CN113816871A - 一种lcz696杂质及其制备方法 - Google Patents
一种lcz696杂质及其制备方法 Download PDFInfo
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- CN113816871A CN113816871A CN202110967285.6A CN202110967285A CN113816871A CN 113816871 A CN113816871 A CN 113816871A CN 202110967285 A CN202110967285 A CN 202110967285A CN 113816871 A CN113816871 A CN 113816871A
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- 239000012535 impurity Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 10
- YNELJETWNMPEEH-UZLBHIALSA-N (2r,4s)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pentanoic acid Chemical compound C1=CC(C[C@H](C[C@@H](C)C(O)=O)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 YNELJETWNMPEEH-UZLBHIALSA-N 0.000 claims abstract description 8
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 8
- 229940014800 succinic anhydride Drugs 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 37
- -1 benzyl halide Chemical class 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 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 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003929 acidic solution Substances 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- VOIHISWOJSDFGQ-AMGIVPHBSA-N benzyl (2r,4s)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pentanoate Chemical compound C([C@H](C[C@@H](C)C(=O)OCC=1C=CC=CC=1)NC(=O)OC(C)(C)C)C(C=C1)=CC=C1C1=CC=CC=C1 VOIHISWOJSDFGQ-AMGIVPHBSA-N 0.000 claims description 4
- DAUBDUGSUUVSMK-FWUDBZNBSA-N benzyl (2r,4s)-4-amino-2-methyl-5-(4-phenylphenyl)pentanoate;hydrochloride Chemical compound Cl.C([C@@H](N)C[C@@H](C)C(=O)OCC=1C=CC=CC=1)C(C=C1)=CC=C1C1=CC=CC=C1 DAUBDUGSUUVSMK-FWUDBZNBSA-N 0.000 claims description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical group BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- SMPAPEKFGLKOIC-UHFFFAOYSA-N oxolane;hydrochloride Chemical compound Cl.C1CCOC1 SMPAPEKFGLKOIC-UHFFFAOYSA-N 0.000 claims description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 2
- TZCYLJGNWDVJRA-UHFFFAOYSA-N 6-chloro-1-hydroxybenzotriazole Chemical compound C1=C(Cl)C=C2N(O)N=NC2=C1 TZCYLJGNWDVJRA-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 2
- 229940073608 benzyl chloride Drugs 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 claims description 2
- 229940070710 valerate Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 14
- 239000013558 reference substance Substances 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract 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 abstract description 2
