Home Cart 0 Sign in  

[ CAS No. 121268-17-5 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 121268-17-5
Chemical Structure| 121268-17-5
Structure of 121268-17-5 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 121268-17-5 ]

Related Doc. of [ 121268-17-5 ]

Alternatived Products of [ 121268-17-5 ]

Product Details of [ 121268-17-5 ]

CAS No. :121268-17-5 MDL No. :MFCD01748233
Formula : C4H18NNaO10P2 Boiling Point : -
Linear Structure Formula :- InChI Key :DCSBSVSZJRSITC-UHFFFAOYSA-M
M.W : 325.12 Pubchem ID :23681107
Synonyms :
Alendronate;MK 217;Fosamax;Adronat;Alendronate (sodium hydrate);G-704650;Alendronate sodium trihydrate;G-704650 Adronat

Safety of [ 121268-17-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 121268-17-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 121268-17-5 ]
  • Downstream synthetic route of [ 121268-17-5 ]

[ 121268-17-5 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 66376-36-1 ]
  • [ 121268-17-5 ]
YieldReaction ConditionsOperation in experiment
79% With sodium carbonate In water for 3 h; Heating All chemicals were commercially purchased from Sigma Aldrich and used without further purification. Sodium carbonate, Na2CO3 (1.06 g, 10 mmol), and alendronic acid (2.49 g, 10 mmol) were added to water (100 mL), and after the evolution of CO2 ceased, the reaction mixture was heated and stirred for ca 3 h. The white crystalline precipitate was washed with hot water and dried at room temperature (yield 1.96 g, 79percent), m.p. 257–260 °C. Anal. Calcd for C4H12NO7P2Na (percent): C 19.27, H 4.82, N 5.62. Found (percent): C 19.43, H 4.76, N 5.52.
Reference: [1] Structural Chemistry, 2018, vol. 29, # 5, p. 1525 - 1531
[2] Patent: WO2005/44831, 2005, A2, . Location in patent: Page/Page column 11
[3] Patent: US2007/66569, 2007, A1, . Location in patent: Page/Page column 2
[4] Patent: WO2007/56417, 2007, A2, . Location in patent: Page/Page column 4
[5] Patent: WO2008/35131, 2008, A1, . Location in patent: Page/Page column 7
[6] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1624 - 1629
[7] Patent: WO2008/35131, 2008, A1, . Location in patent: Page/Page column 7
  • 2
  • [ 1310-73-2 ]
  • [ 121268-17-5 ]
YieldReaction ConditionsOperation in experiment
69.6%
Stage #1: With phosphorous acid; phosphorus trichloride In acetonitrile at 55 - 75℃; for 6 - 9 h;
Stage #2: With water In acetonitrile at 60 - 100℃; for 4 - 6 h;
Stage #3: at 55 - 65℃;
Example 3: Preparation of alendronic acid monosodium salt; A mixture of 4-amino-butyric acid (10. Og, 0.097mol) and phosphorous acid (15.9g, 0.194mol) in acetonitrile (150ml) was heated at a temperature of 55-65°C and phosphorous trichloride (26.6g, 0.194mol) was added slowly under stirring. After completion of the addition, the reaction temperature was raised to 70-750C and the reaction continued for 6-9 hours at the same temperature. The reaction mixture was cooled to 60-650C and water (150ml) was added slowly at the same temperature. The reaction temperature was then increased to 90-1000C and maintained for the next 4-6 hours. The reaction mixture was then cooled to 55-65°C and the reaction mixture pH was adjusted to 4.4-4.8 with sodium hydroxide solution. The reaction mixture was cooled to 25-35°C and the aqueous layer containing the product was separated from the upper acetonitrile layer. The aqueous layer was cooled to and maintained at 0-50C for 3 hours. The solid product was separated by filtration and washed with water and finally with methanol to obtain sodium alendronate. The product was dried in a vacuum oven at 45-5O0C until loss on drying was less than 0.5percent w/w. Yield: 16g (69.6percent). Appearance: almost white powder. Melting range: 234- 238°C (with decomposition).
