CN112374999A - Preparation method of impurity compound for defluorination of cinacalcet hydrochloride - Google Patents
Preparation method of impurity compound for defluorination of cinacalcet hydrochloride Download PDFInfo
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Abstract
The invention relates to the technical field of organic synthesis, and provides a preparation method of a defluorinated impurity of cinacalcet hydrochloride. The method comprises the following steps: the cinacalcet hydrochloride intermediate reacts with a reducing agent in an organic solvent, and the defluorinated impurity crude product obtained by post-treatment of a reaction system is subjected to column chromatography separation and salification to obtain the high-purity defluorinated impurity. The synthesis method can realize the synthesis of the defluorinated impurity compound of the cinacalcet hydrochloride, and has great promotion effects on deeply researching related substances of the cinacalcet hydrochloride, improving the medication safety, reliability and stability of related preparations and controlling the quality of raw medicines and related preparations in the production process.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of a desflurinated impurity compound of cinacalcet hydrochloride.
Background
Cinacalcet hydrochloride is a calcimimetic developed by NPS Pharmaceuticals, usa, and activates calcium receptors in parathyroid glands, thereby reducing secretion of parathyroid hormone (PTH). For use in the treatment of secondary hyperparathyroidism in Chronic Kidney Disease (CKD) patients undergoing dialysis.
The impurity content of a drug is an important criterion for the effectiveness and safety of a drug. Impurities present in the drug directly affect the efficacy of the drug and may lead to non-therapeutically active toxic side effects that must be controlled. It has been found that a particular impurity is produced during the preparation of cinacalcet hydrochloride: (R) -3- (3- (difluoromethyl) phenyl) -N- (1- (naphthyl-1-yl) ethyl) propan-1-amine inorganic acid salt is a defluorinated impurity compound of cinacalcet hydrochloride, and a synthetic method is not reported in documents, and the chemical structural formula is as follows:
in order to control the impurity content of the drug, i.e. limit the impurity content within a certain range, a proper impurity standard substance must be selected in the process of drug quality analysis. The impurity of the hydrochloric acid cinacalcet defluorination is not sold in the market at present, and the compound can only be synthesized.
The synthesis of the compound containing difluoromethyl is always difficult in the related field, and the related difluoromethyl substrate can be obtained only by introducing a specific difluoromethyl-containing structural unit through a specific reaction and then converting the specific difluoromethyl-containing structural unit through a specific mode, so that the preparation method is difficult. Such as: in 2017, Schmitt et al reported the difluoromethylation of SP3 carbon using CHF3 as the difluoromethylating agent, and the use of CHF3 in the process required the difluoromethylation of the substrate in a gas-liquid continuous flow operation. In 2017, the shin-shin topic group reported a nickel-catalyzed cross-coupling reaction of metal nickel-catalyzed aromatics with BrCF2H, but required the use of dangerous nickel, and BrCF2H was prone to difluorocarbene side reactions. In 2017, while the Kamaziri project group used TMSCF2H for the oxydifluoromethylation reaction, expensive catalyst was required, and TMSCF2H itself was difficult to prepare. In the related structure of cinacalcet hydrochloride, no report on the transformation of common trifluoromethyl compounds is found.
Disclosure of Invention
Against the background, the invention aims to provide a preparation method of a cinacalcet hydrochloride defluorinated impurity compound, wherein a common trifluoromethyl compound is selected, and reagents used in the preparation are easy to obtain. The specific technical scheme is as follows.
The designed synthetic route is as follows:
a process for the preparation of a desflurinated impurity compound of cinacalcet hydrochloride, said process comprising the steps of:
a. under the action of a reducing agent, N- ((1)R) -1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) propionamide) is dissolved in an organic solvent to carry out reduction and defluorination reaction;
b. quenching and post-treating the reaction solution to obtain (A), (B)R) -crude 3- (3- (difluoromethyl) phenyl) -N- (1- (naphthalen-1-yl) ethyl) propan-1-amine;
c. separating the crude product obtained in the previous step by column chromatography to obtain high purity (C)R) -3- (3- (difluoromethyl) phenyl) -N- (1- (naphthalen-1-yl) ethyl) propan-1-amine;
d. dissolving the high-purity product obtained in the previous step in an organic solvent to react with inorganic acid to form salt, (b)R) -3- (3- (difluoromethyl) phenyl) -N- (1- (naphthalen-1-yl) ethyl) propan-1-amine mineral acid salt.
