CN115246791A - Method for synthesizing 6-trifluoromethyl uracil and intermediate thereof - Google Patents
Method for synthesizing 6-trifluoromethyl uracil and intermediate thereof Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 25
- IROWWTVZNHKLLE-UHFFFAOYSA-N 6-(trifluoromethyl)-1h-pyrimidine-2,4-dione Chemical compound FC(F)(F)C1=CC(=O)NC(=O)N1 IROWWTVZNHKLLE-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- -1 amino compound Chemical class 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 239000003513 alkali Substances 0.000 claims abstract description 13
- 239000002585 base Substances 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 230000021736 acetylation Effects 0.000 claims abstract description 3
- 238000006640 acetylation reaction Methods 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 6
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- 238000002360 preparation method Methods 0.000 abstract description 8
- 150000002367 halogens Chemical group 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- GNHDVXLWBQYPJE-UHFFFAOYSA-N saflufenacil Chemical compound C1=C(Cl)C(C(=O)NS(=O)(=O)N(C)C(C)C)=CC(N2C(N(C)C(=CC2=O)C(F)(F)F)=O)=C1F GNHDVXLWBQYPJE-UHFFFAOYSA-N 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 229940035893 uracil Drugs 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 description 1
- LITIWTUEINGYRF-UHFFFAOYSA-N 2,2,2-trichloro-n-(4-fluorophenyl)acetamide Chemical compound FC1=CC=C(NC(=O)C(Cl)(Cl)Cl)C=C1 LITIWTUEINGYRF-UHFFFAOYSA-N 0.000 description 1
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 1
- JPVKCHIPRSQDKL-UHFFFAOYSA-N 3-aminobenzenesulfonamide Chemical compound NC1=CC=CC(S(N)(=O)=O)=C1 JPVKCHIPRSQDKL-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 240000006394 Sorghum bicolor Species 0.000 description 1
- 235000011684 Sorghum saccharatum Nutrition 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic 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
- C07D239/28—Heterocyclic 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/06—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
Abstract
The invention provides a method for synthesizing 6-trifluoromethyl uracil and an intermediate thereof. The method comprises the following steps: reacting an amino compound with a halogenated acetylation reagent under the action of alkali 1 to obtain a compound (I), and performing a second step: reacting the compound (I) obtained in the step one with a compound (II) in a certain solvent under the action of a base 2 to obtain a 6-trifluoromethyl uracil compound, wherein the reaction formula is as follows: the method comprises the following steps:
step two:
wherein R is 1 Is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic hydrocarbonA nitrogen-containing heterocycle; x is halogen; r 2 Is hydrogen, substituted or unsubstituted alkyl; r 3 Is a substituted or unsubstituted alkyl group. The method can be applied to the preparation of the difenosulfuron, and has the following advantages: simple operation, safe and easily obtained raw materials, mild reaction, high yield and suitability for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing 6-trifluoromethyl uracil and an intermediate thereof.
Background
6-trifluoromethyl uracil is an important synthetic intermediate, and can be used for synthesizing agricultural medicines. For example, saflufenacil, developed by basf corporation, is a class of 6-trifluoromethyluracil herbicides (WO 2001083459). Saflufenacil is effective in controlling a variety of weeds in corn, sorghum, soybeans, small grain cereals, cotton and fruit trees, is very safe for crops, and has low volatility, "favorable" toxicology and ecological characteristics. Saflufenacil is known by basf corporation as the most successful new herbicide developed over two decades.
At present, the preparation methods of the 6-trifluoromethyl uracil compounds disclosed in the prior art specifically include the following methods:
patent CN100368392 discloses a preparation method of 6-trifluoromethyl uracil, which is to prepare phenyl isocyanate by reacting an amino intermediate with phosgene, thereby synthesizing uracil. The methods all use highly toxic phosgene, and the intermediate phenyl isocyanate is unstable and easy to generate polymerization side reaction (as shown in a reaction formula), so that the method is not suitable for industrial production.
