CN106928126A - 一种酰胺衍生物及其制备方法和在药学上的应用 - Google Patents
一种酰胺衍生物及其制备方法和在药学上的应用 Download PDFInfo
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- CN106928126A CN106928126A CN201611179226.8A CN201611179226A CN106928126A CN 106928126 A CN106928126 A CN 106928126A CN 201611179226 A CN201611179226 A CN 201611179226A CN 106928126 A CN106928126 A CN 106928126A
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- 238000002360 preparation method Methods 0.000 title abstract description 8
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- 238000001949 anaesthesia Methods 0.000 claims abstract description 12
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
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- 238000000034 method Methods 0.000 description 8
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- IBNWGIFHWSUUCL-UHFFFAOYSA-N cyclohexanecarboxamide;hydrochloride Chemical compound Cl.NC(=O)C1CCCCC1 IBNWGIFHWSUUCL-UHFFFAOYSA-N 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- HERPVHLYIHBEFW-ZETCQYMHSA-N diethyl (2s)-2-aminopentanedioate Chemical compound CCOC(=O)CC[C@H](N)C(=O)OCC HERPVHLYIHBEFW-ZETCQYMHSA-N 0.000 description 1
- SKQZPYYDNOLPET-NSHDSACASA-N diethyl (2s)-2-pyrrol-1-ylpentanedioate Chemical compound CCOC(=O)CC[C@@H](C(=O)OCC)N1C=CC=C1 SKQZPYYDNOLPET-NSHDSACASA-N 0.000 description 1
- LJQUGUSRVUMABH-UHFFFAOYSA-N diethyl 2-(piperidin-4-ylmethyl)propanedioate hydrochloride Chemical compound Cl.CCOC(=O)C(C(=O)OCC)CC1CCNCC1 LJQUGUSRVUMABH-UHFFFAOYSA-N 0.000 description 1
- GXOFSUVCMDOCGI-UHFFFAOYSA-N diethyl 2-(pyridin-4-ylmethylidene)propanedioate hydrochloride Chemical compound Cl.CCOC(=O)C(C(=O)OCC)=CC1=CC=NC=C1 GXOFSUVCMDOCGI-UHFFFAOYSA-N 0.000 description 1
- NXBCHPRPTRUHQG-UHFFFAOYSA-N diethyl 2-acetyl-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole-3,3-dicarboxylate Chemical compound C1CCC2CN(C(C)=O)C(C(=O)OCC)(C(=O)OCC)C21 NXBCHPRPTRUHQG-UHFFFAOYSA-N 0.000 description 1
- WPRWPZYYYHWIHH-UHFFFAOYSA-N diethyl 2-bromo-2-(piperidin-4-ylmethyl)propanedioate hydrochloride Chemical compound Cl.CCOC(=O)C(Br)(CC1CCNCC1)C(=O)OCC WPRWPZYYYHWIHH-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- DCRMTISUSQUODA-AXDSSHIGSA-N ethyl (5S)-1,2,3,5,6,7,8,8a-octahydroindolizine-5-carboxylate Chemical compound C(C)OC(=O)[C@H]1N2CCCC2CCC1 DCRMTISUSQUODA-AXDSSHIGSA-N 0.000 description 1
- WWUOYPICOQGXQX-VIFPVBQESA-N ethyl (5s)-8-oxo-6,7-dihydro-5h-indolizine-5-carboxylate Chemical compound CCOC(=O)[C@@H]1CCC(=O)C2=CC=CN12 WWUOYPICOQGXQX-VIFPVBQESA-N 0.000 description 1
- WOLHZTPWHWPOEI-LOACHALJSA-N ethyl 2-[(2S)-2-[(2,6-dimethylphenyl)carbamoyl]piperidin-4-yl]acetate Chemical compound CC1=C(C(=CC=C1)C)NC(=O)[C@H]1NCCC(C1)CC(=O)OCC WOLHZTPWHWPOEI-LOACHALJSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
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- 235000019253 formic acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- XAMUHLXTZRUZDR-UHFFFAOYSA-N hydron;piperidin-2-ylmethanol;chloride Chemical compound Cl.OCC1CCCCN1 XAMUHLXTZRUZDR-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
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- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 description 1
- 229960002409 mepivacaine Drugs 0.000 description 1
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- ZLRZVAMVVPGDSX-UHFFFAOYSA-N n-(2,6-dimethylphenyl)-2-oxocyclohexane-1-carboxamide Chemical compound CC1=CC=CC(C)=C1NC(=O)C1C(=O)CCCC1 ZLRZVAMVVPGDSX-UHFFFAOYSA-N 0.000 description 1
- NRPTXWYBRKRZES-UHFFFAOYSA-N n-(2,6-dimethylphenyl)acetamide Chemical compound CC(=O)NC1=C(C)C=CC=C1C NRPTXWYBRKRZES-UHFFFAOYSA-N 0.000 description 1
- IAHWYHYXNQDZNV-RVDMUPIBSA-N n-[(e)-1-pyridin-2-ylethylideneamino]aniline Chemical compound C=1C=CC=NC=1C(/C)=N/NC1=CC=CC=C1 IAHWYHYXNQDZNV-RVDMUPIBSA-N 0.000 description 1
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 1
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- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
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- 229940052264 other local anesthetics in atc Drugs 0.000 description 1
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- 230000037040 pain threshold Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- DXLGDPCNRBZAPO-UHFFFAOYSA-N piperazine-2-carboxamide hydrochloride Chemical compound Cl.NC(=O)C1CNCCN1 DXLGDPCNRBZAPO-UHFFFAOYSA-N 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical class OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
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- 230000002441 reversible effect Effects 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- TZSZZENYCISATO-WIOPSUGQSA-N rodatristat Chemical compound CCOC(=O)[C@@H]1CC2(CN1)CCN(CC2)c1cc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)nc(N)n1 TZSZZENYCISATO-WIOPSUGQSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
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- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- ZJBQRUABTOUJGJ-ZVAWYAOSSA-N tert-butyl (2S)-2-[(2,6-dimethylphenyl)carbamoyl]-4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1[C@@H](CC(CC1)CC(=O)OCC)C(NC1=C(C=CC=C1C)C)=O ZJBQRUABTOUJGJ-ZVAWYAOSSA-N 0.000 description 1
- ZBCAABIZHHQEGT-SFHVURJKSA-N tert-butyl (2S)-2-[(2,6-dimethylphenyl)carbamoyl]-4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate Chemical compound C(C)(C)(C)OC(=O)N1[C@@H](CC(CC1)=CC(=O)OCC)C(NC1=C(C=CC=C1C)C)=O ZBCAABIZHHQEGT-SFHVURJKSA-N 0.000 description 1
- SFCHTCWNEJRALA-HNNXBMFYSA-N tert-butyl (2S)-2-[(2,6-dimethylphenyl)carbamoyl]-4-oxopiperidine-1-carboxylate Chemical compound CC1=C(C(=CC=C1)C)NC(=O)[C@H]1N(CCC(C1)=O)C(=O)OC(C)(C)C SFCHTCWNEJRALA-HNNXBMFYSA-N 0.000 description 1
- AKQGMGRLHJGDPJ-AWEZNQCLSA-N tert-butyl (2s)-2-[(2,6-dimethylphenyl)carbamoyl]pyrrolidine-1-carboxylate Chemical compound CC1=CC=CC(C)=C1NC(=O)[C@H]1N(C(=O)OC(C)(C)C)CCC1 AKQGMGRLHJGDPJ-AWEZNQCLSA-N 0.000 description 1
- XOMXAOIKQASKRJ-UHFFFAOYSA-N tert-butyl 2-(1h-imidazol-2-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1C1=NC=CN1 XOMXAOIKQASKRJ-UHFFFAOYSA-N 0.000 description 1
- VZRHVBOJVAOGRU-UHFFFAOYSA-N tert-butyl 2-(5-iodo-1H-imidazol-2-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1c1ncc(I)[nH]1 VZRHVBOJVAOGRU-UHFFFAOYSA-N 0.000 description 1
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 1
- JYRWUSXRTGACLY-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylsulfonylphenyl)-[1,2]oxazolo[4,5-d]pyrimidin-7-yl]oxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=NC=NC2=C1ON=C2C1=CC=C(S(C)(=O)=O)C=C1 JYRWUSXRTGACLY-UHFFFAOYSA-N 0.000 description 1
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-N tert-butyl hydrogen carbonate Chemical class CC(C)(C)OC(O)=O XKXIQBVKMABYQJ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
-
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Abstract
本发明提供了一种酰胺衍生物及其制备方法和在药学上的应用,其中该酰胺衍生物化合物选自以下等的结构之一,所述化合物可以用来制备局部麻醉或镇痛领域药物:
Description
技术领域
本发明涉及一种通式(I)所示的酰胺衍生物或其立体异构体、药学上可接受的盐、其制备方法、药物组合,及其在局部麻醉或镇痛等方面的用途。
背景技术
局部麻醉药是指那些在人体的限定范围内能暂时、完全、可逆地阻断神经传导,即在意识未消失的状况下使人体的某一部分失去感觉,以便于外科手术进行的药物,其作用机制是通过与神经膜上的钠离子通道上的某些特定部位结合后,通过钠离子通道的钠离子减少从而改变神经膜电位,导致神经冲动的传导被阻断,最终实现麻醉效果。
目前局麻药中常用的钠离子通道抑制剂主要为卡因类,如普鲁卡因、丁卡因、利多卡因、布比卡因(麻醉时间比利多卡因长2~3倍)或罗哌卡因。罗哌卡因是继布比卡因后的一个新型长效局麻药,毒性反应主要表现为中枢神经和心血管系统的毒性。血药浓度过高时可出现中枢神经系统中毒症状;对心血管系统具有毒性作用,血药浓度过高时可抑制心脏传导和心肌收缩力。对运动神经的阻滞作用与药物浓度有关,浓度为0.2%对感觉神经阻滞较好,但几乎无运动神经阻滞作用,0.75%则产生较好的运动神经阻滞作用。
带电荷的卡因类局部麻醉药还未见在临床上使用。QX-314是利多卡因盐酸盐,待进入细胞膜后可以产生长效的局部麻醉作用。目前已有研究发现,QX314能经TRPV1阳离子通道进入细胞膜,快速引起持久麻醉作用(Craig R.Ries.Anesthesiology.2009;111:122–6)。因TRPV1主要表达在感觉神经元,在运动神经元上表达较少,因此QX314经此通道进入细胞具有选择性,从而能实现运动感觉的分离阻滞。虽然QX-314因安全性问题未进一步研发上市,但为我们研究新的、非剂量依赖的运动感觉分离阻滞的长效局麻药提供了方向。
至今已有较多文献报道了酰胺类衍生物及其在局部麻醉领域的应用。如US4302465公开了一种羟烷基取代的酰胺类局部麻醉化合物,研究显示具有一定的局部麻醉效果。WO9512576公开了一种环烷基取代的酰胺类化合物,以及在局部麻醉方面的应用,文中提到具有一定的局部麻醉效果,比甲哌卡因的效果更好。CN101050200公开了一类烯取代的酰胺类衍生物,及其在局部麻醉领域的应用,其结果显示具有一定的局部麻醉效果,其急性毒性比盐酸左旋布匹卡因小。G.K.Wang(Anesthesiology.1995Dec;83(6):1293-301)报道了一类利多卡因季铵盐衍生物,结果表示该类化合物具有局部麻醉作用,其麻醉时间是利多卡因的3~9倍。CN103601650和CN104382890描述了一种酰胺类阳离子化合物及其在局部神经阻滞药物中的应用,结果表示该类化合物,与QX-314相比,可具有安全性好和神经阻滞效果强等特点,能够在生物体内发挥可逆和持久的局部麻醉作用,可作为长效的和/或实现选择性阻滞的局部麻醉药物或镇痛药物使用,特别是由该化合物与其它局部麻醉药物组成的组合物,在进行神经阻滞时,更能具有起效快、效力强、作用时间长、对神经损伤小等显著的特点。
为了满足临床需要,本发明的目的在于提供一种新颖、快速起效、低毒、长效或感觉运动阻滞分离的钠离子通道抑制剂,及其在局部麻醉或镇痛等方面的应用。
发明内容
本发明涉及如下化合物或其立体异构体以及药学上可以接受的盐:
本发明化合物进一步优选如下化合物:
本发明的所列化合物包括其立体异构体。
本发明优选方案,一种本发明的化合物或其立体异构体以及药学上可以接受的盐,其中该所述的盐选自盐酸盐或氢溴酸盐。
本发明还涉及一种药物组合物,所述药物组合物含有治疗有效剂量的本发明所述的化合物及其立体异构体或药学上可以接受的盐,以及药学上可接受的载体或者赋形剂。
本发明所述的化合物、其立体异构体或其药学上可以接受的盐或本发明所述的药物组合物,在制备局部麻醉或镇痛领域药物中的应用。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合,如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“取代”是指基团中一个或多个氢原子被其它基团取代的情形,如果所述的基团被氢原子取代,形成的基团与被氢原子取代的基团相同。基团被取代的情形,例如氨基、C1-4烷基、C1-4烷氧基、C3-6碳环、3至6元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、氰基、氨基、C1-4烷基或C1-4烷氧基的取代基所取代,形成的基团包括但不限于甲基、氯甲基、三氯甲基、羟基甲基、-CH2OCH3、-CH2SH、-CH2CH2CN、-CH2NH2、-NHOH、-NHCH3、-OCH2Cl、-OCH2OCH2CH3、-OCH2CH2NH2、-OCH2CH2SH、-OCH2CH2OH、1-羟基环丙基、2-羟基环丙基、2-氨基环丙基、4-甲基呋喃基、2-羟基苯基、4-氨基苯基、苯基。
“取代或未取代的”是指基团可以被取代或不被取代的情形,若在本发明中没有指出基团可以被取代,则表示该基团为未取代的情形。
“作为选择”是指“作为选择”之后的方案与“作为选择”之前的方案为并列关系,而不是在前方案中的进一步选择情形。
“药学上可接受的盐”或“其药学上可接受的盐”指的是保持游离酸或游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或有机碱,或所述的游离酸通过与无毒的无机酸或有机酸反应获得的那些盐。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),氘代乙腈(CD3CN),内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
缩写含义:
盐酸乙酸乙酯溶液:指乙醇与乙酰氯以摩尔比1:1的比例分别加入乙酸乙酯中形成的溶液。
PIS:磅/平方英寸。
Boc:叔丁氧羰基。
Wt:质量含量。
Et:乙基。
Ph:苯基。
中间体1
(S)-1-丙基哌啶-2-羧酸(中间体1)
(S)-1-propylpiperidine-2-carboxylic acid
将(S)-哌啶-2-羧酸(40g,0.910mol)、甲醇(500mL)、丙醛(150mL)和钯碳(20g,wt=10%)加入氢化反应瓶,氢气置换三次,加氢气(35PSI)摇摆氢化32小时。液相色谱-质谱联用检测反应毕,用硅藻土过滤,滤饼用无水甲醇(50mL×2)洗涤,合并有机相并蒸干,残留物用乙酸乙酯(100mL)洗涤,过滤,将滤饼烘干,得到白色固体中间1(44.5g,产率83.9%)。
