Synthesis of oxygen-substituted benzocycloheptenes as valuable intermediate compounds for preparing tissue-selective estrogens

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel intermediate compounds and inmproved method for synthesis of compound of the formula (C): . Proposed method is based on using inexpensive parent substances and provides synthesis of intermediate compounds with the high yield and high purity degree being without carrying out procedures for chromatographic purification and can be realized in large-scale industry manufacture. Invention relates to improved methods for synthesis of compound of the formula (I): , compound of the formula (II): , compound of the formula (III): , compound of the formula (VIII): , compound of the formula (IX): , and to a reagent consisting of boron tribromide and 2,6-dimethylpyridine. Method is used for a sparing and selective splitting a methyl group in aromatic methyl ethers.

EFFECT: improved method of synthesis.

12 cl, 8 ex

 

The present invention relates to intermediate products and to a new method of obtaining benzocycloheptene C. Proposed in the invention is a method of obtaining its intermediate products based on the use of inexpensive raw materials, provides high yield and high purity intermediates without operations on their chromatographic purification and allows you to implement a process on an industrial scale.

Compounds of General formula A (WO 00/03979) are compounds with strong anti-estrogenic effect. We are talking about selective estrogen, which is manifested timeselection (selectively with respect to the tissues). This estrogenic effect is manifested primarily in relation to the bone. The advantage of this class of compounds is that in the uterus and liver they have no impact or have it only in the most minimal extent.

These connections can, however, also possess antiestrogenic efficacy that can be confirmed, in particular, testing for the prevention of the growth of the uterus or models of tumors.

Compounds with a similar mode of action known as selective estrogen receptor modulators (SERM). "selective estrogene receptor modulator"). The most famous representatives of what ielem this class of compounds is raloxifene, approved for use as a drug intended for the prevention and treatment of postmenopausal osteoporosis.

Since it usually refers to compounds used in high dosage, there are significant difficulties associated with obtaining active substances in large quantities. Especially important, therefore, for this class of substances remains a need to develop simple and inexpensive synthesis.

Obtaining compounds of General formula

as described in the application WO 00/03979. In the above formula SK, R1and R2denote specific residues side chains, which are explained in more detail in the specified application.

Based on the foregoing, the present invention was used to develop a more efficient method for obtaining compounds of formula (example 9 in WO 00/03979).

The exchange reaction to obtain the desired connection With the exercise according to WO 00/03979 as follows (see examples 8 and 9):

Described in WO 00/03979 synthesis includes a large number of stages and involves several operations chromatographic purification. Large-scale industrial synthesis, when you want to get a few hundred kilograms connection associated with exceptional difficulties. Still the way industrial production timeselection estrogen General formula A, i.e. compounds described in the application WO 00/03979 primarily in example 9 (in this application the connection), dictates the need to develop more effective and involving a smaller number of stages of the synthesis.

In contrast to the synthesis presented in WO 00/03979 proposed in the present invention a new method of obtaining connection is characterized by the fact that the way to get the main intermediate product was reduced due to a significant reduction in the number of stages. However, the further course of the reaction to obtain the final product remained unchanged.

Thanks to simplified technology (several methods of obtaining products in the same apparatus) for connection With the need to allocate only 8 intermediate products.

The table below illustrates the advantages of the new method compared with the prior art.

The total number of stagesChromatographic operationsThe total yield [%]
WO 00/0397916*2<6
the method according to the invention***8**036
Note:

*with simultaneous consideration of the Journ. Med. Chem. (15) (1972), cc.23-27,

** includes phenylboronic acid,

***see example 1 in the present description.

Another important advantage of the invention method is a practical possibility of obtaining products without operations by chromatographic purification and with a high degree of purity.

Proposed in the invention method allows, moreover, to enter further substituted by substituent R2aromatic compounds through the application of the proposed intermediate product of General formula I

where

L denotes a2-C10alkylenes chain, which may be unbranched or branched,

X denotes Cl or Br,

Ar denotes an aromatic or heteroaromatic residue, which optionally may contain up to 3 substituents.

Underlying the invention the task is solved by the compounds of General formula I

where

L denotes a2-C10alkylenes chain, which may be unbranched or branched,

X denotes Cl or Br,

Ar denotes an aromatic or heteroaromatic residue, which optionally may contain up to 3 substituents.

Compounds of General fo the mules I get from the methyl esters of the General formula II

where L, X and Ar have the meanings mentioned for the General formula I, by selective removal of methyl ester using a reagent consisting of tribromide boron and 2,6-dimethylpyridine (in the ratio of 1:1-1:1,5).

The amount of this reagent can be from 1 to 6 EQ. (in terms of tribromide boron and ottsepleny aromatic methyl ether). The above reaction is carried out in aprotic solvents, such as dichloromethane, chloroform or 1,2-dichloromethane, preferably, however, in dichloromethane, at temperatures in the range from -30 to +50°C, preferably from 10 to 30°C.

The extremely high selectivity of cleavage of the aromatic methyl ether in the presence of a tertiary aromatic alilovic esters is the surprise factor. Phenolic products receive high degree of purity and very good output.

Using BBr3for removal of aromatic methyl ethers specialists in principle known (see Synthetic Communications 9 (5), 1979, cc.407-410). Without adding lutidine selective removal is unable to carry out (removal of all aromatic ethers). Only in combination with 2,6-lutidine allows to achieve an unexpected effect selectivity.

