Production of methylene-cycloamines

(24) Race day (11) Publication

87-03-30 ^number 448 983

81-01-20

07 17 The application received as ·

80-07-17

Patent Office (62) National application number (66) International filing date (86) Filing date for European patent application (30)

79-07-19 US 059092 ® Swedish Patent Application □ Completed International Patent Application with Number □ Converted European Patent Application with Number (71) Applicant AH Robins Company Inc, Richmond Va US (72) Inventor A 0. Cale Jr, Mechanicsville Va (74) Representative H Albihns patent agency AB (54) Designation Procedure for the preparation of methylene-cycloamine derivatives (56) Published publications: --- (57) Abstract:

The present invention relates to a process for the preparation of methylene cycloamine derivatives. A substituted acetamide of the formula

<img file="SE448993B_D0001.tif" />

CONH₂ where B? is lower alkyl, phenyl-lower alkyl or cycloalkyl, R² and represents phenyl or lower alkylphenyl and n represents 1 or 2, is allowed to react with bromine and an alkali metal alkoxide and the intermediate thus formed is heated in acidic medium to form a methylene cycloamine product of the formula

<img file="SE448993B_D0002.tif" />

The temperature in the first stage is maintained at 0-50 ° C and in the second stage at 75 ~ 20 ° C. The new compounds are characterized by utility as antidepressant therapeutic agents.

DB 603415

The numbers mom parentheses indicate international identification code, INID code Letter within clamps indicates international document code

448 993

Process for preparing methylcycloamines

The present invention includes a process for the preparation of methylene cycloamines.

The prior art

Of general interest in connection with the present invention may be mentioned the processes for the preparation of compounds such as O ((1-R-3-pyrrolidinyl) -tropho-diphenylacetamides (and -acetonitriles) iA-phenyl-d- (2-pyridyl) acetamides (and -acetonitriles) disclosed in U.S. Pat.

Also of interest are the synthetic methods for preparing antidepressant 3-d isubstituted methylene pyrrolidines which are disclosed in U.S. Patent No. 3,732,247. The methylene pyrrolidines of this patent correspond to the formula

<img file="SE448993B_D0003.tif" />

where R is hydrogen, lower alkyl, phenyl-lower alkyl, substituted phenyl-lower alkyl, cycloalkyl, phenoxy-lower alkyl, phenylamino-lower alkyl and substituted phenyl. wherein said lower alkyl

2 is limited to 2-8 carbon atoms nex · R and R both denote i

phenyl; where F represents lower-alkyl, phenyl-lower-alkyl, cyclo-2-alkyl, phenyl and substituted phenyl and where R represents phenyl and substituted phenyl.

U.S. Patent No. 4,133,881 discloses a process for the preparation of a type of c '1 n:

448 993

<img file="SE448993B_D0004.tif" />

where R is hydrogen, lower alkyl, lower cycloalkyl or phenyl lower alkyl; where R¹ represents phenyl or 2-pyridyl and Y represents carbamoyl or cyano, which compounds exhibit antiarrhythmic activity.

Accordingly, it is an object of the present invention to provide a better process for the preparation of methylene cycloamine compounds, such as J-methylenazetidine compounds, which are characterized by one or other pharmacologically useful properties for counteracting specific physiological shell abnormalities in humans and other mammals.

It is a further object of the present invention to provide a new and effective process for converting a compound such as &lt;X, c ethyl 3-diphenylmethylene pyrrolidine.

Other objects and advantages are set forth in the attached description and examples.

Description of the invention

One or more of the objects of the present invention are achieved by a process for the preparation of methylene cycloamines which comprises reaction of a substituted acetamide compound, described in detail below under modified Hofmann reaction conditions in the presence of alkanol to form a carbamate intermediate and then heating said a carbamate intermediate in an acidic medium to obtain the methyl cyclone amine product. The bar for don hydrolyzes. of the carbamate to an amine that would normally be expected occurs an elimination corresponding to an alkyl carbamate molecule comprising a double bond.

