WO2011054312A1

WO2011054312A1 - Method for preparing gliclazide and its intermediate

Info

Publication number: WO2011054312A1
Application number: PCT/CN2010/078455
Authority: WO
Inventors: 车大庆; 杜小华
Original assignee: 浙江九洲药业股份有限公司
Priority date: 2009-11-09
Filing date: 2010-11-05
Publication date: 2011-05-12
Also published as: CN102050778B; CN102050778A

Abstract

Method for preparing Gliclazide is disclosed, which comprises following steps: reacting p-Toluenesulfonylurea as raw material with hydrazine hydrate to obtain compound IV by condensation; then reacting compound IV with 1,2 -cyclopentane dicarboxylic anhydride to obtain compound II; finally, reducing compound II to obtain Gliclazide. The present method for preparing Gliclazide avoids the use of amino heterocyclic group, and fundamentally solves the oxidation trend of the raw materials. Intermediate compound II and its synthesis method are also disclosed.

Description

格列齐特及其中间体的合成方法 Synthesis method of gliclazide and its intermediates

本申请要求于 2009 年 11 月 9 日提交中国专利局、申请号为 200910154182.7、发明名称为"格列齐特及其中间体的合成方法 "的中国专利申请的优先权，其全部内容通过引用结合在本申请中。技术领域 This application claims priority to Chinese Patent Application No. 200910154182.7, entitled "Synthesis Method of Gliclazide and Its Intermediates", filed on November 9, 2009, the entire contents of which are incorporated by reference. In this application. Technical field

本发明涉及有机化学领域，具体而言，本发明涉及格列齐特及其中间体的合成方法。背景技术 Field of the Invention This invention relates to the field of organic chemistry, and in particular to the method of synthesizing gliclazide and its intermediates. Background technique

格列齐特，英文名： Gliclazide, 分子式： C₁₅H₂₁N₃0₃S, CAS号码： 21187-98-4, 其化学名称为 1- (六氢环戊 [c]吡咯 -2(IH)-基) -3-(4-甲基苯基-) 橫醜脉 ( l-(hexahgdroeycloxpenta[c]pyrrol-2(IH)-yl)-3-[(4-methylphengl) sulphonyl] urea) ) , 化学结构如式 I所示： Gliclazide, English name: Gliclazide, Molecular formula: C ₁₅ H ₂₁ N ₃ 0 ₃ S, CAS number: 21187-98-4, its chemical name is 1-(hexahydrocyclopenta[c]pyrrole-2 (IH) )-yl)-3-(4-methylphenyl-) 丑脉 ( ( l-(hexahgdroeycloxpenta[c]pyrrol-2(IH)-yl)-3-[(4-methylphengl) sulphonyl] urea) ) , the chemical structure is shown in Formula I:

I I

它是第二代磺酰脲类口服降糖药，主要用于 II型即胰岛素依赖型糖尿病的治疗，它不仅能降低血糖，而且可以改善糖尿病患者的凝血功能，改善或延緩糖尿病患者血管并发症的发生，临床上己被广泛使用。 It is a second-generation sulfonylurea oral hypoglycemic agent, mainly used for the treatment of type II, insulin-dependent diabetes mellitus, which not only lowers blood sugar, but also improves blood coagulation function in diabetic patients, and improves or delays vascular complications in diabetic patients. The occurrence has been widely used clinically.

关于格列齐特的报道，最早出现在美国专利 US 3501495 (专利权人: SCIENCE UNION & CIE ) 中，这篇专利早在 1970年 3月 17日公布，其中公开的工艺路线如下： The report on gliclazide first appeared in US Patent US 3,501,495 (patent holder: SCIENCE UNION & CIE), which was published as early as March 17, 1970, and the process route disclosed therein is as follows:

H，H re lux H,H re lux

H_nC

H。C H _n C

H. C

格列^特此条路线存在的问题为：化合物 1生产成本高，市场上难以购得。且化合物 2 (化学名：六氢 -2-环戊并 [c]吡咯基胺，也称氨基杂环）易氧化，整个反应收率不高（还原专利方法，按氨基杂环（即化合物 2 )计算收率为 59.7% ), 不利于工业化生产。 Gleet The problem with this route is: Compound 1 has high production costs and is difficult to obtain on the market. And compound 2 (chemical name: hexahydro-2-cyclopenta[c]pyrrolylamine, also known as amino heterocycle) is easily oxidized, and the overall reaction yield is not high (reduction of the patented method, according to the amino heterocycle (ie compound 2) The calculated yield is 59.7%), which is not conducive to industrial production.

