WO2023098759A1 - DERIVATIVE OF CHIRAL α-AMINOPHOSPHONIC ACID AND PREPARATION METHOD THEREFOR - Google Patents

DERIVATIVE OF CHIRAL α-AMINOPHOSPHONIC ACID AND PREPARATION METHOD THEREFOR Download PDF

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WO2023098759A1
WO2023098759A1 PCT/CN2022/135641 CN2022135641W WO2023098759A1 WO 2023098759 A1 WO2023098759 A1 WO 2023098759A1 CN 2022135641 W CN2022135641 W CN 2022135641W WO 2023098759 A1 WO2023098759 A1 WO 2023098759A1
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aminophosphonic acid
nmr
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chloroform
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邓力
陆家湘
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西湖大学
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Definitions

  • the invention belongs to the technical field of organic synthesis. Specifically, the invention relates to a derivative of chiral ⁇ -aminophosphonic acid and a preparation method thereof.
  • ⁇ -Aminophosphonic acid and its derivatives are a class of natural ⁇ -amino acid analogs with important biological activities. They not only have biological activities such as antiviral, antibacterial, antifungal and anticancer, but also inhibit the activity of various proteolytic enzymes. Activities, such as HIV protease, renase and PTPases, etc. Therefore, it plays an increasingly important role in the development of new drugs and pesticide chemical industry, and has become an important field for the development of organophosphorus chemistry for many years. The absolute configurations of ⁇ -aminophosphonic acid and its derivatives are closely related to their biological activities.
  • (S, R) configuration of Alafosfalin has significantly better than the other three isomers Gram-positive bacteria and negative bacteria inhibition rate. Therefore, it is of great significance to develop an asymmetric strategy with a broad substrate spectrum for the preparation of chiral ⁇ -aminophosphonic acid derivatives.
  • Organic small molecule catalysis has the characteristics of easy catalyst synthesis, relatively mild reaction conditions, environmental friendliness, low biological toxicity, substrate compatibility and adaptability, etc. widely used in production.
  • the invention provides a derivative of chiral ⁇ -aminophosphonic acid and a preparation method thereof.
  • the imine intermediate obtained by the condensation of ⁇ -carbonyl phosphonate and benzylamine as raw materials in the present invention under the action of the betaine (Betaine) catalyst with cinchonaine skeleton, undergoes highly enantioselective imine isotropy Structured reaction, so as to achieve "one-pot" efficient synthesis of such chiral ⁇ -aminophosphonic acid derivatives.
  • the first aspect of the present invention provides a method for catalytically synthesizing chiral ⁇ -aminophosphonic acid derivatives.
  • the ⁇ -aminophosphonic acid derivatives have the structure shown in the following formula:
  • the method comprises the steps of:
  • * represents R configuration or S configuration
  • R 1 is selected from substituted or unsubstituted C 1 -C 16 alkyl
  • R 2 is selected from substituted or unsubstituted C 1 -C 16 alkyl
  • Ar 2 is a substituted or unsubstituted C 6 -C 10 aryl group, or a 5-12 membered heteroaryl group; wherein, the 5-12 membered heteroaryl group optionally has 1-2 fused saturated 5-7 membered ring;
  • Described cinchona base derivative catalyst is selected from following group:
  • PYR is Ar is selected from the group consisting of substituted or unsubstituted C 6 -C 10 aryl, or 5-12 membered heteroaryl;
  • substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl , C 2 -C 4 ester group, nitro group, 3-8 membered cycloalkyl group, 4-8 membered heterocyclic group, or C 6 -C unsubstituted or substituted by one or more substituents selected from the following group 10 aryl or 5-12 membered heteroaryl: halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, tert-butyldimethylsilyl (TBS), tert-butyldimethyl Siloxane (TBSO), Triisopropylsilyl (TIPS).
  • a substituent selected from the group consisting of: halogen, C 1 -C 4 alkyl, C 2 -C 4 alken
  • the amount of the cinchona base derivative catalyst used is 0.0001-0.5 mol%, preferably 0.01-0.05 mol% (based on the amount of the compound of formula II).
  • the inorganic base is selected from the group consisting of potassium phosphate, potassium carbonate, potassium hydroxide, lithium hydroxide, lithium hydroxide monohydrate, potassium bicarbonate, cesium carbonate, potassium hydrogen phosphate, sodium carbonate .
  • the amount of the inorganic base is 10-40 mol%, preferably 15-30 mol% (based on the amount of the compound of formula II).
  • the reaction in another preferred embodiment, is carried out in a solvent selected from the group consisting of toluene, chloroform, diethyl ether, or a combination thereof.
  • the reaction is carried out at -40°C to 40°C, preferably at -30°C to 30°C.
  • the ⁇ -aminophosphonic acid precursor II' has a structure selected from the following group:
  • Ar 2 is p-nitrophenyl.
  • the ⁇ -aminophosphonic acid precursor II' has a structure selected from the following group:
  • the cinchona base derivative catalyst is selected from the following group:
  • Ar is selected from the group consisting of phenyl, naphthyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl;
  • R is selected from the group: Tert-butyl (tBu), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS).
  • the cinchona base derivative catalyst is selected from the following group:
  • PYR is Ar is selected from the group consisting of:
  • the catalyst is Q-4.
  • the imine intermediate II is prepared by the following method:
  • reaction is carried out in chloroform.
  • the method also includes the steps of:
  • the acid is hydrochloric acid.
  • reaction is carried out in tetrahydrofuran.
  • the method also includes the steps of:
  • the acid is hydrochloric acid.
  • the method further includes the step of: recrystallizing the product to obtain purified product IV.
  • the present inventor provides a preparation method of chiral ⁇ -aminophosphonic acid and its derivatives.
  • the imine intermediate obtained by condensation of ⁇ -carbonyl phosphonate and benzylamine as raw materials undergoes a highly enantioselective imine isomerization reaction under the action of a betaine (Betaine) catalyst with a cinchonaine skeleton. , so as to achieve a "one-pot" efficient synthesis of such chiral ⁇ -aminophosphonic acid derivatives.
  • Betaine betaine
  • Betaine betaine organic small molecule catalysts based on cinchona skeleton, which exhibited excellent catalytic activity and enantioselectivity in the isomerization reaction of trifluoromethylimine sex.
  • the catalyst can catalyze the completion of chiral isomerization with high efficiency. Therefore, based on the above findings, the inventors designed a "one-pot" method for efficiently synthesizing such chiral ⁇ -aminophosphonic acid derivatives.
  • the cinchona base derivative catalyst of the present invention has an optically active compound of the following structural formula.
  • Ar is a substituted aromatic hydrocarbon group, and the substituted aromatic hydrocarbon group is arbitrarily selected from 3,5-diaryl aromatic groups.
  • the catalyst is preferably a catalyst selected from the group consisting of:
  • the catalyst is Q-4.
  • R 1 is selected from any alkyl substituent of C1-C16;
  • R 2 is selected from any alkyl substituent of C1-C16;
  • R 3 is an aromatic substituent, specifically a substituted phenyl or heterocyclic aromatic group
  • Ar 2 is an aromatic substituent, specifically a substituted phenyl group or a heterocyclic aromatic group.
  • Preferred ⁇ -aminophosphonates II' are compounds selected from the group consisting of:
  • Ar 2 is p-nitrophenyl.
  • the ⁇ -aminophosphonic acid precursor II' has a structure selected from the following group:
  • the present invention provides a "one-pot", ten-gram-scale method for synthesizing ⁇ -aminophosphonic acid.
  • the method only needs a minimum catalyst dosage of 1 ppm (0.0001 mole %), and only needs one-step recrystallization purification process.
  • the step is to condense benzylamine and ⁇ -carbonyl phosphonate as raw materials to obtain an imine intermediate.
  • enantioselective isomerization reaction occurs, and ⁇ -aminophosphonate is efficiently prepared.
  • recrystallization and purification give high-purity chiral ⁇ -aminophosphonic acid.
  • reaction formula of the inventive method is as follows:
  • R 1 is selected from any alkyl substituent of C1-C16;
  • R 2 is selected from any alkyl substituent of C1-C16;
  • R 3 is an aromatic substituent, specifically a substituted phenyl or heterocyclic aromatic group
  • Ar is an aromatic substituent.
  • each step can be completed in the same system without product separation.
  • the main advantages of the present invention include:
  • the present invention reduces the amount of catalyst from 20 mol% used in the original technology to the lowest 0.0001 mol%, and through one-pot reaction and one-step recrystallization, ⁇ -aminophosphoric acid with high enantioselectivity can be obtained.
  • the preparation method is suitable for industrialization and has the advantages of Industrial application value.
  • Embodiment 1 the synthesis of cinchona base derivative catalyst:
  • ArCH 2 Br represents benzyl bromide
  • Ar can be any other aryl substituent
  • CH 3 CN represents acetonitrile
  • R can be a tert-butyl or silicon-based protecting group.
  • Example 2 Partial cinchona base derivative catalyst and inorganic base screening results
  • Step 1) Add p-nitrobenzylamine (0.2 mmol, 30 mg) and 400 microliters of chloroform in a 2 ml reaction vial, after cooling at zero degrees Celsius for 5 minutes, add compound I (0.2 mmol, 42 mg), in After stirring at this temperature for 10 hours, the imine intermediate II was obtained for the next transformation.
  • Step 2) Add catalyst, inorganic base (20 mol%) and 1.6 ml toluene into another 4 ml reaction flask. After stirring at the specified temperature for 5 minutes, the imine intermediate II in step 1) was directly added to the 4 ml reaction flask at one time and kept stirring at the temperature. During the reaction, the conversion rate of the reaction was detected by NMR, and the chirality (ee) value was measured by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • step 1) add benzylamine (0.2 mmol) and 400 microliters of chloroform in 2 milliliters of reaction vials, after cooling at zero degree Celsius for 5 minutes, add compound I (0.2 mmol), at this temperature Stirring was continued for 10 hours to obtain imine intermediate II for future use.
  • step 2) Catalyst Q-4 (0.025 mol%) and potassium carbonate (20 mol%) were added and dissolved in 1.6 ml of toluene into another 4 ml reaction flask. After stirring at -20°C for 5 minutes, the mixture in step 1) was directly added to the 4 ml reaction flask and continued to stir at -20°C for 24 hours.
  • step 1) add benzylamine (0.2 mmol) and 400 microliters of chloroform in 2 milliliter reaction vials, after cooling at 0 degree Celsius for 5 minutes, add compound I (0.2 mmol), at this temperature Stirring was continued for 10 hours to obtain imine intermediate II for future use.
  • step 2) Catalyst Q-4 (0.05 mol%) and potassium carbonate (20 mol%) were added and dissolved in 1.6 ml of toluene into another 4 ml reaction flask. After stirring at -20°C for 5 minutes, the mixture in step 1) was directly added to the 4 ml reaction flask and continued to stir at -20°C for 12 hours, then warmed up to room temperature and reacted for another 12 hours.
  • Example 4 Preparation of high-purity chiral ⁇ -aminophosphonic acid with one-step recrystallization and purification at ten-gram scale
  • Reaction formula 1 1.0ppm (0.0001mol%) catalyst loading, preparation of chiral ⁇ -aminophosphonic acid in ten-gram scale
  • Step 1) Add p-nitrobenzylamine (50 mmol, 7.61 g) and 50 ml of dry chloroform in a 250 ml dry Shrek tube, and slowly add compound I (51 mmol , 10.6 g dissolved in 30 ml dry chloroform). After the addition, the temperature was slowly raised to 0° C., and stirring was continued at this temperature for 24 hours. According to NMR, the conversion rate was 98%, and the purity was 93%. It was directly used in the next step without post-processing.
  • Step 3) After mixing the oil obtained in step 2) with THF (100 mL), 3N dilute hydrochloric acid (about 30 mL) was added to adjust the pH to 2. Stir overnight at room temperature, and TLC detects that the reaction is complete. Tetrahydrofuran was removed by rotary evaporation under reduced pressure, and the aqueous phase was washed three times with ether. Aqueous ammonia was then added to adjust the pH to 12, followed by extraction with dichloromethane. The organic phase was concentrated to give a pale yellow oil. The obtained oil was mixed with 6N dilute hydrochloric acid (50 ml, 300 mmol, 6 eq), heated to reflux at 100°C overnight, and the reaction was detected by NMR until the reaction was complete.
  • 6N dilute hydrochloric acid 50 ml, 300 mmol, 6 eq
  • Reaction formula 2 Starting from p-chlorobenzylamine, prepare ⁇ -aminophosphonic acid in ten grams at room temperature
  • Step 1) Add p-chlorobenzylamine (50 mmol, 7.08 g) and 80 ml of dry chloroform into a 250 ml dry Shrek tube, and slowly add compound I (51 mmol, 10.62 g dissolved in 20 ml dry chloroform). After the addition, the temperature was slowly raised to 0°C, and stirring was continued at this temperature for 24 hours. The conversion rate was 98% and the purity was 88% as detected by NMR. It was directly used in the next step without post-processing.
  • Step 3) After mixing the oil obtained in step 2) with THF (100 mL), 3N dilute hydrochloric acid (about 30 mL) was added to adjust the pH to 2. Stir overnight at room temperature, and TLC detects that the reaction is complete. Tetrahydrofuran was removed by rotary evaporation under reduced pressure, and the aqueous phase was washed three times with ether. Aqueous ammonia was then added to adjust the pH to 12, followed by extraction with dichloromethane. The organic phase was concentrated to give a pale yellow oil. . The obtained oil was mixed with 6N dilute hydrochloric acid (50 ml, 300 mmol, 6 eq), heated to reflux at 100°C overnight, and the reaction was detected by NMR until the reaction was complete.
  • 6N dilute hydrochloric acid 50 ml, 300 mmol, 6 eq
  • Step 1) Add benzylamine (0.2 mmol) and 400 microliters of chloroform to a 2 ml reaction vial, cool at 0°C for 5 minutes, add compound I (0.2 mmol), and continue stirring at 0°C for 10 hours for later use .
  • the NMR characterization is the same as that of the chiral compound, see the data in Example 3.

Abstract

Disclosed in the present invention is an efficient preparation method for chiral α-aminophosphonic acid and derivatives thereof. The derivatives of α-aminophosphonic acid have a structure as represented by formula (II') below. The method comprises: obtaining an imine intermediate by means of condensation with α-carbonyl phosphonate and benzylamine as raw materials, and then carrying out an imine isomerization reaction with high enantioselectivity under the action of a betaine catalyst having a quinine framework, so that such chiral α-aminophosphonic acid derivatives are efficiently synthesized by a one-pot method. The method of the present invention can obtain a chiral α-aminophosphonic acid by means of one-step recrystallization and purification with a high yield and high enantioselectivity, and has wide industrial production application prospects.

Description

一种手性α-氨基膦酸的衍生物及其制备方法A derivative of chiral α-aminophosphonic acid and its preparation method 技术领域technical field
本发明属于有机合成技术领域，具体地，本发明涉及一种手性α-氨基膦酸的衍生物及其制备方法。The invention belongs to the technical field of organic synthesis. Specifically, the invention relates to a derivative of chiral α-aminophosphonic acid and a preparation method thereof.
