Method of obtaining derivative of d-erythro-2,2-difluoro-2-desoxy-1-oxoribose

FIELD: chemistry.

SUBSTANCE: claimed is method of obtaining derivative of 2,2-difluorine-2-dezoxi-1-oxoribose (I), , where R is , R1 - methyl or ethyl, R2 - C1-3 alkyl, R3 - benzoyl or R4 - phenyl; and M - sodium or potassium, including stages: (i) of interaction of compound (V) with derivative of biphenylcarbonyl obtaining compound (IV) , which has 3-hydroxygroup, protected with biphenylcarbonyl group; (ii) of interaction of compound (IV) with base (sodium carbonate or potassium carbonate) in mixed solvent, which mainly includes water (mixture of water, tetrahydrofurane and methanol), obtaining mixture of 3R-enanthiomer of carboxylate (III) with 3S-enenthiomer of carboxylate (III) and isolation from mixture of 3R-enanthiomer of carboxylate (III)(also claimed as novel compound); (iii) of interaction of compound (III) with 12N HCl obtaining derivative of 5-hydroxy-1-oxoribose (II) ; and (iv) introduction of protection R3 on 5-hydroxygroup of compound (II). Invention method is characterised by possibility of selective production of 3R-enanthiomer of carboxylate (III) by protection of 3-hydroxyl group of formula (V) compound with biphenylcarbonyl group and obtaining derivative of 2,2-difluorine-2-dezoxy-1-oxoribose of formula (I), which has required erythrostructure and is important intermediate compound, used in production of gemcitabine of formula (A) , agent for treatment of non-small cell lung cancer.

EFFECT: elaboration of efficient method of obtaining derivative which can be used in pharmacology.

6 cl, 4 ex

 

The technical field to which the invention relates

This invention relates to a method for producing a high-purity derivatives of D-Erythro-2,2-Diptera-2-deoxy-1-uxoribus.

The prior art inventions

D-Erythro-2,2-Diptera-2-deoxy-1-uxoribus is an important intermediate connection used in receiving gemcitabine formula (A), agent for the treatment of non-small cell lung cancer.

Since gemcitabine is Erythro-enantiomer, with a 3-hydroxy-group oriented downwards (opposite the 5-hydroxy-group in relation to the location of tertrahydrofuran ring ring)to receive gemcitabine is important to develop a method of obtaining Erythro-connections 1-uxoribus with 3-hydroxy-group oriented downward.

The US patent No. 4526988 discloses a method for obtaining compounds of Erythro-1-uxoribus through alkyl-2,2-debtor-3-hydroxy-3-(2,2-dialkylglycerol-4-yl)propionate, a mixture of 3:1 3R-hydroxyanisole formula (B) and 3S-hydroxyanisole formula (B'):

where

R4and R5are independently C1-3the alkyl.

However, this method involves the extraction uneconomical from a mixture of compounds (B) and (B') only 3R-hydroxyanisole formula (B) in order to selectively obtain VC is radiated derived Erythro-1-uxoribus, as compounds (B) and (B') lead to Erythro-compound of formula (C), Treo connection of the formula (C'), respectively, as shown in the reaction Schemes A and B.

Scheme And

Schema

Moreover, the method also has a problem due to the long reaction time, almost four days at room temperature.

Meanwhile, US patents No. 4965374; 5223608 and 5434254 disclose a method of obtaining Erythro-enantiomers of formula (D), as shown in reaction Scheme C, using (i) hydrolysis and azeotropic distillation 3-benzyloxypropionic ether of the formula (E) (mixture of 3:1 3R - and 3S-enantiomer) to give the lactone compounds of formula (F); (ii) protection of 5-hydroxy-group of compounds of formula (F) bentilee the group receiving compound 3,5-dibenzoate formula (G); and (iii) cooling the compounds of formula G) -5˜10°C to precipitate only Erythro-enantiomers of formula (D).

Scheme

where Bz is benzoyl.

However, this method is uneconomical because of its relatively low yield, about 25%, and the use of expensive and toxic triperoxonane acid in excess, in the process of hydrolysis.

