DEC0007749MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Date of registration: June 17, 1953 Advertised on April 12, 1956

GERMAN PATENT OFFICE

PATENT APPLICATION

CLASS 12p GROUP 10 C 7749 IVb / 12 p

Dr. Jean Druey, Riehen, Dr. Albrecht Hüni, Basel,

Dr. Beat Heinrich Ringier, Riehen, and Dr. Alex Staehelin, Basel (Switzerland)

have been named as inventors

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36

Process for the preparation of 6-halo-2-aryl-3-oxo-2,3-dihydropyridazines

The priority of registrations in Switzerland from June 20, 1952, February 13 and April 2, 1963

is used

The invention relates to the production of 6-halo-2-aryl "3-oxo-2, 3-dihydro-pyridazine compounds, especially of those in which aryl is an aromatic radical at most, especially a binuclear radical is a phenyl radical, and halogen is a bromine or, preferably, chlorine atom. These connections are advantageous further substituted, e.g. B. preferably the pyridazine core by alkyl, free or substituted Amino, such as dimethylamino groups or halogen atoms. '■' Ji-

The new pyridazines have valuable pharmacological properties; so they show an antipyretic and analgesic effects and can be used as remedies.

Of particular importance are 6-chloro-2-phenyl-3-0x0-2, 3-dihydropyridazine compounds, preferably 6-chloro-2-phenyl-3-oxo-2,3-dihydro-pyridazine of the formula

509 704/381

C 7749 IVb / 12p

and the . o-chloro-S-dimethylamino ^ -phenyl-s-oxo-2, 3-dihydro-pyridazine of the formula

CH.

These compounds exert a pronounced analgesic effect Effect that is about twice as strong as that of the well-known aminopyridine.

This is all the more surprising since closely related compounds, such as the ^ -Bromo-S-dimethylamino-2-phenyl-3-0x0-2, 3-dihydro-pyridazine, have no effect.

The compounds produced by the process are also important as intermediate products, especially for the production of the corresponding medicinal products 6-Amino-2-aryl-3-oxo-2,3-dihydro-pyridazine.

The new compounds are obtained when 6-oxy-2-aryl-3-oxo-hydro-pyridazine compounds, which have at least one double bond, namely in the 6-position of the pyridazine ring, with halogenating agents and, if necessary, treated with dehydrating agents and, if desired, in compounds obtained which are a halogen atom in the 5-position have, this exchanges for an amino group.

So you can 6-oxy-2-aryl-3-oxo-2, 3-dihydro-pyridazine compounds or their tautomeric forms with halogenating agents, preferably the halides of phosphoric acid, such as phosphorus oxychloride, phosphorus pentachloride, phosphorus pentabromide.

Another embodiment of the process consists in that 6-oxy-2-aryl-3-oxo-2, 3, 4, 5-tetrahydropyridazine compounds or their tautomeric forms are treated with halogenating and dehydrating agents. As a halogenating agent the abovementioned halides of phosphoric acid can be used. By equal means, in particular Phosphorus pentachloride, the dehydrogenation can be carried out.

The described reactions can be carried out in the presence or absence of diluents in the open or closed vessel under pressure

Be like that. It is preferable to work at an elevated temperature.

The starting materials used in the process are known or can be according to known ones Methods are presented.

The invention is described in more detail in the following examples. Between part by weight and volume part has the same relationship as between grams and cubic centimeters. The temperatures are given in degrees Celsius.

example 1

100 parts by weight of 6-oxy-2-phenyl-3-oxo-2,3-dihydro-pyridazine are with 750 parts by volume of Phos

phosphorus oxychloride ι hour on the boiling water- ■■ heated bath, the solution carefully poured onto 5500 parts by weight of ice while stirring and after one hour Stand in the cold of the .- '' educated. Sucked off precipitation. One washes him; with water and recrystallizes it from water. The 6-chloro-2-phenyl-3-oxo-2, 3-dihydro-pyridazine obtained in this way Formula,

melts at 116 to ii8 °.

