CN102603623A - Method for preparing high-purity roflumilast - Google Patents
Method for preparing high-purity roflumilast Download PDFInfo
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- CN102603623A CN102603623A CN2011104426743A CN201110442674A CN102603623A CN 102603623 A CN102603623 A CN 102603623A CN 2011104426743 A CN2011104426743 A CN 2011104426743A CN 201110442674 A CN201110442674 A CN 201110442674A CN 102603623 A CN102603623 A CN 102603623A
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- 238000000034 method Methods 0.000 title claims abstract description 33
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 title abstract description 21
- 229960002586 roflumilast Drugs 0.000 title abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical group SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 15
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 14
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229940126214 compound 3 Drugs 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- 235000015320 potassium carbonate Nutrition 0.000 claims description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 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
- 229940125898 compound 5 Drugs 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 6
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 6
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- BLBDTBCGPHPIJK-UHFFFAOYSA-N 4-Amino-2-chloropyridine Chemical class NC1=CC=NC(Cl)=C1 BLBDTBCGPHPIJK-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 230000017858 demethylation Effects 0.000 claims description 4
- 238000010520 demethylation reaction Methods 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- YZHUMGUJCQRKBT-UHFFFAOYSA-M sodium chlorate Chemical compound [Na+].[O-]Cl(=O)=O YZHUMGUJCQRKBT-UHFFFAOYSA-M 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- -1 carboxylic acid compound Chemical class 0.000 claims description 2
- 150000001805 chlorine compounds Chemical class 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 230000001335 demethylating effect Effects 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- VKJKEPKFPUWCAS-UHFFFAOYSA-M potassium chlorate Chemical compound [K+].[O-]Cl(=O)=O VKJKEPKFPUWCAS-UHFFFAOYSA-M 0.000 claims description 2
- SATVIFGJTRRDQU-UHFFFAOYSA-N potassium hypochlorite Chemical compound [K+].Cl[O-] SATVIFGJTRRDQU-UHFFFAOYSA-N 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract description 9
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 abstract description 4
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 abstract description 4
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 abstract description 4
- 206010061218 Inflammation Diseases 0.000 abstract description 2
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000029936 alkylation Effects 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- MLAZVBDTWHMFRL-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1OCC1CC1 MLAZVBDTWHMFRL-UHFFFAOYSA-N 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- GRDGKQILTBTXSJ-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1OCC1CC1 GRDGKQILTBTXSJ-UHFFFAOYSA-N 0.000 description 1
- QRYSWXFQLFLJTC-UHFFFAOYSA-N 616-82-0 Chemical compound OC(=O)C1=CC=C(O)C([N+]([O-])=O)=C1 QRYSWXFQLFLJTC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 0 CC(C)=C*=COC(*)F Chemical compound CC(C)=C*=COC(*)F 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940006829 daliresp Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000010129 solution processing Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000002512 suppressor factor Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing high-purity roflumilast which is a compound as shown in the formula (I). The compound is an orally taken selective phosphodiesterase 4 (PDE4) inhibitor and is proven to be capable of inhibiting inflammation related to a chronic obstructive pulmonary disease (COPD).
Description
Technical field
The present invention relates to the organic synthesis field, relate in particular to a kind of method for preparing the high purity roflumilast.
Background technology
Roflumilast (Roflumilast), chemical name: 3-(cyclo propyl methoxy)-N-(3,5-dichloropyridine-4-yl)-4-(difluoro-methoxy) BM, structural formula is following:
Roflumilast is the new oral medicine that Nycomed company developed, was used to treat asthma and chronic obstructive pulmonary disease.Roflumilast was ratified to be used for serious chronic obstructive pulmonary disease (COPD) and chronic bronchitis by European Union in June, 2010, and in European Union member countries, its commodity are called Daxas.On February 28th, 2011, it is used for serious COPD treatment drugs approved by FDA, at the commodity of U.S. Daliresp by name.
Roflumilast is a kind of oral selectivity phosphodiesterase 4 (PDE4) suppressor factor.Verified, this medicine can suppress and the relevant inflammation of chronic obstructive pulmonary disease (COPD).Roflumilast is not only first kind of medicine in the serious COPD new therapy, and is first kind of oral pharmaceutical towards COPD patient.The character that it is unique; Help to manage better patients with chronic obstructive pulmonary diseases: when treating severe chronic obstructive pulmonary patient with the bronchodilator drug combination; Roflumilast can provide the additional benefit of further minimizing symptom and disease progression rate, becomes target particular phenotype chronic obstructive pulmonary disease thus and promptly has serious flow limitation relevant with many phlegm with long-term cough and tool first medicine of disease progression history patient repeatedly.
