一种含环丙基手性胺盐酸盐的合成方法A kind of synthetic method containing cyclopropyl chiral amine hydrochloride
技术领域technical field
本发明涉及医药中间体和有机化工中间体合成技术领域,涉及一种含环丙基手性胺盐酸盐的合成方法。The invention relates to the technical field of synthesis of pharmaceutical intermediates and organic chemical intermediates, and relates to a synthesis method of a cyclopropyl-containing chiral amine hydrochloride.
背景技术Background technique
含环丙基手性胺是一类重要的医药中间体,应用及其广泛,例如文献报道其可以用于合成促肾上腺皮质激素释放因子-1(CRF1)受体拮抗剂(J.Med.Chem.2009,52,4173),文献也报道了其用于合成喹唑啉类药物用于治疗癌症(ACS Med.Chem.Lett.2018,9,9,941–946),还有专利报道了其可用于合成Cathepsin S抑制剂用于治疗自身免疫及相关病症(WO2011109470),另有专利报道其可以合成调节Ras活性剂而用于治疗癌症(WO2018212774)。总之,含环丙基手性胺目前在医药合成领域用途广泛,其合成工艺具有较大的开发价值。Cyclopropyl-containing chiral amines are an important class of pharmaceutical intermediates and are widely used. For example, it has been reported in the literature that they can be used to synthesize corticotropin-releasing factor-1 (CRF1) receptor antagonists (J.Med.Chem .2009,52,4173), the literature also reported that it was used to synthesize quinazoline drugs for the treatment of cancer (ACS Med.Chem.Lett.2018,9,9,941–946), and patents reported that it could be used for Synthetic Cathepsin S inhibitors are used for the treatment of autoimmunity and related disorders (WO2011109470), and another patent reports that it can be synthesized to modulate Ras activity agents for the treatment of cancer (WO2018212774). In a word, cyclopropyl-containing chiral amines are currently widely used in the field of pharmaceutical synthesis, and their synthesis processes have great development value.
含环丙基手性胺化合物,其合成的难点在于手性胺结构的形成,通常有两种合成策略,文献综述如下:The difficulty in the synthesis of cyclopropyl-containing chiral amine compounds lies in the formation of the chiral amine structure. There are usually two synthetic strategies. The literature review is as follows:
第一种方法,(J.Med.Chem.2009,52,4173)等专利报道了以N-甲氧基-N-甲基-2-甲氧基乙酰胺为原料,通过环丙烷基化,还原胺化、Cbz保护、手性拆分和脱保护反应生成目标产物,该路线需要5步反应路线较长,且原料价格昂贵,其中手性拆分需要采用HPLC手性柱进行,无法放大工业化,且还原胺化还使用了大量的三乙酰硼氢化钠,且有较大的爆炸风险,不适宜工业化生产。The first method, (J.Med.Chem.2009,52,4173) and other patents reported that N-methoxy-N-methyl-2-methoxyacetamide was used as a raw material, through cyclopropanylation, Reductive amination, Cbz protection, chiral resolution and deprotection reactions generate the target product. This route requires a long 5-step reaction route, and the raw materials are expensive. The chiral resolution needs to be carried out by HPLC chiral column, which cannot be scaled up for industrialization. , and the reductive amination also uses a large amount of sodium triacetylborohydride, and there is a greater risk of explosion, which is not suitable for industrial production.
另一种方法,文献ACS Med.Chem.Lett.2018,9,9,941–946报道了以环丙甲醛为原料,先与手性叔丁基亚磺酰胺缩合,再与格氏试剂烷基化,最后再脱去叔丁亚磺酰基得到产品。该路线中使用手性叔丁基亚磺酰胺,价格昂 贵,产生难闻性气体,并多步反应涉及过柱纯化操作,不适宜工业化生产。Another method, the literature ACS Med.Chem.Lett.2018,9,9,941–946 reported that cyclopropanecarboxaldehyde was used as raw material, firstly condensed with chiral tert-butylsulfinamide, and then alkylated with Grignard reagent, Finally, the tert-butanesulfinyl group is removed to obtain the product. In this route, chiral tert-butyl sulfenamide is used, which is expensive, produces unpleasant gas, and multi-step reaction involves column purification operation, which is not suitable for industrialized production.
