CN85106365A - Racemic half-ester resolution process - Google Patents
Racemic half-ester resolution process Download PDFInfo
- Publication number
- CN85106365A CN85106365A CN85106365.9A CN85106365A CN85106365A CN 85106365 A CN85106365 A CN 85106365A CN 85106365 A CN85106365 A CN 85106365A CN 85106365 A CN85106365 A CN 85106365A
- Authority
- CN
- China
- Prior art keywords
- dibenzyl
- salt
- oxo
- technology
- dehydroabietylamine
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 54
- 230000008569 process Effects 0.000 title claims description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 150000002148 esters Chemical class 0.000 claims abstract description 30
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 claims abstract description 29
- -1 C3-5Cycloalkyl radical Chemical class 0.000 claims abstract description 28
- 238000002425 crystallisation Methods 0.000 claims abstract description 23
- 230000008025 crystallization Effects 0.000 claims abstract description 22
- 230000002829 reductive effect Effects 0.000 claims abstract description 22
- 150000001412 amines Chemical class 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 42
- 238000005516 engineering process Methods 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 28
- 238000005192 partition Methods 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 21
- 230000003287 optical effect Effects 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 claims description 12
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 claims description 12
- 239000011735 vitamin B7 Substances 0.000 claims description 10
- 230000009467 reduction Effects 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 230000004048 modification Effects 0.000 claims description 7
- 238000012986 modification Methods 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 238000000638 solvent extraction Methods 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- IVOZPGJPCDXYIR-UHFFFAOYSA-N C(C1=CC=CC=C1)OC(=O)C=1C=NC(N1)=O Chemical compound C(C1=CC=CC=C1)OC(=O)C=1C=NC(N1)=O IVOZPGJPCDXYIR-UHFFFAOYSA-N 0.000 claims 2
- 238000011084 recovery Methods 0.000 claims 1
- 125000002769 thiazolinyl group Chemical group 0.000 claims 1
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 abstract 4
- 235000000638 D-biotin Nutrition 0.000 abstract 2
- 239000011665 D-biotin Substances 0.000 abstract 2
- FGFSEMWCZBVRHG-UHFFFAOYSA-N 1,3-dibenzyl-6,6a-dihydro-3ah-furo[3,4-d]imidazole-2,4-dione Chemical compound O=C1OCC(N(C2=O)CC=3C=CC=CC=3)C1N2CC1=CC=CC=C1 FGFSEMWCZBVRHG-UHFFFAOYSA-N 0.000 abstract 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 abstract 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 abstract 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 22
- 238000006722 reduction reaction Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 150000002596 lactones Chemical class 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 239000012452 mother liquor Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 125000005594 diketone group Chemical group 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 150000001298 alcohols Chemical group 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- 150000003818 basic metals Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229950010364 phenpromethamine Drugs 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000011833 salt mixture Substances 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 description 1
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- QAPYQYHLNVDEOY-UHFFFAOYSA-N C(=O)(OCC1=CC=CC=C1)C=1C(=NC(N1)=O)C(=O)OCC1=CC=CC=C1 Chemical compound C(=O)(OCC1=CC=CC=C1)C=1C(=NC(N1)=O)C(=O)OCC1=CC=CC=C1 QAPYQYHLNVDEOY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229930194542 Keto Natural products 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- MOOAHMCRPCTRLV-UHFFFAOYSA-N boron sodium Chemical compound [B].[Na] MOOAHMCRPCTRLV-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 150000001840 cholesterol esters Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- GCFAUZGWPDYAJN-UHFFFAOYSA-N cyclohexyl 3-phenylprop-2-enoate Chemical compound C=1C=CC=CC=1C=CC(=O)OC1CCCCC1 GCFAUZGWPDYAJN-UHFFFAOYSA-N 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
- 238000000354 decomposition reaction Methods 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- XEYCPDSRHJFTGU-UHFFFAOYSA-N ethanamine;toluene Chemical compound CCN.CC1=CC=CC=C1 XEYCPDSRHJFTGU-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Racemic half ester shown in formulas Ia and Ib, wherein R is C1-6Alkyl radical, C3-5Cycloalkyl radical, C2-6Alkenyl, benzyl, 1 or 2-phenylethyl. The splitting method comprises the following steps: salifying with (+) -dehydroabietylamine and isolating the diastereomeric salts by crystallization. Optically active cis-1, 3-dibenzyl-5-alkyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid is used as an intermediate for preparing D (+) -biotin. Optically active amine and active 1, 3-dibenzyl-5-alkoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid form diastereomer salt, and the diastereomer salt is reduced to optically active 1, 3-dibenzylhexahydro-1H-furo [3, 4-d]Imidazole-2, 4-dione, the latter being an intermediate in the preparation of D (+) biotin. BZL is benzyl.
