CN111704577A - Preparation method of cinacalcet hydrochloride - Google Patents
Preparation method of cinacalcet hydrochloride Download PDFInfo
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- CN111704577A CN111704577A CN202010571508.2A CN202010571508A CN111704577A CN 111704577 A CN111704577 A CN 111704577A CN 202010571508 A CN202010571508 A CN 202010571508A CN 111704577 A CN111704577 A CN 111704577A
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- cinacalcet
- trifluoromethyl
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- toluene
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- QANQWUQOEJZMLL-PKLMIRHRSA-N cinacalcet hydrochloride Chemical compound Cl.N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 QANQWUQOEJZMLL-PKLMIRHRSA-N 0.000 title claims abstract description 37
- 229960000478 cinacalcet hydrochloride Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 229960003315 cinacalcet Drugs 0.000 claims abstract description 40
- VDHAWDNDOKGFTD-MRXNPFEDSA-N cinacalcet Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 VDHAWDNDOKGFTD-MRXNPFEDSA-N 0.000 claims abstract description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- NMTUHPSKJJYGML-UHFFFAOYSA-N 3-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=CC(C=O)=C1 NMTUHPSKJJYGML-UHFFFAOYSA-N 0.000 claims abstract description 19
- RTCUCQWIICFPOD-SECBINFHSA-N (1r)-1-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C([C@H](N)C)=CC=CC2=C1 RTCUCQWIICFPOD-SECBINFHSA-N 0.000 claims abstract description 14
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940091173 hydantoin Drugs 0.000 claims abstract description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000007112 amidation reaction Methods 0.000 claims abstract description 4
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 90
- -1 3-trifluoromethyl benzylidene Chemical group 0.000 claims description 50
- 238000010438 heat treatment Methods 0.000 claims description 35
- 239000007787 solid Substances 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 30
- 239000012065 filter cake Substances 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 21
- 239000008213 purified water Substances 0.000 claims description 21
- 239000012046 mixed solvent Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 16
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- 238000000967 suction filtration Methods 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- MILYCRZXXXKJFB-UHFFFAOYSA-N 5-[[3-(trifluoromethyl)phenyl]methylidene]imidazolidine-2,4-dione Chemical compound FC(F)(F)C1=CC=CC(C=C2C(NC(=O)N2)=O)=C1 MILYCRZXXXKJFB-UHFFFAOYSA-N 0.000 claims description 5
- 239000012535 impurity Substances 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 3
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 claims description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- 230000008034 disappearance Effects 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 5
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 229910000510 noble metal Inorganic materials 0.000 abstract description 3
- 230000009435 amidation Effects 0.000 abstract description 2
- 239000003638 chemical reducing agent Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 6
- JUQMRSYCLKEWAV-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]propanoic acid Chemical compound OC(=O)C(C)C1=CC=CC(C(F)(F)F)=C1 JUQMRSYCLKEWAV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- VGHOWOWLIXPTOA-UHFFFAOYSA-N cyclohexane;toluene Chemical compound C1CCCCC1.CC1=CC=CC=C1 VGHOWOWLIXPTOA-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000003541 multi-stage reaction Methods 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- KSBWHDDGWSYETA-SNAWJCMRSA-N (E)-3-(trifluoromethyl)cinnamic acid Chemical compound OC(=O)\C=C\C1=CC=CC(C(F)(F)F)=C1 KSBWHDDGWSYETA-SNAWJCMRSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010033963 Parathyroid tumour Diseases 0.000 description 1
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002092 calcimimetic effect Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 208000017997 tumor of parathyroid gland Diseases 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
-
- 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
- C07C209/50—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 carboxylic acid amides
-
- 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
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of cinacalcet hydrochloride, which takes m-trifluoromethylbenzaldehyde, hydantoin and (R) -1- (1-naphthyl) ethylamine as raw materials to prepare cinacalcet through condensation, hydrolysis, amidation and reduction reactions, and the cinacalcet reacts with hydrochloric acid to prepare the cinacalcet hydrochloride. Compared with the existing synthesis method of cinacalcet hydrochloride, the preparation method has the advantages of shorter route, low cost of raw materials, low price of condensing agents such as oxalyl chloride and thionyl chloride, low price of reducing agents such as sodium borohydride, no use of noble metal catalyst palladium carbon, avoidance of hydrogenation reaction steps, low requirement on equipment, adoption of normal pressure reaction operation and suitability for large-scale industrial production.