- 238000005917 acylation reaction Methods 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000002390 rotary evaporation Methods 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000002274 desiccant Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- OVBFMEVBMNZIBR-UHFFFAOYSA-N -2-Methylpentanoic acid Natural products CCCC(C)C(O)=O OVBFMEVBMNZIBR-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- DQPBJYVJQJGKPH-DVECYGJZSA-N benzyl (2r,4s)-4-amino-2-methyl-5-(4-phenylphenyl)pentanoate Chemical compound C([C@@H](N)C[C@@H](C)C(=O)OCC=1C=CC=CC=1)C(C=C1)=CC=C1C1=CC=CC=C1 DQPBJYVJQJGKPH-DVECYGJZSA-N 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 101800000407 Brain natriuretic peptide 32 Proteins 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 229940122586 Enkephalinase inhibitor Drugs 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C07—ORGANIC CHEMISTRY
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
本发明公开了一种LCZ696杂质及其制备方法,包括如下步骤:以(2R,4S)‑5‑([1,1'‑联苯]‑4‑基)‑4‑((叔丁氧羰基)氨基)‑2‑甲基戊酸为原料,用苄基保护羧基,脱除叔丁氧羰基,再依次与琥珀酸酐发生酰基化反应、与醇发生酯化反应,最后脱除苄基保护基得LCZ696杂质。本发明的方法操作简单,效率高,整个工艺实验条件要求低,路线经济环保,可作为杂质研究的对照品用于LCZ696含量测定,有效保障LCZ696的用药安全。
Description
技术领域
本发明属于对照品合成领域,具体涉及一种LCZ696杂质及其制备方法。
背景技术
LCZ696是一种双效血管紧张素受体脑啡肽酶抑制剂,具有独特的作用模式,被认为能够减少衰竭心脏的应变。其作用机理是通过抑制脑啡肽酶的活性,提供血液中B型利钠肽的含量,发挥其保护心脏的作用,同时体内血管紧张素II浓度的增加可进一步加重血管收缩,减少风险心力衰竭患者的心血管死亡及住院治疗慢性心力衰竭(NYHAII-IV级)和降低射血分数,是广大心脑疾病患者的福音。
药物安全是建立在药物的质量可控这一重要物质基础之上的,药物的稳定性、活性成分含量性等是药物安全的关键性指标。药物杂质是影响药物质量的重要因素之一,对药物杂质进行规范研究,并严格控制药物中杂质的含量,是药物品质的重要保证。药物杂质对照品的合成研究对药物检测方法以及质量标准的建立起着强有力的促进作用。因此,需要合成相应的药物杂质为药品研究提供对照品,同时开发简单、高效地制备该化合物的方法对药物杂质的合成和药品质量控制具有重要意义。
发明内容
本发明的目的在于提供一种LCZ696杂质及其制备方法,该方法工艺简单,制备出的产品纯度高,为LCZ696的质量控制提供合格的杂质对照品,有利于用药的安全性。
为了达到上述目的,本发明提供了一种LCZ696杂质,该杂质具有如下式I所示的分子结构:
其中,R为烷基、烯基、炔基、芳基、杂环芳基或杂环基。
本发明还提供了上述LCZ696杂质的制备方法,包括如下步骤:
(1)将(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸溶于有机溶剂,然后与苄卤和碱的反应得到(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸苄酯;具体反应式如下:
(2)将步骤(1)的(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸苄酯与酸性溶液反应得到(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸苄酯盐酸盐;具体反应式如下:
(3)将步骤(2)的(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸苄酯盐酸盐溶于有机溶剂,在碱的作用下与琥珀酸酐反应得到(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯;具体反应式如下:
(4)将步骤(3)的(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯溶于有机溶剂中,在缩合剂及催化剂作用下与醇缩合得到(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-烃氧基丁二酰胺基)-2-甲基戊酸苄酯,最后,将产物溶于有机溶剂,用钯碳催化氢化得到LCZ696杂质;具体反应式如下:
进一步的,该制备方法具体包括如下步骤:
(1)向圆底烧瓶中加入(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸,加入有机溶剂溶解,再加入碱搅拌均匀后,逐滴滴加苄卤,室温剧烈搅拌反应2小时,反应结束后,向反应体系内加入水,用乙酸乙酯萃取,分离有机相,水相再用乙酸乙酯萃取,合并有机相,有机相用饱和食盐水洗涤后,再用无水硫酸钠干燥,过滤除去干燥剂,有机相旋转蒸发除去有机溶剂,得到白色粉末固体;
(2)向圆底瓶中加入步骤(1)的产物,加入酸性溶液,室温搅拌反应6小时,反应结束后,过滤物用甲基叔丁醚重结晶,得到白色固体;
(3)向烧瓶中加入步骤(2)的产物,用有机溶剂溶解,再依次加入碱和琥珀酸酐,室温搅拌反应1小时,反应结束后,过滤除去不溶物,滤液依次用5%盐酸、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,过滤除去干燥剂,旋转蒸发得白色固体;
(4)在圆底烧瓶中加入步骤(3)的产物,用有机溶剂溶解,依次加入缩合剂、催化剂和醇,室温搅拌反应2小时,反应结束后,过滤除去不溶物,滤液依次用5%盐酸、饱和氯化钠溶液洗涤,有机相用无水硫酸钠干燥,过滤除去干燥剂,旋转蒸发得白色固体,在圆底烧瓶中加入该白色固体,用有机溶剂溶解,加入10%钯碳,常压氢化,室温搅拌反应8小时,反应结束后,过滤除去钯碳,旋转蒸发除去溶剂得粗产品,粗品用乙酸乙酯和甲醇重结晶,得白色固体。
进一步的,步骤(1)、步骤(3)、步骤(4)中,所述有机溶剂为二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、二甲亚砜、甲醇、乙醇中的一种或多种。
进一步的,步骤(1)中,所述有机溶剂优选N,N-二甲基甲酰胺或二甲亚砜。
进一步的,步骤(1)中,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸与苄卤的摩尔比为1∶1~2,所述苄卤为苄溴或苄氯,所述碱为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、三乙胺、吡啶或哌啶。
进一步的,步骤(1)中,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸与苄卤的摩尔比优选1∶1~1.2,所述苄卤优选苄溴,所述碱优选碳酸钠或碳酸钾。
进一步的,步骤(2)中,所述酸性溶液为三氟乙酸、氯化氢乙酸乙酯溶液或氯化氢四氢呋喃溶液。
进一步的,步骤(2)中,所述酸性溶液优选氯化氢乙酸乙酯溶液或氯化氢四氢呋喃溶液。
进一步的,步骤(3)中,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸苄酯与琥珀酸酐的摩尔比为1∶1~2,所述碱为碳酸钠、二乙胺、三乙胺、吡啶或哌啶。
进一步的,步骤(3)中,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸苄酯与琥珀酸酐的摩尔比优选1∶1~1.2,所述碱优选三乙胺或哌啶,所述有机溶剂优选二氯甲烷或三氯甲烷。
进一步的,步骤(4)中,所述缩合剂为二环己基碳二亚胺、二异丙基碳二亚胺或1-(3-二甲胺基丙基)-3-乙基碳二亚胺,所述催化剂为4-二甲氨基吡啶、吡啶、三乙胺、N,N-二甲基甲酰胺或6-氯-1-羟基苯并三氮唑,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯与醇的摩尔比为1:1~2,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯与缩合剂的摩尔比为1:1~1.5,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯与催化剂的摩尔比为1:0.1~0.2。
进一步的,步骤(4)中,所述缩合剂优选二环己基碳二亚胺,所述催化剂优选4-二甲氨基吡啶,所述有机溶剂优选二氯甲烷或三氯甲烷,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯与醇的摩尔比为1:1.5~2,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯与缩合剂的摩尔比为1:1.2~1.5,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯与催化剂的摩尔比为1:0.15~0.2。
有益效果
本发明的LCZ696杂质的制备方法,操作简单,效率高,整个工艺实验条件要求低,工艺路线经济环保,可有效保障LCZ696的用药安全。
附图说明
图1是本发明实施例1中(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-乙氧基丁二酰胺基)-2-甲基戊酸的1H NMR图;
图2是本发明实施例1中(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-乙氧基丁二酰胺基)-2-甲基戊酸的MS图;
图3是本发明实施例2中(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-异丙氧基丁二酰胺基)-2-甲基戊酸的1H NMR图;
图4是本发明实施例2中(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-异丙氧基丁二酰胺基)-2-甲基戊酸的MS图。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
实施例1
(1)(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸苄酯的制备
