CA1153383A - Dibenzoxepin derivatives and process for the preparation thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Dibenzoxepin derivatives of formula:
wherein R1 represents a hydrogen atom, a halogen atom, a trihalometyl group or a lower alkoxy group;
R2 represents a hydrogen atom or a lower alkyl group;
R3 represents a carboxyl group, a lower alkoxycarbonyl group, a hydroxymethyl group, a lower alkoxymethyl group or a lower acyloxymethyl group; and Q represents a methylene group, a hydroxymethylene group or a carbonyl group;
salts of such derivatives;
the method for preparing such derivatives and their salts;
the derivatives and their salts having distinctive analgesic, antipyretic, and anti-inflammatory activity, and potent inhibi-tory action on platelet aggregation for humans and animals.

Description

~153383 BACKGROUND OF THE INVENTION
___________________________ 1. Field of the Invention This invention relates to dibenzoxepin derivatives and to processes for preparing the same. More particularly, this invention relates to novel dibenzoxepin derivatives represented by the general formula (I) 10 Rl ~ ~ 4 R12 _ R3 (I) wherein Rl represents a hydrogen atom, a halogen atom, a trihalomethyl group or a lower alkoxy group;
R2 represents a hydrogen atom or a lower alkyl group;
R3 represents a carboxyl group, a lower alkoxycarbonyl group, a hydroxymethyl group, a lower alkoxymethyl group or a lower acyloxymethyl group; and Q represents a methylene group, a hydroxymethylene group or a carbonyl group.
~he invention also relates to salts of such derivatives and to the method of preparing such derivatives and their salts. The compounds have distinctive analgesic, antipyretic, anti-inflamma-tory activity and potent inhibitory activity on platelet aggre-gation for human beinqs and animals.

'~

llS3383 1 2. Description of the Prior Art Up to now, compounds structually similar to those of this invention, xanthone-propionic acid and dibenzothiepinone-acetic acid shown in the following chemical formulae (II) and (III), respectively, are known, and are described in Japanese Patent Publication No. 425/1972, and Collection of Czechoslovak Chemical Communication, Vol. 38, pp. 1602-1604 (1973);

~ ~ CIH3 (II) ~ CHCOOH
o [~H 2COOH ~ I I I ) Compounds having structures as shown in formulae (II) and (III), however, have not proved satisfactory for clinical use because of their undesirable side-effects or insufficient activities as shown hereinafter.

SUMMARY OF THE lNVENTION
_____________________ Accordingly, it is one object of this invention to pro-vide compounds which have excellent analgesic, antipyretic, anti-inflammatory properties and potent inhibitory action on platelet aggregation and can be safely used clinical1y without deleterious side-effects.
Another object is to provide methods for manufacturing such derivatives and their salts.
Further objects will appear hereinafter.
This invention provides dibenzoxepin derivatives repre-sented by the general formula (I) -- 2 _ Rl ~ Q ~ c2 _ R3 ~I) wherein Rl represents a hydrogen atom , a halogen atom, a trihalomethyl group or a lower alkoxy group;
R2 represents a hydrogen atom or a lower alkyl group, R3 represents a carboxyl group, a lower alkoxycarbonyl group, a hydroxymethyl group, a lower alkoxymethyl group or a lower acyloxymethyl group, and Q represents a methylene group, a hydroxymethylene group or a carbonyl group the salts of these dibenzoxepin derivatives and methods for the preparation thereof.
The compounds of this invention can be prepared by one of the methods represented by the following reaction schematics ~A) to (F).

(A) R~CH20~[3_ ~R2 Cyclizatio ~ R1~312R3 (IV) (B) ~ R2 Reduction ~ ~ IR2 CH-R3 ~Rl ~ ~IR3 (V) (C) ~ O R2 Hydrolysis o ~ R
Rl ~ ~ ~ C-R Alcoholysis ~ ~ ~ CHR
~ Q ~ I Decarboxylation 1 (VI) (D) 12 Oxidation > Rl ~ ~ ~R2R3 (VII) (E) R ~ C2R Oxidation R ~ cR2R3 (VIII) o (F) CocH3 xidation R ~ 0 ~ 2COOR2 (IX) In each of the above reaction schematics (A~ to tF), the generic symbols which are employed have the following meanings.
, Rl can be a hydrogen atom, a halogen atom, a trihalomethyl group, or a lower alkoxy group;

~153383 1 R2 can be a hydrogen atom, or a lower alkyl group7 R3 can be a carboxyl group, a lower alkoxycarbonyl group, a hydroxymethyl group, a lower alkoxymethyl group, a lower alkoxycarbonyl group, or a lower acyloxymethyl group;

R4 can be a carboxyl group, a hydroxymethyl group, a lower alkoxymethyl group, a lower alkoxycarbonyl group, a lower acyloxymethyl group, or a cyano group;
X can be a halogen atom, or a hydroxy group, Y can be a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a hydroxymethyl group, a lower alkoxycarbonyl group, a lower acyloxymethyl group, a halocarbonyl group, a carbamoyl group, or . a cyano group;
Z can be a formyl group, a hydroxymethyl group/ or a lower alkoxymethyl group; and .~
. .~, .~

llS3383 1 Q can be a methylene group, a hydroxymethylene group, or a carbonyl group.

DETAILED DESCRIPTION OF THE INVENTION
_____________________________________ Method (A): The desired compounds in accordance with this invention are produced by cyclizing the raw materials in the presence of a suitable condensing agent, or without any condensing agent, and then, if desired, subjecting to the product obtained hydrolysis. As the condensing agent, anhydrous phosphoric acid, anhydrous trifluoroacetic acid, polyphosphoric acid and the ester thereof or the like may preferably be used. Though the reaction conditions vary in accordance with the kind of condensing agent, the reaction is generally carried out by heating the raw materials at from about room temperature (e.g., 20 - 30C) up to about 150C
for several hours in a solvent, such as, benzene, xylene and the like, or without a solvent.
The raw materials (IV) used in this method are novel and can be produced by reacting halomethyl benzene derivatives having the following formula;

R~ 2 W

wherein X represents a halogen atom and W represents a halocarbonyl group, an alkoxycarbonyl group, an aldehyde group, a hydroxymethyl group, a cyanocarbamoyl group or the like and Rl is the same as hereinbefore defined; with phenol derivatives having the following formula;

';

1 l2 HO ~ CHR3 wherein R2 and R3 are the same as hereinbefore defined, in a solvent, in the presence of a base, such as, an alkali metal hydroxide or alkoxide and then, if necessary, by oxidizing, hydrolyzing or alcoholizing the resulting compound.
In greater detail, the raw materials (IV) are produced by reacting the halomethylbenzene derivatives with phenol deriva-tives in an organic solvent, such as, methanol, or dimethylforma-mide, at the boiling temperatures of the solvents for several hours in the presence of a base, such as, an alkali metal hydroxide or methoxide. In this method, phthalides can be used in place of the halomethylbenzene derivatives.
When phthalides are used, the reaction of this step can be easily performed by melting the phthalides with the phenol derivatives without a solvent at a temperature between abou~ 150C
and 250 & . The raw materials (IV) thus produced can be used in Method (A) in a free form or in the form of its alkali metal salt to produce the compounds of this invention.
Method (B): Some of the compounds of this invention can be manufactured by reducing the raw materials (V) by using a con-ventional method, for instance, by reducing the raw materials (V) in the presence of zinc powder in an acidic or alkaline solvent or by using the Clemensen reaction, preferably at a temperature between about room temperature (e.g., 20C - 30C) and about 150C.
Method (C): The compowlds of this invention can be produced by hydrolyzing, alcoholizing or decarboxylating the raw materials, for instance, hy heating the raw materials ~VI) together 1 with sodium hydroxide or an acid, such as sulfuric acid, or hydrochloric acid, in aqueous alcohol.
Method (D): The compounds of this invention can be pro-duced by oxidizing the raw materials (VII) with an oxidizing agent, such as, chromium trioxide or potassium permanganate at low tem-perature in an inorganic or organic solvent.
Method (E): The compounds of this invention can be pro-duced by means of conventional oxidation, for instance, by heating the raw materials (VIII) in the presence of an oxidizing agent such as manganese dioxide in an organic solvent, such as, benzene for several hours.
Method (F): The compounds of this invention can be pro-duced by oxidizing the raw materials (IX) in the presence of thallium nitrate and perchloric acid~ sulfur and morpholine or ammonium polysulfide in an organic solvent.
The thus obtained compounds of this invention have one asymmetric carbon in the case where the substituent R2 is a lower alkyl group. Therefore, a coupler of optical antipodes are present, which can be subjected to optical resolution. For example, they can be subjected to optical resolution using cinchonine, cin-chonidine or optically active a-methylbenzylamine to obtain optically active substances. The substituent R3 in the compounds can be converted into an inorganic or organic salt form of a carboxylic acid, such as, the sodium, aluminum or an ammonium salt, a triethylamine or a diethylamine salt by well known con-ventional methods.
As is apparent from the above description, various methods of preparation can suitably be employed, depending on the kind of dibenzoxepin derivatives which are desired. It is appreciated that the most essential aspect of the present invention resides in the finding of highly distinctive analgesic~ antipyretic, 1 anti-inflammatoryactivity and potent inhibitory action on platelet aggregation of certain novel dibenzoxepin derivatives and salts thereof. However, it also is to be noted that another aspect of the invention resides in the preparation of the dibenzoxepin deri-vatives according to Methods (A) to (F).
The dibenzoxepin derivatives of the invention can be isolated using well known conventional techniques. Usually, it is advisable to recover the compounds in the form of their alkali metal or alkaline earth metal salts. Calcium or sodium salts are particularly preferred because of their utility in medicinal applications.
The compounds of the inventions have a characteristic i2 substituent represented by -CHR3, wherein R2 and R3 have the same meaning as hereinbefore defined, on one portion of the C ring of the dibenzoxepin derivatives. The compounds show excellent anal-gesic, antipyretic, anti-inflammatory activity, and potent inhibi-tory action on platelet aggregation, ordinarily not obtained by well known typical agents, such as, indomethacin, phenylbutazone, aminopyrin or by analogous dibenzoxepins or dibenzothiepines or like compounds which are among the better known analgesic drugs.
Particularly u~eful are the diber.zoxepin derivatives in which the substituent Rl is a hydrogen atom, in which the substituent lR2 -CHR3 is -CH2COOH, or -CH(CH3)COOH, and is linked at the 2- or 3-position of the C ring. Their pharmaceutically acceptable salts also are preferre~.
To demonstrate superiority, the pharmacological proper-ties of several representative compounds of this invention were compared with those of indomethacin and phenylbutazone or the like which are known as typical analgesic or anti-inflammatory g _ 1~53383 1 agents. Test compounds were administered as the free base or in the form of the sodium or calcium salts.