Reference: [1] Patent: WO2008/4000, 2008, A1, . Location in patent: Page/Page column 20
  • 3
  • [ 56-12-2 ]
  • [ 121268-17-5 ]
YieldReaction ConditionsOperation in experiment
82% With phosphorous acid; phosphorus trichloride In methanesulfonic acid at 65℃; Step 1:
Synthesis of 4-amino-1-hydroxybutylidene)bisphosphonic acid (alendronate)
4-Aminobutyric acid (20 g, 0.19 mol) and one equivalent of phosphorous acid H3PO3 (16 g, 0.19) were put in a 250-mL four-necked flask equipped with a mechanical stirrer, a thermometer, and a dropping funnel.
They were dissolved in a minimum of methanesulfonic acid and then the reaction mixture was heated to 65° C.
Maintaining the temperature at 65° C., two equivalents of phosphorus trichloride PCl3 (35 mL, 0.40 mol) were added dropwise in 20 minutes.
The reaction mixture was then stirred at 65° C. overnight.
Next, the reaction mixture was quenched, using iced distilled water, and then the mixture obtained was transferred to a 500-mL three-necked flask.
The mixture was refluxed for 5 hours.
The reaction mixture was brought back to room temperature using an ice bath.
Using an aqueous solution of NaOH at 50percent (by weight), the pH was adjusted to 4.3 to promote precipitation of the bisphosphonic acid.
The precipitate was filtered and dried under vacuum.
Purification of the alendronate consists of performing several washings with anhydrous methanol until the methanesulfonic acid has been removed.
The precipitate was then dried overnight in a heated desiccator (at 40° C.)
Yield: 82percent
IR (cm-1): 1524, 1473, 1168, 1073, 913 cm-1
1H NMR (500 MHz, D2O): 2.93 (m, 2H), 1.88 (m, 4H)
31P NMR {1H} (80.9 MHz, H3PO4/D2O): 18.5 (s).
69.6%
Stage #1: With phosphonic Acid; phosphorus trichloride In acetonitrile at 55 - 75℃;
Stage #2: With water In acetonitrile at 60 - 100℃;
Stage #3: With sodium hydroxide In water; acetonitrile at 55 - 65℃;
A mixture of 4-amino-butyric acid (10.0 g, 0.097 mol) and phosphorous acid (15.9 g, 0.194 mol) in acetonitrile (150 ml) was heated at a temperature of 55-65° C. and phosphorous trichloride (26.6 g, 0.194 mol) was added slowly under stirring. After completion of the addition, the reaction temperature was raised to 70-75° C. and the reaction continued for 6-9 hours at the same temperature. The reaction mixture was cooled to 60-65° C. and water (150 ml) was added slowly at the same temperature. The reaction temperature was then increased to 90-100° C. and maintained for the next 4-6 hours. The reaction mixture was then cooled to 55-65° C. and the reaction mixture pH was adjusted to 4.4-4.8 with sodium hydroxide solution. The reaction mixture was cooled to 25-35° C. and the aqueous layer containing the product was separated from the upper acetonitrile layer. The aqueous layer was cooled to and maintained at 0-5° C. for 3 hours. The solid product was separated by filtration and washed with water and finally with methanol to obtain sodium alendronate. The product was dried in a vacuum oven at 45-50° C. until loss on drying was less than 0.5percent w/w. Yield: 16 g (69.6percent). Appearance: almost white powder. Melting range: 234-238° C. (with decomposition).
60%
Stage #1: at 75℃; for 12 h;
Stage #2: at 105℃; for 3 h;
Stage #3: at 20℃;
2.6 g (0.025 mol) of -γaminobutyric acid and 6.2 g (0.075mol) of phosphorous acid was added into 6.8 mL of MSA on stirring. Then 7.0 mL (0.075 mol) of phosphoryl chloride was added dropwise in ca. 15 min, and the contents of the flask were stirred at 75°C for 12 h. After cooling the mixture to 26°C, 19 mL (1.1 mol) of water was added and the mixture was stirred further at 105°C for 4 h. The pH was adjusted to 1.8 by adding ~12 mL of 50percent aqueous sodium hydroxide to the mixture. Then, the mixture was stirred at room temperature for 2 h and the precipitate was removed by filtration. The crude product was suspended in 50 mL ofwater and the mixture was stirred at 100°C for 1 h, then the pH was adjusted to 4,5. After cooling the mixture to 26°C, the solid product was filtered off to give 5.0 g (60percent) of sodium alendronate trihydrate (8) in a purity of 97percent.