Description
Technical Field
The invention relates to a preparation method of cinacalcet hydrochloride, belonging to the field of drug synthesis.
Background
Cinacalcet hydrochloride, a calcimimetic developed by NPS Pharmaceuticals, usa under the chemical name of N- ((1R) -1- (1-naphthyl) ethyl) -3- (3- (trifluoromethyl) phenyl) propan-1-amine hydrochloride, is clinically used for treating secondary hyperparathyroidism caused by dialysis of chronic kidney diseases and hypercalcemia of patients with parathyroid tumors.
The m-trifluoro methylbenzaldehyde is used as the raw material and is an important method for preparing cinacalcet hydrochloride. Route (1) is represented by patent US6011068, and provides a method for preparing cinacalcet hydrochloride, wherein m-trifluoromethyl benzaldehyde is used as a raw material, m-trifluoromethyl cinnamic acid is obtained through a condensation reaction, m-trifluoromethyl phenylpropionic acid is obtained through palladium-carbon reduction, and cinacalcet hydrochloride is prepared through the steps of amidation, reduction, salt formation and the like. The scheme (2) and the scheme (3) are that m-trifluoromethyl phenylpropionic acid is reduced into alcohol and aldehyde, and then converted into cinacalcet hydrochloride through multi-step reaction. The methods need steps of hydrogenation reduction of palladium carbon and the like, need noble metal catalysts of palladium carbon, have high requirements on equipment for hydrogenation reaction, and have large investment. Therefore, there is a need for improvements to existing processes.
Disclosure of Invention
Based on the problems, the invention provides the preparation method of cinacalcet hydrochloride, which takes m-trifluoromethylbenzaldehyde and hydantoin as raw materials, has shorter steps and low production cost.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of cinacalcet hydrochloride, which takes m-trifluoromethyl benzaldehyde, hydantoin and (R) -1- (1-naphthyl) ethylamine as raw materials to prepare the cinacalcet, and the cinacalcet reacts with hydrochloric acid to prepare the cinacalcet hydrochloride, comprises the following steps:
(1) m-trifluoromethyl benzaldehyde and hydantoin are subjected to condensation reaction to prepare 5- (3-trifluoromethyl benzylidene) imidazoline-2, 4-diketone;
(2) hydrolyzing 5- (3-trifluoromethyl benzylidene) imidazoline-2, 4-dione to generate 2-oxo-m-trifluoromethyl phenylpropionic acid;
(3) preparation of (R) -3-propanoic acid by amidation reaction of 2-oxo-m-trifluoromethyl phenylpropionic acid and (R) -1- (1-naphthyl) ethylamine
(1- (naphthalen-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione;
(4) reduction of (R) -3- (1- (naphthalen-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propan-2, 3-dione to prepare cinacalcet;
(5) cinacalcet hydrochloride cinacalcet is prepared.
