CN108373423B - Preparation method of Sacubitril-valsartan compound and/or eutectic key intermediate Sacubitril calcium - Google Patents
Preparation method of Sacubitril-valsartan compound and/or eutectic key intermediate Sacubitril calcium Download PDFInfo
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- CN108373423B CN108373423B CN201810402315.7A CN201810402315A CN108373423B CN 108373423 B CN108373423 B CN 108373423B CN 201810402315 A CN201810402315 A CN 201810402315A CN 108373423 B CN108373423 B CN 108373423B
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- DDLCKLBRBPYKQS-OXXXZDCLSA-L calcium 4-[[(2S,4R)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate Chemical compound [Ca++].CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(cc1)-c1ccccc1)NC(=O)CCC([O-])=O.CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(cc1)-c1ccccc1)NC(=O)CCC([O-])=O DDLCKLBRBPYKQS-OXXXZDCLSA-L 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000004072 C09CA03 - Valsartan Substances 0.000 title abstract description 7
- 229960004699 valsartan Drugs 0.000 title abstract description 7
- 230000005496 eutectics Effects 0.000 title abstract description 3
- 239000011575 calcium Substances 0.000 claims abstract description 19
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 18
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 9
- 230000032050 esterification Effects 0.000 claims abstract description 6
- 238000005886 esterification reaction Methods 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000007670 refining Methods 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 239000003208 petroleum Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 10
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 9
- 229940011051 isopropyl acetate Drugs 0.000 claims description 9
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical group ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 3
- 239000000920 calcium hydroxide Substances 0.000 claims description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229940014800 succinic anhydride Drugs 0.000 claims description 3
- 238000010009 beating Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229960003953 sacubitril Drugs 0.000 abstract description 11
- -1 Sacubitril valsartan compound Chemical class 0.000 abstract description 9
- 238000005917 acylation reaction Methods 0.000 abstract description 2
- JXTNUXJSXXIIFE-VISDOYDDSA-N (e,4r)-2-methyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-(4-phenylphenyl)pent-2-enoic acid Chemical compound C1=CC(C[C@H](\C=C(/C)C(O)=O)NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 JXTNUXJSXXIIFE-VISDOYDDSA-N 0.000 abstract 1
- 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 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000011734 sodium Substances 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Substances [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 7
- 159000000007 calcium salts Chemical class 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YDSBMWIJMJQNKE-YNDBEVAQSA-N (2r,4s)-4-amino-2-methyl-5-(4-phenylphenyl)pentanoic acid;hydrochloride Chemical compound Cl.C1=CC(C[C@@H](N)C[C@@H](C)C(O)=O)=CC=C1C1=CC=CC=C1 YDSBMWIJMJQNKE-YNDBEVAQSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- NQRAWXHLZGWKRS-FTBISJDPSA-N [Na].C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 Chemical compound [Na].C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NNN=N1 NQRAWXHLZGWKRS-FTBISJDPSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 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 3
- 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 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 2
- 108050000824 Angiotensin II receptor Proteins 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- RRTBVEJIZWGATF-JKSHRDEXSA-M sodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate Chemical compound [Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1 RRTBVEJIZWGATF-JKSHRDEXSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000001373 (E)-2-methylpent-2-enoic acid Substances 0.000 description 1
- OVBFMEVBMNZIBR-UHFFFAOYSA-N -2-Methylpentanoic acid Natural products CCCC(C)C(O)=O OVBFMEVBMNZIBR-UHFFFAOYSA-N 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 241000209051 Saccharum Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- 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 1
- 239000003446 ligand Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a Sacubitril valsartan compound and/or a eutectic key intermediate Sacubitril calcium. The preparation method of Sacubiqu calcium provided by the invention adopts (R, E) -5- ([1,1' -biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-pent-2-enoic acid to carry out hydrogenation, esterification and acylation reactions to obtain the Sacubiqu calcium.
Description
Technical Field
The invention belongs to the field of drug synthesis, relates to a preparation method of a drug intermediate, and particularly relates to a preparation method of a sacubitril valsartan compound and/or a cocrystal key intermediate sacubitril calcium.
Background
The chemical name of the sacubitril calcium sodium valsartan is as follows: the monocalcium pentadecahydrate complex of hexa- [3- ((1S,3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propanoic acid- (S) -3' -methyl-2 ' - (pentanoyl {2 "- (tetrazol-5-yl anion) biphenyl-4 ' -ylmethyl } amino) butanoic acid ] hexadecanoic sodium is a structural analog of my developed norward marketed drug sabotabivalisartan sodium (LCZ 696).
