CN115925520A - 一种间苯三酚的合成方法 - Google Patents
一种间苯三酚的合成方法 Download PDFInfo
- Publication number
- CN115925520A CN115925520A CN202211373467.1A CN202211373467A CN115925520A CN 115925520 A CN115925520 A CN 115925520A CN 202211373467 A CN202211373467 A CN 202211373467A CN 115925520 A CN115925520 A CN 115925520A
- Authority
- CN
- China
- Prior art keywords
- phloroglucinol
- benzene
- diacyloxy
- reaction
- alkali
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 title claims abstract description 42
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 229960001553 phloroglucinol Drugs 0.000 title claims abstract description 42
- 238000010189 synthetic method Methods 0.000 title claims abstract description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 48
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 238000005917 acylation reaction Methods 0.000 claims abstract description 7
- 239000002585 base Substances 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 230000002140 halogenating effect Effects 0.000 claims abstract description 7
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 7
- 150000003000 phloroglucinols Chemical class 0.000 claims abstract description 4
- 230000010933 acylation Effects 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical group ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- STOUHHBZBQBYHH-UHFFFAOYSA-N (3-acetyloxyphenyl) acetate Chemical compound CC(=O)OC1=CC=CC(OC(C)=O)=C1 STOUHHBZBQBYHH-UHFFFAOYSA-N 0.000 claims description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical group O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 150000007517 lewis acids Chemical group 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- YHOBGCSGTGDMLF-UHFFFAOYSA-N sodium;di(propan-2-yl)azanide Chemical compound [Na+].CC(C)[N-]C(C)C YHOBGCSGTGDMLF-UHFFFAOYSA-N 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 21
- 239000007858 starting material Substances 0.000 abstract description 4
- 125000002252 acyl group Chemical group 0.000 abstract description 3
- 125000001309 chloro group Chemical group Cl* 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- NFFQQYJVAZVIDR-UHFFFAOYSA-N (3-acetyloxy-4-chlorophenyl) acetate Chemical compound CC(=O)Oc1ccc(Cl)c(OC(C)=O)c1 NFFQQYJVAZVIDR-UHFFFAOYSA-N 0.000 description 5
