DK141401B - Analogous process for preparing hexahydro-1H-azepine compounds or acid addition or quaternary ammonium salts thereof. - Google Patents

Description

<ii) PUBLICATION 141401 DENMARK (B) Intel. * C 07 D 223/0 * (21) Application No. 4399 / ^ 9 (22) Filed on 15 · ^ S * V9 ^ 9 1¾¾¾ (23) Running Day 15 · » Ug · 19 ^ 9 \ / (44) The application presented and 1 ni nQn

the submission thesis published on 'C' ® & F. I yOV

DIRECTORATE OF

PATENT AND TRADE MARKET (30) Priority requested from it

Aug 16 1968, 5920.1 / 68, GB 4. s ep. 1968, 42060/68, GB

Jan 28 1969s 4694/69, GB

(71) JOHN WYETH & BROTHER LIMITED, Hunt is co mb e Lane South, Taplow, Maidenhead, “Berkshire, GB.

(72) Inventor: John Frederick Ciavalla, 10 The Drive, Isleworth, Middlesex, GB: Alan Chapman White, 5 Sherbourne Drive, Windsor, Berkshire, GB.

(74) Plenipotentiary in the proceedings:

The engineering company Budde, Schou & Co.

(64) Analogous process for preparing hexahydro-1H-azepine compounds or acid addition or quaternary ammonium salts thereof.

The present invention relates to an analogous process for the preparation of novel hexahydro-1H-azepine compounds or acid addition salts or quaternary ammonium salts thereof.

It has been known for some time that compounds containing an azepine ring have a pharmaceutical effect, in particular an analgesic effect. As an example of a commercially available analgesic of this type which does not make use, mention may be made of ethyl 1-methyl-4-phenyl-hexahydroazepine-4-carboxylate, known as ethoheptazine.

Also, other compounds containing an azepine ring are described as possessing pharmaceutical activity, especially analgesic activity. Thus, in US Patent Nos. 2,740,779 and 2,775,588, various azacycloalkanes are disclosed which are said to have different degrees of analgesic effect. In particular, 4-proplonyl-4- (m-hydroxyphenyl) azacycloheptane, which is representative of the compounds of the above-mentioned patent, has been found to have good analgesic activity, but this compound does not have opium antagonistic activity, which means that the connection probably creates habits. It has never been marketed. All of the compounds known from the above-mentioned patents are 4,4-disubstituted hexahydroazepines.

It has now been found that a novel series of hexahydroazepines structurally different from the prior art hexahydroazepines has analgesic activity. These novel compounds are 3,3-disubstituted hexahydroazepines, while the compounds known from the above U.S. Patents are 4,4-disubstituted. Another difference from the known compounds is that they always contain a carbonyl-containing group at the 4-position, whereas the new compounds, on the other hand, contain an alkyl group at the 3-position. In addition, many of the compounds of the present invention have been shown to have opium antagonistic activity in contrast to the known compounds in pharmacological testing. This activity suggests that the novel compounds are unlikely to produce habituation, which is also confirmed by the fact that they have been shown not to replace morphine in morphine-dependent rats.

The novel compounds provided by the process of the invention are hexahydro-1H-azepine compounds of the general formula 'CH2 \ OR1

CH0 CH0, _S

r34 - {Z} (I) k wherein R 1 represents a hydrogen atom, an alkyl group of not more than 6 carbon atoms, a benzyl group or an alkanoyl group of not more than 6 carbon atoms, R means an alkyl group of not more than 6 carbon atoms, R means a hydrogen atom , an alkyl, alkenyl or alkynyl group having a maximum of 6 carbon atoms, a cyclopropylmethyl group, an alkanoyl group having a maximum of 6 carbon atoms, an alkoxycarbonyl group having at most 141401 3 carbon atoms or a phenalkanoyl group having at most 6 carbon atoms in the alkanoyl or β -benzoyl-ethyl group, each of which may be substituted in the benzene ring of up to 5 halogen atoms and / or up to 5 alkyl, alkoxy or haloalkyl groups of not more than 6 carbon atoms, nitro groups, amino group or mono or dialkylamino groups each of which alkyl groups most preferably contains at most 6 carbon atoms and R is a hydrogen atom or an alkyl group having at most 6 carbon atoms, or acid addition salts or quaternary ammonium salts is made of.

When R represents a hydrogen atom, there is only one asymmetric carbon atom in the molecule, and in this way the invention provides both optically active isomers and the racemate, but when R represents an alkyl group, there are two asymmetric carbon atoms and the invention provides all the optical isomers. as well as the race mates. If an optically active isomer is desired, a cleavage can be performed using methods known in the art.

The compounds of the above general formula have been named using the hexahydro-1H-azepine ring as the base unit and numbering from the nitrogen atom in this ring.

Examples of such compounds are: 3- (m-methoxyphenyl) -1-methyl-3-propylhexahydro-1H-azepine, 3- (m-methoxyphenyl) -1,3-dimethylhexahydro-1H-azepine, 3- (m -hydroxyphenyl) -1-methyl-3-propylhexahydro-1H-azepine and 3- (m-hydroxyphenyl) -1,3-dimethylhexahydro-1H-azepine, although it is recognized that said compounds could alternatively be named using m -substituted phenol as a base unit.

The last connection could, e.g. According to the nomenclature of Chemical Abstracts, m- (hexahydro-1,3-dimethyl-1H-azepin-3-yl) -phenol is designated as phenol.

Preferred compounds of the above general formula (I) are hexahydro-1H-azepines in which R is hydrogen or methyl, in R 2 is hydrogen, methyl or acetyl, R is methyl, ethyl, 3 n-propyl, iso-propyl or n -butyl, and R is hydrogen, methyl, ethyl, n-propyl, allyl, 3-methylbut-2-enyl (commonly known as dimethylallyl), propynyl, cyclopropylmethyl, phenacetyl, phenethyl, p-aminophenethyl, β-benzoylethyl, β- (p.-chlorobenzoylethyl) -ethoxy-carbonyl or formyl.

The analogous process of this invention for the preparation of the hexahydro-1H-azepine compounds of formula (I) above is characterized in that a) a tetrahydro- or hexahydroazepine of formula 14U01

- (ch2) j jQ

X __ ^ V-nl \ - \ 2

Y '---- R

1 P

where R and R have the above meanings, X-Y means -N = CHR- or R3N-C-, where R and Y? have the above meanings, and

TEN

0 in 3 * 3 Y means -CH 2 -, or X Y means R N-CH 2 -, - where Y 1 is as defined above and Y 1 is -CO-, reduced, or b) a halogenamine of the general formula R 2 3 - C - CHO · NHC I dd (CH 2) 4 * Hal 2 in which R and R have the above meanings and Hal represents a halogen atom is cyclized, preferably by heating in a solvent in the presence of a base on which it is prepared. connection about Desired when 2 B? means a methyl group, N-demethylated for the preparation of a corresponding compound wherein R 1 is hydrogen or, when R 1 is hydrogen, alkylated or acylated to prepare a corresponding compound wherein R 1 with the meaning of formula (I) other than hydrogen, and / or, when R 1 is different from hydrogen, hydrolyzed or deetherified to produce a corresponding compound wherein R 1 is hydrogen or when R 1 is hydrogen, alkylated or acylated to preparation of a corresponding compound wherein R 1 has one of the meanings stated in connection with formula (I) other than hydrogen, whereupon, if desired, the compound prepared is converted to an acid addition salt or quaternary ammonium salt thereof.

Compounds of the above general formula (II, wherein R 3 is different from alkanoyl and R is different from hydrogen or alkanoyl) can be prepared by "alkylation", as defined below, of a corresponding compound with the general formula (I) wherein 3 1 R is hydrogen and R is different from alkanoyl.

The term "alkylation" in the present application means 3 introduction to the nitrogen atom of the hexahydroazepine ring of a radical R selected from the alkyl, alkenyl, alkynyl, cyclopropylmethyl, phenalkanoyl, phenethyl (which may be substituted in the benzene ring), or 2-Benzoylethyl radicals (which may be substituted in the benzene ring) Many methods for alkylating compounds are known, and the most suitable method for forming a desired product can be used, the following methods being usually preferred.

A compound of the general formula (I) in which R 1 is different from alkanoyl and R is hydrogen may be reacted with a halide of the general formula 3 R 2 -Hal 31 3 wherein R has the same meaning as R except from alkanoyl and hydrogen, and Hal is a halogen atom, in the presence of an acid acceptor such as an alkali metal carbonate, e.g. potassium carbonate, preferably in solution in an organic solvent, e.g. 25-100 ° C, preferably 80-100 ° C.

A 1-methyl group may be introduced into a compound of the general formula (I) in which R, R 1 and R 2 have the meaning given herein, and 3 R is hydrogen, by reductive methylation, e.g. formaldehyde and hydrogen are used in the presence of a hydrogenation catalyst.

Further, the compounds of the general formula (I) wherein R is alkyl or benzyl, R is alkyl, R is alkyl, alkenyl, alkynyl, cyclopropylmethyl, phenethyl, and R is a hydrogen atom can be prepared by alkylation of a hexahydro -2H-azepine-2-one of the general formula UU 01 6 H 'O _vor1 h' O (foRl KVVW R2 (II) (ra> and reduction of the oxo group to a methylene group. Hexahydro-2H-azepine - 2- for example, the one can be converted to an alkali metal salt, for example by reaction with sodium, sodium amide or sodium hydride, and the alkali metal salt can then be reacted with a halide of the general formula 2 "R-Hal 3" in which R is alkyl, alkenyl, alkynyl, cyclopropylmethyl or phenethyl, and the 1-alkylated hexahydro-2H-azepin-2-one can then be reduced.

Compounds of general formula (I) wherein R 1 is different from hydrogen and R is alkanoyl may be prepared by alkanoylation of a corresponding compound of general formula (I) in which R is different from hydrogen, and R is hydrogen.

A particular example of the alkanoylation process is formulation, e.g. heating a compound of the general formula (I), in which R is hydrogen and R is different from hydrogen, with formic acid under reflux.

Compounds of general formula (I) in which R 1 is alkanoyl can be prepared by alkanoylation of a corresponding compound in which R 1 is hydrogen.

2

The compounds of the general formula (I) in which R, R and 3 are R have the above meanings and R is a hydrogen atom can be obtained from the corresponding compounds of the general formula (I) in which R alkyl or benzyl, by leaving the ether group in a manner known per se, e.g. by treating the alkyl or benzyl ethers with hydrogen bromide or boron tribromide or by subjecting the benzyl ethers to hydrogenolysis. If desired, the product obtained can then be alkanoylated, e.g. with acetic anhydride, to give the corresponding compound in which R 1 is alkanoyl.

141AO1 7

A preferred method for preparing compounds of general formula (I) in which R is hydrogen is illustrated in the following. In this method, R and Hal have the meanings set forth above, R 1 is alkyl, and Alk is alkyl, preferably ethyl.

.. OR1 .. OR1 In Hal · (CHc), * C0oAlk | fV)

R2 - CH - CN R2 - C - CN

(IV) / (CH 2) 3 * CO 2 Alk r10-tTA

JyR2 ^ .OR1 (i) <-J i- (VI)

0 ^ »i 2 I

R - C - CHg * NHg (CHg) ^ · COgAlk

A phenyl-substituted aliphatic nitrile of formula (IV) can be reacted with sodium in liquid ammonia followed by an alkyl halogenobutyrate, preferably ethyl 4-iodobutyrate, to form a nitrile ester of formula (V), this nitrile ester can be reduced, e.g. preferably with hydrogen in the presence of palladium on charcoal at room temperature in a solvent such as methyl alcohol, p containing sulfuric acid, and under a pressure of ca. or with hydrogen in the presence of Raney nickel at a temperature of 100-150 ° C in a solvent such as eyclohexane and under pressure of 56 to 84 kg / cm. Low temperatures tend to yield the open-chain product of formula (VI), while higher temperatures tend to yield the product of formula (II). Accordingly, the product of formula (VI) may be heated, e.g. in a solvent such as refluxing toluene or decahydronaphthalene, or with sodium ethoxide in absolute alcohol to give the hexahydro-2H-azepln-2-one of formula (H) which is reduced, e.g. with sodium dihydro-bis (2-methoxyethoxy) aluminate or with lithium aluminum hydride, to give a compound of formula (1) in which 8 KU01 R and means hydrogen or it can be "alkylated" directly with subsequent reduction to form a hexahydroazepine with the general

~ Z

formula (i) in which R is hydrogen and R 1 is alkyl, alkenyl, alkynyl, cyclopropylmethyl or phenethyl.