目前现有的合成路线均存在不足之处,如步骤较长、需使用价格昂贵的试剂、涉及易燃易爆等危险试剂或者生产工艺、需要特殊生产设备、环境污染较为严重等问题,不利于大规模工业化生产。因此,存在对反应简单,成本低廉,易于工业化生产的制备环丙基手性胺的方法的需求。At present, the existing synthetic routes all have shortcomings, such as long steps, the need to use expensive reagents, involving inflammable and explosive and other dangerous reagents or production processes, requiring special production equipment, serious environmental pollution and other problems, which are not conducive to Large-scale industrial production. Therefore, there is a need for a method for preparing a cyclopropyl chiral amine with simple reaction, low cost and easy industrial production.
发明内容SUMMARY OF THE INVENTION
本发明要解决的技术问题是:研制开发一种原料易得,收率较高,品质较好,操作简便,适合工业化生产的含环丙基手性胺盐酸盐的合成方法。The technical problem to be solved by the present invention is to develop a method for synthesizing a cyclopropyl-containing chiral amine hydrochloride, which is easy to obtain from raw materials, has high yield, good quality, and is easy to operate and suitable for industrial production.
为了达到上述目的,本发明采用了以下技术方案:In order to achieve the above object, the present invention adopts the following technical solutions:
具体合成过程的如下:The specific synthesis process is as follows:
环丙甲醛(化合物(I))为起始原料与(R)-1-苯乙胺缩合制得化合物(II),接着与对应格氏试剂烷基化制备得到通式化合物(III),然后氢化脱苄保护得到通式化合物(IV),再拆分成盐制备得到产品通式化合物(V)。Cyclopropanecarboxaldehyde (compound (I)) is the starting material and is condensed with (R)-1-phenethylamine to obtain compound (II), followed by alkylation with the corresponding Grignard reagent to prepare compound (III) of general formula, and then Hydrogenation and debenzylation protection can obtain the compound (IV) of the general formula, and then split into a salt to prepare the product of the general formula (V).
一种含环丙基手性胺盐酸盐的合成方法,包括下述合成步骤:A synthetic method containing cyclopropyl chiral amine hydrochloride, comprising the following synthetic steps:
步骤1)化合物(I)环丙甲醛为起始原料,与(R)-1-苯乙胺缩合制得化合物(II),化合物(I)和(R)-1-苯乙胺在溶剂中反应,反应温度为50~110℃,经过后处理得到化合物(II)或其溶液,所述溶剂为四氢呋喃、甲苯、2-甲基四氢呋喃、甲基叔丁基醚、二氧六环、二氯甲烷中的任意一种或多种,所述环丙甲醛和(R)-1-苯乙胺摩尔比为1:1~3;Step 1) Compound (I) cyclopropanecarbaldehyde is used as starting material, and it is condensed with (R)-1-phenethylamine to obtain compound (II), and compound (I) and (R)-1-phenethylamine are in a solvent The reaction is carried out at a reaction temperature of 50-110° C., and the compound (II) or its solution is obtained after post-treatment, and the solvent is tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, dichloromethane Any one or more of the methane, the cyclopropanecarboxaldehyde and (R)-1-phenethylamine mol ratio is 1:1~3;
步骤2)化合物(II)溶液在-50~100℃,与格氏试剂溶液反应,后处理制备得到通式化合物(III)或其溶液,所述化合物(II)和格氏试剂摩尔比为1:1~10;Step 2) The compound (II) solution is reacted with a Grignard reagent solution at -50 to 100° C., and post-processing is performed to prepare the general formula compound (III) or its solution. The molar ratio of the compound (II) to the Grignard reagent is 1 : 1 to 10;
步骤3)通式化合物(III)溶液在催化剂催化下,在0~100℃,0~10MPa氢气氛围下反应,后处理制备得到通式化合物(IV)或其溶液;Step 3) Under the catalysis of a catalyst, the solution of the compound (III) of the general formula is reacted at 0-100° C. under a hydrogen atmosphere of 0-10 MPa, and the compound of the general formula (IV) or its solution is obtained by post-treatment;
步骤4)通式化合物(IV)或其溶液,加入拆分剂和溶剂进行拆分后,再后处理转化成盐酸盐制备得到通式化合物(V),所述的拆分为(S)-扁桃酸、(S)-乙酰基扁桃酸、L-二苯甲酰酒石酸、L-酒石酸中的任意一种或多种,所述溶剂为甲醇、乙醇、异丙醇、正丙醇、正丁醇、异丁醇、叔丁醇、水中的任意一种或多种,所述化合物(IV)和拆分剂摩尔量比为0:0.5~10;Step 4) Compound (IV) of general formula or its solution, after adding a resolving agent and a solvent for resolution, then post-processing is converted into hydrochloride to prepare compound (V) of general formula, and the resolution is (S) - any one or more of mandelic acid, (S)-acetyl mandelic acid, L-dibenzoyl tartaric acid, L-tartaric acid, and the solvent is methanol, ethanol, isopropanol, n-propanol, n- Any one or more of butanol, isobutanol, tert-butanol, and water, and the molar ratio of the compound (IV) to the resolving agent is 0:0.5 to 10;
作为进一步的优选实施例,步骤1)中,环丙甲醛和(R)-1-苯乙胺摩尔比为1:1~1.5,溶剂为甲苯,反应温度为80~110℃,反应制备化合物(II)。As a further preferred embodiment, in step 1), the molar ratio of cyclopropanecarboxaldehyde and (R)-1-phenethylamine is 1:1 to 1.5, the solvent is toluene, the reaction temperature is 80 to 110 ° C, and the reaction preparation compound ( II).
