阅读说明：本技术 手性3-氨基-4-芳基吡啶氮氧类催化剂及其在四氮唑半缩醛胺酯反应中的应用 (Chiral 3-amino-4-aryl pyridine nitrogen-oxygen catalyst and application thereof in tetrazole hemiacetal amine ester reaction ) 是由 谢明胜 王笑冰 单梦 武晓霞 渠桂荣 郭海明 于 2021-01-06 设计创作，主要内容包括：本发明公开了手性3-氨基-4-芳基吡啶氮氧类催化剂及其在四氮唑半缩醛胺酯反应中的应用,属于有机合成技术领域。通过4-氯吡啶氮氧与芳基硼酸发生Suzuki偶联反应,在吡啶环C4位引入芳基,构筑手性4-芳基吡啶氮氧催化剂,得到4-芳基吡啶氮氧也可作为酰基转移催化剂。该催化剂在具有挑战性的四氮唑、醛和酸酐三组分动态动力学拆分合成2,5-二取代四氮唑半缩醛胺酯的反应中,取得了很好的区域选择性和对映选择性。产物经过衍生,还得到了小分子PCSK9抑制剂PF-07556769。(The invention discloses a chiral 3-amino-4-aryl pyridine nitrogen-oxygen catalyst and application thereof in tetrazole hemiacetal amine ester reaction, and belongs to the technical field of organic synthesis. The 4-aryl pyridine nitrogen oxygen can also be used as an acyl transfer catalyst by leading 4-chloropyridine nitrogen oxygen and aryl boric acid to generate Suzuki coupling reaction and introducing aryl at the C4 position of a pyridine ring to construct a chiral 4-aryl pyridine nitrogen oxygen catalyst. The catalyst obtains good regioselectivity and enantioselectivity in the challenging reaction of synthesizing 2, 5-disubstituted tetrazole hemiacetal amine ester by dynamic resolution of tetrazole, aldehyde and anhydride. The product is derived to obtain a small molecule PCSK9 inhibitor PF-07556769.)

The 3-amino-4-aryl pyridine nitrogen-oxygen catalyst is characterized by having a structural general formula as follows:or an enantiomer thereof; ar is phenyl, naphthyl or substituted phenyl, and the substituent in the substituted phenyl is C1-C4 alkyl, trifluoromethyl, halogen, phenyl, C1-C4 alkoxy; r is C1-C6 alkyl, C3-C8 cycloalkyl, adamantyl, benzyl or benzhydryl.

2. The 3-amino-4-arylpyridine nitroxide catalyst according to claim 1, characterized by the following specific structure:

the application of the 3-amino-4-aryl pyridine nitrogen-oxygen catalyst in catalyzing the synthesis of tetrazole hemiacetal amine ester is characterized by comprising the following steps: reacting tetrazole, aldehyde, acid anhydride and 3-amino-4-aryl pyridine nitrogen-oxygen catalyst in an organic solvent to obtain tetrazole hemiacetal amine ester; the reaction equation is:wherein the 3-amino-4-arylpyridine nitroxide catalyst is of the structure described in claim 1 or 2.

4. Use according to claim 3, characterized in that: r¹Is selected from phenyl, substituted phenyl, cinnamyl, alkenyl, benzyl, C1-C4 alkyl, pyrazole or 1-methyl-4-iodopyrazole, wherein the substituent in the substituted phenyl is halogen, C1-C4 alkyl; r²Selected from C1-C6 alkyl, benzyl, phenethyl or 4-pentenyl; r³Selected from C1-C4 alkyl.

5. Use according to claim 3, characterized in that: the organic solvent is dichloromethane, tetrahydrofuran, toluene, fluorobenzene, mesitylene or dioxane.

6. Use according to claim 3, characterized in that: the molar ratio of the tetrazole to the aldehyde to the anhydride to the nitrogen-oxygen catalyst is 1: 1-4:1-4: 0.05-0.15; the reaction temperature is-20 ℃ to 40 ℃.

The preparation method of the 3-amino-4-aryl pyridine nitrogen-oxygen catalyst is characterized by comprising the following steps:wherein the Ar and R substituents are as defined in claim 1.

8. The method of claim 7, wherein: the three-step reaction is carried out in tetrahydrofuran, toluene or 1, 2-dichloroethane solvent; the reaction temperature is 50-160 ℃.

9. The method of claim 7, wherein: the palladium catalyst consists of PdCl₂dppf or Pd (PPh)₃)₄And Xantphos.

Technical Field

The invention relates to a novel chiral DMAP (dimethyl formamide) catalyst, in particular to a chiral 3-amino-4-aryl pyridine nitrogen-oxygen catalyst and application thereof in catalyzing synthesis of tetrazole hemiacetal amine ester, and belongs to the technical field of asymmetric synthesis in organic chemistry.

Background

Chiral 4-Dialkylaminopyridine (DMAP) catalysts are classical acyl transfer catalysts that are structurally characterized by an N, N '-dialkylamino substituent (e.g., N' -dimethylamino or pyrrolidinyl) at the C4 position of the pyridine ring. Chiral DMAP catalysts with central, planar, spiro and axial chiralities have been reported in succession since the first chiral DMAP reagent reported in 1996 (angelw. chem. int. ed.2011,50,6012; organic chemistry, 2008,28, 574; Tetrahedron lett.2018,59,1787; org. chem. front.2019,6,2624). It is to be emphasized that: these chiral DMAP catalysts are all N, N' -dialkylamino substituted at the C4 position.

In 2017, spivy reported chiral DMAP nitroxide catalysts and used for asymmetric sulfonylation reactions (angelw. chem. int. ed.2017,56,5760). In 2019, the group of guoheming topics developed L-proline derived 3-substituted DMAP nitroxide catalysts for asymmetric Steglich rearrangement reactions (angelw.chem.int.ed.2019, 58,2839). In 2020, the group developed an L-proline derived 2-substituted DMAP nitroxide catalyst for use in asymmetric alcoholysis reactions of azlactones (J.Am.chem.Soc.2020,142, 19226).

In summary, the traditional thinking holds that: the C4 position of the pyridine ring of the chiral DMAP catalyst must be substituted by N, N' -dialkylamino, however, the chiral 4-aryl pyridine nitrogen-oxygen catalyst is constructed by introducing aryl at the C4 position of the pyridine ring and is applied to acyl transfer catalysis, and great uncertainty exists in the aspect of the chiral 4-aryl pyridine nitrogen-oxygen catalyst.

In medicinal chemistry, tetrazole is a valuable heterocyclic compound as an isostere of carboxylic acid. The prodrug of BMS-183920 containing hemiaminal ester fragment showed better bioavailability than 5-substituted tetrazole BMS-183920.

In 2016, the Piotrowski and Kamlet problem groups (J.Am.chem.Soc.2016,138,4818-4823.) attempted to synthesize chiral 2, 5-disubstituted tetrazole hemiacetal amine esters by three-component dynamic kinetic resolution of 5-substituted tetrazole, aldehyde, and anhydride. Wherein, the chiral DMAP catalyst almost obtains racemate; the central chiral DMAP catalyst only gives 24-28% ee; diaryl prolinol DMAP catalyst is almost racemate, and the reaction can obtain better enantioselectivity if and only if 3, 5-bis trifluoromethyl is used for substituting chiral DMAP catalyst. The above experimental results show that: the reaction for constructing chiral 2, 5-disubstituted tetrazole hemiacetal amine ester through dynamic kinetic resolution of three components of 5-substituted tetrazole, aldehyde and anhydride is very difficult and very challenging.

Disclosure of Invention

In order to overcome the technical defects, the invention discloses a novel chiral 3-amino-4-aryl pyridine nitrogen-oxygen catalyst and application thereof in the reaction of tetrazole hemiacetal amine ester. The catalyst structure breaks through the thought limitation that C4 bit of a pyridine ring in a chiral DMAP catalyst must be substituted by N, N' -dialkylamino, and the chiral 4-aryl pyridine nitrogen oxygen catalyst is constructed by introducing aryl into C4 bit of the pyridine ring, so that the 4-aryl pyridine nitrogen oxygen can be used as an acyl transfer catalyst for the first time. The 4-aryl pyridine nitrogen oxygen catalyst is synthesized by the Suzuki coupling reaction of 4-chloropyridine nitrogen oxygen and aryl boric acid. The catalyst obtains good regioselectivity and enantioselectivity in the challenging reaction of synthesizing 2, 5-disubstituted tetrazole hemiacetal amine ester by dynamic resolution of tetrazole, aldehyde and anhydride.

The invention provides a novel structural DMAP catalyst, which is realized by the following technical scheme: the 3-amino-4-aryl pyridine nitrogen-oxygen catalyst has a general structure as follows:

ar is phenyl, naphthyl or substituted phenyl, and the substituent in the substituted phenyl is C1-C4 alkyl, trifluoromethyl, halogen, phenyl, C1-C4 alkoxy; r is C1-C6 alkyl, C3-C8 cycloalkyl, adamantyl, benzyl or benzhydryl.

Under the preferred conditions, the substituent at the C4 position of the pyridine ring is: 3, 5-dimethoxyphenyl group, 3, 5-dimethylphenyl group, 3, 5-bistrifluoromethylphenyl group, 3, 5-di-tert-butylphenyl group, 3,4, 5-trimethoxyphenyl group, 3, 5-di-tert-butylphenyl group, 3, 5-diphenylphenyl group.

A further preferred structure is that C4 is 3, 5-dimethylphenyl:

most preferably, the specific structure is:

the second purpose of the invention is to apply the structural catalyst to the preparation of chiral 2, 5-disubstituted tetrazole hemiaminal ester.

The synthesis process of chiral 2, 5-disubstituted tetrazole hemiaminal ester includes the following steps: mixing tetrazole, aldehyde and acid anhydride and a 3-amino-4-aryl pyridine nitrogen-oxygen catalyst in an organic solvent, and then carrying out asymmetric reaction to obtain a tetrazole hemiaminal ester product. The reaction equation is as follows:

further, in the above reaction equation, R¹Is selected from phenyl, substituted phenyl, cinnamyl, alkenyl, benzyl, C1-C4 alkyl, pyrazole or 1-methyl-4-iodopyrazole, wherein the substituent in the substituted phenyl is halogen, C1-C4 alkyl; r²Selected from C1-C6 alkyl, benzyl, phenethyl or 4-pentenyl; r³Selected from C1-C4 alkyl.

Most preferably, R¹Specifically, phenyl, 2-bromophenyl, 4-bromophenyl, 3-methylphenyl, cinnamyl, alkenyl, tert-butyl, benzyl, methyl, pyrazole, 1-methyl-4-iodopyrazole and the like. R²Methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, benzyl, phenethyl, 4-pentenyl, and the like. R³Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and the like.

Further, in the above technical solution, the organic solvent is dichloromethane, tetrahydrofuran, toluene, fluorobenzene, mesitylene, or dioxane.

Further, in the technical scheme, the molar ratio of the tetrazole to the aldehyde to the anhydride to the 3-amino-4-aryl pyridine nitrogen-oxygen catalyst is 1: 1-4:1-4:0.05-0.15.

Furthermore, in the technical scheme, the reaction temperature is-20 ℃ to 40 ℃, and the reaction time is 6-72 hours.

The third purpose of the invention is to provide a preparation method of the chiral 3-amino-4-aryl pyridine nitrogen-oxygen catalyst.

The preparation method of the chiral 3-amino-4-aryl pyridine nitrogen-oxygen catalyst comprises the following steps: the chiral 3-amino-4-aryl pyridine nitrogen oxygen catalyst is prepared by using 3-bromine 4-nitropyridine nitrogen oxygen and D or L-prolinamide as raw materials through chlorination and subsequent Suzuki coupling reaction, and the reaction equation is as follows:

need to explain: all the equations referred to in the description represent chiral centers.

Further, in the technical scheme, the three steps of reactions are carried out in tetrahydrofuran, toluene or 1, 2-dichloroethane solvent.

Further, in the technical scheme, the reaction temperature of the three steps is 50-160 ℃. Preferably 70-120 ℃.

Further, in the above technical scheme, the third step palladium catalyst is composed of PdCl₂dppf or Pd (PPh)₃)₄And Xantphos.

The invention has the beneficial effects that:

the invention provides a chiral 4-aryl pyridine nitrogen-oxygen catalyst with a novel structure, which is rich in structure and strong in adjustability. The catalyst has the advantages of easily available raw materials, simple synthesis, low cost and high efficiency. The catalytic activity is high. In the dynamic kinetic resolution reaction of the three components of tetrazole, aldehyde and anhydride, a series of chiral tetrazole hemiacetal amine ester products are synthesized, and the catalyst has the advantages of good yield, high enantioselectivity and the like when being used for catalyzing the three-component reaction. The small molecule PCSK9 inhibitor PF-07556769 can be further derived.

Detailed Description

EXAMPLE 1 Synthesis of chiral 4-phenyl-3- (2- (2,6 diisopropylbenzamido) pyrrolidinyl) pyridine nitroxide

Under the protection of nitrogen, chiral 3-pyrrolidinyl-4-chloropyridine nitroxide (125mg,0.31mmol), phenylboronic acid (152mg,1.24mmol), potassium carbonate (171mg,1.24mmol), Pd (PPh) were added in sequence to a 25mL sealed tube₃)₄(17.90mg,0.015mmol), Xant-Phos (14.4mg,0.031mmol) and 2.5mL of toluene were put in a 120 ℃ oil bath and reacted for 40min, and then the stirring was stopped. And monitoring by TLC, after the raw materials are completely reacted, carrying out vacuum concentration to obtain a crude product, and then carrying out column chromatography separation to obtain a light brown solid. In the embodiment, the chiral 3-pyrrolidinyl-4-chloropyridine nitrogen oxide serving as the raw material can be synthesized by referring to Angew.¹H NMR(400MHz,CDCl₃)δ8.35(s,1H),8.08(s,1H),7.85(d,J＝6.4Hz,1H),7.46-7.34(m,5H),7.26(t,J＝7.2Hz,1H),7.12(d,J＝7.6Hz,2H),7.04(d,J＝6.4Hz,1H),4.27(t,J＝7.2Hz,1H),3.24(dd,J＝16.0,9.2Hz,1H),2.98-2.77(m,3H),2.50-2.40(m,1H),2.19-2.05(m,1H),2.00-1.88(m,1H),1.87-1.75(m,1H),1.14(d,J＝6.8Hz,6H),1.06(d,J＝7.2Hz,6H).¹³C NMR(150MHz,CDCl₃)δ171.7,146.2,144.9,138.4,130.9,130.5,129.2,129.0,128.4,128.33,128.29,128.1,123.4,63.3,53.8,31.4,28.9,25.2,23.6,23.4.

Example 2 chiral 4-phenyl-3- (2- (3, 5-bistrifluoromethylbenzamido) pyrrolidinyl) pyridine nitroxide

Under the protection of nitrogen, the tube is sealed by 25mLIn the reaction solution, chiral 3-pyrrolidinyl-4-chloropyridine nitroxide (125mg,0.27mmol), phenylboronic acid (134mg,1.10mmol), potassium carbonate (1.10mmol), Pd (PPh) were added in this order₃)₄(15.59mg,0.0135mmol), Xant-Phos (17.4mg,0.027mmol) and 2.5mL of toluene were placed in a 120 ℃ oil bath and the stirring was stopped after 40min of reaction. And monitoring by TLC, after the raw materials are completely reacted, carrying out vacuum concentration to obtain a crude product, and then carrying out column chromatography separation to obtain a light brown solid. In the embodiment, the chiral 3-pyrrolidinyl-4-chloropyridine nitrogen oxide serving as the raw material can be synthesized by referring to Angew.¹H NMR(400MHz,CDCl₃)δ10.98(s,1H),8.64(s,1H),7.85(d,J＝6.4Hz,1H),7.61-7.47(m,6H),7.46-7.41(m,1H),7.31(s,1H),7.18(d,J＝6.4Hz,1H),4.57(t,J＝7.2Hz,1H),3.24-3.10(m,1H),2.81-2.70(m,1H),2.50-2.36(m,1H),2.20-2.01(m,1H),1.98-1.87(m,1H),1.86-1.74(m,1H).¹³C NMR(150MHz,CDCl₃)δ171.5,145.0,139.6,138.1,132.4,131.9(q,²J_C-F＝33.0Hz),129.1,128.9,128.83,128.76,128.5,127.5,123.0(q,¹J_C-F＝271.5Hz),118.2,117.0,63.3,54.0,31.7,26.0.¹⁹F NMR(565MHz,CDCl₃)δ-63.3.

Example 3 chiral 4- (3, 5-dimethylphenyl) -3- (2- (2, 6-diisopropylbenzamido) pyrrolidinyl) pyridine nitroxide

Under the protection of nitrogen, chiral 3-pyrrolidinyl-4-chloropyridine nitroxide (125mg,0.31mmol), 3, 5-dimethylbenzeneboronic acid (186mg,1.24mmol), potassium carbonate (171mg,1.24mmol), Pd (PPh) were added in this order to a 25mL sealed tube₃)₄(17.90mg,0.015mmol), Xant-Phos (14.44mg,0.031mmol) and 2.5mL of toluene were placed in a 120 ℃ oil bath and the stirring was stopped after 40min of reaction. And monitoring by TLC, after the raw materials are completely reacted, carrying out vacuum concentration to obtain a crude product, and then carrying out column chromatography separation to obtain a light brown solid.¹H NMR(400MHz,CDCl₃)δ8.20(s,1H),7.83(dd,J＝6.4,1.6Hz,1H),7.72(s,1H),7.23(d,J＝8.0Hz,1H),7.11(d,J＝8.0Hz,2H),7.02(d,J＝6.8Hz,1H),6.98(s,1H),6.95(s,2H),4.20(t,J＝7.2Hz,1H),3.25(dt,J＝9.6,7.6Hz,1H),2.93-2.75(m,3H),2.48-2.34(m,1H),2.27(s,6H),2.14-2.04(m,1H),1.94-1.81(m,1H),1.13(d,J＝6.8Hz,6H),1.03(d,J＝6.8Hz,6H).¹³C NMR(150MHz,CDCl₃)δ171.4,146.2,144.9,138.7,138.3,131.3,131.1,130.7,130.1,129.3,128.6,128.1,125.9,123.5,63.6,53.9,31.3,29.0,25.1,23.6,23.5,21.4.

Example 4 chiral 4- (3, 5-bistrifluoromethyl) -3- (2- (2,6 diisopropylbenzamido) pyrrolidinyl) pyridine nitroxide

Under the protection of nitrogen, chiral 3-pyrrolidinyl-4-chloropyridine nitroxide (125mg,0.31mmol), 3, 5-bistrifluoromethylphenylboronic acid (319mg,1.24mmol), potassium carbonate (171mg,1.24mmol), Pd (PPh) were added in sequence to a 25mL sealed tube₃)₄(17.90mg,0.015mmol), Xant-Phos (14.4mg,0.031mmol) and 2.5mL of toluene were put in a 120 ℃ oil bath and reacted for 40min, and then the stirring was stopped. And monitoring by TLC, after the raw materials are completely reacted, carrying out vacuum concentration to obtain a crude product, and then carrying out column chromatography separation to obtain a light brown solid.¹H NMR(400MHz,CDCl₃)δ8.34(s,1H),7.98(s,2H),7.90(s,1H),7.87(d,J＝6.4Hz,1H),7.52(s,1H),7.27(t,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,2H),7.09(d,J＝6.4Hz,1H),4.26(t,J＝7.6Hz,1H),3.18-3.08(m,1H),2.92-2.77(m,3H),2.54-2.41(m,1H),2.21-2.07(m,1H),2.05-1.95(m,1H),1.93-1.80(m,1H),1.14(d,J＝6.8Hz,6H),1.06(d,J＝6.8Hz,6H).¹³C NMR(150MHz,CHCl₃)δ171.6,145.0,139.7,138.4,138.2,132.1(dd,J_C-F＝90.0,57.0Hz),130.3,129.2,129.1,127.8,126.9,124.1,122.2,118.5,117.2,64.0,54.1,31.8,25.7,21.6.¹⁹F NMR(565MHz,CDCl₃)δ-63.2.

Example 5 chiral 4- (3,4, 5-trimethoxyphenyl) -3- (2- (2,6 diisopropylbenzamido) pyrrolidinyl) pyridine nitroxide

Under the protection of nitrogen, chiral 3-pyrrolidinyl-4-chloropyridine nitroxide (125mg,0.31mmol), 3,4, 5-trimethoxyphenylboronic acid (262mg,1.24mmol), potassium carbonate (171mg,1.24mmol), Pd (PPh) were added in sequence to a 25mL sealed tube₃)₄(17.90mg,0.015mmol), Xant-Phos (14.4mg,0.031mmol) and 2.5mL of toluene were put in a 120 ℃ oil bath and reacted for 40min, and then the stirring was stopped. And monitoring by TLC, after the raw materials are completely reacted, carrying out vacuum concentration to obtain a crude product, and then carrying out column chromatography separation to obtain a light brown solid.¹H NMR(400MHz,CDCl₃)δ8.76(s,1H),8.56(s,1H),7.80(d,J＝6.4Hz,1H),7.19(t,J＝7.6Hz,1H),7.09(d,J＝6.4Hz,1H),7.03(d,J＝7.6Hz,2H),6.71(s,2H),4.50(t,J＝7.6Hz,1H),3.87(s,3H),3.80(s,6H),3.33-3.23(m,1H),2.98-2.72(m,3H),2.45-2.34(m,1H),2.23-2.11(m,1H),2.09-1.90(m,2H),1.88-1.74(m,1H),1.04(d,J＝6.8Hz,6H),1.02-0.74(m,6H).¹³C NMR(150MHz,CDCl₃)δ171.7,153.6,145.9,144.7,138.0,133.5,131.3,131.2,130.6,130.2,128.2,127.5,123.3,105.6,62.3,61.1,56.5,53.4,31.1,28.9,25.6,23.5,23.3.

EXAMPLE 6 chiral 4- (3, 5-dimethoxyphenyl) -3- (2- (2, 6-diisopropylbenzamido) pyrrolidinyl) pyridiniumnitride

Under the protection of nitrogen, chiral 3-pyrrolidinyl-4-chloropyridine nitroxide (125mg,0.32mmol), 3, 5-dimethylphenylboronic acid (186mg,1.24mmol), potassium carbonate (171mg,1.24mmol), Pd (PPh) were added in this order to a 25mL sealed tube₃)₄(17.90mg,0.015mmol), Xant-Phos (14.44mg,0.031mmol) and 2.5mL of toluene were placed in a 120 ℃ oil bath and the stirring was stopped after 40min of reaction. And monitoring by TLC, after the raw materials are completely reacted, carrying out vacuum concentration to obtain a crude product, and then carrying out column chromatography separation to obtain a light brown solid.¹H NMR(400MHz,CDCl₃)δ8.48(s,1H),8.29(d,J＝4.8Hz,1H),7.81(s,1H),7.30-7.23(m,1H),7.17-7.08(m,3H),6.99(s,1H),6.95(s,2H),4.38(t,J＝7.6Hz,1H),3.30-3.18(m,1H),2.93-2.82(m,1H),2.76(br,2H),2.50(sextet,J＝6.4Hz,1H),2.26(s,6H),2.18-2.05(m,1H),1.92-1.81(m,2H),1.14(d,J＝6.8Hz,7H),0.99(br,6H).¹³C NMR(150MHz,CDCl₃)δ172.3,146.3,143.1,142.8,140.9,139.8,139.6,138.5,130.6,129.8,128.5,126.0,125.8,123.5,64.6,55.3,31.7,28.8,25.3,23.52,23.49,21.4

Example 7

Comparing the catalytic effects of the chiral 3, 4-diaminopyridine nitrogen-oxygen catalyst and the 3-amino-4-arylpyridine nitrogen-oxygen catalyst in the synthesis of tetrazole hemiacetal amine ester

Example 8 Synthesis of chiral tetrazole hemiacetal amine ester by dynamic kinetic resolution of triazole, aldehyde and anhydride three components

^bThe yield is the isolated yield. By passing¹Determination of the crude reaction mixture by H NMR spectroscopy^cA region selectivity ratio (rr).^dThe ee values were determined by chiral HPLC analysis.

5-phenyl-1H tetrazole (0.1mmol), sodium carbonate (1.1equiv), molecular sieve (60mg), catalyst (0.05eq) and 3mL mesitylene were added in sequence to a 10mL reaction tube and stirred uniformly. Adding aldehyde (4eq) and anhydride (4eq), placing in a low-temperature pump at-20 ℃, reacting for 72 hours, detecting by TLC after the reaction is completed, passing through a column, and separating to obtain a white solid.

The 3-amino-4-aryl pyridine nitrogen oxygen catalyst 18f is used for catalyzing different tetrazole hemiacetal amine ester to synthesize, and the experimental result is as follows:

EXAMPLE 105 Synthesis of phenyl-2H-tetrazolium hemiaminal ester

5-phenyl-1H tetrazole (0.1mmol), sodium carbonate (1.1eq), 5A molecular sieve (60mg), catalyst C18f (0.05eq) and 3mL mesitylene were added in sequence in a 10mL reaction tube and stirred uniformly. Adding acetaldehyde (4eq) and pivalic anhydride (4eq), placing in a low-temperature pump at-20 ℃, reacting for 36h, detecting by TLC after the reaction is completed, passing through a column, separating to obtain a white solid 4a, and obtaining the ee value by chiral HPLC.¹H NMR(400MHz,CDCl₃)δ8.21-8.16(m,2H),7.52-7.46(m,3H),7.34(q,J＝6Hz,1H),2.01(d,J＝6Hz,3H),1.21(s,9H).¹³C NMR(100MHz,CDCl₃)δ176.4,165.3,130.7,129.0,127.2,80.3,38.9,26.9,19.4.

Example 115 Synthesis of phenyl-2H-tetrazole hemiacetal

5-phenyl-1H tetrazole (0.1mmol), sodium carbonate (1.1equiv), 5A molecular sieve (60mg), catalyst C18f (0.05eq) and 3mL mesitylene were added in sequence to a 10mL reaction tube and stirred uniformly. Adding propionaldehyde (4eq) and pivalic anhydride (4eq), placing into a low-temperature pump at-20 ℃, reacting for 36h, detecting by TLC after the reaction is completed, passing through a column, and separating to obtain whiteSolid 4b, ee value obtained by chiral HPLC.¹H NMR(400MHz,CDCl₃)δ8.22-8.13(m,2H),7.53-7.44(m,3H)7.14(td,J＝6.8,1.6Hz,1H),2.46-2.33(m,2H),1.22(s,9H),1.00(td,J＝7.6,1.6Hz,3H).¹³C NMR(150MHz,CDCl₃)δ130.6,129.0,127.3,127.2,84.1,39.0,26.9,26.9,8.72.

Example 122 Synthesis of phenyl-1- (5-phenyl-2H-tetrazol) hemiaminal ester

5-phenyl-1H tetrazole (0.1mmol), sodium carbonate (1.1eq), 5A molecular sieve (60mg), catalyst C18f (0.05eq) and 3mL mesitylene were added in sequence in a 10mL reaction tube and stirred uniformly. Adding phenylacetaldehyde (4eq) and pivalic anhydride (4eq), placing into a low-temperature pump at-20 ℃, reacting for 36h, detecting by TLC after the reaction is completed, passing through a column, separating to obtain a white solid 4z, and obtaining an ee value by chiral HPLC.¹H NMR(400MHz,CDCl₃)δ8.21-8.10(m,2H),7.47(dd,J＝5.2,1.6Hz,3H),7.37(t,J＝7.2Hz,1H),7.30-7.17(m,6H),3.64(d,J＝6.8Hz,2H),1.12(s,9H)¹³C NMR(150MHz,CDCl₃)δ176.2,165.2,133.5,130.7,129.7,129.0,128.9,127.8,127.2,127.2,39.8,38.9,26.8.

