CN106831863B - Montelukast sodium intermediate and its preparation method and application - Google Patents
Montelukast sodium intermediate and its preparation method and application Download PDFInfo
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- CN106831863B CN106831863B CN201710044916.0A CN201710044916A CN106831863B CN 106831863 B CN106831863 B CN 106831863B CN 201710044916 A CN201710044916 A CN 201710044916A CN 106831863 B CN106831863 B CN 106831863B
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- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 title claims abstract description 35
- 229960001951 montelukast sodium Drugs 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 238000006243 chemical reaction Methods 0.000 claims abstract description 87
- 238000000034 method Methods 0.000 claims abstract description 20
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 229960005127 montelukast Drugs 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 239000003513 alkali Substances 0.000 claims description 12
- 102000004377 Thiopurine S-methyltransferases Human genes 0.000 claims description 11
- 108090000958 Thiopurine S-methyltransferases Proteins 0.000 claims description 11
- -1 C1-6Alkoxy Chemical group 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical group [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000010189 synthetic method Methods 0.000 claims description 8
- 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 claims description 7
- 239000002841 Lewis acid Substances 0.000 claims description 7
- 230000004913 activation Effects 0.000 claims description 7
- 150000007517 lewis acids Chemical class 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000000292 calcium oxide Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 3
- 239000000920 calcium hydroxide Substances 0.000 claims description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000007670 refining Methods 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 229910021555 Chromium Chloride Inorganic materials 0.000 claims description 2
- PHSPFUQAZNIVCH-UHFFFAOYSA-M [Mg].[I-].C[N+]1=CC=CC=C1 Chemical compound [Mg].[I-].C[N+]1=CC=CC=C1 PHSPFUQAZNIVCH-UHFFFAOYSA-M 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 claims description 2
- GVPFVAHMJGGAJG-UHFFFAOYSA-L cobalt dichloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 claims description 2
- ICAKDTKJOYSXGC-UHFFFAOYSA-K lanthanum(iii) chloride Chemical compound Cl[La](Cl)Cl ICAKDTKJOYSXGC-UHFFFAOYSA-K 0.000 claims description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 238000003747 Grignard reaction Methods 0.000 claims 1
- 239000012190 activator Substances 0.000 claims 1
- 150000003927 aminopyridines Chemical class 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 17
- 238000003786 synthesis reaction Methods 0.000 abstract description 17
- 239000000126 substance Substances 0.000 abstract description 5
- 230000003287 optical effect Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 230000006641 stabilisation Effects 0.000 abstract 1
- 238000011105 stabilization Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 41
- 239000000543 intermediate Substances 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- 239000012074 organic phase Substances 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000002994 raw material Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000005406 washing Methods 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 13
- 0 *CC1(CBr)CC1 Chemical compound *CC1(CBr)CC1 0.000 description 11
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 235000015424 sodium Nutrition 0.000 description 10
- 235000002639 sodium chloride Nutrition 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 5
- 239000004519 grease Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000007818 Grignard reagent Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 239000012675 alcoholic extract Substances 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- HXBZCHYDLURWIZ-UHFFFAOYSA-N diphenyl hydrogen phosphate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 HXBZCHYDLURWIZ-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- RLICUPZTDXYULB-UHFFFAOYSA-N [Na].C1(CC1)CC(=O)O Chemical compound [Na].C1(CC1)CC(=O)O RLICUPZTDXYULB-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 239000000924 antiasthmatic agent Substances 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- RQNMYNYHBQQZSP-UHFFFAOYSA-M methylmagnesium chloride Chemical class C[Mg]Cl RQNMYNYHBQQZSP-UHFFFAOYSA-M 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003509 tertiary alcohols Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- DAGAQTLMZAEUKX-UHFFFAOYSA-N 3-bromo-1h-pyrrolo[2,3-c]pyridine Chemical compound N1=CC=C2C(Br)=CNC2=C1 DAGAQTLMZAEUKX-UHFFFAOYSA-N 0.000 description 1
- VLWKHQGNKNKARR-UHFFFAOYSA-N C(C)(C)OC(C(C(OOCCCCC)(OC(C)(C)C)OC(C)CC)(C)C)(OCC(C)C)OCCCC Chemical compound C(C)(C)OC(C(C(OOCCCCC)(OC(C)(C)C)OC(C)CC)(C)C)(OCC(C)C)OCCCC VLWKHQGNKNKARR-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JJWLDJKCTAHASY-UHFFFAOYSA-M O1CCCC1.[Mg].[I-].C[N+]1=CC=CC=C1 Chemical compound O1CCCC1.[Mg].[I-].C[N+]1=CC=CC=C1 JJWLDJKCTAHASY-UHFFFAOYSA-M 0.000 description 1
- ZMPJCYAHTJUPMV-UHFFFAOYSA-M P(=O)(OC1=CC=CC=C1)(OC1=CC=CC=C1)[O-].[Cl+] Chemical compound P(=O)(OC1=CC=CC=C1)(OC1=CC=CC=C1)[O-].[Cl+] ZMPJCYAHTJUPMV-UHFFFAOYSA-M 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- AVFUHBJCUUTGCD-UHFFFAOYSA-M [Br-].[Mg+]C Chemical class [Br-].[Mg+]C AVFUHBJCUUTGCD-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 208000029771 childhood onset asthma Diseases 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940088529 claritin Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-M diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)([O-])OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-M 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 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
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229940065725 leukotriene receptor antagonists for obstructive airway diseases Drugs 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 102000003835 leukotriene receptors Human genes 0.000 description 1
- 108090000146 leukotriene receptors Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- UBCJCAPLMBHKPY-UHFFFAOYSA-L magnesium;oxolane;dibromide Chemical compound [Mg+2].[Br-].[Br-].C1CCOC1 UBCJCAPLMBHKPY-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical class COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
-
- 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)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Quinoline Compounds (AREA)
Abstract
The present invention relates to a series of noval chemical compounds and preparation method thereof with following general formula (III).The present invention also relates to application of the noval chemical compound of general formula (III) in Montelukast Sodium synthesis.General formula (III) compound is the key intermediate in Montelukast Sodium building-up process, plays the role of vital, chemical property stabilization for synthesis final goal compound, preparation process reaction condition is mild, yield is high, and optical purity is high, is suitble to large-scale production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical fields, and in particular to a kind of Montelukast Sodium key intermediate and its preparation side
Method, further to application of the intermediate in Montelukast Sodium (Montelukast Sodium) synthesis.
