Morpholine → 6-[3-(Trifluoromethyl)phenyl]-4-pyridazinecarboxylic acid

HRID 52771

반응식

HRID 52771 반응식
[C:1]([O:5]CC)(=[O:4])[C:2]#[CH:3].N1CCOCC1.C(N(C(C)C)CC)(C)C.C(OC([NH:28][N:29]=[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1)[CH:31](Cl)Cl)=O)C.[OH-].[K+]>C(Cl)Cl.C(O)C.O>[F:41][C:40]([F:42])([F:43])[C:36]1[CH:35]=[C:34]([C:30]2[N:29]=[N:28][CH:3]=[C:2]([C:1]([OH:5])=[O:4])[CH:31]=2)[CH:39]=[CH:38][CH:37]=1

참가 물질

9

반응물 5

HCID 8083MorpholineHCID 12182Ethyl propiolateHCID 14797Potassium HydroxideHCID 81531DiisopropylethylamineHCID 53937192[2,2-Dichloro-1-[3-(trifluoromethyl)phenyl]ethylidene]hydrazinecarboxylic acid ethyl ester

생성물 1

HCID 152753066-[3-(Trifluoromethyl)phenyl]-4-pyridazinecarboxylic acid수율 79%

시약·촉매·용매 3

HCID 702Ethanol용매2회HCID 962Water용매HCID 6344Dichloromethane용매2회

실험 절차

Ethyl propiolate (130 mL, 1.28 mole) was stirred under N2 in methylene chloride (2.5 L) at RT while morpholine (112 mL, 1.28 mole) was added dropwise over 20 min. External cooling by means of an ice bath was employed. The mixture was then refluxed for 30 min. and then cooled to RT. Diisopropylethylamine (426.4 mL, 2.45 mole) was then added to the mixture followed by [2,2-dichloro-1-[3-(trifluoromethyl)phenyl]ethylidene]hydrazinecarboxylic acid ethyl ester (400 g, 1.17 mole) which was added dropwise as a solution in methylene chloride (800 mL) over 30 min. The mixture was then refluxed for 18 h, cooled, and partitioned 2 times with water. The organic layer was dried (MgSO4), filtered and evaporated in vacuo to give a crude oil. The crude oil was taken up in 3 L of ethanol and then KOH 302 g of 86.6%, 4.66 moles) was added while the solution was stirred. The mixture was then refluxed under N2 for 2 h. Water (500 mL) was then added and most of the ethanol was removed in vacuo. The mixture was then dissolved in 3 L of water and extracted 3×800 mL with methylene chloride which was discarded. The aqueous layer was then made acidic with 12N HCl to precipitate the pyridazine acid (gas is evolved). The acid is then dried in vacuo to give 6-[3-(trifluoromethyl)phenyl]-4-pyridazinecarboxylic acid (247 g, 79% yield, Compound No. 2) as a brown solid which was recrystallized from ethyl acetate/methanol.

후처리

  1. additionwas added dropwise over 20 min
  2. temperatureExternal cooling by means of an ice bath
  3. temperatureThe mixture was then refluxed for 30 min.
  4. temperatureThe mixture was then refluxed for 18 h
  5. temperaturecooled
  6. custompartitioned 2 times with water
  7. dry with materialThe organic layer was dried (MgSO4)
  8. filtrationfiltered
  9. customevaporated in vacuo
  10. customto give a crude oil
  11. temperatureThe mixture was then refluxed under N2 for 2 h
  12. customwas removed in vacuo
  13. dissolutionThe mixture was then dissolved in 3 L of water
  14. extractionextracted 3×800 mL with methylene chloride which
  15. custommade acidic with 12N HCl to precipitate the pyridazine acid (gas is evolved)
  16. customThe acid is then dried in vacuo

출처 및 근거

ORD 기록
ord-1305149d0e2f453db9a3891d61c6b4af
출처 데이터셋
uspto-grants-1997_04
특허 번호
US05616789

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