1005-38-5|4-Amino-6-chloro-2-(methylthio)pyrimidine| Ambeed

Structure of 1005-38-5

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Quality Control of [ 1005-38-5 ] Purity: 95% SDS Specification

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Product Details of [ 1005-38-5 ]

CAS No. :	1005-38-5
Formula :	C₅H₆ClN₃S
M.W :	175.64
SMILES Code :	C1=C(N=C(N=C1Cl)SC)N
MDL No. :	MFCD00006088
InChI Key :	ISUXMAHVLFRZQU-UHFFFAOYSA-N
Pubchem ID :	70496

Safety of [ 1005-38-5 ]

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

Computational Chemistry of [ 1005-38-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.2
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	43.17
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	77.1 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.64
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	1.66
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.44
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.	0.19
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	1.42
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.27

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.35
Solubility	0.78 mg/ml ; 0.00444 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.89
Solubility	0.225 mg/ml ; 0.00128 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	-2.4
Solubility	0.693 mg/ml ; 0.00394 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.	-6.19 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.	0.55

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)	2.04

Application In Synthesis of [ 1005-38-5 ]

* 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 [ 1005-38-5 ]

[ 1005-38-5 ] Synthesis Path-Downstream 1~54

1
[ 6299-25-8 ]
[ 1005-38-5 ]

Yield	Reaction Conditions	Operation in experiment
97.77%	With ammonia; In tetrahydrofuran; at 50 - 60℃; under 5149.01 - 5884.58 Torr;Autoclave;	[00230] Reagents[00231] Experimental procedure:.bul. ; Take ammonia in THF into a 2 L autoclave and add 4, 6-dichloro-2-(Methylthio) pyrimidine slowly..bul. Heat the reaction mixture to 50-60 ° C and maintain the reaction at 50-60 °C for 3-4 hours (Inbuilt pressure 7- 8 Kg/cm )..bul. Check the progress of the reaction by TLC. Upon completion, the reaction was brought to 25-35 ° C..bul. Concentrate the reaction mixture under vacuum..bul. Charge Hexane and stir for 30-45 minutes at 25-35 ° C..bul. Filter the solid and wash the solid with Hexane..bul. Wash the solid with water (2X400 mL)..bul. Dry the solid at 25-35 °C till M.C reaches to less than 2percent.Yield 352.0 gpercent of Yield: 97.77percent.Purity by HPLC: 99.07percent.Other suitable conditions such as ammonia in MeOH or dioxane could be used accordingly when different analogs are used. Example 1- 2. Preparation of 4-Amino-6-chloro-2- meth lthio)pyrimidine, 6.1
66%	With ammonia; In water; butan-1-ol; at 20 - 80℃; under 2172.08 Torr; for 0.5h;	4,6-Dichloro-2-(methylthio)pyrimidine (10 g, 51 mmol) was dissolved in a mixtureButanol/NH4OH (100 ml/50 ml). It was stirred for V2 h in a sealed tube (internal pressure 42 PSI) heated to 8O0C. After cooling to RT, the organic layer was separated, dried over MgSO4 and concentrated. 6.0 g (66percent) of the desired intermediate was obtained as a colourless solid; mlz (ES+) 175, 177 (MH+).
	With ammonia; In water; isopropyl alcohol; at 100℃; for 15h;	Ammonium hydroxide (50 mL) was added to a solution of 4,6-dicloro-2-methylsulfanyl-pyrimidine (1.9 g, 9.7 mmol) in isopropanol (20 mL) in a sealed tube and the resulting mixture was heated to 100° C. for 15 h. The mixture was brought to RT, poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried and concentrated under vacuum to provide a white solid. MS m/z 176 (MH)+.

With ammonium hydroxide; In ethanol; water; Petroleum ether;

Part C--4-Amino- 6-chloro-2-(methylthio)pyrimidine A reaction mixture consisting of 124.7 g. (0.64 mole) 4,6-dichloro-2-(methylthio)pyrimidine (prepared as in Part B, above), 500 ml. ethanol, and 250 ml. of substantially saturated aqueous ammonia was heated, with stirring, at 100° C. in an autoclave for 6 hrs. After cooling the reaction mixture, water was added, and a precipitate formed. The precipitate was collected on a filter, and recrystallized from a mixture of ether and petroleum ether to give 40 g. of the desired 4-amino-6-chloro-2-(methylthio)pyrimidine having a melting point at 130° to 131° C.

