[go: up one dir, main page]

CN111196759B - Preparation method of cinacalcet hydrochloride and intermediate thereof - Google Patents

Preparation method of cinacalcet hydrochloride and intermediate thereof Download PDF

Info

Publication number
CN111196759B
CN111196759B CN201811364808.2A CN201811364808A CN111196759B CN 111196759 B CN111196759 B CN 111196759B CN 201811364808 A CN201811364808 A CN 201811364808A CN 111196759 B CN111196759 B CN 111196759B
Authority
CN
China
Prior art keywords
gas
cinacalcet
preparation
organic solvent
mass ratio
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201811364808.2A
Other languages
Chinese (zh)
Other versions
CN111196759A (en
Inventor
陈健
于冲冲
王婷婷
应述欢
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Yunshengyan Neoplasm Technology Co ltd
Shenzhen Sinobioway Xinpeng Biological Medicine Co ltd
Shanghai Bocimed Pharmaceutical Research Co Ltd
Original Assignee
Shenzhen Sinobioway Xinpeng Biological Medicine Co ltd
Shanghai Bocimed Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Sinobioway Xinpeng Biological Medicine Co ltd, Shanghai Bocimed Pharmaceutical Co Ltd filed Critical Shenzhen Sinobioway Xinpeng Biological Medicine Co ltd
Priority to CN201811364808.2A priority Critical patent/CN111196759B/en
Publication of CN111196759A publication Critical patent/CN111196759A/en
Application granted granted Critical
Publication of CN111196759B publication Critical patent/CN111196759B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a preparation method of cinacalcet hydrochloride and an intermediate thereof. The invention provides a preparation method of cinacalcet hydrochloride intermediate L-cinacalcet tartrate III, which comprises the following steps (1): in an organic solvent, under the existence of a chiral catalyst and a chiral ligand, carrying out asymmetric hydrogenation reduction reaction on the cinacalcet intermediate II to obtain cinacalcet IV, wherein the chiral catalyst is bis (1, 5-cyclooctadiene) -rhodium trifluoromethanesulfonate, and the chiral ligand is (S) -3,3 '-bis (2, 4, 6-triisopropylphenyl) -1,1' -di-2-naphthol cyclic phosphate; step (2): and (3) carrying out neutralization reaction on the cinacalcet IV and L-tartaric acid in an organic solvent to obtain the cinacalcet L-tartrate III. The preparation method provided by the invention has the advantages of short route steps, simplicity and safety in operation, high total yield, high purity of the prepared product, capability of meeting the requirements of raw material medicines, low production cost and suitability for industrial production.