448 993

According to one embodiment of the present invention, there is obtained a process for the preparation of pharmacologically active methylene cycloamine compounds, consisting of (1) reaction between a substituted acetamide compound and bromine and alkali metal oxide to form a carbamate intermediate, wherein the starting material of said substituted acetamide corresponds to:

<img file="SE448993B_D0005.tif" />

where R¹ represents lower alkyl, phenyl-lower-alkyl or cycloalkyl and-groups; where R and R are phenyl or lower-alkylphenyl and where n is 1 or 2, and (2) heating said carbamate intermediate in acidic medium to give a methylene cycloamine product of the formula:

<img file="SE448993B_D0006.tif" />

where R¹, R², R³ and n previously defined. R² and R³ can be the same or different.

Lower alkyl is meant alkyl groups having 1-8 carbon atoms. By * bycloalkyl is meant cycloalkyl groups having 1-9 carbon atoms.

Illustrative example of R¹-groups represented in formula I are. methyl, ethyl, isopropyl, butyl, isobutyl, hexyl, octyl, cyclopropyl, cyclopentyl, cycloheptyl, phenylethyl, methylbenzyl, phenylpropyl and other equivalent lower alkyl groups, phenyl lower alkyl and cycloalkyl groups.

Illustrative example of R² and R³ groups are phenyl, 4-methylphenyl, 2-ethylphenyl, * 1-isopropylphenyl and the like.

448 993

Preparation of Substituted Cycloamine-Acetamide Starting Material The cycloamine-acetamide compounds, utilized as starting material of the present invention, can be readily prepared by a synthetic process illustrated by the present reaction scheme:

<img file="SE448993B_D0007.tif" />

<td colspan="2">R²</td>

<td>1 1- Na-C-CN 1</td><td> -------&gt;</td>

<td>la R³</td><td>R²J</td>

<td>&gt; R¹ N / -</td><td>-C-CONH</td>

<td> \ /</td><td> 1</td>

<td>(CH₂)_n</td><td>R³</td>

3 . .

where R, R, R and n have been previously defined and Z is -OSO and CH- (oxyloxy) or halide.

The preparation of 1-substituted-3-azetidinols and other 1,3-disubstituted azetidine derivatives is described in Tetrahedron Letters, No. 39, '46.91 (1966), Tetrahedron Letters, no. 23, 2155 (1967), J. Org. Chem., 32, 2972 ​​(1967); Chein. Pharm. Bull. 22, 1H90 (1974);

The above reaction scheme first illustrates the bisubstituted acetonitrile (e.g., ( selected 1R-3-mesyloxiazetidine or an 1R-3-halogenazetidine to form a Df- (1R-3-azethidinyl) - &lt;X^ZThe said acetonitrile derivative is acid hydrolyzed to a c &lt;- (1R-3-azetidinyl) - (-, (X-diphenylacetamide, which is a key material for the novel process for the preparation of methylene cycloamine compounds of the present invention).

The first step in the process according to the invention

The first step in the process of the invention involves reaction

448 993 between the substituted acetamide starting material (e.g., the α- (1R-3-azetidinyl) -cx ', c1-diphenylacetamide described above) with bromine and an alkoxide ion in the presence of alkanol to form a carbamate intermediate. The following reaction scheme illustrates the first step in the process of utilizing bromine and sodium methoxide in methanolic solution;

<img file="SE448993B_D0008.tif" />

RG _f

NaOCH₃

<img file="SE448993B_D0009.tif" />

Said reaction scheme essentially corresponds to a modified Hofnjannonil storage synthesis procedure for converting an amide to a carbamate derivative via a bromide intermediate;

Q-CONH2 + Br₂ + 2No₃ ---&gt; [Q-CONHBr] ---&gt;

[Q-NCO] -, Q-NHCO₂CH₃ + SNaBr + CH₃0H

The alkali metal alkoxide used is preferably a sodium or potassium alcoholate of an alcohol containing between one and eight carbon atoms, e.g. methanol, ethanol, butanol, hexanol, octanol and the like.

To obtain an effective reaction, it is preferred to utilize the alkali metal alkoxide and bromine in at least stoichiometric amounts with respect to the amount of substituted acetamide starting material. For example, for each mole of substituted acetamide, between about 1 and 1.5 moles of bromine and between 2 and 2.5 moles of alkali metal alkoxide can be used.

