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4,6-二羟基嘧啶合成4,6-二氯嘧啶的合成Reaction_08_22_2013_145319

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1. 2 Steps

Page 1

Overview

Steps/Stages

1.1R:NaOMe, S:MeOH, rt; rt → 50°C; 2 h, 50°C1.2R:HCl, S:H2O, pH 2-3

2.1R:POCl3, R:Et3N, rt; rt → 110°C; 2 h, 110°C2.2R:NaOH, S:H2O, cooled, pH 6-7

Notes

1) optimization study, optimized on time,temperature and stoichiometry, 2) scalable,optimization study, optimized on time,

temperature and stoichiometry, overall yieldwas 81.7% from formamide, Reactants: 2,Reagents: 5, Solvents: 2, Steps: 2, Stages: 4,Most stages in any one step: 2

References

Synthesis of 4,6-dichloropyrimidineBy Peng, Jun et al

From Jingxi Huagong Zhongjianti, 39(6), 14-17; 2009

CASREACT ®: Copyright © 2013 American Chemical Society. All Rights Reserved. CASREACT contains reactionsfrom CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformationsdatabase compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproducedunder license. All Rights Reserved.2. Single Step

93%

Overview

Steps/Stages

1.1R:POCl3, R:Et3N, rt; rt → 110°C; 2 h, 110°C1.2R:NaOH, S:H2O, cooled, pH 6-7

Notes

scalable, optimization study, optimized ontime, temperature and stoichiometry, overallyield was 81.7% from formamide, Reactants:1, Reagents: 3, Solvents: 1, Steps: 1, Stages:2, Most stages in any one step: 2

References

Synthesis of 4,6-dichloropyrimidineBy Peng, Jun et al

From Jingxi Huagong Zhongjianti, 39(6), 14-17; 2009

SciFinder®Page 2

24%

Overview

Steps/Stages

1.1R:(Cl3CO)2C=O, C:EtN(Pr-i)2, S:MeCN, rt; 10 min, rt; overnight,

55°C

Notes

green chemistry, green chemistry-wastereduction, Reactants: 1, Reagents: 1,

Catalysts: 1, Solvents: 1, Steps: 1, Stages: 1,Most stages in any one step: 1

References

Process for preparation of chlorinated

heterocyclic compounds using triphosgeneBy Wu, Yong et al

From Faming Zhuanli Shenqing, 10125,01 Dec 2010

OverviewSteps/Stages

Notes

SciFinder®

1.11.2

R:POCl3, C:NMP, rt → 90°C; 3-4 h, 90°C

R:PCl3, R:Cl2, 80-85°C; 85°C → 105°C; 2-5 h, 105-110°C

Page 3

Reactants: 1, Reagents: 3, Catalysts: 1, Steps:1, Stages: 2, Most stages in any one step: 2References

A process of preparing 4,6-dichloropyrimidineusing N-methyl-2-pyrrolidone (NMP)By Jha, Bahuran

From Indian Pat. Appl., 2010MU01376, 26Nov 2010

Overview

Steps/Stages

1.1R:NaOMe, S:MeOH, 6 h, 50°C1.2R:HCl, S:H2O, pH 2-3

2.1R:POCl3, C:Et3N, 3 h, 75°C

Notes

1) other acid alternatively used in stage 2, 2)other catalyst alternatively used, Reactants: 2,Reagents: 3, Catalysts: 1, Solvents: 2, Steps:2, Stages: 3, Most stages in any one step: 2References

Preparation of pyrimidine-containing acrylatederivatives as agrochemical fungicidesBy Yang, Guiqiu et al

From Faming Zhuanli Shenqing, 101696192,21 Apr 2010

Overview

SciFinder®

Steps/Stages

1.1R:POCl3, C:Et3N, 3 h, 75°C

Notes

Page 4

other catalyst alternatively used, Reactants: 1,Reagents: 1, Catalysts: 1, Steps: 1, Stages: 1,Most stages in any one step: 1

References

Preparation of pyrimidine-containing acrylatederivatives as agrochemical fungicidesBy Yang, Guiqiu et al

From Faming Zhuanli Shenqing, 101696192,21 Apr 2010

76%

Overview

Steps/Stages

1.1R:SO2Cl2, S:CH2Cl2, S:MeCN, 0.5 h, 0°C

Notes

Reactants: 1, Reagents: 1, Solvents: 2, Steps:1, Stages: 1, Most stages in any one step: 1References

The efficient one-step chlorination ofmethylsulfanyl group on pyrimidine ringsystem with sulfuryl chlorideBy Ham, Young Jin et al

