CN101575329B - Preparation method of tetrahydrothiophene-3-ketone and intermediate - Google Patents
Preparation method of tetrahydrothiophene-3-ketone and intermediate Download PDFInfo
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- CN101575329B CN101575329B CN2009102032595A CN200910203259A CN101575329B CN 101575329 B CN101575329 B CN 101575329B CN 2009102032595 A CN2009102032595 A CN 2009102032595A CN 200910203259 A CN200910203259 A CN 200910203259A CN 101575329 B CN101575329 B CN 101575329B
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- acid
- ketone
- reaction
- thiophene
- butanone
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- 238000002360 preparation method Methods 0.000 title claims description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 32
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 12
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000005977 Ethylene Substances 0.000 claims abstract description 5
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 28
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- UDNZDMGFDFBONM-UHFFFAOYSA-N 1,4-dichlorobutan-2-one Chemical compound ClCCC(=O)CCl UDNZDMGFDFBONM-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- FNKQXYHWGSIFBK-RPDRRWSUSA-N sapropterin Chemical compound N1=C(N)NC(=O)C2=C1NC[C@H]([C@@H](O)[C@@H](O)C)N2 FNKQXYHWGSIFBK-RPDRRWSUSA-N 0.000 claims description 8
- 229960004617 sapropterin Drugs 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 125000004494 ethyl ester group Chemical group 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 6
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 6
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 5
- GYJASOPNWPKGKT-UHFFFAOYSA-N ClCCC1(OCCO1)CCl Chemical compound ClCCC1(OCCO1)CCl GYJASOPNWPKGKT-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 239000003637 basic solution Substances 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 229910052976 metal sulfide Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 229910021617 Indium monochloride Inorganic materials 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- APHGZSBLRQFRCA-UHFFFAOYSA-M indium(1+);chloride Chemical compound [In]Cl APHGZSBLRQFRCA-UHFFFAOYSA-M 0.000 claims description 2
- 239000011968 lewis acid catalyst Substances 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000003921 oil Substances 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000011814 protection agent Substances 0.000 claims 2
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract 2
- SNWBFNJXVNSVKM-UHFFFAOYSA-N 1,1-dichlorobutan-2-one Chemical compound CCC(=O)C(Cl)Cl SNWBFNJXVNSVKM-UHFFFAOYSA-N 0.000 abstract 1
- 229960004659 ticarcillin Drugs 0.000 abstract 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 11
- 229960004075 ticarcillin disodium Drugs 0.000 description 11
- ZBBCUBMBMZNEME-QBGWIPKPSA-L ticarcillin disodium Chemical compound [Na+].[Na+].C=1([C@@H](C([O-])=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)C=CSC=1 ZBBCUBMBMZNEME-QBGWIPKPSA-L 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 9
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 0 CC1(C)S[C@@](C(C2)(C=O)NC([C@](*)c3c[s]cc3)=O)N2[C@@]1* Chemical compound CC1(C)S[C@@](C(C2)(C=O)NC([C@](*)c3c[s]cc3)=O)N2[C@@]1* 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- PVBRSNZAOAJRKO-UHFFFAOYSA-N ethyl 2-sulfanylacetate Chemical compound CCOC(=O)CS PVBRSNZAOAJRKO-UHFFFAOYSA-N 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- DFEOCZNUBRMXST-UHFFFAOYSA-N 1-chloro-2,2-diethoxybutane Chemical compound CCOC(CC)(CCl)OCC DFEOCZNUBRMXST-UHFFFAOYSA-N 0.000 description 1
- GCOOGCQWQFRJEK-UHFFFAOYSA-N 2-thiophen-3-ylpropanedioic acid Chemical compound OC(=O)C(C(O)=O)C=1C=CSC=1 GCOOGCQWQFRJEK-UHFFFAOYSA-N 0.000 description 1
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 1
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- DSXFPRKPFJRPIB-UHFFFAOYSA-N O=C1CSCC1 Chemical compound O=C1CSCC1 DSXFPRKPFJRPIB-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- JHEIXNWVYNQSRN-UBXQQCHXSA-L [Na+].[Na+].CC1([C@@H](N2C([C@H]([C@H]2S1)NC(C(C=1SC=CC1)C(=O)[O-])=O)=O)C(=O)[O-])C Chemical compound [Na+].[Na+].CC1([C@@H](N2C([C@H]([C@H]2S1)NC(C(C=1SC=CC1)C(=O)[O-])=O)=O)C(=O)[O-])C JHEIXNWVYNQSRN-UBXQQCHXSA-L 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical class [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 159000000009 barium salts Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 1
- -1 tosic acid monohydrate Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a new method for preparing an important intermediate tetrahydrothiophene-3-ketone of ticarcillin sodium and an intermediate of tetrahydrothiophene-3-ketone. The method is characterized in that chloracetyl chloride is taken as a starting material to prepare tetrahydrothiophene-3-ketone by four steps: reaction of ethylene addition, carbonyl protection, cyclization and deprotection. Particularly, the method comprises the following steps: ethylene gas is introduced into chloracetyl chloride, then cyclization reaction is carried out on the obtained 1, 4-glycol protecting carbonyl used for dichloro butanone; finally deprotection is carried out to obtain the subject of tetrahydrothiophene-3-ketone. Compared with the previous process, the invention has the advantages of novel design, high yield, cheap and accessible material, low cost and the like; in addition, the invention has safe and simple operation, and is a new process with industrialized prospect.
