Sodium hydride suspension and its use in flow chemistry reactions

Abstract

The application discloses a sodium hydride suspension liquid, wherein sodium hydride is dispersed in an organic solvent with a density of 1.2-1.5 g / mL or an organic solvent with a viscosity of 5-30 mm 2 / s, a suspension liquid with a concentration of 0.02-0.05 g / mL is formed, and the suspension liquid can be used in a flow chemical reaction. The application has the advantages of safe scale-up production and high reaction yield.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of chemical synthesis, in particular to the technical field of flow chemistry reaction synthesis, and specifically relates to a sodium hydride suspension and application thereof in flow chemistry reaction. BACKGROUND

[0002] Sodium hydride is an ionic hydride with high chemical activity. Powdered sodium hydride can spontaneously combust in humid air, and react violently with water to release hydrogen gas and combust or explode. Therefore, sodium hydride must be dispersed in liquids such as toluene, liquid paraffin and kerosene which are insoluble and non-chemically reactive to sodium hydride, and stored separately from acids, alcohols, water, strong oxidants, oxygen and halogens.

[0003] Sodium hydride cannot be dissolved in organic solvents, and is usually dispersed in oil at a proportion of 25% to 60%. Since sodium hydride is extremely flammable, there is a high risk in participating in a tank reaction, and the reaction safety is low. SUMMARY

[0004] The technical problem to be solved by the present application is to provide a preparation method of sodium hydride suspension and apply it to flow chemistry reaction.

[0005] To solve the above technical problem, the present application adopts the following specific technical scheme:

[0006] In the first aspect of the present application, a sodium hydride suspension is provided, characterized in that sodium hydride is dispersed in an organic solvent with a density of 1.2 to 1.5 g / mL or an organic solvent with a viscosity of 5 to 30 mm 2 / s, to form a suspension with a concentration of 0.02 to 0.05 g / mL.

[0007] In some specific embodiments, the organic solvent with a density of 1.2 to 1.5 g / mL is selected from one or both of dichloromethane (DCM) and 1,2-dichloroethane; and the organic solvent with a viscosity of 5 to 30 mm 2 / s is selected from one or both of paraffin oil and mineral oil.

[0008] In the second aspect of the present application, the application of sodium hydride suspension in flow chemistry reaction is provided, characterized in that the flow chemistry reaction is to pass inert gas into a reactor, mix reaction liquid A with sodium hydride suspension, carry out reaction, mix the system after reaction with reaction liquid C, carry out reaction, add quenching agent, and obtain product after post-treatment.

[0009] Sodium hydride in a suspension of sodium hydride grabs an acidic hydrogen on a reactive group selected from one or more of -OH, -NHR, -CHR2, and reacts with an electrophile; the type of reaction with the electrophile is one or more of a substitution reaction, a wittig reaction, a cyclization reaction; R denotes hydrogen or a substituent.

[0010] In some embodiments, the reaction liquid A is selected from one or more of an imidazole solution, a 4-nitro-1H-indole solution, a 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester solution, a 2,4,5-tribromo-1H-imidazole solution, a 3-nitro-1H-pyrazole solution, a pyrrolidin-2-one solution, a 9H-carbazole, a 4-chloro-6-(trifluoromethyl)pyrimidin-2-amine solution, a tert-butyl N-(2-hydroxyethyl)carbamate solution, a tert-butyl 4-hydroxypiperidine-1-carboxylate solution, a benzyl alcohol solution, a 2,2'-(ethane-1,2-diylbis(oxy))bis(ethan-1-ol) solution, a (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid solution, a (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid, a 2-diethoxyphosphoryl acetic acid ethyl ester solution, a 1-((isocyanomethyl)sulfonyl)-4-methylbenzene solution, a methyl 4-bromo-1H-pyrrole-2-carboxylate solution, a methyl 1H-pyrrole-2-carboxylate solution, a 1-(5-bromo-2-hydroxyphenyl)ethan-1-one solution; the reaction liquid C is selected from one or more of a 2-(chloromethoxy)ethyl trimethylsilane solution, a benzenesulfonyl chloride solution, a MeI solution, a 2-(chloromethoxy)ethyl trimethylsilane solution, a 1-(chloromethyl)-4-methoxybenzene solution, a 2,3,4,5,6-pentafluorobenzene-1-carbaldehyde, a 2,4,5,6-tetrafluorobenzene-1,3-dicarbonitrile, a 2-iodopropane solution, a 3-chloro-2-(chloromethyl)prop-1-ene solution, a 3-bromoprop-1-yne solution, a 3-chloroisonicotinonitrile solution, a tert-butyl 2-bromoacetate solution, a 3-fluoro-2-nitro-pyridine solution, a 1-bromo-2-methoxyethane, a 1,4-dioxaspiro[4.5]dec-8-one solution, a tert-butyl acrylate solution, a (aminooxy)diphenylphosphine oxide solution, a O-(2,4-dinitrophenyl)hydroxylamine solution, a diethyl carbonate solution.

[0011] Further, the reaction liquid A and the reaction liquid C are used in one of the following combinations:

[0012] a1. Reaction solution A is imidazole solution, reaction solution C is 2- (chloromethoxy) ethyl trimethylsilane solution; a2. Reaction solution A is 4-nitro-1H-indole solution, reaction solution C is benzenesulfonyl chloride solution; a3. Reaction solution A is 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester solution, reaction solution C is MeI solution; a4. Reaction solution A is 2,4,5-tribromo-1H-imidazole solution, reaction solution C is 2- (chloromethoxy) ethyl trimethylsilane solution; a5. Reaction solution A is 3-nitro-1H-pyrazole solution, reaction solution C is 2- (chloromethoxy) ethyl trimethylsilane solution; a6. Reaction solution A is pyrrolidin-2-one solution, reaction solution C is 1- (chloromethyl) -4-methoxybenzene solution; a7. Reaction solution A is 9H-carbazole solution, reaction solution C is 2,3,4,5,6-pentafluorobenzene-1-carbonitrile solution; a8. Reaction solution A is 9H-carbazole solution, reaction solution C is 2,4,5,6-tetrafluorobenzene-1,3-dicarbonitrile solution;

[0013] b1. Reaction solution A is 4-chloro-6- (trifluoromethyl) pyrimidine-2-amine solution, reaction solution C is 2-iodopropane solution; b2. Reaction solution A is N- (2-hydroxyethyl) tert-butyl carbamate solution, reaction solution C is 3-chloro-2- (chloromethyl) prop-1-ene solution; b3. Reaction solution A is 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester solution, reaction solution C is 3-bromoprop-1-yne solution; b4. Reaction solution A is benzyl alcohol solution, reaction solution C is 3-chloroisonicotinonitrile solution; b5. Reaction solution A is 2,2'- (ethane-1,2-diylbis (oxy) ) bis (ethane-1-ol) solution, reaction solution C is tert-butyl 2-bromoacetate solution; b6. Reaction solution A is (2S) -2- (tert-butoxycarbonylamino) -3-hydroxypropanoic acid solution, reaction solution C is 3-fluoro-2-nitro-pyridine solution; b7. Reaction solution A is (2S,4R) -1- (tert-butoxycarbonyl) -4-hydroxypyrrolidine-2-carboxylic acid solution, reaction solution C is 1-bromo-2-methoxyethane solution;

[0014] c1. Reaction solution A is ethyl 2-diethoxyphosphorylacetate solution, reaction solution C is 1,4-dioxaspiro [4.5] decan-8-one solution; c2. Reaction solution A is 1- ( (isocyanomethyl) sulfonyl) -4-methylbenzene solution, reaction solution C is tert-butyl acrylate solution; c3. Reaction solution A is methyl 4-bromo-1H-pyrrole-2-carboxylate solution, reaction solution C is (aminooxy) diphenylphosphine oxide solution; c4. Reaction solution A is methyl 1H-pyrrole-2-carboxylate solution, reaction solution C is O- (2,4-dinitrophenyl) hydroxylamine solution; c5. Reaction solution A is 1- (5-bromo-2-hydroxyphenyl) ethan-1-one solution, reaction solution C is diethyl carbonate solution.