Description

Preparation method of cinacalcet hydrochloride and intermediate thereof
Technical Field
The invention relates to a preparation method of cinacalcet hydrochloride and an intermediate thereof.
Background
Cinacalcet Hydrochloride (I), the first drug in a new class of compounds called calcimimetics, activates the calcium receptor in the parathyroid gland, thereby reducing parathyroid hormone secretion. The product can modulate the behavior of the calcium receptors of the parathyroid glands, and reduce the levels of parathyroid hormone, calcium, phosphorus and calcium-phosphorus complexes by increasing the sensitivity of the receptors to the levels of calcium in the bloodstream. Cinacalcet hydrochloride was developed by NPS Pharmaceuticals, usa, and marketed by FDA batch cinacalcet hydrochloride on 3.8.2004 under the trade name sensiprar, 25mg or 75mg specification).
Figure BDA0001868233530000011
Cinacalcet hydrochloride is used for treating secondary hyperparathyroidism in chronic kidney disease patients undergoing dialysis, hypercalcemia in parathyroid cancer patients, and the like. Patients with chronic renal failure often have abnormal bone metabolism and mineralization, manifested as osteoporosis, osteomalacia, etc., i.e., renal osteodystrophy. After a patient with end-stage renal disease is treated by cinacalcet, laboratory indexes reflecting bone metabolism can basically recover to be normal, and symptoms of renal osteopathia such as dyskinesia and bone pain can be obviously improved. These effects are achieved by lowering serum parathyroid hormone. Calcification defense is a relatively rare complication of chronic renal failure patients with poor prognosis. The disease is mainly manifested by skin soft tissue ulcer, necrosis, pain, secondary infection and the like, and high calcium and phosphorus in serum are the most important risk factors for calcification defense. Historically, this disease has lacked a more effective treatment, and parathyroidectomy has only alleviated the condition to some extent. The combination of cinacalcet with bisphosphate and sodium thiosulfate for the treatment of calcification defense can promote ulcer healing and relieve pain of patients.
The synthesis method of cinacalcet hydrochloride which has been published and reported under the prior art conditions is reported in scientific and technical literature, namely, the journal of the Chinese medical industry, 2010,41 (7), 488-490 and the like.
The method reported by scientific and technical literature in the journal of the Chinese medicine industry, 2010,41 (7), 488-490 comprises the following steps: 3-trifluoromethyl benzyl chloride and dimethyl malonate are subjected to condensation reaction, decarboxylation and hydrolysis to obtain 3- (3-trifluoromethyl phenyl) -propionic acid; carrying out condensation reaction on 3- (3-trifluoromethylphenyl) -propionic acid and (R) -1- (naphthalene-1-yl) -ethylamine to obtain (R) -1-naphthalene-1-yl ethyl 3- (3-trifluoromethylphenyl) -1-propionamide; further reduced to cinacalcet and then hydrochlorinated to cinacalcet hydrochloride I.
Figure BDA0001868233530000021
The disadvantages of the above preparation route are: in the finally obtained cinacalcet hydrochloride I, the purity of the product is not high, and specific methods for controlling the content of optical isomers are lacked (the optical purity depends only on the purity of the starting material (R) -1- (naphthalene-1-yl) -ethylamine), and the total yield of the route length is not high, only 36%, and cannot meet the requirements of raw material medicaments (the requirement standard of raw material medicaments is that the purity is more than 99.0%, the single impurity is less than 0.10%, and the optical isomer is less than 0.15%). Therefore, the prior art conditions need to be changed urgently, a preparation method which is simple and convenient to operate needs to be found for preparing the cinacalcet hydrochloride I, the content of the optical isomer generated in the reaction can be controlled, and further a product which meets the standards of raw material medicines is obtained, and meanwhile, the route is short and the total yield is high.
Disclosure of Invention
The invention aims to solve the technical problems of long route, low yield, low optical purity, low purity of the prepared product, incapability of meeting the requirements of raw material medicines, unsuitability for industrial production and the like of the preparation method of cinacalcet hydrochloride in the prior art, and provides a preparation method of cinacalcet hydrochloride and an intermediate thereof. The preparation method has the advantages that the total yield is 62-68%, the prepared product has high purity, meets the requirements of raw material medicines (chemical and optical purity is more than 99.0%, single impurity is less than 0.10%, optical isomer is less than 0.10%, the requirements of the raw material medicines are met), and is suitable for industrial production.
The invention provides a preparation method of cinacalcet hydrochloride intermediate L-cinacalcet tartrate III, which comprises the following steps:
step (1): in an organic solvent, in the presence of a chiral catalyst and a chiral ligand, carrying out asymmetric hydrogenation reduction reaction on the cinacalcet intermediate II to obtain cinacalcet IV, wherein the chiral catalyst is bis (1, 5-cyclooctadiene) -rhodium trifluoromethanesulfonate, and the chiral ligand is (S) -3,3 '-bis (2, 4, 6-triisopropylphenyl) -1,1' -di-2-naphthol cyclic phosphate;
Figure BDA0001868233530000031
step (2): in an organic solvent, carrying out neutralization reaction on the cinacalcet IV obtained in the step (1) and L-tartaric acid to obtain cinacalcet III L-tartrate;
Figure BDA0001868233530000032
step (1) may be a conventional method in the art for such asymmetric hydrogenation reduction reactions, and the following reaction methods and conditions are particularly preferred in the present invention:
in the step (1), the organic solvent is preferably an alcohol solvent, and the alcohol solvent is preferably one or more of ethanol, methanol and isopropanol.
In the step (1), the volume-to-mass ratio of the alcohol solvent to the cinacalcet intermediate II is preferably 1mL/g to 20mL/g, more preferably 2mL/g to 10mL/g, for example, 3mL/g, 5mL/g or 7mL/g.