The patent CN1344258 improves the method for synthesizing 6-trifluoromethyl uracil intermediate, and under the action of alkali, the aminomethyl compound reacts with amine compound to prepare 6- (perfluoroalkyl) uracil compound, but the aminomethyl compound as the raw material has safety problem in preparation of flammable sodium-hydrogen compound, and industrial production is not easy to realize.
Patent CN101821233 describes a method for synthesizing 6-trifluoromethyl uracil, which utilizes 3-aminobenzenesulfonamide to react with chloroformate, and the product is cyclized with 3-amino acrylate to obtain uracil compound. The method is useful for preparing chloroformate which is highly toxic.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a safe, simple and convenient method for synthesizing 6-trifluoromethyl uracil and an intermediate thereof.
A method for synthesizing 6-trifluoromethyl uracil, the method comprising, step one: the amino compound reacts with a halogenated acetylation reagent under the action of alkali 1 to prepare a compound (I), which is represented by the following reaction formula:
wherein, R is 1 Is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic hydrocarbon group, nitrogen-containing heterocycle; x is halogen, preferably chlorine; y is halogen, X 3 CCOO-；
Step two: reacting the compound (I) obtained in the step one with a compound (II) in a certain solvent under the action of a base 2 to obtain a 6-trifluoromethyl uracil compound, wherein the reaction formula is as follows:
wherein, R is 1 And X is as defined above;
said R 2 Is substituted or unsubstitutedAn alkyl group.
The base 1 in the first step is an organic base or an inorganic base, such as alkali metal carbonate, trialkylamine, pyridine and the like, and is preferably pyridine;
the solvent in the second step is an aprotic solvent, such as DMF, DMSO, xylene, and preferably DMF;
the alkali 2 in the second step is alkali metal carbonate or nitrogenous organic alkali, preferably potassium carbonate, sodium carbonate, DMAP and the like;
the molar ratio of the compound (II) to the compound (I) is 1-4; in the second step, the molar ratio of the base 2 to the compound (I) is 1 to 4, preferably 2 to 3;
the reaction temperature is 110-150 ℃, preferably 115-130 ℃.
The method for synthesizing 6-trifluoromethyl uracil can be applied to the preparation of the difenosulfuron, and the preparation method comprises the following steps: the amino compound reacts with halogenated acetyl reagent under the action of alkali 1 to prepare a compound (III), which is represented by the following reaction formula:
wherein, R is 3 Is composed of
Preferably, it is
Wherein R is 4 Is hydrogen, substituted or unsubstituted alkyl; r 5 Is hydrogen, substituted or unsubstituted alkyl; r 6 、R 7 Each independently hydrogen, substituted or unsubstituted alkyl; x is halogen, preferably chlorine; y is halogen, X 3 CCO 2 -；
Step two: reacting the compound (III) obtained in the step one with a compound (II) in a certain solvent under the action of a base 2 to obtain a compound (IV), namely the difenosulfuron, which is represented by the following reaction formula:
wherein, R is 3 、R 4 、R 5 、R 6 、R 7 And X is as defined above;
r is as described 2 Is substituted or unsubstituted alkyl;
the base 1 in the step one is an organic base or an inorganic base, such as alkali metal carbonate, pyridine, triethylamine and the like, and is preferably pyridine;
the solvent in the second step is an aprotic solvent, such as DMF, DMSO, xylene, preferably DMF;
the alkali 2 in the second step is alkali metal carbonate or nitrogenous organic alkali, preferably potassium carbonate, sodium carbonate, DMAP and the like;
the molar ratio of the compound (II) to the compound (III) is 1-4; the molar ratio of the base 2 to the compound (III) is 1 to 4, preferably 2 to 3;
the reaction temperature is 110-150 ℃, preferably 115-130 ℃.
A compound III having the formula:
wherein X is halogen, preferably chlorine; r is 3 Is composed of
Preferably a
Wherein R is 4 、R 5 、R 6 、R 7 Each independently hydrogen, substituted or unsubstituted alkyl.