背景技术Background technique
α-氨基膦酸及其衍生物是一类具有重要生物活性的天然α-氨基酸类似物，其不仅具有抗病毒、抗菌、抗真菌和抗癌等生物活性，还能抑制各种蛋白水解酶的活性，例如HIV蛋白酶、高血压蛋白原酶和PTPases等。因此，在新药开发、农药化工中起到日益重要的作用，并成为多年来有机磷化学发展的重要领域。α-氨基膦酸及其衍生物的绝对构型与其生物活性有着密切相关性。例如：(S,R)构型的阿拉法林(Alafosfalin)具有明显优于其他三个异构体的革兰氏阳性菌和阴性菌抑制率。因此，开发具有底物广谱性的不对称策略制备手性α-氨基膦酸衍生物具有重要意义。有机小分子催化具有催化剂合成容易、反应条件比较温和、环境友好、生物毒性小、底物兼容性和适应性强等特点，已经成为简单方便获得手性分子的高效方法之一，并且已经在工业生产中得到广泛应用。α-Aminophosphonic acid and its derivatives are a class of natural α-amino acid analogs with important biological activities. They not only have biological activities such as antiviral, antibacterial, antifungal and anticancer, but also inhibit the activity of various proteolytic enzymes. Activities, such as HIV protease, renase and PTPases, etc. Therefore, it plays an increasingly important role in the development of new drugs and pesticide chemical industry, and has become an important field for the development of organophosphorus chemistry for many years. The absolute configurations of α-aminophosphonic acid and its derivatives are closely related to their biological activities. For example: (S, R) configuration of Alafosfalin (Alafosfalin) has significantly better than the other three isomers Gram-positive bacteria and negative bacteria inhibition rate. Therefore, it is of great significance to develop an asymmetric strategy with a broad substrate spectrum for the preparation of chiral α-aminophosphonic acid derivatives. Organic small molecule catalysis has the characteristics of easy catalyst synthesis, relatively mild reaction conditions, environmental friendliness, low biological toxicity, substrate compatibility and adaptability, etc. widely used in production.
目前合成手性α-氨基膦酸及其衍生物的主要策略是通过连接亚胺和膦酸酯构筑碳-磷键的Pudovik反应或者Kabachnik–Fields反应获得。近二十年来，不对称有机小分子催化被成功应用于这一碳-磷键构筑的策略，实现手性α-氨基膦酸衍生物的合成。例如氢键催化合成，双功能催化合成，
Figure PCTCN2022135641-appb-000001
酸催化合成；以及手性碱催化合成等方法。亚胺的异构化反应制备功能性手性胺是一种具有良好应用潜力的替代方案。其中，有报道尝试使用金鸡纳碱衍生物催化的亚胺异构化来制备手性α-氨基膦酸衍生物。但是，上述基于有机催化的策略通常催化效率低，催化剂用量高达5-20摩尔％，大大降低了其工业应用潜力。 At present, the main strategy for the synthesis of chiral α-aminophosphonic acid and its derivatives is obtained through Pudovik reaction or Kabachnik–Fields reaction to construct carbon-phosphorus bond by linking imine and phosphonate. In the past two decades, asymmetric organic small molecule catalysis has been successfully applied to this carbon-phosphorus bond construction strategy to realize the synthesis of chiral α-aminophosphonic acid derivatives. Such as hydrogen bond catalyzed synthesis, bifunctional catalyzed synthesis,
Figure PCTCN2022135641-appb-000001
Acid-catalyzed synthesis; and methods such as chiral base-catalyzed synthesis. Isomerization of imines to prepare functional chiral amines is an alternative with good application potential. Among them, an attempt to prepare chiral α-aminophosphonic acid derivatives by the isomerization of imines catalyzed by cinchona base derivatives has been reported. However, the above-mentioned organocatalysis-based strategies usually have low catalytic efficiency, and the catalyst dosage is as high as 5–20 mol%, which greatly reduces their industrial application potential.
鉴于α-氨基膦酸及其衍生物具有重要的应用价值和高效绿色的不对称合成方法的缺乏，本领域亟待开发一种高效率，高选择性，适合放大的α-氨基膦酸及其衍生物制备方法。In view of the important application value of α-aminophosphonic acid and its derivatives and the lack of efficient and green asymmetric synthesis methods, it is urgent to develop a high-efficiency, high-selectivity, suitable for amplification of α-aminophosphonic acid and its derivatives. method of preparation.
发明内容Contents of the invention
本发明提供了一种手性α-氨基膦酸的衍生物及其制备方法。具体地，本发明通过α-羰基膦酸酯和苄胺为原料缩合得到的亚胺中间体，在金鸡纳碱骨架的甜菜碱(Betaine)催化剂作用下，发生高对映选择性的亚胺异构化反应，从而实现“一锅法”高效合成此类手性α-氨基膦酸衍生物。The invention provides a derivative of chiral α-aminophosphonic acid and a preparation method thereof. Specifically, the imine intermediate obtained by the condensation of α-carbonyl phosphonate and benzylamine as raw materials in the present invention, under the action of the betaine (Betaine) catalyst with cinchonaine skeleton, undergoes highly enantioselective imine isotropy Structured reaction, so as to achieve "one-pot" efficient synthesis of such chiral α-aminophosphonic acid derivatives.
本发明的第一方面，提供了一种催化合成手性α-氨基膦酸衍生物的方法，所述的α-氨基膦酸衍生物具有如下式所示的结构：The first aspect of the present invention provides a method for catalytically synthesizing chiral α-aminophosphonic acid derivatives. The α-aminophosphonic acid derivatives have the structure shown in the following formula:
Figure PCTCN2022135641-appb-000002
Figure PCTCN2022135641-appb-000002
所述的方法包括步骤：The method comprises the steps of:
Figure PCTCN2022135641-appb-000003
Figure PCTCN2022135641-appb-000003
(a)在金鸡纳碱衍生物催化剂和无机碱存在下，用亚胺中间体II进行对映选择性异构化反应，制备得到具有光学活性的α-氨基膦酸前体II'：和(a) in the presence of cinchona base derivative catalyst and inorganic base, carry out enantioselective isomerization reaction with imine intermediate II to prepare optically active α-aminophosphonic acid precursor II': and
用所述的α-氨基膦酸前体II'进行水解，得到手性α-氨基膦酸；hydrolysis with the α-aminophosphonic acid precursor II' to obtain chiral α-aminophosphonic acid;
其中，*表示R构型或S构型；Wherein, * represents R configuration or S configuration;
R 1选自取代或未取代的C 1-C 16烷基； R 1 is selected from substituted or unsubstituted C 1 -C 16 alkyl;
R 2选自取代或未取代的C 1-C 16烷基； R 2 is selected from substituted or unsubstituted C 1 -C 16 alkyl;
Ar 2为取代或未取代的C 6-C 10芳基，或5-12元杂芳基；其中，所述的5-12元杂芳基上任选地具有1-2个稠合的饱和5-7元环； Ar 2 is a substituted or unsubstituted C 6 -C 10 aryl group, or a 5-12 membered heteroaryl group; wherein, the 5-12 membered heteroaryl group optionally has 1-2 fused saturated 5-7 membered ring;
所述的金鸡纳碱衍生物催化剂选自下组：Described cinchona base derivative catalyst is selected from following group:
Figure PCTCN2022135641-appb-000004
Figure PCTCN2022135641-appb-000004
其中，PYR为
Figure PCTCN2022135641-appb-000005
Ar选自下组：取代或未取代的C 6-C 10芳基，或5-12元杂芳基； Among them, PYR is
Figure PCTCN2022135641-appb-000005
Ar is selected from the group consisting of substituted or unsubstituted C 6 -C 10 aryl, or 5-12 membered heteroaryl;
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 2-C 4酯基、硝基、3-8元环烷基、4-8元杂环基、或未取代或被选自下组的一个或多个取代基取代的C 6-C 10芳基或5-12元杂芳基：卤素、C 1-C 4烷氧基、C 1-C 4烷硫基、叔丁基二甲基硅基(TBS)、叔丁基二甲基硅氧(TBSO)、三异丙基硅基(TIPS)。 The substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl , C 2 -C 4 ester group, nitro group, 3-8 membered cycloalkyl group, 4-8 membered heterocyclic group, or C 6 -C unsubstituted or substituted by one or more substituents selected from the following group 10 aryl or 5-12 membered heteroaryl: halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, tert-butyldimethylsilyl (TBS), tert-butyldimethyl Siloxane (TBSO), Triisopropylsilyl (TIPS).
在另一优选例中，所述的金鸡纳碱衍生物催化剂的用量为0.0001-0.5mol％，较佳地为0.01-0.05mol％(以式II化合物的用量为基础计)。In another preferred example, the amount of the cinchona base derivative catalyst used is 0.0001-0.5 mol%, preferably 0.01-0.05 mol% (based on the amount of the compound of formula II).
在另一优选例中，所述的无机碱选自下组：磷酸钾、碳酸钾、氢氧化钾、氢氧化锂、一水合氢氧化锂、碳酸氢钾、碳酸铯、磷酸氢钾、碳酸钠。In another preferred example, the inorganic base is selected from the group consisting of potassium phosphate, potassium carbonate, potassium hydroxide, lithium hydroxide, lithium hydroxide monohydrate, potassium bicarbonate, cesium carbonate, potassium hydrogen phosphate, sodium carbonate .
在另一优选例中，所述的无机碱的用量为10-40mol％，较佳地为15-30mol％(以式II化合物的用量为基础计)。In another preferred example, the amount of the inorganic base is 10-40 mol%, preferably 15-30 mol% (based on the amount of the compound of formula II).
在另一优选例中，所述的步骤中，反应在选自下组的溶剂中进行：甲苯、氯仿、乙醚，或其组合。In another preferred embodiment, in the step, the reaction is carried out in a solvent selected from the group consisting of toluene, chloroform, diethyl ether, or a combination thereof.
在另一优选例中，所述的步骤中，反应在-40℃至40℃下进行，较佳地在-30℃至30℃下进行。In another preferred example, in the step, the reaction is carried out at -40°C to 40°C, preferably at -30°C to 30°C.
在另一优选例中，所述的α-氨基膦酸前体II'具有选自下组的结构：In another preferred example, the α-aminophosphonic acid precursor II' has a structure selected from the following group:
Figure PCTCN2022135641-appb-000006
Figure PCTCN2022135641-appb-000006
在另一优选例中，Ar 2为对硝基苯基。 In another preferred embodiment, Ar 2 is p-nitrophenyl.
在另一优选例中，所述的α-氨基膦酸前体II'具有选自下组的结构：In another preferred example, the α-aminophosphonic acid precursor II' has a structure selected from the following group:
Figure PCTCN2022135641-appb-000007
Figure PCTCN2022135641-appb-000007
在另一优选例中，所述的金鸡纳碱衍生物催化剂选自下组：In another preference, the cinchona base derivative catalyst is selected from the following group:
Figure PCTCN2022135641-appb-000008
Figure PCTCN2022135641-appb-000008
其中，PYR为
Figure PCTCN2022135641-appb-000009
Ar为
Figure PCTCN2022135641-appb-000010
Among them, PYR is
Figure PCTCN2022135641-appb-000009
Ar is
Figure PCTCN2022135641-appb-000010
Ar 1选自下组：苯基、萘基、4-甲氧基苯基、3,5-二甲氧基苯基、3,4,5-三甲氧基苯基；R选自下组：叔丁基(tBu)、叔丁基二甲基硅基(TBS)、三异丙基硅基(TIPS)。 Ar is selected from the group consisting of phenyl, naphthyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl; R is selected from the group: Tert-butyl (tBu), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS).
在另一优选例中，所述的金鸡纳碱衍生物催化剂选自下组：In another preference, the cinchona base derivative catalyst is selected from the following group:
Figure PCTCN2022135641-appb-000011
Figure PCTCN2022135641-appb-000011
其中，PYR为
Figure PCTCN2022135641-appb-000012
Ar选自下组： Among them, PYR is
Figure PCTCN2022135641-appb-000012
Ar is selected from the group consisting of:
Figure PCTCN2022135641-appb-000013
Figure PCTCN2022135641-appb-000013
在另一优选例中，所述的催化剂为Q-4。In another preferred example, the catalyst is Q-4.
在另一优选例中，所述的亚胺中间体II是通过以下方法制备的：In another preferred example, the imine intermediate II is prepared by the following method:
Figure PCTCN2022135641-appb-000014
Figure PCTCN2022135641-appb-000014
(a)用α-羰基膦酸酯I与苄胺进行反应，缩合得到亚胺中间体II。(a) react with α-carbonyl phosphonate I and benzylamine, and condense to obtain the imine intermediate II.
在另一优选例中，所述的反应在氯仿中进行。In another preferred embodiment, the reaction is carried out in chloroform.
在另一优选例中，所述的方法还包括步骤：In another preferred example, the method also includes the steps of:
Figure PCTCN2022135641-appb-000015
Figure PCTCN2022135641-appb-000015
(b)在酸存在下，对α-氨基膦酸前体II'进行水解，然后与氨水中和得到式III化合物：其中，式II'和式III的手性中心构型一致。(b) In the presence of acid, the α-aminophosphonic acid precursor II' is hydrolyzed, and then neutralized with ammonia water to obtain the compound of formula III: wherein, the chiral center configurations of formula II' and formula III are consistent.
在另一优选例中，所述的酸为盐酸。In another preferred example, the acid is hydrochloric acid.
在另一优选例中，所述的反应在四氢呋喃中进行。In another preferred example, the reaction is carried out in tetrahydrofuran.
在另一优选例中，所述的方法还包括步骤：In another preferred example, the method also includes the steps of:
Figure PCTCN2022135641-appb-000016
Figure PCTCN2022135641-appb-000016
(c)在酸存在下，用式III化合物进行水解反应，得到式IV化合物。(c) Under the presence of acid, carry out hydrolysis reaction with the compound of formula III to obtain the compound of formula IV.
在另一优选例中，所述的酸为盐酸。In another preferred example, the acid is hydrochloric acid.
在另一优选例中，所述的方法还包括步骤：对产物进行重结晶，得到纯化后的产物IV。In another preferred example, the method further includes the step of: recrystallizing the product to obtain purified product IV.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.
具体实施方式Detailed ways
本发明人经过长期而深入的研究，提供了一种手性α-氨基膦酸及其衍生物的制备方法。本发明通过α-羰基膦酸酯和苄胺为原料缩合得到的亚胺中间体，在金鸡纳碱骨架的甜菜碱(Betaine)催化剂作用下，发生高对映选择性的亚胺异构化反应，从而实现“一锅法”高效合成此类手性α-氨基膦酸衍生物。基于上述发现，发明人完成了本发明。After long-term and in-depth research, the present inventor provides a preparation method of chiral α-aminophosphonic acid and its derivatives. In the present invention, the imine intermediate obtained by condensation of α-carbonyl phosphonate and benzylamine as raw materials undergoes a highly enantioselective imine isomerization reaction under the action of a betaine (Betaine) catalyst with a cinchonaine skeleton. , so as to achieve a "one-pot" efficient synthesis of such chiral α-aminophosphonic acid derivatives. Based on the above findings, the inventors have accomplished the present invention.
基于金鸡纳碱骨架的甜菜碱(Betaine)有机小分子催化剂Betaine Organic Small Molecule Catalyst Based on Cinchona Skeleton
前期，我们课题组发展了一类基于金鸡纳碱骨架的甜菜碱(Betaine)有机小分子催化剂，此类催化剂在三氟甲基亚胺的异构化反应中展现优秀的催化活性和对映选择 性。In the early stage, our research group developed a class of betaine (Betaine) organic small molecule catalysts based on cinchona skeleton, which exhibited excellent catalytic activity and enantioselectivity in the isomerization reaction of trifluoromethylimine sex.
在前期研究过程中，发明人发现该类催化剂的底物适用范围较窄，对于二氟甲基亚胺、烷基亚胺或芳基亚胺等与三氟甲基亚胺结构接近的底物都不具备催化活性：In the previous research process, the inventors found that the scope of substrates of this type of catalyst is relatively narrow. None are catalytically active:
Figure PCTCN2022135641-appb-000017
Figure PCTCN2022135641-appb-000017
然而，对于亚胺膦酸酯，该催化剂却可以高效率地催化完成手性异构化反应。因此，基于上述发现，发明人设计了“一锅法”高效合成此类手性α-氨基膦酸衍生物的方法。However, for imine phosphonates, the catalyst can catalyze the completion of chiral isomerization with high efficiency. Therefore, based on the above findings, the inventors designed a "one-pot" method for efficiently synthesizing such chiral α-aminophosphonic acid derivatives.