From Tetrahedron Letters, 51(35), 4609-4611; 2010

SciFinder®

Overview

Steps/Stages

1.1R:NaOMe, S:MeOH, 3 h, reflux

2.1R:POCl3, C:PhNMe2, S:POCl3, 12 h, reflux

Notes

Page 5

Reactants: 2, Reagents: 2, Catalysts: 1,

Solvents: 2, Steps: 2, Stages: 2, Most stagesin any one step: 1

References

A convenient route for the synthesis of novel2-substituted [1,2,4]triazolo[1,5-c]pyrimidinederivatives

By Li, Chao et al

From Synlett, (14), 2179-2183; 2010

80%

Overview

Steps/Stages

1.1R:POCl3, C:PhNMe2, S:POCl3, 12 h, reflux

Notes

Reactants: 1, Reagents: 1, Catalysts: 1,

Solvents: 1, Steps: 1, Stages: 1, Most stagesin any one step: 1

References

A convenient route for the synthesis of novel2-substituted [1,2,4]triazolo[1,5-c]pyrimidinederivatives

By Li, Chao et al

From Synlett, (14), 2179-2183; 2010

SciFinder®

Overview

Steps/Stages

1.1R:NaOMe, S:MeOH, 15 min, rt; 1 h, rt → 50°C; 4 h, 50°C; 50°C →

35°C; 30-35°C

1.2R:HCl, S:H2O, pH 2-3

2.1R:POCl3, C:PhNMe2, 15 min, rt; 1 h, rt → 75°C; 3 h, 75°C; 75°C

→ 65°C; 55-65°C2.2R:H2O, 0-5°C; pH 5-7

Notes

Page 6

2) optimization study, optimized on reactiontemperature, reaction time, ratio of materials,43.31% overall yield from material, Reactants:2, Reagents: 4, Catalysts: 1, Solvents: 2,Steps: 2, Stages: 4, Most stages in any onestep: 2

References

Synthesis of 4,6-dichloropyrimidineBy Yang, Gui-qiu et al

From Shenyang Huagong Xueyuan Xuebao,23(2), 118-120; 2009

73%

Overview

Steps/Stages

1.1R:POCl3, C:PhNMe2, 15 min, rt; 1 h, rt → 75°C; 3 h, 75°C; 75°C

→ 65°C; 55-65°C1.2R:H2O, 0-5°C; pH 5-7

Notes

optimization study, optimized on reactiontemperature, reaction time, ratio of materials,43.31% overall yield from material, Reactants:1, Reagents: 2, Catalysts: 1, Steps: 1, Stages:2, Most stages in any one step: 2

References

Synthesis of 4,6-dichloropyrimidineBy Yang, Gui-qiu et al

From Shenyang Huagong Xueyuan Xuebao,23(2), 118-120; 2009

SciFinder®Page 7

Overview

Steps/Stages

1.1R:NaOMe, S:MeOH, 15 min, rt; 30 min, rt → reflux1.2R:H2SO4, S:H2O, pH 2

2.1R:Et3N, R:POCl3, 6 h, rt → reflux

Notes

Reactants: 2, Reagents: 4, Solvents: 2, Steps:2, Stages: 3, Most stages in any one step: 2References

Preparation of 4-amino-6-chloropyrimidineBy Chen, Jian-bing

From Huaxue Shiji, 30(11), 863-8; 2008

90%

Overview

Steps/Stages

1.1R:Et3N, R:POCl3, 6 h, rt → reflux

Notes

Reactants: 1, Reagents: 2, Steps: 1, Stages:1, Most stages in any one step: 1

References

Preparation of 4-amino-6-chloropyrimidineBy Chen, Jian-bing

From Huaxue Shiji, 30(11), 863-8; 2008

SciFinder®Page 8

95%

Overview

Steps/Stages

1.1R:POCl3, 15 min, rt

1.2R:Et3N, 60 min, 40-80°C; 40 min, 60-80°C

Notes

Reactants: 1, Reagents: 2, Steps: 1, Stages:2, Most stages in any one step: 2References

Preparation of 4,6-dichloropyrimidineBy Zhou, Chuilong et al

From Faming Zhuanli Shenqing GongkaiShuomingshu, 1830967, 13 Sep 2006

91%

Overview

Steps/StagesNotes

1.1R:(Cl3CO)2C=O, R:C5H5N, S:Dichloroethane, 30 min, < 5°C; 30 h,Reactants: 1, Reagents: 2, Solvents: 1, Steps:

< 5°C; 1 h, rt; 2 h, 60°C1, Stages: 1, Most stages in any one step: 1

References

Preparation of 4,6-dichloropyrimidine from4,6-dihydroxypyrimidine and diphosgene ortriphosgene

