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Chemical Structure| 110-16-7
Chemical Structure| 110-16-7
Structure of 110-16-7 * Storage: {[proInfo.prStorage]}
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Product Details of [ 110-16-7 ]

CAS No. :110-16-7 MDL No. :MFCD00063177
Formula : C4H4O4 Boiling Point : -
Linear Structure Formula :- InChI Key :VZCYOOQTPOCHFL-UPHRSURJSA-N
M.W : 116.07 Pubchem ID :444266
Synonyms :
Chemical Name :Maleic acid

Calculated chemistry of [ 110-16-7 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.0
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 24.41
TPSA : 74.6 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) : -7.25 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.12
Log Po/w (XLOGP3) : -0.34
Log Po/w (WLOGP) : -0.29
Log Po/w (MLOGP) : -0.64
Log Po/w (SILICOS-IT) : -0.81
Consensus Log Po/w : -0.39

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.85

Water Solubility

Log S (ESOL) : -0.21
Solubility : 71.0 mg/ml ; 0.612 mol/l
Class : Very soluble
Log S (Ali) : -0.76
Solubility : 19.9 mg/ml ; 0.172 mol/l
Class : Very soluble
Log S (SILICOS-IT) : 1.34
Solubility : 2520.0 mg/ml ; 21.7 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.8

Safety of [ 110-16-7 ]

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

Application In Synthesis of [ 110-16-7 ]

* 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   1~35

  • 1
  • [ 110-16-7 ]
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Reference: [1] Monatshefte fuer Chemie, 1988, vol. 119, p. 1333 - 1339
  • 2
  • [ 110-00-9 ]
  • [ 108-31-6 ]
  • [ 6118-51-0 ]
  • [ 110-16-7 ]
Reference: [1] Green Chemistry, 2014, vol. 16, # 1, p. 167 - 175
  • 3
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  • [ 123-33-1 ]
Reference: [1] Journal of the American Chemical Society, 1958, vol. 80, p. 3790
  • 4
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  • [ 55240-51-2 ]
Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 12, p. 1794 - 1807
[2] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 7, p. 2209 - 2224
  • 5
  • [ 150-13-0 ]
  • [ 110-16-7 ]
  • [ 17057-04-4 ]
Reference: [1] Journal of the American Chemical Society, 2005, vol. 127, # 22, p. 8036 - 8043
[2] Journal of the Chemical Society, 1957, p. 4133
  • 6
  • [ 591-20-8 ]
  • [ 110-16-7 ]
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  • [ 38169-99-2 ]
Reference: [1] Monatshefte fuer Chemie, 1988, vol. 119, p. 1333 - 1339
  • 7
  • [ 141-78-6 ]
  • [ 110-16-7 ]
  • [ 2459-05-4 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1993, vol. 32, # 2, p. 292 - 293
  • 8
  • [ 110-16-7 ]
  • [ 74-89-5 ]
  • [ 17833-53-3 ]
Reference: [1] Acta Crystallographica, Section C: Crystal Structure Communications, 2000, vol. 56, # 9, p. 1157 - 1158
  • 9
  • [ 106-95-6 ]
  • [ 110-16-7 ]
  • [ 999-21-3 ]
Reference: [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 2, p. 363 - 370
  • 10
  • [ 110-16-7 ]
  • [ 57-13-6 ]
  • [ 923-37-5 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 2002, vol. 75, # 4, p. 855 - 856
  • 11
  • [ 25561-30-2 ]
  • [ 110-16-7 ]
  • [ 354-38-1 ]
  • [ 23508-82-9 ]
  • [ 55982-15-5 ]
Reference: [1] Environmental Science and Technology, 1998, vol. 32, # 16, p. 2357 - 2370
  • 12
  • [ 106-99-0 ]
  • [ 110-16-7 ]
  • [ 2305-26-2 ]
