JPS63132877A - Production of imidazole derivative - Google Patents
Production of imidazole derivativeInfo
- Publication number
- JPS63132877A JPS63132877A JP61278718A JP27871886A JPS63132877A JP S63132877 A JPS63132877 A JP S63132877A JP 61278718 A JP61278718 A JP 61278718A JP 27871886 A JP27871886 A JP 27871886A JP S63132877 A JPS63132877 A JP S63132877A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- formic acid
- group
- ammonium salt
- ammonium
- 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.)
- Granted
Links
- 150000002460 imidazoles Chemical class 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 10
- 150000004675 formic acid derivatives Chemical class 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 abstract description 14
- 229960001380 cimetidine Drugs 0.000 abstract description 11
- 239000002904 solvent Substances 0.000 abstract description 10
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 208000025865 Ulcer Diseases 0.000 abstract 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 abstract 1
- 231100000397 ulcer Toxicity 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 10
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- -1 isobutyryl group Chemical group 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical class OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 2
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PCAUSEZGTJUFRH-UHFFFAOYSA-N 1-cyano-3-ethyl-2-methylguanidine Chemical compound CCN=C(NC)NC#N PCAUSEZGTJUFRH-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- KWIPUXXIFQQMKN-UHFFFAOYSA-N 2-azaniumyl-3-(4-cyanophenyl)propanoate Chemical compound OC(=O)C(N)CC1=CC=C(C#N)C=C1 KWIPUXXIFQQMKN-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KFNNIILCVOLYIR-UHFFFAOYSA-N Propyl formate Chemical compound CCCOC=O KFNNIILCVOLYIR-UHFFFAOYSA-N 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000008431 aliphatic amides Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 229940090948 ammonium benzoate Drugs 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- XJMWHXZUIGHOBA-UHFFFAOYSA-N azane;propanoic acid Chemical compound N.CCC(O)=O XJMWHXZUIGHOBA-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical class NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- APJZJAXVHQZSOU-UHFFFAOYSA-N methyl methanimidate;hydrochloride Chemical compound Cl.COC=N APJZJAXVHQZSOU-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- BHTUNQYYFYCLDV-UHFFFAOYSA-N phenoxymethanediol Chemical compound OC(O)OC1=CC=CC=C1 BHTUNQYYFYCLDV-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、医薬品、特に潰瘍治療薬として有用なシメジ
ン（Ｃｉｍｅｔｉｄｉｎｅ、Ｎ−シアノ−Ｎ’−メチル
−Ｎ“−（２−（（５〜メチル−ＩＨ−イミダゾール−
４−イル）メチルチオ）エチル〕グアニジン）あるいは
シメチジン関連化合物の新規な製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to Cimetidine, N-cyano-N'-methyl-N"-(2-((5- Methyl-IH-imidazole-
The present invention relates to a novel method for producing 4-yl)methylthio)ethyl]guanidine) or cimetidine-related compounds.
従来、シメチジンあるいはシメチジン関連化合物の製造
方法についてはいくつかの提供がなされている（例えば
特開昭４９−７５５７４号、特開昭５１−１２５０７４
号等）が、これらの諸法では高価なイミダゾール誘導体
を出発原料として用い、かつ多段階の反応を経る製造方
法であるためコストが高くつく欠点を有していた。Conventionally, several methods for producing cimetidine or cimetidine-related compounds have been proposed (for example, JP-A-49-75574, JP-A-51-125074).
However, these methods use expensive imidazole derivatives as starting materials and involve multi-step reactions, resulting in high costs.
本発明は、従来法における上記欠点を解消したイミダゾ
ール誘導体の新規な製造方法を提供するものであり、そ
の特徴とするところは、安価でかっ高収率で得られる原
料を用い最終段階でイミダゾール環を形成させることに
よって経済的にシメチジンあるいはシメチジン関連化合
物を得ることができるよう改良した点にある。The present invention provides a new method for producing imidazole derivatives that eliminates the above-mentioned drawbacks of conventional methods.The present invention is characterized by the use of raw materials that are inexpensive and can be obtained in high yields, and in which the imidazole ring is removed in the final step. The present invention has been improved so that cimetidine or a cimetidine-related compound can be economically obtained by forming the following.