Description
Technical field
The present invention relates to field of medicine and chemical technology, particularly relate to a kind of novel process and intermediate thereof for preparing Ticarcillin Disodium important intermediate tetrahydro thiophene-3-ketone.
Background technology
Ticarcillin Disodium is the penbritin class microbiotic by Britain Beecham company exploitation, from 1986 since the listing of states such as the U.S., New Zealand, recorded by American Pharmacopeia, European Pharmacopoeia, British Pharmacopoeia, Japanese Pharmacopoeia etc. at present.Its chemical name is: (2S, 5R, 6R)-3,3-dimethyl-6-[2-carboxyl-2-(2-thienyl) acetamido]-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid disodium salt, structural formula is as follows:
Because of this product has advantages such as curative effect height, side effect be low, clinical use is very extensive.But, because its poor stability, the humidity of environment and potential of hydrogen all compare responsive, difficulty is bigger in the production, so how to select suitable production technique particularly important.
The synthetic route of Ticarcillin Disodium mainly contains two at present: 1) be starting raw material with the chloroacetyl chloride, synthetic intermediate 2-(3-thienyl) propanedioic acid (ester) generates target product with the 6-APA reaction again.This method has cost height, characteristics that yield is low, and the by product of following is many, therefore on producing and inapplicable; 2) be starting raw material with methyl acrylate (ethyl ester), become cyclizing hydrolysis under the alkaline condition, through the synthetic target product of important intermediate tetrahydro thiophene-3-ketone.This route is comparatively succinct, and it is classical to relate to reaction, is that starting raw material tetrahydrobiopterin synthesis thiophene-3 ketone has many shortcomings (subsequent content will be done detailed description) with methyl acrylate (ethyl ester) still, therefore selects suitable explained hereafter tetrahydro thiophene-3-ketone of crucial importance.And as the important intermediate of Ticarcillin Disodium, tetrahydro thiophene-3-ketone is also used in foodstuff additive in a large number, and market demand is very big.
The synthetic route of tetrahydro thiophene-3-ketone mainly contains following several:
People such as Paul Karrer disclose the synthetic method of following tetrahydro thiophene-3-ketone in the U.S. Pat 2408518 of nineteen forty-six mandate.Annulation directly takes place with 1-chloro-4-iodine butanone and sodium sulphite and promptly gets target product in the applicant, this method cost height, and the raw material 1-chloro-4-iodine butanone that relates to preparation difficulty can not satisfy industrial production requirement.
At J.Am.Chem.Soc.1957,79, in 1972-1975 one literary composition, the author is a starting raw material with ethyl thioglycolate and methyl acrylate, through the Michael addition, the Dickemann cyclization, hydrolysis decarboxylation promptly obtains tetrahydro thiophene-3-ketone under the acidic conditions.
This method report is the most popular method of tetrahydrobiopterin synthesis thiophene-3-ketone in all bibliographical informations early.But because the pungency of starting raw material ethyl thioglycolate/methyl esters and methyl acrylate/ethyl ester is bigger, be unfavorable for Workshop Production, and use ether to make solvent on producing, to have very big danger; Add that total recovery also only has 40-50%, produce a large amount of waste water in the production process.Therefore, although this route is widely used at home and abroad, face huge environmental protection pressure.