By Kong, Fanlei and Wu, Guoping

From Faming Zhuanli Shenqing GongkaiShuomingshu, 1687036, 26 Oct 2005

SciFinder®Page 9

93%

Overview

Steps/Stages

1.1R:(Cl3CO)2C=O, R:Et3N, S:Me(CH2)4Me, 30 min, < 5°C; 30 h, <

5°C; 1 h, rt; 2 h, 60°C

Notes

Reactants: 1, Reagents: 2, Solvents: 1, Steps:1, Stages: 1, Most stages in any one step: 1References

Preparation of 4,6-dichloropyrimidine from4,6-dihydroxypyrimidine and diphosgene ortriphosgene

By Kong, Fanlei and Wu, Guoping

From Faming Zhuanli Shenqing GongkaiShuomingshu, 1687036, 26 Oct 2005

91%

Overview

Steps/Stages

1.1R:ClCO2CCl3, R:Et3N, S:Dichloroethane, 30 min, < 5°C; 30 h, <

5°C; 1 h, 50°C; 2 h, 70°C

Notes

Reactants: 1, Reagents: 2, Solvents: 1, Steps:1, Stages: 1, Most stages in any one step: 1References

Preparation of 4,6-dichloropyrimidine from4,6-dihydroxypyrimidine and diphosgene ortriphosgene

By Kong, Fanlei and Wu, Guoping

From Faming Zhuanli Shenqing GongkaiShuomingshu, 1687036, 26 Oct 2005

SciFinder®

18. Single Step

Page 10

94%

Overview

Steps/StagesNotes

1.1R:(Cl3CO)2C=O, R:Et3N, S:Dichloroethane, 30 min, < 5°C; 30 h, 5°C; 1 h, rt; 2 h, 60°C1, Stages: 1, Most stages in any one step: 1

References

Preparation of 4,6-dichloropyrimidine from4,6-dihydroxypyrimidine and diphosgene ortriphosgene

By Kong, Fanlei and Wu, Guoping

From Faming Zhuanli Shenqing GongkaiShuomingshu, 1687036, 26 Oct 2005

OverviewSteps/Stages

Notes

SciFinder®

1.1

S:PhCl, rt → 105°C; 00 min, 290 psi

Page 11

high pressure, an accelerating rate calorimetrysphere was used, Reactants: 3, Solvents: 1,Steps: 1, Stages: 1, Most stages in any onestep: 1

References

Process for synthesis of chlorinatedpyrimidines via phosgenation of imidoylchlorides

By Doyle, Timothy J. et al

From U.S. Pat. Appl. Publ., 200400181, 18Mar 2004

Experimental Procedure

Synthesis of 4,6-Dichloropyrimidine from Formamide Hydrochloride and Acetamide Hydrochloride

0.00123 moles of formamide hydrochloride and 0.00109 moles of acetamide hydrochloride were mixedtogether with a solution of 0.00869 moles of phosgene in 4.9 grams chlorobenzene in an ARC sphere.The sphere was then attached to the ARC and the mixture was heated to 105°C. under autogenouspressure. The above reactants were permitted to react for 00 minutes at a maximum pressure of290 psia. The formation of 4,6-dichloropyrimdine was confirmed by LC and GC/MS. 4,6-Dichloropyrimidine

62%

OverviewSteps/Stages

Notes

SciFinder®

1.11.2

S:MeCN, rt → 125°C, 19 psi

125°C, 400 psi; 3 h, 125°C, 320 psi

Page 12

high pressure, parr reactor was used,

Reactants: 3, Solvents: 1, Steps: 1, Stages: 2,Most stages in any one step: 2

References

Process for synthesis of chlorinatedpyrimidines via phosgenation of imidoylchlorides

By Doyle, Timothy J. et al

From U.S. Pat. Appl. Publ., 200400181, 18Mar 2004

Experimental Procedure

Synthesis of 4,6-Dichloropyrimidine in the Parr Reactor (17328-33) A solution of 3.0536 g formamideand 33.1563 g acetonitrile was prepared and 33.1563 g of the solution was charged to a 100 mlHastelloy-C Parr reactor equiped with valves for addition of materials and venting, a condenser,heating and stirring. The reactor was inerted with nitrogen and vented down to ambient pressure.

