The method of obtaining isoxazolidinone connection, the method of obtaining oxazolidinones connection (options), the method of obtaining aspartate connection, the method of obtaining occasionallythe connection, the method of obtaining methansulfonate connection, the method of obtaining benzylidene connection

 

(57) Abstract:

The invention relates to a new method of obtaining isoxazolidinone the compounds of formula (II) in which R represents an optionally substituted aromatic hydrocarbon group or its salt, by reacting the compounds of formula (1) or its salt with the compound of the formula (2) in the presence of an inorganic base in an aqueous solvent with getting aspartates the compounds of formula (3), which interacts with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of base followed by heating for decarboxylation to obtain the compounds of formula (4), to which is added p-toluensulfonate acid to obtain oxazolidinedione derivative of the formula (5)which then restores the tetrahydrofuran in the presence of NaBH4and methanol to obtain oxazolidinones the compounds of formula (6) and its further interaction with methylchloride in the presence of triethylamine to obtain methanesulfonate derivative of the formula (7), which interacts with the compound of the formula (8) in the presence of potassium carbonate to obtain benzylidene derivative of the formula (9),), which interacts with hydroxylamine in the presence of a base to obtain the compounds of formula (11). The technical result is a new method of obtaining derivatives of isoxazolidinone. 7 S. p. f-crystals.

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The technical field

The present invention relates to a new method for obtaining compounds of formula [11]

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where R represents an optionally substituted aromatic hydrocarbon group, optionally substituted alicyclic hydrocarbon group, optionally substituted heterocyclic group or optionally substituted condensed heterocyclic group,

which is applicable as a therapeutic agent against diabetes, and method for producing the intermediate compound to obtain the compound [11].

Background of the invention

The above-mentioned compound [11] applicable as a therapeutic agent against diabetes, the intermediate connection and the retrieval method is already disclosed in the description W095/18125, and the intermediate connection [6']

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and the method thereof have been specifically described in Journal of Medicinal Chemistry, 1992, Vol. 35, 14, 2625.

But this is x compounds for him not satisfactory. In addition, solvent, base, catalyst and the like for use at each stage is satisfactory for use at the laboratory level, but many of them are difficult to implement in practice and may not be used for industrial production.

Description of the invention

Therefore, several attempts have been made to solve such problems at each stage. To be more specific, considered stages 1-4 of this method (hereafter called method A) described in Journal of Medicinal Chemistry, 1992, Vol. 35, 14, 2625, which are way to obtain the most similar to the method of this invention.

In method A, for example, compound [6'], where R represents phenyl, which is one of the intermediates in this invention, receive the following stages 1 through 4 (see end of description)

Stage 1

According to the method As the compound [1] is in the interaction with the compound [2'] in dichloromethane in presence of triethylamine to obtain compounds [3']. Dichloromethane is used as solvent, is unsuitable for industrial production due to the fact that large quantities after use) is to use safe and economical water solvent (in particular, water) and to solve the problem. It was unexpected that the use of inorganic bases such as potassium carbonate, sodium carbonate and the like as the base, as also observed increases output to 92-97%. As a result, the output could increase by 10% compared to conventional methods.

Stage 2 and stage 3

According to the method And the compound [3'] reacts to 10 equivalents of acetic anhydride in the presence of 6-7 equivalents of triethylamine, using dimethylaminopyridine obtaining compounds [4']. However, to obtain compounds [4'] necessary polariation stage, which involves adding water to the solvent, acetic anhydride, to turn it into acetic acid, followed by separation and purification. This polariation stage requires a lot of time within which the connection [4'] partially decomposed. Were conducted intensive research to solve this problem polyreactive stage, also to improve the output. In the result, it was found that the combination of [4'] can be obtained by adding acetic anhydride in advance in the amount of about 4 equivalents) required for the next stage and use to dimethylaminopropylamine in the next stage without isolation and purification, and cyclization of compounds [4'] using monohydrate p-toluensulfonate acid results in obtaining compounds [5'] with high yield (95-97%). As a result, the output connection [5'] could increase by approximately 40% compared to method A.

The phosphorus oxychloride (RES3used in stage 3 of the method And is toxic with high corrosion ability, so its use is associated with serious limitations, which is very problematic for industrial use. The authors of the present invention found that the monohydrate p-toluensulfonate acid could provide a safe and lightweight use, whereby it was found industrially applicable method of production.

Stage 4

According to the method And connection [5'] lead in the interaction with lydialydia [LiA1H4] in diethyl ether to obtain compound [6']. As socialogical and diethyl ether used here are highly flammable, which makes security problems when they are used in industry. The authors of this invention have solved this problem by using sodium borohydride (NaBH4and tetrahydrofur what I compounds [6'], free from the problems of industrial production.

Unexpectedly that the use of this method, as also found, not only solve the security problem, but also increases the yield up to 85-95%. Therefore, the output could improve compared to method A.

As a way to obtain the final compounds [11'] from compound [6'] is most similar to the method of this invention, the method described in W0 95/18125 (hereafter this method is called method B). The authors of the present invention examined in detail the method B (see the end of the description).

Stage 5

According to the method B, the compound [6'] is contained in the interaction with p-toluensulfonate (TsCl) in dichloromethane in the presence of pyridine to obtain compounds [7'].

Dichloromethane is used as solvent, is subjected to a large restriction on the descent waste when used in large quantities, as mentioned in stage 1 of the method, so it is unsuitable for industrial production. The authors of this invention have found that this compound is also effective to react in toluene, which is safe, and thus this problem has been solved.

What concerning the>/BR>as a by-product, which reduces the yield of the target compound [7']. To solve the problem, used the method basically described as an example in the description of W0 95/18125, but not disclosed in detail as an example. More specifically used mesyl group as the deleted group instead toiley group. Namely methanesulfonanilide (MsCl) was set in the reaction with the compound [6'] instead of TsCl that suddenly gives the target compound [7"]

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with the release of 99-100%.

Stage 6 and stage 7

In method B, the compound [7'] lead in the interaction with the 4-hydroxybenzaldehyde [12] to obtain compounds [13], and then the compound [13] is reacted with a derivative of malonic acid [14] to obtain compounds [9']. At this stage the connection [13] is quite unstable and output connections [9'] from compound [7'] was 65%, which is unsatisfactory. The authors of this invention previously synthesized compound [8] from the compound [12] and the compound [14]

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where R1has the same meaning as above, to improve the yield, and resulted in the interaction of the compound obtained and the compound [7] and found that the compound [9'] can be obtained with high yield (8 is the use of a catalyst to obtain the compound [10'], and the connection [10'] lead in the interaction with hydroxylamine in anhydrous alcohol to obtain the final target compound [11']. At this stage, the output (about 40%) of the final compounds is unsatisfactory. To increase output, the authors of the present invention is not allocated connection [10'] and led the Union during the interaction with hydroxylamine in a mixed solvent of tetrahydrofuran, water and alcohol in the presence of a base (e.g. potassium carbonate, sodium carbonate or sodium methoxide) to obtain the target compound [11'] with high yield (80%).

Although the foregoing relates to a method for obtaining compounds [11'] from compound [6'], there is no need to say that the connection [6'] is also applicable to obtain the following compounds [16]

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where X represents an oxygen atom or a sulfur atom.

As mentioned above, the authors of this invention have studied in detail the problems at each stage to improve the yield of the target compounds and get way, enabling industrial production, they found that the use of the above-mentioned solvent, base, catalyst and the like at each stage results in a target soedineniya of the present invention. That is, this invention is the following (1) to(7).

(1) a Method of obtaining isoxazolidinone the compounds of formula [11]

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where R represents an optionally substituted aromatic hydrocarbon group, optionally substituted alicyclic hydrocarbon group, optionally substituted heterocyclic group or optionally substituted condensed heterocyclic group, or its salt, comprising the stage of:

(a) interaction of compound [1]

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or its salt with the compound of the formula [2]

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where R has a value, which is defined above, in the presence of an inorganic base in an aqueous solvent with getting aspartate derivative of the formula [3]

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where R has a value, which is defined above;

(b) reaction of this compound with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of base followed by heating for decarboxylation to obtain the compounds of formula [4]

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where R has a value, which is defined above;

(C) adding n-toluensulfonate acid without releasing the connection with the receipt of oxazolidine the establishment of this compound in tetrahydrofuran in the presence of NaBH4as a reducing agent and methanol as the activating substance with getting oxazolidinone derivative of the formula [6]

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where R has a value, which is defined above;

(e) reaction of this compound with methylchloride in toluene in the presence of triethylamine as a base-catalyst receiving methanesulfonamide derivative of the formula [7]

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where R has a value, which is defined above;

(f) reaction of this compound with the compound of the formula [8]

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where R1represents lower alkyl, in the presence of potassium carbonate and salts of Quaternary ammonium or Tris[2-(2-methoxyethoxy)ethyl]amine as a catalyst for obtaining benzylidene derivative of the formula [9]

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where R and R1have the meanings defined above;

(g) recovery of this compound in hydrogen atmosphere to obtain a derivative of malonic acid of the formula [10]

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where R and R1have the meanings defined above, and

(h) reaction of this compound with hydroxylamine in the presence of a base.

