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Chemical Structure| 110-16-7 Chemical Structure| 110-16-7
Chemical Structure| 110-16-7

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Maleic acid is used in the synthesis of pyridoindolones as potent inhibitors of Aurora kinases. It is a reagent in the preparation of TiO2/carbon nanotube composites.

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Product Details of Maleic Acid

CAS No. :110-16-7
Formula : C4H4O4
M.W : 116.07
SMILES Code : O=C(O)/C=C\C(O)=O
MDL No. :MFCD00063177
InChI Key :VZCYOOQTPOCHFL-UPHRSURJSA-N
Pubchem ID :444266

Safety of Maleic Acid

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H314-H317-H335-H302+H312
Precautionary Statements:P264-P270-P271-P272-P280-P303+P361+P353-P304+P340-P305+P351+P338-P310-P330-P331-P363-P403+P233-P501
Class:8
UN#:3261
Packing Group:

Application In Synthesis of Maleic Acid

* 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 [ 110-16-7 ]
  • Downstream synthetic route of [ 110-16-7 ]

[ 110-16-7 ] Synthesis Path-Upstream   1~12

  • 1
  • [ 110-16-7 ]
  • [ 115-11-7 ]
  • [ 18305-60-7 ]
YieldReaction ConditionsOperation in experiment
75% With sulfuric acid In di-isopropyl ether; toluene at 40℃; for 4 h; General procedure: A 200 mL four-necked flask was charged with maleic acid (16.3 g, 140 mmol), toluene (10 mL)Diisopropyl ether (30 mL),Sulfuric acid (0.18 mL) was added, and while maintaining the reaction suspension at 30 ° C.,Normal pressure bubbling of isobutene was carried out for 4 hours.An excess amount of isobutene was discharged to the outside of the flask through a paraffin bubbler. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (50 mL × 3 times) and saturated brine (50 mL), dried over magnesium sulfate and the solvent was distilled off under reduced pressure to give maleic acid Di (tert-butyl) ester (23.0 g, 100.8 mmol, yield 72percent). The reaction was carried out in the same manner as in Example 1 except that the reaction temperature was changed from 30 ° C. to 40 ° C. As a result, maleic acid Di (tert-butyl) ester(24.1 g, 105.6 mmol, yield 75percent).
62% With toluene-4-sulfonic acid In 1,2-dimethoxyethane at 40℃; for 2 h; Autoclave 60 mL of ethylene glycol dimethyl ether represented by the general formula (1), 20 g of maleic acid and 4 g of p-toluenesulfonic acid as an acid catalyst were placed in a 300 mL autoclave equipped with a stirrer and a thermometer, 51 g of 2-methylpropylene was injected The reaction was carried out at 40 ° C. for 2 hours with stirring (255 parts by weight of 2-methylpropylene, 260 parts by weight of ethylene glycol dimethyl ether, 20 parts by weight of p-toluenesulfonic acid based on 100 parts by weight of maleic acid). As a result of GC analysis of the obtained reaction solution, the yield of di-tert-butyl maleate was 62percent.
References: [1] Patent: JP5754133, 2015, B2, . Location in patent: Paragraph 0063; 0065.
[2] Patent: JP5678489, 2015, B2, . Location in patent: Paragraph 0034; 0040.
[3] Tetrahedron Letters, 1995, vol. 36, # 41, p. 7459 - 7462.
[4] Acta Chemica Scandinavica (1947-1973), 1967, vol. 21, p. 1963 - 1964.
[5] Bulletin de la Societe Chimique de France, 1974, p. 2985 - 2986.
  • 2
  • [ 67-56-1 ]
  • [ 110-16-7 ]
  • [ 115-11-7 ]
  • [ 18305-60-7 ]
References: [1] Journal of Organic Chemistry, 1975, vol. 40, # 16, p. 2391 - 2394.
  • 3
  • [ 75847-73-3 ]
  • [ 110-16-7 ]
  • [ 76095-16-4 ]
References: [1] Patent: US6335453, 2002, B1, . Location in patent: Example 14.
[2] Patent: US6335453, 2002, B1, . Location in patent: Example 1.
[3] Patent: US6335453, 2002, B1, . Location in patent: Example 5.
[4] Patent: US6335453, 2002, B1, . Location in patent: Example 2.
[5] Patent: US6335453, 2002, B1, . Location in patent: Example 3.
[6] Patent: US6335453, 2002, B1, . Location in patent: Example 4.
[7] Chemical and Pharmaceutical Bulletin, 1986, vol. 34, # 7, p. 2852 - 2858.
[8] Patent: WO2004/101515, 2004, A1, . Location in patent: Page 9.
[9] Patent: WO2014/202659, 2014, A1, . Location in patent: Page/Page column 21.
  • 4
  • [ 110-16-7 ]
  • [ 147-85-3 ]
  • [ 406213-94-3 ]
  • [ 76095-16-4 ]
References: [1] Organic letters, 2002, vol. 4, # 23, p. 4005 - 4008.
  • 5
  • [ 288-32-4 ]
  • [ 7732-18-5 ]
  • [ 877932-98-4 ]
  • [ 110-16-7 ]
  • [ 76095-16-4 ]
