 4 alkoxy, more preferably methoxy;
- Y is selected from halogen, cyano, hydroxyl, and C 1 -C 4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;
- R and A are as defined in formula (I) ;
- the molar ratio of the compound of formula (I) to the compound of formula (VI) is 1.0: 1.0-2.0, for example 1.0: 1.3, 1.0: 1.5, 1.0: 1.6 or 1.0: 1.7.
- the ring closing reaction is carried out in the presence of a polar organic solvent;
- the polar organic solvent is one or mixture of a nitrile, an amide, a sulfoxide, an ester thereof, wherein the nitrile solvent is a reagent such as acetonitrile, acrylonitrile, acrylonitrile, nitrile;
- the amide solvent is a reagent such as N, N-dimethyl formamide, N, N-dimethyl acetamide, N-ethyl formamide;
- the sulfoxide solvent is a reagent such as dimethyl sulfoxide, diethyl sulfoxide, n-propyl sulfoxide;
- the ester solvent is a reagent such as ethyl acetate, propyl acetate, isopropyl acetate; and furthermore, the solvent is one or mixture of acetonitrile (ACN) , N, N, N
- the compound of formula (I) or a pharmaceutically acceptable salt thereof reacts with 3-fluoro-4-isothiocyanato-2-methoxybenzonitrile by a ring closing; the reaction is carried out in the presence of DMF.
- the molar ratio of the compound of formula (I) to 3-fluoro-4-isothiocyanato-2-methoxybenzonitrile is 1.0: 1.0-2.0, for example 1.0: 1.3, 1.0: 1.5, 1.0: 1.6 or 1.0: 1.7.
- the present invention provides a preparation method of a compound of formula (VII) , which comprises using a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (VIII) , and a thio source reagent as raw materials by a ring closing reaction via a one-pot method in an organic solvent to obtain a compound of formula (VII) ;
- Z is selected from hydrogen, halogen, cyano, C 1 -C 4 alkyl optionally substituted by one or more halogens and C 1 -C 4 alkoxy optionally substituted by one or more halogens, preferably C 1 -C 4 alkoxy, more preferably methoxy;
- Y is selected from halogen, cyano, hydroxyl, and C 1 -C 4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;
- R and A are as defined in formula (I) ;
- Z and Y also satisfy the following conditions:
- Z is not methoxy when Y is fluorine and in a neighboring position to Z;
- Y and Z are neither simultaneously fluorine nor methoxy when Y is in a neighboring position to Z;
- the thio source reagent is selected from 1, 1'-thiocarbonylbis (pyridin-2 (1H) -one) thiophosgene O, O'-bis (pyridin-2-yl) thiocarbonate bis (1H-imidazol-1-yl) methanethione bis (1H-benzotriazol-1-yl) methanethione aromatic thiochloroformate (for example, a phenyl thiochloroformate) , preferably
- the organic solvent is an alkylate, an alkyl ether, a cyclic ether, an aryl ether, a chlorinated hydrocarbon, an aryl hydrocarbon, a halogenated aryl hydrocarbon, an alkyl ketone, a C 2 -C 6 nitrile, or an amide in the form of a chain or a ring, wherein the alkylate is ethyl acetate or isopropyl acetate;
- the alkyl ether is an ethyl ether or a methyl tertiary butyl ether; and the cyclic ether is 1, 4-dioxane or 2-methyltetrahydrofuran;
- the aryl ether is anisole;
- the chlorinated hydrocarbon is methylene chloride, chloroform or 1, 2-dichloroethane;
- the aromatic hydrocarbon is toluene or xylene;
- the chlorinated aromatic hydrocarbon is chlorobenzen
- the organic solvent is an alkyl acid ester, a chlorinated hydrocarbon, an aromatic hydrocarbon or an alkyl ketone.
- the organic solvent is ethyl acetate, dichloromethane, chloroform, toluene or acetone.
- the ratio of the compound of formula (I) to the compound of formula (VIII) and the sulfur source reagent is 1: 0.5-5: 1-5, preferably 1: 0.5-2: 1-5, more preferably 1: 1.5-2: 2-5, for example 1: 2: 3.
- the compound of formula (I) is prepared by any of the methods of the second to fifth aspects.
- the compound of formula (I) is prepared by the method in the second aspect, the method comprising: the compound of formula (II) or a pharmaceutically acceptable salt thereof reacts with ROH by esterification reaction to obtain the compound of formula (I) ;
- the method further comprises: the compound of formula (III) or its pharmaceutically acceptable salt reacts with the compound of formula (IV) by substitution reaction to obtain the compound of formula (II) ;
- the present invention provides the use of a compound of formula (I) in the preparation of a compound of formula (VII) ;
- Z is selected from hydrogen, halogen, cyano, C 1 -C 4 alkyl optionally substituted by one or more halogens and C 1 -C 4 alkoxy optionally substituted by one or more halogens, preferably C 1 -C 4 alkoxy, more preferably methoxy;
- Y is selected from halogen, cyano, hydroxyl, and C 1 -C 4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;
- A is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy, preferably C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and C 1 -C 4 haloalkoxy, preferably C 1 -C 4 alkyl, further preferably methyl, ethyl, and tertiary butyl, and further preferably methyl.
- the present invention provides the use of compounds of formula (I) as an impurity control and/or reference standard for the analysis of compounds of formula (VII) ;
- Z is selected from hydrogen, halogen, cyano, C 1 -C 4 alkyl optionally substituted by one or more halogens and C 1 -C 4 alkoxy optionally substituted by one or more halogens, preferably C 1 -C 4 alkoxy, more preferably methoxy;
- Y is selected from halogen, cyano, hydroxyl, and C 1 -C 4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;
- A is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy, preferably C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, and C 1 -C 4 haloalkoxy, preferably C 1 -C 4 alkyl, further preferably methyl, ethyl, and tertiary butyl, and further preferably methyl.
- the present invention has the following excellent effects:
- the present invention provides an intermediate for thiohydantoin pharmaceuticals, i.e., a compound of formula (I) which can be used for the preparation of thiohydantoin pharmaceuticals as shown in formula (VII) , and solves the shortcomings of the existing production process, such as harsh conditions in the ring closing reaction and low yield of the product, etc.; compared with the method in CN102757389B, the method of the present invention abandons the use of hazardous raw materials, such as sodium cyanide, trimethylsilyl cyanide, etc., and the ring closing yield is significantly improved, up to 60%or more;
- the present invention uses, for the first time, the following method, which prepares a compound of formula (II) by combining a compound of formula (III) or pharmaceutically acceptable salts thereof reacting with halogenated carboxylic acids (i.e., compounds of formula (IV) ) in high yields of up to 90%.
- the method provides a basis for the production scale-up of compounds of formula (I) and their subsequent applications, such as the preparation of compounds of formula (VII) ;
- the present invention uses, for the first time, the following method, which prepares a compound of formula (VII) by reacting a compound of formula (I) with 3-fluoro-4-isothiocyanato-2-methoxybenzonitrile via ring closing reaction.
- the compounds of formula (VII) can also be used as a key organic impurity for quality control analysis;
- the preparation method of the present invention is suitable for industrial production, can be scaled up for kilogram-scale production, and the reaction effect is better than or basically equivalent to the small and medium-sized level of the examples of the present invention.
- HPLC condition in example for Assay or purity analysis is as follows:
- Mobile phase binary mobile phase system
- mobile phase B is acetonitrile
- Mobile phase binary mobile phase system, mobile phase A is acetonitrile, mobile phase B is 0.1%v/v formic acid aqueous solution;
- Mobile phase binary mobile phase system, mobile phase A is acetonitrile, mobile phase B is 0.1%v/v formic acid aqueous solution;
- Elution method gradient elution (during gradient elution, the maximum volume percentage of mobile phase A is 95%, and the minimum volume percentage is 30%) ;
- 6-methylpyridin-3-amine 21.62 g, about 0.2 mol
- chlorobutanol hemihydrate 93.19 g, 2.5 eq
- acetone 32.05 g
- tetrahydrofuran 72.15 g
- Sodium hydroxide 40.10 g, 5 eq
- 6-methylpyridin-3-amine (32.4 g, 1.0 eq) was added into the reaction bottle, and added with isopropanol, triethylamine (125 ml, about 3.0 eq) for stirring, and then added with 2-bromo-2-methylpropionic acid (75.2 g, about 1.5 eq) to mix and react.
