DD294255A5 - PROCESS FOR PREPARING TETRAZOLYL SUBSTITUTED PYRIMIDINE DERIVATIVES - Google Patents

Abstract

The invention describes a process for the preparation of tetrazolyl-substituted pyrimidine derivatives. Heterocycles of this type are of interest as intermediates for the synthesis of biologically active compounds. The title compounds are prepared according to the invention by reacting * (formula I) in solvents such as acetonitrile or benzene with carbonyl halides (formula II) in the presence of equimolar amounts of an auxiliary base such as pyridine or triethylamine at temperatures up to the boiling point of the reaction mixture and the * (formula III) with guanidine (formula IV, R3NH2) or Carbonsaeureamidinen (formula IV, R3H, alkyl, aryl) in boiling alcoholic solution in the presence of a basic condensing agent, eg. As sodium alcoholate, brings to the reaction {Pyrimidinderivate; * Intermediates; * Carboxylic acid halides; pyridine; triethylamine; * Guanidine; Carbonsaeureamidine; sodium alcoholate}

Description

mean in the presence of equimolar amounts of an auxiliary base such as pyridine or triethylamine at temperatures up to the boiling point of the reaction mixture umseut and the resulting 1-ary! substituted 5- (1-acyl-2-d! methylamino-vinyl) -1H-tetrazoles III with guanidine (formula IV, R ³ = NH ₂ ) or carboxylic acid amides (formula IV, R ³ = H, alkyl or aryl) in boiling alcoholic (eg methanolic or ethanolic) solution in the presence of a basic condensing agent, e.g. As sodium methoxide or sodium ethoxide, brings to the reaction. The intermediates III are obtained on concentration of the reaction mixture in solid crystalline form together with the hydrohalide of the auxiliary base and are freed from this by washing with water. The reaction components IV (R ³ = NH ₂ , H, alkyl, aryl) can be used in the form of their chelator-stable salts (eg hydrosulfates, hydrochlorides, etc.) and released in the reaction mixture by a corresponding excess ah basic condensing agent.

The starting compounds I are readily accessible by reaction of 3-halo-prop-2-en-1-ylidenedimethyliminium salts with excess sodium azide in alcoholic solution (DD 268690, compare GW FISCHER and M. HERRMANN, J. prakt. Chem ] 963).

The invention will be explained below with reference to 8 embodiments; the yields of V given herein are based on the 1-aryl-5- (2-dimethylamino-vinyl) -1H-tetrazoles I.

embodiments example 1

2-amino-4-methyl-5- (1-phenyl-1H-tetrazol-5-yl) -pyrimidine (V, R ¹ = Ph, R ⁷ = Me, R ³ = NH ₂ )

A hot solution of 2.15 g (10 mmol) of 5- (2-dimethylamino-vinyl) -1-phenyl-1H-tetrazole (I, R ¹ = Ph) in 5 ml of absolute. Acetonitrile and

0.95 g (12 mmol) of dry pyridine is mixed with 0.94 g (12 mmol) of acetyl chloride (II, R ² = Me, X = Cl) and under

Exclusion of moisture 2.5 h. At 80 ° C heated on a water bath. Then you draw the solvent i. Vak. from,

digested the remaining residue with water, filtered off with suction, washed with water and dried over PjO ₆ . The thus obtained

Intermediate III, R ¹ = Ph, R ² = Me, together with 2.25 g (10 mmol) of guanidine sulfate (2IV.H ₂ SO ₄ .0.5 H ₂ O, R ³ = NH ₂ )

20 ml of a 1N ethanolic sodium ethanolate refluxing 3 hr. With magnetic stirring, the

Reaction product already begins to precipitate from the hot solution. After cooling, filtered off with suction, washed with a little Ethanol, then several times with water and dried over P ₂ O ₆ . Yield 1.87g (54%); colorless crystals (from acetonitrile), m.p. Analog receive:

2-Amino-4-methyl-5- [1- (4-methyl-phenyl) -1H-tetrazol-5-yl] -pyrimidine (V, R ¹ = 4-Me-C ₆ H ₄ , R ² = Me , R ³ = NH ₂ ) Yield 83%. Colorless crystals (from acetonitrile), mp. 225-226 ⁰ C.

