JPH0367066B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Background of the Invention The present invention provides 5-methyl-10,11-dihydro-
5H-dibenzo-[a,d]cycloheptene-5,
A new method for producing 10-imine and anxiolytic, antidepressant, anticonvulsant,
It relates to pharmaceutically acceptable salts thereof useful as muscle relaxants and in the treatment of anxiety suppression, minimal brain dysfunction and extrapyramidal mixed diseases such as Parkinson's disease. The product of the novel process of the invention, 5-methyl-10,11-dihydro-5-dibenzo-[a,d]
Cyclohepten-5-10-imine and its enantiomers are well known in the art, eg, Christy et al.
J.Org.Chem. 44 , 3117-3127 (1979), South African Patent No. 78/5291 and corresponding West German Patent Publication No. 2840786. The best method known for the synthesis of this racemate is 5H-dibenzo[a,d]cyclohepten-
It consists of nine steps starting from 5-one, with an overall yield of about 23%. Another method, disclosed in European Patent Application Publication No. 0019866, involves the preparation of the compound in five steps, with an overall yield of 4% of theory. Now, according to the present invention, 5H-dibenzo[a,d]
Cyclohepten-5-one provides a process in four steps with an overall yield of about 64%. DETAILED DESCRIPTION OF THE INVENTION The new method of the present invention is described in flow sheet 1 below.
is displayed. In the formula, R is -OR ¹ and R ¹ is hydrogen or C _1-3 alkyl, or -NR ² R ³ , where R ² and R ³
are each independently hydrogen, C _1-3 alkyl, C _2-3 alkanoyl, or benzenoid aroyl such as benzoyl or toluyl. Alternatively, R ² and R ³ are taken together to form tetramethylene or pentamethylene. R is -OH, _-OCH3 , _-NH2 , -NH _{- COC6H5}
is preferable, and -OH is more preferable. Another method of synthesis is presented in Flow Sheet 2 below. Reagents and Conditions Steps A ₁ and A ₂ are Grignard reactions using methylmagnesium halide, preferably bromide, and are carried out in ethereal solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane. Reaction at -50℃
to about +50°C, preferably about 15-25°C, until the reaction is substantially complete (about 1-2 hours). about 24
Aging of the reactants for too long, even up to an hour, is detrimental. Formation of step B ₁ and B ₂ -substituted amino compound 3 is performed using a mixture of substituted amines and a medium strength organic acid such as dichloroacetic acid, difluoroacetic acid, etc., or mixtures thereof, or in the case of step B ₂ is a strong organic acid, such as trifluoroacetic acid, in an inert organic solvent of a chlorinated C _1-3 alkane (e.g. methylene chloride, 1,2-dichloroethane, chloroform, etc.) using carbinol 2 at about -20 to +50℃, preferably about 15℃
Process at -25°C until the reaction is substantially complete. Steps C ₁ and D ₂ cyclization are carried out in a benzenoid aromatic solvent such as toluene, benzene, dimethylformamide, dimethyl sulfoxide or mixtures thereof, from about 0° to about
By adding the substituted amino compound to an alkali metal halide, amide or alkoxide, especially a strong base such as potassium t-butoxide, at 190°C, preferably about 50° to 125°C, the reaction is substantially complete. Have them do it until they do it. The reaction may be allowed to proceed for about 20 hours or more. Alternatively, for step _C1 , the cyclization is carried out without a strong base in the same solvent as described above, simply by heating the substituted amino compound to a temperature of about 100° or more until ring closure is substantially complete (about 10 to 20°C). time) by heating. Preferably, the cyclization is carried out under an inert atmosphere, such as under nitrogen. Steps _D1 and _C2 are carried out in acetic acid or ethanol, or a mixed solvent thereof, with or without strong mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., at about 20-100°C, preferably about 60°C. ,
Noble metal catalysts (e.g. palladium on carbon, platinum on carbon,
Platinum oxide, Raney nickel, etc., preferably 5%
of the N-R group by catalytic hydrogenation using palladium on carbon). Hydrogenation continues until hydrogen uptake is substantially slowed and consumption is approximately at the theoretical value. The products resulting from the new process of the present invention are racemic mixtures of optically active acids (e.g. (-)-di-
p-Toluoyl-d-tartaric acid and/or (+)-
can be resolved into the corresponding enantiomers by standard techniques such as diastereomeric salt formation with di-p-toluoyl-l-tartaric acid) followed by fractional crystallization and regeneration of the free base. It is. The product according to the novel process of the present invention and its dextrorotary enantiomer can be used in amounts ranging from 0.01 to about 20 mg/kg body weight;
Preferably, dosage levels of about 0.05-2 mg/kg body weight, 1-4 times per day, provide relief from anxiety without causing excessive sedation or sleep. Furthermore, the products and dextrorotatory enantiomers of the process of the invention can be used as anti-depressants, muscle relaxants, anti-convulsants, and, where indicated, as anti-anxiety agents,
Comparable doses are useful in the treatment of complex diseases with minimal brain dysfunction and extrapyramidal dysfunction (eg, Parkinson's disease). It should be noted that the exact therapeutic dose will depend on the medical history of the individual animal or human being treated, and that the exact dose that falls within the above-mentioned index values in the final analysis is left to the judgment of the physician. be understood. Example 1 Step A 5-Methyl-5H-dibenzo[a,d]cyclohepten-5-ol (2) Table: (Ti5
-10°C) 5.96 mol (2.28 mol in diethyl ether, 711 g) of methylmagnesium bromide are added. Then 875.5 g in 2.37 dry THF
(4.25 mol) of “trienone” was added to the above mixture over a period of 1.75 hours, during which time the temperature
Keep at 15-20℃. The temperature of the reaction mixture is allowed to return to room temperature and then stirred overnight. Cool the reaction mixture and add 5.0 moles of ammonium chloride (954 g, 17.85
Slowly add an aqueous solution of mol). Separate the organic layer, add NaCl to the aqueous layer and wash three times with 1.8 ml of ethyl acetate. The organic layers are combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to approximately 1.75 (slurry). to this
Add 0.25 ml of ethyl acetate and warm to dissolve all solids. The solution is then cooled to below 50° C. and 10 portions of hexane are added in portions to form a white fluffy precipitate. This is further cooled (0 to 5°C) for about 1/2 hour. Filter this precipitate with 2 x 1 cold hexane (0-5 °C).
Washing with water and air drying at 50-55°C yields 783 g (83%) of 2 as a white crystalline solid, mp 113.5-115°C. Step B 2-Methyl-5-hydroxyamino-5H-dibenzo[a,d]cycloheptene (3) [Table] A mixture of 0.138 CH ₂ Cl ₂ and 0.138 (1.617 mol) dichloroacetic acid was cooled (Ti20°C). while adding 88.61 g (1.081 mol) of sodium acetate. After the sodium acetate has dissolved, 75.11g
(1.081 mol) of hydroxyamine hydrochloride is added. The slurry was stirred at room temperature for 1.5 hours and then 1.362
of CH ₂ Cl ₂ is added over about 10 minutes. The reaction mixture is then stirred for a further 1.5 hours.
A solution of 60.0 g (0.270 mol) of alcohol 2 in 0.600 CH ₂ Cl ₂ is added to the above reaction over a period of 10 minutes. The reaction is complete after about 0.5 hours. This reaction was carried out in 0.9 g of ice water and 0.3 g.
Stop with _NH4OH (PH~8). After stirring, the separated aqueous layer was washed with 1 x 0.4 _CH2Cl2 , the organic layers _were combined and washed with 1 x 0.8 brine,
Dry _{with Na2SO4} . The reaction mixture is filtered and concentrated under reduced pressure to approximately 0.10. Add 1.1 hexane to this little by little while stirring to form a white precipitate. Cool this for 1 hour (from 0 to 5
0.15 °C), 0.15 °C cold hexane (0 to 5 °C)
Washing with water and air drying at room temperature yields 54.8 g (86%) of 3, a white crystalline solid, which is stored below 0°C. Melting point 130-133℃. By using a method substantially as described in Example 1, Step B, and substituting an equimolar amount of an amine of formula NH ₂ R as defined in the table for the hydroxyamine hydrochloride used therein, the following reaction scheme is prepared: According to the table, 5-methyl-5-(R
-amino)-5H-dibenzo[a,d]cycloheptene is obtained. [Table] Step C 12-Hydroxy-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-
5,11-Imine (4) [Table] A mixture of 50 ml of 10% DMSO/toluene (sieve dried, v/v) and 4.76 g (0.0422 mol) of potassium t-butoxide was heated to 55°C and
10.00 g in ml 10% DMSO/Toluene (0.0422
5 mol) of hydroxyamine solution and
Rinse with ml of toluene. Three minutes after the addition was complete, heating the reaction mixture was stopped and the 50
Add ml of water. Continue stirring the reaction mixture until it reaches room temperature. Separate the aqueous layer, backwash with 20 ml of toluene, and add 5 ml of saline. Wash the organic layer with 3 x 50 ml of water and 1 x 50 ml of brine. These wash solutions and saline solutions are backwashed with 20 ml of toluene. Add another 5 ml of saline to this aqueous layer. Combine the two organic layers, let stand (if any brine remains, separate at this time), and add 1:1 1.2M HCl.
Wash with 3 x 33.3 ml of glacial acetic acid solution (volume/volume). The acid layers are combined, 1.0 g of decolorizing activated carbon is added and the mixture is stirred for 0.5 hour at room temperature. After evaporation, this mixture is used for the next hydrolysis. By making the concentrated acid layer basic (NH ₄ OH), extracting (CH ₂ Cl ₂ ) and crystallizing using a minimum amount of CH ₂ Cl ₂ and hexane (1:8 ratio).
The crystallized ring-closed hydroxyamine 5 is isolated at this point. This substance 12-hydroxy-5-methyl-5H-10,11-dihydro[a,d]
Cycloheptene-5,11-imine (5) exists as two isomers, the combined melting point of which is 138-141°C. Using substantially the same method as described in Example 1, Step C, in place of the 5-methyl-5-hydroxyamino-5H-dibenzo[a,d]cycloheptene used therein, the 5-methyl- 5-(R
By using equimolar amounts of -amino)-5H-dibenzo[a,d]cycloheptene, the following reaction scheme Accordingly, 12-R-5-methyl-10,11-dihydro-5H-dibenzo[a,
d]-cyclohepten-5,10-imine is obtained. [Table] Alternative method Step C 12-Hydroxy-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-
5,10-imine (4) Materials: 5-Methyl-5-hydroxamino-5H-dibenzo[a,d]cycloheptene (3) 2.37g 0.01 mol toluene 200ml A mixture of hydroxamino compound and toluene
Reflux for an hour. The mixture is concentrated in vacuo to 90 ml and extracted with 3 x 50 ml of 2NHCl. extract
Adjust the pH to 10 with NH ₄ OH and extract with 90 ml of CH ₂ Cl ₂ . The extract is dried over Na ₂ SO ₄ , filtered and concentrated to dryness to obtain the desired compound in about 60% yield. Step D ()-5-methyl-10,11-dihydro-5H-
Dibenzo[a,d]cyclopenteno-5,10-imine [Table] 10.00g of ring-closed hydroxylamine 4
(0.0422 mol, based on 100% yield in the previous step) and 1.0 g of decolorizing activated carbon in 100 ml of 1:1 (volume/100 ml)
(volume) in 1.2M HCl/glacial acetic acid and filtered through diatomaceous earth into a 250ml Parr bottle. Rinse the cake with about 15-25 ml of HCl/glacial acetic acid mixture, bringing the total volume of reaction solution to 120 ml. Add 5.4 g (0.061 mol) of sodium acetate and 1.0 g of 5% palladium on carbon to this solution while warming. The mixture is shaken on a Parr apparatus at 60° C. until the rate of hydrogen absorption decreases appreciably. After approximately 3.25 hours, the reaction was degassed with N ₂ , filtered through diatomaceous earth, and diluted with 25 ml of 1:1 (vol/vol) 1.2 mol.
Rinse with HCl/glacial acetic acid. The reaction mass was reduced to 1/2 of its original volume under reduced pressure, 100 ml of ice was added, and the mixture was made alkaline (PH=
8) and add this alkaline solution to 3 x 50 ml of
Extract _{with CH2Cl2} . The organic layers are combined, washed with 1×50 ml of brine, dried over Na ₂ SO ₄ , filtered, and the solution is concentrated under reduced pressure to yield 8.4 g (90%) of 5 as a yellow oil. If left alone, it will crystallize. Melting point 77-85℃. Substantially the same method as described in Example 1, Step D was employed and the 12-hydroxy-
5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine was replaced with an equimolar amount of 12-R-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine. a, d] cyclohepten-5,10-imine (wherein R is -NH ₂ , -
OCH ₃ and −NHCOC ₆ H ₅ ), the following reaction scheme Accordingly, 5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine is obtained in essentially the same yield as the compound obtained previously. Using substantially the same method as described in Steps A through D of Example 1, by substituting an equimolar amount of an amine of formula NH ₂ R for the hydroxylamine used in Step B, the following intermediates are prepared in the procedure. 5-Methyl-5-(R-amino)-5H-dibenzo[a,d]cycloheptene (3) , 12-R-5-methyl-10,11-dihydro-5H-dibenzo[a,
d]cyclohepten-5,11-imine (4) , and finally 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine
(Five). In the formula, R is -OC ₃ H ₇ -n -NH-C ₂ H ₅ -NH _{- COC2H5 -} NH- _{COC6H4CH3 .} Example 2 Step A 5-Methyl-5H-dibenzo[a,d]cyclohepten-5-ol (2) See Example 1, Step A. Step B 5-Methyl-5-azido-5H-dibenzo[a,
d] Cycloheptene (6) Carbinol (1) 10.0 g 4.5 x 10 ^-2 mol NaN ₃ 11.6 g 1.78 x 10 ^5-1 mol CF ₃ CO ₂ H 18.0 ml 2.11 x 10 ^-1 mol 0.25 CH ₂ under nitrogen 11.6g in _Cl2 (1.78×
10 ^-1 mol) of NaN ₃ is placed in a three-necked flask.
While cooling (0℃) add 18.0ml (2.11×10 ^-1
molar) of CF ₃ CO ₂ H are added over 5 minutes.
The reaction was stirred at room temperature for 10 min, and 0.1
10.0 g (4.5 × 10 ^-2 moles) of carbinol in CH ₂ Cl ₂
(for 15 minutes). After 40 minutes 0.100 ice water and 25
Add ml of concentrated NH ₄ OH (PH>8) and stir the reaction for 10 minutes. Separate the organic layer and divide the aqueous layer into 1 x 30 ml
Extract _{with CH2Cl2} . The organic layers are combined, washed with 1 x 100 ml of brine, dried over MgSO ₄ and the solvent removed under reduced pressure to yield 11.0 g of crystalline product, 6 (97%). Melting point 65.5℃-67℃ 1 HNMR (CDCl ₃ ) δ1.90 (s, 3H, CH ₃ ),
6.95 (s, 2H, HC=CH) and 7.00-7.80 (m,
8H, Ar) IR (CDCl ₃ ) 2125 cm ^-1 (N ₃ ) Step C 5-Methyl-5-amino-5H-dibenzo[a,
d] Cycloheptene, (7) azide (6) 7.0 g 2.83 x 10 ^-2 mol PtO ₂ 1.4 g absolute ethanol 210 ml 7.0 g dissolved in 0.21 molar absolute ethanol
(2.83 x 10 ^-2 mol) of 6 was added with 1.4 g of PtO ₂ and placed on a Parshaker under 5 psi of hydrogen at room temperature overnight. The reaction mixture was filtered through Celite,
Remove the solvent from the solution. 50ml of the generated oil
Dissolve in CH ₂ Cl ₂ and extract with 3 x 25 ml of 10% HCl. The aqueous layers are combined, made alkaline with concentrated NH ₄ OH and extracted with 3×25 ml of CH ₂ Cl ₂ . The organic layers are combined, dried over MgSO ₄ and the solvent removed to give the desired amine 7 in 3.85 g (62% yield). 1 HNMR (CDCl ₃ ) 1.77 (s, 3H, CH ₃ ), 2.10
(s, 2H, replaced by NH ₂ D ₂ O), 7.00 (s, 2H,
HC=CH) and 7.05-7.75 (m, 8H, Ar) IR (neat) 3300-3400 (wide _NH2 ), 1580, 1430,
1475cm ^-1 Step D (±)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (5) Amine (7) 0.5g 2.26×10 ^-3 molKO t Bu 0.26g 2.26×10 ^-3 mol DMSO 5.0ml KO of 0.26g (2.26×10 ^-3 mol) under _N2
t-Bu was dissolved in sieve-dried DMSO,
Heat to 75°C. To this is added dropwise 0.5 g (2.26 x 10 ^-3 mol) of amine 7 dissolved in 2.5 ml of DMSO. Heat the reaction to 125°C for approximately 18 hours. Bring the reaction to room temperature, add 10 ml of H ₂ O, 10 ml of ethyl acetate, and stir while exposing the reaction to air.