The reaction medium · for the substituted acetamide conversion to carbamate derivatives can be any anhydrous solvent having acceptable solubility characteristics and which is stable under the conditions of the Hofmann reaction. Examples of suitable solvents are alcohols, ketones, ethers, hydrocarbons, halohydrocarbons and the like. It is particularly advantageous to use methanol as a reaction medium in combination with bromine

448 993 and alkali metal methoxide.

The conversion step of the substituted acetamide in the process of the invention occurs at a temperature in the range of about -10 to 75 ° C and preferably at a temperature in the range of between 0 and 50 ° C.

A full description of variations in the conditions of the Hofmann reaction is given in Organic Reactions, 3, 267 (John Wiley &amp; Sons, New York, 1946); Survey of Organic Synthesis, Buehler and Pearson, (Wiley-Interscience, New York, 1970) and Chem. Ber., 87, 1294 (1954).

The second step of the invention according to the method

The carbamate intermediate produced in the first step of the process according to the invention corresponds to the formula:

<img file="SE448993B_D0010.tif" />

an alkyl group containing between one and eight carbon atoms.

In the second step of the process according to the invention, the carbatri-atelic process is heated in an acidic medium, preferably to a temperature between about 75 and 200 ° C to obtain a methylene cycloamine product of the formula:

<img file="SE448993B_D0011.tif" />

5 bad R, h, R and n were previously defined.

The acidic medium will normally be an aqueous solution of an acid or an acidic aqueous solution of a water miscible solution

448 993 agents such as tetrahydrofuran. If desired, the second step can take place in a reaction medium with an organic phase and an aqueous phase with suitable stirring means to obtain effective contact between the phases.

The acidity of the reaction medium is adjusted with an inorganic acid to maintain at least a normality of 1 'throughout the heating phase. The acidity is preferably obtained using sulfuric acid, preferably with a normality of from 6 to 18. Examples of other suitable acids are hydrochloric acid and phosphoric acid and the like.

The heating phase at. the second step of the process according to the invention takes place for a sufficient period of time to obtain a complete conversion of carbamate intermediates into the methylene cycle in the product. A typical reaction time ranges from about 1 hour to 10 hours, depending on the concentration of the acid and the temperature of the reaction medium. The reaction temperature during the heating phase can vary in the range of about 50 to 250 ° C and is preferably kept in the range, between about 75 and 200 ° C.

After the heating phase is complete, the methylene cycloamine product can be recovered by conventional extraction and distillation. In a typical product recovery process, the reaction product medium is neutralized with a basic reagent and the methylene cycloamine product is extracted with a water immiscible solvent such as benzene or ethyl acetate and the final product is isolated by fractional distillation.

Pharmacology of the methylene cycloamine products prepared by the process of the invention ______________________

As previously described, the process of the invention is applicable in the preparation of pharmacologically active methylene cycloamine compounds, for example, those exhibiting imipramine-enhancing antidepressant activity which correspond to the formula:

<img file="SE448993B_D0012.tif" />

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3 where R, R, R and n were previously defined.

A compound of the above formula may be incorporated as active therapeutic agent in pharmaceutical compositions. The pharmaceutical compositions are prepared in a form suitable for administration to living humans and animals.

Pharmaceutical compositions for oral administration are preferably solid forms and may be taken in the form of capsules, tablets or coated tablets containing conventionally used carriers in the field of pharmacology. Suitable tablet diluents include lactose, potato and corn starch, talc, gelatin, stearic acid, silicas, magnesium stearate and polyvinylpyrrolidone.

For parenteral administration, the carrier or diluent may be a sterile parenterally acceptable fluid (e.g., water) or a parenterally acceptable oil (e.g., peanut oil) enclosed in ampoules.

In rectal administration compositions, the carrier may be a suppository base, such as cocoa butter or a glyceride.

