CN113493385B - 一种合成盐酸布替萘芬的方法 - Google Patents
一种合成盐酸布替萘芬的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 33
- SUMAWDZJEIQACJ-UHFFFAOYSA-N 2-methylpyridine-4-carbaldehyde Chemical compound CC1=CC(C=O)=CC=N1 SUMAWDZJEIQACJ-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229960003273 butenafine hydrochloride Drugs 0.000 title claims abstract description 29
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 78
- 230000002829 reductive effect Effects 0.000 claims abstract description 26
- 239000012065 filter cake Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000284 extract Substances 0.000 claims description 11
- 238000007789 sealing Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000008213 purified water Substances 0.000 claims description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
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- 238000010438 heat treatment Methods 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
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- 239000000047 product Substances 0.000 abstract description 11
- 229960002962 butenafine Drugs 0.000 abstract description 8
- ABJKWBDEJIDSJZ-UHFFFAOYSA-N butenafine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)CC1=CC=C(C(C)(C)C)C=C1 ABJKWBDEJIDSJZ-UHFFFAOYSA-N 0.000 abstract description 8
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- 239000000243 solution Substances 0.000 description 13
- ADAIQTYPTRBLCB-UHFFFAOYSA-N 1-(4-tert-butylphenyl)-n-(naphthalen-1-ylmethyl)methanamine Chemical compound C1=CC(C(C)(C)C)=CC=C1CNCC1=CC=CC2=CC=CC=C12 ADAIQTYPTRBLCB-UHFFFAOYSA-N 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 9
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- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- AKEYUWUEAXIBTF-UHFFFAOYSA-N n-methylnaphthalen-1-amine Chemical compound C1=CC=C2C(NC)=CC=CC2=C1 AKEYUWUEAXIBTF-UHFFFAOYSA-N 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- MPWSRGAWRAYBJK-UHFFFAOYSA-N (4-tert-butylphenyl)methanamine Chemical compound CC(C)(C)C1=CC=C(CN)C=C1 MPWSRGAWRAYBJK-UHFFFAOYSA-N 0.000 description 2
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 2
- XMWGTKZEDLCVIG-UHFFFAOYSA-N 1-(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1 XMWGTKZEDLCVIG-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- WNLMYNASWOULQY-UHFFFAOYSA-N 4-tert-butylbenzoyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)C=C1 WNLMYNASWOULQY-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
