16490-02-1|Pyrimidine-4,6-dicarboxylic acid| Ambeed

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Quality Control of [ 16490-02-1 ] Purity: 95% SDS Specification

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Product Details of [ 16490-02-1 ]

CAS No. :	16490-02-1
Formula :	C₆H₄N₂O₄
M.W :	168.11
SMILES Code :	OC(=O)C1=CC(=NC=N1)C(O)=O
MDL No. :	MFCD00094473
InChI Key :	XIEOKRXVAACBHI-UHFFFAOYSA-N
Pubchem ID :	239360

Safety of [ 16490-02-1 ]

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

Computational Chemistry of [ 16490-02-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	2
Num. H-bond acceptors	6.0
Num. H-bond donors	2.0
Molar Refractivity	35.95
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	100.38 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.08
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	-0.08
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-0.13
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.	-1.12
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	-0.32
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	-0.31

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.07
Solubility	14.3 mg/ml ; 0.0851 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.	-1.58
Solubility	4.46 mg/ml ; 0.0265 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-0.39
Solubility	68.0 mg/ml ; 0.405 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.	-7.38 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)	1.57

Application In Synthesis of [ 16490-02-1 ]

* 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 [ 16490-02-1 ]

[ 16490-02-1 ] Synthesis Path-Downstream 1~35

1
[ 1558-17-4 ]
[ 16490-02-1 ]

Yield	Reaction Conditions	Operation in experiment
		Dimethyl pyrimidine-4,6-dicalpharboxylalphate (llalpha)To a heated solution (75C) of 4,6-dimethylpyrimidine (846 mg, 8.00 mmol) and NaOH (211 mg, 5.28 mmol) in water (3 mL) was added a solution OfKMnO4 (5.28 g in 25 mL water) overl5 min. The resulting mixture was stirred at 80C for 3 hrs. The hot solution was filtered hot and manganese dioxide washed with hot water (8 mL). The filtrate and washings were concentrated to 5 mL and acidified with cone. HCl to pH 2-3. After cooling, the precipitation was collected, yielding 591 mg of crude pyridine-4,6-dicarboxylic acid. The diacid was then dissolved in MeOH (15 mL) and cone. H2SO4 (1.5 mL) was added dropwise carefully. The mixture was refluxed for 24 hrs, cooled to room temperature and concentrated in vacuo. The resultant oily residue was neutralised with sat. NaHCO3 and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with H2O (50 mL) and brine (5OmL), dried over Na2SO4, filtered and concentrated. The product was then purified by column chromatography (petroleum ether 40-60 : EtOAc 5 : 5 to 3 :7) yielding 311 mg (20%) of 11 a as a white solid.

References: [1]Chemische Berichte,1901,vol. 34,p. 3956.
[2]Journal of the Chemical Society,1959,p. 525,528.
[3]Journal of Medicinal Chemistry,2008,vol. 51,p. 7053 - 7056.
[4]Patent: WO2010/43866,2010,A2 .Location in patent: Page/Page column 77.
[5]Journal of Medicinal Chemistry,2017,vol. 60,p. 307 - 321.

2
[ 16490-02-1 ]
[ 289-95-2 ]

References: [1]Journal of the Chemical Society,1959,p. 525,528.

3
[ 16490-02-1 ]
[ 289-95-2 ]
[ 15719-64-9 ]

References: [1]Chemische Berichte,1901,vol. 34,p. 3956.

