CN114656389B - A kind of synthetic method of 1-phenylpyrrolidine - Google Patents

Abstract

The invention belongs to the technical field of preparation of organic synthesis intermediates, and particularly relates to a synthesis method of 1-phenylpyrrolidine. The synthesis method specifically comprises the following steps: sequentially adding a catalyst Cu (II), zinc powder and an organic solvent into a dried schlenk reaction tube under a nitrogen atmosphere, then adding an aromatic nitro compound and 1, 4-butanediol bis (4-methylbenzenesulfonate), reacting at 50-80 ℃ for 8h, adding a mixed liquid of distilled water and ethyl acetate into a reaction liquid for extraction after the aromatic nitro compound is completely converted, mixing an organic phase, adding anhydrous magnesium sulfate for drying, concentrating the organic phase at 40 ℃, and performing column chromatography to obtain the target product 1-phenylpyrrolidine. The method is simple, low in cost and high in yield, and can synthesize the 1-phenylpyrrolidine by one-step reaction, so that the existing synthesis technology is widened.

Description

A kind of synthetic method of 1-phenylpyrrolidine

Technical field

The invention belongs to the technical field of preparation of organic synthesis intermediates, and specifically relates to a class of organic intermediates 1 prepared from aromatic nitro compounds and 1,4-butanediol bis(4-methylbenzenesulfonate) as substrates. -Phenylpyrrolidine method.

Background technique

1-Phenylpyrrolidine is an important organic synthesis intermediate and is widely used in scientific research, drug synthesis, alkaloid synthesis, chemical production and other fields. It is widely found in natural alkaloids, tropane drug molecules, and new drug lead compounds. At the same time, this type of compound is also a commonly used synthetic building block in drug synthesis, and is often used in the total synthesis research of some other natural products with a wide range of biological activities. Therefore, N-aryl-substituted nitrogen heterocycles similar to 1-phenylpyrrolidine have high application value in organic synthesis and pharmaceutical research.

At present, 1-phenylpyrrolidine and its derivatives have been found to have a wide range of physiological activities and can be used as biological enzyme inhibitors or have anti-cancer effects. Some examples of related compounds discovered in pharmaceutical research that have received widespread attention are as follows: Taladegib (A), which was approved for the treatment of locally advanced basal cell carcinoma; Ivosidenib (B), the first mIDH1 enzyme inhibitor to be clinically validated in human trials ); the new generation anaplastic lymphoma kinase inhibitor Brigatinib (C) has strong efficacy in patients with ALK-positive non-small cell lung cancer. In addition, Gilteritinib(D) may improve survival in some patients with acute myeloid leukemia.

Currently, 1-phenylpyrrolidine can be synthesized by the following methods.

1) Reduction reaction of phenyl-2-pyrrolidone and diisobutylaluminum borohydride: First, diisobutylaluminum borohydride needs to be synthesized from diisobutylaluminum hydride (DIBAL) and borane dimethyl sulfide (BMS) , 1-phenyl-2-pyrrolidone (1 equivalent), diisobutylaluminum borohydride (1.1 equivalent) and anhydrous THF were mixed at 0°C. Once all hydrides have been added, the ice bath is removed and the reaction mixture is stirred under an argon atmosphere for an additional hour before work-up to obtain the product. The diisobutylaluminum borohydride (iBu) ₂ AlBH ₄ used in this method cannot be purchased directly, requires complicated synthesis steps, and the reaction needs to be carried out at 0°C and an argon atmosphere, and the reaction conditions are harsh. Reference: Gabriella Amberchan, Rachel A. Snelling, Enrique Moya, J. Org. Chem. 2021, 86, 6207.

2) Deoxyamination reaction of aniline and cyclic ether: This reaction first requires adding aniline, cyclobutyl ether, I ₂ , and NaH ₂ PO ₂ into a closed reaction tube, reacting at 160°C for 11 hours, and then separating. To obtain 1-phenylpyrrolidine, the reaction temperature of 160°C is very demanding. If the temperature is slightly lowered, the yield will drop greatly. Moreover, the by-product contains HI, which is highly corrosive and the treatment process is complicated. Reference: Ying Lin, Dongyang Li, Jingjing Zhang, Zhi Tang, NewJ.Chem., 2021, 45, 21011..

