4-Methylmorpholine → 1-[4-(2-Carbamoylpyridin-4-yloxy)-2-fluorophenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester

HRID 409932Notes

Reaction equation

HRID 409932 reaction equation
S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]([C:15]1([C:18]([OH:20])=O)[CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:21][C:22]1[CH:38]=[CH:37][C:25]([O:26][C:27]2C=CN=C(CC(N)=O)[CH:28]=2)=[CH:24][C:23]=1[F:39].C[N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C[N:48]1CCCC1=O>O1CCCC1.O>[CH2:5]([O:12][C:13]([C:15]1([C:18](=[O:20])[NH:21][C:22]2[CH:38]=[CH:37][C:25]([O:26][C:27]3[CH:43]=[CH:42][N:41]=[C:46]([C:45](=[O:44])[NH2:48])[CH:28]=3)=[CH:24][C:23]=2[F:39])[CH2:16][CH2:17]1)=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 13387N-methyl-2-pyrrolidone2×HCID 24386Thionyl ChlorideHCID 574708601-(Benzyloxycarbonyl)cyclopropanecarboxylic acidHCID 1317316354-(4-Amino-3-fluorophenoxy)pyridine-2-carboxyamide

Product 1

HCID 247884991-[4-(2-Carbamoylpyridin-4-yloxy)-2-fluorophenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Thionyl chloride was added at −20° C. to a solution of 1-(benzyloxycarbonyl)cyclopropanecarboxylic acid (97.98 g) in tetrahydrofuran (200 ml) and N-methylpyrrolidone (200 ml) and stirred for 30 minutes. A solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxyamide (100 g) and N-methylmorpholine (40.91 g) in N-methylpyrrolidone (600 ml) were added to the reaction mixture at the same temperature and stirred for 1 hour at 10° C. Water (100 g) was added to the reaction mixture and stirred for 1 hour at 20° C. After confirming the crystal precipitation, a 1N sodium hydroxide aqueous solution (1 L) was added and further stirred for 19 hours. The precipitated solid was collected by filtration and washed with water (500 g). The obtained solid was dried for 20 hours at 60° C. to give 176.7 g of the title compound.

Workup

  1. stirringstirred for 1 hour at 10° C
  2. stirringstirred for 1 hour at 20° C
  3. customthe crystal precipitation
  4. additiona 1N sodium hydroxide aqueous solution (1 L) was added
  5. stirringfurther stirred for 19 hours
  6. filtrationThe precipitated solid was collected by filtration
  7. washwashed with water (500 g)
  8. customThe obtained solid was dried for 20 hours at 60° C.

Sources & evidence

ORD record
ord-f5229ec57e0440a398aace9b2b83cb4b
Source dataset
uspto-grants-2014_06
Patent number
US08759530B2

Reaction notes

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