US20020052527A1 - Novel process for preparing alendronic acid - Google Patents
Novel process for preparing alendronic acid Download PDFInfo
- Publication number
- US20020052527A1 US20020052527A1 US09/812,469 US81246901A US2002052527A1 US 20020052527 A1 US20020052527 A1 US 20020052527A1 US 81246901 A US81246901 A US 81246901A US 2002052527 A1 US2002052527 A1 US 2002052527A1
- Authority
- US
- United States
- Prior art keywords
- process according
- compound
- formula
- molar ratio
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960004343 alendronic acid Drugs 0.000 title claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 title description 7
- 238000000034 method Methods 0.000 claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 239000012351 deprotecting agent Substances 0.000 claims abstract description 6
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims abstract description 4
- -1 chloro, bromo, iodo, fluoro, hydroxy, amino Chemical group 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims abstract 5
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 11
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 229910019213 POCl3 Inorganic materials 0.000 claims description 5
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 15
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 6
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 6
- 0 *CCCC(C)=O Chemical compound *CCCC(C)=O 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- HMKSXJBFBVGLJJ-UHFFFAOYSA-N 4-(1,3-dioxoisoindol-2-yl)butanoic acid Chemical compound C1=CC=C2C(=O)N(CCCC(=O)O)C(=O)C2=C1 HMKSXJBFBVGLJJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 229920001515 polyalkylene glycol Polymers 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- STXHPGKNMJVJKL-UHFFFAOYSA-N 4-(1,3-dioxoisoindol-2-yl)butanoyl chloride Chemical compound C1=CC=C2C(=O)N(CCCC(=O)Cl)C(=O)C2=C1 STXHPGKNMJVJKL-UHFFFAOYSA-N 0.000 description 1
- NCPQROHLJFARLL-UHFFFAOYSA-N 4-(2,5-dioxopyrrol-1-yl)butanoic acid Chemical compound OC(=O)CCCN1C(=O)C=CC1=O NCPQROHLJFARLL-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- WCVPFJVXEXJFLB-UHFFFAOYSA-N NCCCC(N)=O Chemical compound NCCCC(N)=O WCVPFJVXEXJFLB-UHFFFAOYSA-N 0.000 description 1
- CAKRAHQRJGUPIG-UHFFFAOYSA-M NCCCC(O)(P(=O)(O)O)P(=O)(O)O[Na] Chemical compound NCCCC(O)(P(=O)(O)O)P(=O)(O)O[Na] CAKRAHQRJGUPIG-UHFFFAOYSA-M 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
Definitions
- the present invention relates to new chemical processes for manufacturing bisphosphonic acids, and in particular for manufacturing alendronic acid.
- Alendronate sodium 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium, having the formula
- [0003] is an agent for combating bone resorption in bone diseases including osteoporosis and Paget's disease.
- a well known process for preparing alendronic acid is as follows (see also e.g. GB 2118042):
- 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.
- 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).
- polyalkylene(glycol) As well as toluene participate in this reaction, which renders it inefficient on a large scale.
- the present invention relates to a novel process for preparing of alendronic acid, which comprises the steps of:
- R is an imido group
- 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;
- step (a) reacting the product of step (a) with a deprotecting agent
- 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.
- 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.
- 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].
- step (a) the compound of formula I is reacted with H 3 PO 3
- R is an imido group
- 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;
- R 1 is halogen
- one or more activating agents selected from the group which consists of PCl 3 , PCl 5 and POCl 3 .
- the reaction of step (a) may be performed by using H 3 PO 3 as a solvent.
- a further solvent such as H 3 PO 4 may be used in order to solve this problem.
- 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.
- 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 1.53 g (19.4%).