European patent EP 0127121 has also been reported the method for a kind of tetrahydrobiopterin synthesis thiophene-3-ketone, and it is to be starting raw material with Thiovanic acid and vinylformic acid, obtains Michael adduct, cyclization under the hydrated barta effect, high temperature decarboxylation then under ammonium acetate catalysis.
Recueildes Travaux Chimiques des pays-bas 89 (9/10), 1160-1168 has also reported same method in 1,964 one literary compositions, yield has only 44%.Though this route is shorter, several weak points are arranged: a large amount of hydrated bartas is used in reaction, must produce the barium salt of severe toxicity, and generate a large amount of black polymers, is difficult for handling, and brings very big harm to environment; And 250 ℃ hot conditions is too harsh on producing.
In sum, tetrahydro thiophene-3-ketone technology that can really adapt to suitability for industrialized production of exploitation is of crucial importance.
Summary of the invention
The invention provides the novel process of the important intermediate tetrahydro thiophene-3-ketone of synthetic Ticarcillin Disodium, it has characteristics such as simple to operate, that yield is higher, cost is low, environmental pollution is little, is the novel method of a suitable industrial mass production.
The novel process that the purpose of this invention is to provide the important intermediate tetrahydro thiophene-3-ketone of a synthetic Ticarcillin Disodium.
Another object of the present invention provides a kind of tetrahydro thiophene-3-ketone synthetic intermediate that is used for.
In one embodiment of the present invention, the invention provides a kind of method of synthetic Ticarcillin Disodium important intermediate tetrahydro thiophene-3-ketone, comprise the steps:
A) chloroacetyl chloride and ethene are reacted under lewis acid catalyst (for example aluminum chloride, zinc chloride, boron trifluoride etc.) catalysis, generate 1,4-dichloro butanone;
B) with organic pure R
1OH and R
2OH or HOR
1-R
2OH or this type of pure TMS (trimethyl silicon based) ether, acid anhydrides, protection such as trimethyl orthoformate (ethyl ester) 1, the ketone carbonyl of 4-dichloro butanone obtains formula I compound, here, R
1And R
2Be the alkyl of C1-C6 independently of one another; Z does not exist among the formula I, or R
1With R
2Between singly-bound;
C), obtain formula II and close the ring product with resulting formula I compound of step b) and sulfide M S (for example alkali metalsulphide or hydrogen sulfide) reaction; Z, R among its Chinese style II
1And R
2Definition is as step b);
D) formula II compound hydrolysis under acidic conditions gets tetrahydro thiophene-3-ketone, preferably, and heating hydrolysis under acidic conditions.
In a kind of embodiment preferred of the present invention, the preparation method of tetrahydro thiophene-3-ketone provided by the present invention, preferably; wherein the agent of carbonyl-protection described in the step b) is organic alcohol and this type of pure TMS (trimethyl silicon based) ether; acid anhydrides, trimethyl orthoformate (ethyl ester) etc., organic pure R
1OH, R
2OH or HOR
1-R
2R among the OH
1, R
2Be methyl, ethyl, propyl group or butyl etc. independently of one another; Used protective material and 1, the mol ratio of 4-dichloro butanone is 1: 0.5-10, preferred 1: 1-5; Described being reflected under the heating condition carried out, and temperature of reaction is 50-150 ℃, preferred 50-100 ℃.
In a kind of embodiment preferred of the present invention, the preparation method of tetrahydro thiophene-3-ketone provided by the present invention, preferably, wherein the basic solution of step c) Chinese style I compound and sulfide M S or hydrogen sulfide in molar ratio 1: the 1-10 reaction, here, described basic solution is the aqueous solution of alkali metal hydroxide, and concentration is 0.01-6mol.L
-1, preferred 1-3mol.L
-1Sodium hydroxide, potassium hydroxide solution; Temperature of reaction is 100-200 ℃, preferred 120-160 ℃.
In a kind of embodiment preferred of the present invention, the preparation method of tetrahydro thiophene-3-ketone provided by the present invention, preferably, wherein the reaction of step c) is carried out in organic solvent, be selected to described organic solvent indefiniteness alcohol, ethylene glycol or the N of C1-C4, dinethylformamide equal solvent, or any mixture of two or more solvent wherein.
