A new synthesis process of 4-biphenylformaldehyde

Abstract

The invention discloses a novel synthesis process of 4-biphenyl formaldehyde, and belongs to the technical field of preparation of biphenyl formaldehyde. The specific scheme comprises the following two steps: using p-chlorobenzaldehyde as a starting material and ethylene glycol as an aldehyde group protecting agent, and adopting a trimethyl orthoformate dehydration process or a water separator dehydration process to synthesize an acetal intermediate (2-(4-chlorophenyl)-1,3-dioxane); phenyl magnesium chloride and the acetal intermediate form a biphenyl acetal intermediate under the action of Lewis acid, and finally hydrolyzing and deprotecting under acidic conditions to release a formyl group, so as to prepare 4-biphenyl formaldehyde with high yield and purity. The scheme has mild reaction conditions, low cost and novel synthesis of 4-biphenyl formaldehyde with high yield.

Description

Technical Field

[0001] The invention relates to the technical field related to biphenyl carboxaldehyde, in particular to a new synthesis process of 4-biphenyl carboxaldehyde. Background Art

[0002] 4-Biphenylcarboxaldehyde has unique physical and chemical properties due to its inherent conjugated structure. Therefore, it is widely used in medicine, pesticides, photovoltaic materials, liquid crystal materials, dyes and other fields. It has important industrial application value. Its synthesis method has received much attention from academia and industry. Currently, there are several methods for the synthesis of 4-biphenylcarboxaldehyde:

[0003] 1. A biphenyl synthesis method mainly based on palladium-catalyzed coupling reaction, wherein the main raw materials are p-halobenzaldehyde and phenylboric acid, phenyltin reagent, phenylsiloxane and Grignard reagent, etc., and divalent or zero-valent palladium is used as a catalyst to synthesize biphenyl under alkaline conditions. The metal palladium catalyst used in this method is expensive and the amount used is relatively large, which is not conducive to industrial production and application. The specific synthesis route is:

[0004]

[0005] 2. The second type of synthesis process directly uses biphenyl as the starting material to synthesize 4-biphenyl formaldehyde. First, biphenyl is brominated with liquid bromine to obtain a 4-bromobiphenyl intermediate, and then a biphenyl magnesium reagent or a biphenyl lithium reagent is synthesized through a Grignard reaction or a lithium halogen exchange reaction, and finally an aldehyde group is introduced by reacting with N,N-dimethylformamide (DMF) to finally synthesize 4-biphenyl formaldehyde. This process uses biphenyl as the starting material, avoids the use of precious metal catalysts, and reduces production costs to a certain extent. However, the price of lithium reagents is relatively high, the synthesis conditions of biphenyl metal reagents are relatively harsh, and the yield of the reaction with DMF is not outstanding. These reasons make its industrial production and application still have certain difficulties.

[0006]

[0007] This is the synthesis process of 4-biphenyl carboxaldehyde using biphenyl as the starting material.

[0008] Therefore, the object of the present invention is to provide a novel synthesis method of 4-biphenylcarboxaldehyde with mild reaction conditions, low cost and high yield. Summary of the invention

[0009] The invention aims to provide a new synthesis process of 4-biphenylcarboxaldehyde, which comprises the following steps: using p-chlorobenzaldehyde as a starting material, adopting ethylene glycol as an aldehyde group protecting agent, heating under reflux under acidic conditions to synthesize an acetal intermediate; reacting phenylmagnesium chloride with the acetal intermediate under the action of Lewis acid to form a biphenyl acetal intermediate, and finally hydrolyzing and deprotecting under acidic conditions to release a formyl group to obtain 4-biphenylcarboxaldehyde.

[0010] To achieve the above object, the present invention provides the following technical solution: a preparation process of 4-biphenylcarboxaldehyde, the preparation process comprising the following two steps:

[0011] Using p-chlorobenzaldehyde as a starting material, ethylene glycol as an aldehyde group protecting agent, and using a trimethyl orthoformate dehydration process or a water separator dehydration process to synthesize an acetal intermediate (2-(4-chlorophenyl)-1,3-dioxane);

[0012] Phenyl magnesium chloride and acetal intermediate form biphenyl acetal intermediate under the action of Lewis acid, and finally hydrolyze and deprotect under acidic conditions to release formyl group to prepare 4-biphenyl formaldehyde.

