CN101993379B - Preparation method of cinacalcet hydrochloride - Google Patents
Preparation method of cinacalcet hydrochloride Download PDFInfo
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- CN101993379B CN101993379B CN 201010531079 CN201010531079A CN101993379B CN 101993379 B CN101993379 B CN 101993379B CN 201010531079 CN201010531079 CN 201010531079 CN 201010531079 A CN201010531079 A CN 201010531079A CN 101993379 B CN101993379 B CN 101993379B
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- cinacalcet hydrochloride
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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 27
- 229960000478 cinacalcet hydrochloride Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 22
- QQLIGMASAVJVON-UHFFFAOYSA-N 1-naphthalen-1-ylethanone Chemical compound C1=CC=C2C(C(=O)C)=CC=CC2=C1 QQLIGMASAVJVON-UHFFFAOYSA-N 0.000 claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012069 chiral reagent Substances 0.000 claims abstract description 7
- 150000004820 halides Chemical class 0.000 claims abstract description 7
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- FDMMWNHRDWSSOL-UHFFFAOYSA-N FC(F)(F)C1=CC=CC=C1.[I] Chemical compound FC(F)(F)C1=CC=CC=C1.[I] FDMMWNHRDWSSOL-UHFFFAOYSA-N 0.000 claims description 3
- -1 alkaloid compound Chemical class 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- RUHKUUFAKLLDEY-UHFFFAOYSA-N FC(C1=CC=CC=C1)(F)F.[Br] Chemical compound FC(C1=CC=CC=C1)(F)F.[Br] RUHKUUFAKLLDEY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- NYLUECXRXLRAJH-UHFFFAOYSA-N trifluoromethylbenzene;hydrofluoride Chemical compound F.FC(F)(F)C1=CC=CC=C1 NYLUECXRXLRAJH-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 229930013930 alkaloid Natural products 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 abstract 1
- 238000000034 method Methods 0.000 description 7
- 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 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229960003315 cinacalcet Drugs 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- WJVGMHDMWXHVFE-UHFFFAOYSA-N ethanamine;naphthalene Chemical compound CCN.C1=CC=CC2=CC=CC=C21 WJVGMHDMWXHVFE-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- GWJSQKNYHPYZRN-UHFFFAOYSA-N 2-methylpropane-2-sulfonamide Chemical compound CC(C)(C)S(N)(=O)=O GWJSQKNYHPYZRN-UHFFFAOYSA-N 0.000 description 1
- RUJHATQMIMUYKD-UHFFFAOYSA-N 2-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C(CCN)=CC=CC2=C1 RUJHATQMIMUYKD-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N CC(C(O)=O)c1ccc(cc(cc2)OC)c2c1 Chemical compound CC(C(O)=O)c1ccc(cc(cc2)OC)c2c1 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- RTCUCQWIICFPOD-UHFFFAOYSA-N CC(c1c(cccc2)c2ccc1)N Chemical compound CC(c1c(cccc2)c2ccc1)N RTCUCQWIICFPOD-UHFFFAOYSA-N 0.000 description 1
- RTCUCQWIICFPOD-SECBINFHSA-N C[C@H](c1c(cccc2)c2ccc1)N Chemical compound C[C@H](c1c(cccc2)c2ccc1)N RTCUCQWIICFPOD-SECBINFHSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 201000002980 Hyperparathyroidism Diseases 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- BDFJWKALVSRGSR-UHFFFAOYSA-N butan-1-ol;sodium Chemical compound [Na].CCCCO BDFJWKALVSRGSR-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- PYNUOAIJIQGACY-UHFFFAOYSA-N propylazanium;chloride Chemical compound Cl.CCCN PYNUOAIJIQGACY-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 description 1
- 229940116949 sensipar Drugs 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel preparation method of cinacalcet hydrochloride, belonging to the technical filed of preparation of cinacalcet hydrochloride and comprising the steps of: firstly, with 1-acetonaphthone (II) as a raw material, introducing a chiral reagent, and reducing with sodium borohydride to obtain a compound (III); secondly, dissolving the compound (III) into a proper solvent, and reacting with 3-propiolic halide to obtain a compound (IV); thirdly, adding a proper catalyst into the obtained compound (IV) in a solvent at a certain temperature, and carrying out a coupling reaction with meta-chlorobenzotrifluoride to generate a compound (V); and fourthly, reducing the obtained compound (V) with a proper reducing agent and acidizing with hydrochloric acid to obtain the cinacalcet hydrochloride (I). The cinacalcet hydrochloride is synthesized chirally, and has the advantages of special reaction course, good selectivity, high yield, less reaction steps, safe and simple operation and little environment pollution. The raw material used in the reaction course is easy to obtain, has lower production cost and high optical purity, and is suitable for industrialized production.
