DD232702A1 - PROCESS FOR THE PREPARATION OF 1,2,3,4-TETRAHYDROCHINAZOLIN-2,4-DION VINEGARES, THEIR SALTS AND ESTERS - Google Patents

Abstract

The aim of the invention is biologically active compounds of general formula IV, d. H. 1,2,3,4-Tetrahydro-quinazoline-2,4-dione-acetic acids of the general formula IV c, their salts of the general formula IV b and esters of the general formula IV a, the practice as active ingredients available. According to the invention, a 1-alkoxycarbonylmethyl isatozoic anhydride of the general formula I is reacted with ammonia, urea or an amine, e.g. B. a glycine ester to give a compound of general formula II, either by reaction with a chloroformate in a compound of general formula III or by cyclization with phosgene in a 1,2,3,4-tetrahydro-quinazoline-2,4- dion-acetic acid ester of general formula IV a is transferred. Both from the compounds of general formula III and from the compounds of general formula IV a is prepared by treatment with an alkali metal hydroxide, the salts of the general formula IV b ago. Addition of organic or mineral acids provides the free acids of the general formula IV c. The invention is of interest to the pharmaceutical, agricultural, horticultural and forestry industries.

Description

Process for the preparation of 1,2,3,4-tetrahydroquinazoline-2,4-dione acetic acids, their salts and esters

The invention relates to a process for the preparation of compounds of general formula IV. Ss are 1,2,3,4-xetrahydro-quinazolin-2,4-dione-acetic acids of the general formula IVc, their salts of the general formula IVb and Esters of the general formula IVa.

Application of the invention

The invention is of interest to medicine, the pharmaceutical industry, agriculture, horticulture and forestry,

Char akter istics de r known technical s ch en Los Ungen

A large number of quinazolines are already used in pharmaceutical practice (S. JOHNE, Pharmacie 36, 585 (1981); S. JOHNE, Fortschr. Arzneimittelforschung 26 (1982)). Quinazolines having potency as phytotherapeutic agents, fungicides, acaricides, insecticides or herbicides are also known (I / I SUSSE and S. JOHNE, Z. Chem., 21, 431 (1981)).

Of the 1,2,3,4-tetrahydroquinazoline-2,4-dione-acetic acids of the general formula IVo, only one has already been synthesized which comprises 1,2,3,4-tetrahydroquinazoline-2,4-dione- 1-acetic acid (IVc, H = O, ¹ R = H). It was synthesized by G. Doleschall and K. Lempert (Acta Chim. Acad. Sei. Hung. 45 (4), 357 (1965)) by hydrolysis from 1,2,3,4-tetra-dihydroimidazole / 2. a / quinazoline-2,5-dione, prepared by four steps from phenylglycine-amide-o-carboxylic acid • The salts of the general formula

η α η α ο -ι- Π '-5 η. ι 'ϊ

ITo, the esters of general formula IV and the amides of general formula III are not yet known. Also esters of general formula II have not been described. Of the underlying acids (R = H) only one has already been characterized, the compound with (R) _n = 6-Cl and R = H. The synthesis was carried out by reacting the corresponding o-Aminobenzamides with chloroacetic acid in DMF in the presence of magnesium oxide and sodium iodide for 2.5 hours at 90-100 ⁰ C (MIKI T. and M. ASANO, European Patent Application 0009608, C 07 C 103 / 50). The yield is 44 ^G h of theory.

Object of the invention

The aim of the invention is to provide biologically active compounds of general formula IV practice as active ingredients available.

Dar le supply e d s W esens the invention

The object of the invention is to provide a process for the preparation of compounds of general formula IV, i. of 1,2,3,4-tetrahydro-quinazoline-2,4-dione-acetic acids of the general formula IVc, their salts of the general formula IVb and esters thereof of the general formula IVa to develop.

According to the invention, a 1-alkoxy-carbonyl-methyl-isatoic anhydride of the general formula I is reacted in a multistage process to give the desired compound of the general formula IV. In the process according to the invention, a compound of the general formula II is first prepared from a compound of the general formula I and this is subsequently synthesized either via a compound of the general formula III or via an ester of a tetrahydroquinazoline ^^ dionacetic acid " (General formula IVa), which in the case R = H is also ethyllic directly from the compound of general formula I by reaction with urea, converted into a salt of this acid (general formula IVb), from which the free acid of organic or mineral acids general research

•. 3

mel IVc is obtained.