此后的对于格列齐特合成方法的改进和研究，都是围绕专利 US 3501495中路线的合成思路展开的，基本原理是一致的，基本上都是以氨基杂环（化合物 2 )或其盐酸盐与各种对甲苯磺酰胺或其衍生物反应制得。其中，最为典型的一条路线如下（参考文献：日本专利 JP 5333584, 公开曰期： 1993年 12月 1 ：

The subsequent improvements and researches on the gliclazide synthesis method are all based on the synthetic idea of the route in the patent US 3501495. The basic principle is the same, basically the amino heterocycle (compound 2) or its hydrochloric acid The salt is prepared by reacting various p-toluenesulfonamides or derivatives thereof. Among them, the most typical one is as follows (Reference: Japanese patent JP 5333584, open period: December 1, 1993:

即通过氨基杂环与对甲苯磺酰脲（化合物 3 )进行缩合反应得到最终产物格列齐特。此条工艺虽然现在运用得比较多，但从根本上并没有解决氨基杂环易氧化的问题。 That is, the final product gliclazide is obtained by a condensation reaction of an amino heterocycle with p-toluenesulfonylurea (compound 3). Although this process is now used more, it does not fundamentally solve the problem of easy oxidation of amino heterocycles.

而氨基杂环现在已做为一个合成格列齐特的关键中间体，比较难以获得。它的合成在最新公布的一篇中国专利 CN 101235011 (公开日期： 2008 年 8月 6日，申请人：浙江大学 ) 中描述路线如下： Amino heterocycles are now a key intermediate in the synthesis of gliclazide and are more difficult to obtain. Its synthesis is described in the latest published Chinese patent CN 101235011 (publication date: August 6, 2008, applicant: Zhejiang University):

此反应过程存在的缺点为：该反应条件较难控制，容易发生扩环反应生成六元环的副产物。 The disadvantages of this reaction process are: The reaction conditions are difficult to control, and the ring-opening reaction easily occurs to form a by-product of the six-membered ring.

即格列齐特的合成可以以 1 , 2-环戊烷邻二甲酸酐为原料，先与水合肼反应得到 N-氨基 -1,2-环戊烷邻二甲酰亚胺，然后经硼氢化钾与三氯化铝复合的还原体系还原得到氨基杂环，再与对甲苯磺酰脲缩合得到最终产物格列齐特。发明内容 That is, the synthesis of gliclazide can be carried out by reacting 1,2-cyclopentanephthalic anhydride with hydrazine hydrate to obtain N-amino-1,2-cyclopentane- ortho-imide, and then boron. The reduction system of potassium hydride and aluminum trichloride is reduced to obtain an amino heterocycle, which is then condensed with p-toluenesulfonylurea to obtain the final product gliclazide. Summary of the invention

本发明的目的之一就是提供了一种格列齐特全新的合成方法，该方法打破了格列齐特以往常规的合成思路，与已有方法完全不同，避免了氨基杂环的使用。 One of the objects of the present invention is to provide a novel synthesis method of gliclazide which breaks the conventional synthesis idea of gliclazide and is completely different from the existing method, thereby avoiding the use of an amino heterocycle.