Moreover, US patent No. 5428176 and 5618951 specifies the method of obtaining ether of 2,2-debtor-β-silyloxy-1,3-dioxolane-4-impregnated the new acid of formula (H), having a high content of 3R-illigitimately, the interaction of silicates 2,2-divorcecare with the derived glycerin aldehyde in a solvent such as 1,3-dimethylpropyleneurea (DMPU), as shown in reaction Scheme D.

Scheme D

where R6to R9are alkyl; and R10and R11are C1-3the alkyl.

However, this method also requires an uneconomical process column chromatography for separation 3R-enantiomer, a mixture of enantiomers.

Accordingly, the inventors attempted to develop a rational method for selective receipt of compounds 1-uxoribus with Erythro-structure, and suddenly found the original effective way of obtaining high-purity 2,2-debtor-2-deoxy-1-uxoribus with Erythro-structure.

The invention

Accordingly, the purpose of this invention is the provision of an efficient method for selective receipt derivatives of 2,2-debtor-2-deoxy-1-uxoribus with Erythro-structure.

Another purpose of this invention is the provision of compounds 3R-enantiomer, which can be used in the above method.

In accordance with one aspect of the present invention, provided is a method of obtaining a derivative of 2,2-debtor-2-deoxy-uxoribus formula (I), includes stage (i) interaction of the compounds of formula (V) with biphenylcarboxylic derived by obtaining the compounds of formula (IV)with 3-hydroxy-group-protected biphenylcarboxylic group; (ii) interaction of the compounds of formula (IV) with a base in a mixed solvent containing mainly water, to obtain the 3R-carboxylate enantiomer of formula (III); (iii) interaction of the compounds of formula (III) with acid derivatization of 5-hydroxy-1-uxoribus formula (II); and (iv) protection 5-hydroxypropy the compounds of formula II) with R3:

where R is

R1is stands or ethyl;

R2is C1-3by alkyl;

R3is benzoyl or

R4is phenyl or substituted phenyl; and

M is an ammonium (NH4), sodium or potassium.

In accordance with another aspect of the present invention is provided 3R-enantiomer carboxylate of formula (III):

where R, R1and M have the same values as defined above.

Detailed description of the invention

In non-obvious method, compounds of formulas (IV) and (V) are a mixture of 3R - and 3S-enantiomer in this ratio each.

The method outlined in reaction Scheme I.

A reaction scheme I

where R, R1, R2, R3and M have the same values as defined above.

In reaction Scheme I, a derivative of 2,2-Diptera-2-deoxy-1-uxoribus formula (I) can be obtained with high yield by protecting the 3-hydroxy-group of compounds of formula (V) biphenylcarboxylic group to obtain the compounds of formula (IV); by hydrolysis of compounds of formula (IV) basis of obtaining salt 3R-carboxylate of formula (III), in which 3R-enantiomer of formula (III) can be isolated from the resulting mixture of 3R - and 3S-enantiomer, since only 3R-enantiomer is obtained in the form of solids; removing the protection dioxolane group of the compound (III) acid derivatization of carboxylic acids and the translation of the carboxylic acid derivative in the lactone with distillation of water to obtain 5-hydroxy-1-uxoribus formula (II)with Erythro-structure; and by protecting the 5-hydroxycodone formula (II) in accordance with a customary method.

The method of the invention is characterized in that it is possible to selectively obtain the 3R-enantiomer carboxylate of formula (III) protection by 3-hydroxy-group of compounds of formula (V) biphenylcarboxylic group and derivatization 1-uxoribus formula (I)having the desired Erythro-structure.

Since the method of the invention the compound of formula (III) can b is to be selectively received in the form of solids, it can be easily separated by simple filtration without holding uneconomical column chromatography or other purification processes. Accordingly, the use of the compounds of formula (II) as an intermediate is one feature of the method of the invention, which is suitable for the production of the derived 1-uxoribus on a large scale.

The compound of formula (V)used as starting materials in the method of the invention can be obtained in the usual way, described in US patents No. 4526988; 4965374; 5223608 and 5434254, as shown in reaction Scheme II.

A reaction scheme II

where R, R1and R2have the same values as defined above.

In reaction Scheme II, a compound of formula (V), a mixture of 3:1 3R - and 3S-enantiomer may be obtained by blending cetonid aldehyde of formula (VII) with diverseylever formula (VI) and maintaining the mixture for reaction reformed with zinc.

