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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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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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 |
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: | Ⅱ |
* 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.
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; acetone; acetonitrile; at 20℃;Product distribution / selectivity; | Example 3: Preparation of Salts of the Compound of Formula I; The compound of Formula I was prepared as described in Example 1. Hydrochloric acid (HCl)5 sodium hydroxide (NaOH), acetic acid, lactic acid, succinic acid, malic acid, citric acid, ethanesulfonic acid, maleic acid, methanesulfonic acid, toluenesulfonic acid, phosphoric acid, and sulfuric acid were all United States Pharmacopoeia-National Formulary (USP-NF) grade or ACS grade.Conversion of the compound of Formula I to various salt forms was accomplished via an acid-base reaction in an organic liquid medium followed by a slow evaporation of the organic solvent, except for the mesylate, esylate, and maleate salts which were prepared as described in Example 6, below. An accurately weighed amount of the compound of Formula I (443.4 mg) was dissolved in a total of 8.39 mL of a solvent mixture composed of 7.39 mL acetone and 1 mL methanol. 0.567 mL aliquots of this solution were placed in 1.5 mL polypropylene tubes to yield 30 mg of the solid compound of Formula I upon drying. Tubes containing the compound of Formula I were left overnight in the chemical fume hood to air-dry. Equimolar amounts of the respective cognate acids were added to the vials from acetonitrile (ACN) solutions of the acids (1 mL of 57.86 mM acid solutions). The resulting converted salt suspensions were agitated overnight at room temperature. The following day, the salt suspensions were dissolved by the addition of 0.5 mL of methanol, agitated for 1 hr <n="33"/>and allowed to air dry in the chemical fume hood. Upon drying, the solid salt materials were subjected to microscopic examination and aqueous solubility testing. Microscopic examination was performed with a polarized light microscope to assess the crystalline nature of the materials. The salt solubility studies were performed by adding excess solid salt material to 1 mL of deionized water in 1.5 mL polypropylene tubes and agitating for 48 hr at room temperature. The tubes were then centrifuged at 15,000 rpm for 20 min at 22C in a microcentrifuge. Concentrations of the various salts in the supernatant were measured by HPLC and the pH of each was measured and recorded. The supernatant was then discarded and the pellets were resuspended in deionized water for another solubility determination.HPLC analyses were performed using Waters Alliance 2695 Separation Module equipped with Waters 2996 Diode Array Detector. Separation was performed using 4.6 x 150 mm Synergi Hydro-RP C 18 reversed phase HPLC column at temperature of 35C. Mobile phase conditions consisted of 0.1 % Trifluoroacetic acid (TFA) in water (Solvent A) and 0.1 % TFA in ACN (Solvent B). Flow was maintained at 1 mL/min with the linear gradient elution shown in Table 2.; Quantitative analyses of the compound of Formula I were performed at 254 nm wavelength using an external standard curve.In an attempt to increase the aqueous solubility and dissolution rate of compound of Formula I, initially ten acids were screened for their ability to form salts with the compound of Formula I free base. The acids included relatively weak acids such as acetic and lactic acids. They also included strong acids such as sulfuric, hydrochloric, toluenesulfonic, and methanesulfonic acids as shown in Table 3.The crystalline nature of each of the collected salts was assessed microscopically using a