42831-50-5|5-Methylisoxazole-4-carboxylic acid| Ambeed

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Quality Control of Leflunomide Impurity D Purity: 97% SDS Specification

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Product Details of Leflunomide Impurity D

CAS No. :	42831-50-5
Formula :	C₅H₅NO₃
M.W :	127.10
SMILES Code :	O=C(C1=C(C)ON=C1)O
MDL No. :	MFCD00955655
InChI Key :	VQBXUKGMJCPBMF-UHFFFAOYSA-N
Pubchem ID :	1425240

Safety of Leflunomide Impurity D

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Application In Synthesis of Leflunomide Impurity D

* 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.

Downstream synthetic route of [ 42831-50-5 ]

[ 42831-50-5 ] Synthesis Path-Downstream 1~35

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References: [1]Zhurnal Obshchei Khimii,1958,vol. 28,p. 2736,2743; engl. Ausg. S. 2762, 2768.

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Yield	Reaction Conditions	Operation in experiment
99.9%	With sulfuric acid; In o-tolyl acetic acid;	EXAMPLE 4 Preparation of 5-Methylisoxazole-4-Carboxylic Acid A two-necked flask fitted with mechanical stirrer and a horizontal condenser for distillation was charged with 40.0 g of crude Ethyl-5-methylisoxazole-4-carboxylate and 44 g of 60% sulfuric acid and the mixture was heated to 85 C. with continuous distillation of ethanol from the reaction product. After four hours of heating at 85 C., TLC showed the complete disappearance of the upper spot of ester. The mixture was allowed to cool in the refrigerator and the solid acid was filtered (16.5 g) Filtrate kept at room temperature for second crop. Acid was crystallized in 60 mL 2% acetic acid-Toluene to obtain about 99.9% pure acid (9.5 g). Mother liquor of the final crystallization was kept for second crop. Crystallization was accomplished by: The crude acid was taken in 2% acetic acid-toluene mixture and heated for 30 minutes. Brown oil was separated at the bottom of the flask. The clear organic phase was neatly transferred and kept for crystallization.
60%	With sulfuric acid; In water; at 20℃; for 20.0h;Reflux;	Ethyl-5-methylisoxazole-4-carboxylate 7 g (0.045 mol) was heated under reflux in aqueous sulphuric acid (20 % v/v, 30 ml) for 16 hr followed by cooling to room temperature with stirring for 4 h. The crystallized solid product was filtered and washed using toluene followed by water and dried. The product then was crystallized from ethanol to produce 3.5 g (60 %) of 5-Methylisoxazole-4-carboxylic acid as a white solid, mp. 147-148 C (reported mp. 144-147 C).
	With sulfuric acid; In water; for 16.0h;Heating / reflux;	S-MethyIisoxazole-4-carboxyiic acid:Ethyl-5-methylisoxazole-4-carboxylate 72.58 g (0.47 mol) was taken in 20% v/v aqueous sulphuric acid (193.5 ml) and refluxed for 16 hours. Toluene (73 ml) was added at 90 0C, cooled to 25 to 35 0C and stirred for 4 hours. The crystallized solid product was filtered and washed with toluene (2x36 ml) followed by water (2x72.5 ml). The product was dried under vacuum to get 27.2 g of 5-Methylisoxazole-4-carboxylic acid as an off white solid with 99.5 % HPLC purity having isomeric impurity 0.27 %