- the mixture was protected by nitrogen and heated to reflux for 3 ⁇ 4 h.
- the progress of the reaction was monitored by HPLC (using HPLC test method 1, area normalization statistics) .
- the product formula (II) compound was 91.04% (retention time of 6.69 min)
- the raw material formula (III) compound was 3.89% (retention time of 6.20 min) , and the reaction was completed.
- the inventor also expanded the solvent (such as replacing isopropyl alcohol with methanol, toluene, etc. ) to investigate the effect of different kinds of solvents on the reaction process.
- the results of reaction control were monitored by HPLC (using HPLC test method 1, area normalization statistics) .
- the results showed that the reaction results of methanol and toluene were different from those of isopropyl alcohol.
- the results of control test in methanol system were 80.82% (retention time 9.66 min) and 79.48% (retention time 9.64 min) in toluene system. It indicates that the requirements of the later reaction can be basically met before further optimization.
- a methanol solution of the compound of formula (II) obtained by Method 2 in Example 1 (the theoretical value of the converted compound of formula (II) was 58.3 g, 0.3 mol) was transferred to a reaction bottle, stirred under nitrogen protection. The temperature was controlled at 0 ⁇ 5°C, and sulfoxide chloride (107.1 g, 3.0 eq) was added dropwise, and after the dropwise addition, the flask was stirred for 0.5 ⁇ 1h, the temperature was raised to 25 ⁇ 30°C, and the reaction was carried out overnight.
- the anhydrous sodium sulfate (45 g) was added to organic phase to stir and filtrate.
- the filter cake was washed with methyl tert-butyl ether (200 ml) .
- Anhydrous sodium sulfate (45 g) was added to the organic phase for stirring and filtration.
- the filter cake was washed with methyl tert-butyl ether, and the filtrate was concentrated until no solvent was evaporated, obtaining a pale-yellow oil (34.36 g, the total yield of the two-step was 55.0%.
- the results of reaction control were monitored by HPLC (using HPLC test method 1, area normalization statistics) , the purity was 95.64%by HPLC and the retention time was 14.78 min.
- Salt (sodium salt) of compound of formula (II) was first prepared from compound of formula (III) (A is methyl) and chlorobutanol or its hydrate (hemihydrate) , and then compound of formula (I) was prepared from salt (sodium salt) of compound of formula (II) (R is methyl, A is methyl)
- Step (1)
- Acetone (200 ml) , 6-methylpyridine-3-amine (21.6 g, 0.2 mol) and chlorobutanol hemihydrate (93.2 g, 0.5 mol) were added into a three-way flask, dissolved by stirring under the protection of nitrogen, and the system temperature was controlled to be lower than 30°C.
- Sodium hydroxide (40.1 g, 1.0 mol) was added in batches, and then, after adding, the reaction was stirred at 10°C for 1h, and then heated to 25°C for about 15h.
- the reaction solution was extracted and filtered, the filter cake was washed with acetone (20 ml ⁇ 2) , temperature control ⁇ 50°C.
- the filtrate was concentrated under reduced pressure until no liquid was evaporated, and dichloromethane (100 ml) was added, and stirred for 10 min.
- the product layer was obtained, washed with methylene chloride (100 ml ⁇ 1) , and stirred for 10 min.
- the upper layer was collected to obtain the sodium salt of formula (II) compound which was about 42 g, the yield was about 97.1%, and the HPLC purity was 91.6% (using HPLC test method 2, area normalization statistics, retention time was 2.70 min) .
- Step (2)
- step (1) The sodium salt of the compound of formula (II) obtained in step (1) (42 g, about 0.2 mol) , methanol (200 ml) was added to a 500 ml three-necked flask, protected by nitrogen, stirred to dissolve, and the temperature was controlled ⁇ 20 °C. Then sulfoxide chloride (63.5 g, 0.53 mol) was added by drops, and the reaction was completed at 25°C for about 15h.
- the reaction solution was concentrated and spun dry under reduced pressure. methyl tert-butyl ether (200 ml) and water (200 ml) were added, stirred for 10 min, the pH was adjusted to 8 -9 with anhydrous sodium carbonate, and the organic phase was obtained by standing and phase separation. The aqueous phase was extracted with methyl tert-butyl ether (100 ml ⁇ 2) to stand the solution to combine the organic phase. The filter cake was washed with a small amount of methyl tert-butyl ether. The filtrate was concentrated under reduced pressure and then steamed out without liquid. 21 g brown oil was obtained. The total yield of two steps was about 50%, and the purity of HPLC was 91.3%. (Using HPLC test method 2, area normalization statistics, retention time was 7.36 min) .
- the compound of formula (I) with higher yield can be achieved by using method 2, but the layering in the post-treatment process of step (2) is difficult to manipulate. The water cannot be removed, and the difficulty of batch scale-up production is high.
- 6-methylpyridine-3-amine 0.5 g, 4.62 mmol
- methanol 5 ml
- sodium methanol 1.25 g, 23.15 mmol
- chlorobutanol hemihydrate 2.16 g, 2.15 mmol
- methanol 2.5 ml
- 6-Methylpyridin-3-amine 0.5g, 4.62 mmol
- methyl 2-bromo-2-methylpropionate (1.67 g, 9.07 mmol)
- potassium carbonate (1.92 g, 13.91 mmol)
- DMF 5 mL
- the temperature was raised to 50°C
- potassium iodide 0.1g, 0.60mmol
- the temperature was continued to rise to 70°C for about 5h, and the reaction was completed by TLC monitoring.
- the area ratio of product to raw material was about 20%.
- Formula (I) -1 compound (9.85 g, 0.047 mol) and DMF (13.3 ml) were added into a 50 ml reaction bottle and stirred at room temperature until fully dissolved. Then formula (VI) -1 compound (16.74g, 1.7eq) was added and stirred at room temperature for 23h. At the end of the reaction, ethyl acetate and water were added to extract the organic layer. Washing, saturated salt washing, anhydrous sodium sulfate drying, extraction and filtration, ethyl acetate leaching; The filtrate was combined. The ethyl acetate was removed by spin distillation. DCM (30 ml) was added, and followed by stirring, extraction and filtration, and ethanol was added to the obtained solid. After extraction and filtration, the filter cake was dried. The target product was 11.7 g, and the yield was 64.4%, and the purity was 99.8%by HPLC (using HPLC test method 3, retention time of 12.97 min) .
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Abstract
The present invention belongs to the technical field of pharmaceutical synthesis technology and relates to a pyridyl-substituted thioglycolide intermediate for pharmaceutical use and its preparation method and use. In particular, the present invention discloses compounds of formula (I), which can be used to prepare thioglycolide drugs, and solves the defects of the existing process such as harsh conditions and low yields. The present invention also discloses various preparation methods of compounds of formula (I), which involve novel processes for some upstream intermediates (for example, compounds of formula (II) in the form of carboxylic acids). In addition, the present invention discloses for the first time a method for the synthesis of compounds of formula (I) to obtain thioglycolide analogues by ring closing reaction with aryl isothiocyanate.
Description
The present invention belongs to the technical field of pharmaceutical synthesis and relates to a pyridinyl substituted thiohydantoin pharmaceutical intermediate and its preparation method and use.