Separately, 34 grams of phosgene were condensed in a 150 ml stainless steel sampling cylinder. TheParr reactor was sealed and heated to 124.9°C. using a heating mantle with agitation. The reactorpressure built up to 19 psig. Liquid phosgene was charged to the reactor using 400 psig nitrogen. Thereaction temperature dropped immediately due to the addition of room temperature phosgene, but itrose to 140°C. within 10 minutes due to reaction. The combination of nitrogen pressure and reactionraised the reactor pressure to 320 psig within three minutes after phosgene was charged, at whichtime vent line was opened to slowly bring the reactor pressure down to 200 psig. A Hastelloy C tubularcondenser was used to keep phosgene in the reactor. The highest pressure reached was 366 psig atfour minutes after the phosgene charge. The temperature was controlled at 125°C. for three hour. Thereactor was cooled down to room temperature three hours after phosgene was charged.The reactionmixture was collected and 102.9 g acetonitrile was used to wash the reactor. The resulting 137.9 gslurry was filtered and washed with acetonitrile to give 168.6 g filtrate and 12.25 g filter cake. Analysisof both the filtrate and filter cake gave 62.21% yield on 4,6-dichloropyrimidine. 4,6-Dichloropyrimidine,62.21% yield

OverviewSteps/Stages

Notes

SciFinder®

1.1

R:HCl, S:PhCl, rt → 105°C; 1410 min, 227 psi

Page 13

high pressure, an accelerating rate calorimetrysphere was used, Reactants: 3, Reagents: 1,Solvents: 1, Steps: 1, Stages: 1, Most stagesin any one step: 1

References

Process for synthesis of chlorinatedpyrimidines via phosgenation of imidoylchlorides

By Doyle, Timothy J. et al

From U.S. Pat. Appl. Publ., 200400181, 18Mar 2004

Experimental Procedure

Synthesis of 4,6-Dichloropyrimidine from Formamide and Acetonitrile/HCl 0.00255 moles of formamideand 0.18 grams of acetonitrile/HCl were mixed together with a solution of 0.00795 moles of phosgenein 4.5 grams chlorobenzene in an ARC sphere. The sphere was then attached to the ARC and themixture was heated to 105°C. under autogenous pressure. The above reactants were permitted toreact for 1410 minutes at a maximum pressure of 227 psia. The formation of 4,6-dichloropyrimdinewas confirmed by LC and GC/MS. 4,6-Dichloropyrimidine

Overview

Steps/Stages

1.1S:PhCl, rt → 105°C; 100 min, 250 psi

Notes

high pressure, an accelerating rate calorimetrysphere was used, Reactants: 3, Solvents: 1,Steps: 1, Stages: 1, Most stages in any onestep: 1

References

Process for synthesis of chlorinatedpyrimidines via phosgenation of imidoylchlorides

By Doyle, Timothy J. et al

From U.S. Pat. Appl. Publ., 200400181, 18Mar 2004

Experimental Procedure

SciFinder®Page 14

Synthesis of 4,6-Dichloropyrimidine from Formamide and Acetamide 0.001952 moles of formamideand 0.001947 moles of acetamide were mixed together with a solution of 0.007449 moles of phosgenein 4.2 grams chlorobenzene in an ARC sphere. The sphere was then attached to the ARC and themixture was heated to 105°C. under autogenous pressure. The above reactants were permitted toreact for 100 minutes at a maximum pressure of 250 psia. The formation of 4,6-dichloropyrimdine wasconfirmed by LC and GC/MS. 4,6-Dichloropyrimidine

Overview

Steps/Stages

1.1R:HCl, S:MeCN, rt; rt; rt → 52°C1.2overnight; 1.5 h, 74°C

Notes

Reactants: 3, Reagents: 1, Solvents: 1, Steps:1, Stages: 2, Most stages in any one step: 2References

Process for synthesis of chlorinatedpyrimidines via phosgenation of imidoylchlorides

By Doyle, Timothy J. et al

From U.S. Pat. Appl. Publ., 200400181, 18Mar 2004

Experimental Procedure

Synthesis of 4,6-Dichloropyrimidine from Ethylcyanoformate with Acetonitrile and Phosgene.Preparation of saturated HCl-Acetonitrile mixture: To a 50 ml round bottom flask equipped with amagnetic stirrer, diptube for phosgene addition, ipa-dry ice condenser, thermometer, heating mantleand caustic scrubber was charged 35 gm (0.85 mole) of acetonitrile and anhydrous HCl was bubbledvia diptube at a rate of 0.8 gm/min for about an hour at ambient temperature. The saturated

acetonitrile- HCl mixture collected was about 38 gms total Phosgenation Reaction: To the 50 roundbottom flask containing 27 gms (0.6 mole) of the acetonitrile-HCl mixture prepared above was charged23 gins (0.23 mole) ethylcyanoformate. An additional 4 gm of HCl was bubbled through the mixture toinsure HCl saturation. The mixture was heated to 52°C. and then phosgene (17 gms) was bubblesubsurface via the diptube. At end of the day the reaction was stripped of residual phosgene, cooledand allowed to stand overnight. The next day the mixture was heated for an additional 1.5 hrs at 74°C.The reaction mass was analysed by GC-MS which showed (TIC A %) 3.6% DCP. The presence of theDCP was confirmed by spiking the final reaction mass with an authentic DCP sample and comparingthe resulting GC-MS chromatograms. 4,6-Dichloropyrimidine, yield 3.6%

