Title of Invention	A PROCESS FOR THE POSSESSION OF PURE 3-AMINO-1, 2-PROPANEDIOL
Abstract	ABSTRACT 712/MAS/98 A process for the preparation of pure 3-ainino-l, 2-propanediol containing less than 0,1% of organic impurities such as herein described, and less than 0.05% of inorganic impurities such as herein described comprising the steps of a) extraction of 3-amtno-l, 2-propanediol from a crude composition containing the same using either esters of acetic acid with (C1-C5) straight or branched alcohols or alcohol solvents of formula Alc-OH wherein Ale is a (C3-C7) straight or branched chain at a temperature raging from 20 to 50°C; b) formation of the salts of 3-amino-l,2-propanediol with an acid selected from the group consisting of oxalic acid, an X-Ph-COOH acid, wherein X is a substituent at the phenyl ring Pb such as H, CJ, NO;, Br and (Cj-C^) straight or branched alkyl, orp-toluenesulfonic acid; c) crystallization of the salt formed in step b), from alcohol solvents of formula R-OH, wherein R is a (Ci-Cfi) straight or branched alkyl, or raonoalkylether glycols of the class of (C3-C7) alkyicellosoives, with water content from 0.5% to 60%, depending on the used solvent; d) release and purification of the salt by passing same through ion exchange resms, to give 3-Mnino-l, 2-propanediol as the free base; and further e) purification of said free base by crystallization from alcohols of formula R-OH, wherein R is as defined above.

Title of Invention

A PROCESS FOR THE POSSESSION OF PURE 3-AMINO-1, 2-PROPANEDIOL

Abstract

ABSTRACT 712/MAS/98 A process for the preparation of pure 3-ainino-l, 2-propanediol containing less than 0,1% of organic impurities such as herein described, and less than 0.05% of inorganic impurities such as herein described comprising the steps of a) extraction of 3-amtno-l, 2-propanediol from a crude composition containing the same using either esters of acetic acid with (C1-C5) straight or branched alcohols or alcohol solvents of formula Alc-OH wherein Ale is a (C3-C7) straight or branched chain at a temperature raging from 20 to 50°C; b) formation of the salts of 3-amino-l,2-propanediol with an acid selected from the group consisting of oxalic acid, an X-Ph-COOH acid, wherein X is a substituent at the phenyl ring Pb such as H, CJ, NO;, Br and (Cj-C^) straight or branched alkyl, orp-toluenesulfonic acid; c) crystallization of the salt formed in step b), from alcohol solvents of formula R-OH, wherein R is a (Ci-Cfi) straight or branched alkyl, or raonoalkylether glycols of the class of (C3-C7) alkyicellosoives, with water content from 0.5% to 60%, depending on the used solvent; d) release and purification of the salt by passing same through ion exchange resms, to give 3-Mnino-l, 2-propanediol as the free base; and further e) purification of said free base by crystallization from alcohols of formula R-OH, wherein R is as defined above.