作为进一步的优选实施例,步骤1)中,后处理制备得到化合物(II)或者溶液,进行下一步反应。As a further preferred embodiment, in step 1), compound (II) or a solution is prepared by post-treatment, and the next step is carried out.
作为进一步的优选实施例,步骤2)中,反应温度为-20~60℃,化合物(II)和格氏试剂摩尔比为1:1~1.5。As a further preferred embodiment, in step 2), the reaction temperature is -20 to 60° C., and the molar ratio of compound (II) to Grignard reagent is 1:1 to 1.5.
作为进一步的优选实施例,所述格氏试剂为甲基氯化镁、甲基溴化镁、乙基氯化镁、乙基溴化镁、乙烯基氯化镁、乙烯基溴化镁、乙炔基氯化镁、乙炔基溴化镁、正丙基氯化镁、正丙基溴化镁、异丙基氯化镁、异丙基溴化镁、正丁基氯化镁、正丁基溴化镁、异丁基氯化镁、异丁基溴化镁、叔丁基氯化镁、叔丁基溴化镁,对应的R基团为甲基、乙基、乙烯基、乙炔基、正丙基、异丙基、正丁基、异丁基、叔丁基,As a further preferred embodiment, the Grignard reagent is methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, vinylmagnesium chloride, vinylmagnesium bromide, ethynylmagnesium chloride, ethynylmagnesium bromide Magnesium chloride, n-propyl magnesium chloride, n-propyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, n-butyl magnesium chloride, n-butyl magnesium bromide, isobutyl magnesium chloride, isobutyl magnesium bromide , tert-butylmagnesium chloride, tert-butylmagnesium bromide, the corresponding R groups are methyl, ethyl, vinyl, ethynyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl ,
作为进一步的优选实施例,步骤2)中,后处理制备得到通式化合物(III)或者溶液,进行下一步反应。As a further preferred embodiment, in step 2), the compound of general formula (III) or a solution is prepared by post-treatment, and the next step is carried out.
作为进一步的优选实施例,步骤3)中,反应温度为30~60℃,氢气压力为0.5~1Mpa。As a further preferred embodiment, in step 3), the reaction temperature is 30-60° C., and the hydrogen pressure is 0.5-1 Mpa.
作为进一步的优选实施例,所述催化剂为钯碳、铑碳、铂碳、氧化铂中的任意一种或多种。As a further preferred embodiment, the catalyst is any one or more of palladium carbon, rhodium carbon, platinum carbon and platinum oxide.
作为进一步的优选实施例,步骤3)中,催化剂为钯碳。As a further preferred embodiment, in step 3), the catalyst is palladium carbon.
作为进一步的优选实施例,步骤4)中,拆分试剂为(S)-扁桃酸,通式化合物(IV)和拆分剂摩尔量比为0:0.8~1.5,溶剂为异丙醇,拆分后再转化成盐酸盐,制得、化合物(V)。As a further preferred embodiment, in step 4), the resolving agent is (S)-mandelic acid, the molar ratio of the general formula compound (IV) and the resolving agent is 0:0.8~1.5, the solvent is isopropanol, and the After fractionation, it is converted into hydrochloride to obtain compound (V).
本发明提供的含环丙基手性胺盐酸盐的合成方法具备下述优点:The synthetic method of cyclopropyl-containing chiral amine hydrochloride provided by the invention has the following advantages:
本发明路线相对比较简单,所用的原料均为市售的商业化物料,且原材料相对较为便宜,无复杂的特殊操作,适合于工业化生产;为含环丙基手性胺盐酸盐的合成制备提供一条新的合成方案。The route of the invention is relatively simple, the raw materials used are all commercially available commercial materials, and the raw materials are relatively cheap, without complicated special operations, and suitable for industrial production; it is the synthesis preparation of cyclopropyl-containing chiral amine hydrochloride A new synthetic protocol is provided.