Further, according to the preparation method of the defluorination impurity of cinacalcet hydrochloride, the reaction temperature in the step a is-10 ℃; the quenching temperature in the step b is-10-30 ℃, and the salt forming temperature in the step d is 0-30 ℃.
Further, in the above method for preparing the cinacalcet hydrochloride defluorinated impurity compound, the reducing agent used in the step a is one or more of lithium aluminum hydride, potassium aluminum hydride, sodium dihydro-bis (2-methoxyethoxy) aluminate or diisobutyl aluminum hydride.
Further, in the preparation method of the impurity compound for defluorination of cinacalcet hydrochloride, the molar ratio of the reducing agent to the cinacalcet hydrochloride intermediate in the step a is (5.0-10.0): 1.
further, in the preparation method of the impurity compound for defluorination of cinacalcet hydrochloride, the reaction time in the step a is 24-96 hours.
Further, in the preparation method of the impurity compound defluorinated with cinacalcet hydrochloride, the molar ratio of the salifying acid to the cinacalcet hydrochloride intermediate in the step d is (1.0-1.5): 1.
further, in the preparation method of the impurity compound for defluorination of cinacalcet hydrochloride, the salt forming reaction time in the step d is 0.5-2 hours.
Further, in the above method for preparing the impurity compound by defluorination of cinacalcet hydrochloride, the reducing agent in step a is selected from one or more of lithium aluminum hydride, potassium aluminum hydride, sodium dihydro-bis (2-methoxyethoxy) aluminate and diisobutyl aluminum hydride.
Further, in the above method for preparing the impurity compound by defluorination of cinacalcet hydrochloride, the organic solvent in step a is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and toluene.
Further, in the above method for preparing the cinacalcet hydrochloride defluorinated impurity compound, the quenching agent used in the step b is one or more selected from ice water, acetic acid, aqueous acetic acid solution, aqueous hydrochloric acid solution, aqueous phosphoric acid solution and aqueous sulfuric acid solution.
Further, in the preparation method of the cinacalcet hydrochloride defluorinated impurity compound, the column chromatography solvent in the step c is one or two selected from ethyl acetate, n-hexane and n-heptane.
Further, in the preparation method of the impurity compound defluorinated with cinacalcet hydrochloride, the salt-forming organic solvent in the step d is one or two selected from methyl tert-butyl ether, ethyl acetate, dichloromethane and toluene.
Further, the preparation method of the defluorinated impurity of cinacalcet hydrochloride comprises the following specific steps:
a. the molar ratio is (5.0-10.0): 1 with cinacalcet hydrochloride intermediate: (N- ((1)R) Mixing-1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) propionamide) in an organic solvent, controlling the temperature to be-10 ℃, stirring and reacting for 24-96 h,
b. dropwise adding the reaction liquid into an ice water system with the weight ratio of 10-30 times, quenching, stirring in an ice bath for 0.5-2.0 h after adding, filtering, washing a filter cake with methyl tert-butyl ether, separating liquid, and using methyl tert-butyl for a water layer
Extracting with ether, combining the organic layers, and concentrating under reduced pressure at 35-55 deg.C to obtainR) -3- (3- (difluoromethyl) phenyl) -N- (1- (naphthyl-1-yl) ethyl) propan-1-amine crude product.
c. And (3) separating the crude product obtained in the previous step by column chromatography to obtain a high-purity product, wherein the chromatography solvent is one or more selected from ethyl acetate, n-hexane and n-heptane.
d. And (2) adding the high-purity product obtained in the previous step into an organic solvent, adding 1.0-1.5 eq of inorganic acid at 0-30 ℃ to form salt for about 0.5-2 hours, filtering, and drying in vacuum to obtain a refined (R) -3- (3- (difluoromethyl) phenyl) -N- (1- (naphthyl-1-yl) ethyl) propan-1-amine inorganic acid salt. Furthermore, the impurity compound obtained by the preparation method can be used as a reference substance or used for controlling the quality of cinacalcet hydrochloride.
The invention has the beneficial effects that.
1. Provides a reliable preparation method for obtaining a reference substance of high-purity cinacalcet hydrochloride defluorinated impurities. The purity of the liquid phase reaches 95 percent.
2. Under the condition that no impurity of the hydrochloric acid cinacalcet is sold in the market at present, a convenient and reliable acquisition way is provided for the research of the impurity of the hydrochloric acid cinacalcet. The synthetic reaction material is easy to obtain, the material cost is low, the cost of impurity preparation is greatly reduced, and the method has a great promotion effect on the further research on the safety, reliability and stability of cinacalcet hydrochloride in medicine and the quality control in the production process.