Moreover, 3R-carboxylate of formula (III) can be obtained from compounds of formula (V), as shown in reaction Scheme III.

A reaction scheme III

where R, R1, R2and M have the same values as defined above.

In reaction Scheme III 3R-carboxylate of formula (III) can be obtained in the form of solid substances; (i) protection of 3-hydroxy-group is soedineniya formula (V) biphenylcarboxylic protecting group to obtain the compounds of formula (IV); and (ii) by hydrolysis of compounds of formula (IV) base.

In the method of the invention, the protective group used in stage (i)may be biphenylcarboxylic group, which is bentilee group optionally substituted benzene ring, the benzene ring is substituted by one or more Deputy selected from the group consisting of hydrogen, cyano, halogen, carbalkoxy, toluoyl, nitro, alkoxy, alkyl, dialkylamino. Representative examples of biphenylcarboxylic include such as 2-phenylbenzo (2-biphenylcarboxylic), 4-vinylbenzyl (4-biphenylcarboxylic) and substituted 2-(or 4-) phenylbenzyl, preferably 2-phenylbenzyl and 4-phenylbenzyl.

Hydrophobicity increasing because of two benzene rings biphenylcarboxylic group, makes it possible to separate salt 3R-carboxylate of formula (III) in the form of solids, even in water or water-containing mixed solvent.

On the other hand, in the case of use as a protective group of the hydroxy-group ordinary bentilee group, it is impossible to get salt 3R-carboxylate in water or water-containing mixed solvent.

On the contrary, in the case of the introduction of conventional protective group of the hydroxy-group, such as 1-naphtol, 2-naphtol, pivaloyl or acetyl, 3-hydroxy-group of compounds of formula (V) is very difficult to selectively highlight of the form is Asa reaction mixture 3R-carboxylate of formula (III) in the form of solids.

Connection-based biphenylcarboxylic used in stage (i)may be selected from the group consisting of biphenylcarboxylic (or substituted biphenylcarboxylic), chloride, bromide, cyanide, or azide, which may be commercially obtained or chemically synthesized in accordance with conventional methods.

Also the base used in the neutralization process at the stage (i)may be selected from the group consisting of pyridine, triethylamine, tributylamine, diisopropylethylamine and methylpiperidine, preferably triethylamine; the catalyst used in the acylation may be 4-dimethylaminopyridine or 4-pyrrolidineethanol; and the acylation can be carried out at -25 to 50°C.

During the hydrolysis stage (ii) may be selected from the group consisting of gaseous ammonia, aqueous ammonia, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide and mixtures thereof, preferably sodium bicarbonate, which can be used in amount of 1 equivalent or more, preferably in the range of from 1.5 to 5 equivalents relative to the compound of formula (IV).

Also mixed solvent containing mainly water, can be a mixture of water and an organic solvent selected from the group consisting of tetrahydrofur is on, dioxane, acetonitrile, acetone, isobutyl ketone, methyl ethyl ketone, methanol, ethanol, propanol, ISO-propanol, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, ethyl acetate and mixtures thereof, preferably a mixture of tetrahydrofuran and methanol; and water can be used in an amount of from 3 to 15 ml, preferably from 5 to 11 ml, and the organic solvent is from 3 to 30 ml, preferably from 6 to 18 ml relative to 1.0 g of the compound of formula (IV). The hydrolysis can be carried out at from 5 to 50°C, preferably from 10 to 30°C for from 30 minutes to 2 hours.

The compound of formula (III) can be easily separated from the reaction mixture obtained in stage (ii) removing the organic solvent under reduced pressure, and filtering the resulting mixture; or by extraction of the reaction mixture with an organic solvent and recrystallization of the product from a mixed solvent comprising mainly water.

In the method of the invention 3R-carboxylate of formula (III) can be obtained from compounds of formula (V) with high yield from 60 to 70% through potassium IDN sodium salt, or about 40%, when at the stage (ii) ammonium salt is used as the basis. Moreover, the compound of formula (III)obtained in the method of the invention has a content of 3R-carboxylate more than 99.7 per cent, while the content of 3S-carboxylate less than 0.3% therefore, the value of the enantiomeric excess higher than 99.4 per cent).