	In hydrogenchloride;	(iii) 5-Methylisoxazol-4-yl carboxylic acid <strong>[51135-73-0]Ethyl 5-methylisoxazol-4-yl carboxylate</strong> (65 g) was heated under reflux in 10 M HCl (500 ml) for 3 hours. On cooling the product crystallized out. This was filtered and dried giving 42 g of a white crystalline solid, m.p. 134-136C.
	In hydrogenchloride;	(iii) 5-Methylisoxazol-4-yl carboxylic acid <strong>[51135-73-0]Ethyl 5-methylisoxazol-4-yl carboxylate</strong> (65 g) was heated under reflux in 10M HCl (500 ml) for 3 hours. On cooling the product crystallized out. This was filtered and dried giving 42 g of a white crystalline solid, m.p. 134-136 C.
	In hydrogenchloride;	(iii) 5-Methylisoxazol-4-yl carboxylic acid <strong>[51135-73-0]Ethyl 5-methylisoxazol-4-yl carboxylate</strong> (65 g) was heated under reflux in 10 M HCl (500 ml) for 3 hours. On cooling the product crystallized out. This was filtered and dried giving 42 g of a white crystalline solid, m.p. 134-136 C.

References: [1]Patent: US2003/139606,2003,A1 .
[2]Letters in drug design and discovery,2016,vol. 13,p. 912 - 920.
[3]Journal of Heterocyclic Chemistry,1991,vol. 28,p. 453 - 457.
[4]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1959,vol. 79,p. 836.
Chem.Abstr.,1960,p. 1493.
[5]Journal of the Chemical Society. Perkin transactions I,1988,p. 1875 - 1880.
[6]Patent: WO2007/86076,2007,A2 .Location in patent: Page/Page column 5; 7.
[7]Asian Journal of Chemistry,2010,vol. 22,p. 1503 - 1506.
[8]Patent: EP257882,1991,B1 .
[9]Patent: US4892963,1990,A .
[10]Patent: US4983619,1991,A .
[11]Patent: DE634286,1935, .
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 23,p. 502.

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[ 42831-50-5 ]
[ 67305-24-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; In toluene;	b) A mixture of <strong>[42831-50-5]5-methylisoxazole-4-carboxylic acid</strong> (5 g, 39.4 mm), SOCl2 (15 ml, 205.8 mm) and toluene (15 ml) was heated to 79+-1 C. and stirred for about 4-5 h. Excess SOCl2 and toluene were evaporated under vacuum (50 torr) at 70 C. to give the title compound (>=99% purity) as a pale yellow liquid residue identical to that of Example 1(a).
96%	With thionyl chloride; at 50℃;	5-Methyl isoxazole-4-carboxylic acid (1 g, 7.86 mmol) was dissolved in SOCl2 (3 mL) and stirred at 50 C. After the reaction was completed, the mixture was cooled to room temperature, and then distilled under reduced pressure to obtain 5-methylisoxazole-4-carbonyl chloride (1098 mg, 96%).
	With thionyl chloride; at 26 - 89℃; for 1h;	Thionyl chloride (4.3 ml, 39.5 mmol) was added dropwise to <strong>[42831-50-5]5-methylisoxazole-4-carboxylic acid</strong> (0.44 g, 3.4 mmol) at 26C. The mixture was heated at 89C for 1 hr and allowed to cool. Excess thionyl chloride was evaporated under reduced pressure to give an acid chloride as a brown oil, which was used in the next reaction.

