CN102336705A - 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 16
- 150000001412 amines Chemical class 0.000 title abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 42
- 239000012442 inert solvent Substances 0.000 claims abstract description 9
- 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 claims description 61
- 229960002586 roflumilast Drugs 0.000 claims description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 24
- 238000010992 reflux Methods 0.000 claims description 12
- 238000001291 vacuum drying Methods 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 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
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 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
- 238000007670 refining Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 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
- 239000002253 acid Substances 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 37
- 239000000047 product Substances 0.000 abstract description 7
- 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 description 2
- 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
- 238000003756 stirring Methods 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- -1 carboxylic acid halides Chemical class 0.000 description 26
- 239000000243 solution Substances 0.000 description 23
- 239000007787 solid Substances 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- IGFDIFLMMLWKKY-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid Chemical compound OC(=O)C1=CC=C(OC(F)F)C(OCC2CC2)=C1 IGFDIFLMMLWKKY-UHFFFAOYSA-N 0.000 description 17
- 235000019441 ethanol Nutrition 0.000 description 14
- 238000001914 filtration Methods 0.000 description 11
- 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
- 239000012312 sodium hydride Substances 0.000 description 8
- BSNNYLYELGBSBA-UHFFFAOYSA-N 4-(difluoromethoxy)benzoic acid Chemical compound OC(=O)C1=CC=C(OC(F)F)C=C1 BSNNYLYELGBSBA-UHFFFAOYSA-N 0.000 description 7
- 150000001263 acyl chlorides Chemical class 0.000 description 7
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 229960004050 aminobenzoic acid Drugs 0.000 description 6
- 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
- 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
- 239000002512 suppressor factor Substances 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
- MVRPPTGLVPEMPI-UHFFFAOYSA-N 2-cyclohexylphenol Chemical compound OC1=CC=CC=C1C1CCCCC1 MVRPPTGLVPEMPI-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
- 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
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- VPGJOSRXSVTZQS-UHFFFAOYSA-N NC(N)Oc(c(OCC1CC1)c1)ccc1C(N)=O Chemical compound NC(N)Oc(c(OCC1CC1)c1)ccc1C(N)=O VPGJOSRXSVTZQS-UHFFFAOYSA-N 0.000 description 1
- BAHQHPDHMVTTDB-UHFFFAOYSA-N NC(N)Oc(c(OCC1CC1)c1)ccc1C(Oc1ccc(C2CCCCC2)cc1)=O Chemical compound NC(N)Oc(c(OCC1CC1)c1)ccc1C(Oc1ccc(C2CCCCC2)cc1)=O BAHQHPDHMVTTDB-UHFFFAOYSA-N 0.000 description 1
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- WVUMCMNBXJBXLJ-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1OC(c(cc1)cc(OCC2CC2)c1OC(F)F)=O)=O Chemical compound [O-][N+](c(cc1)ccc1OC(c(cc1)cc(OCC2CC2)c1OC(F)F)=O)=O WVUMCMNBXJBXLJ-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
- 239000007789 gas Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 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
- 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
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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-difluoro-methoxy BM, 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) suppressor factor 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 following:
International monopoly WO93/25517 and WO94/02465 have described the method through phenylformic acid reactive derivative and the substituted BM of amine prepared in reaction dialkoxy.Wherein the phenylformic acid reactive derivative is carboxylic acid halides or acid anhydrides.This reaction can like triethylamine, N-methylmorpholine, or at mineral alkali, like alkalimetal hydride, under the existence like sodium hydride, at inert solvent, like THF, N, be carried out in the dinethylformamide at organic bases.International monopoly WO95/01338 has described the preparation method of the substituted BM of dialkoxy that comprises roflumilast, is with phenylformic acid reactive derivative and amine direct reaction under alkaline condition equally.Above-mentioned preparing 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 for the highly purified roflumilast of preparation in industry.
