JP3046834B2 - Method for synthesizing [4 (5) -methylimidazolyl-5 (4)]-methyl-disulfide - Google Patents
Method for synthesizing [4 (5) -methylimidazolyl-5 (4)]-methyl-disulfideInfo
- Publication number
- JP3046834B2 JP3046834B2 JP2237736A JP23773690A JP3046834B2 JP 3046834 B2 JP3046834 B2 JP 3046834B2 JP 2237736 A JP2237736 A JP 2237736A JP 23773690 A JP23773690 A JP 23773690A JP 3046834 B2 JP3046834 B2 JP 3046834B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- disulfide
- methylimidazolyl
- mol
- methylimidazole
- 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 - Lifetime
Links
- 238000000034 method Methods 0.000 title claims description 6
- 230000002194 synthesizing effect Effects 0.000 title claims description 3
- 238000010992 reflux Methods 0.000 claims description 7
- 150000003868 ammonium compounds Chemical class 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- WREDNSAXDZCLCP-UHFFFAOYSA-N methanedithioic acid Chemical compound SC=S WREDNSAXDZCLCP-UHFFFAOYSA-N 0.000 claims description 2
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 7
- 229960001380 cimetidine Drugs 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 2
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- UYJXRRSPUVSSMN-UHFFFAOYSA-P ammonium sulfide Chemical compound [NH4+].[NH4+].[S-2] UYJXRRSPUVSSMN-UHFFFAOYSA-P 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 2
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 2
- 235000019838 diammonium phosphate Nutrition 0.000 description 2
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000019837 monoammonium phosphate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- ZOMATQMEHRJKLO-UHFFFAOYSA-N 1h-imidazol-2-ylmethanol Chemical compound OCC1=NC=CN1 ZOMATQMEHRJKLO-UHFFFAOYSA-N 0.000 description 1
- RYKANBBWRLXVDN-UHFFFAOYSA-N 5-methyl-1h-imidazole;hydrochloride Chemical compound Cl.CC1=CNC=N1 RYKANBBWRLXVDN-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- -1 mercaptan compound Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
Description
【発明の詳細な説明】 産業上の利用分野 本発明は〔４（５）−メチルイミダゾリル−５
（４）〕−メチル−ジスルフィドの合成方法に関するも
のであり、この化合物は消化器潰瘍治療薬シメチジンの
出発原料として使用出来る有用な化合物である。The present invention relates to [4 (5) -methylimidazolyl-5]
(4)]-Methyl-disulfide, which is a useful compound that can be used as a starting material for cimetidine, a therapeutic drug for gastrointestinal ulcer.
発明が解決しようとする課題 消化器潰瘍治療薬シメチジンは米国スミスクライン社
の発明によるものであり、その合成法については、同社
のものを含め多くの製法が今日知られている。それらの
製法の共通点は次のとおりである。Problems to be Solved by the Invention Cimetidine, a therapeutic drug for gastrointestinal ulcer, was invented by SmithKline of the United States, and many synthetic methods are known today, including those of the company. The common points of those manufacturing methods are as follows.
即ち、４−メチルイミダゾールの塩酸塩とフォルマリ
ンとの高圧反応によって４（５）−メチル−５（４）−
ヒドロキシメチルイミダゾールを生成し、次いで塩化チ
オニル等を用いて前記化合物の水酸基を塩素に置換して
４（５）−メチル−５（４）−クロルイミダゾールとな
し、さらに水酸化ナトリウムを用いて４（５）−メチル
−５（４）−メルカプトイミダゾールとし、この４
（５）−メチル−５（４）−メルカプトイミダゾールを
経由して最終目的物であるシメチジンを得るか、あるい
は４（５）−メチル−５（４）−クロルイミダゾールと
必要とするメルカプタン化合物を一挙に反応させてシメ
チジンとするかのいずれかである。That is, 4 (5) -methyl-5 (4)-is obtained by a high-pressure reaction between 4-methylimidazole hydrochloride and formalin.
Hydroxymethylimidazole is produced, and then the hydroxyl group of the above compound is replaced with chlorine using thionyl chloride or the like to obtain 4 (5) -methyl-5 (4) -chlorimidazole, and then 4 (5) using sodium hydroxide. 5) -Methyl-5 (4) -mercaptoimidazole;
(5) -Methyl-5 (4) -mercaptoimidazole is used to obtain the final target product, cimetidine, or 4 (5) -methyl-5 (4) -chlorimidazole and the required mercaptan compound at once. To give cimetidine.
