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GB2325224A - Preparation of 4,6-dichloropyrimidine - Google Patents

Preparation of 4,6-dichloropyrimidine Download PDF

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Publication number
GB2325224A
GB2325224A GB9807606A GB9807606A GB2325224A GB 2325224 A GB2325224 A GB 2325224A GB 9807606 A GB9807606 A GB 9807606A GB 9807606 A GB9807606 A GB 9807606A GB 2325224 A GB2325224 A GB 2325224A
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range
temperature
phosphorus oxychloride
dichloropyrimidine
dihydroxypyrimidine
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GB9807606A
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GB9807606D0 (en
Inventor
Raymond Vincent Heavon Jones
David John Ritchie
Hannah Sallie Robertson Mccann
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Syngenta Ltd
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Zeneca Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/30Halogen atoms or nitro radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

A process for obtaining 4,6-dichloropyrimidine comprising reacting 4,6-dihydroxypyrimidine with phosphorus oxychloride at 70-110‹C to leave a reaction mixture; and (a) adding water to the reaction mixture at 50-80‹C to give a resulting mixture, and extracting 4,6-dichloropyrimidine from the resulting mixture with an extraction solvent at 30-100‹C; or (b) either (i) when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:4, extracting 4,6-dichloropyrimidine from the reaction mixture with an extraction solvent at 30-100‹C; or (ii) when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:10 or higher, removing excess phosphorus oxychloride by distillation to leave a residue, and extracting 4,6-dichloropyrimidine from the residue with an extraction solvent at 30-100‹C.