3) CN cross-coupling reaction of phenylboronic acid and N-heterocyclic compounds: This reaction uses a new type of nanoparticles as a catalyst, and combines phenylboronic acid, N-heterocyclic compounds, K ₃ PO ₄ , distilled water and catalyst at 60°C The target product can be obtained by reacting for a period of time, but the synthesis of nanoparticles required for this reaction is complicated, and the metal cobalt used in the catalyst is highly toxic, making the operation process complicated. Reference: Seyyedeh Ameneh Alavi G, Mohammad Ali Nasseri, Milad Kazemnejadi, New J. Chem., 2021, 45, 7741..

4) Nickel-catalyzed coupling amination reaction of aryl chlorides and amides: This reaction needs to be maintained under a nitrogen atmosphere at 35°C, and the solvent toluene, aryl chloride, amide, Ni(COD) ₂ , and Apr·HCl, KO ^t Bu and H ₂ O reacted for 24h. This reaction needs to be kept under a nitrogen atmosphere at all times, and the solvent toluene used is a controlled drug, so the conditions are harsh. Reference: Jinpeng Li, Changyu Huang, Daheng Wen, Qingshu Zheng, Org. Lett. 2021, 23, 687..

5) Hydrodehalogenation reaction of aryl halides: This reaction is carried out under a nitrogen atmosphere. Add 2-iodo-1-phenyl-pyrrolidine, catalyst, trace potassium, KO ^t Bu to the pressure tube, and the solvent is dihydrogen. Methyl sulfoxide and dioxane were prepared according to a certain ratio and reacted for 24 hours. This reaction requires nitrogen protection and a pressure tube. Active potassium metal is used in the raw materials. The reaction is very dangerous. The substrate needs to be synthesized by yourself, which is not easy to obtain, and the reaction is not easy to operate. Reference: Bhagat Singh, Jasimuddin Ahmed, Amit Biswas, Rupankar Paira, J.Org.Chem.2021,86,7242..

In summary, although 1-phenylpyrrolidine is an important organic synthesis intermediate, so far, the existing synthesis methods are the reaction of primary aromatic amines as raw materials or the use of dicarbonyl compounds for reductive amination. , but these methods have limitations in the functional tolerance of the substrates, high requirements for conditions, and complex operations, which are not conducive to industrial production. Therefore, it is of great significance to develop a new synthesis method.

Contents of the invention

The object of the present invention is to provide a synthesis method of 1-phenylpyrrolidine, which is simple, low-cost, high-yield and capable of synthesizing 1-phenylpyrrolidine in one step. This method broadens the existing synthesis technology.

In order to achieve the above objects, the technical solutions adopted by the present invention are:

A method for synthesizing 1-phenylpyrrolidine, specifically: in a nitrogen atmosphere, sequentially add catalyst Cu(II), zinc powder, and organic solvent to a dry schlenk reaction tube, and then add aromatic nitro compounds and 1,4-Butanediol bis(4-methylbenzenesulfonate), react at 50-80°C for 8 hours. After the aromatic nitro compounds are completely converted, add a mixture of distilled water and ethyl acetate to the reaction solution. Liquid extraction, combine the organic phases and add anhydrous magnesium sulfate to dry, concentrate the organic phase at 40°C, and obtain the target product 1-phenylpyrrolidine through column chromatography.

Further, the aromatic nitro compound is nitrobenzene or heteroarylbenzene.

Further, the structural formula of nitrobenzene is The structural formula of the heteroaryl benzene is/> Wherein R ¹ is any one or two of hydrogen, halogen, alkyl, aryl, -OMe, -CHO, -CN, -SCH ₃ , but is not limited to these groups.

Further, the molar ratio of the 1,4-butanediol bis(4-methylbenzenesulfonate) to the aromatic nitro compound is 2-3:1.

