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Product Details of [ 77-92-9 ]

CAS No. :77-92-9 MDL No. :MFCD00011669
Formula : C6H8O7 Boiling Point : -
Linear Structure Formula :- InChI Key :KRKNYBCHXYNGOX-UHFFFAOYSA-N
M.W : 192.12 Pubchem ID :311
Synonyms :
Chemical Name :2-Hydroxypropane-1,2,3-tricarboxylic acid

Calculated chemistry of [ 77-92-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.5
Num. rotatable bonds : 5
Num. H-bond acceptors : 7.0
Num. H-bond donors : 4.0
Molar Refractivity : 37.47
TPSA : 132.13 Ų

Pharmacokinetics

GI absorption : Low
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) : -8.69 cm/s

Lipophilicity

Log Po/w (iLOGP) : -1.49
Log Po/w (XLOGP3) : -1.72
Log Po/w (WLOGP) : -1.25
Log Po/w (MLOGP) : -1.48
Log Po/w (SILICOS-IT) : -1.6
Consensus Log Po/w : -1.51

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : 0.38
Solubility : 463.0 mg/ml ; 2.41 mol/l
Class : Highly soluble
Log S (Ali) : -0.54
Solubility : 55.3 mg/ml ; 0.288 mol/l
Class : Very soluble
Log S (SILICOS-IT) : 1.71
Solubility : 9900.0 mg/ml ; 51.5 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.18

Safety of [ 77-92-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P271-P280-P304+P340+P312-P305+P351+P338-P337+P313-P403+P233-P405-P501 UN#:N/A
Hazard Statements:H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 77-92-9 ]

* 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 [ 77-92-9 ]
  • Downstream synthetic route of [ 77-92-9 ]

[ 77-92-9 ] Synthesis Path-Upstream   1~44

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Reference: [1] Asian Journal of Chemistry, 2014, vol. 26, # 22, p. 7867 - 7868
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  • [ 108-46-3 ]
  • [ 6950-82-9 ]
YieldReaction ConditionsOperation in experiment
78% for 0.0666667 h; Microwave irradiation General procedure: Coumarin-4-acetic acid is a known compound (Manwaret al. 2008). The reaction conditions reported for thiscompound were modified and optimized (method A) tosynthesis the analogs 2a–2f. These analogs were also synthesizedby microwave assisted method (method B). Method A A mixture of citric acid (0.02 mol) and sulfuricacid (0.03 mol) was stirred at room temperature for 30 min.The mixture was kept in boiling water bath to removecarbon monoxide (CAUTION: Fume Cupboard). As soonas the evolution of CO gas was slackened, the flask wasremoved from the bath, kept aside for 15 min or till thereaction mixture was free from CO bubbles. The contentswere cooled to 10 °C, and (un)substituted phenol (0.02 mol)cooled to 10 °C was added drop wise. The reaction mixturewas stirred at room temperature for 48 h, and poured overcrushed ice. The precipitates were filtered and dissolved insaturated sodium bicarbonate solution. The solution wasacidified to afford the intermediates 2a–2f. Method B A mixture of citric acid (0.02 mol), sulphuricacid (0.03 mol) and (un)substituted phenol (0.02 mol) washeated in a microwave oven at 10percent power for 4 min. Thereaction mixture was poured over crushed ice and processedsimilarly as in method A to obtain the desired product. 7-Hydroxycoumarin-4-acetic acid (2a) Yield 67percent(method A), 78percent (method B); m.p. 170 °C; IR (FT-IR) vmax(cm−1): 3210 (Ar C–H), 2924 (Al C–H), 1710 (C=O), 1701(C=O lactone), 1458 (C=C), 1130 (C–O), 1290 (C–OH);1H-NMR (DMSO-d6, 400 MHz): δ 11.08 (1H, s, COOH),7.41–6.98 (2H, m, H−5, and H-6), 6.69–6.23 (2H, m H-8,and H-3), 4.93 (1H, dd, OH), 3.02–2.89 (2H, m, CH2); 13CNMR(DMSO-d6, 100 MHz): δ 171.5 (C=O), 160.2 (C-2),112.5 (C-3), 152.4 (C-4), 150.5 (C-8a), 135.2 (C-6), 124.8(C-5), 122.9 (C-7), 120.1 (C-4a), 104.1 (C-8), 37.0 (–CH2).HRMS (+ESI) [M + H]+: 221.0445 (theoretical), 221.0464(found).
68% at 0 - 40℃; 10.0 g (90 mmol) of resorcinol were dissolved in 60 mL of H2SO4 and the mixture was cooled to 0 °C. 19.0 g (90 mmol) of citric acid monohydrate was added slowly to 70 mL of H2SO4 at 0 °C while maintaining the temperature until the addition ended. The solution was stirred every 15 min and the temperature was increased gently over a period of 1.5 h to 40 °C. The mixture turned clear yellow with gas evolution and was left to stand for 15 minutes until the disappearance of bubbles. It was then cooled to 5 °C and the solution of resorcinol was added dropwise maintaining at 5 °C. After the addition the mixture was stirred for 48 h, after which the reaction mixture was slowly poured into 300 g of ice flakes. A white solid started to form immediately and was filtered once all of the ice had melted. The precipitate was suspended in a 5percent solution of sodium bicarbonate, and the solid obtained was filtered and washed: 13.5 g, crystalline solid, 68percent, mp 204-206 °C. 1H NMR (D2O): δ 7.41 (d, 1H, Ar-H, J = 8.8 Hz), 6.74 (dd, 1H, Ar-H, J = 8.8, 2.4 Hz), 6.56 (d, 1H, Ar-H, J = 2.4 Hz), 6.08 (s, 1H, = CH), 3.59 (s, 2H,-CH2-).
68% at 0 - 40℃; for 50.5 h; Resorcinol 10.0 g (90 mmol) were dissolved in H2SO4 96 percent (60 mL) cold and the mixture was cooled to 0 °C. 19.0 g (90 mmol) of citric acid monohydrate was added slowly to 70 mL of H2SO4 96percent at 0 °C while maintaining the temperature until the addition ended. Then stirred every 15 min and the temperature was increased gently for a period of 1.5 h to 40 °C. The mixture turned a clear yellow with gas evolution and left to stand for 15 minutes until the disappearance of bubbles. Then cooled to 5 °C and added dropwise the solution of resorcinol in H2SO4 keeping temperature. After the addition the mixture was allowed to stirred for 48 h. After the time the reaction mixture was slowly poured into 300 g of ice and frost immediately started to form a white solid which was filtered once all of the ice melted. The precipitate formed was suspended in a solution of sodium bicarbonate 5percent, the solid filtered and washing with water cold. (13.5 g, crystalline solid, 68 percent). m.p. 204-206 °C; 1H NMR (D2O): δ 7.35 (d, 1H, Ar-H, J = 8.8 Hz), 6.67 (dd, 1H, Ar-H, J = 8.8, 2.4 Hz), 6.50 (d, 1H, Ar-H, J = 2.4 Hz), 6.00 (s, 1H, =C-H), 3.50 (s, 2H, -CH2-).
