CN106431993B - A kind of preparation method of LCZ-696 key intermediates - Google Patents
A kind of preparation method of LCZ-696 key intermediates Download PDFInfo
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- CN106431993B CN106431993B CN201610824643.7A CN201610824643A CN106431993B CN 106431993 B CN106431993 B CN 106431993B CN 201610824643 A CN201610824643 A CN 201610824643A CN 106431993 B CN106431993 B CN 106431993B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000000543 intermediate Substances 0.000 title claims abstract description 18
- 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 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- 239000000243 solution Substances 0.000 claims abstract description 35
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229940011051 isopropyl acetate Drugs 0.000 claims abstract description 29
- 239000007864 aqueous solution Substances 0.000 claims abstract description 28
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims abstract description 22
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 12
- 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 abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 9
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims abstract description 8
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000000746 purification Methods 0.000 claims abstract description 4
- 238000005352 clarification Methods 0.000 claims abstract description 3
- 239000012074 organic phase Substances 0.000 claims description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 13
- 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 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 10
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 9
- 239000011574 phosphorus Substances 0.000 claims description 9
- 229910052698 phosphorus Inorganic materials 0.000 claims description 9
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 9
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- -1 Isopropyl ester Chemical class 0.000 claims description 4
- 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 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910001947 lithium oxide Inorganic materials 0.000 claims 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 7
- 235000010290 biphenyl Nutrition 0.000 description 6
- 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 5
- 240000003273 Passiflora laurifolia Species 0.000 description 4
- 235000013762 Passiflora laurifolia Nutrition 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 2
- 0 CC(*)=C[C@@](Cc(cc1)ccc1-c1ccccc1)NBr Chemical compound CC(*)=C[C@@](Cc(cc1)ccc1-c1ccccc1)NBr 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 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 2
- 229960004699 valsartan Drugs 0.000 description 2
- 239000001373 (E)-2-methylpent-2-enoic acid Substances 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- FIYPZBHSRLMLKZ-FXFXYLOPSA-N CC(C)(C)OC(N[C@H](C/C(/C=C)=C/CCc1ccccc1)C=O)=O Chemical compound CC(C)(C)OC(N[C@H](C/C(/C=C)=C/CCc1ccccc1)C=O)=O FIYPZBHSRLMLKZ-FXFXYLOPSA-N 0.000 description 1
- XNMLRFLRCLTWFT-VMWRSERWSA-N CC(C)(C)OC(N[C@H](CC(CC1)CCC1c1ccccc1)CO)=O Chemical compound CC(C)(C)OC(N[C@H](CC(CC1)CCC1c1ccccc1)CO)=O XNMLRFLRCLTWFT-VMWRSERWSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 230000024883 vasodilation Effects 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 present invention relates to a kind of preparation methods of LCZ-696 key intermediates；Purpose is to provide the new preparation process that a kind of high income, purity are high, require production equipment LCZ-696 key intermediates low, convenient for industrialized production.By NaHCO3It is added to the water stirring dissolved clarification, by NaHCO3Aqueous solution cools down final constant temperature to 10-20 DEG C, is added dropwise to NaClO solution thereto；Isopropyl acetate, compound I, NaBr are added sequentially in reaction kettle, after 20-35 DEG C of stirring 20-40min fully dissolves, TEMPO is added；By NaHCO3It is reacted in-NaClO aqueous solutions fast drop to chemical compounds I-NaBr-TEMPO isopropyl acetate solution, purification compound II and then prepare compound IV.The beneficial effects of the invention are as follows：So that the yield of compounds Ⅳ is improved by 50% or so of the prior art to 80% or more, and the content of impurity is reduced, the product purity of preparation reaches 99.0% or more, can be directly used for the next step without purification.In addition, reaction temperature is can be controlled within the scope of 10-35 DEG C, the requirement to industrial equipment and operating time is reduced, is conducive to industrialized production significantly.
Description
Technical field
The invention belongs to pharmaceutical chemistry to synthesize field, and in particular to pro-drug AHU-377's prepared by a kind of LCZ-696
The system of key intermediate (R, E) -5- ([1,1'- biphenyl] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2- methyl -2- penetenoic acids
Preparation Method.
Background technology
LCZ696 is a kind of chronic heart failure drug of Novartis's research and development, a kind of economic benefits and social benefits angiotensin receptor enkephalinase inhibition
Agent obtains FDA approvals in July, 2015, for heart failure (HFeEF) patient that ejection fraction reduces, will reduce cardiovascular dead
It dies and is hospitalized risk with heart failure.
