CA1207796A - Intermediates for the preparation of 4-phenyl-1,3- benzodiazepins and methods for preparing the intermediates - Google Patents

Abstract

Abstract of the Disclosure The invention relates to a process for the preparation of an N-methyl-2-amino-?-phenylphenethylamine of the formula VI

VI

in which a compound of the formula III

III

wherein R2 is -C(CH3)3 or -OC(CH3)3 is hydrolyzed. The compound of the formula VI is an intermediate precursor of 4-phenyl-1,3-benzodiazepins, which exhibit activity as antidepressants, analgetics and anti-convulsants.

Description

~77~6 This application is a divisional of Canadian Patent Application Serial number 418~332~ filed Decernber 22~ 1982n .~ The present invention relates to intermediates for the preparation of 4-phenyl-1~3-benzodiazepins, and in parti-cular inter~ediates for the synthesis of the compound 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepin, and its optical antipodes and physiologically acceptable salts.
The compounds 4,5-dihydro-4-phenyl-3H-1,3-benzo-diazepins of the formula 1 0 1~<
~ N ~
X ~ -R' (I) ~9 ' ~y n in which R is hydrogen or alkyl of from 1 to 5 carbon atoms;
R1 is hydrogen, alkyl of from 1 to 5 carbon atoms, cyclo-alkylalkyl of from 4 to 8 carbon atoms or aralkyl havin~
from 1 to 5 carbon atoms in the ~lkyl moiety; X and Y
are the same or different and each can be hydrogen, chlorine, bromine, fluorine, methoxv, alkyl of from 1 to 3 carbon atoms, hydroxy or trifluoromethyl; m is the integer 1 or 2; and n is the integer 1, 2 or 3, their optical antipodes and physiologically acceptable salts are useful as antidepressants, analgetics and anticonvulsants. Of particular interest for these purposes are the hydro-chloride salts of the 4-phenyl-1,3-benzodiazepin of formula (I), wherein R and R' are both methyl, and X and Y are both hydrogen.
The 4-phenyl-1,3-benzodiazepins, methods for their preparation and compounds useful as intermediates in their pxeparation are known from published European Pat. Appl.
No. 0 009 800. The known methods ~f preparation require a relatively lar~e nurnber of steps, the steps are relatively complicated, the starting materials are costly and the yields of the 4-phenyl-1,3-benzodiazepins are less than 77:~
- 3 ~ HOE 81/S 023 desirable.
This invention provides novel intermediate compounds utilized in the prepaxation of the ~phenyl~1,3-benzodiaze-pins of formula (I~. These intermediates hav~ the formula ~NHCOR2 ~ ~II) o~
where Y is -OH; halogen; -N -CH3; P~1S03-; where R1 is a straight chai.n or branched chain alkyl group having 1 to 5 carbon atoms, or aryl; and R2 is -CICH3)3 or -0-C(CH3)3 and ~ ~HCH3 ~

where R2 is -C(CH3)3 or -0-C(C~3)3.
This invention also provides methods for preparing the compounds of the invention.
In addition, this invention provides for the use of the compounds of the invention in the preparation o~ the 4-phenyl-1,3-benzodiazepins of formula (I).
When the compounds of ~he invention are utilized in the synthesis of the 4-ph~nyl-1,3-benzodiaz.pins of formula (I), a smaller number of process steps may be employed, and the ben20diazepins may be prepared in high yields and increased - purity.
Preferred compounds of the formula II are thosein which the substituent Y is hydroxyl, chlorine or bromine.
When Y is halogen, chlorine is particularly preferred.
When Y in formula (II) is R1S03- and R1 is alkyl, a methyl ~2~77~6 , sulfonyl group is preferred. As used throughout the specification and appended claims, the term 'lalkyl" shall mean an acyclic hydrocarbon group containin~ no unsatura-tionO When Y in formula ~II3 is R1S03- and R~ is aryl, the S substituent group will typically be a phenyl sulfonyl, a p~chlorophenyl sulfonyl or a p-toluene sulfonyl group.
The compounds of formula III) and the compounds of formula (III) can be prepared according to the following sequence of reaction.
1. An N-acylated-o~toluidine of the formula o 1'3H~ .
~ 2 (IV) is converted to a dilithio intermediate of the formula 20~ ~ ~ OLi CH2Li where R2 is asdefined above. The N-acylated-o-toluidine of formula (IV) is N-/ (2-methyl)-phenyl_7-2,2-dimethyl-propanamide or N-t-butoxycarbonyl-o-toluidine. Lithiation of aromatic compounds with an n-al~yllithium compound is exemplified in J. M. Muchowski and M.Venuti, 3.0rg. Chem.
45, 4798-g~01 (1980) and W. ~uhrer and HoW~ ~schwend, 3.
Org. Chem. 4~, 1133-1136 (1979). A preferred method according to the present invention involves slowly addin~
a solution o~ alkyllithium, such as n-butyllithium, sec-butyllithium or tert-butyllithium, in a solvent therefor, such as hexane, to a solution of the N-acylated-o-toluidine in an ethereal solvent, such as diethyl ether, tetrahydro-furan, dimethoxyethane, and a hydrocarbon solventl such as 779q6 ~, hexane. The preferred alkyllithium compound i5 n-butyl-lithium. The ethereal solvent and hydrocarbon solvent should be substan~ially inert to the alkyllithiurn to avoid adverse side reactions. The temperature during the addition can range from about -70C to about 30~C, preferably abou~ -10~C to about 30rC. The resulting mixture is aged from about one-half to about 5 hours, preferably about 1 to about 2 hours. The reaction is conveniently carried out at atmospheric pressureO The amount of alkyl-lithium employed is up to about 10 % in excess of the 2mol~r equivalents required for the rea~tion. It is important to exclude moisture from the reaction mixture. Accordingly, the reaction is conveniently conducted in an atmosphere of a substantially dry gas, such as substantially anhydrous nitrogen.