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24. Single Step

Page 15

OverviewSteps/Stages1.1S:PhCl

Notes

alternative prepns. shown, high pressure,

Reactants: 3, Solvents: 1, Steps: 1, Stages: 1,Most stages in any one step: 1

References

Process for synthesis of chlorinatedpyrimidines

By Doyle, Timothy John et al

From PCT Int. Appl., 2002004428, 17 Jan2002

Experimental Procedure

Example 3: Synthesis of 4,6-dichloropyrmidine from formamide and acetamide 0.000886 moles offormamide and 0.002979 moles of acetamide were mixed together with a solution of 0.007448 molesof phosgene in 4.2 grams chlorobenzene in an ARC sphere. The sphere was then attached to the ARCand the mixture was heated to 75°C under autogenous pressure. The above reactants were permittedto react for 1390 minutes at a maximum pressure of 95 psia. The formation of 4,6-dichloropyrimdinewas confirmed by LC and GC/MS. 4,6-dichloropyrimdine

98%

OverviewSteps/Stages

Notes

SciFinder®

1.1

R:O=CCl2, C:MeN+((CH2)7Me)3 •Cl-, S:Xylene

Page 16

alternative prepns. gave lower yields,Reactants: 1, Reagents: 1, Catalysts: 1,

Solvents: 1, Steps: 1, Stages: 1, Most stagesin any one step: 1

References

Synthesis of chlorinated pyrimidinesBy Doyles, Timothy John et al

From PCT Int. Appl., 2002000628, 03 Jan2002

Experimental Procedure

General Procedure for Conversion of 4-chloro-6-methoxypyrimidine (CMP) to 4,6-dichloropyrimidine(DCP): The reaction vessel is a Morton-type flask fitted with a heating mantle, a mechanical agitator, atemperature probe, a phosgene dip pipe (which also serves as a nitrogen inlet when phosgene is notbeing introduced to the reactor), and a dry ice condenser. The dry ice condenser is vented into acaustic scrubber. The reactor is charged with CMP, solvent, and catalyst. The agitator is started andthe mixture is heated to 100 - 110°C. When this temperature range is reached, phosgene gas is

introduced subsurface to the reaction mixture via the dip pipe. Phosgene addition is continued over 3 -5 hours. During the addition, phosgene escaping the reaction mixture is condensed by the dry icecondenser and returned to the reaction mixture. This reflux of phosgene begins shortly after the

phosgene addition is begun, and continues throughout the course of the reaction. After the full chargeof phosgene has been added a post reaction of one hour is usually required to bring the reaction tocompletion. During this time, the reaction mixture continues to stir at the reaction temperature. Theprogress of the reaction is followed by monitoring the disappearance of CMP using liquidchromoatography (and/or gas chromatography). The reaction yield is assessed by liquidchromatographic analysis of the reaction mixture. 4,6-dichloropyrimidine (DCP).

95%

Overview

Steps/Stages

1.1R:Ph3P=O, S:PhCl1.2R:SOCl2

Notes

regioselective, varying solvents or chlorinatingagents decreased yields, Reactants: 1,

Reagents: 2, Solvents: 1, Steps: 1, Stages: 2,Most stages in any one step: 2

References

Regioselective procedure for the productionof 4,6-dichloropyrimidine by the chlorination of4-chloro-6-methoxypyrimidine in the presenceof phosphorus compounds using sulfur-containing chlorination agentsBy Mais, Franz-Josef et al

From Ger. Offen., 19938500, 15 Feb 2001

Experimental Procedure

SciFinder®Page 17

Example 1. 29.0 g of 4-chloro-6-methoxypyrimidine and 5.6 g of triphenylphosphine oxide were addedinto 150 g of chlorobenzene and heated at 140°C under stirring. 35.7 g of thionyl chloride was addeddropwise into the solution over the course of 1 hour. The mixture was then stirred at 140°C. After 6hours, and 11.9 g of thionyl chloride is added dropwise, and then stirred for 6 hours. The mixture wasthen cooled at 25°C. The HPLC analysis showed a content of 9.34% of 4,6-dichloropyrimidine. Thereaction mixture contained only 0.1% 4-chloro-6-methoxypyrimidine (which corresponds to 1.05% ofthe starting material). 4,6-Dichloropyrimidine, Yield: 95.3%. A final weight of 304.1 g.