すなわち、本発明は、一般式（１）
％式％
〔式中、Ｒ１はアシル基、Ｒ２は低級アルキル基を示す
。〕で表わされるα−アシロキシケトン誘導体とギ酸誘
導体およびアンモニウム塩を反応させて式（ｎ）
胃開
〔式中、Ｒ２は前記に同じである。〕で表わされるイミ
ダゾール誘４体を得ることを特徴とするイミダゾール誘
導体の製造方法をその要旨とする。本発明に係る式（１
）で表わされるα−アシロキシケトン誘導体中、ＲＩに
用いられる低級脂肪族アシル基としては、ホルミル基、
アセチル基、プロピオニル基、ブチリル基、イソブチリ
ル基、５ｅｅ−ブチリル基などが挙げられ、特に好まし
くはアセチル基である。またＲ２の低級アルキル基とし
てはメチル基、エチル基、ロープロピル基、イソプロピ
ル基、ロープチル基、５ｅｃ−ブチル基、イソブチル基
などを挙げることができ、好ましくはメチル基である。That is, the present invention is based on the general formula (1) % formula % [wherein R1 represents an acyl group and R2 represents a lower alkyl group]. ] The α-acyloxyketone derivative represented by the formula (n) is reacted with a formic acid derivative and an ammonium salt to obtain a compound of the formula (n) [wherein R2 is as defined above]. The gist of the present invention is a method for producing an imidazole derivative, which is characterized by obtaining an imidazole derivative represented by the following formula. Formula (1) according to the present invention
) Among the α-acyloxyketone derivatives represented by RI, the lower aliphatic acyl group used for RI includes formyl group,
Examples include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a 5ee-butyryl group, and an acetyl group is particularly preferred. Examples of the lower alkyl group for R2 include a methyl group, an ethyl group, a lopropyl group, an isopropyl group, a lopropyl group, a 5ec-butyl group, an isobutyl group, and a methyl group is preferred.
弐（Ｉ）で表わされるα−アシロキシケトン誘導体は、
本出願人による特願昭６１−２０３６４０号「シアノグ
アニジン誘導体及びその製造法」に記載の化合物から、
後述する如く安価かつ高収率で得ることができる。また
、本願発明で用いられるギ酸誘導体としては、例えば、
ギ酸メチル、ギ酸エチル、ギ酸ｎ−プロピル、ギ酸イソ
プロピル、ギ酸ｎ−ブチル、ギ酸フェニルなどのギ酸エ
ステル、オルトギ酸メチル、オルトギ酸エチル、オルト
ギ酸フェニルなどのオルトギ酸エステル、酢酸ホルムア
ミジンなどのホルムアミジン類、ホルムイミド酸メチル
塩酸塩などのイミド酸誘導体などを用いることができ、
中でもオルトギ酸エステルが好ましく、とくにはオルト
ギ酸メチルが好ましい。The α-acyloxyketone derivative represented by (I) is
From the compounds described in Japanese Patent Application No. 61-203640 "Cyanoguanidine Derivatives and Method for Producing the Same" filed by the present applicant,
As described below, it can be obtained at low cost and in high yield. Further, as formic acid derivatives used in the present invention, for example,
Formic acid esters such as methyl formate, ethyl formate, n-propyl formate, isopropyl formate, n-butyl formate, and phenyl formate; orthoformic acid esters such as methyl orthoformate, ethyl orthoformate, and phenyl orthoformate; formamidine such as formamidine acetate; , imidic acid derivatives such as methyl formimidate hydrochloride, etc. can be used,
Among these, orthoformic acid esters are preferred, and methyl orthoformate is particularly preferred.
また、アンモニウム塩としては例えば、ギ酸アンモニウ
ム、酢酸アンモニウム、プロピオン酸アンモニウム、安
息香酸アンモニウム、炭酸アンモニウムなどの有機およ
び無機のアンモニウム塩を用いることができ、特に好ま
しくはギ酸アンモニウムの如き脂肪族有機酸アンモニウ
ム塩である。Further, as ammonium salts, for example, organic and inorganic ammonium salts such as ammonium formate, ammonium acetate, ammonium propionate, ammonium benzoate, and ammonium carbonate can be used, and particularly preferably, ammonium salts of aliphatic organic acids such as ammonium formate are used. It's salt.