[0013] Furthermore, in the process of synthesizing the acetal intermediate by dehydrating trimethyl orthoformate, the molar ratio of p-chlorobenzaldehyde, ethylene glycol, trimethyl orthoformate and trifluoromethanesulfonic acid is 1:(1.1-10):(1.1-4):0.1.

[0014] Furthermore, a process for synthesizing an acetal intermediate by dehydration of trimethyl orthoformate is adopted, and the reaction temperature is 30-110°C.

[0015] Furthermore, in a process for synthesizing an acetal intermediate by dehydration using a water separator, the molar ratio of p-chlorobenzaldehyde, ethylene glycol and trifluoromethanesulfonic acid is 1:(1.1-3):0.1.

[0016] Furthermore, a process for synthesizing an acetal intermediate by dehydration using a water separator is employed, and the reaction temperature is 50-130°C.

[0017] Furthermore, the Lewis acid catalyst used in the reaction of phenylmagnesium chloride and the acetal intermediate is one of zinc chloride, manganese chloride and magnesium chloride.

[0018] Further, phenylmagnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate, and the molar ratio of 2-(4-chlorophenyl)-1,3-dioxane, phenylmagnesium chloride and the catalyst is 1:(1.05-2):(0-0.05).

[0019] Further, phenylmagnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate, and the reaction temperature is -5-50°C.

[0020] Beneficial effects:

[0021] The reaction conditions of the present invention are milder, and compared with the synthesis of biphenyl metal reagents, the reaction conditions are more relaxed. p-Chlorobenzaldehyde is used as the starting material, ethylene glycol is used as the aldehyde group protection reagent, the raw material cost is low, the dehydration process and the operation are relatively simple, which is more conducive to industrial production. DETAILED DESCRIPTION

[0022] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without making any creative work shall fall within the scope of protection of the present invention.

[0023] In the description of the present invention, it should be noted that the terms "upper", "lower", "inner", "outer", "front end", "rear end", "two ends", "one end", "the other end" and the like indicate positions or positional relationships based on the positions or positional relationships shown in the drawings, and are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as limiting the present invention. In addition, the terms "first" and "second" are used for descriptive purposes only and cannot be understood as indicating or implying relative importance.

[0024] In the description of the present invention, it should be noted that, unless otherwise clearly specified and limited, the terms "installed", "provided with", "connected", etc. should be understood in a broad sense. For example, "connected" can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection, or it can be indirectly connected through an intermediate medium, or it can be the internal communication of two components. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0025] Please refer to an embodiment provided by the present invention: using p-chlorobenzaldehyde as a starting material, using ethylene glycol as an aldehyde group protecting agent, heating under reflux under acidic conditions to synthesize an acetal intermediate; phenylmagnesium chloride and the acetal intermediate form a biphenyl acetal intermediate under the action of Lewis acid, and finally hydrolyzing and deprotecting under acidic conditions to release the formyl group to obtain 4-biphenylcarboxaldehyde. Its synthetic route is as follows:

[0026]

[0027] A preparation process of 4-biphenylformaldehyde, the preparation process comprising the following two steps:

[0028] Using p-chlorobenzaldehyde as a starting material, ethylene glycol as an aldehyde group protecting agent, and using a trimethyl orthoformate dehydration process or a water separator dehydration process to synthesize an acetal intermediate (2-(4-chlorophenyl)-1,3-dioxane);

[0029] Phenyl magnesium chloride and acetal intermediate form biphenyl acetal intermediate under the action of Lewis acid, and finally hydrolyze and deprotect under acidic conditions to release formyl group to prepare 4-biphenyl formaldehyde.

[0030] In the process of synthesizing the acetal intermediate by dehydrating trimethyl orthoformate, the molar ratio of p-chlorobenzaldehyde, ethylene glycol, trimethyl orthoformate and trifluoromethanesulfonic acid is 1:(1.1-10):(1.1-4):0.1.

[0031] The process of synthesizing the acetal intermediate by dehydration of trimethyl orthoformate has a reaction temperature of 30-110°C.

