CN106928248A - The method that one kind prepares (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3 b] alcohol of furans 3 - Google Patents
The method that one kind prepares (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3 b] alcohol of furans 3 Download PDFInfo
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- CN106928248A CN106928248A CN201710064302.9A CN201710064302A CN106928248A CN 106928248 A CN106928248 A CN 106928248A CN 201710064302 A CN201710064302 A CN 201710064302A CN 106928248 A CN106928248 A CN 106928248A
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- Prior art keywords
- acid
- methyl
- reaction
- ethylene glycol
- alcohol
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- 238000000034 method Methods 0.000 title claims abstract description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 125000002541 furyl group Chemical group 0.000 title claims abstract description 18
- 150000002240 furans Chemical class 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 69
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical class OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 11
- 229950002366 nafoxidine Drugs 0.000 claims description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- -1 methoxyl methyl Chemical group 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 230000002152 alkylating effect Effects 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical class CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical class OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 235000015177 dried meat Nutrition 0.000 claims description 5
- 150000002170 ethers Chemical class 0.000 claims description 5
- 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 5
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000012973 diazabicyclooctane Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 150000003147 proline derivatives Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000000707 stereoselective effect Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- UIKQNMXWCYQNCS-UHFFFAOYSA-N 2-hydroxybutanal Chemical class CCC(O)C=O UIKQNMXWCYQNCS-UHFFFAOYSA-N 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 119
- 239000000243 solution Substances 0.000 description 31
- 238000001914 filtration Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 238000003756 stirring Methods 0.000 description 22
- 239000012043 crude product Substances 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- 239000012071 phase Substances 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
- 239000012295 chemical reaction liquid Substances 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 230000006837 decompression Effects 0.000 description 10
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Natural products CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 9
- 238000000926 separation method Methods 0.000 description 9
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 5
- 238000006386 neutralization reaction Methods 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FWOHDAGPWDEWIB-UHFFFAOYSA-N 2-bromoethoxymethylbenzene Chemical class BrCCOCC1=CC=CC=C1 FWOHDAGPWDEWIB-UHFFFAOYSA-N 0.000 description 1
- UPIMXDQREQJWMR-UHFFFAOYSA-N 2-chloroethoxymethylbenzene Chemical class ClCCOCC1=CC=CC=C1 UPIMXDQREQJWMR-UHFFFAOYSA-N 0.000 description 1
- JVKXKIBYHWRLOJ-UHFFFAOYSA-N 2-hydroxyethyl methanesulfonate Chemical class CS(=O)(=O)OCCO JVKXKIBYHWRLOJ-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- YWLTZVUIXCDPFF-UHFFFAOYSA-N acetaldehyde;nonane Chemical compound CC=O.CCCCCCCCC YWLTZVUIXCDPFF-UHFFFAOYSA-N 0.000 description 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical group C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000004427 diamine group Chemical group 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- RNWIJLZQJSGBCU-UHFFFAOYSA-N furan-3-ol Chemical compound OC=1C=COC=1 RNWIJLZQJSGBCU-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention belongs to the field of chemical synthesis, the method that one kind prepares DRV intermediate (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3 b] alcohol of furans 3 is disclosed.With the hydroxybutyraldehyde derivative (I) of (R) 3 hydroxyl 4 for raw material; Stereoselective obtains intermediate (II) with ethylene glycol derivative reaction under catalyst action; (3R is cyclized in acid condition after gained intermediate (II) deprotection base; 3aS; 6aR) hexahydro furyl simultaneously [2, the 3 b] alcohol of furans 3.The preparation method raw material is cheap and easy to get, and reaction stereoselectivity is high, and simple to operate, route is short, low cost, is adapted to the industrialized production of DRV.
Description
Technical field
The present invention relates to the field of chemical synthesis, more particularly to one kind prepares (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b]
The method of furan-3-ol.
