Preparation method of 1, 2-dimethyl-3H-cyclopentyl [b] benzothiophene

Abstract

The invention belongs to the field of chemistry and chemical engineering, and particularly discloses a preparation method of 1, 2-dimethyl-3H-cyclopentyl [b] benzothiophene, which comprises the following steps: taking phosphorus pentoxide as a dehydrating agent, preparing an intermediate through dehydration condensation reaction of benzothiophene and methyl butenoic acid, and performing reduction reaction to obtain a target product. Compared with the prior art, the method has the advantages that the use of n-butyllithium which is high in activity and easy to spontaneously ignite, a CuCN reagent which is high in toxicity and (E)-2-methyl-2-butenoyl chloride which is active in chemical property and not easy to store is avoided, so that the production safety is remarkably improved, and the influence on the environment is reduced. Meanwhile, chemical reagents adopted in the method are stable in property and sufficient in market supply, reaction conditions are mild, low-temperature conditions are not needed, and industrial continuous amplification production is better facilitated. Therefore, the preparation method provided by the invention has a wide application prospect, and provides powerful support for industrial production of the 1, 2-dimethyl-3H-cyclopentyl [b] benzothiophene.

Description

Technical Field

[0001] The invention belongs to the field of chemistry and chemical engineering, and specifically relates to an olefin polymerization catalyst and a preparation method thereof. Background Art

[0002] As an excellent olefin polymerization catalyst, metallocene catalyst has been widely used in the field of materials and chemical industry. Since the last century, metallocene catalysts have been rapidly developed, from non-bridged to bridged structures, from di-metallocene to mono-metallocene, from C bridge to Si bridge, from bridged di-metallocene to bridged heteroatom, which have greatly promoted the synthesis, structure and catalytic performance of transition metal complexes and greatly enriched the catalytic performance of metallocene complexes.

[0003] KR102223719 reported a benzothiophene metallocene catalyst that exhibited more advanced polymerization performance in the catalysis of styrene and acetylene analogs. These metallocene catalysts are basically formed by complexing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene with Si or Ti. The literature also introduced the synthesis of 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene, which is first hydrogenated by butyl lithium and then reacted with CuCN to form a copper lithium reagent, and then docked with (E)-2-methyl-2-butenoyl chloride to generate intermediate III, which is cyclized under sulfuric acid conditions, and finally reduced by NaBH4 and dehydrated with p-toluenesulfonic acid to generate the target compound 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene.

[0004]

[0005] In the above process, n-butyl lithium is used as a hydrogen extraction reagent, which is highly active and easily self-ignites, and has a high safety risk when scaled up; CuCN reagent is highly toxic and environmentally unfriendly; (E)-2-methyl-2-butenoyl chloride is chemically active, difficult to preserve, and in short supply in the market. The reaction temperature is low and requires dry ice and liquid nitrogen for cooling, so the above process is only suitable for laboratory small-scale research, not for industrial continuous scale-up production, and has limited application prospects. Summary of the invention

[0006] In order to solve the above problems, we disclose a method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene. In the present invention, phosphorus pentoxide is used as a dehydrating agent, and benzothiophene is directly dehydrated and condensed with methyl butyl acid. The chemical reagent has stable properties and sufficient market supply, mild reaction conditions, greatly improved production safety, and is conducive to industrial production and application.

[0007] The present invention includes the following specific technical solutions:

[0008] A method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene, characterized in that it comprises the following steps:

[0009] (1) Condensation reaction: Phosphorus pentoxide is fully dissolved in a reaction solvent, methyl butyl acrylate is added thereto, and after stirring for a period of time, benzothiophene is added dropwise thereto. After the reaction is completed, water is added to quench the reaction, and the product is extracted with dichloromethane and concentrated to generate intermediate II;

[0010] (2) Reduction reaction: sodium borohydride and tetrahydrofuran are added to the intermediate II, the temperature is raised to reflux, methanol is added dropwise thereto, and reflux and stirring are maintained until the reaction is complete, p-toluenesulfonic acid is added thereto, the temperature is raised to reflux and the reaction is carried out until the intermediate state is completely converted, and the target product I is obtained after washing with water, concentration and crystallization with n-heptane;

[0011] The reaction formula is as follows:

[0012]

[0013] Furthermore, in the above-mentioned method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene, in the reaction of step (1), the reaction solvent is methanesulfonic acid or trifluoromethanesulfonic acid.

[0014] Furthermore, in the above-mentioned method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene, in the reaction of step (1), the molar ratio of phosphorus pentoxide to benzothiophene is 1.2 / 1-1.5 / 1.

[0015] Furthermore, in the above-mentioned method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene, in the reaction of step (1), the molar ratio of methylbutyric acid to benzothiophene is 1.05 / 1-1.2 / 1.

[0016] Furthermore, in the above-mentioned method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene, in the reaction of step (1), the molar ratio of methylbutyric acid to benzothiophene is 1.1 / 1.

[0017] Furthermore, in the above-mentioned method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene, in the reaction of step (1), the volume mass ratio of the reaction solvent to benzothiophene is 5-8 mL / g; preferably 7 mL / g.

[0018] Furthermore, in the above-mentioned method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene, in the reaction of step (1), the reaction temperature is 30°C-50°C, preferably 40-45°C.

[0019] Furthermore, in the above-mentioned method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene, in the reaction of step (1), the reaction time is 5-12 hours.

[0020] The invention also discloses 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene, which is prepared by the above method.

[0021] Compared with the prior art, the present invention has the following outstanding beneficial effects:

[0022] The present invention provides an improved method for synthesizing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene (Compound I), which effectively solves the industrial production problem existing in the prior art. By using phosphorus pentoxide as a dehydrating agent, direct dehydration condensation of benzothiophene and methylbutenoic acid is achieved, avoiding the use of highly active and self-igniting n-butyl lithium, highly toxic CuCN, and chemically active and difficult to preserve (E)-2-methyl-2-butenoyl chloride and other reagents. This improvement not only significantly improves the safety of the production process, but also reduces the negative impact on the environment.

[0023] At the same time, the chemical reagents used in the present invention are stable in nature and have sufficient market supply, and the reaction conditions are mild, and no special cooling equipment and methods are required, which greatly reduces the production cost and equipment requirements. In addition, by optimizing the reaction solvent, reactant ratio, reaction temperature and reaction time, the yield and purity of the target product are further improved.

[0024] In summary, the synthesis method of the present invention has the significant advantages of strong feasibility of industrial production, high production safety, environmental friendliness, low cost, etc., which provides strong support for the industrial production of 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene and has broad application prospects and important economic value. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 HPLC diagram of Example 2 product I;

[0026] Figure 2 HNMR diagram of product I of Example 2;

[0027] Figure 3 MS spectrum of product I in Example 2. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] Comparative Example 1

[0030] Step 1: Preparation of intermediate III

[0031] Add 13.4g benzothiophene and 67ml anhydrous tetrahydrofuran to a 250ml three-necked flask, cool to -70~-78℃ with a dry ice bath, slowly drop 42ml 2.5M n-butyl lithium solution after nitrogen is fully replaced, keep the internal temperature at -70~-78℃, stir for 1h, add 4.5g cuprous cyanide, continue to stir for 0.5h, drop 11.9g methyl butyl chloride, slowly return to room temperature after the addition is complete, stir at room temperature until the reaction of the intermediate control raw material is complete. Add dilute hydrochloric acid to quench the reaction, wash with water and dry with anhydrous sodium sulfate, and directly concentrate to obtain intermediate III