Yield	Reaction Conditions	Operation in experiment
		Another embodiment of the invention are compounds selected from: ... Pyrimidine-4,6-dicarboxylic acid, bis-[(1,3-benzodioxol-5-ylmethyl)-amide]; Pyrimidine-4,6-dicarboxylic acid, bis-(4-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid, bis-(3-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid, bis-(4-carboxy-benzylamide); and Pyrimidine-4,6-dicarboxylic acid, bis-(4-carbomethoxy-benzylamide).
		A compound selected from: ... Pyrimidine-4,6-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl) ester, Pyrimidine-4,6-dicarboxylic acid, bis-(4-chloro-benzylamide); Pyrimidine-4,6-dicarboxylic acid, bis-[(1,3-benzodioxol-5-ylmethyl)-amide], Pyrimidine-4,6-dicarboxylic acid bis-(4-methoxy-benzylamide), Pyrimidine-4,6-dicarboxylic acid, bis-(3-methoxy-benzylamide), Pyrimidine-4,6-dicarboxylic acid, bis-(4-carboxy-benzylamide), and Pyrimidine-4,6-dicarboxylic acid. bis-(4-carbomethoxy-benzylamide)
		The combination according to Embodiment 50, wherein the compound of Formula IF is selected from: ... Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (4-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (3-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid, (4-carbomethoxy-benzylamide), (3-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (3-pyridylmethylamide); Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (3-thiophenemethylamide); Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide, [(1,3-benzodioxol-5-ylmethyl)-amide]; Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzooxadiazol-5-ylmethyl) amide, [(1,3-benzodioxol-5-ylmethyl)-amide]; Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide, (4-methoxy-benzylamide); ...

		The combination according to Embodiment 50, wherein the compound of Formula IF is selected from: ... Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (4-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (3-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid, (4-carbomethoxy-benzylamide), (3-methoxy-benzylamide); Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (3-pyridylmethylamide); Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (3-thiophenemethylamide); Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide, [(1,3-benzodioxol-5-ylmethyl)-amide]; Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzooxadiazol-5-ylmethyl) amide, [(1,3-benzo ioxol-5-ylmethyl)-amide]; Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide, (4-methoxy-benzylamide); ...
	With potassium permanganate;	Intermediate 8: pyrimidine-4,6-dicarboxylic acidPrepared by the KMnO4 oxidation of 2,6-dimethylpyrimidine according to the procedure described in J. Chem. Soc. 525 (1959).

5
[ 16490-02-1 ]
[ 63410-16-2 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 85℃; for 2h;	200mg(1.2 mmol) of <strong>[16490-02-1]pyrimidine-4,6-dicarboxylic acid</strong> were suspended in 0.3ml(4.1mmol) of thionyl chloride. This mixture was heated at 85C for 2h while being stirred. After it had been cooled down to room temperature, 2ml of absolute dichloromethane were added. The suspension was cooled down to 0C and 0.33ml(2.4mmol) of triethylamine was added. 861mg(5.4mmol) of 3-chloro-4-fluorobenzylamine were added while stirring vigorously. The mixture was then stirred for further 15 minutes. It was then diluted with 10ml of dichloromethane after which 10ml of water were added. After 5 minutes, the mixture was transferred into a separating funnel and the phases were separated. The organic phase was washed twice with saturated sodium chloride solution and then dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue which was obtained in this way was dissolved in ethyl acetate. The product was crystallized from the solution by adding heptane. Beige-colored flakes were obtained and were dried under reduced pressure. Yield: 263mg (49%)

References: [1]Chemical Communications,2004,p. 62 - 63.
[2]Patent: US2003/229103,2003,A1 .Location in patent: Page 6.

6
[ 62501-45-5 ]
[ 16490-02-1 ]

References: [1]Journal of the Chemical Society,1959,p. 525,528.

7
[ 4472-44-0 ]
[ 16490-02-1 ]

References: [1]Chemische Berichte,1901,vol. 34,p. 3956.

8
[ 67-56-1 ]
[ 16490-02-1 ]
[ 6345-43-3 ]