In a kind of embodiment preferred of the present invention; the preparation method of tetrahydro thiophene-3-ketone provided by the present invention; preferably; wherein the catalyzer indefiniteness ground used of the selected deprotection base of step d) is mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, Hydrogen bromide, perchloric acid or Periodic acid; perhaps formic acid, acetate, trifluoroacetic acid; trichoroacetic acid(TCA), organic acids such as oxalic acid, chlorsulfonic acid, solid acid or tosic acid also can comprise Bi (NO
3) xH
2O, Ce (OTf)
3, InCl
3Deng salt, temperature of reaction is 0-100 ℃, preferred 50-80 ℃.
In a kind of embodiment preferred of the present invention, the preparation method of tetrahydro thiophene-3-ketone provided by the present invention, preferably, step a) is to d) the used extraction solvent of wherein arbitrary step is sherwood oil, methylene dichloride, ethylene dichloride, chloroform, ethyl acetate, propyl acetate, ethyl formate, or toluene etc., the perhaps mixture of above two or more organic solvent.
More preferably, the invention provides the method for a kind of tetrahydrobiopterin synthesis thiophene-3-ketone, comprise the steps:
A) chloroacetyl chloride and ethene are reacted under aluminum chloride catalysis, generate 1,4-dichloro butanone;
B) spent glycol protection 1 in the presence of acid catalyst, the ketone carbonyl of 4-dichloro butanone obtains 2-(2-chloroethyl)-2-chloromethyl-1, the 3-dioxolane;
C) with 2-(2-chloroethyl)-2-chloromethyl-1,3-dioxolane and sodium sulphite reaction obtain closing ring product 1,4-dioxy-7-thiophene volution nonane;
D) 1, heating hydrolysis under 4-dioxy-7-thiophene volution nonane acidic conditions gets tetrahydro thiophene-3-ketone.
The invention provides a kind of preparation method of synthetic Ticarcillin Disodium important intermediate tetrahydro thiophene-3-ketone, particularly preferably, it comprises the steps:
A), generate 1,4-dichloro butanone with chloroacetyl chloride and ethylene reaction;
B) under 50-100 ℃ of condition, ethylene glycol protection 1, the ketone carbonyl of 4-dichloro butanone; Ethylene glycol and 1 wherein, 4-dichloro butanone is by 1: the molar ratio reaction of 1-5;
C) with 2-(2-chloroethyl)-2-chloromethyl-1,3-dioxolane and sodium sulphite in molar ratio 1: the 1-10 reaction obtains closing ring product 1,4-dioxy-7-thiophene volution nonane;
D) heat 1 under hydrochloric acid catalysis, 4-dioxy-7-thiophene volution nonane makes it slough protecting group and obtains tetrahydro thiophene-3-ketone.
In another embodiment of the invention, the invention provides the formula I compound that is used for tetrahydrobiopterin synthesis thiophene-3-ketone:
Here, R
1And R
2Be the alkyl of C1-C6 independently of one another; Z does not exist, or R
1With R
2Between singly-bound;
Preferably, formula I compound is: 1, and 4-two chloro-2, the 2-dimethoxy-butane, 1,4-two chloro-2,2-diethoxy butane, or 2-(2-chloroethyl)-2-chloromethyl-1, the 3-dioxolane more preferably is 2-(2-chloroethyl)-2-chloromethyl-1, the 3-dioxolane.
The invention provides a kind of novel process of simple to operate, pollution is little, yield is high tetrahydrobiopterin synthesis thiophene-3-ketone.Reaction raw materials is cheap and easy to get, simple to operate, quality of finished product good, is an operational path that industrial prospect is arranged very much.
The invention also discloses a kind of tetrahydro thiophene-3-ketone that adopts aforesaid method to make is the technology of the synthetic Ticarcillin Disodium of starting raw material, and route is as follows:
Characteristics of the present invention are, are starting material with chloroacetyl chloride cheap and easy to get, amount to four-step reaction by ethene addition, carbonyl-protection, cyclization, deprotection, and total recovery is up to 75.2%.Compare with prior art, the present invention has following advantage: 1.. and raw material is cheap and easy to get: for example the chloroacetyl chloride of Cai Yonging is done initial raw material, and its market price is no more than 20 yuan/kg, greatly reduces production cost; 2.. the waste liquid that produces in the production process is less, has reduced the trouble that the three wastes are handled, and also greatly reduces the pressure of environmental protection treatment waste liquid simultaneously; 3.. easy and simple to handle, reaction all is conventional operational condition, need not severe condition, and is lower to equipment requirements, and first three step all need not to handle and promptly can be used for step direct reaction down; 4.. the yield height, Atom economy is good: total recovery is up to 75%, and the purity of product can reach 98.5%; 5.. quality of finished product good, the tetrahydro thiophene-3-ketone synthetic Ticarcillin Disodium foreign matter content that adopts this technology to make is low, by product is few, steady quality is easy to control, is suitable for the Ticarcillin Disodium suitability for industrialized production.