polarized light microscope. As shown in Table 3, microscopic examination of <n="34"/>collected salts indicated that some salts were crystalline and the others were mixtures of crystalline and amorphous phases. When the salts were evaluated for their equilibrium aqueous solubility, they exhibited low levels of solubility and low pH of the saturated solutions. Given the very weakly basic nature of the compound of Formula I, it was assumed that the salts dissociated in aqueous media and mostly reverted back to the free base and the respective free acid counter ions during the equilibration process. The residual solids in these aqueous suspensions were, therefore, collected, and their aqueous solubility was evaluated in freshly added deionized water. As shown in Table 3, the obtained solubility is consistent with that of the free base confirming that the salts reverted back to the free base upon contact with water. The observed behavior of compound of Formula I salts is not an unexpected one given the weak basicity and the low intrinsic aqueous solubility of the compound. A closer inspection of the pH-solubility profile of compound of Formula I in Table 1 reveals that the compound did not attain maximum solubility even at the lowest pH tested, i.e., pH 1.36. This indicates that the pH of a saturated solution of a salt of Formula I is lower than 1.36. Salts that require a low pH to attain the saturated solution are known to be unstable and to revert back to the free base when in contact with aqueous media (Serajuddin A.T. M. and Pudipeddi M. Salt Selection Strategies. In Handbook of Pharmaceutical Salts... | |
In tetrahydrofuran; at 20℃; for 2h;Product distribution / selectivity; | Maleate acid:; One equivalents of maleic acid were slowly added to 3g of API in 20 mL of THF at room temperature. The resulting suspension was equilibrated for two hours before solids were collected by filtration. Solids were dried under vacuum at 500C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; chloroform; for 48h; | A solution of maleic acid was prepared by dissolving 2.2 equivalents of maleic acid in 7: 3 (v/v) CHCI3/ETOH. E-2-METHOXY-N- (3- {4- [3-METHYL-4- (6-METHYL-PYRIDIN-3-YLOXY)- PHENYLAMINO]-QUINAZOLIN-6-YL}-ALLYL)-ACETAMIDE (prepared according to Example 1,2 or 3 above) was dissolved in 70: 30 CHC13/ETOH (v/v), and added drop-wise to the maleic acid solution with stirring. After about 2 days, white crystalline powder precipitated. By polarized light microscopy, the DIMALEATE crystals had a needle habit with strong birefringence. On hot-state polarizing light microscope (PLM), the crystals MELTED/DECOMPOSED AT 1170C. The DSC thermogram showed an endotherm AT ~170C immediately followed by an exotherm. The endotherm and exotherm correspond with the MELT/DECOMPOSITION events seen by hot-stage PLM. Hygroscopicity: 0.6% (by weight) at 90% relative humidity. The PXRD is shown in Figure 2. Characteristic X-ray powder diffraction PEAKS (2-THETA (0. 1), [% RELATIVE INTENSITY] ) : 4.6 [20.4]. 6.0 [41.9], 7.2 [13.1], 9.4 [33], 9.7 [32], 11.2 [27.7], 12.0 [5.2], 14.1 [20], 14.2 [53], 15.5 [63.7], 15.7 [51.2], 18.4 [55], 18.7 [93.4], 19.3 [5], 19.6 [21.9], 20.2 [22.9], 20.4 [16.2], 20.8 [15.5], 21.2 [37.6], 22.4 [22.7], 22 : 8 [68.7], 23.2 [49.2], 23.4 [62.5], 23.8 [18.8], 24.5 [8.7], 24.8 [34.3], 25.2 [100], 25.7 [18.4], 26.4 [11.5], 26.9 [29.5], 27.1 [10.8], 27.4 [57.4], 27.7 [14.3], 27.9 [29.2], 28.4 [9.4], 28.6 [22.4], 29.2 [24], 29.6 [18.9], 29.9 [17.2], 30.7 [13.9], and 31.4 [23.7]. Calculated X-ray diffraction peaks (from SINGLE CRYSTAL) (2-THETA (0. 1), [% RELATIVE INTENSITY] ): 4.7 [21], 6.0 [34.5], 7.2 [18.3], 9.5 [32.3], 9.7 [25.9], 11.3 [32], 12.1 [1.7] 14.0 [20.3], 14.2 [37.8], 15. 6 [37.5], 15.8 [42.1], 18.4 [59.7], 18.8 [100], 19.3 [15.9], 19.7 [22.9], 20.2 [22.9], 20.5 [16.5], 20.8 [18.6], 21.3 [58.8], 22.4 [29.5], 22.8 [75.9], 23.3 [48.3], 23.5 [55. 