Description
The invention relates to suitable-1 shown in the preparation formula I a/b, the novel process of two enantiomorphs of 3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid,
Wherein,
R-has the alkyl of as many as six carbon atom,
The cycloalkyl of 3～5 carbon atoms,
The alkenyl of 2～6 carbon atoms,
Benzyl or 1 or 2 styroyls,
The BZL-benzyl
And by 1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid preparation (3aS, 6aR) and/or (3aR, 6aS)-1,3-dibenzyl six hydrogen-1H-furo [3,4-d] imidazoles-2, the novel process of 4-diketone, it is characterized in that: with optically active amines and optical activity 1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazolidine-formed diastereoisomeric salt of 4-carboxylic acid reduces.
(4S, 5R)-1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid is preparation (3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-and the diketone useful as intermediates: the latter is the key intermediate of preparation (+)-vitamin H.
Previously, once narrated relevant optics partition technology suc as formula the racemic semi-ester shown in the I a/b, wherein, German Patent 2,058,234 have narrated preparation cyclohexyl half ester and have broken with fractionation crystallization with the formed diastereoisomeric salt of (+) ephedrine, and the cholesterol half ester of preparation diastereomer with separate the technology of resulting triethylamine salt thus with fractionation crystallization.Yet the productive rate of these technologies all is lower than 50%, and the ancillary compound one cholesterol price of chirality is expensive, also is difficult to reclaim fully.
Europe publication specification sheets 0,092,194 has been narrated the dividing method of a kind of racemic methyl and ethyl half ester: separate half ester with optically active 1 with crystallization process, the diastereoisomeric salt of 2-phenpromethamine formation.Further method is to make in the supersaturated solution of enantiomorph by raceme that crystal seed makes required partition of enantiomorph to separate out automatically.This method also has the low shortcoming of partition productive rate, only is 30% of theoretical amount.So target of the present invention provides the cheap partition agent of applied cost and with the novel process of the half ester shown in the high yield partition I a/b.
Now find unexpectedly: (+) dehydroabietylamine can be divided into enantiomorph with the racemic modification of formula I a/b as the partition agent, and the productive rate height, and selectivity is good.
Therefore, the invention provides new compound: i.e. (4S, 5R)-and (4R, 5S)-and suitable-1, (+)-westvaco rosin amine salt of 3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid, wherein " alkyl " is meant and has 6 carbon atoms of as many as, alkyl in " alkoxyalkyl " has 2～8 carbon atoms, " cycloalkyl " has 3～5 carbon atoms, and " alkenyl " has 2～6 carbon atoms, benzyl or 1 or the 2-styroyl.
The present invention also provides the partition technology of the racemic semi-ester shown in the formula I a/b,
Wherein,
The alkyl of 6 carbon atoms of R-as many as,
The alkoxyalkyl of 2～8 carbon atoms,
The cycloalkyl of 3～5 carbon atoms,
The alkenyl of 2～6 carbon atoms,
Benzyl or 1 or the 2-styroyl,
The BZL-benzyl
This technology is: the raceme and the optically active amine salify that are broken, separate formed diastereoisomeric salt then, and it is characterized in that: used optically active amines is (+) dehydroabietylamine.
The present invention further provides: resulting optically active suitable-1 according to technology of the present invention, 3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid can be used for preparing D(+)-vitamin H.
Racemic semi-ester of the present invention is to carry out isolating with known standard method.(for example, B.P.H.Boyle, Quart.Rev.25(1971) 323-341).Racemic modification can break mutually with the chromatography chirality; Adding crystal seed way in the also available supersaturated solution, perhaps the way partition of picking with machinery.Further dividing method is formation, separation and the decomposition that utilizes diastereomer.Ideal method is based on the separation of diastereoisomeric salt.The best dividing method of racemic modification shown in the formula I a/b is to be dissolved in suitable organic solvent with racemic modification and a certain amount of (+)-dehydroabietylamine are same, then with the salt recrystallization of (+) dehydroabietylamine of its diastereomer.After telling salt, can remove if necessary debris solvent and another enantiomorph.
To the outer raceme of tearing open that every mol is broken, the amount of required (+)-dehydroabietylamine is 0.5～1 mol, and preferred amount is 0.5～0.7 mol.Used solvent can be water, or a kind of inert organic solvents, preferred solvent be a kind of can with water blended solvent, particularly alcohol, as methyl alcohol, ethanol, Virahol, propyl carbinol or uncle-butanols or the like, ether is as tetrahydrofuran (THF), dioxane, glycol monomethyl first or single ether, glycol dimethyl ether, ketone such as acetone, butanone or isobutyl methyl ketone also can be nitrile, as acetonitrile, or nitro-compound, as Nitromethane 99Min..
Preferred solvent is an alcohols, ketone and ethers, preferably methyl alcohol, ethanol, Virahol, propyl alcohol or tetrahydrofuran (THF).
The also mixture of available above-mentioned solvent.The preferential mixture that is above-mentioned solvent and water with 0.5～50% ratio, particularly 0.5～10%, be the best with 1～5%.
According to the present invention, the temperature that breaks can be selected between the boiling point of-20 ℃ and solvent for use, but to be lower than by the Tc of crystalline enantiomorph salt for well.
Optics partition technology of the present invention is specially adapted to that R is the compound of methyl or ethyl among the formula I a/b.
