JPH01313471A - Production of n-sulfamoylamidine compound - Google Patents
Production of n-sulfamoylamidine compoundInfo
- Publication number
- JPH01313471A JPH01313471A JP63190770A JP19077088A JPH01313471A JP H01313471 A JPH01313471 A JP H01313471A JP 63190770 A JP63190770 A JP 63190770A JP 19077088 A JP19077088 A JP 19077088A JP H01313471 A JPH01313471 A JP H01313471A
- Authority
- JP
- Japan
- Prior art keywords
- compd
- formula
- sulfamide
- compound
- mixture
- 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 6
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000004665 trialkylsilyl group Chemical group 0.000 claims abstract 2
- -1 imidate compound Chemical class 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 18
- 238000000034 method Methods 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000002798 polar solvent Substances 0.000 abstract description 3
- 239000011541 reaction mixture Substances 0.000 abstract description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 abstract 2
- 230000000767 anti-ulcer Effects 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000007787 solid Substances 0.000 description 4
- JTXGYVNOGARALA-UHFFFAOYSA-M tetrabutylazanium chloride trihydrate Chemical compound O.O.O.[Cl-].C(CCC)[N+](CCCC)(CCCC)CCCC JTXGYVNOGARALA-UHFFFAOYSA-M 0.000 description 4
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000005828 desilylation reaction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BVVZNAYIQWLKRH-UHFFFAOYSA-N 2-[dimethyl-(sulfamoylamino)silyl]-2-methylpropane Chemical compound C(C)(C)(C)[Si](NS(=O)(=O)N)(C)C BVVZNAYIQWLKRH-UHFFFAOYSA-N 0.000 description 1
- 229910003600 H2NS Inorganic materials 0.000 description 1
- AYDOWLQVELNYEE-UHFFFAOYSA-N [dimethyl-(sulfamoylamino)silyl]methane Chemical compound C[Si](C)(C)NS(N)(=O)=O AYDOWLQVELNYEE-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- ZTEHTGMWGUKFNE-UHFFFAOYSA-N methyl 3-[[2-(diaminomethylideneamino)-1,3-thiazol-4-yl]methylsulfanyl]propanimidate Chemical compound COC(=N)CCSCC1=CSC(N=C(N)N)=N1 ZTEHTGMWGUKFNE-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- WTZIORLRPKTMHE-UHFFFAOYSA-N n'-sulfamoylpropanimidamide Chemical compound CCC(=N)NS(N)(=O)=O WTZIORLRPKTMHE-UHFFFAOYSA-N 0.000 description 1
- GNFWGDKKNWGGJY-UHFFFAOYSA-N propanimidamide Chemical compound CCC(N)=N GNFWGDKKNWGGJY-UHFFFAOYSA-N 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は抗潰瘍治療剤として有用な次式（１）で示され
るＮ−スルファモイル−３−［（２−／’アニジノチア
ゾールー４−イル）メチルチオ〕プロピオンアミジン（
以下、Ｎ−スルファモイルアミジン化合物と記す）の新
規な製造法忙関する。Detailed Description of the Invention (Industrial Field of Application) The present invention provides N-sulfamoyl-3-[(2-/'anidinothiazole-4- yl) methylthio] propionamidine (
The present invention relates to a novel method for producing N-sulfamoylamidine compounds (hereinafter referred to as N-sulfamoylamidine compounds).
（従来の技術及び発明が解決しようとする課題）前記の
Ｎ−スルファモイルアミジン化合物の製造法としては特
開昭５５−１１８４７６号公報、 同５６−５４６９号
公報、 同５６−５５３８３号公報、同５６−１２２３
６ｇ号公報及び同５６−１０ｐ７７７号公報並びに欧州
特許第８７２１４号公報及び同第１２８１３６号公報等
に記載の方法が知られているが、これら記載の製造法は
収率は多少良くない上に、副生成物が相当多く生成する
という欠点があった。(Prior Art and Problems to be Solved by the Invention) Methods for producing the above-mentioned N-sulfamoylamidine compound are disclosed in JP-A-55-118476, JP-A-56-5469, JP-A-56-55383, 56-1223
The methods described in European Patent Nos. 6g and 56-10p777, European Patent Nos. 87214 and 128136, etc. are known, but the production methods described in these methods have somewhat poor yields, and The drawback was that a considerable amount of by-products were produced.