Androgen receptor antagonist therapy is currently one of the main clinical treatments for prostate cancer. In recent years, scientists have been working on the development of androgen receptor (AR) small molecule antagonists that can treat cancer. And several drugs have been successfully marketed, such as Enzalutamide and Apalutamide. However, the efficacy of these antagonist drugs as monotherapy or combination therapy against resistant prostate cancer is limited. Therefore, there is a need for better AR small molecule antagonists which should have potent antagonistic effects without any agonistic effects, and there is also a need to reduce the observed side effects.
CN102757389B discloses an AR small molecule antagonist of a pyridinyl substituted thiohydantoin pharmaceutical compound. The patent also discloses a preparation method of the pyridinyl substituted thiohydantoin pharmaceutical compound (Example 20) as follows.
The preparation method reacted 3-fluoro-4-isothiocyanato-2-methoxybenzonitrile with 2-methyl-2- (6-methylpyridin-3-yl) aminopropanenitrile under microwave radiation conditions with a yield of 23%. This method obviously could not meet demand of commercial production. In addition, the preparation of the intermediate 2-methyl-2- (6-methylpyridin-3-yl) aminopropionitrile required the use of TMSCN
(trimethylsilyl cyanide) . And the TMSCN is an extremely toxic and highly flammable chemical substance which brings great challenges and hidden dangers to production security, and the TMSCN mainly relied on imports with high cost.
Paragraph [0095] of the specification US2012/0184580A1 discloses a preparation method of thiohydantoin by a ring closing reaction with (hetero) aryl-substituted amino acids and aryl isothiocyanates. However, the method does not disclose examples for the preparation of the related product using heteroaryl (for example pyridyl) substituted amino acids. The method only discloses a ring closing reaction using a sodium salt of amino acid substituted with an aryl group (In particular, phenyl) in example 8 of paragraph [0122] , but the reaction required high temperatures of about 80℃ to 100℃ and more than ten hours, and the yield was low (only 17.02%) . Further, Example 9 in paragraph [0124] discloses a method for preparing 2- [4- (2-dimethylamino ethoxy) -phenylamino] -2-methylpropionic acid sodium salt by the reaction of aromatic amine and chlorobutanol under sodium hydroxide alkaline condition (the yield is 63.06%) . However, it was obvious that the yield of thiohydantoin is low (the total yield of two steps is only 10.73%) by first generating sodium amino acid salt, and then using the sodium salt and aryl isothiocyanate to produce the thiohydantoin, which cannot meet the needs of industrial production.
M.E. Jung et al. (M. E. Jung, S. Ouk, D. Yoo, et al., Structure-Activity Relationship for Thiohydantoin Androgen Receptor Antagonists for Castration-Resistant Prostate Cancer (CRPC) [J] , J. Med. Chem., 2010, 53 (7) : 2779-2796) disclosed that in the preparation of Enzalutamide (i.e., Compound 92 in the article) , a microwave-assisted ring closing reaction was used in CN102757389B, but in a significantly higher yield than that in CN102757389B, reflecting that compounds having the same functional group (or structural fragment) but different specific structures are less generalizable for the same method in the preparation.
At present, there is no efficient and feasible synthesis method for a pyridinyl substituted thiohydantoin pharmaceutical which is unable to guarantee the subsequent clinical drugs use and its subsequent production supply.
Problems to be solved by the Invention.
The purpose of the invention is to provide an intermediate for pyridinyl
substituted thiohydantoin pharmaceuticals, and to be used for the preparation of pyridinyl substituted thiohydantoin pharmaceuticals (in particular, compounds of formula (VII) ) which solves the defects of the prior art for the preparation of pyridinyl substituted thiohydantoin pharmaceuticals, such as high toxicity of raw materials, unstable nature of the intermediates, low reaction yields, and inapplicability for large scale production.
Technical solutions for problem solving.
According to a first aspect of the present invention,
Wherein: R is selected from C1-C6 alkyl; A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.
Preferably, in the compound of formula (I) , R is selected from C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably R is methyl, ethyl or tert-butyl, more preferably R is methyl.
Preferably, in the compound of formula (I) , A is selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkoxy, preferably A is selected from C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tertiary-butyl, preferably A is methyl, ethyl or tertiary-butyl, more preferably A is methyl.
More preferably, in the compound of formula (I) , R and A are not both methyl.
According to a second aspect of the present invention, the present invention provides a preparation method of a compound of formula (I) (Method A) which comprises esterification reaction of a compound of formula (II) or its pharmaceutically acceptable salt thereof reacting with ROH to obtain a compound of formula (I) ;
Wherein: R and A are as defined in formula (I) .
Preferably, in the method A, the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol. Also, the ROH is a solvent used in the reaction for dispersing the dissolved solid reactants.
Preferably, in the method A, the esterification reaction is carried out in the
presence of a catalyst; the catalyst is a chlorinated reagent, an alkylating reagent or an inorganic acid; the chlorinated reagent is thionyl chloride (SOCl2) , phosphorus trichloride (POCl3) , phosphorus pentachloride (PCl5) , or phosgene (COCl2) , etc.; the alkylating reagent is methylene iodide, dimethyl sulphate, or dimethyl carbonate, etc.; and the inorganic acid is sulfuric, phosphoric, or hydrochloric acid, etc., preferably a chlorination reagent.
More preferably, in the method A, the compound of formula (II) or a pharmaceutically acceptable salt thereof reacts with methanol in the presence of thionyl chloride by esterification reaction; furthermore, calculated as the prototype compound, the molar ratio of the thionyl chloride to the compound of formula (II) is 1.5-5.0: 1, for example 2.0: 1, 2.5: 1, 3.0: 1 or 5.0: 1.
Preferably, the method A further which comprises a compound of formula (III) or its pharmaceutically acceptable salt thereof reacting with chlorobutanol or its hydrate thereof to obtain a compound of formula (II) ;
Wherein: n is 0, 0.5 or 1; A is as defined in formula (I) ;
Further, the hydrate of chlorobutanol is chlorobutanol hemihydrate.
Preferably, calculated as the prototype compound, the molar ratio of the compound of formula (III) to the chlorobutanol is 1: 1.1-3.0, for example 1: 1.5, 1: 2, 1: 2.5, or 1: 3.0.
Preferably, the reaction is carried out in the presence of a solvent and alkali, and after the reaction is completed, acid is used for post-treatment.
Further, the solvent is any one or more of a aprotic solvent or a protonic solvent, wherein the aprotic solvent comprises a chained or cyclic C1-C6 aliphatic ketone (for example acetone, butanone) , a chained or cyclic C1-C6 aliphatic ether (for example tetrahydrofuran, dimethyl ether) , etc., and the protonic solvent comprises a chained or cyclic C1-C6 aliphatic alcohol (for example methanol, ethanol, isopropanol, tert-butanol) , preferably the solvent is any one or more of acetone, tetrahydrofuran and tert-butanol.
Further, the alkali is an alkali metal hydroxide, preferably sodium hydroxide.
Preferably, calculated as the prototype compound, the molar ratio of the alkali to
the compound of formula (III) is 2-10: 1, for example 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, or 8: 1.
Further, the acid is an inorganic acid or organic acid, preferably an inorganic acid such as hydrochloric acid, phosphoric acid, or sulfuric acid.
More preferably, in the method A, the compound of formula (III) or a pharmaceutically acceptable salt thereof reacts with chlorobutanol hemihydrate, the reaction is carried out in the presence of acetone, tetrahydrofuran and sodium hydroxide, and at the end of the reaction, post-treatment is carried out using hydrochloric acid; furthermore, calculated as the prototype compound, the molar ratio of the compound of formula (III) to the chlorobutanol hemihydrate is 1 : 1.1-3.0, such as 1: 1.5, 1: 2 or 1: 2.5; and the molar ratio of the sodium hydroxide to the compound of formula (III) is 2-10: 1, such as 3: 1, 4: 1, 5: 1.
