JP2000515882A - （ｓ）―３，４―ジヒドロキシ酪酸の保護されたエステルを合成するための改善された方法 - Google Patents
（ｓ）―３，４―ジヒドロキシ酪酸の保護されたエステルを合成するための改善された方法Info
- Publication number
- JP2000515882A JP2000515882A JP10508813A JP50881398A JP2000515882A JP 2000515882 A JP2000515882 A JP 2000515882A JP 10508813 A JP10508813 A JP 10508813A JP 50881398 A JP50881398 A JP 50881398A JP 2000515882 A JP2000515882 A JP 2000515882A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- formula
- compound
- group
- solvent
- 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.)
- Ceased
Links
- 238000000034 method Methods 0.000 title claims abstract description 60
- 150000002148 esters Chemical class 0.000 title abstract description 11
- DZAIOXUZHHTJKN-VKHMYHEASA-N 3S,4-dihydroxy-butyric acid Chemical compound OC[C@@H](O)CC(O)=O DZAIOXUZHHTJKN-VKHMYHEASA-N 0.000 title abstract description 7
- 230000002194 synthesizing effect Effects 0.000 title 1
- -1 cyclic orthoester Chemical class 0.000 claims abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 56
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 23
- 239000003377 acid catalyst Substances 0.000 claims description 20
- 150000001720 carbohydrates Chemical class 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 16
- 239000000758 substrate Substances 0.000 claims description 12
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 11
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 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 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 8
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 claims description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 239000005913 Maltodextrin Substances 0.000 claims description 3
- 229920002774 Maltodextrin Polymers 0.000 claims description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 3
- 229940035034 maltodextrin Drugs 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 claims description 2
- FGQLGYBGTRHODR-UHFFFAOYSA-N 2,2-diethoxypropane Chemical compound CCOC(C)(C)OCC FGQLGYBGTRHODR-UHFFFAOYSA-N 0.000 claims description 2
- 150000002016 disaccharides Chemical class 0.000 claims description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims 2
- 150000007524 organic acids Chemical class 0.000 claims 2
- 235000005985 organic acids Nutrition 0.000 claims 1
- 230000020477 pH reduction Effects 0.000 claims 1
- FWIBCWKHNZBDLS-UHFFFAOYSA-N 3-hydroxyoxolan-2-one Chemical compound OC1CCOC1=O FWIBCWKHNZBDLS-UHFFFAOYSA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 18
- 238000004821 distillation Methods 0.000 description 18
- 238000004519 manufacturing process Methods 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 16
- FUDDLSHBRSNCBV-VKHMYHEASA-N (4s)-4-hydroxyoxolan-2-one Chemical compound O[C@@H]1COC(=O)C1 FUDDLSHBRSNCBV-VKHMYHEASA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 150000002596 lactones Chemical class 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 4
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- GNGACRATGGDKBX-UHFFFAOYSA-N dihydroxyacetone phosphate Chemical compound OCC(=O)COP(O)(O)=O GNGACRATGGDKBX-UHFFFAOYSA-N 0.000 description 4
- YSEKNCXYRGKTBJ-UHFFFAOYSA-N dimethyl 2-hydroxybutanedioate Chemical compound COC(=O)CC(O)C(=O)OC YSEKNCXYRGKTBJ-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- LEPWUMPXISBPIB-UHFFFAOYSA-N 4-phenylbutanamide Chemical compound NC(=O)CCCC1=CC=CC=C1 LEPWUMPXISBPIB-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 3