Background technology
Montelukast Sodium is the anti-asthmatic medicament developed by United States Merck company, and obtaining the U.S. on 2 20th, 1998 eats
The listing of product Drug Administration (FDA) is ratified, trade name2 months 1998 in Finland and Mexico
City, in October, 1998 in U.S.'s list marketing, then list in the country such as Britain, Canada, Italy, France, Germany in succession.
The leukotriene receptor antagonists of Montelukast Sodium alternatively property, can and leukotriene receptor selectivity in respiratory tract combination,
The effect of Anaphylactic mediator is competitively blocked, and then blocks the reaction of organ dialogue triolefin, improves respiratory inflammation, makes respiratory tract
It is unobstructed, it is a kind of relieving asthma anti-inflammatory and Claritin efficiently, less toxic, safe.It is clinically used for childhood asthma and movement causes to roar
The treatment of asthma, has broad prospects.
The chemistry of Montelukast Sodium is entitled：1- [[[(1R) -1- [3- [(1E) -2- (the chloro- 2- quinoline of 7-) vinyl] benzene
Base] -3- [2- (1- hydroxyl -1- Methylethyls) phenyl] propyl] thio] methyl] cyclopropaneacetic acid sodium, chemical structural formula is such as
Under：
The patent document about the synthetic method of Montelukast Sodium mainly has CN1046711C in the prior art,
CN1139429A, CN1171873C, CN101321732A, CN105294556A, US20050107612A1,
US20080275243A1, US7417149B2, WO20070572271A1, US20080097104A1, WO2009016191A1,
US7189853B2, WO2005105751A1, WO2005105749A2, WO2008072872A1, WO2007116240A1,
WO2008035086A2 etc..
Many about the synthetic method of Montelukast Sodium at present, these methods mainly build C- around chiral carbon and side chain
The strategy of S keys can substantially be summarized as following a few classes：
The first kind, first by intermediate 2- (2- (3- (2- (the chloro- 2- quinolyls of 7-)-ethenylphenyl) -3- hydroxypropyls)
Phenyl) chiral alcoholic extract hydroxyl group is converted into leaving group and obtains intermediate 2 in -2- propyl alcohol, then intermediate 2 and parent under alkaline condition
Core reagent 1- thiopurine methyltransferases cyclopropaneacetic acid (or its analog) obtains intermediate 3 by nucleophilic substitution, then by hydrolysis,
Montelukast Sodium target product is obtained at salt, as shown in synthetic route 1：
Such synthetic method is mainly to react the alcoholic extract hydroxyl group and methylsufonyl chloride that are connected with chiral carbon to generate methanesulfonates
Intermediate 2, but the intermediate is extremely unstable, is easy to happen the side reactions such as elimination, intramolecular cyclization.On the other hand such is reacted
It must be carried out in a low temperature of about -30 DEG C, and product is required to be stored in about -15 DEG C, condition is harsh, is unfavorable for industrial big raw
Production.It is mentioned in patent US20080275243A1 and alcoholic extract hydroxyl group is switched to by chloro thing, the party by intermediate 1 and thionyl chloride reaction
The ee values only 64% of intermediate 2 obtained by method, satisfactory target product can just be obtained by needing to split to crystallize, and whole yield is notable
It reduces, cost significantly improves, while generating a large amount of useless enantiomer by-products.
Hanmi Science Co., Ltd. patent document CN101558042B, CN101808998B and Shanghai Di Sainuo chemical pharmacies
It is disclosed in Co., Ltd patent application document CN105294556A using chlorine phosphate diphenyl ester as electrophilic reagent and chiral
The method that alcoholic extract hydroxyl group reaction prepares montelukast intermediate, it is specific as follows：
In this reaction route, under alkaline condition, the tertiary alcohol is easy to attack and diphenyl phosphate as necleophilic reaction site
Connected chiral carbon, it is more to be easy to happen intramolecular cyclization, side reaction, is unfavorable for purifying products, reduces reaction yield, increases
Economic cost.
Second class, is obtained by the reaction by intermediate 1 after intermediate 2 and intermediate is obtained by the reaction in thioacetic acid or its sylvite
4, intermediate 4 is taken off after acetyl group protection and during 2- (1- (bromomethyl) cyclopropyl) methyl acetate (or its analog) is condensed to yield
Mesosome 3, then Montelukast Sodium target product is obtained by hydrolysis, at salt, as shown in synthetic route 2：
Also there is use (E) -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- oxopropyls] benzoic acid
Methyl esters is starting material, first obtains the analog 4 ' of intermediate 4, then obtains intermediate with methyl-magnesium-bromide Grignard Reagent addition
4, then obtain intermediate 3 with 2- (1- (bromomethyl) cyclopropyl) methyl acetate.