Reference: [1] Medicinal Chemistry Research, 2018, vol. 27, # 1, p. 61 - 71
[2] Tetrahedron Letters, 2012, vol. 53, # 48, p. 6598 - 6601,4
[3] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 23, p. 5732 - 5735
[4] Journal of the Chemical Society, 1950, p. 170,172
[5] Journal of the American Chemical Society, 1950, vol. 72, p. 3987,3989
[6] Journal of the Indian Chemical Society, 1992, vol. 69, # 7, p. 397 - 398
[7] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 21, p. 6324 - 6326
[8] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3443 - 3446
[9] PLoS ONE, 2017, vol. 12, # 12,
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Reference: [1] Synlett, 2012, vol. 23, # 15, p. 2189 - 2194
[2] Dyes and Pigments, 2015, vol. 120, p. 190 - 199
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  • [ 62935-72-2 ]
Reference: [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 32, p. 7777 - 7791
[2] Journal of the American Chemical Society, 1950, vol. 72, p. 3987,3989
[3] Synthetic Communications, 2015, vol. 45, # 17, p. 2043 - 2052
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  • [ 62935-72-2 ]
Reference: [1] Synlett, 2012, vol. 23, # 15, p. 2189 - 2194
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  • [ 99-11-6 ]
YieldReaction ConditionsOperation in experiment
85.18% With urea In water at 185℃; for 2 h; Sonication; High pressure (1) Take 1.2188 g (0.0058 mol) of citric acid and 1.3932 g (0.0231 mol) of urea dissolved in 60 ml of deionized water, sonicate for 10 min, and mix well; (2) The mixture is charged into the reaction vessel, the oven temperature is set to 185 ° C, and the temperature is kept under hydrothermal conditions for 2 h; Cooling to room temperature to obtain a dark green solution; (3) The solution was placed in a constant temperature water bath at 60 ° C, magnetically stirred, and 98percent sulfuric acid was added dropwise to the solution until the pH of the solution was 2-3. A large amount of yellow solid precipitate was observed and centrifuged at 12000 r/min for 10 min. Remove the supernatant, wash it with deionized water multiple times, and drain it. The obtained yellow precipitate was dried in an oven at 60 ° C to obtain 85.18percent of the citrazinic acid product.
Reference: [1] Patent: CN108164458, 2018, A, . Location in patent: Paragraph 0010; 0012; 0013
[2] Journal of the American Pharmaceutical Association (1912-1977), 1956, vol. 45, p. 478
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  • [ 99-11-6 ]
Reference: [1] Patent: DE1011885, 1954, ,
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  • [ 5398-44-7 ]
Reference: [1] Journal of the American Pharmaceutical Association (1912-1977), 1956, vol. 45, p. 478
  • 9
  • [ 77-92-9 ]
  • [ 105-50-0 ]
Reference: [1] European Journal of Organic Chemistry, 2012, # 29, p. 5818 - 5827,10
[2] Gazzetta Chimica Italiana, 1891, vol. 21 I, p. 306
[3] Chemische Berichte, 1916, vol. 49, p. 2704[4] Chemische Berichte, 1920, vol. 53, p. 1917
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  • [ 105-50-0 ]
Reference: [1] European Journal of Organic Chemistry, 2012, # 29, p. 5818 - 5827
[2] Journal of Organic Chemistry, 2018,
[3] Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft, 1967, vol. 300, # 1, p. 53 - 61
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  • [ 4558-59-2 ]
YieldReaction ConditionsOperation in experiment
20% With sodium methylate In methanol REFERENCE EXAMPLE 15
Preparation of 4,6-dimethoxypyrimidine-5-carboaldehyde
43.6g (246 mmol) of 4,6-dichloropyrimidine-5-carboaldehyde was dissolved in 200 m of methanol, and 120g (622 mmol) of 28percent sodium methoxide was added under cooling with ice and then reacted for 2 hours at room temperature.
After completion of the reaction, the solvent was distilled off, and an aqueous citric acid solution was added, followed by extraction with ethyl acetate.
The organic layer was washed with an aqueous sodium hydrogencarbonate solution, an aqueous citric acid solution, water and an aqueous sodium chloride solution in this order, dried and concentrated, and the obtained crude crystals were washed with isopropyl ether to obtain 8.3g (yield: 20percent) of 4,6-dimethoxypyrimidine-5-carboaldehyde.
Reference: [1] Patent: EP1211246, 2002, A1,
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  • [ 67-56-1 ]
  • [ 77-92-9 ]
  • [ 1830-54-2 ]
  • [ 100009-70-9 ]
  • [ 20820-77-3 ]
  • [ 1587-20-8 ]
  • [ 105-45-3 ]
YieldReaction ConditionsOperation in experiment
87.3%
Stage #1: With chlorosulfonic acid In dichloromethane at 10 - 15℃; for 5 - 6 h;
Stage #2: at 3 - 35℃; for 2 h;
490 kg (370 1) of anhydrous methylene chloride are added to 1320 kg (753 1) of chlorosulphonic acid (the ratio of methylene chloride to chlorosulphonic acid is 0.5 : 1 by volume). The temperature of the mixture is adjusted to 10-15 oC, and 665.0 kg of citric acid monohydrate are added to it at a rate of 1.25 kg/minute, while the temperature of the reaction mixture is kept between 10 oC and 15 oC. When the addition has been completed the reaction mixture is stirred at a temperature between 10 oC and 15 oC until no more gas is liberated (at least 6 hours). The reaction mixture is then cooled to 3-5 oC and 640 kg (800 1) of anhydrous methanol are added to it at such a rate that the inner temperature does not exceed 25 oC. The reaction mixture is then warmed to 30-35 oC and stirred at the same temperature for 2 hours. The esterifying reaction is completed under this period. The reaction mixture is cooled to 10- 12 oC and 1300 1 of water are added to it at such a rate that the temperature does not exceed 15 oC. To the mixture 800 ml of methylene chloride are added and it is stirred for 15 minutes. The two-phase mixture is clarified for 30 minutes and the organic phase is separated. The aqueous layer is extracted three times with 400 ml each of methylene chloride. The organic phases are combined and washed first with 1000 1 of water, then with a solution of 75 kg of sodium hydrocarbonate in 1000 1 of water. The pH of the solution is adjusted to a value of about 7 by the addition of sodium hydrocarbonate. The organic phase is separated, washed twice with 750 ml each of water and evaporated in vacuo. Evaporation is carried out under a pressure of 3-5 kPa until the inner temperature rises at most to 75 oC. Thus 535 kg of dimethyl 3- OXOGLUTARATE are obtained, which can be used for the further reaction steps without purification. Qualification by gas chromatography: Purity by gas chromatography: Apparatus: gas chromatograph of HP-6850 type Method: Column : HP-1.25 m x 0. 