Sulfamic Acid → 3-(Cyclopropylmethoxy)-4-(difluoromethoxy)benzoic Acid

HRID 631779

반응식

HRID 631779 반응식
C1(C[O:5]C2C=C(C=CC=2O)C=O)CC1.ClC(F)F.[OH-].[Na+].[CH:21]1([CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=2[O:34][CH:35]([F:37])[F:36])[CH:29]=[O:30])[CH2:23][CH2:22]1.Cl([O-])=O.[Na+].S(=O)(=O)(O)N>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH:21]1([CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=2[O:34][CH:35]([F:36])[F:37])[C:29]([OH:5])=[O:30])[CH2:23][CH2:22]1

참가 물질

8

반응물 6

HCID 5987Sulfamic AcidHCID 6372ChlorodifluoromethaneHCID 14798Sodium HydroxideHCID 189736983-(Cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehydeHCID 23668197Sodium ChloriteHCID 713029773-(Cyclopropylmethoxy)-4-hydroxybenzaldehyde

생성물 1

HCID 23940063-(Cyclopropylmethoxy)-4-(difluoromethoxy)benzoic Acid

시약·촉매·용매 1

HCID 5963Benzyltrimethylammonium chloride촉매

실험 절차

In WO9501338 the reaction of 3-(cyclopropylmethoxy)-4-hydroxy-benzaldehyde with chlorodifluoromethane in the presence of sodium hydroxide and benzyl-trimethylammonium chloride (BTMA) in dioxane/water leads to 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde, which by oxidation with sodium chlorite and sulphamic acid yields 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid. Chlorination of this acid with thionyl chloride in reflux toluene provides the corresponding acyl chloride, which is finally condensed with 3,5-dichloropyridine-4-amine in the presence of sodium hydride in tetrahydrofuran to thus reach roflumilast (I). These procedures are set out in Scheme 1.

출처 및 근거

ORD 기록
ord-44521b88145e401fb7e3c0db6db891fd
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09321726B2

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