Process for preparing alendronic acid

Details Process for preparing alendronic acid Process for preparing alendronic acid

2000-04-21

2001-03-13

Vollano, Jean F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Phosphorus acids or salts thereof

C562S011000, C562S008000

Reexamination Certificate

active

06201148

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new chemical processes for manufacturing bisphosphonic acids, and in particular for manufacturing alendronic acid.
BACKGROUND OF THE INVENTION
Alendronate sodium, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium, having the formula
is an agent for combating bone resorption in bone diseases including osteoporosis and Paget's disease.
Various methods for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, or alendronic acid, are known in the art and have been disclosed in M. I. Kabachnik et al., Synthesis and Acid-Base and Complexing Properties of Amino-Substituted alpha-hydroxylakylidene-diphosphonic Acids, Izu. Akad. Nauk USSR, Ser. Khim, 2,433 (1978) and in U.S. Pat. Nos. 4,407,761, 4,621,077, 4,705,651, 5,039,819 and 5,159,108.
A well known process for preparing alendronic acid is as follows (see also e.g. GB 2118042):
It has been reported that a solidification problem occurs when this process is performed on a large scale. The abbreviation GABA is defined hereinafter as 4(gamma)-aminobutyric acid.
U.S. Pat. No. 4,922,007 describes the preparation of alendronate sodium in trihydrate form, wherein 4-aminobutyric acid is reacted with phosphorous acid and phosphorous trichloride in the presence of methanesulfonic acid followed by the addition of sodium hydroxide. However, it has been reported that methanesulfonic acid reacts with the phosphorus trichloride and under adiabatic conditions the reaction becomes self-heating at 85° C., and an uncontrolled exotherm occurs at >140° C.
WO 98/34940 describes a process for preparing alendronic acid, which comprises reacting 4-aminobutyric acid with phosphorous acid and phosphorous trichloride in the presence of polyalkylene(glycol). However, it was reported that large quantities of polyalkylene(glycol) as well as toluene participate in this reaction, which renders it inefficient on a large scale.
Thus, there remains a need for a homogeneous, safe and efficient process for preparing alendronic acid.
SUMMARY OF THE INVENTION
The present invention relates to a novel process for preparing of alendronic acid, which comprises the steps of:
a) reacting a compound of the formula I with H
3
PO
3
 wherein
R is an imido group; and
R
1
is selected from the group which consists of chloro, bromo, iodo, fluoro, hydroxy, amino, —OR
2
or —OC(O)R
2
, wherein R
2
is C
1
-C
12
alkyl, C
1
-C
12
cycloalkyl, or C
1
-C
12
aryl;
b) reacting the product of step (a) with a deprotecting agent; and
c) recovering alendronic acid.
R is preferably selected from the group which consists of N-phthalimido and N-maleimido.
R
1
is preferably selected from the group which consists of chloro, bromo and hydroxy.
Optionally, the reaction of step (a) may be assisted with one or more of the compounds selected from the group which consists of H
3
PO
4
, PCl
3
, PCl
5
and POCl
3
.
The deprotecting agent of step (b) may be a non-oxidizing acid, preferably selected from the group which consists of HCl and HBr; or selected from the group that consists of HBr together with acetic acid, H
3
PO
3
and H
3
PO
4
.
The present invention also relates to the product made from this process.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
N-phthalimido-GABA and N-phthalimido-GABA chloride are known (See GB 2,248,063 page 5 line 8-10, incorporated herein by reference). N-maleimido-GABA is also known [See J. Med. Chem., 18,1004,(1975), incorporated herein by reference].
According to the present invention in step (a) the compound of formula I is reacted with H
3
PO
3
wherein:
R is an imido group; and
R
1
is selected from the group which consists of chloro, bromo, iodo, fluoro, hydroxy, amino, —OR
2
or —OC(O)R
2
, wherein R
2
is C
1
-C
12
alkyl, C
1
-C
12
cycloalkyl, or C
1
-C
12
aryl;
In some cases, typically when R
1
is halogen, it is sufficient to react the compound of formula I with H
3
PO
3
without the need to use an assisting agent. In other cases it is necessary to use one or more activating agents selected from the group which consists of PCl
3
, PCl
5
and POCl
3
.
As it will be seen in the examples, according to some embodiments of the present invention, the reaction of step (a) may be performed by using H
3
PO
3
as a solvent. According to other embodiments, when a solidification problem occurs, a further solvent such as H
3
PO
4
may be used in order to solve this problem.
In step (b), the product of step (a) is reacted with a deprotecting agent. The compound resulting from this step is alendronic acid.
The process of the present invention may be performed as a “one pot” process.


REFERENCES:
patent: 4407761 (1983-10-01), Blum et al.
patent: 4705651 (1987-11-01), Staibano
patent: 5159108 (1992-10-01), Kieczkowski
patent: 5908959 (1999-06-01), Kubela et al.
patent: 2248063 (1992-03-01), None
CA:124:117423 abs of J Org Chem by Kieczykowski et al 60(25) pp. 8310-8312, 1995.
CA:124:104537 abs of Supramol Chem by Leroux et al 5(4) pp. 267-272, 1995.
CA:129:202991 abs of Zhongguo Yiyao Gongye Zazhi Bianjibu by Jiao et al 29(5) pp. 202-203, 1998.

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