Method for producing 5-hydroxypiperidine-2-carboxylic acid

Patent metadata

Field	Value
Publication number	US-9790181-B2
Application number	US-201415108141-A
Country	US
Kind code	B2
Filing date	Dec 26, 2014
Priority date	Dec 27, 2013
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by formula (10) below:

the method including removing the protecting group from the hydroxyl group in a compound represented by formula (7) below:

(wherein P represents a protecting group, R 3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)

to synthesize a compound represented by formula (8) below:

(wherein R 3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).

First claim

The invention claimed is:

1. A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by the formula (10) below:

the method comprising (i) the step 4 of:
removing the ether protecting group from the hydroxyl group in a compound represented by the formula (7) below:

wherein P represents an ether protecting group that is resistant to basic reaction conditions, R 3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms to synthesize a compound represented by the formula (8) below:

wherein R 3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms.

2. The method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid according to claim 1 , further comprising (ii) the step 5 of:
(a) in the compound (8), hydrolyzing the ester groups, allowing one of the carboxyl groups to react with the hydroxyl group to allow the lactonization, and further decarboxylating the other carboxyl group; or
(b) in the compound (8), hydrolyzing the ester groups, decarboxylating one of the carboxyl groups to form a stereoisomeric mixture of a 2-monocarboxylic acid, and then isomerizing and lactonizing the stereoisomeric mixture;
to synthesize a compound represented by the formula (9) below:

wherein A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms.

3. The method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid according to claim 1 , further comprising (iii) the step 6 of:
cleaving the amide bond in the compound (9) and hydrolyzing the lactone in the compound (9) to synthesize (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid.

4. The method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid according to claim 2 , wherein the step of decarboxylating the carboxyl group in the step 5(a) or the step 5(b) is performed in the presence of an organic base.

5. A method for producing the compound represented by the formula (7) below:

wherein P represents an ether protecting group that is resistant to basic reaction conditions, R 3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms, the method comprising the step 1 of:
protecting the hydroxyl group with an ether protecting group that is resistant to basic reaction conditions in a compound represented by the formula (1) below:

wherein X represents Cl, Br, or I, and R 1 represents a hydrogen atom or an optionally substituted alkyl group containing 1 to 4 carbon atoms to synthesize a compound represented by the formula (2) below:

wherein X represents Cl, Br, or I, R 1 represents a hydrogen atom or an optionally substituted alkyl group containing 1 to 4 carbon atoms, and P represents an ether protecting group that is resistant to basic reaction conditions
and then reducing the ester group in the compound (2) to synthesize a compound represented by the formula (3) below:

wherein X represents Cl, Br, or I, and P represents an ether protecting group that is resistant to basic reaction conditions.

6. The method for producing the compound (7) according to claim 5 , wherein the method comprises
(i) the step 2 of:
esterifying the hydroxyl group in the compound (3) with a sulfonate group to synthesize a compound represented by the formula (4) below:

wherein X represents Cl, Br, or I, R 2 represents an aryl group containing 6 to 12 carbon atoms, an alkyl group containing 1 to 10 carbon atoms, or an aralkyl group containing 7 to 20 carbon atoms
and allowing the compound (4) to react with a compound represented by the formula (5) below:

wherein R 3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms
to synthesize a compound represented by the formula (6) below:

wherein X represents Cl, Br, or I, P represents an ether protecting group that is resistant to basic reaction conditions, R 3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms;
and
(ii) the step 3 of:
cyclizing the compound (6) to synthesize the compound represented by the formula (7) below:

wherein P represents an ether protecting group that is resistant to basic reaction conditions, R 3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms.

7. The method for producing the compound (7) according to claim 6 , wherein the reaction of the compound (4) with the compound (5) in the step 2 is performed in the presence of an iodide salt.

8. The method for producing the compound (7) according to claim 6 , wherein the cyclizing reaction of the compound (6) in the step 3 is performed in the presence of a quaternary ammonium salt.

9. A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by the formula (10) below:

the method comprising
synthesizing the compound (7) by the method according to claim 5 ; and
removing the ether protecting group from the hydroxyl group in the compound (

Assignees

• Api Corp

Inventors

• Takehara Jun
• Murai Masato
• Ohtani Takashi
• Maeda Tomoko
• Hidaka Tsugihiko

Classifications

• C07C309/66

  Methanesulfonates · CPC title

• C07D211/60 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D498/08

  Bridged systems · CPC title

• C07C233/47

  having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title