JPH08119989A - New production of 6-substituted aminopurine derivative and its intermediate - Google Patents

Abstract

PURPOSE: To efficiently obtain the subject derivative adenomatous carcinoma and trypanosoma by reacting a specific 9-(3'-azido-3'-deoxy-D-ribofuranosyl-6- halopurine derivative with an amine and reducing the azide group. CONSTITUTION: A 9-(3'-azido-3'-deoxy-D-ribofuranosyl)-6-chloropurine derivative of formula I (R<1> and R<2> are each H, an acyl or an alkoxycarbonyl; X is a halogen) is reacted with an amine of the formula, MHR<3> R<4> (R<3> and R<4> are each an alkyl) (e.g. dimethylamine) to give a new compound 9-(3'-azido-3'-deoxy- D-ribofuranosyl)-6-dimethylaminopurine of formula II and the azide group at the 3'-position of the compound is reduced to give the objective 6-substituted aminopurine derivative of formula III, having activity against a certain kind of adenomatous carcinoma and trypanosoma, useful for preparing an experimental model of nephrotic disease efficiently and in high yield.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 9- (3'-amino-
The present invention relates to a novel method for producing a 3'-deoxy-D-ribosyl) -6-substituted aminopurine derivative. In addition, this method provides a novel 9- (3'-azido-3'-deoxy-
This is a novel method using a D-ribosyl) -6-substituted aminopurine derivative as an intermediate.

[0002]

2. Description of the Related Art 9- (3'-amino-
3'-deoxy-D-ribosyl) -6-dimethylaminopurine [puromycin aminonucleoside (hereinafter, PAN)] is

[0003]

[Chemical 11]

Having activity against C3H mouse transplanted adenocarcinoma and trypanosomiasis [B. R. BAKETR et al., Journal of American Chemical Society (J. Amer. Chem Soc), 77, 15-
18, p. 1955], and urinary proteinosis (protei).
nuria), hypoproteinemia (hypoproteininem
ia), sodium retention
ion), ascites and hyperlipidemia (h
yperlipidemia) and the like, which are useful compounds for the production of PAN-induced nephrotic disease, which is an experimental model of human diseases [Jose Pedraza-ave].
rri et al., Renal Failure
re), Vol. 14, No. 4, pp. 523-531, 1992.
Year〕. The production method of the above PAN has hitherto been 6-chloropurine and 2,5-di-O-benzoyl-3-deoxy-
9- (2 ′, 5′-di-O-benzoyl-3′-deoxy-3′-phthalimido-β-D-ribofuranosyl obtained by reacting with 3-phthalimido-β-D-ribofuranosyl chloride ) -6-Chloro-9H-purine is sealed and heated in a methanol solution of methylamine to give a 6-amino substitution product, and then the phthalyl group of phthalimide is removed and amination is performed, or 6-chloropurine and 1 -O-acetyl-3-acetamide-
9-obtained by reacting with 2,5-di-O-benzoyl-3-deoxy-D-ribofuranose
(3'-acetamido-2 ', 5'-di-O-benzoyl-3'-deoxy-D-ribofuranosyl) -6-chloropurine is reacted with dimethylamine to give a 6-amino substituent, then barium hydroxide. A method of hydrolyzing by heating in an aqueous solution has been reported [L. GOLD
MAN et al., Journal of Medicinal Chemistry (J. Med. Chem.), Volume 6, 413-423.
P., 1963].

[0005]

[Chemical 12]

However, all of the above-mentioned conventional production methods require a step of removing the protecting group of the amino group of the ribose part, for example, the phthalyl group of the phthalimido group requires heating in a sealed tube, and the acetamide. The removal of the acyl group of the group requires a hydrolysis step using barium hydroxide and an ion exchange chromatography treatment operation after the reaction, which is extremely complicated. Further, the sugar moiety in which the amino group at the 3-position of the ribose moiety is protected by a phthalyl group or an acetyl group is manufactured through many steps, and it cannot be said to be an industrially preferable method.