The preparation method of the cinacalcet hydrochloride comprises the following steps:
(1) adding hydantoin, m-trifluoromethylbenzaldehyde and a solvent into a reactor for dissolving, heating and refluxing for 6-8 h at 100 ℃, stopping heating after TLC detection and the substantial disappearance of the m-trifluoromethylbenzaldehyde, stirring for 8-12 h at room temperature, filtering, washing a filter cake, and performing vacuum drying on the filter cake at 50-55 ℃ to obtain a light yellow solid compound 5- (3-trifluoromethylbenzylidene) imidazoline-2, 4-dione;
(2) adding 5- (3-trifluoromethyl benzylidene) imidazoline-2, 4-diketone into an alkali solution, heating and refluxing for 2h at 105 ℃, stopping heating after the reaction is finished, cooling to room temperature, adjusting the pH value of the solution to 2-4 by hydrochloric acid under an ice bath condition, and crystallizing for 8-12 h; filtering, washing a filter cake, and drying the filter cake in vacuum at 50-55 ℃ to obtain a compound 2-oxo-m-trifluoromethyl phenylpropionic acid;
(3) adding 2-oxo-m-trifluoromethyl phenylpropionic acid into a solvent for dissolving, stirring for 1h, cooling to-10 ℃, then adding a condensing agent, adding N, N-dimethylformamide after adding, heating to 20 ℃, stirring for 1h, then cooling to below 0 ℃, dropwise adding an N-methyl pyrrolidone solution of (R) -1- (1-naphthyl) ethylamine, keeping the temperature and stirring for 1h after dropwise adding, adding purified water and toluene into the reaction solution, stirring for 15min, transferring into a separating funnel, standing for liquid separation, drying, suction filtering and concentrating to obtain a compound (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione;
(4) adding (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione and sodium borohydride into a solvent for dissolving, heating to 40-60 ℃, slowly dropwise adding a Lewis acid solution at the speed of 0.5mL/s, after dropwise adding, keeping the temperature at 55-60 ℃ for reacting for 1h, dropwise adding purified water, and after dropwise adding, carrying out reflux reaction at 90 ℃ for 2 h; concentrating under reduced pressure to remove solvent, adding toluene, transferring the mixed solution into a separating funnel, shaking, standing for separating liquid, drying, vacuum filtering, and concentrating; adding the concentrate into a mixed solvent of toluene and cyclohexane in a volume ratio of 1:1, heating and refluxing at 90 ℃ for 15min, cooling and crystallizing for 2h, carrying out suction filtration, washing a filter cake with the mixed solvent of toluene and cyclohexane, and drying to obtain a cinacalcet white solid;
adding the cinacalcet white solid into a mixed solvent of toluene and n-hexane with a volume ratio of 1:1, heating and refluxing for 1h, dissolving the solid, stopping heating, cooling and crystallizing for 2-4h at 0 ℃, performing suction filtration, washing and drying a filter cake by using the mixed solvent of toluene and cyclohexane to obtain the cinacalcet white solid, wherein the maximum single impurity of cinacalcet is less than 0.10% by recrystallization;
(5) dissolving the cinacalcet white solid in a solvent, heating to 50 ℃, adding hydrochloric acid, dropwise adding purified water, cooling to 0 ℃ after dropwise adding, keeping the temperature and stirring for 2 hours, performing suction filtration, washing a filter cake by using a mixed solvent of an organic solvent and water, and drying to obtain the cinacalcet white solid.
The solvent used in the step (1) is one or a mixture of more than two of water, methanol, ethanol, isopropanol and n-propanol; the solvent used in the step (3) is one or a mixture of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethyl pyrrolidone and N, N-dimethylformamide; the solvent used in the step (4) is one or a mixture of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, cyclohexane and n-hexane; the solvent used in the step (5) is acetone, acetonitrile, methanol, ethanol or isopropanol.
The mol ratio of the m-trifluoromethylbenzaldehyde to the hydantoin in the step (1) is 1: 1-1: 1.5.
The alkali solution in the step (2) is sodium hydroxide solution or potassium hydroxide solution, wherein the solvent for dissolving the alkali is one or a mixture of more than two of water, methanol, ethanol, isopropanol and n-propanol; the molar ratio of the 5- (3-trifluoromethyl benzylidene) imidazoline-2, 4-diketone to the alkali is 1: 1.1-1: 3.0.