96%

Overview

Steps/Stages

1.1R:O=CCl2, S:DMF, S:PhMe

Notes

other amines gave lower yields, Reactants: 1,Reagents: 1, Solvents: 2, Steps: 1, Stages: 1,Most stages in any one step: 1

References

Process for the production of 4,6-dichloropyrimidine by the chlorination of 4-chloro-6-methoxypyrimidine with phosgene inthe presence of nitrogen-containingcompounds

By Mais, Franz-Josef et al

From Ger. Offen., 19935322, 01 Feb 2001

Experimental Procedure

Example 1. 14.5 g of 4-chloro-6-methoxypyrimidine and a mixture of 75 ml of N,N-dimethylformamideand 75 ml of xylene were added together into a stirred vessel and heated with stirring at 130 to 135°C.,and then 99.9 g of gaseous phosgene was passed in, at a constant rate over the course of 3 hours.Phosgene residues were then blown out with nitrogen for 3.5 hours. After cooling, 159.7 g of a two-phase reaction mixture was obtained. Phase separation resulted in 60.8 g of upper, clear xylene phaseand 90.7 g of black lower N,N-dimethylformamide phase (residue: loss on phase separation). TheHPLC contents were 15.57% of 4,6-dichloropyrimidine in the xylene phase and 5.38% in the N,N-dimethylformamide phase. 4-chloro-6-methoxypyrimidine is not detectable in both phases. Thiscorresponds to yields of 63.45% 4,6-dichloropyrimidine in the xylene phase and 32.75% in the N,N-dimethylformamide phase, a total of 96.3% 4,6-dichloropyrimidine was obtained.

SciFinder®Page 18

98%

Overview

Steps/Stages

1.1R:Ph3P=O, S:o-Dichlorobenzene1.2R:HCl1.3R:O=CCl2

Notes

lower yields with other acid chlorides,

Reactants: 1, Reagents: 3, Solvents: 1, Steps:1, Stages: 3, Most stages in any one step: 3References

Procedure for the production of 4,6-dichloropyrimidine by the chlorination of 4-chloro-6-methoxypyrimidine with acid

chlorides in the presence of hydrogen halidesBy Mais, Franz-Josef et al

From Ger. Offen., 19929350, 28 Dec 2000

Experimental Procedure

Example 5. 100 parts by weight of o-dichlorobenzene, 2 parts by weight of triphenylphosphine oxideand 10 parts by weight of 4-chloro-6-methoxypyrimidine were introduced into a stirred vessel. The

mixture was then heated to 130 °C, and 10 parts by weight of gaseous hydrogen chloride was blown intogether with 18 parts by weight of phosgene simultaneously at a constant rate over the course of 4hours. The mixture was then cooled to room temperature. 108.5 parts by weight of reaction mixturewas obtained. Therefore HPLC analysis showed contents of 0.08% 4-chloro-6-methoxypyrimidine and9.37% 4,6-dichloropyrimidine. This corresponds to a 4,6-dichloropyrimidine yield of 98.6% of theory.

96%

OverviewSteps/Stages

Notes

SciFinder®

1.11.2

R:Ph3PCl2, S:o-DichlorobenzeneR:HCl

Page 19

lower yields with other acid chlorides,

Reactants: 1, Reagents: 2, Solvents: 1, Steps:1, Stages: 2, Most stages in any one step: 2References

Procedure for the production of 4,6-dichloropyrimidine by the chlorination of 4-chloro-6-methoxypyrimidine with acid

chlorides in the presence of hydrogen halidesBy Mais, Franz-Josef et al

From Ger. Offen., 19929350, 28 Dec 2000

Experimental Procedure

Example 4. 100 parts by weight of o-dichlorobenzene, 10 parts by weight of 4-chloro-6-methoxypyrimidine and 30 parts by weight of triphenyldichlorophosphorane were introduced into a

stirred vessel and heated to 100°C with stirring. Then 20 parts by weight of gaseous hydrogen chloridewere blown in at a constant rate over the course of 4 hours. The mixture was cooled to room

temperature. 141.0 parts by weight of reaction mixture was obtained. HPLC analysis thereof showedcontents of 0.04% of 4-chloro-6-methoxypyrimidine and 7.02% of 4,6-dichloropyrimidine. Thiscorresponds to a 4,6-dichloropyrimidine yield of 96% of theory.

