Dicyclohexylcarbodiimide → HCID 178513959, compound

HRID 442497Notes

Reaction equation

HRID 442497 reaction equation
[Cl:1][C:2]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.O.C([NH:34][C@H:35]([C:42]([N:44]1[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46]([NH2:48])=[O:47])=[O:43])[CH2:36][C:37]1[N:41]=[CH:40][NH:39][CH:38]=1)(=O)C1NC(=O)NC(=O)C=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:3]=1[C:4]([NH:34][C@H:35]([C:42]([N:44]1[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46]([NH2:48])=[O:47])=[O:43])[CH2:36][C:37]1[N:41]=[CH:40][NH:39][CH:38]=1)=[O:6]

Participants

7

Reactant 4

HCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 2333385-Chloro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acidHCID 178513957HCID 178513957, compound

Product 1

HCID 178513959HCID 178513959, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8471TriethylamineSolvent

Conditions

Temperature
-5 °C

Procedure

4.8 g of 5-chloro orotic acid, 3.6 g of 1-hydroxybenzotriazole and L-histidyl-L-prolinamide dihydrobromide (prepared from 9.7 g N-benzyloxycarbonyl-L-histidyl-L-prolinamide as described in Example 2) are mixed with 150 ml of dimethylformamide. After chilling to -5° C. while stirring 7.0 ml of triethylamine and then the solution of 5.2 g of N,N'-dicyclohexylcarbodiimide in 20 ml of dimethylformamide are added. Under continuous stirring the mixture is stored for 90 minutes at -5° to 0° C. and thereafter for 24 hours, during which time it is allowed to warm to room temperature. The precipitate formed is separated by filtration and the filtrate is evaporated under reduced pressure at a temperature of about 35° C. The residue is treated with 75 ml of water, stored for 12 hours at 0° C. and filtered. The filtrate is stirred for 10 minutes with 75 g of a cationic exchanger in the free acid form (as, for instance, the product named in Example 2). After separating the resin it is washed four times with 250 ml of water each and four times with 50 ml of methanol each. Then the cationic exchanger resin is suspended in 100 ml of water, while stirring treated with 120 ml of 1n ammonia, sucked off and washed six times with 20 ml of 1n ammonia each. The combined ammoniacal filtrates are, at about 35° C. under reduced pressure, evaporated to a small volume and finally lyophylized. The residue is two times recrystallized from water/ethanol (1:1) and thereafter dried in vacuum over phosphorus pentoxide. Thus, 4.7 g (44.8% of the theoretical yield) of 5-chloro-orotyl-L-histidyl-L-prolinamide, melting at 204° - 206° C. are obtained.

Workup

  1. waitfor 24 hours
  2. temperatureto warm to room temperature
  3. customThe precipitate formed
  4. customis separated by filtration
  5. customthe filtrate is evaporated under reduced pressure at a temperature of about 35° C
  6. additionThe residue is treated with 75 ml of water
  7. waitstored for 12 hours at 0° C.
  8. filtrationfiltered
  9. stirringThe filtrate is stirred for 10 minutes with 75 g of a cationic exchanger in the free acid form (as, for instance
  10. customAfter separating the resin it
  11. washis washed four times with 250 ml of water each and four times with 50 ml of methanol each
  12. stirringwhile stirring
  13. additiontreated with 120 ml of 1n ammonia
  14. washwashed six times with 20 ml of 1n ammonia each
  15. customare, at about 35° C. under reduced pressure
  16. customevaporated to a small volume
  17. customrecrystallized from water/ethanol (1:1)
  18. dry with materialdried in vacuum over phosphorus pentoxide

Sources & evidence

ORD record
ord-74cf4203bdd84d3b82414345a1e63a6d
Source dataset
uspto-grants-1977_08
Patent number
US04045556

Reaction notes

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