DE1568217A1 - Process for the preparation of tricyclic derivatives of acetamide - Google Patents

Description

Specimen copy

C. ϊ ". Boehringer & Soehne

G ib K
Mannheim. , .1476.1568217

Process for the preparation of tricyclic derivatives of acetamide

Object of the present invention is a method of manufacture of new tr.icyolisohen derivatives of acetamide. of the general formula I.

in which X is a saturated or unsaturated, straight » chain or branched alkylene group with 1-3 Köhlenaloff atoms, sine oxymethylene, thiaethylene, Thiaethylene group, an optionally alkylated or acylated iminomethylene or optionally altylated carboximide group,

E, hydrogen, a halogen atom, a lower one
Alkyl, alkoxy, trifluoromethyl or alkyl mercapto group,

R_ hydrogen or the hydroxyl group,

R, hydrogen or a lower alkyl group,

R. hydrogen or together with R "a double bond mean.

It has been found that the substances I are valuable pharmacological Properties, e.g. B. muscle relaxing, tranquilizing and have anticonvulsant effects.

The erfindungegemäße Vtrfahren _r is characterized in that, in per se known length either

a) carboxylic acids of the general formula II,

(II)

COOH

in which R ₁ , R ₀ , R ₁ , R. and X are those given above

* ■ ^ 5 4. ■ -,

Have meaning

or reacts their reactive derivatives with ammonia or

b) Nitriles of the more general: Formula III

(in)

in the I:., H _0,. "(, R and X the * · * · j 4

Have meaning

gently saponified, or

c) in the event that R ₀ and R form a double bond, -, ketones of the general formula IV

-A,

(IV),

in which X and R. have the meaning given above,

Bit a » reactive derivative το * ι Acitaeiden of the general formula V

R ₁

rp— β «

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in which R _{7 has} the meaning given above, Alk rine is a lower alkyl group and He is an Alkaline till,

converts, and the products thus obtained for the fill that R _{3 is} a hydroxyl group, if desired, subsequently dehydrated and, in the event that R _{1 and R together represent a double bond, (} if desired, 3 subsequently hydrogenated.

.-. Ia renktionsf-ihi ^ .e derivatives of the carboxylic acids II are particularly the v.-iurehalofjetude and esters in question. In the event that the free acids II are used as starting products, ammonia is formed. r.-ohst the ammonium salts which are pyrolytically or catalytically, preferably dehydrated by adding an acidic catalyst such as p-toluenesulphonic acid, or by adding a dehydrating agent such as carbodiimide, to form ir> n amides of the formula I. If you start from the reactive derivatives of the carboxylic acids II, these are preferably λ ι. an inert: I / 'sungsniittel reacted with ammonia. At a pre-

■ * .; th Vari-t ^ t dos of the method according to the invention are the free w iuren II unoccupied with a halogenating agent such as thionyl chloride the so released acid chlorides without isolation with excess tv.t.

The gentle saponification of the nitriles III is achieved, for example, by: tr.en in alcoholic potassium hydroxide solution or by leaving it to stand at room temperature ^ or ι door effects in alcoholic hydrochloric acid. When using.

I-alcoholic hydrochloric acid go to compounds III, in which R_ represents a hydroxyl group, with simultaneous elimination of water in the substances I, in which R _? and R. together form a double bond.

Suitable reactive derivatives V are, in particular, those correspondingly substituted Alkali salts - preferably sodium salts - the acetamidophos = piionic acid diethyl ester in question; see P. Nylen, Ber. d. dtscluChon * Ges.57t I (1924), p. IO23. The unsaturated directly arising here Substances I (R “and R form a double bond) follow Add? of water and acidic acids (e.g. with carbon dioxide) lus ethers and in Purify in the usual way by distillation and crystallization.

Dii ·., CfT Subsequent dehydration of the compounds which is also desired I is expediently carried out by heating a mixture of glacial acetic acid and mineral acids, preferably hydrochloric acid, or by letting it stand in the case of rauroin alcoholic hydrochloric acid. If desired, a subsequent.

, I hydrogenation of unsaturated compounds to be carried out (R_ and H ^ together form a double bond) .is preferably done by catalytic ^ Hydrogenation or with nascent hydrogen, which e.g. Solution developed by Waesfr with amal-trimmed aluminum.

