一种从 L型取代苯丝氨酸酯制备 苏式小 R-取代苯基 -2-二氯乙酰氯某 -3-氟小丙醇的方法 技术领域 Method for preparing threo small R-substituted phenyl-2-dichloroacetyl chloride from a 3-type substituted phenylserine ester Technical field
本发明涉及一种从 L型取代苯丝氨酸酯制备 D- (-) -苏式 -1-R-取代苯基 -2-二 氯乙酰氨基 -3-氟 -1-丙醇的方法。 进一步说是一种从取代的苯丝氨酸酯的拆分废 液经纯化得到纯的 L型异构体, 经 D型反转和氟代制备 D- (-) -苏式 -1-R-取代苯 基 -2-二氯乙酰氨基 -3-氟小丙醇的简便方法。 背景技术 The present invention relates to a method for preparing D-(-)-threo-1-R-substituted phenyl-2-dichloroacetamino-3-fluoro-1-propanol from L-substituted phenylserine ester. Furthermore, it is a kind of purified L-isomer from the waste liquid of the substituted phenylserine ester, which is purified to obtain D- (-)-threo-1-R-substitution by D-type inversion and fluorination. Convenient method for phenyl-2-dichloroacetamino-3-fluoropropanol. Background technique
氯霉素、 甲砜霉素及氟康尼等药物是一类广谱抗菌素, 特别是对革兰氏阴性 菌抑制效果好。 合成这一大类药物通常涉及 D、 L-型 -1-R-取代苯基 -2-氨基丙二 醇或 D、 L型取代苯丝氨酸酯的拆分, 其中只有 D-型异构体是合成上述药物的 前体, L-型异构体被废弃 (Cutler, R. A., et al, J. Am. Chem. Soc, 74, 5475, 1952; Giordano, C., Tetrahedron Lett., 29, 5561, 1988), 至今没有发现有效利用 L型异构 体的方法。在世界范围内, 这类抗生素及其中间体的用量在万吨以上,每年数以 万吨的 L-异构体被废弃, 不能得到合理利用, 造成极大的浪费。 所以, 人们一 直在寻找。 充分合理地利用 L-型取代苯丝氨酸酯的方法, 从而降低药品成本, 造福于人类。 发明目的 Drugs such as chloramphenicol, methylsulfomycin, and fluconi are a broad-spectrum antibiotic, and they are particularly effective against Gram-negative bacteria. The synthesis of this broad class of drugs usually involves the resolution of D, L-type-1-R-substituted phenyl-2-aminopropanediol or D, L-substituted phenylserine esters, of which only the D-type isomer is synthesized as described above Prodrugs of the drug, L-isomers are discarded (Cutler, RA, et al, J. Am. Chem. Soc, 74, 5475, 1952; Giordano, C., Tetrahedron Lett., 29, 5561, 1988) So far, no effective method has been found to utilize the L-isomer. In the world, the amount of such antibiotics and their intermediates is more than 10,000 tons, and tens of thousands of tons of L-isomers are discarded every year, which cannot be used reasonably and cause great waste. So people are always looking. The method of making full and reasonable use of L-type substituted phenylserine esters, thereby reducing the cost of medicines and benefiting human beings. Object of the invention
本发明的目的是提供一种从 L型取代苯丝氨酸酯制备 D- (-) -苏式 -1-R-取代苯 基 -2-二氯乙酰氨基 -3-氟 -1-丙醇的方法。 系以从工业生产中的拆分废液中提取和 纯化的 L型取代苯丝氨酸酯为原料, 并将 L-型异构体转化为噁唑啉环化物; 进 而转化为高附加值的 D- (-) -苏式 -1-R-取代苯基 -2-二氯乙酰氨基 -3-氟 -1-丙醇。 发明概要 The object of the present invention is to provide a method for preparing D-(-)-threo-1-R-substituted phenyl-2-dichloroacetamino-3-fluoro-1-propanol from L-substituted phenylserine ester. . It is based on the extraction and purification of L-type substituted phenylserine esters from the separated waste liquid in industrial production, and converts the L-type isomers into oxazoline cyclates; and then converts into high-value-added D- (-)-Threo-1-R-substituted phenyl-2-dichloroacetamino-3-fluoro-1-propanol. Summary of invention
本发明的方法是从工业生产中的拆分废液中提取和纯化 L型取代苯丝氨酸酯 1,并以 1为原料经酰化环合和异构化反应生成 D- (-) -苏式 -(4&5 -2- -4- 氧酰 基 -5-R-取代苯基 -2-噁唑啉 2b, 2b经还原可获得 D- (-) -苏式 -(4S,5i?)-2-R2-4-羟甲