1. Analgesic Activity Activit~ On An Inflammed Paw (Randall-Selitto method) Seven male rats of the Donryu strain were used for each dosage level. 0.1 ml of 1~ carrageenan was injected into the subplantar tissue of the left hind paw. After 2 hours, test compounds were administered orally. The pain threshold was determined before and after the carrageenan injection. Analgesic activity was calculated as an analgesic index from the following formula:
Analgesic index = Pain Index T/Pain Index C

Pain Threshold 3 hours after the Carrageenan Injection Pain Index=
Pain Threshold before the Carrageenan Injection Pain Index T: Pain index in the group treated with the test compound Pain Index C: Pain index in the control group The dose corresponding to analgesic index 2.0, i.e., AID2 o~ was calculated from the dose-response curve between the Dose and Analgesic Index. The results obtained are shown in Table 1.

Test Compound 9 ~ ~ CH-R3 AID2.0 R2 (mg/kg, PO) Rl -CH-R3 Q

1 H 2-CH2COOH -C- 3.2 o 1 2 H 3-CH2COOH -C- 0.44 3 H2-CH-COONa " 0.40 4 H3-CHCOOH " 0.18 8-C1 3-CHCOOH " 0.28 6 H 2-CH-CH20H " 1.07 7 Indomethacin 1.50 8 Phenylbutazone 17.2 9 Ketoprofen 1.59 Mefenamic acid 23.8

2. Anti-inflammatory Activity a) Activity On Carrageenan Induced Edema Seven male rats of the Donryu strain were used for each dosage level. Test compounds were administered orally one hour before the carrageenan injection. 0.1 ml of 1~ carrageenan was injected into the subplantar tissue of the left hind paw. The dose corresponding to 30 or 50% inhibition (i.e., ID30 or ID50) was obtained from the mean percentage inhibition of the foot volume determined 2~3 and 4 hours after the carrageenan injection.
The results obtained are shown in Table 2.

Test Compound 7 Q~2_R3 ID30 ID50 10 11 1 (mg/kg,PO) (mg/kg, PO) _ 1 -CH-R3 Q
:LH 2-CH2CE1 0 15.2 1 2 H 3-CH2COOH -C- 0.9 5.3

3 H 2-CHCOOCa " 0.9 3.5

4 H 3-CHCOOH " 0.03 0.73

5 8-C1 3-CHCOOH n O .19 1. 40

6 H 2-CHCH20H " 2.2 6.9 10 7 H 3-CH3COOC2H5 " 0.8 8.6 8 H 3-CHCH20H " 0.1 1.6 9 H 3-CH2COOH-CH2- 2.0 8.6 10 Indomethacin 2.3 8.4 11 Phenylbutazone 25.9 77.7 12 Ketoprofen 2.1 12.2 b) Activity On A Cotton_Pellet Granuloma Seven male rats of the Donryu strain were used for each dosage level. Two pellets per rat were implanted subcutaneously into the flank. Test compounds were administered orally, once daily, for

7 days. The first dose was given immediately after implantation.
After 8 days, the animals were killed, the granuloma were removed, dried, weighed and compared with those of the control group. The results obtained are shown in Table 3.

1~53383 Test Compound

8 ~ ~ CH-R Daily Dry Welght of I I _ r 3 Do9e Granuloma Inhibition 2 (mg/kg + S.E ~mg) (~) 11 1 PO) , Rl -CH-R3 -Q-l H 3-CHCOOH -C- 1.0 40.4 + 2.09 ** 24.1 Il _ 2 H 3-CH2COOH " 1.0 40.1 + 2. 85 ** 24.6 fH3 3 8-Cl 3-CHCOOH " 1.0 41.6 + 1.77 ** 21. 8 4 H 2-CHCOONa " 3.0 45.5 + 1.99 * 14.5 5 Indomethacin l.O 45. 2 + 2.32 * 15.0 6 Phenylbutazone 30.0 40. 2 + 2 .15 ** 24.4 7 Ketoprofen l.O 47.6 + 3.67 * 10.5 8 Control - 53.2 + 1. 77 * Significantly different from control (P < 0.05) ** ~ " (P < 0.01) c) Activity On Adjuvant-Induced Arthritis .
I) Activity On Development Arthritis (Prophylactic Treatment) Ten female rats of the Sprague-Dawley strain were used for each dosage level. The adjuvant (0.6 mg of dead Mycobacterium butyricum in O.l ml of liquid paraffin) was injected into the sub-plantar tissue of the left hind paw. Test compounds were ad-ministered orally once a day for 21 consecutive days starting on the day of adjuvant injection. Inhibition of swelling in the adjuvant-injected paw was evaluated on 21st day after the adjuvant injection. The results obtained are shown in Table 4.

~lS3383 Test Compound ~ C~l-R Daily Body Weight 2 3 Dose Gain( ) Inhibition 11 1 p l2 Rl -CH-R3 Q

1 Control - 11 -2 H 2-CHCOONa -I- 1.00 26 ** 51 + 4.8 **

3 H 3-CHCOOH " 0.25 28 ** 55 + 4.9 **
4 H 3-CH2COOH " 0.50 21 * 55 + 5.4 **

8-C1 3-CHCOOH " 0.25 21 ** 50 + 3.1 **
6 Indomethacin 0.50 18 * 48 + 4.2 **

* Siynificantly different from control (P ~ 0.05) " (P <0.01~

II) Activity On Established Arthritis (Therapeutic Treatment) Six female rats of Sprague-Dawley strain were used for each dosage level. The adjuvant (0.6 mg of dead Mycobacterium butyricum in 0.1 ml of liquid paraffin) was injected intradermally into the tail. Only rats which exhibited marked arthritis on day 15 after adjuvant injection were selected and used for the experi-ment. Test compounds were administered orally once a day for 14 consecutive days starting on day 15 after adjuvant injection. The effects of treatment were assessed by inhibition of both hind feet volume on day 29 after adjuvant injection. The results obtained are shown in Table 5.

TA~LE 5 .
Test Compound R ~ ~ 3RCHR Daily Body Weight 19 ~ , ~ , ~ ,~J 3 Do9e Gain Inhibition 10 11 ~ 2 ~ (g) ~ + S.E
-l2 Rl -CH-R3 Q

1 Control - -7 2 H 2-CHCOONa -C- 1.0 13 * 31 + 2.0 *

3 H 3-CHC00H " 0.25 27 * 30 + 2.1 *

4 H 3-CH2COOH " 0.50 30 * 31 + 1.5 *

5 8-C1 3-CHCOOH " 0.25 19 * 26 + 1.8 *
6 Indomethacin 0.50 16 * 26 + 1.1 *
* Significantly different from control (P < 0.05) 3. Gastric Hemorrhage Test Ten male rats of the Wistar strain were used for each dosage level. Test compounds were given orally to rats which had fasted for 18 hours before administration. 3.5 hours later, occurrence of hemorrhage inside the stomach was examined micro-scopically. When gastric hemorrhage was observed, it was regarded as positive. The 50% Ulcer Dose (UD50) was calculated from the percentage of positive cases according to the method of Litchfield and Wilcoxon.- Results obtained are shown in Table 6.

Test Compound 1~ CRHR 3 , UD 5 0 l0 ll (mg/kg, PO) Rl -CH-R3 Q

l H 2-CH2CH -ICO- 63.0 2 H 3-CH2COOH " 79.9 3 H 2-CHCOOH " 14.l 4 H 3-CHCOOH " ll.4 5 8-Cl 3-CHCOOH " 32.3 6 H 2-CHCOONa " 39.8 7 Indomethacin 6.6 8 Phenylbutazone 96.0

9 Acetylsalicyclic acid 17.4 Ketoprofen 6.8 4. Acute Toxicity Acute toxicity tests were carried out in rats orally.
Each LD50 was calculated from the mortality percentage on the 7th day according to the method of Litchfield and Wilcoxon. Ten male rats of the Donryu strain were used for each dose level. The results obtained are shown in Table 7.