32 MM, 0.17 URN of film thickness Carrier gas: hydrogen Program: 80 oC-5 MINUTES-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxoglutarate 5.77 minutes Enol ether 8.15 minutes Trimethyl aconitate 10. 00 minutes Trimethyl citrate 10. 42 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Result: Methyl acetoacetate: 0.31percent Dimethyl 3-oxoglutarate: 98.33percent Enol ether: 0. 81percent Trimethyl aconitate: 0. 28percent Trimethyl citrate : 0. 09percent Isoftalic acid derivative :- Other contamination (higher than 0,2 percent) Example 2 Into a mixture of 100.0 g (58 ml) of chlorosulphonic acid and 30 ml of methylene chloride 50.0 g of citric acid monohydrate are added within 30 minutes at a temperature between 10 oC and 15 oC. The mixture is stirred at the same temperature for 5 hours, cooled to 3-5 oC and 60 ml of methanol are introduced to it within 15 minutes at such a rate that the temperature does not exceed 25 oC. It is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC and 100 ml of water are added to it within 15 minutes. The thus-obtained mixture is extracted three times with 50 ml each of methylene chloride; the organic phases are combined, washed successively with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of water and evaporated in vacuo. Thus 40.8 g of dimethyl 3- OXOGLUTARATE are obtained. Yield: 98. 5 percent Apparatus : gas chromatograph of HP-6850 type Method : Column: HP-1.25 m x 0.32 mm, film thickness of 0. 17 Am Carrier gas: hydrogen Program: 80 oC-5 minutes-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxo- glutarate 5. 77 minutes Enol ether 8.15 minutes Trimethyl citrate 10.42 minutes Trimethyl aconitate 10.11 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0. 49percent Dimethyl 3-OXOGLUTARATE : 97. 62percent Enol ether: 0.98percent Trimethyl citrate: 0. 13percent Trimethyl aconitate: 0.29percent Isoftalic acid derivative: 0.07percent Other contamination (more than 0.2 percent) Example 3 (comparative example) Example 1 of the Belgian patent specification No. 879,537 A mixture of 212 ml of chlorosulphonic acid and 600 ml of methylene chloride is prepared (the ratio of methylene chloride to chlorosulphonic acid is 2.83 : 1 by volume). Then 200.0 g of citric acid are added to this mixture within 15-20 minutes, the addition rate of citric acid is 13.3 kg/minute, temperature = 20-22 oC. The reaction mixture is stirred at this temperature for 5 hours, cooled to a temperature between 3"C AND 5 C and 320 ml of methanol are added to it within 15 minutes at such a rate that the temperature remain below 25 oC. The reaction mixture is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC, poured into 800 ml of water, stirred vigorously for 15 minutes, clarified for 15 minutes and the phases are separated. The aqueous phase is extracted three times with 150 ml each of methylene chloride. The organic phases are combined, washed once with 400 ml of saturated sodium hydrogen carbonate solution and twice with 200 ml each of water and evaporated in vacuo. Thus 158.2 g of dimethyl 3-oxoglutarate are obtained. Yield: 87. 3 percent. Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0.21percent Dimethyl 3-oxoglutarate: 91.07percent Enol ether: 4.78percent Trimethyl aconitate 0.46percent Trimethyl citrate : 2.27percent Isoftalic acid derivative: 0.53percent Other contamination (higher than 0. 2percent)
Reference: [1] Patent: WO2004/89867, 2004, A2, . Location in patent: Page 20-26
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  • [ 1830-54-2 ]
Reference: [1] Journal of Organic Chemistry, 1957, vol. 22, p. 1385,1388, 1392[2] Journal of Organic Chemistry, 1958, vol. 23, p. 391,393
[3] Patent: US2887508, 1958, ,
[4] Journal of the American Chemical Society, 1971, vol. 93, p. 3969 - 3977
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  • [ 1830-54-2 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1998, vol. 37, # 4, p. 397 - 398
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  • [ 78315-99-8 ]
Reference: [1] Journal of Organic Chemistry, 1957, vol. 22, p. 1385,1388, 1392[2] Journal of Organic Chemistry, 1958, vol. 23, p. 391,393
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  • [ 1587-20-8 ]
YieldReaction ConditionsOperation in experiment
98% at 0 - 20℃; (i) Preparation of 3-hydroxy-3-methoxycarbonyl-pentanedioic acid dimethyl esterTo a stirred solution of citric acid (9.00 g, 46.8 mmol) in absolute methanol at 00C under a nitrogen atmosphere, thionyl chloride (20.50 mL, 0.28 mol) was carefully added. The reaction mixture was stirred at 0°C for an hour then at room temperature overnight. The volatiles were then removed in vacuo. The residual solid was recrystallized from hexane/ethylacetate to yield 10.80 g (98percent) of the title compound as white crystals. 1H NMR (Acetone-^, 200 MHz): δ 2.85 (dd, 4H, J1 = 15.4Hz, J2 = 27.2Hz); 3.60 (s, 6H); 3.72 (s, 3H); 4.50 (br.s, IH). 13C NMR (Acetone-+), calculated: M+ = 234.21.
98% With thionyl chloride In methanol at 0 - 20℃; Inert atmosphere Step 1.
Preparation of Trimethyl Citrate
To a stirred solution of citric acid (9.00 g, 46.8 mmol) in absolute methanol at 0° C. under a nitrogen atmosphere, thionyl chloride (20.50 mL, 0.28 mol, 2 eq.) was carefully added.
The reaction mixture was stirred at 0° C. for an hour then at room temperature overnight.
The volatiles were then removed in vacuum.
The residual solid was recrystallized from hexane/ethyl acetate to yield 10.809 (98percent) of the title compound as white crystals.
94% at 70℃; for 20 h; General procedure: The mixture of citric acid (11 mmol, 2.11 g), MeOH (20 mL) and N-bromosuccinimide (0.77 mmol,0.138 g) was stirred in a 25 mL reactor tube at 70 C for 20 h. After the completion of the reaction,the mixture was cooled to room temperature and alcohol was evaporated under reduced pressure.The residue was dissolved in 50 mL of ethyl acetate, washed with the mixture of 10 mL of saturatedNaHCO3 (aq), 10 mL of 10percent Na2S2O3 (aq) and 25 mL of distilled water and the water phase was extractedwith ethyl acetate (2 25 mL). The organic layers were combined, dried with Na2SO4 and the solventwas evaporated under reduced pressure to furnish methyl citrate as a white solid.Yield: 2.55 g, 99percent.
20.1% at 180℃; for 5 h; FIG. 4 shows examples of CO2-assisted esterification of other kinds of carboxylic polyacids. In FIGS. 4A and 4B, succinic acid was substituted respectively with citric acid, a tricarboxylic acid, and malic acid. The yield of triethylcitrate was reasonable at about 20.1percent, demonstrating that the CO2-assisted protocol can be applied to tricarboxylic acids. The yield of the dimethyl analogue of malic acid was good at about 84.3percent. Hence, the new method of esterification is feasible for general use with other acids.

