3177-20-6|Methyl 2,4-dichloropyrimidine-5-carboxylate| Ambeed

Structure of 3177-20-6

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Quality Control of [ 3177-20-6 ] Purity: 97% SDS Specification

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Product Details of [ 3177-20-6 ]

CAS No. :	3177-20-6
Formula :	C₆H₄Cl₂N₂O₂
M.W :	207.01
SMILES Code :	O=C(C1=CN=C(Cl)N=C1Cl)OC
MDL No. :	MFCD09910342
InChI Key :	FNNAWVXVOHNOFF-UHFFFAOYSA-N
Pubchem ID :	23156323

Safety of [ 3177-20-6 ]

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

Computational Chemistry of [ 3177-20-6 ] 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	4.0
Num. H-bond donors	0.0
Molar Refractivity	43.33
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	52.08 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.0
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	1.98
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.57
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.	0.75
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	2.05
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.67

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.61
Solubility	0.509 mg/ml ; 0.00246 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.	-2.7
Solubility	0.413 mg/ml ; 0.002 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	-2.97
Solubility	0.223 mg/ml ; 0.00108 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	Yes
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	Yes
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.	-6.16 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	0.0
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)	1.75

Application In Synthesis of [ 3177-20-6 ]

* 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.

Upstream synthesis route of [ 3177-20-6 ]
Downstream synthetic route of [ 3177-20-6 ]

[ 3177-20-6 ] Synthesis Path-Upstream 1~1

1
[ 3177-20-6 ]
[ 71406-78-5 ]

References: [1] Journal of the American Chemical Society, 1942, vol. 64, p. 794,797.

[ 3177-20-6 ] Synthesis Path-Downstream 1~35

1
[ 3177-20-6 ]
[ 71406-78-5 ]

References: [1]Journal of the American Chemical Society,1942,vol. 64,p. 794,797.

2
[ 3177-20-6 ]
[ 593-51-1 ]
[ 515824-42-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In water; acetone;	EXAMPLE II 2-chloro-4-methylamino-5-methoxycarbonyl-pyrimidine 19.1 g of potassium carbonate in 50 ml water are added dropwise to 13 g of <strong>[3177-20-6]2,4-dichloro-5-methoxycarbonyl-pyrimidine</strong> and 4.7 g of methylamine-hydrochloride in 500 ml acetone at 0 to 5° C. within one hour. Then the mixture is stirred for one hour in an ice bath. The acetone is largely removed in vacuo and the residue is distributed between water and ethyl acetate. Then the aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are dried and evaporated down. The residue is separated by chromatography through a silica gel column with cyclohexane/ethyl acetate (2:1). Yield: 8,8 g (69percent of theory), melting point: 121° C.

References: [1]Patent: US2003/134838,2003,A1 .

3
[ 42821-92-1 ]
[ 3177-20-6 ]

Yield	Reaction Conditions	Operation in experiment
	In 2-Methylpentane; trichlorophosphate;	i 2,4-Dichloro-5-pyrimidinecarboxylic acid, methyl ester 1,2,3,4-Tetrahydro-2,4-dioxo-5-pyrimidinecarboxylic acid methyl ester (7.0 g) in phosphorus oxychloride (80 ml) was heated under reflux for 16 hours. The phosphorus oxychloride was removed by evaporation under reduced pressure. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluding with 20percent ethyl acetate in isohexane. Yield 4.5 g. 1H NMR: delta (DMSO) 9.05(s, 1H), 4.0(s, 3H).

References: [1]Patent: US6107297,2000,A .

