CN112745304A - Preparation method of Relugolix and intermediate compound - Google Patents
Preparation method of Relugolix and intermediate compound Download PDFInfo
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- CN112745304A CN112745304A CN202011169561.6A CN202011169561A CN112745304A CN 112745304 A CN112745304 A CN 112745304A CN 202011169561 A CN202011169561 A CN 202011169561A CN 112745304 A CN112745304 A CN 112745304A
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- salt
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- saturated
- substituted
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 83
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- AOMXMOCNKJTRQP-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN(C)C)C(C(=O)N(C=2N=NC(OC)=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 AOMXMOCNKJTRQP-UHFFFAOYSA-N 0.000 title abstract description 9
- 229950004238 relugolix Drugs 0.000 title abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 229940126214 compound 3 Drugs 0.000 claims abstract description 14
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 6
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229940125782 compound 2 Drugs 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 26
- 229940125904 compound 1 Drugs 0.000 claims description 19
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 10
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 10
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 238000006722 reduction reaction Methods 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 13
- 239000012535 impurity Substances 0.000 abstract description 9
- 230000017858 demethylation Effects 0.000 abstract description 3
- 238000010520 demethylation reaction Methods 0.000 abstract description 3
- 238000007142 ring opening reaction Methods 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- 239000000203 mixture Substances 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 238000001914 filtration Methods 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
- 239000012065 filter cake Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000013078 crystal Substances 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 6
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical group C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 6
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229940088597 hormone Drugs 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- DTXVKPOKPFWSFF-UHFFFAOYSA-N 3(S)-hydroxy-13-cis-eicosenoyl-CoA Chemical compound NC1=CC=C(Cl)N=N1 DTXVKPOKPFWSFF-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XNSAINXGIQZQOO-UHFFFAOYSA-N L-pyroglutamyl-L-histidyl-L-proline amide Natural products NC(=O)C1CCCN1C(=O)C(NC(=O)C1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-UHFFFAOYSA-N 0.000 description 2
- 102100032251 Pro-thyrotropin-releasing hormone Human genes 0.000 description 2
- 239000000627 Thyrotropin-Releasing Hormone Substances 0.000 description 2
- 101800004623 Thyrotropin-releasing hormone Proteins 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 239000003329 adenohypophysis hormone Substances 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 238000006264 debenzylation reaction Methods 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 210000003016 hypothalamus Anatomy 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- QQKDTTWZXHEGAQ-UHFFFAOYSA-N propyl carbonochloridate Chemical compound CCCOC(Cl)=O QQKDTTWZXHEGAQ-UHFFFAOYSA-N 0.000 description 2
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 229940034199 thyrotropin-releasing hormone Drugs 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- SVDDJQGVOFZBNX-UHFFFAOYSA-N 2-chloroethyl carbonochloridate Chemical compound ClCCOC(Cl)=O SVDDJQGVOFZBNX-UHFFFAOYSA-N 0.000 description 1
- KOHBEDRJXKOYHL-UHFFFAOYSA-N 2-methoxy-n-methylethanamine Chemical compound CNCCOC KOHBEDRJXKOYHL-UHFFFAOYSA-N 0.000 description 1
- FQVJPHCAWYRYCK-UHFFFAOYSA-N 3-(4-methoxyphenyl)propanoyl chloride Chemical compound COC1=CC=C(CCC(Cl)=O)C=C1 FQVJPHCAWYRYCK-UHFFFAOYSA-N 0.000 description 1
- 102000000827 Anterior Pituitary Hormones Human genes 0.000 description 1
- 108010001897 Anterior Pituitary Hormones Proteins 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 108010024118 Hypothalamic Hormones Proteins 0.000 description 1
- 102000015611 Hypothalamic Hormones Human genes 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- ROCTURQQZONMDU-UHFFFAOYSA-N di(imidazol-1-yl)methanone;hydrochloride Chemical compound Cl.C1=CN=CN1C(=O)N1C=CN=C1 ROCTURQQZONMDU-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000000601 hypothalamic hormone Substances 0.000 description 1
- 229940043650 hypothalamic hormone Drugs 0.000 description 1
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 1
- -1 methoxy amino group Chemical group 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a novel preparation method of Relugolix and two novel intermediate compounds. The invention obtains an amino compound 3 by reducing an existing compound 2, then carries out condensation reaction on the compound 3 and methoxylamine or salt thereof to obtain a compound 4, and finally carries out cyclization reaction on the compound 4 to obtain a target compound 1. The preparation method has mild reaction conditions and high reaction controllability; less impurities, no ring-opening and demethylation impurities, good purity, simple post-treatment, high yield, environmental protection, economy and good industrial application prospect.