基 -5-R-取代苯基 -2-噁唑啉 2c, 2c经氟化反应得 D- (-) -苏式 -(4 & 5i?)-2-R2-4-氟甲 基 -5-R-取代苯基 -2-噁唑啉 2d, 上述 2c化合物的羟基还可方便地转化为其他卤 素、醚、酯等基团,将 2d化合物水解开环即能生成 D型- 1-R-取代苯基 -2-氨基 -3- 氟 -1-丙醇 3。最后经过酰化反应,合成得到 D- (-) -苏式 -1-R-取代苯基 -2-二氯乙酰 氨基 -3-氟 -1-丙醇 4a。 发明内容 The method of the present invention is to extract and purify L-type substituted phenylserine ester 1 from the separated waste liquid in industrial production, and use D as the raw material to form D-(-)-threo through acylation and isomerization reaction. -(4 & 5-2--4-oxoacyl-5-R-substituted phenyl-2-oxazoline 2b, 2b can be reduced to obtain D- (-)-threo- (4S, 5i?)-2- R 2 -4-hydroxymethyl 5-R-substituted phenyl-2-oxazoline 2c, 2c is fluorinated to give D-(-)-threo- (4 & 5i?)-2-R 2-4- fluoromethyl- 5-R-substituted phenyl-2-oxazoline 2d, the hydroxyl group of the above 2c compound can also be easily converted into other halogens, ethers, esters and other groups, and the 2d compound can be hydrolyzed and ring-opened to form D- 1- R-substituted phenyl-2-amino-3-fluoro-1-propanol 3. Finally, after acylation, D-(-)-threo-1-R-substituted phenyl-2-dichloroacetamino-3-fluoro-1-propanol 4a was synthesized. Summary of the Invention
本发明的方法可用下述反应式表示: The method of the present invention can be expressed by the following reaction formula:
3a: R =C¾F 4a: R3=CH2F 3a: R = C¾F 4a: R 3 = CH 2 F
其中, R在整个多步反应中是不变的, R=N02, CN, R4S02, R4S, CF3, R1是 C1-s的 垸基, R2是芳基或 R1, R3是 COOR1或 C¾Y, Y是羟基或卤素, 所述芳基是苯 基, 卤代苯基, d_8的垸基取代苯基, 所述 R4是 C1-8的烷基。 Among them, R is invariant in the whole multi-step reaction, R = N0 2 , CN, R 4 S0 2 , R 4 S, CF 3 , R 1 is a fluorenyl group of C 1-s , and R 2 is an aryl group or R 1 and R 3 are COOR 1 or C¾Y, Y is hydroxyl or halogen, the aryl is phenyl, halophenyl, fluorenyl substituted phenyl of d- 8 , and R 4 is C 1-8 alkane base.
用本发明的方法从拆分废液中提取和纯化化合物 1,并由化合物 1合成 D- (-) - 苏式 -1-R-取代苯基 -2-二氯乙酰氨基 -3-氟 -1-丙醇, 可以分别通过下述步骤实现。 The method of the present invention is used to extract and purify compound 1 from the resolution waste liquid, and synthesize D-(-)-threo-1-R-substituted phenyl-2-dichloroacetamino-3-fluoro- 1-propanol can be achieved by the following steps, respectively.
在极性溶剂中, 化合物 1与分子式为 R2COX的酰卤在 -20°C至 10°C反应 0.2~10小时,推荐反应时间为 1〜5小时,反应中若加入氮原子上含有孤对电子的 化合物将有利于反应的进行。反应毕, 抽干溶剂后再加入极性溶剂, 或经减压除 去过量酰卤或不经任何处理, 加入二氯亚砜在室温至 80°C下继续反应 0.2-10小 时, 获得化合物 2a。所述的 L型取代苯丝氨酸酯 1、酰卤、氮原子上含有孤对电 子的化合物和二氯亚砜的摩尔比为 1:0.8~1.5:0~5:0.5~3, 推荐摩尔比依次为 1:0.8~1.2:0.04~4:0.5〜2。 In a polar solvent, Compound 1 reacts with an acid halide of the formula R 2 COX at -20 ° C to 10 ° C for 0.2 to 10 hours, and the recommended reaction time is 1 to 5 hours. Electron-positive compounds will facilitate the reaction. After the reaction, the solvent was drained off and then added with a polar solvent, or excess acid halide was removed under reduced pressure or without any treatment. Dichlorosulfoxide was added and the reaction was continued at room temperature to 80 ° C for 0.2-10 hours to obtain compound 2a. The molar ratio of the L-substituted phenylserine ester 1, the acid halide, the compound containing a lone electron on the nitrogen atom, and the dichlorosulfoxide is 1: 0.8 ~ 1.5: 0 ~ 5: 0.5 ~ 3, and the recommended molar ratios are in order It is 1: 0.8 ~ 1.2: 0.04 ~ 4: 0.5 ~ 2.
D_ 苏式 _(4 5^-2- -4- 氧酰基 -5-R-取代苯基 -2-噁唑啉 2a与碱性物质
反应 0.5~5小时, 可获得化合物 D- (-) -苏式 -(4 & 5 -2- -4- 氧酰基 -5-R-取代苯 基 -2-噁唑啉 2b。 2a与碱性物质摩尔比是 1 :0.1~10,推荐摩尔比依次为 1 :1~3。所 述的酰卤中 R2是前述的 R2, X是卤素。 所述的碱性物质可以是碳酸钠或钾、 碳酸氢钠或钾、 碳酸铵、 二乙胺、 三乙胺、 甲醇钠或钾、 乙醇钠或钾等。 D_threo_ ( 4 5 ^ -2- -4-oxoacyl-5-R-substituted phenyl-2-oxazoline 2a and basic substances After 0.5 ~ 5 hours of reaction, compound D- (-)-threo- (4 & 5-2--4-oxoacyl-5-R-substituted phenyl-2-oxazoline 2b can be obtained. 2a and basic The molar ratio of the substance is 1: 1 to 10, and the recommended molar ratio is 1: 1 to 3. In the acid halide, R 2 is the aforementioned R 2 and X is halogen. The basic substance may be sodium carbonate or Potassium, sodium or potassium bicarbonate, ammonium carbonate, diethylamine, triethylamine, sodium or potassium methoxide, sodium or potassium ethoxide, and the like.