The compound of formula (I)having Erythro-structure can be obtained from compounds of formula (III) vysokointellektualnym way, as shown in reaction Scheme IV.

A reaction scheme IV

where R, R1, R3and M have the same meanings as defined above.

In reaction Scheme IV, a compound of formula (I) can be obtained by (iii) interaction of the compounds of formula (III) with an acid in a solvent to obtain compounds of formula (II)with Erythro-structure as a result of the cascade of reactions involving the neutralization of the carboxylate, remove Italcementi protective group to obtain diol carboxylic acid of the formula (VIII), and the formation of the lactone compounds of the formula (VIII); and (iv) protection of 5-hydroxy-group of compounds of formula (II) protecting group containing a hydrophobic benzene ring.

The acid used in stage inventions (iii) may be a strong acid having a pKa value ranging from -10,0 to 2.0, which can be selected from the group consisting of inorganic acids, such as from 1 to 12N HCl and 1 to 9N H2SO4and organic acids, such as methanesulfonate acid,p-toluensulfonate acid, triperoxonane acid and triftormetilfullerenov acid, preferably 12N HCl is triperoxonane acid, more preferably 12N HCl; used in amounts in the range from 1 to 2 equivalents, preferably 1.1 to 1.5 equivalents relative to the compound of formula (III).

Meanwhile, the product of the reaction in stage (iii) can vary in such a way as to contain 1 to 10 equivalents, preferably 2 to 5 equivalents of water relative to the compound of formula (III), for example, by adding an aqueous solution to it, for example aqueous inorganic acid having an appropriate concentration, or an aqueous solvent such as 95% ethanol, in order to effectively remove soulkilling group. The solvent used in stage (iii)may be selected from the group consisting of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethanol, methanol and isopropanol, preferably acetonitrile.

To remove Italcementi group stage (iii) can be carried out at the boiling temperature of the solvent for 4 to 8 hours; and the resultant mixture may be mixed with such solvents as benzene and toluene azeotrope distilled to remove water from the reaction mixture with getting licensemanager the compounds of formula (II).

At stage (iv) protective group can be selected from the group consisting of benzoyl, phenylbenzyl and substituted benzoyl, preferably 2-phenylbenzyl, 4-phenylbenzyl and zames the frame 2-(or 4-) phenylbenzyl.

Also stage (iv) may be carried out after isolation of the compounds of formula (II)obtained in stage (iii), or conducted without the allocation processin situ.The preferred method isin-situ.

The compound of formula (I)obtained by the method of the invention, demonstrates the high purity of about 99%, the connection 1-uxoribus having the desired Erythro-structure.

Moreover, the method of the invention gives a total yield of 45 to 50%, which is improved by more than 20% compared to conventional methods.

The following examples are intended to further explain the present invention without limiting its scope.

Getting 1: Obtain 2,2-debtor-3-hydroxy-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)propionate (compound of formula (V))

Stage 1: Obtain 1,2-bis-(2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol

100 g of d-mannitol was mixed with 160 ml of 2,2-dimethoxypropane, 240 ml of 1,2-dimethylethanol and 0.1 g of anhydrous SnCl2the mixture was heated to obtain a homogeneous solution was boiled under reflux for 30 min and added 0.2 ml of pyridine. The reaction mixture was cooled to room temperature and drove under reduced pressure to remove solvent. To the residue was added 700 ml of methyl chloride and boiled under reflux for 1 hour. Formed the I mixture was filtered through 10 g of cellica at room temperature and removal of solvent surpassed the filtrate under reduced pressure. The residue was recrystallize from 1 l of hexane, filtered and dried, obtaining to 72.4 g (yield 50%) of the named compound as a white solid.

NMR (300 MHz, CDCl3): of 1.30 (s, 6H), of 1.36 (s, 6H), 2,52 (d, 2H), to 3.67 (t, 2H), 3,91 (m, 2H), 4.04 the-4,14 (m, 4H).

Melting point (So square): 119-121°C.

