CN102026941A - 乙炔基环丙烷的合成方法 - Google Patents
乙炔基环丙烷的合成方法 Download PDFInfo
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- CN102026941A CN102026941A CN2009801116981A CN200980111698A CN102026941A CN 102026941 A CN102026941 A CN 102026941A CN 2009801116981 A CN2009801116981 A CN 2009801116981A CN 200980111698 A CN200980111698 A CN 200980111698A CN 102026941 A CN102026941 A CN 102026941A
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- China
- Prior art keywords
- lithium
- acid
- formula
- alkyl
- compound
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 31
- HZAIHFIZXXSPFA-UHFFFAOYSA-N ethynylcyclopropane Chemical compound [C+]#CC1CC1 HZAIHFIZXXSPFA-UHFFFAOYSA-N 0.000 title abstract 2
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- -1 nitro, amino group Chemical group 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical compound C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 9
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052744 lithium Inorganic materials 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- GUAHPAJOXVYFON-ZETCQYMHSA-N (8S)-8-amino-7-oxononanoic acid zwitterion Chemical compound C[C@H](N)C(=O)CCCCCC(O)=O GUAHPAJOXVYFON-ZETCQYMHSA-N 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- 229910052728 basic metal Inorganic materials 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 4
- 101001051297 Aspergillus oryzae (strain ATCC 42149 / RIB 40) Leucine aminopeptidase A Proteins 0.000 claims description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000003818 basic metals Chemical class 0.000 claims description 3
- 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 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 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 description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- OQOGEOLRYAOSKO-UHFFFAOYSA-N 1,1-dichloro-1-nitroethane Chemical compound CC(Cl)(Cl)[N+]([O-])=O OQOGEOLRYAOSKO-UHFFFAOYSA-N 0.000 claims description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims description 2
- NABHJQWQMBODEZ-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[K] Chemical compound C(C)(C)N(C(C)C)CC[K] NABHJQWQMBODEZ-UHFFFAOYSA-N 0.000 claims description 2