化合物 2b 在极性溶剂中用硼氢化钾或硼氢化钠将其还原成 D- (-) -苏式 -(4S,5i?)-2-R2-4-羟甲基 -5-R-取代苯基 -2-噁唑啉 2c,反应温度为 -10QC至 50°C,反 应时间 1~12小时, 反应中化合物 2b与硼氢化钾或钠的摩尔比依次为 1 :1〜10, 推荐摩尔比为 1 : 1~3, 硼氢化钾或钠可以固体颗粒状态直接加入反应体系中, 也 可配成溶液加入反应体系, 推荐溶剂为水。 Compound 2b is reduced to D- (-)-threo- (4S, 5i?)-2-R 2 -4-hydroxymethyl-5-R- with potassium borohydride or sodium borohydride in a polar solvent. Substituted phenyl-2-oxazoline 2c, the reaction temperature is -10 Q C to 50 ° C, the reaction time is 1-12 hours, and the molar ratio of compound 2b to potassium borohydride or sodium during the reaction is 1: 1 to 10 The recommended molar ratio is 1: 1 ~ 3. Potassium borohydride or sodium can be directly added to the reaction system in the form of solid particles, or it can be formulated as a solution to be added to the reaction system. The recommended solvent is water.
化合物 2c还可以与氟化试剂反应制备 D- (-) -苏式 -(4 & 5i?)-2-R2-4-氟甲基 -5-R- 取代苯基 -2-噁唑啉 2d, 2d经在酸性条件下水解开环, 得 D型 -1-R-取代苯基 -2- 氨基 -3-氟 -1-丙醇 3a, 最后经过二氯乙酰化, 获得 D- (-) -苏式 -1-R-取代苯基 -2-二 氯乙酰氨基 -3-氟 -1-丙醇 4a。 Compound 2c can also be reacted with a fluorinating reagent to prepare D- (-)-threo- (4 & 5i?)-2-R 2 -4-fluoromethyl-5-R- substituted phenyl-2-oxazoline 2d and 2d were hydrolyzed and ring-opened under acidic conditions to obtain D--1-R-substituted phenyl-2-amino-3-fluoro-1-propanol 3a, and finally subjected to dichloroacetylation to obtain D- (-)- Threo-1-R-substituted phenyl-2-dichloroacetamino-3-fluoro-1-propanol 4a.
在极性溶剂中, 化合物 2c与氟化剂反应得化合物 2d。 反应可以在常压下进 行, 也可以在密闭的加压下进行。该反应在惰性气氛中为好。当在常压下进行反 应时, 推荐溶剂是乙腈, 当在密闭耐压容器中进行时, 推荐溶剂为二氯甲垸。反 应温度为 0~120°C, 推荐温度为 10( 20°C, 反应时间为 0.5〜10小时, 推荐时间 为 1~3小时; 化合物 2c与氟化试剂摩尔比为 1 :0.5~3, 推荐摩尔比是 1 : 1~3。 所 述的氟化试剂可以是公开和已知的、分子式为 Et2NSF的 DAST试剂 (Nagabhushan, T. L., US 4235892, 1980)、 Yarovenko试剂 (Shart, C. M., et al, Org. React. , 21, 158, 1974)、 Ishikawa试剂 (Takaoka, A" et al, Bull. Chem. Soc. Jpn., 52, 3377, 1979)。推 荐试剂使用 Ishikawa试剂, 即 R5 2NCF2CFH(CF2)nF,或 CF=CF2和 R5 2NH的混 合物。 其中 R5=d.8的垸基, n=l~7, R产 F或 d_6的全氟烷基。 In a polar solvent, compound 2c is reacted with a fluorinating agent to obtain compound 2d. The reaction can be carried out under normal pressure or under a closed pressure. The reaction is preferably in an inert atmosphere. When the reaction is performed under normal pressure, the recommended solvent is acetonitrile. When the reaction is performed in a closed pressure-resistant container, the recommended solvent is dichloromethane. The reaction temperature is 0 ~ 120 ° C, the recommended temperature is 10 (20 ° C, the reaction time is 0.5 ~ 10 hours, the recommended time is 1 ~ 3 hours; the molar ratio of compound 2c to the fluorinating reagent is 1: 0.5 ~ 3, it is recommended molar ratio is 1: 1 to 3, said fluorinating agent may be known and disclosed, of the formula et 2 NSF DAST reagent (Nagabhushan, TL, US 4235892, 1980), Yarovenko reagent (Shart, CM, et al, Org. React., 21, 158, 1974), Ishikawa reagent (Takaoka, A "et al, Bull. Chem. Soc. Jpn., 52, 3377, 1979). Ishikawa reagent is recommended, which is R 5 2 NCF 2 CFH (CF 2) n F, or CF = CF 2 and a mixture of R 5 2 NH in which R 5 = d. alkyl with 8, n = l ~ 7, R d_ F or a perfluoroalkyl yield 6 base.