Reference: [1] DRP/DRBP Org.Chem.,
[2] Patent: US2262002, 1939, ,
  • 13
  • [ 67-56-1 ]
  • [ 110-16-7 ]
  • [ 115-11-7 ]
  • [ 18305-60-7 ]
Reference: [1] Journal of Organic Chemistry, 1975, vol. 40, # 16, p. 2391 - 2394
  • 14
  • [ 109-01-3 ]
  • [ 60810-77-7 ]
  • [ 60811-17-8 ]
  • [ 110-16-7 ]
  • [ 60811-18-9 ]
Reference: [1] Patent: US4238611, 1980, A,
  • 15
  • [ 52548-59-1 ]
  • [ 52548-62-6 ]
  • [ 110-16-7 ]
  • [ 52548-63-7 ]
Reference: [1] Patent: US4006144, 1977, A,
  • 16
  • [ 75847-73-3 ]
  • [ 110-16-7 ]
  • [ 76095-16-4 ]
Reference: [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
  • 17
  • [ 110-16-7 ]
  • [ 147-85-3 ]
  • [ 406213-94-3 ]
  • [ 76095-16-4 ]
Reference: [1] Organic letters, 2002, vol. 4, # 23, p. 4005 - 4008
  • 18
  • [ 288-32-4 ]
  • [ 7732-18-5 ]
  • [ 877932-98-4 ]
  • [ 110-16-7 ]
  • [ 76095-16-4 ]
Reference: [1] Patent: US5789597, 1998, A,
  • 19
  • [ 82009-36-7 ]
  • [ 110-16-7 ]
  • [ 76095-16-4 ]
  • [ 76095-16-4 ]
Reference: [1] Journal of Organic Chemistry, 1984, vol. 49, # 15, p. 2816 - 2819
  • 20
  • [ 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.
Reference: [1] Patent: EP2468751, 2012, A2, . Location in patent: Page/Page column 27-28
  • 21
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  • [ 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
Reference: [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
  • 22
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Reference: [1] Patent: WO2012/150538, 2012, A1, . Location in patent: Page/Page column 14
  • 23
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  • [ 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
Reference: [1] Patent: WO2013/41604, 2013, A1, . Location in patent: Page/Page column 17; 18
  • 24
  • [ 86-21-5 ]
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  • [ 132-20-7 ]
YieldReaction ConditionsOperation in experiment
5.1 g at 20℃; The reaction vessel was added with 50 ml of ethanol, 5 g of Pheniramine was stirred and dissolved, and 2.9 g of maleic acid was added and stirred at room temperature, and the mixture was filtered, and dried under vacuum at 45 °C to obtain Pheniramine maleate 5.1 g.
Reference: [1] Patent: CN108164455, 2018, A, . Location in patent: Paragraph 0009; 0010; 0058; 0059; 0060; 0062
  • 25
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  • [ 113-92-8 ]
YieldReaction ConditionsOperation in experiment
350 g at -2 - 0℃; for 2.5 h; In tetrahydrofuran solvent, add p-chlorobenzyl pyridine 260g,Sodium amide 95g, the reaction temperature was 20 ~ 25 1 hour,Then, a toluene solution of N, N-dimethylchloroethane was added dropwise,The temperature is controlled at 30 ~ 40 , the dropwise addition is completed, the reaction at 40 ~ 45 for 2 hours,After the reaction, cooled to room temperature, and then washed with water to neutral organic phase, the solvent was recovered,Derived chlorpheniramine concentrate, concentrate vacuum distillation, chlorpheniramine 270g.In 500g anhydrous ethanol was added 130g of maleic acid, stirred to dissolve, chlorpheniramine was added,After the addition, stirring for 30 minutes, cooled to 0 ~ -2 incubated for 2 hours,The filtrate was filtered and the crude chlorpheniramine maleate 390g refined with 1.5 times the absolute amount of ethanol ethyl chlorofenamate maleic acid 350 grams.
