Photochemical synthesis method of vonoprazan intermediate

Abstract

The invention discloses a photochemical synthesis method of a vonoprazan intermediate, and belongs to the technical field of drug intermediate synthesis, the synthesis method comprises the following steps: (1) 2-bromo-1-(2-fluorophenyl) ethyl-1-ketone and acetaldehyde are subjected to a white light irradiation reaction under the action of a photosensitizer and alkali to obtain 4-(2-fluorophenyl)-4-oxobutyraldehyde; (2) carrying out a Paal-Knorr condensation reaction on the 4-(2-fluorophenyl)-4-oxobutyraldehyde and ammonium acetate under the action of an acid catalyst and a dehydrating agent, so as to obtain 2-(2-fluorophenyl)-1H-pyrrole; (3) carrying out formylation reaction on the 2-(2-fluorophenyl)-1H-pyrrole and 1, 1-dichloromethoxymethane under the action of a Lewis acid catalyst, so as to obtain a vonoprazan intermediate; the method has the advantages of cheap and easily available raw materials, high product yield, safe and simple process, mild reaction conditions and low cost, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a photochemical synthesis method for vonoprazan intermediate. Background Technology

[0002] Vonoprazan fumarate (trade name: Takecab) is a novel oral acid-suppressing drug launched by Takeda Pharmaceutical Company of Japan on December 26, 2014, for the treatment of acid-related disorders. This drug belongs to the potassium-competitive acid blocker (P-CAB) class, and works by inhibiting H+ ions on gastric parietal cells. + / K + -ATPase (proton pump) rapidly and persistently reduces gastric acid secretion, targeting gastric acid-related diseases such as gastric ulcers, duodenal ulcers, and reflux esophagitis. It is characterized by rapid action, long-lasting effect, and high safety. The chemical structure of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde (I), a key intermediate in the synthesis of vonoprazan fumarate, is as follows:

[0003] .

[0004] Currently, the main methods for synthesizing this key intermediate (I) reported in the literature are as follows:

[0005] (1) The synthetic route reported in patent WO2007026916 and literature J. Med. Chem. 2012, 55(9): 4446-4456 is as follows:

[0006] ;

[0007] This synthetic method has a long procedure and poor atom economy. It requires the use of a dangerous and expensive palladium on carbon catalyst, an expensive and dangerous diisobutylaluminum hydride (DIBAH) reducing agent, and a ruthenate (TPAP) / N-methylmorpholine-N-oxide (NMO) oxidation system.

[0008] (2) Patent WO2010098351 reports the following synthetic route:

[0009] ;

[0010] The synthetic method reported here is also quite lengthy, requiring a highly active and expensive palladium-on-carbon catalyst, as well as a highly active and dangerous Raney Ni catalyst. Therefore, this method also severely limits the large-scale production of the key intermediate (I).

[0011] (3) Patent CN107935902A discloses the following synthetic route:

[0012] ;

[0013] The reported synthesis method utilizes the synergistic catalysis of palladium and copper bimetals to catalyze the coupling reaction of 2-fluorobenzoic acid with bromide 10 in one step to obtain the target product. However, the bromide 10 used in this route is expensive, and the coupling reaction requires an expensive palladium metal catalyst. In addition, the reaction requires high temperature and nitrogen protection environment, which is not suitable for the industrial production of the key intermediate (I) of vonorazan.

[0014] (4) Patents WO2019131695 and CN116514698A disclose the following synthetic routes:

[0015] ;

[0016] The synthetic method reported here requires an expensive palladium catalyst, as well as an expensive base and a 2-fluoroiodobenzene or 2-fluorobromobenzene substrate in the first step. Furthermore, the coupling reaction requires a high-temperature and nitrogen-protected environment. These factors also make it difficult to reduce the cost of large-scale production of the key intermediate (I). Summary of the Invention

[0017] To address the aforementioned technical problems, this invention provides a photochemical synthesis method for vonorazan intermediates. This method uses inexpensive and readily available raw materials, yields high product rates, employs a safe and simple process, operates under mild reaction conditions, and is low in cost, making it suitable for industrial production.