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- 239000003638 chemical reducing agent Substances 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
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- 231100000171 higher toxicity Toxicity 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- NSNPSJGHTQIXDO-UHFFFAOYSA-N naphthalene-1-carbonyl chloride Chemical compound C1=CC=C2C(C(=O)Cl)=CC=CC2=C1 NSNPSJGHTQIXDO-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
- 229940031439 squalene Drugs 0.000 description 2
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ZOICEQJZAWJHSI-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl)boron Chemical compound [B]C1=C(F)C(F)=C(F)C(F)=C1F ZOICEQJZAWJHSI-UHFFFAOYSA-N 0.000 description 1
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- SQAINHDHICKHLX-UHFFFAOYSA-N 1-naphthaldehyde Chemical compound C1=CC=C2C(C=O)=CC=CC2=C1 SQAINHDHICKHLX-UHFFFAOYSA-N 0.000 description 1
- WUPHOULIZUERAE-UHFFFAOYSA-N 3-(oxolan-2-yl)propanoic acid Chemical compound OC(=O)CCC1CCCO1 WUPHOULIZUERAE-UHFFFAOYSA-N 0.000 description 1
- OKIHXNKYYGUVTE-UHFFFAOYSA-N 4-Fluorothiophenol Chemical compound FC1=CC=C(S)C=C1 OKIHXNKYYGUVTE-UHFFFAOYSA-N 0.000 description 1
- KDVYCTOWXSLNNI-UHFFFAOYSA-N 4-t-Butylbenzoic acid Chemical compound CC(C)(C)C1=CC=C(C(O)=O)C=C1 KDVYCTOWXSLNNI-UHFFFAOYSA-N 0.000 description 1
- 125000003352 4-tert-butyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 235000014435 Mentha Nutrition 0.000 description 1
- 241001072983 Mentha Species 0.000 description 1
- VJKUIHGLHKFWFY-UHFFFAOYSA-N N-[(4-tert-butylphenyl)methyl]-N-methylnaphthalene-1-carboxamide Chemical compound CN(Cc1ccc(cc1)C(C)(C)C)C(=O)c1cccc2ccccc12 VJKUIHGLHKFWFY-UHFFFAOYSA-N 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052980 cadmium sulfide Inorganic materials 0.000 description 1
- UHYPYGJEEGLRJD-UHFFFAOYSA-N cadmium(2+);selenium(2-) Chemical compound [Se-2].[Cd+2] UHYPYGJEEGLRJD-UHFFFAOYSA-N 0.000 description 1
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- 210000000170 cell membrane Anatomy 0.000 description 1
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- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000007265 chloromethylation reaction Methods 0.000 description 1
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- 238000006482 condensation reaction Methods 0.000 description 1
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- 239000012043 crude product Substances 0.000 description 1