Background technology
DRV (structural formula such as formula IV) also known as Da Lunawei, are that a kind of new non-peptides for treating AIDS resist
Reversal of viral protease inhibitors.DRV is researched and developed into first by Tai Boteke (Tibotec) drugmaker of Johnson ＆ Johnson's pharmacy
Work(, is biology in current 6 kinds of protease inhibitors (inverase, Ritonavir, indinavir, NELFINAVIR, An Ruinawei)
Availability highest, it is by blocking the formation from infected host cell surface release new ripe virion
Journey, suppresses the protease of virus and works.
Simultaneously [2,3-b] furan-3-ol (III) (structural formula is as shown in formula III) is synthetically to (3R, 3aS, 6aR) hexahydro furyl
One of key intermediate of Rui Nawei, hexahydro furyl simultaneously has three chiral centres in the molecular structure of [2,3-b] furan-3-ol,
There are eight kinds of possible stereoisomers in theory, due to the influence of bicyclic rigid structure, only four kinds cis and ring solids
Isomers is thermodynamically stable.The method that prior art has been disclosed for various prepare compounds (III), these methods are summarized
Get up to be broadly divided into two major classes, first kind method is all by a lactone intermediate and then by reductive ring open and cyclization system again
Standby (such as WO03022853, US20040162340, US6867321, WO2005095410, JOC 2004,69,7822-29, OL,
2005,26,5917-20, CN201210552770, CN201210588083), such method is all walked using reaction more long substantially
Suddenly, need to use dangerous material nitromethane in Part Methods, the most key be these methods stereoselectivity it is poor, greatly
Part is required for the target isomer single by splitting acquisition, and its accessory substance (i.e. the enantiomer of target product) is difficult to pass through
Short-cut method is then converted to target product, so as to cause production cost high；Equations of The Second Kind method is in the 3- introducing of dihydrofuran ring
The structure fragment of vicinal diamines, then be cyclized prepare target product (such as WO2004033462, WO2012070057, WO2013114382,
WO2008055970, WO2004002975, TL, 1986,32,3715-18), this kind of method equally exist synthetic route it is long, reaction
Condition is harsh, it is industrial be difficult to realize and target product (III) stereoselectivity difference the problems such as.Therefore, the present invention is provided
A kind of simple to operate, route is short, the side of preparation (3R, 3aS, 6aR) hexahydro furyl of low cost simultaneously [2,3-b] furan-3-ol
Method.
The content of the invention
In order to solve the problems, such as synthetic line of the prior art long, complex operation and high cost, the invention provides one
The method for kind preparing (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol.
In order to solve the above-mentioned technical problem, the present invention uses following technical scheme：
The method that one kind prepares (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol, including following synthetic route
In step b or step a~step b：
R therein1、R2It is methyl, cyclohexyl or cyclopenta, R3It is benzyl, THP or MOM.
Described step (a) is for raw material, under catalyst action with (R) -3- hydroxy-4-hydroxymethyl bases butyraldehyde derivatives (I)
Stereoselective obtains intermediate (II) with the reaction of alkylating reagent ethylene glycol derivative, during described step (b) is described
(3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol is cyclized after mesosome (II) deprotection base in acid condition.
In the preparation method that the present invention is provided, its step (a) used catalyst is selected from AMP, nafoxidine, piperidines, dried meat ammonia
Acid or proline derivative, dried meat ammonia alcohol or prolinol derivative；Catalyst and (R) -3- hydroxy-4-hydroxymethyl bases butyraldehyde derivatives (I)
Mol ratio be 0.1:1~2:1.
In the preparation method that the present invention is provided, the alkylating reagent used by step (a) is ethylene glycol derivative, alkylation examination
Agent consumption is 1.0-2.0 times of (R) -3- hydroxy-4-hydroxymethyl bases butyraldehyde derivatives (I)；Preferably, halo (chlorine, bromine, iodine) ethanol spreads out
The ethylene glycol derivative of biological or list OMs, OTs, OTf substitution.