Reference: [1] Molecules, 2006, vol. 11, # 4, p. 263 - 271
[2] Patent: WO2007/14471, 2007, A1, . Location in patent: Page/Page column 30
[3] Patent: US2013/89611, 2013, A1, . Location in patent: Paragraph 0133-0135
[4] Molecules, 2018, vol. 23, # 9,
[5] RSC Advances, 2014, vol. 4, # 100, p. 57297 - 57307
[6] Patent: WO2014/70415, 2014, A1, . Location in patent: Page/Page column 10
[7] Patent: WO2014/99431, 2014, A1, . Location in patent: Page/Page column 19
[8] Patent: US2017/44086, 2017, A1, . Location in patent: Paragraph 0058
[9] Justus Liebigs Annalen der Chemie, 1846, vol. 60, p. 325
[10] Journal of the American Chemical Society, 1934, vol. 56, p. 459
[11] Journal of Pharmacy and Pharmacology, 1950, vol. 2, p. 229
[12] Journal of the American Chemical Society, 1992, vol. 114, # 2, p. 411 - 416
[13] Tetrahedron Letters, 1998, vol. 39, # 47, p. 8563 - 8566
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YieldReaction ConditionsOperation in experiment
7 %Spectr. With hydrogen In water at 200℃; for 6 h; General procedure: 42 mg of citric acid monohydrate was dissolved in 2 mL of solvent; 4 molpercent of Pd/BaS04 (catalyst in powder form) was added and the reactor was flushed 6 times with N2. Then the reactor was loaded with 4 bar H2 and heated to 200°C for a period of 6 h . The conversion of citric acid was >99percent in all cases. Especially the ether solvent tetrahydrofuran allows to reach high yields of methylsuccinic acid .
Reference: [1] Patent: WO2018/65475, 2018, A1, . Location in patent: Page/Page column 16
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  • [ 77-92-9 ]
  • [ 1830-54-2 ]
  • [ 100009-70-9 ]
  • [ 20820-77-3 ]
  • [ 1587-20-8 ]
  • [ 105-45-3 ]
YieldReaction ConditionsOperation in experiment
87.3%
Stage #1: With chlorosulfonic acid In dichloromethane at 10 - 15℃; for 5 - 6 h;
Stage #2: at 3 - 35℃; for 2 h;
490 kg (370 1) of anhydrous methylene chloride are added to 1320 kg (753 1) of chlorosulphonic acid (the ratio of methylene chloride to chlorosulphonic acid is 0.5 : 1 by volume). The temperature of the mixture is adjusted to 10-15 oC, and 665.0 kg of citric acid monohydrate are added to it at a rate of 1.25 kg/minute, while the temperature of the reaction mixture is kept between 10 oC and 15 oC. When the addition has been completed the reaction mixture is stirred at a temperature between 10 oC and 15 oC until no more gas is liberated (at least 6 hours). The reaction mixture is then cooled to 3-5 oC and 640 kg (800 1) of anhydrous methanol are added to it at such a rate that the inner temperature does not exceed 25 oC. The reaction mixture is then warmed to 30-35 oC and stirred at the same temperature for 2 hours. The esterifying reaction is completed under this period. The reaction mixture is cooled to 10- 12 oC and 1300 1 of water are added to it at such a rate that the temperature does not exceed 15 oC. To the mixture 800 ml of methylene chloride are added and it is stirred for 15 minutes. The two-phase mixture is clarified for 30 minutes and the organic phase is separated. The aqueous layer is extracted three times with 400 ml each of methylene chloride. The organic phases are combined and washed first with 1000 1 of water, then with a solution of 75 kg of sodium hydrocarbonate in 1000 1 of water. The pH of the solution is adjusted to a value of about 7 by the addition of sodium hydrocarbonate. The organic phase is separated, washed twice with 750 ml each of water and evaporated in vacuo. Evaporation is carried out under a pressure of 3-5 kPa until the inner temperature rises at most to 75 oC. Thus 535 kg of dimethyl 3- OXOGLUTARATE are obtained, which can be used for the further reaction steps without purification. Qualification by gas chromatography: Purity by gas chromatography: Apparatus: gas chromatograph of HP-6850 type Method: Column : HP-1.25 m x 0. 32 MM, 0.17 URN of film thickness Carrier gas: hydrogen Program: 80 oC-5 MINUTES-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxoglutarate 5.77 minutes Enol ether 8.15 minutes Trimethyl aconitate 10. 00 minutes Trimethyl citrate 10. 42 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Result: Methyl acetoacetate: 0.31percent Dimethyl 3-oxoglutarate: 98.33percent Enol ether: 0. 81percent Trimethyl aconitate: 0. 28percent Trimethyl citrate : 0. 09percent Isoftalic acid derivative :- Other contamination (higher than 0,2 percent) Example 2 Into a mixture of 100.0 g (58 ml) of chlorosulphonic acid and 30 ml of methylene chloride 50.0 g of citric acid monohydrate are added within 30 minutes at a temperature between 10 oC and 15 oC. The mixture is stirred at the same temperature for 5 hours, cooled to 3-5 oC and 60 ml of methanol are introduced to it within 15 minutes at such a rate that the temperature does not exceed 25 oC. It is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC and 100 ml of water are added to it within 15 minutes. The thus-obtained mixture is extracted three times with 50 ml each of methylene chloride; the organic phases are combined, washed successively with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of water and evaporated in vacuo. Thus 40.8 g of dimethyl 3- OXOGLUTARATE are obtained. Yield: 98. 5 percent Apparatus : gas chromatograph of HP-6850 type Method : Column: HP-1.25 m x 0.32 mm, film thickness of 0. 17 Am Carrier gas: hydrogen Program: 80 oC-5 minutes-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxo- glutarate 5. 77 minutes Enol ether 8.15 minutes Trimethyl citrate 10.42 minutes Trimethyl aconitate 10.11 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0. 49percent Dimethyl 3-OXOGLUTARATE : 97. 62percent Enol ether: 0.98percent Trimethyl citrate: 0. 13percent Trimethyl aconitate: 0.29percent Isoftalic acid derivative: 0.07percent Other contamination (more than 0.2 percent) Example 3 (comparative example) Example 1 of the Belgian patent specification No. 879,537 A mixture of 212 ml of chlorosulphonic acid and 600 ml of methylene chloride is prepared (the ratio of methylene chloride to chlorosulphonic acid is 2.83 : 1 by volume). Then 200.0 g of citric acid are added to this mixture within 15-20 minutes, the addition rate of citric acid is 13.3 kg/minute, temperature = 20-22 oC. The reaction mixture is stirred at this temperature for 5 hours, cooled to a temperature between 3"C AND 5 C and 320 ml of methanol are added to it within 15 minutes at such a rate that the temperature remain below 25 oC. The reaction mixture is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC, poured into 800 ml of water, stirred vigorously for 15 minutes, clarified for 15 minutes and the phases are separated. The aqueous phase is extracted three times with 150 ml each of methylene chloride. The organic phases are combined, washed once with 400 ml of saturated sodium hydrogen carbonate solution and twice with 200 ml each of water and evaporated in vacuo. Thus 158.2 g of dimethyl 3-oxoglutarate are obtained. Yield: 87. 3 percent. Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0.21percent Dimethyl 3-oxoglutarate: 91.07percent Enol ether: 4.78percent Trimethyl aconitate 0.46percent Trimethyl citrate : 2.27percent Isoftalic acid derivative: 0.53percent Other contamination (higher than 0. 2percent)
Reference: [1] Patent: WO2004/89867, 2004, A2, . Location in patent: Page 20-26
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  • [ 186581-53-3 ]
  • [ 77-92-9 ]
  • [ 1587-20-8 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1993, vol. 32, # 12, p. 1292 - 1294
[2] Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 1, p. 55 - 62
  • 20
  • [ 77-92-9 ]
  • [ 1587-20-8 ]
Reference: [1] Journal of the Chemical Society - Dalton Transactions, 1997, # 20, p. 3705 - 3712
  • 21
  • [ 77-92-9 ]
  • [ 71-36-3 ]
  • [ 77-94-1 ]
YieldReaction ConditionsOperation in experiment
95.3%
Stage #1: at 80℃; for 3 h; Inert atmosphere
Stage #2: at 130℃;
Step 1, Preparation of choline-based acidic ionic liquid: 0.5mol choline chloride was heated under agitation flask was added 500mL, 0.25mol of citric acid was added, under a nitrogen atmosphere, the conditions of temperature 80 3h, after cooling to give choline-based acidic ionic liquid;Step 2, the esterification reaction: to a stirred with a mechanical, a thermometer, a reflux condenser and a four-necked flask was added 1.0mol trap n-butanol and a step in the choline-based acidic ionic liquid was heated to reflux with stirring the reaction water was separated from the trap, the reaction of the reaction to dryness stopped when re-entering the trap, choline chloride precipitates from the reaction system; the stirring was heated at reflux temperature of 130 , the stirring rate to 1000rpm;Step 3, separated choline chloride: The reaction system of Step II reaction was filtered to obtain a solid product and a liquid phase of choline chloride;Step 4, tributyl citrate purification: step 3 of the liquid product was subjected to atmospheric distillation, and then using mass concentration of 8percent NaHCO3Mass concentration of the solution or NaOH solution (also can be mass concentration of 1percent to 3percent of 1percent to 5percent Na2CO3Alternatively the solution pH) after the residue was washed atmospheric distillation residue to a value of 6, followed by activated carbon was added to the residue decolorized after washing, the activated carbon was removed by filtration, and then the residue was distilled under reduced pressure after filtration, the pressure is 260 Pa, the fraction collected 197 ~ 200 obtain tributyl citrate; the atmospheric distillation temperature of 119 deg.] C; mass of the activated carbon was 5.0percent by mass of citric acid in step a.
