CN105884644A - Advantage forms and preparation method of neutral endopeptidase inhibitor salt - Google Patents
Advantage forms and preparation method of neutral endopeptidase inhibitor salt Download PDFInfo
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- CN105884644A CN105884644A CN201610069332.4A CN201610069332A CN105884644A CN 105884644 A CN105884644 A CN 105884644A CN 201610069332 A CN201610069332 A CN 201610069332A CN 105884644 A CN105884644 A CN 105884644A
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- 0 CCCCN*C Chemical compound CCCCN*C 0.000 description 4
- LKRITQZTTSBWKY-ZFXMFRGYSA-N C/C=C/NC(CCC(C(C)=[N]=C)=[U])=O Chemical compound C/C=C/NC(CCC(C(C)=[N]=C)=[U])=O LKRITQZTTSBWKY-ZFXMFRGYSA-N 0.000 description 1
- XOEKCMLZOZWUSW-CJRXIRLBSA-N CCOC([C@H](C)C[C@H](C)Cc(cc1)ccc1-c1ccccc1)=[U] Chemical compound CCOC([C@H](C)C[C@H](C)Cc(cc1)ccc1-c1ccccc1)=[U] XOEKCMLZOZWUSW-CJRXIRLBSA-N 0.000 description 1
- SRQOBNUBCLPPPH-UHFFFAOYSA-N CCc(cc1)ccc1-c1ccccc1 Chemical compound CCc(cc1)ccc1-c1ccccc1 SRQOBNUBCLPPPH-UHFFFAOYSA-N 0.000 description 1
- ZZLCFHIKESPLTH-UHFFFAOYSA-N Cc(cc1)ccc1-c1ccccc1 Chemical compound Cc(cc1)ccc1-c1ccccc1 ZZLCFHIKESPLTH-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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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 invention discloses advantage forms of compound 1 calcium salt. The effects of quantitative accuracy improvement, synthetic process simplification, production environment optimization and final product quality control are achieved through the advantages on the aspects of fluidity, stability, solubility and the like.
Description
Technical field
The invention belongs to medicinal chemistry art, particularly to the advantage form and preparation method thereof of a kind of neutral endopeptidase inhibitor salt.
Background technology
Compound 1, is a kind of neutral endopeptidase inhibitor (NEPi), and clinic has rush natruresis and diuresis.
Compound 2 is a kind of medicine for anti-heart failure researched and developed by Novartis Co., Ltd, the supramolecular complex (complex) that this compound is combined by non-covalent bond by valsartan and compound 1, has angiotensin receptor and blocks and neutral endopeptidase suppression dual function.Completed clinical trial results shows, compound 2 has the most clinical anti-heart failure effect of relatively enalapril, is a kind of great market potential cardiotonic agents.
In the method for disclosed synthesis compound 2, raw material can use the free acid of compound 1, it would however also be possible to employ the salt of compound 1.But owing to the free acid of compound 1 is difficult to preserve and be inconvenient to feed intake, its salt then embodies more stable physicochemical property, it is also beneficial to operation and the accuracy thereof fed intake, it is made to be particularly suited for producing, therefore the salt synthesis compound 2 using compound 1 in producing is a kind of more excellent selection, and calcium salt is i.e. one of conventional salt.
Chinese patent ZL200680001733.0 discloses the preparation method of a kind of compound 2, and wherein embodiment 3 uses the calcium salt of compound 1 to be that intermediate prepares compound 2, but and the calcium salt why form of undeclared described compound 1.
Chinese patent CN200780034141.3 discloses the preparation technology route of a kind of compound 1 calcium salt, but concrete preparation method is not disclosed, and compound 1 calcium salt using conventional method to prepare is mixed crystal, although may be used for subsequent production, but it is unfavorable for the optimization of the overall preparation technology of compound 2.And in pharmaceutical production, control using the beneficially reaction raising of dosing accuracy, the simplification of synthesis technique, the optimization of production environment, finished product quality of raw material advantage form etc..
