The method of obtaining purine compounds used therein intermediate connection and method thereof

 

(57) Abstract:

The invention relates to an improved method for producing a purine compounds of General formula A, where X is hydrogen, hydroxy, chlorine, Ra and Rb denote hydrogen, acyl. These compounds are used in the pharmaceutical industry. The proposed method lies in the fact that the compound of formula II is subjected to interaction with the compound of the formula V, where R1R2, R3such as that defined above for the compounds of formula I, a, L denotes a leaving group, to obtain compounds of formula VI, which is then decarboxylase. The compound of formula 1, where R1means1-C6-alkyl or phenyl-C1-C6-alkyl, R2means chlorine, R3means an amino group or a protected amino group, into a compound of the formula And by transformation of the radical R3in an unprotected amino group recovery difficult-ester groups CO2R1in CH2HE and, if necessary, translate them into the corresponding acyl derivatives or, if desired, the radical R2in the compound of the formula I is converted into another value corresponding to the value of the radical X in a compound of formula A. what is the object of the claims. It is also proposed a method of obtaining the compounds of formula I. the Invention allows to simplify the process and to obtain the connection formula And with a higher yield, which increased from 10.6% to 40% in comparison with the known method. 3 S. and 4. C.p. f-crystals.

This invention relates to the field of production of chemical compounds, in particular pharmaceutical purine compounds with antiviral activity.

It is known that 2-amino-6-globulin (ACP) formula

< / BR>
is a useful intermediate connection for receipt of antiviral agents, which are nucleoside analogues, such as penciclovir (example 1) (formerly known as BRL 39123) (EP-A-141927) and famciclovir (example 2) (formerly known as BRL 42810) (EP-A-182024), respectively.

Known (EP-A-0302644, C 07 D 473/32, C 07 D 473/18, C 07 D 473/40, 08.02.89) the method of producing compounds of the formula (A):

< / BR>
where X is hydrogen, hydroxy or chlorine;

Raand Rbdenote hydrogen or acyl;

when the compound of the formula (II):

< / BR>
where R2denotes chlorine, a R3denotes an amino group or a protected amino group, is subjected to the interaction with the compound of the formula (V):

< / BR>
where L denotes tsepliaeva GI (VI):

< / BR>
where R1, R2and R3have the above values, which then removes the chlorine group in the 6th position of the molecule, and the resulting connection decarboxylase and then restore to the compounds of formula (A).

The disadvantages of this method, the feature of which is the removal of chargroup 6-th position in the early stage of the process (see reaction schemes 1 and 2 at the end of the description), are multi-stage, the need for isolation of intermediate compounds using technologically disadvantaged column chromatography and, respectively, low total output amounting to 10.6%.

Accordingly, in the present invention was to create a new, technologically more simple and effective method of obtaining compounds of formula (A), which allows to increase the yield of the target product.

The problem is solved in that a method for obtaining compounds of formula (A):

< / BR>
where X is hydrogen, hydroxy or chlorine;

Raand Rbdenote hydrogen or acyl;

when the compound of the formula (II):

< / BR>
where R2denotes chlorine, and R3denotes the amino group or the protection is needful group;

R1represents C1-6alkyl or panels1-6alkyl;

then, the obtained compound of the formula (VI):

< / BR>
where R1, R2and R3have the above values,

decarboxylase with obtaining the compounds of formula (I):

< / BR>
where R1, R2and R3have the above values, and

R3when he is not an amino group into the amino group; and, if necessary, the compound of formula (I) having a difficult ester group CO2R1, restore to the compounds of formula (A), where Raand Rbare hydrogen and, if necessary, make the R2at other values of the radical X in the compounds of formula (A).

The method according to the invention receives, in particular, 9-(4-acetoxy-3-acetoxymethyl-1-yl)-2-aminopurine (famciclovir) and 9-(-4-hydroxy-3-hydroxymethyl-1-yl)guanine (penciclovir).