The compositions are conveniently formulated as unit doses, each unit being suitable to deliver a fixed dose of active ingredient. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred unit dosage forms in accordance with the invention. Each unit dose for oral administration may conveniently contain 10 to 40 mg of active ingredient; each unit dose suitable for intracardiac or intravenous administration may conveniently contain 1 to 2 mg of active ingredient per ml, while each unit dose suitable for intra-muscular administration may conveniently contain 5 to 10 mg of active ingredient per ml. Daily doses should preferably range from 10 to 100 mg. The exact individual dose as well as daily doses are determined in accordance with standard medical principles under the guidance of a physician or veterinarian.

Antidepressant Activity of Methylene-Cycloamine Compounds Antidepressants block many of the physiological effects and effects on the behavior caused by tetrabenazine and

448 993 reserpine, such as motor depression, hypothermia and ptosis. Tetrabenazine is chemically related to reserpine, which causes depression in humans (Davies, Depression, Cambridge University Press, New York, 1964). Because the action of tetrabenazine initiates faster than that of reserpine, the former compound is more commonly used as a tool for the sale of potential antidepressant drugs.

To test the antidepressant activity of methylene-cycloamine compounds, five adult female mice (ICR-DUB strain) received 20 mg / kg IP of the test compound 30 minutes to administer a ptotic dose (32 mg / kg IP) -tetrabenazine (as the methanesulfonate salt). Thirty minutes later, the presence or absence of complete eyelid closure (ptosis) was noted in each animal.

For compounds that cause ptosis blockage in all animals, a value was obtained using at least three geometrically distinct doses to five mice / dose. Protective ED ^_Q values ​​were determined by probability analysis with 95 $ confidence limits and a slope function calculated according to Litchfield and Wilcoxon (A simplifid method of evaluating dose-effect experiments, J. Pharm. Exp. Ther. 96, 99-113, 1949).

Typical values ​​for reference agents with antidepressant activity are shown in Table 1.

Table 1

Blockage of tetrabenazine-induced ptosis in mice

OATH_RFI ($ 95 confidence limits)

Fören3ng ^J slope - mg / kg IP

<td>imipramine</td><td> °,3 0,4 0,5</td><td colspan="2"> (0.1 - 0,6) (0,2 - 0,9) (0,2 - 1,2)</td><td> 2,6 ' 2,5 2,3</td>

<td>viloxazine</td><td> 1,5</td><td> (0,7</td><td> - 3,2)</td><td> 2,5</td>

In accordance with the above-described samples and evaluation procedures, 1-isopropyl-3-diphenylenazetidine oxalate showed an ED ^ mg / kg IP of 2.18 (confidence limits 1.18-4.03) and 1-methyl-3-diphenylenazetidine an ED +₀ mg / kg of 1.48 (confidence limits 0.84-2.5).

448 993 ίο

The antidepressant properties of J-disubstituted methylene-pyrrolidine compounds are disclosed in U.S. Patent No. 3,732,217.

The following examples illustrate the application of the process of the present invention to the preparation of methylene cycloamine compounds and the synthesis of starting materials suitable for this preparation. Reactants and other specific ingredients presented are typical and various modifications can be made with respect to the above discussion without departing from the scope of the invention.

Example 1

The example illustrates the preparation of 3-chloro-1-methyllazetidine hydrochloride.

<img file="SE448993B_D0013.tif" />

A mixture of dilute sodium hydroxide solution and 700 ml of toluene was used to distribute 46 g (0.13¹) mole) 3-diphenylmethoxy-1-methylethylzetidine oxalate. The toluene solution was dried over anhydrous sodium sulfate and further dried by azeotropic distillation of toluene to a final volume of 300 ml. The dried toluene solution was treated with 10 palladium on carbon and hydrogenated at 310 kPa at 80 ° C for 5 hours. The mixture was filtered and 41 g (0.264 mol) of carbon tetrachloride were added to the filtrate. After cooling the resulting solution on an ice-methanol bath, 53 was added₃5 g (0.145 mole) of trioctylphosphine in a batch with stirring. The temperature rose rapidly to a maximum of 50 ° C. The solution is stirred for 30 minutes and distilled at a blowing temperature of 150 ° C. The distillate was acidified with an ethereal solution of hydrogen chloride. The resulting crystals were separated by filtration and dried in vacuo to give 8.5 g of a product (45 L).