具体实施方式Detailed ways
为了使本发明的目的、技术方案和优点更加清楚,以下结合实施例对本发明作进一步说明:In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention is further described below in conjunction with the examples:
实施例1:Example 1:
在氮气氛围下,反应瓶中加入70.1g环丙甲醛(1.0mol,1.0eq)和127.3g(R)-1-苯乙胺(1.05mol,1.05eq),溶解于700g甲苯,升温至80~90℃,反应12小时,降温至10~20℃,加入100g 0.1M盐酸洗涤1次,有机相加入100g无水硫酸镁干燥,过滤,制备得到化合物(II)溶液直接进行下一步反应。Under a nitrogen atmosphere, 70.1g of cyclopropanecarboxaldehyde (1.0mol, 1.0eq) and 127.3g of (R)-1-phenethylamine (1.05mol, 1.05eq) were added to the reaction flask, dissolved in 700g of toluene, and the temperature was raised to 80~ 90 ℃, react for 12 hours, cool down to 10~20 ℃, add 100g of 0.1M hydrochloric acid to wash once, add 100g of anhydrous magnesium sulfate to the organic phase to dry, filter, prepare the compound (II) solution and directly carry out the next step of the reaction.
将化合物(II)甲苯溶液,降温至-20℃,滴加入620mL乙基氯化镁的四氢呋喃溶液(1.1mol,1.1eq),滴加完毕,搅拌30min,加入氯化铵水溶液淬灭,分层,有机相用水洗涤一次,制备得到化合物(III-1)溶液,直接投入下一步反应。The toluene solution of compound (II) was cooled to -20°C, and 620 mL of ethylmagnesium chloride in tetrahydrofuran solution (1.1 mol, 1.1 eq) was added dropwise. The phase was washed once with water to prepare a solution of compound (III-1), which was directly put into the next reaction.
将化合物(III-1)溶液投入高压釜中,加入5g 5%Pd/C,置换成氢气,调节压力至0.5MPa,反应4h,放空出料,过滤,得到化合物(IV-1)的溶液,投入下一步反应。The compound (III-1) solution was put into the autoclave, 5g of 5% Pd/C was added, replaced with hydrogen, the pressure was adjusted to 0.5MPa, the reaction was performed for 4h, vented and discharged, and filtered to obtain the solution of compound (IV-1), Enter the next reaction.
将上步化合物(IV-1)的溶液中加入152.2g(S)-扁桃酸(1.0mol,1.0eq)和200mL的异丙醇,升温至70℃,搅拌2h,降温至10~20℃,过滤,滤饼加入200mL异丙醇20~30℃打浆3h。打浆完毕,过滤得到滤饼,加入500mL甲基叔丁基醚和300mL 5M的氢氧化钠溶液,搅拌30min,分层,取有机相。有机相中加入350mL4M氯化氢的1,4-二氧六环溶液,搅拌1h,过滤,滤饼烘干,得到产品115.7g白色固体,即化合物(V-1),收率85.3%,纯度99.5%,ee值99%。化合物核磁数据如下:
1H NMR(400MHz,D
2O):δ2.07(m,1H),δ1.44(m,2H),δ0.68(t,3H),δ0.67(m,1H),δ0.33(m,2H),δ0.03(m,2H);
13C NMR(400MHz,D
2O):δ56.6,δ24.0,δ10.6,δ6.9,δ1.5。
152.2 g (S)-mandelic acid (1.0 mol, 1.0 eq) and 200 mL of isopropanol were added to the solution of compound (IV-1) in the previous step, the temperature was raised to 70 °C, stirred for 2 h, cooled to 10-20 °C, Filter, add 200 mL of isopropanol to the filter cake and make a slurry at 20-30 °C for 3 h. After beating, filter to obtain a filter cake, add 500 mL of methyl tert-butyl ether and 300 mL of 5M sodium hydroxide solution, stir for 30 min, separate layers, and take the organic phase. 350 mL of 4M hydrogen chloride solution in 1,4-dioxane was added to the organic phase, stirred for 1 h, filtered, and the filter cake was dried to obtain 115.7 g of a white solid product, namely compound (V-1), with a yield of 85.3% and a purity of 99.5%. , the ee value is 99%. The NMR data of the compound are as follows: 1 H NMR (400MHz, D 2 O): δ2.07(m, 1H), δ1.44(m, 2H), δ0.68(t, 3H), δ0.67(m, 1H) ), δ0.33(m, 2H), δ0.03(m, 2H); 13 C NMR (400MHz, D 2 O): δ56.6, δ24.0, δ10.6, δ6.9, δ1.5 .