(2) a Method of obtaining oxazolidinone derivative of the formula [6]

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where R is mn
or its salt in an aqueous solvent with the compound of the formula [2]

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where R has a value, which is defined above in the presence of inorganic base to obtain aspartate derivative of the formula [3]

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where R has a value, which is defined above;

(b) reaction of this compound with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of base followed by heating for decarboxylation to obtain the compounds of formula [4]

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where R has a value, which is defined above;

(c) joining p-toluensulfonate acid without releasing the connection with obtaining oxazolidinedione derivative of the formula [5]

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where R has a value, which is defined above, and

(d) recovery of this compound in tetrahydrofuran in the presence of NaBH4as a reducing agent and methanol as the activating substance.

(3) a Method of obtaining aspartate derivative of the formula [3]

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where R is the value that defined above, or its salt, comprising the reaction of the compound [1]

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or its salt with the compound of the formula [2]

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(4) the Method of obtaining oxazolidinedione derivative of the formula [5]

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where R is the value that defined above, or its salt, comprising the reaction of compounds of formula [3]

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where R has a value, which is defined above, with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of a base with heating for decarboxylation to obtain the compounds of formula [4]

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where R is the value that defined above and the attaching p-toluensulfonate acid without isolation of the compound.

(5) the Method of obtaining oxazolidinone derivative of the formula [6]

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where R is the value that defined above, or its salt, comprising the reaction oxazolidinedione derivative of the formula [5]

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where R has the meaning which is given the definition above, in tetrahydrofuran in the presence of NaBH4as a reducing agent, and methanol as the activating means.

(6) the Method of obtaining methanesulfonate derivative of the formula [7]

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where R is the value that defined above, or its salt, comprising the reaction oxazolidinones proie in the presence of triethylamine as a base-catalyst.

(7) the Method of obtaining benzylidene derivative of the formula [9]

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where R and R1have the meanings defined above, or its salt, comprising the reaction methanesulfonate derivative of the formula [7]

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where R has a value, which is defined above, with a compound of the formula [8]

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where R1has a value, which is defined above, in the presence of potassium carbonate and salts of Quaternary ammonium or Tris[2-(2-methoxyethoxy)ethyl]amine as a catalyst.

Terms used in this description are explained as follows.

Aromatic hydrocarbon group means phenyl, biphenyl, naphthyl and the like. It can be aranceles group, such as benzyl. Preferred is phenyl.

Alicyclic hydrocarbon group means an alicyclic hydrocarbon group having 3 to 7 carbon atoms, and its examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropyl, cyclobutyl, cyclobutadiene, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene and the like, with preference being given alitsiklicheskikh, cycloheptyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl and cycloheptadiene, with special preference given to cyclopentyl and cyclohexyl.

Heterocyclic group is a 5 - or 6-membered heterocycle having as atoms forming the ring, 1-3, preferably 1 or 2 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom, besides carbon atoms, preferably an aromatic heterocycle. Its specific examples include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, dithiazole, DIOXOLANYL, ditolyl, pyrrolidinyl, datadesigner, thiadiazines, morpholinyl, oxazinyl, triazinyl, piperazinil, piperidinyl, pyranyl and tiopronin, with preference given to tieniu, furillo, pyrrolyl, imidazolyl, pyridyl and pyrimidinyl, and particular preference is given to pyridyl, pyrimidinyl and imidazolyl.

