CN106318988B - 一种lcz696关键中间体的制备方法 - Google Patents
一种lcz696关键中间体的制备方法 Download PDFInfo
- Publication number
- CN106318988B CN106318988B CN201610699853.8A CN201610699853A CN106318988B CN 106318988 B CN106318988 B CN 106318988B CN 201610699853 A CN201610699853 A CN 201610699853A CN 106318988 B CN106318988 B CN 106318988B
- Authority
- CN
- China
- Prior art keywords
- compound
- alkaline
- aqueous
- reaction
- water phase
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 32
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 24
- 108091005658 Basic proteases Proteins 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical class CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical class COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 6
- 229940011051 isopropyl acetate Drugs 0.000 claims description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical group CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 150000002148 esters Chemical group 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims 3
- 239000012071 phase Substances 0.000 claims 3
- 239000012670 alkaline solution Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 238000001914 filtration Methods 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- OVBFMEVBMNZIBR-UHFFFAOYSA-N 2-methylvaleric acid Chemical compound CCCC(C)C(O)=O OVBFMEVBMNZIBR-UHFFFAOYSA-N 0.000 description 5
- -1 (tert-butoxycarbonyl) amino Chemical group 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 2
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- HCRBXQFHJMCTLF-ZCFIWIBFSA-N ethyl (2r)-2-methylbutanoate Chemical compound CCOC(=O)[C@H](C)CC HCRBXQFHJMCTLF-ZCFIWIBFSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 description 2
- 229960003953 sacubitril Drugs 0.000 description 2
- 239000001373 (E)-2-methylpent-2-enoic acid Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- HYQYCHQAUPHFKX-VOTSOKGWSA-N Ethyl trans-2-methyl-2-pentenoate Chemical compound CCOC(=O)C(\C)=C\CC HYQYCHQAUPHFKX-VOTSOKGWSA-N 0.000 description 1
- MOFFALDWBPYETF-UHFFFAOYSA-N [Ru+2].IC=1C(=C(C=CC1C)C(C)C)I Chemical class [Ru+2].IC=1C(=C(C=CC1C)C(C)C)I MOFFALDWBPYETF-UHFFFAOYSA-N 0.000 description 1
- HYQYCHQAUPHFKX-UHFFFAOYSA-N alpha-Methyl-beta-aethyl-acrylsaeureaethylester Natural products CCOC(=O)C(C)=CCC HYQYCHQAUPHFKX-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000011291 current first-line treatment Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000001813 ethyl (2R)-2-methylbutanoate Substances 0.000 description 1
