JPH0139429B2 - - Google Patents
Info
- Publication number
- JPH0139429B2 JPH0139429B2 JP17239281A JP17239281A JPH0139429B2 JP H0139429 B2 JPH0139429 B2 JP H0139429B2 JP 17239281 A JP17239281 A JP 17239281A JP 17239281 A JP17239281 A JP 17239281A JP H0139429 B2 JPH0139429 B2 JP H0139429B2
- Authority
- JP
- Japan
- Prior art keywords
- guanidino
- ethylthiomethyl
- formamido
- thiazole
- reaction
- 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
- -1 [2-(formamido)ethylthiomethyl]thiazole Chemical compound 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000005933 dealkoxycarbonylation reaction Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 238000001308 synthesis method Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 5
- 125000006351 ethylthiomethyl group Chemical group [H]C([H])([H])C([H])([H])SC([H])([H])* 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- LKEMDBWZXFLUQE-UHFFFAOYSA-N n-[2-[[2-(diaminomethylideneamino)-1,3-thiazol-4-yl]methylsulfanyl]ethyl]formamide Chemical compound NC(=N)NC1=NC(CSCCNC=O)=CS1 LKEMDBWZXFLUQE-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- OKGXJRGLYVRVNE-UHFFFAOYSA-N diaminomethylidenethiourea Chemical compound NC(N)=NC(N)=S OKGXJRGLYVRVNE-UHFFFAOYSA-N 0.000 description 2
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- UTBKSYHAYRTIIN-UHFFFAOYSA-N methyl 2,4-dichloro-3-oxobutanoate Chemical compound COC(=O)C(Cl)C(=O)CCl UTBKSYHAYRTIIN-UHFFFAOYSA-N 0.000 description 2
- HFLMYYLFSNEOOT-UHFFFAOYSA-N methyl 4-chloro-3-oxobutanoate Chemical compound COC(=O)CC(=O)CCl HFLMYYLFSNEOOT-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- GDENSQSVDRFGSZ-UHFFFAOYSA-N n-(2-sulfanylethyl)formamide Chemical compound SCCNC=O GDENSQSVDRFGSZ-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- DPEYHNFHDIXMNV-UHFFFAOYSA-N (9-amino-3-bicyclo[3.3.1]nonanyl)-(4-benzyl-5-methyl-1,4-diazepan-1-yl)methanone dihydrochloride Chemical compound Cl.Cl.CC1CCN(CCN1Cc1ccccc1)C(=O)C1CC2CCCC(C1)C2N DPEYHNFHDIXMNV-UHFFFAOYSA-N 0.000 description 1
- WSHVQVCBPLNREW-UHFFFAOYSA-N 4-chloro-3-oxobutanoyl chloride Chemical compound ClCC(=O)CC(Cl)=O WSHVQVCBPLNREW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- CIPMPQGRFNDLAP-UHFFFAOYSA-N ethyl 1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=CS1 CIPMPQGRFNDLAP-UHFFFAOYSA-N 0.000 description 1
- GPDFVBIDCBPHSW-UHFFFAOYSA-N ethyl 2,4-dichloro-3-oxobutanoate Chemical compound CCOC(=O)C(Cl)C(=O)CCl GPDFVBIDCBPHSW-UHFFFAOYSA-N 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
Description
【発明の詳細な説明】
本発明は２―グアニジノ―４―〔２―（ホルム
アミド）エチルチオメチル〕チアゾールの合成法
に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for the synthesis of 2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole.
２―グアニジノ―４―〔２―（ホルムアミド）
エチルチオメチル〕チアゾール（）はヒスタミ
ンH2受容体に対する拮抗剤として有用である
（米国特許出願第144946号）が、その既存工業的
製法は必ずしも満足すべきものではない。 2-guanidino-4-[2-(formamide)
Ethylthiomethyl]thiazole () is useful as an antagonist for histamine H2 receptors (US Patent Application No. 144,946), but existing industrial methods for its preparation are not always satisfactory.
本発明の要旨は、
一般式
（式中、ＸおよびＹのいずれか一方はアルコキ
シカルボニル基、他方は水素をそれぞれ表わす。）
で示されるエステルを脱アルコキシカルボニル化
反応に付して２―グアニジノ―４―〔２―（アシ
ルアミド）エチルチオメチル〕チアゾールを得る
点にある。 The gist of the invention is the general formula (In the formula, one of X and Y represents an alkoxycarbonyl group, and the other represents hydrogen.)