（課題を解決するための手段２作用）
本発明者らは、従来のＮ−スルファモイルアミジン化合
物の製造法の欠点を改善すべく鋭意研究を重ねた結果、
収率が極めて良く、副生成物の副生がほとんどない、高
純度のＮ−スルファモイル化合物を簡便に製造できる経
済的な製造法を見出し、本発明を完成するに至った。(Means for Solving the Problems 2) As a result of intensive research to improve the shortcomings of conventional methods for producing N-sulfamoylamidine compounds, the present inventors have found that:
The present inventors have discovered an economical method for easily producing a highly pure N-sulfamoyl compound with extremely good yields and almost no by-products, and have completed the present invention.
すなわち、本発明は一般式
（式中、Ｒ１は低級アルキル基例えばメチル基又はエチ
ル基等を表わす）で示されるイミデート化合物と一般式
％式％（）
等を表わす）で示されるシリル化スルファミドを反応さ
せて一般式
（式中、Ｒ２は前記と同一の意味を表わす）で示される
化合物を生成させ、次いでこの化合物を水溶性アルコー
ル中で脱シリル“化処理することを特徴とする次式
で示されるＮ−スルファモイルアミジン化合物の製造法
である。That is, the present invention combines an imidate compound represented by the general formula (wherein R1 represents a lower alkyl group, such as a methyl group or an ethyl group) and a silylated sulfamide represented by the general formula A compound represented by the general formula (in the formula, R2 represents the same meaning as above) is produced by the reaction, and then this compound is subjected to a desilylation treatment in a water-soluble alcohol. 1 is a method for producing the shown N-sulfamoylamidine compound.
本発明の方法は、前記一般式（ＩＩ）で示されるイミデ
ート化合物と前記一般式（ＩＩＩ）で示されるシリル化
スルファミドを適当な非プロトン性極性溶媒に溶かし、
４０〜６０°Ｃ１好ましくは約ｓｏ’ｃ〜６０°Ｃの温
度で１２時間前後攪拌して反応させることによって前記
一般式（ＥＶ）で示されるシリル化化合物を生成させ、
得られた反応混合物を減圧、下に常法によって濃縮し、
次いで得られた残留物をメタノール等の低級アルコール
に溶かし、更に少量の水と第４級アンモニウム塩とを加
え常温で数時間〜２４時間借拌口説シリル化反応させ、
得られた反応混合物を常法によって後処理することＫよ
つ、て行なわれ、高純度の前記一般式（１１で示される
Ｎ−スルファモイルアミジン化合物が製造でき。The method of the present invention includes dissolving the imidate compound represented by the general formula (II) and the silylated sulfamide represented by the general formula (III) in a suitable aprotic polar solvent,
A silylated compound represented by the general formula (EV) is produced by stirring and reacting at a temperature of 40 to 60 °C, preferably about 60 °C for about 12 hours,
The resulting reaction mixture was concentrated under reduced pressure in a conventional manner,
Next, the obtained residue is dissolved in a lower alcohol such as methanol, a small amount of water and a quaternary ammonium salt are added, and the mixture is stirred at room temperature for several hours to 24 hours to undergo a silylation reaction.
The resulting reaction mixture is post-treated by a conventional method, and a highly pure N-sulfamoylamidine compound represented by the general formula (11) can be produced.
る。Ru.
本発明の方法で使用する非プロトン性極性溶媒としては
、アセトニトリル、 ジオキサン、 テトラヒドロフラ
ン、 Ｎ、Ｎ−Ｅ；メチルホルムアミドが好ましい。As the aprotic polar solvent used in the method of the present invention, acetonitrile, dioxane, tetrahydrofuran, N, NE; methylformamide are preferred.
