[ CAS No. 113583-35-0 ] {[proInfo.proName]}

Name: 113583-35-0|2-Methanesulfonyl-4,6-dimethoxypyrimidine|97%
Brand: Ambeed
SKU: A395114
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Quality Control of [ 113583-35-0 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 113583-35-0 ]

CAS No. :	113583-35-0	MDL No. :	MFCD00672151
Formula :	C₇H₁₀N₂O₄S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ITDVJJVNAASTRS-UHFFFAOYSA-N
M.W :	218.23	Pubchem ID :	838363
Synonyms :

Calculated chemistry of [ 113583-35-0 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.43
Num. rotatable bonds :	3
Num. H-bond acceptors :	6.0
Num. H-bond donors :	0.0
Molar Refractivity :	48.11
TPSA :	86.76 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) :	-7.36 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.54
Log Po/w (XLOGP3) :	0.38
Log Po/w (WLOGP) :	0.98
Log Po/w (MLOGP) :	-0.9
Log Po/w (SILICOS-IT) :	0.19
Consensus Log Po/w :	0.44

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.55
Solubility :	6.13 mg/ml ; 0.0281 mol/l
Class :	Very soluble
Log S (Ali) :	-1.77
Solubility :	3.73 mg/ml ; 0.0171 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.23
Solubility :	1.29 mg/ml ; 0.00592 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.23

Safety of [ 113583-35-0 ]

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

Application In Synthesis of [ 113583-35-0 ]

* 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 [ 113583-35-0 ]
Downstream synthetic route of [ 113583-35-0 ]

[ 113583-35-0 ] Synthesis Path-Upstream 1~7

1
[ 90905-46-7 ]
[ 113583-35-0 ]

Yield	Reaction Conditions	Operation in experiment
84.5%	With sodium tungstate; dihydrogen peroxide; acetic acid In water at 40℃;	Example 10: Preparation of 4, 6-dimethoxy-2-(methylsulfonyl) pyrimidine To 200ml acetic acid was added 3mpercent sodium tungstate. To this, 1.0m 2-methylthio-4,6- dimethoxypyrimidine was added to obtain a mass (clear solution). The mass was heated to 40°C. To the heated mass 2.1m 30percent H₂0₂ was added in 4-8 hours and stirred at 40°c for 3-5 hours. Further, 0.05m 30 percent H₂0₂ was added and stirred at 40°C till complete conversion. Reaction was carried out at 40°c. Reaction mixture was cooled and solids were filtered. The obtained cake was washed with aqueous acetic acid followed by water. The cake was then dried. Yield = 83percent. The filtrate was extracted with ethylene dichloride. The obtained ethylene dichloride layer was concentrated, wt = 42g, yield of product was about 1-1.5percent.

Reference： [1] Asian Journal of Chemistry, 2014, vol. 26, # 1, p. 313 - 314
[2] Journal of Agricultural and Food Chemistry, 2018, vol. 66, # 15, p. 3773 - 3782
[3] Pesticide Science, 1996, vol. 47, # 2, p. 115 - 124
[4] Patent: WO2014/128719, 2014, A2, . Location in patent: Page/Page column 17
[5] Journal of Labelled Compounds and Radiopharmaceuticals, 2006, vol. 49, # 4, p. 339 - 343
[6] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 9, p. 2288 - 2300
[7] Pest Management Science, 2001, vol. 57, # 3, p. 205 - 224
[8] Journal of Medicinal Chemistry, 2004, vol. 47, # 11, p. 2776 - 2795
[9] Journal of Mass Spectrometry, 2007, vol. 42, # 11, p. 1514 - 1521
[10] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 15, p. 4409 - 4412

2
[ 90905-46-7 ]
[ 113583-35-0 ]

Reference： [1] Patent: US5149357, 1992, A,

3
[ 6299-25-8 ]
[ 113583-35-0 ]

Reference： [1] Journal of Mass Spectrometry, 2007, vol. 42, # 11, p. 1514 - 1521
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 11, p. 2776 - 2795
[3] Pest Management Science, 2001, vol. 57, # 3, p. 205 - 224
[4] Patent: WO2014/128719, 2014, A2,

4
[ 20277-69-4 ]
[ 13223-25-1 ]
[ 113583-35-0 ]

Reference： [1] Tetrahedron, 2000, vol. 56, # 27, p. 4739 - 4745

5
[ 1979-98-2 ]
[ 113583-35-0 ]

Reference： [1] Pest Management Science, 2001, vol. 57, # 3, p. 205 - 224
[2] Patent: WO2014/128719, 2014, A2,