Abstract
A novel process for the preparation of alendronic acid is disclosed. The method comprises the steps of reacting a compound of formula I with H3PO3
wherein R is an imido group and R1 is selected from the group consisting of chloro, bromo, iodo, fluoro, hydroxy, amino, —OR2 or —OC(O)R2, wherein R2 is C1-C12 alkyl, C1-C12 cycloalkyl or C1-C12 aryl; and then reacting the product of the first step with a deprotecting agent. Alendronic acid is then recovered. The method is safe, efficient and suitable for use on a large scale.
Description
- The present invention relates to new chemical processes for manufacturing bisphosphonic acids, and in particular for manufacturing alendronic acid.
- 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.
- 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 3PO3
- wherein
- R is an imido group; and
- R 1 is selected from the group which consists of chloro, 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; 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 3PO4, PCl3, PCl5 and POCl3.
- 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 3PO3 and H3PO4.
- The present invention also relates to the product made from this process.
- 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 3PO3
- wherein:
- R is an imido group; and
- R 1 is selected from the group which consists of chloro, bromo, iodo, fluoro, hydroxy, amino, —OR2 or —OC(O)R2, wherein R2 is C1-C12 alkyl, C1-C12 cycloalkyl, or C1-C12 aryl;
- In some cases, typically when R 1 is halogen, it is sufficient to react the compound of formula I 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 PCl3, PCl5 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 H 3PO3 as a solvent. According to other embodiments, when a solidification problem occurs, a further solvent such as H3PO4 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.
- 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.
- A 100 ml nitrogen flushed flask fitted with a mechanical stirrer, 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 HCl (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 1.53 g (19.4%).
- A 100 ml 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, 0.1715 mol, 5 eq.). The mixture was heated to 76° C. and phosphorous trichloride (6 ml, 0.0688 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. 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%).
- A 250 ml 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, 10 g, 0.0429 mol, 1 eq), phosphorous acid (5.3 g, 0.064 mol, 1.5 eq) and ortho-phosphoric 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 HCl 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%).
- A 100 ml 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 heated 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 15 ml 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 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 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.
Claims (23)
1. A process for the preparation of alendronic acid, which comprises the steps of:
a) reacting a compound of the formula I with H3PO3
wherein
R is an imido group; and
R1 is selected from the group which consists of chloro, 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; and
c) recovering alendronic acid.
2. A process according to claim 1 wherein R is selected from the group which consists of N-phthalimido and N-maleimido.
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 H3PO4, PCl3, PCl5 and POCl3.
5. A process according to claim 1 wherein step (b) comprises using one or more deprotecting agents selected from the group which consists of HCl, HBr, acetic acid, H3PO3, and H3PO4.
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° C.
8. A process according to claim 7 in which step (a) is performed at the temperature of between about 80° and about 140° C.
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 130° C.
11. A process according to claim 6 which is performed at the temperature of between about 25° C. and about 180° C.
12. A process according to claim 11 which is performed at 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 H3PO3 is between 1:1 and 1:6.
14. A process according to claim 13 wherein the molar ratio between the compound of formula I and H3PO3 is between 1:2 and 1:5.
15. A process according to claim 4 wherein the molar ratio between the compound of formula I and PCl3 is between 1:1 and 1:6.
16. A process according to claim 15 wherein the molar ratio between the compound of formula I and PCl3 is between 1:2 and 1:3.
17. A process according to claim 4 wherein the molar ratio between the compound of formula I and H3PO4 is between 1:1 and 1:6.
18. A process according to claim 17 wherein the molar ratio between the compound of formula I and H3PO4 is between 1:2 and 1:4.
19. A process according to claim 4 wherein the molar ratio between the compound of formula I and PCl5 is between 1:1 and 1:6.
20. A process according to claim 19 wherein the molar ratio between the compound of formula I and PCl5 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 POCl3 is between 1:1 and 1:6.
22. A process according to claim 21 wherein the molar ratio between the compound of formula I and POCl3 is between 1:2 and 1:3.