Reference: [1] Patent: CN106883167, 2017, A, . Location in patent: Paragraph 0018; 0019
  • 26
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  • [ 88150-47-4 ]
YieldReaction ConditionsOperation in experiment
92.9%
Stage #1: With hydrogen In acetic acid at 20℃; for 4 h;
1.00 g (2.4 mmol) 4-(2-chloro-phenyl)-2-(2-hydroxyimino-ethoxymethyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester (5) was dissolved in 20 ml glacial acetic acid and hydrogenated for four hours at atmospheric pressure and room temperature using 0.062 g palladium 10percent on carbon as catalyst. The catalyst was filtered off after which the acetic acid was evaporated off. The residue was dissolved in ether and washed successively with 10percent sodium bicarbonate solution and water. After drying with MgSO4 the ether was evaporated off and the residue was dissolved in a small volume of ethanol. To the resulting solution 0.28 g (2.4 mmol) of maleic acid was added with cooling. The maleate salt precipitated after a while and was then filtered off and washed with diethyl ether and dried in vacuo, giving 0.9 g of the product as a fine white powder. By addition of a small amount of ether to the mother liquor further 270 mg of product was obtained. Combined yield: 1.17 g = 92.9 percent mp. 170-172 °C [] Elemental analysis: CalculatedC 54.9percentH 5.6percentN 5.3percentCl 6.8percentFoundC 53.86percentH 5.6percentN 5.11percentCl 6.9percentIR: 3392 cm-1; 2946 cm-1; 1688 cm-1; 1648 cm-1;1603 cm-1; 1479 cm-1; 1283 cm-1; 1206 cm-1; 1100 cm-1; 759 cm-1; (KBr) FAB-MS: 409 [MH+],408 [M+],297 [M+-C6H4Cl] NMR: 500 MHz 1H-NMR (D6-DMSO) (δ ppm) : 8.37 (s, 1H, NH); 7.87 (br. s, 3H, NH); 7.10-7.35 (m, 4H, ArH); 6.06 (s, 2H, CH); 5.31 (s, 1H, CH); 4.66 (d. d., 2H, CH2); 3.97 (q, 2H, CH2); 3.66 (t, 2H, CH2); 3.50 (s, 3H, CH3); 3.09 (t, 2H, CH3); 2.3 (t, 3H, CH3); 1.12 (t, 3H, CH3).
33.4%
Stage #1: With sodium tetrahydroborate; nickel dichloride In methanol at -30 - 20℃; for 1.5 h;
0.5 g (1.2 mmol) 4-(2-chloro-phenyl)-2-(2-hydroxyimino-ethoxymethyl)-6-methyl-1,4-dihydro-pyridine--3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester (5) and 0.56 g (2.4 mmol) nickel chloride hydrate was dissolved in 35 ml methanol and cooled to -30 °C. 0.454 g (0.012 mol) sodium borohydride was added in small portions over 30 minutes whereafter the mixture was stirred for 1 hour at room temperature. The mixture was evaporated to dryness and 20 ml of 6N hydrochloric acid was added with stirring. The mixture was filtered and then made alkaline with conc. ammonium hydroxide (pH > 8.5). The filtrate was extracted twice with dichloromethane, and then dried with MgSO4. The organic phase was evaporated to give 0.274 g (56.7 percent) of the crude base. The product was dissolved in a small amount of ethanol. To the resulting solution 0.08 g (0.7 mmol) maleic acid was added with cooling. After a while the maleate salt precipitated and was then filtered off and washed with diethyl ether and dried in vacuo, giving the product as a fine white powder. yield: 0.21 g = 33.4 percent mp. 170-172 °C [] Elemental analysis: CalculatedC 54.9percentH 5.6percentN 5.3percentCl 6.8percentFoundC 54.94percentH 5.65percentN 5.23percentCl 7.05percentIR: 3392 cm-1; 2946 cm-1; 1688 cm-1; 1648 cm-1; 1603 cm-1; 1479 cm-1; 1283 cm-1; 1206 cm-1; 1100 cm-1; 759 cm-1; (KBr) FAB-MS: 409 [MH+],408 [M+],297 [M+-C6H4Cl]
