DD142337A1 - METHOD FOR THE PRODUCTION OF SUBSTITUTED PYRROLO CORNER CLAMPS ON 1,2-A CORNER CLAUSE TO CHINAZOLINONE - Google Patents

Abstract

The aim of the invention is to provide new biologically active agents with Pyrrolof1,2-a-quinazolinone backbone. The object of the invention, a one-step process on the Basis of commercially available or readily available starting materials for Preparation of substituted pyrrolof 1,2-a] quinazolinones of To develop Formula I is solved by adding one if necessary substituted anthranilic acid ester with a substituted T-Kalogen-crotonsäurenitril converts. The implementation takes place in an organic solvent, both polar and dipolar aprotic solvents being suitable, in the presence of a Base, in particular an alkali or alkaline earth metal hydroxide or an organic nitrogen base. If necessary, it is advantageous the Anthranilsäureester in the form of its anion to the reaction bring. This is preferably done by adding metal hydrides, such as sodium hydride, or organometallic compounds, such as Butyllithium.

Description

21141

Process for the preparation of substituted pyrrole © ZT ₉ 2-a7-quinazolinone

The invention relates to a process for the preparation of substituted PyrroloZI ^ - ^ quinazolinones of the general formula I.

, I

Field of application of the invention

The invention is important for medicine, the pharmaceutical industry and agriculture, gardening and farming.

Charakterist ik the most t en tech niche solutions

While several representatives of hydrogenated PyrroloZT, 2 = a_7chi ~ nazolinone derivatives are known and synthesized in different ways, only one PyrroloZT »2-a7-quinazolinone has been synthesized so far, in which the pyrrole ring has an aromatic character; A, BRODRICK, and G. WIBBER-LEY (J. Chem. Soc., Perkin I 1975, 1910-13) obtained 2-cyano-

-2 - 211418

pyrroloZT, 2-.alpha.-quinazolinone- (5) from methyl anthranilate, succinonitrile and ethyl formate. However, this process is not generally applicable, so that substituted pyrrolo / T, 2-a7 quinazolinones of the formula I can not be prepared in this way.

Object of the invention

The aim of the invention is to provide novel biologically active compounds with PyrroloZJ »2-a_7chinazolinone skeleton, which can be prepared by a simple process»

Outline of the essence of the invention

The object of the invention is to develop a one-step process based on commercial or readily available starting materials for the preparation of substituted PyrroloZJ »2-a_7chinazolinonen.

According to the invention, an optionally substituted anthranilic acid ester, in particular the methyl ester, is reacted with a substituted α-halocrotonone nitrile of the formula III, preferably a substituted β-bromo crotononitrile, to give a pyrroloZi, 2α-quinazolinone of the formula I:

In formulas I and III, R is N0 _{o #} CN, COOR- ⁵ , phenyl (optionally substituted), benzoyl (optionally substituted), R and R

for H, alkyl (ζ.ΒCH ₃ or (CH ₂ C), NO ₂ , CN, COOR ³ , phenyl

(optionally substituted), benzoyl (optionally substituted), heterocyc

lus (optionally substituted), R ^{3 is} lower. Alkyl (1-4C), R ¹ and

R or R and R may also together be part of a fused carbocyclic or heterocyclic ring. The corresponding starting materials show the general formulas IV and V,

^x c

R ² -CH

Hal

CN

-CH

shark

CN

For a more detailed explanation, some examples of such compounds of formulas IV and V are listed in Table 1. These ring systems may optionally also contain substituents,

Substituting a substituted anthranilic acid ester, then m »1 to 4 and X for example, halogen, alkyl, alkoxy, OH, NOG" is CN, COOR ⁵ or COR ^, wherein the substituents with M + and / or + I effect preferably become.

In general, X 'is identical to X. However, X ¹ is different from X if'

COOCH ₃

X is the grouping μ f \ j remainder

contains. Then the

Part of X ¹ .

-4 - '21141

COOCH.

If ζ · Β · X is symbolized for V - \

the substituent ρ,

(CH ₂ ) _n -

In the case of such dimeric anthranilic acid esters, m = 1 and η = 0 to 10, preferably 1 to 3 ×

The starting materials for the process according to the invention are either commercially available products, or they can be prepared in a simple manner by known processes. For example, several compounds of formula III by a Knoevenagel reaction / G, Jones, Organic Reactions 15 ^ 204-599 (1967) 7 and subsequent bromination with bromine can be represented _t IT uccinimid bromine or special brominating "

The reaction is carried out in an organic solvent, wherein both polar solvents, for 'example, alcohols, preferably ethanol, propanol, iso-propanol, as well as dipolar aprotic solvents, _e z are B, dimethylformamide, dimethylsulfoxide or hexamethylphosphoric triamide, are suitable. In addition, the presence of a base, in particular an alkali or alkaline earth metal hydroxide or an organic nitrogen base, such as triethylamine, piperidine or pyridine is necessary so that the Bromwasser- = material is formed in the reaction is bound. Optionally, the yield of pyrrolo-T, 2-a7-quinazolinone can be increased considerably by increasing the nucleophilicity of the nitrogen of the anthranilic acid esters used by reacting it in the form of its anion. This is preferably done by adding metal hydrides, such as Natriumhydrid-, or metallor-

ganic compounds, such as lithium butyl, before it is mixed with the hydrogen halonitrile nitrate. The addition of another base is not necessary in these cases.