实施例2:Example 2:
在氮气氛围下,反应瓶中加入70.1g环丙甲醛(1.0mol,1.0eq)和145.5g(R)-1-苯乙胺(1.2mol,1.2eq),溶解于1000g甲苯,升温至80~90℃,反应10小时,降温至10~20℃,加入200g 0.1M盐酸洗涤1次,有机相加入100g无水硫酸镁干燥,过滤,制备得到化合物(II)溶液直接进行下一步反应。Under a nitrogen atmosphere, 70.1g of cyclopropanecarboxaldehyde (1.0mol, 1.0eq) and 145.5g of (R)-1-phenethylamine (1.2mol, 1.2eq) were added to the reaction flask, dissolved in 1000g of toluene, and the temperature was raised to 80~ 90 ℃, react for 10 hours, cool down to 10~20 ℃, add 200g of 0.1M hydrochloric acid to wash once, add 100g of anhydrous magnesium sulfate to the organic phase to dry, filter, prepare a solution of compound (II) and directly carry out the next step of the reaction.
将化合物(II)甲苯溶液,降温至-20℃,滴加入620mL乙烯基溴化镁的四氢呋喃溶液(1.1mol,1.1eq),滴加完毕,搅拌30min,加入氯化铵水溶液淬灭,分层,有机相用水洗涤一次,制备得到化合物(III-2)溶液,直接投入下一步反应。The toluene solution of compound (II) was cooled to -20°C, 620 mL of vinylmagnesium bromide solution in tetrahydrofuran (1.1 mol, 1.1 eq) was added dropwise, the dropwise addition was completed, stirred for 30 min, quenched by adding aqueous ammonium chloride solution, and the layers were separated. , the organic phase was washed once with water to prepare a solution of compound (III-2), which was directly put into the next reaction.
将化合物(III-2)溶液投入高压釜中,加入3g 5%Pd/C,置换成氢气,调节压力至1.0MPa,反应4h,放空出料,过滤,滤液为化合物(IV-2)的溶液,投入下一步反应。The compound (III-2) solution was put into the autoclave, 3g of 5% Pd/C was added, replaced with hydrogen, the pressure was adjusted to 1.0MPa, the reaction was performed for 4h, the material was vented, filtered, and the filtrate was the solution of compound (IV-2) , into the next reaction.
将上步化合物(IV-2)的溶液中加入137.0g(S)-扁桃酸(0.95mol,0.95eq)和200mL的异丙醇,升温至70℃,搅拌2h,降温至10~20℃,过滤,滤饼加入200mL异丙醇20~30℃打浆3h。打浆完毕,过滤得到滤饼,加入500mL甲基叔丁基醚和300mL 5M的氢氧化钠溶液,搅拌30min,分层,取有机相。有机相中加入350mL 4M氯化氢的1,4-二氧六环溶液,搅拌1h,过滤,滤饼烘干,得到产品116.8g白色固体,即化合物(V-2),收率87.4%,纯度99.8%,ee值99.1%。化合物核磁数据如下:
1H NMR(400MHz,D
2O):δ5.81(m,1H),δ5.28(m,2H),δ3.03(m,1H),δ0.95(m,1H),δ0.43(m,4H);
13C NMR(400MHz,D
2O):δ132.5,δ119.4,δ58.3,δ12.8,δ3.3,δ2.6。
137.0 g (S)-mandelic acid (0.95 mol, 0.95 eq) and 200 mL of isopropanol were added to the solution of the compound (IV-2) in the previous step, the temperature was raised to 70 °C, stirred for 2 h, cooled to 10-20 °C, Filter, add 200 mL of isopropanol to the filter cake and make a slurry at 20-30 °C for 3 h. After beating, filter to obtain a filter cake, add 500 mL of methyl tert-butyl ether and 300 mL of 5M sodium hydroxide solution, stir for 30 min, separate layers, and take the organic phase. 350 mL of 4M hydrogen chloride solution in 1,4-dioxane was added to the organic phase, stirred for 1 h, filtered, and the filter cake was dried to obtain 116.8 g of a white solid product, namely compound (V-2), with a yield of 87.4% and a purity of 99.8 %, ee value 99.1%. The NMR data of the compound are as follows: 1 H NMR (400MHz, D 2 O): δ5.81(m, 1H), δ5.28(m, 2H), δ3.03(m, 1H), δ0.95(m, 1H) ), δ0.43 (m, 4H); 13 C NMR (400 MHz, D 2 O): δ132.5, δ119.4, δ58.3, δ12.8, δ3.3, δ2.6.