In the step (1), the ratio of the amount of the chiral catalyst to the amount of the substance of the cinacalcet hydrochloride intermediate II is preferably 0.0001 to 0.01, more preferably 0.0005 to 0.005, for example, 0.0005, 0.001 or 0.002.
In step (1), the ratio of the amount of the chiral ligand to the amount of the substance of cinacalcet hydrochloride intermediate II is preferably 0.0001 to 0.01, more preferably 0.0005 to 0.005, for example 0.0005, 0.002 or 0.001.
In the step (1), the pressure of the asymmetric hydrogenation reduction reaction is preferably 1 atmosphere to 10 atmospheres, and more preferably 2 atmospheres to 8 atmospheres, for example, 2 atmospheres to 4 atmospheres, 4 atmospheres to 6 atmospheres, or 6 atmospheres to 8 atmospheres.
In the step (1), the temperature of the asymmetric hydrogenation reduction reaction is preferably 20 to 70 ℃, and more preferably 25 to 65 ℃, for example, 30 to 40 ℃, 40 to 50 ℃ or 50 to 60 ℃.
In step (1), the progress of the asymmetric hydrogenation reduction reaction can be detected by a monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and is generally the end point of the reaction when the cinacalcet intermediate II disappears, and the time of the asymmetric hydrogenation reduction reaction is preferably 1 hour to 12 hours, more preferably 2 hours to 6 hours, such as 2.5 hours to 3.5 hours or 3.5 hours to 4.5 hours.
The following post-treatment steps are preferably employed in step (1): after the reaction is finished, filtering and concentrating to obtain crude cinacalcet IV. The crude cinacalcet IV is preferably used in the reaction of step (2) without further purification.
Step (2) may be a conventional method of such neutralization reaction in the art, and the following reaction method and conditions are particularly preferred in the present invention:
in the step (2), the organic solvent is preferably an alcohol solvent and/or an ester solvent, and the alcohol solvent is preferably one or more of ethanol, methanol and isopropanol. The ester solvent is preferably isopropyl acetate. When a mixed solvent of an alcohol solvent and an ester solvent is adopted, the mixed solvent of the alcohol solvent and the ester solvent is preferably a mixed solvent of ethanol and isopropyl acetate. When a mixed solvent of an alcohol solvent and an ester solvent is used, the volume ratio of the alcohol solvent to the ester solvent is preferably 0.5 to 2, for example, 1.
In the step (2), the volume-to-mass ratio of the organic solvent to the cinacalcet intermediate II is preferably 1mL/g to 20mL/g, more preferably 2mL/g to 10mL/g, for example 7mL/g.
In the step (2), the mass ratio of the L-tartaric acid to the cinacalcet hydrochloride intermediate II is preferably 1 to 1.5, more preferably 1 to 1.2, for example 1.
In the step (2), the temperature of the neutralization reaction is preferably 40 to 80 ℃, more preferably 50 to 70 ℃, for example, 60 to 65 ℃.
In step (2), the progress of the neutralization reaction can be detected by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and the time of the neutralization reaction is preferably 0.1 hour to 1 hour, more preferably 0.2 hour to 0.8 hour, e.g., 0.5 hour.
In step (2), the following post-treatment steps are preferably employed: and after the reaction is finished, cooling, filtering, washing and drying to obtain the L-cinacalcet tartrate III. The cooling temperature is preferably-5 to 20 ℃, more preferably 0 to 15 ℃, for example, 5 to 10 ℃. The cooling time is preferably 1 hour to 5 hours, and more preferably 1 hour to 2 hours. The filtration, washing and drying can be carried out by methods conventional in the art for such procedures. The organic solvent used for washing is preferably an ester solvent; the ester solvent is preferably isopropyl acetate. The drying is preferably vacuum drying; the temperature of the vacuum drying is preferably 45-55 ℃; the time of the vacuum drying is preferably 12 to 16 hours; the pressure of the vacuum drying is preferably-0.01 MPa to-0.1 MPa.
The L-tartaric acid cinacalcet III prepared by the invention has the HPLC purity of more than 99.50 percent and the chiral isomer content of less than 0.10 percent. For example, HPLC purity 99.63%, chiral isomer content 0.04%; HPLC purity 99.56%, chiral isomer content 0.05%; HPLC purity 99.72%, chiral isomer content 0.03%.
In the present invention, the preparation method of cinacalcet L-tartrate preferably further comprises a preparation method of cinacalcet intermediate II, which comprises the following steps: in an organic solvent, in the presence of organic acid, carrying out condensation reaction on 1-acetonaphthone and 3-trifluoromethyl amphetamine to obtain the cinacalcet intermediate II;
Figure BDA0001868233530000051
the preparation method of the cinacalcet intermediate II can be a conventional method in the field of condensation reaction, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the cinacalcet intermediate II, the organic solvent is preferably an alcohol solvent; the alcohol solvent is preferably ethanol.
In the preparation method of the cinacalcet intermediate II, the volume mass ratio of the organic solvent to the 3-trifluoromethylamphetamine is preferably 1mL/g to 20mL/g, more preferably 2mL/g to 10mL/g, for example 7mL/g.
In the preparation method of the cinacalcet intermediate II, the organic acid is preferably methanesulfonic acid.
In the preparation method of the cinacalcet intermediate II, the mass ratio of the organic acid to the 3-trifluoromethylamphetamine is preferably 0.001 to 0.1, more preferably 0.005 to 0.05, for example 0.01.
In the method for producing cinacalcet intermediate II, the condensation reaction temperature is preferably 40 to 80 ℃, more preferably 50 to 70 ℃, for example, 60 to 65 ℃.
In the preparation method of cinacalcet intermediate II, the progress of the condensation reaction can be detected by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and generally the time when the 3-trifluoromethylamphetamine disappears is taken as the end point of the reaction, and the time of the condensation reaction is preferably 1 hour to 10 hours, more preferably 2 hours to 6 hours, for example 3 hours to 4 hours.
The preparation method of the cinacalcet intermediate II is preferably carried out under the protection of protective gas, and the protective gas is preferably nitrogen and/or argon.