Further, the catalyst Cu (II) is copper (II) sulfate, copper (II) oxalate, copper (II) chloride, copper (II) nitrate, copper (II) bromide, and copper (II) triflate. ), copper (II) hydroxide, copper (II) ethyl acetoacetate, copper (II) trifluoroacetate hydrate, but is not limited to the above catalyst Cu (II).

Further, the usage amount of the catalyst Cu(II) is 3 to 5 mol% of the aromatic nitro compound.

Further, the organic solvent is one of Toluene, 1,4-Dioxane, THF, DMSO, CH ₃ CN, NMP, and DMF, but is not limited to the above organic solvent.

Further, the amount of organic solvent used is 1 mL to 4 mL of organic solvent per millimole of the aromatic nitro compound.

Further, the molar ratio of the zinc powder to the aromatic nitro compound is 1.5:1, and the zinc powder is used to reduce nitrobenzene or heteroaryl benzene.

Further, the eluent of the column chromatography is a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 50:1.

When one of the reaction substrates is nitrobenzene, the reaction equation of the present invention is as follows:

Among them, R ¹ can be a substituent group such as hydrogen, halogen, alkyl or aryl, but is not limited to these groups. Nitrobenzene with various substituents used in the present invention can be obtained commercially; X is 3 to 5, Y is 1.5, T is 50 to 80, and formula A is the target product 1-phenylpyrrolidine.

When one of the reaction substrates is heteroaryl benzene When , the reaction equation of the present invention is similar to the above reaction equation, and the benzene ring of nitrobenzene in the above reaction equation can be replaced by a nitrogen heterocyclic ring.

Compared with the prior art, the beneficial effects of the present invention are:

1. The raw materials in the method of the present invention are cheap and easy to obtain, and meet the requirements of industrial production.

2. There are no complex intermediate links in the reaction in the method of the present invention, and the requirements for experimental operation level are low.

3. The method of the present invention uses nitrobenzene as raw material to synthesize the target product, which broadens the synthesis method of 1-phenyl-pyrrolidine.

Detailed ways

The technical solutions and effects of the present invention will be further described below with reference to specific examples, but the scope of the present invention is not limited thereto.

In the reaction equations of the following examples, I represents nitrobenzene or heteroarylbenzene, and II represents 1,4-butanediol bis(4-methylbenzenesulfonate).

Example 1

The synthesis of Example 1-phenylpyrrolidine 1 is:

Under a nitrogen atmosphere, add copper (II) chloride [2 mg, 0.015 mmol], zinc powder (49 mg, 0.75 mmol), solvent DMF (2 mL), and nitrobenzene (51 μL, 0.5 mmol), 1,4-butanediol bis(4-methylbenzenesulfonate) (321 μL, 1 mmol). React for 8 hours on a heater with a rotating speed of 360 rpm and 65°C. TLC detects that the raw material reaction is complete. Stop the reaction. Extract the reaction mixture with a mixture of distilled water and ethyl acetate with a volume ratio of 1:2. Extract the reaction mixture several times, and combine the organic matter. phase and dried over anhydrous magnesium sulfate. The organic phase was concentrated and separated by column chromatography. The eluent was (ethyl acetate/petroleum ether = 50/1) to obtain 67 mg of the product as a light yellow liquid with a yield of 94%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.17–7.13(m,2H),6.59–6.56(t,1H),6.50–6.48(d,2H),3.22–3.18(m,4H),1.93–1.90 (m,4H). ¹³ C{1H}NMR (100MHz, CDCl ₃ ) δ147.5,128.3,114.5,110.3,46.1,24.2.Ms(EI): m/z=147.5[M]+.

Example 2

The synthesis of Example 1-(p-tolyl)pyrrolidine 2 is:

Under a nitrogen atmosphere, add copper (II) sulfate [4 mg, 0.025 mmol], zinc powder (49 mg, 0.75 mmol), solvent Toluene (0.5 mL), and p-nitrotoluene (69 mg, 0.5mmol), 1,4-butanediol bis(4-methylbenzenesulfonate) (468μL, 1.5mmol). React for 8 hours on a heater with a rotating speed of 200 rpm and 50°C. After TLC detects that the raw material reaction is complete, the reaction is stopped. The reaction mixture is extracted several times with a mixture of distilled water and ethyl acetate with a volume ratio of 1:2, and the organic matter is combined. phase, dried over anhydrous magnesium sulfate, concentrated the organic phase, and then subjected to column chromatography. The eluent was (ethyl acetate/petroleum ether = 50/1) to obtain 76 mg of product as a light yellow liquid with a yield of 94%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.01(d,2H),6.54(d,2H),3.25(t,4H),2.27(s,3H),2.05–1.94(m,4H). ¹³ C {1H}NMR (100MHz, CDCl ₃ ) δ146.7,129.5,124.3,111.6,47.5,25.3,20.5.Ms(EI): m/z=161.5[M]+.

Example 3

The synthesis of 1-(4-fluorophenyl)pyrrolidine 3 in this example is:

Under a nitrogen atmosphere, add copper (II) oxalate [3.8 mg, 0.025 mmol], zinc powder (49 mg, 0.75 mmol), solvent NMP (2 mL), and 4-fluoronitrobenzene ( 70.5 mg, 0.5 mmol), 1,4-butanediol bis(4-methylbenzenesulfonate) (468 μL, 1.5 mmol). React for 8 hours on a heater with a rotating speed of 150 rpm and 80°C. After TLC tests, the raw materials are completely reacted and the reaction is stopped. The reaction mixture is extracted several times with a mixture of distilled water and ethyl acetate with a volume ratio of 1:2, and the organic matter is combined. phase, dried over anhydrous magnesium sulfate, concentrated the organic phase, and then subjected to column chromatography. The eluent was (ethyl acetate/petroleum ether = 50/1) to obtain 77.6 mg of product as a light yellow liquid with a yield of 94%.

¹ HNMR (400MHz, CDCl ₃ ) δ7.01–6.84(m,2H),6.57–6.48(m,2H),3.23(t,4H),2.03–1.95(m,4H). ¹³ C{1H}NMR (100MHz, CDCl ₃ ) δ 155.1, 144.5, 115.4, 112.1, 48.7, 25.6. ¹⁹ F NMR (376MHz, CDCl ₃ ) δ-130.93. Ms (EI): m/z=165.5[M]+.

Example 4

The synthesis of 1-(4-chlorophenyl)pyrrolidine 4 in this example is:

Under a nitrogen atmosphere, add copper (II) nitrate [2.80 mg, 0.015 mmol], zinc powder (49 mg, 0.75 mmol), solvent DMSO (2 mL), and 4-chloronitrobenzene ( 79 mg, 0.5 mmol), 1,4-butanediol bis(4-methylbenzenesulfonate) (312 μL, 1 mmol). React for 8 hours on a heater with a rotating speed of 150 rpm and 70°C. TLC detects that the raw material reaction is complete. Stop the reaction. Extract the reaction mixture with a mixture of distilled water and ethyl acetate with a volume ratio of 1:2. phase, dried over anhydrous magnesium sulfate, concentrated the organic phase, and then subjected to column chromatography. The eluent was (ethyl acetate/petroleum ether = 50/1) to obtain 87 mg of a light yellow liquid product with a yield of 96%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.24–7.11(m,2H),6.54–6.42(m,2H),3.24(t,4H),2.01–1.95(m,4H). ¹³ C{1H} NMR (100MHz, CDCl ₃ ) δ 146.5, 128.2, 120.8, 112.3, 47.4, 25.4.Ms (EI): m/z=181.3[M]+.