For above-mentioned second class synthesis strategy, the unstable problem of mesylate intermediate 2 is equally existed；On the other hand,
Ethanethioyl is introduced, reaction step is increased and thereby reduces economy；Key starting material 2- (1- (bromomethyl) rings simultaneously
Propyl) methyl acetate there is no that producer provides in the market, which is not suitable for industrialized production.
In conclusion the preparation method of Montelukast Sodium is unstable in the prevalence of intermediated chemistry property in the prior art
Determine, be easy to happen the side reactions such as elimination, intramolecular cyclization, severe reaction conditions are unfavorable for industrialized production, anti-asthmatic medicament Meng
The preparing technical field of montelukast sodium needs to develop a kind of more ripe, excellent in stability process route.
Invention content
The present invention provides the compounds with formula (III) general formula, additionally provide the preparation method of general formula (III) compound.
Invention further provides the methods that one kind preparing Montelukast Sodium using general formula (III) compound as key intermediate.
The concrete scheme of the present invention is as follows：
The invention discloses general formula (III) compounds：
Wherein, X represents methyl, C1-6Alkoxy, phenoxy group, benzyloxy；
R1Represent C1-6Alkyl, phenyl, benzyl；
R2Represent C1-6Alkyl, phenyl, benzyl.
C described above1-6Alkyl refers to the linear or branched alkyl group for having 1-6 carbon atom.Such as：Methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl group, tertiary butyl, sec-butyl, amyl, neopentyl, hexyl etc..
C described above1-6Alkoxy refers to the straight or branched alkoxyl with 1~6 carbon atom.Such as：Methoxy
Base, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, amoxy, neopentyl oxygen,
Hexyloxy etc..It is preferred that the straight or branched alkoxyl with 1~4 carbon atom, particularly preferred methoxy or ethoxy.Most preferably
Methoxyl group.
It is preferred that R1Represent phenyl；
It is preferred that R2Represent phenyl；
It is preferred that X represents methyl or C1-4Alkoxy；
Particularly preferred X represents methyl, methoxy or ethoxy；
Preferred compounds of the invention is selected from：
The present invention provides a kind of preparation method of general formula (III) compound, specific route is as follows：
By formula (IV) compound and formula (IVA) compound dissolves in organic solvent, be condensed in the presence of alkali respectively
To formula (III) compound.
Reaction temperature is 0~100 DEG C, preferably 20~50 DEG C；
Reaction time is 1~5h, preferably 2-3h；
The alkali be selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N, N- diisopropylethylamine, 1,
The 11 carbon -7- alkene of 8- diazabicylos [5,4,0], 4-dimethylaminopyridine, pyridine, imidazoles, sodium hydride, sodium hydroxide, hydrogen-oxygen
Change one or more of potassium, cesium hydroxide, calcium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium oxide；Formula
(IV) compound and the molar ratio of the alkali are 1：(1~5), preferably 1：(2~3)；
Formula (IV) compound and formula (IVA) compound molar ratio be 1：(1~5), preferably 1：(1~2).
The present invention also provides the method that one kind preparing Montelukast Sodium using general formula (III) compound as reaction intermediate,
Include the following steps：
(1) 1- thiopurine methyltransferases cyclopropaneacetic acid or its salt are added sequentially to alkali in organic solvent, formula (III) is then added
Compound is stirred to react to obtain formula (II) compound at 20~60 DEG C；Reaction time 2-4h；
(2) Lewis acid activation agent is added in organic solvent, then under -10~5 DEG C of temperature condition, first is added
Base Grignard Reagent stirs 0~1h, then formula (II) compound solution is added to Lewis acid activation agent-methyl Grignard and is reacted
In liquid, Montelukast acid is prepared by addition reaction, and formula (I) compound, i.e. Meng Lusi are obtained further across at salt refining
Special sodium.
Alkali described in above step (1) is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N, N-
Diisopropylethylamine, the 11 carbon -7- alkene of 1,8- diazabicylos [5,4,0], 4-dimethylaminopyridine, pyridine, imidazoles, hydrogenation
In sodium, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium oxide
One or more；Formula (III) compound and the molar ratio of the alkali are 1：(1~5), preferably 1：(2~4)；
Above step (1) Chinese style (III) compound is 1 with the molar ratio of 1- thiopurine methyltransferases cyclopropaneacetic acid or salt：(1~5),
Preferably 1：(2~3)；
Preferably, step (1) described above includes following operation：1- thiopurine methyltransferase cyclopropaneacetic acids are dissolved in two
In methyl sulfoxide, under nitrogen atmosphere, methanol solution of sodium methylate is added, stirs 0.5h, formula (III) compound is then dissolved in two
It in first sulfoxide, and is added into above-mentioned reaction system, is stirred to react 2~4h at 20~60 DEG C, waits for using 1mol/L after completion of the reaction
Dilute hydrochloric acid reaction is quenched, extract, collect organic phase, be concentrated under reduced pressure, dried, obtain formula (II) compound；
Further,
Lewis acid activation agent described in above step (2) is selected from cerous chloride, zinc chloride, lithium chloride, cobalt chloride, chlorination
One or more of lanthanum, chromium chloride；It is preferred that cerous chloride.