Stage 2: Obtain 2,2-dimethyl-[1,3]-dioxolan-4-carbaldehyde

to 72.4 g of compound obtained in stage 1, was dissolved in 724 ml of methyl chloride and added thereto 30 ml of saturated sodium bicarbonate. The mixture was cooled in a water bath and small portions over 20 minutes was added thereto 118 g metaperiodate sodium, maintaining the temperature below 25°C. the Reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction was confirmed by thin-layer chromatography (TLC), the reaction mixture was added 36 g of anhydrous magnesium sulfate and was stirred for 20 minutes the Resulting mixture was filtered and removal of the solvent drove under reduced pressure at 30°S, and the residue was further subjected to distillation at atmospheric pressure at 55°for complete removal of solvent. The reaction balance surpassed at 10 Torr at about 40°receiving of 61.6 g (yield 86%) of the titled compound as a colorless liquid.

NMR (300 MHz, CDCl3):of 1.41 (s, 3H), of 1.47 (s, 3H), 4,07-4,19 (m, 2H), 4,35˜and 4.40 (m, 1H), 9,71 (s, 1H).

Stage 3: Getting ethyl-2,2-debtor-3-hydroxy-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)propionate

To 26 ml of tetrahydrofuran was added 12 g of zinc, there was added 0.51 ml dibromethane, and the reaction mixture stood for 1 min at 60°C. There at 40°With added 0,76 ml trimethylsilylpropyne and left the mixture to interact for 10 minutes, the Reaction mixture was heated to 60°C, was added dropwise a solution of 25.5 ml of ethyl ether bradypterus acid, 30,8 g of compound obtained in stage 2, and 39 ml of tetrahydrofuran, and boil the mixture under reflux for 30 minutes After adding 65 ml of diethyl ether and 260 g of ice was added to 260 ml of 1 N HCl and stirred until complete melting of the ice. The aqueous layer was three times Proektirovanie diethyl ether portions 90 ml), the combined organic layers were sequentially washed with Sodium chloride and sodium bicarbonate portions 65 ml, dried over anhydrous magnesium sulfate and filtered. After removal of solvent the residue was overtaken at 10 Torr, receiving of 28.9 g (57%) of the named compound (R:S=3:1) at 130-140°in the form of a colourless liquid.

NMR (300 MHz, CDCl3): 1,31˜of 1.52 (m, 9H), to 2.67 (s, 1H, (R)-OH), 2,90 (d, 1H, (S)-OH), 3,7˜4,4 (m, 6H).

In the following Examples, the term "-OCOBiPh" or "BiPhOCO-" refer to

HPLC analyses of the compounds of formula (I) and (III) were carried out on a column of YMC pack pro C18 RS (4,6×150 mm, 5 μm) using as eluent a mixture of buffer and acetonitrile (65:35, V/V) for compounds of formula (III)or 80% acetonitrile (for compounds of formula (I)). The buffer was obtained a mixture of 7.0 g of NaClO4, 1,74 g K2HPO4and 1 l of water and the addition of H3PO4to a pH of 2.75.

Example 1: Getting ethyl-2,2-debtor-3-(4-biphenylcarboxylic)hydroxy-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)propionate (compound of formula (IV); R=4-bicarbonic)

To 50.0 g of the compound obtained in the Obtaining 1, was added 500 ml of methylene chloride, was added 42 ml of triethylamine and 51.1 g of 4-biphenylcarboxylic and leave the mixture at room temperature for 6 hours. After adding thereto 360 ml of 1N HCl, the organic layer was successively washed with sodium bicarbonate and NaCl and dried over magnesium sulfate. The residue was filtered and drove under reduced pressure, having to 83.7 g (yield 98%) of the named compound in the form of liquid cream color.

NMR (300 MHz, CDCl3): 1,25˜of 1.74 (m, 9H), 4,11˜4,19 (m, 2H), 4,30˜4,36 (m, 2H), 4,56˜4,58 (m, 2H), 5,72˜of 5.83 (DDD, 1H×1/3), 5,88˜of 6.02 (DDD, 1H×2/3), 7,42˜7,53 (m, 3H), 7,63˜7,73 (DD, 4H), 8,15˜8,17 (d, 2H).