Specific implementation method
By following examples the present invention is described better, but the present invention is not limited by the following examples:
Embodiment 1:
In the dry reaction bottle, add aluminum trichloride (anhydrous) 128g, methylene dichloride 170ml.Stirring also is cooled to-5 ℃, slowly drips chloroacetyl chloride 170g, and feeds ethylene gas 50L.Logical finishing, reaction solution is poured in the 600g frozen water, (2 * 300ml), the merging organic phase is with the salt pickling (2 * 200ml) of 2mol/l with dichloromethane extraction for water, saturated common salt washing (1 * 200ml), anhydrous sodium sulfate drying, concentrate 1,4-dichloro butanone crude product 186.2g, yield 90%, purity＞95%.This intermediate need not purifying, is directly used in the next step.
Embodiment 2:
In 500 milliliters of round-bottomed flasks, add 1,4-dichloro butanone 33.8g, ethylene glycol 14.8g, tosic acid monohydrate 3.3g adds 100 milliliters of toluene again and stirs and make it down to dissolve.Reflux 4 hours is cooled to room temperature, and reaction solution is poured in the frozen water, tells organic layer, water again with toluene extraction (2 * 100ml), merge organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure gets 2-(2-chloroethyl)-2-chloromethyl-1,3-dioxolane crude product 45.1g, yield 100%.This intermediate need not purifying, is directly used in next step reaction.
1H-NMR(300MHz，CDCl
3)δ：3.95(s，4H)，2.67(t，2H)，2.68(s，2H)，2.13(m，2H)。MS for C
6H
10O
2Cl
2(M+Na): theoretical value: 207.01 measured values: 207.16
Embodiment 3:
In the 250ml three-necked bottle, add 9g ethylene glycol, be heated to backflow.Drip 45.1g 2-(2-chloroethyl)-2-chloromethyl-1 simultaneously, 3-dioxolane, the 100ml aqueous solution of 64.4g sodium sulphite.Remain reaction system in the dropping process and be the vigorous reflux state.About 1h dropwises, and continues to reflux 2 hours, is cooled to room temperature.Add 10g sodium-chlor and make water become saturated solution, ethyl acetate extraction (4 * 100ml).Merge organic phase, drying, concentrating under reduced pressure gets 1,4-dioxy-7-thiophene volution nonane crude product 33.8g, yield 95%.This intermediate need not purifying, is directly used in next step reaction.
Embodiment 4
In the 250ml round-bottomed flask, add 33.8g 1,4-dioxy-7-thiophene volution nonane, 10ml concentrated hydrochloric acid and 20ml water, stirring reaction 4h under 70 ℃ of water-baths is cooled to room temperature, adds an amount of sodium-chlor and makes water saturated, ethyl acetate extraction (3 * 50ml), merge organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure, the underpressure distillation of gained oily matter (51-52 ℃/3mmHg), get water white transparency oily thing tetrahydro thiophene-3-ketone 27g, yield 88%, purity＞98.5% (GC).
1H-NMR (400MHz, CDCl
3) δ: 2.50-2.74 (m, 2H), 2.85-3.03 (m, 2H), 3.30 (s, 1H); MS (measured value): 102.20; Ultimate analysis C
4H
6SO experimental value (calculated value): C47.11% (47.03%), H5.80% (5.92%), S31.28% (31.39%).
