CN1157391C - 制备异噁唑甲酰胺及其类似物的方法和中间体 - Google Patents
制备异噁唑甲酰胺及其类似物的方法和中间体 Download PDFInfo
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- CN1157391C CN1157391C CNB008120110A CN00812011A CN1157391C CN 1157391 C CN1157391 C CN 1157391C CN B008120110 A CNB008120110 A CN B008120110A CN 00812011 A CN00812011 A CN 00812011A CN 1157391 C CN1157391 C CN 1157391C
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- formula
- saturated alkyl
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- 238000000034 method Methods 0.000 title claims description 180
- 150000001875 compounds Chemical class 0.000 claims abstract description 322
- 238000002360 preparation method Methods 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims description 120
- 239000011541 reaction mixture Substances 0.000 claims description 72
- 125000000217 alkyl group Chemical group 0.000 claims description 56
- -1 enol ester Chemical class 0.000 claims description 50
- 239000003153 chemical reaction reagent Substances 0.000 claims description 39
- 239000002585 base Substances 0.000 claims description 32
- 102000004190 Enzymes Human genes 0.000 claims description 27
- 108090000790 Enzymes Proteins 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 150000004820 halides Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 7
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 5
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 5
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 239000004474 valine Substances 0.000 claims description 5
- 230000010933 acylation Effects 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 230000007071 enzymatic hydrolysis Effects 0.000 claims description 4
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 claims description 4
- 239000004367 Lipase Substances 0.000 claims description 3
- 102000004882 Lipase Human genes 0.000 claims description 3
- 108090001060 Lipase Proteins 0.000 claims description 3
- 238000010640 amide synthesis reaction Methods 0.000 claims description 3
- 235000019421 lipase Nutrition 0.000 claims description 3
- SYRDJRYYXJKUOD-UHFFFAOYSA-N 5-chloro-4,6-dimethyltriazine Chemical group CC1=NN=NC(C)=C1Cl SYRDJRYYXJKUOD-UHFFFAOYSA-N 0.000 claims description 2
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- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 84
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 38
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 31
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 28
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 28
- 238000004128 high performance liquid chromatography Methods 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 125000003118 aryl group Chemical group 0.000 description 26
- 239000000047 product Substances 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- 229940088598 enzyme Drugs 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- 239000002253 acid Substances 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- 239000000758 substrate Substances 0.000 description 22
- 125000001424 substituent group Chemical group 0.000 description 20
- 125000001072 heteroaryl group Chemical group 0.000 description 19
- 239000002994 raw material Substances 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 18
- 239000012043 crude product Substances 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
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- 239000000741 silica gel Substances 0.000 description 17
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- 238000005406 washing Methods 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 230000002255 enzymatic effect Effects 0.000 description 15
- 239000007789 gas Substances 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 229910052786 argon Inorganic materials 0.000 description 14