6
[ 303-07-1 ]
[ 113583-35-0 ]
[ 125401-75-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With tetrabutylammomium bromide; potassium carbonate In tolueneReflux	0.04 mol of 2,6-dihydroxybenzoic acid was weighed separately,0.05 mol of 2-methanesulfonyl-4,6-dimethoxypyrimidine,0.004 mol of tetrabutylammonium bromide,0.08 mol of potassium carbonate was placed in a reaction vessel,Add 300mL toluene heated reflux reaction 8 ~ 1 Oh,The reaction is cooled and filtered,The filter cake was washed with toluene,dry,The resulting solid was mixed with 500 mL of water,Stir,Dropping 30percent HC1 to the system PH = 3 ~ 4,filter,dry,Was gray and solidbodyBispyribac15.7g,Purity 97percentYield 85percent.
83%	Stage #1: With sodium hydride In N,N-dimethyl acetamide; toluene; paraffin oil at 100℃; for 5 h; Stage #2: at 20℃; for 1 h;	Into a 500 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 60percent sodium hydride (dispersed in liquid paraffin; 6.2 g, 0.155 mol) and Toluene (300 ml) was charged. Subsequently, a solution of 2,6-dihydroxybenzoic acid (7.7 g, 0.05 mol) dissolved in N, N-dimethylacetamide (DMAC; 10 ml) was slowly added dropwise thereto. While stirring the mixture at room temperature, 4,6-dimethoxy-2-methylsulfonylpyrimidine (21.8 g, 0.1 mol) was added in portions. Thereafter, the mixture was stirred at 100 ° C. for 5 hours. As a result, a reaction mixture containing sodium 2,6-bis (4,6-dimethoxypyrimidin-2-yloxy) benzoate was obtained. A small amount of the reaction mixture was sampled, acidified and analyzed by HPLC. The components other than solvent etc. in the reaction mixture were as follows. 82percent of 2- (4,6-dimethoxypyrimidin-2-yloxy) benzoic acid (target product), 2- (4,6- dimethoxypyrimidin-2-yloxy) -6-hydroxybenzoic acid: 2 percent, 4,6-dimethoxy-2-methylsulfonylpyrimidine (raw material): 8percent, 4,6-dimethoxy-2-hydroxypyrimidine (by- product): 3percent. After the reaction mixture was cooled to room temperature, a small amount of methanol was added thereto, and the mixture was stirred at room temperature for 1 hour. The mixture was poured into water and the resulting mixture was partitioned between organic and aqueous layers. The organic layer and the aqueous layer were separated, and an aqueous layer was obtained. Dilute hydrochloric acid was added to the obtained aqueous layer until the pH became 4. Precipitated crystals were collected by filtration, washed with water and dried to obtain 2, 6-bis (4,6-dimethoxypyrimidin-2-yloxy) benzoic acid (17.8 g) as white crystals. Yield: 83percent.

Reference： [1] Patent: CN106083738, 2016, A, . Location in patent: Paragraph 0019; 0020
[2] Patent: JP2018/48180, 2018, A, . Location in patent: Paragraph 0053-0054; 0055; 0058-0059; 0060-0061; 0067

7
[ 113583-35-0 ]
[ 125401-75-4 ]

Reference： [1] Patent: US4906285, 1990, A,

[ 113583-35-0 ] Synthesis Path-Downstream 1~87

1
[ 110-85-0 ]
[ 113583-35-0 ]
[ 106615-46-7 ]

Reference： [1]Chinese Journal of Chemistry,2015,vol. 33,p. 1269 - 1275
[2]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 2288 - 2300

2
[ 90905-46-7 ]
[ 113583-35-0 ]

Yield	Reaction Conditions	Operation in experiment
84.5%	With sodium tungstate; dihydrogen peroxide; acetic acid; In water; at 40℃;	Example 10: Preparation of 4, 6-dimethoxy-2-(methylsulfonyl) pyrimidine To 200ml acetic acid was added 3m% sodium tungstate. To this, 1.0m 2-methylthio-4,6- dimethoxypyrimidine was added to obtain a mass (clear solution). The mass was heated to 40C. To the heated mass 2.1m 30% H202 was added in 4-8 hours and stirred at 40c for 3-5 hours. Further, 0.05m 30 % H202 was added and stirred at 40C till complete conversion. Reaction was carried out at 40c. Reaction mixture was cooled and solids were filtered. The obtained cake was washed with aqueous acetic acid followed by water. The cake was then dried. Yield = 83%. The filtrate was extracted with ethylene dichloride. The obtained ethylene dichloride layer was concentrated, wt = 42g, yield of product was about 1-1.5%.

