CN101220048B - Preparation method of pinanediol ester under ZnCl2 catalysis - Google Patents

Abstract

Translated fromChinese

本发明涉及一种在ZnCl₂存在下合成手性蒎烷二醇酯的方法，采取如下的反应路线：

其中R为脂肪类化合物或芳香类化合物，X为卤素。本方法操作简便，反应流程合理，生产成本低，产品质量好，总收率高达90％以上。对环境无污染，可用于工业化生产。The present invention relates to a kind of method of synthesizing chiral pinanediol ester in the presence of_ZnCl2 , take following reaction route:

Wherein R is an aliphatic compound or an aromatic compound, and X is a halogen. The method is simple and convenient to operate, the reaction process is reasonable, the production cost is low, the product quality is good, and the total yield is as high as more than 90%. It is non-polluting to the environment and can be used in industrialized production.

Description

Translated fromChinese

ZnCl2催化下的蒎烷二醇酯的制备方法Preparation method of pinanediol ester under ZnCl2 catalysis

技术领域technical field

本发明涉及一种在ZnCl₂存在下合成手性蒎烷二醇酯的方法，属于化学合成领域。 The invention relates to a method for synthesizing chiral pinanediol ester in the presence of_ZnCl2 , belonging to the field of chemical synthesis.

背景资料 Background information

含硼类化合物是一类温和的有机路易斯酸，性质比较稳定而且易于操作和处理，是一类重要的有机合成中间体。同时，由于这类化合物对人体毒性很小以及其最终降解成环境友好的硼酸类化合物，所以这类化合物被认为是“绿色产品”。由于有机硼酸化合物易于形成寡聚硼酸酐，因此，在实际合成工作中常常使用有机硼酸酯作为反应中间体。在所有的硼酸酯中，手性的蒎烷二醇酯具有很重要的应用价，由于它的分子中具有四个手性碳而且位阻较大，可以在不对称合成中作为手性诱导试剂。该化合物是合成抗复发性骨髓瘤Velcade的重要中间体(US patent，1998，5,780,454)。 Boron-containing compounds are a kind of mild organic Lewis acids, which are relatively stable and easy to handle and handle. They are an important class of organic synthesis intermediates. At the same time, these compounds are considered as "green products" because they have little toxicity to the human body and eventually degrade into environmentally friendly boric acid compounds. Because organic boronic acid compounds are easy to form oligomeric boric acid anhydrides, organic boronic acid esters are often used as reaction intermediates in practical synthesis. Among all the boronic acid esters, the chiral pinanediol ester has a very important application value. Because it has four chiral carbons in its molecule and has a large steric hindrance, it can be used as a chiral inducer in asymmetric synthesis. reagent. The compound is synthetic anti-relapse myeloma Velcade important intermediates (US patent, 1998, 5,780,454).

在美国专利US 4,525,309中讨论了蒎烷二醇酯的合成方法。发明者采用了以下方法合成目标化合物： The synthesis of pinanediol esters is discussed in US Patent No. 4,525,309. The inventors have adopted the following method to synthesize the target compound:

在该路线中，由原料(I)生成中间体(II)时采用的二卤代金属试剂主要指LiCHCl₂，该化合物是在-100℃下由CH₂Cl₂与n-C₄H₉Li反应生成，此金属试剂对空气和水及其敏感，所以在转移过程中要求非常严格和苛刻。在使用中间体(II)生成产物(III)时，采用了极易吸水的固体ZnCl₂粉末，使得反应中引入了水分，分解了部分的LiCHCl₂，造成产物(III)的产率较低。而且在后处理时由于采用的方法不得当，使得反应的处理比较困难，对产品的纯度造成了一定的影响。 In this route, the dihalogenated metal reagent used when producing intermediate (II) from raw material (I) mainly refers to LiCHCl₂ , which is formed by the reaction of CH₂ Cl₂ and nC₄ H₉ Li at -100°C , this metal reagent is extremely sensitive to air and water, so the requirements are very strict and harsh during the transfer process. When intermediate (II) is used to generate product (III), solid ZnCl₂ powder that is extremely water-absorbing is used, which introduces water into the reaction and decomposes part of LiCHCl₂ , resulting in a low yield of product (III). Moreover, due to the inappropriate method used during post-processing, the processing of the reaction is more difficult, which has a certain impact on the purity of the product.

