CN117247371A - 一种cyp11b2抑制剂baxdrostat的制备方法 - Google Patents
一种cyp11b2抑制剂baxdrostat的制备方法 Download PDFInfo
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- CN117247371A CN117247371A CN202311207594.9A CN202311207594A CN117247371A CN 117247371 A CN117247371 A CN 117247371A CN 202311207594 A CN202311207594 A CN 202311207594A CN 117247371 A CN117247371 A CN 117247371A
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- 229940125155 baxdrostat Drugs 0.000 title claims abstract description 27
- VDEUDSRUMNAXJG-LJQANCHMSA-N n-[(8r)-4-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl]propanamide Chemical compound CN1C(=O)CCC2=CC(C3=CN=CC4=C3CCC[C@H]4NC(=O)CC)=CC=C21 VDEUDSRUMNAXJG-LJQANCHMSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229940123338 Aldosterone synthase inhibitor Drugs 0.000 title claims abstract description 11
- -1 S-tertiary butyl sulfinamide aldehyde ketone Chemical class 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- NJZZUBLIVYKUJM-UHFFFAOYSA-N 6-bromo-1-methyl-3,4-dihydroquinolin-2-one Chemical compound BrC1=CC=C2N(C)C(=O)CCC2=C1 NJZZUBLIVYKUJM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 7
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000004440 column chromatography Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- PNXQJOWNYRUIIT-QGZVFWFLSA-N 6-[(8r)-8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl]-1-methyl-3,4-dihydroquinolin-2-one Chemical compound N[C@@H]1CCCC2=C1C=NC=C2C1=CC=C2N(C)C(=O)CCC2=C1 PNXQJOWNYRUIIT-QGZVFWFLSA-N 0.000 claims description 11
- 108010009911 Cytochrome P-450 CYP11B2 Proteins 0.000 claims description 11
- 102100024329 Cytochrome P450 11B2, mitochondrial Human genes 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 10
- 238000000746 purification Methods 0.000 claims description 10
- IVDFJHOHABJVEH-UHFFFAOYSA-N HOCMe2CMe2OH Natural products CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 claims description 5
- FRQNZGBLRPLODX-SECBINFHSA-N (8r)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine Chemical compound C1=NC=C2[C@H](N)CCCC2=C1Br FRQNZGBLRPLODX-SECBINFHSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims description 3
- PKSBCKIJVULJIF-UHFFFAOYSA-N butane-1-sulfinamide Chemical group CCCCS(N)=O PKSBCKIJVULJIF-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 6
- 238000010009 beating Methods 0.000 claims 6
- 238000002953 preparative HPLC Methods 0.000 claims 6
- 238000001953 recrystallisation Methods 0.000 claims 6
- 239000002904 solvent Substances 0.000 claims 6
- 238000004809 thin layer chromatography Methods 0.000 claims 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims 6
- 235000010338 boric acid Nutrition 0.000 claims 5