- 229940090910 ethyl 2-methylbutyrate Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003304 ruthenium compounds Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/005—Amino acids other than alpha- or beta amino acids, e.g. gamma amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- General Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明公开了一种LCZ696关键中间体的制备方法，本发明涉及一种式i化合物的制备方法，以化合物ii为起始原料，通过Pd/C加氢与碱性蛋白酶催化水解的复合作用，高产率的获得高纯度式i化合物。本发明操作简单，反应条件温和，适合工业化生产。
Description
技术领域
本发明涉及一种LCZ696关键中间体的制备方法，具体涉及（2R, 4S）-5-(联苯-4-基)-4-[(叔丁氧羰基)氨基]-2-甲基戊酸（化合物i）的制备方法，属医药技术领域。
背景技术
LCZ696是由诺华公司研发的抗心衰新药，是由沙库比曲和缬沙坦两个组分构成复合物。LCZ696颠覆了十几年来一成不变的心力衰竭治疗法则，其治疗效果远高于目前的一线治疗药物依那普利，其有望成为超级重磅明星，引领心血管治疗大跨步进入新的时代。
（2R, 4S）-5-(联苯-4-基)-4-[(叔丁氧羰基)氨基]-2-甲基戊酸（化合物i）是LCZ696重要组成部分沙库比曲的关键中间体，其制备方法主要有以下两种：
1）以钌化合物为催化剂促进的不对称氢化还原：
WO2008031567报道了以（R, E）-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基-2-戊烯酸为起始物料，经过不对称氢化得到目标产物。该路线的缺点是还原过程中需要用到价格昂贵且不可回收的催化剂二碘代（对-伞花烃）钌（II）二聚体及配体SL-M004-1，该方法对氧极其敏感，需要对溶剂进行脱气处理，并且反应过程中需要严格无氧，反应条件较苛刻，无论成本还是反应条件，均非常不适合大生产。
2）以Pd/C或Pt/C为催化剂促进的氢化还原：
US5217996、Journal of Medicinal Chemistry，1995，38，1689-1700等报道了（4R）-5-[1,1'-联苯]-4-基-4-[[叔丁氧羰基]氨基]-2-甲基-2-戊烯酸乙酯作为起始物料，经过Pd/C催化氢化，得到目标化合物的消旋体，再经过柱层析得到（2R, 4S）-4-([1,1'-联苯基]-4-基甲基)-4-[(叔丁氧羰基)氨基]-2-甲基丁酸乙酯，水解获得目标产物。该路线的缺点是产品纯化过程中需要柱层析，操作繁琐，收率低，产能小，不利于工业化生产。
发明内容
本发明的目的是提供一种LCZ696关键中间体化合物i的制备方法。
本发明的技术方案是一种化合物i的制备方法，其特征在于，
（1）以式ii化合物为起始原料，碱性条件下，碱性蛋白酶存在时，Pd/C氢化还原；
（2）上步所得产物再经酸化获得化合物i：
具体的，所述方法可以通过以下操作来实现：
向高压反应釜中加入有机溶剂、碱水溶液、起始物料化合物ii、碱性蛋白酶和Pd/C，氮气保护下通入氢气，升温反应；化合物ii反应完毕后，分离出水相，并向水相中加入酸，搅拌析晶，即可得到化合物i。
根据本发明，更为具体的，所述有机溶剂与水不互溶，能够与碱水溶液形成非均相体系，选自酯、卤代烷烃、醚、甲苯，优选乙酸异丙酯、二氯甲烷、甲基叔丁基醚，更优选乙酸异丙酯。
根据本发明，更为具体的，为了保持步骤（1）反应所需的碱性，所述碱水溶液优选氢氧化锂水溶液。
根据本发明，更为具体的，氢化反应压力优选0.8~1.5MPa。
根据本发明，更为具体的，步骤（1）反应温度优选35~45℃，反应时间优选15~18h。
根据本发明，步骤（2）酸化时，可以选择任意能与碱中和的有机酸、无机酸，优选乙酸。
本发明的有益效果是通过Pd/C加氢与碱性蛋白酶催化水解的复合作用，高产率的获得高纯度化合物i，既避免了高价Rh化合物的使用，又不需要柱层析分离纯化，操作简单，反应条件温和，适合工业化生产。
具体实施方式：
为更好的理解本发明内容，下面结合具体实施例作进一步说明，但本发明不仅局限于此。
实施例1
将乙酸异丙酯（750mL）、氢氧化锂（10.6g，0.44mol）配成的750mL水溶液、化合物ii（150g，0.37mol）、碱性蛋白酶（9g）与10% Pd/C（1.3g）依次置于2000mL高压釜中，氮气置换3次，充氢气至0.8MPa，升温至35℃，反应15h。降温，过滤除掉Pd/C与碱性蛋白酶，分液，水相转移至1000mL三口瓶中，搅拌条件下滴加乙酸，析出白色固体，过滤，烘干，得108.3g，收率76.3%，化学纯度99.8%，光学纯度99.3%。
实施例2
将乙酸异丙酯（750mL）、氢氧化锂（10.6g，0.44mol）配成的750mL水溶液、化合物ii（150g，0.37mol）、碱性蛋白酶（9g）与10% Pd/C（1.3g）依次置于2000mL高压釜中，氮气置换3次，充氢气至0.8MPa，升温至45℃，反应15h。降温，过滤除掉Pd/C与碱性蛋白酶，分液，水相转移至1000mL三口瓶中，搅拌条件下滴加乙酸，析出白色固体，过滤，烘干，得115.2g，收率81.2%，化学纯度99.7%，光学纯度98.6%。
实施例3
将乙酸异丙酯（750mL）、氢氧化锂（10.6g，0.44mol）配成的750mL水溶液、化合物（ii）（150g，0.37mol）、碱性蛋白酶（9g）与10% Pd/C（1.3g）依次置于2000mL高压釜中，氮气置换3次，充氢气至1.5MPa，升温至40℃，反应15h。降温，过滤除掉Pd/C与碱性蛋白酶，分液，水相转移至1000mL三口瓶中，搅拌条件下滴加乙酸，析出白色固体，过滤，烘干，得112.4g，收率79.2%，化学纯度99.9%，光学纯度99.3%。
实施例4
将二氯甲烷（750mL）、氢氧化锂（10.6g，0.44mol）配成的750mL水溶液、化合物（ii）（150g，0.37mol）、碱性蛋白酶（9g）与10% Pd/C（1.3g）依次置于2000mL高压釜中，氮气置换3次，充氢气至1.5MPa，升温至40℃，反应18h。降温，过滤除掉Pd/C与碱性蛋白酶，分液，水相转移至1000mL三口瓶中，搅拌条件下滴加乙酸，析出白色固体，过滤，烘干，得116.8g，收率82.3%，化学纯度99.8%，光学纯度98.9%。