1 TA~LE 7 Test Compound C~2lR3 LD50

10 11 1 (mg7kg, Po) Rl -CH-R3 Q

2 H 3-CH2COOH " 110 3 H 2-CHCOONa " 131 H 3-CHCOOH " 34 6 H 2-CHCH20H " 164 7 Indomethacin 19 8 Ketoprofen 101 ~0 5. Inhibitory Action On Platelet Aggregation The compounds of the invention also showed potent inhi-bitory action on platelet aggregation and are useful for the pro-phylactic treatment of microcirculation disorders such as recurrent myocardial infraction and diabetic retinopathy, etc.
The platelet aggregation was measured by the turbidometric method of BORN and CROSS (G.V.R. Born and M.J. Cross: J. Physiol., 1 , 178 (1963)) using a Bryston AG-2 aggregometer.
Guinea pig platelet-rich plasma (PRP) was prepared from 1/10 citrated (3.13~) blood which was obtained by heart puncture under pentobarbital anesthesia.

~53383 1 Collagen 9u9p~nsion was prepared by homogeniz~ng and dispersing 40 mg of bovine tendon collagen (~oehringer Mannheim, Germany) in 10 ml of cold Tris buffered ~0.0154 M, pH 7.4) saline and by centrifuging at 1000 r.p.m. for 5 minutes. The cloudy supernatant was adjusted with the cold Tris-sallne to a 50 transmission at 420 mm.
A cuvette containing 0.4 ml of PRP and 50 pl of the Tris-saline (for controls) or 50 pl of a solution of a test com-pound (for tests) was placed in the aggregometer and allowed to 0 incubate at 30C for 1 minute under magnetic stirring at llOO r.p.m.
The aggregation reaction was initiated by adding 50 ~ul of the collagen suspension.
The inhibitory action was represented as the concentra-tion (mM) of a compound providing 50% inhibition (LD50). The %
inhibition of aggregation by a test compound was calculated as a decrease in the maximum rate of aggregation.
The results obtained are set forth in Table 8.

Test Compound 19 ~ ~ 32CRHR3 Inhibitory Action

11 1 50 (mM) Rl -CH-R3 Q
1 H 2-CH2COOH -C- 0.12 O
2 H 3-CH2COOH " 0.075 3 H 2-CHCOOH . " 0. 4 4 8-C1 2-CH2COOH " 0.21 1~53383 1 5 ~I 2-CH2CON~l2 -~- 0.03 6 8-OCH3 2-CH2COOH " 0.10 7 H 3-CHCOOH " 0.6 7 H d-isomer " 0.06 H l-isomer " 0.75 8 H 3-CH2COOC2H5 " 0-4 9 H 2-CH COOH -C~- 0.6 -H 3-CH2COOH -~ - 0.4 OH

11 H 3 CH CO`OC H C 0.038

12 H 3-CHCH2OH " 0-009 6. Additional Tests For Anti-Inflammatory Activity Further, when the anti-inflammatory activity of a typical compound of this invention, i.e., 6,11-dihydro-11-oxodibenz~b,e]-~xepin-3-acetic acid (1), is compared with a known similar compound, i.e., xanthone-propionic a,id (11), and dibenzothiepinone-acetic acid (111), it is apparent that the effectiveness of the inventive compound is several tens of times greater. The comparison of the anti-inflammatory activity of these compounds is shown in Table 9.

Phenyl-Test Method (1)(11) (111) butazone Inflammed Paw Carrageenan 14.71.0 Caolin -<1.0 <0.75 Granuloma 30 0.5 <1.0 Adjuvant-induced 60 2.5 - 1 Arthritis 1The following detalled example~ illustrate the preparation of the compounds of the invention. Unless otherwise indicated, all parts and percents are by weight.

75 g of 4-(o-carboxybenzyloxy)phenylacetic acid was added to ethyl polyphosphate (prepared from 245 g of phosphoric acid anhydride and 164 ml of ethanol), and the mixture was heated to 1~5C with stirring. Heating was effected with stirring for 1 hour. After cooling, ice water was added to the reaction solution which was then extracted with chloroform. The chloroform layer was washed with water, dried and then concentrated to obtain an oily substance, which was a mixture of 6,11-dihydro-11-oxodibenz-[b,e]oxepin-2-acetic acid and the ethyl ester thereof.
The oily substance was heated under reflux together with 600 ml of 1 N-sodium hydroxide in 60% aqueous ethanol for 30 minutes. The reaction solution was freed from most of the ethanol by distillation under reduced pressure, acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was 2~ washed with water, dried and then concentrated. The residue was dissolved in ethyl acetate, treated with activated carbon and then recrystallized from a mixed solution of ethyl acetate and hexane to obtain 55.0 g of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid having a melting point of 130 to 131C.

Elemental Analysis 16 12 4 -Calculated: C 71.63, H 4.51 Eound : C 71.51, H 4.65 30A mixed solution of 1.0 g of 4-to-carboxybenzyloxy)phenyl-acetic acid and 5.0 g of polyphosphoric acid was heated with stirring 1 to a bath temperature of 130C ~or 5 minutes. After cooling, water was added to the reaction solution which was then extracted with chloroform. The chloroform layer was washed with water, dried and then treated with activated carbon. The solvent was distilled off, and the residue was recrystallized from a mixed solution of ethyl acetate and hexane to obtain 0.80 g of 6,11-dihydro~ oxodibenz-[b,e]oxepin-2-acetic acid having a melting point of 129 to 130.5C.

2.0 g of ethyl 4-(o-carboxybenzyloxy)phenylacetate (m.p.
103 to 105C) was added to 10 g of ethyl polyphosphate and was heated to 125 to 130C with stirring. Heating was effected with stirring for 1 hour. After cooling, water was added to the re-action solution which was then extracted with benzene. The benzene layer was washed with water, dried and then concentrated, The residue was recrystallized from a mixed solution of benzene-hexane to obtain 1.7 g of ethyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate having a melting point of 89 to 90C.

Elemental Analysis 18 16 4 Calculated: C 72.96, H 5.44 Found : C 72.62, H 5.55 2.0 g of methyl 4-(o-carboxybenzyloxy)phenylacetate was heated to 100C together with 10 g of polyphosphoric acid for 1 hour while stirring. After cooling, water was added to the re-action solution, which was then extracted with benzene. The benzene layer was washed with water, dried and then concentrated.
The residue was recrystallized from ether to obtain 1.6 g of methyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate having a melting point of 78 to 79C.

llS3383 1 Elemental Analysis For C17H14O4 Calculated: C 72.33, H 5.00 Found : C 72.39, H 5.05 33.5 g of 2-[4-(o-carboxybenzyloxy)phenyl]propionlc acid and ethyl polyphosphate (prepared from 122.5 g of phosphoric acid anhydride and 82 ml of ethanol) were thoroughly mixed and stirred at 120 to 130C for 30 minutes. After cooling, the reaction solu-tion was dissolved in water and extracted with 500 ml of ether.
The ether layer wa~ washed with an aqueous solution saturated with sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The remaining liquid was dissolved in 200 ml of 1 N-potassium hydroxide in 60% aqueous ethanol, which was then heated under reflux for 30 minutes. The reaction solu-tion was freed from ethanol by distillation and extracted with diethyl ether to remove impurities. The aqueous layer was acidi-fied with hydrochloric acid and extracted with diethyl ether. The ether layer was washed with an aqueous solution saturated with sodium chloride, dried over sodium sulfate and then concentrated under reduced pressure. The remaining liquid was dissolved in chloroform and subjected to chromatography using silica gel (400 g).
The fractions eluted with chloroform and chloroform-methanol (100 : 2) were combined, freed from the solvent by distillation, clissolved in ethyl acetate and treated with activated carbon.
Again, it was freed from the solvent by distillation and dissolved in 125 ml of 1.2 N sodium hydroxide. The solution was shaken with cliethyl ether to extract and remove a very small amount of impuri-ties. The aqueous layer was acidified with hydrochloric acid and again extracted with diethyl ether. The ether layer was washed - with an aqueous solution saturated with sodium chloride, dried over 1 sodium sulfate and then conc~ntrated under reduced pressure. The ~emaining liquid was again dissolved in ethyl acetate and decolor-:ized with activated carbon. The ethyl acetate layer was freed from ~he solvent by distillation and was finally dried under high vacuum while heating to 80C. Thus, there was obtained 25.0 g of ~-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionic acid as a light yellow syrup.
Elemental Analysis For C17H14O4 Calculated: C 72.33, H 5.00 Found : C 72.08, H 5.10 NMR Spectrum tppm CDC13) 1.51 (3 H, d, C-CH3) 3.78 (1 H, q, -C-H) 5.07 (2 H, s, -CH2O-) 6.95 (1 H, d, C4-_) 7.82 (1 H, m~ C10-_) 8.16 (1 H, d, Cl-H) 12.11 (1 H, s, -COOH) 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionic acid thus obtained was converted into a cinchonidine salt. Re-crystallization was repeated from ethyl acetate, and the resulting less-soluble salt was liberated with hydrochloric acid and extracted with chloroform. The chloroform layer was washed with water and then concentrated. The remaining liquid was dissolved in diethyl ether, and petroleum ether was added to precipitate an oily sub-stance. The oily substance was thoroughly dried to obtain a light yellow syrup the elemental analysis of which agreed with that of levo-rotatory 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl) propionic acid. [a]25 _ 39.0 (ethanol). The soluble cinchonidine salt thus obtained in the above procedure was liberated in the 1 same manner to obtain dextro-rotatory 2-(6,11-dihydro-11-oxodibenz-[b,e]oxepin-2-yl)propionic acid. [a]25 ~ 37.1 (ethanol).