49.2%
Stage #1: at 42 - 75℃; for 5.75 - 7.5 h;
Stage #2: With sodium hydroxide In water at 2 - 103℃; for 3 - 8.75 h;
EXAMPLE 1
Preparation of Alendronate Sodium Trihydrate
100 g of 4-aminobutyric acid and 400 ml of p-cresol were taken in a clean and dry round bottom flask followed by stirring for about 15 minutes.
To the resultant solution 120 g of phosphorous acid was added and the mixture subjected to heating to a temperature of about 42° C. with simultaneous stirring.
270 ml of phosphorous trichloride was slowly added to the above reaction mixture at about 62° C. over about 45 minutes.
The resultant suspension was heated to about 75° C. for about 5 hours followed by cooling to about 27° C. 400 ml of water was added to the with simultaneous stirring followed by separating the aqueous layer from the organic layer.
400 ml of water was added to the aqueous layer and subjected to stirring followed by separating the aqueous layer.
The aqueous layer was heated to a temperature of about 103° C. with simultaneous stirring.
The pH of the mass was adjusted to about 4.6 by the addition of a mixture of 412 ml of 50percent aqueous sodium hydroxide solution followed by stirring at about 22° C. for about 3 hours and cooling to 5° C.
The obtained solid was filtered under vacuum followed by washing with 250 ml of chilled water and drying at a temperature of about 65° C. under vacuum to afford 155.0 g (49.2percent) of alendronate sodium trihydrate.
Purity by HPLC: 97.04percent.
4-aminobutyric acid impurity: 0.38percent
Macromer impurity: 2.58percent.
EXAMPLE 3
Preparation of Alendronate Sodium Trihydrate
80 liters of p-cresol was taken into a reactor followed by the addition of 20 kg of 4-aminobutyric acid and 24 kg of phosphorous acid, and the mass was subjected to heating to a temperature of about 62.5° C. for a period of about 1.5 hours. 54 liters of phosphorous trichloride was added to the above reaction mass and subjected to heating to a temperature of about 73.6 for a period of about 6 hours. 140 liters of water was taken into another reactor and cooled to a temperature of about 13° C. followed by the addition of the above obtained reaction mass and subjected to stirring for a period about 30 minutes. The thus obtained mass was subjected to heating at a temperature of about 43.4° C. for a period of about 15 minutes and allowed to settle for a period of about 45 minutes. The aqueous layer was separated and subjected to heating to reflux at 98.9° C. for a period of about 5 hours, followed by cooling to a temperature of about 44.5° C. over a period of about 30 minutes with simultaneous stirring. The reaction mass was allowed to settle for a period of about 45 minutes and the aqueous layer was separated. 90 liters of aqueous sodium hydroxide solution was slowly added to the aqueous layer to produce a pH of 4.33. The reaction mass was subjected to stirring for a period of about 45 minutes followed by cooling to a temperature of about 2° C. over a period of about 8 hours. Finally, the obtained solid material was subjected to centrifugation followed by washing with precooled water and then subjected to centrifugation to afford 34.8 kg of alendronate sodium trihydrate. Purity by HPLC: 99.62 weight percent. 4-amino butyric acid: Not detected. Macromer impurity: 0.37 weight percent. Loss on drying: 17.12percent w/w.