Once a compound of formula Π <, in which R "+ - means alkyl ·, has been prepared, the corresponding compound in which R1 represents hydrogen can be obtained therefrom by cleavage of the ether group as described above.

A less preferred method for preparing compounds of the general formula (Ί) in which R and V? means hydrogen is described below. In this method, R ^ means alkyl or benzyl.

/ OR1 'Γ if Hal (CH) CN Γ Π' VII) ^ Uj

R2 - CH - CN R2 - C - CN

(IV) (CH2yCN

(V) 1 '* 1' .OR ^ CR1 ri (i) - i <- I rm

V V

R 2 - C - CH 2 -NH 2 R 2 - C - CO'NHg (ch 2)

A phenyl-substituted aliphatic nitrile of formula (IV) can be reacted in a manner similar to that previously described, but using, for example, 4-iodo-butyronitrile to form a dinitrile of formula (VII) which, by hydrolysis, eg. with an aqueous alkali metal hydroxide affords the amido acid of formula (VIII); the amido acid is reduced. eg. with lithium aluminum hydride, to the aminohydroxy compound of formula (IX) which is halogenated, e.g. with thionyl chloride and then cyclized in the presence of a base, e.g. an alkali metal carbonate to give the desired compound of formula 9 (I). As a modification of this reaction pathway, a compound of formula (V) may be reduced, e.g. with lithium aluminum hydride, for a compound of formula (IX).

The following three methods can also be used for the preparation of compounds of the general formula (I) in which R is a hydrogen atom. In the first and third methods R 1 is alkyl, while R in the second method is alkyl or benzyl.

vs., 0 * 1 "^^ or1" ζΎ Hal (CH2) 3 CN ^ ζΎ (χι) R2'- CH - COgAlk R2 - C - CC> 2Alk (x) (ch2) 5-cn

(I) 4_ H-N I

T V) 1 "oVa / ® R2 I if you)

A phenyl substituted aliphatic ester of formula (X) is used and reacted with e.g. sodium in liquid ammonia followed by 4-iodobutyronitrile to give the nitrile ester of formula (XI); the nitrile ester can be cyclized as described above by the preferred method of forming the hexahydro-2H-azepin-2-one of formula (III) which is reduced to form a compound of formula (I) in which R and R means hydrogen, or "alkylated" with subsequent reduction to form a compound of formula (I) wherein R is hydrogen and R3 is alkyl, alkenyl, alkynyl, cyclopropylmethyl or phenethyl.

HU 01 (B ^ · 1 'o ^ / OR "

I + Hal-CCHV-N I

R2 - CH - OOAlk in (XII) (X) 1 '

. / 0R I

2V

Ft - C - COgAlk 'λ-'00 (in) R (xiii) 0

A phenyl-substituted aliphatic ester of formula (X) is reacted with e.g. N- (iodobutyl) -phthalimide of formula (XII), to form a compound of general formula (xm) which can be cyclized after removal of the protective phthaloyl group, to form a compound of formula (III ) gives compounds of formula (i) in which R and R 4 represent hydrogen, or alkylation of (III) followed by reduction gives compounds of formula (i) wherein R represents hydrogen and R 6 represents alkyl, alkenyl, alkynyl, cyclopropylmethyl or phenethyl.

i n UU 01 (C). 1 ".. / OR1 .. / OR · 1 ·

NaNH ^ Γ |

Hal (0¾) 4 Hal ^ (nv).

R2 - CH - CN R2 - C - CN

(IY) (CHg ^ Hal-i-i "/ OR1 (I) z_ Μ I (XV), v R4 - C - OH NH0

I CL CL

(ΟΗ ^) 2j_ * Hal

A phenyl-substituted aliphatic nitrile of formula (IV) is converted to an alkali metal derivative thereof, e.g. by reaction with an alkali metal amide, and then reacting with a dihalo-butane, e.g. 1-bromo-4-chlorobutane, to give the halogen nitrile of formula (XIV). Reduction of this to the halogenamine of formula (XV) is carried out by catalytic hydrogenation, whereupon the halogenamine is cyclized to compounds of the general formula (I) by heating in a suitable solvent.

If the hexahydroazepine obtained by any of the above methods is not desired, it can be treated in any of the above or below described ways to form the desired hexahydroazepine.

A preferred method for preparing a compound of general formula (I) in which R is alkyl, R 1 is 3 alkyl or benzyl and R is a hydrogen atom are described below.

UU01 12 l 'l' / 0R / 0R I NaWHg ί \\

Hai (ch2h Hai 'y tov)

R - CH - CN R2 - G - CM

(IV) (CH2) 4'Hal R 'M -1 Γ * ε Ϊ -r. / 0RJ ", Ry ^ yy

η y \ = £ 1 I

VS 0R <_ \] -HI R2-T-5-r ·

(4¾) VI

(XVI) L

R. rV3 or1 H-N] (XVII) wherein R1 'and R2 have the above meaning and R' means alkyl of not more than 6 carbon atoms.

As will be seen, a compound of general formula (IV) which can be prepared by known methods is converted into an alkali metal derivative thereof, e.g. by reaction with an alkali metal amide, and then reacting with a dihalo-butane, e.g. 1-bromo-4-chloro-butane to give a compound of the general formula (XIV). Cycle of this compound to the unsaturated compound of the general formula (XVI) can be effected by reaction with a Grignard reagent. Subsequent reduction gives a compound of general formula (I) in which R? means hydrogen, i.e. a compound of formula (XVII). If the hexahydroazepine produced by this method is not the desired one, it can be treated in any of the ways described above or below to form the desired hexahydroazepine.

141401 13

It is to be understood that the compounds of the present invention prepared by the above reactions are rheemic mixtures. If the pure, optically active isomers are required, these can be obtained by cleavage of a racemic mixture using standard techniques known in the art.

If it is desired to prepare an acid addition salt, a compound of general formula (i) may be treated with a pharmaceutically acceptable acid, e.g. hydrochloric, sulfuric or maleic acid.

Similarly, the free base can be prepared by neutralizing an acid addition salt, e.g. with an alkali metal carbonate. A quaternary ammonium salt can be prepared by reacting the free base with an alkyl halide.

The reactants used in the foregoing reactions are either known compounds which are commercially available or can be prepared by known methods or they are derivatives thereof which can be prepared by well known chemical processes from corresponding starting materials according to the methods described in the art. for the known compounds.

The novel compounds prepared by the process of the present invention have valuable pharmacological action.

In particular, the novel compounds by standard pharmacological methods exhibit an ability to reduce pain and are therefore useful as pain relievers. Furthermore, some of the compounds exhibit the ability to counteract narcotic painkillers. This is especially true of the compounds of Examples 5, 10, 15b, 20, 21, 22 and 28.

In the pharmacological assessment of the properties of the compounds of this invention, the in vivo effects of the compounds on mice are tested according to Haffner's tail clip method (cf. F. Haffner,

Deutsch. With. Wschr. 55, 731 (1929)) or by a "radiant heat on the tail" method according to DlAmour-Smith (J. Pharmacol,] 2, 74 (1941)).

The analgesic antagonism can be tested by a method of Casy et al. described in J. Pharm. Pharmacol. 20, 768 (1968).

UU01 14

The compounds of this invention exhibited analgesic efficacy in the above test procedures when administered orally and / or intraperitoneally at a dosage of about 10%. .10 to approx. 200 mg / kg.

The following examples serve to illustrate the process of the invention.

Example 1.

3- (m-methoxyphenyl) -l-methyl-3-pnopylhexahydro-lH-azepine.

(a) 18.9 g of 2- (m-methoxyphenyl) -pentanitrile in 20 ml of dry ether are added to a stirred suspension of sodium amide (from 2.35 S sodium) in 250 ml of liquid ammonia. The resulting solution is stirred for 30 minutes and 20.5 g of 4-iodobutyronitrile in 40 ml of ether are added dropwise. After completion of the addition, the reaction mixture is stirred for 4 hours. 100 ml of ether are added and the ammonia is allowed to evaporate overnight. 100 ml of water are added, the organic layer is separated and dried over magnesium sulfate and the ether is removed by distillation.

The viscous oily residue is distilled at 158-164 ° C / 0.3 mm Hg to give 5-eyano-5- (m-methoxyphenyl) -ethanitrile as a viscous, colorless liquid.

(b) 7.9 g of the above dinitrile is heated under reflux with a mixture of 30 ml of ethylene glyeol, 2.3 ml of water and 17 g of potassium hydroxide for 3.5 hours. The reaction mixture is poured into 100 ml of water and extracted with ether. After acidification, the aqueous layer is extracted with ether, dried over magnesium sulfate and the ether is evaporated to a small volume until 5-carbamoyl-5- (m-methoxyphenyl) octanoic acid crystallizes to give 5 * 9 g of colorless needles with mp. 172-174 ° C.

(c) 6.2 g of this acid in dry tetrahydrofuran are added dropwise with stirring to a solution of 7.0 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran. The mixture is heated at reflux for 7 hours, cooled and 16 ml of 5N sodium hydroxide is added cautiously. The inorganic material is filtered off and the tetrahydrofuran is removed to give 5-aminomethyl-5- (m-methoxyphenyl) -octan-1-ol as a viscous oil distilled at 132-138 ° C / 0.005 15 141401 mm Hg to give 3.2 g of a colorless glass.

This compound can also be prepared by similar reduction of ethyl 5-cyano-5-m-methoxyphenyloctanoate.

(d) 4.14 g of 5-aminomethyl-5- (m-methoxyphenyl) -octan-1-ol is dissolved in 20 ml of dry chloroform, cooled to 0 ° C and saturated with gaseous hydrogen chloride. Thionyl chloride is added dropwise, keeping the temperature at 0-5 ° C. The reaction mixture is allowed to warm to room temperature, then heated under reflux for 2 hours. The chloroform is removed under reduced pressure leaving an oil added to 50 ml of water and the water-insoluble material extracted with ether and discarded. The aqueous layer is made basic with sodium bicarbonate solution and extracted with ether. After drying over magnesium sulfate, the ether is removed to give 3 # 85 g of a dark oil dissolved in 100 ml of propan-2-ol, 4.0 g of anhydrous potassium carbonate is added and the mixture is heated under reflux for 6 hours. Removal of the potassium carbonate and evaporation of the propan-2-oil gives an oil which is distilled to give 1.8 g of 3- (m-methoxyphenyl) -3-propylhexahydro-1H-azepine as a colorless mobile oil with boiling point H8-120 ° C / 0.001 mm Hg.

(e) 2.77 g of the above hexahydro-1H-azepine p is hydrogenated at 3.2 kg / cm in the presence of 2 ml of 40 # aqueous formaldehyde, 2.0 g of 10 # 1 palladium on charcoal and 100 ml of absolute ethanol . The theoretical amount of hydrogen is absorbed in 20 minutes. Filtration of the catalyst and evaporation of the solvent leave a colorless mobile oil which is treated with 1.3 g of oxalic acid in acetone. 2.32 g of colorless needles of 3- (m-methoxyphenyl) -1-methyl-3-propylhexa-hydro-1H-azepine oxalate are obtained, m.p. 124-126 ° C.