化合物 2d还可以与无机酸或有机酸发生水解开环反应, 得到 3a。 所用溶剂 可以是水、 甲醇、 乙醇、 异丙醇、 冰乙酸等, 推荐溶剂为水。 化合物 2d与无机 酸或有机酸的摩尔比是 1 : 1〜100。 所用酸可以是盐酸、 硫酸、 磷酸等无机酸, 也 可以是甲酸、 冰乙酸、 对-甲苯磺酸和甲磺酸等有机酸。 推荐用盐酸。 反应温度 可以是室温至 120°C, 推荐温度为 80〜120°C, 反应时间为 4小时至 18小时, 推 荐反应时间为 10〜18小时。 2d水解成 3a的反应液需用碱中和后用有机溶剂提 取,提取方法可用分液萃取法或液 -液连续萃取器提取 3a,推荐用液 -液连续萃取
器萃取, 所用萃取溶液可以是***、 乙酸乙酯、 氯仿、二氯甲烷等, 推荐溶剂用 二氯甲烷。 Compound 2d can also undergo a hydrolysis ring-opening reaction with an inorganic or organic acid to obtain 3a. The solvent used can be water, methanol, ethanol, isopropanol, glacial acetic acid, etc. The recommended solvent is water. The molar ratio of compound 2d to the inorganic or organic acid is 1: 1 to 100. The acid used may be an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, or an organic acid such as formic acid, glacial acetic acid, p-toluenesulfonic acid, and methanesulfonic acid. Hydrochloric acid is recommended. The reaction temperature can be room temperature to 120 ° C, the recommended temperature is 80 to 120 ° C, the reaction time is 4 hours to 18 hours, and the recommended reaction time is 10 to 18 hours. The reaction solution of 2d hydrolysis to 3a needs to be neutralized with alkali and extracted with organic solvent. The extraction method can be used to extract 3a by liquid separation or continuous liquid-liquid extractor. The extraction solution used can be ether, ethyl acetate, chloroform, dichloromethane, etc. The recommended solvent is dichloromethane.
化合物 3a经过酰化反应得到目的物 4a,即在极性溶剂中 3a可与酰化剂进行 酰化反应, 反应中若加入碱性物质,如: 氮原子上含有孤对电子的化合物, 及一 价或二价金属的无机碱或低碳醇钠, 将有利于反应的进行。 反应温度可以是 0~100°C,推荐温度是室温,反应时间为 5~36小时,推荐反应时间为 10~18小时。 Compound 3a undergoes an acylation reaction to obtain the target 4a. That is, 3a can undergo an acylation reaction with an acylating agent in a polar solvent. If a basic substance is added to the reaction, such as: a compound containing a lone electron on the nitrogen atom, and Inorganic bases or sodium alkoxides of valent or divalent metals will facilitate the reaction. The reaction temperature can be 0 ~ 100 ° C, the recommended temperature is room temperature, the reaction time is 5 ~ 36 hours, and the recommended reaction time is 10 ~ 18 hours.
3a 酰化剂、碱性物质的摩尔比为 1:1〜10:1〜100, 推荐摩尔比为 1:1.5~3:3〜6。所 用的酰化剂为二氯乙酰氯、二氯乙酰溴、二氯乙酸甲酯或二氯乙酸乙酯, 推荐酰 化剂为二氯乙酸甲酯。 3a The molar ratio of acylating agent and basic substance is 1: 1 ~ 10: 1 ~ 100. The recommended molar ratio is 1: 1.5 ~ 3: 3 ~ 6. The acylating agent used is dichloroacetyl chloride, dichloroacetyl bromide, methyl dichloroacetate or ethyl dichloroacetate. The recommended acylating agent is methyl dichloroacetate.
本发明中所述的氮原子上含有孤对电子的化合物是具有 .24烃基的叔胺、仲 胺、 伯胺、 吡啶、 联二吡啶、 二乙胺类化合物和 NH3。 The compound containing a lone pair electron on the nitrogen atom in the present invention is a tertiary amine, a secondary amine, a primary amine, a pyridine, a bipyridine, a diethylamine compound, and NH 3 having a hydrocarbon group of 24 .