Relevant analyst's prediction, in the European Union area, roflumilast listing sales volume then was 7,000,000, can rise to 1.50 hundred million by 2015.
For synthesizing of roflumilast, the method summary of relevant bibliographical information is following:
(1) one Chinese patent application has been reported the synthetic of roflumilast key intermediate for No. 201010603095.8; This method is a starting raw material with 3-nitro-4-hydroxybenzoate, and alkylation, reduction nitro, diazotization, hydrolysis are passed through by elder generation, the last hydrolysis of alkylation obtains the key intermediate that carboxylic acid is a roflumilast again.
Starting raw material is difficult for obtaining in this route, needs self-control, and has used diazotization reaction, and hazardous is difficult to realize suitability for industrialized production.
(2) document WO 2005026095 has been reported with 3, and 4-resorcylic acid ester is a kind of compound method of starting raw material, and through two step alkylations, hydrolysis obtains the carboxylic acid midbody then earlier, and last with 2,6-two chloro-4-aminopyridine condensations obtain target product.
There is selective problems in the first step reaction in this route, and reaction can take place on two hydroxyls, and what obtain is mixture, is difficult in aftertreatment, separate, and needs through column chromatography purification, and yield is low, is difficult to realize suitability for industrialized production.
(3) document CN101490004 has reported with 3, and the 4-Dihydroxy benzaldehyde is a kind of compound method of starting raw material, and through two step alkylations, oxidation obtains the carboxylic acid midbody then earlier, and last with 2,6-two chloro-4-aminopyridine condensations obtain target product.
There is selective problems equally in the first step reaction in this route, and reaction can take place on two hydroxyls, and what obtain is mixture, is difficult in aftertreatment, separate, and needs through column chromatography purification, and yield is low, is difficult to realize suitability for industrialized production.
(4) document WO 2004033430 has reported that the use o-phenol is raw material in fact, once obtains the carboxylic acid midbody through alkylation, bromination, alkylation again, carboxylated and hydrolysis.
Use low-temp reaction in this route, and used bromine, also used expensive palladium catalyzed reaction, complicated operation, cost is high, is not suitable for suitability for industrialized production.
Summary of the invention
Variety of issue in view of aforesaid method exists is necessary to invent a kind of low cost, operates simple and easy, as to be fit to suitability for industrialized production method.
Therefore, the method that relates in one aspect to preparation I compound of the present invention,
Said method comprising the steps of:
(b) make compound 3 demethylating in the presence of demethylation reagent, obtain compound 4:
(c) make compound 4 in the presence of alkali with monochlorodifluoromethane generation alkylated reaction, obtain compound 5:
(d) compound 5 is oxidized to corresponding carboxylic acid compound 6:
(e) compound 6 usefulness chloride reagents are converted into corresponding chloride compounds 7:
(f) make compound 7 and 3,5-two chloro-4-aminopyridines react in the presence of alkali, obtain formula (I) compound:
Another aspect of the present invention relates to the midbody compound 3 that is used for preparation formula (I) compound:
Embodiment
Summary of the invention part like preceding text is said, the method that relates in one aspect to preparation I compound of the present invention,
In an embodiment of method of the present invention, used demethylation reagent is selected from the step (b), but is not limited to: thiophenol sodium, sulfur alcohol sodium, boron trichloride, boron tribromide or their combination are preferably thiophenol sodium; Solvent used in the reaction is selected from, but is not limited to: DMF, DMSO, NMP, dioxane, toluene, acetonitrile or their combination are preferably DMF or NMP.Temperature of reaction can be for example 0-190 ℃, is preferably 80-140 ℃.Reaction times can be preferably 2-12 hour for for example 1-24 hour.
In an embodiment of method of the present invention; Used alkali is selected from the step (c); But be not limited to: sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, salt of wormwood, yellow soda ash, cesium carbonate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide or their combination are preferably salt of wormwood; Solvent used in the reaction is selected from, but is not limited to acetone, DMF, DMSO, NMP, THF, dioxane, toluene, acetonitrile or their combination, is preferably DMF.Temperature of reaction can be for example 0-100 ℃, is preferably 20-40 ℃.Reaction times can be preferably 8-12 hour for for example 3-24 hour.