7], 23.9 [18.4], 24.6 [18.1], 24.8 [30.3], 25.3 [94.5], 25.8 [14.6], 26.5 [5.1], 26.9 [22.4], 27.1 [20.8], 27.5 [48.4], 27.8 [22.8], 28.0 [23.2], 28.3 [10], 28.7 [15.4], 29.3 [16.3], 29.7 [8.6], 29.9 [8.7], 30.8 [8.3], and 31.5 [11.6]. Single crystal x-ray data are shown in Table 3. TABLE 3-SINGLE CRYSTAL X-RAY data for E-2-METHOXV-N-(3-84-[3-METHVL-4-(6-METHVL-PVRIDIN-3- VIOXV)-PHENVLAMINO1-QUINAZOLIN-6-VL}-ALIVL)-ACETAMIDE DIMALEATE Dimaleate Empirical FORMULAC27H29N503+'2 (C4H304-) Formula weight 701.68 Crystal size (mm) 0.03 x 0.04 x 0.20 Space group P-1 triclinic Unit cell dimensions a = 4.7763 (4) A B = 19. 0308 (14) A C = 19. 1520 (14) A A= 100. 4 P= 90. 2 Y=95. 3 Z (per formular) 2 Density (G/CM3) 1.367 R 0.0648 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; methanol; dichloromethane; acetonitrile; | Example 36 N-{2-[(9-Benzyl-9H-carbazol-4-yl)oxy]ethyl}-N-(2-methoxyethyl)amine A mixture of 2-[(9-benzyl-9H-carbazol-4-yl)oxy]ethylamine (0.103 g, 0.327 mmol), 2-bromoethylmethyl ether (0.050 g, 0.359 mmol), diisopropylethylamine (0.0464 g, 0.359 mmol), acetonitrile (1 mL), and THF (1 mL) is stirred at room temperature for 40 min and then at 70 C. for 43 h. After cooling, the solvents are removed and the residue is chromatographed on silica gel (15 mL) using CH3OH/CH2Cl2 (4/96). The pure product fractions are concentrated to dryness to give 0.044 g (36%) of an oil. Maleic acid (0.013 g) is added and the salt is crystallized from CH2Cl2/CH3OH/hexane to give the title compound; mp 175.0-175.5 C.; 1H NMR (CDCl3) δ2.98, 3.26, 3.39, 3.57, 4.38, 5.51, 6.70, 6.99, 7.12, 7.2-7.4, 8.33. Anal. Calcd for C24H26N2O2.C4H4O4: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.54; H, 6.22; N, 5.81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With sulfuric acid; In methanol; water; toluene; | (1b) 2-(Benzyloxymethyl)morpholine hydrogen maleate 130 g (0.94 mol) of 2-aminoethyl hydrogen sulfate (ester) are added in the course of 10 minutes to 45 ml of 40percent strength caustic soda. After a further 10 minutes' stirring, the above mixture is treated with a solution of 20 g (0.121 mol) of the above epoxide in 90 ml of methanol. The medium is brought to reflux for 1 h, 45 ml of 40percent strength caustic soda are then added and the mixture is brought to reflux for a further 8 h. After being left overnight at room temperature, the mixture is poured into 250 ml of water and 250 ml of toluene, stirring vigorously. The organic phase is separated, the aqueous phase re-extracted with toluene and the toluene phases combined. The organic phase is treated with 2*150 ml of 2N sulfuric acid. The organic base is sorted out of the acidic aqueous phase by adding caustic soda to pH 14, and extracted with 2*100 ml of toluene. The organic phase is washed with saline water, dried over sulfate and then evaporated to dryness. The above oily base (20.4 g), dissolved in 50 ml of isopropyl alcohol, is added to a solution of 11.5 g of maleic acid in 100 ml of the same solvent brought to boiling. After a slight amount of insoluble material is filtered off hot, the product is left to crystallize slowly for 24 h at room temperature, and the derivative of formula: STR10 is recovered in 40percent yield. Empirical formula: C16 H21 NO6 Molecular mass: 323.353 Melting point: 111° Thin layer chromatography: support: silica gel Merck 60 F 254 solvent: chloroform/methanol/ammonia 90:9:1 visualization: UV, iodine Rf: 0.35 Solubility: soluble to 10percent in water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; triethylamine; In methanol; ethyl acetate; N,N-dimethyl-formamide; | EXAMPLES 15-16 Ethyl chloroformate (0.07 ml.) was added to a mixture of <strong>[1072-84-0]imidazole-4-carboxylic acid</strong> (0.08 g.) and triethylamine (1 min.) in DMF (5 ml.) at -5°. The mixture was stirred at room temperature for 0.5 hours