Yield	Reaction Conditions	Operation in experiment
94.4%	With hydrogenchloride; In water; at 65℃; for 3h;Heating / reflux;	10g (0.059 mol) of pyrimidine-4,6-dicarboxylic acid were suspended in 1.4 l of methanol, after which 10.93 ml (0.356 mol) of concentrated hydrochloric acid were added and the mixture was stirred under reflux (65C) for 3 hours (h). The reaction mixture was concentrated under reduced pressure after which the residue was taken up once again in methanol; the mixture was filtered and the resulting solution was concentrated.[0121] Yield 11.02 g (94.4%) MS (ES +): m/e = 197.20
79%	With thionyl chloride; at 0℃; for 5h;Inert atmosphere; Reflux;	SOCl2 (4.76 g, 4 mmol) was added to a solution of pyrimidine-4, 6-dicarboxylic acid (3.40 g, 2 mmol) in MeOH (250 mL) at 0C. The mixture was heated under reflux and stirred for 5 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with saturated aqueous NaHC03 (100 mL), and extracted with EtOAc (100 mL>
	With sulfuric acid; for 24h;Reflux;	Dimethyl pyrimidine-4,6-dicalpharboxylalphate (llalpha)To a heated solution (75C) of 4,6-dimethylpyrimidine (846 mg, 8.00 mmol) and NaOH (211 mg, 5.28 mmol) in water (3 mL) was added a solution OfKMnO4 (5.28 g in 25 mL water) overl5 min. The resulting mixture was stirred at 80C for 3 hrs. The hot solution was filtered hot and manganese dioxide washed with hot water (8 mL). The filtrate and washings were concentrated to 5 mL and acidified with cone. HCl to pH 2-3. After cooling, the precipitation was collected, yielding 591 mg of crude pyridine-4,6-dicarboxylic acid. The diacid was then dissolved in MeOH (15 mL) and cone. H2SO4 (1.5 mL) was added dropwise carefully. The mixture was refluxed for 24 hrs, cooled to room temperature and concentrated in vacuo. The resultant oily residue was neutralised with sat. NaHCO3 and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with H2O (50 mL) and brine (5OmL), dried over Na2SO4, filtered and concentrated. The product was then purified by column chromatography (petroleum ether 40-60 : EtOAc 5 : 5 to 3 :7) yielding 311 mg (20%) of 11 a as a white solid.

References: [1]Patent: US2003/229103,2003,A1 .Location in patent: Page 9.
[2]Patent: WO2019/99977,2019,A2 .Location in patent: Paragraph 00191; 00362; 00363.
[3]Journal of Medicinal Chemistry,2008,vol. 51,p. 7053 - 7056.
[4]Patent: WO2010/43866,2010,A2 .Location in patent: Page/Page column 77.
[5]Journal of Medicinal Chemistry,2017,vol. 60,p. 307 - 321.

9
[ 16490-02-1 ]
[ 109-85-3 ]
Pyrimidine 4,6-dicarboxylic acid di-(2-methoxyethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; triethylamine; In N-methyl-acetamide; dichloromethane; toluene;	Example 1 Pyrimidine 4,6-dicarboxylic acid di-(2-methoxyethyl)-amide (formula I: R1 =CH2 -CH2 -OCH3; R2 =H) 1.7 g of <strong>[16490-02-1]pyrimidine-4,6-dicarboxylic acid</strong> are suspended in 20 ml of toluene, and 2.4 g of thionyl chloride and 0.2 ml of dimethylformamide are added. The mixture is heated to the reflux temperature until no further evolution of gas is to be observed (about 3 hours). About 5 ml of solvent are distilled off, the mixture is cooled to 0-10 C. and 1.9 g of 2-methoxyethylamine and 2.8 ml of triethylamine, dissolved in 10 ml of toluene, are added. The solution is heated slowly to room temperature, stirred at room temperature for 12 hours and evaporated to dryness. The residue is taken up in 50 ml of methylene chloride, the mixture is extracted 3 times by shaking with saturated sodium bicarbonate solution and the organic phase is washed with water, dried with magnesium sulfate and evaporated. The solid is recrystallized from diisopropyl ether. Yield: 2.1 g; melting point: 85-86 C.

References: [1]Patent: US5130317,1992,A .

10
[ 16490-02-1 ]
pyrimidine-4,6-dicarboxylic acid di-(3-hydroxypropyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The compound is prepared analogously to Example 12 from <strong>[16490-02-1]pyrimidine-4,6-dicarboxylic acid</strong> di-(3-methoxypropy--1)-amide (Example 5).

References: [1]Patent: US5130317,1992,A .

11
[ 16490-02-1 ]
4,6-di(chloromethyl)pyrimidine [ No CAS ]
4,6-di-(hydroxymethyl)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	EXAMPLE 61 4,6-bis-[2-(N-Methylthioureido)ethylthiomethyl]pyrimidine <strong>[16490-02-1]4,6-Pyrimidinedicarboxylic acid</strong> is converted to the diethyl ester which is reduced with lithium aluminium hydride in tetrahydrofuran to give 4,6-di(hydroxymethyl)-pyrimidine which on treatment with thionyl chloride gives 4,6-di(chloromethyl)pyrimidine.

