CN106431993A - Method for preparing LCZ-696 key intermediate - Google Patents
Method for preparing LCZ-696 key intermediate Download PDFInfo
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- CN106431993A CN106431993A CN201610824643.7A CN201610824643A CN106431993A CN 106431993 A CN106431993 A CN 106431993A CN 201610824643 A CN201610824643 A CN 201610824643A CN 106431993 A CN106431993 A CN 106431993A
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- 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 18
- 238000000034 method Methods 0.000 title abstract 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 239000000243 solution Substances 0.000 claims abstract description 41
- 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 31
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000007864 aqueous solution Substances 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 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 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 10
- 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
- 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 7
- 238000001816 cooling Methods 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 19
- 208000035126 Facies Diseases 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
- 238000005406 washing Methods 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 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
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 238000005292 vacuum distillation Methods 0.000 claims description 6
- 238000009413 insulation Methods 0.000 claims description 5
- -1 Isopropyl ester Chemical class 0.000 claims description 4
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 229960002303 citric acid monohydrate Drugs 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 230000004044 response 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
- 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 5
- 239000012535 impurity Substances 0.000 abstract description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 abstract 3
- 238000009776 industrial production Methods 0.000 abstract 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 13
- 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- 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
- 230000009286 beneficial effect Effects 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
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000006872 improvement 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
- 239000012074 organic phase Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001629 suppression Effects 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
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 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 invention relates to a method for preparing an LCZ-696 key intermediate, and aims to provide a novel method for preparing the LCZ-696 key intermediate. The LCZ-696 key intermediate has high yield, high impurity and low requirement for production equipment and is easy for industrialized production. The method includes the following steps: 1, adding NaHCO3 in water, conducting stirring and dissolving until the obtained aqueous solution is clarified, cooling the NaHCO3 aqueous solution to 10-20 DEG C, maintaining the temperature constant, and dropwise adding a NaClO solution to the NaHCO3 aqueous solution; 2, adding isopropyl acetate, a compound I and NaBr successively into a reaction kettle, conducting stirring at 20-35 DEG C for 20-40min for sufficiently dissolving, and adding TEMPO; 3, rapidly and dropwise adding the NaHCO3-NaClO aqueous solution in the compound I-NaBr-TEMPO isopropyl acetate solution obtained in step 2, purifying a compound II, and then preparing a compound IV. The method has the advantages that the yield of the compound IV is increased to 80% or above from about 50% in the prior art, the content of impurities is reduced, the purity of the prepared product reaches 99.0% or above, and thus the prepared product can be directly used in a following reaction without being purified. Moreover, the reaction temperature can be controlled in the range of 10 to 35 DEG C, the requirements for industrial equipment and operation time are reduced, and industrial production is thus greatly facilitated.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesizes field and in particular to a kind of prodrug AHU-377 of LCZ-696 preparation
The system of key intermediate (R, E) -5- ([1,1'- biphenyl] -4- base) -4- ((tertbutyloxycarbonyl) amino) -2- methyl -2- penetenoic acid
Preparation Method.
Background technology
LCZ696 is a kind of chronic heart failure medicine of Novartis's research and development, a kind of economic benefits and social benefits angiotensin receptor enkephalinase suppression
Agent, obtains FDA approval, heart failure (HFeEF) patient reducing for ejection fraction, will reduce cardiovascular dead in July, 2015
Die and heart failure is in hospital risk.
LCZ696 is the complex of the hypertension drug Valsartan of AHU-377 and Novartis.Wherein AHU-377 can block threat
It is responsible for the mechanism of action of 2 kinds of polypeptides reducing blood pressure, Valsartan then can improve vasodilation, stimulate body excretion sodium and water.
AHU-377 is a kind of prodrug, and its chemical name is：4- (((2S, 4R) -1- ([1,1 '-diphenyl] -4-
Base) -5- ethyoxyl -4- methyl -5- oxo -2- amyl group)-amino) -4- ketobutyric acid, and Chinese entitled (R, E) -5- ([1,1'-
Biphenyl] -4- base) -4- ((tertbutyloxycarbonyl) amino) -2- methyl -2- penetenoic acid is one of crucial intermediate of AHU-377.Should
The preparation method of key intermediate is either less in journal article or patent documentation at home and abroad to be reported.