Therefore the advantage form of compound 1 calcium salt of a kind of applicable compound 2 industrialized production is found, it is made to pass through the advantage of the aspects such as mobility, stability, dissolubility, the effects such as the control reaching the raising of dosing accuracy, the simplification of synthesis technique, the optimization of production environment, finished product quality, are the prior art technical issues that need to address.
Summary of the invention
It is an object of the invention to overcome the shortcoming of prior art, it is provided that a kind of advantage form of a kind of compound 1 calcium salt, it has the advantages such as dissolution velocity fast, good fluidity, good stability, is suitable for industrialized production compound 2.
The advantage form of compound 1 calcium salt of the present invention, its X-ray powder diffraction (XRD) spectrogram is as shown in Figure 1 or 2；Can be seen that, the XRD spectra of the advantage form of described compound 1 calcium salt does not embodies sharp-pointed absworption peak, it it is only the absorption that non-pointed occurs between 10～30 ° at 2 θ shift values, more specifically, described compound 1 calcium salt advantage form XRD spectra is the absorption occurring non-pointed between 15～25 ° at 2 θ shift values, meeting this area for unbodied definition, the advantage form of the most described compound 1 calcium salt is amorphous.
The advantage form of compound 1 calcium salt of the present invention, its DSC spectrogram display product fusing point/decomposition temperature near 227 DEG C, i.e. 227 ± 3 DEG C；Concrete, its DSC spectrogram 56.0 ± 3 DEG C, 126.7 ± 3 DEG C, 205.2 ± 3 DEG C, have endothermic peak at 227.2 ± 3 DEG C, in DSC spectrogram, 56.0 ± 3 DEG C, 126.7 ± 3 DEG C should be solvent endothermic peak, owing to described compound 1 calcium salt advantage form is amorphous, it will be appreciated by a person skilled in the art that in described compound 1 calcium salt advantage form DSC spectrogram, can there is bigger displacement fluctuation because of solvent species, the difference of testing conditions in solvent endothermic peak, even lacks；More specifically, compound 1 calcium salt advantage form of the present invention has DSC spectrogram as shown in Figure 3；
The advantage form of compound 1 calcium salt of the present invention, can be containing the free moisture content within 10%, as its TG spectrogram can be for shown in Fig. 4 or Fig. 5；
Comprehensive descision understands, and the advantage form of described compound 1 calcium salt is amorphous, and the moisture content that TG spectrogram embodies is free water, is conducive to removing the moisture content in product by extending drying time.
It is demonstrated experimentally that the present invention provide compound 1 calcium salt have compared with the more preferable solubility property of prior art, be presented as in use can reach faster molten clearly.Concrete, owing to producing compound 2, harshness is required for dicyandiamide solution, reaction condition, first have to compound 1 calcium salt clear in the exsolution of dicyandiamide solution middle reaches during production, if raw material is molten clear the most thoroughly bigger on the impact of subsequent reactions step.More specifically, the compound 1 calcium salt advantage form that the present invention provides, its every 100g sample free molten clear time in isopropyl acetate with HYDROCHLORIC ACID MIXED SOLVENT is within 10 minutes, time needed for prior art products, faster molten clear speed was conducive to the production of industrial compound 2 then more than 30 minutes.It addition, as amorphous, its stability and mobility all meet the industrialized production requirement for intermediate, are also beneficial to the quantitative of subsequent reactions.Knowable to comprehensive, the advantage form of described compound 1 calcium salt is more suitable in the industrialized production of compound 2 compared with compound 1 calcium salt of prior art.
Another object of the present invention is to provide the preparation method of the advantage form of a kind of compound 1 calcium salt, as follows:
The preparation method of the advantage form of a kind of compound 1 calcium salt, it is characterised in that described preparation method comprises following step:
(1) with A-1 as raw material, after esterification, obtain A-2, then react with succinic anhydride and prepare compound 1 (A-3)；
(2) compound 1 is dissolved in isopropyl acetate, instills the sodium hydrate aqueous solution of 1～1.2 equivalent 1N, at a temperature of less than 45 DEG C, stir into salt；
(3) separatory, merging aqueous phase；
(4) under room temperature to (2) gained aqueous phase at the uniform velocity, be slowly dropped into 0.15～0.25g/mL calcium chloride solution, the instillation time controls within 20min；
(5) filtering drying after the temperature of holding less than 70 DEG C stirs 0.5-24 hour with rotating speed for 150-250r/min, obtains the advantage form of compound 1 calcium salt.
