CN109503404A - A kind of preparation method of LCZ-696 key intermediate - Google Patents
A kind of preparation method of LCZ-696 key intermediate Download PDFInfo
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- CN109503404A CN109503404A CN201811624992.XA CN201811624992A CN109503404A CN 109503404 A CN109503404 A CN 109503404A CN 201811624992 A CN201811624992 A CN 201811624992A CN 109503404 A CN109503404 A CN 109503404A
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Abstract
The present invention relates to a kind of preparation methods of LCZ-696 key intermediate, comprising the following steps: step 1: preparation NaHCO3- NaClO aqueous solution: step 2: isopropyl acetate, NaBr being added sequentially in reaction kettle, after completely dissolution, TEMPO is added in 25-40 DEG C of stirring 30-45min；Step 3: by the standby NaHCO 3-NaClO aqueous solution fast drop of step 1 into isopropyl acetate solution, reactor temperature constant temperature is at 20-40 DEG C, reaction time 2-7h；Step 4: be added dropwise sodium thiosulfate terminate reaction, reaction product stratification, collect organic phase, organic phase successively washed with 3 aqueous solution of NaHCO and NaCl aqueous solution after to obtain the final product；Step 5: phosphorus ylide being added in isopropyl acetate solution, 35-40 DEG C of reaction 1h is added Citric Acid Mono and terminates reaction, and keep the temperature 1h, liquid separation, washing, obtains organic phase, vacuum distillation, lithium hydroxide is added, 80-85 DEG C of heat preservation reflux 1.5h, cool down crystallization, it is 6-8eq that lithia, which adds equivalent, obtains LCZ-696 intermediate.The present invention is conducive to industrialized production significantly.
Description
Technical field
The present invention relates to a kind of preparation methods of LCZ-696 key intermediate.
Background technique
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 approval 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 the hypertension drug Valsartan of AHU-377 and 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- amyl)-amino) -4- ketobutyric acid, and entitled (R, the E) -5- ([1,1'- of Chinese
Biphenyl] -4- base) -4- ((tertbutyloxycarbonyl) amino) -2- methyl -2- penetenoic acid is one of the intermediate of AHU-377 key.It should
The preparation method of key intermediate is less either in journal article or patent document at home and abroad to be reported.
Summary of the invention
In order to solve the above technical problems, the object of the present invention is to provide a kind of preparation methods of LCZ-696 key intermediate.
To achieve the above object, the present invention adopts the following technical scheme:
A kind of preparation method of LCZ-696 key intermediate, comprising the following steps:
Step 1: preparation NaHCO3- NaClO aqueous solution: by NaHCO3It is added to the water stirring dissolved clarification, by NaHCO3Aqueous solution drop
Warm final constant temperature is added dropwise to NaClO solution to 20-30 DEG C thereto；
Step 2: isopropyl acetate, NaBr being added sequentially in reaction kettle, 25-40 DEG C of stirring 30-45min sufficiently dissolves
Afterwards, TEMPO is added；
Step 3: by the standby NaHCO3-NaClO aqueous solution fast drop of step 1 into isopropyl acetate solution, reaction kettle
Interior thermostatic is at 20-40 DEG C, reaction time 2-7h；
Step 4: sodium thiosulfate is added dropwise and terminates reaction, reaction product stratification collects organic phase, and organic phase is successively used
After NaHCO3 aqueous solution and the washing of NaCl aqueous solution to obtain the final product；
Step 5: phosphorus ylide being added in isopropyl acetate solution, 35-40 DEG C of reaction 1h is added Citric Acid Mono and terminates
Reaction, and 1h is kept the temperature, liquid separation, washing obtains organic phase, it is evaporated under reduced pressure, addition lithium hydroxide, 80-85 DEG C of heat preservation reflux 1.5h,
Cool down crystallization, and it is 6-8eq that the lithium hydroxide, which adds equivalent, obtains LCZ-696 intermediate.
Preferably, NaClO available chlorine content used is not less than mass fraction 7% in the step 1.
Preferably, NaClO available chlorine content used is not more than mass fraction 9% in the step 1.
Preferably, the equivalent that adds of NaClO is 0.85-1.60eq in the step 1.
Preferably, the equivalent that adds of NaClO is 1.30-1.75eq in the step 1.
Preferably, the NaHCO3-NaClO aqueous temperature being added dropwise in step 3 is 25-35 DEG C.
Preferably, the NaHCO3-NaClO aqueous temperature being added dropwise in step 3 is 25-30 DEG C.
