DK154505B - METHOD FOR PREPARING 6-ARYL-SUBSTITUTED 4H-S-TRIAZOLO- (3,4-C) -THIENO- (2,3-E) -1,4-DIAZEPINES - Google Patents

Description

in

DK 154505 B

Compounds of formula I and their preparation from compounds of formula II are known from Liebigs Annalen der Chemie 1978, pages 1257-1265. It describes the transfer of starting materials of formula II to final products of formula I according to the following scheme:

R 1> s> - (/ R, N- (

10 Y T YY Y

R2, SCH-Hal1 R / Yh-NH

^ vY114 2 r5 \ Yv4

15 Γ J -a.?··> · L J

n / Methanol 7 χ / 7 ♦ / II / Ila. / 20

^ XN

TjC>

p / XC = .N

"15 yV * 4 ^^ wherein R ^, R ^ R ^, R ^ / R ^, Hal ^ and Ha ^ ter (¾ in exact meanings).

However, it has been shown that this road is associated with certain disadvantages:

In order to obtain good yields of Ila a medium must be used.

DK 154505 B

2 has a large excess of liquid ammonia (I: NHg fl. = 1: 180). Due to the aggressiveness (mucosal irritation) and toxicity of the slightly volatile ammonia (boiling point -33.4 ° C, MAK value 35 mg / irf *), all work operations 5 must be carried out gas tight. This means the use of an autoclave and gas tight wires. After reaction with ammonia, the reaction mixture must be aerated through a special washer installed for health and environmental protection reasons. Finally, the work-up, which takes place in a stirrer apparatus, must also be worked using a special washer installed for this purpose.

All of the work processes described above are very time consuming and costly for the reasons stated.

The object of the invention is therefore to simplify and lessen the process and - taking into account the ever stricter environmental protection regulations - to give it an environmentally friendly design.

This object is achieved according to the invention by an improved process for the preparation of the final products, 6-aryl-substituted 4H-s-triazolo- [3,4-c] -thieno- [2,3-e] 1,4-diazepines with the general formula

Nx R3 —S \ TY>. .

) -L / i

RyyR '

30 I

wherein and R 2, which may be the same or different, represent hydrogen or halogen atoms or alkyl groups of 1-2 carbon atoms, or R 2 and R 2 together form an alkylene chain of 3-4 carbo atoms, R 2 represents a hydrogen, chloro or bromine atom, a straight chain or branched alkyl group having 1-3 carbon atoms, 3

DK 154505 B

a ω-hydroxyalkyl group having 1-3 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, or a 5- or 6-membered saturated ring attached to the rest of the molecule over one of its carbon atoms and containing an oxy -5 gene, sulfur or nitrogen atom, a nitrogen-containing ring being optionally substituted at the nitrogen atom with an alkyl group of up to 3 carbon atoms, or the group / ¾1

-N

10, R 3, where 1 and R 2, which may be the same or different, represent hydrogen, an alkyl group of 1-4 carbon atoms or a hydroxyalkyl group of 2-3 carbon atoms, or 15 R 3 'and R 3 "together form a 4- or 5-membered alkylene chain, which may be optionally substituted once or twice by methyl, or R3 'and R3' together with the nitrogen atom to which they are attached form a morpholino group, and R may be the same or different, denote a hydrogen, fluorine, chlorine or bromine atom, or physiologically acceptable acid addition salts thereof, the process of the invention being characterized by reacting a dihalide of the general formula ·, 11 «gjx I · wherein R 1, R 2, R 3, R 4 and R 2. have the above meanings, and Hal 1 and Hal 2, which may be the same or different, each represent a halogen atom, such as e.g. fluorine, 35

DK 154505 B

4 chlorine, bromine or iodine, with hydroxylamine at a temperature between 20 and 150 ° C in organic solvents, with the addition of potassium iodide and a difficult alkylable base such as e.g. Ν, Ν-diisopropylethylamine, dicyclohexylethylamine or 4-hydroxy-2,2,6,6-tetramethylpiperidine and the hydroxylamine compound thus obtained of the general formula

RlXvz / S \ vzz ^ —C

D / \ CH-l / · III

K2 '"" OH

wherein R 1, R 2, R 3, R 2 and R 6 have the above meanings; a) are converted with a water-splitting agent such as e.g.

