CN86105909A - 制备n-氨磺酰-3-(2-胍基-噻唑-4-基-甲硫基)-丙脒的方法 - Google Patents
制备n-氨磺酰-3-(2-胍基-噻唑-4-基-甲硫基)-丙脒的方法 Download PDFInfo
- Publication number
- CN86105909A CN86105909A CN86105909.3A CN86105909A CN86105909A CN 86105909 A CN86105909 A CN 86105909A CN 86105909 A CN86105909 A CN 86105909A CN 86105909 A CN86105909 A CN 86105909A
- Authority
- CN
- China
- Prior art keywords
- thiazole
- base
- guanidine radicals
- sulphonamide
- amidine
- 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 - Lifetime
Links
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
- C07D277/32—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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Abstract
本发明涉及通过由式(III)S-(2-胍基-噻唑-4-基-甲基)-异硫脲的二盐酸盐就地用碱处理所得到的2-胍基-噻唑-4-基-甲硫醇的S-烷基化制备式(I)N-氨磺酰-3-(2-胍基-噻唑-4-基-甲硫基)-丙脒(famotidine)的新方法，该方法包括用式(II)N-氨磺酰-3-卤代-丙脒进行S-烷基化(式II中X代表卤素)。
Description
本发明涉及通过由式（Ⅲ）S-（2-胍基-噻唑-4-基-甲基）-异硫脲的二盐酸盐
所得到的2-胍基-噻唑-4-基-甲硫醇的S-烷基化制备式（Ⅰ）N-氨磺酰-3-（2-胍基-噻唑-4-基-甲硫基）丙脒（famotidine）的新方法。
Famotidine是最有希望的抗溃疡化合物之一，基于组胺H2-受体阻断机理，抑制胃溃疡和肠道溃疡。它的效力比甲腈咪胍约高一个数量级（Arznein、Forsch.，32，734/1982/），它的日用剂量仅1×40mg，相应的甲腈咪胍的日用剂量为4×200mg，并且它不具有抗雄激素活性。
制备famotidine的许多方法都是已知的技术，例如，美国专利说明书4，283，408号（Yamanouchi）。第一次描述用3-（2-胍基-噻唑-4-基-甲硫基）-丙腈作原料的方法。首先用已知化学方法来制备盐酸化亚氨基甲基醚，然后将其转化为相应的碱，获得产率为92.0%的油状的产物。将亚氨醚碱与二当量硫酰胺在甲醇介质中共沸转化成famotidine，用柱色谱法分离famotidine，得到产率为64.4%离。总产率为59.2%。
该方法的主要缺点是用柱色谱法分离，这就使得该方法实际上不适合于工业应用。另一缺点是硫酰胺的用量高。
同一公司在欧洲专利申请128，736号中公开了一种改进方法，仅仅通过制备和使用实质上是高纯度的亚氨醚碱，能避免色谱提纯。从3-（2-胍基-噻唑-4-基-甲硫基）丙腈来制备固体亚氨醚碱，产率为78.8%，将其与2.2摩尔当量的硫酰胺在甲醇介质中，温度为20-30℃的条件下反应三天。所得到的产率为62%的粗产物在含水的二甲基甲酰胺中重结晶，将所得到的物质溶解在水和乙酸的混合物后，再用碱使之沉淀。粗famotidi-ne的总产率相应地仅48.8%。该方法的主要缺点是硫酰胺的用量高，该过程包括许多且麻烦的步骤，且花费很多时间。
按美国专利说明书4，496，737号（Merck）使用3-（甲硫基）-丙腈作为原料，将其转化为相应的亚氨醚碱，产率为67.2%。将所得到的油状产物与1.5摩尔当量的硫酰胺一起煮沸20小时，回收多余的硫酰胺后，用柱色谱法分离产物，产率中等（26.0%）。用间-氯过苯甲酸，在氯仿和甲醇的混合物中，将所得到的N-氨磺酰-3-（甲硫基）-丙脒氧化成相应的亚砜（产率83.4%）。然后将亚砜化合物与三乙基胺，在乙醇介质中煮沸20-30小时，进行消去反应。用色谱法分离所得的式（Ⅳ）N-氨磺酰-丙脒，其产率为37.2%。
根据描述，然后将式（Ⅲ）S-（2-胍基-噻唑-4-基-甲基-异硫脲
在含水的甲醇中就地制备相应的硫醇化合物。将硫醇化合物与式（Ⅳ）N-氨磺酰-丙烯脒进行碱-催化加成反应，即能制备出famotidine，并用柱色谱法分离之，产率为35.6%。该方法的主要优点是式（Ⅳ）的反应剂能提供famotidine的全部侧链，即其与从式（Ⅲ）的异硫脲鎓盐就地得到的2-胍基-噻唑-4-基-甲硫醇的反应直接生产出famotidine。但该方法也有如下缺点：
a）.从3-（甲硫基）-丙腈用四步法经几天时间制备出N-氨磺酰-丙烯脒，产率极低。随后的各步产物包括famotidine在内，都要用色谱法分离。
b）生成famotidine最后一步的产率是相当一般的（35.6%），因而专门加工成本高。