and then treated with a solution of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobutyl)pyrimidine (0.2 g.) in DMF (2 ml.). The mixture was stirred at room temperature for 4 hours, then evaporated to dryness. The residual gum was partitioned between EtOAc and 2 N aqueous HCl and the acid layer was then basified with 11 N aqueous sodium hydroxide and extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated to dryness. The residual gum was purified by preparative thin layer chromatography on Merck 60 F-254 plates using EtOAc/MeOH/aqueous ammonia (s.g. 0.88) 6:1:1 v/v/v as developing solvent. Two products were obtained by extracting appropriate bands of the chromatogram using MeOH/aqueous ammonia (s.g. 0.88) 10:1 v/v and evaporating to dryness. Both residual gums were dissolved in EtOAc and treated with excess of a solution of maleic acid in EtOAc. The resulting solids were filtered to give the separate products. The more polar band gave N-[4-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yl)butyl]imidazol-4- ylcarboxamide bis maleate (0.02 g.), m.p. 155°-159° (decomp.). The less polar band gave ethyl N-[4-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yl)butyl]-carbamate hydrogen maleate monohydrate (0.06 g.), m.p. 152°-156°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 5,5-dimethyl-1,3-cyclohexadiene; diethyl ether; ethanol; water; acetone; toluene; Petroleum ether; | EXAMPLE II 285 g (2.2 mole) of 1-methylpiperidin-2-ylmethanol in 1.25 liters of anhydrous xylene are added drop-wise under reflux to a solution of 216.5 g (1 mole) of p-methyl-a-phenylbenzyl chloride dissolved in 1.25 liters of anhydrous xylene. When the addition is completed, the mixture is refluxed for another 4 hours. The precipitate consisting of 1-methylpiperidin-2-ylmethanol hydrochloride is filtered off. The filtrate is washed with water until it is neutral and dried with sodium sulphate. The xylene is distilled off and the residue is dissolved in a mixture of 500 ml of ethanol and 2 liters of diethyl ether. 100 g of maleic acid, dissolved in 250 ml of ethanol, are added under stirring. The precipitate, consisting of 1-methyl-2-[(p-methyl-a-phenylbenzyl)oxymethyl]piperidine maleate is filtered off and digested in acetone. The salt is filtered off again and dissolved in water. The solution is made alkaline with 2 N sodium hydroxide and extracted with diethyl ether. The extract is dried over sodium sulphate and the ether is evaporated. The residue, consisting of 83 g of the base, is dissolved in 900 ml of acetone and then methyl bromide is introduced with stirring at room temperature until no further precipitation takes place. 1800 ml of petroleum ether (boiling range 40°-60° C.) are added to effect complete precipitation of the methobromide formed. The precipitate is filtered off and dried over sodium sulphate. To remove p-methyl-a-phenyl-benzylalcohol, present as a contaminant, the product is refluxed for 6 hours in 1000 ml of toluene. Filtration yields 90 g of 1,1-dimethyl-2[[(p-methyl-a-phenylbenzyl)oxy]methyl]piperidinium bromide. Melting point 180.2°-180.9° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; methanol;Product distribution / selectivity; | Cooling MethodICRF- 187 freebase was dissolved in the desired crystallization solvent or mixture of solvents (Table 2A). These solvents were chosen such that the <strong>[24584-09-6]dexrazoxane</strong> freebase is soluble in the solvents but the salts formed from the reaction of the freebase and acids when the respective acids are added to the crystallization solvents are not soluble. Equimolar amount of the desired acid - i.e. sulfuric, maleic, methanesulfonic or hydrochloric acid - was added to the solvent to form a solution. The salt precipitated in the solution. The precipitates, which were typically not crystalline or were partially crystalline are collected