[0015] The main products after the reaction of sodium hydride suspension and the reaction solution of a1-a8 are 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole, 1-(phenylsulfonyl)-4-nitro-indole, 1,2-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester, 2,4,5-tribromo-1-(5,5-dimethyl-2-oxa-5-silahex-1-yl)imidazole, 3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole, 1-[(4-methoxyphenyl)methyl]tetrahydropyrrol-2-one, pentacarbazolyl benzonitrile, 2,4,5,6-tetracarbazoyldicyano benzene;

[0016] The main products after the reaction of sodium hydride suspension and the reaction solution of b1-b7 are 4-chloro-N-isopropyl-6-(trifluoromethyl)pyrimidin-2-amine, 6-methylene-1,4-oxazepane-4-carboxylic acid tert-butyl ester, 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylic acid tert-butyl ester, 3-(benzyloxy)isonicotinonitrile, 3,6,9,12-tetraoxatetradecane-1,14-dicarboxylic acid di-tert-butyl ester, N-(tert-butoxycarbonyl)-O-(2-nitropyridin-3-yl)-L-serine, (2S,4R)-1-(tert-butoxycarbonyl)-4-(2-methoxyethoxy)pyrrolidine-2-carboxylic acid;

[0017] The main products after the reaction of sodium hydride suspension and the reaction solution of c1-c5 are 2-(1,4-dioxaspiro[4.5]dec-8-ylidene)acetic acid ethyl ester, 1H-pyrrole-3-carboxylic acid tert-butyl ester, 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester, 1-amino-1H-pyrrole-2-carboxylic acid methyl ester, 3-(5-bromo-2-hydroxyphenyl)-3-oxopropionic acid ethyl ester.

[0018] In some specific embodiments, the concentration of the reaction solution A is 0.1-0.2 g / mL, and the concentration of the reaction solution C is 0.05-0.3 g / mL.

[0019] In some specific embodiments, the quencher is water, which is flowed into the reactor during or after the reaction; the flow rate ratio of the reaction solution A, sodium hydride suspension, reaction solution C, and quencher is 0.6-1.9:1:0.6-1.9:0.8-1.6.

[0020] In some specific embodiments, the reaction solution A and sodium hydride suspension are mixed and reacted in the first reactor, and then the mixture is flowed into the microchannel reactor; the reaction solution C is flowed into the microchannel reactor; the flow rate ratio is 1:0.5-1.

[0021] In some specific embodiments, the reaction time of the reaction liquid A with the sodium hydride suspension is 1-10 min, and the reaction temperature is 0-50℃; the reaction time of the reacted system with the reaction liquid C is 1-12 min, and the reaction temperature is 0-100℃; the reaction time after adding the water is 1-5 min, and the reaction temperature is 0-25℃.

[0022] Preferably, the reaction time of the reaction liquid A with the sodium hydride suspension is 4-10 min, and the reaction temperature is 0-25℃.

[0023] Further preferably, the reaction time of the reaction liquid A with the sodium hydride suspension is 4-10 min, and the reaction temperature is 0-5℃; the reaction time of the reacted system with the reaction liquid C is 1-12 min, and the reaction temperature is 0-100℃; the reaction time after adding the water is 3.2-5 min, and the reaction temperature is 0-5℃.

[0024] In some specific embodiments, the step of post-treatment is one of the following two modes: a) including washing, extraction, and concentration under reduced pressure; b) adding water to precipitate.

[0025] Further, the mode a) of the step of post-treatment includes adding the reaction liquid into a saturated ammonium chloride aqueous solution, extracting with an organic solvent, and concentrating under reduced pressure, wherein the organic solvent is one or more selected from dichloromethane, ethyl acetate, methyl tert-butyl ether, and isopropyl acetate.

[0026] Specifically, the sodium hydride suspension can be used in a wide range of flow chemistry reactions, such as alkylation and acylation reactions of some heterocyclic nitrogen atoms, and the products of these reactions include:

[0027]

[0028] Specifically, the sodium hydride suspension can also be used in some aminoalkylation and alcohol alkylation reactions, N and O atom nucleophilic reactions, and reactions requiring strong base to abstract hydrogen to proceed, and the products of these reactions include:

[0029]

[0030] Specifically, the sodium hydride suspension can also be used in some wittig reactions and other carbon-carbon bond formation reactions or nitrogen-nitrogen bond formation reactions, which are mainly characterized by the abstraction of hydrogen at the alpha position of a carbonyl group or the formation of a nitrogen-nitrogen bond from an amino group, and the products of these reactions include:

[0031]

[0032] Compared with the prior art, the present application has the following beneficial effects:

[0033] 1. Sodium hydride is stably suspended in an organic liquid phase, which solves the problem that sodium hydride cannot be stably fed in a flow chemical reaction, and can be used in a flow chemical reaction.

[0034] 2. The continuous flow mode can effectively solve the reaction safety problem of sodium hydride in a tank reactor, and safely realize scale-up reaction.

[0035] 3. When sodium hydride is quenched, it releases a large amount of heat and generates a large amount of hydrogen. By using a flow chemical reaction mode, the overall reaction is quenched under the protection of inert gas, which is low-risk and safe and reliable.

[0036] 4. High reaction yield, combined with a microchannel reactor, which can further improve the yield.

[0037] The concept, specific structure and technical effects of the present application will be further described below with reference to the accompanying drawings, so as to fully understand the purpose, features and effects of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 is a flow chemical reaction schematic diagram of example 1.

[0039] Figure 2 is a flow chemical reaction schematic diagram of example 2. DETAILED DESCRIPTION

[0040] In order to make the technical means, creative features, purposes and effects of the application easy to understand, the present application will be further described below in combination with specific drawings. However, the present application is not limited to the following examples.

[0041] It should be noted that the structure, proportion, size, etc. shown in the drawings attached to the present specification are only used to cooperate with the content disclosed in the specification, so as to be understood and read by those skilled in the art, and do not define the limiting conditions for the implementation of the present application, therefore, they do not have technical substantial significance, and as long as they do not affect the effects and purposes that can be achieved by the present application, they should still fall within the scope of the technical content disclosed by the present application.

[0042] Example 1

[0043]

[0044] Reaction liquid A: 5g imidazole dissolved in 50mL DMF.

[0045] Reaction liquid B: 3.8g NaH (60% content) suspended in 92.5mL DCM.

[0046] Reaction liquid C: 13.5g 2-(chloromethoxy) ethyl trimethylsilane dissolved in 50mL DMF.