In the preparation method that the present invention is provided, solvent used by step (a) be selected from dichloromethane, chloroform, toluene, DMF,
DMSO or DMA；Alkali used by step (a) is selected from triethylamine, DIPEA, DABCO, DBU, DBN, pyridine, methyl piperidine, bicarbonate
Sodium or sodium carbonate.
In the preparation method that the present invention is provided, in the step (a), added in alkylating reagent ethylene glycol derivative
Temperature when catalyst and (R) -3- hydroxy-4-hydroxymethyl base butyraldehyde derivatives (I) is -20~0 DEG C, and reaction temperature during reaction is 25
~80 DEG C.
Preferably, the acid used by step (b) is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid or p-methyl benzenesulfonic acid.
Preferably, the solvent used by step (b) is alcohols or ethers；The alcohols is selected from methyl alcohol, ethanol, isopropanol or second
Glycol, the ethers is selected from tetrahydrofuran, 2- methyltetrahydrofurans, methyl tertiary butyl ether(MTBE) or dioxane.
Preferably, the reaction temperature of step (b) is 20~100 DEG C.
It is further preferable that the reaction temperature of step (b) is 50~80 DEG C.
(3R, 3aS, the 6aR) hexahydro furyl prepared present invention also offers such as above-mentioned method simultaneously [2,3-b] furans-
3- alcohol.
It should be noted that step (b) is cyclized or removed under acid condition after deprotection base by compound (II)
Protection group and cyclisation are carried out at " in one pot ".
Further, R is worked as3During for benzyl and its derivative protection group, step (b) includes two-step reaction, that is, hydrogenate de- R3Protect
The reaction of shield base and ring-closure reaction；Wherein, the catalyst that hydrogenation is used is Raney Ni or Pd/C, and Hydrogen Vapor Pressure is 1-
5atm, solvent is the conventional hydrogenation solvents such as methyl alcohol, ethanol, tetrahydrofuran, ethyl acetate；The acid that ring-closure reaction is used is salt
Acid, sulfuric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, phosphoric acid and nitric acid, ring-closure reaction temperature are 20-100 DEG C, more preferably 50-80
℃。
And work as R3For during the protection group of removing, Deprotection and cyclization exist in step (b) under the acid conditions such as THP, MOM
" in one pot " is completed, and solvent used is ethers (such as tetrahydrofuran, dioxane), alcohols (such as methyl alcohol, ethanol) in the step
Deng hydrophilic solvent；The acid for using is hydrochloric acid, sulfuric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, phosphoric acid and nitric acid etc., and reaction temperature is 20-
100 DEG C, more preferably 50-80 DEG C.
The preparation method of the compound (I) used by the present invention can be obtained by two methods, and concrete technology route is as follows：
Process route one：
Process route two：
The invention provides the method that one kind prepares (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol, the party
Compared with prior art, there is advantages below in method：(1) raw material is cheap and easy to get, and reaction stereoselectivity is high, and accessory substance is few, so that
Cause low production cost, the yield of (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol is greatly improved；
(2) preparation method is simple to operate, and reaction scheme is short, is adapted to the industrialized production of DRV.
Specific embodiment
The invention discloses the method that one kind prepares (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol, ability
Field technique personnel can use for reference present disclosure, be suitably modified technological parameter realization.In particular, it is all similar to replace
Change and change apparent to those skilled in the art, they are considered as being included in the middle of the present invention.The present invention
Method and application be described by preferred embodiment, related personnel can substantially not depart from present invention, essence
Realize and apply skill of the present invention to method described herein and using being modified or suitably changing with combining in god and scope
Art.
In order that those skilled in the art can be better understood from the present invention, with reference to specific embodiment to the present invention
It is described in further detail.