本发明中所述的极性溶剂可以是一种或一种以上的***, 四氢呋喃、 氯仿、 二氯甲烷、 二氯乙垸、 三氯乙垸、 甲醇、 乙醇、 吡啶、三乙胺、 甲苯、 乙腈和水 等。 釆用本发明的方法可以分步从化合物 1合成化合物 2, 也可以采用连续的一 锅法直接合成化合物 2, 由化合物 2再经分步法合成化合物 4a, 不仅方法简便, 产率高, 成本低, 而且构型转化完全, 是一种从 L型取代苯丝氨酸酯向 D型的 氟甲砜霉素转化的有效简易方法,从而解决了利用拆分法制备氟尼康的无效对映 体的废弃问题, 减少环境污染, 具有实用的经济价值。 具体实施方式 The polar solvent described in the present invention may be one or more kinds of diethyl ether, tetrahydrofuran, chloroform, dichloromethane, dichloroacetamidine, trichloroacetamidine, methanol, ethanol, pyridine, triethylamine, toluene, Acetonitrile and water.釆 The method of the present invention can be used to synthesize compound 2 from compound 1 in a stepwise manner, or compound 2 can be directly synthesized by a continuous one-pot method, and compound 4a can be synthesized from compound 2 by a stepwise method. Low, and complete configuration conversion, it is an effective and simple method to convert L-type substituted phenylserine ester to D-type flumethoxin, thereby solving the waste of preparing the invalid enantiomers of flunicon by resolution Problems, reduce environmental pollution, and have practical economic value. detailed description
通过下述实施例将有助于理解本发明, 但并不限制本发明内容。 实施例 1 提取和纯化 L- (-) -苏式 -3-(4-甲砜基)苯丝氨酸乙酯 取 500ml的工业生产中的拆分废液 (L型异构体: e.e>80%), 减压浓缩, 得 粘稠液体, 用 400ml水溶解, 加入活性炭 10g, 室温搅拌 0.5小时, 过滤, 滤液 用浓氨水调 pH=8〜9, 析出固体, 静置, 过滤, 滤饼用 100ml冰冷的水轻洗, 抽 干后, 固体与 200ml乙酸乙酯混合搅拌 1小时, 过滤, 干燥后, 得 32g类白色固 体, 在 320ml无水乙醇中重结晶,趁热过滤,冷却静置, 过滤,得白色晶体 21g。
[α] = -13.4° ~ -13.6° (c=l, DMF) 实施例 2 D- (-) -苏式 -(4 & 5i?)-2-苯基 -4-轻甲基 -5-(4-甲砜基)苯基 -2-噁唑啉的制备 取 L-型异构体 50g,放入反应瓶中,加入 1,2-二氯乙烷 300ml,无水乙醇 100ml, 三乙胺 37ml, 冰盐浴, 控制混合物温度在 5°C以下, 在搅拌下滴加苯甲酰氯的 1,2-二氯乙烷溶液 (苯甲酰氯 22ml, 1,2-二氯乙烷 22ml), 约 1.5小时滴完。 加毕, 室温搅拌 2小时, 减压蒸干溶剂, 加入 1,2-二氯乙烷 300ml, 室温下滴加二氯亚 砜 27ml, 约 1.5小时滴完, 加热至 45QC, 搅拌 2小时。将反应液小心倒入 300ml 碎冰中, 搅拌至碎冰熔化, 分出有机相, 水洗有机相 (300ml), 饱和碳酸钠溶液 洗 (300ml), 水洗 (300ml X 3), 无水硫酸钠干燥 (5g)。 过滤, 减压蒸干溶剂, 得粘 稠液体,加入 500ml无水甲醇,搅拌均匀,在室温下滴加甲醇钠溶液 (2g钠, 100ml 无水甲醇), 约 0.5小时滴完, 再继续室温搅拌 2小时, 加入冰醋酸 5ml中和反 应液。取 25g硼氢化钾溶于 100ml水,将此溶液滴加到反应液中,控制反应温度 低于 50°C, 加毕, 室温搅拌 12小时, 过滤, 得白色固体: 32g, 收率 55.6%。 The following examples will help to understand the present invention, but not limit the present invention. Example 1 Extraction and purification of L-(-)-threo-3- (4-methylsulfonyl) phenylserine ethyl ester 500 ml of the industrial waste liquid (L-isomer: ee> 80%) ), Concentrated under reduced pressure to obtain a viscous liquid, dissolved in 400 ml of water, added 10 g of activated carbon, stirred at room temperature for 0.5 hours, and filtered. The filtrate was adjusted to a pH of 8 to 9 with concentrated ammonia water, a solid was precipitated, left to stand, filtered, and 100 ml of filter cake was used. Wash gently with ice-cold water. After drying, mix the solid with 200 ml of ethyl acetate and stir for 1 hour, filter, and dry to obtain 32 g of white solid, recrystallize in 320 ml of absolute ethanol, filter while hot, cool to stand, and filter To obtain 21 g of white crystals. [α] = -13.4 ° ~ -13.6 ° (c = 1, DMF) Example 2 D- (-)-threo- (4 & 5i?)-2-phenyl-4-light methyl-5- Preparation of (4-methylsulfonyl) phenyl-2-oxazoline: Take 50 g of L-type isomers, put them in a reaction flask, add 300 ml of 1,2-dichloroethane, 100 ml of absolute ethanol, and triethyl 37ml of amine, ice-salt bath, control the temperature of the mixture below 5 ° C, and add 1,2-dichloroethane solution of benzoyl chloride (benzoyl chloride 22ml, 1,2-dichloroethane 22ml) with stirring. It is finished in about 1.5 hours. After the addition is complete, stir at room temperature for 2 hours, evaporate the solvent under reduced pressure, add 300ml of 1,2-dichloroethane, dropwise add 27ml of dichlorosulfoxide at room temperature, finish the dripping in about 1.5 hours, heat to 45 Q C, and stir for 2 hours . Pour the reaction solution carefully into 300ml crushed ice, stir until the crushed ice melts, separate the organic phase, wash the organic phase with water (300ml), wash with saturated sodium carbonate solution (300ml), wash with water (300ml X 3), and dry over anhydrous sodium sulfate (5g). Filter and evaporate the solvent under reduced pressure to obtain a viscous liquid. Add 500ml of anhydrous methanol and stir well. Add sodium methoxide solution (2g sodium, 100ml of anhydrous methanol) dropwise at room temperature. After about 0.5 hours, finish dripping and continue stirring at room temperature. After 2 hours, 5 ml of glacial acetic acid was added to neutralize the reaction solution. 25 g of potassium borohydride was dissolved in 100 ml of water, and the solution was added dropwise to the reaction solution to control the reaction temperature below 50 ° C. After the addition, the mixture was stirred at room temperature for 12 hours and filtered to obtain a white solid: 32 g, yield 55.6%.