According to the above aspect of the present invention, the present invention has at least the following advantages:
The present invention is can be improved compared with prior art to 80% or more, and reduces the content of impurity, the product of preparation
Purity reaches 99.0% or more, can be directly used for the next step without purification.In addition, reaction temperature can be controlled in 10-35 DEG C of model
In enclosing, the requirement to industrial equipment and operating time is reduced, is conducive to industrialized production significantly.
The above description is only an overview of the technical scheme of the present invention, in order to better understand the technical means of the present invention,
And can be implemented in accordance with the contents of the specification, with presently preferred embodiments of the present invention, detailed description is as follows below.
Specific embodiment
With reference to embodiment, the embodiment of the present invention is furthur described in detail.Following embodiment is used for
Illustrate the present invention, but is not intended to limit the scope of the invention.
In order to enable those skilled in the art to better understand the solution of the present invention, right below in conjunction with the embodiment of the present invention
Technical solution in the embodiment of the present invention is clearly and completely described, it is clear that described embodiment is only the present invention one
Section Example, instead of all the embodiments.Based on the embodiment of the present invention, those skilled in the art are not making creation
Property labour under the premise of every other embodiment obtained, shall fall within the protection scope of the present invention.
Embodiment
Step 1 prepare compound I-NaBr- isopropyl acetate solution: 0.1833mol chemical compounds I, the isopropyl acetate of 1L,
The NaBr of 1.00mol is added in 2L flask, and 35min is stirred at 20 DEG C, and then temperature is controlled to 25 DEG C, and TEMPO is added；
Step 2 prepares NaClO-NaHCO3 aqueous solution: 1.25molNaHCO3 is dissolved in 360ml water, molten at a temperature of 16 DEG C
The NaClO aqueous solution of the effective chlorine containing 0.220mol is added dropwise in liquid；
The NaClO-NaHCO3 aqueous solution that step 3 prepares step 2 is added dropwise in isopropyl acetate solution, at a temperature of 14 DEG C
It is dripped off in 82min, hypo solution is then added and terminates reaction, layering takes organic phase, is washed using NaCl aqueous solution；
Phosphorus ylide is added in step 4, and 32 DEG C of reaction 1h are added Citric Acid Mono and terminate reaction, and keep the temperature 1h.Liquid separation, water
It washes to obtain organic phase；
Step 5 is added 1.3mol lithium hydroxide, and 85 DEG C of heat preservations flow back 1h, and cool down crystallization, suction filtration, dry in LCZ-696
Mesosome 56.1g, molar yield 80.25%, purity 99.30%.
Embodiment one
I-NaBr- isopropyl acetate solution of step 1 prepare compound: the isopropyl acetate of 0.1833mol compound I, 1L,
The NaBr of 1.10mol is added in 2L flask, 40 DEG C of stirring 30min, is cooled to 30 DEG C, and TEMPO is added；
Step 2 prepares NaClO-NaHCO3 aqueous solution: 1.25molNaHCO3 is dissolved in 360ml water, molten at a temperature of 11 DEG C
The NaClO aqueous solution of the effective chlorine containing 0.250mol is added dropwise in liquid；
The NaClO-NaHCO3 aqueous solution that step 3 prepares step 2 is added dropwise in isopropyl acetate solution, in 95n under 35 degree
It inside drips off, five water hypo solutions is then added and terminate reaction, layering takes organic phase, is washed using NaCl aqueous solution；
Phosphorus ylide is added in step 4, and 35 DEG C of reaction 1h are added Citric Acid Mono and terminate reaction, and keep the temperature 1.Liquid separation, washing
Obtain organic phase；
Step 5 is added 1.3mol lithium hydroxide, and 80 DEG C of heat preservations flow back 1h, and cool down crystallization, suction filtration, dry in LCZ-696
Mesosome 55.4g, molar yield 79.05%, purity 99.20%.
The present invention is can be improved compared with prior art to 80% or more, and reduces the content of impurity, the product of preparation
Purity reaches 99.0% or more, can be directly used for the next step without purification.In addition, reaction temperature can be controlled in 10-35 DEG C of model
In enclosing, the requirement to industrial equipment and operating time is reduced, is conducive to industrialized production significantly.