Description

CHEMICAL PROCESS The present invention concerns 4,6-dichloropyrimidine, an intermediate in the agrochemical industry.
Processes for preparing 4,6-dichloropyrimidines are reported in the literature (see, for example, GB2287466, EP-A1-0682018, EP-A1-0697406, EP-A 1-0761653 and WO95/2 166).
The present invention provides a process for obtaining 4,6-dichloropyrimidine comprising reacting 4,6-dihydroxypyrimidine with phosphorus oxychloride at a temperature in the range 70-1 10"C to leave a reaction mixture; and (a) adding water to the reaction mixture at a temperature in the range 50-80"C to give a resulting mixture, and extracting 4,6-dichloropyrimidine from the resulting mixture with an extraction solvent at a temperature in the range 30-1000C; or (b)either (i) when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:4 (preferably 1:2 to 1:3.5), extracting 4,6-dichloropyrimidine from the reaction mixture with an extraction solvent at a temperature in the range 30 100"C; or (ii)when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:10 or higher, removing excess phosphorus oxychloride by distillation to leave a residue, and extracting 4,6-dichloropyrimidine from the residue with an extraction solvent at a temperature in the range 30-100 C.
The reaction of 4,6-dihydroxypyrimidine and phosphorus oxychloride may be carried out as a melt or in the presence of a solvent. When a solvent is used, the solvent is the same as the extraction solvent employed.
It is preferred that the molar ratio of 4,6-dihydroxypyrimidine: phosphorus oxychloride is in the range 1:2 to 1:10 (especially 1:2 to 1:7).
In step (a) above it is preferred that the amount of water added is, or is between: the amount required to just flilly hydrolyse any chlorinated phosphorus compounds remaining after the reaction of 4,6-dihydroxypyrimidine and phosphorus oxychloride, and the amount required to partially hydrolyse the phosphorus oxychloride such that there is no phosphorus oxychloride remaining.
Thus, for example, if one mole of 4,6-dihydroxypyrimidine is reacted with five moles of phosphorus oxychloride, and if it is assumed that one mole of 4,6-dichloroxypyrimidine is produced, then it is preferred that the amount of water added is, or is between, 3 and 13 moles.
In step (b)(ii) it is preferred that the distillation is carried out under reduced pressure.
Suitable extraction solvents are solvents that are inert under the conditions used and that are poor solvents for phosphorus by-products produced during the reaction and should have a boiling point such that the solvent and the 4,6-dichloropyrimidine can be easily separated by distillation. Such solvents are unsaturated or saturated hydrocarbons (such as aromatic solvents (for example toluene or xylene), straight or branched chain hydrocarbons (for example pentane, hexane or heptane) or optionally alkyl substituted Cos 7 cycloalkanes (for example cyclohexane, cyclopentane or methylcyclohexane)), ethers (for example methyl tert-butylether) or halogenated aromatics (such as halobenzenes (for example chlorobenzene or fluorobenzene)). Preferred extraction solvents are n-hexane, methylcyclohexane, toluene or cyclohexane. It is particularly preferred that the extraction solvent is methylcyclohexane.
It is preferred that the extraction of 4,6-dichloropyrimidine with an extraction solvent is carried out at a temperature in the range 50-800C.
It is preferred that the extraction of 4,6-dichloropyrimidine with an extraction solvent is by an exhaustive extraction technique such as a multistage extraction (for example counter-current extraction).
When the phosphorus oxychloride reacts with 4,6-dihydroxypyrimidine phosphorus by-products are produced. These by-products can be converted back to phosphorus oxychloride by reacting them with phosphorus pentachloride or a mixture of phosphorus trichloride and chlorine. (See, for example, the disclosures in US3845194 and W094/1 4774.) In one aspect the present invention provides a process for obtaining 4,6dichloropyrimidine comprising reacting 4,6-dihydroxypyrimidine with phosphorus oxychloride, optionally in the presence of a base or a salt of a base, at a temperature in the range 70-110"C to leave a reaction mixture; and (a) adding water to the reaction mixture at a temperature in the range 50-809C to give a resulting mixture, and extracting 4,6-dichloropyrimidine from the resulting mixture with an extraction solvent at a temperature in the range 30-100"C; or (b) and when no base or salt of a base is used, either (i) when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:3.5, extracting 4,6-dichloropyrimidine from the reaction mixture with an extraction solvent at a temperature in the range 30-100"C; or (ii)when the molar ratio of 4,6-dihydroxypyrimidine:phosphoms oxychloride is in the range 1:2 to 1:10 or higher, removing excess phosphorus oxychloride by distillation to leave a residue, and extracting 4,6-dichloropyrimidine from the residue with an extraction solvent at a temperature in the range 30-100 C.
Suitable bases include secondary and tertiary amines, particularly amines of formula R'R2R3N wherein R', R2 and R3 are, independently, C"0 alkyl (especially C,4 alkyl) or C34 cycloalkyl or R' and R2 join to form a piperidine or pyrrolidine ring, or R3 may also be hydrogen. Saturated hindered amines include, for example, N,N-diisopropylethylamine (Hünig's base), triethylamine, N N-diisopropylmethylamine, N.N-diisopropylisobutylamine, X,N-diisopropyl-2-ethylbutylamine, N.N-dicyclohexylmethylamine, N,Ndicyclohexylethylamine, N-tert-butylcyclohexylamine, N-methylpyrrolidine or Nethylpiperidine. Salts of bases include hydrochloride salts, especially hydrochloride salts of any of the foregoing bases.
In another aspect the present invention provides a process for obtaining 4,6dichloropyrimidine comprising reacting 4,6-dihydroxypyrimidine with phosphorus oxychloride in the presence of a base or a salt of a base at a temperature in the range 70 11 00C to leave a reaction mixture; adding water to the reaction mixture at a temperature in the range 50-80"C to give a resulting mixture; and extracting 4,6-dichloropyrimidine from the resulting mixture with an extraction solvent at a temperature in the range 30-100 C.
