JPH01238573A - Production of guanidine derivative - Google Patents
Production of guanidine derivativeInfo
- Publication number
- JPH01238573A JPH01238573A JP63060270A JP6027088A JPH01238573A JP H01238573 A JPH01238573 A JP H01238573A JP 63060270 A JP63060270 A JP 63060270A JP 6027088 A JP6027088 A JP 6027088A JP H01238573 A JPH01238573 A JP H01238573A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- reaction
- compound shown
- methylamine
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 150000002357 guanidines Chemical class 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 5
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract description 6
- 239000006227 byproduct Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000007795 chemical reaction product Substances 0.000 abstract description 4
- 208000007107 Stomach Ulcer Diseases 0.000 abstract description 2
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 abstract description 2
- 208000000718 duodenal ulcer Diseases 0.000 abstract description 2
- 239000011261 inert gas Substances 0.000 abstract description 2
- 229960003151 mercaptamine Drugs 0.000 abstract description 2
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- 201000005917 gastric ulcer Diseases 0.000 abstract 1
- 238000000034 method Methods 0.000 description 9
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 8
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 4
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- -1 diacetyl halide Chemical class 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 3
- VKWDKDAWFFPNDD-UHFFFAOYSA-N 1,3-dithiolan-2-ylidenecyanamide Chemical compound N#CN=C1SCCS1 VKWDKDAWFFPNDD-UHFFFAOYSA-N 0.000 description 2
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 2
- VFWUYASTZCOUKN-UHFFFAOYSA-N 2-[(5-methyl-1h-imidazol-4-yl)methylsulfanyl]ethanamine;dihydrochloride Chemical compound Cl.Cl.CC=1N=CNC=1CSCCN VFWUYASTZCOUKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical compound [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- GCYDEHNKSNMNMN-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methanethiol Chemical compound CC=1NC=NC=1CS GCYDEHNKSNMNMN-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- APZXPRHPPCTRHN-UHFFFAOYSA-N 4-(chloromethyl)-5-methyl-1h-imidazole Chemical compound CC=1NC=NC=1CCl APZXPRHPPCTRHN-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000003710 Histamine H2 Receptors Human genes 0.000 description 1
- 108090000050 Histamine H2 Receptors Proteins 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、式（Ｉ［Ｉ）で示されるグアニジン誘導体、
すなわちＮ−シアノ−Ｎ゛−メチル−Ｎ”−（２−（（
４−メチル−５−イミダゾリル）メチルチオ）エチル〕
グアニジンの製造法に関するものである。Detailed Description of the Invention [Industrial Field of Application] The present invention provides a guanidine derivative represented by the formula (I[I),
That is, N-cyano-N゛-methyl-N''-(2-((
4-Methyl-5-imidazolyl)methylthio)ethyl]
This invention relates to a method for producing guanidine.
上記化合物（Ｉ［［）は、ヒスタミンＨ２受容拮抗作用
を有する化合物で、胃および十二指腸潰瘍治療薬として
代用な化合物であり、−船名をシメチジンとして知られ
ている。The above-mentioned compound (I [[) is a compound having a histamine H2 receptor antagonistic effect, and is a substitute compound as a therapeutic agent for gastric and duodenal ulcers, and is known as cimetidine.
従来、式（Ｉ［［］の化合物の製造法としては、４−メ
チル−５−クロルメチルイミダゾールを原料とする方法
（特開昭５６４４２２７１号）、４−メチル−５−メル
カプトメチルイミダゾールを原料とする方法（特公昭５
４−４０５７４号、特公昭６０−５６７０９号、特公昭
６１−４０６６７号）あるいはハロゲン化ジアセチルを
原料とする方法等、種々の方法が知られている。また式
ＣＩ）で表される化合物
を用いる方法としては、特公昭５２−４３８３２号、特
公昭５６−１３０９号、特公昭５９−１４４６０号等の
方法が知られている。Conventionally, methods for producing the compound of formula (I[[]) include a method using 4-methyl-5-chloromethylimidazole as a raw material (Japanese Patent Application Laid-open No. 56442271), and a method using 4-methyl-5-mercaptomethylimidazole as a raw material. How to do it (Tokuko Sho 5)
Various methods are known, such as Japanese Patent Publication No. 4-40574, Japanese Patent Publication No. 60-56709, Japanese Patent Publication No. 61-40667) or a method using diacetyl halide as a raw material. Further, as a method using a compound represented by formula CI), methods such as those disclosed in Japanese Patent Publication No. 43832-1983, Japanese Patent Publication No. 1309-1982, and Japanese Patent Publication No. 14460-1988 are known.
