Acetic Acid → Carvedilol

HRID 1455623Notes

Reaction equation

HRID 1455623 reaction equation
C(N)C1C=CC=CC=1.C(O)(=O)C.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:31][O:32][C:33]1[C:38]([O:39][CH2:40][CH2:41][N:42]([CH2:50][CH:51]([OH:67])[CH2:52][O:53][C:54]2[C:59]3[C:60]4[C:65]([NH:66][C:58]=3[CH:57]=[CH:56][CH:55]=2)=[CH:64][CH:63]=[CH:62][CH:61]=4)CC2C=CC=CC=2)=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OC(=O)C)C.[Pd]>[CH3:31][O:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][NH:42][CH2:50][CH:51]([OH:67])[CH2:52][O:53][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[NH:66][C:65]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[C:59]=12

Participants

7

Reactant 4

HCID 176Acetic Acid2×HCID 7504BenzylamineHCID 50207104-Oxiranylmethoxy-9H-carbazole2×HCID 110383641-{benzyl[2-(2-methoxyphenoxy)ethyl]amino}-3-(9H-carbazol-4-yloxy)propan-2-ol3×

Product 1

HCID 2585Carvedilol

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 8857Ethyl AcetateSolvent2×

Procedure

To 450 ml ethylacetate, 70 g (0.27 moles) of anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 3.65 g (0.06 moles) of acetic acid and 25 g (0.105 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to reflux for 24 hrs ( TLC control for checking conversion to N-benzyl carvedilol). To the above reaction mixture, a second lot of 3.65 g (0.06 moles) of acetic acid and 25 g (0.105 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is further heated to reflux for 24 hrs (TLC control for checking conversion to N-benzyl carvedilol). The reaction mixture is cooled to ambient temperature and subjected to hydrogenation reaction. To this solution of N-benzyl carvedilol in ethylacetate, (7 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 3.5-4.5 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 12-15% v/v aqueous ammonia (1 volume w. r .t. to the carbazole). 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 (50 ml) to obtain carvedilol (45 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (41 g).

Workup

  1. temperaturethe reaction mixture is heated
  2. temperaturethe reaction mixture is further heated
  3. customsubjected to hydrogenation reaction
  4. filtrationThe reaction mixture is filtered
  5. washthe filtrate is washed with 12-15% v/v aqueous ammonia (1 volume w
  6. customis separated
  7. concentrationconcentrated
  8. customto remove ethylacetate
  9. additionTo the resultant syrupy mass n-butanol (100 ml) is added
  10. customthe crystals separated by filtration
  11. washwashed successively with n-butanol (50 ml) and toluene (50 ml)

Sources & evidence

ORD record
ord-8d1dd0b36a6b4e73bcfbc4bbce9ff934
Source dataset
uspto-grants-2009_01
Patent number
US07482471B2

Reaction notes

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