Methyl grignard reagent is in methyl-magnesium-chloride, methyl-magnesium-bromide or methylpyridinium iodide magnesium described in above step (2)
One kind, preferred methyl-magnesium-chloride；Formula (II) compound and the molar ratio of the methyl grignard reagent are 1：(3~10), preferably
It is 1：(4~6)；
Above step (2) Chinese style (II) compound and the molar ratio of Lewis acid activation agent are 1：(0~2), preferably 1：
(1~1.5)；
Preferably, step (2) described above includes following operation：Cerous chloride is added in tetrahydrofuran,
50~80 DEG C are warming up to, 1h is stirred, is cooled to -10~5 DEG C, under -10~5 DEG C of temperature conditions, methyl-magnesium-chloride tetrahydrochysene is added
Tetrahydrofuran solution stirs 0.5~1h, then the tetrahydrofuran solution of formula (II) compound is passed through addition in adding in reaction system
Reaction prepares Montelukast acid, and obtains formula (I) compound i.e. montestron sodium further across at salt refining.
Unless otherwise indicated, the following term in claims and specification has following meaning：
In the present inventionIndicate the site chemically reacted；
In the present invention, " LG " indicates leaving group, such as OMs, OTs, Cl, Br, I, phosphate；
In the present invention, term " compound " includes not only the compound itself, further includes its pharmaceutically acceptable salt
Or its solvate.
The present invention provides novel key intermediates of montestron sodium and preparation method thereof, while providing a synthesis
The new technology route of montestron sodium.The chemical property of the key intermediate is stablized, when being used to prepare Montelukast Sodium can gram
It takes in existing preparation route using the tertiary alcohol as necleophilic reaction site, it is easy to the chiral carbon that attack is connected with leaving group, Yi Fa
Intramolecular cyclization, the disadvantage more than side reaction, and entire reaction process mild condition are given birth to, chiral carbonoid will not be sent out in reaction process
Changing, optical purity is high, is easy to purify, be suitable for industrialized large-scaled production.
Specific implementation mode
Further illustrated the present invention below by embodiment, for a person skilled in the art, should not will under
Row embodiment is interpreted as limitation of the present invention, instructs according to prior art, is modified or improved to it and belongs to the present invention's
In protection domain.
Embodiment 1：The synthesis of III a of intermediate
IV a compounds (50g, 109.2mmol) of formula are dissolved in 500mL dichloromethane, addition triethylamine (22.1g,
218.4mmol), diphenyl phosphate chloride (44g, 163.8mmol) is added dropwise, after being added dropwise, rises at 30 DEG C and stirs 3h, TLC inspections
Surveying raw material, the reaction was complete.Reaction solution is poured into the dilute hydrochloric acid of 500mL 1mol/L, extraction and separation organic phase uses saturated carbon successively
Sour hydrogen sodium solution and brine It simultaneously collect organic phase, are concentrated under reduced pressure after drying, decoloration to get 74.5g oily formulas
III a compounds, yield 99%.MS:690[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40 (d, J=8.8Hz, 1H), 8.04 (d, J=1.6Hz,
1H), 8.02-7.99 (d, J=8.8Hz, 1H), 7.93-7.91 (d, J=8.8Hz, 1H), 7.90-7.86 (d, J=16.4Hz,
1H), 7.82 (s, 1H), 7.80-7.78 (d, J=7.2Hz, 1H), 7.75-7.73 (d, J=6.8Hz, 1H), 7.61-7.59
(dd, J=8.4Hz, 1.6Hz, 1H), 7.51-7.50 (d, J=16.4Hz, 1H), 7.47-7.10 (m, 15H), 5.75-5.70
(m, 1H), 3.76 (s, 3H), 3.03-2.96 (td, J=12.8Hz, 4.8Hz, 1H), 2.86-2.78 ((td, J=12.8Hz,
4.8Hz,1H),2.37-2.36(m,1H),2.34-2.33(m,1H)
Embodiment 2：The synthesis of III b of intermediate
IV b compounds (50g, 105.9mmol) of formula are dissolved in 500mL ethyl acetate, addition triethylamine (32.1g,
317.7mmol), diphenyl phosphate chloride (56.9g, 211.8mmol) is added dropwise, after being added dropwise, rises at 50 DEG C and stirs 2h, TLC
Detecting raw material, the reaction was complete.Reaction solution is poured into the dilute hydrochloric acid of 500mL 1mol/L, extraction and separation organic phase, successively with full
With sodium bicarbonate solution and brine It and collect organic phase, be concentrated under reduced pressure after drying, decoloration to get 72.3g oil
III b compounds of shape formula, yield 97%.MS:704[M+H]
Embodiment 3：The synthesis of III c of intermediate
IV b compounds (30g, 63.6mmol) of formula are dissolved in 300mL toluene, are cooled to 0 DEG C, N, N- diisopropyls is added
Ethamine (41.1g, 317.8mmol) is added dropwise diethyl chloro-phosphate (54.8g, 317.8mmol), after being added dropwise, rises to 100 DEG C
Lower stirring 1h, TLC detect raw material, and the reaction was complete.Reaction solution is poured into the dilute hydrochloric acid of 300mL 1mol/L, 300mL second is added
Acetoacetic ester extracts, and organic phase with saturated sodium bicarbonate solution and brine It and collects organic phase successively, by drying, decoloration