[0032] The invention discloses a process for synthesizing an acetal intermediate by dehydration using a water separator, wherein the molar ratio of p-chlorobenzaldehyde, ethylene glycol and trifluoromethanesulfonic acid is 1:(1.1-3):0.1.

[0033] The process of synthesizing acetal intermediates by dehydration using a water separator has a reaction temperature of 50-130°C.

[0034] The Lewis acid catalyst used in the reaction of phenylmagnesium chloride and acetal intermediate is one of zinc chloride, manganese chloride and magnesium chloride.

[0035] Phenyl magnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate, and the molar ratio of 2-(4-chlorophenyl)-1,3-dioxane, phenyl magnesium chloride and the catalyst is 1:(1.05-2):(0-0.05).

[0036] Phenyl magnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate, and the reaction temperature is -5-50°C.

[0037] Synthesis process 1 of acetal intermediate (using trimethyl orthoformate as dehydration reagent)

[0038]

[0039] Synthesis process of acetal intermediate

[0040] Example 1

[0041] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (124g), and trimethyl orthoformate (84.8g) to a 500mL three-necked flask in sequence. Stir and cool to 0-5℃, then add 3g of trifluoromethanesulfonic acid, keep the system temperature below 10℃, and heat to reflux for 5h after the addition is complete. After the reaction is completed, distill under reduced pressure to recover the solvent, and the recovered liquid is used for the next batch of reactions. After concentrating to near dryness, control the temperature of the concentrated solution to below 5℃, and adjust the pH to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, with the amounts of (100mL+50mL+50mL) respectively, combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain 31.3g of colorless transparent liquid (HPLC purity ≥99%) of acetal intermediate, with a yield of 84.8%.

[0042] Example 2

[0043] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (124g), trifluoromethanesulfonic acid (3g) in a 500mL three-necked flask, stir and cool to 0-5℃, then add trimethyl orthoformate (84.8g). Keep the system temperature below 10℃, and heat to reflux for 5h after the addition is complete. After the reaction is completed, distill under reduced pressure to recover the solvent, and use the recovered liquid for the next batch of reactions. After concentrating to near dryness, control the temperature of the concentrated solution to below 5℃, and adjust the pH to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, the dosage is (100mL+50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain the acetal intermediate as a colorless transparent liquid 29.3g (HPLC purity ≥99%), with a yield of 79.4%.

[0044] Example 3

[0045] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (24.8g), and trimethyl orthoformate (84.8g) to a 500mL three-necked flask in sequence. Stir and cool to 0-5°C, then add 3g of trifluoromethanesulfonic acid, keep the system temperature below 10°C, and heat to reflux for 5h after the addition is complete. After the reaction is completed, the solvent is recovered by vacuum distillation, and the recovered liquid is used for the next batch of reactions. After concentrating to near dryness, the temperature of the concentrated solution is controlled below 5°C, and the pH is adjusted to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, the amount used is (100mL+50mL+50mL), the organic phase is combined and concentrated to an oily substance, and distilled under high vacuum at 130°C. The steam temperature is collected at a fraction of 95°C to obtain acetal intermediate as a colorless transparent liquid of 28.96g (HPLC purity ≥99%), with a yield of 78.5%.

[0046] Example 4

[0047] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (13.64g), and trimethyl orthoformate (84.8g) to a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g of trifluoromethanesulfonic acid, keep the system temperature below 10℃, and heat to reflux for 5h after the addition is complete. After the reaction is completed, distill under reduced pressure to recover the solvent, and the recovered liquid is used for the next batch of reactions. After concentrating to near dryness, control the temperature of the concentrated solution to below 5℃, and adjust the pH to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, with the amounts of (100mL+50mL+50mL) respectively, combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain acetal intermediate as a colorless transparent liquid 29.7g (HPLC purity ≥99%), with a yield of 80.5%.

[0048] Example 5

[0049] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (124g), and trimethyl orthoformate (25.5g) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g of trifluoromethanesulfonic acid, keep the system temperature below 10℃, and heat to reflux for 5h after the addition is complete. After the reaction is completed, distill under reduced pressure to recover the solvent, and the recovered liquid is used for the next batch of reactions. After concentrating to near dryness, control the temperature of the concentrated solution to below 5℃, and adjust the pH to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, with the amounts of (100mL+50mL+50mL) respectively, combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain the acetal intermediate as a colorless transparent liquid 28.78g (HPLC purity ≥99%), with a yield of 78.0%.