through filtration on a filter and dried by vacuum. Methanol was then added to the dried powder and heated to 65°C to dissolve the entire salt. The solution then cooled in a controlled manner to 5°C overnight in RS-IO Chemblock Reaction Station (Barnstead International, Dubuque, IA). The crystals are then harvested on a filter and dried at < 40°C. <n="46"/>Anti-Solvent MethodICRF- 187 freebase was dissolved in the desired crystallization solvent or mixture of solvents (Table 1). Equimolar amount of the acid - i.e. sulfuric, maleic, methanesulfonic or hydrochloric acid - was added to the solvent or mixtures of solvents to form a solution but the total solution volume is such that the salt formed in-situ remains dissolved in the solution or is soluble in the solution. While the solution was being gently stirred, an anti-solvent (Table 2A) was slowly added until the salt begins to precipitate from the solution. Additional anti-solvent is added until sufficient salt is formed. The crystals was then harvested on a filter and dried at <4O0C.Solvent Evaporation method ICRF- 187 freebase is dissolved in dioxane. Equimolar amount of the acid - i.e. sulfuric, maleic, methanesulfonic or hydrochloric acid - was added to the solvent or mixtures of solvents to form a solution. The salt precipitated in the solution. With gently stirring, minimum amount of water was added until the salt is completely dissolved. Nitrogen was introduced into the solution and the solvents were slowly evaporated until salt precipitation appeared. Additional anti-solvent is added until sufficient salt is formed. The crystals are then harvested on a filter and dried at < 40°C.Direct precipitation methodICRF- 187 freebase was dissolved in dioxane. Equimolar amount of the acid - i.e. sulfuric, maleic, methanesulfonic or hydrochloric acid - was added to the solvent or mixtures of solvents to form a solution. The salt precipitated in the solution. The crystals are then harvested on a filter and dried at < or = 40°C.X-ray powder diffraction analysesThe XRPD analyses were performed using a Shimadzu XRD-6000 X-ray powder diffractometer using Cu Ka radiation. The instrument was equipped with a long fine focus X-ray tube. The tube voltage and amperage were set to 40 kV and 40 <n="47"/>mA, respectively. The divergence and scattering slits were set at 1° and the receiving slit was set at 0.15 mm. Diffracted radiation was detected by a NaI scintillation detector. A Psi-2Psi continuous scan at 37min (0.4 sec/0.02o step) from 2.5 to 40° 2Psi was used. A silicon standard was analyzed to check the instrument alignment. Data were collected and analyzed using XRD-6000 v. 4.1. The peak lists were generated with the Shimadzu software using default peak picking parameters on smoothed, background-subtracted, Ka1 -corrected traces. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19%; 10%; 35%; 20%; 8% | With dihydrogen peroxide;methyltrioxorhenium(VII); In dichloromethane; water; acetonitrile; at 20℃; | Comparative examples 1 to 3: Oxidation of 5-hydroxymethyl furfural in homogeneous conditions; 5-hydroxymethyl furfural (HMF) was oxidized with 10 equivalents of hydrogen peroxide (35percent by weight in aqueous solution) in the presence of methyltrioxo rhenium in an amount of 5percent by weight of HMF, at a temperature about 200C during 24 to 48 hours, until the conversion of furfural was complete, in various solvents. The results of the reactions are summarized in Table 1 below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23%; 6%; 11%; 16%; 29% | With dihydrogen peroxide;methyltrioxorhenium(VII); In ethanol; water; at 20℃; | Comparative examples 1 to 3: Oxidation of 5-hydroxymethyl furfural in homogeneous conditions; 5-hydroxymethyl furfural (HMF) was oxidized with 10 equivalents of hydrogen peroxide (35percent by weight in aqueous solution) in the presence of