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Product Details of [ 1830-54-2 ]

CAS No. :1830-54-2 MDL No. :MFCD00008462
Formula : C7H10O5 Boiling Point : -
Linear Structure Formula :CH3OC(O)CH2C(O)CH2C(O)OCH3 InChI Key :RNJOKCPFLQMDEC-UHFFFAOYSA-N
M.W : 174.15 Pubchem ID :74591
Synonyms :
Dimethyl-3-oxoglutarate

Calculated chemistry of [ 1830-54-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.57
Num. rotatable bonds : 6
Num. H-bond acceptors : 5.0
Num. H-bond donors : 0.0
Molar Refractivity : 38.53
TPSA : 69.67 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) : -7.37 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.41
Log Po/w (XLOGP3) : -0.01
Log Po/w (WLOGP) : -0.32
Log Po/w (MLOGP) : -0.33
Log Po/w (SILICOS-IT) : 0.41
Consensus Log Po/w : 0.23

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.52
Solubility : 52.9 mg/ml ; 0.304 mol/l
Class : Very soluble
Log S (Ali) : -1.0
Solubility : 17.3 mg/ml ; 0.0991 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.79
Solubility : 28.4 mg/ml ; 0.163 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.73

Safety of [ 1830-54-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280 UN#:N/A
Hazard Statements:H317 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1830-54-2 ]

* 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 [ 1830-54-2 ]
  • Downstream synthetic route of [ 1830-54-2 ]