3. The method has an active guiding function on the consistency evaluation of the localization of cinacalcet hydrochloride.
Description of the drawings.
FIG. 1: the liquid phase map of the depluorinated impurity of cinacalcet hydrochloride synthesized in the example 1 of the invention.
FIG. 2: the mass spectrum of the depluorinated impurity of the cinacalcet hydrochloride synthesized in the embodiment 1 of the invention.
FIG. 3: the hydrogen spectrum of the depluorinated impurity of the cinacalcet hydrochloride synthesized in the embodiment 1 of the invention.
FIG. 4: the heavy water exchange hydrogen spectrum of the depluorinated impurity of the cinacalcet hydrochloride synthesized in the embodiment 1 of the invention.
The specific implementation mode is as follows:
the following specific examples, which are provided in connection with the reaction scheme for the preparation of the desflurinated impurity compound of cinacalcet hydrochloride described in the present invention, are intended to further illustrate the preparation process of the present invention and are not to be construed as limiting the invention.
Example 1
a. To a 250ml single-neck bottle was added 10g of cinacalcet hydrochloride intermediate (N- ((1)R) -1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) propionamide), 80g tetrahydrofuran, and cooling to 0-5 ℃ in an ice bath under the protection of nitrogen. 9.1g of LiAlH4 was added slowly and the reaction was warmed to reflux for 72 hours.
b. Cooling to 5-15 deg.C, adding into 100g ice water bath, quenching, and stirring for 1 hr. Filtering, washing with 20g of methyl tert-butyl ether, separating, adding 20g of methyl tert-butyl ether into an aqueous layer, washing, separating, combining organic layers, and concentrating under reduced pressure at 40 ℃ until the organic layers are dried to obtain a light brown oily crude product.
c. And (3) performing column chromatography separation, wherein an eluent is ethyl acetate: n-ethane =1:8, giving 0.8g of oil.
d. Adding 10g of methyl tert-ether for dissolving, dropwise adding 0.3g of hydrochloric acid, separating out the solid, filtering, and drying to obtain 0.86g of off-white solid, namely the defluorinated cinacalcet hydrochloride impurity with the purity of HPLC impurity of 95%, wherein the HPLC spectra, mass spectrum spectra and hydrogen spectrum spectra of the attached figures 1, 2 and 3 are respectively shown in the figure.
Example 2
a. To a 250ml single-neck bottle was added 8g of cinacalcet hydrochloride intermediate (N- ((1)R) -1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) propionamide), 100g of 2-methyltetrahydrofuran, and cooling to 0-5 ℃ in an ice bath under the protection of nitrogen. 10.0g of potassium aluminum hydride was slowly added thereto, and the mixture was heated to reflux for 64 hours.
b. Cooling to 5-15 deg.C, adding into 100g ice water bath, quenching, and stirring for 1 hr. Filtration, 16g
Washing with methyl tert-butyl ether, separating, adding 16g of methyl tert-butyl ether into the water layer, washing with liquid, separating, combining the organic layers, and concentrating under reduced pressure at 40 ℃ until the organic layers are dried to obtain a light brown oily crude product.
c. And (3) performing column chromatography separation, wherein an eluent is ethyl acetate: n-ethane =1:10, yielding 0.6g of oil.
d. And adding 10g of methyl tertiary ether for dissolving, dropwise adding 0.25g of sulfuric acid, separating out solids, filtering, and drying to obtain 0.64g of off-white solids, namely the desflurinated impurity sulfate of cinacalcet.
Example 3
a. To a 250ml single-neck bottle was added 10g of cinacalcet hydrochloride intermediate (N- ((1)R) -1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) propionamide), 100g dichloromethane, and cooling to 0-5 ℃ in an ice bath under the protection of nitrogen. 15.0g of sodium dihydro-bis (2-methoxyethoxy) aluminate are slowly added and the reaction is brought to reflux for 70 hours.
b. Cooling to 5-15 deg.C, adding 100g of ice-acetic acid aqueous solution, quenching, and stirring for 1h in ice bath. Filtering, washing with 20g of methyl tert-butyl ether, separating, adding 20g of methyl tert-butyl ether into an aqueous layer, washing, separating, combining organic layers, and concentrating under reduced pressure at 40 ℃ until the organic layers are dried to obtain a light brown oily crude product.
c. And (3) performing column chromatography separation, wherein an eluent is ethyl acetate: n-heptane =1:8, giving 0.9g of oil.
d. And adding 10g of methyl tert-ether for dissolving, dropwise adding 0.36g of hydrochloric acid, separating out a solid, filtering, and drying to obtain 0.8g of a white-like solid, namely the defluorinated impurity of cinacalcet hydrochloride.
