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Chemical Structure| 97-67-6
Chemical Structure| 97-67-6
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Product Details of [ 97-67-6 ]

CAS No. :97-67-6 MDL No. :MFCD00064213
Formula : C4H6O5 Boiling Point : -
Linear Structure Formula :- InChI Key :BJEPYKJPYRNKOW-REOHCLBHSA-N
M.W : 134.09 Pubchem ID :222656
Synonyms :
(S)-Hydroxybutanedioic acid;(S)-E 296;L-Malic acid;(S)-2-Hydroxysuccinic acid

Calculated chemistry of [ 97-67-6 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.5
Num. rotatable bonds : 3
Num. H-bond acceptors : 5.0
Num. H-bond donors : 3.0
Molar Refractivity : 26.05
TPSA : 94.83 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) : -8.01 cm/s

Lipophilicity

Log Po/w (iLOGP) : -0.01
Log Po/w (XLOGP3) : -1.26
Log Po/w (WLOGP) : -1.09
Log Po/w (MLOGP) : -1.37
Log Po/w (SILICOS-IT) : -1.25
Consensus Log Po/w : -1.0

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : 0.32
Solubility : 280.0 mg/ml ; 2.09 mol/l
Class : Highly soluble
Log S (Ali) : -0.24
Solubility : 78.0 mg/ml ; 0.582 mol/l
Class : Very soluble
Log S (SILICOS-IT) : 1.53
Solubility : 4510.0 mg/ml ; 33.7 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.27

Safety of [ 97-67-6 ]

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 [ 97-67-6 ]

* 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 [ 97-67-6 ]
  • Downstream synthetic route of [ 97-67-6 ]

[ 97-67-6 ] Synthesis Path-Upstream   1~24

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  • [ 500-05-0 ]
  • [ 110-17-8 ]
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  • 4
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  • 5
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  • [ 926-61-4 ]
Reference: [1] Chemische Berichte, 1884, vol. 17, p. 936[2] Justus Liebigs Annalen der Chemie, 1891, vol. 264, p. 262,272
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Reference: [1] Chemische Berichte, 1884, vol. 17, p. 936[2] Justus Liebigs Annalen der Chemie, 1891, vol. 264, p. 262,272
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YieldReaction ConditionsOperation in experiment