本发明所述的金鸡纳碱衍生物催化剂具有如下结构式的光学活性化合物。The cinchona base derivative catalyst of the present invention has an optically active compound of the following structural formula.
Figure PCTCN2022135641-appb-000018
Figure PCTCN2022135641-appb-000018
上式中：Ar为取代的芳烃基，所述的取代的芳烃基任意选自3，5-二芳基芳香基。In the above formula: Ar is a substituted aromatic hydrocarbon group, and the substituted aromatic hydrocarbon group is arbitrarily selected from 3,5-diaryl aromatic groups.
该反应中，催化剂优选为选自下组的催化剂：In this reaction, the catalyst is preferably a catalyst selected from the group consisting of:
Figure PCTCN2022135641-appb-000019
Figure PCTCN2022135641-appb-000019
最优选地，所述的催化剂为Q-4。Most preferably, the catalyst is Q-4.
本发明所述制备α-氨基膦酸酯的对映体和消旋体反应式如下式所示：The enantiomer and the racemate reaction formula of preparing α-aminophosphonate described in the present invention are shown in the following formula:
Figure PCTCN2022135641-appb-000020
Figure PCTCN2022135641-appb-000020
上式中：R 1选自为C1-C16的任何烷基取代基； In the above formula: R 1 is selected from any alkyl substituent of C1-C16;
R 2选自为C1-C16的任何烷基取代基； R 2 is selected from any alkyl substituent of C1-C16;
R 3为芳香取代基，具体为取代的苯基或杂环芳香基； R 3 is an aromatic substituent, specifically a substituted phenyl or heterocyclic aromatic group;
Ar 2为芳香取代基，具体为取代的苯基或杂环芳香基。 Ar 2 is an aromatic substituent, specifically a substituted phenyl group or a heterocyclic aromatic group.
优选的α-氨基膦酸酯II'为选自下组的化合物：Preferred α-aminophosphonates II' are compounds selected from the group consisting of:
Figure PCTCN2022135641-appb-000021
Figure PCTCN2022135641-appb-000021
在另一优选例中，Ar 2为对硝基苯基。 In another preferred embodiment, Ar 2 is p-nitrophenyl.
在另一优选例中，所述的α-氨基膦酸前体II'具有选自下组的结构：In another preferred example, the α-aminophosphonic acid precursor II' has a structure selected from the following group:
Figure PCTCN2022135641-appb-000022
Figure PCTCN2022135641-appb-000022
“一锅法”合成性α-氨基膦酸的方法"One-pot" method for the synthesis of α-aminophosphonic acid
本发明提供一种“一锅法”、十克规模级合成性α-氨基膦酸的方法。该方法最低只需要1ppm(0.0001摩尔％)的催化剂用量，而且只需要一步重结晶纯化过程。其步骤是以苄胺和α-羰基膦酸酯为原料，缩合得到亚胺中间体。再在金鸡纳碱衍生物催化剂和无机碱的参与下，发生对映选择性异构化反应，高效制备α-氨基膦酸酯。通过盐酸水解后，重结晶纯化得到高纯度手性α-氨基膦酸。The present invention provides a "one-pot", ten-gram-scale method for synthesizing α-aminophosphonic acid. The method only needs a minimum catalyst dosage of 1 ppm (0.0001 mole %), and only needs one-step recrystallization purification process. The step is to condense benzylamine and α-carbonyl phosphonate as raw materials to obtain an imine intermediate. Then, under the participation of cinchona base derivative catalyst and inorganic base, enantioselective isomerization reaction occurs, and α-aminophosphonate is efficiently prepared. After hydrolysis with hydrochloric acid, recrystallization and purification give high-purity chiral α-aminophosphonic acid.
本发明方法的反应式如下式所示：The reaction formula of the inventive method is as follows:
Figure PCTCN2022135641-appb-000023
Figure PCTCN2022135641-appb-000023
上式中：R 1选自为C1-C16的任何烷基取代基； In the above formula: R 1 is selected from any alkyl substituent of C1-C16;
R 2选自为C1-C16的任何烷基取代基； R 2 is selected from any alkyl substituent of C1-C16;
R 3为芳香取代基，具体为取代的苯基或杂环芳香基； R 3 is an aromatic substituent, specifically a substituted phenyl or heterocyclic aromatic group;
Ar为芳香取代基。Ar is an aromatic substituent.
上述方法中，各步骤之间可不经产物分离，于同一体系中完成。In the above method, each step can be completed in the same system without product separation.
与现有技术相比，本发明的主要优点包括：Compared with the prior art, the main advantages of the present invention include:
本发明将催化剂用量从原来技术所用的20mol％降低至最低0.0001mol％，并且通过一锅法反应，进行一步重结晶即可得到高对映选择性的α-氨基磷酸，制备方法适合工业化，具有产业应用价值。The present invention reduces the amount of catalyst from 20 mol% used in the original technology to the lowest 0.0001 mol%, and through one-pot reaction and one-step recrystallization, α-aminophosphoric acid with high enantioselectivity can be obtained. The preparation method is suitable for industrialization and has the advantages of Industrial application value.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.
实施例1：金鸡纳碱衍生物催化剂的合成：Embodiment 1: the synthesis of cinchona base derivative catalyst:
Figure PCTCN2022135641-appb-000024
Figure PCTCN2022135641-appb-000024
反应式中，ArCH 2Br表示苄溴，Ar可以是其他任意芳基取代基；CH 3CN表示乙腈；R可以是叔丁基或者硅基保护基。 In the reaction formula, ArCH 2 Br represents benzyl bromide, Ar can be any other aryl substituent; CH 3 CN represents acetonitrile; R can be a tert-butyl or silicon-based protecting group.
在20毫升的反应管中，将化合物A(0.5毫摩尔,287毫克)和化合物苄溴B(0.5毫摩尔)溶解于5毫升乙腈中。将反应在室温条件下搅拌24小时至反应完全。反应液在减压旋蒸浓缩后，粗产物通过硅胶柱层析分离(二氯甲烷/甲醇＝20/1),得到产物C。部分催化剂表征如下：In a 20 mL reaction tube, compound A (0.5 mmol, 287 mg) and compound benzyl bromide B (0.5 mmol) were dissolved in 5 mL of acetonitrile. The reaction was stirred at room temperature for 24 hours until complete. After the reaction solution was concentrated by rotary evaporation under reduced pressure, the crude product was separated by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain product C. Some catalysts are characterized as follows:
结构式：Structural formula:
Figure PCTCN2022135641-appb-000025
Figure PCTCN2022135641-appb-000025
性状：白色固体Appearance: white solid
1H NMR(500MHz,Methanol-d 4)δ8.64(d,J＝4.6Hz,1H),8.06(d,J＝9.2Hz,1H),7.84(d,J＝2.5Hz,1H),7.71–7.44(m,11H),7.29(tt,J＝7.4,1.2Hz,1H),7.12–7.02(m,2H),6.81(d,J＝2.3Hz,4H),6.50(t,J＝2.3Hz,2H),5.19–4.96(m,4H),4.75(d,J＝12.5Hz,1H),4.24(t,J＝9.6Hz,1H),4.02–3.92(m,1H),3.84(s,13H),3.52–3.43(m,1H),3.26(dt,J＝11.9,9.1Hz,1H),3.07(ddd,J＝12.1,9.0,2.7Hz,1H),2.57–2.39(m,2H),1.94–1.81(m,3H),1.55–1.46(m,1H),1.29(d,J＝4.7Hz,1H),0.74(s,9H). 13C NMR(126MHz,Methanol-d 4)δ165.10,162.24,160.82,153.00,141.49,140.16,139.43,135.59,134.93,131.95,131.21,130.93,129.50,129.30,127.93,127.74,122.43,119.36,117.59,108.21,103.86,98.96,66.20,63.02,57.84,55.04,54.57,37.98,28.10,27.29,23.03,22.47.HRMS(ESI/[M-Br] +)Calcd for C 62H 62ClN 4O 7 +m/z 1009.4302,found 1009.4308. 1 H NMR (500MHz, Methanol-d 4 )δ8.64(d, J=4.6Hz, 1H), 8.06(d, J=9.2Hz, 1H), 7.84(d, J=2.5Hz, 1H), 7.71 –7.44(m,11H),7.29(tt,J=7.4,1.2Hz,1H),7.12–7.02(m,2H),6.81(d,J=2.3Hz,4H),6.50(t,J=2.3 Hz, 2H), 5.19–4.96(m, 4H), 4.75(d, J=12.5Hz, 1H), 4.24(t, J=9.6Hz, 1H), 4.02–3.92(m, 1H), 3.84(s ,13H),3.52–3.43(m,1H),3.26(dt,J＝11.9,9.1Hz,1H),3.07(ddd,J＝12.1,9.0,2.7Hz,1H),2.57–2.39(m,2H ),1.94–1.81(m,3H),1.55–1.46(m,1H),1.29(d,J＝4.7Hz,1H),0.74(s,9H). 13 C NMR(126MHz,Methanol-d 4 ) δ165.10,162.24,160.82,153.00,141.49,140.16,139.43,135.59,134.93,131.95,131.21,130.93,129.50,129.30,127.93,127.74,122.43,1 19.36, 117.59, 108.21, 103.86, 98.96, 66.20, 63.02, 57.84, 55.04, 54.57, 37.98, 28.10, 27.29, 23.03, 22.47. HRMS (ESI/[M-Br] + ) Calcd for C 62 H 62 ClN 4 O 7 + m/z 1009.4302, found 1009.4308.
Figure PCTCN2022135641-appb-000026
Figure PCTCN2022135641-appb-000026
性状：白色固体Appearance: white solid
1H NMR(500MHz,Methanol-d 4)δ8.64(d,J＝4.6Hz,1H),8.07(d,J＝9.2Hz,1H),7.80–7.44(m,12H),7.33–7.26(m,1H),7.07(t,J＝7.7Hz,2H),6.78(d,J＝2.3Hz,4H),6.50(d,J＝2.3Hz,2H),5.69(ddd,J＝17.3,10.5,6.9Hz,1H),5.16–4.94(m,4H),4.16(t,J＝9.1Hz,1H),3.83(s,12H),3.65–3.52(m,2H),3.18(td,J＝11.5,5.2Hz,1H),2.65(d,J＝9.0Hz,1H),2.35(dd,J＝13.8,7.8Hz,1H),1.92(q,J＝3.2Hz,1H),1.87–1.75(m,1H),1.54–1.42(m,1H),1.17–1.06(m,1H),0.73(s,9H). 13C NMR(126MHz,Methanol-d 4)δ160.79,146.08,141.50,140.13,139.53,136.91,134.95,131.91,131.20,131.07,129.79,128.91,128.89,127.95,127.75,122.69,122.32,119.25,119.15,116.46,108.24,103.43,98.94,83.70,71.06,67.18,63.90,61.02,54.56,50.69,37.49,28.11,26.39,23.80,22.16.HRMS(ESI/[M-Br] +)Calcd for C 62H 62ClN 4O 7 +m/z 1009.4302,found 1009.4311. 1 H NMR (500MHz, Methanol-d 4 ) δ8.64 (d, J = 4.6Hz, 1H), 8.07 (d, J = 9.2Hz, 1H), 7.80–7.44 (m, 12H), 7.33–7.26 ( m, 1H), 7.07(t, J=7.7Hz, 2H), 6.78(d, J=2.3Hz, 4H), 6.50(d, J=2.3Hz, 2H), 5.69(ddd, J=17.3, 10.5 ,6.9Hz,1H),5.16–4.94(m,4H),4.16(t,J＝9.1Hz,1H),3.83(s,12H),3.65–3.52(m,2H),3.18(td,J＝ 11.5, 5.2Hz, 1H), 2.65(d, J=9.0Hz, 1H), 2.35(dd, J=13.8, 7.8Hz, 1H), 1.92(q, J=3.2Hz, 1H), 1.87–1.75( m,1H),1.54–1.42(m,1H),1.17–1.06(m,1H),0.73(s,9H). 13 C NMR(126MHz,Methanol-d 4 )δ160.79,146.08,141.50,140.13,139.53 ,136.91,134.95,131.91,131.20,131.07,129.79,128.91,128.89,127.95,127.75,122.69,122.32,119.25,119.15,116.46,108.24,103.43,9 8.94, 83.70, 71.06, 67.18, 63.90, 61.02, 54.56, 50.69 ,37.49,28.11,26.39,23.80,22.16.HRMS(ESI/[M-Br] + )Calcd for C 62 H 62 ClN 4 O 7 + m/z 1009.4302,found 1009.4311.
Figure PCTCN2022135641-appb-000027
Figure PCTCN2022135641-appb-000027
性状：白色固体Appearance: white solid
1H NMR(500MHz,Chloroform-d)δ10.43(s,1H),8.63(d,J＝4.6Hz,1H),8.56(d,J＝2.5Hz,1H),8.08(d,J＝9.1Hz,1H),8.00–7.92(m,2H),7.76–7.46(m,7H),7.46–7.39(m,1H),7.28(t,J＝7.8Hz,2H),7.15(d,J＝4.5Hz,1H),7.01(s,4H),6.57(d,J＝11.8Hz,1H),5.55(dd,J＝7.5,3.6Hz,2H),5.03–4.90(m,1H),4.76(q,J＝9.5,6.5Hz,2H),4.37(d,J＝11.8Hz,1H),3.97(d,J＝22.9Hz,18H),3.32(dd,J＝13.1,10.5Hz,1H),3.20(td,J＝11.5,6.1Hz,1H),3.16–3.01(m,1H),2.58(dt,J＝8.1,3.9Hz,1H),2.07(q,J＝3.1Hz,1H),1.98–1.84(m,1H),1.68–1.57(m,1H),1.57–1.45(m,2H),1.37–1.27(m,1H),0.76(s,9H). 13C NMR(126MHz,Chloroform-d)δ164.86,163.15,157.77,153.20,152.90,145.85,143.52,140.00,137.67,136.52,135.38,134.88,134.24,132.09,131.57,131.30,129.56,129.50,129.15,128.62,128.14,124.65,123.68,121.38,118.27,117.69,107.49,104.30,84.15,72.51,65.19,62.12,60.95,59.85,56.41,50.13,37.15,29.00,25.95,24.90,23.17.HRMS(ESI/[M-Br] +)Calcd for C 64H 66ClN 4O 7 +m/z 1069.4513,found 1069.4503. 1 H NMR (500MHz, Chloroform-d) δ10.43(s, 1H), 8.63(d, J=4.6Hz, 1H), 8.56(d, J=2.5Hz, 1H), 8.08(d, J=9.1 Hz,1H),8.00–7.92(m,2H),7.76–7.46(m,7H),7.46–7.39(m,1H),7.28(t,J＝7.8Hz,2H),7.15(d,J＝ 4.5Hz, 1H), 7.01(s, 4H), 6.57(d, J＝11.8Hz, 1H), 5.55(dd, J＝7.5, 3.6Hz, 2H), 5.03–4.90(m, 1H), 4.76( q,J=9.5,6.5Hz,2H),4.37(d,J=11.8Hz,1H),3.97(d,J=22.9Hz,18H),3.32(dd,J=13.1,10.5Hz,1H), 3.20(td,J=11.5,6.1Hz,1H),3.16–3.01(m,1H),2.58(dt,J=8.1,3.9Hz,1H),2.07(q,J=3.1Hz,1H),1.98 –1.84(m,1H), 1.68–1.57(m,1H), 1.57–1.45(m,2H), 1.37–1.27(m,1H), 0.76(s,9H). 13 C NMR (126MHz, Chloroform- d) δ164.86, 163.15, 157.77, 153.20, 152.90, 145.85, 143.52, 140.00, 137.67, 136.52, 135.38, 134.88, 134.24, 132.09, 131.57, 131.30, 129.56, 129.50, 129.15, 128.62, 128.14, 124.65, 123.68, 121.38, 118.27,117.69,107.49,104.30,84.15,72.51,65.19,62.12,60.95,59.85,56.41,50.13,37.15,29.00,25.95,24.90,23.17.HRMS(ESI/[M-Br] + )Cal cd for C 64 H 66 ClN 4 O 7 + m/z 1069.4513, found 1069.4503.
