2 phenylbenzo(b)furans and-tifany and method of production thereof

 

(57) Abstract:

The invention relates to derivatives of 2-phenyl-benzo(b) furan and thiophene, which may be suitable for the treatment of dependent estrogenos diseases, such as prostatic hyperplasia, breast cancer, endometrial cancer, populating infertility and melanoma. To obtain benzo(b) teofanov orthodontistry cyclist using a mixture of sulfurylchloride and pyridine. Thus orthodontistry turns into the reaction at the appropriate sulfochloride that using pyridine goes with the elimination of methyl chloride in an appropriate Floralife and then cyclized in the separation of HCl in benzo(b). 2 S. and 1 C.p. f-crystals, 5 PL. 4 Il.

The invention concerns 2-phenylbenzo(b)furan - -teofanov, method of receiving and containing these compounds pharmaceuticals.

New furans and tifany are characterized by the General formula

< / BR>
in which

R1and R2independently from each other represent a hydrogen atom, alkyl group with 1-10 carbon atoms, benzyl group.

X is oxygen atom or sulfur,

n is an integer from 4 to 12, R3denotes the amino group - NR7R8, the mi of carbon or R7- R8together denote alkylenes group - (CH2)m- or a group - (CH2)2O (CH2)2-, with m an integer 2, 3, 4, 5, or 6, or, if R3is hydrogen, X is an oxygen atom and n is an integer from 5 to 12, or X is a sulfur atom and n is an integer from 0 to 12.

Preferred as the residues R1and R2are alkanoyloxy group of acetic, propionic, butyric, isoalkanes, trimethyloxonium, nylon, acrylic, crotonic, p, Caprylic, pelargonate, decanoas, 3-cyclopentylpropionate and benzoic acids.

The remainder R1may be in position 4, 5, 6 and 7 Bicycle, especially suitable are clauses 5 and 6.

As the alkyl groups of R7and R8suitable are the remains of methyl, ethyl, propyl, butyl, penttila, hexyl, heptyl, Attila, Manila and decanal. As cycloalkyl groups should be particularly residues cyclopentyl and cyclohexyl.

The invention in particular relates to the following compounds:

-5-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan,

-6-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan

-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl is)benzo(b)furan,

-3-ethyl-6-hydroxy-2-(4-hydroxyphenyl)-benzo(b)furan,

-5-hydroxy-2-(4-hydroxyphenyl)-3-propellant(C)furan,

-6-hydroxy-2-(4-hydroxyphenyl)-3-propellant(C)furan,

-3-butyl-5-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan,

-3-butyl-6-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan,

-5-hydroxy-2-(4-hydroxyphenyl)-3-(6 - N-piperidyl - hexyl)-benzo(b)furan,

-6-hydroxy-2-(4-hydroxyphenyl)-3-(6 - N-piperidinyl)- benzo(b)furan,

-6-hydroxy-2-(4-hydroxyphenyl)benzo(b)thiophene,

-6-hydroxy-2-(4-hydroxyphenyl)-3-methylbenzo(b)thiophene,

-3-ethyl-6-hydroxy-2-(4-hydroxyphenyl)benzo(b)thiophene,

-6-hydroxy-2-(4-hydroxyphenyl)-3-propellant(b)thiophene,

-6-hydroxy-2-(4-hydroxyphenyl)-3-(6-N-piperidinyloxy)- benzo(b)thiophene.

The invention relates to a method for producing 2-phenylbenzo(b)-furan-teofanov General formula I.

If this

(a) if X is oxygen, the compound of General formula IIa

< / BR>
in which

R1and R2independently of each other denotes alkyl group with 1-4 carbon atoms,

R3means or -(CH2)2-R, -(CH2)2-Hal, and Hal is a halogen atom and in particular a bromine atom, denote the vinyl OST and ether groups to compounds of General formula Ia

< / BR>
and if R3represents -(CH2)2Hal, the halogen conversion of compounds of formula Ia with primary, secondary or cyclic amine of the formula HNR7R8exchanged for the corresponding residue of an amine - NR7R8, or by transformation with coralcalcium formula H-S-R9exchanged for the appropriate balance of tittarelli-S-R9and oxidized with hydrogen peroxide or other oxidant in the sulfoxide-S(O)-R9or if R3denotes a vinyl remnant, by the final hydroxylation of the vinyl double bond, translating hydroxy-group in the better separated the group and its analogy with the case when R3denotes a halogen atom, is replaced by an amine residue NR7R8or the rest of tittarelli-S-R9and oxidized to sulfoxide-S(O)R9or if R3denotes a residue-CH2-C(O)NR7R8the last is stored as R3or carbonyl group is fully restored with the help of sociallyengaged and free hydroxyl group optionally aeriferous or converted to an ester, or

(b) if X should be grey, the compound of General formula is and means - (CH2)2-R, -(CH2)2-Hal, and Hal is a halogen atom and in particular a bromine atom, or vinyl residue-CH=CH2, ciclitira using a mixture of sulfurylchloride and pyridine to the corresponding derivative of benzo(b)thiophene of the General formula 1b

< / BR>
and then if R3represents -(CH2)2Hal or vinyl residue-CH=CH2as in paragraph (a) for these two cases, subjected to further conversion of compound of General formula Ib and then, if necessary, by using a Lewis acid splitting of the ether group and a free hydroxyl group optionally etherification or converted into ester.

(C) if X should be grey, the compound of General formula IIc

< / BR>
in which

R1and R2have the same meaning as in formula IIa, alleroed using hydride halides of the acids of General formula R3-(CH2)n-3-C(O)X and R3and n have the same meaning as in formula IIa, X is a chlorine atom or bromine, and then restored with

LiAlH4/AlCl3in connection with the General formula Ic

< / BR>
and further converted, as described in paragraph (a).

For alkyl reprove, butyl, isobutyl, tertiary butyl and in particular methyl groups.

Cyclization of compounds of General formula IIa in compounds of General formula Ia using Lewis acid proceeds at (simultaneous) the cleavage of the ether groups R1-O - and R2-O -, and the formation of the corresponding free hydroxy compounds.

As a reagent for cyclization and cleavage of the ether are suitable bartered, mortified, trichloride aluminum, silicon tetrachloride, tribromide aluminum, mertiolate sodium and trimethylsilylmethyl. The reaction is carried out at temperatures from -70 to 200oC. as solvents for the cyclization and cleavage of the ether used inert solvents. Should be called aliphatic halogenougljovodonika, as for example, methylene chloride, aromatic hydrocarbons, such as chlorobenzene, dichlorobenzene and dimethylformamide, and acetonitrile. However, suitable are aliphatic ethers with alkyl residues with 1 to 6 carbon atoms.

For held, if necessary, the esterification of the phenolic hydroxyl groups are taken into consideration methods commonly used in chemistry for the esterification. HB presence of strong acids, as, for example, triperoxonane acid, Perlina acid or p-toluensulfonate, at room temperature or slightly elevated temperatures, or transform by using a carboxylic acid anhydride in the presence of a tertiary amine at a temperature of 20-80oC.

If tertiary amines are used together, pyridine and 4-dimethylamino-pyridine, etherification may be carried out preferably at room temperature

Other operations to obtain the proposed benzo(b) furans General formula I (X=O) are conducted in accordance with standard methods of organic chemistry. Joining the main fragment-NR7R8the compounds of General formula Ia, in which R3represents -(CH2)2-Hal is carried out by boiling W - halogen compounds in the corresponding Amina.

Selective final hydroxylation of the vinyl double bond, i.e., if R3is-CH=CH2that is achieved by gidroborudovaniya, for example, using a 9-borabicyclo ((3.3.1) nonane. Then formed w-gidroksosoedinenii means, for example, by treatment with methanesulfonanilide and triethylamine in an appropriate mesilate.

To obtain benzo(b)teofanov General formula I (X=S) orthodontistry General formula IIb tsiklitiria using a mixture of sulfurylchloride and pyridine. Thus orthodontistry petramala in the reaction in the appropriate sulfochloride that using pyridine goes when removal is metalloid in the appropriate Floralife and then tsiklitiria in the separation of HCl into the corresponding benzo(b)thiophene. If necessary, a further transformation is carried out as described for the case of benzo(b) furan

Alternatively come from unsubstituted in the third position of the heterocycle and the side chains are introduced by acylation Friedel-up and subsequent recovery using LiAlH4/AlCl3.

It was found that the proposed compounds of General formula I possess strong antiestrogenic properties. Compounds with antiestrogenic properties, i.e. substances with inhibitory activity is, for example, tamoxifen Eur. J. Cancer Clin. Oncol, 1985, 21, 985 und J. S. Patterson, "10 Years of Tamoxifen in Breast Cancer" in Hormonal Manipulation of Cancer; Peptides, Growth Factors and New (Anti) steroidal Agents, Raven Press, New York (1987).

Steroid antiestrogens are described in European patent application N 0138504. Antiestrogenic indole derivatives are already known from the patent Germany N 3232968, J. Med. Chem, 1983, 26, 113; J. Med. Chem., 1984, 27, 1439, Eur. J. Cancer. Clin. Oncol. 1985, 21, 531 und Cancer Treatment Reviews 1984, 11, 147 and N-aminoalkylindole, which along with a strong antiestrogenic activity have a negligible estrogenic activity, is known from European patent application N 0348341.

Gidroksilirovanii 2-phenylindole, which are available in the form of diamine-platinum (11)-complex compounds, named paved the application Germany N 3730746.

Compounds according to the invention of General formula I have a pronounced affinity to the estradiol-receptor and displace competitive 3H-17 - estradiol from the receptor. In vivo they have a strong anti-estrogenic effects on the uterus of the mouse and drag estrogen-stimulating the growth of the uterus to 100%. Estrogenic effects in these trials failed to prove or were able to confirm in a very minor extent. The compounds inhibit the growth of hormone sawh breast cells (MCF-7).

Compounds in accordance with the invention suitable for the treatment of estrogen-dependent diseases such as prostatic hyperplasia, breast cancer, endometrial cancer, populating infertility and melanoma.

The following pharmacological tests show the effectiveness of the compounds in accordance with the invention.

Table 1 provides an overview of the tested compounds of General formula I and their relative means of binding (RBAx) to the estrogen receptor of veal tripe per 17 - estradiol = 100.

The order of testing is described in Cancer Treatment Reviews 1984, 11, 147.

From table 1 it follows that the connection 104a, 104b, 102a, 106b, 106a, 63a and 62a find the greatest tool compared to estradiol.

Table 2 shows estrogenic and antiestrogenic activity of compounds 62a, 62b, 68a, 68b, 102a, 102b, 104a, 104b, 106a and 106b. These activities were found in the test vivo infantile mouse. This test is described in detail in Cancer Treatment Reviews 1984, 11, 147 and J. Med. Chem. 1984, 27, 1439.

Table 3 shows the results of studies of the cytotoxic activity of compounds 61a, 62a, 63a, 68a and 68b, as well as 102a, 104a, 106a and 102b, 104b, 106a, 119b compared to tamoxifen is but strong inhibition of cell growth.

Data on the relative affinity of binding of the RBA in relation to estrogennouu receptor 2-phenylbenzo ()-furan and 2-phenylbenzo ()-thiophenol summarized in separate tables 4, 5. In the table the branch circuit refers to the structure -(CH2)n-R3.

Specified in the tables of compounds of General formula I, which include the amino group NR7R8as the radical R3received the above described ways.

The invention relates also to pharmaceutical preparations that contain at least one compound of General formula I and the use of these compounds for the treatment of estrogen-dependent diseases and tumors.

Compounds in accordance with the invention are suitable for preparing pharmaceutical compositions and dosage forms. The pharmaceutical composition or drug containing as active substance one or more of the proposed compounds, optionally in a mixture with other pharmacologically or pharmaceutically effective substances. Preparation of medicines is carried out in a known manner, and can be used and conventional pharmaceutical auxiliary substances, as well as proceeding substances are taken into account, for example, those that are recommended or indicated in the following literature as adjuvants for pharmacy, cosmetics and related fields: Ulmans Encyklopadie der technischen Chemie, Band 4 (1953), pp. 1-39; Journal of Pharmaceutical Sciences, Band 52 (1963), page 918 and subsequent; H. v. Czetsch-Lindenwald, Hilfsstoffe fur Pharmazip und angrenzende Gebiete; Pharm. Ind., Heft 2, 1961, page 72 and subsequent; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete K. G. Cantor Aulendorf in Wurttemberg 1971

The compounds can be administered orally or parenterally, for example, intraperitoneally, intramuscularly, subcutaneously or transcutaneous. Connections can also be implanted in tissue. Enter the number of connections varies within a wide range and can cover any effective amount. Depending on the treated condition and the form of the introduction of a number of input connections can be from 0.01 to 100 mg/kg body weight, pre-from 0.1 to 20 mg/kg body weight.

For oral administration used capsules, pills, pills and so on, Unit dosing, along with the active substance may contain pharmaceutically portable media, such as starch, sugar, sorbitol, gelatin, lubricants, silicic acid, talc and so on, the Department Is

For parenteral administration the active substance can be dissolved or suspendibility in physiologically-tolerated solvents. As solvents are often used oils with or without adding the agent of dissolution, surface-active agents, agents for the preparation of suspensions or emulsifier. Examples of used oils are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.

Connections can also be used in the form of injections, a long acting or preparation of the implant, which can be manufactured in such a manner that a slow release of the active substance.

Implants can contain as inert materials such as biodegradable polymers or synthetic silicones, such as silicone rubber. Active substances for transcutaneous application can be terminated in addition, for example, in the patch.

The following recipe and examples are intended for a more detailed explanation of the invention.

A reaction scheme for producing compounds in accordance with the invention, as well as necessary for R>
In a round bottom flask with a capacity of 250 ml is heated under reflux 20,0 g (of 0.11 mole) of 2,4-dimethoxyacetophenone, 19.32 g (0,22 mole) of the research (19.3 ml) and 7,12 g (0,22 mole of sulfur for approximately 20 hours at a temperature of 135oC. Then the excess morpholine is removed in vacuum. The remaining thiomorpholine its shades without further purification.

Saponification. The brown oil is mixed with 90.0 g of a 50 percent STAKE in 160 ml of ethanol and heated for 6 hours under reflux. Then largely distilled alcohol, diluted with water and filtered off the solid precipitate. While cooling with ice acidified with concentrated hydrochloric acid, extracted three times with dichloromethane, dried with MgSO4, filtered and concentrated in vacuo, water-jet pump. The crude product is recrystallized from water. The beige color crystals, melting point 106-108oC, yield: 51%.

Getting anhydrides of acids

A mixture of 0.5 mole of carboxylic acid and 0.5 mol of patalenitsa phosphorus is stirred for 1/2 hour while cooling with ice. Then heated for 1 hour at a temperature of 60oC and remove the formed phosphorylchloride in vacuum. The residue is mixed with absolute the cleanup.

The acid chloride 2,5-dimethoxyphenylacetic acid (50a)

Colorless oil; yield: 97%

IR spectrum (film): 1805 cm-1(S; C = 0).

The acid chloride 2,4-dimethoxyphenylacetic acid (50b)

Yellow oil; yield: 95%

IR spectrum (film): 1810 cm-1(S; C = 0).

The acylation according to the Friedel-Crafts

A solution of 0.05 mole of carboxylic acid in 150 ml of 1,2-dichloroethane mix from 10.8 g (0.1 mole) of anisole. With stirring and ice cooling are added in several portions of 13.3 g (0.1 mol) of trichloride aluminum. Stirred over night at room temperature and then add about 200 ml of ice water. After separation of the organic phase the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed twice with a 10% sodium lye and three times with water, dried with MgSO4, filtered and concentrated in vacuo. The residue is purified by chromatography on a column (silica gel 60; dichloromethane) and recrystallized from ethanol.

2-(2,5-acid)-1-(4-methoxyphenyl)alanon (51a)

The source of the link: acid chloride 2,5-dimethoxyphenylacetic acid (50a) anisole

Colorless crystals; melting point 100-102oC; exit paraffin) are suspended in 80 ml of absolute dimethylformamide and stirred for 15 minutes at a temperature of 0oC. Then drops add a solution of 4.0 g (14 mmol) of 1,2-diarylethene in 40 ml of absolute dimethylformamide and stirred until the gas evolution stops (approximately 30 minutes). To the cooled mixture drops add a solution of 21,0 mmol of alkylhalogenide in 20 ml of absolute dimethylformamide. The mixture is stirred for 1/2 hour at a temperature of 0oC, remove the cooling bath and stirred for 1/2 hour at room temperature. Excess sodium hydride destroyed by injection into the icy water. The hydrolysate is shaken out three times with simple ether, washed twice with water, dried with MgSO4, filtered and concentrated in vacuo water-jet pump. The remainder chromatographic with dichloromethane through a silica gel 60. The crystalline products were recrystallized from ethanol.

2-(2,5-acid)-1-(4-methoxyphenyl)propanone (53a)

Starting compound: 2-(2,5-acid)-1- (4-methoxyphenyl)alanon (51a)

Methyliodide

Colorless crystals; melting point: 97 - 98oC; yield: 71%

2-(2,4-acid)-1-(4-methoxyphenyl)propanone (53b)

Starting compound: 2-(2,4-acid-1-(4-methoxyphenyl)alanon (51)

methyliodide

Bestv the l)butanone (54a)

Starting compound: 2-(2,5-acid)-1- (4-methoxyphenyl)alanon (51a)

ethyliodide

The yellow oil; yield: 67%

IR spectrum (film): 1680 cm-1(S; C=O).

2-(2,4-acid)-1-(4-methoxyphenyl)butanone (54b)

Starting compound: 2-(2,4-acid)-1- (4-methoxyphenyl)alanon (51b)

ethyliodide

The yellow oil; yield: 69%

IR spectrum (film): 1680 cm-1(S; C=O).

2-(2,5-acid)-1-(4-methoxyphenyl)pentane (55a)

Starting compound: 2-(2,5-acid)-1- (4-methoxyphenyl)alanon (51a)

propyliodide

The yellow oil; yield: 81%

IR spectrum (film): 1680 cm-1(S; C=O).

2-(2,4-acid)-1-(4-methoxyphenyl)pentane (55b)

Starting compound: 2-(2,4-acid)-1- (4-methoxyphenyl)alanon (51b)

propyliodide

The yellow oil; yield: 72%

IR spectrum (film): 1680 cm-1(S; C=O)

2-(2,5-acid)-1-(4-methoxyphenyl)hexane (56a)

Starting compound: 2-(2,5-acid)-1- (4-methoxyphenyl)alanon (51a)

butylated

Colorless crystals; melting point: 62 - 63oC;

yield: 83%

2-(2,4-acid)-1-(4-methoxyphenyl)hexane (56b)

Starting compound: 2-(2,4-acid)-1- (4-IU is SUP> (S; C=O).

8-bromo-2-(2,5-acid)-1-(4-methoxyphenyl)octanone (59a)

In this case, the cooled mixture of 1,2-diarylethene and sodium hydride drops added to a solution of 1,6-dibromohexane. As initial products served 2-(2,5-acid)-1- (4-methoxyphenyl)alanon (51a) and 1,6-dibromohexane.

The yellow oil; yield: 61%

IR spectrum (film): 1675 cm-1(S; C=O).

8-bromo-2-(2,4-acid)-1-(4-methoxyphenyl)octanone (59b)

In this case, the cooled mixture of 1,2-diarylethene and sodium hydride drops added to a solution of 1,6-dibromohexane. As initial products served 2-(2,4-acid)-1- (4-methoxyphenyl)alanon (51a) and 1,6-dibromohexane.

The yellow oil; yield: 48%

IR spectrum (film): 1675 cm-1(S; C=O).

Methylation of thiophenols

In 100 ml of absolute dimethylformamide are suspended 5.3g (to 0.22 mole) of sodium hydride and within 30 minutes, stirred in an ice bath. At a temperature of 0oC slowly add drops of 0.15 mol of thiophenol in 50 ml of absolute dimethylformamide. The mixture is stirred until a considerable flatulence. Then, while cooling with ice drops add a solution of 22.7 g (0,16 mol; 2,44 ml) METI agravat to room temperature and continue stirring for another 60 minutes. Excess sodium hydride is removed by infusion into the icy water. The hydrolysate is shaken out three times with a simple ether. The combined organic phase is thoroughly washed with water, dried with MgSO4, filtered and concentrated in vacuo. The residue is purified by chromatography on a column (silica gel 60; dichloromethane) or by distillation in a vacuum.

3-methoxyphenyl-methyl sulfide (69)

Starting materials: 3-mercaptoacetic; methyliodide

Colorless oil; boiling point 57 - 58oC (0.1 mm); output: 95%

1H NMR (CDCl3): d = 2,47 (s, 3H, -SCH3), of 3.78 (s, 3H, -OCH3); 6,58 - 6,97 (m; 3H, ArH), 7,22 (t, 3J = 8Hz, 1H, ArH).

The acid chloride 4-methoxyphenylacetic acid (70)

The receipt shall be in accordance with the above method of Obtaining anhydrides of acids

Colorless oil; boiling point: 79 - 81oC (0.1 mm); output: 96%; IR spectrum (film): 1800 cm-1(S; C=0).

1-(4-methoxy-2-methylthiophenyl)-2-(4-methoxyphenyl)alanon (71)

The synthesis is carried out by analogy with the above procedure for acylation Friedel-

Starting materials: 3-methoxyphenyl-methyl sulfide (69)

The acid chloride 4-methoxyphenylacetic acid (70)

Chrome - 9oC; yield: 48%.

1-(4-methoxy-2-methylthiophenyl)-2-(4-methoxyphenyl)ethanol (72)

50,0 ml simple absolute ether are placed 0.3 g (7.9 mmol) of lithium aluminum hydride and cooled in an ice bath to a temperature of 0 to 5oC. 1-(4-methoxy-2-methylthiophenyl)-2-(4-methoxyphenyl)-Etalon (71) (6.8 mmol) is dissolved in absolute simple ether and the solution slowly drops added to a suspension of lithium aluminum hydride. Then heated for 1 hour to boil. After cooling, carefully hydrolized with water and acidified with diluted hydrochloric acid until all of the aluminum hydroxide will not turn into a solution. Then extracted three times with simple ether, washed twice with water, dried with MgSO4, filtered and concentrated in vacuo water-jet pump. The product was then purified using chromatography on a column of silica gel 60 (solvent dichloromethane/simple ether (19:1).

Colorless needles; melting point: 69 - 70oC;

yield: 93%

Getting a 1-alkyl-1,2-diarylethenes

While blowing nitrogen 1.2 g (49,5 the mmol) magnesium turnings activate a small amount of iodine by heating. Then, in the presence of nitrogen is 49.5 mmol of alkylhalogenide in 20 ml of absolute question is on air. After adding alkylhalogenide the mixture is boiled for 1 hour. After cooling, the mixture is mixed with 5.0 g (16.5 mmol) of a solution of 1-(4-methoxy-2-were)-2-(4-methoxyphenyl)ethanol (71) in 40 ml of absolute simple ether and heated for 2 hours at the boil under reflux. The cooled reaction mixture was hydrolized with water, acidified with diluted hydrochloric acid and extracted three times with simple ether. The combined organic phases are washed with water, filtered and concentrated in vacuo water-jet pump. The remainder chromatographies with dichloromethane through a silica gel

2-(4-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)propan-2-ol (73)

Starting materials: 1-(4-methoxy-2-methylthiophenyl)-2-(4-methoxyphenyl)alanon (71)

Methyliodide

The yellow oil; yield: 82%

IR spectrum (film): 3420 cm-1(m; br; -OH).

2-(4-methoxy-2-methylthiophenyl)-1-(methoxyphenyl)butane-2-ol (74)

Starting materials: 1-(4-methoxy-2-methylthiophenyl)-2-(4-methoxyphenyl)alanon (71)

ethyliodide

The yellow oil; yield: 78%

IR spectrum (film): 3560 cm-1(m; br; -OH).

2-(4-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)-pentane)-2-ol (75)

Starting materials: 1-(
IR spectrum (film); 3560 cm-1(m; br; -OH).

2-(4-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)-3 - phenylpropane-2-ol (76)

Starting materials: 1-(4-methoxy-2-methylthiophenyl)-2- (4-methoxyphenyl)alanon (71)

Benzylchloride

The yellow oil; yield: 44%

The IR spectrum (film): 3560 cm-1(m; br; -OH).

2-hydroxy-2-(4-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)- Oct-7-ene (77)

In this case, to obtain a Grignard reagent as solvent is absolute tetrahydrofuran. As initial products served 6-bromo-1-hexane and 1-(4-methoxy-2-methylthiophenyl)-2-(4-methoxyphenyl)alanon (71).

The yellow oil; yield: 85%

IR spectrum (film): 3560 cm-1(m, br, -OH).

Dehydratase 1-alkyl-1,2-diarylethenes

Alcohol (about 5.0 g/dissolved in 100 ml of toluene, mixed with 10.0 g of oxalic acid and heated for 24 hours with a water separator with phlegm. After cooling, oxalic acid is filtered off and the mixture is thoroughly washed with toluene. The organic phase is washed with water, dried with MgSO4and undertaking filtered. After removal of solvent in vacuo carry out chromatography using dichloromethane/petroleum ether 40 - 60oC (1: 1, alhammadi, can produce up to four isomers. However, it was found, respectively, only two isomers that could not be divided. The ratio of isomers formed is more than 50% on the side of the formed 1-alkenes.

1-(4-methoxy-2-methylthiophenyl)-2-(4-methoxyphenyl)Atan (78)

Starting materials: 1-(4-methoxy-2-methylthiophenyl)-2- (4-methoxyphenyl)ethanol (72)

Colorless crystals; melting point: 69 - 70oC; yield: 79%

2-(4-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)propene (79)

Starting materials: 2-(4-methoxy-2-methylthiophenyl)-1- (4-methoxyphenyl)propan-2-ol (73)

Colorless crystals; melting point: 55 - 58oC; yield: 85%.

2-(4-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)buta-1-ene (81)

Starting materials: 2-(4-methoxy-2-methylthiophenyl)-1- (4-were)-butane-2-ol (74)

Colorless oil; yield: 76%

1H-NMR (CDCl3): d = 0,96- (t; 3J=7Hz; 3H, -CH2CH3); is 2.40 (s, 3H, - SCH3); 2,66 (q;3J=7Hz; 2H, -CH2CH3in ), 3.75 (s, 3H, -OCH3); 6,36-7,16 (m; 7H, ArH); 7,31 (d;3J=9Hz; 1H, ArH).

2-(4-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)Penta-1-ene-(83)

Starting materials: 2-(4-methoxy-2-methylthiophenyl)-1-(4-methoxy - phenyl)pentane-2-ol (75)

The yellow oil; yield: 882CH3); 2,41 (s; 3H, -SCH3); 2,34-2,74 (m; 2H; CH2CH2CH3); 3,75 (s; 3H-CH3); 3,83 (s; 3H, -OCH3); 6,37-7,8 (m; 8H, ArH).

2-(4-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)-3-phenyl - prop-1-EN-(85)

Starting materials: 2-(4-methoxy-2-methylthiophenyl)-1- (4-methoxyphenyl)-3-phenylpropane-2-ol (76)

The yellow crystals (ethanol); melting point: 98-101oC; yield: 82%.

2-(4-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)OCTA - 1,7-diene (87)

Starting materials: 2-hydroxy-2-(4-methoxy-2-methylthiophenyl)-1- (4-methoxyphenyl)Oct-7-ene (77)

Colorless oil; yield 95%.

1H-NMR (CDCl3): d = 1,22-2,84 (m; 8H, -(CH2)4-); 2.40 a (s; 3H, -SCH3); and 3.72 (s, -OHC3); 3,80 (s; 3H-OCH3); 4,70-of 5.05 (m; 2H, -CH2CH=CH2); 5,28-6,02 (m; 1H, -CH2CH=CH2); 6,26-7,24 (m; 8H, ArH).

2-bromo-4-methoxyphenylalanine (133) and 4-bromo-2-methoxyphenylalanine (134)

A solution of 20.0 g (106,9 mmol) 3-bromoanisole in 100 ml of absolute dichloromethane cooled in an ice bath to 0oC. Then slowly add drops of 25.0 g (214,0 mmol, 14,2 ml), chlorosulfonic acid (approximately 45 minutes). In case of loss of derivatives chlorosulfonic acid, later they again pass into the solution. If the formation of HCl leads to PR is not appreciably increase the formation of HCl. Over the next 30 minutes, stir the mixture in an ice bath, poured on ice water, divided phase in a separating funnel and extracted twice the aqueous phase with dichloromethane. The combined organic phases are washed with water, dried with MgSO4, filtered and concentrated in vacuo. The residue is purified by chromatography on a column (silica gel 60; dichloromethane). During the synthesis of the two isomers are formed, which at this stage are not separated.

Connection: 133: 2-bromo-4-methoxyphenylalanine

Compound 134: 4-bromo-2-methoxyphenylacetonitrile

The ratio of the isomers is strongly dependent on the reaction conditions, the formation of compound 133 prevails. Subsequent data are for isomeric mixture.

Colorless crystals (ethanol); melting point is 79-80oC

Yield: 97%

C7H6O3SBrCl 285,5: calculated: C - 29,44 H - 2,12

found: C - 29,43 H - 1,92

2-bromo-4-methoxyphenylacetone (135) and 4-bromo-2-methoxyphenylacetone (136)

A mixture of 1.12 g (36,2 mmol) of red phosphorus, and 4.5 ml of glacial acetic acid and to 53.0 mg (0.2 mmol) of iodine are heated to a light boil in a three-neck flask with reflux condenser. When constantly maintained temperature dorsatum the mixture is heated with phlegm for 2 hours. Then slightly cooled, mixed with 0.8 ml of water and boil again for 1 hour. After cooling, diluted with 50 ml of water and extracted three times with dichloromethane. The combined organic phases are washed with water, dried with MgSO4, filtered and concentrated in vacuo. The remainder chromatographic using petroleum ether 40-60oC/ acetic ether (9: 1. volumetric part) through silica gel 60. Connection 135 and 136 are not separated.

Colorless oil; boiling point (73-76oC) (0.1 mm); yield: 71%; IR spectrum (film): 2560 cm-1(w-SH).

2-bromo-4-methoxyphenylacetate (137)

A by-product during the synthesis of compounds 135 and 136. The output ranges from 0 to 40%.

Butter yellow;

IR spectrum (film): 1710 cm-1(s; C=O).

2-bromo-4-methoxyphenyl-methyl sulfide (No. 138), and 4-bromo-2-methoxyphenyl-methyl sulfide (139)

The synthesis is carried out by analogy with the method for the methylation of thiophenols. As initial products use a mixture of 135 and 136. The resulting thioester mixture is separated by chromatography on a column (silica gel 60) using petroleum ether 40-60oC/acetic ether (9:1, volume). The output depends on the ratio of the images is s (ethanol); melting point: 54-55oC; output 20-54%.

The second fraction: 2-bromo-4-methoxyphenyl-methyl sulfide (No. 138), colorless oil; boiling point: 81-86oC (0.1 mm); output 40-70%.

1H-NMR (CDCl3) = 2,44 (s; 3H, - SCH3), 3,79 (s; 3H, -OCH3); 6,86 (dd; 3J = 9Hz;4J = 3Hz; 1H; ArH), 7,16 (d4J = 3Hz, 1H, ArH); 7,20 (d;3J = 9Hz; 1H, ArH).

Getting alkyl-4-methoxybenzyl-ketones

Equipment must always be in a nitrogen atmosphere!

A solution of 0.3 mole allylanisole of halide from 0,3 mol (7,3 g) of magnesium shavings and 0.3 mole Olkiluoto of halide in 200 ml of absolute ether are mixed with vigorous stirring (stirrer KPC) portions 0.15 mol (32,8 g) of anhydrous cadmium chloride. Heat the mixture to boiling for 30 minutes, replace the reflux condenser distillation bridge and drove about 150 ml of ether. The residue is mixed with 250 ml of absolute benzene. Under vigorous stirring slowly at room temperature drops) was added a solution of 0.2 mole (36,9 g) chloride 4-methoxyphenylacetic acid (70) in 70 ml of absolute benzene. Then the mixture for 1 hour, heated at phlegm. After cooling, carefully hydrolyzing with 2N hydrochloric acid. The organic phase is separated in a separating voranc is istratii remove the drying agent, in vacuum to remove solvent and the residue is distilled in a vacuum oil pump.

1-(4-methoxyphenyl)butane-2-he (140)

Original products: chloride 4-methoxyphenylacetic acid (70);

ethyliodide

Colorless oil; boiling point: 72-76oC (0.1 mm);

yield: 59%; IR spectrum (film): 1720 cm-1(S; C = 0).

1-(4-methoxyphenyl)pentane-2-he (141)

Original products: chloride 4-methoxyphenylacetic acid (70);

propyliodide

Oil light yellow color; boiling point: 84-88oC (0.1 mm); yield: 51%

IR spectrum (film): 1720 cm-1(S, C = 0).

Getting a 1-alkyl-1,2-diarylethenes

When injection of nitrogen activate 0.5 g (21,4 mmol) magnesium turnings by heating with iodine vapours of iodine). Then to the activated magnesium chips slowly drops add a solution of 5.0 g (21,4 of millimole) of 2-bromo-4-methoxyphenyl sulfide (138) in 30 ml of absolute tetrahydrofuran. The reaction is accelerated by the boiling of the solvent with simultaneous lightening of the reaction solution. The Grignard reagent is heated for one hour with phlegm. After cooling drops add a solution of 24.0 mmol of the appropriate ketone in 20 ml of absolute tetrahydrofuran, in raisat extracted three times with ether, washed with saturated sodium bicarbonate solution and water and dried with MgSO4. The drying substance is removed by filtration, the solvent is removed in vacuo and the residue chromatographic using petroleum ether 40-60oC/acetic ether (3: 1, body part) through silica gel 60. in the case may be insulated already formed by removal of water stilbene as a follow-on product, which crystallized from ethanol.

2-(5-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)-propan-2-ol (142)

Starting compound: 2-bromo-4-methoxyphenyl-methyl sulfide (No. 138), 4-methoxyphenylacetone

The yellow oil; yield: 27%

IR spectrum (film): 3440 cm-1(S; br; -OH).

2-(5-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)propene (145)

A by-product upon receipt 142.

Colorless crystals (EtOH/; melting point: 112-113oC; yield: 13%.

2-(5-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)-butane - 2-ol (143)

Starting compound: 2-bromo-4-methoxyphenyl-methyl sulfide (138)

1-(4-methoxyphenyl)butane-2-he (140)

The yellow oil; yield: 25%

IR spectrum (film): 3550 cm-1(m; br; -OH).

2-(5-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)but-2-ene (147)

2-(5-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)-penten-2-ol (144)

Starting materials: 2-bromo-4-methoxyphenyl-methyl sulfide (138)

1-(4-methoxyphenyl)-pentane-2-he (141)

The yellow oil; yield: 46%

IR spectrum (film): 3540 cm-1(m; br; -OH).

The dehydration of 1-alkyl-1,2-diarylethenes

The synthesis is carried out by analogy with the method for dehydration of alcohols (before connection (78)). The resulting isomers could not be separated.

2-(5-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)-propene (145)

Starting compound: 2-(5-methoxy-2-were)-1- (4-methoxyphenyl)-propan-2-ol (142)

Analytical data, see the previous Chapter "Getting 1-alkyl-1,2-diarylethenes".

2-(5-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)-but-1-ene (147)

Starting compound: 2-(5-methoxy-2-methylthiophenyl)-1- (4-methoxyphenyl)-butane-2-ol (143)

Analytical data see above.

2-(5-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)-Penta-1-ene-(149)

Starting compound: 2-(5-methoxy-2-methylthiophenyl)-1- (4-methoxyphenyl)-pentane-2-ol(144)

The yellow oil; yield: 83%.

1H-NMR (CDCl3): d= 0,27 (s; 3J=7Hz; 3H; CH2CH2CH3); 1,38-1,82 (m; 2H; CH2CH2CH3); 2,39 (s, 3H, -SCH
Cleavage of the ester and cyclization

A solution of 4.0 mmol of 1,2-diarylethenes 8.0 ml of absolute dichloromethane is cooled in purged with nitrogen equipment in an ice bath to 0oC and slowly (approximately 10 min) is mixed with a solution of 4.0 g (16.0 mmol; 1.5 ml) bartered in 5.0 ml of absolute dichloromethane. The mixture is stirred for 1/2 hour at a temperature of 5-10oC, remove the ice bath and stirred overnight at room temperature. Then, while cooling with ice add as many drops of 10% sodium bicarbonate solution, until a violent reaction, mixed with 20 ml of acetic ether and stirred for 15 minutes at room temperature. The phases are separated in a separating funnel. The aqueous phase is shaken out three times with water, the combined organic phases are washed with water and dried with MgSO4. After filtering off the drying substances remove the solvent in vacuo. The remainder chromatographic with dichloroethane/acetic ether (9:1) over silica gel 60. The products crystallized as a rule, from hot dichloromethane.

1) 5-hydroxy-2-)4-hydroxyphenyl)benzo(b)furan (60a)

Parent compound: 2-(2,5-acid)-1- (4-methoxyphenyl)ateither)benzo(b)furan (60b)

Parent compound: 2-(2,4-acid)-1- (4-methoxyphenyl)alanon (51b)

Beige crystals; melting point: 239-241oC; yield: 23%.

3) 5-hydroxy-2-(hydroxyphenyl)-3-methylbenzo(b)furan (61a)

Parent compound: 2-(2,5-acid)-1- (4-methoxyphenyl)propanone (53a)

Yellowish crystals; melting point: 154-155oC; yield: 53%.

4) 6-hydroxy-2-(hydroxyphenyl)-3-methylbenzo(b)furan (61b)

Parent compound: 2-(2,4-acid)-1-(4-methoxyphenyl)- propanone (53b)

Colorless crystals; melting point 191-192oC; yield: 21%.

5) 3-ethyl-5-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan (62a)

Parent compound: 2-(2,5-acid)-1-(4-methoxyphenyl)butanone (54a)

Colorless crystals; melting point: 163-164oC; yield: 30%.

6) 3-ethyl-6-hydroxy-2-(4-hydroxyphenylazo(b)furan (62b)

Parent compound: 2-(2,4-acid)-1-(4-methoxyphenyl)-butanone (54b)

Beige crystals; melting point: 125-127oC; yield: 19%.

7) 5-hydroxy-2-(4-hydroxyphenyl)-3-propellant(b)furan (63a)

Parent compound: 2-(2,5-acid)-1-(4-methoxyphenyl)pentane (55a).

Colorless crystals; melting point: 127-1 the ie: 2-(2,4-acid)-1-(4-methoxyphenyl)pentane (55b)

Colorless crystals; melting point: 151-152oC; yield: 23%.

9) 3-butyl-5-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan (64a)

Parent compound: 2-(2,5-acid)-1-(4-methoxyphenyl)-hexane (56a)

Colorless crystals; melting point: 124-125oC; yield: 40%.

10) 3-butyl-6-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan (64b)

Parent compound: 2-(2,4-acid)-1-(4-methoxyphenyl)hexane (56b)

Colorless needles; melting point: 169-170oC; yield: 29%

11) 3-(6-bromohexyl)-5-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan (67a)

Source connection: 8-bromo-2-(2,5-acid)-1-(4-methoxyphenyl)octanone (59a)

Colorless crystals; melting point decomposition 146-148oC; yield: 40%.

12) 3-(6-bromohexyl)-6-hydroxy-2-(4-hydroxyphenyl)benzo(b) furan (67b)

Source connection: 8-bromo-2-(2,4-acid)-1-(4-methoxyphenyl)octanone (59a)

Colorless crystals; melting point: 89-91oC; yield: 43%.

The method for substitution of the piperidine

In a round flask with a capacity of 100 ml with a reflux condenser was dissolved 0.2 mmole of 3-(6-bromacil)benzo(b)furans 67a and 67b, respectively, in 50 ml of piperidine and heated for 4 hours at phlegm. After Okha (19:1) through neutral aluminum oxide with a degree of activity 2.

13) 5-hydroxy-2-(4-hydroxyphenyl)-3- (6-N-piperidinyl)benzo(b)furan (68a)

Source connection: 3-(6-bromohexyl)-5-hydroxy-2- (4-hydroxy)benzo(b)furan (67a)

Light beige crystals; melting point: 190-191oC; yield 36%.

6-Hydroxy-2-(4-hydroxyphenyl)-3- (6-N-piperidinyl)benzo(b)furan (68b)

Source connection: 3-(6-bromohexyl)-6-hydroxy-2- (4-hydroxyphenyl)benzo(b)furan (67b)

Light beige crystals; melting point: 115oC with decomposition; yield: 36%.

Cyclization in benzo(b)tifany*)< / BR>
*) Ruwet, A. und Renson, M. Bull. Soc. Chim. Belg., 1970, 79, 593-599

14.0 mmol 1,2-diarylethene dissolved in 20 ml of absolute chloroform and cooled in an ice bath to 0oC. and Then slowly drops add a solution of 14.5 mmol (1,96 g, 1,17 ml) sulfurylchloride in 10 ml of absolute chloroform. After an hour of stirring in an ice bath to remove the solvent in vacuo, and the temperature of the water bath should not exceed 40oC. the Oily residue is mixed with 20 ml of absolute pyridine and heated for hours at the phlegm. After cooling the mixture, it was poured on ice water, acidified with conc. hydrochloric acid and extracted three times with dichloromethane. The joint is in a vacuum. The remainder chromatographic using dichloromethane/Pereladova ether 40-60oC (1:1, volume). The product is crystallized, usually from ethanol. Were allocated two isomers, as used 1,2-diarylethene was introduced in the form of a mixture of isomers.

14) 6-methoxy-2-(4-methoxyphenyl)benzo(b)thiophene (89b)

Source connection: 1-(4-methoxy-2-methylthiophenyl)- 2-(4-methoxyphenyl)-Atan (78).

Colourless crystals; (EtOH); melting point: 191-193oC; in the literature melting point: 193-194oC; yield: 82%.

15) 6-methoxy-2-(4-methoxyphenyl)-3-methylbenzo(b)thiophene (90b)

The original connection of 2-(4-methoxy-2-methylthiophenyl)-1- (4-methoxyphenyl)-propene (79).

Colorless needles (EtOH); melting point: 98-99oC; yield: 41%.

16) 3-ethyl-6-methoxy-2-(4-methoxyphenyl)benzo(b)thiophene (92b)

The original connection of 2-(4-methoxy-2-methylthiophenyl)-1- (4-methoxyphenyl)buta-1-ene (81)

Colorless crystals; melting point: 90-91oC; yield: 38%.

17) 6-methoxy-2-(4-methoxyphenyl)-3-propellant(b)thiophene (94b)

Parent compound: 2-(4-methoxy-2-methylthiophenyl)-1- (4-methoxyphenyl)-Penta-1-ene (83).

Colorless needles (EtOH); melting point: 96-97oC; yield: 41%.

18) yl)- 1-(4-methoxyphenyl)OCTA-1,7-diene (87)

Oil light yellow color; yield: 53%.

Cleavage of the ether

Equipment purging with nitrogen!

4.0 mmole tsepliaeva alkoxysilane dissolve 6.5 moles of absolute dichloromethane and cooled in an ice bath. For each CNS group dissolved 1,05 g (4.2 mmol) or 0.4 ml of bartered (99,99%) in 2 ml of absolute dichloromethane and slowly (approximately 10 minutes) add drops in the presence of nitrogen. Stir the mixture for approximately 30 minutes at a temperature of 3-5oC, remove the ice bath and stirred for 2 hours at room temperature. When re-cooling mixed with sodium bicarbonate solution as long as you do not stop the rapid hydrolysis reaction. Mix the mixture with acetic ether, stirred for 30 minutes at room temperature and separate phase in a separating funnel. The aqueous phase is twice extracted with acetic ester. The combined organic phases are washed twice with water, dried with MgSO4filter and remove the solvent in vacuo (bath temperature 30-40oC). The original product is purified by chromatography on a column (silica gel 60). As the mobile phase used a mixture of dichloromethane/vinegar is alsogo amounts of acetic ether.

19) 6-hydroxy-2-(4-hydroxyphenyl)benzo(b)thiophene (101b)

Source connection: 6-methoxy-2-(4-methoxyphenyl)benzo(b)thiophene (89b)

Colorless crystals; melting point: 252-254oC; yield: 63%.

20) 6-hydroxy-2-(4-hydroxyphenyl)-3-methylbenzo(b)thiophene (102b)

Source connection: 6-methoxy-2-(4-methoxyphenyl)-3 - methylbenzo(b)thiophene (90b)

Beige crystals; melting point: 223-225oC; yield: 36%.

21) 3-ethyl-6-hydroxy-2-(4-hydroxyphenyl)benzo(b)thiophene (104b)

Source connection: 3-ethyl-6-methoxy-2- (4-methoxyphenyl)benzo(b)thiophene (92b)

Colorless crystals; melting point: 160-161oC; yield: 31%.

22) 6-hydroxy-2-(4-hydroxyphenyl)-3-propellant(b)thiophene (106b)

Source connection: 6-methoxy-2-(4-methoxyphenyl)-3-propellant(b)thiophene (94b)

Colorless crystals; melting point: 115-117oC; yield: 43%.

Hydroporinae using 9-borabicyclo-(3.3.1)nonan (9-BBN)*)< / BR>
*) Zablocki, J. A. et al., J. Med. Chem., 1987, 30, 829-838.

To a solution of 1.4 mmole alkene in 5.0 ml of absolute tetrahydrofuran drops added at a temperature of 0oC in nitrogen atmosphere of 17.0 ml of 0.5 M 9-BBN (8.4 mmol) in absolute tetrahydrofuran. After a 40-minute paramasivam for another 5 minutes. Then add 3.0 ml of 3N sodium liquor, again stirred for 5 minutes under ice cooling and slowly drops add 3.0 ml of 30% hydrogen peroxide solution. The reaction mixture is stirred for 30 minutes and then mixed with 10 ml saturated sodium bicarbonate solution. The mixture is shaken out three times with acetic ester, thoroughly washed with water and dried with MgSO4. The drying substance is removed by filtration, the solvent is removed in vacuo and the residue chromatographic using a mixture of dichloromethane/acetic ester (4:1, body part) through silica gel 60.

23) 3-(6-hydroxyhexyl)-6-methoxy-2- (4-methoxyphenyl)benzo(b)thiophene (110b)

Source connection: 3-(Gex-5-EN-1-yl)-6-methoxy-2- (4-methoxyphenyl)benzo(b)thiophene (98b).

Colorless oil; yield 73%; IR spectrum (film): 3360 cm-1(s, br, -OH).

Methanesulfonamide spirits

In the presence of nitrogen, 2.0 mmole primary alcohol was dissolved in 20 ml of absolute tetrahydrofuran and mixed with 20,0 the mmol of triethylamine (2.0 g, 2.8 ml). Then at room temperature is added slowly in drops a solution of 10.0 mmol of methanesulfonanilide (1.4 g, 1.0 ml) in 5.0 ml of absolute tetrahydrofuran. Immediately a white wasp is extracted with acetic ester. The combined organic phases are washed with saturated sodium chloride solution and water, dried with MgSO4, filtered and concentrated in vacuo. The residue is purified via chromatography (silica gel 60) using dichloromethane as mobile phase. Crystalline products precrystallization from ethanol.

24) 3-(6-methanesulfonylaminoethyl)-6-methoxy-2- (4-methoxyphenyl)benzo(b)thiophene (113b)

Starting compound: 3-(6-hydroxyphenyl)-6-methoxy-2- (4-methoxyphenyl)benzo(b)thiophene (110b)

Methanesulfonanilide

Colorless oil; yield: 76%

IR spectrum (film): 1340 cm-1; 1170 cm-1(s; -SO2O-).

Substitution using piperidine

A solution of 1.0 mmole of methansulfonate in 4 ml of acetonitrile/triethylamine (1:1 volume parts) is mixed with 5.0-mmol of piperidine (0,43 g, 0.5 ml) and stirred over night at room temperature. Excess piperidine is removed along with the solvent in vacuo. The residue in acetic ether, washed twice with water and dried with MgSO4. The drying substance is removed by filtration, the solvent is removed in vacuo and the residue chromatographic using a mixture of acetic ether/triethylamine (30:1, body part) through the e products: 3-(6-methanesulfonylaminoethyl)-6-methoxy - 2-(4-methoxyphenyl)benzo(b)thiophene (113b); piperidine.

The yellow oil; yield: 60%.

1H-NMR (CaCl3): d = 1,10-1,80 (m; 14H, -(CH2)7-); 2,10-of 2.45 (m, 6H, -N(CH23) 2,80 (t;3J = 7Hz; 2H1= (CH2CH2); of 3.84 (s, 3H, -OCH3); 3,86 (s, 3H, -OCH3); 7,01 (dd,3J = 9Hz; 4J=2Hz; 1H, ArH) 7,31 (d;4J = 2Hz; 1H, ArH); to 7.61 (d,3J=9Hz; 1H, ArH); 6,97, 7,44 (AA'BB';3J = 9Hz; 4H, ArH).

Cleavage of the ether

Cleavage is carried out by analogy with the method before connecting 101b. As a solvent used 20-fold amount of absolute dichloromethane. Raw foods chromatographies using mixtures of acetic ether (triethylamine) ethanol over silica gel 60. The products crystallized from a mixture of dichloromethane/acetic ester with the addition of hexane.

26) 6-hydroxy-2-(4-hydroxyphenyl)-3- (6-N-piperidinyloxy)benzo(b)thiophene (119b)

Source connection: 6-methoxy-2-(4-methoxyphenyl)-3- (6-N-piperidinyloxy)benzo(b)thiophene (116b); the mobile phase for chromatography on a column: acetic ether/Netz/EtOH (10/10I, v/v/v) of Beige crystals: melting point: 115oC with decomposition; yield: 46%.

Cyclization of 1,2-diarylethenes*< / BR>
*) Ruwet, A. und Renson, M., Bull.Soc.Chim.Belg., 1970, 79, 593-599.

The synthesis is carried out in accordance is as mixtures of isomers. Byproducts are other derivatives of benzo(b)teofanov, which optionally chlorinated C4-atom.

27) 5-methoxy-2-(4-methoxyphenyl)-3-methylbenzo(b)-thiophene (90a)

Original product: 2-(5-methoxy-2-methylthiophenyl)- 1-(4-methoxyphenyl)propane (145)

Colorless crystals (EtOH); melting point: 106-107oC; yield: 41%.

28) 3-ethyl-5-methoxy-2-(4-methoxyphenyl)benzo(b)thiophene (92a)

Original product: 2-(5-methoxy-2-methylthiophenyl)-1-(4-methoxyphenyl)buta-1-ene-(147)

Colorless crystals (EtOH); melting point: 116-117oC; yield: 48%.

29) 5-methoxy-2-(4-methoxyphenyl)-3-propellant(b)thiophene (94a)

Original product: 2-(5-methoxy-2-methylthiophenyl)-1-(4-methoxy - phenyl)Penta-1-ene (149).

Colorless crystals: (EtOH); melting point: 76-77oC; yield 47%.

