WO2007056417A2 - Synthesis of alendronate sodium trihydrate - Google Patents
Synthesis of alendronate sodium trihydrate Download PDFInfo
- Publication number
- WO2007056417A2 WO2007056417A2 PCT/US2006/043422 US2006043422W WO2007056417A2 WO 2007056417 A2 WO2007056417 A2 WO 2007056417A2 US 2006043422 W US2006043422 W US 2006043422W WO 2007056417 A2 WO2007056417 A2 WO 2007056417A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- water
- sodium
- synthesis
- alendronic acid
- alendronate sodium
- Prior art date
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 27
- 229960004343 alendronic acid Drugs 0.000 title claims abstract description 27
- 230000015572 biosynthetic process Effects 0.000 title abstract description 7
- 238000003786 synthesis reaction Methods 0.000 title abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- 239000002002 slurry Substances 0.000 abstract description 5
- 238000002425 crystallisation Methods 0.000 abstract description 4
- 230000008025 crystallization Effects 0.000 abstract description 4
- 159000000000 sodium salts Chemical class 0.000 abstract description 3
- DCSBSVSZJRSITC-UHFFFAOYSA-M alendronate sodium trihydrate Chemical compound O.O.O.[Na+].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O DCSBSVSZJRSITC-UHFFFAOYSA-M 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- 150000004682 monohydrates Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003518 caustics Substances 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 239000002920 hazardous waste Substances 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 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 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
Definitions
- This invention describes a process for the synthesis of alendronate sodium trihydrate from the reaction of alendronic acid, either anhydrous or in a hydrated state, in an aqueous slurry with sodium hydroxide in water.
- the pH is adjusted into the range 4.3 — 4.4, the solution is concentrated and the sodium salt thus formed is isolated by crystallization from water.
- the current manufacturing process for alendronate sodium trihydrate is a three step manufacturing process that relies on the use of a continuous reactor for the production of sodium
- This invention provides processes for the preparation of a compound of formula I:
- I comprising the steps : a) reacting alendronic acid with strong base in water; b) adjusting the pH to between 4.3 and 4.4; c) concentrating the solution; d) crystallizing the salt from water.
- a slurry of alendronic acid in water is reacted with a strong base. This step is performed at a temperature of about 40 0 C to about 6O 0 C. In a subclass of the invention, this step is performed at a temperature of about 58°C to about 60 0 C.
- the alendronic acid is anhydrous or hydrated. In a subclass of the invention, the alendronic acid is monohydrated.
- the strong base is sodium hydroxide, sodium carbonate or sodium hydrogen carbonate. In a subclass of the invention, the strong base is sodium hydroxide.
- the pH is adjusted to between 4.3 and 4.4.
- the pH can be adjusted with sodium hydroxide or hydrochloric acid, or with other acids and bases as is known in the art.
- the solution is then concentrated by methods known in the art, including distillation and reverse osmosis.
- the solution is concentrated by distillation.
- alendronate sodium trihydrate salt is crystallized from water. This crystallization can also be performed with seeding.
- Schemes 1 & 2 describe processes for the synthesis of alendronate sodium trihydrate from the reaction of alendronic acid (either anhydrous or hydrated) in an aqueous slurry with sodium hydroxide in water at temperature of 58 — 60°C.
- the pH is adjusted into the range 4.3 — 4.4, the solution is concentrated and the sodium salt thus formed is isolated by crystallization.
- the batch is filtered at 58 - 60 0 C & concentrated to a final volume of 0.132 Its (228 g/lt) where it is cooled to 0 - 5°C (2°C actual) and aged for a minimum of 10 hours. The batch is then isolated and washed with 10 mis of DIW pre-cooled to 1-5°C.
- the batch is dried to a LOD specification of 16.1 - 17.1 % w/w.
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention describes a process for the synthesis of alendronate sodium trihydrate from the reaction of alendronic acid, either anhydrous or in a hydrated state, in an aqueous slurry with sodium hydroxide in water. The pH is adjusted into the range 4.3 - 4.4, the solution is concentrated and the sodium salt thus formed is isolated by crystallization from water.