LCZ696 is the compound of AHU-377 and the hypertension drug Valsartan of Novartis.Wherein AHU-377 can block threat
It is responsible for the mechanism of action of reduce blood pressure 2 kinds of polypeptides, Valsartan can then improve vasodilation, and stimulation body drains sodium and water.
AHU-377 is a kind of pro-drug, its chemical name is：4- (((2S, 4R) -1- ([1,1 '-diphenyl] -4-
Base) -5- ethyoxyl -4- methyl -5- oxo -2- amyls)-amino) -4- ketobutyric acids, and Chinese entitled (R, E) -5- ([1,1'-
Biphenyl] -4- bases) -4- ((tertbutyloxycarbonyl) amino) -2- methyl -2- penetenoic acids are one of the intermediates of AHU-377 keys.It should
The preparation method of key intermediate is less either in journal article or patent document at home and abroad to be reported.
Following synthetic route is disclosed in patent CN101516831B：
Compounds Ⅳ is (R, E) -5- ([1,1'- biphenyl] -4- bases) -4- ((tertbutyloxycarbonyl) in said synthesis route
Amino) -2- methyl -2- penetenoic acids, route decision compounds Ⅳ yield and the committed step for whether capableing of industrialized production are
Compound I (Chinese name (R)-tertiary butyl (1- ([1,1'- biphenyl] -4- bases) -3- hydroxy propane -2- bases) carbamate) makes
Standby compound II (Chinese name (R)-tertiary butyl (1- ([1,1'- biphenyl] -4- bases) -3- carbonyl propane -2- bases) carbamic acids
Ester), further prepare compound III (Chinese name (R, E) -5- ([1,1'- biphenyl] -4- bases) -4- ((tertbutyloxycarbonyl) ammonia
Base) -2- methyl -2- pentenoic acid ethyl esters).Exothermic heat of reaction is violent when compound I prepare compound II, and the temperature of NaClO is added dropwise
It is required that it is low, usually -20 DEG C or so, and be easy peroxidating and form carboxylic acid, cause yield relatively low, and wanted to the cooling system of equipment
Ask high, it is difficult to industrial volume production.
Invention content
The purpose of the invention is to provide a kind of high income, purity it is high, to production equipment require it is low, convenient for industrial metaplasia
The new preparation process of the LCZ-696 key intermediates of production.
To achieve the above object, the technical solution adopted by the present invention is：A kind of preparation method of LCZ-696 key intermediates
Including step：
A. NaHCO is prepared3- NaClO aqueous solutions：By NaHCO3It is added to the water stirring dissolved clarification, by NaHCO3Aqueous solution cools down most
Whole constant temperature is added dropwise to NaClO solution thereto to 10-20 DEG C；
B. prepare compound I-NaBr-TEMPO isopropyl acetates solution：Successively by isopropyl acetate, compound I, NaBr
It is added in reaction kettle, after 20-35 DEG C of stirring 20-40min fully dissolves, TEMPO is added；
C. prepare compound II：NaHCO prepared by step A3- NaClO aqueous solutions fast drop is to chemical compounds I-NaBr-
In TEMPO isopropyl acetate solution, reactor temperature constant temperature is at 10-35 DEG C, reaction time 1-5h；
D. purification compound II：Sodium thiosulfate is added dropwise or five water sodium thiosulfate solutions terminate reaction, reaction product
Stratification collects organic phase, organic phase priority NaHCO3After aqueous solution and the washing of NaCl aqueous solutions to obtain the final product, compound ii
Isopropyl acetate solution；
E. prepare compound IV；
Wherein：The structural formula of the compound I is：
The structural formula of the compound II is：
The structural formula of the compound III is：
The structural formula of the compound IV is：
Further, the step E includes the following steps：To the isopropyl acetate solution of compound ii made from step D
Middle addition phosphorus ylide, 30-35 DEG C of reaction 1h, is added Citric Acid Mono and terminates reaction, and keep the temperature 0.5h.Liquid separation, washing, obtains
Organic phase, vacuum distillation, obtains the organic matter of compound III；Lithium hydroxide is added, 78-82 DEG C of heat preservation reflux 1h, cool down crystallization, institute
It is 6-8eq to state lithium hydroxide and add equivalent, and the equivalent that adds is in terms of compound I.
Further, NaClO available chlorine contents used are not less than mass fraction 6.5% in the step A.
It is further preferred that NaClO available chlorine contents used are not more than mass fraction 8.5% in the step A.
Further, the equivalent that adds of NaClO is 0.80-1.50eq in the step A, and the equivalent that adds is with compound
I is counted.