Ms m/z(ESI):172.2[M+H+]。
实施例1
N-(2,6-二甲基苯基)-2-甲基-(哌啶-1-基)丙酰胺盐酸盐(化合物1)
N-(2,6-dimethylphenyl)-2-methyl-2-(piperidin-1-yl)propanamidehydrochloride
第一步:2-溴-N-(2,6-二甲基苯基)-2-甲基丙酰胺(1b)
2-bromo-N-(2,6-dimethylphenyl)-2-methylpropanamide
将2,6-二甲基苯胺-2-甲酰胺(10g,82.6mmol)及三乙胺(16.7g,165.2mmol)溶于二氯甲烷(200mL)中,降温到0℃,再将2-溴-2-甲基丙酰基溴(20.9g,90.9mmol)滴加到反应液,加完后升到室温下搅拌2小时。向反应液加入饱和氯化铵水溶液(200mL),分液,有机相用饱和氯化钠(80mL)水溶液洗涤,无水硫酸钠干燥,过滤,旋干,粗品用正己烷(200mL)打浆,过滤,烘干得到黄色固体化合物1b(20g,产率90%)。
1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),7.14-7.08(m,3H),2.17(s,6H),2.03(s,6H)。
第二步:N-(2,6-二甲基苯基)-2-甲基-2-(哌啶-1-基)丙酰胺(1c)
N-(2,6-dimethylphenyl)-2-methyl-2-(piperidin-1-yl)propanamide
将哌啶(0.315g,3.7mmol)溶于四氢呋喃(15mL)中,降温至0℃,加入氢化钠(0.11g,2.77mmol),反应0.5小时后,再将化合物1b(0.5g,1.85mmol)溶于四氢呋喃(5mL)中滴加到反应液中,加毕于室温下反应2小时。将反应用饱和氯化铵水溶液(50mL)淬灭,水相用乙酸乙酯(30mL×2)萃取,合并有机相用饱和氯化钠水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,旋干,粗品用柱层析分离纯化(石油醚/乙酸乙酯(v/v)=20:1~10:1)得到白色固体化合物1c(0.4g,产率:79%)。
Ms m/z(ESI):275.3[M+H+]。
第三步:N-(2,6-二甲基苯基)-2-甲基-(哌啶-1-基)丙酰胺盐酸盐(化合物1)
N-(2,6-dimethylphenyl)-2-methyl-2-(piperidin-1-yl)propanamidehydrochloride
室温下,将化合物1c(0.4g,1.45mmol)溶于乙酸乙酯(5mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0mol/L),搅拌反应1小时。将反应液过滤,滤饼用正己烷洗涤,干燥后得到白色固体化合物1(0.405g,产率:90%)。
Ms m/z(ESI):275.3[M+H+];
1H NMR(400MHz,DMSO)δ10.16(s,1H),9.83(s,1H),7.29-6.87(m,3H),3.38(d,2H),3.08(q,2H),2.16(s,6H),1.98(m,2H),1.86(m,2H),1.73(m,7H),1.47-1.41(m,1H)。
实施例2
N-(2,6-二甲基苯基)-2-甲基-2-吗啉基丙酰胺盐酸盐(化合物2)
N-(2,6-dimethylphenyl)-2-methyl-2-morpholinopropanamide hydrochloride
第一步:N-(2,6-二甲基苯基)-2-甲基-2-吗啉基丙酰胺(2a)
N-(2,6-dimethylphenyl)-2-methyl-2-morpholinopropanamide
将二乙胺盐酸盐(0.643g,7.4mmol)溶于四氢呋喃(20mL)中,降温至0℃,加入氢化钠(0.22g,5.55mmol),搅拌反应0.5小时后,再将化合物1b(1g,3.7mmol)溶于四氢呋喃(5mL)中滴加到反应液中,加毕于室温下反应2小时。将反应用饱和氯化铵水溶液(50mL)淬灭,水相用乙酸乙酯(30mL×2)萃取,合并有机相用饱和氯化钠水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,旋干,粗品用柱层析分离纯化(石油醚/乙酸乙酯(v/v)=20:1~5:1)得到白色固体化合物2a(0.8g,产率:78%)。
Ms m/z(ESI):277.2[M+H+]。
第二步:N-(2,6-二甲基苯基)-2-甲基-2-吗啉基丙酰胺盐酸盐(化合物2)
N-(2,6-dimethylphenyl)-2-methyl-2-morpholinopropanamide hydrochloride
室温下,将化合物2a(0.5g,1.85mmol)溶于乙酸乙酯(10mL),加入氯化氢的乙酸乙酯溶液(4mL,4.0M),搅拌反应1小时。将反应液过滤,正己烷洗涤,干燥后得到白色固体化合物2(0.49g,产率:85%)。
Ms m/z(ESI):277.3[M+H+];
1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),10.04(s,1H),7.14-7.10(m,3H),3.99-3.95(m,4H),3.47-3.34(m,4H),2.16(s,6H),1.79(s,6H)。
实施例3
2-(二乙氨基)-N-(2,6-二甲基苯基)-2-甲基丙酰胺盐酸盐(化合物3)
2-(diethylamino)-N-(2,6-dimethylphenyl)-2-methylpropanamidehydrochloride
第一步:2-(二乙氨基)-N-(2,6-二甲基苯基)-2-甲基丙酰胺(3a)
2-(diethylamino)-N-(2,6-dimethylphenyl)-2-methylpropanamide
将二乙胺盐酸盐(0.811g,7.4mmol)溶于四氢呋喃(20mL)中,降温至0℃,加入氢化钠(0.37g,9.25mmol),搅拌反应0.5小时后,再将化合物1b(1g,3.7mmol)溶于四氢呋喃(5mL)中滴加到反应液中,加毕于室温下反应2小时。将反应用饱和氯化铵水溶液(50mL)淬灭,水相用乙酸乙酯(30mL×2)萃取,合并有机相用饱和氯化钠水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,旋干,粗品用柱层析分离纯化(石油醚/乙酸乙酯(v/v)=20:1~10:1)得到白色固体化合物3a(0.41g,产率:41%)。
Ms m/z(ESI):263.3[M+H+]。
第二步:2-(二乙氨基)-N-(2,6-二甲基苯基)-2-甲基丙酰胺盐酸盐(化合物3)
2-(diethylamino)-N-(2,6-dimethylphenyl)-2-methylpropanamidehydrochloride
室温下,将化合物3a(0.4g,1.52mmol)溶于乙酸乙酯(6mL),加入氯化氢的乙酸乙酯溶液(4mL,4.0M),搅拌反应1小时。将反应液过滤,正己烷洗涤,干燥后得到白色固体化合物3(0.36g,产率:80%)。
Ms m/z(ESI):263.3[M+H+];
1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.34(s,1H),7.17-7.10(m,3H),3.32-3.19(m,4H),2.16(s,6H),1.77(s,6H),1.36(t,6H)。
实施例4
1-(2,6-二甲基苯基)-3-(哌啶-1-基)吡咯烷-2-酮盐酸盐(化合物4)
1-(2,6-dimethylphenyl)-3-(piperidin-1-yl)pyrrolidin-2-onehydrochloride
第一步:3-溴-1-(2,6-二甲基苯基)吡咯烷-2-酮(4a)
3-bromo-1-(2,6-dimethylphenyl)pyrrolidin-2-one
将2,6-二甲基苯胺(5g,41.3mmol)及磷酸钾(6.98g,20.65mmol)溶于乙腈(80mL)中,降温至0℃,将2,4-二溴丁酰氯(13.08g,49.56mmol)滴加到反应中,搅拌反应2个小时,再将氢氧化钠(3.3g,82.6mmol)的50%水溶液滴加到反应液中,加毕于室温下反应2小时。向反应液加水(80mL),水相用乙酸乙酯(50mL×2)萃取,合并有机相用饱和氯化钠水溶液(80mL)洗涤,无水硫酸钠干燥,过滤,旋干,粗品用柱层析分离纯化(石油醚/乙酸乙酯(v/v)=10:1~3:1)得到白色固体化合物4a(8g,产率:72%)。
Ms m/z(ESI):268.1[M+H+];
1H NMR(400MHz,CDCl3)δ7.18-7.06(m,3H),4.55(q,1H),3.92-3.86(m,1H),3.53-3.44(m,1H),2.92-2.74(m,1H),2.58-2.43(m,1H),2.29(s,3H),2.20(s,3H)。
第二步:1-(2,6-二甲基苯基)-3-(哌啶-1-基)吡咯烷-2-酮(4b)
1-(2,6-dimethylphenyl)-3-(piperidin-1-yl)pyrrolidin-2-one
室温下,将化合物4a(1g,3.73mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入碳酸钾(1.03g,7.46mmol)及哌啶(0.47g,5.59mmol),加毕于80℃下反应2小时。向反应液中加水(100mL),用乙酸乙酯(30mL×3)萃取,合并有机相用饱和食盐水溶液(50mL×2)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品柱层析纯化(石油醚/乙酸乙酯(v/v)=1:1),得到油状液体化合物4b(0.5g,产率49.5%)。
Ms m/z(ESI):273.2[M+H+]。
第三步:1-(2,6-二甲基苯基)-3-(哌啶-1-基)吡咯烷-2-酮盐酸盐(化合物4)
1-(2,6-dimethylphenyl)-3-(piperidin-1-yl)pyrrolidin-2-onehydrochloride
室温下,将化合物4b(0.4g,1.47mmol)溶于乙酸乙酯(5mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0M),搅拌反应0.5小时。将反应液过滤,正己烷洗涤,干燥后得到白色固体化合物4(0.4g,产率:88%)。
Ms m/z(ESI):273.2[M+H+];
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),7.23-7.13(m,3H),4.59-4.54(m,1H),3.88-3.85(m,1H),3.68-3.52(m,2H),3.34(m,2H),3.01(m,1H),2.68-2.54(m,2H),2.20(s,3H),2.12(s,3H),1.86(m,4H),1.73(m,1H),1.43(m,1H)。
实施例5
N-(2,6-二甲基苯基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺盐酸盐(化合物5)
N-(2,6-dimethylphenyl)-2-propyloctahydrocyclopenta[c]pyrrole-1-carboxamide hydrochloride
第一步:二乙基2-乙酰基-3-羟基六氢环戊并[c]吡咯-1,1-(2H)-二甲酸酯(5b)
diethyl 2-acetyl-3-hydroxyhexahydrocyclopenta[c]pyrrole-1,1(2H)-dicarboxylate
室温下,将乙酰氨基丙二酸二乙酯(36g,0.166mol)溶于乙醇(300mL)中,降温到0℃,将钠(0.767g,0.033mol)加到反应中,搅拌反应20分钟,再将1-环戊烯甲醛(16g,0.166mol)滴加到反应中,升至室温下搅拌3小时。向反应液加入乙酸(5mL),再将反应液浓缩,用乙酸乙酯(400mL)溶液萃取,有机相依次用饱和碳酸氢钠饱水溶液(200mL)、氯化钠水溶液(100mL)洗涤,有机相中加入无水硫酸钠干燥,过滤,旋干,得到黄色油状液体化合物5b(50g,产率95%)。
Ms m/z(ESI):314.1[M-H+]。
第二步:二乙基-2-乙酰六氢环戊并[c]吡咯-1,1-(2H)-二甲酸酯(5c)
diethyl 2-acetylhexahydrocyclopenta[c]pyrrole-1,1(2H)-dicarboxylate
将化合物5b(25g,0.80mol)溶于二氯甲烷(300mL)中,将三乙基硅氢(18.53g,0.16mol)加至反应液中,降温至0℃,再将三氟乙酸(91g,80mol)滴加至反应液中,升至室温搅拌反应4小时。将反应液浓缩,加入二氯甲烷(300mL)溶解,有机相依次用饱和碳酸氢钠水溶液(100mL)、氯化钠水溶液(100mL)洗涤,有机相中加入无水硫酸钠干燥,过滤,旋干,得到黄色油状液体化合物5c(24g,产率100%)。
Ms m/z(ESI):298.3[M-H+]。
第三步:1,2,3,3a,4,5,6,6a-八氢环戊并[c]吡咯-3-羧酸氢溴酸盐(5d)
1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylic acidhydrobromide
将化合物5c(23g,0.774mol)溶于氢溴酸水溶液(200mL)及乙酸(50mL)中,升温至120℃下反应10小时。将反应液冷却,浓缩得到固体,用甲基叔丁基醚(100mL)打浆,过滤,洗涤,干燥后得到灰色固体化合物5d(18g,产率98%)。
Ms m/z(ESI):156.3[M+H+]。
第四步:2-(叔丁氧基羰基)八氢环戊并[c]吡咯-1-羧酸(5e)
2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylicacid
将化合物5d(18g,0.076mol)溶于水(200mL)及二氧六环(200mL)中,降温至0℃,将碳酸氢钠(16g,0.19mol)分批加入反应液,再将二碳酸二叔丁基酯(24.9g,0.114mol)滴加到反应中,加毕,于室温下反应4小时。向反应液加入水(100mL),水相用乙酸乙酯(100mL×4)萃取除去杂质,水相用2mol/L的盐酸溶液调节pH值至2~3,水相再用乙酸乙酯(200mL×3)萃取,合并有机相,加入无水硫酸钠干燥,过滤,浓缩,得到黄色油状液体化合物5e(13g,产率67%)。
Ms m/z(ESI):278.2[M+Na+]。
第五步:反式-叔丁基-1-(2,6-二甲基苯基)六氢环戊并[c]吡咯-2(1H)-羧酸酯(5f)
Trans-Tert-butyl1-(2,6-dimethylphenylcarbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
将化合物5e(4g,15.6mmol)溶于二氯甲烷(60mL),加入2,6-二甲基苯苯胺(2.26g,18.7mmol)、三乙胺(3.15g,31.2mmol)以及2-氯-1-甲基碘代吡啶(5.97g,31.2mmol),加毕,于40℃反应8小时。向反应液加入二氯甲烷(80mL),有机相用饱和碳酸氢钠水溶液(50mL)、饱和氯化钠水溶液(50mL)洗涤,有机相中加入无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚/乙酸乙酯(v/v)=40:1~5:1),得到白色固体反式-叔丁基-1-(2,6-二甲基苯基)六氢环戊[c]吡咯-2(1H)-羧酸酯5f(2.4g,产率43%)以及白色固体顺式-叔丁基-1-(2,6-二甲基苯基)六氢环戊[c]吡咯-2(1H)-羧酸酯(1.2g,产率21%)。
反式-叔丁基-1-(2,6-二甲基苯基)六氢环戊[c]吡咯-2(1H)-羧酸酯5f:
1H NMR(400MHz,MeOD)δ7.10(m,3H),4.27(d,1H),3.79(d,1H),2.81(m,2H),2.25(s,6H),2.09(s,1H),1.90(m,2H),1.70(m,2H),1.49(m,11H);
Ms m/z(ESI):381.3[M+Na+]。
顺式-叔丁基-1-(2,6-二甲基苯基)六氢环戊[c]吡咯-2(1H)-羧酸酯:
1H NMR(400MHz,MeOD)δ7.08(m,3H),4.66(m,1H),3.89(m,1H),3.09(m,1H),2.80(s,1H),2.27(2,6H),1.85(m,4H),1.68(m,1H),1.58(m,1H),1.49(s,9H);
Ms m/z(ESI):381.3[M+Na+]。
第六步:反式-N-(2,6-二甲基苯基)八氢环戊并[c]吡咯-1-甲酰胺盐酸盐(5g)
Trans-N-(2,6-dimethylphenyl)octahydrocyclopenta[c]pyrrole-1-carboxamide hydrochloride
将化合物5f(2.4g,6.7mmol)溶于乙酸乙酯(30mL)中,再将盐酸乙酸乙酯(6mL,4mol/L)溶液滴加到反应中,室温下反应2小时。将反应液直接旋干得到白色固体化合物5g(1.9g,产率96%)。
Ms m/z(ESI):259.3[M+H+]。
第七步:(1R,3aS,6aR)-N-(2,6-二甲基苯基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺(5h-1)
(1R,3aS,6aR)-N-(2,6-dimethylphenyl)-2-propyloctahydrocyclopenta[c]pyrrole-1-carb oxamide
(1S,3aR,6aS)-N-(2,6-二甲基苯基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺(5h-2)
(1S,3aR,6aS)-N-(2,6-dimethylphenyl)-2-propyloctahydrocyclopenta[c]pyrrole-1-carb oxamide
将反式-N-(2,6-二甲基苯基)八氢环戊[c]吡咯-1-甲酰胺盐酸盐5g(0.6g,2.04mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入碳酸钾(0.704g,5.1mmol)以及溴代正丙烷(0.376g,3.06mmol),加毕于80℃下反应2小时。冷却,向反应液中加水(50mL),水相用乙酸乙酯(20mL×3)萃取,合并有机相,用饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析(石油醚/乙酸乙酯(v/v)=10:1~1:1)纯化以及用SFC(MGⅡpreparative SFC,Column:Whelk O1(S,S),250×30mm I.D.5μm.Mobile phase:Afor CO2and B for Methanol(0.1%NH3H2O))分离,得到白色固体(1R,3aS,6aR)-N-(2,6-二甲基苯基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺(5h-1)(保留时间:3.20min,0.24g,ee%=99.5%,产率39%)和白色固体(1S,3aR,6aS)-N-(2,6-二甲基苯基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺(5h-2)(保留时间:3.73min,0.26g,ee%=99.4%,产率42%)。
Ms m/z(ESI):301.3[M+H+]。
第八步:(1R,3aS,6aR)-N-(2,6-二甲基苯基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺盐酸盐(5-1)
(1R,3aS,6aR)-N-(2,6-dimethylphenyl)-2-propyloctahydrocyclopenta[c]pyrrole-1-carb oxamide hydrochloride
将(1R,3aS,6aR)-N-(2,6-二甲基苯基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺(5h-1)(0.22g,0.73mmol)溶于乙酸乙酯(4mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0M),室温下搅拌反应1小时。将反应液直接旋干,得到白色固体(1R,3aS,6aR)-N-(2,6-二甲基苯基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺盐酸盐(5-1)(0.24g,产率100%)。
Ms m/z(ESI):301.3[M+H+];
1H NMR(400MHz,MeOD)δ7.27-7.04(m,3H),4.02-3.86(m,2H),3.23-3.15(m,2H),3.07-2.85(m,3H),2.26(s,6H),2.11(d,1H),1.95-1.66(m,7H),1.04(t,3H)。
化合物(1S,3aR,6aS)-N-(2,6-二甲基苯基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺盐酸盐(5-2)参考上述方法可得。
Ms m/z(ESI):301.3[M+H+];
1H NMR(400MHz,MeOD)δ7.17-6.88(m,3H),3.91-3.66(m,2H),3.10-3.03(m,1H),2.91-2.87(m,2H),2.83-2.75(m,1H),2.14(s,6H),1.98(m,1H),1.87-1.52(m,7H),0.93(t,3H)。
实施例6
2-(1-丙基哌啶-2-基)-1H-吲哚盐酸盐(化合物6)
2-(1-propylpiperidin-2-yl)-1H-indole hydrochloride
第一步:2-(1-(2-苯基亚肼基)乙基)吡啶(6b)
2-(1-(2-phenylhydrazono)ethyl)pyridine