[0007]

The present invention provides 9- (3 '
-Amino-3'-deoxy-D-ribosyl) -6-substituted aminopurine derivative, and 9- (3'-azido-3 ', which is a useful intermediate compound used in the method
-Deoxy-D-ribosyl) -6-dialkylaminopurine derivative and a method for producing the same.

[0008]

The present inventors have found that 9-
(3'-amino-3'-deoxy-D-ribosyl) -6
As a result of earnest research on a method for industrially producing a substituted aminopurine derivative, 3-azido-3-deoxy-D-
Dimethyl 9- (3'-azido-2 ', 5'-di-O-acyl-3'-deoxy-D-ribofuranosyl) -6-chloropurine derivative obtained by using ribose derivative and 6-chloropurine derivative as raw materials. The present invention has been completed by finding that the above-mentioned PAN compound can be obtained in a high yield and a high purity by a simple method by reacting with an amine and reducing the obtained 6-amino substitution product. The production method of the present invention uses a group of compounds in which the azido group is substituted in the sugar moiety in each of the above reaction steps, and reduces the azido group in the final step to easily obtain the target compound in good yield and It can be obtained with a high degree of purity and has particular advantages in terms of operability, yield and product purity that cannot be expected from the conventional techniques.

The method for preparing the compound of formula (I) according to the present invention is described below. The present invention has the formula (II)

[0010]

[Chemical 13]

(Wherein X represents a halogen atom) or a silyl derivative of the compound and a compound of formula (III)

[0012]

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A compound of formula (IV) obtained by reacting with a compound of the formula (wherein R ¹ and R ² are the same or different and each represents an acyl group or an alkoxycarbonyl group)

[0014]

[Chemical 15]

(Wherein R ¹ , R ² and X have the same meanings as defined above) and a compound of formula (V) HNR ³ R ⁴ (V) (wherein R ³ , R ⁴ are the same or different) A compound of formula (VI)

[0016]

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(Wherein R ¹ and R ² are the same or different and represent a hydrogen atom, an acyl group or an alkoxycarbonyl group, and R ³ and R ⁴ are the same or different and represent a hydrogen atom or an alkyl group) Formula (I) characterized by reducing

[0018]

[Chemical 17]

A method for producing a compound of the formula (wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above). The manufacturing method of the present invention can be represented by the following reaction formula.

[0020]

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The compound of the above formula (II) is a known compound which is commercially available. The compound of formula (III) can be easily obtained by a production method according to a known method described below.

In this specification, X is a halogen atom and represents, for example, chlorine, bromine, iodine or the like.

The acyl group represents an aliphatic or aromatic acyl group. The aliphatic acyl group has, for example, 2 to 6 carbon atoms.
A lower acyl group of, preferably an acetyl group,
Examples of the aromatic acyl group include an alkyl group, a nitro group, and a benzoyl group which may be substituted with a halogen atom.

The alkyl group is not particularly limited,
Methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl and the like can be mentioned. Preferably it is a methyl group.

Examples of the alkoxycarbonyl group include an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group and the like, a benzyloxycarbonyl group and the like.

The compound of the above formula (IV) is a compound of the formula (II) or a silylated derivative of the compound and a compound of the formula (III)
It can be obtained by reacting the compound of (1) with a solvent in the presence of a catalyst.

The silylated derivative of the compound of formula (II) is
It can be obtained by a conventional method by reacting the compound of formula (II) with a silylating agent at an appropriate temperature between room temperature and the reflux temperature of the solvent.

Examples of the silylating agent include hexamethyldisilazane and trimethylchlorosilane.

The reaction time for silylation depends on the type of raw material,
It depends on the reaction temperature, the type of basic substance, the type of solvent and other conditions, but it is usually within a few hours.

The temperature range for the reaction of the compound of formula (II) or the silylated derivative of the compound with the compound of formula (III) is 0 ° C to the reflux temperature of the solvent, preferably 0 ° C to 100 ° C.
More preferably, it is room temperature.