Description
TITLE OF THE INVENTION
SYNTHESIS OF ALENDRONATE SODIUM TRIHYDRATE
BACKGROUND OF THE INVENTION This invention describes a process for the synthesis of alendronate sodium trihydrate from the reaction of alendronic acid, either anhydrous or in a hydrated state, in an aqueous slurry with sodium hydroxide in water. The pH is adjusted into the range 4.3 — 4.4, the solution is concentrated and the sodium salt thus formed is isolated by crystallization from water.
The current manufacturing process for alendronate sodium trihydrate is a three step manufacturing process that relies on the use of a continuous reactor for the production of sodium
Pyrophosphonate from GABA (γ-aminobutyric acid), which is described in U.S. Patent No. 5,510,517. The instant invention provides safety and environmental advantages over the current manufacturing process.
With the current manufacturing process, there is a large decomposition exotherm in Sodium Pyrophosphonate @ ~ 1200C, which results if the reaction mass is allowed to heat adiabatically. Strict controls, such as the emergency quench and the use of a continuous reactor to minimise reaction volumes, contribute to safe running of the reactor. In addition, the crude step involves a pressure hydrolysis. The process of the instant invention eliminates both of these steps, and thus results in a process that is safer to run. Furthermore, the current process is reliant on the use of hazardous raw material such as
Phosphorous Acid, Phosphorous Trichloride (PCl3) and Methane Sulphonic Acid (MSA). Manipulating these substances on such a large scale represents a significant challenge to manufacturing personnel. Also, the current process produces hazardous waste that must be incinerated. The process of the instant invention eliminates the reliance on hazardous raw materials and limits the production of hazardous wastes.
SUMMARY OF THE INVENTION
This invention provides processes for the preparation of a compound of formula I:
comprising reacting alendronic acid with strong base in water; adjusting the pH to 4.3-4.4; concentrating the solution; and crystallizing the salt from water.
DETAILED DESCRIPTION OF THE INVENTION
A process for preparing a compound of formula I:
I comprising the steps : a) reacting alendronic acid with strong base in water; b) adjusting the pH to between 4.3 and 4.4; c) concentrating the solution; d) crystallizing the salt from water. A slurry of alendronic acid in water is reacted with a strong base. This step is performed at a temperature of about 400C to about 6O0C. In a subclass of the invention, this step is performed at a temperature of about 58°C to about 600C. In a class of the invention, the alendronic acid is anhydrous or hydrated. In a subclass of the invention, the alendronic acid is monohydrated. In another class of the invention, the strong base is sodium hydroxide, sodium carbonate or sodium hydrogen carbonate. In a subclass of the invention, the strong base is sodium hydroxide.
After the strong base is reacted with the alendronic acid, the pH is adjusted to between 4.3 and 4.4. The pH can be adjusted with sodium hydroxide or hydrochloric acid, or with other acids and bases as is known in the art.
The solution is then concentrated by methods known in the art, including distillation and reverse osmosis. Optionally, the solution is concentrated by distillation.
Finally, the alendronate sodium trihydrate salt is crystallized from water. This crystallization can also be performed with seeding.
Schemes 1 & 2 describe processes for the synthesis of alendronate sodium trihydrate from the reaction of alendronic acid (either anhydrous or hydrated) in an aqueous slurry with sodium hydroxide in water at temperature of 58 — 60°C. The pH is adjusted into the range 4.3 — 4.4, the solution is concentrated and the sodium salt thus formed is isolated by crystallization.
SCHEME l
SYNTHESIS OF ALENDRONATE SODIUM TRIHYDRATE FROM ALENDRONIC ACID
MONOHYDRATE
ALENDRONATE SODIUM TRIHYDRATE
SCHEME 2
SYNTHESIS OF ALENDRONATE SODIUM TRUΪYDRATE FROM ALENDRONIC ACID
ANHYDROUS
A
ALENDRONATE SODIUM TRIHYDRATE
The following example further illustrates the details for the preparation of the alendronate sodium trihydrate. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedure can be used to prepare this compound. All temperatures are degrees Celsius unless otherwise noted.