4
[ 67-56-1 ]
[ 2972-52-3 ]
[ 3177-20-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h;	To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461mg, 94percent) was dissolved in IPA (20 mL) and followed by the addition of traw-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwisely. The resulting mixture was stirred at 0 °C for 90 min. After which butylamine (208.8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg, 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified on ISCO to provide methyl 2-(butylamino)-4-(((trans-4-hydroxycyclohexyl)amino)pyrimidine-5- carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDCl3) delta 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H), 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.1 1 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J - 9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) delta 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1 , 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+.
94%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h;	To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropyeihylamine (369 mg, 2,86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461rng, 94percent) was dissolved in IPA (20 ml,) and followed by the addition of trans-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwiseiy. The resulting mixture was stirred at 0 °C for 90 min. After which buiyiamine (208,8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg., 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4, filtered and concentrated. The residue was purified on ISCO to give methyl 2-(butylamino)-4-((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDCl3) delta 9.21 (s, 1H), S.77 (s, 1H), 6.29 (s, 1H), 4.81 - 4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.1 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J - 9.7 Hz, 2H), 2.35 - 2.25 (m, 2H), 2.23 - 2.00 (m, 6H), 1 ,67 (t, J- 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) delta 167.9, 162,5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41. L 33.8, 31 ,7, 30.3, 20.1, 13,8; MS m/z 323.20 [M+H]+
94%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h;	Methyl 2-(butYlaminoV4-(((tra^^ (0734) (0735) To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461mg, 94percent) was dissolved in IP A (20 mL) and followed by the addition of tra5'-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwisely. The resulting mixture was stirred at 0 °C for 90 min. After which butylamine (208.8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg, 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried filtered and concentrated. The residue was purified on ISCO to provide methyl 2-(butylamino)-4-(((traj,-4-hydroxycyclohexyl)amino)pyrimidine-5 - carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDC13) delta 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H), 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.11 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J = 9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDC13) delta 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1, 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+.

References: [1]Patent: WO2013/177168,2013,A1 .Location in patent: Page/Page column 34; 35.
[2]Patent: WO2014/85225,2014,A1 .Location in patent: Page/Page column 18; 19; 28; 29.
[3]Patent: WO2015/157127,2015,A1 .Location in patent: Page/Page column 167.
[4]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4857 - 4859.
[5]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4642 - 4646.
[6]Journal of Medicinal Chemistry,2013,vol. 56,p. 9693 - 9700.
[7]ChemMedChem,2017,vol. 12,p. 207 - 213.

5
[ 3177-20-6 ]
[ 877201-35-9 ]
[ 1062653-69-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4642 - 4646.

6
[ 3177-20-6 ]
[ 1073435-74-1 ]
[ 1073438-02-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 120℃; for 2h;	Example 16 9-[2-Chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-cyano-7,9-dihydro-8H-purin-8-one A mixture of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (0.41 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline hydrochloride (0.81 g) and N,N-diisopropylethylamine (0.73 mL) in acetonitrile (9 mL) was stirred at 120°C in a reaction vessel equipped with a reflux condenser for 2 hours. The reaction mixture was cooled to room temperature. To the mixture was added water (9 mL), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give methyl 2-chloro-4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-pyrimidine-5-carboxylate (0.88 g). To the suspension of the obtained methyl 2-chloro-4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-pyrimidine-5-carboxylate (0.35 g) in dimethyl sulfoxide (6 mL) were added a solution of potassium cyanide (0.13 g) in water (1 mL) and 1,4-diazabicyclo[2,2,2]octane (25 mg), and the mixture was stirred at 30°C for 10 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water twice and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate = 1/1), and collected by filtration. The collected solids were washed with the same solvent, and dried under reduced pressure to give methyl 4-[2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenylamino]-2-cyanopyrimidine-5-carboxylate (0.22 g). To the obtained methyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl-amino]-2-cyanopyrimidine-5-carboxylate (0.12 g) were added tetrahydrofuran (3 mL), water (1.5 mL) and lithium hydroxide monohydrate (30 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate = 1/1), and collected by filtration. The collected solids were washed with the same solvent, and dried under reduced pressure to give 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-2-cyanopyrimidine-5-carboxylic acid (75 mg). To this material were added 1,4-dioxane (2 mL), triethylamine (0.066 mL) and diphenylphosphoryl azide (0.034 mL), and the mixture was stirred at room temperature for 1 hour, and then heated at reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 1/1 - 1/3) to give the title compound (46 mg).