发明内容Contents of the invention

本发明提供了一种合成(III)的新方法和新路线，用于制备手性的蒎烷二醇酯(III)。 The present invention provides a new method and new route for synthesizing (III), which are used to prepare chiral pinanediol ester (III). the

为达到上述目的，本发明采取如下的反应路线： To achieve the above object, the present invention takes the following reaction scheme:

R为脂肪类化合物或芳香类化合物，X为卤素。 R is an aliphatic compound or an aromatic compound, and X is a halogen. the

制备方法为：用易于制备和保存的格氏试剂RMgX与原料（1）反应生成中间体（2），（2）再在路易斯酸无水ZnCl₂的催化下生成手性的蒎烷二醇酯（III）。 The preparation method is as follows: use Grignard reagent RMgX, which is easy to prepare and store, to react with raw material (1) to generate intermediate (2), and then generate chiral pinanediol ester under the catalysis of Lewis acid anhydrous ZnCl₂ (III).

本发明中原料（1）的制备参见以下参考文献： The preparation of raw material (1) in the present invention sees the following references:

（1）Rathke, M. W.; Chao, E.; Wu, G. J. Organomet. Chem. 1976, 122, 145-149. (1) Rathke, M. W.; Chao, E.; Wu, G. J. Organomet. Chem. 1976, 122, 145-149.

（2）Elgendy, S.; Deadman, J.; Patel, G.; Green, D.; Chion, N.; Goodwin, C. A.; Scully, M. F.; Kakkar, V. V.; Claeson, G. Tetrahedron Lett. 1992, 33, 4209-4212. (2) Elgendy, S.; Deadman, J.; Patel, G.; Green, D.; Chion, N.; Goodwin, C. A.; Scully, M. F.; Kakkar, V. V.; , G. Tetrahedron Lett. 1992, 33, 4209-4212.

（3）Matteson, D. S. Chem. Rev. 1989, 89, 1535-1551. (3) Matteson, D. S. Chem. Rev. 1989, 89, 1535-1551.

合成（III）的反应条件为： The reaction conditions of synthetic (III) are:

（1）制备格氏试剂RMgX时，金属Mg与卤代物RX的摩尔比为1:1~2，优选为1:1.2~1.5。溶剂为苯、甲苯、乙醚、四氢呋喃、二氧六环。最优溶剂为乙醚。 (1) When preparing Grignard reagent RMgX, the molar ratio of metal Mg to halide RX is 1:1~2, preferably 1:1.2~1.5. The solvents are benzene, toluene, ether, tetrahydrofuran, dioxane. The optimal solvent is diethyl ether. the

（2）在惰气保护下，将格式试剂RMgX在-40~ -100℃下滴加到被溶剂溶解的化合物（1）中，再进行下一步操作。 (2) Under the protection of inert gas, add the Grignard reagent RMgX dropwise to the compound (1) dissolved in the solvent at -40~-100 °C, and then proceed to the next step. the

所述惰气为N₂、Ar； The inert gas is N₂ , Ar;

所述溶剂为苯、甲苯、石油醚、乙醚、四氢呋喃、二氧六环，优选的溶剂为乙醚和四氢呋喃，最优选的溶剂为乙醚； Described solvent is benzene, toluene, sherwood oil, ether, tetrahydrofuran, dioxane, and preferred solvent is ether and tetrahydrofuran, and most preferred solvent is ether;

反应的最佳温度为-60~ -78℃。 The optimum temperature for the reaction is -60~-78°C. the

（3）当格氏试剂滴加完毕后，马上加入催化剂无水ZnCl₂，然后使反应自然缓慢升至室温，在惰气保护下继续反应。一般反应时间为8~30小时，最佳反应时间为15~24小时。反应结束后，滤除未溶解的ZnCl₂，向滤液中加入ZnCl₂去除液，分液，有机相再用饱和食盐水洗涤。无水Na₂SO₄干燥。真空下蒸去溶剂，即得产品。 (3) After the Grignard reagent is added dropwise, immediately add the catalyst anhydrous ZnCl₂ , then let the reaction naturally rise to room temperature slowly, and continue the reaction under the protection of inert gas. The general reaction time is 8~30 hours, and the best reaction time is 15~24 hours. After the reaction, the undissolved ZnCl₂ was filtered off, the ZnCl₂ removal liquid was added to the filtrate, the liquid was separated, and the organic phase was washed with saturated brine. Dry over anhydrous Na₂ SO₄ . The solvent was evaporated under vacuum to obtain the product.

本发明中所指的ZnCl₂去除液是指质量浓度为10~40％的NH₄Cl、(NH₄) ₂SO₄、NH₄NO₃等强酸弱碱盐溶液。 The ZnCl₂ removal solution referred to in the present invention refers to strong acid and weak base salt solutions such as NH₄ Cl, (NH₄ )₂ SO₄ , NH₄ NO₃ , etc., with a mass concentration of 10-40%.