(Found: C = $ 64.8, H = $ 8.3, N = 4.0 #.

C19H29N05 requires: C = 64.9 #, H = 8.3 #, N = 4.0 #)

Example 2.

3- (m-hydroxyphenyl) -l-methyl-3-propylhexahydro-lH-azepine.

3.28 g of the oxalate of Example 1 are heated under reflux with 30 ml of 48-50 # hydrobromic acid for 3 hours. The hydrogen bromide is removed under reduced pressure and the residual oil is dried by repeated re-evaporation with 100 ml of propan-2-ol.

The oil is crystallized from acetone to form 2.28 g of fine white needles. Recrystallization from a mixture of propan-2-ol and ether gives the hydrobromide of 3- (m-hydroxyphenyl) -1-methyl-3-propylhexahydro-1H-azepine as colorless, hygroscopic needles, m.p. Il8-126 ° C.

16 141401

Found: C = $ 58.35, H = 8.15, N = $ 4.35.

Cl6H26BrN0 requires: c = $ 58.6, H = $ 8.0, N = $ 4.3.

The hydrobromide can be converted to the free base by treatment with aqueous sodium carbonate solution and recrystallization from petroleum ether (bp 100-120 ° C), m.p. 119-121 ° C.

Found: C = $ 77.8, H = $ 10.1, N = $ 5.3. cl6H25N0 c = $ 77.9, H = $ 10.2, N = $ 5.7.

Example 3

3- (m-Methoxyphenyl) -3-propylhexahydro-1H-azepine.

(a) 75.6 g (0.4 mol) of 2- (m-methoxyphenyl) pentanitrile in 200 ml of dry ether are added to a stirred suspension of sodium amide (from 9.4 g of sodium) in 400 ml of liquid ammonia. The mixture is stirred for 30 minutes, then 99.25 g (0.4 mole) of ethyl 4-iodo-butyrate is added dropwise in 200 ml of dry ether. The mixture is stirred at refluxing liquid ammonia for 5 hours. 10 g of ammonium chloride are added and the mixture is allowed to warm to room temperature.

300 ml of water are added, the organic layer is separated, washed with water, 2N sulfuric acid and water. After drying over magnesium sulfate and removing the ether, the product is distilled to give 77.6 g of ethyl 5-cyano-5- (m-methoxyphenyl) octanoate with b.p.

15β-157 ° 0 at 0.02 mm Hg, n ^ p 1.5020.

Ethyl 5-eyano-5- (m-methoxyphenyl) -etanoate can also be prepared by hydrolysis for 50 hours of 5-cyano-5- (m-methoxyphenyl) octanitrile with a mixture of sulfuric acid and ethyl alcohol in the volume ratio 1:10 .

(b) 32.0 g of ethyl 5-cyano-5- (m-methoxyphenyl) octanoate is hydrogenated at an initial pressure of 84 kg / cm and a final temperature of 140 ° C in 400 ml of cyclohexane with approx. 8 g nickel catalyst for 18 hours. Removal of the catalyst and evaporation of the cyclohexane give a colorless viscous oil which crystallizes from ethyl acetate to give 18.3 g of colorless needles of 6- (m-methoxyphenyl) -6-propyl-hexahydro-2H-azepin-2-one with m.p. 109-110 ° C.

When the reduction is carried out at a lower temperature, the product mainly consists of ethyl 5-aminomethyl-5- (m-methoxyphenyl) octanoate. Closure of this compound to prepare 6- (m-methoxyphenyl) -6-propylhexahydro-2H-azepin-2-one can be obtained by refluxing for 18 hours in decalin or by refluxing with a solution of absolute ethanol sodium ethoxide. .

17

U14CM

(c) 12 g of 6- (m-methoxyphenyl) -6-propylhexahydro-2H-azepin-2-one In 200 ml of dry tetrahydrofuran is added dropwise to a stirred suspension of 12 g of lithium aluminum hydride in 200 ml of ether and the mixture is stirred thereon. heated at reflux for 7 hours. The reaction mixture is decomposed by the addition of 12 ml of water, 24 ml of 2N sodium hydroxide followed by 12 ml of water. The organic material which precipitates is filtered off, the solvents are removed and the residual colorless oil is distilled off to give 9 * 8 g of 3- (m-methoxyphenyl) -3-propylhexahydro-1H-azepine with b.p.

123-124 ° C / 0.15 mm Hg.

Example 4

3- (m-methoxyphenyl) -1,3-dimethyl-hexahydro-lH-azepln.

(a) 25.2 g of 2- (m-methoxyphenyl) propionitrile is reacted with sodium amide (from}, 6 g of sodium) in 300 ml of liquid ammonia and 38.5 g of ethyl 4-iodobutyrate according to that of Example 3 (a) ) method described. After similar work-up, the product is distilled to give 22.5 g of ethyl 5-cyano-5- (m-methoxyphenyl) hexanoate with b.p.

132-142 ° C / 0.003 mm Hg.

(b) 15 # 2 g of this compound is hydrogenated at an initial pressure of 70 kg / cm and a final temperature of 140 C in the presence of ea. 6 g nickel catalyst in 250 ml cyclohexane for 20 hours. The catalyst is removed by filtration, the cyclohexane is removed to give 14.1 g of a viscous oil which is heated under reflux in decalin in a nitrogen atmosphere for 20 hours. The decalin is removed under reduced pressure and the residue is crystallized from ethyl acetate to give 5.3 g of colorless needles of 6- (m-methoxyphenyl) -6-methyl-hexahydro-2H-azepin-2-one, mp 114-115 ° C.

An additional 2.7 g of crystalline material can be obtained by distilling the mother liquors, followed by recrystallization from ethyl acetate.

(c) 11.7 g of the above hexahydro-2H-azepin-2-one in dry tetrahydrofuran are added to a suspension of 12 g of lithium aluminum hydride in 200 ml of ether. The procedure described in Example 3 (c) is followed and the product obtained is distilled to give 8.9 g of 3- (m-methoxyphenyl) -3-methylhexahydroazepine, b.p.118-125 ° C / 0.5 mm Hg.

1.8 UU01 (d) 8.75 g of 5- (m-methoxyphenyl) -3-methylhexahydro-1H-azepine is reacted with 4 ml of 40 $ aqueous formaldehyde in the presence of 1.5 g of 10 $ palladium on charcoal for 100 hours. ethanol in the presence of hydrogen at 40 atmospheric pressure in the manner described in Example 1 (e) to give 7 * 7 g of 3- (m-methoxyphenyl) -1,5-dimethylhexa-hydro-1H-azepine as a colorless oil, bp 106-107 ° C / 0.4 mm Hg, njp = 1.5339.

Pound: C = 76 * 8 $, H = 9 * 8 $, N = 5 * 9 $.

C15H23W0 c = 77 * 2 $, H = 9 * 9 $ * N = 6 * 0 $.

The hydrochloride of mp 154-155 ° O can be prepared by treatment with propan-2-ol and a solution of hydrogen chloride in ether.

Pound: C = 66.7 $ * H = 8.9 $ * N = 5 * 0 $.

C- ^ H ^ NO.HCl requires: C = 66.7 $, H = 8.9 $ * H = 5 * 2 $.

Example 5

3- (m-Hydroxyphenyl) -1,3-dimethyl-hexahydro-1H-azepine.

5.1 g of the product of Example 4 is heated under reflux with 50 ml of 48-50 $ hydrobromic acid for 3 hours. The hydrogen bromide is removed under reduced pressure and the residual oil is dried by repeated evaporation from propan-2-ol. 3- (m-Hydroxy-phenyl) -1,3-hexamethyl-hexahydro-1H-azepine crystallizes as the hydrobromide in 6.0 g of colorless needles from a mixture of propan-2-ol and ether, m.p. 174-175 ° C.

Found: C = 55 * 8 $, H = 7 * 2 $, N = 4.4 $ C14H21N0.HBr requires: C = 56.0 $, H = 7.4 $, N = 4.6 $.

Example 6

3- (m-acetoxyphenyl) -1,3-dimethyl-hexahydro-lH-azepine.

2.0 g of the product of Example 5 is heated under reflux with 6 ml of acetic anhydride and 3 ml of pyridine for 3 hours. The reaction mixture is evaporated to a brown oil which is dissolved in water and made basic with sodium bicarbonate solution. The basic material is extracted with ether, dried over magnesium sulfate and evaporated to a colorless oil. The oil is dissolved in propan-2-ol and treated with a solution of hydrogen chloride in dry ether to give the hydrochloride of 3- (m-aeetoxyphenyl) -1,3-dimethylhexahydro-1H-azepine. Yield 1.7 g * m.p. l64-l65 ° C.

Pound: C = $ 64.3, H = $ 8.2, N = $ 4.6.

Cl6H24N02C1 requires: c = 64.55 $ * H = 8.1 $, N = 4.7 $.

19 141401

Example 7

3- (m-acetoxyphenyl) -l-methyl-3-propylhexahydro-lH-azepine.

The procedure of Example 6 is followed but using 1.5 g of (m-hydroxyphenyl) -1-methyl-β-propylhexahydro-1H-azepine (prepared according to Example 2) as starting material to give 1.36 g of 3- ( m-acetoxyphenyl) -1-methyl-1-propylhexa-hydro-1H-azepine after basification with sodium carbonate, bp 176-178 ° C / 0.01 mm Hg.

Found: C = $ 74.8, H = $ 9.5 »N = $ 4.8.

Cl8H27NO2 requires: c = $ 74.7, H = $ 9.4, N = $ 4.8.

Example 8.

(m-Methoxyphenyl) -2,5-dimethylhexahydro-1H-azepine.

(a) 64 g of 2- (m-methoxyphenyl) propionitrile are added to a stirred suspension of 18 g of sodium amide in 160 ml of dry toluene at 60 ° C. After completion of the addition, 20 ml of dry tetrahydrofuran is added and the mixture is stirred at 80 ° C for 1 hour. This mixture is then added dropwise to a solution of 72 g of 1-bromo-4-chlorobutane in 200 ml of dry toluene at 5-10 ° C under nitrogen over 2 hours, the mixture is allowed to warm to room temperature and stirred overnight. The reaction mixture is poured into water and the toluene layer is separated. The organic layer is washed successively with 2N hydrochloric acid and water.

After drying over magnesium sulfate and evaporation of the solvent, after careful distillation, 4 g, 4 g of 6-chloro-2- (m-methoxy-phenyl) -2-methyl-hexannitrile as a colorless oil, is obtained, boiling point 152-154 ° C / 0. , 8 mm Hig.

Found: G = 67.0 ^, H = 7.3 $ * N = 5.1% · C 14 H 18 ClNO requires: C = 66.90, H = J, 2%, N = 6.0 $.

(b) 3.13 S of the chlorine nitrile from section (a) in 100 ml of dry toluene is added to 0.0285 moles of methyl magnesium iodide in 20 ml of ether under a stream of nitrogen. After completion of the addition, the ether is distilled from the reaction mixture until the internal temperature is 90 ° C and then heated to this temperature for 24 hours. After cooling, the reaction mixture is poured into a mixture of ice and ammonium chloride, the aqueous layer is separated and extracted with benzene. The combined organic layers are dried over magnesium sulfate and evaporated under reduced pressure at 40 ° C to give a viscous oil. The oil is repeatedly extracted with boiling ether to give a yellow gum which precipitates from 1.0 g of pale yellow rhombus of 3- (m-methoxy-phenyl) -2, -dimethyl-4,5, from propan-2-ol. 6,7-tetrahydro-3H-azepine hydroiodide, mp 164-168 ° C. The compound can be recrystallized from propan-2-ol.

