HU207303B - Process for producing substituted pyrimidine derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of a compound of formula (II): wherein R, hydrogen or C1-C4 alkyl are hydrogen, C1-C10 alkyl or C3-6 cycloalkyl, or R6; and R 2 together form a - (CH 2) 4 - or - (CH 2) 5 - group, n is an integer of 0, 1 or 2. The process according to the invention comprises: (a) reacting a compound of formula (VII) with (IV); with a compound of Formula I - R 1; and R2 is as defined in the reaction, b) reacting a compound of formula XII - R (and R2 is as defined in the specification) with ammonia and, if desired, forming a compound of formula (II) wherein n = 0; oxidized to a compound of formula (II) wherein n is 1 or 2, and wherein R and R2 are as defined above H 2 N Nsc HN (IV) HU 207 303 BA description: 8 pages (including 4 sheets)

Description

The present invention relates to a process for the preparation of a substituted pyrimidine derivative of formula II:

R 1 is hydrogen or C 1-6 alkyl,

R _{2 is} hydrogen, C 1-10 alkyl, or

C3-C6 cycloalkyl; or R 1 and R ₂ together form - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ -;

n is 0, l or 2.

The compounds of formula (II) are useful starting materials for the preparation of insecticidal and ectoparasiticidal compounds.

The preparation of compounds of formula (II) may be summarized as follows:

a) Compounds of formula II in which n is 0, for example according to Scheme A.

The N-cyano-dithiocarbonimidic acid dimethyl ester of formula (V) and the salt of formula (VI) formed by reaction with malononitrile are used as starting materials in this process. Trav. Ch 90! 1971, 463; J. Chem. Soc., Chem. Comm. 1974. 350], by cyclization with 5N hydrochloric acid from the salt of Formula VI and then reacting the resulting pyridinidine of Formula VII with a corresponding amine of Formula IV to form a compound of Formula II. where n = 0.

b) Compounds of formula II wherein n is 0 may also be prepared according to Scheme B.

The sodium salt of the urea of formula (IX) in Scheme E and the uracil of formula (X) are known (see J. Chem. Soc., Chem. Comm. 1974, 350; Helv. Chim, Act. 1985, 1155]. The novel substituted pyrimidines of formulas XI and XII are prepared in a manner known per se. Reaction of compound (XII) with ammonia yields compound (II) where n = 0.

c) The compounds of formula II wherein n is 1 or 2 may be prepared in a manner known per se by oxidation of compounds of formula II wherein n = 0 [See, The Chemistry of Heterocyclic Compounds, Volume 16: Pyrimidines , Intersc. Publ. Inc., N. Y., 1959],

The process of the present invention relates to the steps outlined above, and more particularly comprises:

A process for the preparation of compounds of formula II wherein:

R _(is a hydrogen atom, a C1-6 alkyl group;

R _{2 is} hydrogen, C 1-10 alkyl, or C 3-6 cycloalkyl; obsession

R 1 and R _{2 taken} together are a - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ - radical;

n is 0, 1 or 2, characterized in that

a) reacting a compound of formula VII with a compound of formula IV: R ₁ and R ₂ are as defined above; obsession

b) a compound of formula XII

R and R ₂ are reacted with ammonia as defined above and the resulting compound of formula II wherein n is 0 is optionally oxidized to a compound of formula II wherein n is 1 or 2.

While commercial products are more concentrated agents, the final product will usually employ diluted formulations with substantially lower concentrations of the active ingredient.

The agents may contain additional additives, such as stabilizers, antifoams, viscosity regulators, binders, preservatives, and nutrients, or other active ingredients to achieve a specific effect.

Example 1

Preparation of 2-cyclopropylimidino-4-amino-5-cyano-6-methylthiopyrimidine

i) To a solution of 2-cyano-3-cyano-amino-3-methylthioacrylonitrile sodium salt (93 g) in water (425 ml) was added dropwise 650 ml of concentrated hydrochloric acid while cooling with ice water. The reaction mixture is then stirred for about 12 hours at room temperature. The resulting precipitate was filtered and treated with aqueous sodium carbonate solution. The resulting 2-chloro-4-amino-5-cyano-6-methylthiopyrimidine (m.p. 168 ° C) was suspended in acetonitrile (250 ml) and 11.4 g of cyclopropylamine was added dropwise under reflux with vigorous stirring. The reaction mixture is then stirred for about 12 hours and water is added. The precipitate formed is filtered off. There was thus obtained the title compound (XIV) (compound 3.1), m.p. 215-218 ° C.