Cleavage of the ether

Cleavage is carried out by analogy with the General technique

The initial products are purified using chromatography on a column (silica gel 60) using a mixture of dichloromethane/acetic ether (9:1, body part) as mobile phase. The products crystallized from hot dichloromethane.

30) 5-hydroxy-2-(4-hydroxyphenyl)-3-methylbenzo(b)thiophene (102a)

Original product: 204-205oC; yield: 71%.

31) 3-ethyl-5-methoxy-2-(4-hydroxyphenyl)benzo(b)thiophene (104a)

The original product 3-ethyl-5-methoxy-2-(4-methoxyphenyl(b)thiophene (92a)

Colorless crystals; melting point: 173-174oC; yield: 78%.

32) 5-hydroxy-2-(4-hydroxyphenyl)-3-propellant(b)thiophene (106a)

Original product: 5-methoxy-2-(4-methoxyphenyl)-3-propyl-benzo(b)thiophene (94a).

Colorless crystals; melting point: 152-153oC; output is 81%.

The introduction of the side chain in the 2-phenylbenzo(b)tifany

a) 3-(6-Bromhexine)-6-methoxy-2- (4-methoxyphenyl)benzo(b)thiophene

A solution of 1.09 g (5.13 mmol) of acid chloride of 6-Bromhexine acid in 50 ml of 1,2-dichloroethane is mixed with 1.40 g (5,13 mmole) 6-methoxy-2-(4-methoxyphenyl)benzo(b)thiophene; then three servings add to 0.80 g (615 mmol) AlCl3under stirring at room temperature. Then stirred for further 1 hour, wash in cold icy water and Astrovirus with ether. After washing with saturated NaCl solution and dried (MgSO4remove the solvent and purify the residue by chromatography on a column (SiO2; CH2Cl2)/petroleum ether 3:1). Receive a yellow oil with a yield of 55%.

b) 3-(6-bromohexyl)-6-methods the Fira. After cooling in an ice bath, add drops 161,6 mg (1,21 mmole) AlCl3in 1 ml of dry ether. After minutes the ice bath is removed and at a low boil add drops in 2 ml of dry ether 542 mg (1,21 mmol) 3-(6-Bromhexine)-6-methoxy-2-(4-methoxyphenyl)benzo(b)thiophene. After 30 minutes successively added by drops while cooling with ice, 2 ml water and 2 ml bN H2SO4. The mixture is extracted with ether. After washing with water and drying, the ether is removed and the product precrystallization of n-hexane.

Get colorless crystals, boiling point: 93-95oC, yield 80%.1Jones CD. Jevmikov MG., AJ., Peters MK, Black LJ., Thompson AR., Falcone JF., Clemens J. A; J. Med.Chem 1984, 27, 1057-1966.

1. 2 phenylbenzo (b) furans or tifany General formula I

< / BR>
where R1and R2independently from each other represent a hydrogen atom, alkyl group with 1 to 10 carbon atoms, benzyl group;

X is oxygen atom or sulfur;

n is an integer from 4 to 12;

R3denotes the amino group - NR7R8while R7and R8independently of one another denote hydrogen atom or alkyl group with 1 to 10 carbon atoms, or R7- R8together denote alkylenes group - (CH2)

2. 2 phenylbenzo(b)furans or tifany formula I on p. 1, representing

3-ethyl-5-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan,

3-ethyl-6-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan,

5-hydroxy-2-(4-hydroxyphenyl)-3-propellant(C)furan,

6-hydroxy-2-(4-hydroxyphenyl)-3 - propellant(C)furan,

3-butyl-5-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan,

3-butyl-6-hydroxy-2-(4-hydroxyphenyl)benzo(b)furan,

5-hydroxy-2-(4-hydroxyphenyl)-3-(6-N - piperidinyl)- -benzo(b)furan,

6-hydroxy-2-(4-hydroxyphenyl)-3-(6-N-piperidinyl)- -benzo(b)furan,

6-hydroxy-2-(4-hydroxyphenyl)-3-methylbenzo(b)thiophene,

3-ethyl-6-hydroxy-2-(4-hydroxyphenyl)benzo(b)thiophene,

6-hydroxy-2-(4-hydroxyphenyl)-3-propellant(b)thiophene,

6-hydroxy-2-(4-hydroxyphenyl)-3-(6-N-piperidinyloxy)- benzo(b)thiophene.

3. The method of obtaining 2 - phenylbenzo(b)furans General formula I on p. 1, characterized in that the compound of General formula IIa

< / BR>
where R1and R2independently of one another denote an alkyl group with 1 to 4 carbon atoms;

R3represents -(CH2THE-CH = CH2or-CH2-C(O)NR7R8values of R7, R8listed in paragraph 1, is subjected to cyclization with acid Lewis proceeding with the removal of ester groups to obtain the compounds of General formula Ia

< / BR>
with the subsequent interaction of the compounds Ia in which R3= -(CH2)2- Hal, with the corresponding primary, secondary or cyclic amine and receiving compound I where R3group NR7R8or if R3- vinyl residue in the compound Ia, the last gidroksilnuyu translate to compound Ia, where R3= -(CH2)2Hal, and subjected to the interaction with the corresponding primary, secondary or cyclic amine to obtain the compound I where R3group NR7R8or, if R3means the group-CH2C(O)NR7R8, carbonyl group fully restore using sociallyengaged, a hydroxyl group optionally atrificial.

 

Same patents:

The invention relates to the field of organic synthesis and relates to new organic compounds, method of their obtaining for several options and pharmaceutical compositions containing these compounds

The invention relates to the field of organic synthesis and relates to new organic compounds, method of their obtaining for several options and pharmaceutical compositions containing these compounds

The invention relates to new 8-carbonylation 2-aminotetraline, their enantiomers and salts, processes for their preparation, pharmaceutical preparations on their basis and use of such compounds in therapy

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): that are useful as antagonists of prostaglandin IP (I2 or PGI2). Invention proposes compound of the formula (I) wherein each R1, R2 and R3 means independently in each case aryl or heteroaryl; R4 means -COOH or tetrazolyl; A, B, m, p, q, n and r are determined in the invention description. Also, invention relates to separated isomers, racemic or nonracemic mixtures of isomers and to their pharmaceutically acceptable salts or solvates also. Also, invention relates to pharmaceutical compositions comprising indicated compounds, to a method for their preparing and using as therapeutic agents. Invention provides the development of pharmaceutical composition possessing property of antagonists of IP wherein antagonists of these receptors can prevent states associated with excessive bleeding, for example, (but not only) hemophilia and hemorrhage and relieve septic shock-associated hypotension and diminish formation of edemas.

EFFECT: valuable medicinal properties of compounds.

28 cl, 15 sch, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula II or their pharmaceutically acceptable salts, where R1 is H or C1-C10 alkyl; R2 is H or C1-C10 alkyl; n ranges from 0 to 4; p ranges from 0 to 1; R3 and R4 represent H, as well as to pharmaceutical compositions based on said derivatives and methods of treating cardiac arrhythmia using these compositions.

EFFECT: increased effectiveness of composition and method of treatment.

15 cl, 12 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of new complexing analytical reagents which are suitable for doping nanoparticles and for use in luminescence-spectral analysis, biochip technology, as well as extractants of ions of heavy and rare-earth metals. Description is given of complexing benzo-containing heterocyclic compounds, which contain a β-dicarbonyl substitute with fluorinated radicals of formula: HetAr-C(O)CH2C(O)CF3, where HetAr= ,

which form luminescent complexes with Eu3+ ions. Proposed compounds are on the same level as compounds with closely resembling structure with regards to duration of luminescence and bonding efficiency, although they are easily accessible with respect technology of production and have high water solubility >10-4 mol/l, which enables their use in making conceptually new biochips with time, spatial and spectral signal selection.

EFFECT: high output of desired product.

1 cl, 5 dwg, 1 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: carboxylic acid compounds are presented by formula (I) where R1 represents (1) hydrogen atom, (2) C1-4alkyl; E represents -CO-; R2 represents (1) halogen atom, (2) C1-6 alkyl, (3) trihalogen methyl; R3 represents (1) halogen atom, (2) C1-6alkyl; R4 represents (1) hydrogen atom; R5 represents (1) C1-6alkyl; represents phenyl; G represents (1) C1-6alkylene; represents 9-12-merous bicyclic heterocycle containing heteroatoms, chosen of 1-4 nitrogen atoms, one or two oxygen atoms; m represents 0 or an integer 1 to 4, n represents 0 or an integer 1 to 4, and i represents 0 or an integer 1 to 11 where R2 can be identical or different provided m is equal to 2 or more, R3 can be identical or different provided n is equal to 2 or more, and R5 can be identical or different provided i is equal to 2 or more; both R12 and R13, independently represent (1) C1-4alkyl, (2) halogen atom, (3) hydroxyl or (4) hydrogen atom, or R12 and R13 together represent (1) oxo or (2) C2-5alkylene and where provided R12 and R13 simultaneously represent hydrogen atom, carboxylic acid compound presented by formula (I), represents a compound chosen from the group including the compounds (1) - (32), listed in cl.1 of the patent claim. Besides the invention concerns a pharmaceutical composition based in the compound of formula I and to application of the compound of formula I for making the pharmaceutical composition.

