Process for producing 2-hydroxymethylmorpholine salt

1. A method of producing a 2-hydroxymethylmorpholine salt of formula (3)

wherein A is an acidic counter anion, and n is an integer of 1 or 2, comprising crystallizing the salt from a solution containing 2-hydroxymethylmorpholine of formula (1)

1,4-oxazepane compound of formula (2)

and an acid selected from an inorganic acid, a carboxylic acid and a sulfonic acid.

2. The production method according to claim 1 comprising mixing a composition containing the 2-hydroxymethylmorpholine of formula (1) and the 1,4-oxazepane compound of formula (2) with an acid to allow crystallization.

3. The production method according to claim 2 , wherein the composition containing the 2-hydroxymethylmorpholine of formula (1) and the 1,4-oxazepane compound of formula (2) is obtained by reacting an epihalohydrin of formula (4)

wherein X is a chlorine atom or a bromine atom, with an N-protected ethanolamine of formula (5)

wherein R is a protecting group selected from a C 1-6 alkyl group, an ally group and a benzyl group, to give a reaction composition containing an N-protected 2-hydroxymethylmorpholine of formula (8)

wherein R is as defined above, and an N-protected 1,4-oxazepane compound of formula (9)

wherein R is as defined above, and then subjecting the reacting composition to deprotection to remove R.

4. The production method according to claim 1 , which comprises a step of subjecting a composition containing an N-protected 2-hydroxymethylmorpholine of formula (8)

wherein R is a protecting group selected from a C 1-6 alkyl group, an allyl group and a benzyl group, and an N-protected 1,4-oxazepane compound of formula (9)

wherein R is as defined above, to deprotection in the presence of an acid to remove R to give a reaction composition containing 2-hydroxymethylmorpholine of formula (1)

1,4-oxazepane compound of formula (2)

and an acid, and then allowing crystallization.

5. The production method according to claim 4 , wherein the composition containing the N-protected 2-hydroxymethylmorpholine of formula (8) and the N-protected 1,4-oxazepane compound of formula (9) is obtained by reacting an epihalohydrin of formula (4)

wherein X is a chlorine atom or a bromine atom, with an N-protected ethanolamine of formula (5)

wherein R is a protecting group selected from a C 1-6 alkyl group, an allyl group and a benzyl group.

6. The production method according to claim 1 , wherein the acid is an inorganic acid selected from hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid and nitric acid.

7. The production method according to claim 1 , wherein the acid is a carboxylic acid selected from formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, oxalic acid, benzoic acid, p-nitrobenzoic acid, fumaric acid, maleic acid and terephthalic acid.

8. The production method according to claim 1 , wherein the acid is a sulfonic acid selected from methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid.

9. The production method according to claim 1 , wherein the salt is crystallized from a solution of at least one kind of solvent selected from water, alcohol solvents, ether solvents, aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, halogen solvents, ester solvents, ketone solvents and nitrile solvents.

10. The production method according to claim 9 , wherein the salt is crystallized from a solution of an ester solvent.

11. The production method according to claim 3 , wherein R is a benzyl group.

12. The production method according to claim 1 , wherein the 2-hydroxymethylmorpholine salt is an optically active form.

13. The production method according to claim 4 , wherein R is a benzyl group.