Mp: 206~209oC, [a]D 24=116.0o (c=2.5, DMF). Mp: 206 ~ 209 o C, [a] D 24 = 116.0 o (c = 2.5, DMF).
MS (CI, NH3): m/z = 332 (M+l)+. MS (CI, NH 3 ): m / z = 332 (M + l) +.
1H NMR (300MHz, DMSO-d6) δ ppm: 3.16 (s, 3H, CH3), 3.62 (m, 1H, CHAHB), 3.79 (m, 1H, CHAHB), 4.13 (m, 1H, NCH), 5.12 (t, 1H, J=5.7Hz, OH), 5.69 (d, 1H, J=6.4, OCH), 7.56 (m, 5Harom), 7.98 (m, 4Harom). 1H NMR (300MHz, DMSO-d6) δ ppm: 3.16 (s, 3H, CH 3 ), 3.62 (m, 1H, CH A H B ), 3.79 (m, 1H, CH A H B ), 4.13 (m, 1H, NCH), 5.12 (t, 1H, J = 5.7Hz, OH), 5.69 (d, 1H, J = 6.4, OCH), 7.56 (m, 5Harom), 7.98 (m, 4Harom).
元素分析: C17H17N04S Elemental analysis: C 17 H 17 N0 4 S
C 61.29 (61.61), H 5.08 (5.17), N 4.16 (4.23), S 9.83 (9.68). 实例 3 D- (-) -苏式 -2-苯基 -4-氟甲基 -5-(4-甲砜基)苯基 -2-噁唑啉的制备 取实例 2所得产品 30g (在异丙醇中重结晶, 并在 P205中干燥过夜), 放入耐 压封口瓶中, 封口瓶抽真空, 置换成氮气, 加入 300ml干燥的二氯甲垸, 最后加 入新蒸的 Ishikawa试剂 21.4ml (Takaoka, A., et al, Bull. Chem. Soc. Jpn., 52, 3377, 1979)。 旋紧瓶盖, 放入预先加热至 100-120°C的油浴中, 反应 2小时。 冷却至 室温, 打开瓶盖, 取出反应液, 用少量二氯甲垸和水轻洗反应瓶, 洗液与反应液 合并, 水洗有机相, 用 0.5N氢氧化钠溶液洗, 最后用水洗, 无水 Na2S04干燥。 过滤, 滤液减压蒸干溶剂。 在异丙醇中重结晶, 得浅黄色或类白色固体: 24.5g,
收率: 82%。 为进一步纯化, 产品还可再一次重结晶, 可以得到白色晶体。 C 61.29 (61.61), H 5.08 (5.17), N 4.16 (4.23), S 9.83 (9.68). Example 3 D- (-)-threo-2-phenyl-4-fluoromethyl-5- (4 - preparation methylsulfonyl) phenyl-2-oxazoline product obtained from example 2 30g (recrystallized from isopropanol, P 2 0 5 and dried overnight), placed in sealed pressure bottle, sealed The bottle was evacuated, replaced with nitrogen, 300 ml of dry dichloromethane, and finally 21.4 ml of freshly distilled Ishikawa reagent (Takaoka, A., et al, Bull. Chem. Soc. Jpn., 52, 3377, 1979) . Tighten the bottle cap tightly, put it in an oil bath heated to 100-120 ° C in advance, and react for 2 hours. Cool to room temperature, open the bottle cap, take out the reaction solution, wash the reaction bottle lightly with a small amount of methylene chloride and water, combine the washing solution with the reaction solution, wash the organic phase with water, wash with 0.5N sodium hydroxide solution, and finally wash with water. Water Na 2 S0 4 was dried. It was filtered, and the filtrate was evaporated to dryness of the solvent under reduced pressure. Recrystallized from isopropanol to give a pale yellow or off-white solid: 24.5g, Yield: 82%. For further purification, the product can be recrystallized again to obtain white crystals.
Mp: 117-119°C. Mp: 117-119 ° C.
MS: m/z 334 (M+l)+. MS: m / z 334 (M + l) + .