实施例3:Example 3:
在氮气氛围下,反应瓶中加入70.1g环丙甲醛(1.0mol,1.0eq)和133.4g(R)-1-苯乙胺(1.1mol,1.1eq),溶解于1000g甲苯,升温至100~105℃,反应18小时,降温至10~20℃,加入200g 0.1M盐酸洗涤1次,有机相加入100g无水硫酸镁干燥,过滤,制备得到化合物(II)溶液直接进行下一步反应。Under a nitrogen atmosphere, 70.1g of cyclopropanecarboxaldehyde (1.0mol, 1.0eq) and 133.4g of (R)-1-phenethylamine (1.1mol, 1.1eq) were added to the reaction flask, dissolved in 1000g of toluene, and the temperature was raised to 100~ 105 ℃, react for 18 hours, cool down to 10~20 ℃, add 200g of 0.1M hydrochloric acid to wash once, add 100g of anhydrous magnesium sulfate to the organic phase to dry, filter, and prepare the compound (II) solution and directly carry out the next step of the reaction.
将化合物(II)甲苯溶液,降温至20℃,滴加入620mL异丙基氯化镁的四氢呋喃溶液(1.1mol,1.1eq),滴加完毕,搅拌30min,加入氯化铵水溶液淬灭,分层,有机相用水洗涤一次,制备得到化合物(III-3)溶液,直接投入下一步反应。The toluene solution of compound (II) was cooled to 20°C, and 620 mL of isopropylmagnesium chloride solution in tetrahydrofuran (1.1 mol, 1.1 eq) was added dropwise. The phase was washed once with water to prepare a solution of compound (III-3), which was directly put into the next reaction.
将化合物(III-3)溶液投入高压釜中,加入10g 5%Pd/C,置换成氢气,调节压力至1.0MPa,反应2h,放空出料,过滤,滤液为化合物(IV-3)的溶液,投入下一步反应。The compound (III-3) solution was put into the autoclave, 10g of 5% Pd/C was added, replaced with hydrogen, the pressure was adjusted to 1.0MPa, the reaction was performed for 2h, the material was vented and discharged, filtered, and the filtrate was the solution of compound (IV-3) , into the next reaction.
将上步化合物(IV-3)的溶液中加入155.3g(S)-乙酰基扁桃酸(0.8mol,0.8eq)和300mL的异丙醇,升温至70℃,搅拌2h,降温至10~20℃,过滤,滤饼加入300mL异丙醇20~30℃打浆3h。打浆完毕,过滤得到滤饼,加入500mL甲基叔丁基醚和300mL 5M的氢氧化钠溶液,搅拌30min,分层,取有机相。有机相中加入350mL 4M氯化氢的1,4-二氧六环溶液,搅拌1h,过滤,滤饼烘干,得到产品125.3g白色固体,即化合物(V-3),收率83.7%,纯度99.6%,ee值99.0%。化合物核磁数据如下:
1HNMR(400MHz,D
2O):δ2.0(m,1H),δ1.74(m,1H),δ0.74(d,6H),δ0.67(m,1H),δ0.23(m,4H);
13C NMR(400MHz,D
2O):δ61.2,δ29.5,δ15.7,δ9.0,δ3.0。
155.3g (S)-acetylmandelic acid (0.8mol, 0.8eq) and 300mL isopropanol were added to the solution of the compound (IV-3) in the previous step, the temperature was raised to 70°C, stirred for 2h, and cooled to 10-20 ℃, filter, add 300 mL of isopropanol to the filter cake to make slurry at 20-30 ℃ for 3 hours. After beating, filter to obtain a filter cake, add 500 mL of methyl tert-butyl ether and 300 mL of 5M sodium hydroxide solution, stir for 30 min, separate layers, and take the organic phase. 350 mL of 4M hydrogen chloride solution in 1,4-dioxane was added to the organic phase, stirred for 1 h, filtered, and the filter cake was dried to obtain 125.3 g of a white solid product, namely compound (V-3), with a yield of 83.7% and a purity of 99.6 %, ee value 99.0%. The NMR data of the compound are as follows: 1 HNMR (400MHz, D 2 O): δ2.0(m, 1H), δ1.74(m, 1H), δ0.74(d, 6H), δ0.67(m, 1H) , δ 0.23 (m, 4H); 13 C NMR (400 MHz, D 2 O): δ 61.2, δ 29.5, δ 15.7, δ 9.0, δ 3.0.