The condensing agent in the step (3) is oxalyl chloride or thionyl chloride; the volume-to-mass ratio (mL/g) of the solvent to the 2-oxo-m-trifluoromethylphenylpropionic acid is 4: 1-15: 1; the mol of the condensing agent and the 2-oxo-m-trifluoromethyl phenylpropionic acid is 3: 1-1: 1; the volume-to-mass ratio (mL/g) of the N, N-dimethylformamide to the 2-oxo-m-trifluoromethylphenylpropionic acid is 1: 1-1: 5; the volume-mass ratio (mL/g) of N-methylpyrrolidone to (R) -1- (1-naphthyl) ethylamine in the N-methylpyrrolidone solution of (R) -1- (1-naphthyl) ethylamine is 4: 1-10: 1; the volume-to-mass ratio (mL/g) of the purified water to the 2-oxo-m-trifluoromethylphenylpropionic acid is 5: 1-15: 1; the volume of the toluene and the purified water is 5: 1-0.5: 1.
The Lewis acid in the step (4) is boron trifluoride diethyl etherate solution or boron trifluoride tetrahydrofuran solution; the molar ratio of the (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione, sodium borohydride and Lewis acid is 1:2: 2-1: 6: 6.
The volume-to-mass ratio (mL/g) of the solvent in the step (4) to the (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione is 5: 1-15: 1; the volume ratio of the purified water to the solvent is 1: 3-2: 1; the volume-to-mass ratio (mL/g) of the toluene to the (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione is 5: 1-15: 1; the volume-to-mass ratio (mL/g) of the toluene-n-hexane mixed solvent to the cinacalcet white solid is 5: 1-15: 1.
The volume-to-mass ratio (mL/g) of the solvent to the cinacalcet in the step (5) is 5: 1-12: 1; the molar ratio of the hydrochloric acid to the cinacalcet is 1: 1-4: 1; the volume ratio of the purified water to the solvent is 1: 1-5: 1.
The synthetic process route of the invention is as follows:
the invention has the beneficial effects that:
1. the method adopts m-trifluoromethylbenzaldehyde, hydantoin and (R) -1- (1-naphthyl) ethylamine as raw materials to prepare (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-diketone, then prepares cinacalcet by reduction, and the cinacalcet reacts with hydrochloric acid to prepare cinacalcet hydrochloride, which does not relate to the step of preparing m-trifluoromethylphenylpropionic acid by multi-step reaction of m-trifluoromethylbenzaldehyde.
2. Compared with the existing synthesis method of cinacalcet hydrochloride, the cinacalcet hydrochloride prepared by the method has the advantages of shorter steps, low production cost, no use of a noble metal catalyst palladium-carbon, avoidance of hydrogenation reaction steps and lower equipment requirement, the condensing agent used by the method is low-price oxalyl chloride, thionyl chloride and the like, and the reducing agent is low-price sodium borohydride, so that the method is suitable for large-scale industrial production.
3. The method can prepare the cinacalcet hydrochloride with higher purity by optimizing technical parameters in the preparation method, the purity of the cinacalcet hydrochloride is up to more than 99.6 percent, the maximum single impurity is less than 0.10 percent, and the medicinal requirements can be met by fewer reaction steps.
Drawings
FIG. 1 shows the hydrogen spectrum of a compound obtained in example five of the present invention;
FIG. 2 is a carbon spectrum of a compound obtained in example five of the present invention;
FIG. 3 is a mass spectrum of a compound obtained in example V of the present invention.
Detailed Description
EXAMPLE A preparation of the Compound 5- (3-trifluoromethylbenzylidene) imidazoline-2, 4-dione
21.0g hydantoin, 34.8g m-trifluoromethylbenzaldehyde, 200mL water and 20mL absolute ethyl alcohol are added into a 500mL reaction bottle, heating reflux is carried out for 6h at 100 ℃, after the m-trifluoromethylbenzaldehyde basically disappears through TLC detection, heating is stopped, stirring is carried out for 10h at room temperature, filtering is carried out, a filter cake is washed by a small amount of absolute ethyl alcohol, and drying is carried out in vacuum at 50 ℃ under the vacuum degree of-0.09 MPa, so that 43.5g of compound 5- (3-trifluoromethylbenzylidene) imidazoline-2, 4-diketone light yellow solid is obtained, and the yield is 85.0% (calculated by the m-trifluoromethylbenzaldehyde).