Example 131- (5- (4-bromophenyl) -2H-tetrazol) hemiaminal ester Synthesis

4-bromo-5-phenyl-1H tetrazole (0.1mmol), sodium carbonate (1.1eq), 5A molecular sieve (60mg), catalyst 18f (0.05eq) and 3mL mesitylene were sequentially added to a 10mL reaction tube and stirred uniformly. Adding acetaldehyde (4eq) and pivalic anhydride (4eq), placing in a low-temperature pump at-20 ℃, reacting for 36h, detecting by TLC after the reaction is completed, passing through a column, separating to obtain a white solid 4q, and obtaining an ee value by chiral HPLC.¹H NMR(400MHz,CDCl₃)δ8.10-8.01(m,2H),7.68-7.58(m,2H),7.32(q,J＝6.0Hz,1H),2.00(d,J＝6.0Hz,3H),1.21(s,9H).¹³C NMR(150MHz,CDCl₃)δ176.4,164.5,132.3,128.7,126.2,125.1,80.3,38.9,26.9,19.5.

Example Synthesis of 141- (5-styryl-2H-tetrazol-2-yl) hemiaminal ester

5-cinnamon-1H tetrazole (0.1mmol), sodium carbonate (1.1eq), 5A molecular sieve (60mg), catalyst C18f (0.05eq) and 3mL mesitylene are sequentially added into a 10mL reaction tube and stirred uniformly. Adding phenylacetaldehyde (4eq) and pivalic anhydride (4eq), placing into a low-temperature pump at-20 ℃, reacting for 36h, detecting by TLC after the reaction is completed, passing through a column, separating to obtain white solid 4u, and obtaining the ee value by chiral HPLC.¹H NMR(400MHz,CDCl₃)δ7.79(d,J＝16.4Hz,1H),7.57(d,J＝6.8Hz,2H),7.47-7.33(m,3H),7.30(q,J＝6.4Hz,1H),7.16(d,J＝16.4Hz,1H),1.99(d,J＝6.0Hz,3H),1.20(s,9H).¹³C NMR(150MHz,CDCl₃)δ176.4,164.44,137.18,135.75,129.31,129.01,127.35,113.35,80.09,39.0,26.90,19.37.

Example 153-amino-4-arylpyridine nitroxide-based catalyst catalysis of tetrazole hemiacetal amine ester product derivatization

5- (4-iodo-1-methyl-1H-pyrazol-5-yl) -2H-tetrazole (0.1mmol), sodium carbonate (1.1eq), a 5A molecular sieve (60mg), a catalyst ent-C18f (0.05eq) and 3mL mesitylene are sequentially added into a 10mL reaction tube and uniformly stirred. Then aldehyde (4eq) and anhydride (4eq) were added, placed in a-20 ℃ cryopump, reacted for 72h, after completion of the reaction, checked by TLC, then purified by flash chromatography to give the product 4 mm.¹H NMR(400MHz,CDCl₃)δ7.63(s,1H),7.39(q,J＝6.0Hz,1H),4.22(s,3H),2.63(p,J＝6.8Hz,1H),2.04(d,J＝6.0Hz,3H),1.19(dd,J＝13.2,7.2Hz,6H).¹³C NMR(150MHz,CDCl₃)δ174.9,156.8,145.3,131.6,80.4,60.8,40.4,33.9,19.5,18.8,18.7

4mm is taken as a raw material, and a small molecular PCSK9 inhibitor PF-07556769 can be synthesized by a synthesis method with 2 steps in a reference (J.Am.chem.Soc.2016,138, 4818).

Compared with the prior art, the method breaks through the thought limit that the C4 bit of pyridine must be dialkyl amino, designs and synthesizes novel chiral 4-aryl pyridine nitrogen oxides, and provides reference for developing more kinds of chiral 4-substituted pyridine nitrogen oxides as effective nucleophilic organic catalysts. And is used as an effective acyl transfer catalyst in challenging dynamic kinetic resolution reactions of tetrazole, aldehyde and anhydride. Deriving 4-aryl-pyridine nitrogen oxide by using 5mol percent of 3, 5-dimethylphenyl, and catalyzing aliphatic aldehyde, acid anhydride and 5-substituted tetrazole to react to obtain corresponding 2, 5-disubstituted tetrazole hemiaminal. In addition, the current methods can also be used to synthesize the small molecule PCSK9 inhibitor PF-07556769.

The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.