Patent US4029661A successfully refreshed from Google Patents.
US4029661A
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US
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Process for producing 5-fluorouracil and derivatives thereof in acid and/or alcohol solvents
Assignee: PCR Group Inc
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Filing: 1972-07-13
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Granted: 1977-06-14
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Expires: 1992-07-13
Abstract
Abstract Direct fluorination of uracil, cytosine and their derivatives, in the presence of a non-aqueous solvent, by fluorine gas to produce 5-fluorouracil, 5-fluorocytosine, 5-fluorouracil derivatives and 5-fluorocytosine derivatives is disclosed. The non-aqueous solvent is an acid or alcohol, which can be partly or fully fluorinated or chlorinated, of up to 8 carbon atoms, such as trifluoroacetic acid. Novel compounds produced by the reaction, such as 5,5-difluoro-5,6-dihydro-6-(2,2,2-trifluoroethoxy) uracil are also disclosed. The derivatives and 5-fluorocytosine are useful as germicidal and antineoplastic agents while 5-fluorouracil itself is a known cancer chemotherapy agent.
Inventors
- 👤 Paul D. Schuman
- 👤 Geraldine Westmoreland
- 👤 Roy Anderson
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 16:34
CPC Classifications
C; C07; C07D; C07D239/00; C07D239/02; C07D239/20; C07D239/22
Claims Analysis
Total Claims: 28
Claim 1
Independent Claim
228 words
A process for the fluorination of pyrimidines, said process consisting essentially of reacting, in a solvent of the formula: Cx" 2 y"--(cy" 2 ) n --COOH or Cx 2 y--(cy 2 ) n --CH 2 OH, wherein X and Y are independently hydrogen, bromine, chlorine or fluorine, X" and Y" are independently bromine, chlorine, or fluorine, and n is an integer from 0 to 6, at a temperature of about the solvent freezing point to about the solvent boiling point, a pyrimidine of the formula ##STR24## with at least about a stoichiometric amount of gaseous fluorine to produce a compound of the formula: ##STR25## wherein R 1 is hydrogen, fluorine, chlorine, bromine or lower alkyl, R 2 is hydrogen or lower alkyl, R 3 is R 1 or, taken with R 5 , a 5,6-double bond, R 4 is hydrogen or lower alkyl, R 5 is Cx 2 y--(cy 2 ) n --CH 2 O--, Cx" 2 y"--(cy" 2 ) n --COO--, a 5,6-double bond when taken with R 3 , or a 1,6-double bond when taken with R 6 , R 6 is hydrogen or a 1,6-double bond when taken with R 5 , Y 1 is -NH 2 and Z and Z 1 together are a 3,4-double bond or else Y 1 and Z taken with the 4-carbon atom, are carbonyl and Z 1 is hydrogen.
Claim 2
Dependent Claim
228 words
A process for the fluorination of pyrimidines, said process consisting essentially of reacting, in a solvent of the formula: Cx" 2 y"--(cy" 2 ) n --COOH or Cx 2 y--(cy 2 ) n --CH 2 OH, wherein X and Y are independently hydrogen, bromine, chlorine or fluorine, X" and Y" are independently bromine, chlorine, or fluorine, and n is an integer from 0 to 6, at a temperature of about the solvent freezing point to about the solvent boiling point, a pyrimidine of the formula ##STR24## with at least about a stoichiometric amount of gaseous fluorine to produce a compound of the formula: ##STR25## wherein R 1 is hydrogen, fluorine, chlorine, bromine or lower alkyl, R 2 is hydrogen or lower alkyl, R 3 is R 1 or, taken with R 5 , a 5,6-double bond, R 4 is hydrogen or lower alkyl, R 5 is Cx 2 y--(cy 2 ) n --CH 2 O--, Cx" 2 y"--(cy" 2 ) n --COO--, a 5,6-double bond when taken with R 3 , or a 1,6-double bond when taken with R 6 , R 6 is hydrogen or a 1,6-double bond when taken with R 5 , Y 1 is -NH 2 and Z and Z 1 together are a 3,4-double bond or else Y 1 and Z taken with the 4-carbon atom, are carbonyl and Z 1 is hydrogen.