Among the international monopoly WO2004/080967; Reactive derivative (formula IV) 3-cyclo propyl methoxy-4-difluoro-methoxy Benzoyl chloride 99min. and 2.2 normal 4-amino-3 with 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid; An alkali metal salt of 5-dichloropyridine (formula V) is at conventional inert solvent; Like N, in the dinethylformamide, in 20～30 ℃ of following prepared in reaction roflumilasts.
Its Chinese style V compound is that an alkali metal salt effect of the 5-dichloropyridine and the trimethyl carbinol obtains through 4-amino-3.
Wherein: B in the formula V compound
+Be positively charged ion, for example, alkali metal cation, preferred potassium ion.
The gained bullion can obtain the product of purity＞99%, content＜0.1% of impurity N-(3,5-dichloropyridine-4-yl)-3-cyclo propyl methoxy-4-hydroxybenzamide with the mixed solvent recrystallization of Virahol and water.
The described method of WO2004/080967 has preferentially been used and has been surpassed 2 normal formula V compounds, is unfavorable for cost and controllable quality.Reaction directly is added drop-wise to highly basic (an alkali metal salt of the trimethyl carbinol) and 4-amino-3 with undressed 3-cyclo propyl methoxy-4-difluoro-methoxy Benzoyl chloride 99min.; In the mixture of 5-dichloropyridine; React comparatively violent; Wayward, generating more impurity need 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 suppressor factor that comprise roflumilast; But still all be direct and formula V compound reaction through the reactive derivative of 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid; The compound method to roflumilast is not optimized, and has the difficult and yield problem of lower of Control of Impurities equally.
This area still needs a kind of by product few, the high method for preparing roflumilast of refining back total recovery.The present invention meets this demand.
Summary of the invention
The present invention is through 4-amino-3; The negatively charged ion of 5-dichloropyridine (formula I) carries out amidate action with 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid aromatic ester (formula II) and obtains N-(3; 5-dichloropyridine-4-yl)-3-cyclo propyl methoxy-4-difluoro-methoxy BM (formula III), i.e. roflumilast.Specifically be that the 5-dichloropyridine is dissolved in the inert solvent with 4-amino-3,4-amino-3,5-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, obtains the solution of formula I compound after the insulated and stirred; In formula II compound and formula I compound mol ratio is that 1: 1.0～2.0 ratios join formula II compound in the above-mentioned solution; Reaction adds water after accomplishing, and regulates pH to 2～4, the solid that filtering separation is separated out; The roflumilast bullion 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
7Naphthenic base, 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, THF, toluene, N, one or more in dinethylformamide and the N-Methyl pyrrolidone, preferred N, dinethylformamide;
The temperature of reaction of said amidate action is 10～50 ℃, and the reaction times is between several minutes to 1 day.
According to bullion and ethanol mass volume ratio is that the ratio of 1: 5～8 (W/V) adds bullion in the ethanol, reflux 0.5～1 hour, and naturally cooling crystallization 5～10 hours filters, and vacuum-drying makes the purified roflumilast.
Carry out reflux in the prepared roflumilast bullion adding ethanol, through crystallization, vacuum-drying makes the purified roflumilast, its purity >=99.8%;
Roflumilast bullion and ethanol mass volume ratio are 1: 5～8 (W/V) in the said treating process;
Ethanol according to the invention is meant 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-cyclo propyl methoxy-4-difluoro-methoxy-benzoic 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-cyclo propyl methoxy-4-difluoro-methoxy-benzoic 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.
Said organic solvent is methylene dichloride, trichloromethane, THF, toluene, N, dinethylformamide or N-Methyl pyrrolidone;
Said alkali is nitrogenous organic base, comprises diisopropylethylamine, triethylamine, Trimethylamine 99, trimethylene diamines, N, accelerine, pyridine, 1.8-diazabicylo (5.4.0) hendecene-7 or N-methylmorpholine;
The temperature of reaction of said phenol acylation reaction is 0～40 ℃.