References: [1]Patent: WO2011/97594,2011,A2 .Location in patent: Page/Page column 100-101.
[2]Chemistry - A European Journal,1999,vol. 5,p. 3450 - 3458.
[3]Patent: WO2007/141571,2007,A2 .Location in patent: Page/Page column 25.
[4]American Chemical Journal,1904,vol. 32,p. 353.
[5]Patent: US2005/288502,2005,A1 .Location in patent: Page/Page column 20.
[6]Patent: US4199583,1980,A .
[7]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 42 - 46.

2
[ 1074-41-5 ]
[ 1005-38-5 ]

References: [1]Journal of the Chemical Society,1944,p. 678.

3
[ 110-89-4 ]
[ 1005-38-5 ]
[ 96225-84-2 ]

References: [1]Journal of Organic Chemistry,1954,vol. 19,p. 1793,1798.

4
[ 1005-38-5 ]
[ 124-40-3 ]
[ 52222-40-9 ]

Yield	Reaction Conditions	Operation in experiment
73%	In methanol; at 80℃; for 18h;	6-chloro-2-(methylthio)pyrimidin-4-amine (3.98g, 22.7mmol) is added to a solution of dimethylamine (2.0M in methanol, 2OmL). The mixture is heated to 8O0C for 18h. The reaction is allowed to cool, the precipitate is collected, washed with ethanol, (3.1g, 73percent)

References: [1]Patent: WO2009/22185,2009,A2 .Location in patent: Page/Page column 32.
[2]Journal of Organic Chemistry,1954,vol. 19,p. 631,635.

5
[ 1005-38-5 ]
[ 109-89-7 ]
[ 99182-45-3 ]

References: [1]Heterocycles,1985,vol. 23,p. 611 - 616.
[2]Journal of Organic Chemistry,1954,vol. 19,p. 1793,1798.

6
[ 1005-38-5 ]
[ 62-53-3 ]
2-methylsulfanyl-N⁴-phenyl-pyrimidine-4,6-diyldiamine [ No CAS ]

References: [1]American Chemical Journal,1905,vol. 34,p. 190.

7
[ 1005-38-5 ]
[ 62-53-3 ]
N²,N⁴-diphenyl-pyrimidine-2,4,6-triyltriamine [ No CAS ]

References: [1]American Chemical Journal,1905,vol. 34,p. 190.
[2]American Chemical Journal,1905,vol. 34,p. 190.

8
[ 1005-38-5 ]
[ 74-89-5 ]
[ 96225-63-7 ]

References: [1]Journal of Organic Chemistry,2016,vol. 81,p. 3780 - 3789.
[2]Journal of the Chemical Society,1943,p. 383,384.
Journal of the Chemical Society,1944,p. 318,321.

9
[ 1005-38-5 ]
[ 100-61-8 ]
[ 108481-08-9 ]

References: [1]Journal of Organic Chemistry,1954,vol. 19,p. 1793,1798.

10
[ 1005-38-5 ]
[ 3289-35-8 ]

References: [1]American Chemical Journal,1904,vol. 32,p. 353.

11
[ 1005-38-5 ]
[ 63931-22-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; In dichloromethane; at 20℃; for 1h;	To a cold stirring solution of 10 g (52.2 mmol) 6-chloro-2- (methylsulfinyl)pyrimidine-4-amine in 450 ml of DCM, 10 g (56.2 mmol) of N- bromosuccinimide were added, and stirring was continued for 1 hour at room temperature to provide 5-bromo-6-chloro-2-(methylthio)pyrimidine-4-amine, which was used without further purification in the next step (see intermediate 3). The end of the reaction is followed by thin layer chromatography.
	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0℃; for 0.166667h;	To a cooled solution of 6-chloro-2-(methylthio)pyrimidin-4-amine (15.0 g, 85 mmol) in DM F (150 ml) was added N-bromosuccinimide (16.7 g, 94 mmol) portionwise with stirring at 0 °C. After 10 min the reaction was quenched by the addition of water at 0 °C. The reaction mixture was diluted with brine and extracted 3 times with EtOAc. The combined organic phases were washed twice with saturated aqueous NaHC03solution, then brine, separated, and filtered through a phase separator with Na2S04to dry. The filtrate was concentrated in vacuo to give the title compound (18.8 g, 74 mmol, 80 percent yield, 92percent purity) as colorless solid which was used in the next step without further purification. M/z = 254/256/258 [M+H]+, Rt = 0.95 min (UPLC 2 min), 1 H NMR (600 MHz, DMSO-d6) delta 8.03 (br s, 1 H), 7.25 (br s, 1 H), 2.42 (s, 3H).