[0018] The technical solution adopted in this invention is as follows:

[0019] This invention provides a photochemical synthesis method for a vonorazan intermediate, the synthesis method comprising the following steps:

[0020] (1) 2-bromo-1-(2-fluorophenyl)ethyl-1-one and acetaldehyde undergo a photoreaction under the action of a photosensitizer and a base to obtain 4-(2-fluorophenyl)-4-oxobutyraldehyde;

[0021] (2) 4-(2-fluorophenyl)-4-oxobutyraldehyde and ammonium acetate undergo Paal-Knorr condensation reaction under the action of acid catalyst and dehydrating agent to obtain 2-(2-fluorophenyl)-1H-pyrrole;

[0022] (3) 2-(2-fluorophenyl)-1H-pyrrole reacts with 1,1-dichloromethoxymethane in the presence of a Lewis acid catalyst to undergo a formylation reaction to obtain the vonorazan intermediate;

[0023] The structural formula of the vonorazan intermediate is: .

[0024] Furthermore, the synthesis method specifically includes the following steps:

[0025] (1) Dissolve the photosensitizer and 2-bromo-1-(2-fluorophenyl)ethyl-1-one in a solvent, add N,N,N',N'-tetraethylethylenediamine and acetaldehyde aqueous solution, and irradiate with white light at -5~0℃ for 1.5~2.5 h. After the reaction is completed, 4-(2-fluorophenyl)-4-oxobutyraldehyde is obtained after post-treatment.

[0026] (2) Dissolve 4-(2-fluorophenyl)-4-oxobutyraldehyde in a solvent, add molecular sieve, ammonium acetate and acid catalyst, stir the reaction at room temperature for 1.5~2.5 h, after the reaction is completed, quench the reaction system, and after post-treatment purification, obtain 2-(2-fluorophenyl)-1H-pyrrole.

[0027] (3) Dissolve 2-(2-fluorobenzene)-1H-pyrrole and Lewis acid catalyst in a solvent, and add 1,1-dichloromethoxymethane dropwise at -15~25℃. After the addition is complete, continue stirring for 1~1.5h. After post-treatment purification, vonorazan intermediate is obtained.

[0028] Furthermore, in step (1), the photosensitizer is 4CzIPN; the base is N,N,N',N'-tetraethylethylenediamine; and the solvent is chloroform.

[0029] In step (1), the molar ratio of 2-bromo-1-(2-fluorophenyl)ethyl-1-one, acetaldehyde, photosensitizer, and N,N,N',N'-tetraethylethylenediamine is 1:10~11:0.001~0.003:0.9~1.1; and the concentration of 2-bromo-1-(2-fluorophenyl)ethyl-1-one in the solvent is 0.2~0.5 M.

[0030] In step (1), the post-processing method is as follows: the organic phase is extracted and separated, concentrated and purified by silica gel column chromatography, and the eluent is a mixed solvent composed of petroleum ether and ethyl acetate in a ratio of 30:1 to 5:1.

[0031] In step (2), the molecular sieve is 4A molecular sieve; the acid catalyst is acetic acid; and the solvent is methanol.

[0032] In step (2), the molar ratio of 4-(2-fluorophenyl)-4-oxobutyraldehyde to ammonium acetate is 1:1.5~2.0; the mass of the molecular sieve and the acid catalyst are 15~25 wt% and 2~5 wt% of the mass of 4-(2-fluorophenyl)-4-oxobutyraldehyde, respectively; and the concentration of 4-(2-fluorophenyl)-4-oxobutyraldehyde in the solvent is 0.05~0.1 M.

[0033] In step (2), the post-processing method is as follows: the quenched reaction solution is concentrated and purified by silica gel column chromatography, and the eluent is a mixed solvent composed of petroleum ether and ethyl acetate in a ratio of 35~45:1.

[0034] In step (3), the Lewis acid catalyst is anhydrous aluminum chloride; the solvent is a mixed solvent composed of dichloromethane and nitromethane in a volume ratio of 1:1.

[0035] In step (3), the molar ratio of 2-(2-fluorobenzene)-1H-pyrrole, Lewis acid catalyst, and 1,1-dichloromethoxymethane is 1:2~3:1~1.5; the concentration of 2-(2-fluorobenzene)-1H-pyrrole in the solvent is 0.1~0.3 M.

[0036] In step (3), the post-processing method is as follows: the reaction solution is poured into ice water, the organic phase is extracted, and the organic phase is concentrated and then recrystallized in a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 8 to 12:1.

[0037] The photochemical synthesis method for vonorazan intermediates provided by this invention first involves reacting 2-bromo-1-(2-fluorophenyl)ethyl-1-one and acetaldehyde under white light irradiation in the presence of a photosensitizer and a base to obtain 4-(2-fluorophenyl)-4-oxobutyraldehyde. This photoreaction can be scaled up to the gram scale, has mild reaction conditions, does not require anhydrous or oxygen-free operation, and has advantages such as low catalyst dosage and simple post-reaction processing. In addition, the N,N,N',N'-tetraethylethylenediamine hydrobromide generated in the photoreaction system can be recovered from N,N,N',N'-tetraethylethylenediamine by post-treatment with sodium hydroxide aqueous solution.

[0038] Subsequently, the prepared 4-(2-fluorophenyl)-4-oxobutyraldehyde underwent a Paal-Knorr condensation reaction under the action of an acid catalyst and a dehydrating agent to yield 2-(2-fluorophenyl)-1H-pyrrole. In this reaction, the condensation of the carbonyl group with the ammonia source produces water as a byproduct. The micropores of the dehydrating agent (4A molecular sieve) can adsorb the water produced in the reaction, driving the reaction towards the product. Simultaneously, it can also adsorb trace amounts of water from the methanol solvent in the system, maintaining a dry environment and preventing water from inhibiting the condensation reaction. The carbonyl group needs to be protonated to enhance its electrophilicity, thus facilitating the nucleophilic addition-condensation reaction with ammonium acetate. Adding a small amount of acid catalyst can supplement acidic sites, accelerate the protonation process of the carbonyl group, and increase the reaction rate.

[0039] Finally, 2-(2-fluorophenyl)-1H-pyrrole and 1,1-dichloromethoxymethane underwent a formylation reaction in the presence of a Lewis acid catalyst to obtain the vonorazan intermediate.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] The photochemical synthesis method of vonorazan intermediate provided by this invention uses inexpensive and readily available raw materials. The N,N,N',N'-tetraethylethylenediamine used in step (1) can be recovered with a high recovery rate. The product yields in steps (2) and (3) reach 98% and 93% respectively. The product yield is high, and the process is safe and simple, with mild reaction conditions and low cost, making it suitable for industrial production. Attached Figure Description

[0042] Figure 1 The 1H NMR spectrum of 4-(2-fluorophenyl)-4-oxobutyraldehyde;

[0043] Figure 2 The carbon NMR spectrum of 4-(2-fluorophenyl)-4-oxobutyraldehyde;

[0044] Figure 3 The NMR fluorine spectrum of 4-(2-fluorophenyl)-4-oxobutyraldehyde;

[0045] Figure 4 The 1H NMR spectrum of 2-(2-fluorophenyl)-1H-pyrrole;

[0046] Figure 5 The carbon NMR spectrum of 2-(2-fluorophenyl)-1H-pyrrole;

[0047] Figure 6 The NMR fluorine spectrum of 2-(2-fluorophenyl)-1H-pyrrole;

[0048] Figure 7 The 1H NMR spectrum of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde, an intermediate of vonoprazan;

[0049] Figure 8 The carbon NMR spectrum of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde, an intermediate of vonoprazan;

[0050] Figure 9 The NMR fluorine spectrum of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde, an intermediate of vonoprazan;

[0051] Figure 10 This is a synthetic route for 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde, the vonorazan intermediate in Example 1. Detailed Implementation

[0052] The present invention will now be described in detail with reference to the embodiments.

