Diisopropylethylamine → (1S,2S,4R)-4-(4-((S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol

HRID 715630Notes

Reaction equation

HRID 715630 reaction equation
Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[CH2:15][C@H:14]([OH:16])[C@H:13]([CH2:17][OH:18])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C>CC(O)CC>[C@@H:20]1([NH:19][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([C@H:11]4[CH2:15][C@H:14]([OH:16])[C@H:13]([CH2:17][OH:18])[CH2:12]4)[C:4]=3[N:5]=[CH:6][N:7]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 70000841-Aminoindane, (S)-HCID 57336811(1S,2S,4R)-4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentan-1-ol

Product 1

HCID 58944696(1S,2S,4R)-4-(4-((S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanolYield 77.3%

Reagents, catalysts & solvents 1

HCID 6568(+-)-2-ButanolSolvent

Conditions

Temperature
55 °C

Procedure

A jacketed reactor was charged with (1S,2S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol (30.8 Kg, 115.05 mol), 2-butanol (198.5 Kg), (S)-(+)-1-aminoindane (16.95 Kg, 127.26 mol) and diisopropylethylamine (19.45 Kg, 150.50 mol). The mixture was heated to 55±5° C. and then moved to a mobile vessel. The reactor was then rinsed with 2-butanol (15.6 Kg) at 55±5° C. which was moved to the mobile vessel. The mobile vessel contents were then transferred to a pressure reactor and 2-butanol (51 L) was used to rinse the mobile vessel. The reaction mixture was then heated to 135±5° C. and adjusted to a pressure of 8 bar. The mixture was then stirred until reaction was complete by HPLC analysis. The mixture was cooled to 30±10° C. and transferred to a mobile vessel via a plate filter. The pressure reactor was rinsed with 2-butanol (43.1 L). The contents of the mobile vessel were then charged to a jacketed reactor via an in-line filter and the vessel rinsed with 2-butanol (39.2 Kg). The mixture was heated to 50±5° C. and concentrated under reduced pressure to about 50 L. The mixture was cooled to 20±5° C. and then dichloromethane (256 Kg) added over a period of about 3 hours. The mixture was stirred for a further 9.5 hours and then further cooled to 0±5° C. and stirred for about 4 hours. The solid product was isolated by filtration and washed with dichloromethane (82 Kg) at 0±5° C. The solids were then dried under reduced pressure at 40±5° C. to constant weight. A reactor was charged with water (371 Kg) and the dried solids and the mixture stirred at 20±5° C. for about 14.5 hours. The solid product was isolated by filtration and washed with water (371 Kg). The solids were then dried under reduced pressure at 50±5° C. to afford the title compound (32.4 Kg) as a white solid. 1H NMR (300 MHz, DMSO, 6): 8.15 (s, 1H), 7.71 (d, 1H), 7.07-7.29 (m, 5H), 6.61 (d, 1H), 5.88 (dd, 1H), 5.24-5.38 (m, 1H), 4.60 (d, 1H), 4.26-4.37 (m, 2H), 3.53-3.65 (m, 1H), 3.35-3.46 (m, 1H), 2.90-3.04 (m, 1H), 2.75-2.90 (m, 1H), 2.33-2.56 (m, 2H), 2.04-2.14 (m, 2H), 1.88-2.03 (m, 2H), 1.74-1.87 (m, 1H).

Workup

  1. custommoved to a mobile vessel
  2. washThe reactor was then rinsed with 2-butanol (15.6 Kg) at 55±5° C. which
  3. customThe mobile vessel contents were then transferred to a pressure reactor
  4. washto rinse the mobile vessel
  5. temperatureThe reaction mixture was then heated to 135±5° C.
  6. temperatureThe mixture was cooled to 30±10° C.
  7. customtransferred to a mobile vessel via a plate
  8. filtrationfilter
  9. washThe pressure reactor was rinsed with 2-butanol (43.1 L)
  10. additionThe contents of the mobile vessel were then charged to a jacketed reactor via
  11. filtrationan in-line filter
  12. washthe vessel rinsed with 2-butanol (39.2 Kg)
  13. temperatureThe mixture was heated to 50±5° C.
  14. concentrationconcentrated under reduced pressure to about 50 L
  15. temperatureThe mixture was cooled to 20±5° C.
  16. additiondichloromethane (256 Kg) added over a period of about 3 hours
  17. stirringThe mixture was stirred for a further 9.5 hours
  18. temperaturefurther cooled to 0±5° C.
  19. stirringstirred for about 4 hours
  20. customThe solid product was isolated by filtration
  21. washwashed with dichloromethane (82 Kg) at 0±5° C
  22. customThe solids were then dried under reduced pressure at 40±5° C. to constant weight
  23. additionA reactor was charged with water (371 Kg)
  24. stirringthe dried solids and the mixture stirred at 20±5° C. for about 14.5 hours
  25. customThe solid product was isolated by filtration
  26. washwashed with water (371 Kg)
  27. customThe solids were then dried under reduced pressure at 50±5° C.

Sources & evidence

ORD record
ord-c769251b0e0d4c7d952c52509c704686
Source dataset
uspto-grants-2015_11
Patent number
US09187482B2

Reaction notes

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