Embodiment 1
Step (a)：2- benzyloxy 1- iodoethane (31.4g, 0.12mol) and DABCO (16.1g, 0.13mol) are dissolved in
In 300mL dichloromethane, -20 DEG C are cooled to after being stirred at room temperature 30 minutes, to sequentially adding (R) -2,2- diformazans in the mixed liquor
Base-DOX -4- acetaldehyde (14.4g, 0.1mol) and nafoxidine (7.1g, 0.1mol).Gained reaction solution is heated up
Stirring reaction adds 100 milliliters of water and 100 milliliters of hydrochloric acid of 1N after 24 hours to 25 DEG C and at such a temperature, stirs 30 minutes
After separate organic phase, organic phase anhydrous magnesium sulfate after saturated common salt water washing is dried, and filtering, filtrate decompression is concentrated to give II, point
Sterling 19.5g is obtained after, yield is 70%.
Step (b)：Compound (II) (30g, 0.11mol), 3.0 grams of 10%Pd/C and 200mL methyl alcohol are placed in round bottom and burnt
In bottle, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressures.Filtering, adds 100 milliliters of the hydrochloric acid of 3N in filtrate,
After gained mixture is heated to 60 DEG C of reactions 3 hours, room temperature is cooled to, add triethylamine neutralization reaction liquid to alkalescence.Concentration is anti-
Answer liquid to dry, add ethyl acetate, filtering, filter cake to be washed with ethyl acetate, combined ethyl acetate phase, ethyl acetate phase concentration
12.9g compounds III is obtained to dry rear column chromatography for separation.Yield is 90%.
Embodiment 2
Step (a)：2- benzyloxy 1- iodoethane (52.3g, 0.20mol) and triethylamine (13.1g, 0.13mol) are dissolved in
In 300mL dichloromethane, -20 DEG C are cooled to after being stirred at room temperature 30 minutes；To sequentially adding (R) -2,2- diformazans in the mixed liquor
Base-DOX -4- acetaldehyde (14.4g, 0.1mol) and nafoxidine (1.42g, 0.02mol), by gained reaction solution liter
Stirring reaction after 24 hours, adds the hydrochloric acid of 100mL water and 100mL1N to temperature to 25 DEG C and at such a temperature, after stirring 30 minutes
Organic phase is separated, organic phase anhydrous magnesium sulfate after saturated common salt water washing is dried, and filtering, filtrate decompression is concentrated to give II, separates
Sterling 17.5g, yield are obtained afterwards：63%.
Step (b)：Compound (II) (35g, 0.13mol), 3.5g10%Pd/C and 250mL tetrahydrofurans are placed in round bottom
In flask, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressures.Filtering, adds 100mL water and 30mL first in filtrate
Sulfonic acid, after gained mixture is heated to 50 DEG C of reactions 5 hours, is cooled to room temperature, adds triethylamine neutralization reaction liquid to alkalescence.It is dense
Contracting reaction liquid adds ethyl acetate, filtering, filter cake to be washed with ethyl acetate, combined ethyl acetate phase, ethyl acetate phase to dry
Through separating to obtain 14.7g compounds III after being concentrated to dryness.Yield：87%.
Embodiment 3
Step (a)：By 2- (2- iodine ethyoxyl) tetrahydrochysene -2H- pyrans (51.2g, 0.20mol) and triethylamine (21.2g,
0.21mol) it is dissolved in 300mL chloroforms, 0 DEG C is cooled to after being stirred at room temperature 30 minutes；To being sequentially added in the mixed liquor (14.4g,
0.1mol) (R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde and L- prolinol derivatives L-2- (diphenyl-triphen silica
Methyl) nafoxidine (25.5g, 0.05mol), gained reaction solution rises to 40 DEG C and at such a temperature stirring reaction after 10 hours,
The hydrochloric acid of 100mL water and 100mL1N is added, stirring separates organic phase, organic phase nothing after saturated common salt water washing after 30 minutes
Water magnesium sulfate is dried, and filtering, filtrate decompression is concentrated to give compound II crude products.
Step (b)：To the hydrochloric acid 100mL that tetrahydrofuran 200mL, 3N are added in the crude product, gained reaction solution is heated to 65
DEG C reaction 6 hours.Add triethylamine up to reaction liquid is in alkalescence, concentration of reaction solution body adds ethyl acetate, filters to dry.
