[ CAS No. 6345-43-3 ] {[proInfo.proName]}

Name: 6345-43-3|Dimethyl pyrimidine-4,6-dicarboxylate|95%
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Quality Control of [ 6345-43-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 6345-43-3 ]

CAS No. :	6345-43-3	MDL No. :	MFCD05864412
Formula :	C₈H₈N₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AJTJKDWVSIIOIR-UHFFFAOYSA-N
M.W :	196.16	Pubchem ID :	239362
Synonyms :

Calculated chemistry of [ 6345-43-3 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	4
Num. H-bond acceptors :	6.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.59
TPSA :	78.38 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) :	-7.08 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.62
Log Po/w (XLOGP3) :	0.58
Log Po/w (WLOGP) :	0.05
Log Po/w (MLOGP) :	-0.43
Log Po/w (SILICOS-IT) :	0.6
Consensus Log Po/w :	0.48

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.47
Solubility :	6.57 mg/ml ; 0.0335 mol/l
Class :	Very soluble
Log S (Ali) :	-1.8
Solubility :	3.12 mg/ml ; 0.0159 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.81
Solubility :	3.04 mg/ml ; 0.0155 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.93

Safety of [ 6345-43-3 ]

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 [ 6345-43-3 ]

* 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 [ 6345-43-3 ]
Downstream synthetic route of [ 6345-43-3 ]

[ 6345-43-3 ] Synthesis Path-Upstream 1~3

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
[ 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

3
[ 1558-17-4 ]
[ 6345-43-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 1, p. 307 - 321

[ 6345-43-3 ] Synthesis Path-Downstream 1~59

2
[ 929-59-9 ]
[ 6345-43-3 ]
6,9-dioxa-3,12,15,17-tetraazabicyclo[12.3.1]octadeca-1⁽¹⁸⁾,14,16-triene-2,13-dione [ No CAS ]
6,9,23,26-tetraoxa-3,12,15,17,20,29,32,34-octaazatricyclo[29.3.1.1^14,18]hexatriaconta-1⁽³⁵⁾,14,16,18⁽³⁶⁾,31,33-hexaene-2,13,19,30-tetraone [ No CAS ]

Reference： [1]Helvetica Chimica Acta,2004,vol. 87,p. 156 - 166

3
[ 6345-43-3 ]
[ 10406-25-4 ]
C₁₅H₁₂N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	In N,N-dimethyl-formamide; at 60℃;	Example 5; Step A; 4-Cyanolbenzylamine (1.1 g, 8.33 mmol), 4,6-pyrimidine dicarboxylic acid methyl ester (1.77 g, 8.33 mmol) were dissolved in N,N-dimethylformamide (20 mL). The reaction was stirred 60 C. overnight and concentrated. The brown solid was purification with ethyl acetate and hexane (gradient) to give product as light brown solid (1.18 g, 48% yield).

Reference： [1]Patent: US2008/21024,2008,A1 .Location in patent: Page/Page column 71-72

4
[ 6345-43-3 ]
[ 140-75-0 ]
C₁₄H₁₂FN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 60℃; for 24h;	Preparative Example 13; Step A; A solution of commercially available <strong>[6345-43-3]pyrimidine-4,6-dicarboxylic acid dimethyl ester</strong> (1.61 g) and 4-fluorobenzylamine (1.23 g) in DMF (30 mL) was stirred at 60 C. for 24 h. The solvent was evaporated to dryness, the residue dissolved in THF/H2O 1:1 (10 mL) and LiOH H2O (314 mg) was added. The resulting mixture was stirred at rt for 2 h and H2O (50 mL) was added. The reaction mixture was extracted with DCM and acidified with concentrated HCl. The formed precipitate was filtered off and washed with H2O to afford the title compound (1.147 g; 51%). [MH]+=276.

