A synthesis process for fluorene methyloxycarbonyl chloride

Abstract

The purpose of this invention is to provide a synthesis process for fluorene methyloxycarbonyl chloride, belonging to the field of organic synthesis technology. This invention uses 9-fluorenemethanol and dimethyl carbonate as starting materials, and sequentially carries out four core reactions: p-toluenesulfonic acid-catalyzed carbonylation reaction, sodium hydroxide saponification and hydrolysis, dilute hydrochloric acid acidification, and pyridine-catalyzed acyl chloride, to prepare high-purity fluorene methyloxycarbonyl chloride. The process of this invention is green and safe, with high step conversion rate, product purity meets standards, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a synthesis process of fluorenemethyloxycarbonyl chloride. Background Technology

[0002] Fluorenyl methoxycarbonyl chloride (Fmoc-Cl), also known as 9-fluorenyl methyl chloroformate or 9-fluorenylmethyl chloroformate, is a core amino protecting agent in peptide synthesis. It has advantages such as mild reaction conditions, high selectivity for removal, and good compatibility with various amino acids, and is widely used in pharmaceutical intermediates, peptide drugs, and biomolecule modification.

[0003] The prior art CN103408427A discloses a method for preparing 9-fluorenemethylchloroformate. The method involves adding chloroform, 9-fluorenemethanol, and triphosgene to a reactor and stirring for 30 minutes. Under ice bath conditions, a chloroform solution of 4-dimethylaminopyridine is added dropwise, and the reaction is carried out for 2-4 hours. The reactants in the reactor are filtered to obtain a white solid and a filtrate. The filtrate is then desolventized under reduced pressure, cryogenically crystallized, washed with an organic solvent, and dried to obtain a white 9-fluorenemethylchloroformate solid.

[0004] The prior art CN101245001A discloses a method for synthesizing 9-fluorenemethyl chloroformate, in which 9-fluorenemethanol and triphosgene are reacted in an organic solvent in the presence of a catalyst in an ice bath for 0.5-3 hours; the temperature is then increased to 20-50℃ and the reaction is continued for 1-5 hours.

[0005] The prior art CN118026843A discloses a method for preparing 9-fluorenyl methyl chloroformate. 9-fluorenyl methanol and solid phosgene are added to a reaction system containing dichloromethane and mixed thoroughly. A catalyst is then slowly added dropwise below 5°C. After the addition is complete, the reaction is maintained at this temperature, then the temperature is raised to room temperature to continue the reaction, yielding a crude product. The reaction system is then cooled to below 10°C, and the crude product is thoroughly washed and recrystallized using petroleum ether to obtain the product 9-fluorenyl methyl chloroformate.

[0006] Existing technologies mostly use 9-fluorenylmethanol to react directly with highly toxic acyl chlorides such as phosgene and triphosgene. Although the process route is short, it has many technical drawbacks: First, phosgene is a highly toxic gas, and triphosgene easily decomposes to produce phosgene during the reaction, which places extremely high demands on the sealing of production equipment and the safety protection of operators, posing a great safety hazard; Second, a large amount of acidic gas is produced as a byproduct during the reaction, and the tail gas treatment is difficult, which can easily cause environmental pollution; Third, the reaction selectivity is poor, there are many byproducts, the product purification is difficult, and the purity of the final product is difficult to meet the stringent requirements of high-end peptide synthesis; Fourth, the catalysts and solvents used in conventional processes are difficult to recover, the atom utilization rate is low, and the production cost is high.

[0007] Some improved processes employ stepwise synthesis methods, but these generally suffer from problems such as low catalyst activity, insufficient reaction conversion, and harsh conditions in the hydrolysis and acylation steps, resulting in low overall process yields and hindering stable industrial production. Therefore, developing a safe, mild, high-purity, and environmentally friendly process for the synthesis of fluorene methyloxycarbonyl acyl chloride has become a pressing technical challenge in this field. Summary of the Invention

[0008] This invention addresses the shortcomings of existing fluorenemethyloxycarbonyl chloride synthesis processes, such as the use of highly toxic reagents, high safety risks, numerous byproducts, low product purity, and environmentally unfriendly processes. It provides a synthesis process for fluorenemethyloxycarbonyl chloride that achieves green and safe reaction processes, high step conversion rates, compliant product purity, and suitability for industrial production.