Filter cake is washed with ethyl acetate, is concentrated after combined ethyl acetate phase, obtains compound III crude products, and crude product is obtained after column chromatography for separation
9.1g compound III sterlings, yield is 70%.
Embodiment 4
Step (a)：2- benzyloxy 1- iodoethane (31.4g, 0.12mol) and triethylamine (13.1g, 0.13mol) are dissolved in
In 300mL dichloromethane, -10 DEG C are cooled to after being stirred at room temperature 30 minutes；To sequentially adding (R) -2,2- diformazans in the mixed liquor
Base-DOX -4- acetaldehyde (14.4g, 0.1mol) and L- dried meat ammonia alcohol (10.1g, 0.1mol), gained reaction solution rises to 80
DEG C and stirring reaction after 15 hours at such a temperature, add the hydrochloric acid of 100mL water and 100mL1N, stirring has been separated after 30 minutes
Machine phase, organic phase anhydrous magnesium sulfate after saturated common salt water washing is dried, and filtering, filtrate decompression is concentrated to give II, obtains pure after separation
Product 22.8g, yield：82%.
Step (b)：Compound (II) (30g, 0.11mol), 3.0g10%Pd/C and 200mL isopropanols are placed in into round bottom to burn
In bottle, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressures.Filtering, adds the p-methyl benzenesulfonic acid of 3N in filtrate
100mL, after gained mixture is heated to 20 DEG C of reactions 3 hours, is cooled to room temperature, adds triethylamine neutralization reaction liquid to alkalescence.
Concentration of reaction solution body adds ethyl acetate, filtering, filter cake to be washed with ethyl acetate, combined ethyl acetate phase, ethyl acetate to dry
Through separating to obtain 12.9g compounds III after being mutually concentrated to dryness.Yield：90%.
Embodiment 5
Step (a)：By 2- benzyloxy 1- chloroethanes (20.4g, 0.12mol) and the carbon -7- alkene of 1,8- diazabicylo 11
(abbreviation DBU) (16.1g, 0.13mol) is dissolved in 300mL toluene, and -20 DEG C are cooled to after being stirred at room temperature 30 minutes；To the mixing
(R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde (14.4g, 0.1mol) and L- diphenylprolinols are sequentially added in liquid
(38.0g, 0.15mol), gained reaction solution rises to 40 DEG C and stirring reaction after 20 hours, adds 100 milliliters of water at such a temperature
With 100 milliliters of hydrochloric acid of 1N, organic phase is separated after stirring 30 minutes, organic phase anhydrous magnesium sulfate after saturated common salt water washing is done
Dry, filtering, filtrate decompression is concentrated to give II, and sterling 14.2g, yield are obtained after separation：51%.
Step (b)：Compound (II) (30g, 0.11mol), 3.0g10%Pd/C and 200mL isopropanols are placed in into round bottom to burn
In bottle, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressures.Filtering, adds 100 milliliters of the sulfuric acid of 3N in filtrate,
After gained mixture is heated to 80 DEG C of reactions 3 hours, room temperature is cooled to, add triethylamine neutralization reaction liquid to alkalescence.Concentration is anti-
Answer liquid to dry, add ethyl acetate, filtering, filter cake to be washed with ethyl acetate, combined ethyl acetate phase, ethyl acetate phase concentration
To after doing through separating to obtain 12.9g compounds III.Yield is 90%.
Embodiment 6
Step (a)：By 2- (2- iodine ethyoxyl) tetrahydrochysene -2H- pyrans (30.7g, 0.12mol) and triethylamine (13.1g,
0.13mol) it is dissolved in 300mL DMF, 0 DEG C is cooled to after being stirred at room temperature 30 minutes；To being sequentially added in the mixed liquor (14.4g,
0.1mol) (R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde and L- prolinol derivatives (L-2- (diphenyl-triphen silicon
Oxygen methyl) nafoxidine) (102g, 0.2mol), gained reaction solution rises to 25 DEG C and at such a temperature stirring reaction 17 hours
Afterwards, the hydrochloric acid of 100mL water and 100mL1N is added, stirring separates organic phase after 30 minutes, and organic phase is through saturated common salt water washing
Anhydrous magnesium sulfate is dried afterwards, and filtering, filtrate decompression is concentrated to give compound II crude products.