- UCXUKTLCVSGCNR-UHFFFAOYSA-N diethylsilane Chemical compound CC[SiH2]CC UCXUKTLCVSGCNR-UHFFFAOYSA-N 0.000 description 1
- VDCSGNNYCFPWFK-UHFFFAOYSA-N diphenylsilane Chemical compound C=1C=CC=CC=1[SiH2]C1=CC=CC=C1 VDCSGNNYCFPWFK-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
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- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- NVSYANRBXPURRQ-UHFFFAOYSA-N naphthalen-1-ylmethanamine Chemical compound C1=CC=C2C(CN)=CC=CC2=C1 NVSYANRBXPURRQ-UHFFFAOYSA-N 0.000 description 1
- 229910052755 nonmetal Inorganic materials 0.000 description 1
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 1
- 229920001843 polymethylhydrosiloxane Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
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- 239000001632 sodium acetate Substances 0.000 description 1
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- 238000001228 spectrum Methods 0.000 description 1
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- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/14—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups
- C07C209/16—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明属于药物合成技术领域,具体涉及一种合成盐酸布替萘芬的方法;以N‑(4‑叔丁基苄基)‑萘甲胺与甲醇为原料,在催化剂作用下,合成布替萘芬。再经HCl/有机溶剂成盐,过滤,滤饼减压干燥后即为盐酸布替萘芬;本发明所制得的产品具有较高的纯度、收率。
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种合成盐酸布替萘芬的方法。
背景技术
盐酸布替萘芬(butenafine hydrochloride),化学名为N-(4-叔丁基苯基)-N-甲基-1-萘甲胺盐酸盐,是由日本科研株式会社研发的烯丙胺类抗真菌药,并于1992年在日本首次上市,商品名Mentax。本品能高选择性地抑制真菌角鲨烯环氧化酶活性,并抑制真菌体内角鲨烯和麦角固醇的生物合成,从而破坏真菌细胞膜生成,导致真菌死亡。具有抗菌谱广、抗菌活性高、复发率低、副作用小等特点,并被广泛应用于临床。其化学结构如下所示:
目前报道的关于布替萘芬的合成工艺主要有以下几种:
主流工艺是采用专利EP221781,CN1597660A、CN1727325A、CN101077858A及文献Yakugaku Zasshi,1991,111(2):126-137、中国医药工业杂志,1999,(3):102-103等报道的方法。该工艺采用萘(或其下游中间体)为原料先经氯甲基化合成1-氯甲基萘,再与甲胺反应生成N-甲基萘甲胺,后与对叔丁基卤苄缩合、成盐,制得得盐酸布替萘芬。路线如下:
该路线虽然具有原料易得、操作简单等优点。但反应多在干燥DMF中用无水碳酸钠或无水碳酸钾作缚酸剂进行反应。DMF沸点较高,回收不便;对叔丁基溴苄通常由对甲基叔丁苯溴代而得,制备时副产物多,污染较大,成本较高,为对其进行精制,常涉及减压蒸馏等苛刻操作,不适合工业化车间生产。同时由于N-烷基化反应时所用侧链卤代烃过量且反应温度较高,使得极易生成二取代杂质,进而生成季铵盐结构中间体,同时成品合成时也容易生成季铵盐杂质,不仅产品纯度较低,同时通过进一步精制后,总收率也较低(杂质相关结构如下所示)。
专利US5021458则以1-萘甲酸为原料,经氯化亚砜氯化得1-萘甲酰氯,再与1-(4-叔丁基苯)-N-甲基甲胺缩合得N-(4-叔丁基苄)-N-甲基-1-萘甲酰胺,最后经氢化铝锂还原、成盐,制得盐酸布替萘芬。路线如下:
此外,该专利还报道了以对叔丁基苯甲酸为原料,经氯化亚砜氯化得对叔丁基苯酰氯,与N-甲基萘甲胺缩合得4-叔丁基-N-甲基-N-(甲基萘)苯甲酰胺,后经氢化铝锂还原、成盐,制得盐酸布替萘芬的方法。路线如下:
但这两种方法均需要用到毒性、刺激性较大的酰氯,对设备要求较高,需要在特种反应间进行;同时还原反应需要用到活性较强的氢化铝锂,不仅操作危险性较强,同时生产成本较高,不适合大规模制备。
专利CN105130823B公开了一种以4-叔丁基苄胺为原料,与1-萘甲酰氯和甲酸在有机溶剂中,以有机硅烷化合物[二苯基硅烷、二乙基硅烷、聚(甲基氢硅氧烷)、苯基硅烷]为还原剂,在非金属硼类化合物[三乙基硼、三(五氟苯基硼)]为催化剂下发生N-甲基化反应,同时酰胺键被还原,而得到布替萘芬的方法。路线如下:
文献Angew.Chem.Int.Ed.,2015,54,9042-9046则以1-萘甲酸为原料,经苯硼酸催化后再经有机硅烷化合物及非金属硼类化合物还原后,以甲酸为碳源制得布替萘芬。路线如下:
但是,该类方法进行还原反应时应用到价格较高,毒性及腐蚀性较大的有机硅烷化合物和非金属硼类化合物,使得生产成本较高,不适合工业化生产。
德国应用化学Angew.Chem.Int.Ed.,2014,53(41),11010-11014报道了以1-萘甲醛和4-叔丁基苄胺为原料,以二氧化碳为碳源,在钌催化下制备目标产物。路线如下:
但是,该方法中的整个过程操作复杂,而且伴有大量无机盐副产物生成。而且,上述终产物的转化过程需要在很高的压力[CO2/H2(20/60bar)]下进行,对设备操作要求性较高,同样不适合工业化生产。
J.Org.Chem.,2018,83,11886-11895则在硒化镉/硫化镉、可见光催化条件下,经4-氟苯硫醇还原,再在偶氮二甲酸二异丙酯(DIAD)及三苯基膦(TPP)存在下,与碘甲烷反应制得目标产品。路线如下:
但该工艺用到毒性较大的重金属镉化合物合成关键中间体,其限量要求极低;制备目标产品时以毒性较大,沸点较低的碘甲烷为碳源引入甲基,同样会引入N-多烃化的季铵盐杂质,此外反应后生成的三苯基氧膦由于溶解性较差,反复精制后的收率较低。
综上所述,在已经被报道的制备布替萘芬的技术方法中,主要存在以下问题:
(1)以卤代烷烃进行N-烷基化反应,不仅容易产生N-过烷基化杂质,需要进一步精制导致收率较低,同时采用卤代烷这种基因毒性试剂进行N-烷基化反应,对于药物质量标准要求更加严格。
(2)通过酰胺还原引入N-烷基侧链,但需要应用到氢化铝锂或者有机硅烷化合物/非金属硼类化合物为还原剂,不仅反应条件较苛刻,同时使得生产成本较高;
(3)还原氨化过程需要应用毒性较大的重金属镉化合物,使得成品检测限度极低。
鉴于现有技术存在的较多问题,研究寻找一条反应条件温和,操作过程简便,产品收率高、纯度高,生产成本低的适合工业化生产布替萘芬的制备方法仍是目前需要解决。
发明内容
针对目前布替萘芬制备技术存在的问题,本发明提供了一种合成盐酸布替萘芬的方法。该方法不仅避免基因毒性试剂碘甲烷的应用,同时可有效避免N-过烷基化杂质,所制得的目标产品具有较高的纯度、收率。
本发明的具体技术方案如下:
一种合成盐酸布替萘芬的方法,N-(4-叔丁基苄基)-1-萘甲胺与甲醇反应后得到盐酸布替萘芬,反应式如下:
一种合成盐酸布替萘芬的方法,具体包括以下步骤:
惰性气体保护下,将催化剂、N-(4-叔丁基苄基)-1-萘甲胺和甲醇加入密封装置中,密封控温至反应结束后,反应液降至室温后,反应液加入纯化水中,有机溶剂萃取,萃取液减压浓缩至干后经HCl/有机溶剂成盐,过滤,滤饼减压干燥后即为盐酸布替萘芬。
优选的,所述催化剂为CpRuCl(PPh3)2,RuCl2(PPh3)2中的一种或其组合,其中特别优选RuCl2(PPh3)2。
优选的,所述N-(4-叔丁基苄基)-1-萘甲胺与催化剂的投料摩尔比为1:0.5%~5%,其中特别优选1:2%。
优选的,所述N-(4-叔丁基苄基)-1-萘甲胺与甲醇投料质量体积比为1:1~50,g/mL,其中特别优选1:2,g/mL。甲醇在此反应中,即作为反应底物又作为反应溶剂,量多时并不影响反应。
优选的,所述控温反应,可将密封装置置于温度为80~110℃加热设备中;所述加热装置可选用油浴加热,电热套,蒸汽加热,电炉等加热设备。所述密封设备可选用密封玻璃管,密封性能好的不锈钢反应釜,密封Schlenk装置等设备;本发明优选Schlenk装置进行验证。
优选地,控温反应时间为5~12小时;也可进行检测确定。
优选的,所述萃取溶剂为二氯甲烷,氯仿,乙酸乙酯中的一种或其组合。
优选的,所述HCl/有机溶剂为HCl/甲醇,HCl/乙醇,HCl/异丙醇,HCl/1,4-二氧六环,HCl/乙酸乙酯中的一种或其组合,其中特别优选HCl/甲醇。
优选的,所述HCl/有机溶剂的浓度为0.5~4mol/L,其中特别优选2mol/L。
本发明中,所述的惰性气体通常选择氮气、氩气,其中特别优选氩气。
与现有技术相比,本发明取得的技术效果是:
(1)通过甲醇对N-(4-叔丁基苄基)-1-萘甲胺的单取代反应进行N-烷基化反应,可有效避免N-过烷基化杂质,且本发明收率和纯度都有所提高。
(2)采用价廉的甲醇作为碳源,不仅可有效避免基因毒性试剂碘甲烷的使用,同时生产成本有效降低。
(3)经过一步成盐,对粗品进行精制的同时得到目标产品,反应步骤少,后处理处理简单,更适于工业化生产。
具体实施方式
下面通过实施例来进一步说明本发明,应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属于本发明要求保护的范围。
实验所用物料:化合物N-(4-叔丁基苄基)-1-萘甲胺可购买,也可参照现有公开的技术制备;其他实验所用物料未标明来源和规格的均为市售分析纯或化学纯。
本发明采用HPLC测定布替萘芬的纯度,色谱条件如下:
色谱柱:Welch Ultimate XB-C18(4.6mm×150mm,3.0μm);
流动相:醋酸盐缓冲液(取醋酸钠18.0g,冰醋酸9.8mL,用水稀释至1000mL)-甲醇-异丙醇(17:70:13);
柱温:30℃;
检测波长:282nm;
流速:1.0mL/min;
进样量:10μL。
以下各实施例中,未详细描述的各种过程和方法是本领域中公知的常规方法。
实施例1