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- 238000006722 reduction reaction Methods 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 235000011121 sodium hydroxide Nutrition 0.000 description 11
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 11
- 239000003513 alkali Substances 0.000 description 10
- 230000001376 precipitating effect Effects 0.000 description 10
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 229950006238 nadide Drugs 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- 101710088194 Dehydrogenase Proteins 0.000 description 8
- 108010020056 Hydrogenase Proteins 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 150000001469 hydantoins Chemical class 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 239000002002 slurry Substances 0.000 description 8
- YXMISKNUHHOXFT-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) prop-2-enoate Chemical compound C=CC(=O)ON1C(=O)CCC1=O YXMISKNUHHOXFT-UHFFFAOYSA-N 0.000 description 7
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 7
- 239000004280 Sodium formate Substances 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
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- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 7
- 235000019254 sodium formate Nutrition 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 description 6
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 6
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- CAYJBRBGZBCZKO-BHGBQCOSSA-N ethyl (e,4s)-4-[[(2r,5s)-2-[(4-fluorophenyl)methyl]-6-methyl-5-[(5-methyl-1,2-oxazole-3-carbonyl)amino]-4-oxoheptanoyl]amino]-5-[(3s)-2-oxopyrrolidin-3-yl]pent-2-enoate Chemical compound C([C@@H](/C=C/C(=O)OCC)NC(=O)[C@@H](CC(=O)[C@@H](NC(=O)C1=NOC(C)=C1)C(C)C)CC=1C=CC(F)=CC=1)[C@@H]1CCNC1=O CAYJBRBGZBCZKO-BHGBQCOSSA-N 0.000 description 6
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- QSVVJJRBBMPZEW-UHFFFAOYSA-N oxirane-2-carboxylic acid;potassium Chemical compound [K].OC(=O)C1CO1 QSVVJJRBBMPZEW-UHFFFAOYSA-N 0.000 description 5
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
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- 125000003545 alkoxy group Chemical group 0.000 description 4
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 4
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 4
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- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 4
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- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 4
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- 239000008367 deionised water Substances 0.000 description 4
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- ABWVLWHPVBHFLQ-UHFFFAOYSA-M sodium;2-oxo-3-phenylpropanoate;hydrate Chemical compound O.[Na+].[O-]C(=O)C(=O)CC1=CC=CC=C1 ABWVLWHPVBHFLQ-UHFFFAOYSA-M 0.000 description 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
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- 239000012258 stirred mixture Substances 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 125000000542 sulfonic acid group Chemical group 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
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- 229940095064 tartrate Drugs 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical compound FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 1
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- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
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- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical group OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
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- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
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Abstract
Description
psi;甘油填充;精密度±3% | ||||
16 | 蠕动管路 | 过氧化物处理的聚硅氧烷 | 0.19”内径 | Cole Parmer |
17 | 带有蠕动泵头#77201-62的挠性控制变速驱动#77200-12 | 316 SS滚子 | 流速10-333mL/min(与#16配套) | Cole Parmer |
