CN1152570A - 制备(4,5)-反式-噁唑烷的新方法 - Google Patents
制备(4,5)-反式-噁唑烷的新方法 Download PDFInfo
- Publication number
- CN1152570A CN1152570A CN96112021A CN96112021A CN1152570A CN 1152570 A CN1152570 A CN 1152570A CN 96112021 A CN96112021 A CN 96112021A CN 96112021 A CN96112021 A CN 96112021A CN 1152570 A CN1152570 A CN 1152570A
- Authority
- CN
- China
- Prior art keywords
- oxygen
- alkyl
- oxazolidines
- trans
- formula
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 31
- 238000004519 manufacturing process Methods 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 23
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000003368 amide group Chemical group 0.000 claims abstract description 4
- -1 alkyl lithium compounds Chemical class 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 238000006317 isomerization reaction Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- 150000003818 basic metals Chemical class 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- FEMRXDWBWXQOGV-UHFFFAOYSA-N potassium amide Chemical class [NH2-].[K+] FEMRXDWBWXQOGV-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 150000001371 alpha-amino acids Chemical group 0.000 abstract 2
- 235000008206 alpha-amino acids Nutrition 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- 239000002585 base Substances 0.000 description 11
- 229940024606 amino acid Drugs 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- BIAZEQPYCCADLD-YFKPBYRVSA-N (2s)-2-(ethylamino)pentanedioic acid Chemical compound CCN[C@H](C(O)=O)CCC(O)=O BIAZEQPYCCADLD-YFKPBYRVSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- VGGGPCQERPFHOB-UHFFFAOYSA-N Bestatin Natural products CC(C)CC(C(O)=O)NC(=O)C(O)C(N)CC1=CC=CC=C1 VGGGPCQERPFHOB-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000219112 Cucumis Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 102000004377 Thiopurine S-methyltransferases Human genes 0.000 description 1
- 108090000958 Thiopurine S-methyltransferases Proteins 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 239000006035 Tryptophane Substances 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- QFAADIRHLBXJJS-ZAZJUGBXSA-N amastatin Chemical compound CC(C)C[C@@H](N)[C@H](O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(O)=O QFAADIRHLBXJJS-ZAZJUGBXSA-N 0.000 description 1
- 108010052590 amastatin Proteins 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
-
- 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 Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及通过用强碱异构化，从相应的顺式化合物来制备式(I)(4、5)-反式-2-氧-噁唑烷的方法，其中R1为α-氨基酸的特征基，R2为烷基并且R3为氢，胺，酰胺或尿烷保护基或式-C(O)-R4基，其中R4代表烷基或一个或多个彼此由一个或多个酰胺键连接的α-氨基酸。