The 6-oxy-2-phenyl-3-0x0-2, 3-dihydropyridazine used as starting material can be prepared in the following way: 235 parts by weight of maleic anhydride are dissolved in 2000 parts by volume of glacial acetic acid and with a solution of 270 parts by weight of phenylhydrazine in 500 parts by volume Glacial acetic acid refluxed for 3 hours. The hot solution is then poured into 700 parts by volume of water with stirring, whereupon crystallization occurs. The cooled mixture is suction filtered, the residue is washed with water, dissolved in 1N soda solution for cleaning and precipitated again after filtering with 2N hydrochloric acid. The precipitate is suction filtered, washed with water and dried. The thus obtained 6-oxy-2-phenyl-3-0x0-2, 3-dihydro-pyridazine melting at 272-274 ^0th

Example 2

49 parts by weight of 6-oxy-2- (p-chlorophenyl) -3-oxo-2,3-dihydro-pyridazine are 300 parts by volume Phosphorus oxychloride heated on a boiling water bath for 1 hour. The solution is carefully taken Stir poured onto ice and, after standing in the cold for a while, suction off the precipitate formed, washed with water and dried. The 6-chloro-2- (p-chlorophenyl) -3-oxo-2,3-dihydro-pyridazine obtained in this way the formula

melts after recrystallization from benzene-petroleum ether at 138 to 140 ^0th

The 6-oxy-2- (p-chlorophenyl) "3-oxo-2,3-dihydro-pyridazine used as starting material can be represented as follows: 66 parts by weight of p-chlorophenylhydrazine in 122 parts by volume of glacial acetic acid become a solution of 76 parts by weight of maleic anhydride Glacial acetic acid added in 670 parts by volume and the mixture

704/381

C 7749 IVb / 12 ρ

Heated to boiling under reflux for 3 hours. 240 parts by volume of water are added to the hot solution and the mixture is allowed to crystallize while cooling. The crystals are filtered off with suction, washed with water and dried. The thus obtained 6-oxy-2- (p-chlorophenyl) -3-0x0-2, 3-dihydro-pyridazine melting at 280-282 ^0th

Example 3

3 parts by weight of 6-oxy-2-phenyl-4 (or -5-) -methyl-3-0x0-2, 3-dihydro-pyridazine with 15 parts by volume of phosphorus oxychloride are on the for some time heated boiling water bath. The phosphorus oxychloride is then largely distilled off and the Poured residue onto ice. After standing for a long time, the solid fraction is filtered off with suction and washed with water and recrystallized several times from absolute ethanol. The 6-chloro-2-phenyl-4- (or -5-) -methyl-3-oxo-2,3-dihydro-pyridazine of the formula

CH, -

melts at 136 to 137 ⁰ .

The 6-oxy-2-phenyl-4- (or -5-) -methyl-s-oxo ^, 3-dihydro-pyridazine from F. = 226 to 228 ⁰ used as starting material can be obtained in the usual way.

Example 4

5 parts by weight of 6-oxy-2-phenyl-3-oxo-2,3-dihydropyridazine with 12 parts by weight of phosphorus

Pentabromide mixed and heated ^{to 125 to 130 0} in an oil bath for 3 hours. The reaction mixture is poured into 50 parts by volume of water, the excess of the phosphorus pentabromide decomposing. After standing for 15 hours, it is suction filtered and the gray-brown product obtained is washed with water and dried in vacuo. To clean it, it is dissolved in hot benzene. Petroleum ether is added to the solution until a flaky by-product precipitates, and 6-bromo-2-phenyl-3-oxo-2,3-dihydropyridazine is added from the benzene-petroleum ether solution, which has been filtered and cleaned with animal charcoal the formula

N— <·

Br

for crystallization. It melts at 122 to 124 °

Example 5

85 parts by weight of o-Oxy-S-chloro ^ -phenyl ^ -oxo ^, 3-dihydro-pyridazine are heated to 100 ° with 680 parts by volume of phosphorus oxychloride for ι hour. The solution is decomposed with ice-containing dilute sodium hydroxide solution and extracted with ether. After drying over Potash, the ether is evaporated and the residue is recrystallized from cyclohexane. The thus obtained 5, 6-dichloro-2-phenyl "3-oxo-2, 3-dihydro-pyridazine of the formula

Cl-

Cl

melts at 138 ⁰ .