In an embodiment of method of the present invention, used oxygenant is selected from the step (d), but is not limited to: hydrogen peroxide, Youxiaolin, VAL-DROP, potassium hypochlorite, Potcrate, potassium permanganate or their combination are preferably hydrogen peroxide or VAL-DROP; Solvent used in the reaction is selected from, but is not limited to: water, acetic acid, methyl alcohol, ethanol or their combination.Temperature of reaction can be for example 0-100 ℃, is preferably 10-40 ℃.Reaction times is preferably for example 3-24 hour, is preferably 3-10 hour.
In an embodiment of method of the present invention, used chloride reagent is selected from the step (e), but is not limited to: sulfur oxychloride, oxalyl chloride, phosphorus trichloride or their combination are preferably sulfur oxychloride or oxalyl chloride.
In an embodiment of method of the present invention; Used alkali is selected from the step (f); But be not limited to sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide, butyllithium, hexamethyldisilazane lithium, hmds base potassium, sodium hydride or their combination, be preferably potassium tert.-butoxide.
In an embodiment of method of the present invention, method of the present invention is further comprising the steps of:
(a) make compound 1 and compound 2 in the presence of alkali, carry out alkylated reaction, obtain compound 3:
Wherein X is a leavings group, is selected from Cl, Br, I, OMs and OTs.
In an embodiment of method of the present invention; Alkali used in the step (a) can be selected from; But be not limited to: sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, salt of wormwood, yellow soda ash, cesium carbonate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide or their combination are preferably salt of wormwood; Solvent used in the reaction is selected from, but is not limited to: acetone, N, dinethylformamide (DMF), DMSO 99.8MIN. (DMSO), N-Methyl pyrrolidone (NMP), THF (THF), dioxane, toluene, acetonitrile or their combination are preferably DMF.Temperature of reaction can be for example 0-100 ℃, is preferably 20-40 ℃.Reaction times can be preferably 8-12 hour for for example 3-24 hour.
In an embodiment of method of the present invention, said method also comprises the step of the formula of being further purified (I) compound, comprising: with the thick product of formula (I) compound with the acidic aqueous solution processing of pulling an oar; With the slurry suction filtration that obtains, and with the mixed solvent recrystallization of filter cake with alcohol and water.
In an embodiment of method of the present invention, comprise in the described acidic aqueous solution, but be not limited to: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or their combination are preferably hydrochloric acid; The concentration of described acidic aqueous solution is 0-90%, is preferably 5-20%.In an embodiment of method of the present invention, alcohol used in the recrystallization is selected from, but is not limited to: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol or their combination are preferably Virahol; The content of water can be preferably 10-30% for for example 0-80% in the mixed solvent.
Another aspect of the present invention relates to the midbody compound 3 that is used for preparation formula (I) compound:
Embodiment
Below will combine embodiment that preparation method of the present invention is described in more detail.Yet art technology person should be appreciated that following examples only are for illustrative purposes, but not to qualification of the present invention.Protection scope of the present invention should be limited appending claims.
The preparation of embodiment 1:3-(cyclo propyl methoxy)-4-methoxybenzaldehyde (compound 3)
In reaction flask, add 3-hydroxyl-4-methoxybenzaldehyde (compound 1,15.2g, 0.1mol), the brooethyl Trimetylene (compound 2, wherein X is Br, 16.2g, 0.12mol), salt of wormwood (41.4g, 0.36mol) and DMF (200mL).Make this mixture room temperature reaction 8 hours, complete through the TLC detection reaction.In reaction solution, add ETHYLE ACETATE (200mL), use distilled water wash.Water phase separated and organic phase are used ethyl acetate extraction with water.Merge organic phase, use anhydrous sodium sulfate drying.Boil off solvent under the decompression, obtain compound 3, be off-white color solid 20.2g, yield is 98%.
1H?NMR(CDCl
3)：δ9.84(1H，s)，7.47-7.44(1H，d，J＝2.0Hz)，7.39(1H，s)，6.98-7.00(1H，d，J＝8.4Hz)，3.97(3H，s)，3.97-3.92(2H，d，J＝22Hz)，1.30-1.32(1H，m)，0.69-0.66(2H，m)，0.39-0.38(2H，m)。
The preparation of embodiment 2:3-(cyclo propyl methoxy)-4-hydroxy benzaldehyde (compound 4)
With compound 3 (10.3g 50mmol) is dissolved among the NMP (150mL), and add the thiophenol sodium water solution (～36.7%w/w, 0.1mol).The mixing solutions that obtains in 190～200 ℃ of stirring reactions 1 hour, is cooled to room temperature then.Reaction mixture is poured in the zero(ppm) water (500mL), with ethyl acetate extraction (2 * 100mL).Water is regulated pH to 1～2 with hydrochloric acid (6.0M), with ethyl acetate extraction (3 * 100mL).Merge organic phase, use anhydrous sodium sulfate drying.Boil off solvent under the decompression, obtain compound 4, be off-white color solid 7.68g, yield is 80%.