The preparation method of the cinacalcet intermediate II preferably adopts the following post-treatment steps: and after the reaction is finished, removing the solvent, washing and concentrating to obtain the cinacalcet intermediate II. The concentration may be carried out by a method conventional in the art for such procedures. The organic solvent used for washing is preferably an alkane solvent; the alkane solvent is preferably n-heptane and/or n-hexane. The concentration is preferably vacuum concentration; the temperature of the vacuum concentration is preferably 45-55 ℃, and the pressure of the vacuum concentration is preferably-0.085 MPa-0.1 MPa.
The preparation method of the L-cinacalcet tartrate III preferably adopts the following synthetic route:
Figure BDA0001868233530000071
the invention also provides a preparation method of the cinacalcet hydrochloride I, which comprises the following steps: after the L-cinacalcet tartrate III is prepared according to the method, carrying out neutralization reaction on the L-cinacalcet tartrate III and inorganic base in an organic solvent to obtain cinacalcet IV; then carrying out neutralization reaction on the cinacalcet IV and hydrochloric acid to obtain cinacalcet hydrochloride I;
Figure BDA0001868233530000072
the preparation method of cinacalcet hydrochloride I described in the present invention may be a conventional method in this type of neutralization reaction in the art, and the following reaction method and conditions are particularly preferred in the present invention:
in the preparation method of the cinacalcet hydrochloride I, the organic solvent is preferably an ester solvent; the ester solvent is preferably isopropyl acetate.
In the preparation method of the cinacalcet hydrochloride I, the volume-to-mass ratio of the organic solvent to the L-tartaric acid cinacalcet III is preferably 1 to 20mL/g, more preferably 2 to 5mL/g, for example 3mL/g.
In the preparation method of the cinacalcet hydrochloride I, the inorganic base is preferably sodium carbonate. The sodium carbonate may be used in the form of an aqueous solution thereof. When the sodium carbonate is used in the form of an aqueous solution thereof, the mass concentration of the aqueous solution of sodium carbonate is preferably 1% to 10%, more preferably 2% to 8%, for example 5%, and the mass concentration refers to the mass percentage of sodium carbonate to the total mass of the aqueous solution of sodium carbonate.
In the method for preparing cinacalcet hydrochloride I, the ratio of the amount of the inorganic base to the amount of the L-tartaric acid cinacalcet III is preferably 1 to 5, more preferably 1 to 1.5, for example 1.1, 1.24 or 1.5.
In the method for preparing cinacalcet hydrochloride I, the mass ratio of the hydrochloric acid to the L-tartaric acid cinacalcet III is preferably 1 to 5, more preferably 1 to 1.5, for example 1.1, 1.24 or 1.5. The hydrochloric acid can be a conventional commercially available hydrochloric acid reagent, the mass concentration of the hydrochloric acid reagent is preferably 10-37%, and the mass concentration refers to the mass percentage of hydrogen chloride in the total mass of the hydrochloric acid solution.
In the method for preparing cinacalcet I hydrochloride, the temperature of the neutralization reaction is preferably 0 to 40 ℃, more preferably 5 to 35 ℃, for example 15 to 20 ℃.
In the method for producing cinacalcet hydrochloride I, the time for the neutralization reaction is preferably 0.1 to 5 hours, more preferably 0.2 to 4 hours, for example, 0.5 hours or 1 to 2 hours.
In the invention, the preparation method of the cinacalcet hydrochloride preferably adopts the following synthetic route:
Figure BDA0001868233530000081
the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.
The positive progress effects of the invention are as follows: the preparation method provided by the invention has the advantages of short route steps, simple and safe operation, high total yield of 62-68%, high purity of the prepared product, low production cost and suitability for industrial production, and the prepared product meets the requirements of raw material medicines (chemical and optical purity is more than 99.0%, single impurity is less than 0.10%, and optical isomer is less than 0.10%.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Detailed Description
Example 1: preparation of cinacalcet hydrochloride intermediate II (refer to the method for synthesizing line 1 in patent CN200980136709.1 description)
Figure BDA0001868233530000091
Under the protection of nitrogen, 100g (0.587 mol) of 1-acetonaphthone and 100g (0.492 mol) of 3-trifluoromethylamphetamine are added into 700mL of ethanol, then 0.48g (0.00499 mol) of methanesulfonic acid is added, the mixture is heated to 60-65 ℃ and stirred for 3-4 hours, and the solvent is removed by vacuum concentration (-0.085 MPa to-0.1MPa, 45-55 ℃). Adding 350mL of n-heptane, stirring for 1-2 hours at 15-20 ℃, standing, removing supernatant and repeating for three times; vacuum concentration (-0.085 MPa-0.1MPa, 45-55 ℃) gave 161.0g of cinacalcet intermediate II, 92.05% yield, 98.37% HPLC purity.
Example 2: preparation of cinacalcet L-tartrate III
Figure BDA0001868233530000092
To the hydrogenation vessel were added 20g (0.0563 mol) of cinacalcet intermediate II, 27mg (0.0000576 mol) of bis (1, 5-cyclooctadiene) -rhodium trifluoromethanesulfonate, (S) -3,3 '-bis (2, 4, 6-triisopropylphenyl) -1,1' -bis-2-naphthol cyclic phosphate (L;) 44mg (0.0000584 mol) and 100mL of ethanol. Hydrogenating for 2.5-3.5 hours under the condition that the hydrogen pressure is 4-6 atmospheric pressure and the temperature is 40-50 ℃.
Cooling, filtering, washing with ethanol, and vacuum concentrating (45-55 ℃ and-0.085 MPa-0.1 MPa) to remove the solvent to obtain crude cinacalcet IV. Then, 70mL of isopropyl acetate was added, the mixture was stirred and filtered, and a solution of 8.45g of L-tartaric acid in 70mL of ethanol was added to the filtrate. Heating to 60-65 deg.C, stirring for 0.5 hr, cooling to 5-10 deg.C, stirring for 1-2 hr, filtering, washing with isopropyl acetate for 1 time, vacuum drying at 45-55 deg.C to-0.01 MPa to-0.1 MPa for 12-16 hr to obtain white solid L-cinacalcet tartrate III,22.5g, yield 78.82%, HPLC purity 99.63%, and enantiomer content 0.04% (chiral HPLC).