methyltrioxo rhenium in an amount of 5percent by weight of HMF, at a temperature about 200C during 24 to 48 hours, until the conversion of furfural was complete, in various solvents. The results of the reactions are summarized in Table 1 below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 15 - 30℃; for 41h; | Example 1General Procedure for Preparation of <strong>[173334-57-1]Aliskiren</strong> CompoundsAn ethanolic solution of acid (selected from the list of acids detailed in Table 1 attached below) was added to a stirred 0.1 M ethanolic solution of aliskiren base (AKN) (5 ml, 0.5 mmol), and the solution was stirred for an hour at room temperature. Ethanol was evaporated under vacuum at 40 C., and the solid was dried under vacuum at the same temperature overnight. The solid was analyzed by XRPD.Table 1 summarizes the various experiments performed to obtain aliskiren compounds using different acids and their XRPD interpretation: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In water; at 20℃; for 0.75h;Product distribution / selectivity; | Example 12<strong>[173334-57-1]Aliskiren</strong> MaleateA solution of 1 13.5 mg (0. 9786 mmol) of maleic acid in 4 ml water was added to 540 mg (0. 979 mmol) <strong>[173334-57-1]Aliskiren</strong> free base and the resulting mixture was shaken well at room temperature for 45 min resulting in a milky solution. This was frozen, using liquid nitrogen, and was lyophilized for 4 h to yield 575 mg (88 %) of a white solid.LCMS purity: 99.5 %.Melting point: 61 C - 71 C.DSC shows a broad endotherm at 197.9 C.IR: 2960, 2875.7, 1708.4, 1660.1 , 1585.9, 1516, 1475.1 cm"1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.1% | The processes described in Examples 2 to 4 were repeated under slightly different reaction conditions (such as varying the redox catalyst (e.g., Pt/C), the reducing system (e.g., a formate salt with redox catalyst or a dithionite salt without redox catalyst; cf. also Example 5), the ester solvent, the reaction temperatures and times, the amounts of reactants, and washing/purification reagents) and flupirtine maleate was obtained with yield and purity values similar to those presented above in Examples 2 to 4. For example, the following procedure has been used to prepare flupirtine maleate. A round bottom flask (1 L) was charged with acetonitrile (200 niL), followed by ANFP (20.0 g, 76 mmol), sodium dithionite (55.0 g, 315 mmol) and 29% aqueous ammonia (250 mL). The reaction mixture was stirred and gently heated at 36 to 37C for 60 min. The mixture was heated up to 44C over 35 min and then gradually cooled. The colour turned from yellow (starting material) to white. Acetonitrile, ammonia and water were removed by distillation at reduced pressure on a rotary evaporator. After distillation the mixture was diluted with water (100 mL) and ethyl acetate (310 mL) under a nitrogen stream. The water layer was separated and discarded. The air sensitive ethyl acetate layer was treated with ethyl chloroformate (14.5 mL, 151 mmol), while stirring and slowly flushing with nitrogen for 30 min. Triethylamine (25 mL, 179 mmol) was added and stirred for 30 min. An aqueous solution of maleic acid prepared from maleic acid (14.0 g, 120 mmol) and water (160 mL) was added to the reaction mixture. The mixture was maintained at 40C for 1 h, then cooled to 20C. The precipitate was collected by filtration, the vessel and the precipitate were washed with an additional portion of ethyl acetate (55 mL). The obtained wet product was dried in a vacuum drying oven at 50C, until the loss on drying was less than 1.0%. Yield: 29.5 g (94.3%> assay, 66.2 mmol; 87.1%> of theory); purity: 99.84%. | |