94.1% at 95 - 143℃; for 6.33333 h; A 1 L four-necked flask equipped with a stirrer, thermometer, condenser and distillate receiver was charged with 192.0 g (1.0 mole) of anhydrous citric acid, 267.0 g (3.6 moles) of butanol and 1.9 g of sulfuric acid. The mixture was heated to 95°C over a period of 20 minutes while being stirred at atmospheric pressure. While recovering butanol and water generated as by-products of esterification in the receiver, stirring was continued for 3 hours until the reaction temperature reached 105°C. Subsequently, while recovering butanol and water generated as by-products of esterification in the receiver, 222.0 g (3.0 moles) of additional butanol was added at a reaction temperature of 101 to 143°C over a period of 3 hours to complete the reaction. After the completion of the reaction, the reaction product was cooled to 60°C, and at the same temperature (60°C), neutralized by adding sodium carbonate in an amount corresponding to twice the acid value of the reaction product (i.e., 2.0 g) and 120.0 g of water. Subsequently, the organic layer was washed with 120.0 g of water and heated to 120°C. Excess butanol was recovered until the pressure reached about 4 kPa, and steam distillation was performed at the same pressure at 120°C for 1 hour to remove low-boiling components from the reaction product, to thereby obtain 329.0 g of a colorless transparent liquid. The yield was 94.1percent and the acid value of the product was 0.025 (mg KOH/g).
84.4% With toluene-4-sulfonic acid In toluene at 90 - 110℃; for 4 h; With a stirrer,Trap,Snake-shaped condenser,Necked flask equipped with a stirrer and a thermometer, 3.6 mol (266.4 g) of n-butanol was added,Citric acid 0.6 mol (210 g),P-toluenesulfonic acid (9.53 g)Toluene 50 ml.During heating from 90 ° C to 110 ° C,From the first drop of water began to reflux for 4 hours.During the reaction, the lower water layer of the water separator was continuously released and measured with a graduated cylinderWater quantity.After the esterification reaction, the excess toluene and ethanol were distilled off under reduced pressure,The reaction product is then distilled under reduced pressure to give tributyl citrate.After completion of the reaction,The product esterification rate was 96.3percentThe yield of tributyl citrate was 84.4percent.
Reference: [1] Tetrahedron, 2006, vol. 62, # 2-3, p. 422 - 433
[2] Angewandte Chemie - International Edition, 2009, vol. 48, # 1, p. 168 - 171
[3] Green Chemistry, 2014, vol. 16, # 11, p. 4649 - 4653
[4] Patent: CN104447306, 2016, B, . Location in patent: Paragraph 0044-0048; 0052
[5] Patent: EP1491523, 2004, A1, . Location in patent: Page 16
[6] RSC Advances, 2014, vol. 4, # 100, p. 57297 - 57307
[7] Patent: CN106278881, 2017, A, . Location in patent: Paragraph 0017; 0018
[8] Archives of Biochemistry, 1950, vol. 28, p. 274,275
[9] Industrial and Engineering Chemistry, 1955, vol. 47, p. 797
[10] Journal of Pharmacy and Pharmacology, 1950, vol. 2, p. 229
[11] Bulletin of the Chemical Society of Ethiopia, 2011, vol. 25, # 1, p. 147 - 150
[12] Catalysis Communications, 2012, vol. 25, p. 41 - 44
[13] Patent: WO2013/148255, 2013, A1, . Location in patent: Page/Page column 19-21
[14] Patent: CN104803847, 2016, B, . Location in patent: Paragraph 0027; 0028
[15] Patent: CN105646226, 2016, A, . Location in patent: Paragraph 0010
[16] Patent: WO2017/85745, 2017, A1, . Location in patent: Page/Page column 9
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  • [ 77-92-9 ]
  • [ 71-36-3 ]
  • [ 118068-28-3 ]
  • [ 142-96-1 ]
  • [ 77-94-1 ]
  • [ 101996-65-0 ]
Reference: [1] Patent: EP1849764, 2007, A1, . Location in patent: Page/Page column 21-22
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  • [ 7664-93-9 ]
  • [ 77-92-9 ]
  • [ 71-36-3 ]
  • [ 77-94-1 ]
Reference: [1] Industrial and Engineering Chemistry, 1955, vol. 47, p. 797
  • 24
  • [ 6372-14-1 ]
  • [ 77-92-9 ]
  • [ 59830-60-3 ]
Reference: [1] Patent: US5362912, 1994, A,
  • 25
  • [ 60822-47-1 ]
  • [ 121-43-7 ]
  • [ 77-92-9 ]
  • [ 98546-51-1 ]
Reference: [1] Patent: US6307047, 2001, B1,
  • 26
  • [ 150-59-4 ]
  • [ 77-92-9 ]
  • [ 5560-59-8 ]
YieldReaction ConditionsOperation in experiment
92% at 45 - 50℃; At temperatures between 45 and 50 ° C,The citric acid (57.5g, 0.3mol)In 240 mL of ethyl acetateAnd 120 mL of isopropyl alcoholOf the mixed solvent,The above obtained alvain free base (85 g, 0.3 mol)In 100 mL of ethyl acetate,Drop finished,Continue to reflux state stirring 0.5 ~ 1h,Natural cooling to 20 ~ 30 ° C,A large amount of white solid precipitated,Filter,washing,Get citrate alverine about128g. The above-obtained aliskine citrate was about 128 g, and the mixture was stirred at a temperature of 45 to 50 ° C and dissolved in a mixed solvent of N-methylpyrrolidone (260 mL) and water (260 mL). The appropriate amount of DMF was about 55 mL, 0 ° C, static crystallization of 4-5h, filter precipitation of crystals, filtration precipitation of crystals, 35 ~ 40 ° C vacuum drying, humidity control in the 20 ~ 40percent relative humidity, that was white solid 122g, the yield of about 92percent, HPLC purity 99.7percent.