[0009] The present invention adopts the following technical solution: A synthesis process for fluorenemethyloxycarbonyl chloride, using 9-fluorenemethanol and dimethyl carbonate as starting materials, involves four core reactions: p-toluenesulfonic acid-catalyzed carbonylation, sodium hydroxide saponification and hydrolysis, dilute hydrochloric acid acidification, and pyridine-catalyzed acyl chloride, to prepare high-purity fluorenemethyloxycarbonyl chloride. The specific steps include: S1. Carbonylation reaction: 9-fluorenylmethanol and dimethyl carbonate are added to the reaction vessel in proportion, stirred and heated to 60-85℃, p-toluenesulfonic acid catalyst is added, and the reaction is maintained at this temperature for 5-9 hours to complete the carbonylation reaction; after the reaction is completed, the unreacted dimethyl carbonate is recovered by vacuum distillation to obtain fluorenylmethyloxycarbonyl carbamate intermediate, which can be directly proceeded to the next step of the reaction without purification. S2. Saponification and hydrolysis reaction: Add the fluorene methoxycarbonyl carbamate intermediate to an aqueous sodium hydroxide solution, heat to 40-60℃, and stir for 3-6 hours for saponification and hydrolysis until the intermediate is completely hydrolyzed to obtain a sodium fluorene methoxycarbonyl carbamate mixture. S3. Acidification with dilute hydrochloric acid: Cool the saponified and hydrolyzed sodium fluorenemethyloxycarbonylformate mixture to 10-25℃, slowly add dilute hydrochloric acid to adjust the pH of the system to 2-4, and stir to acidify for 0.5-1.5h until sodium fluorenemethyloxycarbonylformate is completely converted into fluorenemethyloxycarbonylformic acid; allow to stand and separate the layers, separate the organic phase, wash with water until neutral, and dry to obtain pure fluorenemethyloxycarbonylformic acid; S4. Pyridine-catalyzed acyl chloride reaction: The dried pure fluorenemethyloxycarbonyl carboxylic acid was dissolved in dichloromethane, pyridine was added as a catalyst, the temperature was lowered to 0-15℃, and thionyl chloride was slowly added dropwise. After the addition was completed, the reaction was kept at the temperature for 2-4 hours. After the reaction was completed, dichloromethane, excess thionyl chloride and reaction byproducts were removed by vacuum distillation, and high-purity fluorenemethyloxycarbonyl acyl chloride was obtained by recrystallization.

[0010] Furthermore, in S1, the molar ratio of 9-fluorenylmethanol to dimethyl carbonate is 1:1.5-2.5.

[0011] Furthermore, in S1, the amount of p-toluenesulfonic acid used is 3-8% of the mass of 9-fluorenemethanol.

[0012] Further, in S2, the molar ratio of sodium hydroxide to fluorene methoxycarbonyl carbamate intermediate is 1.2-2:1; the concentration of the sodium hydroxide aqueous solution is 1.5-2 mol / L.

[0013] Furthermore, in S4, the molar ratio of thionyl chloride to fluorenemethyloxycarbonylformic acid is 1.3-2:1.

[0014] Furthermore, in S4, the amount of pyridine used is 5-10% of the molar amount of thionyl chloride.

[0015] The reaction mechanism of this invention is as follows: (1) Carbonylation: 9-fluorenylmethanol undergoes transesterification carbonylation with dimethyl carbonate under the acidic catalysis of p-toluenesulfonic acid, introducing a carbonyl group to generate fluorenyl methoxycarbonyl carbamate. The mechanism is as follows: ; (2) Saponification and hydrolysis: Fluorene methoxycarbonyl carbamate undergoes ester hydrolysis under alkaline conditions to generate the corresponding sodium carboxylate, achieving stable transformation of the intermediate. The mechanism is as follows: ; (3) Acidification: Sodium carboxylate undergoes a metathesis reaction with dilute hydrochloric acid to generate free fluorenemethyloxycarbonylformic acid. The mechanism is as follows: ; (4) Acyl chloride: Fluorenemethyloxycarbonyl carboxylic acid undergoes an acyl substitution reaction with thionyl chloride under the catalysis of pyridine-binding acid, where the hydroxyl group is replaced by a chlorine atom to generate the target product, fluorenemethyloxycarbonyl acyl chloride. The mechanism is as follows: .

[0016] This invention employs p-toluenesulfonic acid to catalyze the carbonylation reaction of 9-fluorenylmethanol with dimethyl carbonate, achieving efficient carbonylation under mild conditions and replacing traditional highly toxic carbonylation reagents; Optimize the saponification-hydrolysis-acidification process to achieve efficient conversion of intermediates, reduce the generation of by-products, and improve the selectivity of subsequent acyl chloride reactions; Using pyridine as an acyl chloride chelate catalyst reduces the activation energy of the reaction, improves the acyl chloride conversion rate, and simplifies the product purification process. We will construct a mild, green, and high-yield synthesis process for fluorene methyloxycarbonyl chloride, addressing the three core issues of safety, environmental protection, and purity in existing processes.

[0017] The specific beneficial effects are as follows: 1. Significantly improved process safety: By eliminating highly toxic acyl chloride reagents such as phosgene and triphosgene, and using low-toxicity conventional chemical raw materials such as dimethyl carbonate and thionyl chloride, no highly toxic gases are generated during the reaction process, reducing production safety risks and reducing tail gas treatment pressure. 2. Mild reaction conditions: Each step of the reaction is carried out at normal pressure and medium and low temperature, without the need for high temperature and high pressure equipment, reducing equipment investment and energy consumption, and is easy to operate, making it suitable for continuous industrial production; 3. High product yield and purity: The stepwise reaction has strong selectivity and few byproducts. Each intermediate does not require complex purification before proceeding to the next reaction. The overall process yield is ≥85%, and the final purity of fluorene methyloxycarbonyl chloride is ≥99.5%, meeting the requirements of high-end peptide synthesis. 4. Green and environmentally friendly: Dimethyl carbonate is a green and environmentally friendly carbonylation reagent. It requires less catalyst, dichloromethane solvent can be recycled, and reagents such as dilute hydrochloric acid and sodium hydroxide are easy to neutralize and treat, resulting in a significant reduction in the amount of waste discharged. 5. Controllable cost: Raw materials are readily available, the process steps are simple, no special reagents or equipment are required, and catalysts and solvents can be recycled, effectively reducing the cost of industrial production. Attached Figure Description

[0018] Figure 1 The fluorene methoxycarbonyl carbamate prepared in Example 1 of this invention 1 HNMR image.

[0019] Figure 2 The fluorenemethyloxycarbonylformic acid prepared in Example 1 of this invention 1 HNMR image.

[0020] Figure 3 The fluorene methoxycarbonyl chloride prepared in Example 1 of this invention 1 HNMR image. Detailed Implementation

[0021] To make the technical problems to be solved, the technical solutions, and the beneficial effects of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0022] Example 1 A process for synthesizing fluorene methyloxycarbonyl chloride includes the following steps: S1, Carbonylation reaction: 1 mol of 9-fluorenylmethanol and 2 mol of dimethyl carbonate were added to the reaction vessel, and the mixture was stirred and heated to 75°C. 5% p-toluenesulfonic acid by mass of 9-fluorenylmethanol was added, and the reaction was maintained at this temperature for 7 hours. After the reaction was completed, dimethyl carbonate was recovered by vacuum distillation to obtain fluorenyl methoxycarbonyl carbamate intermediate. The prepared fluorene methoxycarbonyl carbamate1 HNMR image as follows Figure 1 As shown, 1 H NMR (400 MHz, CDCl3) δ 7.79(d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 21H), 7.34 (t, J = 7.5Hz, 2H), 4.44 (d, J = 7.5 Hz, 2H), 4.28 (t, J = 7.5 Hz, 10H), 3.85 (s, 3H).

[0023] S2, Saponification and Hydrolysis: Add 500 mL of 1.8 mol / L sodium hydroxide aqueous solution, heat to 50℃, stir and hydrolyze for 4 h to obtain sodium fluorene methoxycarbonyl formate mixture; S3. Acidification treatment: Cool the saponified and hydrolyzed sodium fluorene methoxycarbonylformate mixture to 20°C, add 1 mol / L dilute hydrochloric acid dropwise to adjust the pH to 3.0, and stir to acidify for 1 hour; allow to stand and separate the layers, separate the organic phase, wash with water 3 times until neutral, and dry with anhydrous sodium sulfate to obtain pure fluorene methoxycarbonylformate. The preparation of fluorenemethyloxycarbonylformic acid 1 HNMR image as follows Figure 2 As shown, 1 H NMR (400 MHz, CD3CN) δ 7.84 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 7.7 Hz, 2H), 7.44 (t, J = 7.8 Hz, 2H), 7.36 (t, J =7.6 Hz, 2H), 4.76 (d, J = 6.2 Hz, 2H), 4.33 (t, J = 6.9 Hz, 1H).

[0024] S4. Acyl chloride: Dissolve pure fluorenemethyloxycarbonylformic acid in 300 mL of dichloromethane, add 0.1 mol of pyridine, cool to 10 °C, and slowly add 1.6 mol of thionyl chloride dropwise. After the addition is complete, keep the reaction at this temperature for 3 h. After the reaction is complete, remove dichloromethane and excess thionyl chloride by vacuum distillation, and recrystallize from n-hexane to obtain the fluorenemethyloxycarbonyl acyl chloride product with a yield of 88.2% and a purity of 99.6%.

