CN108530371A - One planting sand library is than bent sodium salt, Sha Ku than the eutectic object of bent free acid and acetic acid, the Preparation method and use of its crystal form, crystal form - Google Patents
One planting sand library is than bent sodium salt, Sha Ku than the eutectic object of bent free acid and acetic acid, the Preparation method and use of its crystal form, crystal form Download PDFInfo
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- CN108530371A CN108530371A CN201810355622.4A CN201810355622A CN108530371A CN 108530371 A CN108530371 A CN 108530371A CN 201810355622 A CN201810355622 A CN 201810355622A CN 108530371 A CN108530371 A CN 108530371A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/08—Acetic acid
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- 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
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- 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
- C07B2200/07—Optical isomers
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- 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
Abstract
The present invention relates to husky library shown in a kind of formula IV than bent sodium salt, Sha Ku than the eutectic object of bent free acid and acetic acid, a kind of crystal form of the eutectic object and the preparation method of the crystal form, and use the method that there is the eutectic object of above-mentioned crystal form to prepare LCZ696.Eutectic object provided by the present invention can form stable crystal form, and not easy to moisture absorption, the eutectic object better heat stability, convenient for the husky library of purification than song, be conducive to storage, help to synthesize LCZ696.And eutectic object provided by the present invention can be directly used for preparing LCZ696, it is not necessary to carry out additional ion exchange, contribute to the type and content for controlling counter cation.
Description
Technical field
The present invention relates to pharmaceutical polymorphs field, more particularly to a planting sand library than bent sodium salt, Sha Ku than bent free acid with
The Preparation method and use of the eutectic object of acetic acid, its crystal form, the crystal form.
Background technology
LCZ696 is a kind of Novel blood pressure-reducing drug developed by Novartis (Novartis) company, which contains the Valsartan of Novartis
(Diovan, common name：Valsartan) and experimental drug sand library ratio song (Sacubitril；Two kinds of components such as AHU-377), wherein
Sha Ku is than the mechanism of action of bent 2 kinds of polypeptides that threat can be blocked to reduce blood pressure, and the medicine is in acquisition on July 7th, 2015 U.S. FDA batch
Standard reduces cardiovascular death and heart failure and is hospitalized wind for heart failure (heart failure) patient that ejection fraction reduces
Danger.LCZ696 is typically to be matched in excessive sodium hydrate aqueous solution and organic molten by equimolar amounts by Diovan and Sacubitril
The in the mixed solvent of agent carries out cocrystallization and obtains, and the chemical composition of LCZ696 is as shown in Formula II, chemical composition Diovan：
Sacubitril：Na：H2O=1：1：3：2.5.
The important component of Sha Ku ratio Qu Zuowei LCZ696 receives significant attention, and Sha Ku is than bent chemical name：
4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]
Amino } -4-oxobutanoic acid, Chinese name：4- { [(2S, 4R) -1- (4- xenyls) -5- ethyoxyl -4- methyl -5-
Oxo -2- amyls] amino } -4- ketobutyric acids, chemical structural formula is as shown in formula III：
Sha Ku by chain alkyl in molecular structure itself than song due to being influenced, and husky library is thicker than bent in large-scale production process
Product are all colourless viscous liquids, and to cause Sha Ku not to be easily purified than song, the uppity difficulty of quality is unfavorable for purifying, storage
It deposits and follow-up LCZ696 formulation developments.And it is furtherd investigate through inventor and finds that husky library is inhaled than the bent sodium salt formed with sodium hydroxide
It is moist big, stable crystal form cannot be formed, quality control and storage are unfavorable for.Although in addition, patent US5217996,
WO2006086456, WO2007056546 and WO2007056546, which disclose husky library ratio song, can also be prepared into various salt form chemical combination
Object, such as alkali metal salt, alkali salt, alkylamine salt, hydroxyalkyl amine salt etc. are still prepared by the salt type compound of gained
LCZ696 need to further dissociate, and to cause the residual of other cations or amine, should not control other sun that contend with of LCZ696
Ion and the content for remaining organic amine.
It is therefore desirable to develop a kind of more stable coherent condition of the husky library than bent sodium salt, to overcome husky library in the prior art
Than the purification of bent sodium salt difficulty, it is easy to moisture absorption, be difficult to form stable crystal form, quality is difficult to control, is unfavorable for storing and is not met
The defect that LCZ696 exploitations need.