The reaction time depends on the type of raw material, reaction temperature,
Although it varies depending on the type of basic substance, the type of solvent and other conditions, it is usually 0.5 to 17 hours.

Solvents include aromatic hydrocarbons such as benzene, toluene, xylene, chloroform, methylene chloride, dichloroethane, carbon tetrachloride, 1,2-dichloropropane,
Examples thereof include alkyl halides such as 1,1,2,2-tetrachloroethane, ethers such as dioxane and tetrahydrofuran, acetonitrile and the like.

As a catalyst, a Lewis acid such as tin tetrachloride, zinc chloride, boron fluoride, etherate of boron fluoride, aluminum chloride, titanium tetrachloride, antimony chloride, ferric chloride, zirconium tetrachloride, Tin tetrabromide,
Examples thereof include zinc bromide, silver nitrate, etc., or trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, p-toluenesulfonic acid, 2,4-dinitrophenol, etc.

The compound of the formula (IV) is obtained by catalyzing the compound of the formula (II) or the silyl derivative of the compound and the compound of the formula (III) without using a solvent, such as p-toluenesulfonic acid or 2,4-dinitro. In the presence of phenol, etc.,
It can also be obtained by heating and melting.

The compound of formula (VI) can be obtained by reacting the compound of formula (IV) with the compound of formula (V) in a solvent.

Examples of the compound of the formula (V) include monoalkylamines such as methylamine, ethylamine, propylamine and butylamine, dialkylamines such as dimethylamine, diethylamine, dipropylamine and dibutylamine, and benzylamine. be able to.

The amount of the compound of formula (V) used is the same as that of formula (IV)
At least 1 mol per mol of the compound of is preferred.

The reaction temperature is not particularly limited, but it is preferably room temperature.

The reaction time varies depending on the type of raw material, reaction temperature, type of basic substance, type of solvent and other conditions, but it is usually several minutes to about 4 hours.

The compound of the formula (VI) in which R ¹ and R ² are the same or different acyl groups or acyloxycarbonyl groups are the compounds of the formula (VI) in which R ¹ and / or R ² are hydrogen. It can be obtained by a conventional method, for example, by acylation with acetic anhydride.

The compound of formula (I) can be obtained by reacting the compound of formula (VI) in an appropriate solvent in the presence of a reducing agent.

Examples of the reducing agent include palladium / carbon, lithium aluminum hydride, triphenylphosphine, dithioerythrol, dithiothreitol, ethanedithiol and the like. For example, catalytic reduction can be carried out under mild conditions in the presence of palladium / carbon.

The solvent may be an inert solvent, for example, polar or non-polar solvents such as acetonitrile, chloroform, dichloroethane, methylene chloride, nitromethane, toluene, dimethylformamide, acetone, dimethylacetamide, hexamethylphosphoramide. , Dimethyl sulfoxide, pyridine, lutidine and the like. For example, pyridine is preferable when triphenylphosphine is used as the reducing agent.

The reaction temperature is not particularly limited, but is preferably room temperature. The reaction time varies depending on the type of raw material, reaction temperature, type of solvent and other conditions, but is usually several minutes to 2 hours.

By the above reduction reaction, the compound of formula (I) can be obtained in good yield and purity. After the reaction, the residue can be easily crystallized by adding an appropriate solvent.

As the solvent used for crystallization, for example, water,
Acetic acid or alcohols such as methanol, ethanol, isopropyl alcohol and the like, and these solvents and ethers such as isopropyl ether and esters such as methyl acetate and ethyl acetate can be mixed and used.

According to the present invention, it is possible to provide a method for obtaining the compound of formula (I) in a simple manner with high yield and high purity. Separation and purification of the reaction product of each step can be carried out by appropriately combining commonly used means. The compounds of formula (IV) and formula (VI) can be directly used for the reaction of the next step without isolation and purification.