Its advantage of the preparation method of roflumilast according to the 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 is amino-3 with 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid aromatic ester and 4-, 5-dichloropyridine anionic reactive, and 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; Roflumilast bullion purity＞99% that obtains, refining back product gas purity >=99.8% is higher than the 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 according to the invention than prior art.
Embodiment
Below in conjunction with embodiment the present invention is made further detailed description, but is 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 dissolves entirely after adding the 6.6ml triethylamine, will be added in the above-mentioned solution by the 5.66g 3-cyclo propyl methoxy-drips of solution of the freshly prepd acyl chlorides of 4-difluoro-methoxy-benzoic acid in the 30ml methylene dichloride, dropwises and is warming up to 20 ℃ of stirrings.After TLC showed that reaction is accomplished, 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 directly be used for step reaction down.
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; With 6.84g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid p-nitrophenyl ester is at 45ml N, the drips of solution in the dinethylformamide is added in the above-mentioned mixed solution insulated and stirred, dropwises to be warming up to 10 ℃ of stirrings after 15 minutes.TLC shows the reaction completion 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 bullion 6.89g of getting of final vacuum is washed in filtration on a small quantity.
Add in the above-mentioned roflumilast bullion in the ethanol of 45ml 90% (V/V), reflux 1 hour stirs; Wait to clarify back naturally cooling crystallization 10 hours, and separated out solid filtering, get purified roflumilast 5.86g (yield: 81%) after the vacuum-drying; Purity is 99.9%, fusing point: 159.5 ℃.Nuclear magnetic data is following:
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)
Instance 3: the preparation of roflumilast
Under nitrogen protection, 20 ℃ of stirrings, 1.75g 4-is amino-3, and the 5-dichloropyridine is dissolved in 15ml N; Dinethylformamide adds 0.87g sodium hydroxide, insulated and stirred after 15 minutes with 2.74g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid p-nitrophenyl ester at 20ml N; Drips of solution in the dinethylformamide is added in the above-mentioned mixed solution, and 50 ℃ are continued to stir 5 hours, and TLC shows the reaction completion; Reaction solution is poured in the 180ml water, transferred pH to 2, have a large amount of white solids to separate out; Filter, wash the dry roflumilast bullion 2.12g of getting of final vacuum on a small quantity.
Add in the above-mentioned roflumilast bullion in the ethanol of 15ml 80% (V/V), reflux 50 minutes stirs; Waited to clarify back naturally cooling crystallization 8 hours; Separate out solid filtering, (yield: 66%), purity is 99.8% to get purified roflumilast 1.92g after the vacuum-drying; Fusing point: 159.6 ℃, nuclear magnetic data is consistent with embodiment 2.
Instance 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 2.50g 3-cyclo propyl methoxy that insulated and stirred after 15 minutes makes embodiment 1-4-difluoro-methoxy-benzoic acid p-nitrophenyl ester is at 20ml N, and the drips of solution in the dinethylformamide is added in the above-mentioned mixed solution, is warming up to 40 ℃ and continues to stir.TLC demonstration reaction is accomplished 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 the dry roflumilast bullion 2.35g of getting of final vacuum on a small quantity.
Add in the above-mentioned roflumilast bullion in the ethanol of 16ml 100% (V/V), reflux 1 hour stirs; Waited to clarify back naturally cooling crystallization 10 hours; Separate out solid filtering, (yield: 72%), purity is 99.9% to get purified roflumilast 1.91g 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, carry out prepared in reaction according to embodiment 1 said preparation method and 1.8g 3-cyclo propyl methoxy-freshly prepd acyl chlorides of 4-difluoro-methoxy-benzoic acid and obtain 2.0g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid phenyl ester.