98% at 25℃; Cooling with ice Thionyl chloride (117 g, 0.98 mol) was added to the solution of L-malic acid (59.9 g, 0.45 mol) in methanol (400 mL) in ice-water bath. The resulting reaction mixture was stirred overnight at room temperature (rt, 25 °C) after the completion of the addition. The reaction was monitored with TLC (EtOAc:MeOH =10:1). The solvent was removed in vacuo. Saturated NaHCO3 solution (200 mL) was added, and the aqueous phase extracted with EtOAc (3 × 150 mL). The combined organic phases were washed successively with water (3 × 80 mL), brine (3 × 80 mL) and dried over Na2SO4, and the solvent was removed under reduced pressure. The ester 2 was isolated as light yellow oil in 98percent yield (71.5 g, 0.44 mol).
94%
Stage #1: for 0.166667 h;
Stage #2: at 20℃;
To a 2 L flask charged with stir bar andanhydrous methanol (500 mL) was added acetyl chloride (22.4 mL, 315 mmol, 0.6equiv) dropwise. The resultant solution was stirred for 10 min at rt, then (S)-malic acid(70.55 g, 526 mmol) was added. The reaction was stirred overnight at rt, thenconcentrated in vacuo. Silica gel chromatography (96:4 CH2Cl2/MeOH) afforded the titlecompound as a pale yellow oil (80.57 g, 94percent), with spectroscopic data in agreementwith literature values.15
80%
Stage #1: at 20℃; for 0.166667 h; Inert atmosphere
Stage #2: at 20℃; for 18 h; Inert atmosphere
Acetyl chloride (8.21 mL, 116 mmol) was added to methanol (150 mL) at room temperature followed after 10 min by (S)-malic acid (25 g, 186 mmol). The solution was stirred at room temperature for 18 h before the volatile components were evaporated under reduced pressure. The resultant residue was purified by flash column chromatography using CH2Cl2/MeOH (95:5) as eluent to afford the title compound 23 (22.67 g, 80percent) as a yellow oil. The spectroscopic data was in agreement with those reported in the literature.24 Rf (5percent MeOH/CH2Cl2) 0.51; [α]D20 +1.6 (c 0.80 in CHCl3); lit.24 [α]D25 +3.1 (c in 0.80, CHCl3); δH (300 MHz; CDCl3; Me4Si) 2.72 (2H, dd, J 16.4, 4.4 Hz, H-3), 3.35 (1H, br s, OH), 3.61 (3H, s, C-4OMe), 3.67 (3H, s, C-1OMe), 4.42 (1H, dd, J 6.3, 4.4 Hz, H-2); δC (75 MHz; CDCl3; Me4Si) 38.4 (CH2, C-3), 51.9 (CH3, C-4OMe), 51.6 (CH3, C-1OMe), 67.2 (CH, C-2) 170.9 (CO, C-4), 173.6 (CO, C-1).
67.2% for 3 h; Reflux In a reaction vessel23.6 g (0.2 mol)L-malic acid,And methanol was added40 ml,To dissolve,Concentrated sulfuric acid was then added4ml,After heating under reflux for 3 hours,Cooled to room temperature,The reaction solution was poured into water,Fully stirred,The residue was diluted with dichloromethane (50 ml * 3)extraction,The organic phases were combined,Washed,Dried over anhydrous sodium sulfate,stress reliever,After recovery of the solvent by distillation,To give dimethyl L-malate as a white solid18.8 g,Yield64.8percent.

