CA1159826A - Dibenzo [a,d] cycloheptene derivatives and process for production thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel compounds, dibenzo[a,d]cycloheptene derivatives, of the general formula I

wherein Rl represents a hydrogen atom, a halogen atom or a lower alkyl group, R2 and R3 each represent a hydrogen atom or a lower alkyl group, and Z represents a group of the formula -?=CH- or -?-CH2-. These novel compounds are useful as non-steroidal anti-inflammatory agents free from gastrointestinal lesions. The compounds of formula I can be prepared, for example, by cyclizing a compound of the general formula II

wherein Rl and R2 are as defined above, X represents a hydroxyl group or a halogen atom, one Y represents a group of the formula -CH2COX and the other Y
represents a hydrogen atom; optionally hydrolyzing the cyclized product; and optionally esterifying the product, and/or etherifying its enol group.

Description

59~6 This invention relates to novel dibenzo[a,d]cyclohep-tene derivatives of the general formula 1 ~ CRCOOR3 wherein R1 represents a hydrogen atom, a halogen atom or a lower alkyl group, R2 and R3 each represent a hydrogen atom or a lower alkyl group, and Z represents a group of the formula -f=C~- or -C-C112-.

Many non-steroidal anti-inflammatory agents have been known in the past, but they cause side-effects such as gastrointestinal lesions.
It is an objec-t oE this invention therefore to provide non-steroidal anti-inflammatory agents free from such defects.
We have now found that the novel dibenzo[a,d]cycloheptene derivatives of general formula I have strong anti-inflammatory activity with very little gastrointestinal lesions.
The novel compound of general formula I can be prepared by cyclizing a compound of the general formula

- 2 -; ~ 1 159~26 ~,~3 ~ (II) wherein Rl and R2 are as defined above, X
represents a hydroxyl group or a halogen atom, one Y represents a group of the formula -CH2COX and the other Y represents a hydrogen atom, optionally hydrolyzing the cyclized product, and there-after optionally esterifying it, and/or etherifying its enol group.
~he compound of formula (II) is also a novel compound and can be produced by reducing the carbonyl group of a compound of the general formula Rl ~ ` ~ ~ CHCOOH (III) wherein Rl and R2 are as defined, and one Y' represents a group of the formula -CH2COOH
and the other Y' represents a hydrogen atom, to a methylene gIOUp~ and optionally halogenating the resulting product.
~he compound of general formula (III) can be produced, for example, by -the following method.
For example, a compound of the general formula ~ ` 115982~

o Rl ~ ~ i ~ CHCOOH (IIIa) wherein Rl a~d R2 are as defined above, can be produced by heating a compound of the general formula O
Rl ~ ~3 CH2 wherein Rl and R2 are as defined above, under reflux in benzene together wi-th ethylene glycol in the presence of an acid to form a ketal compound of the general formula r~
0 ~0 ~\ --J R

wherein Rl and R2 are as defined above, brominating the resul-ting compound by the action of ~-bromosuccinimide in carbon tetrachloride, treating the product with sodium cyanide or potassium cyanide in a mixture of ethanol and water to form a compound of the general formula ~ 1~9826 o o ~ 3 wherein Rl and R2 are as defined above, hydrolyzing the resul-ting compound in a sodium hydroxide solution, deketalizing the compound in a mixture Of hydrochloric acid and ethanol to form a compound of the general formula \~ C COO C2HS

wherein Rl and R2 are as defined h~reinabove and hydrolyzing the product in a sodium hydroxide solution.
~ikewise, a compound of the general formula (IIIb) wherein Rl and R2 are as defined above, can be produced from a compound of the general formula `" 11598~6 o \

wherein Rl and R2 are as defined above.
In the production of the compound (I) from the compound (III), the carbonyl group of the compound (III) is reduced to a methylene group by the action of a reducin~ a~ent, and optionally hydrolyzing the product and halogenating the carboxyl group to form the compound of formula (II).
Reduction of the carbonyl group is perfor~ed by using such a reducing agent as zinc powder, a powder of a zinc-copper alloy, red phosphorus, or zinc amalgam.
The reaction is carried out preferably in a solvent.
When zinc powder, or a powder of zinc-copper alloy is used as the reducing agent, a 5 - ~/0 basic aqueous solution is preferred as the solvent. Examples of the base are sodium hydroxide, potassium hydroxide or ammonia.
The reaction temperature is usually 50 to 110C. When zinc amalgam is used as the reducing agent, an aqueous solvent acidified with hydrochloric acid is preferred as the solvent. The aqueous solvent may, for example, be water, hydrous methanol, hydrous ethanol, hydrous pro-panol, or mixtures of theseO The reaction proceeds smo-othly at a temperature of 50 to 100Co Subsequently, the partially esterified product g ~ ~

is hydrolyzed in a customary manner with a base such as sodium hydroxide or potassium hydroxide in a solvent, preferably such as a mix-ture of ethanol and water.
Of the compounds falling within the general formula (II), a 2-(4-substituted benzyl)phenylacetic acid derivative of the general formula -a~2- ~ -CHCOOH (II") - wherein R2 is as defined hereinabove, can be produced by reducing a compound of the general .formula ~ ( V) COO.R4 wherein R2 is as defined above, and RL~ re-presents a hydrogen atom or a lower alkyl group, to form an alcohol compound of the general formula 1 2 (VI) wherein R2 is as defined above, halogenating the alcohol compound and then treating it with a cyamide, and hydrolyzing the product of the general formula 2~

-- ~3 (VII) wherein R2 is as defined above.
The compound of formula (V) is obtained, for example, by reacting ethyl 2-benzylbenzoate with acetyl chloride, acetic anhydride or a,a_dichlorome-thyl methyl ether in the presence of anhydrous aluminum chloride or stannic chloride.
Reduc-tion of the compound of formula (V) is carried out in a solvent using a reducing agent. Examples of preferred reducing agents are lithium aluminum hydride, sodium borohydride-aluminum chloride, and sodium bis(2-methoxyethoxy)aluminum hydride. The solvent may, for example, be ether, tetrahydrofuran, diglyme, benzene, toluene, or mixtures thereof. The reaction temperature is from room temperature to the boiling point of the sol~ent.
The resulting alcohol compound (VI) is halogenat-~d in a customary manner and then treated with a cyanide to form the product of formula (VII). The halogenation is carried out a-t 0 to 150C using an ordinary halogenat ing agent such as thionyl chloride, phosphorus tribromide, phosphorus pentachloride or phosphorus oxJchloride in the absence of a solvent or in the presence of an iner-t solvent such as benzene, carbon tetrachloride, 1,2-di-chloroethane or chloroform. The cyanation is carried -1 ~ 5982 out in an inert solvent using a cyanation agent such as potassium cyanide or sodium cyanideO Exa~ples of the solvent are hydrous ethanol, dimethyl formamide, dimethyl acetamide, dime-thyl sulfoxide, sulfolane, and hexamethyl-phosphoramide. Addi-tion of a quaternary salt of an amine~
such as tetrabutyl ammonium chloride or benzyl triethyl ammonium chloride, promotes the cyanation.
Hydrolysis of the product (VII) is carried out in a customary manner, for example, by heating the com-pound in hydrous alcohol in the presence of a base suchas sodium hydroxide or potassium hydroxide~
The 2-(4~substituted benzyl)phenylacetic acid derivatives of formula (II") can also be prepared by reacting a co~pound of the general formula ~ CH2 ~ COCH2R2 (VIII) \COCH3 wherein R2 is as defined above, with a lower alcohol in the presence of a thallium (III) salt, and optionally hydrolyzing the product (ester).
~ he compound of formula (VIII) is also a novel compound, and can be prepared, for example, by the action of an acid chloride or acid anhydride on o-benzylaceto-phenone in the presence of anhydrous aluminum chloride.
Methanol, ethanol, propanol, butanol, etc. can be used as the lower alcoholO ~hallium trini-trate is preferred as the thallium (III) salt, and thallium I ~5g~2~