After being acidified by compound 1 calcium salt obtained as above, repeat the above steps can improve compound 1 calcium salt purity further, and the form of gained compound 1 calcium salt is constant.
Concrete, in above-mentioned preparation process, described equivalent is all to calculate relative to the consumption of A-2 in above-mentioned steps (1).
In above-mentioned steps (2), the purpose adding sodium hydrate aqueous solution is to make compound 1 become sodium salt, and the sodium hydrate aqueous solution adding 1～1.2 equivalent 1N (1mol/L) is conducive to compound 1 fully to become salt, and will not hydrolyze.
In above-mentioned steps (4), the saturation of solution system is maintained the scope beneficially separated out with amorphous form by the calcium chloride solution instilling 0.15～0.25g/mL, and the amount of described calcium chloride is preferably 0.5～1.0 equivalents.
In above-mentioned steps (5), the temperature of crystallize all can prepare described advantage form below 70 DEG C, and as temperature can elect room temperature or 70 DEG C as, described room temperature is 25 ± 5 DEG C；Product is conducive to uniformly to separate out with rotating speed for 150-250r/min stirring, it is preferred that described rotating speed is 180r/min.
This preparation method ensure that the calcium salt of compound 1 uniformly separates out on the whole, and the calcium salt purity of gained compound 1 is high, form is uniform, and reaction yield, response time are in more excellent level.
The present invention has such advantages as relative to prior art and beneficial effect:
1, providing the advantage form of a kind of compound 1 calcium salt, this advantage form is amorphous, it has beneficial effects such as free speed is fast, purity is high, stability is high, good fluidity.
2, providing the preparation method of a kind of compound 1 calcium salt advantage form, the method can be accomplished scale production the advantage form of described compound 1 calcium salt.
Accompanying drawing explanation
The XRD spectra of Fig. 1 embodiment 2 gained compound 1 calcium salt advantage form
The XRD spectra of Fig. 2 embodiment 3 gained compound 1 calcium salt advantage form
Fig. 3 embodiment 2, the DSC spectrogram of embodiment 3 gained compound 1 calcium salt advantage form
The TG spectrogram of Fig. 4 embodiment 2 gained compound 1 calcium salt advantage form
The TG spectrogram of Fig. 5 embodiment 3 gained compound 1 calcium salt advantage form
The HPLC spectrogram of Fig. 6 embodiment 2 gained compound 1 calcium salt advantage form
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but the embodiment of invention is not limited to this.
In following example:
X-ray powder diffraction uses sharp shadow (Empyrean) X-ray diffractometer equipment Inspection, testing conditions: Cu target K alpha ray, voltage 40KV, electric current 40mA, launches slit 1/32 °, antiscatter slits 1/16 °, antiscatter slits 7.5mm, 2 θ scopes: 3 °-40 °, step-length 0.02 °, often step time of staying 40s.
Differential scanning calorimetry spectrogram uses Germany's NETZSCH company DSC204F1 differential scanning calorimeter equipment Inspection, testing conditions: atmosphere: N2, 20mL/min；Scanning imaging system: be warming up to 250 DEG C with 10 DEG C/min from room temperature, records heating curve.
Water content uses Germany's NETZSCH company's T G209 thermogravimetric analyzer equipment Inspection, testing conditions: atmosphere: N2, 20mL/min；Scanning imaging system: room temperature-500 DEG C, heating rate: 10 DEG C/min.