[0050] Example 6

[0051] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (124g), and trimethyl orthoformate (42.4g) to a 500mL three-necked flask in sequence. Stir and cool to 0-5℃, then add 3g of trifluoromethanesulfonic acid, keep the system temperature below 10℃, and heat to reflux for 5h after the addition is complete. After the reaction is completed, the solvent is recovered by vacuum distillation, and the recovered liquid is used for the next batch of reactions. After concentrating to near dryness, the temperature of the concentrated solution is controlled below 5℃, and the pH is adjusted to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, the amount used is (100mL+50mL+50mL), the organic phase is combined and concentrated to an oily substance, and distilled under high vacuum at 130℃. The steam temperature is collected at 95℃, and the acetal intermediate is obtained as a colorless transparent liquid of 31.47g (HPLC purity ≥99%), with a yield of 85.3%.

[0052] Example 7

[0053] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (124g), and trimethyl orthoformate (84.8g) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g of trifluoromethanesulfonic acid, keep the system temperature below 10℃, and heat to 30℃ after the addition is complete to react for 5h. After the reaction is completed, the solvent is recovered by vacuum distillation, and the recovered liquid is used for the next batch of reactions. After concentrating to near dryness, the temperature of the concentrated solution is controlled below 5℃, and the pH is adjusted to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, the amount used is (100mL+50mL+50mL), the organic phase is combined and concentrated to an oily substance, and distilled under high vacuum at 130℃. The steam temperature is collected at 95℃, and the acetal intermediate is obtained as a colorless transparent liquid of 26.3g (HPLC purity ≥99%), with a yield of 71.3%.

[0054] Example 8

[0055] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (124g), and trimethyl orthoformate (84.8g) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g of trifluoromethanesulfonic acid, keep the system temperature below 10℃, and heat to 40℃ for 5h after the addition is complete. After the reaction is completed, distill under reduced pressure to recover the solvent, and the recovered liquid is used for the next batch of reactions. After concentrating to near dryness, control the temperature of the concentrated solution to below 5℃, and adjust the pH to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, with the amounts of (100mL+50mL+50mL) respectively, combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain acetal intermediate as a colorless transparent liquid 26.7g (HPLC purity ≥99%), with a yield of 72.6%.

[0056] Example 9

[0057] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (124g), and trimethyl orthoformate (84.8g) to a 500mL three-necked flask in sequence. Stir and cool to 0-5℃, then add 3g of trifluoromethanesulfonic acid, keep the system temperature below 10℃, and heat to 50℃ after the addition is complete to react for 5h. After the reaction is completed, the solvent is recovered by vacuum distillation, and the recovered liquid is used for the next batch of reactions. After concentrating to near dryness, the temperature of the concentrated solution is controlled below 5℃, and the pH is adjusted to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, the amount used is (100mL+50mL+50mL), the organic phase is combined and concentrated to an oily substance, and distilled under high vacuum at 130℃, and the steam temperature is collected at a fraction of 95℃, and the acetal intermediate is obtained as a colorless transparent liquid of 29g (HPLC purity ≥99%), with a yield of 78.6%.

[0058] Example 10

[0059] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (124g), and trimethyl orthoformate (84.8g) to a 500mL three-necked flask in sequence. Stir and cool to 0-5℃, then add 3g of trifluoromethanesulfonic acid, keep the system temperature below 10℃, and heat to 60℃ after the addition is complete to react for 5h. After the reaction is completed, the solvent is recovered by vacuum distillation, and the recovered liquid is used for the next batch of reactions. After concentrating to near dryness, the temperature of the concentrated solution is controlled below 5℃, and the pH is adjusted to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, the dosage is (100mL+50mL+50mL), the organic phase is combined and concentrated to an oily substance, and distilled under high vacuum at 130℃, and the steam temperature is collected at a fraction of 95℃, and the acetal intermediate is obtained as a colorless transparent liquid of 29.9g (HPLC purity ≥99%), with a yield of 81.2%.

