15903-66-9|3-Methylisothiazole-4-carboxylic acid| Ambeed

CAS No. :	15903-66-9
Formula :	C₅H₅NO₂S
M.W :	143.16
SMILES Code :	CC1=NSC=C1C(O)=O
MDL No. :	MFCD00030523
InChI Key :	BOTUFHIAKJCIPY-UHFFFAOYSA-N
Pubchem ID :	588692

Safety of [ 15903-66-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Application In Synthesis of [ 15903-66-9 ]

* 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 [ 15903-66-9 ]

[ 15903-66-9 ] Synthesis Path-Downstream 1~41

1
[ 17265-59-7 ]
[ 15903-66-9 ]

References: [1]Journal of the Chemical Society,1963,p. 2032 - 2039.

2
[ 67048-61-7 ]
[ 15903-66-9 ]

References: [1]Journal of Organic Chemistry,1978,vol. 43,p. 3736 - 3742.

3
[ 58850-81-0 ]
[ 15903-66-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium hydroxide; In 1,2-dimethoxyethane; water; at 120℃; for 12h;Sealed tube; Inert atmosphere;	In a sealed tube, a solution of 3-methyl-1,2-thiazole-4-carbonitrile (500 mg, 4.03 mmol) in ethylene glycol (12.6 ml) and H2O (0.9 ml) under N2 was treated with KOH (520 mg, 9.26 mmol). The RM was heated at 120 C for 12 h. The residue was diluted with H2O (20 ml), the resulting solution acidified to pH ~2 by addition of 6 M HCl (aq.), and the mixture extracted with EtOAc (3 x 15 ml). The organic phase was concentrated under reduced pressure to give the title compound as a yellow solid. Y = 78 %. LCMS (ESI): m/z: [M+H]+ 144.0.

References: [1]Patent: WO2020/249664,2020,A1 .Location in patent: Paragraph 01545-01546.
[2]Journal of the Chemical Society,1963,p. 2032 - 2039.

4
[ 15903-66-9 ]
[ 10284-34-1 ]

References: [1]Journal of the Chemical Society,1963,p. 2032 - 2039.

6
[ 49570-33-4 ]
[ 15903-66-9 ]

References: [1]Journal of Organic Chemistry,1978,vol. 43,p. 3736 - 3742.

7
[ 15903-66-9 ]
[ 23031-80-3 ]

References: [1]Journal of the Chemical Society,1963,p. 2032 - 2039.

8
[ 15903-66-9 ]
[ 74410-97-2 ]

References: [1]Journal of the Chemical Society,1963,p. 2032 - 2039.

9
[ 15903-66-9 ]
[ 15901-51-6 ]

References: [1]Journal of the Chemical Society,1963,p. 2032 - 2039.

10
[ 15903-66-9 ]
[ 92290-33-0 ]

References: [1]Journal of the Chemical Society,1963,p. 2032 - 2039.

11
[ 15903-66-9 ]
[ 89179-69-1 ]

References: [1]Journal of the Chemical Society,1963,p. 2032 - 2039.

12
[ 92498-49-2 ]
[ 15903-66-9 ]

References: [1]Journal of the Chemical Society,1963,p. 2032 - 2039.