Example 3: preparation of cinacalcet L-tartrate III
Figure BDA0001868233530000101
To the hydrogenation vessel were added 60g (0.169 mol) of cinacalcet intermediate II, 40mg (0.0000854 mol) of bis (1, 5-cyclooctadiene) -rhodium trifluoromethanesulfonate, (S) -3,3 '-bis (2, 4, 6-triisopropylphenyl) -1,1' -bis-2-naphthol cyclic phosphate (L:) 65mg (0.0000863 mol) and 180mL of ethanol. Hydrogenating for 3.5-4.5 hours under the hydrogen pressure of 6-8 atm and the temperature of 30-40 ℃.
Cooling, filtering, washing with ethanol, and vacuum concentrating (at 45-55 deg.C and-0.085 MPa-0.1 MPa) to remove solvent to obtain crude cinacalcet IV product. 210mL of isopropyl acetate was added, the mixture was stirred and filtered, and a solution of 25.4g of L-tartaric acid in 210mL of ethanol was added to the filtrate. Heating to 60-65 deg.C, stirring for 0.5 hr, cooling to 5-10 deg.C, stirring for 1-2 hr, filtering, washing with isopropyl acetate for 1 time, vacuum drying (45-55 deg.C, -0.01 MPa-0.1 MPa) for 12-16 hr to obtain the off-white solid L-cinacalcet tartrate III,64.3g, yield 75.01%, HPLC purity 99.56%, and enantiomer content 0.05% (chiral HPLC).
Example 4: preparation of L-cinacalcet tartrate III
Figure BDA0001868233530000111
To the hydrogenation vessel were added 20g (0.0563 mol) of cinacalcet intermediate II, 53mg (0.000113 mol) of bis (1, 5-cyclooctadiene) -rhodium trifluoromethanesulfonate, (S) -3,3 '-bis (2, 4, 6-triisopropylphenyl) -1,1' -bis-2-naphthol cyclic phosphate (L;) 87mg (0.000116 mol) and 140mL of ethanol. Hydrogenating for 2.5-3.5 hours under the condition that the hydrogen pressure is 2-4 atm and the temperature is 50-60 ℃.
Cooling, filtering, washing with ethanol, and vacuum concentrating (at 45-55 deg.C and-0.085 MPa-0.1 MPa) to remove solvent to obtain crude cinacalcet IV product. Then, 70mL of isopropyl acetate was added, the mixture was stirred and filtered, and a solution of 8.45g of L-tartaric acid in 70mL of ethanol was added to the filtrate. Heating to 60-65 deg.C, stirring for 0.5 hr, cooling to 5-10 deg.C, stirring for 1-2 hr, filtering, washing with isopropyl acetate for 1 time, vacuum drying at 45-55 deg.C to-0.01 MPa to-0.1 MPa for 12-16 hr to obtain white solid L-cinacalcet tartrate III,22.9g, yield 80.22%, HPLC purity 99.72%, and enantiomer content 0.03% (chiral HPLC).
Example 5: preparation of cinacalcet hydrochloride I
Figure BDA0001868233530000121
Under the protection of nitrogen, 22.0g (0.0433 mol) of cinacalcet L-tartrate III prepared in example 2 is added into 66mL of isopropyl acetate, and 100mL (0.047 mol) of sodium carbonate aqueous solution with the mass concentration of 5% (the mass concentration refers to the mass percentage of the sodium carbonate to the total mass of the sodium carbonate aqueous solution) is slowly dripped. Stirring for 1-2 hours at 15-20 ℃, standing and layering, and taking an organic layer; adding 30mL of isopropyl acetate into the water layer, stirring for 1-2 hours at 15-20 ℃, standing, layering, and taking an organic layer; after the organic layers are combined, sodium bicarbonate water solution with the mass concentration of 7% (the mass concentration refers to the mass percentage of the sodium bicarbonate to the total mass of the sodium bicarbonate water solution) and sodium chloride water solution with the mass concentration of 10% (the mass concentration refers to the mass percentage of the sodium chloride to the total mass of the sodium chloride) are respectively added in sequence, stirred, stood and separated out the water layer. Drying the organic layer sodium sulfate, and then vacuum concentrating (the temperature is 35-55 ℃, and the pressure is-0.08 MPa-0.1 MPa) to remove most of the solvent to obtain oily matter. Then 30mL of acetonitrile is added, 4.0mL (0.048 mol) of commercially available concentrated hydrochloric acid is added under stirring at 15-20 ℃, then the mixture is stirred for 0.5 hour at 15-20 ℃, 270mL of water is added, and the mixture is cooled to 5-10 ℃ and stirred for 1-2 hours. Filtering, washing with water, and vacuum drying at 45-55 deg.c to-0.01-0.1 MPa for 12-16 hr to obtain white solid. Adding 100mL of isopropanol into the solid, stirring for 0.5 hour at 65-70 ℃, adding 20mL of n-heptane, cooling to 5-10 ℃, and stirring for 1-2 hours. Filtering, washing with n-heptane, and vacuum drying (45-55 deg.C, 0.01-0.1 MPa) for 12-16 h to obtain white solid of cinacalcet hydrochloride I,15.6g, 91.42% yield (66.3% yield in three steps based on 3-trifluoromethylamphetamine), 99.89% HPLC purity (maximum single impurity 0.04%), and 0.04% enantiomer content (chiral HPLC).
Example 6: preparation of cinacalcet hydrochloride I
Figure BDA0001868233530000131
Under the protection of nitrogen, 64.0g (0.126 mol) of cinacalcet L-tartrate III prepared in example 3 is added into 192mL of isopropyl acetate, and 330mL (0.156 mol) of sodium carbonate aqueous solution with the mass concentration of 5% (the mass concentration refers to the mass percentage of sodium carbonate in the total mass of the sodium carbonate aqueous solution) is slowly dripped. Stirring for 1-2 hours at 15-20 ℃, standing and layering, and taking an organic layer; adding 90mL of isopropyl acetate into the water layer, stirring for 1-2 hours at 15-20 ℃, standing, layering, and taking an organic layer; after the organic layers are combined, sodium bicarbonate water solution with the mass concentration of 7% (the mass concentration refers to the mass percentage of sodium bicarbonate to the total mass of the sodium bicarbonate water solution) and sodium chloride water solution with the mass concentration of 10% (the mass concentration refers to the mass percentage of sodium chloride to the total mass of the common salt water) are respectively added in sequence, and then stirring, standing and separating out the water layer are carried out. Drying the organic layer sodium sulfate, and then vacuum concentrating (the temperature is 35-55 ℃, and the pressure is-0.08 MPa-0.1 MPa) to remove most of the solvent to obtain oily matter. Then 88mL of acetonitrile was added, 13.0mL (0.156 mol) of concentrated hydrochloric acid available on the market was added under stirring at 15 to 20 ℃, followed by stirring at 15 to 20 ℃ for 0.5 hour, adding 792mL of water, cooling to 5 to 10 ℃ and stirring for 1 to 2 hours. Filtering, washing with water, and vacuum drying at 45-55 deg.c to-0.01-0.1 MPa for 12-16 hr to obtain white solid. 290mL of isopropanol is added into the solid, the mixture is stirred for 0.5 hour at the temperature of 65-70 ℃, 58mL of n-heptane is added, and the mixture is cooled to the temperature of 5-10 ℃ and stirred for 1-2 hours. Filtering, washing with n-heptane, and vacuum drying (45-55 deg.C, 0.01 MPa-0.1 MPa) for 12-16 h to obtain white solid of cinacalcet hydrochloride I,45.1g, yield of 90.81% (based on 3-trifluoromethylamphetamine, three-step total yield of 62.7%), HPLC purity of 99.91% (maximum single impurity of 0.03%), and enantiomer content of 0.07% (chiral HPLC).