- 230000035484 reaction time Effects 0.000 claims 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 4
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 4
- 239000004327 boric acid Substances 0.000 claims 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 239000002841 Lewis acid Substances 0.000 claims 2
- 239000012448 Lithium borohydride Substances 0.000 claims 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims 2
- 150000007517 lewis acids Chemical class 0.000 claims 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 2
- 239000011734 sodium Substances 0.000 claims 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 2
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 claims 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 1
- AEAYSTJDKCJGAH-UHFFFAOYSA-N 6-chloro-1-methyl-3,4-dihydroquinolin-2-one Chemical compound ClC1=CC=C2N(C)C(=O)CCC2=C1 AEAYSTJDKCJGAH-UHFFFAOYSA-N 0.000 claims 1
- QYMYRURANOPZIX-UHFFFAOYSA-N 6-iodo-1-methyl-3,4-dihydroquinolin-2-one Chemical compound IC1=CC=C2N(C)C(=O)CCC2=C1 QYMYRURANOPZIX-UHFFFAOYSA-N 0.000 claims 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims 1
- HKUZCFPBIZXXMQ-UHFFFAOYSA-N CC(C)(C)[S+]=N Chemical compound CC(C)(C)[S+]=N HKUZCFPBIZXXMQ-UHFFFAOYSA-N 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 1
- 239000005456 alcohol based solvent Substances 0.000 claims 1
- 125000005619 boric acid group Chemical class 0.000 claims 1
- 150000001642 boronic acid derivatives Chemical class 0.000 claims 1
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 239000012280 lithium aluminium hydride Substances 0.000 claims 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 239000001632 sodium acetate Substances 0.000 claims 1
- 235000017281 sodium acetate Nutrition 0.000 claims 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims 1
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- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims 1
- 239000011701 zinc Substances 0.000 claims 1
- 229910052725 zinc Inorganic materials 0.000 claims 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
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- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 14
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及CYP11B2抑制剂BAXDROSTAT的制备方法。具体而言,本发明提供了两种制备方案。一:由4‑卤代‑6,7‑二氢异喹啉‑8(5H)‑酮与S‑叔丁基亚磺酰胺醛酮缩合反应,经硼氢化钠还原,再与联硼酸频那醇酯反应,经Suzuki偶联反应,脱保护基,与丙酰氯反应得到Baxdrostat;二:方案一中的步骤2的产物(S)‑N‑(4‑卤代‑6,7‑二氢异喹啉‑8(5H))‑叔丁基磺酰亚胺先脱保护,再与6‑溴‑1‑甲基‑3,4‑二氢喹啉‑2(1H)‑酮的Suzuki偶联反应,再与烯丙基氯反应得到Baxdrostat。
Description
技术领域
本发明属于化学药物合成领域,涉及CYP11B2抑制剂BAXDROSTAT的两种制备方法。
背景技术