Invention content
To achieve the goals above, the present invention provides a kind of eutectic object as shown in formula IV,
The powder X-ray of the crystal form of the present invention also provides a kind of eutectic object as shown in formula IV, the eutectic object with the crystal form is penetrated
Line difraction spectrum has the characteristic peak indicated below by 2 angles θ：5.3 ° ± 0.2 °, 10.6 ° ± 0.2 °, 19.9 ± 0.2 °, 20.8 ±
0.2°。
In some embodiments, the powder x-ray diffraction spectrum of the eutectic object with the crystal form is with below by 2 θ
The characteristic peak that angle indicates：5.3 ° ± 0.2 °, 10.6 ° ± 0.2 °, 10.9 ° ± 0.2 °, 17.5 ± 0.2 °, 19.9 ± 0.2 °, 20.3
± 0.2 °, 20.8 ± 0.2 °, 22.2 ± 0.2 °.
In in preferred embodiments, the powder x-ray diffraction spectrum of the eutectic object with the crystal form is with following
The characteristic peak indicated by 2 angles θ：5.3 ° ± 0.2 °, 10.6 ° ± 0.2 °, 10.9 ° ± 0.2 °, 12.3 ° ± 0.2 °, 14.8 ° ±
0.2 °, 15.9 ° ± 0.2 °, 16.9 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.5 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.4 ° ± 0.2 °,
19.9 ° ± 0.2 °, 20.3 ° ± 0.2 °, 20.8 ° ± 0.2 °, 21.6 ° ± 0.2 °, 21.9 ° ± 0.2 °, 22.2 ° ± 0.2 °, 26.9 °
± 0.2 °, 27.3 ± 0.2 °, 27.7 ° ± 0.2 °.
In some embodiments, each characteristic peak has in the powder x-ray diffraction spectrum of the eutectic object with the crystal form
Diffracted intensity as shown in the table：
In some embodiments, the melting range of the eutectic object with the crystal form is 118~120 DEG C, and DSC peak temperatures are
119.01℃
It is known to ordinary skill in the art to be, diffracted intensity opposite with shown in the application crystal form XRD differs ±
Diffracted intensity within 20% is in the error range that crystal form XRD of the present invention can be born with respect to diffracted intensity.
The present invention also provides a kind of preparation methods of the eutectic object with above-mentioned crystal form, comprise the steps of：By husky library
In methylene chloride than the dissolving of bent free acid, sodium acetate is added and then filters and collect filtrate in 30~35 DEG C of insulation reactions,
By in gained filtrate added drop-wise to normal heptane, and crystallize.
In some embodiments, the time of reaction is 0.5~2 hour, preferably 1 hour.
It in some embodiments, will be in the normal heptane of gained filtrate added drop-wise to 0~5 DEG C.
In some embodiments, crystallization carries out in the range of 0~5 DEG C.
In some embodiments, further include the steps that by gained crystal filtration and or drying after crystallization.
In some embodiments, Sha Ku is 1 than the bent molar ratio with sodium acetate:(1.0~1.2), preferably 1:1.1.
In some embodiments, Sha Ku is 1mol than bent the ratio between the volume of molal quantity and dichloromethane:(1~2) L,
1mol:1.5L。
In some embodiments, the volume ratio of dichloromethane and normal heptane is 1:(5~15), preferably 1:10.
Purposes of the eutectic object in preparing LCZ696 as shown in formula IV that the present invention also provides a kind of.
The present invention also provides a kind of purposes of the eutectic object in preparing LCZ696 as shown in formula IV with above-mentioned crystal form.
In some embodiments, LCZ696 is prepared in such use to carry out using following methods：There to be above-mentioned crystal form
Eutectic object be dissolved in the in the mixed solvent of isopropyl acetate and acetone, Valsartan is added after the dissolved clarification that heats up, hydrogen-oxygen is then added dropwise
The aqueous solution for changing sodium, is evaporated off a part of solvent, then adds isopropyl acetate after dripping off, solvent will be evaporated off and add isopropyl acetate
The step of ester, operates 2~3 times repeatedly, and then cool down crystallization, filtration drying, such as is dried in vacuo, and obtains LCZ696.
Preferably, the molar ratio of eutectic object and Valsartan is 1:0.95~1.10, preferably 1:1.05.