Example 7: preparation of cinacalcet hydrochloride I
Figure BDA0001868233530000132
Under the protection of nitrogen, 22.0g (0.0433 mol) of cinacalcet L-tartrate III prepared in example 4 is added into 66mL of isopropyl acetate, and 140mL (0.066 mol) of sodium carbonate aqueous solution with the mass concentration of 5% (the mass concentration refers to the mass percentage of the sodium carbonate to the total mass of the sodium carbonate aqueous solution) is slowly dripped. Stirring for 1-2 hours at 15-20 ℃, standing and layering, and taking an organic layer; adding 30mL of isopropyl acetate into the water layer, stirring for 1-2 hours at 15-20 ℃, standing, layering, and taking an organic layer; after the organic layers are combined, sodium bicarbonate water solution with the mass concentration of 7% (the mass concentration refers to the mass percentage of the sodium bicarbonate to the total mass of the sodium bicarbonate water solution) and sodium chloride water solution with the mass concentration of 10% (the mass concentration refers to the mass percentage of the sodium chloride to the total mass of the salt water) are respectively added in sequence, and then the mixture is stirred, kept stand and separated out to obtain a water layer. Drying the organic layer sodium sulfate, and then vacuum concentrating (the temperature is 35-55 ℃, and the pressure is-0.08 MPa-0.1 MPa) to remove most of the solvent to obtain oily matter. Then 30mL of acetonitrile is added, 5.4mL (0.065 mol) of commercially available concentrated hydrochloric acid is added under stirring at 15-20 ℃, then the mixture is stirred for 0.5 hour at 15-20 ℃, 270mL of water is added, and the mixture is cooled to 5-10 ℃ and stirred for 1-2 hours. Filtering, washing with water, and vacuum drying at 45-55 deg.c and-0.01-0.1 MPa for 12-16 hr to obtain white solid. Adding 100mL of isopropanol into the solid, stirring for 0.5 hour at 65-70 ℃, adding 20mL of n-heptane, cooling to 5-10 ℃, and stirring for 1-2 hours. Filtering, washing with n-heptane, and vacuum drying (45-55 deg.C, 0.01 MPa-0.1 MPa) for 12-16 h to obtain white solid of cinacalcet hydrochloride I,15.8g, 92.54% yield (68.2% total yield in three steps based on 3-trifluoromethylamphetamine), 99.92% HPLC purity (maximum single impurity 0.03%), and 0.03% enantiomer content (chiral HPLC).
Comparative example: preparation of cinacalcet hydrochloride I (according to the methods reported in literature, journal of chinese medical industry, 2010,41 (7), 488-490)
Figure BDA0001868233530000151
8.8g of dimethyl malonate is put into 100mL of tetrahydrofuran, cooled to 0-5 ℃, added with 3.0g of 60% sodium hydride in batches and stirred for 30 minutes. A solution of 11.6g of 3-trifluoromethylbenzyl chloride in 40mL of tetrahydrofuran was added dropwise thereto, followed by stirring for 2 hours. Quenching with dilute hydrochloric acid, adding water, concentrating under reduced pressure to remove most tetrahydrofuran, extracting with methyl tert-butyl ether, washing with water, drying, concentrating under reduced pressure to remove solvent, and distilling under high vacuum to obtain 11.3g of dimethyl 3-trifluoromethyl benzyl malonate. 6.6g of dimethyl 3-trifluoromethylbenzylmalonate was added to 55mL of N, N-dimethylformamide and 5mL of water, 2.0g of sodium chloride was added thereto, and the mixture was heated to 150 ℃ and stirred for 6 hours. Adding water, extracting with methyl tert-butyl ether, washing with water, drying, concentrating under reduced pressure to remove solvent to obtain 4.5g of methyl 3-trifluoromethylphenylpropionate. Methyl 3-trifluoromethylphenylpropionate (4.5 g) was added to 60mL of methanol and 1mL of water, and then 3.9g of sodium hydroxide was added thereto, followed by stirring at room temperature for 4 hours. Adjusting the pH value to 2-3 by concentrated hydrochloric acid, adding water, extracting by methyl tert-butyl ether, washing by water, drying, decompressing, concentrating and removing the solvent to obtain 3-trifluoromethyl phenylpropionic acid 3.9g. The whole batch of 3-trifluoromethyl phenylpropionic acid is added with 45mL of toluene and 13mL of thionyl chloride, heated to 100 ℃ and stirred for 6 hours, after decompression and concentration, added with 30mL of dichloromethane, cooled to 0-5 ℃, added with 3.0g of (R) -1- (naphthalene-1-yl) -ethylamine, 5.4g of triethylamine and 30mL of dichloromethane, and stirred for 4 hours at room temperature. After water was added, the mixture was extracted with methyl tert-butyl ether, washed with water, dried and concentrated under reduced pressure to remove the solvent, whereby 5.1g of N- [1- (R) -1- (naphthyl) -ethyl ] -3- (trifluoromethyl) phenylacrylamide was obtained. Adding 3.4g of N- [1- (R) -1- (naphthyl) -ethyl ] -3- (trifluoromethyl) phenylacrylamide into 80mL of tetrahydrofuran, cooling to 0-5 ℃, dropwise adding the mixture into a mixed system of 3.0g of sodium borohydride and 80mL of tetrahydrofuran, and dropwise adding a solution of 16g of boron trifluoride diethyl etherate and 40mL of tetrahydrofuran. Heating to 65 deg.C, stirring for 3 hr, cooling, adding water, extracting with ethyl acetate, washing with water, drying, concentrating under reduced pressure to remove solvent to obtain yellow oily crude cinacalcet 4.7g. Adding 40mL of ethanol into the whole batch of crude cinacalcet, dropwise adding 12mL of concentrated hydrochloric acid, heating to 70 ℃, stirring for 2 hours, concentrating under reduced pressure, and recrystallizing with ethyl acetate to obtain 3.2g of cinacalcet hydrochloride I, wherein the total yield is 36%, the HPLC purity is 99.56%, and the maximum single impurity is 0.21%.