Formula (II) used as the starting material
The compound of I) is a known 3-azido-3-deoxy-
From 1,2-O-isopropylideneribose, first, a protecting group such as an acyl group was introduced into the 5-position hydroxyl group, and then the 1- and 2-position hydroxy protecting groups were subjected to elimination reaction to give a compound By reacting the hydroxyl groups at the 1- and 2-positions with an activator, such as an anhydrous acylating agent, the compound of formula (II
It can be a compound of I).

As described above, the method of the present invention provides a method for obtaining a compound of formula (I) from a halogenopurine derivative of formula (II) and a compound of formula (III) by a simple operation in good purity and yield. did it.

The yield in each step of the present invention is extremely high, and the intermediate obtained in each step can be transferred to the next step without isolation and purification.

Formula (IV) and formula (VI) according to the present invention
Are novel compounds. These compounds can be isolated as stable crystals. The above compounds produce the following acids and addition salts. Addition salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Mention may be made of addition salts of sulfonic acids.

The invention will be described in more detail in the following Reference Examples and Examples. Reference Example 1 Method for producing 3-azido-3-deoxy-1,2-isopropylidene-D-ribose 3-azido-3-deoxy-1,
28.07 g of 2-diisopropylidene-D-ribose was dissolved in 100 ml of dioxane, and a suspension of 25.0 g of sodium periodate in 100 ml of aqueous solution was added thereto under ice cooling. After stirring for 30 minutes, the precipitate was filtered off, washed with dioxane, and 100 ml of methanol was added to the filtrate, 5.0 g of sodium borohydride was added under ice cooling, and the mixture was stirred for 30 minutes. After the solvent was distilled off, the mixture was separated with chloroform water, and the aqueous layer was extracted with chloroform. The organic layer was dried and then concentrated to obtain 21 g (86.9%) of 3-azido-3-deoxy-1,2-isopropylidene-D-alofuranose as a yellow oily residue. H ¹ -NMR (δ ppm; CDCl ₃ ): 5.82 (1
H, d, J = 3.7 Hz), 4.75 (1H, t, J =
3.7 Hz, 3.7 Hz, 4.3 to 3.9 (2H,
m), 3.8 to 3.5 (2H, m), 1.59 (3H,
s), 1.38 (3H, s)

Reference Example 2 Production Method of 3-Azido-3-deoxy-1,2,5-triacetylribose a) 21.48 g of the compound obtained in Reference Example 1 was dissolved in 100 ml of acetonitrile and 18.0 triethylamine was added.
ml, acetic anhydride 12.0 ml and a catalytic amount of dimethylaminopyridine were added, and the mixture was stirred at room temperature for 30 minutes. After the reaction,
After concentrating to dryness and separating with chloroform-water, the organic layer was dried and the solvent was distilled off. b) Dissolve the residue in 50 ml of 90% trifluoroacetic acid,
It was left at room temperature. After 20 minutes, the mixture was concentrated to dryness, and toluene was added to the residue for azeotropic drying. c) The residue was dissolved in 100 ml of acetonitrile, 36.0 ml of triethylamine and 24.0 ml of acetic anhydride.
(0.25 mol) and a catalytic amount of dimethylaminopyridine were added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was concentrated to dryness,
The mixture was separated with chloroform-water, the organic layer was dried and the solvent was distilled off to give 2-azido-3-deoxy-1,2,5-triacetylribose (25.9 g, 86%) as a yellow oily residue. Obtained. H ¹ -NMR (δ ppm; CDCl ₃ ): 6.14 (1
H, s), 5.35 (1H, d, J = 4.6 Hz),
4.4-4.0 (4H), 2.18 (3H, s), 2.
11 (3H, s), 2.09 (3H, s) C-NMR (δ ppm; CDCl ₃ ): 170.3,
169.5, 168.7, 98.2, 79.8, 75.
7, 63.7, 60.8, 21.0, 20.5, 20.
6