98%

OverviewSteps/Stages1.1

Notes

lower yields with other acid chlorides,

Reactants: 1, Reagents: 3, Steps: 1, Stages:2, Most stages in any one step: 2

References

Procedure for the production of 4,6-dichloropyrimidine by the chlorination of 4-chloro-6-methoxypyrimidine with acid

chlorides in the presence of hydrogen halidesBy Mais, Franz-Josef et al

From Ger. Offen., 19929350, 28 Dec 2000

R:SOCl2,

1.2

R:HCl

Experimental Procedure

Example 7. 100 parts by weight of thionyl chloride, 30 parts by weight of phosphine oxide and 28.9parts by weight of 4-chloro-6-methoxypyrimidine were introduced into a stirred vessel. The mixture wasthen heated to 80 °C with stirring. At this temperature, 25 parts by weight of gaseous hydrogen

chloride was passed in at a constant rate over the course of 4 hours. 130 parts by weight of a reactionmixture was obtained by cooling to room temperature. Therefore HPLC analysis showed 0.30% 4-chloro-6-methoxypyrimidine and 22.61% 4,6-dichloropyrimidine, which corresponds to a 4,6-dichloropyrimidine yield of 98.6% of theory.

SciFinder®Page 20

97%

Overview

Steps/Stages

1.1R:PCl5, S:PhCl1.2R:HCl

Notes

lower yields with other acid chlorides,

Reactants: 1, Reagents: 2, Solvents: 1, Steps:1, Stages: 2, Most stages in any one step: 2References

Procedure for the production of 4,6-dichloropyrimidine by the chlorination of 4-chloro-6-methoxypyrimidine with acid

chlorides in the presence of hydrogen halidesBy Mais, Franz-Josef et al

From Ger. Offen., 19929350, 28 Dec 2000

Experimental Procedure

Example 6. 110 parts by weight of chlorobenzene, 46 parts by weight of phosphorus pentachloride and28.9 parts by weight of 4-chloro-6-methoxypyrimidine were introduced into a stirred vessel. The

mixture was stirred at 100°C and 20 parts by weight of gaseous hydrogen chloride were passed in to aconstant rate in 8 hours. 175 parts by weight of reaction mixture was obtained by cooling to roomtemperature. HPLC analysis thereof showed 0.15% 4-chloro-6-methoxypyrimidine and 16.55% 4,6-dichloropyrimidine. This corresponds to a 4,6-dichloropyrimidine yield of 97.2% of theory.

98%

OverviewSteps/Stages

Notes

SciFinder®

1.11.2

R:POCl3, R:DMFR:HCl

Page 21

lower yields with other acid chlorides,

Reactants: 1, Reagents: 3, Steps: 1, Stages:2, Most stages in any one step: 2

References

Procedure for the production of 4,6-dichloropyrimidine by the chlorination of 4-chloro-6-methoxypyrimidine with acid

chlorides in the presence of hydrogen halidesBy Mais, Franz-Josef et al

From Ger. Offen., 19929350, 28 Dec 2000

Experimental Procedure

Example 3. 80 parts by weight of phosphorus oxychloride, 20 parts by weight of 4-chloro-6-methoxypyrimidine and 2 parts by weight of N,N-dimethylformamide were stirred at 80°C. Over thecourse of 6 hours, 25 parts by weight of gaseous hydrogen chloride were passed into the mixture at aconstant rate. After cooling to room temperature, a reaction mixture in an amount of 87.2 parts byweight was obtained. HPLC analysis showed 0.17% by weight of 4-chloro-6-methoxypyrimidine and23.3% by weight of 4,6-dichloropyrimidine. corresponding to a 4,6-dichloropyrimidine yield of 98.4% oftheory.

100%

Overview

Steps/Stages

1.1R:O=CCl2, C:Ph3P=O, S:PhNO2

Notes

alternative prepn. gave lower yields,Reactants: 1, Reagents: 1, Catalysts: 1,

Solvents: 1, Steps: 1, Stages: 1, Most stagesin any one step: 1

References

Chlorintion process for the preparation of 4,6-dichloropyrimidine from 4,6-dihydroxypyrimidine using

