WO2023184731A1 - 一种4- 10硼酸-l-苯丙氨酸中间体的制备方法 - Google Patents

一种4- 10硼酸-l-苯丙氨酸中间体的制备方法 Download PDF

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WO2023184731A1
WO2023184731A1 PCT/CN2022/100177 CN2022100177W WO2023184731A1 WO 2023184731 A1 WO2023184731 A1 WO 2023184731A1 CN 2022100177 W CN2022100177 W CN 2022100177W WO 2023184731 A1 WO2023184731 A1 WO 2023184731A1
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陶璐璐
朱逸凡
范敏华
洪超
丁元春
郭卫革
陆翠军
周胜军
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海南普利制药股份有限公司
浙江普利药业有限公司
安徽普利药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the invention relates to the technical field of boron-containing drugs for boron neutron capture therapy, and specifically relates to a preparation method of 4-10 boric acid-L-phenylalanine intermediate.
  • Boron neutron capture therapy is a new type of radiotherapy method. It introduces 10 B-containing drugs into the body through oral administration or injection, and selectively accumulates them in cancer cells, and then uses them to treat cancer cells. The ions irradiate the lesion, causing 10 B to undergo a 10 B(n, ⁇ ) 7 Li nuclear reaction, and the resulting particles and 7 Li ions are used to kill cancer cells within the cell range.
  • boron neutron capture therapy (BNCT) is considered to be a more effective method of treating tumors, compared with current methods of surgery, radiotherapy, chemotherapy, immunotherapy, and gene therapy for cancer. In comparison, it has the characteristics of accurate positioning and significant curative effect.
  • L -10 BPA 4-( 10 B) dihydroxyboronyl-L-phenylalanine (4-( 10 B)borono-L-phenylalanine, L- 10 BPA) is currently known to be able to treat cancer using boron neutron capture therapy (BNCT) important boride.
  • L -10 BPA has the following structure:
  • the boron element existing in nature contains about 19.9% of 10 boron ( 10 B) and about 80.1% of 11 boron ( 11 B).
  • borides enriched in 10 boron are needed in BNCT. Therefore, many researchers are still actively developing methods suitable for the synthesis of L- 10 BPA, especially methods suitable for the synthesis of L- 10 BPA rich in 10 boron.
  • the compound of formula 4 is a key intermediate in the synthesis of L- 10 BPA and has the following structure:
  • N-BOC-4-iodo-L-phenylalanine and tri-n-butyl borate are basically used as starting materials, and the compound of formula 4 is prepared through a boronation reaction. Then, 4-10boronic acid-L-phenylalanine is prepared through deprotection reaction.
  • n-butyllithium is used in the reported process, which has high activity and is more dangerous during scale-up production. The reaction needs to be carried out at -80°C to -70°C, which requires high equipment.
  • commercially available tri-n-butyllithium borate Butyl ester is of reagent grade and there is no stable supply. Therefore, there are certain difficulties in industrial production of this route. For example: CN104447822A discloses the following synthesis route:
  • the reported yield is 65.1%, the reaction temperature is -80°C, and L- 10 BPA is prepared from the compound of formula 4, with a total process yield of 62.8%.
  • CN106467556A reports boronization using boron-10 acid and 4-iodo-L-phenylalanine and tri-n-butyl borate as starting materials.
  • method for preparing 4-10 boric acid-L-phenylalanine by deprotection The raw materials of this route are relatively easy to obtain, n-butyllithium is not used, the reaction temperature is relatively mild, and there are no special requirements for equipment; however, compared with the above route, the total yield of the two-step reaction of boronization and deprotection is low. It is 53.3%, and the Grignard reagent and sodium hydride are used in the process, both of which have high activity, so there are certain difficulties in industrial production.
  • Its public reaction route is as follows:
  • a method for preparing a compound of formula iv it is prepared by using a compound of formula iii as a raw material, reacting with a boronation reagent and a Grignard reagent.
  • R is an amino protecting group, and the protecting group is selected from Boc, Bn, Cbz or Fmoc; X is Br or I.
  • the Grignard reagent is an alkyl magnesium halide or an aryl magnesium halide.
  • the alkyl magnesium halide is an alkyl magnesium chloride or an alkyl magnesium bromide, wherein the alkyl group is selected from propyl, isopropyl, Butyl, tert-butyl, cyclohexyl and tert-amyl;
  • the aryl magnesium halide is aryl magnesium chloride or aryl magnesium bromide, wherein the aryl group is selected from phenyl or aryl containing 1-3 heteroatoms.