Alternatively, preferably, the method A further comprises a substitution reaction of a compound of formula (III) or a pharmaceutically acceptable salt thereof with a compound of formula (IV) to obtain a compound of formula (II) ;
Wherein: X is Cl, Br or I, preferably Cl or Br, further preferably Br; A are as defined in formula (I) .
Preferably, calculated as the prototype compound, the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1.1-2.0: 1, for example 1.1: 1, 1.35: 1, 1.5: 1, or 1.8: 1.
Preferably, the substitution reaction is carried out in the presence of a solvent.
Further, the solvent is any one or more of an aprotic solvent or a protonic solvent, wherein the aprotic solvent comprises an aromatic hydrocarbon (for example benzene, toluene, dimethylbenzene, etc. ) , and the protonic solvent comprises a chain or cyclic C1-C6 aliphatic alcohol (for example methanol, ethanol, isopropanol, tertiary butyl alcohol, etc. ) .
Preferably, the substitution reaction is carried out in the presence of an alkali.
Further, the alkali is an alkali metal alkyd, an alkali metal carbonate, an alkali metal hydroxide or a nitrogenous organic alkali, wherein the alkali metal alkyd comprises sodium methanol, sodium ethanol, sodium tert-butanol, potassium tert-butanol, etc., preferably potassium tert-butanol; the alkali metal carbonate comprises sodium carbonate, potassium carbonate, cesium carbonate, lithium
carbonate, etc., preferably cesium carbonate; the alkali metal hydroxide comprises sodium hydroxide, potassium hydroxide, lithium hydroxide etc., preferably sodium hydroxide or potassium hydroxide; the nitrogenous organic alkalis include triethylamine (TEA) , N, N-diisopropylethylamine (DIPEA) , 4-dimethylaminopyridine (DMAP) etc.; the alkali is preferably nitrogenous organic alkalis, and more preferably N, N-diisopropylethylamine or triethylamine. Preferably, calculated as the prototype compound, the molar ratio of the alkali to the compound of formula (III) is 1-6: 1, for example 1.5: 1, 2: 1, 3: 1, 4: 1 or 5: 1.
More preferably, the compound of formula (III) or a pharmaceutically acceptable salt thereof reacts with 2-bromo-2-methylpropionic acid in the presence of isopropanol and triethylamine by a substitution reaction; furthermore, calculated as the prototype compound, the molar ratio of the 2-bromo-2-methylpropionic acid to the compound of formula (III) is 1.1-2.0: 1, for example 1.1: 1, 1.35: 1, 1.5: 1 or 1.8.1; the molar ratio of the triethylamine to the compound of formula (III) is 1-6: 1, for example 1.5: 1, 2: 1, 3: 1, 4: 1 or 5: 1.
According to a third aspect of the present invention, the present invention provides a preparation method of a compound of formula (I) (Method B) which comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof reacting with a compound of formula (V) by substitution reaction to obtain a compound of formula (I) ;
Wherein: X is Cl, Br or I, preferably Cl or Br, further preferably Br; R and A are as defined in formula (I) .
Preferably, calculated as the prototype compound, the molar ratio of the compound of formula (V) to the compound of formula (III) is 1.1-2.0: 1, for example 1.1: 1, 1.35: 1, 1.5: 1 or 2.0: 1.
Preferably, in the method B, the substitution reaction is carried out in the presence of a solvent.
Further, the solvent is a chain or cyclic C1-C6 aliphatic amide (for example N, N-dimethylformamide, N, N-dimethylacetamide, etc. ) .
Preferably, in the method B, the substitution reaction is carried out in the presence of an alkali.
Further, the alkali is an alkali metal carbonate or a nitrogenous organic alkali, wherein the alkali metal carbonate comprises sodium carbonate, potassium carbonate etc., and the nitrogenous organic alkali comprises N, N-diisopropylethylamine (DIPEA) , 4-dimethylaminopyridine (DMAP) etc.; preferably, the alkali is an alkali metal carbonate, preferably potassium carbonate; even more preferably, calculated as the prototype compound, the molar ratio of the alkali to the formula (III) compound in a molar ratio of 1-6: 1, for example 1.5: 1, 2: 1, 3: 1, 4: 1 or 5: 1.
More preferably, in the method B, the compound of formula (III) or a pharmaceutically acceptable salt thereof reacts with 2-bromo-2-methylpropionic acid by substitution reaction in the presence of N, N-dimethylformamide and potassium carbonate; further, calculated as the prototype compound, the molar ratio of the methyl 2-bromo-2-methylpropionate to the compound of formula (III) is 1.1-2.0: 1, for example 1.1: 1, 1.35: 1, 1.5: 1 or 2.0: 1, preferably 2.0: 1; the molar ratio of the potassium carbonate to the compound of formula (III) is 1-6: 1, for example 1.5: 1, 2: 1, 3: 1, 4: 1 or 5: 1.
According to a fourth aspect of the present invention, the present invention provides a preparation method of a compound of formula (I) (Method C) which comprises a compound of formula (III) or its pharmaceutically acceptable salt thereof reacting with a chlorobutanol or its hydrate in the presence of an alkali to obtain a compound of formula (II) -M, and then reacts with ROH by esterification reaction to obtain a compound of formula (I) ;
Wherein: n is 0, 0.5 or 1; m is 1 or 2, preferably 1; Mm+ is a cation of an alkali metal or alkaline earth metal, preferably Na+, K+ or Ca2+, preferably Na+; R and A are as defined in formula (I) .
Further, in the first step of the method C, the hydrate of chlorobutanol is chlorobutanol hemihydrate.
Preferably, in the first step of the method C, calculated as the prototype compound, the molar ratio of the compound of formula (III) to the chlorobutanol is 1: 1.1-3.0, for example 1: 1.5, 1: 2, 1: 2.5 or 1: 3.0.
Preferably, in the first step of the method C, the reaction is carried out in the presence of a solvent.
Further, the solvent is any one or more of aprotic solvents, wherein the aprotic solvents include chained or cyclic C1-C6 aliphatic ketones (for example acetone, butanone) , chained or cyclic C1-C6 aliphatic ethers (for example tetrahydrofuran, dimethyl ether) , etc., preferably the solvent is any one or more of acetone, tetrahydrofuran.
Further, in the first step of the method C, the alkali is an alkali metal hydroxide or alkaline earth metal hydroxide, preferably sodium hydroxide, potassium hydroxide or calcium hydroxide, more preferably sodium hydroxide. In other words, the compound of formula (II) -M is a sodium, potassium or calcium salt corresponding to the compound of formula (II) .
Preferably, in the first step of the method C, calculated as the prototype compound, the molar ratio of the alkali to the compound of formula (III) is 2-10: 1, for example 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, or 8: 1.
More preferably, in the first step of the method C, the compound of formula (III) or a pharmaceutically acceptable salt thereof reacts with chlorobutanol hemihydrate, the reaction is carried out in the presence of acetone and sodium hydroxide; furthermore, calculated as the prototype compound, the molar ratio of the compound of formula (III) to the chlorobutanol hemihydrate is 1: 1.1-3.0, for example 1: 1.5, 1: 2 or 1: 2.5; the molar ratio of the sodium hydroxide to the compound of formula (III) is 2-10: 1, for example 3: 1, 4: 1, 5: 1.
Preferably, in the second step of the method C, the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol. Also, the ROH is a solvent used in the reaction to disperse the dissolved solid reactants.
Preferably, in the second step of the method C, the esterification reaction is carried out in the presence of a catalyst; the catalyst is a chlorinated reagent, an alkylating reagent or an inorganic acid; the chlorinated reagent is SOCl2, POCl3 or COCl2, etc.; the alkylating reagent is methylene iodide, dimethyl sulphate or dimethyl carbonate, etc.; and the inorganic acid is sulphuric acid, phosphoric acid or hydrochloric acid, etc., more preferably a chlorinated reagent, and even more preferably SOCl2.
