JPS58134092A - Theobromine derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(R and R<1> are lower alkyl or aryl). EXAMPLE:1-(5-Methylthio-5-methylsulfonylhexyl)-3,7-dimethylxanthine. USE:A precursor for pentoxifylline. PROCESS:A 5-alkyl(or aryl)thio-5-alkyl(or aryl)sulfonylhexyl halide of formula II (X is halogen), e.g. 5-methylthio-5-methylsulfonylhexyl chloride, obtained from an alkyl(or aryl)1-alkyl(or aryl)thioethyl sulfone and a halobutane is reacted with theobromine in the presence of a base, e.g. sodium hydride.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel theopromine derivatives represented by the general formula (wherein R and R1 are the same or different lower alkyl or aryl groups).

The theobromine derivative represented by the above general formula of the present invention can be converted into pentoxifylline by hydrolysis.

Conventionally, as a method for producing pentoxifylline, 9
) A method of reacting theopromine with an ω-haloketone derivative (see Japanese Patent Publication No. 45-21308), ■ A method of reacting theopromine with an ω-sulfonyloxyketone derivative (see Japanese Patent Application Laid-open No. 54-36291), 1+Theobium A method of reacting a silyl derivative of a amine with an ω-haloketone derivative (see 4IIlp! No. 1983-27596)
, 2) A method of introducing a side chain having a hydroxy group into theopromine and oxidizing it [Patent Publication No. 54-22517 C
9-51298)], a method of condensing an a7toacetic acid ester with a haloalkylated product of thioprogin and then decarboxylating it (see Japanese Patent No. 81FI45-21308), (
f) A method of reacting an alkali metal salt of theopromine with a halogenated hexine and then hydrating it (Japanese Patent Laid-Open No. 55-45
See No. 661 χ(t)) Method 1 of reacting theopromine with a hexyl halide having thio and sulfinyl substituents at the gem position, and then hydrolyzing it 1, 1982-15628
0) etc. are known.

However, in the method marked above, since the condensation with the ω-8hekaton derivative is carried out in the presence of a base, the ω-
The base itself cannot avoid attack on the ketone group of the 8-heketone, and by-products are generated. In order to avoid this drawback, a method has been proposed in which the ω-haloketone group is protected as a ketal (see Japanese Patent Publication No. 54-44698). Industrial methods □ and Iyō are disadvantageous because they require several reaction techniques. On the other hand, method - requires a multi-step reaction process in order to obtain the ω-sulfonyloxyketone derivative that serves as the other raw material.

Therefore, even if the condensation of theopromine and ω-sulfonytetraoxyketone itself proceeds with a good yield, the synthesis of raw materials for the condensation itself is not easy and cannot be adopted as an industrial method at all. In addition, method C→ uses a silylated form of thioproquine as a raw material, but this raw material is manufactured from theopromine using an expensive silylating agent, and theopromine was considered to be the starting material. However, this method is not attractive as an industrial method because the reaction process is long and the operations are complicated. Furthermore, in the method (2), it is not easy to produce the human stomach xyalkylated theopromine itself, which is the raw material. In addition, in the method (to), selective production of the tetraalkylated product of theop0<n as a raw material K11
111 points are 111'l', ', 1. In order to selectively obtain only the target product, K is the reaction condition □...
,.

It is difficult to set up the items. In addition, method (2) is not preferable for water conservation, and because it uses highly toxic heavy metal salts, the product is not suitable for use as a medicine. In addition, in the method (g), a mixture of exo and endo cis and trans isomers of theop-a(one derivative ferthiosubstituted olefin) is produced, which is difficult to industrially purify. It's hard to say.

The present inventors have made intensive studies to overcome these drawbacks of conventional methods, and have discovered that the theopromine derivative represented by the above general formula (1) is an excellent pentoxifylline precursor, and have developed the present invention. was completed.

The compound of the present invention can be produced, for example, by the method shown below.

5-alkyl (or aryl) thio-5-alkyl (or aryl) sulfonylhexyl group represented by the general formula (where B and W are as described above, and X is a halogen atom) React with light totheopromine in the presence of a base.

Examples of bases used include alkali metal hydrides such as sodium hydride and potassium hydride, sodium carbonate,
Alkali metal carbonates such as potassium carbonate, alkyllithiums such as butyllithium, lithium dialkylamides such as lithium diisopropylamide, lithium diethylamide, etc. can be used.

It is preferable to use a solvent for the reaction, such as diethyl ether, tetrahydrochloride, dioquinone, etc.f)
Ether solvents, aliphatic and aromatic hydrocarbons such as hexane and benzene toluene, polar aprotic solvents such as dimethylformamide, etc. can be used.

The reaction proceeds at -78 to 150°C, and varies depending on the base and solvent used, but for example, when using sodium hydride as the base and dimethylformamide as the solvent,
A suitable temperature is 0 to 100°C.

In this case, the reaction proceeds while forming an alkali metal salt of theobium 0(
It is also possible to prepare and use an alkali metal salt of the same.