20 thionyl chloride, methanesulfonic acid chloride, 2-bromo-N-methylpyridinium iodide, 2-chloro-N-methylpyridinium iodide or dicyclohexylcarbodiimide, at temperatures between 20 and 150 ° C in an organic solvent for the corresponding compound of general formula I, or 25 b ) is converted with an oxidizing or dehydrogenating agent such as e.g. yellow mercury (II) oxide or potassium permanganate at temperatures from -25 ° C to + 100 ° C in an organic solvent for the corresponding N-oxide of the general formula TY> 35 ®2? = Ν · ΐ10 ma T 1

DK 154505 B

5 wherein R 1, R 2 / R 3, R 4 and R 5 have the above meanings and this is transmitted by reduction with a reducing agent such as e.g. phosphorus trichloride, phosphorus tribromide, triphenylphosphine, triethylphosphite, di-n-propylsulfoxylate or iron pentacarbonyl, in the corresponding compound of the general formula I, whereupon the compound of the general formula I is optionally transferred in the usual manner in a physiologically acceptable acid addition salt.

The process proceeds through the following reaction scheme: 6

DK 1 & 4505 B

N · «N

R3— \ r3_ \

WY

RZ ΧΉ-Hal-, R0 'NCH-ir

i 1 2 ΰ I V ° H

nh2oh 'R5 J ^ SRA

ϊ - *. · 'IJ

^ / KZb J / <d / Qt <§? / -tø (ii) Z / (m) 4 z z «g

Gr / «-H

-N /> β V / / / - »./ ^ s f v \. R3_yN \

** Υγ \ VVH

V | = iSi0 V

T T -—> YY

(Ilia) (I) wherein R., R2, R3, R4, Rj, Halj and Hal2 have the meanings given above.

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7

The reaction of a dihalide of formula II with hydroxylamine is carried out as mentioned in organic solvents, e.g. in lower alcohols such as methanol, ethanol or isopropanol. There is thus obtained a hydroxylamine compound of the general formula III which is transferred either by water decomposition (pathway a) or by oxidation of the molecule to form the corresponding N-oxide and subsequent reduction (pathway b) in a final product of formula I.

In the first case (path a), the hydroxy-amine compound III is dissolved in an organic solvent, e.g. methylene chloride, chloroform, ethylene chloride or chlorobenzene, and are converted as mentioned. Particularly gentle water decomposition is achieved with thionyl chloride since the reaction here proceeds already at room temperature.

In the second case (path b), the hydroxylamine compound III is dissolved in an organic solvent, e.g. methylene chloride, chloroform, ethylene chloride or acetone, and is converted as mentioned, the reduction 20 being carried out at temperatures between 20 and 150 ° C.

The final products of general formula I can be transferred in their usual physiologically acceptable acid addition salts in the usual manner. Acids suitable for salt formation are

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8 e.g. hydrogen halide acids, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid, methane or toluene sulfonic acid and the like.

The preparation of the compounds of the general formula II used as starting materials is known; it is made e.g. according to the Belgian Patent Specification no.

No. 844,170 or German Patent Application No. 28,308,222 from a triazolo-thieno-oxazepine 10 of the general formula ^ N \ is V./S\/N-

li li \ IV

i-f * 2 r / \ ch_0 20 "s-f | T ~ R4 (groups R 1, R 2, R 3, R 4 and R 5 have the above 25 meanings) by cleavage of the oxazepine ring at the oxygen atom and treatment of a compound of the general formula

R3 - N

R, .S. JL- £ ΧΉο-0Η Ύ if R / 35 2 1 * 5 liT * 4

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9 (the groups R 1, R 2 / R 9, R 2 and R 2 have the meanings given above) with a phosphorus or sulfur halide.

The working time required for the new process is only half of the working time which, depending on the operation of the autoclave and requires an effort to absorb the large amounts of ammonia, must be used for the prior process. Since the investments in the known process are also substantially higher, the new method results in a saving in production costs of about 35%.

