NOVEL PROCESS FOR PREPARING ALENDRONIC ACID
FIELD OF THE INVENTION
The present invention relates to new chemical accesses for manufacturing bispho:;phonic acids, and ir. particular "or manufacturing alerdronic acid,
BACKGROUND OF THE INVENTK )N
Alendronate sodium, 4-amino-1-hydroxyburylidene- 1,1-bi-phosphonic acid monosodium, having the formula
(Formula Removed)
is an agent for combating bone resorption in bone diseases inc uding 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 a!., Synthesis and Acid-Base and Compicxing Properties of Amino-Substituted a!pha-hydroxylakylidene~diphosph omc Ac ds, Izu. Akad. Nauk USSR, Ser. Khim, 2,433 (1978) and in U.S, Patent numbers 4,407,761, 4,621,077, 4,735,651, 5,039,819 and 5,159,108.
A well known process for preparing alendronic acid is as follows (see also e.g. GB 2118042):
(Formula Removed)
It has been reported that a solidification problerr occurs when his process is performed or a large scale. The abbreviation GABA is defined hereinafter as 4(gamma)-aminobutyric acid,
U.S. Patent No. 4,922,007 describes the preparation of alendronate sodium in trihydrate form, wherein 4-aminobutyric acic is reacied with phosphorous acid and phosphorous trichloride in the presence of methanesul fonic acid followed by the addition of sodium hydroxide. However, it has been reported that methanesulfonic acid reacts with the phosphorus trichloride ant; under adiabatic conditions the reaction becomes self-heating at 85°C, aid an uncontrolled exotherm occurs at >140°C.
WO 98/34940 describes a process for preparing ilendronic acid, which comprises reacting 4-aminobutyric acid with phosphorous acid and phosphorous trichloride in the presence of polyalkylene(glycol). However, it was reported that largi 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 1 wkh H3PO3
(Formula Removed)
wherein R is an imido group; and
R1 is selected from the group which consists of chloro, bromo, lodo, fluoro, hydroxy,
amino, -OR- or -OC(O)R2, wherein R2 is C1-C12 alkyl, C1-C12 cycloalkyl, or C1-C12
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.
R1 is preferably selected from the group which consists of chloro, bromo and hydroxy.
Optionally, the reaction of step (a) may be assisted with one cr more of the compounds selected from the group which consists of H3PO4, PC13, PCl5 and PGCI3.
The deprotecting agent of step (b) may 3e a nor-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 acic, H3PO3 and H5PO4.
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) tie compound of formula I is reacted with H3PO3
(Formula Removed)
wherein:
R is an imido group; and
R1 is selected from the group which consists of chloro, bromo, lodo, fluoro, hydroxy, amino, -OR2 or -OC(O)R3, wherein R2 is C1-C12 alleyl, C1-C12 cycloalkyl, or C1-C12aryl;
compound of formula 1 with H3PO3 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 PCI 3, PC15 and POCl3.
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 H3PO3 as a solvent. According to other embodiments, when a solidificaticn problem occurs, a further solvent such as H3PO4 may be used in order to solve th s 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 rerformed as a "one pot" process.
EXAMPLES
The following examples are given for the purpose of illustrating the present invention and shall not be construed as being limitations on the scope or spirit of the invention.
EXAMPLE 1
A 100ml nitrogen flushed flask fitted with a mechanical stirrsr, reflux condenser and a thermometer, was charged with N-prthalimido-GABA chloride (4-phthalimidobutanoyl chloride, 8 g, 0.0318 mol, 1 eq) and phosphorous acid (S.2 g, 0.0635 mot, 2 eq.). Trie mixture was heated to 130°C and kept at this temperature for 4 hours. 6N HC1 (40 ml) were added dropwise and the reaction mixture was refluxed for 18 hours. After cooling to 5°C the phthalic acid was removed by filtration and the reaction mixture was distilled to dryness, ethanol (95%, 100 ml) was added, and alendronic acid was precipitated. The reaction mixture was refluxed for 1 hour and cooled to 25°C. Alendronic acid was collected by filtration, washed with 23 ml of 95% ethanot and dried in a vacuum oven to give 3.53 g (19.4%).