实施例2：部分金鸡纳碱衍生物催化剂和无机碱筛选结果Example 2: Partial cinchona base derivative catalyst and inorganic base screening results
Figure PCTCN2022135641-appb-000028
Figure PCTCN2022135641-appb-000028
步骤1)：在2毫升反应瓶中加入对硝基苄胺(0.2毫摩尔,30毫克)和400微升氯仿，零摄氏度冷却5分钟后，加入化合物I(0.2毫摩尔,42毫克)，在该温度下继续搅拌10小时后,得到亚胺中间体II用于下一步转化。Step 1): Add p-nitrobenzylamine (0.2 mmol, 30 mg) and 400 microliters of chloroform in a 2 ml reaction vial, after cooling at zero degrees Celsius for 5 minutes, add compound I (0.2 mmol, 42 mg), in After stirring at this temperature for 10 hours, the imine intermediate II was obtained for the next transformation.
步骤2)：在另一4毫升反应瓶中加入催化剂和无机碱(20摩尔％)和1.6毫升甲苯。在指定温度下搅拌5分钟后，步骤1)中的亚胺中间体II直接全部一次加入到该4毫升反应瓶中并保持该温度下搅拌。反应过程中，用核磁检测反应的转化率，用高效液相色谱(HPLC)测量手性(ee)值。Step 2): Add catalyst, inorganic base (20 mol%) and 1.6 ml toluene into another 4 ml reaction flask. After stirring at the specified temperature for 5 minutes, the imine intermediate II in step 1) was directly added to the 4 ml reaction flask at one time and kept stirring at the temperature. During the reaction, the conversion rate of the reaction was detected by NMR, and the chirality (ee) value was measured by high performance liquid chromatography (HPLC).
Figure PCTCN2022135641-appb-000029
Figure PCTCN2022135641-appb-000029
a)转化率通过 31P NMR测定； b)ee值通过HPLC测定； c)83％分离产率； d)转化数＝17,000。 a) Conversion determined by 31 P NMR; b) ee value determined by HPLC; c) 83% isolated yield; d) Number of conversions = 17,000.
实施例3：不对称合成手性α-氨基膦酸衍生物Example 3: Asymmetric synthesis of chiral α-aminophosphonic acid derivatives
反应式1：Reaction 1:
Figure PCTCN2022135641-appb-000030
Figure PCTCN2022135641-appb-000030
反应式1中：步骤1)：在2毫升反应瓶中加入苄胺(0.2毫摩尔)和400微升氯仿，在零摄氏度冷却5分钟后，加入化合物I(0.2毫摩尔)，在该温度下继续搅拌10小时得到亚胺中间体II以备用。步骤2)：在另一4毫升反应瓶中加入催化剂Q-4(0.025摩尔％)和碳酸钾(20摩尔％)溶解于1.6毫升甲苯中。在-20摄氏度搅拌5分钟后，步骤1)中的混合物直接加入到该4毫升反应瓶中继续在-20摄氏度搅拌24小时。反应结束后，反应液直接通过去活化硅胶过滤除去碳酸钾，减压旋蒸除去溶剂，残留物经过去活化硅胶柱层析(石油醚/乙酸乙酯＝90/10-70/30)分离获得目标产物II'。In reaction formula 1: step 1): add benzylamine (0.2 mmol) and 400 microliters of chloroform in 2 milliliters of reaction vials, after cooling at zero degree Celsius for 5 minutes, add compound I (0.2 mmol), at this temperature Stirring was continued for 10 hours to obtain imine intermediate II for future use. Step 2): Catalyst Q-4 (0.025 mol%) and potassium carbonate (20 mol%) were added and dissolved in 1.6 ml of toluene into another 4 ml reaction flask. After stirring at -20°C for 5 minutes, the mixture in step 1) was directly added to the 4 ml reaction flask and continued to stir at -20°C for 24 hours. After the reaction, the reaction solution was directly filtered through deactivated silica gel to remove potassium carbonate, the solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by deactivated silica gel column chromatography (petroleum ether/ethyl acetate=90/10-70/30) to obtain Target product II'.
下列为部分化合物II'的表征：The following are the characterizations of some compounds II':
Figure PCTCN2022135641-appb-000031
Figure PCTCN2022135641-appb-000031
淡黄色油状物,83％产率(0.2毫摩尔规格,56毫克),99％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝95/5,1.0毫升/分钟,λ280nm,t major＝7.75分钟,t minor＝9.80分钟],
Figure PCTCN2022135641-appb-000032
＝+66.32(c＝1.76,CHCl 3),TLC(PE/EA＝1/1；R f＝0.3). 1H NMR(600MHz,CDCl 3)δ8.42(d,J＝5.0Hz,1H),8.26(dt,J＝8.7,2.1Hz,2H),7.92(dt,J＝8.7,2.2Hz,2H),4.73(dpd,J＝7.6,6.2,5.2Hz,2H),3.88(dq,J＝13.7,6.9Hz,1H),1.56(dd,J＝17.7,6.9Hz,3H),1.40–1.26(m,12H). 13C NMR(151MHz,CDCl 3)δ160.86(d,J＝16.4Hz),149.20,141.36(d,J＝3.2Hz),129.01,123.90,71.15(dd,J＝28.9,7.0Hz),64.31(d,J＝158.0Hz),24.08(ddd,J＝24.2,11.7,4.1Hz),16.79(d,J＝5.9Hz). 31P NMR(203MHz,CDCl 3)δ22.12.IR(薄膜):v 2980,1639,1600,1521,1344,1220,1104cm -1.HRMS(ESI/[M+H] +):Calcd.for C 15H 24N 2O 5P m/z 343.1423,found m/z 343.1457. Pale yellow oil, 83% yield (0.2 mmol scale, 56 mg), 99% ee [Daicel Chiralcel OD-3, Hexanes/IPA=95/5, 1.0 ml/min, λ280nm, t major =7.75 min, t minor = 9.80 minutes],
Figure PCTCN2022135641-appb-000032
=+66.32 (c=1.76, CHCl 3 ), TLC (PE/EA=1/1; R f =0.3). 1 H NMR (600MHz, CDCl 3 ) δ8.42 (d, J=5.0Hz, 1H) ,8.26(dt,J=8.7,2.1Hz,2H),7.92(dt,J=8.7,2.2Hz,2H),4.73(dpd,J=7.6,6.2,5.2Hz,2H),3.88(dq,J =13.7,6.9Hz,1H), 1.56(dd,J=17.7,6.9Hz,3H),1.40–1.26(m,12H). 13 C NMR(151MHz,CDCl 3 )δ160.86(d,J=16.4 Hz), 149.20, 141.36(d, J=3.2Hz), 129.01, 123.90, 71.15(dd, J=28.9, 7.0Hz), 64.31(d, J=158.0Hz), 24.08(ddd, J=24.2, 11.7 ,4.1Hz),16.79(d,J=5.9Hz). 31 P NMR(203MHz,CDCl 3 )δ22.12.IR(thin film):v 2980,1639,1600,1521,1344,1220,1104cm -1 . HRMS (ESI/[M+H] + ): Calcd. for C 15 H 24 N 2 O 5 P m/z 343.1423, found m/z 343.1457.
Figure PCTCN2022135641-appb-000033
Figure PCTCN2022135641-appb-000033
淡黄色油状物,84％产率(0.2毫摩尔规格,70毫克),98％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝6.35分钟,t minor＝9.27分钟],
Figure PCTCN2022135641-appb-000034
＝+5.76(c＝1.25,CHCl 3),TLC(PE/EA＝1/1；R f＝0.6), 1H NMR(500MHz,Chloroform-d)δ8.36(d,J＝5.1Hz,1H),8.33–8.17(m,2H),7.99–7.80(m,2H),4.86–4.61(m,2H),3.62(ddd,J＝13.6,9.3,4.2Hz,1H),2.07–1.95(m,2H),1.37–1.20(m,19H),1.15(ht,J＝5.9,4.0,3.1Hz,1H),0.84(t,J＝6.9Hz,3H). 13C NMR(126MHz,Chloroform-d)δ161.59(d,J＝16.6Hz),149.31,141.43(d,J＝3.5Hz),129.18(d,J＝1.6Hz),124.05,71.23(dd,J＝19.4,7.1Hz),70.09(d,J＝156.5Hz),31.77,30.26(d,J＝4.8Hz),28.89,27.01(d,J＝14.8Hz),24.23(ddd,J＝18.9,8.0,4.2Hz),22.71,14.18. 31P NMR(203MHz,Chloroform-d)δ21.61.IR(薄膜):v 2928,2857,1638,1600,1523,1374,1344,2245,1105cm -1.HRMS(ESI/[M+H] +):Calcd.for C 20H 34N 2O 5P m/z 413.2200,found m/z 413.2203. Pale yellow oil, 84% yield (0.2 mmol scale, 70 mg), 98% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =6.35 min, t minor = 9.27 minutes],
Figure PCTCN2022135641-appb-000034
=+5.76 (c=1.25, CHCl 3 ), TLC (PE/EA=1/1; R f =0.6), 1 H NMR (500MHz, Chloroform-d) δ8.36 (d, J=5.1Hz, 1H ),8.33–8.17(m,2H),7.99–7.80(m,2H),4.86–4.61(m,2H),3.62(ddd,J＝13.6,9.3,4.2Hz,1H),2.07–1.95(m , 2H), 1.37–1.20(m, 19H), 1.15(ht, J＝5.9, 4.0, 3.1Hz, 1H), 0.84(t, J＝6.9Hz, 3H). 13 C NMR (126MHz, Chloroform-d )δ161.59(d, J=16.6Hz), 149.31, 141.43(d, J=3.5Hz), 129.18(d, J=1.6Hz), 124.05, 71.23(dd, J=19.4,7.1Hz), 70.09 (d, J = 156.5Hz), 31.77, 30.26 (d, J = 4.8Hz), 28.89, 27.01 (d, J = 14.8Hz), 24.23 (ddd, J = 18.9, 8.0, 4.2Hz), 22.71, 14.18 .31 P NMR(203MHz,Chloroform-d)δ21.61.IR(thin film):v 2928,2857,1638,1600,1523,1374,1344,2245,1105cm -1 .HRMS(ESI/[M+H] + ): Calcd. for C 20 H 34 N 2 O 5 P m/z 413.2200, found m/z 413.2203.
Figure PCTCN2022135641-appb-000035
Figure PCTCN2022135641-appb-000035
淡黄色油状物,72％产率(0.2毫摩尔规格,65毫克),97％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝14.13分钟,t minor＝22.02分钟],
Figure PCTCN2022135641-appb-000036
＝-14.58(c＝1.18,CHCl 3),TLC(PE/EA＝1/1；R f＝0.5), 1H NMR(600MHz,Chloroform-d)δ8.35(d,J＝5.1Hz,1H),8.29–8.19(m,2H),7.95–7.84(m,2H),7.07(dd,J＝5.1,1.2Hz,1H),6.87(dd,J＝5.1,3.4Hz,1H),6.74(dt,J＝3.5,1.1Hz,1H),4.70(dtt,J＝12.3,7.8,6.1Hz,2H),3.66(ddd,J＝13.8,9.6,4.0Hz,1H),2.84(tt,J＝8.0,1.2Hz,2H),2.15–2.03(m,2H),1.71(dddd,J＝18.5,9.8,7.5,5.8Hz,1H),1.65–1.51(m,1H),1.35–1.21(m,12H). 13C NMR(151MHz,Chloroform-d)δ161.86(d,J＝16.2Hz),149.29,144.79,141.26(d,J＝3.3Hz),129.16,126.82,124.37,123.99,123.13,71.29(dd,J＝27.1,7.1Hz),69.64(d,J＝156.3Hz),29.86(d,J＝4.7Hz),29.51,29.23(d,J＝14.8Hz),24.16(ddd,J＝24.2,11.8,4.1Hz). 31P NMR(202MHz,Chloroform-d)δ21.10.IR(薄膜):v 2979,2932,1638,1600,1521,1344,1239,1105,978cm -1.HRMS(ESI/[M+H] +):Calcd.for C 21H 30N 2O 5PS m/z 453.1613,found m/z 453.1611. Pale yellow oil, 72% yield (0.2 mmol scale, 65 mg), 97% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =14.13 min, t minor = 22.02 minutes],
Figure PCTCN2022135641-appb-000036
=-14.58 (c=1.18, CHCl 3 ), TLC (PE/EA=1/1; R f =0.5), 1 H NMR (600MHz, Chloroform-d) δ8.35 (d, J=5.1Hz, 1H ), 8.29–8.19(m,2H),7.95–7.84(m,2H),7.07(dd,J＝5.1,1.2Hz,1H),6.87(dd,J＝5.1,3.4Hz,1H),6.74( dt,J＝3.5,1.1Hz,1H), 4.70(dtt,J＝12.3,7.8,6.1Hz,2H), 3.66(ddd,J＝13.8,9.6,4.0Hz,1H), 2.84(tt,J＝ 8.0,1.2Hz,2H),2.15–2.03(m,2H),1.71(dddd,J＝18.5,9.8,7.5,5.8Hz,1H),1.65–1.51(m,1H),1.35–1.21(m, 12H). 13 C NMR (151MHz, Chloroform-d) δ161.86 (d, J=16.2Hz), 149.29, 144.79, 141.26 (d, J=3.3Hz), 129.16, 126.82, 124.37, 123.99, 123.13, 71.29 (dd, J=27.1,7.1Hz),69.64(d,J=156.3Hz),29.86(d,J=4.7Hz),29.51,29.23(d,J=14.8Hz),24.16(ddd,J=24.2 , 11.8, 4.1Hz). 31 P NMR (202MHz, Chloroform-d) δ21.10.IR (thin film): v 2979,2932,1638,1600,1521,1344,1239,1105,978cm -1 .HRMS (ESI /[M+H] + ): Calcd. for C 21 H 30 N 2 O 5 PS m/z 453.1613, found m/z 453.1611.