The final products of the general formula I as well as their acid addition salts have a pronounced anticonvulsant, sedative, anxiolytic and anti-aggressive effect in the dose range of 0.1 to 3 mg / kg at very low toxicity.

The invention is further illustrated by the following examples.

Example 1 8-Bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazolo- [3,4-c] -thieno- [2,3-e] -1,4-diazepine.

a) 8-Bromo-6- (o-chlorophenyl) -5-hydroxy-1-methyl-4H, 6H-s-triazolo- [3,4-c] -thieno- [2,3-e] -1; 4-diazepine.

30 g (0.06 mol) of 3-methyl-4- [3- (o-chlorophenyl-bromomethyl) -5-bromothienyl (2)] - 5-chloromethyl-1,2,4-triazole are heated at reflux with 10.1 g (0.06 mol) of potassium iodide, 116 g (0.89 mol) of N, N-diisopropylethylamine and 32.4 g (0.47 mol) of hydroxylamine hydrochloride in 1000 ml of methanol in 2.5 hours. Subsequently, 30 are extracted from insoluble matter, the solvent is distilled off, the residue is taken up in methylene chloride and washed with water, the methylene chloride phase is dried and evaporated and the residue is recrystallized from ethanol.

Yield of 8-bromo-6- (o-chlorophenyl) -5-hydroxy-1-methyl-4H, 6H-s-triazolo- [3,4-c] -thieno- [2,3-e] -1 4-diazepine: 22.3 g = 90.3% of theoretical yield with m.p.

215-217 ° C.

DK 154505 B

B) Title compound by route a, 7.5 g (0.018 mol) of 8-bromo-6- (o-chlorophenyl) -5-hydroxy-1-methyl-4H, 6H-s-triazolo [3,4-c] -thieno- [2,3-e] - 1,4-diazepine is stirred with 10/2 g (0/086 mol) of thionyl chloride in 240 ml of methylene chloride at room temperature for 2 hours. Then add. water during the cooling / methylene chloride phase is separated and washed with dilute ammonia / the organic phase is dried and evaporated / and the residue is recrystallized from ethanol.

Yield of 8-bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazolo [3,4-c] -thieno- [2,3-e] -1,4-diazepine : 6.55 g = 92.6% of theoretical yield with m.p. 208-210 ° C,

In further experiments yields between 89 and 95% of theory were obtained.

C) Title compound by road (b) 2/0 g (0.0048 mol) of 8-bromo-6- (o-chlorophenyl) -5-hydroxy-1-methyl-4H, 6H-s-triazolo [3.4 -c] -thieno- [2,3-e] -1,4-diazepine is dissolved in 240 ml of acetone at room temperature and 1.5 g of potassium permanganate is added and the mixture is stirred for 45 minutes at room temperature.

The suspension is diluted with chloroform. Suction is obtained from the tartar, the rose-colored solution is filtered through active cow / diatomaceous earth and evaporated and the residue is crystallized with ether.

Yield of 8-bromo-6- (o-chlorophenyl) -5-N-oxide-1-methyl-4H-s-triazolo- [3,4-c] -thieno- [2,3-e] -1 4-diazepine: 1.8 g = 91.7% of theoretical yield with m.p.

272-273 ° C.

β) 4.5 g (0.01 mole) of the above N-oxide is heated under reflux with 10.7 g (0.078 mole) of phosphorus trichloride in 300 ml of chloroform for 2 hours. The solution is added to ice water and washed with sodium hydroxide solution and then with water. The organic phase is dried and evaporated and the residue is recrystallized from methyl-ethyl ketone.

Yield of 8-bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazolo [3,4-c] -thieno- [2,3-e] -1,4-diazepine: 3, 5 g =

DK 154505 B

11 88.9% of theoretical yield with m.p. 208-210 ° C,

The N-oxide obtained according to Example 1 c) can also be prepared as follows: 1.0 g (0.0024 mol) of 8-bromo-6- (o-chlorophenyl) -5-5 hydroxy-1-methyl 4H, 6H-s-triazolo- [3,4-e] -thieno- [2,3-e] -1,4-diazepine is dissolved at room temperature in 70 ml of acetone and 30 ml of chloroform. With stirring, 1.1 g (0.005 mole) of yellow mercury oxide is added portionwise within 5 minutes. Then, a total of 10 ml of water is added dropwise and stirred for 4 hours at room temperature.