In according to preferred example of the present invention, used fractionation crystallization and separated the diastereomer salt mixture.For this reason, the racemic semi-ester shown in the formula I a/b at first uses (+) dehydroabietylamine of equivalent to be converted into the diastereomer salt mixture.The reaction of racemic semi-ester and optically active amines can be solvent-free or carry out in the presence of organic solvent.Preferred solvent is non-polar solvent, particularly chloroparaffin, as methylene dichloride, and chloroform, trichloroethane, 1,2-ethylene dichloride or tetracol phenixin, or hydrocarbon polymer, as hexane, sherwood oil, benzene, toluene or dimethylbenzene.Also available above-mentioned mixture.
Remove the salt of being told the back of desolvating and in above-mentioned solvent, carry out crystallization to carry out the optics partition.In preferred example according to the present invention, narrated along 1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid and suitable-1, the optics partition of (+)-salt that dehydroabietylamine generated of 3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid.
The technology according to the present invention, (+) of the optically active half ester shown in the I a/b-westvaco rosin amine salt can obtain the acid of free half ester again with acid or alkaline purification.The alkali that is fit to has: the oxyhydroxide of basic metal or alkaline-earth metal, the carbonate of basic metal or alkaline-earth metal or supercarbonate, ammonium salt and strong organic bases.Preferred alkali is alkali metal hydroxide and ammonia particularly sodium hydroxide and potassium hydroxide.
Suitable acid is strong organic acid, for example, formic acid or acetate, the example of mineral acid has phosphoric acid or nitric acid, and preferred ore deposit acid is hydrochloric acid or Hydrogen bromide.The best is sulfuric acid preferably, because (+) dehydroabietylamine can generate the hydrosulfate of indissoluble, this salt is easy to crystallization, thereby is easily separated with filter method, thereby with the used partition agent of recovered in high yields.
For from their westvaco rosin amine salt middle reaches from going out suc as formula the optical activity half ester shown in the I a/b, select acid usually for use, because half ester is to the less stable of alkali.
The amount of used acid can change in wide scope, but the diastereoisomeric salt that every mol broke needs 1 mol acid at least, preferentially adopts 1～1.5 mol.
Available appropriate solvent is dissolved diastereoisomeric salt, and preferred solvent is a water, then acid is added in this solution so that half ester is free.Can be used organic solvent extraction by the free half ester, for example use ether, toluene, ethyl acetate, methylene dichloride or their mixture.As needs, extracting solution washing back except that desolvating, is just drawn required optical activity half ester.
In order to reclaim partition reagent (+)-dehydroabietylamine, can alkalize with highly basic in the solution after extraction, make the partition agent free.Available ammonia, sodium hydroxide solution or potassium hydroxide solution alkalization.Alkalization back organic solvent extraction, method is similar to the method for the active half ester of above-mentioned dissociated optical.
If the sulfuric acid with optimal selection decomposes diastereoisomeric salt, then (+)-dehydroabietylamine is separated out with the hydrosulfate form of indissoluble, with filtering or after the centrifugal method branch told, available aforesaid method adds strong alkali solution made the partition agent free, solvent extraction is then recyclable should the partition agent.
The described initial substance of technology of the present invention, suc as formula the racemic modification half ester shown in the I a/b, its preparation method is known, for example, German Patent 2,058,234 or the method for European publication specification sheets 0,092194, be by suitable-1,3-dibenzyl-2-oxo-imidazole alkane-4, the preparation of 5-dicarboxylic anhydride, can be with this acid anhydrides and corresponding pure in inert solvent, for example benzene, react in toluene or the dimethylbenzene, preferable reaction conditions is at high temperature to react.
According to the present invention prepared suitable-1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid, can use known method, people's method of reporting (Helv.Chem.Acta53(1970) such as Gerecke for example, 991-999) be reduced to optically active 1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-diketone.Free optical activity half ester can be used as the initial substance of this reduction reaction.Yet also (+) of available its diastereomer-westvaco rosin amine salt is as initial substance.This class technological process has outstanding advantage.
German Patent 2,058,248 have narrated preparation (3aS, 6aR)-and the technology of lactone, with suitable-1,3-dibenzyl-2-oxo-imidazole alkane 4, the cholesterol ester of 5-dicarboxylic acid and cyclohexyl ester are divided into its enantiomorph, and corresponding enantiomorph is converted into required lactone with reduction reaction.But this process yields is lower than 50% theoretical amount, and is somewhat expensive and can not reclaim fully as the cholesterol of chirality ancillary compound, and in the technology of this application patent, the half ester of unwanted enantiomorph need recycle once more.
Publication specification sheets 0,081,047 pair of above-mentioned technology in Europe has been done improvement.Improve in the technology at this, the carboxyl of unwanted half ester is converted into acyl chlorides earlier, reduce requiredly then (3S, 6R)-lactone.But because diastereomeric separation efficient is low, chirality ancillary compound price is expensive, and this technology does not have important economic value.