Reference: [1] Patent: EP1030841, 2004, B1, . Location in patent: Page 11-12
[2] Patent: EP1030841, 2004, B1, . Location in patent: Page 12
  • 27
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  • [ 110-16-7 ]
  • [ 88150-47-4 ]
YieldReaction ConditionsOperation in experiment
91.5%
Stage #1: at 25℃;
Stage #2: at 30℃; for 4 h;
Into the reactor add 290kg of methylamine solution, under stirring add 59 kg of Phthaloyl Amlodipine, stirring at a temperature of 25 ° C for more than 20 hours, cool down to 20 ° C, filter, wash the filter residue with drinking water until the pH of the water is ≤10, the filter residue is rinsed with purified water, dried, and dried at 60 ° C, until the water is ≤1.5percent, cool down at normal temperature, discharge, obtained Amlodipine: 10g of Amlodipine and 100ml of water add into 250ml eggplant bottle, stir at room temperature, and dissolve 3.9 g of maleic acid into 40 ml of water, at a constant temperature of 30 ° C, drip into the Amlodipine solution into the eggplant-shaped bottle by using the dropping funnel, after the addition, continue to stir for 4 hours, filter by suction, wash the filter cake twice with water, and vacuum dry at 65 ° C for more than 8 hours, obtained white block of Amlodipine Maleate crude, yield 91percent, purity 99.2percent; Take 10g crude Amlodipine Maleate, adds into 250ml eggplant shaped bottle, and then add 80ml methanol into the eggplant shaped bottle, heat at 60 ° C, stir to completely dissolve the material, cool at 50 ° C, add 1g of activated carbon, stir to warm at 65 ° C, stir for 30min, heat filtration, remove activated carbon, and add 20ml of methanol to clean the eggplant shaped bottle, distill it under reduced pressure, and steam to a volume of 40ml, add 120 ml of ethyl acetate, azeotropic distillation is carried out, the volume is distilled off to 50 ml, the temperature is lowered at room temperature, then lowered at 0 ° C, stirred for 2 h, suction filtered, and dried under reduced pressure, obtained Amlodipine Maleate, the yield is 91.5 percent, and the purity is 99.5 percent;
Reference: [1] Patent: CN108358833, 2018, A, . Location in patent: Paragraph 0013; 0023-0025
[2] Patent: US4572909, 1986, A,
  • 28
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  • [ 88150-47-4 ]
YieldReaction ConditionsOperation in experiment
91.2% at 21 - 24℃; for 1 h; Preparation of 3-Ethyl, 5-methyl (4RS) 2-[(2-AMINOETHOXY) METHYLL-4-(2-CHLOROPHENYL)-6-METHYL 1,4- dihydropyridine-3, 5-dicarboxylate maleate (I) Amlodipine base (80. 0 g, 0.196 mol) was added into toluene (552 mL) at 21-24 °C. To dissolve the base methanol (65 ML) was added to above solution. Maleic acid (22.7 g, 0.196 mol) was disolved in MEOH (67 mL) and was added to above solution at 21-24 °C. The solution was stirred for Ih at this temperature and the salt was filtered off. The crystals were washed with diethylether (100 ML) and ethyl acetate (100 mL) and dried to give 93.7 g of AMLODIPINE maleate as a white solid in 91. 2percent YIELD. 1H-NMR (DMSO) 8 8.37 (s, 1H), 7. 79 (s, 3H), 7.20 (m, 4H), 6.00 (s, 2H), 5.38 (s, 1H) 4.68 (d, 1H), 4. 55 (d, IH), 3.95 (m, 2H), 3.60 (m, 2H), 3. 48 (S, 3H), 2.95 (M, 2H), 2.28 (s, 3H), 1.08 (t, 3H). 13C-NMR (DMSO) 8 167.8, 167.7, 166.9, 146.3, 145.9, 145.2, 136.4, 131.8, 131. 6, 129.7, 128.5, 128.1, 102.9, 102.6, 67.3, 67. 2, 60.1, 51. 2,40. 3,37. 3,19. 0,14. 7.