[0032] Step 2: Preparation of intermediate II

[0033] Add 67ml of concentrated sulfuric acid to a 250ml three-necked flask, cool to 0℃, add the concentrated intermediate III to the concentrated sulfuric acid, slowly return to room temperature and stir until the intermediate III reacts completely, add 67ml of water and 67ml of ethyl acetate to the reaction solution, stir thoroughly and separate the organic phase, wash the organic phase twice with 67ml×2 water, and directly concentrate the organic phase to obtain intermediate II

[0034] Step 3: Preparation of target product I

[0035] To the concentrated intermediate II, 134 ml of tetrahydrofuran and 7.6 g of sodium borohydride were added, the temperature was raised to reflux, 6.7 ml of methanol was slowly added dropwise, and the reflux reaction was maintained until the intermediate II was completely reacted; 17.2 g of anhydrous p-toluenesulfonic acid was added thereto, and the reflux stirring was continued until the intermediate state was completely reacted; the organic phase was concentrated to dryness, ethyl acetate was added thereto to fully dissolve, and the mixture was washed with saturated sodium bicarbonate solution and semi-saturated brine respectively, dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness, 134 ml of n-heptane was added thereto for recrystallization, and 11.2 g of an off-white solid was obtained with a yield of 56%.

[0036] Example 1

[0037] Step 1: Preparation of intermediate II

[0038] Add 94 ml of methanesulfonic acid and 21.3 g of phosphorus pentoxide to a 250 ml three-necked flask. After fully dissolving, add 12 g of methyl butyl acrylate in batches and stir at room temperature for 1 hour. Slowly drop 13.4 g of benzothiophene in the mixture. After the addition is complete, heat to 40-50 °C and stir until the benzothiophene reacts completely. Add saturated sodium carbonate solution to quench the reaction, add 60 ml × 2 dichloromethane to extract twice, combine the organic phases, wash with water, dry over anhydrous sodium sulfate, and concentrate to obtain intermediate II.

[0039] Step 2: Preparation of target product I

[0040] To the concentrated intermediate II, 134 ml of tetrahydrofuran and 7.6 g of sodium borohydride were added, the temperature was raised to reflux, 6.7 ml of methanol was slowly added dropwise, and the reflux reaction was maintained until the intermediate II was completely reacted; 17.2 g of anhydrous p-toluenesulfonic acid was added thereto, and the reflux stirring was continued until the intermediate state was completely reacted; the organic phase was concentrated to dryness, ethyl acetate was added thereto to fully dissolve, and the mixture was washed with saturated sodium bicarbonate solution and semi-saturated brine respectively, dried over anhydrous sodium sulfate, and the organic phase was concentrated to dryness, 134 ml of n-heptane was added thereto for recrystallization, and 12.6 g of an off-white solid was obtained with a yield of 63%.

[0041] Example 2

[0042] Step 1: Preparation of intermediate II

[0043] Add 1390kg of methylsulfonic acid and 185kg of phosphorus pentoxide to a 3000L reactor, stir at room temperature for 1h, then add 110kg of methylbutyric acid in batches, and continue stirring at room temperature for 1h. Slowly drop 134kg of benzothiophene, raise the temperature to 40-45℃ after the addition is complete, and keep stirring until the benzothiophene reacts completely. Drop 1400kg of 10% sodium carbonate solution to quench the reaction, add 800kg×2 dichloromethane to extract twice, combine the organic phases, wash with 670kg of water, and concentrate at 40-45℃ until the distillate is drop-shaped.

[0044] Step 2: Preparation of target product I

[0045] Add 1200kg of tetrahydrofuran and 76kg of sodium borohydride to a 3000L reactor, raise the temperature to 60-65°C, slowly drop 60kg of methanol thereinto, maintain the temperature at 60-65°C to react until the intermediate II reacts completely; add 17.2g of anhydrous p-toluenesulfonic acid thereto, continue to maintain reflux stirring until the intermediate state reacts completely; concentrate at 40-45°C until the distillate is in a drop shape, add 1200kg of ethyl acetate thereto, stir at room temperature for 2h, wash the organic phase with 600kg of 5% sodium bicarbonate solution and 600kg of 10% brine respectively, concentrate at 40-45°C until the distillate is in a drop shape, add 900kg of n-heptane thereto for recrystallization, and obtain 120kg of off-white solid with a yield of 60%.