人类肾上腺皮质球状带区域分泌的醛固酮是一种盐皮质激素,通过调节肾脏对钠离子的重吸收,维持水盐平衡。过量的醛固酮不适当地激活盐皮质激素受体,会增加血浆体积,导致血压升高。除此之外,醛固酮水平过高会造成心肌及血管间质纤维化,导致心室和血管重构,诱发白细胞浸润造成及冠脉和心肌损伤、心律失常。醛固酮合成酶(Aldosteronesynthase,AS,由CYP11B2基因编码)控制醛固酮的合成,几十年来一直是治疗高血压的药理学靶点。由于产生醛固酮的酶和产生皮质醇的酶有有93%是相同的。因此,研发出一种既能抑制醛固酮产生又对皮质醇没有影响的药物是很困难的。CYP11B2通过三步序列产生。从11-去氧皮质酮(DOC)开始,在C-11处的初始羟基化提供皮质酮,其在C-18处羟基化以提供18-羟基皮质酮。18-羟基皮质酮然后经历最终的C-18氧化(醇到醛)以提供醛固酮。重要的是,CYP11B2是催化最终氧化生成醛固酮的唯一酶。
一种最初被发现是作为醛固酮合酶(CYP11B2)的有效抑制剂,具有降低醛固酮的性能,但同时又能够有力地抑制11β-羟化酶(CYP-11B1)而降低血皮质醇,最终因为这个原因停止了对高血压的治疗。研究人员的后续工作主要集中在提高其对醛固酮合酶的选择性上。Whitehead研究小组以吡啶环取代原有的苯环,设计并合成了一系列吡啶并咪唑化合物和苯并吡唑化合物。对CYP11B2文献的调查显示还有其他几种利用吡啶和咪唑金属结合药效基团(MBG)提供适度选择性的筛选方法。这些方法随后被开发为选择性抑制剂。在保持优化的MBG赋予的高选择性的同时,研究人员利用对支架其余部分的修饰来增强效力。
Baxdrostat是一种小分子高选择性醛固酮合酶抑制剂[Aldosterone synthaseinhibitors],能够高选择性抑制醛固酮合成酶,而不会阻断盐皮质激素受体。临床前和I期研究表明,与皮质醇合成酶相比,Baxdrostat对醛固酮合成酶具有非常高的选择性(100:1)。醛固酮合成酶仅在肾上腺的小部分细胞中产生,身体的其他部位不产生这种酶,因此预期不会产生脱靶效应。BrigHTN 2期研究结果显示,醛固酮合成酶抑制剂(ASI)Baxdrostat显著降低了难治性高血压患者的血压水平。接受Baxdrostat 2mg治疗的患者收缩压水平降低超过20mmHg;当调整安慰剂组观察到的收缩压降低后,Baxdrostat2 mg组收缩压平均降低11.0mmHg。该研究结果同期发表于《新英格兰医学杂志》。BrigHTN 2期的研究者还检测了患者的血浆Baxdrostat水平、血清和尿液醛固酮水平以及血清皮质醇活性。Baxdrostat三个剂量组的24小时尿醛固酮水平均有下降,但血清皮质醇水平不变。也就是说,Baxdrostat在不降低皮质醇的情况下降低了醛固酮水平并增加了血浆肾素活性,支持其生物学效应和选择性。
发明内容
鉴于上述情况,CYP11B2抑制剂BAXDROSTAT的制备非常重要。本发明人通过实验研究发明了CYP11B2抑制剂BAXDROSTAT的两种制备方案。
本发明所述化合物用以下两种路线制备:
方案一
由原料4-卤代-6,7-二氢异喹啉-8(5H)-酮与S-叔丁基亚磺酰胺进行醛酮缩合反应得到(S,Z)-N-(4-卤代-6,7-二氢异喹啉-8(5H)-叔丁基磺酰亚胺;
经过硼氢化钠还原得到化合物得到(S)-N-(4-溴-6,7-二氢异喹啉-8(5H))-叔丁基磺酰亚胺;
(S)-N-(4-卤代-6,7-二氢异喹啉-8(5H))-叔丁基磺酰胺与联硼酸频那醇酯反应得到化合物(S)-N-叔丁基磺酰胺-6,7-二氢异喹啉-8(5H))-4-频那醇酯;
再经过与6-溴-1-甲基-3,4-二氢喹啉-2(1H)-酮的Suzuki偶联反应得到化合物(S)-2-甲基-N-((R)-4-(1-甲基-2-氧代-1,2,3,4-四氢喹啉-6-基)-5,6,7,8-四氢异喹啉-8-基)叔丁基磺酰亚胺;
步骤4)中的产品经过脱叔丁磺酰基保护基得到(R)-6-(8-胺基-5,6,7,8-四氢异喹啉-4-基)-1-甲基-3,4-二氢喹啉-2(1H)-酮;
最后化合物(R)-6-(8-胺基-5,6,7,8-四氢异喹啉-4-基)-1-甲基-3,4-二氢喹啉-2(1H)-酮中的胺基与丙酰氯反应得到目标化合物Baxdrostat。
方案二
方案一中的步骤2的产物(S)-N-(4-卤代-6,7-二氢异喹啉-8(5H))-叔丁基磺酰亚胺先进行脱胺基的叔丁磺酰基保护得到化合物(R)-4-卤代-5,6,7,8-四氢异喹啉-8-胺;
脱胺基保护后的(R)-4-卤代-5,6,7,8-四氢异喹啉-8-胺反应得到化合物(R)-4-溴-5,6,7,8-四氢异喹啉-8-胺与联硼酸频那醇酯;
步骤2)中所得到的化合物经过与6-溴-1-甲基-3,4-二氢喹啉-2(1H)-酮的Suzuki偶联反应得到(R)-6-(8-胺基-5,6,7,8-四氢异喹啉-4-基)-1-甲基-3,4-二氢喹啉-2(1H)-酮;
最后化合物(R)-6-(8-胺基-5,6,7,8-四氢异喹啉-4-基)-1-甲基-3,4-二氢喹啉-2(1H)-酮中的胺基与烯丙基氯反应得到目标化合物Baxdrostat。
具体实施例
下面通过实施例对本发明做进一步描述说明,但并不因此而限制本发明的内容。
实施例1
步骤A
将化合物4-溴-6,7-二氢异喹啉-8(5H)-酮(1.56g,6.9mmol)和(S)-叔丁基亚磺酰胺(2.51g,20.7mmol)溶于四氢呋喃20mL中,加入钛酸乙酯(10.08mL,48.28mmol),升温至65℃搅拌反应48小时。冷却至室温,加入乙酸乙酯和水,搅拌15分钟,所得固体过滤除去。分液,有机相用无水硫酸钠干燥,过滤,减压蒸干,得到粗产物(S,Z)-N-(4-溴-6,7-二氢异喹啉-8(5H)-叔丁基磺酰亚胺,直接用于下一步。
步骤B
将化合物(S,Z)-N-(4-溴-6,7-二氢异喹啉-8(5H)-叔丁基磺酰亚胺(1.98g,6mmol)溶于四氢呋喃15mL中,降温至-45℃。加入硼氢化钠(0.34g,9.0mmol),自然回到室温搅拌反应18小时。加冰水淬灭,二氯甲烷萃取。所得有机相再用饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。残余物通过柱层析纯化,得到化合物(S)-N-(4-溴-6,7-二氢异喹啉-8(5H))-叔丁基磺酰亚胺(755mg,产率38%)。LC/MS(ESI):m/z=331.2[M+H]+.