EFFECT: there are produced new carboxylic acid derivatives with antagonistic activity with respect to DP receptor.

14 cl, 74 ex

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to novel cyclohexane derivatives of formula (I) or their pharmaceutically acceptable salts having inhibitory effect on Na+-glucose cotranspoter (SGLT2), as well as to pharmaceutical compositions based on the said compounds and their use in preventing or treating diabetes, diabetic complications caused by hyperglycaemia or obesity. , where A is -O-; n is an equal to 0 or 1; R6 and R7 each independently represents a hydrogen atom or a C1-C6alkyl group, m is an integer selected from 1-3; Q is selected from Q1 - Q5, given in formula 2.

EFFECT: obtaining novel cyclohexane derivatives or their pharmaceutically acceptable salts and preparation of a pharmaceutical composition based on the said compounds.

15 cl, 19 dwg, 11 tbl, 86 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of (R)-2-arylpropionamides of general formula I, in which Ar is phenyl group, substituted in 3(meta) position by group R1, selected from: linear or branched C1-C8-alkanoyl, C3-C6- cycloalkanoyl, heteroarylcarbonyl, C1-C6-alkylaminocarbonyl, arylaminocarbonyl, C1-C6-alkylamino, C1-C6-acylamino, arylamino, benzoylamino, aryloxy, heteroaryl, C1-C6-alkoxycarbonyl, C6-aryloxycarbonyl, C1-C8-alkansulfonyl, arylsulfonyl, or 3,4-dihydro-1H-quinolyl-2-on; R is selected from: -H, OH; - heteroaryl group is selected from: pyridine, pyrimidine, pyrrole, thiophene, furan, indole, thiazole, oxazole; - α or β carboxyl residue can consist of straight or branched C1-C6-alkyl, C3-C6-cycloalkyl, optionally substituted with other carboxyl (COOH) group; - residue with formula SO2Rd, in which Rd is C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl or pyridyl, on condition that compounds of formula I are not the following compounds: (R)-2-(3-phenoxyphenyl)-propanoyl-phenylglycine; (R)-2-( phenoxyphenyl)-propanoyl-glycine; (R)-2-[(3'-acetyl)phenyl]-R-4''-pyrimidyl)propionamide. Invention also relates to method of obtaining formulaI compound and application of formula I compound for preparation of medications for treatment of diseases including C5a induced hemotaxis of human PMNs.

EFFECT: obtained are novel derivatives of (R)-2-arylpropionamide, possessing useful biological properties.

9 cl, 3 dwg, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: present invention describes novel compounds of formula (I), where substitutes R1, R2, R3, Ar and A are described in the formula of invention, having histone deacetylase inhibiting activity, use thereof and methods for synthesis of said compounds.

EFFECT: improved composition properties.

15 cl, 72 ex, 9 tbl, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula formula (1) formula (2) or to their hydrate, solvate, salt or tautomer form where R1 independently represents H or halogen; R2 represents H or --R10-NR11R12 where R10 represents C1-C6 alkylene; R11 and R12 independently represent H, C1-C4 alkyl; and R3 independently represents H or halogen. Besides, the invention covers methods of preparing the compounds of the present invention.

EFFECT: new compounds which can find application for preparing the compounds applicable for treatment or prevention of cardiac arrhythmia.

6 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where each radical R-R5 and Y assume values given in the description, or salts thereof, which have GPR40 receptor modulating action.

EFFECT: intensification of secretion of insulin or an agent for preventing or treating diabetes, and a pharmaceutical composition based on said compounds.

17 cl, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein A means benzene ring optionally substituted with one or more the following groups: -OR2 wherein R2 mean linear or branched (C1-C5)-alkyl; X means -CH=, -CH2-, -N= or -NH-radical; Y means radical -CH2, oxygen or sulfur atom or group -NR7 wherein R7 means hydrogen atom or linear or branched (C1-C5)-alkyl; R1 means hydrogen atom, linear or branched (C1-C5)-alkyl, and to pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition showing anti-diabetic activity. The pharmaceutical composition comprises compound of the general formula (I) as an active component and an inert excipient. Invention provides bicyclic derivatives of guanidine eliciting anti-diabetic activity.

EFFECT: valuable medicinal properties of compounds and composition.

8 cl, 2 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-aminocyclohexanol of the general formula (I) being optionally as their physiologically acceptable salts and first of all physiologically compatible acids. In compound of the general formula (I) R1 and R2 mean independently of one another hydrogen atom (H) or (C1-C8)-alkyl that can be saturated or unsaturated but both R1 and R2 can't mean simultaneously H, or residues R1 and R form a ring in common and mean (CH2)3-6; R2 means unsubstituted phenyl or phenyl substituted with halogen atom that is added through saturated or unsaturated, branched or linear (C1-C4)-alkyl group; R4 means heteroaryl chosen from 5-membered heteroaryl wherein heteroatoms are chosen from nitrogen, oxygen or sulfur atoms and each of these atoms is condensed with benzene ring and means unsubstituted or monosubstituted (C1-C8)-alkyl; -CHR6R7, -CHR6-CH2R7, -CHR6-CH2-CH2R7, -CHR6-CH2-CH2-CH2R7 wherein R6 represents H; R7 represents phenyl that can be unsubstituted or mono- either multi-substituted with halogen atoms. Also, invention relates to a method for synthesis of compounds of the formula (I) and a medicinal agent based on thereof. Synthesized compounds can be sued for preparing a medicinal agent designated for treatment of pain being first of all acute, visceral, neuropathic or chronic pain, and to a medicinal agent designated for treatment of diseases mediated by function of ORL1-receptor, for example, such as fear state, epilepsy, cardiovascular diseases.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and drug.

10 cl, 1 tbl, 21 ex

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to compound of formula (I) in which m represents integer number, equal 1 or 2; R1 represents group, selected, in particular from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, naphtyl, chinolinyl, isochinolinyl, benzisoxazolyl, tienopyridinyl, said group is possibly substituted with one or several groups of R3, similar or different from each other or by group R4, R2 represents group of general formula CHR5CONHR6, R3 represents halogen atom or one of the following groups: piano, nitro, C1-6-alkyl, C1-6-alkoxy, C1-6-trifluoralkyl, C1-6-trifluoralkoxy, benzyloxy, phenyloxy, R4 represents group, selected, in particular from phenyl, benzofuranyl, naphtyl; one orseveral groups R4 can by substituted with one or several groups R3, similar or different from each other; R5 represents hydrogen atom or C1-3-akyl group; R6 represents hydrogen atom or alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl -C1-3-alkylene group; as base, salts of binding of acid, hydrate or solvate. Also invention relates to method of obtaining compound of formula I, its use as medicine and to based on it pharmacological composition.

EFFECT: novel derivatives of 1-pyperazine and 1-homopyperazincarboxilates, useful for prevention or treatment of pathology, in which endogen cannabinoids and/or any other substrates, metabolised by ferment FAAH, participate.

12 cl, 3 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula II or their pharmaceutically acceptable salts, where R1 is H or C1-C10 alkyl; R2 is H or C1-C10 alkyl; n ranges from 0 to 4; p ranges from 0 to 1; R3 and R4 represent H, as well as to pharmaceutical compositions based on said derivatives and methods of treating cardiac arrhythmia using these compositions.

EFFECT: increased effectiveness of composition and method of treatment.

15 cl, 12 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel chromane derivatives of formula I: or their pharmaceutically acceptable salts, where: m equals 0 or 1; p equals 2; q equals 2; Ar is phenyl which is possibly substituted with a halogen atom; each R1 is independently a halogen; R2 is ; n equals 1 or 2; each of R3 and R4 is independently hydrogen or C1-12-alkyl; each of R5 and R6 is independently hydrogen or C1-12-alkyl; and each of R7 and R8 is independently hydrogen or C1-12-alkyl; or one of R7 and R8 is hydrogen and the other is a 5- or 6-member heterocyclyl containing one nitrogen atom, or R7 and R8 together with the nitrogen atom with which they are bonded can form an amidinyl group, a urea group, a guanidinyl group or a pyrrolidine ring which is possibly substituted with an amine group.

EFFECT: obtaining novel chromane derivatives and pharmaceutical compositions having 5-HT6 and/or 5-HT2a receptor modulator activity.

22 cl, 11 ex, 1 tbl

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