References: [1]Patent: US3950353,1976,A .

12
iron(II) perchlorate hexahydrate [ No CAS ]
[ 16490-02-1 ]
manganese(II) perchlorate hexahydrate [ No CAS ]
([FeMn(pyrimidine-4,6-dicarboxylate)2(H₂O)5]*2H₂O)(n) [ No CAS ]

References: [1]Inorganic Chemistry,2008,vol. 47,p. 5267 - 5277.

13
[ 16490-02-1 ]
manganese(II) perchlorate hexahydrate [ No CAS ]
[Mn(pyrimidine-4,6-dicarboxylate)(H₂O)3](n) [ No CAS ]

References: [1]Inorganic Chemistry,2008,vol. 47,p. 5267 - 5277.

14
[ 16490-02-1 ]
[ 100-46-9 ]
[ 135002-40-3 ]

Yield	Reaction Conditions	Operation in experiment
		1.7 g of <strong>[16490-02-1]pyrimidine-4,6-dicarboxylic acid</strong> are suspended in 20 ml of toluene and 2.4 g of thionyl chloride and 0.2 ml of dimethylformamide are added. The mixture is heated to reflux until it is no longer possible to observe any gas evolution (about 3 hours (h)). About 5ml of solvent are distilled off and the mixture is then cooled down to from 0C to 10C and 2.7 g of benzylamine, dissolved in 10 ml of toluene, are added. The solution is slowly heated to room temperature, then stirred at room temperature for 12 hours and evaporated down to dryness. The residue is taken up in 50 ml of methylene chloride and the solution is extracted 3 times by shaking with saturated sodium hydrogen carbonate solution; the organic phase is washed with water, dried with magnesium sulfate and evaporated. The solid is recrystallized from diisopropyl ether. Yield: 2.1 m.p.: 131C to 132C.

References: [1]Patent: US2003/229103,2003,A1 .Location in patent: Page 5-6.

15
[ 6345-43-3 ]
[ 16490-02-1 ]

Yield	Reaction Conditions	Operation in experiment
86%		Pyrimidine-4,6-dicarboxylic acid (8a)To a solution of 11a (170 mg, 0.87 mmol) in MeOH (5 mL) was added IN NaOH (5 mL, 5.00 mmol). The solution was stirred for 2 hrs at room temperature. The solvent was then removed by evaporation and the concentrated solution acidified with 5N HCl to pH 2-3. The resultant white precipitate was collected by filtration and washed with H2O (2 mL) to yield 125 mg (86%) of 8a.

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7053 - 7056.
[2]Patent: WO2010/43866,2010,A2 .Location in patent: Page/Page column 77.

16
[ 16490-02-1 ]
[ 1206480-82-1 ]
[ 1206479-99-3 ]

Yield	Reaction Conditions	Operation in experiment
		Example 14: Synthesis of Compound 112; 2-Chloro-4,6-dimethoxy-l,3,5-triazine was stirred in anhydrous THF. N- Methylmorpholine was added. The resulting mixture was stirred at room temperature for 30 minutes. Then aniline and <strong>[16490-02-1]pyrimidine-4,6-dicarboxylic acid</strong> were added. The mixture was stirred at room temperature for 24 hours. Then the solvent was evaporated completely in vacuum. Water was added and the mixture was stirred for 4 hours. The solid precipitate was collected and purified by silica gel column with dichloromethane and ethyl acetate as eluents. The Boc -protected compound was deprotected using 4N HCl dioxane solution overnight at room temperature to generate the final product.

References: [1]Patent: WO2010/14573,2010,A1 .Location in patent: Page/Page column 115-116.