At German Patent 2,331, narrated in 244 preparation (3R, 6S) and (3S, 6R)-technology of lactone.This technology will be by suitable-1,3-dibenzyl-2-oxo-imidazole alkane-4, suitable-1 of 5-dicarboxylic acid and a kind of optically active amines gained, 3-dibenzyl hexahydropyrrolo is [3,4-d] imidazoles-2,4 also, the 6-triketone carries out asymmetric reduction, subsequently with the acid amides alkylol cpd hydrolysis of gained and required lactone.
The shortcoming of this technology is that the optically active amines price is expensive and separation yield is not high equally.
Europe publication specification sheets 84 though 892 described diastereomeric separation yields are high, needs the difficult optically active amines that obtains equally.
On the other hand, suitable-1 of enantiomorph, 3-dibenzyl-2-oxo-imidazole-4, the 5-dicarboxylic acid is the good method that a class prepares the optical activity half ester with the salt-forming reaction of (+)-dehydroabietylamine, each optically active enantiomorph all can be by currently known methods, for example the method for being narrated at European publication specification sheets 84,892 is converted to required optically active lactone.
In above-mentioned technological process, before reduction reaction, half ester can be told through strong acid treatment from the diastereoisomeric salt that they and optically active amines are generated.
In the reduction reaction of proceed step by step subsequently, reductive agent can be earlier with free half ester in the acidic hydrogen effect of carboxyl, thereby consumed the reductive agent of equivalent, following step reduction reaction just can not be carried out.
So find a kind of technological process, to reduce suitable accordingly-1,3-dibenzyl-2-oxo-imidazole alkane-4,5-dicarboxylic acid half ester prepares optically active 1,3-dibenzyl tetrahydrochysene-4H-furo [3,4-d] imidazoles-2, the 4-diketone, this technology should make reductive agent be able to than good utilisation and simple to operate, and it is high that the chemical purity of isolating product and optical purity are wanted.
Now find unexpectedly, optically active amines and optical activity 1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-formed diastereoisomeric salt of 4-carboxylic acid can be reduced, and chemical yield and optical yields are all high, and do not disturb with the component of amine.
Like this, the present invention also provides by 1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid preparation (3aS, 6aR)-and/or (3aR, 6aS)-1,3-dibenzyl six hydrogen-1H-furo [3,4-d] imidazoles-2, the technology of 4-diketone is characterized in that: optically active amines and optical activity 1, the diastereomer that 3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid forms can be reduced.
The invention further relates to the optical activity 1 of utilizing prepared provided by the invention, 3-dibenzyl six hydrogen-1H-furo [3,4-d] imidazoles-2, the 4-diketone prepares D(+)-vitamin H.
In the present invention and the method for the diastereoisomeric salt that reason optical activity half ester is generated is identical with the method for the free half ester of known reduction.
According to selected reductive agent, from having 4S, 5R or 4R, the half ester salt of 5S configuration can obtain not only that (3aR 6aS)-lactone, also can obtain (3aS, 6aR) lactone.
For example, as will (4S, 5R) carboxyl of half ester salt reduces, product be (3aR, 6aS) lactone, and when reducing its carbalkoxy, obtain (3aS, 6aR) lactone of configuration.Reduction (4R, 5S)-the configuration dependency of products therefrom during half ester salt, with above-mentioned opposite.
The appropriate reductant example of reduction carboxyl is: hydroborate, and as diborane.
Suitable solvent is that reductive agent is shown organic solvent inert, for example hydrocarbon polymer, for example benzene or toluene etc.; Ethers, ether for example, ethylene glycol bisthioglycolate alkyl oxide, 2-ethoxyethyl ether, tetrahydrofuran (THF) or dioxane etc.Preferred solvent is: ring-type ethers, for example tetrahydrofuran (THF) and dioxane.Also available above mixture.
Reduction reaction temperature with between-20～+ 40 ℃ for well, preferentially be-10～+ 30, particularly between 0～20.Required reductive agent hydride amount is chosen between 0.8 and 3 equivalents of theoretical amount, preferentially selects 1～2 equivalent for use, particularly 1～1.5 equivalent.For example, when with diborane during as reductive agent, preferable consumption is: every mol half ester salt is with 0.5～0.75 molar diborane.
Diborane can be used for reduction reaction, but it also uses currently known methods to take place with " original position ", for example, diborane takes place in " original position " in available sodium boron or its ether affixture, the solvent that the method that this " original position " made can preferentially adopt the half ester reduction reaction to be suitable for makes the diborane solution of gained can be used as the medium of reduction reaction subsequently.
The example of the reductive agent that the reduction carbalkoxy is suitable for is compound hydroborate, and as lithium borohydride, sodium borohydride or hydroboration calcium, and aluminum hydride compound are as diisobutylaluminium hydride and diethyl aluminium hydride sodium.
The used solvent of reduction reaction preferably will be the inert solvent to reductive agent under reaction conditions, reactant should be partially soluble in this solvent at least.
For the reductive agent that can use in water-bearing media, suitable examples of solvents is a water, alcohols such as methyl alcohol, ethanol, Virahol, ethylene glycol or glycol ether, ethers such as tetrahydrofuran (THF) or dioxane.The also mixture of the mixture of available these solvents or they and the immiscible solvent of water.