References: [1]Patent: EP2143724,2010,A1 .Location in patent: Page/Page column 49.

7
[ 622-40-2 ]
[ 3177-20-6 ]
[ 887136-81-4 ]
[ 887136-80-3 ]

Yield	Reaction Conditions	Operation in experiment
		Alternatively, instead of the hydrazone linkage describe above, the compounds may have an amide linkage (see Scheme I below). The synthesis consists of 3 steps. First, to a stirred solution of 4-(2-hydroxyethyl)morpholine (B) (2.8 g, 21.3 mmol) in anhydrous THF (45 mL) at 0 0C, sodium hydride, 60percent dispersion in mineral oil, (0.9 g, 22.5 mmol) is added in three portions under nitrogen purge. Ice-bath was removed and a mixture is stirred at room temperature for 20-30 minutes. The mixture is cooled to 0 0C and added drop-wise (using syringe or dropping funnel) under nitrogen purge to a solution of methyl 2,4-dichloropyrirnidine carboxylate (A) (4.03 g, 19.4 mmol) in anhydrous THF (35 mL) at 0 0C. The resultant solution is stirred for 30 minutes at 0 0C, followed by 30 minutes at room temperature. It is then quenched carefully with ice-water (115mL) and diluted with ethyl acetate (115 mL). Organic layer is separated, water layer extracted once with ethyl acetate, combined ethyl acetate extracts are washed with brine and dried over anhydrous sodium sulfate. Concentration, followed by column chromatography with gradient eluation (hexane : ethyl acetate, 1:1; hexane : ethyl acetate,l:2; ethyl acetate; dichloromethane-acetone-methanol, 3:1:01) affords 3 fractions: first (0.56 g, 9.5percent ) - mostly isomer C, second (1.28 g, 21.8percent)- a mixture of C and D, and byproduct (E), third (0.7 g, 11.9percent) - mostly isomer (D). EPO <DP n="99"/>In the second step, a solution of compound C (0.6 g, 2 mmol), 5-amino-2,3- dimethylindole (F) (0.32 g, 2 mmol) and DIPEA (0.28 g, 2.2 mmol)in dioxane is heated at reflux for two hours. Ethyl acetate and water are added to the concentrated reaction mixture, water layer extracted with ethyl acetate, combined ethyl acetate extracts washed with brine and dried over anhydrous sodium sulfate. Product G (0.64 g, 75percent) is isolated by column chromatography with gradient eluation (ethyl acetate; dichloromethane- acetone-methanol, 3:1:01).In the same manner compound D is converted into product H.Compounds H is then converted into their corresponding amides (I) using appropriate amines following general procedure for amide formation.To a stirred mixture of ester (1 mmol) and amine (1.05 mmol) in toluene (3.2 mL)., 2 M solution of trimethylaluminum in toluene (1.6 eq) is added drop-wise under nitrogen purge. The reaction mixture is stirred until gas evolution halted, and then mixture is micro waved at 120 0C for 5-7 minutes (Emrys Optimizer). To the reaction mixture were added IN NaOH solution and dichloromethane, organic layer separated, washed with water, brine and dried over anhydrous sodium sulfate. Flash column chromatography purification affords about 65-75percent of a desired amide (I).

References: [1]Patent: WO2006/53109,2006,A1 .Location in patent: Page/Page column 97-98.

8
[ 3177-20-6 ]
[ 1346708-80-2 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4857 - 4859.

9
[ 3177-20-6 ]
[ 1332708-03-8 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4857 - 4859.

10
[ 3177-20-6 ]
[ 1332708-08-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4857 - 4859.

11
[ 3177-20-6 ]
[ 1332708-10-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4857 - 4859.

12
[ 3177-20-6 ]
[ 1332708-09-4 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4857 - 4859.

13
[ 3177-20-6 ]
[ 1332708-11-8 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4857 - 4859.

14
[ 3177-20-6 ]
[ 78-81-9 ]
[ 1332708-02-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4857 - 4859.