Reference： [1]Patent: US2008/21024,2008,A1 .Location in patent: Page/Page column 81

5
[ 6345-43-3 ]
[ 100-46-9 ]
methyl-6-benzylcarbamoylpyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	In DMF (N,N-dimethyl-formamide); at 50℃; for 4h;	2.55 g (0.01299 mol) of the resulting compound <strong>[6345-43-3]dimethyl pyrimidine-4,6-dicarboxylate</strong> were dissolved in 100 ml of dimethylformamide (DMF), after which 1.42 ml (0.01299 mol) of benzylamine were added and the mixture was heated to 50C. After 4 hours, the solution is concentrated under reduced pressure. The residue is chromatographed through a 500 ml silica gel column using heptane/ethyl acetate (1:1). Fractions containing the compound methyl-6-benzylcarbamoylpyrimidine-4-carboxylate were concentrated. Yield: 1.268 g (36%) MS (ES +): m/e = 272.20

Reference： [1]Patent: US2003/229103,2003,A1 .Location in patent: Page 9

6
[ 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.

Reference： [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

7
[ 3731-53-1 ]
[ 6345-43-3 ]
[ 691003-11-9 ]

Reference： [1]Patent: WO2004/41788,2004,A1 .Location in patent: Page/Page column 48-49

8
[ 5071-96-5 ]
[ 6345-43-3 ]
6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 80℃; for 18h;	A solution of commercially available <strong>[6345-43-3]pyrimidine-4,6-dicarboxylic acid dimethyl ester</strong> (1.96 g) and commercially available 3-methoxy-benzylamine (1.38 mL) in dry N,N-dimethylformamide (10 mL) was placed in a preheated oil bath (80 C.). After stirring at this temperature for 18 h the mixture was concentrated and flash filtered (silica, cyclohexane/ethyl acetate). The obtained material was suspended in dry tetrahydrofurane (10 mL) and treated with a solution of lithium hydroxide (642 mg) in water (15 mL). The resulting mixture was stirred at room temperature for 16½ h, diluted with water (35 mL), washed with dichloromethane (3×50 mL) and acidified by addition of a 1M aqueous solution of hydrochloric acid (20 mL). The formed precipitate was isolated by suction, washed with water (2×50 mL) again suspended/dissolved in water (200 mL) and ultrasonificated for 5 min. The remaining precipitate was isolated by suction and dried under reduced pressure to afford the title compound (700 mg; 24%). [MH]+=288.
	In N,N-dimethyl-formamide; at 80℃; for 18h;	Preparative Example 202; Step A; A solution of commercially available <strong>[6345-43-3]pyrimidine-4,6-dicarboxylic acid dimethyl ester</strong> (1.96 g) and commercially available 3-methoxy-benzylamine (1.38 mL) in dry N,N-dimethylformamide (10 mL) was placed in a preheated oil bath (80 C.). After stirring at this temperature for 18 h the mixture was concentrated and flash filtered (silica, cyclohexane/ethyl acetate). The obtained material was suspended in dry tetrahydrofuran (10 mL) and treated with a solution of lithium hydroxide (642 mg) in water (15 mL). The resulting mixture was stirred at room temperature for 16½ h, diluted with water (35 mL), washed with dichloromethane (3×50 mL) and acidified by addition of a 1M aqueous solution of hydrochloric acid (20 mL). The formed precipitate was isolated by suction, washed with water (2×50 mL) again suspended/dissolved in water (200 mL) and ultrasonificated for 5 min. The remaining precipitate was isolated by suction and dried under reduced pressure to afford the title compound (700 mg; 24%). [MH]+288.

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 307 - 321
[2]Patent: WO2004/41788,2004,A1 .Location in patent: Page/Page column 46
[3]Patent: US2006/173183,2006,A1 .Location in patent: Page/Page column 127
[4]Patent: US2007/155739,2007,A1 .Location in patent: Page/Page column 38-39

9
[ 6345-43-3 ]
(2,3-dihydro-1-benzofuran-5-yl)methanamine [ No CAS ]
[ 691003-13-1 ]

Reference： [1]Patent: WO2004/41788,2004,A1 .Location in patent: Page/Page column 50

10
[ 261951-68-2 ]
[ 6345-43-3 ]
methyl 6-((4-fluoro-3-methylbenzyl)carbamoyl)pyrimidine-4-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 307 - 321
[2]Patent: WO2004/41788,2004,A1 .Location in patent: Page/Page column 44