Embodiment 6: the preparation of roflumilast
Under nitrogen protection, ice bath stirred, with 1.45g 4-amino-3, the 5-dichloropyridine was dissolved in 10ml N, dinethylformamide; Add 0.64g sodium hydride (60%), insulated and stirred is after 15 minutes in batches, and 2.0g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid phenyl ester that embodiment 5 is made is at 15ml N; Drips of solution in the dinethylformamide is added in the above-mentioned mixed solution, dropwises to be warming up to 20 ℃ of stir abouts 1 hour, and TLC shows the reaction completion; Ice bath slowly drips water 5ml down, and reaction solution is poured in the 150ml water, transfers pH to 4; There are a large amount of white solids to separate out, filter, wash the dry roflumilast bullion 1.64g of getting of final vacuum on a small quantity.
Add in the above-mentioned roflumilast bullion in the ethanol of 11ml 90% (V/V), reflux 42 minutes stirs; Waited to clarify back naturally cooling crystallization 7 hours; Separate out solid filtering, (yield: 71%), purity is 99.8% to get purified roflumilast 1.50g 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, carry out prepared in reaction according to embodiment 1 said preparation method and 1.7g 3-cyclo propyl methoxy-freshly prepd acyl chlorides of 4-difluoro-methoxy-benzoic acid and obtain 2.0g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid the methoxyl group phenyl ester.
Embodiment 8: the preparation of roflumilast
Under nitrogen protection, ice bath stirred, with 1.33g 4-amino-3, the 5-dichloropyridine was dissolved in 10ml N, dinethylformamide; Add 0.59g sodium hydride (60%), insulated and stirred is after 15 minutes in batches, 2.0g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid that embodiment 7 is made to the methoxyl group phenyl ester at 15ml N; Drips of solution in the dinethylformamide is added in the above-mentioned mixed solution, dropwises to be warming up to 30 ℃ of stir abouts 2 hours, and TLC shows the reaction completion; Ice bath slowly drips water 5ml down, and reaction solution is poured in the 150ml water, transfers pH to 3; There are a large amount of white solids to separate out, filter, wash the dry roflumilast bullion 1.71g of getting of final vacuum on a small quantity.
Add in the above-mentioned roflumilast bullion in the ethanol of 12ml 95% (V/V), reflux 50 minutes stirs; Waited to clarify back naturally cooling crystallization 7 hours; Separate out solid filtering, (yield: 70%), purity is 99.9% to get purified roflumilast 1.55g 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, carry out prepared in reaction according to embodiment 1 said preparation method and 1.7g3-cyclo propyl methoxy-freshly prepd acyl chlorides of 4-difluoro-methoxy-benzoic acid and obtain 2.0g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid the fluorobenzene ester.
Embodiment 10: the preparation of roflumilast
Under nitrogen protection, ice bath stirred, with 1.32g 4-amino-3, the 5-dichloropyridine was dissolved in 10ml N, dinethylformamide; Add 0.59g sodium hydride (60%), insulated and stirred is after 15 minutes in batches, 2.0g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid that embodiment 9 is made to the fluorobenzene ester at 15ml N; Drips of solution in the dinethylformamide is added in the above-mentioned mixed solution, dropwises to be warming up to 40 ℃ of stir abouts 1 hour, and TLC shows the reaction completion; Ice bath slowly drips water 5ml down, and reaction solution is poured in the 150ml water, transfers pH to 4; There are a large amount of white solids to separate out, filter, wash the dry roflumilast bullion 1.85g of getting of final vacuum on a small quantity.
Add in the above-mentioned roflumilast bullion in the ethanol of 10ml 95% (V/V), reflux 30 minutes stirs; Waited to clarify back naturally cooling crystallization 7 hours; Separate out solid filtering, (yield: 75%), purity is 99.9% to get purified roflumilast 1.72g 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, carry out prepared in reaction according to embodiment 1 said preparation method and 0.9g3-cyclo propyl methoxy-freshly prepd acyl chlorides of 4-difluoro-methoxy-benzoic acid and obtain 1.2g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid the cyclo propyl methoxy phenyl ester.