EXAMPLE_6 A mixture of 17.1 g of 3-(o-carboxyloxy)phenylacetic acid and 200 g of polyphosphoric acid was heated with stirring to 70 to 85 C for 75 minutes. After cooling, the reaction solution was dissolved in water and extracted with chloroform. The chloro-form layer was concentrated under reduced pressure, and the re-maining liquid was dissolved in an aqueous solution of sodiumhydroxide and extracted with benzene to remove impurities. The aqueous layer was acidified with hydrochloric acid and extracted ~ith chloroform. The chloroform layer was treated with activated carbon and then concentrated to obtain 7.1 g of a semi-crystalline residue which was a mixture of 6,11-dihydro-11-oxodi~enz[b,e]oxepin-3-acetic acid and 6,11-dihydro-11-oxodibenz~b,e]oxepin-1-acetic acid in the ratio of about 7 : 1. This was recrystallized from a mixed solution of ethyl acetate-hexane to obtain 4.8 g of the almost pure 3-acetic acid derivative as primary crystals, and further to obtain 0.77 g of a mixture of the 3-acetic acid deriva-tive and the l-acetic acid derivative (almost 1 : 1 by weight) as secondary crystals.
The above primary crystals were further recrystallized from ethyl acetate-hexane to obtain 3.9 g of pure 6,11-dihydro-11-oxodibenz[b,e]oxepin-3-acetic acid.
Melting Point: 110.5 to 111.5C
Elemental Analysis For C16H12O4 -Calculated: C 71.63, H 4.51 Found : C 71.46, H 4.50 1 NMR Spectrum (ppm CDC13) 3.65 (2 H, 9, -CH2COOH) 5.16 (2 H, s, -CH2O-) 6.95 (1 H, d, C4-H) 7.88 (1 H, m, C10 H) 8-19 (1 H, d, Cl-H) When the above secondary crystals were separated and purified using silica gel chromatography, 6,11-dihydro-11-oxodi-benz[b,e]oxepin-l-acetic acid could be isolated.

NMR Spectrum 3.92 (2 H, s, -CH2COOH) 5.21 (2 H, s, -CH2O-) 7.88 (1 H, m, Clo~H) A mixed solution of 2.33 g of 4-(p-chloro-1-carboxy-benzyloxy)phenylacetic acid and 20 g of ethyl polyphosphate was heated with stirring to 125 to 130C for 2 hours. Water was added to the reaction solution which was then extracted with chloroform.
The chloroform layer was washed with water, and the solvent was then distilled off. The remaining liquid was heated under reflux together with 60 ml of 1 N-potassium hydroxide-60~ aqueous ethanol solution. The reaction solution was freed from the ethanol by distillation, acidified with hydrochloric acid and then extracted with chloroform. The chloroform layer was washed with water and dried, and the solvent was then distilled off. The residue was purified through silica gel chromatography using a mixed solution of chloroform and methanol. Recrystallization from chloroform gave 6,11-dihydro-11-oxo-9-chlorodibenz~b,e]oxepin-2-acetic acid having a melting point of 171 to 173C.

1 Elemental Analysis For C16H1104Cl -Calculated: C 63.48, H 3.66, Cl 11.71 Found : C 63.39, H 3.80, Cl 11.60 40 g of 2-~3-(o-carboxybenzyloxy)phenyl]propionic acid ~md 200 g of ethyl polyphosphate were thoroughly mixed and heated with stirring to 120C for 50 minutes. After cooling, 500 ml of water was added to the reaction solution, ~7hich was then extracted with 700 ml of diethyl ether. The ether layer was washed with an aqueous solution saturated with sodium chloride and then concentra-ted. The remaining liquid was dissolved in 240 ml of 1 N-potassium hydroxide-60% aqueous ethanol which was then heated under reflux i-.or 30 minutes. The reaction solution was freed from the ethanol by distiliation and extracted with diethyl ether to remove impuri-1:ies. The aqueous layer was acidified with hydrochloric acid and extracted with diethyl ether. The ether layer was washed with 2m aqueous solution saturated with sodium chloride, dried over c;odium sulfate and then concentrated under reduced pressure. The crystalline residue was recrystallized from ethyl acetate-hexane to obtain 29.2 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)-propionic acid having a melting point of ~5.5 to 117 C.
Elemental Analysis For C17H14O4 Calculated: C 72.33, H 5.00 Found : C 72.62, H 4.91 Cyclohexylamine salt (from ethanol).
Melting Point: 191 to 192 C (decomposition) 10.0 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)-propionic acid thus obtained was dissolved in ethyl acetate, to which 4.29 g of d-a-methylbenzylamine was added to form a salt.

1 Recryqtallization waq repeated from eth~l acetate. The resulting :Less-soluble salt was liberated with hydrochloric acid and ex-tracted with diethyl ether. The ether layer was washed with water, dried and then concentrated. Recrystallization from ether-petro-leum ether gave dextro-rotatory 2-(6,11-dihydro-11-oxodibenz[b,e]-oxepin-3-yl)propionic acid having a melting point of 102 to 104C.
[a]25 + 38.6 (ethanol).
Elemental Analysis For cl7Hl4O4 Calculated : C 72.33r H 5.00 Found : C 72.49, H 5.07 The soluble salt obtained in the above procedure was ; :Liberated with hydrochloric acid and then converted into the l-a-~nethylbenzylamine salt. Recrystallization was repeated using-ethyl acetate. The resulting less~soluble salt was liberated in the same manner as described above and recrystallized to obtain :Levo-rotatory 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)propionic acid having a melting point of 102 to 104C. [a325 _ 39.3 (ethanol).
Elemental Analysis For CL7H14O4 Calculated: C 72.33, H 5.00 Found : C 72.36, H 5.09 ; 3.0 g of 2-[4-(2-carboxy-5-chlorobenzyloxy)phenyl]pro-~; pionic acid and 20 g of ethyl polyphosphate were reacted at 130 to :L35C for 2 hours while stirring. 50 ml of water was added to the reaction solution which was then extracted with diethyl ether.
The ether layer was washed with water and dried, and the solvent was then distilled off. The remaining oily substance was heated under reflux with 50 ml of an aqueous solution of 10% potassium hydroxide - 50% ethanol for 10 minutes. The reaction solution .

. .
.

" ` ~153383 ~as concentrated, mixed with water and then extracted with chloro-~orm to remove by-products. The aqu~ous layer was acidified with hydrochloric acid and extracted with chloroform. The chloroform :Layer was washed with water and dried, and the solvent was distilled off. The remaining oily substance was purified using silica gel chromatography (eluent-chloroform : methanol, 100 : 1 by volume) and then recrystallized from isopropyl ether-hexane to obtain 2-(8-chloro-6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionic acid having a melting point of 112 to 114C.
Elemental Analysis For C17H1304Cl Calculated: C 64.46, H 4.14, Cl 11.19 Found : C 64.31, H 4.28, Cl 11.06 By repeating substantially the same procedures as in Example 9, various other dibenzoxepin derivatives were prepared.
The results obtained are summarized in the following Table.

1 ~ CHR3 IR2 Melting Point Mo. Rl -C-R (C) __ 11 9-Cl " 132-133 12 8-F " 153-154

13 8-C1 2-CH2COOH 193-195

14 8-OCH3 ICH'3 165-166 8-O~H3 3-CH2COOH 170-171 ~153383 A mixture of 10.0 g of 2-~4-(o-carboxybenzyloxy)phenyl]-n-propanol acetate and 100 g of ethyl polyphosphate was heated with stirring to a bath temperature of 120 to 130C for 25 minutes.
l~fter cooling, ice water was added to the reaction solution, which was then extracted wi~h chloroform. The chloroform layer was washed with water and dried, and the solvent was then distilled off.
The remaining liquid was purified using silica gel chromatography, with benzene as a solvent, to obtain 6.4 g of a light yellow syrup of 2-(1-methyl-2-acetoxyethyl)-6,11-dihydro-dibenz[b,e]oxepin-11-one .
Elemental Analysis For ClgH18O4 Calculated: C 73.53, H 5.85 Found : C 73.38, H 5.95 Infrared Spectr~m (liquid fi~m metho_) 1642 cm 1 (carbonyl in ll-position), 1735 cm 1 (carbonyl in acetoxy group) NMR Spectrum (in heavy chloroform, ppm) 1.28 (3 H, d, CH-CH3) 1.95 (3 H, s, CO-C_3) 3.08 (1 H, m, -CH-CH2) 4.12 (2 H, d, -CH-CH2-O-) 5.12 (2 H, s, -CH2-O- in 6-position 8.05 (1 H, d, Cl-H) In the above reaction, when polyphosphoric acid was used in place of ethyl polyphosphate and the condition of heating to a llS3383 1 bath temperature o~ 70 to 80C for 20 minutes was applied, ~he desired 2-(1-methyl-2-acetoxyethyl)-6,11-dihydrodibenz[b,e]oxepin-ll-one could also be obtained in high yield.

