Diethylamine → HCID 86665161, compound

HRID 1907893Notes

Reaction equation

HRID 1907893 reaction equation
[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:25])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:22](O)=[O:23])[CH:11]=3)=[N:6][CH:7]=1.S(Cl)(Cl)=O.C(NCC)C.C(N(CC)C(C)C)(C)C.[NH2:44][C:45]1([C:49]2[N:53]([CH3:54])[C:52]3[CH:55]=[C:56](/[CH:59]=[CH:60]/[C:61]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])=[O:62])[CH:57]=[CH:58][C:51]=3[N:50]=2)[CH2:48][CH2:47][CH2:46]1>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]([CH3:25])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:22]([NH:44][C:45]2([C:49]4[N:53]([CH3:54])[C:52]5[CH:55]=[C:56](/[CH:59]=[CH:60]/[C:61]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])=[O:62])[CH:57]=[CH:58][C:51]=5[N:50]=4)[CH2:46][CH2:47][CH2:48]2)=[O:23])[CH:11]=3)=[N:6][CH:7]=1

Participants

7

Reactant 5

HCID 8021DiethylamineHCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 58111217(E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylateHCID 589073602-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylic acid

Product 1

HCID 86665161HCID 86665161, compoundYield 97.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
25 °C

Procedure

To the suspension of 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylic acid II (see Step 4) (33.36 g, 90.0 wt %, containing ˜0.2 equiv of NMP from previous step, 75.00 mmol) in THF (133.4 g) was added thionyl chloride (10.71 g). The mixture was stirred at 25±5° C. for at least 1 h. After the conversion was completed as determined by HPLC (as derivative of diethylamine), the mixture was cooled to 10±5° C. and N,N-diisopropylethylamine (378.77 g, 300 mmol) below 25° C. A solution of (E)-butyl 3-(2-(1-aminocyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate VI (25.86 g, 97.8 Wt %, 77.25 mmol) dissolved in THF (106.7 g) was added at a rate to maintain the temperature of the content ≦25° C. The mixture was stirred at 25±5° C. for at least 30 min for completion of the amide formation. The mixture was distilled at normal pressure to remove ca. 197 mL (171.5 g) of volatiles (Note: the distillation can also be done under reduced pressure). The batch was adjusted to 40±5° C., and MeOH (118.6 g) was added. Water (15.0 g) was added and the mixture was stirred at 40±5° C. until crystallization occurred (typically in 30 min), and held for another 1 h. Water (90 g) was charged at 40±5° C. over 1 h, and the batch was cooled to 25±5° C. in 0.5 h, and held for at least 1 h. The solid was filtered, rinsed with a mixture of MeOH (39.5 g), water (100 g), and dried in vacuo (≦200 Torr) at 50±5° C. to give (E)-butyl 3-(2-(1-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido)cyclobutyl)-1-methyl-1H-benzo[d]imidazol-6-yl)acrylate VII (51.82 g, 96.6% yield) with a HPLC purity of 98.0 A % (240 nm) and 99.0 Wt %.

Workup

  1. temperaturethe mixture was cooled to 10±5° C.
  2. additionwas added at a rate
  3. temperatureto maintain the temperature of the content ≦25° C
  4. distillationThe mixture was distilled at normal pressure
  5. customto remove ca. 197 mL (171.5 g) of volatiles (Note
  6. distillationthe distillation
  7. customwas adjusted to 40±5° C.
  8. additionMeOH (118.6 g) was added
  9. additionWater (15.0 g) was added
  10. stirringthe mixture was stirred at 40±5° C. until crystallization
  11. customtypically in 30 min
  12. additionWater (90 g) was charged at 40±5° C. over 1 h
  13. temperaturethe batch was cooled to 25±5° C. in 0.5 h
  14. waitheld for at least 1 h
  15. filtrationThe solid was filtered
  16. washrinsed with a mixture of MeOH (39.5 g), water (100 g)
  17. customdried in vacuo (≦200 Torr) at 50±5° C.

Sources & evidence

ORD record
ord-86cdf1564ca24e138b099ea4545e19a3
Source dataset
uspto-grants-2013_12
Patent number
US08598183B2

Reaction notes

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