- 150000001555 benzenes Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CRUILBNAQILVHZ-UHFFFAOYSA-N 1,2,3-trimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1OC CRUILBNAQILVHZ-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
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- 230000000694 effects Effects 0.000 description 4
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- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 description 2
- SPSSULHKWOKEEL-UHFFFAOYSA-N 2,4,6-trinitrotoluene Chemical compound CC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O SPSSULHKWOKEEL-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
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- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
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- LGXAANYJEHLUEM-UHFFFAOYSA-N 1,2,3-tri(propan-2-yl)benzene Chemical compound CC(C)C1=CC=CC(C(C)C)=C1C(C)C LGXAANYJEHLUEM-UHFFFAOYSA-N 0.000 description 1
- GMVJKSNPLYBFSO-UHFFFAOYSA-N 1,2,3-tribromobenzene Chemical compound BrC1=CC=CC(Br)=C1Br GMVJKSNPLYBFSO-UHFFFAOYSA-N 0.000 description 1
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- 150000005207 1,3-dihydroxybenzenes Chemical class 0.000 description 1
- SXXLKZCNJHJYFL-UHFFFAOYSA-N 4,5,6,7-tetrahydro-[1,2]oxazolo[4,5-c]pyridin-5-ium-3-olate Chemical compound C1CNCC2=C1ONC2=O SXXLKZCNJHJYFL-UHFFFAOYSA-N 0.000 description 1
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- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
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- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000956 myotropic effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一种间苯三酚的合成方法,属于药物合成技术领域。本发明采用间苯二酚为起始原料溶于有机溶剂,与碱及酰化试剂反应生成1,3‑二酰氧基苯,起始原料价格低廉,来源广泛;1,3‑二酰氧基苯溶于有机溶剂中,加入催化剂及卤代试剂,发生卤代反应生成4‑卤代‑1,3‑二酰氧基苯,反应条件温和,异构体杂质限度低,后处理简单,产品纯度高;4‑卤代‑1,3‑二酰氧基苯与强碱混合,水解反应生成间苯三酚盐,随后酸化,纯化后获得间苯三酚纯品,无需添加催化剂,酰基与氯原子可同时被水解,无需额外脱保护步骤,反应操作简便,后处理简单,产品质量高,满足药用间苯三酚的要求。
Description
技术领域
本发明属于药物合成技术领域,更具体地说,涉及一种间苯三酚的合成方法。
背景技术
间苯三酚(Phloroglucinol,即1,3,5-三羟基苯),是由法国Laboratoire L.Lafon公司研发的一种亲肌性非阿托品非罂粟碱类纯平滑肌解痉药,能够直接作用于肠胃道和泌尿生殖道的平滑肌。与其他平滑肌解痉药相比,间苯三酚在解除平滑肌痉挛的同时,不会产生一系列抗胆碱副作用,不会引起低血压、心率加快、心率失常等症状,对心血管功能影响较小。间苯三酚主要用于治疗消化系统和胆道功能障碍引起的急性痉挛性疼痛,急性痉挛性尿道、膀胱、肾绞痛,妇科痉挛性疼痛,解痉止痛作用快、效果显著、耐受性好。
目前已公布的间苯三酚合成方法主要有硝基苯法、异丙苯法、三甲氧基苯法、卤代苯法几种。陈杨英等在染料工业(2000,38(4):24-25)中公开了一种硝基苯法制备间苯三酚的工艺:原料三硝基甲苯(TNT)经甲基氧化成羧酸、硝基还原为胺、胺基酸水解生成酚等步骤获得间苯三酚;硝基苯法具有原料来源广、价格低、总收率高的优点,但反应后处理困难,产生大量废酸污染环境,且原料为炸药,存在安全隐患。
