397308-78-0|4-Hydroxy-2-(methylthio)pyrimidine-5-carboxylic acid| Ambeed

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Quality Control of [ 397308-78-0 ] Purity: 97% SDS Specification

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Product Details of [ 397308-78-0 ]

CAS No. :	397308-78-0
Formula :	C₆H₆N₂O₃S
M.W :	186.19
SMILES Code :	OC1=NC(=NC=C1C(=O)O)SC
MDL No. :	MFCD09759031
InChI Key :	MOAJQWKFKCJUKP-UHFFFAOYSA-N
Pubchem ID :	295895

Safety of [ 397308-78-0 ]

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

Computational Chemistry of [ 397308-78-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	2
Num. H-bond acceptors	5.0
Num. H-bond donors	2.0
Molar Refractivity	42.74
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	108.61 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.91
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.1
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.6
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-0.36
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.37
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.52

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.93
Solubility	2.21 mg/ml ; 0.0119 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.97
Solubility	0.198 mg/ml ; 0.00106 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.95
Solubility	20.9 mg/ml ; 0.112 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.65 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.66

Application In Synthesis of [ 397308-78-0 ]

* 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 [ 397308-78-0 ]

[ 397308-78-0 ] Synthesis Path-Downstream 1~35

1
[ 5909-24-0 ]
[ 10519-96-7 ]
[ 397308-78-0 ]

Yield	Reaction Conditions	Operation in experiment
73%		A. 4-Chloro-2-methylsulfanylpyrimidine-5-carbonyl chloride A slurry of potassium trimethylsilyl oxide (90% tech., 40 g, 0.31 mol) in 1,2-dimethoxyethane (300 mL) was added, slowly over 20 min, to a solution of ethyl-4-chloro-2-methylthio-5-pyrimidinecarboxylate (Aldrich, 15 g, 64 mmol) in 1,2-dimethoxyethane (100 mL). Said addition, being mildly exothermic, may warrant the use of an ice bath to maintain ambient temperature conditions during addition. After addition was complete, the resulting suspension was stirred at ambient temperature for 1 h, then warmed to reflux for 36 h, then allowed to cool to ambient temperature. Reaction mixture was quenched with 1 M HCl(aq), then extracted with ethyl acetate and dried using sodium sulfate to produce a crude solid (11 g). Said crude solid was then recrystallized in ethyl acetate to afford 4-hydroxy-2-methylsulfanylpyrimidine-5-carboxylic acid as a white solid (8.8 g, 47 mmol, 73% yield). MS (-ESI) m/z 185 (M-, 100). An aliquot of this material (3.00 g, 16.1 mmol) was diluted with thionyl chloride (90 mL) followed by DMF (0.20 mL) and the resulting solution was warmed to reflux. After 1 hour at reflux, the solution was allowed to cool to ambient temperature and was concentrated in vacuo to afford a beige solid which was triturated once from hot toluene and then once again from hot hexanes (i.e., in both instances the soluble material was the desired fraction). This afforded, after concentration in vacuo, the titled compound as a white solid (3.90 g, 15.6 mmol, 97% yield). 1H NMR (300 MHz, CDCl3) delta 9.15 (s, 1H), 2.63 (s, 3H).

References: [1]Patent: US7176310,2007,B1 .Location in patent: Page/Page column 48.