Reference： [1]Asian Journal of Chemistry,2014,vol. 26,p. 313 - 314
[2]Journal of Agricultural and Food Chemistry,2018,vol. 66,p. 3773 - 3782
[3]Pesticide Science,1996,vol. 47,p. 115 - 124
[4]Patent: WO2014/128719,2014,A2 .Location in patent: Page/Page column 17
[5]Journal of labelled compounds and radiopharmaceuticals,2006,vol. 49,p. 339 - 343
[6]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 2288 - 2300
[7]Pest Management Science,2001,vol. 57,p. 205 - 224
[8]Journal of Medicinal Chemistry,2004,vol. 47,p. 2776 - 2795
[9]Journal of Mass Spectrometry,2007,vol. 42,p. 1514 - 1521
[10]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4409 - 4412

3
[ 113583-35-0 ]
[ 178306-47-3 ]
[ 178306-45-1 ]

Yield	Reaction Conditions	Operation in experiment
82%		2.8 6 g (10 mmol) of <strong>[178306-47-3]methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate</strong> were dissolved in 40 ml of dimethylformamide,Then 0.3 g (12 mmol) sodium hydride was added.The mixture was stirred for 1 hour,Then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added.After stirring at room temperature for 24 hours,Carefully hydrolyze with 10 ml of water,The pH was adjusted to 5 with acetic acid,The solvent was removed by distillation under high vacuum.The residue was placed in 100 ml of ethyl acetate,Wash with water,And dried over magnesium sulfate,The solvent was distilled off.The residue was mixed with 10 ml of ether,The resulting precipitate was collected by suction filtration.After drying, 3.48 g (82%) of a white powder remained. Melting point 81 C.
	In N-methyl-acetamide; water; ethyl acetate;	Example 3 Methyl 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate 2.86 g (10 mmol) of <strong>[178306-47-3]methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate</strong> were dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride was added. The mixture was stirred for 1 h and then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added. After stirring at room temperature for 24 h, cautious hydrolysis was carried out with 10 ml of water, the pH was adjusted to 5 with acetic acid, and the solvent was removed by distillation under high vacuum. The residue was taken up in 100 ml of ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was distilled out. The residue was mixed with 10 ml of ether, and the resulting precipitate was filtered off with suction. After drying, 3.48 g (82%) of a white powder remained. Melting point 81 C.
	In N-methyl-acetamide; water; ethyl acetate;	EXAMPLE 3 Methyl 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate 2.86 g (10 mmol) of <strong>[178306-47-3]methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate</strong> were dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride was added. The mixture was stirred for 1 h. and then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added. After stirring at room temperature for 24 h., cautious hydrolysis was carried out with 10 ml of water, the pH was adjusted to 5 with acetic acid, and the solvent was removed by distillation under high vacuum. The residue was taken up in 100 ml of ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was distilled out. The residue was mixed with 10 ml of ether, and the resulting precipitate was filtered off with suction. After drying, 3.48 g (82%) of a white powder remained.

Reference： [1]Patent: JP5700378,2015,B2 .Location in patent: Paragraph 0064
[2]Journal of Medicinal Chemistry,1996,vol. 39,p. 2123 - 2128
[3]Patent: US5932730,1999,A
[4]Patent: US6030975,2000,A

4
[ 136192-84-2 ]
[ 113583-35-0 ]
[ 119158-69-9 ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium carbonate; In N,N-dimethyl-formamide;	REFERENCE EXAMPLE 2 Preparation of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-formylbenzoate (Intermediate product No. 18) 13.8 g of potassium carbonate and 50 ml of DMF were placed in a 200 ml eggplant type flask, and 11.1 g of methyl 2-formyl-6-hydroxybenzoate and 14.6 g of 4,6-dimethoxy-2-methanesulfonylpyrimidine were added thereto with stirring. The mixture was stirred at 80 C. for 1 hour, and the resultant liquor was poured into an ice water after cooling. An oily product thus precipitated was extracted with ethyl acetate, and was dried with magnesium sulfate anhydride. Ethyl acetate was distilled off under reduced pressure, and the residue thus obtained was purified by column chromatography to obtain 11.0 g of the aimed compound (melting point=91 to 93 C.) at a yield of 52%.