为了实现上述目的，本发明采用的技术方案如下： In order to achieve the above object, the technical solution adopted by the present invention is as follows:

本发明的方法是以对甲苯磺酰脲（化合物 V ) 为原料，与水合肼 ( Ν₂Η₄·Η₂0 )经缩合反应得到 Ν-[(4-甲基苯基)磺酰基] -酰肼甲酰胺 (化合物 IV );化合物 IV再与 1,2-环戊烷邻二甲酸酐（化合物 III )反应得到 1-(1,3- 二羰基-六氢环戊二烯并 [c]吡咯 -2(1Η)-基) -3-对甲苯磺酰脲（化合物 II ); 最后将化合物 II进行还原反应得到格列齐特（式 I化合物）。 The method of the invention uses p-toluenesulfonylurea (compound V) as a raw material, and is condensed with hydrazine hydrate (Ν ₂ Η ₄ ·Η ₂ 0 ) to obtain hydrazine-[(4-methylphenyl)sulfonyl]- Hydrazide carboxamide (compound IV); compound IV is further reacted with 1,2-cyclopentanephthalic anhydride (compound III) to give 1-(1,3-dicarbonyl-hexahydrocyclopentadienyl[c] Pyrrole-2(1Η)-yl)-3-p-toluenesulfonylurea (Compound II); Finally, compound II is subjected to a reduction reaction to obtain gliclazide (a compound of formula I).

本发明合成格列齐特的方法具有如下特点：在对甲苯磺酰脲上先引入氨基，再与酸酐进行反应，避免了氨基杂环的使用，从根本上解决了原料易被氧化的问题，使得反应中杂质降低，产品品质提高，合成格列齐特的总收率高，比现有技术的 59.7%提高了 10多个百分点；且整体反应路线短，反应条件容易控制，成本低，对于工业化生产具有很高的利用价值和经济价值。 The method for synthesizing gliclazide of the invention has the following characteristics: firstly introducing an amino group on p-toluenesulfonylurea, and then reacting with an acid anhydride, thereby avoiding the use of an amino heterocyclic ring, thereby fundamentally solving the problem that the raw material is easily oxidized, The impurities in the reaction are lowered, the product quality is improved, and the total yield of the synthesized gliclazide is high, which is more than 10% higher than the prior art 59.7%; and the overall reaction route is short, the reaction conditions are easy to control, and the cost is low, Industrial production has high utilization value and Economic Value.

本发明的格列齐特的合成方法中，中间体化合物 II是新化合物，该化合物也构成了本发明的重要特征，因此，本发明的另一目的在于提供了一种格列齐特中间体化合物 II及其合成方法，即将式（IV )化合物与 1,2-环戊烷邻二甲 Π, 其合成路线如下： In the synthesis method of gliclazide of the present invention, the intermediate compound II is a novel compound which also constitutes an important feature of the present invention, and therefore, another object of the present invention is to provide a gliclazide intermediate. Compound II and its synthesis method, that is, the compound of formula (IV) and 1,2-cyclopentane-o-dimethyl hydrazine, the synthesis route is as follows:

作为优选，由式（IV )化合物与 1,2-环戊烷邻二甲酸酐（ΠΙ )生成化合物 II的反应中以对甲苯磺酸为催化剂。 Preferably, p-toluenesulfonic acid is used as a catalyst in the reaction of the compound of the formula (IV) with 1,2-cyclopentanephthalic anhydride (ΠΙ) to form the compound II.

本发明提供的格列齐特的合成方法步骤 c: 式（Π )化合物进行还原反应得到式（I )所示格列齐特的反应中，优选以硼氢化锂作为催化剂： The method for synthesizing gliclazide provided by the present invention is c: a compound of the formula (Π) is subjected to a reduction reaction to obtain a gliclazide represented by the formula (I), preferably using lithium borohydride as a catalyst:

在本发明的实施例中，无水氯化锂与滴加硼氢化钠的 THF溶液作用，形成硼氢化锂，硼氢化锂作为反应的催化剂。 In an embodiment of the invention, anhydrous lithium chloride is reacted with a solution of sodium borohydride in THF to form lithium borohydride, lithium borohydride as a catalyst for the reaction.