ギ酸誘導体、アンモニウム塩の使用量は共に通常式（１
）のα−アシロキシケトン誘導体１モルに対して１ない
し１００モルであり、好ましくは２ないし２０モルであ
る。本発明においては、溶媒を使用しなくても行うこと
ができるが、溶媒を用いることが好ましい。この場合の
溶媒としては、例えばメタノール、エタノール、ロープ
ロバノール、イソプロパツールなどのアルコール系溶媒
、ジエチルエーテル、ジオキサン、テトラヒドロフラン
などのエーテル系の溶媒、Ｎ、Ｎ−ジメチルホルムアミ
ド、Ｎ、Ｎ−ジエチルホルムアミド、ホルムアミド、ア
セアミドなどの脂肪族アミド系溶媒などが好ましい。こ
れらの溶媒の使用量は式（Ｉ）のα−アシロキシケトン
誘導体１重量部に対し０．５ないし１００重量部、好ま
しくは２ないし５０重量部である。The amounts of formic acid derivatives and ammonium salts to be used are both according to the usual formula (1
) is 1 to 100 mol, preferably 2 to 20 mol, per 1 mol of the α-acyloxyketone derivative. Although the present invention can be carried out without using a solvent, it is preferable to use a solvent. Examples of solvents in this case include alcoholic solvents such as methanol, ethanol, lowobanol, and isopropanol, etheric solvents such as diethyl ether, dioxane, and tetrahydrofuran, N,N-dimethylformamide, and N,N-diethylformamide. Preferred are aliphatic amide solvents such as , formamide and aceamide. The amount of these solvents used is 0.5 to 100 parts by weight, preferably 2 to 50 parts by weight, per 1 part by weight of the α-acyloxyketone derivative of formula (I).
反応温度は０℃ないし１５０℃、好ましくは４０℃ない
し１１０°Ｃである。反応温度は０．１ないし４０時間
、好ましくは０．５ないし２０時間である。反応後、目
的物である式（ｎ）で表わされるイミダゾール誘導体を
得るには、反応混合物中の溶媒を留去後、再結晶あるい
はクロマトグラフィーなどの通常用いられる一般的な精
製手段を用いることができる。The reaction temperature is 0°C to 150°C, preferably 40°C to 110°C. The reaction temperature is 0.1 to 40 hours, preferably 0.5 to 20 hours. After the reaction, in order to obtain the target imidazole derivative represented by formula (n), it is possible to distill off the solvent in the reaction mixture and then use commonly used purification means such as recrystallization or chromatography. can.
以下、本発明の方法を実施例によって具体的に説明する
。Hereinafter, the method of the present invention will be specifically explained using examples.
実施例Ｉ
Ｎ−（２−アセトキシ−３−オキソブチルチオ）エチ／
Ｌ／−Ｎ’−シアノーＮ＃−メチルグアニジン１５５Ｂ
。Example I N-(2-acetoxy-3-oxobutylthio)ethyl/
L/-N'-cyano N#-methylguanidine 155B
.
オルトギ酸メチル２９０ｍｇをホルムアミド２．５ ｄ
に溶かした後、ギ酸アンモニウム１７０ｍｇを加え、１
００℃で２時間攪拌した。反応混合物中のホルムアミド
を減圧留去したのち、残香をシリカゲルクロマトグラフ
ィー（溶出溶媒；クロロホルム：メタノール＝１１）に
て単離、精製し、次いでイソプロパツールから再結晶し
て白色結晶の目的物３６ｍｇを得た（収率２６％）。290 mg of methyl orthoformate and 2.5 d of formamide
170mg of ammonium formate was added, and 1
The mixture was stirred at 00°C for 2 hours. After distilling off the formamide in the reaction mixture under reduced pressure, the residual aroma was isolated and purified by silica gel chromatography (elution solvent: chloroform:methanol = 11), and then recrystallized from isopropanol to obtain 36 mg of the desired product as white crystals. was obtained (yield 26%).