In addition, the general formula (5-
Alkyl(or aryl)thio-5-alkyl(or aryl)sulfonylhexyl halide general formula (Otori) (wherein, B and W are as described above). (or aryl) thioethyl:: sulfone and general formula 〇 (wherein, X and
l is a hydrogen atom. ) is obtained by reacting dihalobutane with dihalobutane (see Reference Examples below).

In addition, the alkyl (or aryl) 1-alkyl (or aryl) thioethyl sulfone represented by the general formula (1) is a compound that can be easily obtained from acetaldehyde (see reference example below); Examples include 1-methylthioethylsulfone, ethyl 1-ethylthioethylsulfone, phenyl 1-phenylthioethylsulfone, and methyl 1-phenylthioethylsulfone.

Theobromine, the other raw material, is easily available industrially and is a compound that has already been used as a raw material for producing pentoxifylline.
” 111j j.

Method - 1- represented by 雫 (in the formula, X is the above-mentioned 89)
(4-Halobutyl)-3,7-dimethylxanthine and alkyl (or aryl) represented by the general formula
React with 1-alkyl (or monoyl) thioethyl sulfone in the presence of a base.

Examples of the base to be used include lithium dialkylamides such as lithium tetraviramide, lithium diethyl and the like, and alkyl lithiums such as butyllium and the like.

In carrying out the reaction, it is preferable to use a solvent, including ethereal solvents such as diethyl ether, tetrahydrofuran and dioxane, aliphatic and aromatic hydrocarbons such as hexane, benzene and toluene, and polar non-solvents such as dimethylformand. Proton solvents and round threads made of combinations of these solvents can be suitably used.

The reaction proceeds at a temperature of -78 to 150°C, but a temperature of -78 to 30°C is preferred from the viewpoint of smooth reaction. This is a compound obtained by reacting dihalobutane with dihalobutane.

The theobromine derivative represented by general formula (j) is
It is hydrolyzed in the presence of mineral acids such as hydrochloric acid and sulfuric acid, or Lewis acids such as aluminum chloride, titanium trichloride, and titanium tetrachloride, to give pentoxifylline in quantitative yield (see reference examples below). ,.

The present invention will be explained in more detail below using Reference Examples and Examples.

Reference example 1 Methyl mercap p y in a flask while cooling with cryogen
(0.94mol, 459) was collected, acetaldehyde (0.46mol 1.20JF) and hydrochloric acid (3.5g1) were added thereto, and the temperature was gradually raised to room temperature.2.
Stir for 5 hours.

Further, the mixture was stirred at room temperature for 1 hour while blowing hydrogen chloride gas. The reaction solution was washed with water and dilute aqueous sodium hydroxide solution, and then dried over anhydrous magnesium sulfate. Distillation (15
4-156°C) diacetaldehyde dimethyl mercaptal (34.08jl) was obtained.

Yield 61107 Heptaldehyde dimethyl mercaptal (0.12 mo 1.14.041) was dissolved in acetic acid (25 t
7) Dissolve K and add 30-hydrogen peroxide solution (0,12
mol.

12.98.9) was added dropwise. After stirring for 1 hour under water cooling and 14.5 hours at room temperature, methylene chloride (50 shakes/h) was added, and the mixture was neutralized with potassium legate. The reaction solution was extracted with methylene chloride, and the organic phase was dried over sodium sulfate and potassium carbonate. The solvent was evaporated to give methyl 1-methylthioethyl sulfoxide (14,61>), which was used in the next reaction without further purification.
v) and water ('20 y) K, combed, and powdered potassium permanganese on a water bath (0.11 mol.

16.7 g) was added little by little. The mixture was further warmed to room temperature and stirred until the purple color of the reaction solution disappeared. After the solid matter in the reaction solution was filtered off, the filtrate was concentrated, and the residue was dissolved again in methylene chloride and dried over sodium sulfate.

The nine reaction products obtained by distilling off the solvent were purified by column chromatography (silica gel, methylene chloride) to obtain methyl 1-methylthioethyl sulfone (13,48SJ
F) was obtained as colorless crystals. Yield: 76 cm.

Reference Example 2 Under an argon atmosphere, methyl 1-methylthioethylsulfone (9.9 mmof, 1.52 g) was dissolved in anhydrous THF (3
A hexane solution (15%) (6,411I) of n-butyllithium was added dropwise at -78°C, and 1
Stir for 5 minutes. Once the temperature was raised to 0°C 1:・□, it was cooled again to -78°C and 1,4-dichlorobutane (
11.7 mmol, 1.49 Ji') was added dropwise.
Stirred for 0 minutes.

The mixture was further heated at KO°C for 10 minutes and then at room temperature for 22 hours.