A solution of the base, 3-chloro-1-methylazetidine was prepared by partitioning 3-chloromethyllazetidine hydrochloride between toluene and dilute sodium hydroxide, drying the toluene solution with anhydrous sodium sulfate, and passing the solution through a 2 x 50 cm column. with molecular sieve # 4a.

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Example 2

The example illustrates the preparation of γ1, of-diphenyl- &lt;X- (1-isopropyl-J-azetiynyl) acetonitrile.

<img file="SE448993B_D0014.tif" />

Method A.

To 250 ml of triethylamine was added II¹) g (0.4 mol) 1-isopropyl-3-azetidinyl mesylate oxalate. About 250 ml of dry toluene was added followed by 77 g of anhydrous magnesium sulfate, after which the mixture was mixed for about one minute and then filtered. The filtrate was added over a period of one hour to a refluxing mixture prepared by refluxing 18.5 g (0.44 mole) 57 in sodium hydride (in mineral oil) and 77.2 g (0.4 mole) diphenylacetonitrile in 1500 ml dry toluene for 3 hours. The mixture was refluxed for 2 hours, cooled and extracted with dilute hydrochloric acid. The organic phase was extracted five times with water and all aqueous phases were combined. The aqueous phase was made basic with sodium hydroxide and extracted with chloroform which was dried (sodium sulfate) and concentrated. The residue was crystallized from isooctane to give 68 g (58%) of a product having a melting point of 92-95 ° C. Recrystallization from isoctane raised the melting point to 93-95 ° C.

Analysis: calculated for C₂₀hrs₂₂N₂: C 82.72 H 7.64 N 9.65 obtained ·. C, 82.72; H, 7.73; N, 9.55

Method B.

A mixture of 40.42 g (.0.96 mole) of 57% sodium hydride and 168 g (0.87 mole) of diphenylacetonitrile was refluxed in a liter of dry toluene for 3 hours. In separate flasks, 100 g (0.87 mole) of methanesulfonyl chloride drip was added at 20 ° C to a stirred 3 cc of 100 g (0.87 mole) of 1-isopropyl-3-azetidinol and 101 g (1 mole). triethylamine in 700 ml of dry benzene. The mixture was stirred at 25 ° C for 2 hours and filtered. The filter cake was washed with benzene. The combined filtrates were added dropwise over a period of time

448 993 about 30 minutes to the refluxing preparation of the sodium salt of diphenylacetonitrile. After refluxing for 1.5 hours, the cooled solution was washed with water and extracted with dilute hydrochloric acid followed by extraction with water. The aqueous extracts were combined, made basic with sodium hydroxide and extracted / with chloroform. The chloroform solution was dried (sodium sulfate) and concentrated. The residue was crystallized from isooctane to give 142 g (56 $) of the product.

Example 3

The example illustrates the preparation of β, (Χ- -diphenyl-³X-1-cyclohexyl-J-azetidinyl) acetonitrile.

CN

Methylene chloride containing 191 g (1.0 mole) of 1-cyclohexyl-3-azetidinol hydrochloride was extracted with dilute aqueous sodium hydroxide and the organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dry benzene and mixed with 116 g (1.0-5 mol) of triethylamine and then cooled on an ice bath. To the cold stirred solution was added dropwise 115 g of methanesulfonyl chloride and stirring was continued at room temperature for 3 hours after which the mixture was filtered. To one liter of dry toluene containing 50.0 g (1.0 mole) of sodium hydride at 45 ~ 50 ° C was added 193 g (1 mole) of diphenylacetonitrile and the mixture was refluxed with stirring for 2 hours. To this solution, the previous filtrate was quickly added dropwise. After the addition was complete, reflux continued. desiccate for 2 hours and then the solution is stirred overnight. An equivalent volume of isooctane was added and the solution was extracted for 4 hours with dilute hydrochloric acid solution. The acid phases, obtained at each extraction, were combined, dried, basic with a mixture of 50 $ sodium hydroxide and ice, and extracted with chloroform. The chloroform phase was dried, filtered and concentrated in vacuo. The residue was crystallized by the addition of isopropyl ether and the solid was recrystallized from isopro13

448 99 l of pyl ether * to obtain 58.0 g (18 of a product melting at 111-114 ° C.

