Methods for producing of lipids

Patent metadata

Field	Value
Publication number	US-2024208894-A1
Application number	US-202218551619-A
Country	US
Kind code	A1
Filing date	Apr 6, 2022
Priority date	Apr 9, 2021
Publication date	Jun 27, 2024
Grant date	—

Abstract

The present disclosure provides methods for producing a compound having a chemical formula of Formula I, wherein R 3 and R 2 are independently a i) linear or branched or cyclic, ii) saturated or unsaturated, and iii) substituted or unsubstituted hydrocarbon group comprising 1 to 30 carbon atoms; R 3 is a i′) lincar or branched or cyclic. ii′) saturated or unsaturated, and iii′) substituted or unsubstituted hydrocarbon group: and L 1 , L 2 and L 3 independently are linkers.

First claim

We claim:

1 . A method for producing a compound having a chemical formula of Formula I,

wherein R 1 and R 2 are independently a i) linear or branched or cyclic, ii) saturated or unsaturated, and iii) substituted or unsubstituted hydrocarbon group comprising 1 to 30 carbon atoms,
R 3 is a i) linear or branched or cyclic, ii) saturated or unsaturated, and iii) substituted or unsubstituted hydrocarbon group,
L 1 , L 2 and L 3 are independently linkers,
the method comprising:
a) reacting a first acyl chloride having a chemical formula of R 1 —(CO)—Cl with a first diol having a chemical formula of HO-L 1 —CH 2 —OH to form a first ester alcohol having a chemical formula of R 1 —C(O)—O-L′—CH 2 —OH, and reacting a second acyl chloride having a chemical formula of R 2 —(CO)—Cl with a second diol having a chemical formula of HO-L′—CH 2 —OH to form a second ester alcohol having a chemical formula of R 2 —C(O)—O-L′—CH 2 —OH,
b) oxidizing the first ester alcohol with a first oxidizing agent to form a first ester aldehyde having a chemical formula of R 1 —C(O)—O-L 1 —CHO, and oxidizing the second ester alcohol with a second oxidizing agent to form a second ester aldehyde having a chemical formula of R 2 —C(O)—O-L 2 —CHO; and
c) reducing the first and second ester aldehyde in presence of a reducing agent and an amine having a chemical formula of R 3 -L 3 —NH 2 , to form the compound of Formula I,

wherein the method does not involve isolation and/or purification by chromatography of the first ester alcohol, the second ester alcohol, the first ester aldehyde, or the second ester aldehyde before forming the compound of Formula I, and/or wherein the method does not involve using a first ester alcohol, second ester alcohol, first ester aldehyde, or second ester aldehyde isolated and/or purified by chromatography.

2 . The method of claim 1 , wherein the first acyl chloride is formed by reacting a first fatty acid having a chemical formula of R 1 —COOH with a first oxychloride, and the second acyl chloride is formed by reacting a second fatty acid having a chemical formula of R 2 —COOH with a second oxychloride, wherein the first and the second oxychloride are independently thionyl chloride, phosphoryl chloride, oxalyl chloride, or any combinations thereof.

3 . The method of claim 2 , wherein a first fatty acid solution is contacted with a first oxychloride solution and a second fatty acid solution is contacted with a second oxychloride solution.

4 . The method of claim 2 , wherein the first fatty acid and the first oxychloride are reacted at a temperature of 15° C. to 30° C., and the second fatty acid and the second oxychloride are reacted at a temperature of 15° C. to 30° C.

5 . The method of claim 2 , wherein the first fatty acid and the first oxychloride are reacted in presence of dimethylformamide (DMF), and the second fatty acid and the second oxychloride are reacted in presence of DMF.

6 . The method of claim 1 , wherein the first acyl chloride and the first diol are reacted in presence of a first tertiary amine, and the second acyl chloride and the second diol are reacted in presence of a second tertiary amine.