向100ml的圆底烧瓶中加入(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸(8.0g,20.8mmol),加入DMF(40ml)溶解,再加入碳酸钾(4.0g,29.0mmol)搅拌均匀后,逐滴滴加苄溴(4.0g,23.1mmol)。室温(25℃)剧烈搅拌反应2小时,TLC监测反应历程。反应结束后,向反应体系内加入50ml水,用乙酸乙酯(100mL)萃取,分有机相。水相再用乙酸乙酯(50mL)萃取,合并有机相。有机相用饱和食盐水洗涤(75mL×3次)后,再用无水硫酸钠干燥。过滤除去干燥剂,有机相旋转蒸发除去有机溶剂,得到白色粉末固体9.0g,收率91.8%。
(2)(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸苄酯盐酸盐的制备
向250ml圆底瓶中加入(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸苄酯(9.0g),加入氯化氢的四氢呋喃溶液(100mL),室温(25℃)搅拌反应6小时,TLC监测反应历程。反应结束后,过滤得白色固体。所得固体用甲基叔丁醚重结晶,得到白色固体7.1g,收率91.3%。
(3)(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯
向250ml烧瓶中加入(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸苄酯盐酸盐(7.0g,17.1mmol),用二氯甲烷(120ml)溶解,再依次加入三乙胺(5.2g,51mmol)和琥珀酸酐(2.05g,20.5mol)。室温(25℃)搅拌反应1小时,TLC监测反应历程。反应结束后,过滤除去不溶物,滤液依次用5%盐酸(50mL)洗涤、饱和氯化钠溶液洗涤(50mL×2次),有机相用无水硫酸钠干燥。过滤除去干燥剂,旋转蒸发得白色固体7.1g,收率87.6%。
(4)(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-乙氧基丁二酰胺基)-2-甲基戊酸的制备。
在100mL的圆底烧瓶中加入(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯(3.0g,6.3mmol),用二氯甲烷(50mL)溶解,依次加入DCC(1.56g,7.6mmol)、DAMP(0.12g,1.0mmol)和乙醇(0.58g,12.6mmol)。室温(25℃)搅拌反应2小时,TLC监测反应历程。反应结束后,过滤除去不溶物,滤液依次用5%盐酸(25mL)洗涤、饱和氯化钠溶液洗涤(25mL×2次),有机相用无水硫酸钠干燥。过滤除去干燥剂,旋转蒸发得白色固体2.9g,收率92.5%。
在50mL圆底烧瓶中加入上述白色固体(2g,4mmol),用甲醇(15mL)溶解,加入10%钯碳(0.2g),常压氢化。室温(25℃)搅拌反应8小时。反应结束后,过滤除去钯碳,旋转蒸发除去溶剂得粗产品,粗品用乙酸乙酯和甲醇重结晶,得白色固体1.48g,收率90.2%。MS(ESI):410.52(M-H);1H NMR(500MHz,CDCl3)δ7.59(d,J=7.4Hz,2H),7.54(d,J=8.0Hz,2H),7.44(t,J=7.6Hz,2H),7.35(t,J=7.3Hz,1H),7.26(t,J=9.9Hz,2H),6.25–6.14(m,1H),4.34(p,J=10.1Hz,1H),4.19–4.06(m,2H),2.95–2.80(m,2H),2.68(dt,J=17.2,6.9Hz,1H),2.54(ddd,J=14.4,12.6,7.0Hz,2H),2.49–2.40(m,2H),1.96(ddd,J=13.8,10.8,2.9Hz,1H),1.59(ddd,J=14.2,11.0,3.3Hz,1H),1.25(t,J=7.1Hz,3H),1.20(d,J=6.9Hz,3H).
实施例2
同实施例1,与实施例1不同的是第(4)步:
(4)(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-异丙氧基丁二酰胺基)-2-甲基戊酸的制备。
在100mL的圆底烧瓶中加入(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯(3.5g,7.4mmol),用二氯甲烷(50mL)溶解,依次加入DCC(1.56g,7.6mmol)、DAMP(0.12g,1.0mmol)和异丙醇(0.67g,11.1mmol)。室温(25℃)搅拌反应3小时,TLC监测反应历程。反应结束后,过滤除去不溶物,滤液依次用5%盐酸(25mL)洗涤、饱和氯化钠溶液洗涤(25mL×2次),有机相用无水硫酸钠干燥。过滤除去干燥剂,旋转蒸发得白色固体3.4g,收率89.2%。
在50mL圆底烧瓶中加入上述白色固体(3g,5.8mmol),用甲醇(20mL)溶解,加入10%钯碳(0.3g),常压氢化。室温(25℃)搅拌反应8小时。反应结束后,过滤除去钯碳,旋转蒸发除去溶剂得粗产品,粗品用乙酸乙酯和甲醇重结晶,得白色固体2.6g,收率85.7%。MS(ESI):424.47(M-H);1H NMR(500MHz,CDCl3)δ7.59(d,J=8.0Hz,2H),7.55(d,J=8.0Hz,2H),7.45(t,J=7.6Hz,2H),7.36(t,J=7.3Hz,1H),7.25(d,J=8.0Hz,2H),6.13(d,J=8.8Hz,1H),5.04–4.96(m,1H),4.34(s,1H),2.90(dd,J=14.0,6.1Hz,1H),2.84(dd,J=14.0,7.2Hz,1H),2.70–2.62(m,1H),2.57–2.42(m,4H),1.99–1.93(m,1H),1.61–1.54(m,1H),1.24(dd,J=6.2,2.5Hz,6H),1.20(d,J=6.8Hz,3H).