The above is only a preferred embodiment of the present invention, it is not intended to restrict the invention, it is noted that for this skill
For the those of ordinary skill in art field, without departing from the technical principles of the invention, can also make it is several improvement and
Modification, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (7)
1. a kind of preparation method of LCZ-696 key intermediate, which comprises the following steps:
Step 1: preparation NaHCO3- NaClO aqueous solution: 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 to 20-30 DEG C thereto；
Step 2: isopropyl acetate, NaBr are added sequentially in reaction kettle, 25-40 DEG C of stirring 30-45min after completely dissolution,
TEMPO is added；
Step 3: warm in reaction kettle by the standby NaHCO 3-NaClO aqueous solution fast drop of step 1 into isopropyl acetate solution
Spend constant temperature at 20-40 DEG C, reaction time 2-7h；
Step 4: sodium thiosulfate is added dropwise and terminates reaction, reaction product stratification collects organic phase, and organic phase is successively used
After 3 aqueous solution of NaHCO and the washing of NaCl aqueous solution to obtain the final product；
Step 5: phosphorus ylide being added in isopropyl acetate solution, 35-40 DEG C of reaction 1h is added Citric Acid Mono and terminates instead
It answers, and keeps the temperature 1h, liquid separation, washing obtains organic phase, is evaporated under reduced pressure, and lithium hydroxide, 80-85 DEG C of heat preservation reflux 1.5h, drop is added
Warm crystallization, it is 6-8eq that the lithium hydroxide, which adds equivalent, obtains LCZ-696 intermediate.
2. a kind of preparation method of LCZ-696 key intermediate according to claim 1, it is characterised in that: the step 1
In NaClO available chlorine content used be not less than mass fraction 7%.
3. a kind of preparation method of LCZ-696 key intermediate according to claim 1, it is characterised in that: the step 1
In NaClO available chlorine content used be not more than mass fraction 9%.
4. a kind of preparation method of LCZ-696 key intermediate according to claim 1, it is characterised in that: the step 1
The equivalent that adds of middle NaClO is 0.85-1.60eq.
5. a kind of preparation method of LCZ-696 key intermediate according to claim 1, it is characterised in that: the step 1
The equivalent that adds of middle NaClO is 1.30-1.75eq.
6. a kind of preparation method of LCZ-696 key intermediate according to claim 1, it is characterised in that: dripped in step 3
The NaHCO 3-NaClO aqueous temperature added is 25-35 DEG C.
7. a kind of preparation method of LCZ-696 key intermediate according to claim 1, it is characterised in that: dripped in step 3
The NaHCO 3-NaClO aqueous temperature added is 25-30 DEG C.
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| US5217996A (en) * | 1992-01-22 | 1993-06-08 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
| WO2008031567A1 (en) * | 2006-09-13 | 2008-03-20 | Novartis Ag | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of nep inhibitors |
| WO2012025501A1 (en) * | 2010-08-23 | 2012-03-01 | Novartis Ag | Process for the preparation of intermediates for the manufacture of nep inhibitors |
| CN105985225A (en) * | 2015-02-12 | 2016-10-05 | 博瑞生物医药（苏州）股份有限公司 | Preparation methods for LCZ-696 and intermediate thereof |
| CN106318988A (en) * | 2016-08-23 | 2017-01-11 | 威海迪素制药有限公司 | Preparation method of LCZ696 key intermediate |
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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 |
| CN108047092A (en) * | 2018-01-12 | 2018-05-18 | 重庆市碚圣医药科技股份有限公司 | A kind of synthetic method of LCZ696 intermediates |
| CN108299226A (en) * | 2017-01-12 | 2018-07-20 | 南京红杉生物科技有限公司 | A kind of synthetic method of AHU377 calcium salts |
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2018
- 2018-12-28 CN CN201811624992.XA patent/CN109503404A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5217996A (en) * | 1992-01-22 | 1993-06-08 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
| WO2008031567A1 (en) * | 2006-09-13 | 2008-03-20 | Novartis Ag | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of nep inhibitors |
| WO2012025501A1 (en) * | 2010-08-23 | 2012-03-01 | Novartis Ag | Process for the preparation of intermediates for the manufacture of nep inhibitors |
| CN105985225A (en) * | 2015-02-12 | 2016-10-05 | 博瑞生物医药（苏州）股份有限公司 | Preparation methods for LCZ-696 and intermediate thereof |
| CN106318988A (en) * | 2016-08-23 | 2017-01-11 | 威海迪素制药有限公司 | Preparation method of LCZ696 key intermediate |
| CN106431993A (en) * | 2016-09-14 | 2017-02-22 | 重庆市碚圣医药科技股份有限公司 | Method for preparing LCZ-696 key intermediate |
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| CN108299226A (en) * | 2017-01-12 | 2018-07-20 | 南京红杉生物科技有限公司 | A kind of synthetic method of AHU377 calcium salts |
| 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 |
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Application publication date: 20190322 |