Figure PCTCN2022135641-appb-000037
Figure PCTCN2022135641-appb-000037
淡黄色油状物,73％产率(0.2毫摩尔规格,56毫克),97％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝7.46分钟,t minor＝11.21分钟],
Figure PCTCN2022135641-appb-000038
＝+1.46(c＝1.21,CHCl 3),TLC(PE/EA＝1/1；R f＝0.5), 1H NMR(500MHz,Chloroform-d)δ8.37(d,J＝5.1Hz,1H),8.32–8.22(m,2H),7.97–7.86(m,2H),5.75(dddd,J＝16.3,11.1,7.3,5.3Hz,1H),5.00(d,J＝1.5Hz,1H),4.97(dt,J＝7.7,1.7Hz,1H),4.71(dddd,J＝16.0,12.3,7.5,6.1Hz,2H),3.69(ddd,J＝13.2,10.1,3.0Hz,1H),2.12(ddddt,J＝21.5,10.6,8.2,5.9,2.7Hz,3H),1.98–1.89(m,1H),1.39–1.23(m,12H). 13C NMR(126MHz,Chloroform-d)δ162.16(d,J＝16.1Hz),149.37,141.35(d,J＝3.5Hz),137.35,129.18,124.07,115.83,71.32(dd,J＝24.8,7.0Hz),68.94(d,J＝156.5Hz),30.82(d,J＝15.4Hz),29.27(d,J＝4.4Hz),24.23(ddd,J＝17.6,8.7,4.1Hz). 31P NMR(203MHz,Chloroform-d)δ21.38.IR(薄膜):v 2979,2933,1639,1601,1522,1344,1240,1105,977cm -1.HRMS(ESI/[M+H] +):Calcd.for C 18H 28N 2O 5P m/z 383.1730,found m/z 383.1737. Pale yellow oil, 73% yield (0.2 mmol scale, 56 mg), 97% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =7.46 min, t minor = 11.21 minutes],
Figure PCTCN2022135641-appb-000038
=+1.46 (c=1.21, CHCl 3 ), TLC (PE/EA=1/1; R f =0.5), 1 H NMR (500MHz, Chloroform-d) δ8.37 (d, J=5.1Hz, 1H ),8.32–8.22(m,2H),7.97–7.86(m,2H),5.75(dddd,J＝16.3,11.1,7.3,5.3Hz,1H),5.00(d,J＝1.5Hz,1H), 4.97(dt, J=7.7,1.7Hz,1H),4.71(dddd,J=16.0,12.3,7.5,6.1Hz,2H),3.69(ddd,J=13.2,10.1,3.0Hz,1H),2.12( ddddt, J＝21.5, 10.6, 8.2, 5.9, 2.7Hz, 3H), 1.98–1.89(m, 1H), 1.39–1.23(m, 12H). 13 C NMR (126MHz, Chloroform-d) δ162.16( d,J=16.1Hz),149.37,141.35(d,J=3.5Hz),137.35,129.18,124.07,115.83,71.32(dd,J=24.8,7.0Hz),68.94(d,J=156.5Hz), ( film): v 2979,2933,1639,1601,1522,1344,1240,1105,977cm -1 .HRMS(ESI/[M+H] + ): Calcd.for C 18 H 28 N 2 O 5 P m/ z 383.1730, found m/z 383.1737.
Figure PCTCN2022135641-appb-000039
Figure PCTCN2022135641-appb-000039
淡黄色油状物,72％产率(0.2毫摩尔规格,60毫克),93％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝7.45分钟,t minor＝9.72分钟],
Figure PCTCN2022135641-appb-000040
＝-3.33(c＝0.66,CHCl 3),TLC(PE/EA＝1/1；R f＝0.3), 1H NMR(600MHz,Chloroform-d)δ8.40(d,J＝5.1Hz,1H),8.28–8.22(m,2H),7.94–7.87(m,2H),4.71(dddd,J＝26.0,12.3,7.4,6.1Hz,2H),3.79–3.70(m,1H),3.62(s,3H),2.41(ddd,J＝12.7,6.3,1.5Hz,1H),2.38–2.27(m,3H),1.37–1.24(m,12H). 13C NMR(151MHz,Chloroform-d)δ173.37,162.70(d,J＝15.6Hz),149.44,141.20(d,J＝3.7Hz),129.24,124.07,71.56(dd,J＝43.7,7.0Hz),68.42(d,J＝156.0Hz),51.79,31.11(d,J＝14.3Hz),26.14(d,J＝4.0Hz),24.21(ddd,J＝25.1,12.7,4.2Hz). 31P NMR(202MHz,Chloroform-d)δ20.50.IR(薄膜):v 2980,1735,1638,1600,1522,1345,1239,1105,978cm -1.HRMS(ESI/[M+H] +):Calcd.for C 18H 28N 2O 7P m/z 415.1634,found m/z 415.1631. Pale yellow oil, 72% yield (0.2 mmol scale, 60 mg), 93% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =7.45 min, t minor = 9.72 minutes],
Figure PCTCN2022135641-appb-000040
=-3.33 (c=0.66, CHCl 3 ), TLC (PE/EA=1/1; R f =0.3), 1 H NMR (600MHz, Chloroform-d) δ8.40 (d, J=5.1Hz, 1H ),8.28–8.22(m,2H),7.94–7.87(m,2H),4.71(dddd,J＝26.0,12.3,7.4,6.1Hz,2H),3.79–3.70(m,1H),3.62(s ,3H),2.41(ddd,J＝12.7,6.3,1.5Hz,1H),2.38–2.27(m,3H),1.37–1.24(m,12H). 13 C NMR(151MHz,Chloroform-d)δ173. 37,162.70(d,J=15.6Hz),149.44,141.20(d,J=3.7Hz),129.24,124.07,71.56(dd,J=43.7,7.0Hz),68.42(d,J=156.0Hz),51.79, 31.11(d, J=14.3Hz), 26.14(d, J=4.0Hz), 24.21(ddd, J=25.1,12.7,4.2Hz). 31 P NMR(202MHz, Chloroform-d)δ20.50.IR( thin film): v 2980,1735,1638,1600,1522,1345,1239,1105,978cm -1 .HRMS(ESI/[M+H] + ): Calcd.for C 18 H 28 N 2 O 7 P m/ z 415.1634, found m/z 415.1631.
Figure PCTCN2022135641-appb-000041
Figure PCTCN2022135641-appb-000041
淡黄色油状物,59％产率(0.2毫摩尔规格,48毫克),90％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝11.63分钟,t minor＝19.01分钟],
Figure PCTCN2022135641-appb-000042
＝+0.57(c＝0.91,CHCl 3),TLC(PE/EA＝1/1；R f＝0.3), 1H NMR(500MHz,Chloroform-d)δ8.40(d,J＝5.2Hz,1H),8.26(d,J＝8.7Hz,2H),7.91(d,J＝8.5Hz,2H),4.71(ddt,J＝10.7,7.6,6.3Hz,2H),3.67(ddd,J＝14.1,9.2,4.3Hz,1H),3.54(t,J＝6.6Hz,2H),2.16(tdd,J＝14.4,7.7,4.3Hz,2H),1.83(ddq,J＝15.7,9.3,6.3Hz,1H),1.72(ddq,J＝13.5,9.7,6.7Hz,1H),1.39–1.23(m,12H). 13C NMR(126MHz,Chloroform-d)δ162.08(d,J＝15.7Hz),149.27,141.03(d,J＝3.6Hz),129.08(d,J＝1.7Hz),123.94,71.36(dd,J＝27.2,7.1Hz),68.96(d,J＝156.0Hz),44.38,29.96(d,J＝14.7Hz),28.01(d,J＝4.5Hz),24.07(ddd,J＝18.9,10.4,4.2Hz). 31P NMR(203MHz,Chloroform-d)δ20.65.IR(薄膜):v 2980,1707,1638,1601,1522,1344,1237,1104,980cm -1.HRMS(ESI/[M+H] +):Calcd.for C 17H 27ClN 2O 5P m/z 405.1341,found m/z 405.1349. Pale yellow oil, 59% yield (0.2 mmol scale, 48 mg), 90% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =11.63 min, t minor = 19.01 minutes],
Figure PCTCN2022135641-appb-000042
=+0.57 (c=0.91, CHCl 3 ), TLC (PE/EA=1/1; R f =0.3), 1 H NMR (500MHz, Chloroform-d) δ8.40 (d, J=5.2Hz, 1H ), 8.26(d, J=8.7Hz, 2H), 7.91(d, J=8.5Hz, 2H), 4.71(ddt, J=10.7, 7.6, 6.3Hz, 2H), 3.67(ddd, J=14.1, 9.2,4.3Hz,1H),3.54(t,J=6.6Hz,2H),2.16(tdd,J=14.4,7.7,4.3Hz,2H),1.83(ddq,J=15.7,9.3,6.3Hz,1H ), 1.72 (ddq, J＝13.5, 9.7, 6.7Hz, 1H), 1.39–1.23 (m, 12H). 13 C NMR (126MHz, Chloroform-d) δ162.08 (d, J＝15.7Hz), 149.27 ,141.03(d,J=3.6Hz),129.08(d,J=1.7Hz),123.94,71.36(dd,J=27.2,7.1Hz),68.96(d,J=156.0Hz),44.38,29.96(d , J = 14.7Hz), 28.01 (d, J = 4.5Hz), 24.07 (ddd, J = 18.9, 10.4, 4.2Hz). 31 P NMR (203MHz, Chloroform-d) δ20.65.IR (thin film): v 2980,1707,1638,1601,1522,1344,1237,1104,980cm -1 .HRMS(ESI/[M+H] + ):Calcd.for C 17 H 27 ClN 2 O 5 P m/z 405.1341, found m/z 405.1349.
Figure PCTCN2022135641-appb-000043
Figure PCTCN2022135641-appb-000043
淡黄色油状物,64％产率(0.2毫摩尔规格,38毫克),96％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝95/5,1.0毫升/分钟,λ254nm,t major＝8.11分钟,t minor＝10.47分钟],
Figure PCTCN2022135641-appb-000044
＝+17.26(c＝0.95,CHCl 3),TLC(EA；R f＝0.4), 1H NMR(500MHz,Chloroform-d)δ8.78–8.59(m,2H),8.32(d,J＝5.0Hz,1H),7.67–7.52(m,2H),4.72(dpd,J＝7.6,6.0,4.0Hz,2H),3.86(dq,J＝13.8,6.9Hz,1H),1.54(dd,J＝17.7,6.9Hz,3H),1.37–1.25(m,12H). 13C NMR(126MHz,Chloroform-d)δ161.43(d,J＝16.6Hz),150.60,142.77(d,J＝3.1Hz),122.18,71.30(dd,J＝22.3,7.1Hz),64.41(d,J＝158.1Hz),24.22(ddd,J＝21.7,10.3,4.1Hz),16.89(d,J＝6.0Hz). 31P NMR(202MHz,Chloroform-d)δ22.10.IR(薄膜):v3443,2979,2935,1640,1598,1558,1227,1105,986cm -1.HRMS(ESI/[M+H] +):Calcd.for C 14H 24N 2O 3P m/z 299.1519,found m/z 299.1514. Pale yellow oil, 64% yield (0.2 mmol scale, 38 mg), 96% ee [Daicel Chiralcel OD-3, Hexanes/IPA=95/5, 1.0 ml/min, λ254nm, t major =8.11 min, t minor = 10.47 minutes],
Figure PCTCN2022135641-appb-000044
=+17.26 (c=0.95, CHCl 3 ), TLC (EA; R f =0.4), 1 H NMR (500 MHz, Chloroform-d) δ8.78–8.59 (m, 2H), 8.32 (d, J=5.0 Hz,1H),7.67–7.52(m,2H),4.72(dpd,J=7.6,6.0,4.0Hz,2H),3.86(dq,J=13.8,6.9Hz,1H),1.54(dd,J= 17.7,6.9Hz,3H),1.37–1.25(m,12H). 13 C NMR(126MHz,Chloroform-d)δ161.43(d,J=16.6Hz),150.60,142.77(d,J=3.1Hz) ,122.18,71.30(dd,J=22.3,7.1Hz),64.41(d,J=158.1Hz),24.22(ddd,J=21.7,10.3,4.1Hz),16.89(d,J=6.0Hz). 31 P NMR(202MHz,Chloroform-d)δ22.10.IR(thin film):v3443,2979,2935,1640,1598,1558,1227,1105,986cm -1 .HRMS(ESI/[M+H] + ): Calcd. for C 14 H 24 N 2 O 3 P m/z 299.1519, found m/z 299.1514.
Figure PCTCN2022135641-appb-000045
Figure PCTCN2022135641-appb-000045
0.05摩尔％催化剂，室温反应12小时。淡黄色油状物,70％产率(0.2毫摩尔规格,46毫克),99％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝98/2,1.0毫升/分钟,λ254nm,t major＝6.48分钟,t minor＝8.01分钟],
Figure PCTCN2022135641-appb-000046
＝+53.87(c＝1.24,CHCl 3),TLC(PE/EA＝1/1；R f＝0.6), 1H NMR(500MHz,Chloroform-d)δ8.30(d,J＝4.8Hz,1H),7.68(d,J＝8.4Hz,2H),7.37(d,J＝8.4Hz,2H),4.73(ddtd,J＝12.5,8.0,6.2,1.8Hz,2H),3.80(dq,J＝13.7,6.9Hz,1H),1.53(dd,J＝17.9,6.9Hz,3H),1.37–1.25(m,12H). 13C NMR(126MHz,Chloroform-d)δ161.96(d,J＝16.6Hz),137.07(d,J＝1.3Hz),134.69(d,J＝3.1Hz),129.72(d,J＝1.5Hz),129.06,71.13(dd,J＝13.3,7.1Hz),64.20(d,J＝158.5Hz), 24.25(ddd,J＝22.7,7.8,4.2Hz),17.06(d,J＝5.7Hz). 31P NMR(203MHz,Chloroform-d)δ22.88.IR(薄膜):v 2978,2934,1638,1595,1490,1374,1221,1105,978cm -1.HRMS(ESI/[M+H] +):Calcd.for C 15H 24ClNO 3P m/z 332.1177,found m/z 332.1179. 0.05 mol% catalyst, reacted at room temperature for 12 hours. Pale yellow oil, 70% yield (0.2 mmol scale, 46 mg), 99% ee [Daicel Chiralcel OD-3, Hexanes/IPA=98/2, 1.0 ml/min, λ254nm, t major =6.48 min, t minor = 8.01 minutes],
Figure PCTCN2022135641-appb-000046
=+53.87 (c=1.24, CHCl 3 ), TLC (PE/EA=1/1; R f =0.6), 1 H NMR (500MHz, Chloroform-d) δ8.30 (d, J=4.8Hz, 1H ),7.68(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),4.73(ddtd,J=12.5,8.0,6.2,1.8Hz,2H),3.80(dq,J= 13.7, 6.9Hz, 1H), 1.53 (dd, J＝17.9, 6.9Hz, 3H), 1.37–1.25 (m, 12H). 13 C NMR (126MHz, Chloroform-d) δ161.96 (d, J＝16.6 Hz), 137.07(d, J=1.3Hz), 134.69(d, J=3.1Hz), 129.72(d, J=1.5Hz), 129.06, 71.13(dd, J=13.3,7.1Hz), 64.20(d ,J=158.5Hz), 24.25(ddd,J=22.7,7.8,4.2Hz),17.06(d,J=5.7Hz). 31 P NMR(203MHz,Chloroform-d)δ22.88.IR(thin film): v 2978,2934,1638,1595,1490,1374,1221,1105,978cm -1 .HRMS(ESI/[M+H] + ):Calcd.for C 15 H 24 ClNO 3 P m/z 332.1177,found m /z 332.1179.
