WO2007010556A1 - Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof - Google Patents
Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof Download PDFInfo
- Publication number
- WO2007010556A1 WO2007010556A1 PCT/IN2006/000255 IN2006000255W WO2007010556A1 WO 2007010556 A1 WO2007010556 A1 WO 2007010556A1 IN 2006000255 W IN2006000255 W IN 2006000255W WO 2007010556 A1 WO2007010556 A1 WO 2007010556A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- hydroxybutylidene
- acid
- salts
- bisphosphonic acid
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 18
- 150000003839 salts Chemical class 0.000 title claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 title description 5
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 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 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims abstract description 6
- 239000011541 reaction mixture Substances 0.000 claims abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims abstract 2
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 abstract description 6
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 abstract description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 abstract description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000007711 solidification Methods 0.000 description 4
- 230000008023 solidification Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 3
- 238000005954 phosphonylation reaction Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 229960004343 alendronic acid Drugs 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 0 *P(C(CCCN)(O)P(O)(O)=O)(O)=O Chemical compound *P(C(CCCN)(O)P(O)(O)=O)(O)=O 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010020584 Hypercalcaemia of malignancy Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001162 anti-hypercalcemic effect Effects 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940001490 fosamax Drugs 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000011551 heat transfer agent Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000008750 humoral hypercalcemia of malignancy Diseases 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 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 Table
- 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 ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or 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)
Definitions
- the invention relates to an improved industrial process for the production of 4- amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof.
- 4-amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid commonly known as Alendronic acid is an antihypercalcemic agent effective in the treatment or prevention of diseases involving hypercalcemia of pregnancy, Paget's disease and osteoporosis.
- Alendronic acid is marketed as its monosodium salt tri hydrate represented by formula (I) under the brand name FOSAMAX by Merck.
- ⁇ -amino-1- hydroxyalkylidene-1 ,1-bisphosphonic acids in general and 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid in particular.
- the synthesis consists of reacting the corresponding ⁇ -amino acid with a mixture of phosphorus acid and one of the three phosphorus chlorides PCI 3 , POCI 3 or PCI 5 , quenching the reaction mixture with water or a non-oxidizing aqueous acid followed by heating to hydrolyze the phosphorous intermediates to the final product.
- US Patent No. 4,407,761 teaches a process to prepare 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid wherein the reaction is carried out at about 100 °C in chlorobenzene as a diluent which does not solubilize the reaction components and serves only as a heat transfer agent.
- the process is unsuitable for large scale production as the reaction remain a two phase system and gradually thickens into a non-stirrable mass with local solidification.
- methanesulfonic acid has safety concerns. Methansulfonic acid reacts with PCI 3 and under adiabatic conditions the reaction becomes self- heating at 85 °C and an uncontrolled exotherm occurs at >140 0 C. This fact was recognized by the inventors in Example 1 of US 4,922,007. The inventors in a subsequent publication J. Org. Chem., 1995, 60, 8310-8312 have mentioned about the safety concerns.
- the object of the present invention is to provide a process to prepare 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid or salts that overcomes the non homogeneity, solidification and safety problems associated with prior art synthesis.
- the present invention provides a process for the production of 4- amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof which comprises: (a) reacting 4-aminobutyric acid with a suitable phosphonating agent in a solvent such as sulfolane
- the present invention involves the phosphonylation of 4-aminobutyric acid with a suitable phosphonating agent selected from: a mixture of phosphorous acid and
- PCI 3 a mixture of phosphorous acid and PCI 5 , a mixture of phosphorous acid and
- POCl 3 in a solvent such as sulfolane, diglyme and diphenyl oxide, followed by hydrolysis of the resulting mixture using water and then recovering 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof.
- the phosphonylation reaction is carried out in a solvent such as sulfolane, diglyme and diphenyl oxide at a suitable temperature between 30 °C to 80 ° v r ->,
- the process of the present invention may also be carried out in other solvents such diglyme and diphenyl oxide.
- the phosphonylation of 4-amino butyric acid is preferably carried out using phosphorous acid and phosphorous trichloride
- hydrolysis is carried out by adding water and heating to about 80 0 C to 100 °C in water.
- the 4-amino-1-hydroxybutylidene-1 ,1- bisphosphonic acid or its salt is isolated by adjusting the pH to 4 to 4.5 by the addition of a base such as aq. NaOH or aq. KOH.
- 4-amino-1-hydroxybutylidene-1 ,1 -bisphosphonic acid is isolated as its sodium salt.
- Figure 1 shows the powder X-ray diffraction pattern for the 4-amino-1- hydroxybutylidene-1 ,1 -bisphosphonic acid mono sodium trihydrate obtained by the process disclosed in the present invention.
- 4-amino-1-hydroxybutylidene-1 ,1 -bisphosphonic acid monosodium trihydrate in a pharmaceutical composition is useful for treatment of some bone disorders, such as osteoporosis and hypercalcemia of malignancy.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
A process is provided for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof which comprises of: (a) reacting 4-aminobutyric acid with a mixture of phosphorous acid and phosphorous trichloride in solvent selected from sulfolane, diglyme and diphenyl oxide (b) hydrolyzing the resulting reaction mixture from step (a) with water (c) recovering the said 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof.