Sacubitril valsartan sodium (LCZ696), an angiotensin receptor enkephalinase inhibitor (ARNi) developed by nova, was approved by the FDA at 2015.07.08 for chronic heart failure patients with reduced ejection fraction and reduced risk of cardiovascular death and hospitalization for heart failure. LCZ696 is a supramolecular complex formed by Sacubitril (AHU-377) and valsartan in a ratio of 1:1, has a unique dual action mechanism of enkephalinase and angiotensin receptors, shows great advantages compared with the existing therapeutic drugs, and is known as one of the most important progresses in the cardiovascular field in the past decade.
The Sacubitril is one of the components of Sacubitril calcium sodium and Sacubitril valsartan sodium (LCZ696), the chemical name of the Sacubitril calcium sodium is 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopent-2-yl) amino) -4-oxobutyric acid, and the structural formulas of free acid and calcium salt are as follows:
in the disclosed method for synthesizing sacubitril calcium sodium and sacubitril valsartan sodium (LCZ696), sacubitril or calcium salt thereof (CN200680001733.0, CN201510758232.8) is needed, and the calcium salt form has better stability, is more beneficial to storage and is more convenient to use.
In the prior art, a plurality of documents are reported for the synthesis of the Sacubitril or the calcium salt thereof, wherein the following synthetic route is reported in Nowa in Chinese patent CN 200780034141.3.
The reaction steps of the route are long, expensive rhodium or ruthenium chiral catalysts and special ligands are needed, the conventional palladium-carbon hydrogenation scheme disclosed in the patent is poor in stereoselectivity, multiple times of refining are needed, and the amplification is not facilitated.
Chinese patents CN201610247438.9, CN201510317119.6 and CN201510890026.2 all report the preparation of Sacubitril calcium, but all adopt a scheme of firstly preparing sodium salt and then converting the sodium salt into calcium salt, have long steps and low efficiency, and are not beneficial to industrial production.
Therefore, it is necessary to develop a method for preparing Sacubitril calcium acetate, which is simple and convenient to operate, low in cost and more suitable for industrial scale-up. The present invention meets such a need.
Disclosure of Invention
The invention aims to provide a method for preparing Sacubitril calcium, which is simple and convenient to operate, low in cost and more suitable for industrial amplification. The method comprises the following specific steps: a preparation method of Sacubiqu calcium is characterized by comprising the following steps:
the compound I reacts with an acylating agent in the presence of calcium-containing base to generate Sacubitril calcium.
Optionally, the calcium-containing base is one or more of calcium hydroxide, calcium hydrogen phosphate, and calcium carbonate.
Optionally, the molar ratio of calcium-containing base to compound I is calcium-containing base: compound I ═ (0.5-5): 1, preferably (1-3): 1.
optionally, the preparation method further comprises a refining step, wherein a refining system is a mixture of an organic solvent and water, and the volume ratio of the organic solvent: water 1: (0.5 to 5), preferably 1: (1-3). Wherein the organic solvent is selected from one or more of alcohols, ketones, acetonitrile or tetrahydrofuran, wherein the alcohols are preferably methanol and ethanol, and the ketones are preferably acetone.
Alternatively, the compound I is prepared by the following method:
compound III is prepared by a hydrogenation step to compound II, which is prepared by an esterification step to compound I.
Optionally, the hydrogenation step comprises a refining step, wherein a refining system is a mixed solvent of isopropyl acetate and petroleum ether, and the volume ratio of the isopropyl acetate: petroleum ether is 1: (0.5 to 5), preferably 1: (1-3).
Optionally, the esterification step comprises a refining step, and the compound I is refined by adopting petroleum ether beating.
The invention also provides application of the preparation method in synthesizing Sacubitril calcium sodium or Sacubitril sodium or other salt compounds and/or co-crystals of Sacubitril.