Depending on the desired product, the reaction of the 1-alkoxycarbonyl-ethyl-isatoic anhydride with ammonia, urea or an amine is obtained from the compounds of the general formula II by reaction with a chloroformate, the compounds ^{1 of} the general formula III or by reaction with phosgene 1,2,3,4-tetrahydro-china-2-one-2,4-dione-acetic acid esters of general formula IVa Both from the compounds of general formula III and from the compounds of general formula IVa are prepared by treatment with an alkali metal hydroxide, preferably Potassium hydroxide, the salts of general formula IVb ago.

In the general formulas, E is halogen, HO ₂ J CII, alkyl, alkoxy; R ¹ 'for E ¹ , M or H; R ^{1 is} alkyl (G ₁ -C ₄ ); R ^{2 is} H or an unsubstituted or substituted alkyl, aryl or heterocyclic radical, eg CH ₂ COOE *; R ^{3 is} alkyl (C, -C, _O ): M is alkali metal and η is 0 to 4. R in the general formula IV is alkyl (C 1 -C 4), alkali metal or H, in the general formulas II, III and IVa alkyl (C ^ -C,)? in the general formula IVb alkali metal and in the general formula IVc H.

Compounds of general formula II with R = H v / earth by reacting an isatoic anhydride of general formula I with ammonia in solution or suspension or by melting with urea at 150-250 ⁰ C. In the latter case, however, a mixture of the compounds of the general

2 nen formulas II and IVa obtained. However, if R is intended to symbolize an alkyl, aryl or heterocyclic radical, it also being possible for this radical to be substituted, ammonia is used instead of ammonia

an amine R - IiHp used, also in solution or suspension. The reaction proceeds under COp development. ^;

CHpCOOR is for example a suitable substituted alkyl

rest R ² . Should R ² in the general formulas for GH ₉ COOR ⁴

hen, the reaction partner R-NHp of the compound of general formula I is a glycine ester. It is also possible

to use the C-lycin ester in the form of its hydrochloride; the release of the ester then takes place by addition of an organic or inorganic base which can "bind" HCl.

2 Ar ^ ^1- I or heterocyclic radicals R must be designed "

2, that the amine used R ~ ^ϊίΗ 2 ^ei - ' ^{Jie r} elatrv high basicity' has and in the case of substituted aryl or heterocyclic radicals, the substituents undergo no reaction with the compound of general formula I. The heterocyclic amines can sooo aromatic as well as partially or fully hydrogenated Examples which may be mentioned are: aminoimidazole, aminopyrrole, aminopyrazole, aminopyridine, aminothiazole, aminothiophene, aminofuran, aminotriazole, aminotetrazine, aminobenzotriazoles, aminobenzothiophenes, aminopyrimidinones, aminopiperazines.

The compounds of the general formula II are converted into the compounds of the general formula III with a chloroformate in an inert organic solvent with heating in the presence or in the absence of a base which can bind HCl, It can also be reacted with an excess of chloroformate , which then serves as a solvent, to be worked.

By means of phosgene compounds of the general formula II are cyclized to 1, 2,3,4-tetrahydro-quinazolin-2,4 - diones of the general formula IVa. This is done by introducing or adding dropwise phosgene to a solution or suspension of compounds of general formula II in an inert organic solvent in the presence of an organic or inorganic base which can bind HCl, for example tart. Amines, pyridine, NapCCu, sodium alcoholate. The organic base can be used simultaneously as a solvent. Sin small excess of phosgene is an advantage. The yields can be increased if initially worked under cooling and optionally heated towards the end of the reaction.

In the case of H = H, the 1,2,3,4-tetrahydro-quinazoline-2,4-dione of the general formula IVa can also be obtained directly from the isatoic anhydride of the general formula I by reacting with urea in a solvent performs.

The preparation of the compounds of the general formula IVb from the compounds of the general formula III or IVa is carried out, for example, in an alcohol by adding an aqueous alkali metal hydroxide solution, preferably a potassium hydroxide solution, and heating the reaction mixture.

It is not necessary to purify or isolate the compounds of the general formulas II, III and IVa prepared prior to their further reaction by the process according to the invention; they can be used as crude product for the next process stage.

