Potassium Carbonate → Linagliptin

HRID 2172571Notes

Reaction equation

HRID 2172571 reaction equation
[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:41][CH2:40][CH2:39][C@@H:38]([NH2:42])[CH2:37]1>C(C(C)=O)C(C)C>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:36]2[CH2:37][C@H:38]([NH2:42])[CH2:39][CH2:40][CH2:41]2)=[N:18][C:17]2[N:16]([CH3:29])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 667606(R)-3-AMINOPIPERIDINEHCID 247500498-Bromo-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione

Product 1

HCID 10096344LinagliptinYield 80.6%

Reagents, catalysts & solvents 1

HCID 7909Methyl Isobutyl KetoneSolvent

Conditions

Temperature
95 °C

Procedure

1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine (11.5 gm) were added to the reaction mixture at 30° C. The reaction mixture was heated to 95° C. and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30° C. and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at 30° C. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) was added drop-wise at 30° C. The mixture was stirred for one hour at 30° C. and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45° C. Toluene (100 mL) was added to the residue and stirred for 3 hours at 30° C. Filtered the compound and washed with Toluene (40 mL) and dried the compound at below 60° C. under vacuum to give 16.8 gm of Linagliptin. Purity: 98.91%, PXRD pattern: FIG. 2.

Workup

  1. customequipped with a mechanical stirrer
  2. temperaturemaintained at that temperature for 8 hours
  3. temperatureThe reaction mixture was cooled to 30° C.
  4. filtrationfiltered
  5. washwashed with MIBK (40 mL)
  6. additionThe filtrate was charged into another flask
  7. additionadded 10% aqueous acetic acid solution
  8. customThe aqueous layer was separated
  9. washwashed with 60 mL of dichloromethane
  10. additionThe aqueous layer was charged into another flask
  11. addition200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) was added drop-wise at 30° C
  12. stirringThe mixture was stirred for one hour at 30° C.
  13. customthe organic layer was separated
  14. extractionthe aqueous layer was extracted with 100 ml of dichloromethane
  15. customevaporated under vacuum at below 45° C
  16. additionToluene (100 mL) was added to the residue
  17. stirringstirred for 3 hours at 30° C
  18. filtrationFiltered the compound
  19. washwashed with Toluene (40 mL)
  20. customdried the compound at below 60° C. under vacuum

Sources & evidence

ORD record
ord-bba044c7ae99490b861d9cc19f815e15
Source dataset
uspto-grants-2015_06
Patent number
US09056112B2

Reaction notes

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