The o-oxy-S-chloro-2-phenyl-3-oxo-2, 3-dihydropyridazine used as starting material can be obtained in the following manner: 400 parts by weight: chloromaleic anhydride is mixed with 311 parts by volume of phenylhydrazine and 2200 parts by volume of glacial acetic acid for 3 hours Refluxed. After standing at 20 ° for 15 hours, the precipitate is filtered off and washed with glacial acetic acid. It is purified by dissolving it in dilute sodium hydroxide solution, filtering and precipitating with dilute hydrochloric acid and crystallizing it / from glacial acetic acid. The thus obtained 6-oxy-5-chloro-2-phenyl-3-0x0-2,3-dihydro-pyridazin melts with decomposition at 270 ^0th

Example 6

16 parts by weight of 6-oxy-2-phenyl-3-oxo-2, 3, 4, 5-tetrahydropyridazine are triturated with 120 parts by weight of phosphorus pentachloride and gradually ^{heated to 130 to 140 0} , at which temperature the mixture is left for 10 minutes. Then one adds 160 parts by volume of phosphorus oxychloride and heated for 30 minutes at an oil bath temperature of no ^0th The solution is decomposed with ice-containing dilute sodium hydroxide solution and extracted with ether. The ether extract is dried over potash and evaporated to dryness. The residue is recrystallized from a mixture of cyclohexane and methanol at a ratio of 10: 1, then from a mixture of the same at a ratio of 1: 2 and finally from methanol. The 4,6-dichloro-2-phenyl-3-oxo-2,3-dihydropyridazine obtained in this way melts at in to 112 ^° .

Example 7

6.9 parts by weight of 6-oxy-2- naphthyl- (2 ') -3-oxo-2,3-dihydro-pyridazine are in 15 parts by volume of phosphorus oxychloride ι hour on the water bath at 95 ° heated, whereby solution occurs. The solution is then carefully poured onto water, the Temperature by adding ice at 40 to 50 °

509 704/381

C 7749 IVb / 12 p

is held. It is left to stand on this and, after a while, the light gray residue is suctioned off. The 6-chloro-2-naphthyl- (2 ') -3-oxo-2,3-dihydro-pyridazine of the formula obtained in this way
O

crystallizes from alcohol in long white needles that melt ^{at 155 to 156 0.}

The 6-oxy-2-naphthyl- (2 ') "3-oxo-2 used as starting material, 3-dihydro-pyridazine can be obtained as follows: 10.3 parts by weight /? - naphthylhydrazine are dissolved warm in 50 parts by volume of glacial acetic acid and with a solution of 6.4 parts by weight Maleic anhydride added in 25 parts by volume of glacial acetic acid. The mixture is refluxed for 1 hour cooked, whereby solution occurs first. After a while, crystallization sets in. One lets cool and suck off the yellow-white precipitate. The 6-oxy-2-naphthyl- (2 ') - 3-oxo-2 obtained in this way, 3-dihydro-pyridazine melts at 268 to 270 °.

Example 8

8.2 parts by weight of 6-oxy-2-naphthyl- (i ') -3-oxo-2, 3-dihydro-pyridazine and 20 parts by volume of phosphorus oxychloride are heated on a boiling water bath for 1 hour. The solution is poured into 40 parts by volume of lukewarm water (40 to 50 ⁰ ), the temperature being kept ^{at 40 to 50 0 by adding ice.} The result is a brown resin that slowly disintegrates. The brown residue is suction filtered and boiled with water, filtered and left to stand for several hours to crystallize.

The white product thus obtained is 6-chloro-2-naphthyl- (i ') - 3-0x0-2, 3-dihydro-pyridazine of the formula

It melts at 118 to 120 ⁰ .