Full Text	The invention relates to a process for the preparation of 3-amino-l, 2-propanediol. 3-Amino-l, 2-propanediol of formula (I), commonly known as isoserinol, is widely used as building-block of non-ionic iodinated X-ray contrast agents, as well as in the synthesis of antiinflammatories, analgesics and cosmetics. The major industrial application of said products lies in the synthesis of a number of non-ionic X-ray contrast agents, such as : lohexol, lopentol, lopromide, loversoj, loxilan, lodixanol. Physicians and the authorities which grant drug marketing authorizations, require drugs with very low levels of impurities in order to minimize any involved risks of side-effects or toxic effects for the patient. As far as iodinated contrast agents are concerned, such a requirement is due to the total amount of administered product, which is much higher than that of other medicaments. By way of example, the injected dose of contrast agent can reach and even exceed 150 g. The high purity level of the compound of formula (I) is therefore extremely important in order to avoid formation of any by-products and assure high purity standards to the final products. In literature, a number of methods for the purification of compound (I) are reported, the most widely used being distillation under vacuum (see, for example, EP 470004), and other procedures to remove water contained in the crude, always under reduced Accordingly the present invention therefore provides a process for the preparation of pure 3-amino-l,2-propanediol containing less than 0.1% of organic impurities and less than 0.05% of inorganic impurities comprising the steps of a) extraction of 3-amino-l,2-propanediol from a crude composition containing the same using either esters of acetic acid with (Cp Cj) straight or branched alcohols or alcohol solvents of formula Alc-OH wherein Ale is a (C3-C7) straight or branched chain at a temperature ranging from 20 to 50'*C; b) formation of the salts of 3-amino-l,2-propanediol with an acid selected from the group consisting of oxalic acid, and X-Ph-COOH acid, wherein X is a substituent at fte phenyl ring Ph such as H, CI, NO2, Br and (C1-C4) straight or branched alkyl, or p-toluenesulfonic acid; c) crystallization of the salt formed in step b), from alcohol solvents of formula R-OH, wherein R is a (Ci-Cg) straight or branched alkyl, or monoalkylether glycols of the class of (C3-C7) alkylcellosolves, with water content from O.SVo to 60%, depending on the used solvent, d) release and purification of the salt by passing same through ion exchange resins, to give 3-amino-l, 2-propanediol as the free base; and furttier e) purification of said free base by crystallization from alcohols of formula R-OH, wherein R is as defined above. Accordingly the present mvention therefore provides a process for the preparation of pure 3-amino-l,2-propanediol containmg less than 0.1% of organic impurities such as herein described and less than 0.05% of inorganic impurities such as herein described comprising the steps of a) extraction of 3-ammo-l,2-propanediol from a crude composition containing the sane using either esters of acetic acid with (C1-C5) straight or branched alcohols or atcohol solvents of formula Alc-OH wherein Ale is a (C3-C7) straight or branched chain at a temperature ranging from 20 to 50°C; b) formation of the salts of 3-amino-l,2-propanediol with dn acid selected from the group consisting of oxalic acid, Md X-Ph-COOH acid, wherein X is a substiluent at the phenyl ring Ph such as H, CI, NO2, Br and (C1-C4) straight or branched aikyl, or p-toluenesulfonic acid; c) crystallization of the salt formed in step b), from alcohol solvents of formula R-OH, wherein R is a (Ci-Ce) straight or branched alkyl, or moooaikylelher glycols of the class of (C3-C7) alkylcellosolves, with water content from 0.5% to 6OY0, depending on the used solvent; d) release and purification of the salt by passing same through ion excbmige resins, to give 3-amino-l, 2-propMiediol as the free base; and further e) purification of said free base by crystallization from alcohols of formula R-OH. wherein R is as defined above. 1. A process for the preparation of pure 3-amino-l, 2-propanecliol containing less than 0.1% of organic impurities such as herein described, and less than 0.05% of inorganic impurities such as herein described comprising the steps of a) extraction of 3-«nino-l, 2- propanediol from a crude composition containing the same using either esters of acetic acid with (C1-C5) straight or branched alcohols or alcohol solvents of formula A!c-OH wherein Ale is a (C3-C7) straight or branched chain at a temperature ranging from 20 to SO^C; b) formation of the salts of 3-amino-l,2-propanediol with an acid selected from the group consisting of oxalic acid, an X-Ph-COOH acid, wherein X is a subslituent at the phenyl ring Ph such as H, CI, NOj, Br and (C1-C4) straight or branched alkyl. or p-toiuenesulfonic acid; c) crystallization of the salt formed in step b), from alcohol solvents of formula R-OH, wherein R is a(Ci-Cs) straight or branched alkyl, or monoalkylether glycols of the class of (C3-C7) alkylcellosolves, with water content from 0.5% to 60%. depending on the used solvent; d) release and purification of the salt by passing same through ion exchange resins, to give 3-amino-l, 2-propanediol as the free base; and further e) purification of said free base by crystallization from alcohols of formula R-OH, wherein R is as defined above. 2. The process according to claim 1, in which the solvent used in step a) is selected from butyl n-acetate and n-nentanoI_ 16. The process according to claim I, wherein the said is acid oxalate, the water content ranges from 0.5 to 30% and the solvent to product ratio ranges from 0.5.1 to 6:1 parts by weight. 17. The process according to claim 1, wherein the salt is selected from chiorobenzoate and nitrobenzoate, the water content ranges from 0.5 to 30%, the solvent to product ratio ranges from 1:0.5 to 1:5 parts by weight and the base is released by elution through regenerated sulfonic resins. 18. The process according to claim 1, wherein the salt is para- toluenesulfonate, the water content ranges from 0.5 to 30%, the solvent to product ratio ranges from 1 to 5 parts by weight and the base is released by elution through strong aiionic resins regenerated in the free base or the chloride forms. 19. The process according to claim 1, wherein 4.7% aqueous ammonia is used. 20. The process according to claim 1, wherein the crystallization alcohol of step e) has a water content from 0.5 to 5%. 21. The process according to claim 20 wherein the crystallization alcohol is selected from n-butanot, 2-butanol, isobutanol and n-pentanol. 22. The process according to claim 21. wherein the crystallization solvent of step b) is n-butanol. 23. A process for the preparation of pure 3-amino-l, 2-propanediol substantially as hereinbefore described.