Reference： [1]Patent: US5118339,1992,A
[2]Pesticide Science,1996,vol. 47,p. 327 - 335

5
[ 113583-35-0 ]
[ 136192-86-4 ]
[ 136192-79-5 ]

Yield	Reaction Conditions	Operation in experiment
71.3%	In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;	REFERENCE EXAMPLE 5 Preparation of methyl 2-[(4,6-dimethoxypyrimidin-2yl)oxy]-6-propionylbenzoate (Intermediate product No. 17) 0.78 g of 3-hydroxy-2-methoxycarbonylpropiophenone and 0.85 g of 2-methylsulfonyl-4,6-dimethoxypyrimidine were dissolved in 60 ml of DMF (dimethylformamide), and 0.15 g of sodium hydride (60% oil dispersion) was added thereto under cooling with ice. The resultant mixture was stirred at room temperature for 8 hours, and an ice water was added thereto. The resultant reaction liquor was extracted with ethyl acetate, and the extracted product was washed with a saturated salt aqueous solution, and was dried with magnesium sulfate anhydride. After distilling off the solvent, the mixture was purified by column chromatography, and was crystallized with isopropyl ether to obtain 0.92 g of the aimed compound (melting point=120 to 122 C.) at a yield of 71.3%.

Reference： [1]Pesticide Science,1996,vol. 47,p. 327 - 335
[2]Patent: US5118339,1992,A

6
[ 121129-31-5 ]
[ 113583-35-0 ]
methyl 2-(4,6-dimethoxypyrimidin-2-yloxy)-3,3-dimethylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide;	(b2) Preparation of methyl (+/-)-2-(4,6-dimethoxy-2-pyrimidinyloxy)-3,3-dimethylbutanoate 2.18 g (10.0 mmol) of 4,6-dimethoxy-2-methyl-sulfonylpyrimidine and 1.62 g (11.0 mmol) of methyl (+/-)-2-hydroxy-3,3-dimethylbutanoate were heated in the presence of 2.07 g (15.0 mmol) of potassium carbonate in 20 ml of N,N-dimethylformamide to 60 with stirring. After 3 hours, the solvent was removed in a rotary evaporator at 60 C./20 mbar. The residue was taken up in 40 ml of water and 40 ml of ethyl acetate. After the organic phase had been separated off, the aqueous phase was again extracted with 40 ml of ethyl acetate. The combined organic phases was washed with water, dried over magnesium sulfate and evaporated. The title product was obtained in a yield of 2.76 g (93.8 percent of theory) in the form of pale yellowish crystals (GC content 96.6 percent).

Reference： [1]Tetrahedron,2000,vol. 56,p. 4739 - 4745
[2]Patent: US5840892,1998,A

7
[ 20277-69-4 ]
[ 13223-25-1 ]
[ 113583-35-0 ]

Reference： [1]Tetrahedron,2000,vol. 56,p. 4739 - 4745

8
[ 113583-35-0 ]
[ 135217-37-7 ]
[ 135186-78-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triphenylphosphine; sodium hydroxide; In water; isopropyl alcohol; at 75℃; for 3h;Inert atmosphere;	Compound 5 (3.46 g, 19.2 mmoL), triphenylphosphine (0.50 g, 1.9 mmoL), and NaOHsolution (6.48 g, 12.5% wt% in water) were added to isopropanol (10 mL), then 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine 7 (4.31 g 19.8 mmoL) was added. The reaction mixturewas heated to 75C for 3h under a nitrogen atmosphere. Subsequently, acetic acid(2.42 g, 80% wt% in water) was added to the mixture, which was heated for another 1h.After cooling to ambient temperature, the product was filtered off, washed with 3 mLwater and 3 mL isopropanol, then dried under vacuum at 45C. Compound 1 wasobtained as a pale yellow solid (5.63 g, 92%), with a purity of 98%. Mp 164.5-164.8 C(lit mp 159-160C9); 1H NMR (400 MHz, CDCl3) d 7.83 (d, J D 7.6 Hz, 1H), 7.66 (t,J D 7.6 Hz, 1H), 7.43 (d, J D 7.6 Hz, 1H), 5.73 (s, 1H), 5.51 (q, J D 6.6 Hz, 1H), 3.72 (s,6H), 1.63 (d, J D 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 170.82, 168.70, 168.12,152.50, 135.77, 133.74, 130.97, 126.75, 121.89, 86.82, 77.39, 76.75, 76.18, 53.94, 20.52.