Claims (9)

1. A preparation method of cinacalcet hydrochloride I is characterized by comprising the following steps:
step (1): in an organic solvent, under the existence of a chiral catalyst and a chiral ligand, carrying out asymmetric hydrogenation reduction reaction on the cinacalcet intermediate II to obtain cinacalcet IV, wherein the chiral catalyst is bis (1, 5-cyclooctadiene) -rhodium trifluoromethanesulfonate, and the chiral ligand is (S) -3,3 '-bis (2, 4, 6-triisopropylphenyl) -1,1' -di-2-naphthol cyclic phosphate;
Figure FDA0003987463560000011
step (2): in an organic solvent, carrying out neutralization reaction on the cinacalcet IV obtained in the step (1) and L-tartaric acid to obtain cinacalcet L-tartrate;
Figure FDA0003987463560000012
and (3): in an organic solvent, carrying out neutralization reaction on the L-tartaric acid cinacalcet III and an inorganic base to obtain cinacalcet IV; then carrying out neutralization reaction on the cinacalcet IV and hydrochloric acid to obtain cinacalcet hydrochloride I;
Figure FDA0003987463560000013
2. a process for the preparation of cinacalcet I hydrochloride according to claim 1, characterized in that:
in the step (1), the organic solvent is an alcohol solvent;
and/or the presence of a gas in the gas,
in the step (1), the volume-to-mass ratio of the organic solvent to the cinacalcet intermediate II is 1 mL/g-20 mL/g;
and/or the presence of a gas in the gas,
in the step (1), the mass ratio of the chiral catalyst to the cinacalcet hydrochloride intermediate II is 0.0001-0.01;
and/or the presence of a gas in the gas,
in the step (1), the mass ratio of the chiral ligand to the cinacalcet hydrochloride intermediate II is 0.0001-0.01;
and/or the presence of a gas in the gas,
in the step (1), the pressure of the asymmetric hydrogenation reduction reaction is 1-10 atmospheric pressures;
and/or the presence of a gas in the gas,
in the step (1), the temperature of the asymmetric hydrogenation reduction reaction is 20-70 ℃;
and/or the presence of a gas in the gas,
in the step (1), the time of the asymmetric hydrogenation reduction reaction is 1-12 hours;
and/or the presence of a gas in the gas,
the step (1) adopts the following post-treatment steps: after the reaction is finished, filtering and concentrating to obtain crude cinacalcet IV.
3. A process for the preparation of cinacalcet I hydrochloride according to claim 1, characterized in that:
in the step (1), the organic solvent is one or more of ethanol, methanol and isopropanol;
and/or the presence of a gas in the gas,
in the step (1), the volume-to-mass ratio of the organic solvent to the cinacalcet intermediate II is 2-10 mL/g;
and/or the presence of a gas in the gas,
in the step (1), the mass ratio of the chiral catalyst to the cinacalcet hydrochloride intermediate II is 0.0005-0.005;
and/or the presence of a gas in the gas,
in the step (1), the mass ratio of the chiral ligand to the cinacalcet hydrochloride intermediate II is 0.0005-0.005;
and/or the presence of a gas in the gas,
in the step (1), the pressure of the asymmetric hydrogenation reduction reaction is 2-8 atmospheric pressures;
and/or the presence of a gas in the gas,
in the step (1), the temperature of the asymmetric hydrogenation reduction reaction is 25-65 ℃;
and/or the presence of a gas in the atmosphere,
in the step (1), the time of the asymmetric hydrogenation reduction reaction is 2 to 6 hours;
and/or the presence of a gas in the gas,
the crude cinacalcet IV was used in the reaction of step (2) without further purification.
4. A process for the preparation of cinacalcet I hydrochloride according to claim 1, characterized in that:
in the step (2), the organic solvent is an alcohol solvent and/or an ester solvent;
and/or the presence of a gas in the gas,
in the step (2), the volume-to-mass ratio of the organic solvent to the cinacalcet intermediate II is 1 mL/g-20 mL/g;
and/or the presence of a gas in the gas,
in the step (2), the mass ratio of the L-tartaric acid to the cinacalcet hydrochloride intermediate II is 1-1.5;
and/or the presence of a gas in the gas,
in the step (2), the temperature of the neutralization reaction is 40-80 ℃;
and/or the presence of a gas in the gas,
in the step (2), the time of the neutralization reaction is 0.1 to 1 hour;
and/or the presence of a gas in the gas,
in the step (2), the following post-treatment steps are adopted: and after the reaction is finished, cooling, filtering, washing and drying to obtain the L-cinacalcet tartrate III.
5. A process for the preparation of cinacalcet I hydrochloride according to claim 1, characterized in that:
in the step (2), the organic solvent is one or more of ethanol, methanol and isopropanol;
and/or the presence of a gas in the gas,
in the step (2), the organic solvent is isopropyl acetate;
and/or the presence of a gas in the gas,
in the step (2), the volume-to-mass ratio of the organic solvent to the cinacalcet intermediate II is 2 mL/g-10 mL/g;
and/or the presence of a gas in the gas,
in the step (2), the mass ratio of the L-tartaric acid to the cinacalcet hydrochloride intermediate II is 1-1.2;
and/or the presence of a gas in the atmosphere,
in the step (2), the temperature of the neutralization reaction is 50-70 ℃;
and/or the presence of a gas in the gas,
in the step (2), the time of the neutralization reaction is 0.2 to 0.8 hour.
6. A process for the preparation of cinacalcet I hydrochloride according to claim 1, characterized in that: the preparation method of the cinacalcet intermediate II comprises the following steps: in an organic solvent, in the presence of organic acid, carrying out condensation reaction on 1-acetonaphthone and 3-trifluoromethyl amphetamine to obtain the cinacalcet intermediate II;
Figure FDA0003987463560000041
7. the process for preparing cinacalcet I hydrochloride of claim 6, wherein:
in the preparation method of the cinacalcet intermediate II, the organic solvent is an alcohol solvent;
and/or the presence of a gas in the gas,
in the preparation method of the cinacalcet intermediate II, the volume mass ratio of the organic solvent to the 3-trifluoromethyl amphetamine is 1-20 mL/g;
and/or the presence of a gas in the atmosphere,
in the preparation method of the cinacalcet intermediate II, the organic acid is methanesulfonic acid;
and/or the presence of a gas in the gas,
in the preparation method of the cinacalcet intermediate II, the mass ratio of the organic acid to the 3-trifluoromethyl amphetamine is 0.001-0.1;
and/or the presence of a gas in the gas,
in the preparation method of the cinacalcet intermediate II, the condensation reaction temperature is 40-80 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the cinacalcet intermediate II, the condensation reaction time is 1-10 hours;
and/or the presence of a gas in the atmosphere,
the preparation method of the cinacalcet intermediate II is carried out under the protection of protective gas;
and/or the presence of a gas in the gas,
the preparation method of the cinacalcet intermediate II preferably adopts the following post-treatment steps: and after the reaction is finished, removing the solvent, washing and concentrating to obtain the cinacalcet intermediate II.
8. The process for preparing cinacalcet I hydrochloride of claim 6, wherein:
in the preparation method of the cinacalcet intermediate II, the organic solvent is ethanol;
and/or the presence of a gas in the gas,
in the preparation method of the cinacalcet intermediate II, the volume mass ratio of the organic solvent to the 3-trifluoromethyl amphetamine is 2 mL/g-10 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the cinacalcet intermediate II, the mass ratio of the organic acid to the 3-trifluoromethyl amphetamine is 0.005-0.05;
and/or the presence of a gas in the gas,
in the preparation method of the cinacalcet intermediate II, the condensation reaction temperature is preferably 50-70 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the cinacalcet intermediate II, the condensation reaction time is 2 to 6 hours;
and/or the presence of a gas in the gas,
when the preparation method of the cinacalcet intermediate II is carried out under the protection of protective gas, the protective gas is nitrogen and/or argon.
9. The process for preparing cinacalcet hydrochloride I of claim 1, wherein:
in the step (3), the organic solvent is an ester solvent;
and/or the presence of a gas in the gas,
in the step (3), the volume-mass ratio of the organic solvent to the L-cinacalcet tartrate III is 1-20 mL/g;
and/or the presence of a gas in the gas,
in the step (3), the inorganic base is sodium carbonate;
and/or the presence of a gas in the gas,
in the step (3), the mass ratio of the inorganic base to the L-cinacalcet tartrate III is 1-5;
and/or the presence of a gas in the gas,
in the step (3), the mass ratio of the hydrochloric acid to the L-tartaric acid cinacalcet III is 1-5;
and/or the presence of a gas in the gas,
in the step (3), the temperature of the neutralization reaction is 0-40 ℃;
and/or the presence of a gas in the gas,
in the step (3), the time of the neutralization reaction is 0.1 to 5 hours.
CN201811364808.2A 2018-11-16 2018-11-16 Preparation method of cinacalcet hydrochloride and intermediate thereof Active CN111196759B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811364808.2A CN111196759B (en) 2018-11-16 2018-11-16 Preparation method of cinacalcet hydrochloride and intermediate thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811364808.2A CN111196759B (en) 2018-11-16 2018-11-16 Preparation method of cinacalcet hydrochloride and intermediate thereof