In yet another aspect the present invention provides a process for obtaining 4,6dichloropyrimidine comprising reacting 4,6-dihydroxypyrimidine with phosphorus oxychloride in the absence of a base or a salt of a base at a temperature in the range 70-11 00C to leave a reaction mixture; adding water to the reaction mixture at a temperature in the range 50-80"C to give a resulting mixture; and extracting 4,6-dichloropyrimidine from the resulting mixture with an extraction solvent at a temperature in the range 30-100 C.
In a flirther aspect the present invention provides a process for obtaining 4,6dichloropyrimidine comprising reacting 4,6-dihydroxypyrimidine with phosphorus oxychloride, optionally in the presence of a base or a salt of a base, at a temperature in the range 80-90"C to leave a reaction mixture; and (a) adding water to the reaction mixture at a temperature in the range 60-80"C to give a resulting mixture, the amount of water being, or being between, the amount required to just fully hydrolyse any chlorinated phosphorus compounds remaining after the reaction of 4,6-dihydroxypyrimidine and phosphorus oxychloride, and the amount required to partially hydrolyse the phosphorus oxychloride such that there is no phosphorus oxychloride remaining; and extracting 4,6-dichloropyrimidine from the resulting mixture with methylcyclohexane at a temperature in the range 50-80"C; or (brand when no base or salt of a base is used, either (i) when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:3.5, extracting 4,6-dichloropyrimidine from the reaction mixture with methylcyclohexane at a temperature in the range 50-80"C; or (ii)when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:10 or higher, removing excess phosphorus oxychloride by distillation to leave a residue, and extracting 4,6-dichioropyrimidine from the residue with methylcyclohexane at a temperature in the range 50-80"C.
Examples 1, 3, 4, 5, 6, 7 and 8 illustrate the invention. Example 2 does not form part of the present invention. Throughout the Examples the abbreviation hplc means high pressure liquid chromatography.
EXAMPLE 1 4,6-Dihydroxypyrimidine (5g, 1 equivalent) and phosphorus oxychloride (15g, 2.2 equivalents) were stirred at 85-900C for 2 hours. The reaction mixture was cooled to 600C and methylcyclohexane added. The methylcyclohexane was separated and the reaction mixture extracted 6 times with methylcyclohexane (total 130ml of methylcyclohexane used).
The methylcyclohexane extracts were combined and evaporated in vacuo to leave 4,6dichloropyrimidine (3.0g, 99% pure by qualitative hplc; no phosphorus detected by 31P NMR).
EXAMPLE 2 4,6-Dihydroxypyrimidine (20g, 1 equivalent) and phosphorus oxychloride (136.6g, 5 equivalents) were stirred at 900C for 2 hours. The reaction mixture was cooled to 600C and extracted with methylcyclohexane (3 x 150my) at 60-70"C. The methylcyclohexane extracts were combined and evaporated in vacuo to leave 4,6-dichloropyrimidine as an orange, waxy solid. The solid was dried in a dessicator and yielded 4,6-dichloropyrimidine (15.2g, 57.9% pure by quantitative hplc).
EXAMPLE 3 4,6-Dihydroxypyrimidine (20g, 1 equivalent) and phosphorus oxychloride (136.3g, 5 equivalents) were stirred at 90"C for 2 hours. The reaction mixture was cooled and excess phosphorus oxychloride removed by distillation (pressure 180-1 50mm Hg; temperature of reaction mixture 66-70"C; head temperature 46"C) to leave a residue. The residue was extracted at 60-700C with methylcyclohexane (3 x 150ml). The extracts were combined and evaporated in vacuo to leave 4,6-dichloropyrimidine as a crystalline material. The material was dried in a dessicator and yielded 4,6-dichloropyrimidine (11.15g; 98.7% pure by qualitative hplc; only a trace of phosphorus detected by 31P NMR).
EXAMPLE 4 4,6-Dihydroxypyrimidine (20g, 1 equivalent) and phosphorus oxychioride (136.6g, 5 equivalents) were stirred at 90"C for 2 hours. The reaction mixture was cooled to 600C and methylcyclohexane (150rnl) and water (42ml, 13 equivalents; slow addition) were added sequentially maintaining the temperature in the range 60-70"C. The resulting mixture was stirred for 1 hour at 60-700C, the organic layer separated and the aqueous extracted with methylcyclohexane (2 x 150ml). The organic extracts were combined and evaporated in vacuo to leave 4,6-dichloropyrimidine as a white crystalline material (0.2g, 99.8% pure by qualitative hplc; no phosphorus detected by 31P NMR).
EXAMPLE 5 4,6-Dihydroxypyrimidine (20g, 1 equivalent) and phosphorus oxychloride (136.6g, 5 equivalents) were stirred at 900C for 2 hours. The reaction mixture was cooled to 60"C and methylcyclohexane (lSOml) and water (9.6ml, 3 equivalents; slow addition) were added sequentially maintaining the temperature in the range 60-70"C. The resulting mixture was stirred for 1 hour at 60-70"C, the organic layer separated and the aqueous extracted with methylcyclohexane (2 x 150ml). The organic extracts were combined and evaporated in vacuo to leave 4,6-dichloropyrimidine (4.6g, 96.4% pure by qualitative hplc; no phosphorus detected by 31P NMR).
EXAMPLE 6 4,6-Dihydroxypyrimidine (20g, 1 equivalent) and phosphorus oxychloride (60.2g, 2.2 equivalents) were stirred at 900C for 2 hours. The reaction mixture was cooled to 600C and methylcyclohexane (lSOml) added. The methylcyclohexane was separated and the reaction mixture extracted with further amounts of methylcyclohexane (2x150ml). The mt 'icyclohexane extracts were combined and evaporated in vacuo to leave 4,6dichloropyrimidine as a white solid (6.4g, 99.1% pure by qualitative hplc, 97.02% pure by quantitative hplc).
EXAMPLE 7 4,6-Dihydroxypyrimidine (20g, 1 equivalent) and phosphorus oxychloride (82.lug, 3 equivalents) were stirred at 90"C for 2 hours. The reaction mixture was cooled to 600C, methylcyclohexane (lOOm!) added and this was stirred at 600C for 1 hour. The methylcyclohexane was separated and the reaction mixture extracted with further amounts of methylcyclohexane (3x100ml). The methylcyclohexane extracts were combined and evaporated in vacuo to leave 4,6-dichloropyrimidine as yellow crystals (8.5g, 99.7% pure by qualitative hplc, 92.75% pure by quantitative hplc).
EXAMPLE 8 4,6-Dihydroxypyrimidine (20g, 1 equivalent) and phosphorus oxychloride (82.1 g, 3 equivalents) were stirred at 900C for 2 hours. The reaction mixture was cooled and excess phosphorus oxychloride removed by distillation (pressure 150mm Hg, temperature 65-70"C) to leave a residue. The residue was extracted at 60-700C with methylcyclohexane (4 x 1 00ml). The extracts were combined and evaporated in vacuo to leave 4,6dichloropyrimidine as a crystalline material (6.9g; 99.5% pure by qualitative hplc, 93.2% pure by quantitative hplc).