実施例２〜３
実施例１においてギ酸アンモニウムの代わりに表１記載
のアンモニウム塩を用いる以外は実施例１と同様の方法
で反応を行ったところ、シメチジンが表１の収率で得ら
れた。Examples 2 to 3 When the reaction was carried out in the same manner as in Example 1 except that the ammonium salt shown in Table 1 was used instead of ammonium formate in Example 1, cimetidine was obtained in the yield shown in Table 1.
表 １
実施例４〜７
実施例１においてホルムアミドの代わりに表２記載の溶
媒を用いる以外は実施例１と同様の方法で反応を行った
ところ、シメチジンが表２の収率で得られた。Table 1 Examples 4 to 7 When the reaction was carried out in the same manner as in Example 1 except that the solvent shown in Table 2 was used instead of formamide in Example 1, cimetidine was obtained in the yield shown in Table 2.
表 ２
実施例８〜１０
実施例１においてオルトギ酸メチルの代わりに表３記載
のギ酸誘導体を用いる以外は実施例１と同様の方法で反
応を行ったところ、シメチジンが表３の収率で得られた
。Table 2 Examples 8 to 10 When the reaction was carried out in the same manner as in Example 1 except that the formic acid derivatives listed in Table 3 were used instead of methyl orthoformate in Example 1, cimetidine was obtained in the yield shown in Table 3. It was done.
表 ３
実施例１１
Ｎ−（２−ホルミノ「オキシ−３−オキソブチルチオ）
エチル−Ｎ′−シアノ−Ｎ“−メチルグアニジン１３６
ｍｇ、オルトギ酸メチル５３０ｍｇをホルムアミド２゜
５−に溶かし、ギ酸アンモニウム３２０ｍｇを加え、１
００℃で２時間攪拌した。実施例１と同様に後処理して
白色結晶の目的物（シメチジン） ２８ｍｇを得た（収
率２２％）。Table 3 Example 11 N-(2-formino “oxy-3-oxobutylthio”)
Ethyl-N'-cyano-N"-methylguanidine 136
Dissolve 530 mg of methyl orthoformate in 2.5-mg of formamide, add 320 mg of ammonium formate, and dissolve 530 mg of methyl orthoformate.
The mixture was stirred at 00°C for 2 hours. Post-treatment was carried out in the same manner as in Example 1 to obtain 28 mg of the target product (cimetidine) as white crystals (yield 22%).
参考例１
５Ｍ二口フラスコに、Ｎ−（２−クロロ−３−オキソブ
チルチオ）エチル−Ｎ′−シアノ−Ｎ＃−メチルグアニ
ジン（特願昭６１−２０３６４０号記載の化合物）０．
６４ｇ 、メタノール１０−１無水酢酸ナトリウム０゜
３１ｇを入れ、室温にて８時間攪拌した。メタノールを
減圧留去し水を加え酢酸エチルで抽出した。Reference Example 1 In a 5M two-necked flask, 0.0% of N-(2-chloro-3-oxobutylthio)ethyl-N'-cyano-N#-methylguanidine (the compound described in Japanese Patent Application No. 1983-203640) was added.
64 g of methanol 10-1 and 0.31 g of anhydrous sodium acetate were added, and the mixture was stirred at room temperature for 8 hours. Methanol was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate.
無水硫酸マグネシウムで乾燥した後、酢酸エチルを減圧
留去して褐色液体の目的物０．５７ｇを得た（収率８３
％）。After drying over anhydrous magnesium sulfate, ethyl acetate was distilled off under reduced pressure to obtain 0.57 g of the desired product as a brown liquid (yield: 83
%).
’ Ｈ−ＮＭＲスペクトル（ＣＤＣ１ｓ−ＭｅＯＤ−ｄ
４；ＰＰ１１）（ａ）ｏｒ（ｂ） ２．
２０（３Ｈ，５）（ａ）ｏｒ（ｂ） ２
．２７（３ｔｌ、 ５）（ｃ）
２．８０（２Ｈ，ｍ）（ｄ）
２．８６（３Ｈ，ｄ、Ｊ＝５．４Ｈｚ）（ｅ）
３．００（２Ｈ，ｍ）（ｆ）
３．４２（２Ｈ，ｍ）（ｇ）
５．２６（ＬＨ，ｄｄ、Ｊ＝５．４ａｎｄ７
．２Ｈｚ）（ｈ） ６．５０〜６
．８８（２Ｂ、ｍ）参考例２
参考例１において、無水酢酸ナトリウムに代えてギ酸ナ
トリウムを用いたほかは参考例１と同様に反応を行った
。参考例１と同様に後処理したところ、褐色液体の目的
物を得た（収率４６％）。' H-NMR spectrum (CDC1s-MeOD-d
4; PP11) (a) or (b) 2.