本发明的另一目的在于提供了一种由化合物 V合成化合物 IV的方法，即以对甲苯磺酰脲（化合物 V ) 为原料，与水合肼 ( Ν₂Η₄·Η₂0 )经缩合反应得到 Ν-[(4-甲基苯基)磺酰基] -酰肼甲酰胺 (化合物 IV ) , 其合成路线如下： Another object of the present invention is to provide a method for synthesizing Compound IV from Compound V, which comprises the condensation reaction of hydrazine hydrate ( Ν ₂ Η ₄ · Η ₂ 0 ) with p-toluenesulfonylurea (Compound V) as a raw material. Ν-[(4-Methylphenyl)sulfonyl]-hydrazidecarboxamide (Compound IV) was obtained, which was synthesized as follows:

具体实施方式

detailed description

为更好的理解本发明的内容，下面结合具体实施例作进一步说明。其中 1,2-环戊烷邻二甲酸酐（化合物 III ) 的合成参考英国专利 GB 2291873 (公开日期： 1996年 2月 7日，申请人： ZENECA公司）实施例例 1中第二步反应的描述，具体路线如下：

实施例 1: N-[(4-曱基苯基)磺酰基] -酰肼曱酰胺（化合物 IV )的合成在 500ml反应瓶中加入对甲苯磺酰脲（化合物 V )30g,碳酸钠 19.5g, 正丁醇 200ml, 水合肼 llg, 加毕，加热至回流，保温 12小时，保温毕，冷却至室温后加入 300ml水，分去有机层，水层用盐酸调节 PH=7, 有大量白色固体析出，抽滤，水洗，温品在 65~70°C干燥 12小时得到 23g目标产物 N-[(4-甲基苯基)磺酰基] -酰肼甲酰胺（化合物 IV ) , 收率 71.6%。 For a better understanding of the contents of the present invention, further description will be made in conjunction with the specific embodiments. The synthesis of 1,2-cyclopentane o-dicarboxylic anhydride (Compound III) is described in the second step of the reaction of the example of the British Patent GB 2291873 (Publication date: February 7, 1996, Applicant: ZENECA) Description, the specific route is as follows:

Example 1: Synthesis of N-[(4-nonylphenyl)sulfonyl]-hydrazide amide (Compound IV) Into a 500 ml reaction flask was added 30 g of p-toluenesulfonylurea (Compound V), sodium carbonate 19.5 g , n-butanol 200ml, hydrazine hydrated llg, added, heated to reflux, kept for 12 hours, after heat preservation, after cooling to room temperature, add 300ml of water, separate the organic layer, the water layer is adjusted with hydrochloric acid PH = 7, a large amount of white solid Precipitation, suction filtration, water washing, and drying at a temperature of 65 to 70 ° C for 12 hours gave 23 g of the desired product N-[(4-methylphenyl)sulfonyl]-hydrazide carboxamide (Compound IV) in a yield of 71.6%.

实施例 2: N-[(4-曱基苯基)^酰基] -酰肼曱酰胺（化合物 IV )的合成在 500ml反应瓶中加入对甲苯磺酰脲（化合物 V ) 30g,碳酸钠 19.5g, 正丁醇 200ml, 水合肼 llg, 加毕，加热至回流，保温 12小时，保温毕，减压蒸馏回收正丁醇 150ml后加入 300ml水，常压蒸馏 50ml, 冷却至室温，用盐酸调节 PH=7,有大量白色固体析出，抽滤，水洗，温品在 65~70°C 干燥 12小时得到 30g目标产物 N-[(4-甲基苯基)磺酰基] -酰肼甲酰胺（化合物 IV ), 收率 93.4%。实施例 3: 1-(1,3-二羰基-六氢环戊二烯并 [c]吡咯 -2(1H)-基) -3-对曱苯磺酰脲 (化合物 II ) 的合成 Example 2: Synthesis of N-[(4-nonylphenyl) acyl]-hydrazide amide (Compound IV) To a 500 ml reaction flask was added p-toluenesulfonylurea (Compound V) 30 g, sodium carbonate 19.5 g , n-butanol 200ml, hydrazine hydrated llg, added, heated to reflux, kept for 12 hours, after heat preservation, 150ml of n-butanol was recovered by distillation under reduced pressure, 300ml of water was added, 50ml was distilled at atmospheric pressure, cooled to room temperature, and pH was adjusted with hydrochloric acid. =7, a large amount of white solid precipitated, suction filtration, water washing, and the product was dried at 65-70 ° C for 12 hours to obtain 30 g of the target product N-[(4-methylphenyl)sulfonyl]-hydrazidecarboxamide. Compound IV), yield 93.4%. Example 3: Synthesis of 1-(1,3-dicarbonyl-hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-p-phenylenesulfonyl urea (Compound II)