The starting materials of general formula I can be prepared by known methods (e.g., G.E. HARDTMAHIi, G. EOLetab and D.H. PFISTSH, J. He'terocycl., Chem. 1_2, 565 (1975)).

The process according to the invention enables the preparation of compounds of the general formulas III and IV in good yields.

The compounds of the general formulas III and IV are biologically active. Among them are those which show antiallergic, fungicidal and / or plant growth-influencing effects.

The invention will be explained below by some embodiments.

Exporting approximately b o te pie 1 e In spieJLJ.

2.7 g of 6-chloro-1-methoxycarbonylmethyl-3,1-benzoxazine-2,4-dione

R ¹ chloride and 1.5 ml of triethylamine are dissolved in 60 ml of abs. Ethanol up

(I, (H) ₇₁ = 6-Cl, H ¹ = CH ₃ ), 1.4 g of glycine methyl ester hydroquinone

to stop the COp development (30-50 min.) Stirred. Towards the end is heated to 30-50 ⁰ C. The solvent is distilled off in vacuo and the residue is refluxed for 3-4 hours with 30 ml of ethyl chloroformate The excess of ethyl chloroformate is distilled off in vacuo and the residue is dissolved in 70 ml of absolute ethanol, 3.2 g of potassium hydroxide dissolved in 5 are dissolved ml water, cooking for 2 hours under reflux, allowed to cool and is filtered off, mp> 360 ⁰ C, yield:.. 3.2 g (76% of theory..) ^a Dikaliuni-6-ehlor-3.1-benzoxazin-2,4 dione-1,3-diacetate (IVb, (R) _n = 6-Cl, R ² =

CH ₅ COOR ⁴ , R ⁴ = M = K).

3 g of dipotassium 6-chloro-3,1-benzo-azine-2,4-dione-1,3-diacetate (IYb, (R) _n = 6-Cl, R ² = CH ₂ COOR ⁴ , R ⁴ = M = K) are dissolved in 20 ml of water and acidified with conc. Hydrochloric acid to pH 1-2 added. The mixture is heated to complete dissolution, filtered, allowed to cool, filtered off and crystallized. . Mp 357-360 ⁰ C, yield:. 1.1 g (50 # d (Th) 6-chloro-3,1 'benzoxazin-2,4-dione-1,3-diacetic acid (IVc (R). ₇ = 6-Cl, R ² = CH ₉ COOR ⁴ ,

4 N

R ⁴ = H) ..

Example 3

900 mg of N- (2-aminocarbonylphenyl) -glycine methyl ester (II, η = 0, R = CH, R = H) and 25 ml of ethyl chloroformate are refluxed for 4-5 hours. The excess of ethyl chloroformate is distilled off in vacuo and the residue in 50 ml of abs. Ethanol dissolved. 1.1 g of potassium hydroxide, dissolved in 5. ml of water, are added, then heated under reflux for 2 hours. It is allowed to cool, filtered off with suction and washed with abs. Ethanol. Mp.> 360 ⁰ C, yield: 850 mg (72% of theory..) Of potassium 1,2,3,4-tetrahydro-quinazoline-2,4-dione-1-acetate (IVb, η = 0, R ² = H, M - K).

In case 4 .

2.5 g of 1-Stiioxyca, r "bGrLylmetiiyl-3j-1-TDe: aaoxasiji-2,4-dione (Ι, η = O, R = CpH ₁ -) are added to a solution of 1.1 g of triethylamine and 1.3 g of glycine ethyl ester hydrochloride in 70 ml of abs. Etlianol give eye under stirring. at the end of the COP ^ evelopment is heated for 1 hour at 40-50 ⁰ G. Man the alcohol is distilled off in vacuo, the residue is taken up in 100 ml of pyridine, and outputs with cooling and stirring 1.5 g. phosgene to Mach 1 hour v / ill be heated for 30 minutes under Bückfluß and evaporated in Vakuumbis to dryness The residue is recrystallized from chloroform, mp 116-117 ⁰ Cj yield:... (. 51 7J d Th.) 1.7 g ^a i ^^^ - Tetrahydro-ohiiiazolin ^^ - aion-i .3-

jt O

ethyl acetate (IVa, η = C, R '= CpH _5. , R "= CH _o C00C ₂ H _c ).

