4-Methylmorpholine → HCID 131715017, compound

HRID 980402Notes

Reaction equation

HRID 980402 reaction equation
[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19](O)=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[Cl:39][C:40](OCC(C)C)=O.Cl.ClCC(CCl)=O.[NH2:54][C@H:55]([C:60]([OH:62])=O)[CH2:56][CH:57]([CH3:59])[CH3:58]>C1COCC1.CC(C)=O>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:54][C@H:55]([C:60]([CH2:40][Cl:39])=[O:62])[CH2:56][CH:57]([CH3:58])[CH3:59])=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1

Participants

7

Reactant 4

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 131714619HCID 131714619, compoundHCID 131715016HCID 131715016, compound

Product 1

HCID 131715017HCID 131715017, compoundYield 253.9%

Reagents, catalysts & solvents 2

HCID 180AcetoneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 4.00 g (9.4 mmol) of Z-Phe-Gly-Ala-OH and 0.95 g of N-methylmorpholine in 100 mL of THF was cooled to -20° under nitrogen, and then 1.28 g of isobutyl chloroformate was added. After 5 minutes a solution of 1.14 g of leucine chloromethyl ketone hydrochloride in dry acetone was added, followed by 0.95 g of N-methylmorpholine. The resulting reaction mixture was stirred and allowed to warm to about 25° over a period of 2 hours. Solvent was evaporated, and the resulting residue was dissolved in ethyl acetate. This solution was washed with ice water, followed by cold 5% citric acid. The resulting solution was dried and then solvent was evaporated to leave 5.63 g of a frothy solid. This material was triturated overnight with 250 mL of ether. The resulting gel-like product was filtered from the ether and washed with additional ether, providing 3.10 g of crude product as a fine white powder. A 2.56 g portion was dissolved in 25 mL of warm ethyl acetate, forming a cloudy solution. This solution was filtered through carbon (Celite) and an additional 200 mL of ether was added. After seeding, 1.15 g of fine needle-like crystals of Z-Phe-Gly-Ala-LeuCH2Cl precipitated and were collected. These crystals melted at 138°-141.8°; δD25 -59° (C=0.45 g/100 mL in acetone).

Workup

  1. customThe resulting reaction mixture
  2. temperatureto warm to about 25° over a period of 2 hours
  3. customSolvent was evaporated
  4. dissolutionthe resulting residue was dissolved in ethyl acetate
  5. washThis solution was washed with ice water
  6. customThe resulting solution was dried
  7. customsolvent was evaporated

Sources & evidence

ORD record
ord-7298d47f72bc4beb9eeaf029897d3e8c
Source dataset
uspto-grants-1987_01
Patent number
US04636492

Reaction notes

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