Description
本发明涉及从相应的顺式化合物制备(4，5)-反式-噁唑烷的新方法。尤其，本发明涉及制备式(I)(4，5)-反式-2-氧-噁唑烷的方法其中
R1为α-氨基酸的特征基，
R2为烷基并且
R3为氢，胺，酰胺或尿烷保护基或式-C(O)-R4基，其中
R4代表烷基或一个或多个彼此通过一个或多个酰胺键连接的α-氨基酸。
这些化合物在制备β-氨基羧酸衍生物中是重要的中间体，它们是制备药理活性物质，尤其是那些适于治疗病毒感染，降低血压和控制肿瘤物质的基础构件。
Herranz等人(J.Org.Chem.(1990)55，2232-2234)描述了利用三甲基硅保护的氰基醇合成(2S，3R)-3-氨基-2-羟基-苯基丁酸来制备贝他定和阿码他定
Patel等人(J.Med.Chem.(1993)36，2431-2447)描述了利用激活的酮来制备血管紧张肽原酶抑制剂。在合成2-氧-噁唑烷中间体中，要求通过层析和结晶充分加工处理相应的前体。
例如，Melon等人(Bull.Soc.Chim.Fr.(1992)129，585-593)描述了制备(4，5)-反式-2-氧-噁唑烷的进一步的合成路线。
现在，意外地发现本发明方法可得到具有高度立体选择性的反式构型的式(I)化合物。本发明方法包括通过强碱的方法，将(4，5)-顺式-2-氧-噁唑烷酮转变成相应的(4，5)-反式-2-氧-噁唑烷酮。
详细地说，该方法涉及通过强碱的方法将式(II)(4，5)-顺式-2-氧-噁唑烷的异构化其中
R1为α-氨基酸，尤其α-氨基羧酸的特征基，
R2为烷基并且
R3为氢，胺，酰胺或尿烷保护基或式-C(O)-R4基其中R4代表烷基或一个或多个彼此通过一个或多个酰胺键连接的α-氨基酸，
得到式(I)化合物其中式(I)中的R1，R2和R3如上定义。
优选的方法是将上述式(II)(4，5)-顺式-2-氧-噁唑烷异构化，其中R1为α-氨基羧酸的特征基，R2为低级烷基并且R3为氢或苄基，苯甲酰基，乙酰基或烯丙基。
尤其优选的方法是将上述式(II)(4，5)-顺式-2-氧-噁唑烷异构化，其中R1为天然或合成α-氨基羧酸的特征基，例如苄基，环己基甲基或苯基，R2为低级烷基并且R3为氢。
例如，本发明方法适于制备(4S，5R)-4-苄基-2-氧-噁唑烷-5-羧酸甲酯和(4S，5R)-4-环己基甲基-2-氧-噁唑烷-5-羧酸甲酯。
通常在-20℃-+80℃，优选在+20℃-+45℃的温度下进行反应。
本发明方法中所使用的碱主要为强碱，如碱金属或碱土金属的醇化物，即醇化物，其中烃链包含如关于R2所述的烷基，锂，钠或钾的氨基化物，烷基锂化合物或烷基镁卤化物。甲醇钠或叔丁醇钾是优选的。
本领域技术人员从技术说明中会知道怎样制备用作起始物质的相应的顺式-2-氧-噁唑烷或相应的顺式/反式-2-氧-噁唑烷混合物并且，例如，在欧洲专利申请EP0635493中描述了该制备方法。因此，例如，通过α-羟基-β-氨基酸酯与相应的羧基化试剂反应，可制备顺式-2-氧-噁唑烷。例如顺式-2-氧-噁唑烷用于合成HW蛋白酶抑制剂。
在本领域任一技术人员都熟知的惰性溶剂中进行该方法。术语“惰性溶剂”指在所述反应条件下为惰性的溶剂。例如，可使用溶剂如甲苯，四氢呋喃(THF)、或与R2基相应的醇。
在本发明范围内，术语“α-氨基酸的特征基”指天然或合成α-氨基羧酸H2NCH(R1)COOH中的R1基。例如，天然α-氨基羧酸中的R1基为甲基(在丙氨酸中)，异丙基(缬氨酸)，仲丁基(亮氨酸)，甲硫基乙基(甲硫氨酸)，苄基(苯丙氨酸)，3-吲哚基甲基(色氨酸)，羟甲基(丝氨酸)，1-羟乙基(苏氨酸)，巯甲基(半胱氨酸)，对-羟基苄基(酪氨酸)，氨基甲酰基甲基(天冬酰胺)，氨基甲酰基乙基(谷氨酸)，4-氨基丁基(赖氨酸)，3-胍基丙基(精氨酸)和5-咪唑基甲基(组氨酸)。在合成α-氨基或氨酸羧酸中将环己基甲基和苯基看作R1基的实例。因此，R1包括烷基，优选低级烷基，以及芳基，烷氧基和芳烷基。
术语“烷基”单指或合指含有1-24，优选1-12个碳原子的环状，支链或直链单价烃基。术语“低级烷基”包含具有1-8，优选1-4个碳原子的直链或支链饱和烷基如甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，戊基，己基，庚基，辛基等。术语“烷氧基”单指或并指烷基醚基或低级烷基醚基，其中术语烷基或低级烷基具有上述含义，例如，甲氧基，乙氧基，正丙氧基，异丙氧基，正丁氧基，异丁氧基，仲丁氧基，叔丁氧基等。
术语“芳基”单指或并指带有或不带有一个或多个选自烷基，烷氧基，卤素，羟基，氨基，硝基，硫等取代基的苯基或萘基，例如，苯基，对甲苯基，4-甲氧基苯基，4-叔丁氧基苯基，4-氟苯基，4-氯苯基，4-羟苯基，1-萘基，2-萘基等。术语“芳烷基”单指或并指上述烷基，其中由上述芳基取代氢原子。其实例为苄基，2-苯乙基等。
例如，胺，酰胺或尿烷保护基包括如苄基，苯甲酰基，烯丙基，乙酰基或叔丁氧基羰基。
术语“卤素”表示氟、氯、溴或碘。
如果需要，用适宜的分离或纯化方法，例如通过过滤，提取，结晶，柱层析，制备型HPLC，薄层层析或这些方法的联合或其它由技术说明中已知的方法，将按照本发明方法得到的化合物分离和纯化。
例如，在合成紫杉酚中，按上述方法制备的化合物可用于合成药用化合物。Magnus和Pye(J.Chem.Soc.Chem.Commun.，(1995)1933-1934)描述了用于制备紫杉酚衍生物的反应系列。这里通过本发明化合物简单的酯化作用，可诱导产生在环系A上紫杉酚的侧链。其中在一个反应步骤中，得到正确的立体化学。
下列实施例说明本发明。
实施例1制备(4S，5R)-4-苄基-2-氧-噁唑烷-5-羧酸甲酯
将70.0g 4-苄基-2-氧-噁唑烷-5-羧酸甲酯的(4S，5S)-和(4S，5R)-异构体混合物(92∶8)的溶液和在700ml THF中的7.0g叔丁醇钾在20℃下搅拌4小时并在45℃下搅拌2小时，将溶液用半饱和氯化钠溶液洗涤两次，经MgSO4干燥，过滤并将滤液蒸发得到68g(97％)95％的(4S，5R)-4-苄基-2-氧-噁唑烷-5-羧酸甲酯(薄层层析(SiO2，乙酸乙酯：Rs：0.5)。
