KR810000611B1 - Process for preparing prepionic acid derivatives - Google Patents

Abstract

Title compds. (I; X = O or H2; Y = CH or N; A = O or S; R1 = C1-5 lower alkoxy), useful as antiinflammatory agent, were prepd. by the reaction of R'H and II(R3 = hydroxy or amino). Thus, 289 g 2-[4'-(α-cyanoethyl)-phenylthio -phenyl acetic acid and 5.8 g polyphosphoric acid were stirred at 100≰C for 30 min to give 110 mg 2-(10,11-dihydro-11-oxodibenzo[b,f thiepin-2-yl) propionamide (m.p. 180.8-184.8≰C).

Description

Method for preparing propionic acid derivatives.

The present invention relates to novel propionic acid derivatives and methods for their preparation.

The present inventors studied various compounds and found that the propionic acid derivatives of the following structural formula (I) have excellent anti-inflammatory action.

Where X is oxygen or two hydrogen atoms,

V is CH or N,

A is oxygen or sulfur atom

R is a hydroxyl group, an amino group, or a C ₁ -C ₅ lower alkoxy group.

It is therefore one object of the present invention to provide novel propionic acid derivatives represented by formula (I).

Another object of the present invention is to provide a propionic acid derivative of formula (I) having strong anti-inflammatory action.

Another object of the present invention is to provide a novel process for preparing propionic acid derivatives of formula (I).

The compound of formula (I) is divided into the following formulas (II) and (III);

Where A, X and R are as defined above.

The -CH (CH ₃ ) COR groups in the compounds (II) and (III) are either at the 2-, 3- or 4- positions of the formula (II) and 8-, 9- or 10- of the formula (III) Any position may be substituted.

Compounds of formulas (II) and (III) are further represented by the following formulas (IV) and (V); And divided into (VI) and (VII), respectively.

Wherein X and R are as defined above.

The compound of formula (IV) is divided into the following formulas (VIII) and (IX).

Where R is as defined above.

The compound of formula (V) is further divided into the following formulas (X) and (XI).

Where R is as defined above.

The compound of formula (VI) is further divided into the following formulas (VII) and (XIII).

Where R is as defined above.

Structural formula (VII) is subdivided into the following structural formulas (XIV) and (XV).

Where R is as defined above.

Structural formulas (VIII)-(XV) are subdivided based on the position of the substituted -CH (CH ₃ ) COR.

Preferred compounds of formula (I) are compounds of formulas (XIII), (X), (XIII) and (XV).

Especially preferred among these compounds are compounds of the formula (XVI)-(XIX).

Where R is as defined above.

According to the invention the present compounds of formula (I) are prepared by any of the processes as shown below.

[Step 1]

Where Y and A are as defined above.

According to this process 1, the compound of formula (XXI) is prepared by cyclization of the compound of formula (XX) or an active derivative thereof in the presence of a condensate.

Examples of suitable condensing agents that can be used include polyphosphoric acid, polyphosphoric acid esters, and the like. The reaction is preferably carried out at 80-150 ° C. for 0.5-4 hours with or without solvent.

Starting materials of formula (XX) are prepared according to the following scheme:

Where Y and A are as defined above

R ₁ is a lower alkoxy group of C ₁ -C ₅ ,

B and C are halogen atoms, hydroxyl groups, mercapto groups or metal salts thereof (wherein C is a hydroxy group, melcapto group or metal salt thereof, B is a halogen atom and when C is a halogen atom, B is a hydroxy group, mul Earthenware or a metal salt thereof) and Z is a halogen atom.

That is, the compound of formula (XXII) is reacted with an acetophenone derivative of formula (XXIII) to obtain a compound of formula (XXIV) and esterified with a lower alcohol to obtain a compound of formula (XXV) to reduce the compound of formula (XXVI). To obtain a compound of formula (XXVII) to react with a metal cyanide to obtain a compound of formula (XXVIII) to hydrolyze to obtain a compound of formula (XX).

Alternatively, compounds of formula (XXV) may be prepared by reacting lower alkyl esters of compounds of formula (XXII) with compounds of formula (XXIII).

[Step 2:]

Where Y and A are as defined above.

According to this process 2, the compound of formula (XXX) is prepared by reacting the compound of formula (XXI) with hydrazine or semicarbazide, and reacting the hydrazone or seikabazone of formula (XXIX) with alkaline reagent.

In preparing compounds of formula (XXIX) from compounds of formula (XXI) the reaction is carried out without solvent but preferably in organic solvents such as alcohols such as methanol and ethanol, ethers such as dioxane and tatrahydrofuran. It can be performed under time reflux conditions.

In preparing compounds of formula (XXX) from compounds of formula (XXIV), compounds of formula (XXIX) can be prepared by inert solvents that do not participate in the reaction, such as alcohols such as ethanol, t-butanol and diethylene glycol; Ethers such as dioxane and tetrahydrofuran are reacted with alkali reagent in diethylene glycol for 1-5 hours at 100-200 ° C.

Alkali reagents that can be used in this reaction include potassium hydroxide, sodium hydroxide and metal alkoxides.

[Step 3:]

Wherein Y, A and R are as defined above.

According to this step 3, the compound of formula (XXXII) is prepared by reducing the compound of formula (XXXI), preferably by clemenzen reduction. The reaction is preferably carried out under reflux conditions in the presence of zinc or zinc-amalgam for 1-4 hours in an inert solvent containing a small amount of concentrated hydrochloric acid and water.

[Step 4:]

Where Y, A and X are as defined above,

R ₂ is an amino group or a C ₁ - C ₅ of a lower alkoxy group.

This reaction is carried out in a conventional manner. That is, the reaction is preferably carried out at room temperature gum using a catalyst, i.e. potassium hydroxide, sodium hydroxide, hydrochloric acid and sulfuric acid, in an aqueous solvent such as methanol and ethanol containing small amounts of water.

[Step 5:]

Where X, Y and A are as defined above,

R ₁ is a C ₁ -C ₅ lower alkoxy group,

R ₃ is a hydroxy group or an amino group.

This reaction is carried out in a conventional manner. That is, the reaction is preferably carried out 1-5 hours at room temperature-boiling point using an acid, for example sulfuric acid and hydrochloric acid, in alcohol R ₇ H, where R is as defined above.

[Step 6:]

X, Y and A are as defined above.

In the preparation of the compound of the formula (XXXVII) from the compound of the formula (XXXIV), the use of diazomentane is preferred. That is, diazomethane dissolved in diethyl ether is added to a solution of the compound of formula (XXXIV), and the mixture is stirred at room temperature to obtain a compound of structure (XXXVII) having high yield.

[Step 7:]

Where X, Y and A are as defined above,

R ₄ is a hydroxy group or a lower alkoxy group of C ₁ -C ₅ .

According to this process 7, the compound of formula (XXXVIII), its acid halide, its mixed acid anhydride or its activated ester is not involved in the reaction, such as methylene chloride, benzene, toluene or chloroform at room temperature or reflux. React with ammonia under conditions. When using free propionic acid derivatives of the formula (XXXIV), condensing agents, ie dicyclohexyl carbodiimides, can be used.

The compounds of the present invention exhibit oral and parenteral activity and can be formulated in formulations for oral, parenteral, rectal or topical administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid formulations the active compound is admixed with at least one inert diluent, ie sucrose, lactose or starch. Such forms also include additional materials other than inert diluents, such as lubricants such as magnesium stearate, as in the usual examples. For capsule tablets and pills, the formulation may also include a buffer. Tablets and pills can also be prepared with enteric coatings.

Liquid dosage forms for oral administration include emulsions, solutions, suspensions, syrups and exciples that contain pharmaceutically acceptable and inert diluents commonly used in techniques such as purified water and alcohols. In addition to inert diluents, such compositions may include media such as wetting, emulsifying and suspending agents and sweetening, flavoring and fragrances. Formulations according to the invention for parenteral administration include sterile aqueous or non-aqueous, suspensions or emulsions. Examples of non-aqueous solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.

Rectal compositions are suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or suppository waxes.

The dosage of the active ingredient in the composition of the present invention may vary;

However, there is a need for an amount of the active ingredient to obtain a suitable formulation. The dosage chosen depends on the desired therapeutic effect through administration during the treatment period. In general, mammals are dosed at 0.4-20 mg / kg body weight to achieve effective relief of inflammation.

Compounds of the present invention represented by formula (I) have excellent anti-inflammatory effects.

That is, oral administration of the compound according to the present invention to group 1 consisting of 5-7 wister males weighing about 100 g and edema in the hind paws by subcutaneous injection of 0.1 ml of 1% carakenine 1 hour after administration of the test compound. Triggered and the volume of the hind paw was measured with a differential volumetric meter. The results obtained are shown in Table 1.