Description
Technical field:
The present invention relates to a kind of new preparation method of cinacalcet hydrochloride who is used for the treatment of the hyperparathyroidism medicine.The preparing technical field that belongs to cinacalcet hydrochloride.
Background technology:
2004, FDA Food and Drug Administration ratified the secondary hyperparathyroidism that can treat the chronic nephropathy dialysis patient by Amgen production, can treat again the too much new drug cinacalcet of Parathyroid carninomatosis people blood calcium.Cinacalcet hydrochloride is N-[1-(R)-(-)-naphthyl] ethyl]-3-[3-(trifluoromethyl) phenyl]-the international name of 1-propylamin hydrochloride, No. CAS is 364782-34-3, chemical formula is C
22H
22F
3NHCl, its structural formula is as follows:
Cinacalcet hydrochloride is a kind of oral Sensipar, is this type of medicine that the first is ratified by FDA.In the U.S., it is with title
Sell; In Europe, it is with name
With
Disappear and sell.It is granted is used for the treatment of chronic's the Secondary cases hyperthyroidism of dialysis and the hypercalcinemia that treatment suffers from thyroid cancer patients.
United States Patent (USP) the 6th, 211 has been described cinacalcet and pharmaceutical acceptable acid muriate additive salt thereof, but the embodiment of any preparation cinacalcet or cinacalcet hydrochloride is not provided for No. 244.
Drugs 2002,27 (9), and 831-836 discloses according to United States Patent (USP) the 6th, 211, the general method of describing in No. 244 prepares the synthetic schemes of cinacalcet hydrochloride, and namely naphthalene ethylamine and 3-(3-trifluoromethyl) propionic acid is through the catalysis of isopropyl titanate, and synthetic route is as follows:
The shortcoming of this technique is: 1. side reaction is serious, and productive rate is low; 2. use expensive and hypertoxic sodium cyanoborohydride arranged as reductive agent, being unfavorable for suitability for industrialized production.In addition, this patent does not illustrate the synthesis technique of important intermediate R-1-naphthalene ethylamine and 3-(3-trifluoromethyl) propionic acid, causes performance difficulty.
International patent is: WO 2008/058235 A2 discloses the technique of other three kinds of synthetic cinacalcets, and synthetic route is as follows respectively:
These three kinds of methods are similar, with Drugs 2002,27 (9), the disclosed route of 831-836 is also roughly the same, but in the embodiment 3 and 4 of WO2008/058235 A2 patent, provided the method with the synthetic R-1-naphthalene ethylamine of 1-acetonaphthone, i.e. 1-acetonaphthone and ammonium formiate reaction obtains the 1-naphthalene ethylamine of racemization, use again D (+) Naproxen Base to split, namely get (R)-1-naphthalene ethylamine.Synthetic route is as follows:
Although the synthesis step that WO2008/058235 A2 patent provides is more comprehensive, also has shortcomings: 1. generate by product serious, and obtain the naphthalene ethylamine process and need split, productive rate is lower; 2. used and poisonous reagent harmful to environment in reaction process, as HOBt (azimidobenzene), DCC (dicyclohexylcarbodiimide) etc.; 3. product will be purified through separating for several times, and step is various, is unfavorable for suitability for industrialized production.