Following synthetic route is disclosed in patent CN101516831B：
In said synthesis route, compounds Ⅳ is (R, E) -5- ([1,1'- biphenyl] -4- base) -4- ((tertbutyloxycarbonyl)
Amino) -2- methyl -2- penetenoic acid, this route determines compounds Ⅳ yield and whether is capable of the committed step of industrialized production and is
Compound I (Chinese full name (R)-tert-butyl group (1- ([1,1'- biphenyl] -4- base) -3- hydroxy propane -2- base) carbamate) makes
Standby compound II (Chinese full name (R)-tert-butyl group (1- ([1,1'- biphenyl] -4- base) -3- carbonyl propane -2- base) carbamic acid
Ester), prepare compound III (Chinese name (R, E) -5- ([1,1'- biphenyl] -4- base) -4- ((tertbutyloxycarbonyl) ammonia further
Base) -2- methyl -2- pentenoic acid ethyl ester).During this compound I prepare compound II, exothermic heat of reaction is violent, the temperature of Deca NaClO
Require low, usually -20 DEG C about, and easy peroxidating forms carboxylic acid, leads to yield relatively low, and will to the cooling system of equipment
Ask high it is difficult to industrial volume production.
Content of the invention
The invention aims to providing, a kind of high income, purity are high, to producing, equipment requirements are low, be easy to industrial metaplasia
The new preparation process of the LCZ-696 key intermediate producing.
For achieving the above object, the technical solution used in the present invention is：A kind of preparation method of LCZ-696 key intermediate
Including step：
A. prepare NaHCO3- NaClO aqueous solution：By NaHCO3It is added to the water stirring molten clear, by NaHCO3Aqueous solution is lowered the temperature
Whole constant temperature, to 10-20 DEG C, is added dropwise to NaClO solution thereto；
B. prepare compound I-NaBr-TEMPO isopropyl acetate solution：By isopropyl acetate, compound I, NaBr successively
It is added in reactor, after 20-35 DEG C of stirring 20-40min fully dissolves, add TEMPO；
C. prepare compound II：NaHCO by the preparation of step B3- NaClO aqueous solution fast drop is to compounds I-NaBr-
In TEMPO isopropyl acetate solution, reactor temperature constant temperature at 10-35 DEG C, response time 1-5h；
D. purify compound II：Deca sodium thiosulfate or five water sodium thiosulfate solution terminating reactions, product
Stratification, collects organic faciess, organic faciess priority NaHCO3Obtain final product after aqueous solution and NaCl solution washing, compound ii
Isopropyl acetate solution；
E. prepare compound IV；
Wherein：The structural formula of described compound I is：
The structural formula of described compound II is：
The structural formula of described compound III is：
The structural formula of described compound IV is：
Further, described step E comprises the steps：The isopropyl acetate solution of the compound ii being obtained to step D
Middle addition phosphorus ylide, 30-35 DEG C of reaction 1h, add citric acid monohydrate terminating reaction, and be incubated 0.5h.Divide liquid, washing, obtain
Organic faciess, vacuum distillation, obtain the Organic substance of compound III；Add Lithium hydrate, 78-82 DEG C of insulation backflow 1h, crystallize of lowering the temperature, institute
Stating Lithium hydrate and adding equivalent is 6-8eq, and the described equivalent that adds is in terms of compound I.
Further, in described step A, NaClO available chlorine content used is not less than mass fraction 6.5%.
It is further preferred that NaClO available chlorine content used is not more than mass fraction 8.5% in described step A.
Further, in described step A, the equivalent that adds of NaClO is 0.80-1.50eq, and the described equivalent that adds is with compound
I counts.
It is further preferred that the equivalent that adds of NaClO is 1.20-1.60eq in described step A, the described equivalent that adds is to change
Compound I counts.