For the reductive agent that can work with water, suitable solvent is not only ethers, as ether, the ethylene glycol bisthioglycolate alkyl oxide, diethylene glycol dialkyl ether, tetrahydrofuran (THF) or dioxane can use, and can use hydrocarbon polymer, particularly benzene and toluene and so on, the also mixture of available above-mentioned solvent.
Temperature of reaction can be selected between-70 ℃ to+100 ℃, is between-70 ℃ to+30 ℃ to the more excellent temperature of aluminiferous reductive agent, particularly-40 ℃ between+30 ℃.The temperature that the boracic reductive agent is preferentially selected for use is between-10 ℃ to+100 ℃, particularly between 0 ℃ to 80 ℃.
Required reduction dosage is to select between 0.8～3 equivalent of theoretical amount, between 1～2 equivalent, preferentially is between 1～1.5 equivalent particularly.For example, as use sodium borohydride, the required sodium borohydride of every mol half ester salt is preferentially selected 0.75～1.25 mol for use.
At used initial substance, 1 of diastereomer, in 3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylate structure, " carbalkoxy " is meant the carbalkoxy with 6 carbon atoms of as many as, " alcoxyl carbalkoxy " is meant to have 2～8 carbon atoms; " chain ene keto carbonyl " is meant to have 2～6 carbon atoms, carbobenzoxy-(Cbz) or 1 or 2-benzene ethoxycarbonyl.
According to technological process of the present invention, preferentially select 1 for use, 3-dibenzyl-5-methoxycarbonyl, 5-ethoxycarbonyl and salt that the 5-carbobenzoxy-(Cbz)-2-oxo-imidazole alkane-the 4-carboxylic acid is become with optically active amines raw material as reduction reaction.
All optically active amines all suit as the optical activity amine salt component of partition racemic semi-ester, for example, and Deutsches Reichs-Patent 2,058,248 described ephedrine, European publication specification sheets 92,194 is described 1,2-phenpromethamine, and (+)-dehydroabietylamine particularly.The preferred example of technology has just been used the diastereomeric salt of (+)-dehydroabietylamine according to the present invention.
This technological operation is easy.Diastereoisomeric salt as initial substance is known, perhaps can be by currently known methods, as the method preparation of European publication specification sheets 92,194.Reactant is mixed, will heat under this reaction mixture stirring or be cooled to react required temperature, reaction be promptly carried out.But method is that diastereoisomeric salt (dissolving in appropriate solvent as needs) is slowly joined in the reductive agent preferably.Reaction times is 0.5～40 hour, is good with 1～8 hour.After reaction is finished, add acid and carry out acidifying, for example can add ore deposit acid, example hydrochloric acid or sulfuric acid, with appropriate solvent abstraction reaction thing optically active lactone, solvent is ether, ethyl acetate, methylene dichloride, chloroform or toluene then.
After solvent removed, can obtain the required lactone of very pure crystallization shape generally speaking.If necessary, product can be further purified with chromatography or crystallization process.
In order to reclaim optically active amines, the solution alkalization after will extracting with highly basic for example, use ammonia, and sodium hydroxide solution or potassium hydroxide solution alkalization with above-mentioned dissociated optical activated lactone similar approach extraction, are told amine then.
Optically active (3aS, 6aR)-1,3-dibenzyl tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4-(1H)-diketone, can transfer D(+ to by currently known methods)-vitamin H, for example, at German Patent 2,058,234 or German Patent 2,331,244 in narrated these methods.
A technology is simple, method completely further is preparation D(+ to the partition of the half ester shown in formula I a/b efficient is high so the invention provides)-vitamin H provides the route of a tool superiority.
Reduction optically active amines and optically active 1 have been the present invention further provides, the diastereomeric salt that 3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid forms, preparation optical activity 1,3-dibenzyl-six hydrogen-1H-furo [3,4-d] imidazoles-2, the technology of 4 diketone, its chemistry and optical purity are all high, thereby are preparation D(+)-vitamin H provides a superior simply operational path of economy.