Description
Technical Field
The invention relates to the technical field of a preparation method of Relugolix.
Background
Relugolix is a gonadotropin releasing hormone (GnRH) antagonist. The secretion of anterior pituitary hormones is feedback-controlled by peripheral hormones secreted from the target organs of the respective hormones and by secretion-regulating hormones from the hypothalamus. It has been confirmed to date as hypothalamic hormones, including thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH). These secretion-regulating hormones from the hypothalamus exhibit their actions through receptors which are thought to be present in the anterior pituitary. Therefore, GnRH antagonists are expected to prevent or treat anterior pituitary hormone-dependent diseases.
The methods described in literature 1, patents 2 and 3 are known methods reported in the literature for the preparation of Relugolix at home and abroad.
Document 1: J.Med.chem.2011,54, 4998-
Patent 2: WO2004/067535
Patent 3: WO2014/051164
Known synthetic route one (j.med.chem.2011,54, 4998-:
the synthetic route is characterized by substituting bromine of compound 11 with N- (2-methoxyethyl) methylamine to obtain compound 12; reducing the compound 12 to obtain a compound 13; condensing compound 13 with methoxylamine to form compound 14; hydrolyzing compound 14 to provide compound 15; the product obtained by condensing the compound 15 and 3-amino-6-chloropyridazine is further substituted and cyclized in the presence of sodium methoxide to obtain a compound 16; dimethylamine carries out substitution reaction on the compound 16 to obtain the final product. The synthesis method has long reaction route and low yield of the last step, which is only about 40 percent, and is not suitable for large-scale industrial application.
Known synthetic route two (WO 2004/067535):
the synthetic route adopts a compound 17 and 3-amino-6-chloropyridazine to condense to obtain a compound 18; cyclizing the compound 18 with sodium methoxide to obtain a compound 19; carrying out debenzylation reaction on the compound 19 to obtain a compound 20; methyl iodide methylates compound 20 to obtain the product. The synthesis method has long route and low total yield, and the yield of the sodium methoxide cyclization reaction is 26%; debenzylation of Pd/C with yield of 71% and generation of ring-opened demethoxylated impurities; methyl iodide methylation reaction, yield 17%. At the same time, expensive and high-toxicity methyl iodide is also used, which is obviously not suitable for large-scale industrial application.
Known synthetic route three (WO 2014/051164):
and (3) cyclizing the compound 23 to obtain a compound 24, then carrying out Pd-C/H2 reduction on the compound 24 in hydrochloric acid to obtain a compound 25, and then condensing the compound 25 and a methoxy amino group to obtain Relugolix. The synthetic route of the method has appropriate reaction steps and high yield. However, this method has a fatal problem that ring-opening impurities and demethylation impurities are generated at the reduction step, and these two impurities can be further reacted to derive new impurities, and remain in the final target product and are difficult to remove. And is not suitable for practical production and application.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a novel preparation method of Relugolix. Two new intermediate compounds are provided simultaneously.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
compound 3 or a salt thereof of the formula:
r is substituted or unsubstituted C1-C6Saturated or unsaturated alkyl, C1-C6An alkaryl group. Preferably, such as methyl, ethyl, propyl, allyl, chloroethyl, benzyl,
And the like.
A process for producing compound 3 or a salt thereof, which comprises subjecting compound 2 or a salt thereof to a reduction reaction to obtain:
r is substituted or unsubstituted C1-C6Saturated or unsaturated alkyl, C1-C6An alkaryl group. Preferably, such as methyl, ethyl, propyl, allyl, chloroethyl, benzyl,
And the like.
The reducing agent used in the reduction reaction comprises palladium carbon/hydrogen, palladium carbon/ammonium formate, Raney nickel/hydrogen, sodium hydrosulfite, zinc powder, iron powder, hydrazine hydrate and the like.
Compound 4 of the formula:
r is substituted or unsubstituted C1-C6Saturated or unsaturated alkyl, C1-C6An alkaryl group. Preferably, such as methyl, ethyl, propyl, allyl, chloroethyl, benzyl,
And the like.
