CN102336705B - Method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine - Google Patents
Method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 13
- 150000001412 amines Chemical class 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 43
- 239000012442 inert solvent Substances 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- -1 3-cyclo propyl Chemical group 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 229940059260 amidate Drugs 0.000 claims description 3
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 29
- 239000000047 product Substances 0.000 abstract description 8
- 239000006227 byproduct Substances 0.000 abstract description 5
- ISIQAMHROGZHOV-UHFFFAOYSA-N 3,5-dichloropyridin-4-amine Chemical compound NC1=C(Cl)C=NC=C1Cl ISIQAMHROGZHOV-UHFFFAOYSA-N 0.000 abstract 1
- 238000007112 amidation reaction Methods 0.000 abstract 1
- 150000001450 anions Chemical class 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 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 description 56
- 229960002586 roflumilast Drugs 0.000 description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- 238000003756 stirring Methods 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 239000002253 acid Substances 0.000 description 28
- 239000012043 crude product Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 23
- 239000007787 solid Substances 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 235000019441 ethanol Nutrition 0.000 description 14
- 238000001914 filtration Methods 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 238000001291 vacuum drying Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 9
- 238000010792 warming Methods 0.000 description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 150000001263 acyl chlorides Chemical class 0.000 description 7
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 5
- 229960004050 aminobenzoic acid Drugs 0.000 description 5
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000007670 refining Methods 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- HBGGXOJOCNVPFY-UHFFFAOYSA-N diisononyl phthalate Chemical compound CC(C)CCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCC(C)C HBGGXOJOCNVPFY-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- LBLBOIFGYPHXGS-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl chloride Chemical compound FC(F)OC1=CC=C(C(Cl)=O)C=C1OCC1CC1 LBLBOIFGYPHXGS-UHFFFAOYSA-N 0.000 description 2
- YQUQWHNMBPIWGK-UHFFFAOYSA-N 4-isopropylphenol Chemical compound CC(C)C1=CC=C(O)C=C1 YQUQWHNMBPIWGK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KPEQNVSFOMKHAZ-UHFFFAOYSA-N 2-aminobenzoic acid;phenol Chemical compound OC1=CC=CC=C1.NC1=CC=CC=C1C(O)=O KPEQNVSFOMKHAZ-UHFFFAOYSA-N 0.000 description 1
- FAACMIZCSWBJHO-UHFFFAOYSA-N 3-cyclopropyl-2-methoxyphenol Chemical compound C1(CC1)C=1C(=C(C=CC1)O)OC FAACMIZCSWBJHO-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- OAHMVZYHIJQTQC-UHFFFAOYSA-N 4-cyclohexylphenol Chemical compound C1=CC(O)=CC=C1C1CCCCC1 OAHMVZYHIJQTQC-UHFFFAOYSA-N 0.000 description 1
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- HNKMANVQAQLGHR-UHFFFAOYSA-N O=C(c(cc1)cc(OCC2CC2)c1OC(F)F)Oc1ccccc1 Chemical compound O=C(c(cc1)cc(OCC2CC2)c1OC(F)F)Oc1ccccc1 HNKMANVQAQLGHR-UHFFFAOYSA-N 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940090668 parachlorophenol Drugs 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 230000009325 pulmonary function Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010850 salt effect Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine, which is implemented by carrying out amidation reaction on anions of 4-amino- -3,5-dichloropyridine and 3-cyclopropylmethoxy-4-difluoro-aryl-methoxybenzoate under inert solvent neutralized alkaline conditions. The preparation method disclosed by the invention has the advantages of mild reaction conditions, fewer byproducts and simple after-treatment, and obviously lowers the synthesis cost; the purity of the refined product is at least 99.8%; and the invention is more suitable for industrial large-scale production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry preparation field, being specifically related to structural formula is N-(3,5-dichloropyridine-4-yl)-3-cyclo propyl methoxy-4-difluoromethoxybenzoamine amine, the preparation method of general roflumilast by name.