Claim 3
Dependent Claim
20 words
Process as claimed in claim 1 wherein said solvent is of the formula: Cx" 2 y"--(cy" 2 ) n --COOH--.
Claim 4
Dependent Claim
12 words
Process as claimed in claim 2 wherein said solvent is trifluoroacetic acid.
Claim 5
Dependent Claim
22 words
Process as claimed in claim 1, wherein the reaction solvent has the formula: Cx 2 y--(cy 2 ) n --CH 2 OH.
Claim 6
Dependent Claim
12 words
Process as claimed in claim 4 wherein X and Y are halogen.
Claim 7
Dependent Claim
11 words
Process as claimed in claim 5 wherein said halogen is fluorine.
Claim 8
Dependent Claim
20 words
Process as claimed in claim 1, wherein Y is --NH 2 and Z and Z' together are a 3,4-double bond.
Claim 9
Dependent Claim
22 words
Process as claimed in claim 1 wherein the molar ratio of fluorine to said pyrimidine is from about 1:1 to about 2:1.
Claim 10
Dependent Claim
32 words
Process as claimed in claim 1 wherein an effluent gas stream is discharged from the reaction zone and the reaction is continued at least until fluorine is detected in the effluent gas.
Claim 11
Dependent Claim
12 words
Process as claimed in claim 1, wherein X" and Y" are fluorine.
Claim 12
Dependent Claim
176 words
A process for the fluorination of uracil and derivatives thereof consisting essentially of reacting in a solvent at a temperature of about 0° C. to about the solvent boiling point, a uracil derivative of the formula: ##STR26## with at least about a stoichiometric amount of gaseous fluorine to prepare a compound of the formula: ##STR27## wherein R 1 is a hydrogen, fluorine, chlorine, bromine or lower alkyl, R 2 is hydrogen or lower alkyl, R 3 is hydrogen, fluorine, chlorine, bromine, lower alkyl or taken with R 5 a 5,6-double bond, R 4 is hydrogen or lower alkyl, R 5 is a 5,6-double bond when taken with R 3 or a 1,6-double bond when taken with R 6 and R 6 is hydrogen or a 1,6-double bond when taken with R 5 , the reaction conducted in a solvent which is Cx" 2 y"(cy" 2 ) n --COOH wherein X" and Y" are independently bromine, chlorine or fluorine, and n is an integer from 0 to 6, and heating the resulting product to produce said compound.
Claim 13
Dependent Claim
176 words
A process for the fluorination of uracil and derivatives thereof consisting essentially of reacting in a solvent at a temperature of about 0° C. to about the solvent boiling point, a uracil derivative of the formula: ##STR26## with at least about a stoichiometric amount of gaseous fluorine to prepare a compound of the formula: ##STR27## wherein R 1 is a hydrogen, fluorine, chlorine, bromine or lower alkyl, R 2 is hydrogen or lower alkyl, R 3 is hydrogen, fluorine, chlorine, bromine, lower alkyl or taken with R 5 a 5,6-double bond, R 4 is hydrogen or lower alkyl, R 5 is a 5,6-double bond when taken with R 3 or a 1,6-double bond when taken with R 6 and R 6 is hydrogen or a 1,6-double bond when taken with R 5 , the reaction conducted in a solvent which is Cx" 2 y"(cy" 2 ) n --COOH wherein X" and Y" are independently bromine, chlorine or fluorine, and n is an integer from 0 to 6, and heating the resulting product to produce said compound.
Claim 14
Dependent Claim
12 words
The process of claim 11, wherein each X" and Y" is fluorine.
