반응 #510160

ord-369d0a3e05424cedb61b679c473739c8

반응 방정식

CN(C)C(On1nnc2cccnc21)=[N+](C)C.F[P-](F)(F)(F)(F)F
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid
CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
4-(tert-Butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid
CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Intermediate 1
CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
4-(tert-Butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid
NC(c1ccc(Cl)cc1)C1CC1
(4-chlorophenyl)(cyclopropyl)methanamine
NC(c1ccc(Cl)cc1)C1CC1
Intermediate 3
NC(c1ccc(Cl)cc1)C1CC1
(4-chlorophenyl)(cyclopropyl)methanamine
CCN(C(C)C)C(C)C
DIPEA
NC1(C(=O)NC(c2ccc(Cl)cc2)C2CC2)CCN(c2ncnc3[nH]ccc23)CC1
4-amino-N-((4-chlorophenyl)(cyclopropyl)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide
수율 79.0%

용매

반응 조건

온도
50°CELSIUS
상세 조건
See reaction.notes.procedure_details.

후처리

  1. 1
    기타The crude product was purified by ion exchange chromatography
  2. 2
    세척The desired product was eluted from the column
  3. 3
    기타were evaporated to dryness
  4. 4
    workup.ADDITIONTFA (5 mL) was added
  5. 5
    workup.STIRRINGThe reaction mixture was stirred for 1 hour
  6. 6
    기타the crude product was purified by ion exchange chromatography
  7. 7
    세척The desired product was eluted from the column
  8. 8
    기타were evaporated to dryness
  9. 9
    기타to afford the crude material as a white solid
  10. 10
    기타This material was triturated under cold methanol

실험 절차

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.228 g) was added to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.181 g), (4-chlorophenyl)(cyclopropyl)methanamine (Intermediate 3) (0.091 g) and DIPEA (0.261 mL) in DMA (5 mL) at 25° C. The resulting solution was stirred at 50° C. for 1 hour. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This crude material was suspended in dichloromethane (25 mL), and TFA (5 mL) was added. The reaction mixture was stirred for 1 hour, then the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford the crude material as a white solid. This material was triturated under cold methanol to give the pure product, 4-amino-N-((4-chlorophenyl)(cyclopropyl)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.167 g, 79%).

출처

DOI: 10.6084/m9.figshare.5104873.v1특허: US08101623B2uspto-grants-2012_01