More preferably, in the second step of the method C, the compound of formula (II) or a pharmaceutically acceptable salt thereof reacts with methanol by an esterification reaction in the presence of a sulfoxide chloride; furthermore, the molar ratio of the sulfoxide chloride to the compound of formula (II) , calculated as the
prototype compound, is 1.5-5.0: 1, for example, 2.0: 1, 2.5: 1, 3.0: 1 or 5.0: 1.
According to a fifth aspect of the present invention, the present invention provides a preparation method of a compound of formula (I) (Method D) which comprises a one-pot reaction of the compound of formula (III) or its pharmaceutically acceptable salt thereof reacting with a 2-trichloromethyl-2-propanol or its hydrate thereof in the presence of an alkali and ROH to obtain a compound of formula (I) .
Wherein: n is 0, 0.5 or 1; R and A are as defined in formula (I) .
Further, in the method D, the hydrate of chlorobutanol is chlorobutanol hemihydrate.
Preferably, in the method D, calculated as the prototype compound, the molar ratio of the compound of formula (III) to the chlorobutanol is 1: 1.1-3.0, for example 1: 1.5, 1: 2, 1: 2.5 or 1: 3.0.
Preferably, in the method D, the alkali is an alkali metal alcohol, preferably sodium methanol, sodium ethanol, sodium tert-butanol or potassium tert-butanol.
Preferably, in the method D, calculated as the prototype compound, the molar ratio of the alkali to the compound of formula (III) is 2-10: 1, for example 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, or 8: 1.
Preferably, in the method D, the ROH is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol. Also, the ROH is a solvent used in the reaction for dispersing the dissolved solid reactants.
More preferably, in the method D, the compound of formula (III) or a pharmaceutically acceptable salt thereof reacts with chlorobutanol hemihydrate that the reaction is carried out in the presence of sodium methanol and methanol; furthermore, the molar ratio of the compound of formula (III) to the chlorobutanol hemihydrate, calculated as the prototype compound, is 1: 1.1-3.0, for example 1: 1.5, 1: 2, or 1 : 2.5; the molar ratio of the sodium methanolate to the compound of formula (III) is 2-10: 1, for example 3: 1, 4: 1, 5: 1.
According to a sixth aspect of the present invention, the present invention provides a preparation method for a compound of formula (VII) which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof reacting with a compound of formula (VI) by a ring closing reaction to obtain a compound of formula
(VII) ;
Wherein:
Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens and C1-C4 alkoxy optionally substituted by one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;
Y is selected from halogen, cyano, hydroxyl, and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;
R and A are as defined in formula (I) ;
Preferably, in the preparation method, the molar ratio of the compound of formula (I) to the compound of formula (VI) is 1.0: 1.0-2.0, for example 1.0: 1.3, 1.0: 1.5, 1.0: 1.6 or 1.0: 1.7.
Preferably, in the preparation method, the ring closing reaction is carried out in the presence of a polar organic solvent; further, the polar organic solvent is one or mixture of a nitrile, an amide, a sulfoxide, an ester thereof, wherein the nitrile solvent is a reagent such as acetonitrile, acrylonitrile, acrylonitrile, nitrile; the amide solvent is a reagent such as N, N-dimethyl formamide, N, N-dimethyl acetamide, N-ethyl formamide; the sulfoxide solvent is a reagent such as dimethyl sulfoxide, diethyl sulfoxide, n-propyl sulfoxide; the ester solvent is a reagent such as ethyl acetate, propyl acetate, isopropyl acetate; and furthermore, the solvent is one or mixture of acetonitrile (ACN) , N, N-dimethylformamide (DMF) , dimethylsulfoxide (DMSO) , isopropyl acetate (IPAc) thereof, preferably DMF.
More preferably, in the preparation method, the compound of formula (I) or a pharmaceutically acceptable salt thereof reacts with 3-fluoro-4-isothiocyanato-2-methoxybenzonitrile by a ring closing; the reaction is carried out in the presence of DMF. Further, the molar ratio of the compound of formula (I) to 3-fluoro-4-isothiocyanato-2-methoxybenzonitrile is 1.0: 1.0-2.0, for example 1.0: 1.3, 1.0: 1.5, 1.0: 1.6 or 1.0: 1.7.
According to a seventh aspect of the present invention, the present invention provides a preparation method of a compound of formula (VII) , which comprises using a compound of formula (I) or a pharmaceutically acceptable salt thereof, a
compound of formula (VIII) , and a thio source reagent as raw materials by a ring closing reaction via a one-pot method in an organic solvent to obtain a compound of formula (VII) ;
Wherein:
Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens and C1-C4 alkoxy optionally substituted by one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;
Y is selected from halogen, cyano, hydroxyl, and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;
R and A are as defined in formula (I) ;
Preferably, in the preparation method, Z and Y also satisfy the following conditions:
Z is not methoxy when Y is fluorine and in a neighboring position to Z; and
Y and Z are neither simultaneously fluorine nor methoxy when Y is in a neighboring position to Z;
Preferably, in the preparation method, the thio source reagent is selected from 1, 1'-thiocarbonylbis (pyridin-2 (1H) -one) thiophosgeneO, O'-bis (pyridin-2-yl) thiocarbonatebis (1H-imidazol-1-yl) methanethionebis (1H-benzotriazol-1-yl) methanethionearomatic thiochloroformate
(for example, a phenyl thiochloroformate) , preferably
Preferably, in the preparation method, the organic solvent is an alkylate, an alkyl ether, a cyclic ether, an aryl ether, a chlorinated hydrocarbon, an aryl hydrocarbon, a halogenated aryl hydrocarbon, an alkyl ketone, a C2-C6 nitrile, or an amide in the form of a chain or a ring, wherein the alkylate is ethyl acetate or isopropyl acetate; The alkyl ether is an ethyl ether or a methyl tertiary butyl ether; and the cyclic ether is 1, 4-dioxane or 2-methyltetrahydrofuran; The aryl ether is anisole; The chlorinated hydrocarbon is methylene chloride, chloroform or 1, 2-dichloroethane; The aromatic hydrocarbon is toluene or xylene; The chlorinated aromatic hydrocarbon is chlorobenzene; The alkyl ketone is acetone, butanone or methyl isobutyl ketone; The C2-C6 nitrile is acetonitrile, propionitrile, n-butyronitrile or isobutyronitrile; The amide in the form of a chain is N, N-dimethylformamide or N, N-dimethylacetamide; The cyclic amide is N-methyl-2-pyrrolidone.
More preferably, the organic solvent is an alkyl acid ester, a chlorinated hydrocarbon, an aromatic hydrocarbon or an alkyl ketone.
Further preferably, the organic solvent is ethyl acetate, dichloromethane, chloroform, toluene or acetone.
Preferably, in the method, calculated by molar ratio, the ratio of the compound of formula (I) to the compound of formula (VIII) and the sulfur source reagent is 1: 0.5-5: 1-5, preferably 1: 0.5-2: 1-5, more preferably 1: 1.5-2: 2-5, for example 1: 2: 3.
Further, in the preparation method of the sixth or seventh aspect, the compound of formula (I) is prepared by any of the methods of the second to fifth aspects.
Preferably, in the preparation method of the sixth or seventh aspect, the compound of formula (I) is prepared by the method in the second aspect, the method comprising: the compound of formula (II) or a pharmaceutically acceptable salt thereof reacts with ROH by esterification reaction to obtain the compound of formula (I) ;
Wherein: the definitions of R and A and the conditions of the esterification reaction are as described in the second aspect.
More preferably, the method further comprises: the compound of formula (III) or its pharmaceutically acceptable salt reacts with the compound of formula (IV) by substitution reaction to obtain the compound of formula (II) ;
Wherein: the definitions of A and X and the conditions of the substitution reaction are as described in the second aspect.
