JPS6138198B2 - - Google Patents
Info
- Publication number
- JPS6138198B2 JPS6138198B2 JP54095261A JP9526179A JPS6138198B2 JP S6138198 B2 JPS6138198 B2 JP S6138198B2 JP 54095261 A JP54095261 A JP 54095261A JP 9526179 A JP9526179 A JP 9526179A JP S6138198 B2 JPS6138198 B2 JP S6138198B2
- Authority
- JP
- Japan
- Prior art keywords
- theobromine
- general formula
- reaction
- represented
- oxohexyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical class CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 10
- 229960004559 theobromine Drugs 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- -1 5-oxohexyl halide Chemical class 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- DJUPAAZTISXZSF-UHFFFAOYSA-N 6-iodohexan-2-one Chemical compound CC(=O)CCCCI DJUPAAZTISXZSF-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- APQHKWPGGHMYKJ-UHFFFAOYSA-N Tributyltin oxide Chemical compound CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC APQHKWPGGHMYKJ-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
【発明の詳細な説明】
本発明は新規テオブロミン誘導体及びその製法
に関し、更に詳しくは一般式
（但し、Ｒは低級アルキル基を表わす。）
で示される新規テオブロミン誘導体及びその製法
に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel theobromine derivative and a method for producing the same, more specifically, the general formula (However, R represents a lower alkyl group.) The present invention relates to a novel theobromine derivative represented by the following and a method for producing the same.
本発明の化合物〔〕は新規化合物であり、
N1位に置換基を有するテオブロミン誘導体、例
えば冠血管拡張作用及び赤血球変形能改善作用を
有する１―（５―オキソヘキシル）テオブロミン
を合成するための出発原料として極めて有用な化
合物である。 The compound [] of the present invention is a new compound,
It is an extremely useful compound as a starting material for the synthesis of theobromine derivatives having a substituent at the N1 position, such as 1-(5-oxohexyl)theobromine, which has coronary vasodilation and red blood cell deformability-improving effects.
従来１―（５―オキソヘキシル）テオブロミン
を合成する方法としては、テオブロンのアルカリ
金属塩に５―オキソヘキシルハライドを作用させ
る方法が知られている。（特公昭45−21308）。し
かしながら、該方法は強アルカリ性条件下比較的
高温で実施しなければならず工業的に必らずしも
有利な方法でなかつた。 As a conventional method for synthesizing 1-(5-oxohexyl)theobromine, a method in which 5-oxohexyl halide is reacted with an alkali metal salt of theobrone is known. (Special Publication 1977-21308). However, this method had to be carried out under strongly alkaline conditions and at a relatively high temperature, and was not necessarily an advantageous method from an industrial perspective.
本発明者らは、種々研究を重ねた結果、前記一
般式〔〕で示される１―（トリアルキルスタニ
ル）テオブロミンがN1位に置換基を有するテオ
ブロミン誘導体の出発原料として極めて有用であ
ることを見出し、本発明を完成するに至つた。 As a result of various studies, the present inventors have found that 1-(trialkylstannyl)theobromine represented by the above general formula [] is extremely useful as a starting material for theobromine derivatives having a substituent at the N1 position. They discovered this and completed the present invention.
本発明によれば、化合物〔〕はテオブロミン
と一般式
（但し、Ｒは前記と同一意味を有する。）
で示されるビス（トリアルキル錫）オキサイドを
反応させることにより容易に製することができ
る。ビス（トリアルキル錫）オキサイドの好まし
い例としては、前記一般式〔〕においてＲがメ
チル基、エチル基、ｎ―プロピル基、ｎ―ブチル
基、ｎ―ペンチル基である化合物が挙げられ、よ
り好ましくはＲがｎ―ブチル基である化合物が挙
げられる。 According to the present invention, the compound [] is theobromine and the general formula (However, R has the same meaning as above.) It can be easily produced by reacting the bis(trialkyltin) oxide shown below. Preferred examples of bis(trialkyltin) oxide include compounds in which R is a methyl group, ethyl group, n-propyl group, n-butyl group, or n-pentyl group in the general formula [], and more preferably Examples include compounds in which R is an n-butyl group.
本反応は適当な溶媒中加熱下に好適に実施する
ことができる。反応溶媒としては、例えばベンゼ
ン，トルエン，キシレン等の不活性溶媒が好まし
い。また反応温度は50℃〜250℃が好ましい。と
りわけ本反応は反応溶媒の沸点下に加熱還流し
て、生成する水を共沸にて除去しつつ実施するの
がよい。この場合反応の終点は初めけん濁状態に
あるテオブロミンが溶消し、かつ還流溶媒中に水
分が共沸して来なくなることによつて知ることが
できる。生成した化合物〔〕の単離は、例えば
反応混合物を減圧下に濃縮し、残油分を減圧蒸留
に附すことにより容易に実施することができる。 This reaction can be suitably carried out under heating in a suitable solvent. As the reaction solvent, inert solvents such as benzene, toluene, and xylene are preferred. Moreover, the reaction temperature is preferably 50°C to 250°C. In particular, this reaction is preferably carried out while heating to reflux below the boiling point of the reaction solvent and removing the produced water azeotropically. In this case, the end point of the reaction can be determined by the fact that theobromine, which is initially in a suspended state, dissolves and water ceases to azeotrope into the refluxing solvent. The produced compound [] can be easily isolated, for example, by concentrating the reaction mixture under reduced pressure and subjecting the residual oil to distillation under reduced pressure.