Condensed heterocyclic group is a ring in which 5 - or 6-membered heterocycles having as an atom constituting the ring, 1-3, preferably is Ino aromatic heterocycles were condensed, or ring in which such a heterocycle, preferably aromatic heterocycle, and 4-6-membered aromatic hydrocarbon ring, preferably a benzene ring, was condensed. Specific examples include forosocial, imidazothiazoles, teenistujail, theNational, imidazopyridines, cyclopentadienyl, pyrrolopyrazole, cyclopentadienyl, theNational, oxadiazolidine, benzofurazanyl, thiadiazolidine, diazolidinyl, triazolopyrimidines, triazolopyridines, benzotriazolyl, oxazolopyridine, oxazolopyridine, benzoxazolyl, triazolopyridazines, triazolopyrimidines, benzisothiazole, benzothiazolyl, pyrazoloacridine, pyrazolidine, imidazopyridines, purinol, pyrazolopyrimidines, pyrazolopyrimidines, imidazopyridines, pyranopyrazoles, benzimidazolyl, indazoles, benzoxadiazole, benzodioxolyl, decylpyrimidine, benzodithiol, indolizinyl, indolyl, isoindolyl, properidine, properidine, benzofuranyl, isobenzofuranyl, thienopyridines, thienopyrimidines, tiandixing, thienopyridines, sensational, isobenzofuranyl, cyclopentadienyl, cyclopentadienyl, benzothiadiazine, benzotriazines, pyridoxine, benzoxazines, Pinel, cinnoline, hintline, honokalani, benzoxanthenes, benzodioxolyl, benzodithiol, naphthyridine, ethanolic, hinely, benzopyranyl, benzothiophene, bromanil, isopropanol, indolinyl and the like, with preference given benzoxazolyl, benzisothiazole, benzothiazolyl, benzimidazolyl, indazoles, benzoxadiazole, benzodioxolyl, benzonitrile, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothieno, isobenzofuranyl, benzothiadiazine, benzotriazines, benzoxazines, benzothiazines, cinnoline, girasolereale, khinoksalinona, benzoxadiazole, benzodioxolyl, benzodithiol, ishinryu, Honolulu, benzopyranyl, benzothiophene, chromanol, isochroman and indolinyl, with particular preference given to indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothieno, isobenzofuranyl, ishinryu and Honolulu.

Lower alkyl is a linear or branched alkyl having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl and the like, with preference given to alkyl, nieuwboer, and special preference is given to the stands.

Optionally substituted means that the group may be substituted by 1 to 3 substituents, which may be the same or different. Their specific examples include lower alkyl such as methyl, ethyl, propyl, butyl, tert-butyl and the like; lower alkoxy, such as methoxy, ethoxy, propoxy, butoxy, tert-butoxy and the like; halogen atom; nitro; cyano; hydroxy; acyl (e.g. lower alkanoyl, such as formyl, acetyl, propionyl, butyryl, isobutyryl and the like, aroyl, such as benzoyl, naphtol and the like); aryloxy (acyl Deputy defined above), such as formyloxy, the atomic charges, propionyloxy, butyryloxy, isobutyryloxy, benzoyloxy and the like; aralkylated, such as benzyloxy, penetrate, phenylpropoxy and the like; mercapto; lower alkylthio, such as methylthio, ethylthio, propylthio, butylthio, isobutyric, tert-butylthio and the like; amino; lower alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino and the like; di(lower)alkylamino, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino and the like; carboxy; lower Albanel, tert-butoxycarbonyl and the like; acylamino (acyl Deputy defined above); trifluoromethyl; phosphoryl; sulfonyl; sulfonyloxy; carbarnoyl; sulfamoyl; lower alkylphosphonate, such as methylphosphonate, ethylphosphonate, propylphosphonate, isopropylacetanilide and the like; methylendioxy; lower alkoxymethyl, such as methoxypropanol, ethoxypropanol, propoxymethyl, isopropoxycarbonyl and the like; lower alkylsulfonyl, such as methylsulphonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, tert-butylsulfonyl and the like; lower alkylsulfonyl, such as methylsulfonylamino, ethylsulfonyl, propylsulfonyl, butylsulfonyl, tert-butylsulfonyl and the like; and the like, with preference given hydroxy, lower alkyl, lower alkoxy, aralkylated, mercapto, lower alkylthio, nitro, halogen atom, trifluoromethyl, amino, di(lower)alkylamino, lower alkylamino, acyl, cyano, carbamoyl, acyloxy, sulfonyl, carboxy and the lower alkoxycarbonyl and special preference hydroxy, lower alkyl and lower alkoxy. As used here, the lower means that the number of carbon atoms preferably costume, if only they form non-toxic salts with the compounds of the above formulas[3], [5]-[7], [9] and [11]. Specific examples include alkali metal salts such as sodium salt, potassium salt and the like; salts of alkaline earth metals such as magnesium salt, calcium salt and the like; ammonium salt; salts of organic bases, such as salts of trimethylamine, salts of triethylamine, pyridine salt, picolinate salt, salt dicyclohexylamine, salts of N,N'-dibenziletilendiaminom and the like, and salts with amino acids such as lysine salt, arginine salt, and the like.