  • Heteroyl group the heteroatom is taken from an oxygen or nitrogen atom, and the position of the heteroatom is at any position on the aryl group; the aryl group is substituted or unsubstituted.
  • the aryl group includes at least one phenyl, pyridyl, pyrimidinyl, oxazolyl, oxadiazolyl or triazolyl group. More preferably, the aromatic group is phenyl. More preferably, the Grignard reagent is is isopropyl magnesium chloride, tert-butyl magnesium chloride, cyclohexyl magnesium chloride, tert-amyl magnesium chloride or phenyl magnesium chloride.
  • the boronated reagent has the structure of formula a:
  • R 1 and R 2 are each independently an alkyl group, which may be the same or different; or R 1 and R 2 may be cyclized with the connected oxygen and boron atoms to form a 5- or 6-membered ring.
  • the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, and isobutyl.
  • the structure after cyclization of R 1 and R 2 with the connected oxygen and boron atoms is: Wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from hydrogen or alkyl, and the alkyl is methyl or ethyl .
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen or methyl.
  • R 3 , R 4 , R 5 and R 6 are all methyl.
  • the Grignard reagent in the present invention can be prepared by conventional Grignard reagent preparation methods in the art.
  • alkyl magnesium halide is prepared by performing Grignard reaction between halogenated alkane and metal magnesium in an organic solvent at 0 to 80°C under the protection of an inert gas to obtain a reaction solution containing alkyl magnesium halide.
  • the Grignard reaction temperature is 0-60°C.
  • the molar ratio of the metal magnesium to the haloalkane is 1: (1-3); preferably 1: (1.2-2).
  • the mass-volume ratio of the alkyl magnesium halide to the organic solvent is 1:3-6, where the unit of mass is grams and the unit of volume is milliliters.
  • the organic solvent is at least one of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, toluene, benzene or petroleum ether.
  • the reaction time for the preparation of the Grignard reagent is 0.5 to 5 hours; preferably, the reaction time is 1 to 3 hours.
  • the metal magnesium includes but is not limited to magnesium powder, magnesium strips or magnesium shavings.
  • the boronating reagent can be prepared by conventional boronating reagent preparation methods in the art. For example, in the following preparation method of a compound of formula a, boric acid, isobutanol and R 1 (OH) R 2 (OH) are reacted in organic solvent 2 to prepare the compound of formula a.
  • R 1 and R 2 are the same as before.
  • a method for preparing a compound of formula iv structure dissolve the compound of formula iii structure in organic solvent 3, add it to a Grignard reagent for reaction, and then add a boronating reagent to prepare the compound of formula iv structure,
  • R is a protecting group
  • X is Cl, Br or I.
  • the definitions of the formatting reagent and the boronating reagent are the same as the previous definitions.
  • the reaction system temperature is -30 ⁇ 30°C; preferably, the reaction system temperature is -20 ⁇ 20°C; more preferably, the reaction system temperature is -10 ⁇ 10°C.
  • the organic solvent 3 is at least one of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, toluene, benzene or petroleum ether.
  • the preparation method is carried out in the presence of an inert gas, which is a conventional inert gas in this field, such as nitrogen, argon, etc.
  • an inert gas which is a conventional inert gas in this field, such as nitrogen, argon, etc.
  • the molar ratio of the compound of formula iii to the Grignard reagent is 1:(1-8), preferably 1:(1-6).
  • the mass-to-volume ratio of the compound of formula iii to the organic solvent III is 1:(1-10), preferably 1:(2-6); wherein the unit of mass is gram and the unit of volume is ml.
  • the reaction time for the Grignard exchange between the compound of formula iii and the Grignard reagent is 0.5 to 5 hours, preferably 1 to 3 hours.
  • the organic solvent three is at least one of diethyl ether, tetrahydrofuran, dioxane, methyl tert-butyl ether, toluene, benzene or petroleum ether.
  • the organic solvent is conducive to the complete mixing of the reaction raw materials, improves the utilization rate of the raw materials, reduces the occurrence of side reactions, and is also conducive to the dissolution of the products prepared in each step of the reaction in the reaction system, ensuring the smooth progress of the next step of the reaction. .
  • the molar ratio of the compound of formula iii to the boronating reagent is 1: (1-6), preferably 1: (2-5).
