Benzylamine → Carvedilol

HRID 1455627Notes

Reaction equation

HRID 1455627 reaction equation
C(N)C1C=CC=CC=1.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:27][O:28][C:29]1[C:34]([O:35][CH2:36][CH2:37][N:38]([CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]2[C:55]3[C:56]4[C:61]([NH:62][C:54]=3[CH:53]=[CH:52][CH:51]=2)=[CH:60][CH:59]=[CH:58][CH:57]=4)CC2C=CC=CC=2)=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OC(=O)C)C.C(O)(=O)C.[Pd].[Cl-].[Cl-].[Zn+2]>[CH3:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][NH:38][CH2:46][CH:47]([OH:63])[CH2:48][O:49][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]2[NH:62][C:61]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:55]=12

Participants

8

Reactant 3

HCID 7504BenzylamineHCID 50207104-Oxiranylmethoxy-9H-carbazoleHCID 110383641-{benzyl[2-(2-methoxyphenoxy)ethyl]amino}-3-(9H-carbazol-4-yloxy)propan-2-ol2×

Product 1

HCID 2585Carvedilol

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 3007855ZincchlorideCatalystHCID 176Acetic AcidSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

To 400 ml ethylacetate, 70 g (0.27 moles) anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 10.25 g (0.075 moles) of anhydrous ZnCl2 and 50 g (0.21 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to 70-75° C. for 3 hrs (TLC control for checking conversion to N-benzyl carvedilol). The reaction mixture is cooled to ambient temperature and quenched into 100 ml of ˜12-15% aqueous ammonia. The aqueous layer separated, and the product enriched organic layer is washed with water till neutral pH. The organic layer is charcoalised, filtered and the filtrate subjected to hydrogenation reaction. To this solution of N-benzyl carvedilol in ethylacetate, 5 ml acetic acid is added, followed by (7 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 4.0 Kg/cm2 at temperature of 60-70° C. for a period of about 8 hours. The reaction mixture is filtered and the filtrate is washed with 40 ml of 12-15% v/v aqueous ammonia. The product enriched organic layer is separated and concentrated to remove ethylacetate. To the resultant syrupy mass n-butanol (100 ml) is added and the solution is stirred for about 10 hours, the crystals separated by filtration, washed successively with n-butanol (50 ml) and toluene (100 ml) to obtain carvedilol (55.4 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (49 g).

Workup

  1. customquenched into 100 ml of ˜12-15% aqueous ammonia
  2. customThe aqueous layer separated
  3. washis washed with water till neutral pH
  4. filtrationfiltered
  5. customthe filtrate subjected to hydrogenation reaction
  6. additionis added
  7. filtrationThe reaction mixture is filtered
  8. washthe filtrate is washed with 40 ml of 12-15% v/v aqueous ammonia
  9. customis separated
  10. concentrationconcentrated
  11. customto remove ethylacetate
  12. additionTo the resultant syrupy mass n-butanol (100 ml) is added
  13. customthe crystals separated by filtration
  14. washwashed successively with n-butanol (50 ml) and toluene (100 ml)

Sources & evidence

ORD record
ord-1a4c269d61974be2920e4f2802e83c73
Source dataset
uspto-grants-2009_01
Patent number
US07482471B2

Reaction notes

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