20(3H,5)(a)or(b) 2
．． 27 (3tl, 5) (c)
2.80 (2H, m) (d)
2.86 (3H, d, J=5.4Hz) (e)
3.00 (2H, m) (f)
3.42 (2H, m) (g)
5.26 (LH, dd, J=5.4and7
．． 2Hz) (h) 6.50~6
．． 88 (2B, m) Reference Example 2 The reaction was carried out in the same manner as in Reference Example 1, except that sodium formate was used in place of anhydrous sodium acetate. After post-treatment in the same manner as in Reference Example 1, the desired product was obtained as a brown liquid (yield: 46%).
Claims (1)
低級アルキル基を示す。〕で表わされるα−アシロキシ
ケトン誘導体とギ酸誘導体およびアンモニウム塩を反応
させることを特徴とする式（II） ▲数式、化学式、表等があります▼（II） 〔式中、Ｒ＾２は前記に同じである。〕で表わされるイ
ミダゾール誘導体の製造方法。(1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 represents a lower aliphatic acyl group, and R^2 represents a lower alkyl group. ] Formula (II) characterized by reacting an α-acyloxyketone derivative represented by a formic acid derivative and an ammonium salt ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R^2 is the is the same as ] A method for producing an imidazole derivative represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61278718A JPS63132877A (en) | 1986-11-25 | 1986-11-25 | Production of imidazole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61278718A JPS63132877A (en) | 1986-11-25 | 1986-11-25 | Production of imidazole derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63132877A true JPS63132877A (en) | 1988-06-04 |
| JPH0586948B2 JPH0586948B2 (en) | 1993-12-14 |
Family
ID=17601225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61278718A Granted JPS63132877A (en) | 1986-11-25 | 1986-11-25 | Production of imidazole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63132877A (en) |
-
1986
- 1986-11-25 JP JP61278718A patent/JPS63132877A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0586948B2 (en) | 1993-12-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR920002295B1 (en) | Process for the preparation of pyrrolidone derivatives | |
| US4581452A (en) | Production of 5-perfluoroalkyldihydrouracil derivatives | |
| JPS63258861A (en) | Production of nitroethene derivative | |
| JPS63132877A (en) | Production of imidazole derivative | |
| EP0276574B1 (en) | Alpha-acyloxyketone derivatives | |
| KR950011445B1 (en) | Cyanoguanidine derivatives and process fo rpreparation thereof | |
| JPS6360969A (en) | Production of imidazole derivative | |
| JPS62155268A (en) | Synthesis of nizatidine | |
| JP3215552B2 (en) | Method for producing monoacylhydrazines | |
| JP2004217542A (en) | Method for producing 4,5-dialkoxycarbonylimidazole | |
| US6562979B1 (en) | Process for the preparation of substituted benzisothiazole compounds | |
| JP3037399B2 (en) | Preparation of imidazole derivatives | |
| JPS63201172A (en) | Production of imidazole derivative | |
| JPS6160673A (en) | Preparation of guanidinothiazole derivative | |
| JPS63201171A (en) | Production of imidazole derivative | |
| KR100277510B1 (en) | Method for preparing tetrahydrocarbazolone derivative | |
| JPS5852995B2 (en) | Method for producing furfural derivatives | |
| JPS6360971A (en) | Production of imidazole derivative | |
| JPH0379345B2 (en) | ||
| JPS63192747A (en) | Formate of formamidine | |
| JP2004099544A (en) | Method for producing 4,5-dialkoxycarbonylimidazole | |
| JPS63190872A (en) | Production of cyanoguanidine derivative | |
| JPS6317869A (en) | Production of 2-lower alkyl-4-amino-5-formylpyrimidine | |
| JPH0586944B2 (en) | ||
| JPS633864B2 (en) |