[ CAS No. 16490-02-1 ] {[proInfo.proName]}

Name: 16490-02-1|Pyrimidine-4,6-dicarboxylic acid|95%
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SKU: A133911
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Quality Control of [ 16490-02-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 16490-02-1 ]

CAS No. :	16490-02-1	MDL No. :	MFCD00094473
Formula :	C₆H₄N₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XIEOKRXVAACBHI-UHFFFAOYSA-N
M.W :	168.11	Pubchem ID :	239360
Synonyms :

Calculated chemistry of [ 16490-02-1 ]

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 :	100.38 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.38 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.08
Log Po/w (XLOGP3) :	-0.08
Log Po/w (WLOGP) :	-0.13
Log Po/w (MLOGP) :	-1.12
Log Po/w (SILICOS-IT) :	-0.32
Consensus Log Po/w :	-0.31

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.07
Solubility :	14.3 mg/ml ; 0.0851 mol/l
Class :	Very soluble
Log S (Ali) :	-1.58
Solubility :	4.46 mg/ml ; 0.0265 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.39
Solubility :	68.0 mg/ml ; 0.405 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.57

Safety of [ 16490-02-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

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.

Upstream synthesis route of [ 16490-02-1 ]
Downstream synthetic route of [ 16490-02-1 ]

[ 16490-02-1 ] Synthesis Path-Upstream 1~5

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

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: With sodium hydroxide In methanol at 20℃; for 2 h; Stage #2: With hydrogenchloride In water	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 (86percent) of 8a.

Reference： [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 22, p. 7053 - 7056
[2] Patent: WO2010/43866, 2010, A2, . Location in patent: Page/Page column 77

2
[ 1558-17-4 ]
[ 16490-02-1 ]

Reference： [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, # 22, p. 7053 - 7056
[4] Patent: WO2010/43866, 2010, A2, . Location in patent: Page/Page column 77
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 1, p. 307 - 321

3
[ 62501-45-5 ]
[ 16490-02-1 ]

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

4
[ 4472-44-0 ]
[ 16490-02-1 ]

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

5
[ 67-56-1 ]
[ 16490-02-1 ]
[ 6345-43-3 ]

Yield	Reaction Conditions	Operation in experiment
94.4%	With hydrogenchloride In water at 65℃; for 3 h; 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 (65°C) 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 (94.4percent) MS (ES +): m/e = 197.20

Reference： [1] Patent: US2003/229103, 2003, A1, . Location in patent: Page 9
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 22, p. 7053 - 7056
[3] Patent: WO2010/43866, 2010, A2, . Location in patent: Page/Page column 77
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 1, p. 307 - 321

[ 16490-02-1 ] Synthesis Path-Downstream 1~88

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.

Reference： [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 ]

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

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

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

4
[ 62501-45-5 ]
[ 16490-02-1 ]

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

5
[ 4472-44-0 ]
[ 16490-02-1 ]

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

6
[ 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.

Reference： [1]Patent: US5130317,1992,A

7
[ 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).

Reference： [1]Patent: US5130317,1992,A

8
[ 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.

Reference： [1]Patent: US3950353,1976,A

9
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 ]

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

10
[ 16490-02-1 ]
manganese(II) perchlorate hexahydrate [ No CAS ]
[Mn(pyrimidine-4,6-dicarboxylate)(H₂O)3](n) [ No CAS ]

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

11
[ 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.

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

12
[ 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.

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

13
[ 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%.

Reference： [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

14
[ 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).

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

15
[ 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 ]

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

16
[ 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 ]

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

17
[ 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 ]

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

18
[ 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 ]

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

19
[ 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 ]