专利JP1988048254与JP1989012737等公开了异丙苯法制备间苯三酚的工艺:此工艺以均三异丙苯为起始原料,在碱性加热条件下使用氧气氧化,可以获得一系列氧化产物,随后在酸性条件下使用过氧化物氧化为单一的THPO,最后酸化水解获得间苯三酚;异丙苯法具有反应收率高、原料来源丰富、反应条件温和、工艺成熟的优点,但第一次氧化阶段产物结构复杂,难以进行质量控制,不适合用于药用间苯三酚的合成。
专利CN106866378公开了一种三甲氧基苯法制备间苯三酚的工艺:以1,3,5-三甲氧基苯为起始原料,使用氯化铝脱除甲醚,之后碱化、精制后获得间苯三酚;此方法制备间苯三酚收率高,但是反应条件苛刻,杂质难以分离,且有大量废酸生成。
卤代苯法起始原料可选自二羟基卤代苯、三氯苯、三溴苯、六氯苯等,其中以二羟基卤代苯为原料的方法具有原料来源丰富、价格低廉、反应温和的特点,适合用于药用间苯三酚的生产。专利CN103641687公开了一种二羟基卤代苯法制备间苯三酚的工艺:以间苯二酚为原料,其用NBS溴代获得4-溴间苯二酚,随后在铜催化下与氢氧化钾反应获得间苯三酚盐,酸化精制后获得间苯三酚;该方法操作简便,但NBS溴代一步区域选择性差,存在多取代及2-溴取代的副产物,难以纯化,水解步骤需要铜催化,会带来金属残留,影响最终间苯三酚成品的质量。
附图说明
图1为二乙酰氧基苯的1HNMR图谱;
图2为4-氯-1,3-二乙酰氧基苯的1H NMR图谱;
图3为间苯三酚的1H NMR图谱。
发明内容
针对现有技术存在的上述问题,本发明所要解决的技术问题在于提供一种反应条件温和、化学选择性高、中间体纯化简单、产品质量高的间苯三酚合成方法。
为了解决上述技术问题,本发明所采用的技术方案如下:
一种间苯三酚的合成方法,步骤如下:
其中,R选自甲酰基、乙酰基、苯甲酰基;
(1)酰化反应:将间苯二酚溶于有机溶剂,与碱及酰化试剂反应生成1,3-二酰氧基苯;
(2)卤代反应:1,3-二酰氧基苯溶于有机溶剂中,加入催化剂及卤代试剂,反应生成4-卤代-1,3-二酰氧基苯;
(3)水解反应:4-卤代-1,3-二酰氧基苯与强碱混合,反应生成间苯三酚盐,随后酸化,获得间苯三酚粗品,纯化后获得间苯三酚纯品。
优选地,步骤(1)所述溶剂选自丙酮、N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃中。
优选地,步骤(1)所述碱为非亲核性的有机碱或无机碱,更优选自碳酸钠、碳酸钾、碳酸铯、氢化钠、三乙胺、二异丙基乙基胺、1,8-二氮杂双环[5.4.0]十一碳-7-烯、吡啶、4-二甲氨基吡啶;所述碱加入摩尔量与间苯二酚摩尔量之比为4.0∶1-8.0∶1,更优选5.0∶1-6.0∶1;
优选地,步骤(1)所述酰化试剂选自甲酸酐、N,N-二甲基甲酰胺、甲酸甲酯、甲酸乙酯、乙酰氯、乙酸酐、乙酸乙酯、苯甲酰氯、苯甲酸酐;
优选地,所述酰化试剂的加入摩尔量与间苯二酚摩尔量之比为3.0∶1-8.0∶1,更优选4.0∶1-5.0∶1。
优选地,步骤(2)所述有机溶剂选自二氯甲烷、二氯乙烷、氯仿、丙酮、乙腈、四氢呋喃、甲基叔丁基醚。
优选地,步骤(2)所述催化剂为路易斯酸,更优选自氯化铝、氯化铁、三氯化硼、三氟化硼乙醚、三甲基氯硅烷、三氟甲磺酸三甲基硅酯。
优选地,步骤(2)所述卤代试剂选自N-氯代琥珀酰亚胺、二氯亚砜、三氯化磷、五氯化磷、液溴、N-溴代琥珀酰亚胺、1,3-二溴-5,5-二甲基海因、三溴化磷,且氯代较溴代化学选择性更优;所述卤代试剂的加入摩尔量与1,3-二乙酰氧基苯摩尔量之比为0.9∶1-1.5∶1,更优选1.1∶1-1.2∶1。
优选地,步骤(3)所述强碱选自氢氧化钠、氢氧化钾、正丁基锂、叔丁基锂、二异丙基胺基锂、二异丙基胺基钠、双三甲基硅基胺基锂、双三甲基硅基胺基钠;所述碱加入摩尔量与4-卤代-1,3-二乙酰氧基苯质量之比为3.0∶1-6.0∶1,更优选4.0∶1-5.0∶1;向反应体系中加入碱10%质量的水可以促进反应进行,反应结束后加入碱5.0-8.0倍质量的水将所有固体溶解。
优选地,步骤(3)中水解反应温度为130-180℃,更优选150-160℃。
优选地,步骤(3)所述酸选自硫酸、盐酸、磷酸;反应体系酸化后,pH值应控制在1-3之间。
相比于现有技术,本发明的有益效果为:
1)本发明采用间苯二酚为起始原料,价格低廉,来源广泛;间苯二酚制备成1,3-二酰氧基苯反应收率高、后处理简便、产品质量高;
2)因酰基位阻效应的影响,1,3-二酰氧基苯卤代反应的区域选择性远高于间苯二酚的卤代反应,反应条件温和,异构体杂质限度低;4-卤代-1,3-二酰氧基苯水溶性远远低于4-卤代-1,3-羟基苯,后处理简单,产品纯度高;
3)4-卤代-1,3-二酰氧基苯碱水解无需添加催化剂,酰基与氯原子可同时被水解,无需额外脱保护步骤,反应操作简便,后处理简单,产品间苯三酚质量高,符合药典规定标准。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面结合具体实施例对本发明进一步进行描述。
实施例1
(1)酰化反应
将间苯二酚(200g,1.82moL)溶于丙酮(5L)中,依次加入碳酸钾(1.25kg,9.1moL)和乙酸酐(854mL,9.1moL),加毕后于30℃下搅拌反应3h;反应结束后过滤去除碳酸钾,减压蒸去溶剂,继续调节真空度-0.095Mpa减压蒸馏,收集173-178℃馏分,得1,3-二乙酰氧基苯(305g,1.56moL,86%)。
1H NMR(400MHz,Chloroform-d)δ7.37(t,J=8.2Hz,1H),6.98(dd,J=8.2,2.2Hz,2H),6.92(t,J=2.2Hz,1H),2.29(s,6H).