[0047] As shown in Figure 1 The first reactor, the second reactor, the third reactor, and the collector were connected to form a closed system. N2was sufficiently introduced into the first reactor, reaction liquid A was added into the first reactor at a flow rate of 3.597 mL / min, reaction liquid B was added into the first reactor at a flow rate of 6.403 mL / min, the reaction temperature was controlled at 0°C, and the reaction was carried out for 5 min; the reaction liquid in the first reactor flowed into the second reactor, reaction liquid C was added into the second reactor at a flow rate of 4.053 mL / min, the reaction temperature was controlled at 25°C, and the reaction was carried out for 7.1 min; the reaction liquid in the second reactor flowed into the third reactor, water was added into the third reactor at a flow rate of 7 mL / min, the quenching reaction temperature was controlled at 0°C, and the reaction was carried out for 4.7 min. After the reaction was completed, the reaction liquid was added into 50 mL of saturated ammonium chloride aqueous solution, extracted with 50 mL of dichloromethane, and the organic phase was concentrated under reduced pressure to obtain 6.1 g of 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole in the form of yellow oil, and the calculated yield was 42%.

[0048] MS detection result: M+1 (199.0);

[0049] NMR detection result: 1 H NMR (400 MHz, DMSO-d6) δ = 7.77 (s, 1H), 7.25 (s, 1H), 6.92 (s, 1H), 5.32 (s, 2H), 3.49-3.40 (m, 2H), 0.85-0.79 (m, 2H), -0.05 (s, 9H).

[0050] Example 2

[0051]

[0052] Reaction liquid A: 5 g of imidazole was dissolved in 50 mL of DMF.

[0053] Reaction liquid B: 3.8 g of NaH (60% content) was suspended in 50 mL of mineral oil.

[0054] Reaction liquid C: 13.5 g of 2-(chloromethoxy)ethyltrimethylsilane was dissolved in 50 mL of DMF.

[0055] As shown in Figure 2 The first reactor, the second reactor, the third reactor, and the collector were connected to form a closed system. N2was sufficiently introduced into the first reactor, reaction liquid A was added into the first reactor at a flow rate of 3.597 mL / min, reaction liquid B was added into the first reactor at a flow rate of 6.403 mL / min, the reaction temperature was controlled at 0°C, and the reaction was carried out for 5 min.

[0056] The above reacted liquid was flowed into the second reactor (microchannel reactor) at a flow rate of 10 mL / min, reaction liquid C was flowed into the second reactor (microchannel reactor) at a flow rate of 6.687 mL / min, the outer diameter of the microchannel reactor was 1 / 8 inch, the holdup volume was 16.8 mL, the reaction temperature was controlled at 25°C, and the reaction time was 1.1 min; water was added to the third reactor at a flow rate of 7 mL / min, the quenching reaction temperature was controlled at 0°C, and the reaction time was 4.2 min. After the reaction was completed, the reaction liquid was added to 50 mL of saturated ammonium chloride aqueous solution, extracted with 50 mL of ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain 10.9 grams of 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole, yellow oil, with a calculated yield of 75%.

[0057] MS detection result: M+1 (199.0);

[0058] NMR detection result: 1 H NMR (400 MHz, DMSO-d6) δ = 7.81 (s, 1H), 7.30 (s, 1H), 6.97 (s, 1H), 5.36 (s, 2H), 3.52-3.47 (m, 2H), 0.89-0.85 (m, 2H), 0.00 (s, 9H)

[0059] Example 3

[0060]

[0061] Reaction liquid A: 5 g of 4-nitro-1H-indole was dissolved in 50 mL of DMF.

[0062] Reaction liquid B: 1.9 g of NaH (60% content) was suspended in 45 mL of DCM.

[0063] Reaction liquid C: 6 g of phenylsulfonyl chloride was dissolved in 50 mL of DMF.

[0064] The first reactor, the second reactor, the third reactor, and the collector are connected to form a closed system. N2is sufficiently introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 5.211 mL / min, and reaction liquid B is added into the first reactor at a flow rate of 4.798 mL / min. The reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 5.377 mL / min. The reaction temperature is controlled at 0 ℃, and the reaction is carried out for 7.1 min. The reaction liquid in the second reactor flows into the third reactor. Water is added into the third reactor at a flow rate of 7 mL / min. The quenching reaction temperature is controlled at 0 ℃, and the reaction is carried out for 4.7 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution, extracted with 50 mL of dichloromethane, and separated. The organic phase is concentrated under reduced pressure to obtain 7.8 g of 1-(phenylsulfonyl)-4-nitro-indole in the form of yellow oil, and the calculated yield is 85%.

[0065] NMR detection results: 1 H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J = 8.3 Hz, 1H), 8.25-8.19 (m, 2H), 8.12-8.05 (m, 2H), 7.78-7.71 (m, 1H), 7.67-7.58 (m, 3H), 7.37 (d, J = 3.8 Hz, 1H).

[0066] Example 4

[0067]

[0068] Reaction liquid A: 5 g of 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester is dissolved in 50 mL of THF.

[0069] Reaction liquid B: 1.6 g of NaH (60% content) is suspended in 38 mL of DCM.

[0070] Reaction liquid C: 5.6 g of MeI is dissolved in 50 mL of THF.

[0071] The first reactor, the second reactor, the third reactor, and the collector are connected to form a closed system. N2is fully introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 5.531 mL / min, and reaction liquid B is added into the first reactor at a flow rate of 4.469 mL / min. The reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 5.705 mL / min. The reaction temperature is controlled at 25 ℃, and the reaction is carried out for 7.1 min. The reaction liquid in the second reactor flows into the third reactor. Water is added into the third reactor at a flow rate of 7 mL / min. The quenching reaction temperature is controlled at 0 ℃, and the reaction is carried out for 4.7 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution, extracted with 50 mL of dichloromethane, and separated. The organic phase is concentrated under reduced pressure to obtain 5.3 g of 1,2-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester in the form of yellow oil, and the calculated yield is 99%.

[0072] MS detection result: M+1 (168.0);

[0073] NMR detection result: 1 H NMR (400 MHz, DMSO-d6) δ = 6.75 (d, J = 2.9 Hz, 1H), 6.40 (d, J = 3.0 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.60 (s, 3H), 2.52 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0074] Example 5

[0075]

[0076] Reaction liquid A: 5 g of 2,4,5-tribromo-1H-imidazole is dissolved in 50 mL of DMF.

[0077] Reaction liquid B: 0.8 g of NaH (60% content) is suspended in 19 mL of DCM.

[0078] Reaction liquid C: 2.9 g of (2-(chloromethoxy)ethyl)trimethylsilane is dissolved in 50 mL of DMF.

[0079] The first reactor, the second reactor, the third reactor, and the collector are communicated to form a closed system. N2is fully introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 14.431 mL / min, and reaction liquid B is added into the first reactor at a flow rate of 5.569 mL / min. The reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 14.76 mL / min. The reaction temperature is controlled at 25 ℃, and the reaction is carried out for 2.9 min. The reaction liquid in the second reactor flows into the third reactor. Water is added into the third reactor at a flow rate of 7 mL / min. The quenching reaction temperature is controlled at 0 ℃, and the reaction is carried out for 2.9 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution. The aqueous phase is extracted with 50 mL of dichloromethane. The organic phase is concentrated under reduced pressure to obtain 6.6 g of 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole in the form of yellow oil, and the calculated yield is 93%.

[0080] MS detection result: M+1 (376.8);

[0081] NMR detection result: 1 H NMR (400 MHz, DMSO-d6) δ = 5.36 (s, 2H), 3.62 (t, J = 7.9 Hz, 2H), 3.35 (s, 2H), 0.90 (t, J = 7.9 Hz, 2H), 0.00 (s, 8H).

[0082] Example 6

[0083]

[0084] Reaction liquid A: 5 g of 3-nitro-1H-pyrazole is dissolved in 50 mL of DMF.