Although the report about the cinacalcet synthetic method is a lot, its limitation is arranged, as low in productive rate, step is various, the poisonous or harm environment etc. of the reagent of use.
Summary of the invention:
The object of the invention is to, provide that a kind of to have a yield high, operational safety is simple, and production cost is low, and environmental pollution is little, is applicable to the new preparation method of cinacalcet hydrochloride of suitability for industrialized production.
The present invention realizes above-mentioned purpose by following technical solution:
The preparation method that a kind of cinacalcet hydrochloride is new, described cinacalcet hydrochloride is the Chiral Amine compounds, it is characterized in that: it comprises the following steps:
The first step: with the 1-acetonaphthone
Be starting raw material, with suitable dissolution with solvents (quantity of solvent is 8～12mL/g 1-acetonaphthone), under 20～200 ℃ of temperature condition, introduce chiral reagent and isopropyl titanate (mol ratio of chiral reagent and 1-acetonaphthone is 1: 1～2: 1), (mol ratio of isopropyl titanate and 1-acetonaphthone is 0.5: 1～2: 1), then use sodium borohydride reduction (mol ratio of sodium borohydride and 1-acetonaphthone is 1: 1～2: 1), namely obtain compound (III)
The preferred temperature of described temperature of reaction is 50～120 ℃, and optimum temps is 60～80 ℃;
Described suitable solvent includes but are not limited to a kind of in following material: methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), normal heptane, toluene, methyl tertiary butyl ether;
Described chiral reagent includes but are not limited to a kind of in following material: the amine of chirality, the acid amides of chirality, the amino acid of chirality; Wherein take the chirality t-butyl sulfonamide as optimal selection;
Second step: the compound (III) that obtains in the first step is dissolved in (quantity of solvent is 8～12mL/g compound III) in suitable solvent, under 0～100 ℃ of temperature condition, alkalization (alkali that adds is 1.0～2.0 equivalents), add 3-propiolic halide (mol ratio of 3-propiolic halide and compound III is 1: 1～2: 1), reaction obtains compound (IV) again
Described suitable reagent includes but are not limited to a kind of in following material: methyl alcohol, ethanol, Virahol, methyl tertiary butyl ether, ether, ethyl acetate, tetrahydrofuran (THF);
The preferred temperature of described temperature of reaction is 20～80 ℃, and optimum temps is 40～60 ℃;
The compound that is used for alkalizing includes but are not limited to a kind of in following material: sodium hydride, sodium methylate, sodium ethylate, n-propyl alcohol, sodium isopropylate, propyl carbinol sodium, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate; Sodium hydride wherein, sodium tert-butoxide, potassium tert.-butoxide are optimal selection;
Described 3-propiolic halide is 3-chloroallylene or 3-propargyl bromide;
The 3rd step: with the compound (IV) that obtains in second step, be dissolved in suitable solvent at 20～180 ℃ of temperature in (quantity of solvent is 8～12mL/g compound IV), add again a halogen phenylfluoroform (mol ratio of a halogen phenylfluoroform and compound IV is 0.8: 1～2: 1), add again diethylamine and suitable catalyzer (mol ratio of diethylamine and compound IV is 0.8: 1～2: 1), (the catalyzer add-on is 0.5～2 mole of catalysis equivalent), namely obtain compound (V)
The preferred temperature of described temperature of reaction is 50～160 ℃, and optimum temps is 50～80 ℃;
Described suitable reagent includes but are not limited to a kind of in following material: methyl alcohol, ethanol, Virahol, methyl tertiary butyl ether, glycol dimethyl ether, ethyl acetate, tetrahydrofuran (THF);
Described suitable catalyzer includes but are not limited to a kind of in following material: palladium, Palladous chloride, palladium iodide, cuprous iodide;
Described halogen phenylfluoroform is: a fluoride trifluoro toluene, meta-chlorobenzotrifluoride, iodine phenylfluoroform between a 5 bromine benzotrifluoride reaches;
The 4th step: will add suitable solvent (quantity of solvent is 8～12mL/g compound V) in the 3rd compound (V) that obtain of step, (pressure is 5Kg/cm to pass into hydrogen at the temperature of-20～200 ℃
2) and add catalyzer (catalyzer and compound V weight ratio are 1: 4.5～1: 5.5), then add hydrochloric acid (mol ratio of hydrochloric acid and compound V is 1: 1～2: 1) in the reduzate that obtains, namely obtain target product cinacalcet hydrochloride (I)
Described suitable solvent includes but are not limited to a kind of in following material: methyl alcohol, ethanol, Virahol, acetone, ethyl acetate, ether, methyl tertiary butyl ether, normal heptane, toluene, tetrahydrofuran (THF);
The preferred temperature of described temperature of reaction is 0～100 ℃, and optimum temps is 50～70 ℃;
Described suitable reducing catalyst includes but are not limited to a kind of in following material: palladium carbon, metal platinum, metallic nickel, metal Ru, metal rhodium.