  • the reaction time of the boronization step is 0.1 to 6 hours, and preferably, the reaction time is 0.5 to 3 hours.
  • the mass-to-volume ratio of the compound of formula iii to the added water is 1:(1-10), preferably 1:(2-6); wherein the unit of mass is gram and the unit of volume is ml.
  • the step of adjusting the pH is further included.
  • the pH is adjusted to 2-6, and more preferably, the pH is adjusted to 3-4.
  • the acid used to adjust the pH is preferably hydrochloric acid, sulfuric acid, phosphoric acid, etc.
  • the acid is diluted to 1-20% w/v before use.
  • the preparation method of 4-10 boric acid-L-phenylalanine intermediate provided by the present invention can effectively improve the purity and yield of 4-10 boric acid-L-phenylalanine, and avoid It eliminates ultra-low temperature reaction, has low equipment requirements, reduces process difficulty, and is environmentally friendly. It is a green and environmentally friendly process suitable for industrial production of 4-10 boric acid-L-phenylalanine.
  • the preparation method of 4-10 boric acid-L-phenylalanine intermediate provided by the invention has the advantages of high yield and purity, and low production cost.
  • the prepared 4-10 boric acid-L-phenylalanine key intermediate and 4-10 boric acid-L-phenylalanine do not require purification, the HPLC content is greater than 98%, and the total product yield is greater than 80%, fully meeting the requirements of modern fine chemical synthesis, and the raw materials are easy to obtain, simple to operate, and highly safe. , capable of realizing the industrial production of 4-10 boric acid-L-phenylalanine.
  • Figure 1 is the HPLC spectrum of the reaction solution of Example 11.
  • Figure 2 is the HPLC purity spectrum of the product of Example 11.
  • Figure 3 is the HPLC purity spectrum of 4-10 boric acid-L-phenylalanine prepared in Example 24.
  • Examples 12-17 are based on the method of Example 11, using different reaction reagents boric acid ester to obtain (S)-N-tert-butoxycarbonyl-4-( 10 B)dihydroxyborylphenylalanine. rate and HPLC purity.