Claim 15
Dependent Claim
151 words
A process for the fluorination of uracil and derivatives thereof consisting essentially of reacting in a solvent at a temperature of about 0° C to about the solvent boiling point, a uracil derivative of the formula: ##STR28## with at least about a stoichiometric amount of gaseous fluorine to prepare a compound of the formula: ##STR29## wherein R 1 is hydrogen, fluorine, chlorine, bromine or lower alkyl, R 2 is hydrogen or lower alkyl, R 3 is hydrogen, fluorine, chlorine, bromine, or lower alkyl, R 4 is hydrogen or lower alkyl, R 5 is CX 2 Y(CY 2 ) n --CH 2 O--, wherein X, Y and n are defined below, R 6 is hydrogen, the reaction conducted in a solvent which is Cx 2 y--(cy 2 ) n --CH 2 OH wherein X and Y are independently hydrogen, bromine, chlorine or fluorine, and n is an integer from 0 to 6.
Claim 16
Dependent Claim
151 words
A process for the fluorination of uracil and derivatives thereof consisting essentially of reacting in a solvent at a temperature of about 0° C to about the solvent boiling point, a uracil derivative of the formula: ##STR28## with at least about a stoichiometric amount of gaseous fluorine to prepare a compound of the formula: ##STR29## wherein R 1 is hydrogen, fluorine, chlorine, bromine or lower alkyl, R 2 is hydrogen or lower alkyl, R 3 is hydrogen, fluorine, chlorine, bromine, or lower alkyl, R 4 is hydrogen or lower alkyl, R 5 is CX 2 Y(CY 2 ) n --CH 2 O--, wherein X, Y and n are defined below, R 6 is hydrogen, the reaction conducted in a solvent which is Cx 2 y--(cy 2 ) n --CH 2 OH wherein X and Y are independently hydrogen, bromine, chlorine or fluorine, and n is an integer from 0 to 6.
Claim 17
Dependent Claim
20 words
The process of claim 13 wherein the reaction is conducted at a temperature of about 52° to about 75° C.
Claim 18
Dependent Claim
11 words
The process of claim 13 wherein the reaction solvent is trifluoroethanol.
Claim 19
Dependent Claim
22 words
The process of claim 11, wherein the molar ratio of fluorine to said uracil derivative is from about 1:1 to about 2:1.
Claim 20
Dependent Claim
20 words
The process of claim 11, wherein the reaction is continued at least until fluorine is detected in the effluent gas.
Claim 21
Dependent Claim
21 words
The process of claim 11, wherein the reaction solvent is selected from the group consisting of trifluoroacetic acid, and trichloroacetic acid.
Claim 22
Independent Claim
28 words
A method for producing 5-fluorouracil comprising reacting uracil with fluorine in trifluoroacetic acid at a temperature from about 14° to about 58° C in an inert gas atmosphere.
Claim 23
Independent Claim
28 words
A method for producing 5-fluorouracil comprising reacting uracil with fluorine in trifluoroacetic acid at a temperature from about 14° to about 58° C in an inert gas atmosphere.
Claim 24
Dependent Claim
11 words
The method of claim 19, wherein said inert gas is nitrogen.
Claim 25
Dependent Claim
22 words
The process of claim 13 wherein the molar ratio of fluorine to said uracil derivative is from about 1:1 to about 2:1.
Claim 26
Dependent Claim
20 words
The process of claim 13 wherein the reaction is continued at least until fluorine is detected in the effluent gas.
Claim 27
Dependent Claim
11 words
The process of claim 14, wherein X and Y are halogen.
Claim 28
Dependent Claim
10 words
The process of claim 23, wherein said halogen is fluorine.
References Cited (Backward Citations)
US3682917A
Cited
US3846429A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1980-06-13 | 1980-12-13 | 1981-06-14 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1984-06-13 | 1984-12-13 | 1985-06-14 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1988-06-13 | 1988-12-13 | 1989-06-14 | $7700.00 | Window Closed / Lapsed |