EXAMPLE 1
PREPARATION OF ALENDRONATE SODIUM TRIHYDRATE FROM ALENDRONIC ACID
(MONOHYDRATE OR ANHYDROUS)
To a slurry of Alendronϊc Acid Monohydrate (24.7 g, 92.5 mmol) in water (~ 286 g, 15.88 mol) at 58 - 600C was added, dropwise a solution of 47% caustic (~ 7.95 g, 3.695 g as NaOH, 92.5 mmol) in water (~ 20 g, 1.11 mol) over ~ 30 minutes. The batch dissolves as the caustic is added. The pH is adjusted into the range 4.3 - 4.4 at 58 — 600C with sodium hydroxide or hydrochloric acid.
The batch is filtered at 58 - 600C & concentrated to a final volume of 0.132 Its (228 g/lt) where it is cooled to 0 - 5°C (2°C actual) and aged for a minimum of 10 hours. The batch is then isolated and washed with 10 mis of DIW pre-cooled to 1-5°C.
The batch is dried to a LOD specification of 16.1 - 17.1 % w/w.
Claims
1. A process for preparing a compound of formula I:
comprising the steps :
a) reacting alendronic acid with strong base in water; b) adjusting the pH to between 4.3 and 4.4; c) concentrating the solution; d) crystallizing the salt from water.
2. The process of Claim 1 wherein the alendronic acid is anhydrous or hydrated.
3. The process of Claim 3 wherein the alendronic acid is monohydrated.
4. The process of Claim 1 wherein the strong base is sodium hydroxide, sodium carbonate or sodium hydrogen carbonate.
5. The process of Claim 4 wherein the strong base is sodium hydroxide.
6. The process of Claim 2 wherein step a) is performed at a temperature of about
400C to about 600C.
7. The process of Claim 6 wherein step a) is performed at a temperature of about
58°C to about 600C.
8. The process of Claim 1 wherein the solution is concentrated by distillation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US73417905P | 2005-11-07 | 2005-11-07 | |
| US60/734,179 | 2005-11-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2007056417A2 true WO2007056417A2 (en) | 2007-05-18 |
| WO2007056417A3 WO2007056417A3 (en) | 2007-07-05 |
Family
ID=37944596
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2006/043422 WO2007056417A2 (en) | 2005-11-07 | 2006-11-03 | Synthesis of alendronate sodium trihydrate |
Country Status (3)
| Country | Link |
|---|---|
| AR (1) | AR058168A1 (en) |
| TW (1) | TW200736268A (en) |
| WO (1) | WO2007056417A2 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5510517A (en) * | 1993-08-25 | 1996-04-23 | Merck & Co., Inc. | Process for producing N-amino-1-hydroxy-alkylidene-1,1-bisphosphonic acids |
| WO1998034940A1 (en) * | 1997-02-11 | 1998-08-13 | Apotex Inc. | Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid |
| WO2000012517A1 (en) * | 1998-08-27 | 2000-03-09 | Teva Pharmaceutical Industries Ltd. | Novel hydrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof |
-
2006
- 2006-10-30 AR ARP060104748 patent/AR058168A1/en not_active Application Discontinuation
- 2006-11-03 WO PCT/US2006/043422 patent/WO2007056417A2/en active Application Filing
- 2006-11-03 TW TW095140904A patent/TW200736268A/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5510517A (en) * | 1993-08-25 | 1996-04-23 | Merck & Co., Inc. | Process for producing N-amino-1-hydroxy-alkylidene-1,1-bisphosphonic acids |
| WO1998034940A1 (en) * | 1997-02-11 | 1998-08-13 | Apotex Inc. | Process for the production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid |
| WO2000012517A1 (en) * | 1998-08-27 | 2000-03-09 | Teva Pharmaceutical Industries Ltd. | Novel hydrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| TW200736268A (en) | 2007-10-01 |
| WO2007056417A3 (en) | 2007-07-05 |
| AR058168A1 (en) | 2008-01-23 |
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