18 | 带有蠕动泵头的挠性控制仪表板驱动#77201-60 | 316 SS滚子 | 流速0.2-20mL/min(与#19配套) | Cole Parmer |
19 | 蠕动管 | 铂处理的聚硅氧烷 | 0.06”内径 | Cole Parmer |
20 | 水管倒钩到插入式NPT的接头 | PVDF | 3/8”外径×”NPT | Cole Parmer |
21 | 管路 | 过氧化物处理的聚硅氧烷 | 3/8”内径 | Cole Parmer |
22 | 卫生法兰到水管倒钩的接头 | PVDF | 31/32”×3/8”外径 | Cole Parmer |
23 | 到过滤器的泵管线 | 合成橡胶 | ”内径 | Cole Parmer |
24 | T型热电偶和数字显示装置 | Teflon涂覆的304SS | ”外径 | J-KEM |
25 | 插入内螺纹UNF的适配管 | Teflon | ”外径×”28UNF | Cole Parmer |
26 | 外螺纹NPT的内接头 | PVDF | ”NPT | Cole Parmer |
27 | 外螺纹NPT到内螺纹NPT的接头衬套 | PTFE | ”NPT×”NPT | Cole Parmer |
42 | 热交换器-在两头带有管配件的改进的graham型冷凝器 | 玻璃 | 38cm内部×47cm总长;反应器体积80mL×冷却体积510mL | San DiegoGlass Tech |
43 | 管 | 合成橡胶 | ”内径 | Cole Parmer |
44 | 刚性管 | PTFE | ”内径×5/16”外径 | Cole Parmer |
45 | 机械搅拌器 | 玻璃/聚四氟乙烯 | 按需要 | Chem Glass |
46 | 气体扩散器 | 玻璃 | Coarse frit | Chem Glass |
47 | 管 | Tygon R3603 | 5/16”内径 | Fisher |
48 | 带数字显示的PH探针;pn 59002-02 | 密封硅胶填充 | ”×4” | Cole Parmer |
49 | 管 | 合成橡胶 | ”内径 | Cole Parmer |
50 | 反应器主要环形管(管子) | 合成橡胶 | ”内径 | Cole Parmer |
原料 | 来源 | 量 | MW | 摩尔数 |
16 | --- | 170g粗品 | 393.2 | 0.364 |
二氯甲烷(ACS) | Fisher | 2.9L | --- | --- |
DIPEA(2.1eq.)d=0.742 | Aldrich | 133mL | 129.3 | 0.764 |
5-甲基异噁唑-3-甲酰氯(1.1eq.) | MaybridgeChem.Co. | 58g | 145.6 | 0.400 |
1N HCl | Stock | 0.8L | --- | --- |
饱和碳酸氢钠 | Stock | 0.8L | --- | --- |
无水硫酸钠 | Fisher | 100g | --- | --- |
17 | --- | 164g | 402.18 | --- |
原料 | 来源 | 量 | MW | 摩尔数 |
17 | --- | 164g(粗品) | 402.2 | 0.364 |
THF | Fisher | 115mL | --- | --- |
KH2PO4缓冲液 | Stock | 12L | 0.1M | --- |
KH2PO4(>99.5%) | Fluka | 163g | 136.1 | 1.2 |
NaOH(10N) | Stock | ~40mL | 40 | --- |
PPL-Type II(粗品)0.75g/g | Aldrich | 123g | 粗品 | --- |
HCl(浓) | Fisher | ~80mL | --- | --- |
12 | --- | 142g | 390.2 | --- |
原料 | 当量 | Mmol | FW | 量 |
10 | 1.5 | 1.8 | 326.39 | 751mg |
TFA | 12.0 | 18.0 | 114.02 | 1.4mL |
DCM | 10mL/g 10 | -- | -- | 7.6mL |
N-甲基吗啉 | 10.0 | 15.0 | 101.15 | 1.6mL |
DMF | 7mL/g 12 | -- | -- | 4.1mL |
CDMT | 1.05 | 1.6 | 175.58 | 281mg |
DMF | 4mL/g CDMT | -- | -- | 1.1mL |
水 | 42mL/g 12 | -- | -- | 24.7mL |
Claims (24)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US15036599P | 1999-08-24 | 1999-08-24 | |
US60/150,365 | 1999-08-24 |
Related Child Applications (1)
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CNA2004100054455A Division CN1524960A (zh) | 1999-08-24 | 2000-08-23 | 制备异噁唑甲酰胺及其类似物的方法和中间体 |
Publications (2)
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CN1382139A CN1382139A (zh) | 2002-11-27 |
CN1157391C true CN1157391C (zh) | 2004-07-14 |
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CNB008120110A Expired - Fee Related CN1157391C (zh) | 1999-08-24 | 2000-08-23 | 制备异噁唑甲酰胺及其类似物的方法和中间体 |
CNA2004100054455A Pending CN1524960A (zh) | 1999-08-24 | 2000-08-23 | 制备异噁唑甲酰胺及其类似物的方法和中间体 |
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CNA2004100054455A Pending CN1524960A (zh) | 1999-08-24 | 2000-08-23 | 制备异噁唑甲酰胺及其类似物的方法和中间体 |
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EP (1) | EP1206470A2 (zh) |
JP (1) | JP2003511350A (zh) |
KR (1) | KR20020030795A (zh) |
CN (2) | CN1157391C (zh) |
AU (1) | AU778062B2 (zh) |
BR (1) | BR0013323A (zh) |
CA (1) | CA2376509A1 (zh) |
CZ (1) | CZ2002634A3 (zh) |
HK (1) | HK1051363A1 (zh) |
HU (1) | HUP0203315A3 (zh) |
IL (1) | IL147862A0 (zh) |
MX (1) | MXPA02001947A (zh) |
PL (1) | PL357162A1 (zh) |
WO (1) | WO2001014576A2 (zh) |
ZA (1) | ZA200200506B (zh) |
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CN1198838C (zh) | 1998-04-30 | 2005-04-27 | 阿格罗尼制药公司 | 抗小rna病毒化合物及其制备方法和用途 |
ES2230135T3 (es) | 1999-08-04 | 2005-05-01 | Agouron Pharmaceuticals, Inc. | Compuestos y composiciones anti-picornavirales; utilizaciones farmaceuticas y materiales utilizados para su sintesis. |
US6774243B2 (en) | 1999-08-24 | 2004-08-10 | Agouron Pharmaceuticals, Inc. | Efficient synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates |
PE20020157A1 (es) | 1999-12-03 | 2002-02-22 | Agouron Pharma | Compuestos derivados de piridona como inhibidores de proteasas de picornaviral 3c, composiciones, sus usos farmaceuticos y materiales para su sintesis |
PA8515201A1 (es) | 2000-04-14 | 2002-10-24 | Agouron Pharma | Compuestos y composiciones antipicornavirales; sus usos farmaceuticos y los materiales para su sintesis |
HUP0301331A3 (en) | 2000-06-14 | 2004-03-01 | Agouron Pharmaceuticals Inc La | Antipicornaviral compounds process for their preparation and compositions containing them, their pharmaceutical uses, and intermediates for their synthesis |
DE10208007A1 (de) * | 2002-02-26 | 2003-09-18 | Forschungszentrum Juelich Gmbh | Verfahren zur Herstellung von Alkoholen aus Substraten mittels Oxidoreduktasen, Zweiphasensystem umfassend eine wässrige Phase und eine organische Phase sowie Vorrichtung zur Durchführung des Verfahrens |
CN106831657B (zh) * | 2017-02-23 | 2019-07-16 | 江苏工程职业技术学院 | 一种环氧丙酸钾的制备方法 |
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DE2426651C3 (de) * | 1974-06-01 | 1982-04-08 | Bayer Ag, 5090 Leverkusen | (-)-Antipode des 3-(p-Chlorphenyl)-2-chlorpropionsäuremethylesters, Verfahren zu dessen Herstellung sowie dessen Verwendung als Herbizid |
DE2930087A1 (de) * | 1979-07-25 | 1981-02-26 | Biotechnolog Forschung Gmbh | Verfahren zur kontinuierlichen enzymatischen umwandlung von wasserloeslichen alpha -ketocarbonsaeuren in die entsprechenden alpha -hydroxycarbonsaeuren |
JPH0623131B2 (ja) * | 1984-08-07 | 1994-03-30 | 三井東圧化学株式会社 | α−ケト酸のアルカリ金属塩の製造法 |
JPH066539B2 (ja) * | 1986-03-14 | 1994-01-26 | 三共株式会社 | α−ハイドロキシカルボン酸誘導体の製法 |
FR2686897B1 (fr) * | 1992-02-05 | 1995-07-13 | Sonertec | Procede en continu de fabrication d'acides organiques. |
US5360927A (en) * | 1994-01-24 | 1994-11-01 | Development Center For Biotechnology | Process for the preparation of monohydrated sodium phenylpyruvate |
US5869697A (en) * | 1994-05-02 | 1999-02-09 | Council Of Scientific & Industrial Research | Process for preparing diltiazem |
-
2000
- 2000-08-23 CA CA002376509A patent/CA2376509A1/en not_active Abandoned
- 2000-08-23 IL IL14786200A patent/IL147862A0/xx unknown
- 2000-08-23 HU HU0203315A patent/HUP0203315A3/hu unknown
- 2000-08-23 WO PCT/US2000/023032 patent/WO2001014576A2/en not_active Application Discontinuation
- 2000-08-23 AU AU67970/00A patent/AU778062B2/en not_active Ceased
- 2000-08-23 PL PL00357162A patent/PL357162A1/xx not_active Application Discontinuation
- 2000-08-23 CN CNB008120110A patent/CN1157391C/zh not_active Expired - Fee Related
- 2000-08-23 JP JP2001518887A patent/JP2003511350A/ja active Pending
- 2000-08-23 KR KR1020027002323A patent/KR20020030795A/ko not_active Application Discontinuation
- 2000-08-23 EP EP00955830A patent/EP1206470A2/en not_active Withdrawn
- 2000-08-23 CN CNA2004100054455A patent/CN1524960A/zh active Pending
- 2000-08-23 BR BR0013323-0A patent/BR0013323A/pt not_active IP Right Cessation
- 2000-08-23 MX MXPA02001947A patent/MXPA02001947A/es unknown
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Also Published As
Publication number | Publication date |
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WO2001014576A3 (en) | 2001-08-30 |
CZ2002634A3 (cs) | 2002-09-11 |
IL147862A0 (en) | 2002-08-14 |
AU778062B2 (en) | 2004-11-11 |
JP2003511350A (ja) | 2003-03-25 |
HK1051363A1 (en) | 2003-08-01 |
WO2001014576B1 (en) | 2001-09-27 |
CN1524960A (zh) | 2004-09-01 |
MXPA02001947A (es) | 2002-10-31 |
PL357162A1 (en) | 2004-07-26 |
CN1382139A (zh) | 2002-11-27 |
KR20020030795A (ko) | 2002-04-25 |
ZA200200506B (en) | 2003-06-25 |
HUP0203315A3 (en) | 2003-12-29 |
WO2001014576A2 (en) | 2001-03-01 |
AU6797000A (en) | 2001-03-19 |
HUP0203315A2 (hu) | 2003-02-28 |
CA2376509A1 (en) | 2001-03-01 |
EP1206470A2 (en) | 2002-05-22 |
BR0013323A (pt) | 2002-04-02 |
WO2001014576A8 (en) | 2002-06-20 |
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