实施例5
将甲基叔丁基醚（750mL）、氢氧化锂（10.6g，0.44mol）配成的750mL水溶液、化合物（ii）（150g，0.37mol）、碱性蛋白酶（9g）与10% Pd/C（1.3g）依次置于2000mL高压釜中，氮气置换3次，充氢气至1.0MPa，升温至40℃，反应15h。降温，过滤除掉Pd/C与碱性蛋白酶，分液，水相转移至1000mL三口瓶中，搅拌条件下滴加乙酸，析出白色固体，过滤，烘干，得112.5g，收率79.3%，化学纯度99.8%，光学纯度99.4%。
实施例6
将甲苯（750mL）、氢氧化锂（10.6g，0.44mol）配成的750mL水溶液、化合物（ii）（150g，0.37mol）、碱性蛋白酶（9g）与10% Pd/C（1.3g）依次置于2000mL高压釜中，氮气置换3次，充氢气至1.0MPa，升温至40℃，反应15h。降温，过滤除掉Pd/C与碱性蛋白酶，分液，水相转移至1000mL三口瓶中，搅拌条件下滴加乙酸，析出白色固体，过滤，烘干，得119.2g，收率80.4%，化学纯度99.7%，光学纯度99.3%。
Claims (4)
1.一种式i化合物的制备方法，其特征在于，
（1）以式ii化合物为起始原料，碱性条件下，碱性蛋白酶存在时，Pd/C氢化还原，反应温度35～45℃，氢化压力0.8～1.5MPa，反应体系为非均相，其中，有机相为与水不互溶的有机溶剂，水相为碱性水溶液；
（2）上步所得产物经酸化即可获得化合物i：
具体的，所述方法可以通过以下操作来实现：
向高压反应釜中加入有机溶剂、碱水溶液、起始物料化合物ii、碱性蛋白酶和Pd/C，氮气保护下通入氢气，升温反应；化合物ii反应完毕后，分离出水相，并向水相中加入酸，搅拌析晶，即可得化合物i。
2.根据权利要求1所述的制备方法，其特征在于，所述有机相选自酯、卤代烷烃、甲苯、甲基叔丁基醚。
3.根据权利要求1所述的制备方法，其特征在于，所述碱性水溶液选自氢氧化锂水溶液。
4.根据权利要求1所述的制备方法，其特征在于，所述有机相选自乙酸异丙酯。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610699853.8A CN106318988B (zh) | 2016-08-23 | 2016-08-23 | 一种lcz696关键中间体的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610699853.8A CN106318988B (zh) | 2016-08-23 | 2016-08-23 | 一种lcz696关键中间体的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106318988A CN106318988A (zh) | 2017-01-11 |
| CN106318988B true CN106318988B (zh) | 2020-11-03 |
Family
ID=57741078
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610699853.8A Active CN106318988B (zh) | 2016-08-23 | 2016-08-23 | 一种lcz696关键中间体的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106318988B (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106966926B (zh) * | 2017-04-01 | 2018-10-19 | 沧州那瑞化学科技有限公司 | 一种lcz696中间体的制备方法 |
| CN109503404A (zh) * | 2018-12-28 | 2019-03-22 | 凯瑞斯德生化(苏州)有限公司 | 一种lcz-696关键中间体的制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5217996A (en) * | 1992-01-22 | 1993-06-08 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
| CN106187808A (zh) * | 2015-05-08 | 2016-12-07 | 苏州鹏旭医药科技有限公司 | Ahu-377的制备方法、ahu-377中间体及ahu-377中间体的制备方法 |
-
2016
- 2016-08-23 CN CN201610699853.8A patent/CN106318988B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5217996A (en) * | 1992-01-22 | 1993-06-08 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
| CN106187808A (zh) * | 2015-05-08 | 2016-12-07 | 苏州鹏旭医药科技有限公司 | Ahu-377的制备方法、ahu-377中间体及ahu-377中间体的制备方法 |
Non-Patent Citations (2)
| Title |
|---|
| Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors;Gary M. Ksander,et al;《J. Med. Chem》;19951231;1689-1700 * |
| LCZ696中间体的合成;丛日刚，等;《精细化工中间体》;20161031;第46卷;22-24 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106318988A (zh) | 2017-01-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101356166B (zh) | 利用环化脱水作用制备3-羟基四氢呋喃的方法 | |