式（１）の化合物を用いる従来の製造方法ではいずれも
原料として式（ＩＶ）で示される化合物（式中、Ｘは０
、Ｓ、またはＮＨを示す）を用いる。このため、式〔Ｉ
〕の化合物と式（、ｒＶ ）の化合物とを反応させる際
、多量のメチルメルカプタンＣ１，Ｓ）！が副生ずる。In all conventional production methods using the compound of formula (1), the compound represented by formula (IV) (wherein X is 0
, S, or NH). For this reason, the formula [I
] and the compound of formula (, rV ), a large amount of methyl mercaptan C1,S)! is a by-product.
このメチルメルカプタンは毒性及び引火性が強く、しか
も極めて悪臭の強い化合物であり、多量にこれを副生ず
る従来の方法は、工業的に実施するに際して、安全上お
よび設備上も、除害設備を必要とする等種々問題のある
方法である。Methyl mercaptan is a compound that is highly toxic and flammable, as well as has an extremely strong odor. Conventional methods that produce large amounts of this as a by-product require detoxification equipment for safety and equipment reasons when carried out industrially. This method has various problems such as
〔問題を解決するための手段および作用〕本発明者等は
、従来法の上記した重大な欠点を解決することを目的に
鋭意検討を行った結果、式（ＩＶ）の化合物を用いない
式（１）の化合物の新規な製造法を見出し、本発明を完
成するに到ったものである。[Means and effects for solving the problem] As a result of intensive studies aimed at solving the above-mentioned serious drawbacks of the conventional methods, the present inventors have developed a method of formula (IV) that does not use the compound of formula (IV). We have discovered a new method for producing the compound 1) and have completed the present invention.
すなわち、本発明は式（１）で表される化合物と弐（Ｉ
Ｉ）で表される化合物
Ｒ１
（式中、Ｒ１、Ｒ２、Ｒ３およびＲ４は各々、水素原子
、低級アルキル基、フェニル基、−ｏＲｓまたは−ＣＯ
ＯＲｓを示し、互いに同じであってもよく、異なってい
でもよい。また、Ｒ３は水素原子、低級アルキル基また
はアルカリ金属を示す）
とを反応させ、次いでメチルアミンを反応させることを
特徴とする弐（ＩＩＩ）で表されるグア丑ジン誘導体
の製造法である。That is, the present invention provides a compound represented by formula (1) and
Compound R1 represented by I) (wherein R1, R2, R3 and R4 are each a hydrogen atom, a lower alkyl group, a phenyl group, -oRs or -CO
ORs and may be the same or different from each other. In addition, R3 represents a hydrogen atom, a lower alkyl group, or an alkali metal.
本発明で用いる式（１）の化合物は、例えば４−メチル
イミダゾールとホルムアルデヒドおよびシステアミンと
の反応によって容易に得られるもので、単体の状態であ
ってもよく、あるいは、例えば塩酸、硫酸等との塩の状
態であってもよい。The compound of formula (1) used in the present invention is easily obtained, for example, by the reaction of 4-methylimidazole with formaldehyde and cysteamine, and may be in the form of a simple substance, or may be obtained by reacting with, for example, hydrochloric acid, sulfuric acid, etc. It may be in the form of salt.
本発明で用いる式（ｎ）の化合物は、式（Ｖ）の化合物
（式中、阿はアルカリ金属を示す）
と式（Ｖｌ）で示される化合物
ｚ Ｒｓ
ＩＩ
Ｒ１−Ｃ−Ｃ−Ｒ４（Ｖｌ）
Ｘ
（式中、Ｒ２、Ｒｔ、 ｌｈおよびＲ４は式（ＩＩ）と
同じであり、Ｘはハロゲン原子を示す）
との反応により容易に得ることが出来る。The compound of formula (n) used in the present invention is a compound of formula (V) (in the formula, A represents an alkali metal) and a compound of formula (Vl) z Rs II R1-C-C-R4 (Vl ) X (wherein R2, Rt, lh and R4 are the same as in formula (II), and X represents a halogen atom).
式（１）の化合物と式（１１）の化合物との反応は、通
常、中性ないしアルカリ性下で行われる。The reaction between the compound of formula (1) and the compound of formula (11) is usually carried out under neutral or alkaline conditions.
即ち、式（１）の化合物が単体の状態の場合には式（ｒ
）と式（ＩＩ）の化合物の反応に際しては何らｐＨ１！
節の必要はないが、式（Ｉ）の化合物が塩の状態である
場合には、式（１）と式（ＩＩ）の化合物の反応に際し
て、アルカリ金属の水酸化物等を適宜添加して反応系を
中性ないしアルカリ性に保つ必要がある。That is, when the compound of formula (1) is in a simple state, the compound of formula (r
) and the compound of formula (II) at pH 1!