A process for producing a compound 4 or a salt thereof, which comprises subjecting a compound 3 or a salt thereof and methoxylamine or a salt thereof to a condensation reaction under a condensing agent condition to obtain:
r is substituted or unsubstituted C1-C6Saturated or unsaturated alkyl, C1-C6An alkaryl group. Preferably, such as methyl, ethyl, propyl, allyl, chloroethyl, benzyl,
And the like.
The condensing agent used in the above condensation reaction includes: 1, 1' -carbonyldiimidazole and its salts, triphosgene, chloroformate, pivaloyl chloride, and the like.
Further, the compound 3 used in the above condensation reaction is obtained by the method of the present invention.
A process for producing Compound 1 or a salt thereof, which comprises subjecting Compound 4 or a salt thereof to cyclization reaction under basic conditions to give:
r is substituted or unsubstituted C1-C6Saturated or unsaturated alkyl, C1-C6An alkaryl group. Preferably, such as methyl, ethyl, propyl, allyl, chloroethyl, benzyl,
And the like.
The base used in the above cyclization reaction includes: sodium methoxide, sodium ethoxide, potassium tert-butoxide (sodium, lithium), sodium hydride, DBU, DBN and the like.
Further, the compound 4 of the above cyclization reaction is obtained by the method of the present invention.
The invention has the beneficial effects that:
the invention obtains an amino compound 3 by reducing an existing compound 2, then carries out condensation reaction on the compound 3 and methoxy amine or salt thereof to obtain a compound 4, and finally carries out cyclization reaction on the compound 4 to obtain a compound 1. The preparation method has mild reaction conditions and high reaction controllability; less impurities, no ring-opening and demethylation impurities, good purity, simple post-treatment, high yield, environmental protection, economy and good industrial application prospect.
Detailed Description
The present invention is described in detail below by way of examples, it should be noted that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention, and that those skilled in the art can make many insubstantial modifications and adaptations of the present invention based on the above disclosure.
Example 1: preparation of Compound 3-a
Compound 2-a (25.0g) was poured into methanol (200.0ml), to which 10% Pd/C (2.5g) and ammonium formate (4.77g) were added, and stirred at 50. + -. 5 ℃ for 4 hours. After the reaction, the mother liquor was collected by filtration, and the filter cake was washed with methanol. Raising the temperature of the mother liquor to 40 +/-5 ℃, stirring for 1 hour, reducing the temperature to 5 +/-5 ℃, filtering and collecting crystals, and washing a filter cake by using cold methanol. Drying under reduced pressure gave compound 3-a (22.0 g). 92% yield and 99.64% HPLC purity.
1H NMR(400MHz,Chloroform-d)δ14.06(d,J＝27.0Hz,1H),8.56(d,J＝9.6Hz,1H),7.66(s,1H),7.54(d,J＝8.1Hz,2H),7.24(d,J＝8.1Hz,2H),7.16–7.07(m,1H),6.98(d,J＝9.5Hz,1H),6.73(t,J＝7.7Hz,2H),5.03(s,2H),4.23(s,1H),4.10(s,4H),3.82(s,3H),3.49(s,2H),2.19(s,6H),1.77(s,1H),1.64(s,2H),1.01(s,1H),0.79(t,J＝7.1Hz,2H).
Example 2: preparation of Compound 4-a
Compound 3-a (10.0g) and 1, 1' -carbonyldiimidazole (5.31g) were charged into methylene chloride (40.0ml), N-diisopropylethylamine (4.24g) was added to the mixture, and stirred at 20. + -. 5 ℃ for 1 to 2 hours (hereinafter referred to as reaction mixture A).
Methoxylamine hydrochloride (13.6eq) was charged into dichloromethane (60.0ml), and N, N-diisopropylethylamine (21.18g) was added to the mixture, and stirred at 25 ± 5 ℃ for 1 hour (hereinafter referred to as reaction mixture B). Reaction mixture B was slowly added to reaction mixture A at 0. + -. 5 ℃ and stirred at the same temperature for 1-2 hours. To the reaction mixture was added a saturated sodium bicarbonate solution at 0. + -. 5 ℃ and stirred for 30 minutes, then it was left to stand, and the organic phase was separated, washed with a saturated sodium bicarbonate solution, the organic solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate and isopropyl ether to give compound 4-a (10.67 g). yield 95% and HPLC purity 99.73%.