[0085] Reaction liquid B: 2.1 g of NaH (60% content) is suspended in 19 mL of DCM.

[0086] Reaction liquid C: 8.1 g of (2-(chloromethoxy)ethyl)trimethylsilane is dissolved in 50 mL of DMF.

[0087] The first reactor, the second reactor, the third reactor and the collector are communicated to form a closed system. N2 is fully introduced into the first reactor, reaction liquid A is added into the first reactor at a flow rate of 9.715 mL / min, reaction liquid B is added into the first reactor at a flow rate of 10.285 mL / min, the reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5 min; the reaction liquid in the first reactor flows into the second reactor, reaction liquid C is added into the second reactor at a flow rate of 10.281 mL / min, the reaction temperature is controlled at 25 ℃, and the reaction is carried out for 5 min; the reaction liquid in the second reactor flows into the third reactor, water is added into the third reactor at a flow rate of 7 mL / min, the quenching reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution, the aqueous phase is extracted with 50 mL of dichloromethane, the organic phase is concentrated under reduced pressure, and 8.6 g of 3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole is obtained in the form of yellow oil, and the calculated yield is 78%.

[0088] MS detection result: M+1 (304.9);

[0089] NMR detection result: 1 H NMR (400 MHz, DMSO-d6) δ = 8.25 (d, J = 2.6 Hz, 1H), 7.15 (d, J = 2.6 Hz, 1H), 5.59 (s, 2H), 3.67-3.61 (m, 2H), 0.95-0.87 (m, 2H), 0.03-0.03 (m, 9H).

[0090] Example 7

[0091]

[0092] Reaction liquid A: 5 g of pyrrolidin-2-one is dissolved in 50 mL of DMF.

[0093] Reaction liquid B: 4.7 g of NaH (60% content) is suspended in 110 mL of DCM.

[0094] Reaction liquid C: 9.7 g of 1-(chloromethyl)-4-methoxybenzene is dissolved in 100 mL of DMF.

[0095] The first reactor, the second reactor, the third reactor, and the collector are communicated to form a closed system. N2 is sufficiently introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 3.9 mL / min, and reaction liquid B is added into the first reactor at a flow rate of 6.1 mL / min. The reaction temperature is controlled at 0 ℃, and the reaction is carried out for 10 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 5.9 mL / min. The reaction temperature is controlled at 50-25 ℃, and the reaction is carried out for 12.4 min. The reaction liquid in the second reactor flows into the third reactor. Water is added into the third reactor at a flow rate of 7 mL / min. The quenching reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5 min. After the reaction is completed, the reaction liquid is added into 250 mL of hydrochloric acid aqueous solution (1 M). The aqueous phase is extracted with 210 mL of ethyl acetate. The organic phase is separated with salt water (300 mL). The organic phase is concentrated under reduced pressure to obtain 3.3 g of 1-(4-methoxybenzyl)pyrrolidin-2-one, a colorless liquid, with a calculated yield of 50.4%.

[0096] NMR detection results: 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.17 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 4.40 (s, 2H), 3.80 (s, 3H), 3.26 (t, J = 7.1 Hz, 2H), 2.46 (t, J = 8.1 Hz, 2H), 1.99 (quin, J = 7.6 Hz, 2H).

[0097] Example 8

[0098]

[0099] Reaction liquid A: 22.1 g of 9H-carbazole was dissolved in 50 mL of DMF.

[0100] Reaction liquid B: 5.7 g of NaH (60% content) was suspended in 50 mL of DCM.

[0101] Reaction liquid C: 5 g of 2,3,4,5,6-pentafluorobenzonitrile was dissolved in 50 mL of DMF.

[0102] The first reactor, the second reactor, the third reactor, and the collector are connected to form a closed system. N2 is sufficiently introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 10 mL / min. Reaction liquid B is added into the first reactor at a flow rate of 10 mL / min. The reaction temperature is controlled at 0°C. The reaction is carried out for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 10 mL / min. The reaction temperature is controlled at 25°C. The reaction is carried out for 30 min. The reaction liquid in the second reactor flows into the third reactor. 10% ammonium chloride aqueous solution is added into the third reactor at a flow rate of 20 mL / min. The quenching reaction temperature is controlled at 0°C. The reaction is carried out for 5 min. After the reaction is completed, the reaction liquid is extracted with 500 mL dichloromethane twice. The organic phase is concentrated under reduced pressure to obtain a crude product. The crude product is suspended in 10 mL ethyl acetate and stirred for 10 min. The filter cake is collected by filtration and washed with a small amount of petroleum ether. The mother liquor is further purified by column chromatography (eluent: dichloromethane / methanol = 5:1 to 2:1). A total of 10.5 g of pentakis-carbazolyl benzonitrile is obtained in the form of a yellow solid. The calculated yield is 44%.

[0103] MS detection result: M+1 (929);

[0104] NMR detection result: 1 H NMR (400 MHz, DMSO-d6) δ = 8.18 (d, J = 7.8 Hz, 2H), 7.95 (s, 1H), 7.89-7.80 (m, 6H), 7.79-7.63 (m, 7H), 7.44-7.34 (m, 5H), 7.32 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.4 Hz, 2H), 7.16-7.05 (m, 7H), 6.77-6.56 (m, 9H).

[0105] Example 9

[0106]

[0107] Reaction liquid A: 73.5 g 9H-carbazole was dissolved in 200 mL DMF.

[0108] Reaction liquid B: 18 g NaH (60% content) was suspended in 200 mL paraffin oil.

[0109] Reaction liquid C: 20 g 2,4,5,6-tetrafluoroisophthalonitrile was dissolved in 200 mL DMF.

[0110] The first reactor, the second reactor, the third reactor, and the collector are in communication to form a closed system. N2 is sufficiently introduced into the first reactor, reaction liquid A is added into the first reactor at a flow rate of 11.549 mL / min, reaction liquid B is added into the first reactor at a flow rate of 3.451 mL / min, the reaction temperature is controlled at 0°C, and the reaction is performed for 5 min; the reaction liquid in the first reactor flows into the second reactor, reaction liquid C is added into the second reactor at a flow rate of 9.109 mL / min, the reaction temperature is controlled at 25°C, and the reaction is performed for 7.1 min; the reaction liquid in the second reactor flows into the third reactor, water is added into the third reactor at a flow rate of 7 mL / min, the quenching reaction temperature is controlled at 0°C, and the reaction is performed for 5 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution, filtered, to obtain a part of the crude product, the aqueous phase is extracted with 50 mL of dichloromethane, the organic phase is concentrated under reduced pressure, and the crude products are combined and purified by a silica gel column with petroleum ether:dichloromethane = 10:1 to 3:1, to obtain 70 g of 2,4,5,6-tetrakis(9H-carbazol-9-yl)isophthalonitrile in the form of yellow oil, and the calculated yield is 75%.

[0111] NMR detection results: 1 H NMR (400 MHz, DMSO-d6) δ = 8.36 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.86 (dd, J = 1.3, 7.0 Hz, 2H), 7.80-7.68 (m, 3H), 7.57-7.40 (m, 3H), 7.13 (dtd, J = 1.2, 7.4, 18.5 Hz, 4H), 6.87-6.78 (m, 1H), 6.75-6.67 (m, 1H).

[0112] Example 10

[0113]

[0114] Reaction liquid A: 5 g of 4-chloro-6-(trifluoromethyl)pyrimidin-2-amine was dissolved in 50 mL of DMF.

[0115] Reaction liquid B: 2 g of NaH (60% content) was suspended in 47.5 mL of DCM.