实施例2制备(4S，5R)-4-环己基甲基-2-氧-噁唑烷-5-羧酸甲酯
为制备上述化合物，在实施例1条件下，将通过氢化(4S，5R)-4-苄基-2-氧-噁唑烷-5-羧酸甲酯得到的(4S，5S)-4-环己基甲基-2-氧-噁唑烷-5-羧酸甲酯进行反应。得到(4S，5R)-4-环己基甲基-2-氧-噁唑烷-5-羧酸甲酯，产率大约为95％。
Claims (11)
1.制备(4、5)-反式-2-氧-噁唑烷的方法，该方法包括用强碱的方法，将式(II)(4，5)-顺式-2-氧-噁唑烷异构化其中
R1为α-氨基酸的特征基，
R2为烷基并且
R3为氢，胺，酰胺或尿烷保护基或式-C(O)-R4基，其中R4代表烷基或一个或多个彼此通过一个或多个酰胺键连接的α-氨基酸，得到式(I)化合物其中式(I)中的R1，R2和R3如上定义。
2.权利要求1的方法，其中R1为α-氨基羧酸的特征基，R2为低级烷基并且R3为氢或苄基，乙酰基，苯甲酰基或烯丙基。
3.权利要求2的方法，其中R1为天然或合成α-氨基羧酸的特征基，R2为低级烷基并且R3为氢。
4.权利要求3的方法，其中R1为环己基甲基，苯基或苄基。
5.权利要求1-4中任一方法，其中所使用的强碱为碱金属或碱土金属醇化物，锂，钠或钾氨基化物，烷基锂化合物或烷基镁卤化物。
6.权利要求1-5中任一方法，其中所使用的强碱为甲醇钠或叔丁醇钾。
7.权利要求1-6中任一方法，其中在-20℃-+80℃下进行异构化。
8.权利要求7的方法，其中温度为+20℃-+45℃。
9.权利要求1-8中任一方法，其中所使用的溶剂为甲苯，四氢呋喃或醇。
10.权利要求1-9中任一方法，其中所使用的起始物质为顺式/反式-2-氧-噁唑烷混合物。
11.按照权利要求1-10的方法可制备的化合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH313195 | 1995-11-06 | ||
| CH3131/95 | 1995-11-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1152570A true CN1152570A (zh) | 1997-06-25 |
Family
ID=4249292
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96112021A Pending CN1152570A (zh) | 1995-11-06 | 1996-11-04 | 制备(4,5)-反式-噁唑烷的新方法 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US5670653A (zh) |
| EP (1) | EP0771792B1 (zh) |
| JP (1) | JP2907781B2 (zh) |
| KR (1) | KR100197459B1 (zh) |
| CN (1) | CN1152570A (zh) |
| AT (1) | ATE180775T1 (zh) |
| DE (1) | DE59602077D1 (zh) |
| DK (1) | DK0771792T3 (zh) |
| ES (1) | ES2133877T3 (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001024763A2 (en) | 1999-10-01 | 2001-04-12 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| JP4372538B2 (ja) | 2001-05-23 | 2009-11-25 | 株式会社カネカ | β−ヒドロキシエチルアミン化合物のオキサゾリジノン誘導体ならびにβ−ヒドロキシエチルアミン化合物の製造法 |
| KR100686117B1 (ko) * | 2005-05-04 | 2007-02-26 | 엘지전자 주식회사 | 식기세척기 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5455353A (en) * | 1993-03-24 | 1995-10-03 | Hoffmann-La Roche Inc. | 4-(benzyl-2-oxo-oxazolidin-5 ylmethyl)N tertbutyl-decahydroisoquinoline-3-carboxamides |
-
1996
- 1996-10-28 JP JP8284820A patent/JP2907781B2/ja not_active Expired - Lifetime
- 1996-10-30 US US08/739,565 patent/US5670653A/en not_active Expired - Fee Related
- 1996-10-31 EP EP96117478A patent/EP0771792B1/de not_active Expired - Lifetime
- 1996-10-31 DK DK96117478T patent/DK0771792T3/da active
- 1996-10-31 ES ES96117478T patent/ES2133877T3/es not_active Expired - Lifetime
- 1996-10-31 AT AT96117478T patent/ATE180775T1/de active
- 1996-10-31 DE DE59602077T patent/DE59602077D1/de not_active Expired - Fee Related
- 1996-11-04 CN CN96112021A patent/CN1152570A/zh active Pending