[0025] The prepared fluorene methyloxycarbonyl chloride 1 HNMR image as follows Figure 3 As shown, 1 H NMR (400 MHz, CDCl3) δ 7.79 (d,J = 7.8 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.41 (m, 4H), 4.56 (d, J = 7.6 Hz, 2H), 4.31(t, J = 7.6 Hz, 1H).

[0026] Example 2 A process for synthesizing fluorene methyloxycarbonyl chloride includes the following steps: S1, Carbonylation reaction: 1 mol of 9-fluorenylmethanol and 1.8 mol of dimethyl carbonate were added to the reaction vessel, stirred and heated to 70°C, and 6% by mass of p-toluenesulfonic acid of 9-fluorenylmethanol was added. The reaction was kept at this temperature for 8 hours. After the reaction was completed, dimethyl carbonate was recovered by vacuum distillation to obtain fluorene methyloxycarbonyl carbamate intermediate. S2, Saponification and Hydrolysis: Add 500 mL of 1.5 mol / L sodium hydroxide aqueous solution, heat to 55℃, and stir for 3.5 h to hydrolyze and obtain a mixture of sodium fluorene methoxycarbonyl carboxylate; S3. Acidification treatment: Cool the saponified and hydrolyzed sodium fluorene methoxycarbonylformate mixture to 15°C, add 1 mol / L dilute hydrochloric acid dropwise to adjust the pH to 2.5, and stir to acidify for 0.8 h; allow to stand and separate the layers, separate the organic phase, wash with water 3 times until neutral, and dry with anhydrous sodium sulfate to obtain pure fluorene methoxycarbonylformate. S4. Acyl chloride: Dissolve pure fluorenemethyloxycarbonylformic acid in 250 mL of dichloromethane, add 0.08 mol of pyridine, cool to 8 °C, and slowly add 1.5 mol of thionyl chloride dropwise. After the addition is complete, keep the reaction at this temperature for 2.5 h. After the reaction is complete, remove dichloromethane and excess thionyl chloride by vacuum distillation, and recrystallize from n-hexane to obtain the fluorenemethyloxycarbonyl acyl chloride product with a yield of 86.5% and a purity of 99.5%.

[0027] Example 3 A process for synthesizing fluorene methyloxycarbonyl chloride includes the following steps: S1, Carbonylation reaction: 1 mol of 9-fluorenylmethanol and 1.5 mol of dimethyl carbonate were added to the reaction vessel, and the mixture was stirred and heated to 60°C. Then, 3% by mass of p-toluenesulfonic acid of 9-fluorenylmethanol was added, and the reaction was maintained at this temperature for 9 hours. After the reaction was completed, dimethyl carbonate was recovered by vacuum distillation to obtain fluorenyl methoxycarbonyl carbamate intermediate. S2, Saponification and Hydrolysis: Add 500 mL of 1.5 mol / L sodium hydroxide aqueous solution, heat to 40℃, stir and hydrolyze for 6 h to obtain a mixture of sodium fluorene methoxycarbonyl formate; S3. Acidification treatment: Cool the saponified and hydrolyzed sodium fluorene methoxycarbonylformate mixture to 10°C, add 1 mol / L dilute hydrochloric acid dropwise to adjust the pH to 2.0, and stir to acidify for 0.5 h; allow to stand and separate the layers, separate the organic phase, wash with water 3 times until neutral, and dry with anhydrous sodium sulfate to obtain pure fluorene methoxycarbonylformate. S4. Acyl chloride: Dissolve pure fluorenemethyloxycarbonylformic acid in 250 mL of dichloromethane, add 0.065 mol of pyridine, cool to 0 °C, and slowly add 1.3 mol of thionyl chloride dropwise. After the addition is complete, keep the reaction at this temperature for 2 h. After the reaction is complete, remove dichloromethane and excess thionyl chloride by vacuum distillation, and recrystallize from n-hexane to obtain the fluorenemethyloxycarbonyl acyl chloride product with a yield of 85.1% and a purity of 99.5%.

