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Chemical Structure| 56-12-2
Chemical Structure| 56-12-2
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Product Details of [ 56-12-2 ]

CAS No. :56-12-2 MDL No. :MFCD00008226
Formula : C4H9NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :BTCSSZJGUNDROE-UHFFFAOYSA-N
M.W : 103.12 Pubchem ID :119
Synonyms :
4-Aminobutyric acid;GABA;Mielomade;Mielogen;DF 468;Aminalon;Piperidic acid;Gamma-aminobutyric acid;4-Aminobutanoic acid

Calculated chemistry of [ 56-12-2 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.75
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 25.82
TPSA : 63.32 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -9.18 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.72
Log Po/w (XLOGP3) : -3.17
Log Po/w (WLOGP) : -0.19
Log Po/w (MLOGP) : -0.39
Log Po/w (SILICOS-IT) : -0.56
Consensus Log Po/w : -0.72

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 3.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 1.72
Solubility : 5360.0 mg/ml ; 52.0 mol/l
Class : Highly soluble
Log S (Ali) : 2.41
Solubility : 26400.0 mg/ml ; 256.0 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.04
Solubility : 95.1 mg/ml ; 0.923 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.0

Safety of [ 56-12-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 56-12-2 ]

* 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 [ 56-12-2 ]
  • Downstream synthetic route of [ 56-12-2 ]

[ 56-12-2 ] Synthesis Path-Upstream   1~22

  • 1
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  • [ 2517-04-6 ]
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  • [ 56-12-2 ]
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  • 5
  • [ 108-31-6 ]
  • [ 56-12-2 ]
  • [ 57078-98-5 ]
YieldReaction ConditionsOperation in experiment
48% at 130℃; for 4 h; 20.0 g (193.9 mmol) of 4-aminobutyric acid is mixed with 19 g of maleic acid anhydride, 290 ml of acetic acid, and it is heated for 4 hours in an oil bath at [130XB0;C.] It is azeotropically concentrated by evaporation with repeated addition of toluene, the residue is dissolved in dichloromethane and purified by chromatography on fine silica gel. 17.1 g (93.4 mmol, [48percent)] of the title compound is isolated as a crystalline solid. [1H-NMR] (CDC13): [8] = 1.93 (2H), 2.38 (2H), 3.60 (2H), 6.71 (2H) ppm.
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[3] Synthesis, 2008, # 8, p. 1316 - 1318
[4] Patent: WO2004/12735, 2004, A2, . Location in patent: Page/Page column 45-46
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 22, p. 5926 - 5931
[6] Organic and Biomolecular Chemistry, 2009, vol. 7, # 17, p. 3400 - 3406
[7] Patent: WO2013/162757, 2013, A1, . Location in patent: Sheet 7
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  • 6
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  • 7
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  • [ 109-73-9 ]
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  • 8
  • [ 383-63-1 ]
  • [ 56-12-2 ]
  • [ 50632-83-2 ]
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[3] European Journal of Organic Chemistry, 2012, # 29, p. 5774 - 5788,15
[4] European Journal of Organic Chemistry, 2012, # 29, p. 5774 - 5788
[5] Journal of Organic Chemistry, 2004, vol. 69, # 21, p. 7072 - 7082
[6] Journal of Medicinal Chemistry, 2011, vol. 54, # 14, p. 4954 - 4963
  • 9
  • [ 431-47-0 ]
  • [ 56-12-2 ]
  • [ 50632-83-2 ]
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  • 10
  • [ 67-56-1 ]
  • [ 56-12-2 ]
  • [ 13031-60-2 ]
YieldReaction ConditionsOperation in experiment
96% at 0 - 20℃; for 2 h; Cooling with ice General procedure: To a solution of amino substituted fatty acid derivatives 10a-10d (10 mmol) in 20 mL methanol was added thionyl chloride (20 mmol) dropwise under ice bath. After stirring at room temperature for about 2 h, the solution was evaporated to give the desired products 11a-11d. Methyl 4-aminobutanoate hydrochloride (11a). White solid; yield 96.0percent; 1H NMR (400 MHz, D2O) d 3.46 (s, 3H), 2.79 (t, J = 7.6 Hz, 2H), 2.28 (t, J = 7.3 Hz, 2H), 1.77-1.67 (m, 2H). ESI-MS: calcd for [M + H-HCl]+ m/z: 118.1, found: 118.1.
95% at 0 - 20℃; for 3 h; General procedure: To a stirred solution of the appropriate amino acid in MeOH at 0°C SOCl2 was slowly added. The solution was then removed from the ice bath and stirred at rt for 3h. The reaction was then concentrated in vacuo leaving the methyl ester amino acid as the hydrochloride salt.
94% for 1 h; Reflux To an ice-cold solution of GABA(1 equiv) in methanol (50 mL), SOCl2 (1.2 equiv) was addeddropwise and then the mixture was heated to reflux for 1hto yield the white solid in vacuum at 40°C. The product wasrecrystallized in ethanol–ether (1 : 2) solution. Yield 94percent, mp118.3–120°C.
87% at 0℃; General procedure: Thionyl chloride (10 mL) was slowly added to a cold suspension solution of the appropriate aminoacid (50 mmol) in methanol (50 mL) at 0 °C. The reaction mixture was stirred for 8–10 h and thenconcentrated on a rotary evaporator. The white precipitate formed was washed with anhydrous etherand then dried under vacuum. All data agreed with the reported data [43,44].