In an autoclave, 100 gm. 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine is taken in 500 ml. 1, 4-dioxane and 20 ml aqueous ammonia solution. 10 gm of raney nickel is added under nitrogen atmosphere and hydrogenated at 75-80C for 2-3 hours under 4-5 kg pressure. After completion of the reaction, the reaction mass is cooled and filtered at 40- 45Cthen in filtrate 45 ml of ethyl chloroformate is added slowly at 5- 10C. The temperature is raised to 25-30C and 80 ml triethyl amine is added under nitrogen atmosphere. The reaction mass, is heated at 55- 60C under stirring for 3-4 hours. After completion of the reaction, the reaction mass is distilled up to 70-80% under vacuum. This concentrated reaction mass is added into aqueous solution of maleic acid (72 gm in 2000 ml DM water at 65-70C and maintained at 65-70C for 2 hours under nitrogen to get crude Flupirtine Maleate as a solid. The reaction mass is cooled to 25-30C in 5-6 hours and maintained at this temperature for next 2-3 hours then filtered. The wet cake is washed with 200 ml water and dried to get 145 gm of flupirtine maleate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 45℃;Product distribution / selectivity; | <strong>[500287-72-9]Rilpivirine</strong> base Form II (0.30 g, 0.82 mmol) was dissolved in THF (6 mL) at 45C. Maleic acid (105 mg, 0.90 mmol, 1.1 eq) was dissolved in THF (3 mL) at room temperature and the resulting solution was then added portion- wise to the solution containing <strong>[500287-72-9]Rilpivirine</strong> base at 45C with stirring. The reaction mixture was removed from the heat source and precipitation was observed after stirring for about 20 min. The stirring was continued at room temperature for about 17 h. The precipitate was isolated by filtration to give <strong>[500287-72-9]Rilpivirine</strong> maleate form 1. Drying of this material in a vacuum oven at 50C for 17 h afforded the same polymorphic form as was identified prior to drying, as confirmed by XRD analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.4 g | Example 9 Synthesis of trans-(6S)-4-ethylamino-5,6-dihydro-6-methyl-7,7-dioxo-4H-thieno[2,3-b]thiopyran-2-sulfonamide maleate salt Compound of formula (VII) and (VIII) Borane THF (176.9 g, 1M solution in THF) was added dropwise to a suspension of <strong>[147200-03-1]trans-(6S)-4-acetylamino-5,6-dihydro-6-methyl-7,7-dioxo-4H-thieno[2,3-b]thiopyran-2-sulfonamide</strong> (20.0 g, 59.1 mmol) in THF (36.7 g) at 38 C. under nitrogen atmosphere in 7 hours. The mixture was left under stirring at 38 C. for 10 hours and was then transferred to a solution of diluted hydrochloric acid at 60 C. The quench suspension was diluted with THF (19.5 g) and stirred under reflux for 1.5 hours. The mixture was then cooled, purified and diluted with THF (41.5 g) and demineralised water (18.7 g). The mixture was concentrated up to a volume of 100 mL, the pH adjusted to 7.5, and lastly the mixture was diluted with ethyl acetate (200.8 g). The aqueous phase was separated and counter-extracted with ethyl acetate (22.7 g). The combined organic phases were washed with demineralised water (17.5 g) and then concentrated under vacuum to a volume of approximately 30 mL. The mixture was then diluted with ethyl acetate (142.6 g) and concentrated to a volume of approximately 30 mL. 1/3 of the solution was subjected to a change of solvent with acetone (102.2 g) by distilling repeatedly up to 10 g of residues. The residue was diluted with acetone (16.0 g), and maleic acid (6.6 g, 20% solution in acetone) was added to the mixture at 40 C. After the addition process, the temperature was brought to 20 C., the solid was filtered and washed with acetone (8.2 g, in 2 portions), then dried to give trans-(6S)-4-ethylamino-5,6-dihydro-6-methyl-7,7-dioxo-4H-thieno[2,3-b]thiopyran-2-sulfonamide maleate salt (4.4 g, titre trans+cis 88.3%, de 99.6%, ee 99.9%). 