1H?NMR(CDCl
3)：δ9.81(1H，s)，7.43-7.40(1H，d，J＝2.0Hz)，7.38(1H，s)，7.06-7.04(1H，d，J＝4.0Hz)，3.96-3.94(2H，d，J＝6.8Hz)，1.33-1.29(1H，m)，0.70-0.66(2H，m)，0.39-0.36(2H，m)。
The preparation of embodiment 3:3-(cyclo propyl methoxy)-4-difluoro-methoxy phenyl aldehyde (compound 5)
With compound 4 (5.77g, 30mmol), K
2CO
3(12.42g, 90mmol) and DMF (100mL) be mixed in the there-necked flask, feed Freon gas then, 45 ℃ the reaction 6 hours.The TLC demonstration reacts completely.Reaction solution is poured in the zero(ppm) water, with twice of ethyl acetate extraction.Organic phase is washed with saturated sodium-chloride, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent obtains compound 5, is yellow oily liquid 7.05g, and yield is 97%.
1H?NMR(CDCl
3)：δ9.92(1H，s)，7.47-7.44(1H，d，J＝2.0Hz)，7.43(1H，s)，7.32-7.30(1H，d，J＝4.0Hz)，6.94-6.57(1H，d，J＝150Hz)，3.96-3.94(2H，d，J＝6.8Hz)，1.34-1.30(1H，m)，0.70-0.65(2H，m)，0.39-0.36(2H，m)。
The preparation of embodiment 4:3-(cyclo propyl methoxy)-4-difluoro-methoxy-benzoic acid (compound 6)
In reaction flask, add compound 5 (0.5g, 2.1mmol) and aqueous sodium hydroxide solution (30%, 10mL).Under vigorous stirring, (30%, 50mL), and control reaction temperature is about 45 ℃ to drip ydrogen peroxide 50.After dropwising, continue under this temperature and reacted 5 hours.After reacting completely, add sodium sulfite solution, use ethyl acetate extraction.Tell organic phase, wash organic phase, and use anhydrous sodium sulfate drying with Hydrogen chloride.The pressure reducing and steaming solvent obtains compound 6, is faint yellow solid 0.82g, and yield is 80%.
1H?NMR(CDCl
3)：δ7.74-7.73(1H，d，J＝2.0Hz)，7.71(1H，s)，7.26-7.23(1H，d，J＝14.0Hz)，6.93-6.56(1H，d，J＝150Hz)，3.96-3.94(2H，d，J＝6.8Hz)，1.34-1.30(1H，m)，0.70-0.66(2H，m)，0.39-0.37(2H，m)。
Embodiment 5: the preparation of roflumilast (formula (I) compound)
In reaction flask, add compound 6 (15g, 0.058mol), a small amount of DMF and sulfur oxychloride (300mL).Made the said mixture back flow reaction 4 hours.Pressure reducing and steaming sulfur oxychloride, resistates are treated and directly be used for next step reaction.
With 3,5-two chloro-4-aminopyridines (19g 0.12mol) is dissolved among the DMF (400mL), and the adding potassium tert.-butoxide (17g, 0.15mol).With the mixture that obtains in 0 ℃ of following stirring reaction 0.5 hour.Add the above-mentioned acyl chlorides midbody that obtains.With the mixture that obtains stirring reaction 6 hours under room temperature.After reaction finishes, reaction solution is poured in the zero(ppm) water, with ethyl acetate extraction three times.Merge organic phase, use the saturated common salt water washing, use anhydrous sodium sulfate drying.The pressure reducing and steaming solvent obtains the off-white color solid, is roflumilast bullion 19.5g, and yield is 82%.