Example 1:
A) with 250 gram (0.743 mol) suitable-1,3-dibenzyl-six hydrogen-1H-furo [3,4-d]-imidazoles-2,4, the 6-triketone, the suspended substance of 59.7 gram (1.283 mol) ethanol and 2 liter benzene refluxed 2 hours, concentrate then and make its crystallization, 256 grams (90% theoretical value) suitable-1,3-dibenzyl-2-oxo-imidazole alkane-5-ethoxycarbonyl-4-carboxylic acid, 93 ℃ of molten points
B) 57.4 gram (0.15 mol) racemic cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid and 42.8 gram (0.15 mol) (+)-dehydroabietylamines are dissolved in 375 milliliters of tetrahydrofuran (THF)s, at room temperature add 7.5 ml waters, this solution is cooled to-70 ℃, get (the 4R of 47.7 grams (95% theoretical value), 5S)-and suitable-1, the westvaco rosin amine salt crystallization of 3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, [α]
25 365=+47.1 ℃.In mother liquor, add 400 ml waters or 500 milliliters of hexanes get 49.8 grams (98% theoretical value) (4S, 5R)-suitable-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, [α]
25 365=+61.24 ℃
Example 2:
The racemic cis of equivalent-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid and (+) dehydroabietylamine are dissolved in ethanol (every mol with 4～5 liters), add 10% water again, being cooled to-10 ℃ makes it separate out crystallization, get (the 4R of 89% yield (theoretical value), 5S)-and suitable-1, the westvaco rosin amine salt of 3-dibenzyl-5-ethoxy carbonyl-2-oxo-imidazole alkane-4-carboxylic acid.[α]
25 365＝48.1℃
Mother liquor is contracted to about 2/3 volume, with equal-volume water dilution, isolate (4S, 5R)-suitable-1, the westvaco rosin amine salt (92% yield) of 3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, [α]
25 365=63.6 ℃.Mother liquor concentrates once more, and raffinate is handled with 100 milliliters of diisopropyl ether, gets (the 4R of 9% yield (theoretical value), 5S)-and (4S, 5R)-and suitable-1, the mixture of (+)-dehydroabietylamine diastereoisomeric salt of 3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carbonyl acid can be once more in separation.
Example 3:
With 26.8 gram (0.07 mol) racemic cis-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid and 20g(0.07 mol) the solution evaporation of (+)-dehydroabietylamine in 80 milliliters of methylene dichloride to doing.Get the ethyl half ester acid westvaco rosin amine salt of the diastereomer of 45.6 grams (97.5% theoretical value) from the diisopropyl ether crystallization, [α]
25 365=+54.9 ℃
Example 4:
Gained is suitable in example 3-1, and 3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid can break with crystallization method with the ethanol that contains 10% water with the diastereomeric salt of (+) dehydroabietylamine.
The crystallization of at first separating out have (4R, 5S)-configuration, [α]
25 365=+46.2 ℃
Add entry (be equivalent to organic solvent volume 50%) in the mother liquor after separating out crystallization first, diisopropyl ether or sherwood oil can get crystallization shape salt, its be configured as (4S, 5R), [α]
25 365=+63.6 ℃.
Example 5:
Repeat the operation described in the example 4, wherein, replace ethanol with the Virahol that contains 5% water, amount that can be suitable with example 4 (4R, 5S)-diastereomeric salt.
Example 6:
Repeat the operation described in the example 4, and replace ethanol, output and example 4 gained suitable with the tetrahydrofuran (THF) that contains 2% water.
Example 7:
Racemic suitable-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid can break with being similar to example 4 working method, but the amount that adds entry reduces to 5%.Productive rate is suitable to 7 with the example 4 of the corresponding ethyl half ester of partition.
(4S, 5R)-suitable-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, [α]
25 365=+39 ℃
(4R, 5S)-suitable-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, [α]
25 365=+67 ℃
Example 8:
Repeat the operation in the example 7, but replace ethanol with the Virahol that contains 3% water.The gained productive rate is suitable with example 7.
Example 9: repeat the operation of example 7, but replace ethanol with the tetrahydrofuran (THF) that contains 1% water, yield level is identical with example 7.
Example 10:
Repeat the operation of example 7, but replace ethanol to contain 2% water, its productive rate can be suitable with example 7.
Example 11:
With 177.8 gram racemic cis-1,3-dibenzyl-5-carbobenzoxy-(Cbz)-2-oxo-imidazole alkane-4-carboxylic acid is (from suitable-1,3-dibenzyl-six hydrogen-1H-furo [3,4-d]-imidazoles-2,4,6-triketone and phenylcarbinol make with example 1a method) and 117.8 gram (+)-dehydroabietylamines be dissolved in 800 milliliters of toluene, make it 0 ℃ of crystallization after adding 40 ml waters.138.6 grams (95% yield) (4R, 5S)-suitable-1,3-dibenzyl-5-carbobenzoxy-(Cbz)-2-oxo-imidazole alkane-4-carboxylic acid, [α]
25 365=+45.2, optical purity 99%.
Mother liquid evaporation is extremely done.Resistates is handled and crystallization at room temperature with methyl tertiary butyl ether, 135.8 grams (93% yield) (4S, 5R)-suitable-1,3-dibenzyl-5-benzyloxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, [α]
25 365=+54.2 ℃, optical purity: 〉=99%.
Example 12:
A) 23.3 gram (4S, 5R)-suitable-1, the dehydroabietylamine salt suspension of 3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid is in 200 ml waters and 200 milliliters of ethyl acetate, under agitation add 35 milliliters of 2N sulphuric acid solns, filter, get 12.18 gram (90.6% yield) (+)-dehydroabietylamine hydrosulfates.The organic layer of filtrate is told, washing, drying is removed and to be desolvated, residue is with the diisopropyl ether crystallization, 12.7 grams (94.8% yield) (4S, 5R)-suitable-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid; [α]
25 365=-23.8 ℃.