7 . The method of claim 1 , wherein the method further comprises,
adding a first base to a first esterification-product mixture comprising the first ester alcohol to form a first biphasic medium, said first biphasic medium comprises i) a first organic medium comprising the first ester alcohol, and ii) a first aqueous medium, and adding a second base to a second esterification-product mixture comprising the second ester alcohol to form a second biphasic medium, said second biphasic medium comprises i) a second organic medium comprising the second ester alcohol, and ii) a second aqueous medium.

8 . The method of claim 1 , wherein the oxidation of the first ester alcohol with the first oxidizing agent is catalyzed using a first oxidation catalyst, and the oxidation of the second ester alcohol with the second oxidizing agent is catalyzed using a second oxidation catalyst.

9 . The method of claim 1 , wherein the method further comprises,
washing a first oxidation-product mixture comprising the first ester aldehyde, and washing a second oxidation-product mixture comprising the second ester aldehyde, wherein the first ester aldehyde in the washed first oxidation-product mixture, and the second ester aldehyde in the washed second oxidation-product mixture is reduced in step (c).

10 . The method of claim 1 , wherein the reducing agent in step (c) comprises hydrogen (H 2 ).

11 . The method of claim 10 , wherein the reduction of the first and second ester aldehydes is quenched with a base.

12 . The method of claim 1 , further comprising at least partially purifying the compound of Formula I by extraction, precipitation, silica gel chromatography, polymer resin chromatography, or a combination thereof.

13 . The method of claim 1 , wherein the method does not involve isolation and/or purification by chromatography of the first acyl chloride or the second acyl chloride before forming the compound of Formula I, and/or wherein the method does not involve using a first acyl chloride or second acyl chloride isolated and/or purified by chromatography.

14 . A salt having the chemical formula of Formula III:

wherein R 1 and R 2 are independently a i) linear or branched or cyclic, ii) saturated or unsaturated, and iii) substituted or unsubstituted hydrocarbon group comprising 1 to 30 carbon atoms,
R 3 is a i′) linear or branched or cyclic, ii′) saturated or unsaturated, and iii′) substituted or unsubstituted hydrocarbon group,
L 1 , L 2 and L 3 are independently linkers, and
X − is chloride, bromide, iodide, sulfate, acetate, mesylate, tosylate, (1R)-(—)-10-camphorsulfonate, 1,2-ethanedisulfonate, oxalate, dibenzoyl-L-tartarate, phosphate, L-tartarate, maleate, fumarate, succinate, or malonate.

15 . The salt of claim 14 , wherein R 1 and R 2 are independently a branched, saturated, unsubstituted alkyl group comprising 1 to 30 carbons.

16 . The salt of claim 14 , wherein R 1 and R 2 are the same.

17 . The salt of claim 14 , wherein L 1 and L 2 are the same.

18 . The salt of claim 14 , wherein i) R 1 and R 2 are different, and/or ii) L 1 and L 2 are different.

19 . The salt of claim 14 , wherein the salt is in a crystallized form.

20 . A method for forming a salt of claim 14 , the method comprising contacting the compound of Formula I with an acid having a chemical formula of HX.

21 . A method of purifying a compound of Formula I,

wherein R 1 and R 2 are independently a i) linear or branched or cyclic, ii) saturated or unsaturated, and iii) substituted or unsubstituted hydrocarbon group comprising 1 to 30 carbon atoms,
R 3 is a i) linear or branched or cyclic, ii) saturated or unsaturated, and iii) substituted or unsubstituted hydrocarbon group,
L 1 , L 2 and L 3 are independently linkers,
the method comprising purifying by chromatography, and eluting the compound of Formula I with an eluant mixture of n-heptane and ethyl acetate,
whe

Assignees

• Pfizer

Inventors

• Do Nga My
• Eisenbeis Shane Allen
• Salman Omar Abdelrahman

Classifications

• C07C229/24

  having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid · CPC title

• C07C227/08

  by reaction of ammonia or amines with acids containing functional groups · CPC title

• C07C67/29

  by introduction of oxygen-containing functional groups · CPC title

• C07C219/12

  having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07C219/06

  having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton · CPC title