41%
Stage #1: With phosphonic Acid; phosphorus trichloride In sulfolane at 25 - 65℃; for 0.116667 h; Microwave irradiation
Stage #2: With water; sodium hydroxide In sulfolane at 150℃; for 0.166667 h; Microwave irradiation
3.8 mmol (1 equiv) of the respective carboxylic acid (658 mg 3-pyridylacetic acid hydrochloride for 1, 478 mg imidazol-1-yl-acetic acid for 2, 339 mg β-alanine for 3, 392 mg γ-aminobutyric acid for 4, 499 mg 6-aminohexanoic acid for 5) were added to 11.4 mmol (3 equiv) H3PO3 in a dry flask. 1.6 mL of distilled sulfolane was added and the contents were heated briefly to dissolve the solids. The solution was cooled down to approximately 25-35 °C, and 11.4 mmol (3 equiv) of PCl3 were immediately added. The flask was then placed in a Milestone Ethos Synth Microwave Synthesis Labstation and fitted with a condenser through which cold water was passed. The following microwave programs were applied:For synthesis of 1: 3 min ramp to 65 °C, followed by 15 s at 65 °C. For synthesis of 2: 3 min ramp to 65 °C, followed by 45 s at 65 °C.For synthesis of 3: 3 min ramp to 65 °C, followed by 15 s at 65 °C.For synthesis of 4: 3 min ramp to 65 °C, followed by 4 min at 65 °C.For synthesis of 5: 3 min ramp to 65 °C, followed by 4 min at 65 °C.The power was automatically adjusted to reach and maintain the temperature designated by the program, which is determined by a built-in IR sensor in the microwave reactor. For the synthesis of intermediates 1 and 2, the power fluctuated between 0 and a max of 300-400 W, while for 3, 4, and 5, the max power was typically 200-300 W.The solid mixture after microwave irradiation consists of intermediate phosphorus compound together with a yellow-orange unwanted side product which can be removed by centrifugation before or after hydrolysis. The reaction mixture was quenched with 6 mL of H2O, yielding a clear solution that was then transferred to a 50 mL sealed quartz reaction vessel and was hydrolyzed to the bisphosphonic acid in the microwave reactor with a 6 min ramp to 150 °C, followed by 4 min at 150 °C. The power applied fluctuated between 0 and a max of 450-500 W. The pH of the hydrolysis mixtures for acids 1, 3, 4, and 5 was adjusted15 with NaOH and the mixture then aged at 0-5 °C until crystallization of the products was complete. Acids 4 and 5 were precipitated as monosodium salts by stirring with 2-5 mL ethanol for 1-2 h at room temperature. Acid 2 was precipitated by the addition of 9 mL acetone to the acidic hydrolysis mixture and stirring for 3-4 h at room temperature. The white crystalline products were then filtered and washed with cold H2O and acetone or ethanol and then dried under vacuum at 45 °C to constant weight.15 with NaOH and the mixture then aged at 0-5 °C until crystallization of the products was complete. Acids 4 and 5 were precipitated as monosodium salts by stirring with 2-5 mL ethanol for 1-2 h at room temperature. Acid 2 was precipitated by the addition of 9 mL acetone to the acidic hydrolysis mixture and stirring for 3-4 h at room temperature. The white crystalline products were then filtered and washed with cold H2O and acetone or ethanol and then dried under vacuum at 45 °C to constant weight.

Reference: [1] Bioconjugate Chemistry, 2014, vol. 25, # 2, p. 224 - 230
[2] Patent: US2015/150981, 2015, A1, . Location in patent: Paragraph 0447; 0448; 0449; 0450; 0451; 0452; 0453
[3] Heteroatom Chemistry, 2017, vol. 28, # 3,
[4] Patent: US2009/198062, 2009, A1, . Location in patent: Page/Page column 7
[5] Letters in Drug Design and Discovery, 2015, vol. 12, # 4, p. 253 - 258
[6] Patent: US2007/142636, 2007, A1, . Location in patent: Page/Page column 6-7; 7
[7] Tetrahedron Letters, 2011, vol. 52, # 18, p. 2285 - 2287
[8] Journal of Organic Chemistry, 1995, vol. 60, # 25, p. 8310 - 8312
[9] Patent: US2007/142636, 2007, A1, . Location in patent: Page/Page column 8
[10] Patent: US2007/142636, 2007, A1, . Location in patent: Page/Page column 7-8
[11] Patent: US2007/142636, 2007, A1, . Location in patent: Page/Page column 8
[12] Patent: US2007/173645, 2007, A1, . Location in patent: Page/Page column 3-4
[13] Patent: US2007/173645, 2007, A1, . Location in patent: Page/Page column 3
[14] Patent: US2007/173645, 2007, A1, . Location in patent: Page/Page column 4
  • 4
  • [ 616-45-5 ]
  • [ 121268-17-5 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: With phosphorus trichloride In water at 65 - 110℃; for 7.33333 - 7.41667 h;
Stage #2: at 60 - 75℃; for 9 h;
EXAMPLE 1 To a 250 ml reaction vessel equipped with a water condenser, 8.5 gm (0.1 mol) pyrrolidone, and 33.5 ml water was added under nitrogen atmosphere. Then, 17.2 gm (0.125 mol) PCl3 was added drop-wise to the mixture while stirring for 20-25 minutes below 65° C., and then it was heated to reflux (i.e., 105 to 110° C.) for 7 hours or until the disappearance of pyrrolidone was observed (monitored by TLC method). The water from the reaction mass was then distilled off after complete disappearance of pyrrolidone. The mass was then cooled to 60° C. and mixed with 59.24 gm methane sulphonic acid and 41.39 gm (0.3 mol) PCl3 was added drop-wise while maintaining the temperature below 75° C. The reaction mixture was further maintained at 75° C. for 9 hours. On completion of phosphonation, the reaction mixture was cooled to 40° C., and then 85 ml of water was added and refluxed for 6 hours. The mass was cooled to 70-75° C. and treated with charcoal (0.1 gm) and filtered. The filtrate was adjusted to a pH of 4.3 by mixing with 50-percent sodium hydroxide solution and cooled to 0-5° C. for 8 hours. The precipitated sodium alendronate was filtered off, washed with cold water, and dried under vacuum at 50° C. to produce 26.8 gm of product (yield 82percent), having a melting point of between 255 and 258° C.