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The carboxylic acids II used as starting materials are obtained by extracting ketones of the general Poreel IV bit unified fatty acid; j ester (for example tert-butyl acetate) in the presence of an alkaline condensing agent. The here as intermediates : '"; M

formed hydroxyteters of Foratl VI ■ -

R ^/ XJOO-alkyl
4th

in the R., R ,, R. and X the above Have meaning

can be converted into the desired carboxylic acids IT "~ by careful acid hydrolysis7 in which R_ denotes a hydroxyl group. Under strong hydrolysis conditions (e.g. glacial acetic acid / 6 η hydrochloric acid), dehydration and saponification to unsaturated carboxylic acids II (R ₂ and R form a double bond) which, if desired, catalytically or with amalgaDiertem aluminum to the saturated acids II (R. and R. represent hydrogen are hydrogenated). It is iber invention nnr.h possible umzaretzen the ester VI with ammonia and immediately prior to the Refrain from isolating the free carboxylic acids :: II.

The nitriles III used as starting materials are in our application File number B 86 165 IVb / l2o and are identified by an Art "Aldol condensation" of ketones of the formula IV with nitriles of the formula VII

- C * I (VII)

<° in which R _{5 has} the meaning given above,

«^ In the presence of a basic condensing agent - preferably ^ Lithium amide in liquid ammonia - and, if necessary, subsequent OI dehydration or hydrogenation obtained. O

In the examples below, the process according to the invention is

explained in more detail. 1 ■ - - - - *

* '* BAD OBGiNAl

example 1 II-carboxamido-methylene-6,11-dihydro-dibenz [b, e loxepin

25 »4 S (0.1 mol) 6, ll-dihydro-dibenzo [b, e] oxepin-ll-yl-acetic acid (melting point 114-115 °) are refluxed with 40 ml of thionyl chloride for 2 hours. It is then evaporated, taken up in 100 ml of ether or tetrahydrofuran and treated with approx. 50 ml of liquid ammonia. The excess ammonia is then allowed to evaporate overnight, the ammonium chloride which has separated out is filtered off with suction and the solvent is removed in vacuo. The residue is then recrystallized from isopropanol or alcohol. The yield of II-carboxamido-methylene-6, II-dihydro-dibenz [b, e] oxepin is 79 ^a ß> the Theor.j mp 205 °.

Example 2

11-carboxamido-methyl-6,11-dihydro-dibenz fb, eloxepin

3 »3g (0.1 mol) of the 11-carboxamido-.aetaylen-6, ll-dihydro-dibenz [b, e] oxepin prepared according to Example 1 are dissolved in 100 ml of tetrahydro = fort · and after adding the same amount by weight 50 ml of water are added dropwise to amalgamated aluminum grit over a period of 3 hours. The reaction is then allowed to continue via power, and the solution is evaporated in vacuo. The evaporation residue can be recrystallized from liquid ester or isopropanol. The yield of II-carboxamido-methyl-6,11-dihydro-dibenz [b, e] oxepin is 86 i "of the Theor.} Fp. I4O-I4I ^0th

Example 3

5-carboxamido-meth _{l ylene-10?} II-dihydro- ^ H -dibenzo [a _t d1oyclohefiten -23.1 g (0.1 mol) 5-cyanomethylene-10, II-dihydro-5H-dibenzo [a, d] =

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cycloheptene (m.p. 105-106 °) are with the same amount of weight Potassium hydroxide was heated to boiling for four hours in a mixture of 100 ml of water and 100 ml of alcohol. Then you dilute old water, The precipitate is filtered off with suction and recrystallized from isopropanol. The yield of S-carboxamido-ethylene-lOjll-dihydro-SH-dibenzota,;! V cyclohepten is 65 # the theor.} pp. 166-167 °.

Example 4 5-Carbox-iroido-methyl-10 _t II-dihydro-5H-dibenzo [a _t d1cyclohepten

Variant a: In a manner analogous to that described in Example 1, is obtained using 10, ll-dihydro-5H-dibenzo [a, d] cyolohepten-5-yl-acetic acid (Pp. 163-164o) with a yield of $ 82 the Theor. S-carboxamido-methyl-lOjll-dihydro-SH-dibenzota.dlcyolohepten; 137-130 °.

Variant bs In a manner analogous to that described in Example 2, 0.1 mol of the 5-carboxaaidomethylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene prepared according to Example 3 is obtained in a yield of) 0 io Theor. 5-carboxamido-methyl-10 _r II-dihydro-5H-dibenzo »[a, d] cycloheptene, m.p. 137-138 °.