  • Examples 18-23 are prepared according to the method of Example 11 at different reaction temperatures. The yield and HPLC purity.

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Abstract

本发明涉及一种用于硼中子捕获疗法的含硼药物技术领域，具体涉及一种4- 10硼酸-L-苯丙氨酸中间体的制备方法，所述制备方法由式iii结构化合物为原料，与硼化试剂，格式试剂反应制备得到，其中所述硼化试剂具有式(a)结构： R 1和R 2各自独立的为烷基，可以相同，也可以不同；或R 1和R 2可以与相连的氧和硼原子环合形成5或6元环；R为氨基保护基；X为卤素。利用该方法制备得到的4- 10硼酸-L-苯丙氨酸无需进行纯化，HPLC含量大于98％，产品总收率大于80％，完全满足现代精细化工合成要求，能够实现4- 10硼酸-L-苯丙氨酸的工业化生产。

Description

一种4- 10硼酸-L-苯丙氨酸中间体的制备方法 技术领域
本发明涉及一种用于硼中子捕获疗法的含硼药物技术领域，具体涉及一种4- 10硼酸-L-苯丙氨酸中间体的制备方法。
背景技术
硼中子俘获疗法(boronneutron capture therapy,BNCT)是一种新型的放疗方法，它是将含 10B药物通过口服或注射方法引入体内，并使之选择性地聚集在癌细胞中，然后用中子照射病变部位，使 10B发生 10B(n，ɑ) 7Li核反应，利用由此产生的粒子和 7Li离子在细胞范围内杀死癌细胞。经过几十年的探索，研究和临床实验，硼中子俘获治疗(BNCT)被认为是一种比较有效的治疗肿瘤的方法，与现行的外科手术，放疗化疗，免疫治疗，基因治疗癌症的方法相比，具有定位准确，疗效显著的特点。4-( 10B)二羟基硼基-L型苯丙氨酸(4-( 10B)borono-L-phenylalanine,L- 10BPA)为目前已知能利用硼中子捕捉疗法(BNCT)治疗癌症的重要硼化物。L- 10BPA具有如下结构：
Figure PCTCN2022100177-appb-000001
自然界中存在的硼元素包含约19.9％的 10硼( 10B)以及约80.1％的 11硼( 11B)，然而，BNCT中需要富集 10硼的硼化物。因此，许多研究者仍积极发展能适用 于合成L- 10BPA的方法，尤其是适用于合成富含 10硼的L- 10BPA的方法。式4化合物是合成L- 10BPA的关键中间体，具有如下结构：
Figure PCTCN2022100177-appb-000002
关于该步骤反应，目前现有技术中基本上均是以N-BOC-4-碘-L-苯丙氨酸和硼酸三正丁酯为起始物料，经过硼化反应制备得到式4化合物，然后再经过脱保护反应制备4- 10硼酸-L-苯丙氨酸。但报道的工艺中要用到正丁基锂，其活性较高，放大生产时较危险，且反应需在-80℃至-70℃进行，对于设备要求较高；另外，市售硼酸三正丁酯为试剂级，无稳定货源，因此，此路线工业化生产有一定的困难。例如：CN104447822A公开了以下合成路线：
Figure PCTCN2022100177-appb-000003
其报道的产率为65.1％，反应温度为-80℃，再由式4化合物制备得到L- 10BPA，工艺总收率为62.8％。
在上述现有技术的基础之上，后继专利申请进行了改进，如CN106467556A报道了以硼-10酸和4-碘-L-苯丙氨酸和硼酸三正丁酯为起始物料，硼化、脱保护制备4- 10硼酸-L-苯丙氨酸的方法。该路线原料均较易获得，且未使用正丁基锂，反应温度也较温和，对设备无特殊要求；但与路线上述路线相比，硼化和 脱保护两步反应总收率偏低，为53.3％，且工艺中用到格式试剂和氢化钠，其活性均较高，工业化生产有一定的困难。其公开的反应路线如下：
Figure PCTCN2022100177-appb-000004
因此亟需开发一种反应条件温和、产率高，利于工业化生产的L- 10BPA生产方法。
发明内容
为了解决现有技术中存在的问题，本发明采用如下技术方案，
一种式iv结构化合物的制备方法：是由式iii结构化合物为原料，与硼化试剂，格式试剂反应制备得到，
Figure PCTCN2022100177-appb-000005
其中R为氨基保护基，所述保护基选自Boc、Bn、Cbz或Fmoc；X为Br或I。
其中所述格式试剂为烷基卤化镁，芳香基卤化镁，优选的，所述烷基卤化镁为烷基氯化镁或烷基溴化镁，其中所述烷基选自丙基、异丙基、丁基、叔丁基、环己基和叔戊基；所述芳香基卤化镁为芳香基氯化镁或芳香基溴化镁，其中所述芳香基选自苯基或含1-3个杂原子的芳杂基，该杂原子取自氧或氮原子，杂原子的位置在芳香基上任一位置；所述芳香基取代或未取代。优选的，所述的芳香基包括至少一个苯基、吡啶基、嘧啶基、噁唑基、噁二唑基或三氮唑基。更优选的，所述的芳香基为苯基。更为优选的，所述格氏试剂为异丙基氯化镁、叔丁基氯化镁、环己基氯化镁、叔戊基氯化镁或苯基氯化镁。