步骤C
向(S)-N-(4-溴-6,7-二氢异喹啉-8(5H))-叔丁基磺酰亚胺(0.66g,2mmol)、联硼酸频那醇酯(1.05g,2.1mmol)、AcOK(0.578g,6mmol)在甲苯(10mL)中的混合物中添加Pd(dppf)Cl2(0.144g,0.2mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混合物并浓缩,得到残留物。向残余物中加入EtOAc(15mL)和水(10mL)。用盐水(50mL)洗涤有机相,用无水硫酸钠干燥,过滤并浓缩,得到残留物。残余物通过柱色谱法(SiO2)纯化,用30-40%乙酸乙酯在石油醚中洗脱,得到(S)-N-叔丁基磺酰胺-6,7-二氢异喹啉-8(5H))-4-硼酸频那醇酯(0.45g,产率60%)。LC/MS(ESI):m/z=378.3[M+H]+.
步骤D
于反应瓶中加入化合物6-溴-1-甲基-3,4-二氢喹啉-2(1H)-酮(0.29g,1.2mmol),(S)-N-叔丁基磺酰胺-6,7-二氢异喹啉-8(5H))-4-硼酸频那醇酯(0.42g,1.26mmol),双三苯基磷二氯化钯(84mg,0.12mmol),碘化亚铜(38mg,0.2mmol),三乙胺(1.01g,10.0mmol)和N,N-二甲基甲酰胺15mL。氮气置换3次,搅拌下90℃反应过夜。冷却至室温,反应液用乙酸乙酯和水稀释,乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。残余物通过柱层析纯化,得到化合物(S)-2-甲基-N-((R)-4-(1-甲基-2-氧代-1,2,3,4-四氢喹啉-6-基)-5,6,7,8-四氢异喹啉-8-基)叔丁基磺酰亚胺(0.37g,产率74%)为黄色固体。LC/MS(ESI):m/z=411.5[M+H]+.
步骤E
将化合物(S)-2-甲基-N-((R)-4-(1-甲基-2-氧代-1,2,3,4-四氢喹啉-6-基)-5,6,7,8-四氢异喹啉-8-基)叔丁基磺酰亚胺(0.33g,0.80mmol)溶于二氯甲烷1mL中,加入三氟乙酸1mL,搅拌反应1小时。反应液减压浓缩。残余物通过反向制备柱纯化,得到化合物(R)-6-(8-胺基-5,6,7,8-四氢异喹啉-4-基)-1-甲基-3,4-二氢喹啉-2(1H)-酮(0.24g,产率97%)。LC/MS(ESI):m/z=307.1[M+H]+.
