CN110128298B - Synthetic method of Sacubitril intermediate - Google Patents
Synthetic method of Sacubitril intermediate Download PDFInfo
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- CN110128298B CN110128298B CN201910511651.XA CN201910511651A CN110128298B CN 110128298 B CN110128298 B CN 110128298B CN 201910511651 A CN201910511651 A CN 201910511651A CN 110128298 B CN110128298 B CN 110128298B
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- 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 title claims description 12
- 229960003953 sacubitril Drugs 0.000 title claims description 12
- 238000010189 synthetic method Methods 0.000 title claims description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- -1 N-tert-butoxycarbonylamino Chemical group 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 229940100321 entresto Drugs 0.000 description 2
- ZASXKEGREHRXDL-CAWNUZPDSA-H hexasodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]amino]butanoate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1 ZASXKEGREHRXDL-CAWNUZPDSA-H 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 229940122586 Enkephalinase inhibitor Drugs 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- 230000007674 genetic toxicity Effects 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 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
- 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
Abstract
The invention discloses a synthesis method of a Sacubibara intermediate, which takes 2- (N-tert-butoxy) amino-3- (4-bromophenyl) propionaldehyde and phenylboronic acid as reaction raw materials, and takes an organic solvent as a reaction solvent to carry out reaction under the action of alkali and a catalyst to obtain the intermediate. The method can obtain the SacuBaqu intermediate with high yield through the combined reaction of a proper catalyst, alkali and solvent, and meanwhile, the reaction raw materials are cheap and easy to obtain, the operation is simple, the reaction condition is mild and easy to control, the production cost is low, the reaction steps are short, the process is reliable, the subsequent treatment is very convenient, and the method is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a synthetic method of a Sacubitril intermediate.
Background
Sacubitril (Sacubitril), an enkephalinase inhibitor developed by Noval, Switzerland, the trisodium hemipentahydrate Entresto formed with the angiotensin II receptor inhibitor valsartan, was first approved by the FDA for marketing in 2015 for the first time in 7 months, and is clinically used for the treatment of chronic heart failure of grade II-IV and with a reduced ejection fraction.
The method for synthesizing the Sacubitril serving as an important raw material of Entresto and the preparation of an intermediate are reported, wherein the intermediate (I) is one of common synthetic intermediates, and the structural formula of the intermediate is as follows:
two references were found in the literature for the synthesis of this intermediate (I). The intermediate (I) is obtained by 5 steps of reaction from methyl 2- (N-tert-butoxycarbonylamino) -3- (4-hydroxy) phenylpropionate reported in J.Med.chem.1995,38,1689-1700 (shown in the following formula). The method has the advantages of long reaction steps, complex operation and complex post-treatment, and the method needs to pass through the trifluoromethanesulfonate compound with genetic toxicity impurities.
Secondly, the intermediate (I) is obtained by directly carrying out a Tempo oxidation reaction on a biphenyl hydroxyl compound (shown as the following formula) reported in a document CN 101516831B. Although the method is simple, the used raw material biphenyl hydroxy compound is not easy to obtain, and industrial production is difficult to realize.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a synthetic method of a Sacubitril intermediate, compared with the prior art, the method can obtain the Sacubitril intermediate at high yield through the combined reaction of a proper catalyst, alkali and a solvent, and solves the problems of complexity, difficult raw material acquisition and difficult realization of industrial production of the existing preparation method.
The technical scheme is as follows: the invention relates to a synthesis method of a Sacubibara intermediate, which takes 2- (N-tert-butoxycarbonyl) amino-3- (4-bromophenyl) propionaldehyde and phenylboronic acid as reaction raw materials, takes an organic solvent as a reaction solvent under the action of alkali and a catalyst, and carries out reaction to obtain an intermediate (I), and the intermediate (I) is represented by the following reaction formula:
further, the molar ratio of the phenylboronic acid to the 2- (N-tert-butoxycarbonyl) amino-3- (4-bromophenyl) propanal is 1.1-1.5: 1.
