(R)-N-Fmoc-2-(7'-octenyl) alanine synthesis
- Product Name:(R)-N-Fmoc-2-(7'-octenyl) alanine
- CAS Number:945212-26-0
- Molecular formula:C26H31NO4
- Molecular Weight:421.53
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Yield:-
Reaction Conditions:
with sodium carbonate in tetrahydrofuran;water; pH=8.5 - 9 at 20 - 25;Large scale;
Steps:
I; 1.1g Example 1g Preparation of Crystalline N-Fmoc-(R)-α-methyl-α-aminodec-9-enoic acid
Example 1g Preparation of Crystalline N-Fmoc-(R)-α-methyl-α-aminodec-9-enoic acid 1.55 kg (1.0 equiv.) of 37 2-amino-2-methyl-dec-9-enoic acid.HCl (XIII) was suspended in 22 water and polished filtered to remove trace amounts of D-BPB.HCl from the solution. 17 Methyl tert-butyl ether was added and the aqueous product layer was extracted once with methyl tert-butyl ether. The aqueous product layer was re-charged and 7 tetrahydrofuran was added. A 20% aqueous sodium carbonate solution (2.75 equiv.) was charged to the mixture followed by Fmoc-OSu (0.89 equiv.). The mixture was allowed to react at 20-25° C. while maintaining the pH between 8.5-9.0 with additional amounts of the 20% 42 sodium carbonate solution until the reaction was complete. The mixture was pH adjusted down to pH 2.0-2.5 with conc. hydrochloric acid. Tetrahydrofuran was distilled off and methyl tert-butyl ether was charged. The layers were separated and the organic layer was washed 3 more times with additional water. The organic layer was then concentrated under vacuum and co-stripped with methyl tert-butyl ether. The resulting crude 4 oil was re-dissolved in methyl tert-butyl ether and cyclohexylamine (1.10 equiv.) was added slowly to obtain a pH range of 8.5-9.0. The slurry was agitated at ambient temperature (20-25° C.) for 3 hours and the solid product salt (XIV) was isolated by filtration. The solids were rinsed twice with additional methyl tert-butyl ether and the solid wetcake was recharged to a clean reactor. The wetcake was recrystallized from tetrahydrofuran and methyl tert-butyl ether to improve the purity. The solid salt was suspended in methyl tert-butyl ether and water and the pH adjusted to 2.0-2.5 with 25% sulfuric acid. The organic product layer was washed with water until all of the cyclohexylamine was removed. The organic product layer was concentrated and co-stripped with hexanes to a loose oil. The product (IIa) was then crystallized out of chloroform and hexanes and dried at <0° C. under a 1.0 cfm nitrogen sweep. Yield: 1.12 kg, 41.5%
References:
Aileron Therapeutics, Inc.;Darlak, Krzysztof;Kawahata, Noriyuki;Athamneh, Sameer Ahmed US2014/128581, 2014, A1 Location in patent:Paragraph 0087; 0156; 0157