A mixture of 0.5 g of 2-14-(o-carboxybenzyloxy)phenyl]-n-propanol and 5 g of ethyl polyphosphate was heated to a bath temperature of 120C for 1 hour while stirring. After cooling, water was added to the reaction solution, and insoluble substances were filtered out. The insoluble substances were heated under reflux together with 40 ml of 2.5 N sodium hydroxide - containing 50~ aqueous ethanol for 4 hours. The reaction solution was freed from ethanol by distillation, neutralized with hydrochloric acid and then extracted with chloroform. The chloroform layer was washed with water, dried and then concentrated. The residue was purified using silica gel chromatography and recrystallized from ~iethyl ether - petroleum ether to obtain 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-n-propanol having a melting point of 83 to 85C.

A mixture of 19.1 g of 2-[3-(o-carboxybenzyloxy)phenyl]-n-propanol acetate and 191 g of ethyl polyphosphate was heated at a bath temperature of 115 to 125C for 1 hour while stirring.
After cooling, ice water was added to the reaction solution, which was then extracted with benzene. The benzene layer was washed ~ith water and dried, and the solvent was then distilled off. The remaining liquid was purified through silica gel chromatography with benzene and a mixed solution of benzene and ethyl acetate as solvents to obtain 12.6 g of a light yellow syrup of 3-(1-methyl-2-acetoxyethyl)-6,11-dihydrodibenz[b,e]oxepin-11-one.

1 Elemen~al Analy~is For C~ 8O4 .
Calculated: C 73.S3, H 5.85 Found : C 7 3 . 30, H 5 . 9 8 Infrared Absorption Spectrum (liquid film method) 1640 cm l (carbonyl in ll-position), 1740 cm 1 (carbonyl in acetoxy group) NMR Spectrum (in heavy chloroform, ppm) 1. 28 (3 H, d, CH-CH3) 1.99 (3 H, s, COCH3) 3.08 (1 H, m, -CH-CH2) fH3 4.15 (2 H, d, --CH--CH2-O-) 5.15 (2 H, s, -CH2-O- in 6-position) 8. 20 (1 H, d, Cl-H) 0. 40 g of methyl 4-(o-chlorocarbonylbenzyloxy)phenyl-acetate was heated at 165C for l. 5 hours under a nitrogen atmosphere. After cooling, the reaction mixture was suspended ~0 in chloroform and filtered. The residue was recrystallized from methanol to obtain 0. 25 g of methyl 6,11-dihydro-11-oxodibenz-[b,e]oxepin-2-acetate having a melting point of 76 to 77C.

3 g of zinc powder was added to a solution of l.0 g of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid and 20 ml of acetic acid, which was then heated under reflux for 2 hours while stirring. The reaction solution was filtered, and the filtrate was concentrated and, after adding water, extracted with chloro-Eorm. The chloroform layer was washed with water, dried and then " ` 1153383 1 concentrated, and the re~idue wa9 rcary~tallized from benzene to~btain 0.76 g of 6,11-dihydrodibenz[b,e]oxepin-2-acetic acid having a melting point of 165.5 to 166.5C.
Elemental Analysis For C16H14O3 Calculated: C 75.57, H 5.55 Found : C 75.75, H 5.54 0.5 g of 8-chloro-6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid was subjected to reduction in the same manner as in E'xample 23 to obtain 0.40 g of 8-chloro-6,11-dihydrodibenz[b,e]-c,xepin-2-acetic acid having a melting point of 194 to 195C.
Elemental Analysis For C16H13O3Cl Calculated: C 66.56, H 4.54, Cl 12.28 Found : C 66.40, H 4.64, Cl 12.11 A mixed solution of 5.0 g of zinc powder, 0.5 g of mercury (II) chloride, 7.5 ml of water and 0.25 ml of concentrated hydrochloric acid was vigorously stirred for 5 minutes. The aqueous layer was removed by decantation, and to the resulting zinc amalgam were added 3.8 ml of water, 5.0 ml of concentrated hydrochloric acid, 7.5 ml of toluene and 0.8 g of 6,11-dihydro-11-cixodibenz[b,e]oxepin-3-acetic acid. Heating was effected under reflux for 3 hours while vigorously stirring. The reaction solu-tion was filtered, and the filtrate was extracted with diethyl ; ether. The organic layer was washed with water, dried and then concentrated. The residue was purified using silica g~l chroma-t:ography and then recrystallized from chloroform - petroleum ether t:o obtain 6,11-dihydrodibenz[b,e]oxepin-3-acetic acid having a melting point of 155 to 156C.

1~53383 1 Elemental Analysiq For C16H14O3 _ Calculated: C 75.57, H 5.55 Found : C 75.77, H 5.58 0.5 g of ethyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-3-acetate was subjected to reduction in the same manner as in Example 23 to obtain 0.3 g of ethyl 6,11-dihydrodibenzlb,e]oxepin-3-acetate having a melting point of 44.5 to 45.5C.
Elemental Analysis Por C18H18O3 Calculated: C 76.57, H 6.43 Found : C 76.78, H 6.54 0.1 g of ethyl 6,11-dihydrodibenz[b,e]oxepin-3-acetate thus obtained was heated under reflux with 6 ml of 1 N-sodium hydroxide - containing 60% aqueous ethanol for 30 minutes. The reaction solution was freed from ethanol through distillation lmder reduced pressure and acidified with hydrochloric acid to precipitate crystals. The crystals were recrystallized from chloroform - petroleum ether to obtain 0.08 g of 6,11-dihydro-clibenz[b,e]oxepin-3-acetic acid having a melting point of 155 to ~56C.

-0.5 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-propionic acid was subjected to reduction in the same manner as in Example 23. After purifying the resulting oily residue using silica gel chromatography, 0.3 g of an oily substance of 2-(6,11-dihydrodibenz[b,e]oxepin-2-yl)propionic acid was obtained.
NMR Spectrum (ppm. CDC13) 1.43 (3 H, d, C-CH3) 3.60 (1 H, q, -C-H) 1 4.14 (2 H, s, -CH2-) 5.20 (2 H, s, -CH2O-) 9.93 (1 H, s, -COOH) 1.0 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)-propionic acid was subjected to reduction in the same manner as ln Example 27 to obtain 2-(6,11-dihydrobenz~b,e]oxepin-3-yl)-propionic acid having a melting point of 115 to 117C.
Elemental Analysis For C17H16O3 Calculated: C 76.10, H 6.01 Found : C 75.90, H 6.07 0.2 g of 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-acetic acid was subjected to reduction in the same manner as in Example 23 to obtain 0.15 g of 6,11-dihydrodibenz[b,e]oxepin-2-acetic acid having a melting point of 165.5 to 166.5C.

0.5 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)-n-propanol was subjected to reduction in the same manner as in Example 23 to obtain an oily substance. It was a mixture of 2-(6,11-dihydrodibenz[b,e]oxepin-3-yl)-n-propanol and the acetate thereof. The oily substance was heated under reflux together with

15 ml of 1 N-sodium hydroxide - containing 60~ aqueous ethanol for L hour. The reaction solution was freed from ethanol through distillation under reduced pressure, acidified with hydrochloric ; acid and extracted with chloroform. The chloroform layer was washed with water, dried and then concentrated. The resulting oily substance was purified through silica gel chromatography to 1 obtain 0.26 g of an oily substance of 2-(6,11-dihydrodibenzlb,e]-oxepin-3-yl)-n-propanol.
NMR Spectrum (ppm, CDC13j 1.14 (3 H, d, C-CH3) 1.56 (1 H, s, OH) 2.80 (1 H~ m, -C-H) 3.58 (2 H, d, -CH2OH) 4.19 ~2 H, s, -CH2-) 5.25 (2 H, s, -CH20-) 5.44 g of 3-(1-methyl-2-acetoxyethyl)-6,11-dihydrodibenz-[b,e]oxepin-ll-one was heated under reflux with 200 ml of 0.5 N
!iodium hydroxide - containing 50% aqueous ethanol for 1 hour. The reaction solution was freed from ethanol by distillation, neutra-Lized with hydrochloric acid and then extracted with benzene. Thebenzene layer was washed with water and dried, and the solvent was lthen distilled off. The remaining syrup was purified using silica gel chromatography to obtain a light yellow syrup. The syrup was dissolved in diethyl ether, to which petroleum ether was added to ~;ettle the syrup. After removing the supernatant liquid by decan-l'ation and then drying, there was obtained 2.46 g of a light yellow syrup of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)-n-propanol.
Elemental Analysis For C17H16O3 Calculated: C 76.10, H 6.01 Found : C 75.97, H 6.16 Infrared Absorption Spectrum (liquid film method) ; 1638 cm 1 (carbonyl in ll-position) NMR Spectrum (in heavy chloroform, ppm) 3~ 1.23 (3 H, d, CH-CE~3) 1.91 (1 H, s, OEI~

1~53383 2.93 (1 H, m, -CH-CH2) 3.68 (2 H, d, -CHCH2-O-) 5.10 (2 H, s~ -CH2-O- in 6-position) 8.15 (1 H, d, C1-H) 1.5 g of ethyl 6,11-dihydro-11-oxodibenz~b,e]oxepin-2-acetate was heated under reflux together with 100 ml of 1 N-potassium hydroxide - 60% aqueous ethanol for 1 hour for hydrolysis.
l'he reaction solution was concentrated, acidified with dilute hydrochloric acid and extracted with chloroform. The chloroform layer was washed with water, dried and then concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain ].1 g of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid.
Melting point: 130 to 131.5C.

3.41 g of 2~ methyl-2-acetoxyethyl)-6,11-dihydrodi-; 20 benz[b,e]oxepin-ll-one was heated under reflux together with ]00 ml of 0.5 N-sodium hydroxide - 50% aqueous ethanol for 1 hour. The reaction solution was freed from ethanol by distillation, neutralized with hydrochloric acid and then extracted with chloro-form. The chloroform extract was purified using silica gel chroma-tography and recrystallized from diethyl ether - petroleum ether t:o obtain 2.09 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-n-propanol having a melting point of 83 to 8~C.
Elemental Analysis For Cl7H16O3 -Calculated: C 76.10, H 6.01 Found : C 76.17, H 6.01 A mixture of 0.5 g of 6,11-dihydro-11-oxodibenz[b,e]oxepin-:2-acetonitrile having a melting point of 76 to 77C, 5 ml o ethanol and 0.2 ml of sulfuric acid was refluxed ~or 10 hours. After ~ooling, the reaction mixture was poured into ice water. The solution was neutralized with sodium carbonate and extracted with chloroform. The chloroform solution was washed with water, dried cmd concentrated. The residue was recrystallized from ethanol to obtain ethyl 6,11-dihydro-ll-oxodibenz[b,e]oxepin-2-acetate.

A mixture of 0.5 g of 6,11-dihydro-11-oxodibenz[b,e]-oxepin-3-acetonitrile having a melting point of 124 to 126C,5 ml of ethanol and 5 ml of 5 N-sodium hydroxide solution was refluxed i-or 5 hours. After cooling, the reaction solution was acidified with hydrochloric acid and extracted with chloroform. The chloro-~orm solution was washed, dried and concentrated. The residue was recrystallized from ethyl acetate to obtain 6,11-dihydro-ll-oxodibenz[b,e]oxepin-3-acetic acid.

By repeating substantially the same procedures as in Example 35, 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid was prepared from oily ethyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-cyanoacetate.

-By repeating substantially the same procedures as in Example 35, 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid was prepared from dimethyl 6,11-dihydro-ll-oxodibenz[b,e]oxepin-3-malonate having a melting point of 108 to 110C.

llS33l~3 1 EX~M~ 3 a = .
By repeatin~ substantially the same procedures as in Example 35, 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)propionic acid was prepared from dimethyl(6,11-dihyd~o-11-oxodibenz[b,e]-oxepin-3-yl)-2-methylmalonate.

A mixture of 100 mg of 2-carbamoylmethyl-5,11-dihydro-11-oxodibenz[b,e]oxepin, 0.6 ml of concentrated hydrochloric acid and 20 ml of water was refluxed for 1.5 hours. After cooling, the reaction solution was extracted with diethyl ether. The ether c;olution was washed with water and dried. The solvent was distilled off from the solution to obtain 95 mg of 6,11-dihydro-11-oxodibenz-b,e]oxepin-2-acetic acid.

2.7 g of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-aceto-nitrile was heated at 120C with S0 ml of 50%
sulfuric acid for 2 hours. After cooling, 150 ml of water was added to the reaction solution, which was then extracted with chloroform. The chloroform layer was extracted twice with 100 ml of a 2 N sodium hydroxide solution, and the alkaline water layer was adjusted to a pH of 3 with hydrochloric acid and again ex-tracted with chloroform. The chloroform layer was washed with water, dried and then concentrated to obtain 2.0 g of 6,11-dihydro-ll-oxodibenz[b,e]oxepin-2-acetic acid having a melting point of 129 to 130C.

1 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)-n-propanol was dissolved in a mixed solvent of 10 ml of acetone and2.5 ml of water, to which 1.57 g of potassium permanganate was " 1153383 dded. Stirrin~ was eff~cted at room temperature (e.g., 20 - 30C) Eor 5 hours. After adding 150 ml of water and a small amount of concentrated hydrochloric acid, extraction was effected with di-ethyl ether. The ether layer was washed with water and dried, and 1the solvent was then distilled off. The residue thus obtained was purified using silica gel column chromatography and then recrystal-:Lized from diethyl ether-petroleum ether to obtain 2-(6,11-dihydro-~ oxodibenz[b,e]oxepin-3-yl)propionic acid having a melting point c)f 115.5 to 117C.
Elemental Analysis For C17H14O4 Calculated: C 72.33, H 5.00 Found : C 72.45, H 5.01 lg of 2-(6,11-dihydro-11-oxodibenz~b,e]oxepin-3-yl)-n-propanol was dissolved in 20 ml of acetic acid, to which 746 mg of chromium trioxide was then added. Stirring was effected at room temperature (e.g., 20 - 30C) for 1 hour. After adding 100 ml of water and 240 ml of 1 N-NaOH, extraction was effected with diethyl ether.
The ether layer was washed with water and dried, and the solvent was then distilled off. The residue was purified through silica gel column chromatography and recrystallized from diethyl ether-petroleum ether to obtain 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)propionic acid having a melting point of 115.5 to 117C.

1 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-n-propanol was dissolved in a mixed solvent of 10 ml of acetone and 2 5 ml of water, to which 1.176 g of potassium permanganate was added. Stirring was effected at room temperature (e.g., 20 - 30C) for 4 hours. After adding 100 ml of water and a small amount o ,~ ~

1 concentrated hydrochloric acid, extrAction was effected with ~iethyl ether. The ether layer was washed with water and dried, the solvent was then distilled off. The remaining syrup was purified using silica gel column chromatography to obtain a light yellow syrup. It was dissolved in diethyl ether, to which petro-leum ether was added to settle the syrup. After removing the upernatant liquid through decantation and then drying, a light ~ellow syrup of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-propionic acid was obtained.
Elemental Analysis For C17H14O4 Calculated: C 72.33, H 5.00 Found : C 72.50, H 4.98 1.0 g of 6,11-dihydrodibenz~b,e]oxepin-3-acetic acid and 5 g of manganese dioxide were added into 50 ml of benzene. After the mixture was stirred at 40 to 50C for 30 minutes, the insoluble <;ubstance was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chroma-l_ography to obtain 10 mg of pure 6,11-dihydro-11-oxodibenz[b,e]-oxepin-3-acetic acid.

0.2 g of 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-acetic acid and 1.3 g of manganese dioxide were added to 50 ml of benzene. After the mixture was refluxed for 5 mintues, the :Lnsoluble material was filtered off. The solvent was distilled off from the filtrate to obtain an oily substance. The oily sub-stance was subjected to silica gel chromatography to obtain 95 mg o~ 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid.

~153383 EXAMPLE ~6 2.362 g of thallium nitrate containing three molecules of crystallized water and 2.5 ml of 70% of perchloric acid were clissolved in 10 ml of methanol. To the solution, 1.26 g of 2-2Icetyl-6,11-dihydro-ll-oxodibenz[b,e]oxepin was added. After e;tirring the mixture at room temperature (e.g., 20 - 30C) for ~I hours, 300 ml c)f water was added to the reaction mixture. The mixture was extracted with chloroform. The chloroform extract t:hus obtained was washed with water, dried and the solvent was 0 clistilled off. The residue was subjected to silica gel chromato-qraphy and recrystallized from diethyl ether to obtain methyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate having a melting point of 78 to 79C.

By repeating substantially the same procedures as in Example 46, methyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-3-acetate h,aving a melting point of 55.5 to 56.5C was prepared from 3-acetyl-6,11-dihydro-11-oxodibenz[b,e]oxepin having a melting point 20 ~'f 160 to 161C.

To 10 ml of concentrated ammonia solution, 1 g of sulfur ~as added and saturated with hydrogen sulfide. Then, 1.26 g of 2-acetyl-6,11-dihydro-11-oxodibenz[b,e]oxepin and 5 ml of dioxane were added. The solution was tightly enclosed in a hard glass t:ube, and was heated at 160 to 170C for 20 hours. After the reaction, the solution was concentrated to dryness and the residue was washed with hot methanol. The methanol solution was concen-t:rated and the residue was refluxed in 100 ml of 5~ hydrochloric 30acid for 2 hours. After cooling, the solution was extracted with ~53383 chloroform. The chloroform solution was washed with water, dried and the solvent was distilled off. The residue was subjected to silica gel chromatography and recrystallized from ethyl acetate to obtain 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid having a melting point of 129.5 to 130.5C.

By repeating substantially the same procedures as in Example 48, 6,11-dihydro-11-oxodibenz[b,e]oxepin-3-acetic acid 10 was prepared from 3-acetyl-6,11-dihydro-11-oxodibenz[b,e~oxepin having a melting point of 160 to 161C.

A mixture of 1.26 g of 2-acetyl-6,11-dihydro-11-oxodi-benz[b,e]oxepin, 200.4 mg of sulfur and 10 ml of morpholine was refluxed for 19 hours. After concentration, water was added to the residue and extracted with chloroform. The chloroform solu-tion was washed with water, dried and the solvent was distilled c,ff. 150 ml of 5% hydrochloric acid was added to the residue and the solution was refluxed for 2 hours. After cooling, the solution 20 was extracted with chloroform. The chloroform solution was washed with water, dried and the solvent was distilled off. The residue u~as subjected to silica gel chromatography and recrystallized from ethyl acetate to obtain 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid.
The following Examples A to D show detailed synthetic procedures for the preparation of some typical starting compounds used in the present invention.

EX~5PLE A

16.1 g of phthalide and 23.1 g of disodium-2-(4-hydroxy-phenyl)propionate were thoroughly mixed and heated with stirring 1~53383 1 at 210 to 220C ~or 40 minutes and then at 220 to 230C for 20 minutes. After cooling, the mixture was dissolved in 200 ml of water and acidified with hydrochloric acid. The precipitated crystals were filtered out and recry9tallized from water-contain-lng ethanol to obtain 25.0 g of 2-~4-(o-carboxybenzyloxy)phenyl]-propionic acid having a melting point of 156 to 15~.5C.
Elemental Analysis For C17H16O5 Calculated: C 67.99, H 5.37 Found : C 68.20, H 5.43 EXAMPLE B
10 ml of ethanol was added to a mixture of 3.37 g of ~i-chlorophthalide and 3.94 g of disodium-4-hydroxyphenylacetate.
E~eating was effected with stirring at a bath temperature of 200 t:o 230C for 1 hour, using a reflux condenser. After cooling, 1:he reaction solution was dissolved in 100 ml of water and filtered to remove insoluble substances. The aqueous layer was acidified ith hydrochloric acid. The precipitated crystals were filtered out, washed with water and then recrystallized from water-contain-ing methanol to obtain 4-(p-chloro-o-carboxybenzyloxy)phenylacetic acid having a melting point of 206 to 209C.
Elemental Analysis For C16H13O5Cl Calculated: C 59.92, H 4.09, Cl 11.06 Found : C 59.97, H 4.04, Cl 10.62 EXAMPLE C
A mixed solution of 24 g of 2-(4-hydroxyphenyl)propionic acid, 13.7 g of lithium aluminum hydride and 1 liter of tetra-hydrofuran was heated under reflux for 6 hours. After cooling, t:he reaction solution was acidified by adding ice water and hydro-c:hloric acid and then extracted with chloroform. The chloroform :layer was washed with an aqueous solution saturated with codium ~-hloride and dried. Then, the solvent was distilled off, and distillation was effected. The fraction distilling at 147 to 149C
(under a reduced pressure of 3 to 3.5 mmHg) solidified and was ecrystallized from benzene to obtain 19.4 g of 2-(4-hydroxyphenyl)--propanol having a melting point of 96 to 100C.
Elemental ~nalysis For CgH1202 Calculated: C ?1.02, H 7.95 Found : C 71.13, H 7.72 A solution of 3.04 g of 2-(4-hydroxyphenyl)-n-propanol i hus obtained, 0.46 g of metallic sodium and 20 ml of ethanol was added to a mixed solution of 3.03 g of 2-cyanobenzyl chloride and :20 ml of ethanol. Heating was effected under reflux for 2.5 hours.
rrhe reaction solution was filtered, and water was added to the i~iltrate, which was then acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was washed with water and dried, and the solvent was then distilled off. The residue was recrystallized from diethyl ether to obtain 4.0 g of 2-[4-(o-cyanobenzyloxy)phenyl]-n-propanol having a melting point of 70 to 80C.
Elemental Analysis For C17H17N02 .
Calculated: C 76.38, H 6.41, N 5.24 Found : C 76.16, H 6.57, N 5.09

17.0 g of 2-[4- (o-cyanobenzyloxy)phenyl]-n-propanol thus obtained was heated under reflux together with 200 ml of 10 N
sodium hydroxide for 2.3 hours. After cooling, the reaction solution was acidified with hydrochloric acid, and the precipi-l ated crystals were recrystallized from acetone to obtain 15.1 g 30 of 2-[4-(o-carboxybenzyloxy)phenyl]-n-propanol having a melting point of 147 to 149.5C.

E,Lemental AnalysiS For C17H18O4 Calculated: C 71.31, H 6.34 ~-Found : C 71.29, H 6.25 13.4 g of 2-[4-(o-carboxybenzyloxy)phenyl]-n-propanol 1~us obtained was dissolved in 100 ml oi~ pyridine, and 15 g of acetic anhydride was added. Then, this was allowed to stand at room temperature (e.g., 20 - 30C) overnight. Ice water was added to the reaction solution, which was then acidified with hydrochloric acid. The precipitated crystals were filtered out, dried and then recrystallized from diethyl ether - petroleum ether 1o obtain 14.1 g of 2-[4-(o-carboxybenzyloxy)phenyl]-n-propanol acetate having a melting point of 83 to 88C.

Elemental Analysis For ClgH20O5 Calculated: C 69.50, H 6.14 Found : C 69.46, H 6.08 EXAMPLE D
13.3 g of 4-hydroxybenzyl cyanide was dissolved in a sodium ethylate solution (prepared from 2.3 g of metallic sodium and 100 ml of ethanol). This solution was added dropwise to a ~;olution of 19.9 g of ethyl o-chloromethylbenzoate and 50 ml of ethanol, and then heating was effected under reflux for 2 hours.
The reaction solution was freed from ethanol by distillation and after adding water, extracted with chloroform. The chloroform :Layer was washed with water and then concentrated. 200 ml of 1 N-potassium hydroxide - 60~ ethanol solution was added, and heat-ing was effected under stirring at 50C for 1 hour. The reaction solution was freed from ethanol by distillation, acidified with hydrochloric acid and then extracted with chloroform. The chloro-i-orm layer was washed with water and dried over sodium sulfate, 1 ~Ind the solvent was then distilled off to obtain 20.5 g of crude ~-(o-carboxybenzyloxy)benzyl cyanide.
5 g of 4-(o-carboxybenzyloxy)benzyl cyanide thus obtained was heated to 125 to 130C with 30 g of ethyl polyphosphate for ]l hour while stirring. After cooling, water was added to the eaction solution, which was then extracted with chloroform. The c:hloroform layer was washed with an aqueous solution of sodium bicarbonate and water, and dried. Then, the solvent was distilled off, and the residue was recrystallized from ethyl acetate to c~btain 3.4 g of 6,11-dihydro~ oxodibenz[b,e]oxepin-2-acetonitrile having a melting point of 121 to 123C.
Elemental Analysis For C16HllO2N

Calculated: C 77.09, H 4.45, N 5.62 Found : C 76.53, H 4.65, N 5.36 The 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetonitrile could be also synthesized by the following procedure. 2.0 g of 2-methyl-6,11-dihydrodibenz[b,e]oxepin-11-one was dissolved in 'i ml of dibromoethane. The solution was heated to 150C, to which a mixed solution of 1.7 g of bromine and 2 ml of dibromoethane was added dropwise under the irradiation of a 250 watt tungsten ]amp. After cooling, 20 ml of chloroform was added to the reaction solution, which was then washed with water and dried. Then, the c;olvent was distilled off, and the residue was mixed with isopropyl e!ther and allowed to stand. The precipitated crystals were re-crystallized from isopropyl ether to obtain 2-bromomethyl-6,11-clihydrodibenz[b,e]oxepin-ll-one having a melting point of 109 to ~10C.
Elemental Analysis For C15HllO2Br , Calculated: C 59.43, H 3.66, Br 26.36 Found : C 59.65, H 3.80, Br 26.38 ~lS3383 1 A mixed solu-tion oE L.0 g oE 2-bromome~hyl-6,ll-dihydro-d:ibenz[b,e]oxepin-ll-one thus obtained, 0.6 g of sodium cyanide, 1.5 ml of water, 1.5 ml of dimethylformamide and 7 ml of dioxane was heated under stirring to 80C for 2 hours. After cooling, 41) ml of water was added to the reaction solution, which was then extracted with ethyl acetate. The ethyl acetate layer was washed w:ith water and dried, and the solvent was then distilled off. The residue was subjected to silica gel chromatography and eluted with isopropyl ether. The eluate was concentrated and dried, and re-tO crystallization from ethyl acetate gave 0.62 g of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetonitrile having a melting point of 121 t~ 123C

1 SUPPL~MENTARY DC~C'I,OSURE

100 ml of dry benzene solution havinq dissolved therein 3.14 g of ethyl 3-(0-carboxybenzyloxy)phenylaceta-te and 25 g of thionyl chloride was refluxed for 2 hours. After the solvent was distilled off a small amount of benzene was added to the residue followed by concentrating it to dryness to completely remove excessive thionyl chloride to obtain 3.2 g oi-- oily product of ethyl 3-(0-chlorocarbonylbenzyloxy)phenylacetate.
IR spectrum (liquid film method) 1755 cm 1 (carboxylic acid chloride) 1725 cm 1 (ester) The thus obtained ethyl 3-(0-chlorocarbonylbenzyloxy) phenylacetate in an amount of 3.2 g was heated at 175 - 185C
with stirring for 5 hours in nitrogen gas stream. After the reaction was completed, the product was separated using a silica gel column chromatography using chloroform as a solvent and then recrystallized from petroleum ether-diethyl ether to obtain 300 mg of ethyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-3-acetate having a :~0 melting point of 35 - 36C.
Elemental Analysis for C18 H16 4 Found C 72.82 H 5.51 Calcd.C 72.96 H 5.44 While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without department from the spirit and scope thereof.

Claims (40)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the production of compounds of the general formula (I) (I) wherein R1 represents a hydrogen atom, a halogen atom other than fluorine or a lower alkoxy group; R2 represents a hydrogen atom or a lower alkyl group; R3 represents a hydrogen atom or a lower alkyl group; or pharmaceutically acceptable salts thereof, selected from the group of processes consisting of;
(a) cyclizing a compound of the general formula (II) (II) wherein R1, R2 and R3 are as hereinbefore defined; and X represents a halogen atom or a hydroxy group; whereafte the cyclized product obtained is, if desired, hydrolyzed, (b) hydrolyzing a compound of the general formula (III) (III) Claim 1 continued ...

whexein R4 represents a carbamoyl group, a cyano group or an alkoxycarbonyl group and R1 and R2 represent the same meaning as described above, (c) alcoholyzing a compound of the general formula (IV) (IV) wherein R5 represents a carboxyl group and R1 and R2 represent the same meaning as described above, in the presence of a lower alcohol, (d) decarboxylating a compound of the general formula (V), (V) wherein R6 represents a carboxyl group, a lower alkoxy-carbonyl group or a cyano group, and R1, R2 and R3 represent the same meaning as described above, (e) oxidizing a compound of the general formula (VI) (VI)
1. Claim 1 continued ...
   
   wherein R7 represents a formyl group, a hydroxymethyl group or an alkoxymethyl group and R1 and R2 represent the same meaning as described above, (f) oxidizing a compound of the general formula (VII) (VII) wherein R8 represents a hydrogen atom or a hydroxy group and R1, R2 and R3 represent the same meaning as described above, and (g) oxidizing a compound of the general formula (VIII) (VIII) wherein R1 represents the same meaning as described above.
2. 2. A process for the production of compounds of the general formula I as defined in claim 1 which comprises the process as defined in claim 1(a).
3. 3. A process for the production of compounds of the general formula I as defined in claim 1 which comprises the process as defined in claim 1(b)
4. 4. A process for the production of compounds of the general formula I as defined in claim 1 which comprises the process as defined in claim 1(c).
5. 5. A process for the production of compounds of the general formula I as defined in claim 1 which comprises the process as defined in claim 1(d).
6. 6. A process for the production of compounds of the general formula I as defined in claim 1 which comprises the process as defined in claim 1(e).
7. 7. A process for the production of compounds of the general formula I as defined in claim 1 which comprises the process as defined in claim 1(f).
8. 8. A process for the production of compounds of the general formula I as defined in claim 1 which comprises the process as defined in claim 1(g).
9. 9. A compound of the general formula I as defined in claim 1 whenever prepared by the process as defined in claim 1.
10. 10. A compound of the general formula I as defined in claim 1 whenever prepared by the process as defined in claim 2.
11. 11. A compound of the general formula I as defined in claim 1 whenever prepared by the process as defined in claim 3.
12. 12. A compound of the general formula I as defined in claim 1 whenever prepared by the process as defined in claim 4.
13. 13. A compound of the general formula I as defined in claim 1 whenever prepared by the process as defined in claim 5.
14. 14. A compound of the general formula I as defined in claim 1 whenever prepared by the process as defined in claim 6.
15. 15. A compound of the general formula I as defined in claim 1 whenever prepared by the process as defined in claim 7.
16. 16. A compound of the general formula I as defined in claim 1 whenever prepared by the process as defined in claim 8.
    
    17. A process for the preparation of the compound repre-sented by the formula which comprises selecting a process from the group of processes comprising:
    (a) cyclizing a compound of the formula wherein X is a hydrogen atom or a hydroxy group;
    (b) hydrolyzing a compound of the formula wherein R4 is a carbamoyl group, a cyano group or an alkoxycarbonyl group;
17. Claim 17 continued:
    
    (c) decarboxylating a compound of the formula (d) oxidizing a compound of the formula wherein R7 is a formyl group or a hydroxymethyl group;
    (e) oxidizing a compound of the formula wherein R7 is a hydrogen atom or a hydroxy group;
    (f) oxidizing a compound of the formula .
    
    18. 6,11-Dihydro-11-oxodibenz[b,e]oxepin-3-acetic acid of the formula
18. Claim 18 continued:
    
    whenever prepared by the process as claimed in claim 17.
19. 19. A process as claimed in claim 1 for the preparation of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl) propionic acid which comprises cyclizing a compound of the formula wherein X is a halogen atom or a hydroxy group.
20. 20. 2-(6,11-Dihydro-11-oxodibenz[b,e]oxepin-3-yl)propionic acid whenever prepared by the process as claimed in claim 19.
    
    21. A process for the production of 2-(6,11-dihydro-11-oxo-dibenz[b,e] oxepin-2-yl)propionic acid represented by the formula which comprises selecting a process from the group of processes consisting of:
    (a) cyclizing a compound of the formula C]laim 21 continued:
    
    wherein X is a halogen atom or a hydroxy group and R3 is a hydrogen atom or a lower alkyl group;
    (b) hydrolizing a compound of the formula wherein R4 is a carbamoyl group or a cyano group;
    (c) decarboxylating a compound of the formula wherein R3 is a hydrogen atom or a lower alkyl group R6 is a carboxyl group, a lower alkoxycarbonyl group or a cyano group;
    (d) oxidizing a compound of the formula
21. Claim 21 continued:
    wherein R7 is a formyl group or a hydroxymethyl group;
    (e) oxidizing a compound of the formula wherein R8 is a hydrogen atom or a hydroxy group;
    (f) oxidizing a compound of the formula
22. 22. 2-(6,11-Dihydro-11-oxodibenz [b,e]oxepin-2-yl) propionic acid represented by the formula whenever prepared by the process as claimed in claim 21.
    23. A process as claimed in claim 1 for preparing 2-(8-chloro-6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)propionic acid of the formula
23. Claim 23 continued:
    
    which comprises cyclizing wherein X is a halogen atom or a hydroxy group.
24. 24. 2-(8-Chloro-6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)propionic acid of the formula whenever prepared by the process as claimed in claim 23.
    
    25. A process as claimed in claim 1 for preparing 8-fluoro-6,11-dihydro-11-oxodibenz[b,e]oxepin-3-acetic acid of the formula which comprises cyclizing a compound of the formula
25. Claim 25 continued:
    
    wherein X is a halogen atom or a hydroxy group.
26. 26. 8-Fluoro-6,11-dihydro-11-oxodibenz[b,e]oxepin-3-acetic acid of the formula whenever prepared by the process as claimed in claim 25.
27. 27. A process as claimed in claim 1 for preparing 2-(8-chloro-6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionic acid which comprises cyclizing a compound of wherein X is a halogen atom.
28. 28. 2-(8-Chloro-6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl) propionic acid whenever prepared by the process as claimed in claim 27.
29. 29. A process as claimed in claim 1 for preparing 2-(8-fluoro-6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl)propionic acid which comprises cyclizing a compound of the formula wherein X is a halogen atom or a hydroxy group.
30. 30. 2-(8-Fluoro-6,11-dihydro-11-oxodibenz[b,e]oxepin-3-yl) propionic acid whenever prepared by the process as claimed in claim 29.
31. 31. A process as claimed in claim 1 for preparing 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionic acid which comprises cyclizing a compound of the formula wherein X is a halogen atoms.
32. 32. 2-(6,11-Dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionic acid whenver prepared by the process as claimed in claim 31.
    33. A process as claimed in claim 1 for preparing 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid of the formula
33. Claim 33 continued .......
    
    which comprises selecting a process from the group of processes consisting of:
    (a) cyclizing a compound of the formula wherein X is a halogen atom or a hydroxy group and R3 represents a hydrogen atom or a lower alkyl group;
    (b) hydrolizing a compound of the formula wherein R4 is a carbamoyl group or a cyano group;
    
    (c) decarboxylating a compound of the general formula wherein R3 is a hydrogen atom or a lower alkyl group,R6 is a carboxyl group, a lower alkoxycarbonyl group or a cyano group;
    (d) oxidizing a compound of the general formula wherein R7 is a formyl group or a hydroxymethyl group;
    (e) oxidizing a compound of the general formula
34. 34. 6,11-Dihydro-11-oxodibenz/b,e/oxepin-2-acetic acid whenever prepared by the process as claimed in claim 33.
35. 35. A process for the preparation of 6,11-dihydro-11-oxodibenz/b,e/oxepin-2-acetic acid which comprises cyclizing 4-(2-carboxybenzyloxy)phenyl acetic acid.
36. 36. 6,11-Dihydro-11-oxodibenz/b,e/oxepin-2-acetic acid, whenever prepared by the process as claimed in claim 35 or an obvious chemical equivalent thereof.
37. 37. A process for the production of compounds of the general formula (I) (I) wherein R1 represents a hydrogen atom, a halogen atom or a lower alkoxy group; R2 represents a hydrogen atom or a lower alkyl group; R3 represents a hydrogen atom or a lower alkyl group and pharmaceutically acceptable salts thereof which comprises cyclizing a compound of the general formula (II) (II) wherein R1, R2 and R3 are as above defined.
38. 38. A compound of the general formula (I) as defined in claim 37 whenever prepared by the process as claimed in claim 37 or an obvious chemical equivalent thereof.
    
    CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE
39. 39. A process as claimed in claim 1 for preparing ethyl-(6,11-dihydro-11-oxodibenz/b,e/oxopin-3-acetate which comprises cyclizing a compound of the formula wherein X is a halogen atom.
40. 40. Ethyl-(6,11-dihydro-ll-oxodibenz/b,e/oxepin-3-acetate whenever prepared by the process as claimed in claim 39.