Full Text

The invention relates to a process for the preparation of 3-amino-l, 2-propanediol.
3-Amino-l, 2-propanediol of formula (I), commonly known as isoserinol, is widely used as building-block of non-ionic iodinated X-ray contrast agents, as well as in the synthesis of antiinflammatories, analgesics and cosmetics.
The major industrial application of said products lies in the synthesis of a number of non-ionic X-ray contrast agents, such as : lohexol, lopentol, lopromide, loversoj, loxilan, lodixanol.
Physicians and the authorities which grant drug marketing authorizations, require drugs with very low levels of impurities in order to minimize any involved risks of side-effects or toxic effects for the patient.
As far as iodinated contrast agents are concerned, such a requirement is due to the total amount of administered product, which is much higher than that of other medicaments. By way of example, the injected dose of contrast agent can reach and even exceed 150 g.
The high purity level of the compound of formula (I) is therefore extremely important in order to avoid formation of any by-products and assure high purity standards to the final products.
In literature, a number of methods for the purification of compound (I) are reported, the most widely used being distillation under vacuum (see, for example, EP 470004), and other procedures to remove water contained in the crude, always under reduced

Accordingly the present invention therefore provides a process for the preparation of pure 3-amino-l,2-propanediol containing less than 0.1% of organic impurities and less than 0.05% of inorganic impurities comprising the steps of a) extraction of 3-amino-l,2-propanediol from a crude composition containing the same using either esters of acetic acid with (Cp Cj) straight or branched alcohols or alcohol solvents of formula Alc-OH wherein Ale is a (C3-C7) straight or branched chain at a temperature ranging from 20 to 50'*C;
b) formation of the salts of 3-amino-l,2-propanediol with an acid selected from the group consisting of oxalic acid, and X-Ph-COOH acid, wherein X is a substituent at fte phenyl ring Ph such as H, CI, NO2, Br and (C1-C4) straight or branched alkyl, or p-toluenesulfonic acid;
c) crystallization of the salt formed in step b), from alcohol solvents of formula R-OH, wherein R is a (Ci-Cg) straight or branched alkyl, or monoalkylether glycols of the class of (C3-C7) alkylcellosolves, with water content from O.SVo to 60%, depending on the used solvent,
d) release and purification of the salt by passing same through ion exchange resins, to give 3-amino-l, 2-propanediol as the free base; and furttier
e) purification of said free base by crystallization from alcohols of formula R-OH, wherein R is as defined above.

Accordingly the present mvention therefore provides a process for the preparation of pure 3-amino-l,2-propanediol containmg less than 0.1% of organic impurities such as herein described and less than 0.05% of inorganic impurities such as herein described comprising the steps of
a) extraction of 3-ammo-l,2-propanediol from a crude composition
containing the sane using either esters of acetic acid with (C1-C5) straight or
branched alcohols or atcohol solvents of formula Alc-OH wherein Ale is a
(C3-C7) straight or branched chain at a temperature ranging from 20 to 50°C;
b) formation of the salts of 3-amino-l,2-propanediol with dn acid selected from the group consisting of oxalic acid, Md X-Ph-COOH acid, wherein X is a substiluent at the phenyl ring Ph such as H, CI, NO2, Br and (C1-C4) straight or branched aikyl, or p-toluenesulfonic acid;
c) crystallization of the salt formed in step b), from alcohol solvents of formula R-OH, wherein R is a (Ci-Ce) straight or branched alkyl, or moooaikylelher glycols of the class of (C3-C7) alkylcellosolves, with water content from 0.5% to 6OY0, depending on the used solvent;
d) release and purification of the salt by passing same through ion excbmige resins, to give 3-amino-l, 2-propMiediol as the free base; and further
e) purification of said free base by crystallization from alcohols of formula R-OH. wherein R is as defined above.