trinitrate supported on acidic mon-tmorilloni-te is especial-ly preferredO
~ his reaction is preferably carried out in the presence of an acid catalyst. Examples of preferred acid catalysts are mineral acids such as perchloric acid, nitric acid or hydrochloric acid. ~he reaction may be carried out in the absence of a solvent or in the pres-ence of an inert solvent. Examples of the inert solvent are methylene chloride, carbon tetrachloride, toluene and mixtures of these. ~he reaction temperature is usually room temperature to -the boiling point of the reaction mixture. Generally, the reaction is comple-ted in 1 to 40 hours.
Use of thallium trinitrate as the thallium (III) salt supported on acidic montmorillonite, for } B example K-10 (a product of Sued Chemie Companh), promotes the reaction, and the reaction time can be shortened to from 0.5 to 2 hours. ~hallium trinitrate can be supported on a carrier by a method described, for example, in Journal of the American Chemical ~ociety, Vol. 98, page 6750, 1971. In this case, thallium trinitrate and methanol adsorbed to the surface of the acidic montmoril-lonite serve as reagents Xydrolysis of the ester of the general formula 2 ~ ~ 5 ~ Tr~e 1~ k ~ ~ ~ -wherein R2 is as defined above, and R5 re-presen-ts a lower alkyl group, can be performed by known rneans using a mineral acid such as hydrochloric acid or sulfuric acid or an alkali such as sodium hydroxide or potassium hydroxide.
A compound of general formula (II) in which X
is halogen can be produced by halogenating the carboxyl group of -the compound so obtained at 0 to 150C with an ordinary halogena-ting agent such as thionyl chloride, phosphorus -tribromide, phosphorus pentachloride or phosphorus oxychloride in the absence of a solvent or in the presence of an inert solvent such as benzene, toluene, xylene, ether, chloform or dichloroethane. or dichloro-ethane.
Cycliza-tion of -the compound of formula (II) may be carried out in the presence of a condensing agent such as polyphosphoric acid, polyphosphoric acid esters or phosphoric anhydride when X is a hydroxyl group, and in the presence of a Friedel Crafts reac-tion catalys-t such as aluminum chloride, zinc chloride, stannous chloride, stannic chloride, titanium trichloride, boron trifluoride, antimony pentachloride or phosphoric an-hydride when X is a halogen atom.
When X is a hydroxyl group, the cyclization reaction does not particularly require a solvent, bu-t the use of benzene, xylene, acetic acid, dimethyl sul-foxide, sulfolane, etc. as a solvent is permissible.
~he reaction temperature is usually from room temperature `"` ~` 11598~6 1~ --to 150C. When X is a halogen atom, it is preferred to use an inert solvent such as nitrobenzene, nitromethane, dichloromethane, dichloroethane or carbon disulfide.
The reaction proceeds smoothly at -30 to +100C.
According -to a preferred embodimen-t of this invention, the compound of this invention is produced by cyclizing a compound of the general formula Rl ~ ~ CH2COX (II') wherei.n Rl, X and Y are as defined above, optionally hydrolyzing the cyclized product to form a compound of the general formula Rl ~ ~ ~ ~ CH2COOH (I') wherein Rl is as defined above, and Z' represents a group of the formula -C=CH- or OH
-C-CH2_ , o esterifying and enol-etherifying -the compound, and there-after optionally subjecting the resulting compound of the general formula Rl ~3 CH2COOR 3 (IV) i''"~` 1 ~g~6 wherein Rl is as defined above, R'3 represents a lower alkyl group, and Z" represents a group of -the formula -C=CH- , OR'3 to alkylation, dealkylation of the enol ether group, ~nd/or hydrolysis.
Cyclization of the compound of formula (II') can be performed by the method described hereinabove.
~ o esterify and enol-e-therify the compou~d of formula (I') simultaneously, the compound of formula (I') is reacted with a lower alcohol in the presence of, for example, thionyl chloride, phosphorus pentachloride, phosphorus -tribromide, phosphorus oxychloride, etc.
Examples of the lower alcohol are methanol, e-thanol, n-propanol, isopropanol, and n-butanol. ~here can be used a solvent, for example the aforesaid lower alcohols, and inert solvents such as benzene, -toluene, xylene, n-hexane, ether, tetrahydrofuran, chloroform, and dichloromethane.
~he reaction temperature is usually from room temperature to 120C.
~he compound of formula (IV) may also be obtained by esterifying the compound of formula (I') and then sub-ject~ng it to the aforesaid reaction. ~he esterifica-tion reaction of the compouna of formula (I') is carried out using a lower alcohol in the presence of an ordinary inorganic acid such as hydrogen chloride, hydrogen bromide or sulfuric acidO ~he aforesaid lower alcohols, and inert solvents such as benzene, toluene, xylene or 15982~`

_ 14 -mixtures thereof may be used as a reaction solvent. ~he reaction temperature is preferably 60 to 120C.
When -the compound of formula ~IV) i5 subjected to dealkylation of the enol e-ther group or to hydrolysis, a compound of formula (I) in which R2 is a hydrogen atom can be obtained. To obtain a compound of formula (I) in which R2 is a lower alkyl group, the compound of formula (I~) is alkylated, for example, in the following manner.
~he compound of formula (IV) is reacted with an alkyl halide in the presence of a base in a dry solvent. Examples of the base are lithium alkyl amides, lithium amide, n-butyl li-thium, phenyl lithium, sodium hydride or sodium amide. Examples of the solvent are inert solvents such as ether, tetrahydrofuran, dimethoxy_ ethane, diglyme, dioxane, benzene, toluene, hexane, dimethyl formamide, dimethyl acetamide, hexame-thylphos-phoramide, and liquid ammonia. Preferably, the reaction is carried out in a stream of an inert gas such as nitrogen~ The reaction temperature is usually -60 to +100C.
When the resulting compound is hydrolyzed in the presence of a base or an acid, a compound of formula (I) in which R~ is a hydrogen atom can be obtained in a high yield. ~he base may, for example, be sodium hydro-xide, potassium hydroxide, ~tc., and the acid may, for example, be hydrochloric acid, hydrobromic acid, etc.
Usually, wa-ter or a mixture of water and a lower alcohol is used as a solvent. It may be used in admixture with an organic solvent such as benzene, toluene or hexane.
The reaction proceeds smoothly at room temperature to 130C.
The compound of formula (I) in which R3 is a hydrogen atom can also be produced by dealkylating the enol ether group of the alkylated product, and then hydrolyzing the resulting product by the method described above. Dealkylation of the enol ether group is carried out in the presence of a protonic acid or a Lewis acidO
When a protonic acid such as hydrochloric acid or hydro-bromic acid is used, the reaction temperature is prefer-ably 0 to 30C. The reaction usually proceeds smoothly in water, a lower alcohol or a mixture of -these. An organic solvent such as benzene, hexane and ether may also be used in admixture. When a Lewis acid such as boron tribromide or boron trichloride is used, the reac-tion temperature is preferably from -30C to 0C. The reaction is preferably carried out in an organic solvent such as hexane, chloroform, and dichloromethane.
~he final desired products can be isolated and purified in a customary manner by, for example, extrac-tion, recrystalization, chromatography, etc. in suitable combinations.
The an-ti-inflamma-tory activity, analgesic activity and ulcerogenic activity of the novel dibenzo-~a,d~cycloheptene derivatives of this inven-tion were tested by the following me-thods.

- '-`' 1 15g~26 ~A) Anti-inflammatory activity Each of test compounds was orally administered to groups of male Donryu rats weighing 130 to 150 g (8 to 10 rats per group), and one hour later, 0.1 ml of a 1% carrageenin solution was injected subcutaneously into the hind paw of each rat. After injection of carrageenin, the volume of the paw was measured at predetermined periods, and the percent inhibition against a control group was calculated. lhe results are shown in Table 1. It is seen from Table 1 that the dibenzo(a,d)cycloheptene derivatives Ia, Ib, Ic, Ih and Ii exhibited excellent anti-inflammatory activity, and in particular, the efficacy of the compound Ii was stronger than that of indomethacin as a comparison.
(B) Analgesic activity Using male ICR mice weighing 25 to 30 g ~10 mice per group), there was measured the number of writhing syndromes induced when a 1% solution of acetic acid was intraperitoneally injected at a dose of 10 ml/kg. The percent inhibition against a control group was calculated. The results are shown in Table 2. It is seen from Table 2 that the ED50 value (52 mg/kg) of the compound Ii was ten times that (5.0 mg/kg) of indomethacin, and therefore the analgesic activity of the compound II is one-tenth of that of indomethacin.
(C) Ulcerogenic activity Each of the test compounds was orally administered to male Donryu rats weighing 150 to 170 g which had been caused to fast for 9 hours. Sixteen hours later, the rats were sacrificed under ether anesthesia. The ` 1 1~9~2B

stomach was removed from each rat, and the number of animals which showed hemorrhagic and/or ulcerous spots in the gastric wall was calculatedO The results are shown in ~able ~. It is seen from ~able 3 that the compound Ii scarcely caused gastric lesions even in doses which would evidently exhibit anti-inflammatory activity. rrhe UD50 value (15 mg/kg) of the compound Ii was 7.9 times -the ED/~o value (1.9 mg/kg) of its an-ti-inflammatory activityO On the other hand, the IJD50 value (11.7 mg/kg) of indomethacin was only 1.2 times the ED40 value (9.8 mg/kg) of its anti-inflammatory acticity.
~ he results of these tests demonstra-te that the compound Ii is a useful anti-inflammatory agent which has very po-tent anti-inflammatory activity and weak analgesic activity, but its ulcerogenic ac-tivity is extremely weak. It is also seen that the compounds Ia, Ib, Ic and Ih evidently show anti-inflammatory activity although their activity is weaker than that of indome-thacin. Furthermore, it is seen that the ulcero-genic activi-t~es of the compounds Ia and Ib are much weaker than that of indomethacin.

1 15~26 . _ ~ Ll~ ~ ~ ___ ~.._ ... .__ .. _ h _ . _ ~5 O~ ~0 o ro ~ ~ r~co C~u~. ~
o o 00 o, ooLr~ C' ,D ~ .... __. _ _ _ .~ ~ L~ ~a) o ~u~ O o~
._ _ __ a) ~ ~ o N~ ~ ~ 0 0 ~ N~ 00 ~ ~D ~
.~ ~ ~U~ ~ ~ ~o 00~ o~ ~ i~i ~1 h ~ ~ _____ _ . _ ,1 ~1 ~ o ~u o ~ ~ a~ ~ o ~ LOC' ~ Lr~
~ ~ ___ N ~ ~\i ~1 ~ ~ O ~ ~ __ ~ ~

L .- ~ i - ` r - ` 11 1 5 9 8 ~ ~;
~ 19 ~
..
t:O h Vl (S~ 0 o a~
._ ~ ~
~o 0 o o vl r~ r~

c~ r(~co r ~-~9 ~ ~

_ _ h ~rl ~5) o o rt~ vl r~ 1 o ;~;~ Lt\ 2 rt~ ~ r~ rd . ,o ~
~0 ~ ~rl 0 r~ o o r~
r-~ r~ N~ .
. ._ ~ ."
vl u~ o vl u~o vl h ~ (v ~ 0 ~
I ,J h o0 ~ ~
,~ ,1 0 râ '~ ~ ~
a~ u~ O o vl C) ~ ~ ~o a~ ,a) ~ovp~ o ~o CO~ Vl ~ ~ ~ ,~
O ~1 ~1 h a~
a) ~
~ ~ ~ a) ~D
vl~ o ~ ~ h a)I vl ,1~ C) r vl P~ ~ ~
0 ^ c.) a~ *
E~ vl ~ ~ ~ -' rd i 0H
(:~J ~ H
~_ ~ 15~8~

_ 20 -Compound Dose writhing Inhibition __ (mgikg) syndromes (%) (mg/kg) , _ ( ~
(Ii) Control 22.9 t 1 o 77 0 52.0 10.0 19.7 + 1.77 14.0 2000 15.2 + 1.28 33~6 40O0 12.5 ~ 1065 45.4 8000 9.7 + 1.93 57.6 _ _ Indomethaci] 1 Control 20.0 + 1.31 0 5oo 1.25 lL~.6 + 2.35 27.7 2.5 12.0 + 0092 40~6 5~o 1005 + 1.40 ~8.0 10.0 7,.6 ~ 1.15 62.4 'D 0 6~,0 + 0.94 70.3 L

(**): A 1% carbo~ymethyl cellulose solution was orally administered in a dose of 10 ml/k~;.
(**): A do se-response line was drawn from the percent inhibition of the administered groups, and the dose which caused 50~/0 inhibition was calcula-ted.