15
[ 3177-20-6 ]
[ 1110772-04-7 ]
[ 1403864-38-9 ]

Yield	Reaction Conditions	Operation in experiment
67%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -78℃; for 1h;	To a stirring solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (4.00 g, 19.32 mmol) in THF (85 mL) was added DIEA (3.37 mL, 19.32 mmol). The resulting mixture was cooled to -78 °C in a dry ice/acetone bath. A solution of (lS,3R)-3- aminocyclohexanol (2.448 g, 21.25 mmol; prepared as described in Tetrahedron:Asymmetry 15:2051-2056(2004)) in 40 mL THF was added at such a rate that the temperature remained at -78 °C. The resulting mixture was stirred at -78 °C for 1 h. The reaction mixture was then concentrated to dryness and diluted with 200 mL ethyl acetate and 75 mL of a 1 : 1 mixture of water and an aqueous saturated sodium bicarbonate solution. The layers were separated and the aqueous layer back-extracted with 100 mL ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil that solidified upon standing. The solid was triturated with diethyl ether (5 mL), filtered, rinsed with diethyl ether (5 mL) and dried in vacuo to afford methyl 2-chloro-4-((lR,3S)-3-hydroxycyclohexylamino)pyrimidine-5-carboxylate (3.7 g, 12.95 mmol, 67percent yield) that was used without further purification. MS (ESI) m/z 286.0 [M+l]+.

References: [1]Patent: WO2012/145569,2012,A1 .Location in patent: Page/Page column 105.

16
[ 3177-20-6 ]
methyl 2-((1r,4r)-4-(difluoromethoxy)cyclohexylamino)-4-((1R,3S)-3hydroxycyclohexylamino)pyrimidine-5-carboxylate [ No CAS ]

References: [1]Patent: WO2012/145569,2012,A1 .

17
[ 3177-20-6 ]
2-((1r,4r)-4-(difluoromethoxy)cyclohexylamino)-4-((1R,3S)-3hydroxycyclohexylamino)pyrimidine-5-carboxylic acid [ No CAS ]

References: [1]Patent: WO2012/145569,2012,A1 .

18
[ 3177-20-6 ]
2-((1r,4r)-4-(difluoromethoxy)cyclohexylamino)-4-((1R,3S)-3-hydroxycyclohexylamino)pyrimidine-5-carboxamide [ No CAS ]

References: [1]Patent: WO2012/145569,2012,A1 .

19
[ 3177-20-6 ]
[ 1456693-55-2 ]
[ 1456693-45-0 ]

Yield	Reaction Conditions	Operation in experiment
77.3%		A solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (27 mg, 0.13 mmol) in dichloroethane / i-butanol (1: 1, 2mL) was cooled to 0°C. ZnCl2 solution (1.0 M in ether, 0.29 mL, 0.29 mmol, 2.2 eq.) was added. After stirring for lh, a solution of (R)-methyl 1- isopropyl-7-(methylsulfonyl)-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyrazine-8- carboxylate (30 mg, 0.09 mmol) in dichloroethane / i-butanol (1: 1, 2 mL) was added slowly at 0°C. The mixture was stirred at rt overnight. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL X 3). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-l- isopropyl-7-(methylsulfonyl)-l,2,3,4-tetrahydrobenzo[4,5]irnidazo[l,2-a]pyrazine-8- carboxylate (34 mg, 77.3percent yield) as a solid.
77.3%		A solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (27 mg, 0.13 mmol) in dichloroethane / i-butanol (1: 1, 2mL) was cooled to 0°C. ZnCl2 solution (1.0 M in ether, 0.29 mL, 0.29 mmol, 2.2 eq.) was added. After stirring for lh, a solution of (R)-methyl 1- isopropyl-7-(methylsulfonyl)-l,2,3,4-tetrahydrobenzo[4,5]irnidazo[l,2-a]pyrazine-8- carboxylate (30 mg, 0.09 mmol) in dichloroethane / i-butanol (1: 1, 2 mL) was added slowly at 0°C. The mixture was stirred at rt overnight. Water (10 mL) was added and the mixture was extracted with EtOAc (10 mL X 3). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 2-(4-chloro-5-(methoxycarbonyl)pyrimidin-2-yl)-l- isopropyl-7-(methylsulfonyl)-l,2,3,4-tetrahydrobenzo[4,5]irnidazo[l,2-a]pyrazine-8- carboxylate (34 mg, 77.3percent yield) as a solid.

