Title of Invention

"A PROCESS FOR THE PREPARATION OF ALENDRONIC ACID"

Abstract

A process for the preparation of alendronic acid, 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 18O°C with the optional inclusion of PC13, PCl5, POCI3:(Formula Removed) wherein R is an imido group selected from N-phthalimido and; N-maleimido; and Ri is selected from the group which consists of chloro, bromo, iodo, fluoro, hydroxy, amino, -OR2 or OC[O)R2, wherein R2 is C1-C12alkyl, C1-C12 cycloalkyl, or C1-C12 aryl; b) reacting the product of step (a) with a deprotecting agent such as herein described at a temperature of between 25°C and 18O°C; and c) recovering alendronic acid.

Full Text

NOVEL PROCESS FQRPREPARING ALENDRONIC ACID FIELD OF THE INVENIflON The present invention relates to new chemical orocesses for manufacturing bisphosphonic acids, and in particular for manufacturing alerdronic acid, BACKGROUND OF THE INVENTION Alendronate sodium, 4-amino-l-bydroxybutylidene-1,1-bisphosphonic 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-l-hydroxybutylidene-l,l-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 Complcxing Properties of Amino-Substituted alpha-hydroxylakylidene-diphosphonic Ac ds, Izu, Akad. Nauk USSR, Ser. Khim, 2,433 (1978) and in U.S. Patent numbers 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): (Formula Removed) Alendronic Acid It has been reported that a solidification problen, occurs when this process is performed on 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 acici is reacied with phosphorous acid and phosphorous trichloride in the presence of methanesul Tonic 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 excitherm 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, il was reported chat 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: (Formula Removed) wherein R is an imido group; and R1 is selected from the group which consists of chlora, bromo, iodo. fluoro, hydroxy, amino, -OR2 or -OC(0)R2, wherein R1 is C1-C12 alky], C1-C12 cycloalkyl, or C1-C12 aryl; b) reacting th« product of step (a) with a deprotettting agent; and c) recovering alendronic acid. R is preferably selected from the group which jonsists of N-phthalimido and N-mEileimido. R! is preferably selected from the group which consists of chloro, bromo and hydroxy. Optionally, the reaction of step (a) may be assi; ted with one or more of the compounds selected from the group which consist; of H3PO)4, PC13, PCl3 and POC13. The deprotecting agent of step (b) may be a nor-oxidizing acid, preferably selected from the group which consists of HCI and HBr; or selected from the group that consists of HBr together with acetic acic, H3P03 andH3PO4. The present invention also relates to the product made from this process. ETAILED DESCRIPTION OF PREFERRED EMBODIMENTS N'phthalimido-OABA andN-phthalimido-GABA chloride are known (See GB 2,248,063 page 5 line 8-10, incorporated hersin 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 R! is selected from the group which consists of'chloro, bromo, iodo, J'luoro, hydroxy, amino, -OR: or -OC(O)R2, wherein R2 is C1-C12 alky!, C1-C|2 cycloalkyl, or C,-C12 aryl; compound of formula 1 with H3P03 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 PC13, PCI, and POC13. As it will be seen in the examples, according to some embodiments of the present invention, the reaction of step (a) may be psrfornnel by using H3F03 as a solvent. According to other embodiments, when a solidification problem occurs, a further solvent such as H3PO4 may be used in order to :so!ve this problem. In step (b), the product of step (a) is reacted with a deprotectir.g agent.The compound resulting from this step is alendronic acid. The process of the present invention may be f erformed 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-phthalimido-GABA chloride (4-phthalimidobutanoyl chloride, 8 g, 0.0318 mol, 1 eq) and phosphorous acid (5.2 g, 0,0635 mol, 2 eq.). The mixture was heated to 130°C and kept at this temperature for 4 hours. 6N HCI (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 (959'o, 100 ml) was added, and alendronic acid was precipitated. The reaction mixture was rofluxed 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 1.53 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 c urged with N • phthalimido-GABA (4-phthalimidobutanoic acid, 8 g, 0.0343 nol, 1 eq) and phosphorous acid (14.06 Cr, 0.1715 mol, 5 eq.). The mixture was heated to "56'Cand phosphorous trichloride (6 ml, 0.0688 mol, 2 eq.) were: added 'Iropwise durir.g 15 minutes. The reaction mixture was heated to 80 °C and kept al this temperamre 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 5CC the pithalic 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 rr echanical stirrer, a reflux condenser, a dropping funnel and a thermometer, 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-phospKoric 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 1 !