Embodiment 12: the preparation of roflumilast
With 0.88g 4-amino-3, the 5-dichloropyridine is dissolved in 7ml N, dinethylformamide under nitrogen protection, ice bath stir; Add 0.40g sodium hydride (60%), insulated and stirred is after 15 minutes in batches, 1.2g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid that embodiment 11 is made to the fluorobenzene ester at 10ml N; Drips of solution in the dinethylformamide is added in the above-mentioned mixed solution, dropwises to be warming up to 40 ℃ of stir abouts 3 hours, and TLC shows the reaction completion; Ice bath slowly drips water 3ml down, and reaction solution is poured in the 100ml water, transfers pH to 2; There are a large amount of white solids to separate out, filter, wash the dry roflumilast bullion 0.92g of getting of final vacuum on a small quantity.
Add in the above-mentioned roflumilast bullion in the ethanol of 6ml 95% (V/V), reflux 30 minutes stirs; Wait to clarify 5 hours crystallizatioies of back naturally cooling; Separate out solid filtering, (yield: 73%), purity is 99.8% to get purified roflumilast 0.87g 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, carry out prepared in reaction according to embodiment 1 said preparation method and 2.0g3-cyclo propyl methoxy-freshly prepd acyl chlorides of 4-difluoro-methoxy-benzoic acid and obtain 2.47g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid p-isopropyl phenyl ester.
Embodiment 14: the preparation of roflumilast
With 0.95g 4-amino-3, the 5-dichloropyridine is dissolved in 10ml N, dinethylformamide under nitrogen protection, ice bath stir; Add 0.42g sodium hydride (60%), insulated and stirred is after 15 minutes in batches, and 2.0g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid p-isopropyl phenyl ester that embodiment 13 is made is at 15ml N; Drips of solution in the dinethylformamide is added in the above-mentioned mixed solution, dropwises to be warming up to 20 ℃ of stir abouts 2 hours, and TLC shows the reaction completion; Ice bath slowly drips water 3ml down, and reaction solution is poured in the 125ml water, transfers pH to 3.4; There are a large amount of white solids to separate out, filter, wash the dry roflumilast bullion 1.75g of getting of final vacuum on a small quantity.
Add in the above-mentioned roflumilast bullion in the ethanol of 12ml 95% (V/V), reflux 0.5 hour stirs; Wait to clarify 5 hours crystallizatioies of back naturally cooling; Separate out solid filtering, (yield: 75%), purity is 99.8% to get purified roflumilast 1.61g after the vacuum-drying; Fusing point: 159.9 ℃, nuclear magnetic data is consistent with embodiment 2.
Embodiment 15:3-cyclo propyl methoxy-4-dichloromethane aminobenzoic acid is to the preparation of cyclohexylphenol
Under nitrogen protection, ice bath stir; 1.15g is joined in the 10ml methylene dichloride cyclohexylphenol, carry out prepared in reaction according to embodiment 1 said preparation method and 1.5g 3-cyclo propyl methoxy-freshly prepd acyl chlorides of 4-difluoro-methoxy-benzoic acid and obtain 2.03g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid the cyclohexyl phenyl ester.
Embodiment 16: the preparation of roflumilast
With 0.65g 4-amino-3, the 5-dichloropyridine is dissolved in 5ml N, dinethylformamide under nitrogen protection, ice bath stir; Add 0.3g sodium hydride (60%), insulated and stirred is after 15 minutes in batches, 1.5g 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid that embodiment 13 is made to the cyclohexyl phenyl ester at 12ml N; Drips of solution in the dinethylformamide is added in the above-mentioned mixed solution, dropwises to be warming up to 30 ℃ of stir abouts 3 hours, and TLC shows the reaction completion; Ice bath slowly drips water 3ml down, and reaction solution is poured in the 100ml water, transfers pH to 3.5; There are a large amount of white solids to separate out, filter, wash the dry roflumilast bullion 1.10g of getting of final vacuum on a small quantity.