(2)卤代反应
将1,3-二乙酰氧基苯(305g,1.56moL)溶于乙腈(3.0L)中,30℃搅拌下分批加入N-氯代琥珀酰亚胺(261g,1.96moL)溶液,随后将三甲基氯硅烷(27mL,0.3moL),滴加完毕后继续反应3h;反应结束减压蒸去溶剂,加入乙酸乙酯(2.0L),用水(1L)洗涤三次,有机相用无水硫酸钠干燥,过滤,减压蒸去溶剂,得4-氯-1,3-二乙酰氧基苯粗品;向4-氯-1,3-二乙酰氧基苯粗品中加入甲苯(500mL),加热回流,随后自然冷却搅拌析晶,冷却至室温后继续降温至5~10℃搅拌析晶2h,过滤,滤饼以预冷的甲苯(50mL)洗涤,真空干燥,得4-氯-1,3-二乙酰氧基苯(317g,1.39moL,89%)。
1H NMR(400MHz,Chloroform-d)δ7.42(d,J=8.2,1H),7.01-6.96(m,2H),2.34(s,3H),2.28(s,3H).
(3)水解反应
将4-氯-1,3-二乙酰氧基苯(317g,1.39moL)与氢氧化钾(1.44kg,25.7moL)混合,加入水(144mL),密封升温至150℃反应5h;反应结束后冷却至50℃,缓慢加入水(8.5L),并继续冷却至室温;向反应溶液中加入盐酸(6N),调节pH至2,过滤;滤液用乙酸乙酯(2.0L)萃取,分出有机层,减压蒸去溶剂,得间苯三酚粗品;向间苯三酚粗品中加入水(300mL),活性炭(10g),加热至回流,搅拌1h,趁热过滤,随后自然冷却析晶,冷却至室温后继续降温至5~10℃析晶2h,过滤,产品用冷的纯化水浇洗,真空干燥,得间苯三酚(134g,1.07moL,77%)。
1H NMR(400MHz,DMSO-d6)δ8.91(s,3H),5.64(s,3H).
Claims (10)
2.根据权利要求1所述的间苯三酚的合成方法,其特征在于,步骤(1)所述的酰化反应中的有机溶剂选自丙酮、N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃;所述碱为非亲核性的有机碱或无机碱;所述的酰化试剂选自甲酸酐、N,N-二甲基甲酰胺、甲酸甲酯、甲酸乙酯、乙酰氯、乙酸酐、乙酸乙酯、苯甲酰氯、苯甲酸酐。
3.根据权利要求2所述的间苯三酚的合成方法,其特征在于,步骤(1)所述的碱选自碳酸钠、碳酸钾、碳酸铯、氢化钠、三乙胺、二异丙基乙基胺、1,8-二氮杂双环[5.4.0]十一碳-7-烯、吡啶、4-二甲氨基吡啶。
4.根据权利要求3所述的间苯三酚的合成方法,其特征在于,步骤(1)所述的碱与间苯二酚摩尔质量之比为4.0∶1~8.0∶1。
5.根据权利要求3所述的间苯三酚的合成方法,其特征在于,步骤(1)所述的酰化试剂与间苯二酚摩尔质量之比为3.0∶1~8.0∶1。
6.根据权利要求1所述的间苯三酚的合成方法,其特征在于,步骤(2)所述的卤代反应中的有机溶剂选自二氯甲烷、二氯乙烷、氯仿、丙酮、乙腈、四氢呋喃、甲基叔丁基醚;所述的催化剂为路易斯酸;所述的卤代试剂选自N-氯代琥珀酰亚胺、二氯亚砜、三氯化磷、五氯化磷、液溴、N-溴代琥珀酰亚胺、1,3-二溴-5,5-二甲基海因、三溴化磷。
7.根据权利要求6所述的间苯三酚的合成方法,其特征在于,步骤(2)所述的卤代试剂与1,3-二乙酰氧基苯摩尔质量之比为0.9∶1~1.5∶1。
8.根据权利要求1所述的间苯三酚的合成方法,其特征在于,步骤(3)所述的水解反应中的强碱选自氢氧化钠、氢氧化钾、正丁基锂、叔丁基锂、二异丙基胺基锂、二异丙基胺基钠、双三甲基硅基胺基锂、双三甲基硅基胺基钠;所述的酸选自硫酸、盐酸、磷酸。
9.根据权利要求8所述的间苯三酚的合成方法,其特征在于,所述的强碱与4-卤代-1,3-二乙酰氧基苯摩尔质量之比为3.0∶1~6.0∶1。
10.根据权利要求1所述的间苯三酚的合成方法,其特征在于,步骤(3)所述的水解反应温度为130~180℃。
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