2-Amino-5- [1- (4-ethyl-phenyl) -1H-tetrazol-5-yl) -4-methylpyrimidine (V, R ¹ = 4-Et-C _e H ₄ , R ² = Me , R ³ = NH ₂ ) Yield 75%. Colorless platelets (from ethanol), mp 197-198 ⁰ C.

2-Amino-6-H- (4-methoxyphenyl) -1H-tetrazol-5-yl] -4-methyl-pyrimidine (V, R ¹ = 4-MeO-C "H ₄ , R ² = Me, R ³ = NH ₂ ) Yield 89%. Colorless crystals (from ethanol), mp 193-194 ⁰ C.

2-Amino-5-I1- (4-fluoro-phenyl) -1H-tetrazol-5-yl] -4-methyl-pyrimidine (V, R ¹ = 4-FC _e H ₄ , R ² = Me, R ³ = NH ₂ ) yield 79%. Colorless flake (from acetonitrile), mp. 225-226 ⁰ C.

2-Amino-5- [1- (4-chloro-phenyl) -1H-tetrazol-5-yl-4-methylpyrimidine (V, R ¹ = 4-Cl-CeH ₄ , R ² = Me, R ³ = NH ₂ ) yield 77%. Colorless leaves (from acetonitrile), mp 251-252 ⁰ C (dec.).

2-amino-5- [1- (4-bromo-phenyl) -1H-tetrazol-5-yl-4-methylpyrimidine (V, R ¹ = 4-Br-C ₈ H ₄ , R ² = Me, R ³ = NH ₂ ) Yield 83%. Colorless Leaflets (made of Dioxane), m.p. 257-258 ⁰ C (Zers.)

2-Amino-5- (1- (4-iodo-phenyl) -1H-tetrazol-5-yl-4-methyl-pyrimidine (V, R '= 4 C ₄ H ₄ , R ² = Me, R ³ = NH ₂ ) Yield 86% Colorless flakes (from dioxane), mp 256-257 ⁰ C (dec.).

2. Amlno-5-l1- (4-biphenylyl) -1H-tetrazol-5-yl-4-methyl-pyrimidine (V, R ¹ -4-Ph-C ₉ H ₄ , R ² = Me, R ³ = NH ₂ ) yield 70%. Colorless crystals (from dioxane), mp 222-223 ⁰ C

2-Amino-4-ethyl-5- (1-phenyl-1H-tetrazol-5-yl) pyrimidine (V, R ¹ = Ph, R ² = Et, R ³ = NH ₂ ) Yield 81%. Colorless crystals (from methanol); mp. 170-171 ⁰ C.

2-Amino-2-ethyl-5- | 1- (4-methylphenyl) -1H-tetrazol-5-yl) -pyrimidine (V, R * = 4-Me-CgH ₄ , R ² = Et, R ³ = NH ₂ ) Yield 90%. Colorless crystals (from methanol), mp 157-158 ⁰ C

2-ΑΓηίηο-5- (1-ρηβηγΜΗ · ΙβΐΓ8ζοΙ-5-γΙ) · 4 · ρΓοργΙ · ρνΓίπιΙα1η (V, R ¹ - Ph, R ² = Pr ₁₁ R ³ = NH ₂ ) Yield 88%. Colorless crystals (from methanol); mp. 132-133 ⁰ C.

2 ^ Ιηο-5- [1- (4ββΙηνΙ · ρηβηνΙ) -1Η-ΙβΐΓβζοΙ · 5-νΙ) -4-ρΓθρνΙ-ρνΜπ ^ Ιη (V, R ¹ = 4-Me-C, H ₄ , R ² = Pr, R ³ = NH ₂ ) yield 86%. Colorless crystals (from methanol); mp. 180-181 ⁰ C.

