Isopropanol → Sitagliptin

HRID 445978Notes

Reaction equation

HRID 445978 reaction equation
C(O)(C)C.O.[C:6]([C@@:14]([C:29]([OH:31])=[O:30])([OH:28])[C@@:15]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([OH:19])[C:16]([OH:18])=[O:17])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][CH:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45]>CO>[C:20]([C@@:15]([C:16]([OH:18])=[O:17])([OH:19])[C@@:14]([C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:28])[C:29]([OH:31])=[O:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][C@H:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45]

Participants

6

Reactant 3

HCID 3776IsopropanolHCID 113066913-Amino-1-(3-(trifluoromethyl)-5,6-dihydro(1,2,4)triazolo(4,3-a)pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-oneHCID 130366077Dibezoyl-L-tartaric acid monohydrate

Product 2

HCID 4369359SitagliptinHCID 12362976dibenzoyl-L(+)tartaric acid

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
62.5 °C

Procedure

In a 25 mL round bottom flask Isopropanol (1.25 mL) and Dibenzoyl-L-tartaric acid monohydrate (0.462 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (0.5 g) dissolved in methanol (1.0 mL) was added into reaction mixture at 60-65° C. over a period of 15 min. It was stirred for 15-30 min. at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature and stirred for 30-60 min. The salt was filtered and washed with a mixture of IPA: MeOH (2:1, 3 mL). An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt off (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-0.358 g, % Y-37.8%, Purity by HPLC-97.5%, % Chiral purity by HPLC of R-isomer 99.6%). % of weight loss by TGA-4.7%. m.p.-156-160° C.

Workup

  1. additionwas added into reaction mixture at 60-65° C. over a period of 15 min
  2. customSolid salt was precipitated
  3. temperatureIt was gradually cooled to room temperature
  4. stirringstirred for 30-60 min
  5. filtrationThe salt was filtered
  6. washwashed with a mixture of IPA: MeOH (2:1, 3 mL)

Sources & evidence

ORD record
ord-586331393186486d8fc6729d8e2a2c52
Source dataset
uspto-grants-2013_07
Patent number
US08476437B2

Reaction notes

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