> minutes, The reaction mixture was heated to 80 CC 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 ?A hours. After cooling to 5'C the phthalic acid was removed by filtration and the reaction mixture was distilled to dryness. Ethanol (95%, 125 rnl) was added, and aleadronic acid was precipitated. The reaction mixrure was refluxed for I 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 mol, 1 eq) and phosphorous acid (11.2 g, 0.136 mol, 5 eq.). The mixture was leated 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 5CC the malsic acid was removed by filtration and tie reaction mixture was distilled to dryness, Ethanol (95%, 100 ml) was added, and alendronic acid was precipitated. The reaction mixrure was refluxed for 1 hour and cooled to 25 °C.Alendronic acid was collected by filtration, washed with 25 ml of 95% cthanol 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 skill ed in the art to which the invention pertains that variations and modifications Df 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 . A process for the preparation of alenc ronic acid, which comprises the steps of: a) reacting a compound of the formula I wi wherein R is an imido group; and R1 is sdected from the group which consists o Tchloro, bromo, iodo, fluoro, hydroxy, amino, -OR2 or -OC(O)R% wherein RJ is C1-CI2 alkyl, C1-C12, cycJoalkyl, or C,-C13 aryl; b) reacting the product of step (a) with a depro :ecting agent; and c) recovering alendronic acid. 2. A process according to claim 1 wherein R is selected from the group which consists cf N-phthalimido and N-maleinr do. 3. A process according to claim 1 wherein R1 is selected from the group which consists of chloro, bromo and hydroxy. 4. A process according to claim 1 wherein step (a) further comprises the use of one or more of the compounds selected from the group which consists of H,P04, PC13, PCI, and POC13. 5. A process according to claim I whereh step (b) comprises using one or more deprotecting agents selected from the group which consists of HCl, HBr, acetic acid, H3PO3, and H3P04, 6. A process according to claim 1, wherein steps (a) and (b) take place in a single vessel. 7. A process according to claim 1 in which step (a) is performed at the temperature of between about 25 °C and about 180 0C. 8. A process according to claim 7 in whici step (a) is performed at the temperature of between about 80° and about 1400C. 9. A process according to claim 1 in which step (b) is performed at the temperature of between about 25 °C and about 130°C. 10. A process according to claim 9 in which step (b) is performed at the temperature of between about 100°C and about 1300C. 11. A process according to claim 6 which is performed at the temperature of between about 25 0C and about 1800C. 12. A process according to claim 11 which :s performed an the temperature of between about 80°C and about 140°C. 13. A process according to claim 1 wherein the molar ratio between the compound of formula I and H3PO, is between 1:1 and 1:6. 14. A process according to claim 13 wherein the molar rat:o between the compound of formula I and H3PO3 is between 3:2 and 1:5. 15. A process according to claim 4 wherein the molar ratio between the compound of formula I and PCl is bet/ween 11 and 1:6. 16. A process according to claim 15 wherein the molar ratio between the compound of formula 1 and PCl is between 1:2 and 1:3. 17. A process according to claim 4 wherdn the molar rutio between the compound of formula I and H3PO4 is between 1:1 and 1:6. 18. A process according to claim 17 whei ein the molar ratio between the compound of formula I and H,P04 is between 1:2 and 1:4. 19. A process according to claim 4 where in the molar ratio between the compound of formula I and PClj is between 1:1 and 1:6. 20. A process according to claim 19 wherein the molar ratio between the compound of formula 1 and PC13 is between 1:2 and 1:3, 21. A process according to claim 4• wherein the molar ratio between the compound of formula I and POC13 is between 1:1 and 1:6. 22. A process according to claim 21 where in the molar ratio between the compound of formula I and POCJ3 is between 1:2 and 1:3. 23. Alendronic acid prepared according to the process of claim 1. 10

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in-pct-2001-0727-del-correspondence-po.pdf

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in-pct-2001-0727-del-form-1.pdf

in-pct-2001-0727-del-form-13.pdf

in-pct-2001-0727-del-form-19.pdf

in-pct-2001-0727-del-form-2.pdf

in-pct-2001-0727-del-form-3.pdf

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in-pct-2001-0727-del-pct-101.pdf

in-pct-2001-0727-del-pct-210.pdf

in-pct-2001-0727-del-pct-220.pdf

in-pct-2001-0727-del-pct-308.pdf

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in-pct-2001-0727-del-pct-409.pdf

in-pct-2001-0727-del-pct-416.pdf

in-pct-2001-0727-del-petition-137.pdf

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