Example 4
a. To a 250ml single neck bottle was added 12g of cinacalcet hydrochloride intermediate (N- ((1)R) -1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) propionamide), 100g toluene, and cooling to 0-5 ℃ in an ice bath under the protection of nitrogen. Slowly add 20g of diisobutylaluminum hydride, and the reaction mixture was heated to reflux for 72 hours.
b. Cooling to 5-15 deg.C, adding 100g ice water, quenching, and stirring in ice bath for 1 h. Filtering, washing with 20g of methyl tert-butyl ether, separating, adding 20g of methyl tert-butyl ether into an aqueous layer, washing, separating, combining organic layers, and concentrating under reduced pressure at 40 ℃ until the organic layers are dried to obtain a light brown oily crude product.
c. And (3) performing column chromatography separation, wherein an eluent is ethyl acetate: n-heptane =1:10, yielding 1.0g of oil.
d. And adding 10g of methyl tertiary ether for dissolution, dropwise adding 0.30g of phosphoric acid, separating out a solid, filtering, and drying to obtain 0.72g of a white-like solid, namely the desflurinated impurity phosphate of cinacalcet.
Example 5
The structure of the defluorinated impurity cinacalcet hydrochloride obtained in example 1 was confirmed by analyzing the hydrogen spectrum and mass spectrum, respectively.
(1) Nuclear magnetic resonance spectroscopy hydrogen spectroscopy
Instrument model and test condition
The instrument model is as follows: INOVA 300 model nuclear magnetic resonance spectrometer
And (3) testing conditions are as follows: deuterated DMSO (solvent); TMS (internal standard)
Hydrogen spectrum data and analysis result
A. Chemical structural formula labeled with atomic position:
B. test data and attribution
TABLE 1 NMR data and affiliation of test samples
③ analysis
The nuclear magnetic resonance hydrogen spectrum shows that the structure of the test sample conforms to the structure of the defluorinated impurity of the cinacalcet hydrochloride.
(2) Mass spectrometry
Instrument model
Waters Xevo TQ
② test conditions
An ion source: ESI
Scanning range: 50-1000m/z
Third test data and attribution
Table 2 main data and attribution of mass spectrometric test of test article
Analysis: the resolution mass spectrum data show that the molecular weight of the sample conforms to the defluorinated impurity structure of the cinacalcet hydrochloride.
(3) Conclusion
Firstly, the high-resolution mass spectrum of a sample confirms that the formula weight of M + H excimer ions is M/z =340.16, and the sample conforms to the structure of defluorination impurities of cinacalcet hydrochloride;
② 1H-NMR spectrum confirms that the hydrogen atom type and position of the sample are consistent with the defluorination impurity structure of cinacalcet hydrochloride.
In summary, the following steps: the structure of the test sample is consistent with the structure of defluorination impurity of cinacalcet hydrochloride. The method successfully prepares the high-purity cinacalcet hydrochloride defluorination impurity, provides a convenient and reliable acquisition way for the research of the cinacalcet hydrochloride defluorination impurity, and has great promotion effect on the more deep research of the quality of cinacalcet hydrochloride and the related medication safety, reliability, stability and quality control in the production process.
It is to be understood that the above description is not intended to limit the present invention, and the present invention is not limited to the above examples, and those skilled in the art may make modifications, hairstyles, additions and substitutions within the spirit and scope of the present invention.
Claims (9)
1. A kind ofA preparation method of a impurity compound for defluorination of cinacalcet hydrochloride, wherein the impurity compound is (A)R) -3- (3- (difluoromethyl) phenyl) -N- (1- (naphthalen-1-yl) ethyl) propan-1-amine hydrochloride, said process comprising the steps of:
a. under the action of a reducing agent, (N- ((1)R) -1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) propionamide) is dissolved in an organic solvent to carry out reduction and defluorination reaction;
b. quenching and post-treating the reaction solution to obtain (A)R) -crude 3- (3- (difluoromethyl) phenyl) -N- (1- (naphthalen-1-yl) ethyl) propan-1-amine;
c. high purity (obtained by column chromatography of the crude product obtained in the above step)R) -3- (3- (difluoromethyl) phenyl) -N- (1- (naphthalen-1-yl) ethyl) propan-1-amine;
d. dissolving the chromatographic product obtained in the previous step in an organic solvent to react with inorganic acid to form salt, (a)R) -3- (3- (difluoromethyl) phenyl) -N- (1- (naphthalen-1-yl) ethyl) propan-1-amine mineral acid salt.