Step (b)：To the hydrochloric acid 100mL that tetrahydrofuran 200mL, 3N are added in the crude product, gained reaction solution is heated to 60
DEG C reaction 6 hours.Add triethylamine up to reaction liquid is in alkalescence, concentration of reaction solution body adds ethyl acetate, filters to dry.
Filter cake is washed with ethyl acetate, is concentrated after combined ethyl acetate phase, obtains compound III crude products, and crude product is obtained after column chromatography for separation
9.1g compound III sterlings, yield is 72%.
Embodiment 7
Step (a)：By 2- benzyloxy 1- bromoethanes (25.7g, 0.12mol) and 1,5- diazabicyclo [4.3.0] -5- nonyls
Alkene (DBN) (16.1g, 0.13mol) is dissolved in 300 milliliters of dichloromethane, and -10 DEG C are cooled to after being stirred at room temperature 30 minutes；To this
(R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde (14.4g, 0.1mol) and 1- amino -2- first are sequentially added in mixed liquor
Oxygen methyl nafoxidine (AMP) (2.6g, 0.02mol).Gained reaction solution is warming up to 25 DEG C and at such a temperature stirring reaction
After 24 hours, the hydrochloric acid of 100mL water and 100mL1N is added, stirring separates organic phase after 30 minutes, and organic phase is through saturated aqueous common salt
Anhydrous magnesium sulfate is dried after washing, filtering, and intermediate sterling 13.9g, yield are separated to obtain after filtrate decompression concentration：50%.
Step (b)：By midbody compound (II) (35g, 0.13mol), 3.5g10%Pd/C and 250mL2- methyl tetrahydrochysenes
Furans is placed in round-bottomed flask, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressures.Filtering, adds in filtrate
100mL water and 30mL methanesulfonic acids, after gained mixture is heated to 100 DEG C of reactions 5 hours, are cooled to room temperature, in adding triethylamine
With reaction solution to alkalescence.Concentration of reaction solution body adds ethyl acetate, filtering, filter cake to be washed with ethyl acetate to dry, merges acetic acid
Ethyl ester phase, ethyl acetate phase be concentrated to dryness after through separating to obtain 14.7g compounds III.Yield：87%.
Embodiment 8
Step (a)：The iodohydrin (25.9g, 0.12mol) and diisopropyl ethyl amine (DIPEA) that MOM is protected
(16.8g, 0.13mol) is dissolved in 300mL DMSO, and 0 DEG C is cooled to after being stirred at room temperature 30 minutes；Add successively in the mixed liquor
Enter (14.4g, 0.1mol) (R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde and L-2- (diphenyl-triphen silica methyl)
Nafoxidine (10.2g, 0.02mol).Gained reaction solution rises to 25 DEG C and stirring reaction after 17 hours, is added at such a temperature
The hydrochloric acid of 100 milliliters of water and 100mL1N, stirring separates organic phase after 30 minutes, and organic phase is anhydrous after saturated common salt water washing
Magnesium sulfate is dried, and filtering, filtrate decompression is concentrated to give compound II crude products.
Step (b)：To the hydrochloric acid 100mL that dioxane 200mL, 3N are added in the crude product, gained reaction solution is heated to 50
DEG C reaction 6 hours.Add triethylamine up to reaction liquid is in alkalescence, concentration of reaction solution body adds ethyl acetate, filters to dry.
Filter cake is washed with ethyl acetate, is concentrated after combined ethyl acetate phase, obtains compound III crude products, and crude product is obtained after column chromatography for separation
9.8g compound III sterlings, yield is 75%.