1H NMR(400MHz,Chloroform-d)δ14.09(d,J＝27.4Hz,1H),8.57(d,J＝9.5Hz,1H),7.15–7.08(m,1H),7.05(d,J＝8.3Hz,1H),6.97(d,J＝9.5Hz,1H),6.79–6.63(m,3H),5.02(s,2H),4.22(s,1H),4.09(s,4H),3.83(s,2H),3.48(s,2H),2.19(s,6H),1.76(s,1H),1.64(s,2H),1.26(s,1H),1.00(s,1H),0.79(t,J＝7.4Hz,2H).
Example 3: preparation of Compound 1
Compound 4-a (5.0g) was added to methanol (50.0ml), and sodium methoxide (0.59g) was added to the mixture, followed by stirring at room temperature for 2 to 3 hours. Cooling to 0 deg.C or lower, stirring for 2-4 hr, filtering to collect crystal, washing filter cake with methanol at 50-60 deg.C, and drying under reduced pressure. The resulting solid was put into tetrahydrofuran, the mixture was raised to 60 ± 5 ℃ and stirred at the same temperature for 1 hour, the mixture was cooled to 0 ℃ and aged at the same temperature for 2 hours with stirring. The crystals were collected by filtration and the filter cake was washed with tetrahydrofuran. The filter cake was recrystallized from dimethyl sulfoxide (DMSO) and ethanol to give Compound 1(4.25 g). Yield: 93% and 99.68% HPLC purity.
Example 4: synthesis of Compound 3-b
Compound 2-b (25.0g) was charged into methanol (250.0ml), Raney nickel (2.5g) was added thereto, and the mixture was stirred under a hydrogen pressure of 0.1-0.2MPa at 25. + -. 5 ℃ for 4-5 hours. After the reaction, the mother liquor was collected by filtration, and the filter cake was washed with methanol. Raising the temperature of the mother liquor to 40 +/-5 ℃, stirring for 1 hour, cooling to 5 +/-5 ℃, crystallizing, filtering and collecting crystals, and washing a filter cake by using cold methanol. Drying under reduced pressure at 50 ℃ or lower gave compound 3-b (21.71 g). 91% yield, HPLC purity 99.76%.
1H NMR(400MHz,Chloroform-d)δ14.09(d,J＝32.1Hz,1H),8.56(d,J＝9.6Hz,1H),7.10(d,J＝6.7Hz,1H),7.05(d,J＝8.1Hz,1H),6.97(d,J＝9.5Hz,1H),6.78–6.62(m,3H),5.00(s,2H),4.26–4.14(m,2H),4.09(s,3H),3.83(s,2H),3.48(s,2H),2.19(s,7H),1.35(d,J＝15.1Hz,2H),1.26(d,J＝1.7Hz,1H),0.92–0.75(m,1H).
Example 5: synthesis of Compound 4-b
Compound 3-b (10.0g) and ethyl chloroformate (2.73g) were charged into methylene chloride (40.0ml), and stirred at 30. + -. 5 ℃ for 2 to 3 hours (hereinafter referred to as reaction mixture A).
Methoxyamine hydrochloride (14.0g) was charged into methylene chloride (60.0ml), and triethylamine (16.96g) was added to the mixture, and stirred at 35. + -. 5 ℃ for 1 hour (hereinafter referred to as reaction mixture B). Reaction mixture B was slowly added to reaction mixture A at 25. + -. 5 ℃ and stirred at the same temperature for 2-3 hours. To the reaction mixture was added a saturated sodium bicarbonate solution at 0 ± 5 ℃, stirred for 30 minutes, then allowed to stand, and the organic phase was separated, washed with a saturated sodium bicarbonate solution, and the organic solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate and isopropyl ether to give compound 4-b (10.49 g). 93% yield, HPLC purity 99.53%.
1H NMR(400MHz,Chloroform-d)δ14.06(d,J＝28.0Hz,1H),8.56(d,J＝9.4Hz,1H),7.64(s,1H),7.57–7.50(m,2H),7.23(d,J＝3.8Hz,3H),7.14(d,J＝2.5Hz,1H),7.12(d,J＝2.6Hz,1H),6.73(t,J＝7.9Hz,3H),5.01(s,2H),4.10(s,3H),3.83(s,3H),3.49(s,2H),2.19(s,7H),1.42(s,2H),0.90–0.83(m,1H).