The 6-oxy-2-naphthyl- (i ') "3-oxo-2 used as starting material, 3-dihydro-pyridazine can be obtained as follows: 16.4 parts by weight of a-naphthylhydrazine are dissolved in 80 parts by weight of glacial acetic acid and a solution of 10.4 parts by weight of maleic anhydride glacial acetic acid added in 40 parts by volume. The mixture is refluxed for 3 hours, then after cooling to 40 parts by volume of water poured with stirring, a yellowish product crystallized. The 6-oxy-2-naphthyl- (1 ') - 3-0x0-2 obtained in this way 3-dihydro-pyridazine melts at 283 to 285 ° (decomposition). 65 '

Example 9

88 parts by weight of 6-oxy-2- (p-tolyl) -3-oxo-2,3-dihydropyridazine are heated to 100 ° for 1 hour with 600 parts by volume of phosphorus oxychloride. The excess phosphorus oxychloride is decomposed with dilute, ice-containing sodium hydroxide solution and the mixture is extracted with ether. The ether solution is dried over potash, evaporated to dryness and the residue is recrystallized from methanol. The 6 - chloro - 2 - (p - tolyl) - 3 - oxo - 2, 3 - dihydro - obtained in this way. pyridazine of the formula
O

NO ₉

CH,

' ^C1
melts at 108 to 109 °.

The 6-oxy compound used as starting material can be obtained as follows: 51 parts by weight of p-tolylhydrazine are refluxed with 41 parts by weight of maleic anhydride in 400 parts by volume of glacial acetic acid for 2 hours. The solution is then mixed with 200 parts by volume of water and left to stand for 15 hours, during which time crystallization occurs. It is filtered, the filter material is dissolved in dilute sodium hydroxide solution for cleaning and it is precipitated again with hydrochloric acid. Finally the precipitate is recrystallized from glacial acetic acid. The thus obtained 6-oxy-2- (p-tolyl) "3-oxo-2, 3-dihydro-pyridazine melting at 242-244 ^0th

Example 10

10 parts by weight of 6-oxy-2- (p-nitrophenyl) -3-oxo-2,3-dihydro-pyridazine are heated with 25 parts by volume of phosphorus oxychloride 2 ¹ ₂ hours on a boiling water bath. Then the mixture is poured at 40 to 50 ⁰ in water, being maintained by the addition of ice at this temperature. The 6-chloro-2- (p-nitrophenyl) -3-oxo-2,3-dihydro-pyridazine of the formula

crystallizes out. It can be recrystallized from ethyl acetate and then melts at 195 to 196 ⁰ . The 6-oxy-2- (p-nitrophenyl) -3-oxo-2,3-dihydro-pyridazine used as starting material can be prepared as follows: 40 parts by weight of 6-oxy-2-phenyl-3-0x0-2, 3 -dihydro-pyridazine are concentrated with 80 parts by volume. Nitric acid stirred and within

704/381

C 7749 IVb / 12p

60 minutes with 80 Vplum parts conc. Sulfuric acid at 0 to 5 ⁰ slowly added. The mixture is stirred for a further 2 hours at 0 to ^{10 ° C.} and then slowly mixed with 320 parts by volume of water. the

^ff 5 "The temperature rises to 35 °. After cooling, the pale yellow nitro derivative is suction filtered. The crude product is dissolved in saltwater solution, filtered with animal charcoal, precipitated with 2N hydrochloric acid, suction filtered and dried. The 6-oxy-2- ( p-nitrophenyl) -3-oxo-2, 3-

s £ o dihydro-pyridazine melts at 289 to 291 ⁰ .

Example 11

14.25 parts by weight of the 5, 6-dichloro-2-phenyl-3-oxo-2, 3-dihydropyridazine described in Example 5

15 of the F. = 138 ⁰ are refluxed in 200 parts by volume of alcohol with 9 parts by weight of morpholine for 4 hours. The reaction product crystallizes out on cooling. It is suction filtered, washed with a little aqueous alcohol and again under

2Ö treatment with animal charcoal recrystallized from alcohol. The 6-chloro-5-morpholino-2-phenyl-3-oxo-2,3-dihydro-pyridazine of the formula

Γ. ■. '■. ·. ^: o

1

Cl

melts at 168 to 169 ⁰ .