室温下,将2-乙酰基吡啶(10g,82.6mmol)溶于乙醇(80mL)中,再将苯肼(17.85g,165.2mmol)加到反应中,回流反应1小时。将反应液冷却至室温,有固体析出,过滤,滤饼用冷乙醇洗涤,干燥后得到黄色固体化合物6b(11g,产率:63%)。
Ms m/z(ESI):212.2[M+H+]。
第二步:2-(吡啶-2-基)-1H-吲哚(6c)
2-(pyridin-2-yl)-1H-indole
室温下,将化合物6b(10g,47.4mmol)与多聚磷酸(80.1g,237mmol)混合,然后加热到150℃反应2小时。将反应液冷却,用饱和氢氧化钠溶液调节pH≈10,水相用二氯甲烷(200mL×2)萃取,合并有机相用饱和氯化钠水溶液(100mL)洗涤,无水硫酸钠干燥,过滤,旋干,粗品用柱层析(石油醚/乙酸乙酯(v/v)=5:1)分离纯化得到黄色固体化合物6c(4g,产率:43%)。
Ms m/z(ESI):195.2[M+H+];
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.63(d,1H),7.90(m,2H),7.53(dd,2H),7.29(m,1H),7.07(m,3H)。
第三步:2-(哌啶-2-基)-1H-吲哚(6d)
2-(piperidin-2-yl)-1H-indole
室温下,将化合物6c(0.5g,2.57mmol)溶于乙酸(10mL),再二氧化铂(0.116g,0.514mmol)加入到反应中,抽真空,用氢气置换三次,在氢气球下,50℃搅拌反应4小时。将反应液过滤,旋干,然后用饱和碳酸氢钠溶液调节pH≈8,水相用二氯甲烷(30mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,旋干得到黄色固体化合物6d(0.35g,产率:68%)。
Ms m/z(ESI):201.2[M+H+]。
第四步:2-(1-丙基哌啶-2-基)-1H-吲哚(6e)
2-(1-propylpiperidin-2-yl)-1H-indole
室温下,将化合物6d(0.35g,1.75mmol)溶于N,N-二甲基甲酰胺(10mL)中,再加入碳酸钾(0.483g,3.5mmol)及溴代正丙烷(0.258g,2.1mmol),加毕于80℃下反应4小时。向反应液中加水(50mL),用乙酸乙酯(30mL×2)萃取,合并有机相用饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析纯化(二氯甲烷/甲醇(v/v)=100:1~20:1),得到油状液体化合物6e(0.28g,产率:66%)。
Ms m/z(ESI):243.3[M+H+]。
第五步:2-(1-丙基哌啶-2-基)-1H-吲哚盐酸盐(化合物6)
2-(1-propylpiperidin-2-yl)-1H-indole hydrochloride
将化合物6e(0.22g,0.9mmol)溶于乙酸乙酯(4mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0M),室温下搅拌反应0.5小时。将反应液过滤,正己烷洗涤,干燥后得到淡黄色固体化合物6(0.21g,产率:83%)。
Ms m/z(ESI):243.2[M+H+];
1H NMR(400MHz,DMSO-d6)δ11.44(d,1H),10.74(s,1H),7.57(t,1H),7.41(d,1H),7.14(dd,1H),7.04(t,1H),6.69(t,1H),4.43(m,1H),3.65(d,1H),3.09(m,1H),2.83-2.60(m,2H),2.46-2.26(m,1H),2.02(m,2H),1.88(m,2H),1.80-1.41(m,3H),0.72(t,3H)。
实施例7
2-((3,5-二甲基苯氧基)甲基)-1-丙基哌啶盐酸盐(化合物7)
2-((3,5-dimethylphenoxy)methyl)-1-propylpiperidine hydrochloride
第一步:2–((3,5-二甲基苯氧基)甲基)吡啶(7c)
2-((3,5-dimethylphenoxy)methyl)pyridine
在冰浴下,将2-吡啶甲醇(10g,91.7mmol)缓慢滴加到二氯亚砜(50mL)中,加完于室温反应2小时。将反应液直接旋干,产品溶于N,N-二甲基甲酰胺(100mL)中,再将3,5-二甲基苯酚(11.2g,91.7mmol)与碳酸钾(25.3g,183.4mmol)加到反应中,升至100℃搅拌反应12小时。将反应冷却,向反应液加水(200mL),水相用甲基叔丁基醚(100mL×3)萃取,合并有机相用氢氧化钠水溶液(100mL)及饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,滤液蒸干黄色液体化合物7c(12g,产率61%)。
Ms m/z(ESI):214.2[M+H+];
1H NMR(400MHz,CDCl3)δ8.59(d,1H),7.71(dd,1H),7.52(d,1H),7.21(dd,1H),6.62(s,3H),5.18(s,2H),2.27(s,6H)。
第二步:2-((3,5-二甲基苯氧基)甲基)哌啶(7d)
2-((3,5-dimethylphenoxy)methyl)piperidine
将化合物7c(2g,9.38mmol)溶于乙酸(30mL)中,加入二氧化铂(213mg,0.938mmol),将反应体系抽真空后通入氢气置换三次,在氢气球下,40℃反应5小时。垫硅藻土抽滤,过滤,滤饼用乙醇(20mL×2)洗涤,将滤液浓缩,粗品用乙酸乙酯(50mL)溶解,依次用饱和碳酸氢钠水溶液(50mL)、饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析纯化(二氯甲烷/甲醇(v/v)=50:1~20:1),得到黄色油状液体化合物7d(0.8g,产率39%)。
Ms m/z(ESI):220.3[M+H+]。
第三步:2-((3,5-二甲基苯氧基)甲基)-1-丙基哌啶(7e)
2-((3,5-dimethylphenoxy)methyl)-1-propylpiperidine
室温下,将化合物7d(0.8g,3.65mmol)溶于N,N-二甲基甲酰胺(10mL)中,再加入碳酸钾(0.755g,5.47mmol)及溴代正丙烷(0.538g,4.38mmol),加毕于80℃下反应4小时。向反应液中加水(50mL),用乙酸乙酯(20mL×3)萃取,合并有机相,用饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析纯化(二氯甲烷/甲醇(v/v)=50:1~20:1),得到黄色油状液体化合物7e(0.76g,产率:80%)。
Ms m/z(ESI):262.3[M+H+]。
第四步:2-((3,5-二甲基苯氧基)甲基)-1-丙基哌啶盐酸盐(化合物7)
2-((3,5-dimethylphenoxy)methyl)-1-propylpiperidine hydrochloride
将化合物7e(0.76g,2.91mmol)溶于乙酸乙酯(10mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0M),室温下搅拌反应1小时。将反应液直接旋干,得到黄色油状液体化合物7(0.86g,产率99.5%)。
Ms m/z(ESI):262.3[M+H+];
1H NMR(400MHz,MeOD)δ6.70-6.57(m,3H),4.40-4.11(m,2H),3.61-3.58(m,2H),3.30-3.11(m,3H),2.30(s,6H),2.02-1.96(m,3H),1.94-1.90(m,3H),1.86-1.84(m,2H),1.04-0.99(m,3H)。
实施例8
2-(4,5-二苯基-1H-咪唑-2-基)-1-丙基哌啶盐酸盐(化合物8)
2-(4,5-diphenyl-1H-imidazol-2-yl)-1-propylpiperidine hydrochloride
第一步:叔丁基-2-(4,5-二苯基-1H-咪唑-2-基)哌啶-1-羧酸酯(8c)
tert-butyl 2-(4,5-diphenyl-1H-imidazol-2-yl)piperidine-1-carboxylate
室温下,将二苯基乙二酮(1g,4.76mmol)与叔丁基-2-甲酰哌啶-1-羧酸酯(1.01g,4.76mmol)溶于叔丁醇(30mL),再将醋酸铵(0.806g,10.47mmol)加到反应中,升至80℃搅拌反应6小时。将反应液旋干,加水(50mL),水相用乙酸乙酯(50mL×2)萃取,合并有机相用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,过滤,滤液蒸干,粗品用柱层析分离纯化(石油醚/乙酸乙酯(v/v)=20:1~5:1)得到白色固体化合物8c(1.53g,产率80%)。
Ms m/z(ESI):404.3[M+H+];
1H NMR(400MHz,MeOD)δ7.83-6.93(m,10H),5.51-5.37(m,1H),4.20-3.97(m,1H),3.19-3.11(m,1H),2.54-2.35(m,1H),1.99-1.78(m,1H),1.76-1.60(m,3H),1.59-1.37(m,10H)。
第二步:2-(4,5-二苯基-1H-咪唑-2-基)哌啶盐酸盐(8d)
2-(4,5-diphenyl-1H-imidazol-2-yl)piperidine hydrochloride
将化合物8c(1.5g,3.72mmol)溶于乙酸乙酯(30mL)中,滴加入氯化氢的乙酸乙酯溶液(4mL,4.0M),室温反应4时。将反应液过滤,滤饼用乙酸乙酯(10mL)洗涤,干燥后得到化合物8d(1.15g,产率90%)。
Ms m/z(ESI):304.2[M+H+]。
第三步:2-(4,5-二苯基-1H-咪唑-2-基)-1-丙基哌啶(8e)
2-(4,5-diphenyl-1H-imidazol-2-yl)-1-propylpiperidine
室温下,将化合物8d(0.5g,1.47mmol)溶于N,N-二甲基甲酰胺(10mL)中,再加入碳酸钾(0.446g,3.32mmol)及溴代正丙烷(0.2g,1.62mmol),加毕于80℃下反应2小时。向反应液中加水(50mL),用乙酸乙酯(20mL×2)萃取,合并有机相用饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析纯化(二氯甲烷/甲醇(v/v)=50:1~20:1),得到白色固体化合物8e(0.355g,产率:70%)。
Ms m/z(ESI):346.3[M+H+]。
第四步:2-(4,5-二苯基-1H-咪唑-2-基)-1-丙基哌啶盐酸盐(化合物8)
2-(4,5-diphenyl-1H-imidazol-2-yl)-1-propylpiperidine hydrochloride
将化合物8e(0.345g,1.0mmol)溶于乙酸乙酯(15mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0M),室温下搅拌反应1小时。将反应液过滤,滤饼用正己烷洗涤,干燥得到白色固体化合物8(0.35g,产率91%)。
Ms m/z(ESI):346.3[M+H+];
1H NMR(400MHz,MeOD)δ7.60-7.47(m,10H),3.94(d,1H),3.33(m,2H),3.15-3.14(m,1H),2.69-2.66(m,1H),2.40(d,1H),2.16-2.10(m,3H),1.90-1.87(m,3H),0.99(t,3H)。
实施例9
(S)-N-(2-甲基-4-(三氟甲氧基)苯基)-1-丙基哌啶-2-甲酰胺盐酸盐(化合物9)
(S)-N-(2-methyl-4-(trifluoromethoxy)phenyl)-1-propylpiperidine-2-carboxamide hydrochloride
第一步:(S)-N-(2-甲基-4-(三氟甲氧基)苯基)-1-丙基哌啶-2-甲酰胺(9b)
(S)-N-(2-methyl-4-(trifluoromethoxy)phenyl)-1-propylpiperidine-2-carboxamide
将中间体1(0.35g,2.04mmol)溶于二氯甲烷(10mL),加入三乙胺(0.226g,2.24mmol)冷却至0℃,搅拌下滴加氯甲酸异丁酯(0.305g,2.24mmol),加毕于冰浴下搅拌1小时,再滴加化合物9a(0.487g,2.55mmol)到反应中,加毕于室温下搅拌6小时。向反应液加入水(30mL)分液,水相用二氯甲烷(10mL×2)萃取,合并有机相用饱和食盐水(30mL)洗涤,用无水硫酸钠干燥,过滤,滤液蒸干,粗品用柱层析分离纯化(石油醚/乙酸乙酯(v/v)=20:1~10:1)得到油状液体产品化合物9b(0.3g,产率42%)。
Ms m/z(ESI):345.3[M+H+]。
第二步:(S)-N-(2-甲基-4-(三氟甲氧基)苯基)-1-丙基哌啶-2-甲酰胺盐酸盐(化合物9)
(S)-N-(2-methyl-4-(trifluoromethoxy)phenyl)-1-propylpiperidine-2-carboxamide hydrochloride
室温下,将化合物9b(0.2g,0.58mmol)溶于乙酸乙酯(4mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0mol/L),搅拌反应0.5小时。将反应液过滤,正己烷洗涤,干燥后得到白色固体化合物9(0.2g,产率90%)。
Ms m/z(ESI):345.3[M+H+];
1H NMR(400MHz,D2O)δ7.25(m,3H),4.09(q,1H),3.71(d,1H),3.11-3.05(m,3H),2.35m,1H),2.21(s,3H),1.98-1.61(m,7H),0.93(t,3H)。
实施例10
N-(2,6-二甲基苯基)-2-(吡咯烷-1-基)环己基甲酰胺盐酸盐(化合物10)
N-(2,6-dimethylphenyl)-2-(pyrrolidin-1-yl)cyclohexanecarboxamidehydrochloride
第一步:2-氧代环己烷羧酸(10b)
2-oxocyclohexanecarboxylic acid
向反应瓶中加入氢氧化钠(5.5g,137.5mmol)和水(240mL),搅拌溶解后,冰浴冷却,加入化合物10a(20.0g,117.5mmol),加完冰浴搅拌3小时,升至室温静止过夜。冰浴冷却反应液,浓盐酸调节体系pH值至2,冰浴继续搅拌45分钟,过滤,真空干燥,得到白色固体化合物10b(14g,产率84%),未经纯化直接用于下步反应。
第二步:2,2-二甲基-5,6,7,8-四氢-4H-苯唑[d][1,3]二恶烷-4-酮(10c)
2,2-dimethyl-5,6,7,8-tetrahydro-4H-benzo[d][1,3]dioxin-4-one
向反应瓶中加入化合物10b(8.1g,57.1mmol),醋酐(11.7g,11.5mmol)和丙酮(16mL),搅拌溶解后,降温至-5℃,滴加浓硫酸(1.3g,12.8mmol),滴完升至0℃反应4小时。将反应液倾入10%碳酸钠水溶液(100mL)中,加入乙酸乙酯萃取(80mL×3)合并有机相,无水硫酸钠干燥,过滤,减压浓缩至干,得到棕色固体化合物10c(8g,产率77%)。
MS m/z(ESI):183.3[M+1]。
第三步:N-(2,6-二甲基苯基)-2-氧代环己烷碳酰胺(10d)
N-(2,6-dimethylphenyl)-2-oxocyclohexanecarboxamide
向反应瓶中加入化合物10c(0.2g,1.1mmol),2,6-二甲基苯胺(0.4g,3.3mmol),178℃微波反应20分钟。向反应液中加入乙酸乙酯(50mL),有机相以1mol/L盐酸水溶液洗涤(20mL×2),有机相无水硫酸钠干燥,过滤,减压浓缩,硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=10:1-7:1)得到黄色固体化合物10d(0.18g,产率70%)。
MS m/z(ESI):246.3[M+1];
1H NMR(400MHz,CDCl3)δ8.61(s,1H),7.13–7.05(m,3H),3.41(dd,1H),2.64–2.48(m,2H),2.33(t,2H),2.24(d,6H),2.12–2.01(m,3H),1.82(d,1H)。
第四步:顺-N-(2,6-二甲基苯基)-2-(吡咯烷-1-基)环己烷碳酰胺(10e)
Cis-N-(2,6-dimethylphenyl)-2-(pyrrolidin-1-yl)cyclohexanecarboxamide
向反应瓶中分别加入化合物10d(0.57g,2.3mmol),四氢吡咯(0.41g,5.8mmol),醋酸(0.42g,7.0mmol)和二氯甲烷(10ml),室温下加入三乙酰氧基硼氢化钠(2.0g,9.3mmol),加完室温搅拌20小时。向反应液中加入二氯甲烷和水各(30ml),搅拌分液,水相以二氯甲烷萃取(20mL×2),合并有机相,无水硫酸钠干燥,过滤,减压浓缩,硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=10:1-7:1)得到白色固体化合物10e(0.46g,产率66%)。
MS m/z(ESI):301.3[M+1];
1H NMR(400MHz,CDCl3)δ11.19(s,1H),7.05(s,3H),2.92(s,1H),2.76–2.62(m,4H),2.40(dt,1H),2.23(d,6H),1.98(d,1H),1.84–1.71(m,6H),1.59(t,2H),1.42–1.26(m,3H)。
手性制备液相分离纯化得化合物10e-1(0.19g,异构体1,t=3.58min)和化合物10e-2(0.19g,异构体2,t=5.41min)。
制备条件如下:
设备:Sepiatec prep SFC 100preparative SFC(SFC-12);
柱:ChiralPak IC,250×30mm I.D.,5μm;
流动相:A为CO2,B为乙醇;
梯度:B 40%;
流速:60mL/min;
柱温:38℃;
波长:220nm。
第五步:顺-N-(2,6-二甲基苯基)-2-(吡咯烷-1-基)环己烷碳酰胺盐酸盐(化合物10-1和化合物10-2)
Cis-N-(2,6-dimethylphenyl)-2-(pyrrolidin-1-yl)cyclohexanecarboxamidehydrochloride
向反应瓶中分别加入化合物10e-1(0.19g,0.64mmol,异构体1)和二氯甲烷(2mL),冰浴冷却,滴加盐酸乙酸乙酯溶液(2mL),加完升至室温搅拌30分钟,过滤,滤饼以乙酸乙酯洗涤(2mL×1),得到白色固体化合物10-1(0.13g,产率60%)。
MS m/z(ESI):301.2[M+1];
1H NMR(400MHz,MeOD)δ7.17–7.11(m,3H),3.86–3.69(m,1H),3.58(t,1H),3.51(dd,1H),3.38–3.29(m,1H),3.17–3.10(m,1H),2.57(d,1H),2.27(s,6H),2.22–1.94(m,7H),1.90–1.72(m,2H),1.52(t,2H)。
参照化合物10e-1的方法合成化合物10-2。
MS m/z(ESI):301.2[M+1];
1H NMR(400MHz,MeOD)δ7.17–7.11(m,3H),3.86–3.69(m,1H),3.58(t,1H),3.51(dd,1H),3.38–3.29(m,1H),3.17–3.10(m,1H),2.57(d,1H),2.27(s,6H),2.22–1.94(m,7H),1.90–1.72(m,2H),1.52(t,2H)。
实施例11
(S)-N-(4-(二氟甲氧基)-2,6-二甲基苯基)-1-丙基哌-2-甲酰胺盐酸盐(化合物11)
(S)-N-(4-(difluoromethoxy)-2,6-dimethylphenyl)-1-propylpiperidine-2-carboxamide hydrochloride
第一步:5-(二氟甲氧基)-1,3-二甲基-2-硝基苯(11c)
5-(difluoromethoxy)-1,3-dimethyl-2-nitrobenzene
室温下,将3,5-二甲基-4-硝基苯酚(3.34g,20mmol)与氢氧化钾(22.4g,400mmol)溶于乙腈(80mL)和水(80mL)中,降温到0℃,将溴氟甲基膦酸二乙酯(10.68g,40mmol)滴加到反应中,升至室温搅拌反应2小时。反应液用乙酸乙酯(50mL×3)萃取,合并有机相用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,过滤,滤液蒸干,粗品用柱层析分离纯化(石油醚/乙酸乙酯(v/v)=20:1~10:1)得到化合物11c(3.7g,产率90%)。
1H NMR(400MHz,CDCl3)δ6.88(s,2H),6.52(t,1H),2.33(s,6H)。
第二步:4-(二氟甲氧基)-2,6-二甲基苯胺(11d)
4-(difluoromethoxy)-2,6-dimethylaniline
将化合物11c(3.7g,17mmol)溶于乙醇(40mL)中,加入钯碳(370mg,wt=10%),将反应体系抽真空后通入氢气置换三次,在氢气球下,室温反应8小时。垫硅藻土抽滤,过滤,滤饼用乙醇(20mL×2)洗涤,将滤液浓缩得到白色固体化合物11d(3g,产率94%)。
Ms m/z(ESI):188.2[M-H+]。
第三步:(S)-N-(4-(二氟甲氧基)-2,6-二甲基苯基)-1-丙基哌啶-2-甲酰胺(11e)
(S)-N-(4-(difluoromethoxy)-2,6-dimethylphenyl)-1-propylpiperidine-2-carboxamide