82%
Stage #1: at 65 - 110℃; for 7.33333 - 7.41667 h; Heating / reflux
Stage #2: at 60 - 75℃; for 9 h;
Example 1 To a 250 ml reaction vessel equipped with water condenser, 8.5 gm (0.1 mol) pyrrolidone, and 33.5 ml water was added under nitrogen atmosphere. Then 17.2 gm (0.125 mol) PCl3 was added drop-wise to the mixture under stirring over 20 - 25 minutes below 65 °C and was heated to reflux (105 -110 °C) for 7 hours or till the disappearance of pyrrolidone (monitored by TLC method). The water from the reaction mass was distilled off after complete disappearance of pyrrolidone. The mass was then cooled to 60 °C and mixed with 59.24 gm methane sulphonic acid and 41.39 gm (0.3 mol) PCl3 was added drop-wise while maintaining the temperature below 75 °C. The reaction mixture was further maintained at 75 °C for 9 hours. On completion of phosphonation, reaction mixture cooled to 40 °C and 85 ml of water was added and was refluxed 6 hours. Mass was cooled to 70 -75 °C and treated with charcoal (0.1 gm) and filtered. The filtrate was adjusted to a pH of 4.3 by mixing with 50percent sodium hydroxide solution and cooled to 0-5 °C for 8 hours. The precipitated sodium alendronate was filtered off, washed with cold water and dried under vacuum at 50 °C gave 26.8 gm title product (yield 82percent), melting point 255 - 258 °C.
81%
Stage #1: at 20 - 110℃; for 3.33333 - 8.41667 h; Heating / reflux
Stage #2: at 60 - 75℃; for 9 h;
Example 2 In a 250 reaction vessel equipped with water condenser, 8.5 gm (0.1 mol) pyrrolidone, 14 ml water and 11.5 gm methane sulphonic acid was added under nitrogen atmosphere. At room temperature 17.2 gm (11 ml, 0.125 mol) PCl3 was added drop-wise to the mixture under stirring over 20 -25 minutes while maintaining temperature below 65 °C and was heated to reflux (105-110 °C) for 8 hours or till the disappearance of pyrrolidone (monitored by TLC method). The mass was then cooled to 60 °C and mixed with 48.13 gm methanesulphonic acid and 55.26 gm PCl3 (0.402 mol) was added drop-wise while maintaining the temperature below 75 °C. The reaction mixture was further maintained at 75 °C for 9 hours. On completion of phosphonation, reaction mixture cooled to 40 °C and 85 ml of water was added and was refluxed 6 hours. Mass was cooled to 70 -75 °C and treated with charcoal (0.1 gm) and filtered. The filtrate was adjusted to a pH of 4.3 by mixing with 50percent sodium hydroxide solution and cooled to 0-5 °C for 8 hours. The precipitated sodium alendronate was filtered off, washed with cold water and dried under vacuum at 50 °C gave 26.4 gm title product (yield 81 percent), melting point 255 - 258 °C; Example 4 In a 250 reaction vessel equipped with water condenser, 8.5 gm (0.1 mol) pyrrolidone, 33.5 ml water and 11.5 g methane sulphonic acid was added under nitrogen atmosphere. At room temperature 17.2 gm (11 ml, 0.125 mol) PCl3 was added drop-wise to the mixture under stirring over 20 -25 minutes while maintaining temperature below 65 °C and was heated to reflux (105-110 °C) for 3 hours or till the disappearance of pyrrolidone (monitored by TLC method). The water present in the reaction mass was then removed by distillation. The mass was then cooled to 60 °C and mixed with 48.2 gm methanesulphonic acid and 41.39 gm (0.3 mol) PCl3 was added drop-wise while maintaining the exotherm below 75 °C. The reaction mixture was further maintained at 75 °C for 9 hours. On completion of phosphonation, reaction mixture cooled to 40 °C and 85 ml of water was added and was refluxed 6 hours. Mass was cooled to 70 - 75 °C and treated with charcoal (0.1 gm) and filtered. The filtrate was adjusted to a pH of 4.3 by mixing with 50percent sodium hydroxide solution and cooled to 0-5 °C for 8 hours. The precipitated sodium alendronate was filtered off, washed with cold water and dried under vacuum at 50 °C gave 26.4 gm title product (yield 81percent), melting point 255 - 258 °C.