References: [1] Patent: US5789597, 1998, A, .
  • 6
  • [ 82009-36-7 ]
  • [ 110-16-7 ]
  • [ 76095-16-4 ]
  • [ 76095-16-4 ]
References: [1] Journal of Organic Chemistry, 1984, vol. 49, # 15, p. 2816 - 2819.
  • 7
  • [ 50-00-0 ]
  • [ 110-16-7 ]
  • [ 85650-56-2 ]
YieldReaction ConditionsOperation in experiment
52.3%
Stage #1: With sodium hydroxide In dichloromethane; water
Stage #2: With formic acid In water; toluene at 60℃; for 2 h;
Example 27. Synthesis of asenapine maleate (compound trans-I maleate) [Show Image] 66.0 g (0.21 mol) of trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole hydrochloride (compound trans-XVIII hydrochloride), as obtained in Example 22, were suspended in 500 mL of dichloromethane. 1 M aqueous sodium hydroxide was added until the pH was adjusted to above 10. The aqueous phase was extracted and washed with 500 mL of dichloromethane. The combined organic phases were evaporated to dryness to obtain trans-5-chloro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (compound trans-XIX) as a free base, which was dissolved in a mixture of 34.81 g (0.43 mol) of a 37 percent aqueous solution of formaldehyde, 33.94 g (0.65 mol) of 88 percent formic acid, and 500 mL of toluene. The resulting mixture was heated to 60 C and stirred at this temperature for 2 hours. After cooling to room temperature, pH was adjusted to 10 by addition of 1 M aqueous sodium hydroxide. The aqueous layer was extracted and washed with 500 mL of toluene. The organic phases were combined, washed with 500 mL of saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give asenapine (free base) as an oil, which was subsequently dissolved in 500 mL of isopropanol at 50 C. Then, 27.23 g (0.23 mol) of maleic acid and 5.0 g of active charcoal were added, and the resulting mixture was stirred at 65 C for 1 hour. The suspension was filtered, and the solid was washed with 50 mL of hot isopropanol. The filtrate was cooled slowly to 10 C, and seeded with asenapine maleate at this temperature. After stirring for 2 hours at 10 C, the resulting suspension was filtered, and the solid was washed with 50 mL of cold isopropanol. The solid was recrystallized from 500 mL of isopropanol and dried at 70 C under reduced pressure, until constant weight, to obtain 45.0 g of asenapine maleate (compound trans-I maleate) as a white powder. Yield: 52.3 percent. Purity (HPLC, method 1): 99.8 percent. Assay (titration with NaOH): 100.2 percent.
References: [1] Patent: EP2468751, 2012, A2, . Location in patent: Page/Page column 27-28.
  • 8
  • [ 65576-45-6 ]
  • [ 110-16-7 ]
  • [ 85650-56-2 ]
YieldReaction ConditionsOperation in experiment
98.86% at 0 - 20℃; for 2 h; e) Preparation of Asenapine maleate salt Trans- 1 l-chloro-2,3, 3a, 12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (Asenapine base) (10.0 gm) obtained as above was dissolved in mixture of ethanol (10 ml) and methyl tertiary butyl ether (50 ml) at room temperature. To this solution, maleic acid (4.3 gm) dissolved in ethanol (13.0 ml) was slowly added at room temperature. The reaction mass was stirred for 1 hour at room temperature and then cooled to 0° C - 5° C and was stirred for 1 hour. The reaction mass was filtered and washed with methyl tertiary butyl ether (25 ml) and dried under reduced pressure at 45° C for 1 hour to obtain 13.9 gm of Asenapine maleate salt. Total yield: 98.86 percent Impurity VII: 0.02percent, Impurity VIII: not detected; Impurity X: not detected; Impurity IXa and IXb : not detected; Impurity 'Μ' RRT-3.1: not detected HPLC Purity: 99.94percent
91% at 20℃; Example 13: Preparation of Asenapine Maleatetra"5-(5-Chloro-2-methyl-2,3,3, 12b-tetrahydro-lH-dibenz[2,3;6,7] oxepino-[4,5- c] pyrrole (Asenapine) (1.65 g, 5,77 mmol) is dissolved in absolute ethanol (8.25 ml) and stirred at room temperature for 10 minutes. Maleic Acid (804 mg, 6.93 mmol) is added and stirred until complete dissolution. The solution is seeded with Asenapine Maleate monoclinic form and stirred overnight at room temperature. The obtained suspension is cooled down to 0°C in an ice bath and stirred for one hour, filtered and washed with cold absolute ethanol (1,65 ml). The obtained product is dried for 24 hours at 45°C.2, 11 g of Asenapine Maleate monoclinic form (91percent) is obtained as a white solid. HPLC purity: 99, 1 percent. No presence of cis isomer is observed.1H-RMN: (CDOH, 200 MHz): 3.14 (s, 3H), 3.79-3.82 (m, 2H), 3.91-3.94 (m, 2H), 4.06-4.11 (m, 2H), 6.23 (s, 2H), 7.16-7.31 (m, 7H).