[0116] Reaction liquid C: 12.9 g of 2-iodopropane was dissolved in 50 mL of DMF.

[0117] The first reactor, the second reactor, the third reactor, and the collector are communicated to form a closed system. N2is fully introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 5.083 mL / min, and reaction liquid B is added into the first reactor at a flow rate of 4.917 mL / min. The reaction temperature is controlled at 0 ℃, and the reaction is performed for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 5.626 mL / min. The reaction temperature is controlled at 25 ℃, and the reaction is performed for 38.4 min. The reaction liquid in the second reactor flows into the third reactor. Water is added into the third reactor at a flow rate of 7 mL / min. The quenching reaction temperature is controlled at 0 ℃, and the reaction is performed for 5 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution. The aqueous phase is extracted with 50 mL of dichloromethane. The organic phase is concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA=0% to 1%) to obtain 1.53 g of 4-chloro-N-isopropyl-6-(trifluoromethyl)pyrimidin-2-amine, a colorless liquid, with a calculated yield of 26%.

[0118] MS detection result: M+1 (240.0);

[0119] NMR detection result: 1 H NMR (400 MHz, DMSO-d6) δ = 8.45-8.08 (m, 1H), 4.10-3.86 (m, 1H), 1.14 (d, J = 6.6 Hz, 6H).

[0120] Example 11

[0121]

[0122] Reaction liquid A: 5 g of N-(2-hydroxyethyl)tert-butylcarbamate is dissolved in 50 mL of DMF.

[0123] Reaction liquid B: 3.1 g of NaH (60% content) is suspended in 75 mL of DCM.

[0124] Reaction liquid C: 4.1 g of 3-chloro-2-(chloromethyl)prop-1-ene is dissolved in 50 mL of DMF.

[0125] The first reactor, the second reactor, the third reactor, and the collector are communicated to form a closed system. N2 is sufficiently introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 4.105 mL / min, reaction liquid B is added into the first reactor at a flow rate of 5.895 mL / min, the reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 4.053 mL / min, the reaction temperature is controlled at 25 ℃, and the reaction is carried out for 7.1 min. The reaction liquid in the second reactor flows into the third reactor. Water is added into the third reactor at a flow rate of 7 mL / min, the quenching reaction temperature is controlled at 0 ℃, and the reaction is carried out for 4.7 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution, extracted with 50 mL of dichloromethane, and separated. The organic phase is concentrated under reduced pressure to obtain 3.3 g of 6-methylene-1,4-oxazepane-4-carboxylic acid tert-butyl ester in the form of yellow oil, and the calculated yield is 49%.

[0126] NMR detection results: 1 H NMR (400 MHz, DMSO-d6) δ = 5.02-4.89 (m, 2H), 4.14-3.97 (m, 4H), 3.66-3.59 (m, 2H), 3.44-3.38 (m, 2H), 1.40 (br d, J = 4.0 Hz, 9H).

[0127] Example 12

[0128]

[0129] Reaction liquid A: 1 g of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester is dissolved in 10 mL of THF.

[0130] Reaction liquid B: 0.2 g of NaH (60% content) is suspended in 5 mL of DCM.

[0131] Reaction liquid C: 0.6 g of 3-bromoprop-1-yne is dissolved in 10 mL of THF.

[0132] The first reactor, the second reactor, the third reactor, and the collector are communicated to form a closed system. N2 is sufficiently introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 9.805 mL / min, and reaction liquid B is added into the first reactor at a flow rate of 4.901 mL / min. The reaction temperature is controlled at 0 ℃, and the reaction is performed for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 9.68 mL / min. The reaction temperature is controlled at 25 ℃, and the reaction is performed for 4.1 min. The reaction liquid in the second reactor flows into the third reactor. Water is added into the third reactor at a flow rate of 7 mL / min. The quenching reaction temperature is controlled at 0 ℃, and the reaction is performed for 5 min. After the reaction is completed, the reaction liquid is added into 30 mL of saturated ammonium chloride aqueous solution. The aqueous phase is extracted with 30 mL of ethyl acetate. The organic phase is washed with brine (30 mL) and separated. The organic phase is concentrated under reduced pressure to obtain 0.8 g of 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylic acid tert-butyl ester in the form of yellow oil, and the calculated yield is 67%.

[0133] NMR detection result: 1 H NMR (400 MHz, CHLOROFORM-d) δ = 4.13 (d, J = 2.4 Hz, 2H), 3.79-3.55 (m, 3H), 3.03 (ddd, J = 3.4, 9.4, 13.3 Hz, 2H), 2.35 (t, J = 2.4 Hz, 1H), 1.85-1.69 (m, 2H), 1.55-1.44 (m, 2H), 1.39 (s, 9H).

[0134] Example 13

[0135]

[0136] Reaction liquid A: 5 g of benzyl alcohol is dissolved in 50 mL of DMF.

[0137] Reaction liquid B: 2.2 g of NaH (60% content) is suspended in 50 mL of mineral oil.

[0138] Reaction liquid C: 6.4 g of 3-fluoroisonicotinonitrile is dissolved in 50 mL of DMF.

[0139] The first reactor, the second reactor, the third reactor, and the collector are communicated to form a closed system. N2 is sufficiently introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 11.088 mL / min, and reaction liquid B is added into the first reactor at a flow rate of 8.912 mL / min. The reaction temperature is controlled at 0°C, and the reaction is performed for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 9.289 mL / min. The reaction temperature is controlled at 15°C, and the reaction is performed for 85.4 min. The reaction liquid in the second reactor flows into the third reactor. Water is added into the third reactor at a flow rate of 7 mL / min. The quenching reaction temperature is controlled at 0°C, and the reaction is performed for 5 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution. The aqueous phase is extracted with 50 mL of DCM. The organic phase is concentrated under reduced pressure and purified by a silica gel column (PE:EA = 10:1 to 3:1) to obtain 4 g of 3-(benzyloxy)isonicotinonitrile in the form of yellow oil, and the calculated yield is 77%.

[0140] MS detection result: M+1 (211.1);

[0141] NMR detection result: 1 H NMR (400 MHz, DMSO-d6) δ = 8.78 (s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 7.79 (d, J = 4.8 Hz, 1H), 7.55-7.48 (m, 2H), 7.47-7.40 (m, 2H), 7.40-7.32 (m, 1H), 5.44 (s, 2H).

[0142] Example 14

[0143]

[0144] Reaction liquid A: 2.5 g of 2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-1-ol) is dissolved in 25 mL of THF.

[0145] Reaction liquid B: 1.4 g of NaH (60% content) is suspended in 33.8 mL of DCM.

[0146] Reaction liquid C: 13.5 g of tert-butyl 2-bromoacetate is dissolved in 25 mL of THF.

[0147] The first reactor, the second reactor, the third reactor, and the collector are in communication to form a closed system. N2is sufficiently introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 4.818 mL / min, and reaction liquid B is added into the first reactor at a flow rate of 5.819 mL / min. The reaction temperature is controlled at 0°C, and the reaction is carried out for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 4.905 mL / min. The reaction temperature is controlled at 25°C, and the reaction is carried out for 13.4 min. The reaction liquid in the second reactor flows into the third reactor. Water is added into the third reactor at a flow rate of 7 mL / min. The quenching reaction temperature is controlled at 0°C, and the reaction is carried out for 5 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution. The aqueous phase is extracted with 50 mL of DCM. The organic phase is concentrated under reduced pressure and purified by silica gel column (PE:EA = 10:1 to 1:1) to obtain 2.6 g of di-tert-butyl 3,6,9,12-tetraoxatetradecane-1,14-dicarboxylate in the form of yellow oil, and the calculated yield is 41%.