The technical scheme of the invention has the following beneficial effects:
1. in the hydrogenation step, the isopropyl acetate/petroleum ether is adopted for recrystallization, and the prepared compound II ((2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-pentanoic acid) has high purity and low cost;
2. in the esterification step, petroleum ether is selected as a solvent for purification and pulping, so that the yield is high, the purity is high, the cost is lower, and the post-treatment is simpler and more convenient;
3. in the acylation step, the calcium-containing alkali is adopted, so that the Saccharum sinensis Roxb calcium can be directly obtained, and the method has the advantages of less working procedures, low cost, simplicity and easiness in operation, contribution to industrial production and the like, and solves the problems of long steps, low efficiency and the like in the scheme of firstly preparing sodium salt and then converting the sodium salt into calcium salt in the prior art. By matching with a proper refining system, the Sacubitril calcium with HPLC purity higher than 99% can be obtained, and can be directly used for preparing Sacubitril calcium sodium or Sacubitril sodium or other salt compounds and/or co-crystals of Sacubitril valsartan.
The specific implementation mode is as follows:
the present invention will be described in further detail with reference to the following examples, which are provided for illustration only and are not intended to limit the scope of the present invention, and any equivalent replacement in the field made in the light of the present disclosure is included in the scope of the present invention.
The structure of the compound is nuclear magnetic resonance (1H NMR) or MS.
Nuclear magnetic resonance apparatus (1H NMR is Bruker AVANCE-400, nuclear magnetic resonance: (1H NMR) shifts () are given in parts per million (ppm) and the solvent determined is DMSO-d6Internal standard is Tetramethylsilane (TMS), and chemical shift is 10-6(ppm) is given as a unit.
The invention will be further illustrated with reference to the following specific examples:
EXAMPLE 1 preparation of Compound II ((2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-pentanoic acid)
Adding (R, E) -5- ([1,1' -biphenyl) into a hydrogenation container under stirring]-4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-pent-2-enoic acid (compound III) (75g, 0.20mol), 10% palladium on carbon (Pd/C) (3.0g) and ethanol (750 ml) were reacted under maintained pressure (1.0MPa, 25 ℃) for 20 hours while introducing hydrogen gas. Filtering, concentrating to dryness, adding isopropyl acetate/petroleum ether with proper proportion for recrystallization, and drying to obtain a white solid (compound II), wherein the specific data are shown in the following table.1H NMR(DMSO-d6)12.01(s,1H),7.63(d,2H,J＝7.6Hz),7.56(d,2H,J＝8.0Hz),7.47-7.43(m,2H),7.35(d,1H,J＝7.2Hz),7.24(d,2H,J＝8.0Hz),6.73(d,1H,J＝8.8Hz),3.67-3.66(m,1H),2.68(d,2H,J＝6.8Hz),2.45-2.42(m,1H),1.78-1.71(m,1H),1.32(s,9H),1.40-1.32(m,1H),1.06(d,3H,J＝6.8Hz).
| Isopropyl acetate: proportion of Petroleum Ether (volume ratio) | Mass yield | HPLC | Isomer (2R,4R) |
| 1：0.5 | 50.2％ | 99.8％ | 0.18％ |
| 1：1 | 58.3％ | 99.7％ | 0.24％ |
| 1：3 | 66.9％ | 99.6％ | 0.32％ |
| 1：5 | 73.8％ | 99.1％ | 0.45％ |
EXAMPLE 2 preparation of Compound I ((2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methyl-pentanoic acid hydrochloride)
Adding (2R,4S) -5- ([1,1' -biphenyl) into a reaction bottle under stirring]-4-yl) -4- ((tert-butoxycarbonyl) amino) -2-methyl-pentanoic acid (compound II) (45g, 0.12mol), ethanol 225ml, thionyl chloride (69.3g, 0.58mol) was added dropwise at 5 ℃, and after completion of addition, the temperature was raised to 40 ℃ for 4 hours of reaction. Concentrating to dry, pulping with petroleum ether, filtering, and drying to obtain white solid (compound I)39.5g with mass yield of 87.8%.1H NMR(DMSO-d6)8.33(s,3H),7.68-7.64(m,4H),7.49-7.45(m,2H),7.38-7.36(m,3H),4.01-3.96(m,2H),3.38-3.36(m,1H),3.12-3.08(m,1H),2.85-2.74(m,2H),1.89-1.83(m,1H),1.66-1.60(m,1H),1.09(t,3H, J ═ 12.4Hz),1.07(d,3H, J ═ 5.2Hz) HPLC 99.8%, isomer ≤ 0.2%.
