DD232699A1 - PROCESS FOR THE PREPARATION OF CHINAZOLIN-4-ON-3-ALKANSAURES AND THEIR ESTERS - Google Patents

Abstract

The aim of the invention is to provide the quinazolin-4-one-3-alkane acids or their esters of the general formula II practice in a sufficient amount and inexpensively available. According to the invention, an isatoic anhydride of the general formula I is reacted with an aliphatic amino acid H 2 N-Z-COOH in solution or suspension at a p H value between 7 and 12 and subsequently a compound of the general formula II is prepared with a condensing agent yielding a methine group. These compounds are of interest to the medical, pharmaceutical and agricultural, horticultural and forestry industries.

Description

Process for the preparation of CMnazolin-4-one-3-alkanoic acids and their esters

The invention relates to a process for the preparation of quinazolin-4-one-3-alkansäur9n and their esters of general formula II.

Field of application of the invention

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

Ch arak teristik the known technical solutions

There are a large number of quinazolines which are used as drugs in medicines (S.-JOHN, Pharmacie 36, 585 (1981); S. JOHIE, Fortschr. Arzneimittelforschung 26, 259 (1982)). Other quinazolines are useful as phyto-effectors, fungicides, acaricides, insecticides or herbicides (M.SUSSE and S. JOME, Z. Chem. 21., 431 (1981)).

BR BAKER, MV QUSRRT, AF KADISH, and JH WILLIAMS (J. Org. Chem. 17, 35 (1952)) synthesized the 3- (CMnazoliii-4-one-3- ^v l) -n-propionic acid ethyl ester (II. n = 0, R = -C ₂ H ₅ , Z = CHpCHp) from isatoic anhydride by reaction with β-Alaninethjlest'er and cyclization with triethyl orthoformate and the corresponding propionic acid (II: n = 0, R = H, Z = CH ₂ CHp) as hydrochloride by hydrolysis with hydrochloric acid.

M. 1933 * 13 ') i

S. JOHNE and B. JIMG (Pharmazie 33, 299 (1978)) synthesized the compounds of general formula II with n = 0 and Z = (CH ₂ ) ^ or Z = (CH ₂ ) ^ by reaction of isatoic anhydride with the corresponding amino acid ester hydrochlorides in absolute ethanol in the presence of triethylamine to the corresponding o-aminobenzoylaminocarboxylic acid cyclized with triethyl orthoformate.

IL S. SINTAK, IA MAZUR, PM STEBLYUK, PM KOCHERGIU (Farm Zh. (Kiev) 1J77 (3), 84) obtained 2- (quinazolin-4-on-3-yl) -propionic acid (II: n = O, R ¹ = H, Z = CHCH ₃ ) by alkaline hydrolysis τοη 2,3-dihydro-3-methyl-imidazo / 1,2-c / quinazolin-2-one, which was prepared over several stages, and by refluxing τοη quinazolin-4-one with 2-bromo-. Propionic acid in sodium hydroxide solution in low yield.

Z. CSUROS, R. SOOS, J. PALINKAS (Acta Chim. (Budapest) 63, 215 (1970)) prepared 3- (quinazolin-4-on-3-yl) -propionic acid (II; n = O, R ¹ = H, Z = (CH ₂ ) ₂ ) over several stages. Starting from τοη DMF in toluene was obtained with phosgene (CH ^) ₅ NCH ₉ Cl. This was reacted with methyl anthranilate in chloroform to give the hydrochloride τοη 2- (CH ₃ ) pNCffaNCgH ^ COgCH ^ and then converted into the above propionic acid by reaction with β-alanine in methanol.

LR CROOK, ABA JANSEH, K.E., Y. SPENCER and DH TfATSON (British Patent 1,036,694) prepared ethyl 4- (quinazolin-4-on-3-yl) -n-butyrate hydrochloride (II: n = 0, R = C ₂ H ₅ , Z = (CH ₂ ) ,,) over several reaction stages.

The disadvantage of these methods Tor.allem is that absolute solvents and expensive and / or technically difficult to handle starting materials Must be used and the reaction z. T. over several Reaktionsschrltte -_ runs.

Aim of the invention

It is an object of the invention to provide the compounds of the general formula II in sufficient quantities and cost-effective in practice.

cheap to provide.

Explanation of the essence of the invention

The object of the invention is to develop a simple process for the preparation of quinazolin-4-one-3-allcansäuren the general formula Hb and their esters of the general formula Ha, which by technically easy to handle "bare and inexpensive starting materials and only a small Number of reaction steps is characterized.

According to the invention, an isatoic anhydride of the general formula I is reacted with an aliphatic amino acid HpN-Z-COOH in solution or suspension in an organic solvent and / or water at a pH value between 7 and 12 to terminate the CO.sub.2 evolution and by subsequent Reaction with a methine-producing condensing agent prepared by heating a compound of general formula II.