Reference: [1] Patent: WO2004/58711, 2004, A1, . Location in patent: Page 15
[2] Patent: WO2005/23769, 2005, A1, . Location in patent: Page/Page column 11-12
[3] Pharmazie, 2008, vol. 63, # 5, p. 356 - 360
  • 29
  • [ 88150-46-3 ]
  • [ 110-16-7 ]
  • [ 88150-47-4 ]
Reference: [1] Patent: US4572908, 1986, A,
[2] Patent: US4572909, 1986, A,
  • 30
  • [ 26839-75-8 ]
  • [ 110-16-7 ]
  • [ 26921-17-5 ]
Reference: [1] Tetrahedron, 2007, vol. 63, # 14, p. 3026 - 3030
  • 31
  • [ 26839-75-8 ]
  • [ 110-16-7 ]
  • [ 26921-17-5 ]
Reference: [1] Tetrahedron, 2007, vol. 63, # 14, p. 3026 - 3030
  • 32
  • [ 61718-80-7 ]
  • [ 870-24-6 ]
  • [ 110-16-7 ]
  • [ 61718-82-9 ]
YieldReaction ConditionsOperation in experiment
161 mg
Stage #1: With potassium hydroxide In water; dimethyl sulfoxide; toluene at 40 - 45℃;
Stage #2: at 20 - 30℃;
(0045) Stage—2: Preparation of Crude Fluvoxamine Maleate Formula I (0046) To a prepared solution of dimethyl sulphoxide (575 ml), potassium hydroxide flakes (114.64 gm) and water (69 ml), stage-1 (115 gm) was added at temperature 40-45° C. The reaction mixture was stirred to get clear solution followed by adding 2-chloroethylamine hydrochloride (8636 gm) drop wise into the reaction mixture at temperature 40-45° C. and maintained for 1-2 hour. Water (1150 ml) was added in to the reaction mixture at temperature 25-30° C. and stirred for 20-25 minutes. Then toluene (575 ml×2) was added and stirred for 30 minutes and preceded for separation of layers followed by washing the toluene layer with water (1150×5 ml). The solution of maleic acid (48.47 gm) dissolved in water (98 ml) was added into above obtained toluene layer and stirred at temperature 25-30° C. for 2-3 hours. The reaction mixture was cooled to 0-5° C. and maintained for 30-40 minutes at the same temperature. The obtained material was washed with toluene, filtered and such dried. The wet cake was then added hexane (600 ml) and stirred for 30 minutes at temperature 25-30° C., filtered, washed with hexane and dried to get 161 gm of title compound. HPLC purity: >98.5percent
Reference: [1] Patent: US2016/168080, 2016, A1, . Location in patent: Paragraph 0045; 0046; 0047
  • 33
  • [ 61747-22-6 ]
  • [ 870-24-6 ]
  • [ 110-16-7 ]
  • [ 61718-82-9 ]
Reference: [1] Patent: US6433225, 2002, B1,
  • 34
  • [ 110-16-7 ]
  • [ 122320-73-4 ]
  • [ 155141-29-0 ]
YieldReaction ConditionsOperation in experiment
96% for 1 h; Heating; Reflux Example 3
Preparation of Rosiglitazone Maleate
93.3 g (261.0 mmol) of Rosiglitazone base as prepared in example 2 and 36.4 g (313.2 mmol) of maleic acid were suspended in 510 mL of isopropanol.
The suspension was heated to reflux temperature for 1 hour.
The initial suspension turned into a clear colorless solution.
The resulting solution was cooled down to 10° C. and filtered using a Buechner funnel.
The filter cake was washed with 200 mL of isopropanol. 105.0 g of crude Rosiglitazone maleate were obtained (85percent yield, 99.57percent purity by HPLC).
41.1 g (86.9 mmol) of the crude solid and 1.7 g (14.5 mmol) of maleic acid were suspended in 200 mL of ethanol (0.17 equivalents of maleic acid per 2.3 liters of ethanol which is approximately a maleic acid:ethanol ratio of about 13.5). The suspension was heated to reflux temperature for 20 minutes. The resulting solution was cooled down to 65° C. Seeding particles of the desired polymorph of Rosiglitazone maleate were added to the solution. The resulting suspension was cooled down to 0° C. and filtered using a Buechner funnel. The filter cake was washed with 50 mL of ethanol. 39.5 g of Rosiglitazone maleate were obtained (96percent yield, 99.89percent purity by HPLC), m.p. 120.6-121.7° C.