[0148] NMR detection results: 1 H NMR (400 MHz, DMSO-d6) δ = 3.99 (s, 4H), 3.60-3.51 (m, 12H), 1.43 (s, 18H).

[0149] Example 15

[0150]

[0151] Reaction liquid A: 5 g of (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid is dissolved in 75 mL of DMF.

[0152] Reaction liquid B: 2 g of NaH (60% content) is suspended in 50 mL of DCM.

[0153] Reaction liquid C: 3.3 g of 3-fluoro-2-nitro-pyridine is dissolved in 50 mL of DMF.

[0154] The first reactor, the second reactor, the third reactor and the collector are communicated to form a closed system. N2 is fully introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 11.274 mL / min, reaction liquid B is added into the first reactor at a flow rate of 8.726 mL / min, the reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5.2 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 8.581 mL / min, the reaction temperature is controlled at 25 ℃, and the reaction is carried out for 10.4 min. The reaction liquid in the second reactor flows into the third reactor. Ammonium chloride aqueous solution is added into the third reactor at a flow rate of 7 mL / min, the quenching reaction temperature is controlled at 0 ℃, and the reaction is carried out for 4.2 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution, extracted with 50 mL of dichloromethane, and separated. The organic phase is concentrated under reduced pressure to obtain 4.7 g of N-(tert-butoxycarbonyl)-O-(2-nitropyridin-3-yl)-L-serine, a colorless oil, with a calculated yield of 59%.

[0155] NMR detection results: 1 H NMR (400 MHz, DMSO-d6) δ = 8.13 (dd, J = 0.9, 4.5 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.76 (dd, J = 4.5, 8.5 Hz, 1H), 7.17 (br d, J = 7.5 Hz, 1H), 4.53-4.45 (m, 1H), 4.43-4.35 (m, 2H), 1.38 (s, 9H).

[0156] Example 16

[0157]

[0158] Reaction liquid A: 5 g of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid was dissolved in 50 mL of DMF.

[0159] Reaction liquid B: 3.5 g of NaH (60% content) was suspended in 50 mL of mineral oil.

[0160] Reaction liquid C: 6 g of 1-bromo-2-methoxyethane was dissolved in 50 mL of DMF.

[0161] The first reactor, the second reactor, the third reactor, and the collector are communicated to form a closed system. N2 is fully introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 11.024 mL / min, and reaction liquid B is added into the first reactor at a flow rate of 3.976 mL / min. The reaction temperature is controlled at 0°C, and the reaction is performed for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 11.122 mL / min. The reaction temperature is controlled at 25°C, and the reaction is performed for 57.4 min. The reaction liquid in the second reactor flows into the third reactor. Water is added into the third reactor at a flow rate of 7 mL / min. The quenching reaction temperature is controlled at 0°C, and the reaction is performed for 5 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution. The aqueous phase is extracted with 50 mL of DCM. The organic phase is concentrated under reduced pressure and purified by a silica gel column (PE:EA = 10:1 to 1:1) to obtain 1.2 g of (2S,4R)-1-(tert-butoxycarbonyl)-4-(2-methoxyethoxy)pyrrolidine-2-carboxylic acid in the form of yellow oil, with a calculated yield of 20%.

[0162] NMR detection results: 1 H NMR (400 MHz, CHLOROFORM-d) δ = 4.43-4.22 (m, 1H), 4.13-4.03 (m, 1H), 3.61-3.40 (m, 6H), 3.31 (s, 3H), 2.46-2.02 (m, 2H), 1.46-1.31 (m, 9H).

[0163] Example 17

[0164]

[0165] Reaction liquid A: 22.2 g of 2-diethoxyphosphoryl ethyl acetate was dissolved in 144 mL of THF.

[0166] Reaction liquid B: 5.1 g of NaH (60% content) was suspended in 117.6 mL of DCM.

[0167] Reaction liquid C: 15.4 g of 1,4-dioxaspiro[4.5]decan-8-one was dissolved in 147 mL of THF.

[0168] The first reactor, the second reactor, the third reactor, and the collector are communicated to form a closed system. N2 is fully introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 5.635 mL / min, and reaction liquid B is added into the first reactor at a flow rate of 4.365 mL / min. The reaction temperature is controlled at 0 ℃, and the reaction is performed for 5.2 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 5.249 mL / min. The reaction temperature is controlled at 25 ℃, and the reaction is performed for 6.4 min. The reaction liquid in the second reactor flows into the third reactor. An aqueous solution is added into the third reactor at a flow rate of 7 mL / min. The quenching reaction temperature is controlled at 0 ℃, and the reaction is performed for 3.2 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution, extracted with 100 mL of ethyl acetate, and separated. The organic phase is concentrated under reduced pressure to obtain 22 g of ethyl 2-(1,4-dioxaspiro[4.5]dec-8-ylidene)acetate, which is a colorless oil. The calculated yield is 99%.

[0169] NMR detection results: 1 H NMR (400 MHz, DMSO-d6) δ = 5.68 (s, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.90 (s, 4H), 2.94-2.84 (m, 2H), 2.41-2.28 (m, 2H), 1.67 (td, J = 6.7, 16.3 Hz, 4H), 1.20 (t, J = 6.8 Hz, 3H).

[0170] Example 18

[0171]

[0172] Reaction liquid A: 5 g of 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester is dissolved in 50 mL of DMF.

[0173] Reaction liquid B: 1.1 g of NaH (60% content) is suspended in 27.5 mL of DCM.

[0174] Reaction liquid C: 6.3 g of (aminooxy)diphenylphosphine oxide is dissolved in 50 mL of DMF.

[0175] The first reactor, the second reactor, the third reactor and the collector are communicated to form a closed system. N2 is fully introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 13.025 mL / min, reaction liquid B is added into the first reactor at a flow rate of 6.975 mL / min, the reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 13.291 mL / min, the reaction temperature is controlled at 25 ℃, and the reaction is carried out for 3 min. The reaction liquid in the second reactor flows into the third reactor. An aqueous solution is added into the third reactor at a flow rate of 7 mL / min, the quenching reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5 min. After the reaction is completed, the reaction liquid is added into 50 mL of saturated ammonium chloride aqueous solution, extracted with 50 mL of dichloromethane, and separated. The organic phase is concentrated under reduced pressure to obtain a crude product, which is added into 20 mL of hydrochloric acid dioxane solution, precipitated, filtered, and 4.4 g of product 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester hydrochloride is obtained in the form of white solid, and the calculated yield is 70%.

[0176] NMR detection results: 1 H NMR (400 MHz, DMSO-d6) δ = 7.24 (d, J = 2.3 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 5.32 (s, 3H), 3.76 (s, 3H).

[0177] Example 19

[0178]

[0179] Reaction liquid A: 5 g of 1H-pyrrole-2-carboxylic acid methyl ester is dissolved in 50 mL of DMF.

[0180] Reaction liquid B: 3.2 g of NaH (60% content) is suspended in 75 mL of DCM.

[0181] Reaction liquid C: 8.1 g of O-(2,4-dinitrophenyl)hydroxylamine is dissolved in 50 mL of DMF.