Example 2: Obtain 2,2-debtor-3R-(4-biphenylcarboxylic)hydroxy-3-(2,2-dimethyl-[1,3]dioxolan-4-yl)propion is the potassium (compound of formula (III); R=4-biphenylcarboxylic)

Method And

It is 83.8 g of the compound obtained in example 1 was added to 1.4 l of a mixture of tetrahydrofuran and methanol (2:3, V/V)was added 107 g of potassium carbonate dissolved in 750 ml of water. The mixture was stirred for 30 min and left under reduced pressure to remove organic solvent. After filtration, the solid is added to 100 ml of ether, stirred it up, was filtered, washed with ether and dried, obtaining 60.1 g (yield 70%) of the named compound as a white solid.

HPLC: R-isomer 99,86%, S-isomer of 0.11%.

NMR (300 MHz, DMSO)with 1.07 (s, 3H), 1,22 (s, 3H), 3,99 (t, 1H), 4,11 (t, 1H), 4,49 (t, 1H), 5,88 (DDD, 1H), 7,38˜rate of 7.54 (m, 3H), of 7.75 (d, 2H), a 7.85 (d, 2H), 8,07 (d, 2H).

Method In

To 90,4 g of the compound obtained in example 1 was added 600 ml of a mixture of tetrahydrofuran and methanol (1:1, V/V)was added to 54.4 g of potassium carbonate dissolved in 500 ml of water. The mixture was stirred for 1 hour, washed twice with hexane portions of 500 ml, were Proektirovanie 500 ml of ethyl acetate and left under reduced pressure to remove solvent. The resulting solid was mixed with 100 ml of water and 300 ml offrom-propyl alcohol, was heated to dissolve and added 700 ml offrom-propyl alcohol. The resulting mixture has stood at room temperature for 2 hours for recrystallization t is ejogo substances, which was filtered, washedfrom-propyl alcohol and dried, obtaining 62,5 g (yield 65%) of the named compound as a white solid.

HPLC: R-isomer 99.91 per cent, the S-isomer of 0.06%.

NMR (300 MHz, DMSO)with 1.07 (s, 3H), 1,22 (s, 3H), 3,99 (t, 1H), 4,11 (t, 1H), 4,49 (t, 1H), 5,88 (DDD, 1H), 7,38˜rate of 7.54 (m, 3H), of 7.75 (d, 2H), a 7.85 (d, 2H), 8,07 (d, 2H).

Example 3: Obtaining D-Erythro-2-deoxy-2,2-diftorbenzofenon-1-ilos-3-(4-phenyl)benzoate (the compound of formula (II); R=4-biphenylcarboxylic, R3=benzoyl)

Method: Receiving a selection of each product at each stage

Stage 1: Getting D-Erythro-2-deoxy-2,2-diftorbenzofenon-1-ilos-3-(4-phenyl)benzoate (the compound of formula (II); R=4-biphenylcarboxylic)

10 g of the compound obtained in example 2 was dispersible in 60 ml of acetonitrile, was added 2.5 ml of 12N HCl and boil the mixture under reflux for 6 hours. To it was added 60 ml of toluene and surpassed the reaction mixture to remove solvent. This process was repeated twice. To the residue was added 100 ml of ether, filtered to remove KCl and drove under reduced pressure to remove solvent. To the resulting residue were added 50 ml of ether there was added 100 ml of hexane in order to cause crystallization of solids. The solid was isolated by filtration (the first portion of solids); and pereg is Ali the filtrate under reduced pressure and subjected him to the second stage of recrystallization, using 20 ml of ether and 50 ml of hexane, receiving a second portion of solids. The solids were combined and dried under vacuum to obtain 5.9 g (yield 75%) of these substances in the form of a white solid.

NMR (300 MHz, CDCl3): 1,8˜2,4 (sird s, 1H), 3,78˜was 4.02 (DD, 1H), 4,11˜4,13 (DD, 1H), 4,71˜to 4.73 (m, 1H), 5,79˜by 5.87 (m, 1H), 7,44˜rate of 7.54 (m, 3H), of 7.64˜7,66 (d, 2H), 7,21˜of 7.75 (d, 2H).

Melting point (so square): 107-111°C.

Stage 2: Getting D-Erythro-2-deoxy-2,2-Diptera-pentofuranose-1-ilos-5-benzoyl-3-(4-phenyl)benzoate

15.0 g of the compound obtained in stage 1, was added to 150 ml of methylene chloride, and under stirring at room temperature, it was added dropwise 6.9 ml of pyridine, there is slowly added 7.4 ml of benzoyl chloride dissolved in 40 ml of methylene chloride, keeping the temperature from 5 to 10°C. the Reaction mixture was left for 7 hours at room temperature to neutralize the pyridine in a mixture there was added 105 ml of 1N HCl and then added water to cause separation of the organic layer. The organic layer was separated, sequentially washed with 100 ml of saturated sodium bicarbonate and NaCl, dried over magnesium sulfate and filtered. The remaining solution was passed under reduced pressure, obtaining a solid cream color. Solid the second substance has recrystallize from a mixture of ether and hexane (5:1, about/about)with a 16.8 g of the above compound (yield: 86%).

NMR (300 MHz, CDCl3): 4,90˜and 4.75 (DDD, 2H), 5,10 (DD, 1H), by 5.87 (DDD, 1H), 7,65˜to 7.50 (m, 5H), 7,78˜to 7.67 (m, 3H), 7,81 (d, 2H), 8,13 (d, 2H), 8,23 (d, 2H).

Melting point (so square): 130-131°C.

HPLC purity: 99,21% (threo-isomer has not been detected).

Method: obtainin situ

Mixed 232 ml of acetonitrile with a population of 38.8 g of the compound obtained in Example 2, and 9.2 ml of 12N HCl, and boil the mixture under reflux for 6 hours. After adding thereto 464 ml of toluene, the reaction mixture was distilled to remove water and acetonitrile as long as the temperature was above 100°C. the Resulting concentrate was filtered and kept at reduced pressure, obtaining foamy solid. The solid is dissolved in 300 ml of ethyl acetate, there under stirring was added 14 ml of pyridine and added 15 ml of benzoyl chloride dissolved in 75 ml of ethyl acetate. The mixture stood at room temperature for 6 hours and to neutralize the pyridine was added 210 ml of 1N HCl. The organic layer was separated, sequentially washed with portions of 150 ml of water, saturated sodium bicarbonate and NaCl, dried over magnesium sulfate and kept at reduced pressure, obtaining a solid cream color. The solid was recrystallize from a mixture of afire hexane (5:1, about/about)with 28.4 g of the above compound (yield: 72%) as a white solid.

NMR (300 MHz, CDCl3): 4,90˜and 4.75 (DDD, 2H), 5,10 (DD, 1H), by 5.87 (DDD, 1H), 7,65˜to 7.50 (m, 5H), 7,78˜to 7.67 (m, 3H), 7,81 (d, 2H), 8,13 (d, 2H), 8,23 (d, 2H).

The melting temperature (TPL): 130-131°C.

HPLC purity: 99,05% (threo-isomer has not been detected).

Example 4: Obtaining D-Erythro-2-deoxy-2,2-diftorbenzofenon-1-ilos-3,5-di(4-phenyl)benzoate (the compound of formula (I); R and R3= 4-bicarbonic)

Method: Receiving a selection of each product at each stage

Stage 1: Getting D-Erythro-2-deoxy-2,2-diftorbenzofenon-1-ilos-3-(4-phenyl)benzoate (the compound of formula (II); R = 4-biphenylcarboxylic)

To obtain these compounds was repeated process stage 1 of method a of Example 2 to obtain the above compound (yield 75%).

Stage 2: Getting D-Erythro-2-deoxy-2,2-diftorbenzofenon-1-ilos-3,5-di(4-phenyl)benzoate

To 20 g of compound obtained in stage 1, was added 300 ml of chloroform, with stirring at room temperature there was added to 9.5 ml of pyridine and added 10.1 ml 4-biphenylcarboxylic dissolved in 55 ml of chloroform. The reaction mixture was left for 6 hours at room temperature, the remaining pyridine was neutralized 140 ml of 1N HCl. The organic layer was separated, sequential matching is consequently washed in portions of 150 ml of water, saturated sodium bicarbonate and NaCl, dried over magnesium sulfate and kept at reduced pressure, obtaining a solid cream color. The solid was recrystallize from a mixture of acetate and hexane (3:1, V/V)with 21.8 g of the above compound (yield: 72%) as a white solid.