The compound is preferably
The substituted alkyl or substituted aromatic hydrocarbon group in the invention refers to alkyl or aromatic hydrocarbon group which is substituted by hydrogen atom with one or more substituent groups, wherein the substituent groups are atoms or functional groups. For example, substituents that may be present include, but are not limited to: (C1-C7) alkyl, aryl, heteroaryl, halogen, cyano, nitro, carbonyl, and the like.
Compared with the prior art, the preparation method of 6-trifluoromethyl uracil provided by the invention has the following advantages:
(1) Avoiding the use of highly toxic phosgene and chloroformate compounds. The preferred trichloroacetyl chloride reagent is low in toxicity, safe and easy to obtain, and is suitable for industrial production;
(2) The trichloroacetamide intermediate is stable, and the preparation and use of unstable isocyanate intermediates (highly sensitive to water, self-polymerization and the like) are avoided.
(3) The total reaction yield is high, and the method is suitable for industrial production.
Detailed Description
The following examples further illustrate some of the features of the present invention, but the invention is not limited by the following examples in its content and scope of protection
Example 1:
under the protection of nitrogen, DCM (5 mL), the compound N- (2-chloro-4-fluoro-5-amino-benzoyl) -N '-isopropyl-N' -methylsulfonamide (0.32 g) and pyridine (0.1 g) were sequentially added into a 25mL three-necked flask, stirred and cooled, trichloroacetyl chloride (0.2 g) was added dropwise, the temperature was controlled at 0-5 ℃, and the temperature was maintained until the reaction of the raw materials was completed. Water and DCM were added, the organic layer was washed with water, with aqueous sodium bicarbonate, dried and concentrated to give N- [ 2-chloro-4-fluoro-5- { (trichloroethoxycarbonyl) -amino } benzoyl ] -N '-isopropyl-N' -methylsulfonamide as a yellow solid, 0.46 g.
Nuclear magnetic data of intermediate: 1 H NMR(500MHz,CDCl 3 )δ8.54(d,J＝8.0Hz,1H),8.52(s,1H),7.25(d,J＝10.0Hz,1H),4.24(dq,J＝13.4,6.7Hz,1H),2.90(s,3H),1.16(s,3H),1.15(s,3H).
N 2 under protection, DMF3ml, N- [ 2-chloro-4-fluoro-5- { (trichloroethoxycarbonyl) -amino } benzylAcyl radical]-N '-isopropyl-N' -methylsulfonamide (0.32 g), 3-amino-4, -ethyl trifluorocrotonate (0.366 g), potassium carbonate (0.18 g), reacted at 120 ℃ for 3 hours, cooled to room temperature, added with water and ethyl acetate to react, the aqueous layer was made acidic, extracted with ethyl acetate, the organic layer was washed and concentrated to give 0.28g of a product. The yield thereof was found to be 84%.
Nuclear magnetic data:
1 H NMR(500MHz,DMSO-d6)δ12.83(s,1H),12.28(s,1H),7.83(d,J＝9.5Hz,1H),7.78(d,J＝7.6Hz,1H),6.46(s,1H),4.10(dq,J＝13.3,6.6Hz,1H),2.83(s,3H),1.14(d,J＝6.7Hz,6H).
example 2:
N 2 under the protection, 5mL of DCM, the compound para-fluoroaniline (1.11 g) and pyridine (0.87 g) are sequentially added into a reaction flask, stirred and cooled, trichloroacetyl chloride (1.85 g) is added dropwise, and the T is maintained<The reaction is basically completed at the temperature of 8 ℃. DCM and water were added and the organic layer was washed with water, sodium bicarbonate solution, dried and concentrated to give 2.5g of a solid.
Into a reaction flask, 5ml of DMF, the compound N-p-fluorophenyl trichloroacetamide (0.5 g), and ethyl 3-amino-4, 4-trifluorocrotonate (0.73 g), sodium carbonate (0.5 g), N 2 Under protection, heating to 130 ℃, reacting for 2h, cooling, adding water and ethyl acetate for extraction, adjusting the water layer to acidity, extracting with ethyl acetate, washing the organic layer, and concentrating to obtain 0.43g of product with the yield of 80%.