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  • 15
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YieldReaction ConditionsOperation in experiment
99% at 0 - 35℃; Step 1 (Synthesis of Compound 34-2) (0217) Compound 34-1 (80 g, 600 mmol) was dissolved in anhydrous ethanol (500 mL), and thionyl chloride (100 mL, 1.5 mmol) was added at 0□, the mixture was stirred at 0□ for 20 minutes. Then the temperature was raised to room temperature, the reaction mixture was stirred overnight, concentrated under reduced pressure, and then extracted with EtOAc (1000 mL×3). The organic phases were combined, sequentially washed with water (500 mL×2), saturated sodium chloride solution (500 mL×2), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography with an eluent system (PE: EtOAc=20:1) to obtain the product 113 g compound 34-2, yield: 99percent. (0218) 1H NMR (400 MHz, CDCl3) δ: 4.47 (q, J=4.8 Hz, 1H), 4.26 (dq, J=2.4, 7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.28 (d, J=4.8 Hz, 1H), 2.72-2.89 (m, 2H), 1.20-1.34 (m, 6H).
94% With Amberlite IR120 resin (H+ form) In chloroform (2S)-MaNc acid (100 g, 0.746 mol) was suspended in a mixture of CHCI3/EtOH (3:4, 350 ml), Amberlite IFM 20 resin (H+ form, 40 g) was added and the mixture was heated under Dean-Stark reflux conditions. After reaction the resin beads were removed by filtration and washed with CHCI3. The washings were added to the filtrate and the solvent was removed under reduced pressure. High vacuum distillation (1 15°C/1 mmHg) afforded diethyl malate (2) (132 g, 94percent). [α]D -10.6 (neat). 1H NMR (300 MHz, CDCI3): δ 4.449 (dd, 1 H, J 4.7, 6.0, H-2), 4.248 (dq, 1 H, J 10.9, 7.2, OCH2CH3), 4.229 (dq, 1 H, J 10.9, 7.2, OCH2CH3), 4.200 (q, 2H, J 7.0, OCH2CH3), 3.52 (s, 1 H, OH), 2.808 (dd, 1 H, J 16.3, 4.7, H-2a), 2.751 (dd, 1 H, J 16.3, 6.0, H-2b), 1.270 (t, 3H, J7.0, Me), 1.235 (t, 3H, J 7.0, Me). 13C NMR (75 MHz, CDCI3): δ 173.26S and 170.38S (C- 1 and C-4), 67.25D (C-2), 61.85T and 60.83T (2 x CH2O), 38.69T (C-3), 14.00Q (2 x CH3).
88% for 20 h; Reflux (S)-Maleic acid (49, 10.0 g) was dissolved in EtOH (80 mL) and H2S04 (0.25 mL) was added. The solution was refluxed for 20 h, quenched with Et3N (0.5 mL) and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (petroleum ether EtOAc, 10: 1 to 1 : 1) to yield 2 (12.5 g, 65.9 mmol, 88 percent) as colorless syrup. The analytical data were in accordance with P. Wipf et al., Chem. - Eur. J. 8: 1670-1681 (2002).
88% for 20 h; Reflux (5)-Maleic acid (49, 10.0 g) was dissolved in EtOH (80 mE) and H2504 (0.25 mE) was added. The solution was refluxed for 20 h, quenched with Et3N (0.5 mE) and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (petroleum ether/ EtOAc, 10:1 to 1:1) to yield 2 (12.5 g, 65.9 mmol, 88percent) as colorless syrup. The analytical data were in accordance with P. Wipfet al., Chem.-Eur J. 8:1670-1681 (2002).
74% for 17 h; Reflux 64 (Scheme 13): To an ethanol (0.8 ml/mmol) solution of the (S)-Malicacid 63 at room temperature catalytic amount of concentrated HCI was added and the reaction was refluxed for a period of 17 h. After this duration the reaction was bought to room temperature and the solvent was evaporated. The resulting suspension was diluted with Et2O and then washed with saturated aqueous NaHCO3 solution (3 x 50 ml) and finally with brine solution. Combined organic portions were dried over Na2SO4, filtered and concentrated. The resulting oily product is subjected to vacuum distillation to yield (S)-Diethyl malate. Isolated yield (74percent) [B.p 122 °C at 2 mm].
71% at 20℃; for 16 h; L-(-)-Malic acid (12 g, 89.5 mmol) was dissolved in anhydrous ethanol (50 ml). Thionyl chloride (3.3 ml, 44.8 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted in diethyl ether (200 ml)and washed with saturated sodium bicarbonate (2 × 80 ml) and brine (1 × 80 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to yield the crude product,which was purified by silica gel chromatography to afford the product as a clear liquid. Yield:12.1 g, 71percent.