1H NMR (300 MHZ, DMSO-d6) 6 ppm: 3.23 (s, 3H), 4.3-4.5 (m, IH), 4.6-4.9 (m,lH), 5.8 (d, IH, J=6Hz), 7.5-7.7 (m, 5H), 7.99 (d, 4H, J=9Hz). 1H NMR (300 MHZ, DMSO-d6) 6 ppm: 3.23 (s, 3H), 4.3-4.5 (m, IH), 4.6-4.9 (m, lH), 5.8 (d, IH, J = 6Hz), 7.5 -7.7 (m, 5H), 7.99 (d, 4H, J = 9Hz).
元素分析: C17H16N03SF Elemental analysis: C 17 H 16 N0 3 SF
C 61.42 (61.24), H 4.83 (4.84), N 4.15 (4.20), F 5.34 (5.67), S 9.68 (9.62). 实例 4 D- (-) -苏式 -l-(4-甲砜基)苯基 -2-氨基 -3-氟 -1-丙醇的制备 取实例 3中所得产品 9.07g悬浮于 6N盐酸 150ml中, 加热回流, 反应 12小 时, 悬浮液用 2N的 NaOH溶液调 pH=l l~12, 将混合物转移至液-液连续萃取器 中, 用 400ml二氯甲烷提取产品, 加热回流 10小时, 分出有机相, 无水硫酸镁 干燥, 过滤, 蒸干溶剂, 得白色固体, 6.27g, 收率 93%。 C 61.42 (61.24), H 4.83 (4.84), N 4.15 (4.20), F 5.34 (5.67), S 9.68 (9.62). Example 4 D- (-)-threo-l- (4-methylsulfone) Preparation of phenyl-2-amino-3-fluoro-1-propanol Take 9.07 g of the product obtained in Example 3 and suspend it in 150 ml of 6N hydrochloric acid, heat and reflux for 12 hours, and adjust the suspension to pH = 11 with 2N NaOH solution ~ 12, transfer the mixture to a liquid-liquid continuous extractor, extract the product with 400 ml of dichloromethane, heat under reflux for 10 hours, separate the organic phase, dry over anhydrous magnesium sulfate, filter, and evaporate the solvent to obtain a white solid, 6.27 g, yield 93%.
Mp: 111~1130C, [ ]24=-36.5° (c=l, MeOH). Mp: 111 ~ 113 0 C, [] 24 = -36.5 ° (c = l, MeOH).
MS: m/z 248(M+1)+. MS: m / z 248 (M + 1) + .
1H NMR (300M Hz, DMSO-d6) δ ppm: 1.54 (br s, 2H), 2.9-3.1 (m, IH), 3.2 (s, 3H), 4.05-4.5 (m, 2H), 4.69 (d, 1H, J=6Hz), 5.69 (br,s,lH), 7.61 (d, 2H, J=9Hz), 7.88 (d, 2H, J=9Hz). 1H NMR (300M Hz, DMSO-d6) δ ppm: 1.54 (br s, 2H), 2.9-3.1 (m, IH), 3.2 (s, 3H), 4.05-4.5 (m, 2H), 4.69 (d, 1H, J = 6Hz), 5.69 (br, s, lH), 7.61 (d, 2H, J = 9Hz), 7.88 (d, 2H, J = 9Hz).
元素分析 oHwNC SF Elemental analysis oHwNC SF
C 48.22 (48.56), H 5.48 (5.71), N 5.58 (5.67), F 7.93 (7.68), S 13.08 (12.97). 实例 5 D- (-) -苏式 -l-(4-甲砜基)苯基 -2-二氯乙酰氨基 -3-氟 -1-丙醇的制备 取实例 4所得产品 5.55g溶于 55ml干燥的甲醇中, 加入三乙胺 3.06ml和二 氯乙酸甲酯 11.4ml, 室温搅拌 18小时, 蒸干溶剂, 加入甲苯和水混合溶剂, 静 置, 过滤, 得粗品, 在异丙醇-水中重结晶, 得白色固体, 6.7g, 收率 84%。 C 48.22 (48.56), H 5.48 (5.71), N 5.58 (5.67), F 7.93 (7.68), S 13.08 (12.97). Example 5 D- (-)-threo-l- (4-methylsulfone) Preparation of phenyl-2-dichloroacetamino-3-fluoro-1-propanol Take 5.55 g of the product obtained in Example 4 and dissolve it in 55 ml of dry methanol, add 3.06 ml of triethylamine and 11.4 ml of methyl dichloroacetate. Stir at room temperature for 18 hours, evaporate the solvent, add a mixed solvent of toluene and water, let it stand, filter, and obtain the crude product. Recrystallize in isopropanol-water to obtain a white solid, 6.7 g, yield 84%.
Mp: 152-154°C. [ ]24 = 17.9° (c=l, DMF). Mp: 152-154 ° C. [] 24 = 17.9 ° (c = l, DMF).
MS: m/z 360 (M+l)+. MS: m / z 360 (M + l) + .
1H NMR (300MHz, DMSO-d6) 5 ppm: 3.17 (s, 3H), 4.2-4.5 (m, 2H), 4.55-4.75 (m, IH), 5.00 (m, IH), 6.17 (d, IH, J=9Hz), 6.46 (s, IH), 7.62 (d, 2H, J=9Hz), 7.87 (d, 2H, J=9Hz), 8.62 (d, IH, J=9Hz).