Although this clause is not necessary, when the compound of formula (I) is in the form of a salt, an alkali metal hydroxide or the like may be added as appropriate during the reaction of the compound of formula (1) and formula (II). It is necessary to keep the reaction system neutral or alkaline.
この反応の生成物とメチルアミンとの反応は、式（１〕
と式（ＩＩ）の化合物の反応の生成物を分離精製した後
に行ってもよく、また式（１）と式（ｎ）の化合物の反
応の終了後直ちにメチルアミンを加えて反応を行っても
よい。The reaction between the product of this reaction and methylamine is expressed by the formula (1)
The reaction may be carried out after separating and purifying the product of the reaction between the compound of the formula (II) and the compound of the formula (II), or the reaction may be carried out by adding methylamine immediately after the reaction of the compound of the formula (1) and the formula (n) is completed. good.
式（＋）と式（１１）の化合物の反応およびこの反応生
成物とメチルアミンとの反応のいづれもメタノール、イ
ソプロパツール等のアルコールあるいはアセトニトリル
等の溶媒中で行われる。Both the reaction of the compound of formula (+) and formula (11) and the reaction of this reaction product with methylamine are carried out in an alcohol such as methanol or isopropanol, or a solvent such as acetonitrile.
反応はいずれも０〜１００°Ｃ１好ましくは２０〜５０
°Ｃで行い、好ましくは窒素等の不活性ガスの雰囲気下
で行う。All reactions are carried out at 0 to 100°C, preferably 20 to 50°C.
The reaction is carried out at °C, preferably under an atmosphere of an inert gas such as nitrogen.
式（１）と式（ＩＩ）の化合物の反応は、式ＣＩ〕／（
ｎ）のモル比０．９〜１．１で行い、メチルアミンとの
反応はメチルアミンの過剰のもとで行う。The reaction between the compounds of formula (1) and formula (II) is represented by formula CI]/(
n) at a molar ratio of 0.9 to 1.1, and the reaction with methylamine is carried out in an excess of methylamine.
反応終了液から式（１）の化合物を取り出すには、反応
終了後、脱溶媒、抽出、濾過等通常の操作により副生物
等と分離する。その後、再結晶等の操作によって精製し
、高純度の式（１１１３の化合物を得る。In order to take out the compound of formula (1) from the reaction-completed solution, after the reaction is completed, it is separated from by-products by conventional operations such as desolvation, extraction, and filtration. Thereafter, it is purified by operations such as recrystallization to obtain a highly pure compound of formula (1113).
本発明により有害物質であるメチルメルカプタンの副生
が全くない極めて安全で、かつ経済的に優れた式（［［
［）の化合物の製造が可能になった。The present invention provides an extremely safe and economically superior formula ([[
It became possible to produce the compound [).
以下に実施例をあげて本発明を更に詳しく説明する。 The present invention will be explained in more detail with reference to Examples below.
実施例１
反応フラスコに４−メチル−５−（（２−アミノエチル
）チオメチル〕イミダゾールニ塩酸塩２４．４ｇ（０，
１０モル）、Ｎ−シアノ−２−イミノ−１，３−ジチオ
ラン１４．４ｇ（０，１０モル）およびメタノール５０
０ｍ１を入れ均−液とした。窒素ガスをわずかに流しな
がら、滴下ロートより５％水酸化ナトリウム−メタノー
ル液１６０ｇを温度２０〜２５°Ｃで２時間で滴下した
０滴下後、更に同じ温度で２時間攪拌を続けた。１．３
−ジチオランが消失したことを確認した後、４０％メチ
ルアミン−メタノール液３８．８ｇ （０，５０モル）
を加え、２５〜３０°Ｃで２４時間撹拌した。Example 1 24.4 g of 4-methyl-5-((2-aminoethyl)thiomethyl]imidazole dihydrochloride (0,
10 mol), 14.4 g (0.10 mol) of N-cyano-2-imino-1,3-dithiolane and 50 mol of methanol.
0ml was added to make a homogenized liquid. While flowing nitrogen gas slightly, 160 g of a 5% sodium hydroxide-methanol solution was added dropwise from the dropping funnel at a temperature of 20 to 25°C over 2 hours. After the dropwise addition, stirring was continued for an additional 2 hours at the same temperature. 1.3
- After confirming that dithiolane has disappeared, 38.8 g (0.50 mol) of 40% methylamine-methanol solution
was added and stirred at 25-30°C for 24 hours.