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 3
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960005370 atorvastatin Drugs 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- FUDDLSHBRSNCBV-GSVOUGTGSA-N (4r)-4-hydroxyoxolan-2-one Chemical compound O[C@H]1COC(=O)C1 FUDDLSHBRSNCBV-GSVOUGTGSA-N 0.000 description 2
- DLVZBSZXZDGKQY-UHFFFAOYSA-N 2,2-dihydroxybutanoic acid Chemical compound CCC(O)(O)C(O)=O DLVZBSZXZDGKQY-UHFFFAOYSA-N 0.000 description 2
- DZAIOXUZHHTJKN-UHFFFAOYSA-N 2-Desoxy-D-glycero-tetronsaeure Natural products OCC(O)CC(O)=O DZAIOXUZHHTJKN-UHFFFAOYSA-N 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- ADHRFDCBLJVNFO-UHFFFAOYSA-N 4-methyl-3-oxo-n-phenylpentanamide Chemical compound CC(C)C(=O)CC(=O)NC1=CC=CC=C1 ADHRFDCBLJVNFO-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010020961 Hypocholesterolaemia Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 2
- 239000001639 calcium acetate Substances 0.000 description 2
- 229960005147 calcium acetate Drugs 0.000 description 2
- 235000011092 calcium acetate Nutrition 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- LOQFROBMBSKWQY-ZCFIWIBFSA-N ethyl (3r)-4-cyano-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@H](O)CC#N LOQFROBMBSKWQY-ZCFIWIBFSA-N 0.000 description 2
- AIZRKZQHJNWBEI-YFKPBYRVSA-N ethyl (3s)-4-bromo-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@H](O)CBr AIZRKZQHJNWBEI-YFKPBYRVSA-N 0.000 description 2
- OMSUIQOIVADKIM-UHFFFAOYSA-N ethyl 3-hydroxybutyrate Chemical compound CCOC(=O)CC(C)O OMSUIQOIVADKIM-UHFFFAOYSA-N 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 2
- 230000000737 periodic effect Effects 0.000 description 2
- 125000001639 phenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000000526 short-path distillation Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- WGNSGQNASYNCBU-GSVOUGTGSA-N (3r)-4-bromo-3-hydroxybutanoic acid Chemical compound BrC[C@H](O)CC(O)=O WGNSGQNASYNCBU-GSVOUGTGSA-N 0.000 description 1
- ADZQCEUEGXRCJY-SCSAIBSYSA-N (3r)-4-cyano-3-hydroxybutanoic acid Chemical compound N#CC[C@@H](O)CC(O)=O ADZQCEUEGXRCJY-SCSAIBSYSA-N 0.000 description 1
- SSZWWUDQMAHNAQ-VKHMYHEASA-N (R)-3-chloro-1,2-propanediol Chemical compound OC[C@@H](O)CCl SSZWWUDQMAHNAQ-VKHMYHEASA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- MXMUAWYZLLHAEA-UHFFFAOYSA-N 2-(1,3-dioxan-4-yl)acetic acid Chemical compound OC(=O)CC1CCOCO1 MXMUAWYZLLHAEA-UHFFFAOYSA-N 0.000 description 1
- BNGGGQKEDABCQY-UHFFFAOYSA-N 2-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid Chemical compound CC1(C)OC(CCN)CC(CC(O)=O)O1 BNGGGQKEDABCQY-UHFFFAOYSA-N 0.000 description 1
- GODYJJJBRGLOET-UHFFFAOYSA-N 2-[6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid Chemical compound CC1(C)OC(CC#N)CC(CC(O)=O)O1 GODYJJJBRGLOET-UHFFFAOYSA-N 0.000 description 1
- GQKIPHLPMKOMBV-UHFFFAOYSA-N 2-hydroxy-3-oxohexanoic acid Chemical compound CCCC(=O)C(O)C(O)=O GQKIPHLPMKOMBV-UHFFFAOYSA-N 0.000 description 1
- ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- FUDDLSHBRSNCBV-UHFFFAOYSA-N 4-hydroxyoxolan-2-one Chemical compound OC1COC(=O)C1 FUDDLSHBRSNCBV-UHFFFAOYSA-N 0.000 description 1