2
[ 397308-78-0 ]
[ 55084-66-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; N,N-dimethyl-formamide; at 90.0℃; for 3h;	The <strong>[397308-78-0]4-hydroxy-2-(methylthio)pyrimidine-5-carboxylic acid</strong> (35.8 g, 192 mmol) was treated with 500 mL of thionyl chloride and 0.75 mL of DMF. The mixture was stirred at 90 C for 3 hrs. After cooling to ambient the mixture was concentrated, re-dissolved in hot toluene (~50 mL) and the unsoluble particle filtered. The filtrate was concentrated to give 4-chloro-2-(methylthio)pyrimidine-5-carbonyl chloride (42.46 g, 190 mmol, 99 % yield) as a white solid.1H NMR (300 MHz, DMSO-d6) delta 8.99 (s, 1H), 2.58 (s, 3H).
97%	With thionyl chloride; In N,N-dimethyl-formamide; for 1h;Heating / reflux;	A slurry of potassium trimethylsilyl oxide (90% tech., 40 g, 0.31 mol) in 1,2-dimethoxyethane (300 mL) was added, slowly over 20 min, to a solution of ethyl-4-chloro-2-methylthio-5-pyrimidinecarboxylate (Aldrich, 15 g, 64 mmol) in 1,2-dimethoxyethane (100 mL). Said addition, being mildly exothermic, may warrant the use of an ice bath to maintain ambient temperature conditions during addition. After addition was complete, the resulting suspension was stirred at ambient temperature for 1 h, then warmed to reflux for 36 h, then allowed to cool to ambient temperature. Reaction mixture was quenched with 1 M HCl(aq), then extracted with ethyl acetate and dried using sodium sulfate to produce a crude solid (11 g). Said crude solid was then recrystallized in ethyl acetate to afford <strong>[397308-78-0]4-hydroxy-2-methylsulfanylpyrimidine-5-carboxylic acid</strong> as a white solid (8.8 g, 47 mmol, 73% yield). MS (-ESI) m/z 185 (M-, 100). An aliquot of this material (3.00 g, 16.1 mmol) was diluted with thionyl chloride (90 mL) followed by DMF (0.20 mL) and the resulting solution was warmed to reflux. After 1 hour at reflux, the solution was allowed to cool to ambient temperature and was concentrated in vacuo to afford a beige solid which was triturated once from hot toluene and then once again from hot hexanes (i.e., in both instances the soluble material was the desired fraction). This afforded, after concentration in vacuo, the titled compound as a white solid (3.90 g, 15.6 mmol, 97% yield). 1H NMR (300 MHz, CDCl3) delta 9.15 (s, 1H), 2.63 (s, 3H).
83.59%	With thionyl chloride; In N,N-dimethyl-formamide; at 100.0℃; for 2h;	To a stirred solution of 9 <strong>[397308-78-0]4-hydroxy-2-(methylthio)pyrimidine-5-carboxylic acid</strong> (2.5 g, 13.44 mmol, 1 eq) in 47 DMF (2.5 mL) was added 825 SOCl2 (10 mL) and the resultant mixture was heated at 100 C. for 2 h. After completion, the mixture was cooled to RT was then concentrated in vacuo to give 826 4-chloro-2-(methylthio)pyrimidine-5-carbonyl chloride (2.65 g, 83.59%) as an off-white solid. (0870) LCMS: 224 [M+1]+

With thionyl chloride; at 80.0℃; for 18h;

In a 250mL round bottom flask with magnetic stir bar, 4-hydroxy-2- (methylsulfanyl)pyrimidine-5-carboxylic acid (12 g, 64.45 mmol, 1.00 eq.) was suspended in thionyl chloride (120 mL). The resulting solution was stirred for 18 h at 80 C, and then concentrated under reduced pressure to afford the acid chloride intermediate.

References: [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 1481 - 1486.
[2]Patent: US7176310,2007,B1 .Location in patent: Page/Page column 48.
[3]Patent: US2019/106436,2019,A1 .Location in patent: Paragraph 0866; 0869-0870.
[4]Patent: US2014/275023,2014,A1 .Location in patent: Paragraph 0290; 0291.
[5]Patent: WO2015/61247,2015,A2 .Location in patent: Paragraph 00618.

3
[ 53554-29-3 ]
[ 397308-78-0 ]

References: [1]Patent: US2014/275023,2014,A1 .Location in patent: Paragraph 0290; 0291.

4
[ 397308-78-0 ]
C₁₃H₁₆ClN₃O₃S [ No CAS ]

References: [1]Patent: US2014/275023,2014,A1 .