2. In order to prepare a compound of formula (II) in which Y is a hydroxyl group, the dilithio intermediate of formula (V~ is quenched with henzaldehyde as an electro-phile. The aqueous work up of the reaction mixture provides the compound of formula (II) in which Y is hydroxyl.
The temperature of addition of the benzaldehyde can range from about -78C to about 35C, preferably from a~out 0 to about 25C. The mixture is aged for a period of about 5 minutes to about one hour. The amount of benzaldehyde employed is from about one to about 2 molar equivalents based on the dilithio intermediate of formula (V). The ~uenching with benzaldehyde is conveniently conducted at atmospheric pressure and in a substantially dry e.g~, dry nitrogen; atmosphere.
In order to prepare a compound of formula ~II) in which Y is halogen, a compound of formula (II) in which Y is hydroxyl is carefully halogenated to provide the corresponding halide. This convexsion can be conveniently pexformed by any method known in the art for converting a benzylic alcohol to the corresponding halide. For instance, a compound according to formula (II) in which .. ;

~2~7~6 Y is a hydro~yl group can be dissolved in a suitable solvent therefox. Typical solvents are non-hydroxylic solvents, such as non-hydroxylic halogenated solvents, or non-nucleophilic amines, such as pyridine or a tertiary amine, such as trimethyl amine. Reaction with about 1 to about 2 equivalents, preferably about 1.1 equivalents, of thionyl chloride at about 0 to about 50C, preferably about 20 to about 30C, can be carried out for a period of about 1 to about 16 hours. Ohter known chlorinating agents, such as phosphorus oxychloride or phosphorus penta-chloride can also be employed. The method selected should not result in hydrolysis of the propanamide group or the N-(t-butoxycarbonyl~ group. For example, the hydroxy compound can alternatively be reacted with a phosphorus trihalide, such as phosphorus tribromide, under standard reaction conditions. In a preferred method according to this invention, a compound of formula (II~ in which Y is hydxoxyl i.~ preferah].y at lea~t partial].y dissolved in a solvent, such as methylene chloride or pyridine, and khen chlorinated ~y reaction with thionyl chloride. Preferably, the thionyl chloride is employed in about a 10 ~ stoichio-metric excess. The reaction is mildly exokhermic and can be carried out with additional heating.until substantially complete as evidenced by cessation in evolution of sulfur dioxide and hydrogen chloride. The resulting halide can be recovered and purified using conventional techniques..
If a compound of formula (II) in which Y is a hydroxyl group is reacted with an appropriate alkyl or aryl sulfonyl chloride or alkyl or aryl sulfonyl anhydride, it is possible to prepare compounds according to formula (II~
in which Y is R~SO3- as previously defined. ~or example, reackion of the hydroxy compound (II~ with an alkyl sulfonyl chloride, such as methane sulfon~l chloride, will yield a compound of formula (II) in which Y is an alkyl sulfonyl group. Similarly, reackion of ~he hydroxy compound (II) with phenyl sulfonyl chloride or anhydride, p-chlorophenyl ~ .