将中间体1(0.457g,2.67mmol)溶于二氯甲烷(20mL),加入三乙胺(0.405g,4.0mmol),降温至0℃,搅拌下滴加氯甲酸异丁酯(0.436g,3.2mmol),加完冰浴下搅拌1小时,再将化合物11d(0.5g,2.67mmol)加到反应中,然后回流反应10小时。向反应液加入水(30mL)分液,水相用二氯甲烷(10mL×2)萃取,合并有机相用饱和食盐水(30mL)洗涤,用无水硫酸钠干燥,过滤,滤液蒸干,粗品用柱层析分离纯化(石油醚/乙酸乙酯(v/v)=10:1~1:2)得到黄色固体化合物11e(0.22g,产率24%)。
Ms m/z(ESI):341.3[M+H+]。
第四步:(S)-N-(4-(二氟甲氧基)-2,6-二甲基苯基)-1-丙基哌-2-甲酰胺盐酸盐(化合物11)
(S)-N-(4-(difluoromethoxy)-2,6-dimethylphenyl)-1-propylpiperidine-2-carboxamide hydrochloride
将化合物11e(0.2g,0.588mmol)溶于乙酸乙酯(4mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0M),室温下搅拌反应1小时。将反应液过滤,滤饼用正己烷洗涤,干燥得到淡黄色固体化合物11(0.2g,产率90%)。
Ms m/z(ESI):341.3[M+H+];
1H NMR(400MHz,MeOD)δ7.02-6.64(m,3H),4.15-4.11(m,1H),3.71(d,1H),3.24-3.11(m,3H),2.43(d,1H),2.25(s,6H),2.04-1.98(m,3H),1.94-1.72(m,4H),1.03(t,3H)。
实施例12
3-(哌啶-1-基)-4,5-二氢-1H-苯并[b]氮杂-2(3H)-酮盐酸盐(化合物12)
3-(piperidin-1-yl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-onehydrochloride
第一步:3-(哌啶-1-基)-4,5-二氢-1H-苯并[b]氮杂-2(3H)-酮(12b)
3-(piperidin-1-yl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one
室温下,将3-溴-4,5-二氢-1H-苯并[b]氮杂-2(3H)-酮(1g,4.16mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入碳酸钾(1.14g,8.32mmol)及哌啶(0.53g,6.24mmol),加毕于80℃下反应2小时。将反应液冷却,加冰水(40mL),有白色固体析出,过滤,滤饼用水(20mL)、石油醚(20mL)洗涤,干燥,得到白色固体化合物12b(0.5g,产率50%)。
Ms m/z(ESI):245.2[M+H+]。
第二步:3-(哌啶-1-基)-4,5-二氢-1H-苯并[b]氮杂-2(3H)-酮盐酸盐(化合物12)
3-(piperidin-1-yl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-onehydrochloride
室温下,将化合物12b(0.4g,1.63mmol)溶于乙酸乙酯(25mL),加入氯化氢的乙酸乙酯溶液(4mL,4.0mol/L),搅拌反应0.5小时。将反应液过滤,正己烷洗涤,干燥后得到白色固体化合物12(0.39g,产率85%)。
Ms m/z(ESI):245.2[M+H+];
1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.92(s,1H),7.37-7.30(m,2H),7.22-7.18(t,1H),7.07(d,1H),3.89(m,1H),3.44-3.41(m,2H),3.02-2.92(m,2H),2.85-2.72(m,2H),2.61-2.55(m,1H),2.38-2.31(m,1H),1.92-1.83(m,1H),1.76-1.66(m,4H),1.34-1.24(m,1H)。
实施例13
(S)-N-(2,6-二甲基-4-(2,2,2-三氟乙氧基)苯基)-1-丙基哌啶-2-甲酰胺盐酸盐(化合物13)
(S)-N-(2,6-dimethyl-4-(2,2,2-trifluoroethoxy)phenyl)-1-propylpiperidine-2-carboxami de hydrochloride
第一步:1,3-二甲基-2-硝基-5-(2,2,2-三氟乙氧基)苯(13b)
1,3-dimethyl-2-nitro-5-(2,2,2-trifluoroethoxy)benzene
室温下,将3,5-二甲基-4-硝基苯酚(11a)(2g,12mmol)溶于N,N-二甲基甲酰胺(30mL)中,将2,2,2-三氟乙基三氟甲磺酸酯(13a)(3.34g,14.4mmol)与碳酸铯(35.09g,15.6mmol)加到反应中,升温80℃搅拌反应2小时。将反应冷却,向反应液加入水(30mL),搅拌10分钟,有白色固体析出,过滤,滤饼依次用水(30mL)洗涤及石油醚(30mL)洗涤,干燥后得到白色固体化合物13b(2.53g,产率85%)。
1H NMR(400MHz,CDCl3)δ6.67(s,2H),4.36(q,2H),2.32(s,6H)。
第二步:2,6-二甲基-4-(2,2,2-三氟乙氧基)苯胺(13c)
2,6-dimethyl-4-(2,2,2-trifluoroethoxy)aniline
将化合物13b(2g,8mmol)溶于乙醇(30mL)中,加入钯碳(200mg,wt=10%)),将反应体系抽真空后通入氢气置换三次,在氢气球下,室温反应16小时。垫硅藻土抽滤,过滤,滤饼用乙醇(10mL×2)洗涤。将滤液浓缩得到白色固体化合物13c(1.6g,产率91%)。
Ms m/z(ESI):220.2[M-H+]。
第三步:(S)-N-(2,6-二甲基-4-(2,2,2-三氟乙氧基)苯基)-1-丙基哌啶-2-甲酰胺(13d)
(S)-N-(2,6-dimethyl-4-(2,2,2-trifluoroethoxy)phenyl)-1-propylpiperidine-2-carboxamide
将中间体1(0.39g,2.28mmol)溶于二氯甲烷(20mL),加入三乙胺(0.345g,3.42mmol),冷却至0℃,搅拌下滴加氯甲酸异丁酯(0.372g,2.73mmol),加毕于冰浴下搅拌1小时,再将化合物13c(0.5g,2.28mmol)加到反应中,加毕于室温下搅拌6小时。向反应液加入水(30mL)分液,水相用二氯甲烷(10mL×2)萃取,合并有机相用饱和食盐水(30mL)洗涤,用无水硫酸钠干燥,过滤,滤液蒸干,粗品用柱层析分离纯化(石油醚/乙酸乙酯(v/v)=10:1~1:1)得到白色固体产品化合物13d(0.45g,产率53%)。
Ms m/z(ESI):373.3[M+H+]。
第四步:(S)-N-(2,6-二甲基-4-(2,2,2-三氟乙氧基)苯基)-1-丙基哌啶-2-甲酰胺盐酸盐(化合物13)
(S)-N-(2,6-dimethyl-4-(2,2,2-trifluoroethoxy)phenyl)-1-propylpiperidine-2-carboxami de hydrochloride
将化合物13d(0.4g,1.07mmol)溶于乙酸乙酯(10mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0mol/L),室温下搅拌反应1小时。将反应液直接旋干,得到白色固体化合物13(0.43g,产率98%)。
Ms m/z(ESI):373.3[M+H+];
1H NMR(400MHz,MeOD)δ6.82(s,2H),4.53(q,2H),4.16-4.11(m,1H),3.70(d,1H),3.23-3.01(m,3H),2.42(d,1H),2.23(s,6H),2.03-1.94(m,2H),1.86-1.75(m,4H),1.40-1.26(m,1H),1.03(t,3H)。
实施例14
2,6-二甲基-4-((1-丙基哌啶-2-基)甲氧基)吡啶盐酸盐(化合物14)
2,6-dimethyl-4-((1-propylpiperidin-2-yl)methoxy)pyridinehydrochloride
第一步:哌啶-2-基甲醇盐酸盐(14b)
piperidin-2-ylmethanol hydrochloride
将叔丁基-2-(羟甲基)哌啶-1-羧酸叔丁酯(14a)(4g,18.6mmol)溶于乙酸乙酯(20mL),加入氯化氢的乙酸乙酯溶液(20mL,4.0M),在40℃下搅拌反应4小时。将反应液直接旋干,得到白色固体化合物14b(2.8g)。
Ms m/z(ESI):116.3[M+H+]。
第二步:2,6-二甲基-4-(哌啶-2-基甲氧基)吡啶(14c)
2,6-dimethyl-4-(piperidin-2-ylmethoxy)pyridine
在冰浴下,将化合物14b(1g,6.6mmol)溶于N,N-二甲基甲酰胺(20mL)中,降温0℃,将氢化钠(0.506g,13.2mmol)加到反应中,搅拌反应20分钟,再将4-氯-2,6-二甲基吡啶(0.93g,16.6mmol)加到反应中,升至120℃搅拌反应6小时。将反应冷却,向反应液加水(80mL),用乙酸乙酯(30mL×4)萃取,合并有机相用无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析纯化(二氯甲烷/甲醇(v/v)=50:1~10:1),得到黄色油状液体化合物14c(1g,产率70%)。
Ms m/z(ESI):221.3[M+H+];
1H NMR(400MHz,CDCl3)δ6.50(s,2H),3.94-3.82(m,2H),3.00-2.92(m,2H),2.65(m,2H),2.46(s,6H),1.86(d,1H),1.68-1.63(m,2H),1.52-1.26(m,3H)。
第三步:2,6-二甲基-4-((1-丙基哌啶-2-基)甲氧基)吡啶(14d)
2,6-dimethyl-4-((1-propylpiperidin-2-yl)methoxy)pyridine
室温下,将化合物14c(0.8g,3.63mmol)溶于N,N-二甲基甲酰胺(10mL)中,再加入碳酸钾(0.751g,5.44mmol)及溴代正丙烷(0.536g,4.35mmol),加毕于80℃下反应4小时。向反应液中加水(50mL),用乙酸乙酯(30mL×3)萃取,合并有机相,用饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析纯化(二氯甲烷/甲醇(v/v)=50:1~10:1),得到黄色油状液体化合物14d(0.5g,产率:52%)。
Ms m/z(ESI):263.2[M+H+];
1H NMR(400MHz,CDCl3)δ6.50(s,2H),4.12-3.95(m,2H),2.94(d,1H),2.72-2.63(m,2H),2.47-2.31(m,8H),1.76-1.51(m,7H),1.39-1.26(m,1H),0.87(t,3H)。
第四步:2,6-二甲基-4-((1-丙基哌啶-2-基)甲氧基)吡啶盐酸盐(化合物14)
2,6-dimethyl-4-((1-propylpiperidin-2-yl)methoxy)pyridinehydrochloride
将化合物14d(0.4g,1.52mmol)溶于乙酸乙酯(5mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0M),室温下搅拌反应1小时。将反应液直接旋干,得到黄色油状液体化合物14(0.45g)。
Ms m/z(ESI):263.2[M+H+];
1H NMR(400MHz,MeOD)δ7.36(s,2H),4.82-4.70(m,1H),4.63-4.59(m,1H),3.62-3.58(m,2H),3.27-3.13(m,3H),2.68(s,6H),2.07-1.70(m,8H),1.07-1.02(m,3H)。
实施例15
2-((2,6-二甲基苯基)氨基甲酰基)-1-丙基环己亚胺盐酸盐(化合物15)
2-((2,6-dimethylphenyl)carbamoyl)-1-propylazepan-1-ium chloride
第一步:1-丙基环己亚胺-2-羧酸(15b)
1-propylazepane-2-carboxylic acid
将15a(1.0g,7.0mmol),甲醇(10mL),丙醛(2.5mL),Pd/c(0.5g,10%)加入氢化反应瓶中,氢气置换三次,加氢气(35PSI)摇摆氢化32小时。液相色谱-质谱联用仪检测反应毕,用硅藻土过滤,滤饼用无水甲醇(10mL×3)洗涤,合并有机相并蒸干,得到灰白色固体15b,直接用于下一步。
Ms m/z(ESI):186.2[M+H+]。
第二步:N-(2,6-二甲基苯基)-1-丙基环己亚胺-2-甲酰胺(15c)
N-(2,6-dimethylphenyl)-1-propylazepane-2-carboxamide
向反应瓶中加入化合物15b(1.3g,6.98mmol)和二氯甲烷(15mL),搅拌溶解后,冰浴冷却,依次加入三乙胺(1.063mL,7.68mmol)、氯甲酸异丁酯(0.996g,7.68mmol),冰浴下反应1小时后,加入化合物1a(1.058g,8.73mmol),升至室温搅拌反应6小时。加入水(10mL),二氯甲烷(10mL),搅拌分液,水层以二氯甲烷萃取(10mL×3),合并有机相,无水硫酸钠干燥,过滤,将滤液减压浓缩,硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=5:1-1:1)得到白色固体15c(0.8g,产率40%)。
将白色固体15c手性制备液相分离纯化得一对对映异构体,化合物15c-1(0.36g,peak 1)和化合物15c-2(0.32g,peak 2)。手性制备分离方法:仪器:Thar 200preparativeSFC(SFC-7);色谱柱:Whelk O1(S,S),300×50mm I.D.,10μm;流动相:Afor CO2and B forEthanol(0.1%NH3H2O);梯度:B 40%;流速:200mL/min;背压:100bar;柱温:38℃;波长:220nm;周期:~4.5min。
MS m/z(ESI):289.3[M+H]。
第三步:2-((2,6-二甲基苯基)氨基甲酰基)-1-丙基环己亚胺盐酸盐(对应异构体化合物15-1和化合物15-2)
2-((2,6-dimethylphenyl)carbamoyl)-1-propylazepan-1-ium chloride
向反应瓶中分别加入化合物15c-1(0.203g,0.7mmol,peak 1),和乙酸乙酯(2mL),冰浴冷却,滴加盐酸乙酸乙酯溶液(1mL),加完升至室温搅拌30分钟,减压除去大部分溶剂,过滤烘干得到白色固体化合物15-1(0.18g,产率78.6%)。
MS m/z(ESI):289.3[M+H+];
1H NMR(400MHz,MeOD)δ7.25–7.05(m,3H),4.46(t,J=4.8Hz,1H),3.63–3.53(m,1H),3.48(dd,J=13.3,7.8Hz,1H),3.28–3.09(m,2H),2.42(dd,J=10.4,5.0Hz,2H),2.25(s,6H),2.05(dd,J=16.9,10.8Hz,1H),2.02–1.77(m,5H),1.77–1.63(m,2H),1.04(t,J=7.4Hz,3H)。
参照化合物15-1的合成方法制备得化合物15-2。
MS m/z(ESI):289.3[M+H];
1H NMR(400MHz,MeOD)δ7.25–7.05(m,3H),4.46(t,J=4.8Hz,1H),3.63–3.53(m,1H),3.48(dd,J=13.3,7.8Hz,1H),3.28–3.09(m,2H),2.42(dd,J=10.4,5.0Hz,2H),2.25(s,6H),2.05(dd,J=16.9,10.8Hz,1H),2.02–1.77(m,5H),1.77–1.63(m,2H),1.04(t,J=7.4Hz,3H)。
实施例16
(2S)-2-((2,6-二甲基苯基)氨甲酰基)-1-(2-(((2-甲氧基-4-(((E)-8-甲基壬基-6-烯酰胺)甲基)苯氧基)羰基)氧)乙基)-1-丙基哌啶-1-鎓溴化物(化合物16-1)
(2S)-2-((2,6-dimethylphenyl)carbamoyl)-1-(2-(((2-methoxy-4-(((E)-8-methylnon-6-enamido)methyl)phenoxy)carbonyl)oxy)ethyl)-1-propylpiperidin-1-ium bromide
(2S)-2-((2,6-二甲基苯基)氨甲酰基)-1-(2-(((2-甲氧基-4-((8-甲基壬酰胺)甲基)苯氧基)羰基)氧)乙基)-1-丙基哌啶-1-鎓溴化物(化合物16-2)
(2S)-2-((2,6-dimethylphenyl)carbamoyl)-1-(2-(((2-methoxy-4-((8-methylnonanamido)methyl)phenoxy)carbonyl)oxy)ethyl)-1-propylpiperidin-1-iumbromide
第一步:(2S)-2-(2,6-二甲基苯基)-1-(2-乙氧基-2-氧代乙基)-1-1-丙基哌啶-1-鎓溴化物(16b)
(2S)-2-(2,6-dimethylphenylcarbamoyl)-1-(2-ethoxy-2-oxoethyl)-1-propylpiperidinium bromide
将(S)-N-(2,6-二甲基苯基)-1-丙基哌啶-2-甲酰胺(5g,18.2mmol)溶于乙腈(50mL),加入溴乙酸乙酯(15.2g,91.1mmol),在80℃下搅拌反应12小时。将反应液直接旋干;加入甲基叔丁基醚(50mL)搅拌,倒掉上清液,再重复三次,干燥得到黄色固体化合物16b(7g,产率87.5%)。
Ms m/z(ESI):361.2[M+H+]。
第二步:(2S)-2-((2,6-二甲基苯基)氨基甲酰基)-1-(2-羟乙基)-1-丙基哌啶-1-鎓溴化物(16c)
(2S)-2-(2,6-dimethylphenylcarbamoyl)-1-(2-hydroxyethyl)-1-propylpiperidinium bromide
将化合物16b(5.5g,12.47mmol)和氯化锂(1.06g,24.94mmol)溶于甲醇(80mL)中,降温到0℃,将硼氢化钠(1.18g,31.17mmol)分三批加到反应中,升至50℃搅拌反应8小时。将反应液过滤,滤液减压浓缩后,粗品用柱层析纯化(二氯甲烷/甲醇(v/v)=100:1~10:1),得到白色固体化合物16c(2.2g,产率44%)。
Ms m/z(ESI):319.3[M+H+];
1H NMR(400MHz,MeOD)δ7.19-7.12(m,3H),4.71-4.56(m,1H),4.10-4.02(m,3H),3.87-3.65(m,4H),3.53(m,1H),2.54-2.52(m,1H),2.37-2.25(m,7H),1.97-1.79(m,6H),1.13-0.96(m,3H)。
第三步:(E)-2-甲氧基-4-((8-甲基壬基-6-烯酰胺)甲基)苯基-4-硝基苯基碳酸酯(16d-1)
(E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 4-nitrophenylcarbonate
2-甲氧基-4-((8-甲基壬酰胺)甲基)苯基(4-硝基苯基)碳酸酯(16d-2)
2-methoxy-4-((8-methylnonanamido)methyl)phenyl(4-nitrophenyl)carbonate
室温下,将天然辣椒素(1.52g,5mmol,含有质量比1:1的辣椒素和氢化辣椒素)溶于二氯甲烷(20mL)中,再加入三乙胺(1.01g,10mmol)及4-硝基苯基碳酰氯(1.0g,5mmol),加完于室温下反应4小时。向反应液中加二氯甲烷(50mL),有机相用饱和食盐水溶液(30mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,柱层析纯化(石油醚/乙酸乙酯(v/v)=10:1~1:1),得到黄色固体化合物16d-1和16d-2(共2g,产率85%)。
Ms m/z(ESI):471.3[M+H+]。
第四步:(2S)-2-((2,6-二甲基苯基)氨甲酰基)-1-(2-(((2-甲氧基-4-(((E)-8-甲基壬基-6-烯酰胺)甲基)苯氧基)羰基)氧)乙基)-1-丙基哌啶-1-鎓溴化物(化合物16-1)
(2S)-2-((2,6-dimethylphenyl)carbamoyl)-1-(2-(((2-methoxy-4-(((E)-8-methylnon-6-enamido)methyl)phenoxy)carbonyl)oxy)ethyl)-1-propylpiperidin-1-ium bromide
(2S)-2-((2,6-二甲基苯基)氨甲酰基)-1-(2-(((2-甲氧基-4-((8-甲基壬酰胺)甲基)苯氧基)羰基)氧)乙基)-1-丙基哌啶-1-鎓溴化物(化合物16-2)
(2S)-2-((2,6-dimethylphenyl)carbamoyl)-1-(2-(((2-methoxy-4-((8-methylnonanamido)methyl)phenoxy)carbonyl)oxy)ethyl)-1-propylpiperidin-1-iumbromide
将化合物16d-1和16d-2混合物(0.8g,2.0mmol)溶于丙酮(30mL),再将吡啶(0.316g,4.0mmol)、4-二甲氨基吡啶(0.048g,0.4mmol)、(E)-2-甲氧基-4-((8-甲基壬基-6-烯酰胺)甲基)苯基-4-硝基苯基碳酸酯(1.41g,3.0mmol)依次加入反应中,氮气保护下室温反应16小时。将反应液直接旋干,粗品用柱层析纯化(二氯甲烷/甲醇(v/v)=100:1~20:1)后,再用制备高效液相色谱(乙腈/0.1%乙酸铵))纯化得到白色固体化合物16-1(保留时间6.157min,0.2g,产率13.7%)和白色固体产品化合物16-2(6.364min,0.2g,产率15%)。