1 1~9~25 Table 3 , . _ . _ _~
Compound Dose Number of animals Ulcer UD50 , with ulcer/ inde~ (~) value (mg/kg) number of animal~ (Mean ~ SE) (mg/kg) ~ . _ used (%) _ ..... _ (**~ __ .
Ii 3.13 1/8 ( 12~ 5) 0 o 13 + 0 ~14 ( 7 o56~
6~25 2/8 (2500) 0~25 + 0017 29~7 ) 12.5 4/8 (50~0) 0~50 + 0~20 25~0 5/8 (620 5) 0~88 ~ 30 50 oO 8/8 ( 100 ) 2~75 + 0~ 2LI-.. _ ___ .~ .. .. ,_ ~ ~
Indo- 3 .13 0/8 ( 0 ) 0 11~ 7 methacin (708 _ 6~25 2/8 (25~0) 0~37 + 0026 17~6) 12~5 4/8 (50O0) 1~38+ 0~53 A~ 25~0 7/8 (87~5) ~+ -35 _ S0~0 8/8 (100 ) 3O12 + 0O12 (*): Calculatea by the Adami's methodO
(**): Calculated by the ~itchfield-Wilcoxon's methodO
The parenthesized values show 95/0 confidence limits.

59Q~B

~ he following 5xamples illustrate the present invention more specifically.
Example 1 (A) A solu-tion of 308 g of 2-(L~-carboxymethylbenzoyl)-phenylace-tic acid in 15 ml of methanol was added to 900 g of zinc amalgam, 17.5 ml of concO hydrochloric acid and 7.5 ml of waterO ~he mix-ture was heated under reflux for 5 hours with s-tirringO After the reaction, -the reaction mixture was cooled, and the zinc amalgam was removed by decantation. Wa-ter (100 ml) was added, and -the mixture was extracted with e-therO ~he e-thereal layer was washed wi-th a saturated aqueous solution of sodium chloride.
~he ether was distilled off to afford a yellow oily pro-duct~ Methanol (20 ml) was added -to dissolve it. ~hen, 15 60 m] of a 10% sodium hydroxide solution was added to the solution, and the solution was hea-ted under reflux for 3 hours with stirringO After the reaction, the reaction mixture was cooled, acidified wi-th concO hydrochloric acid, and extracted with ethsr. ~he e-thereal layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate.
~he ether was then distilled off. ~he residue was chroma-tographed on a silica gel column using a mixture of chloroform and methanol (95:5) as an eluentO A solid was obtained from the eluate. Recrystallization from ether afforded 1~67 g of 2-(L~-carboxymethylbenzyl)phenylacetic acid as colorless plate-like crystals h~ving a melting point of 155 to 156Co 1 159~2~

NMR spectrum (CDC13/DMSO-d6=10:1):
ppm 3.53 (4H, s, -CH2COOH x 2),

3.97 (2H, s, -CH2-), 6.9 - 7.3 (8H7 aromatic proton), 10.25 (2H, bs, -COOH x 2; disappeared in D20)o Compounds NosO 1 to 7 shown in Table 4 were prepared in the same manner as above.

. ~ 1 59~

--~ô _ ~D O N~ ~D U~
o~ tC U~
~ ~ _ ~ ~ U~ CO 0~ ~ C' ~ C`
~1 O V ~I C~
~ _ _ [~ ~O ~ O C-o ~ r~
o o o o o ~ o a~ Lr~
~ ~ C~
~ O V ~1 ~ ~ ~ ~ ~ ~
1~1 t~ C- ~ C` C' C' ~D C' _ V _ _ ~ ~
c~c~ ~d O ~ O O O V O
E-l rl ~ ~OLr~ O ~O Lr\ ~O
~i ~ Pi~
~ _ P~ ~ C' C' ~I C' C~ C' C' /---\ o~1 o ~1 ~1~\J ~ ~1 ~1 ~1 1~ V V ~ V V V V
a~
t~ ~ ~ ~ 1:
C~l rrl d 0 0 0 0 0 0 , ~ ,1 a :/--\ ~1 ~ O 0 0 ~0 ~ 0 00 ~0 0 u~ ~r P~ ~1~I X ~1 ~~I fl ,-1 ~1 ~ r I
C) o ,~
a)~ l ~ ~ I~ ~ 4 ~ I
Lr\
~) o ~ t~
V u~ ~ O
~ do ~ ~ ~ Lr~
'~ 1 00 00 ~ I
u~ ) O O

o o o ~ ~ ~ v ov v E~ I m N

~q U~ V

O O ~ ~0 O O o o ,J
V V V V V
E~ ~ ~ ~U ~ I
E~ ~V V ~V
i ~

~ ~ o ~

59~2B

(B) Polyphosphoric acid (20 g) was heated to 120 to 125C, and with stirring, 2.9 g of 2-(4-carboxyrnethyl-benzyl)phenylacetic acid was added ~he mixture was stirred for 2 hou~s at the same temperatureO After the 5 reacti on, the reaction mixture was cooled, and ice water was added. ~he solution was extracted with e-thyl ace tate O
~he e-thyl acetate layer was washed with a saturated aqueous solution of sodiurn chloride, and dried over an-hydrous magnesium sulf ate. 'rhe ethyl acetate was then 10 distilled off. Irhe residue was chromatographed on a silica gel column using chloroform as an eluent. A
slightly yellow solid was obtained from the elua te .
Recrys talliz ation from a mixture of e-ther and n-hexane afforded 1.52 g of 10,11-dihydro-11-oxo-5H-dibenzo~a,d~
15 cycloheptene-2-acetic acid as colorless needle-like crys-tals having a melting point of 171 to 173. 'rhe product is expressed by -the following formula 8 ~-- CH2COOH

Elemental analysis value for C17H140~j:
Calcula-ted (%): C 76.7 H 5. 3 ~Qund ~%): C 760 3 H 50 2 g8~

- 26 _ NMR spectrum (CDC13):
Sppm ~o65 (2H, s, -CH2COOH),

4.12 (2H, s, -CH2-), 4018 (2H, s, -~H2-), 7.0 - 704 (6H, aromatic proton), 7.94 (lH, s, proton at the l-position), 10.26 (lH, bs, -COOH; disappeared in D20)o Example 2 ~o a mixture of 15 g of polyphosphoric acid and 10 ml of sulfolane was added 1.5 g of 2-benzyl-5-carboxymethylphenylacetic acid, and the mixture was heated at 100 -to 110C for 2 hours with s-tirring. After the reaction, the reaction mixture was cooled, and dis-solved in ice waterO ~he solution was extracted with ethyl acetate, and washed with water~ The ethyl acetate layer was extracted with a 2% aqueous solution of sodium hydroxide. The aqueous layer was acidified with 10%
hydrochloric acid. ~he precipitated solid was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfateO ~he ethyl acetate was then distilled offO
Recrystallization of the residue from a mixture of ethyl acetate and n-hexane afforded 0052 g of 10,11-dihydro-10-oxo-5H-dibenzo~a,d~cycloheptene-2-acetic acid as a colorless crystalline powder having a melting point of 163 to 165Co 159~2~

Elemental analysis values for Clr~H1403:
Calculated (%): C 7607 H 5.3 Found (%): C 7607 H 5~L~
IR spectrum (KBr) An absorption at-tributed -to the carboxyl group a-t 3500 - 2300 cm~l and 1700 cm~l; and an absorption attributed to the carbonyl group at 1670 cm~lO
ExamPle 10 (A) ~hionyl chloride (6 ml) was added to 1.6 g of 2-(3-carboxymethylbenzyl)phenylacetic acid, and -the mix-ture was heated under reflux for 3 hours with s~irring.
After the reaction, -the reaction mixture was cooled, and the excess of thionyl chloride was distilled offO
Thus, 2-(3-chlorocarbonylmethylbenzyl)phenylacetyl chloride as a slightly yellow oily subs-tance was obtained quantitativelyO
IR spectrum:
An absorption at-tributed to -the carboxylic acid chloride at 1795 cm lo NMR spectrum (CDC13):
ppm 3096 (2X, s, -CH2-), 4.01 (4H, s, -CH2COCl x 2), 6.8 - 7.4 (8H, aromatic proton).
(B) Dichloromethane (60 ml) was added to 1.8 g o~
2-(3-chlorocarbonylmethylbenzyl)phenylacetyl chloride.
To the resul-ting solu-tion was added at a time 1.8 g of powdery anhydrous aluminum chloride with s-tirring and ` 1 159~2~

_ 28 ice coolingO The mixture was stirred a-t this -tempera-ture for 45 minutesO After -the reaction,the reaction mixture was poured into a mixture of ice water and hydro-chloric acid, and the dichloromethane layer was separatedO
The aqueous layer was extracted with dichloromethane.
The dichloromethane layerswere combined, and washed with a saturated aqueous solution of sodium chloride~ The di-chloromethane was then dis-tilled off. To the residue was added 30 ml of a ~/o aqueous solution of sodiwn hydroxide, and the mixture was stirred at room temperature for 1 hour, and acidified with 10% hydrochloric acidO The separated oily ma-terial was ex-tracted wi-th ethyl acetate, washed with a satur~ted aqueous solu-tion of sodium chloride, and dried over anhydrous magnesium sulfate.
The ethyl acetate was distilled off. The residue was chromatographed on a silica gel column using chloroform as an eluent. Slightly yellow crys-tals were obtained from the eluate. Recrys-talliza-tion from a mixture of ether and ethanol afforded 0091 g of 10,11-dihydro-11-oxo-5H-dibenzo[a~d~cycloheptene-3-acetic acid as color-less needle-like crystals having a melting point of 178 to 181CJ
Elemental analysis values for C17H1403:
Calculated (%): C 7607 E 5.3 Found (%): C 7609 H 503 ~ "
1 1~98.