- QBOSLABQNDNVEH-UHFFFAOYSA-N 6-(2,3-dihydroxypropyl)-1,3-dioxin-4-one Chemical compound OCC(O)CC1=CC(=O)OCO1 QBOSLABQNDNVEH-UHFFFAOYSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-isoascorbic acid Chemical compound OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 102000001390 Fructose-Bisphosphate Aldolase Human genes 0.000 description 1
- 108010068561 Fructose-Bisphosphate Aldolase Proteins 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 206010021024 Hypolipidaemia Diseases 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 229910052776 Thorium Inorganic materials 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000012267 brine Substances 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
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- OKGHLVCDEIYKRR-UHFFFAOYSA-L calcium 7-[2-hydroxy-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]heptanoate Chemical compound CC(C)C1=C(C(=C(N1CCCCCCC(=O)[O-])O)C2=CC=CC=C2)C(=O)NC3=CC=CC=C3.CC(C)C1=C(C(=C(N1CCCCCCC(=O)[O-])O)C2=CC=CC=C2)C(=O)NC3=CC=CC=C3.[Ca+2] OKGHLVCDEIYKRR-UHFFFAOYSA-L 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- FESAXEDIWWXCNG-UHFFFAOYSA-N diethyl(methoxy)borane Chemical compound CCB(CC)OC FESAXEDIWWXCNG-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000010350 erythorbic acid Nutrition 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- AIZRKZQHJNWBEI-RXMQYKEDSA-N ethyl (3r)-4-bromo-3-hydroxybutanoate Chemical compound CCOC(=O)C[C@@H](O)CBr AIZRKZQHJNWBEI-RXMQYKEDSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- PUYCICVJCRLABY-UHFFFAOYSA-N heptane;oxolane Chemical compound C1CCOC1.CCCCCCC PUYCICVJCRLABY-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940026239 isoascorbic acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229960002160 maltose Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- KCKWOJWPEXHLOQ-BYPYZUCNSA-N methyl (3s)-3,4-dihydroxybutanoate Chemical compound COC(=O)C[C@H](O)CO KCKWOJWPEXHLOQ-BYPYZUCNSA-N 0.000 description 1
- HJBXZWUERBJYGL-UHFFFAOYSA-N methyl 2-(1,3-dioxan-4-yl)acetate Chemical compound COC(CC1OCOCC1)=O HJBXZWUERBJYGL-UHFFFAOYSA-N 0.000 description 1
- KCKWOJWPEXHLOQ-UHFFFAOYSA-N methyl 3,4-dihydroxybutanoate Chemical compound COC(=O)CC(O)CO KCKWOJWPEXHLOQ-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 229930014626 natural product Natural products 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- HWSHVKNLMBMKSR-GHMZBOCLSA-N tert-butyl 2-[(4r,6r)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate Chemical compound CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1 HWSHVKNLMBMKSR-GHMZBOCLSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings 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
- C07D317/34—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Furan Compounds (AREA)
- Pyrane Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2236996P | 1996-07-29 | 1996-07-29 | |
| US60/022,369 | 1996-07-29 | ||
| PCT/US1997/011654 WO1998004543A1 (en) | 1996-07-29 | 1997-07-01 | Improved process for the synthesis of protected esters of (s)-3,4-dihydroxybutyric acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2000515882A true JP2000515882A (ja) | 2000-11-28 |
| JP2000515882A5 JP2000515882A5 (OSRAM) | 2005-03-10 |
Family
ID=21809241