[0053] Example 1

[0054] A photochemical synthesis method for the vonorazan intermediate 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde includes the following steps:

[0055] (1) Preparation of 4-(2-fluorophenyl)-4-oxobutyraldehyde:

[0056] The photosensitizer 4CzIPN (47.4 mg, 0.1 mol%) and 2-bromo-1-(2-fluorophenyl)ethyl-1-one (13.02 g, 60.0 mmol) were dissolved in 270 mL of CHCl3. Then, N,N,N',N'-tetraethylethylenediamine (9.3 g, 54.0 mmol) and 40 wt% acetaldehyde aqueous solution (66.2 g, 600 mmol) were added to the system sequentially. The mixture was stirred at -5 °C and irradiated with a 30 W white LED for 2 h. After the reaction was completed, the two-phase reaction mixture was separated by a separatory funnel to obtain a chloroform organic phase and an aqueous phase. The aqueous phase was extracted three times with 100 mL of DCM. The organic phases were combined to obtain a dichloromethane organic phase and an aqueous phase. The chloroform and dichloromethane organic phases were combined, dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The concentrate was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a ratio of 30:1 to 5:1 as the eluent. The collected product solution was concentrated and dried to obtain 6.50 g of a light yellow liquid, 4-(2-fluorophenyl)-4-oxobutyraldehyde, with a yield of 60%.

[0057] Washing the aqueous phase with 50 mL of a 30 wt% sodium hydroxide solution releases N,N,N',N'-tetraethylethylenediamine hydrobromide as N,N,N',N'-tetraethylethylenediamine, forming the upper organic layer. This organic layer is then separated, concentrated, and dried to recover 8.64 g of N,N,N',N'-tetraethylethylenediamine, achieving a recovery rate of 93%. In this photoreaction step, N,N,N',N'-tetraethylethylenediamine ultimately forms N,N,N',N'-tetraethylethylenediamine hydrobromide, which dissolves in the aqueous phase. Washing the aqueous phase with sodium hydroxide converts N,N,N',N'-tetraethylethylenediamine hydrobromide into N,N,N',N'-tetraethylethylenediamine, which is then released to form the upper organic phase, thus achieving rapid separation and recovery of N,N,N',N'-tetraethylethylenediamine.

[0058] The nuclear magnetic resonance (NMR) spectrum of 4-(2-fluorophenyl)-4-oxobutyraldehyde (II) is characterized as follows:

[0059] 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.92-7.88 (m, 1H), 7.57-7.51(m, 1H), 7.27-7.22 (m, 1H), 7.18-7.13 (m, 1H), 3.35-3.31 (m, 2H), 2.92 (t, J= 6.4 Hz, 2H), such as Figure 1 As shown.

[0060] 13 C NMR (100 MHz, CDCl3) δ 200.5, 195.9 (d, J = 3.6 Hz), 162.0 (d, J =253.1 Hz), 134.7 (d, J = 9.3 Hz), 130.5 (d, J = 3.1 Hz), 124.8 (d, J = 11.9Hz), 124.4 (d, J = 3.8 Hz), 116.6 (d, J = 23.1 Hz), 37.4 (d, J = 2.2 Hz), 35.8 (d, J = 8.8 Hz), such as Figure 2 As shown.

[0061] 19 F NMR (376 MHz, CDCl3) δ -108.79, such as Figure 3 As shown.

[0062] (2) Preparation of 2-(2-fluorophenyl)-1H-pyrrole:

[0063] 4-(2-fluorophenyl)-4-oxobutyraldehyde (3.6 g, 20.0 mmol) was dissolved in 300 mL of methanol, and 0.72 g of 4A molecular sieve, NH4OAc (2.32 g, 30.0 mmol) and 0.1 mL of acetic acid were added. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with solid Na2CO3, and the solvent was removed under reduced pressure. The concentrate was purified by silica gel column chromatography using a mixed solvent of PE / EA in a volume ratio of 40:1 as the eluent. The collected product solution was concentrated and dried to obtain 3.16 g of colorless liquid 2-(2-fluorophenyl)-1H-pyrrole, with a yield of 98%.

[0064] The nuclear magnetic resonance (NMR) spectrum of 2-(2-fluorophenyl)-1H-pyrrole is characterized as follows:

[0065] 1H NMR (500 MHz, CDCl3) δ 8.99 (br, 1H), 7.61-7.58 (m, 1H), 7.13-7.05(m, 3H), 6.88 (s, 1H), 6.65 (s, 1H), 6.30 (d, J = 2.5 Hz, 1H), as Figure 4 As shown.