本発明者は前者の方法である４（５）−メチル−５
（４）−メルカプトイミダゾール経由のシメチジンの合
成方法に着目し、シメチジンの合成工程を簡素化させる
ために、４（５）−メチル−５（４）−メルカプトイミ
ダゾールの前駆体となりうる〔４（５）−メチルイミダ
ゾリル−５（４）〕−メチル−ジスルフィドの新規な合
成方法を提供することを目的とした。The present inventors have proposed the former method, 4 (5) -methyl-5.
Focusing on the method of synthesizing cimetidine via (4) -mercaptoimidazole, it can be a precursor of 4 (5) -methyl-5 (4) -mercaptoimidazole in order to simplify the synthesis process of cimetidine [4 (5 ) -Methylimidazolyl-5 (4)]-methyl-disulfide.
課題を解決するための手段 本発明者等は鋭意試験研究を重ねた結果、 構造式 で示される４（５）−メチルイミダゾール−５（４）−
ジチオカルボン酸とアンモニウム化合物の水溶液を加熱
還流したのち、常法に従って後処理をすることにより、
〔４（５）−メチルイミダゾリル−５（４）〕−メチル
−ジスルフィドが得られることを見い出し、本発明を完
遂した。Means for Solving the Problems The present inventors have conducted intensive testing and research and found that the structural formula 4 (5) -Methylimidazole-5 (4)-represented by
After heating and refluxing the aqueous solution of the dithiocarboxylic acid and the ammonium compound, by performing a post-treatment according to a conventional method,
[4 (5) -Methylimidazolyl-5 (4)]-methyl-disulfide was found to be obtained, and the present invention has been accomplished.
本発明の実施に当たって用いられる４（５）−メチル
イミダゾール−５（４）−ジチオカルボン酸は、４−メ
チルイミダゾールと二硫化炭素から容易に得られる。
（特公昭60−29707号公報参照） またアンモニウム化合物の代表的なものとしては、硫
化アンモニウム、燐酸二水素アンモニウム、燐酸水素二
アンモニウム、酢酸アンモニウム、塩化アンモニウム及
び蟻酸アンモニウム等である。4 (5) -Methylimidazole-5 (4) -dithiocarboxylic acid used in the practice of the present invention is easily obtained from 4-methylimidazole and carbon disulfide.
Representative examples of ammonium compounds include ammonium sulfide, ammonium dihydrogen phosphate, diammonium hydrogen phosphate, ammonium acetate, ammonium chloride and ammonium formate.
本発明の〔４（５）−メチルイミダゾリル−５
（４）〕−メチル−ジスルフィドの性質を次示する。[4 (5) -Methylimidazolyl-5] of the present invention
(4)] The properties of -methyl-disulfide are shown below.
構造式 塩基性無色結晶、m.p.176〜179℃（メタノール）水及び
アセトンに可溶。Structural formula Basic colorless crystals, mp 176-179 ° C (methanol) Soluble in water and acetone.
TLC（シリカ，メタノール，I2発色）:Rf0.55〜0.66KBr νcm-1:3400（56）,3210（47）,3120（42）,2990（40） 2920（36）,2610（50）,1605（62）,1467（48） 1405（62）,1355（80）,1282（62）,1250（58） 1242（58）,1230（60）,1190（76）,1155（82） 1075（59）,955（58）,805（55）,750（80） 650（81） カッコ内は透過率（％） NMR（CD3OD）：δ 7.50,d（Ｊ＝4.0Hz）,2H（２位プロ
トン）;3.71,s,4H（メチレン）;2.20,d（Ｊ＝5.86Hz）,
6H（メチル） Mass:m/e256,254（M+）,192, 実施例１ ４（５）−メチルイミダゾール−５（４）−ジチオカ
ルボン酸0.025モル（4.0g）及び燐酸水素二アンモニウ
ム［(NH4)2HPO4］0.025モル（3.3g）を20mlの水と共に
３時間加熱還流した。次いで水層を除去し、残留する不
要物に系が酸性となるまで燐酸水溶液を加えて加温し、
これに活性炭を加えて濾過を行い、その濾液に炭酸カリ
ウムを加えて中和し、析出してくる不要物を濾別除去し
たのち、この濾液を減圧乾固し、乾固物をメタノールで
再結晶して目的物の〔４（５）−メチルイミダゾリル−
５（４）〕−メチル−ジスルフィド1.5g（収率46モル
％）を得た。TLC (silica, methanol, I 2 color): Rf0.55~0.66KBr νcm -1: 3400 ( 56), 3210 (47), 3120 (42), 2990 (40) 2920 (36), 2610 (50), 1605 (62), 1467 (48) 1405 (62), 1355 (80), 1282 (62), 1250 (58) 1242 (58), 1230 (60), 1190 (76), 1155 (82) 1075 (59) ), 955 (58), 805 (55), 750 (80) 650 (81) The transmittance in parentheses (%) NMR (CD 3 OD): δ 7.50, d (J = 4.0 Hz), 2H (2nd position) Proton); 3.71, s, 4H (methylene); 2.20, d (J = 5.86 Hz),
6H (methyl) Mass: m / e256,254 (M + ), 192, Example 1 0.025 mol (4.0 g) of 4 (5) -methylimidazole-5 (4) -dithiocarboxylic acid and 0.025 mol (3.3 g) of diammonium hydrogenphosphate [(NH 4 ) 2 HPO 4 ] with 20 ml of water The mixture was heated under reflux for 3 hours. Then, the aqueous layer was removed, and the remaining unnecessary substances were heated by adding a phosphoric acid aqueous solution until the system became acidic,
Activated carbon was added to the mixture, and the mixture was filtered.The filtrate was neutralized by adding potassium carbonate. Unnecessary substances precipitated were removed by filtration, and the filtrate was dried under reduced pressure. After crystallization, the desired product [4 (5) -methylimidazolyl-
5 (4)]-methyl-disulfide (1.5 g, yield 46 mol%).
実施例２ ４（５）−メチルイミダゾール−５（４）−ジチオカ
ルボン酸0.025モル（4.0g）及び燐酸二水素アンモニウ
ム［NH4H2PO4］0.05モル（5.8g）を30mlの水と共に２時
間加熱還流した。以下実施例１と同様の処理を行い、目
的物の〔４（５）−メチルイミダゾリル−５（４）〕−
メチル−ジスルフィド1.0g（収率30モル％）を得た。Example 2 0.025 mol (4.0 g) of 4 (5) -methylimidazole-5 (4) -dithiocarboxylic acid and 0.05 mol (5.8 g) of ammonium dihydrogen phosphate [NH 4 H 2 PO 4 ] were added together with 30 ml of water. Heated to reflux for an hour. Thereafter, the same treatment as in Example 1 was carried out to obtain the desired product [4 (5) -methylimidazolyl-5 (4)]-
1.0 g of methyl-disulfide (30 mol% yield) was obtained.
実施例３ ４（５）−メチルイミダゾール−５（４）−ジチオカ
ルボン酸0.025モル（4.0g）及び酢酸アンモニウム［CH3
COONH4］0.05モル（3.9g）を20mlの水と共に１時間加熱
還流した。以下実施例１と同様の処理を行い、目的物の
〔４（５）−メチルイミダゾリル−５（４）〕−メチル
−ジスルフィド1.3g（収率40モル％）を得た。Example 3 0.025 mol (4.0 g) of 4 (5) -methylimidazole-5 (4) -dithiocarboxylic acid and ammonium acetate [CH 3
[COONH 4 ] 0.05 mol (3.9 g) was heated to reflux with 20 ml of water for 1 hour. Thereafter, the same treatment as in Example 1 was carried out to obtain 1.3 g (yield 40 mol%) of the target product [4 (5) -methylimidazolyl-5 (4)]-methyl-disulfide.