Example 2

2-amino-4-phenyl-5- (1-phenyl-H-tetrazol-5-yl) -pyrimidine (V, R ¹ = R ² = Ph, R ³ = NH ₂ )

2.15 g (10 mmol) of 5- (2-dimethylaminophenyl) -1-phenyl-1H-tetrazole (I, R '= Ph) are dissolved in 10 ml of absolute. Benzen with 1.21 g (12mmol)

anhydrous triethylamine and 1.69 g (12 mmol) of benzoyl chloride (II, R ² = Ph, X = Cl) refluxing for 4 hours with exclusion of moisture. Then distilled the plentiful half of the solvent I. Vak. and lets crystallize in the cold. The crystal mixture is filtered off with suction, freed from triethylamine hydrochloride by washing with water and dried. The resulting intermediate III (R '= R ² = Ph) is combined with 2.25 g (10 mmol) guanidine sulfate (2IV.H ₂ SO ₄ .0.5 H ₂ O, R ³ = NH ₂ ) in 20 ml of 1N methanolic sodium methoxide solution 4 hours under magnetic

Stirring refluxed. After cooling, the product is filtered off with suction, first with methanol, then several times with water

washed and dried. Yield 2.50 g (79%); colorless platelets (made of dioxane), mp 267-268 ⁰ C (Zers.).

Example 3

2-amino-5-H- (4-methylphenyl) -1H-tetrazol-5-yl] -4-phenyl-pyrimidine (V, R ¹ = 4-Me-C ₈ H ₄ , R ² = Ph, R ³ «NH ₂ )

A hot solution of 2.29 g (lOmmol) of 5- (2-dimethylamino-vinyl) -1- (4-methyl-phonyl) -1H-tetrazole (I, R '= 4-Me-C ₆ H ₄₎ in 5ml

absol. Acetonitrile and 0.95 g (12 mmol) of dry pyridine is treated with 1.69 g (12 mmol) of benzoyl chloride (II, R ² = Ph, X = Cl) and heated with exclusion of moisture for 3 hrs. At 8O ⁰ C on a water bath. Then draw the solvent i. Vak. The residue is digested with cold water, filtered off, washed with water and dried over P ₂ Oe. The thus obtained

Intermediate III, R ¹ = 4-Me-C _e H ₄ , R ² -Ph is used together with 2.25 g (10 mmol) of guanidine sulfate (2IV.H ₂ SO ₄ .0.5 H ₂ O, R ³ = NH ₂ ) in 20 ml of a 1N ethanolic sodium ethanolate solution refluxing for 3 hours with magnetic stirring, the

The former slowly dissolves and at the same time the final product begins to separate. After cooling, the solution is filtered off with suction, washed first with ethanol, then several times with water and dried over P ₂ O ₆ . Yield 2.88g (87%); colorless leaves (out

Dioxane), mp. 269-27O ⁰ C. Analog receive:

2-Amino-5-l1- (4-ethyl-phenyl) -1H-tetrazol-5-yl-4-phenyl-pyrimidine (V, R ¹ = 4-Et-C ₆ H ₄ , R ² = Ph, R ³ = NH ₂ ) yield 85%. Colorless crystals (from dioxane), mp 244-245 ⁰ C.

2-Amino-5- [1- (4-methoxyphenyl) -1H-tetrazol-5-yl] -4-phenyl-pyrimidine (V, R ¹ = 4-MeO-C ₆ H ₄ , R ² = Ph , R ³ = NH ₂ ) Yield 75%. Colorless leaflets (dioxane), mp 246-247 ⁰ C.

2-Amino-5- [1- (4-fluoro-phenyl) -1H-tetrazol-5-yl] -4-phenyl-pyrimidine (V, R ¹ = 4-FC ₆ H ₄ , R ² = Ph, R ³ = NH ₂ ) yield 85%. Colorless leaflets (made of dioxane), mp 274-275 ⁰ C (Zers.).