实施例4:Example 4:
在氮气氛围下,反应瓶中加入70.1g环丙甲醛(1.0mol,1.0eq)和133.4g(R)-1-苯乙胺(1.1mol,1.1eq),溶解于1000g甲苯,升温至100~105℃,反应18小时,降温至10~20℃,加入200g 0.1M盐酸洗涤1次,有机相加入100g无水硫酸镁干燥,过滤,制备得到化合物(II)溶液直接进行下一步反应。Under a nitrogen atmosphere, 70.1g of cyclopropanecarboxaldehyde (1.0mol, 1.0eq) and 133.4g of (R)-1-phenethylamine (1.1mol, 1.1eq) were added to the reaction flask, dissolved in 1000g of toluene, and the temperature was raised to 100~ 105 ℃, react for 18 hours, cool down to 10~20 ℃, add 200g of 0.1M hydrochloric acid to wash once, add 100g of anhydrous magnesium sulfate to the organic phase to dry, filter, and prepare the compound (II) solution and directly carry out the next step of the reaction.
将化合物(II)甲苯溶液,降温至40℃,滴加入620mL乙炔基氯化镁的四氢呋喃溶液(1.1mol,1.1eq),滴加完毕,搅拌30min,加入氯化铵水溶液淬灭,分层,有机相用水洗涤一次,制备得到化合物(III-4)溶液,直接投入下一步反 应。The toluene solution of compound (II) was cooled to 40°C, and 620 mL of ethynylmagnesium chloride solution in tetrahydrofuran (1.1 mol, 1.1 eq) was added dropwise. Wash once with water to prepare a solution of compound (III-4), which is directly put into the next reaction.
将化合物(III-4)溶液投入高压釜中,加入2g 5%Pd/C,置换成氢气,调节压力至0.2MPa,反应10h,放空出料,过滤,滤液为化合物(IV-4)的溶液,投入下一步反应。Put the compound (III-4) solution into the autoclave, add 2g 5% Pd/C, replace it with hydrogen, adjust the pressure to 0.2MPa, react for 10h, vent and discharge, filter, and the filtrate is the solution of compound (IV-4) , into the next reaction.
将上步化合物(IV-4)的溶液中加入358.3gL-二苯甲酰酒石酸(1.0mol,1.0eq)和300mL的异丙醇,升温至70℃,搅拌2h,降温至10~20℃,过滤,滤饼加入500mL异丙醇20~30℃打浆3h。打浆完毕,过滤得到滤饼,加入500mL甲基叔丁基醚和300mL 5M的氢氧化钠溶液,搅拌30min,分层,取有机相。有机相中加入350mL 4M氯化氢的1,4-二氧六环溶液,搅拌1h,过滤,滤饼烘干,得到产品106.2g白色固体,即化合物(V-4),收率80.7%,纯度99.5%,ee值99.2%。化合物核磁数据如下:
1H NMR(400MHz,D
2O):δ3.79(m,1H),δ2.85(s,1H),δ1.14(m,1H),δ0.51(m,4H);
13C NMR(400MHz,D
2O):δ74.7,δ74.2,δ44.7,δ10.6,δ1.6。
Add 358.3 g of L-dibenzoyltartaric acid (1.0 mol, 1.0 eq) and 300 mL of isopropanol to the solution of the compound (IV-4) in the previous step, heat up to 70 °C, stir for 2 h, cool down to 10-20 °C, Filter, add 500 mL of isopropanol to the filter cake and make a slurry at 20-30 °C for 3 hours. After beating, filter to obtain a filter cake, add 500 mL of methyl tert-butyl ether and 300 mL of 5M sodium hydroxide solution, stir for 30 min, separate layers, and take the organic phase. 350 mL of 4M hydrogen chloride solution in 1,4-dioxane was added to the organic phase, stirred for 1 h, filtered, and the filter cake was dried to obtain 106.2 g of a white solid product, namely compound (V-4), with a yield of 80.7% and a purity of 99.5 %, ee value 99.2%. The NMR data of the compound are as follows: 1 H NMR (400MHz, D 2 O): δ3.79(m, 1H), δ2.85(s, 1H), δ1.14(m, 1H), δ0.51(m, 4H) ); 13 C NMR (400 MHz, D 2 O): δ74.7, δ74.2, δ44.7, δ10.6, δ1.6.