Figure PCTCN2022135641-appb-000047
Figure PCTCN2022135641-appb-000047
0.5摩尔％催化剂，20摩尔％氢氧化钾，室温反应64小时。淡黄色油状物,68％产率(0.2毫摩尔规格,42毫克),96％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝98/2,1.0毫升/分钟,λ254nm,t minor＝8.37分钟,t major＝10.50分钟],
Figure PCTCN2022135641-appb-000048
＝-2.44(c＝0.64,CHCl 3),TLC(PE/EA＝1/1；R f＝0.6), 1H NMR(600MHz,Chloroform-d)δ8.30(d,J＝4.7Hz,1H),7.64(d,J＝7.9Hz,2H),7.20(d,J＝7.8Hz,2H),4.74(dp,J＝7.4,6.1Hz,2H),3.78(dq,J＝13.7,6.9Hz,1H),2.38(s,3H),1.53(dd,J＝17.9,6.9Hz,3H),1.37–1.25(m,12H). 13C NMR(126MHz,Chloroform-d)δ163.20(d,J＝16.5Hz),141.38,133.68(d,J＝3.1Hz),129.46,128.54,71.05(dd,J＝7.0,3.7Hz),64.22(d,J＝158.5Hz),25.14–23.75(m),21.71,17.16(d,J＝5.5Hz). 31P NMR(202MHz,Chloroform-d)δ23.36.IR(薄膜):v 2920,2850,1658,1632,1468cm -1.HRMS(ESI/[M+H] +):Calcd.for C 16H 27NO 3P m/z 312.1723,found m/z 312.1742. 0.5 mol% catalyst, 20 mol% potassium hydroxide, react at room temperature for 64 hours. Pale yellow oil, 68% yield (0.2 mmol scale, 42 mg), 96% ee [Daicel Chiralcel OD-3, Hexanes/IPA=98/2, 1.0 ml/min, λ254nm, t minor =8.37 min, t major = 10.50 minutes],
Figure PCTCN2022135641-appb-000048
=-2.44 (c=0.64, CHCl 3 ), TLC (PE/EA=1/1; R f =0.6), 1 H NMR (600MHz, Chloroform-d) δ8.30 (d, J=4.7Hz, 1H ),7.64(d,J=7.9Hz,2H),7.20(d,J=7.8Hz,2H),4.74(dp,J=7.4,6.1Hz,2H),3.78(dq,J=13.7,6.9Hz ,1H),2.38(s,3H),1.53(dd,J＝17.9,6.9Hz,3H),1.37–1.25(m,12H). 13 C NMR(126MHz,Chloroform-d)δ163.20(d, J=16.5Hz), 141.38, 133.68(d, J=3.1Hz), 129.46, 128.54, 71.05(dd, J=7.0, 3.7Hz), 64.22(d, J=158.5Hz), 25.14–23.75(m) , 21.71, 17.16 (d, J=5.5Hz). 31 P NMR (202MHz, Chloroform-d) δ23.36.IR (thin film): v 2920, 2850, 1658, 1632, 1468cm -1 .HRMS (ESI/[ M+H] + ): Calcd. for C 16 H 27 NO 3 P m/z 312.1723, found m/z 312.1742.
Figure PCTCN2022135641-appb-000049
Figure PCTCN2022135641-appb-000049
室温反应48小时。淡黄色油状物,71％产率(0.2毫摩尔规格,43毫克),98％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝8.28分钟,t minor＝10.84分钟],
Figure PCTCN2022135641-appb-000050
＝74.89(c＝1.08,CHCl 3),TLC(EA；R f＝0.4), 1H NMR(500MHz,Chloroform-d)δ8.06(d,J＝4.6Hz,1H),6.81–6.51(m,1H),6.07(d,J＝3.3Hz,1H),4.73(dpd,J＝7.5,6.2,4.6Hz,2H),3.71(dq,J＝14.0,6.9Hz,1H),2.35(s,3H),1.55(dd,J＝18.0,7.0Hz,3H),1.32(ddd,J＝17.3,9.6,6.1Hz,12H). 13C NMR(126MHz,Chloroform-d)δ156.08,151.88(d,J＝15.3Hz),150.30(d,J＝3.7Hz),116.93,108.40,71.11(dd,J＝10.5,7.1Hz),63.80(d,J＝156.2Hz),25.26–23.52(m),17.07(d,J＝5.3Hz),14.15. 31P NMR(203MHz,Chloroform-d)δ23.16.IR(薄膜):v 3448,2978,2931,1638,1531,1221,1105,978cm -1.HRMS(ESI/[M+H] +):Calcd.for C 14H 25NO 4P m/z 302.1516,found m/z 302.1521. React at room temperature for 48 hours. Pale yellow oil, 71% yield (0.2 mmol scale, 43 mg), 98% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =8.28 min, t minor = 10.84 minutes],
Figure PCTCN2022135641-appb-000050
=74.89 (c=1.08, CHCl 3 ), TLC (EA; R f =0.4), 1 H NMR (500MHz, Chloroform-d) δ8.06 (d, J=4.6Hz, 1H), 6.81–6.51 (m ,1H),6.07(d,J=3.3Hz,1H),4.73(dpd,J=7.5,6.2,4.6Hz,2H),3.71(dq,J=14.0,6.9Hz,1H),2.35(s, 3H), 1.55(dd, J＝18.0, 7.0Hz, 3H), 1.32(ddd, J＝17.3, 9.6, 6.1Hz, 12H). 13 C NMR (126MHz, Chloroform-d) δ156.08, 151.88(d, J =15.3Hz), 150.30(d, J=3.7Hz), 116.93, 108.40, 71.11(dd, J=10.5,7.1Hz), 63.80(d, J=156.2Hz), 25.26–23.52(m), 17.07( d, J=5.3Hz), 14.15. 31 P NMR (203MHz, Chloroform-d) δ23.16.IR (thin film): v 3448,2978,2931,1638,1531,1221,1105,978cm -1 .HRMS( ESI/[M+H] + ): Calcd. for C 14 H 25 NO 4 P m/z 302.1516, found m/z 302.1521.
反应式2：Reaction 2:
Figure PCTCN2022135641-appb-000051
Figure PCTCN2022135641-appb-000051
反应式2中，步骤1)：在2毫升反应瓶中加入苄胺(0.2毫摩尔)和400微升氯仿，在0摄氏度冷却5分钟后，加入化合物I(0.2毫摩尔)，在该温度下继续搅拌10小时得到亚胺中间体II以备用。步骤2)：在另一4毫升反应瓶中加入催化剂Q-4(0.05摩尔％)和碳酸钾(20摩尔％)溶解于1.6毫升甲苯中。在-20摄氏度搅拌5分钟后，步骤1)中的混合物直接加入到该4毫升反应瓶中继续在-20摄氏度搅拌12小时，升温至室温另外反应12小时。反应结束后，反应液直接通过去活化硅胶过滤除去碳酸钾，减压旋蒸除去溶剂，残留物经过去活化硅胶柱层析(石油醚/乙酸乙酯＝90/10-70/30)分离获得目标产物II'。In reaction formula 2, step 1): add benzylamine (0.2 mmol) and 400 microliters of chloroform in 2 milliliter reaction vials, after cooling at 0 degree Celsius for 5 minutes, add compound I (0.2 mmol), at this temperature Stirring was continued for 10 hours to obtain imine intermediate II for future use. Step 2): Catalyst Q-4 (0.05 mol%) and potassium carbonate (20 mol%) were added and dissolved in 1.6 ml of toluene into another 4 ml reaction flask. After stirring at -20°C for 5 minutes, the mixture in step 1) was directly added to the 4 ml reaction flask and continued to stir at -20°C for 12 hours, then warmed up to room temperature and reacted for another 12 hours. After the reaction, the reaction solution was directly filtered through deactivated silica gel to remove potassium carbonate, the solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by deactivated silica gel column chromatography (petroleum ether/ethyl acetate=90/10-70/30) to obtain Target product II'.
下列为挑选的产物II'的表征：The following are characterizations of selected products II':
Figure PCTCN2022135641-appb-000052
Figure PCTCN2022135641-appb-000052
淡黄色油状物,63％产率(0.2毫摩尔规格,52毫克),94％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝13.20分钟,t minor＝18.00分钟],
Figure PCTCN2022135641-appb-000053
＝-133.19(c＝1.52,CHCl 3),TLC(PE/EA＝1/1；R f＝0.5), 1H NMR(500MHz,Chloroform-d)δ8.26–8.18(m,2H),7.88(d,J＝4.8Hz,1H),7.83–7.75(m,2H),7.22–7.16(m,2H),7.16–7.12(m,1H),7.11–7.05(m,2H),4.79(dh,J＝7.6,6.1Hz,2H),3.81(ddd,J＝12.1,10.8,2.5Hz,1H),3.38(ddd,J＝13.8,7.6,2.5Hz,1H),3.23(ddd,J＝13.8,10.9,7.1Hz,1H),1.42–1.28(m,12H). 13C NMR(126MHz,Chloroform-d)δ162.11(d,J＝17.5Hz),149.32,141.27(d,J＝3.1Hz),138.26(d,J＝16.5Hz),129.73,129.06(d,J＝1.4Hz),128.49,126.69,124.02,71.56(d,J＝157.8Hz),71.54(dd,J＝16.7,7.0Hz),37.15(d,J＝4.1Hz),24.29(ddd,J＝19.9,8.2,4.3Hz). 31P NMR(203MHz,Chloroform-d)δ20.76.IR(薄膜):v 2979,2932,1638,1600,1521,1343,1247,1104,979cm -1.HRMS(ESI/[M+H] +):Calcd.for C 21H 28N 2O 5P m/z 419.1730,found m/z 419.1729. Pale yellow oil, 63% yield (0.2 mmol, 52 mg), 94% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =13.20 min, t minor = 18.00 minutes],
Figure PCTCN2022135641-appb-000053
=-133.19 (c=1.52, CHCl 3 ), TLC (PE/EA=1/1; R f =0.5), 1 H NMR (500MHz, Chloroform-d) δ8.26–8.18 (m, 2H), 7.88 (d,J=4.8Hz,1H),7.83–7.75(m,2H),7.22–7.16(m,2H),7.16–7.12(m,1H),7.11–7.05(m,2H),4.79(dh ,J=7.6,6.1Hz,2H),3.81(ddd,J=12.1,10.8,2.5Hz,1H),3.38(ddd,J=13.8,7.6,2.5Hz,1H),3.23(ddd,J=13.8 ,10.9,7.1Hz,1H),1.42–1.28(m,12H). 13 C NMR(126MHz,Chloroform-d)δ162.11(d,J=17.5Hz),149.32,141.27(d,J=3.1Hz ), 138.26(d, J=16.5Hz), 129.73, 129.06(d, J=1.4Hz), 128.49, 126.69, 124.02, 71.56(d, J=157.8Hz), 71.54(dd, J=16.7, 7.0Hz ), 37.15 (d, J=4.1Hz), 24.29 (ddd, J=19.9, 8.2, 4.3Hz). 31 P NMR (203MHz, Chloroform-d) δ20.76.IR (thin film): v 2979, 2932, 1638,1600,1521,1343,1247,1104,979cm -1 .HRMS(ESI/[M+H] + ):Calcd.for C 21 H 28 N 2 O 5 P m/z 419.1730,found m/z 419.1729 .
Figure PCTCN2022135641-appb-000054
Figure PCTCN2022135641-appb-000054
淡黄色油状物,79％产率(0.2毫摩尔规格,69毫克),92％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝10.68分钟,t minor＝15.46分钟],
Figure PCTCN2022135641-appb-000055
＝-90.46(c＝1.01,CHCl 3),TLC(PE/EA＝1/1；R f＝0.4), 1H NMR(500MHz,Chloroform-d)δ8.23(d,J＝8.7Hz,2H),7.91(d,J＝4.8Hz,1H),7.81(d,J＝8.6Hz,2H),7.10–6.99(m,2H),6.94–6.81(m,2H),4.78(ddq,J＝12.2,7.2,6.1Hz,2H),3.76(ddd,J＝12.3,10.8,2.6Hz,1H),3.34(ddd,J＝14.0,7.6,2.7Hz,1H),3.21(ddd,J＝13.9,10.8,7.4Hz,1H),1.41–1.26(m,12H). 13C NMR(126MHz,Chloroform-d)δ162.07(d,J＝17.3Hz),161.60(d,J＝244.9Hz),149.22,140.95(d,J＝3.1Hz),133.76(dd,J＝16.6,3.2Hz),130.98(d,J＝7.9Hz),128.92(d,J＝1.4Hz),123.90,115.14(d,J＝21.2Hz),71.43(d,J＝157.6Hz),71.43(dd,J＝14.9,7.1Hz),36.22(d,J＝4.1Hz),26.83–21.05(m). 31P NMR(203MHz,Chloroform-d)δ20.46. 19F NMR(565MHz,Chloroform-d)δ-116.38.IR(薄膜):v 2980,2934,1369,1600,1521,1509,1375,1344,1219,1104,981cm -1.HRMS(ESI/[M+H] +):Calcd.for C 21H 27FN 2O 5P m/z 437.1636,found m/z 437.1653. Pale yellow oil, 79% yield (0.2 mmol scale, 69 mg), 92% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =10.68 min, t minor = 15.46 minutes],
Figure PCTCN2022135641-appb-000055
=-90.46 (c=1.01, CHCl 3 ), TLC (PE/EA=1/1; R f =0.4), 1 H NMR (500MHz, Chloroform-d) δ8.23 (d, J=8.7Hz, 2H ),7.91(d,J=4.8Hz,1H),7.81(d,J=8.6Hz,2H),7.10–6.99(m,2H),6.94–6.81(m,2H),4.78(ddq,J= 12.2,7.2,6.1Hz,2H),3.76(ddd,J=12.3,10.8,2.6Hz,1H),3.34(ddd,J=14.0,7.6,2.7Hz,1H),3.21(ddd,J=13.9, 10.8,7.4Hz,1H),1.41–1.26(m,12H). 13 C NMR(126MHz,Chloroform-d)δ162.07(d,J=17.3Hz),161.60(d,J=244.9Hz),149.22 ,140.95(d,J=3.1Hz),133.76(dd,J=16.6,3.2Hz),130.98(d,J=7.9Hz),128.92(d,J=1.4Hz),123.90,115.14(d,J ＝21.2Hz), 71.43(d, J＝157.6Hz), 71.43(dd, J＝14.9, 7.1Hz), 36.22(d, J＝4.1Hz), 26.83–21.05(m). 31 P NMR (203MHz, Chloroform-d) δ20.46. 19 F NMR (565MHz, Chloroform-d) δ-116.38. IR (film): v 2980,2934,1369,1600,1521,1509,1375,1344,1219,1104,981cm - 1.HRMS (ESI/[M+H] + ):Calcd.for C 21 H 27 FN 2 O 5 P m/z 437.1636,found m/z 437.1653.
Figure PCTCN2022135641-appb-000056
Figure PCTCN2022135641-appb-000056
淡黄色油状物,68％产率(0.2毫摩尔规格,58毫克),88％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝16.05分钟,t minor＝20.66分钟],
Figure PCTCN2022135641-appb-000057
＝-148.55(c＝1.10,CHCl 3),TLC(PE/EA＝1/1；R f＝0.5), 1H NMR(500MHz,Chloroform-d)δ8.29–8.16(m,2H),7.87(d,J＝4.8Hz,1H),7.84–7.74(m,2H),7.05–6.92(m,2H),6.79–6.65(m,2H),4.78(dtd,J＝7.5,6.2,5.1Hz,2H),3.80–3.73(m,1H),3.72(s,3H),3.31(ddd,J＝14.0,7.3,2.5Hz,1H),3.16(ddd,J＝14.0,10.9,6.8Hz,1H),1.43–1.26(m,12H). 13C NMR(126MHz,Chloroform-d)δ162.04(d,J＝17.7Hz),158.35,149.28,141.28(d,J＝3.1Hz),130.69,130.21(d,J＝16.9Hz),129.07,124.00,113.83,71.80(d,J＝157.4Hz),71.46(dd,J＝14.5,7.1Hz),55.33,36.22(d,J＝4.0Hz),24.27(ddd,J＝19.3,7.3,4.2Hz). 31P NMR(202MHz,Chloroform-d)δ20.91.IR(薄膜):v 2979,2934,1639,1600,1512,1344,1245,1177,1105,978cm -1.HRMS(ESI/[M+H] +):Calcd.for C 22H 30N 2O 6P m/z 449.1836,found m/z 449.1854. Pale yellow oil, 68% yield (0.2 mmol scale, 58 mg), 88% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =16.05 min, t minor = 20.66 minutes],
Figure PCTCN2022135641-appb-000057
=-148.55 (c=1.10, CHCl 3 ), TLC (PE/EA=1/1; R f =0.5), 1 H NMR (500MHz, Chloroform-d) δ8.29–8.16 (m, 2H), 7.87 (d,J=4.8Hz,1H),7.84–7.74(m,2H),7.05–6.92(m,2H),6.79–6.65(m,2H),4.78(dtd,J=7.5,6.2,5.1Hz ,2H),3.80–3.73(m,1H),3.72(s,3H),3.31(ddd,J＝14.0,7.3,2.5Hz,1H),3.16(ddd,J＝14.0,10.9,6.8Hz,1H ),1.43–1.26(m,12H) .13 C NMR(126MHz,Chloroform-d)δ162.04(d,J＝17.7Hz),158.35,149.28,141.28(d,J＝3.1Hz),130.69,130.21 (d, J=16.9Hz),129.07,124.00,113.83,71.80(d,J=157.4Hz),71.46(dd,J=14.5,7.1Hz),55.33,36.22(d,J=4.0Hz),24.27 (ddd, J=19.3, 7.3, 4.2Hz). 31 P NMR (202MHz, Chloroform-d) δ20.91.IR (thin film): v 2979,2934,1639,1600,1512,1344,1245,1177,1105 ,978cm -1 .HRMS(ESI/[M+H] + ):Calcd.for C 22 H 30 N 2 O 6 P m/z 449.1836,found m/z 449.1854.
