JPH04182470A - Method of preparing n-cyano-n'-methyl-n"-(2-(((5- methyl-1h-4-imidazolylmethyl)methyl)thio)ethyl) guanidine - Google Patents
Method of preparing n-cyano-n'-methyl-n"-(2-(((5- methyl-1h-4-imidazolylmethyl)methyl)thio)ethyl) guanidineInfo
- Publication number
- JPH04182470A JPH04182470A JP2308947A JP30894790A JPH04182470A JP H04182470 A JPH04182470 A JP H04182470A JP 2308947 A JP2308947 A JP 2308947A JP 30894790 A JP30894790 A JP 30894790A JP H04182470 A JPH04182470 A JP H04182470A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- thio
- formula
- trimethylsilyl
- mmol
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title description 10
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 title description 6
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 title description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 title description 3
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960001380 cimetidine Drugs 0.000 claims abstract description 14
- MHGGQXIPBPGZFB-UHFFFAOYSA-N methyl n-cyano-n'-methylcarbamimidothioate Chemical compound CSC(=NC)NC#N MHGGQXIPBPGZFB-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000004519 manufacturing process Methods 0.000 claims description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 8
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 5
- GWYSIEWOWQGMRA-UHFFFAOYSA-N 2-trimethylsilylsulfanylethanamine Chemical compound C[Si](C)(C)SCCN GWYSIEWOWQGMRA-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 3
- QPRIOGQBGWABFY-UHFFFAOYSA-N 1-trimethylsilylethanamine Chemical compound CC(N)[Si](C)(C)C QPRIOGQBGWABFY-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003699 antiulcer agent Substances 0.000 abstract description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 2
- 150000002541 isothioureas Chemical class 0.000 abstract 1
- -1 methyl-IH-4-imidazolyl Chemical group 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 description 3
- APZXPRHPPCTRHN-UHFFFAOYSA-N 4-(chloromethyl)-5-methyl-1h-imidazole Chemical compound CC=1NC=NC=1CCl APZXPRHPPCTRHN-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000000370 acceptor Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 3
- 239000003513 alkali Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- KHOQXNHADJBILQ-UHFFFAOYSA-N trimethyl(sulfanyl)silane Chemical compound C[Si](C)(C)S KHOQXNHADJBILQ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、式（Ｉ）
シメチヂン
のＮ−シアノ−Ｎ′−メチル−Ｎ”−［２−［［（５−
メチル−ＩＨ−４−イミダゾリル）メチル〕チオコニチ
ル］グアニジンの製造のための新規且つ改善された方法
に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to N-cyano-N'-methyl-N''-[2-[[(5-
A new and improved process for the production of methyl-IH-4-imidazolyl)methyl]thioconityl]guanidine.
本発明を要約すれば、Ｎ−シアノ−Ｎ゛−メチル−Ｎ”
−［２−［［（５−メチル−ＩＨ−４−イミダゾリル）
メチル］チオ］エチル］グアニジンは、式のＮ−シアノ
−Ｎ゛−メチル−８−メチル−イソチオ尿素を、式（ｎ
）
式中、Ｘは、Ｃ１、Ｂｒ、１１０−Ｔｓ又はＯ−Ｍｅｓ
である、
の化合物の一つと２− ［（トリメチルシリル）チオコ
ニタンアミンとの反応の生成物と反応させることにより
製造されることである。To summarize the present invention, N-cyano-N゛-methyl-N”
-[2-[[(5-methyl-IH-4-imidazolyl)
Methyl]thio]ethyl]guanidine converts N-cyano-N'-methyl-8-methyl-isothiourea of the formula (n
) where X is C1, Br, 110-Ts or O-Mes
is prepared by reacting one of the compounds with the product of the reaction of 2-[(trimethylsilyl)thioconitanamine.
シメチヂンという名称で知られている式（Ｉ）の化合物
は周知の抗潰瘍剤であり、治療上広（使用されている。The compound of formula (I), known under the name cimetidine, is a well-known anti-ulcer agent and is widely used therapeutically.