- WOWJWPXBKOURTA-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[Na] Chemical compound C(C)(C)N(C(C)C)CC[Na] WOWJWPXBKOURTA-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WXZIKFXSSPSWSR-UHFFFAOYSA-N [Li]CCCCC Chemical compound [Li]CCCCC WXZIKFXSSPSWSR-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-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
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical group [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 claims description 2
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 claims description 2
- XBEREOHJDYAKDA-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].CC[CH2-] XBEREOHJDYAKDA-UHFFFAOYSA-N 0.000 claims description 2
- JZTGYMSFBMJXDM-UHFFFAOYSA-N lithium;trimethyl(trimethylsilyloxy)silane Chemical compound [Li].C[Si](C)(C)O[Si](C)(C)C JZTGYMSFBMJXDM-UHFFFAOYSA-N 0.000 claims description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 2
- OMPRBJYWJMLNGP-UHFFFAOYSA-N potassium;trimethyl(trimethylsilyloxy)silane Chemical compound [K].C[Si](C)(C)O[Si](C)(C)C OMPRBJYWJMLNGP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- YAJATQWDNWKSKE-UHFFFAOYSA-N sodium;trimethyl(trimethylsilyloxy)silane Chemical compound [Na].C[Si](C)(C)O[Si](C)(C)C YAJATQWDNWKSKE-UHFFFAOYSA-N 0.000 claims description 2
- 150000001339 alkali metal compounds Chemical class 0.000 claims 1
- AIRYVOBWESROTH-UHFFFAOYSA-N 1,1-dimethoxyethylcyclopropane Chemical compound COC(C)(OC)C1CC1 AIRYVOBWESROTH-UHFFFAOYSA-N 0.000 abstract description 4
- 125000003396 thiol group Chemical class [H]S* 0.000 abstract 2
- 239000000047 product Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000003377 acid catalyst Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 239000008241 heterogeneous mixture Substances 0.000 description 3
- 239000011973 solid acid Substances 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- RXXZLYVECUNNLX-UHFFFAOYSA-N 1-cyclopropylethenethiol Chemical compound C=C(C1CC1)S RXXZLYVECUNNLX-UHFFFAOYSA-N 0.000 description 2
- IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- VWWMOACCGFHMEV-UHFFFAOYSA-N dicarbide(2-) Chemical compound [C-]#[C-] VWWMOACCGFHMEV-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- SLGWESQGEUXWJQ-UHFFFAOYSA-N formaldehyde;phenol Chemical compound O=C.OC1=CC=CC=C1 SLGWESQGEUXWJQ-UHFFFAOYSA-N 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- KCVYFJJCVIVNOA-UHFFFAOYSA-N