81%
Stage #1: With methanesulfonic acid; phosphorus trichloride In water at 20 - 110℃; for 12.3333 - 17.4167 h;
Stage #2: at 40℃; for 6 h; Heating / reflux
Stage #3: With sodium hydroxide In water at 0 - 5℃; for 8 h;
EXAMPLE 2; In a 250 reaction vessel equipped with a water condenser, 8.5 gm (0.1 mol) pyrrolidone, 14 ml water, and 11.5 gm methane sulphonic acid were added under a nitrogen atmosphere. At room temperature, 17.2 gm (11 ml, 0.125 mol) PCl3 was added drop-wise to the mixture while stirring for 20 to 25 minutes while maintaining the temperature below 65° C. Then, the mixture was heated to reflux (i.e., 105 to 110° C.) for 8 hours or till the disappearance of pyrrolidone was observed (monitored by TLC method). The mass was then cooled to 60° C. and mixed with 48.13 gm methanesulphonic acid and 55.26 gm PCl3 (0.402 mol) was added drop-wise while maintaining the temperature below 75° C. The reaction mixture was further maintained at 75° C. for 9 hours. On completion of phosphonation, the reaction mixture was cooled to 40° C., and then 85 ml of water was added and refluxed for 6 hours. The mass was cooled to 70 to 75° C. and treated with charcoal (0.1 gm), and then filtered. The filtrate was adjusted to a pH of 4.3 by mixing it with 50-percent sodium hydroxide solution and cooled to 0-5° C. for 8 hours. The precipitated sodium alendronate was filtered off, washed with cold water, and dried under vacuum at 50° C. to produce 26.4 gm of product (yield 81percent), having a melting point of between 255 and 258° C.; EXAMPLE 4 In a 250 reaction vessel equipped with a water condenser, 8.5 gm (0.1 mol) pyrrolidone, 33.5 ml water, and 11.5 g methane sulphonic acid were added under a nitrogen atmosphere. At room temperature, 17.2 gm (11 ml, 0.125 mol) PCl3 was added drop-wise to the mixture while stirring for 20 to 25 minutes while maintaining the temperature below 65° C. It was then heated to reflux (i.e., 105 to 110° C.) for 3 hours or until the disappearance of pyrrolidone was observerd (i.e., monitored by TLC method). The water present in the reaction mass was then removed by distillation. The mass was then cooled to 60° C. and mixed with 48.2 gm methanesulphonic acid and 41.39 gm (0.3 mol) PCl3, which was added drop-wise, while maintaining the exotherm below 75° C. The reaction mixture was further maintained at 75° C. for 9 hours. On completion of phosphonation, the reaction mixture was cooled to 40° C., and then 85 ml of water was added and refluxed 6 hours. The mass was then cooled to 70 to 75° C., treated with charcoal (0.1 gm), and then filtered. The filtrate was adjusted to a pH of 4.3 by mixing with 50-percent sodium hydroxide solution and cooled to 0-5° C. for 8 hours. The precipitated sodium alendronate was then filtered off, washed with cold water and dried under vacuum at 50° C. to produce 26.4 gm of product (yield 81-percent), having a melting point of between 255 and 258° C.