2-Amino-5- (1- (4-chloro-phenyl) -1H-tetrazol-5-yl-4-phenyl-pyrimidine (V, R '= 4-CPC ₆ H ₄ , R ² = Ph, R ³ = NH ₂ ) Yield 90% Colorless crystals (from dioxane), mp 284-285 ⁰ C (dec.).

2-Amino-5- | 1- (4-bromo-phenyl) -1H-tetrazol-5-yl] -4-phenyl-pyrimidine (V, R ¹ = 4-Br-C ₆ H ₄ , R ² = Ph , R ³ = NH ₂ ) Yield 84%. Colorless Leaflets (made of dioxane), m.p. 285-286 ⁰ C (Zers.)

2-amino-5- (1- (4-iodo-phenyl) -1H-tetrazol-5-yl] -4-phenyl-pyrimldin (V, R ¹ = 4-1-C ₆ H _4, R ² = Ph , R ³ = NH ₂ ) Yield 81% Colorless crystals (from dioxane), mp 285-286 ⁰ C (dec.).

2-Amino-4- (3-fluoro-phenyl) -5- (1-phenyl-1H-tetrazol-5-yl) -pyrimidine (V, R ¹ = Ph, R ² = 3-FC ₆ H ₄ , R ³ = NH ₂ ) Yield 53%. Colorless crystals (from acetonitrile), mp. 206-207 ⁰ C.

2-Amino-4- (3-chlorophenyl) -5- (1-phenyl-1H-tetrazol-5-yl) -pyrimidine (V, R ¹ = Ph, R ² = 3-CI-C ₆ H ₄ , R ³ = NH ₂ ) Yield 82%. Colorless crystals (from acetonitrile), mp 208-209 ⁰ C.

2-Amino-4- (4-chloro-phenyl) -5- (1-phenyl-1H-tetrazol-5-yl) -pyrimidine (V, R ¹ = Ph, R ² = 4-CI-C ₆ H ₄ , R ³ = NH ₂ ) Yield 84%. Colorless crystals (from acetonitrile), mp. 217-218 ⁰ C.

Example 4

4-methyl-5- (1-phenyl-1H-tetrazol-5-yl) -pyrimidine (V, R ¹ = Ph, R ² = Me, R ³ = H)

2.15 g (10 mmol) of 5- (2-dimethylamino-vinyl) -1-phenyl-1H-tetrazole (I, R * = Ph) are obtained according to Example 1 in 5 ml of absolute. Acetonitrile and 0.95 g (12 mmol) of dry pyridine with 0.94 g (12 mmol) of acetyl chloride (II, R ² = Me, X = Cl) to the intermediate III, R ¹ = Ph,

R ² = Me reacted. The latter is heated together with 2.08 g (20 mmol) of formamidine acetate (IV · AcOH, R ³ = H) In 20 ml of 1N

Ethanoliecher sodium ethanolate solution for 3 hours under magnetic stirring at reflux, then distilled off 15 ml of ethanol and the residue is taken up in diethyl ether after cooling. The organic phase is washed several times with water, with

Dried sodium sulfate and concentrated, wherein the reaction product separates crystalline. Yield 1.34g (56%); colorless Crystals (from cyclohexane), mp. 114-116 ⁰ C. Example 5

5-H- (4-methoxy-phenyl) -1H-tetrazol-5-yl) -4-methyl-pyrimidine (V, R ¹ = 4-MeO-C ₆ H ₄ , R ² = Me, R ³ = H ) 2.45 g (10 mmol) of 1- (4-methoxy-phenyl) -5- (2-dimothylamino-vinyl) -1H-tetrazole (I, R * = 4-MeO-C ₆ H ₄ ) are obtained in accordance with Example 1 in 5ml ebsol. Acetonitrile and 0.95 g (12 mmol) of dry pyridine with 0.94 g (12 mmol) of acetyl chloride (II, R ² = Me, X = Cl) for