Found: C = 50.35 #, H = 6.2 #, N = 3.8%.

C15H21NO * HI: = 50.2%, H = 6.0%, Ή = 3.8%.

(c) 6.1 g of the above tetrahydroazepine hydroiodide are added portionwise to a refluxing solution of 1.5 g of aluminum lithium hydride in 200 ml of ether. After completion of the addition, 100 ml of dry tetrahydrofuran is added and the mixture is heated under reflux for 4 hours. After cooling to room temperature, the reaction mixture is decomposed by the addition of 1.5 ml of water and 3 ml of 2N sodium hydroxide. Filtration and evaporation give an oil which is distilled to give 3.1 g of 3- (m-methoxyphenyl) -2,3-dimethylhexahydro-1H-azepine as a colorless oil, boiling point 128-130 ° C / 0.5 mm Hg.

Found: C = 71.15%, H = 9.9%, N = 5.8%.

C15 H25 W0 c = 77.2%, H = 9.9%, N = 6.0%.

The above oil is dissolved in propan-2-ol and treated with a solution of hydrogen chloride in dry ether to give colorless needles of the hydrochloride, mp 166-167 ° C.

Found: C = 66.8%, H = 8.8%, N = 5.0 #.

C15H23NO * HCl requires: C = 66.7%, H = 9.0 #, N = 5.2 #.

Example 9

1,2,3-Trimethyl-3- (m-methoxyphenyl) hexahydro-lH-azepine.

3.0 g of the azepine of Example 8 (c) in 100 ml of absolute ethanol containing 2 ml of 40% aqueous formaldehyde are hydrogenated p at an initial pressure of 3.4 kg / cm. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and 2.21 g of the product is obtained as an oil, boiling point 104-110 ° C / 0.01 mm Hg. Found: C = 78.0 #, H = 10.2 #, N = 5.4 #.

Cl6H25H0 requires: C = 77.9 #, H = 10.2 #, N = 5.7 #.

The above oil is converted to the hydrobromide in propan-2-ol with 50 # aqueous hydrogen bromide. The product is recrystallized from propan-2-ol and has a melting point of 232-235 ° C.

Found: C = 58.5 #, H = 8.0 #, N = 4.2 #.

Cl6H25N0.HBr requires: C = 58.4 #, H = 8.0 #, N = 4.3 #.

Example 10 21 3- (m-Hydroxyphenyl) -1,2,3-trimethylhexylthydro-1H-azepine.

2.1 g of the azepine of Example 9 is heated under reflux with 50 # of hydrogeribromic acid for 2 hours. After cooling, 2.06 g of colorless coarse rhombus of the hydrobromide, mp 234-236 ° C, are obtained. The product can be obtained either as needles with melting point 23O - 231 ° C, or as rhombs with melting point 234-240 ° C, purified 250 ° C, after recrystallization from methanol. It has been demonstrated that these two crystal forms are identical, by mutual conversion, IR spectrum and analysis.

Found: C = 57 * 3 # * H = $ 7.8, N = 4.2 #.

Clc.Ho, N0.HBr requires: C = 57 * 3 # * H = 8.0 #, N = 4.6 #.

15 23

Example 11.

3-butyl-3- (m-methoxyphenyl) -1-methylhexahydro-lH-azepine.

(a) Ethyl 5-eyano-5- (m-methoxyphenyl) nonanoate is prepared by the method described in Example 3 (a), using sodium amide (from 5.36 g of sodium) in 400 ml of liquid ammonia, 45 g of 2- (m-methoxyphenyl) hexanitrile and 53 * 4 g of ethyl butyl 4-iodobutyrate. The product is available as a colorless oil (48.7 g), boiling point 150-166 ° C / 0.01 mm Hg.

(b) 30.0 g of the product of Example 11 (a) is hydrogenated in the presence of ca. 6 g of Raney nickel and 400 ml of cyclohexane by the method described in Example 303). The product is recrystallized from ethyl acetate to give 15 * 12 g of 6-butyl-6- (m-methoxyphenyl) hexahydro-2H-azepin-2-one, m.p. 108-109 ° C.

(c) 12.2 g of the product of Example 11 (b) in 200 ml of dry tetrahydrofuran is reduced with 12 g of aluminum lithium hydride in 200 ml of dry ether in the manner described in Example 3 (c). The product is distilled, boiling at 130-140 ° C / 0.25 mm Hg to give 7.14 g of 3-butyl-3- (m-methoxyphenyl) hexahydro-1H-azepine as a colorless mobile oil.

(d) 7.14 g of the secondary base of Example 11 (c) is methylated reductively as described in Example 1 (e). 5 * 01 g of 3-butyl ~ 3- (m-methoxyphenyl) -1-methylhexahydro-1H-azepine, which is obtained as a crude oil from the reaction mixture, is converted to. its oxalate, mp 147--150 ° C.

Found: C = $ 65.5, H = $ 8.6, N = $ 3 * 75.

Cl8H29NO * C2H2 ° C - 65.6, H = 8.6%, N = 3.8%.

141401 ??

Example L2.

3-butyl-3- (m-hydroxyphenyl) -1-methylhexahydro-lH-azepine.

1 g of the oxalate of Example 11 (d) is heated under reflux with 40 ml of 50% hydrogen bromic acid for 2 hours. The product is isolated by the method described in Example 2 and converted to the free base. Recrystallization from petroleum ether (bp 80-100 ° C) gives 1.7 S 2-butyl-5- (m-hydroxyphenyl) -1-methylhexahydro-1 H-azepine, mp 116-118 ° C.

Pound: C = 78.0%, H = 10.5%, N = 5.25%.

C17H27NO c = 78.1%, H = 10.4%, N = 5 * 4%.

Example 15

3-Ethyl-3- (m-methoxyphenyl) hexahydro-1H-azepine.

(a) Ethyl 5-cyano-5- (m-methoxyphenyl) heptanoate is prepared in the manner described in Example 5 (a) using sodium amide (from 5.74 g of sodium) in 150 ml of liquid ammonia and 26, 3 g of 2- (m-methoxyphenyl) -butyronitrile. The product is distilled, boiling point l48-155 ° C / 0.01 mm Hg to give 27.1 g of a colorless liquid.

(b) 20.5 g of the product of Example 13 (a) in 200 ml of cyclohexane is hydrogenated in the presence of ea. 6 g of Raney nickel in the manner described in Example 3 (b). The product obtained after distillation is recrystallized from ethyl acetate to give 10.0 g of 6-ethyl-6- (m-methoxyphenyl) hexahydro-2H-azepin-2-one, m.p. 87-88 ° C.

(c) 9.1 g of the azepinone of Example 15 (b) in 50 ml of dry tetrahydrofuran and 50 ml of ether are added dropwise to a stirred suspension of 7.5 g of aluminum lithium hydride in 50 ml of dry ether. After refluxing for 3 hours, the reaction mixture is worked up in the manner described in Example 3 (c) and distilled to give 7.66 g of 3-ethyl-3- (m-methoxyphenyl) hexahydro-1H-azepine as a colorless oil , boiling point 108-110 ° C / 0.01 mm Hg.

UU01 25

The starting material for section (o), 6-ethyl-6- (m-methoxyphenyl) -hexahydro-2H-azepin-2-one may also be prepared as follows: (a) A mixture of 16.0 g of ethyl-5 eyano-5- (m-methoxyphenyl) - heptanoate, 11.9 ml of concentrated sulfuric acid and 2.0 g of palladium-on-charcoal catalyst in 125 ml of methanol are hydrogenated at room temperature and a pressure of 5.5 kg / cm 2 and Parr hydrogenator. The catalyst is filtered off, washed with methanol, and the filtrate and washings are combined and evaporated in vacuo. The residue is basified with 0.880 ammonia solution, extracted with ether, dried over magnesium sulfate and evaporated to give 15 * 2 g of 5-aminomethyl-5- (m-methoxyphenyl) heptanoate.

(b) The above amino ester is heated under reflux in 200 ml of toluene for 24 hours, the ethanol / toluene azeotrope released is removed by distillation in a suitable column. The excess toluene is evaporated in vacuo and the residue is crystallized from a mixture of ethyl acetate and petroleum ether, boiling at 60-80 ° C to give 8.05 g of 6-ethyl-6- (m-methoxyphenyl) hexahydro-2H-azepine. 2-one, mp 87-89 ° C.

Example 14.

5-ethyl-5- (m-hydroxyphenyl) hexahydro-lH-azepine.

2.2 g of the product of Example 13 (c) is heated under reflux with 50 # hydrogen bromic acid for 1.5 hours. The reaction mixture is evaporated to dryness and re-evaporated with 3 portions of pro-pan-2-ol. The resulting oil is dissolved in propan-2-ol and diluted with ether. 2.5 g of 3-ethyl-3- (m-hydroxyphenyl) -hexahydro-1H-azepine is obtained as its hydrobromide, m.p. 183-185 ° C.

Found: C = $ 55.9, Η = $ 7.43, Ν = $ 4.35.

Cl4H2lN0 * HBr 0 = 56 * EYE H = 7.4 $, N = 4.7 $.

Example 15

3-Ethyl ~ 3- (m-hydroxyphenyl) -1-methylhexahydro-1H-azepine.

(a) 5.1-3 g of the azepine of Example 13 (c) is methylated reductively in the manner described in Example 1 (e). The resulting crude oil is converted to 4.9 g of the hydrobromide, mp 142-143 ° G. Recrystallization from propan-2-ol raises the melting point of the resulting 3-ethyl-3- (m-methoxyphenyl) -1-methylhexahydro-1H-aze-pin hydrobromide to 143-144 ° C.

Found: C = $ 58.8, H = $ 8.2, N = $ 4.0.

C15H23N0 * HBr c = $ 58.6, H = $ 8.0, N = $ 4.3.

(b) 2.85 g of the methoxy compound of Example 15 (a) is refluxed with 15 ml of 80 $ hydrogen bromic acid for 2 hours and worked up in the manner described in Example 5. 2.47 g of 3-ethyl-3- (m-hydroxyphenyl) -1-methylhexahydro-1H-azepine is obtained as its hydrobromide, mp 221-222 ° C.

Found: C = $ 57.4, H = $ 7.8, N = $ 4.3.

C ^ H ^ NO.HBr requires: C = 57.4 $, H = 7.7 $, N = 4.5 $.

Example 16.

3- (m-hydroxyphenyl) -3-propylhexahydro-lH-azepine.

6.1 g of the product of Example 3 (c) is heated under addition. Reflux with 40 ml of 50 $ hydrogen bromic acid for 2.5 hours. The product is worked up as described in Example 15 (b) to give 5.88 g of hydrobromide of 3 ”(m-hydroxyphenyl) -3-propylhexahydro-1H-aze -pin, m.p. 74-78 ° C, as a hygroscopic solid.

Found: C = $ 57.4, H - $ 7.8, N = $ 4.5.

C, J-H- NO.HBr requires: C = 57, $ 4, H - 7.7 $, N = 4.5 $. ib 23.

Example 17

l-Carbethoxy-3- (m-hydroxyphenyl) -3-propyl-hexahydro-lH-azepine.

1 ml of ethyl chloroformate in 10 ml of chloroform is added to a cooled solution of 3.14 g of the product of Example 16 in 10 ml of chloroform and 2.03 g of triethylamine. After completion of the addition, the reaction mixture is stirred at room temperature for 2 hours. Ether is added to precipitate the triethylamine hydrochloride / hydrobromide and the filtrate is washed with water. Evaporation gives a glass which is distilled, boiling point 210-220 ° C (bath temperature) at 0.005 mm Hg to give 1.54 g of viscous oil.

Found: C = 70.2 $, H = 8.95 *, N = 4.35 *.