13
[ 15903-66-9 ]
[ 75-65-0 ]
[ 876191-56-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With diphenylphosphoranyl azide; triethylamine;Heating / reflux;	To a solution of <strong>[15903-66-9]3-methyl-isothiazole-4-carboxylic acid</strong> (method 33) (14.8 g, 103 mmol) in anhydrous t-BuOH (100 mL) triethyl amine (10.5 g, 104 mmol) was added followed by the dropwise addition of diphenylphosphoryl azide (28.6 g, 104 mmol) and the resulting mixture was heated at reflux overnight after which the TLC showed the complete disappearance of the starting material. The reaction mixture was cooled to room temperature and poured into ice cold water (500 mL). The aqueous layer was extracted with ether (3*100 mL) and the combined organic layers were washed with satd, NaHCO3 (100 mL), brine (100 mL) and dried (Na2SO4). Concentration of the ether solution provided the crude product, which was purified by column chromatography to get the pure product as light brown crystals. Yield 21.4 g (97%). Having the following properties 1H NMR (300 MHz) δ 1.53 (s, 9H), 2.40 (s, 3H), 6.50 (s, 1H), 8.66 (s, 1H).
74%	With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine; at 90℃; for 12h;Inert atmosphere;	To a solution of <strong>[15903-66-9]3-methyl-1,2-thiazole-4-carboxylic acid</strong> (390 mg, 2.72 mmol) in tert- butanol (20 ml) under N2 were added DPPA (750 mg, 2.72 mmol) and DIPEA (0.71 ml, 4.09 mmol). The RM was heated at 90 C for 12 h. The solution was concentrated under reduced and the resulting residue purified by column chromatography (silica, 9- 17 % EtOAc in petrol) to give the title compound as a yellow solid. Y = 74 %. LCMS (ESI): m/z: [M+H]+ = 215.0.

References: [1]Patent: US2006/41128,2006,A1 .Location in patent: Page/Page column 19.
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 6734 - 6750.
[3]Patent: WO2020/249664,2020,A1 .Location in patent: Paragraph 01547-01548.

14
[ 15901-51-6 ]
[ 15903-66-9 ]

Yield	Reaction Conditions	Operation in experiment
79%		To a solution of 3-methyl-isothiazole-4-carboxylic acid ethyl ester (method 32) (23.3 g, 136 mmol) in THF (200 mL) aqueous NaOH (6.5 g, 162 mmol, in 100 ml of water) was added and the mixture was stirred at room temperature for 16 h. The TLC of the reaction mixture showed the complete disappearance of the starting material. The reaction mixture was cooled in an ice bath and acidified to pH 5 using 6M HCl and the resultant mixture was extracted with ether (3*100 mL). The ether layers were combined, washed with water (100 mL), brine (100 mL), dried (Na2SO4) and concentrated to about 10 mL. Addition of hexanes to the above mixture resulted in the precipitation of the product, which was filtered off, washed with hexanes and dried to provide the pure product as a tan powder. Yield 15.3 g (79%). Having the following properties: 1H NMR (300 MHz) δ 2.39 (s, 3H), 8.98 (s, 1H).

References: [1]Patent: US2006/41128,2006,A1 .Location in patent: Page/Page column 19.
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 6734 - 6750.

15
[ 876191-55-8 ]
[ 15903-66-9 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 6734 - 6750.

16
C₇H₁₁NO₃ [ No CAS ]
[ 15903-66-9 ]

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 6734 - 6750.

17
[ 1420625-84-8 ]
[ 15903-66-9 ]

References: [1]Patent: WO2013/12918,2013,A1 .
[2]Patent: WO2013/12915,2013,A1 .
[3]Patent: US2013/267521,2013,A1 .

18
[ 74410-97-2 ]
[ 15903-66-9 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: [00563] To a solution of 3-methylisothiazole-4-carboxylate (E-3) (4.73 g, 30.1 mmol) in THF-MeOH-H20 (2: 1 : 1, 50 mL), NaOH (3.61 g, 90.3 mmol) is added and the resulting mixture is stirred at 40 C for 16 h. The mixture is allowed to cool to RT and then acidified with concentrated HCl to adjust the pH to 2-3. The precipitate is collected by filtration, rinsed with water and dried in vacuo to afford the product, 3-methylisothiazole-4-carboxylic acid (E-4).
	With water; sodium hydroxide; In tetrahydrofuran; methanol; at 40℃; for 16h;	To a solution of 3-methylisothiazole-4-carboxylate (G-3) (4.73 g, 30.1 mmol) in THF-MeOH-H20(2: 1 : 1, 50 mL), NaOH (3.61 g, 90.3 mmol) is added and the resulting mixture is stirred at 40 C for 16 h. The mixture is allowed to cool to RT and then acidified with concentrated HCl to adjust the pH to 2-3. The precipitate is collected by filtration, rinsed with water and dried in vacuo to afford the product, 3-methylisothiazole-4-carboxylic acid (G-4).
	With sodium hydroxide; In tetrahydrofuran; methanol; water; at 40℃; for 16h;	General procedure: To a solution of 3-methylisothiazole-4-carboxylate (C-3) (4.73 g, 30.1 mmol) in THF-MeOH-H2O (2:1:1, 50 mL), NaOH (3.61 g, 90.3 mmol) is added and the resulting mixture is stirred at 40 C. for 16 h. The mixture is allowed to cool to RT and then acidified with concentrated HCl to adjust the pH to 2-3. The precipitate is collected by filtration, rinsed with water and dried in vacuo to afford the product, 3-methylisothiazole-4-carboxylic acid (C-4).