The ester represented by is subjected to a dealkoxycarbonylation reaction to obtain 2-guanidino-4-[2-(acylamido)ethylthiomethyl]thiazole.
本発明方法は次式によつて示される。 The method of the present invention is represented by the following equation.
（式中、ＸおよびＹは前記と同意義を有する。）
上記定義において、アルコキシカルボニル基と
してはメトキシカルボニル、エトキシカルボニ
ル、プロポキシカルボニル、ブトキシカルボニ
ル、ペンチルオキシカルボニルなどが例示され
る。 (In the formula, X and Y have the same meanings as defined above.) In the above definition, examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and pentyloxycarbonyl.
本発明にかかる脱アルコキシカルボニル化反応
はエステルの加水分解と脱炭酸反応が同時に進行
する反応〔Krapcho et al.，J.Org.Chem.，43，
138（1978）〕であつて、アルカリ金属ハライド
（例えば、塩化リチウム、ヨウ化リチウム、ヨウ
化カリウム、塩化ナトリウムなど）の存在下含水
溶媒（例えば、ジメチルホルムアミド、ジメチル
スルホキシドなど）中使用する溶媒の沸点程度に
加熱して実施される。 The dealkoxycarbonylation reaction according to the present invention is a reaction in which ester hydrolysis and decarboxylation reaction proceed simultaneously [Krapcho et al., J.Org.Chem., 43 ,
138 (1978)] in the presence of an alkali metal halide (e.g., lithium chloride, lithium iodide, potassium iodide, sodium chloride, etc.) in an aqueous solvent (e.g., dimethylformamide, dimethyl sulfoxide, etc.). It is carried out by heating to about the boiling point.
原料物質として使用されるエステル（）は下
記の反応式により容易に合成され得る。 Ester () used as a raw material can be easily synthesized by the following reaction formula.
ａ（式においてＸ＝水素、Ｙ＝アルコキシ
カルボニル基の場合）：
〔式中、ＺおよびZ′はそれぞれハロゲン（例え
ば、塩素、臭素、ヨウ素など）を表わし、Ｒは前
記と同意義を表わす。〕
ｂ（式においてＸ＝アルコキシカルボニル
基、Ｙ＝水素の場合）：
〔式中、Ｒ，ＺおよびZ′はそれぞれ前記と同意
義を有する。〕
本発明方法は好収率で進行し、出発物質として
工業的に安価なジケテンが利用できるので、目的
物質（）の工業的製造法として好適である。 a (in the formula, when X = hydrogen and Y = alkoxycarbonyl group): [In the formula, Z and Z' each represent a halogen (eg, chlorine, bromine, iodine, etc.), and R has the same meaning as above. ] b (in the formula, when X = alkoxycarbonyl group and Y = hydrogen): [In the formula, R, Z and Z' each have the same meanings as above. ] The method of the present invention proceeds with a good yield and industrially inexpensive diketene can be used as a starting material, so it is suitable as an industrial method for producing the target substance ().
以下に本発明方法の実施例および参考例を示
す。 Examples and reference examples of the method of the present invention are shown below.
実施例 １
２―グアニジノ―４―〔２―（ホルムアミド）
エチルチオメチル〕―５―エトキシカルボニルチ
アゾール650mg、塩化リチウム214mg、ジメチルス
ルホキシド５mlおよび水0.7mlからなる懸濁液を
190〜195℃にて12時間撹拌下に還流する。反応液
に水10mlを加え、アンバーライトIRC―50（Ｈ型）
を用いてイオン交換クロマトグラフイーに付し、
５％アンモニア水で溶出し、溶出液を濃縮して油
状物を得る。これをシリカゲルによるカラムクロ
マトグラフイーに付し、酢酸エチル／メタノール
（４：１、ｖ／ｖ）で溶出し、溶出液を濃縮し、
油状物として２―グアニジノ―４―〔２―（ホル
ムアミド）エチルチオメチル〕チアゾール245mg
を得る。収率48.1％。モノマレイン酸塩は融点
146〜148℃を示す。Example 1 2-guanidino-4-[2-(formamide)
A suspension consisting of 650 mg of ethylthiomethyl]-5-ethoxycarbonylthiazole, 214 mg of lithium chloride, 5 ml of dimethyl sulfoxide, and 0.7 ml of water was prepared.