氩气保护下,将RuCl2(PPh3)2(0.14g,0.2mmol)、N-(4-叔丁基苄基)-1-萘甲胺(3.03g,0.01mol)、甲醇(6mL)加入Schlenk装置中,密封后置于控温100℃油浴中反应7h后,反应液降至室温后,反应液加入纯化水(50mL)中,搅拌10min后二氯甲烷(50mL×3)提取,合并萃取液减压浓缩至干,加入HCl/甲醇(40mL,2mol/L)成盐,继续搅拌析晶2~3h后过滤,滤饼减压干燥后即为盐酸布替萘芬,收率95.6%,HPLC:99.89%。
实施例2
氩气保护下,将RuCl2(PPh3)2(34.8mg,0.05mmol)、N-(4-叔丁基苄基)-1-萘甲胺(3.03g,0.01mol)、甲醇(6mL)加入Schlenk装置中,密封后置于控温110℃油浴中反应6h后,反应液降至室温后,反应液加入纯化水(50mL)中,搅拌10min后二氯甲烷(50mL×3)提取,合并萃取液减压浓缩至干,加入HCl/甲醇(40mL,2mol/L)成盐,继续搅拌析晶2~3h后过滤,滤饼减压干燥后即为盐酸布替萘芬,收率89.6%,HPLC:99.82%。
实施例3
氩气保护下,将RuCl2(PPh3)2(0.35g,0.5mmol)、N-(4-叔丁基苄基)-1-萘甲胺(3.03g,0.01mol)、甲醇(6mL)加入Schlenk装置中,密封后置于控温90℃油浴反应12h后,反应液降至室温后,反应液加入纯化水(50mL)中,搅拌10min后二氯甲烷(50mL×3)提取,合并萃取液减压浓缩至干,加入HCl/甲醇(40mL,2mol/L)成盐,继续搅拌析晶2~3h后过滤,滤饼减压干燥后即为盐酸布替萘芬,收率94.1%,HPLC:99.73%。
实施例4
氩气保护下,将RuCl2(PPh3)2(0.42g,0.6mmol)、N-(4-叔丁基苄基)-1-萘甲胺(3.03g,0.01mol)、甲醇(6mL)加入Schlenk装置中,密封后置于控温90℃油浴中反应10h后,反应液降至室温后,反应液加入纯化水(50mL)中,搅拌10min后二氯甲烷(50mL×3)提取,合并萃取液减压浓缩至干,加入HCl/甲醇(40mL,2mol/L)成盐,继续搅拌析晶2~3h后过滤,滤饼减压干燥后即为盐酸布替萘芬,收率93.2%,HPLC:99.72%。
实施例5
氩气保护下,将CpRuCl(PPh3)2(0.15g,0.2mmol)、N-(4-叔丁基苄基)-1-萘甲胺(3.03g,0.01mol)、甲醇(6mL)加入玻璃管中,封管后置于控温110℃的电炉中反应6h后,反应液降至室温后,反应液加入纯化水(50mL)中,搅拌10min后乙酸乙酯(50mL×4)提取,合并萃取液减压浓缩至干,加入HCl/乙酸乙酯(40mL,2mol/L)成盐,继续搅拌析晶2~3h后过滤,滤饼减压干燥后即为盐酸布替萘芬,收率95.1%,HPLC:99.79%。
实施例6
氮气保护下,将RuCl2(PPh3)2(0.14g,0.2mmol)、N-(4-叔丁基苄基)-1-萘甲胺(3.03g,0.01mol)、甲醇(3mL)加入不锈钢高压釜装置中,密封后置于控温100℃电炉中反应7h后,反应液降至室温后,反应液加入纯化水(30mL)中,搅拌10min后二氯甲烷(30mL×3)提取,合并萃取液减压浓缩至干,加入HCl/乙醇(20mL,4mol/L)成盐,继续搅拌析晶2~3h后过滤,滤饼减压干燥后即为盐酸布替萘芬,收率93.4%,HPLC:99.82%。
实施例7
氩气保护下,将RuCl2(PPh3)2(0.14g,0.2mmol)、N-(4-叔丁基苄基)-1-萘甲胺(3.03g,0.01mol)、甲醇(15mL)加入Schlenk装置中,密封后置于控温100℃油浴中至反应4h后,反应液降至室温后,反应液加入纯化水(80mL)中,搅拌10min后氯仿(80mL×3)提取,合并萃取液减压浓缩至干,加入HCl/异丙醇(80mL,0.5mol/L)成盐,继续搅拌析晶2~3h后过滤,滤饼减压干燥后即为盐酸布替萘芬,收率85.3%,HPLC:99.71%。
实施例8
氩气保护下,将RuCl2(PPh3)2(0.14g,0.2mmol)、N-(4-叔丁基苄基)-1-萘甲胺(3.03g,0.01mol)、甲醇(18mL)加入Schlenk装置中,密封后置于控温100℃油浴中至反应6h后,反应液降至室温后,反应液加入纯化水(100mL)中,搅拌10min后二氯甲烷(100mL×3)提取,合并萃取液减压浓缩至干,加入HCl/1,4-二氧六环,(100mL,2mol/L)成盐,继续搅拌析晶2~3h后过滤,滤饼减压干燥后即为盐酸布替萘芬,收率95.3%,HPLC:99.84%。
Claims (4)
1.一种合成盐酸布替萘芬的方法,其特征在于,N-(4-叔丁基苄基)-1-萘甲胺与甲醇反应后得到盐酸布替萘芬,反应式如下:
;
具体包括以下步骤:惰性气体保护下,将催化剂、N-(4-叔丁基苄基)-1-萘甲胺和甲醇加入密封装置中,密封控温至反应结束后,反应液降至室温后,反应液加入纯化水中,有机溶剂萃取,萃取液减压浓缩至干后经HCl/有机溶剂成盐,过滤,滤饼减压干燥后即为盐酸布替萘芬;
所述催化剂为RuCl2(PPh3)2;
所述控温反应,将密封装置置于温度为80~110℃加热设备中;
所述N-(4-叔丁基苄基)-1-萘甲胺与催化剂的投料摩尔比为1:0.5%~5%。
2.如权利要求1所述的合成盐酸布替萘芬的方法,其特征在于,所述N-(4-叔丁基苄基)-1-萘甲胺与甲醇投料质量体积比为1:1~50,g/mL。
3.如权利要求1所述的合成盐酸布替萘芬的方法,其特征在于,萃取溶剂为二氯甲烷、氯仿、乙酸乙酯中的一种或其组合。
4.如权利要求1所述的合成盐酸布替萘芬的方法,其特征在于,所述HCl/有机溶剂为HCl/甲醇,HCl/乙醇,HCl/异丙醇,HCl/1,4-二氧六环,HCl/乙酸乙酯中的一种或其组合。
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