Compounds of General formula II are obtained from compounds of General formula II

where

Ar denotes an aromatic or heteroaromatic residue, which optionally may contain up to 3 substituents, and

R is a perfluorinated remotemachine1-C8alkyl group, preferably CF3C4F9or8F17,

interaction with fenabrave acids of General formula IV

where L and X have the meanings specified for formula I, with the help of well-known experts methods palladium catalyzed reaction of a combination of Suzuki (Journ. Org. Chem. 64, 1999, cc.6797-6803; Chem. Rev. 95, 1995, cc.2457-2483; Pure Appl. Chem. 63, 1991, cc.419-422; Synlett, 1990, cc.221-223; Journ. Org. Chem. 58, 1993, cc.2201-2208). For these purposes may be used commercially available Pd-catalysts, such as Pd(PPh3)4orPd(Cl2)(PPh3)2(information about other catalysts, see, for example, in the STREM catalog No. 18, 1999-2001, Chemicals for research, metals, inorganics and organometallics).

Compounds of General formula III is obtained from ketones of General formula V

where Ar is the value specified for General formula I, the interaction is carried out by known methods specialists receive inultiple (see Journ. Amer. Soc., EN, 96, 1974, cc.1100-1110; Chem. Ber., GE, 110, 1977; Tetrahedron Lett, EN, 23, 1, 1982, cc.117-120; Synthesis, EN, 1, 1981, cc.29-30; Tetrahedron Lett, EN, 40, 29, 1999, cc.5337-534), with a reagent of General formula VI

where

R has the value given for the General formula III, and

Nu denotes a leaving group such as F, Cl, J or R-SO3-.

Particularly successful has proven combination of nonatherosclerotic and DBU (databaseconnection) in THF at 0°C. thus Obtained nonathlete unexpectedly high resistance, and if necessary, they can be isolated in solid form. Typically, however, the solutions of the crude product is directly used in the subsequent reactions. Compounds of General formula VI are commercially available products (suppliers: firm Aldrich, Fluorochem, and others).

Compounds of General formula IV can be obtained from compounds of General formula VII

where L and X have the meanings mentioned for the General formula I, and Hal denotes a halogen atom such as Cl, Br or J, known in the art methods of obtaining phenylboronic acids from haloaromatic compounds (see Houben-Weyl, "Methods der organiscen Chemie", published by Georg Thieme Verlag Stuttgart, New York, 1982, volume 13/3A, cc.637 and later).

Especially useful was to use n-utility for the exchange of halogen to metal, after which the lithium compound is subjected to interaction with B(OMe)3and then hydrolyzing the acid with the formation of the desired PR is izvorovo phenylboronic acid.

The process of obtaining compounds of General formula VII are carried out by methods known in the art of obtaining simple phenolic esters (see Mol. Cryst. Liq. Cryst, EN, 158, 1988, cc.209-240; Synth. Commun., EN 28, 16, 1998, cc.3029-3040; Journ. Chem. Soc. Perkin Trans., EN, 2, 1989, cc.2041-2054) from the corresponding halophenols and symmetric or asymmetric of dihaloalkanes (for example 5-bromo-1-chloropentane). The corresponding phenols and dihalogenide are commercially available products.

Obtaining ketones of General formula V in cases where Ar denotes a phenyl residue, described in Indian Journ. Chem., August 1996, vol 25V, cc.832-837. Described in this publication multistage sequence of receipt of this intermediate product, first, time consuming, and secondly, it is extremely difficult to implement on an industrial scale.

In contrast to this technology, especially in terms of large-scale industrial production, the most suitable to obtain compounds of General formula V from compounds of General formula VIII, where Ar is the value specified for General formula I, with the help of well-known specialists of the methods of cyclization (closed loop) by the reaction of the Friedel-(Chem. Rev. 70, 1970, s).

As especially preferred, you can call the use of polyphosphoric acid at temperatures in the range from 80 to 120°C.

Polifos the priori acid can be purchased on the market or use freshly prepared.

Compounds of General formula VIII receive in turn a known manner from compounds of General formula IX

by catalytic hydrogenation (see Houben-Weyl, "Methods der organischen Chemie", published by Georg Thieme Verlag Stuttgart, New York 1980, vol 4/1, part 1, cc.14 and later).

Compounds of General formula VIII can be obtained by reaction of a product in one device based on 3-methoxybenzaldehyde

which catalyzed the basis of interaction with acetaldehyde converted into 3-otoxicity aldehyde (see Organic Reactions, volume 16, 1968, cc.1 and forth; Justus Liebigs Ann. Chem. 412, 1917, s)

and without allocation then subjected to the reaction of Knoevenagel interaction with the compound of General formula X

where Ar is the value specified for the General formula I (obtaining the compounds VIII, including the conditions of the reaction Knoevenagel, see Organic Reactions, volume 15, 1967, SS. 204 and below).

Compounds of General formula X are commercially available products (suppliers, for example, the firm Aldrich, Fluka, and others) or they can easily be obtained by known special techniques used to obtain alloxanic acids (see Journ. Amer. Chem. Soc. 78, 1956, s; Can. Journ. Chem., EN 7031992, SS. 992-999; Journ. Amer. Chem. Soc., EN 11251990, SS. 1894-1896; Recl. Trav. Chim. Pays-Bas, 70, 1951, SS. 977, 983; Jurn. Amer. Chem. Soc. 69, 1947, s).

Upon receipt cinnamic aldehyde appropriate, it has been found that the use of inorganic base, such as NaOH, KOH, preferably KOH. The reaction is carried out in water at temperatures in the range from 1 to 30°C. While acetaldehyde can be applied up to 5 EQ. Especially preferred option proved, in which acetaldehyde and the base are added in small portions with intervals before each subsequent addition of 10-30 minutes

For the reaction of Knoevenagel it is preferable to use as the basis of acetanhydride, and triethylamine. The reaction proceeds at a temperature in the range from 60°With temperatures of distillation.