Preferably, the molar ratio of eutectic object and sodium hydroxide is 1:2.25~3.00, preferably 2.5.
Preferably, crystallization carries out at a temperature of 20~30 DEG C at a temperature of preferably 25 DEG C.
Preferably, the mass concentration of sodium hydrate aqueous solution is 10%.
Preferably, solvent is evaporated off using vacuum distillation.
Preferably, described the step of solvent is evaporated off, carries out at a temperature of 35 ± 5 DEG C；When adding isopropyl acetate, reaction
The temperature of system is 40 ± 3 DEG C.
Preferably, the step of heat preservation is respectively further comprised after described the step of solvent is evaporated off and adds isopropyl acetate
Suddenly, preferably soaking time is 0.5 hour.
The beneficial effects of the present invention are：
(1) the eutectic object with crystal form of the present invention can be stabilized, and not easy to moisture absorption, the eutectic object better heat stability,
Convenient for the husky library of purification than bent, conducive to storage, help to synthesize LCZ696.
(2) the eutectic object with crystal form of the present invention can be directly used for preparing LCZ696, it is not necessary to additional ion exchange is carried out,
Contribute to the type and content of control counter cation.
Description of the drawings
Fig. 1 is the eutectic object prepared by present example 11HNMR schemes；
Fig. 2 is the XPRD figures of the eutectic object prepared by present example 1；
Fig. 3 is the DSC figures of the eutectic object prepared by present example 1；
The XPRD figures that Fig. 4 is the LCZ696 prepared by present example 2；
The DSC figures that Fig. 5 is the LCZ696 prepared by present example 2.
Specific implementation mode
To make those skilled in the art more fully understand technical scheme of the present invention, with reference to specific embodiment and
The invention will be further described for attached drawing.
In embodiment it is used sand library than bent free acid according to disclosed in patent US5217996 preparation method synthesize.
Device information used in embodiment：
1HNMR is measured using 400 Nuclear Magnetic Resonance of Brukeravance；
Powder X-ray RD diffraction is measured using Panaco " X'pert Powder " powder x-ray diffraction, copper palladium, incidence wave
It is long：1.54 angstrom；
Atomic emission spectrum is measured using Thermo Fisher inductively coupled plasmas (ICP) Atomic Emission Spectrometer AES；
DSC tests are carried out using plum Teller-support benefit differential scanning calorimeter, sample loading volume 5.00mg, heating rate
10.00K/min；
KF methods are surveyed moisture test and are carried out using plum Teller-support benefit karl Fischer moisture tester, method：Coulomb
Method, volumetric method.
High performance liquid chromatograph model Waters 2695.
Acetic acid content is measured using Headspace Gas Chromatography method in eutectic object, gas chromatograph model Agilent-7890.
It is the operational instances of the present invention below
Comparative example：Preparations of the Sha Ku than bent sodium salt
50mL ethyl alcohol is added in reaction bulb, 50mL tetrahydrofurans, for Sha Ku than bent free acid grease 4.11g, stirring is molten
Clearly, 2mol/L sodium hydrate aqueous solution 6mL are added, 20~25 DEG C of room temperature is reacted 1 hour, and reaction terminates, removed under reduced pressure 50mL
After solvent, there is fluffy solid generation, under nitrogen flowing filter gained fluffy solid, is dried in vacuo, get Sha Ku is than bent sodium salt
3.91g, yield 90%, chromatographic purity 99.1%.
Example 1：Sha Ku than bent sodium salt, Sha Ku than bent free acid and the eutectic object IV of acetic acid preparation
150mL dichloromethane is added in reaction bulb, Sha Ku stirs dissolved clarification, add than bent free acid grease 41.1g
Anhydrous sodium acetate 9.0g, is warming up to 30~35 DEG C of insulation reactions 1 hour, and heat preservation terminates, filtering.It is added in another reaction bulb
1500mL normal heptanes are cooled to 0~5 DEG C, at this temperature, by back filtering gained dichloromethane solution be slowly added dropwise to
In normal heptane, drop finishes, and 0~5 DEG C of control temperature keeps the temperature 1 hour.Filtering, decompressing and extracting obtain eutectic object IV 38g, yield 83%,
Chromatographic purity 99.3%.