After be concentrated under reduced pressure to get III c compounds of 38g oilies formula, yield 98%.MS:608[M+H]
Embodiment 4：The synthesis of III d of intermediate
IV d compounds (40g, 82.3mmol) of formula are dissolved in 400mL tetrahydrofurans, are cooled to 0 DEG C, 4- diformazan ammonia is added
Diisopropyl chlorophosphate (16.5g, 82.3mmol) is added dropwise in yl pyridines (10.1g, 82.3mmol), after being added dropwise, is kept for 0 DEG C
Lower stirring 5h, TLC terminate reaction after detecting raw material fundamental reaction.Reaction solution is poured into the dilute hydrochloric acid of 400mL1mol/L
In, 400mL ethyl acetate is added, organic phase uses saturated sodium bicarbonate solution and brine It successively, collects organic phase, through dry
It is dry, decolourize and be concentrated under reduced pressure to get III d compounds of 50g oilies formula, yield 93.5%.MS:650 [M+H] embodiments 5：
The synthesis of III e of intermediate
IV e compounds (10g, 22.6mmol) of formula are dissolved in 100mL acetonitriles, addition sodium hydroxide (2.712g,
67.8mmol), diphenyl phosphate chloride (18.2g, 67.8mmol) is added dropwise, after being added dropwise, rises at 40 DEG C and stirs 2.5h, TLC
Detection raw material reaction finishes, and terminates reaction.Reaction solution is poured into the dilute hydrochloric acid of 100mL 1mol/L, 100mL acetic acid is added
Ethyl ester extraction and separation organic phase uses saturated sodium bicarbonate solution and brine It successively, collects organic phase, through drying, decoloration
After be concentrated under reduced pressure to get III e compounds of 15g oilies formula, yield 98.7%.MS:674[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40 (d, J=8.8Hz, 1H), 8.04 (d, J=1.6Hz,
1H), 8.02-7.99 (d, J=8.8Hz, 1H), 7.93-7.91 (d, J=8.8Hz, 1H), 7.90-7.86 (d, J=16.4Hz,
1H), 7.82 (s, 1H), 7.80-7.78 (d, J=7.2Hz, 1H), 7.75-7.73 (d, J=6.8Hz, 1H), 7.61-7.59
(dd, J=8.4Hz, 1.6Hz, 1H), 7.51-7.50 (d, J=16.4Hz, 1H), 7.47-7.10 (m, 15H), 5.75-5.70
(m,1H),2.91-2.84(m,1H),2.76-2.69(m,1H),2.53(s,3H),2.34-2.31(m,1H),2.36-2.28
(m,1H)
Embodiment 6：The synthesis of III f of intermediate
IV f compounds (10g, 19.2mmol) of formula are dissolved in 100mL 2- butanone, addition potassium hydroxide (2.2g,
38.4mmol), diphenyl phosphate chloride (10.3g, 38.4mmol) is added dropwise, after being added dropwise, rises at 30 DEG C and stirs 3h, TLC inspections
It surveys raw material reaction to finish, terminates reaction.Reaction solution is poured into the dilute hydrochloric acid of 100mL 1mol/L, 100mL acetic acid second is added
Ester extracts, and organic phase uses saturated sodium bicarbonate solution and brine It successively, collects organic phase, is carried out after drying, decoloration
It is concentrated under reduced pressure to get III f compounds of 15g oilies formula, yield 98.7%.
MS:752[M+H]
Embodiment 7：The synthesis of intermediate II a
1- thiopurine methyltransferases cyclopropaneacetic acid (16g, 109.5mmol) is dissolved in 160mL dimethyl sulfoxides, nitrogen protection condition
Under, at 20 DEG C or so, the methanol solution (37.5g, 208.1mmol) of 30wt% sodium methoxides is added dropwise, finishes, reacts at room temperature 0.5h,
III a compounds (37.8g, 54.8mmol) are dissolved in 380ml dimethyl sulfoxides and are added in reaction system, after be warming up to 30 DEG C and stir
It mixes reaction 3h, TLC detection raw material and terminates reaction after completion of the reaction.Reaction solution is added to the cold dilute hydrochloric acid of 300mL 1mol/L
In, solid is precipitated in 0 DEG C of temperature control, filters, and filter cake is dissolved in ethyl acetate, saturated common salt water washing 2 times, collects by filter cake washing
Organic phase is concentrated under reduced pressure after drying, decoloration to get II a compounds of 35.8g yellowish-brown oilies formula.By yellowish-brown oily
II a compounds of formula are dissolved in 215mL ethyl acetate, under nitrogen protection, dicyclohexyl amine (27.7g, 152.7mmol) are added dropwise, finishes,
5h is stirred at room temperature, a small amount of solid is precipitated, 430mL n-hexanes are slowly added dropwise, finish, 12h is stirred at room temperature, filters, filter cake is with 1:1
Ethyl acetate/n-hexane mixed solvent washing, 50 DEG C of dryings obtain the dicyclohexyl amine salt 41.2g of II a compounds of formula, and yield is
97.7%.MS:586[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.48-8.46 (d, J=8.4Hz, 1H), 8.36 (brs, 1H), 8.05
(s, 1H), 8.05-8.03 (d, J=8Hz, 1H), 8.01-7.99 (d, J=8.8Hz, 1H), 7.96-7.92 (s, J=16Hz,
1H), 7.76-7.74 (d, J=7.2Hz, 1H), 7.70 (s, 1H), 7.65-7.17 (m, 7H), 3.93 (t, 1H), 3.76 (s,
3H),2.94(m,1H),2.80(m,1H),2.30(m,2H),2.11(m,2H),1.98(m,2H),0.39(m,4H)
Embodiment 8：The synthesis of intermediate II b
1- thiopurine methyltransferase cyclopropaneacetic acid sodium (12.5g, 74.4mmol) is dissolved in 125mL dimethylformamides, nitrogen is protected
Potassium tert-butoxide (12.7g, 113.6mmol) is added under the conditions of shield at 20 DEG C or so, 0.5h is reacted at room temperature later, by III b chemical combination of formula