Analysis: calculated for ^{C, 85.59;} 7.93 N 8.48 obtained: C 83.24 H 7.9¹) N 8.27

The same procedure was followed using 1-ethyl-3-azetidinol hydrochloride instead of 1-cyclohexyl-3-azetidinol hydrochloride (X, oc-diphenyl--ί - (1-ethyl-3-azetidinyl) acetonitrile).

Example 4

The example illustrates the preparation of (X, W-diphenyl-OC- (1-methyl-3-azetidinyl) acetamide hydrochloride (starting material).

<img file="SE448993B_D0015.tif" />

To 60 ml of concentrated sulfuric acid heated to 60 ° C was added 21.7 g (0.082 mol) of lx,^!'-Diphenyl-3' - (1-methyl-3-azetidinyl) acetonitrile at an amount per unit time that the temperature was kept at 60 ° -70 ° C. The resulting solution was heated to 70 ° C for 18 hours and extracted with chloroform. The chloroform extract was dried over sodium sulfate and concentrated and the residue crystallized from ethyl acetate-1sopropyl alcohol to give 13.8 g of free base (60 L) melting at 171 ~ 174 ° C. The base was treated with hydrogen chloride in isobutyl methyl ketone and the salt was recrystallized from isopropyl alcohol to give 9 g of a product melting at 182-185 ° C.

Analysis:

calculated for C₁₈hrs₂₁C1N₂O: C 68.24 H 6.68 N 8.84 · obtained: C 67.88 H 6.72 N 8.78

Example. _5

The example illustrates the preparation of -diphenyl-X- (1-isopropyl-3-azetidinyl) acetamide (starting material).

448 993

<img file="SE448993B_D0016.tif" />

To 80 ml of concentrated sulfuric acid, heated to 70 ° C, was added 25 g (0.86 mole) of O₂-Cenf-diphenyl-fX-C--isopropyl-J · The solution was heated to 70 ° C for 18 hours and put on ice. The mixture was basified with 50 L of sodium hydroxide (under cooling with ice) and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized from ethyl acetate-ethanol to give 15.7 g (59 $) of a product melting at 181-18 hours.⁰C.

Analysis:

calculated for θ₂0^Η24^Ν2 ° Γ · ^{C 77.89 H 7.811 N 9.08}obtained C 77.89 H 7.88 N 8.98

If the same procedure was followed using (\^z, [Y-diphenylGf-d-ethyl-J-azetidinylacetonitrile instead of the 1-isopropyl derivative, C^/, (X-diphenyl - '&lt;- (l-ethyl-3-azetidinyl) acetamide.

Example 6

The example illustrates the preparation of 1x ', pf-diphenyl-of-1- (1-phenylethyl) -5-azetidinyl] acetamide Starting Material).

<img file="SE448993B_D0017.tif" />

To 100 ml of concentrated sulfuric acid heated to 70 ° C was added, with stirring, 50 g (0.142 mole) of β that the temperature could be maintained at 65 ° 70 ° C. The solution was heated

Ϊ5

448 993 to 72-75 ° C for 18 hours. The acidic solution was poured onto ice and then made basic with 50% aqueous sodium hydroxide and extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and concentrated by distillation. The residue was crystallized from isopropyl ether to give 28.5 g (54) 6) of a material melting at 152-153.5 ° C. A sample was recrystallized from isopropyl ether isopropyl alcohol to give a product melting at 153^_154 ° C.

Analysis:

calculated for θ₂5^Η26^Ν2^{81: C 81.05 H 7.07 N 7.56}obtained _: C 80.83 H 7.07 N 7.4θ ”

If the same procedure was followed using [xioph-diphenyl-oc - (1-cyclohexyl-3-azetidinyl) acetonitrile in place of the 1-phenylethyl derivative, O; v-di-phenyl- (1-cyclohexyl-3- azetidinyl) acetamide.