Reference： [1]Organic Preparations and Procedures International,2017,vol. 49,p. 382 - 388
[2]Pest Management Science,2001,vol. 57,p. 205 - 224

9
[ 113583-35-0 ]
rac-(1SR,9bSR)-1-hydroxy-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diazabenzo[a]cyclobuta[c]cycloheptene-2,4-dione [ No CAS ]
1-(4,6-dimethoxy-pyrimidin-2-yloxy)-5-methyl-9b-phenyl-5,9b-dihydro-1H-2a,5-diaza-benzo[a]cyclobuta[c]cycloheptene-2,4-dione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 2776 - 2795

10
[ 1979-98-2 ]
[ 113583-35-0 ]

Reference： [1]Pest Management Science,2001,vol. 57,p. 205 - 224
[2]Patent: WO2014/128719,2014,A2

11
[ 178306-50-8 ]
[ 113583-35-0 ]
methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3,3-diphenylbutyrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;	Example 9 methyl 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3,3-diphenylbutyrate 1.2 g (4.4 mmol) of methyl 2-hydroxy-3,3-diphenylbutyrate were dissolved in 10 ml of absolute DMF and, under nitrogen, 1.2 g (8.8 mmol) of K2CO3 and 0.97 g (4.4 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added.. The mixture was stirred at room temperature for 16 hours.. It was then evaporated, and the residue was taken up in water and extracted three times with ethyl acetate.. The combined organic phases were dried over MgSO4 and concentrated. 1.8 g of crude product were obtained and were reacted further without purification. 1H-NMR [CDCl3], delta=2.0 (s, 3H); 3.25 (s, 3H); 3.9 (s, 6H)); 5.75 (d, 1H); 5.8 (s, 1H); 7.1-7.3 (m, 10H).

Reference： [1]Patent: US6686369,2004,B1 .Location in patent: Page column 18

12
[ 197971-91-8 ]
[ 113583-35-0 ]
2-(4,6-dimethoxy-2-pyrimidinyloxy)-3,3-diphenylvaleronitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 72h;	Example 14 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3,3-diphenylvaleronitrile 7.0 g (27.9 mmol) of 2-hydroxy-3,3-diphenylvaleronitrile were dissolved in 100 ml of DMF (abs.) and, under nitrogen, 7.57 g (55.7 mmol) of potassium carbonate and 6.1 g (27.9 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added, and the mixture was stirred at room temperature for 72 hours.. The mixture was concentrated under reduced pressure, and the residue was taken up in water and extracted three times with ethyl acetate.. The combined organic phases were dried over MgSO4, and the solvent was evaporated off.. The crude product was chromatographed on silica gel with n-heptane/ethyl acetate (20:1).. 8.8 g (81%) of product were obtained. 1H-NMR [CDCl3], delta=0.8 (t, 3H); 2.45 (dq, 2H); 3.95 (s, 6H), 5.8 (s, 1H); 6.25 (s, 1H); 7.2-7.4 (m, 10H).

Reference： [1]Patent: US6686369,2004,B1 .Location in patent: Page column 19-20

13
[ 67912-61-2 ]
[ 113583-35-0 ]
[ 420138-40-5 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate; In 1,4-dioxane; for 11h;Heating / reflux;	The resulting intermediate n-propyl 4-(2-hydroxy-benzylamino) benzamide (22.7 g, 0.08 mol), 17.44 g (0.08 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine are dissolved into 500 ml dioxane. 22 g (0.16 mol) of potassium carbonate is added at room temperature. The mixture is warm to reflux temperature for 11 hours, then suction filtered. The filter cake is washed with dioxane (50 ml*2) and the mother liquor is concentrated and recrystallized from ethyl acetate, giving 25.4 g of white solid product n-propyl 4-[2-(4,6-dimethoxy-2-pyrimidinyloxy)-benzylamino]-benzamide (I-78). The yield is 75%. m.p.: 96-97 C.; m/z: 423 (M+); 1H-NMR (CDCl3, delta): 7.14-7.88 (m, 8H), 6.51 (d, 1H), 5.78 (s, 1H), 4.45 (s, 2H), 4.19 (t, 2H), 3.80 (s, 6H), 1.77 (m, 2H), 1.03 (t, 3H) ppm

Reference： [1]Patent: US2003/220198,2003,A1 .Location in patent: Page/Page column 8

14
isopropyl 4-(2-hydroxybenzylamino)benzoate [ No CAS ]
[ 113583-35-0 ]
isopropyl 4-({2-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzyl}amino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In 1,4-dioxane; for 12h;Heating / reflux;	The resulting intermediate i-propyl 4-(2-hydroxy-benzylamino)benzamide (23.3 g, 0.082 mol), 18.0 g (0.083 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine are dissolved into 500 ml dioxane. 23 g (0.167 mol) of potassium carbonate is added at room temperature and the mixture is refluxed for 12 hours, then suction filtered. The filter cake is washed with dioxane (50 ml*2) and the mother liquor is concentrated and recrystallized from ethyl acetate, giving 27 g of white solid product i-propyl 4-[2-(4,6-dimethoxy-2-pyrimidinyloxy)-benzylamino]benzamide (I-79). The yield is 78%. m.p.: 83-84 C.; m/z: 423 (M+); 1H-NMR (CDCl3, delta): 7.11-7.86 (m, 6H), 6.52 (m, 2H), 5.77 (m, 1H), 5.22 (m, 1H), 4.43 (m, 2H), 3.80 (s, 6H), 3.70-3.90 (m, 1H), 1.35 (m, 6H)ppm.