)'7796 " .

sulfonyl chloride or anhydride or p-toluene sulfonyl chloride or anhydride will yield the corresponding aryl sulfonates. These reactions can be carried out by employing well-knot~n conditions for reactiny hydroxy compounds with alkyl or aryl sulfonyl chlorides and an-hydrides to form the corresponding alkyl and aryl sulfonates. Typically, the hydroxy compound of formula ~II) in ethereal or hydrocarbon solvents can be reacted with alkyl or aryl sulfonyl chlorides or alkyl or aryl sulfonyl t0 anhydrides at a temperature of ab~ut -10DC to about 70C, preferably at a temperature of about 0~C to about 40C.
Compounds according to formula (II) in which Y is OH
-N-CH3 can be prepared by quenching the dilithio inter-mediate of formula ~V) with an appropriate nitrone. Moreparticularly, the temperature of addition of the nitrone can range from about 78C to about 35C, preferably from about 0 to about 25C. The mixture is aged for a period of about 5 minutes to about one hour. The amount of nitrone employed is from about one to about 2 molar equivalents based on the dilithio intermediate of formula (IV~. In a preferred method according to the invention, the dilithio interme~iate of formula (IV) is reacted with about a stoichiometric amount of ~-phenyl-N-methyl nitrone at about 0C to about 25~C. The quenching is ronveniently conducted at atmospheric pressure and in a substantially moisture-free, e.~., dry nitrogen, atmosphere. After agueous work up, the resulting compound can then be recovered and purified using conventional techniques.

3. The conversion of the intermediate of formula (II) into a 2-methylamino-substituted compound having the - foxmula (III) ~\~ NHCOR2 ~ ~ 3 (III) ~.3 .

~ ~2~79~
- 8 - HOE ~1/S 023 wherein R2 is -C(CH3)3 or -O-C~CH3)3 can be carried out as follows. ~hen the substituent Y in formula tII) is a hydrox~,l group, the compound is first converted to the corresponding halide or alkyl or aryl sulfonate as des-cribed abo~e. The halide or alkyl or aryl sulfonate isreacted with monomethyl amine. The r~action can be carried out in a solvent9 such as 2-propanol, at a temperature of about 80 to about 120C~ The reaction can be conducted for about 1 to about 12 hours at a pressure oE about 1 bar to about 6.8 bar. The amount of monomethyl amine will typically be about 1 to about 10 molar equivalents based on the halide or sulfonate of formula (IIJ. A large excess of monomethylamine is preferably employed to ensure substantially complete conversion to the 2-methylamine-substituted compound of formula (III3. OH
When the substituent Y in formula (II) is -N-CH3, the 2-methylamine-substituted compound of formula (III) can be prepared by reduction of an N-methyl hydroxylamine of formula (II) with a noble metal catalyst, such as platinum or palladium. For example, an N-methyl hydroxyl-amine of formula (II) can be reacted in methanol and in the presence of hydrogen gas with a palladium on carbon catalyst. The reaction can generally be carried out at about room temperature and atmospheric pressure until substantially complete. The reaction time will typically be about one hour .
An alternate method of preparing the compound of formula (II) via alkyl and aryl sulfonates is as follo~s.
The dilithio intermediate of ormula (V) is quenched with benzaldehyde as described in stage 2 above. Instead of ~orking up the reaction mixture in aqueous phase at the end of the reaction, an alkyl or aryl sulfonic anhydride is added to the reaction mixture. For example, about 1 to about 2 equivalents of methane sulfonic anhydride can be added to the reaction mixture. The resulting reaction is carried out at about 0 to about 20~C until substantially .

7~6 - ~ - HOE 81/S ~23 complete, which will typically be about 30 minutes to about 1 hour. An alkyl or aryl sulfonate intermediate is formed~ which can be converted to the compound of formula (III) by reaction with monomethyl amine. More particularly, monomethyl amine can be bubbled into the xeaction mixture containing the sulfonate intermediate. The amine should be added slowly to avoid side reactions Typicallyl about 3 to about 5 equivalents of monomethyl amine are added during the course of the reaction. The reaction can be carried out at about 0~ to about ~0~C, preferably at about 0 to about 20C, until complete, typically for about 1 to about 2 hours. The compound of formula (III) can then be recovered from the reaction mixture and purified usin~ con-ventional techniques.