53.26 g at 60℃; for 0.25 h; Preparation of monoclinic Form H of asenapine maleate from the base similar to the method disclosed in WO2006/106135. irai-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-lH-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole (asenapine) was prepared according to Example 3 of WO2008/003460 by Ullman cyclisation of trans-N-methyl-2-(2-hydroxyphenyl)-3-(2-bromo-5-chlorphenyl)-pyrrolidine. The crude base compound was purified by chromatography using a mixture of dichloromethane and methanol (20: 1 v/v) as eluent. 45.23 g of the purified base (HPLC: 97percent+) were dissolved in 100 ml ethanol and the solution was added dropwise to a solution of 18.37 g maleic acid in 22.0 ml Ethanol at 60°C. After stirring at 60°C for another 15 min the solution was cooled down spontaneously to RT. At about 30°C seed crystals of form H were added and product started to precipitate immediately. Then 375 ml ethyl ether was added dropwise and the suspension was stirred at RT for 3h. The suspension was cooled down to 10 °C within 10-15 minutes and stirred for one hour at 10 °C. The solid was filtered off, washed with 20ml ethyl ether and dried at 40°C overnight to yield 53.26 g of asenapine maleate (HPLC: 99percent+). XRPD: complies to reference of monoclinic polymorph (not shown) DSC: peak at 144.4°C Particle size distribution: d(0.1) = 1.6, d(0.5) = 50.6, d(0.9) = 1 15.2 and d(0.95) = 128.2
References: [1] Patent: WO2013/24492, 2013, A2, . Location in patent: Page/Page column 24.
[2] Patent: WO2012/13766, 2012, A1, . Location in patent: Page/Page column 34.
[3] Patent: US2006/229352, 2006, A1, . Location in patent: Page/Page column 6.
[4] Patent: WO2011/159903, 2011, A2, . Location in patent: Page/Page column 41.
[5] Patent: WO2012/40845, 2012, A1, . Location in patent: Page/Page column 20-22.
[6] Patent: WO2012/38975, 2012, A2, . Location in patent: Page/Page column 38.
[7] Patent: WO2012/123325, 2012, A1, . Location in patent: Page/Page column 33-34.
[8] Patent: WO2013/41435, 2013, A1, . Location in patent: Page/Page column 28.
  • 9
  • [ 110-16-7 ]
  • [ 85650-56-2 ]
References: [1] Patent: WO2012/150538, 2012, A1, . Location in patent: Page/Page column 14.
  • 10
  • [ 110-16-7 ]
  • [ 85650-56-2 ]
YieldReaction ConditionsOperation in experiment
53.26 g
Stage #2: at 20 - 60℃;
Preparation of monoclinic Form H of Asenapine Maleate from the base similar to the method disclosed in WO2006/106135. trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1 H-dibenz [2,3:6,7]oxepino[4,5-c] pyrrole (Asenapine) was prepared according to Example 3 of WO2008/003460 by Ullman cyclisation of trans-N-methyl-2-(2-hydroxyphenyl)-3-(2-bromo-5-chlorphenyl)-pyrrolidine. The crude base compound was purified by chromatography using a mixture of dichloromethane and methanol (20:1 v/v) as eluent. 45.23 g of the purified base (HPLC: 97percent+) were dissolved in 100 ml ethanol and the solution was added dropwise to a solution of 18.37 g maleic acid in 22.0 ml Ethanol at 60°C. After stirring at 60°C for another 15 min the solution was cooled down spontaneously to RT. At about 30°C seed crystals of form H were added and product started to precipitate immediately. Then 375 ml ethyl ether was added dropwise and the suspension was stirred at RT for 3h. The suspension was cooled down to 10 °C within 10-15 minutes and stirred for one hour at 10 °C. The solid was filtered off, washed with 20ml ethyl ether and dried at 40°C overnight to yield 53.26 g of asenapine maleate (HPLC: 99percent+). XRPD: complies to reference of monoclinic polymorph DSC: peak at 144.4°C Particle size distribution: d(0.1 ) = 1.6, d(0.5) = 50.6, d(0.9) = 1 15.2 and d(0.95) = 128.2
References: [1] Patent: WO2013/41604, 2013, A1, . Location in patent: Page/Page column 17; 18.
  • 11
  • [ 26839-75-8 ]
  • [ 110-16-7 ]
  • [ 26921-17-5 ]
References: [1] Tetrahedron, 2007, vol. 63, # 14, p. 3026 - 3030.
[2] Patent: CN108299279, 2018, A, . Location in patent: Paragraph 0127-0131.
  • 12
  • [ 26839-75-8 ]
  • [ 110-16-7 ]
  • [ 26921-17-5 ]
References: [1] Tetrahedron, 2007, vol. 63, # 14, p. 3026 - 3030.
 

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