Reference： [1]Patent: US2003/220198,2003,A1 .Location in patent: Page/Page column 8

15
C₁₆H₁₈N₂O₃ [ No CAS ]
[ 113583-35-0 ]
[ 420138-68-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate; In 1,4-dioxane; for 11h;Heating / reflux;	[0053] 2.190 g (7.66 mmol) of the resulting compound above, 1.670 g (7.66 mmol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine are dissolved into 30 ml of dioxane. 2.114 g (15.32 mmol) potassium carbonate is added at room temperature. The mixture is refluxed to react for 11 hours, and then suction filtered. The filter cake is washed with 20 ml dioxane and the mother liquor is concentrated. The residual product is added into 10 ml of ethanol while stirring, then suction filtered, to give 2.83 g of white solid product, N-{4-[2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxybenzyl amino]phenyl}acetamide. The yield is 87.0%. The product is purified by recrystallization from ethyl acetate.

Reference： [1]Patent: US2003/220198,2003,A1 .Location in patent: Page/Page column 13

16
[ 7152-24-1 ]
[ 113583-35-0 ]
[ 269719-56-4 ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;	PREPARATION EXAMPLE 2 1-(4,6-Dimethoxypyrimidin-2-yl)-2-methylthiobenzimidazole (Compound Number I-4) 2-Methylthiobenzimidazole (0.50 g) was dissolved in dimethylformamide (10 ml), and sodium hydride (60% purity, oily) (0.13 g) was added thereto at room temperature. After stirring for 1 hour, 2-methylsulfonyl-4,6-dimethoxypyrimidine (0.67 g) was added at room temperature, followed by stirring for 8 hours. Ice water was added, followed by extraction with ethyl acetate, washing with a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 0.80 g of the desired product as a white powder (m.p. 135-137 C.)

Reference： [1]Patent: US6576631,2003,B1

17
[ 33350-17-3 ]
[ 113583-35-0 ]
2-(4,6-dimethoxypyrimidin-2-yl)-oxy-3,3-dimethylbutyronitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With acetic acid; In N-methyl-acetamide; water;	2-(4,6-Dimethoxypyrimidin-2-yl)-oxy-3,3-dimethylbutyronitrile 29.5 g (0.14 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine were suspended in 180 ml of absolute dimethylformamide, and 20 g (0.18 mol) of 3,3-dimethyl-2-hydroxybutyronitrile were added. 5.2 g of 80% strength sodium hydride were then added a little at a time at 0 C., and the mixture was stirred for 3 hours at 60 C. After cooling, 10 g of acetic acid and 20 ml of water were added and the reaction mixture was poured onto 500 ml of water. The resulting precipitate was filtered off under suction and dried. 32.4 g of a white powder having a melting point of 88-89 C. were obtained (yield: 92% of theory).

Reference： [1]Patent: US5318945,1994,A

18
methyl 3-hydroxy-6-(1-pyrrolidinyl)picolinate [ No CAS ]
[ 113583-35-0 ]
methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-pyrrolidinyl)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With potassium carbonate; In N,N-dimethyl-formamide;	EXAMPLE 1 Preparation of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-pyrrolidinyl)picolinate (Compound No. 317) 1.55 g (7 mmol) of methyl 3-hydroxy-6-(1-pyrrolidinyl)picolinate, 1.83 g (8.4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.96 g (7 mmol) of potassium carbonate were added to 50 ml of DMF and reacted at 100 C. for 3 hours. After completion of the reaction, the reaction product was poured into ice water, extracted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off, and the residue was crystallized from diisopropyl ether to obtain the desired product. Amount: 2.11 g (yield: 84%), melting point: 151-153 C.
84%	With potassium carbonate; In N,N-dimethyl-formamide;	EXAMPLE 1 Preparation of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-pyrrolidinyl)picolinate (Compound No. 317) 1.55 g (7 mmol) of methyl 3-hydroxy-6-(1-pyrrolidinyl)picolinate, 1.83 g (8.4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.96 g (7 mmol) of potassium carbonate were added to 50 ml of DMF and reacted at 100C for 3 hours. After completion of the reaction, the reaction product was poured into ice water, extracted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off, and the residue was crystallized from diisopropyl ether to obtain the desired product. Amount: 2.11 g (yield: 84%), melting point: 151-153C