In the framework of the task proposed is a method of obtaining the compounds of formula (I):

< / BR>
where R1, R2and R3have the above specified values,

when the compound of the formula (II):

< / BR>
where R2denotes chlorine, a R3denotes an amino group or a protected amino group, is subjected to interaction>then, the obtained compound of the formula (VI):

< / BR>
where R1, R2and R3have the above values,

decarboxylase and, if necessary, the compound of formula (I) is transformed into other compounds of formula (I).

In the framework of the task also proposed compound of formula (I) or its salt:

< / BR>
where R1, R2and R3such as defined above.

Preferred is the above-described compound or its salt, where R1denotes methyl or ethyl, a R3denotes the amino group.

Most preferred is a compound which is 2-amino-6-chloro-9-(methyl-2-carbomethoxybiphenyl-4-yl)purine.

The method according to the invention, in which chargroup removed only at the final stage after stage decarboxylation, provides a significant technological advantage, can significantly simplify the process stage, in particular, by eliminating stages column chromatography, to reduce their number, as well as significantly increase the yield of the target product to 41%.

The following examples illustrate the invention.

EXAMPLE 1

(Product stage 1)

P is, ritrovare ester 3-bromopropane-1,1,1-tricarboxylic acid (20,33 g of 57.3 mmol), potassium carbonate (11.1 g, 80,3 mol) and dimethylformamide (190 ml) is stirred at a temperature of from 60 to 63oC for 22 hours Then the hot reaction mixture is filtered through a layer of celite and the precipitate washed with dimethylformamide (30 ml). The filtrate and wash liquid are combined and the solvent is removed by distillation in high vacuum to obtain the crude reddish-brown oil. It is dissolved in methanol (140 ml), cooled to 20oC and then added with stirring a solution of sodium methoxide (1.2 g) in methanol (40 ml). After about 20 min, a precipitate, and the stirring is continued for just a period of 1 h, the Reaction mixture was then cooled to 15oC and kept at this temperature for 30 minutes the Product is filtered, washed with methanol (10 ml) and dried at 40oC for 16 h under vacuum.

Yield: 12.0 g of product 95% purity.

EXAMPLE 2

(product stage 2)

9-(4-acetoxy-3-acetoxymethyl-1-yl) -2-amino-6-chloro-purine

A mixture of 2-amino-6-chloro-9-(methyl-2-carbomethoxybiphenyl-4-yl)purine (32.7 g, 0.1 mol), sodium borohydride (11,5 g, 0.3 mol) and methylenechloride (125 ml) paramesh MESI support equal 20-22oC by cooling. Leave the reaction mixture is mixed for another 1.5 hours, water is Added (100 ml) and then dropwise - concentrated hydrochloric acid (20-22 ml) to pH in the range of 6.7-7.0 and maintaining the temperature of the reaction mixture is about 20-22oC. Methylenechloride and the methanol removed under vacuum until the volume of the reaction mixture reaches 150 ml. of the Reaction mixture is cooled to 5oC and stirred at this temperature for 30 minutes the precipitate is filtered off and the remaining on the filter product is washed with cold water (20 ml). The obtained wet solid (40-50 g) was stirred with triethylamine (15 ml), 4-dimethylaminopyridine (1.0 g) in methylenechloride (250 ml). Dropwise within 20 to 30 minutes add acetic anhydride (75 ml, of 0.79 mol) with such speed, to control dephlegmation. The reaction mixture is refluxed 1.5 hours, the Reaction mixture is cooled to 20oC and neutralize 20% (wt./wt.) a solution of sodium hydroxide to a pH of 6.4 to 6.5. Layer methylenechloride separated and the aqueous phase extracted with methylenechloride (100 ml). United methylenechloride phase is evaporated to the dry state. The crude wet solid is recrystallized from a mixture of 3:1 methanol: water is anal:water (0oC) and dried at 40oC for 16 h in a vacuum furnace.

Yield: 23 g of the product 97-98% purity.