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10508813A Ceased JP2000515882A (ja) | 1996-07-29 | 1997-07-01 | （ｓ）―３，４―ジヒドロキシ酪酸の保護されたエステルを合成するための改善された方法 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US5998633A (OSRAM) |
| EP (1) | EP0915866B1 (OSRAM) |
| JP (1) | JP2000515882A (OSRAM) |
| KR (1) | KR100447370B1 (OSRAM) |
| CN (1) | CN1093126C (OSRAM) |
| AT (1) | ATE215078T1 (OSRAM) |
| AU (1) | AU3515497A (OSRAM) |
| CO (1) | CO4950542A1 (OSRAM) |
| DE (1) | DE69711391T2 (OSRAM) |
| DK (1) | DK0915866T3 (OSRAM) |
| ES (1) | ES2176756T3 (OSRAM) |
| HU (1) | HU226465B1 (OSRAM) |
| IL (1) | IL127058A (OSRAM) |
| PT (1) | PT915866E (OSRAM) |
| TR (1) | TR199900191T2 (OSRAM) |
| WO (1) | WO1998004543A1 (OSRAM) |
| ZA (1) | ZA976705B (OSRAM) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4926955B2 (ja) * | 2005-05-31 | 2012-05-09 | 興和株式会社 | 光学活性ｐｐａｒ活性化化合物及びその製造中間体の製造法 |
Families Citing this family (49)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5998633A (en) * | 1996-07-29 | 1999-12-07 | Warner-Lambert Company | Process for the synthesis of protected esters of (S)-3,4-dihydroxybutyric acid |
| KR100332703B1 (ko) * | 1998-07-24 | 2002-08-27 | 삼성정밀화학 주식회사 | 광학활성을갖는(s)-3,4-에폭시부티르산염의제조방법 |
| CN1316008A (zh) | 1998-07-24 | 2001-10-03 | 三星精密化学株式会社 | 制备α－(1,4)－连接的寡糖的方法 |
| US6713290B2 (en) | 1998-07-24 | 2004-03-30 | Samsung Fine Chemicals Co., Ltd. | Process for preparing optically pure (S)-3-hydroxy-γ-butyrolactone |
| US6235930B1 (en) * | 1999-03-31 | 2001-05-22 | Board Of Trustees Operating Michigan State University | Process for the preparation of 3,4-dihydroxybutanoic acid and derivatives thereof from substituted pentose sugars |
| HU227840B1 (en) * | 1999-05-06 | 2012-05-02 | Egis Gyogyszergyar Nyilvanosan M Kod Ruszvunytarsasag | Intermediates of atorvastatin synthesis and process for producing them |
| DE60026737T2 (de) * | 1999-12-17 | 2006-09-21 | Pfizer Science And Technology Ireland Ltd., Dun Laoghaire | Verfahren zur herstellung von kristallin atorvastin kalcium |
| WO2001044180A1 (en) | 1999-12-17 | 2001-06-21 | Warner Lambert Research And Development Ireland Limited | A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt |
| JP4598917B2 (ja) * | 2000-04-28 | 2010-12-15 | ダイセル化学工業株式会社 | ラクトンの製造方法 |
| KR100645665B1 (ko) | 2000-07-27 | 2006-11-13 | 에스케이 주식회사 | (ｓ)-베타-하이드록시-감마-부티로락톤의 연속 제조방법 |
| EP1734034A3 (en) | 2001-01-09 | 2007-01-03 | Warner-Lambert Company LLC | Carboxylic acid salts of beta-alanine esters or -amides |
| US6476235B2 (en) | 2001-01-09 | 2002-11-05 | Warner-Lambert Company | Process for the synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide |
| WO2002057229A1 (en) * | 2001-01-19 | 2002-07-25 | Biocon India Limited | FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN) |
| AP1571A (en) | 2001-06-29 | 2006-02-10 | Warner Lambert Co | Crystalline forms of 'R-(R* ,R*)!-2-(4- fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-'phenylamino)carbonyl!-1H-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin) |
| CA2451159A1 (en) * | 2001-07-06 | 2003-01-16 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of 7-amino syn 3,5-dihydroxy heptanoic acid derivatives via 6-cyano syn 3,5-dihydroxy hexanoic acid derivatives |
| KR100598079B1 (ko) * | 2002-02-25 | 2006-07-07 | 바이오콘 리미티드 | 신규의 보로네이트 에스테르 |
| GB0211716D0 (en) | 2002-05-22 | 2002-07-03 | Phoenix Chemicals Ltd | Process |
