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PROCESS FOR PREPARATION OF N-PROTECTED-(3R,4S)-4-AMINO-2,6-DIMETHYLHEPT-1-EN-3-OL

IP.com Disclosure Number: IPCOM000236004D
Publication Date: 2014-Apr-02
Document File: 7 page(s) / 91K

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PROCESS FOR PREPARATION OF N-PROTECTED-(3R,4S)-4-AMINO-2,6- DIMETHYLHEPT-1-EN-3-OL

    Described hereinafter, a process for the preparation of N-protected-(3R,4S)-4-amino- 2,6-dimethylhept-1-en-3-ol (referred to as Compound P-III-R), which can be an intermediate in the synthesis of (S)-4-Methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1- oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4- phenylbutanamido) pentanamide.

    For the purpose of clarity and as an aid in the understanding the following terms and abbreviations are defined below:

Compound P-III-R N-protected- (3R,4S)-4-amino-2,6-dimethylhept-1-en-3-ol

Compound P-III-S N-protected-(3S,4S)-4-amino-2,6-dimethylhept-1-en-3-ol

Compound P-II N-protected-(S)-4-amino-2,6-dimethylhept-1-en-3-one


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Wherein the P can be either Boc or Cbz protecting group or any other suitable protecting group. For example,

Compound P-III-R Tert-butyl-((3R,4S)-3-hydroxy-2,6-dimethylhept-1-en-4- yl)carbamate

Compound P-III-R Benzyl-((3R,4S)-3-hydroxy-2,6-dimethylhept-1-en-4- yl)carbamate

    The process described herein utilize different aluminium alkoxides as the reducing agent. For example, the reducing agent can be selected from: (Al(OEt)3, Al(OiPr)3, Al(OsecBu)3 or Al(OtBu)3).

Example 1: Prepation of tert-butyl ((3R,4S)-3-hydroxy-2,6-dimethylhept-1-en-4-

yl)carbamate

    (S)-tert-butyl (2,6-dimethyl-3-oxohept-1-en-4-yl)carbamate (511 mg, 2.0 mmol) was dissolved at room temperature in 2-propanol (5 mL) and Al(OiPr)3 (447 mg, 2.2 mmol) was added to colorless solution. Reaction mixture (unhomogenous white suspension) was stirred at room temperature for 1 hour, then another 5 mL of 2-propanol was added, reaction mixture was warmed up to reflux temperature and stirred for 1 more hour (TLC in ethyl acetate : hexane 1 : 2 showed complete conversion). Reaction mixture was cooled to room temperature and solvent was removed under diminished pressure. The remain was diluted with ethyl acetate (25 mL) and stirred with saturated K,Na-tartrate (25 mL) for 1 hour at room


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temperature (until clear 2-layer solution is obtained). Water layer was removed and organic layer was washed once more with saturated K,Na-tartrate (25 mL) and water (2×25 mL), dried over anhydrous. MgSO4 and evaporated to dryness to obtain crude tert-butyl (3- hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate (506 mg, 98.4 % yield). Isomer ratio (R,S) : (R,R) is 143 : 1 and overall chromatographic purity 80.9 area %.

Example 2: Preparation of tert-butyl ((3R,4S)-3-hydroxy-2,6-dimethylhept-1-en-4-

yl)carbamate

    (S)-tert-butyl (2,6-dimethyl-3-oxohept-1-en-4-yl)carbamate (5.11 g, 20 mmol) was dissolved at room temperature in 2-propanol (50 mL) and Al(OiPr)3 (4.47 g, 22 mmol) was added to colorless solution. Reaction mixture (white suspension) was warmed up to reflux temperature and stirred for 2 hours (TLC in ethyl acetate : hexane 1 : 2 showed complete conversion). Reaction mixture was cooled to ro...