23. Alendronic acid prepared according to the process of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/812,469 US20020052527A1 (en) | 1999-02-17 | 2001-03-20 | Novel process for preparing alendronic acid |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25163499A | 1999-02-17 | 1999-02-17 | |
| PCT/US2000/003586 WO2000049026A1 (en) | 1999-02-17 | 2000-02-11 | Novel process for preparing alendronic acid |
| US09/812,469 US20020052527A1 (en) | 1999-02-17 | 2001-03-20 | Novel process for preparing alendronic acid |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2000/003586 Continuation WO2000049026A1 (en) | 1999-02-17 | 2000-02-11 | Novel process for preparing alendronic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US20020052527A1 true US20020052527A1 (en) | 2002-05-02 |
Family
ID=22952795
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/556,091 Expired - Fee Related US6201148B1 (en) | 1999-02-17 | 2000-04-21 | Process for preparing alendronic acid |
| US09/812,469 Abandoned US20020052527A1 (en) | 1999-02-17 | 2001-03-20 | Novel process for preparing alendronic acid |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/556,091 Expired - Fee Related US6201148B1 (en) | 1999-02-17 | 2000-04-21 | Process for preparing alendronic acid |
Country Status (29)
| Country | Link |
|---|---|
| US (2) | US6201148B1 (en) |
| EP (1) | EP1169326B1 (en) |
| JP (1) | JP3930251B2 (en) |
| KR (1) | KR100665633B1 (en) |
| AT (1) | ATE271057T1 (en) |
| AU (1) | AU770312B2 (en) |
| BG (1) | BG64851B1 (en) |
| BR (1) | BR0010112A (en) |
| CA (1) | CA2363317C (en) |
| CZ (1) | CZ296921B6 (en) |
| DE (1) | DE60012165T2 (en) |
| DK (1) | DK1169326T3 (en) |
| EA (1) | EA003861B1 (en) |
| EE (1) | EE04593B1 (en) |
| ES (1) | ES2222188T3 (en) |
| HK (1) | HK1041004B (en) |
| HR (1) | HRP20010606B1 (en) |
| HU (1) | HUP0200342A3 (en) |
| IL (1) | IL144941A0 (en) |
| IS (1) | IS6050A (en) |
| MX (1) | MXPA01008332A (en) |
| NO (1) | NO20013984L (en) |
| NZ (1) | NZ513551A (en) |
| PL (1) | PL350126A1 (en) |
| PT (1) | PT1169326E (en) |
| SK (1) | SK285163B6 (en) |
| WO (1) | WO2000049026A1 (en) |
| YU (1) | YU59401A (en) |
| ZA (1) | ZA200106816B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030206954A1 (en) * | 2001-12-24 | 2003-11-06 | Lerner E. Itzhak | Dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material, and process and tooling for producing it |
| US20040052843A1 (en) * | 2001-12-24 | 2004-03-18 | Lerner E. Itzhak | Controlled release dosage forms |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU770312B2 (en) * | 1999-02-17 | 2004-02-19 | Teva Pharmaceutical Industries Ltd. | Novel process for preparing alendronic acid |
| ES2153794B1 (en) * | 1999-08-06 | 2001-10-16 | Medichem Sa | PROCEDURE FOR OBTAINING THE 4-AMINO-1-HYDROXIBUTILIDEN-1,1-BISPHOSPHONIC ACID AND ITS TRIHYDRATED MONOSODIC SALT. |
| TR200101250A2 (en) * | 2001-05-10 | 2003-04-21 | E�S Eczaciba�I �Zg�N K�Myasal �R�Nler Sanay� A.�. | Process for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or its salts |
| ITMI20020908A1 (en) | 2002-04-29 | 2003-10-29 | Chemi Spa | ALENDRONATE SODIUM PREPARATION PROCESS |
| HUP0300227A2 (en) * | 2003-01-28 | 2004-09-28 | Richter Gedeon Vegyészeti Gyár Rt. | Process for preparing 2-substituted-1-hidroxyetylidene-1,1-bisphosphonic acids and their salts with high purity |