In the general formulas R is alkyl, alkoxy, halogen, NO ₂ , CN, OH, CF ₃ or SO ₂ NH ₂ , R ^{1 is} H or alkyl, η is 0 to 4, where in the cases η = 2, 3 or 4 R is the same or different and Z is alkylene (straight-chain (C ₂ -C-Iq) or branched (chain length between N and COOR: C.-C- ₁₀ )) which optionally contains multiple bonds and / or OH, alkoxy, dialkylamino, CONH ₂ , CN, C0N (alkyl) ₂ , halogen, COOK, COO alkyl, substituted an optionally substituted aromatic or an optionally substituted heterocycle.

The adjustment of the pH to pH 7 to 12 is preferably carried out by adding a tertiary amine, for example triethylamine or 4-bimeth3'-laminopyridine, or by using the aliphatic amino acid H ₂ NZ-COOH as salt, for example as ammonium salt , The use of a buffer system is also possible.

The reaction of the isatoic anhydride of general formula I with the aliphatic amino acid is accomplished by thorough mixing of the reaction mixture, e.g., with stirring

Room temperature or carried out with heating, wherein expediently 80 ⁰ C should not be exceeded. After completion of the CCU development, the solvent is generally separated and then a methine-supplying condensing agent is added.

Purification of the residue prior to the addition of this condensing agent is not required. Preferred condensing agents in the case of straight-chain alkylene groups Z are trialkyl orthoformate or formic acid (also aqueous solutions of this acid), compounds of the general formula Hb being obtained. However, when the alkylene group Z is branched, it is preferable to use a trialkyl orthoformate to obtain a compound of the general formula Ha.

The condensation with formic acid is carried out in excess and under reflux, the reaction with orthoformic acid trialkyl ester by slow heating (bath temperatures up to 150 ⁰ C) with thorough mixing of the reaction mixture. In this case, longer reaction times are required for the preparation of the compounds of general formula Ha. It is expedient to constantly remove the resulting alcohols from the reaction mixture, for example by distilling off. The compounds of general formula Ha obtained by reaction with trialkyl orthoformate can be converted by hydrolysis into the compounds of general formula Hb.

In order to prepare compounds of general formula II wherein Z is an alkylene group containing multiple bonds, it is both possible to start from amino acids H ₂ NZ-COOH with the same Z and to use amino acids in which Z is a saturated but substituted alkylene group ', wherein the substituent is eliminated during the reaction of the invention to form a multiple bond. Such suitable substituents for the elimination are, for example, OH, CN or halogens.

The process according to the invention is based on technically easy-to-handle and cost-effective starting materials which are commercially available products or can be prepared by known processes A further advantage consists in the small number of reaction steps and in the fact that absolute solvents are not required Implementation can also be carried out in aqueous solutions or in water.

Apart from the representatives mentioned in the characteristics of the known technical solutions, the compounds of general formula II are new. They are biologically active and useful as plant growth regulators, fungicides or antiallergic agents.

The invention will be explained below by some embodiments.

From tro d run g sbe ispie le

example ^

3.2 g of isatoic anhydride, 2.0 g of β-alanine and 3.4 ml of triethylamine are stirred in 40 ml of water until the evolution of COp has ended (about 2 hours). The end is heated to 40-45 ⁰ C. The water is distilled off in vacuo and the residue is refluxed with 70 ml of formic acid for 6-10 hours. The formic acid is distilled off in vacuo and the residue is recrystallized from methanol. (.. 82% of theory): mp 187-189 ⁰ C, yield. -Propionic acid 3.6 g of ^a 3- (quinazolin-4-on-3-yl) (lib: Z = CH ₂ CH _2, n = 0 ).

Beisj) iel_2

1.6 g of isatoic anhydride, 1.0 g <X-alanine and 1.4 g 4-dimethylaminopyridine are stirred in 60 ml 7 / ater 3 hours at 40-50 ⁰ C. The water is distilled off in vacuo and the residue with 50 ml of triethyl orthoformate in

"heated distillation apparatus to 150 ^'0 C. bath temperature 3-10 hours after the Orthoester is distilled off in vacuo and the residue recrystallized from ethanol, mp 97-99 ⁰ C, yield:... (. 46 # d Th.) 1.0 g ^a to 2- (quinazolin-4-on-3-yl) -propionic acid ethyl ester (Ha: Z = CHCEL, n = 0, R ¹ = C ₂ H ₅ ).

Example 3 ...

1.6 g of isatoic anhydride, 1.1 g ^ aminobutyric acid and 1.5 ml of triethylamine are stirred in 50 ml of Y / ater until completion of the COP development "at 50. ⁰ C. The water is distilled off in vacuo and the residue treated with 60 ml of 80 $ strength aqueous formic acid is heated under reflux for 8-10 hours, the formic acid is distilled off in vacuo and the residue recrystallized from glacial acetic acid, mp 123-126 ⁰ C, yield:... (. 70% of theory.) 1.6 g of ^a 4- (Chinazοlin- 4-on-3-yl) -butyric acid (lib: Z = CH ₂ CH ₂ CH ₂ , η = θ).