Reference： [1]Patent: US5403816,1995,A
[2]Patent: EP567133,1993,A1

19
methyl 6-amino-3-hydroxypicolinate [ No CAS ]
[ 113583-35-0 ]
[ 152824-30-1 ]

Yield	Reaction Conditions	Operation in experiment
81.3%	With potassium carbonate; In N,N-dimethyl-formamide;	Preparation of methyl 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate A DMF suspension (50 ml) of 3.0 g (17.8 mmol) of methyl 6-amino-3-hydroxypicolinate, 3.9 g (17.8 mmol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine and 1.23 g (8.9 mmol) of potassium carbonate in a 100 ml round bottomed flask, was stirred at 80 C. for 4 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was washed with water, dried, concentrated and purified by silica gel chromatography (n-hexane/AcOEt=1/1+0.1 MeOH) to obtain 4.43 g (yield: 81.3%) of the desired product. Colorless prism crystals, melting point: 74-75 C.

Reference： [1]Patent: US5403816,1995,A

20
methyl 6-acetylamino-3-hydroxypicolinate [ No CAS ]
[ 113583-35-0 ]
[ 152824-41-4 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate; In N,N-dimethyl-formamide;	0.78 g (3.7 mmol) of the obtained methyl 6-acetylamino-3-hydroxypicolinate, 0.81 g (3.7 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.51 g (3.7 mmol) of potassium carbonate were added to 50 ml of DMF, and the mixture was reacted at 80 C. for two hours. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried and concentrated. The oily product thereby obtained was purified by column chromatography to obtain methyl 6-acetylamino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate. Amount: 0.90 g (yield: 70%), melting point: 80-85 C.
70%	With potassium carbonate; In N,N-dimethyl-formamide;	0.78 g (3.7 mmol) of the obtained methyl 6-acetylamino-3-hydroxypicolinate, 0.81 g (3.7 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.51 g (3.7 mmol) of potassium carbonate were added to 50 ml of DMF, and the mixture was reacted at 80C for two hours. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried and concentrated. The oily product thereby obtained was purified by column chromatography to obtain methyl 6-acetylamino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate. Amount: 0.90 g (yield: 70%), melting point: 80-85C

Reference： [1]Patent: US5403816,1995,A
[2]Patent: EP567133,1993,A1

21
methyl 6-methylamino-3-hydroxypicolinate [ No CAS ]
[ 113583-35-0 ]
3-(4,6-dimethoxypyrimidin-2-yl)oxy-6-(N-methylamino)-picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.0%	With potassium hydroxide; potassium carbonate; citric acid; In water; dimethyl sulfoxide;	Process for producing 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-methylaminopicolinic acid (Second method) 10.5 mg (0.0576 mmol) of methyl 6-methylamino-3-hydroxypicolinate, 11.6 mg (0.0532 mmol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine, 8.8 mg (0.637 mmol) of potassium carbonate and 0.5 ml of dry dimethylsulfoxide were mixed. The mixture was stirred at room temperature for 5 hours, and then a 10% potassium hydroxide aqueous solution (corresponding to 90 mg, 0.160 mmol) was added thereto. The mixture was reacted at room temperature for one hour, and then 2.0 ml of water was added to the reaction mixture. Further, 1.0 ml of a 10% citric acid aqueous solution was added thereto, and the mixture was left to stand, whereby crystals precipitated. After being thoroughly precipitated, the crystals were filtered under suction and washed with water. The crystals were dried to obtain 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-methylaminopicolinic acid. Colorless prism crystals, 13.7 mg (yield: 84.0%)
84.0%	With potassium hydroxide; potassium carbonate; citric acid; In water; dimethyl sulfoxide;	Process for producing 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-methylaminopicolinic acid (Second method) 10.5 mg (0.0576 mmol) of methyl 6-methylamino-3-hydroxypicolinate, 11.6 mg (0.0532 mmol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine, 8.8 mg (0.637 mmol) of potassium carbonate and 0.5 ml of dry dimethylsulfoxide were mixed. The mixture was stirred at room temperature for 5 hours, and then a 10% potassium hydroxide aqueous solution (corresponding to 90 mg, 0.160 mmol) was added thereto. The mixture was reacted at room temperature for one hour, and then 2.0 ml of water was added to the reaction mixture. Further, 1.0 ml of a 10% citric acid aqueous solution was added thereto, and the mixture was left to stand, whereby crystals precipitated. After being thoroughly precipitated, the crystals were filtered under suction and washed with water. The crystals were dried to obtain 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-methylaminopicolinic acid. Colorless prism crystals, 13.7 mg (yield: 84.0%)