EXAMPLE 3 preparation of Sacubitril calcium (calcium 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopent-2-yl) amino) -4-oxobutyrate)
(2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methyl-pentanoic acid hydrochloride (compound I) (36g, 0.10mol), succinic anhydride (9.7g, 0.10mol) and DMF 90ml are added into a reaction flask under stirring, an appropriate amount of calcium-containing base (one or more than one kind of mixture) is added in batches at 0-10 ℃, and after the addition, the temperature is raised to 25 ℃ for reaction for 4 hours. Adding water, pulping, and filtering to obtain crude product. Adding a mixed system of an organic solvent and water in a proper proportion for recrystallization, filtering and drying to obtain a white-like solid (Sacubitril calcium) with isomers less than or equal to 0.1 percent, and other data are shown in the following table.
Example 4 preparation of Sacubitrocalcium (calcium 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopent-2-yl) amino) -4-oxobutyrate)
Adding (2R,4S) -5- ([1,1' -biphenyl) into a reaction kettle under stirring]-4-yl) -4-amino-2-methyl-pentanoic acid hydrochloride (compound I) (3.6kg, 10mol), succinic anhydride (970g, 10mol) and DMF 9L, 10mol of calcium hydroxide was added in portions at 0-10 ℃, after addition, the temperature was raised to 25 ℃ to complete the reaction. Adding water, pulping, and filtering to obtain crude product. Recrystallizing with ethanol/water at a volume ratio of ethanol to water of 1:1, filtering, and drying to obtain white solid, i.e. Sacubitril calcium, with a mass yield of 88.6%, HPLC purity of 99.6%, and isomer content of less than or equal to 0.1%.1H NMR(DMSO-d6)7.97(d,1H,J＝7.8Hz),7.62(d,2H,J＝7.8Hz),7.55(d,2H,J＝7.8Hz),7.44-7.42(m,2H),7.34-7.31(m,1H),7.24(d,2H,J＝7.8Hz),3.97(q,2H,J＝4.4Hz),3.95-3.93(m,1H),2.76-2.73(m,1H),2.65-2.62(m,1H),2.51-2.48(m,1H),2.32-2.25(m,4H),1.77-1.73(m,1H),1.43-1.39(m,1H),1.09(t,3H,J＝4.8Hz),1.04(d,3H,J＝7.2Hz).ESI-MS m/z:412[M-Ca+H]+.
In summary, the preparation method of the sacubitril calcium provided by the invention adopts (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methyl-pentanoic acid hydrochloride to react with an acylating agent in the presence of calcium-containing alkali, and the sacubitril calcium is prepared through a one-step reaction. Compared with the prior documents CN201610247438.9, CN201510317119.6 and CN201510890026.2, the method has the problems of long steps, low efficiency, inconvenience for industrialization and the like because the method firstly acidylates, then prepares sodium salt and finally converts the sodium salt into calcium salt.
Claims (7)
1. A preparation method of Sacubiqu calcium is characterized by comprising the following steps:
preparing a compound II from a compound III through a hydrogenation step, preparing a compound I from a compound II through an esterification step, and reacting the compound I with an acylating agent in the presence of a calcium-containing base to generate Sacubitril calcium;
wherein, the hydrogenation step comprises a refining step, a refining system is a mixed solvent of isopropyl acetate and petroleum ether, and the volume ratio of the isopropyl acetate: petroleum ether is 1: (0.5 to 5); the calcium-containing alkali is calcium hydroxide, and the acylating agent is succinic anhydride.
2. The process according to claim 1, wherein the molar ratio of calcium-containing base to compound I is calcium-containing base: compound I ═ (0.5-5): 1.
3. the process according to claim 2, wherein the molar ratio of calcium-containing base to compound I is calcium-containing base: compound I ═ (1-3): 1.
4. the preparation method according to claim 1, further comprising a refining step, wherein the refining system is a mixture of an organic solvent and water, and the volume ratio of the organic solvent: water 1: (0.5-5), wherein the organic solvent is selected from one or more of alcohols, ketones, acetonitrile or tetrahydrofuran.
5. The method according to claim 4, wherein the volume ratio of the mixed solvent of the organic solvent and water is: water 1: (1-3).
6. The preparation method according to claim 1, wherein the hydrogenation step comprises a refining step, and the refining system is a mixed solvent of isopropyl acetate and petroleum ether, and the volume ratio of the isopropyl acetate: petroleum ether is 1: (1-3).
7. The process according to claim 1, wherein the esterification step comprises a refining step of refining compound I by beating with petroleum ether.
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