| WO2007083240A2 (en) * | 2006-01-20 | 2007-07-26 | Aurobindo Pharma Limited | An improved process for the preparation of bisphosphonic acids |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US22A (en) * | 1836-09-05 | Spbcificatioh | ||
| US562A (en) * | 1838-01-09 | Scale beam and weight | ||
| US6201148B1 (en) * | 1999-02-17 | 2001-03-13 | Teva Pharmaceuticals Industries, Ltd. | Process for preparing alendronic acid |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3016289A1 (en) * | 1980-04-28 | 1981-10-29 | Henkel KGaA, 4000 Düsseldorf | METHOD FOR PRODUCING OMEGA-AMINO-1-HYDROXYALKYLIDEN-1,1-BIS-PHOSPHONIC ACIDS |
| IT1201087B (en) * | 1982-04-15 | 1989-01-27 | Gentili Ist Spa | PHARMACOLOGICALLY ACTIVE BIPPHOSPHONES, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS |
| US4621107A (en) * | 1982-08-12 | 1986-11-04 | Lagow Richard J | Fluorinated elastomeric materials |
| IT1196315B (en) * | 1984-10-29 | 1988-11-16 | Gentili Ist Spa | PROCEDURE FOR THE PREPARATION OF DIPHOSPHONIC ACIDS |
| US5039819A (en) * | 1990-09-18 | 1991-08-13 | Merck & Co., Inc. | Diphosphonate intermediate for preparing an antihypercalcemic agent |
| US5159108A (en) * | 1990-09-18 | 1992-10-27 | Merck & Co., Inc. | Process for preparing an antihypercalcemic agent |
| GB2248063A (en) * | 1990-09-18 | 1992-03-25 | Merck & Co Inc | Phthalimido alkanoyl phosphonates |
| CA2197267C (en) * | 1997-02-11 | 2000-02-08 | Yong Tao | Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof |
-
2000
- 2000-02-11 AU AU34886/00A patent/AU770312B2/en not_active Ceased
- 2000-02-11 HU HU0200342A patent/HUP0200342A3/en unknown
- 2000-02-11 AT AT00913437T patent/ATE271057T1/en not_active IP Right Cessation
- 2000-02-11 PL PL00350126A patent/PL350126A1/en not_active Application Discontinuation
- 2000-02-11 KR KR1020017010358A patent/KR100665633B1/en not_active IP Right Cessation
- 2000-02-11 PT PT00913437T patent/PT1169326E/en unknown
- 2000-02-11 DE DE60012165T patent/DE60012165T2/en not_active Expired - Fee Related
- 2000-02-11 JP JP2000599764A patent/JP3930251B2/en not_active Expired - Fee Related
- 2000-02-11 EE EEP200100436A patent/EE04593B1/en not_active IP Right Cessation
- 2000-02-11 IL IL14494100A patent/IL144941A0/en not_active IP Right Cessation
- 2000-02-11 ES ES00913437T patent/ES2222188T3/en not_active Expired - Lifetime
- 2000-02-11 WO PCT/US2000/003586 patent/WO2000049026A1/en active IP Right Grant
- 2000-02-11 DK DK00913437T patent/DK1169326T3/en active
- 2000-02-11 EA EA200100894A patent/EA003861B1/en not_active IP Right Cessation
- 2000-02-11 CZ CZ20012942A patent/CZ296921B6/en not_active IP Right Cessation
- 2000-02-11 EP EP00913437A patent/EP1169326B1/en not_active Expired - Lifetime
- 2000-02-11 BR BR0010112-5A patent/BR0010112A/en not_active Application Discontinuation
- 2000-02-11 SK SK1186-2001A patent/SK285163B6/en unknown
- 2000-02-11 NZ NZ513551A patent/NZ513551A/en unknown
- 2000-02-11 MX MXPA01008332A patent/MXPA01008332A/en active IP Right Grant
- 2000-02-11 CA CA002363317A patent/CA2363317C/en not_active Expired - Fee Related
- 2000-02-11 YU YU59401A patent/YU59401A/en unknown
- 2000-04-21 US US09/556,091 patent/US6201148B1/en not_active Expired - Fee Related
-
2001
- 2001-03-20 US US09/812,469 patent/US20020052527A1/en not_active Abandoned