4. The compound of formula (III) is then hydrolyzed to provide an N~methyl-2-amin~-~-phenylphenethylamine as a free base of the formula ~ 'H2 ~ ~ IHCH3 (VI) ~ .

or as its salt, e.g., dihydrochloride. The aromatic amine of formula (VI) is the immediate precursor of the 4-phenyl-1,3-benzodiazepins of formula (I). Thus, it will be understood that the salts of the compound of formula (VI) can be general be the same as the salts of the compounds of formula (I).
In one methodl the compound of formula (III~ is reacted with about 2 molar equivalents of a strong mineral acid, such as hydrochloric acid, hydrobromic acid or sulfuric acid. 6 N hydrochloric acid is the acid of choice. The reaction is conveniently conducted at atmospheric ~2~7~6 ~ - 10 - HOE 81/S 023 - pressure and at a temperature of from about 70~ to the reflux temperature of the solvent employed in the reaction for a period of about 12 to about 48 hours to provide a diacid salt, which can then be recrystallized. A solvent, such as ether or an aromatic solvent, is emp]oyed to remove any side products while retaining the diacid salt in aqueous phase. If desired, the diacid salt can be basified to provide the free base.

5. The aromatic amine of formula (VI) in free base or salt form can be cyclized with a compound of the formula 2 5I CH3l C H o-f-CH or CH30-C-CH3 C2H50 ~H30 (VII) ~VIII~
to provide the 4-phenyl-1,3-ben70dia7epins of formula (I~.
This cyclization can be carried out in the presence of an acid catalyst, such as ethanolic hydrochloric acid.
Alternatively, the monoacid or diacid salt of the compound of formula (VI) can be cyclized with a compound of formula (VII) or formula (VIII) in a polar solvent, such as aceto-nitrile or acetic acid. Use of acetonitrile makes it unnecessary to add an acid catalyst to the reaction mixture.
The reaction can be conducted at a temperature of from about 25~C to the reflux temperature of the reaction mi~ture and at atmospheric pressure for at least about 1 hour, typically about 1 to about 8 hours. About 1 to about 5 molar equivalents, preferably about 2 molar equivalents, of the compound of formula (VII) or formula ~VIII~ ~re empl oyed.
The invention is described in greater detail in the following examples in which all parts,proportions, ratios and percentages are by weig~t unless otherwise indicated.

~ ~077~96 ~ HOE 81/S 023 Example 1 - Synthesis ~f trimethylacetyl ~hloride A solution of trimethylacetic acid (20q.3 g, 2.0 mol) in methylene chloride (400 ml) containing a catalytic amount of DMF (0.5 g) was stirred under a dry nitrogen atmosphere and treated with SOCl2(258 g, 2.06 mol~.
Following the addition of SOCl2 (about 5 minutes) the reaction tempexature dropped from 21C to 13C; at the same time, a vigorous evolution of HCl and SO2 occurred.
After 5 hours, the reaction was heated to reflux and maintained at this temperature for 2 hours. At this time, the conversion of trimethylacetic acid to trimethylacetyl chloride was quantitative. The crude product, without concentration or distillation, can be employed directly in the synthesis of N-/ (~methyl)phenyl 7- 2~2-dimethyl propanamide.
xample 2 - Synthesis of N-/ (2-methyl)phenyl 7-- 2,2-dimethyl propanamide ~a) ~ ~ipha~ic solution of o-toluidine (1Q7.2 g, 1.0 mol) in methylene chloride ~500 ml~ and water (150 ml~
containing sodium carbonate (69 g, 0.65 mol) was treated ~ith trimethylacetyl chloride (120.6 g, 1.0 mol). The rate of addition of trimethylacetyl chloride was adjusted so as to maintain the reaction at ~entle reflux. After 45 minutes the addition was complete. The organic layer was separated, washed with water, and concentrated in vacuo.
The crude N-/ (2-methyl~phenyl_7-2,2~dimethylpropanamide was slurried in 2 % aqueous HCl, filtered and washed with H2O until the filtrate was neutral. After drying in vacuo (50C, 20 mm), N-/ (2-methyl3phenyl_7-2,2-dimethylpropan-30 amide (178 g, 0.93 mol) was obtained in 93 ~ yield (m.p.
109 110C).
~` (b) A biphasic solution of o-toluidine (214.4 g, 2.0 mol~ in methylene chloride (200 ml) and water (250 ml) containing sodium carbonate (117 g, 1.1 ~ol) was treated with trimethylacetyl chloride (about 2.0 mol in methylene chloride from Example 1). The addition of trimethylacetyl chloride was complete after 50 minutes; the temperature . .