It is further preferred that the equivalent that adds of NaClO is 1.20-1.60eq in the step A, it is described to add equivalent to change
Close object I meters.
Still more preferably, in the step A NaClO add equivalent be 1.20-1.40eq, it is described add equivalent with
Compound I meters.
Further, the NaHCO being added dropwise in the step C3- NaClO aqueous temperatures are 10-35 DEG C.
It is further preferred that the NaHCO being added dropwise in the step C3- NaClO aqueous temperatures are 10-15 DEG C.
Further, the equivalent that adds of NaBr is 2-5eq in the step B, NaHCO in the step A3Add equivalent
For 2-8eq, the equivalent that adds of sodium thiosulfate or five water sodium thiosulfate is 0.4-1.6eq in the step D, is stated in step E
The equivalent that adds of phosphorus ylide is 1.1-1.5eq, and the dosage is in terms of compound I
The beneficial effects of the invention are as follows：So that compounds Ⅳ yield by the prior art 50% or so improve to 80% with
On, and the content of impurity is reduced, the product purity of preparation reaches 99.0% or more, can be directly used for the next step without carrying
It is pure.In addition, reaction temperature is can be controlled within the scope of 10-35 DEG C, the requirement to industrial equipment and operating time is reduced, it is significantly sharp
In industrialized production.
Specific implementation mode
With reference to specific embodiment, the present invention will be further described.The embodiment is only the preferred implementation of the present invention
Example, is not intended to restrict the invention, for those skilled in the art, the present invention can have various changes and change
Change.All within the spirits and principles of the present invention, any modification, equivalent replacement, improvement and so on should be included in the present invention
Protection domain within.The equivalent that adds of sodium thiosulfate or five water sodium thiosulfate is 0.4-0.16eq, phosphorus leaf in embodiment
The equivalent that adds of vertical moral is 1.1-1.5eq, and dosage is in terms of compound I.
Embodiment one
Step 1 prepare compound I-NaBr- isopropyl acetate solution：0.1833mol chemical compounds Is, the isopropyl acetate of 1L,
The NaBr of 1.00mol is added in 2L flasks, and 30min is stirred at 20 DEG C, and then temperature is controlled to 20 DEG C, and TEMPO is added；
Step 2 prepares NaClO-NaHCO3Aqueous solution：1.25molNaHCO3Be dissolved in 360ml water, at a temperature of 10-15 DEG C
The NaClO aqueous solutions of the effective chlorine containing 0.220mol are added dropwise in solution；
The NaClO-NaHCO that step 3 prepares step 23The isopropyl acetate that aqueous solution is added drop-wise to compound I-NaBr is molten
It in liquid, being dripped off in 80min at a temperature of 10-15 DEG C, hypo solution is then added and terminates reaction, layering takes organic phase,
It is washed using NaCl aqueous solutions, obtains the isopropyl acetate solution of compound ii；
Phosphorus ylide is added to the isopropyl acetate solution of compound ii in step 4, and a water lemon is added in 30 DEG C of reaction 1h
Acid terminates reaction, and keeps the temperature 0.5h.Liquid separation, washing obtain organic phase, are evaporated under reduced pressure to compound III；
Step 5 is in the middle addition 1.3mol lithium hydroxides of compound III obtained, and 80 DEG C of heat preservation reflux 1h, cool down crystallization,
It filters, dries to obtain compound IV 56.1g, molar yield 80.25%, purity 99.30%.
Embodiment two
I-NaBr- isopropyl acetate solution of step 1 prepare compound：The isopropyl acetate of 0.1833mol compounds I, 1L,
The NaBr of 1.10mol is added in 2L flasks, and 35 DEG C of stirring 30min are cooled to 20 DEG C, TEMPO is added；
Step 2 prepares NaClO-NaHCO3Aqueous solution：1.25molNaHCO3Be dissolved in 360ml water, at a temperature of 5-10 DEG C
The NaClO aqueous solutions of the effective chlorine containing 0.250mol are added dropwise in solution；
The NaClO-NaHCO that step 3 prepares step 23The isopropyl acetate that aqueous solution is added drop-wise to compound I-NaBr is molten
It in liquid, is dripped off in 90min at a temperature of 25-30 DEG C, five water hypo solutions is then added and terminate reaction, layering takes organic
Phase is washed using NaCl aqueous solutions, obtains the isopropyl acetate solution of compound ii；
Phosphorus ylide is added to the isopropyl acetate solution of compound ii in step 4, and a water lemon is added in 35 DEG C of reaction 1h
Acid terminates reaction, and keeps the temperature 0.5h.Liquid separation, washing obtain organic phase, are evaporated under reduced pressure to compound III；
1.3mol lithium hydroxides are added in step 5 in compound III obtained, and 80 DEG C of heat preservation reflux 1h, cool down crystallization, takes out
Filter, dries to obtain compounds Ⅳ 55.4g, molar yield 79.05%, purity 99.20%.