化合物16-1:
Ms m/z(ESI):650.5[M+H+];
1H NMR(400MHz,MeOD)δ7.20-7.06(m,5H),6.92-6.89(m,1H),5.43-5.32(m,2H),4.79-4.72(m,2H),4.50-4.02(m,5H),3.84(s,3H),3.34-3.32(m,3H),2.64-2.34(m,2H),2.31-2.17(m,9H),1.95-1.62(m,10H),1.45-1.29(m,2H),1.10(m,3H),1.02-0.82(m,6H)。
化合物16-2:
Ms m/z(ESI):652.5[M+H+];
1H NMR(400MHz,MeOD)δ7.20-7.06(m,5H),6.91-6.89(dd,1H),4.77-4.72(m,2H),4.50-4.26(m,5H),4.10-3.97(m,1H),3.86-3.84(m,4H),3.69-3.57(m,2H),2.59-2.39(m,2H),2.28-2.25(m,8H),2.05-1.85(m,7H),1.67-1.62(m,2H),1.55-1.48(m,1H),1.42-1.30(m,6H),1.21-1.04(m,4H),1.02-0.90(d,6H)。
实施例17
(2S)-N-(2,6-二甲基苯基)-1-(4-羟基环己基)吡咯烷-2-甲酰胺盐酸盐(化合物17)
(2S)-N-(2,6-dimethylphenyl)-1-(4-hydroxycyclohexyl)pyrrolidine-2-carboxamide hydrochloride
第一步:(2S)-2-[(2,6-二甲基苯基)氨基甲酰基]吡咯烷-1-羧酸叔丁酯(17a)
tert-butyl(2S)-2-[(2,6-dimethylphenyl)carbamoyl]pyrrolidine-1-carboxylate
向反应瓶中加入N-叔丁氧羰基-L-脯氨酸(3.45g,30mmol)、2,6-二甲基苯胺(3.64g,30mmol)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(11.5g,30.3mmol)、N,N-二异丙基乙基胺(11.6g,90,mmol)和N,N-二甲基甲酰胺(80mL),室温反应16小时,体系加入乙酸乙酯300mL,有机层用饱和氯化钠水溶液(300mL×2)洗涤,无水硫酸钠干燥,减压浓缩,残留物残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)=6:1),得到黄色固体化合物17a(4.38g,46%)。
MS m/z(ESI):317.2[M-H+];
1H NMR(400MHz,CDCl3)δ8.29(s,1H),7.18–6.98(m,3H),4.51(s,1H),3.50(s,2H),2.46(s,1H),2.21(s,6H),2.03(t,3H),1.48(d,9H)。
第二步:(2S)-N-(2,6-二甲基苯基)吡咯烷-2-甲酰胺盐酸盐(17b)
(2S)-N-(2,6-dimethylphenyl)pyrrolidine-2-carboxamide hydrochloride
向反应瓶中加入化合物17a(4.52g,10mmol),室温下滴加4mol/L的盐酸乙酸乙酯溶液(36mL),室温反应1小时,过滤,将滤饼用乙酸乙酯(15mL×2)洗涤,得到的白色固状的化合物17b(3.0g,产率83%)。
第三步:(2S)-N-(2,6-二甲基苯基)-1-(4-羟基环己基)吡咯烷-2-甲酰胺(17c)
(2S)-N-(2,6-dimethylphenyl)-1-(4-hydroxycyclohexyl)pyrrolidine-2-carboxamide
向反应瓶中依次加入化合物17b(1.02g,4mmol)、4-羟基环己酮(0.913g,8mmol)和1,2-二氯乙烷(10mL),室温反应60分钟,分批多次加入三乙酰氧基硼氢化钠(2.54g,12mmol),加完室温反应6小时。将体系抽滤,减压浓缩,残留物用硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)=30:1),得到白色固体化合物17c(1.3g)。
MS m/z(ESI):317.3[M+H+]。
第四步:(2S)-N-(2,6-二甲基苯基)-1-(4-羟基环己基)吡咯烷-2-甲酰胺盐酸盐(化合物17)
(2S)-N-(2,6-dimethylphenyl)-1-(4-hydroxycyclohexyl)pyrrolidine-2-carboxamide hydrochloride
向反应瓶中加入化合物17c(0.32g,1.0mmol),室温下滴加4mol/L的盐酸乙酸乙酯溶液(5mL),室温反应1小时,过滤,将滤饼用乙酸乙酯(3mL×2)洗涤,得到白色固化合物17(0.30g,产率95%)。
MS m/z(ESI):317.3[M+H+];
1H NMR(400MHz,D2O)δ7.29–7.11(m,3H),4.64(dt,1H),3.87–3.73(m,1H),3.63(tt,1H),3.35(dd,2H),2.77–2.61(m,1H),2.31(dt,1H),2.26–1.72(m,13H),1.71–1.49(m,2H),1.49–1.23(m,2H)。
实施例18
(5S,8aR)-N-(2,6-二甲基苯基)八氢吲嗪-5-甲酰胺盐酸盐(化合物18)
(5S,8aR)-N-(2,6-dimethylphenyl)octahydroindolizine-5-carboxamidehydrochloride
第一步:(S)-二乙基2-(1H-吡咯-1-基)戊二酸酯(18c)
(S)-diethyl 2-(1H-pyrrol-1-yl)pentanedioate
(2S)-2-氨基戊二酸二乙酯(42.57g,209.5mmol),2,5-二甲氧基四氢呋喃(27.68g,209.4mmol),醋酸钠(1.72g,21.0mmol),200mL醋酸加入到反应瓶中,80℃反应2小时,原料消失,停止反应;硅藻土过滤,浓缩,二氯甲烷(100mL)溶解,同体积10%盐酸洗涤,干燥,浓缩,柱层析(石油醚:乙酸乙酯(v:v)=50:1),得化合物18c(30.1g,产率:56.7%)。
1H NMR(400MHz,CDCl3):δ6.72(t,2H),6.18(t,2H),4.72-4.68(m,1H),4.20-4.09(m,4H),2.48-2.39(m,1H),2.27-2.11(m,3H),1.27-1.22(m,6H)。
第二步:(S)-乙基8-氧-5,6,7,8-四氢吲嗪-5-羧酸酯(18d)
(S)-ethyl 8-oxo-5,6,7,8-tetrahydroindolizine-5-carboxylate
氮气保护下,将三溴化硼的二氯甲烷(60mL)溶液滴加到化合物18c的二氯甲烷(60mL)溶液中,室温反应1小时,停止反应,加水10mL,然后饱和碳酸氢钠溶液中和,分液,水层用二氯甲烷(100mL×1)萃取,无水硫酸钠干燥,浓缩,柱层析(石油醚:乙酸乙酯(v:v)=40:1),得化合物18d(10g,产率51%);
1H NMR(400MHz,CDCl3):δ7.05(dd,1H),6.88(dd,lH),6.30(dd,lH),4.91-4.89(m,lH),4.25-4.19(m,2H),2.61-2.51(m,4H),1.25(t,3H)。
第三步:(5S)-乙基八氢吲嗪-5-羧酸酯(18e)
(5S)-ethyl octahydroindolizine-5-carboxylate
将化合物18d(0.22g,0.99mmol)溶于醋酸(2mL),加入0.22g 10%钯碳,氢气置换,20个大气压下反应48小时,停止反应。过滤,减压除去醋酸,柱层析(石油醚:乙酸乙酯(v:v)=50:1),得化合物18e(0.05g,产率20%)。
1H NMR(400MHz,CDCl3):δ4.25-4.17(m,2H),3.25(t,1H),2.76(d,1H),2.04-1.92(m,1H),1.91-1.76(m,5H),1.66-1.50(m,3H),1.50-1.27(m,8H)。
第四步:(5S)-八氢吲嗪-5-羧酸(18f)
(5S)-octahydroindolizine-5-carboxylic acid
将化合物18e(1.2g,6.1mmol)溶于3mL乙醇,加入氢氧化钠(0.16g,4.13mmol)的水溶液(1mL),室温反应2小时,停止反应。反应液加入3mol/L盐酸水溶液调pH至2-3,浓缩除去乙醇,用氯仿等体积萃取三次,合并有机相,无水硫酸钠干燥,浓缩,柱层析(石油醚:乙酸乙酯(v:v)=5:1),得化合物18f(0.87g,产率85%)。
1H NMR(400MHz,CD3OD):δ4.02-3.93(m,2H),3.25-3.18(m,1H),3.08-3.00(m,1H),2.39-2.26(m,2H),2.15-2.02(m,4H),1.79-1.53(m,4H)。
第五步:(5S,8aR)-N-(2,6-二甲基苯基)八氢吲嗪-5-甲酰胺盐酸盐(化合物18)
(5S,8aR)-N-(2,6-dimethylphenyl)octahydroindolizine-5-carboxamidehydrochloride
将化合物18f(0.1g,0.6mmol),2,6-二甲基苯胺(0.086g,0.71mmol),碳二亚胺(EDCI)(0.12g,0.63mmol),二氯甲烷(2mL)加入到反应瓶中,室温搅拌3小时,停止反应。减压蒸馏除去二氯甲烷,加入5mL水和1mL盐酸(3mol/L),乙酸乙酯萃取(5mL×3),有机相用水洗(20mL×2),饱和碳酸氢钠洗(20mL×1),无水硫酸钠干燥,过滤,减压浓缩后得白色固体。将该固体溶于2mL乙酸乙酯,滴加3mol/L盐酸至无白色固体析出,过滤,乙酸乙酯洗涤,干燥,得产物化合物18(0.07g,产率42%)。
1H NMR(400MHz,CD3OD):δ7.16-7.10(m,3H),4.16(d,1H,J=12.0Hz),3.86-3.81(m,1H),3.37-3.33(m,1H),3.16-3.11(m,1H),2.48-2.40(m,1H),2.30-2.25(m,1H),2.23(s,6H),2.15-1.61(m,8H)。
实施例19
(S)-N-(4-氟-2,6-二甲基苯基)-1-丙基哌啶-2-甲酰胺盐酸盐(化合物19)
(S)-N-(4-fluoro-2,6-dimethylphenyl)-1-propylpiperidine-2-carboxamidehydrochloride
将(S)-哌啶-2-羧酸(40g,0.910mol),甲醇(500mL),丙醛(150mL)钯碳(20g,10%)加入氢化反应瓶中,H2置换三次,加H2(35PSI)摇摆氢化32小时。LC-MS检测反应毕,用硅藻土过滤,滤饼用无水甲醇(50mL×2)洗涤,合并有机相并蒸干,残留物用乙酸乙酯(100mL)搅拌洗涤,过滤,将滤饼烘干得到白色固体(S)-1-丙基哌啶-2-羧酸(19b)(44.5g,产率83.9%),直接用于下一步。Ms m/z(ESI):172.2[M+H+]。
将(S)-N-丙基-2-哌啶甲酸(19b)(1.50g,10.5mmol)溶于二氯甲烷(20mL),氮气保护,冷却至0℃,依次加入三乙胺(1.2mL,8.77mmol)和氯甲酸异丁酯(1.20g,8.77mmol),搅拌1小时后,加入4-氟-2,6-二甲基苯胺(1.46g,8.77mmol),自然升至室温,继续搅拌10小时。反应液中加水(20mL),分离有机相,水相用二氯甲烷(20mL×2)萃取,合并有机相并用无水硫酸钠干燥,减压浓缩后柱层析(石油醚:乙酸乙酯(v:v)=2:1),得白色固体(0.72g)。将上述固体溶于乙酸乙酯(10mL)中,滴加盐酸乙酸乙酯溶液(4mL,4mol/L),搅拌30分钟,过滤,固体用乙酸乙酯(10mL)洗涤,减压蒸出残留溶剂,得目标产物化合物19(0.42g,产率:14.59%,HPLC:97.18%)。
1HNMR(400MHz,MeOD):δ6.98(d,2H),δ4.36(s,1H),δ4.51(d,1H),δ3.09-2.93(m,3H),δ2.30(d,1H),δ2.17(s,6H),δ1.83-1.54(m,7H),δ0.90(t,3H)。
实施例20
(S)-N-(1,3-苯并噻唑-2-)1-丙基哌啶-2-甲酰胺盐酸盐(化合物20)
(S)-N-(1,3-benzothiazol-2-yl)-1-propyl-piperidin-1-ium-2-carboxamidechloride
将苯并[d]噻唑-2-氨基(0.60g,4.0mmol)溶于二氯甲烷(10mL),依次加入(S)-N-丙基-2-哌啶甲酸(0.82g,4.8mmol)和二甲基氨基吡啶(DMAP)(0.20g,1.6mmol),搅拌下滴加二环己基碳二亚胺(DCC)(2.48g,12.0mmol)的二氯甲烷(10mL)溶液,室温下搅拌14小时。过滤,减压浓缩滤液,柱层析(石油醚:乙酸乙酯(v/v)=4:1),得白色固体化合物20c(0.48g,产率:39.5%,LC-MS(m/z)=304.3,HPLC:90.8%)。
取上述固体(0.15g,0.5mmol)溶于乙酸乙酯(3mL)中,滴加盐酸乙酸乙酯溶液(1mL,4mol/L),产生白色沉淀,继续搅拌30分钟,过滤,乙酸乙酯(10mL)洗涤,减压除去溶剂,得目标产物化合物20(0.15g,产率:89.8%,HPLC:97.44%)。
1HNMR(400MHz,D2O):δ7.82(d,1H),δ7.66(d,1H),δ7.52-7.49(m,1H),δ7.41-7.37(m,1H),δ4.22(dd,1H),δ3.88(d,1H),δ3.25-3.11(m,3H),δ2.42-2.38(m,1H),δ2.11-1.73(m,7H),δ1.02(t,3H)。
实施例21
(S)-N-(4-乙氧基-2,6-二甲基苯基)-1-丙基哌啶-2-甲酰胺盐酸盐(化合物21)
(S)-N-(4-ethoxy-2,6-dimethylphenyl)-1-propylpiperidine-2-carboxamidehydrochloride
第一步:5-乙氧基-1,3-二甲基-2-硝基苯(21a)
5-ethoxy-1,3-dimethyl-2-nitrobenzene
室温下,将3,5-二甲基-4-硝基苯酚11a(10g,59.82mmol)溶于丙酮(50mL)中,将碳酸钾(10.34g,74.78mmol)与碘乙烷(11.66g,74.78mmol)加到反应中,升温60℃搅拌反应6小时,补加碘乙烷(4.67g,29.94mmol),65℃下反应4小时。将反应冷却,旋蒸掉其中溶剂,加入乙酸乙酯(100mL),水(100mL),搅拌10分钟,静置分层,水相用乙酸乙酯(100mL×2)萃取,合并,用饱和食盐水(100mL×2)洗涤,有机相加入无水硫酸钠干燥,过滤浓缩,得到黄色固体化合物21a(11.68g)。
Ms m/z(ESI):196.1[M-H+]。
第二步:4-乙氧基-2,6-二甲基苯胺(21b)
4-ethoxy-2,6-dimethylaniline
将化合物21a(11.68g,59.82mmol)溶于甲醇(100mL)中,加入钯碳(2.34g,wt=10%)),将反应体系抽真空后通入氢气置换三次,在氢气球下,室温反应7小时。垫硅藻土抽滤,过滤,滤饼用甲醇(10mL×2)洗涤。将滤液浓缩后经柱层析纯化(石油醚/乙酸乙酯(v/v)=20:1~5:1),得到紫褐色固体化合物21b(7.8g,产率79%)。
Ms m/z(ESI):166.2[M-H+]。
第三步:(S)-N-(4-乙氧基-2,6-二甲基苯基)-1-丙基哌啶-2-甲酰胺(21c)
(S)-N-(4-ethoxy-2,6-dimethylphenyl)-1-propylpiperidine-2-carboxamide
将中间体1(0.34g,2.0mmol)溶于二氯甲烷(5mL),加入三乙胺(0.22g,2.2mmol),冷却至0℃,搅拌下滴加氯甲酸异丁酯(0.30g,2.2mmol),加毕于冰浴下搅拌10分钟,再将化合物21b(0.41g,2.5mmol)加到反应中,加毕于室温下搅拌1小时。向反应液加入水(20mL),二氯甲烷(20mL)分液,有机相用水(20mL×2)洗涤,用无水硫酸钠干燥,过滤,滤液蒸干,粗品用柱层析分离纯化(石油醚/乙酸乙酯(v/v)=10:1~3:1)得到白色固体化合物21c(0.34g,产率54%)。
Ms m/z(ESI):319.3[M+H+]。
第四步:(S)-N-(4-乙氧基-2,6-二甲基苯基)-1-丙基哌啶-2-甲酰胺盐酸盐(化合物21)
(S)-N-(4-ethoxy-2,6-dimethylphenyl)-1-propylpiperidine-2-carboxamidehydrochloride
将化合物21c(0.32g,1.0mmol)溶于乙酸乙酯(5mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0mol/L),有白色固体析出,室温下搅拌反应5分钟。过滤,用少量乙酸乙酯淋洗,得到白色固体化合物21(0.24g,产率68.6%)。
Ms m/z(ESI):319.3[M+H+];
1H NMR(400MHz,CDCl3)δ6.58(s,2H),3.99(q,1H),3.93-3.88(dd,2H),3.59-3.56(d,1H),3.08-2.96(m,3H),2.31-2.27(d,1H),2.08(s,6H),1.91-1.88(d,3H),1.85-1.59(m,4H),1.28-1.25(t,3H),0.91(t,3H)。
实施例22
2-((2,6-二异丙基苯酚)甲基)-1-乙基哌啶盐酸盐(化合物22)
2-((2,6-diisopropylphenoxy)methyl)-1-ethylpiperidine hydrochloride
第一步:2-((2,6-二异丙基苯酚)甲基)吡啶(22b)
2-((2,6-diisopropylphenoxy)methyl)pyridine
室温下,将2-(氯甲基)吡啶(2.34g,18.3mmol)、丙泊酚22a(3.26g,18.3mmol)及N,N-二甲基甲酰胺(30mL)依次加入到50mL圆底烧瓶中,再加入碳酸铯(8.94g,27.5mmol),升温至85℃反应12小时。反应结束后,反应液中加入50mL水,用乙酸乙酯(50mL×3)萃取,合并有机相,饱和食盐水洗(50mL×2),无水硫酸钠干燥有机相,减压浓缩,柱层析(石油醚:乙酸乙酯=5:1)的产物化合物22b(3.2g,产率65%。
Ms m/z(ESI):270.3[M+H+]。
第二步:2-((2,6-二异丙基苯酚)甲基)哌啶(22c)
2-((2,6-diisopropylphenoxy)methyl)piperidine
将化合物22b(3g,11.15mmol),加入到20mL乙酸中,再加入氧化铂(0.43g,wt=17%),氢化反应釜中(40PSI)反应2天。将反应液过滤,减压浓缩除去乙酸,氨水中和至pH至9,乙酸乙酯萃取(20mL×2),饱和食盐水洗(20mL×2),无水硫酸钠干燥,减压浓缩,得到产物化合物22c(1.2g,产率40%)。
Ms m/z(ESI):276.3[M+H+]。
第三步:2-((2,6-二异丙基苯酚)甲基)-1-乙基哌啶(22d)
2-((2,6-diisopropylphenoxy)methyl)-1-ethylpiperidine
将化合物22c(0.47g,1.7mmol)溶于N,N-二甲基甲酰胺(5mL)中,依次加入碘乙烷(0.291g,1.87mmol)及碳酸钾(0.283g,2.05mmol),室温反应2小时,反应结束后,向体系中加入20mL水,乙酸乙酯萃取(20mL×2),合并有机相,饱和食盐水洗(30mL),无水硫酸钠干燥,减压浓缩,柱层析(石油醚:乙酸乙酯(v/v)=5:1),得到化合物21d(0.23g,产率46%)。
Ms m/z(ESI):304.4[M+H+]。
第四步:2-((2,6-二异丙基苯酚)甲基)-1-乙基哌啶盐酸盐(化合物22)
2-((2,6-diisopropylphenoxy)methyl)-1-ethylpiperidine hydrochloride
将化合物22d(0.23g,0.76mmol),溶于乙酸乙酯(3mL)中,加入10mL盐酸的乙酸乙酯溶液(4mol/L),反应2小时,减压浓缩除去乙酸乙酯,得化合物22(0.237g)。
Ms m/z(ESI):304.4[M+H+];
1H NMR(400MHz,CDCl3):δ7.27–7.21(m,3H),4.12-4.10(m,1H),3.98–3.95(m,1H),3.63-3.60(m,2H),3.32-3.18(m,2H),3.16–3.05(m,3H),1.88–1.60(m,6H),1.39–1.36(t,3H),1.10-1.18(q,12H)。
实施例23
(S)-2-(1-丙基哌啶-2-基)苯并[d]噻唑盐酸盐(化合物23)
(S)-2-(1-propylpiperidin-2-yl)benzo[d]thiazole hydrochloride
第一步:(S)-2-(哌啶-2-基)苯并[d]噻唑(23b)
(S)-2-(piperidin-2-yl)benzo[d]thiazole
将2-氨基苯硫酚23a(1.5g,11.9mmol)及(S)-哌啶-2-羧酸(1.57g,11.9mmol)加入到50mL圆底烧瓶中,再加入多聚磷酸(20mL),升温至200℃反应2小时,反应结束后,冷至室温,加入5%氢氧化钠溶液调节至pH至9,二氯甲烷萃取(100mL×2),合并有机相,饱和食盐水洗(50mL×2),无水硫酸钠干燥有机相,减压浓缩,柱层析(石油醚:乙酸乙酯(v/v)=5:1),得到化合物23b(0.8g,产率0.35%)。
Ms m/z(ESI):219.2[M+H+]。
第二步:(S)-2-(1-丙基哌啶-2-基)苯并[d]噻唑(23c)
(S)-2-(1-propylpiperidin-2-yl)benzo[d]thiazole