2. The method of claim 1, wherein the reducing agent in step a is selected from one or more of lithium aluminum hydride, potassium aluminum hydride, sodium dihydro-bis (2-methoxyethoxy) aluminate, or diisobutyl aluminum hydride.
3. The method according to claim 1, wherein the organic solvent in step a is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and toluene.
4. The method of claim 1, wherein the quenching in step b is performed by one or more quenching agents selected from ice water, acetic acid, aqueous acetic acid solution, aqueous hydrochloric acid solution, aqueous phosphoric acid solution and aqueous sulfuric acid solution.
5. The preparation method of claim 1, wherein the column chromatography is performed in step c, and the solvent is one or two selected from ethyl acetate, n-hexane and n-heptane.
6. The method according to claim 1, wherein the organic solvent in step d is one or two selected from the group consisting of methyl tert-butyl ether, ethyl acetate, dichloromethane and toluene.
7. The method according to claim 1, wherein the inorganic acid in step d is one selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid.
8. The preparation method of claim 1, which specifically comprises the steps of:
a. the molar ratio is (5.0-10.0): 1 with (N- ((1)R) Dissolving-1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) propionamide) in an organic solvent, controlling the temperature to be-10 ℃, and stirring for reacting for 24-96 h;
b. dropwise adding 10-30 times of a quenching agent into the reaction solution, stirring for 0.5-2.0 h in an ice bath after the addition is finished, filtering, washing a filter cake with methyl tert-butyl ether, separating liquid, extracting a water layer with methyl tert-butyl ether, combining organic layers, and performing filtration on the mixture
Concentrating under reduced pressure at 35-55 ℃: (R) -crude 3- (3- (difluoromethyl) phenyl) -N- (1- (naphthalen-1-yl) ethyl) propan-1-amine;
c. the crude product obtained in the previous step is eluted and separated by column chromatography to obtain high purity (A)R) -3- (3- (difluoromethyl) phenyl) -N- (1- (naphthalen-1-yl) ethyl) propan-1-amine, wherein the eluting solution is selected from one or two of ethyl acetate, N-hexane and N-heptane;
d. high purity (R) Dissolving (E) -3- (3- (difluoromethyl) phenyl) -N- (1- (naphthyl-1-yl) ethyl) propan-1-amine in a mailing solvent, adding 1.0-1.5 eq of inorganic acid at 0-30 ℃ to form a salt for 0.5-2 hours, filtering, and drying in vacuum to obtain (A)R) -3- (3- (difluoromethyl) phenyl) -N- (1- (naphthalen-1-yl) ethyl) propan-1-amine mineral acid salt.
9. Use of the desflurinated impurity compound of cinacalcet hydrochloride obtained by the preparation method according to any one of claims 1 to 8 as a reference substance or in controlling the quality of cinacalcet hydrochloride.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008058236A2 (en) * | 2006-11-08 | 2008-05-15 | Dr. Reddy's Labortories, Ltd. | Methods for preparing cinacalcet hydrochloride |
| US20110318417A1 (en) * | 2008-12-08 | 2011-12-29 | Actavis Group Ptc Ehf | Highly pure cinacalcet or a pharmaceutically acceptable salt thereof |
| CN107963965A (en) * | 2017-11-30 | 2018-04-27 | 常州市阳光药业有限公司 | The preparation method of m-trifluoromethyl benzenpropanoic acid |
| CN110437076A (en) * | 2019-08-22 | 2019-11-12 | 江苏嘉逸医药有限公司 | A kind of synthetic method of high-purity hydrochloric acid cinacalcet |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008058236A2 (en) * | 2006-11-08 | 2008-05-15 | Dr. Reddy's Labortories, Ltd. | Methods for preparing cinacalcet hydrochloride |
| US20110318417A1 (en) * | 2008-12-08 | 2011-12-29 | Actavis Group Ptc Ehf | Highly pure cinacalcet or a pharmaceutically acceptable salt thereof |
| CN107963965A (en) * | 2017-11-30 | 2018-04-27 | 常州市阳光药业有限公司 | The preparation method of m-trifluoromethyl benzenpropanoic acid |
| CN110437076A (en) * | 2019-08-22 | 2019-11-12 | 江苏嘉逸医药有限公司 | A kind of synthetic method of high-purity hydrochloric acid cinacalcet |
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Application publication date: 20210219 |