IR spectrum (KBr):
~n absorption attribu-ted to -the carboxyl group at 3500 - 2300 cm 1 and 1695 cm 1; and an absorption at-tributed to the carbonyl group at 1660 c~
NMR spectrum (CDC13/DMS0-d6=5:1) ~ppm 3.59 (2H, s, -CH2COOH), 4.12 (2H, s, -CH2-)~
4.25 (2H~ s, -CH2 )~
6.9 - 800 (7H, aromatic proton).
In -the same manner as above, -the following compounds were producedO
(i) 8-chloro-lo~ll-dihydro-lo-oxo-5H-dibenzo~a~d) cycloheptene-2-ace-tic acid Form: slightly yellow needle-like crystals~
Melting point: 167 -to 169C
(recrys-tallized from ethyl acetate/n-hexane).
Elemental analysis values for C17H13C103:
Calculated (/0): C 67.9 H 4.4 Found (%): C 67.6 H 4.7 (ii) 8-Fluoro-10,11-dihydro-11-oxo-5H-dibenzo~a,d~-cycloheptene-2-acetic acid Form: colorless needle~like crystals~
Melting point: 172 to 174C
(recrystallized from ethyl acetate/
n-hexane).

~ ~59~
!

Elemental analysis values for C17H13F03 Calculated (%) C 7108 H 4.6 ~ound (%): C 72.0 H 4.4 Example 4 (A) Dry benzene (15 ml) and 10 ml of thionyl chloride were added to 300 g of 2-t4-(1-carboxyethyl) benzyl~phenylacetic acid, and the mixture was heated under reflux for 2 hours with stirringO After the reac-tion, the reaction mix-ture was cooled, and benzene and the excess of thionyl chloride were distilled off.
There was quantitatively obtained 2-~4-(1-chlorocarbonyl-ethyl)benzyl~phenylacetyl chloride as a slightly yellow oily substanceO
I~ spectrum (neat):
An absorption attributed to the carboxylic acid chloride group at 1790 cm 1.
(B) In 100 ml of 1,2-dichloroethane was dissolved 3.36 g of 2-[~-(1-chlorocarbonylethyl)benzyl~phenylace-tyl chloride. The solution was cooled to -30C, and 6.0 g of powdery anhydrous aluminum chloride was added at a time. The mixture was stirred at this tempera-ture for 30 minutes. ~fter the reaction, the reaction mixture was poured into ice waterj and the 1,2-dichloroethane layer was separated and washed with a saturated aqueous solution of sodium chlorideO The 1,2-dichloroethane was distilled off. The residue was dissolved in 10 ml of ether, and the solution was extracted with 50 ml of a 5%
aqueous solution of sodium hydroxideO The aqueous layer - ~ 159~26 ~ 31 ~
was acidified wit~ 10% hydrocllloric acid under ice cool-ing. ~he separated oil~ substance was extracted with ether, washed with a sa-turated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfateO ~he ether was then distilled offO Recrystal-lization of the residue from ether afforded 1023 g of 2-(10,11-dihydro-ll-oxo-5H-dibenzo[a,d~cyclohepten-2-l)propionic acid as colorless prismatic crystals having a melting point of 134 to 136Co Elemental analysis values for C18H1603:-Calcula-ted (,~): C 7701 H 508 Found (%): C 76.8 H 5.7 IR spectrum (KBr):
An absorption attributed to the carboxyl group at 3500 - 2300 cm~l and 1685 cm~l; and an absorption attribu-ted to the carbonyl group at 1665 cm~lo NMR spectrum (CDC13):
ppm 1044 ( 3H~ d, -ICH-CH3), C~II Co~
3~70 (lH, q, -CHCH3), COQH
4.13 (2H, s, -CEI2-), 4.20 (2H, s, -CH2-), 7~0 - 705 (6H~ aromatic proton), 8000 (lH, s, proton at the 1 position), 9~95 (lH~ br, -COOH; disappeared in D20)o 9~26 Example 5 In 100 ml of dichloromethane was dissolved 3036 g of 2-~4-(1-chlorocarbonylethyl)benzyl~phenylacetyl chlorideO The solution was cooled to -30C, and 6 ml of antimony pentachloride was added at a timeO The mixture was stirred at this temperature for 30 minutes. After the reaction~ the reaction mixture was poured into ice waterO ~he dichloromethane layer was separated, and washed with a satura-ted aqueous solution of sodium chloride. The dichloromethane was distilled off, and the residue was dissolved in 10 ml of ether~ The solution was extrac-ted with 50 ml of a 5% aqueous solution of sodium hydroxideO The aqueous layer was acidified with 10% hydrochloric acid under ice coolingO The separated oily substance was extracted with ether, washed wi-th a sa-turated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The ether was -then distilled off. Recrystalliza-tion of the residue from ether afforded 1097 g of 2-(10,11-dihydro-11-oxo-5H-dibenzo~a,d~cyclohepten-2-yl)propionic acid as colorless prismatic crystals having a melting point of 134 to 1~6Co ~xam~le 6 (A) Dry benzene (10 ml) and 007 ml of thionyl chloride were added to 0.295 g of 2-(~-carboxymethylbenzyl) phenylacetic acid, and the mixture was heated under reflux for 4 hours with stirringO After the reaction, the reac-tion mixture was cooled, and the solvent was distilled off -to afford quantitatively 2-(4-chlorocarbonylmethyl-- ~3 -benzyl)phenylacetyl chloride as a brown oily substanceO
IR spectrum:
An absorp-tion attributed to the carboxylic acid chloride group at 1780 cm~l.
(B) In 10 ml of dichloroethane was disso]~ed 0.33 g of 2-(4-chlorocarbonylmethylbenzyl)phenylacetyl chloride, and 0.58 g of anhydrous stannic chloride was added to the solution under ice cooling and stirring~ ~he mixture was stirred under ice cooling for 30 minutes, and then at room temperature for 1 hour. Af-ter the reaction, -the reaction mixture was poured into ice waterO ~he di-chloroethane layer was separated, and the aqueous layer was extracted with chloroformO The dichloroethane layer and -the chloroform layer were combined, and washed with a saturated aqueous solution of sodium chloride. ~hen, a 1~/~ aqueous solu-tion of sodium hydroxide was added, and the mixture was vigorously stirred a-t room -temperature for 30 minutes. ~he aqueous layer was separated and acidified with 10% hydrochloric acid. ~he separated oily substance was extracted with ether. ~he ethereal layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. ~he ether was distilled off. Recrystallization of the residue from a mixture of e-ther and n-hexane afforded 0.132 g of 10,11-dihydro~ oxo-5~-dibenzo~a,d~cycloheptene-2-acetic acid as colorless needle-like crystals having a melting point of 171 to 173Co 8 2 ~

Exam~le 7 In 50 ml of dichloroethane was dissolved in 300 g of 2-benzyl-4-chlorocarbonylmethylphenylacetyl chlorideu l~ith stirring at room temperature, 5.0 g of a solution of boron trifluoride etherate was added to the solution. ~he mi~ture was stirred for 2 hours, and worked up in the same way as in Example 6 to afford 1.42 g of 10,11-dihydro-10-oxo-5H-dibenzo~a,d~cyclo-hep-tene-3-acetic acid as a colorless crys-talline powder (recrystallized from a mixture of methanol and n-hexane) having a melting point of 1~6 -to 188Co Elemental analysis values for C17H1403:
Calculated (%): C 76.7 H 5~3 ~ound (%): C 76.5 H 501 ExamPle 8 (A) A mix-ture of 25 ml of 30% aqueous ammonia and 12.5 ml of wa-ter was added to 17.5 g of active zinc powderO The mix-ture was heated at 80C with s-tirring.
A saturated aqueous solution of copper sulfate (0.8 ml) was added, and then, a solution of 3.0 g of 4-t-butyl-2-(4-carboxymethylbenzoyl)phenylacetic acid in 25 ml of ethanol was added dropwise. ~he mixture was stirred at the same temperature for 30 hoursO After the reaction, the reaction mixture was cooled, and the insoluble matter was separated by filtration. ~he filtrate was acidified with conc. hydrochloric acid, and extracted with ethyl acetate. Ihe extract was washed with water and then wi-th a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The ethyl acetate was distilled off~ Recrystallization of the residue from a mixture of ethyl acetate and n-hexane afforded 1.7 g of 4-t-butyl-2-(4-carboxymethylbenzyl)-phenylacetic acid as colorless needle-like crystals hav-ing a melting point of 138 -to 139Co NMR spectrum (CDC13):
ppm 1.2L~ ~9H, s, C(C ~ ~, 3~ 58 (4H, bs, -CH2COOH x 2), 3.97 (2EI~ s~ -CH2-), 6.9 - 7.3 (7H, aromatic pro-ton), 10051 (2H, bs, -COOH x 2; disappeared in D20).
(B) The resulting carbo~Jlic acid was conver-ted to L~-t-butyl-2-(L~-chlorocarbonylmethylbenzyl)phenylacetyl chloride in a customary mannerO Then, 1.4 g of the re-sul-ting acid chloride was dissolved in 21 ml of carbon disulfide, ~nd with stirring at room temperature, 1.1 g of zinc chloride was addedO The mixture was stirred for 2 hours under refluxO After the reaction, the reaction mix-ture was cooled, and poured into ice waterO ~he carbon disulfide layer was separatedO The aqueous layer was extracted with chloroform. The carbon disulfide layer and the chloroform layer were combined, washed with a saturated aqueous solution of sodium chloride, and ex-tracted with a 10% aqueous solution of sodium hydroxideOThe aqueous layer was acidified with 10,~ hydrochloric acid, and the sep~rated oily substance was extracted with ethyl acetate. The ethyl ace-ta-te layer was dried over anhydrous -`~ 1 159~

sodium sulfateO The ethyl acetate was distilled off, and the residue was chromatographed on a silica gel column using chloroform as an eluent. From the eluate, C D 48 g of 7-t-butyl-10,11-dihydro-1~-oxo-5H-dibenzo~a,d~-cycloheptene-2-acetic acid was obtained as an amorphous solid.
IR spectrum (~Br):
An absorption a-ttributed -to -the carboxyl group at 3600 - 2400 cm 1 and 1700 cm 1; and an absorption at-tributed to the carbonyl group at 1670 cm~lD
NMR spectrum (CDC13):
ppm 1030 (9H, s, -CH3 x 3), 3060 (2H, s, -CH2-), 4~12 (2H, s, -CH2-), .19 (2H~ s~ -C_ 2-)~
7.0 - 8.2 (6H, aromatic pro-ton), 8065 (lH~ bs, -COOH; disappeared in D20)~
ExamPle 9 In 3 ml of a 12% ethanol solution of hydrogen chloride was dissolved 0.1~ g of 10,11-dihydro-11-oxo-5H-dibenzo~a,d~cycloheptene-3-acetic acid obtainea in Example 3. The solu-tion was heated under reflux for 30 minutes with stirringO After the reac-tion, the reaction mixture was cooled, and the solvent was distilled off. Water was added to the residue, and the mixture was extracted with etherO ~he ethereal layer was washed with a saturated aqueous solution of sodium chloride, and dried over 9 ~ 2 anhydrous magnesium sulfaten ~hen, -the ether was dis-til-led off~ ~he residue was chromatographed on a silica gel column using benzene as an eluent. ~rom the eluate, 0O12 g of ethyl 10,11-dihydro-11-oxo-5H-dibenzo~a,d~-cyclohep-tene-3-aceta-te was obtained as a slightly yellow oily substanceO
Refractive index: ~nD4~ = 1.5845 Elemental analysis values for C19H1803:
Calculated (%): C 77.5 H 6.2 ~ound (%): C 77.3 H 604 NMR spectrum (CDC13):
Sppm 1.20 (3EI, t, -OCH2CH~), 3.47 (2H, s, -CH2COOC2H5), 4.06 (2~I, s, -CH2-)~
4.10 (2H, q, -OCH2Cf~
4.15 (2H, s, -CH2-), 7.0 - 801 (7H, aromatic proton).
Example 10 In 50 ml of a saturated methanol solution of hydrogen chloride was dissolved 6012 g of 10,11-dihydro- -ll-oxo-5H-dibenzota,d~cycloheptene-2-acetic acid obtained in Example 1. ~he solution was s-tirred for 2 hours under ice cooling. Af-ter the reac-tion, -the reaction mixture was worked up in the same way as in Example 9 to afford 604 g of methyl 10,11-dihydro-11-oxo-5H-dibenzo~a,d~-cycloheptene-2-acetate as colorless needle-like crystals (recrys-tallized from ether/n-hexane) having a melting point of 111 to 112O5Co 1 15~82 Elemental analysis values for C18H1603:
Calculated (%): C 77.1 ~ 5.6 ~ound (%): ~ 7702 H 5.7 Example 11 In 50 ml of dry methanol was dissolved 6.3 g of methyl 10,11-dihydro~ oxo-5I~-dibenzo~a,d~cycloheptene-2-acetate obtained in Example 10. Thionyl chloride (7 g) was added, and the solution was heated under reflux for 2 hours with stirring. After the reaction, -the reac-tion mixture was cooled, and methanol was dis-tilled off.
The residue was dissolved in 200 ml of benzene. The benzene solution was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate~ The benzene was then distilled off.
The residue was chromatographed on a silica gel column using benzene as an eluentO A slightly yellow solid was ob-tained from the eluateO Recrystalliza-tion from n-hexane afforded ~o6 g of methyl 11-methoxy-5H-dibenzo-~a,d~cycloheptene-2-acetate as colorless needle-like crys-tals having a mel-ting point of 72 to 73~O
IR spectrum (KBr):
An absorption attributed to the ester group at 1730 cm~l; and an absorption attributed -to the enol ether group at 1240 cm~l.

1 1 ~9~

NMR spectrum (CDC13) ~ppm 3.~5 (2H, s, -C~I2-), 3.61 (3H, s, -COOCH3), 3.65 (2H, s, -CH2-), 3.87 (3H, s, -OCH3), 6.25 (lH, s, pro-ton at the 10-position), 7O0 - 707 (7E, aromatic proton).
Example 12 In 18 ml of methanol was dissolved 2.1 g of 10,11-dihydro~ oxo-5H-dibenzo~a,d~cycloheptene-2-acetic acid obtained in Example 1. ~hionyl chloride (201 g) was added, and the solution was heated under reflux for 3 hours with stirringO After -the reaction, the reaction mixture was cooled, and then worked up in the same way as in Example 11 to afford 2.5 g of methyl 11-methoxy-5H-dibenzo~a,d~cycloheptene-2-acetate as colorless needle-like crystals having a melting poin-t of 72 to 73C.
Elemental analysis values for C19H1803:
Calculated (%): C 77~5 H 60 2 Found (%): C 77.6 H 6.3 Example 1~
In 2 ml of ethanol was dissolved 0.1 g of 10,11-dihydro-10-oxo-5H-dibenzo~a,d~cyclokeptene-3-acetic acid obtained in Example ~. Thionyl chloride (0.1 g) was added, and the solu-tion was heated under reflux for 2 hours with stirring After the reaction, the reaction mixture was cooled, and then worked up in the same way as in Example 11 to afford 0.08 g of ethyl 10-ethoxy-5H-11~9~2~
_ 40 -dibenzo~a,d~cycloheptene-~-acetate as a colorless oily subs-tanceO
Refractive index: nD4 = 1.5944 ~lemen-tal analysis values for C21H2203:
~alculated (%): ~ 78.2 H 6.9 ~ound (%): ~ 7709 H 607 IR spectrum (neat):
An absorption at-tributed to the es-ter group a-t 1720 cm 1; and an absorption attribu-ted to the enol ether grou~ a-t 1235 cm lo Under a nitrogen stream, 1.2 ml of diisopropyl-amine was dissolved in 10 ml of dry tet ~ drofuran. A
15% n-hexane solution of n-butyl li-thium~was added with stirring to the solution cooled with acetone-dry ice.
The mixture was stirred for 20 minutes under cooling with acetone-dry icea Then, a solution of 1077 g of methyl ll-methoxy-5H-diben30~a,d~cycloheptene-2-acetate obtained in 5xample 12 in 6 ml of dry tetrahydrofuran was added gradually. The mixture was stirred for 20 minutes. A
solution of 0~4 g of methyl iodide in 3 ml of dry tetra-hydrofuran was gradually added, and the mixture was stir-red for 1 hourO To the resulting reaction mix-ture was added 5 ml of a saturated aqueous solution of ammonium chloride. The tetrahydrofuran layer was separated, and dried over anhydrous magnesium sulfate~ The solvent was distilled off. The resulting slightly yellow oily sub-s-tance was chromatographed on a silica gel column using 9~

benzene as an eluent. From the elua-te, 1075 g of me-thyl 2-(11-methoxy-5H-dibenzo~a,d~cyclohepten~-2-yl)propionate as a colorless oily substanceO
Refractive index: nD4 = 1~6058 ~MR spec-trum (CDC13):
~ppm l.L~ (3H, d, -CH-CH3), 3.5~ (3H, s, -COOCH3), 3056 (lH, q, -CH-CH3), 3060 (2H, s, -CH2-), 3085 (3H~ s, -OC~I3), 6.23 (lH, s, proton at the 10-position), 7.0 - 705 (7H, aromatic proton)O
Example 15 ,Small pieces of ferric ni-trate nonahydrate were added to 75 ml of liquid ammonia, and subsequently 0.733 g of metallic sodium was added little by li-ttleO
The mixture was stirred for 30 minutesD To the stirred mixture was added dropwise over the course of 10 minu-tes a solution of 6025 g of methyl 11-methoxy-5H-dibenzo-ta,d~cycloheptene-2-aceta-te obtained in Example 12 in 12 ml of dry toluene~ ~he mixture was stirred for 25 minutes, and a solution of 1D98 ml of methyl iodide in 2 ml of dry toluene was added dropwise over the course of 2 minu-tesO The mixture was further stirred for 1 hour, and then 1083 g of ammonium chloride and 12 ml of toluene were addedO Ammonia was released at room temperatureO

9~2~

_ 42 -~hen, 24 ml of l~/o hydrochloric acid was added under ice cooling and stirring, and the mixture was stirred for 15 minutesO Ether (100 ml) and 100 ml of water were added to extrac-t -the solutionO ~he organic layer was succes_ sively washed with wa-ter, a 10,~ aqueous solution of sodium thiosulfate and a sa-turated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate.
~he solven-t was distilled off~ rrhe residue was chroma-tographed on a silica gel column using benzene as an eluent. ~'rom the eluate, 5091 g of methyl 2-(11-me-thoxy-5H-dibenzo[a~d~cyclohepten-2-yl)propionate was obtained as a colorless oily substanceO
~e~
Six millili-ters of 47% hydrobromic acid was added to 0051 g of methyl 11-methoxy-5H-dibenzo~a,d~-cycloheptene-2-acetate obtained in Example 12, and the mixture was stirred at room temperature for 2 hours~
After the reaction, water was added to the reaction mix-ture, and the mixture was extracted with ether. ~he ethereal layer was washed wi-th a saturated aqueous solu-tion of sodium chloride, and the ether was distilled offO
Recrystallization of the residue from n-hexane afforded 0~4-3 g of methyl 10,11-dihydro-11-oxo-5H-dibenzo~a,d~-cycloheptene-2-acetate as colorless needle-like crystals having a melting point of 111 to 112Co Example 17 In 10 ml of benzene was dissolved 1046 g of methyl 2-(11-methoxy-5~I-dibenzo~a,d~cyclohepten-2-yl)-~ I 159~

- 4~ -propionate ob-tained in ~xample 14, and 16 ml of 47%
hydrobromic acid was addedO ~he mixture was vigorously stirred at room tempera-ture for 4 hours. ~fter the reac--tion, water (50 ml) was added to the reaction mix-ture~
~he benzene layer was separated, washed with a sa-turated a~ueous solution of sodium chloride, and dried over an-hydrous sodium sulfateO ~he benzene was distilled off.
Recrystallization of -the residue from a mixture of ether and n-hexane afforded 1 D 21 g of methyl 2-(10,11-dih~dro-11-e~y-5H-dibenzo[a~d)cyclohepten-2 yl)propiona-te as colorless needle-like crystals having a melting point of 121 to 123Co Elemental analysis values for C19Hl~G3 Calculated (%): C 77 ~ 5 I~ 60 2 Found (%)~ C 7701 H 5.9 Example 18 In 2 ml of methanol was dissolved Ool g of methyl lo~ dihydro-ll-oxo-5H-dibenzo[a~d~cycloheptene 2-acetate ob-tained in ~xample 16, and 6 ml of a 10%
20 aqueous solution of sodium hydroxide was added. ~he mix-ture was hea-ted under reflux for 2 hours with stirring.
After the reac-tion, the reaction mixture was cooled, and water was added. ~he mixture was acidified with 10%
hydrochloric acid, and the precipitated solid was ex-25 tracted with ether. ~he ethereal layer was washed witha saturated a~ueous solu-tion of sodium chloride and then dried over anhydrous magnesium sulfate. ~he ether was distilled offO Recrystallization of the residue from a J l S9826 _ 4L~ _ mixture of ether and n-hexane afforded 0.082 g of 10,11-dihydro-ll-oxo-5H-dibenæo~a,d~cycloheptene-2-acetic acid as colorless needle-like crys-tals having a melting point of 171 to 173Co In the same manner as above, the following compounds were producedO
(i) 2-(10,11-dihydro-11-oxo-5H-dibenzo[a,d~cyclo-hepten-2-yl)propionic acid Form: colorless needle-like crystals (recrystallized from n-hexane) Melting point: 135 to 136C
(ii) ll-methoxy-5H-dibenzo~a,d~cycloheptene-2-acetic acid Form: colorless needle-like crystals (recrystallized from ethyl acetate/n-hexane) Melting point: 174 to 175C
Elemental analysis values for C18H1603:
Calculated (%): C 77.1 H 5.8 Found (%): C 76.8 H 5O5 (iii) 2-(11-methoxy-5H-dibenzota,d~cyclohepten-2-yl)-propionic acid Form: colorless amorphous Solid IR spectrum (KBr):
~n absorption attributed to the carboxyl group at 3500 ~ 2300 cm~l and 1695 cm~l; and an absorption attributed to the enol ether group a-t 1240 cm lo Q~2 ~MR spectrum (CDCl3):
ppm 1042 (3H, d, -CHCH3), COOH
3 65 (lH, q, -CHCH~5), COOH
3.85 (3H, s, -OCH3), 6.23 (lH, s, proton at the 10-position), 6.95 7.70 (7H, aromatic proton), 905 (lH, br, -COOH; disappeared in D20)o Example 19 Six milliliters of 47~(, hydrobromic acid was added to 0.32 g of methyl ll-methoxy-5H-dibenzo[a~d~-cycloheptene-2-acetate ob-tained in Example ll, and the mixture was stirred at lOO to 125C for 30 minu-tesO After the reaction, the reaction mix-ture was cooled, and water was added. The mixture was extracted with ether. The ethereal layer was washed with a saturated aqueous solu-tion of sodium chloride, and dried over anhydrous magne-sium sulfa-teO The ether was distilled offO Recrystal-lization of -the residue from a mixture of methanol and n-hexane afforded 0.22 g of lO,ll-dihydro-ll-oxo-5H-dibenzo~a~d~cycloheptene-2-acetic acid as colorless needle-like crystals.
Example ?
In l ml of xylene was dissolved Ool g of ethyl lO-ethoxy-5H-dibenzo~a,d~cycloheptene-~-acetate ob-tained in Example 13, and 5 ml of 47',''i hydrobromic acid was addedn The mixture was heated under reflux for 2 ho-urs with 1 1~9~6 vigorous stirringO After the reaction, the reaction mixture was cooled, and then worked up in the same way as in Example 19 to afford ~07 g of 10,11-dihydro-10-oxo-5H~dibenzo~a,d~cycloheptene-3-ace-tic acid as a color-less crystalline powder (recrystallized from a mixture ofmethanol and n-hexane) having a melting poin-t of 186 to 18705Co eferential Exa~3~1e 1 (A) Anhydrous aluminwn chloride (456 g) was sus-pended in 1.1 li-ters of 1,2-dichloroethane, and a solu-tion of ~28.6 g of ace-tyl chloride in 2 liters of 1,2-aichloroethane was added dropwise under ice cooling and stirring. '~he mixture was stirred for 30 minu-tes ~mder ice cooling, and then, a solution of 456 g of ethyl 2-banzylbenzoa-te in 0.6 liter of 1,2-dichloroe-thane was added dropwise. '~he mixture was stirred for 2.5 hours at room temperature. ~fter the reaction, the reaction mixture was poured into 4 liters of a mixture of ice water and concO hydrochloric acid, and the 1,2-dichloroethane layer was separated. '~he aqueous layer was extracted with 1,2-dichloroethaneO ~he 1,2-dichloroethane layers were combined, washed with a 5% aqueous solution of sodium hydroxide and a satura-ted aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfa-te.
'~he solvent was distilled off. ~he resulting yellow oily subs-tance was distilled under reduced pressure -to afford 510 g of 4-(2-ethoxycarbonylbenzyl)acetophenone as a pale yellow oily substance having a boiling point of 164 to '-' 'l1~9 165C (0015 to 0~17 mmHg)D
¢lemental analysis values for C18H1803:
Calculated (%): C 76~6 H 6.4 Found (%): C 76.5 H 603 IR spectrum (neat):
~n absorption at-tributed to the ester group at 1715 cm 1; and an absorption attributed to the carbonyl group at 1680 cm~10 N~R spectrum (CDC13):
~ppm 1~30 (3H~ t~ J=705 Hz~ -COOCH2CH3)~
2.49 (3H, s, -COCH3), 4024 (2H, q, J=7.5 Hz~ -COOCH2CH3) L~.40 (2~I, s, -C~I2-), 7.0 - 8.1 (8H, aromatic proton).
(B) A solution of 130 g of 4-(2-ethoxycarbonyl-benzyl)acetophenone in 0.2 liter of diglyrne was added dropwise to a solution of 34O1 g of sodium boroh~dride in 006 liter of diglymeO Then, a solution of 4505 g of aluminum chloride in 0017 liter of diglyme was added dropwise, and the mixture was stirred at room temperature for 1 hour and then at 50C for 1 hourO Under ice cooling,

5 liters of a mixture of ice and 10% hydrochloric acid was added, and the mixture was vigorously s-tirredO ~he in-soluble matter was collected by filtration, dried, and recrystallized from benzene to afford 136 g of (l-hydroxy~
ethyl)-4-(2-hydroxymethylbenzyl)benzene as colorless ne-edle-like crys-tals having a melting point of 96 to 97C~

9g~
-_ 48 -Elemental analysis values for C16H1802:
Calculated (/6) C 79.3 ~I 7.5 ~ound (%): C 79.3 E 705 IR spectrum (KBr) ~n absorption attribu-ted to -the hydroxyl group at 3320 cm~l.
NMR spectrum (CDC13/DM~O-d6=lO l) ~ppm 1~38 (3H, d, ~=7.5 Hz, OH
-CH-CH3), 3094 (2~I, s, -CH2-), 4049 (2EI, s, -CH20H), 4.50 (2H, s, -OH x 2; disappeared in D20), 4.77 (lH, q, J=705 Hz, OH
-CH-CH3), ~.9 - 7.6 (8H, aromatic proton)O
(C) In 20 ml of benzene was suspended 4.85 g of (l-hydroxyethyl)-4-(2-hydroxymethylbenzyl)benzene, and with stirring under ice cooling, 6~0 ml of thionyl chloride was added dropwise. ~he mix-ture was stirred at room tem-perature for 2 hours and then at 65C for 15 minutes.
After the reaction, the reaction mixture was cooled, and the solvent was distilled off. ~he residue was dissolved in ether, and the ethereal layer was washed with a 10%
aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodi~m chloride and dried over an-hydrous magnesium sulfateO ~he ether was distilled off -to afford 5.6 g of (1-chloroethyl)-4-(2-chlorome-thyl-benzyl)benzene as a colorless liquidO

9~2~
~ , .
- 49 _ Elemental analysis values for C16H16~12:
Calculated (%) C 68.8 H 5.8 ~ound (%) C 68.9 ~ 5.8 NMR spectrum (CDC13):
ppm 1.81 (3H, d, J=705 Hz, Cl -CH-CH3), 4.11 (2H, s, -CH2-), 4049 (2H, s, -CH2Cl~, 5.03 (lH, q, J=7.5 Hz, Cl -CH-CH3), 6095 _ 7 o 45 (~, aromatic proton).
(D) Sodium cyanide (204 g) and 0.8 g of benzyl triethyl ammonium chloride were added to 30 ml of di-methyl formamide, and with stirring, a solution of 5.6 g of (l-chloroethyl)-4-(2-chloromethylbenzyl)benzene in 10 ml of dimethyl formamide was added. ~he mixture was stirred at 40C for 1 hour and then at 70C for 20 hours.
After the reaction, the reaction mixture was cooled, and 70 ml of water was addedO The mixture was extracted with ether. ~he ethereal layer was washed with water, dried over anhydrous magnesium sulfate and distilled off to remove the etherO ~he resulting pale yellow oily sub_ stance was chromatographed on a silica gel column using benzene as an eluent. From the eluate, 3.4 g of (1-cyanoethyl)-4-(~-cyanomethylbenzyl)benzene was obtained as a colorless liquidO This compound crystallized by stimulating the reac-tor wall through addition of n hexaneO
Recrystallization from a mixture of ether and n-hexane afforded colorless needle-like crystals having a melting point of 61 to 64C.
Elemental analysis values for C18H16N2:
Calculated (/0): C 83.0 H 6.2 N 10.8 ~ound (/0): C 82.6 H 6.2 N 10.4 IR spectrum (KBr):
An absorption at-tributed to the cyano group at 2240 cm~10 NMR spectrum (CDC13):
~ ppm 1.37 (3H, d, J=7.5 Hz, CN
-CHCH3), 3052 (2H, s, -CH2CN), 3.83 (lH, q, J=7.5 Hz, CN
-CH~H3), 4.00 (2H, s, -CE~2-),

6.95 - 7~5 (8H, aromatic proton).
15 (E) In 5 ml of ethanol was dissolved 1.72 g of (l-cyanoethyl)-4-(cyanomethylbenzyl)benzene, and 3 ml of a 50/0 aqueous solution of potassium hydroxide was added.

~he mixture was heated under reflux ~or 15 hours. After the reaction, the reaction mixture was cooled, and 30 ml of water was addedO The mixture was washed with ether, and the aqueous layer was acidified with conc. hydro-chloric acid. The precipi-tated solid was extracted with ethyl acetate~ ~he ethyl acetate layer was washed with a sa-turated aqueous solution of sodiurn chloride, dried over anhydrous magnesium sulfate, and distilled o~f -to remove the ethyl acetate. ~he residual brown solid was g ~ 2 ~

recrystallized from benzene to afford 1.~1 g of 2-[4~
carboxyethyl)benzyl~phenylacetic acid as colorless prisma-tic crystals having a melting point of 135 to 137C.
Elemental analysis values for C18H1804:
Calculated (%): C 7205 H 601 Found (%): C 7202 H 601 IR spectrum (KBr):
An absorption attributed to the carboxyl group at 3600 - 2300 cm~l and 1695 cm~10 NMR 'spectrum (CDC13/DMSO~d6_10:1):
,gppm 1.38 (3H, d, J=7.5 Hz, COOH
-CH-CH3), 3.52 (2H, s, -CH2COOH), 3.60 (lH, q, J=7.5 Hz, COOH
_C_-CH3)~
3.95 (2H, s, -CH2-),

7.12 (8Ii, aromatic proton), 10.8 - 12.2 (2H, br, -COOH x 2; disappeared in D20)o Referential Example 2 (A) Ethyl 2-benzylbenzoate (54.0 g) was dissolved in 100 ml of dichloromethane, and with stirring, 121.3 g of stannic chloride was added while cooling the solution with a mix-ture of ice and sodium chloride. The mixture was stirred for 1 hour Subsequently, 86 g of a,a-di-chloromethyl methyl ether was added dropwise over 1 hour, and then the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was 9 8 ~ 6 poured into 1 liter of ice wa-ter, and s-tirred. ~he di-chloromethane layer was separated, washed with water, a sa-turated aqueous solution of sodium carbonate and sub-sequently with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfateO
The dichloromethane was distilled off~ To -the residue was added 250 ml of a saturated aqueous solution of sodiurn bisulfite~ and the mixture was vigorousl~ s-tirred.
The precipita-ted crystals were collected by fil-tration, and washed with 100 ml of a saturated aqueous solution of sodiurn chloride and then with 100 ml of ether. The crystals were then suspended in 500 ml of wa-ter, and wi-th s-tirring, 120 g of sodium carbonate was added little by little over the course of 15 minutesO The mixture was stirred for 2 hours. The separated oily subs-tance was ex-tracted with 300 ml of etherO ~he ethereal layer was washed with water and dried over anhydrous magnesium sulfateO ~he ether was distilled off to afford 43~3 g of 4-(2-ethoxycarbonylbenz~l)benzaldehyde as a red oily substanceO
IR spectrum (neat):
An absorption a-ttributed -to -the carbonyl group at 1705 cm~lO

C) ~ ~982~

NMR spectrum (CDC13):
Sppm 1025 (3H~ t, -CG2CH2CH3), LL.20 (2H, q, -C02CH2CH3), L~o41 (2H, s~ -CH2-)' 700 - 800 (8H, aromatic proton), 9086 (lH, S1 -CH0).
(B) Sodium borohydride (706 g) was added -to 200 ml of diglyme, and with stirring at room temperature, a solution of 3903 g of 4-(2-ethoxycarbonylbenzyl)benzal-dehyde in 50 ml of diglyme was added dropwise over the course of ~5 MinutesO Subsequently, a solution of 9033 g of anhydrous aluminum chloride in 50 ml of di~lyme was added dropwise over the course of 15 minutesO 'rhe mix-ture was stirred at room temperature for 2 hours, and then at 45 -to 50C for 1 'nourO ~he reaction mixture was poured into about 3 liters of ice wa-ter, and s-tirred.
'rhe pre~cipi-ta-ted crystals were collected by filtration, washed with water, dried, and recrys-tallized from benzene to afford 28.2 g of 4-(2-hydroxymethylbenzyl)benzyl al-cohol as colorless needle-like crystals having a melting point of 101.5 to 102Co Elemental analysis values for C15H1602:
Calculated (/0) C 78.9 H 701 ~ound (~6): C 7808 H 702 IR spectrum (KBr):
An absorption attribu-ted to the hydroxyl group at 3310 and 3200 cm~10 9~26 C) NMR spectrum (CDC13/DMSO-d6=1:1):
ppm 4000 (2H, s, -CH2-), 4.00 - 4.35 (2H, m, -OH x 2; disappeared in D20 ) ~
4.54 (2H, s, -CH20H), 4.62 (2H, s, -CH20H), 6.9 - 705 (8H, aromatic proton).
(C) Benzene (130 ml) and 5203 g of thionyl chloride were added to 25 g of 4-(2-hydroxyme-thylbenzyl)benzyl alcohol, and the mixture was stirred at room temperature 10 for 2.5 hoursO 'rhe solven-t was distilled off. ~he re-siaue was dissolved in 100 ml of benzene and washed with water. ~he benæene layer was dried over anhydrous magnesium sulIate, and distilled off to afford 28 g of 4-chloromethyl-(2-chloromethylbenzyl)benzene as a pale yellow oily substance.
NMR spectrum (CDC13):
~ppm 4.07 (2H, s, -C_2-), 4-.40 (2H, s, -C_2Cl), 4.43 (2H, s, -CH2C1), 6.9 - 7.3 (8H, aromatic proton).
(D) Potassium cyanide (15.58 g) was dissolved in 33 m~ of water, and with stirring, 116 ml of ethanol was added. ~he mixture was heated to 70 to 75Co ~hen, ~6.42 g of 4-chloromethyl-(2-chloromethylbenzyl)benzene 25 was added over the course of 15 minutes, and the mixture was heated under reflux for 4 hours with stirringl ~he reaction mixture was cooled, ancl the insoluble matter 9~2 was removed by filtrationO The solvent was distilled off.
Benzene (100 ml) was added to the residueO ~he benzene solution was washed with water, and then with a saturated aqueous solution of sodium chloride. The benzene layer was dried over anhydrous magnesium sulfate, and the benzene was distilled off. To the residue was added 80 ml of ethanol, and 120 ml of a 20% aqueous solution of sodium hydroxide was added. The mixture was heated under reflux for 16 hours wi-th s-tirring. Af-ter the reaction, the reaction mix-ture was cooled, and the solvent was distilled offO The residue was concentrated to half of its original volwne. Water (100 ml) was added, ~md the Mixture was washed wi-th 50 ml of ether. The aqueous layer was acidified with 10% hydrochloric acid, and the precipi-tated solid was extracted wi-th ethyl aceta-te. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfateO The ethyl acetate was distilled off.
The crys-talline residue was recrystallized from a mixture of ethyl acetate and n-hexane -to afford 2200 g of 2~
carboxymethylbenzyl)phenylacetic acid as slightly yellow needle-like crystals having a melting point of 155 to 156Co Referential Exa~mple 3 2~ Thallium trini-trate (0.49 g) was dissolved in 30 ml o~ methanol, and 005 ml of 70,' perchloric acid was added. Under ice cooling, a solution of 0013 g of L~-(2-acetylbenzyl)ace-tophenone in 008 ml of carbon tetrachlQride was addedO '~he mixture was then stirred at room tempera--ture for 40 hoursO The precipitated colorless crystalline insoluble ~atter was removed by fil-tration. To the fil-trate was added -three times its volume of water, and the mixture was extrac-ted with chloroformO The chloroform layer was washed with a 10% aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and distilled off to remove the chloroformO ~he resulting brown oily substance was chromatographed over a silica gel colunln using chloroform as an eluent to afford 0.04 g of methyl 2-(4-methoxJcarbonylmethylbenzyl)phenylaceta-te as a yellowish oily substance.
IR spectrum (neat):
An absorption attributed to the ester group a-t 1730 cm 1.
NMR spectrum (CC14):
~ppm 3.42 (4H, s, -CH2COOCH3 x 2), 3.49 (3H, s, -C~I2COOCH3), 3056 (3~, s, -CH2COOCH3), 308L~ (2H, s, -C~I2-), 6.9 - 7.2 (8H, aroma-tic proton)O
Referential Example 4 In 20 ml of carbon -tetrachloride was dissolved 0.50 g of 4-(2-acetylbenzyl)acetophenone, and 6.7 g of thallium trinitrate adsorbed to acidic montmorillonite (K-10) was added. ~he mixture was stirred at room tem-perature for 1 hourO ~he insoluble matter was removed by filtrationO ~he carbon te-trachloride layer was washed with water, and dried over anhydrous magnesium sulfate.
~he carbon tetrachloride was distilled off to afford 0048 g of methyl 2-(4-me-thoxycarbonylmethylbenzyl)phenyl-acetate as a yellowish oily substanceO
The oily substance (0043 g) was dissolved in

8 ml of ethanol, and 8 ml of a 20k aqueous solution of potassium hydroxide was addedO The mixture was hea-ted under reflux for 2 hours. ~he ethanol was distilled off, and the aqueous layer was washed wi-th ether. ~he aqueous layer was then acidified wi-th conc. hydrochloric acid, and the resul-ting colorless crystalline precipitate was collected by filtration, and recrystallized from ethyl acetate -to afford 0.26 g of 2-(4-carboxymethylbenzyl)-phenylacetic acid as a colorless crystalline powder having a melting point of 155 to 156Co Elemental analysis values for C17H1604:
Calculated (,~): C 71.8 H 5.7 Found (%): C 71.6 H 5 06 IR spectrum (KBr):
An absorption attributed to the carbox~l group at 3500 - 2300 cm~l and 1690 cm~l.
NM~I spectrum (CDC13/DMSO-d6=10:1):
ppm 3.53 (4H, s, -CH2COOH x 2), 3097 (2H~ s, -C_2-), 6.9 - 703 (8H, aromatic proton), 10025 (2H, bs, -COOH x 2: disappeared in D20)o Referential ExarnPle 5 In 60 ml of carbon tetrachloride was dissolved ,~ 1 15982 2066 g of 4-(2-acetylbenzyl)propiophenone, and 36.0 g of thallil~n trinitrate adsorbed to acidic montmorillonite (~-10) was added. ~he mixture was heated under reflux for 1 hourO After the reaction, the reaction mixture was cooled, and then the insoluble matter was removed by filtrationO The carbon te-trachloride layer was washed with water, dried over anhydrous magnesium sulfate, and distilled off -to afford 2068 g of methyl 2-~4-(1-methox~-carbonylethyl)benzyl~phenylacetate as a yellowish oily substance.
IR spectrum (neat):
An absorption attributed to the ester group at 1730 cm~lO
NMR spectrum (CC14):
~ppm 1.40 (3H, d, J=7 Hz, COOCH3 3.42 (lH, q, J=7 Hz, COOCH3 - CHCH2 ), 3044 (2H, s, -CH2COOCH3), 3.46 (3H~ s, -COOCH3), 3.50 (3H, s, -COOCH3), 4~92 (2H, S7 -CH2-) ~
6~3 - 702 ~8H, aromatic proton)O
~he oily substance (2.54 g) was dissol~ed in 20 ml of ethanol, and 20 ml of a 20% aqueous solution of potassium hydroxide was added. ~he mixture was heated under reflux for 3 hoursO The ethanol was distilled off.
The aqueous layer was washed with ether, acidified with (-- 1 159828 ',9 conc. hydrochloric acid, and extracted with ethyl acetate. 'rhe ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and distilled offO
The resul-ting yellowish crystalline powder was recrystal-lized from benzene to afford 1.03 g of 2-~4-(1-carboxy-e-thyl)benzyl~phenylacetie acid as a colorless crystalline powder having a melting point of 135 to 136C.
The s-tarting 4-(2-ace-tylbenzyl)propiophenone was prepared by the following method.
Anhydrous aluminum chloride (26.6 g) was sus-pendsd in 60 ml of carbon disulfide, and under ice cool-ing, a solu-tion of 37.0 g of propionyl chloride in 60 ml of earbon disulfide was added dropwissO The mixture was stirred at room tempera-ture for 30 minutes. The mixture was cooled wi-th iee, and a solu-tion of 8~ g of o-benzyl-aee-tophenone in 60 ml of carbon disulfide was added drop-wise. The mixture was stirred for 15 minutes under iee cooling. After the reaetion, the reaction mix-ture was poured into a mixture of 300 ml of ice and 100 ml of conc.
hydroehlorie acid, and the earbon disulfide layer was separatedO The aqueous layer was extraeted with ether.
The organic layers were combined, washed with a 10%
aqueous solution of sodium bicarbonate and a saturated aqueous solu-tion of sodium chloride, dried o~er anhydrous magnesium sulfate, and distilled offO The resulting pale yellow oily subs-tance was chromatographed on a silica gel colu~n using chloroform as an eluent-to afford 9.4 g of L~-(2-acetylbenzyl)propiophenone as a pale yellow oily 1 1~9826 substanceO
On standing for a while, this compound crystal-lizedO Recrystallization from ethanol afforded yellowish prismatic crystals having a melting point of 56~5 to 5705C.
Elemental analysis values for C18H1802:
Calcula ted (%): C 8102 H 6.8 Found (%): C 81.0 H 608 IR spe ctrum (KBr):
An absorption attributed to the carbonyl group at 1675 cm~lu N~1R spectrum (CDC13):
~ppm 1.01 (3H, -t, J=7 ~Iz, -COCH2CH3), 2029 (3H, s, -COCH3), 2u32 (2H, 9, J=7 Hz, -COCH2-CH3), L~ol9 (2H, s, -CH2-)~
6.85 - 7080 (8H, aromatic proton)O
In the same way as above, 4-(2-ace-tylbenzyl)-acetophenone was preparedO
Form: yellow oily Elemental analysis values for C17H1602:
Calculated (/0): C 80..9 H 604 ~ound (,~): C 8008 H 6.4 IR spec-trum (neat):
An absorption attributed to the carbonyl group at 1680 cm~l.

(~ ~1598~
.

NMR spectrum ( CCl,~
~'ppm 2046 (3H, s, -COCH3), 2. 50 ( 3H, s, -COCH3), 4. 32 ~2H, s. -CH2-), 7005 - 8.,91 (8H, aromatic proton),

Claims (16)

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

1. A process for preparing a dibenzo[a,d]cycloheptene derivative of the general formula I

wherein R1 represents a hydrogen atom, a halogen atom or a lower alkyl group, R2 and R3 each represent a hydrogen atom or a lower alkyl group, and Z represents a group of the formula or -?-CH2-, which comprises:

(a) cyclizing a compound of the general formula II

wherein R1 and R2 are as defined above, X represents a hydroxyl group or a halogen atom, one Y represents a group of the formula -CH2COX, and the other Y
represents a hydrogen atom, optionally hydrolyzing the cyclized product, and optionally esterifying the product and/or etherifying its enol group; or (b) reducing the carbonyl group of a compound of the general formula III

wherein R1 and R2 are as defined above, one Y' represents a group of the formula -CH2COOH, and the other Y' represents a hydrogen atom, to a methylene group, optionally converting the product to a carboxylic acid halide, cyclizing the product, optionally hydrolyzing it, and then optionally esterifying it and/or etherifying its enol group.

2. A process for preparing a dibenzo[a,d]cycloheptene derivative of formula I as defined in claim 1 which comprises cyclizing a compound of the general formula II' wherein Rl is as defined above, X represents a hydroxyl group or a halogen atom, one Y represents a group of the formula -CH2COX, and the other Y represents a hydrogen atom, optionally hydrolyzing the cyclized product, to form a compound of the general formula I' wherein Rl is as defined above, and Z' represents a group of the formula or-, esterifying and enol-etherifying this compound to form a compound of the general formula IV

wherein Rl is as defined above, R'3 represents a lower alkyl group, and Z"
represents a group of the formula -, and optionally subjecting the resulting compound to alkylation, dealkylation of the enol ether group, and/or hydrolysis.

3. A process according to claim 1 or 2 wherein the compound of formula II
or II' is obtained by reducing the carbonyl group of a compound of the general formula wherein R1 and R2 are as defined in claim 1, one Y' represents a group of the formula -CH2COOH and the other Y' represents a hydrogen atom, to a methylene group and optionally halogenating the resulting product.

4. A process according to claim 1 wherein R1 is hydrogen, fluorine, chlorine or a tert.butyl group, Z is an oxo-containing group, R2 is hydrogen or methyl, R3 is hydrogen and the -CH(R2)COOH group occupies the 2- or 3-position.

5. A process according to claim 2 which comprises further reaction to etherify the enol form of group Z and to esterify the carboxy group -CH(R2)COOH
to obtain a compound in which R3 is methyl or ethyl.

6. A dibenzo[a,d]cycloheptene derivative of formula I as defined in claim 1 when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

7. A process according to claim 1 wherein R1 is hydrogen, Z is an oxo-containing group and the oxygen atom of the oxo group occupies the 11-position, R2 and R3 are both hydrogen and the carboxymethyl group occupies the 2-position.

8. A process for preparing 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cyclo-heptene-2-acetic acid which comprises cyclizing 2-(4-carboxymethylbenzyl)-phenylacetic acid in the presence of polyphosphoric acid.

9. A process for preparing 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cyclo-heptene-2-acetic acid which comprises reacting 2-(4-carboxymethylbenzyl)phenyl-acetic acid with thionyl chloride to form 2-(4-chlorocarbonylmethylbenzyl)-phenylacetyl chloride and cyclizing this compound in the presence of stannic chloride.

10. A process according to claim 8 or 9 wherein the 2-(4-carboxymethyl-benzyl)phenylacetic acid is obtained by reducing 2-(4-carboxymethylbenzoyl)-phenylacetic acid by reaction with zinc amalgam.

11. The compound 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-2-acetic acid when prepared by a process according to claim 8 or 9 or an obvious chemical equivalent thereof.

12. A process according to claim 1 wherein R1 is hydrogen, Z is an oxo-containing group and the oxygen atom of the oxo group is in the 11-position, R2 is methyl, R3 is hydrogen and the CH(CH3)COOH group is in the 2-position.

13. A process for preparing 2-(10,11-dihydro-11-oxo-5H-dibenzo[a,d]cyclo-heptene-2-yl)propionic acid which comprises cyclizing 2-[4-(1-chlorocarbonyl-ethyl)benzyl]phenylacetyl chloride in the presence of aluminum chloride or antimony pentachloride.

14. A process according to claim 13 wherein the 2-[4-(1-chlorocarbonyl-ethyl)benzyl]phenylacetyl chloride is obtained by reacting 2-[4-(1-carboxyethyl)-benzyl]phenylacetic acid with thionyl chloride.

15. A process according to claim 14 wherein the 2-[4-(1-carboxyethyl)-benzyl]phenylacetic acid is obtained by acetylating ethyl 2-benzylbenzoate by reaction with acetyl chloride in the presence of aluminum chloride, reducing the obtained 4-(2-ethoxycarbonylbenzyl)acetophenone with sodium borohydride, reacting the obtained (1-hydroxyethyl)-4-(2-hydroxymethylbenzyl)benzene with thionyl chloride, reacting the obtained (1-chloroethyl)-4-(2-chloromethylbenzyl)-benzene with sodium cyanide in the presence of benzyl triethyl ammonium chloride to obtain (1-cyanoethyl)-4-(2-cyanomethylbenzyl)benzene and subjecting this compound to hydrolysis to obtain the required 2-[4-(1-carboxyethyl)benzyl]-phenylacetic acid.

16. The compound 2-(10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-2-yl)propionic acid when prepared by a process according to claim 13, 14 or 15 or an obvious chemical equivalent thereof.