| CN106318988B (zh) | 一种lcz696关键中间体的制备方法 | |
| CN103524345B (zh) | 一种醋酸甲酯制丙烯酸甲酯的产品分离工艺 | |
| CN101798271B (zh) | 一种(±)-去甲肾上腺素的制备方法 | |
| CN107312007B (zh) | 2(2-乙氧基-2-氧代乙基)-8-甲基-5,6-二氢咪唑并吡嗪羧酸叔丁酯的制法 | |
| TW201527275A (zh) | 方法 | |
| CN102584622B (zh) | 一种l-2-氨基丁酰胺盐酸盐的制备方法 | |
| CN101239923B (zh) | (s,s)n-(1-乙氧羰基-3-苯丙基)-l-氨基酸衍生物的制备方法与精制方法 | |
| KR102273086B1 (ko) | 2,3-부탄다이올을 제조하기 위한 방법 | |
| Suerbaev et al. | Synthesis of biological active esters of the isovaleric acid by isobutylene hydroalkoxycarbonylation | |
| CN114805167A (zh) | 一种布立西坦的制备方法 | |
| CN103183592B (zh) | 2-氯-1，1，1-三烷氧基乙烷的制备方法 | |
| CN101743218B (zh) | 光学活性反式-2-氨基环己醇的制备方法及其中间体 | |
| WO2000063199A1 (fr) | Procede de preparation de 3-hydroxytetrahydrofurane | |
| CN110396072A (zh) | (s)-3-羟基四氢呋喃的制备方法 | |
| CN103626771A (zh) | 一种多尼培南的制备工艺 | |
| CN114349635B (zh) | 一种度鲁特韦核心中间体的合成方法 | |
| JP5397706B2 (ja) | 高純度１−ベンジル−３−アミノピロリジンの製造方法 | |
| CN110092802B (zh) | 一种制备曲贝替定中间体的方法 | |
| CN106397383A (zh) | 异色满‑4‑酮的还原胺化及拆分 | |
| CN111004272B (zh) | 奥利司他手性中间体的制备方法 | |
| CN107325102A (zh) | 自催化双亲混合溶剂中合成1,5,7‑三氮杂双环[5.5.0]癸‑5‑烯的工艺方法 | |
| CN114105781A (zh) | 一种中间体的制备方法 | |
| CN102173979A (zh) | 一种催化加氢制备对异丙基环己醇的方法 | |
| CN107513046A (zh) | 一种可比司他的合成方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20200925 Address after: 264205 Guangzhou East Road South and an East Road East, Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Applicant after: Dijia Pharmaceutical Group Co.,Ltd. Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: 264205 Weihai City, Shandong Province south of No.18 Road, north of No.19 Road, east of No.3 Road, west of wuzhuhe River, Gushan Town, economic zone, Weihai City, Shandong Province Applicant before: WEIHAI DISU PHARMACEUTICAL Co.,Ltd. Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210611 Address after: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 Wendeng economic and Technological Development Zone, Weihai City, Shandong Province Patentee before: Dijia Pharmaceutical Group Co.,Ltd. Patentee before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee after: Dijia Pharmaceutical Group Co.,Ltd. Address before: 264205 268 Tianrun Road, Wendeng economic and Technological Development Zone, Weihai, Shandong Patentee before: Dijia Pharmaceutical Group Co.,Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method for key intermediates of LCZ696 Effective date of registration: 20230426 Granted publication date: 20201103 Pledgee: Weihai Branch of Shanghai Pudong Development Bank Co.,Ltd. Pledgor: Dijia Pharmaceutical Group Co.,Ltd. Registration number: Y2023980039205 |