C18 H27 NO3 c = 70.85 *, H = 8.95 *, N - 4.65 *.

Example 18.

l-allyl-3- (m-hydrpxyphenyl) O-propyjhexahydro-lH-azepine.

A mixture of 4.3 g of the product of Example 16, 1.655 g of 3-bromoprop-1-ene and 8.1 g of anhydrous potassium arbonate in 100 ml of butan-2-one is heated under reflux with stirring for 16 hours. The reaction mixture is cooled and the solid is removed by filtration. Removal of the solvent gives an oil which is dissolved in acid and extracted with ether * these ether extracts are discarded. The acid layer is made basic with concentrated ammonia solution and extracted with ether. After drying, the ether is removed to give a viscous oil to give 2.5 g of a crystalline toluene-p-sulfonate salt, mp 126-127 ° C.

Found: C = 67.55 *, H = 8.05 *, N = 3.05 *.

C18N27N0, C7H8 ° 3S requires: c = 67.45 *, H = 8.05 *, N = 3.05 *.

Example 19.

3- (m-hydroxyphenyl) -3-methylhexahydro-lH-azepine.

12.64 g of the product of Example 4 (c) in 120 ml of 50 $ aqueous hydrobromic acid are refluxed for 1 hour.

The acid is removed by evaporation under reduced pressure and the product is dried by azeotropic distillation with propan-2-ol. The product (15.6 g) crystallizes as its hydrobromide, a white solid, from propan-2-ol, mp 203-204 ° C.

Found: C = 54.35 *, H = 6.8 $, N = 4.755 *.

C13H19N0, HBr requirements,: c = 54.555 *, H = 7.0J *, N * 4.55 *.

Example 20

l-allyl-3- (m-hydroxyphenyl) -3-methyl ~ hexahydro-lH-azepine.

2.86 g of the product of Example 19 is heated under reflux with stirring with a mixture of 2.8 g of anhydrous potassium carbonate, 1.21 g of 3-bromoprop-1-ene and 100 ml of butan-2-one for 20 hours. Pet solid is removed by filtration and the filtrate is evaporated 26 to a viscous oil. The oil is dissolved in ether and the basic material is isolated in the usual manner. Distillation gives 1.62 g of a viscous oil, boiling point l60-l65 ° C / 0.001 mm Hg.

Pound: C = $ 78.4, H = $ 9.5, N = $ 5.65.

Cl 6 H 2 N0 requires: C = $ 78.3, H = $ 9.45, N = $ 5.7.

Example 21.

3- (m-Hydroxypheny1) -2,3-dimethyl-hexahydro-lH-azepine.

4.6 g of the azepine of Example 8 (c) is heated under reflux with 10 ml of 50 $ aqueous hydrobromic acid for 2 hours. The solvent is removed under reduced pressure and the orange oil is repeatedly evaporated with propan-2-ol. The product crystallizes from a mixture of propan-2-ol and ether as a colorless hydrobromide in a yield of 3.55 g, mp 163-165 ° C.

Pound: C = $ 55.9, H = $ 7.4, N = $ 4.7.

Gl4H21WG, HBr requires: c * 5.60 $, H = 7.4 $, N = 4.7 $.

Example 22.

l-allyl-2,3-dimethyl-3- (m-hydroxypheny1) hexahydro-IH-azepine.

1.5 g of 2,3-dimethyl-3-[(hydroxyphenyl) -hexahydro-1H-azepine hydrobromide (prepared according to Example 21) is heated under reflux with 2.8 g of anhydrous potassium carbonate and 0.6 g of 1-bromo-2 propylene in 75 ml of propan-2-one for 16 hours. The reaction mixture is cooled, filtered and evaporated to an oil which is dissolved in propan-2-ol and acidified with 50 $ aqueous hydrogen bromide. Repeated evaporation with small amounts of propan-2-ol removes the last traces of water and the product is crystallized from • 800 mg of propan-2-ol, mp 212-214 ° C.

Found: C = $ 60.0, H = $ 7.95, N = $ 4.0.

C.ryH-j-NO.NBr requires: C = 59.9 $, H = 7.7 $, N - 4.1 $.

1 (2 5

Example 23

3- (m-Acetoxyphenyl) -3-ethylhexahydro-1H-azepine.

1.5 g of the azepine hydrobromide of Example 14 is heated in a sealed tube with a mixture of hydrogen bromide in 5 ml of glacial acetic acid and 3 ml of ethyl ethyl bromide for 2 hours at 100 ° C. The tube is cooled and the reaction mixture is evaporated to dryness at room temperature and reduced pressure. 25 ml of propan-2-ol is also added and evaporated at room temperature. The residue is recrystallized from a mixture of propan-2-one and ether to give 1.36 g of whitish needles, m.p. 120-125 ° C. The product is recrystallized from a mixture of propan-2-one 27 UU01 and ether 725 mg of 5- (m-acetoxyphenyl) -3-ethylhexa-hydro-1H-azepine, m.p. 125-130 ° C (does not become clear).

Found: C = $ 56.1, H = 1.1%, N = $ 4.0.

Cl6H25N024HBr requires: c = $ 56.15, H = 7.1 $, N = 4.1 $.

Example 24.

5- (m-Acetoxyphenyl) -1-acetyl-3-ethylhexahydro-1H-azepln.

The azepine hydrobromide of Example 14 is heated under reflux for 5 hours with 5 ml of acetyl bromide and 10 ml of 45 # hydrogen bromide in acetic acid. The acetic acid and acetyl bromide are removed under reduced pressure and the last traces are removed by co-distillation with toluene. The residue is distilled to give 0.47 g of a pale yellow glass, boiling point 170-180 ° C / 0.5 mm Hg.

Found: C = 71 * $ 25, H = $ 8.4, N = $ 4.6.

C18H25N05 claims: c = $ 71.25, H = 8.51, N = $ 4.6.

Example 25

5- (m-hydroxyphenyl) -3-isopropyl-lH-propylhexahydro azepln.

(a) 37.8 g of 2- (m-methoxyphenyl) -3-methylbutyronitrile are added dropwise to a suspension of sodium amide (from 4.6 g of sodium) in 200 ml of liquid ammonia. After completion of the addition, the reaction mixture is stirred at -30 ° C for 0.5 hour, then 50.8 g of ethyl 4-iodo-butyrate is added dropwise in 150 ml of ether. The reaction mixture is stirred for 3 hours and allowed to stand overnight. The reaction mixture is worked up as described in Example 3 (a). The product is distilled to give 28.6 g of ethyl 5-eyano-5-m-methoxyphenyl-6-methylheptanoate, b.p.146-148 ° C / 0.01 mm Hg.

(b) 24.8 g of the above ester are hydrogenated in 250 ml of cyclohexane in the presence of ca. 6.0 g nickel catalyst as described in Example 4 (b). Removal of the solvent gives 4.69 g of white crystals, mp 146-148 ° C. Recrystallization from ethyl acetate gives colorless needles of 6- (m-methoxyphenyl) -6-methylhexahydro-2H-azepin-2-one, mp 148-150 ° C.

Found: C = $ 73.7, H = $ 9.0, N = $ 5.2.

Cl 6 H 2 NO 2 requires: C - 73.35 $, H = 8.9 $, N = 5.4 $.

(e) 6.8 g of the above azepinone. in 150 ml of tetrahydrofuran is reduced with 5.0 g of lithium aluminum hydride as described in Example 3 (c). The product is distilled to give 6.1 g of colorless oil, 28 14.401 boiling point 110-112 ° C / 0.01 mm Hg. The product can be converted to a hydrobromide and recrystallized from a mixture of propan-2-one and ether, mp 170-171 ° C.

Found: C = $ 58.65, H = $ 8.0, N = $ 4.5.

Cl6H25N0, HBr two: c = 58.6 $, H = 8.0 $, N = 4.5 $ · (d) 2.5 g of azepine from section (c) is heated under reflux with 10 ml 50 $ aqueous hydrochloric acid for 1 hour. The solvent is removed under reduced pressure and the last traces of water are removed by azeotropic distillation with propan-2-ol. 2.08 g of 5- (m-hydroxyphenyl) -5-iso-propylhexahydro-1H-azepine are obtained as its hydrobromide as colorless needles, mp 95-98 ° C from a mixture of propan-2-ol and ether.

Found: C = $ 57.4, H = $ 8.1, N = $ 4.0.

C- ^ H ^ NO.HBr requires: C = 57.5 $, H = 7.7 $, N = 4.5 $.

Example 26

5- (m-hydroxyphenyl) -l-methyl-5-lso-propylhexahydro-lH-azepine.

(a) 5.0 g of 5- (m-methoxyphenyl) -5-iso-propylhexahydro-1H-azepine (prepared according to Example 25 (c)) is reacted with 3 ml of 40% aqueous formaldehyde in the presence of 2.0 g 10% palladium on charcoal in 80 ml of ethanol in a Parr hydrogenator as described in Example 1 (e). After working up, 3.0 g of raw product is used for the next experiment.

(b) 5.0 g of product from the reaction of section (a) is heated under reflux with 50 $ aqueous hydrogen bromide for 1 hour. The solvent is removed under reduced pressure and the product dissolved in water and converted to the free base. After extraction with benzene, drying and removal of the solvent, 5.0 g of 5- (m-hydroxyphenyl) -1-methyl-5-isopropylhexahydro-1H-azepine is obtained as a fumarate, m.p. 180-82 ° C.

Found: C = $ 66.0, H = $ 8.5, N = $ 5.8.

cl6H25N0 * C4H4 ° 4 requires: c = 66.1 $, H = 8.0 $, N = 5.85 $.

Example 27

5-butyl ~ 5 ~ (m-hydroxyphenyl) hexahydro-lH-azepine.

1.61 g of the azepine of Example 11 (c) is heated under reflux with 5 ml of 50 $ aqueous hydrobromic acid for 1.5 hours. The solvent is evaporated to an oil under reduced pressure and the product is dried by repeated evaporation with portions of propane-2-ol. 1.64 g of hydrobromide of J-butyl-J- (m-hydroxyphenyl) hexahydro---azepine are obtained as whitish, hygroscopic needles, mp 88-94 ° C.

29 141401

Found: C = 58.5556, H = 8.2, N = 4.0.

Cl6H25N0, HBr requires: 0 = $ 58.7, H = $ 8.0, N = $ 4.5.

Example 28.

l-allyl-5-ethyl-3- (m-hydroxyphenyl) hexahydro-lH-azepine.

A mixture of 5 * 0 g of 5-ethyl-5- (m-hydroxyphenyl) -hexa-hydro-1H-azepine hydrobromide (prepared according to Example 14Ί, 1.2 g of allyl bromide and 5.0 g of potassium carbonate in 40 ml of acetone is heated at reflux for 16 hours Excess acetone is removed under reduced pressure, 1 ml of acetic anhydride is added, heated for 1 hour to 100 g and then basified with sodium carbonate solution. then the basic extract is dried over magnesium sulfate and evaporated in vacuo to give 2.6 g of crude allyl derivative.

The residue is dissolved in the minimal amount of isopropanol and then 50% hydrogen bromic acid is added until the solution is slightly acidic. The precipitated brown oil is crystallized from a mixture of acetone and ether and then recrystallized from a mixture of ethanol and ether to give 1.55 g of 1-allyl-5-ethyl-5- (m-hydroxyphenyl) -hexahydro-1H -azepine as its hydrobromide, mp 141-142 ° C.

Found: C = $ 60.1, H = $ 7.7, N = $ 5.9.

C17H25N0.HBr requires: C = $ 60.15, H = 7.7 $, N = 4.1 $.

Example 29.

5-Ethyl-l-formyl-5- (m-hydroxyphenyl) hexahydro-lH-azepine.