According to an eighth aspect of the present invention, the present invention provides the use of a compound of formula (I) in the preparation of a compound of formula (VII) ;
Wherein:
Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens and C1-C4 alkoxy optionally substituted by one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;
Y is selected from halogen, cyano, hydroxyl, and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;
A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, preferably C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy, preferably C1-C4 alkyl, further preferably methyl, ethyl, and tertiary butyl, and further preferably methyl.
According to a ninth aspect of the present invention, the present invention provides the use of compounds of formula (I) as an impurity control and/or reference standard for the analysis of compounds of formula (VII) ;
Wherein:
Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens and C1-C4 alkoxy optionally substituted by one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;
Y is selected from halogen, cyano, hydroxyl, and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;
A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, preferably C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy, preferably C1-C4 alkyl, further preferably methyl, ethyl, and tertiary butyl, and further preferably methyl.
The beneficial effect of the invention
Compared with the prior art, the present invention has the following excellent effects:
1) The present invention provides an intermediate for thiohydantoin pharmaceuticals, i.e., a compound of formula (I) which can be used for the preparation of thiohydantoin pharmaceuticals as shown in formula (VII) , and solves the shortcomings of the existing production process, such as harsh conditions in the ring closing reaction and low yield of the product, etc.; compared with the method in CN102757389B, the method of the present invention abandons the use of hazardous raw materials, such as sodium cyanide, trimethylsilyl cyanide, etc., and the ring closing yield is significantly improved, up to 60%or more;
2) The present invention uses, for the first time, the following method, which prepares a compound of formula (II) by combining a compound of formula (III) or pharmaceutically acceptable salts thereof reacting with halogenated carboxylic acids (i.e., compounds of formula (IV) ) in high yields of up to 90%. The method provides a basis for the production scale-up of compounds of formula (I) and their subsequent applications, such as the preparation of compounds of formula (VII) ;
3) The present invention uses, for the first time, the following method, which prepares a compound of formula (VII) by reacting a compound of formula (I) with
3-fluoro-4-isothiocyanato-2-methoxybenzonitrile via ring closing reaction. When the compounds of formula (VII) are prepared by the method of the present invention, the compounds of formula (I) can also be used as a key organic impurity for quality control analysis;
4) The preparation method of the present invention is suitable for industrial production, can be scaled up for kilogram-scale production, and the reaction effect is better than or basically equivalent to the small and medium-sized level of the examples of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The technical program of the present invention is further elaborated below in accordance with specific examples. Unless otherwise indicated, the instruments, consumables, reagents, etc., used in the following examples are available by conventional commercial means.
The HPLC condition in example for Assay or purity analysis is as follows:
● HPLC test method 1
Column: C18 (150 mm × 4.6 mm × 2.7 μm) ;
Mobile phase: binary mobile phase system, mobile phase A is 100 mM ammonium acetate aqueous solution (pH = 7.8) , mobile phase B is acetonitrile;
Elution time: 45 min;
Elution method: gradient elution (during gradient elution, the maximum volume percentage of mobile phase A is 95%, the minimum volume percentage is 25%) ;
Detection wavelength: 268 nm.
● HPLC test method 2
Column: C18 (150 mm × 4.6 mm × 2.7 μm) ;
Mobile phase: binary mobile phase system, mobile phase A is acetonitrile, mobile phase B is 0.1%v/v formic acid aqueous solution;
Elution time: 25 min;
Elution method: gradient elution (during gradient elution, the maximum volume percentage of mobile phase A is 30%and the minimum volume percentage is 10%) ;
Detection wavelength: 220 nm.
● HPLC test method 3
Column: C18 (150 mm × 4.6 mm × 5 μm) ;
Mobile phase: binary mobile phase system, mobile phase A is acetonitrile,
mobile phase B is 0.1%v/v formic acid aqueous solution;
Elution time: 37 min;
Elution method: gradient elution (during gradient elution, the maximum volume percentage of mobile phase A is 95%, and the minimum volume percentage is 30%) ;
Detection wavelength: 268 nm.
Example 1: Preparation of compounds of formula (II) (A is methyl)
Method 1: Compound of formula (III) (A is methyl) and chlorobutanol or its hydrate (hemihydrate) were as raw materials
6-methylpyridin-3-amine (21.62 g, about 0.2 mol) , chlorobutanol hemihydrate (93.19 g, 2.5 eq) , acetone (32.05 g) , and tetrahydrofuran (72.15 g) were sequentially added into the reaction bottle, and then dissolved with stirring in an ice bath. Sodium hydroxide (40.10 g, 5 eq) was added into the reaction which was stirred for 30 min, and the reaction was monitored by TLC.
After the raw material disappeared, the filtrate was filtered and concentrated to no liquid. And the acetone and dichloromethane were added for extraction, washing and stratification. Product layer was taken (the purity was 89.3%by HPLC) . Methanol solution of hydrogen chloride was added. The pH was adjusted to 6 for filtrating to get filtrate. After concentrating by reducing pressure, product of brown-red oil was obtained (46.54 g, the purity was 89.3%based on the HPLC test results of sodium carboxylate) . The product was used directly in the subsequent reaction without further purification. The weight of the product exceeded the theoretical yield, and it was assumed that the product might contain undrained methanol and unreacted chlorobutanol.
In addition, in method 1, when delamination was performed before adding HCl/MeOH, it was difficult to delaminate because the product is the corresponding sodium carboxylate at this time, but subsequent acidification can still be achieved.
1H-NMR (400 MHz, DMSO-d6) : δ 7.77-7.78 (d, J=2.88, 1H) , 6.93 (d, J=8.4Hz, 1H) , 6.72-6.75 (dd, J1=2.88Hz, J2=8.36Hz, 1H) , 2.27 (s, 3H) , 1.41 (s, 6H) .
Method 2: Compound of formula (III) (A is methyl) and compound of formula
IV (X is Br) were as raw materials
6-methylpyridin-3-amine (32.4 g, 1.0 eq) was added into the reaction bottle, and added with isopropanol, triethylamine (125 ml, about 3.0 eq) for stirring, and then added with 2-bromo-2-methylpropionic acid (75.2 g, about 1.5 eq) to mix and react. The mixture was protected by nitrogen and heated to reflux for 3～4 h. The progress of the reaction was monitored by HPLC (using HPLC test method 1, area normalization statistics) . The product formula (II) compound was 91.04% (retention time of 6.69 min) , and the raw material formula (III) compound was 3.89% (retention time of 6.20 min) , and the reaction was completed.
After cooling down and filtration, the filtrate was concentrated to be solvent-free, anhydrous methanol was added and distilled under reduced pressure to moisture ≤ 0.3%to obtain a reddish of brown oily material, namely the methanol solution of the compound of formula (II) (95.2 g) , and HPLC detection was performed (using HPLC test method 1, area normalization statistics) . The product was 91.19% (retention time of 6.75 min) , and the raw material was 4.11% (retention time of 6.24 min) . The product was used directly in the subsequent reaction without further purification.
In the early development process, the inventors had studied the reaction conditions above. Isopropyl alcohol is used as solvent for different dosage (2 –5 g) of compound of formula (III) . The amount of 2-bromo-2-methylpropionic acid is fixed at 1.5 times the molar amount of the compound of formula (III) (that is 1.5 eq, based on the compound of formula (III) ) . Different types of bases and their dosage were screened, in particular triethylamine (3.0 eq) , cesium carbonate (1.5 eq) , potassium hydroxide (2.5 eq) , sodium hydroxide (2.5 eq) , potassium tert-butanol (2.5 eq) , to investigate the effects of different types of bases on the reaction process. The results of reaction control were monitored by HPLC (using HPLC test method 1, area normalization statistics) . They were triethylamine (90.58%, retention time 9.79 min) , cesium carbonate (87.47%, retention time 7.33min) , potassium hydroxide (88.05%, retention time 7.30min) , sodium hydroxide (82.89%, retention time 7.29 min) , potassium tert-butanol (71.62%, retention time) . The retention time is 6.80min) . The results show that different types of an alkali can achieve excellent conversion rate. Among them, the preferred nitrogenous organic alkali (triethylamine) was the best.