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  • [ 52079-23-9 ]
YieldReaction ConditionsOperation in experiment
99.9%
Stage #1: at 25℃; for 2 h;
Stage #2: for 12 h;
EXAMPLE 1
(S)-Dihydro-3-hydroxy-2 (3H)-furanone
10 g of L-(-)-malic acid is stirred in 45 ml of trifluoroacetic acid anhydride for 2 hours at 25° C.
Then, it is concentrated by evaporation in a vacuum, 7 ml of methanol is added to the residue, and it is allowed to stir for 12 more hours.
Then, it is concentrated by evaporation in a vacuum.
The residue that is obtained is dissolved in 150 ml of absolute tetrahydrofuran.
It is cooled to 0° C., and 150 ml of borane-tetrahydrofuran complex is added and allowed to stir for 2.5 more hours at 0° C. Then, 150 ml of methanol is added.
It is allowed to stir for one more hour at room temperature and then concentrated by evaporation in a vacuum.
The crude product that is obtained is dissolved in 80 ml of toluene. 5 g of Dowex(R) (activated, acidic) is added, and it is refluxed for one hour.
Then, Dowex(R) is filtered off, and the filtrate is concentrated by evaporation in a vacuum.
The crude product that is obtained (7.61 g, 99.9percent) is used without purification in the next step.
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  • [ 1140909-48-3 ]
YieldReaction ConditionsOperation in experiment
72.9%
Stage #1: at 65 - 70℃; for 5 h; Inert atmosphere; Reflux
Stage #2: With pyrographite In butanone at 65℃; for 1 h;
In the reactor, to sequentially free alkali card abundantly for Nepal 100.3g (0.2mol), L-malic acid 26.9g (0.2mol), butanone 3L, temperature regulation to 70 °C, heating and stirring under nitrogen protection, oven to the 65 ±5 °C, is added to the purification of water 150 ml, dissolved cleaning, oven to 65 ±5 °C start timing, under the protection of nitrogen reflux reaction 5h, then adding 10g activated carbon 5,65 ±5 °C decolourizations 1h, hot filtering, the filtrate into the other in a reaction vessel, the reaction liquid is reduced below about 45 °C time, a small amount of white solid started to precipitate, crystallization at room temperature stirring sleepovers, centrifugal, taken out after the fast disintegrating, 40-50 °C vacuum drying 24h, getting white or white solid powder 92.7g (yield 72.9percent).
45.5 kg at 74℃; for 2 h; Large scale Cyclopropane- 1 , 1 -dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyl)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK 188.6 kg) and water (37.3 kg) were charged to a reactor and the mixture was heated to reflux (approximately 74 °C) for approximately 2 hours. The reactor temperature was reduced to 50 to 55 °C and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of starting material (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1133.2 kg) (approximate residual volume 711 L; KF < 0.5 percent w/w) at approximately 74 °C. The temperature of the reactor contents was reduced to 20 to 25 °C and held for approximately 4 hours resulting in solid precipitate which was filtered, washed with MEK. (448 kg) and dried under vacuum at 50 °C to afford the title compound (45.5 kg).
45.5 kg at 74℃; for 2 h; Large scale Preparation of cyclopropane-1 ,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenylj-amide (4-fluoro-phenyl)-amide, malate salt[00125] Cyclopropane- 1,1 -dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)— phenyl]—amide (4-fluoro-phenyl)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor and the mixture was heated to reflux (approximately 74 °C) for approximately 2 hours. The reactor temperature was reduced to 50 to 55 °C and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of starting material (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1133.2 kg) (approximate residual volume 711 L; KF 0.5 percent w/w) at approximately 74 °C. The temperature of the reactor contents was reduced to 20 to 25 °C and held for approximately 4 hours resulting in solid precipitate which was filtered, washed with MEK (448 kg) and dried under vacuum at 50 °C to afford the title compound (45.5 kg).