A mixture of 1.5 g of 5-ethyl-5- (m-hydroxyphenyl) hexahydro-1H-azepine (prepared according to Example 14 and 10 ml of Q5 $ formic acid is heated to 160 ° C for 16 hours. excess formic acid in vacuo gives an oily residue which is dissolved in benzene, washed with water, dilute sodium carbonate solution and water, dried over magnesium sulfate and evaporated to give 1.2 g of crude product, then fractional distillation gives 0.5 g of the product, boiling point 240-250 ° C / 0.001 mm Hg.

Found: C = $ 72.4, H = $ 8.65, N = $ 5.6.

C15H2lNO2 requires: c = $ 72.8, H = $ 8.5, N = $ 5.7

UU01

Example 30.

1-Carbethoxy ^ -ethyl ^ -fm-hydroxyphenyl ^ -hexahydro-1H-azepine.

To a stirred and ice-cooled solution of 4.0 g of 3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine hydrobromide (prepared according to Example 14) in 20 ml of chloroform is added a solution of 2.66 g triethylamine in 10 ml of chloroform followed by dropwise addition of a solution of 1.44 g of ethyl chloroformate in 10 ml of chloroform. The solution obtained after stirring for 2 hours at ice temperature is allowed to stand for an additional 16 hours at room temperature. Ether is added to precipitate the mixture of triethylamine hydrochloride and triethylamine hydrobromide which is then filtered off. The filtrate is washed with water, dried over magnesium sulfate, evaporated under reduced pressure and subjected to fractional distillation to give 2.1 g of 1-carbethoxy-3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine, boiling point 172 -80 ° C / 0.001 mm Hg.

Found: C = $ 70.3, H = $ 8.8, N = $ 4.9. c17H24N03 lameri c = $ 70.35, H = 8.3 $, N = $ 4.8.

Example 3i.

3-Ethyl-3- (m-methoxy phenyl) -hexahydro-1H-azepine.

A solution of 12.3 S of 6-ethyl-6- (m-methoxyphenyl) -hexa-hydro-2H-azepin-2-one in 30 ml of sodium-dried benzene is added dropwise to 56 ml of benzene solution of 40.34 g of sodium bicarbonate. dihydro-bis- (2-methoxy-ethoxy) aluminate. The mixture is then heated under reflux for 5 hours and the complex is then decomposed by the addition of 2N sodium hydroxide solution. The organic layer is separated and then extracted with dilute hydrochloric acid. The acidic extract is basified by the addition of 0.880 ammonia solution and extracted with ether which, after drying over magnesium sulfate, evaporates to a reduced pressure to give 7.0 g of 3-ethyl-3 ~ (m-methoxyphenyl) hexahydro-1H-azepine , boiling point 108-110 ° C / 0.01 mm Hg. This compound has also been prepared by lithium aluminum hydride reduction of the same 2H-azepin-2-one as further described in Example 13 '3- (m-Methoxyphenyl) -3-ethylhexahydroazepine.

141401 31

Example 32.

(a) 70 g of 2- (m-methoxyphenyl) -butyronitrile are added dropwise to a stirred suspension of 18 g of sodium amide in 160 ml of dry toluene at 70 ° C. After completion of the addition, the mixture is stirred at 80 ° C for 1 hour. 20 ml of anhydrous tetrahydrofuran are added to make the solution homogeneous, cooled and slowly added over 2 hours to a stirred solution of 72 g of l-bromo-4-chlorobutane in 200 ml of toluene at 10--15 ° C. The reaction mixture is allowed to warm to room temperature and allowed to stand overnight. 100 ml of water are added, the organic layer is separated and washed with dilute acid, dried over magnesium sulfate and distilled to give 69.5 g of colorless oil, boiling point 150-151 ° C / 0.005 mm Hg.

(b) 13.2 g of the chloro nitrile of section (a) is hydrogenated at an initial pressure of 3 * 5 kg / cm in the presence of 100 ml of methanol containing 75 nil of concentrated sulfuric acid and 3 g of 1Q #! s palladium on charcoal. Hydrogen uptake ceases when 1 mole of hydrogen has been absorbed. The catalyst is filtered off and replaced with a fresh portion of 3 g and an additional 5 ml of concentrated sulfuric acid. An additional 1 mole of hydrogen is absorbed. After removing the catalyst and evaporating the methanol under reduced pressure, the product is dissolved

1 water, basified with concentrated ammonia solution and extracted with ether and dried. Evaporation gives 14 g of oil consisting mainly of 2-ethyl-2- (m-methoxyphenyl) -6-chloro-hexylamine. The product is dissolved in 2 N hydrochloric acid and added dropwise to 4 liters 1 N

sodium hydroxide solution at 50 ° C. The temperature is raised to 100 C over 2 hours and the mixture is heated to 100 C for 3 hours. The reaction mixture is cooled, concentrated to 1 liter and extracted with ether. The basic material is isolated by an acid-base extraction of the ether solution and distilled to give 3 * 7 g of colorless oil, boiling point 112-120 ° C (0.05 mm Hg. The hydrobromide is obtained in the usual manner and is identical to the hydrobromide according to Example 13 (c).

32 UU01

Example 33

(-) - 3-Ethyl-3- (m-hydroxyphenyl) -hexahydro-1H-azepine (a) A solution of 172 g (i) -3-ethyl-3- (m-hydroxyphenyl) -hexahydro-1H-azepine in 1 liter of ethanol is treated with a solution of 118 g of D (+) tartaric acid in ethanol. The excess alcohol is evaporated, the residue is treated with isopropanol, cooled, the precipitate is filtered off and purified to constant optical rotation by repeated recrystallization from ethanol. 48.2 g of D (+) - tartrate salt of (-) - 3-ethyl-3- (m-hydroxy-phenyl) -hexahydro-1H-azepine are obtained, m.p. 171-172 ° C, -28.9 ° (C = 2 $ in dimethylformamide).

(b) Dissolve 10.8 g of the above salt in water, make basic with 0.880 ammonium hydroxide solution and extract with ether. The organic extract is washed with sodium bicarbonate solution and water, dried, evaporated and the oily residue distilled in vacuo to give 6.5 g of (-) - 3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine. -62.2 ° (C = 2 $ in chloroform).

Analysis:

Pound: C = 76, gi, H = 9.9%, N = 6.3 $ C14¾1 ^0k; ps3ver: C = 77.2 $, H = 9.9 $, N = 6.0 $.

By the material D (+) - tartaric acid is meant the natural material commonly sold under this designation. It actually has L-con fi guration (see Merck Index, 8th Edition, 1968, page 1014).

Example 34.

(+) - 3-Ethyl-3- (m-hydroxyphenyl) -hexahydro-1H-azepine (a) The isopropanol parent fluids obtained after removal of the D (+) tartrate of (-) - hexahydro-azepine from Example 33, is evaporated to dryness, the oily residue is dissolved in water and then made basic by the addition of 2N sodium carbonate solution. The mixture is then extracted with benzene, the extract washed with water, dried (MgSO 4) and evaporated to give an oily residue. Dissolving this oil in ethanol, treating with L (-) - tartaric acid, evaporating the ethanol and treating the residue with isopropanol gives 43.5 g of L (-) - tartrate salt of (+) - 3-ethyl-3-phenyl-hydroxyphenyl ) -hexahydro - ΙΗ-azepine, m.p. 171-172 ° C, + 29.1 ° (C = 2 $ in dimethylformamide).

(b) Dissolve 15.8 g of the above salt in water, make basic with 0.880 ammonium hydroxide solution and extract with ether. The organic extract is washed with sodium bicarbonate solution and water, dried and evaporated, and the oily residue is distilled in vacuo to give 8.1 g of (+) - 3-ethyl-3- (m-hydroxyphenyl) hexahydro-1 H azepine, + 6.5.6 ° (C = 2 # in chloroform).

Analysis:

Found: C = 77, thaw, H = 9, thaw, N = 5.9 # C14H21N0 requires: c = 77, thaw, H = 9.9 #, N = 6.0 #.

Example 55

(-) - l-methyl-3-ethyl-3- (m-hydroxyphenyl) hexahydro-lH-azepine

A mixture of 3 * 2 g of the product of Example 33 »1 * 2 g of 10 # palladium on charcoal, 3 nil 36 # of aqueous formaldehyde and 100 ml of ethanol is shaken in a hydrogen atmosphere at an initial pressure of 3.5 kg / cm. The theoretical amount of hydrogen is absorbed in 10 minutes, then the mixture is filtered and the filtrate is evaporated to dryness.

The residual oil is dissolved in isopropanol and treated with ethereal hydrogen chloride to give 1.82 g of hydrochloride of (-) - 1-methyl-3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine with m.p. 2-4-26 ° C and £ ~ a-9 ° (C = 2 # in water) after recrystallization from ethanol.

Analysis:

Found: C = 66.9 #, H = 9.1 #, N = 5.2 #.

C15H23N0, HCl requires: c = 66.8 #, H = 9.3 #, N = 5.2 #.

Example 36.

(+) - l-Methyl-5-ethyl-5- (m-hydroxyphenyl) hexahydro-lH-azepine

A mixture of 2.0 g of the product of Example 34, 1.0 g of 10 # palladium on charcoal, 2.0 ml of 40 # aqueous formaldehyde and 100 ml of ethanol is shaken in a hydrogen atmosphere at an initial pressure of 3.5 kg / cm. The theoretical amount of hydrogen is absorbed in 10 minutes, then the mixture is filtered and the filtrate is evaporated to dryness.

After evaporation with 50 ml of benzene, the residue crystallizes. Recrystallization from benzene gives 0.95 g of (+) - 1-methyl-3-ethyl-3- - (m-hydroxyphenyl) hexahydro-1H-azepine, m.p. 130-131 ° C, + 24 ° (C = 1.9 # in chloroform).

Analysis:

Found: C = 77.6 #, H = 10.1 #, N = 5.9 # C- ^ H ^ NO requires: C = 77.2 #, H = 9.9 #, N - 6.0 # .

Treatment of a solution of the above base in isopropanol with ethereal hydrogen chloride gives the hydrochloride of (+) - 1-methyl-3-ethyl-3- (m-hydroxyphenyl) -hexahydro-1H-azepine, which after recrystallization lisation from a mixture of ethanol and ether has srap. 213-215 ° C and + 9 ° C (C = 2 $ in water).

Analysis: Found: C = $ 66.5. H = $ 9.25, N = $ 5.0.

C15H23N0, HCl requires: c ® $ 66.8, H = $ 9.3, N = $ 5.2.

Example 37.

(-) - 1-Α1ΐ7ΐ-5-βίΙΐ7ΐ-3- (m-hydroxyphenyl) hexahydro-lH-azepine

A mixture of 3.0 g of the product of Example 33, 2.0 g of potassium carbonate and 2.1 g of allyl bromide in 75 ml of methyl ethyl ketone is stirred and heated under reflux for 24 hours. The mixture is then cooled, filtered and evaporated under reduced pressure to give an oily residue which is distilled in vacuo (boiling point 140-160 ° C / 4.0 x 10- 3 mm Hg) and the distillate is crystallized from a mixture of benzene and petroleum ether (bp 40-60 ° C) to give 1.2 g of (-) - 1-allyl-3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine with m.p. 69-70 ° C and -α_7 ° -33 * 2 (C = 2 $ in chloroform).

Analysis:

Found: C = 78.6 $, H = 9.7 $, N = 5.5 $ C17H25NO requires: C = 78.7 $, H = 9.7 $, N = 5.4 $.