Example 6: synthesis of Compound 1
Compound 4-b (5.0g) was charged into methanol (40.0ml), DBU (2.05g) was added to the mixture and stirred at 0 + -5 deg.C for 2-4 hours, crystals were collected by filtration, and the cake was washed with cold methanol and dried under reduced pressure at 45 + -5 deg.C. The resulting solid was put into tetrahydrofuran, and the mixture was raised to 60 ± 5 ℃ and stirred at the same temperature for 1 hour. The mixture was cooled to 5 ± 5 ℃ and aged at the same temperature for 2 hours with stirring. The crystals were collected by filtration, the filter cake was washed with tetrahydrofuran, and the filter cake was recrystallized from dimethyl sulfoxide (DMSO) and ethanol to give compound 1(4.15 g). Yield: 89% and HPLC purity 99.78%.
Example 7: synthesis of Compound 3-c
Compound 2-c (25.0g) was charged into ethanol (200.0ml), to which was added 10% sodium hydroxide solution (31.32g), sodium thiosulfate (12.38g) was added in portions, and the mixture was stirred at 50-60 ℃ for 4 hours. After the reaction, the organic solvent was concentrated under reduced pressure. Adding ethyl acetate for extraction, separating liquid and collecting an organic phase. Washing with saturated saline solution, drying with anhydrous sodium sulfate, and decolorizing with active carbon. Filtering, and concentrating the filtrate to dryness. Adding ethanol, heating to 40 + -5 deg.C, stirring for 1 hr, cooling to 5 + -5 deg.C, crystallizing, filtering, collecting crystal, and washing filter cake with cold ethanol. Drying under reduced pressure at 50 ℃ or lower gave compound 3-c (22.02 g). 92% yield and 99.54% HPLC purity.
Example 8: synthesis of Compound 4-c
Compound 3-c (10.0g) and propyl chloroformate (2.82g) were charged into chloroform (40.0ml), and stirred at 35. + -. 5 ℃ for 2 to 3 hours (hereinafter referred to as reaction mixture A).
Methoxylamine hydrochloride (13.72g) was charged into chloroform (60.0ml), and N, N-diisopropylethylamine (21.24g) was added to the mixture, and stirred at 30. + -. 5 ℃ for 1 to 2 hours (hereinafter referred to as reaction mixture B). Reaction mixture B was slowly added to reaction mixture A at 0. + -. 5 ℃ and stirred at the same temperature for 1-2 hours. To the reaction mixture was added a saturated sodium bicarbonate solution at 0. + -. 5 ℃ and stirred for 30 minutes, then it was left to stand, and the organic phase was separated, washed with a saturated sodium bicarbonate solution, the organic solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate and isopropyl ether to give compound 4-c (10.13 g). yield 90% and HPLC purity 99.53%.
Example 9: synthesis of Compound 1
Compound 4-c (5.0g) was put into methanol (50.0ml), potassium tert-butoxide (1.65g) was added to the mixture and stirred at 15. + -. 5 ℃ for 2-4 hours, crystals were collected by filtration, the cake was washed with cold methanol, the cake thus obtained was put into tetrahydrofuran, the mixture was raised to 60. + -. 5 ℃ and stirred at the same temperature for 1 hour. The mixture was cooled to 5 ± 5 ℃ and aged for 2 hours with stirring at the same temperature. The crystals were collected by filtration and the filter cake was washed with tetrahydrofuran. The filter cake was recrystallized from dimethyl sulfoxide (DMSO) and ethanol to give Compound 1(4.04 g). Yield: 88% and 99.72% purity by HPLC.
Example 10: synthesis of Compound 3-d
Compound 2-c (25.0g) was put into methanol (250.0ml), heated to 50-60 ℃ and hydrazine hydrate (2.36g) was added dropwise. After the dripping is finished, stirring is carried out for 4 hours under the condition of heat preservation. After the reaction, the organic solvent was concentrated under reduced pressure. Adding ethyl acetate for extraction, separating liquid and collecting an organic phase. Washing with saturated saline solution, drying with anhydrous sodium sulfate, and decolorizing with active carbon. Filtering, and concentrating the filtrate to dryness. Adding methanol, heating to 40 + -5 deg.C, stirring for 1 hr, cooling to 5 + -5 deg.C, crystallizing, filtering, collecting crystal, and washing filter cake with cold methanol. Drying under reduced pressure at 50 ℃ or lower gives compound 3-d (22.80). yield 95% and HPLC purity 99.62%.