Embodiment 9
Step (a)：By THP protect ethylene glycol methanesulfonates (26.9g, 0.12mol) and triethylamine (13.1g,
0.13mol) it is dissolved in 300mL DMAs, 0 DEG C is cooled to after being stirred at room temperature 30 minutes；To in the mixed liquor according to
Secondary addition (14.4g, 0.1mol) (R) -2,2- dimethyl -1,3- dioxolanes -4- acetaldehyde and L- prolinol derivatives L-2- (two
Phenyl-triphen silica methyl) nafoxidine (10.2g, 0.02mol).Gained reaction solution rises to 25 DEG C and stirs at such a temperature
After reaction 17 hours, the hydrochloric acid of 100mL water and 100mL1N is added, stirring separates organic phase after 30 minutes, and organic phase is through saturation
Anhydrous magnesium sulfate is dried after brine It, and filtering, filtrate decompression is concentrated to give compound II crude products.
Step (b)：To the hydrochloric acid 100mL that ethanol 200mL, 3N are added in the crude product, gained reaction solution is heated to 50 DEG C instead
Answer 6 hours.Add triethylamine up to reaction liquid is in alkalescence, concentration of reaction solution body adds ethyl acetate, filters to dry.Filter cake
Washed with ethyl acetate, concentrated after combined ethyl acetate phase, obtain compound III crude products, crude product obtains 7.9g after column chromatography for separation
Compound III sterlings, yield is 61%.
Embodiment 10
Step (a)：2- benzyloxy 1- iodoethane (31.4g, 0.12mol) and methyl piperidine (13.9g, 0.14mol) is molten
In 300mL dimethyl sulfoxide (DMSO)s, 0 DEG C is cooled to after being stirred at room temperature 30 minutes；To sequentially added in the mixed liquor (R) -2- (Isosorbide-5-Nitrae -
Dioxo spiro [4,5] decane acetaldehyde (18.4g, 0.1mol) and L- dried meat ammonia alcohol (2.02g, 0.02mol).Gained reaction solution rises to 50
DEG C and stirring reaction after 15 hours at such a temperature, add the hydrochloric acid of 100mL water and 100mL1N, stirring has been separated after 30 minutes
Machine phase, organic phase anhydrous magnesium sulfate after saturated common salt water washing is dried, and filtering, filtrate decompression is concentrated to give II, obtains pure after separation
Product 23.9g, yield：75%.
Step (b)：Compound (II) (32g, 0.1mol), 3.0g10%Pd/C and 200mL methyl alcohol are placed in round-bottomed flask
In, gained reaction solution hydrogenation 1 hour under 1atm Hydrogen Vapor Pressures.Filtering, adds the hydrochloric acid 100mL of 3N, gained in filtrate
After mixture is heated to 50 DEG C of reactions 3 hours, room temperature is cooled to, add triethylamine neutralization reaction liquid to alkalescence.Concentration of reaction solution
Body adds ethyl acetate, filtering, filter cake to be washed with ethyl acetate to dry, and combined ethyl acetate phase, ethyl acetate phase is concentrated to dryness
By separating to obtain 11.8g compounds III.Yield：91%.
Embodiment 11
Step (a)：The iodohydrin (25.9g, 0.12mol) and the sodium carbonate of (13.8g, 0.13mol) that MOM is protected are dissolved in
In 300mL dichloromethane, 0 DEG C is cooled to after being stirred at room temperature 30 minutes；To sequentially adding (R) -2- (Isosorbide-5-Nitraes-dioxy in the mixed liquor
Miscellaneous spiral shell [4,5] nonane acetaldehyde (17.0g, 0.1mol) and L-2- (diphenyl-triphen silica methyl) nafoxidine (10.2g,
0.02mol).Gained reaction solution rises to 25 DEG C and stirring reaction after 17 hours, adds 100mL water and 100mL1N at such a temperature
Hydrochloric acid, stirring separates organic phase after 30 minutes, and organic phase anhydrous magnesium sulfate after saturated common salt water washing is dried, filtering, filter
Liquid is concentrated under reduced pressure to obtain compound II crude products.