References: [1]Patent: WO2013/12918,2013,A1 .Location in patent: Paragraph 00563.
[2]Patent: WO2013/12915,2013,A1 .Location in patent: Page/Page column 00704.
[3]Patent: US2013/267521,2013,A1 .Location in patent: Paragraph 0771; 0839.

19
[ 15903-66-9 ]
[ 1383546-18-6 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a solution of 3-methylisothiazole-4-carboxylic acid (E-4) (3.9 g, 27.3 mmol) in anhydrousTHF (150 mL) at -78 C under argon, n-butyllithium solution (27.3 mL, 68.3 mmol) is added dropwise and the resulting mixture is stirred at -78 C for 1 h. To this mixture, a solution of iodide (13.9 g, 54.6 mmol) in THF (50 mL) is added slowly and the resulting mixture is stirred at RT for 1 h. The mixture is acidified with concentrated HCl to adjust the pH to 3-4, and then extracted with ethyl acetate. The organic layer is washed with aqueous Na2S03 solution. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2S04 and filtered. The filtrate is concentrated in vacuo to afford the product, 5-iodo-3-methylisothiazole-4-carboxylic acid (E-5).
		To a solution of 3-methylisothiazole-4-carboxylic acid (G-4) (3.9 g, 27.3 mmol) in anhydrousTHF (150 mL) at -78 C under argon, n-butyl lithium solution (27.3 mL, 68.3 mmol) is added dropwise and the resulting mixture is stirred at -78 C for 1 h. To this mixture, a solution of iodide (13.9 g, 54.6 mmol) in THF (50 mL) is added slowly and the resulting mixture is stirred at RT for 1 h. The mixture is acidified with concentrated HC1 to adjust the pH to 3-4, and then extracted with ethyl acetate. The organic layer is washed with aqueous Na2S03 solution. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2S04 and filtered. The filtrate is concentrated in vacuo to afford the product, 5-iodo-3- methylisothiazole-4-carboxylic acid (G-5).
		General procedure: To a solution of 3-methylisothiazole-4-carboxylic acid (C-4) (3.9 g, 27.3 mmol) in anhydrous THF (150 mL) at -78 C. under argon, n-butyl lithium solution (27.3 mL, 68.3 mmol) is added dropwise and the resulting mixture is stirred at -78 C. for 1 h. To this mixture, a solution of iodine (13.9 g, 54.6 mmol) in THF (50 mL) is added slowly and the resulting mixture is stirred at RT for 1 h. The mixture is acidified with concentrated HCl to adjust the pH to 3-4, and then extracted with ethyl acetate. The organic layer is washed with aqueous Na2SO3 solution. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 5-iodo-3-methylisothiazole-4-carboxylic acid (C-5).

References: [1]Patent: WO2013/12918,2013,A1 .Location in patent: Paragraph 00564.
[2]Patent: WO2013/12915,2013,A1 .Location in patent: Paragraph 00705.
[3]Patent: US2013/267521,2013,A1 .Location in patent: Paragraph 0772; 0839.

20
[ 15903-66-9 ]
[ 1420830-24-5 ]