Example 7

The example illustrates the preparation of in phenyl-O- (1-methyl-3-pyrrolidinylacetamide (starting material)).

<img file="SE448993B_D0018.tif" />

<img file="SE448993B_D0019.tif" />

To 240 ml of concentrated sulfuric acid was added 60 g (0.21 mole) of C₂, ((diphenyl) -1- (1-ethyl-3-pyrrolidine in new 1.) acetone in tril. The complete solution was obtained and allowed to stand at 70 ° C for 24 hours The solution was poured on ice, made basic with ammonium hydroxide and extracted with about 1000 ml of ethyl acetate. ) · Ό1 \ Ί. ·: &lt;· Rti 11 oi.J: ri ng 200 ml. IV white 1: r obtained from cooling was recrystallized from an ethyl acetate-ligroin mixture to give 34 g (52.5 lb) of a mixture melting at 141-142 ° C.

448 993

Analysis:

calculated for ^C20^hrs24^N2^O:obtained:

C.77.80 H 7.8 * 1 N 9.09

G 79.70 H 8.18 N 8.83

Example 8

The example illustrates the preparation of CX- (1-cyclohexyl-3-pyrrolidinyl) - Οί, Οί-diphenylacetamide (starting material).

To 80 ml of concentrated sulfuric acid was added 20 g (0.057 mole) of C- (cyclohexyl-3-pyrrolidinyl) -K, os-d ifenyl) acetone tril. The mixture was shaken until everything had dissolved under cooling on an ice bath until no heat was developed. The solution was heated to 70 ° C for eight hours, quenched on ice and basified with ammonium hydroxide. The resulting white solid precipitate was taken up in ethyl acetate and the solution was dried over sodium sulfate. The solution was concentrated and the remaining oil was taken up in hot ligroin, filtered and allowed to stand overnight at room temperature. The resulting crystals were recrystallized from ligroin to give 9.0 g (A2.5%); mp 119-121 ° C. Analysis:

calculated for C ^H C ^NgO: C 79.51 H 8.3 8. N 7.73 obtained: C 79.69 H 8.51 N 7.58

Example 9

Example b, illustrates the preparation of 1-methyl-3-diphenylmethylenazetidine.

448 993

<img file="SE448993B_D0020.tif" />

To 150 ml of methanol were added 4.6 (0.20 moles) of sodium tablets and under dissolution 14.0 g (0.05 moles) of Οί, α-diphenyl- (X- (1-methyl-3-azetidinyl)) were added. To this stirred suspension was added dropwise 16.0 g (0.10 mol) of liquid bromine while maintaining the temperature at room temperature with cooling in an ice bath, stirring was continued for 2 hours, the solution was concentrated in vacuo and the residue treated with 100 ml of 6N sulfuric acid. and refluxed for 18 hours. The acid mixture was basified with sodium hydroxide and extracted with chloroform. The chloroform phase was dried, filtered and concentrated in vacuo.

the residue was dissolved in isopropanol and treated with maleic acid and the salt was recrystallized from isopropanol. The salt was partitioned between isopropyl ether and dilute sodium hydroxide. The ether was dried, filtered and concentrated in vacuo, the residue crystallized from isooctane to give 7.0 g with a melting point of 93 ° 95 ° C.

Analysis: Calculated for C ^H ^N: C 86.76 H 7.28 N 5.95 obtained: C 86.74 H 7.34 N 5.81

Following the same procedure was followed using 1-ethyl derivative or 1-cyclohexyl derivative instead of 1-methyl derivative 1-ethyl-3-diphenylmethylenazetidine and 1-cyclohexyl-3-diphenylmethylenazetidine were obtained.

448 993

Example 10

The example illustrates the preparation of 1-isopropyl-3-diphenylmethylenazetidine oxalate.

