US5034529A
Expired / Lapsed
US
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Process for the production of thiophosphoric acid esters of hydroxypyrimidines
Assignee: Novartis Corp
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Filing: 1989-03-03
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Granted: 1991-07-23
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Expires: 2009-03-03
Abstract
Abstract In a process for the production of a thiophosphoric acid ester of formula I ##STR1## wherein R 1 is lower alkyl, lower alkenyl, lower alkoxy(lower)alkyl or lower alkylmercapto(lower)alkyl, R 2 is hydrogen, lower alkyl or lower alkenyl and R 3 and R 4 are lower alkyl, which comprises reacting a dialkyl phosphoric acid halide of formula II ##STR2## wherein Hal is chlorine or bromine and R 3 and R 4 are as defined hereinabove, with a hydroxypyrimidine of formula III ##STR3## wherein R 1 and R 2 have the significance given to them above, at elevated temperatures and in the presence of an organic solvent and an acid-binding agent, the improvement which comprises adding the reactant of formula II to an essentially dry mixture of the hydroxypyrimidine of formula III and the acid-binding agent in the presence of a low molecular weight water-insoluble aliphatic or cycloaliphatic ketone as organic solvent after removing the water of reaction from said mixture.
Inventors
- 👤 William A. Freeman
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-29 17:59
CPC Classifications
C; C07; C07F; C07F9/00; C07F9/02; C07F9/547; C07F9/645; C07F9/6509; C07F9/6512
Claims Analysis
Total Claims: 20
Claim 1
Independent Claim
159 words
In a process for the production of a thiophosphoric acid ester of formula I ##STR7## wherein R 1 is lower alkyl, lower alkenyl, lower alkoxy(lower)alkyl or lower alkylmercapto(lower)alkyl, R 2 is hydrogen, lower alkyl or lower alkenyl and R 3 and R 4 are lower alkyl, which comprises reacting a dialkyl phosphoric acid halide of formula II ##STR8## wherein Hal is chlorine or bromine and R 3 and R 4 are as defined hereinabove, with a hydroxypyrimidine of formula III ##STR9## wherein R 1 and R 2 have the significance given to them above, at elevated temperatures and in the presence of an organic solvent and an acid-binding agent, the improvement which comprises adding the reactant of formula II to an essentially dry mixture of the hydroxypyrimidine of formula III and the acid-binding agent in the presence of a lower molecular weight water-insoluble aliphatic or cycloaliphatic ketone as organic solvent after removing the water of reaction from said mixture.
Claim 2
Dependent Claim
159 words
In a process for the production of a thiophosphoric acid ester of formula I ##STR7## wherein R 1 is lower alkyl, lower alkenyl, lower alkoxy(lower)alkyl or lower alkylmercapto(lower)alkyl, R 2 is hydrogen, lower alkyl or lower alkenyl and R 3 and R 4 are lower alkyl, which comprises reacting a dialkyl phosphoric acid halide of formula II ##STR8## wherein Hal is chlorine or bromine and R 3 and R 4 are as defined hereinabove, with a hydroxypyrimidine of formula III ##STR9## wherein R 1 and R 2 have the significance given to them above, at elevated temperatures and in the presence of an organic solvent and an acid-binding agent, the improvement which comprises adding the reactant of formula II to an essentially dry mixture of the hydroxypyrimidine of formula III and the acid-binding agent in the presence of a lower molecular weight water-insoluble aliphatic or cycloaliphatic ketone as organic solvent after removing the water of reaction from said mixture.
Claim 3
Dependent Claim
34 words
A process of claim 1, wherein the organic solvent is selected from branched and straight chain C 5 -C 8 aliphatic ketones and cyclic ketones containing a total of 5 to 7 carbon atoms.
Claim 4
Dependent Claim
15 words
A process of claim 2, wherein the organic solvent is methyl isobutyl ketone or cyclohexanone.
Claim 5
Dependent Claim
22 words
A process of claim 2, wherein there is employed 1.5 to 3 parts of solvent per part of compound of formula III.