NMR (300 MHz, CDCl3): 4,72˜4,79 (m, 2H), to 5.03 (q, 1H), of 5.84˜USD 5.76 (m, 1H), of 7.48˜7,44 (m, 6H), 7,72˜of 7.60 (m, 8H), 8,15˜8,07 (m, 4H).

Melting point (so square): 137-139°C.

HPLC purity: 98,95% (threo-isomer has not been detected).

Method: Obtainin situ

to 40.0 g of the compound obtained in Example 2 was added to 240 ml of acetonitrile there was added 10 ml of 12N HCl and boil the mixture under reflux for 6 hours. After adding thereto 250 ml of toluene, the reaction mixture was surpassed for the removal of water and acetonitrile, cooled to room temperature, filtered, and passed under reduced pressure, after 5-hydroxy-1-uxoribus as intermediate compounds. The intermediate compound was dissolved in 480 ml of ethyl acetate, there was added the mixture to 21.8 ml of pyridine, 39 g of 4-biphenylcarboxylic and left to interact at room temperature for 12 hours. To neutralize the remaining pyridine to the reaction mixture were added 320 ml of 1N HCl; the organic layer was separated, placentas is tion was washed with portions 160 ml of water, saturated sodium bicarbonate and NaCl, dried and filtered. The filtrate is passed under reduced pressure to remove solvent and the residue was recrystallize from a mixture of ethyl acetate and hexane (3:1, V/V)with 31.9 per g of the above compound (yield: 65%) as a white solid.

NMR (300 MHz, CDCl3): 4,72˜4,79 (m, 2H), to 5.03 (q, 1H), of 5.84˜USD 5.76 (m, 1H), of 7.48˜7,44 (m, 6H), 7,72˜of 7.60 (m, 8H), 8,15˜8,07 (m, 4H).

Melting point (so square): 137-139°C.

HPLC purity: 98,33% (threo-isomer has not been detected).

Although the invention has been described with regard to the above-mentioned specific embodiments, it should be realised that the person skilled in the art can be made of various modifications and changes also fall within the scope of the invention as defined in the attached claims.

1. The method of obtaining the derivative of 2,2-Diptera-2-deoxy-1-uxoribus formula (I), including the stage (i) interaction of the compounds of formula (V) with a derivative of biphenylcarboxylic with obtaining the compounds of formula (IV)with 3-hydroxy-group-protected biphenylcarboxylic group;

(ii) the interaction of the compounds of formula (IV) with a base in a mixed solvent comprising mainly water, to obtain a mixture of 3R-enantiomer carboxylate formula (III) with the 3S-enantiomer carboxylate formula (III), and selection of 3R-enantiomer carboxylate formula (III);

where the base is a carbonate of sodium or potassium carbonate and a mixed solvent comprising mainly water, is a mixture of water, tetrahydrofuran and methanol;

(iii) the interaction of the compounds of formula (III) with 12N HCl to obtain the derived 5-hydroxy-1-uxoribus formula (II); and

(iv) the introduction of protection R35-hydroxy-group of compounds of formula (II)

where R is;

R1is stands or ethyl;

R2is1-3by alkyl;

R3is benzoyl or;

R4is phenyl; and

M is sodium or potassium.

2. The method according to claim 1, in which biphenylcarboxylic group on stage (i) is 2-biphenylcarboxylic or 4-biphenylcarboxylic.

3. The method according to claim 1, wherein the base used in stage (ii)is potassium carbonate.

4. The method according to claim 1, wherein the acid used in stage (iii)is used in an amount varying in the range from 1.1 to 1.5 equivalents relative to the compound of formula (II).

5. 3-EN is ntimer the carboxylate of the formula (III)

where R is;

R1is stands or ethyl;

R4is phenyl; and

M is sodium or potassium.

6. The method according to claim 1, in which the allocation of 3 R-enantiomer of the carboxylate on the stage (ii) is carried out by removing the tetrahydrofuran and methanol under reduced pressure, and filtering the mixture; or by extraction of the mixture with ethyl acetate and recrystallization of the product from a mixed solvent consisting of water and propyl alcohol.



 

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1 tbl, 1 ex

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