実施例４ ４（５）−メチルイミダゾール−５（４）−ジチオカ
ルボン酸0.025モル（4.0g）及び塩化アンモニウム［NH4
Cl］0.05モル（2.7g）を50mlの水と共に３時間加熱還流
した。以下実施例１と同様の処理を行い、目的物の〔４
（５）−メチルイミダゾリル−５（４）〕−メチル−ジ
スルフィド0.6g（収率18モル％）を得た。Example 4 0.025 mol (4.0 g) of 4 (5) -methylimidazole-5 (4) -dithiocarboxylic acid and ammonium chloride [NH 4
Cl] (0.05 mol, 2.7 g) was heated to reflux with 50 ml of water for 3 hours. Thereafter, the same processing as in Example 1 is performed, and [4]
0.6 g (yield 18 mol%) of (5) -methylimidazolyl-5 (4)]-methyl-disulfide was obtained.
実施例５ ４（５）−メチルイミダゾール−５（４）−ジチオカ
ルボン酸0.025モル（4.0g）及び蟻酸アンモニウム［HCO
ONH4］0.05モル（3.1g）を40mlの水と共に１時間加熱還
流した。以下実施例１と同様の処理を行い、目的物の
〔４（５）−メチルイミダゾリル−５（４）〕−メチル
−ジスルフィド1.3g（収率40モル％）を得た。Example 5 0.025 mol (4.0 g) of 4 (5) -methylimidazole-5 (4) -dithiocarboxylic acid and ammonium formate [HCO
ONH 4 ] (0.05 mol, 3.1 g) was heated to reflux with 40 ml of water for 1 hour. Thereafter, the same treatment as in Example 1 was carried out to obtain 1.3 g (yield 40 mol%) of the target product [4 (5) -methylimidazolyl-5 (4)]-methyl-disulfide.
実施例６ ４（５）−メチルイミダゾール−５（４）−ジチオカ
ルボン酸0.025モル（4.0g）及び硫化アンモニウム［(NH
4)2S］0.05モル（約6ml）を30mlの水と共にオートクレ
ーブ中に入れ、１時間加熱反応した。以下実施例１と同
様の処理を行い、目的物の〔４（５）−メチルイミダゾ
リル−５（４）〕−メチル−ジスルフィド0.5g（収率15
モル％）を得た。Example 6 0.025 mol (4.0 g) of 4 (5) -methylimidazole-5 (4) -dithiocarboxylic acid and ammonium sulfide [(NH
4) 2 S] placed 0.05 mol (approximately 6ml) in autoclave together with water 30 ml, was heated for 1 hour the reaction. Thereafter, the same treatment as in Example 1 was carried out to obtain 0.5 g of the desired product [4 (5) -methylimidazolyl-5 (4)]-methyl-disulfide (yield 15
Mol%).
発明の効果 従来の方法では高圧反応を行う必要があったが、本発
明の方法によれば安価な出発原料から常圧反応でシメチ
ジンの前駆体を容易に量産することができる。Effect of the Invention In the conventional method, a high-pressure reaction had to be performed. However, according to the method of the present invention, a precursor of cimetidine can be easily mass-produced from an inexpensive starting material by an atmospheric pressure reaction.
Claims (1)
ジチオカルボン酸とアンモニウム化合物の水溶液を加熱
還流させることを特徴とする、構造式 で示される〔４（５）−メチルイミダゾリル−５
（４）〕−メチル−ジスルフィドの合成方法。1. Structural formula 4 (5) -Methylimidazole-5 (4)-represented by
A structural formula characterized in that an aqueous solution of a dithiocarboxylic acid and an ammonium compound is heated to reflux. [4 (5) -methylimidazolyl-5
(4)] A method for synthesizing -methyl-disulfide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2237736A JP3046834B2 (en) | 1990-09-07 | 1990-09-07 | Method for synthesizing [4 (5) -methylimidazolyl-5 (4)]-methyl-disulfide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2237736A JP3046834B2 (en) | 1990-09-07 | 1990-09-07 | Method for synthesizing [4 (5) -methylimidazolyl-5 (4)]-methyl-disulfide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04120061A JPH04120061A (en) | 1992-04-21 |
| JP3046834B2 true JP3046834B2 (en) | 2000-05-29 |
Family
ID=17019714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2237736A Expired - Lifetime JP3046834B2 (en) | 1990-09-07 | 1990-09-07 | Method for synthesizing [4 (5) -methylimidazolyl-5 (4)]-methyl-disulfide |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3046834B2 (en) |
-
1990
- 1990-09-07 JP JP2237736A patent/JP3046834B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04120061A (en) | 1992-04-21 |
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