Proposed in the invention method can also be used to obtain the compounds of General formula XI

where Ar, L and X have the meanings mentioned for the General formula I, but instead of halophenols General formula VII as the original substances using appropriate gloucosamine haloaromatic compounds of General formula XII and further work the same way:

Compounds of General formula XII are known from the literature and some of them are commercially available products.

As the preferred residues L on the VAT, for example, -C2H4-, -C3H6-, CH2-CH(CH3)-CH2- 4H8-, -C5H10-, -C6H12-, -C7H14-, -C8H16-. Most preferred of these residue-C5H10-.

X represents preferably a chlorine atom.

As the rest of Ar include, for example, several residues of the following formula:

Especially preferred are phenyl, peredelnyj and titanovyi the rest.

Below the invention is explained in more detail based on examples

Example 1

Example 1A

(2Z,4E)-5-(3-methoxyphenyl)-2-phenylpentane-2,4-diene acid

To 750g (5,5 mole) 3-methoxybenzaldehyde in 3750 ml of water add 310 ml of 20%aqueous sodium hydroxide. Then for 30 min added dropwise 160 ml of acetaldehyde dissolved in 450 ml of water, so that the internal temperature did not exceed 30°C. thereafter, this operation is repeated 7 times (first 310 ml of 20%aqueous KOH, and then 160 ml of acetaldehyde/450 ml water/30 min). After adding the last portion stirred for 30 min at room temperature. Next add 3750 ml of methyl tert-butyl ether and thoroughly stirred for 15 minutes the Organic phase is separated and mixed with 250 ml of glacial acetic acid and 250 ml of water. PEFC is a 5-minute stirring 1500 ml of water and stirred for another 5 minutes The organic phase is separated, and then concentrating it to dryness in a vacuum.

To the residue (oil of orange) add 748,80 g (5,5 mol) of phenylacetic acid, 1000 ml of acetic anhydride and 1470 ml of triethylamine and 4 hours to heat up to 100°C. and Then at a pressure of 15 mbar the solvent is distilled off and the residue allowed to warm to room temperature. After that, the residue is dissolved in 2500 ml of methyl tert-butyl ether. Then cooled to 0°and dropwise added slowly to 600 ml of concentrated hydrochloric acid. Then add 2000 ml of water and stirred for 5 minutes the Organic phase is separated and mixed with 1100 ml of 50%aqueous sodium hydroxide. Next add 830 ml of water. Within 30 min intensively stirred and the aqueous phase is separated (the product in the water phase). The organic phase is again separated by mixing with 1100 ml of caustic soda and 830 ml of water. The aqueous phase is separated and combined with the first aqueous phase.

Both the combined aqueous phases add 1700 ml metal-tert-butyl ether and intensively stirred for 5 minutes and Then the aqueous phase is separated and with concentrated hydrochloric acid the pH value is set at 1.5. Fell in the sludge acid is extracted with 4000 ml of methyl tert-butyl ether. The organic phase is concentrated to dryness in vacuo. Then add 2000 ml of ethanol and about 1000 the l of ethanol is distilled off in vacuum. Then re-add 1000 ml of ethanol and precipitated precipitate was separated by stirring for 1 h at 0°C. then filtered off from the precipitate and washed with 350 ml of cold ethanol.

Light yellow solid is dried in vacuum at 40°C.

Output: 1094 g (71% of theory) of a solid of light yellow color.

Elemental analysis:

Rasch.With 77,12N of 5.75
..With 77,23N of 5.84

Example 1B

5-(3-methoxyphenyl)-2-phenylpentane acid

1000 g (3,567 mol) of the compound indicated in the heading of example 1A is dissolved in 8 l of tetrahydrofuran and add 75 g of palladium catalyst 30 (10%Pd/C). Then hydronaut at room temperature at a pressure of 2 bars. Then filtered off from the catalyst, washed with 500 ml of tetrahydrofuran and the solution concentrated to dryness in vacuum.

Output: 1015 g (100% of theory) of colorless viscous oil.

Elemental analysis:

Rasch.With 76,03N 7,09
..With 76,12N 7,15

Example 1V

7-methoxy-2-phenyl-1-benzocoumarin

To 560 g (1.97 mol) of the compound indicated in the heading of example 1B, add 5.6 kg 115%floor is phosphoric acid for 3 h and heated to 95° C. Then the solution is allowed to cool to 50°and With this the still warm solution is poured into 9 liters of a mixture of water with ice. Next, add 5000 ml of methyl tert-butyl ether and intensively stirred for 10 minutes the Organic phase is separated, and the aqueous phase is again washed with 1500 ml of methyl tert-butyl ether. The combined organic phases are washed once with 4000 ml of water, and then 1200 ml of 5%aqueous caustic soda. The organic phase is separated and mixed with 280 g of activated charcoal. After 2 hours boiling under reflux activated carbon is filtered off, washed with a small amount of methyl tert-butyl ether and the filtrate concentrated to dryness in vacuum.

Output: 456,5 g (87% of theory) of colorless oil, which crystallizes upon standing.

Elemental analysis:

Rasch.With 81,17N for 6.81
..With 81,29N 7,02

Example 1G

4-[(5-chloropentyl)oxy]phenylboronic acid

1000 g (5,78 mole) of 4-bromophenol, 1125,7 g (6,069 mole) 1-bromo-5-chloropentane and 1118,3 g (8,092 mole) of potassium carbonate load in 4000 ml of dimethylformamide and within 5 h stirred at 60°C. the Mixture is cooled to 20°and add 3500 ml of toluene. Then filtered off from the precipitated precipitated salts and the salts washed three times, toloo the om portions at 3500 ml. DMF/toluene filtrate is mixed with 4000 ml of water and during 5 minutes and stir. Colorstream phase is separated, and the aqueous phase is once washed with 3000 ml of toluene. Then colorstream phases are combined and within 20 min mix with 4000 ml of 5%aqueous caustic soda. After that colorstream phase is separated, washed with 4000 ml of water and evaporated to dryness in a vacuum. The residue is dissolved in 9 l of tetrahydrofuran and cooled to an internal temperature -65°C. Then slowly added dropwise 2860 ml n-utility (a 1.6 molar in hexane) in such a way that the temperature did not exceed -60°C. At this temperature -65°stirred for 30 minutes Then added dropwise 1291 g trimethylol ester of boric acid and stirred for 2 h at -65°C. Then warmed to -20°C. For further processing cautiously add on drops of a solution of 2200 ml of water/methanol (1:1 ratio) so that the temperature did not exceed -15°C. Upon completion of the specified carefully add add 11 l 2n. aqueous hydrochloric acid and stirred for 1 h at 0°C. Then the temperature is allowed to rise to room temperature, the organic phase is separated, and the aqueous phase is extracted once 5000 ml and once with 2000 ml of methyl tert-butyl ether.

The organic phases are combined and stirred with 11 l of 2n. caustic soda within 30 minutes The aqueous phase is separated (product) and twice washed with methyl tert-butyl ether portions 3000 ml pH Value of the aqueous phase by addition of 6N. hydrochloric acid is set to 1, then add 6000 ml of methyl tert-butyl ether for 2 h and stirred at room temperature. The organic phase is separated, once washed with 3000 ml of water and finally evaporated to dryness in vacuum.

Output: 1219,5 g (87% of theory) solid pink color.

Elemental analysis:

Rasch.With 68,45N of 6.73Cl 6,97In 2,12
..From 68.59N 6,84Cl 6,89In 2,03

Example 1D

5-{4-[(5-chloropentyl)oxy]phenyl}-2-methoxy-6-phenyl-8,9-dihydro-7H-benzocycloheptene

81,67 g (306,64 mmole) of the compound indicated in the heading of example 1B, was dissolved in 400 ml of tetrahydrofuran/tert-butyl methyl ether and the solution is cooled to 3°C. Then the solution is added 56,02 g (367,97 mmole) of databaseconnect (DBU), while maintaining the temperature at level 3°C. Then washed with 40 ml of THF. Next add 111,46 g (367,97 mmole) of foramerica perftoran-1-sulfonic acid (3°C), washed 40,86 ml of methyl tert-butyl ether, and the temperature during the addition should not Ave is in excess of 8° C. After 12 hours stirring at 3°to the reaction solution was added with 10°With 290 ml of 10%aqueous potassium carbonate solution (in terms of a 3.5-fold amount of educt) and stirred for 5 minutes the Organic phase is separated and concentrated in vacuo to a volume of about 500 ml of thus Obtained solution of the crude nonflat use at a later stage.

78,08 g (321,97 mmole) of the compound indicated in the heading of example 1, is dissolved at room temperature in 390 ml of MTB and to the solution add 310 ml of 2-molar aqueous solution of K2CO3. Then add 1,076 g chloride bis(triphenylphosphine)palladium(II) (1,533 mmole, 0,005 mol. equiv.) suspended in 10 ml of methyl tert-butyl ether. After that add the above solution nonflat and within 30 minutes, heated under reflux. Then cooled to room temperature and mixed with 455 ml of 2n. aqueous NaOH. Then stirred for 15 min at room temperature. The organic phase is separated and stirred at 20 for 15 min at room temperature with 455 ml of 2n. aqueous HCl.

The organic phase is separated and mixed with 15 g of activated charcoal. After that within a short period of time heated to a temperature of distillation and still hot solution is filtered through diatomaceous earth. Then twice washed with methyl tert-butyl ether is orciani 100 ml. The filtrate is concentrated at 40°With vacuum. To the residue add 455 ml of methanol and the resulting precipitate was stirred for 6 h at room temperature. The suspension is cooled to 5°C, filtered and washed with 100 ml of cold methanol. Finally dried at 40°C in vacuum.

Output: to 112.4 g (82% of theory) of colourless crystalline solid.

Elemental analysis:

Rasch.With 77,92N 6,99Cl of 7.93
..With 78,07N 7,10Cl 7,87

Example 1E

5-{4-[(5-chloropentyl)oxy]phenyl}-6-phenyl-8,9-dihydro-7H-benzocycloheptene-2-ol

127,51 g (508,93 mmole) tribromide boron dissolved at room temperature in 650 ml of dichloromethane. To this solution slowly at 0°add a solution of 57,26 g (534,37 mmole) of 2,6-dimethylpyridine in 320 ml of dichloromethane (to ensure that the temperature remains below 0°). Then the solution is cooled to 0°C. Further, it is allowed to warm to 20°and added dropwise a solution of 65,00 g (145,4 mmole) of the compound indicated in the heading of example 1D (solution in 300 ml dichloromethane), while the internal temperature should not exceed 20°C. After 4 hours stirring at 20°the solution is cooled to 0°and intensive re is eshiwani carefully added dropwise a mixture of 10 ml of water and 65 ml tetrahydrofuran (THF). Then to the reaction solution carefully add 1250 ml of water and stirred for 30 min at 20°C. the Organic phase is separated and the aqueous phase is extracted with 325 ml of dichloromethane. The organic phase is separated. Both organic phases are combined and mixed with 13 g of NaHCO3and 312 ml of water. The organic phase for 30 min stirred at 20°together with a solution of NaHCO3. The organic phase is separated and concentrated in vacuo to a volume of about 300 ml (crystallization begins to achieve the required volume). The crystalline suspension is mixed with 300 ml of acetone and 40°and a pressure of 300 mbar distilled off about 320 ml of solvent. Then for 1 h, stirred at 0°C. the Crystals are filtered and washed with a small amount of cold acetone. From the mother liquor after concentration, you can get another crystalline fraction.

Output: 51,6 g (82% of theory) of colorless crystalline powder.

Elemental analysis:

Rasch.With 77,67N 6,75Cl 8,19
..With 77,54N 6,92Cl 8,03

Example 1G

5-(4-{5-[(4,4,5,5,5-pentafluorophenyl)sulfanyl]pentyloxy} phenyl)-6-phenyl-8,9-dihydro-7H-benzocycloheptene-2-ol

100 g (230,9 mmole) of the compound, is shown in the header of example 1E, and 132,1 g (881,1 mmole) of sodium iodide are heated in 1000 ml of methyl ethyl ketone (MEK) for 16 h under reflux. Then under reduced pressure, distilled approximately 650 ml of solvent and mixed with 1500 ml of water. During the next 15 min, stirred at room temperature, the precipitation is filtered off and washed with a mixture of 240 ml of cold ethanol and 160 ml of water. Still a little wet precipitate is dissolved in 1200 ml of tetrahydrofuran. When normal pressure is distilled 400 ml of tetrahydrofuran and added dropwise to 400 ml of methanol. To this solution was added another solution prepared in a separate flask as follows: 64,8 g (274,2 mmole) 4,4,5,5,5-pentecontaetia dissolved under nitrogen atmosphere in 300 ml of methanol and, at room temperature add 51 ml of 30%aqueous solution of methanolate sodium (Meon). During the next 30 min, stirred at room temperature. After combining both solutions they leave for 1 hour for mixing.

For subsequent processing was concentrated in vacuo to a residual volume of about 350 ml and Then to the residue add 800 ml of water and stirred for 30 min at 10°C. then filtered and washed with a mixture of 360 ml of water and 40 ml of methanol. Finally dried in vacuum at 40°C.

Output: of 124.1 g (91% of theory) of colorless crystalline powder.

Elemental analysis:

table width="90%" border="1" cellpadding="0" cellspacing="0" frams="all"> Rasch.With 67,10N 5,97S 5,43F 16,08..With 66,95N 6,11S 5,33F 15,92

Example 1Z

5-(4-{5-[(RS)-(4,4,5,5,5-pentafluorophenyl)sulfinil]pentyloxy} phenyl)-6-phenyl-8,9-dihydro-7H-benzocycloheptene-2-ol

100 g (169,3 mmole) of the compound indicated in the heading of example 1G, dissolved in a mixture of 800 ml of acetone and 500 ml of methanol. Then carefully add 175 ml of water. After that add 36,20 g (169,3 mmole) of periodate sodium and stirred for 16 h at room temperature. Next, add 1000 ml of dichloromethane and 1300 ml of water and stirred for 30 min at room temperature. The organic phase is separated and concentrated in vacuo to half volume. To the residue add 950 ml of toluene and at normal pressure carefully distilled off low-boiling components (dichloromethane and methanol). Then heated to a temperature that provides a distillation of about 50 ml of toluene. Then the temperature allowed to fall to room, and the product crystallizes. After stirred for 30 min at 10°and the precipitation is filtered off. Then slightly washed twice with cold toluene and finally dried in vacuum at 50°C.

Output: 99,6 g (97% of theory) of colorless crystalline powder.

Ale is ntny analysis:

Rasch.With 65,33N of 5.81S 5,28F 15,66
..With 65,56N 5,93S 5,12F 15,47

The following are other examples illustrating the receipt of universal intermediate product of General formula I.

In the following tables summarize the output and shows the elemental analysis of other compounds. These compounds can be obtained similar to that described in example 1 by.

Analogously to example 1A were obtained the following compounds, however, the difference is that instead of phenylacetic acid used another akriluksusnoy acid:

Akriluksusnoy acid Ar-CH2-COOHOutput:% of theory
Rasch. With 72,58 lower than the 5.37 N N to 4.98

detecting. With 72,43 N 5,41 N 4,87
61
Rasch. With 72,58 lower than the 5.37 N N to 4.98

detecting. With 72,40 N 5,48 N a 4.83
59
Rasch. With 72,58 lower than the 5.37 N N to 4.98

detecting. 72,38 N 5,51 N 4,80
57
Rasch. S,47 N 5,07 F 6,37

detecting. With 72,34 N 5,16 F 6,25
70
Rasch. With 67,11 N 4,93 S 11,20

detecting. With 67,01 N 5,12 S 11,04
63

Analogously to example 1B was carried out by hydrogenation system with dual connectivity:

ArOutput:% of theory
Rasch. With 71,56 of 6.71 N N 4,91

detecting. With 71,48 N For 6.81 N 4,87
99
Rasch. With 71,56 of 6.71 N N 4,91

detecting. With 71,43 N 6,85 N a 4.83
100
Rasch. With 71,56 of 6.71 N N 4,91

detecting. With 71,40 N 6,88 N 4,80
100
Rasch. With 71,51 N 6,33 F 6,28

detecting. With 71,62 N 6,44 F 6,21
100
Rasch. With 66,18 N 6,25 S 11,04

detecting. With 66,03 to 6.43 N S 10,92
99

Analogously to example 1B was carried out by cyclization with the formation of benzoapyrene:

ArOutput:% of theory
Rasch. With 76,38 N 6,41 N 5,24

detecting. With 76,29 N 6,55 N 5,13
85
Rasch. With 76,38 N 6,41 N 5,24

detecting. With 76,23 N 6,54 N 5,10
86
Rasch. With 76,38 N 6,41 N 5,24

detecting. With 76,26 N 6,50 N 5,17
81
Rasch. With 76,04 N 6,03 F 6,68

detecting. With 75,91 N 6,12 F 6,63
87
Rasch. With 70,56 of 5.92 N S 11,77

detecting. With 70,45 N 6,05 S 11,68
82

Analogously to example 1D through nonathlete carried out the reaction mix Suzuki:

ArOutput:% of theory
Rasch. With 75,07 N 6,75 N 3,13 Cl to $ 7.91

detecting. With 74,87 N 6,85 N 3,02 Cl 7,83
76
Rasch. With 75,07 N 6,75 N 3,13 Cl to $ 7.91

detecting. With 74,83 N 6,83 N 3,11 Cl 7,80
80
Rasch. With 75,07 N 6,75 N 3,13 Cl to $ 7.91

detecting. With 74,85 N 6,80 N 3.04 From Cl a 7.85
76
Rasch. With 74,91 N 6,50 F 4.09 To Cl 7,62

detecting. With 74,87 N 6,61 F 4,01 Cl 7,5
81
Rasch. With over 71.58 N 6,45 S 7,08 Cl 7,83

detecting. With 71,49 N 6,55 S 6,98 Cl of 7.75
75

Analogously to example 1E was tsalala simple methyl esters using BBr3/2,6-lutidine:

ArOutput:% of theory
Rasch. With 74,73 N 6,50 N 3,23 Cl 8,17

detecting. With 74,65 N 6,63 N 3,15 Cl 8,08
77
Rasch. With 74,73 N 6,59 N 3,23 Cl 8,17

detecting. With 74,61 N 6,61 N 3,10 Cl 8,11
78
Rasch. With 74,73 N 6,50 N 3,23 Cl 8,17

detecting. With 74,58 N 6,70 N 3,07 Cl 8,05
74
Rasch. With 77,58 N 6.73 X F 4,23 Cl of 7.90

detecting. With 77,45 N 6,87 F 4,13 Cl 7,81
88
Rasch. With 74,20 N 6,69 S 7,34 Cl 8,11

detecting. With 74,09 N 6,79 S 7,25 Cl 8,02
75

1. The method of obtaining compounds of General formula I

where L denotes a2-C10alkylenes chain, which may be unbranched or branched;

X denotes Cl or Br;

Ar denotes phenyl,

characterized in that the methyl group in the aromatic simple methyl ether, in the compound of General formula II

otscheplaut using a reagent consisting of tribromide boron and 2,6-dimethylpyridine.

2. The method of obtaining compounds of General formula II

where L denotes a2-C10alkylenes chain, which may be unbranched or branched;

X denotes Cl or Br;

Ar denotes phenyl,

characterized in that the compound of General formula III

where Ar denotes phenyl;

R is a perfluorinated remotemachine1-C8alkyl group, preferably CF3With4F9or C8F17,

subjected to interaction with the compound of General formula

where L denotes a2-C10alkylenes chain, which may be unbranched or branched;

X denotes Cl or Br,

when palladium catalysis (reaction mix by Suzuki).

3. The method according to claim 2, characterized in that the catalyst based on palladium complex compound contains either Pd(0)or Pd(II).

Cab obtain the compounds of General formula III

where Ar denotes phenyl;

R is a perfluorinated remotemachine1-C8alkyl group, preferably CF3C4F9or C8F17,

characterized in that the compound of General formula V

where Ar has the above meaning, is subjected to the interaction with the compound of General formula VI

where R is a perfluorinated remotemachine1-C8alkyl group, preferably CF3C4F9or C8F17;

Nu denotes a leaving group such as F, Cl, J or-R-SO3-using this organic or inorganic base in an aprotic solvent.

5. The method of obtaining compounds of formula VIII

where Ar denotes phenyl, characterized in that the compound of General formula IX

hydronaut using a catalyst.

6. The method of obtaining compounds of formula IX

where Ar denotes phenyl,

characterized in that 3-methoxybenzaldehyde and acetaldehyde during the catalysis of base produces the t 3-otoxicity aldehyde and then the aldehyde in the subsequent reaction of the condensation on Knoevenagel subjected to interaction with phenylacetic acid.

7. The method of obtaining connection

characterized in that according to claim 5 get the connection formula IX, the connection according to claim 4 hydronaut with obtaining the compounds of formula VIII, the connection cyclist with polyphosphoric acid to obtain the compounds of formula V is a compound according to claim 3 is subjected to interaction with the compound of General formula VI to obtain compounds of General formula III is a compound according to claim 2 is subjected to interaction with the compound of General formula IV with obtaining compounds of General formula II, where according to claim 1, the methyl ester of the compound of General formula II otscheplaut obtaining compounds of General formula I, which are then subjected to further processing for connection With.

8. The compounds of formula

where X denotes a chlorine atom or bromine.

9. The compound of the formula

10. The use of the reagent, consisting of tribromide boron and 2,6-dimethylpyridine, for sparing and selective removal of the methyl group in simple aromatic methyl ethers.

11. The use of the reagent, consisting of tribromide boron and 2,6-dimethylpyridine, for sparing and selective removal of the methyl group in the aromatic simple methyl esters when stored and present in the source connection of the higher alkyl aromatic ethers.

12. The reagent, consisting of tribromide boron and 2,6-dimethylpyridine designed for the selective removal of the methyl group in the aromatic simple methyl esters in the presence of the higher alkyl aromatic ethers.

Both the priority date apply equally to all claims.



 

Same patents:

FIELD: organic chemistry, perfumery.

SUBSTANCE: invention relates to an aromatizing composition containing at least compound of the formula (I): as an active component wherein values w, m, P, X, G, Q and n are given in claim 1 of the invention description, and one or more aromatizing component. Also, invention relates to a method for improving, enhancing or modifying odor, to a method for aromatizing surface, method for enhancing or prolonging the diffusion effect of component on surface and to novel compounds of the formula (I) with exception of compounds enumerated in claim 10 of the invention description and to invention relating to aromatizing article using compounds of the formula (I).

EFFECT: valuable cosmetic properties of compounds.

13 cl, 14 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to synthesis of 1,3-dicarbonyl compounds and to a new method for preparing 4-substituted alkyl-3-oxobutanoates of the formula: wherein: R is C6H5CH2, 2-F-6-ClC6H3CH2, 2,6-Cl2C6H3CH2, 1-C10H7CH2, Ph2CH; Alk is Me; R is 1-AdCH2; Alk is i-Pr that are used precursors of antiviral agents of pyrimidine order. Method involves acylation of 2,2-dimethyl-1,3-dioxane-4,6-dione with acyl chlorides in dichloromethane in the presence of triethylamine followed by alcoholysis of 5-(1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione wherein acylation is carried out with acyl chlorides in the presence of trimethylsilyl chloride in the mole ratio 2,2-dimethyl-1,3-dioxane-4,6-dione : acyl chloride : trimethylsilyl chloride : triethylamine = (1-2):1:1.1:3.5, respectively, with formation of an intermediate product 5-[1-(trimethylsilyloxy)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione that is subjected for hydrolysis with formation of 5-(1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione and its following alcoholysis and formation of the end product. Method provides enhancing yield and purity of claimed compounds.

EFFECT: improved method for preparing.

2 cl, 8 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new method for production of m- or p-substituted α-arylalkanecarboxylic acids of general formula I

from respective α-hydroxylated derivatives using inexpensive reagents and without converting of any reducible groups such as ester or ketone ones in side chains. In formula R is hydrogen, C1-C6-alkyl; R1 is hydrogen, linear or branched C1-C6-alkyl, phenyl, p-nitrophenyl, alkali or earth-alkali cation or cation of pharmaceutically acceptable ammonia salt: A is C1-C4-alkyl, aryl, optionally substituted with one or more alkyl, hydroxy, etc., aryloxy, arylcarbonyl; A is in m- or p-sites; P - linear or branched C1-C6-flkyl, phenyl, nitrophenyl. Claimed method includes the next steps: a) converting of compounds of formula II to compound of formula III either by reaction of II with compound of formula in presence of organic or inorganic base or by reaction of II with thiophene of formula and followed by reaction of obtained product with HNRaRb, wherein Ra andRb are as defined above; b) thermal rearrangement of III to form IIIb ; c) catalytic dehydration of IIIb to form IIIc ; and d) optional hydrolysis of IIIc to obtain target compound of formula I. Also are disclosed new compounds of formulae III and IIIb.

EFFECT: new α-arylalkanecarboxylic acids and intermediates thereof.

6 cl, 5 ex

-ketocarboxylic acids" target="_blank">

The invention relates to an improved method of transesterification of esters-ketocarboxylic acid with the structural formula (I), the alcohol of formula (II) R3HE, and R1, R2, R3means a branched, unbranched or cyclic, saturated or unsaturated C1-C6is an alkyl group or benzyl group, and R1and R2are not the same, which are used as, for example, intermediates for biologically active substances for agro - and pharmaceutical industry, as solvents, and so on

The invention relates to an improved process for the preparation of ester 2-alkylidene-4-bromocatechol acid of the formula (3), where R1and R2each independently from each other represent a lower alkyl group with 1-5 carbon atoms, which is used as an intermediate connection upon receipt of the substances for pharmaceutical purposes, such as antibiotics

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The invention relates to a method for obtaining compounds of formula I, where X denotes the radical, inert under the conditions of the reaction; m is 0; R3denote hydrogen, CH3CH2F or CHF2Y denotes a group OR4N(R5)2or N(CH3)OCH3; R4and R5each independently of one another denotes hydrogen or C1-C8alkyl or (R5)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring, according to which (a) conduct the interaction of the compounds of formula II, where X and m have the above for formula I, values and R1and R2each independently of one another denote WITH1-C6alkyl, C1-C6alkenyl, C1-C6alkoxyalkyl or3-C6cycloalkyl or R1and R2together with the nitrogen atom form an unsubstituted or substituted 6 - or 7-membered ring which in addition to the nitrogen atom may contain an additional nitrogen atom, in an aprotic solvent with an organolithium compound of formula III, where R7denotes an organic anionic radical; b) carry out the interaction of the obtained lithium complex with the compound of the formula IV, where)2or N(CH3)OCH3; R4stands WITH1-C8alkyl; R6represents C1-C8alkyl; or R6)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring with obtaining the compounds of formula V; C) is connected in any order in 1) is subjected to occimiano 0-methylhydroxylamine or are occimiano hydroxylamine, and then methylated, formatierung or diftormetilirovaniya; 2) enter into interaction with the ether of Harborview acid

-methoxykynuramine acids" target="_blank">

The invention relates to a method of producing methylamino- methoxykynuramine acids of the formula I, where Y represents a C-organic radical through reaction of Pinner interaction achilleid formula II with an alcohol and subsequent interaction of the formed in the Pinner reaction of ester of the formula (IV) with hydroxylamine to obtain the oxime of the formula V by methylation of the oxime of the formula V to oximoula ether of the formula VI or b) somethingitaliano obtaining oximoula ester of formula VI, followed by interaction oximoula ester of formula VI with methylamine, characterized in that in the reaction of Pinner used alcohol of the formula III R-OH, boiling point above 75C