90%
Stage #1: at 45 - 50℃;
Stage #2: at 5 - 30℃; for 2 h;
5- [4- [2- (N-METHYL-N- (2-PYRIDYL) amino) ethoxy] benzyl] thiazolidine-2,4-dione (rosiglitazone free base, 50GMS, 0. 140MOL) was charged in 100ML methanol and a solution of maleic acid (18. 7gms, 0.16 mol) in methanol (SOML) was added under stirring and was further heated to 45-50°C to obtain a clear solution. This solution was filtered (hot) through celite and ethyl acetate (500ML) was added slowly to this clear filtrate under stirring at 25-30°C, and further stirred for 1 hour at 30°C, then chilled to 5-10°C and stirred at the same temperature for LHOUR. The solid obtained was filtered under argon atmosphere and washed with 50ML ethyl acetate. This solid was dried under vacuum at 50-55°C to get rosiglitazone maleate Form A (60GMS) in 90percent yield.
79% for 0.5 h; Heating / reflux A 500 ml balloon flask is charged with 20 g (56.0 mmoles) of rosiglitazone base and 6.50 g (56.0 mmoles) of maleic acid. To these solids are added 160 ml of water and 80 ml of absolute ethanol. The mixture obtained is brought to reflux for 30' to obtain a clear solution. The solution is filtered on a panel of celite and allowed to cool to ambient temperature. The resultant solid is filtered on a Buchner filter, washed twice with 20 ml of water each time. A product is discharged which when desiccated under vacuum at 45-50°C for 12 hours weighs 21.0 g (yield 79percent) and consists of rosiglitazone maleate Form II. The water content of the desiccated product is 0.3percent.
76% Heating / reflux A mixture of 30 ml of acetic acid and 350 ml of ethanol was poured to a mixture of 50 g of crude free rosiglitazone base I and 16.5 g of maleic acid. The suspension obtained was stirred and heated to the boil until a solution was formed. Then the heating was stopped, and the mixture was stirred, under slow cooling, for 4 hours, followed by stirring overnight at 10 °C. The mixture was filtered, and the filter cake was washed with ethanol (2 x 25 ml). After drying in a vacuum drier, 50.2 g of a finely crystalline product with a melting point of 121 - 125 0C was obtained. The yield of crystallization was 76 percent.
75% for 0.5 h; Heating / reflux A 500 ml balloon flask is charged with 15 g (42.0 mmoles) of rosiglitazone base and 9.70 g (84.0 mmoles) of maleic acid. To these solids are added 150 ml of ethanol, and the mixture obtained is brought to reflux for 30'. The mixture is then slowly cooled to ambient temperature and the resultant solid is filtered on a Buchner filter, washing twice with 20 ml of ethanol each time. A product is discharged which when desiccated under vacuum at 45-50°C for 12 hours weighs 14.9 g (yield 75percent) and consists of rosiglitazone maleate Form III.
75% for 0.5 h; Heating / reflux A 500 ml balloon flask is charged with 20 g (56.0 mmoles) of rosiglitazone base and 6.50 g (56.0 mmoles) of maleic acid. To these solids are added 350 ml of water, and the mixture obtained is brought to reflux for 30'. The mixture is then slowly cooled to ambient temperature and the resultant solid is filtered on a Buchner filter, washing twice with 20 ml of water each time. A product is discharged which when desiccated under vacuum at 45-50°C for 12 hours weighs 19.9 g (yield 75percent) and consists of rosiglitazone maleate Form II. The water content of the desiccated product is 0.3percent. A 500 ml balloon flask equipped with reflux condenser and dropping funnel is charged with 20 g (56.0 mmoles) of rosiglitazone base and 330 ml of deionised water. In a becker are charged 6.50 g (56.0 mmoles) of maleic acid and 23 ml of deionised water, whereby a solution is formed. The solution obtained is then charged in the dropping funnel. The suspension of rosiglitazone base in water is heated to reflux and from the dropping funnel the solution of maleic acid is added in approximately 5'. The mixture is then slowly cooled to ambient temperature and the resultant solid is filtered on a Buchner filter, washing twice with 20 ml of water each time. A product is discharged which when desiccated under vacuum at 45-50°C for 12 hours weighs 20.5 g (yield 77percent) and consists of rosiglitazone maleate Form II. The water content of the desiccated product is 0.4percent.