将化合物23b(0.8g,3.66mmol),加入到15mL N,N-二甲基甲酰胺中,再加入溴代丙烷(0.9g,7.13)及碳酸钾(1.01g,8.32mmol),后加入碘化钠(0.054g,0.366mmol)升温至85℃反应8h,反应结束后,向体系中加入30mL水,乙酸乙酯萃取(30mL×3)合并有机相,饱和食盐水洗(40mL×4),无水硫酸钠干燥,减压浓缩,柱层析(石油醚:乙酸乙酯(v/v)=30:1),得到化合物23c(0.84g,产率72%)。
Ms m/z(ESI):261.2[M+H+]。
第三步:2-(1-丙基哌啶-2-基)苯并[d]噻唑盐酸盐(化合物23)
2-(1-propylpiperidin-2-yl)benzo[d]thiazole hydrochloride
将化合物23c(0.8g,3.07mmol)溶于乙酸乙酯(5mL)中,加入盐酸乙酸乙酯溶液(2mL,4mol/L),室温反应1小时,反应结束后,减压浓缩得到化合物23(0.9g,产率99%)。
Ms m/z(ESI):261.3[M+H+];
1H NMR(400MHz,CDCl3):δ8.07-8.05(d,2H),7.64-7.52(m,2H),4.83–4.80(d,2H),3.78–3.86(d,1H),3.31-3.20(d,1H),2.96-2.95(m,1H),2.36-2.32(m,1H),2.16-1.52(m,7H),0.75-0.71(m,3H)。
实施例24
1-烯丙基-2-((2,6-二甲基苯基)氨基甲酰基)奎宁环-1-基溴化物(化合物24)
1-allyl-2-((2,6-dimethylphenyl)carbamoyl)quinuclidin-1-ium bromide
第一步:二乙基2-(吡啶基-4-亚甲烯基)丙二酸酯盐酸盐(24b)
diethyl 2-(pyridin-4-ylmethylene)malonate hydrochloride
室温下,将吡啶4-甲醛(21.4g,0.2mol)溶于甲苯(60mL)中,依次加入丙二酸二乙酯(32g,0.2mol)和哌啶(0.2mL,0.002mol)。加毕回流分水20小时。将反应液旋干后,将乙醚(200mL)加入反应液中,滴加4mol/L的盐酸乙酸乙酯溶液(50mL),析出黄色固体,过滤得到化合物24b(26g,产率50%)。
Ms m/z(ESI):250.2[M-H+]。
第二步:二乙基2-(哌啶基-4-亚甲基)丙二酸酯盐酸盐(24c)
diethyl 2-(piperidin-4-ylmethyl)malonate hydrochloride
将化合物24b(25g,0.087mol)溶于乙醇(25mL)和水(25mL)中,将二氧化铂(0.3g)加至反应液中,抽真空氢气置换三次后,通入氢气于室温搅拌反应10小时。将反应液过滤,旋干,得到黄色油状液体化合物24c(20g,产率78.1%)。
Ms m/z(ESI):280.2[M-H+]。
第三步:二乙基2-溴-2-(哌啶基-4-亚甲基)丙二酸酯盐酸盐(24d)
diethyl 2-bromo-2-(piperidin-4-ylmethyl)malonate hydrochloride
将化合物24c(2.0g,6.84mmol)溶于氯仿(20mL)中,将溴素(1.1g,6.84mmol)滴加到反应液中,加毕于室温反应8小时。将反应液浓缩得到黄色固体化合物24d(2.6g)。
Ms m/z(ESI):332.3[M+H+]。
第四步:二乙基奎宁环-2,2-二甲酸二乙酯(24e)
diethyl quiuclidine-2,2-dicarboxylate
将化合物24d(2.55g,6.84mmol)溶于水(20mL)中,将碳酸钾(1.0g)分批加入反应液,加毕,于55℃反应6小时。用甲基叔丁基醚(30mL×4)萃取产品,合并有机相,加入无水硫酸钠干燥,过滤,浓缩,得到黄色油状液体化合物24e(1.3g,产率73.8%)。
Ms m/z(ESI):256.2[M+1]。
第五步:奎宁环-2-甲酸氢溴酸盐(24f)
quinuclidine-2-carboxylic acid hydrobromide
将化合物24e(1.3g,5.09mmol)溶于溶于氢溴酸水溶液(20mL)及乙酸(5mL)中,升温至120℃下反应10小时。将反应液冷却,浓缩得到固体,干燥后得到灰色固体化合物24f(1g)。
Ms m/z(ESI):155.1[M+H+]。
第六步:N-(2,6-二甲基苯基)奎宁环-2-甲酰胺(24g)
N-(2,6-dimethylphenyl)quinuclidine-2-carboxamide
将化合物24f(0.19g,1.0mmol)溶于二氯甲烷(20mL),加入2,6-二甲基苯苯胺(0.15g,1.2mmol)、三乙胺(0.40g,4.0mmol)以及2-氯-1-甲基碘代吡啶(0.38g,1.5mmol),加毕,于40℃反应8小时。向反应液加入二氯甲烷(30mL),有机相用饱和碳酸氢钠溶液(20mL)、饱和氯化钠(20mL)洗涤,有机相中加入无水硫酸钠干燥,过滤,浓缩,柱层析分离(二氯甲烷/甲醇(v/v)=20:1~10:1),得到浅黄色固体化合物24g(0.13g,产率50%)。
Ms m/z(ESI):259.3[M+H+]。
第七步:1-烯丙基-2-((2,6-二甲基苯基)氨基甲酰基)奎宁环-1-基溴化物(化合物24)
1-allyl-2-((2,6-dimethylphenyl)carbamoyl)quinuclidin-1-ium bromide
将N-(2,6-二甲基苯基)奎宁环-2-甲酰胺24g(0.26g,1.0mmol)溶于乙腈(15mL)中,再将烯丙基溴(0.36g,3.0mmol)溶液滴加到反应中,加毕回流6小时。将反应液直接旋干,高效液相色谱法制备得到白色固体化合物24(0.06g,产率16%)。
Ms m/z(ESI):299.3[M]。
1H NMR(400MHz,MeOD)δ7.06-7.01(m,3H),6.05-5.98(m,1H),5.64-5.57(m,1H),4.47(m,1H),4.27-4.24(m,1H),4.16-4.11(m,1H),3.87–3.82(m,1H),3.59-3.58(m,1H),3.44-3.36(m,2H),2.47-2.46(m,1H),2.27(s,1H),2.14(s,6H),,2.00-1.95(m,4H)。
实施例25
(E)-2,6-二甲基-N-(1-(哌啶-1-基)亚乙基)苯胺盐酸盐(化合物25)
(E)-2,6-dimethyl-N-(1-(piperidin-1-yl)ethylidene)anilinehydrochloride
第一步:N-(2,6-二甲基苯基)乙酰胺(25a)
N-(2,6-dimethylphenyl)acetamide
将2,6-二甲基苯胺1a(10g,0.083mol),三乙胺(16.69g,0.165mol)加入反应瓶中,加入二氯甲烷(100mL),冰浴,搅拌下滴加入化合物乙酸酐(12.64g,0.124moL),加毕,于室温下搅拌10小时。将反应液中加入饱和食盐水(100mL),搅拌后分液,水相用二氯甲烷(50mL×2)萃取,合并有机相,并用无水硫酸钠干燥,过滤,将滤液蒸干,残留物加入石油醚(50mL)搅拌30分钟,过滤,滤饼用石油醚(50mL×2)洗涤,得白色固体化合物25a(粗产品13g,产率:96.5%),直接用于下一步。
Ms m/z(ESI):164.2[M+H+];
1H NMR(400MHz,CDCl3)δ7.8-7.10(m,1H),δ7.09-7.04(m,2H),δ6.90-9.77(d,1H),δ2.27-2.18(t,9H)。
第二步:(E)-2,6-二甲基-N-(1-(哌啶-1-基)亚乙基)苯胺(25b)
(E)-2,6-dimethyl-N-(1-(piperidin-1-yl)ethylidene)aniline
将化合物25a(3g,0.018mol)溶于甲苯(30mL)中,于室温下加入三氯氧磷(2.825g,0.018mol)于室温下搅拌2小时。然后将哌啶(1.564g,0.018mol)溶于甲苯(30mL)中并滴加入反应液中,加热回流12小时。将反应液蒸干,加入乙酸乙酯(50mL)和饱和碳酸氢钠溶液(50mL)搅拌分液,水相用用乙酸乙酯(50mL×2)萃取,合并有机相并用饱和食盐水(100mL×3)洗涤,有机相用无水硫酸钠干燥,过滤并蒸干,残留物用硅胶柱层析(CH2Cl2/MeOH=30/1-15/1)分离纯化,得到白色固体化合物25b(0.8g,产率18.5%),直接用于下一步。
Ms m/z(ESI):231.2[M+H+]。
第三步:(E)-2,6-二甲基-N-(1-(哌啶-1-基)亚乙基)苯胺盐酸盐(化合物25)
(E)-2,6-dimethyl-N-(1-(piperidin-1-yl)ethylidene)anilinehydrochloride
将化合物25b(0.46g,1.99mmol)溶于甲醇(2mL),加入浓盐酸(0.331mL,3.98mmol)于室温下搅拌1小时,将反应液中的甲醇蒸去后冻干,得到化合物25(0.52g,产率:97%)。
Ms m/z(ESI):231.3[M+H+];
1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),δ7.29-7.23(dt,3H),δ4.01(s,2H),δ3.69(s,2H),δ2.19(s,6H),δ2.04(s,3H),δ1.72(s,6H)。
实施例26
(S)-1-(二氟甲基)-2-(1-丙基哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(化合物26)
(S)-1-(difluoromethyl)-2-(1-propylpiperidin-2-yl)-1H-benzo[d]imidazole dihydrochloride
第一步:(S)-2-(哌啶-2-基)-1H-苯并[d]咪唑(26a)
(S)-2-(piperidin-2-yl)-1H-benzo[d]imidazole
将(S)-1-(叔丁氧羰基)哌啶-2-甲酸(8.3g,0.0362mol),邻苯二胺(3.9g,0.0362mol)及多聚磷酸(20mL)加入反应瓶中,加热到200℃搅拌2小时。加入冰水(30mL)及浓氨水(30mL)使之溶解并调pH9-10,于0℃下搅拌30分钟,过滤得到黄色固体化合物26a(4.0g,收率54.9%)。
Ms m/z(ESI):202.2[M+H+];
1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),δ7.47(s,2H),δ7.13-6.91(m,2H),δ3.90-3.87(dd,1H),3.04-3.01(d,2H),δ2.72-2.66(m,1H),δ1.96-1.93(m,1H),δ1.84-1.81(dd,1H),1.61-1.44(m,4H)。
第二步:(S)-叔丁基2-(1H-苯并[d]咪唑-2-基)哌啶-1-甲酸酯(26b)
(S)-tert-butyl 2-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate
将化合物26a(4.0g,0.0199mol)溶于乙醇(20mL),加入碳酸钾(5.49g,0.0398mol)的水(20mL)溶液,搅拌下滴加入二碳酸叔丁酯(5.2g,0.0239mol),加毕,于室温下搅拌2小时,有大量不溶物析出,向反应液中加入二氯甲烷(20mL),体系溶清,搅拌2小时,TLC检测已反应完,浓缩除去有机溶剂,用乙酸乙酯(50mL*3)萃取,合并有机相,并用饱和食盐水洗涤(100mL x 1),有机相用无水硫酸钠干燥,过滤,浓缩,残留物用石油醚(10mL x 2)洗涤过滤,烘干得到微红色固体化合物26b(5.0g,产率83%),直接用于下一步。
Ms m/z(ESI):302.23[M+H+]。
第三步:(S)-叔丁基2-(1-(二氟甲基)-1H-苯并[d]咪唑-2-基)哌啶-1-甲酸酯(26c)
(S)-tert-butyl
2-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate
将化合物26b(1g,3.32mmol)溶于乙腈(20mL)及水(20mL),加入氢氧化钾(3.72g,66.4mmol)搅拌溶清,冷却至0℃,氮气保护下滴加入二乙基(溴二氟甲基)膦酸酯(1.77g,6.64mmol),加毕,于室温下搅拌3小时,向反应液中加入饱和食盐水(50mL),用乙酸乙酯(50mL x 3)萃取,合并有机相并用饱和食盐水(50mL x 2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液蒸干,得到白色固体化合物26c(1.1g,产率:94%)。
Ms m/z(ESI):352.3[M+H+]。
第四步:(S)-1-(二氟甲基)-2-(哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(26d)
(S)-1-(difluoromethyl)-2-(piperidin-2-yl)-1H-benzo[d]imidazoledihydrochloride
将化合物26c(1.1g,3.13mmol)溶于二氯甲烷(10mL)中,加入氯化氢的乙酸乙酯溶液(3.13mL,12.52mmol),加毕,于室温下搅拌3小时,将反应液蒸干,得到白色固体化合物26d(1.0g,产率:98%)。
Ms m/z(ESI):252.2[M+H+]。
第五步:(S)-1-(二氟甲基)-2-(1-丙基哌啶-2-基)-1H-苯并[d]咪唑(26e)
(S)-1-(difluoromethyl)-2-(1-propylpiperidin-2-yl)-1H-benzo[d]imidazole
将化合物26d(1.0g,3.13mmol)溶于DMF(10mL)中,加入碳酸钾(0.864g,6.26mmol)及正溴丙烷(0.577g,4.695mmol),加毕,于85℃下搅拌2小时,向反应液中加入冰冷饱和食盐水(50mL),用乙酸乙酯(50mL x 3)萃取,合并有机相并用饱和食盐水(50mL x 2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液蒸干,柱层析(石油醚/乙酸乙酯=10:1-3:1)得到无色油状化合物26e(380mg,产率:42%)。
Ms m/z(ESI):294.3[M+H+]。
第六步:(S)-1-(二氟甲基)-2-(1-丙基哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(化合物26)
(S)-1-(difluoromethyl)-2-(1-propylpiperidin-2-yl)-1H-benzo[d]imidazole dihydrochloride
将化合物26e(330mg,1.126mmol)溶于乙酸乙酯(10mL)中,加入氯化氢的乙酸乙酯溶液(2.25mL,4.5mmol)加毕于室温下搅拌1小时,将反应液蒸干,得到白色固体化合物26(300mg,产率:72.8%)。
Ms m/z(ESI):294.3[M+H+]。
1H NMR(400MHz,CD3OD)δ8.26-7.97(m,1H),δ7.82-7.78(m,2H),δ7.50-7.43(p,2H),δ5.03-5.00(d,1H),3.89-3.86(d,1H),δ3.49-3.21(m,1H),δ3.14-2.91(m,2H),δ2.36-2.33(d,1H),2.16-1.64(m,7H),0.89-0.85(t,3H)。
实施例27
(S)-2-(1-(2,2,2-三氟乙基)哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(化合物27)
(S)-2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-benzo[d]imidazole
第一步:(S)-2-(1-(2,2,2-三氟乙基)哌啶-2-基)-1H-苯并[d]咪唑(27a)
(S)-2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-benzo[d]imidazole
将化合物26a(1g,4.975mmol)溶于N,N-二甲基甲酰胺(10mL)中,搅拌下加入碳酸铯(2.1g,6.467mmol)及2,2,2-三氟乙基三氟甲磺酸酯(1.27g,5.473mmol),加毕,于80℃搅拌6小时,将反应液冷却到室温加入冰水混和物(100mL)中,用乙酸乙酯(50mL x 3)萃取,合并有机相并用饱和食盐水(100mL x 2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液蒸干,柱层析(石油醚/乙酸乙酯(v/v)=2:1-1:1)得到白色固体化合物27a(0.25g,产率:17.8%)。
Ms m/z(ESI):284.3[M+H+]。
第二步:(S)-2-(1-(2,2,2-三氟乙基)哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(化合物27)
(S)-2-(1-(2,2,2-trifluoroethyl)piperidin-2-yl)-1H-benzo[d]imidazoledihydrochloride
将化合物27a(0.25g,0.883mmol)溶于乙酸乙酯(5mL)中,加入氯化氢的乙酸乙酯溶液(0.88mL,3.53mmol),加毕,于室温下搅拌2小时,将反应液蒸干,得到白色固体化合物27(0.3g,产率:95%)。
Ms m/z(ESI):258.3[M+H+-73];
1H NMR(400MHz,DMSO-d6)δ110.17(s,1H),δ9.18-9.16(d,1H),δ8.37(S,2H),δ7.79-7.73(dd,2H),7.42-7.32(m,2H),δ5.66-5.43(m,2H),δ4.86-4.81(t,1H),δ3.33-3.30(d,1H),δ3.15-3.13(d,1H)δ2.06-1.70(m,6H)。
实施例28
(S)-1-甲基-2-(1-丙基哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(化合物28)
(S)-1-methyl-2-(1-propylpiperidin-2-yl)-1H-benzo[d]imidazoledihydrochloride
第一步:(S)-叔丁基2-(1-甲基-1H-苯并[d]咪唑-2-基)哌啶-1-甲酸酯(28a)
(S)-tert-butyl 2-(1-methyl-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate
将化合物26b(1g,3.32mmol)溶于四氢呋喃(10mL)中,降温到0℃,搅拌下加入氢化钠(0.159g,3.98mmol)搅拌20分钟,滴加入碘甲烷(0.566g,3.98mmol),加毕,于室温下搅拌2小时,将反应液中加入冰水混和物中(50mL),用乙酸乙酯(100mLx 3)萃取,合并有机相并用饱和食盐水(100mL x 2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液蒸干,得到黄色固体产物粗品化合物28a(1.2g),直接用于下一步。
Ms m/z(ESI):316.3[M+H+];
1H NMR(400MHz,DMSO-d6)δ7.63-7.61(d,1H),δ7.53-7.51(d,1H),δ7.26-7.16(dt,2H),δ5.57(s,1H),3.88-3.84(d,1H),δ3.76(s,3H),δ3.31-3.22(dd,1H),δ2.11-1.58(m,5H),δ1.58-1.44(m,10H)。
第二步:(S)-1-甲基-2-(哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(28b)
(S)-1-methyl-2-(piperidin-2-yl)-1H-benzo[d]imidazoledihydrochloride
将化合物28a(1.0g,3.17mmol)溶于乙酸乙酯(10mL)中,加入氯化氢的乙酸乙酯溶液(3.13mL,12.52mmol),加毕,于室温下搅拌4小时,将反应液蒸干,得到白色固体化合物28b(1.0g)。
Ms m/z(ESI):215.2[M+H+]。
第三步:(S)-1-甲基-2-(1-丙基哌啶-2-基)-1H-苯并[d]咪唑(28c)
(S)-1-methyl-2-(1-propylpiperidin-2-yl)-1H-benzo[d]imidazole
将化合物28b(0.914g,3.17mmol)溶于DMF(10mL)中,加入碳酸钾(1.75g,12.68mmol)及正溴丙烷(0.585g,4.76mmol),加毕,于85℃下搅拌4小时,将反应液中加入冰水混和物(100mL)中,用乙酸乙酯(100mL x 3)萃取,合并有机相并用饱和食盐水(100mL x2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液蒸干,柱层析(石油醚/乙酸乙酯=10:1-3:1)得到无色油状产物化合物28c(700mg,产率:85%)。
Ms m/z(ESI):258.3[M+H+]。
第四步:(S)-1-甲基-2-(1-丙基哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(化合物28)
(S)-1-methyl-2-(1-propylpiperidin-2-yl)-1H-benzo[d]imidazoledihydrochloride
将化合物28c(600mg,2.33mmol)溶于乙酸乙酯(10mL)中,加入氯化氢的乙酸乙酯溶液(2.33mL,9.32mmol)加毕于室温下搅拌2小时,将反应液蒸干,得到白色固体化合物28a(400mg,产率:52%)。
Ms m/z(ESI):258.3[M+H+-73]。
1H NMR(400MHz,CD3OD)δ7.94-7.66(m,4H),δ5.39(S,1H),δ4.22(S,3H),δ3.98-3.95(d,1H),3.61-2.92(m,3H),δ2.49-2.39(d,2H),δ2.20-1.78(m,6H),δ0.91-0.87(t,3H).