- 1996-11-05 KR KR1019960052158A patent/KR100197459B1/ko not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0771792A1 (de) | 1997-05-07 |
| JPH09169744A (ja) | 1997-06-30 |
| EP0771792B1 (de) | 1999-06-02 |
| ES2133877T3 (es) | 1999-09-16 |
| DK0771792T3 (da) | 1999-11-15 |
| ATE180775T1 (de) | 1999-06-15 |
| KR970027061A (ko) | 1997-06-24 |
| US5670653A (en) | 1997-09-23 |
| DE59602077D1 (de) | 1999-07-08 |
| KR100197459B1 (ko) | 1999-06-15 |
| JP2907781B2 (ja) | 1999-06-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1926102A (zh) | N－保护的4－酮脯氨酸衍生物的制备方法 | |
| EP0774453B1 (en) | Process for producing 3-amino-2-oxo-1-halogenopropane derivatives | |
| Koh et al. | Reaction of (R)-pantolactone esters of alpha-bromoacids with amines a remarkable synthesis of optically active alpha-amino esters | |
| CN1300111C (zh) | 制备高纯度培哚普利的方法及在其合成中有用的中间体 | |
| AU2009301209B2 (en) | Pseudoproline dipeptides | |
| CN1152570A (zh) | 制备(4,5)-反式-噁唑烷的新方法 | |
| CN1064348C (zh) | 卤代α－氨基酮和α－氨基醇及其制备新方法 | |
| US6090913A (en) | Transesterification and other conversion reactions of acid derivatives, using an amidine base | |
| CN101472939A (zh) | 假脯氨酸二肽 | |
| US6639094B2 (en) | Process for producing α-aminoketone derivatives | |
| IL126717A (en) | Process for the production of azathidine acid - 2 carboxyls free of enantiomers | |
| US6538160B2 (en) | Process for producing α-aminohalomethyl ketone derivatives | |
| US6169200B1 (en) | Method for producing α-hydroxy-β-aminocarboxylic acids | |
| US20040124144A1 (en) | Process for the purification of N-carboxyanhydrides of amino acids | |
| US5095114A (en) | Process for the enantiomer-selective preparation of γ-keto-δ-amino acid derivatives | |
| KR20160081864A (ko) | 티올기를 갖는 d-체 또는 l-체 아미노산 유도체의 제조 방법 | |
| US7122696B2 (en) | Processes for preparation of N-protected-β-amino alcohols and N-protected-β-amino epoxides | |
| US5959141A (en) | 1-amino-2-hydroxycycloalkanecarboxylic acid derivatives | |
| Easton | Free-radical reactions for the stereoselective synthesis of amino acid derivatives | |
| Kawai et al. | Optical resolution and absolute configuration of N‐Benzyloxycarbonyl‐α‐alkoxyglycines | |
| EP0434743A1 (en) | Methods for preparing captopril and its analogues | |
| FR2859471A1 (fr) | Procede pour la fabrication d'un compose enantiopur | |
| EP0432204A1 (en) | Derivatives and precursors of captopril and its analogues | |
| JPH08231477A (ja) | 光学活性β−アミノエステル類の製造方法 | |
| EP0262010A1 (fr) | Procédé d'estérification stéréospécifique d'un mélange d'acides aminés par réaction dudit mélange en solution dans l'alcool d'estérification en présence de papaine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |