DD152933A5 - PROCESS FOR THE PREPARATION OF 4-PHENYL-2 (1H) -CHONOZOLINONES AND -ETETRAHYDRO-2 (1H) -CHINAZOLINONES - Google Patents

Abstract

The invention relates to a novel process for the preparation of 4-phenyl-2 (1H) -quinazolinones and -4a, 5,6,8a-tetrahydro-2 (1H) -quinazolinones with valuable pharmacological, in particular analgesic and antiperspirant properties. The process according to the invention for the preparation of the compounds of the formula (I) is characterized in that compounds of the formula (II) are reacted with compounds of the formula (III), the reaction product is hydrolyzed and, if necessary, the compounds of the formula (I) are further oxidized. The process according to the invention is used in the chemical or pharmaceutical industry.

Description

57 880 18

Process for the preparation of 4-phenyl-2 (1H) -quinazolinones

and -t etrahydro-li-l) -china zo lin one n ^ ₁ _

You want η ei sc; eb e t of re ning.

The invention relates to a novel process for preparing 4-phonyl-2 (1H) -quinazolinones and 4α, 5,6,8a-tetrahydro-2 (1H) -quinazolinones having valuable pharmacological, in particular analgesic and antiinflammatory properties.

In particular, the invention relates to a process for the preparation of compounds of the formula I.

I ₁

where rxn

for C ^ ₅ -AlkVl, C ₃ _ ₆ -Cyi <loalkyl, C ^ g

alkyl, C ₁ _ _r haloalkyl, allyl or propargyl,

ι R3 1 R ^ and Rg are independently hydrogen, fluorine, chlorine, bromine, C ^ ₄ alkyl / C _1-4 -alkoxy, C ^ ₄ -AIkV thio, nitro or trifluoromethyl, wherein at least two of the substituents R, R ₃ , R and

12o 12 * 80

AP C 07 D / 222 771

57 880 18

Rg are hydrogen,

Y and Yp independently of one another denote hydrogen, fluorine, chlorine, bromine, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy or trifluoromethyl.

JL "" * 4 · 3. * - *!

t-en, and ring A the structures

(a) R

has "

Various processes for the preparation of 4-phenyl-2 (1H) -quinazolinones are known, for example, B * by cyclization of 2'-Am in benzenes,

DD-PS 75 514 and 100 950 describe the preparation of 2 (1H) -quinazolinones by cyclization of 2-aminobenzophenones with alkyl carbamates or "described with urea." From German DE-OS 1 695 769, 2 230 393, 1 805 501 and 2 307 800 are furthermore the compounds of the formula I in which A has the structure (b). They are analgesic and anti-inflammatory effective «

12. 12. 80

AP C 07 D / 222 771

57,880 IS

Zie l of Erf indung

The aim of the invention is to provide a simple and economical process, with the 4-phenyl-2 (IH) -chinaz-olinone and tetrahydro-2 (lH) -quinazolinones in good yield j can be prepared

yi / esens d the invention

The invention is based on the objective to achieve a significant increase aer yields and a reduction in costs by by first preparing a quinazolinedione and choose a phenyl group is introduced "

The introduction of the phenyl group takes place almost exclusively in the 4-position of Chinazolindions and not equally in the 2- and 4-position.

According to the invention, compounds of the formula I are obtained by reacting compounds of the formula II

II

^ 100-5222

wherein R, -R ₅ and A have the above meaning, with compounds of the formula III,

^Y l

III

in which Y, and Y "have the abovementioned meaning, and Z is lithium or a group of the formula -MgX in which X is chlorine, bromine or iodine, the reaction product is hydrolyzed and, if necessary, compounds of the formula I in which A is the structure ( a) has, to compounds. of formula I, wherein A has the structure (b), oxidized.

The reaction of compounds of formula II with compounds of formula III is conveniently carried out ^in: conducted under anhydrous conditions and, if necessary, with · a 'excess of compounds of the formula III an inert organic solvent such as tetrahydrofuran, dioxane, dimethoxyethane or Diäthylather. The reaction temperatures are conveniently between 0 ° and 60 °, preferably between 30 and 50 ° C. According to a preferred embodiment, the compounds of the formula II are first treated with sodium hydride and then reacted only with compounds of the formula III. An excess of compounds of formula III is then no longer necessary.

The hydrolysis of the reaction product can be carried out in a manner known per se, e.g. with water, diluted mineral acids or "weakly acid" compounds, such as ammonium chloride or "tartaric acid", "" carried out.

- p

100-5222

If the hydrolysis of the reaction product in which A has the structure (a) is carried out under weakly acidic or neutral conditions, intermediates of the formula Ia,

Ia

wherein R, -Rj-

Y, and

have the above meaning arise, which in compounds of formula I, wherein A has the structure (a), can be converted, for. by treatment with a dehydrating agent.

The compounds of the formula I in which A has the structure (a) can be converted into compounds of the formula I in which. A having the structure (b) oxidizes, e.g. with sulfur, selenium, benzoquinone, tetracyanoethylene, triphenylmethyl perchlorate or a catalyst such as palladium on charcoal, nickel or e.g. Iron oxide. Suitable temperatures are between 200 and 210 ° C. If desired, it is also possible to work in the presence of an inert organic solvent, for example o-dichlorobenzene, decalin or dodecylbenzene.

^r v) fi

100-5222

The compounds of formula II are novel and are also the subject of the present invention. They can be prepared by reacting compounds of formula IV,

IV

wherein

and A have the above meaning, and R

Alkyl, hydrolyzed and, if necessary, obtained compounds of formula II, wherein A has the structure (a), to compounds of formula ___ II, wherein A has the structure (b), oxidized.

The hydrolysis is conveniently carried out in an alkaline medium at room temperature. "Alkali hydroxides, such as sodium or potassium hydroxide, e.g. ethanolic sodium hydroxide are used for this purpose. The process is preferably carried out in the presence of hydrogen peroxide.

The oxidation can be carried out as described above for the compounds of the formula I.

The compounds of formula IV are novel and are also the subject of the present invention. They can be prepared by reacting compounds of formula V,

«*, Μ 2 $ r! 100-5222

771

⁵ I ¹

C, N-COOR C CH

Il

CH

^R 3

with compounds of the formula VI,

R ₂ -CH = CH-CN VI

wherein R - R ₁ . and R have the above meaning, reacted and if necessary obtained compounds of formula IV, wherein A has the structure (a), to compounds of formula IV, wherein A has the structure (b), oxidized.

The reaction of compounds of formula V with compounds of formula VI can be carried out in the presence or absence of a solvent at temperatures between 120 and 140 ° C. As the solvent, o-dichlorobenzene, decalin and xylene can be used.

The oxidation can be carried out as described above for the compounds of the formula I.

If an oxidation of compounds of the formulas I, II and IV in which A has the structure (a) is required, then this can be conveniently carried out without prior isolation of these compounds.

I eat 12 * 12, SO

AP C 07 D / 222

57 880 18 - ö

The compounds of formula V can be obtained by Verbinduncsen the formula VlI

^R 5 ^R

VII

with compounds of the formula VIII

X'-COOR VIII,

in which R ₁ , R 1 -R _r and R have the above meanings and X ¹ denotes chlorine or bromine, reacts «

The reaction is conveniently carried out at room temperature in an inert organic solvent such as benzene, toluene, hexane or methylene chloride. An acid binder such as diethylaniline or 2,4,6-trimethylpyridine may be used.

The compounds of formulas III, VI, VII and VIII are either known or can be prepared in manner known per se _β the final products and intermediates can be isolated in a conventional manner and purified.

The compounds of the formula I in which Λ has the structure (b) are known z, B * from DE-OS 1 695 769, 2 230 393, 1 805 501 and 2 307 80S. They are z, B * anaigetic and anti-inflammatory effective «

J I - yt ^ _ 100-5222

The compounds of formula I wherein A has the structure (a) are novel and also form an object of the present invention.

If in compounds of the formula I R 1 is alkyl, it is preferably isopropyl. If R 1 is haloalkyl, this is preferably 2,2,2-trifluoroethyl, and if R 1 is cycloalkylalkyl it is preferably cyclopropylmethyl. R is preferably phenyl or halophenyl, in particular fluorophenyl, especially 4-fluorophenyl. ·.

A particularly preferred group of compounds of the formula I are compounds of the formula Ib,

R. ¹

ib

wherein

R 'is C ₁ _ ₅ alkyl, C ^ g-cycloalkyl, C ₃ _ ₆ cycloalkyl-C, alkyl., C, - polyhaloalkyl, allyl or propargyl,

R 'is hydrogen, fluorine, chlorine, bromine, C, - alkyl, C.-rAlkoxy, C._ ₃ ~ alkylthio, nitro or trifluoromethyl and γ' and Υ '' independently of one another represent hydrogen, fluorine, chlorine, bromine, C., -alkyl, C _1-4 -alcohol or

I 12 «12. 80

AP C 07 D / 222 771 57 880.18

Trifluoromethyl, but only one of the substituents Y. ' and Y _? 'Trifluoromethyl can mean »

As compounds of the formula I which can be prepared by the process according to the invention, mention may be made of:

1-isopropyl-4-methyl (4-fluorophenyl) -7-methyl-2 (1H) -quinazolinone,

l-isopropyl-4-phenyl-2 (1H) -quinazolinone,

- i-1-gopropyl-4'-phenyl-6-methoxy-2 (1H) -quinolineolinone, and

- l- (β-trifluoroethyl) -4-phenyl-6-chloro-2 (1H) -quinazolinone _e Ausführunqsbeispiel

The invention will be explained in more detail below with reference to some examples. All temperatures are given in degrees Celsius.

12771

100-5222

Example · 1: 1-Iso-phenyl-4-phenyl-1-7-reethyl-2 (IH) -quinasolinone

To a solution of 657 g Diäthylanilin in 2L toluene 416 g of methyl chloroformate are added dropwise with stirring within about 5 Hinuten, then 500 g of N- (3-methyl-2-butenylidene) -isopropvlamin in 500 ml of toluene are added dropwise with stirring within 2 hours , where the

.ML. Temperature is maintained at 25-30 ° C. After completion of the addition, the reaction mixture is stirred for 1 hour and then treated with 400 ml of water and 90 ml of concentrated hydrochloric acid. The organic phase is washed with 600 ml of saturated aqueous sodium bicarbonate solution and with 600 ml of water, dried and concentrated in vacuo to give the title compound.

b) Z- (N-iso-chloro-N-carbomethoxanuno) -4-rnethyl-benzonitrile

.. 915 g of N-isopropyl-N- (3-methyl-l, 3-butadienyl) -carbamic acid methyl ester are heated without solvent to 120 ° and treated dropwise at this temperature with 345 g of acrylonitrile. After completion of the dropwise addition is stirred for one hour at 140 °. The result. standing 2 ~ (N-isopropyl-N-carbonethoxyamino) -4-methyl-3-cyclohexene-nitrile is heated to 2 00 ° and treated within 2 hours in portions with 386 g of sulfur powder and then stirred for 2 hours at 205 °. The reaction mixture is distilled under high vacuum at 110-120 ° (0.1 torr) and the residue from benzine fraction

22,771 " X ¹⁰⁰ " ⁵²²²

recrystallized to obtain the title compound of mp. 100-101 °.

dion

To a suspension of 300 g of 2- (N-isopropyl-N-carbomethoxyamino) -4-methyl-benzonitrile in 750 ml of Kasser and 2 34 ml of ION sodium hydroxide solution, 576 g of a 40% strength hydrogen peroxide solution are added within 80 minutes. drips. The clear solution is concentrated with 19 5 ml conc.

Hydrochloric acid acidified, v / obei 'the title compound fails, Smpr 250-251 ° Γ - "- -

13.08 g of 1-isopropyl-7-methylquinazoline-2,4-dione are added in portions with constant evolution of hydrogen to a suspension of 1.8 g of sodium hydride in 25 ml of tetrahydrofuran. 40 ml of a 2N solution of phenylmagnesium bromide in tetrahydrofuran are added to the now almost clear solution at 40 ° and the resulting suspension is stirred for 15 hours at 40 °. After addition of water, the tetrahydrofuran is removed in vacuo and the residue taken up in methylene chloride and 30 ml of 12% hydrochloric acid. The organic phase is concentrated to give the title compound, which recrystallized from toluene at 140-143 ° melts.

..25_. When using 40 ml of a 2N 4-Fluororphenylmagnesiumbromidlösung gives l-isopropyl-4- (4-fluorophenyl) -7-methyl-2 (IK) -quinazolinone, mp. 174-176 °.

fji - ^ f- 100-5222

Example 2: 1-Isopr- opyl -4- (4-fluorophenyl) -7-methyl'2 (IH) -quinazolinone . ,

A solution of 100 g of 2- (N-isopropyl-N-carbomethoxyamino) -4-methyl-3-cyclohexene-nitrile in 700 ml of 9 5% ethanol is treated with 90 ml of conc. Sodium hydroxide added. 600 ml of a 40% strength hydrogen peroxide solution are added dropwise to the mixture within 4 hours with stirring to an internal temperature of 35 ° and the stirring is continued at room temperature overnight. After concentration in vacuo, the residue is taken up in water and toluene and the aqueous phase is extracted twice with toluene. The combined toluene extracts are washed with water and concentrated in vacuo to give the title compound.

A stirred suspension of 2.37 g of sodium hydride in 45 ml of tetrahydrofuran is added in portions at room temperature with 13.32 g of 1-isopropyl-7-methyl-4a, 5,6,8atetrahydro-2,4 (IH) -quinazolinedione and the mixture stirred for 45 min. At an internal temperature of 4 ° C., 39 ml of a 2N solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran are added dropwise thereto over 2 hours, and the resulting suspension is stirred for 15 hours at 40 °. Then the reaction mixture, while cooling with ice, is admixed with 2 ml of 15% hydrochloric acid and the solvent is removed in vacuo.

100-5222

removed. The residue is taken up in water and methylene chloride and the methylene chloride phase is evaporated to dryness in vacuo to give the title compound.

Using aqueous ammonium chloride solution instead of 15% hydrochloric acid gives 1-isopropyl-4- (4-fluorophenyl) -4-hydroxy-7-methyl-4a, 5,6,8a-tetrahydro-2 (IH) -quinazolinone , Mp 154-158 °, which can be converted by treatment with hydrochloric acid in the title compound.

zolinon

17/4 g of 1-isopropyl 1-4- (4-fluorophenyl) -7-methyl-4a, 5, 6, 8a-tetrahydro-2 (IH) -quinazolinone vzerden dissolved in 50 ml of decalin hot and at 140 ° portions mixed with 4 g of sulfur powder. After completion of the addition, stirring is continued at 160 ° for one hour. The mixture is diluted with toluene and extracted several times with 15% hydrochloric acid. The acidic aqueous phase is underlaid with methylene chloride and neutralized with sodium hydroxide under ice cooling. The aqueous phase is extracted with methylene chloride and the combined methylene chloride extracts are concentrated in vacuo. The concentrate is chromatographed on silica gel using dichloromethane and methanol as eluent. After recrystallization from toluene, the title compound of mp. 174-176 °.

3700 / IG / SE

Claims (3)

57 880 18 -AS Invention claim 1. Process for the preparation of compounds of the formula I, wherein R _{1 is} G _1-5 -alkyl, C, g-cycloalkyl, C ₁ -C 6 -cycloalkyl-C ₁ -alkyl, C ₁ -C -haloalkyl, allyl or propargyl, Ro, R-, R * and R ^ independently of one another are hydrogen, chlorine, chlorine, bromine, C ₁ -C 4 -alkyl, C ₁ -C 4 -alkoxy, C ₁ -C 4 -alkylthio, nitro or trifluoromethyl, 100-5222 wherein at least two of the substituents R ₂ , R ^, R ^ and R _{5 are} hydrogen, Y. and y.sup.4 independently of one another denote hydrogen, fluorine, chlorine, bromine, C, .alpha.) 'L, C,., - alkoxy or trifluoromethyl, and ring A the structures (A) has, characterized in that one a) for the preparation of compounds of the formula I in which R ₁ to R ₁ -, Y -, Y ₂ and ring A have the above meanings, compounds of the formula II, II wherein R, -R ₅ and A have the above meaning, with compounds of the formula III, III 100-5222 where Y, and Y _{2 have the} above meaning, and Z for. ''."Lithium or a group of the formula -MgX, wherein X is chlorine, bromine or iodine, reacting, the reaction product hydrolyzed and, if necessary, compounds of formula I, wherein A has the structure (a), to compounds of formula I, wherein A has the structure (b), oxidized, b) for the preparation of compounds of formula I, wherein r; Y, and Y _{2 have the} above meaning, and R, up A has the structure (a), compounds of the formula Ia, Ia wherein R, to R Y .. and Y ~ have the above meaning, a dehydration subject, or c) for the preparation of compounds of formula I, wherein R, to Rr, Y, and Y _{2 have the} above meaning, and A having the structure (b), compounds of the formula Ia dehydration and thus obtained compounds of formula I, wherein A has the structure (a), oxidized. 57 880 18 2. The method according to item 1a) or 1c) for the preparation of compounds of formula I mentioned in point 1, wherein R ₁ to Rr, Y ₁ and Yp have the meaning given in point 1, and Λ has the structure (b) characterized in that corresponding compounds of the formula I in which A has the structure (a) are oxidized. 3. The method according to item 1a), characterized in that treating compounds of formula II first with sodium hydride.