Intermediate III, R ¹ = 4-MeO-C ₆ H ₄ , R ² = Me reacted. The latter is heated together with 2.08g (20mmol) Formamidine acetate (IV AcOH, R ³ = H) in 20 ml of 1N ethanolic sodium ethoxide solution for 3 hours with magnetic stirring on Reflux and then distilled off 15 ml of ethanol. From the residue, the reaction product separates on cooling and Trituration, optionally with dropwise addition of some water, crystalline from. It sucks, washes several times Water and dried over P ₂ O ₆ . Yield 2.34g (87%); colorless crystals (from methanol), mp. 143-144 ⁰ C. Analog receive:

5- (1- (4-Chloro-phenyl) -1H-tetrazol-5-yl] -4-methyl-pyrimidine (V, R ¹ = 4-CI-C ₆ H ₄ , R ² = Me, R ³ = H) 60% yield. Colorless crystals (from methanol); mp. 133-134 ⁰ C.

5- [1- (4-Bromo-phenyl) -1H-tetrazol-5-yl) -4-methyl-pyrimidine (V, R ¹ = 4-Br-C ₆ H ₄ ... R ² -Me, R ³ = H) Yield 61%. Colorless crystals (from methanol); mp. 153-154 ⁰ C.

5- (1- (4-iodo-phenyl) -1H-tetrazol-5-yll-4-methyl-| .pyrimldln (V, R ¹ = 4-1-C ₆ H _4, R ² = Me, R ³ = H) 58% yield. Colorless crystals (from benzene), mp. 170-171 ⁰ C.

4-phenyl-5- (1-phenyl-!H-tetrazol-5-yl) -pyrylmagnolone (V, R ¹ = R ² = Ph, R ³ = H) Yield 69%. Colorless crystals (from methanol), mp 121-122 ⁰ C

5- [1- (4-methyl-phenyl) -1H-tetrazol-5-yl | -4-phenyl-pyrimidine (V, R ^1-4-Me-C ₆ H _4, R ² = Ph, R ³ = H) Yield 56%. Colorless needles (from methanol), mp 164-165 ⁰ C.

5- [1- (4-methoxy-phenyl) -1H-tetrazol-5-yl] -4-phenyl-pyrimidJn (V, R '= 4-MeO-C ₆ H _4, R ² = Ph, R ³ = H) Yield 82%. Colorless crystals (from methanol); mp. 128-129 ⁰ C.

Examples

2,4-dimethyl-5-l1- (4-methyl-phenyl) -1H-tetrazol-5-yl] -pyrimidine (V, R ¹ = 4-Me-C ₆ H ₄ , R ² = R ³ = Me ) 2.29 g dOmmol) 5- (2-dimethylamino-vinyl) -1- (4-methyl-phenyl) -1H-tetrazole (I, R ¹ = 4-Me-CjH ₄ ) are in accordance with Example 1 in 5ml absolute. Acetonitrile and 0.95 g (12 mmol) of dry pyridine with 0.94 g (12 mmol) of acetyl chloride (II, R ² = Me, X = Cl) for

Intermediate III, R ¹ = 4-Me-CgH ₄ , R ² = Me reacted. The latter is heated together with 1.89g (20mmol) Acetamidine hydrochloride (IV · HCl, R ³ = Me) ethanol in 20 ml of a 1N sodium ethoxide solution for 3 h., With magnetic Stirring at reflux. After distilling off 15 ml of ethanol, take the cooled residue in diethyl ether washes the

organic phase several times with water, dried with sodium sulfate and concentrated, the reaction product slowly crystallized. Yield 1.82g (68%); colorless crystals (from diethyl ether), mp. 111-112 ° C.

Example 7

5- [H ₄ -chlorophenyl] -1 H -tetrazol-5-yl] -2,4-dimethyl-pyrimidine (V, R ¹ = 4-Cf-C ₈ H ₄ , R ² = R ³ = Me) 2.50 g dOmmol) 1- (4-chlorophenyl) -5- (2-dimethylamino-vinyl) -1 H-tetrazole (I, R ¹ = 4-CI-CeH ₄ ) are in accordance with Example 1 in 5ml absol. Acetonitrile and 0.95 g (12 mmol) of dry pyridine with 0.94 g (12 mmol) of acetyl chloride (II, R ² = Me, X = Cl) for

