DE2234174A1 - PROCESS FOR THE PRODUCTION OF QUINAZOLINONS - Google Patents

Description

Patent attorneys

Dipl.-Ing. P. Wirth

Dr. V. Schn-isd-Kowarzik Dipl. Lao. G. Dannenberg Dr. P. WC inhold, Dr. D. Gudel

6 Frankfurt / M., Gr. Eschenheimer Str. 39.

Case ΰΟΟ-6301 / C

2 2 3 4 17 Λ

SAVSOZ Baetl / Setartis

Process for the preparation of Chxnazolinonen

The invention relates to a «method of manufacture of quinazolinones of the formula I,

^(CH 2 »n

wherein either R..and R _{3 are the} same or different

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and in each case hydrogen, fluorine, chlorine or alkyl with 1-3 carbon atoms, or R. and R each represent hydroxyl or R and R each denote alkoxy 1-2 carbon atoms, or one of the substituents R and R for bromine, hydroxy or alkoxy with 1-2 carbon atoms and the other is hydrogen, η is 1, 2 or 3 and either R is alkyl with 1-5 Denotes carbon atoms or R denotes a radical of the formula III or IV

CH ₃ ¹¹¹ IV

where M is 1 or 2 and either Y and Y are the same or different and each are hydrogen, fluorine, chlorine or alkyl with 1-3 carbon atoms, or Y and Y _{1 are} each hydroxy, or Y and Y- each denotes alkoxy with 1-2 carbon atoms, or one of the substituents Y and Y denotes bromine, hydroxy or alkoxy with 1-2 carbon atoms and the other denotes hydrogen, however

1) at most two of the substituents R, R ", Y and Y. stand for hydroxy,

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) R ₁ and R each do not represent hydroxy, if Y

■ L

or Y is

. or Y is alkoxy with 1 or 2 carbon atoms

3) Y and Y. each do not represent hydroxy if R ₁ or R "is alkoxy with 1 or 2 carbon atoms

■ L ■ £ »

mean,

4) at least one of the substituents R ₁ and R is not hydrogen, fluorine or chlorine and R. and R_ are not simultaneously alkoxy with 1 or 2 carbon atoms, if R is alkyl with 1-5 carbon atoms or a radical of the formula III , in which m is the number 1, and Y and Y are hydrogen.

According to the invention one arrives at the compounds of the formula I, by

a) compounds of the formula V,

wherein R, R and R have the above meaning with compounds of formula VI,

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VI

^(CH 2> n

where η has the above meaning, W stands for oxygen or sulfur and R. is alkyl with 1-4 carbon atoms or benzyl, reacts in the presence of an inert organic solvent,

b) for the preparation of compounds of the formula Ia,

Yes

< ^G Vn

in which η has the above meaning and R ¹ , R ¹ and R 'have the same meaning as R, R and R, with the exception that none of these substituents can mean or contain hydroxy, compounds of the formula VII,

N "CH ₂ - (CH ₂ ) _n -OH

VII

wherein n, R ¹ , R 'and R' have the above meaning, with a cyclization medium. reacted and the reaction product treated with an acid binder, or

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c) for the production of hydroxy-substituted compounds formula Ib, -

Ib

where η has the above meaning and R

as well as R,

R ¹ 'have the same meaning as R, R. _OUWiC ^ _, 2 12

with the exception that at least one of the substituents R ¹¹ , R ¹ and R ' ¹ denotes or contains hydroxy, corresponding alkoxy-substituted compounds of the formula Ick,

Ick

where η has the above meaning and R ¹¹¹ , R ^'11 and R' ^l! have the same meaning as R, R ₁ and R ₂ , with the exception that at least one of the substituents R ¹ * ', R " ¹ , RJI ₁ " is alkoxy with 1 or 2 carbon

R ¹ '

' ^E 2

denotes or contains atoms, and that R, ¹ ″ and R can each represent alkoxy with 1 or 2 carbon atoms, if R " ¹¹ does not denote a radical of the formula III or IV in which Y or Y ₁ denotes hydroxy or alkoxy with 1 or 2 carbon atoms.

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The process a) is conveniently carried out at temperatures of 20-160 ⁰ C, for example 20 and 140 ° C, preferably 80 and 120 ° C. Cyclic ethers and aromatic solvents which can conveniently be used at reflux temperature, such as toluene or dioxane, are suitable as solvents. The process is preferably carried out in the presence of a base such as sodium hydroxide or sodium carbonate. The compounds of the formula III can be used in the form of their free bases or their acid addition salts, in the latter case preferably an amount of base sufficient to neutralize the acid is used.

Process b) represents a cyclization reaction which is known per se It can be carried out using cyclizing agents customary for this purpose, for example using phosphorus chloride or bromide, thionyl chloride or bromide, preferably phosphorus chloride or in particular thionyl chloride is used. The process can be carried out in the presence of an inert organic solvent be carried out, for example a halogenated hydrocarbon such as methylene chloride or chloroform or an aromatic solvent such as benzene or pyridine. Optionally can be used as the reaction medium also use an excess of cyclizing agent. the subsequent treatment with an acid binder> for example an inorganic base or a tert. Amine, is preferably carried out after any cyclizing agent that may still be present has been removed.

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The process c) can be used for the hydrolysis of
Carry out alkoxy groups to hydroxyl groups in the usual manner, for example by treatment with aqueous hydrobromic acid at elevated temperature, for example at temperatures between 40 and 150 ^° C.

The compounds of the formula I can be known per se Way is isolated and cleaned. The free. Bases can be converted into acid addition salts in the usual way and vice versa.

The starting products of the formulas V and VI are known or can be produced in a manner known per se.

The / uisgangsprodukte of the formula VII can be prepared Are, by adding compounds of the formula VIII,

VIII

wherein R ¹ , R ', R' and R _{4 have the} above meaning,
with compounds of the formula IX>

H "N - CH ₀ - (CH") - OH ζ ζ ζ η

IX

where η has the above meaning.

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The process is conveniently carried out at. Temperatures between O and 120 ⁰ C, preferably 20 to 80 ⁰ C, and using a üeberschusses of compounds of formula IX. The process is preferably carried out in the presence of an inert organic solvent, for example a chlorinated carbon such as chloroform or methylene chloride.

The compounds of the formula VII can be isolated and purified in a manner known per se.

The compounds of the formula IX are known.

The starting products of the formula VIII can be prepared by adding compounds of the formula X,

R ¹

wherein R ¹ , R ¹ and R 'have the above meaning with an alkyl iodide or benzyl iodide of the formula XI,

R ₄ J XI

wherein R has the above meaning.

The process is conveniently carried out at temperatures between 0 and 1OO ° C, preferably 15 to 60 ⁰ C,

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as well as in an inert organic solvent, for example an alcohol with 1τ5 carbon atoms, such as ethanol, or an ether such as dioxane, with ethanol being preferred.

The compounds of the formula VIII can be isolated and purified in a manner known per se. The connections of the formulas X and XI are known or can be prepared in a manner known per se.

The compounds of the formula Ick which are outside the scope of the formula I are known and can be analogous to the already described process a) or b) produce.

The compounds of formula I are medicaments. They have a particular bronchodilator effect, so that they can be used as bronchodilators. the The dose to be administered daily here is, for example, 20-1500 mg, preferably administered in partial amounts between 5 and 750 mg, two to four times a day or in sustained release form.

The compounds of formula I can with conventional pharmaceutical Diluents, carriers or auxiliaries combined and administered, for example, in the form of capsules or tablets. The compounds of formula I can also be administered by inhalation therapy, for example using spray devices,

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vapors or aerosols.

The compounds of the formula I can be used in the form of their free bases or in the form of their acid addition salts with pharmaceutically harmless acids are used, which correspond to the activity of the free bases. For example, inorganic acids such as hydrochloric acid or organic acids are suitable for salt formation, like methanesulfonic acid.

Of the compounds of the formula I, those are preferred in which R stands for benzyl or substituted benzyl, in particular p-chlorine, p-bromine or p-fluorobenzyl radicals. Of these, those compounds are preferred in which R and R_ each denote hydrogen, and of these compounds in particular those "in which η is 1 or 2. Above all, however the 4-halobarethyl compounds are preferred in which η stands for the number 1, in particular 10- (4'-fluorobenzyl) -2,3-dihydroimidazo [2,1-b] quinazoline-5 (10H) on.

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Example 1 ; 10- (4'-fluorobenzyl) -2,3-dihydroimidazo-

[2,1-b] quinazolin-5 (IQH) -one [method a)]

A solution of 16.3 g of isatic anhydride in 200 ml of dimethylacetamide is 5.0 g at room temperature a 57% solution of sodium hydride in mineral oil was added. The resulting mixture is stirred for 20 minutes, then mixed with 16 g of p-fluorobenzyl chloride and about Stirred for hours at room temperature. The resulting mixture is concentrated in vacuo to about half of its volume, whereupon a mixture of ice and water is added, the precipitate obtained is filtered off, washed with water, through Suction dries and washes with pentane. The solid obtained is then dissolved in methylene chloride with sodium sulfate dried, treated with activated charcoal and - with about its double volume of diethyl ether added, wherein the N- (p-fluorobenzyl) -isatic anhydride crystallizes out, which melts at 142-145 ° C.

M10H) _- on

A solution of 5.4 g of N- (p-fluorobenzyl) isatic anhydride, 2.5 g of 2-methylmercaptoimidazoline and one Cookies (100 mg) sodium hydroxide in 75 ml dioxane is made

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Heated to reflux for 4 hours. The mixture obtained is evaporated to dryness, the residue is dissolved in methylene chloride, washes with water and extracted twice with IN hydrochloric acid. The combined aqueous extracts are washed with methylene chloride and then with diethyl ether and made basic with sodium carbonate. The precipitate obtained is filtered off, washed thoroughly with water, dried by suction, in methylene chloride dissolved, dried with sodium sulfate and coated with activated charcoal treated, whereupon the methylene chloride is exchanged for methanol. The one that crystallizes out here 10- (4'-fluorobenzyl) -2,3-dihydroimidazo [2,1-b] quinazolin-5 (1011) -one, melts at 192-195 ° C.

A suspension of 3.6 g of the product thus obtained in 30 ml of abs. Ethanol is mixed with anhydrous hydrogen chloride saturated with ice cooling, and the resulting The solution is concentrated in vacuo to half its original volume. Activated charcoal is then added and filtered through cellite. Finally 50 ml of diethyl ether are added, whereby the 10- (4'-fluorobenzyl) -2,3-dihydroimidazo [2,1-b] quinazolin-2 (1011) -one in the form of the hydrochloride crystallizes out, which melts at 235-238 ° C and then again at about 320 ° C.

Beis piel 2: 10- (4'-fluorobenzyl) -2,3-di h ydroimidazo-

[2, lb] -quinazolin-5 (IQH) -one [method b)]

li ^ SiE ^ CilSYllz ^ I ^ hio-l
4-on

A suspension of 75 g of N-p-fluorobenzylanthranilic acid

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- 223417

in 500 ml of pyridine is added in portions over 1 hour to a boiling solution of 32 g of ammonium thiocyanate and 47 ml of benzoyl chloride in 120 ml of anhydrous acetone given. The mixture is cooled and concentrated. The residue is mixed with 250 ml of methanol, and the crystalline precipitate is filtered off and washed with water, whereby the title compound is obtained.

A mixture of 5 g of the product obtained according to process step a), 40 ml of ethanol and 4 ml of methyl iodide is added to Stirred room temperature for 3 hours. Then 4 ml 6 M potassium hydride is added and the mixture is left to stand overnight. The precipitate is filtered off and washed with water, ethanol and ether, whereby the title compound is obtained.

c) 1- (p_-Fluorbenzy_l) -2-- (2rhy_ (lro3tYäthy.l) ä ^m i ^no "1-oli.i nar'.o] I iion

A mixture of 2.8 g of the crude product according to the above occurrence (b), 15 ml of iUitlumülamLn and 40 ml of chloroime is stirred for 2 hours at room temperature . 60 ° C 'orhltaL ·, Im Anrichlu ¹ ;:; Then the solvent is removed in vacuo, the residue is dissolved in ethyl acetate / benzene (1: 1) and extracted three times with water. The organic phase is dried and evaporated in vacuo, whereby.'man to a crude l.üok- '. stMiid the TiU'lvorbindunq reached.

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223AV / 4

quinazoline-5_ (10H) _2on

0.5 g of the crude product obtained in process step c) are dissolved in 10 ml of thionyl chloride, and the mixture obtained is heated to 80 ° C. for 2 hours. The thionyl chloride is then stripped off in vacuo, the residue is treated with ice / 6N sodium hydroxide solution, and the solid is dissolved in methylene chloride, whereupon it is extracted with water and with saturated sodium chloride solution. After drying and evaporation in vacuo, the backpack is recrystallized from anther and thus the title compound is obtained, which melts at ^{L 192--195 0 G.}

Example 3: [method a) or b)]

Analogous to example 1 or 2 or the following example 5 and by using suitable starting materials in appropriate !! narrow one arrives at the following compounds:

a) IL (3 ', 4'-dimethoxybenzyl) -2,3,4,11-tetrahydro-pyrimido [2, l-bJchinazolin-6-on _/ mp. 142-144 ⁰ C.

l ·) 1 () - (Γ •, l .: thyLbenzyl) -2,3-dihYdroimida?: o [2, lb] 'chin ι'. ) 1 in- ') (LOII) -on, m.p. dos fell hansulfonats ? 0J ? LnV,

o) 10-U ¹ -Fo.thyLbfiizyl) -2, 3-dihydroimidazo [2,1-bJ chinazo.Lin-5 (LOH) -one, mp. ties methanesulphonate

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d) 10 ~ I.4ienäthy 1-2,3-dihydro-imidazo [2,1-b] quinazolin-5 (10II) -one. M.p. of "methanesulfonate 237-239 ⁰ C *,

e) 10- (3 ', 4' -Dimcthoxybenzy 1) -2,3 - dlhydroinudazo [2, 1-b] quinazolin-5 (IOII) -one, melting point of the methanesulfonate 180-182 ⁰ C,

f) 10- (cx-methylbenzyl) -2, 3-dihydroiinidazo [2, 1-b] quinazolin-5. (1OH) -one, Snip. 136-138 ° C,

g) 10-Benzyl-7-methoxy-2, 3-d.i hydroimida ^ o [2, 1-b] quinazolin-5 (10H) -one, Snip. 173-175 ° C,

h) 12- (3 ', 4' -Dimethoxybenzy1) -2,3,4,5-tetrahydro {1211) diazepino [2.1b] quinazolin-7-one, m.p. 134-13C ^C C,

i) 11- (4 '-Fluorbenzyl) -2,3,4,1 l ~ to.trahydropyrimiclo L2, lb] quinazolin-C-one, mp. 154-156 ⁰ C.

j.) 10- (3 ¹ _f 4 * -Dif luorbenzyl) -2, 3-dihydroimidazo [2, 1-b] quinazolin-5 (IOII) -one, m.p. 209-211 ° C,

k) 10- (3'-fluorobenzyl) -2,3-dihydrodmidazo [2,1-b] quinazolin-5 (1011) -one. M.p. of hydrochloride 262-264 ⁰ C,

1) 10- (2'-fluorobenzyl) -2,3-dihydroimidazo [2 , 1-b] quinazolin-5 (10H) -one, melting point of the hydrochloride 251-255 ° C,

m) 10-eenzyl-7-hydroxy-2,3-dihydroiinidazo [2,1-b] quinazolin-5 (10H) -one, .. m.p. 225-227 ° C (only according to . Example 1),

η) 10- (4'-chlorobenzyl) -2,3-dihydroimidazo [2; 1-b] quinazolin-5 (10H) -one,

o) 10- (4'-bromobenzyl) -2,3-dihydro-imidazo [2,1-b] quinazolin-5 (LDN) -one, mp. 175-177 ⁰ C. ₁

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ρ) ll- (4 ^l -chlorobenzyl) -2,3,4, ll-tetrahydropyrimido j

[2, l-b] quinazolin-6-one, m.p. 178-18O ° C, j

q) 10- (2,6-dichlorobenzyl) -2,3-dihydroimidazo [2,1-b]!

quinazolin-5 (10H) -one _f mp. 164-166 ° C. ^j

Example 4 ; 10-Benzyl-7-hydroxy-2,3-dihydroimidazo ■ }

[2,1-b] quinazolin-5 (IQH) -one [method c) J.

1 g of 10-benzyl-7-methoxy-2,3-dihydroimidazo [2, JL-b] china-j

zolin-5 (1OH) -one slowly becomes IO ml of 48% bromine water- «

given chemical acid, and the resulting mixture is heated I

with stirring for 2 hours under reflux. After cooling down 1

the precipitate is filtered off and dissolved in 1 N sodium hydroxide I.

solved. The solution obtained is washed twice with
Methylench.lorid and slowly acidify it with 2N hydrochloric acid to about pH 6. The resulting
crystalline material is filtered off, washed with water,
dried by suction and in chloroform as well as in one
Small amount of methanol dissolved, treated with activated charcoal
and concentrated on the steam bath, the 10-benzyl-7-hydroxy-2,3-dihydroimidazo [2,1-] quinazolin-5 (10H) -one, which melts at 225-227 ° C., crystallizes out.

Example 5 ; 10- (4'-Fluorobenzyl) -2,3-dihydroimidazo [2,1-b] quinazolin-5 (IQH) -one [method a) 3

a) N- (£ ~ fluorobenzYl) -isatinic anhydride

A solution of 3.2 kg of isatic anhydride in 15 kg
Dimethylacetamide is added under nitrogen and stirring

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of a 57% dispersion of 880 g of sodium hydride in mineral oil was added, keeping the temperature below 25 ⁰ C. The resulting mixture is heated to about 60.degree. C. and held at about 55-60.degree. C. for 1 hour. It is then cooled to 20-30 ° C. and 3.0 kg of p-fluorobenzychloride are added to the mixture. This is followed by heating again to about 60 ° C. for about 4 hours. It is then ^{cooled again to 20 °} C., whereupon 17.4 kg of ice and finally 24 kg of water are added. The mixture is stirred for 15 minutes, the solids are filtered off, washed several times with 2 kg of water each time and finally three times with 0.7 kg of diethyl ether which melts at 14O-143 ° C,

to) IQlX ^ -Flu ^ rbe ^ zy ^ l ^ -g ^ S ^ d ^ h ^^

! One approach of the 26 kg of toluene, 2,5 kg of 2-methylmercapto \ imidazoline hydroiodide, 2.4 kg N- (p-fluorobenzyl) -isatinj anhydride and 1.55 kg of powdered anhydrous sodium carbonate is 18 to 20 hours in a reaction vessel heated to reflux, to which a caustic wash tower is closed. What arises from the reaction. Water <3 is collected in a Dean-Stark trap. The reaction mixture is cooled to 20 ° C. and 10 kg of water are added. The mixture is stirred for about 30 minutes, the solids are collected and washed several times. jev; hurry 2 kg of water and three times with. 0.8 kg ToluoXv The solids are

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under reduced pressure, dried (about 55 ⁰ C) and so leads to a crude product, which melts at 196-198 ⁰ C. The crude product is dissolved at 50 ° C. in 14 kg of chloroform and 4 kg of ethanol, and the solution obtained is treated with 0.1 kg of activated carbon for about 10 minutes to decolorize. The activated carbon is filtered off through Cellit, and the solids are precipitated by concentrating the filtrate to a volume of about 8 liters. The concentrate obtained in this way is cooled to 0-5 ° C., the solids are filtered off, washed with cold ethanol and then with diethyl ether, and dried under reduced pressure, resulting in 10- (4'-fluorobenzyl) -2,3-dihydroimidazo [2, lb] ~ quinazolin-5 (10H) -one, which melts at 197-198 ° C.

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Claims (8)

Claim: Process for the preparation of quinazolinones of the formula I, wherein either R and R_ are identical or different and each represent hydrogen, fluorine, chlorine or alkyl with 1-3 carbon atoms, or R ₁ and R ₂ each represent hydroxy or R ₁ and R each represent alkoxy with 1-2 carbon atoms, or one of the substituents R and R is bromine, hydroxy or alkoxy with 1-2 carbon atoms and the other is hydrogen, η is 1, 2 or 3 and either R is alkyl with 1-5 carbon atoms or R is a radical of the formula III or IV III H C- I \ = ώ CH ₃ IV Y. in which M is the number 1 or 2 and either Y and Y. are identical or different and each hydrogen, fluorine, chlorine or alkyl with 1-3 209884 / U02 - 2G - 600-6301 / C Mean carbon atoms, or Y and Y. each represent Hydroxy, or Y and Y are each alkoxy with 1-2 ' Mean carbon atoms, or one of the substituents Y and Y ₁ bromine, hydroxy or alkoxy with 1-2 carbon I means atoms and the other is hydrogen, where however '' i 1) at most two of the substituents R. _r R, Y and Y. j stand for hydroxy, j 2) R ₁ and R ₀ each do not represent hydroxy if Y "; . or Y is alkoxy of 1 or 2 carbon atoms; stands, . ' 3) Y and Y ₁ each do not represent hydroxy if 'R ₁ or R is alkoxy with 1 or 2 carbon atoms mean, 4) at least one of the substituents R. and R. not
represents hydrogen, fluorine or chlorine and R
as well as R not at the same time alkoxy with 1 or 2
Carbon atoms, if R denotes alkyl with
1-5 carbon atoms or a radical of the formula III
stands, in which m is the number 1, and Y and Y _T stands for hydrogen characterized in that ί * the compounds of the formula I are obtained by 209884/1402 600-6301 / C a) compounds of the formula V, wherein R, R ₁ and R _{3 have the} above meaning, with compounds of the formula VI ·, · R ₄ W VI. • ^(ci y " where η has the above meaning, W for oxygen or Is sulfur and R- is alkyl with 1-4 carbon atoms or benzyl in the presence of an inert organic Reacts solvent. b) for the preparation of compounds of formula Ia, Yes 2 η where η has the above meaning and ^ R ^f , R 'and R' have the same meaning as R, R ₁ and R_, with the exception that none of these substituents mean or can contain hydroxy, compounds of the formula VII, 209884/1402 CCO-63O1 / C N -CH ₀ - (CH) -OH VII Wherein n _f R ', R' and R 'have the above meaning, is reacted with a cyclizing agent and the reaction product is treated with an acid binder, or c) for the production of hydroxy-substituted compounds of formula Ib, Ib ¹ ', R "and where n has the above meaning and R ¹ R ¹ 'have the same meaning as R, R and R ^, with the exception that at least one of the substituents R ¹¹ , RJ ¹ and R' ¹ is or contains hydroxy, 'corresponding alkoxy -substituted compounds of the Formula Ick, < ^CH 2> n Ick 209884 / U0 2 - 23 - 600-6301 / C where η has the above meaning and R '" _f R' ¹¹ and R '" have the same meaning as R, R ₁ and R ₀ , with the exception that at least one of the substituents R ¹¹¹ , R ^ltf , R ^ "is alkoxy with 1 or 2 carbon atoms denotes or contains, and that furthermore R ″ ¹ and R ^{'11 can} each stand for alkoxy with 1 or 2 carbon atoms, if R' ¹¹ does not denote a radical of the formula III or IV in which Y or Y _{1 denotes} Hydroxy or alkoxy with 1 or 2 carbon atoms is ^ hydrolyzed. 209884/1402 - 24 - 600-6301 / C 2. Quinazolinone in claim 1 mentioned formula I, wherein R, R ₁ , R ₀ and n have the meaning mentioned. 3. Quinazolinonanach claim 2, characterized in that R is a radical of the formula mentioned in claim 1. III is in which R ₁ , R "and η have the meaning given in claim 1. 4. quinazolinones according to claim 2, characterized in that R is p ~ chlorobenzyl, p-bromobenzyl or p-fluorobenzyl and R 1, R 1 and η have the meaning given in claim 1 own. 5. quinazolinones according to claim 2-4, characterized in that R, and R ₂ each represent hydrogen. 6. quinazolinones according to claim 2-5, characterized in that η denotes the number 1 or 2. 7. quinazolinones according to claim 2-6, characterized in that η stands for the number 1. 8.- Pharmaceutical preparation, characterized by a content of quinazolinones of those mentioned in claim 1 Formula I. 209884 / U02