また、反応原料として使用する前記一般式（［１）で示
されるシリル化スルファミドはスルファミド（Ｈ２ＮＳ
０２ＮＨ２）とへキサメチルジシラザン（Ｃ（ＣＨ３）
ｓ Ｓ ＋ ：） ２ ）又はｔ−ブチルジメチルシ
リルクロリドＣｔ−Ｃ４Ｈ，（ＣＨ３）２５ｉＣ７，］
等のトリアルキルシリル化剤を反応させることにより容
易に調製することができ、あらかじめ調製されたものを
使用してもよいし、あるいはＮ−スルファモイルアミジ
ン化合物の製造に際し使用する反応器中で上記のように
して使用の直前に調製して使用することもできる。In addition, the silylated sulfamide represented by the general formula ([1)] used as a reaction raw material is sulfamide (H2NS
02NH2) and hexamethyldisilazane (C(CH3)
s S + :) 2 ) or t-butyldimethylsilyl chloride Ct-C4H, (CH3)25iC7,]
It can be easily prepared by reacting a trialkyl silylating agent such as N-sulfamoylamidine compound, and it can be prepared in advance, or it can be prepared in a reactor used for producing the N-sulfamoylamidine compound. It can also be prepared and used immediately before use as described above.
本発明の方法においては前記一般式（ＩＩ）で示される
イミデート化合物と前記一般式（Ｅｌｌ）で示されるス
ルファミド化合物との反応により中間生成物として前記
一般式（ｒＶ）で示されるシリル化化合物が生成するが
、これは単離して次の脱シリル化反応に供することもで
きるが、通常は単離せずにそのまま即時に水溶性アルコ
ールを加えて脱シリル此処！することによって一浴で、
簡便に高収率で目的とする前記一般式（１）で示される
Ｎ−スルファモイルアミジン化合物を製造することがで
きる。In the method of the present invention, the silylated compound represented by the general formula (rV) is produced as an intermediate product by the reaction of the imidate compound represented by the general formula (II) with the sulfamide compound represented by the general formula (Ell). Although this product can be isolated and subjected to the next desilylation reaction, it is usually not isolated and is immediately added with a water-soluble alcohol to desilylate it. By taking a bath,
The desired N-sulfamoylamidine compound represented by the general formula (1) can be easily produced in high yield.
本発明の方法は、（１）全収率が良（、反応操作が簡便
であること、（２〕従来の製造法で問題となる副生成物
が全く生成せず高純度のＮ−スルファモイルアミジン化
合物が製造できること、（３）一つの反応器で全工程を
遂行させる事が可能であり、目的生成物の分離が容易で
且つ高純度で製造できること等の利点を有する。The method of the present invention has (1) a good overall yield (and simple reaction operation), and (2) no by-products, which are problematic in conventional production methods, are produced and high purity N-sulfur is produced. It has the advantages of being able to produce a moylamidine compound, and (3) being able to carry out all the steps in one reactor, making it easy to separate the target product, and producing it with high purity.
（実施例）
以下、参考例及び実施例により本発明を更に詳細に説明
する。(Example) Hereinafter, the present invention will be explained in more detail with reference to Reference Examples and Examples.
参考例
スルファミド（９，８５’）をアセトニトリル（＋ｏｏ
ｍｚ）に懸濁させ、次いでこれにヘキサメチルジシラザ
ン（１２ｙｄ）を加え、加熱還流下に反応させ澄明な反
応溶液を得た。この反応溶液を減圧下に濃縮し、Ｎ−）
リメチルシリルスルファミド（１６，８９）を得た。Reference Example Sulfamide (9,85') was mixed with acetonitrile (+oo
mz), then hexamethyldisilazane (12yd) was added thereto, and the mixture was reacted under heating under reflux to obtain a clear reaction solution. The reaction solution was concentrated under reduced pressure and N-)
Limethylsilylsulfamide (16,89) was obtained.
融点：５７〜５８°Ｃ
” Ｈ−ＮＭＲ（ＣＤ Ｃ１３）δ値：０．３Ｃ５，９
Ｈ，−３１（Ｃ）Ｉ５）３］実施例Ｉ
Ｎ−トリメチルシリルスルファミド（２６，７ｆ）をア
セトニトリル（＋５０１１１／）に溶解し、これにメチ
ル ３４（２−グアニジノチアゾール−４−イル）メチ
ルチオ〕プロピオンイミデート（２４，６５’）を加え
、攪拌下５０°Ｃで１２時間反応させた。得られた反応
液から減圧下に溶媒を留去して残留物を得、これにメタ
ノール（＋５０ｄ）を加えて溶解し、次いでテトラブチ
ルアンモニウムクロライド・３水和物（５り）と水（＋
５−）を加え、攪拌上常温で約３時間反応させた後、４
０Ｃで１夜放置した。次いで生成した固体をｒ過し、Ｄ
ＭＦ −Ｈ２０混合溶媒で結晶化させ、３−〔（２−グ
アニジノチアゾール−４−イル）メチルチオ］−Ｎ−ス
ルファモイルプロピオンアミジン（２４，２Ｐ）を得た
。Melting point: 57-58°C ” H-NMR (CD C13) δ value: 0.3C5,9
H, -31(C)I5)3] Example I N-trimethylsilylsulfamide (26,7f) was dissolved in acetonitrile (+50111/) and methyl 34(2-guanidinothiazol-4-yl)methylthio ] Propionimidate (24,65') was added, and the mixture was reacted at 50°C for 12 hours with stirring. The solvent was distilled off from the resulting reaction solution under reduced pressure to obtain a residue, which was dissolved in methanol (+50d), and then tetrabutylammonium chloride trihydrate (5) and water (+
5-) was added and reacted with stirring at room temperature for about 3 hours.