步骤F
于反应瓶中加入(R)-6-(8-胺基-5,6,7,8-四氢异喹啉-4-基)-1-甲基-3,4-二氢喹啉-2(1H)-酮(100mg,0.33mmol),三乙胺(51mg,0.5mmol),4ml四氢呋喃,冰水浴冷却后缓慢滴加丙酰氯(46.25mg,0.5mmol)的0.5ml四氢呋喃溶液。加完后继续搅拌4小时。反应液用甲醇淬灭反应并减压蒸干。残余物通过柱层析纯化,得到目标化合物Baxdrostat(46mg,产率38%)。LC/MS(ESI):m/z=363.1[M+H]+.H NMR(400MHz,CDCl3)ppm 1.22(t,3H)1.79(s,3H)2.07(s,1H)2.28(q,2H)2.43-2.68(m,2H)2.71(t,2H)2.82-3.12(m,2H)3.40(s,3H)5.34(d,1H)5.78(d,1H)7.05(d,1H)7.09(s,1H)7.17(d,1H)8.28(s,1H)8.49(s,1H)
实施例2
步骤A
将化合物(S)-N-(4-溴-6,7-二氢异喹啉-8(5H))-叔丁基磺酰亚胺(1.65g,5mmol)溶于二氯甲烷20mL中,加入三氟乙酸20mL,搅拌反应1小时。反应液减压浓缩。残余物通过反向制备柱纯化,得到化合物(R)-4-溴-5,6,7,8-四氢异喹啉-8-胺(1.07g,产率94%)。LC/MS(ESI):m/z=226.0[M+H]+.
步骤B
向(R)-4-溴-5,6,7,8-四氢异喹啉-8-胺(0.86g,3.8mmol)、联硼酸频那醇酯(2g,4mmol)、AcOK(1.10g,11.4mmol)在甲苯(10mL)中的混合物中添加Pd(dppf)Cl2(0.27g,0.38mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混合物并浓缩,得到残留物。向残余物中加入EtOAc(10mL)和水(10mL)。用盐水(10mL)洗涤有机相,用无水硫酸钠干燥,过滤并浓缩,得到残留物。残余物通过柱色谱法(SiO2)纯化,用30-40%乙酸乙酯在石油醚中洗脱,得到(R)-8-氨基-5,6,7,8-四氢异喹啉-4-硼酸频那醇酯(0.68g,产率65%)。LC/MS(ESI):m/z=274.1[M+H]+.
步骤C
于反应瓶中加入化合物6-溴-1-甲基-3,4-二氢喹啉-2(1H)-酮(0.72g,3.0mmol),(R)-8-氨基-5,6,7,8-四氢异喹啉-4-硼酸频那醇酯(0.99g,3.6mmol),双三苯基磷二氯化钯(210mg,0.3mmol),磷酸钾一水合物(204mg,0.9mmol),溶解于二氧六环和水(9:1,30mL)。氮气置换3次,搅拌下90℃反应过夜。冷却至室温,反应液用乙酸乙酯和水稀释,乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。残余物通过柱层析纯化,得到化合物(R)-6-(8-胺基-5,6,7,8-四氢异喹啉-4-基)-1-甲基-3,4-二氢喹啉-2(1H)-酮(0.81g,产率88%)。LC/MS(ESI):m/z=307.1[M+H]+.接下来步用与实施例1中最后一步类似的方法制备得到目标化合物Baxdrostat。
实施例3
步骤A
将化合物4-溴-6,7-二氢异喹啉-8(5H)-酮(1.88g,6.9mmol)和(S)-叔丁基亚磺酰胺(2.51g,20.7mmol)溶于四氢呋喃20mL中,加入钛酸乙酯(10.08mL,48.28mmol),升温至65℃搅拌反应48小时。冷却至室温,加入乙酸乙酯和水,搅拌15分钟,所得固体过滤除去。分液,有机相用无水硫酸钠干燥,过滤,减压蒸干,得到粗产物(S,Z)-N-(4-溴-6,7-二氢异喹啉-8(5H)-叔丁基磺酰亚胺,直接用于下一步。LC/MS(ESI):m/z=376.2[M+H]+.
步骤B
将化合物(S,Z)-N-(4-碘-6,7-二氢异喹啉-8(5H)-叔丁基磺酰亚胺(2.26g,6mmol)溶于四氢呋喃15mL中,降温至-45℃。加入硼氢化钠(0.36g,9.0mmol),自然回到室温搅拌反应18小时。加冰水淬灭,二氯甲烷萃取。所得有机相再用饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。残余物通过柱层析纯化,得到化合物(S)-N-(4-碘-6,7-二氢异喹啉-8(5H))-叔丁基磺酰亚胺(1.04g,产率46%)。LC/MS(ESI):m/z=378.0[M+H]+.