B) 12.18 (+) dehydroabietylamine hydrosulfates that restrain with example 12a gained are suspended in 200 ml waters, adding strong caustic makes this suspension be adjusted to PH12, with twice of each 100 milliliters of methylbenzene extraction, extracting solution merges, after washing, the drying, be evaporated to (+)-dehydroabietylamine of dried 8.9 grams (88.9% yield), this material can be reused the partition in racemic mixture.
Example 13:
The operating performance of application example 12 can obtain:
(4S, 5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid: [α]
25 365=-12.75 ℃
(4R, 5S)-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid: [α]
25 365=+18.2 ℃.
Example 14:
The optical activity of gained suitable-1 in example 12,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid, be reduced to corresponding optical activity 1 with lithium borohydride, 3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-diketone, working method is reported similar to people such as Gerecke: Helv, Chim, Acta53(1970) 991-999
(3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d]-imidazoles-2,4-(1H)-productive rate of diketone is 88.5%, 119.4 ℃ of fusing points, [α]
25 365=+240.6 ℃.According to German Patent 2,058,234 or German Patent 2,331,244, this lactone can be converted into D-(+)-vitamin H.
Example 15:
With the method for example 14, can be with enantiotopic suitable-1,3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-5-carboxylic acid reduces with lithium borohydride, obtains:
(3aS, 6aR)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d]-imidazoles-2,4-(1H)-diketone, yield 97.4%, [α]
25 365=+208 ℃
(3aR, 6aS)-1,3-dibenzyl-tetrahydrochysene-4H-furo [3,4-d]-imidazoles-2,4-(1H)-diketone, quantitative yield, [α]
25 365=-206 ℃
Example 16:
4 gram sodium borohydrides are suspended in 250 milliliters of tetrahydrofuran (THF)s and are heated to backflow, then with the 60.8 (4S that restrain, 5R)-1,3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazolidine-4-carboxylic acid (+)-westvaco rosin amine salt is (with example 1b, 2,3 or 4 narration methods make) solution in 150 milliliters of tetrahydrofuran (THF)s was added drop-wise in the suspension of above-mentioned sodium borohydride in 4 hours, finishes, with this reaction solution stirring and refluxing 1 hour.
Reactant is cooled to 20 ℃, is added drop-wise in the reactant with 300 milliliters of 3N sulphuric acid solns and decomposes.Under reduced pressure boil off most of solvent, the gained sedimentation and filtration washes with water.
Add ethanol in the filtrate and heating makes its dissolving, the cooling post crystallization is separated out, filter, washing with alcohol, 27.3 grams (93% yield) (3aS, 6aR)-1,3-dibenzyl tetrahydrochysene-4H-furo [3,4-d]-imidazoles-2,4-(1H)-diketone; 119 ℃ of fusing points, [α]
25 365=+208.7(c=1, benzene).
Mother liquor is concentrated into dried, handles recyclable 33.1 gram dehydroabietylamine sulfur hydrogen salts with methylene dichloride.
Example 17:
33.4 gram (4R, 5S)-1, (+) westvaco rosin amine salt of 3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid is (with example 1B, 2,4,5 or 6 methods preparations) solution under agitation slowly is added drop-wise in 170 milliliter of 0.15 molar diborane tetrahydrofuran solution in 0 ℃.Finish, continue to stir 5 hours at 0 ℃, decompose with dilution heat of sulfuric acid then, working method is similar to example 16.14.6 grams (91% yield) (3aS, 6aR)-1,3-dibenzyl tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4-(1H)-diketone; Fusing point: 118.8,
[α]
25 365=+206.4(c=1, benzene)
Example 18
Method with example 16, with d-1-phenyl-2-to toluene ethamine and (4S, 5R)-1, the salt that 3-dibenzyl carbonyl-2-oxo-imidazole alkane-the 4-carboxylic acid is become (by European publication specification sheets 92,194 described method preparations) is used sodium borohydride reduction in tetrahydrofuran (THF).89% yield (3aS, 6aR)-1,3-dibenzyl tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4(1H)-diketone.
This lactone compound can be by German Patent 2,058, and 234 or 2,331,244 described methods are converted into D-(+)-vitamin H.
Example 19:
With the method that is similar to example 17, in tetrahydrofuran (THF) with diborane with (4R, 5S)-1, d-1-phenyl-the 2-of 3-dibenzyl-5-methoxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid reduces to toluene ethylamine salt (preparing with European publication specification sheets 92,194 described methods), can get (the 3aS of 92% yield, 6aR)-1,3-dibenzyl tetrahydrochysene-4H-furo [3,4-d] imidazoles-2,4-(1H)-diketone.