反応後、反応液を濃縮し、クロロホルムで副生物を抽出
、除去した。残渣よりメタノールを用いて目的物を抽出
し、抽出液を濃縮して固形分を得た。イソプルパノール
用いて２回再結晶を行い、白色の結晶１３．６ｇを得た
。この物はＩＲ−スペクトルによりＮ−シアノ−Ｎｏ−
メチル−Ｎ”−〔２−（（４−メチル−５−イミダゾリ
ル）メチルチオ）エチル）グアニジンであることを確認
した。After the reaction, the reaction solution was concentrated, and by-products were extracted and removed with chloroform. The target product was extracted from the residue using methanol, and the extract was concentrated to obtain a solid content. Recrystallization was performed twice using isopropanol to obtain 13.6 g of white crystals. This product was determined by IR-spectrum to be N-cyano-No-
It was confirmed that it was methyl-N''-[2-((4-methyl-5-imidazolyl)methylthio)ethyl)guanidine.
融点１３９〜１４１°Ｃ
元素分析（ｉ（ｗｔ％）： Ｃ＋ｏＨ＋ｂＮｂＳとして
計算値 Ｃ＝４７．６ ｏ−６，４Ｎ＝３３．３ ３
・１２．７実測値 Ｃ・４７．４ Ｈ・６．７ Ｎ
＝３３．２ ３＝１２．５実施例２
反応フラスコに４−メチル−５−（（２−アミノエチル
）チオメチル〕イミダゾールニ塩酸塩２４．４ｇ（０，
１０モル）＝Ｎ−シアノー２−イミノー４−メチル−１
，３−ジチオラン１４．２ｇ（０，０９モル）およびメ
タノール５００ｍ ｌを入れた。窒素ガスをわずかに流
しながら、滴下ロートより５％水酸化ナトリウム−メタ
ノール液１６０ｇを温度３０〜３５°Ｃで２時間で滴下
し、更にその温度で２時間撹拌を続けた。ｌ、３−ジチ
オランが消失したことを確認した後、４０％メチルアミ
ン−メタノール液７８ｇ（１，０モル）を加え、３０〜
３５°Ｃで２４時間撹拌して反応を行った。反応液につ
いて液体クロマトグラフィーで分析した結果、Ｎ−シア
ノ−Ｎｏ−メチル−Ｎ”−（２−（（４−メチル−５−
イミダゾリル）メチルチオ）エチル］グアニジンの生成
率は６８％であった。Melting point 139-141°C Elemental analysis (i (wt%): Calculated value as C+oH+bNbS C=47.6 o-6,4N=33.3 3
・12.7 Actual value C・47.4 H・6.7 N
=33.2 3=12.5 Example 2 24.4 g of 4-methyl-5-((2-aminoethyl)thiomethyl]imidazole dihydrochloride (0,
10 moles) = N-cyano 2-imino 4-methyl-1
, 3-dithiolane (14.2 g (0.09 mol)) and methanol (500 ml) were added. With a slight flow of nitrogen gas, 160 g of a 5% sodium hydroxide-methanol solution was added dropwise from the dropping funnel at a temperature of 30 to 35°C over 2 hours, and stirring was continued at that temperature for another 2 hours. After confirming that l,3-dithiolane had disappeared, 78 g (1,0 mol) of 40% methylamine-methanol solution was added, and 30~
The reaction was carried out by stirring at 35°C for 24 hours. As a result of liquid chromatography analysis of the reaction solution, N-cyano-No-methyl-N”-(2-((4-methyl-5-
The production rate of imidazolyl)methylthio)ethyl]guanidine was 68%.
