Potassium Carbonate → Linagliptin

HRID 2172569Notes

Reaction equation

HRID 2172569 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+].Cl.Cl.[NH:38]1[CH2:43][CH2:42][CH2:41][C@@H:40]([NH2:44])[CH2:39]1>C(C(C)=O)C(C)C>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:38]2[CH2:39][C@H:40]([NH2:44])[CH2:41][CH2:42][CH2:43]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 16211333(3R)-Piperidin-3-amine--hydrogen chloride (1/2)HCID 247500498-Bromo-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione

Product 1

HCID 10096344LinagliptinYield 84.4%

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 dihydrochloride (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 room temperature. 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 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. Isopropyl alcohol (100 mL) was added to the residue and stirred for 3 hours at room temperature. Filtered the compound and washed with isopropyl alcohol (20 mL) and dried the compound at below 60° C. under vacuum to give 17.6 gm of Linagliptin. PXRD pattern: FIG. 2, Purity: 99.0%

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 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. additionIsopropyl alcohol (100 mL) was added to the residue
  17. stirringstirred for 3 hours at room temperature
  18. filtrationFiltered the compound
  19. washwashed with isopropyl alcohol (20 mL)
  20. customdried the compound at below 60° C. under vacuum

Sources & evidence

ORD record
ord-70942f387f56465aad00cd4cc4edc377
Source dataset
uspto-grants-2015_06
Patent number
US09056112B2

Reaction notes

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