In an analogous manner, starting from 2-phenyl-5,6-dibromo-3-oxo-2,3-dihydro-pyridazine, the 2-Phenyl-5-mo ^ holino-6-bromo-3-oxo-2, 3-dihydropyridazine with a melting point of 171.5 to 172.5 °.

Example 12

16 parts by weight of the 5, 6-dichloro-2-phenyl-3-oxo-2, 3-dihydropyridazine of F. == 138 ⁰ described in 200 parts by volume of alcohol with 12 parts by weight of piperidine are refluxed for 5 hours. The reaction product crystallizes out on cooling. It is sucked off, with ver-45; washed with dilute alcohol and recrystallized again from alcohol by treatment with animal charcoal. The 6-chloro-5-piperidino-2-phenyl-3-oxo-2,3-dihydropyridazine of the formula

melts at 118.5 to 119.5 °.

Example 13

2.7 parts by weight of o-Oxy-S-morpholino ^ -phenyl-3-0x0-2, 3-dihydro-pyridazine are slowly heated to 50 to 100 ° with 40 parts by volume of phosphorus oxychloride, everything going into solution. The temperature is kept at 100 ° for 1 hour. . After cooling, the mixture is poured onto ice and made alkaline by adding solid potash. Then it is extracted with ether, the ethereal solution is washed with water, dried and evaporated. The residue crystallizes from alcohol in fine needles vom.F. = 167 ° and is identical to the o-chloro-S-morpholino ^ -phenyl-s-oxo-2, 3 _: dihydro-pyridazine described in Example 11. The 6-oxy-5 ~ morpholino-2-phenyl-3-oxo-2,3-dihydro-pyridazine used as starting material can be obtained as follows: o-Oxy-S-bromo ^ -phenyl ^ -oxo ^, 3 -dihydro-pyridazine (obtained by boiling 180 parts by weight of bromomaleic anhydride and 108 parts by weight of phenylhydrazine in 400 parts by volume of glacial acetic acid for 2 hours, filtering off the product that crystallizes out on cooling, washing with plenty of ether, dissolving in soda solution, filtering with animal charcoal and precipitating with dilute hydrochloric acid; F. = 259 to 261 °), are heated with 300 parts by volume of alcohol and 19 parts by weight of morpholine in a closed tube to 180 ° for 8 hours. The crystallized crude product is suction filtered and recrystallized from alcohol by treatment with animal charcoal. The 6-oxy-5-morpholino-2-phenyl-3-oxo-2,3-dihydro-pyridazine of the formula

OH

melts at 242.5 to 243 °.

In an analogous manner, the 6-oxy-5-piperidino-2-phenyl-3-oxo-2, 3-dihydro-pyridazine to the 6-CUor-5-piperi.dino-2-pb.enyl described in Example 12 3-oxo-2, 3-dihydro-pyridazine are chlorinated. The 6-oxy-5-piperidino-2-phenyl-3-oxo-2,3-dihydropyridazine used as starting material can be obtained as follows: 5.3 parts by weight of the above-mentioned 6-oxy-5-bromo-2-phenyl -3-oxo-2,3-dihydro-pyridazines are ^{heated with 4 parts by weight of piperidine in 150 cm 3 of} absolute alcohol in a closed tube to 150 to 160 ° for 8 hours. The alcohol is distilled off, the residue is dissolved in a large amount of ethyl acetate, the solution is washed with water and dilute hydrochloric acid, dried and evaporated. The residue is recrystallized from alcohol. The 6-oxy-5-piperidino-2-phenyl-3-oxo-2,3-dihydro-pyridazine of the formula obtained in this way

OH

melts at 252 to 253 °.

509 704/381

C 7749 IVb / 12 ρ

Example 14.