Reflux with stirring at 190-195°C for 12 hours. Add 10ml of water to the reaction solution and add Amberlite IRC-50 (H type)
Subjected to ion exchange chromatography using
Elute with 5% aqueous ammonia and concentrate the eluate to obtain an oil. This was subjected to column chromatography using silica gel, eluted with ethyl acetate/methanol (4:1, v/v), and the eluate was concentrated.
2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole 245 mg as oil
get. Yield 48.1%. Monomaleate has a melting point
Shows 146-148℃.
実施例 ２
２―グアニジノ―４―〔（２―（ホルムアミド）
エチルチオ）（１―メトキシカルボニル）メチル〕
チアゾール340mg、ヨウ化リチウム500mgおよびジ
メチルホルムアミド2.5mlからなる混合液を150℃
で１時間撹拌する。反応液から溶媒を減圧留去
し、残渣をシリカゲルにてカラムクロマトグラフ
イーに付し、酢酸エチル／メタノール（４：１、
ｖ／ｖ）で溶出する。溶出液を濃縮し、油状物と
して２―グアニジノ―４―〔２―（ホルムアミ
ド）エチルチオメチル〕チアゾール135mgを得る。
収率48.6％。Example 2 2-guanidino-4-[(2-(formamide)
ethylthio)(1-methoxycarbonyl)methyl]
A mixture of 340 mg of thiazole, 500 mg of lithium iodide and 2.5 ml of dimethylformamide was heated at 150°C.
Stir for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was subjected to column chromatography on silica gel, and ethyl acetate/methanol (4:1,
v/v). The eluate was concentrated to obtain 135 mg of 2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole as an oil.
Yield 48.6%.
実施例 ３
原料として２―グアニジノ―４―〔２―（ホル
ムアミド）エチルチオメチル〕―５―メトキシカ
ルボニルチアゾール（融点167〜172℃（分解））
を使用して、実施例１の反応を行い、同様の収率
で２―グアニジノ―４―〔２―（ホルムアミド）
エチルチオメチル〕チアゾールを得る。Example 3 2-guanidino-4-[2-(formamido)ethylthiomethyl]-5-methoxycarbonylthiazole (melting point 167-172°C (decomposition)) as a raw material
The reaction of Example 1 was carried out using 2-guanidino-4-[2-(formamide)
Ethylthiomethyl]thiazole is obtained.
実施例 ４
原料として２―グアニジノ―４―〔（２―（ホ
ルムアミド）エチルチオ）（１―エトキシカルボ
ニル）メチル〕チアゾール・マレイン酸塩（融点
160〜162℃（分解））を使用して、実施例２の反
応を行い、同様の収率で２―グアニジノ―４―
〔２―（ホルムアミド）エチルチオメチル〕チア
ゾールを得る。Example 4 2-guanidino-4-[(2-(formamido)ethylthio)(1-ethoxycarbonyl)methyl]thiazole maleate (melting point
The reaction of Example 2 was carried out using a temperature of 160-162°C (decomposition) to give 2-guanidino-4-
[2-(formamido)ethylthiomethyl]thiazole is obtained.
参考例 １
グアニルチオ尿素8.9ｇおよびアセトン150mlか
らなる溶液に２，４―ジクロルアセト酢酸エチル
〔Chem.Abstr.，74，3229v（1971）〕15.0ｇを加
え、室温下に２時間撹拌する。反応液を減圧濃縮
し、残渣にエタノール150mlを加え、２時間還流
する。反応液を約1/3容量まで減圧濃縮し、析出
する結晶を取し、エタノールで洗浄し、融点
230〜237℃（分解）の結晶として２―グアニジノ
―４―クロルメチル―５―エトキシカルボニルチ
アゾール塩酸塩15.1PHを得る。収率64.4％。Reference example 1 15.0 g of ethyl 2,4-dichloroacetoacetate [Chem.Abstr., 74 , 3229v (1971)] is added to a solution consisting of 8.9 g of guanylthiourea and 150 ml of acetone, and the mixture is stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 150 ml of ethanol was added to the residue, and the mixture was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure to about 1/3 volume, the precipitated crystals were collected, washed with ethanol, and the melting point
2-guanidino-4-chloromethyl-5-ethoxycarbonylthiazole hydrochloride 15.1PH is obtained as crystals at 230-237°C (decomposition). Yield 64.4%.