Example 1 9- (5'-acetyl-3'-azido-3'-deoxyribosyl) -6-chloropurine a) 6-chloropurine 14.0 g, compound 25. To a suspension of 9 g and 200 ml of acetonitrile, 14 ml of trimethylsilyl chloride, 20 ml of hexamethyldisilazane and 18 ml of trimethylsilyltrifluoromethanesulfonate were added, and the mixture was stirred at room temperature.
The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate for neutralization and extracted with chloroform. After the organic layer was dried, the solvent was distilled off, and 9- (5′-acetyl-3′-azido-3′-deoxyribosyl) -6 was obtained.
-Chloropurine was obtained as a brown residue. H-NMR (δ ppm; CDCl ₃ ): 8.70 (1
H, s), 8.22 (1H, s), 6.11 (1H,
d, J = 3.6 Hz), 5.96 (1H, dd, J =
4.1 Hz, 3.0 Hz), 4.70 (1 H, t),
4.2-4.5 (3H, m), 2.20 (3H, s),
2.08 (3H, s) C-NMR (δ ppm; CDCl ₃ ): 170.2,
169.6, 152.1, 152.0, 151.0, 1
44.2, 132.4, 88.0, 80.3, 75.
1,62.7,60.4,20.6

Example 2 9- (3'-azido-3'-deoxyribosyl) -6-
Dimethylaminopurine To the compound obtained in Example 1 was added 200 ml of dimethylamine aqueous solution, and the mixture was stirred at room temperature.
After 4 hours, the mixture was concentrated to dryness, methanol was added to the residue for crystallization, and 9- (3′-azido-3′-deoxyribosyl)-
13.5 g of 6-dimethylaminopurine as colorless crystals
Obtained. H-NMR [(δ ppm; CDCl ₃ -CD ₃ OD
(5: 1)]: 8.20 (1H, s), 7.95 (1
H, s), 5.33 (1H, d, J = 6.8 Hz),
5.0-5.2 (1H, m), 4.2-4.3 (2H,
m), 3.84 (2H, dd, J = 10.5Hz, J =
1.7 Hz), 3.51 (6 H, s) C-NMR (δ ppm; DMSO-d ₆ ): 154.
5,151.7,149.7,138.5,120.
1, 88.3, 83.2, 74.2, 62.2, 61.
8, 38.1, 38.1

Example 3 9- (3'-azido-3'-deoxyribosyl) -6-
Trimethylsilyl chloride 1 was added to a suspension of 14.0 g of dimethylaminopurine 6-chloropurine, 25.9 g of the compound obtained in Reference Example 2 and 200 ml of acetonitrile.
4 ml, hexamethyldisilazane 20 ml, and trimethylsilyl triflate 18 ml were added, and the mixture was heated under reflux for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate for neutralization and extracted with chloroform. After drying the organic layer, the solvent was distilled off to obtain a brown residue. 200 ml of an aqueous dimethylamine solution was added to the residue, and the mixture was stirred at room temperature. After 4 hours, the mixture was concentrated to dryness, methanol was added to the residue for crystallization, and 93.5 g (49%) of 9- (3'-azido-3'-deoxyribosyl) -6-dimethylaminopurine was obtained as colorless crystals. It was The result of instrument analysis is
It was equivalent to Example 2.

Example 4 9- (3'-amino-3'-deoxyribosyl) -6-
Dimethylaminopurine 9- (3'-azido-3'-deoxyribosyl) -6-dimethylaminopurine 13.5 g
Was dissolved in 100 ml of pyridine, 55 g of triphenylphosphine was added, and the mixture was stirred at room temperature for 1 hour, then aqueous ammonia was added, and the mixture was further stirred for 1 hour. After the reaction solution was concentrated to dryness, ether was added and the mixture was rubbed to deposit a precipitate. The precipitate was collected by filtration, dissolved in water, the insoluble material was filtered off, the filtrate was concentrated to dryness, and recrystallized from ethanol to give 9- (3'-amino-
9.65 g (yield 79%) of 3'-deoxyribosyl) -6-dimethylaminopurine was obtained as colorless needle crystals. H-NMR (δ ppm; D ₂ O): 8.10 (1H,
s), 7.81 (1H, s), 5.95 (1H, d, J
= 2.4 Hz), 4.4-4.6 (1 H, m), 3.9
-4.2 (3H, m), 3.5-3.7 (1H, m),
3.15 (6H, s) C-NMR (δ ppm; D ₂ O-Dioxane):
153.4, 151.3, 147.9, 137.3, 1
18.5, 89.1, 84.9, 74.9, 60.7,
51.7, 38.6, 38.6