Embodiment 1
The preparation of compound 1 (A-3)
Under room temperature, A-1 (15g) is dissolved in 150ml dehydrated alcohol；It is heated to 60 DEG C, after being slowly added dropwise 8.5ml thionyl chloride, is warming up to 70 DEG C of reaction 2h；Decompression distillation, obtains white solid, and after adding 150ml normal heptane, decompression removes the volume of half, and pull an oar under ice bath 20min；Filtering, solid normal heptane rinses, and 30 DEG C of dry 10h obtain white solid (A-2) 13.4g.
Under room temperature, 13.4g A-2 is equipped with the flask of 250ml isopropyl acetate (IPAC)；Being sequentially added into 11.7g (16ml) triethylamine and 4.9g succinic anhydride, normal-temperature reaction consumes completely to A-2；Directly filtering, filter cake IPAC washes, the faint yellow thick liquid 22g (A-3) of merging filtrate decompression.
Embodiment 2
The preparation of compound 1 calcium salt (A-5) advantage form
Under room temperature, the 22g A-3 prepared according to embodiment 1 method is dissolved in 200ml IPAC；Drip 1.2 equivalents (relative to A-2) sodium hydrate aqueous solution (1N), be stirred at room temperature to fully becoming salt；Separatory, combining water layer (about 80ml)；
Under room temperature, the aqueous solution containing A-4 being added bis-mouthfuls of bottles of 250ml, the most at the uniform velocity drip calcium chloride water (3.6g calcium chloride is dissolved in 20ml water), 10min drips complete, stirs 3 hours with rotating speed for 180r/min under room temperature；Filter, filter cake wash with water after again at 30 DEG C vacuum decompression dry 6h, obtain compound 1 calcium salt (A-5) advantage form 21g.After testing, its XRD spectra as it is shown in figure 1, DSC spectrogram as it is shown on figure 3, its TG spectrogram as shown in Figure 4.HPLC spectrogram (Fig. 6) shows, its purity of gained is 98.6%.
Embodiment 3
The preparation of compound 1 calcium salt (A-5) advantage form.
The 22g A-3 prepared according to embodiment 1 method is dissolved in 200ml IPAC；Dripping 1.1 equivalents (relative to A-2) sodium hydrate aqueous solution (1N) under ice bath, 40 DEG C of stirrings are to fully becoming salt；Separatory, combining water layer；The most at the uniform velocity dripping calcium chloride water (3.1g calcium chloride is dissolved in 20ml water) toward the aqueous solution containing A-4 after being warming up to 70 DEG C, 8min drips complete, is warming up to 70 DEG C and stirs 2 hours for 180r/min with rotating speed；Filtering after being cooled to 50 DEG C, filter cake washes rear nitrogen purging 1h with water, and at 80 DEG C, vacuum decompression dries 48h, obtains compound 1 calcium salt (A-5) advantage form 18g (purity 99.2%).After testing, its XRD spectra as in figure 2 it is shown, DSC spectrogram as it is shown on figure 3, its TG spectrogram as shown in Figure 5.
It can be seen that the stability of described advantage form is high, meet this area requirement for intermediate quality；It addition, extend drying time, improve the free water dried in temperature beneficially removing product.
Embodiment 4
The preparation of compound 1 calcium salt (A-5) advantage form
The 22g A-3 prepared according to embodiment 1 method is dissolved in 200ml IPAC；Dripping 1 equivalent (relative to A-2) sodium hydrate aqueous solution (1N) under ice bath, 35 DEG C of stirrings are to fully becoming salt；Separatory, combining water layer；The most at the uniform velocity dripping calcium chloride water (3.3g calcium chloride is dissolved in 20ml water) toward the aqueous solution containing A-4 under room temperature, 15min drips complete, is warming up to 60 DEG C and stirs 3 hours for 200r/min with rotating speed；Filtering after being cooled to 50 DEG C, filter cake washes rear nitrogen purging 1h with water, and at 60 DEG C, vacuum decompression dries 50h, obtains compound 1 calcium salt (A-5) advantage form 16g (purity 99.3%).