所述硼化试剂具有式a结构：
Figure PCTCN2022100177-appb-000006
其中R 1和R 2各自独立的为烷基，可以相同，也可以不同；或R 1和R 2可以与相连的氧和硼原子环合形成5或6元环。
优选的，所述烷基选自甲基，乙基，丙基，异丙基，正丁基，异丁基。优选的，R 1和R 2与相连的氧和硼原子环合后的结构为
Figure PCTCN2022100177-appb-000007
其中R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立的选自氢或烷基，所述烷基为甲基或乙基。
优选的，R 1和R 2与相连的氧和硼原子环合后的结构为
Figure PCTCN2022100177-appb-000008
其中R 3、R 4、R 5、R 6各自独立的选自氢或甲基，优选的R 3、R 4、R 5、R 6均为甲基。
优选的，本发明中格式试剂的制备可采用本领域常规的格氏试剂的制备方法制备得到。例如，烷基卤化镁的制备为，在惰性气体保护下，卤代烷烃和金属镁在有机溶剂中，于0～80℃进行格氏反应，得到含烷基卤化镁的反应液。优选的，格式反应温度为0-60℃。所述金属镁与卤代烷烃的摩尔比为1:(1～3)；优选为1:(1.2～2)。
优选的，所述格式试剂的制备，所述烷基卤化镁与有机溶剂一的质量体积比为1:3～6，其中，质量的单位是克，体积的单位是毫升。所述有机溶剂一为乙醚、四氢呋喃、甲基四氢呋喃、二氧六环、甲基叔丁基醚、甲苯、苯或石油醚中至少一种。
优选的，所述格式试剂的制备，反应时间为0.5～5h；优选的为1～3h。
可选的，所述格式试剂的制备，所述金属镁包括但不限于镁粉、镁条或镁屑。
优选的，硼化试剂的制备可采用本领域常规的硼化试剂的制备方法制备得到。例如，如下式a结构的化合物的制备方法，在有机溶剂二中，使硼酸、异丁醇及R 1(OH)R 2(OH)反应以制得所述的式a结构化合物。
Figure PCTCN2022100177-appb-000009
其中R 1和R 2的定义与前文相同。
优选的，一种式iv结构化合物的制备方法：将式iii结构化合物溶于有机溶剂三中，加入格式试剂中进行反应，随后加入硼化试剂制备得到所述的式iv结构化合物，
Figure PCTCN2022100177-appb-000010
其中R为保护基，X为Cl，Br或I。
所述格式试剂和硼化试剂的定义与前文定义相同。
优选的，反应体系温度为-30～30℃；优选的，反应体系温度为-20～20℃；更为优选的，反应体系温度为-10～10℃。
优选的，所述有机溶剂三为乙醚、四氢呋喃、甲基四氢呋喃、二氧六环、甲基叔丁基醚、甲苯、苯或石油醚中至少一种。
优选的，所述制备方法在惰性气体存在下进行，所述惰性气体为本领域常规的惰性气体，如氮气、氩气等。
优选的，所述式iii化合物与格式试剂的摩尔比为1:(1～8)，优选为1:(1～6)。
优选的，所述式iii化合物与有机溶剂三的质量体积比为1:(1～10)，优选的为1:(2～6)；其中，质量的单位是克，体积的单位是毫升。
优选的，所述式iii化合物与格式试剂进行格式交换的反应时间为0.5～5h，优选为1～3小时。
所述有机溶剂三为乙醚、四氢呋喃、二氧六环、甲基叔丁基醚、甲苯、苯或石油醚中至少一种。
所述有机溶剂有利于反应原料之间充分混合，提高原料的利用率，减少副反应的发生，同时还有利于各步反应制备得到的产物溶解于反应体系中，保证了下一步反应的顺利进行。
优选的，所述式iii化合物与硼化试剂的摩尔比为1：(1～6)，优选为1：(2～5)。
优选的，硼化步骤反应时间为0.1～6h，优选的，反应时间为0.5～3小时。
优选的，反应完毕后，进一步包括加水淬灭的步骤。优选的，所述式iii化合物与加入水的质量体积比为1:(1～10)，优选的为1:(2～6)；其中，质量的单位是克，体积的单位是毫升。
优选的，反应完毕后，进一步包括调节pH的步骤，优选的将pH调节到2-6，更为优选的，将pH调节到3-4。调节pH所用的酸优选为盐酸、硫酸、磷酸等。优选的，将所述酸进行稀释后再应用，稀释至1-20％w/v。
相对于现有技术，本发明提供的4- 10硼酸-L-苯丙氨酸中间体的制备方法，能够有效的提高4- 10硼酸-L-苯丙氨酸的纯度和收率，且避免了超低温反应，对设备要求低，降低了工艺难度，且对环境友好，是一种绿色环保且适合工业化生产的4- 10硼酸-L-苯丙氨酸的工艺。本发明提供的4- 10硼酸-L-苯丙氨酸中间体的制备方法具有收率和纯度高，生产成本低的优点，制备得到的4- 10硼酸-L-苯丙氨酸关键中间体及4- 10硼酸-L-苯丙氨酸均无需进行纯化，HPLC含量大于98％，产品总收率大于80％，完全满足现代精细化工合成要求，且原料易得，操作简单，安全性高，能够实现4- 10硼酸-L-苯丙氨酸的工业化生产。