本发明的目的是提供制备famotidine的新方法，该方法能制备产率高、纯度好且无需任何柱色谱步骤的famotidine。
由式（Ⅲ）化合物得到的2-胍基-噻唑基-甲硫醇可就地与式（Ⅱ）N-氨磺酰-3-囟代-丙脒盐酸盐
在含水的醇介质中和室温条件下，很容易进行S-烷基化，本发明就是根据这一发现而进行的。在反应结束时，famotidine作为结晶产物分离出来，可通过过滤，将其从溶解在含水醇介质的NaCl中离析。
在我们的实验中，我们惊奇地发现式（Ⅱ）N-氨磺酰-（3-囟代）-丙脒的盐酸盐是优秀的S-烷基化试剂。首次证实，在碱性含水醇介质中，由此反应物生成了上面引证的专利说明书所描述的N-氨磺酰-丙烯脒。按文献数据，用3-氯丙酸衍生物进行的烷基化反应通常通过相应的丙烯酸衍生物发生，即遵循消除-加成机理。我们能得到70%的产率，相当于美国专利说明书4，496，733号中产率的两倍，且所需产物从反应混合物中以纯的、结晶形式沉淀出，这些都支持S-烷基化按照取代机理（SN2）进行的推测。我们已进一步实验证实，式（Ⅱ）化合物中氯化氢的消除反应不生成式（Ⅳ）的丙烯酸脒衍生物，而是通过过分子内的成环作用生成3-氨基-4，5-二氢-1，2，6-噻二嗪-S，S-二氧化物，该化合物不与式（Ⅲ）化合物在碱性介质中生成的硫醇盐反应。N-氨磺酰-（3-囟代）-丙脒的脒部分原封不动地保留，这也是令人十分惊奇的，特别是考虑到上面专利说明书所提到的低产率的情况，换句话说，脒易于水解是众所周知的[Houben Weyl-Muller：Methoden der organischen Chemie 8，703（1952）]。
因此，本发明涉及通过由式（Ⅲ）S-（2-胍基-噻唑-4-基-甲基）-异硫脲的二盐酸盐
就地得到的2-胍基-噻唑-4-基-甲硫醇的S-烷基化制备式（Ⅰ）N-氨磺酰-3-（2-胍基-噻唑-4-基-甲硫基）丙脒（又称之为famotidine）
的新方法，该方法包括与式（Ⅱ）N-氨磺酰-3-囟代丙脒进行S-烷基化，
（X代表囟素）。
烷基化最好在碱性水溶液中进行。作为碱如NaOH，最好使用40%的水溶液。
根据本发明方法的优选实施方案，将含水的醇性NaOH溶液在搅拌下滴加到式（Ⅲ）S-（2-胍基-噻唑-4-基-甲基）-异硫脲的二盐酸盐和N-氨磺酰-（3-氯）-丙脒的盐酸盐的水溶液中。在将溶液冷却后，过滤出反应期间沉淀的产物（famotidine），用水洗涤，然后用异丙醇洗涤并干燥。
本发明的优点可以总结如下：
a）避免使用式（Ⅳ）N-氨磺酰-丙烯脒，该物质的制备过程复杂，产率很低。
b）最终产物能易于分离，质量好，纯度高。
c）产率，甚至工业规模的产率都较高（70-72%）。
本发明将借助于下列不受限制的实施例详细说明。
实施例
将4.0ml 10N的NaOH溶液（0.04摩尔）和6.0毫升乙醇的混合液在25-30℃，搅拌下滴加到3.04g（0.001摩尔）S-（2-胍基-噻唑-4-基-甲基）-异硫脲的二盐酸盐和2.22克（0.01摩尔）N-氨磺酰-（3-氯）-丙脒的盐酸盐溶于8.0ml的去离子水的溶液中，将所得到均相混合物（PH＝11）再搅拌1.5小时并用冰水将其冷却1小时。过滤出产物，用去离子水洗涤两次，再用异丙醇洗涤二次，干燥直至恒重，得到famotidine 2.40克（71.2%）。
熔点：（159）-160至162℃，
在165℃分解。
红外光谱：NH23506，3452，3400;
NH 3360，3377，3240;
C＝N 1639;
C＝N（共轭）1604分叉;
SO21288，1145cm-1
质子核磁共振光谱（DMSOd6）：
S-CH2-CH2-N 2.6ppm 多重峰
Ar-CH2-S 3.6ppm 单峰
Ar-H 6.5ppm 单峰
NH，NH23.5;6.8;7.4;
8.3，ppm，分叉，可相互变化。
Claims (5)
1、通过由通式(Ⅲ)S-(2-胍基-噻唑-4-基-甲基)-异硫脲的二盐酸盐
用碱就地处理所得到的2-胍基-噻唑-4-基-甲硫醇的S-烷基化制备式(Ⅰ)N-氨磺酰-3-(2-胍基-噻唑-4-基-甲硫基)丙脒(famotidine)
的方法，该方法包括与式(Ⅱ)N-氨磺酰-3-囟代-丙脒(式中X代表囟素)。
进行S-烷基化。
2、根据权利要求1所述的方法，其中烷基化反应在水和具有1-4个碳原子的醇的碱性混合液中进行。
3、根据权利要求1和2任一项所述的方法，该方法包括使用NaOH作为碱。
4、根据权利要求4所述的方法，其中所使用的NaOH为40%的水溶液。
5、根据权利要求3和4任一项所述的方法，其中将碱加入反应混合物的温度为0-50℃，最好是20-30℃。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU3424/85 | 1985-09-11 | ||
| HU853424A HU194845B (en) | 1985-09-11 | 1985-09-11 | Process for production of n-sulphamil-3-/2-guanidintiazolil-4-methil-tio/-propion-amidin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN86105909A true CN86105909A (zh) | 1987-05-13 |