<img file="SE448993B_D0021.tif" />

• (COOH)₂

To 125 ml of methanol were added 18.1 g (0.336 mole) of sodium methoxide and 26 g (0.084 mole) of CX, O (~ di-phenyl- &lt;X '(1-isopropyl-3-azetidinyl) acetamide). 26.8 g (0.168 mole) of bromine over a period of 30 minutes and the resulting solution was heated to reflux for two hours and concentrated The residue was dissolved in 6N sulfuric acid and heated to reflux for 2 hours and extracted with isopropyl ether. The acid phase was made basic with sodium hydroxide and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was treated with 0.08 moles of oxalic acid in ethanol. The resulting crystals were recrystallized three times from ethanol to give 3 g (10%) having a melting point of 20V205 ° C.

Analysis:

Calculated for: C, 71.35, H, 6.56, N, 3.96, obtained: C, 70.95; H, 6.53; N, 3.90

The above procedure was followed until the addition of the oxalic acid using 1-phenyl-ethyl derivative or 1- (1-phenylethyl) derivative instead of 1-isopropyl derivative to obtain 1-phenylethyl-3-diphenylmethylenazetidine and 1- (l-phenylethyl) -3-diphenyl-metylenazetidin.

Example 11

The example illustrates the preparation of 1-methyl-3-diphenylmethylene pyrrolidine.

448 993

P ^ 'b ch₃

To a solution of 59.5 g (1.1 mole) of sodium methoxide in 850 ml of methanol was added 81 g (0.276 mole) of γ, oC-diphenyl - [- (1-methyl-3-pyrrolidinyl) acetamide. To this stirred solution was added dropwise 90 g (0.56 mol) of bromine in 150 ml of methanol and the solution was heated to reflux for 1.5 hours. The solution was concentrated in vacuo and the residue partitioned between chloroform and water. The chloroform phase was concentrated and the residue was dissolved in 600 ml of 6N sulfuric acid, which was heated to 100 ° C for 2.5 hours. The solution was basified with sodium hydroxide and extracted with ethyl acetate. The extract was concentrated and distilled. Yield h2 g. Boiling point 150-160 ° 0 at 0.2 mm Hg. Some were recrystallized several times from the iso-octane to give a product having a melting point of 73-74 ° C.

Analysis:

for C 86.70 H 7.68 N 5.62 obtained: C 86.77 H 7.62 N 5.60

The procedure as above was followed but using (X, a-diphenyl-O- (1-ethyl-3-piperidinyl) acetamide or% &lt;X-diphenyl 1-04 (1-ethyl-4-azepinyl) acetamide as starting material to give 1- ethyl 3-diphenylmethylene pyrrolidine or 1-ethyl-4-diphenylmethylenazepine.

Example 12

The example illustrates the preparation of α ', α-diphenyl-C (- (1-methyl-3-acetidinyl) acetonitrile (starting material).

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Procedure A

To 4 g (0.11 mole) of sodium amide in 300 ml of toluene was added 21 g (0.11 mole) of diphenylacetonitrile and the mixture was stirred under reflux in a nitrogen atmosphere for 11 hours. The heat was removed and the solution of 3-chloro-1-methyllazetidine was added at such an amount per unit time that the reflux was maintained. The solution was refluxed for 4 hours, allowed to stand overnight, washed with water and extracted with dilute hydrochloric acid. The acidic aqueous phase was made basic with dilute sodium hydroxide and extracted twice with isopropyl ether. The solution was dried (sodium sulfate) and concentrated. The residue was recrystallized from ligroin to give 6.7 g (27%) of a product having a melting point of 113 ~ 115 ° C.

Analysis:

calculated for C_Ighrs₁₈N₂: C 82.41 H 6.92 N 10.68 obtained; C 82.31 H 6.98 N 10.51 Method B

To 800 ml of ethanol was added 59 g (0.13 mol) of X⁰6- [1 (1phenylethyl) -3-azetidinyl] acetonitrile metobromide, 7.12 g (0.013 mole) of potassium hydroxide and 0.25 g of $ 10 palladium on carbon. The mixture was shaken in a Parr hydrogenator at room temperature under an initial pressure of 310 kPa hydrogen for 24 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was crystallized from isooctane. A product was obtained in an amount of 21.7 g (64 $) having a melting point of 112-115 ° C.

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