HCID 4710, compound → N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-N-[(1-cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-L-alaninamide

HRID 326411Notes

Reaction equation

HRID 326411 reaction equation
ON1C2C=CC=CC=2N=N1.[NH2:11][CH:12]([CH:20]([OH:27])[CH:21]([OH:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[N:28]1([S:34]([NH:37][C@H:38]([C:46]([NH:48][C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]2[N:52]=[C:53]([NH2:56])[S:54][CH:55]=2)=[O:47])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:36])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(N(CC)CC)C>[N:28]1([S:34]([NH:37][C@H:38]([C:46]([NH:48][C@H:49]([C:57]([NH:11][CH:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:20]([OH:27])[CH:21]([OH:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:58])[CH2:50][C:51]2[N:52]=[C:53]([NH2:56])[S:54][CH:55]=2)=[O:47])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:35])=[O:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1

Participants

7

Reactant 4

HCID 4710HCID 4710, compoundHCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 11038203N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-L-alanine

Product 1

HCID 20832958N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-N-[(1-cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-L-alaninamide

Reagents, catalysts & solvents 2

HCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent3×

Conditions

Temperature
25 °C

Procedure

1-N-Hydroxybenzotriazole, 190.6 g, 395.0 g of [2S (2R*,3S*,4R*)]-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol (U.S. Pat. No. 4,680,284 and 4,845,079), 682.4 g (1.62 mol) of N-(4-morpholinyl-sulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-L-alanine and 20 L of ethyl acetate are charged into a 50 L reactor and the slurry is stirred. Triethylamine, 107.1 g with 0.5 L of ethyl acetate, is added to the mixture and stirred for 1 hour at 30° C. A solution of 300.0 g of dicyclohexylcarbodiimide dissolved in 2.5 L of ethyl acetate is added to the reaction mixture over 15 to 30 minutes. The slurry is warmed to 35° to 40° C. and stirred at that temperature for 48 hours, cooled to 25° C., and the solids removed by filtration. The filtrate is washed with 0.5N aqueous hydrochloric acid solution (4 L), saturated sodium bicarbonate solution (4×4 L), and water (2 L). The solution is concentrated to a thick slurry under vacuum, chilled to 5° C., and the crude product solid collected by filtration and dried under vacuum at 40° C. The crude product and 4 L of isopropanol are charged into a 12 L reactor and the slurry is heated to 45° C. Water, 1 L, is added and heating continued to 60° C. The solution is cooled slowly to crystallize the product and then chilled to 10° C. The slurry is filtered and the cake is washed with cold isopropanol. After drying at 40° C. under vacuum, 770 g of [1S-(1R*,2S*,3R*)]-N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-N-[(1-cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-L-alaninamide is obtained as white needles of >99% purity by HPLC; mass spectrum (fast atom bombardment): 709.2 M+.

Workup

  1. stirringstirred for 1 hour at 30° C
  2. additionis added to the reaction mixture over 15 to 30 minutes
  3. temperatureThe slurry is warmed to 35° to 40° C.
  4. stirringstirred at that temperature for 48 hours
  5. customthe solids removed by filtration
  6. washThe filtrate is washed with 0.5N aqueous hydrochloric acid solution (4 L), saturated sodium bicarbonate solution (4×4 L), and water (2 L)
  7. concentrationThe solution is concentrated to a thick slurry under vacuum
  8. temperaturechilled to 5° C.
  9. filtrationthe crude product solid collected by filtration
  10. customdried under vacuum at 40° C
  11. additionThe crude product and 4 L of isopropanol are charged into a 12 L reactor
  12. temperaturethe slurry is heated to 45° C
  13. additionWater, 1 L, is added
  14. temperatureheating
  15. customcontinued to 60° C
  16. temperatureThe solution is cooled slowly
  17. customto crystallize the product
  18. temperaturechilled to 10° C
  19. filtrationThe slurry is filtered
  20. washthe cake is washed with cold isopropanol
  21. dry with materialAfter drying at 40° C. under vacuum, 770 g of [1S-(1R*,2S*,3R*)]-N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-N-[(1-cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-L-alaninamide
  22. customis obtained as white needles of >99% purity by HPLC

Sources & evidence

ORD record
ord-146a72f6636e4e6aa932513ca4340b82
Source dataset
uspto-grants-1993_12
Patent number
US05268483

Reaction notes

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