ii) 20 g of N, N-diethylaniline are slowly added dropwise to a mixture of 18.3 g of 5-cyano-6-methylthioururacil and 80 ml of phosphorus oxychloride. The reaction mixture was refluxed for 1.5 hours and then concentrated. To the residue was added 200 ml of ice water, stirred, filtered and washed with water. After drying, the crude product is chromatographed on silica gel (eluent: 6: 3: 1 toluene-chloroform-acetic acid). 22 g of the thus obtained 2,4-dichloro-5-cyano-6-methylthiopyrimidine (m.p. 118-120 ° C) are dissolved in 200 ml of acetonitrile and at -10 ° C a solution of 11.4 g of cyclopropylamine in 40 ml of acetonitrile is obtained. drip it. The reaction mixture was stirred for 2 hours at room temperature and then poured into 2 liters of ice water. The resulting residue was filtered. 16.1 g of the thus obtained 2-cyclopropylamino-4-chloro-5-cyano-6-methyl-thiopyrimidine (m.p. 139-141 ° C) are stirred in 100 ml of acetonitrile. To the resulting slurry was added 300 ml of 30% aqueous ammonia solution and stirred at reflux for 10 hours at room temperature and for 5 hours. The reaction mixture was cooled, and the resulting solid residue was filtered and washed with water. Recrystallization from 150 ml of methylcellosolve afforded the title compound of the formula (i), m.p. 215-218 ° C.

HU 207 303 Β

Example 2

a) Preparation of 2-diethylamino-4-amino-5-cyano-6-methylsulfonylpyrimidine

2-Diethylamino-4-amino-5-cyano-6-methyl-thiopyrimidine (47.5 g) was added to 650 ml of methylene chloride and then 88.7 g of 3-chloroperbenzoic acid were added without cooling. The reaction mixture was stirred for 2 hours and then filtered. The filtrate was evaporated and the residue was slurried with diethyl ether and filtered. There is thus obtained the title compound (XVII) (compound 3.2), m.p. 170-172 ° C.

b) Preparation of 2-diethylamino-4,6-diamino-5-cyanopyrimidine

To a mixture of 300 ml of 30% aqueous ammonia and 100 ml of 1 acetonitrile was added 26.9 g of 2-diethylamino-4-amino-5-cyano-6-methylsulfonylpyrimidine (a) prepared at room temperature. The reaction mixture is refluxed for about 12 hours, cooled and the precipitate formed is filtered off. It is then treated with water and filtered. The title compound (XVIII) m.p. 222-224 'Con (Compound 1.2) is obtained.

The following compounds of formula II are prepared as described above:

Compound number Ri r ₂ r ₃ n Melting point (° C) 3.3 H -ch ₃ H 0 270-274 3.4 H -C ₃ H ₇ (i) H 0 171-173 3.5 - (CH ₂ ) ₄ - H 0 198-200 3.6 - (CH ₂ ) _s - H 0 204-206 3.7 H -C (CH ₃ ) ₃ H 0 194-196 3.8 H -CH (CH ₃ ) -C ₂ H ₅ H 0 143-145 3.9 H -CH (C ₂ H ₅ ) ₂ H 0 151-153 3:10 -ch ₃ -ch ₃ H 0 216-218 3:11 -c ₂ h ₅ -c ₂ h ₅ H 0 131 3:12 -ch ₃ -c ₂ h ₅ H 0 158-160 3:13 -ch ₃ -C ₄ H ₉ (n) H 0 158-160 3:14 -C ₃ H ₇ (n) -C ₃ H ₇ (n) H 0 160-162 3:15 -C ₄ H ₉ (n) -C ₄ H ₉ (n) H 0 120-122 3:16 H H H 0 270 (during decay) 3:17 H cyclopropyl H 2 167-170 3:18 -ch ₃ -ch ₃ H 2 237-239 3:19 -C ₃ H ₇ (n) -C ₃ H ₇ (n) H 2 222-225 3:20 -C ₄ H ₉ (n) -C ₄ H ₉ (n) H 2 165-167 3:21 -ch ₃ -c ₂ h ₅ H 2 203-205 3:22 - (CH ₂ ) ₄ - H 2 235-237 3:23 - (CH ₂ ) ₅ - H 2 204-207 3:24 -ch ₃ -C ₄ H ₉ (n) H 2 190-191

Patent Claim Point

Claims (2)

Patent Claim Point A process for the preparation of compounds of formula (H) wherein: 50 R 1 is hydrogen or C 1-6 alkyl; R _{2 is} hydrogen, C 1-10 alkyl, or C 3 -C 6 cycloalkyl, or R ₁ and R _{2 taken} together form a - (CH ₂ ) ₄ - or - (CH ₂ ) ₅ group, 55 n being an integer from 0.1 to 2, characterized in that a) reacting a compound of Formula VII with a compound of Formula IV, wherein R ₁ and R ₂ are as defined herein; b) reacting a compound of formula XII, R ₁ and R _{2 as} defined herein, with ammonia and, if desired, oxidizing the resulting compound of formula II wherein n = 0 to a compound of formula II , wherein n is 1 or 2, and wherein R 1 and R ₂ are as defined above.