以上所述,仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,任何熟悉本专业的技术人员,在不脱离本发明技术方案范围内,当可利用上述揭示的技术内容做出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明技术方案的范围内。
Claims (7)
2.权利要求1所述的LCZ696杂质的制备方法,其特征在于:包括如下步骤:
(1)将(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸溶于有机溶剂,然后与苄卤和碱的反应得到(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸苄酯;具体反应式如下:
(2)将步骤(1)的(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸苄酯与酸性溶液反应得到(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸苄酯盐酸盐;具体反应式如下:
(3)将步骤(2)的(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸苄酯盐酸盐溶于有机溶剂,在碱的作用下与琥珀酸酐反应得到(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯;具体反应式如下:
(4)将步骤(3)的(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯溶于有机溶剂中,在缩合剂及催化剂作用下与醇缩合得到(2R,4S)-5-([1,1'-联苯]-4-基)-4-(4-烃氧基丁二酰胺基)-2-甲基戊酸苄酯,最后,将产物溶于有机溶剂,用钯碳催化氢化得到LCZ696杂质;具体反应式如下:
3.根据权利要求2所述的LCZ696杂质的制备方法,其特征在于:步骤(1)、步骤(3)、步骤(4)中,所述有机溶剂为二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、二甲亚砜、甲醇、乙醇中的一种或多种。
4.根据权利要求2所述的LCZ696杂质的制备方法,其特征在于:步骤(1)中,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-((叔丁氧羰基)氨基)-2-甲基戊酸与苄卤的摩尔比为1∶1~2,所述苄卤为苄溴或苄氯,所述碱为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、三乙胺、吡啶或哌啶。
5.根据权利要求2所述的LCZ696杂质的制备方法,其特征在于:步骤(2)中,所述酸性溶液为三氟乙酸、氯化氢乙酸乙酯溶液或氯化氢四氢呋喃溶液。
6.根据权利要求2所述的LCZ696杂质的制备方法,其特征在于:步骤(3)中,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-氨基-2-甲基戊酸苄酯与琥珀酸酐的摩尔比为1∶1~2,所述碱为碳酸钠、二乙胺、三乙胺、吡啶或哌啶。
7.根据权利要求2所述的LCZ696杂质的制备方法,其特征在于:步骤(4)中,所述缩合剂为二环己基碳二亚胺、二异丙基碳二亚胺或1-(3-二甲胺基丙基)-3-乙基碳二亚胺,所述催化剂为4-二甲氨基吡啶、吡啶、三乙胺、N,N-二甲基甲酰胺或6-氯-1-羟基苯并三氮唑,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯与醇的摩尔比为1:1~2,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯与缩合剂的摩尔比为1:1~1.5,所述(2R,4S)-5-([1,1'-联苯]-4-基)-4-(3-羧基丙酰胺基)-2-甲基戊酸苄酯与催化剂的摩尔比为1:0.1~0.2。
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CN107311909A (zh) * | 2017-06-22 | 2017-11-03 | 东南大学 | 一种lcz696杂质对照品的制备方法 |
CN110133150A (zh) * | 2019-05-31 | 2019-08-16 | 重庆三圣实业股份有限公司 | 一种分离测定lcz696异构体杂质的方法 |
CN110133149A (zh) * | 2019-05-31 | 2019-08-16 | 重庆三圣实业股份有限公司 | 一种分离测定lcz696及其杂质的方法 |
CN112666294A (zh) * | 2020-12-29 | 2021-04-16 | 重庆三圣实业股份有限公司 | 一种分离测定沙库巴曲钙盐及其杂质的方法 |
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CN107311909A (zh) * | 2017-06-22 | 2017-11-03 | 东南大学 | 一种lcz696杂质对照品的制备方法 |
CN110133150A (zh) * | 2019-05-31 | 2019-08-16 | 重庆三圣实业股份有限公司 | 一种分离测定lcz696异构体杂质的方法 |
CN110133149A (zh) * | 2019-05-31 | 2019-08-16 | 重庆三圣实业股份有限公司 | 一种分离测定lcz696及其杂质的方法 |
CN112666294A (zh) * | 2020-12-29 | 2021-04-16 | 重庆三圣实业股份有限公司 | 一种分离测定沙库巴曲钙盐及其杂质的方法 |
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