Claims (7)

1. A process for obtaining 4,6-dichloropyrimidine comprising reacting 4,6 dihydroxypyrimidine with phosphorus oxychloride at a temperature in the range 70 110 C to leave a reaction mixture; and (a) adding water to the reaction mixture at a temperature in the range 50-800C to give a resulting mixture, and extracting 4,6-dichloropyrimidine from the resulting mixture with an extraction solvent at a temperature in the range 30 100"C; or (b) either (i) when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:4, extracting 4,6 dichloropyrimidine from the reaction mixture with an extraction solvent at a temperature in the range 30-100 C; or (ii) when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:10 or higher, removing excess phosphorus oxychloride by distillation to leave a residue, and extracting 4,6-dichloropyrimidine from the residue with an extraction solvent at a temperature in the range 30-100 C.
2. A process according to claim 1 comprising reacting 4,6-dihydroxypyrimidine with phosphorus oxychloride, optionally in the presence of a base or a salt of a base, at a temperature in the range 70-110"C to leave a reaction mixture; and (a) adding water to the reaction mixture at a temperature in the range 50-80"C to give a resulting mixture, and extracting 4,6-dichloropyrimidine from the resulting mixture with an extraction solvent at a temperature in the range 30-100 C; or (b) and when no base or salt of a base is used, either (i) when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:
3.5, extracting 4,6-dichloropyrimidine from the reaction mixture with an extraction solvent at a temperature in the range 30-100 C; or (ii) when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:10 or higher, removing excess phosphorus oxychloride by distillation to leave a residue, and extracting 4,6-dichloropyrimidine from the residue with an extraction solvent at a temperature in the range 30-100"C.
3. A process according to claim 1 comprising reacting 4,6-dihydroxypyrimidine with phosphorus oxychloride in the presence of a base or a salt of a base at a temperature in the range 70-110"C to leave a reaction mixture; adding water to the reaction mixture at a temperature in the range 50-80"C to give a resulting mixture; and extracting 4,6-dichloropyrimidine from the resulting mixture with an extraction solvent at a temperature in the range 30-100 C.
4. A process according to claim 1 comprising reacting 4,6-dihydroxypyrimidine with phosphorus oxychloride in the absence of a base or a salt of a base at a temperature in the range 70-110"C to leave a reaction mixture; adding water to the reaction mixture at a temperature in the range 50-80"C to give a resulting mixture; and extracting 4,6 dichloropyrimidine from the resulting mixture with an extraction solvent at a temperature in the range 30-100 C.
5. A process according to claim 1 comprising comprising reacting 4,6 dihydroxypyrimidine with phosphorus oxychloride, optionally in the presence of a base or a salt of a base, at a temperature in the range 80-90"C to leave a reaction mixture; and (a) adding water to the reaction mixture at a temperature in the range 60-80"C to give a resulting mixture, the amount of water being, or being between, the amount required to just fully hydrolyse any chlorinated phosphorus compounds remaining after the reaction of 4,6-dihydroxypyrimidine and phosphorus oxychloride, and the amount required to partially hydrolyse the phosphorus oxychloride such that there is no phosphorus oxychloride remaining; and extracting 4,6-dichloropyrimidine from the resulting mixture with methylcyclohexane at a temperature in the range 50-80"C; or (b) and when no base or salt of a base is used, either (i) when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:3.5, extracting 4,6-dichloropyrimidine from the reaction mixture with methylcyclohexane at a temperature in the range 50-80"C; or (i)when the molar ratio of 4,6-dihydroxypyrimidine:phosphorus oxychloride is in the range 1:2 to 1:10 or higher, removing excess phosphorus oxychloride by distillation to leave a residue, and extracting 4,6-dichloropyrimidine from the residue with methylcyclohexane at a temperature in the range 50-80"C.
6. A process according to claim 1 substantially as described in any one of Examples 1, 3, 4,5,6,7or8.
7. 4,6-Dichloropyrimidine whenever made by a process claimed in any one of claims 1 to6.
GB9807606A 1997-05-14 1998-04-08 Preparation of 4,6-dichloropyrimidine Withdrawn GB2325224A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001009105A1 (en) * 1999-07-28 2001-02-08 Bayer Aktiengesellschaft Method for the production of 4,6-dichloropyrimidine with the aid of phosgene
WO2001000591A3 (en) * 1999-06-26 2001-05-25 Bayer Ag Method for producing 4,6-dichloropyrimidine
US6441170B1 (en) 1999-06-26 2002-08-27 Bayer Akitnegesellschaft Method of producing 4,6-dichloropyrimidine with acid chlorides
CN102675216A (en) * 2012-03-20 2012-09-19 河北临港化工有限公司 Novel purifying treatment process for 4,6-dichloropyrimidine
WO2015043093A1 (en) * 2013-09-24 2015-04-02 重庆紫光化工股份有限公司 Method for preparing 4,6-dichloropyrimidine
CN106187912A (en) * 2016-07-19 2016-12-07 安徽广信农化股份有限公司 A kind of production technology of 4,6 dichloro pyrimidines