Example 11: synthesis of Compound 4-d
Compound 3-d (10.0g) and triphosgene (6.76g) were charged into methylene chloride (40.0ml), and stirred at 0 ℃ for 1-2 hours (hereinafter referred to as reaction mixture A)
An amine (12.68g) was charged into methylene chloride (60.0ml), and triethylamine (15.36g) was added to the mixture, and stirred at 25. + -. 5 ℃ for 1 hour (hereinafter referred to as reaction mixture B). Reaction mixture B was slowly added to reaction mixture a at 0 ℃ and stirred at the same temperature for 1-2 hours. To the reaction mixture was added a saturated sodium bicarbonate solution at ± 5 ℃, stirred for 30 minutes, then allowed to stand, and the organic phase was separated and washed with a saturated sodium bicarbonate solution. The organic solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate and isopropyl ether to give compound 4-d (10.48 g). 94% yield, and 99.66% HPLC purity.
Example 12: synthesis of Compound 1
Compound 4-d (5.0g) was put into methanol (50.0ml), lithium methoxide (0.49g) was added to the mixture, and stirred at 30. + -. 5 ℃ for 3-5 hours, crystals were collected by filtration, and the cake was washed with cold methanol and dried under reduced pressure at 45. + -. 5 ℃. The solid was put into tetrahydrofuran, and the mixture was raised to 60 ± 5 ℃ and stirred at the same temperature for 1-2 hours. The mixture was cooled to 5 ± 5 ℃ and aged for 2 hours with stirring at the same temperature. The crystals were collected by filtration, the filter cake was washed with tetrahydrofuran, and the filter cake was recrystallized from dimethyl sulfoxide (DMSO) and ethanol to give compound 1(3.64 g). Yield: 85% and 99.72% purity by HPLC.
Example 13: synthesis of Compound 3-e
Compound 2-e (25.0g) was charged into methanol (200.0ml), and a saturated aqueous solution of ammonium chloride (4.37g) was added thereto, and iron powder (5.0g) was added in portions and heated to 50-60 ℃. After the dripping is finished, stirring is carried out for 4 hours under the condition of heat preservation. After the reaction, filtering, and decompressing and concentrating the filtrate to remove the organic solvent. Adding ethyl acetate for extraction, separating liquid and collecting an organic phase. Washing with saturated saline solution, drying with anhydrous sodium sulfate, and decolorizing with active carbon. Filtering, and concentrating the filtrate to dryness. Adding methanol, heating to 40 + -5 deg.C, stirring for 1 hr, cooling to 5 + -5 deg.C, crystallizing, filtering, collecting crystal, and washing filter cake with cold methanol. Drying under reduced pressure at 50 ℃ or lower gives compound 3-d (22.17 g). 93% yield, and 99.72% purity by HPLC.
Example 14: synthesis of Compound 4-e
Compound 3-e (10.0g) and pivaloyl chloride (2.9g) were charged into acetonitrile (40.0ml), and stirred at 30. + -. 5 ℃ for 2 to 3 hours (hereinafter referred to as reaction mixture A).
Methoxylamine hydrochloride (14.33g) was charged into acetonitrile (60.0ml), and triethylamine (17.37g) was added to the mixture, and the mixture was stirred at 35. + -. 5 ℃ for 1 hour (hereinafter referred to as reaction mixture B). Reaction mixture B was slowly added to reaction mixture A at 5. + -. 5 ℃ and stirred at the same temperature for 2-3 hours. To the reaction mixture was added a saturated sodium bicarbonate solution at ± 5 ℃, stirred for 30 minutes, left to stand, and the organic phase was separated, the aqueous phase was extracted with dichloromethane 100ml x2, the organic phases were combined, washed with a saturated sodium bicarbonate solution, and the organic solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate and isopropyl ether to give compound 4-b (10.20 g). yield 90% and HPLC purity 99.33%.
Example 15: synthesis of Compound 1
Compound 4-e (5.0g) was poured into methanol (50.0ml), and sodium ethoxide (1.04g) was added to the mixture, which was stirred for 2 to 3 hours. Cooling to 0 deg.C or lower, stirring for 2-4 hr, filtering to collect crystal, washing filter cake with methanol at 50-60 deg.C, and drying under reduced pressure. The resulting solid was put into tetrahydrofuran, the mixture was raised to 60 ± 5 ℃ and stirred at the same temperature for 1 hour, the mixture was cooled to 0 ℃ and aged at the same temperature for 2 hours with stirring. The crystals were collected by filtration and the filter cake was washed with tetrahydrofuran. The filter cake was recrystallized from dimethyl sulfoxide (DMSO) and ethanol to give Compound 1(4.37 g). Yield: 91% and 99.38% HPLC purity.