附图说明
图1为实施例11反应液HPLC谱图。
图2为实施例11产物HPLC纯度谱图。
图3为实施例24制备得到的4- 10硼酸-L-苯丙氨酸HPLC纯度谱图。
具体实施方式
为了更好地理解本发明的技术方案，下面结合具体的实施例对本发明的技术方案做进一步说明，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。
实施例1：频哪醇硼10酸异丁酯的制备
向反应瓶中加入硼酸(1000g，16.2mol)，异丁醇1L，升温至回流，分水至无明显水层后，反应体系中加入频哪醇(2000g,16.9mol)，升温至回流，反应1h后，开始常压浓缩至不滴液，再减压浓缩回收馏分为BPA03频哪醇硼10酸异丁酯。
实施例2：式a结构化合物的制备
Figure PCTCN2022100177-appb-000011
实施例2-10的硼酸酯的制备反复，本领域的技术人员可以按照实施例1的方法调整不同的反应底物得到。
Figure PCTCN2022100177-appb-000012
Figure PCTCN2022100177-appb-000013
实施例11：式4化合物的制备
Figure PCTCN2022100177-appb-000014
反应瓶中加入2000mL异丙基氯化镁(1.3mol/L,溶剂四氢呋喃)，搅拌降温至0℃，滴加(S)-N-叔丁氧羰基-4-碘基苯丙氨的四氢呋喃溶液(300g溶解于1000mL,0.76mol)，滴加完毕，保温搅拌2h，频哪醇硼 10酸异丁酯(700g,3.5mol)，控温0℃，反应半小时后，加水500mL淬灭反应，反应液送HPLC检测，如图1，对应的数据如表1，减压浓缩后，用10％磷酸水溶液调节体系pH至3-4，过滤， 滤饼用500mL水洗涤，干燥后得(S)-N-叔丁氧羰基-4-( 10B)二羟基硼基苯丙氨217g，收率92.4％，HPLC纯度99.86％，如图2，对应的数据如表2。
表1
RT[min] Area Area％ Height Type Width[min]
2.957 10.475 0.06 2.33 BV 0.12
3.052 22.191 0.13 3.31 VB 0.21
11.896 32.813 0.19 1.88 BB 1.12
17.137 5.328 0.03 0.53 BB 0.34
20.873 14.278 0.08 1.43 BB 0.42
24.109 121.349 0.70 12.02 BB 0.63
24.920 13410.552 77.64 965.92 BV 1.32
25.938 177.963 1.03 7.96 VB 0.83
27.944 7.020 0.04 0.63 BB 0.43
28.578 52.904 0.31 3.90 BB 0.69
30.364 2418.746 14.00 203.47 BB 0.79
30.779 24.080 0.14 2.75 BB 0.31
32.103 162.340 0.94 12.85 BB 0.72
33.375 10.971 0.06 0.78 BB 0.48
34.296 35.377 0.20 2.78 BB 0.45
36.040 202.545 1.17 14.61 BV 0.95
36.490 498.636 2.89 41.61 VB 0.55
46.448 64.840 0.38 2.92 BBA 1.39
Sum 17272.41        
表2
RT[min] Area Area％ Height Type Width[min]
4.899 4.409 0.04 0.37 BB 0.55
24.103 3.359 0.03 0.34 BB 0.43
24.897 11158.190 99.86 798.02 BB 1.93
30.359 8.218 0.07 0.76 BB 0.48
Sum 11174.17        
以下实施例12-17是按照实施例11的方法，换用不同的反应试剂硼酸酯得到(S)-N-叔丁氧羰基-4-( 10B)二羟基硼基苯丙氨的收率及HPLC纯度。
Figure PCTCN2022100177-appb-000015
Figure PCTCN2022100177-appb-000016
以下实施例18-23是按照实施例11的方法，在不同的反应温度下制备得到(S)-N-叔丁氧羰基-4-( 10B)二羟基硼基苯丙氨的收率及HPLC纯度。
实施例 体系反应温度(℃) 收率(％) 纯度(％)
18 -30 93.2 99.86
19 -10 94.5 99.84
20 5 93.4 99.81
21 10 91.7 99.23
22 20 89.8 99.10
23 30 87.9 98.87
实施例24：4- 10硼酸-L-苯丙氨酸的制备