After testing, products obtained therefrom is identical with embodiment 2 products obtained therefrom.
Embodiment 5
The preparation of compound 1 calcium salt (A-5) advantage form
The 22g A-3 prepared according to embodiment 1 method is dissolved in 200ml IPAC；Dripping 1.1 equivalents (relative to A-2) sodium hydrate aqueous solution (1N) under ice bath, 40 DEG C of stirrings are to fully becoming salt；Separatory, combining water layer；The most at the uniform velocity dripping calcium chloride water (3.1g calcium chloride is dissolved in 20ml water) toward the aqueous solution containing A-4 after being warming up to 50 DEG C, 10min drips complete, stirs 5 hours with rotating speed for 250r/min；Filtered while hot, filter cake washes rear nitrogen purging 1h with water, and at 80 DEG C, vacuum decompression dries 56h, obtains compound 1 calcium salt (A-5) advantage form 21g (purity 97.9%).
After testing, products obtained therefrom is identical with embodiment 2 products obtained therefrom.
Embodiment 6
According to patent CN200780034141.3 process route chart, prepare compound 1 calcium salt (purity 99.3%) according to conventional reaction condition.
Take 100g patented product and the product prepared according to embodiment 2 and embodiment 3 method respectively, the synthesis technique of simulated compound 2, the hydrochloric acid of the 2N (2mol/L) being equivalent to compound 14 equivalents of calcium salt it is slowly added dropwise after i.e. adding 1L isopropyl acetate under room temperature, and record it and dissociate the molten clear time, as follows:
| Sample | The molten clear time |
| CN200780034141.3 product | >30min |
| Embodiment 2 | ≤10min |
| Embodiment 3 | ≤10min |
It can be seen that under the same terms the molten clear time of this patent product be significantly shorter than prior art products obtained therefrom, and becoming apparent from more greatly of embodying (in 5 kilograms and the other production of higher level) in industrialization large-scale production of the gap of this molten clear time.
Further finding in detection, the mobile performance of this patent product is also substantially better than CN200780034141.3 product.
Embodiment 7
Detection of Stability
Compound 1 calcium salt (purity 99.3%) that will prepare according to patent CN200780034141.3 process route chart in embodiment 4, and the product that foundation embodiment 2 and embodiment 3 method prepare stores 3 months under 60 DEG C of high temperature, gained stability result is as follows:
| Sample | Purity (0 day) | Purity (3 months) |
| CN200780034141.3 product | 99.3% | 94.9% |
| Embodiment 2 | 98.6% | 97.5% |
| Embodiment 3 | 99.2% | 98.0% |
It can be seen that the storage stability that this patent product is under the high temperature conditions is apparently higher than prior art products, it is known that this patent product relatively prior art products is more suitable for industrialized production.
Above-described embodiment is the present invention preferably embodiment; but embodiments of the present invention are also not restricted to the described embodiments; the change made under other any spirit without departing from the present invention and principle, modify, substitute, combine, simplify; all should be the substitute mode of equivalence, within being included in protection scope of the present invention.
Claims (11)
1. the advantage form of the compound being shown below 1 calcium salt, it is characterised in that the XRD spectra of the advantage form of described compound 1 calcium salt does not embodies sharp-pointed absworption peak.
The advantage form of compound 1 calcium salt the most according to claim 1, it is characterised in that the XRD spectra of the advantage form of described compound 1 calcium salt is the absorption occurring non-pointed between 10～30 ° at 2 θ shift values.
3. according to the advantage form of compound 1 calcium salt described in claim 1 or 2 any one, it is characterised in that the XRD spectra of the advantage form of described compound 1 calcium salt is the absorption occurring non-pointed between 15～25 ° at 2 θ shift values.
4. according to the advantage form of compound 1 calcium salt described in claim 1-3 any one, it is characterised in that the XRD spectra of the advantage form of described compound 1 calcium salt is as shown in Figure 1 or 2.
5. according to the advantage form of compound 1 calcium salt described in claim 1-4 any one, it is characterised in that the fusing point of the advantage form of described compound 1 calcium salt or decomposition temperature are at 227 ± 3 DEG C.