Example 4

2.9 g of isatoic anhydride, 2.1 g of D, L-serine and 2.8 ml of triethylamine are stirred in 100 ml of water for 3 hours. The water is distilled off in vacuo and the residue with 40 ml Orthoameisensäuretrirnethylester 3 hours), refluxed. After distilling off the trimethyl orthoformate, the residue is purified by column chromatography and recrystallized from methanol. . (.. 24% of theory): mp 132 ⁰ C, yield 950 mg of ^a 2- (quinazolin-4-on-3-yl) -acrylic acid methyl ester (Ha: Z = C = CH _2, n = 0, R ¹ = CH ₃ ).

The following table contains more. Examples of compounds of the general formula II which can be prepared according to the invention are synthesized in the same manner as described in Examples 1 to 4.

- 7 (R) _n R ¹ Z SchiTip ( ⁰ C) yield (% of th.)

η = O H n = 0 H 6,8-Br ₂ P F 2 5 6-Br H 6,8-Br ₂ H 6-3r H 6,8-Br ₂ H 6,8-Cl ₂ H 6-Br CH ₃ n = 0 C r ¹ 6-Cl C ₀ H, - 6,8-Br ₂ ^C 2 ^H 5 6-Cl

CHCH ₃ 205 65

C = CH ₂ 206-210 43

CHCH ₃ 120 30 ^a

I ₂ CKp 218-220 '61 ^a

CHpCHp 230-232 70 ^a

CH ₂ CH ₂ Cn ₂ I94-I96 41 ^a

CHpCKpCHp 235-238 53 ^a

πΐτ f ("n" PPR / A ⁹ "

un _o · 1 oO- 1 o2 4 J

CH ₂ 75-77 73 ^a

CH ₂ 146-148 66 ^a

CHCH ₃ 120. 30 ^a

Cn ^ CHp -214-2 ¹ S o1

C: i _o Cii C OH) Ch ₀ 106-109 51

based on the "corresponding isatoic anhydride"

2.9.Bb-

AO

Il

Tr

N H

Il

"ir

, ι «ι * \ Λ" ΐ Λ ^ 10 ^u "3 - '· ^ ¹

Claims (9)

ErfindungsarLsprucL. 1. A process for the preparation of quinazolin-4-one-3-alkanoic acids and their esters of the general formula II, characterized in that an isatoic anhydride of the general formula I with an aliphatic amino acid HpN-Z-COOH in solution or suspension in a organic solvent and / or water "at a pH between 7 and 12 Ms to complete the COp development and by subsequent reaction with a methine-forming condensing agent produces a Verbiadung of the general formula II under heating, wherein in the general formulas R for alkyl, alkoxy, halogen, HO ₂ , CN, OH, CF ₃ or SO ₂ NH ₂ , R ^{1 is} H or alkyl, η is O to 4, where in the cases n = 2, 3 or 4, the R is the same or are different, and Z is alkylene (straight-chain (Cp-Gjq) or branched (chain length between N and COOR: C, -C ^ q)) which optionally contains multiple bonds and / or by OH, alkoxy, dialkylamino, CONH ₉ , CN , C0N (alkyl) ₂ , halogen, COOH, COOalkyl, an optionally substituted aromatic or an optionally substituted heterocycle is substituted. 2. The method according to item 1, characterized in that adjusting the pH to pH 7 to 12 by adding a tertiary amine or the aliphatic amino acid H ₂ NZ-COOH used as a salt or a buffer system used. 3. The method according to item 1 and 2, characterized in that the reaction of the aliphatic amino acid with the isatoic anhydride of the general formula I is carried out at room temperature or temperatures up to 80 ⁰ C and with thorough mixing of the reaction mixture. 4. The method according to item 1, characterized in that the solvent is separated before the addition of the methine-producing condensing agent. 5. The method according to any one of items 1 to 4, characterized in that are used as condensing orthoformate or formic acid. 6. The method according to item 1 "to 5, characterized dai3 one carries out the condensation in the case of the compounds having straight-chain alkylene Z with formic acid or its aqueous solutions by boiling at reflux or with a trialkyl orthoformate by slow heating and thereby the compounds of the general formula Hb manufactures. 7. The method according to item 1 to 5, characterized in that the condensation is carried out in the case of the compounds with branched alkylene group Z with Orthoameisensäuretrialkyl- ester and thereby produces the compounds of general formula Ha, which is optionally a hydrolysis to the corresponding acids of the general Subjecting formula Ub. 8. The method according to any one of items 1, .. 5, 6 or 7, characterized in that formed during the cyclization alcohols are distilled off during the reaction. 9. The method according to any one of items 1 to 8, characterized in that for the preparation of compounds of general formula II in which Z is an alkylene group containing multiple bonds, amino acids HpN-Z-COOH be used in which Z is a saturated but substituted alkylene group, wherein OH, CN or halogen is suitable as a substituent. For this 1 page formulas