EXAMPLE 2
A 100ml nitrogen flushed flask fitted with a mechanical stirrer, a reflux condenser, a dropping funnel and a thermometer, was charged with N-phthalimido-GABA (4-phthalimidobutanoic acid, 8 g, 0.0343 mol, 1 eq) and phosphorous acid (14.06 Cr, 0.1735 mol, 5 eq.). The mixture vas heated to 76°C and phosphorous trichloride (6 ml, 0,0688 mo!, 2 eq.) were added dropwise during 15 minutes. The reaction mixture was heated to 80 °C and kept al this temperature for 3 hours. 48% aqueous solution of HBr (40 ml) were added dropwise and the reaction mixture was refluxed for 18 hours. After cooling to 5°C the phthalic acid was removed by filtration and the reaction mixture was distilled to dryness. Ethanol
(95%, 100 ml) was added, and alendronic acid was precipitated. The reaction mixture was refluxed for 1 hour and cooled to 25°C. Alendronic acid was collected by filtration, washed with 25 ml of 95% ethanol and dried in a vacuum oven to give 3.25 g(38%).
EXAMPLE 3
A 250ml nitrogen flushed flask fitted with a jr echanical stirrer, a reflux condenser, a dropping funnel and a thermometsr, was charged with N-phthalimido-GABA (4-phthalimidobutanoic acid, 10 g, 0.0429 mol, 1 eq), phosphorous acid (5.3 g, 0.064 mol, 1.5 eq) and orthc-phospl oric acid (16.8 g, 0,01714 mol, 4 eq). The mixture was heated to 76°C and phosphorous trichloride (7.5 ml, 0.0857 mol, 2 eq.) were added dropwise during 15 minutes, The reaction mixture was heated to 80°C and kept at this temperature for 3 hours. A solution (70 ml) of 6N HC1 was added dropwise and the and the reaction mixture was refluxed for 24 hours. After cooling to 5°C the phthalic acid was removed by filtration and the reaction mixture was distilled to dryness. Ethanol (95%, 125 ml) was added, and alendronic acid was precipitated. The reaction mixture was refluxed for 1 hour and cooled to 25 °C, Alendronic acid was collected by filtration, washed with 25 ml of 95% ethanol and dried in a vacuum oven to give 6.11 g (57%).
EXAMPLE 4
A 100ml nitrogen flushed flask fitted with a mechanical stirrer, a reflux condenser, a dropping funnel and a thermometer, was charged with N-maleimido-GABA (4-maleimidobutanoic acid, 5 g, 0,0273 mcl, 1 eq) and phosphorous acid (11.2 g, 0.136 mot, 5 eq.). The mixture was icated to 76°C and phosphorous trichloride (4.8 ml, 0.0546 mol, 2 eq.) were added dropwise during 15 minutes. The reaction mixture was heated to 80°C and kept at this temperature for 16 hours. A mixture of 15 ml 48% aqueous solution of HBr and 15ml glacial acetic acid was added dropwise and the reaction mixture was refluxed for 18 hours. After cooling to 5°C the maleic acid was removed by filtration and the reaction mixture was distilled to dryness.. Ethanol (95%, 100 ml) was added, and alendronic add was precipitated. The reaction mixture was refluxed for 1 hour and cooled to 25 °C.
Alendronic acid was; collected by filtration, washed with 25 ml of 95% ethanol and dried in a vacuum oven to give 1.43 g (21%).
Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiment may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.

WE CLAIM:
1. Alendronic acid prepared by the process which comprises the steps
of:
a) reacting an imidobutanoyl compound of the formula I with phosphorous acid (H3PO3) at a temperature of between 25°C and 180°C with the optional inclusion of PCI3, PCIs, H3PO4 or POCLs:
(Formula Removed)
I wherein R is an imido group; and
R1 is selected from the group which consists of chioro, bromo, iodo, fluoro, hydroxy, amino, -OR2 or OC(O)R2, wherein R2 is C1-C12 alkyl, C1-C12 cycloalkyl, or C1-C12 aryl;
b) reacting the product of step (a) with a deprotecting agent at a temperature of between 25°C and 180°C; and
c) recovering alendranic acid.
2. A process for the preparatipn of alendronic add substantially as herein described with reference to and as illustrated in the foregoing examples.