[0060] Embodiment 11

[0061] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (124g), and trimethyl orthoformate (84.8g) to a 500mL three-necked flask in sequence. Stir and cool to 0-5℃, then add 3g of trifluoromethanesulfonic acid, keep the system temperature below 10℃, and heat to reflux for 4h after the addition is complete. After the reaction is completed, distill under reduced pressure to recover the solvent, and the recovered liquid is used for the next batch of reactions. After concentrating to near dryness, control the temperature of the concentrated solution to below 5℃, and adjust the pH to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, with the amounts of (100mL+50mL+50mL) respectively, combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain acetal intermediate as a colorless transparent liquid 29.2g (HPLC purity ≥99%), with a yield of 79.3%.

[0062] Example 12

[0063] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (124g), and trimethyl orthoformate (84.8g) to a 500mL three-necked flask in sequence. Stir and cool to 0-5℃, then add 3g of trifluoromethanesulfonic acid, keep the system temperature below 10℃, and heat to reflux for 6h after the addition is complete. After the reaction is completed, distill under reduced pressure to recover the solvent, and the recovered liquid is used for the next batch of reactions. After concentrating to near dryness, control the temperature of the concentrated solution to below 5℃, and adjust the pH to neutral (pH=7) with 20% sodium hydroxide solution. Extract with ethyl acetate three times, with the amounts of (100mL+50mL+50mL) respectively, combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain 31.07g of acetal intermediate as a colorless transparent liquid (HPLC purity ≥99%), with a yield of 84.2%.

[0064] Synthesis process 2 of acetal intermediate (dehydration using water separator)

[0065] Embodiment 13

[0066] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (24.8g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to reflux reaction for 5h, until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with a 5% sodium hydroxide solution. Separate the organic phase, extract the water phase with toluene twice, the amount used is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain 31.9g of acetal intermediate as a colorless transparent liquid (HPLC purity ≥99%), with a yield of 86.5%.

[0067] Embodiment 14

[0068] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (14.9g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to reflux reaction for 5h, until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with a 5% sodium hydroxide solution. Separate the organic phase, extract the water phase with toluene twice, the amount used is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain acetal intermediate as a colorless transparent liquid 27.9g (HPLC purity ≥99%), with a yield of 75.6%.

[0069] Embodiment 15

[0070] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (18.6g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to reflux reaction for 5h, until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with 5% sodium hydroxide solution. Separate the organic phase, extract the water phase with toluene twice, the amount is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain acetal intermediate as a colorless transparent liquid 29.37g (HPLC purity ≥99%), with a yield of 79.6%.

[0071] Example 16

[0072] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (37.2g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to reflux reaction for 5h, until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with a 5% sodium hydroxide solution. Separate the organic phase, extract the water phase with toluene twice, the amount used is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain 31.8g of acetal intermediate as a colorless transparent liquid (HPLC purity ≥99%), with a yield of 86.4%.

[0073] Embodiment 17

[0074] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (24.8g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to 50℃ and react for 5h until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with a 5% sodium hydroxide solution. Separate the organic phase, extract the water phase with toluene twice, the amount used is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain acetal intermediate as a colorless transparent liquid 20.0g (HPLC purity ≥99%), with a yield of 54.2%.

[0075] Embodiment 18

[0076] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (24.8g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to 60℃ and react for 5h until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with a 5% sodium hydroxide solution. Separate the organic phase, extract the water phase with toluene twice, the amount used is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain acetal intermediate as a colorless transparent liquid 25.2g (HPLC purity ≥99%), with a yield of 68.3%.

[0077] Embodiment 19

[0078] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (24.8g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to 70℃ and react for 5h until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with a 5% sodium hydroxide solution. Separate the organic phase, extract the water phase with toluene twice, the amount used is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain acetal intermediate as a colorless transparent liquid 27g (HPLC purity ≥99%), with a yield of 73.2%.

[0079] Embodiment 20

[0080] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (24.8g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to 80℃ and react for 5h until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with a 5% sodium hydroxide solution. Separate the organic phase, extract the water phase with toluene twice, the amount used is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain acetal intermediate as a colorless transparent liquid 27.6g (HPLC purity ≥99%), with a yield of 75%.