[0066] 13 C NMR (125 MHz, CDCl3) δ 158.5 (d, J = 242.4 Hz), 126.9 (d, J =9.25 Hz), 126.8, 126.6 (d, J = 4.63 Hz), 124.6 (d, J = 3.38 Hz), 120.2 (d, J= 10.38 Hz), 119.2 (d, J = 2.4 Hz), 116.2 (d, J = 23.0 Hz), 109.4, 107.5, such as Figure 5 As shown.

[0067] 19 F NMR (470 MHz, CDCl3) δ -119.07 (d, J = 6.58 Hz, 1F), as Figure 6 As shown.

[0068] (3) Preparation of vonorazan intermediate 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde:

[0069] 2-(2-fluorobenzene)-1H-pyrrole (2.42 g, 15.0 mmol) and anhydrous aluminum trichloride (8.69 g, 36.0 mmol) were dissolved in 150 mL of a mixed solvent of dichloromethane and nitromethane in a volume ratio of 1:1. 1,1-dichloromethoxymethane (2.07 g, 18.0 mmol) was added dropwise at -20 °C, and the mixture was stirred for 1.5 h. After the reaction was complete, the mixture was poured into 300 mL of ice water and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a brown solid. This solid was then recrystallized from a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1. After filtration and drying, 2.63 g of a white solid, 5-(2-fluorobenzene)-1H-pyrrole-3-carboxaldehyde, was obtained, with a yield of 93%.

[0070] The nuclear magnetic resonance (NMR) spectrum of 5-(2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde is characterized as follows:

[0071] 1H NMR (500 MHz, CDCl3) δ 9.84 (s, 2H, -CHO and NH), 7.63-7.60 (m,1H), 7.54 (s, 1H), 7.25-7.21 (m, 1H), 7.19-7.11 (m, 2H), 7.05 (s, 1H), as Figure 7 As shown.

[0072] 13 C NMR (125 MHz, CDCl3) δ 185.8, 158.8 (d, J = 243.6 Hz), 129.5,128.6 (d, J = 9.13 Hz), 128.1, 127.2, 127.0 (d, J = 3.5 Hz), 124.9 (d, J =3.5 Hz), 118.8 (d, J = 11.5 Hz), 116.3 (d, J = 23.0 Hz), 106.0, as Figure 8 As shown.

[0073] 19 F NMR (470 MHz, CDCl3) δ -117.99-118.05 (m, 1F), as Figure 9 As shown.

[0074] As can be seen from this embodiment, the preparation process of the vonorazan intermediate provided by the present invention uses inexpensive and readily available raw materials. The N,N,N',N'-tetraethylethylenediamine used in step (1) can be recovered with a high recovery rate. The product yields in steps (2) and (3) reach 98% and 93% respectively. The process is safe and simple, the reaction conditions are mild, the cost is low, and it is suitable for industrial production.

[0075] The above detailed description of a photochemical synthesis method for a vonorazan intermediate, with reference to the embodiments, is illustrative rather than limiting. Several embodiments may be listed within the defined scope. Therefore, variations and modifications without departing from the overall concept of the present invention should be within the protection scope of the present invention.

Claims

1. A photochemical synthesis method for a vonorazan intermediate, characterized in that, The synthesis method includes the following steps: (1) 2-bromo-1-(2-fluorophenyl)ethyl-1-one and acetaldehyde undergo a photoreaction under the action of a photosensitizer and a base to obtain 4-(2-fluorophenyl)-4-oxobutyraldehyde; (2) 4-(2-fluorophenyl)-4-oxobutyraldehyde and ammonium acetate undergo Paal-Knorr condensation reaction under the action of acid catalyst and dehydrating agent to obtain 2-(2-fluorophenyl)-1H-pyrrole; (3) 2-(2-fluorophenyl)-1H-pyrrole reacts with 1,1-dichloromethoxymethane in the presence of a Lewis acid catalyst to undergo a formylation reaction to obtain the vonorazan intermediate; The structural formula of the vonorazan intermediate is: .