在 500ml反应瓶中加入对甲苯磺酸 3.0g, N-[(4-甲基苯基)磺酰基] -酰肼甲酰胺（化合物 IV ) 19.5g, 1,2-环戊烷邻二甲酸酐（化合物 III ) 15g, 甲苯 200ml, 加毕，加热至回流，回流分水 12小时，分水毕，减压蒸馏回收甲苯 150ml后加入 300ml水，常压蒸馏回收有水甲苯 100ml,冷却至室温，抽滤，水洗，温品在 65~70°C干燥 12小时得到 18g目标产物 1-(1,3- 二羰基-六氢环戊二烯并 [c]吡咯 -2(1H)-基) -3-对甲苯磺酰脲（化合物 II ), 收率 60.2%。 To a 500 ml reaction flask was added 3.0 g of p-toluenesulfonic acid, N-[(4-methylphenyl)sulfonyl]-hydrazidecarboxamide (Compound IV) 19.5 g, 1,2-cyclopentane orthophthalic anhydride (Compound III) 15g, toluene 200ml, after adding, heated to reflux, refluxing water for 12 hours, water separation, 150ml of toluene was distilled under reduced pressure, 300ml of water was added, 100ml of water toluene was recovered by atmospheric distillation, and cooled to room temperature. After suction filtration, washing with water, the product was dried at 65-70 ° C for 12 hours to obtain 18 g of the target product 1-(1,3-dicarbonyl-hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3 - p-toluenesulfonylurea (Compound II), yield 60.2%.

对甲苯磺酸在此反应中起到酸催化的作用。实施例 4: 格列齐特的合成 P-toluenesulfonic acid acts as an acid catalyze in this reaction. Example 4: Synthesis of gliclazide

在 500ml瓶中加入 10g的 1-(1,3-二羰基-六氢环戊二烯并 [c]吡咯 -2(1H)-基) -3-对甲苯磺酰脲（化合物 Π ), THF200ml, 无水氯化锂 1.5g, 加热升温至 50°C , 緩慢滴加硼氢化钠的 THF溶液（ 1.6g硼氢化钠溶解在 20mlTHF中），滴毕，升温至回流，保温 5小时，保温毕，蒸馏回收 THFlOOml, 冷却至室温，滴加 150ml水，室温搅拌 1小时，抽滤，水洗，产物在 70~75°C烘 12小时得到 6.8g目标产物 (格列齐特）, 收率 73.9%。 Add 10 g of 1-(1,3-dicarbonyl-hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-p-toluenesulfonylurea (Compound Π) to a 500 ml bottle, THF 200 ml , 1.5 g of anhydrous lithium chloride, heating to 50 ° C, slowly adding sodium borohydride solution in THF (1.6 g of sodium borohydride dissolved in 20 ml of THF), dripping, heating to reflux, holding for 5 hours, heat preservation THF lOOml was distilled off, cooled to room temperature, 150 ml of water was added dropwise, stirred at room temperature for 1 hour, suction-filtered, washed with water, and the product was baked at 70-75 ° C for 12 hours to obtain 6.8 g of the target product (gliclazide), yield 73.9%. .