Background technology
Roflumilast (Roflumilast) obtains European Union's approval listing as first di(2-ethylhexyl)phosphate enzyme 4 (PDE 4) inhibitor optionally on July 6th, 2010, is used for the treatment of chronic obstructive pulmonary disease (COPD).Roflumilast can improve pulmonary function, reduces the acute episode of chronic bronchitis rate.The preparation method who has reported at present is as follows:
International monopoly WO93/25517 and WO94/02465 have described the method for the benzamide that replaces by phenylformic acid reactive derivative and amine reaction preparation dialkoxy.Wherein the phenylformic acid reactive derivative is carboxylic acid halides or acid anhydrides.This reaction can be at organic bases, such as triethylamine, N-methylmorpholine, or at mineral alkali, such as alkalimetal hydride, under the existence such as sodium hydride, at inert solvent, as carrying out in tetrahydrofuran (THF), the DMF.International monopoly WO95/01338 has described the preparation method of the benzamide of the dialkoxy replacement that comprises roflumilast, is with phenylformic acid reactive derivative and amine direct reaction under alkaline condition equally.Above-mentioned preparation method's shortcoming is to tend to cause generating the by product N-(3 that exceeds standard, 5-dichloropyridine-4-yl)-3-cyclo propyl methoxy-4-hydroxybenzamide, and this by product repeatedly all can not reduce behind the recrystallization, is not suitable at the highly purified roflumilast of industrial preparation.
Among the international monopoly WO2004/080967,4-amino-3 with reactive derivative (formula IV) the 3-cyclo propyl methoxy of 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid-4-difluoro-methoxy Benzoyl chloride and 2.2 equivalents, the an alkali metal salt of 5-dichloropyridine (formula V) is at conventional inert solvent, such as N, in the dinethylformamide, in 20～30 ℃ of lower reaction preparation roflumilasts.
Its Chinese style V compound is that an alkali metal salt effect of 5-dichloropyridine and the trimethyl carbinol obtains by 4-amino-3.
Wherein: B in the formula V compound
+Be positively charged ion, for example, alkali metal cation, preferred potassium ion.
The gained crude product can obtain the product of purity＞99%, the content of impurity N-(3,5-dichloropyridine-4-yl)-3-cyclo propyl methoxy-4-hydroxybenzamide＜0.1% with the mixed solvent recrystallization of isopropyl alcohol and water.
The described method of WO2004/080967 has preferentially been used the formula V compound that surpasses 2 equivalents, is unfavorable for the control of cost and quality product.Reaction directly is added drop-wise to undressed 3-cyclo propyl methoxy-4-difluoro-methoxy Benzoyl chloride highly basic (an alkali metal salt of the trimethyl carbinol) and 4-amino-3, in the mixture of 5-dichloropyridine, react comparatively violent, wayward, generating more impurity need to carry out above recrystallization twice with corresponding more solvent, causes product loss to cause yield on the low side.
International monopoly WO2005/026095, WO2006/040645, WO2008/006509 have introduced the preparation method of a series of PDE4 inhibitor that comprise roflumilast, but still all be direct by the reactive derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid and the reaction of formula V compound, the synthetic method of roflumilast is not optimized, has equally the difficult and yield problem on the low side of Control of Impurities.
This area still needs a kind of by product few, the refining rear high method for preparing roflumilast of total recovery.The present invention meets this demand.
Summary of the invention
The present invention is by 4-amino-3, the negatively charged ion of 5-dichloropyridine (formula I) carries out amidate action with 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid aromatic ester (formula II) and obtains N-(3,5-dichloropyridine-4-yl)-3-cyclo propyl methoxy-4-difluoromethoxybenzoamine amine (formula III), i.e. roflumilast.Specifically with 4-amino-3, the 5-dichloropyridine is dissolved in the inert solvent, 4-amino-3, and 5-dichloropyridine and inert solvent mass volume ratio are 1: 7～20 (W/V).Press 4-amino-3, the mol ratio of 5-dichloropyridine and alkali is 1: 1.0～3.0 ratio adding alkali, obtain the solution of formula I compound after the insulated and stirred, be that 1: 1.0～2.0 ratios join formula II compound in the mentioned solution in formula II compound and formula I compound mol ratio, Hou Jiashui is finished in reaction, regulates pH to 2～4, the solid that filtering separation is separated out, the roflumilast crude product that obtains, purity＞99%.
Wherein: the R of formula II is the hydrogen of ortho position, a position or contraposition, halogen, nitro, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
3-C
7Cycloalkyl, C
3-C
7Cycloalkyloxy.
The mol ratio of formula II compound and formula I compound is 1: 1.0～2.0, preferred 1: 1.1～1.3.