The salt of compound [1] can be different and include, for example, salt with accession inorganic acid such as hydrochloride, sulfate, phosphate, hydrobromide and the like; salt with the accession of organic acids, such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, ascorbic acid, methanesulfonate acid, benzylmalonate acid and the like; alkali metal salts such as sodium salt, potassium salt and the like; salts of alkaline earth metals, such to the role of trimethylamine, salt of triethylamine, pyridine salt, picolina salt, dicyclohexylamine salt, N,N'-dibenzyl-ethylendiamine salt and the like; and the like.

The method of obtaining compounds [11] and intermediate compounds are described in detail (see the end of the description).

A common way to obtain

Stage 1

The compound [1] or its salt lead in the interaction with the compound [2] in aqueous solvent in the presence of an inorganic base to obtain the compound [3].

Water is the solvent that should be used for this reaction, in particular, represents water, which may contain a polar solvent, such as methanol, ethanol, acetic acid and the like, in an amount which does not interfere with the reaction.

The inorganic base is a potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and the like, with preference given to sodium carbonate.

The reaction temperature is from -20 to -50oC, preferably from 0 to 30oC. the reaction Time is 2-24 hours, preferably 2-5 hours

Stage 2

Compound [4] can be obtained by react the m catalyst, followed by heating. The compound obtained tsiklitiria by adding acid, such as p-toluensulfonate acid and the like, without isolation, can be obtained compound [5].

Preferably an organic solvent that can be used for the reaction is toluene. To go to the next reaction without isolating the compound [4], is used acetic anhydride in an amount necessary for the following reaction, preferably about 4 equivalent.

An example of a base is a tertiary amine. Preferred is N-methylmorpholine or pyridine, and a more preferred N-methylmorpholin. The base is preferably used in amounts of 0.25 to 1.0 equivalent.

The catalyst preferably is dimethylaminopyridine.

Acid required to obtain the compound [5] from the compound [4], preferred is a monohydrate p-toluensulfonate acid.

The temperature of the heating when the decarboxylation is from 40 to 70oWith, preferably 55-60oC. the reaction Time decarboxylation is 4-48 hours, preferably 4-24 hours

The temperature of the cyclization reaction is 70-100oWith that PR is 3

Connection [5] restore in a solvent using a reducing agent to obtain compounds [6] . Using activating substances for reducing the reaction takes place smoothly.

The solvent that can be used for the reaction, preferred is tetrahydrofuran.

Reducing agent is preferably sodium borohydride (NaBH4).

Activating substance for reducing agent is preferably methyl alcohol.

The reaction temperature is from 30 to 100oWith, preferably 40-80oC. the reaction Time is 1-10 hours, preferably 1-2 hours

Stage 4

Connection [6] lead in the interaction with methanesulfonanilide (methylchloride) in a solvent in the presence of a base to obtain compound [7].

The solvent that can be used for the reaction, preferably is an organic solvent, such as toluene, dichloromethane and the like, with preference given to toluene.

An example of a base is a tertiary amine. Preferred are triethylamine and N-methylmorpholine, with special preference given to tritium is 0.5-24 h, preferably 1-10 hours

Stage 5

Connection [7] lead in the interaction with the compound [8] in a solvent in the presence of a base and using a catalyst to obtain the compound [9].

The solvent that can be used for the reaction, preferably is toluene.

The preferred base is potassium carbonate.

The catalyst is a Quaternary ammonium salt such as tetrabutylammonium bromide, Tetramethylammonium bromide, tetraethylammonium bromide, tetraethylammonium chloride, designed chloride, benzyltriethylammonium chloride, benzyltriethylammonium bromide and the like, or Tris[2-(2-methoxyethoxy)ethyl] amine, with preference given to tetrabutylammonium bromide and Tris[2-(2-methoxyethoxy)ethyl]amine.

The reaction temperature is 0 to 150oWith, preferably 10-120oC. the reaction Time ranges from 5 to 24 h, preferably 6-10 hours

Stage 6

Connection [9] restore in hydrogen atmosphere in a solvent, using a catalyst recovery connection is obtained [10]. Without releasing the connection lead into interaction with hydroxylamine in a solvent in the presence of onmore be used for the reaction, is an organic solvent, such as methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, acetic acid, and the like, or mixed of them, the solvent, which is preferably tetrahydrofuran.

Catalyst recovery is palladium on charcoal, palladium black and the like, which preferably is palladium on coal.

The reaction time of recovery varies from 4 to 24 h, preferably 6-10 hours

The solvent that can be used for the reaction of receipt of compounds [10] connections [11], is methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane, acetic acid, water and the like, or mixed of them solvent. Preferred is a mixed solvent of methanol, tetrahydrofuran and water.

The reason is, for example, potassium carbonate, sodium carbonate, sodium methoxide or ethoxide sodium. Preferred is potassium carbonate.

The reaction temperature is preferably from 0 to 50oWith, preferably 20-30oC. the reaction Time is from 4 to 24 h, preferably 6-10 hours

Examples

P is connected [1]; 183,6 g) was dissolved in water (800 ml). This solution was cooled to 5oWith under stirring and the solution was added sodium carbonate (265 g) in water (1 l). To this reaction mixture was added benzoyl chloride (121,9 ml) in 5oC for 1 h 20 min After mixing at 10-18oC for 2 h to the reaction mixture were added water (1.2 l) and the reaction mixture was made homogeneous. There was added dichloromethane (0.5 l) to separate the solution, and the organic layer was removed. To the aqueous layer was added concentrated hydrochloric acid to reach pH 2, was added ethyl acetate (1.5 l) and was extracted. The aqueous layer was additionally extracted with ethyl acetate (0.5 l) and the organic layers were combined. The organic layer was sequentially washed with water (1 l), saturated salt solution (1 l) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to about half the quantity, and the precipitated crystals were collected by filtration. The filtrate was further concentrated under reduced pressure to about half the quantity, and loose precipitated crystals were collected by filtration. The obtained crystals were dried to obtain the compound of the title (compound [3]; 229,9 g, yield of 91.5%).

Example 3. Getting 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (compound [6] (R=phenyl)

Methyl 2-(5-methyl-2-phenyl-4-oxazolyl)AC is Tria (27,81 g) at room temperature. This suspension was heated to 60oC and stirred, was added dropwise methyl alcohol (57,9 ml) within 1 h After adding dropwise, the reaction mixture was cooled to room temperature and was added dropwise water (35 ml). The mixture was stirred at room temperature for 1 h and filtered to remove solid components. Solid component is washed with tetrahydrofuran, and the washing liquid was combined with the previous filtrate which was then concentrated under reduced pressure. To the residue was added ethyl acetate (1 l) and after dilution for the separation was added water (1 l). The aqueous layer was again extracted with ethyl acetate (0.5 l) and the organic layers were combined and sequentially washed with a saturated solution of sodium bicarbonate (1 l) and saturated salt solution (1 l) and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain crude crystals (compound [6]; 149 g). The crystals are recrystallized from a mixed solvent of n-hexane (1 l) and ethyl acetate (0.2 l) to obtain the compound named in the title (connection [6]; 134 g, yield of 89.7%).

So pl. 73,0-73,8oWITH

1H-NMR (300 MHz, CDCl3, TMC)
-1.

FAB-MS: TO 204.1 (M+N)+< / BR>
Example 4. Getting 2-(5-methyl-2-phenyl-4-oxazolyl)ethylmethanesulfonate (compound [7] (R=phenyl))

2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (compound [6]; 108,6 g) obtained in example 3 was dissolved in toluene (600 ml) was added methanesulfonamide (45,4 ml), followed by stirring under ice cooling. To this solution was dropwise added triethylamine (81,7 ml) under cooling with ice. After stirring for 1 h was added toluene (1 l) was added 1 N. hydrochloric acid (1 l) for separation. The aqueous layer was again extracted with toluene (0.5 l). The combined organic layers are then washed with water (1 l), saturated sodium hydrogen carbonate solution (1 l) and saturated salt solution (1 l) and dried over anhydrous magnesium sulfate. The desiccant was filtered, and the filtrate was concentrated under reduced pressure to obtain the compound named in the title (connection [7]; 150 g; yield 100%) as crystals.