液体クロマト分析
液体クロマト 島津ＬＣ−５Ａ
カラム Ｕｎｉｓｉｌ Ｑ ＣＮ４．６ φＸ
２５０ｍｍ
移動相 ０．ＯＩＭ−（ＮＨ，） Ｈ２ＰＯ４水
：メタノール： ＣＨ３ＣＮ・１５：１５ニア０（ｐＨ
・３．５）流ｆｆｉ １＋ｎｌ／ｍｉｎ検出
ＵＶ ２２９ｎｍ
実施例３
反応フラスコにＮ−シアノ−２−イミノ−１，３−ジチ
オラン１４．４ｇ（０，１０モル）およびメタノール３
００ｍ１を入れた。窒素ガスをわずかに流し撹拌しなが
ら３０〜３５°Ｃで４−メチル−５−（（２−アミノエ
チル）千オメチル〕イミダゾールのメタノール液４２．
８ｇ（０，１０モル）を３時間で滴下し、更に２時間撹
拌を続けて反応を行った。１．３−ジチオランが消失し
たことを確認した後、更に４０％メチルアミン−メタノ
ール７
２０〜２５°Ｃで２０時間撹拌して反応を行った。反応
液について液体クロマトグラフィーで分析した結果、Ｎ
−シアノ−Ｎ゛−メチル−Ｎ″−（２−Ｎ４−メチル−
５−イミダゾリル）メチルチオ）エチル〕グアニジンの
生成率は７４％であった。Liquid chromatography analysis Liquid chromatography Shimadzu LC-5A column Unisil Q CN4.6 φX
250mm Mobile phase 0. OIM-(NH,) H2PO4 water: methanol: CH3CN・15:15 nia 0 (pH
・3.5) Flow ffi 1+nl/min detection UV 229nm Example 3 14.4 g (0.10 mol) of N-cyano-2-imino-1,3-dithiolane and 3 methanol were added to the reaction flask.
I put in 00ml. Methanol solution of 4-methyl-5-((2-aminoethyl)1,000-methyl)imidazole at 30-35°C with stirring under a slight flow of nitrogen gas 42.
8 g (0.10 mol) was added dropwise over 3 hours, and the reaction was continued with stirring for an additional 2 hours. After confirming that 1,3-dithiolane had disappeared, the reaction was further stirred in 40% methylamine-methanol 7 at 20 to 25°C for 20 hours. As a result of liquid chromatography analysis of the reaction solution, N
-cyano-N゛-methyl-N''-(2-N4-methyl-
The production rate of 5-imidazolyl)methylthio)ethyl]guanidine was 74%.
本発明は、式〔■〕で表される化合物を原料として用い
うることを見出したことにより、従来法では避けること
が出来なかった毒性および引火性が強く、かつ極めて悪
臭の強いメチルメルカプタンの副性を本質的に抑制する
ことを可能とした極めて安全でかつ経済性に優れた新規
なＮ−シアノ−Ｎ’−メチル−Ｎ”−（２−Ｎ４−メチ
ル−５−イミダゾリル）メチルチオ）エチル〕グアニジ
ンの製造法を提供するものである。The present invention has discovered that the compound represented by the formula [■] can be used as a raw material, thereby making it possible to use methyl mercaptan as a substitute for methyl mercaptan, which is highly toxic, flammable, and has an extremely foul odor, which could not be avoided using conventional methods. A novel N-cyano-N'-methyl-N''-(2-N4-methyl-5-imidazolyl)methylthio)ethyl that is extremely safe and economically superior, which makes it possible to essentially suppress the A method for producing guanidine is provided.
特許出願人 三井東圧化学株式会社Patent applicant: Mitsui Toatsu Chemical Co., Ltd.
Claims (1)
水素原子、低級アルキル基、フェニル基、−ＯＲ＿５ま
たは−ＣＯＯＲ＿５を示し、互いに同じであってもよく
、異なっていてもよい。また、Ｒ＿５は水素原子、低級
アルキル基またはアルカリ金属を示す） とを反応させ、次いでメチルアミンを反応させることを
特徴とする式〔III〕で表されるグアニジン誘導体の製
造法 ▲数式、化学式、表等があります▼〔III〕[Claims] 1) Compound represented by formula [I]▲There are mathematical formulas, chemical formulas, tables, etc.▼Compounds represented by [I] and formula [II]▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (wherein R_1, R_2, R_3 and R_4 are each,
It represents a hydrogen atom, a lower alkyl group, a phenyl group, -OR_5 or -COOR_5, and may be the same or different. In addition, R_5 represents a hydrogen atom, a lower alkyl group, or an alkali metal) A method for producing a guanidine derivative represented by the formula [III] characterized by reacting the guanidine derivative with a hydrogen atom, a lower alkyl group, or an alkali metal, and then reacting with methylamine ▲ Numerical formula, chemical formula, There are tables, etc. ▼ [III]
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63060270A JPH01238573A (en) | 1988-03-16 | 1988-03-16 | Production of guanidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63060270A JPH01238573A (en) | 1988-03-16 | 1988-03-16 | Production of guanidine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01238573A true JPH01238573A (en) | 1989-09-22 |
Family
ID=13137277
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63060270A Pending JPH01238573A (en) | 1988-03-16 | 1988-03-16 | Production of guanidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01238573A (en) |
-
1988
- 1988-03-16 JP JP63060270A patent/JPH01238573A/en active Pending
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