Claims (16)
1, following formula, the partition technology of Ia/b racemic semi-ester
Wherein,
The alkyl of 6 carbon atoms of R-as many as, the alkoxyalkyl of 2～8 carbon atoms, the cycloalkyl of 3～5 carbon atoms, the key thiazolinyl of 2～6 carbon atoms,
Benzyl or 1 or 2 styroyls,
The BZL-benzyl
This resolution process is: make half ester and optically active amine salify, with the diastereomer of gained separately.It is characterized in that: used optically active amines is (+)-dehydroabietylamine,
2, technology according to claim 1 is characterized in that: the diastereoisomeric salt of (+)-dehydroabietylamine and racemic semi-ester I a/b addition gained, and wherein a pair of diastereoisomeric salt can preferentially be separated out with crystallization shape from solution,
3, technology according to claim 2 is characterized in that: each molar racemic modification solution, need to add 0.1～1 molar (+)-dehydroabietylamine,
4, technology according to claim 1 is characterized in that: the raceme mixture of formula I a/b is converted into the mixture of two pairs of diastereoisomeric salts with the effect of (+)-dehydroabietylamine, wherein a pair of diastereoisomeric salt can preferentially be separated out with crystallization shape,
5, according to the described technology of claim 4, it is characterized in that: it is 1～1.5 mol that the racemoid that every mol broke generates diastereoisomeric salt needed (+) dehydrogenation-rosin Amine D,
6, according to each described technology of claim 1 to 4, in the optics partition used solvent be aqueous can with water blended organic solvent,
7, according in the claim 1 to 5 each, the R among its Chinese style I a/b is methyl or ethyl,
8, according in the claim 1 to 5 each, the recovery method of wherein used partition agent (+) dehydroabietylamine is: with diastereoisomeric salt and effect of sulfuric acid, form the hydrosulfate of insoluble, with gained salt and highly basic effect, use solvent extraction, promptly recyclable (+) dehydroabietylamine, and can be used further to the partition of racemic modification
9, from 1,3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-4-carboxylic acid preparation (3as, 6aR) and/or (3aR, 6aS)-1,3-dibenzyl six hydrogen-1H furo [3,4-d] imidazoles-2, the technology characteristics of 4-diketone is: with optically active amine and optically active 1, the diastereoisomeric salt that 3-dibenzyl-5-carbalkoxy-2-oxo-imidazole alkane-the 4-carboxylic acid is generated reduces.
10, technology according to claim 9 is characterized in that: the carboxyl of diastereomer half ester salt reduced,
11, technology according to claim 9 is characterized in that: the carbalkoxy of diastereomer half ester salt reduced,
12, according to each the described technology in the claim 9 to 11, it is characterized in that: optically active amine is (+)-dehydroabietylamine,
13, according in the claim 9 to 11 each, wherein said preparation (3aS, 6aR)-1,3-dibenzyl six hydrogen-1H-furo [3,4-d] imidazoles-2,4-diketone technology, it is characterized in that: (4S, 5R)-1, (+)-westvaco rosin amine salt sodium borohydride reduction of 3-dibenzyl-5-methoxyl group and/or 5-oxyethyl group and/or 5-benzyloxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid
14, according in the claim 9 to 11 each, preparation (3aS, 6aR)-1,3-dibenzyl-six hydrogen-1H-furo [3,4-d] imidazoles-2, the technology of 4-diketone, it is characterized in that: (4R, 5S)-1, (+)-westvaco rosin amine salt of 3-dibenzyl-5-methoxyl group and/or 5-oxyethyl group and/or 5-benzyloxycarbonyl-2-oxo-imidazole alkane-4-carboxylic acid reduces with diborane
15, according to claim 1, gained optically active suitable-1,3-dibenzyl-2-oxo-imidazole alkane-4,5-dicarboxylic acid half ester can be used for preparing D-(+)-vitamin H,
16, according to claim 9 to 14, the optical activity 1 that makes, 3-dibenzyl six hydrogen-1H-furo [3,4-d] imidazoles-2, the 4-diketone can be used for preparing D(+)-vitamin H.
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| CN 85106365 CN1031461C (en) | 1985-08-24 | 1985-08-24 | Resolution process of racemic semi-ester |
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| CN 85106365 CN1031461C (en) | 1985-08-24 | 1985-08-24 | Resolution process of racemic semi-ester |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037191A (en) * | 2015-06-28 | 2015-11-11 | 南京林业大学 | Dehydroabietylamine imidazole organic salt, and preparation method and application thereof |
| CN110804062A (en) * | 2019-11-06 | 2020-02-18 | 浙江工业大学 | Synthesis method of (3S,6R) -1, 3-dibenzyl tetrahydrofuran imidazole-2, 4-diketone |
-
1985
- 1985-08-24 CN CN 85106365 patent/CN1031461C/en not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037191A (en) * | 2015-06-28 | 2015-11-11 | 南京林业大学 | Dehydroabietylamine imidazole organic salt, and preparation method and application thereof |
| CN105037191B (en) * | 2015-06-28 | 2017-03-01 | 南京林业大学 | A kind of dehydroabietylamine imidazoles organic salt and preparation method thereof, application |
| CN110804062A (en) * | 2019-11-06 | 2020-02-18 | 浙江工业大学 | Synthesis method of (3S,6R) -1, 3-dibenzyl tetrahydrofuran imidazole-2, 4-diketone |
| CN110804062B (en) * | 2019-11-06 | 2021-03-30 | 浙江工业大学 | Synthesis method of (3S,6R) -1, 3-dibenzyl tetrahydrofuran imidazole-2, 4-diketone |
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| CN1031461C (en) | 1996-04-03 |
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