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of fluorinated ester. The process involves the re-esterification step wherein compound of the formula: RAF-COOCF2-RAF and compound of the formula: RA-CH2OH are subjected for the re-esterification reaction in the molar ratio = 1:(1-2) to yield RAF-COOCH2-RA, and the fluorination step wherein the synthesized compound is fluorinated with yielding the reaction product in the amount exceeding the mole amount before the re-esterification reaction and comprising compound of the formula: RAF-COOCF2-RAF wherein RA means a monovalent (C1-C20)-hydrocarbon group, monovalent halogen-containing (C1-C20)-hydroarbon group, monovalent heteroatom-containing (C1-C20)-hydrocarbon group or monovalent (C1-C20)-hydrocarbon group containing halogen atom and heteroatom, and RAF means the same group as RA group or monovalent hydrocarbon group prepared by fluorination of RA group.

EFFECT: improved method of synthesis.

FIELD: industrial organic synthesis.

SUBSTANCE: invention, in particular, relates to production of fatty acid alkyl esters via catalytic reesterification of triglycerides/fatty acids mixture. During this reaction, ester phase containing fatty acid alkyl esters and glycerol phase containing fatty acids are formed in reaction mixture. Phases are separated from each other. Fatty acids are isolated from glycerol phase in the form of fatty acid phase. The latter is further combined with triglycerides/fatty acids mixture and fatty acids contained in resulting mixture in amount about 10% are esterified with alcohol to produce esterification mixture containing triglycerides and fatty acid alkyl esters. This mixture is then subjected to reesterification with alcohol to produce additional amount of fatty acid alkyl esters. Esterification is effected in presence of acid catalysts and reesterification in presence of alkali catalysts.

EFFECT: improved economic characteristics of process due to recovery of additional amount of desired product.

7 cl

FIELD: industrial organic synthesis.

SUBSTANCE: invention relates to improved process of producing compounds of general formula I: (I), which are preferably used as antioxidants. In formula I, R1 and R2 . independently of each other, represent C1-C8-alkyl, cyclopentyl, and cyclohexyl, m is 1, 2, or, 3 (preferably 2), n is integer from 1 to 4, and R3 represents n-valent linear or branched C4-C30-alkyl chain optionally interrupted with oxygen atom. Process consists in reaction of compounds having general formula II: (II), in which R represents C1-C3-alkyl, with compounds depicted by general formula R3(OH)n (III), where R3 and n are such as defined above. Reaction is carried out at substantially neutral pH in presence of at least one, dissolved or suspended in reaction mixture, carboxylic acid alkali metal salt, provided that carboxylic acid in question is at least partially volatile under reaction conditions. Preferred salts are alkali metal formate and alkali metal acetate.

EFFECT: enabled conduction of reaction in absence of carrier and in substantially neutral medium and thus a number of drawbacks of the prior technical level is avoided.

16 cl, 8 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to the improved method for re-esterification of fat and/or oil of biological origin by alcoholysis. Method involves preparing fat and/or oil of biological origin for re-esterification process in suitable capacity followed by alcoholysis by addition of monoatomic alcanol and catalyst to the prepared fat and/or oil. Amino acid or derivative of amino acid metallic salt insoluble in monoatomic alcanols is used as a catalyst. Also, invention relates to fatty acid monoesters preparing by indicated method that are used as diesel fuel. This simple method provides preparing the end product with high yield that is not contaminated with catalytic material impurities.

EFFECT: improved method for re-esterification.

19 cl, 28 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing β-(4-hydroxy-3,5-di-tert.-butylphenyl)propionic acid esters that are used in polymeric industry as stabilizing agents. Method is carried out by the re-esterification reaction of β-(4-hydroxy-3,5-di-tert.-butylphenyl)propionic acid methyl ester with polyhydric alcohols at enhanced temperatures (130-190°C) in the inert gas flow in the presence of catalyst comprising the following components, wt.-%: sodium 4-(β-methylcarboxyethyl)-2,6-di-tert.-butylphenolate, 30.0-45.5, and sodium aluminate, 54.5-70.0. Indicated compounds of alkaline metal are used in the amount 0.7-6.0 mole% of the amount of β-hydroxy-3,5-di-tert.-butylphenol)propionic acid methyl ester. Invention provides enhancing yield and improving color index, reducing cost of the process and reducing amount of by-side products formed.

EFFECT: improved preparing method.

2 cl, 1 tbl, 10 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing β-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid esters that are used in industry of polymers as stabilizing agents. Method involves carrying out the process of the ester interchange reaction of β-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid methyl ester with polyhydric alcohols in inert gas flow at enhanced temperatures (130-190°C in the presence of the following components, wt.-%: 2,6-di-tert.-butylphenolate sodium, 1.5-3.6; 4-(β-methylcaboxyethyl)-2,6-di-tert.-butylphenolate sodium, 4.0-8.6; sodium acrylate, 2.1-6.4; 2,6-di-tert.-butylphenol, the balance. Indicated compounds of alkaline metal are used in the amount 0.4-5.1 wt.-% of the amount of β-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid methyl ester as measure for the sum of 4-(β-methylcarboxyethyl)-2,6-di-tert.-butylphenolate sodium, alkaline metal 2,6-di-tert.-butylphenolate and sodium acrylate. Invention provides increasing yield of the end product and its enhanced quality.

EFFECT: improved preparing method.

2 cl, 1 tbl, 10 ex

The invention relates to an improved method of obtaining pentaerythrol-tetrakis-[3-(3,5-di-tert-butyl-4 oksifenil)-propionate], used as a colorless treatment effective, non-toxic low volatile stabilizer for rubbers, plastics and other polymeric materials
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