Furthermore, the molar ratio of the catalyst to the 2- (N-tert-butoxycarbonyl) amino-3- (4-bromophenyl) propanal is 0.02-0.05: 1.
Further, the catalyst is tetrakis (triphenylphosphine) palladium or palladium acetate.
Further, the molar ratio of the base to the 2- (N-tert-butoxycarbonyl) amino-3- (4-bromophenyl) propanal is 1-2: 1.
Further, the base is an alkali metal carbonate.
Further, the alkali is sodium carbonate or potassium carbonate.
Further, the organic solvent is DMF, DMA or DMSO.
Further, the synthesis method is carried out at the reflux temperature of the organic solvent.
Has the advantages that: the synthesis method provides a new idea for synthesizing the intermediate of the Shakubaqu, and the intermediate of the Shakubaqu can be obtained at high yield by reacting at a reflux temperature through the combination of a proper catalyst, alkali and a solvent without harsh reaction conditions; meanwhile, the reaction raw materials are nontoxic, cheap and easy to obtain, the operation is simple, the reaction conditions are mild and easy to control, the production cost is low, the reaction steps are short, the process is reliable, the subsequent treatment is very convenient, and the method is suitable for industrial large-scale production.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further described below with reference to examples:
example 1
Adding 1mol of 2- (N-tert-butoxycarbonyl) amino-3- (4-bromophenyl) propanal, 0.02mol of tetrakis (triphenylphosphine) palladium, 20mL of DMF and 40mL of sodium carbonate aqueous solution (2mol of sodium carbonate dissolved in 40mL of water) into a 100mL three-necked flask, and adding 1.1mol of phenylboronic acid while stirring to obtain a mixture solution;
and then heating the mixture solution to generate reflux reaction, cooling the mixture solution to room temperature after the reaction is finished, quenching redundant phenylboronic acid by using hydrogen peroxide, adding methyl tert-butyl ether for extraction, washing an organic phase by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and concentrating to obtain an intermediate, wherein the yield can reach 89%.
Example 2
Adding 1mol of 2- (N-tert-butoxycarbonyl) amino-3- (4-bromophenyl) propanal, 0.05mol of tetrakis (triphenylphosphine) palladium, 50mL of DMA (methyl methacrylate) and 20mL of potassium carbonate aqueous solution (1mol of potassium carbonate is dissolved in 20mL of water) into a 200mL three-necked bottle, and adding 1.5mol of phenylboronic acid while stirring to obtain a mixture solution;
and then heating the mixture solution to generate reflux reaction, cooling the mixture solution to room temperature after the reaction is finished, quenching redundant phenylboronic acid by using hydrogen peroxide, adding methyl tert-butyl ether for extraction, washing an organic phase by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and concentrating to obtain an intermediate, wherein the yield can reach 93%.
Example 3
Adding 1mol of 2- (N-tert-butoxycarbonyl) amino-3- (4-bromophenyl) propanal, 0.03mol of palladium acetate, 30mL of DMSO and 40mL of potassium carbonate aqueous solution (2mol of potassium carbonate is dissolved in 40mL of water) into a 200mL three-necked bottle, and adding 1.3mol of phenylboronic acid while stirring to obtain a mixture solution;
and then heating the mixture solution to generate reflux reaction, cooling the mixture solution to room temperature after the reaction is finished, quenching redundant phenylboronic acid by using hydrogen peroxide, adding methyl tert-butyl ether for extraction, washing an organic phase by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and concentrating to obtain an intermediate, wherein the yield can reach 90%.
Claims (4)
1. A synthetic method of a Sacubitril intermediate is characterized by comprising the following steps: taking 2- (N-tert-butoxycarbonyl) amino-3- (4-bromophenyl) propanal and phenylboronic acid as reaction raw materials, reacting under the action of alkali and a catalyst and an organic solvent as a reaction solvent to obtain an intermediate (I), wherein the reaction formula is as follows:
the molar ratio of the phenylboronic acid to the 2- (N-tert-butoxycarbonyl) amino-3- (4-bromophenyl) propanal is 1.1-1.5: 1;
the molar ratio of the catalyst to the 2- (N-tert-butoxycarbonyl) amino-3- (4-bromophenyl) propanal is 0.02-0.05: 1;
the catalyst is tetrakis (triphenylphosphine) palladium or palladium acetate;
the molar ratio of the alkali to 2- (N-tert-butoxycarbonyl) amino-3- (4-bromophenyl) propanal is 1-2: 1;
the base is an alkali metal carbonate.