[ 1830-54-2 ] Synthesis Path-Upstream   1~37

  • 1
  • [ 1830-54-2 ]
  • [ 5694-95-1 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 29, p. 4907 - 4911
[2] Tetrahedron Letters, 2000, vol. 41, # 40, p. 7619 - 7622
  • 2
  • [ 1830-54-2 ]
  • [ 73027-79-9 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 7, p. 787 - 792
  • 3
  • [ 1830-54-2 ]
  • [ 6950-82-9 ]
Reference: [1] Chemistry of Natural Compounds, 2004, vol. 40, # 5, p. 434 - 443
  • 4
  • [ 1830-54-2 ]
  • [ 62935-72-2 ]
Reference: [1] Chemistry of Natural Compounds, 2004, vol. 40, # 5, p. 434 - 443
  • 5
  • [ 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
  • 6
  • [ 16695-14-0 ]
  • [ 1830-54-2 ]
Reference: [1] Chemical & Pharmaceutical Bulletin, 1981, vol. 29, # 10, p. 2762 - 2768
[2] Tetrahedron Letters, 1981, vol. 22, # 34, p. 3245 - 3246
  • 7
  • [ 105-45-3 ]
  • [ 616-38-6 ]
  • [ 1830-54-2 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1989, vol. 108, # 2, p. 51 - 56
  • 8
  • [ 77-92-9 ]
  • [ 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
  • 9
  • [ 67-56-1 ]
  • [ 542-05-2 ]
  • [ 1830-54-2 ]
Reference: [1] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1922, vol. 121, p. 146
[2] Annales de Chimie (Cachan, France), 1891, vol. <6> 23, p. 165
[3] Chemische Berichte, 1916, vol. 49, p. 2704[4] Chemische Berichte, 1920, vol. 53, p. 1917
[5] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1922, vol. 121, p. 146
[6] Russian Journal of Organic Chemistry, 2010, vol. 46, # 4, p. 517 - 519
  • 10
  • [ 67-56-1 ]
  • [ 77-92-9 ]
  • [ 1830-54-2 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1998, vol. 37, # 4, p. 397 - 398
  • 11
  • [ 40018-26-6 ]
  • [ 1830-54-2 ]
  • [ 865187-80-0 ]
  • [ 53562-51-9 ]
YieldReaction ConditionsOperation in experiment
51% With lithium bromide In 1,4-dioxane for 20 h; Reflux A solution of dimethyl acetone-1,3-dicarboxylate (7) (51.4 g, 0.296 mol) in 1,4-dioxane (75 mL) and then LiBr (28.2 g, 0.325 mol) were added to a stirred suspension of 2,5-dihydroxy-1,4-dithiane (30.0 g, 0.197 mol) in 1,4-dioxane (300 mL). The mixture was stirred at reflux for 20 h. The mixture was filtered into a separating funnel and extracted with ethyl acetate (500 mL) and water (70 mL). The water layer was re-extracted with ethyl acetate (2.x.250 mL) and the combined organic layers were washed with aq HCl (500 mL, 1 M), aq NaHCO3 (5percent), aq NaOH (500 mL, percent10) and then with brine (500 mL). The solution was dried over MgSO4 and the solvent was evaporated. The crude product was purified by column chromatography (350 g) eluting with hexane/ethyl acetate (7:2) and then (5:2) to give monoester 10 as the first fraction. The desired diester 9 was isolated as the second fraction.
Reference: [1] Tetrahedron, 2011, vol. 67, # 45, p. 8679 - 8684
  • 12
  • [ 1830-54-2 ]
  • [ 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
  • 13
  • [ 1830-54-2 ]
  • [ 5164-76-1 ]
Reference: [1] Journal of the American Chemical Society, 1969, vol. 91, p. 7359 - 7371
  • 14
  • [ 1830-54-2 ]
  • [ 7250-55-7 ]
YieldReaction ConditionsOperation in experiment
94% With sodium tetrahydroborate In methanol at 0 - 20℃; for 24 h; To a stirred solution of dimethyl 3-oxoglutarate (17.7ml, 120.6mmol) in MeOH (315 mL) at 0 °C was added portion wise NaBH4 (3.9g, 102.5 mol). The reaction was allowed to reach room temperature. After 24 h, the reaction mixture was quenched by addition of solid citric acid until pH reached 5 to 6. To the reaction mixture was added silica gel (ca. 1g) and the solvent was distilled off. The residue was purified by column chromatography on silicagel (EtOAc:hexane, 1:1) to afford the dimethyl 3-hydroxyglutarate (19.98g, 94percent)as a colorless oil.
Reference: [1] Journal of the Brazilian Chemical Society, 2011, vol. 22, # 1, p. 172 - 175
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3650 - 3653
[3] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1567 - 1569
[4] RSC Advances, 2016, vol. 6, # 27, p. 22737 - 22748
[5] Journal of the American Chemical Society, 2009, vol. 131, # 49, p. 17980 - 17985