11
[ 6345-43-3 ]
[ 612088-38-7 ]

Yield	Reaction Conditions	Operation in experiment
Ca. 100%	With water; sodium hydroxide; In methanol; at 0 - 20℃; for 2h;	Sodium hydroxide (632 mg, 15.8 mmol) was added to a solution of compound 81-1 (3.10 g, 15.8 mmol) in MeOH (60 mL) and H20 (6 mL) at 0C. The resulting mixture was stirred for 2 h at room temperature, then acidified with 1M HC1 aqueous to pH of 3. The mixture was concentrated to dryness. The residue was azeotroped two times with THF (50 mL portions) to afford crude compound 81-2 (3.30 g, -100% yield), which was used for next step without further purification.
86%	With methanol; sodium hydroxide; at 20℃; for 1h;Inert atmosphere;	To a 100 ml round bottom flask containing a stir bar is added commercially available pyrimidine-4,6- dicarboxylic acid dimethyl ester (19) (obtained from Aldrich). To the solid was added a solution comprising 0.2 grams of sodium hydroxide dissolved in 10 ml anhydrous methanol and mixture stirred at room temperature under a nitrogen atmosphere for 1 hour. To the reaction mixture was then added 1.2 ml of a solution comprising 4 M hydrochloric acid in dioxane and mixture stirred for 10 minutes. To the reaction mixture was then added ~2 grams of silica gel (Si02), and the volatile components removed under reduced pressure and solid added to a column and purified via column chromatography (Si02, 40% ethylacetate in hexane) to give 0.77 grams (86%) of Pyrimidine-4,6-dicarboxylic acid monomethyl ester compound (20). XH NMR (300 MHz, CD3OD) delta 4.04 (s, 3H), 8.59 (s, 1H), 9.46 (s, 1H). LC-MS (M+H) 183.
76%		To a solution of sodium hydroxide (1.00 g) in dry methanol (50 mL) was added commercially available <strong>[6345-43-3]pyrimidine-4,6-dicarboxylic acid dimethyl ester</strong> (4.91 g). The resulting suspension was stirred at room temperature for 1 h. Then a 4M solution of hydrochloric acid in dioxane (6.25 mL) was added and stirring at room temperature was continued for 10 min. The mixture was concentrated and purified by flash chromatography (silica, dichloromethane/methanol) to afford the title compound (3.48 g; 76%). [MH]+=183.

76%

Preparative Example 200; Step A; To a solution of sodium hydroxide (1.00 g) in dry methanol (50 mL) was added commercially available [6345-43-3]pyrimidine-4,6-dicarboxylic acid dimethyl ester (4.91 g). The resulting suspension was stirred at room temperature for 1 h. Then a 4M solution of hydrochloric acid in dioxane (6.25 mL) was added and stirring at room temperature was continued for 10 min. The mixture was concentrated and purified by flash chromatography (silica, dichloromethane/methanol) to afford the title compound (3.48 g; 76%). [MH]+=183.

Reference： [1]Patent: WO2019/99977,2019,A2 .Location in patent: Paragraph 00362; 00364
[2]Patent: WO2014/62204,2014,A1 .Location in patent: Page/Page column 38
[3]Patent: US2006/173183,2006,A1 .Location in patent: Page/Page column 125
[4]Patent: US2007/155739,2007,A1 .Location in patent: Page/Page column 38

12
[ 6345-43-3 ]
pyrimidine-4,6-dicarbohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrazine hydrate; In ethanol; for 18h;Reflux;	General procedure: A solution of the corresponding dimethyl ester (10mmol) and hydrazine hydrate (10.9mL, 11.2g, 220mmol) in ethanol (150mL) was heated under reflux for 18h and then cooled to room temperature. The precipitate was filtered, washed twice with ethanol, once with ether, and dried, to give the bis(acylhydrazide) which was sufficiently pure and employed without further purification.
	With hydrazine hydrate; In methanol;	Example 14 Pyrimidine-4,6-dicarboxylic acid dihydrazide (formula I: R1 =--NH2; R2 =H) 2 g of <strong>[6345-43-3]dimethyl pyrimidine-4,6-dicarboxylate</strong> (prepared in accordance with the method of H. Yamada, Heterocycles, 13, 235 (1979)) are dissolved in 75 ml of methanol at room temperature. 1.1 g of hydrazine hydrate are added. A yellow precipitate is formed and is stirred for 3 hours and then filtered off with suction. Yield: 1.9 g; melting point:

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 178,p. 13 - 29
[2]Patent: US5130317,1992,A

13
[ 6345-43-3 ]
[ 27298-97-1 ]
C₁₅H₁₄BrN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	In N,N-dimethyl-formamide; at 70℃; for 72h;	Preparative Example 204; Step A; A solution of commercially available <strong>[6345-43-3]pyrimidine-4,6-dicarboxylic acid dimethyl ester</strong> (7.14 g) and commercially available (S)-1-(4-bromophenyl)ethylamine (5.06 g) in dry N,N-dimethylformamide (30 mL) was heated to 70 C. for 3 d. The solution was diluted with ethyl acetate and washed with 1N HCl, water and brine. Purification by flash filtered (silica, cyclohexane/ethyl acetate 7:3) afforded the intermediate (5.65 g; 61%) as a colourless oil. [MH]+=364/366.

Reference： [1]Patent: US2007/155739,2007,A1 .Location in patent: Page/Page column 39

14
[ 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.

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

15
[ 6345-43-3 ]
4,6-pyrimidinebis(carboxylic acid amide) [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 13298 - 13301
[2]Chemical Communications,2010,vol. 46,p. 4755 - 4757

16
[ 6345-43-3 ]
C₆H₂N₆S₄ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 13298 - 13301

17
[ 6345-43-3 ]
C₂₆H₆F₂₄Mn₂N₆O₈S₄ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 13298 - 13301

18
[ 6345-43-3 ]
[ 50844-89-8 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 13298 - 13301

19
[ 6345-43-3 ]
N4,N4,N4,N6,N6,N6-hexakis(trimethylsilyl)pyrimidine-4,6-dicarboxamidine [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 13298 - 13301

20
[ 6345-43-3 ]
4,6-bis(1,2,3,5-dithiadiazolium)pyrimidine dichloride [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 13298 - 13301

21
[ 6345-43-3 ]
[ 1605325-10-7 ]

Reference： [1]Patent: WO2014/62204,2014,A1

22
[ 6345-43-3 ]
[ 1605325-11-8 ]

Reference： [1]Patent: WO2014/62204,2014,A1

23
[ 6345-43-3 ]
6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Patent: WO2014/62204,2014,A1

24
[ 6345-43-3 ]
6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2014/62204,2014,A1
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 307 - 321

25
[ 6345-43-3 ]
4-([6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid methyl ester [ No CAS ]

Reference： [1]Patent: WO2014/62204,2014,A1

26
[ 6345-43-3 ]
[ 448949-22-2 ]

Reference： [1]Patent: WO2014/62204,2014,A1

27
[ 6345-43-3 ]
[ 1605324-78-4 ]

Reference： [1]Patent: WO2014/62204,2014,A1

28
[ 6345-43-3 ]
[ 1605324-79-5 ]

Reference： [1]Patent: WO2014/62204,2014,A1

29
[ 6345-43-3 ]
[ 1605324-80-8 ]

Reference： [1]Patent: WO2014/62204,2014,A1

30
[ 6345-43-3 ]
[ 1605324-81-9 ]