7~6 - ~2 - HOE 81/S 023 ranged between 37-50C during the addition. The ~7arm organic phase was separaied and the aqueous phase was extracted with methylene chloride ~2 x 100 ml). The combined methylene chloride solution was wasl-ea with 1N
~Cl (2 x 100 ml~, H2O (3 x 200 ml), 10 % NaCl (100 ml3, and concentrated in vacuo ( 25C at 30 mm) to give free flowing crystalline N-/ ~2-methyl)phenyl_7-2,2-dimethyl-propanamide. ~inal dryiny tat 60C, 30 mm, 24 hours) gave N-/ (2-methyl)phenyl_7-2,2-dimethylpropanamide (379 g, 1.98 mol) in 99 ~ yield. The melting point of the product was 108~ C. This product can be used directly in Example 3 without recrystallization.
Example 3 - Synthesis of N-12-(2-hydroxy 2-phenyl-ethyl~-phenyl]-2,2-dimethylpropanamide A stirred solution of N-1(2-methyl)phenyl]-2,2-dimethyl-propanamide ~95.6 g, 0.5 mol) in THF (500 ml) was cooled to GC and treated with 1.6M n-butyllithium in hexane (628 ml, 0.1 mol). The addition of n-butyllithium was complete after 45 minutes. During the addition, the tempe-rature of the mixture was maintained below 10C with external cooling. The resultant dianion solution was aged for 2 hours at 0C until the homogeneous orange solution became a yellow heterogeneous slurry. The dianion was then quenched with benzaldehyde (63.6 g, 0.6 mol) and aged for 15 minutes at about 24 C. The reaction mixture was diluted with ether (200 ml), treated with crushed ice (200 g), and stirred for 5 minutes. The organic phase was separated, washed with saturated sodium chloride (250 ml)l dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residual oil was crystallizea from hexane, filtered and recrystallized from dichloromethane 1500 ml reflux) to give N-~2-(2-hydroxy-2-phenylethyl)-phenyl]~
2,2-dimethylpropanamide (87 g, 0.29 mol) in 58 % yield.
The product had a melting point of 183 to 184C.
Example 4 - Synthesis of N-[2-(2-chloro-2-phenylethyl) phenyl~-2,2-dimethylpropanamide N-[2-(2-hydroxy-2-phenylethyl~phenyl~-2,2-dimethyl-.

propanamide (29.74 g, 0.1 mol) was partially dissolved in dichloromethane (120 ml)~ Thionyl chloride (12.69 g, 0.11 mol, 1.1 equiv.) was added over a 3-minute period to the resulting mixture. A substantially homogeneous solution formed with moderate evolution of hydrogen chloride and sulfur dioxide. The reaction mixture was maintained below 27~C~ When ~volution of gas ceased, the reaction mixture was worked up by washing the mixture with saturated sodium bicarbonate solution until the aqueous phase remained neutral ~pH = 6.5 to 7). The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo ti give 31.89 g of product. The product was purified by silica gel chromatography (CH2C12/hexane, 50:50, followed by CH2C12) to give a guantitative yield of an off-white crystalline product having a melting point of 87~-~2C.
Example ~ - Synthesis of N-~2-~2-methylamino-2-phenylethyl)-phenyl]-2,2-dimethylpropanamide N-12-(2-chloro-2-phenylethyl)phenyl]-2,2-dimethyl-propanamide (1.0 g, 3.17 mol) was reacted with monomethyl amine (7 g of ~0 ~ aqueous solution) in 2-propanol (3 ~).
The mixture was heated to 80C and stirred for 1 hour.
~ormation of product was indicated by TLC ~silica gelJ
70 ethyl acetate/30 methanol).
Example 6 Synthesis of N-methyl-2-amino-c-phenyl-phenethylamine dihydrochloride (a) N-[2-12-methylamino-2-phenylethyl-phenyl]-2,2-dimethyl-propanamide (62 g, 0.2 mol) was dissolved in 5 N
HCl (124 g) and stirred under a nitrogen atmosphere at 100C for 24 hours. The warm reaction mixture (about 35-40C~ was extracted with toluene (2 x 100 ml) to effect recovery of trimethylacetic acid. The aqueous phase was dried by azeotropic distillation with toluene (200 ml) using a Dean-Stark phase separator. The product was collec-ted by filtration, slurried in hot 2-propanol (200 ml), . . .