The used alkali of preparation I compound is selected from NaOH, NaOt-Bu or NaH, preferred NaH;
Reacting used inert solvent is aprotic solvent, is selected from methylene dichloride, tetrahydrofuran (THF), toluene, DMF and the N-Methyl pyrrolidone one or more, preferred DMF;
The temperature of reaction of described amidate action is 10～50 ℃, and the reaction times is between several minutes to 1 day.
Be that the ratio of 1: 5～8 (W/V) adds crude product in the ethanol according to crude product and ethanol mass volume ratio, reflux 0.5～1 hour, naturally cooling crystallization 5～10 hours filters, and vacuum-drying makes refining roflumilast.
Carry out reflux in the prepared roflumilast crude product adding ethanol, through crystallization, vacuum-drying makes refining roflumilast, its purity 〉=99.8%;
Roflumilast crude product and ethanol mass volume ratio are 1: 5～8 (W/V) in the described treating process;
Ethanol of the present invention refers to that concentration is the ethanolic soln of 80%～100% (V/V), and preferred concentration is the ethanolic soln of 90%～95% (V/V).
Starting raw material thing 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid aromatic ester (formula II) is with phenol or substituted phenol (formula VII compound) carry out the phenol acylation reaction and are prepared from organic solvent and under the alkaline condition accordingly by 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid reactive derivative (formula VI compound) among the present invention.
Wherein: R is identical with the R of formula II compound in the formula VII compound.
Described organic solvent is methylene dichloride, trichloromethane, tetrahydrofuran (THF), toluene, DMF or N-Methyl pyrrolidone;
Described alkali is nitrogenous organic base, comprises diisopropylethylamine, triethylamine, Trimethylamine 99, trimethylene diamines, DMA, pyridine, 1.8-diazabicylo (5.4.0) hendecene-7 or N-methylmorpholine;
The temperature of reaction of described phenol acylation reaction is 0～40 ℃.
Its advantage of the preparation method of roflumilast of the present invention is:
1: the method for the invention has significantly reduced the consumption of formula I compound, and production cost is significantly reduced, but also it is amino-3 to have reduced 4-, 5-dichloropyridine residual.
2: the present invention 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid aromatic ester and 4-amino-3,5-dichloropyridine anionic reactive, condition is more gentle controlled, aftertreatment is simple, is convenient to production operation, has reduced the generation of by product, be convenient to quality control, the roflumilast crude product purity that obtains＞99%, the purity of refining rear product 〉=99.8% is higher than purity and the yield of literature method products obtained therefrom.
Be more suitable for the highly purified roflumilast of scale operation according to the method for preparing roflumilast of the present invention than prior art.
Embodiment
The present invention is described in further detail below in conjunction with embodiment, but be not limitation of the present invention, all any this areas of doing according to the disclosure of invention be equal to replacement, all belong to protection scope of the present invention.
The preparation of embodiment 1:3-cyclo propyl methoxy-4-dichloromethane aminobenzoic acid p-NP
Under nitrogen protection, ice bath stir; the 3.31g p-NP is joined in the 60ml methylene dichloride; be partly dissolved and be suspension liquid; p-NP is entirely molten after adding the 6.6ml triethylamine; to be added drop-wise in the mentioned solution by the solution of the freshly prepd acyl chlorides of 5.66g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid in the 30ml methylene dichloride, and dropwise and be warming up to 20 ℃ of stirrings.After TLC showed that reaction is finished, the reaction solution concentrating under reduced pressure added the 50ml absolute ethyl alcohol and stirring in residuum, filtered, the 50ml washing, a small amount of absolute ethanol washing gets white solid, the dry product 7.65g that gets, content＞98%, two step yield: 92%, can be directly used in the next step.
Embodiment 2: the preparation of roflumilast
Under nitrogen protection, ice bath stir; with 3.24g 4-amino-3; the 5-dichloropyridine is dissolved in 30ml N; dinethylformamide; add 1.44g sodium hydride (60%) in batches; insulated and stirred was added drop-wise to the solution of 6.84g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid p-nitrophenyl ester in the 45ml DMF in the above-mentioned mixed solution after 15 minutes, dropwised to be warming up to 10 ℃ of stirrings.The TLC demonstration is reacted and is finished after about 15 minutes, slowly drips water 10ml under the ice bath, and reaction solution is poured in the 350ml water, transfers pH to 3.2, has a large amount of white solids to separate out, and the dry roflumilast crude product 6.89g of getting of final vacuum is washed in filtration on a small quantity.
Add in the ethanol of 45ml 90% (V/V) in the above-mentioned roflumilast crude product, reflux 1 hour, stir, wait clarifying rear naturally cooling crystallization 10 hours, separate out solid filtering, (yield: 81%), purity is 99.9% to the roflumilast 5.86g that must make with extra care after the vacuum-drying, fusing point: 159.5 ℃.Nuclear magnetic data is as follows:
1H-NMR(300MHz，DMSO-d6)δ：0.38(d，2H)，0.60(d，2H)，1.18～1.35(m，1H)，3.99(d，2H)，6.99，7.23，7.48(t，1H)，7.37(d，1H)，7.66(d，1H)，7.71(s，1H)，8.77(s，2H)，10.64(s，1H)
Example 3: the preparation of roflumilast
Under nitrogen protection, 20 ℃ of stirrings; with 1.75g 4-amino-3; the 5-dichloropyridine is dissolved in 15ml N; dinethylformamide; add 0.87g sodium hydroxide; insulated and stirred after 15 minutes with 2.74g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid p-nitrophenyl ester at 20ml N; solution in the dinethylformamide is added drop-wise in the above-mentioned mixed solution; 50 ℃ are continued to stir 5 hours, and TLC demonstration reaction is finished, and reaction solution is poured in the 180ml water; transfer pH to 2; there are a large amount of white solids to separate out, filter, wash on a small quantity the dry roflumilast crude product 2.12g of getting of final vacuum.
Add in the ethanol of 15ml 80% (V/V) in the above-mentioned roflumilast crude product, reflux 50 minutes, stir, wait clarifying rear naturally cooling crystallization 8 hours, separate out solid filtering, (yield: 66%), purity is 99.8% to the roflumilast 1.92g that must make with extra care after the vacuum-drying, fusing point: 159.6 ℃, nuclear magnetic data is consistent with embodiment 2.
Example 4: the preparation that sieve chlorine department is special
Under nitrogen protection, ice bath stir; with 1.60g 4-amino-3; the 5-dichloropyridine is dissolved in 15ml N; dinethylformamide; add 1.10g sodium tert-butoxide NaOt-Bu; the solution of 2.50g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid p-nitrophenyl ester in the 20ml DMF that insulated and stirred after 15 minutes makes embodiment 1 is added drop-wise in the above-mentioned mixed solution, is warming up to 40 ℃ and continues to stir.TLC demonstration reaction is finished after about 2 hours, and reaction solution is poured in the 180ml water, transfers pH to 2.4, has a large amount of white solids to separate out, and filters, and washes on a small quantity the dry roflumilast crude product 2.35g of getting of final vacuum.
Add in the ethanol of 16ml 100% (V/V) in the above-mentioned roflumilast crude product, reflux 1 hour, stir, wait clarifying rear naturally cooling crystallization 10 hours, separate out solid filtering, (yield: 72%), purity is 99.9% to the roflumilast 1.91g that must make with extra care after the vacuum-drying, fusing point: 159.4 ℃, nuclear magnetic data is consistent with embodiment 2.
The preparation of embodiment 5:3-cyclo propyl methoxy-4-dichloromethane aminobenzoic acid phenol
Under nitrogen protection, ice bath stir; 0.8g phenol is joined in the 20ml methylene dichloride, react according to embodiment 1 described preparation method and the freshly prepd acyl chlorides of 1.8g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid and prepare 2.0g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid phenyl ester.
Embodiment 6: the preparation of roflumilast
In nitrogen protection; ice bath stirs lower; with 1.45g 4-amino-3; the 5-dichloropyridine is dissolved in 10ml N; dinethylformamide; add 0.64g sodium hydride (60%) in batches; after the insulated and stirred 15 minutes, the solution of 2.0g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid phenyl ester in the 15ml DMF that embodiment 5 is made is added drop-wise in the above-mentioned mixed solution; dropwise and be warming up to 20 ℃ of stir abouts 1 hour; TLC demonstration reaction is finished, and slowly drips water 5ml under the ice bath, and reaction solution is poured in the 150ml water; transfer pH to 4; there are a large amount of white solids to separate out, filter, wash on a small quantity the dry roflumilast crude product 1.64g of getting of final vacuum.
Add in the ethanol of 11ml 90% (V/V) in the above-mentioned roflumilast crude product, reflux 42 minutes, stir, wait clarifying rear naturally cooling crystallization 7 hours, separate out solid filtering, (yield: 71%), purity is 99.8% to the roflumilast 1.50g that must make with extra care after the vacuum-drying, fusing point: 159.7 ℃, nuclear magnetic data is consistent with embodiment 2.
The preparation of embodiment 7:3-cyclo propyl methoxy-4-dichloromethane aminobenzoic acid p methoxy phenol
Under nitrogen protection, ice bath stir; the 0.9g p methoxy phenol is joined in the 20ml methylene dichloride, react according to embodiment 1 described preparation method and the freshly prepd acyl chlorides of 1.7g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid and prepare 2.0g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid to the methoxyl group phenyl ester.
Embodiment 8: the preparation of roflumilast
In nitrogen protection; ice bath stirs lower; with 1.33g 4-amino-3; the 5-dichloropyridine is dissolved in 10ml N; dinethylformamide; add 0.59g sodium hydride (60%) in batches; after the insulated and stirred 15 minutes, the 2.0g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid that embodiment 7 is made is added drop-wise in the above-mentioned mixed solution the solution of methoxyl group phenyl ester in the 15ml DMF; dropwise and be warming up to 30 ℃ of stir abouts 2 hours; TLC demonstration reaction is finished, and slowly drips water 5ml under the ice bath, and reaction solution is poured in the 150ml water; transfer pH to 3; there are a large amount of white solids to separate out, filter, wash on a small quantity the dry roflumilast crude product 1.71g of getting of final vacuum.
Add in the ethanol of 12ml 95% (V/V) in the above-mentioned roflumilast crude product, reflux 50 minutes, stir, wait clarifying rear naturally cooling crystallization 7 hours, separate out solid filtering, (yield: 70%), purity is 99.9% to the roflumilast 1.55g that must make with extra care after the vacuum-drying, fusing point: 159.5 ℃, nuclear magnetic data is consistent with embodiment 2.
The preparation of embodiment 9:3-cyclo propyl methoxy-4-dichloromethane aminobenzoic acid para-chlorophenol
Under nitrogen protection, ice bath stir; the 0.8g p-fluorophenol is joined in the 20ml methylene dichloride, react according to embodiment 1 described preparation method and the freshly prepd acyl chlorides of 1.7g3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid and prepare 2.0g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid to the fluorobenzene ester.
Embodiment 10: the preparation of roflumilast
In nitrogen protection; ice bath stirs lower; with 1.32g 4-amino-3; the 5-dichloropyridine is dissolved in 10ml N; dinethylformamide; add 0.59g sodium hydride (60%) in batches; after the insulated and stirred 15 minutes, the 2.0g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid that embodiment 9 is made is added drop-wise in the above-mentioned mixed solution the solution of fluorobenzene ester in the 15ml DMF; dropwise and be warming up to 40 ℃ of stir abouts 1 hour; TLC demonstration reaction is finished, and slowly drips water 5ml under the ice bath, and reaction solution is poured in the 150ml water; transfer pH to 4; there are a large amount of white solids to separate out, filter, wash on a small quantity the dry roflumilast crude product 1.85g of getting of final vacuum.
Add in the ethanol of 10ml 95% (V/V) in the above-mentioned roflumilast crude product, reflux 30 minutes, stir, wait clarifying rear naturally cooling crystallization 7 hours, separate out solid filtering, (yield: 75%), purity is 99.9% to the roflumilast 1.72g that must make with extra care after the vacuum-drying, fusing point: 159.8 ℃, nuclear magnetic data is consistent with embodiment 2.
Embodiment 11:3-cyclo propyl methoxy-4-dichloromethane aminobenzoic acid is to the preparation of cyclo propyl methoxy phenol
Under nitrogen protection, ice bath stir; 0.6g is joined in the 10ml methylene dichloride cyclo propyl methoxy phenol, react according to embodiment 1 described preparation method and the freshly prepd acyl chlorides of 0.9g3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid and prepare 1.2g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid to the cyclo propyl methoxy phenyl ester.
Embodiment 12: the preparation of roflumilast
In nitrogen protection; ice bath stirs lower to 0.88g 4-amino-3; the 5-dichloropyridine is dissolved in 7ml N; dinethylformamide; add 0.40g sodium hydride (60%) in batches; after the insulated and stirred 15 minutes; the 1.2g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid that embodiment 11 is made to the fluorobenzene ester at 10ml N; solution in the dinethylformamide is added drop-wise in the above-mentioned mixed solution, dropwises to be warming up to 40 ℃ of stir abouts 3 hours, and TLC demonstration reaction is finished; slowly drip water 3ml under the ice bath; reaction solution is poured in the 100ml water, transferred pH to 2, have a large amount of white solids to separate out; filter, wash on a small quantity the dry roflumilast crude product 0.92g of getting of final vacuum.
Add in the ethanol of 6ml 95% (V/V) in the above-mentioned roflumilast crude product, reflux 30 minutes, stir, wait clarifying 5 hours crystallizatioies of rear naturally cooling, separate out solid filtering, (yield: 73%), purity is 99.8% to the roflumilast 0.87g that must make with extra care after the vacuum-drying, fusing point: 159.9 ℃, nuclear magnetic data is consistent with embodiment 2.
The preparation of embodiment 13:3-cyclo propyl methoxy-4-dichloromethane aminobenzoic acid australol
Under nitrogen protection, ice bath stir; 1.18g is added australol in the 10ml methylene dichloride, react according to embodiment 1 described preparation method and the freshly prepd acyl chlorides of 2.0g3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid and prepare 2.47g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid p-isopropyl phenyl ester.
Embodiment 14: the preparation of roflumilast
In nitrogen protection; ice bath stirs lower to 0.95g 4-amino-3; the 5-dichloropyridine is dissolved in 10ml N; dinethylformamide; add 0.42g sodium hydride (60%) in batches; after the insulated and stirred 15 minutes; the 2.0g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid p-isopropyl phenyl ester that embodiment 13 is made is at 15ml N; solution in the dinethylformamide is added drop-wise in the above-mentioned mixed solution; dropwise and be warming up to 20 ℃ of stir abouts 2 hours; TLC demonstration reaction is finished; slowly drip water 3ml under the ice bath; reaction solution is poured in the 125ml water, transferred pH to 3.4, have a large amount of white solids to separate out; filter, wash on a small quantity the dry roflumilast crude product 1.75g of getting of final vacuum.
Add in the ethanol of 12ml 95% (V/V) in the above-mentioned roflumilast crude product, reflux 0.5 hour, stir, wait clarifying 5 hours crystallizatioies of rear naturally cooling, separate out solid filtering, (yield: 75%), purity is 99.8% to the roflumilast 1.61g that must make with extra care after the vacuum-drying, fusing point: 159.9 ℃, nuclear magnetic data is consistent with embodiment 2.
The preparation of embodiment 15:3-cyclo propyl methoxy-4-dichloromethane aminobenzoic acid p-cyclohexylphenol
Under nitrogen protection, ice bath stir; the 1.15g p-cyclohexylphenol is joined in the 10ml methylene dichloride, react according to embodiment 1 described preparation method and the freshly prepd acyl chlorides of 1.5g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid and prepare 2.03g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid to the cyclohexyl phenyl ester.
Embodiment 16: the preparation of roflumilast
In nitrogen protection; ice bath stirs lower to 0.65g 4-amino-3; the 5-dichloropyridine is dissolved in 5ml N; dinethylformamide; add 0.3g sodium hydride (60%) in batches; after the insulated and stirred 15 minutes; the 1.5g 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid that embodiment 13 is made to the cyclohexyl phenyl ester at 12ml N; solution in the dinethylformamide is added drop-wise in the above-mentioned mixed solution, dropwises to be warming up to 30 ℃ of stir abouts 3 hours, and TLC demonstration reaction is finished; slowly drip water 3ml under the ice bath; reaction solution is poured in the 100ml water, transferred pH to 3.5, have a large amount of white solids to separate out; filter, wash on a small quantity the dry roflumilast crude product 1.10g of getting of final vacuum.
Add in the ethanol of 8ml 90% (V/V) in the above-mentioned roflumilast crude product, reflux 30 minutes, stir, wait clarifying 5 hours crystallizatioies of rear naturally cooling, separate out solid filtering, (yield: 67%), purity is 99.8% to the roflumilast 0.98g that must make with extra care after the vacuum-drying, fusing point: 159.6 ℃, nuclear magnetic data is consistent with embodiment 2.
Embodiment 17:
The roflumilast that embodiment 2～4, embodiment 6, embodiment 8, embodiment 10, embodiment 12, embodiment 14, embodiment 16 are made is measured impurity with the product that preparation method A by the WO2004/080967 patent disclosure makes by the HPLC Self-control method, area normalization method is measured content, contrast yield (in the 3-cyclopropylmethoxy-4-difluoromethoxybenzoacid acid), the result is as follows:
WO2004/080967 patent sample is to be prepared according to method A among the embodiment of WO2004/080967 patent disclosure, makes roflumilast sample 4.1g, yield: 56%, and purity is 99.2%, fusing point: 159.1 ℃.
Claims (8)
1. one kind prepares N-(3,5-dichloropyridine-4-yl)-method of 3-cyclo propyl methoxy-4-difluoromethoxybenzoamine amine, it is characterized in that, in inert solvent and under the alkaline condition, formula I and formula II compound are carried out amidate action prepare the formula III compound;
Wherein: R is the hydrogen of ortho position, a position or contraposition among the formula II, halogen, nitro, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
3-C
7Cycloalkyl, C
3-C
7Cycloalkyloxy.
2. preparation method according to claim 1 is characterized in that, the 4-amino-3 that preparation I compound is used, and the mol ratio of 5-dichloropyridine and alkali is 1:1.0 ~ 3.0.
3. preparation method according to claim 1 is characterized in that, described alkali is NaOH, NaOt-Bu or NaH.
4. preparation method according to claim 3 is characterized in that, described alkali is NaH.
5. preparation method according to claim 1 is characterized in that, inert solvent is selected from one or more in methylene dichloride, tetrahydrofuran (THF), toluene, DMF and the N-Methyl pyrrolidone.
6. preparation method according to claim 5 is characterized in that, inert solvent is DMF.
7. preparation method according to claim 1 is characterized in that, the mol ratio of formula II compound and formula I compound is 1:1.0 ~ 2.0.
8. preparation method according to claim 7 is characterized in that, the mol ratio of formula II compound and formula I compound is 1:1.1 ~ 1.3.
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| WO2012147098A2 (en) * | 2011-04-28 | 2012-11-01 | Glenmark Generics Limited | Novel process for the preparation of 3-(cyclopropylmethoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy) benzamide |
| WO2014060464A1 (en) | 2012-10-17 | 2014-04-24 | Interquim, S.A. | Process for preparing roflumilast |
| CN103232390B (en) * | 2013-05-10 | 2014-06-11 | 成都合迅医药技术有限公司 | Refining method for high-purity roflumilast |
| CN103497150A (en) * | 2013-10-12 | 2014-01-08 | 国药集团致君（苏州）制药有限公司 | Refining method for high-purity roflumilast |
| CN105646338B (en) * | 2016-03-10 | 2018-03-16 | 杨兆辉 | A kind of preparation method of roflumilast |
| CN106883171B (en) * | 2017-03-01 | 2019-09-06 | 山东裕欣药业有限公司 | A kind of compound and preparation method thereof for treating COPD |
| CN106866519B (en) * | 2017-03-01 | 2019-09-06 | 山东裕欣药业有限公司 | A kind of roflumilast crystal-form compound and preparation method thereof |
| CN111777550A (en) * | 2020-06-01 | 2020-10-16 | 山东希尔康泰药业有限公司 | Production and preparation method of roflumilast crystalline powder raw material medicine |
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| CN1701062A (en) * | 2003-03-10 | 2005-11-23 | 奥坦纳医药公司 | Novel process for the preparation of roflumilast |
| CN102093194A (en) * | 2010-12-24 | 2011-06-15 | 江苏先声药物研究有限公司 | New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid |
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| CN1701062A (en) * | 2003-03-10 | 2005-11-23 | 奥坦纳医药公司 | Novel process for the preparation of roflumilast |
| CN102093194A (en) * | 2010-12-24 | 2011-06-15 | 江苏先声药物研究有限公司 | New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid |
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