n'-[[diethoxy(methyl)silyl]methyl]hexane-1,6-diamine Chemical compound CCO[Si](C)(OCC)CNCCCCCCN KCVYFJJCVIVNOA-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229920001568 phenolic resin Polymers 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- ZSUXOVNWDZTCFN-UHFFFAOYSA-L tin(ii) bromide Chemical compound Br[Sn]Br ZSUXOVNWDZTCFN-UHFFFAOYSA-L 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- OGYGFBZFWNMNHB-UHFFFAOYSA-N 1,4-dimethylcyclohexa-2,4-diene-1-sulfonic acid Chemical compound CC1=CCC(C)(S(O)(=O)=O)C=C1 OGYGFBZFWNMNHB-UHFFFAOYSA-N 0.000 description 1
- HVCFCNAITDHQFX-UHFFFAOYSA-N 1-cyclopropylethanone Chemical class CC(=O)C1CC1 HVCFCNAITDHQFX-UHFFFAOYSA-N 0.000 description 1
- VDJSNCWPUWWWLH-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid;hydrate Chemical compound O.OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O VDJSNCWPUWWWLH-UHFFFAOYSA-N 0.000 description 1
- ZMCHBSMFKQYNKA-UHFFFAOYSA-N 2-aminobenzenesulfonic acid Chemical compound NC1=CC=CC=C1S(O)(=O)=O ZMCHBSMFKQYNKA-UHFFFAOYSA-N 0.000 description 1
- PAUDQWJTTVPGHZ-UHFFFAOYSA-N 2-hydroxy-5-sulfobenzoic acid;hydrate Chemical compound O.OC(=O)C1=CC(S(O)(=O)=O)=CC=C1O PAUDQWJTTVPGHZ-UHFFFAOYSA-N 0.000 description 1
- VRBVUAYEXFCDPE-UHFFFAOYSA-N 2-pyridin-2-ylethanesulfonic acid Chemical compound OS(=O)(=O)CCC1=CC=CC=N1 VRBVUAYEXFCDPE-UHFFFAOYSA-N 0.000 description 1
- RGIIAYDCZSXHGL-UHFFFAOYSA-N 2-pyridin-4-ylethanesulfonic acid Chemical compound OS(=O)(=O)CCC1=CC=NC=C1 RGIIAYDCZSXHGL-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- CYJJLCDCWVZEDZ-UHFFFAOYSA-N 8-aminonaphthalene-1-sulfonic acid Chemical compound C1=CC(S(O)(=O)=O)=C2C(N)=CC=CC2=C1 CYJJLCDCWVZEDZ-UHFFFAOYSA-N 0.000 description 1
- LGDFHDKSYGVKDC-UHFFFAOYSA-N 8-hydroxyquinoline-5-sulfonic acid Chemical compound C1=CN=C2C(O)=CC=C(S(O)(=O)=O)C2=C1 LGDFHDKSYGVKDC-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910021555 Chromium Chloride Inorganic materials 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 238000006223 Seyferth-Gilbert homologation reaction Methods 0.000 description 1
- 229910052581 Si3N4 Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 229910021623 Tin(IV) bromide Inorganic materials 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 229910021550 Vanadium Chloride Inorganic materials 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 150000000475 acetylene derivatives Chemical class 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- QDHFHIQKOVNCNC-UHFFFAOYSA-N butane-1-sulfonic acid Chemical compound CCCCS(O)(=O)=O QDHFHIQKOVNCNC-UHFFFAOYSA-N 0.000 description 1