2.5 g of 1,2,3,4-tetrahydro-quinazolin-2,4-dione-1-acetic acid ethyl ester (IVa η = 0, R ¹ = CpH ₅ , R ² = H) are dissolved in 100 ml of ethanol and washed with 1.7 Glacial hydroacid dissolved in 10 ml of water heated for 2 hours under reflux. Han cools, sucks and rinses with abs. Ethanol. Mp. ">> 360 ⁰ C, Yield: 2.4 g of potassium 1,2,3,4-tetrahydro-chinazo lin-2,4-dione-1-acetate (IVb, η = (d 87 # Th.). O ₅ R "= H, M = Z).

In sp_ iel 6

SOO 'mg of potassium-1'-tetrahydro-ohinazoline-E1-dione-i-aceta (IVb, η = Ο, R ² = H, IJ = K) are dissolved in 10 ml of water. Hit hydrochloric acid is acidified to pH 1-2 and then sucked off. It is recrystallized from liethanol / sisigig. . Mp 295-298 ⁰ C, yield: 470 mg (73 of theory 3..) Of 1,2,3,4-tetrahydro-china, 2olin-2,4-dione-1-essigsäur.e (IVc, η = 0, R ² = H).

^a based on the starting compound of the general formula

For this 2 pages formulas

CH, COOR

R ¹ = R ¹ R ¹ = M

NHR '

NH-CH ₂ COOR

CHoCOOR

CH ₂ COOR ¹

NHR '

N-CH ₂ COOR I 3 O = C-OR ³

IE

,1

CH ₂ COOH

W. c

CH ₂ COOM IZ b

Claims (9)

1. Process for the preparation of 1,2,3,4-tetrahydroquinazo li: a-2,4-dione-acetic acids, their salts and esters of general formula IV, characterized in that A) a 1-alkoxycarbonyl Imet hy 1-isat ο acid anhydride of general formula I by reaction with ammonia or an amine in solution or suspension or by melting with urea in an ester of the general formula II. And this either with a chloroformate to a compound of the general formula III or with phosgene to a 1.2 _? 3j4-Tetrahydro-quinazoline-2,4-dione-acetic acid ester of the general formula "IVa implements or B) a -1-Alkoxyca.rbonylmethy! -Isatosäureanhydrid of the general formula I by reaction with urea directly into an ester of the general formula IVa (with R = H) converts and by treating the resulting compound of general formula III or IVa with an alkali metal hydroxide produces a salt of general formula IVb, is released from the organic or mineral acids, the corresponding acid of general formula IVc, wherein in the general formulas 3. for halogen, NO ₂ , CN, alkyl, alkoxy? E ¹ 'for R ¹ , M or H; H ^{1 is} alkyl (C ₁ -C ₄ ); R ^{2 is} H or an unsubstituted or substituted alkyl, aryl or heterocyclic radical; ΣΓ ³ for alkyl (C ₁ -C ₁₀ ); M for lkalimetall and η stand for 0 to 4. 2. The method according to item 1, characterized in that the compounds of the general formulas I-I, -Ιϊΐ- and .IVa ^ ror- = the further reaction is not purified, but used as a crude product. 3. The method according to item 1 and 2, characterized in that as the amine for the reaction of the compound of the general Formula I is used to compound of the general formula II, a glycine ester. 4. The method according to item 3, characterized in that the glycine ester used in the form of its hydrochloride and in the presence of an organic or inorganic base, which can bind HCl is reacted. 5. The method according to any one of items 1 to 4, characterized in that the reaction for the compound of general formula III with chloroformate in an inert organic solvent under He ^T <vä.rmen or serving as a solvent excess of chloroformate is performed. 6. The method according to item 5, characterized in that in the Preparation of the compound of general formula III is carried out in the presence of a base. 7. The method according to one of the functons 1 to 4, characterized in that the cyclization of the compound of general formula II with phosgene to the compound of general formula IVa in solution or suspension in the presence of an organic or inorganic base, which can bind HCl, by operating in an inert organic solvent or in an excess of base serving as a solvent. 8. The method according to any one of items 1 to 7, characterized in that the salts of the general 5'ormel IVb are prepared from the compounds of general formulas III or IVa by adding an aqueous alkali metal hydroxide solution and heating the reaction mixture. 9. The method according to item S, characterized in that the Kaliusisalze the general formula IVb are prepared.