Description
PROCESS FOR THE PRODUCTION OF 4-AMINO-1- HYDROXYBUTYLIDENE-LI-BISPHOSPHONIC ACID OR SALTS THEREOF
FIELD OF THE INVENTION
The invention relates to an improved industrial process for the production of 4- amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof.
BACKGROUND OF THE INVENTION
4-amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid commonly known as Alendronic acid is an antihypercalcemic agent effective in the treatment or prevention of diseases involving hypercalcemia of pregnancy, Paget's disease and osteoporosis.
Alendronic acid is marketed as its monosodium salt tri hydrate represented by formula (I) under the brand name FOSAMAX by Merck.
Several methods are known in the art for the synthesis of ω-amino-1- hydroxyalkylidene-1 ,1-bisphosphonic acids in general and 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid in particular. The synthesis consists of reacting the corresponding ω-amino acid with a mixture of phosphorus acid and one of the three phosphorus chlorides PCI3, POCI3 or PCI5, quenching the reaction mixture with water or a non-oxidizing aqueous acid followed by heating to hydrolyze the phosphorous intermediates to the final product.
US Patent No. 4,407,761 teaches a process to prepare 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid wherein the reaction is carried out at about 100 °C in chlorobenzene as a diluent which does not solubilize the reaction components and serves only as a heat transfer agent. The process is unsuitable
for large scale production as the reaction remain a two phase system and gradually thickens into a non-stirrable mass with local solidification.
In US 4,922,007, the above said problem of solidifcation was overcome by using methanesulfonic acid to solubilize the reaction components and keep it fluid up to completion of the reaction.
However, the use of methanesulfonic acid has safety concerns. Methansulfonic acid reacts with PCI3 and under adiabatic conditions the reaction becomes self- heating at 85 °C and an uncontrolled exotherm occurs at >140 0C. This fact was recognized by the inventors in Example 1 of US 4,922,007. The inventors in a subsequent publication J. Org. Chem., 1995, 60, 8310-8312 have mentioned about the safety concerns.
It is evident from the above that there is a need for simple, safe and non hazardous process for the large scale production of 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof.
OBJECT OF THE PRESENT INVENTION
The object of the present invention is to provide a process to prepare 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid or salts that overcomes the non homogeneity, solidification and safety problems associated with prior art synthesis.
The inventors of present invention have found that the use of solvent such as sulfolane overcomes the non homogeneity, solidification and safety problems that are associated with prior art synthesis.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the production of 4- amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof which comprises:
(a) reacting 4-aminobutyric acid with a suitable phosphonating agent in a solvent such as sulfolane
(b) hydrolyzing the resulting reaction mixture by heating with water, (c) recovering the said 4-amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof.
DETEAILED DESCRIPTION OF THE INVENTION
The present invention involves the phosphonylation of 4-aminobutyric acid with a suitable phosphonating agent selected from: a mixture of phosphorous acid and
PCI3, a mixture of phosphorous acid and PCI5, a mixture of phosphorous acid and
POCl3 in a solvent such as sulfolane, diglyme and diphenyl oxide, followed by hydrolysis of the resulting mixture using water and then recovering 4-amino-1- hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof. The phosphonylation reaction is carried out in a solvent such as sulfolane, diglyme and diphenyl oxide at a suitable temperature between 30 °C to 80 ° vr->,
The reaction is schematically represented as follows:
OH
H '02N1N' Y Il 1 ^0O
O
O)
The use of sulfolane overcomes the non homogeneity, solidification and safety problems.
The process of the present invention may also be carried out in other solvents such diglyme and diphenyl oxide.
The phosphonylation of 4-amino butyric acid is preferably carried out using phosphorous acid and phosphorous trichloride
After the completion of the reaction, hydrolysis is carried out by adding water and heating to about 80 0C to 100 °C in water. The 4-amino-1-hydroxybutylidene-1 ,1- bisphosphonic acid or its salt is isolated by adjusting the pH to 4 to 4.5 by the addition of a base such as aq. NaOH or aq. KOH.
In a preferred embodiment 4-amino-1-hydroxybutylidene-1 ,1 -bisphosphonic acid is isolated as its sodium salt.
Figure 1 shows the powder X-ray diffraction pattern for the 4-amino-1- hydroxybutylidene-1 ,1 -bisphosphonic acid mono sodium trihydrate obtained by the process disclosed in the present invention.
4-amino-1-hydroxybutylidene-1 ,1 -bisphosphonic acid monosodium trihydrate in a pharmaceutical composition is useful for treatment of some bone disorders, such as osteoporosis and hypercalcemia of malignancy.
The following example is illustrative of the practice of the invention without being limiting any way.
