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Phosphoric Acid → (3R)-3-cyclopropyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate salt

HRID 928513
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 928513
[CH:1]1([C@H:4]([N:8]2[CH:12]=[C:11]([C:13]3[C:14]4[CH:21]=[CH:20][NH:19][C:15]=4[N:16]=[CH:17][N:18]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[OH:22][P:23]([OH:26])([OH:25])=[O:24]>C(O)(C)C>[P:23]([OH:26])([OH:25])([OH:24])=[O:22].[CH:1]1([C@H:4]([N:8]2[CH:12]=[C:11]([C:13]3[C:14]4[CH:21]=[CH:20][NH:19][C:15]=4[N:16]=[CH:17][N:18]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
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Komponenten

4

Edukt 2

HCID 1004Phosphoric AcidHCID 59420134(3R)-3-cyclopropyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile

Produkt 1

HCID 68472838(3R)-3-cyclopropyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate saltAusbeute 94,5 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 3776IsopropanolLösungsmittel2×

Reaktionsbedingungen

Temperatur
77 °C

Versuchsvorschrift

A suspension of (3R)-3-cyclopropyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-30, 60.0 g, 0.2158 mol, 1.0 equiv) in isopropanol (IPA, 900 mL) was heated to 77° C. to give a clear pale yellow solution. A solution of crystalline H3PO4 (23.3 g, 0.2374 mol, 1.1 equiv) in IPA (200 mL) was added in a steady stream from an addition funnel at 77-79° C., rinsing the addition funnel with IPA (25 mL). An immediate turbidity was developed followed by formation of a white suspension. After about half amount of the H3PO4 solution had been added the suspension became extremely thick. An additional amount of IPA (100 mL) was added to facilitate stirring. When addition was complete the suspension was heated at 75° C. for 1 h with the suspension becoming more mobile but remaining very thick. The suspension was cooled to room temperature over 1 h and the solids were collected by filtration and washed with 50% IPA/heptane (750 mL) and dried. The solids were triturated with heptane (1.2 L) with stirring for overnight before being collected by filtration and washed with heptane (300 mL) and dried in vacuum oven at 40-50° C. to constant weight to afford (3R)-3-cyclopropyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile phosphate salt ((R)-31, Phosphate, 76.7 g, 81.2 g theoretical, 94.5% yield) as a fine white crystalline solid. For (R)-31: 1H NMR (DMSO-d6, 400 MHz) δ ppm 12.2 (bs, 1H), 9.62 (bs, 3H, H3PO4), 8.77 (s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 7.59 (q, 1H, J=2.0 Hz), 6.98 (d, 1H, J=2.7 Hz), 4.04 (m, 1H), 3.37 (dd, 1H, J=16.8, 8.0 Hz), 3.28 (dd, 1H, J=16.8, 5.1 Hz), 1.43 (m, 1H), 0.68 (m, 1H), 0.49 (m, 3H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 152.2, 150.9, 149.9, 139.3, 130.4, 127.0, 120.8, 118.1, 112.9, 100.0, 62.6, 23.3, 15.7, 4.3, 3.8; C15H14N6 (MW, 278.31), LCMS (EI) m/e 279.1 (M++H).

Aufarbeitung

  1. customto give a clear pale yellow solution
  2. washrinsing the addition funnel with IPA (25 mL)
  3. additionAfter about half amount of the H3PO4 solution had been added the suspension
  4. additionAn additional amount of IPA (100 mL) was added
  5. additionWhen addition
  6. temperaturewas heated at 75° C. for 1 h with the suspension
  7. temperatureThe suspension was cooled to room temperature over 1 h
  8. filtrationthe solids were collected by filtration
  9. washwashed with 50% IPA/heptane (750 mL)
  10. customdried
  11. customThe solids were triturated with heptane (1.2 L)
  12. stirringwith stirring for overnight
  13. filtrationbefore being collected by filtration
  14. washwashed with heptane (300 mL)
  15. customdried in vacuum oven at 40-50° C. to constant weight

Quellen und Nachweise

ORD-Eintrag
ord-fe86f46889c745caa21fe38f7ba56caf
Quelldatensatz
uspto-grants-2016_03
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09290506B2

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