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 description 1
- YNYHGRUPNQLZHB-UHFFFAOYSA-M copper(1+);trifluoromethanesulfonate Chemical compound [Cu+].[O-]S(=O)(=O)C(F)(F)F YNYHGRUPNQLZHB-UHFFFAOYSA-M 0.000 description 1
- GZWXEFRPSWBAGC-UHFFFAOYSA-N copper;trifluoromethanesulfonic acid Chemical compound [Cu].OS(=O)(=O)C(F)(F)F GZWXEFRPSWBAGC-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- CNFDGXZLMLFIJV-UHFFFAOYSA-L manganese(II) chloride tetrahydrate Chemical compound O.O.O.O.[Cl-].[Cl-].[Mn+2] CNFDGXZLMLFIJV-UHFFFAOYSA-L 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 239000002808 molecular sieve Substances 0.000 description 1
- PDKHNCYLMVRIFV-UHFFFAOYSA-H molybdenum;hexachloride Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Mo] PDKHNCYLMVRIFV-UHFFFAOYSA-H 0.000 description 1
- 229910052901 montmorillonite Inorganic materials 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- RPESBQCJGHJMTK-UHFFFAOYSA-I pentachlorovanadium Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[V+5] RPESBQCJGHJMTK-UHFFFAOYSA-I 0.000 description 1
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- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DVECLMOWYVDJRM-UHFFFAOYSA-N pyridine-3-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CN=C1 DVECLMOWYVDJRM-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
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- 239000011347 resin Substances 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- APPHYFNIXVIIJR-UHFFFAOYSA-K scandium bromide Chemical compound Br[Sc](Br)Br APPHYFNIXVIIJR-UHFFFAOYSA-K 0.000 description 1
- HUIHCQPFSRNMNM-UHFFFAOYSA-K scandium(3+);triiodide Chemical compound [Sc+3].[I-].[I-].[I-] HUIHCQPFSRNMNM-UHFFFAOYSA-K 0.000 description 1
- QUJLPICXDXFRSN-UHFFFAOYSA-N scandium;trifluoromethanesulfonic acid Chemical compound [Sc].OS(=O)(=O)C(F)(F)F QUJLPICXDXFRSN-UHFFFAOYSA-N 0.000 description 1
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical class O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