現在、シメチヂンの製造に数種の方法が知られており、
例えばＥＳ第４７６０７３号、ＥＳ第４８５８５６号、
ＡＴ第３６６３７３６号及びＤＥ第３２２３８０２号に
開示されているように、最も利用されている方法は下記
のように表すことができる：
しかし上記方法は・
１）両工程の反応の副生物としてメチルメルカプタンが
生成すること；
２）例えば下記の加水分解的転換化合物：Ｎ−シアノ−
Ｎ’−［２−［［（５−メチル−ＩＨ−４−イミダゾリ
ル）メチル］チオ］エチル］尿素Ｎ−メチル−Ｎ’−［
２−［［（５−メチル−ＩＨ−４−イミダゾリル−４−
イル）メチル］チオ］エチル］尿素
等のシメチヂンの幾つかの“典型的な”不純物の形成を
必ず伴う、水性雰囲気中での縮合を行うこと；のような
、幾つかの欠点を有している。Currently, several methods are known for producing cimetidine.
For example, ES No. 476073, ES No. 485856,
As disclosed in AT 3,663,736 and DE 3,223,802, the most utilized process can be expressed as follows: However, the above process: 1) Methyl mercaptan as a by-product of the reaction in both steps. 2) For example, the following hydrolytically converted compounds: N-cyano-
N'-[2-[[(5-methyl-IH-4-imidazolyl)methyl]thio]ethyl]urea N-methyl-N'-[
2-[[(5-methyl-IH-4-imidazolyl-4-
It has several disadvantages, such as carrying out the condensation in an aqueous atmosphere, which necessarily involves the formation of some "typical" impurities of cimetidine, such as yl)methyl]thio]ethyl]urea. There is.
本発明の方法は、無水的雰囲気中でのシメチヂンの製造
を可能とするものである。更に本発明は、−数式■の適
当なイミダゾールから出発して単一工程で完遂される。The method of the present invention allows the production of cimetidine in an anhydrous atmosphere. Furthermore, the invention can be accomplished in a single step starting from a suitable imidazole of the formula (1).
更なる利点は、反応に使用されるメルカプタンの大部分
を、より一層揮発性で、取り扱い易（、且つ廃棄し易い
トリメチルシリルメルカプタンで置き換えたことに関係
する。A further advantage relates to the replacement of most of the mercaptan used in the reaction with trimethylsilyl mercaptan, which is more volatile and easier to handle (and dispose of).
本工程は下記の反応径路図で説明される：上記の反応径
路図において、Ｘは、Ｃ１、Ｂｒ、Ｔ、 Ｏ−Ｔ ｓ、
Ｏ−Ｍｅ ｓのような置換し易い基である。This process is illustrated in the following reaction path diagram: In the above reaction path diagram, X is C1, Br, T, OT s,
It is an easily substituted group such as O-Me s.
化合物■と２− ［（トリメチルシリル）チオロ−エタ
ンアミンは、好適にはアセトニトリル、Ｎ、Ｎ−シメチ
ルホルムアミド及びニトロメタンのような溶剤中で、必
要に応じ、１，４−ジアザビシクロ［２，２，２］オク
タン、トリエチルアミン、ジイソプロピルエチルアミン
及び類似物のような酸受容体及び例えばトリメチルシリ
ル沃化物及びアルカリ沃化物の存在において行われる。Compounds ■ and 2-[(trimethylsilyl)thiolo-ethanamine are optionally combined with 1,4-diazabicyclo[2,2,2 ] in the presence of acid acceptors such as octane, triethylamine, diisopropylethylamine and the like and e.g. trimethylsilyl iodide and alkali iodide.
シメチヂンは、単一工程で実施することにより高収率及
び高純度で得られることが好ましい。下記の実施例は更
に本発明を説明するものである。Cimetidine is preferably obtained in high yield and purity by carrying out in a single step. The following examples further illustrate the invention.
実施例 １
１３９ （１００ミリモル）の５−クロロメチル−５−
メチル−ＩＨ−イミダゾールｎ（Ｘ＝ＣＩ）を２００８
１のアセトニトリルに溶解した１５９（１００ミリモル
）の２− ［（トリメチルシリル）チオコーエタンアミ
ンと混合する。混合物を撹拌しながら１１．２５９ （
１００ミリモル）の１．４−ジアザビシクロ［２，２，
２］オクタン及び触媒としてＫＩを添加し、混合物を６
時間還流する。Example 1 139 (100 mmol) of 5-chloromethyl-5-
Methyl-IH-imidazole n (X=CI) 2008
Mix 159 (100 mmol) of 2-[(trimethylsilyl)thiokoethanamine dissolved in 1 part of acetonitrile. 11.259 ( while stirring the mixture
100 mmol) of 1,4-diazabicyclo[2,2,
2] Add octane and KI as catalyst and reduce the mixture to 6
Reflux for an hour.
５３ｍＡ’のアセトニトリルに溶解した１２．９９（１
００ミリモル）のＮ−シアノ−Ｎｏ−メチル−８−メチ
ル−イソチオ尿素を添加し、そこから反応の進行を薄層
クロマトグラフィーにより観察しながら、イソチオ尿素
が消滅するまで還流を継続する。12.99 (1
00 mmol) of N-cyano-No-methyl-8-methyl-isothiourea is added, and reflux is continued until the isothiourea disappears while observing the progress of the reaction by thin layer chromatography.
終わりに溶剤を減圧下で蒸発し、残留物を１０ＱｍＡ’
の１０％ＨＣＩで回収する。得られる水相を５０１のト
ルエンで洗浄し、両相を分離する。水相のｐＨをＮＨ，
ＯＨで９に調節し、濾過する。At the end the solvent was evaporated under reduced pressure and the residue was reduced to 10QmA'
Collect with 10% HCI. The resulting aqueous phase is washed with 501 g of toluene and the two phases are separated. The pH of the aqueous phase is NH,
Adjust to 9 with OH and filter.
粗製生成物をイソプロピルアルコールで再結晶する。融
点１４０．５℃のシメチヂンが得られる（収率は、４−
クロロメチル−５−メチル−ＩＨ−イミダゾールを基準
として８８％である）。The crude product is recrystallized from isopropyl alcohol. Cimetidine with a melting point of 140.5°C is obtained (yield: 4-
88% based on chloromethyl-5-methyl-IH-imidazole).
実施例 ２
２６．６９ （１００ミリモル）の４−トシルオキソ−
メチル−５−メチル−ＩＨ−イミダゾール（■）（此処
でＸ＝Ｏ−Ｔｓ）を２００１１のアセトニトリルに溶解
した１５９（１００ミリモル）の２− ［（トリメチル
シリル）チオロ−エタンアミンと混合する。反応は実施
例１と同様に行われる。Example 2 26.69 (100 mmol) of 4-tosyloxo-
Methyl-5-methyl-IH-imidazole (■) (where X=O-Ts) is mixed with 159 (100 mmol) of 2-[(trimethylsilyl)thiolo-ethanamine dissolved in 20011 acetonitrile. The reaction is carried out analogously to Example 1.
融点１４０℃のシメチヂンが得られる（収率は４−トシ
ルオキシ−メチル−５−メチル−ＩＨ−イミダゾールを
基準として８１％である）。Cimetidine with a melting point of 140 DEG C. is obtained (yield 81% based on 4-tosyloxy-methyl-5-methyl-IH-imidazole).
実施例 ３
１３９ （１００ミリモル）の４−クロロメチル−５−
メチル−ＩＨ−イミダゾール■（此処でＸ＝０１）を２
００ｍ１のＮ、Ｎ−ジメチルホルムアミドに溶解した１
５９ （１００ミリモル）の２−［（トリメチルシリル
）チオロ−エタンアミンと混合する。混合物を撹拌しな
がら１１．２５ｇ（１００ミリモル）の１．４−ジアザ
ビシクロ［２，２，２］オクタン及び触媒としてＫｌを
添加し、次いで混合物を１００℃に５時間加熱する。Example 3 139 (100 mmol) of 4-chloromethyl-5-
Methyl-IH-imidazole■ (here X=01) is 2
1 dissolved in 00 ml of N,N-dimethylformamide
59 (100 mmol) of 2-[(trimethylsilyl)thiolo-ethanamine. 11.25 g (100 mmol) of 1,4-diazabicyclo[2,2,2]octane and Kl as catalyst are added to the mixture while stirring, and the mixture is then heated to 100 DEG C. for 5 hours.
５０ｍ１のＮ、Ｎ−ジメチルホルムアミドに溶解した１
２．９９ （１００ミリモル）のＮ−シアン−Ｎ’−メ
チル−８−メチル−イソチオ尿素を添加し、そこから反
応の進行を薄層クロマトグラフィーにより観察しながら
、イソチオ尿素が消滅するまで加熱を継続する。反応を
実施例１のように行い、融点１４０℃のシメチヂンが得
られる（収率は４−クロコメチル−５−メチル−ＩＨ−
イミダゾールを基準として９０％である）。1 dissolved in 50 ml of N,N-dimethylformamide
Add 2.99 (100 mmol) of N-cyan-N'-methyl-8-methyl-isothiourea and heat until the isothiourea disappears while observing the progress of the reaction by thin layer chromatography. continue. The reaction is carried out as in Example 1, giving cimetidine with a melting point of 140°C (yield: 4-crocomethyl-5-methyl-IH-
90% based on imidazole).
実施例 ４
２６．６ｇ（１００ミリモル）の４−トシルオキシ−メ
チル−５−メチル−ＩＨ−イミダゾール（■）（此処で
Ｘ＝Ｏ−Ｔｓ）を２００厘ｌのＮ。Example 4 26.6 g (100 mmol) of 4-tosyloxy-methyl-5-methyl-IH-imidazole (■) (where X=O-Ts) were dissolved in 200 l of N.
Ｎ−ジメチルホルムアミドに溶解した１５ｇ（１００ミ
リモルンの２−［（トリメチルシリル−エタンアミンと
混合する。反応は実施例３と同様に行われる。15 g (100 mmol) of 2-[(trimethylsilyl-ethanamine) dissolved in N-dimethylformamide are mixed. The reaction is carried out analogously to Example 3.
融点１４０℃のシメチヂンが得られる（収率は、４−ト
シルオキシ−メチル−５−メチル−ＩＨ−イミダゾール
を基準として８０％である）。Cimetidine with a melting point of 140 DEG C. is obtained (yield 80% based on 4-tosyloxy-methyl-5-methyl-IH-imidazole).
実施例 ５
１３９ （１００ミリモル）の４−クロロメチル−５−
メチル−ＩＨ−イミダゾール■（此処でＸ＝Ｃ１）を２
００１Ａのアセトニトリルに溶解した１５９ （１００
ミリモル）の２−［（トリメチルシリル）チオ］−エタ
ンアミンと混合する。混合物を撹拌しながら１２．９５
９ （１００ミリモル）のジイソプロピルエチルアミン
及び触媒としてＫＩを添加し、混合物を６時間還流する
。反応は実施例１のように行われる。Example 5 139 (100 mmol) of 4-chloromethyl-5-
Methyl-IH-imidazole■ (here X=C1) is 2
159 (100
mmol) of 2-[(trimethylsilyl)thio]-ethanamine. 12.95 while stirring the mixture.
9 (100 mmol) of diisopropylethylamine and KI as catalyst are added and the mixture is refluxed for 6 hours. The reaction is carried out as in Example 1.
融点１４０℃のシメチヂンが得られる（収率は、４−ク
ロロメチル−５−メチル−ＩＨ−イミダゾールを基準と
して８５％である）。Cimetidine with a melting point of 140 DEG C. is obtained (yield 85% based on 4-chloromethyl-5-methyl-IH-imidazole).
実施例 ６
２６．６９ （１００ミリモル）の４−トシルオキシメ
チル−５−メチル−ＩＨ−イミダゾール（■）（此処で
Ｘ＝Ｏ−Ｔｓ）を２００ｍ１（ｒ）７セトニトリルに溶
解した１５９ （１００ミリモル）の２− ［（トリメ
チルシリル）チオ］−エタンアミンと混合する。反応は
実施例１と同様に行われる。Example 6 159 (100 mmol) of 26.69 (100 mmol) of 4-tosyloxymethyl-5-methyl-IH-imidazole (■) (where X=O-Ts) was dissolved in 200 ml (r) ) of 2-[(trimethylsilyl)thio]-ethanamine. The reaction is carried out analogously to Example 1.
融点１４０℃のシメチヂンが得られる（収率は、４−ト
シルオキシメチル−５−メチル−ＩＨ−イミダゾールを
基準として８３％である）Ｃ本発明の主なる特徴及び態
様は以下の通りである。Cimetidine with a melting point of 140 DEG C. is obtained (the yield is 83% based on 4-tosyloxymethyl-5-methyl-IH-imidazole).The main features and aspects of the invention are as follows.
１式
％式％
チオ尿素を、式■
式中、Ｘは、ＣＩ、Ｂｒ、Ｉ、０−Ｔｓ又はＯ−Ｍｅｓ
である、
の化合物の一つと２− ［（トリメチルシリル）チオ］
エタンアミンとの反応の生成物と反応させることから成
る、式（Ｉ）
のシメチジンの製造方法。1 Formula % Formula % Thiourea is represented by the formula ■ where X is CI, Br, I, 0-Ts or O-Mes.
One of the compounds and 2-[(trimethylsilyl)thio]
A process for the preparation of cimetidine of formula (I), comprising reacting it with the product of its reaction with ethanamine.
２、化合物■と２− ［（トリメチルシリル）チオ］エ
タンアミンとの間の反応が酸受容体の存在において及び
極性溶剤中で行われる、上記１に記載の方法。2. The method according to 1 above, wherein the reaction between compound (1) and 2-[(trimethylsilyl)thio]ethanamine is carried out in the presence of an acid acceptor and in a polar solvent.
３ 酸受容体が１，４−ジアザビシクロ［２，２゜２］
オクタン、トリエチルアミン、ジイソプロピルエチルア
ミンの間から選択され、及び溶剤がアセトニトリル、Ｎ
、Ｎ−ジメチルホルムアミドオッニトロメタンの間から
選択される、上記２に記載の方法。3 Acid acceptor is 1,4-diazabicyclo[2,2゜2]
octane, triethylamine, diisopropylethylamine, and the solvent is acetonitrile, N
, N-dimethylformamidoonitromethane.
４、トリメチルシリル沃化物及びアルカリ沃化物の間か
ら選択された触媒を用いることを含んで成る、上記２又
は３に記載の方法。4. The method according to 2 or 3 above, comprising using a catalyst selected between trimethylsilyl iodide and alkali iodide.
Claims (1)
素を、式（II） ▲数式、化学式、表等があります▼（II） 式中、Ｘは＜Ｃｌ、Ｂｒ、Ｉ、Ｏ−Ｔｓ又はＯ−Ｍｅｓ
である、 の化合物の一つと２−［（トリメチルシリル）チオ］エ
タンアミンとの反応の生成物と反応させることから成る
、式（ I ） ▲数式、化学式、表等があります▼（ I ） のシメチジンの製造方法。[Claims] 1. N-cyano-N'-methyl-S-methyl-isothiourea of the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼(II) In the formula, X is <Cl, Br, I, O-Ts or O-Mes
of cimetidine of the formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc. Production method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2308947A JPH04182470A (en) | 1990-11-16 | 1990-11-16 | Method of preparing n-cyano-n'-methyl-n"-(2-(((5- methyl-1h-4-imidazolylmethyl)methyl)thio)ethyl) guanidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2308947A JPH04182470A (en) | 1990-11-16 | 1990-11-16 | Method of preparing n-cyano-n'-methyl-n"-(2-(((5- methyl-1h-4-imidazolylmethyl)methyl)thio)ethyl) guanidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04182470A true JPH04182470A (en) | 1992-06-30 |
Family
ID=17987172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2308947A Pending JPH04182470A (en) | 1990-11-16 | 1990-11-16 | Method of preparing n-cyano-n'-methyl-n"-(2-(((5- methyl-1h-4-imidazolylmethyl)methyl)thio)ethyl) guanidine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04182470A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6747849B1 (en) | 2000-03-21 | 2004-06-08 | Hitachi Global Storage Technologies Netherlands B.V. | High performance suspension with reduced flow-induced vibration |
-
1990
- 1990-11-16 JP JP2308947A patent/JPH04182470A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6747849B1 (en) | 2000-03-21 | 2004-06-08 | Hitachi Global Storage Technologies Netherlands B.V. | High performance suspension with reduced flow-induced vibration |
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