17
[ 16490-02-1 ]
[ 1224096-01-8 ]
[ 1224096-02-9 ]

Yield	Reaction Conditions	Operation in experiment
79.1%	With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine; In tetrahydrofuran; at 20℃; for 24.5h;Product distribution / selectivity;	2-Chloro-4,6-dimethoxy-1,3,5-triazine (5.97 g, 34 mmol) was stirred in anhydrous THF (200 mL). N-Methylmorpholine (7.5 ml, 68 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes. Then, (R)-tert-butyl 3-(2,6-diamino-4-(trifluoromethyl)phenoxy)pyrrolidine-1-carboxylate (10.84 g, 30 mmol) and <strong>[16490-02-1]pyrimidine-4,6-dicarboxylic acid</strong> (2.48 g, 14.8 mmol) were added. The mixture was stirred at room temperature for 24 hours. The solvent was evaporated completely in vacuum. Water (250 mL) was added and the mixture was stirred for 4 hours. After filtration, the yellow cake was washed with water (3×100 mL) and stirred in water (250 mL) for 4 hours. The filtration and washing procedure was repeated twice. The solid was dried in the air and stirred in dichloromethane (20 mL) for 30 minutes, followed by ultrasonic treatment for 1 hour. After filtration, the yellow cake was quickly washed with cold dichloromethane (2×10 mL). The product (10.0 g, yield: 79.1%) was used as such for subsequent reaction
	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 25h;Inert atmosphere; Large scale;	Compound 4 (1.6 kg) is coupled with <strong>[16490-02-1]pyrimidine-4,6-dicarboxylic acid</strong> (383 g) in the presence of 1-[(3-(dimethylamino)-propyl)]-3-ethylcarbodiirnide hydrochloride (1.29 kg), in pyridine, under inert atmosphere, at ambient temperature. After 25 hours, the reaction mixture is diluted in water (92 kg), a solid is separated out, which is collected by filtration and dried at 37-40C, and crude compound is purified by trituration with ethyl acetate/heptanes for three times. Yield: 1.34 kg (70%), expected Purity about: 87.5%.

References: [1]Patent: US2010/105703,2010,A1 .Location in patent: Page/Page column 14; 15.
[2]Patent: WO2016/133733,2016,A1 .Location in patent: Page/Page column 36; 37.

18
[ 16490-02-1 ]
[ 1257443-01-8 ]
[ 1257443-69-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; for 14h;	Next, to a suspension of pyrimidine«4,6-dicarboxytic acid (325 mg, 1.935 mmol), (R)-Z- amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride (250 mg, 0.774 mmol), WSC hydrochloride (148 mg, 0.774 mmol) and HOAt (105 mg, 0.774 mmol) in DMF (4 mL) and H2O (1 mL) is added DIPEA (0.135 mL, 0.774 mmol). After stirring for 14 hours, the reaction is quenched with H2O, and the products are extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (R)-6-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2- ytearbamoyl)py?midine-4-carboxyi»c acid (84.8 mg). HPLC retention time = 1.32 minutes (condition B); MS (m+1) = 434.1 ; 1H NMR (400 MHz, DMSO-t/6) delta ppm 1.12 (t, J = 7.0 Hz1 3 H) 2.65 (A of ABX, Jab « 15.4 Hz, Jax = 5.8 Hz1 1 H) 2.73 (B of ABX, Jab ~ 15.4 Hz, Jbx * 7.9 Hz) 2.91 (A of ABX1 Jab - 13.6 Hz, Jax « 6.1 Hz, 1 H) 3.01 (B of ABX1 Jab ~ 13.6 Hz, Jbx s 8.2 Hz1 1 H) 4.01 (q, J - 7.0 Hz, 2 H) 4.59 - 4.68 (m, 1 H) 7.29 - 7.35 (m, 3 H) 7.41 - 7.45 (m, 2 H) 7.55 ~ 7.63 (m, 4 H) 8.32 (d, J = 1.35 Hz1 1 H) 9.19 (d. J = 9.1 Hz, 1 H) 9.50 (d, J = 1.35 Hz, 1 H) 14.11 (br s, 1 H).
84.8 mg	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; for 14h;	To (R)-ethyl-4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (300 mg, 0.782 mmol) is added a solution of 4M HCl in 1,4-dioxane (3.92 mL, 15.65 mmol) at room temperature. After stirring for 1 hour, the reaction mixture is concentrated under reduced pressure to give (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride. (0265) Next, to a suspension of <strong>[16490-02-1]pyrimidine-4,6-dicarboxylic acid</strong> (325 mg, 1.935 mmol), (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester hydrochloride (250 mg, 0.774 mmol), WSC hydrochloride (148 mg, 0.774 mmol) and HOAt (105 mg, 0.774 mmol) in DMF (4 mL) and H2O (1 mL) is added DIPEA (0.135 mL, 0.774 mmol). After stirring for 14 hours, the reaction is quenched with H2O, and the products are extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. (0266) The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (R)-6-(1-(biphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylcarbamoyl)pyrimidine-4-carboxylic acid (84.8 mg). HPLC retention time = 1.32 minutes (condition B); MS (m+1) = 434.1; 1H NMR (400 MHz, DMSO-d6) delta ppm 1.12 (t, J = 7.0 Hz, 3 H) 2.65 (A of ABX, Jab = 15.4 Hz, Jax = 5.8 Hz, 1 H) 2.73 (B of ABX, Jab = 15.4 Hz, Jbx = 7.9 Hz) 2.91 (A of ABX, Jab = 13.6 Hz, Jax = 6.1 Hz, 1H) 3.01 (B of ABX, Jab = 13.6 Hz, Jbx = 8.2 Hz, 1 H) 4.01 (q, J = 7.0 Hz, 2 H) 4.59 - 4.68 (m, 1 H) 7.29 - 7.35 (m, 3 H) 7.41 - 7.45 (m, 2 H) 7.55 - 7.63 (m, 4 H) 8.32 (d, J = 1.35 Hz, 1 H) 9.19 (d. J = 9.1 Hz, 1 H) 9.50 (d, J = 1.35 Hz, 1 H) 14.11 (brs, 1 H).