50％水素化ナトリウム102mgおよび乾燥ジメチ
ルホルムアミド２mlからなる溶液に−10〜−５℃
にてＮ―ホルミルシステアミン111mgおよび乾燥
ジメチルホルムアミド２mlからなる懸濁液を滴下
し、同温度下に30分間撹拌する。これに２―グア
ニジノ―４―クロルメチル―５―エトキシカルボ
ニルチアゾール329mgを−４〜０℃にて少量ずつ
加え、約１時間で室温に戻し、室温下に２時間撹
拌する。反応液を減圧濃縮し、残渣をシリカゲル
によるカラムクロマトグラフイーに付し、酢酸エ
チル／メタノール（４：１，ｖ／ｖ）で溶出す
る。溶出液を濃縮し、得られる油状物をエーテル
で洗浄して結晶化する。結晶に含水メタノール20
mlを加え、１時間還流し、溶媒を留去する。得ら
れる結晶をエーテルで洗浄し、２―グアニジノ―
４―〔２―（ホルムアミド）エチルチオメチル〕
―５―エトキシカルボニルチアゾール305mgを得
る。収率86.7％。融点145〜147℃（分解）。 A solution consisting of 102 mg of 50% sodium hydride and 2 ml of dry dimethylformamide at -10 to -5°C.
A suspension consisting of 111 mg of N-formylcysteamine and 2 ml of dry dimethylformamide was added dropwise thereto, and the mixture was stirred at the same temperature for 30 minutes. To this, 329 mg of 2-guanidino-4-chloromethyl-5-ethoxycarbonylthiazole was added little by little at -4 to 0°C, the mixture was warmed to room temperature in about 1 hour, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography on silica gel, eluting with ethyl acetate/methanol (4:1, v/v). The eluate is concentrated and the resulting oil is washed with ether and crystallized. Water-containing methanol 20% in crystals
ml, refluxed for 1 hour, and the solvent was distilled off. The obtained crystals were washed with ether and 2-guanidino-
4-[2-(formamido)ethylthiomethyl]
-305 mg of 5-ethoxycarbonylthiazole is obtained. Yield 86.7%. Melting point 145-147°C (decomposition).
元素分析 C11H17N5O3S2として
計算値 Ｃ，39.86；Ｈ，5.17；Ｎ，21.13；Ｓ，
19.35（％）
実験値 Ｃ，39.85；Ｈ，5.12；Ｎ，20.80；Ｓ，
19.65（％）
NBR（DMSO）， δ 4.03（ｓ，2H）
7.97（ｓ，1H）
参考例 ２
ジケテン29.5ｇおよび四塩化炭素80mlからなる
溶液を−20℃に冷却し、これに塩素24.9ｇおよび
四塩化炭素100ｇからなる溶液を内温０℃以下に
て滴下する。得られる４―クロルアセトアセチル
クロリドを含む反応液を−15℃以下に冷却しなが
ら、これにメタノール11.2ｇ、ピリジン38.0mlお
よび塩化メチレン160mlからなる混合液を−40℃
に冷却して滴下する。反応液に水を加え、有機層
を分取し、水洗し、乾燥し、減圧濃縮する。残渣
をシリカゲルにてカラムクロマトグラフイーに付
し、エーテル：ｎ―ヘキサン（１：１，ｖ／ｖ）
で溶出する。溶出液を減圧濃縮し、残渣を蒸留し
て沸点90〜97℃／13mmＨｇの油状物として４―ク
ロルアセト酢酸メチル21.5ｇを得る。 Elemental analysis C 11 H 17 N 5 O 3 S 2 Calculated value C, 39.86; H, 5.17; N, 21.13; S,
19.35 (%) Experimental value C, 39.85; H, 5.12; N, 20.80; S,
19.65 (%) NBR (DMSO), δ 4.03 (s, 2H) 7.97 (s, 1H) Reference example 2 A solution consisting of 29.5 g of diketene and 80 ml of carbon tetrachloride is cooled to -20°C, and a solution consisting of 24.9 g of chlorine and 100 g of carbon tetrachloride is added dropwise thereto at an internal temperature of 0°C or less. While cooling the resulting reaction solution containing 4-chloroacetoacetyl chloride to below -15°C, a mixture of 11.2 g of methanol, 38.0 ml of pyridine, and 160 ml of methylene chloride was added to -40°C.
Cool and drip. Water is added to the reaction solution, and the organic layer is separated, washed with water, dried, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel, and ether:n-hexane (1:1, v/v)
Elutes with The eluate was concentrated under reduced pressure, and the residue was distilled to obtain 21.5 g of methyl 4-chloroacetoacetate as an oil with a boiling point of 90-97°C/13 mmHg.
