HU213938B - Process for the production of pirimidine derivatives - Google Patents

Abstract

 In the general formula of pyrimidine derivatives (I), R0 is halo, R5SO2- is a general formula wherein R5 is a C1-4 alkyl group, or R0 is a (a) generic tube moiety in which R1 and R2 are both hydrogen, R3 is 1-4 carbon atoms, cyclic pellet, R4 is a cycloalkyl ring having 3 to 6 carbon atoms, or a 3-6 carbon atoms cyclically-substituted cyclic hollow core substituted with a metal tube or a mortar, i.e., if R0 is (a) a general-purpose tuber, R3 can only be a mainstream cores. ŕ

Description

The present invention relates to novel pyrimidine derivatives of general formula (I).

The new compounds (I) wherein Ro is halogen, R ₅ SO ₂ - group wherein

R5 is C1-C4 alkyl, or Ro is a radical of formula (a) wherein:

Ri and _R2 are both hydrogen,

R ₃ represents C 1-4 alkyl, cyclopropyl, methyl cyclopropyl, or mono-substituted by formyl group (-CHO);

R 4 is C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl monosubstituted with methyl or halogen, provided that when R ₃ is R _{3 is} only formyl.

One of the subgroups of compounds of the present invention is the compound of formula (IA)

Ro is halogen, R _{5 is} SO ₂ , wherein R 5 is as defined above,

R ₃ 'is as defined above for R ₃ ,

R4 'is as defined above.

When Rq is halogen, it is preferably chlorine or bromine.

Another subgroup of compounds of the present invention are compounds of formula (IB)

R _b R ₂ and R 4 are as defined above.

As used herein, halogen means fluorine, chlorine, bromine or iodine.

The compounds of formula (I) are valuable intermediates for the preparation of the 2-anilino-pyrimidine derivatives of formula (A) which have a pest control effect. In Formula A, R ₁ , R ₂ , R 4 are as defined above, R ₃ is not as defined above, but -CHO.

The novel intermediates of the present invention can be prepared using known live compounds: for example, compounds of formula IA containing Ro 'are halogen, prepared analogously to St. Angerstein, Bér. Dtsch. Chem. Ges., 34, 3956 (1901) and Kosolapoff, G.M., J. Org. Chem., 26, 1895. (161).

Other methods of preparation analogous to those described herein have already been reported in the literature.

The novel compounds are prepared by:

(a) for the preparation of compounds of formula IA in which:

Ro 'is halogen,

R ₃ 'and R 4 are as described above, treated with an excess of phosphorus oxyhalhalide of the above 2-hydroxypyrimidine derivative of formula (II) wherein R ₃ ' and R 4 are as defined in formula (IA). At a temperature of 110 ° C, or

b) for the preparation of compounds of formula IA in which

R _p 'is a halogen atom, R ₅ SO ₂ - group wherein R5 is as defined above,

R ₃ 'and R 4 are the 2- (alkylthio) pyrimidine derivatives of formula (III) as defined in process (a) wherein R ₃ ', R 4 and R 5 are as defined in formula (IA) in this process. oxidized with an oxidizing agent, or

c) for the preparation of compounds of formula IB wherein R 1, R ₂ and R 4 are as defined above, an acetal of formula IV wherein R 1, R ₂ and R 4 are as defined above, Ro is C 1 -C 4 hydrolyzed in the presence of an alkyl group acid in water or in an aqueous solvent mixture at a temperature of 20-100 ° C.

Process (a) may be carried out with or without a solvent; the reaction temperature is preferably the reflux temperature of the phosphorus oxyhalide.

Preferably, peroxide is used as the oxidizing agent in process b).

The hydrolysis of process c) is preferably carried out using an inorganic acid, preferably a hydrogen halide such as hydrofluoric acid, hydrochloric acid or hydrobromic acid or sulfuric acid; phosphoric acid or nitric acid and suitable organic acids such as acetic acid or toluenesulfonic acid may also be used.

The aqueous solvent mixture used is preferably an alcohol or dimethylformamide solvent mixture, but other mixtures of the solvents listed below may also be used.