45.5 kg at 50 - 74℃; Large scale Cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyl)-amide (13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor, and the mixture was heated to reflux (approximately 74 °C) for approximately 2 hours. The reactor temperature was reduced to 50 to 55 °C, and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yloxy)-phenyl]- amide (4-fluoro-phenyl)-amide (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg), and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1133.2 kg) (approximate residual volume 711 L; KF < 0.5 percent w/w) at approximately 74 °C. The temperature of the reactor contents was reduced to 20 to 25 °C and held for approximately 4 hours, resulting in solid precipitate which was filtered, washed with MEK (448 kg), and dried under vacuum at 50 °C to afford the title compound (45.5 kg).
45.5 kg at 25℃; Preparation of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoliue-4-yloxy)-phenylj-amide (4-fluoro-phenyl)-amide, malate salt[002751 Cyclopropane-1, 1 -dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)—phenylJ-- amide (4-fluoro-phenyl)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor and the mixture was heated to refiux (approximately 74 °C) for approximately 2 hours. The reactor temperature was reduced to 50 to 55 °C and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of starting material (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1133.2 kg) (approximate residual volume 711 L; KF s 0.5 percent w/w) at approximately 74°C. The temperature of the reactor contents was reduced to 20 to 25 °C and held for approximately 4 hours resulting in solid precipitate which was filtered, washed with MEK (448 kg) and dried under vacuum at 50 °C to afford the title compound (45.5 kg).
45.5 kg at 74℃; for 2 h; Large scale [001231 Cyclopropane- 1,1 -dicarboxylic acid [4-(6, 7-dimethoxy- quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyl)-amide (13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor, and the mixture was heated to reflux (approximately 74 °C) for approximately 2 hours. The reactor temperature was reduced to 50 to 55 °C, and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of cyclopropane- 1,1 -dicarboxylic acid {4-(6,7-d imethoxy- quinoline-4-yloxy)-phenyL]-amide (4- fluoro-phenyl)-amide (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg), and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1133.2 kg) (approximate residual volume 711 L; KF <0.5 percent w/w) at approximately 74 °C. The temperature of the reactor contents was reduced to 20 to 25 °C and held for approximately 4 hours, resulting in solid precipitate which was filtered, washed with MEK (448 kg), and dried under vacuum at 50 °C to afford the title compound (45.5 kg).
45.5 kg at 74℃; for 2 h; Large scale 10101] Cyclopropane-1 , 1 -dicarboxylic acid [4-(6,7- dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro- phenyl)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor and the mixture was heated to reflux (approximately 74° C.) for approximately 2 h. The reactor temperature was reduced to 50 to 55° C. and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of 1-5 (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1133.2 kg) (approximate residual volume 711 L; KF<0.5percent w/w) at approximately 74° C. The temperature of the reactor contents was reduced to 20 to 25° C. and held for approximately 4 hours resulting in solid precipitate which was filtered, washed with MEK (448 kg) and dried under vacuum at 50° C. to afford the title compound (45.5 kg).
45.5 kg With butanone In water at 74℃; Large scale The cyclopropane -1,1-dicarboxylic acid [4 - (6,7-dimethoxy-quinolin-4-yloxy)-phenyl]- acid amide (4-fluoro-phenyl)- acid amide (1-5 ; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) in into the reactor, and the mixture is heated to reflux (about 74 °C) and is maintained at about 2 hours. The temperature of the reactor to 50-55°C, and filtering reactor content. To 1-5 (13.3 kg), L-malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg) similar to consumption, the above-mentioned such sequential step is repeated two or more times. At about 74 °C lower, using MEK (1133.2 kg) under atmospheric pressure to azeotropically dried combined filtrate (about the residual volume 711 L; KF 0.5 weight percent). The temperature of the reactor contents to 20-25 °C and about 4 hours, to produce solid precipitation, filtration and in MEK (448 kg) washing, in the 50 °C the lower vacuum drying, to obtain the title compound (45.5 kg).