1H-NMR(300MHz，CDCl
3)δ：3.80-3.92(m，4H)，3.61(s，2H)，3.42(m，2H)，1.85(t，2H)。
Claims (11)
1. the method for tetrahydrobiopterin synthesis thiophene-3-ketone comprises the steps:
A) chloroacetyl chloride and ethene are reacted under lewis acid catalyst catalysis, generate 1,4-dichloro butanone;
B) with carbonyl-protection agent protection 1, the ketone carbonyl of 4-dichloro butanone obtains formula I compound, here, and R
1And R
2Be the alkyl of C1-C6 independently of one another; Z does not exist among the formula I, or R
1With R
2Between singly-bound;
C), obtain formula II and close the ring product with resulting formula I compound of step b) and sulfide M S reaction; Z, R among its Chinese style II
1And R
2Definition is as step b), and here, described sulfide M S is alkali metalsulphide or hydrogen sulfide basic solution;
D) formula II compound hydrolysis under acidic conditions gets tetrahydro thiophene-3-ketone.
2. method according to claim 1, wherein the agent of carbonyl-protection described in the step b) is organic alcohol or its trimethyl silicon based ether, trimethyl orthoformate or ethyl ester; Described organic alcohol is R
1OH, R
2OH or HOR
1-R
2OH, wherein R
1, R
2Definition is as claim 1.
3. method according to claim 2, wherein said carbonyl-protection agent and 1, the mol ratio of 4-dichloro butanone is 1: 0.5-10; Described being reflected under the heating condition carried out, and temperature of reaction is 50-150 ℃.
4. method according to claim 1, wherein the basic solution of step c) formula I compound and alkali metalsulphide or hydrogen sulfide in molar ratio 1: the 1-10 reaction, here, described basic solution is the aqueous solution of alkali metal hydroxide, concentration is 0.01-6mol.L
-1Temperature of reaction is 100-200 ℃.
5. method according to claim 1, wherein the reaction of step c) is carried out in organic solvent, and described organic solvent is selected from alcohol or the N of C1-C4, dinethylformamide solvent, or the mixture of these two kinds of solvents.
6. method according to claim 1, wherein the reaction of step c) is carried out in organic solvent, and described organic solvent is selected from ethylene glycol or N, dinethylformamide solvent, or the mixture of these two kinds of solvents.
7. method according to claim 1, wherein the catalyzer used of the selected deprotection base of step d) is mineral acid or organic acid or Bi (NO
3) xH
2O, Ce (OTf)
3, InCl
3Salt, described mineral acid are sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, Hydrogen bromide, perchloric acid or Periodic acid; Described organic acid is formic acid, acetate, trifluoroacetic acid, trichoroacetic acid(TCA), oxalic acid, chlorsulfonic acid or tosic acid.
8. method according to claim 7, wherein the temperature of reaction of step d) is 0-100 ℃.
9. according to the described method of each claim in the claim 1 to 8, step a) is to d) the used extraction solvent of wherein arbitrary step is sherwood oil, methylene dichloride, ethylene dichloride, chloroform, ethyl acetate, propyl acetate, ethyl formate, or toluene, the perhaps mixture of above two or more organic solvent.
10. the method for tetrahydrobiopterin synthesis thiophene-3-ketone comprises the steps:
A) chloroacetyl chloride and ethene are reacted under aluminum chloride catalysis, generate 1,4-dichloro butanone;
B) spent glycol protection 1 in the presence of acid catalyst, the ketone carbonyl of 4-dichloro butanone obtains 2-(2-chloroethyl)-2-chloromethyl-1, the 3-dioxolane;
C) with 2-(2-chloroethyl)-2-chloromethyl-1,3-dioxolane and sodium sulphite reaction obtain closing ring product 1,4-dioxy-7-thiophene volution nonane;
D) 1, heating hydrolysis under 4-dioxy-7-thiophene volution nonane acidic conditions gets tetrahydro thiophene-3-ketone.
11. the preparation method of a tetrahydro thiophene-3-ketone, it comprises the steps:
A), generate 1,4-dichloro butanone with chloroacetyl chloride and ethylene reaction;
B) under 50-100 ℃ of condition, ethylene glycol protection 1, the ketone carbonyl of 4-dichloro butanone; Ethylene glycol and 1 wherein, 4-dichloro butanone is by 1: the molar ratio reaction of 1-5;
C) with 2-(2-chloroethyl)-2-chloromethyl-1,3-dioxolane and sodium sulphite in molar ratio 1: the 1-10 reaction obtains closing ring product 1,4-dioxy-7-thiophene volution nonane;
D) heat 1 under hydrochloric acid catalysis, 4-dioxy-7-thiophene volution nonane makes it slough protecting group and obtains tetrahydro thiophene-3-ketone.
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