本发明人经过反复实验后发现，而且经过实践证明，在此反应中，催化剂ZnCl₂的质量是决定反应收率及产品质量的关键因素。ZnCl₂在真空及脱水剂的作用下，可以在较低温度下脱水。通常，在常压和大于180℃下脱水制得的ZnCl₂呈暗灰色，为块状固体，不利于在反应条件下溶解，造成产品收率低，产品质量差，并且后处理时较难除去。 The inventor found after repeated experiments, and it has been proved by practice that in this reaction, the quality of the catalyst_ZnCl is a key factor determining the reaction yield and product quality. ZnCl₂ can be dehydrated at a lower temperature under the action of vacuum and dehydrating agent. Usually, the ZnCl₂ obtained by dehydration at normal pressure and above 180 ° C is dark gray and blocky solid, which is not conducive to dissolution under reaction conditions, resulting in low product yield, poor product quality, and difficult to remove during post-processing .

发明中所指的低温脱水的ZnCl₂，是指温度在40～200℃之间，真空度在0.01～100mmHg， 并在脱水系存在的条件下制备的ZnCl₂，脱水在1～20小时完成。 The low-temperature dehydrated ZnCl₂ referred to in the invention refers to the ZnCl₂ prepared in the presence of a dehydration system at a temperature of 40-200°C, a vacuum of 0.01-100mmHg, and the dehydration is completed within 1-20 hours.

脱水系是指五氧化二磷、浓硫酸、浓磷酸、分子筛、KOH或变色硅胶等。 The dehydration system refers to phosphorus pentoxide, concentrated sulfuric acid, concentrated phosphoric acid, molecular sieve, KOH or color-changing silica gel, etc. the

本发明人经过大量的实验还发现，如将极易吸水的无水ZnCl₂制备成其乙醚溶液，在反应中格氏试剂加完后利用同一滴加装置将这一溶液加入反应器中，不但避免了直接加入固体ZnCl₂会吸水这一难题，而且反应的收率也会提高。 The inventor also finds that through a large amount of experiments, if the anhydrous_ZnCl that is very easy to absorb water is prepared into its ether solution, after the Grignard reagent is added in the reaction, this solution is added to the reactor by the same dripping device, not only The difficult problem of water absorption caused by directly adding solid ZnCl₂ is avoided, and the yield of the reaction will also be improved.

本发明的有益效果是操作简便，反应流程合理，生产成本低，产品质量好，总收率高达90％以上。对环境无污染，可用于工业化生产。 The invention has the beneficial effects of simple operation, reasonable reaction process, low production cost, good product quality and a total yield of over 90%. It is non-polluting to the environment and can be used in industrialized production. the

具体实施方式Detailed ways

下面结合实施例对本发明做进一步说明： The present invention will be further described below in conjunction with embodiment:

实施例1低温脱水ZnCl₂的制备 Embodiment 1 The preparation of low temperature dehydration_ZnCl

将500g工业级氯化锌在真空下(5mmHg)，加热至150℃，在机械搅拌下连续保温10小时，蒸出来的水分用适量的五氧化二磷吸收，得到约480g白色粉术状无水氯化锌。 Heat 500g of industrial-grade zinc chloride to 150°C under vacuum (5mmHg), keep warm for 10 hours under mechanical stirring, absorb the evaporated water with an appropriate amount of phosphorus pentoxide, and obtain about 480g of white powder-like anhydrous Zinc chloride. the

实施例2格氏试剂叔丁基溴化镁的制备 The preparation of embodiment 2 Grignard reagent tert-butylmagnesium bromide