73% for 0.5 h; Heating / reflux A 250 ml balloon flask equipped with mechanical stirring, coolant and thermometer, is charged with 10 g (28.0 mmoles) of rosiglitazone base, 3.25 g (28.0 mmoles) of maleic acid and 75 ml of isopropanol. The mixture is brought to reflux and maintained for 30' under such conditions. The mixture is then slowly cooled to ambient temperature and the product is filtered on a Buchner filter, washing twice with 10 ml of isopropanol. The filtered product is then desiccated for 12 hours at 45-50°C. 9.7 g of rosiglitazone maleate Form I (yield 73percent) are obtained. The content of residual isopropanol in the product is 0.16percent by weight.
73% Heating / reflux A mixture of 4.0 g 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -2,4-thiazolidine- dione and 1.31 g maleic acid are stirred in 37 ml absolute ethanol and heated at boiling temperature until a clear solution is obtained. 0.4 g charcoal is added and after 5 min the hot solution is filtered and allowed to cool to room temperature under stirring. After standing in a refrigerator at4 C for 17 hours, the precipitated product is filtered and dried at50 C under vacuum for 20 hours to give 3.9 g (73percent) of the product.
73% for 0.5 - 1 h; Heating / reflux 10 g (28.0 mmol) of rosiglitazone base, 3.25 g (28.0 mmol) of maleic acid and 120 ml ofa 2 : 1 mixture of water and ethanol are introduced into a 250-ml flask provided withmechanical agitation, a cooler and a thermometer. The mixture is heated under refluxand maintained under those conditions for 30 minutes. The mixture is then slowly cooledto ambient temperature and the product is filtered on a Buchner funnel, washing twicewith 10 ml of water. The filtered product is then dried for 12 hours at 45-50°C. 9.7 g ofform V rosiglitazone maleate are obtained (yield 73percent).EXAMPLE 2Synthesis of form V rosiglitazone maleate20 g (56.0 mmol) of rosiglitazone base and 6.50 g (56.0 mmol) of maleic acid areintroduced into a 500-ml flask. 160 ml of water and 80 ml of ethanol are added to thosesolids and the mixture obtained is heated under reflux for 60 minutes. The mixture isthen slowly cooled to ambient temperature and 80 ml of water are added thereto. Theresultant solid is filtered on a Buchner funnel, washing twice with 20 ml of water eachtime. A product is discharged which, after being dried under vacuum at 45-50°C for 12hours, weighs 19.9 g (yield 75percent) and is constituted by form V rosiglitazone maleate.The water content of the dried product is 1.3percent.EXAMPLESSynthesis of form V rosiglitazone maleate15 g (42.0 mmol) of rosiglitazone base and 4.85 g (42.0 mmol) of maleic acid areintroduced into a 500-ml flask. 60 ml of ethanol and 120 ml of water are added to thosesolids and the mixture obtained is heated under reflux for 60 minutes. The mixture isthen cooled to 80°C and is seeded with a small amount of form V rosiglitazone maleate.The mixture is then cooled slowly to ambient temperature and the resultant solid isfiltered on a Buchner funnel, washing twice with 20 ml of a 2 : 1 water-ethanol mixture.A product is discharged which, after being dried under vacuum at 45-50°C for 12 hours,weighs 19.9 g (yield 75percent) and is constituted by form V rosiglitazone maleate.
72% for 0.5 h; Heating / reflux Example 1 is repeated, using isopropyl acetate as solvent in place of the isopropanol. After desiccation, 9.5 g of rosiglitazone maleate Form I (yield 72percent) are obtained.