| JP2005539018A (ja) * | 2002-08-06 | 2005-12-22 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | ５−（４−フルオロフェニル）−１−［２−（（２ｒ，４ｒ）−４−ヒドロキシ−６−オキソ−テトラヒドロ−ピラン−２−イル）エチル］−２−イソプロピル−４−フェニル−１ｈ−ピロール−３−カルボン酸フェニルアミドの製造方法 |
| US20060052617A1 (en) * | 2002-09-18 | 2006-03-09 | Sk Corporation | Continuous process for the production of optically pure (s)-beta-hydroxy-y-butyrolactone |
| US7414119B2 (en) * | 2002-09-20 | 2008-08-19 | Verenium Corporation | Aldolases, nucleic acids encoding them and methods for making and using them |
| US6713639B1 (en) | 2002-10-28 | 2004-03-30 | Council Of Scientific And Industrial Research | Process for preparing enantiomerically pure (S)-3-hydroxy-gamma-butyrolactone |
| RU2337905C2 (ru) * | 2003-04-14 | 2008-11-10 | Уорнер-Ламберт Компани Ллс | Способ получения фениламида 5-(4-фторфенил)-1-[2-((2r,4r)-4-гидрокси-6-оксотетрагидропиран-2-ил)этил]-2-изопропил-4-фенил-1h-пиррол-3-карбоновой кислоты |
| ES2323366T3 (es) * | 2003-04-22 | 2009-07-14 | Biocon Limited | Procedimiento novedoso para la reduccion estereoselectiva de beta-cetoesteres. |
| US7790197B2 (en) * | 2003-06-09 | 2010-09-07 | Warner-Lambert Company Llc | Pharmaceutical compositions of atorvastatin |
| US20040253305A1 (en) * | 2003-06-12 | 2004-12-16 | Luner Paul E. | Pharmaceutical compositions of atorvastatin |
| US20050271717A1 (en) | 2003-06-12 | 2005-12-08 | Alfred Berchielli | Pharmaceutical compositions of atorvastatin |
| US7655692B2 (en) * | 2003-06-12 | 2010-02-02 | Pfizer Inc. | Process for forming amorphous atorvastatin |
| CN1852894A (zh) * | 2003-09-17 | 2006-10-25 | 沃尼尔·朗伯有限责任公司 | [R－(R*, R*)]－2－(4－氟苯基) －β,δ－二羟基－5－(1－甲基乙基) －3－苯基－4－[(苯基氨基)羰基] －1 H－吡咯－1－庚酸的结晶形式 |
| WO2005068642A2 (en) | 2003-10-01 | 2005-07-28 | Board Of Trustees Operating Michigan State University | Bacterial synthesis of 1,2,4-butanetriol enantiomers |
| KR100829268B1 (ko) * | 2004-04-16 | 2008-05-13 | 화이자 프로덕츠 인코포레이티드 | 비정질 아토바스타틴 칼슘의 제조 방법 |
| BRPI0510713A (pt) | 2004-05-05 | 2007-11-20 | Pfizer Prod Inc | formas de sal de ácido [r-(r*,r*)]-2-(4-fluorofenil)-beta, delta-diidróxi-5-(1-metiletil)-3-fenil-4-[(fenilamino)ca rbonil]-1h-pirrol-1- heptanóico |
| MX2007000765A (es) | 2004-07-20 | 2007-03-28 | Warner Lambert Co | Formas cristalinas de sal de calcio del acido (r-(r*, r*))-2- (4-fluorofenil)- beta,gama- dihidroxi-5- (1-metiletil)-3 -fenil-4-((fenilamino) (carbonil)-1ih -pirrol-1- heptanoico (2:1). |
| CN101048141A (zh) | 2004-10-28 | 2007-10-03 | 沃尼尔·朗伯有限责任公司 | 形成非晶形的阿托伐他汀的方法 |
| JP2008521878A (ja) * | 2004-12-02 | 2008-06-26 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | 非晶質アトルバスタチンの医薬組成物及びその製造のための方法 |
| CA2547216A1 (en) | 2005-09-21 | 2007-03-21 | Renuka D. Reddy | Process for annealing amorphous atorvastatin |
| WO2007057755A1 (en) | 2005-11-21 | 2007-05-24 | Warner-Lambert Company Llc | Novel forms of [r-(r*,r*)]-2-(4-fluorophenyl)-b,b-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-hept anoic acid magnesium |
| US20110165641A1 (en) * | 2006-03-31 | 2011-07-07 | The Board Of Trustees Of Michigan State University | Synthesis of 1,2,4-Butanetriol Enantiomers from Carbohydrates |
| EP2054518A2 (en) * | 2006-07-19 | 2009-05-06 | Board of Trustees of Michigan State University | Microbial synthesis of d-1,2,4-butanetriol |
| KR100850558B1 (ko) | 2008-01-02 | 2008-08-06 | 조동옥 | 아토르바스타틴의 효율적인 제조방법 |