Example 16: synthesis of Compound 3-f
Compound 2-f (25.0g) was put into methanol, acetic acid (8.35g) was added, and zinc powder (10.0g) was added in portions. Heating to 50-60 deg.C, stirring for 4 hr. After the reaction, filtering, and decompressing and concentrating the filtrate to remove the organic solvent. Adding ethyl acetate for extraction, separating liquid and collecting an organic phase. Washing with saturated saline solution, drying with anhydrous sodium sulfate, and decolorizing with active carbon. Filtering, and concentrating the filtrate to dryness. Adding methanol, heating to 40 + -5 deg.C, stirring for 1 hr, cooling to 5 + -5 deg.C, crystallizing, filtering, collecting crystal, and washing filter cake with cold methanol. Drying under reduced pressure at 50 ℃ or lower gave compound 3-f (20.90 g). yield 87% and HPLC purity 99.72%.
Example 17: synthesis of Compound 4-f
Compound 3-f (10.0g) and 1, 1' -carbonyldiimidazole hydrochloride (4.71g) were charged into methylene chloride (40.0ml), N-diisopropylethylamine (3.75g) was added to the mixture, and stirred at 20. + -. 5 ℃ for 1 to 2 hours (hereinafter referred to as reaction mixture A).
Methoxylamine hydrochloride (12.13g) was charged into methylene chloride (60.0ml), and N, N-diisopropylethylamine (18.77g) was added to the mixture, and stirred at 25. + -. 5 ℃ for 1 hour (hereinafter referred to as reaction mixture B). Reaction mixture B was slowly added to reaction mixture A at 0. + -. 5 ℃ and stirred at the same temperature for 1-2 hours. To the reaction mixture was added a saturated sodium bicarbonate solution at 0. + -. 5 ℃ and stirred for 30 minutes, then it was left to stand, and the organic phase was separated, washed with a saturated sodium bicarbonate solution, the organic solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate and isopropyl ether to give compound 4-f (9.54 g). yield 86% and HPLC purity 99.73%.
Example 18: synthesis of Compound 1
Compound 4-f (5.0g) was poured into methanol (45.0ml), and sodium hydride (0.24g) was added to the mixture, which was stirred for 2 to 3 hours. The reaction solution was poured into ice-cold 2M acetic acid-sodium acetate buffer solution at pH 6.8, cooled to 0 ℃ or lower, stirred for 2 to 4 hours, filtered to collect crystals, and the cake was washed with methanol and dried under reduced pressure at 50 to 60 ℃. The resulting solid was put into tetrahydrofuran, the mixture was raised to 60 ± 5 ℃ and stirred at the same temperature for 1 hour, the mixture was cooled to 0 ℃ and aged at the same temperature for 2 hours with stirring. The crystals were collected by filtration and the filter cake was washed with tetrahydrofuran. The filter cake was recrystallized from dimethyl sulfoxide (DMSO) and ethanol to give Compound 1(3.79 g). Yield: 92% and 99.68% HPLC purity.
Example 19: synthesis of Compound 2-b
Referring to the example process of patent WO2014/051164, compound 2-b is obtained.
Example 20: synthesis of Compound 2-a
Referring to the example method for compound 2-b, propyl chloroformate was used instead of ethyl chloroformate to give compound 2-a.
Example 21: synthesis of Compound 2-c
Referring to the example method for compound 2-b, allyl chloroformate was used instead of ethyl chloroformate to give compound 2-c.
Example 22: synthesis of Compound 2-d
Referring to the example procedure of patent compound 2-b, benzyl chloroformate was substituted for ethyl chloroformate to give compound 2-d.
Example 23: synthesis of Compound 2-e
Referring to the example procedure of patent compound 2-b, methyl chloroformate was used instead of ethyl chloroformate to give compound 2-e.
Example 24: synthesis of Compound 2-f
Referring to the example procedure of patent compound 2-b, 4-methoxybenzyl acetyl chloride was used instead of ethyl chloroformate to give compound 2-f.