Example 5 9- (3'-Azido-3'-deoxy-2 ', 3'-diacetylribosyl) -6-dimethylaminopurine Acetic anhydride was added to the compound obtained in Example 2 and stirred at room temperature. After the addition, the reaction solution was concentrated to dryness, and 9- (3'-azido-3'-
Deoxy-2 ′, 3′-diacetylribosyl) -6-dimethylaminopurine was quantitatively obtained. H-NMR (δ ppm; CDCl ₃ ): 8.31 (1
H, s), 7.79 (1H, s), 5.9-6.0 (2
H, m), 4.8-4.9 (1H, m), 4.2-4.
5 (3H, m), 3.51 (6H, s), 2.19 (3
H, s), 2.08 (3H, s) C-NMR (δ ppm; CDCl ₃ ): 170.3,
169.7, 155.0, 152.6, 150.0, 1
37.1, 120.8, 87.8, 79.9 ,. 75.
4,63.0,60.5,38.5,38.5,20.
6,20.5

[0059]

INDUSTRIAL APPLICABILITY 9- (3′-azido-3′-deoxy-D obtained by reacting a 3-azido-3-deoxy-D-ribose derivative with a 6-chloropurine derivative
9- (3'-amino-3'-deoxyribosyl) -6-substituted aminopurine by reacting a -ribofuranosyl) -6-chloropurine derivative with an amine derivative and reducing the resulting 6-amino-substituted product. It was possible to provide a method of obtaining a derivative in a simple manner with high yield and high purity. Further, the compounds of formula (IV) and formula (VI) are useful as intermediates in the production of the compound of formula (I), and the 6-substituted aminopurine derivative described above can be easily produced by way of these compounds. Could be manufactured in good yield and purity.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Takeshi Endo 5 No. 1778 Hirono, Kamiichi-cho, Nakashinkawa-gun, Toyama Prefecture

Claims (6)

[Claims] 1. Formula (IV): (Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom, an acyl group or an alkoxycarbonyl group, and X represents a halogen atom) and a compound of the formula (V) HNR ³ R ⁴ (V) (wherein , R ³ , R ⁴ are the same or different and each represents an alkyl group), and the resulting compound of the formula (VI) (In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, an acyl group, or an alkoxycarbonyl group, and R ³ , R ⁴
Are the same or different and each represents a hydrogen atom or an alkyl group), and a compound of formula (I) (Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above). 2. Formula (II): (Wherein X represents a halogen atom) or a silyl derivative of the compound and a compound of formula (III) (Wherein R ¹ and R ² are the same or different and each represents an acyl group or an alkoxycarbonyl group), and the compound of the formula (IV) (Wherein R ¹ , R ² and X have the same meanings as described above) and a compound of the formula (V) HNR ³ R ⁴ (V) (wherein R ³ , R ⁴ are the same or different and each represents an alkyl group). The compound of formula (VI) obtained by reacting (In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, an acyl group, or an alkoxycarbonyl group, and R ³ , R ⁴
Are the same or different and each represents a hydrogen atom or an alkyl group), and a compound of formula (I) (Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above). 3. The method according to claim 1 or 2, wherein R ³ and R ⁴ are methyl. 4. Formula (IV): (Wherein R ¹ , R ² and X have the same meanings as described above). 5. A compound represented by the formula (VI): (In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, an acyl group, or an alkoxycarbonyl group, and R ³ , R ⁴
Are the same or different and each represents an alkyl group). 6. The compound according to claim 5, wherein R ³ and R ⁴ are methyl.