	With thionyl chloride; sodium carbonate; In chloroform;	EXAMPLE 1 2-Cyano-3-hydroxythiocrotonic acid-S-phenyl ester A 72 ml. portion of thionyl chloride is added dropwise to a mixture of 70.24 g. of <strong>[42831-50-5]5-methylisoxazole-4-carboxylic acid</strong> [H. Yasuda, Yakugaku Zasshi, 79, 836-838 (1959); C. A. 53, 21885d] and 64.44 g. of sodium carbonate in 250 ml. of chloroform. The mixture is heated gently on a steam bath for 4 hours, then the solid is filtered and the filtrate is evaporated to an oil. This oil is distilled at 4.5 mm. and the material boiling at 68-70 C. is collected, giving 65.23 g. of 5-methylisoxazole-4-carbonyl chloride.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 5h;	Preparation 4 N-(6-Amino-5-chloropyrazin-2-yl)-5-methylisoxazole-4-carboxamide Oxalyl chloride (0.8 ml, 10.3 mmol) was added to a solution of 5-Methyl-isoxazole-4-carboxylic acid (1 g, 6.9 mmol) in dichloromethane (30 ml) followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 5 hours before concentrating in vacuo and azeotroping with dichloromethane. The residue was taken up in pyridine (3 ml) and added to a solution of 3-chloro-pyrazine-2,6-diamine (Preparation 1) (0.65 g, 4.6 mmol) in anhydrous pyridine (30 ml) and the mixture heated at 50 C. for 3 hours before cooling to room temperature and concentrating in vacuo. The residue was purified by silica gel column chromatography, eluding with ethyl acetate:heptane 1:1, to afford the product as a white solid (360 mg). 1H-NMR (d6-DMSO): 2.51 (s, 3H), 6.71 (br, s, 2H), 8.35 (s, 1H), 9.12 (s, 1H), 10.63 (br, s, 1H). MS m/z 254 [MH]+
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2.25h;Product distribution / selectivity;	Step 5: To generate the acid chloride a suspension of 5-methyl-1 ,2-oxazole-4-carboxylic acid (39 mg, 0.30 mmol) in CH2CI2 (0.5 mL) at 0 C was added oxalyl chloride (50 muIota_, 1.2 mmol) and DMF (1 drop). The suspension was allowed to stir for a further 15 min at 0 C followed by 2 h at room temperature. The resulting mixture was concentrated in vacuo to give a dark oil. The oil was twice suspended in n-hexanes (2 x 1 mL) and concentrated in vacuo. A solution of 7-acetyl-10a-(4-chlorophenyl)-2,3, 10, 10a-tetrahydro-1 H,5H-imidazo[1 ,2- a]pyrrolo[1 ,2-c ]pyrazin-5-one (20 mg, 61 muetaetaomicronIota) in pyridine (0.5 mL) was added to a suspension of the acid chloride (generated as above; 0.30 mmol) in pyridine (0.5 mL) and CH2CI2 (0.5 mL) at 0 C . The resultant mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with a saturated aqueous solution of NaHC03 (25 mL) and extracted with CH2CI2 containing 20% of propan-2-ol (3 x 25 mL). The organic layers were combined, dried and concentrated in vacuo to yield a crude brown residue that was partially purified using flash chromatography (Biotage SP4, 12 g cartridge, 0-10%MeOH gradient in CH2CI2) to give a mixture (10 mg) containing the desired product which was further purified by flash chromatography (2 x Biotage SP4, 12 g cartridge, C18 phase, 20-40% acetonitrile gradient in water) to give 7-acetyl-10a-(4-chlorophenyl)-1-[(5-methyl-1 ,2- oxazol-4-yl)carbonyl]-2,3, 10, 10a-tetrahydro-1 H,5H-imidazo[1 ,2-a]pyrrolo[1 ,2-c ]pyrazin-5-one (24) as a solid (3.5 mg, yield 14%).
	With thionyl chloride; at 50℃;	The <strong>[42831-50-5]5-methylisoxazole-4-carboxylic acid</strong> (1) (1 g, 7.86 mmol) inSOCl2 (3 mL) was heated at 50 C until compound 1 disappeared inTLC. After reaction was terminated, the mixture was cooled toambient temperature and solvent was evaporated under reducedpressure. 5-methylisoxazole-4-carbonyl chloride, a crude yellow oil(2) (96%)was used for the next step without additional purification;1H NMR (400 MHz, DMSO) d 8.77 (1H, s), 2.64 (3H, s).