Figure PCTCN2022135641-appb-000058
Figure PCTCN2022135641-appb-000058
无色油状物,56％产率(0.2毫摩尔规格,5毫克),84％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝6.80分钟,t minor＝8.22分钟],
Figure PCTCN2022135641-appb-000059
＝-153.92(c＝1.00,CHCl 3),TLC(PE/EA＝1/1；R f＝0.6), 1H NMR(500MHz,Chloroform-d)δ8.21(d,J＝8.7Hz,2H),7.82(d,J＝4.6Hz,1H),7.78(d,J＝8.7Hz,2H),6.91(d,J＝ 8.5Hz,2H),6.66(d,J＝8.4Hz,2H),4.79(dpd,J＝7.6,6.2,3.0Hz,2H),3.74(td,J＝11.1,2.6Hz,1H),3.30(ddd,J＝13.9,7.2,2.6Hz,1H),3.13(ddd,J＝13.9,11.0,7.0Hz,1H),1.42–1.25(m,12H),0.92(s,9H),0.10(s,6H). 13C NMR(126MHz,Chloroform-d)δ161.96(d,J＝18.0Hz),154.36,149.28,141.27(d,J＝2.8Hz),130.88(d,J＝16.8Hz),130.68,129.04,123.97,120.09,71.83(d,J＝158.5Hz),71.43(dd,J＝12.9,6.9Hz),36.31(d,J＝4.0Hz),25.80,24.47–24.11(m),18.35,-4.32. 31P NMR(203MHz,Chloroform-d)δ20.93.IR(薄膜):v 2930,2958,1640,1601,1523,1509,1344,1250,1104,981cm -1.HRMS(ESI/[M+H] +):Calcd.for C 27H 42N 2O 6PSi m/z 549.2544,found m/z 549.2544. Colorless oil, 56% yield (0.2 mmol, 5 mg), 84% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =6.80 min, t minor = 8.22 minutes],
Figure PCTCN2022135641-appb-000059
=-153.92 (c=1.00, CHCl 3 ), TLC (PE/EA=1/1; R f =0.6), 1 H NMR (500MHz, Chloroform-d) δ8.21 (d, J=8.7Hz, 2H ),7.82(d,J=4.6Hz,1H),7.78(d,J=8.7Hz,2H),6.91(d,J=8.5Hz,2H),6.66(d,J=8.4Hz,2H), 4.79(dpd, J=7.6, 6.2, 3.0Hz, 2H), 3.74(td, J=11.1, 2.6Hz, 1H), 3.30(ddd, J=13.9, 7.2, 2.6Hz, 1H), 3.13(ddd, J＝13.9,11.0,7.0Hz,1H),1.42–1.25(m,12H),0.92(s,9H),0.10(s,6H). 13 C NMR(126MHz,Chloroform-d)δ161.96(d ,J=18.0Hz),154.36,149.28,141.27(d,J=2.8Hz),130.88(d,J=16.8Hz),130.68,129.04,123.97,120.09,71.83(d,J=158.5Hz),71.43 (dd, J=12.9, 6.9Hz), 36.31(d, J=4.0Hz), 25.80, 24.47–24.11(m), 18.35, -4.32. 31 P NMR (203MHz, Chloroform-d) δ20.93.IR (Film):v 2930,2958,1640,1601,1523,1509,1344,1250,1104,981cm -1 .HRMS(ESI/[M+H] + ): Calcd.for C 27 H 42 N 2 O 6 PSi m/z 549.2544, found m/z 549.2544.
Figure PCTCN2022135641-appb-000060
Figure PCTCN2022135641-appb-000060
淡黄色油状物,71％产率(0.2毫摩尔规格,69毫克),87％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝12.83分钟,t minor＝12.76分钟],
Figure PCTCN2022135641-appb-000061
＝-161.70(c＝1.25,CHCl 3),TLC(PE/EA＝1/1；R f＝0.5), 1H NMR(500MHz,Chloroform-d)δ8.27–8.20(m,2H),8.02(d,J＝4.9Hz,1H),7.87–7.79(m,2H),7.25(d,J＝8.5Hz,1H),7.22(d,J＝2.1Hz,1H),6.94(dd,J＝8.2,2.1Hz,1H),4.83–4.67(m,2H),3.77(ddd,J＝13.4,10.6,2.9Hz,1H),3.30(ddd,J＝14.0,7.8,2.9Hz,1H),3.22(ddd,J＝13.9,10.5,7.8Hz,1H),1.39–1.26(m,12H). 13C NMR(126MHz,Chloroform-d)δ162.61(d,J＝16.2Hz),149.45,140.91(d,J＝3.2Hz),138.59(d,J＝16.5Hz),132.37,131.58,130.77,130.34,129.15,129.14,124.09,71.73(dd,J＝20.6,7.1Hz),70.91(d,J＝156.5Hz),36.44(d,J＝4.0Hz),24.24(ddd,J＝15.0,9.4,4.2Hz). 31P NMR(203MHz,Chloroform-d)δ19.83.IR(薄膜):v 2979,2934,1639,1600,1522,1469,1344,1248,1101,979cm -1.HRMS(ESI/[M+H] +):Calcd.for C 21H 26Cl 2N 2O 5P m/z 487.0951,found m/z 487.0953. Pale yellow oil, 71% yield (0.2 mmol scale, 69 mg), 87% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =12.83 min, t minor = 12.76 minutes],
Figure PCTCN2022135641-appb-000061
=-161.70 (c=1.25, CHCl 3 ), TLC (PE/EA=1/1; R f =0.5), 1 H NMR (500MHz, Chloroform-d) δ8.27–8.20 (m, 2H), 8.02 (d,J=4.9Hz,1H),7.87–7.79(m,2H),7.25(d,J=8.5Hz,1H),7.22(d,J=2.1Hz,1H),6.94(dd,J= 8.2,2.1Hz,1H),4.83–4.67(m,2H),3.77(ddd,J＝13.4,10.6,2.9Hz,1H),3.30(ddd,J＝14.0,7.8,2.9Hz,1H),3.22 (ddd, J=13.9, 10.5, 7.8Hz, 1H), 1.39–1.26(m, 12H). 13 C NMR (126MHz, Chloroform-d) δ162.61(d, J=16.2Hz), 149.45, 140.91( d,J=3.2Hz),138.59(d,J=16.5Hz),132.37,131.58,130.77,130.34,129.15,129.14,124.09,71.73(dd,J=20.6,7.1Hz),70.91(d,J= 156.5Hz), 36.44 (d, J=4.0Hz), 24.24 (ddd, J=15.0, 9.4, 4.2Hz). 31 P NMR (203MHz, Chloroform-d) δ19.83.IR (thin film): v 2979, 2934,1639,1600,1522,1469,1344,1248,1101,979cm -1 .HRMS(ESI/[M+H] + ):Calcd.for C 21 H 26 Cl 2 N 2 O 5 P m/z 487.0951 ,found m/z 487.0953.
Figure PCTCN2022135641-appb-000062
Figure PCTCN2022135641-appb-000062
淡黄色油状物,75％产率(0.2毫摩尔规格,69毫克),90％ee[Daicel Chiralcel OD-3,Hexanes/IPA＝97/3,1.0毫升/分钟,λ280nm,t major＝17.33分钟,t minor＝23.05分钟],
Figure PCTCN2022135641-appb-000063
＝-176.44(c＝1.11,CHCl 3),TLC(PE/EA＝1/1；R f＝0.5), 1H NMR(500MHz,Chloroform-d)δ8.31–8.12(m,2H),7.95(d,J＝4.9Hz,1H),7.88–7.75(m,2H),6.62(d,J＝7.9Hz,1H),6.59(d,J＝1.8Hz,1H),6.52(dd,J＝8.0,1.7Hz,1H),5.85(dd,J＝8.4,1.5Hz,2H),4.77(dh,J＝7.7,6.1Hz,2H),3.75(ddd,J＝12.5,10.9,2.5Hz,1H),3.28(ddd,J＝13.9,7.5,2.5Hz,1H),3.14(ddd,J＝14.0,10.8,6.9Hz,1H),1.40–1.26(m,12H). 13C NMR(126MHz,Chloroform-d)δ162.10(d,J＝17.2Hz),149.31,147.67,146.25,141.23 (d,J＝3.2Hz),131.97(d,J＝16.9Hz),129.07(d,J＝1.4Hz),124.02,122.70,109.85,108.21,100.99,71.68(d,J＝157.0Hz),71.50(dd,J＝16.2,7.1Hz),36.87(d,J＝3.9Hz),25.77–23.03(m). 31P NMR(203MHz,Chloroform-d)δ20.64.IR(薄膜):v 2979,2933,1638,1601,1522,1489,1443,1344,1244,1103,1037,978cm -1.HRMS(ESI/[M+H] +):Calcd.for C 22H 28N 2O 7P m/z 463.1629,found m/z 463.1632. Pale yellow oil, 75% yield (0.2 mmol scale, 69 mg), 90% ee [Daicel Chiralcel OD-3, Hexanes/IPA=97/3, 1.0 ml/min, λ280nm, t major =17.33 min, t minor = 23.05 minutes],
Figure PCTCN2022135641-appb-000063
=-176.44 (c=1.11, CHCl 3 ), TLC (PE/EA=1/1; R f =0.5), 1 H NMR (500MHz, Chloroform-d) δ8.31–8.12 (m, 2H), 7.95 (d,J=4.9Hz,1H),7.88–7.75(m,2H),6.62(d,J=7.9Hz,1H),6.59(d,J=1.8Hz,1H),6.52(dd,J= 8.0,1.7Hz,1H),5.85(dd,J＝8.4,1.5Hz,2H),4.77(dh,J＝7.7,6.1Hz,2H),3.75(ddd,J＝12.5,10.9,2.5Hz,1H ), 3.28 (ddd, J＝13.9, 7.5, 2.5Hz, 1H), 3.14 (ddd, J＝14.0, 10.8, 6.9Hz, 1H), 1.40–1.26 (m, 12H). 13 C NMR (126MHz, Chloroform -d) δ162.10(d, J=17.2Hz), 149.31, 147.67, 146.25, 141.23 (d, J=3.2Hz), 131.97(d, J=16.9Hz), 129.07(d, J=1.4Hz) ,124.02,122.70,109.85,108.21,100.99,71.68(d,J=157.0Hz),71.50(dd,J=16.2,7.1Hz),36.87(d,J=3.9Hz),25.77–23.03(m). 31 P NMR (203MHz, Chloroform-d) δ20.64.IR (thin film): v 2979,2933,1638,1601,1522,1489,1443,1344,1244,1103,1037,978cm -1 .HRMS(ESI/ [M+H] + ): Calcd. for C 22 H 28 N 2 O 7 P m/z 463.1629, found m/z 463.1632.
实施例4：十克级规格，一步重结晶纯化制备高纯度手性α-氨基膦酸Example 4: Preparation of high-purity chiral α-aminophosphonic acid with one-step recrystallization and purification at ten-gram scale
反应式1：1.0ppm(0.0001摩尔％)催化剂负载，十克级规格制备手性α-氨基膦酸Reaction formula 1: 1.0ppm (0.0001mol%) catalyst loading, preparation of chiral α-aminophosphonic acid in ten-gram scale
Figure PCTCN2022135641-appb-000064
Figure PCTCN2022135641-appb-000064
步骤1)：在250毫升干燥史莱克管中加入对硝基苄胺(50毫摩尔，7.61克)和50毫升干燥氯仿，在-20摄氏度冷却5分钟后，缓慢滴加化合物I(51毫摩尔，10.6克溶解于30毫升干燥氯仿中)。加料结束后，缓慢升温至0摄氏度，并在该温度下继续搅拌24小时。NMR检测转化率98％，纯度93％。不经后处理，直接用于下一步。Step 1): Add p-nitrobenzylamine (50 mmol, 7.61 g) and 50 ml of dry chloroform in a 250 ml dry Shrek tube, and slowly add compound I (51 mmol , 10.6 g dissolved in 30 ml dry chloroform). After the addition, the temperature was slowly raised to 0° C., and stirring was continued at this temperature for 24 hours. According to NMR, the conversion rate was 98%, and the purity was 93%. It was directly used in the next step without post-processing.
步骤2)：在1000毫升反应瓶中加入催化剂Q-4(0.0001摩尔％,0.05毫克),碳酸钾(30摩尔％,2.1克)和4毫升去离子水溶解于400毫升甲苯中。在-20摄氏度搅拌10分钟后，步骤1)中的混合物直接加入到该1000毫升反应瓶中继续在-20摄氏度搅拌10天(转化率92％，ee＝93％)。反应结束后，反应液直接通过去活化硅胶过滤除去碳酸钾，减压除去溶剂得到淡黄色油状物，用于下一步反应。Step 2): Catalyst Q-4 (0.0001 mol%, 0.05 mg), potassium carbonate (30 mol%, 2.1 g) and 4 ml of deionized water were dissolved in 400 ml of toluene in a 1000 ml reaction flask. After stirring at -20°C for 10 minutes, the mixture in step 1) was directly added to the 1000 ml reaction flask and continued to stir at -20°C for 10 days (conversion rate 92%, ee=93%). After the reaction, the reaction solution was directly filtered through deactivated silica gel to remove potassium carbonate, and the solvent was removed under reduced pressure to obtain a light yellow oil, which was used for the next reaction.
步骤3)：将步骤2)所得油状物与四氢呋喃(100毫升)混合后，加入3N稀盐酸(约30毫升)将pH调至2。室温下搅拌过夜，TLC检测反应完全后。减压旋蒸除去四氢呋喃，水相用乙醚洗涤三次。后加入氨水将pH调至12，再用二氯甲烷萃取。有机相浓缩后得到淡黄色油状物。将得到的油状物和6N稀盐酸(50毫升,300毫摩尔,6当量)混合，100摄氏度加热回流过夜，核磁检测至反应完全。将水旋蒸除去，得到半固体产物。向其中加入乙醇(15毫升)加热至完全溶解，再滴加甲基环氧乙烷(7.5毫升)。然后将其置于室温下搅拌30分钟，抽滤后滤饼用乙醇/甲基环氧乙烷(15毫升，V/V＝2:1)洗涤，得到产物IV，呈白色固体4.5克，总产率72％。Step 3): After mixing the oil obtained in step 2) with THF (100 mL), 3N dilute hydrochloric acid (about 30 mL) was added to adjust the pH to 2. Stir overnight at room temperature, and TLC detects that the reaction is complete. Tetrahydrofuran was removed by rotary evaporation under reduced pressure, and the aqueous phase was washed three times with ether. Aqueous ammonia was then added to adjust the pH to 12, followed by extraction with dichloromethane. The organic phase was concentrated to give a pale yellow oil. The obtained oil was mixed with 6N dilute hydrochloric acid (50 ml, 300 mmol, 6 eq), heated to reflux at 100°C overnight, and the reaction was detected by NMR until the reaction was complete. The water was removed by rotary evaporation to obtain a semi-solid product. Ethanol (15 ml) was added thereto and heated until completely dissolved, and then methyloxirane (7.5 ml) was added dropwise. Then it was placed at room temperature and stirred for 30 minutes, and the filter cake was washed with ethanol/methyloxirane (15 milliliters, V/V=2:1) after suction filtration to obtain product IV, which was 4.5 grams of white solid. Yield 72%.