The reaction temperature is preferably 30-60 ° C. In addition to the solvents already mentioned, for example, the following solvents may be used in the processes described above, in addition to the solvents already mentioned, such as halogenated hydrocarbons, in particular chlorinated hydrocarbons, e.g. , carbon tetrachloride, trichloroethane, trichlorethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, 1,1-dichloroethane, 1,2-cis-dichloroethylene, chlorobenzene , fluorobenzene, bromobenzene, dichlorobenzene, dibromobenzene, chlorotoluene, trichlorotoluene, or ethers such as ethyl propyl ether, methyl t-butyl ether, n-butyl ethyl ether, di (n-butyl) ether, diisobutyl ether, diisoamyl ether, diisopropyl ether, anisole, cyclohexylmethyl ether, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, thioanisole, dichloro diethyl ether - or nitro substituted hydrocarbons, such as nitro butane, nitroethane, nitrobenzene, chloronitrobenzene, o-nitrotoluene or nitriles such as acetonitrile, butyronitrile, isobutyronitrile, benzonitrile, m-chlorobenzonitrile, or aliphatic or cycloaliphatic hydrocarbons such as heptane, hexane, octane, nonane, cymol, boiling point 70-190 ° C, benzene fractions, cyclohexane, methylcyclohexane, decalin, petroleum ether, Ugrine, trimethylpentanes such as 2,3,3-trimethylpentane, or esters such as ethyl acetate, acetate acetate, isobutyl acetate, or amides such as formamide, methylformamide, dimethylformamide, or ketones such as acetone, methyl ethyl ketone, or alcohols, particularly lower aliphatic alcohols such as methanol , ethanol, n-propanol, isopropanol and isomers of butanol - or optionally

HU 213 938 Β water. Mixtures of the solvents and diluents listed may also be used.

The following non-limiting Examples illustrate the present invention in greater detail.

Example 1

Preparation of 2-anilino-4-formyl-6-cyclopropylpyrimidine (compound 2.1)

12.3 g (39.3 mmol) of 2-anilino-4- (formyl diethylacetal) -6-cyclopropylpyrimidine, 4 g (39.3 mmol) of concentrated hydrochloric acid and 75 ml of water under vigorous stirring for 14 hours. Heat at 50 ° C and add 2 g (198.6 mmol) of concentrated hydrochloric acid and stir at this temperature for an additional 24 hours. After cooling to room temperature, the beige slurry was added with 50 mL of ethyl acetate and adjusted to pH neutral with 7 mL of 30% sodium hydroxide solution. The ethyl acetate solution was separated, dried over sodium sulfate, filtered and the solvent was evaporated. The tan solid was purified by recrystallization from isopropanol (20 mL) in the presence of activated carbon. The yellow crystals melted at 112-114 ° C (7.9 g, 33 mmol, 84%).

Example 2

Preparation of 2-hydroxy-4-methyl-6-cyclopropylpyrimidine U (g) (100 mmol) and 1-cyclopropyl-1,3-butanedione (12.6 g, 100 mmol) in ethanol (35 ml) were added to concentrated hydrochloric acid (15 ml) at room temperature. The mixture was allowed to stand for 10 days at room temperature and then concentrated in a rotary evaporator at a bath temperature of up to 45 ° C. The residue was dissolved in ethanol (20 ml), after which time the hydrochloride of the reaction product precipitated. Diethyl ether (20 ml) was added with stirring, the white crystals precipitated were filtered off, washed with a mixture of ethanol and diethyl ether and dried. The filtrate was concentrated and recrystallized from ethanol: diethyl ether (1: 2) to give additional hydrochloride. The white crystals have a melting point above 230 DEG C., Yield: 12.6 g (67.5 mmol, 67.5%) hydrochloride.

Example 3

Preparation of 2-chloro-4-methyl-6-cyclopropylpyrimidine (compound 3.1)

2-Hydroxy-4-methyl-6-cyclopropylpyrimidine hydrochloride (52.8 g, 0.24 mol) was added with stirring at room temperature (100 mL, 1.1 mol) and phosphorus oxychloride (117 g, 0.79 mol). ) to a mixture of diethylaniline; while the temperature rises to 63 ° C. The reaction mixture was heated to 110 ° C for 2 hours, then cooled to room temperature and poured into a mixture of ice water and methylene chloride with stirring. The organic layer was separated and washed with neutral aqueous saturated sodium bicarbonate solution. Evaporation of the solvent gave 116.4 g of an oil consisting of the reaction product and diethylaniline. The separation of diethylaniline and purification of the crude reaction product was carried out by column chromatography on silica gel with hexane: diethyl acetate (3: 1). The colorless oil which crystallized after a few days had a refractive index of n ²⁵ = 1.5419, yield 35.7 g (0.21 mol, 87.5%), m.p. 33-34 ° C.