[0081] Embodiment 21

[0082] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (24.8g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to 90℃ and react for 5h until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with a 5% sodium hydroxide solution. Separate the organic phase, extract the water phase with toluene twice, the amount used is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain acetal intermediate as a colorless transparent liquid 28.4g (HPLC purity ≥99%), with a yield of 77.1%.

[0083] Embodiment 22

[0084] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (24.8g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to 100℃ and react for 5h until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with a 5% sodium hydroxide solution. Separate the organic phase, extract the water phase with toluene twice, the amount used is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain the acetal intermediate as a colorless transparent liquid 29.59g (HPLC purity ≥99%), with a yield of 80.2%.

[0085] Embodiment 23

[0086] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (24.8g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to reflux reaction for 4h, until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with 5% sodium hydroxide solution. Separate the organic phase, extract the water phase with toluene twice, the amount is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain acetal intermediate as a colorless transparent liquid 29.9g (HPLC purity ≥99%), with a yield of 81%.

[0087] Embodiment 24

[0088] At room temperature, add p-chlorobenzaldehyde (28.1g), ethylene glycol (24.8g), and toluene (150mL) in a 500mL three-necked flask. Stir and cool to 0-5℃, then add 3g trifluoromethanesulfonic acid, keep the system temperature below 10℃, install a water separator and a reflux condenser, heat to reflux reaction for 6h, until no new water droplets are produced in the water separator, and separate the water phase produced in the system. After the reaction, control the system temperature below 5℃, and adjust the pH to neutral (pH=7) with a 5% sodium hydroxide solution. Separate the organic phase, extract the aqueous phase with toluene twice, the amount used is (50mL+50mL), combine the organic phases and concentrate to an oily substance, distill under high vacuum at 130℃, collect the steam temperature of 95℃ fraction, and obtain 31.88g of acetal intermediate as a colorless transparent liquid (HPLC purity ≥99%), with a yield of 86.4%.

[0089] Synthesis process of 4-biphenylcarboxaldehyde

[0090]

[0091] Synthesis process of 4-biphenylcarboxaldehyde

[0092] Embodiment 25

[0093] Weigh 2-(4-chlorophenyl)-1,3-dioxane (36.9 g) and dry anhydrous manganese dichloride (1.25 g) in a dry 500 mL three-necked round-bottom flask, add dry tetrahydrofuran (230 mL) under a nitrogen atmosphere, replace the nitrogen atmosphere again after the addition is complete, and stir at room temperature until the solid is dissolved. Cool the reaction system to -5 to -10 ° C and start adding phenylmagnesium chloride solution (105 mL, concentration 2 mol / L). After the addition is complete, react at a temperature of -5 to 0 ° C for 5 hours, and monitor the reaction (thin layer chromatography, TLC) until the reaction is complete. After the reaction, 6 mol / L HCl aqueous solution was slowly added dropwise to the system until pH = 1-2. After stirring for 1 hour, the mixture was allowed to stand for stratification. The aqueous phase was extracted twice with ethyl acetate (150 + 50 mL). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent. The filtrate was purified by column chromatography to obtain 23.74 g (purity 98%) of an off-white solid with a yield of 65.2%.

[0094] Embodiment 26

[0095] Weigh 2-(4-chlorophenyl)-1,3-dioxane (36.9 g) in a dry 500 mL three-necked round-bottom flask, add dry tetrahydrofuran (230 mL) under nitrogen atmosphere, replace with nitrogen again after adding, and stir at room temperature until the solid dissolves. Cool the reaction system to -5 to -10 ° C and start to drop phenylmagnesium chloride solution (105 mL, concentration 2 mol / L). After the dropwise addition, react at -5 to 0 ° C for 5 hours, monitor the reaction (thin layer chromatography, TLC) until the reaction is complete. After the reaction is completed, slowly drop 6 mol / L HCl aqueous solution into the system until pH = 1-2, stir for 1 hour and then stand for stratification, extract the aqueous phase with ethyl acetate twice (150 + 50 mL), combine the organic phases, wash twice with saturated brine, dry over anhydrous sodium sulfate, filter, and remove the solvent by vacuum distillation of the filtrate. Purify by column chromatography to obtain 12.8 g of off-white solid (purity 98%), with a yield of 35.3%.