Intermediate III, R '= 4-ChC ₆ H ₄ , R ² = Me reacted. The latter is heated together with 1.89 g (20 mmol) Acetamidine hydrochloride (IV · HCl, R ³ = Me) in 20 ml of 1N ethanolic sodium ethoxide solution for 3 hours under magnetic Stirring at reflux and then distilled off 15 ml of ethanol. The formed during cooling and grinding crystals

filtered off with suction, washed first with a little ethanol, then several times with water and dried. Yield 2.06 g (72%); colorless

Crystals (from methanol), mp 176-177 ⁰ C. Analog receive:

5- [1- (4-Bromo-phenyl) -1H-tetrazol-5-yl] -2,4-dimethyl-pyrimidine (V, R ¹ = 4-Br-C ₄ H ₄ , R ² = R ³ = Me)

Yield 90%. Colorless crystals (from methanol), mp 204-205 ⁰ C.

2-Mothyl-4-phenyl-5- (1-phenyl-1H-tetrazol-5-yl) -pyrimidine (V, R ¹ = R ² = Ph, R ³ = Me)

Yield 82%. Colorless crystals (from methanol), mp 130-131 ° C.

2-Methyl-5 '(1- (4-methyl-phenyl) -1H-tetrazol-5-yl-4-phenyl-pyrimidine (V, R ¹ = 4-Me-C ₈ H ₄ , R ² = ph, R ³ = Me)

Yield 85%. Colorless crystals (from methanol), mp 166-167 ⁰ C.

5- (1- (4-methoxy-phenyl) -1 H-tetrazol-5-yl] -2-methyl-4-phenyl-pyrim! D! N (V, R ¹ = 4-MeO-CJH _4, R ² = Ph, R ³ = Me)

Yield 62%. Colorless crystals (from methanol); mp. 148-149 ⁰ C.

5- | 1- (4-chloro-phenyl) -1 H-tetrazol-5-yll-2-methyl-4-phenyl-pyrimldin (V, R ¹ = 4-CI-C ₈ H _4, R ² = Ph , R ³ »Me)

Yield 91%. Colorless needles (from methanol); mp. 170-171 ⁰ C.

5-I1- (4-Bromo-phenyl) -1H-tetrazol-5-yl] -2-methyl-4-phenyl-pyrimidine (V, R ¹ -4-Br-C ₈ H ₄ , R ² = Ph , R ³ = Me)

Yield 85%. Colorless needles (made of ethanol), mp 186-187 ⁰ C. Example 8

4-Methyl-2-phenyl-5- (1-phenyl-H-tetrazol-5-yl) -pyrimidine (V, R ¹ = R ³ = Ph, R ² = Me) 2.15g dOmmol) 5- (2- Dimethylamino-vinyl) -1-phenyl-1 H-tetrazole (I, R ¹ = Ph) are in accordance with Example 1 in 5ml absol. Acetonitrile and O, 95g (12 mmol) of dry pyridine with 0.94 g (12 mmol) of acetyl chloride (II, R ² = Me, X = Cl) to give the intermediate III, R ¹ - Ph,

R ² = Me and these analogously to Example 7 in 20 ml of 1N ethanolic sodium ethoxide solution with 3.13 g (20 mmol) Benzamidine hydrochloride (IV · KCl, R ³ = Ph)) reacted. From the remaining after distilling off 16 ml of ethanol Residue begins on cooling, dropwise addition of water and rubbing the reaction product crystallize,

whose deposition is completed by further addition of water. After aspirating, washing with water and

Drying results in 1.77 g (56%) of crude crystals. Recrystallization from methanol gives colorless crystals of mp. Analog receive:

4-Methyl-5- [1- (4-methylphenyl) -1-H-tetrazol-5-yl-2-phenyl-pyrimidine (V, R ¹ = 4-Me-C ₈ H ₄ , R ² = Me, R ³ = Ph)

Yield 90%. Colorless crystals (from methanol), mp 117-118 ° C.