Object (20g, 28.4mmol) is dissolved in 200ml dimethylformamides and is added into reaction system, is warming up to 60 DEG C of reactions 2h, TLC
Detection raw material terminates reaction after completion of the reaction.Reaction solution is added into the cold dilute hydrochloric acid of 200mL1mol/L, 0 DEG C of temperature control, is precipitated
Solid filters, and filter cake is dissolved in ethyl acetate by filter cake washing, and saturated salt solution washes twice, and collects organic phase, dry, is taken off
Color is concentrated under reduced pressure to get II b compounds of 22g yellowish-brown oilies formula.By the grease by embodiment 7 at two hexamethylenes
The method of amine salt obtains the dicyclohexyl amine salt 21.1g of II b compounds of formula, yield 95%.MS:600[M+H]
Embodiment 9：The synthesis of intermediate II b
1- thiopurine methyltransferase cyclopropaneacetic acid potassium (30.3g, 164.5mmol) is dissolved in 300mL dimethylformamides, nitrogen is protected
Shield is added potassium tert-butoxide (18.4g, 164.5mmol), finishes at 20 DEG C or so, 0.5h is reacted at room temperature, by III c compounds
(20g, 32.9mmol) is dissolved in 200ml dimethylformamides and adds in reaction system, and 2h is reacted at 20 DEG C, and TLC detects raw material
Reaction is terminated after completion of the reaction.Reaction solution is added into the cold dilute hydrochloric acid of 200mL1mol/L, 0 DEG C of temperature control, solid is precipitated, taken out
Filter, filter cake washing, filter cake is dissolved in ethyl acetate, and saturated salt solution washes twice, and collects organic phase, dry, is decolourized, is carried out
It is concentrated under reduced pressure to get II b compounds of 23g yellowish-brown oilies formula.By the grease by the side at dicyclohexyl amine salt in embodiment 7
Method obtains the dicyclohexyl amine salt 23.6g of II b compounds of formula, yield 92%.
Embodiment 10：The synthesis of intermediate II d
1- thiopurine methyltransferase cyclopropaneacetic acid lithiums (2.4g, 15.4mmol) are dissolved in 25mL ethyl acetate, nitrogen protection, 20
DEG C or so, 1,8- diazabicylos [5,4,0] 11 carbon -7- alkene (2.3g, 15.4mmol) is added, finishes, reacts at room temperature 0.5h,
III d compounds (10g, 15.4mmol) of formula are dissolved in 100mL ethyl acetate and are added dropwise in reaction solution, finishes, is warming up to 40
DEG C reaction 4h, TLC detect raw material fundamental reaction after terminate reaction.Reaction solution is added to cold dilute salt of 100mL 1mol/L
In acid, solid is precipitated in 0 DEG C of temperature control, filters, and filter cake is dissolved in ethyl acetate, saturated common salt water washing 2 times, receives by filter cake washing
Collect organic phase, dry, decoloration is concentrated under reduced pressure to get II d compounds of 10g yellowish-brown oilies formula.By the grease by implementation
The method at dicyclohexyl amine salt in example 7 obtains the dicyclohexyl amine salt 10.9g of II d compounds of formula, yield 90%.MS:614[M
+H]
Embodiment 11：The synthesis of intermediate II e
1- thiopurine methyltransferases cyclopropaneacetic acid (9.8g, 66.9mmol) is dissolved in 100mL acetonitriles, nitrogen protection, on 20 DEG C of left sides
The right side is added potassium hydroxide (3.8g, 66.9mmol), finishes, and 0.5h is reacted at room temperature, by III e compounds (15g, 22.3mmol) of formula
It is dissolved in 150mL acetonitriles and is added dropwise in reaction solution, finish, be warming up to 30 DEG C of reaction 3h, TLC detection raw material reactions and finish, eventually
Only react.Reaction solution is added in the cold dilute hydrochloric acid of 150mL 1mol/L, 0 DEG C of temperature control, solid is precipitated, filtered, filter cake washing will
Filter cake is dissolved in ethyl acetate, saturated common salt water washing 2 times, collects organic phase, dry, decoloration, be concentrated under reduced pressure to get
II e compounds of 16.6g yellowish-brown oilies formula.The grease is obtained into II e of formula by the method at dicyclohexyl amine salt in embodiment 7
The dicyclohexyl amine salt 15.4g of compound, yield 92%.MS:570[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:12.03 (s, 1H), 8.48-8.46 (d, J=8.4Hz, 1H), 8.02-
7.25(m,14H),3.93(t,1H),3.76(s,3H),2.84(m,1H),2.68(m,1H),2.52(s,3H),2.30(s,
2H),2.11(s,2H),2.05(s,2H),0.36(m,4H)
Embodiment 12：The synthesis of intermediate II f
1- thiopurine methyltransferases cyclopropaneacetic acid (3.9g, 26.6mmol) is dissolved in 100mL acetonitriles, nitrogen protection, on 20 DEG C of left sides
The right side is added the sodium hydride (1.1g, 26.6mmol) of 60wt%, finishes, react at room temperature 0.5h, by III f compounds of formula (10g,
It 13.3mmol) is dissolved in 150mL acetonitriles and is added dropwise in reaction solution, finish, be warming up to 50 DEG C of reaction 2h, it is anti-that TLC detects raw material
It should finish, terminate reaction.Reaction solution is added into the cold dilute hydrochloric acid of 100mL 1mol/L, 0 DEG C of temperature control, solid is precipitated, filtered,