66.9% at 20℃; 13.5 g of the above liquid was dissolved in 100 ml of absolute ethanol and dissolved by stirring. Then, 9.2 g (0.048 mol) of citric acid was dissolved in 100 ml of absolute ethanol, and the solid was stirred at room temperature to precipitate a solid.Filtering, washing and drying.Recrystallization from ethanol to obtain 15.2g of Alvulin citrate.Yield: 66.9percent.
Reference: [1] Patent: CN105461569, 2016, A, . Location in patent: Paragraph 0023; 0049-0050
[2] Patent: CN103508898, 2016, B, . Location in patent: Paragraph 0013; 0016; 0017
  • 27
  • [ 77-92-9 ]
  • [ 91424-40-7 ]
Reference: [1] Asian Journal of Chemistry, 2014, vol. 26, # 22, p. 7867 - 7868
  • 28
  • [ 24424-99-5 ]
  • [ 7424-00-2 ]
  • [ 77-92-9 ]
  • [ 51301-86-1 ]
Reference: [1] Patent: EP1211249, 2002, A1,
  • 29
  • [ 77-92-9 ]
  • [ 112885-42-4 ]
YieldReaction ConditionsOperation in experiment
88%
Stage #1: With sodium hydroxide In dichloromethane; water for 0.5 h; Heating / reflux
Stage #2: at 0℃; for 0.5 h; Heating / reflux
1.04 g (2 [MMOL)] of compound [(VIII)] and 15 mi of 1.77 M hydrochloric acid in ethyl acetate are stirred at 50 [C] for 2 hours and at 0 [C] for 2 hours. The precipitated crystals are filtered and washed 2 x with cooled ethyl acetate to give 0.93 g (94 percent) mosapride dihydrochloride. Mp. 144-155 [C.] To the mosapride [DIHYDROCHLORIDE] salt obtained the above manner, 20 ml of [DICHLOROMETHANE,] 10 [ML] of water and 1.2 [ML] of 4 M aqueous sodium hydroxide solution are added. The organic phase is separated and the aqueous phase extracted with [2X10] [ML] of [DICHLOROMETHANE.] The combined organic phases are dried over anhydrous sodium sulphate, filtered and the solvent evaporated under reduced pressure. To the residue 23 [ML] of 10percent aqueous citric acid solution is added, refluxed for 30 minutes and cooled to 0 [C.] The precipitated product is filtered and washed 2 x with water to give 0.91 g (88percent) of the title compound. Mp : [110-113 C.]
Reference: [1] Patent: WO2003/106440, 2003, A2, . Location in patent: Page 9-10
  • 30
  • [ 112885-34-4 ]
  • [ 77-92-9 ]
  • [ 112885-42-4 ]
YieldReaction ConditionsOperation in experiment
88.7% at 50 - 65℃; 4-Acetylamino-5-chloro-2-ethoxy-n-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (20.00 g, 0.046 mol)Into a reaction flask containing 200 ml of methanol,The solution was heated and refluxed at 65 ° C, dissolved completely, cooled to 50 ° C, and an aqueous solution of citric acid was added.The reaction is kept for 30-45 minutes. After the reaction, the temperature is lowered, crystallization, suction filtration,Mosapride citrate was obtained (yield 88.7percent, purity 99.93percent).
Reference: [1] Patent: CN108341788, 2018, A, . Location in patent: Paragraph 0069; 0070; 0074; 0079; 0080; 0081-0087
  • 31
  • [ 112885-41-3 ]
  • [ 77-92-9 ]
  • [ 112885-42-4 ]
YieldReaction ConditionsOperation in experiment
95.45% at 80 - 110℃; for 0.5 h; Citric acid monohydrate (84.67 g) and water (850 ml) were charged at ambient temperature and stirred to dissolve the solid. The reaction mass was heated up to 80°C and mosapride free base (85 g) was charged at 80°C. The heterogeneous mass was stirred and heated up to reflux (95 °C to 110°C). The clear solution was stirred at reflux temperature for 30 minutes. The reaction mass was cooled down to 0°C and was stirred at 0°C to 5°C for 30 minutes. The solid was filtered and washed with water (2 X 170 ml). The solid was suck dried and unloaded. The solid was dried at 60°C for 15 hours under vacuum to give the title compound.Yield: 125 g (95.45percent)Water content: 6.28percentD-II Impurity: 0.269
94.7% at 50℃; for 1 h; General procedure: Stirring blade, three-necked flask 100mL fitted with a thermometer, HPLC and thepurity 99.94percent of the amide compound 10.0g (23.8mmol) prepared in Preparation Example 1,ethanol 80g, and water 80g was added, stirring to obtain a slurry. The resulting slurry waswarmed to 50 ° C. Then, 13.6g citric acid (71.2mmol) was dropped to gradually the slurry overa period of (temperature 50 ° C of the aqueous solution) for 10 minutes aqueous solution ofcitric acid dissolved in water 20g, amide compound and citric acid was reacted (the temperatureof the reaction solution at the time of aqueous citric acid dropwise addition was adjusted to 50 °C (reaction temperature 50 ° C)). After the aqueous solution of citric acid dropping, and allowedto react for 1 hour at 50 ° C (reaction temperature 50 ° C. The reaction solution wasconfirmed by visual observation that became clear during this time. ). Thereafter, the resultantreaction solution was cooled slowly to 10 ° C, and held for 1 hour. The precipitated solid wasfiltered off by vacuum filtration and the cake was washed twice with water 30g. Obtained afterdrying under reduced pressure a white solid at an external temperature of 40 ° C, as a whitesolid 4-amino-5-chloro-2-ethoxy -N - [[4- (4-fluoro-benzyl) -2-morpholinyl] methyl] It wasobtained benzamide citrate 2 hydrate (citrate dihydrate) 14.1g (21.8mmol). Yield: 91.4percent, HPLCpurity: 99.94percent, by-products: (not detected) undetected, water content: 5.8percent, quantitative value:was 100.5percent. The results are shown in Table 1. Incidentally, the yield of citrate dihydrate is avalue obtained by measuring the mass of simply obtained solid.