[0046] 1H-NMR (400M, DMSO) δ7.95 (t, J=8 Hz, 2H), 7.37 (t, J=8 Hz, 1H), 7.28 (t, J=8 Hz, 1H), 3.36 (t, J=4 Hz, 2H), 2.26 (s, 3H), 2.03 (s, 3H). MS (ESI): m / z 223 (M+Na). HPLC purity analysis of product I is shown in Figure 1 , NMR images are shown in Figure 2 , mass spectrum see Figure 3 As can be seen from the figure, the purity of the product I obtained by this preparation method is above 98.5%.

[0047] From the above comparative examples and embodiments, it can be concluded that in view of the defects in the prior art, the condensation and cyclization steps use reagents such as n-butyl lithium, CuCN, (E)-2-methyl-2-butenoyl chloride, which are not conducive to industrial production and amplification, and the reaction temperature is low, and special equipment and cooling methods are required. The present invention uses phosphorus pentoxide as a dehydrating agent to directly condense benzothiophene and methylbutenoic acid into a ring, eliminating highly toxic and dangerous reagents such as n-butyl lithium and CuCN. The operation safety is improved, it is environmentally friendly, and it is conducive to the process to achieve industrial production.

[0048] The above are only a few preferred embodiments of the present invention, which are described in a more specific and detailed manner, but they cannot be understood as limiting the scope of the present invention. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene, characterized in that: The following steps are involved: (1) Condensation reaction: Phosphorus pentoxide is fully dissolved in a reaction solvent, methyl butyl acrylate is added thereto, and after stirring for a period of time, benzothiophene is added dropwise thereto. After the reaction is completed, water is added to quench the reaction, and the product is extracted with dichloromethane and concentrated to generate intermediate II; (2) Reduction reaction: sodium borohydride and tetrahydrofuran are added to the intermediate II, the temperature is raised to reflux, methanol is added dropwise thereto, and reflux and stirring are maintained until the reaction is complete, p-toluenesulfonic acid is added thereto, the temperature is raised to reflux and the reaction is carried out until the intermediate state is completely converted, and the target product I is obtained after washing with water, concentration and crystallization with n-heptane; The reaction formula is as follows:

2. The method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene according to claim 1, characterized in that: In the reaction of step (1), the reaction solvent is methanesulfonic acid or trifluoromethanesulfonic acid.

3. The method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene according to claim 1, characterized in that: In the reaction of step (1), the molar ratio of phosphorus pentoxide to benzothiophene is 1.2 / 1-1.5 / 1.

4. The method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene according to claim 1, characterized in that: In the reaction of step (1), the molar ratio of methylbutyric acid to benzothiophene is 1.05 / 1-1.2 / 1.

5. The method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene according to claim 4, characterized in that: In the reaction of step (1), the molar ratio of methylbutyric acid to benzothiophene is 1.1 / 1.

6. The method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene according to claim 1, characterized in that: In the reaction of step (1), the volume mass ratio of the reaction solvent to benzothiophene is 5-8 mL / g, preferably 7 mL / g.

7. The method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene according to claim 1, characterized in that: In the reaction of step (1), the reaction temperature is 30°C-50°C, preferably 40-45°C.

8. The method for preparing 1,2-dimethyl-3H-cyclopentyl[b]benzothiophene according to claim 1, characterized in that: In the reaction of step (1), the reaction time is 5-12 hours.

9. 1,2-Dimethyl-3H-cyclopentyl[b]benzothiophene, characterized in that Prepared by the method according to any one of claims 1 to 8.

Images