[6] Canadian Journal of Chemistry, 1988, vol. 66, # 6, p. 1422 - 1424
[7] Angewandte Chemie - International Edition, 2008, vol. 47, # 50, p. 9743 - 9746
[8] Journal of Organic Chemistry, 1997, vol. 62, # 15, p. 5057 - 5061
[9] Tetrahedron, 1997, vol. 53, # 40, p. 13757 - 13768
[10] Chemische Berichte, 1953, vol. 86, p. 186,188
[11] Zhurnal Obshchei Khimii, 1952, vol. 22, p. 1467[12] Chem.Abstr., 1953, vol. 47, p. 5949
[13] Chemische Berichte, 1953, vol. 86, p. 186,188
[14] Journal of the American Chemical Society, 1961, vol. 83, p. 4228 - 4233
[15] Journal of the American Chemical Society, 1969, vol. 91, p. 7359 - 7371
[16] Tetrahedron, 1987, vol. 43, # 1, p. 45 - 58
[17] Journal of Organic Chemistry, 1998, vol. 63, # 9, p. 3037 - 3040
[18] Il Farmaco; edizione scientifica, 1978, vol. 33, # 4, p. 237 - 252
  • 15
  • [ 1830-54-2 ]
  • [ 106-95-6 ]
  • [ 7250-55-7 ]
  • [ 111086-20-5 ]
  • [ 147528-53-8 ]
Reference: [1] Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2260 - 2264
  • 16
  • [ 1830-54-2 ]
  • [ 106-95-6 ]
  • [ 7250-55-7 ]
  • [ 111086-20-5 ]
Reference: [1] Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2260 - 2264
  • 17
  • [ 1830-54-2 ]
  • [ 106-95-6 ]
  • [ 7250-55-7 ]
  • [ 147528-53-8 ]
Reference: [1] Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2260 - 2264
  • 18
  • [ 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
  • 19
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  • [ 4670-09-1 ]
Reference: [1] Organic Letters, 2011, vol. 13, # 1, p. 118 - 121
  • 20
  • [ 1830-54-2 ]
  • [ 201595-00-8 ]
  • [ 1245735-97-0 ]
  • [ 17790-74-8 ]
Reference: [1] Arkivoc, 2010, vol. 2010, # 4, p. 74 - 89
  • 21
  • [ 1830-54-2 ]
  • [ 118247-88-4 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 9, p. 2363 - 2369
  • 22
  • [ 1830-54-2 ]
  • [ 122-51-0 ]
  • [ 79398-27-9 ]
YieldReaction ConditionsOperation in experiment
67%
Stage #1: at 120℃; for 1.5 h;
Stage #2: With ammonia In water for 1 h; Cooling with ice
Stage #3: With hydrogenchloride In water
3-Oxo-pentanedioic acid dimethyl ester (100 g, 575 mmol), (EtO)3CH (95 mL, 575 mmol), Ac2O (108 mL) and HOAc (108 mL) were mixed and heated at 120° C. for 1.5 hours, then allowed to cool to 25° C.
The volatiles were removed under reduced pressure while maintaining the water bath around 85° C.
To the crude liquid was added aqueous NH3 (25percent, 150 mL) in portions with swirling in an ice bath and the stirring was continued for 1 hour.
The mixture was acidified by the addition of 6 N HCl.
The yellow precipitate was collected by filtration, boiled in toluene, cooled and filtered to give 4,6-dihydroxy-nicotinic acid methyl ester as an orange solid. (Yield 65 g, 67percent).
1H NMR (300 MHz, d6-DMSO): δ 8.06 (s, 1H), 5.65 (s, 1H), 3.83 (s, 3H). LC-MS: [M+H]+ 170.
55%
Stage #1: at 150℃; for 4 h;
Stage #2: at 100℃; for 1 h;
A (460.0 g, 2.64 mol) and triethyl orthoformate (586.5 g, 3.96 mol) were dissolved in 690 mL of acetic anhydride,After stirring at 150 ° C for 4 hours,The reaction mixture was volume-concentrated to 600 mL at 100 ° C.Slowly add 920 mL of NH3 · H2O with stirring, and after 1 hour,The reaction mixture was acidified with 2.3 L of 5 mol / L HCl.The precipitate was collected by filtration and dried to give 243.0 g of product B in 55percent yield.
46%
Stage #1: at 130℃; for 2 h;
Stage #2: With ammonia In water for 0.5 h;
Stage #3: With hydrogenchloride In water
A solution containing dimethyl-1, 3-acetonedicarboxylate (2000 g, 11.5 mol), ethyl orthoformate (1947 mL, 11.5 mol), and acetic anhydride (2168 mL, 23.0 mol) was heated at 130 °C for 2 h. The reaction was allowed to be cooled to room temperature then concentrated in vacuo to 1500 mL. The crude reaction was cooled in ice bath and aqueous ammonia (2 L) was added in portions with stirring. After 30 min, the mixture was acidified with concentrated HC1 (-300 mL) and the suspension was filtered. The crude product was dried under vacuum to give methyl 4,6- dihydroxynicotinate (900 g, 46percent) which was taken on directly into the next step.