Separate the aqueous layer and backwash with 5 ml of ethyl acetate. Wash the first ethyl acetate layer with 2 x 10 ml of _H2O . The ethyl acetate backwash was then extracted twice with 10 ml each of this water. Both organic layers were combined, washed with 1 x 10 ml of brine, dried with _MgSO4 , and the solvent removed to yield 0.4
g of 5 is obtained with a yield of 80%. Optical resolution Preparation of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclopentene-5,10-imine di-p-toluoyl- l -tartaric acid and acetone [Table] Cyclic amine 5 (284.4 g, 1.29 mol) in 402 ml of acetone, filtered through a medium glass filter, and heated with a
into a three-necked flask. A solution of 519 g (1.28 moles) of the split acid in about 600 ml of warm acetone is filtered into another similar flask and an additional 60 ml of acetone is used to rinse the glass filter. Warm the amine solution to 40°C and quickly add the splitting acid solution while stirring (approximately 40°C for Ti).
Add the seeds to this solution, return to room temperature, and leave overnight while stirring. The mixture was filtered and the white fine crystalline product was washed with 4 x 200 ml of cold acetone (10°C) at 55°C.
Air drying yields 331 g (0.497 mol; 39%) of the diastereomeric salt. [α] ²⁵ _D = +
127.7°, (C=1, absolute ethanol). A solution of 330 g of this concentrated salt in 3.0 methylene chloride is added to 6.0 1:3 concentrated ammonium hydroxide/water (v/v) and stirred. _{CH2Cl2 _}
Separate the layers and dilute the basic aqueous layer with 2 x 1.5 CH ₂ Cl ₂
Extract with Combine the organic layers, dry with _MgSO4 ,
Filter and concentrate to a viscous oil (119.6 g). This viscous oil is dissolved in 254 ml of acetone and strained into a three-necked flask as described above and rinsed with 208 ml of acetone. 200.7g dissolved in 254ml acetone
A solution of (0.497 mol) of the split acid is filtered as described above, rinsed with 208 ml of acetone and added to the amine solution at 42-43°C. Add the seeds to the reaction mixture, return to room temperature, and leave overnight with stirring. Filter out the white precipitate,
× Wash with 100ml of cold acetone (10℃),
Air drying at 60°C yields 294.2 g (89%) of crystalline salt. Melting point 137-138℃ (decomposition); [α] ²⁵ _D
= +132.2° (C=1, absolute ethanol). Preparation of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate [Table] [Table] Add 293 g (0.44 mol) of amine salt. Dissolve in 2.7 parts of CH ₂ Cl ₂ and add 5.2 parts of 1:3 concentrated ammonium hydroxide/water. Separate the alkaline aqueous layer and 2x
Wash with 1.35 _mL of _CH2Cl2 , combine the organic layers, and add _MgSO4.
Dry, filter, and concentrate under reduced pressure to a viscous oil (105 g). This viscous oil was dissolved in 282 ml of absolute ethanol, filtered through a medium glass filter, placed in two three-necked flasks equipped with a mechanical stirrer and a thermometer, and filtered with 145 ml of absolute ethanol. Rinse. 51.07g dissolved in 141ml absolute ethanol
A solution of maleic acid (0.44 mol) was filtered as described above, rinsed with 78 ml of absolute ethanol, and rapidly warmed with stirring to an amine solution (44 mol) of maleic acid.
℃). Stir the reaction mixture for 10 minutes (Ti 47°C), add the seeds, and stir gently overnight at room temperature. Filter the white precipitate, wash with 4 x 100 ml of cold absolute ethanol (5°C) and dry in vacuo at 50-60°C.
129.1g (87%) of crystalline (+)-5-methyl-
10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate is obtained. Melting point 205.5-206.5℃ (decomposition). Measured optical rotation [α] ²⁵ _D = +114.7 (C=1, methanol).