实施例29
(S)-2-(1-丁基哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(化合物29)
(S)-2-(1-butylpiperidin-2-yl)-1H-benzo[d]imidazoledihydrochloride
第一步:(S)-2-(1-丁基哌啶-2-基)-1H-苯并[d]咪唑(29a)
(S)-2-(1-butylpiperidin-2-yl)-1H-benzo[d]imidazole
将化合物26a(1g,4.975mmol)溶于N,N-二甲基甲酰胺(25mL)中,搅拌下加入碳酸钾(1.37g,9.95mmol)及正溴丁烷(1.02g,7.462mmol),加毕,于室85℃搅拌4小时,将反应液冷却到室温加入冰水混和物(100mL)中,用乙酸乙酯(50mL x 3)萃取,合并有机相并用饱和食盐水(100mL x 2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液蒸干,柱层析(石油醚/乙酸乙酯(v/v)=2:1-1:1)得到白色固体化合物29a(1.0g,产率:78.7%)。
Ms m/z(ESI):258.3[M+H+]。
第二步:(S)-2-(1-丁基哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(化合物29)
(S)-2-(1-butylpiperidin-2-yl)-1H-benzo[d]imidazoledihydrochloride
将化合物29a(0.5g,1.945mmol)溶于二氯甲烷(10mL)中,加入氯化氢的乙酸乙酯溶液(2mL,8mmol),加毕,于室温下搅拌1小时,将反应液化气蒸干,得到白色固体产物化合物29(0.6g,产率:93%)。
Ms m/z(ESI):258.3[M+H+-73]。
1H NMR(400MHz,DMSO-d6)δ11.63-11.05(d,3H),δ7.71(S,2H),δ7.36(S,2H),δ5.05-4.76(t,1H),3.88-3.66(t,1H),δ3.37-3.23(d,1H),δ2.94-2.92(d,2H),δ2.33-1.16(m,10H),δ0.86-0.75(t,3H)。
实施例30
(S)-2-(1-丙基哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(化合物30)
(S)-2-(1-propylpiperidin-2-yl)-1H-benzo[d]imidazole dihydrochloride
第一步:(S)-2-(1-丙基哌啶-2-基)-1H-苯并[d]咪唑(30a)
(S)-2-(1-propylpiperidin-2-yl)-1H-benzo[d]imidazole
将化合物26a(2.01g,0.010mol)溶于N,N-二甲基甲酰胺(50mL)中,加入碳酸钾(2.76g,0.020mol)及正溴丙烷(1.845g,0.015mol),加热到85℃搅拌4小时。加入冰水(100mL),析出固体过滤,硅胶柱层析(二氯甲烷/甲醇=20:1),得到白色固体化合物30a(1.259g;产率52%)。
Ms m/z(ESI):244.3[M+H+]。
第二步:(S)-2-(1-丙基哌啶-2-基)-1H-苯并[d]咪唑二盐酸盐(化合物30)
(S)-2-(1-propylpiperidin-2-yl)-1H-benzo[d]imidazole dihydrochloride
将化合物30a(1.25g,0.005mol)溶于无水甲醇(5mL)中,加入氯化氢的乙酸乙酯溶液(5mL,0.020moL),于室温下搅拌1小时后,将反应液浓缩干,加入(5mL)水,冻干得到白色固体产物化合物30(1.2g,收率:83.5%)。
Ms m/z(ESI):244.3[M+H+];
1H NMR(400MHz,DMSO-d6)δ12.69(s,2H),δ11.79-11.27(d,1H)δ7.74(s,2H),δ7.40(s,2H),δ5.07-4.84(t,1H),δ3.86-3.69(t,1H),δ3.37-3.24(m,1H),δ2.92-2.91(d,2H),δ2.38-2.19(m,2H),δ1.99-1.57(m,6H)δ0.78-0.74(t,3H)。
实施例31
(E)-N'-环己基-N-(2,6二甲基苯基)乙脒盐酸盐(化合物31)
第一步:(E)-N'-环己基-N-(2,6-二甲基苯基)乙脒(31b)
(E)-N'-cyclohexyl-N-(2,6-dimethylphenyl)acetimidamide
将N-(2,6-二甲基苯基)乙酰胺31a(3g,0.018mol)溶于甲苯(30mL)中,于室温下加入三氯氧磷(3.4g,0.022mol)于室温下搅拌2小时。然后将环己胺(2.186g,0.022mol)溶于甲苯(30mL)中并滴加入反应液中,加热回流12小时。将反应液蒸干,加入乙酸乙酯(50mL)和饱和碳酸氢钠溶液(50mL)搅拌分液,水相用乙酸乙酯(50mL x2)萃取,合并有机相并用饱和食盐水(100mL x 3)洗涤,有机相用无水硫酸钠干燥,过滤并蒸干,HPLC制备分离纯化得到白色固体化合物31b(0.7g,产率15.5%),直接用于下一步。
Ms m/z(ESI):245.3[M+H+]。
第二步:(E)-N'-环己基-N-(2,6二甲基苯基)乙脒盐酸盐(化合物31)
(E)-N-cyclohexyl-N'-(2,6-dimethylphenyl)acetimidamid hydrochloride
将化合物31b(0.46g,1.99mmol)溶于乙酸乙酯(5mL),加入氯化氢的乙酸乙酯溶液(1mL,4.0mmol)于室温下搅拌1小时,将反应液蒸得到化合物31(0.7g,产率:87%)。
以上反应步骤中,化合物31a和化合物31含有其互变异构体结构。
Ms m/z(ESI):231.3[M+H+-36];
1H NMR(400MHz,D2O)δ78.34-7.22(m,3H),δ3.71-3.64(m,0.61H),δ3.60-3.55(m,0.42H),δ2.51(s,1H),δ2.18(d,6H),δ2.09-2.01(m,1H),δ1.9(s,1.5H),δ1.84-0.95(m,9H)。
实施例32
N-(2,4-二甲基噻吩-3-基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺盐酸盐(32)
N-(2,4-dimethylthiophen-3-yl)-2-propyloctahydrocyclopenta[c]pyrrole-1-carboxamid e hydrochloride
第一步:叔丁基-1-((2,4-二甲基噻吩-3-基)氨基甲酰基)六氢环戊[c]吡咯-2(1H)-羧酸酯(32a)
tert-butyl1-((2,4-dimethylthiophen-3-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
将2-(叔丁氧基羰基)八氢环戊[c]吡咯-1-羧酸5e(4g,15.6mmol)溶于二氯甲烷(60mL),加入2,4-二甲基噻吩-3-胺(2.37g,18.7mmol)、三乙胺(3.15g,31.2m mol)以及2-氯-1-甲基碘代吡啶(5.97g,31.2mmol),加毕,于40℃反应6小时。向反应液加入二氯甲烷(50mL),有机相用饱和碳酸氢钠溶液(50mL)、饱和氯化钠溶液(50mL)洗涤,有机相中加入无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚/乙酸乙酯(v/v)=30:1~1:1),得到黄色固体产品32a的两个光学异构体32a-1(1.8g,产率32%)和32a-2(0.8g,产率14%)。
Ms m/z(ESI):387.3[M+Na+];
32a-1:1H NMR(400MHz,MeOD)δ6.79(s,1H),4.20(d,1H),3.85-3.66(m,1H),2.77(s,2H),2.26(s,3H),2.06(m,4H),1.95-1.81(m,2H),1.78-1.63(m,2H),1.62-1.25(m,11H)。
32a-2:1H NMR(400MHz,MeOD)δ6.78(s,1H),4.60(s,1H),3.86(s,1H),3.11(s,2H),2.80(s,1H),2.32(s,3H),2.08(s,3H),1.93-1.53(m,6H),1.54-1.36(m,9H)。
第二步:N-(2,4-二甲基噻吩-3-基)八氢环戊[c]吡咯-1-甲酰胺(32b)
N-(2,4-dimethylthiophen-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide
32b-1和32b-2是32b的两个光学异构体
将32a-1(1.8g,4.9mmol)溶于二氯甲烷(10mL)中,降温到0℃,再将三氟乙酸(10mL)滴加到反应,加毕于室温下反应2小时。将反应液直接旋干,用二氯甲烷(50mL)溶解,有机相用饱和碳酸氢钠(50mL)及饱和食盐水溶液(30mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,得到白色固体32b-1(1.2g,产率:92%)。
Ms m/z(ESI):265.2[M+H+]。
32b-2的制备方法可参考32b-1。
第三步:N-(2,4-二甲基噻吩-3-基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺(32c)
N-(2,4-dimethylthiophen-3-yl)-2-propyloctahydrocyclopenta[c]pyrrole-1-carboxamide
32c-1和32c-2是32c的两个光学异构体
将32b-1(1.1g,4.2mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入碳酸钾(0.86g,6.2mmol)以及溴代正丙烷(0.61g,5.0mmol),加毕于80℃下反应2小时。冷却,向反应液中加冰水(30mL),有白色固体析出,搅拌10分钟,过滤,滤饼用水(20mL)、石油醚(20mL)洗涤,干燥后得到白色固体32c-1(0.85g,产率67%)。
Ms m/z(ESI):307.3[M+H+]。
32c-2的制备方法可参考32c-1。
第四步:N-(2,4-二甲基噻吩-3-基)-2-丙基八氢环戊并[c]吡咯-1-甲酰胺盐酸盐(32)
N-(2,4-dimethylthiophen-3-yl)-2-propyloctahydrocyclopenta[c]pyrrole-1-carboxamide hydrochloride
32-1和32-2是32的两个光学异构体
将32c-1(0.8g,3.0mmol)溶于乙酸乙酯(15mL),加入氯化氢的乙酸乙酯溶液(4mL,4.0M),室温下搅拌反应1小时。将反应液直接旋干,产品用正己烷打浆,过滤,干燥后得到白色固体32-1(0.95g,产率93%)。
Ms m/z(ESI):307.3[M+H+];
1H NMR(400MHz,MeOD)δ6.87(s,1H),3.98(q,1H),3.85(d,1H),3.26-3.10(m,2H),3.04-2.87(m,3H),2.31(s,3H),2.14-2.01(m,4H),1.97-1.58(m,7H),1.04(t,3H)。
32-2的制备方法可参考32-1。
32-2:Ms m/z(ESI):307.3[M+H+];
1H NMR(400MHz,MeOD)δ6.85(s,1H),4.48(d,1H),3.59-3.38(m,2H),3.29-2.99(m,3H),2.32(s,3H),2.15-2.09(m,4H),2.00-1.44(m,7H),1.03(t,3H)。
实施例33
2-(4-(2,6-二甲基苯基)-1H-咪唑-2-基)-1-丙基哌啶盐酸盐(33)
2-(4-(2,6-dimethylphenyl)-1H-imidazol-2-yl)-1-propylpiperidinehydrochloride
第一步:叔丁基-2-(1H-咪唑-2-基)哌啶-1-羧酸酯(33b)
tert-butyl 2-(1H-imidazol-2-yl)piperidine-1-carboxylate
将化合物1-叔丁氧羰基-2-哌啶甲醛33a(5g,23.4mmol)溶于甲醇(40mL),降温至0℃,搅拌下滴加氨/甲醇(20mL,7M),加完室温下搅拌0.5小时,再将乙二醛(6.78g,117mmol)滴加到上述反应液中,室温反应4小时。将反应液蒸干,粗品用柱层析分离纯化(石油醚/乙酸乙酯(v/v)=10:1~2:1)得到黄色固体产品叔丁基-2-(1H-咪唑-2-基)哌啶-1-羧酸酯33b(2.6g,产率45%)。
1H NMR(400MHz,MeOD)δ7.01(s,2H),5.40(d,1H),4.21-3.95(m,1H),3.04-2.77(m,1H),2.49-2.31(m,1H),1.95-1.38(m,14H)。
第二步:叔丁基-2-(4,5-二碘-1H-咪唑-2-基)哌啶-1-羧酸酯(33c)
tert-butyl 2-(4,5-diiodo-1H-imidazol-2-yl)piperidine-1-carboxylate
将叔丁基-2-(1H-咪唑-2-基)哌啶-1-羧酸酯33b(2.6g,10.35mmol)溶于二氯甲烷(60mL)中,降温到0℃,再将N-碘代丁二酰亚胺(4.65g,20.7mmol)加入反应液,加毕于冰浴下反应2小时。向反应液加入二氯甲烷(50mL)溶解,有机相用10%亚硫酸钠(80mL)及饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,得到黄色固体叔丁基-2-(4,5-二碘-1H-咪唑-2-基)哌啶-1-羧酸酯33c(5g,产率96%)。
Ms m/z(ESI):504.0[M+H+];
第三步:叔丁基-2-(5-碘-1H-咪唑-2-基)哌啶-1-羧酸酯(33d)
tert-butyl 2-(5-iodo-1H-imidazol-2-yl)piperidine-1-carboxylate
将叔丁基-2-(4,5-二碘-1H-咪唑-2-基)哌啶-1-羧酸酯33c(5g,9.94mmol)溶于乙醇(30mL)和水(70mL)中,再将亚硫酸钠(11.27g,89.46mmol)加到反应液,回流下反应18小时。将反应液浓缩除去乙醇,水相用乙酸乙酯(50mL×3)萃取,合并有机相,用饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析纯化(石油醚/乙酸乙酯(v/v)=10:1~2:1),得到白色固体叔丁基-2-(5-碘-1H-咪唑-2-基)哌啶-1-羧酸酯33d(2.5g,产率:67%)。
Ms m/z(ESI):378.0[M+H+];
1H NMR(400MHz,CDCl3)δ7.05(s,1H),5.33(d,1H),3.94(d,1H),3.49(s,1H),2.79-2.40(m,2H),2.09-1.55(m,4H),1.56-1.37(m,9H)。
第四步:叔丁基2-(5-(2,6-二甲基苯基)-1H-咪唑-2-基)哌啶-1-羧酸酯(33e)
tert-butyl 2-(5-(2,6-dimethylphenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate
将叔丁基-2-(5-碘-1H-咪唑-2-基)哌啶-1-羧酸酯33d(1.5g,3.98mmol)溶于二氧六环(20mL)和水(5mL)中,再将2,6-二甲基苯硼酸(0.895g,5.96mmol),碳酸铯(2.59g,7.96mmol)以及[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.233g,0.318mmol)加到反应液中,用氮气置换三次,在氮气下,80℃下反应6小时。向反应液加入水(20mL),水相用乙酸乙酯(20mL×3)萃取,合并有机相,用饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析纯化(石油醚/乙酸乙酯(v/v)=10:1~2:1),得到白色固体叔丁基2-(5-(2,6-二甲基苯基)-1H-咪唑-2-基)哌啶-1-羧酸酯33e(0.65g,产率:46%)。
Ms m/z(ESI):356.3[M+H+];
第五步:2-(5-(2,6-二甲基苯基)-1H-咪唑-2-基)哌啶(33f)
2-(5-(2,6-dimethylphenyl)-1H-imidazol-2-yl)piperidine
将叔丁基2-(5-(2,6-二甲基苯基)-1H-咪唑-2-基)哌啶-1-羧酸酯33e(0.65g,1.8mmol)溶于二氯甲烷(5mL)中,降温到0℃,再将三氟乙酸(5mL)滴加到反应液中,加毕于室温下反应1小时。将反应液直接旋干,用二氯甲烷(30mL)溶解,有机相用饱和碳酸氢钠(30mL)及饱和食盐水溶液(30mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,得到白色固体2-(5-(2,6-二甲基苯基)-1H-咪唑-2-基)哌啶33f(0.43g,产率:92%)。
Ms m/z(ESI):256.3[M+H+];
第六步:2-(4-(2,6-二甲基苯基)-1H-咪唑-2-基)-1-丙基哌啶(33g)
2-(4-(2,6-dimethylphenyl)-1H-imidazol-2-yl)-1-propylpiperidine
室温下,将2-(5-(2,6-二甲基苯基)-1H-咪唑-2-基)哌啶33f(0.43g,1.7mmol)溶于N,N-二甲基甲酰胺(10mL)中,再加入碳酸钾(0.35g,2.5mmol)及溴代正丙烷(0.25g,2.0mmol),加毕于80℃下反应6小时。向反应液中加水(50mL),用乙酸乙酯(20mL×3)萃取,合并有机相,用饱和食盐水溶液(30mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用制备HPLC纯化,得到白色固体2-(4-(2,6-二甲基苯基)-1H-咪唑-2-基)-1-丙基哌啶33g(0.15g,产率:30%)。
Ms m/z(ESI):298.3[M+H+];
1H NMR(400MHz,MeOD)δ7.18-7.08(m,3H),6.81(s,1H),3.40(q,1H),3.17(q,1H),2.32(m,1H),2.23-2.02(m,8H),1.89-1.64(m,5H),1.56-1.32(m,3H),0.82-0.73(m,3H)。
第七步:2-(4-(2,6-二甲基苯基)-1H-咪唑-2-基)-1-丙基哌啶盐酸盐(33)
2-(4-(2,6-dimethylphenyl)-1H-imidazol-2-yl)-1-propylpiperidinehydrochloride
将2-(4-(2,6-二甲基苯基)-1H-咪唑-2-基)-1-丙基哌啶33g(0.1g,0.34mmol)溶于乙酸乙酯(5mL),加入氯化氢的乙酸乙酯溶液(1mL,4.0M),室温下搅拌反应1小时。将反应液直接旋干,得到白色固体2-(4-(2,6-二甲基苯基)-1H-咪唑-2-基)-1-丙基哌啶盐酸盐33(0.11g,产率98%)。
Ms m/z(ESI):298.3[M+H+];
1H NMR(400MHz,MeOD)δ7.57(s,1H),7.27-7.18(m,1H),7.11(d,2H),4.67(d,1H),3.71(d,1H),3.15(d,1H),2.93-2.75(m,2H),2.39(q,,1H),2.25(d,1H),2.11(s,6H),2.03-1.92(m,3H),1.71(m,2H),1.59-1.49(m,1H),0.84(t,3H).
实施例34
2-(4-(4-乙基苯基)-1H-咪唑-2-基)-1-丙基哌啶盐酸盐(34)
2-(4-(4-ethylphenyl)-1H-imidazol-2-yl)-1-propylpiperidinehydrochloride
第一步:叔丁基2-(5-(4-乙基苯基)-1H-咪唑-2-基)哌啶-1-羧酸酯(34b)
tert-butyl 2-(5-(4-ethylphenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate
将叔丁基-2-(5-碘-1H-咪唑-2-基)哌啶-1-羧酸酯33d(1.2g,3.2mmol)溶于二氧六环(12mL)和水(3mL)中,再将4-乙基苯硼酸(0.72g,4.8mmol),碳酸铯(2.1g,6.4mmol)以及[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.19g,0.25mmol)加入反应液,用氮气置换三次,在氮气下,80℃下反应4小时。向反应液加入水(20mL),水相用乙酸乙酯(20mL×3)萃取,合并有机相,用饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析纯化(石油醚/乙酸乙酯(v/v)=10:1~3:1),得到白色固体叔丁基2-(5-(4-乙基苯基)-1H-咪唑-2-基)哌啶-1-羧酸酯34b(1g,产率:88%)。
Ms m/z(ESI):356.4[M+H+];
第二步:2-(5-(4-乙基苯基)-1H-咪唑-2-基)哌啶(34c)
2-(5-(4-ethylphenyl)-1H-imidazol-2-yl)piperidine
将叔丁基2-(5-(4-乙基苯基)-1H-咪唑-2-基)哌啶-1-羧酸酯34b(1g,2.81mmol)溶于二氯甲烷(8mL)中,降温到0℃,再将三氟乙酸(8mL)滴加到反应液中,加毕于室温下反应1小时。将反应液直接旋干,残余物用二氯甲烷(30mL)溶解,有机相用饱和碳酸氢钠(30mL)及饱和食盐水溶液(30mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,得到白色固体2-(5-(4-乙基苯基)-1H-咪唑-2-基)哌啶34c(0.69g,产率:96%)。
Ms m/z(ESI):256.3[M+H+];
第三步:2-(4-(4-乙基苯基)-1H-咪唑-2-基)-1-丙基哌啶(34d)
2-(4-(4-ethylphenyl)-1H-imidazol-2-yl)-1-propylpiperidine
室温下,将2-(5-(4-乙基苯基)-1H-咪唑-2-基)哌啶34c(0.65g,2.5mmol)溶于N,N-二甲基甲酰胺(10mL)中,再加入碳酸钾(0.53g,3.8mmol)及溴代正丙烷(0.34g,2.8mmol),加毕于80℃下反应4小时。向反应液中加水(50mL),用乙酸乙酯(20mL×3)萃取,合并有机相,用饱和食盐水溶液(30mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析(二氯甲烷/甲醇(v/v)=100:1~10:1)纯化,得到白色固体2-(4-(4-乙基苯基)-1H-咪唑-2-基)-1-丙基哌啶34d(0.5g,产率70%)。
Ms m/z(ESI):298.3[M+H+];
1H NMR(400MHz,CDCl3)δ9.54(s,1H),7.68(s,1H),7.40(s,1H),7.20-7.11(m,4H),3.51(d,1H),3.18(d,1H),2.65(q,2H),2.35(s,1H),2.10(m,2H),2.03-1.95(m,1H),1.86-1.63(m,3H),1.55-1.30(m,3H),1.23(t,3H),0.77(t,3H).