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[4] Chemistry - A European Journal, 2012, vol. 18, # 18, p. 5767 - 5776
[5] Journal of Medicinal Chemistry, 2006, vol. 49, # 20, p. 6094 - 6103
[6] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 16, p. 5950 - 5961
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[8] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1431 - 1437
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[10] European Journal of Organic Chemistry, 2012, # 29, p. 5774 - 5788,15
[11] European Journal of Organic Chemistry, 2012, # 29, p. 5774 - 5788
[12] European Journal of Medicinal Chemistry, 2018, vol. 154, p. 44 - 59
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[15] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 10, p. 967 - 978
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[17] Molecules, 2013, vol. 18, # 12, p. 14747 - 14759
[18] Molecules, 2008, vol. 13, # 5, p. 1111 - 1119
[19] Chemistry of Natural Compounds, 2014, vol. 50, # 2, p. 317 - 320[20] Khim. Prir. Soedin., 2014, vol. 2, p. 278 - 281,4
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[25] Journal of Organic Chemistry, 2015, vol. 80, # 15, p. 7693 - 7701
[26] Chemistry - A European Journal, 2016, vol. 22, # 3, p. 890 - 895
[27] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 12, p. 1185 - 1190
[28] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 4, p. 428 - 432
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[30] Patent: CN107827815, 2018, A, . Location in patent: Paragraph 0118; 0119
  • 11
  • [ 56-12-2 ]
  • [ 13031-60-2 ]
Reference: [1] Patent: US5354753, 1994, A,
[2] Patent: US4722810, 1988, A,
[3] Patent: US4742068, 1988, A,
  • 12
  • [ 75-36-5 ]
  • [ 56-12-2 ]
  • [ 13031-60-2 ]
Reference: [1] Anti-Cancer Drugs, 2018, vol. 29, # 2, p. 145 - 156
  • 13
  • [ 56-12-2 ]
  • [ 74-88-4 ]
  • [ 6249-56-5 ]
Reference: [1] Analytical Chemistry, 2008, vol. 80, # 23, p. 9298 - 9309
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 47, p. 14842 - 14846[3] Angew. Chem., 2016, vol. 128, # 47, p. 15063 - 15068,6
[4] Analytical Chemistry, 2006, vol. 78, # 12, p. 4175 - 4183
  • 14
  • [ 50-00-0 ]
  • [ 56-12-2 ]
  • [ 69954-66-1 ]
Reference: [1] Patent: WO2014/18913, 2014, A2, . Location in patent: Page/Page column 48
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2213 - 2236
  • 15
  • [ 50-00-0 ]
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  • [ 56-12-2 ]
  • [ 69954-66-1 ]
Reference: [1] Chemical Biology and Drug Design, 2016, p. 363 - 369
  • 16
  • [ 64-17-5 ]
  • [ 56-12-2 ]
  • [ 6937-16-2 ]
Reference: [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 5, p. 825 - 831
[2] Chemische Berichte, 1900, vol. 33, p. 2235
[3] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 6, p. 2336 - 2350
[4] Patent: US2007/219196, 2007, A1, . Location in patent: Page/Page column 36
[5] European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 11 - 20
  • 17
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  • [ 100-51-6 ]
  • [ 56-12-2 ]
  • [ 26727-22-0 ]
YieldReaction ConditionsOperation in experiment