| JP2009256316A (ja) | 2008-03-28 | 2009-11-05 | Daicel Chem Ind Ltd | β−ヒドロキシ−γ−ブチロラクトンの製造方法 |
| CN101337906B (zh) * | 2008-08-15 | 2012-06-27 | 河南豫辰精细化工有限公司 | 一种4-甲基-3-氧代-n-苯基戊酰胺的制备方法 |
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| US20140335179A1 (en) | 2011-07-01 | 2014-11-13 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Micronized crystals of atorvastatin hemicalcium |
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| CN117447350A (zh) * | 2023-10-26 | 2024-01-26 | 河南豫辰药业股份有限公司 | 一种阿托伐他汀m4有机废物综合再利用方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2710688B2 (ja) * | 1990-10-09 | 1998-02-10 | 鐘淵化学工業株式会社 | ４―ブロモ―３―ヒドロキシ酪酸エステル誘導体の製造法 |
| CA2049536C (en) * | 1991-05-13 | 1999-07-06 | Rawle I. Hollingsworth | Process for the preparation of 3,4-dihydroxybutanoic acid and salts thereof |
| JP3351563B2 (ja) * | 1992-12-03 | 2002-11-25 | 鐘淵化学工業株式会社 | ３−ヒドロキシ酪酸誘導体の製造法 |
| US5998633A (en) * | 1996-07-29 | 1999-12-07 | Warner-Lambert Company | Process for the synthesis of protected esters of (S)-3,4-dihydroxybutyric acid |
-
1997
- 1997-07-01 US US09/230,397 patent/US5998633A/en not_active Expired - Fee Related
- 1997-07-01 IL IL12705897A patent/IL127058A/en not_active IP Right Cessation
- 1997-07-01 TR TR1999/00191T patent/TR199900191T2/xx unknown
- 1997-07-01 AT AT97931557T patent/ATE215078T1/de not_active IP Right Cessation
- 1997-07-01 ES ES97931557T patent/ES2176756T3/es not_active Expired - Lifetime
- 1997-07-01 JP JP10508813A patent/JP2000515882A/ja not_active Ceased
- 1997-07-01 CN CN97195996A patent/CN1093126C/zh not_active Expired - Fee Related
- 1997-07-01 KR KR10-1999-7000721A patent/KR100447370B1/ko not_active Expired - Fee Related
- 1997-07-01 AU AU35154/97A patent/AU3515497A/en not_active Abandoned
- 1997-07-01 PT PT97931557T patent/PT915866E/pt unknown
- 1997-07-01 EP EP97931557A patent/EP0915866B1/en not_active Expired - Lifetime
- 1997-07-01 HU HU9904348A patent/HU226465B1/hu not_active IP Right Cessation
- 1997-07-01 DE DE69711391T patent/DE69711391T2/de not_active Expired - Fee Related
- 1997-07-01 DK DK97931557T patent/DK0915866T3/da active
- 1997-07-01 WO PCT/US1997/011654 patent/WO1998004543A1/en not_active Ceased
- 1997-07-28 CO CO97042973A patent/CO4950542A1/es unknown
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4926955B2 (ja) * | 2005-05-31 | 2012-05-09 | 興和株式会社 | 光学活性ｐｐａｒ活性化化合物及びその製造中間体の製造法 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20000029648A (ko) | 2000-05-25 |
| WO1998004543A1 (en) | 1998-02-05 |
| CN1093126C (zh) | 2002-10-23 |
| EP0915866B1 (en) | 2002-03-27 |
| KR100447370B1 (ko) | 2004-09-08 |
| DE69711391D1 (de) | 2002-05-02 |
| ATE215078T1 (de) | 2002-04-15 |
| DK0915866T3 (da) | 2002-06-10 |
| ES2176756T3 (es) | 2002-12-01 |
| CN1223647A (zh) | 1999-07-21 |
| HK1020728A1 (en) | 2000-05-19 |
| HU226465B1 (en) | 2008-12-29 |
| CO4950542A1 (es) | 2000-09-01 |
| HUP9904348A3 (en) | 2004-03-01 |
| PT915866E (pt) | 2002-07-31 |
| EP0915866A1 (en) | 1999-05-19 |
| AU3515497A (en) | 1998-02-20 |
| US5998633A (en) | 1999-12-07 |
| ZA976705B (en) | 1998-02-10 |
| IL127058A (en) | 2001-07-24 |
| HUP9904348A2 (hu) | 2000-04-28 |
| IL127058A0 (en) | 1999-09-22 |
| DE69711391T2 (de) | 2002-11-07 |
| TR199900191T2 (xx) | 1999-04-21 |
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