反应式2：对氯苄胺出发，室温下十克规格制备α-氨基膦酸Reaction formula 2: Starting from p-chlorobenzylamine, prepare α-aminophosphonic acid in ten grams at room temperature
Figure PCTCN2022135641-appb-000065
Figure PCTCN2022135641-appb-000065
步骤1)：在250毫升干燥史莱克管中加入对氯苄胺(50毫摩尔,7.08克)和80毫升干燥氯仿，在-20摄氏度冷却5分钟后，缓慢滴加化合物I(51毫摩尔，10.62克溶解于20毫升干燥氯仿中)。加料结束后，缓慢升温至0摄氏度，并在该温度下继续搅拌24小时，NMR检测转化率98％，纯度88％。不经后处理，直接用于下一步。Step 1): Add p-chlorobenzylamine (50 mmol, 7.08 g) and 80 ml of dry chloroform into a 250 ml dry Shrek tube, and slowly add compound I (51 mmol, 10.62 g dissolved in 20 ml dry chloroform). After the addition, the temperature was slowly raised to 0°C, and stirring was continued at this temperature for 24 hours. The conversion rate was 98% and the purity was 88% as detected by NMR. It was directly used in the next step without post-processing.
步骤2)：在1000毫升反应瓶中加入催化剂Q-4(0.05摩尔％,28.8毫克),膦酸钾(30摩尔％,3.18克)和4毫升去离子水溶解于400毫升甲苯中。在室温搅拌10分钟后，步骤1)中的混合物直接加入到该1000毫升反应瓶中继续在室温搅拌24小时(转化率>97％，ee＝99％)。反应结束后，反应液直接通过去活化硅胶过滤除去膦酸钾，减压除去溶剂得到淡黄色油状物，用于下一步反应。Step 2): Catalyst Q-4 (0.05 mol%, 28.8 mg), potassium phosphonate (30 mol%, 3.18 g) and 4 ml of deionized water were dissolved in 400 ml of toluene in a 1000 ml reaction flask. After stirring at room temperature for 10 minutes, the mixture in step 1) was directly added into the 1000 ml reaction flask and continued to stir at room temperature for 24 hours (conversion>97%, ee=99%). After the reaction, the reaction solution was directly filtered through deactivated silica gel to remove potassium phosphonate, and the solvent was removed under reduced pressure to obtain a light yellow oil, which was used for the next reaction.
步骤3)：将步骤2)所得油状物与四氢呋喃(100毫升)混合后，加入3N稀盐酸(约30毫升)将pH调至2。室温下搅拌过夜，TLC检测反应完全后。减压旋蒸除去四氢呋喃，水相用乙醚洗涤三次。后加入氨水将pH调至12，再用二氯甲烷萃取。有机相浓缩后得到淡黄色油状物。。将得到的油状物和6N稀盐酸(50毫升,300毫摩尔,6当量)混合，100摄氏度加热回流过夜，核磁检测至反应完全。将水旋蒸除去，得到半固体产物。向其中加入乙醇(15毫升)加热至完全溶解，再滴加甲基环氧乙烷(7.5毫升)。然后将其置于室温下搅拌30分钟，抽滤后滤饼用乙醇/甲基环氧乙烷(15毫升，V/V＝2:1)洗涤。得到产物IV，呈白色固体4.0克，总产率64％。Step 3): After mixing the oil obtained in step 2) with THF (100 mL), 3N dilute hydrochloric acid (about 30 mL) was added to adjust the pH to 2. Stir overnight at room temperature, and TLC detects that the reaction is complete. Tetrahydrofuran was removed by rotary evaporation under reduced pressure, and the aqueous phase was washed three times with ether. Aqueous ammonia was then added to adjust the pH to 12, followed by extraction with dichloromethane. The organic phase was concentrated to give a pale yellow oil. . The obtained oil was mixed with 6N dilute hydrochloric acid (50 ml, 300 mmol, 6 eq), heated to reflux at 100°C overnight, and the reaction was detected by NMR until the reaction was complete. The water was removed by rotary evaporation to obtain a semi-solid product. Ethanol (15 ml) was added thereto and heated until completely dissolved, and then methyloxirane (7.5 ml) was added dropwise. Then it was stirred at room temperature for 30 minutes, and the filter cake was washed with ethanol/methyloxirane (15 ml, V/V=2:1) after suction filtration. Product IV was obtained as a white solid, 4.0 g, in an overall yield of 64%.
产物α-氨基膦酸表征：Product α-aminophosphonic acid characterization:
Figure PCTCN2022135641-appb-000066
Figure PCTCN2022135641-appb-000066
白色固体,
Figure PCTCN2022135641-appb-000067
＝-16.5(c＝1.0in 1.0M NaOH). 1H NMR(500MHz,Deuterium Oxide)δ3.40–3.21(m,1H),1.29(dd,J＝15.5,7.3Hz,3H). 13C NMR(126MHz,Deuterium Oxide)δ44.08(d,J＝148.5Hz),13.15(d,J＝2.7Hz). 31P NMR(203MHz,Deuterium Oxide)δ15.76. white solid,
Figure PCTCN2022135641-appb-000067
=-16.5 (c=1.0in 1.0M NaOH). 1 H NMR (500MHz, Deuterium Oxide) δ3.40–3.21 (m, 1H), 1.29 (dd, J=15.5, 7.3Hz, 3H). 13 C NMR (126MHz, Deuterium Oxide) δ44.08(d, J＝148.5Hz), 13.15(d, J＝2.7Hz). 31 P NMR (203MHz, Deuterium Oxide) δ15.76.
实施例5：消旋α氨基膦酸衍生物制备Example 5: Preparation of racemic α-aminophosphonic acid derivatives
Figure PCTCN2022135641-appb-000068
Figure PCTCN2022135641-appb-000068
步骤1)：在2毫升反应瓶中加入苄胺(0.2毫摩尔)和400微升氯仿，在0摄氏度冷却5分钟后，加入化合物I(0.2毫摩尔)，在0摄氏度继续搅拌10小时以备用。Step 1): Add benzylamine (0.2 mmol) and 400 microliters of chloroform to a 2 ml reaction vial, cool at 0°C for 5 minutes, add compound I (0.2 mmol), and continue stirring at 0°C for 10 hours for later use .
步骤2)：在另一4毫升反应瓶中加入四丁基溴化铵(20摩尔％)和氢氧化钾(1.0当量)溶解于1.6毫升甲苯中。在室温搅拌5分钟后，步骤1)中的混合物直接加入到该4毫升反应瓶中继续搅拌1小时。反应结束后，反应液直接通过去活化硅胶过滤，减压旋蒸除去溶剂，残留物经过柱层析(石油醚/乙酸乙酯＝90/10-70/30)分离获得目标消旋产物II'。核磁表征和手性化合物相同，可参见实施例3数据。Step 2): Tetrabutylammonium bromide (20 mol%) and potassium hydroxide (1.0 equivalent) were dissolved in 1.6 ml of toluene into another 4 ml reaction flask. After stirring at room temperature for 5 minutes, the mixture in step 1) was directly added to the 4 ml reaction flask and stirred for 1 hour. After the reaction, the reaction solution was directly filtered through deactivated silica gel, the solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by column chromatography (petroleum ether/ethyl acetate=90/10-70/30) to obtain the target racemic product II' . The NMR characterization is the same as that of the chiral compound, see the data in Example 3.
在本发明提及的所有文献都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，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

  1. 一种催化合成手性α-氨基膦酸衍生物的方法，所述的α-氨基膦酸衍生物具有如下式所示的结构：A method for catalytically synthesizing chiral α-aminophosphonic acid derivatives, the α-aminophosphonic acid derivatives have a structure as shown in the following formula:
    Figure PCTCN2022135641-appb-100001
    Figure PCTCN2022135641-appb-100001
    其特征在于，所述的方法包括步骤：It is characterized in that the method comprises the steps of:
    Figure PCTCN2022135641-appb-100002
    Figure PCTCN2022135641-appb-100002
    (a)在金鸡纳碱衍生物催化剂和无机碱存在下，用亚胺中间体II进行对映选择性异构化反应，制备得到具有光学活性的α-氨基膦酸前体II'：和(a) in the presence of cinchona base derivative catalyst and inorganic base, carry out enantioselective isomerization reaction with imine intermediate II to prepare optically active α-aminophosphonic acid precursor II': and
    用所述的α-氨基膦酸前体II'进行水解，得到手性α-氨基膦酸；hydrolysis with the α-aminophosphonic acid precursor II' to obtain chiral α-aminophosphonic acid;
    其中，*表示R构型或S构型；Wherein, * represents R configuration or S configuration;
    R 1选自取代或未取代的C 1-C 16烷基； R 1 is selected from substituted or unsubstituted C 1 -C 16 alkyl;
    R 2选自取代或未取代的C 1-C 16烷基； R 2 is selected from substituted or unsubstituted C 1 -C 16 alkyl;
    Ar 2为取代或未取代的C 6-C 10芳基，或5-12元杂芳基；其中，所述的5-12元杂芳基上任选地具有1-2个稠合的饱和5-7元环； Ar 2 is a substituted or unsubstituted C 6 -C 10 aryl group, or a 5-12 membered heteroaryl group; wherein, the 5-12 membered heteroaryl group optionally has 1-2 fused saturated 5-7 membered ring;
    所述的金鸡纳碱衍生物催化剂选自下组：Described cinchona base derivative catalyst is selected from following group:
    Figure PCTCN2022135641-appb-100003
    Figure PCTCN2022135641-appb-100003
    其中，PYR为
    Figure PCTCN2022135641-appb-100004
    Ar选自下组：取代或未取代的C 6-C 10芳基，或5-12元杂芳基；     Among them, PYR is
    Figure PCTCN2022135641-appb-100004
    Ar is selected from the group consisting of substituted or unsubstituted C 6 -C 10 aryl, or 5-12 membered heteroaryl;
    所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、C 2-C 4酯基、硝基、3-8元环烷基、4-8元杂环基、或未取代或被选自下组的一个或多个取代基取代的C 6-C 10芳基或5-12元杂芳基：卤素、C 1-C 4烷氧基、C 1-C 4烷硫基、叔丁基二甲基硅基(TBS)、叔丁基二甲基硅氧(TBSO)、三异丙基硅基(TIPS)。 The substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl , C 2 -C 4 ester group, nitro group, 3-8 membered cycloalkyl group, 4-8 membered heterocyclic group, or C 6 -C unsubstituted or substituted by one or more substituents selected from the following group 10 aryl or 5-12 membered heteroaryl: halogen, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, tert-butyldimethylsilyl (TBS), tert-butyldimethyl Siloxane (TBSO), Triisopropylsilyl (TIPS).
  2. 如权利要求1所述的方法，其特征在于，所述的金鸡纳碱衍生物催化剂的用量为0.0001-0.5mol％，较佳地为0.01-0.05mol％(以式II化合物的用量为基础计)。method as claimed in claim 1, is characterized in that, the consumption of described cinchona base derivative catalyst is 0.0001-0.5mol%, is preferably 0.01-0.05mol% (based on the consumption of formula II compound ).
  3. 如权利要求1所述的方法，其特征在于，所述的α-氨基膦酸前体II'具有选自下组的结构：The method according to claim 1, wherein the α-aminophosphonic acid precursor II' has a structure selected from the group consisting of:
    Figure PCTCN2022135641-appb-100005
    Figure PCTCN2022135641-appb-100005
  4. 如权利要求1所述的方法，其特征在于，所述的α-氨基膦酸前体II'具有选自下组的结构：The method according to claim 1, wherein the α-aminophosphonic acid precursor II' has a structure selected from the group consisting of:
    Figure PCTCN2022135641-appb-100006
    Figure PCTCN2022135641-appb-100006
  5. 如权利要求1所述的方法，其特征在于，所述的金鸡纳碱衍生物催化剂选自下组：method as claimed in claim 1, is characterized in that, described cinchona base derivative catalyst is selected from lower group:
    Figure PCTCN2022135641-appb-100007
    Figure PCTCN2022135641-appb-100007
    其中，PYR为
    Figure PCTCN2022135641-appb-100008
    Ar为
    Figure PCTCN2022135641-appb-100009
    Among them, PYR is
    Figure PCTCN2022135641-appb-100008
    Ar is
    Figure PCTCN2022135641-appb-100009
    Ar 1选自下组：苯基、萘基、4-甲氧基苯基、3,5-二甲氧基苯基、3,4,5-三甲氧基苯基；R选自下组：叔丁基(tBu)、叔丁基二甲基硅基(TBS)、三异丙基硅基(TIPS)。 Ar is selected from the group consisting of phenyl, naphthyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl; R is selected from the group: Tert-butyl (tBu), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS).
  6. 如权利要求5所述的方法，其特征在于，所述的金鸡纳碱衍生物催化剂选自下组：method as claimed in claim 5, is characterized in that, described cinchona base derivative catalyst is selected from lower group:
    Figure PCTCN2022135641-appb-100010
    Figure PCTCN2022135641-appb-100010
    其中，PYR为
    Figure PCTCN2022135641-appb-100011
    Ar选自下组：     Among them, PYR is
    Figure PCTCN2022135641-appb-100011
    Ar is selected from the group consisting of:
    Figure PCTCN2022135641-appb-100012
    Figure PCTCN2022135641-appb-100012
  7. 如权利要求1所述的方法，其特征在于，所述的亚胺中间体II是通过以下方法制备的：The method according to claim 1, wherein the imine intermediate II is prepared by the following method:
    Figure PCTCN2022135641-appb-100013
    Figure PCTCN2022135641-appb-100013
    (a)用α-羰基膦酸酯I与苄胺进行反应，缩合得到亚胺中间体II。(a) react with α-carbonyl phosphonate I and benzylamine, and condense to obtain the imine intermediate II.
  8. 如权利要求1所述的方法，其特征在于，所述的方法还包括步骤：method as claimed in claim 1, is characterized in that, described method also comprises the step:
    Figure PCTCN2022135641-appb-100014
    Figure PCTCN2022135641-appb-100014
    (b)在酸存在下，对α-氨基膦酸前体II'进行水解，然后与氨水中和得到式III化合物：其中，式II'和式III的手性中心构型一致。(b) In the presence of acid, the α-aminophosphonic acid precursor II' is hydrolyzed, and then neutralized with ammonia water to obtain the compound of formula III: wherein, the chiral center configurations of formula II' and formula III are consistent.
  9. 如权利要求8所述的方法，其特征在于，所述的方法还包括步骤：method as claimed in claim 8, is characterized in that, described method also comprises the step:
    Figure PCTCN2022135641-appb-100015
    Figure PCTCN2022135641-appb-100015
    (c)在酸存在下，用式III化合物进行水解反应，得到式IV化合物。(c) Under the presence of acid, carry out hydrolysis reaction with the compound of formula III to obtain the compound of formula IV.
  10. 如权利要求9所述的方法，其特征在于，所述的方法还包括步骤：对产物进行重结晶，得到纯化后的产物IV。The method according to claim 9, further comprising the step of: recrystallizing the product to obtain purified product IV.
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