Potassium Carbonate → Linagliptin

HRID 2172574Notes

Reaction equation

HRID 2172574 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 10096344Linagliptin

Reagents, catalysts & solvents 1

HCID 7909Methyl Isobutyl KetoneSolvent

Conditions

Temperature
100 °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 (8.4 gm) were added to the reaction mixture at 26° C. The reaction mixture was heated to 100° C. and maintained at that temperature for 4 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 200 mL of 10% aqueous acetic acid solution and stirred for 30 minutes at 28° 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) were added drop-wise at 28° C. (pH is ≧10). The mixture was stirred for one hour at 28° C. and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and divided into 5 equal parts.

Workup

  1. customequipped with a mechanical stirrer
  2. temperaturemaintained at that temperature for 4 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 200 mL of 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) were added drop-wise at 28° C. (pH is ≧10)
  12. stirringThe mixture was stirred for one hour at 28° C.
  13. customthe organic layer was separated
  14. extractionthe aqueous layer was extracted with 100 ml of dichloromethane

Sources & evidence

ORD record
ord-57794937e7cc4d4eb6fc07307804ee0d
Source dataset
uspto-grants-2015_06
Patent number
US09056112B2

Reaction notes

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