EXAMPLE 3

(product stage 3)

a) 9-(4-acetoxy-3-acetoxymethyl-1-yl)- 2-aminopurine-famciclovir

A mixture of 9-(4-acetoxy-3-acetoxymethyl-1-yl)-2-amino-6-chloropurine (15,4 g, 43 mmol), 5% palladium on coal book (6.16 g), triethylamine (6.6 ml, 47 mmol) and ethyl acetate (77 ml) was stirred at 50oC in an atmosphere of hydrogen at a pressure of 1 bar (100 kPa) in an autoclave within 3-5 hours After completion of the reaction the mixture is removed from the autoclave, washed with ethyl acetate (30 ml), keeping the washing liquid at the 50oC. Through a layer of celite main filter the reaction mixture, and then the washing liquid and finally ethyl acetate (30 ml). Water (46 ml) is added to the combined mixture of an ethyl acetate filtrate and washing liquids. The ethyl acetate is evaporated until dry to obtain the crude white solid. It is recrystallized from n-butanol (62 ml), stirred and cooled solution at 0-5oC for 3 h before filtering. Filtered the product and washed with uterine fluids. Solid resuspended in n-heptane (50 ml), stirred 30 minutes and filtered. Protodrake-3-hydroxymethyl-1-yl)guanine - of penciclovir

A mixture of 9-(4-acetoxy-3-acetoxymethyl-1-yl)-2-amino-6-chloropurine (10 g, 28.1 mmol), formic acid (96%, 6.3 ml) and water (55 ml) is stirred and refluxed for about 4 hours After cooling, the solution is alkalinized by mixing with sodium hydroxide solution (12.5 M, 27 ml) and the resulting solution is stirred for 1.5 hours, the Solution is neutralized by adding formic acid. The resulting suspension is heated to the temperature of reflux distilled (about 105oC), then cooled to 40-45oC and stirred for about 3 hours the Crude product is isolated and washed with water (20 ml). The isolated product was dissolved in sodium hydroxide solution (3 M, 80 ml). Add coal (about 1.5 g) and stirred suspension of about 1 h, and then the charcoal is removed by filtration and washed with water (20 ml). The solution is neutralized by adding acetic acid, the precipitate re-dissolved by heating to about 100oC, and then cooled. Precipitated precipitated product is stirred for about 3 h, and then exhale, washed with water (2x20 ml) and dried.

Output 5,3-5,5,

1. The method of obtaining compounds of formulas AND

< / BR>
where X denotes hydrogen, hydroxy or chlorine;

Raand Rb
R3denotes an amino group or a protected amino group,

subjected to interaction with the compound of the formula V

< / BR>
where L denotes tsepliaeva group;

R1stands WITH1-6alkyl or panels1-6alkyl;

wherein the obtained compound of the formula VI

< / BR>
where R1, R2and R3have the above values,

decarboxylase with obtaining the compounds of formula I

< / BR>
where R1, R2and R3have the above meanings;

R3when he is not an amino group into the amino group,

and, if necessary, the compound of formula I having a difficult ester group CO2R1, restore to the compounds of formula A, where Raand Rbare hydrogen, and, if necessary, make the R2at other values of the radical X in the compounds of formula A.

2. The method according to p. 1, characterized in that get 9-(4-acetoxy-3-acetoxymethyl-1-yl)-2-aminopurine (famciclovir).

3. The method according to p. 1, characterized in that get 9-(4-hydroxy-3-hydroxymethyl-1-yl)guanine(penciclovir).

4. The method of obtaining the compounds of formula I

< / BR>
where R1, R2and R3have BR>R3denotes an amino group or a protected amino group,

subjected to interaction with the compound of the formula V

< / BR>
where L denotes halogen;

R1stands WITH1-4alkyl,

wherein the obtained compound of the formula VI

< / BR>
where R1, R2and R3have the above values,

decarboxylase and, if necessary, the compound of formula I is transformed into other compounds of formula I.

5. The compound of formula I or its salt

< / BR>
where R1, R2and R3such, as defined in paragraph 1.

6. Connection on p. 5 or its salt, where R1denotes methyl or ethyl, and R3denotes the amino group.

7. Connection on p. 6, characterized in that it is a 2-amino-6-chloro-9-(methyl-2-carbomethoxybiphenyl-4-yl)purine.

 

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