Example 58

(+) -1-Allyl-ethyl-5- (hydroxyphenyl) -hexahydro-1H-azepine

A mixture of 3.0 g of the product of Example 34, 2.0 g of potassium carbonate and 2.1 g of allyl bromide in 75.0 ml of methyl ethyl ketone is stirred and heated under reflux for 12 hours. The mixture is then cooled, filtered and evaporated under reduced pressure to give an oily residue which is distilled in vacuo (boiling point 140-150 ° C / 5.0 x 10 4 mm Hg) and the distillate is crystallized from a mixture of benzene and petroleum ether (bp 40-60 ° C) to give 2.0 g (+) - 1-allyl-3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-aze-pin, mp 70, 0-70.5 ° C and +33.3 (C = 2.4 $ in chloroform).

Analysis:

Found * C = $ 78.8, H = $ 9.8, N = $ 5.3 C17H25M0 requires c = $ 78.7, H = $ 9.7, N = $ 5.4.

55 U1401

Example 39

(-) - 3-Ethyl-3- (m-hydroxyphenyl) -1- (prop-2-ynyl) -hexahydro-1H-azepine A mixture of 3.0 g of the product of Example 33, 2.0 g of potassium carbonate and 2.1 g of 3-bromoprop-1-yn 1 dry dimethylformamide is stirred at room temperature for 24 hours. The mixture is cooled, filtered, the filtrate is evaporated to dryness under reduced pressure, and the residual oil is distilled in vacuo (b.p.160-180 ° C / 4.0 x 10 x³ mm Hg) to give 1.8 g (-) -3-ethyl-3- (m-hydroxyphenyl) -1- (prop-2-ynyl) -hexahydro-1H-azepine, -35 ° 5 ° (C = 2.4 # in chloroform).

Analysis:

Found: C = 80.0 #, H = 9.0 #, N = 5.2 # C17H_ ^ N0 requires: C = 79.3 #, H = 9.0 #, N = 5.4 #.

1 f 25

Example 40.

(+) - 3-Ethyl-3- (m-hydroxyphenyl) -1- (prop-2-ynyl) -hexahydro-1H-azepine A mixture of 3.5 g of the product of Example 34, 2.5 g of potassium carbonate and 2.5 g of 3-bromoprop-1-yn in dry dimethylformamide is stirred at room temperature for 24 hours. The mixture is then cooled, filtered, the filtrate is evaporated to dryness under reduced pressure, and the residual oil is distilled in vacuo (b.p. 160-180 ° C / 5.0 x 10 mm Hg) to give 2.5 g (+) - 3 -ethyl-3- (m-hydroxy-phenyl) -1- (prop-2-ynyl) -hexahydro-1H-azepine, [α] D 7 + 4 + 33.3 ° (C = 2.4 # in chloroform).

Analysis:

Found: C = 79.5 #, H = 9.0 #, N = 5.4 # C17H23N0 requires; C = 79.3 #, H = 9.0 #, N = 5.4 #.

Example 41.

(-) - 3-Ethyl-3- (m-hydroxyphenyl) -1- (3-methylbut-2-enyl) -hexahydro- 1 H -azepine

A mixture of 3.0 g of the product of Example 33, 2.0 g of potassium carbonate and 2.2 g of 1-chloro-3-methylbut-2-ene in 100 ml of methyl ethyl ketone is stirred and heated at 80 ° C for 14 hours. . The cooled mixture is then filtered, the filtrate is evaporated to dryness under reduced pressure and the residual oil is distilled in vacuo (boiling point 180 ° C / 5 x 10 6 mm Hg) to give 2.2 g of (-) -3- (m-hydroxyphenyl) -1- (2-methylbut-2-enyl) -hexahydro-1H-azepine, -1.7 ° (C = 2.4 $ 1 chloroform).

Analysis:

Pound: C = 78.8 $, H = 10.2 $, N = 4.9 $ C19H29N0 requires: C = 79.4 $, H = 10.2 $, N = 4.8 $.

Example 42

(+) -3-Ethyl-3- (m-hydroxyphenyl) -1- (3-methylbutyl-2-enyl) -hexahydro- 1 H -azepine

A mixture of 2.19 g of the product of Example 34, 2.0 g of potassium carbonate and 1.05 g of 1-chloro-3-methylbut-2-ene in 50 ml of methyl ethyl ketone is stirred and heated under reflux for 20 hours. The cooled mixture is then filtered, the filtrate is evaporated to dryness, the residue is dissolved in 2N hydrochloric acid and washed with benzene. The acidic aqueous solution is made basic by the addition of 2N sodium hydroxide solution, extracted with ether and the dried extract is evaporated to give a residual oil which is distilled in vacuo (bp 240-245 ° C / 5.42 x 10 (mm) Hg) to give 1.76 g (+) - 3-ethyl-3- (m-hydroxyphenyl) -1- (2-methylbut-2-enyl) -hexahydro-1H-azepine, +54 (C = 2 $ in chloroform).

Analysis:

Found: C = 79.7 $, H = 10.4 $, N = 5.1 $ c19H29H0 requires: C = 79.4 $, H = 10.2 $, N = 4.8 $.

Example 43

(-) - 1-Cyclopropylmethyl-3-ethyl-3- (m-hydroxyphenyl) hexahydro-1 H-azepine (a) A solution of 2.19 g of the product of Example 33 and 1.05 g of triethylamine in chloroform is treated dropwise with 1.06 g of cyclopropane arboxylic acid chloride, keeping the temperature below 20 ° C. The reaction mixture is then stirred at room temperature overnight, poured into water, the organic layer is separated and washed with dilute hydrochloric acid and water. Evaporation of the dried chloroform solution gives 3.15 g of oily (-) - 1-cyclopropylcarbonyl-3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine.

(b) A solution of 3.45 g of the above oil in dry ether is added to a stirred suspension of 1.6 g of aluminum lithium hydride in 50 ml of ether and then heated under reflux for 4 hours. The mixture is then cooled and the complex decomposed by the addition of 2 ml of water, 4 ml of 2N sodium hydroxide and the precipitated inorganic material is filtered off. Evaporation of the filtrate and recrystallization of the residue from benzene give 1.75 g of (-) - 1-cyclopropylmethyl-3-ethyl-3- (m-hydroxyphenyl) -hexahydro-1H-azepine with m.p. 115-116 ° C and -34.7 ° (C = 2 # in chloroform).

Analysis:

Found: C = 79.5 $, H = 10.256, N = 5.256 ^ 18 ^ 27 ^ requires: C = 79.1 $, H = 10.0 / 6, N = 5 »I56.

Example 44

(+) - 1-Cyclopropylmethyl-3-ethyl-3- (1-hydroxyphenyl) -hexahydro-1H- -azepine ____ (a) A solution of 3.5 g of the product of Example 34 and 1.65 g of triethylamine in 40 ml of chloroform are treated dropwise with 1.68 g of cyclopropane carboxylic acid chloride, keeping the temperature below 10 ° C. The reaction mixture is then stirred at room temperature for 2 hours, poured into water, the organic layer is separated and washed with dilute hydrochloric acid and water. Evaporation of the dried chloroform solution gives 4.3 g of oily (+) - 1-cyclopropylcarbonyl-3-ethyl-3- (m-hydroxy-phenyl) -hexahydro-1H-azepine.

(b) A solution of 4.3 g of the above oil in 80 ml of dry ether is added dropwise to a stirred suspension of 2.0 g of aluminum lithium hydride in 50 ml of ether and then heated under reflux for 2 hours. The mixture is then cooled and the complex is decomposed by the addition of 2.0 ml of water, 4.0 ml of 2N sodium hydroxide and the precipitated inorganic material is filtered off, Evaporation of the filtrate and recrystallization of the residue from benzene gives 1.3 g (+) - 1-cyclopropyl-methyl-3-ethyl-3- (m-hydroxyphenyl) -hexahydro-1H-azepine, m.p. 117-118 ° C and 335 ° C + 33 ° (C = 1% in chloroform).

Analysis:

Found: C = 79.4 $, H = 10.156, N = 5.156

Cl8H27NO requires: c = 79.1 $, H = 10.056, N = 5.156.

Example 45

(-) - 3-ethyl-3- (m-hydroxyphenyl) -L (n-propyl) hexahydro-lH-azepine

Reaction of 3.0 g of the product of Example 33 with propyl bromide in acetone containing potassium carbonate in the manner given in Example 37 gives (-) - 3-ethyl-3- (m-hydroxyphenyl) -1- (n-propyl) -hexa-hydro-1H-azepine (boiling point 200-210 ° C / 1.0 x 10-mm mm Hg), -38 ° (C = 2 $ in chloroform). The product is crystallized from benzene-petroleum ether (boiling point 60-80 ° C) to give 0.9 g of colorless rhombus, m.p. 82-83 ° C, -38 ° (C = 2 # in chloroform).

Analysis:

Pound: C = 78.4.5 $, H = 10.4 #, N = 5.5 # C17H27N0 ^ requires: C ~ 78.1 #, H = 10.4 $, N = 5.4 $.

Example 46

(+) - 3-ethyl-5- (m-hydroxyphenyl) -1- (n-propyl) hexahydro-lH-azepine

Reaction of 5.0 g of the product of Example 34 with propyl bromide in acetone containing potassium carbonate in the manner given in Example 37 gives (+) - 3-ethyl-3- (m-hydroxyphenyl) -1- (n-propyl) -hexa-hydro-1H-azepine (b.p. 190-200 ° c / l, 0 x 10-i mm Hg), + 40 ° (C = 2 $ in chloroform).

The product is recrystallized from benzene-petroleum ether (bp 60-80 ° C) to give 0.9 g, m.p. 82-83 ° C, + 38 ° (C = 2 $ in chloroform).

Analysis:

Pound: C = 78.5 $, H = 10.6 $, N = 5.5 $ C17H27N0 requires: c = 78.1 $, H = 10.4 $, N = 5.4 $.

Example 47.

(-) - 1-Cyclopropylmethyl-3-ethyl-3- (m-acetoxyphenyl) hexahydro-1H-_____-azepine 0.01 mol of acetyl chloride is added dropwise at 10-15 ° C to a stirred solution of (-) - 1 -cyclopropylmethyl-3-ethyl-3-Cm-hydroxy-phenyl) -hexahydro-1H-azepine in 50 ml of methylene dichloride and 2 ml of triethylamine. The reaction mixture is allowed to warm to room temperature and left overnight. After pouring into water, the organic layer is separated, washed with water, then dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure and the oil is converted to the hydrochloride by dissolving in acetone and treating with a solution of hydrogen chloride in dry ether. The hydrochloride is obtained in the form of 1.2.5 g colorless rhombs, m.p. -64 ° C, -28 ° (C = 2 $ in water).

Analysis:

Pound: C = 68.5 $, H = 8.7 $, N = 4.1 $ C20H29N02'HC1 c = 68.2 $, H = 8.6 $, N = 4.0 $.

141401 39

Example 48.

1-Cyclopropylmethyl-3-ethyl-3- (m-hydroxyphenyl) -hexahydro-1H- -azeplin 2.42 g of cyclopropane carboxylic acid chloride is added dropwise to a stirred solution of 5 g of 3-ethyl-3- (m-hydroxyphenyl) -hexahydro -1H-aze-pin in 70 ml of chloroform and 5 ml of triethylamine while keeping the temperature below 20 ° C. When the addition is complete, the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into water and the organic layer is separated and washed with dilute hydrochloric acid. After drying over anhydrous magnesium sulfate, the solvent is removed, leaving a residue which crystallizes by etheration with ether. Yield 5.5 g, m.p. 129-131 ° C.

Analysis:

Found: C = $ 75.1, H = $ 8.8, N = $ 4.8.

cl8H25NO2 requires: c = 75.25 #, H = 8.8g, N = 4.9 $.