	With thionyl chloride; In toluene; for 3h;Reflux;	To a solution of <strong>[42831-50-5]5-methylisoxazole-4-carboxylic acid</strong> SM (500 mg, 4.0 mmol) in toluene(10 mL) was added SOd2 (720 mg, 6.0 mmol). The mixture was heated to reflux for 3 hours. Thereaction mixture was concentrated under reduced pressure to obtain 5-methylisoxazole-4-carbonyl chloride compound 1 (550 mg, crude) without further purification.
	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 12h;Reflux;	Thionylchloride (3.53 g, 0.0278 mol) was added to a solutionof 5-Methylisoxazole-4-carboxylic acid (2.7 g, 0.0185 mol) in anhydrous dichloromethane (50 ml) with catalytic drops of DMF. The reaction was heated under reflux for 12 h then followed by removing the solvent under reduced pressure. DCM (20 ml) was added and evaporated 3 times to produce a brown oil that was used directly in the next step.
	With thionyl chloride; at 50℃;	5-Methylisoxazole-4-carboxylic acid (1 g, 7.86 mmol) was added to SOCl 2 (3 mL) and stirred at 50 C. After completion of the reaction, the reaction mixture was cooled and then distilled under reduced pressure to remove volatile materials to obtain crude yellow oil (96%)
0.59 mol	With thionyl chloride; at 45℃;	A round bottomed flask equipped with a mechanical stiner, condenser, thermometer pocket and a stopper were added 5-Methylisoxazole-4-carboxylic acid (3.00 g, 0.02 mol) and Thionyl chloride (14.66 g, 0.12 mol) and the reaction mixture was gradually heated to 45±5C and stined at same temperature for 2 to 3 h. The progress of the reaction was monitored by TLC (Acid chloride was analyzed as corresponding methyl ester by quenching the samplein methanol). After the completion of reaction, the reaction mixture was concentrated under reduced pressure at 45±5C to afford 5-Methylisoxazole-4-carbonyl chloride as a liquid (0.59 mol).
	With thionyl chloride; In N-methyl-acetamide;	(iv) 5-Methylisoxazol-4-yl carbonyl chloride Thionyl chloride (118 g) was added to <strong>[42831-50-5]5-methylisoxazol-4-yl carboxylic acid</strong> (42 g) and stirred at room temperature as dimethylformamide (0.2 ml) was added. The solution was heated under reflux for 2 hours with stirring. Excess thionyl chloride was removed in vacuo at 50C, then the residue was distilled through a 15 cm Vigreaux column at reduced pressure to give an oil, b.p. 32-34C/0.1 mm Hg.
	With thionyl chloride; In N-methyl-acetamide;	(iv) 5-Methylisoxazol-4-yl carbonyl chloride Thionyl chloride (118 g) was added to <strong>[42831-50-5]5-methylisoxazol-4-yl carboxylic acid</strong> (42 g) and stirred at room temperature as dimethylformamide (0.2 ml) was added. The solution was heated under reflux for 2 hours with stirring. Excess thionyl chloride was removed in vacuo at 50 C., then the residue was distilled through a 15 cm Vigreaux column at reduced pressure to give an oil, b.p. 32-34 C./0.1 mm Hg.
	With thionyl chloride; In N-methyl-acetamide;	(iv) 5-Methylisoxazol-4-yl carbonyl chloride Thionyl chloride (118 g) was added to <strong>[42831-50-5]5-methylisoxazol-4-yl carboxylic acid</strong> (42 g) and stirred at room temperature as dimethylformamide (0.2 ml) was added. The solution was heated under reflux for 2 hours with stirring. Excess thionyl chloride was removed in vacuo at 50 C., then the residue was distilled through a 15 cm Vigreux column at reduced pressure to give an oil, b.p. 32-34 C./0.1 mmHg.

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[17]Patent: WO2016/44770,2016,A1 .Location in patent: Page/Page column 677.
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[21]Patent: EP257882,1991,B1 .
[22]Patent: US4892963,1990,A .
[23]Patent: US4983619,1991,A .

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(Z)-N-(5-bromo-2-cyanobenzofuran-3-yl)-2-cyano-3-hydroxy-2-butenamide [ No CAS ]