[0096] Embodiment 27

[0097] Weigh 2-(4-chlorophenyl)-1,3-dioxane (36.9 g) and dry anhydrous manganese dichloride (1.25 g) in a dry 500 mL three-necked round-bottom flask, add dry tetrahydrofuran (230 mL) under nitrogen atmosphere, replace with nitrogen again after addition, and stir at room temperature until the solid is dissolved. Cool the reaction system to -5 to -10 ° C and start to drop phenylmagnesium chloride solution (150 mL, concentration 2 mol / L). After the addition is complete, react at -5 to 0 ° C for 5 hours, and monitor the reaction (thin layer chromatography, TLC) until the reaction is complete. After the reaction, 6 mol / L HCl aqueous solution was slowly added dropwise to the system until pH = 1-2. After stirring for 1 hour, the mixture was allowed to stand for stratification. The aqueous phase was extracted twice with ethyl acetate (150 + 50 mL). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent. The filtrate was purified by column chromatography to obtain 18.57 g (purity 98%) of an off-white solid with a yield of 51%.

[0098] Embodiment 28

[0099] Weigh 2-(4-chlorophenyl)-1,3-dioxane (36.9 g) and dry anhydrous manganese dichloride (1.25 g) in a dry 500 mL three-necked round-bottom flask, add dry tetrahydrofuran (230 mL) under nitrogen atmosphere, replace with nitrogen again after addition, and stir at room temperature until the solid is dissolved. Cool the reaction system to -5 to -10 ° C and start to drop phenylmagnesium chloride solution (200 mL, concentration 2 mol / L). After the addition is complete, react at -5 to 0 ° C for 5 hours, and monitor the reaction (thin layer chromatography, TLC) until the reaction is complete. After the reaction, 6 mol / L HCl aqueous solution was slowly added dropwise to the system until pH = 1-2. After stirring for 1 hour, the mixture was allowed to stand for stratification. The aqueous phase was extracted twice with ethyl acetate (150 + 50 mL). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent. The filtrate was purified by column chromatography to obtain 17.04 g (purity 98%) of an off-white solid with a yield of 46.8%.

[0100] Embodiment 29

[0101] Weigh 2-(4-chlorophenyl)-1,3-dioxane (36.9 g) and dry anhydrous manganese dichloride (1.25 g) in a dry 500 mL three-necked round-bottom flask, add dry tetrahydrofuran (230 mL) under nitrogen atmosphere, replace with nitrogen again after addition, and stir at room temperature until the solid is dissolved. Cool the reaction system to 5-10°C and start adding phenylmagnesium chloride solution (105 mL, concentration 2 mol / L). After the addition is complete, react at 5-10°C for 5 hours, and monitor the reaction (thin layer chromatography, TLC) until the reaction is complete. After the reaction, 6 mol / L HCl aqueous solution was slowly added dropwise to the system until pH = 1-2. After stirring for 1 hour, the mixture was allowed to stand for stratification. The aqueous phase was extracted twice with ethyl acetate (150 + 50 mL). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent. The filtrate was purified by column chromatography to obtain 21.96 g (purity 98%) of an off-white solid with a yield of 60.3%.

[0102] Embodiment 30

[0103] Weigh 2-(4-chlorophenyl)-1,3-dioxane (36.9 g) and dry anhydrous manganese dichloride (1.25 g) in a dry 500 mL three-necked round-bottom flask, add dry tetrahydrofuran (230 mL) under nitrogen atmosphere, replace with nitrogen again after addition, and stir at room temperature until the solid is dissolved. Cool the reaction system to 5-10°C and start adding phenylmagnesium chloride solution (105 mL, concentration 2 mol / L). After the addition is complete, react at 15-20°C for 5 hours, and monitor the reaction (thin layer chromatography, TLC) until the reaction is complete. After the reaction, 6 mol / L HCl aqueous solution was slowly added dropwise to the system until pH = 1-2. After stirring for 1 hour, the mixture was allowed to stand for stratification. The aqueous phase was extracted twice with ethyl acetate (150 + 50 mL). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent. The filtrate was purified by column chromatography to obtain 19.74 g (purity 98%) of an off-white solid with a yield of 54.2%.