EXAMPLE two preparation of the Compound 2-oxo-m-trifluoromethylbenzenepropanoic acid
Adding 43g of 5- (3-trifluoromethyl benzylidene) imidazoline-2, 4-diketone light yellow solid and 200mL of 5% sodium hydroxide solution into a 500mL reaction bottle, heating and refluxing at 105 ℃ for 2h, stopping heating after the reaction is finished, cooling to room temperature, adjusting the pH value of the solution to 3 by using 10% hydrochloric acid under an ice bath condition, and stirring for crystallization for 9 h; filtering, washing the filter cake with a small amount of ethanol, and vacuum drying at 50 ℃ to obtain 30.8g of the compound 2-oxo-m-trifluoromethyl phenylpropionic acid with the yield of 75.1%.
EXAMPLE preparation of the three compound (R) -3- (1- (naphthalen-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propan-2, 3-dione
Adding 29.5g of 2-oxo-m-trifluoromethyl phenylpropionic acid and 150mL of anhydrous tetrahydrofuran into a 500mL reaction bottle, stirring for 30min, cooling to-10 ℃, dropwise adding 22.1g/14.7mL of oxalyl chloride, adding 10mL of N, N-dimethylformamide after addition, slowly heating to 20 ℃, stirring for 1h, then cooling to below 0 ℃, dropwise adding 21.0g of (R) -1- (1-naphthyl) ethylamine in N-methylpyrrolidone solution 82.2g of [ (R) -1- (1-naphthyl) ethylamine dissolved in 100mL of N-methylpyrrolidone, the mass percent concentration is 17.0% ], after dropwise adding, stirring at constant temperature for 1h, adding the reaction solution into 300mL of purified water, adding 200mL of toluene, stirring for 15min, transferring into a 1000mL separating funnel, standing, separating, drying the organic phase with anhydrous sodium sulfate overnight, the mixture was filtered by suction and concentrated to give 36.2g of (R) -3- (1- (naphthalen-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propan-2, 3-dione as a white solid in 74.0% yield.
EXAMPLE preparation of the Tetracompound cinacalcet
Adding 35.0g of (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-diketone white solid, 350mL of tetrahydrofuran solution and 17.2g of sodium borohydride into a 1000mL reaction flask, heating to 50 ℃, slowly dropwise adding 58mL of boron trifluoride diethyl etherate solution at a dropwise adding speed of about 0.5mL/s, keeping the temperature at 55-60 ℃ for reaction for 1h after about 2h of dropwise adding is finished, then dropwise adding 200mL of purified water, and carrying out reflux reaction at 90 ℃ for 2h after dropwise adding is finished. Concentrating under reduced pressure to remove tetrahydrofuran solution in the mixed solvent, adding 200mL of toluene, transferring the mixed solution into a 1000mL separating funnel, shaking, standing, separating, and drying with anhydrous sodium sulfate. And (5) carrying out suction filtration and concentration. Adding 100mL of toluene and 100mL of cyclohexane into the concentrate, heating and refluxing for 15min at 90 ℃, cooling and crystallizing for 2h, carrying out suction filtration, washing a filter cake by using a small amount of mixed solvent of toluene and cyclohexane, and carrying out vacuum drying on the filter cake at 50 ℃ to obtain 24.3g of cinacalcet white solid, wherein the yield is 74.9% and the purity is 99.24%.
Adding 23.0g of cinacalcet white solid, 90mL of toluene and 90mL of n-hexane into a 500mL reaction bottle, heating and refluxing for 60min at 90 ℃, dissolving the solid, stopping heating, cooling and crystallizing for more than 2h at 0 ℃, performing suction filtration, washing a filter cake by using a small amount of toluene-cyclohexane mixed solvent (the volume ratio of toluene to cyclohexane is 1: 1), and performing vacuum drying on the filter cake at 50 ℃ to obtain 19.2g of cinacalcet white solid, wherein the yield is 83.5% (the yield is the recrystallization yield in the step) and the purity is 99.63% (area normalization method).