[0028] Example 4 A process for synthesizing fluorene methyloxycarbonyl chloride includes the following steps: S1, Carbonylation reaction: 1 mol of 9-fluorenylmethanol and 2.5 mol of dimethyl carbonate were added to the reaction vessel, and the mixture was stirred and heated to 85°C. Then, 8% by weight of p-toluenesulfonic acid of 9-fluorenylmethanol was added, and the reaction was maintained at this temperature for 5 hours. After the reaction was completed, dimethyl carbonate was recovered by vacuum distillation to obtain fluorenyl methoxycarbonyl carbamate intermediate. S2, Saponification and Hydrolysis: Add 500 mL of 2.0 mol / L sodium hydroxide aqueous solution, heat to 60℃, stir and hydrolyze for 3 h to obtain sodium fluorene methoxycarbonyl formate mixture; S3. Acidification treatment: Cool the saponified and hydrolyzed sodium fluorene methoxycarbonylformate mixture to 25°C, add 1 mol / L dilute hydrochloric acid dropwise to adjust the pH to 4.0, and stir to acidify for 1.5 h; allow to stand and separate the layers, separate the organic phase, wash with water 3 times until neutral, and dry with anhydrous sodium sulfate to obtain pure fluorene methoxycarbonylformate. S4. Acyl chloride: Dissolve pure fluorenemethyloxycarbonylformic acid in 300 mL of dichloromethane, add 0.2 mol of pyridine, cool to 15 °C, and slowly add 2 mol of thionyl chloride dropwise. After the addition is complete, keep the reaction at this temperature for 4 h. After the reaction is complete, remove dichloromethane and excess thionyl chloride by vacuum distillation, and recrystallize from n-hexane to obtain the fluorenemethyloxycarbonyl acyl chloride product with a yield of 87.8% and a purity of 99.6%.

[0029] The above are preferred embodiments of the present invention. For those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A process for synthesizing fluorene methyloxycarbonyl chloride, characterized in that: The steps include the following: S1. Carbonylation reaction: 9-fluorenylmethanol and dimethyl carbonate are added to the reaction vessel in proportion, stirred and heated to 60-85℃, p-toluenesulfonic acid catalyst is added, and the reaction is maintained at this temperature for 5-9 hours to complete the carbonylation reaction; after the reaction is completed, the unreacted dimethyl carbonate is recovered by vacuum distillation to obtain fluorenylmethyloxycarbonyl carbamate intermediate, which can be directly proceeded to the next step of the reaction without purification. S2. Saponification and hydrolysis reaction: Add the fluorene methoxycarbonyl carbamate intermediate to an aqueous sodium hydroxide solution, heat to 40-60℃, and stir for 3-6 hours for saponification and hydrolysis until the intermediate is completely hydrolyzed to obtain a sodium fluorene methoxycarbonyl carbamate mixture. S3. Acidification with dilute hydrochloric acid: Cool the saponified and hydrolyzed sodium fluorenemethyloxycarbonylformate mixture to 10-25℃, slowly add dilute hydrochloric acid to adjust the pH of the system to 2-4, and stir to acidify for 0.5-1.5h until sodium fluorenemethyloxycarbonylformate is completely converted into fluorenemethyloxycarbonylformic acid; allow to stand and separate the layers, separate the organic phase, wash with water until neutral, and dry to obtain pure fluorenemethyloxycarbonylformic acid; S4. Pyridine-catalyzed acyl chloride reaction: Dissolve the dried pure fluorenemethyloxycarbonyl carboxylic acid in dichloromethane, add pyridine as a catalyst, cool to 0-15℃, slowly add thionyl chloride, and keep the reaction at the temperature for 2-4 hours after the addition is complete; after the reaction is completed, remove dichloromethane, excess thionyl chloride and reaction byproducts by vacuum distillation, and obtain high-purity fluorenemethyloxycarbonyl acyl chloride by recrystallization; The molar ratio of thionyl chloride to fluorenemethyloxycarbonylformic acid is 1.3-2:1; The amount of pyridine used is 5-10% of the molar amount of thionyl chloride.

2. The synthesis process of fluorenemethyloxycarbonyl chloride according to claim 1, characterized in that: In S1, the molar ratio of 9-fluorenylmethanol to dimethyl carbonate is 1:1.5-2.

5.

3. The synthesis process of fluorenemethyloxycarbonyl chloride according to claim 1, characterized in that: In S1, the amount of p-toluenesulfonic acid used is 3-8% of the mass of 9-fluorenemethanol.

4. The synthesis process of fluorenemethyloxycarbonyl chloride according to claim 1, characterized in that: In S2, the molar ratio of sodium hydroxide to fluorene methoxycarbonyl carbamate intermediate is 1.2-2:1; the concentration of the sodium hydroxide aqueous solution is 1.5-2 mol / L.

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