实施例5:Example 5:
在氮气氛围下,反应瓶中加入70.1g环丙甲醛(1.0mol,1.0eq)和133.4g(R)-1-苯乙胺(1.1mol,1.1eq),溶解于1000g甲苯,升温至100~105℃,反应18小时,降温至10~20℃,加入200g 0.1M盐酸洗涤1次,有机相加入100g无水硫酸镁干燥,过滤,制备得到化合物(II)溶液直接进行下一步反应。Under a nitrogen atmosphere, 70.1g of cyclopropanecarboxaldehyde (1.0mol, 1.0eq) and 133.4g of (R)-1-phenethylamine (1.1mol, 1.1eq) were added to the reaction flask, dissolved in 1000g of toluene, and the temperature was raised to 100~ 105 ℃, react for 18 hours, cool down to 10~20 ℃, add 200g of 0.1M hydrochloric acid to wash once, add 100g of anhydrous magnesium sulfate to the organic phase to dry, filter, and prepare the compound (II) solution and directly carry out the next step of the reaction.
将化合物(II)甲苯溶液,降温至60℃,滴加入667mL正丁基溴化镁的四氢呋喃溶液(1.2mol,1.2eq),滴加完毕,搅拌30min,加入氯化铵水溶液淬灭, 分层,有机相用水洗涤一次,制备得到化合物(III-5)溶液,直接投入下一步反应。The toluene solution of compound (II) was cooled to 60°C, and 667 mL of n-butylmagnesium bromide solution in tetrahydrofuran (1.2 mol, 1.2 eq) was added dropwise. , the organic phase was washed once with water to prepare a solution of compound (III-5), which was directly put into the next reaction.
将化合物(III-5)溶液投入高压釜中,加入2g 5%Pd/C,置换成氢气,调节压力至0.2MPa,反应10h,放空出料,过滤,滤液为化合物(IV-5)的溶液,投入下一步反应。The compound (III-5) solution was put into the autoclave, 2g of 5% Pd/C was added, replaced with hydrogen, the pressure was adjusted to 0.2MPa, the reaction was performed for 10h, the material was vented, filtered, and the filtrate was the solution of compound (IV-5) , into the next reaction.
将上步化合物(IV-4)的溶液中加入228.3g(S)-扁桃酸(1.5mol,1.5eq)和300mL的异丙醇,升温至70℃,搅拌2h,降温至10~20℃,过滤,滤饼加入500mL异丙醇20~30℃打浆3h。打浆完毕,过滤得到滤饼,加入500mL甲基叔丁基醚和300mL 5M的氢氧化钠溶液,搅拌30min,分层,取有机相。有机相中加入350mL4M氯化氢的1,4-二氧六环溶液,搅拌1h,过滤,滤饼烘干,得到产品144.4g白色固体,即化合物(V-5),收率88.2%,纯度99.2%,ee值99.3%。化合物核磁数据如下:
1HNMR(400MHz,D
2O):δ2.1(m,1H),δ1.54(m,2H),δ1.32(m,2H),δ1.27(m,2H),δ0.74(t,3H),δ0.67(m,1H),δ0.28(m,4H);
13C NMR(400MHz,D
2O):δ59.8,δ30.5,δ27.7,δ22.5,δ15.7,δ12.8,δ2.8。
228.3 g (S)-mandelic acid (1.5 mol, 1.5 eq) and 300 mL of isopropanol were added to the solution of the compound (IV-4) in the previous step, the temperature was raised to 70 °C, stirred for 2 h, cooled to 10-20 °C, Filter, add 500 mL of isopropanol to the filter cake and make a slurry at 20-30 °C for 3 hours. After beating, filter to obtain a filter cake, add 500 mL of methyl tert-butyl ether and 300 mL of 5M sodium hydroxide solution, stir for 30 min, separate layers, and take the organic phase. 350 mL of 4M hydrogen chloride solution in 1,4-dioxane was added to the organic phase, stirred for 1 h, filtered, and the filter cake was dried to obtain 144.4 g of a white solid product, namely compound (V-5), with a yield of 88.2% and a purity of 99.2%. , the ee value is 99.3%. The NMR data of the compound are as follows: 1 HNMR (400MHz, D 2 O): δ2.1(m, 1H), δ1.54(m, 2H), δ1.32(m, 2H), δ1.27(m, 2H) , δ0.74(t, 3H), δ0.67(m, 1H), δ0.28(m, 4H); 13 C NMR (400MHz, D 2 O): δ59.8, δ30.5, δ27.7 , δ22.5, δ15.7, δ12.8, δ2.8.
以上所述仅为本发明的优选实施方式,并非因此限制本发明的专利范围,凡是利用本发明所作的等效变换,均在本发明的专利保护范围内。The above descriptions are only the preferred embodiments of the present invention, and are not intended to limit the patent scope of the present invention. All equivalent transformations made by using the present invention are within the scope of the patent protection of the present invention.