Example 5 5-carboxanido-meth.vlen-5H-dibenzora, d] cycloheptene

iii iÄ £!} i_ ^a i * ^{n &} naloger manner as described in Example 1, are obtained from 24.8 g (0.1 mol) of 5H-dibenzo [a, d] cyclohepten -5-ylideneacetic (mp. 207- 209 °) bit of a yield of 87 jC the theor. S-cirboxamido-methylene-Sfl-dibeneotajdjoyclohepten} Mp. 144-145 °.

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Bs variant in an analogous manner as described in Example J, receives ean "äüiTÖ" l Hol S-cyanomethyl-SH-dibenzta ^ loyolohepten (Pp, 102-103 ° C) with a yield of 63 i "of the Theor. S-carboxamido-methylene-SH-dibenzo [a, d] cyolohepten} mp. 144-145 *

Example 6 5-Carboxafflido-methyl-5H-dibenzofa, d1cyclohepteTi

In a manner analogous to that described in Example 2, one obtains from 0.1 mol of the 5-carboxamido-methylene-5H-dibenzo [a, d] cyoloheptene prepared according to Example 5 with a yield of 81 ^ the theor. 5-carboxamido-methyl-5H-dibenzo [a, d] cycloheptene; 207-208 °.

Example 7

In a manner analogous to that described in Example 1, the following substances «

II-carboxamido-methylene-6, II-dih.ydro-dibenzo [b, e1thiepin; Mp. 209-210 ° (yield SO YES of theory),

ll-niethyl-6-Carboxaniido ₁ ll-dihydro-dibenzo [b, e Ithiepin; Mp. 194-195 ° (yield Iß . -I. Th.),

12-carboxamido-niethylen-7tl2-dihydro-6H-dibenzorbie] thiocin; Mp. 171-173 ° (yield 72 # of theory),

ll-carboxaniido-methylene-2-roethyl-6, ll-dihydro-dibenzTb.eloxepin; Mp. 202 ° (yield 7Θ $ of theory ).

The following acids are used as the starting product:

· / ·, ^BA D ORIGINAL

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26.8 g of 6, ll-dihydro-dibenzo [b, e] thiepin-ll-ylidene-eBsigsämre ·

(M.p. 180-101 °)} -

27.0 g of 6, ll-dihydro-dibenzo [b _t e] thiepin-ll-yl-acetic acid • (mp. 208-209 °) J

28.2 g of 7,12-dihydro-6H-dibenzo [b, e] thiocin-12-ylidene-acyl acid (M.p. 1 "8-19O) *

26.6 g of 2-methyl-6, ll-dihydro-dibenz [b, *] oxepin-ll-ylidene-acetic acid} (M.p. 209-211 °).

Example 8 II-carboxamido-niethyl-methyl-o.II-dihydro-dibenzib-eioxepin

In a manner analogous to that described in Example 2, one obtains from 0.1 mol of the II-Oarboxamido-niethylen prepared according to Example 7 2-methyl-6, ll-dihydro-dibenz [b, e] oxepin bit 76 yield the theor. II-carboxamido-methyl-2-ethyl-6, II-dihydro-diben [b, e] -oxepine; M.p. 146.

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• A

Claims (1)

Claim in the X a saturated or unsaturated, straight chain or branched alkylene group with 1-5 carbon atoms, an oxymethylene, thiamethylene, Thiaäthylenjruppe, an optionally alkylated or ncyl-ierte iminomethylene or optionally alkylated oxymide group, R ₁ hydrogen, a halogen atom, a lower alkyl, alkoxy, triluoromethyl or alkyl nercapto group » R ₂ MasserwtQff or the hydroxy group, fi. Hydrogen or a lower alkyl group, R. hydrogen or together with R_ a double 4 ^ meaning characterized in that one either in a manner known per se a) carboxylic acids of the general formula II, (H) ₁ COQH " ^f 909881/1550 8AD ORIGINAL in which R., R-, R ,, R. and X have the meaning given above, or reacting their reactive derivatives with ammonia or b) nitriles of the general formula III C-R ₁ (HD. in which R, R, R, R- and X are the oVen . have given meaning » gently saponified, o-der ö) for the Pail, that R and B. also form JteppelbindjäOig, ketones of the universal Faraml TT ¹ ! in the X and R. the meaning given above to have, Bit «Ines reactive derivative ron luie-teaiden of the general © aeiireii = P - C 4 © Hey © in the Ä, the above a Meaning hit, Alk is a lower alkyl group and He is an alkali metal, 909881/1550 " converts, and the products obtained in the event that R is a hydroxyl group, if desired, subsequently dehydrated and, in the event that H_ and R together represent a double bond , if desired, are subsequently hydrogenated » ORIGINAL 909881/1550