在严格干燥过的250mL三颈瓶中加入搅拌磁子，装上冷凝管及恒压滴液漏斗，在冷凝管的上口装置氯化钙干燥管。反应瓶内装入3.1g(0.13mol)镁屑、15ml无水乙醚及一小粒碘片。在滴液漏斗中混合16.2ml(0.16mol)溴代叔丁烷和15ml乙醚。先向瓶内滴入约5ml混合液，水浴温度加热为30℃。数分钟后，溶液呈微沸状态，碘的颜色消失，溶液变为灰色。刚开始反应较为剧烈，可用冰块降温。待反应缓和后，从冷凝管上端加入25ml无水乙醚，开始搅拌，并慢慢滴入剩余的溴代叔丁烷的乙醚溶液，控制滴加速度，使反应液呈微沸状态。滴加完毕后，待大部分镁屑消失后，在水浴中加热回流，使剩余的镁屑作用完全。使反应体系慢慢冷却，备用。 Add a stirring magnet to a strictly dried 250mL three-necked bottle, install a condenser tube and a constant pressure dropping funnel, and install a calcium chloride drying tube at the top of the condenser tube. 3.1g (0.13mol) of magnesium chips, 15ml of anhydrous ether and a small iodine tablet were placed in the reaction bottle. 16.2 ml (0.16 mol) of bromo-tert-butane and 15 ml of diethyl ether were mixed in a dropping funnel. First drop about 5ml of the mixed solution into the bottle, and heat the temperature of the water bath to 30°C. After a few minutes, the solution was slightly boiling, the color of iodine disappeared, and the solution turned gray. The reaction is violent at first, and can be cooled with ice cubes. After the reaction is moderated, add 25ml of anhydrous diethyl ether from the upper end of the condenser, start stirring, and slowly drop in the remaining diethyl ether solution of tert-bromobutane, control the rate of addition, so that the reaction solution is in a slightly boiling state. After the dropwise addition, after most of the magnesium chips disappear, heat and reflux in a water bath to make the remaining magnesium chips fully act. Allow the reaction system to cool slowly and set aside. the

实施例3格氏试剂苄基氯化镁的制备 The preparation of embodiment 3 Grignard reagent benzyl magnesium chloride

在严格干燥过的1.0L三颈瓶的中间口装置机械搅拌，另外两个侧口分别装置恒压滴液漏斗和冷凝管，冷凝管的上口装置氯化钙干燥管。在反应瓶中预先加入150mL干燥的无水乙醚，然后加入11.2g(0.46mol)的镁屑。将反应装置放在20～23℃的水浴槽中。将75.9g(0.60mol)氯苄和350mL干燥的乙醚混合在滴液漏斗中，并将一小部分混合液滴入反应瓶中引发反应。反应一旦开始，溶液颜色变为灰黑色，此时缓慢启动搅拌。慢慢加入剩余的混合液，使反应保持微沸，总共滴加时间约10h。冷却，将反应液转移到干燥的瓶中密封，备用。 The middle port of the strictly dried 1.0L three-necked bottle is equipped with mechanical stirring, and the other two side ports are respectively equipped with a constant pressure dropping funnel and a condenser tube, and the upper port of the condenser tube is equipped with a calcium chloride drying tube. Add 150 mL of dry anhydrous ether in advance in the reaction flask, and then add 11.2 g (0.46 mol) of magnesium chips. Place the reaction device in a water bath at 20-23°C. Mix 75.9g (0.60mol) benzyl chloride and 350mL dry diethyl ether in the dropping funnel, and drop a small part of the mixture into the reaction flask to initiate the reaction. Once the reaction started, the color of the solution turned gray-black, at which point stirring was started slowly. Slowly add the remaining mixed solution to keep the reaction slightly boiling, and the total addition time is about 10h. After cooling, transfer the reaction solution to a dry bottle and seal it for later use. the

实施例4  4-甲基-2-氯-丁基硼酸-α-蒎烷二醇酯 Example 4 4-methyl-2-chloro-butylboronic acid-α-pinanediol ester

4-甲基-2-氯-丁基硼酸-α-蒎烷二醇酯的分子结构式为： The molecular structural formula of 4-methyl-2-chloro-butylboronic acid-α-pinanediol ester is:

其具体制法如下： Its specific method is as follows:

在150ml的三口瓶中，加入用20mL乙醚溶解的二氯甲基硼酸-α-蒎烷二醇酯7.89g(30mmol)，室温下搅拌。通入干燥的氮气，并将体系降温至-78℃，然后慢慢滴加制好的叔丁基溴化镁的乙醚溶液50mL(30mmol)，滴加完毕后，一次性加入溶有2.45g(18mmol)的干燥的ZnCl₂粉术的乙醚溶液15ml。自然升至室温，继续在室温下搅拌18h后反应完毕。过滤除去ZnCl₂及反应生成的MgBr₂，滤液分别用20％的NH₄Cl溶液和饱和NaCl溶液洗涤，有机相用无水硫酸钠干燥。减压蒸除溶剂。浓缩后柱层析分离(乙酸乙酯∶石油醚＝1∶200)得无色液体7.88g，收率92.5％。 In a 150 ml three-necked flask, 7.89 g (30 mmol) of dichloromethylboronic acid-α-pinanediol ester dissolved in 20 mL of ether was added, and stirred at room temperature. Pass through dry nitrogen, and cool the system down to -78°C, then slowly add 50mL (30mmol) of the prepared tert-butylmagnesium bromide ether solution dropwise, after the dropwise addition, add 2.45g ( 18mmol) of dry ZnCl₂ powder technique in ether solution 15ml. Naturally rose to room temperature, continued to stir at room temperature for 18h after the reaction was complete. ZnCl₂ and MgBr₂ generated by the reaction were removed by filtration, the filtrate was washed with 20% NH₄ Cl solution and saturated NaCl solution respectively, and the organic phase was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. After concentration, it was separated by column chromatography (ethyl acetate: petroleum ether = 1:200) to obtain 7.88 g of a colorless liquid, with a yield of 92.5%.