Subsequently, the insoluble matter is washed off, washed with chloroform, the phases are separated and the organic phase is dried over sodium sulfate. The solution is then evaporated in vacuo and the residue is added with 30 ml of ether and allowed to crystallize with stirring.

The yield of 8-bromo-6- (o-chlorophenyl) -5-N-oxide-1-methyl-4H-s-triazolo [3,4-e] -thieno- [2,3-e] -1, 4-diazepine amounts to 0.9 g = 90.4% of theoretical yield with m.p. 272-273 ° C, Example 2 1,8-Dibromo-6- (o-chlorophenyl) -4H-s-triazolo- [3,4-c] -thieno- [2,3-e] -1,4 -diazepine, a) 1,8-Dibromo-6- (o-chlorophenyl) -5-hydroxy-4H, 6H-s-triazolo [3,4-c] -thieno [2,3-e] -1 · , 4-diazepine.

16 g (0.026 mol) of 3-bromo-4- [3- (o-chlorophenyl-bromomethyl) -5-bromo-thienyl (2)] - 5-bromomethyl-1,2,4-triazole (m.p. 148 ° C) is refluxed with 4.3 g (0.026 mole) of potassium iodide, 51.2 g (0.40 mole) of Ν, yl-diisopropylethylamine and 14.3 g (0.21 mole) of hydroxylamine hydrochloride. in 530 ml of methanol for 5 hours. Then, from insoluble matter, the solvent is evaporated off, the solvent is distilled off in vacuo at 40 ° C, the residue is taken up in methylene chloride, washed with water, dried and evaporated the methylene chloride phase, and the residue is recrystallized from acetic acid ethyl ester.

Yield of the title compound: 10.9 g = 87.8% of theoretical yield with m.p.

DK 154505 B

12

188-190 ° C

b) Title connection by road a.

5 g (0.011 mol) of 1,8-dibromo (-6Ho-chlorophenyl) -5-hydroxy-4H, 6H-Si-triazolo- [3,4-O] -thieno- [2,3-e] -1, 4-diaz & -5-pin is stirred at room temperature with 3.5 g (0.012 mol) of 2-bromo-1-methylpyridinium iodide and 2.8 g (0.023 mol) of 1,5-diazabicyclo [4.3.0] non-5 one (DBN) in 370 ml of methylene chloride for 1 hour, then the organic phase is washed with aqueous sodium thiosulfate solution and with water, dried and evaporated and the residue is recrystallized from methanol.

Yield of 1,8-dibromo-6- (o-chlorophenyl) -4H-s-triazolo- [3,4-c] -thieno- [2,3-e] 1,4-diazepine: 4.3 g = 85.1% of theoretical yield with m.p. 209-210 ° C.

By analogy with the examples given, the following 15 products were prepared through the indicated intermediates:

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13

H

vo O vo CVi 00 -i 00 C \ 1 O

+> OH-iOvtnHHVOH

cmcmhhcmcmcmhcm 5, o

'go I I I I I I I I I

S ft -i CO -i O!> · Cm VO H C *

R4 g O O * i CJV in H rri VO O

tj CO CMCMHHCMCMCMHCM

H

01

cO

H

H O CM VO O O 00

M IS C * - -d- ΚΊ VO CM

1 CM CM CM CM H CM

I + »O

£ - * 0 III I I I III

S 3.

riti 0 oo o <t oo ω is

H. Oe VOIS <rCMtn CM

O) k rg CM CM CM CM H CM

g ft W

H VO Η H KV H VO 00 CO O

η σισννο vo tn cm σνοοσν

1 Η HHH CM CM CM HHH

iSo 111 I I I III

0) 30 00 03 H OV -i m vo oo H-d · σ> oo m vo cm oiooco H O ft Η H ri CM CM CM rri rri rri 0) g

g ft CO

oT MæaffiKæKffiK

ri i — I rri, rri rri Η rri rri rri

Cd O & iOOOOOUO

* / cd m m m S ^ \ —7 h «te a I k \ 7 w o« 000 T ['cd4 ææ®w®®ææ® η. π ir i ii u u h h b cd ocqcMpqmrtrøPQffi o