References: [1]Patent: WO2010/136493,2010,A1 .Location in patent: Page/Page column 91.
[2]Patent: EP2640375,2016,B1 .Location in patent: Paragraph 0263-0266.

19
[ 66-71-7 ]
[ 16490-02-1 ]
manganese(II) chloride dihydrate [ No CAS ]
sodium perchlorate [ No CAS ]
[ 7732-18-5 ]
Mn4(μ-pyrimidine-4,6-dicarboxylate)3(H2O)4(1,10-phenanthroline)(ClO4)2*11H2O [ No CAS ]

References: [1]European Journal of Inorganic Chemistry,2011,p. 68 - 77.

20
[ 66-71-7 ]
[ 16490-02-1 ]
manganese(II) chloride dihydrate [ No CAS ]
[ 7732-18-5 ]
potassium nitrate [ No CAS ]
Mn4(μ-pyrimidine-4,6-dicarboxylate)3(H2O)4(1,10-phenanthroline)(NO3)2*11H2O [ No CAS ]

References: [1]European Journal of Inorganic Chemistry,2011,p. 68 - 77.

21
[ 13755-29-8 ]
[ 66-71-7 ]
[ 16490-02-1 ]
manganese(II) chloride dihydrate [ No CAS ]
[ 7732-18-5 ]
Mn4(μ-pyrimidine-4,6-dicarboxylate)3(H2O)4(1,10-phenanthroline)(BF4)2*11H2O [ No CAS ]

References: [1]European Journal of Inorganic Chemistry,2011,p. 68 - 77.

22
[ 66-71-7 ]
[ 16490-02-1 ]
manganese(II) chloride dihydrate [ No CAS ]
[ 7732-18-5 ]
Mn2(μ-pyrimidine-4,6-dicarboxylate)2(H2O)2(1,10-phenanthroline)*8H2O [ No CAS ]

References: [1]European Journal of Inorganic Chemistry,2011,p. 68 - 77.

23
[ 16490-02-1 ]
[ 7732-18-5 ]
dysprosium nitrate [ No CAS ]
([Dy2(μ3-pyrimidine-4,6-dicarboxylate)(μ4-pyrimidine-4,6-dicarboxylate)(μ-oxalate)0.5(H2O)2]*2H2O)n [ No CAS ]