Reference: [1] Patent: WO2011/107903, 2011, A1, . Location in patent: Page/Page column 11
[2] Patent: JP5743474, 2015, B2, . Location in patent: Paragraph 0065; 0069; 0071
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  • [ 77-92-9 ]
  • [ 85157-21-7 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 1, p. 153 - 158
  • 33
  • [ 19957-52-9 ]
  • [ 77-92-9 ]
  • [ 50-41-9 ]
YieldReaction ConditionsOperation in experiment
361 g
Stage #1: With 1,3-dichloro-5,5-dimethylhydantoin; acetic acid In toluene at 60℃; for 2 h;
Stage #2: at 0℃; for 4.5 h; Heating
The reaction mixture was brought to 60° C. and, maintaining this temperature, 500 mL of acetic acid were added during 30′. The water content was checked below 500 ppm (Karl Fischer titration).A warm solution (50-60° C.), prepared with 60 g of dichloro dimethyl hydantoin (1,3-dichloro-5,5-dimethyl hydantoin; abbreviated DCDMI) (0.474 mol. equiv.) in 600 mL of toluene, was slowly added to the reaction mixture during 90′ maintaining the temperature at about 60° C. After checking the conversion by HPLC, a small addition of DCDMI solution was necessary in order to have the starting material below 0.5percent. The reaction mixture was cooled to 15-20° C. and treated slowly with 750 mL of water and, up to pH 12, approximately 1000 mL of aqueous sodium hydroxide 30percent w/w solution. After stirring for 30′, the layers were separated and the organic phase was washed with 3×250 mL of water and concentrated by vacuum distillation thus obtaining 280 g of Clomiphene, as an oil containing some residual toluene of formula (I) and (II).The oil obtained in the previous step was taken up with 625 mL of acetone, the clear solution warmed to gentle boiling and a solution composed of 142.5 g of citric acid monohydrate and 1000 mL of acetone was slowly added during 30′. The reaction mixture was stirred while slowly cooling to 0° C. and then 4 hours at 0° C. The product was filtered, washed with acetone and dried under vacuum obtaining 361 g of Clomiphene citrate, the molar yield was 94.1percent. HPLC purity >98percent (A/Apercent).
Reference: [1] Patent: US2016/152551, 2016, A1, . Location in patent: Paragraph 0098; 0101; 0102; 0103; 0104; 0105
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  • [ 50-41-9 ]
YieldReaction ConditionsOperation in experiment
30.8 g for 0.0833333 h; Reflux 25.0 g of the clomiphene cis-trans isomer mixture obtained in Example 1 was dissolved in 25 mL of absolute ethanol, 12.18 g of anhydrous citric acid was added, and the mixture was heated to reflux for 5 minutes, and the temperature was gradually lowered until the temperature was 20 °C no solid precipitation, the ice bath after cooling and stirring for half an hour, ice bath cooling and stirring for half an hour, precipitation of white viscous solid, adding tert-butyl methyl ether 50mL diluted to continue after ice bath for half an hour, filtration, solid with a small amount of tert-butyl methyl ether washing and dried to give 30.8 g of clomiphene citrate, 97.53percent.
Reference: [1] Patent: CN107033013, 2017, A, . Location in patent: Paragraph 0059; 0060
  • 35
  • [ 748-97-0 ]
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  • [ 54965-24-1 ]
  • [ 54965-24-1 ]
YieldReaction ConditionsOperation in experiment
7.5 g
Stage #1: With hydrogenchloride In water; isopropyl alcohol for 5 h; Reflux
Stage #2: at -5 - 10℃; for 10 h;
1) 20 g of raw material (formula I) was added to the three-necked flask, 180 ml of isopropyl alcohol was added, dissolved by stirring, 50 ml of hydrochloric acid was added, and the mixture was heated under reflux for 5 hours. HPLC to monitor the E isomer greater than 35percent (HPLC Figure 1), cooled to room temperature crystallization 2h, Filtration, filter cake can be recycled, the filtrate by adding 120ml of water, if solid, filter, take the filtrate, adjust the pH to sodium with sodium hydroxide, There is a solid precipitation, extracted with ethyl acetate to the organic layer without obvious color, pure water to weak alkaline, Dried over anhydrous sodium sulfate and filtered to dryness to give 10 g of an oily substance, i.e., a mixture of Z-tamoxifen and e-tamoxifen, with an E isomer content greater than 65percent (HPLC Figure 2); 10 ml of the above sample was added with 10 ml of acetone. After stirring and stirring, 5 g of citric acid was added, stirred and dissolved, cooled at -5-10 ° C for 10 h, The filter cake was washed with acetone to give 12 g of a mixture of tamoxifen citrate and tamoxifen citrate (E isomer content greater than 70percent) (HPLC Figure 3); Take the above 12g solid, add 60ml of water and 12ml of ethanol, dissolved in activated carbon after decolorization 0.5h, hot filter, the filtrate -5-25 ° C cooling crystallization, Filtration, filter cake with acetone beating washing, drying, 8g E-tamoxifen citrate (content greater than 98.5percent, HPLC shown in Figure 4); according to the above method for secondary recrystallization, So that 7.5gE-tamoxifen citrate (content of more than 99.5percent, HPLC Figure shown in Figure 5).
Reference: [1] Patent: CN103992234, 2016, B, . Location in patent: Paragraph 0055-0059
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  • [ 54965-24-1 ]
Reference: [1] Pharmaceutical Research, 2006, vol. 23, # 4, p. 806 - 812
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  • [ 185836-75-3 ]
Reference: [1] Patent: US5753659, 1998, A,
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  • [ 77-92-9 ]
  • [ 220996-80-5 ]
Reference: [1] Patent: US5968938, 1999, A,
[2] Patent: US6090805, 2000, A,
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  • [ 101048-76-4 ]
  • [ 222978-02-1 ]
Reference: [1] Patent: US6441017, 2002, B1,
  • 40
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  • [ 68858-20-8 ]
  • [ 77-92-9 ]
  • [ 150114-97-9 ]
Reference: [1] Patent: US2016/158377, 2016, A1, . Location in patent: Paragraph 1060
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  • [ 351456-45-6 ]
Reference: [1] Patent: US2002/161022, 2002, A1,
  • 42
  • [ 77-92-9 ]
  • [ 1201902-80-8 ]
Reference: [1] Patent: CN106496259, 2017, A, . Location in patent: Paragraph 0056; 0057; 0058; 0067; 0071; 0076; 0081