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- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- UIYCHXAGWOYNNA-UHFFFAOYSA-N vinyl sulfide Chemical compound C=CSC=C UIYCHXAGWOYNNA-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- CKLHRQNQYIJFFX-UHFFFAOYSA-K ytterbium(III) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Yb+3] CKLHRQNQYIJFFX-UHFFFAOYSA-K 0.000 description 1
- PCMOZDDGXKIOLL-UHFFFAOYSA-K yttrium chloride Chemical compound [Cl-].[Cl-].[Cl-].[Y+3] PCMOZDDGXKIOLL-UHFFFAOYSA-K 0.000 description 1
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- LSWWNKUULMMMIL-UHFFFAOYSA-J zirconium(iv) bromide Chemical compound Br[Zr](Br)(Br)Br LSWWNKUULMMMIL-UHFFFAOYSA-J 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/04—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
- C07C1/321—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a non-metal atom
- C07C1/322—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a non-metal atom the hetero-atom being a sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- C07C2531/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
乙炔基环丙烷在通过(1,1-二甲氧基乙基)-环丙烷与硫醇进行反应并从中间体脱去硫醇的两步工艺中制备得到。
Description
技术领域
本发明涉及式
的乙炔基环丙烷的制备的两步法,乙炔基环丙烷是药物活性成分合成过程中的一种中间体,药物活性成分如抗病毒剂:(-)6-氯-4-环丙基乙炔基-4-三氟甲基-1,4-二氢-2H-3,1-苯并噁嗪-2-酮,其是一种高效的人体免疫缺抗病毒(HIV)逆转录酶抑制剂(WO-A96/22955)。
背景技术
美国专利US-B-6552239公开的式I的化合物的合成方法是从环丙甲醛和重氮膦酸酯开始的。这一反应也被称为Seyferth-Gilbert炔合成。环丙甲醛是将(1,1-二氯乙基)环丙烷脱去两个氯化氢分子而制得。该方法的缺陷是:谐二氯化物的制备需要极端严格的条件(例如PCL5),并且每生产一当量的产品,将有至少两当量的卤化物废物不得不处理。
专利EP-A-0936207和专利GB-A-2355724都公开了一种环丙烷闭环方法。1,3-二卤丙烷与乙炔衍生物反应,所产生的戊炔在有机金属化合物(例如正丁基锂)存在时就会环化。在接下来的一个或者两个步骤中,就可以得到式I的化合物。这些从1,3-二卤丙烷开始的方法每生成一当量的产品,也生成至少两当量的卤化物废物。其另一个缺陷是,规模生产状态下的反应温度非常低,大约只有-70℃到-100℃。
在专利EP-A 922686公开的另一种方法中,两当量的甲醇直接从(1,1-二甲氧基乙烯基)环丙烷脱去。
专利US 6297410还公开了另一种方法,其中,在消除(elimination)过程中,烯炔副产品就产生了,并且副产品与产品极难分离。
专利US 6072094所述的方法涉及到一个顺反乙烯基硫醚混合物的消除步骤。所述的乙烯基硫醚的制备需要硅烷化试剂。由于初始物质的正反式平衡性质,产品不得不从两种不同的初始化合物中分离。既然实施最后的步骤使用了顺反式异构混合物,那么就会涉及到顺式和反式消除。然而,顺式消除的最佳反应条件不同于反式消除。
发明内容
因此,本发明的目的是提供一种制备乙炔基环丙烷的替代方法,该方法不需要非常低的温度,生成的卤化物废物很少甚至没有。最后,将建立一种方法,该方法最后的消除步骤是始于一种简单的化合物,而不是一种异构混合物。
根据本发明,上述目的是通过以下的步骤实现的。
本发明主张的是式
的乙炔基环丙烷的制备方法,其中,在第一步中,式
的(1,1-二甲氧基乙基)环丙烷与式
HSR1 III
的硫醇进行反应,其中R1选自C1-C6烷基、C3-C6环烷基、芳香基和芳烷基,其中每一个烷基、环烷基、芳香基和芳烷基可携带一个或者多个卤原子、硝基、氨基和/或选自C1-6-烷基、C1-6烷氧基和C3-6环烷基的进一步的取代基,其中该种进一步的取代基可选地由一个或者多个卤原子取代,每一当量式II的化合物就有两当量的甲醇被脱去,并且获得式
的化合物,其中R1的定义如上所述,
该发明方法的第二步中,式III的硫醇被脱去,以形成式I的化合物。