In addition, during the early development process, the inventor also expanded the solvent (such as replacing isopropyl alcohol with methanol, toluene, etc. ) to investigate the effect of different kinds of solvents on the reaction process. The results of reaction control were monitored by HPLC (using HPLC test method 1, area normalization statistics) . The results showed that the reaction results of methanol and toluene were different from those of isopropyl alcohol. The results of control test in methanol system were 80.82% (retention time 9.66 min) and 79.48% (retention time 9.64 min) in toluene system. It indicates that the requirements of the later reaction can be basically met before further optimization.
Example 2: Preparation of compounds of formula (I) (R is methyl, A is methyl)
Method 1: Compounds of formula (II) (A is methyl) and alcohol (methanol) were used as raw materials
A methanol solution of the compound of formula (II) obtained by Method 2 in Example 1 (the theoretical value of the converted compound of formula (II) was 58.3 g, 0.3 mol) was transferred to a reaction bottle, stirred under nitrogen protection. The temperature was controlled at 0～5℃, and sulfoxide chloride (107.1 g, 3.0 eq) was added dropwise, and after the dropwise addition, the flask was stirred for 0.5～1h, the temperature was raised to 25～30℃, and the reaction was carried out overnight.
The temperature was controlled by 40～50℃, the reaction liquid was concentrated to solvent-free evaporation, and added with methanol to the concentrated material, and the concentration is again concentrated to dry. Methyl tert-butyl ether (400 ml) and water (400 g) was added to stir for 10min. Sodium carbonate was added to neutralize. The pH was adjusted to 8～9. After standing and phase separation, the organic phase was collected. The aqueous phase was extracted with methyl tert-butyl ether (200ml*2) twice, combined with the organic phase. saturated aqueous sodium chloride (200 ml) was added to wash and stir for 10min. The fraction solution was stand. The anhydrous sodium sulfate (45 g) was added to organic phase to stir and filtrate. The filter cake was washed with methyl tert-butyl ether (200 ml) . Anhydrous sodium sulfate (45 g) was added to the organic phase for stirring and filtration. The filter cake was washed with methyl tert-butyl ether, and the filtrate was concentrated
until no solvent was evaporated, obtaining a pale-yellow oil (34.36 g, the total yield of the two-step was 55.0%. The results of reaction control were monitored by HPLC (using HPLC test method 1, area normalization statistics) , the purity was 95.64%by HPLC and the retention time was 14.78 min.
1H-NMR (400 MHz, CDCl3) : δ 7.94 (d, J=2.8Hz, 1H) , 6.94 (d, J=8.36Hz, 1H) , 6.81-6.84 (dd, J1=2.92Hz, J2=8.36Hz, 1H) , 4.01 (s, 1H) , 3.71 (s, 3H) , 2.42 (s, 3H) , 1.54 (s, 6H) .
Method 2: Salt (sodium salt) of compound of formula (II) was first prepared from compound of formula (III) (A is methyl) and chlorobutanol or its hydrate (hemihydrate) , and then compound of formula (I) was prepared from salt (sodium salt) of compound of formula (II) (R is methyl, A is methyl)
Step (1) :
Acetone (200 ml) , 6-methylpyridine-3-amine (21.6 g, 0.2 mol) and chlorobutanol hemihydrate (93.2 g, 0.5 mol) were added into a three-way flask, dissolved by stirring under the protection of nitrogen, and the system temperature was controlled to be lower than 30℃. Sodium hydroxide (40.1 g, 1.0 mol) was added in batches, and then, after adding, the reaction was stirred at 10℃ for 1h, and then heated to 25℃ for about 15h.
The reaction solution was extracted and filtered, the filter cake was washed with acetone (20 ml × 2) , temperature control ≤ 50℃. The filtrate was concentrated under reduced pressure until no liquid was evaporated, and dichloromethane (100 ml) was added, and stirred for 10 min. After standing and phase separation, the product layer was obtained, washed with methylene chloride (100 ml × 1) , and stirred for 10 min. After standing and phase separation, the upper layer was collected to obtain the sodium salt of formula (II) compound which was about 42 g, the yield was about 97.1%, and the HPLC purity was 91.6% (using HPLC test method 2, area normalization statistics, retention time was 2.70 min) .
Step (2) :
The sodium salt of the compound of formula (II) obtained in step (1) (42 g, about 0.2 mol) , methanol (200 ml) was added to a 500 ml three-necked flask, protected by nitrogen, stirred to dissolve, and the temperature was controlled ≤20 ℃. Then sulfoxide chloride (63.5 g, 0.53 mol) was added by drops, and the reaction was completed at 25℃ for about 15h.
The reaction solution was concentrated and spun dry under reduced pressure. methyl tert-butyl ether (200 ml) and water (200 ml) were added, stirred for 10 min, the pH was adjusted to 8 -9 with anhydrous sodium carbonate, and the organic phase was obtained by standing and phase separation. The aqueous phase was extracted with methyl tert-butyl ether (100 ml×2) to stand the solution to combine the organic phase. The filter cake was washed with a small amount of methyl tert-butyl ether. The filtrate was concentrated under reduced pressure and then steamed out without liquid. 21 g brown oil was obtained. The total yield of two steps was about 50%, and the purity of HPLC was 91.3%. (Using HPLC test method 2, area normalization statistics, retention time was 7.36 min) .
The compound of formula (I) with higher yield can be achieved by using method 2, but the layering in the post-treatment process of step (2) is difficult to manipulate. The water cannot be removed, and the difficulty of batch scale-up production is high.
Method 3: Preparation of compounds of formula (I) (R is methyl, A is methyl) from compounds of formula (III) (A is methyl) with chlorobutanol or its hydrates (hemihydrate) by one-pot method in the presence of an alkali (sodium methanol) and an alcohol (methanol)
6-methylpyridine-3-amine (0.5 g, 4.62 mmol) and methanol (5 ml) were added into a 50 mL reaction bottle, and sodium methanol (1.25 g, 23.15 mmol) was added under stirring at room temperature. Then, after cooling in an ice bath, chlorobutanol hemihydrate (2.16 g, 2.15 mmol) and methanol (2.5 ml) was added by drops. The
mixture continued to stir and react for 10 min, and the system was heated to 40℃. The heat preservation reaction was held for 3h, and the reaction was completed by TLC monitoring. According to the TLC point plate controlled in the reaction, the area ratio of product to raw material was about 20%.
The experimental results indicated that the specific structure of the compounds of formula (III) was likely to have a direct influence on their suitability for the one-pot reaction described above, and although the compounds of formula (I) can be obtained as well, the scope for further optimization in terms of yield was likewise relatively limited.
Method 4: Compounds of formula (III) (A is methyl) and compounds of formula (V) (X is Br, R is methyl) were as raw materials
6-Methylpyridin-3-amine (0.5g, 4.62 mmol) , methyl 2-bromo-2-methylpropionate (1.67 g, 9.07 mmol) , potassium carbonate (1.92 g, 13.91 mmol) and DMF (5 mL) were mixed in a 50 ml reaction bottle. Under stirring conditions, the temperature was raised to 50℃, potassium iodide (0.1g, 0.60mmol) was added, and the temperature was continued to rise to 70℃ for about 5h, and the reaction was completed by TLC monitoring. According to the reaction control TLC point plate, the area ratio of product to raw material was about 20%.
In order to further improve the yield of method 4, the inventors had tried to replace the potassium carbonate used as an alkali with an organic alkali (such as triethylamine, pyridine, etc. ) , but no reaction occurred.
The experimental results showed that the specific structure of the compound of formula (III) was likely to directly affect whether it was suitable for direct substitution reaction with the corresponding halogenated acid ester, and although the compound of formula (I) can be obtained as well, the space for further optimization in terms of yield was relatively limited.