References: [1]Patent: WO2013/138568,2013,A1 .Location in patent: Page/Page column 91; 92.
[2]Patent: WO2015/195922,2015,A1 .Location in patent: Paragraph 00185.

20
[ 3177-20-6 ]
[ 1456692-77-5 ]
[ 1456692-78-6 ]

References: [1]Patent: WO2013/138568,2013,A1 .
[2]Patent: US2015/250787,2015,A1 .
[3]Patent: WO2015/195922,2015,A1 .
[4]Patent: US2016/113930,2016,A1 .

21
[ 3177-20-6 ]
[ 1456693-47-2 ]

References: [1]Patent: WO2013/138568,2013,A1 .
[2]Patent: WO2015/195922,2015,A1 .

22
[ 3177-20-6 ]
[ 411235-57-9 ]
[ 1401350-08-0 ]

Yield	Reaction Conditions	Operation in experiment
26%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In tetrahydrofuran; for 4h;Inert atmosphere; Reflux;	To a solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (852 mg, 4 mmol) and cyclopropylboronic acid (344 mg, 4 mmol) in THF (10 mL) was added K3PO4 (3.1g, 12 mmol) followed by Pd(dppf)Cl2 (292 mg, 0.4 mmol) under N2. The mixture was refluxed for 4 h until the material was disappeared. The reaction mixture was cooled to rt. THF was removed under vacuum. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL X 3). The organic layers were dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (220 mg, 26percent yield) as a white solid.
26%	In tetrahydrofuran; water;	(S)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2 (1H)-yl)pyrimidin-5-yl)methanol To a solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (852 mg, 4 mmol) and cyclopropylboronic acid (344 mg, 4 mmol) in THF (10 mL) was added K3PO4 (3.1 g, 12 mmol) followed by Pd(dppf)Cl2 (292 mg, 0.4 mmol) under N2. The mixture was refluxed for 4 h until the material was disappeared. The reaction mixture was cooled to rt. THF was removed under vacuum. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL*3). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (220 mg, 26percent yield) as a white solid.
26%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In tetrahydrofuran; at 20℃; for 4h;Inert atmosphere; Reflux;	To a solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (852 mg, 4 mmol) and cyclopropylboronic acid (344 mg, 4 mmol) in THF (10 mL) was added K3PO4 (3.1g, 12 mmol) followed by Pd(dppf)Cl2 (292 mg, 0.4 mmol) under N2. The mixture was refluxed for 4 h until the material was disappeared. The reaction mixture was cooled to rt. THF was removed under vacuum. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL X 3). The organic layers were dried over anhydrous Na2S04, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (220 mg, 26percent yield) as a white solid.

26%

In tetrahydrofuran; water;

Example 20 (R)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol and (S)-(4-cyclopropyl-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-5-yl)methanol To a solution of <strong>[3177-20-6]methyl 2,4-dichloropyrimidine-5-carboxylate</strong> (852 mg, 4 mmol) and cyclopropylboronic acid (344 mg, 4 mmol) in THF (10 mL) was added K3PO4 (3.1 g, 12 mmol) followed by Pd(dppf)Cl2 (292 mg, 0.4 mmol) under N2. The mixture was refluxed for 4 h until the material was disappeared. The reaction mixture was cooled to rt. THF was removed under vacuum. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL*3). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (220 mg, 26percent yield) as a white solid.