Example 4

a) Preparation of 2- (methylmercapto) -4-methyl-6-cyclopropylpyrimidine

To a solution of 5-methylisothiourea sulfate (69.5 g, 0.25 mole) and anhydrous sodium acetate (41 g, 0.5 mole) in glacial acetic acid (375 mL) was added dropwise 63 g (0.5 mole) over 10 minutes at room temperature. 1-Cyclopropyl-1,3-butanedione and then the mixture was heated under reflux for 14 hours. After heating to room temperature, the resulting material is washed with 100 ml of glacial acetic acid. The filtrate was concentrated in a rotary evaporator and the brown oil was poured into 600 ml of water with stirring. After extraction with methylene chloride (2 x 200 mL), the extracts were concentrated in a rotary evaporator and the residual oil was distilled under high vacuum; b.p. 81-82 ° C / 30 Pa. Yield: 64.8% (0.36 mol, 72%).

b) Preparation of 2- (methylsulfonyl) -4-methyl-6-cyclopropylpyrimidine (compound 4.1) g (0.1 mol) of 2- (methylmercapto) -4-methyl-6-cyclopropylpyrimidine was dissolved. In 100 ml acetic acid and at 0 ° C, stirring was added 28.3 g (0.25 mol) of 30% hydrogen peroxide for 1 hour. After the dropwise addition, the reaction solution was heated to 70 ° C for 2 hours, cooled to room temperature and poured into 800 ml of ice water with stirring. The precipitated white crystals were filtered off and dried, m.p. 74-86 ° C.

The following Tables 1, 2 and 3 list, by way of example, some of the novel compounds of the invention.

Table 1: Compounds of Formula IB

Serial number of compound Ri r ₂ R4 Physical constant 2.1 H H ~ \ L 112-114 ° C 2.2 H H z ^cl * \ l mp: 123-127 ° C 2.3 H H / Hí \ l M.p. 87-90 ° C 2.5 H H / - \ l Mp 128-132 ° C

Table 2: Compounds of formula IA, Rq is halogen

Serial number of compound Fish r ₃ R4 Physical constant 3.1 Cl -ch ₃ - <! Mp: 33-34 ° C 3.2 Cl -ch ₃ _ / I \ l oil n ^ ³ : 1.5432

HU 213 938 Β

Table 2 (continued)

The compound row- Ups- today Fish R ₃ R4 Physical constant 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3:10 3:11 3:12 3:14 3:15 3:17 3:20 3:21 3:22 3:23 3:24 3:28 3:29 Cl Cl Cl Cl Cl Cl Cl Br Cl Cl Cl Cl Cl Br Cl Cl Cl Cl Cl Br -ch ₃ -ch ₃ -ch ₃ -C ₃ H ₇ _ _t zj '\ l ch ₃ -ch ₂ -ch-ch ₃ _ / i \ l -ch ₃ -H n -C ₄ H 9 -ch ₃ -ch ₃ -c ₂ H ₅ -CH ₃ -C ₂ H ₅ CH ₃ sec-C ^ H CH ₃ / "./ [\ l _-CH3 _, z * \, í / i \ l - • 0 - <! ^- '\ z - <! / Hj / Hi - <! • - ^z '\ l • .Zl \ l _?> I \ l z * ^r -d / CH, - <! / - <| - <! CHj - ^Z Í \ l z ^F - <! / Hj, / í \ l Z | \ l M.p. 32-35 ° C M.p. 28-31 ° C M.p. 42-45 ° C

Serial number of compound Fish r ₃ R4 Physical constant 3:30 Br -ch ₃ z ^cl zí 3:31 Cl nC ₃ H ₇ \ l - <! 3:32 Cl _ch ₃ / 3:33 Br -c ₂ h ₅ / H Cl 3:35 Br -c ₂ h ₅ 1 z \ 3:36 Cl -ch ₃ z ^cl - ^z i 3:40 Cl - <! \ l - ^z í • 3:43 Br - <! - <i •

Table 3 Compounds of Formula IA, Rg 'is R5SO2

Serial number of compound Fish r ₃ ' R4 Physical constant 4.1 -ch ₃ -ch ₃ -Z 74-86 ° C 4.2 -ch ₃ -ch ₃ 4.3 nC ₄ H, -ch ₃ - <i 4.4 -ch ₃ -ch ₃ 4.6 4.8 -ch ₃ c ₂ h ₅ -ch ₃ -ch ₃ Z ^r \ l / - <| 4:10 -ch ₃ / H - <[ / H - <i 84-89 ° C 4:12 -ch ₃ -ch ₃ / Hí - <i 4.13 -ch ₃ -ch ₃ Ai, 4:15 -c ₂ h ₅ -ch ₃ -. ^z i '\ l