72%
Stage #1: With pyrographite In acetone at 27℃; for 0.5 h; Heating / reflux
Stage #2: at 30 - 40℃; for 18 h;
5- [4- [2- (N-METHYL-N- (2-PYRIDYL) amino) ethoxy] benzyl] THIAZOLIDINE-2, 4-dione (rosiglitazone free base, LOOGMS, 0. 280MOL) was suspended in 500ML of dry acetone and a solution of maleic acid (38.99gms, 0. 336MOL) in 200ML of dry acetone was added at 27°C to obtain a clear solution. Activated charcoal (5GMS) was added and refluxed for 30 minutes. The solution was filtered (hot) through celite. To the clear filtrate seeds of Form A were added at 40°C and stirred for 18 hours at 30°C. The precipitated solid was filtered under argon atmosphere and washed with 100ml of dry acetone. The resulting solid was dried under vacuum at 30°C for 5 hours, and at 50°C for 6 hours, to obtain rosiglitazone maleate Form A (95GMS) in 72percent yield.
71%
Stage #1: at 27 - 82℃; for 0.5 h; Heating / reflux
Stage #2: at 25 - 30℃; for 5 h;
5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] THIAZOLIDINE-2, 4-dione (rosiglitazone free base, 50GMS, 0. 140MOL) was stirred with 250ML of dry acetonitrile and a suspension of maleic acid (19. 50GMS, 0. 168MOL) in 100ML of dry acetonitrile was added at 27°C to obtain a clear solution, followed by reflux for 30 minutes at 80-82°C. The reaction mass was gradually allowed to cool to 30°C and stirred for 5 hours at 25-30°C. The precipitated solid was filtered under argon atmosphere and washed with 50ML of dry acetonitrile. The filtered solid obtained was dried under vacuum at 30°C for 5 hours, and at 50°C for 6 hours, to obtain rosiglitazone maleate Form A (45GMS) in 71percent yield.

Reference: [1] Patent: US2009/234128, 2009, A1, . Location in patent: Page/Page column 5-6
[2] Patent: WO2005/21541, 2005, A2, . Location in patent: Page/Page column 15
[3] Patent: EP1468997, 2004, A2, . Location in patent: Page 7
[4] Patent: WO2006/125402, 2006, A1, . Location in patent: Page/Page column 20
[5] Patent: EP1468997, 2004, A2, . Location in patent: Page 7
[6] Patent: EP1468997, 2004, A2, . Location in patent: Page 6-7
[7] Patent: EP1468997, 2004, A2, . Location in patent: Page 6
[8] Patent: WO2004/62667, 2004, A1, . Location in patent: Page/Page column 17
[9] Patent: WO2005/49610, 2005, A1, . Location in patent: Page/Page column 15
[10] Patent: WO2006/10653, 2006, A1, . Location in patent: Page/Page column 4-5
[11] Patent: EP1468997, 2004, A2, . Location in patent: Page 7
[12] Patent: WO2005/21541, 2005, A2, . Location in patent: Page/Page column 15
[13] Patent: WO2005/21541, 2005, A2, . Location in patent: Page/Page column 15-16
[14] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 11
[15] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 12-13
[16] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 13
[17] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 10
[18] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 13
[19] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 14-15
[20] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 11
[21] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 10
[22] Patent: WO2004/85435, 2004, A1, . Location in patent: Page 13
[23] Patent: WO2005/21541, 2005, A2, . Location in patent: Page/Page column 14
[24] Patent: WO2005/21541, 2005, A2, . Location in patent: Page/Page column 16
[25] Patent: WO2005/95390, 2005, A2, . Location in patent: Page/Page column 16
[26] Patent: WO2005/95390, 2005, A2, . Location in patent: Page/Page column 15
[27] Patent: US2007/293546, 2007, A1, . Location in patent: Page/Page column 9
[28] Patent: WO2005/49532, 2005, A2, . Location in patent: Page/Page column 13-14
  • 35
  • [ 96219-87-3 ]
  • [ 110-16-7 ]
  • [ 325715-02-4 ]
Reference: [1] Patent: US2012/28045, 2012, A1,
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