4.0 g of the above-prepared amide in anhydrous tetrahydrofuran are added to a stirred suspension of 1.1 g of lithium aluminum hydride in 70 ml of anhydrous ether. When the addition is complete, the mixture is refluxed for 3 hours and cooled, successively adding 1 ml of water, 2 ml of 2N sodium hydroxide and 2 ml of water. The inorganic material is filtered off and the solvent is removed leaving a colorless oil. The oil is dissolved in isopropanol and an equimolar amount of racemic tartaric acid is added and the tartrate is obtained as colorless rhombs. Yield 1.0 g, m.p. 150-152 ° C.

Analysis:

Found: C = 62.1%, H = 7.9 $, N = 3 »1 $

Cl8H25N0'C4H6 ° 6 requires: c = 62.4 #, H = 7 »5 $, N = 3.3 $ ·

Example 49.

3-ethyl-3- (m-hydroxyphenyl ·) -! - (prop-2-ynyl) hexahydro-lH-azepine.

5.0 g of 3-Ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine, 3.04 g of 3-bromo-1-propyne and 3> 45 g of anhydrous potassium carbonate in 80 ml of dry dimethylformamide are stirred at room temperature for 24 hours. .

The solid is filtered off and the dimethylformamide is removed at reduced pressure. The residue is dissolved in 2N hydrochloric acid and extracted with ether. The aqueous layer is made basic and extracted again with ether. After drying over anhydrous magnesium sulfate, the solvent is removed at reduced pressure and the residue distilled to give U1401 a colorless glass. Yield 3.9 g, b.p. (= bath temperature) 240-260 ° C at 0.01 mm Hg.

Analysis:

Found: C = 80.0 $ H = 9 * 1 $, N = 5 * 3 $ C- ^ H ^ NO requires: C = 79.3%, H = 9.0%, N = 5.4 $.

Example 50 · 3-Ethyl-3- (m-hydroxyphenyl) -1- (n-propyl) hexahydro-1H-azepine 2.15 g of 3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine 1.35 g of n-propyl bromide and 2.0 g of anhydrous potassium carbonate in a mixture of 60 ml of dry dimethylformamide and 40 ml of dry tetrahydrofuran are heated under reflux for 14 hours. After removal of solid, the reaction mixture is worked up as described in Example 49 * and the residue distilled to give a colorless glass. Yield 1.1 g, b.p. 200--220 ° C at 0.01 mm Hg.

Analysis:

Found: C = 78.4 $, H = 10.7 $ * N = 5 * 1 $ C17H27N0 requires: C = 7δ, Χ $, H = 10.4 $, N = 5 * 4 $.

Example 51 "1-Allyl-3-ethyl-3- (m-hydroxyphenyl) -hexahydro-1H-azepine.

6.0 g of 3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine hydrobromide, 2.4 g of allyl bromide, 6.0 g of anhydrous potassium carbonate and 80 ml of acetone are heated at reflux for 14 hours. The potassium carbonate is filtered off and the acetone is removed at reduced pressure. The residue is dissolved in acid and extracted with ether. The aqueous layer is made basic with ammonia and the oil is extracted into ether. After drying, the solvent is removed at reduced pressure, leaving an oil which is treated with an equivalent amount of concentrated hydrobromic acid. After removal of the water at reduced pressure, the residue is crystallized from isopropanol ether. Yield 5 * 5 g * m.p. 168-169 ° C.

Analysis:

Found: C = $ 59.9 * H = $ 7.8, N = $ 4.0.

Cn „H HR-NO.HBr requires: C = 60.15 $, H = 7.7 $, N = 4.1 $.

25 141401 41

Example 52.

3-Ethyl-3- (m-hydroxyphenyl) -1 - (2-methylbut-2-enyl) -hexahydro-1H -_-azeplin 3-Ethyl-3- (m-hydroxyphenyl) -hexahydro-1H-azepine hydrobromide, 1.82 g of 1-chloro-3-methyl-2-butene, 2.5 g of anhydrous potassium carbonate, 0.1 g of sodium iodide and 160 ml of methyl ethyl ketone are heated under reflux, with stirring for 14 hours. The solid is filtered off and the organic layer is evaporated to an oil at reduced pressure. The residue is dissolved in 2N hydrochloric acid and extracted with ether. The aqueous layer is made basic and the basic material is isolated by extraction with ether. After drying over magnesium sulfate, the solvent is removed. and the product distilled to give 2.3 g of colorless oil, b.p. at 180-80 ° C at 0.01 mm Hg.

Analysis:

Found: C = $ 79.1, H = $ 10.1, N = $ 5.2

CiqH2gN0 requires: C = 79.4 $, H = 10.2 $, N = 4.9 $.

As indicated above, the present compounds have analgesic effect as shown in standard experiments on experimental animals. Many show an analgesic effect similar to the effect of codeine phosphate, and do not appear to be accustomed and to be free of certain undesirable side effects that frequently occur with analgesics, such as the tendency to cause convulsions and / or constipation.

The following tables summarize some of the pharmacological tests performed. The compounds were sorted for pain relief by a modification of the "rat tail" according to D'Amour and Smith, J. Pharm. 72.: 74, 1941. The test material was administered subcutaneously at a dosage level of 25 mg / kg, and analgesia in the animals was determined as a percentage of the total possible analgesia that could occur during the experimental period.

Table I

42 141401

Compound Optical% analgesic response in rats Opium antago-produced form of 25 mg / kg subcutaneously nistitic effect. <20 20-29 30-39 40-49 50-59 ^ 60 in rats according to Example No. _, _____ x | - + o) xx) - + 1 (e) (DL) + 2 (HBr salt) (DL) + 2 (base) (DL) + 5 (DL) + + 6 (DL) + + 7 (DL) + 8 (DL) + 9 (DL) + 10 (DL) + + 11 (DL) + 12 (DL) + 13 (DL) + 14 (DL) + 15 (a) (DL) + 15 (b) ( DL) + + 16 (DL) + 17 (DL) + 18 (DL) + 19 (DL) + 20 (DL) + + 21 (DL) + + 22 (DL) + + 23 (DL) + 24 (DL ) + 25 (DL) + 26 (DL) + 27 (DL) + 28. (DL) + + 33 (L) + 35 (L) + + 36 (D) + + 37 (L) + 38 (D) + ° o) + 43 141401

Table I (continued)

Compound Optical% analgesic response in rats Opium antagonist-produced form of 25 mg / kg subcutaneous nistitic action according to Example <20 20-29 30-39 40-49 50-59 ^ 60 in rat pel.

39 (L) + 40 (D) + ° 00) + 42 (D) + + 43 (L) + + 44 (D) + + 45 (L) + + 46 (D) + + 47 (L) ++ 48 (DL) ++ 49 (DL) + 50 (DL) ++. , 52 (DL) + + x) Ethoheptazine (known compound) xx) Codeine phosphate (known compound) o) 100 mg / kg subcutaneously o) 1 mg / kg subcutaneously ooo) 12.5 mg / kg subcutaneously

It will be seen from Table I that all tested compounds prepared by the process of the invention are significantly more analgesically effective than the related compound ethoheptazine, taking into account that the known compound is administered at a 4-fold dose.

Furthermore, it will be seen that a large number of the tested compounds exhibit opium antagonistic effect, indicating that they will not cause addiction problems.

Table II compares the analgesic mean dose (AD ^g), convulsive mean dose (CD5Q) and lethal mean dose (LD ^g) of certain compounds of the present invention with the corresponding values for codeine phosphate and d-propoxyphene hydrochloride. In these experiments, the test materials were administered intraperitoneally to mice.

141401 44

Table II

CD50 ^ 50

Test Material AD ^ Q CD50 ^ 50 AD50 ^ 50

Codeine Phosphate 25.5 Π2 127 4.39 4.98 d-Propoxyphene Hydrochloride 45 5 120 190 2.64 4.18

Product manufactured according to ex 2 25 »5 28 95 1.10 .3» 73 "" "" 7 22.8 53 150 2.32 6.58 "" "" 14 15 »92 x 61.25 x 3» 85 "" " "16 37 x 140 x 3» 78 "" "" 18 40.1 50.4 127.3 1.26 3.18 "" "" 23 14.0 x 70 x 5.0 "" "" 28 12, 0 70.0 70.0 5.8 5.8 x No evidence of convulsive properties.

A somewhat similar comparison of the analgesic and toxic properties of these compounds on the basis of oral administration to mice is shown in Table III.

Table III

CP50 LD50

Test material A ^ 50 ^ 50 ^ 50 A ^ 50 ^ 50

Codeine Phosphate 54 410 410 7.59 7.59 d-Propoxyphene Hydrochloride 125 - 285 2.28 2.28

Product manufactured according to ex 2 88 220 560 2.50 6.36 "" "" 7 65 240 530 3.69 8.15 "" "" 14 31.11 x 142.9 x 4.59 "16 68 x 600 x 8, 82 "" "" 18 160.3 254.6> 360 1.59> 2.24 x No sign of convulsive properties 45 U1401

It will be seen from the above tables that the compounds of the present invention have very potent analgesic properties and that the analgesic effect is attained in at least several at a dosage much less than the lethal or convulsive doses.

It has been found that the compounds prepared according to Examples 5, 6, 10, 20, 21, 22 and 28 also exhibit morphine antagonistic effect. This is a strong sign that such connections will prove not to be used.

It has long been known that many painkillers, e.g. codeine, has constipative effect, and this is usually quite undesirable. Qualitatively, d-propoxyphene has the same undesirable side effects as codeine. A number of the compounds of this invention have been tested by two methods to assess this effect. Decreases in the number of excretions from individual rats after dosing with the compounds of this invention are taken as a measure of constipation. An alternative method that has been used has been the determination of the rate at which an inert colored dye (charcoal) passes through the small intestine after dosing with test compound. In all such experiments that have been performed, the present compounds appear to be less constipating than codeine and d-propoxyphene.

In addition to the above test results, it has also been found that the compounds of Examples 36, 38, 40, 42 and 44, all of which are D-enantiomers, counteract some or all of the symptoms of severe morphine intoxication in rats, such as respiratory depression, corneal reflex inhibition , muscle stiffness and diminished motor activity. In addition, the compounds of Examples 35, 37, 39 and 43 (all L-enantiomers) have greater pain-relieving activity than the corresponding D-enantiomers (Examples 36, 38, 40 and 44).

The compounds of Examples 35 »36, 37 and 43 all show greater activity than pentazocin in an mouse anti-convulsion trial (Proc. Soc. Exp. Biol. Med., (1957)» 729-731). This is a measure of severe pain relief activity.

Claims (1)

46 1AU01 Patent Claims. Analogous Process for the Preparation of Hexahydro-1H-Azepine Compounds of the General Formula / CH-CH fH2% o 1 _____ χ --- \ J2. RX (I) r / R where R 1 represents a hydrogen atom, an alkyl group of not more than 6 carbon atoms, a benzyl group or an alkanoyl group of not more than 6 earbone atoms, R means an alkyl group of not more than 6 earbone atoms, alkenyl or alkynyl group having not more than 6 earbone atoms, a cyclopropylmethyl group, an alkanoyl group having not more than 6 earbone atoms, an alkoxycarbonyl group having at most 6 earbone atoms, or a phenalkanoyl group having at most 6 earbone atoms in the alkanoyl moiety, phenethyl or (3) each of these groups being substituted in the benzene ring with up to 5 halogen atoms and / or up to 5 alkyl, alkoxy or haloalkyl groups having up to 6 earbone atoms, nitro groups, amino groups or mono or dialkylamino groups each having at most 6 earbone atoms and R is a hydrogen atom or an alkyl group having a maximum of 6 earbone atoms, or acid addition salts or quaternary ammonium salts thereof, characterized in that a) a tetrahydro- or hexahydroazepine of the formula / -γ1-1 N ------ -1 wherein R and R have the meanings given above, XY means -N = CHR- or R ^ NC- wherein R and R 2 have the meanings given above ir o