DK 154505 B

14 H _ co m vo

+) vO 'in CM

Ai 'Η H CM

P O

'ti O I I I

0 m -vo m <r

Ai Pi VO -d "CM

. 3 m 'H - H «i — l ω <d

H

H vo <1 *

H -4- O

, +> O ^ * ΪΨ 1

Hti · in CM

H O & «4 O

Φ P Λ CM CM

g p * w

H

j ~ j m o c * -

H VO Η H

H CM CM

1 +> 0

ε · * ο * i i i (!) 3 4 ft cm co m

r-f O s VO O H

0) A ω iH CM CM

S Pi m cd a a - a

Η Η H

05 O O. Q

6 A A «/ v

m xm a and S

a and CM CM CM

o o o o o

CM

a a a a

ri. U fj P

us a - a a

Claims (1)

Wherein N and R 2, which may be the same or different, represent hydrogen or halogen atoms or alkyl groups of 1-2 carbon atoms, or R 2 and R 2 together form an alkylene chain having Represents a hydrogen, chlorine or bromine atom, a straight or branched alkyl group having 1-3 carbon atoms, a 'ω-hydroxyalkyl group having 1-3 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, or a 5 -or 6-membered saturated ring attached to the remainder of the molecule over one of its carbon atoms and containing an oxygen, sulfur or nitiogen atom, an nitrogen-containing ring optionally substituted by the nitrogen atom with an alkyl group having up to 3 carbon atoms, or the group / V 30 \ R3 "wherein R3" and R3 "which may be the same or different, represent hydrogen, an alkyl group having 1-4 carbon atoms or a hydroxyalkyl group having 2-3 carbon atoms, or 35 R ^ and R₂ together form a 4- or 5-membered alkylene chain which may optionally be substituted once or twice by methyl, or R3 'and R3' together with the nitrogen atom to which they are attached form a morpholine group and R4 and R5 which may be the same or different represent a hydrogen, fluorine, chlorine or bromine atom, or physiologically acceptable acid addition salts thereof, characterized by reacting a dihalide of the general formula 10 Τι ΓΓ ^ CH-rHal, [I II 11 o S ^ CH -Hal, Rg in 1 wherein R 1, R 2,, R 1 and R 2 have the above meanings, and Hal 1 and Hal 2, which may be the same or different, each represent a halogen atom such as e.g. fluorine, chlorine, bromine or iodine, with hydroxylamine at a temperature between 20 and 150 ° C in organic solvents with the addition of potassium iodide and a difficult alkylable base such as e.g. Ν, Ν-diisopropylethylamine, di-cyclohexylethylamine or 4-hydroxy-2,2,6,6-tetramethylpiperidine, and the hydroxylamine compound thus obtained of the general formula R 3 Wherein R 1, R 2 / R 2, R 2 and R 2 have the above meanings; a) are converted with a water-splitting agent such as e.g. thionyl chloride, methanesulfonic acid chloride, 2-bromo-N-methylpyridinium iodide, 2-chloro-N-methylpyridinium iodide or dicyclohexylcarbodiimide, at temperatures between 20 and 150 ° C in an organic solvent for the corresponding compound of general formula I, or b) is converted with an oxidizing or dehydrogenating agent such as e.g. yellow mercury (II) oxide or potassium permanganate at temperatures from -25 ° C to + 100 ° C in an organic solvent for the corresponding N-oxide of the general formula N. 15 * 3 2 I ^ 0 kJ wherein R 1, R 2, R 2, R 2 and R 2. have the above meanings and this is transmitted by reduction with a reducing agent such as e.g. phosphorus trichloride, phosphorus tribromide, triphenylphosphine, triethylphosphite, di-n-propylsulfoxylate or iron pentacarbonyl, in the corresponding compound of the general formula I, whereupon the compound of the general formula I is optionally transferred in the usual manner in a physiologically acceptable acid addition salt .