Reference: [1] Patent: US2012/184562, 2012, A1, . Location in patent: Page/Page column 6; 17
[2] Patent: CN106854177, 2017, A, . Location in patent: Paragraph 0016; 0018; 0024; 0030
[3] Patent: WO2014/210354, 2014, A1, . Location in patent: Page/Page column 40
[4] Patent: WO2012/110860, 2012, A1, . Location in patent: Page/Page column 98
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  • [ 79398-27-9 ]
YieldReaction ConditionsOperation in experiment
53%
Stage #1: at 130℃; for 1.5 h;
Stage #2: With ammonia In water at 0℃; for 1 h;
Example 1
Synthesis of 2,4-dichloro-5-nitro-pyridine
Dimethyl-1,3-acetonedicarboxylate (50.0 g, 287 mmol), triethylorthoformate (47.8 mL, 287 mmole), and acetic anhydride (54.2 mL, 102 mmol) were combined and heated to 130° C. for 1.5 h then allowed to cool to 25° C.
The volatiles were removed in vacuo while maintaining the water bath around 85° C. until the volume of the reaction was reduced to about 25 mL.
This crude liquid was poured into a 2000 mL flask and cooled in an ice bath.
To this cooled flask was added 75 mL of concentrated aqueous NH3 in portions with swirling.
After 1 hour the mixture was acidified by the addition of 6 N HCl (~250 mL).
The yellow precipitate was collected by vacuum filtration and allowed to dry under a stream of air.
The crude powder was boiled in 200 mL of benzene and allowed to cool and filtered to provide 4,6-dihydroxy-nicotinic acid methyl ester as an orange solid (25.7 g, 53percent).
Reference: [1] Patent: US2006/217417, 2006, A1, . Location in patent: Page/Page column 12
[2] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 1363 - 1366
[3] Journal of the Chinese Chemical Society, 2016, vol. 63, # 9, p. 758 - 769
  • 24
  • [ 1830-54-2 ]
  • [ 4637-24-5 ]
  • [ 79398-27-9 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 7, p. 787 - 792
  • 25
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  • [ 85157-21-7 ]
Reference: [1] Heterocycles, 1992, vol. 34, # 2, p. 273 - 291
  • 26
  • [ 1830-54-2 ]
  • [ 65973-52-6 ]
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[2] Patent: WO2012/110860, 2012, A1,
[3] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 7, p. 787 - 792
[4] Patent: WO2014/210354, 2014, A1,
[5] Patent: CN106854177, 2017, A,
[6] Journal of the Chinese Chemical Society, 2016, vol. 63, # 9, p. 758 - 769
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Reference: [1] Patent: US2013/178478, 2013, A1,
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2683 - 2691
[3] Patent: US2004/77653, 2004, A1,
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YieldReaction ConditionsOperation in experiment
22.5 g
Stage #1: With Ni(acac)2 In 1,4-dioxane for 16 h; Reflux
Stage #2: for 0.583333 h; Reflux
Example 63
2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one
A mixture of dimethyl acetone-1,3-dicarboxylate (200 g, 1.15 mol), cyanamide (48.3 g, 1.15 mol), and Ni(acac)2 (14.75 g, 0.0574 mol) in dioxane (200 mL) was heated to reflux for 16 h and then cooled to room temperature.
The precipitate was filtered off, and the solid was mixed with methanol (200 mL) and stirred for 30 min and filtered again to give 93 g product (44percent yield).
In a 1 L flask with a reflux condenser was added the product from step one (93.0 g, 0.505 mol) and POCl3 (425 mL) and the reaction mixture was heated to reflux for 35 min. POCl3 (300 mL) was evaporated under vacuum.
The residue was poured into ice and water (400 mL), which was neutralized with KOH to pH 6-7.
The precipitate was filtered off and extracted with ethyl acetate (2*300 mL).
The organic solution was concentrated and purified by column chromatography to give methyl 2-amino-4,6-dichloropyridine-3-carboxylate (22.5 g, 20.1percent).
Reference: [1] Patent: US2013/281397, 2013, A1, . Location in patent: Paragraph 0588; 0589
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[2] Patent: US2013/281398, 2013, A1,
[3] Patent: WO2015/103355, 2015, A1,
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