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  • [ 1201902-80-8 ]
Reference: [1] Patent: CN106496259, 2017, A, . Location in patent: Paragraph 0059; 0060; 0061; 0062
  • 44
  • [ 1201903-03-8 ]
  • [ 77-92-9 ]
  • [ 1201902-80-8 ]
YieldReaction ConditionsOperation in experiment
98% at 25 - 74℃; Step 4: 4-(/?.S)-(carboxymethyl)-2-((/?)-l-(2-(2,5-dichlorobenzamido)acetamido)-3- methylbutyl)-6-oxo-l,3,2-dioxaborinane-4-carboxylic acid (1-1)[0314] Form 1: To a solution of citric acid (2.75 g, 14.3 mmol) in EtOAc (85 mL) with an internal temperature of about 74 0C was added N,N',N"-{boroxin-2,4,6-triyltris[[(lR)-3-methylbutane-l,l- diyl]imino(2-oxoethane-2,l-diyl)] }tris(2,5-dichlorobenzamide) (5.00 g, 4.87 mmol) as a solid. The solution was cooled uncontrolled until the internal temperature was about 25 0C and the mixture was stirred overnight. The resulting precipitate was collected by filtration to yield 2,2'-{2-[(lR)-l-({ [(2,5- dichlorobenzoyl)amino]acetyl }amino)-3-methylbutyl]-5-oxo-l,3,2-dioxaborolane-4,4-diyl}diacetic acid Form 1 as a crystalline solid (6.65 g, 88 percent). 1H NMR (500 MHz, DMSOd6, δ 110 0C): 10.08 (s, IH), 8.69 (s, IH), 7.61 (s, IH), 7.52 (d, J = 1.3 Hz, 2H), 4.26 (d, J = 5.5 Hz, 2H), 2.70 (q, J = 14.5 Hz, 4H), 2.70 (bs, IH), 1.72 (sept, J - 6.5 Hz, IH), 1.42 (ddd, J = 5.2 Hz, J = 8.6 Hz, J = 13.9 Hz, IH), 1.28 (ddd, J = 5.3, J = 9.4 Hz, J = 14.3 Hz, IH), 0.91 (dd, J = 3.3 Hz, J = 6.6 Hz, 6H). MS (m/z) in CH3CN: [M+Na] calculated for C20H23BCl2N2NaO9, 539.1; found, 539.1.[0315] The XRPD data for 1-1 Form 1 is shown in FIGURE 1 and in Table 1. Table 1: XRPD Data 1-1 Form 1[0316] The Differential Scanning Calorimetry (DSC) data for 1-1 Form 1 is shown in FIGURE 2. The profile is characterized by an endothermic transition with an onset temperature of 191.8 0C with a melt of 198.8 "C. A second endothermic transition corresponding to decomposition has an onset temperature of 225 0C. These temperatures have an error of +/- 5 °C.[0317] The Thermal Gravimetric Analysis (TGA) data for 1-1 Form 1 is shown in FIGURE 2. The profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 oC/min. The weight loss represents a loss of about 0.72 percent of the weight of <n="65"/>the sample as the temperature is changed from 50 0C to 200 °C. These temperatures have an error of +/- 5 0C.[0318] Form 2: To a solution of citric acid (10.1 g, 52.6 mmol) in EtOAc (300 mL) with an internal temperature of about 74 °C was added a solution of N,N',N"-{boroxin-2,4,6-triyltris[[(lR)-3- methylbutane-l,l-diyl]imino(2-oxoethane-2,l-diyl)] }tris(2,5-dichlorobenzamide) (20.O g, 19.5 mmol) in EtOAc (60 mL). The solution was cooled slowly (about 0.33 °C/min) until the internal temperature was about 60 °C and the mixture was stirred for 3 h. The resulting slurry was cooled slowly (rate of about 0.12 °C/min) until the internal temperature was about 25 0C and the mixture was stirred overnight. The resulting precipitate was collected by filtration to yield 4-(/?,S)-(carboxymethyl)-2- ((R)- 1 -(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo- 1 ,3,2-dioxaborinane-4- carboxylic acid Form 2 as a crystalline solid (26.7g, 98 percent). 1H NfMR (500 MHz, DMSO d6, δ 110 0C): 10.08 (s, IH), 8.69 (s, IH), 7.61 (s, IH), 7.52 (d, J = 1.3 Hz, 2H), 4.26 (d, J = 5.5 Hz, 2H), 2.70 (q, J = 14.5 Hz, 4H), 2.70 (bs, IH), 1.72 (sept, J - 6.5 Hz, IH), 1.42 (ddd, J = 5.2 Hz, J = 8.6 Hz, J = 13.9 Hz, IH), 1.28 (ddd, J = 5.3, J = 9.4 Hz, J = 14.3 Hz, IH), 0.91 (dd, J = 3.3 Hz, J = 6.6 Hz, 6H). 13C NMR (100 MHz, DMSO-Cl6, δ 100 0C): 21.65, 23.34, 25.09, 38.39, 38.98, 42.07, 76.25, 128.97, 129.14, 130.94, 131.48, 131.73, 137.05, 165.44, 170.23, 175.74, 177.43. MS (m/z) in CH3CN: [M+Na] calculated for C20H23BCl2N2NaO9, 539.1; found, 539.1.[0319] 4-(/?;5)-(carboxymethyl)-2-((/?)-l-(2-(2,5-dichlorobenzamido)acetamido)-3- methylbutyl)-6-oxo-l,3,2-dioxaborinane-4-carboxylic acid Form 2 was also prepared by adding a solution of citric acid (21 g, 0.11 mmol) in THF (80 mL) to a solution of N,N',N"-{boroxin-2,4,6- triyltris[[(lR)-3-methylbutane-l,l-diyl]imino(2-oxoethane-2,l-diyl)]tris(2,5-dichlorobenzamide) (40 g, 0.11 mmol) in THF (80 mL) at 60 0C. The solution was then seeded with Form 2 crystals (400 mg). After stirring for 30 min at 60 0C, EtOAc (400 mL) was added over a period of 9 h. After complete addition of the EtOAc, the temperature was lowered to 20 0C over 5 h. The resulting suspension was filtered to collect 4-(fi,S)-(carboxymethyl)-2-((/?)-l-(2-(2,5- dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-l,3,2-dioxaborinane-4-carboxylic acid Form 2 as a crystalline solid (40 g, 70 percent).[0320] 4-(/?,5)-(carboxymethyl)-2-((/?)-l-(2-(2,5-dichlorobenzamido)acetamido)-3- methylbutyl)-6-oxo-l,3,2-dioxaborinane-4-carboxylic acid Form 2 was also prepared in the same general manner using the conditions described in Table 2. <n="66"/> Table 2: Additional conditions for preparation of 1-1 Form 2[0321] 4-(Λ,5)-(carboxymethyl)-2-((Λ)-l-(2-(2,5-dichlorobenzamido)acetamido)-3- methylbutyl)-6-oxo-l ,3,2-dioxaborinane-4-carboxylic acid Form 2 was also prepared by dissolving in acetone followed by addition of EtOAc as an antisolvent.[0322] The XRPD data for 1-1 Form 2 is shown in FIGURE 3 and in Table 3. Table 3: XRPD Data 1-1 Form 2[0323] The Differential Scanning Calorimetry (DSC) data for 1-1 Form 2 is shown in FIGURE 4. The profile is characterized by an endothermic transition with an onset temperature of 206.5 0C with a melt of 219.9 0C. A second endothermic transition corresponding to decomposition has an onset temperature of 225 0C. These temperatures have an error of +/- 5°C.[0324] The Thermal Gravimetric Analysis (TGA) data for 1-1 Form 2 is shown in FIGURE 4. The profile graphs the percent loss of weight of the sample as a function of temperature, the temperature rate change being about 10 °C/min. The weight loss represents a loss of about 1.1 percent of the weight of <n="67"/>the sample as the temperature is changed from 50 0C to 200 0C. These temperatures have an error of +/- 5°C.
Reference: [1] Patent: WO2009/154737, 2009, A1, . Location in patent: Page/Page column 63
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