5
[ 397308-78-0 ]
[ 100426-81-1 ]

References: [1]Patent: US2014/275023,2014,A1 .

6
[ 397308-78-0 ]
C₁₇H₁₅N₃O₅S [ No CAS ]
C₁₇H₁₅N₃O₄S [ No CAS ]

References: [1]Patent: US2014/275023,2014,A1 .

7
[ 397308-78-0 ]
C₁₇H₁₄BrN₃O₃S [ No CAS ]

References: [1]Patent: US2014/275023,2014,A1 .

8
[ 397308-78-0 ]
C₁₇H₁₄BrN₃O₄S [ No CAS ]

References: [1]Patent: US2014/275023,2014,A1 .

9
[ 397308-78-0 ]
C₁₇H₁₄BrN₃O₅S [ No CAS ]

References: [1]Patent: US2014/275023,2014,A1 .

10
[ 397308-78-0 ]
C₂₃H₁₉BrN₄O₄ [ No CAS ]

References: [1]Patent: US2014/275023,2014,A1 .

11
[ 397308-78-0 ]
C₁₈H₁₉N₃O₃S [ No CAS ]

References: [1]Patent: US2014/275023,2014,A1 .

12
[ 397308-78-0 ]
C₁₈H₁₇N₃O₃S [ No CAS ]

References: [1]Patent: US2014/275023,2014,A1 .

13
[ 397308-78-0 ]
C₁₈H₁₇N₃O₄S [ No CAS ]
C₁₈H₁₇N₃O₅S [ No CAS ]

References: [1]Patent: US2014/275023,2014,A1 .

14
[ 397308-78-0 ]
4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxamide [ No CAS ]

References: [1]Patent: WO2015/61247,2015,A2 .

15
[ 397308-78-0 ]
2-(methylsulfanyl)-4-(4-phenoxyphenoxy)pyrimidine-5-carboxamide [ No CAS ]

References: [1]Patent: WO2015/61247,2015,A2 .

16
[ 397308-78-0 ]
2-methanesulfonyl-4-(4-phenoxyphenoxy)pyrimidine-5-carboxamide [ No CAS ]

References: [1]Patent: WO2015/61247,2015,A2 .

17
[ 397308-78-0 ]
tert-butyl 3-[[5-carbamoyl-4-(4-phenoxyphenoxy)pyrimidin-2-yl]amino]piperidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2015/61247,2015,A2 .

18
[ 397308-78-0 ]
4-(4-phenoxyphenoxy)-2-[(piperidin-3-yl)amino]pyrimidine-5-carboxamide [ No CAS ]

References: [1]Patent: WO2015/61247,2015,A2 .

19
[ 397308-78-0 ]
2-[(1-cyanopiperidin-3-yl)amino]-4-(4-phenoxyphenoxy)pyrimidine-5-carboxamide [ No CAS ]

References: [1]Patent: WO2015/61247,2015,A2 .

20
[ 397308-78-0 ]
[ 2106-02-7 ]
N-(2-chloro-4-fluoro-phenyl)-4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.6 g		A stirred solution of 9 <strong>[397308-78-0]4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxylic acid</strong> (5.0 g, 26.9 mmol) and 109 2-chloro-4-fluoro-aniline (4.30 g, 29.57 mmol) in 200 mL of 24 Toluene was purged with nitrogen gas for 15 min. To the above solution 91 PCl3 (50 mL) was added. Reaction was heated at 100 C. for 48 h. Progress of reaction was monitored by LCMS. After completion of reaction, solvent was removed under reduced pressure, residue was basified with saturated solution of 56 sodium bicarbonate. In basified layer, 19 ethyl acetate (200 mL) was added, and then stirred for 10 m in. Precipitated compound was filtered off and washed with 50 mL of 7 water and dried under vacuum to obtain 110 N-(2-chloro-4-fluoro-phenyl)-4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxamide (2.60 g). LCMS: 314 [M+1]+

References: [1]Patent: US2019/106436,2019,A1 .Location in patent: Paragraph 0276-0278.