Example 5

The synthesis of 4-(pyrrolidin-1-yl)benzonitrile 5 in this example is:

Under a nitrogen atmosphere, add copper (II) hydroxide [1.46 mg, 0.015 mmol], zinc powder (49 mg, 0.75 mmol), solvent 1,4-Dioxane (1 mL), and p-nitrogen in order to a dry 25 mL schlenk reaction flask. 1,4-butanediol bis(4-methylbenzenesulfonate) (312 μL, 1 mmol). React for 8 hours on a heater with a rotating speed of 150 rpm and 70°C. TLC detects that the raw material reaction is complete. Stop the reaction. Extract the reaction mixture with a mixture of distilled water and ethyl acetate with a volume ratio of 1:2. phase, dried over anhydrous magnesium sulfate, concentrated the organic phase, and then subjected to column chromatography. The eluent was (ethyl acetate/petroleum ether = 50/1) to obtain 82 mg of a light yellow liquid product with a yield of 95%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.46–7.41(m,2H),6.53(d,2H),3.34–3.21(m,4H),2.13–1.96(m,4H). ¹³ C{1H} NMR (100MHz, CDCl ₃ ) δ 150.3, 133.4, 121.5, 111.3, 96.3, 47.7, 25.5. Ms (EI): m/z=172.6[M]+.

Example 6

The synthesis of 1-(4-(trifluoromethyl)phenyl)pyrrolidine 6 in this example is:

Under a nitrogen atmosphere, add anhydrous copper (II) acetate (2.72 mg, 0.015 mmol), zinc powder (49 mg, 0.75 mmol), solvent CH ₃ CN (2 mL), and 4-nitrate in order to a dry 25 mL schlenk reaction flask. Trifluorotoluene (95.6 mg, 0.5 mmol), 1,4-butanediol bis(4-methylbenzenesulfonate) (468 μL, 1.5 mmol). React for 8 hours on a heater with a rotating speed of 200 rpm and 70°C. TLC detects that the raw material reaction is complete. Stop the reaction. Extract the reaction mixture with a mixture of distilled water and ethyl acetate with a volume ratio of 1:2. phase, dried over anhydrous magnesium sulfate, concentrated the organic phase, and then subjected to column chromatography. The eluent was (ethyl acetate/petroleum ether = 50/1) to obtain 104 mg of a light yellow liquid product with a yield of 97%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.43 (d, 2H), 6.54 (d, 2H), 3.33 (t, 4H), 2.02 (td, 4H). ¹³ C{1H} NMR (100MHz, CDCl ₃ )δ148.4,125.5(q,),124.2,115.3,109.5,46.3,24.7. ¹⁹ F NMR (376MHz, CDCl ₃ )δ-60.55.Ms(EI): m/z=215.3[M]+.

Example 7

The synthesis of 8-(1-pyrrolidinyl)-quinoline 7 in this example is:

Under a nitrogen atmosphere, add copper (II) triflate (II) [5.42 mg, 0.015 mmol], zinc powder (49 mg, 0.75 mmol), solvent THF (2 mL), and 7-nitrate in order to a dry 25 mL schlenk reaction bottle. Quinoline (87 mg, 0.5 mmol), 1,4-butanediol bis(4-methylbenzenesulfonate) (468 μL, 1.5 mmol). React for 8 hours on a heater with a rotating speed of 200 rpm and 80°C. After TLC detects that the raw material reaction is complete, the reaction is stopped. The reaction mixture is extracted several times with a mixture of distilled water and ethyl acetate with a volume ratio of 1:2, and the organic matter is combined. phase, dried over anhydrous magnesium sulfate, concentrated the organic phase, and then subjected to column chromatography. The eluent was (ethyl acetate/petroleum ether = 50/1) to obtain 92 mg of product as a light yellow liquid with a yield of 93%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.77–8.74(m,1H),8.05–8.01(m,1H),7.42–7.25(m,2H),7.18–7.14(m,1H),6.84–6.81 (m,1H),3.74–3.72(m,4H),2.06–1.92(m,4H). ¹³ C{1H}NMR(100MHz,CDCl ₃ )δ146.5,141.3,135.4,129.5,127.1,120.5,116.5, 111.2,52.3,25.3.Ms(EI):m/z＝198.3[M]+.