４―クロルアセト酢酸メチル21.5ｇおよび塩化
メチレン45mlからなる溶液に−５〜０℃に冷却下
スルフリルクロリド11.5mlおよび塩化メチレン25
mlからなる溶液を滴下し、室温下に４時間撹拌す
る。反応液を減圧濃縮し、残渣を蒸留し、沸点71
〜73℃／２mmＨｇの油状物として２，４―ジクロ
ルアセト酢酸メチル22.9ｇを得る。収率86.8％。 To a solution consisting of 21.5 g of methyl 4-chloroacetoacetate and 45 ml of methylene chloride was added 11.5 ml of sulfuryl chloride and 25 ml of methylene chloride while cooling at -5 to 0°C.
ml of the solution was added dropwise and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was distilled, and the boiling point was 71.
22.9 g of methyl 2,4-dichloroacetoacetate are obtained as an oil at ~73°C/2 mmHg. Yield 86.8%.
２，４―ジクロルアセト酢酸メチル9.25ｇおよ
び塩化メチレン50mlからなる溶液に撹拌下―５〜
０℃に冷却しながらＮ―ホルミルシステアミン
5.26ｇ、トリエチルアミン5.05ｇおよび塩化メチ
レン50mlからなる溶液を滴下し、−５〜５℃にて
1.5時間撹拌する。反応液を減圧濃縮し、残渣に
酢酸エチルを加え、不溶物を去する。液をシ
リカゲルによるカラムクロマトグラフイーに付
し、酢酸エチルで溶出する。溶出液を濃縮し、油
状物を得る。これをエーテルで洗浄して結晶化さ
せ、４―クロル―２―〔２―（ホルムアミド）エ
チルチオ〕アセト酢酸メチル7.60PH得る。収率
56.6％。 Add 5~ to a solution of 9.25 g of methyl 2,4-dichloroacetoacetate and 50 ml of methylene chloride while stirring.
N-formylcysteamine while cooling to 0°C.
A solution consisting of 5.26g of triethylamine, 5.05g of triethylamine, and 50ml of methylene chloride was added dropwise at -5 to 5℃.
Stir for 1.5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue to remove insoluble matter. The solution was subjected to column chromatography using silica gel and eluted with ethyl acetate. Concentrate the eluate to obtain an oil. This is washed with ether and crystallized to obtain 7.60 PH of methyl 4-chloro-2-[2-(formamido)ethylthio]acetoacetate. yield
56.6%.
NMR（CDCl3） δ 3.87（ｓ，3H）
4.60（ｓ，2H）
8.07（br.s，1H）
４―クロル―２―〔２―（ホルムアミド）エチ
ルチオ〕アセト酢酸メチル1.03ｇ、グアニルチオ
尿素510mg、ヨウ化カリウム710mgおよびアセトン
10mlからなる懸濁液を室温下25時間撹拌する。反
応液にトリエチルアミン409mgを加え、不溶物を
去し、液を濃縮する。残渣をシリカゲルによ
るカラムクロマトグラフイーに付し、メタノー
ル／酢酸エチル（１：９、ｖ／ｖ）で溶出する。
溶出液を濃縮し、油状物として２―グアニジノ―
４―〔（２―（ホルムアミド）エチルチオ）（１―
メトキシカルボニル）メチル〕チアゾール1.02ｇ
を得る。収率78.5％。 NMR (CDCl 3 ) δ 3.87 (s, 3H) 4.60 (s, 2H) 8.07 (br.s, 1H) Methyl 4-chloro-2-[2-(formamido)ethylthio]acetoacetate 1.03g, guanylthiourea 510mg, potassium iodide 710mg and acetone
The suspension consisting of 10 ml is stirred at room temperature for 25 hours. Add 409 mg of triethylamine to the reaction solution, remove insoluble matter, and concentrate the solution. The residue is subjected to column chromatography on silica gel and eluted with methanol/ethyl acetate (1:9, v/v).
The eluate was concentrated and 2-guanidino-
4-[(2-(formamido)ethylthio)(1-
methoxycarbonyl)methyl]thiazole 1.02g
get. Yield 78.5%.
