CN103193609B - (s)-2-苄氧基戊-3-酮的合成工艺 - Google Patents
(s)-2-苄氧基戊-3-酮的合成工艺 Download PDFInfo
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- CN103193609B CN103193609B CN201310101575.8A CN201310101575A CN103193609B CN 103193609 B CN103193609 B CN 103193609B CN 201310101575 A CN201310101575 A CN 201310101575A CN 103193609 B CN103193609 B CN 103193609B
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- Prior art keywords
- acid amides
- reaction
- benzyloxy
- organic layer
- benzyl
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- 238000000034 method Methods 0.000 title claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 title abstract description 5
- DEOOBELFQJXOAE-JTQLQIEISA-N (2s)-2-phenylmethoxypentan-3-one Chemical compound CCC(=O)[C@H](C)OCC1=CC=CC=C1 DEOOBELFQJXOAE-JTQLQIEISA-N 0.000 title abstract 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- -1 amide compound Chemical class 0.000 claims abstract description 39
- 239000012044 organic layer Substances 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 23
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 20
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229940073608 benzyl chloride Drugs 0.000 claims abstract description 18
- 238000005406 washing Methods 0.000 claims abstract description 18
- 239000003513 alkali Substances 0.000 claims abstract description 15
- 239000010410 layer Substances 0.000 claims abstract description 13
- 229940116333 ethyl lactate Drugs 0.000 claims abstract description 10
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 239000000706 filtrate Substances 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- 150000001408 amides Chemical class 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 238000000926 separation method Methods 0.000 claims description 9
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 8
- 239000003039 volatile agent Substances 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 238000013517 stratification Methods 0.000 claims description 2
- 230000009466 transformation Effects 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000010992 reflux Methods 0.000 abstract description 17
- 238000001816 cooling Methods 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 4
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 abstract 1
- 230000003321 amplification Effects 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 229950002366 nafoxidine Drugs 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 34
- 238000003756 stirring Methods 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 238000000605 extraction Methods 0.000 description 15
- 238000010907 mechanical stirring Methods 0.000 description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical class COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 229960001589 posaconazole Drugs 0.000 description 6
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000000977 initiatory effect Effects 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 229910052749 magnesium Inorganic materials 0.000 description 5
- 238000010606 normalization Methods 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 238000004454 trace mineral analysis Methods 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- 239000007818 Grignard reagent Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003444 phase transfer catalyst Substances 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- LZCLXQDLBQLTDK-BYPYZUCNSA-N ethyl (2S)-lactate Chemical compound CCOC(=O)[C@H](C)O LZCLXQDLBQLTDK-BYPYZUCNSA-N 0.000 description 1
- 210000003746 feather Anatomy 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
Abstract
Description
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CN201310101575.8A CN103193609B (zh) | 2013-03-27 | 2013-03-27 | (s)-2-苄氧基戊-3-酮的合成工艺 |
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CN201310101575.8A CN103193609B (zh) | 2013-03-27 | 2013-03-27 | (s)-2-苄氧基戊-3-酮的合成工艺 |
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CN103193609A CN103193609A (zh) | 2013-07-10 |
CN103193609B true CN103193609B (zh) | 2014-10-08 |
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CN103819321B (zh) * | 2014-03-07 | 2016-03-30 | 天津凯美威生物医药科技有限公司 | (s)-2-苄氧基-3-戊酮的制备方法 |
CN103936564B (zh) * | 2014-03-28 | 2016-05-11 | 济南康和医药科技有限公司 | 泊沙康唑中间体(2s,3r)-2-苄氧基-3-戊醇的制备方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
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JPH01216965A (ja) * | 1988-02-25 | 1989-08-30 | Sagami Chem Res Center | 2−アルコキシブロピオン酸アミド誘導体の製造方法 |
US5616777A (en) * | 1995-04-19 | 1997-04-01 | Schering Corporation | Chiral hydrazine derivatives |
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Effective date of registration: 20191219 Address after: 242000 Meixi Road and Wolong Lane Intersection of Feichuan Office in Xuancheng City, Anhui Province Patentee after: Xuancheng Youdu Technology Service Co.,Ltd. Address before: 318000 No. 81 Binhai Road, rock head Industrial Development Zone, Jiaojiang District, Zhejiang, Taizhou Patentee before: ZHEJIANG REGENT CHEMICAL CO.,LTD. |
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Effective date of registration: 20221214 Address after: 276000 west of jiangouya village, Luoxi street, high tech Zone, Linyi City, Shandong Province Patentee after: SHANDONG GEXIN PRECISION CO.,LTD. Address before: 242000 intersection of Meixi Road and Wolong lane, Feicai office, Xuancheng City, Anhui Province Patentee before: Xuancheng Youdu Technology Service Co.,Ltd. |
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Granted publication date: 20141008 |
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