The synthesis route that cinacalcet hydrochloride of the present invention (I) is described with chemical structural formula is as follows:
The present invention's beneficial effect compared with prior art is:
1, the present invention is that chirality is synthetic, and the reaction circuit is unique, and selectivity is good, and yield is high, and reactions steps is few, and process choice is reasonable, and is simple to operate.
2, raw material sources of the present invention are convenient, and cost is low; Environmental pollution is little, and operational safety is applicable to suitability for industrialized production.
Embodiment:
Below in conjunction with a specific embodiment, the present invention is further described, but the present invention not only is confined to following embodiment.
The first step: preparation compound (III)
Add 1-acetonaphthone (1.7g) in the round-bottomed flask of 100mL, dissolve with tetrahydrofuran (THF) (20mL), add again (R)-t-butyl sulfonamide (2.2g), reaction mixture is heated to 70 ℃, then add the 2.8g isopropyl titanate in flask, after approximately 10min adds, insulation reaction 22h.Complete with the TLC monitoring reaction, then be cooled to approximately 0 ℃.Sodium borohydride (0.5g) is dissolved in tetrahydrofuran (THF) (3mL), is cooled to 0 ℃, slowly be added in above-mentioned reaction mixture, approximately 10min, after adding, be heated to normal temperature and insulated and stirred 5h.After the TLC monitoring reaction is complete, be cooled to 0 ℃.Stir again 5min, the suspension liquid that obtains is filtered, and filter cake washs with ethyl acetate (10mL), and washings adds saturated NaCl (10mL), water is used ethyl acetate extraction three times again, each extraction ethyl acetate amount used is 10mL, merges organic phase and uses dried over sodium sulfate, filters, filtrate normal temperature concentrating under reduced pressure, and dry, namely get compound (III) 2.15g, yield is 78%.
Second step: preparation compound (IV)
Separately get the round-bottomed flask of a 50mL, the compound (III) that the first step is obtained adds, and dissolves with the 25mL methyl tertiary butyl ether, is heated to add after 50 ℃ the sodium tert-butoxide of 0.8g, then adds 3-chloroallylene 0.9g, insulated and stirred 3h.The TLC monitoring reaction is complete, adds water 25mL extraction and goes out, and tells organic layer, be cooled to 5 ℃, namely there is crystal to separate out, keeps this temperature to continue to stir, to be crystallized complete, filter, filter cake is used methyl alcohol 10mL successively, water 10mL washing, decompression (200mmHg) drying, namely get compound (IV) 2.12g, yield is 68%.