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2287466A (en) * 1994-03-12 1995-09-20 Huels Chemische Werke Ag Preparation of chloropyrimidines
WO1996023776A1 (en) * 1995-01-30 1996-08-08 Zeneca Limited Process for preparing 4,6-dichloro-pyrimidine
EP0745593A2 (en) * 1995-06-02 1996-12-04 DSM Chemie Linz GmbH Process of preparation of pure 4,6-dichloropyrimidine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2287466A (en) * 1994-03-12 1995-09-20 Huels Chemische Werke Ag Preparation of chloropyrimidines
WO1996023776A1 (en) * 1995-01-30 1996-08-08 Zeneca Limited Process for preparing 4,6-dichloro-pyrimidine
EP0745593A2 (en) * 1995-06-02 1996-12-04 DSM Chemie Linz GmbH Process of preparation of pure 4,6-dichloropyrimidine

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001000591A3 (en) * 1999-06-26 2001-05-25 Bayer Ag Method for producing 4,6-dichloropyrimidine
US6441170B1 (en) 1999-06-26 2002-08-27 Bayer Akitnegesellschaft Method of producing 4,6-dichloropyrimidine with acid chlorides
US6822095B1 (en) 1999-06-26 2004-11-23 Bayer Aktiengesellschaft Method for producing 4,6-dichloropyrimidine
WO2001009105A1 (en) * 1999-07-28 2001-02-08 Bayer Aktiengesellschaft Method for the production of 4,6-dichloropyrimidine with the aid of phosgene
US6441171B1 (en) 1999-07-28 2002-08-27 Bayer Aktiengesellschaft Method for the production of 4,6-dichloropyrimidine with the aid of phosgene
CN102675216A (en) * 2012-03-20 2012-09-19 河北临港化工有限公司 Novel purifying treatment process for 4,6-dichloropyrimidine
CN102675216B (en) * 2012-03-20 2014-10-08 河北临港化工有限公司 Novel purifying treatment process for 4,6-dichloropyrimidine
WO2015043093A1 (en) * 2013-09-24 2015-04-02 重庆紫光化工股份有限公司 Method for preparing 4,6-dichloropyrimidine
CN106187912A (en) * 2016-07-19 2016-12-07 安徽广信农化股份有限公司 A kind of production technology of 4,6 dichloro pyrimidines

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