[0182] The first reactor, the second reactor, the third reactor, and the collector are communicated to form a closed system. N2is fully introduced into the first reactor. Reaction liquid A is added into the first reactor at a flow rate of 4.1 mL / min, and reaction liquid B is added into the first reactor at a flow rate of 5.9 mL / min. The reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5 min. The reaction liquid in the first reactor flows into the second reactor. Reaction liquid C is added into the second reactor at a flow rate of 4.2 mL / min. The reaction temperature is controlled at 50 ℃, and the reaction is carried out for 7 min. The reaction liquid in the second reactor flows into the third reactor. Water is added into the third reactor at a flow rate of 7 mL / min. The quenching reaction temperature is controlled at 0 ℃, and the reaction is carried out for 5 min. After the reaction is completed, the reaction liquid is added into 250 mL of saturated ammonium chloride aqueous solution. The aqueous phase is extracted with 210 mL of EtOAc, washed with 300 mL of brine, separated, and concentrated under reduced pressure to obtain 4.5 g of 1-amino-1H-pyrrole-2-carboxylic acid methyl ester in the form of a yellow solid, with a calculated yield of 80%.

[0183] NMR detection result: 1 H NMR (400 MHz, METHANOL-d4) δ = 7.22 (dd, J = 1.9, 2.8 Hz, 1H), 6.96 (dd, J = 1.8, 4.3 Hz, 1H), 6.27 (dd, J = 2.9, 4.3 Hz, 1H), 3.88 (s, 3H).

[0184] Example 20

[0185]

[0186] Reaction liquid A: 5 g of 1-(5-bromo-2-hydroxyphenyl)ethan-1-one is dissolved in 50 mL of toluene.

[0187] Reaction liquid B: 2 g of NaH (60% content) is suspended in 45 mL of DCM.

[0188] Reaction liquid C: 3.3 g of diethyl carbonate is dissolved in 50 mL of toluene.

[0189] The first reactor, the second reactor, the third reactor, and the collector are communicated to form a closed system. N2 is fully introduced into the first reactor, reaction liquid A is added into the first reactor at a flow rate of 4.378 mL / min, reaction liquid B is added into the first reactor at a flow rate of 5.622 mL / min, the reaction temperature is controlled at 0 ℃, and the reaction is performed for 5 min; the reaction liquid in the first reactor flows into the second reactor, reaction liquid C is added into the second reactor at a flow rate of 4.267 mL / min, the reaction temperature is controlled at 100 ℃, and the reaction is performed for 14 min; the reaction liquid in the second reactor flows into the third reactor, water is added into the third reactor at a flow rate of 7 mL / min, the quenching reaction temperature is controlled at 0 ℃, and the reaction is performed for 5 min. After the reaction is completed, the reaction liquid is added into 250 mL of hydrochloric acid aqueous solution (1 M), the aqueous phase is extracted with 210 mL of EtOAc, washed with 300 mL of brine, separated, and the organic phase is concentrated under reduced pressure to obtain 2.85 g of 3-(5-bromo-2-hydroxyphenyl)-3-oxopropanoic acid ethyl ester in the form of a yellow solid, and the calculated yield is 51%.

[0190] MS detection result: M+1 (284.8);

[0191] NMR detection result: 1 H NMR (400 MHz, CHLOROFORM-d) δ = 11.70 (s, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.51 (dd, J = 2.3, 8.9 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H).

[0192] Comparative Example 1

[0193]

[0194] At 0 ℃, 229.14 g of NaH (60% content) was added into 1.8 L of DMF. At 0 ℃, 300.00 g of imidazole was added into the above reaction liquid, and stirred at 0 ℃ for 1 h. At 0 ℃, 808.13 g of 2-(chloromethoxy)ethyl trimethylsilane was added dropwise into the reaction liquid, and stirred at 20-25 ℃ for 2 h. The reaction liquid was poured into 10 L of ice water, and stirred at 0 ℃ for 10 min; extracted with ethyl acetate (3 L*2), washed with brine (4 L*3), and concentrated to obtain a crude product. The crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate PE / EA = 20:1 to 1:1) to obtain 1.05 kg of product 2-(imidazol-1-ylmethoxy)ethyl trimethylsilane, and the yield was 60%.

[0195] Comparative Example 2

[0196]

[0197] At 0°C, 639.96 g of NaH (60% content) was added into 4 L of NMP. At 0°C, 800.00 g of 3-chloro-2-(chloromethyl)prop-1-en was added into the above reaction solution, and stirred at 0°C for 0.5 h. At 0-10°C, 1.08 kg of N-(2-hydroxyethyl)carbamic acid tert-butyl ester was added into the reaction solution dropwise, and stirred at 25°C for 2 h. The reaction solution was poured into 25 L of ice water, and stirred at 0°C for 10 min. Ethyl acetate extraction (10 L*4), salt water washing (5 L*3), and concentration to obtain the crude product. Column chromatography purification (eluent: petroleum ether / ethyl acetate = 100:1 to 3:1) to obtain 1.7 kg of product 6-methylene-1,4-oxazepane-4-carboxylic acid tert-butyl ester, with a yield of 62%.

[0198] Comparative Example 3

[0199]

[0200] At 0°C, 499.38 g of NaH (60% content) was added into 23 L of THF. At 0°C, 2.26 kg of 2-diethoxyphosphoryl acetic acid ethyl ester was added into the above reaction solution dropwise, and stirred at 0°C for 1 h. At 0°C, 1.5 kg of 1,4-dioxaspiro[4.5]decan-8-one was added into the reaction solution dropwise, and stirred at -20°C for 2 h. 10 L of water was added into the reaction solution at 0-10°C to quench. 2-methyltetrahydrofuran extraction (10 L*1), salt water washing (5 L*2), and concentration to obtain the crude product 2-(1,4-dioxaspiro[4.5]dec-8-ylidene)acetic acid ethyl ester, with a yield of 95%.

[0201] The product yields of Example 1 and Example 2 are 42% and 75% respectively, and it can be seen that the product yield of the present application in the flow chemical reaction is better, and the yield can be further increased from 42% to 75% in combination with the micro-channel reactor, which is higher than the product yield of 60% in Comparative Example 1. The product yield of some flow chemical reactions can be higher than that of the tank type reaction, and more importantly, the technical scheme of the present application can effectively solve the reaction safety problem of sodium hydride in the tank type reaction, and safely realize the scale-up reaction.

[0202] Further researches on the above reactions are shown in the following table.

[0203] Table 1: Product yield of each reaction

[0204]

[0205]

[0206] Note: the mass of reaction liquid A, reaction liquid B, reaction liquid C refers to reactants, excluding solvents.

[0207] The preferred embodiments of the present application have been described in detail above. It should be understood that modifications and variations to the preferred embodiments could be made by those skilled in the art without being creative labor. Therefore, any technical solutions obtained by logical analysis, reasoning or limited experiments based on the concept of the present application in the prior art should be within the protection scope defined by the claims.