かくして得られた化合物〔〕はN1位置換テ
オブロミンの出発原料として有用な化合物であ
り、例えば該化合物〔〕を５―オキソヘキシル
ハライド（例えば、５―オキソヘキシルヨージ
ド，５―オキソヘキシルブロミド）と縮合させる
ことにより、医薬として有用な１―（５―オキソ
ヘキシル）テオブロミンを製することができる。
本縮合反応は適当な溶媒（例えば、１，２―ジク
ロルエタン，アセトニトリル）中加熱下に好適に
実施することができる。 The thus obtained compound [] is a useful compound as a starting material for N -1 -substituted theobromine. 1-(5-oxohexyl)theobromine, which is useful as a medicine, can be produced by condensation with
This condensation reaction can be suitably carried out under heating in a suitable solvent (eg, 1,2-dichloroethane, acetonitrile).
実施例 １
テオブロミン18.0ｇ，ビス（トリ―ｎ―ブチル
錫）オキサイド35.64ml及びトルエン200mlの混合
物をデイーン・スターク型反応装置にて共沸して
生成する水分を分離除去しつつ24時間加熱還流す
る。反応液を減圧下に濃縮し、残油分を減圧蒸留
することにより、１―トリ―ｎ―ブチルスタニ
ル）テオブロミン46ｇを油状物として得る。収率
98％B.p.189℃（0.6mmHg）
Mass；ｍ／ｅ；412（M+−C4H9）299，297，
215，180，162，109，82
UV；λＣＣｌ ４ｎａｘ．280nm.
NMR（CCl4）δ：0.5−2.4（ｍ，27H），3.53
（Ｓ，3H，３−CH3），3.98（ｓ，3H，
７−CH3），7.42（ｓ，1H，８−Ｈ）
参考例 １
１−（トリ―ｎ―ブチルスタニル）テオブロミ
ン4.69ｇの１，２−ジクロルエタン50ml溶液に、
５−オキソヘキシルヨージド2.37ｇを加えて加熱
還流下に一夜かく拌する。反応液を減圧下に濃縮
し、残査にジクロルメタン150mlを加えて溶解す
る。該溶液を水洗し、乾燥後溶媒を減圧留去す
る。残査をシリカゲルクロマトグラフイー（溶
媒；クロロホルム：アセトン＝10：３）で精製し
た後，イソプロパノールから再結晶することによ
り、１−（５−オキソヘキシル）テオブロミン
2.03ｇを得る。収率73％M.p.101℃〜103℃。Example 1 A mixture of 18.0 g of theobromine, 35.64 ml of bis(tri-n-butyltin) oxide, and 200 ml of toluene was azeotropically distilled in a Dean-Stark reactor, and the resulting water was separated and removed while heating under reflux for 24 hours. . The reaction solution was concentrated under reduced pressure, and the residual oil was distilled under reduced pressure to obtain 46 g of 1-tri-n-butylstannyl)theobromine as an oil. yield
98%Bp189℃ (0.6mmHg) Mass; m/e; 412 (M + −C 4 H 9 ) 299, 297,
215, 180, 162, 109, 82 UV; λ CCl 4nax. 280nm. NMR (CCl 4 ) δ: 0.5-2.4 (m, 27H), 3.53
(S, 3H, 3-CH 3 ), 3.98 (s, 3H,
7-CH 3 ), 7.42 (s, 1H, 8-H) Reference Example 1 In a solution of 4.69 g of 1-(tri-n-butylstannyl)theobromine in 50 ml of 1,2-dichloroethane,
Add 2.37 g of 5-oxohexyl iodide and stir under heating under reflux overnight. The reaction solution was concentrated under reduced pressure, and 150 ml of dichloromethane was added to the residue to dissolve it. The solution is washed with water, dried, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel chromatography (solvent: chloroform:acetone = 10:3) and then recrystallized from isopropanol to obtain 1-(5-oxohexyl)theobromine.
Obtain 2.03g. Yield 73% Mp 101℃~103℃.
Claims (1)
る特許請求の範囲第１項記載の化合物。 ３ 一般式 （但し、Ｒは低級アルキル基を表わす。） で示されるビス（トリアルキル錫）オキサイドと
テオブロミンを反応させることを特徴とする一般
式 （但し、Ｒは前記と同一意味を有する。） で示されるテオブロミン誘導体の製法。 ４ 一般式〔〕においてＲがｎ―ブチル基であ
る特許請求の範囲第３項記載の製法。[Claims] 1. General formula (However, R represents a lower alkyl group.) Theobromine derivative 2 represented by the following: The compound according to claim 1, wherein R in the general formula [] is an n-butyl group. 3 General formula (However, R represents a lower alkyl group.) A general formula characterized by reacting bis(trialkyltin) oxide and theobromine represented by (However, R has the same meaning as above.) A method for producing a theobromine derivative represented by the following. 4. The production method according to claim 3, wherein R in the general formula [] is an n-butyl group.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9526179A JPS5618991A (en) | 1979-07-25 | 1979-07-25 | Theobromine derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9526179A JPS5618991A (en) | 1979-07-25 | 1979-07-25 | Theobromine derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5618991A JPS5618991A (en) | 1981-02-23 |
| JPS6138198B2 true JPS6138198B2 (en) | 1986-08-28 |
Family
ID=14132815
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9526179A Granted JPS5618991A (en) | 1979-07-25 | 1979-07-25 | Theobromine derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5618991A (en) |
-
1979
- 1979-07-25 JP JP9526179A patent/JPS5618991A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5618991A (en) | 1981-02-23 |
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