HU 213 938 Β

Table 3 (continued)

Serial number of compound Fish r ₃ R4 Physical constant 4:16 -ch ₃ C2H5 -Z M.p. 64-68 ° C \ l 4:17 -c ₂ h ₅ -ch ₃ - <[ zi 4:18 nC ₃ H ₇ -ch ₃ \ j CH? I / I 4:19 -ch ₃ -ch ₃ \ l , CH / ^J 4:20 nC ₃ H ₇ -ch ₃ - <i z 4:21 -CH ₃ -ch ₃ _ _> / j '"\ l / zj 4:22 nC ₃ H ₇ -ch ₃ \ l / H 4:24 -ch ₃ C2H5 Zi \ t cl / 4:25 -ch ₃ -ch ₃ zj \ j > CH) Z ' 4.26 C2H5 -ch ₃ .zj \ l zj 4:29 -ch ₃ - \ j \ l Mp 54-58 ° C cl / 4:30 nC ₃ H ₇ -ch ₃ _yj \ l

PATENT CLAIMS

Claims (9)

PATENT CLAIMS A process for the preparation of a pyrimidine derivative of formula (I): wherein: Ro is halogen, R _{5 is} SO ₂ - in which R5 is C1-C4 alkyl, or Ro is a radical of formula (a) wherein: Ri and _R2 are both hydrogen, R ₃ is C 1-4 alkyl, cyclopropyl, cyclopropyl or methyl formally substituted with methyl; R 4 is C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl monosubstituted with methyl or halogen, provided that when R ₃ is a group R _{3 is} only a formyl group, a) for the preparation of compounds of formula IA wherein Ro 'is halogen, R ₃ 'is as defined for R _{3 in the} preamble, and R4 is a 2-hydroxypyrimidine derivative of formula (II) as defined herein, wherein R ₃ 'and R 4 are as defined in formula (IA) and is treated with an excess of phosphorus oxyhalimide at 50-110 ° C. C or b) for the preparation of compounds of formula IA in which Ro 'is a group of the formula R 5 SO ₂ , wherein R 5 is as defined in the present specification, R ₃ 'and R 4 are a 2-alkylthio-pyrimidine derivative of formula (III) as defined in process a) wherein R ₃ , R 4 and R 5 are as defined in formula (IA) in this process. oxidised by an oxidizing agent, or c) (IB) R preparing compounds of the formula: wherein, _R2 and R4 are as defined in the fixed stone First - an acetal of formula (IV) - R wherein R ₂ and R 4 are as defined above, Ro is 1- Hydrolyze in the presence of a C4 alkyl acid in water or aqueous solvent mixture at 20-100 ° C. (Priority: September 27, 1988) Process (a) according to claim 1, characterized in that the reaction is carried out at the reflux temperature of the phosphorus oxyhalide. (Priority: 27.09.1988) 3. A process according to claim 1 for the preparation of pyrimidine derivatives of the formula IA in which Ro 'is chlorine, R ₃ 'is C 1-4 alkyl, R4 is C3-6 cycloalkyl, or mono-methyl or halogen substituted C 3-6 cycloalkyl, wherein the starting material used is (II) 2-hydroxy-pyrimidine derivative of formula wherein R ₃ and R 4 are in as defined in the claim. (Priority: September 28, 1987) Process according to claim 3, characterized in that the reaction is carried out at the reflux temperature of phosphorus oxychloride. (Priority: September 28, 1987) A process according to claim 1 for the preparation of pyrimidine derivatives of the general formula IA wherein Ro 'represents a chlorine atom R ₃ 'is C 1-4 alkyl, cyclopropyl or cyclopropyl monosubstituted with methyl, and R 4 is C 3 -C 6 cycloalkyl, or C 3 -C 6 cycloalkyl monosubstituted with methyl or halogen, characterized in that the starting material is the 2-hydroxypyrimidine derivative (Π) wherein R ₃ 'and R 4 are as defined in this claim. (Priority: April 4, 1988) HU 213 938 Β Process b) according to claim 1, characterized in that the oxidizing agent is a peracid. (Priority: September 27, 1988) Process c) according to claim 1, characterized in that the acid is hydrogen halide or sulfuric acid. (Priority: September 27, 1988) The process c) of claim 1 or the process of claim 7, wherein the aqueous solvent mixture is an alcoholic or dimethylformamide solvent mixture. (Priority: September 27, 1988) Process c) according to claim 1 or process 7 or 8, characterized in that the reaction is carried out at a temperature of 30-60 ° C.