It is parallel to take three parts of 1 gained eutectic objects of embodiment, the moisture of these eutectic objects is measured with karl Fischer Moisture Meter
Content is 0.15wt.%~0.30wt.%, and the mass percentage for being far unsatisfactory for hydrone there are one at least containing in eutectic object is wanted
It asks, it was demonstrated that the crystallization water is free of in the eutectic object molecular composition.As shown in Fig. 1, the nuclear magnetic resonance of eutectic object obtained by the present embodiment
Two hydrogen of the Sha Ku than bent methylene are represented in hydrogen spectrum at 4.00ppm, integral is 1.98；First in acetic acid is represented at 1.80ppm
3 hydrogen of base, integral are 1.48, therefore are calculated as Sha Ku than the ratio between bent and acetate 1.98/2 according to integral ratio:1.48/
3=2:1, i.e., husky library is 2 than the bent molar ratio with acetic acid in the eutectic object:1.
In addition, use Headspace Gas Chromatography method to measure acetic acid content in the eutectic object meets eutectic object IV for 6.58wt.%
In the Theoretical Percent content (6.55wt.%) containing 2 molecule acetic acid, 2 molecule acetic acid are contained in indirect proof eutectic object IV.
The following table 2 is the sodium ions content data that 1 gained eutectic object of embodiment is measured through atomic emission spectrometry (ICP), sample
Product 1 and 2 are respectively two parts of samples being obtained at random from 1 gained eutectic object of embodiment, every part of sample horizontal survey 3 times.As a result
It indicates that sodium ion average content is 3.69wt.% in 1 gained eutectic object of embodiment, calculates get Sha Ku than bent mole with sodium ion
Than being 4:3.
2 ICP atomic emission spectrometry replicate test result statistical forms of table
The powder x-ray diffraction spectrum of eutectic object obtained by the present embodiment is as shown in Fig. 2, wherein 2 angles θ of characteristic peak and opposite
Diffracted intensity see the table below 3：
Characteristic peak parameter shown in the X ray diffracting spectrum of 3 embodiment of table, 1 gained eutectic object
The fusing point of eutectic object obtained by the present embodiment is at 118-120 DEG C, and DCS peak values are 119.01 DEG C, specifically such as Fig. 3 institutes
Show.
Table 4 is the hygroscopicity contrast table of comparative example and 1 products therefrom of embodiment, by the table it is found that room temperature high humidity environment
Decentralization postpones, and eutectic object changes less in quality obtained by the application, and the husky library in comparative example is shown than bent sodium salt weightening 20%
Strong hygroscopicity is shown.
4 comparative example of table and 1 products therefrom of example hygroscopicity contrast table (indicated with compound by weight, 25 DEG C of environment temperature,
Relative humidity 75%)
Example 2：LCZ696 is prepared by eutectic object IV
The eutectic object IV (64g, 142mmol) prepared by 1 the method for embodiment is dissolved in isopropyl acetate 60mL and third
Valsartan (63g, 145mmol) is added after being warming up to 50~55 DEG C of stirring dissolved clarifications, then in this in the in the mixed solvent of ketone 1220mL
At a temperature of be added dropwise 142g sodium hydrate aqueous solution (10%, 355mmol) after, keep the temperature 2 hours at 40~45 DEG C, be then cooled to
(25~30 DEG C) of room temperature keeps the temperature 2 hours.It is warming up to 40 ± 3 DEG C after heat preservation, isopropyl acetate 600mL is added dropwise, drop finishes, in 40
± 3 DEG C keep the temperature 0.5 hour.Heat preservation terminates, 35 ± 5 DEG C of decompression abjection 760mL solvents of temperature control.It is de- to finish, 40 ± 3 DEG C are warming up to, drop
Isopropyl acetate 920mL, drop is added to finish, 40 ± 3 DEG C of temperature control keeps the temperature 0.5 hour.Heat preservation terminates, 35 ± 5 DEG C of decompression abjections of temperature control
1200mL solvents then heat to 40 ± 3 DEG C, and isopropyl acetate 1200mL is added dropwise, and drop finishes, and keeps the temperature 0.5 hour.Then temperature control 35
± 5 DEG C, decompression abjection 1200mL solvents.It is de- to finish, it is cooled to 20-25 DEG C and keeps the temperature 3 hours.Heat preservation crystallization terminates, and is filtered under diminished pressure, obtains
Wet product.Wet product 35 DEG C of temperature control in baking oven is dried under reduced pressure 12 hours to obtain LCZ696 finished product 116g, yield 85%, HPLC purity
99.94%.X-ray powder diffraction, the DSC data of gained LCZ696 is shown in Fig. 4, Fig. 5, is kissed with the data that Novartis Co., Ltd reports
It closes, crystal form is reported consistent with Novartis Co., Ltd.