实施例5  3-苯基-2-氯-丙基硼酸-α-蒎烷二醇酯 Example 5 3-phenyl-2-chloro-propylboronic acid-α-pinanediol ester

3-苯基-2-氯-丙基硼酸-α-蒎烷二醇酯的分子结构式为： The molecular structural formula of 3-phenyl-2-chloro-propylboronic acid-α-pinanediol ester is:

制备方法如下： The preparation method is as follows:

在500ml的三口瓶中，加入用100mL乙醚溶解的二氯甲基硼酸-α-蒎烷二醇酯35.5g(135mmol)，室温下搅拌。通入干燥的氮气，并将体系降温至-60℃，然后慢慢滴加制好的苄基氯化镁的乙醚溶液200mL(135mmol)，滴加完毕后，一次性加入溶有11.03g(81mmol)的干燥的ZnCl₂粉末的乙醚溶液80ml。自然升至室温，继续在室温下搅拌过夜反应。过滤除去ZnCl₂及反应生成的MgCl₂，滤液分别用15％的NH₄NO₃溶液和饱和NaCl溶液洗涤，有机相用无水硫酸钠干燥。减压蒸除溶剂。浓缩后柱层析分离(乙酸乙酯∶石油醚＝1∶120)得无色液体40.73g，收率94.7％。 Into a 500ml three-neck flask, add 35.5g (135mmol) of dichloromethylboronic acid-α-pinanediol ester dissolved in 100mL of ether, and stir at room temperature. Pass dry nitrogen, and cool the system down to -60°C, then slowly add 200mL (135mmol) of the prepared benzylmagnesium chloride ether solution, after the dropwise addition, add 11.03g (81mmol) of Diethyl ether solution of dry ZnCl₂ powder 80ml. Naturally warmed to room temperature, the reaction was continued to stir overnight at room temperature. ZnCl₂ and MgCl₂ generated by the reaction were removed by filtration, the filtrate was washed with 15% NH₄ NO₃ solution and saturated NaCl solution respectively, and the organic phase was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. After concentration, it was separated by column chromatography (ethyl acetate:petroleum ether=1:120) to obtain 40.73 g of a colorless liquid, with a yield of 94.7%.

Claims (10)

1. the preparation method of a pinane diol ester, its reaction scheme is following:

A in noble gas protection down, is dissolved in Grignard reagent RMgX in the solvent and raw material 1 reaction generation midbody 2, and wherein R is aliphatics substituting group or aromatic substituents, and X is a halogen;

B, midbody 2 are again at anhydrous ZnCl₂Diethyl ether solution catalysis generate down the pinane diol ester III of chirality.

2. preparation method according to claim 1 is characterized in that the described solvent of step a is benzene, toluene, sherwood oil, ether, THF or dioxane.

3. preparation method according to claim 2 is characterized in that the further preferred ether of the described solvent of step a.

4. preparation method according to claim 1 is characterized in that the said noble gas of step a is N₂Or Ar.

5. preparation method according to claim 1 is characterized in that step a temperature of reaction is-40～-100 ℃.

6. preparation method according to claim 1 is characterized in that the said reaction of step b slowly rises to room temperature naturally.

7. preparation method according to claim 1, the reaction times that it is characterized in that step b is 8 ~ 30 hours.

8. preparation method according to claim 7 is characterized in that preferred 15 ~ 24 hours of reaction times of step b.

9. preparation method according to claim 1, after the reaction that it is characterized in that step b finishes, the undissolved ZnCl of filtering₂, in filtrating, add ZnCl again₂Remove liquid.

10. preparation method according to claim 9 is characterized in that said ZnCl₂Removing liquid is that mass concentration is 10 ~ 40% NH₄Cl, (NH₄)₂SO₄Or NH₄NO₃Solution.