步骤C
向(S)-N-(4-碘-6,7-二氢异喹啉-8(5H))-叔丁基磺酰亚胺(0.76g,2mmol)、联硼酸频那醇酯(1.05g,2.1mmol)、AcOK(0.578g,6mmol)在甲苯(10mL)中的混合物中添加Pd(dppf)Cl2(0.144g,0.2mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混合物并浓缩,得到残留物。向残余物中加入EtOAc(15mL)和水(10mL)。用盐水(50mL)洗涤有机相,用无水硫酸钠干燥,过滤并浓缩,得到残留物。残余物通过柱色谱法(SiO2)纯化,用30-40%乙酸乙酯在石油醚中洗脱,得到(S)-N-叔丁基磺酰胺-6,7-二氢异喹啉-8(5H))-4-硼酸频那醇酯(0.51g,产率68%)。LC/MS(ESI):m/z=378.2[M+H]+.
接下来的三步用与实施例1中同样的方法制备得到目标化合物Baxdrostat。
实施例4
步骤A
将化合物(S)-N-(4-碘-6,7-二氢异喹啉-8(5H))-叔丁基磺酰亚胺(1.89g,5mmol)溶于二氯甲烷20mL中,加入三氟乙酸20mL,搅拌反应1小时。反应液减压浓缩。残余物通过反向制备柱纯化,得到化合物(R)-4-碘-5,6,7,8-四氢异喹啉-8-胺(1.32g,产率96%)。LC/MS(ESI):m/z=274.0[M+H]+.
步骤B
向(R)-4-碘-5,6,7,8-四氢异喹啉-8-胺(1.04g,3.8mmol)、联硼酸频那醇酯(2g,4mmol)、AcOK(1.10g,11.4mmol)在甲苯(10mL)中的混合物中添加Pd(dppf)Cl2(0.27g,0.38mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混合物并浓缩,得到残留物。向残余物中加入EtOAc(10mL)和水(10mL)。用盐水(10mL)洗涤有机相,用无水硫酸钠干燥,过滤并浓缩,得到残留物。残余物通过柱色谱法(SiO2)纯化,用30-40%乙酸乙酯在石油醚中洗脱,得到(R)-8-氨基-5,6,7,8-四氢异喹啉-4-硼酸频那醇酯(0.75g,产率72%)。LC/MS(ESI):m/z=274.1[M+H]+.H NMR(400MHz,CDCl3)ppm 1.22(t,3H)1.79(s,3H)2.07(s,1H)2.28(q,2H)2.43-2.68(m,2H)2.71(t,2H)2.82-3.12(m,2H)3.40(s,3H)5.34(d,1H)5.78(d,1H)7.05(d,1H)7.09(s,1H)7.17(d,1H)8.28(s,1H)8.49(s,1H
接下来的两步用与实施例2中同样的方法制备得到目标化合物Baxdrostat。
上述实例仅用于说明本发明的实施方式,但本发明不仅仅局限于上述实例。在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内,本发明要求保护范围由权利要求书及其等效物界定。
Claims (8)
1.一种CYP11B2抑制剂BAXDROSTAT的制备方法,其特征在于,有两种合成方案方案一的具体步骤为:
1)由原料4-卤代-6,7-二氢异喹啉-8(5H)-酮与S-叔丁基亚磺酰胺进行醛酮缩合反应得到(S,Z)-N-(4-卤代-6,7-二氢异喹啉-8(5H)-叔丁基磺酰亚胺
2)经过硼氢化钠还原得到化合物得到(S)-N-(4-溴-6,7-二氢异喹啉-8(5H))-叔丁基磺酰亚胺