dichlorophosphorane chlorinating agentsBy Whitton, Alan John et al

From U.S., 6160117, 12 Dec 2000

Experimental Procedure

SciFinder®Page 22

EXAMPLE 1 4,6-Dihydroxypyrimidine (5.18 g at 98% strength; 0.045 mol) triphenylphosphine oxide(3.13 g at 98% strength; 0.011 mol) and nitrobenzene (100 ml) were charged to a 250 ml flangedround bottom vessel fitted with down draft agitator, electric stirrer, thermometer, Drykold/acetone coldtrap, pressure equalising dropping funnel, condenser with cold trap, and NaOH scrubber. The systemwas purged with nitrogen to check for leaks, and Drykold/acetone charged to the cold traps. The 4,6-dihydroxypyrimidine mixture was heated to 60°C. before phosgene (18 g at 99% strength; 0.18 mol)was charged via a dip leg. During the addition a small amount of phosgene started to reflux. Thephosgene charge took 20 minutes. The mixture was heated to 105°C. When the temperature was90°C., a large amount of gassing was seen. This resulted in a high amount of phosgene refluxing tothe cold trap. After 20 minutes the reaction mixture was a clear reddish colour. After 40 minutes thegassing rate was very slow, and a small amount of undissolved solid was seen. The reaction mixturewas sampled, then held for a further hour, by which time all gassing had ceased. HPLC analysisindicated that the reaction was complete. The reaction mixture was allowed to cool and unreactedphosgene was removed by purging with nitrogen. The reaction mixture was cooled to 30°C. beforebeing drowned out with water (100 ml). This resulted in a two phase mixture. Both phases weresampled and analysed by HPLC. Analysis indicated a quantitative yield of 4,6-dichloropyrimidine.

OverviewSteps/Stages1.1R:POCl3

Notes

85-90°, extn. with methylcyclohexane,

Reactants: 1, Reagents: 1, Steps: 1, Stages:1, Most stages in any one step: 1

References

Preparation of 4,6-dichloropyrimidine bychlorination of 4,6-dihydroxypyrimidine withphosphorus oxychloride.

By Jones, Raymond Vincent Heavon et alFrom Brit. UK Pat. Appl., 2325224, 18 Nov1998

SciFinder®Page 23

93%

Overview

Steps/Stages

1.1R:POCl3, R:PCl3, R:Cl2

Notes

Reactants: 1, Reagents: 3, Steps: 1, Stages:1, Most stages in any one step: 1

References

Preparation of 4,6-dichloropyrimidine from4,6-dihydroxypyrimidine.By Cramm, Guenther et al

From Ger. Offen., 192533, 16 Apr 1998

86%

Overview

Steps/Stages

1.1R:PCl3, R:POCl3

Notes

85-90.deg., Reactants: 1, Reagents: 2, Steps:1, Stages: 1, Most stages in any one step: 1References

Manufacture of 4,6-dichloropyrimidinesBy Cramm, Guenther et al

From Ger. Offen., 19531299, 27 Feb 1997

SciFinder®Page 24

Overview

Steps/Stages

1.1R:Et3N, R:POCl3

Notes

HYDROXIDE, Reactants: 1, Reagents: 2,Steps: 1, Stages: 1, Most stages in any onestep: 1

References

Preparation of pure 4,6-dichloropyrimidine.By Huber, Wolfgang et al

From Eur. Pat. Appl., 745593, 04 Dec 1996

Overview

Steps/Stages

1.1R:POCl3, C:Et3N

Notes

Reactants: 1, Reagents: 1, Catalysts: 1, Steps:1, Stages: 1, Most stages in any one step: 1References

Preparation of pure 4,6-dichloropyrimidine.By Huber, Wolfgang et al

From Ger. Offen., 19524283, 09 Jan 1997

SciFinder®Page 25

97%

Overview

Steps/Stages

1.1R:POCl3, R:Cl2, R:PCl3, C:104-90-5

Notes

Reactants: 1, Reagents: 3, Catalysts: 1, Steps:1, Stages: 1, Most stages in any one step: 1References

Preparation of polychloropyrimidinesBy Steffan, Guido

From Eur. Pat. Appl., 697406, 21 Feb 1996

81%

Overview

Steps/Stages

1.1R:O=CCl2, R:PhNMe2, S:MeCN

Notes

50°, 5.5 h, Reactants: 1, Reagents: 2,

Solvents: 1, Steps: 1, Stages: 1, Most stagesin any one step: 1

References

Preparation of 4,6-dichloropyrimidine.By Bowden, Martin Charles et al

From PCT Int. Appl., 9529166, 02 Nov 1995

SciFinder®Page 26

Overview

Steps/Stages

1.1C:13453-07-1

Notes

Reactants: 1, Catalysts: 1, Steps: 1, Stages: 1,Most stages in any one step: 1

References

Derivatives of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamideBy Nilsson, Bjoern M. et al

From Journal of Medicinal Chemistry, 31(3),577-82; 1988

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