Gained LCZ696 each component content datas see the table below：
| Sha Ku ratios Qu Hanliang | Valsartan content | Sodium ions content | Moisture | |
| Theoretical value | 42.8% | 45.3% | 7.2% | 4.7% |
| Measured value | 42.7% | 45.2% | 7.3% | 4.8% |
Claims (10)
1. a kind of eutectic object as shown in formula IV,
2. a kind of crystal form of the eutectic object as shown in formula IV, which is characterized in that the X-ray powder of the eutectic object with the crystal form
Difraction spectrum has the characteristic peak indicated below by 2 angles θ：5.3 ° ± 0.2 °, 10.6 ° ± 0.2 °, 19.9 ± 0.2 °, 20.8 ±
0.2°；
Preferably, the powder x-ray diffraction spectrum of the eutectic object with the crystal form is with the characteristic peak indicated below by 2 angles θ：
5.3 ° ± 0.2 °, 10.6 ° ± 0.2 °, 10.9 ° ± 0.2 °, 17.5 ± 0.2 °, 19.9 ± 0.2 °, 20.3 ± 0.2 °, 20.8 ±
0.2 °, 22.2 ± 0.2 °；
It is furthermore preferred that the powder x-ray diffraction spectrum of the eutectic object with the crystal form is with the feature indicated below by 2 angles θ
Peak：5.3 ° ± 0.2 °, 10.6 ° ± 0.2 °, 10.9 ° ± 0.2 °, 12.3 ° ± 0.2 °, 14.8 ° ± 0.2 °, 15.9 ° ± 0.2 °,
16.9 ° ± 0.2 °, 17.1 ° ± 0.2 °, 17.5 ° ± 0.2 °, 18.8 ° ± 0.2 °, 19.4 ° ± 0.2 °, 19.9 ° ± 0.2 °, 20.3 °
± 0.2 °, 20.8 ° ± 0.2 °, 21.6 ° ± 0.2 °, 21.9 ° ± 0.2 °, 22.2 ° ± 0.2 °, 26.9 ° ± 0.2 °, 27.3 ±
0.2 °, 27.7 ° ± 0.2 °.
3. crystal form according to claim 2, which is characterized in that the melting range of the eutectic object with the crystal form is 118~120
DEG C, DSC peak temperatures are 119.01 DEG C.
4. a kind of preparation method of the eutectic object with crystal form described in Claims 2 or 3, comprises the steps of：By husky library than bent
Free acid dissolves in methylene chloride, and sodium acetate is added and then filters and collect filtrate in 30~35 DEG C of insulation reactions, by institute
It states in filtrate added drop-wise to normal heptane, and crystallizes.
5. preparation method according to claim 4, which is characterized in that the time of the reaction be 0.5~2 hour, preferably 1
Hour.
6. preparation method according to claim 4 or 5, which is characterized in that by the positive heptan of the filtrate added drop-wise to 0~5 DEG C
In alkane；
Preferably, the crystallization carries out within the scope of 0~5 DEG C；
Preferably, further include the steps that by crystal filtration and or drying after the crystallization.
7. preparation method according to any one of claim 4 to 6, which is characterized in that the sand library is than bent and sodium acetate
Molar ratio is 1:(1.0~1.2), preferably 1:1.1；
Preferably, the husky library is 1mol than bent the ratio between the volume of molal quantity and dichloromethane:(1~2) L, preferably 1mol:
1.5L；
Preferably, the volume ratio of the dichloromethane and normal heptane is 1:(5~15), preferably 1:10.
8. purposes of the eutectic object according to claim 1 in preparing LCZ696.
9. with the purposes according to the eutectic object of crystal form described in Claims 2 or 3 in preparing LCZ696.