3)(S)-N-(4-卤代-6,7-二氢异喹啉-8(5H))-叔丁基磺酰胺与双硼片呐醇硼酸酯反应得到化合物(S)-N-叔丁基磺酰胺-6,7-二氢异喹啉-8(5H))-4-片呐醇硼酸酯
4)再经过与6-溴-1-甲基-3,4-二氢喹啉-2(1H)-酮的Suzuki偶联反应得到化合物(S)-2-甲基-N-((R)-4-(1-甲基-2-氧代-1,2,3,4-四氢喹啉-6-基)-5,6,7,8-四氢异喹啉-8-基)叔丁基磺酰亚胺
5)步骤4)中的产品经过脱叔丁磺酰基保护基得到(R)-6-(8-胺基-5,6,7,8-四氢异喹啉-4-基)-1-甲基-3,4-二氢喹啉-2(1H)-酮
6)最后化合物(R)-6-(8-胺基-5,6,7,8-四氢异喹啉-4-基)-1-甲基-3,4-二氢喹啉-2(1H)-酮中的胺基与丙酰氯反应得到目标化合物Baxdrostat
方案二的具体步骤为
1)方案一中的步骤2的产物(S)-N-(4-卤代-6,7-二氢异喹啉-8(5H))-叔丁基磺酰亚胺先进行脱胺基的叔丁磺酰基保护得到化合物(R)-4-卤代-5,6,7,8-四氢异喹啉-8-胺
2)脱胺基保护后的(R)-4-卤代-5,6,7,8-四氢异喹啉-8-胺反应得到化合物(R)-4-溴-5,6,7,8-四氢异喹啉-8-胺与双硼片呐醇硼酸酯
3)步骤2)中所得到的化合物经过与6-溴-1-甲基-3,4-二氢喹啉-2(1H)-酮的Suzuki偶联反应得到(R)-6-(8-胺基-5,6,7,8-四氢异喹啉-4-基)-1-甲基-3,4-二氢喹啉-2(1H)-酮
4)最后化合物(R)-6-(8-胺基-5,6,7,8-四氢异喹啉-4-基)-1-甲基-3,4-二氢喹啉-2(1H)-酮中的胺基与烯丙基氯反应得到目标化合物Baxdrostat。
2.如权利要求1所述一种CYP11B2抑制剂BAXDROSTAT的制备方法,其特征在于,方案一种的步骤(1)中,4-卤代-6,7-二氢异喹啉-8(5H)-酮中的卤素基团可以为Cl、溴、碘、OTf;胺基提供试剂选自S-叔丁基亚磺酰胺、R-叔丁基亚磺酰胺或者它们的混合物中的一种或几种;方案一种的第四步产品和方案二第二步中的产品选自其对应化合物结构的硼酸酯或者硼酸;方案一或者方案二中,与硼酸或者硼酸发生suzuki偶联的中间体选自6-溴-1-甲基-3,4-二氢喹啉-2(1H)-酮、6-氯-1-甲基-3,4-二氢喹啉-2(1H)-酮或者6-碘-1-甲基-3,4-二氢喹啉-2(1H)-酮中的一种或者几种。
3.如权利要求1所述一种CYP11B2抑制剂BAXDROSTAT的制备方法,其特征在于,方案一第一步反应温度选自20-240℃,反应时间选自0.5-72h。所用溶剂选自甲苯、四氯化碳、氯苯、二苯甲醚、正己烷、正庚烷、正戊烷、石油醚、苯、THF、2-Me-THF、DME、MTBE、乙醚、丁醚、异丙醚、DMA、DMSO等中的一种或几种。所用辅助试剂可以选自钛酸乙酯或者钛酸异丙酯中的一种或者两种。产品选自粗品往下用,纯化可以选自过柱子、打浆、Prep-TLC、Prep-HPLC或者重结晶,。
4.如权利要求1所述的一种CYP11B2抑制剂BAXDROSTAT的制备方法,其特征在于,方案一步骤二反应温度选自-78-150℃,反应时间选自0-72h。所用溶剂选自甲苯、四氯化碳、氯苯、二苯甲醚、正己烷、正庚烷、正戊烷、石油醚、苯、THF、2-Me-THF、DME、MTBE、乙醚、丁醚、异丙醚、DMA、DMSO、水、甲醇、乙醇、异丙醇等中的一种或几种。所用还原剂可以选自硼氢化钠、氰基硼氢化钠、醋酸硼氢化钠、四氢铝锂、硼氢化锂、硼氢化锌、硼氢化锂中的一种或者几种。加或者不加路易斯酸,优选不加路易斯酸。产品选自粗品往下用,纯化可以选自过柱子、打浆、Prep-TLC、Prep-HPLC或者重结晶。