99% for 5 h; Reflux A suspension of γ-aminobutanoic acid (GABA) 1 (3.50 g, 0.034 mol), benzyl alcohol (7.30 g, 7 mL,0.068 mmol) and p-toluenesulfonic acid monohydrate (PTSA) (7.10 g, 0.037 mol) in PhMe (200 mL) was heated toreflux for 5 h with azeotropic removal of water. The reaction mixture was concentrated to a one third of the volumeand the product precipitated by addition of Et2O (100 mL). The precipitate was filtered, dissolved in CH3OH (60 mL)and again precipitated by addition of Et2O (100 ml), giving after filtration and drying the benzyl ester 2 (12.30 g,99percent) as white crystals. M.p. 106.2-106.7 C (Et2O); IR(ATR): 3100, 3039, 2942, 1732, 1642, 1532, 1188, 1125 cm-1;1H NMR (200 MHz, CD3OD): δ=7.71 (d, J=8.0 Hz, 2H, HPTSA), 7.37-7.30 (m, 5H, HCAr), 7.20 (d, J=8.4 Hz, 2H,HPTSA), 5.11 (s, 2H, H2CBn), 2.95 (t, J=7.5 Hz, 2H, H2C(4)GABA), 2.47 (t, J=7.3 Hz, 2H, H2C(2)GABA), 2.33 (s, 3H,H3CPTSA), 1.92 (quint, J=7.4 Hz, 2H, H2C(3)GABA) ppm; 13C NMR (50 MHz, CD3OD): δ=173.83 (CO2Bn), 143.35,141.82, 137.43, 129.91, 129.59, 129.30, 126.91 (CAr), 67.44 (CH2Bn), 40.00 (CH2(4)GABA), 31.59 (CH2(2)GABA), 23.65(CH2(3)GABA), 21.30 (CH3PTSA) ppm; MS(ESI): Calcd for C11H16NO2 (M+H)+: 194.1181, found: 194.1167.
93% for 24 h; Dean-Stark; Reflux Example 6: Preparation of benzyl 4-(4-hydroxy-3,6-dioxo-5-tridecylcyclohexa-l,4- dienylamino)butanoate (11) Gamma aminobutyricacid 11 a. Tos late salt (10): A solution of l.OOg (9.70 mmol) of 4-aminobutanoic acid, 2.02 g (1.08 mmol) of p- toluenesulfonic acid monohydrate and 1.24 mL (1.29 g, 1.24 mmol) of benzyl alcohol in 20 mL of toluene was heated to reflux, using a Dean-Stark distilling receiver, for 24 h. The reaction mixture was cooled to room temperature and diluted with 20 mL of anhydrous diethyl ether to afford p- toluenesulfonate 10 as a crystalline, colorless solid: yield 3.30 g (93percent); silica gel TLC Rf 0.47 (9: 1 chloroform-methanol); NMR (CDC13) δ 1.89 (quin, 2H, J= 7.3 Hz), 2.28-2.40 (m, 5H), 2.87 (dt, 2H, J= 12.8 and 6.3 Hz), 5.04 (s, 2H), 7.1 1 (d, 2H, J= 7.9 Hz), 7.27-7.37 (m, 5H) and 7.76-7.85 (m, 5H); 13C NMR (CDC13) δ 21.4, 22.6, 30.9, 39.3, 66.5, 126, 128.30, 128.35, 128.6, 129.2, 135.9, 140.9, 141.2 and 172.3.
90% Dean-Stark; Reflux GABA, 5.0 g (48.49 mmol), and 10.25 g (53.88 mmol) of p-toluenesulphonic acid (monohydrate), and 20.88 g (193.08 mmol) of benzyl alcohol were mixed in 60 mL of toluene. The reaction mixture was stirred and heated to reflux. During the heating all solids dissolved. Water from reaction was collected by a Stark&Dean trap. The mixture were left to cool at room temperature and then at 5 °C overnight. The solids were filtered and washed with cold toluene and vacuum dried. The solid was recrystallized from 1:1 ethyl alcohol-ethyl ether. 2 was obtained as a water and DCM soluble white crystals: 15.9 g (90 percent), mp 106.5-107 °C, 500MHz 1H NMR (CDCl3): δ 1.87 (q, 2H, -CH2-), 2.31 (t, 5H, -CH2-CO, CH3-Ph), 2.87 (t, 2H, -CH2-N), 5.20 (s, 2H, -CH2O), 7.08 (d, 2H, Ar), 7.26-7.33 (m, 5H, Ar), 7.73 (d, 2H, Ar). 13C NMR (CDCl3, 126 MHz): δ 21.3, 29.67, 31.48, 42.33, 66.45, 127.10. 127.61, 128.21, 128.90, 130.05, 136.10, 139.45, 142.07,173.15. IR (cm-1) 3480, 3045, 2980, 1748, 1182, 1110, 1020, 1009, 723, 691. Anal. Calcd. for C18H23NO5S: C, 59.16; H, 6.34, N, 3.83, S, 8.77 . Found: C, 59.28, H, 6.27, N, 3.87, S. 8.82.
84% for 14 h; Dean-Stark; Reflux; Inert atmosphere A 2L 3-necked flask was fitted with a mechanical stirred, a Dean-Stark trap, reflux condenser, and a nitrogen inlet. The flask was charged with 4- aminobutanoic acid (41 .522 g, 0.403 mol), p-toluenesulfonic acid (91 .912 g, 0.048 mol), and benzyl alcohol (201 mL). The resulting cloudy solution was heated at reflux for 14 h. At the end of the reflux period, n-hepate (175 mL) was added to the hot reaction solution. The reaction was allowed to cool to ambient temperature. The resulting white crystals were isolated via vacuum filtration and recrystallized from 6:1 ethyl acetate/n-hepate to give 124.2 g (84percent yield) of the desired product as a white solid. 1H NMR (400 MHz, CDCI3, δ) 7.71 (5H, d), 7.31 (5H, m), 7.13 (2H, d), 5.02 (2H, s), 2.87 (2H, m), 2.32 (5H, m), 1 .85 (2H, m).