1H NMR: deltaH (ppm) (400 MHz, DMSO) 8.2 (2H, bs, SO2NH2), 7.8 (1H, s, CH), 6.05 (2H, CH=CH), 4.6 (1H, bs, CH), 4.0 (1H, m, CH), 3.2 (1H, m, ½ AB, NH-CH2), 3.0 (1H, m, ½ AB, NH-CH2), 2.7-2.5 (2H, m, CH2), 1.4 (3H, d, J=7 Hz, CH3), 1.2 (3H, m, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In water; at 90℃; for 58.0h;Autoclave; High pressure; | A mixture of Ag2O (11.6 mg, 0.05 mmol), bpz (19 mg, 0.1 mmol), maleic acid (11.6 mg, 0.1 mmol), 5 mL H2O, and 0.15 mL pyridine was heated to 90 C for 8 h in a 25 mL Teflon-lined reaction vessel, kept at 90 C for 50 h, then slowly cooled to 30 C in 10 h. The pH values of the system were 6.06 and 6.10 before and after the hydrothermal reaction, respectively. Colorless block crystals of 1 were isolated by filtration, washed with H2O, and dried in air. Anal. Calcd (found) for C17H22AgN6O2: C, 45.35 (45.79); H, 4.92 (4.88); N,18.66 (18.59) %. IR (KBr): nu(cm-1) = 3144(w), 2920(w), 2799(w), 1578(s), 1416(w), 1364(s), 1299(w), 1160(w), 1026(w), 972(w), 863(w), 778(w), 662(w), 526(w), 497(w), 432(w). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethyl acetate; | The reaction proceeded similarly in both acetonitrile and ethylacetate. A solution of maleic acid (2b) (0.14 g, 0.0012 mol) inethyl acetate (3 mL) was added dropwise to a solution of3tridiphenylphosphinopropanoic acid (1) (0.3 g, 0.0012 mol) inEtOAc (5 mL) with continuous stirring. The reaction reachedcompletion within several minutes to form a white precipitate,which was filtered on a Shott funnel, washed with diethyl ether,and dried in vacuo. The product 3a is well soluble in water andethanol with heating, insoluble in acetonitrile, m.p. 80 C (fromethanol). The yield was 0.381 g (86%). IR (Nujol), ν/cm-1: 1600(COO-); 1700 (COOH). 1H NMR, δ: 2.43-2.57 (m, 2 H,PCH2CH2; 1 H, CHCH2); 2.58-2.78 (m, 2 H, CHCH2);2.43-2.57 (m, 2 H, PCH2); 7.53-7.80 (m, 10 H, Ar). 13C (δ: 17.39(d, PCH2, 1JP,C = 54.2 Hz); 26.0 (d, PCHCH2, 2JP,C = 1.3 Hz);26.45 (d, PCH2CH2, 2JP,C = 1.3 Hz); 31.30 (d, PCH, 2JP,C == 46.6 Hz); 114.60 (d, Cipso, 1JP,C = 83.4 Hz); 130.05 (d, Co,2JP,C = 29.75 Hz); 133.57 (d, Cm, 3JP,C = 9.4 Hz); 135.30 (d, Cp,4JP,C = 2.5 Hz); 169.51 (d, C(O)O, 3JP,C = 1.5 Hz); 173.58(d, C(O)O, 3JP,C = 14.3 Hz); 174.09 (d, C(O)O, 2JP,C = 17.1 Hz).31P NMR, δ: 28.7. Found (%): C, 57.69; H, 4.69; P, 7.12.C18H19O4P. Calculated (%): C, 58.30; H, 4.86; P, 7.19. Showssigns of decarboxylation upon prolonged storage (several months). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium hydroxide; at 140.0℃; for 72h;pH 7.0;Autoclave; | A solution of H2male (0.2mmol) in 8mL H2O was adjusted to pH 7 with dilute NaOH. Then bix (0.2mmol) and Zn(NO3)2·6H2O (0.2mmol) in 12mL H2O were added. The mixture was added to a 20mL Teflon-lined stainless autoclave and this was sealed and heated to 140C for 3days, then cooled to room temperature to give colorless crystals of 3 in 42% yield (0.039g). Anal. Calc. for C20H22N4O5Zn (3): C, 51.79; H, 4.78; N, 12.08. Found: C, 51.61; H, 4.64; N, 11.96%. IR data (cm-1): 3457 m, 3127 m, 1607 s, 1590 s, 1506 w, 1419 m, 1369 s, 1310 m, 1297 m, 1273 w, 1184 w, 1155 w, 1039 w, 1010 w, 852 w, 758 m, 743 s, 672 m, 629 m |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.6 g | In acetone; for 0.5h;Reflux; | To a mixture of 4-(piperidin-3-yl) aniline (Compound 16) (0.5 g) in acetone (5 mL), maleic acid (0.36 g) was charged at reflux temperature. The reaction mass was stirred at reflux temperature for 30 minute. The reaction mass was cooled to 20-25C and stirred further for 3 h. The solid obtained was filtered, washed with acetone (3 mL) and dried under vacuum at 50-55C to afford the titled compound (Yield: 0.6 g; HPLC Purity: >98.80% ). |
Tags: 110-16-7 synthesis path| 110-16-7 SDS| 110-16-7 COA| 110-16-7 purity| 110-16-7 application| 110-16-7 NMR| 110-16-7 COA| 110-16-7 structure
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H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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The concentration of the dissolution solution you need to prepare is mg/mL