Example 8

The synthesis of Example 5-pyrrolebenzo[b]thiophene 8 is as follows:

Under a nitrogen atmosphere, add copper (II) bromide [3.35 mg, 0.015 mmol], zinc powder (49 mg, 0.75 mmol), solvent N-methylpyrrolidone (2 mL), and 5- Nitrobenzothiophene (89.6 mg, 0.5 mmol), 1,4-butanediol bis(4-methylbenzenesulfonate) (468 μL, 1.5 mmol). React for 8 hours on a heater with a rotating speed of 200 rpm and 80°C. After TLC detects that the raw material reaction is complete, the reaction is stopped. The reaction mixture is extracted several times with a mixture of distilled water and ethyl acetate with a volume ratio of 1:2, and the organic matter is combined. phase, dried over anhydrous magnesium sulfate, concentrated the organic phase, and then subjected to column chromatography. The eluent was (ethyl acetate/petroleum ether = 50/1) to obtain 116 mg of product as a light yellow liquid with a yield of 96%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.65(d,1H),7.33(d,1H),7.14(d,1H),6.94(d,1H),6.78–6.73(m,1H),3.38– 3.23(m,4H),2.08–1.92(m,4H). ¹³ C{1H}NMR(100MHz, CDCl ₃ )δ146.1,141.3,127.5,126.4,123.7,112.9,112.3,104.5,48.3,25.7.Ms( EI):m/z＝203.3[M]+.

Although the embodiments of the present invention have been shown and described, those of ordinary skill in the art will understand that various changes, modifications, and substitutions can be made to these embodiments without departing from the principles and spirit of the invention. and modifications, the scope of the invention is defined by the appended claims and their equivalents.

Claims (7)

1. The synthesis method of the 1-phenylpyrrolidine derivative is characterized by comprising the following steps of: sequentially adding a catalyst Cu (II), zinc powder and an organic solvent into a dried schlenk reaction tube under the nitrogen atmosphere, then adding an aromatic nitro compound and 1, 4-butanediol bis (4-methylbenzenesulfonate), reacting for 8 hours at 50-80 ℃, adding a mixed liquid of distilled water and ethyl acetate into a reaction liquid for extraction after the aromatic nitro compound is completely converted, mixing an organic phase, adding anhydrous magnesium sulfate for drying, concentrating the organic phase at 40 ℃, and obtaining a target product 1-phenylpyrrolidine derivative through column chromatography;

the aromatic nitro compound isWherein R is ¹ Is hydrogen, halogen, alkyl, aryl, -OMe, -CHO, -CN, -SCH ₃ Either or both of them;

the catalyst Cu (II) is one of copper (II) sulfate, copper (II) oxalate, copper (II) chloride, copper (II) nitrate, copper (II) bromide, copper (II) triflate, copper (II) hydroxide and anhydrous copper (II) acetate;

the 1-phenylpyrrolidine derivative isWherein R is ¹ Is hydrogen, halogen, alkyl, aryl, -OMe, -CHO, -CN, -SCH ₃ Either or both of them.

2. The method for synthesizing 1-phenylpyrrolidine derivatives according to claim 1, wherein a molar ratio of 1, 4-butanediol bis (4-methylbenzenesulfonate) to the aromatic nitro compound is 2-3:1.

3. The method for synthesizing 1-phenylpyrrolidine derivatives according to claim 1, wherein the catalyst Cu (II) is used in an amount of 3 to 5mol% based on the aromatic nitro compound.

4. The method for synthesizing 1-phenylpyrrolidine derivatives according to claim 1, wherein the organic solvent is toluene, 1,4-dioxane, THF, DMSO, CH ₃ CN, NMP, DMF.

5. The method for synthesizing 1-phenylpyrrolidine derivatives according to claim 1, wherein the organic solvent is used in an amount of 1mL to 4mL per millimole of the aromatic nitro compound.

6. The method for synthesizing the 1-phenylpyrrolidine derivative according to claim 1, wherein the molar ratio of zinc powder to aromatic nitro compound is 1.5:1.

7. The method for synthesizing 1-phenylpyrrolidine derivatives according to claim 1, wherein the eluent for column chromatography is a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 50:1.