1. A process for the preparation of pure 3-amino-l, 2-propanecliol
containing less than 0.1% of organic impurities such as herein
described, and less than 0.05% of inorganic impurities such as herein
described comprising the steps of a) extraction of 3-«nino-l, 2-
propanediol from a crude composition containing the same using
either esters of acetic acid with (C1-C5) straight or branched alcohols
or alcohol solvents of formula A!c-OH wherein Ale is a (C3-C7)
straight or branched chain at a temperature ranging from 20 to SO^C;
b) formation of the salts of 3-amino-l,2-propanediol with an acid
selected from the group consisting of oxalic acid, an X-Ph-COOH
acid, wherein X is a subslituent at the phenyl ring Ph such as H, CI,
NOj, Br and (C1-C4) straight or branched alkyl. or p-toiuenesulfonic
acid; c) crystallization of the salt formed in step b), from alcohol
solvents of formula R-OH, wherein R is a(Ci-Cs) straight or branched
alkyl, or monoalkylether glycols of the class of (C3-C7)
alkylcellosolves, with water content from 0.5% to 60%. depending on
the used solvent; d) release and purification of the salt by passing
same through ion exchange resins, to give 3-amino-l, 2-propanediol
as the free base; and further e) purification of said free base by
crystallization from alcohols of formula R-OH, wherein R is as
defined above.
2. The process according to claim 1, in which the solvent used in step a)
is selected from butyl n-acetate and n-nentanoI_

16. The process according to claim I, wherein the said is acid oxalate, the water content ranges from 0.5 to 30% and the solvent to product ratio ranges from 0.5.1 to 6:1 parts by weight.
17. The process according to claim 1, wherein the salt is selected from chiorobenzoate and nitrobenzoate, the water content ranges from 0.5 to 30%, the solvent to product ratio ranges from 1:0.5 to 1:5 parts by weight and the base is released by elution through regenerated sulfonic resins.
18. The process according to claim 1, wherein the salt is para-
toluenesulfonate, the water content ranges from 0.5 to 30%, the
solvent to product ratio ranges from 1 to 5 parts by weight and the
base is released by elution through strong aiionic resins regenerated
in the free base or the chloride forms.
19. The process according to claim 1, wherein 4.7% aqueous ammonia is used.
20. The process according to claim 1, wherein the crystallization alcohol of step e) has a water content from 0.5 to 5%.
21. The process according to claim 20 wherein the crystallization alcohol is selected from n-butanot, 2-butanol, isobutanol and n-pentanol.

22. The process according to claim 21. wherein the crystallization
solvent of step b) is n-butanol.
23. A process for the preparation of pure 3-amino-l, 2-propanediol
substantially as hereinbefore described.

Documents:

712-mas-1998 abstract.pdf

712-mas-1998 claims.pdf

712-mas-1998 correspondence others.pdf

712-mas-1998 description (complete).pdf

712-mas-1998 form-2.pdf

712-mas-1998 form-26.pdf

712-mas-1998 form-4.pdf

712-mas-1998 form-6.pdf

712-mas-1998 others.pdf

712-mas-1998 petition.pdf

« Previous Patent

Next Patent »

Patent Number

187745

Indian Patent Application Number

712/MAS/1998

PG Journal Number

30/2009

Publication Date

24-Jul-2009

Grant Date

03-Jan-2003

Date of Filing

02-Apr-1998

Name of Patentee

M/S. DIBRA S.P.A

Applicant Address

PIAZZA VELASCA 5, MILANO,

Inventors:

#	Inventor's Name	Inventor's Address
1	DESANTIS NICOLA	VIA E FOLLI 50, MILANO,

PCT International Classification Number

C07C 89/04

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	MI97A000782	1997-04-04	Italy