Water was added to the reaction mixture, extracted with methylene chloride, and the organic phase was dried over potassium legate and magnesium sulfate, and then the solvent was distilled off. The obtained reaction product was subjected to column chromatography (
The product was purified using silica gel, a 3:1 mixed solvent of methylene chloride and n-hexane) to obtain 5-methylthio-5-methylsulfonylhexyl tetralide (1,31,9) as a colorless liquid. Yield 6262-0N: 60MHz, jppm (
CDqr-, Le 1.57 (3H.

s) t 1.4-2.3 (6H, m), 2.24 (
3H,s).

3.03(3)1. s), 3.57 (2H, m).

IR(neat): 1294, 1140cIt.

Example 1 Sodium hydride A (1.7 mmoJ, 0.0B29
．． 50S oil) was washed with n-hexane, dimethylforma was used as a suspension (7 w/), and thioprone (1
, 4 mmol, 0.25 N) and stirred at 100° C. for 30 minutes. After returning to room temperature, 5-methylthio-5-methylsulfonylhexyl chloride (1.7 mmol) was added.

A solution of 0.36.9) in dimethylformamide (3 m/) was added and pressed at 100°C for 4 hours. Water was added to the reaction mixture, extracted with dichloroform, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1-(5-If%
Thio-5-methylsulfonylhexyl)-3,7-dimethylxanthine (0.36 g) was obtained as crystals. Yield: 67 cm. For elemental analysis, recrystallization was performed using an inproper tool.

Melting point: 114-116°C.

Elemental analysis value: C45H24N4S204° Theoretical value: C
, 46, 37; H, 6, 23, N, 14.42.

S, 16.51%.

Actual value: C, 46, 50: H, 6, 18; N, 14
．． 45: 8.16.27 Rumor.

NMR: 60MHz, jppm (CDCl2).

1.53 (s, 5H), 1.50-2.10 (m,
6H).

2.23 (s, 5H),! 1.00 (s, 5H),! 1
．． 5ri (s, 3H), 3.93 (s, 5H),
3.77-4.15 (-2H), 7.20 (s, IH
).

IR(KBr): 2950,1710.1665,1
558°1283, 1140c+a.

Reference Example 3 l-(5-Me?ruthio-5-methylsulfonylhexyl)-3,7-dimethylxanthine (0,26 mmoj,
100sv) was dissolved in methanol (5*/), concentrated hydrochloric acid (0.3ml) was added, and the mixture was stirred at 70°C for 2 hours.

Water was added, neutralized with sodium carbonate, and extracted with chlorotetraform. After washing the extract with water and drying with magnesium sulfate,
The solvent was distilled off under reduced pressure to obtain pentoxifylline (70%) as crystals. Yield: 97 cm.

For elemental analysis, recrystallization was performed from isopropanol6
, 1' (1 melting point = 104~1
05℃.

Elemental analysis value 13H1BN403 ffl1m value: C, 56, 10, 11, 6, 52; N
, 20.13%.

Actual measurements: C, 56,05, H, 6,42, N, 20.
Section 15.

NM: 60MHz, Jppm (CDCI, ).

7.44 (@, IH), 5.9Hm 101.
5H), 3.53(s, 3H), 2.20~2
．． 63 (m, 2H), 2.13 (s, 3H), 1
．． 40-1.87 (m, 2H).

Patent Applicant Procedures Amendment (Spontaneous) December 27, 1980 Commissioner of the Patent Office Kazuo Wakasugi 1゜Indication of Case 1982! Patent Application No. 16287 2゜Name of the Invention Theobromine Derivative 36 Relationship with the Amendment Case Patent Applicant 5, Contents of the Supplement (1) 'T between lines 5 and 6 on page 16 of the specification of the present application
” Insert nj:.

Reference Example 4 Diisopropylamide 7 (767W, 7.58mmo/
) in anhydrous THF (5d) solution at 78c in butyllithium-hexane solution (4,35IIL, 6.5mm
) was added dropwise, and the mixture was further stirred with OC for 5 minutes. this,
Methyl 1-methylthioethylsulfone (1,001g,
6.49 mmol) of anhydrous THF (10 rats) and stirred with IO molecules for 20 min.
Cool to 8C and l-bromo-4-rioo-butane (1,
45 g, 8.46 mmoJ) of anhydrous THF (10 ml
> Slowly inject the solution tube into the skin. -78U for 1 hour, OC for 1 hour, and room temperature for 0.5 hours. Pumped water 201117 was added and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate, and subjected to reduced pressure 111I#i, and the resulting reaction product was purified by column chromatography (silica gel, chloroform) to obtain 5-methylthio-5-methylsulfonylhexyl chloride. (1,261 g) was obtained as a colorless liquid.

Yield 79%.

NM几I)L is the same as Reference Example 2.

Elemental analysis value: C, H170□S, C4 theoretical value: U
, 39.25; H+ 7.00; St 26.19;
C/, 14.48 chi.

Real piece ringing @: C, 39, 13; H, 7, 04;
8. 26.05;C1,14,59L''

Claims (1)

[Scope of Claims] A thioprooxy derivative represented by the general formula (wherein B and B1 are the same or different lower alkyl groups or aryl groups)0