2. The method for synthesizing the Sacubitril intermediate according to claim 1, characterized in that: the alkali is sodium carbonate or potassium carbonate.
3. The method for synthesizing the Sacubitril intermediate according to claim 1, characterized in that: the organic solvent is DMF, DMA or DMSO.
4. The method for synthesizing the Sacubitril intermediate according to claim 1, characterized in that: the synthesis process is carried out at the reflux temperature of the organic solvent.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5354892A (en) * | 1992-01-22 | 1994-10-11 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
| CN102010287A (en) * | 2010-10-20 | 2011-04-13 | 石家庄诚志永华显示材料有限公司 | Method for synthesizing (trans)-4-alkyl-3-alkene biphenyl derivative monomer liquid crystals |
| CN106397273A (en) * | 2015-07-31 | 2017-02-15 | 四川海思科制药有限公司 | Improved preparation method of sacubitril intermediate |
| CN106588698A (en) * | 2016-11-18 | 2017-04-26 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of N-Boc biphenyl alaninal |
| WO2017152755A1 (en) * | 2016-03-10 | 2017-09-14 | 深圳市塔吉瑞生物医药有限公司 | Substituted biphenyl compound and pharmaceutical composition thereof |
| CN108675943A (en) * | 2018-06-13 | 2018-10-19 | 常州亚邦制药有限公司 | The preparation method of one planting sand library Ba Qu key intermediates |
-
2019
- 2019-06-13 CN CN201910511651.XA patent/CN110128298B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5354892A (en) * | 1992-01-22 | 1994-10-11 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
| CN102010287A (en) * | 2010-10-20 | 2011-04-13 | 石家庄诚志永华显示材料有限公司 | Method for synthesizing (trans)-4-alkyl-3-alkene biphenyl derivative monomer liquid crystals |
| CN106397273A (en) * | 2015-07-31 | 2017-02-15 | 四川海思科制药有限公司 | Improved preparation method of sacubitril intermediate |
| WO2017152755A1 (en) * | 2016-03-10 | 2017-09-14 | 深圳市塔吉瑞生物医药有限公司 | Substituted biphenyl compound and pharmaceutical composition thereof |
| CN106588698A (en) * | 2016-11-18 | 2017-04-26 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of N-Boc biphenyl alaninal |
| CN108675943A (en) * | 2018-06-13 | 2018-10-19 | 常州亚邦制药有限公司 | The preparation method of one planting sand library Ba Qu key intermediates |
Non-Patent Citations (3)
| Title |
|---|
| A Versatile Tandem Catalysis Procedure for the Preparation of Novel Amino Acids and Peptides;Mark J. Burk et al;《J. Am. Chem. Soc.》;19941231;第116卷;10847-10848 * |
| Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors;Gary M. Ksander et al;《J. Med. Chem》;19951231;第38卷;1689-1700 * |
| 沙库巴曲有关物质的合成;白文钦等;《中国医药工业杂志》;20181231;第49卷(第10期);1392-1398 * |
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Effective date of registration: 20231122 Address after: 211800 building 12-83, 29 buyue Road, Qiaolin street, Pukou District, Nanjing City, Jiangsu Province Patentee after: NANJING YIXINHE PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Patentee after: NANJING F&S PHARMATECH CO.,LTD. Patentee after: Jiangsu litaer Pharmaceutical Co.,Ltd. Address before: 211800 No. 29 Buyue Road, Pukou Economic Development Zone, Qiaolin Street, Pukou District, Nanjing City, Jiangsu Province Patentee before: NANJING YIXINHE PHARMACEUTICAL TECHNOLOGY Co.,Ltd. |