| CN1013674B CN1013674B (zh) | 1991-08-28 |
Family
ID=10963968
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN86105909A Expired CN1013674B (zh) | 1985-09-11 | 1986-09-11 | 制备n-氨磺酰-3-(2-胍基-噻唑-4-基-甲硫基)-丙脒的方法 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US4835281A (zh) |
| JP (1) | JPH0645609B2 (zh) |
| KR (1) | KR910000237B1 (zh) |
| CN (1) | CN1013674B (zh) |
| AR (1) | AR240319A1 (zh) |
| AT (1) | AT386824B (zh) |
| AU (1) | AU587279B2 (zh) |
| BE (1) | BE905409A (zh) |
| CA (1) | CA1263120A (zh) |
| DD (1) | DD249479A5 (zh) |
| DK (1) | DK169920B1 (zh) |
| ES (1) | ES2001677A6 (zh) |
| FI (1) | FI86423C (zh) |
| GB (1) | GB2180237B (zh) |
| GE (1) | GEP19960471B (zh) |
| GR (1) | GR862308B (zh) |
| HU (1) | HU194845B (zh) |
| NL (1) | NL8602225A (zh) |
| NO (1) | NO163010C (zh) |
| PT (1) | PT83348B (zh) |
| SE (1) | SE8603797L (zh) |
| SU (1) | SU1450743A3 (zh) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU194845B (en) * | 1985-09-11 | 1988-03-28 | Richter Gedeon Vegyeszet | Process for production of n-sulphamil-3-/2-guanidintiazolil-4-methil-tio/-propion-amidin |
| HU196775B (en) * | 1986-08-05 | 1989-01-30 | Richter Gedeon Vegyeszet | Process for production of morfologically unique new modifications of famotidin and medical compositions containing such substances |
| NO882037L (no) * | 1987-06-22 | 1988-12-23 | Marga Para La Investigacion Sa | Famotidin, polymerte former og fremstilling derav. |
| US5731442A (en) * | 1997-03-11 | 1998-03-24 | Albemarle Corporation | Synthesis of thiazole derivatives |
| US5856500A (en) * | 1997-03-11 | 1999-01-05 | Albemarle Corporation | Synthesis of thiazole derivatives |
| AU772188B2 (en) * | 1998-11-17 | 2004-04-08 | Nitromed, Inc. | Nitrosated and nitrosylated H2 receptor antagonist compounds, compositions and methods of use |
| US20110143340A1 (en) * | 2007-11-01 | 2011-06-16 | Biocept, Inc. | Non-invasive isolation of fetal nucleic acid |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6056143B2 (ja) * | 1979-08-02 | 1985-12-09 | 山之内製薬株式会社 | アミジン誘導体ならびにその製造法 |
| US4808589A (en) * | 1982-02-20 | 1989-02-28 | Smith Kline & French Laboratories Limited | Pyrimidone derivatives |
| US4496737A (en) * | 1982-09-27 | 1985-01-29 | Merck & Co., Inc. | Process for preparing sulfamylamidine antisecretory agents |