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[2] Organic and Biomolecular Chemistry, 2009, vol. 7, # 11, p. 2327 - 2337
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[4] Patent: WO2014/59158, 2014, A1, . Location in patent: Page/Page column 38-39
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  • [ 119072-54-7 ]
  • [ 56-12-2 ]
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YieldReaction ConditionsOperation in experiment
39% at 40℃; for 24 h; Inert atmosphere General procedure: To a solution of γ-aminobutyric acid (1.0 mmol, 1 equiv) in 2,2,2-trifluoroethanol (10 mL) were added the aldehyde (1.0 mmol, 1 equiv) and the isocyanide (1.0 mmol, 1 equiv). Unless otherwise indicated, the mixture was stirred and heated at 40 °C for 24 h. The solution was then concentrated in vacuo and the product was isolated by column chromatography on silica gel
Reference: [1] Synthesis (Germany), 2017, vol. 49, # 7, p. 1664 - 1674
  • 20
  • [ 56-12-2 ]
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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
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[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
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  • [ 82911-69-1 ]
  • [ 56-12-2 ]
  • [ 116821-47-7 ]
YieldReaction ConditionsOperation in experiment
73% With sodium hydrogencarbonate In water; acetonitrile at 20℃; for 3 h; To a solution of GAB A (2.00 g, 19.4 mmol, in 14 mL 10percent NaHC03), Fmoc-OSu (4 g, 11.7 mmol, in 40 mL ACN) was added drop-wise over a period of 2 h at room temperature. The mixture was allowed to stir at room temperature for an additional hour. ACN was removed under reduced pressure and the aqueous layer acidified to pH 1 with 10percent HCl. The precipitate was washed with two 20 mL portions of water, 20 mL ethyl acetate and dried under reduced pressure. Fmoc-GABA was obtained as a white solid in 73percent yield (2.8 g). [65] NMR (DMSO-d6, 400 MHz): δ 7.89 (d, 2H, J = 7.4 Hz), 7.44 (d, 2H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.5 Hz), 7.35 (s, 1H), 7.33 (t, 2H, J = 7.0 Hz), 4.30 (d, 2H, J = 7 Hz), 4.21 (t, 1H, J = 6.7 Hz), 3.01 ( q, 2H, J = 5.6 Hz ), 2.20 ( t, 2H, J = 7.3 Hz ), 1.63 (q, 2H, J = 7.1 Hz); 13C NMR (DMSO-d6, 100 MHz): δ 142.6, 139.4, 137.4, 128.9, 127.2, 124.2, 121.3, 120.0, 109.6, 77.5, 61.8, 51.1, 31.6; MS (ESI+): m/z (intensity), 325.8 ([M+H]+, 100percent).
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[2] Patent: WO2018/144880, 2018, A1, . Location in patent: Paragraph 64-65
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[2] Tetrahedron Letters, 1998, vol. 39, # 28, p. 5117 - 5120
[3] Bioorganic Chemistry, 1996, vol. 24, # 1, p. 50 - 58
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[5] Patent: US2003/143591, 2003, A1,
[6] Russian Journal of General Chemistry, 2010, vol. 80, # 12, p. 2572 - 2589
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