TABLE 1

Compound 1: 2- (10,11-dihydro-11-oxodibenzo [b, f] thipin-2-yl) -propionamide

2: 2- (10,11-dihydro-11-oxodibenzo [b, f] thiin-2-yl) -propionic acid

3: ethyl 2- (10,11-dihydro-11-oxodibenzo [b, f] thiin-2-yl) -propionate

4: 2- (10,11-dihydrobenzo [b, f] thiin-2-yl) -propionic acid

5: ethyl 2- (10,11-dihydrobenzo [b, f] thien-2-yl) -propionate

6: 2- (10,11-dihydro-11-oxodibenzo [b, f] thiin-3-yl) -propionic acid

7: ethyl 2- (10,11-dihydro-11-oxodibenzo [b, f] thiin-3-yl) -propionate

8: ethyl 2- (10,11-dihydrobenzo [b, f] thipin-3-yl) -propionate

9: 2- (10,11-dihydrobenzo [b, f] thiin-3-yl) -propionic acid

10: 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-2-yl) -propionamide

11: ethyl 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-2-yl) -propionate

12: 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-2-yl) -propionic acid

13: 2- (10,11-dihydrodibenzo [b, f] oxepin-2-yl) -propionic acid

14: ethyl 2- (10,11-dihydrodibenzo [b, f] oxepin-2-yl) -propionate

15: 2- (10,11-dihydrodibenzo [b, f] oxepin-2-yl) -propionamide

16: 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-3-yl) -propionic acid

17: 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-4-yl) -propionamide

18: 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-4-yl) -propionic acid

19: 2- (10,11-dihydrodibenzo [b, f] oxepin-4-yl) -propionic acid

20: 2- (5,6-hydro-6-oxobenzo [b] pyrido [3,2-f] thiepin-8-yl) -propionic acid

21: 2- (5,6-dihydrobenzo [b] pyrido [3,2-f] thiin-8-yl) -propionic acid

22: Ethyl 2- (5,6-dihydrobenzo [b] pyrido [3,2-f] thiepin-8-yl) -propionate

23: 2- (5,6-dihydrobenzo [b] pyrido [3,2-f] thiepin-8-yl) -propionamide

24: 2- (5,6-dihydrobenzo [b] pyrido [3,2-f] thiin-9-yl) -propionic acid

25: ethyl 2- (5,6-dihydrobenzo [b] pyrido [3,2-f] thiepin-9-yl) -propionate

26: 2- (5,6-dihydro-6-oxobenzo [b] pyrido [3,2-f] oxepin-8-yl) -propionic acid

27: 2- (5,6-dihydrobenzo [b] pyrido [3,2-f] oxepin-8-yl) -propionic acid

28: ethyl 2- (5,6-dihydrobenzo [b] pyrido [3,2-f] oxepin-8-yl) -propionate

29: 2- (5,6-dihydrobenzo [b] pyrido [3,2-f] oxepin-8-yl) -propionamide

30: 2- (10,11-dihydrodibenzo [b, f] thiepin-2-yl) -propionamide

As can be seen from the results in Table 1, the compounds have significant effects, in particular the compounds represented by the formulas (XVI), (XVII), (XVIII) and (XIV) are widely used as anti-inflammatory agents. It has an excellent effect compared to flufenamic acid and indomethacin.

The invention is described in more detail below in connection with the examples, but the invention is not limited to the examples.

Example 1

[2- (10,11-Dihydro-11-oxodibenzo [b, f] thiepin-2-yl) -propionamide:]

-시아노에틸)-페닐티오]-페닐초산에 5.8g의 폴리포스포린산을 가하고 혼합물을 100℃에서 30분간 교반했다. 여기에 방수를 가하고 혼합물을 초산에틸로 추출하고 추출물을 포화 탄산수소나트륨 용액으로 세척한 후 다시 포화 염화나트륨 용액으로 세척하고 무수황산 나트륨 상에서 건조했다. 용매를 증류하여 버리고 270mg의 연갈색 오일을 얻어 실리카겔상에서 크로마토그라피하고 n-헥산/아세톤(3/1)로 용출했다.289 mg 2- [4 '-(

5.8 g of polyphosphoric acid was added to -cyanoethyl) -phenylthio] -phenylacetic acid, and the mixture was stirred at 100 degreeC for 30 minutes. Water was added thereto and the mixture was extracted with ethyl acetate and the extract was washed with saturated sodium hydrogen carbonate solution and then again with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off and 270 mg of light brown oil was obtained, chromatographed on silica gel and eluted with n-hexane / acetone (3/1).

110 mg of the title compound were obtained as pale yellow crystals having a melting point of 180.8-184.8 ° C. This was recrystallized from acetone / n-hexane to obtain a crystal having a melting point of 190.0-192.5 ° C.

: 3530,3420(NH₃), 1660(C=0)IR

: 3530,3420 (NH ₃ ), 1660 (C = 0)

NMR (CDCl ₃ ) δ: 1.42 (3H, d, J = 8 Hz, = CH-CH ₃ ), 3.52 (1N, q, J = 8 Hz, = CH-CH ₃ ), 4.28 (2H, s, -CH ₂ -CO-), 5.30-5.82 (2H, wide, -CONH ₂ ), 7.0-7.64 (6H, m, directional quantum 8.01 (1H, s, C ₁ -H)

Example 2

[2- (10,11-Dihydro-11-oxodibenzo [b, f] thiepin-2-yl) -propionic acid]

150 mg of potassium hydroxide, 1 ml of ethanol and 1 ml of water were added to 105 mg of the product of Example 1 and the resulting mixture was refluxed for 6 hours. After cooling, water was added thereto and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, a reddish brown oil was obtained, chromatographed on silica gel, and eluted with n-hexane / acetone (15/2). 45 mg of pale yellow oil was obtained and crystallized from n-hexane to give 28 mg of the title compound as a white crystal having a melting point of 141-146 ° C. Some of the crystals were further recrystallized from benzene / n-hexane to give crystals having a melting point of 155-156.5 ° C.

: 1710, 1675(C=0)IR

1710, 1675 (C = 0)

NMR (CDCl ₃ ) δ: 1.39 (3H, d, J = 8 Hz, = CHCH ₃ ), 3.62 (1N, q, J = 8 Hz, = CHCH ₃ ), 4.22 (2H, s, -CO-CH ₂ -6.89 -7.53 (6H, m, directional quantum), 7.95 (1H, d, J = 2 Hz, C ₁ - H ), 9.81-10.09 (1H, b, s, -COOH)

Example 3

[Ethyl 2- (10,11-dihydro-11-oxodibenzo [b, f] thiin-2-yl) -propionate:]

200 mg of 2- (10,11-dihydro-11-oxodibenzo [b, f] thiin-2-yl) -propionamide was dissolved in 4 ml of ethanol, 0.4 ml of concentrated sulfuric acid was added, and the mixture was stirred for 1 hour. It was stirred to reflux. The solvent was distilled off, the residue was obtained, some ice was added, the mixture was extracted with ethyl acetate, the extract was washed with saturated sodium carbonate solution, again with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give a brown oil which was chromatographed on silica gel and eluted with benzene-chloroform. 141 mg of the title compound in light yellow oil were obtained.

: 1730, 1680(C=0)IR

: 1730, 1680 (C = 0)

NMR (CDCl ₃ ) δ: 1.06 (3H, t, J = 7 Hz, -CH ₂ CH ₃ ), 1.34 (3H, d, J = 7 Hz, CHCH ₃ ), 3.58 (1H, q, J = 7 Hz, = CHCH ₃ ), 3.98 (2H, q, J = 7 Hz, -CH ₂ CH ₃ ), 4.23 (2H, s, -COCH _2- ), 6.96-7.70 (6H, m, directional quantum), 8.02 (1H, d, J = 2Hz, C ₁ -H)

MS (m / e): 326 (M ⁺ )

Example 4

[2- (10,11-Dihydro-11-hydrazo dibenzo [b, f] thiepin-2-yl) -propion amide:]

30 mg of 2- (10,11-dihydro-11-oxodibenzo [b, f] thiin-2-yl) -propionamide was dissolved in 2 ml of ethanol, 0.3 ml of hydrazine hydrate was added and the mixture was stirred for 2 hours. Refluxed. After cooling, the solvent was distilled off and the residue was obtained, extracted with chloroform and the extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off and 32 mg of title compound of yellow crystals was obtained.

: 3400-3100(NH₂), 1660(C=0)IR

: 3400-3100 (NH ₂ ), 1660 (C = 0)

MS (m / e) 311 (M ⁺ )

Example 5

[2- (10,11-Dihydrodibenzo [b, f] thien-2-yl) -propionic acid:]

A mixture of 32 mg of 2- (10,11-dihydro-11-hydrazodibenzo [b, f] thiepin-2-yl) -propionamide, 800 mg of potassium hydroxide and 8 ml of diethylene glycol at 150 ° C. It stirred for 1.5 hours. After cooling, water was added thereto, the mixture was acidified with hydrochloric acid, extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a brown oil, which was subjected to thin layer chromatography to obtain 10 mg of the title compound as a pale yellow oil. This was crystallized from benzene-n-hexane to give a colorless crystal having a melting point of 103-104.5 占 폚.

: 1705 (C=0)IR

1705 (C = 0)

MS (m / e): 284 (M ⁺ )

Example 6

[Ethyl 2- (10,11-dihydrodibenzo [b, f] thiin-2-yl) -propionate:]

To 100 mg of 2- (10,11-dihydrodibenzo [b, f] thiepin-2-yl) propionic acid, 2 ml of ethanol containing 17% hydrogen chloride was added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off and the residue was obtained by adding ice water, extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, a light brown oil was obtained, chromatographed on silica gel, and eluted with benzene-chloroform. 96 mg of the title compound as a pale yellow oil was obtained.

: 1730 (C=0)IR

: 1730 (C = 0)

NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7 Hz, -CH ₂ CH ₃ ), 1.43 (3H, d, J = 7HZ, = CHCH ₃ ), 3.28 (4H, S, -CH ₂ CH ₂ ), 3.60 (1H, q, J = 7 Hz, = CHCH ₃ ), 4.07 (2H, q, J = 7 Hz, -CH ₂ CH ₃ ), 6.80-7.50 (7H, m, directional quantum)

MS (m / e): 312 (M ⁺ )

Example 7

[2- (10,11-Dihydrodibenzo [b, f] thiepin-2-yl) -propionamide:]

55 mg of 2- (10,11-dihydrodibenzo [b, f] thien-2-yl) -propionic acid was dissolved in 0.5 ml of a chloroform solution containing 0.02 ml of triethylamine, and the resulting mixture was ice-cooled. It was added dropwise to 0.5 ml of chloroform solution containing 0.02 ml of ethyl chlorocarbonate over minutes. The mixture was stirred at the same temperature for 10 minutes, ammonia gas was introduced and stirred at room temperature for 30 minutes. After the reaction was completed, water was added thereto and the resulting mixture was extracted with chloroform. The extract was washed with dilute sodium hydroxide solution and again with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, light brown crystals were obtained, chromatographed on silica gel, and eluted with chloroform to obtain light yellow crystals. Recrystallization from benzene-n-hexane gave 26 mg of the title compound having a melting point of 135-135.5 占 폚.

: 3380, 3180,(NH₂), 1650(C=0)IR

: 3380, 3180, (NH ₂ ), 1650 (C = 0)

NMR (CDCl ₃ ) δ: 1.47 (3H, t, J = 7Hz, CH ₂ CH ₃ ), 3.32 (4H, S, -CH ₂ CH _2- ), 3.49 (1H, q, J = 7Hz, = CHCH ₃ ), 5.34 (2H, bs,, -CONH ₂ ), 6.80-7.60 (7H, m, directional quantum)

MS (m / e): 283 (M ⁺ )

Example 8

[2- (10,11-Dihydro-11-oxodibenzo [b, f] thien-3-yl) propionamide:]

-시아노에틸)-페닐티오)-페닐초산에 36g의 폴리포스포린산을 가하고 혼합물을 100-105℃에서 1시간 교반했다. 냉각시킨 후, 여기에 빙수를 가하고 생성된 혼합물을 초산에틸로 추출했다. 추출물을 포화탄산나트륨 용액으로 세척한 후 포화염화나트륨 용액으로 세척하고 무수황산나트륨상에서 건조시켰다. 용매를 증류해 버리고 1.64g의 연갈색 오일을 얻어 실리카겔상에서 크로마토그라피하고 n-헥산/아세톤 5/1-1/1)로 용출하여 연귤색 결정인 타이틀 화합물 990mg을 얻었다. 아세톤으로부터 재결정시켜 융점 178-179℃를 갖는 연황색 결정을 얻었다.1.8 g of 2- [3 '-(

36 g of polyphosphoric acid was added to -cyanoethyl) -phenylthio) -phenylacetic acid, and the mixture was stirred at 100-105 degreeC for 1 hour. After cooling, ice water was added thereto and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium carbonate solution and then with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, 1.64 g of light brown oil was obtained, chromatographed on silica gel, and eluted with n-hexane / acetone 5 / 1-1 / 1) to obtain 990 mg of the title compound as pale orange crystals. Recrystallization from acetone gave a pale yellow crystal having a melting point of 178-179 ° C.

: 3350(CONN₂), 1680(C=0)IR

3350 (CONN ₂ ), 1680 (C = 0)

NMR (CDCl ₃ ) δ: 1.50 (3H, d, J = 7 Hz, CHC H ₃ ), 3.57 (1H, q, J = 7 Hz = C H CH ₃ ), 4.32 (2H, S, -CO-C H ₂ 5.24-5.82 (2H, bs,, CON H ₂ ), 7.02-7.72 (6H, m, directional quantum), 8.12 (1H, d, J = 8 Hz, C ₁ -H)

Example 9

[2- (10,11-Dihydro-11-oxodibenzo [b, f] thiin-3-yl) propionic acid:]

To 250 mg of 2- (10,11-dihydro-11-oxodibenzo [b, f] thien-3-yl) propionamide was added 3 ml of ethanol, 400 mg of potassium hydroxide and 2 ml of water and the mixture was allowed to mix for 4.5 hours. It stirred and refluxed. After cooling, the solvent was distilled off, a residue was obtained, 1N-sodium hydroxide solution was added thereto, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off and 250 mg of light brown oil was obtained and chromatographed on silica gel to obtain 117 mg of the title compound as a pale yellow oil.

: 1715, 1675(C=0)

1715, 1675 (C = 0)

NMR (CDCl ₃ ) δ: 1.50 (3H, d, J = 7 Hz, CHC H ₃ ), 3.76 (1H, q, J = 7 Hz = C H CH ₃ ), 4.30 (2H, S, -CO-C H ₂ -), 7.02-7.65 (6H, m, directional quantum), 8.12 (1H, d, J = 8 Hz, C ₁ -H), 8.87 (1H, b, s, COO H )

MS (m / e): 298 (M ⁺ )

Example 10

[Ethyl 2- (10,11-dihydro-11-oxodibenzo [b, f] thiin-3-yl) propionate:]

300 ml of 2- (10,11-dihydro-11-oxodibenzo [b, f] thien-3-yl) propionamide was dissolved in 3 ml of ethanol, 0.3 ml of concentrated sulfuric acid was added, and the mixture was refluxed for 3.5 hours. . The solvent was distilled off, a residue was obtained, ice cubes were added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a brown oil which was chromatographed on silica gel and eluted with chloroform to give 277 mg of the title compound as a light brown oil.

: 1730, 1675(C=0)

: 1730, 1675 (C = 0)

NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7 Hz, -CH ₂ C H ₃ ), 1.48 (3H, d, J = 7 Hz, CHC H ₃ ), 3.66 (1H, q, J = 7 Hz = C H CH ₃ ), 4.08 (2H, q, J = 7 Hz, = C H ₂ CH ₃ ), 4.30 (2H, S, -CO-CH _2- ), 7.00-7.66 (6H, m, directional quantum), 8.08 (1H, d, J = 8 Hz, C ₁ -H)

Example 11

[Ethyl 2- (10,11-dihydrodibenzo [b, f] thiin-3-yl) propionate:]

172 mg of ethyl 2- (10,11-dihydro-11-oxodibenzo [b, f] thiin-3-yl) propionate was dissolved in 1 ml of toluene in a small amount of zinc-amalgam, 0.5 ml of concentrated Hydrochloric acid and 0.4 ml of water were added and the mixture was refluxed for 4 hours. After cooling, the mixture was filtered and the filtrate was extracted with benzene. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a yellow oil, which was subjected to thin layer chromatography to give 26 mg of the title compound as a pale yellow oil.

NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7 Hz, -CH ₂ CH ₃ ), 1.40 (3H, d, J = 7 Hz, CHCH ₃ ), 3.20 (4H, S, -CH ₂ CH _2- ), 3.50 (1H, q, J = 7 Hz = CHCH ₃ ), 3.98 (2H, q, J = 7 Hz, -CH ₂ CH ₃ ), 6.80-7.36 (7H, m, directional quantum)

Example 12

[2- (10,11-Dihydro dibenzo [b, f] thiin-3-yl) propionic acid:]

A mixture of 26 mg ethyl 2- (10,11-dihydro dibenzo [b, f] thipin-3-yl) propionate, 1 ml ethanol, 200 mg potassium hydroxide and 1 ml water was stirred at room temperature for 1 hour. . The solvent was distilled off, the residue was obtained, acidified with hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 24 mg of the title compound as a pale yellow oil.

: 1715(C=0),

: 1715 (C = 0),

NMR (CDCl ₃ ) δ: 1.44 (3H, d, J = 7 Hz, = CHC H ₃ ), 3.26 (4H, S, -C H ₂ CH _2- ), 3.60 (1H, q, J = 7 Hz = C H CH ₃ ), 6.88-7.44 (7H, m, directional quantum), 9.72 (1H, b, s, COO H )

MS (m / e): 284 (M ⁺ )

Example 13

[2- (10,11-Dihydro-11-oxodibenzo [b, f] thien-3-yl) propionic acid]

A mixture of 83 mg ethyl 2- (10,11-dihydro-11-oxodibenzo [b, f] thipin-3-yl) propionate, 0.8 ml ethanol, 120 mg potassium hydroxide and 0.8 m water It stirred at room temperature for 2 hours. The solvent was distilled off, the residue was obtained, acidified with hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrochloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a brown oil which was chromatographed on silica gel and eluted with chloroform to give 59 mg of the title compound as a pale yellow oil. Its IR spectrum results correspond to that of the compound obtained in Example 9.

Example 14

[2- (10,11-Dihydro-11-oxodibenzo [b, f] oxepin-2) -propionamide]

-시아노에틸)-페녹시]-페닐초산에 15g의 폴리포스포린산을 가하고 혼합물을 100℃에서 0.5시간 교반했다. 냉각시킨 후, 여기에 얼음 몇조각을 가하고 혼합물을 초산에틸로 추출했다. 추출물을 포화탄산수소나트륨 용액으로 세척한 후 다시 포화염화나트륨 용액으로 세척하고 무수황산나트륨 상에서 건조했다. 용매를 증류해 버리고 항색오일을 얻어 실리카겔 상에서 크로마토그라피한 후 클로로포름으로 용출시켜 황색오일의 타이틀 화합물 378mg 얻었다. 이것을 초산에틸-n-헥산으로부터 결정화시켜 융점 154-155℃을 갖는 연황색 결정을 얻었다.730mg 2- [4 '-(

15 g of polyphosphoric acid was added to -cyanoethyl) -phenoxy] -phenylacetic acid, and the mixture was stirred at 100 degreeC for 0.5 hour. After cooling, a few pieces of ice were added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and then again with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give a color oil which was chromatographed on silica gel and eluted with chloroform to give 378 mg of the title compound as a yellow oil. This was crystallized from ethyl acetate-n-hexane to give a pale yellow crystal having a melting point of 154-155 占 폚.

: 3400, 3200(NH₂),1650(C=0)

: 3400, 3200 (NH ₂ ), 1650 (C = 0)

NMR (CDCl ₃ ) δ: 1.42 (3H, d, J = 7 Hz, = CHCH ₃ ), 3.58 (1H, q, J = 7 Hz = CHCH ₃ ), 4.02 (2H, S, COCH ₂ ), 6.08, 6.52 ( 2, H b, s, -CONH ₂ ), 6.84-7.62 (6H, m, directional quantum), 7.92 (1H, d, J = 3 Hz, C ₁ -H)

MS (m / e): 281 (M ⁺ )

Example 15

[Ethel 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-2) -propionate]

62 mg of 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-2-yl) -propionamide was added to 3 ml of concentrated sulfuric acid in 2 ml of ethanol and the mixture was stirred for 4 hours. It was refluxed. After the reaction was completed, the solvent was distilled off, a residue was obtained, ice was added thereto, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, brown oil was added, chromatographed on silica gel, and eluted with chloroform to obtain 58 mg of the title compound as a pale yellow oil.

: 1730, 1680(C=0)

: 1730, 1680 (C = 0)

NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7Jz, -CH ₂ C H ₃ ), 1.48 (3H, d, J = 7Hz, = CHC H ₃ ), 3.72 (1H, q, J = 7Hz = C H CH ₃ ), 4.80 (2H, S, = C H ₂ ), 4.10 (2H, q, J = 7 Hz, -C H ₂ CH ₃ ),, 7.10-7.64 (6H, m, directional quantum), 7.97 (1H, doublet, J = 3 Hz, C ₁ -H)

MS (m / e): 310 (M ⁺ )

Example 16

[2- (10,11-Dihydro-11-oxodibenzo [b, f] oxepin-2) -propionic acid]

151 mg of ethyl 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-2) -propionate was dissolved in 2 ml of ethanol, and 400 mg of potassium hydroxide was dissolved in 2 ml of water. The mixture was stirred at room temperature for 0.5 hour. After the reaction was completed, water was added thereto and the mixture was extracted with benzene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give a light brown oil which was chromatographed on silica gel and eluted with chloroform to give 112 mg of the title compound as a pale yellow oil. This was crystallized from a mixed solvent of ethyl acetate-n-hexane to give light yellow crystals having a melting point of 156-157 占 폚.

: 1700(쇼울더), 1680(C=0)

: 1700 (Shoulder), 1680 (C = 0)

NMR (CDCl ₃ ) δ: 1.48 (3H, d, J = 7Hz, = CHC H ₃ ), 3.72 (1H, q, J = 7Hz = C H CH ₃ ), 4.04 (2H, S, = C H ₂ ) ,, 7.05-7.74 (6H, m, directional quantum), 7.92 (1H, d, J = 3Hz, C ₁ -H)

MS (m / e): 282 (M ⁺ )

Example 17

[2- (10,11-Dihydrodibenzo [b, f] oxepin-2) -propionic acid:]

To 145 mg of 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-2) -propionamide in 5 ml of ethanol, 10 drops of hydrazine hydrate were added and the mixture was stirred for 3 hours at reflux. I was. After the reaction was completed, the solvent was distilled off to obtain a residue, to which 10 ml of diethylene glycol and 500 mg of sodium hydroxide were added, and the resulting mixture was stirred at 132-133 ° C. for 1 hour. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was reextracted with saturated sodium hydrogen carbonate solution. This alkaline extract was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a brown oil which was chromatographed on silica gel and eluted with chloroform to give 65 mg of the title compound as a pale yellow oil.

: 1710(C=0)

1710 (C = 0)

NMR (CDCl ₃ ) δ: 1.44 (3H, d, J = 7 Hz, = CHCH ₃ ), 3.10 (4H, s, -CH ₂ CH _2- ), 3.63 (1H, q, J = 7 Hz = CHCH ₃ ), 66.8-7.28 (6H, m, directional quantum)

MS (m / e): 268 (M ⁺ )

Example 18

[Ethyl 2- (10,11-dihydrodibenzo [b, f] oxepin-2) -propionate:]

190 mg of 2- (10,11-dihydrodibenzo [b, f] oxepin-2) -propionic acid was dissolved in 5 ml of ethanol containing 10% hydrogen chloride and the resulting mixture was stirred for 1.5 hours at room temperature. The solvent was distilled off, the residue was obtained and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give a light brown oil which was chromatographed on silica gel and eluted with benzene to give 185 mg of the title compound as a pale yellow oil.

: 1730(C=0)

: 1730 (C = 0)

NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7Hz, -CH ₂ CH ₃ ) _, 1.42 (3H, d, J = 7Hz, = CHCH ₃ ), 3.12 (4H, S, -CH ₂ CH ₂ 3.62 (1H, q, J = 7 Hz = C H CH ₃ ), 4.10 (2H, q, J = 7 Hz, -CH ₂ CH ₃ ), 6.86-7.28 (7H, m, directional quantum)

MS (m / e): 296 (M ⁺ )

Example 19

[2- (10,11-Dihydrodibenzo [b, f] oxepin-2-yl) -propionamide]

132 mg of 2- (10,11-dihydrodibenzo [b, f] oxepin-2-yl) -propionic acid was dissolved in 2 ml of benzene, 0.6 ml of thionyl chloride and 3 drops of pyridine were added and the mixture was allowed to come to room temperature. After stirring for 1 hour, the mixture was refluxed with stirring for 1 hour. The solvent was distilled off, the residue was obtained, dissolved in 2 ml of chloroform, and the resulting solution was added to 2 ml of 28% aqueous ammonia. The mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with 1N sodium hydroxide solution and then with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give a tan oil which was chromatographed on silica gel and eluted with chloroform / methanol (200/1). The eluate was crystallized from benzene-n-hexane to give 115 mg of the title compound as light yellow crystals with a melting point of 122.5-123 ° C.

: 332, 3160(NH₂), 1660(c=0)

: 332, 3160 (NH ₂ ), 1660 (c = 0)

NMR (CDCl ₃ ) δ: 1.48 (3H, d, J = 7 Hz, = CHCH ₃ ), 3.12 (4H, S, -CH ₂ CH _2- ), 3.52 (1H, q, J = 7 Hz = CHCH ₃ ), , 5.10, 5.90 (2H, b, s, -CONH ₂ ), 6.90-7.60 (7H, m, directional quantum)

MS (m / e): 267 (M ⁺ )

Example 20

[2- (10,11-Dihydro-11-oxodibenzo [b, f] oxepin-3-yl) -propionamide:]

-시아노에틸)-렌옥시]페닐초산에 22g의 폴리포스포린산을 가하고 혼합물을 100-105℃에서 1시간 교반했다. 냉각시킨 후, 여기에 빙수를 가하고 혼합물을 초산에틸로 추출했다. 추출물을 포화탄산나트륨용액으로 세척하고 다시 포화염화나트륨 용액으로 세척한 후 무수황산나트륨 상에서 건조했다. 용매를 증류해 버리고 갈색 오일을 얻어 실리카겔상에서 크로마토그라피한 후 n-헥산/아세톤(5/1-1/1)로 용출시켜 연갈색 오일의 타이틀 화합물 680mg을 얻었다. 이것을 클로로포름으로부터 결정화시켜 n-헥산/아세톤(2/1)로 세척하여 융점 159-160℃를 갖는 무색결정을 얻었다.1.1 g of 2- [3 '-(

22 g of polyphosphoric acid was added to -cyanoethyl) -lenoxy] phenylacetic acid, and the mixture was stirred at 100-105 degreeC for 1 hour. After cooling, ice water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium carbonate solution and again with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a brown oil which was chromatographed on silica gel and eluted with n-hexane / acetone (5 / 1-1 / 1) to give 680 mg of the title compound as a light brown oil. This was crystallized from chloroform and washed with n-hexane / acetone (2/1) to give colorless crystals having a melting point of 159-160 ° C.

: 3500, 3400(CONH₂), 1680(c=o)

: 3500, 3400 (CONH ₂ ), 1680 (c = o)

NMR (CDCl ₃ ) δ: 1.50 (3H, d, J = 7 Hz, = CHCH ₃ ), 3.67 (1H, q, J = 7 Hz, = CHCH ₃ ), 4.03 (2H, S, -CO-CH ₂ ), , 6.18, 6.48 (2H, b, S, -CONH ₂ ), 7.04-7.48 (6H, m, directional quantum), 7.98 (1H, d, J = 8 Hz, C ₁ - H )

Example 21

[2- (10,11-Dihydro-11-oxodibenzo [b, f] oxepin-3-yl) -propionic acid:]

A mixture of 340 mg 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-3-yl) -propionamide, 3 ml of ethanol, 500 mg of potassium hydroxide and 3 ml of water was refluxed for 8 hours. did. After cooling, the ethanol was distilled off to obtain a residue, which was added 1N-sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off and 380 mg of brown oil was chromatographed on silica gel to give 157 mg of the title compound as a yellow oil.

: 1715, 1680(c=o)

: 1715, 1680 (c = o)

NMR (CDCl ₃ ) δ: 1.52 (3H, d, J = 7 Hz, = CHCH ₃ ), 3.76 (1H, q, J = 7 Hz, = CHCH ₃ ), 4.00 (2H, S, -CO-CH ₂ ), , 7.10, 7.40 (6H, m, directional quantum), 7.92 (1H, d, j = 8HZ, C1-H), 10.36 (1H, d, S, COOH)

MS (m / e): 282 (M ⁺ )

Example 22

[Ethyl 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-3-yl) -propionate:]

50 mg of 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-3-yl) -propionamide was dissolved in 2 ml of ethanol, 0.2 ml of concentrated sulfuric acid was added, and the mixture was stirred for 5 hours. By reflux. The solvent was distilled off, the residue was obtained and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off to give a yellow oil which was chromatographed on silica gel and eluted with chloroform to obtain 55 mg of the title compound as a pale yellow oil.

: 1730, 1680(c=o)

: 1730, 1680 (c = o)

NMR (CDCl ₃ ) δ: 1.10 (3H. T. J = 7 Hz, -CH ₂ CH ₃ ), 1.52 (3H, d, J = 7 Hz, -CHCH ₃ ), 3.74 (1H, q, J = 7 Hz, = CHCH ₃ ), 4.06 (2H, S, -COCH _2- ),, 4.11 (2H, q, J = 7 Hz, -CH ₂ CH ₃ ), 7.04-7.36 (6H, m, directional quantum), 8.00 (1H, d, J = 8 Hz, C ₁ - H )

MS (m / e): 310 (M ⁺ )

Example 23

[Methyl 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-3-yl) -propionate:]

100 mg of 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-3-yl) -propionamide in 2 ml of methanol was added to 0.2 ml of concentrated sulfuric acid and the mixture was stirred for 4 hours. Refluxed. After cooling, the solvent was triturated, a residue was obtained, ice was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 95 mg of the title compound as a pale yellow oil.

: 1730, 1680(c=o)

: 1730, 1680 (c = o)

Example 24

[Methyl2- (10,11-dihydrobenzo [b, f] oxepin-3-yl) -propionate:]

Dissolve 95 mg of methyl 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-3-yl) -propionate in 1 ml of toluene in a small amount of zinc-amalgam, 0.3 ml Concentrated hydrochloric acid and 0.2 ml of water were added and the mixture was refluxed with stirring for 1 hour. After cooling, the mixture was filtered and the filtrate was extracted with benzene. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a pale yellow oil, and thin layer chromatography was carried out to obtain 30 mg of the title compound as a pale yellow oil.

NMR (CDCl ₃ ) δ: 1.44 (3H, d, J = 7Hz, = CHCH ₃ ), 3.14 (4H, S, -CH ₂ CH _2- ), 3.56 (3H, S, -COOCH _3- ),, 3.60 (1H, q, J = 7 Hz, = CHCH ₃ ), 6.72-7.14 (7H, m, directional quantum)

Example 25

[2- (10,11-Dihydrodibenzo [b, f] oxepin-3-yl) -propionic acid]

A mixture of 30 mg methyl 2- (10,11-dihydrodibenzo [b, f] oxepin-3-yl) -propionate, 1 ml ethanol, 200 mg potassium hydroxide and 1 ml water is stirred at room temperature for 15 minutes did. The solvent was distilled off, the residue was obtained and acidified with hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give 28.4 mg of the title compound as a pale yellow oil.

: 1705(c=o)

: 1705 (c = o)

NMR (CDCl ₃ ) δ: 1.42 (3H, d, J = 7 Hz, = CHC H ₃ ), 2.99 (4H, S, -CH ₂ C H _2- ), 3.56, (1H, q, J = 7 Hz, = C H CH ₃ ), 6.70-7.14 (7H, m, directional quantum)

268 (M ⁺ )

Example 26

[2- (10,11-Dihydro-11-oxodibenzo [b, f] oxepin-3-yl) -propionamide:]

-시아노에틸)-페녹시]페닐초산에 7g의 폴리포스포린산을 가하고 혼합물을 87-89℃에서 2시간 교반했다. 여기에 얼음 몇 조각을 가하고 혼합물을 초산에틸로 추출하고 추출물을 포화탄산수소나트륨 용액으로 세척후 다시 포화염화나트륨 용액으로 세척한 후 무수황산나트륨상에서 건조했다. 용매를 증류해 버리고 황색오일을 얻어 실리카겔상에서 크로마토그라피한 후 클로로포름으로 용출시키고 아세톤-n-헥산으로부터 결정화시켜 융점 177-178.5℃를 갖는 연황색 결정의 타이틀 화합물 292mg을 얻었다.349 mg 2- [2 '-(

7 g of polyphosphoric acid was added to cyanoethyl) -phenoxy] phenylacetic acid, and the mixture was stirred at 87-89 ° C for 2 hours. A few pieces of ice were added thereto, the mixture was extracted with ethyl acetate, and the extract was washed with saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, yellow oil was obtained, chromatographed on silica gel, eluted with chloroform and crystallized from acetone-n-hexane to give 292 mg of the title compound as light yellow crystals having a melting point of 177-178.5 ° C.

: 3430(NH₂), 1670(C=O)

: 3430 (NH ₂ ), 1670 (C = O)

MS (m / e): 281 (M ⁺ )

Example 27

[2- (10,11-Dihydro-11-oxodibenzo [b, f] oxepin-4-yl) -propionic acid:]

100 mg of 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-3-yl) -propionamide was dissolved in 2 ml of ethanol and 400 mg of potassium hydroxide was dissolved in 2 ml of water. It was added and the mixture was refluxed with stirring for 6.5 hours. After the reaction was completed, the solvent was distilled off, a transfer was obtained, a 2N-sodium hydroxide solution was added thereto, and the resulting mixture was extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, a brown oil was obtained, chromatographed on silica gel, eluted with chloroform and crystallized from acetone -n-hexane to give 85 mg of the title compound as a pale yellow crystal having a melting point of 159-160 ° C.

: 1710, 1680(C=O)

1710, 1680 (C = O)

NMR (CDCl ₃ ) δ: 1.59 (3H, d, J-7Hz, = CHCH ₃ ), 4.10 (2H, S, -CH ₂ CO-),, 4.54 (1H, q, J = 7Hz, = CHCH ₃ ) , 7.12-8.02 (7H, m, directional quantum)

MS (m / e): 282 (M ⁺ )

Example 28

[2- (10,11-Dihydrodibenzo [b, f] oxepin-4-yl) propionic acid:]

80 mg of 2- (10,11-dihydro-11-oxodibenzo [b, f] oxepin-4-yl) -propionamide was dissolved in 4 ml of ethanol, 0.3 ml of hydrazine hydrate was added and the mixture was stirred for 8 hours. It was refluxed with stirring. The solvent was distilled off, a light yellow oil was obtained, and 3 ml of diethyl glycol and 400 mg of sodium hydroxide were added thereto, and the resulting mixture was stirred at 125 ° C. for 1 hour. Water was added to the mixture, and the resulting solution was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was extracted with saturated sodium hydrogen carbonate solution. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, light yellow crystals were obtained and recrystallized from benzene-n-hexane to obtain 37 mg of the title compound as light yellow crystals having a melting point of 133-133.5 ° C.

: 1700(C=O)

1700 (C = O)

NMR (CDCl ₃ ) δ: 1.50 (3H, d, J = 7 Hz, CHCH ₃ ), 3.10 (4H, S, -CH ₂ CH _2- ),, 4.30 (1H, q, J = 7 Hz, = CHCH ₃ ) , 6.80-7.30 (7H, m, directional quantum), 9.48 (1H, b, s-COO H )

MS (m / e): 268 (M ⁺ )

Example 29

[2- (5,6-Dihydro-6-oxobenzo [b] pyrido [3,2-f] thiepin-8-yl) -propionamide:]

-시아노에틸)-페닐티오]-3-피리딜초산 및 2g의 폴리폴스포린산의 혼합물을 150℃에서 65분간 교반했다. 냉각시킨 후, 여기에 빙수를 가하고 혼합물을 농수산화나트륨용액 및 3% 수산화나트륨용액으로 중화시킨 다음 알카리로 만들었다. 생성된 혼합물을 초산에틸로 추출하고 추출물을 3%수산화나트륨 용액으로 세척한 후 무수황산나트륨상에서 건조했다. 용매를 증류해 버리고 36mg의 황색점착성 물질을 얻어 실리카겔상에서 크로마토그라피한 후 n-헥산/아세톤(2/1)로 용출시켜 무색의 점착성 물질인 타이틀 화합물 25mg을 얻었다. 이것을 에탄올로 고체화시켜 175-180℃인 결정을 얻었다. 이것을 에탄올로부터 재결정시켜 융점이 190-192.5℃인 결정을 얻었다.101mg 2- [4 '-(

A mixture of cyanoethyl) -phenylthio] -3-pyridylacetic acid and 2 g of polypolsporic acid was stirred at 150 ° C. for 65 minutes. After cooling, ice water was added thereto and the mixture was neutralized with concentrated sodium hydroxide solution and 3% sodium hydroxide solution and then made alkaline. The resulting mixture was extracted with ethyl acetate and the extract was washed with 3% sodium hydroxide solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give 36 mg of a yellow sticky substance which was chromatographed on silica gel and eluted with n-hexane / acetone (2/1) to give 25 mg of the title compound as a colorless sticky substance. This was solidified with ethanol to obtain crystals of 175-180 ° C. This was recrystallized from ethanol to obtain a crystal having a melting point of 190-192.5 占 폚.

: 3520, 3420(NH₂), 1680(C=O)

3520, 3420 (NH ₂ ), 1680 (C = O)

NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = SHz, = CHCH ₃ ), 3.12 (2H, S, -CONH _2- ),, 3.54 (1H, q, J = 8Hz, = CHCH ₃ ), 4.16 (2H, S, -COCH _2- ), 6.40-8.40 (6H, m, directional quantum)

Example 30

[2- (5,6-Dihydro-6-oxobenzo [b] pyrido [2,2-f] thiin-8-yl) -propionic acid:]

In 101 mg of 2- (5,6-dihydro-6-oxobenzo [b] pyrido [3,2-f] thiepin-8-yl) -propionamide, 0.4 g of potassium hydroxide, 1 ml of water and 4 ml Ethanol was added and the mixture was refluxed with stirring for 5 hours. After cooling, water and 3% sodium hydroxide solution were added thereto, followed by addition of a small amount of diethyl ether, and the mixture was shaken. The aqueous layers were combined, acidified with acetic acid, thereto was added sodium chloride and the resulting mixture was extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, 115 mg of brown sticky material was obtained, chromatographed on silica gel, and eluted with chloroform / methanol (100 / 1-20 / 1) to obtain 83 mg of the title compound as a colorless sticky material. This was washed with n-hexane to solidify to give colorless crystals having a melting point of 141-143 ° C.

: 1720, 1670(C=O)

: 1720, 1670 (C = O)

NMR (CDCl ₃ ) δ: 1.46 (3H, d, J = 8 Hz, = CHCH ₃ ), 3.70, (IH, q, J = 8 Hz, = CHCH ₃ ), 4.24 (2H, S, -COCH _2- ), 7.00-8.40 (6H, m, directional quantum)

MS (m / e) 299 (M ⁺ )

Example 31

[Methyl 2- (5,6-dihydro-6-oxobenzo [b] pyrido [3,2-f] thiepin-8-yl) -propionate:]

Dissolve 54 mg of 2- (5,6-dihydro-6-oxobenzo [b] pyrido [3,2-f] thipin-8-yl) propionic acid in ethanol and 5 ml of diazomethane ether solution. The mixture was stirred at room temperature for 1 hour. Acetic acid was added thereto to decompose the excess reagent, and the solution was alkaline with saturated sodium bicarbonate solution and the mixture was extracted with acetic acid. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, 51 mg of oil-like substance was obtained, chromatographed on silica gel, eluted with benzene / chloroform (1 / I) to obtain a colorless oil-like substance, crystallized from ethanol and colorless with a melting point of 98-99.5 ° C 40 mg of the title compound of the crystal was obtained.

: 1730, 1670(C=O)

: 1730, 1670 (C = O)

NMR (CDCl ₃ ) δ: 1.45 (3H, d, J = 8 Hz, = CHCH ₃ ), 3.60, (3H, S, -COOCH ₃ and IH, m, = CHCH), 4.22 (2H, S, -COCH ₂ 7.20-8.02 (6H, m, directional quantum)

MS (m / e): 313 (M ⁺ )

Example 32

[2- (5,6-Dihydro-6-hydrazobenzo [b] pyrido [3,2-f] thipin-8-yl) -propionamide:]

134 mg of a mixture of 2- (5,6-dihydro-6-oxobenzo [b] pyrido [3,2-f] thiepin-8-yl) -propionamide, 1.5 ml hydrazine hydrate and 10 ml ethanol The mixture was stirred for 1.5 hours to reflux. The solvent was distilled off, the residue was taken up in chloroform and washed with the resulting mixture and dried over anhydrous sodium sulfate. The solvent was distilled off and 139 mg of title compounds of light yellow crystals were obtained.

: 3600-3300 1660(C=O)

3600-3300 1660 (C = O)

MS (m / e) 312 (M ⁺ )

Example 33

[2- (5,6-Dihydrobenzo [b] pyrido [3,2-f] thiin-8-yl) -propionic acid:]

74 mg 2- (5,6-dihydro-6-hydrazobenzo [b] pyrido [3,2-f] thiepin-8-yl) -propionamide, 18 g potassium hydroxide and 18 ml diethylene glycol The mixture was stirred at 130-140 ° C. for 4 hours. After cooling, water was added thereto, the mixture was acidified with acetic acid, and extracted with chloroform. After washing with water, the mixture was dried over anhydrous sodium sulfate. The solvent was distilled off to give a brown oil which was chromatographed on silica gel and eluted with chloroform-methanol to give 36 mg of the title compound as a pale yellow oil. This was crystallized from ethyl acetate to obtain colorless crystals having a melting point of 181-183 ° C.

: 1700(C=O)

1700 (C = O)

NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 8 Hz, = CHCH ₃ ), 3., 12 (4H, m, -CH ₂ CH _2- ), 3.58 (1H, q, J = 8 Hz, = CHCH ₃ ), 7.00-8.40 (6H, m, directional quantum)

Example 34

[Ethyl 2- (5,6-dihydro benzo [b] pyrido [3,2-f] thiepin-8-yl) -propionate:]

30 mg of 2- (5,6-dihydro benzo [b] pyrido [3,2-f] thiepin-8-yl) -propionic acid are dissolved in 2 ml of ethanol containing hydrogen chloride and the mixture is allowed to stand at room temperature for 1 hour. Stirred. After completion of the reaction, the mixture was alkaline with saturated sodium hydrogen carbonate solution and extracted with chloroform, then the extract was washed with water and with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give a yellow oil which was chromatographed on silica gel and eluted with benzene-chloroform to give 27 mg of the title compound as a colorless oil.

: 1712(C=O)

1712 (C = O)

NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7H ₂ , -CH ₂ CH ₃ ), 1.42 (3H, d, J = 7Hz, = CHCH ₃ ), 3., 20 (3H, m,- _{CH 2 CH 2 -), 3.58} (IH 3 m, -CHCH 3 -), 4.10 (2H, m, CH 2 CH 3), 7.00-8.30 (6H, m, aromatic protons)

MS (m / e) 313 (M ⁺ )

Example 35

[2- (5,6-Dihydrobenzo [b] pyrido [3,2-f] thiin-8-yl) -propionamide:]

50 mg of 2- (5,6-dihydro benzo [b] pyrido [3,2-f] thiepin-8-yl) -propionic acid is dissolved by heating in a mixed solvent of 20 ml of methylene chloride and 20 drops of chloroform. 50 mg of dicyclo hexylcarbodiimide was added thereto with ice cooling, and then 3 ml of methylene chloride contained in liquid ammonia was added dropwise thereto. The resulting mixture was stirred under nitrogen stream for 1.5 hours. After the reaction was completed, a few pieces of ice and acetic acid were added to the mixture, and the resulting mixture was extracted with chloroform. The extract was washed with saturated sodium hydrogen carbonate solution and then again with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was chromatographed on silica gel, and eluted with n-hexane / acetone (4 / 1-1 / 1) to obtain a colorless solid. This was recrystallized from ethyl acetate to obtain 38 mg of colorless crystals of the title compound having a melting point of 173.5-175 ° C.

3350,3160(NH₂) 1680(C=O)

3350,3160 (NH ₂ ) 1680 (C = O)

_{NMR (CDCl 3) δ: 1.44} (3H, t, J = 7H 2, = CHCH 3),, 3.04-3.25 (4H, m, -CH 2 CH 2 -), 3.45 (IH, q, J = 7Hz = CHCH ₃ ), 5.50 (2H, b, s = CONH ₂ ), 6.80-8.10 (6H, m, directional quantum)

MS (m / e): 284 (M ⁺ )

Example 36

[2- (5,6-Dihydro-6-oxozenzo [b] pyrido [3,2-f] thipin-9-yl) -propionamide:]

-시아노에틸)-페닐티오]-3-피리딜초산 및 120g의 폴리포스포린산의 혼합물을 160℃에서 2시간 교반했다. 냉각시킨 후 여기에 빙수를 가하고 생성된 혼합물을 농암모니아로 알카리화한 후 클로로포름으로 추출했다. 추출물을 포화염화나트륨 용액으로 세척하고 무수황산나트륨 상에서 건조했다. 용매를 증류해 버리고 점착성 물질을 얻어 실리카겔 상에서 크로마토그라피한 후 클로로/포름 에탄올(50/1)로 용출시켜 고체물질을 얻었다. 이것을 클로로포름-n-헥산으로부터 재결정시켜 융점 161-162℃인 연황색 분말의 타이틀 화합물 1.8g을 얻었다.6 g of 2- [3 '-(

A mixture of cyanoethyl) -phenylthio] -3-pyridyl acetic acid and 120 g of polyphosphoric acid was stirred at 160 ° C. for 2 hours. After cooling, ice water was added thereto, and the resulting mixture was alkaline with ammonia and then extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, a tacky substance was obtained, chromatographed on silica gel, and eluted with chloro / form ethanol (50/1) to obtain a solid substance. This was recrystallized from chloroform-n-hexane to obtain 1.8 g of the title compound of light yellow powder having a melting point of 161-162 ° C.

3450, 3420(NH₃), 1680(C=O)

3450, 3420 (NH ₃ ), 1680 (C = O)

NMR [(CD ₃ ) ₂ SO] δ: 1.30 (3H, d, J = 7H ₂ , = CHCH ₃ ), 3.22 (2H, s, -CONH ₂ ),, 4.61 (1H, q, J = 7Hz CHCH ₃ ), 4.24 (2H, s, -COCH _2- ), 6.70-8.36 (6H, m, directional quantum)

MS (m / e): 298 (M ⁺ )

Example 37

[2- (5,6-Dihydro-6-oxobenzo [b] pyrido [3,2-f] thiepin-9-yl) -propionic acid]

100 mg of 2- (5,6-dihydro-6-oxobenzo [b] pyrido3,2-f-thiepin-9-yl) -propionamide, 170 mg of potassium hydroxide, 1.5 ml of water and 3 ml of The mixture of ethanol was refluxed for 5 hours. After cooling, the solvent was distilled off, a residue was obtained, ice water was added thereto, the resulting mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a solid material which was recrystallized from benzene to obtain 70 mg of the title compound as a light yellow powder having a melting point of 150-151 ° C.

: 1720, 1680(C=O)

: 1720, 1680 (C = O)

NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 7H ₂ , = CHCH ₃ ),, 3.73 (1H, q, J = 7Hz, CHCH ₃ ), 4.22 (2H, S, -COCH _2- ), 7.12-8.04 (5H, m, directional quantum), 8.32 (1H, d, J = 5 Hz, directional quantum)

MS (m / e): 299 (M ⁺ )

Example 38

[Methyl 2- (5,6-dihydro-6-oxobenzo [b] pyrido [3,2-f] thiin-9-yl) -propionate:]

The etherification of diazomentane in 30 mg of 2- (5,6-dihydro-6-oxobenzo [b] pyrido [3,2-f] thiinpin-9-yl) -propionic acid in 5 ml of ethanol The solution was added dropwise at 0 ° C. to decompose the excess reagents, followed by addition of chloroform and water. The organic layers were combined, washed with 5% sodium hydrogen carbonate solution and saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was chromatographed on silica gel, eluted with benzene / chloroform (4/1) to give 30 mg of the title compound as a colorless sticky substance.

: 1740, 1680(C=O)

1740, 1680 (C = O)

NMR (CDCl ₃ ) δ: 1.50 (3H, d, J = 7H ₂ , = CHCH ₃ ),, 3.70 (3H, S, -COOCH ₃ ), 3.76 (1H, q, J = 7Hz, = CHCH ₃ ), 4.31 (2H, S, -COCH _2- ), 7.20-8.24 (5H, m, directional quantum), 8.40 (1H, d, J = 4 Hz, directional quantum)

MS (m / e): 313 (M ⁺ )

Example 39

[2- (5,6-Dihydro-6-hydrorazobenzo [b] pyrido [3,2-f] thiepin-9-yl) -propionamide:]

A mixture of 400 mg 2- (5,6-dihydro-6-oxobenzo [b] pyrido [3,2-f] thiepin-9-yl) -propionamide, 1 g hydrazine hydrate and 10 ml ethanol 3 hours reflux. After cooling, the mixture was evaporated to dryness to remove the solvent, and the residue was obtained and re-notified from benzene / ethanol (10/1) to give 350 mg of the title compound as a pale yellow powder.

: 3400-3170 (NH₂), 1670(C=O)

: 3400-3170 (NH ₂ ), 1670 (C = O)

MS (m / e): 312 (M ⁺ )

Example 40

[2- (5,6-Dihydrobenzo [b] pyrido [3,2-f] thiin-9-yl) -propionic acid:]

300 mg of 2- (5,6-dihydro-6-hydrazo benzo [b] pyrido [3,2-f] thiepin-9-yl) -propion amide, 15 ml of diethylene glycol and 1.5 g of hydroxide The mixture of potassium was stirred at 130 ° C. for 2 hours. After cooling, the mixture was acidified with acetic acid and extracted with chloroform, then the extract was washed with saturated sodium solution and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was chromatographed on silica gel, and eluted with chloroform to obtain a solid material. This was recrystallized from benzene to obtain 150 mg of the title compound as a colorless crystal having a melting point of 161-162 ° C.

: 1720(C=O)

1720 (C = O)

NMR [(CD ₃ ) ₂ SO] δ: 1.30 (3H, d, J = 7H ₂ , = CHCH ₃ ), 2.90-3.32 (4H broad doublet, -CH ₂ CH _2- ), 3.56 (1H, q, J = 7Hz, = CHCH ₃ ), 6.96-7.52 (5H, m, directional quantum), 8.14 (1H, d, J = 5Hz, directional quantum)

MS (m / e): 285 (M ⁺ )

Example 41

[Ethyl 2- (5,6-dihydro benzo [b] pyrido [3,2-f] thiepin-9-yl) -propionate:]

To 40 mg of 2- (5,6-dihydro benzo [b] pyrido [3,2-f] thiepin-9-yl) -propionic acid was added 15 ml of ethanol containing hydrogen chloride and the mixture was stirred at room temperature for 3 hours. did. The solvent was distilled off, a residue was obtained, ice water was added thereto, and the resulting mixture was alkaline with 5% sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off, an oily substance was obtained, chromatographed on silica gel, and eluted with benzene / chloroform (1/1) to obtain 35 mg of the title compound as an oil.

: 1735(C=O)

1735 (C = O)

NMR (CCl ₃ ) δ: 1.17 (3H, t, J = 7H ₂ , -CH ₂ CH ₃ ), 1.40 (3H, d, J = 7Hz, = CHCH ₃ ) ,, 2.94-3.28 (4H, m,- CH ₂ CH ₂ ), 3.51 (1H, q, J = 7 Hz, = CHCH ₃ ), 4.00 (2H, q, J = 7 Hz, -CH ₂ CH ₃ ), 6.70-7.36 (5H, m, directional quantum), 8.07 (1H, d, J = 4 Hz, C ₂ -H)

MS (m / e): 313 (M ⁺ )

Example 42

[2- (5,6-Dihydrobenzo [b] pyrido [3,2-f] thiin-9-yl) -propionamide:]

Mix 80 mg of 2- (5,6-dihydro benzo [b] pyrido [3,2-f] thiepin-9-yl) -propionic acid, 120 mg of dicyclohexylcarbodiimide and 5 ml of chloroform. It stirred at 20 degreeC under nitrogen flow. To this was added dropwise 1 ml of chloroform containing excess ammonia and the resulting mixture was stirred at 0 ° C. for 2 hours and at room temperature for 1 hour. 50 g of ice water was added thereto, and the mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with water, 5% sodium bicarbonate solution and again with water and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was obtained, dissolved in ethyl acetate and filtered. The solvent was removed from the filtrate and the residue was chromatographed on silica gel and eluted with chloroform / ethanol (100/1) to give 63 mg of the title compound as a colorless sticky substance.

: 3530, 3400(NH₂),1680(C=O)

: 3530, 3400 (NH ₂ ), 1680 (C = O)

NMR (CCl ₃ ) δ: 1.44 (3H, d, J = 7 Hz, = CHCH ₃ ), 3.00-3.30 (4H, m, -CH ₂ CH ₂ ), 3.48 (1H, q, J = 7 Hz, = CHCH ₃ ), 5.60-6.08 (2H, broad s, -CONH ₂ ), 6.80-7.40 (5H, m, directional quantum), 8.16 (1H, d, J = 4 Hz, directional quantum)

MS (m / e): 284 (M ⁺ )

Example 43

[2- (5,6-Dihydro-6-oxobenzo [b] pyrido [3,2-f] oxepin-8-yl) -propionamide:]

-시아노에틸)페녹시]-3-피리딜초산에 3g의 폴리포스포린산을 가하고 혼합물을 130℃에서 3시간 교반했다. 냉각시킨후, 여기에 빙수를 가해 생성된 혼합물을 수산화나트륨으로 알카리화 하고 초산에틸로 추출했다. 추출물을 세척하고 무수황산나트륨 상에서 건조했다. 용매를 증류해버리고 32mg의 갈색고체를 얻어 실리카겔상에서 크로마토그라피한후 클로로포름으로 용출시켜 박층크로마토그라피를 행하여 융점(분해) 200-220℃인 무색결정의 타이틀 화합물 15mg을 얻었다.147 mg of 2- [4 '-(

3 g of polyphosphoric acid was added to cyanoethyl) phenoxy] -3-pyridylacetic acid, and the mixture was stirred at 130 ° C for 3 hours. After cooling, ice water was added thereto, and the resulting mixture was alkaline with sodium hydroxide and extracted with ethyl acetate. The extract was washed and dried over anhydrous sodium sulfate. The solvent was distilled off, 32 mg of brown solid was obtained, chromatographed on silica gel, eluted with chloroform, and thin layer chromatography was performed to obtain 15 mg of the title compound as a colorless crystal having a melting point (decomposition) of 200-220 ° C.