Claim 6
Dependent Claim
35 words
A process of claim 1, wherein the hydroxypyrimidine of formula III is present in 2-20% molar excess and the acid-binding agent is present in 1-18% molar excess, both relative to the compound of formula II.
Claim 7
Dependent Claim
12 words
A process of claim 1, wherein the acid-binding agent is sodium hydroxide.
Claim 8
Dependent Claim
24 words
A process of claim 1, wherein the reactant of formula II is O,O-diethyl thiophosphoric acid chloride and the reactant of formula III is 2-isopropyl-6-methyl-4-hydroxypyrimidine.
Claim 9
Dependent Claim
46 words
A process of claim 1, wherein 1 mole of O,O-diethyl thiophosphoric acid chloride is added to an essentially dry mixture of 1.06-1.12 moles of 2-isopropyl-6-methyl-4-hydroxypyrimidine and 1.04-1.08 moles of sodium hydroxide, at an initial reaction temperature of 45°-85° C., in methyl isobutyl ketone as organic solvent.
Claim 10
Dependent Claim
50 words
A process of claim 1 wherein said acid-binding agent is added to a mixture of said hydroxypyrimidine of formula III in said low molecular weight water-insoluble aliphatic or cycloaliphatic ketone and all water is removed by distillation of the water azeotrope prior to addition of the compound of formula II.
Claim 11
Dependent Claim
21 words
A process of claim 1 wherein said acid binding agent is added in the form of an aqueous dispersion or solution.
Claim 12
Dependent Claim
22 words
A process of claim 10, wherein the acid binding agent is in the form of about a 50% aqueous sodium hydroxide solution.
Claim 13
Dependent Claim
35 words
A process of claim 10, wherein the hydroxypyrimidine of formula III is present in 2-20% molar excess and the acid-binding agent is present in 1-18% molar excess, both relative to the compound of formula II.
Claim 14
Dependent Claim
15 words
A process of claim 12, wherein the acid-binding agent is about 50% aqueous sodium hydroxide.
Claim 15
Dependent Claim
24 words
A process of claim 10, wherein the reactant of formula II is O,O-diethyl thiophosphoric acid chloride and the reactant of formula III is 2-isopropyl-6-methyl-4-hydroxypyrimidine.
Claim 16
Dependent Claim
57 words
A process of claim 13 wherein 1.04-1.08 moles of about 50% aqueous sodium hydroxide is added to 1.06-1.12 moles of 2-isopropyl-6-methyl-4-hydroxypyrimidine in methyl isobutyl ketone as solvent, all water is removed by azeotropic distillation and one mole of O,O-diethyl thiophosphoric acid chloride is added to the essentially dry mixture at an initial reaction temperature of 45°-85° C.
Claim 17
Dependent Claim
20 words
A process of claim 1 wherein said acid binding agent is added in the form of a finely divided solid.
Claim 18
Dependent Claim
15 words
A process of claim 16, wherein the acid-binding agent is finely divided solid sodium hydroxide.
Claim 19
Dependent Claim
35 words
A process of claim 17, wherein the hydroxypyrimidine of formula III is present in 2-20% molar excess and the acid-binding agent is present in 1-18% molar excess, both relative to the compound of formula II.
Claim 20
Dependent Claim
57 words
A process of claim 17 wherein 1.04-1.08 moles of finely divided solid sodium hydroxide is added to 1.06-1.12 moles of 2-isopropyl-6-methyl-4-hydroxypyrimidine in methyl isobutyl ketone as solvent, all water is removed by azeotropic distillation and one mole of O,O-diethyl thiophosphoric acid chloride is added to the essentially dry mixture at an initial reaction temperature of 45°-85° C.
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 1994-07-22 | 1995-01-21 | 1995-07-23 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1998-07-22 | 1999-01-21 | 1999-07-23 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2002-07-22 | 2003-01-21 | 2003-07-23 | $7700.00 | Window Closed / Lapsed |