It was left overnight at 0C. The formed solid was then filtered and D
Crystallization was performed using a mixed solvent of MF-H20 to obtain 3-[(2-guanidinothiazol-4-yl)methylthio]-N-sulfamoylpropionamidine (24,2P).
融点＝１６３〜１６４°Ｃ
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ値： ６．４５（ｓ
、ＩＨ）、 ３．６０（ｓ。Melting point = 163-164°C 1H-NMR (DMSO-d6) δ value: 6.45 (s
, IH), 3.60 (s.
２Ｈ）、 ２．６５（ｍ、２Ｈ）。2H), 2.65 (m, 2H).
２．５０（ｍ、２Ｈ）。2.50 (m, 2H).
実施例２
Ｎ−（ｔ−ブチルジメチルシリル）スルファミド（３，
５９）をアセトニトリル（＋！ｌ＋−）にｆ［し、これ
忙メチル ３−［（２−グアニジノチアゾール−４−イ
ル）メチルチオ〕プロピオンイミデート（２，５Ｆ ）
を加え、攪拌下６０°Ｃで１２時間反応させた。得られ
た反応液から減圧下に溶媒を留去して残留物を得、これ
にメタノール（１〇−）を加えて溶解し、次いでテトラ
ブチルアンモニウムクロライド・３水和物（２２）と水
（５−）を加え、攪拌下に常温で１夜反応させた。次い
で生成した固体をｒ過し、減圧乾燥し３−［（２−グア
ニジノチアゾール−４−イル）メチルチオクーＮ−スル
ファモイルプロピオンアミジン（２，１？）を得た。Example 2 N-(t-butyldimethylsilyl)sulfamide (3,
59) in acetonitrile (+!l+-) and then diluted with methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate (2,5F).
was added, and the mixture was reacted at 60°C for 12 hours with stirring. The solvent was distilled off from the resulting reaction solution under reduced pressure to obtain a residue, which was dissolved by adding methanol (10-), and then mixed with tetrabutylammonium chloride trihydrate (22) and water ( 5-) was added, and the mixture was reacted overnight at room temperature with stirring. The resulting solid was then filtered and dried under reduced pressure to obtain 3-[(2-guanidinothiazol-4-yl)methylthiocou N-sulfamoylpropionamidine (2,1?).
実施例３
スルファミド（１４，８９）をアセトニトリル（７０−
）に懸濁させ、次いでこれにヘキサメチルジシラザン（
１６ｍ／）を加え、加熱還流下に５時間反応させた後、
減圧下に濃縮した。得られた残留物にアセトニトリル（
８０ｉ）を加えて溶解し、次いでメチル ３−ＣＣ２−
グアニジノチアゾリル−４−イル）メチルチオ〕プロピ
オンイミデー）（２７，３ｆ）を加え、攪拌下４０〜５
０°Ｃで１２時間反応させた。得られた反応液から減圧
下忙溶媒を留去して残留物を得、これにメタノール（＋
５Ｏ−）を加えて溶解し、次いでテトラアンモニウムク
ロライド・３水和物（５９）と水（１５−）を加え、攪
拌下に常温で２４時間反応させ（攪拌すると結晶性固体
が生成する）、その後４°Ｃで１夜放置した。次いで反
応液を１過し、得られた固体を冷メタノール（２０−）
で洗滌した後、ＤＭＦ −Ｈ２０混合溶媒から結晶化さ
せ３−［（２−グアニジノチアゾール−４−イル）メチ
ルチオクーＮ−スルファモイルプロピオンアミジン（２
８ｔ）を得た。Example 3 Sulfamide (14,89) was converted into acetonitrile (70-
) and then suspended in hexamethyldisilazane (
After adding 16 m/) and reacting for 5 hours under heating and reflux,
Concentrate under reduced pressure. Add acetonitrile (
80i) and dissolve, then methyl 3-CC2-
Add guanidinothiazolyl-4-yl)methylthio]propionimide) (27,3f) and stir for 40-50 min.