Still more preferably, in described step A NaClO add equivalent be 1.20-1.40eq, described add equivalent with
Compound I counts.
Further, in described step C Deca NaHCO3- NaClO aqueous temperature is 10-35 DEG C.
It is further preferred that in described step C Deca NaHCO3- NaClO aqueous temperature is 10-15 DEG C.
Further, in described step B, the equivalent that adds of NaBr is 2-5eq, NaHCO in described step A3Add equivalent
For 2-8eq, in described step D, the equivalent that adds of sodium thiosulfate or five water sodium thiosulfate is 0.4-1.6eq, states in step E
The equivalent that adds of phosphorus ylide is 1.1-1.5eq, and described dosage is all in terms of compound I
The invention has the beneficial effects as follows：Make the yield of compounds Ⅳ by the 50% about of prior art improve to 80% with
On, and reducing the content of impurity, the product purity of preparation reaches more than 99.0%, and can be directly used for the next step need not carry
Pure.Additionally, reaction temperature can be controlled in the range of 10-35 DEG C, reduce the requirement to industrial equipment and operating time, significantly profit
In industrialized production.
Specific embodiment
With reference to specific embodiment, the present invention will be further described.Described embodiment is only being preferable to carry out of the present invention
Example, is not limited to the present invention, and for a person skilled in the art, the present invention can have various changes and become
Change.All any modification, equivalent substitution and improvement within the spirit and principles in the present invention, made etc., should be included in the present invention
Protection domain within.In embodiment, the equivalent that adds of sodium thiosulfate or five water sodium thiosulfate is 0.4-0.16eq, phosphorus leaf
The equivalent that adds of vertical moral is 1.1-1.5eq, and dosage is all in terms of compound I.
Embodiment one
Step 1 prepare compound I-NaBr- isopropyl acetate solution：0.1833mol compounds I, the isopropyl acetate of 1L,
The NaBr of 1.00mol, is added in 2L flask, stirs 30min at 20 DEG C, and then temperature control, to 20 DEG C, adds TEMPO；
Step 2 prepares NaClO-NaHCO3Aqueous solution：1.25molNaHCO3Be dissolved in 360ml water, at a temperature of 10-15 DEG C
It is added dropwise to the NaClO aqueous solution of the effective chlorine containing 0.220mol in solution；
The NaClO-NaHCO that step 2 is prepared by step 33The isopropyl acetate that aqueous solution is added drop-wise to compound I-NaBr is molten
In liquid, drip off in 80min at a temperature of 10-15 DEG C, be subsequently adding hypo solution terminating reaction, layering takes organic faciess,
Using NaCl solution washing, obtain the isopropyl acetate solution of compound ii；
Step 4, to the isopropyl acetate solution of compound ii, adds phosphorus ylide, 30 DEG C of reaction 1h, adds a water Fructus Citri Limoniae
Sour terminating reaction, and it is incubated 0.5h.Liquid, washing is divided to obtain organic faciess, vacuum distillation obtains compound III；
In the middle addition 1.3mol Lithium hydrate of prepared compound III, 80 DEG C are incubated backflow 1h to step 5, crystallize of lowering the temperature,
Sucking filtration, dries to obtain compound IV dry product 56.1g, molar yield 80.25%, purity 99.30%.