Nuclear magnetic data: 1 H NMR(500MHz,DMSO-d6)δ12.51(s,1H),7.38–7.33(m,2H),7.30(dd,J＝12.2,5.5Hz,2H),6.35(s,1H).
example 3:
DCM (25 ml), n-butylamine (5 g) and pyridine (6.45 g) are added into a 100ml three-neck flask in sequence under the protection of nitrogen, the temperature is reduced to 0-5 ℃ by stirring, then trichloroacetyl chloride (14.8 g) is added dropwise, the temperature is controlled to 0-5 ℃ until the raw materials react completely. Water and DCM were added to the reaction system, washed with water by layers, washed with sodium bicarbonate solution, dried and concentrated to give 14.2g of yellow liquid N-trichloroacetyln-butylamine.
N 2 Adding DMF3ml and N-trichloroacetyl N-butyl into a reaction bottle under protectionAmine (1 g), 3-amino-4, 4-trifluoro-ethyl crotonate (1.1 g) and sodium carbonate (0.54 g), stirring, heating to 130 deg.C, reacting for 3 hr, cooling, adding water and ethyl acetate, and extracting. The aqueous layer was made acidic, extracted with ethyl acetate, the organic layer was washed and concentrated to give 0.97g of product in 90% yield.
Nuclear magnetic data: 1 H NMR(500MHz,CDCl 3 )δ10.15(s,1H),6.14(s,1H),4.00–3.88(m,2H),1.68–1.55(m,4H),1.43–1.31(m,2H),0.95(t,J＝7.4Hz,3H).
Claims (10)
1. a method for synthesizing 6-trifluoromethyl uracil comprises the following steps,
the method comprises the following steps: the amino compound reacts with a halogenated acetylation reagent under the action of alkali 1 to obtain a compound (I), which is represented by the following reaction formula:
wherein, R is 1 Is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic hydrocarbon group, or nitrogen-containing heterocycle; x is halogen; y is halogen, X 3 CCOO-；
Step two: reacting the compound (I) obtained in the step one with a compound (II) in a certain solvent under the action of a base 2 to obtain a 6-trifluoromethyl uracil compound, wherein the reaction formula is as follows:
wherein, R is 1 And X is as defined above;
said R 2 Is a substituted or unsubstituted alkyl group.
2. The method of claim 1, wherein the base 1 is an organic base or an inorganic base; the solvent is an aprotic solvent; the alkali 2 is alkali metal carbonate or nitrogen-containing organic alkali.
3. The process of claim 1, wherein X is chlorine; the alkali 1 is alkali metal carbonate, trialkylamine and pyridine; the solvent is DMF, DMSO or xylene; the alkali 2 is potassium carbonate, sodium carbonate and DMAP.
4. The process of claim 3, wherein the base 1 is pyridine; the solvent is DMF.
5. The method according to claim 1, wherein the molar ratio of compound (II) to compound (I) is 1 to 4; the molar ratio of the base 2 to the compound (I) is 1 to 4; the reaction temperature is 110-150 ℃.
6. The process according to claim 5, wherein the molar ratio of the base 2 to the compound (I) is 2 to 3; the reaction temperature is 115-130 ℃.
7. A compound III of the formula:
wherein X is halogen;
R 3 is composed of
R 4 、R 5 、R 6 、R 7 Each independently hydrogen, substituted or unsubstituted alkyl.
8. A compound according to claim 7, wherein X is chloro.
9. The compound of claim 8, which isCharacterized in that R 3 Is composed of
R 5 、R 6 、R 7 Each independently hydrogen, substituted or unsubstituted alkyl.
10. The compound of claim 9, wherein compound III has the following structural formula:
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| CN1989111A (en) * | 2004-07-22 | 2007-06-27 | 巴斯福股份公司 | Method for the production of 3-phenyl(thio)uracils and dithiouracils |
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