So pl. 88,2-89,0oWITH

1H-NMR (300 MHz, CDCl3, TMC)

: a 2.36 (3H, s), 2,96 (3H, s), 2,96 (2H, t, J=6.6 Hz), a 4.53 (2H, t, J= 6.6 Hz), 7,39-7,47 (3H, m), 7,94-to 7.99 (2H, m)

IR(KBR): 1637, 1340, 1160, 981, 961, 869, 692 cm-1< / BR>
FAB-MS: 282,1 (M+N)+< / BR>
Example of getting 1. Politikalnut (289,2 ml) and toluene (1,12 ml), was added acetic acid (13,2 ml) and piperidine (11,4 ml). After dehydration by boiling under reflux at an internal temperature equal to 70-75oC for 4 h the mixture was cooled to an internal temperature of not more than 10oC and stirred for another 1 h the Precipitated crystals were collected by filtration and washed with toluene (350 ml) to obtain the compound named in the title (connection [8]; 523,7 g, yield 96,4%).

So pl. 157,4-158,0oWITH

1H-NMR (300 MHz, CDCl3, TMC)

: a-3.84 (3H, s), a 3.87 (3H, s), 5,71 (1H, m), for 6.81-6,84 (2H, m), 7,26-7,34 (2H, m), of 7.70 (1H, s)

IR(KBR): 3340, 1740, 1670, 1320, 1070, 840 cm-1< / BR>
Example 5. Getting dimethyl[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] benzylidene]malonate (compound [9] (R=phenyl, R1=methyl))

2-(5-methyl-2-phenyl-4-oxazolyl)ethylmethanesulfonate obtained in example 4 (compound [7]; 24.4 g) and dimethyl 2-(4-hydroxybenzylidene)malonate obtained in example obtain 1 (compound [8]; 20,5 g), was mixed with tetrabutylammonium bromide (1.4 g) and toluene (210 ml). The mixture was heated to 90oWith and dissolved. Was added potassium carbonate (13,2 g) and the mixture was stirred at 110oC for 6 hours the Reaction mixture was cooled with ice was added water (210 ml), followed by stirring. After settling the aqueous layer was removed and the organic is toatl and the aqueous layer was removed. The organic layer was concentrated and the concentrated residue was dissolved in methanol (150 ml) under heating. The reaction mixture was cooled to 10oWith or less and the reaction mixture was stirred for 1 h the resulting crystals were collected by filtration and washed with methanol (65 ml) to obtain the compound named in the title (compound [9]; 31.1 g, yield 85,0%).

So pl. 104,0-105,0oWITH

1H-NMR (300 MHz, CDCl3, TMC)

: is 2.37 (3H, s) to 2.99 (2H, t, J=6,7 Hz), 3,82 (3H, s), 3,85 (3H, s), 4,28 (2H, t, J=6,7 Hz), 6.89 in (2H, d, J=6.8 Hz), 7,35-the 7.43 (5H, m), of 7.70 (1H, s), of 7.97 (2H, m)

IR(KBR): 1729, 1706, 1606, 1252, 1066 cm-1< / BR>
FAB-MS: 422,1 (M+N)+< / BR>
Example 6. Getting 4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-benzyl] -3,5-isoxazolidinone (compound [11] (R=phenyl))

Dimethyl [4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] benzylidene] malonate (compound [9] ; 2.5 g) obtained in example 5 was dissolved in tetrahydrofuran (20 ml) was added 5% Pd-C (150 mg). The mixture is vigorously stirred in a hydrogen atmosphere at normal temperature and normal pressure. After 8 h the catalyst was filtered and to the filtrate was added hydroxylamine (360 mg), methanol (4 ml) and potassium carbonate (574 mg). Was added dropwise water (4 ml) and the mixture was stirred at room temperature in those who l). The mixture was extracted twice with simple ether and dried over magnesium sulfate. The solvent is evaporated and the resulting solid is recrystallized twice from methanol to obtain the compound named in the title (compound [11]; 650 mg, yield 80%).

Industrial applicability

As can be seen from the above, the method of this invention makes possible an extremely efficient production of the compounds of formula [11] and intermediate compounds for him, which is applicable as therapeutic agents for diabetes, high yield compared to conventional methods. The method of this invention highly practical and fully applicable in the industry.

This application is based on application 104098/1998 filed in Japan, the contents of which are incorporated here by reference.

1. The method of obtaining isoxazolidinone the compounds of formula [11]

< / BR>
in which R represents an optionally substituted aromatic hydrocarbon group, or its salt, comprising the following stages:

(a) interaction of compound [1]

< / BR>
or its salt with the compound of the formula [2]

< / BR>
where R is as defined above, in the presence of inorganic as defined above;

(b) interaction of the compounds of formula [3] with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of base followed by heating for decarboxylation to obtain the compounds of formula [4]

< / BR>
where R is as defined above;

(c) adding n-toluensulfonate acid without isolating the compounds of formula [4] with getting oxazolidinedione derivative of the formula [5]

< / BR>
where R is as defined above;

(d) recovering the compound of formula [5] in tetrahydrofuran in the presence of NaBH4as the reducing agent and methanol as the activating agent with obtaining oxazolidinone derivative of the formula [6]

< / BR>
where R is as defined above;

(e) interaction of the compounds of formula [6] with methylchloride in toluene in the presence of triethylamine as a basic catalyst to obtain methanesulfonate derivative of the formula [7]

< / BR>
where R is as defined above;

(f) the interaction of the compounds of formula [7] with the compound of the formula [8]

< / BR>
where R1represents lower alkyl, in the presence of potassium carbonate and Quaternary ammonium salt or Tris[2-(2-methoxyethoxy)ethyl/SUP> such as defined above;

(g) recovering the compounds of formula [9] in the atmosphere of hydrogen to obtain a derivative of malonic acid of the formula [10]

< / BR>
where R and R1such as defined above; and

(h) the interaction of the compounds of formula [10] with hydroxylamine in the presence of a base to obtain the compounds of formula [II] or its salt.

2. The method of obtaining oxazolidinone derivative of the formula [6]

< / BR>
where R is as defined in paragraph 1, or its salt, comprising the following stages:

(a) interaction of compound [1]

< / BR>
or its salt in an aqueous solvent with the compound of the formula [2]

< / BR>
where R is as defined above, in the presence of an inorganic base to obtain aspartate derivative of the formula [3]

< / BR>
where R is as defined above;

(b) interaction of the compounds of formula [3] with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of base followed by heating for decarboxylation to obtain the compounds of formula [4]

< / BR>
where R is as defined above;

(C) adding n-toluensulfonate acid without isolating the compounds of formula [4] with getting oxazolidine formula [5] in tetrahydrofuran in the presence of NaBH4as the reducing agent and methanol as the activating agent to obtain compounds of formula [6] or its salt.

3. The method of obtaining aspartate derivative of the formula [3]

< / BR>
where R is as defined in paragraph 1, or its salt, including interaction connection [1]

< / BR>
or its salt with the compound of the formula [2]

< / BR>
where R is as defined above, in an aqueous solvent, in the presence of an inorganic base to obtain the compounds of formula [3] or its salt.

4. The method of obtaining oxazolidinedione derivative of the formula [5]

< / BR>
where R is as defined in paragraph 1, or its salt, including interaction of the compounds of formula [3]

< / BR>
where R is as defined above, with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of a base, heating to decarboxylation to obtain the compounds of formula [4]

< / BR>
where R is as defined above,

and adding p-toluensulfonate acid without isolating the compounds of formula [4] to obtain the compounds of formula [5] , or its salt.

5. The method of obtaining oxazolidinone derivative of the formula [6]

< / BR>
where R is the same as R>
where R is as defined above, in tetrahydrofuran in the presence of NaBH4as the reducing agent and methanol as the activating agent to obtain compounds of formula [6] or its salt.

6. The method of obtaining methanesulfonate derivative of the formula [7]

< / BR>
where R is as defined in paragraph 1, or its salt, including interaction oxazolidinone derivative of the formula [6]

< / BR>
where R is as defined above, with methylchloride in toluene in the presence of triethylamine as a basic catalyst to obtain the compounds of formula [7] or its salt.

7. The method of obtaining benzylidene derivative of the formula [9]

< / BR>
where R is as defined in paragraph 1, and R1represents lower alkyl, or salts thereof, including interaction methanesulfonate derivative of the formula [7]

< / BR>
where R is as defined above, with a compound of the formula [8]

< / BR>
where R1such as defined above, in the presence of potassium carbonate and Quaternary ammonium salt or Tris[2-(2-methoxyethoxy)ethyl] amine as a catalyst for obtaining the compounds of formula [9] or its salt.

 

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< / BR>
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C6HRwhere R' C6H5C6H5C6H4-,< / BR>
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