Filter cake is washed, and filter cake is dissolved in ethyl acetate, saturated common salt water washing 2 times, and organic phase is collected, dry, and decoloration is depressurized
Concentration is to get II f compounds of 12g yellowish-brown oilies formula.The grease is obtained by the method at dicyclohexyl amine salt in embodiment 7
To the dicyclohexyl amine salt 9.9g of Formula II f compounds, yield 90%.MS:648[M+H]
Embodiment 13：The preparation of Montelukast Sodium
Step 1：The preparation of montelukast acid
Cerous chloride (4.2g, 17.1mmol) is suspended in 100mL tetrahydrofurans, nitrogen protection, is warming up to 65 DEG C and stirs
1h is mixed, is cooled to -5 DEG C, 22.8mL methyl-magnesium-chlorides tetrahydrofuran solution (68.4mmol, 3mol/L) is added dropwise, finishes, is stirred
II a compounds (10g, 17.1mmol) of formula are dissolved in 100mL tetrahydrofurans and are added dropwise in reaction solution, finish by 1h, keep 0
DEG C reaction 1.5h.TLC detection raw material reactions finish, and terminate reaction.Reaction solution is added in the cold dilute hydrochloric acid of 100mL 1mol/L,
Dichloromethane extracts, saturated common salt water washing 2 times, collects organic phase, dry, and decoloration is concentrated under reduced pressure to get 9.8g yellow
Oily Formulas I ' compound montelukast acid, yield 98%.MS:584[M-H]
Step 2：The preparation of Montelukast Sodium
By Formulas I ' compound (9.8g, 16.7mmol) is dissolved in 60mL methanol, the first of sodium hydroxide is slowly added dropwise at room temperature
Alcoholic solution stops being added dropwise when the pH value of reaction solution is 9~10, and after stirring 30min, decompression boils off solvent, and residue is dissolved in
Then 100mL normal heptanes are slowly added dropwise in 30mL toluene, 4h is stirred after being added dropwise, filtering, and solid vacuum at 50~60 DEG C is dry
Dry 12h is to get Montelukast Sodium 9.6g, yield 95%.
Embodiment 14：The preparation of Montelukast Sodium
Step 1：The preparation of montelukast acid
55.7mL methyl-magnesium-bromides toluene solution (167mmol, 3mol/L) is added to 100mL toluene, is cooled to -10
DEG C, then II b compounds (10g, 16.7mmol) of formula are dissolved in 100mL toluene, under nitrogen protection, are added dropwise in reaction solution,
It finishes, keeps -5 DEG C of reaction 5h.TLC detection raw material reactions finish, and terminate reaction.The cold of 100mL 1mol/L is added in reaction solution
In dilute hydrochloric acid, dichloromethane extraction, saturated common salt water washing 2 times collects organic phase, dry, and decoloration is concentrated under reduced pressure, i.e.,
Obtain 8.3g yellow oilies Formulas I ' compound montelukast acid, yield 85%.
Step 2：The preparation of Montelukast Sodium
By Formulas I ' 7.8g Montelukast Sodiums are prepared by the method at sodium salt in embodiment 13 in compound, and yield is
90%.
Embodiment 15：The preparation of Montelukast Sodium
Step 1：The preparation of montelukast acid
Zinc chloride (4.4g, 32.6mmol) is suspended in 100mL tetrahydrofurans, under nitrogen atmosphere with 5 DEG C of temperature strips
Under part, continue to stir 40min after 16.3mL methyl-magnesium-chlorides tetrahydrofuran solution (48.9mmol, 3mol/L) is added dropwise, by II d of formula
Compound (10g, 16.3mmol) is dissolved in 100mL tetrahydrofurans and is added dropwise in reaction system, continues after being added dropwise anti-
Answer 4h.Reaction is terminated after detecting raw material fundamental reaction through TLC.Reaction solution is added to the cold dilute hydrochloric acid of 100mL 1mol/L
In, dichloromethane extraction, saturated common salt water washing 2 times, collect organic phase, be concentrated under reduced pressure after drying, decoloration to get
8.8g yellow oilies Formulas I ' compound montelukast acid, yield 92%.
Step 2：The preparation of Montelukast Sodium
By Formulas I ' 8.4g Montelukast Sodiums are prepared by the method at sodium salt in embodiment 13 in compound, and yield is
92%.
Embodiment 16：The preparation of Montelukast Sodium
Step 1：The preparation of montelukast acid
Lithium chloride (1.1g, 26.3mmol) is suspended in 100mL tetrahydrofurans, under the conditions of -10 DEG C, 35mL first is added dropwise
Base magnesium bromide tetrahydrofuran solution (105mmol, 3mol/L) simultaneously stirs 0.5h, and II e compounds (10g, 17.5mmol) of formula is molten
It in 100mL tetrahydrofurans and is added dropwise in reaction system, reacts 5h.Reaction is terminated after completion of the reaction through TLC detection raw materials.It will
Reaction solution is added in the cold dilute hydrochloric acid of 100mL1mol/L, and dichloromethane extraction, saturated common salt water washing 2 times collects organic phase,
It is concentrated under reduced pressure after drying, decoloration to get 9.2g yellow oilies Formulas I ' compound montelukast acid, yield 90%.MS:
584[M-H]
Step 2：The preparation of Montelukast Sodium
By Formulas I ' 8.8g Montelukast Sodiums are prepared by the method at sodium salt in embodiment 8 in compound, and yield is
92%.