References: [1]American Chemical Journal,1905,vol. 34,p. 190.
[2]Patent: WO2014/114695,2014,A1 .Location in patent: Page/Page column 26.
[3]Patent: WO2018/146612,2018,A1 .Location in patent: Page/Page column 51; 52.

12
[ 108-24-7 ]
[ 1005-38-5 ]
[ 38897-12-0 ]

Yield	Reaction Conditions	Operation in experiment
	at 135℃; for 5h;Heating / reflux;	Acetic anhydride (10.4 MI, 0. 11 MOL) was added to 6-chloro-2- (methylthio) pyrimidin-4-amine (2.5 g, 0.01 mol) and the reaction mixture was refluxed at 135 °C for 5 hr. The reaction mixture was cooled to room temperature and basified to pH 7 with saturated sodium bicarbonate solution (20 ML). The mixture was partitioned between EtOAc and water, the organic layer was washed with water and brine, dried over MgS04 and concentrated to give the title compound (2.62 g). MS (ES . : 218 (MH+) for C7HGCINO3S

References: [1]Heterocycles,1985,vol. 23,p. 611 - 616.
[2]Patent: WO2005/26149,2005,A1 .Location in patent: Page/Page column 86.

13
[ 27467-92-1 ]
[ 1005-38-5 ]
[ 81587-41-9 ]

References: [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 302 - 318.

14
[ 4083-64-1 ]
[ 1005-38-5 ]
[ 133030-35-0 ]

References: [1]Australian Journal of Chemistry,1991,vol. 44,p. 129 - 134.

15
[ 33761-31-8 ]
[ 1005-38-5 ]
[ 81587-39-5 ]

References: [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 302 - 318.

16
[ 1005-38-5 ]
[ 16182-04-0 ]
[ 133030-34-9 ]

References: [1]Australian Journal of Chemistry,1991,vol. 44,p. 129 - 134.

17
[ 1005-38-5 ]
[ 74619-77-5 ]

References: [1]Heterocycles,1985,vol. 23,p. 611 - 616.

18
[ 1005-38-5 ]
[ 66380-47-0 ]

Yield	Reaction Conditions	Operation in experiment
94.9%	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 4h;	To a stirred solution of 10.0 g (57.2 mmol) of 6-chloro-2-(methylthio)pyrimidine-4-amine in 300 ml of dichloromethane were added during 30 minutes a solution of 15.3 g (68.6 mmol) of m-chloroperbenzoic acid (77 percent ) (Aldrich) dissolved in 200 ml of DCM. The reaction mixture was stirred at room temperature for 4 hours. The white precipitate formed was filtered, washed several times with DCM and then after drying gave 10.4 g (94.9 percent) of the intermediate 1.1H-RMN (300 MHz, DMSO-d6): 8 = 3.28 (s, 3H), 6.64 (s, 1H), 8.1 1 (s, 2H).
1 g	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 4h;	To a solution of 1.0 g (5.7 mmol) of 6-chloro-2- (methylthio) pyrimidin-4-amine in 50 mL of methylene chloride was added 1.5 g (6.9 mmol) M-chloroperbenzoic acid (77percent) solution.The reaction mixture was stirred for 4 hours at room temperature.The resulting white precipitate was filtered, washed with methylene chloride several times, dried,1.0 g of intermediate (F) was obtained

References: [1]Patent: WO2011/121418,2011,A1 .Location in patent: Page/Page column 24.
[2]Heterocycles,1985,vol. 23,p. 611 - 616.
[3]Patent: CN107286146,2017,A .Location in patent: Paragraph 0139; 0142-0144.

20
[ 7664-41-7 ]
[ 1005-38-5 ]
[ 1004-38-2 ]

References: [1]American Chemical Journal,1904,vol. 32,p. 353.

21
ammonium hydroxide [ No CAS ]
[ 1005-38-5 ]
[ 1005-39-6 ]

References: [1]American Chemical Journal,1905,vol. 34,p. 190.

22
[ 7726-95-6 ]
[ 1005-38-5 ]
[ 63931-22-6 ]

References: [1]American Chemical Journal,1905,vol. 34,p. 190.

24
[ 6299-25-8 ]
[ 7664-41-7 ]
[ 1005-38-5 ]

References: [1]American Chemical Journal,1904,vol. 32,p. 353.

25
4-oxy-2-methylsulfanyl-6-amino-pyrimidine [ No CAS ]
[ 1005-38-5 ]

References: [1]American Chemical Journal,1905,vol. 34,p. 190.

26
[ 13214-66-9 ]
[ 1005-38-5 ]
2-methylsulfanyl-N-(4-phenyl-butyl)-pyrimidine-4,6-diamine [ No CAS ]