The reaction was carried out at 0°C for 12 hours. The solvent was distilled off from the resulting reaction solution under reduced pressure to obtain a residue, which was mixed with methanol (+
5O-) and dissolve it, then add tetraammonium chloride trihydrate (59) and water (15-), and react with stirring at room temperature for 24 hours (stirring produces a crystalline solid), Thereafter, it was left at 4°C overnight. Then, the reaction solution was filtered once, and the obtained solid was poured into cold methanol (20-).
After washing with
8t) was obtained.
Claims (1)
イミデート化合物と一般式 Ｈ＿２ＮＳＯ＿２ＮＨＲ＿２（III） （式中、Ｒ＿２はトリアルキルシリル基を表わす）で示
されるシリル化スルファミドを反応させて一般式 ▲数式、化学式、表等があります▼（IV） （式中、Ｒ＿２は前記と同一の意味を表わす）で示され
る化合物を生成させ、次いでこの化合物を水溶性アルコ
ール中で脱シリル化処理することを特徴とする次式 ▲数式、化学式、表等があります▼（ I ） で示されるＮ−スルファモイルアミジン化合物の製造法
。[Claims] An imidate compound represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (in the formula, R_1 represents a lower alkyl group) and the general formula H_2NSO_2NHR_2 (III) (in the formula, R_2 represents a trialkylsilyl group) to react with a silylated sulfamide represented by the general formula ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (IV) (wherein R_2 represents the same meaning as above) The N-sulfamoylamidine compound represented by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) characterized by producing a compound and then desilylating this compound in a water-soluble alcohol Manufacturing method.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR6994 | 1986-08-23 | ||
| KR1019880006994A KR900004907B1 (en) | 1988-06-10 | 1988-06-10 | The preparation for n - sulfamoyl -3- ((2-guanidinothiazole -4- yl) methylthio) propion amidine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01313471A true JPH01313471A (en) | 1989-12-18 |
Family
ID=19275113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63190770A Pending JPH01313471A (en) | 1988-06-10 | 1988-08-01 | Production of n-sulfamoylamidine compound |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPH01313471A (en) |
| KR (1) | KR900004907B1 (en) |
| DE (1) | DE3831162A1 (en) |
| GB (1) | GB2220415B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5856500A (en) * | 1997-03-11 | 1999-01-05 | Albemarle Corporation | Synthesis of thiazole derivatives |
| US5731442A (en) * | 1997-03-11 | 1998-03-24 | Albemarle Corporation | Synthesis of thiazole derivatives |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59227870A (en) * | 1983-06-07 | 1984-12-21 | Yamanouchi Pharmaceut Co Ltd | Novel 2-guanidinothiazoline derivative and its preparation |
| DE3644246A1 (en) * | 1986-06-20 | 1987-12-23 | Uriach & Cia Sa J | Process for the preparation of 3-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]-N-(aminosulp honyl)propaneimideamide |
-
1988
- 1988-06-10 KR KR1019880006994A patent/KR900004907B1/en not_active IP Right Cessation
- 1988-08-01 JP JP63190770A patent/JPH01313471A/en active Pending
- 1988-09-05 GB GB8820830A patent/GB2220415B/en not_active Expired - Lifetime
- 1988-09-13 DE DE3831162A patent/DE3831162A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| DE3831162C2 (en) | 1992-02-20 |
| GB2220415B (en) | 1991-12-18 |
| DE3831162A1 (en) | 1989-12-14 |
| GB8820830D0 (en) | 1988-10-05 |
| KR900004907B1 (en) | 1990-07-09 |
| GB2220415A (en) | 1990-01-10 |
| KR900000346A (en) | 1990-01-30 |
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