NMR（CDCl3） δ 2.6〜2.9（ｍ，2H） 3.5〜3.2（ｍ，2H） 3.60（ｓ，3H） 4.77（ｓ，1H） 6.77（ｓ，1H） 8.07（ｓ，1H） NMR (CDCl 3 ) δ 2.6-2.9 (m, 2H) 3.5-3.2 (m, 2H) 3.60 (s, 3H) 4.77 (s, 1H) 6.77 (s, 1H) 8.07 (s, 1H)
Claims (1)
シカルボニル基、他方は水素をそれぞれ表わす。）
で示されるエステルを脱アルコキシカルボニル化
反応に付すことを特徴とする２―グアニジノ―４
―〔２―（ホルムアミド）エチルチオメチル〕チ
アゾールの合成法。[Claims] 1. General formula (In the formula, one of X and Y represents an alkoxycarbonyl group, and the other represents hydrogen.)
2-guanidino-4 characterized by subjecting the ester represented by to a dealkoxycarbonylation reaction
- Synthesis method of [2-(formamido)ethylthiomethyl]thiazole.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17239281A JPS5872572A (en) | 1981-10-27 | 1981-10-27 | Synthetic method for 2-guanidino-4-(2-(formamide) ethylthiomethyl)thiazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17239281A JPS5872572A (en) | 1981-10-27 | 1981-10-27 | Synthetic method for 2-guanidino-4-(2-(formamide) ethylthiomethyl)thiazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5872572A JPS5872572A (en) | 1983-04-30 |
| JPH0139429B2 true JPH0139429B2 (en) | 1989-08-21 |
Family
ID=15941074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17239281A Granted JPS5872572A (en) | 1981-10-27 | 1981-10-27 | Synthetic method for 2-guanidino-4-(2-(formamide) ethylthiomethyl)thiazole |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5872572A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20230349922A1 (en) | 2020-08-11 | 2023-11-02 | Université De Strasbourg | H2 Blockers Targeting Liver Macrophages for the Prevention and Treatment of Liver Disease and Cancer |
-
1981
- 1981-10-27 JP JP17239281A patent/JPS5872572A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5872572A (en) | 1983-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3895028A (en) | Alpha-(2-phenylbenzothiazol-5-yl)propionic acid | |
| KR850000923B1 (en) | Process for preparing piroxicam | |
| US20060148866A1 (en) | Novel process for preparing pramipexole and its optical isomeric mixture by reduction with sodium triacetoxyborohydride | |
| EP0000200A1 (en) | New N-amidino-3,5-diamino-6-substituted-2-pyrazinecarboxamides and process for preparing same | |
| EP3088391B1 (en) | Method for producing benzyl ester 2-aminonicotinate derivative | |
| JPH0139429B2 (en) | ||
| AU600838B2 (en) | Process for the preparation of dextrorotatory 3-(3-pyridyl)-1H, 3H-pyrrolo(1,2-c)-7-thiazolecarboxylic acid | |
| JP2000026418A (en) | Novel method for producing derivatives of 4-phenyl-1,2,3,6-tetrahydropyridine and intermediates used | |
| JPH0331265A (en) | Production of tetrahydropyrimidine derivatives | |
| JP2640980B2 (en) | N @ 6, N @ 6--disubstituted-adenosine-3 ', 5'-cyclic phosphoric acid and process for producing the same | |
| JP3059007B2 (en) | Method for producing 1- (2-carboxyphenyl) indazole derivative | |
| JPS621941B2 (en) | ||
| JPH0452272B2 (en) | ||
| JPH0234943B2 (en) | ||
| JPH0139428B2 (en) | ||
| JP2903805B2 (en) | Preparation of optically active benzyl glycidyl ether | |
| JP3499896B2 (en) | Method for producing 2'-deoxynucleosides | |
| JPS637554B2 (en) | ||
| JP3007962B2 (en) | Fluorinated α-indolepropionic acids, production method thereof and plant growth regulator containing the same as active ingredient | |
| JP3272340B2 (en) | Method for producing 1-[(cyclopent-3-en-1-yl) methyl] -5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione | |
| JPH0832681B2 (en) | 2-Yododobutyrophenone derivative and process for producing the same | |
| JPH1029981A (en) | Method for producing hexahydropyridazines | |
| JPH05213903A (en) | Production of acyclonucleoside derivative | |
| US20090281301A1 (en) | Manufacturing Process of 2' ,2' - Difluoronucleoside and Intermediate | |
| Orr et al. | Improved Synthesis of 5-benzyl-2-thiouracils |