Step (b)：To the hydrochloric acid 100mL that tetrahydrofuran 200mL, 3N are added in above-mentioned crude product, gained reaction solution is heated to
50 DEG C are reacted 6 hours.Add triethylamine up to reaction liquid is in alkalescence, concentration of reaction solution body adds ethyl acetate, mistake to dry
Filter.Filter cake is washed with ethyl acetate, is concentrated after combined ethyl acetate phase, obtains compound III crude products, and crude product is after column chromatography for separation
10.0g compound III sterlings are obtained, yield is 77%.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
1. the method that one kind prepares (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol, it is characterised in that including such as
Step b or step a~step b in lower synthetic route：
Wherein, R1、R2It is methyl, cyclohexyl or cyclopenta, R3It is benzyl, THP trtrahydropyranyl (THP) or methoxyl methyl (MOM)；
Described step (a) is the solid under catalyst action for raw material with (R) -3- hydroxy-4-hydroxymethyl bases butyraldehyde derivatives (I)
Intermediate (II) is optionally obtained with the reaction of alkylating reagent ethylene glycol derivative, described step (b) is the intermediate
(II) (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol is cyclized after deprotection base in acid condition.
2. the method for claim 1, it is characterised in that the catalyst of described step (a) is selected from 1- amino -2- methoxies
Methyl nafoxidine (AMP), nafoxidine, piperidines, proline or proline derivative, dried meat ammonia alcohol or prolinol derivative；Institute
The catalyst stated is 0.1 with the mol ratio of compound shown in the formula I:1~2:1.
3. the method for claim 1, it is characterised in that the alkylating reagent ethylene glycol derivative of the step (a) is
Halo (chlorine, bromine, iodine) ethylene glycol derivative or the ethylene glycol derivative of list OMs, OTs, OTf substitution；Described alkylating reagent
Consumption is 1.0-2.0 times of the mol ratio of compound shown in the formula I.
4. the method for claim 1, it is characterised in that the solvent of the step (a) is selected from dichloromethane, chloroform, first
Benzene, DMF (DMF), dimethyl sulfoxide (DMSO) (DMSO) or DMA (DMA)；The step (a)
Alkali be selected from triethylamine, diisopropyl ethyl amine (DIPEA), triethylenediamine (DABCO), 1,8- diazabicylos 11
Carbon -7- alkene (DBU), 1,5- diazabicyclos [4.3.0] -5- nonenes (DBN), pyridine, methyl piperidine, sodium acid carbonate or carbonic acid
Sodium.
5. the method for claim 1, it is characterised in that in the step (a), derives to alkylating reagent ethylene glycol
It is -20~0 DEG C, reaction during reaction that temperature when catalyst and (R) -3- hydroxy-4-hydroxymethyl base butyraldehyde derivatives (I) is added in thing
Temperature is 25~80 DEG C.
6. the method for claim 1, it is characterised in that the acid used by the step (b) is selected from hydrochloric acid, sulfuric acid, first sulphur
Acid or p-methyl benzenesulfonic acid.
7. the method for claim 1, it is characterised in that the solvent of the step (b) is alcohols or ethers；Described alcohol
Class is selected from methyl alcohol, ethanol, isopropanol or ethylene glycol, and described ethers is selected from tetrahydrofuran, 2- methyltetrahydrofurans, methyl- tert fourth
Base ether or dioxane.
8. the method for claim 1, it is characterised in that the reaction temperature of the step (b) is 20~100 DEG C.
9. method as claimed in claim 9, it is characterised in that the reaction temperature of the step (b) is 50~80 DEG C.
10. (3R, 3aS, 6aR) hexahydro furyl simultaneously [2,3-b] furan-3-ol that prepared by the method for claim 1.
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| CN115433194A (en) * | 2022-09-13 | 2022-12-06 | 上海毕得医药科技股份有限公司 | Synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115433194A (en) * | 2022-09-13 | 2022-12-06 | 上海毕得医药科技股份有限公司 | Synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative |
| CN115433194B (en) * | 2022-09-13 | 2023-06-23 | 上海毕得医药科技股份有限公司 | Synthesis method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative |
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