Reference： [1]Patent: WO2014/62204,2014,A1

31
[ 261951-68-2 ]
[ 6345-43-3 ]
[ 544678-85-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	In N,N-dimethyl-formamide; at 85℃; for 24h;Inert atmosphere; Microwave irradiation;	To a thick walled glass vessel containing a stir bar and 23 mg (0.11 mmole) of commercially available <strong>[6345-43-3]dimethyl pyrimidine-4,6-dicarboxylate</strong> (obtained from Oakwood Products) (19) was added a large excess (0.25 ml) of commercially available 4-Fluoro-3-methyl-benzylamine (50) (obtained from Aldrich) and 0.5 ml of anhydrous dimethylformamide and mixture heated while stirring under closed nitrogen atmosphere at 85 C using microwave radiation (Biotage) for 24 hours. The volatile components of the reaction mixture were removed under reduced pressure to give a solid which was recrystallized from diethyl ether to give 0.42 grams (87%) of Pyrimidine-4,6-dicarboxylic acid bis-(4-fluoro-3-methyl-benzylamide) (51) as a white crystal solid. 1H NMR (300 MHz, CD3OD) delta 2.23 (s, 6H), 4.55 (s, 4H), 6.85-7.30 (m, 6H), 8.66 (s, 1H), 9.34 (s, 1H). LC-MS (M+H) 411.

Reference： [1]Patent: WO2014/62204,2014,A1 .Location in patent: Page/Page column 50

32
[ 6345-43-3 ]
[ 112245-13-3 ]
C₁₈H₃₀N₄O₄ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2015,vol. 54,p. 14036 - 14039

33
[ 6345-43-3 ]
[ 112245-13-3 ]
C₁₈H₂₆N₄O₂ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2015,vol. 54,p. 14036 - 14039

34
[ 6345-43-3 ]
C₁₇H₂₀N₂O₂*ClH [ No CAS ]
C₄₀H₄₀N₆O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22 mg		Example 112 A solution of 1 M aqueous LiOH (0.75 mL, 0.75 mmol) was added to a stirred solution of <strong>[6345-43-3]dimethyl pyrimidine-4,6-dicarboxylic acid</strong> (70 mg, 360 mupiiotaomicron) in THF (1 mL) and the reaction mixture was stirred at rt overnight and then concentrated to dryness. The crude residue was dissolved into DMF (1 mL) and 4M HC1 in 1,4-dioxane (0.19 mL, 0.76 mmol) and stirred until the mixture became clear. A portion (0.1 mmol, 235 uL) of this crude solution was combined with a solution of an HC1 salt of Intermediate 4 (67.4 mg, 210 muiotaetaomicron) in DMF (0.83 mL) and DIPEA (0.07 mL, 400 muiotaetaomicron) and the crude reaction mixture was then treated with HATU (84 mg, 220 muiotatauiotaomicron) and stirred at rt for 3 h. The reaction mixture was concentrated, diluted with EtOAc (-1.5 mL) and washed with water (1 mL) and then brine (1 mL). The organic component was concentrated and the residue was dissolved into MeOH, filtered and purified by preparative HPLC to yield the title compound (22 mg). LC-MS retention time = 2.21 min; m/z = 701.4 [M+H]+. (Column: Waters BEH C18, 2.0 x 50 mm, 1.7-muiotaeta particles. Solvent A = 95% Water : 5% Acetonitrile : 10 mM NH4OAc. Solvent B = 5% Water : 95% Acetonitrile : 10 mM NH4OAc. Flow Rate = 0.5 mL/min. Start % B = 0. Final % B = 100. Gradient Time = 3 minutes, then a 0.5-minute hold at 100% B. Wavelength = 220 nm). NMR (500 MHZ, methanol^) delta ppm 9.39 (s, 1H), 8.45 (s, 1H), 7.41 - 7.19 (m, 7H), 7.08 - 6.84 (m, 11H), 4.93 (t, J=7.2 Hz, 2H), 4.90 - 4.85 (m, 2H), 3.85 (s, 6H), 3.22 (s, 6H), 3.11 (dd, J=13.2, 7.0 Hz, 2H), 2.93 (dd, J=13.4, 7.5 Hz, 2H).

Reference： [1]Patent: WO2016/172425,2016,A1 .Location in patent: Page/Page column 242; 243

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[ 6345-43-3 ]
N4-(4-(2-fluoroethoxy)benzyl)-N6-(3-methoxybenzyl)pyrimidine-4,6-dicarboxamide [ No CAS ]