第四步:2-(4-(4-乙基苯基)-1H-咪唑-2-基)-1-丙基哌啶盐酸盐(34)
2-(4-(4-ethylphenyl)-1H-imidazol-2-yl)-1-propylpiperidinehydrochloride
将2-(4-(4-乙基苯基)-1H-咪唑-2-基)-1-丙基哌啶34d(0.45g,1.5mmol)溶于乙酸乙酯(5mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0M),室温下搅拌反应1小时。将反应液直接旋干,得到白色固体2-(4-(4-乙基苯基)-1H-咪唑-2-基)-1-丙基哌啶盐酸盐34(0.45g,产率95%)。
Ms m/z(ESI):298.3[M+H+];
1H NMR(400MHz,MeOD)δ7.93-7.85(m,1H),7.66(dd,2H),7.29(d,2H),3.79(d,1H),3.48(td,2H),2.93(s,2H),2.66-2.44(m,3H),2.23(d,1H),1.94(m,2H),1.74(m,2H),1.64-1.50(m,2H),1.16(t,3H),0.83(t,3H).
实施例35
第一步:(S)-叔丁基2-(2,6-二甲基苯基)-4-氧代哌啶-1-羧酸酯(35b)
(S)-tert-butyl 2-(2,6-dimethylphenylcarbamoyl)-4-oxopiperidine-1-carboxylate
将(S)-1-(叔丁氧基羰基)-4-氧代哌啶-2-羧酸35a(2.43g,10mmol)溶于二氯甲烷(30mL),再将2,6-二甲基苯胺(1.2g,10mmol)以及1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.29g,12mmol)加到反应中,室温下反应5小时。向反应液加二氯甲烷(20mL),有机相用饱和氯化钠(30mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析纯化(石油醚/乙酸乙酯(v/v)=10:1~2:1),得到白色固体(S)-叔丁基2-(2,6-二甲基苯基)-4-氧代哌啶-1-羧酸酯35b(2.5g,产率72%)。
Ms m/z(ESI):369.3[M+Na+];
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.11-7.04(m,3H),5.09(d,1H),4.04-3.72(m,2H),2.98(d,1H),2.77-2.37(m,3H),2.19(m,6H),1.53(s,9H)。
第二步:(S)-叔丁基2-(2,6-二甲基苯基)-4-(2-乙氧基-2-氧代亚乙基)哌啶-1-羧酸叔丁酯(35c)
(S)-tert-butyl2-(2,6-dimethylphenylcarbamoyl)-4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate
将(S)-叔丁基2-(2,6-二甲基苯基)-4-氧代哌啶-1-羧酸酯35b(2g,5.78mmol)溶于甲苯(30mL)中,再将(三苯基膦烯)乙酸乙酯(2.01g,5.78mmol)加到反应液中,升至回流反应4小时。将反应液减压浓缩后,粗品用柱层析纯化(石油醚/乙酸乙酯(v/v)=10:1~4:1),得到白色固体(S)-叔丁基2-(2,6-二甲基苯基)-4-(2-乙氧基-2-氧代亚乙基)哌啶-1-羧酸叔丁酯35c(2.2g,产率92%)。
Ms m/z(ESI):417.3[M+H+];
1H NMR(400MHz,CDCl3)δ7.78(brs,1H),7.15-6.95(m,3H),5.84(d,1H),5.04-4.89(m,1H),4.17-4.09(m,4H),3.60-3.04(m,2H),2.67(m,1H),2.45(m,1H),2.19(s,6H),1.50(s,9H),1.32-1.23(m,3H)。
第三步:(2S)-叔丁基2-(2,6-二甲基苯基)-4-(2-乙氧基-2-氧代乙基)哌啶-1-羧酸叔丁酯(35d)
(2S)-tert-butyl2-(2,6-dimethylphenylcarbamoyl)-4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate
室温下,将(S)-叔丁基2-(2,6-二甲基苯基)-4-(2-乙氧基-2-氧代亚乙基)哌啶-1-羧酸叔丁酯35c(2.2g,5.28mmol)溶于甲醇(30mL)中,再加入钯碳(0.22g,质量分数:10%),用氢气置换三次,在氢气球下室温反应6小时。将反应液过滤,滤饼用甲醇(20mL)洗涤,有机相减压浓缩后,得到白色固体(2S)-叔丁基2-(2,6-二甲基苯基)-4-(2-乙氧基-2-氧代乙基)哌啶-1-羧酸叔丁酯35d(2.1g,产率:95%)。
Ms m/z(ESI):419.3[M+H+];
第四步:乙基-2-((2S)-2-(2,6-二甲基苯基氨甲酰基)哌啶-4-基)乙酸乙酯(35e)
ethyl 2-((2S)-2-(2,6-dimethylphenylcarbamoyl)piperidin-4-yl)acetate
将(2S)-叔丁基2-(2,6-二甲基苯基)-4-(2-乙氧基-2-氧代乙基)哌啶-1-羧酸叔丁酯35d(2g,4.78mmol)溶于二氯甲烷(10mL)中,降温到0℃,再将三氟乙酸(10mL)滴加到反应液中,加毕于室温下反应4小时。将反应液旋干,用二氯甲烷(50mL)溶解,有机相用饱和碳酸氢钠(50mL)以及饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,得到白色固体乙基-2-((2S)-2-(2,6-二甲基苯基氨甲酰基)哌啶-4-基)乙酸乙酯35e(1.52g,产率:100%)。
Ms m/z(ESI):319.3[M+H+];
第五步:乙基-2-((2S)-2-(2,6-二甲基苯基氨甲酰基)-1-丙基哌啶-4-基)乙酸乙酯(35f)
ethyl 2-((2S)-2-(2,6-dimethylphenylcarbamoyl)-1-propylpiperidin-4-yl)acetate
室温下,将乙基-2-((2S)-2-(2,6-二甲基苯基氨甲酰基)哌啶-4-基)乙酸乙酯35e(1.5g,4.71mmol)溶于N,N-二甲基甲酰胺(15mL)中,再加入碳酸钾(0.975g,7.06mmol)及溴代正丙烷(0.696g,5.66mmol),加毕于80℃下反应4小时。向反应液中加水(50mL),用乙酸乙酯(30mL×3)萃取,合并有机相,用饱和食盐水溶液(50mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析纯化(二氯甲烷/甲醇(v/v)=50:1~20:1),得到白色固体乙基-2-((2S)-2-(2,6-二甲基苯基氨甲酰基)-1-丙基哌啶-4-基)乙酸乙酯35f(1.52g,产率:90%)。
Ms m/z(ESI):361.3[M+H+];
1H NMR(400MHz,MeOD)δ7.12-7.08(m,3H),4.16-4.11(m,2H),3.31-3.17(m,1H),2.99-2.88(m,1H),2.73-2.62(m,1H),2.32-2.02(m,11H),1.99-1.38(m,6H),1.25(m,3H),0.99-0.91(m,3H)。
第六步:(2S)-N-(2,6-二甲基苯基)-4-(2-羟乙基)-1-丙基哌啶-2-甲酰胺(35g)
(2S)-N-(2,6-dimethylphenyl)-4-(2-hydroxyethyl)-1-propylpiperidine-2-carboxamide
冰浴下,将四氢铝锂(0.316g,8.32mmol)溶于四氢呋喃(25mL)中,再将乙基-2-((2S)-2-(2,6-二甲基苯基氨甲酰基)-1-丙基哌啶-4-基)乙酸乙酯35f(1.5g,4.16mmol)溶于四氢呋喃(5mL)滴加入反应液中,加毕于室温下反应2小时。向反应液中加四氢呋喃(25mL),用冰水(1mL)淬灭反应,无水硫酸钠干燥,过滤,将滤液减压浓缩后,得到黄色固体(2S)-N-(2,6-二甲基苯基)-4-(2-羟乙基)-1-丙基哌啶-2-甲酰胺35g(1.3g,产率:98%)。
Ms m/z(ESI):319.4[M+H+];
第七步:(S)-2-((2,6-dimethylphenyl)carbamoyl)-1-propylquinuclidin-1-ium chloride(35)
(S)-2-((2,6-二甲基苯基)氨基甲酰基)-1-丙基奎宁-1-鎓氯化物
室温下,将(2S)-N-(2,6-二甲基苯基)-4-(2-羟乙基)-1-丙基哌啶-2-甲酰胺(35g)(1.2g,3.77mmol)溶于二氯甲烷(20mL)中,降温到0℃,再将二乙胺基三氟化硫(3.03g,1.85mmol)滴加到反应液中,冰浴下反应6小时。反应用饱和碳酸氢钠溶液(30mL)淬灭,分液,水相用二氯甲烷(20mL×3)萃取,合并有机相,用饱和食盐水溶液(30mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩后,粗品用柱层析(二氯甲烷/甲醇(v/v)=100:1~10:1),再用制备HPLC纯化,得到白色固体(S)-2-(2,6-二甲基苯基)-1-丙基-1-氮鎓二环[2.2.2]辛烷(0.3g,产率:26%)。
将用制备HPLC纯化的(S)-2-(2,6-二甲基苯基)-1-丙基-1-氮鎓二环[2.2.2]辛烷用甲醇溶解,加入氯化氢的乙酸乙酯溶液,反应后浓缩得到白色固体产品(S)-2-((2,6-二甲基苯基)氨基甲酰基)-1-丙基奎宁-1-鎓氯化物35。
Ms m/z(ESI):301.3[M+H+];
1H NMR(400MHz,DMSO)δ10.73(s,1H),7.14-7.08(m,3H),4.81(t,1H),4.27(q,1H),3.61(d,1H),3.48-3.40(m,3H),3.18-3.15(m,1H),2.48-2.37(m,1H),2.24(m,1H),2.17(s,6H),1.84-1.74(m,7H),0.90(t,3H)。
第八步:(2S,4R)-N-(2,6-二甲基苯基)-4-(2-氟乙基)-1-丙基哌啶-2-甲酰胺盐酸盐(2S,4R)-N-(2,6-dimethylphenyl)-4-(2-fluoroethyl)-1-propylpiperidine-2-carboxamide hydrochloride
将(2S,4R)-N-(2,6-二甲基苯基)-4-(2-氟乙基)-1-丙基哌啶-2-甲酰胺(0.12g,0.375mmol)溶于乙酸乙酯(4mL),加入氯化氢的乙酸乙酯溶液(2mL,4.0M),室温下搅拌反应1小时。将反应液直接旋干,得到白色固体(2S,4R)-N-(2,6-二甲基苯基)-4-(2-氟乙基)-1-丙基哌啶-2-甲酰胺盐酸盐(0.13g,产率97%)。
Ms m/z(ESI):321.3[M+H+];
1H NMR(400MHz,MeOD)δ7.08-7.01(m,3H),4.54(t,1H),4.42(t,1H),4.16(q,1H),3.68-3.54(m,1H),3.13-2.97(m,3H),2.38(q,1H),2.13(s,6H),2.03-1.88(m,13H),1.86-1.48(m,6H),0.91(t,3H)。
实施例36
(S)-1-烯丙基-N-(2,6-二甲基苯基)-1-丙基-哌啶-2-甲酰胺溴化物(化合物36)
(S)-1-allyl-N-(2,6-dimethylphenyl)-1-propyl-piperidin-1-ium-2-carboxamide bromide
将罗哌卡因(1.55g,5.7mmol)溶于干燥乙腈(25mL)中,加入烯丙基溴(0.82g,6.8mmol),室温反应60小时,减压浓缩后柱层析(DCM:MeOH=30:1)得粘稠液体(S)-1-烯丙基-N-(2,6-二甲基苯基)-1-丙基-哌啶-2-甲酰胺溴化物(36)(0.88g,产率:39.46%,HPLC:96.71%)。
1HNMR(400MHz,CDCl3):δ10.07(s,1H),δ7.14-7.05(m,3H),δ6.02-5.90(m,1H),δ5.76-5.63(m,2H),δ5.05-5.00(m,1H),δ4.20-4.00(m,2H),δ3.85-3.74(m,1H),δ3.38-3.32(m,2H),δ3.24-3.18(m,1H),δ2.42-2.26(m,2H),δ2.19(s,6H),δ1.90-1.83(m,6H),δ1.01-0.96(m,3H)。
实施例37
2,6-二甲基-N-((1-丙基哌啶-2-基)甲基)苯基酰胺盐酸盐(37)
2,6-dimethyl-N-((1-propylpiperidin-2-yl)methyl)benzamidehydrochloride
第一步:叔丁基2-((2,6-二甲基苯基酰胺)甲基)哌啶-1-羧酸脂(37b)
tert-butyl 2-((2,6-dimethylbenzamido)methyl)piperidine-1-carboxylate
将草酰氯(10mL)及2,6-二甲基苯甲酸37a(1.5g,7.0mmol)依次加入到50mL圆底烧瓶中,加入一滴DMF,反应2h,反应结束后,减压除去溶剂草酰氯,向其中加入二氯甲烷(10mL)溶解,再依次加入叔丁基2-(氨甲基)哌啶-1-羧酸脂(1.25g,8.7mmol)及三乙胺(1.95mL,14.0mmol),室温反应3h,反应结束后,加入水20mL,用二氯甲烷萃取(20mL*2),合并有机相,饱和食盐水洗(50mL*2),无水硫酸钠干燥有机相,减压浓缩,柱层析(石油醚:乙酸乙酯=5:1)得叔丁基2-((2,6-二甲基苯基酰胺)甲基)哌啶-1-羧酸脂(37b)(2.4g,产率90%)。
Ms m/z(ESI):369.3[M+Na+]。
第二步:2,6-二甲基-N-(哌啶-2-甲基)苯基酰胺(37c)
2,6-dimethyl-N-(piperidin-2-ylmethyl)benzamide
将叔丁基2-((2,6-二甲基苯基酰胺)甲基)哌啶-1-羧酸脂37b(204mg,6.9mmol),加入到20mL乙酸乙酯中,再加入HCl的乙酸乙酯溶液(4N,20mL),反应2h,反应结束后,减压除去溶剂,加入氨水调节pH=9,二氯甲烷萃取(30ml*3)合并有机相,饱和食盐水洗(40ml*4),无水硫酸钠干燥,减压浓缩得到粘稠状黄色液体2,6-二甲基-N-(哌啶-2-甲基)苯基酰胺37c(1.8g,100%)。
Ms m/z(ESI):247.3[M+H+]。
第三步:2,6-二甲基-N-((1-丙基哌啶-2-基)甲基)苯酰胺(37d)
2,6-dimethyl-N-((1-propylpiperidin-2-yl)methyl)benzamide
将2,6-二甲基-N-(哌啶-2-甲基)苯基酰胺37c(1g,4.0mmol)溶于DMF(10mL)中,依次加入碳酸钾(0.67g,4.87mmol)及溴丙烷(0.598g,4.87mmol),室温反应3h,反应结束后,向体系加入20mL水,乙酸乙酯萃取(20mL*3),合并有机相,饱和食盐水洗(30mL*3),无水硫酸钠干燥,减压浓缩,柱层析(二氯甲烷:甲醇=30:1)得淡黄色油状产物2,6-二甲基-N-((1-丙基哌啶-2-基)甲基)苯酰胺37d(0.687g,49%)。
Ms m/z(ESI):289.3[M+H+]。
第4步:2,6-二甲基-N-((1-丙基哌啶-2-基)甲基)苯基酰胺盐酸盐(37)
2,6-dimethyl-N-((1-propylpiperidin-2-yl)methyl)benzamidehydrochloride
将2,6-二甲基-N-((1-丙基哌啶-2-基)甲基)苯酰胺37d(0.687g,2.38mmol),加入到5mL乙酸乙酯中,再加入HCl的乙酸乙酯溶液(4Mol/L,5mL),反应2h,反应结束后,减压浓缩得到泡沫状固体2,6-二甲基-N-((1-丙基哌啶-2-基)甲基)苯基酰胺盐酸盐37(0.694g,94%)。
Msm/z(ESI):289.4[M+H+]。
1H NMR(400MHz,CDCl3):δ7.12-7.08(m,1H),6.98(d,2H),3.98(m,0.7H),3.81(m,0.37H),,3.67(m,0.69H),3.53(m,1.31H),3.43–3.04(m,4H),2.22(s,6H),1.87-1.53(m,8H),0.98-0.94(t,3H)。
生物测试
1,对豚鼠皮肤的浸润麻醉效应
罗哌卡因和本发明化合物对豚鼠皮肤的浸润麻醉通过豚鼠皮内丘疹法测定
体重300~400g的豚鼠,于实验前一日,剃净其背部前后各一处直径为4~5cm大小的皮区。实施例化合物溶于生理盐水,浓度0.5%;在豚鼠备好的皮区内以27G针头皮内注射0.25毫升,形成丘疹。在下表所示时间点用大头针以适度力度刺激丘疹处皮肤,每次测试在丘疹中央及外周随机选择6点刺激,每一点之间的刺激间隔3~6秒,观察并记录试验豚鼠的疼痛反射(嘶叫,颤抖等);有疼痛反射记为1,无疼痛反射记为0,直至所有刺激点全部恢复疼痛反应。每组6只动物,计算无疼痛反射的刺激数占总刺激次数的百分比,记为抑制率,增加超过50%判定为局部麻醉有效。化合物对豚鼠皮肤的浸润麻醉效应通过以上的实验进行测定,测得结果见表1:
表1对豚鼠皮肤的浸润麻醉效应
结论:通过豚鼠皮内丘疹法进行测定结果显示,本发明化合物对豚鼠皮肤的局部麻醉有效持续时间≥2小时,特别是化合物8、11、29和22明显优于对照组罗哌卡因。
2对大鼠尾神经的感觉阻滞
罗哌卡因和本发明化合物对大鼠尾神经的感觉阻滞通过大鼠热甩尾法测定。
200-250g雄性SD大鼠,每组5只,实验前用75%乙醇纱布擦净鼠尾,墨汁涂于尾部的下1/3处作为光刺激的标志。大鼠固定于固定器,以YLS-12A鼠尾光照测痛仪(济南益延科技发展有限公司)测试大鼠耐受光照热痛时间(潜伏时间,即开始照射至移开尾巴的时间)。为保护鼠尾免受烧伤,设定最大照射时间为10秒。先测试各动物基础潜伏时间,调整温度,使基础潜伏时间为3-4秒。0.5%实施例化合物溶于生理盐水,于鼠尾双侧尾神经旁分别注射100微升。注射后按下表所示时间点测试尾部对热刺激的反应潜伏时间。大鼠尾部的感觉功能阻滞通过比较给药前后大鼠对热刺激的反应潜伏时间增加程度判定,按下列公式计算最大可能效应百分比MPE%:MPE%=100×(测试潜伏时间-基础潜伏时间)/(最大照射时间-基础照射时间)。增加超过50%判定为感觉阻滞。反复连续测试时,将测痛部位稍加移动。本发明化合物对大鼠尾神经的感觉阻滞效应通过以上的实验进行测定,测得结果见表2:
表2对大鼠尾神经的感觉阻滞效应
化合物编号 | 感觉阻滞持续时间(小时) |
罗哌卡因 | 2 |
16c | 10 |
结论:通过大鼠热甩尾法测定结果显示,本发明化合物对大鼠的感觉阻滞时间≥2小时,特别是化合物16c明显优于对照组罗哌卡因。
Claims (6)
1.一种化合物或其立体异构体以及药学上可以接受的盐,其中该化合物选自以下结构之一:
2.根据权利要求1所述的化合物或其立体异构体以及药学上可以接受的盐,所述的盐选自盐酸盐或者氢溴酸盐。
3.一种化合物或其立体异构体以及药学上可以接受的盐,其中该化合物选自如下结构之一:
4.根据权利要求3所述的化合物或其立体异构体以及药学上可以接受的盐,其中所述的盐选自盐酸盐或者氢溴酸盐。
5.一种药物组合物,所述药物组合物含有治疗有效剂量的权利要求1~4中任一项所述的化合物及其立体异构体或药学上可以接受的盐,以及药学上可接受的载体或者赋形剂。
6.权利要求1~4中任一项所述的化合物、其立体异构体或其药学上可以接受的盐或权利要求5所述的药物组合物,在制备局部麻醉或镇痛领域药物中的应用。
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