Claims

1. An application of a sodium hydride suspension in a fluid chemical reaction, characterized in that, The flow chemical reaction involves introducing an inert gas into a reactor, mixing reaction solution A with a sodium hydride suspension, reacting the mixture, then mixing the resulting system with reaction solution C, reacting the mixture again, adding a quencher, and finally post-processing to obtain the product. The reaction solution A and sodium hydride suspension are mixed and reacted in the first reactor, and the mixture flows into a microchannel reactor. Reaction solution C also flows into the microchannel reactor. The flow rate ratio is 1:0.5~1. The sodium hydride suspension is formed by dispersing sodium hydride in an organic solvent with a density of 1.2~1.5 g / mL or an organic solvent with a viscosity of 5~30 mm² / s, to form a suspension with a concentration of 0.02~0.05 g / mL. The reaction solution A is selected from imidazole solution, 4-nitro-1H-indole solution, ethyl 2-methyl-1H-pyrrole-3-carboxylate solution, 2,4,5-tribromo-1H-imidazole solution, 3-nitro-1H-pyrazole solution, pyrrolidine-2-one solution, 9H-carbazole, 4-chloro-6-(trifluoromethyl)pyrimidin-2-amine solution, N-(2-hydroxyethyl)carbamate tert-butyl ester solution, 4-hydroxypiperidine-1-carboxylate tert-butyl ester solution, benzyl alcohol solution, and 2,2'-(ethane-1,2-dimethylbis(oxygen)) One or more of the following: bis(ethane-1-ol) solution, (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid solution, (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid solution, ethyl 2-diethoxyphosphoryl acetate solution, 1-((isocyanomethyl)sulfonyl)-4-toluene solution, methyl 4-bromo-1H-pyrrole-2-carboxylate solution, methyl 1H-pyrrole-2-carboxylate solution, and 1-(5-bromo-2-hydroxyphenyl)ethane-1-one solution; The reaction solution C is selected from one or more of the following: 2-(chloromethoxy)ethyltrimethylsilane solution, benzenesulfonyl chloride solution, MeI solution, 2-(chloromethoxy)ethyltrimethylsilane solution, 1-(chloromethyl)-4-methoxybenzene solution, 2,3,4,5,6-pentafluorobenzene-1-carboxylonitrile, 2,4,5,6-tetrafluorobenzene-1,3-dicarboxylonitrile, 2-iodopropane solution, 3-chloro-2-(chloromethyl)prop-1-ene solution, 3-bromoprop-1-yne solution, 3-chloroisocyanuric acid nitrile solution, tert-butyl 2-bromoacetate solution, 3-fluoro-2-nitropyridine solution, 1-bromo-2-methoxyethane, 1,4-dioxospiro[4.5]dec-8-one solution, tert-butyl acrylate solution, (aminooxy)diphenylphosphine oxide solution, O-(2,4-dinitrophenyl)hydroxylamine solution, and diethyl carbonate solution.

2. The application according to claim 1, characterized in that, The organic solvent with a density of 1.2~1.5 g / mL is selected from one or two of dichloromethane and 1,2-dichloroethane; the organic solvent with a viscosity of 5~30 mm² / s is selected from one or two of paraffin oil and mineral oil.

3. The application according to claim 1, characterized in that, The sodium hydride in the sodium hydride suspension captures acidic hydrogen from the reactive group and then reacts with the electrophilic reagent; the reactive group is selected from one or more of -OH, -NHR, and -CHR2; the type of reaction with the electrophilic reagent is one or more of substitution reaction, Wittig reaction, and cyclization reaction; R refers to hydrogen or a substituent.

4. The application according to claim 1, characterized in that, The reaction solution A and the reaction solution C are in one of the following combinations: a1. Reaction solution A is an imidazole solution, and reaction solution C is a 2-(chloromethoxy)ethyltrimethylsilane solution; a2. Reaction solution A is a 4-nitro-1H-indole solution, and reaction solution C is a benzenesulfonyl chloride solution; a3. Reaction solution A is ethyl 2-methyl-1H-pyrrole-3-carboxylate solution, and reaction solution C is MeI solution; a4. Reaction solution A is 2,4,5-tribromo-1H-imidazolium solution, and reaction solution C is 2-(chloromethoxy)ethyltrimethylsilane solution; a5. Reaction solution A is a 3-nitro-1H-pyrazole solution, and reaction solution C is a 2-(chloromethoxy)ethyltrimethylsilane solution; a6. Reaction solution A is a pyrrolidone-2-one solution, and reaction solution C is a 1-(chloromethyl)-4-methoxybenzene solution; a7. Reaction solution A is 9H-carbazole solution, and reaction solution C is 2,3,4,5,6-pentafluorobenzene-1-carboxynitrile solution; a8. Reaction solution A is 9H-carbazole solution, and reaction solution C is 2,4,5,6-tetrafluorobenzene-1,3-dicarboxynitrile solution; b1. Reaction solution A is a 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine solution, and reaction solution C is a 2-iodopropane solution; b2. Reaction solution A is N-(2-hydroxyethyl)carbamate tert-butyl ester solution, and reaction solution C is 3-chloro-2-(chloromethyl)prop-1-ene solution; b3. Reaction solution A is a tert-butyl 4-hydroxypiperidine-1-carboxylate solution, and reaction solution C is a 3-bromoprop-1-yne solution; b4. Reaction solution A is benzyl alcohol solution, and reaction solution C is 3-chloroisocyanuric acid nitrile solution; b5. Reaction solution A is a 2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-1-ol) solution, and reaction solution C is a tert-butyl 2-bromoacetate solution; b6. Reaction solution A is (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid solution, and reaction solution C is 3-fluoro-2-nitro-pyridine solution; b7. Reaction solution A is (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid solution, and reaction solution C is 1-bromo-2-methoxyethane solution; c1. Reaction solution A is ethyl 2-diethoxyphosphoryl acetate solution, and reaction solution C is 1,4-dioxolane[4.5]dec-8-one solution; c2. Reaction solution A is a 1-((isocyanomethyl)sulfonyl)-4-toluene solution, and reaction solution C is a tert-butyl acrylate solution; c3. Reaction solution A is a methyl 4-bromo-1H-pyrrole-2-carboxylate solution, and reaction solution C is a (aminooxy)diphenylphosphine oxide solution; c4. Reaction solution A is a methyl 1H-pyrrole-2-carboxylate solution, and reaction solution C is an O-(2,4-dinitrophenyl)hydroxylamine solution; c5. Reaction solution A is a 1-(5-bromo-2-hydroxyphenyl)ethane-1-one solution, and reaction solution C is a diethyl carbonate solution.

5. The application according to claim 4, characterized in that, The concentration of reaction solution A is 0.1~0.2 g / mL, and the concentration of reaction solution C is 0.05~0.3 g / mL.

6. The application according to claim 5, characterized in that, The quenching agent is water, which flows into the reactor during or after the reaction; the flow rate ratio of the reaction solution A, sodium hydride suspension, reaction solution C, and quenching agent is 0.6~1.9:1:0.6~1.9:0.8~1.

6.

7. The application according to claim 6, characterized in that, The reaction time of reaction solution A with sodium hydride suspension is 1-10 min, and the reaction temperature is 0-50℃; the reaction time of the system after reaction with reaction solution C is 1-12 min, and the reaction temperature is 0-100℃; the reaction time after adding water is 1-5 min, and the reaction temperature is 0-25℃.

8. The application according to claim 7, characterized in that, The reaction time between reaction solution A and sodium hydride suspension is 4-10 min, and the reaction temperature is 0-25℃.

9. The application according to claim 8, characterized in that, The reaction temperature between reaction solution A and sodium hydride suspension is 0~5℃; the reaction time after adding water is 3.2~5 min, and the reaction temperature is 0~5℃.

10. The application according to claim 1, characterized in that, The post-processing steps can be selected from one of the following two methods: a) including washing, extraction, and vacuum concentration; b) adding water and precipitation.

11. The application according to claim 10, characterized in that, The post-processing step a) includes adding the reaction solution to a saturated ammonium chloride aqueous solution, extracting with an organic solvent, and concentrating under reduced pressure; wherein the organic solvent is selected from one or more of dichloromethane, ethyl acetate, methyl tert-butyl ether, and isopropyl acetate.

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