5.如权利要求1所述的一种CYP11B2抑制剂BAXDROSTAT的制备方法,其特征在于,方案一步骤三和方案二步骤二反应温度选自10-200℃,反应时间选自0-72h溶剂选自乙醚、乙腈、THF、DMF、DME、1,4-二氧六环、H2O、NMP、DMA、DMSO、苯、甲苯中的一种或者两种。反应所用的催化剂可选自为双(三苯基膦)-二氯化钯、二(三苯基膦)二茂铁二氯化钯、二(三苯基膦)二茂铁二氯化钯二氯甲烷复合物、Pd2(dba)3、pd(dppe)Cl2中的一种或几种,化合物的0.01%-20%(M/M摩尔比),反应中所用的碱选自三乙胺、乙二胺、二异丙基乙胺、咪唑、哌啶、吡啶、CsCO3、KOAc、NaOAc、K2CO3、tBuOK、tBuONa中的一种。用量的1-10倍(M/M摩尔比)。纯化可以选自过柱子、打浆、Prep-TLC、Prep-HPLC或者重结晶。
6.如权利要求1所述的一种CYP11B2抑制剂BAXDROSTAT的制备方法,其特征在于,两个制备方案中susuki偶联反应的反应温度选自10-200℃,反应时间选自0-72h,溶剂选自乙醚、乙腈、THF、DMF、DME、1,4-二氧六环、H2O、NMP、DMA、DMSO、苯、甲苯中的一种或者几种。反应所用的催化剂可选自为双(三苯基膦)-二氯化钯、二(三苯基膦)二茂铁二氯化钯、二(三苯基膦)二茂铁二氯化钯二氯甲烷复合物、Pd2(dba)3、pd(dppe)Cl2、四三苯基磷钯、二(三苯基膦)二茂铁二氯化镍中的一种或几种,化合物的0.01%-20%(M/M摩尔比),反应中所用的碱选自三乙胺、乙二胺、二异丙基乙胺、咪唑、哌啶、吡啶、CsCO3、KOAc、NaOAc、K2CO3、Na2CO3、Li2CO3、tBuOK、tBuONa、K3PO4、NaOH、KOH、Ba(OH)2中的一种中的一种。用量的1-10倍(M/M摩尔比)。纯化可以选自过柱子、打浆、Prep-TLC、Prep-HPLC或者重结晶。
7.如权利要求1所述的一种CYP11B2抑制剂BAXDROSTAT的制备方法,其特征在于,两个制备方案中脱叔丁亚磺酰基反应的反应温度选自10-200℃,反应时间选自0-72h,溶剂选自DCM、1,2-二氯乙烷,氯苯、乙腈、THF、2-MeTHF、DMF、DME、1,4-二氧六环、H2O、NMP、DMAC、DMSO的一种或几种,所用的酸选自三氟乙酸、盐酸中的一种或两种,酸的当量选自≥1eq.产品选自粗品往下用,纯化可以选自过柱子、打浆、Prep-TLC、Prep-HPLC或者重结晶。
8.如权利要求1所述的一种CYP11B2抑制剂BAXDROSTAT的制备方法,其特征在于,最后一步与丙酰氯反应的反应温度选自-50-100℃,反应时间选自0-24h,溶剂选自DCM、1,2-二氯乙烷,氯苯、乙腈、THF、2-MeTHF、DMF、DME、1,4-二氧六环、H2O、NMP、DMAC、DMSO中的一种或几种,所用的碱选自三乙胺、乙二胺、二异丙基乙胺、咪唑、哌啶、吡啶、DMAP、CsCO3、KOAc、NaOAc、K2CO3、Na2CO3中的一种或几种,反应的淬灭剂选自甲醇乙醇、异丙醇等醇类溶剂或者H2O中的一种或几种。产品纯化可以选自过柱子、打浆、Prep-TLC、Prep-HPLC或者重结晶。
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