Example 25: synthesis of Compound 2-g
Referring to the example procedure of patent compound 2-b, chloroethyl chloroformate was used instead of ethyl chloroformate to give compound 2-e.
Example 26: synthesis of Compound 1
Starting with compound 2-g, compound 1 was obtained by referring to example 1, example 2, and example 3 in this order.
The related art can prepare Relugolix (Compound 1), a compound or a pharmaceutical composition for use in a gonadotropin releasing hormone (GnRH) antagonist, according to the method of the present invention. Compared with the existing preparation methods (J.Med.chem.2011,54, 4998-.
Claims (12)
1. Compound 3 or a salt thereof of the formula:
r is substituted or unsubstituted C1-C6Saturated or unsaturated alkyl, C1-C6An alkaryl group.
2. Compound 3 or a salt thereof according to claim 1, wherein: r is methyl, ethyl, propyl, allyl, chloroethyl, benzyl or
3. A process for producing compound 3 or a salt thereof, which comprises subjecting compound 2 or a salt thereof to a reduction reaction to obtain:
r is substituted or unsubstituted C1-C6Saturated or unsaturated alkyl, C1-C6An alkaryl group.
4. A process for producing compound 3 or a salt thereof according to claim 3, wherein: the reducing agent comprises: palladium carbon/hydrogen, palladium carbon/ammonium formate, raney nickel/hydrogen, sodium hydrosulfite, zinc powder, iron powder and hydrazine hydrate.
5. Compound 4 of the formula:
r is substituted or unsubstituted C1-C6Saturated or unsaturated alkyl, C1-C6An alkaryl group.
6. Compound 4 or a salt thereof according to claim 5The method is characterized in that: r is methyl, ethyl, propyl, allyl, chloroethyl, benzyl or
7. A process for producing a compound 4 or a salt thereof, which comprises subjecting a compound 3 or a salt thereof and methoxylamine or a salt thereof to a condensation reaction under a condensing agent condition to obtain:
r is substituted or unsubstituted C1-C6Saturated or unsaturated alkyl, C1-C6An alkaryl group.
8. A process for the preparation of compound 4 or a salt thereof according to claim 7, wherein: the condensing agent comprises: 1, 1' -carbonyldiimidazole and its salts, triphosgene, chloroformates and pivaloyl chloride.
9. A process for the preparation of compound 4 or a salt thereof according to claim 7, wherein: the compound 3 is obtained by the production method according to claim 3 or 4.
10. A process for producing Compound 1 or a salt thereof, which comprises subjecting Compound 4 or a salt thereof to cyclization reaction under basic conditions to give:
r is substituted or unsubstituted C1-C6Saturated or unsaturated alkyl, C1-C6An alkaryl group.
11. A process for the preparation of compound 1 or a salt thereof according to claim 10, wherein: the alkali comprises: sodium methoxide, sodium ethoxide, potassium tert-butoxide (sodium, lithium), sodium hydride, DBU and DBN.
12. A process for the preparation of compound 1 or a salt thereof according to claim 10, wherein: the compound 4 is obtained by the preparation method of any one of claims 7 to 9.
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| CN113620972A (en) * | 2021-02-02 | 2021-11-09 | 奥锐特药业(天津)有限公司 | Rugosril new crystal form and preparation method thereof |
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| CN115417883A (en) * | 2022-09-16 | 2022-12-02 | 浙江科聚生物医药有限公司 | Crystal form of Rui Lu Geli and preparation method thereof |
| CN115594688A (en) * | 2021-06-28 | 2023-01-13 | 成都倍特药业股份有限公司（Cn） | Preparation method of Rui Lu Geli intermediate |
| CN115650950A (en) * | 2022-11-03 | 2023-01-31 | 江西同和药业股份有限公司 | Rui Lu Geli intermediate and preparation method thereof, and amide condensation method |
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| CN115417883A (en) * | 2022-09-16 | 2022-12-02 | 浙江科聚生物医药有限公司 | Crystal form of Rui Lu Geli and preparation method thereof |
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| WO2024126674A1 (en) | 2022-12-15 | 2024-06-20 | Medichem, S.A. | Process for the preparation of relugolix |
| CN115785062A (en) * | 2022-12-27 | 2023-03-14 | 常州制药厂有限公司 | Method for preparing intermediate of Rui Lu Geli by continuous hydrogenation |
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