5- [1- (4-Fluoro-phenyl) -1H-tetrazol-5-yl-4-methyl-2-phenyl-pyrimidine (V, R '= 4-FC ₈ H ₄ , R ² = Me, R ³ = Ph)

Yield 81%. Colorless needles (from ethanol), mp. 153-154 ⁰ C.

2,4-Dlphenyl-5- (1-phenylm H-tetrazol-5-yl) -pyrlmidine (V, R ¹ - R ¹ - R ³ = Ph)

Yield 90%; Colorless crystals (from acetonitrile), mp 182-183 ⁰ C.

5- [1- (4-Methyl-phenyl) -1H-tetrazol-5-yl] -2,4-dl-phenyl-pyrimidine (V, R ¹ = 4-Me-C ₈ H ₄ , R ² = R ³ = Ph)

Yield 89%. Colorless crystals (from acetonitrile), mp 159-160 ⁰ C.

5- | 1- (4-ethyl-phenyl) -1H-tetrazol-5-ylJ-2,4-diphenyl-pyrimidine (V, R ¹ = 4-Et-C ₈ H ₄ , R ² = R ³ = Ph)

Yield 87%. Colorless crystals (from ethanol), mp. 170-171 ⁰ C.

5- [1- (4-Methoxy-phenyl) -1H-tetrazol-5-yl) -2,4-diphenyl-pyrimidine (V, R ¹ = 4-MeO-C ₈ H ₄ , R ² = R ³ = Ph)

Yield 83%. Colorless crystals (from ethanol), mp 144-145 ⁰ C.

5- [1- (4-Fluoro-phenyl) -1H-tetrazol-5-yl) -2,4-diphenyl-pyrimidine (V, R ¹ = 4-FC ₈ H ₄ , R ² = R ³ = Ph )

Yield 85%. Colorless needles (from acetonitrile), mp. 154-155 ⁰ C.

FormeIseite

H ₃ C

H ₃ C

N-CH = CH

+ R ² COX

-HX

H ₃ C,

H ₃ C

COR ² N-CH = C

,1

+ r3-C *

IV

NH NH · - (CH ₃ J ₂ NH, -H ₂ O

R ¹

ρ i ¹ · Π ι- 7 4

Claims (1)