Embodiment 17：The preparation of Montelukast Sodium
Step 1：The preparation of montelukast acid
Lanthanum chloride (3.6g, 15.4mmol) and lithium chloride (0.65g, 15.4mmol) are suspended in 100mL toluene, room temperature
1h is stirred, is cooled to 0 DEG C, 20.5mL methylpyridinium iodide magnesium tetrahydrofuran solutions (61.6mmol, 3mol/L) are added dropwise in nitrogen protection,
It finishes, stirs 1h, II f compounds (10g, 15.4mmol) of formula are dissolved in 100mL tetrahydrofurans and are added dropwise in reaction solution, are added
Finish, keeps 0 DEG C of reaction 3h.TLC detection raw material reactions finish, and terminate reaction.Reaction solution is added to cold dilute salt of 100mL1mol/L
In acid, dichloromethane extraction, saturated common salt water washing 2 times collects organic phase, dry, decoloration, be concentrated under reduced pressure to get
8.5g yellow oilies Formulas I ' compound montelukast acid, yield 94%.
Step 2：The preparation of Montelukast Sodium
By Formulas I ' 7.9g Montelukast Sodiums are prepared by the method at sodium salt in embodiment 8 in compound, and yield is
90%.
Claims (10)
1. a kind of general formula (III) compound represented and its pharmaceutically acceptable salt：
Wherein：
X indicates methyl, C1-6Alkoxy, phenoxy group, benzyloxy；
R1Indicate C1-6Alkyl, phenyl, benzyl；
R2Indicate C1-6Alkyl, phenyl, benzyl.
2. general formula (III) compound represented according to claim 1 and its pharmaceutically acceptable salt, wherein X indicates first
Base, methoxy or ethoxy；R1、R2Indicate phenyl.
3. the preparation of general formula (III) compound represented and its pharmaceutically acceptable salt described in a kind of claims 1 or 2
Method, this method include：By formula (IV) compound and formula (IVA) compound is dissolved in organic solvent, in the presence of alkali instead
It should obtain formula (III) compound；
Synthetic route is as follows：
4. the preparation method of general formula (III) compound represented according to claim 3 and its pharmaceutically acceptable salt,
It is characterized in that：The alkali is selected from triethylamine, N, N- diisopropylethylamine, 11 carbon -7- alkene of 1,8- diazabicylos, 4- diformazans
Aminopyridine, pyridine, imidazoles, NaH, NaOH, KOH, Ca (OH)2、NaHCO3、Na2CO3、K2CO3、Cs2CO3, in CsOH or CaO
It is one or more of；Formula (IV) compound and the molar ratio of the alkali are 1：(1~5)；Formula (IV) compound and formula
(ⅣA) compound molar ratio be 1：(1~5).
5. the preparation method of general formula (III) compound represented according to claim 3 and its pharmaceutically acceptable salt,
It is characterized in that：Reaction temperature is 0~100 DEG C, and the reaction time is 1~5h.
6. a kind of synthetic method of Montelukast Sodium, which is characterized in that shown in the general formula (III) described in claims 1 or 2
Compound as intermediate, method and step is：
(1) 1- thiopurine methyltransferases cyclopropaneacetic acid or its salt and alkali are sequentially added in organic solvent, formula (III) compound are then added,
It is stirred to react 2~4h at 20~60 DEG C, obtains formula (II) compound；
(2) Lewis acid activation agent is added in organic solvent, then under -10~5 DEG C of temperature conditions, methyl Grignard is added
Reagent stirs 0~1h, then formula (II) compound solution is added in Lewis acid activation agent-methyl Grignard reaction solution, instead
1.5~5h is answered, Montelukast acid is prepared by addition reaction, and montestron sodium is obtained further across at salt refining,
7. the synthetic method of Montelukast Sodium according to claim 6, which is characterized in that alkali is selected from described in step (1)
Triethylamine, N, N- diisopropylethylamine, 11 carbon -7- alkene of 1,8- diazabicylos, 4-dimethylaminopyridine, pyridine, imidazoles,
NaH、NaOH、KOH、Ca(OH)2、NaHCO3、Na2CO3、K2CO3、Cs2CO3, one or more of CsOH or CaO；Formula (III) is changed
The molar ratio for closing object and the alkali is 1：(1~5).
8. the synthetic method of Montelukast Sodium according to claim 6, which is characterized in that the Louis described in step (2)
This acid activators is selected from one or more of cerous chloride, zinc chloride, lithium chloride, cobalt chloride, lanthanum chloride, chromium chloride.
9. the synthetic method of Montelukast Sodium according to claim 6, it is characterised in that：Formula described in step (2)
(II) compound and the molar ratio of Lewis acid activation agent are 1：(1~1.5).
10. the synthetic method of Montelukast Sodium according to claim 6, it is characterised in that：Methyl lattice described in step (2)
Family name's reagent is methyl-magnesium-chloride, methyl-magnesium-bromide or methylpyridinium iodide magnesium；Formula (II) compound and methyl Grignard rub
You are than being 1：(3~10).
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| KR100774088B1 (en) * | 2006-12-14 | 2007-11-06 | 한미약품 주식회사 | Method of preparing montelukast and intermediates used therein |
| EP2502910A1 (en) * | 2011-03-15 | 2012-09-26 | Laboratorios Lesvi, S.L. | Camphorsulfonic salt of a key Montelukast intermediate |
| CN105294556A (en) * | 2014-06-06 | 2016-02-03 | 上海迪赛诺化学制药有限公司 | Method for preparing montelukast acid |
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