EXAMPLE preparation of the pentacompound cinacalcet hydrochloride
Adding 100mL of acetone and 18.0g of cinacalcet white solid into a 500mL reaction bottle, heating to 50 ℃, adding 10mL of hydrochloric acid, dropwise adding 200mL of purified water, cooling to 0 ℃, keeping the temperature and stirring for 2h, performing suction filtration, washing a filter cake by using a small amount of acetone-water mixed solvent (the volume ratio of the acetone to the purified water is 1: 2), and performing vacuum drying on the filter cake at 50 ℃ to obtain 15.2g of cinacalcet hydrochloride white solid, wherein the yield is 77.2%, the purity is 99.68%, and the maximum single impurity content is less than 0.10%.
The obtained cinacalcet hydrochloride compound was analyzed by hydrogen, carbon and mass spectrometry, and the results are shown in fig. 1 to 3.
EXAMPLE preparation of the hexacompound cinacalcet
Adding 35.0g of (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-diketone white solid, 420mL of tetrahydrofuran solution and 13.8g of sodium borohydride into a 1000mL reaction flask, heating to 55 ℃, slowly dropwise adding 51mL of boron trifluoride tetrahydrofuran solution at a dropwise adding speed of about 0.5mg/mL, after about 2h of dropwise adding, preserving heat for 1h, then dropwise adding 200mL of purified water, and after dropwise adding, carrying out reflux reaction at 90 ℃ for 2 h. Concentrating under reduced pressure to remove tetrahydrofuran solution in the mixed solvent, adding 200mL of toluene, transferring the mixed solution into a 1000mL separating funnel, shaking, standing, separating, and drying with anhydrous sodium sulfate. And (5) carrying out suction filtration and concentration. Adding 100mL of toluene and 100mL of cyclohexane into the concentrate, heating and refluxing for 15min at 90 ℃, cooling and crystallizing for 2h, carrying out suction filtration, washing a filter cake by using a small amount of toluene and cyclohexane mixed solvent (the volume ratio of toluene to cyclohexane is 1: 1), and carrying out vacuum drying on the filter cake at 50 ℃ to obtain 23.4g of cinacalcet white solid, wherein the yield is 72.0 percent and the purity is 99.18 percent.
Adding 23.0g of cinacalcet white solid, 90mL of toluene and 90mL of n-hexane into a 500mL reaction bottle, heating and refluxing for 30min at 90 ℃, dissolving the solid, stopping heating, cooling and crystallizing for 2-4h at 0 ℃, performing suction filtration, washing a filter cake by using a small amount of toluene-cyclohexane mixed solvent (the volume ratio of toluene to cyclohexane is 1: 1), and performing vacuum drying on the filter cake at 50 ℃ to obtain 18.6g of cinacalcet white solid, wherein the yield is 80.9% (the yield is the recrystallization yield in the step) and the purity is 99.65% (area normalization method).
EXAMPLE preparation of the heptad cinacalcet hydrochloride
Adding 100mL of absolute ethyl alcohol and 18.0g of cinacalcet white solid into a 500mL reaction bottle, heating to 50 ℃, adding 10mL of hydrochloric acid, dropwise adding 200mL of purified water, cooling to 0 ℃, keeping the temperature and stirring for 2h, performing suction filtration, washing a filter cake with a small amount of ethanol-water mixed solvent (the volume ratio of the ethyl alcohol to the purified water is 1: 2), and performing vacuum drying on the filter cake at 50 ℃ to obtain 16.4g of cinacalcet hydrochloride white solid, wherein the yield is 82.0%, the purity is 99.72%, and the maximum single impurity is less than 0.10%.