The 3rd step: preparation compound (V)
Get the flask of a clean 50mL, add iodine phenylfluoroform between 3g, use the 10mL dissolve with ethanol, obtain an iodine phenylfluoroform ethanol.The compound (IV) that the upper step obtains is used the 25ml dissolve with ethanol, be heated to 80 ℃, slowly drip wherein got ready between iodine phenylfluoroform ethanol, time for adding is 5min approximately, add again 2 moles of catalysis equivalent palladium and 0.8g diethylamine, stir about 6h at this temperature.The TLC monitoring reaction is complete, filters, and filtrate is cooled to 20 ℃, namely has crystal to separate out, continue to stir 30min, to be crystallized complete, filter, filter cake is used toluene 10mL successively, water 10mL washing, decompression is dry to 200mmHg, namely gets compound (V) 3.01g, and yield is 66%.
The 4th step: preparation compound (I)
The compound (V) that obtains is dissolved in MTBE (30mL), adds the 5%Pd/C of 0.6g, be heated to 60 ℃, stir, then with 5Kg/cm
2Pressure pass into hydrogen 4h.After the TLC monitoring reaction is complete, with reacting liquid filtering, filtrate decompression distillation, desolventizing, again residue is dissolved in tetrahydrofuran (THF) (20mL), stirs, with the aqueous sodium carbonate washing of 30mL10%, layering, tell organic layer, water layer adds methylene dichloride 30mL again, tells organic layer after layering.Merge organic phase, underpressure distillation adds the acetic acid ethyl dissolution of 5mL in the debris that obtains, then adds the diethyl ether liquid (20mL) of hydrochloric acid, stirs 30min, and underpressure distillation obtains crude salt.Add the 3mL ethyl acetate, filter, with cold ethyl acetate washing, 40 ℃ of lower vacuum (200mmHg) drying obtains 2.56g cinacalcet hydrochloride white crystalline powder to the white crystal that obtains again, and yield is 65%.
Fusing point: 180～184 ℃.
1H?NMR(CDCl
3-DMSO-d
6)(δppm)：10.62(1H，bs)，10.07(1H，bs)，7.16-8.5(1H，m)，5.19(1H，q)，2.75(2H，t)，2.52(2H，m)，2.28(2H，m)，1.98(3H，d)。
MS(m/z)：358[M+1]。
The present invention adopts chirality synthetic, and synthetic route is unique, and selectivity is good, and yield is high; Simple to operate, cost is low, pollutes littlely, is fit to suitability for industrialized production.
Claims (5)
1. the preparation method of a cinacalcet hydrochloride, described cinacalcet hydrochloride is the Chiral Amine compounds, it is characterized in that: it comprises the following steps:
The first step: take the 1-acetonaphthone as starting raw material, it is the suitable dissolution with solvents of 8～12mL/g1-acetonaphthone with quantity of solvent, under 20～200 ℃ of temperature condition, introduce chiral reagent and isopropyl titanate, the mol ratio of chiral reagent and 1-acetonaphthone is 1: 1～2: 1, and the mol ratio of isopropyl titanate and 1-acetonaphthone is 0.5: 1～2: 1, then uses sodium borohydride reduction, the mol ratio of sodium borohydride and 1-acetonaphthone is 1: 1～2: 1, namely obtains compound (III)
Second step: the compound (III) that obtains in the first step is dissolved in the suitable solvent that quantity of solvent is 8～12mL/g compound III, under 0～100 ℃ of temperature condition, alkalization, the alkali that adds is 1.0～2.0 equivalents, add again the 3-propiolic halide, the mol ratio of 3-propiolic halide and compound III is 1: 1～2: 1, and reaction obtains compound (IV)
The 3rd step: with the compound (IV) that obtains in second step, being dissolved in quantity of solvent at 20～180 ℃ of temperature is in the suitable solvent of 8～12mL/g compound IV, add again a halogen phenylfluoroform, between the mol ratio of halogen phenylfluoroform and compound IV be 0.8: 1～2: 1, add again diethylamine and suitable catalyzer, the mol ratio of diethylamine and compound IV is 0.8: 1～2: 1, and the catalyzer add-on is 0.5～2 mole of catalysis equivalent, namely obtains compound (V)
The 4th step: be the suitable solvent of 8～12mL/g compound V with adding quantity of solvent in the compound (V) that obtains in the 3rd step, passing into pressure at the temperature of-20～200 ℃ is 5Kg/cm
2Hydrogen and add palladium catalyst carbon, palladium catalyst carbon and compound V weight ratio are 1: 4.5～1: 5.5, then add hydrochloric acid in the reduzate that obtains, the mol ratio of hydrochloric acid and compound V is 1: 1～2: 1, namely obtains target product cinacalcet hydrochloride (I)
The synthesis route that cinacalcet hydrochloride of the present invention (I) is described with chemical structural formula is as follows:
2. the preparation method of a kind of cinacalcet hydrochloride according to claim 1, is characterized in that, in the first step:
Described temperature of reaction is 60～80 ℃;
Described suitable solvent comprises a kind of in following material: methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), normal heptane, toluene, methyl tertiary butyl ether;
Described chiral reagent is (R)-t-butyl sulfonamide.