| ES526303A0 (es) * | 1983-10-07 | 1985-04-01 | Inke Sa | Procedimiento para la obtencion de (-1amino-3-(((2-((diaminometileno) amino)-4-tiazolil)metil)tio)propilideno)sulfamida |
| ES8506665A1 (es) * | 1984-05-07 | 1985-08-01 | Inke Sa | Procedimiento para la obtencion de la 1-amino-3-2-diamino-metilen-amino-4-tiazolil-metil-tio-propiliden-sulfamida. |
| ES536322A0 (es) * | 1984-09-27 | 1985-08-01 | Bioiberica | Procedimiento para la obtencion del n-aminosolfenil-3-(((2-guanidin-4-tiazonil)metil)tio) propionamidina |
| ES536803A0 (es) * | 1984-10-17 | 1985-08-01 | Inke Sa | Procedimiento para la obtencion de la (1-amino-3(((2-((diamino-metilen) amino)-4-tiazolil)metil)tio)propiliden)sulfamida |
| HU194845B (en) * | 1985-09-11 | 1988-03-28 | Richter Gedeon Vegyeszet | Process for production of n-sulphamil-3-/2-guanidintiazolil-4-methil-tio/-propion-amidin |
| HU193608B (en) * | 1985-09-11 | 1987-11-30 | Richter Gedeon Vegyeszet | Process for production of new dervatives of n-sulphanol-propion-amidine |
| JP3751649B2 (ja) * | 1994-12-01 | 2006-03-01 | 関西ペイント株式会社 | 自動車外板塗膜の一時保護方法 |
-
1985
- 1985-09-11 HU HU853424A patent/HU194845B/hu unknown
-
1986
- 1986-08-22 CA CA000516617A patent/CA1263120A/en not_active Expired
- 1986-09-03 NL NL8602225A patent/NL8602225A/nl not_active Application Discontinuation
- 1986-09-08 AR AR305176A patent/AR240319A1/es active
- 1986-09-08 KR KR1019860007508A patent/KR910000237B1/ko not_active IP Right Cessation
- 1986-09-09 SU SU864028107A patent/SU1450743A3/ru active
- 1986-09-09 DD DD86294264A patent/DD249479A5/de unknown
- 1986-09-09 GR GR862308A patent/GR862308B/el unknown
- 1986-09-10 GB GB8621742A patent/GB2180237B/en not_active Expired
- 1986-09-10 FI FI863657A patent/FI86423C/fi not_active IP Right Cessation
- 1986-09-10 AT AT0243486A patent/AT386824B/de not_active IP Right Cessation
- 1986-09-10 DK DK434586A patent/DK169920B1/da not_active IP Right Cessation
- 1986-09-10 PT PT83348A patent/PT83348B/pt unknown
- 1986-09-10 JP JP61211792A patent/JPH0645609B2/ja not_active Expired - Lifetime
- 1986-09-10 NO NO863616A patent/NO163010C/no not_active IP Right Cessation
- 1986-09-10 AU AU62569/86A patent/AU587279B2/en not_active Expired
- 1986-09-10 BE BE0/217144A patent/BE905409A/fr not_active IP Right Cessation
- 1986-09-10 SE SE8603797A patent/SE8603797L/xx not_active Application Discontinuation
- 1986-09-11 ES ES8601790A patent/ES2001677A6/es not_active Expired
- 1986-09-11 CN CN86105909A patent/CN1013674B/zh not_active Expired
-
1987
- 1987-07-23 US US07/077,095 patent/US4835281A/en not_active Expired - Lifetime
-
1993
- 1993-06-14 GE GEAP1993867A patent/GEP19960471B/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN86105909A (zh) | 制备n-氨磺酰-3-(2-胍基-噻唑-4-基-甲硫基)-丙脒的方法 | |
| CN111116441A (zh) | 一种含有磺酸基的硫叶立德的合成方法及其应用 | |
| US4158013A (en) | N-Cyano-N'-alkynyl-N"-2-mercaptoethylguanidines | |
| KR20020067575A (ko) | Ｎ-메틸-ｎ＇-니트로구아니딘의 제조방법 | |
| CA1180338A (en) | Method for the preparation of 1,3-disubstituted 4,5- cis-dicarboxy-2-imidazolidones | |
| CN1114595C (zh) | 制备异硫氰酸吡啶基甲酯的方法 | |
| EP0269650A1 (en) | Synthesis of antiulcer compounds | |
| US4076745A (en) | Process for calcium salts α-ketocarboxylic acids | |
| SU886744A3 (ru) | Способ получени N-циан-N @ -метил-N @ 2-[(5-метилимидазол-4-ил)-метилтио]-этил-гуанидина | |
| EP0528941A1 (en) | Process for preparing cephalexin monohydrate | |
| CN86100111A (zh) | 碱性硫醚及其盐的制备方法 | |
| CN1214012C (zh) | 制备羰基二咪唑的方法 | |
| HUT58285A (en) | Process for producing substituted ethylene derivatives | |
| US4720552A (en) | Process for the preparation of acid addition salts of 4(5)-methyl-5(4)-thiomethyl imidazole | |
| EP0127413A2 (en) | Preparation of thiazine derivatives | |
| Dodson et al. | The Reaction of Ethyl α-and γ-Bromoacetoacetates with S-Alkylisothioureas | |
| JPH0113469B2 (zh) | ||
| SU313353A1 (ru) | Способ получения бензимидазолил-2-метилового эфира фенилдитиокарбаминовой кислоты | |
| KR20230034630A (ko) | 설폰산나트륨염 화합물의 제조방법 | |
| CN1948307A (zh) | 5－(2－吡啶基)－2－巯基－1,3,4－噻二唑的制备方法 | |
| CN116332811A (zh) | 双三氟甲烷磺酰亚胺甲脒化合物结构及其制备方法 | |
| KR20230037258A (ko) | 설폰산나트륨염 화합물의 제조방법 | |
| KR890003843B1 (ko) | 데스옥시프룩토실 세로토닌 및 크레아티닌의 복(複) 황산염의 제조방법 | |
| KR850001700B1 (ko) | 아미디노 우레아 유도체의 제조방법 | |
| KR870001793B1 (ko) | N-설파모일-3-(2-구아니디노티아졸-4-일메틸티오)프로피온아미딘 유도체의 제조방법 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C13 | Decision | ||
| C14 | Grant of patent or utility model | ||
| C17 | Cessation of patent right |