本发明方法相对于现有技术的一个优点是:在反应过程中,没有卤化物废物产生。
另一个优点是:不加热反应混合物,其第二个步骤也能实施。因此,产生不期望有的副产品的危险就减少了。另外,用本方法生产,其总体产率(按(1,1-二甲氧基乙基)环丙烷计算)是用专利EP-A 922686的总体产率的两倍多。
还有一个优点是:其消除步骤从一种单一的初始化合物开始。因此,异构混合物的问题就避免了。此外,本发明提供了一种利用廉价的试剂合成乙炔基环丙烷的有效方法。
不像专利US 6072094所公开的方法,其中(2-环丙基乙烯基)硫烷基苯的E-和Z-异构体的混合物脱去一当量的苯硫酚,以生产中等产率的乙炔基环丙烷,本发明的(1-环丙基乙烯基)硫烷基苯提供了一个更大空间可及性的质子,并且不涉及顺反式消除,因此,获得的产率更高。
术语“C1-Cn烷基”,例如“C1-C18烷基”,代表有一至n个碳原子的直链或者支链烷基。C1-C18烷基代表的基团如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、辛基、癸基、十二烷基和十八烷基。
术语“C1-Cn烷氧基”,例如“C1-C6烷氧基”,代表有一个至n个碳原子的直链或者支链烷氧基。C1-C6烷氧基代表的基团如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基和己氧基。
术语“C3-Cn环烷基”,例如“C3-C10环烷基”,代表有3个至n个碳原子的环脂族基团。C3-C10环烷基代表的物质如单环和多环体系,例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基或者冰片基。
术语芳基代表一种芳族基团,其可以用一个或者多个卤原子、氨基和/或可选地取代的C1-C6烷基、C1-C6烷氧基团或双-C1-C6烷基氨基团可选地取代。C6-C20芳基代表诸如苯基、萘基及其如上所列物的衍生物。
术语芳烷基也代表一种芳族基团,其中芳烷基部分的烷基部分是直链C1-C8烷基,并且芳基部分选自苯基、萘基、呋喃基、噻吩基、苯并[b]呋喃基、苯并[b]噻吩基,其可以用一个或者多个卤素原子、芳香基团和/或可选地取代的C1-C6烷基、C1-C6烷氧基或双-C1-C6烷基氨基团可选地进行取代。
优选地,所述方法的第一步在至少有一种酸催化剂存在时实施。此外,该酸催化剂可能是一种固体酸或者作为如三氯化铁这样的盐被添加。进一步优选地,所述催化剂是一种非挥发性的无机或者有机酸。所述有机酸也能够以其酸酐的形式存在。
本发明中的合适的无机酸,包括硫酸、亚硫酸、磷酸、亚磷酸、硝酸、氢溴酸、盐酸、高氯酸和硼酸,还有路易斯酸,例如包括氯化亚锡、四氯化锡、二溴化锡、四溴化锡、三氟化硼、醚合三氟化硼、三烷基铝、二烷基氯化铝、一烷基二氯化铝、氯化铝、三氯化硼、三溴化硼、溴化钪、氯化钪、碘化钪、氯化钛、溴化钛、三氯化铁、氯化钒、氯化铬、氯化锰、氯化锆、溴化锆、溴化锌、氯化锌、氯化钇、氯化钼、氯化钌以及镧系氯化物,例如三氯化镧、三氯化铈或者三氯化镱。
合适的有机酸包括链烷磺酸,例如甲磺酸、丁烷磺酸、(+,-或者±)-1-樟脑磺酸和芳烃磺酸,例如,氨基苯-2-磺酸、8-氨基-萘-1-磺酸、苯磺酸、2,5-二氨基苯磺酸、5,6-双(二甲基氨基)-1-萘磺酸、4-羟基-2-萘磺酸、4-羟基-3-亚硝酸-1-萘磺酸四水化物、8-羟基喹啉-5-磺酸、1-萘磺酸、2-萘磺酸、1,5-萘二磺酸、2,6-萘二磺酸、2,7-萘二磺酸、苯基硼酸、2,4,6-三硝基苯磺酸水合物、2-(2-吡啶基)乙烷磺酸、2-(4-吡啶基)乙烷磺酸、3-吡啶磺酸、(2-羟基吡啶基)甲烷磺酸、对氨基苯磺酸、2-磺基苯甲酸水合物、5-磺基水杨酸水合物、对甲苯磺酸或者2,4-二甲苯磺酸,还有有机路易斯酸,例如三氟甲基磺酸钪、三氟甲基磺酸银、三氟甲基磺酸铜(I)以及三氟甲基磺酸铜(II)。
合适的无机固体酸催化剂可选自酸性氧化铝、酸性硅酸铝盐和/或酸性硅酸盐,例如酸性沸石(zeolithes)或者蒙脱石,每一种都适合作为非均相催化剂。
第二步优选在有至少一当量的强碱存在时实施,优选至少两当量,更优选在2.5至3当量。在碱性条件下,乙炔基环丙烷最可能首先是作为一种乙炔化合物以去除质子化方式生产的,其中乙炔化合物在进行水处理(aqueous workup)时,再被质子化,从而生产出式I的最终产品。
合适的强碱是有机的“超级碱”或碱金属碱。
有机超级碱意指包含有多环化合物的氮,多环化合物有高的质子亲和力和碱度,并且包含延伸的π-***(π-systems),例如,1,5-二氮杂二环[4.3.0]-壬-5-烯(DBN),或者1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)。
根据本发明方法的意图,属于强碱金属碱的例子有烷基碱金属,其中可选地,其烷基部分有进一步的取代基;C1-C6烷基酰胺碱金属,其中可选地,其烷基部分有进一步的取代基;芳香碱金属化合物,其中芳香基部分有进一步的取代基;或者碱金属氮化硅,其中,可选地,其甲硅烷基部分有进一步的取代基。合适的碱金属碱的例子是甲基锂、乙基锂、丙基锂、异丙基锂、正丁基锂、异丁基锂、叔丁基锂、戊烷基锂、己基锂、三苯基亚甲基锂、苯基锂、甲苯基锂、二异丙氨基锂(LDA)、二异丙氨基钾(KDA)、二异丙氨基钠(NDA)、(3-氨基丙基)酰胺锂(LAPA)、(3-氨基丙基)酰胺钾(KAPA)、(3-氨基丙基)酰胺钠(NAPA)、双(三甲基硅烷基)酰胺钾、六甲基二硅氧烷锂(LiHMDS)、六甲基二硅氧烷钾(KHMDS)、六甲基二硅氧烷钠(NaHMDS)。