The fiction, contemporary method is characterized by the easy accessibility of the starting materials. A particular advantage is that the three-membered heterocyclic ring system of the compounds prepared by this process is synthesized by only one reaction step and in good yields.

The compounds prepared by the process according to the invention are novel, biologically active and have in particular hypnotic and anticonvulsive properties. Moreover, they are effective pesticides.

The invention will be explained below by some embodiments *

Ausführungebeispiele

To 5 * 0'g. (20 mmol) cC-cyano-ß-bromornethyi-cinnamonitrile in 50 ml of propanol is added dropwise with stirring slowly at 80 ⁰ C 3.0 g (20 mmol) of methyl anthranilate in 10 ml of propanol to «stirring every 15 minutes 2.75 ml Triethylamine in 20 ml of propanol was added dropwise. The temperature is allowed to cool for a further hour _{and then} it is filtered off with suction. It is recrystallised from DMF. Mp _e 317-19 ⁰ C (dec *) · t Yield 4.7 g (83) f 2-phenyl-3 "cyano-pyrroloZi" 2 ~ a7china2olinon- (5)

To 5.88 g (20 mmol) of oCi-cyano-ß-bromomethyl-cinnamic acid ethyl ester in 50 ml abs'A'thanol is added dropwise with stirring slowly at 90 ⁰ C 3.0 g (20 mmol) of methyl anthranilate in 10 ml of ethanol to. After 20 minutes, 800 mg of NaOH in 10 ml of ethanol are slowly dropped dropwise, allowed to stand overnight and

-6-211418

sucks off. It is recrystallized from abs "ethanol. Yield .: 3.9 g (53% d.Th.) Mp. 193-4 ⁰ C (dec.) 2-phenyl ~ 3-ethoxycarbonyl-pyrrolo-ZI "2-a7chinazolinon- (5)

'Example 3

To 3 » _: 0 g (20 mmol) of methyl anthranilate in 100 ml of abs» THF at - 72 ⁰ C are added dropwise 128. mg of lithium butyl in the form of a 20% solution in hexane with stirring. To the resulting yellow solution is slowly added dropwise a precooled solution of 3 »7 g (20 mmol) of cC-cyano-ß-bromomethyl-crotonsäurenitril in 20 ml abs. THP too. It is allowed to warm to room temperature with a cold bath (about 3 days), acidified with acetic acid, the THF distilled off and poured into water. "The precipitated oil solidifies. In the other case, it is taken up in ethanol and recrystallized from ethanol. . Mp 316-18 ⁰ C (dec.) Yield .: 3.8 g (85% of theory) of 2-methyl-3-cyano-pyrrolysine Io β, ^ - ajchinazolinon- (5)

Example 4

3.0 g (20 mmol) of methyl anthranilate are slowly added dropwise to 4.64 g (20 mmol) of cO-cyano-.beta.-bromomethyl-crotonsäureäthylester in 30 ml of DMF. It is heated to 30-40 ⁰ C and slowly added dropwise 2.8 ml of triethylamine in 5 ml of DMF. The mixture is allowed to stand overnight, poured into water, filtered off and crystallized from methanol to "mp 228-230 ⁰ C (dec.). Yield: 3.0 g (50% of theory) of 2-methyl-3-ethoxycarbonyl -pyrroloZi, 2-a7-chinazolinon- (5)

Example 5

3.8 g (25.2 mmol) of methyl anthranilate are placed in 100 ml iso-propanol at 80 ⁰ C with stirring, 5.5 g (25.2 mmol) of ca-cyano-y-bromo-crotonsäureäthylester in 10 ml iso- Propanol added dropwise. After 10 minutes, 2.4 g of pyridine are added dropwise in ml of isopropanol, refluxed for one hour and stirred and allowed to stand overnight. Isopropanol is stripped off in vacuo, mixed with water and filtered with suction.

141

It is recrystallized from methanol / DMF (10: 1). . Mp 198-200 ⁰ C (dec.) · Yield: 2.7 S (42% of theory) of 3-Ä'thoxycarbonyl-pyrroloZH, 2-a7chinazolinon- (5)

Example 6

To 1.18 g (5 mmol) of methylene-bis-5,5 ^r -anthranilic acid methyl ester dissolved in 10 ml of DMF are 2.4? g (10 mmol) et- cyano ß-bromomethyl-cinnamonitrile added in 10 ml of DMF and heated to 50 ⁰ C. With stirring, 1 g of triethylamine, allowed to stand overnight, poured into water and filtered off with suction. It is recrystallized from DMF. Mp.> 560 ⁰ C (decomp.) Yield: 2.4 g (41% of theory) of methylene-bis-7i7 * ~ Z2-phenyl-3-cyano-pyrroloZfi, 2-a7chinazolinon- (5l7

Example 7

To 1.65 B (10 mmol) of 2-amino-5-methyl-benzoic acid methyl ester in 20 ml of DMSO, 1.85 g (10 mmol) of o ^ -cyano-ß-bromomethylcrotonsäurenitril are added dropwise. The mixture is heated for 10 minutes at 40 ⁰ C, allowed to cool and are 1 g of triethylamine added, allowed to stand overnight and poured into water. The solidified oil is recrystallized from methanol. . Mp 293-96 ⁰ C (dec.) Yield: 1.6 g (68% of theory) of 2-methyl-3-cyano-7-methyl-pyr ~, 2 ~ a7chinazolinon- (5)

Example 8

3.0 g (20 mmol) of methyl anthranilate are dissolved in 25 ml of DMSO. One gives 480 mg of sodium hydride, and after completion of the evolution of hydrogen is added dropwise at * 5 - 10 ⁰ C 5j44 g (20 mmol) of 2-Bromcyclohexylidencyanessigsäureäthylester to. It is allowed to stand overnight, poured into water and acidified with acetic acid. The precipitated product is recrystallized from methanol. If no crystallization occurs, the viscous oil is separated by column chromatography (benzene / acetone) and then recrystallized from methanol. . Mp 202-203 ⁰ C (decomp.) Yield: 350mg 1,2,3,4-Tetrahj'dro-5-carbonyl äthoxj ^r "indoloZT, 2-a7chinazolinon- (7)

ο ! HU

AA-

CD I

O O -

CM

ac

VJ

Z o

L-

χ ο

Claims (3)

Claim of invention . 1. Process for the preparation of substituted pyrrolo / ^; T, 2 ~ a7-quinazolinones of general formula I, characterized in that an optionally substituted anthranilic acid ester is reacted with a substituted f -halo-crotonsäurenitril of general formula III to give the corresponding pyrrolo-ZH, 2-a7-quinazolinone, wherein in the formulas I and III R for NO ₀ , CN, COOIr, optionally substituted 12 tes phenyl or optionally substituted benzoyl, R and R for H, alkyl, NO ₂ , CN, COOR *, optionally substituted phenyl, optionally substituted benzoyl or an optionally substituted 1 1? heterocycle but R and R or R and R also together part of a fused carbon or heterocyclic ring system, Έ / lower alkyl ( 1-4C ), m is an integer from 1 to 4, η is an integer from 0 to 10 and X ¹ H, halogen, alkyl, alkoxy, OH, NO ₂ , CN, COOR ⁵ or COR ⁵ , if necessary also CC H ₂ ) _n - mean. R ¹ \ CH CN shark Process according to item 1, characterized in that the methyl ester of the formula II in which X is H, halogen, alkyl, alkoxy, OH, NO ₂ , CN, COOR ^ or COR ^, if appropriate also for., Is used as anthranilic acid ester COOCH. wherein substituents with + M and / or + I effect are preferred, m is an integer from 1 to 4 and η is an integer from 0 to 10. NH ₂ Process according to items 1 and 2, characterized in that the α-bromocarbonitrile of the formula III (Hai = Br) is used as the α-halocarbonitrile, the substituent being
given meaning. 1 2 where the substituents R, R and R are as defined above. 4 ·. Process according to item 1 to 3, characterized in that the reaction is carried out in a polar solvent, for. As an alcohol takes place. 5. The method according to item 1 to 3, characterized in that the reaction in a dipolar aprotic solvent, z. As dimethylformamide, dimethyl sulfoxide or hexamethyl-'phosphorsäuretriamid occurs t. 6. -Process according to item 1 to 5>, characterized in that the reaction in the presence of a base, in particular an alkali or alkaline earth metal hydroxide, or a λ ο πι ¹ · ¹ -ί η? η. i ~ < 1 1 »j - ··   - >>. 211418 organic nitrogen base, such as triethylamine, piperidine or pyridine, is performed. Process according to items 1 to 6, characterized in that the optionally substituted anthranilic acid ester is reacted in the form of its anion, preferably by adding a metal hydride, for example sodium hydride, or an organometallic acid, before mixing with the substituted α-halocarbonitrile Compound, such as lithium butyl, is added. To do this, 1 soap formulas