References: [1]Patent: WO2013/138568,2013,A1 .Location in patent: Page/Page column 93.
[2]Patent: US2015/250787,2015,A1 .
[3]Patent: WO2015/195922,2015,A1 .Location in patent: Paragraph 00188.
[4]Patent: US2016/113930,2016,A1 .

23
[ 3177-20-6 ]
[ 27489-62-9 ]
C₁₂H₁₆ClN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 0℃; for 1.5h;	To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461mg, 94percent) was dissolved in IPA (20 mL) and followed by the addition of traw-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwisely. The resulting mixture was stirred at 0 °C for 90 min. After which butylamine (208.8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg, 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified on ISCO to provide methyl 2-(butylamino)-4-(((trans-4-hydroxycyclohexyl)amino)pyrimidine-5- carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDCl3) delta 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H), 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.1 1 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J - 9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) delta 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1 , 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+.
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 0℃; for 1.5h;	To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropyeihylamine (369 mg, 2,86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461rng, 94percent) was dissolved in IPA (20 ml,) and followed by the addition of trans-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwiseiy. The resulting mixture was stirred at 0 °C for 90 min. After which buiyiamine (208,8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg., 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4, filtered and concentrated. The residue was purified on ISCO to give methyl 2-(butylamino)-4-((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDCl3) delta 9.21 (s, 1H), S.77 (s, 1H), 6.29 (s, 1H), 4.81 - 4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.1 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J - 9.7 Hz, 2H), 2.35 - 2.25 (m, 2H), 2.23 - 2.00 (m, 6H), 1 ,67 (t, J- 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) delta 167.9, 162,5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41. L 33.8, 31 ,7, 30.3, 20.1, 13,8; MS m/z 323.20 [M+H]+
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 0℃; for 1.5h;	Methyl 2-(butYlaminoV4-(((tra^^ (0734) (0735) To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. Then the solvent was removed. The residue (461mg, 94percent) was dissolved in IP A (20 mL) and followed by the addition of tra5'-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwisely. The resulting mixture was stirred at 0 °C for 90 min. After which butylamine (208.8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg, 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3X). The combined organic layers were dried filtered and concentrated. The residue was purified on ISCO to provide methyl 2-(butylamino)-4-(((traj,-4-hydroxycyclohexyl)amino)pyrimidine-5 - carboxylate (682.6 mg, 89percent over 3 steps). 1H NMR (400 MHz, CDC13) delta 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H), 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.11 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J = 9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDC13) delta 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1, 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+.

References: [1]Patent: WO2013/177168,2013,A1 .Location in patent: Page/Page column 34; 35.
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 9693 - 9700.
[3]Patent: WO2014/85225,2014,A1 .Location in patent: Page/Page column 18; 19.
[4]Patent: WO2015/157127,2015,A1 .Location in patent: Page/Page column 167.

24
[ 3177-20-6 ]
2-(butylamino)-4-(((1r,4r)-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxylic acid [ No CAS ]

References: [1]Patent: WO2013/177168,2013,A1 .
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 9693 - 9700.
[3]Patent: WO2014/85225,2014,A1 .
[4]Patent: WO2015/157127,2015,A1 .

25
[ 3177-20-6 ]
methyl 2-(butylamino)-4-(((trans)-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxylate [ No CAS ]

References: [1]Patent: WO2013/177168,2013,A1 .
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 9693 - 9700.
[3]Patent: WO2014/85225,2014,A1 .
[4]Patent: WO2015/157127,2015,A1 .

26
[ 3177-20-6 ]
2-(butylamino)-N-(4-fluorobenzyl)-4-(((trans)-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxamide [ No CAS ]

References: [1]Patent: WO2013/177168,2013,A1 .
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 9693 - 9700.
[3]Patent: WO2014/85225,2014,A1 .
[4]Patent: WO2015/157127,2015,A1 .

27
[ 3177-20-6 ]
2-(butylamino)-4-[(4-hydroxycyclohexyl)amino]-N-[1-(pyrimidin-2-yl)piperidin-4-yl]pyrimidine-5-carboxamide [ No CAS ]