- 2001-08-16 BG BG105825A patent/BG64851B1/en unknown
- 2001-08-16 NO NO20013984A patent/NO20013984L/en not_active Application Discontinuation
- 2001-08-16 HR HR20010606A patent/HRP20010606B1/en not_active IP Right Cessation
- 2001-08-16 IS IS6050A patent/IS6050A/en unknown
- 2001-08-17 ZA ZA200106816A patent/ZA200106816B/en unknown
-
2002
- 2002-02-27 HK HK02101492.9A patent/HK1041004B/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US22A (en) * | 1836-09-05 | Spbcificatioh | ||
| US562A (en) * | 1838-01-09 | Scale beam and weight | ||
| US6201148B1 (en) * | 1999-02-17 | 2001-03-13 | Teva Pharmaceuticals Industries, Ltd. | Process for preparing alendronic acid |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030206954A1 (en) * | 2001-12-24 | 2003-11-06 | Lerner E. Itzhak | Dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material, and process and tooling for producing it |
| US20040052843A1 (en) * | 2001-12-24 | 2004-03-18 | Lerner E. Itzhak | Controlled release dosage forms |
| US20050112202A1 (en) * | 2001-12-24 | 2005-05-26 | Lerner E. I. | Dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material, and process and tooling for producing it |
| US20060233880A1 (en) * | 2001-12-24 | 2006-10-19 | Teva Pharmaceutical Industries Ltd. | Controlled release dosage forms |
| US7611722B2 (en) | 2001-12-24 | 2009-11-03 | Teva Pharmaceutical Industries Ltd. | Dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material, and process and tooling for producing it |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3857706B2 (en) | Use of specific diluents to make bisphosphonic acid | |
| EP0971938B1 (en) | Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof | |
| HU211908A9 (en) | Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof | |
| JPH0120159B2 (en) | ||
| JP2005523938A (en) | Process for producing bisphosphonic acids and salts thereof | |
| US7361761B2 (en) | Process for the preparation of bisphosphonic acid | |
| US20090281320A1 (en) | Process for the preparation of [1-hydroxy-2-(3-pyridinyl)ethylidene] bisphosphonic acid and hemipentahydrate monosodium salt thereof | |
| KR0178779B1 (en) | Process for purifying aminoethylenephosphonic acids for pharmaceutical use | |
| WO2007109542A2 (en) | Process for manufacturing bisphosphonic acids | |
| US20080194525A1 (en) | Process of Making Geminal Bisphosphonic Acids and Pharmaceutically Acceptable Salts and/or Hydrates Thereof | |
| US6201148B1 (en) | Process for preparing alendronic acid | |
| EP1205484B1 (en) | Process for producing 4-amino-1-hidroxybutylidene-1,1-bisphosphonic acid and its trihydrated monosodic salt | |
| JP3046438B2 (en) | Method for producing aminodiphosphonic acids | |
| US20070149486A1 (en) | Process for manufacture of 4-amino-hydroxybutylidene-1,1-bisphosphonic acid and its salts | |
| JPH01249787A (en) | 1-hydroxy-omega-(alkyl-or arylphosphinyl)- alkane-11-diphosphonic acid and its salt, and production thereof | |
| JPH0358354B2 (en) | ||
| JPS6058996A (en) | Manufacture of phosphonomethylated amino acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: TEVA PHARMACEUTICALS INDUSTRIES LTD., ISRAEL Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LIDOR-HADAS, RAMY;LIFSHITZ, REVITAL;REEL/FRAME:011894/0334 Effective date: 20010513 |
|
| STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |