Diisopropylethylamine → HCID 131730824, compound

A solution of 10d (83.5 mg, 0.485 mmol.) in anhydrous dimethylformamide (4 ml) was cooled to 0° C. before adding N,N-diisopropylethylamine (340 uL, 1.94 mmol.) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (185 mg, 0.485 mmol.) The reaction mixture was stirred at 0° C. for 20 minutes before addition of (S)-1-{(S)-2-((S)-2-amino-3-methylbutyryl amino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (E)-hexa-3,5-dienyl ester (285 mg, 0.485 mmol.)* in anhydrous dimethylformamide (4 ml). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was the diluted with pH7 phosphate buffer (0.5M, 20 ml) then extracted with ethyl acetate (3×20 ml). The combined extract was washed with brine (3×20 ml), dried over sodium sulfate, filtered and evaporated to give a brown gum. The gum was purified on a silica column eluting with 60% ethyl acetate, 40% hexane to yield 11a as a colourless solid (133 mg, 37%). 1H NMR δ (300 MHz NMR, CDCl3) 0.17-0.21 (s, 6H), 0.87-0.96 (m, 6H) 0.96-1.01 (s, 9H), 1.14-1.20 (d, 3H, J=7.1 Hz), 1.35-1.85 (m, 7H), 2.08-2.21 (m, 3H), 2.39-2.53 (m, 3H), 2.65-3.01 (m, 3H), 3.31-3.45 (m, 4H), 3.50-3.57 (d, 1H, J=11.2), 4.09-4.35 (m, 5H), 4.93-5.20 (m, 3H), 5.57-5.90 (m, 3H), 6.08-6.19 (m, 1H), 6.25-6.40 (m, 1H), 6.45-6.59 (m, 2H), 6.64-6.75 (m, 2H), 6.78-6.85 (d, 1H, J=7.8 Hz), 7.07-7.15 (t, 1H, J=7.8 Hz). LCMS (m/z) 741.44 [M+H] Tr=5.72 min. (S)-1-{(S)-2-((S)-2-amino-3-methylbutyryl amino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (E)-hexa-3,5-dienyl ester was prepared from the corresponding BOC protected product ((S)-((E)-hexa-3,5-dienyl)1-((S)-2-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanamido)-3-(3-(tert-butyldimethylsilyloxy)phenyl)propanoyl)piperazine-3-carboxylate) in a similar manner to that described for the preparation of 3b from 3a. In turn, (S)-((E)-hexa-3,5-dienyl)1-((S)-2-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanamido)-3-(3-(tert-butyldimethylsilyloxy)phenyl)propanoyl)piperazine-3-carboxylate was prepared as described in the synthesis of 3a except substituting (E)-hexa-3,5-dien-1-ol for but-3-en-1-ol.

1. extractionthen extracted with ethyl acetate (3×20 ml)
2. extractionThe combined extract
3. washwas washed with brine (3×20 ml)
4. dry with materialdried over sodium sulfate
5. filtrationfiltered
6. customevaporated
7. customto give a brown gum
8. customThe gum was purified on a silica column
9. washeluting with 60% ethyl acetate, 40% hexane

ORD record

ord-3e0f1fd172d840238fd7c27cf09f45b0

Source dataset

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08513184B2