EXAMPLE
A mixture of 4-amino butyric acid (10 Kg, 97.0 mol) and phosphorous acid (28 Kg, 340.0 mol) in sulfolane (50 lit) was heated to 70-75 ° C for about 30 min and cooled to 40-45 ° C. PCI3 (33.28 Kg, 242.0 mol) was added dropwise at 40-45 0C and stirred at 60-65 0C for 12 hrs. After the completion of the reaction, reaction mixture was cooled to 40-45 0C and water (100 lit) was added and heated to 95- 100 0C for 7 hrs. The reaction mixture was cooled, filtered, and the pH of the filtrate was adjusted to 4.3-4.4 with 50% aqueous NaOH. The formed crude product was filtered and recrystallized in water, washed with cold water (25 lit)
followed by 95 % ethanol (25 lit) and dried under vaccum at 40 0C to get pure 4- amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid mono sodium trihydrate. Yield: 55% Purity by HPLC: 99.92%
Claims
1. A process for the preparation of 4-amino-1-hydroxybutylidene-1 ,1- bisphosphonic acid or salts thereof which comprises:
(a) reacting 4-aminobutyric acid with a phosphonating agent in sulfolane
(b) hydrolyzing the resulting reaction mixture from step (a) by heating with water,
(c) recovering said 4-amino-1-hydroxybutylidene-1 ,1-bisphosphonic acid or salts thereof.
2. The process according to claim 1 , wherein the phosphonating agent is selected from: a mixture of phosphorous acid and PCI3, a mixture of phosphorous acid and PCI5, a mixture of phosphorous acid and POCI3.
3. The process according to claim 1 and claim 2, wherein the phosphonating agent is phosphorous acid and PCI3.
4. The process according to claim 1 , wherein step (a) is conducted at a temperature of about 30 to 80 °C.
5. The process according to claim 1 , wherein step (b) is conducted at a temperature of about 80 to 100 °C.
6. The process according to claim 1 wherein 4-amino-1-hydroxybutylidene- 1 ,1-bisphosphonic acid is recovered as its monosodium salt trihydrate.
7. The process according to claim 1 wherein 4-amino-1-hydroxybutylidene- 1 ,1-bisphosphonic acid is recovered.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN636KO2005 | 2005-07-20 | ||
| IN636/KOL/2005 | 2005-07-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007010556A1 true WO2007010556A1 (en) | 2007-01-25 |
Family
ID=37420743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2006/000255 WO2007010556A1 (en) | 2005-07-20 | 2006-07-18 | Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2007010556A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008056129A1 (en) * | 2006-11-06 | 2008-05-15 | Hovione Inter Limited | Process for the preparation of biphosphonic acids and salts thereof |
| CN101284848B (en) * | 2008-06-10 | 2013-09-11 | 石药集团欧意药业有限公司 | Synthetic method of clinic effect of alendronate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005044831A2 (en) * | 2003-08-21 | 2005-05-19 | Sun Pharmaceutical Industries Limited | A process for preparation of bisphosphonic acid compounds |
-
2006
- 2006-07-18 WO PCT/IN2006/000255 patent/WO2007010556A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005044831A2 (en) * | 2003-08-21 | 2005-05-19 | Sun Pharmaceutical Industries Limited | A process for preparation of bisphosphonic acid compounds |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008056129A1 (en) * | 2006-11-06 | 2008-05-15 | Hovione Inter Limited | Process for the preparation of biphosphonic acids and salts thereof |
| CN101284848B (en) * | 2008-06-10 | 2013-09-11 | 石药集团欧意药业有限公司 | Synthetic method of clinic effect of alendronate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2018477C (en) | Process for preparing 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic, acid monosodium salt trihydrate | |
| EP0971938B1 (en) | Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof | |
| US7439385B2 (en) | Process for the preparation of biphosphonic derivatives | |
| US20080194525A1 (en) | Process of Making Geminal Bisphosphonic Acids and Pharmaceutically Acceptable Salts and/or Hydrates Thereof | |
| US7361761B2 (en) | Process for the preparation of bisphosphonic acid | |
| JP3911287B2 (en) | Method for preparing 4-amino-1-hydroxybutylidene-1,1-biphosphonic acid (4-Amino-1-hydroxybutyride-1,1-biphosphonicacid) | |
| EP1836210B1 (en) | Process for the preparation of [1-hydroxy-2-(3-pyridinyl)ethyliden]bisphosphonic acid and hemi-pentahydrate monosodium salt thereof | |
| WO2007010556A1 (en) | Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof | |
| US8076483B2 (en) | Process for the preparation of pure risedronic acid or salts | |
| WO2007068678A1 (en) | Process for the preparation of 3-pyridyl-1-hydroxyethylidene-1,1-biphosphonic acid and hydrated forms thereof | |
| US7414151B2 (en) | Process for manufacture of 4-amino-hydroxybutylidene-1, 1-bisphosphonic acid and its salts | |
| JP5220843B2 (en) | Multi-step synthesis of ibandronate | |
| US20100317859A1 (en) | Process for the Preparation of Risedronate Sodium | |
| EP2609101B1 (en) | Process for the preparation of 3-(n-methyl-n-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid salt or derivatives thereof | |
| WO2008035131A1 (en) | An improved process for the preparation of bisphosphonic acid | |
| JP4437887B2 (en) | Method for producing N4-acyl-2'-deoxycytidines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| WWW | Wipo information: withdrawn in national office |
Country of ref document: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 06780536 Country of ref document: EP Kind code of ref document: A1 |