Add in the above-mentioned roflumilast bullion in the ethanol of 8ml 90% (V/V), reflux 30 minutes stirs; Wait to clarify 5 hours crystallizatioies of back naturally cooling; Separate out solid filtering, (yield: 67%), purity is 99.8% to get purified roflumilast 0.98g after the vacuum-drying; Fusing point: 159.6 ℃, nuclear magnetic data is consistent with embodiment 2.
Embodiment 17:
Embodiment 2～4, embodiment 6, embodiment 8, embodiment 10, embodiment 12, embodiment 14, embodiment 16 roflumilast that makes and the product that makes by the disclosed preparation method A of WO2004/080967 patent are measured impurity through the HPLC Self-control method; Area normalization method is measured content; Contrast yield (in 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid), the result is following:
WO2004/080967 patent sample is to prepare according to method A among the disclosed embodiment of WO2004/080967 patent, makes roflumilast sample 4.1g, yield: 56%, and purity is 99.2%, fusing point: 159.1 ℃.
Claims (10)
1. a method for preparing N-(3,5-dichloropyridine-4-yl)-3-cyclo propyl methoxy-4-difluoro-methoxy BM is characterized in that, in inert solvent with alkaline condition under, 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
7Naphthenic base, 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. according to the described preparation method of claim 1～2, it is characterized in that said alkali is NaOH, NaOt-Bu or NaH.
4. preparation method according to claim 3 is characterized in that, said alkali is NaH.
5. according to the described preparation method of claim 1～4, it is characterized in that inert solvent is selected from methylene dichloride, THF, toluene, N, one or more in dinethylformamide and the N-Methyl pyrrolidone.
6. preparation method according to claim 5 is characterized in that, inert solvent is N, dinethylformamide.
7. according to the described preparation method of claim 1～6, it 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.
9. the method for a refining roflumilast bullion; It is characterized in that, the roflumilast bullion was added in the ethanol that concentration is 80%～100% (V/V) reflux 0.5～1 hour, naturally cooling crystallization 5～10 hours; Filter, vacuum-drying makes the purified roflumilast.
10. preparation method according to claim 9 is characterized in that, roflumilast bullion and alcoholic acid mass volume ratio are 1: 5～8 (W/V).
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103232390A (en) * | 2013-05-10 | 2013-08-07 | 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 |
| WO2014060464A1 (en) | 2012-10-17 | 2014-04-24 | Interquim, S.A. | Process for preparing roflumilast |
| CN105646338A (en) * | 2016-03-10 | 2016-06-08 | 陈红 | Preparation method of Roflumilast |
| CN106866519A (en) * | 2017-03-01 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of roflumilast crystal-form compound and preparation method thereof |
| CN106883171A (en) * | 2017-03-01 | 2017-06-23 | 山东裕欣药业有限公司 | It is a kind of to treat compound of COPD 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126468A (en) * | 1993-07-02 | 1996-07-10 | 比克·古尔顿·劳姆贝尔格化学公司 | Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors |
| 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 |
-
2011
- 2011-10-28 CN CN 201110336727 patent/CN102336705B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126468A (en) * | 1993-07-02 | 1996-07-10 | 比克·古尔顿·劳姆贝尔格化学公司 | Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors |
| 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 |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2012147098A3 (en) * | 2011-04-28 | 2013-03-21 | Glenmark Generics Limited | Novel process for 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 |
| CN103232390A (en) * | 2013-05-10 | 2013-08-07 | 成都合迅医药技术有限公司 | Refining method for high-purity 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 |
| CN105646338A (en) * | 2016-03-10 | 2016-06-08 | 陈红 | Preparation method of Roflumilast |
| CN105646338B (en) * | 2016-03-10 | 2018-03-16 | 杨兆辉 | A kind of preparation method of roflumilast |
| CN106866519A (en) * | 2017-03-01 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of roflumilast crystal-form compound and preparation method thereof |
| CN106883171A (en) * | 2017-03-01 | 2017-06-23 | 山东裕欣药业有限公司 | It is a kind of to treat compound of COPD and preparation method thereof |
| 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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