1H?NMR(CDCl
3)：δ8.58(2H，s)，7.69(2H，br)，7.49(1H，s)，7.47-7.46(1H，d，J＝2.0Hz)，7.30-7.26(1H，d，J＝14.0Hz)，6.94-6.56(1H，d，J＝150Hz)，3.98-3.96(2H，d，J＝6.8Hz)，1.34-1.30(1H，m)，0.70-0.66(2H，m)，0.39-0.36(2H，m)。
Embodiment 6: the purifying of roflumilast (formula (I) compound)
(19.5g 0.048mol) joins in 10% hydrochloric acid (200mL) stirring at room 0.5 hour with the thick product of the roflumilast that obtains among the embodiment 5.Filter, add the mixed solution of Virahol (300mL) and zero(ppm) water (30mL) in the filter cake.Be warming up to backflow, add small amount of activated decolouring 0.5 hour.Suction filtration makes the filter cake naturally cooling separate out crystal while hot.Filter, obtain white solid 15.5g, yield is 79.5%.HPLC purity is 99.5%, and fusing point is 157-158 ℃.
Claims (9)
1. the method for preparing formula (I) compound,
Said method comprising the steps of:
(b) make compound 3 demethylating in the presence of demethylation reagent, obtain compound 4:
(c) make compound 4 in the presence of alkali with monochlorodifluoromethane generation alkylated reaction, obtain compound 5:
(d) compound 5 is oxidized to corresponding carboxylic acid compound 6:
(e) compound 6 usefulness chloride reagents are converted into corresponding chloride compounds 7:
(f) make compound 7 and 3,5-two chloro-4-aminopyridines react in the presence of alkali, obtain formula (I) compound:
2. method according to claim 1, wherein in step (b), described demethylation reagent is selected from thiophenol sodium, sulfur alcohol sodium, boron trichloride, boron tribromide or their combination, is preferably thiophenol sodium; Used solvent is selected from DMF, DMSO, NMP, dioxane, toluene, acetonitrile or their combination in the reaction, is preferably DMF or NMP.
3. method according to claim 1 and 2; Wherein in step (c); Described alkali is selected from sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, salt of wormwood, yellow soda ash, cesium carbonate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide or their combination, is preferably salt of wormwood; Used solvent is selected from acetone, DMF, DMSO, NMP, THF, dioxane, toluene, acetonitrile or their combination in the reaction, is preferably DMF.
4. according to the described method of aforementioned arbitrary claim, wherein in step (d), described oxygenant is selected from hydrogen peroxide, Youxiaolin, VAL-DROP, potassium hypochlorite, Potcrate, potassium permanganate or their combination, is preferably hydrogen peroxide or VAL-DROP.
5. according to the described method of aforementioned arbitrary claim, wherein in step (e), described chloride reagent is selected from sulfur oxychloride, oxalyl chloride, phosphorus trichloride or their combination, is preferably sulfur oxychloride or oxalyl chloride.
6. according to the described method of aforementioned arbitrary claim; Wherein in step (f); Used alkali is selected from sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide, butyllithium, hexamethyldisilazane lithium, hmds base potassium, sodium hydride or their combination in the reaction, is preferably potassium tert.-butoxide.
7. according to the described method of aforementioned arbitrary claim, it is further comprising the steps of:
(a) make compound 1 and compound 2 in the presence of alkali, carry out alkylated reaction, obtain compound 3:
Wherein X is a leavings group, is selected from Cl, Br, I, OMs and OTs.
8. method according to claim 7; Wherein in step (a); Described alkali is selected from sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, salt of wormwood, yellow soda ash, cesium carbonate, sodium ethylate, sodium methylate, sodium tert-butoxide, potassium tert.-butoxide or their combination, is preferably salt of wormwood; Used solvent is selected from acetone, DMF, DMSO, NMP, THF, dioxane, toluene, acetonitrile or their combination in the reaction, is preferably DMF.
9. compound 3:
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| CN102850266A (en) * | 2012-08-24 | 2013-01-02 | 郑州明泽医药科技有限公司 | Preparation method of Roflumilast |
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| CN104447244A (en) * | 2014-10-29 | 2015-03-25 | 成都森科制药有限公司 | Roflumilast intermediates and preparation method of roflumilast |
| CN105017011A (en) * | 2015-06-03 | 2015-11-04 | 青岛辰达生物科技有限公司 | Preparation method of intermediate of roflumilast for treatment of chronic obstructive pulmonary disease |
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| CN105017011A (en) * | 2015-06-03 | 2015-11-04 | 青岛辰达生物科技有限公司 | Preparation method of intermediate of roflumilast for treatment of chronic obstructive pulmonary disease |
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