Reference： [1]Patent: US5403816,1995,A
[2]Patent: EP567133,1993,A1

22
2-trimethylsilylethyl 6-(1-propenyl)salicylate [ No CAS ]
[ 113583-35-0 ]
2-trimethylsilylethyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-propenyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.6%	With potassium carbonate; In ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 1 Preparation of 2-trimethylsilylethyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-propenyl)benzoate (Compound No. 1) In a 50 ml round bottom-flask, there were charged 2-trimethylsilylethyl 6-(1-propenyl)salicylate (3.1 g, 11.0 mmol), 4,6-dimethoxy-2-methylsulfonylpyrimidine (2.4 g, 11.0 mmol), potassium carbonate (1.8 g, 13.0 mmol) and 10 ml of N,N-dimethylformamide (hereinafter referred to as "DMF"), and the resultant mixture was reacted for 1 hour at 80 C. After cooling the reaction mixture, DMF was distilled off under reduced pressure, and the residue thus obtained was dissolved in ethyl acetate, washed with water and a saturated salt water, dried with anhydrous sodium sulfate and concentrated. The resultant residue was purified by silica gel column chromatography to obtain 2.0 g (yield: 47.6%) of the aimed product (colorless transparent viscous liquid).

Reference： [1]Patent: US5401711,1995,A

23
[ 65996-17-0 ]
[ 113583-35-0 ]
ethyl 2-bromo-4-[(4,6-dimethoxy-2-pyrimidinyl)methyl]nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With diisopropylamine In tetrahydrofuran; hexane; water; ethyl acetate	27 (Table D, cpd. no. 523) EXAMPLE 27 Preparation of ethyl 2-bromo-4-[(4,6-dimethoxy-2-pyrimidinyl)methyl]nicotinate (Table D, cpd. no. 523) 7.32 g of ethyl 2-bromo-4-methyl nicotinate and 150 ml of THF are cooled in a dry ice/acetone bath under N2 atmosphere, 30 ml of LDA are added over 5 mins and the mixture stirred for 30 mins. 6.55 g of 2-methylsulphonyl-4,6-dimethoxypyrimidine are added as a solid, rinsing with 50 ml of THF, and the mixture stirred cold for 2 hrs and slowly allowed to warm. The THF is evaporated, ca 75 ml of water added and the mixture extracted three times with methylene dichloride. The combined extracts are evaporated and the residue taken up with 20 ml of 25% ethyl acetate/hexane and flash chromatographed using 2 l of 25% ethyl acetate/hexane in 50 ml fractions. Fractions 7 to 14 are combined, evaporated and placed in a Kugelrohr at ca 105° for 2 hrs. The residue is taken up in 20 ml of 10% ethyl acetate/hexane and flash chromatographed with 2 l 10% ethyl acetate/hexane in 50 ml portions to yield title compound (NMR) in fractions 18 to 32.

Reference： [1]Current Patent Assignee: BASF SE - US5506192, 1996, A

24
[ 150968-04-0 ]
[ 113583-35-0 ]
[ 150967-56-9 ]

Yield	Reaction Conditions	Operation in experiment
50.0%	With potassium carbonate; In N,N-dimethyl-formamide;	EXAMPLE 3 (Process A) Preparation of ethyl 4-(4,6-dimethoxypyrimidin-2-yloxy)-2-methylthiomethylthiophene-3-carboxylate (Compound No. 170) 50 ml of N,N-dimethylformamide was added to 3.5 g (15.1 mmol) of ethyl 4-hydroxy-2-methylthiomethylthiophene-3-carboxylate, 3.3 g (15.1 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 2.1 g (15.2 mmol) of potassium carbonate, and the mixture was heated and stirred at from 90 to 100 C. for 2 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 2.8 g (yield: 50.0%) of the desired product.

Reference： [1]Patent: US5527763,1996,A

25
[ 21240-84-6 ]
[ 113583-35-0 ]
[ 155008-23-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In N,N-dimethyl-formamide;	EXAMPLE 1 Preparation of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-4-formyl-3-methylbenzothiophene (Compound No. 104) A mixture comprising 2.1 g of 4-formyl-5-hydroxy-3-methylbenzothiophene, 2.4 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.8 g of potassium carbonate in 30 ml of N,N-dimethylformamide, was heated and stirred at 70 C. for 3 hours. The mixture was returned to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 3.1 g (yield: 86%) of the desired compound.