特别优选地,强碱选自:KAPA、LAPA、NAPA、LDA、KDA、NDA、LiHMDS和NaHMDS。
最优选地,强碱选自:KAPA、LAPA和NAPA。
下面的例子是说明本发明的方法是怎样实施的,但不是对本发明方法的限制。
实施例
实施例1:(1,1-二甲氧基-乙基)-环丙烷(II)
在25℃条件下,向装有50克(0.59摩尔)环丙基甲基酮的烧瓶分别加入原甲酸三甲酯82克(0.77摩尔)、甲醇200mL(4.94摩尔)和对甲基磺酸0.25克(1.45毫摩尔)。将配得的溶液在25℃条件下搅拌2小时。将0.15克(2.78毫摩尔)的甲醇钠加入到正处于剧烈搅拌条件下的溶液中。在减压(大约250-300毫巴)状态下去除甲酸甲酯、甲醇和原甲酸三甲酯。剩余物用100毫升盐水清洗,并用15克硫酸钠干燥。最后就获得浓度为45-65%的(1,1-二甲氧基乙基)环丙烷无色液体。
实施例2:(1-环丙基乙烯基硫烷基)-苯(IV)
将(1,1-二甲氧基乙基)环丙烷1.3克(0.10摩尔)、苯硫酚11克(0.10摩尔)、甲苯250毫升和10-樟脑磺酸700克(3毫摩尔)分别加入附有漏斗的烧瓶里。压力平衡滴液漏斗装上分子筛(珠)(beads),并在顶部安装回流冷凝器。溶液在130℃(洗浴温度)下回流20小时。混合物用10%的NaOH水溶液(2×50毫升)和盐水清洗,并用5克硫酸钠干燥。在减压状态下除去甲苯,得到一种包含46%的(1-环丙基乙烯基硫烷基)苯的油。初加工产品可以进一步纯化,例如蒸馏。
实施例3:乙炔基环丙烷(I)
KAPA(氨基丙基酰胺钾)或者由氢化钾和1,3-二氨基丙烷(Brown,C.A.J.,Org.Chem.1978.43.3083-3084)原位生成,或者在有Fe(NO3)3催化剂存在时,由钾和1,3-二氨基丙烷(Kimmel,T等人.Org.Chem.1984,49.2494-2496)原位生成。将(1-环丙基乙烯基)硫烷基苯358毫克(2.03毫摩尔)滴加到烧瓶里,烧瓶装有于0℃(水浴温度)新生成的KAPA溶液(10毫升,在1,3-二氨基丙烷里,浓度1.27摩尔/升,12.7毫摩尔)。混合物在25℃下搅拌3小时,接着冷却到0℃。将冰水添加到混合物里。在初加工产品中,乙炔基环丙烷的产率是88%。混合物用2×50毫升的AcOH水溶液和100毫升的盐水清洗,并用2克的Na2SO4干燥。初加工产品通过蒸馏纯化。沸点是:50-51℃。
Claims (8)
2.根据权利要求1所述的方法,其特征在于,所述第一步是在有酸性催化剂存在时实施的。
3.根据权利要求2所述的方法,其特征在于,所述催化剂是无机酸或有机酸,或其酸酐。
4.根据权利要求1至3中任意一项所述的方法,其特征在于,所述第二步是在至少有2当量,优选至少3当量,更优选至少6当量的强碱存在时实施的。
5.根据权利要求4所述的方法,其特征在于,所述强碱是有机超级碱或者碱金属碱。
6.根据权利要求5所述的方法,其特征在于,所述有机超级碱是1,5-二氮杂-二环[4.3.0]-壬-5-烯(DBN),或者1,8-二氮杂-双环[5.4.0]十一碳-7-烯(DBU)。
7.根据权利要求5所述的方法,其特征在于,所述的碱金属碱选自可选地取代的烷基碱金属、可选地取代的C1-C6烷基酰胺碱金属、芳香基碱金属化合物和叠氮化硅碱金属。
8.根据权利要求5所述的方法,其特征在于,所述的碱金属碱选自甲基锂、乙基锂、丙基锂、异丙基锂、正丁基锂、异丁基锂、叔丁基锂、戊烷基锂、己基锂、三苯基亚甲基锂、苯基锂、甲苯基锂、二异丙氨基锂(LDA)、二异丙氨基钾(KDA)、二异丙氨基钠(NDA)、(3-氨基丙基)酰胺锂(LAPA)、(3-氨基丙基)酰胺钾(KAPA)、(3-氨基丙基)酰胺钠(NAPA)、双(三甲基硅烷基)酰胺钾、六甲基二硅氧烷锂(LiHMDS)、六甲基二硅氧烷钾(KHMDS)和六甲基二硅氧烷钠(NaHMDS)。
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CN107698417A (zh) * | 2017-09-21 | 2018-02-16 | 宁波九胜创新医药科技有限公司 | 一种含炔基环丙化合物的制备方法 |
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CN114206349A (zh) | 2019-04-17 | 2022-03-18 | 指南针探路者有限公司 | 治疗神经认知障碍、慢性疼痛及减轻炎症的方法 |
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CN106278792B (zh) * | 2016-08-10 | 2019-01-22 | 裴卿 | 一种环丙基乙炔的制备方法 |
CN107698417A (zh) * | 2017-09-21 | 2018-02-16 | 宁波九胜创新医药科技有限公司 | 一种含炔基环丙化合物的制备方法 |
CN107698417B (zh) * | 2017-09-21 | 2020-08-25 | 宁波九胜创新医药科技有限公司 | 一种含炔基环丙化合物的制备方法 |
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