Claims (1)

[Claims] 1 (a) Structural formula compound in an ethereal solvent from -50 to +50℃
By reacting with methylmagnesium halide, the structural formula (b) reacting 2 with a substituted amine of formula NH ₂ -R and a medium strength organic acid in a chlorinated C _1-3 alkane at -20 to +50°C; Structural formula to produce a substituted amino compound (wherein R is -
OR ¹ , R ¹ is hydrogen or C _1-3 alkyl, or R is -NR ² R ³ , in which case R ² and R ³ are each independently hydrogen, C _1-3 alkyl, C _{2- 3} alkanoyl or benzenoid aroyl;
Or R ₂ and R ₃ together form tetramethylene or pentamethylene. ), (c) 3 is reacted with a strong base in a benzenoid aromatic solvent, dimethyl sulfoxide, dimethyl formamide or their solvents at a temperature of 0° to 190°C, or in the above-mentioned solvents without a strong base. , 100
The structural formula is obtained by heating above ℃. and (d) reacting with hydrogen in a solvent in the presence of a noble metal catalyst. A method for producing a racemic compound. 2 (a) Structural formula By reacting a compound of formula NH ₂ -R with a substituted amine of formula NH 2 -R and a moderate strength organic acid in a chlorinated C _1-3 alkane at -20° to +50°C, a compound of structural formula to produce a substituted amino compound (wherein R is -
OR ¹ and R ¹ is hydrogen or C _1-3 alkyl, or R is -NR ² R ³ , where R ² and R ³ are independently hydrogen, C _1-3 alkyl, C _2-3 Alkanoyl or benzenoid aroyl, or R ² and R ³
together form tetramethylene or pentamethylene. ) (b) reacting 3 with a strong base in a benzenoid aromatic solvent, dimethylsulfoxide, dimethylformamide or mixtures thereof at 0° to 190°C;
Alternatively, by heating above 100° in the above solvent without using a strong base, the structural formula and (c) reacting hydrogen with 4 in the presence of a noble metal catalyst in a solvent. Claim 1 for producing a racemic compound of
The method described in section. 3 (a) Structural formula in a benzenoid aromatic solvent, dimethyl sulfoxide, dimethyl formamide, or a mixture thereof with a strong base at 0° to 190°C, or in the above solvent without a strong base.
By heating above 100°, the structural formula to prepare a compound (wherein R is ^-OR1 ,
R ¹ is hydrogen or C _1-3 alkyl, or R is -
NR ² R ³ , where R ² and R ³ are independently hydrogen, C _1-3 alkyl, C _2-3 alkanoyl or benzenoid aroyl, or R ² and R ³ taken together to form tetramethylene or pentamethylene. ), (b) Structural formula consisting of the step of reacting hydrogen with 4 in a solvent in the presence of a noble metal catalyst A method according to claim 1 for producing a racemic compound of 4 Structural formula (wherein R is -OR ¹ and R ¹ is hydrogen or C _1-3 alkyl, or R is -NR ² R ³ and R ² and R ³ are independently hydrogen, C _1-3 alkyl,
C _2-3 alkanoyl, or benzenoid aroyl, or R ² and R ³ taken together to form tetramethylene or pentamethylene) in a solvent,
Structural formula consisting of reaction with hydrogen in the presence of a noble metal catalyst A method according to claim 1 for producing a racemic compound of 5 R is -OH, _-OCH3 , _-NH2 or -
Claims 1, 2 and 3 which are NHCOC ₆ H ₅
or the method described in any of Section 4. 6 Claims 1, 2, where R is -OH
3. The method described in any one of paragraphs 3 and 4. 7 (a) Structural formula compound in an ethereal solvent from -50° to +50°C
By reacting with methylmagnesium halide in (b) 2 was reacted with sodium azide and an organic acid in a chlorinated C _1-3 alkane at −20 to +50°C to produce a carbinol of structural formula (c) 6 is reacted with hydrogen in a solvent in the presence of a noble metal catalyst to produce a compound of structural formula (d) reacting 7 with a strong base in a benzenoid aromatic solvent, dimethyl sulfoxide, dimethyl formamide or a mixture thereof at 0°C to 190°C; Structural formula A method for producing a racemic compound of 8 (a) Structural formula was reacted with an organic acid and sodium azide in a chlorinated C _1-3 alkane at −20° to +50°C to obtain the structural formula (b) 6 is reacted with hydrogen in a solvent in the presence of a noble metal catalyst to obtain the structural formula (c) reacting 7 with a strong base in a benzenoid aromatic solvent, dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof at 0°C to 190°C. A method according to claim 1 for producing a racemic compound of 9 (a) Structural formula The structural formula is obtained by reacting the compound with hydrogen in a solvent in the presence of a noble metal catalyst. (b) Structural formula is reacted with a strong base in a benzenoid aromatic solvent, dimethylformamide, dimethyl sulfoxide, or a mixture thereof at 0°C to 190°C. 8. A method according to claim 7 for producing a racemic compound of 10 Structural formula The structural formula consists of reacting the compound with a strong base in a benzenoid aromatic solvent, dimethyl sulfoxide, dimethyl formamide, or a mixture thereof at a temperature of 0° to 190°C. 8. A method according to claim 7 for producing a racemic compound of