6. according to the advantage form of compound 1 calcium salt described in claim 1-5 any one, it is characterised in that the DSC spectrogram of the advantage form of described compound 1 calcium salt has endothermic peak at 205.2 ± 3,227.2 ± 3 DEG C.
The advantage form of compound 1 calcium salt the most according to claim 6, it is characterised in that the DSC spectrogram of the advantage form of compound 1 calcium salt also has endothermic peak at 56.0 ± 3,126.7 ± 3 DEG C.
8. according to the advantage form of compound 1 calcium salt described in claim 1-7 any one, it is characterised in that the advantage form of described compound 1 calcium salt has DSC spectrogram as shown in Figure 3.
9. the preparation method of the advantage form of compound 1 calcium salt as described in claim 1-8 any one, it is characterised in that it is characterized in that described preparation method comprises following step:
(1) with A-1 as raw material, after esterification, obtain A-2, then react with succinic anhydride and prepare compound 1；
(2) compound 1 is dissolved in isopropyl acetate, instills the sodium hydrate aqueous solution of 1～1.2 equivalent 1N, at a temperature of less than 45 DEG C, stir into salt；
(3) separatory, merging aqueous phase；
(4) under room temperature to (2) gained aqueous phase at the uniform velocity, be slowly dropped into 0.15～0.25g/mL calcium chloride solution, the instillation time controls within 20min；
(5) filtering drying after the temperature of holding less than 70 DEG C stirs 0.5-24 hour with rotating speed for 150-250r/min, obtains the advantage form of compound 1 calcium salt.
The preparation method of the advantage form of compound 1 calcium salt the most according to claim 9, it is characterised in that the mixing time in described step (4) is 2-5 hour.
11. according to the preparation method of the advantage form of compound 1 calcium salt described in claim 9 or 10 any one, it is characterised in that the temperature in described step (5) is room temperature, and rotating speed is 180r/min, and mixing time is 2-5 hour.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015100837063 | 2015-02-15 | ||
| CN201510083706 | 2015-02-15 | ||
| CN201510170158 | 2015-04-10 | ||
| CN2015101701588 | 2015-04-10 |
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| CN105884644A true CN105884644A (en) | 2016-08-24 |
| CN105884644B CN105884644B (en) | 2020-06-09 |
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| CN201610069332.4A Active CN105884644B (en) | 2015-02-15 | 2016-02-01 | Neutral endopeptidase inhibitor salt dominant form and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106496055A (en) * | 2016-10-09 | 2017-03-15 | 杭州科巢生物科技有限公司 | A kind of key component sand storehouse of anti-heart failure new drug is than bent novel synthesis |
| 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 |
| CN107188817A (en) * | 2017-05-22 | 2017-09-22 | 杭州瑞法康科技有限公司 | A kind of husky storehouse of high-purity is than novel crystal forms of bent half calcium salt monohydrate and preparation method thereof |
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| CN101098689A (en) * | 2005-11-09 | 2008-01-02 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an nep inhibitor |
| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
| 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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- 2016-02-01 CN CN201610069332.4A patent/CN105884644B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098689A (en) * | 2005-11-09 | 2008-01-02 | 诺瓦提斯公司 | Pharmaceutical combinations of an angiotensin receptor antagonist and an nep inhibitor |
| CN101516831A (en) * | 2006-09-13 | 2009-08-26 | 诺瓦提斯公司 | Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors |
| 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106496055A (en) * | 2016-10-09 | 2017-03-15 | 杭州科巢生物科技有限公司 | A kind of key component sand storehouse of anti-heart failure new drug is than bent novel synthesis |
| 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 |
| CN107188817A (en) * | 2017-05-22 | 2017-09-22 | 杭州瑞法康科技有限公司 | A kind of husky storehouse of high-purity is than novel crystal forms of bent half calcium salt monohydrate and preparation method thereof |
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| CN105884644B (en) | 2020-06-09 |
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