6.4 parts by weight of the described in Example 5, 5, 6-dichloro-2-phenyl-3-oxo-2, 3-dihydro-pyridazine be on with 20 parts by volume of alcoholic dimethylamine solution (about 30 ° / _o pure) in sealed tube for 6 hours 170 ⁰ heated. It is evaporated to dryness, the residue is extracted by shaking with ether and water, the ether extract is dried over potash, the ether is evaporated and the residue is recrystallized from a mixture of 2 parts by volume of benzene and 1 part by volume of isopropyl ether.

The o-chloro-S-dimethylamino ^ -phenyl-3-0x0-2 obtained in this way, 3-dihydro-pyridazine of the formula

CH,

CH,

melts at 125 to 127 °. .

In an analogous manner, starting from 2-Phenyl-5, 6-dibromo-3-oxo-2,3-dihydro-pyridazine das 2-phenyl-5-dimethylammo-6-bromo-3-oxo-2,3-dihydropyridazine from F. = 124.5 to 125.5 °.

Example 15

2.5 parts by weight of 2-phenyl-5-bromo-6-oxy-3-oxo-2, 3-dihydro-pyridazin be triturated with 5 parts by weight of phosphorus and as long as heated to 140 ⁰ until the melt solidifies again. It is then triturated with 1N soda solution, taken up in methylene chloride, the methylene chloride solution with. Washed water, dried and evaporated. Recrystallization twice from 'methanol gives 2-phenyl-5, 6-dibromo-3-oxo-2 _s 3-dihydro-pyridazine of the formula. '. ...

¹ ■■ '■■ "' ο '-ν. ■',; ■ Λ"'.

Br-I N

iri fine matted needles from F .. = 140 to 142 ⁰ . ■ ■■ ::. . . Example 16 ^: ■ '■' ■

3 parts by weight of 2-phenyl-4-methyl-6-oxy-3-QXO-

2,3-dihydro-pyridazine are heated with 15 parts by volume of phosphorus oxychloride I ¹ Z for ₂ hours on a boiling water bath. After the phosphorus oxychloride has been distilled off in vacuo, the mixture is carefully poured onto ice water to which potash has been added and extracted with ether. After drying, the ether is evaporated and the residue is crystallized from methanol. The 2-phenyl-4-methyl-6-chloro-3-oxo-2,3-dihydro-pyridazine of the formula obtained in this way
O

CH,

melts at 133 to 134 °.

The 2-phenyl-4-methyl-6-oxy-3-oxo-2, 3-dihydro-pyridazine used as starting material can as the following are obtained: 86> 4 parts by weight of phenylhydrazine in 200 parts by volume of glacial acetic acid with a solution of 95 parts by weight of citraconic anhydride Boiled under reflux for 4 hours. After cooling, N-anilino-citraconimide which has crystallized out becomes suction filtered, the solution evaporated in vacuo, the residue dissolved in chloroform and this solution with a dilute soda solution with which the N-anilino-citraconimide was previously washed out, extracted. The soda extract is acidified with hydrochloric acid and the colorless precipitate formed is filtered off with suction. The mixture of 2-phenyl-4-methyl- and 2-phenyl-5-methyl-6-oxy-3-oxo-2,3-dihydro-pyridazine obtained in this way can by fractional crystallization with. Methyl alcohol be separated. The first crystallizing ^ -phenyl-S-methyi-o-oxy ^ -oxp ^, 3-dihydro-pyridazine melts at 226 to 228 °, the more soluble 4-methyl isomer at 168 to 169.5 °.

Claims (1)

:: Claim: ■ '. .. \ · ■ '.. Process for the preparation of 6-halo-2-aryl-3-oxo-2, 3-dihydro-pyridazines, characterized in that one ö-Oxy ^ aryl ^ -oxo-hydropyridazine compounds ,, the at least one double bond, namely in the 6-position of the pyridazine ring have, treated with halogenating agents and, if necessary, with dehydrating agents and, if desired, in compounds obtained which have a halogen atom in the 5-position, exchanging this for an amino group. Referred publications:
Ber. German _: -chem. Ges., Vol. 24, p. 3150, and Vol. 37, p. 3641; , ·· ■ ' British Patent No. 656 228.