: 3440, 3180(NH₂),1680(C=O)

: 3440, 3180 (NH ₂ ), 1680 (C = O)

NMR [(CD ₃ ) ₂ SO] δ: 1.30 (3H, d, J = 7Hz, = CHCH ₃ ), 3.66 (1H, q, J = 7Hz, = CHCH ₃ ), 4.10 (2H, s, -COCH _2- ), 6.80 (1H, S, -CONH ₂ ) 7.30-8.40 (7H, m, directional quantum and -CONH ₂ )

MS (m / e): 282 (M ⁺ )

Example 44

[2- (5,6-Dihydro-6-oxobenzo [b] pyrido [3,2-f] oxepin-8-yl) -propionic acid:]

100 mg 2- (5,6-dihydro-6-oxo benzo [b] pyrido [3,2-f] oxepin-8-yl) -propionamide, 400 mg potassium hydroxide, 1.20 ml water and 3.75 The mixture of ml ethanol was refluxed with stirring for 6 hours. After cooling, water was added thereto and the resulting mixture was washed with ethyl acetate. The aqueous layer was washed with acetic acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, 106 mg of the residue was obtained, chromatographed on silica gel, and eluted with chloroform to obtain 52 mg of the title compound as a pale yellow oil.

: 1710,1685(C=O)

: 1710,1685 (C = O)

NMR (CDCl ₃ ) δ: 1.50 (3H, d, J = 8 Hz, = CHCH ₃ ), 3.74 (1H, q, J = 8 Hz, = CHCH ₃ ), 4.03 (2H, s, -COCH _2- ), 7.20-8.30 (6H, m, directional quantum)

MS (m / e): 283 (M ⁺ )

Example 45

[2- (5,6-Dihydrobenzo [b] pyrido [3,2-f] oxepin-8-yl) -propionic acid:]

Dissolve 300 mg of 2- (5,6-dihydro-6-oxobenzo [b] pyrido [3,2-f] oxepin-8-yl) -propionamide in 30 ml of ethanol and 5 ml of hydrazine hydrate. The mixture was added dropwise and the mixture was refluxed with stirring for 1 hour. After the reaction was completed, the solvent was removed in midstream to obtain a solid substance, to which 30 ml of diethylene glycol and 700 mg of sodium hydroxide were added, and the resulting mixture was stirred at 130 ° C. under nitrogen for 3 hours. After cooling, water was added thereto and the mixture was washed with ethyl acetate. The aqueous layer was acidified with acetic acid and extracted with ethyl acetate, then the extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was chromatographed on silica gel, and eluted with n-hexane / acetone (5 / 1-2 / 1) to obtain 29 mg of oil. This was crystallized from ethyl acetate to obtain 17 mg of the title compound as a colorless acicular crystal having a melting point of 182.5 to 184 ° C.

: 1710(C=O)

1710 (C = O)

NMR (CDCl ₃ ) δ: 1.50 (3H, d, J = 8 Hz, = CHCH ₃ ), 3.04 (4H, s, -CH ₂ CH _2- ), 3.65 (1H, q, J = 8 Hz, = CHCH ₃ ), 6.90-8.10 (6H, m, directional quantum)

MS (m / e): 269 (M ⁺ )

Example 46

[Ethyl 2- (5,6-dihydro benzo [b] pyrido [3,2-f] oxepin-8-yl) -propionate:]

30 mg of 2- (5,6-dihydrobenzo [b] pyrido [3,2-f] oxepin-8-yl) propionic acid was dissolved in 0.5 ml of ethanol and 2 ml of ethanol saturated with hydrogen chloride gas. The mixture was stirred at room temperature for 1 hour. The mixture was alkaline with saturated sodium bicarbonate and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, an oily substance was obtained, chromatographed on silica gel, and eluted with chloroform / benzene (1 / 4-1 / 3) to obtain 30 mg of the title compound as a colorless oil.

: 1730(C=O)

1730 (C = O)

NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 8 Hz, = CH ₂ CH ₃ ), 1.35 (3H, d, J = 7 Hz, = CHCH ₃ ), 2.94 (4H, s, -CH ₂ CH _2- ), 3.33 (1H, q, J = 7 Hz, = CHCH ₃ ), 3.84 (2H, q, J = 8 Hz, -CH ₂ CH ₃ ), 6.50-7.78 (6H, m, directional quantum)

MS (m / e): 297 (M ⁺ )

Example 47

[2- (5,6-dihydro benzo [b] pyrido [3,2-f] oxepil-8-yl) propionamide:]

To a 10 ml solution of methylene chloride containing 50 mg of 2- (5,6-dihydro benzo [b] pyrido [3,2-f] oxepin-8-yl) propionic acid and 50 mg of dicyclohexylcarbodiimide 5 ml of methylene chloride saturated with ammonia was added, and the mixture was ice-cooled and stirred for 2 hours. Acetic acid and ice were added thereto, and the resulting mixture was extracted with chloroform. The extract was washed with saturated sodium bicarbonate solution and then with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was obtained, extracted with ethyl acetate, and the solvent was removed from the extract. The resulting residue was chromatographed on silica gel and eluted with n-hexane / acetone (4 / 1-1 / 1) to give 22 mg of the title compound as white crystals. This was recrystallized from ethyl acetate to obtain colorless crystals having a melting point of 162-165 占 폚.

: 3350, 3180(NH₂), 1680(C=O)

: 3350, 3180 (NH ₂ ), 1680 (C = O)

NMR (CDCl ₃ ) δ: 1.50, 3.11 (4H, s, -CH ₂ CH _2- ), 3.55 (1H, q, J = 7Hz, = CHCH ₃ ), 5.75 (2H, broad s, -NH ₂ ) , 6.95-8.15 (6H, m, directional quantum)

MS (m / e): 268 (M ⁺ )

Example 48

[2- (5,6-Dihydro-6-oxobenzo [b] pyrido [3,2-f] oxepin-9-yl) propionamide:]

-시아노에틸)-페녹시]-3-피리딜초산 및 30g의 폴리스포린산의 혼합물을 150℃에서 2시간 교반했다. 냉각시킨 후, 여기에 빙수를 가하고 혼합물을 10%암모니아수로 알카리화한 후 클로로포름으로 추출했다. 추출물을 포화염화나트륨 용액으로 세척하고 무수황산나트륨 상에서 건조했다. 용매를 증류해 버리고 오일을 얻어 실리카겔 상에서 크로마토그라피 한후 클로로포름/에탄올(50/1)로 용출시켜 고체상 물질을 얻었다. 이것을 메탄올로 부터 재결정시켜 융점 89-90℃의 연황색 분말인 타이틀화합물 250mg을 얻었다.1.3 g of 2- [3 '-(

-Cyanoethyl) -phenoxy] -3-pyridylacetic acid and a mixture of 30 g of polysporinic acid were stirred at 150 ° C for 2 hours. After cooling, ice water was added thereto and the mixture was alkaline with 10% ammonia water and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, an oil was obtained, chromatographed on silica gel, and eluted with chloroform / ethanol (50/1) to obtain a solid material. This was recrystallized from methanol to obtain 250 mg of the title compound as a pale yellow powder with a melting point of 89-90 ° C.

: 3540,3420(NH₂),1680(C=O)

: 3540,3420 (NH ₂ ), 1680 (C = O)

MS (m / e): 282 (M ⁺ )

Example 49

[2- (5,6-Dihydro-6-oxobenzo [b] pyrido [3,2-f] oxepin-9-yl) propionic acid:]

40 mg of 2- (5,6-dihydro-6-oxobenzo [b] pyrido [3,2-f] oxepin-9-yl) propionamide, 180 mg of potassium hydroxide, 1.5 ml of water and 5 ml of The mixture of ethanol was refluxed with stirring for 5 hours. After cooling, the solvent was distilled off to obtain a residue, ice water was added thereto, the mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off, an oil was obtained, chromatographed on silica gel, and eluted with chloroform-ethanol to obtain 20 mg of the title compound as a pale yellow powder.

: 1710, 1680(C=O)

1710, 1680 (C = O)

MS (m / e): 283 (M ⁺ )

Claims (1)

A process for preparing a compound of formula (I) by reacting a compound of formula (II) with R ₁ H.

X is oxygen or two hydrogen atoms, Y is CH or N, A is oxygen or sulfur atom, R ₁ is C ₁ -C ₅ lower alkoxy group, and R ₃ is hydroxy or amino group.