Embodiment three
I-NaBr- isopropyl acetate solution of step 1 prepare compound：The isopropyl acetate of 0.1833mol compounds I, 1L,
The NaBr of 1.10mol is added in 2L flasks, and 25 DEG C of stirring 30min are cooled to 20 DEG C, TEMPO is added；
Step 2 prepares NaClO-NaHCO3Aqueous solution：1.25molNaHCO3Be dissolved in 360ml water, at a temperature of 5-10 DEG C
The NaClO aqueous solutions of the effective chlorine containing 0.280mol are added dropwise in solution；
The NaClO-NaHCO that step 3 prepares step 23The isopropyl acetate that aqueous solution is added drop-wise to compound I-NaBr is molten
It in liquid, being dripped off in 90min at a temperature of 25-30 DEG C, hypo solution is then added and terminates reaction, layering takes organic phase,
It is washed using NaCl aqueous solutions, obtains the isopropyl acetate solution of compound ii；
Phosphorus ylide is added to the isopropyl acetate solution of compound ii in step 4, and a water lemon is added in 35 DEG C of reaction 1h
Acid terminates reaction, and keeps the temperature 0.5h.Liquid separation, washing obtain organic phase, are evaporated under reduced pressure to compound III；
1.3mol lithium hydroxides are added in step 5 in compound III obtained, and 80 DEG C of heat preservation reflux 1h, cool down crystallization, takes out
Filter, dries to obtain compounds Ⅳ 54.94g, molar yield 78.69%, purity 99.50%.
Example IV
I-NaBr- isopropyl acetate solution of step 1 prepare compound：The isopropyl acetate of 0.1833mol compounds I, 1L,
The NaBr of 2.0mol is added in 2L flasks, and 25 DEG C of stirring 30min are cooled to 20 DEG C, TEMPO is added；
Step 2 prepares NaClO-NaHCO3Aqueous solution：1.25molNaHCO3Be dissolved in 360ml water, at a temperature of 5-10 DEG C
The NaClO aqueous solutions of the effective chlorine containing 0.184mol are added dropwise in solution；
The NaClO-NaHCO that step 3 prepares step 23The isopropyl acetate that aqueous solution is added drop-wise to compound I-NaBr is molten
It in liquid, being dripped off in 60min at a temperature of 20-25 DEG C, hypo solution is then added and terminates reaction, layering takes organic phase,
It is washed using NaCl aqueous solutions, obtains the isopropyl acetate solution of compound ii；
Phosphorus ylide is added to the isopropyl acetate solution of compound ii in step 4, and a water lemon is added in 20 DEG C of reaction 1h
Acid terminates reaction, and keeps the temperature 0.5h.Liquid separation, washing obtain organic phase, are evaporated under reduced pressure to compound III；
1.3mol lithium hydroxides are added in step 5 in compound III obtained, and 80 DEG C of heat preservation reflux 1h, cool down crystallization, takes out
Filter, dries to obtain compounds Ⅳ 55.94g, molar yield 80.00%, purity 99.00%.
Claims (9)
1. a kind of preparation method of LCZ-696 key intermediates, it is characterised in that：Including step：
A. NaHCO is prepared3- NaClO aqueous solutions：By NaHCO3It is added to the water stirring dissolved clarification, by NaHCO3Aqueous solution cooling is final permanent
Temperature is added dropwise to NaClO solution thereto to 10-20 DEG C；
B. prepare compound I-NaBr-TEMPO isopropyl acetates solution：Isopropyl acetate, compound I, NaBr are sequentially added
Into reaction kettle, after 20-35 DEG C of stirring 20-40min fully dissolves, TEMPO is added；
C. prepare compound II：NaHCO prepared by step A3- NaClO aqueous solutions fast drop is to chemical compounds I-NaBr-TEMPO
In isopropyl acetate solution, reactor temperature constant temperature is at 10-35 DEG C, reaction time 1-5h；
D. purification compound II：Sodium thiosulfate is added dropwise or five water sodium thiosulfate solutions terminate reaction, reaction product is stood
Organic phase, organic phase priority NaHCO are collected in layering3After aqueous solution and the washing of NaCl aqueous solutions to obtain the final product, the acetic acid of compound ii
Isopropyl ester solution；
E. phosphorus ylide is added into the isopropyl acetate solution of compound ii made from step D, 30-35 DEG C of reaction 1h is added
Citric Acid Mono terminates reaction, and keeps the temperature 0.5h, liquid separation, and washing obtains organic phase, is evaporated under reduced pressure, obtains compound III；Hydrogen is added
Lithia, 78-82 DEG C heat preservation reflux 1h, cool down crystallization, the lithium hydroxide add equivalent be 6-8eq, it is described add equivalent with
Compound I meters；
Prepare compound IV；
Wherein：The structural formula of the compound I is：
The structural formula of the compound II is：
The structural formula of the compound III is：
The structural formula of the compound IV is：
2. the preparation method of LCZ-696 key intermediates according to claim 1, it is characterised in that：Institute in the step A
It is not less than mass fraction 6.5% with NaClO available chlorine contents.