21
[ 397308-78-0 ]
[ 363-51-9 ]
N-(2-chloro-6-fluoro-phenyl)-4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.8%		A stirred solution of 9 <strong>[397308-78-0]4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxylic acid</strong> (5.70 g, 30.65 mmol, 1.0 eq) and 237 2-chloro-6-fluoro-aniline (4.50 g, 30.65 mmol, 1.0 eq) in 24 toluene (200 mL) was purged with nitrogen gas for 15 min. To the above solution 91 PCl3 (30 mL) was added. The reaction was heated at 100 C. for 72 h. Progress of reaction was monitored by LCMS. After completion of reaction, solvent was removed under reduced pressure, residue was diluted with a mixture of 238 diethyl ether: 30 MeOH (10:1) (100 mL) stirred for 15 min then filtered off. Solid was suspended in MeOH (20 mL), stirred for 5 min, filtered off and washed with MeOH (10 mL), and then dried under vacuum to obtain of 239 N-(2-chloro-6-fluoro-phenyl)-4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxamide (5.0 g, 52.8%). (0370) LCMS: 314 [M+1]+

References: [1]Patent: US2019/106436,2019,A1 .Location in patent: Paragraph 0368-0370.

22
[ 397308-78-0 ]
[ 87-63-8 ]
N-(2-chloro-6-methylphenyl)-4-hydroxy-2-(methylthio)pyrimidine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With phosphorus trichloride; In toluene; at 100.0℃; for 72h;	To a stirred solution of 9 <strong>[397308-78-0]4-hydroxy-2-(methylthio)pyrimidine-5-carboxylic acid</strong> (5 g, 26.88 mmol, 1.0 eq) in 24 toluene (100 mL) were added 279 2-chloro-6-methylaniline (3.8 g, 26.88 mmol, 1 eq) and 91 PCl3 (25 mL). The reaction mixture was allowed to stir at 100 C. for 72 h. Progress of reaction was monitored by LCMS. After consumption of starting material, solvent was removed under reduced pressure, residue was diluted with diethyl ether (100 mL) and MeOH (10 mL) stirred at rt for 10 min then filtered off and dried under vacuum to obtain 280 N-(2-chloro-6-methylphenyl)-4-hydroxy-2-(methylthio)pyrimidine-5-carboxamide (4 g, 48%). (0405) LCMS: 310 [M+1]+

References: [1]Patent: US2019/106436,2019,A1 .Location in patent: Paragraph 0403-0405.

23
[ 5909-24-0 ]
[ 397308-78-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With water; sodium hydroxide; In ethanol; at 110.0℃; for 2h;	To a stirred solution of 5 ethyl 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate (10 g, 43.1 mmol, 1.0 eq) in 150 mL of 6 ethanol: 7 water (2:1) was added 8 NaOH (17.2 g, 431 mmol, 10 eq). Reaction was heated at 110 C. for 2 h. Progress of reaction was monitored by LCMS. Upon the consumption of starting material, solvent was removed under reduced pressure. Residue was diluted with 100 mL of water and pH of mixture was adjusted up to 5 with 3N HCl solution. Precipitated compound was filtered off, washed with water (50 mL) and dried under vacuum to obtain the desired 9 product, 10 4-hydroxy-2-methyl sulfanyl-pyrimidine-5-carboxylic acid (6.0 g, 75%). (0219) LCMS: 187 [M+1]+

References: [1]Patent: US2019/106436,2019,A1 .Location in patent: Paragraph 0217; 0218-0219.

24
[ 397308-78-0 ]
3-(2-chloro-4-fluoro-phenyl)-7-methylsulfanyl-2H-pyrimido[5,4-e][1,3]oxazin-4-one [ No CAS ]