Reference: [1] Patent: CN105503717, 2016, A, . Location in patent: Paragraph 0050
[2] Patent: WO2010/83414, 2010, A1, . Location in patent: Page/Page column 26 - 27
[3] Patent: WO2012/109510, 2012, A1, . Location in patent: Page/Page column 31
[4] Patent: WO2013/59788, 2013, A1, . Location in patent: Paragraph 0070; 0071; 0072
[5] Patent: WO2013/43840, 2013, A1, . Location in patent: Paragraph 00119; 00131
[6] Patent: WO2013/166296, 2013, A1, . Location in patent: Paragraph 00125
[7] Patent: WO2014/165786, 2014, A1, . Location in patent: Paragraph 00206
[8] Patent: WO2015/164869, 2015, A1, . Location in patent: Paragraph 00263; 00275
[9] Patent: WO2015/177758, 2015, A1, . Location in patent: Page/Page column 18; 19
[10] Patent: WO2016/22697, 2016, A1, . Location in patent: Paragraph 00111; 00123
[11] Patent: US2016/772, 2016, A1, . Location in patent: Paragraph 0095; 0101
[12] Patent: TWI516477, 2016, B, . Location in patent: Page/Page column 31; 35; 36
  • 23
  • [ 97-67-6 ]
  • [ 1140909-48-3 ]
YieldReaction ConditionsOperation in experiment
21.34 kg
Stage #1: With sodium carbonate In tetrahydrofuran; water; ethyl acetate at 25 - 30℃; for 0.5 h; Large scale
Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25 - 65℃; for 3 h; Large scale
A mixture of water (135 its) and N-(4-((6,7-dimethoxyquinolin-4-yloxy)phenyl)-N-(4- fluorophenyl)cyclopropane- 1,1 -dicarboxamide hydrochloride (20.0 kgs) was stirred for 10 minutes at 25-30°C. Aqueous sodium carbonate solution was added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. Tetrahydrofuran (1 50 Its) and ethyl acetate (15 Its) were added’to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted twice with tetrahydrofuran and ethyl acetate mixture. Combined the organic layers and washed with aqueous sodium chloride solution. Carbon powder was added to the organic layer at 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with tetrahydrofuran. Distilled off the solvent completely from the obtained filtrate under reduced pressure and co-distilled with tetrahydrofuran. To the obtained, compound, tetrahydrofuran (216 Its) and water (2.2 Its) were added at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 20 minutes at the same temperature. The reaction mixture was slowly added to a solution of L-malic acid (5.70 kgs) and methyl isobutyl ketone (500 Its) and seeding cryta1s of compound of Iormuls-I a at 25-30°C and stirred the reaction mixture for 3 hours at the same temperature. Filtered the reaction mixture and washed with methyl isobutyl ketone. To the obtained compound, methyl isobutylketone (40 Its) was added at 25-30°C and stirred for 3 hours at the same temperature. Filtered the reaction mixture, washed with methyl isobutylketone and dried to get the title compound. The obtained compound was micronized using conventional techniques to get the desired particle size. Methyl isobutyl ketone (200 lts) was added to the micronized compound at 25-30°C and stirred form 3 hours at the same temperature. Filtered the compound and washed with methyl isobutyl ketone and dried to get title compound.Yield: 21.34 kgs; Purity by HPLC: 99.96percent.
Reference: [1] Patent: WO2018/104954, 2018, A1, . Location in patent: Page/Page column 26-28; 33; 34
  • 24
  • [ 190728-25-7 ]
  • [ 97-67-6 ]
  • [ 1140909-48-3 ]
YieldReaction ConditionsOperation in experiment
24 g
Stage #1: With potassium carbonate In tetrahydrofuran; water at 0 - 30℃; for 2 h;
Stage #2: at 25 - 75℃; for 1.16667 h;
Thionyl chloride (36.10 kgs) was slowly added to the mixture of l-((4-fluorophenyl) carbamoyl)cyclopropane carboxylic acid (22.60 kgs) and tetrahydrofuran (120 lts) at 25-30°C and stirred for 9 hours at the same temperature. The reaction mixture was slowly added to a pre-cool ed mixture of 4-((6,7-dimethoxyquinolin-4-yloxy)anil me (20.0 kgs), aqueous potassium carbonate solution (83.70 kgs of potassium carbonate in 120 Its of water) and tetrahydrofuran (120 Its) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Both the organic and aqueous layers were separated and water was added to the aqueous layer at 25-30°C. Extracted the aqueous layer with ethyl acetate. Combine the organic layers. Aqueous hydrochloric acid solution (15 lts of HC1 in 145 lts of water) was, added to the organic layer at 25-30°C and stirred the reaction mixture for 3 hours at the same temperature. Filtered the, precipitated solid, washed with tetrahydrofuran and ethyl acetate. To the obtained compound, water (lot-4) was added at 25- ‘30°C and stirred for •2 hours at the same temperature. Filtered the reaction mixture and washed with water. To the obtained compound, water (595 Its) and hydrochloric acid (1 .0 Its) were added at 25-30°C and stirred for.2 hours at the same temperature. Filtered the reaction mixture and washed with water. To the obtained compound, isopropanol (435 Its) was added at 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Dimethyl sulfoxide (235 Its) was added to the obtained compound at 25-30°C and stirred for 45 ’iinutes at the same temperature. Filtercd the reaction mixture. Ethyl acetate (720 Its) was added to the obtained filtrate at 2 5-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.Yield: 32.99 kgs; Purity by HPLC: 99.8 5percent.
Reference: [1] Patent: WO2018/104954, 2018, A1, . Location in patent: Page/Page column 28; 29; 32; 33
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