3. the preparation method of LCZ-696 key intermediates according to claim 1, it is characterised in that：Institute in the step A
It is not more than mass fraction 8.5% with NaClO available chlorine contents.
4. the preparation method of LCZ-696 key intermediates according to claim 1, it is characterised in that：In the step A
The equivalent that adds of NaClO is 0.80-1.50eq, and the equivalent that adds is in terms of compound I.
5. the preparation method of LCZ-696 key intermediates according to claim 1, it is characterised in that：In the step A
The equivalent that adds of NaClO is 1.20-1.60eq, and the equivalent that adds is in terms of compound I.
6. the preparation method of LCZ-696 key intermediates according to claim 5, it is characterised in that：In the step A
The equivalent that adds of NaClO is 1.20-1.40eq, and the equivalent that adds is in terms of compound I.
7. the preparation method of LCZ-696 key intermediates according to claim 1, it is characterised in that：It is dripped in the step C
The NaHCO added3- NaClO aqueous temperatures are 10-35 DEG C.
8. the preparation method of LCZ-696 key intermediates according to claim 7, it is characterised in that：It is dripped in the step C
The NaHCO added3- NaClO aqueous temperatures are 10-15 DEG C.
9. the preparation method of LCZ-696 key intermediates according to claim 1, it is characterised in that：In the step B
The equivalent that adds of NaBr is 2-5eq, NaHCO in the step A3The equivalent that adds be 2-8eq, thiosulfuric acid in the step D
The equivalent that adds of sodium or five water sodium thiosulfate is 0.4-1.6eq, and the equivalent that adds of phosphorus ylide is 1.1- in the step E
1.5eq, the dosage is in terms of compound I.
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| CN108047093A (en) * | 2017-11-29 | 2018-05-18 | 南通常佑药业科技有限公司 | A kind of preparation method of xenyl aminopropan aldehyde compound |
| CN109503404A (en) * | 2018-12-28 | 2019-03-22 | 凯瑞斯德生化(苏州)有限公司 | A kind of preparation method of LCZ-696 key intermediate |
| CN112745246A (en) * | 2020-12-30 | 2021-05-04 | 重庆市碚圣医药科技股份有限公司 | Purification method of shakubiqu intermediate |
| CN114805135A (en) * | 2022-03-29 | 2022-07-29 | 浙江美诺华药物化学有限公司 | Synthetic method of key intermediate of Sacubitril |
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| WO2015154673A1 (en) * | 2014-04-10 | 2015-10-15 | Zhaoyin Wang | Novel prodrugs and combinations for treatment of hypertension and cardiovascular diseases |
| CN105026361A (en) * | 2012-08-31 | 2015-11-04 | 浙江九洲药业股份有限公司 | New process |
| CN105168205A (en) * | 2015-08-18 | 2015-12-23 | 泰力特医药（湖北）有限公司 | Preparation method for dual inhibitor LCZ696 of angiotensin II receptor and neprilysin |
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| CN105026361A (en) * | 2012-08-31 | 2015-11-04 | 浙江九洲药业股份有限公司 | New process |
| WO2015154673A1 (en) * | 2014-04-10 | 2015-10-15 | Zhaoyin Wang | Novel prodrugs and combinations for treatment of hypertension and cardiovascular diseases |
| CN105168205A (en) * | 2015-08-18 | 2015-12-23 | 泰力特医药（湖北）有限公司 | Preparation method for dual inhibitor LCZ696 of angiotensin II receptor and neprilysin |
| CN105254589A (en) * | 2015-10-15 | 2016-01-20 | 上海博氏医药科技有限公司 | Method for preparing midbody of heart failure medicine |
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