A process for the preparation of tetrazolyl-substituted pyrimidine derivatives of the general formula V in which R ^{1 is} an aryl radical, R ^{2 is} an alkyl or aryl radical and R ^{3 is} an amino group, hydrogen, an alkyl radical or an aryl radical, characterized in that 1-substituted-5- (2-Dimethylaminovinyl) -1H-tetrazoles of the formula I, in which R ^{1 represents} an aryl radical, in solvents such as acetonitrile or benzene mit Carbonsäurehalogeniden of formula II, in which R ^{2 is} an alkyl or aryl radical and X is a halogen atom, preferably Chlorine, in the presence of equimolar amounts of an auxiliary base such as pyridine or triethylamine at temperatures up to the boiling point of the reaction mixture and the resulting formed 1-arylsubstituierten 5- (1-acyl-2-dimethylamino-vinyl) -1H-tetrazoles III with guanidine ( Formula IV, R ³ = NH ₂ ) or Carbonsäureamidinen (formula IV, R ³ = H, alkyl or aryl) in boiling alcoholic (eg methanolic or ethanolic) solution in the presence of a basic en condensation agent, for. As sodium methoxide or sodium ethoxide, brings to the reaction. For this 1 page formulas Field of application of the invention The invention relates to a process for the preparation of tetrazolyl-substituted pyrimidine derivatives of the general formula V in which R ^{1 is} an aryl radical, R ^{2 is} an alkyl or aryl radical and R ^{3 is} an amino group, hydrogen, an alkyl radical or an aryl radical. Heterocycles of this type are of interest as intermediates for the synthesis of biologically active compounds. Characteristic of the known state of the art Tetrazolyl-substituted pyrimidine derivatives of the formula V are hitherto unknown (see FR BENSON, Chem. Rev. 41 [1947] 1; FRBENSON in "Heterocyclic Compounds" [Ed. RC Elderfieldj, Vol. 8, p.1, Wiley, New York, Vol. RN BUTLER, Adv. Heterocycl Chem 21 [1977] 324; RN BUTLER in "Comprehensive Heterocyclic Chemistry" [Hrsg. AR Katritzky and CW Rees), Vol. 5, Part 4 A, p. 791, Pergamon Press, Oxford, 1984).
For other tetrazolypyrimidines, the following production methods have been described in the literature: a) reaction of cyanopyrimidines (or cyanopyrimidones) with sodium or ammonium azide to pyrimidine derivatives with N-unsubstituted 1H-tetrazol-5-yl radical (for example, J. P. Horowitz and AJTOMSON, J. Org. Chem. 26 (1961) 3392; DH KIM and AA SANTILLI, US 3816423, CA 81 [1974] 120687; PTJUBY and R. A. PARTYKA, DE 2705609, CA 87 [1977] PT JUBY, TWHUDYMA, M.BROWN, JMESSERY and RAPARTYKA, J M.M.Chem 25 (1982) 1146, Fujisawa Pharmaceutical Co., Ltd., JP 57176981, CA 98 [1983] 143453, Y. HONMA, Y. SEKINE, T.HASHIYAMA, M.TAKEDA, Y.ONO and K.K. .TSUZURAHARA, Chem. Pharm. Bull. 30 [1982] 4314; K. KOSEGI, M.SAWADA and T.ICHIKAWA, JP6191184, CA.105 [1986] 208920; W.RIED and S. ABOUL-FETOUH, Chem.-Ztg. 112 [1988] 135); b) Introduction of an N-linked tetrazolyl radical by substitution of suitable pyrimidine derivatives (eg BKSNELL, RSELIAS and PFH FREEMAN, S.African 6701373, CA 71 [1969] 91517, A. KÖNNECKE, R.DÖRE and E. LIPPMANN, Tetrahedron Lett 1978,2071); c) Reaction of N-pyrimidylbenzamides with PCI ₅ and conversion of the benzimidchlorides formed by means of HN ₃ into (5-aryl-1H-tetrazol-1-yl) -pyrimidine derivatives (K. KAMALA, PJRAO and KKREDDY, Bull. Chem. Soc Jpn. 61 [1988] 3791). However, tetrazolylpyrimidines of the formula V can not be prepared by any of the processes mentioned under a) -c) because of their different substitution and linking pattern. A known principle for the construction of pyrimidine rings is the reaction of guanidine or amidines with enaminoketones of the general structure R ₂ N-CH = CR'-COR "(compare H. BREDERECK, F. EFFENBERGER and H. BOTSCH, Chem. 97 [1964] 3397; B. GRAFFE, M.-C.SACQUET, M.-C.BELLASSOUED-FARGEAU and P. MAITTE, J. Heterocycl Chem., 23, 1853 (1986), 1753.) For the synthesis of tetrazolylpyrimidines of the Formula V would require enaminoketones by this method in which R 'represents a 1-AryM H-letrazol-5-yl residue; tetrazolyl-substituted enaminoketones of this type are heretofore unknown. Object of the invention The invention has for its object a method by which tetrazolyl-substituted pyrimidine derivatives of the formula V can be prepared in a simple manner from readily available starting materials. Explanation of the essence of the invention The invention is based on the object tetrazolylpyrimidines of the formula V in which R ^{1 is} an aryl radical, R ^{2 is} an alkyl or aryl radical and R ^{3 is} an amino group, hydrogen, an alkyl or an aryl radical, from suitable 1,5-disubstituted tetrazoles manufacture. The object is achieved according to the invention by reacting 1-substituted 5- (2-dimethylamino-vinyl) .1H-tetrazoles of the formula I in which R ^{1 is} an aryl radical in solvents such as acetonitrile or benzene with carbonyl halides of the formula II, in the R ^{2 is} an alkyl or aryl radical and X is a halogen atom, preferably chlorine,