779~

refiltered and dried in vacuo t30 mm) at 45C for 12 hours to give N-methyl-2-amino-~-phenylphenethylamine di-hydrochloride (58.7 g, 0.196 mol) in 9~ ~ yield. The product had a melting point of 251-253C.
(b) N-[2-(2-methylamino~2-phenylethyl)phenyl]-2,2-dimethyl-propanamide (155 g, 0.5 mol) was dissolved in

6 N HCl (310 g) and stirred under a nitro~en atmosphere at 100C for 28 hours. The reaction mixture was cooled to 23C and toluene (200 ml) was added. Stirring was continued until the proauct had crystallized from the aqueous phase. The product was collected by filtration, washed with toluene (2 x 50 ml~ and dried in vacuo (30 mm) at 60C for 50 hours to give N-methyl-2-amino-~.-phenylphellethyl-amine dihydrochloride (139 g, 93 % yield). The melting point of the product was 252-254C. The organic phase of the filtrate was concentrated in vacuo ti give a 58 ~
recovery of trimethylacetic acid. The aqueous phase of the filtrate afford2d a seeond crop oL N-rn~hyl-2-alnino-~-phenylphenethylamine dihydrochloride (9.3 g, 6 %~. The total yield of product was 99 %.
Example 7 - Synthesis of 2,3-dimethyl-4-3H-1,3-benzodiazepin hydrochloride A heterogene~us mixture of N-methyl-2-amino-~-phenyl-phenethylamine dihydrochloride (150 g, 0.5 mol) in aceto-nitrile (500 ml; was treated with triethylorthoacetate (202 ml, 1.1 mol) and heated to 70C for 2 hours with stirring under a dry nitrogen atmosphere. The reaction mix-ture was filtered, concentrated in vacuo, and the residual solid recrystallized from 2-propanol at -10C to give 30 2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepin hydrochloride (118 g, 0.413 mol) in 83 % yield. The product had a melting point of 239.5-241C.
Example_8 - Synthesis of 2,3-dimethyl-4 phenyl-3H-1,3-benzodiazepin (~ree base) 3S A heterogeneous mixture of the dihydrochloride salt of N-ethyl-2-amino-~-phenylphenethylamine (9 g, 0.03 molJ

. . .

77~6 - 15 - HOE_81/S 023 in acetonitrile (36 cc dried over 4 ~ molecular sieves3 was treated with triethylorthoacetate (g.73 g, 11 cc, O b 06 mol) and heated to 70C with stirring under a dry nitrogen atmosphere. At 50~C (after about 15 minutes of heating) the reaction mixture became homogeneous. ~he reaction reaction mixture was concentra~ed in vacuo and partitioned between 100 ml toluene and 50 ml 5 ~ NaOH.
The toluene phase was washed with 10 ~ NaCl, dried over sodium sulfate, filtered and concentrated in vacuo ti give a light yellow-bro~ solid product, which was shown by GC
to be 96.7 ~ 2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepin.
This crude product free base was r~crystallized from 15 ml 2-propanol at 82C, diluted with 30 ml hexane and dried at 45C (30 mm -Eor 12 hours). 4.64 g 10.0185 mol) of product with a melting point of 144.5-145.4C were obtained at a yield of 61.8 %. A second crop was re-crystallized from 5 ml 2-propanol, washed with 3 ml hexane and dried at 40C (30 mm for 12 hours). 1.92 g (0.0077 mol) of product with a melting point of 143.5-144.5C were 2Q obtained at a yield of 25.6 %. The mother liquor (0.64 g~
from the first crop contained 0.24 g of product representing a yield of 3.2 %.
Example 9 - Conversion of 2,3-dimethyl-4-phenyl-3H~
1,3-benzodiazepin ~free base) to hydro-chloride salt 1.9 g 50.0759 mol) of the free base 2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepin was dissolved in 2-propanol and treated at 5-10C with an excess of 2-propanol saturated with anhydrous HCl. The monohydrochloride salt of the 2/3-dimethyl-4-phenyl-3H-1,3-benzodiazepin was recrystallized from solution and recovered by filtration.
The monohydrochloride salt had a melting point of 241-242C. The salt was dxied ~60C, 30 mm, 24 hours) to yield 1.50 g of a white crystalline powder.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of an N-methyl-2-amino-?-phenylphenethylamine of the formula VI

VI

in which a compound of the formula III

III

wherein R2 is -C(CH3)3 or -OC(CH3)3 is hydrolyzed.