向反应瓶中加入实施例11制备得到的(S)-N-叔丁氧羰基-4-( 10B)二羟基硼基苯丙氨(200g，0.65mol)，1000mL丙酮和150mL水以及150mL盐酸，加热至55℃反应2h，降温后，用氢氧化钠溶液调节pH至6.0-7.0，过滤，干燥后得4- 10 硼酸-L-苯丙氨酸125g，收率92.5％，HPLC纯度99.94％，见图3，对应的数据如下。
RT[min] Area Area％ Height Type Width[min]
4.469 4.062 0.0231 0.62 BB 0.40
5.124 17548.473 99.9424 2145.29 BBA 1.96
9.488 4.852 0.0276 0.31 BV 0.72
14.887 1.204 0.0069 0.15 BB 0.22
Sum 17558.59        

Claims (10)

  1. 一种式(iv)结构化合物的制备方法，是由式(iii)结构化合物为原料，与硼化试剂，格式试剂反应制备得到，
    Figure PCTCN2022100177-appb-100001
    其中所述硼化试剂具有式(a)结构：
    Figure PCTCN2022100177-appb-100002
    其中R 1和R 2各自独立的为烷基，可以相同，也可以不同；或R 1和R 2可以与相连的氧和硼原子环合形成5或6元环；
    R为氨基保护基；
    X为卤素。
  2. 根据权利要求1所述的制备方法，其中所述保护基选自Boc、Bn、Cbz或Fmoc；X为Br或I；所述格式试剂为烷基卤化镁或芳香基卤化镁。
  3. 根据权利要求2所述的制备方法，其中所述烷基卤化镁为烷基氯化镁或烷基溴化镁，其中所述烷基选自丙基、异丙基、丁基、叔丁基、环己基和叔戊基；所述芳香基卤化镁为芳香基氯化镁或芳香基溴化镁，其中所述芳香基选自苯基或含1-3个杂原子的芳杂基，该杂原子取自氧或氮原子，杂原子的位置在芳香基上任一位置；所述芳香基取代或未取代。优选的，所述的芳香基包括至少一个苯基、吡啶基、嘧啶基、噁唑基、噁二唑基或三氮唑基。更优选的，所述的芳香基为苯基。更为优选的，所述格氏试剂为异丙基氯化镁、叔丁基氯化镁、环己基氯化镁、叔戊基氯化镁或苯基氯化镁。
  4. 根据权利要求1所述的制备方法，其中所述烷基选自甲基，乙基，丙基，异丙基，正丁基，异丁基；或，R 1和R 2与相连的氧和硼原子环合后的结构为
    Figure PCTCN2022100177-appb-100003
    其中R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11和R 12各自独立的选自氢或烷基，所述烷基为甲基或乙基。
  5. 根据权利要求4所述的制备方法，其中R 1和R 2与相连的氧和硼原子环合后的结构为
    Figure PCTCN2022100177-appb-100004
    其中R 3、R 4、R 5、R 6各自独立的选自氢或甲基，优选的R 3、R 4、R 5、R 6均为甲基。
  6. 一种式(iv)结构化合物的制备方法，将式(iii)结构化合物溶于有机溶剂中，加入格式试剂中进行反应，随后加入硼化试剂制备得到所述的式(iv)结构化合物，
    Figure PCTCN2022100177-appb-100005
    其中R，X，格式试剂和硼化试剂的定义与权利要求1-5任一权利要求所述的定义相同。
  7. 根据权利要求6所述的制备方法，反应体系温度为-30～30℃；优选的，反应体系温度为-20～20℃；更为优选的，反应体系温度为-10～10℃。
  8. 根据权利要求6所述的制备方法，所述有机溶剂为乙醚、四氢呋喃、甲基四氢呋喃、二氧六环、甲基叔丁基醚、甲苯、苯或石油醚中至少一种。
  9. 根据权利要求6所述的制备方法，其中所述式(iii)化合物与格式试剂的摩尔比为1:(1～3)，优选为1:(1～2)；所述式(iii)化合物与有机溶剂的质量体积比为1:(1～10)，优选的为1:(2～6)；所述式(iii)化合物与格式试剂进行格式交换的反应时间为0.5～5h，优选为1～3小时；所述有机溶剂三为乙醚、四氢呋喃、二氧六环、甲基叔丁基醚、甲苯、苯或石油醚中至少一种；所述式(iii)化合物与硼化试剂的摩尔比为1：(1～6)，优选为1：(2～5)；硼化步骤反应时间为0.1～6h，优选的，反应时间为0.5～3小时。
  10. 根据权利要求6所述的制备方法，进一步包括加水淬灭的步骤，其中所述式(iii)化合物与加入水的质量体积比为1:(1～10)，优选的为1:(2～6)；进一步包括调节pH的步骤，优选的将pH调节到2-6，更为优选的，将pH调节到3-4。调节pH所用的酸优选为盐酸、硫酸、磷酸等。优选的，将所述酸进行稀释后再应用，稀释至1-20％w/v。
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