元素分析: C12H14N04C12SF 1H NMR (300MHz, DMSO-d6) 5 ppm: 3.17 (s, 3H), 4.2-4.5 (m, 2H), 4.55-4.75 (m, IH), 5.00 (m, IH), 6.17 (d, IH, J = 9Hz), 6.46 (s, IH), 7.62 (d, 2H, J = 9Hz), 7.87 (d, 2H, J = 9Hz), 8.62 (d, IH, J = 9Hz). Elemental analysis: C 12 H 14 N0 4 C1 2 SF
C 40.48 (40.23), H 3.93 (3.94), N 3.86 (3.91), CI 19.76 (19.80), F 5.39 (5.30), S 8.95 (8.95). 实例 6 C 40.48 (40.23), H 3.93 (3.94), N 3.86 (3.91), CI 19.76 (19.80), F 5.39 (5.30), S 8.95 (8.95). Example 6
按实例 1至实例 4方法可以制备化合物, 产物分析结果如下: Compounds can be prepared according to the methods of Examples 1 to 4, and the results of product analysis are as follows:
D-苏式 -(1 25)-1-(4-硝基苯基) -2-氨基 -3-氟小丙醇 D-threo- (1 25) -1- (4-nitrophenyl) -2-amino-3-fluorosmall propanol
1H NMR: 1.50 (2H, br s), 2.95-3.1 (m, IH), 4.05-4.4 (m, 2H), 4.60 (d, J=6Hz, IH), 5.70 (br s, IH), 7.55 (d, J=9Hz, 2H), 8.10 (d, J=9Hz, 2H). 1H NMR: 1.50 (2H, br s), 2.95-3.1 (m, IH), 4.05-4.4 (m, 2H), 4.60 (d, J = 6Hz, IH), 5.70 (br s, IH), 7.55 ( d, J = 9Hz, 2H), 8.10 (d, J = 9Hz, 2H).
元素分析: 理论值: C (50.47), H (5.14), N (13.08), S (14.95). Elemental analysis: Theoretical values: C (50.47), H (5.14), N (13.08), S (14.95).
分析值: C (50.46), H (5.18), N (13.00), S (14.94). Analytical values: C (50.46), H (5.18), N (13.00), S (14.94).
D-苏式 -(li?,2S)小(4-甲硫基苯基) -2-氨基 -3-氟 -1-丙酸: D-threo- (li?, 2S) small (4-methylthiophenyl) -2-amino-3-fluoro-1-propionic acid:
1H NMR: 1.45 (2H, br s), 2.48 (s, 3H), 2.95-3.15 (m, IH), 4.05-4.5 (m, 2H), 4.60 (d, J=6Hz, IH), 5.69 (br s, IH), 7.60 (d, J=8-9Hz, 2H), 7.94 (d, J=8.9Hz, 2H). 1H NMR: 1.45 (2H, br s), 2.48 (s, 3H), 2.95-3.15 (m, IH), 4.05-4.5 (m, 2H), 4.60 (d, J = 6Hz, IH), 5.69 (br s, IH), 7.60 (d, J = 8-9Hz, 2H), 7.94 (d, J = 8.9Hz, 2H).
元素分析: 理论值: C (55.81), H (6.51), N (6.51), S (14.8). Elemental analysis: Theoretical values: C (55.81), H (6.51), N (6.51), S (14.8).
分析值: C (55.85), H (6.49), N (6.46), S (14.6). 实例 7 Analytical values: C (55.85), H (6.49), N (6.46), S (14.6). Example 7
按实例 5的方法制备 D- (-) -苏式 -1-(4-甲硫基)苯基 -2-二氯乙酰氨基 -3-氟小丙 醇, 产物分析结果如下: D-(-)-threo-1- (4-methylthio) phenyl-2-dichloroacetamino-3-fluorosmall propanol was prepared according to the method of Example 5. The product analysis results are as follows:
1H NMR: 2.48 (s, 3H), 4.2-4.5 (m, 2H), 4.55-4.75 (m, 1H), 5.00 (m, IH), 6.17 (d, IH, J=9Hz), 6.46 (s, IH), 7.62 (d, J=9Hz, 2H), 7.87 (d, J=9Hz, 2H), 8.62 (d, 2H, J=9Hz). 1H NMR: 2.48 (s, 3H), 4.2-4.5 (m, 2H), 4.55-4.75 (m, 1H), 5.00 (m, IH), 6.17 (d, IH, J = 9Hz), 6.46 (s, IH), 7.62 (d, J = 9Hz, 2H), 7.87 (d, J = 9Hz, 2H), 8.62 (d, 2H, J = 9Hz).
元素分析: 理论值: C (44.18), H (4.33), N (4.29), CI (21.73), F (5,82), S (9.83). Elemental analysis: Theoretical values: C (44.18), H (4.33), N (4.29), CI (21.73), F (5,82), S (9.83).
分析值: C (44.12), H (4.30), N (4.23), CI (21.77), F (5.79), S (9.79).
Analytical values: C (44.12), H (4.30), N (4.23), CI (21.77), F (5.79), S (9.79).