10. purposes according to claim 9, which is characterized in that the preparation LCZ696 is carried out using following methods：It will tool
The have the right eutectic object of the crystal form of requirement 2 or 3 is dissolved in the in the mixed solvent of isopropyl acetate and acetone, after the dissolved clarification that heats up plus
Enter Valsartan, the aqueous solution of sodium hydroxide is then added dropwise, a part of solvent is evaporated off after dripping off, then adds isopropyl acetate, it will
The step of solvent is evaporated off and adds isopropyl acetate operates 2~3 times repeatedly, and then cool down crystallization, and filtration drying obtains LCZ696；
It is furthermore preferred that the molar ratio of the eutectic object and Valsartan is 1:0.95~1.10, more preferred 1:1.05；
It is furthermore preferred that the molar ratio of the eutectic object and sodium hydroxide is 1:2.25~3.00, more preferred 2.5；
It is furthermore preferred that the crystallization at a temperature of 20~30 DEG C, carries out at a temperature of preferably 25 DEG C；
It is furthermore preferred that the solvent that is evaporated off is carried out using vacuum distillation；
It is furthermore preferred that described the step of solvent is evaporated off, carries out at a temperature of 35 ± 5 DEG C；It is described when adding isopropyl acetate, instead
It is 40 ± 3 DEG C to answer the temperature of system；
It is furthermore preferred that the step of respectively further comprising heat preservation after described the step of solvent is evaporated off and adds isopropyl acetate, more
It is 0.5 hour to add preferred soaking time.
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|---|---|---|---|
| CN201711450855 | 2017-12-27 | ||
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019127994A1 (en) * | 2017-12-27 | 2019-07-04 | 浙江天宇药业股份有限公司 | Sacubitril sodium salt, eutectic of sacubitril free acid and acetic acid, crystal form thereof, method for preparing crystal form, and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201810326D0 (en) * | 2018-06-22 | 2018-08-08 | Johnson Matthey Plc | Crystalline form of sacubitril, its preparation and use |
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| CN106977417A (en) * | 2016-01-15 | 2017-07-25 | 常州方楠医药技术有限公司 | One planting sand storehouse is than crystal formation of bent sodium salt and preparation method thereof |
| CN107082746A (en) * | 2017-03-23 | 2017-08-22 | 广州隽沐生物科技有限公司 | A kind of preparation method of AHU sodium salts crystal formation |
| CN107188820A (en) * | 2017-07-12 | 2017-09-22 | 浙江三门恒康制药有限公司 | One planting sand storehouse is than novel crystal forms of bent sodium salt and preparation method thereof |
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| US5217996A (en) * | 1992-01-22 | 1993-06-08 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
| WO2019127994A1 (en) * | 2017-12-27 | 2019-07-04 | 浙江天宇药业股份有限公司 | Sacubitril sodium salt, eutectic of sacubitril free acid and acetic acid, crystal form thereof, method for preparing crystal form, and use thereof |
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| CN105837464A (en) * | 2015-01-15 | 2016-08-10 | 四川海思科制药有限公司 | Sacubitril sodium crystal forms, preparation method and application thereof |
| WO2017009784A1 (en) * | 2015-07-14 | 2017-01-19 | Cadila Healthcare Limited | Solid state forms of trisodium salt of valsartan/sacubitril complex and sacubitril |
| WO2017097275A1 (en) * | 2015-12-11 | 2017-06-15 | Zentiva, K.S. | Solid forms of (2r,4s)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2- -methylpentanoic acid ethyl ester, its salts and a preparation method |
| CN106977417A (en) * | 2016-01-15 | 2017-07-25 | 常州方楠医药技术有限公司 | One planting sand storehouse is than crystal formation of bent sodium salt and preparation method thereof |
| WO2017191620A1 (en) * | 2016-05-06 | 2017-11-09 | Sun Pharmaceutical Industries Limited | A crystalline form of a salt of sacubitril and a process of its preparation |
| CN107082746A (en) * | 2017-03-23 | 2017-08-22 | 广州隽沐生物科技有限公司 | A kind of preparation method of AHU sodium salts crystal formation |
| CN107188820A (en) * | 2017-07-12 | 2017-09-22 | 浙江三门恒康制药有限公司 | One planting sand storehouse is than novel crystal forms of bent sodium salt and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019127994A1 (en) * | 2017-12-27 | 2019-07-04 | 浙江天宇药业股份有限公司 | Sacubitril sodium salt, eutectic of sacubitril free acid and acetic acid, crystal form thereof, method for preparing crystal form, and use thereof |
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| CN108530371B (en) | 2020-09-01 |
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