Embodiment two
Step 1 prepare compound I-NaBr- isopropyl acetate solution：0.1833mol compound I, the isopropyl acetate of 1L,
The NaBr of 1.10mol, is added in 2L flask, 35 DEG C of stirring 30min, is cooled to 20 DEG C, adds TEMPO；
Step 2 prepares NaClO-NaHCO3Aqueous solution：1.25molNaHCO3Be dissolved in 360ml water, at a temperature of 5-10 DEG C
It is added dropwise to the NaClO aqueous solution of the effective chlorine containing 0.250mol in solution；
The NaClO-NaHCO that step 2 is prepared by step 33The isopropyl acetate that aqueous solution is added drop-wise to compound I-NaBr is molten
In liquid, drip off in 90min at a temperature of 25-30 DEG C, be subsequently adding five water hypo solution terminating reactions, layering takes organic
Phase, using NaCl solution washing, obtains the isopropyl acetate solution of compound ii；
Step 4, to the isopropyl acetate solution of compound ii, adds phosphorus ylide, 35 DEG C of reaction 1h, adds a water Fructus Citri Limoniae
Sour terminating reaction, and it is incubated 0.5h.Liquid, washing is divided to obtain organic faciess, vacuum distillation obtains compound III；
Step 5 adds 1.3mol Lithium hydrate, 80 DEG C of insulation backflow 1h, crystallize of lowering the temperature in prepared compound III, takes out
Filter, dries to obtain compounds Ⅳ dry product 55.4g, molar yield 79.05%, purity 99.20%.
Embodiment three
Step 1 prepare compound I-NaBr- isopropyl acetate solution：0.1833mol compound I, the isopropyl acetate of 1L,
The NaBr of 1.10mol, is added in 2L flask, 25 DEG C of stirring 30min, is cooled to 20 DEG C, adds TEMPO；
Step 2 prepares NaClO-NaHCO3Aqueous solution：1.25molNaHCO3Be dissolved in 360ml water, at a temperature of 5-10 DEG C
It is added dropwise to the NaClO aqueous solution of the effective chlorine containing 0.280mol in solution；
The NaClO-NaHCO that step 2 is prepared by step 33The isopropyl acetate that aqueous solution is added drop-wise to compound I-NaBr is molten
In liquid, drip off in 90min at a temperature of 25-30 DEG C, be subsequently adding hypo solution terminating reaction, layering takes organic faciess,
Using NaCl solution washing, obtain the isopropyl acetate solution of compound ii；
Step 4, to the isopropyl acetate solution of compound ii, adds phosphorus ylide, 35 DEG C of reaction 1h, adds a water Fructus Citri Limoniae
Sour terminating reaction, and it is incubated 0.5h.Liquid, washing is divided to obtain organic faciess, vacuum distillation obtains compound III；
Step 5 adds 1.3mol Lithium hydrate, 80 DEG C of insulation backflow 1h, crystallize of lowering the temperature in prepared compound III, takes out
Filter, dries to obtain compounds Ⅳ dry product 54.94g, molar yield 78.69%, purity 99.50%.
Example IV
Step 1 prepare compound I-NaBr- isopropyl acetate solution：0.1833mol compound I, the isopropyl acetate of 1L,
The NaBr of 2.0mol, is added in 2L flask, 25 DEG C of stirring 30min, is cooled to 20 DEG C, adds TEMPO；
Step 2 prepares NaClO-NaHCO3Aqueous solution：1.25molNaHCO3Be dissolved in 360ml water, at a temperature of 5-10 DEG C
It is added dropwise to the NaClO aqueous solution of the effective chlorine containing 0.184mol in solution；
The NaClO-NaHCO that step 2 is prepared by step 33The isopropyl acetate that aqueous solution is added drop-wise to compound I-NaBr is molten
In liquid, drip off in 60min at a temperature of 20-25 DEG C, be subsequently adding hypo solution terminating reaction, layering takes organic faciess,
Using NaCl solution washing, obtain the isopropyl acetate solution of compound ii；
Step 4, to the isopropyl acetate solution of compound ii, adds phosphorus ylide, 20 DEG C of reaction 1h, adds a water Fructus Citri Limoniae
Sour terminating reaction, and it is incubated 0.5h.Liquid, washing is divided to obtain organic faciess, vacuum distillation obtains compound III；
Step 5 adds 1.3mol Lithium hydrate, 80 DEG C of insulation backflow 1h, crystallize of lowering the temperature in prepared compound III, takes out
Filter, dries to obtain compounds Ⅳ dry product 55.94g, molar yield 80.00%, purity 99.00%.