Claims (9)
1. The preparation method of cinacalcet hydrochloride is characterized in that the cinacalcet is prepared by taking m-trifluoromethylbenzaldehyde, hydantoin and (R) -1- (1-naphthyl) ethylamine as raw materials, and the cinacalcet reacts with hydrochloric acid to prepare the cinacalcet hydrochloride, and comprises the following steps:
(1) m-trifluoromethyl benzaldehyde and hydantoin are subjected to condensation reaction to prepare 5- (3-trifluoromethyl benzylidene) imidazoline-2, 4-diketone;
(2) hydrolyzing 5- (3-trifluoromethyl benzylidene) imidazoline-2, 4-dione to generate 2-oxo-m-trifluoromethyl phenylpropionic acid;
(3) amidation reaction of 2-oxo-m-trifluoromethyl phenylpropionic acid and (R) -1- (1-naphthyl) ethylamine to prepare (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione;
(4) reduction of (R) -3- (1- (naphthalen-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propan-2, 3-dione to prepare cinacalcet;
(5) cinacalcet hydrochloride cinacalcet is prepared.
2. A method of preparing cinacalcet hydrochloride according to claim 1, comprising the steps of:
(1) adding hydantoin, m-trifluoromethylbenzaldehyde and a solvent into a reactor for dissolving, heating and refluxing for 6-8 h at 100 ℃, stopping heating after TLC detection and the substantial disappearance of the m-trifluoromethylbenzaldehyde, stirring for 8-12 h at room temperature, filtering, washing a filter cake, and performing vacuum drying on the filter cake at 50-55 ℃ to obtain a light yellow solid compound 5- (3-trifluoromethylbenzylidene) imidazoline-2, 4-dione;
(2) adding 5- (3-trifluoromethyl benzylidene) imidazoline-2, 4-diketone into an alkali solution, heating and refluxing for 2h at 105 ℃, stopping heating after the reaction is finished, cooling to room temperature, adjusting the pH value of the solution to 2-4 by hydrochloric acid under an ice bath condition, and crystallizing for 8-12 h; filtering, washing a filter cake, and drying the filter cake in vacuum at 50-55 ℃ to obtain a compound 2-oxo-m-trifluoromethyl phenylpropionic acid;
(3) adding 2-oxo-m-trifluoromethyl phenylpropionic acid into a solvent for dissolving, stirring for 1h, cooling to-10 ℃, then adding a condensing agent, adding N, N-dimethylformamide after adding, heating to 20 ℃, stirring for 1h, then cooling to below 0 ℃, dropwise adding an N-methyl pyrrolidone solution of (R) -1- (1-naphthyl) ethylamine, keeping the temperature and stirring for 1h after dropwise adding, adding purified water and toluene into the reaction solution, stirring for 15min, transferring into a separating funnel, standing for liquid separation, drying, suction filtering and concentrating to obtain a compound (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione;
(4) adding (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione and sodium borohydride into a solvent for dissolving, heating to 40-60 ℃, slowly dropwise adding a Lewis acid solution at the speed of 0.5mL/s, after dropwise adding, keeping the temperature at 55-60 ℃ for reacting for 1h, dropwise adding purified water, and after dropwise adding, carrying out reflux reaction at 90 ℃ for 2 h; concentrating under reduced pressure to remove solvent, adding toluene, transferring the mixed solution into a separating funnel, shaking, standing for separating liquid, drying, vacuum filtering, and concentrating; adding the concentrate into a mixed solvent of toluene and cyclohexane in a volume ratio of 1:1, heating and refluxing at 90 ℃ for 15min, cooling and crystallizing for 2h, carrying out suction filtration, washing a filter cake with the mixed solvent of toluene and cyclohexane, and drying to obtain a cinacalcet white solid;
adding the cinacalcet white solid into a mixed solvent of toluene and n-hexane with a volume ratio of 1:1, heating and refluxing for 1h, dissolving the solid, stopping heating, cooling and crystallizing for 2-4h at 0 ℃, performing suction filtration, washing and drying a filter cake by using the mixed solvent of toluene and cyclohexane to obtain the cinacalcet white solid, wherein the maximum single impurity of cinacalcet is less than 0.10% by recrystallization;
(5) dissolving the cinacalcet white solid in a solvent, heating to 50 ℃, adding hydrochloric acid, dropwise adding purified water, cooling to 0 ℃ after dropwise adding, keeping the temperature and stirring for 2 hours, performing suction filtration, washing a filter cake by using a mixed solvent of an organic solvent and water, and drying to obtain the cinacalcet white solid.
