Trifluoroacetic acid → Etrasimod Impurity 47

HRID 534278

반응식

HRID 534278 반응식
Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCN([C:24]2[C:25](=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:27][CH:28]=2)CC1.C(OC1C=CC(NN)=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(O)(=O)C.C(O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:24]3[C:25](=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:27][C:28]=3[C:12]=2[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1

참가 물질

7

반응물 4

HCID 6422Trifluoroacetic acidHCID 5613924-Benzyloxyphenylhydrazine2회HCID 3016725(4-(Benzyloxy)phenyl)hydrazine monohydrochlorideHCID 4066927Ethyl 2-(2-morpholinocyclopent-2-en-1-ylidene)acetate2회

생성물 1

HCID 77442336Etrasimod Impurity 47

시약·촉매·용매 2

HCID 176Acetic Acid용매HCID 702Ethanol용매

반응 조건

온도
60 °C

실험 절차

To a 400 L glass-lined reactor equipped with overhead agitation, jacket temperature control, and a nitrogen inlet was added (4-(benzyloxy)phenyl)hydrazine hydrochloride (21.08 kg, 1.000 mole equiv.), ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate (22.02 kg, 1.104 mole equiv.), ethanol (51.2 kg, 2.429 mass equiv.), and acetic acid (36.8 kg, 1.746 mass eq.). After the reactor contents are allowed to stand for 10 minutes, agitation and then heating to 60° C. to 65° C. (60° C. target) was started. While stirring at that temperature, samples of the reaction mixture were taken over intervals of approximately 30 minutes and analyzed by HPLC for (4-(benzyloxy)phenyl)hydrazine, ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate, and hydrazone content. When (4-(benzyloxy)phenyl)hydrazine HPLC % area was <1, TFA (11.6 kg, 101.7 mol, 1.200 mole equiv., 0.550 mass equiv.) was charged over approximately 1 hour while the stirred reaction mixture was maintained at 60° C.±5° C. with reactor jacket cooling. As stirring at 60° C. to 65° C. was continued, the hydrazone and imine content of the reaction mixture was monitored by HPLC. After stirring at 60° C. to 65° C. for at least 12 hours the imine content of the reaction mixture was <5% area by HPLC, and the stirred reaction mixture was cooled to 20° C. to 25° C. over approximately 3 hours. Stirring was maintained at that temperature to allow isomerization of the Z isomer to the desired E isomer. The E isomer crystallizes from the reaction mixture. The Z isomer and E isomer % area content of the reaction mixture was monitored by HPLC during this period of stirring at 20° C. to 25° C., which was continued until the Z-isomer content of the reaction mixture was <15% area by HPLC.

후처리

  1. customTo a 400 L glass-lined reactor equipped with overhead agitation, jacket temperature control, and a nitrogen inlet
  2. customwere taken over intervals of approximately 30 minutes
  3. additionwas charged over approximately 1 hour while the stirred reaction mixture
  4. temperaturewas maintained at 60° C.±5° C. with reactor jacket
  5. temperaturecooling
  6. stirringAs stirring at 60° C. to 65° C.
  7. customthe stirred reaction mixture
  8. temperaturewas cooled to 20° C. to 25° C. over approximately 3 hours
  9. stirringStirring
  10. temperaturewas maintained at that temperature
  11. customThe E isomer crystallizes from the reaction mixture
  12. waitThe Z isomer and E isomer % area content of the reaction mixture was monitored by HPLC during this period
  13. stirringof stirring at 20° C. to 25° C.

출처 및 근거

ORD 기록
ord-e0f07b2b6c144413829de541021bf998
출처 데이터셋
uspto-grants-2014_10
특허 번호
US08853419B2

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