2. The photochemical synthesis method of the vonorazan intermediate according to claim 1, characterized in that, The synthesis method specifically includes the following steps: (1) Dissolve the photosensitizer and 2-bromo-1-(2-fluorophenyl)ethyl-1-one in a solvent, add N,N,N',N'-tetraethylethylenediamine and acetaldehyde aqueous solution, and irradiate with white light at -5~0℃ for 1.5~2.5 h. After the reaction is completed, 4-(2-fluorophenyl)-4-oxobutyraldehyde is obtained after post-treatment. (2) Dissolve 4-(2-fluorophenyl)-4-oxobutyraldehyde in a solvent, add molecular sieve, ammonium acetate and acid catalyst, stir the reaction at room temperature for 1.5~2.5 h, quench the reaction system after the reaction is completed, and 2-(2-fluorophenyl)-1H-pyrrole is obtained after post-treatment purification. (3) Dissolve 2-(2-fluorobenzene)-1H-pyrrole and Lewis acid catalyst in a solvent, and add 1,1-dichloromethoxymethane dropwise at -15~25℃. After the addition is complete, continue stirring for 1~1.5h. After post-treatment purification, vonorazan intermediate is obtained.

3. The photochemical synthesis method of the vonorazan intermediate according to claim 2, characterized in that, In step (1), the photosensitizer is 4CzIPN; the base is N,N,N',N'-tetraethylethylenediamine; and the solvent is chloroform.

4. The photochemical synthesis method of the vonorazan intermediate according to claim 2 or 3, characterized in that, In step (1), the molar ratio of 2-bromo-1-(2-fluorophenyl)ethyl-1-one, acetaldehyde, photosensitizer, and N,N,N',N'-tetraethylethylenediamine is 1:10~11:0.001~0.003:0.9~1.1; and the concentration of 2-bromo-1-(2-fluorophenyl)ethyl-1-one in the solvent is 0.2~0.5 M.

5. The photochemical synthesis method of the vonorazan intermediate according to claim 2, characterized in that, In step (2), the molecular sieve is 4A molecular sieve; the acid catalyst is acetic acid; and the solvent is methanol.

6. The photochemical synthesis method of the vonorazan intermediate according to claim 2 or 5, characterized in that, In step (2), the molar ratio of 4-(2-fluorophenyl)-4-oxobutyraldehyde and ammonium acetate is 1:1.5~2.0; the mass of the molecular sieve and the acid catalyst are 15~25 wt% and 2~5 wt% of the mass of 4-(2-fluorophenyl)-4-oxobutyraldehyde, respectively; and the concentration of 4-(2-fluorophenyl)-4-oxobutyraldehyde in the solvent is 0.05~0.1M.

7. The photochemical synthesis method of the vonorazan intermediate according to claim 2 or 5, characterized in that, In step (2), the post-processing method is as follows: the quenched reaction solution is concentrated and purified by silica gel column chromatography, and the eluent is a mixed solvent composed of petroleum ether and ethyl acetate in a ratio of 35~45:

1.

8. The photochemical synthesis method of the vonorazan intermediate according to claim 2, characterized in that, In step (3), the Lewis acid catalyst is anhydrous aluminum chloride; the solvent is a mixed solvent composed of dichloromethane and nitromethane in a volume ratio of 1:

1.

9. The photochemical synthesis method of the vonorazan intermediate according to claim 2 or 8, characterized in that, In step (3), the molar ratio of 2-(2-fluorobenzene)-1H-pyrrole, Lewis acid catalyst, and 1,1-dichloromethoxymethane is 1:2~3:1~1.5; the concentration of 2-(2-fluorobenzene)-1H-pyrrole in the solvent is 0.1~0.3 M.

10. The photochemical synthesis method of the vonorazan intermediate according to claim 2 or 8, characterized in that, In step (3), the post-processing method is as follows: the reaction solution is poured into ice water, the organic phase is extracted, and the organic phase is concentrated and then recrystallized in a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 8 to 12:1.

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