Hydrochloric Acid → (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

HRID 1429654노트

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HRID 1429654 반응식
Cl.[NH4+].[Cl-].Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C@:15]12[CH2:23][O:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[C@H:20]1[CH2:19][S:18][C:17]([NH2:28])=[N:16]2.[OH-].[Na+]>[Fe].C(O)C>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([F:5])=[C:7]([C@:15]23[CH2:23][O:22][C@H:21]([C:24]([F:26])([F:25])[F:27])[C@H:20]2[CH2:19][S:18][C:17]([NH2:28])=[N:16]3)[CH:8]=1

참가 물질

7

반응물 4

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 25517Ammonium ChlorideHCID 70496439(4aS,5S,7aS)-7a-(2-fluoro-5-nitrophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine hydrochloride

생성물 1

HCID 60168330(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine수율 95.5%

시약·촉매·용매 2

HCID 23925Iron촉매HCID 702Ethanol용매2회

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온도
65 °C

실험 절차

Ethanol (0.975 L) was added to iron powder (62.5 g, 1.12 mol) under nitrogen atmosphere. Concentrated HCl (9.03 mL) was added at ambient temperature and the suspension was heated to 65° C. for 1.5 h. The suspension was then cooled to 50° C., and sat. aq. NH4Cl (299 g) were added. The temperature of the reaction mixture was allowed to reach 50° C., and (4aS,5S,7aS)-7a-(2-fluoro-5-nitrophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine hydrochloride (75.0 g, 187.0 mol) was added in portions while maintaining temperature below 68° C. After 30 min, ethanol (0.45 L) was added, and the reaction mixture was cooled to 20−25° C. over 1 h. The suspension was stirred for 2 h and filtered over Celite (75 g) rinsing with ethanol (0.972 L). The solution was concentrated under vacuum to a brown solid. Water (0.9 L) was added followed by 3.0 N NaOH (0.187 L, 560 mmol) while maintaining temperature below 35° C. The resulting suspension was stirred for 1 h at 20−25° C. The suspension was filtered, and the solid was rinsed with cold water (0.38 L). The solid was dried under vacuum at 40−45° C. over 24 h to obtain the title compound (57.7 g, 95.5%). 1H NMR (500 MHz, DMSO) δ ppm 6.81 (dd, J=12.5, 8.6 Hz, 1H), 6.62 (dd, J=7.0, 2.9 Hz, 1H), 6.50-6.42 (m, 1H), 6.16 (s, 2H), 4.96 (s, 2H), 4.72-4.54 (m, 1H), 4.35 (d, J=7.8 Hz, 1H), 3.74 (dd, J=7.8, 2.5 Hz, 1H), 3.18-3.08 (m, 1H), 3.01 (dd, J=13.9, 3.0 Hz, 1H). 2.84 (dd, J=13.8, 3.8 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 156.20 (d, JCF=243.0 Hz), 148.73, 145.49, 127.86 (d, JCF=11.0 Hz), 116.79 (d, JCF=24.8 Hz), 116.10 (d, JCF=3.3 Hz), 114.10 (d, JCF=8.0 Hz), 78.89, 76.57 (q, JCF=31.0 Hz), 66.35, 36.35, 23.11.

후처리

  1. temperatureThe suspension was then cooled to 50° C.
  2. customto reach 50° C.
  3. temperaturewhile maintaining temperature below 68° C
  4. temperaturethe reaction mixture was cooled to 20−25° C. over 1 h
  5. filtrationfiltered over Celite (75 g)
  6. washrinsing with ethanol (0.972 L)
  7. concentrationThe solution was concentrated under vacuum to a brown solid
  8. additionWater (0.9 L) was added
  9. temperaturewhile maintaining temperature below 35° C
  10. stirringThe resulting suspension was stirred for 1 h at 20−25° C
  11. filtrationThe suspension was filtered
  12. washthe solid was rinsed with cold water (0.38 L)
  13. customThe solid was dried under vacuum at 40−45° C. over 24 h

출처 및 근거

ORD 기록
ord-43446d500ef94d8e800953814a4baa81
출처 데이터셋
uspto-grants-2015_01
특허 번호
US08940734B2

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