61.26%
Stage #1: at 105℃; for 9 h; Heating / reflux
Stage #2: With phosphorus trichloride In phosphoric acid at 20 - 110℃; for 9.5 h;
Example 3 In a reaction vessel, 17.0 g(0.2 mol) pyrrolidone, 22 ml water and 23 gm methane sulphonic acid were taken and was heated to reflux (105 °C) for 9 hours or till the disappearance of pyrrolidone (monitored by TLC method). The mass was cooled to room temperature and PCl3 (17.5 ml, 0.199 mol) was added drop-wise while maintaining the temperature below 65 °C. Further the reaction was stirred at 60-65 °C for 30 minutes and then the temperature was raised to 110 °C, water was continuously distilled under vacuum. The mass was then cooled to 60 °C and added a further quantity of 90.39 gm (57.5 ml, 0.6565 mol) PCl3 was added drop-wise while maintaining the temperature below 60 °C followed by 25.5 ml of H3PO4 slowly into the mass. Then the reaction mixture was maintained at 75 °C for 9 hours. On completion of phosphonation, reaction mixture cooled to 55 °C and 170 ml of water was added and refluxed the mass for 6 hours. Mass cooled to 60 °C and treated with charcoal (0.1 gm) and filtered. The filtrate was adjusted to a pH of 4.3 by mixing with 50percent sodium hydroxide solution and cooled to 0-5 °C for 8 hours. The precipitated sodium alendronate was filtered off, washed with cold water and dried under vacuum at 50 °C gave 39.3 gm title product (yield 61.26 percent), melting point 255 - 258 °C.
61.26%
Stage #1: With methanesulfonic acid In water at 105℃; for 9 h;
Stage #2: With phosphorus trichloride In water at 20 - 110℃; for 0.5 h;
EXAMPLE 3 In a reaction vessel, 17.0 g (0.2 mol) pyrrolidone, 22 ml water, and 23 gm methane sulphonic acid were mixed and then heated to reflux (i.e., 105° C.) for 9 hours or till the disappearance of pyrrolidone was observed (monitored by TLC method). The mass was then cooled to room temperature and PCl3 (17.5 ml, 0.199 mol) was added drop-wise while maintaining the temperature below 65° C. The reaction mixture was stirred at 60 to 65° C. for 30 minutes, then the temperature was raised to 110° C. Water was continuously distilled under vacuum. The mass was then cooled to 60° C. A further quantity of 90.39 gm (57.5 ml, 0.6565 mol) PCl3 was then added drop-wise while maintaining the temperature below 60° C., followed by 25.5 ml of H3PO4 slowly into the mass. Then the reaction mixture was maintained at 75° C. for 9 hours. On completion of phosphonation, the reaction mixture was cooled to 55° C., and 170 ml of water was added and refluxed for 6 hours. The mass was cooled to 60° C., treated with charcoal (0.1 gm), and then filtered. The filtrate was adjusted to a pH of 4.3 by mixing with 50-percent sodium hydroxide solution and cooled to 0-5° C. for 8 hours. The precipitated sodium alendronate was filtered off, washed with cold water, and dried under vacuum at 50° C., which yielded 39.3 gm of product (yield 61.26percent), having a melting point of between 255 and 258° C.

Reference: [1] Patent: US2007/149486, 2007, A1, . Location in patent: Page/Page column 3
[2] Patent: EP1803727, 2007, A1, . Location in patent: Page/Page column 5
[3] Patent: EP1803727, 2007, A1, . Location in patent: Page/Page column 5-6
[4] Patent: US2007/149486, 2007, A1, . Location in patent: Page/Page column 3-4
[5] Patent: EP1803727, 2007, A1, . Location in patent: Page/Page column 5
[6] Patent: US2007/149486, 2007, A1, . Location in patent: Page/Page column 4
  • 5
  • [ 183959-44-6 ]
  • [ 121268-17-5 ]
Reference: [1] Phosphorus, Sulfur and Silicon and Related Elements, 2001, vol. 173, p. 1 - 25
Same Skeleton Products
Historical Records