在本实施例中，无水氯化锂与滴加硼氢化钠的 THF溶液作用，形成硼氢化锂，硼氢化锂作为反应的催化剂。综上所述，本发明涉及一种格列齐特及其中间体的合成方法，该方法以对甲苯磺酰脲为原料，与水合肼经缩合反应得到化合物 IV；化合物 IV 再与 1,2-环戊烷邻二甲酸酐反应得到化合物 Π;最后将化合物 II进行还原反应得到格列齐特。其中，化合物 II是新中间体化合物。利用本发明合成格列齐特，避免了氨基杂环的使用，从根本上解决了原料易被氧化的问题。需要说明的是，在本发明中提及的所有文献在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，以上所述的是本发明的具体实施例及所运用的技术原理，在阅读了本发明的上述内容之后，本领域技术人员可以对本发明作各种改动或修改而不背离本发明的精神与范围，这些等价形式同样落在本发明的范围内。 In this example, anhydrous lithium chloride is added to a solution of sodium borohydride in THF to form lithium borohydride and lithium borohydride as a catalyst for the reaction. In summary, the present invention relates to a method for synthesizing gliclazide and an intermediate thereof, which comprises a p-toluenesulfonylurea as a raw material, and a condensation reaction with hydrazine hydrate to obtain a compound IV; a compound IV and 1, 2 - cyclopentane o-dicarboxylic anhydride is reacted to obtain a compound hydrazine; finally, compound II is subjected to a reduction reaction to obtain gliclazide. Among them, the compound II is a new intermediate compound. By using the present invention to synthesize gliclazide, the use of the amino heterocycle is avoided, and the problem that the raw material is easily oxidized is fundamentally solved. It is to be noted that all of the documents referred to in the present application are hereby incorporated by reference in their entirety as if they are individually incorporated by reference. In addition, it should be understood that the above-described embodiments of the present invention and the technical principles of the present invention can be variously modified or modified by those skilled in the art without departing from the invention. The spirit and scope of the invention are also within the scope of the invention.

Claims

权利要求 Rights request

1、式（Π) 所示化合 1, the formula (Π) shown in the combination

2、式（Π)所示化合物的合成方法，包括将式（IV)化合物与 1,2- 环戊烷邻二甲酸酐（ΠΙ)反应： 2. A method for synthesizing a compound of the formula (Π) which comprises reacting a compound of the formula (IV) with 1,2-cyclopentane orthophthalic anhydride (ΠΙ):

。

.

3、根据权利要求 2所述的合成方法，其特征在于，所述反应以对甲苯磺酸为催化剂。 The method according to claim 2, wherein the reaction uses p-toluenesulfonic acid as a catalyst.

4、格列齐特的合成方法，包括将式（Π)化合物进行还原反应得到式所示格列齐特 4. The synthesis method of gliclazide, which comprises reducing the compound of the formula (Π) to obtain the gliclazide represented by the formula

5、根据权利要求 4所述的合成方法，其特征在于，所述还原反应以硼氢化锂为催化剂。 The synthesis method according to claim 4, wherein the reduction reaction uses lithium borohydride as a catalyst.

6、根据权利要求 4或 5所述的合成方法，其特征在于，包含以下步骤： 6. The method of synthesizing according to claim 4 or 5, comprising the steps of:

步骤 a: 由式（V) 化合物与水合肼经缩合反应生成式（IV) 所示化合物； Step a: a compound represented by formula (IV) is obtained by condensation reaction of a compound of formula (V) with hydrazine hydrate;

步骤 b: 将式（IV)化合物与 1,2-环戊烷邻二甲酸酐（III)反应生成式（Π) 所示化合物；步骤 c: 式（Π)化合物进行还原反应得到式（I)所示格列齐特; Step b: reacting a compound of the formula (IV) with 1,2-cyclopentane orthophthalic anhydride (III) to form a compound of the formula (Π); Step c: a compound of formula (Π) is subjected to a reduction reaction to obtain gliclazide represented by formula (I);

V IV V IV

7、一种合成式（IV) 所示化合物的方法，其特征在于，由式（V) 化合物与水合肼经缩合反应生成式（IV) 所示化合物： A method for synthesizing a compound of the formula (IV), which is characterized in that a compound of the formula (V) is condensed with hydrazine hydrate to form a compound of the formula (IV):

(V) (IV) (V) (IV)