Claims (10)
1. a kind of preparation method of LCZ-696 key intermediate it is characterised in that：Including step：
A. prepare NaHCO3- NaClO aqueous solution：By NaHCO3It is added to the water stirring molten clear, by NaHCO3Aqueous solution cooling is finally permanent
Temperature, to 10-20 DEG C, is added dropwise to NaClO solution thereto；
B. prepare compound I-NaBr-TEMPO isopropyl acetate solution：Isopropyl acetate, compound I, NaBr are sequentially added
To in reactor, after 20-35 DEG C of stirring 20-40min fully dissolves, add TEMPO；
C. prepare compound II：NaHCO by the preparation of step B3- NaClO aqueous solution fast drop is to compounds I-NaBr-TEMPO
In isopropyl acetate solution, reactor temperature constant temperature at 10-35 DEG C, response time 1-5h；
D. purify compound II：Deca sodium thiosulfate or five water sodium thiosulfate solution terminating reactions, product stands
Layering, collects organic faciess, organic faciess priority NaHCO3Obtain final product after aqueous solution and NaCl solution washing, the acetic acid of compound ii
Isopropyl ester solution；
E. prepare compound IV；
Wherein：The structural formula of described compound I is：
The structural formula of described compound II is：
The structural formula of described compound III is：
The structural formula of described compound IV is：
2. LCZ-696 key intermediate according to claim 1 preparation method it is characterised in that：Described step E includes
Following steps：Phosphorus ylide is added, 30-35 DEG C is reacted 1h in the isopropyl acetate solution of the compound ii being obtained to step D, plus
Enter citric acid monohydrate terminating reaction, and be incubated 0.5h.Divide liquid, washing, obtain organic faciess, vacuum distillation, obtain compound III has
Machine thing；Add Lithium hydrate, 78-82 DEG C of insulation backflow 1h, crystallize of lowering the temperature, it is 6-8eq that described Lithium hydrate adds equivalent, described
Add equivalent in terms of compound I.
3. LCZ-696 key intermediate according to claim 1 preparation method it is characterised in that：Institute in described step A
It is not less than mass fraction 6.5% with NaClO available chlorine content.
4. LCZ-696 key intermediate according to claim 1 preparation method it is characterised in that：Institute in described step A
It is not more than mass fraction 8.5% with NaClO available chlorine content.
5. LCZ-696 key intermediate according to claim 1 preparation method it is characterised in that：In described step A
The equivalent that adds of NaClO effective chlorine is 0.80-1.50eq, and the described equivalent that adds is in terms of compound I.
6. LCZ-696 key intermediate according to claim 5 preparation method it is characterised in that：In described step A
The equivalent that adds of NaClO is 1.20-1.60eq, and the described equivalent that adds is in terms of compound I.
7. LCZ-696 key intermediate according to claim 6 preparation method it is characterised in that：In described step A
The equivalent that adds of NaClO is 1.20-1.40eq, and the described equivalent that adds is in terms of compound I.
8. LCZ-696 key intermediate according to claim 1 preparation method it is characterised in that：Drip in described step C
Plus NaHCO3- NaClO aqueous temperature is 10-35 DEG C.
9. LCZ-696 key intermediate according to claim 8 preparation method it is characterised in that：Drip in described step C
Plus NaHCO3- NaClO aqueous temperature is 10-15 DEG C.
10. LCZ-696 key intermediate according to claim 2 preparation method it is characterised in that：In described step B
The equivalent that adds of NaBr is 2-5eq, NaHCO in described step A3Add equivalent be 2-8eq, thiosulfuric acid in described step D
The equivalent that adds of sodium or five water sodium thiosulfate is 0.4-1.6eq, and the equivalent that adds stating phosphorus ylide in step E is 1.1-
1.5eq, described dosage is all in terms of compound I.
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| CN106946742A (en) * | 2017-03-28 | 2017-07-14 | 常州沃腾化工科技有限公司 | A kind of preparation method of the bent intermediates of the low Sha Kubi of triphenylphosphinc oxide content |
| 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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| 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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