Example III: Preparation of compounds of formula (VII) (R is methyl, A is methyl)
Formula (I) -1 compound (9.85 g, 0.047 mol) and DMF (13.3 ml) were added into a 50 ml reaction bottle and stirred at room temperature until fully dissolved. Then formula (VI) -1 compound (16.74g, 1.7eq) was added and stirred at room temperature for 23h. At the end of the reaction, ethyl acetate and water were added to extract the organic layer. Washing, saturated salt washing, anhydrous sodium sulfate drying, extraction and filtration, ethyl acetate leaching; The filtrate was combined. The ethyl acetate was removed by spin distillation. DCM (30 ml) was added, and followed by stirring, extraction and filtration, and ethanol was added to the obtained solid. After extraction and filtration, the filter cake was dried. The target product was 11.7 g, and the yield was 64.4%, and the purity was 99.8%by HPLC (using HPLC test method 3, retention time of 12.97 min) .
1H-NMR (400 MHz, DMSO-d6) : δ 8.50 (s, 1H) , 7.79-7.86 (dd, J1=7.6Hz, J2=17.6Hz, 2H) , 7.49 (t, J=10Hz, 2H) , 4.13 (s, 3H) , 2.54 (d, J=22.4Hz, 3H) , 1.52 (s, 6H) .
In addition, the inventor had tried to investigate different solvents (such as acetonitrile, isopropyl acetate, dimethyl sulfoxide or their mixtures) under the condition of fixed reaction temperature (20-25℃) , molar ratio of formula (VI) -1 compound to formula (I) -1 compound (1.5eq) and other reaction conditions, and can achieve excellent conversion, wherein acetonitrile was used as a solvent, it needed to be heated at 40-80℃ to be converted completely.
Claims (11)
- A compound of formula (I) or its pharmaceutically acceptable salt thereof;
Wherein:R is selected from C1-C6 alkyl, preferably C1-C4 alkyl, more preferably methyl, ethyl or tert-butyl, further preferably methyl;A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy, preferably C1-C4 alkyl, more preferably methyl, ethyl or tert-butyl, further preferably methyl;Preferably, R and A are not both methyl. - A preparation method for a compound of formula (I) according to claim 1, which comprises esterification reaction of a compound of formula (II) or its pharmaceutically acceptable salt thereof with ROH to obtain a compound of formula (I) ;
wherein: R and A are as defined in formula (I) . - The preparation method according to claim 2, which comprises a compound of formula (III) or its pharmaceutically acceptable salt thereof reacting with chlorobutanol or its hydrate thereof to obtain a compound of formula (II) ;
Wherein: n is 0, 0.5 or 1; A is as defined in formula (I) ;Or, the compound of formula (III) or its pharmaceutically acceptable salt reacts with the compound of formula (IV) by substitution reaction to obtain the compound of formula (II) ;
Wherein: X is Cl, Br or I, preferably Cl or Br, further preferably Br; A are as defined in formula (I) . - The preparation method of a compound of formula (I) according to claim 1, which comprises a compound of formula (III) or its pharmaceutically acceptable salt thereof reacting with a compound of formula (V) to obtain a compound of formula (I) :
Wherein: X is Cl, Br or I, preferably Cl or Br, further preferably Br; R and A is as defined in formula (I) . - The preparation method of a compound of formula (I) according to claim 1, which comprises a compound of formula (III) or its pharmaceutically acceptable salt thereof reacting with a chlorobutanol or its hydrate in the presence of an alkali to obtain a compound of formula (II) -M, and then reacts with ROH by esterification reaction to obtain a compound of formula (I) ;
Wherein: n is 0, 0.5 or 1; m is 1 or 2, preferably 1; Mm+ is a cation of an alkali metal or alkaline earth metal, preferably Na+, K+ or Ca2+, preferably Na+; R and A are as defined in formula (I) . - The preparation method of a compound of formula (I) according to claim 1, which comprises a one-pot reaction of the compound of formula (III) or its pharmaceutically acceptable salt thereof reacting with a chlorobutanol or its hydrate thereof in the presence of an alkali and ROH to obtain a compound of formula (I) ;
Wherein: n is 0, 0.5 or 1; R and A are as defined in formula (I) . - A preparation method of a compound of formula (II) , which comprises a compound of formula (III) or a pharmaceutically acceptable salt thereof reacting with a compound of formula (IV) conducts by substitution reaction to obtain a compound of formula (II) ;
Wherein: X is Cl, Br or I, preferably Cl or Br, more preferably Br; A is as defined in formula (I) . - A preparation method for a compound of formula (VII) , which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof reacting with a compound of formula (VI) by a ring closing reaction to obtain a compound of formula (VII) ;
Wherein:Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens and C1-C4 alkoxy optionally substituted by one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;Y is selected from halogen, cyano, hydroxyl, and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;R and A are as defined in formula (I) ;Preferably, the compound of formula (I) is prepared by the preparation method according to any one of claims 2-6;More preferably, the compound of formula (I) is prepared by the preparation method according to claim 2;Further preferably, the compound of formula (I) is prepared by the preparation method according to claim 3. - A preparation method for a compound of formula (VII) , which comprises using a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (VIII) , and a thio source reagent as raw materials by a ring closing reaction via a one-pot method in an organic solvent to obtain a compound of formula (VII) ;
Wherein:Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens and C1-C4 alkoxy optionally substituted by one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;Y is selected from halogen, cyano, hydroxyl, and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;R and A are as defined in formula (I) ;Preferably, Z and Y also satisfy the following conditions:Z is not methoxy when Y is fluorine and in a neighboring position to Z; andY and Z are neither simultaneously fluorine nor methoxy when Y is in a neighboring position to Z;Alternatively,Preferably, the compound of formula (I) is prepared by the preparation method according to any one of claims 2-6;More preferably, the compound of formula (I) is prepared by the preparation method according to claim 2;Further preferably, the compound of formula (I) is prepared by the preparation method according to claim 3. - A use of a compound of formula (I) according to claim 1 for the preparation of a compound of formula (VII) ;
Wherein:Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens and C1-C4 alkoxy optionally substituted by one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;Y is selected from halogen, cyano, hydroxyl, and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, preferably C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy, preferably C1-C4 alkyl, further preferably methyl, ethyl, and tertiary butyl, and further preferably methyl. - A use of a compound of formula (I) according to claim 1, which is used as an impurity control and/or reference standard for the analysis of a compound of formula (VII) ;
Wherein:Z is selected from hydrogen, halogen, cyano, C1-C4 alkyl optionally substituted by one or more halogens and C1-C4 alkoxy optionally substituted by one or more halogens, preferably C1-C4 alkoxy, more preferably methoxy;Y is selected from halogen, cyano, hydroxyl, and C1-C4 alkoxy optionally substituted by one or more halogens, preferably halogen, more preferably fluorine;A is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy, preferably C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy, preferably C1-C4 alkyl, further preferably methyl, ethyl, and tertiary butyl, and further preferably methyl.
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| US20120184580A1 (en) * | 2009-04-09 | 2012-07-19 | Medivation Prostate Therapeutics, Inc. | Substituted di-arylhydantoin and di-arylthiohydantoin compounds and methods of use thereof |
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| CN104341351A (en) * | 2013-07-30 | 2015-02-11 | 北京海步国际医药科技发展有限公司 | Novel diarylthiohydantoin derivative and its application |
| WO2022161469A1 (en) * | 2021-01-29 | 2022-08-04 | 苏州开拓药业股份有限公司 | Intermediate for thiohydantoin drug, and preparation method therefor and use thereof |
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| US20120184580A1 (en) * | 2009-04-09 | 2012-07-19 | Medivation Prostate Therapeutics, Inc. | Substituted di-arylhydantoin and di-arylthiohydantoin compounds and methods of use thereof |
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