Publications (2)

Publication Number Publication Date
CN111196759A CN111196759A (en) 2020-05-26
CN111196759B true CN111196759B (en) 2023-03-24

Family

ID=70743939

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811364808.2A Active CN111196759B (en) 2018-11-16 2018-11-16 Preparation method of cinacalcet hydrochloride and intermediate thereof

Country Status (1)

Country Link
CN (1) CN111196759B (en)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6211244B1 (en) * 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
CN101627023A (en) * 2006-12-12 2010-01-13 拜尔坡特拉有限公司 Catalytic process for asymmetric hydrogenation
CN101993379A (en) * 2010-10-22 2011-03-30 湖北能特科技股份有限公司 Novel preparation method of cinacalcet hydrochloride
CN102039182A (en) * 2009-10-19 2011-05-04 中国石油化工股份有限公司 Iron-based catalyst for olefin oligomerization and preparation method and application thereof
CN102050688A (en) * 2010-12-07 2011-05-11 中国科学院化学研究所 Asymmetric catalytic hydrogenation method for ketone-derived N-alkylimine
CN102307845A (en) * 2009-02-19 2012-01-04 Zach系统股份公司 Process for preparing cinacalcet hydrochloride
JP2015113319A (en) * 2013-12-13 2015-06-22 国立研究開発法人産業技術総合研究所 Rhodium catalyst and method for manufacturing optically active compound using the same
CN104829460A (en) * 2015-05-11 2015-08-12 常州市阳光药业有限公司 Synthesis method of cinacalcet hydrochloride and intermediate thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6211244B1 (en) * 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
CN101627023A (en) * 2006-12-12 2010-01-13 拜尔坡特拉有限公司 Catalytic process for asymmetric hydrogenation
CN102307845A (en) * 2009-02-19 2012-01-04 Zach系统股份公司 Process for preparing cinacalcet hydrochloride
CN102039182A (en) * 2009-10-19 2011-05-04 中国石油化工股份有限公司 Iron-based catalyst for olefin oligomerization and preparation method and application thereof
CN101993379A (en) * 2010-10-22 2011-03-30 湖北能特科技股份有限公司 Novel preparation method of cinacalcet hydrochloride
CN102050688A (en) * 2010-12-07 2011-05-11 中国科学院化学研究所 Asymmetric catalytic hydrogenation method for ketone-derived N-alkylimine
JP2015113319A (en) * 2013-12-13 2015-06-22 国立研究開発法人産業技術総合研究所 Rhodium catalyst and method for manufacturing optically active compound using the same
CN104829460A (en) * 2015-05-11 2015-08-12 常州市阳光药业有限公司 Synthesis method of cinacalcet hydrochloride and intermediate thereof

Also Published As

Publication number Publication date
CN111196759A (en) 2020-05-26

Similar Documents

Publication Publication Date Title
CN116332774A (en) Preparation method of high chiral purity meta-hydroxylamine bitartrate
CN111196759B (en) Preparation method of cinacalcet hydrochloride and intermediate thereof
US10577309B2 (en) Method for preparing pregabalin intermediate 3-isobutylglutaric acid monoamide
CN114805167A (en) Preparation method of brivaracetam
CN113651746A (en) Preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde
JP5749260B2 (en) Method for producing neramexane
CN110437076B (en) Synthesis method of high-purity cinacalcet hydrochloride
HRP20030438A2 (en) A process for the preparation of 1-(aminomethyl) cyclohexaneacetic acid
WO2007080470A2 (en) A method for the purification of levetiracetam
CN110204418A (en) A kind of method of highly effective hydrogenation dechlorination purification trichloro-benzenes
CN107963965B (en) Preparation method of m-trifluoromethyl phenylpropionic acid
CN1842514A (en) Cycloalkylaminoacid compounds, processes for making and uses thereof
US20020091287A1 (en) Process for separating the diastereomeric bases of 2-[(Dimethylamino)methyl] -1-(3-methoxyphenyl) cylohexanol
CN1297875A (en) Process for producing 4-methoxyl methyl-2,3,5.6-tetrachlorophenmethylol
US20120130130A1 (en) Method of preparing neramexane
CN106966934B (en) A kind of preparation method of dialkyl dithio amino formate
CN111777518A (en) Synthetic preparation method of phenylethanolamine A labeled by stable isotope
US20100312010A1 (en) Process for the Preparation of (S)-Pregabalin
US7235693B2 (en) Process for chlorinating tertiary alcohols
EP1412340A2 (en) Process for the preparation of citalopram hydrobromide
CN115073303B (en) A preparation method of terbinafine hydrochloride Z-isomer
JP2008520666A (en) Method for purifying benzphetamine hydrochloride
WO2005121066A1 (en) The preparation method of (1 r,2s)-(-)-ephedrine or its hydrochloride
CN107382655B (en) Method for purifying tert-amylbenzene
RU2196765C2 (en) Method of isolation and purification of (rr,ss)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol (tramadol) hydrochloride

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CP03 Change of name, title or address
CP03 Change of name, title or address

Address after: 201203 Building 1, Lane 647, Songtao Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai

Patentee after: Shanghai Yunshengyan neoplasm Technology Co.,Ltd.

Patentee after: SHENZHEN SINOBIOWAY XINPENG BIOLOGICAL MEDICINE Co.,Ltd.

Address before: Room A679-04, Building No. 2, 351 GuoShoujing Road, China (Shanghai) Free Trade Pilot Area, Pudong New Area, Shanghai, 201203

Patentee before: SHANGHAI BOCIMED PHARMACEUTICAL Co.,Ltd.

Patentee before: SHENZHEN SINOBIOWAY XINPENG BIOLOGICAL MEDICINE Co.,Ltd.

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20230529

Address after: 201306 building 24, No. 356, ZHENGBO Road, Lingang xinpian District, China (Shanghai) pilot Free Trade Zone, Fengxian District, Shanghai

Patentee after: Shanghai bozhiyan new drug research Co.,Ltd.

Patentee after: SHENZHEN SINOBIOWAY XINPENG BIOLOGICAL MEDICINE Co.,Ltd.

Address before: 201203 Building 1, Lane 647, Songtao Road, Zhangjiang hi tech park, Zhangjiang hi tech park, Pudong New Area, Shanghai

Patentee before: Shanghai Yunshengyan neoplasm Technology Co.,Ltd.

Patentee before: SHENZHEN SINOBIOWAY XINPENG BIOLOGICAL MEDICINE Co.,Ltd.