3. the preparation method of a kind of cinacalcet hydrochloride according to claim 1, is characterized in that, in second step:
Described suitable reagent comprises a kind of in following material: methyl alcohol, ethanol, Virahol, methyl tertiary butyl ether, ether, ethyl acetate, tetrahydrofuran (THF);
Described temperature of reaction is 40～60 ℃;
Described alkaloid compound is sodium tert-butoxide;
Described 3-propiolic halide is 3-chloroallylene or 3-propargyl bromide.
4. the preparation method of a kind of cinacalcet hydrochloride according to claim 1, is characterized in that, in the 3rd step:
Described temperature of reaction is 50～80 ℃;
Described suitable reagent comprises a kind of in following material: methyl alcohol, ethanol, Virahol, methyl tertiary butyl ether, glycol dimethyl ether, ethyl acetate, tetrahydrofuran (THF);
Described catalyzer is: palladium, cuprous iodide;
Described halogen phenylfluoroform is: a fluoride trifluoro toluene, meta-chlorobenzotrifluoride, iodine phenylfluoroform between a 5 bromine benzotrifluoride reaches.
5. the preparation method of a kind of cinacalcet hydrochloride according to claim 1, is characterized in that, in the 4th step:
Described suitable solvent comprises a kind of in following material: methyl alcohol, ethanol, Virahol, acetone, ethyl acetate, ether, methyl tertiary butyl ether, normal heptane, toluene, tetrahydrofuran (THF);
Described temperature of reaction is 50～70 ℃.
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| CN102976953A (en) * | 2011-09-05 | 2013-03-20 | 上海药明康德新药开发有限公司 | Preparation method of chiral alpha-difluoromethyl phenyl ethylamine |
| CN103664577B (en) * | 2012-09-06 | 2015-04-08 | 北京万生药业有限责任公司 | Preparation method of cinacalcet intermediate |
| CN106831441B (en) * | 2017-01-23 | 2019-04-02 | 江苏康思尔医药科技有限公司 | A kind of preparation method of cinacalcet hydrochloride |
| CN111196759B (en) * | 2018-11-16 | 2023-03-24 | 上海博志研新药物技术有限公司 | Preparation method of cinacalcet hydrochloride and intermediate thereof |
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| US6211244B1 (en) * | 1994-10-21 | 2001-04-03 | Nps Pharmaceuticals, Inc. | Calcium receptor-active compounds |
| WO2008058235A2 (en) * | 2006-11-08 | 2008-05-15 | Dr. Reddy's Laboratories, Ltd. | Processes for the preparation of cinacalcet |
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| US6211244B1 (en) * | 1994-10-21 | 2001-04-03 | Nps Pharmaceuticals, Inc. | Calcium receptor-active compounds |
| WO2008058235A2 (en) * | 2006-11-08 | 2008-05-15 | Dr. Reddy's Laboratories, Ltd. | Processes for the preparation of cinacalcet |
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