3. The method for preparing cinacalcet hydrochloride according to claim 1 or 2, characterized in that the solvent used in step (1) is one or a mixture of two or more of water, methanol, ethanol, isopropanol, and n-propanol; the solvent used in the step (3) is one or a mixture of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethyl pyrrolidone and N, N-dimethylformamide; the solvent used in the step (4) is one or a mixture of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, cyclohexane and n-hexane; the solvent used in the step (5) is acetone, acetonitrile, methanol, ethanol or isopropanol.
4. The method for preparing cinacalcet hydrochloride according to claim 1 or 2, characterized in that the molar ratio of m-trifluoromethylbenzaldehyde to hydantoin in step (1) is 1:1 to 1: 1.5.
5. The method for preparing cinacalcet hydrochloride according to claim 1 or 2, characterized in that the alkali solution in step (2) is a sodium hydroxide solution or a potassium hydroxide solution, wherein the solvent used for dissolving the alkali is one or a mixture of two or more of water, methanol, ethanol, isopropanol, and n-propanol; the molar ratio of the 5- (3-trifluoromethyl benzylidene) imidazoline-2, 4-diketone to the alkali is 1: 1.1-1: 3.0.
6. The method for preparing cinacalcet hydrochloride according to claim 1 or 2, wherein the condensing agent in step (3) is oxalyl chloride or thionyl chloride; the volume-to-mass ratio (mL/g) of the solvent to the 2-oxo-m-trifluoromethylphenylpropionic acid is 4: 1-15: 1; the mol of the condensing agent and the 2-oxo-m-trifluoromethyl phenylpropionic acid is 3: 1-1: 1; the volume-to-mass ratio (mL/g) of the N, N-dimethylformamide to the 2-oxo-m-trifluoromethylphenylpropionic acid is 1: 1-1: 5; the volume-mass ratio (mL/g) of N-methylpyrrolidone to (R) -1- (1-naphthyl) ethylamine in the N-methylpyrrolidone solution of (R) -1- (1-naphthyl) ethylamine is 4: 1-10: 1; the volume-to-mass ratio (mL/g) of the purified water to the 2-oxo-m-trifluoromethylphenylpropionic acid is 5: 1-15: 1; the volume of the toluene and the purified water is 5: 1-0.5: 1.
7. The method for preparing cinacalcet hydrochloride according to claim 1 or 2, characterized in that the lewis acid of step (4) is boron trifluoride diethyl etherate solution or boron trifluoride tetrahydrofuran solution; the molar ratio of the (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione, sodium borohydride and Lewis acid is 1:2: 2-1: 6: 6.
8. The method for preparing cinacalcet hydrochloride according to claim 1 or 2, characterized in that the volume-to-mass ratio (mL/g) of the solvent of step (4) to (R) -3- (1- (naphthalen-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione is 5:1 to 15: 1; the volume ratio of the purified water to the solvent is 1: 3-2: 1; the volume-to-mass ratio (mL/g) of the toluene to the (R) -3- (1- (naphthalene-1-yl) ethylamino) -1- (3- (trifluoromethyl) phenyl) propane-2, 3-dione is 5: 1-15: 1; the volume-to-mass ratio (mL/g) of the toluene-n-hexane mixed solvent to the cinacalcet white solid is 5: 1-15: 1.
9. The preparation method of cinacalcet hydrochloride according to claim 1 or 2, characterized in that the volume-to-mass ratio (mL/g) of the solvent to cinacalcet in step (5) is 5:1 to 12: 1; the molar ratio of the hydrochloric acid to the cinacalcet is 1: 1-4: 1; the volume ratio of the purified water to the solvent is 1: 1-5: 1.
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