[0104] Embodiment 31

[0105] Weigh 2-(4-chlorophenyl)-1,3-dioxane (36.9 g) and dry anhydrous manganese dichloride (1.25 g) in a dry 500 mL three-necked round-bottom flask, add dry tetrahydrofuran (230 mL) under a nitrogen atmosphere, replace the nitrogen atmosphere again after the addition is complete, and stir at room temperature until the solid is dissolved. Cool the reaction system to 5 to -10 ° C and start adding phenylmagnesium chloride solution (105 mL, concentration 2 mol / L). After the addition is complete, react at a temperature of 25 to 30 ° C for 5 hours, and monitor the reaction (thin layer chromatography, TLC) until the reaction is complete. After the reaction, 6 mol / L HCl aqueous solution was slowly added dropwise to the system until pH = 1-2. After stirring for 1 hour, the mixture was allowed to stand for stratification. The aqueous phase was extracted twice with ethyl acetate (150 + 50 mL). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent. The filtrate was purified by column chromatography to obtain 18.2 g (purity 98%) of an off-white solid with a yield of 50%.

[0106] Embodiment 29

[0107] Weigh 2-(4-chlorophenyl)-1,3-dioxane (36.9 g) and dry anhydrous manganese dichloride (1.25 g) in a dry 500 mL three-necked round-bottom flask, add dry tetrahydrofuran (230 mL) under nitrogen atmosphere, replace with nitrogen again after addition, and stir at room temperature until the solid is dissolved. Cool the reaction system to 5 to -10 ° C and start to drop phenylmagnesium chloride solution (105 mL, concentration 2 mol / L). After the addition is complete, react at 35 to 45 ° C for 5 hours, and monitor the reaction (thin layer chromatography, TLC) until the reaction is complete. After the reaction, 6 mol / L HCl aqueous solution was slowly added dropwise to the system until pH = 1-2. After stirring for 1 hour, the mixture was allowed to stand and decomposed. The aqueous phase was extracted twice with ethyl acetate (150 + 50 mL). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent and purified by column chromatography to obtain 15.3 g (purity 98%) of an off-white solid with a yield of 42%.

[0108] Embodiment 30

[0109] Weigh 2-(4-chlorophenyl)-1,3-dioxane (36.9 g) and dry anhydrous zinc chloride (2.5 g) in a dry 500 mL three-necked round-bottom flask, add dry tetrahydrofuran (230 mL) under a nitrogen atmosphere, replace the nitrogen atmosphere again after the addition is complete, and stir at room temperature until the solid is dissolved. Cool the reaction system to -5 to -10 ° C and start to drop phenylmagnesium chloride solution (105 mL, concentration 2 mol / L). After the addition is complete, react at a temperature of -5 to 0 ° C for 5 hours, and monitor the reaction (thin layer chromatography, TLC) until the reaction is complete. After the reaction, 6 mol / L HCl aqueous solution was slowly added dropwise to the system until pH = 1-2. After stirring for 1 hour, the mixture was allowed to stand for stratification. The aqueous phase was extracted twice with ethyl acetate (150 + 50 mL). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent and purified by column chromatography to obtain 23.63 g (purity 98%) of an off-white solid with a yield of 64.9%.

[0110] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any figure mark in a claim should not be considered as limiting the claim to which it relates.

Claims

1. A preparation process of 4-biphenylcarboxaldehyde, characterized in that: the preparation process comprises the following two steps: Using p-chlorobenzaldehyde as a starting material, ethylene glycol as an aldehyde group protecting agent, and using a trimethyl orthoformate dehydration process or a water separator dehydration process to synthesize an acetal intermediate 2-4-chlorophenyl-1,3-dioxane; Phenyl magnesium chloride and acetal intermediate form biphenyl acetal intermediate under the action of Lewis acid, and finally hydrolyze and deprotect under acidic conditions to release formyl group, so as to prepare 4-biphenyl formaldehyde with high yield and purity.

2. A novel synthesis process of 4-biphenylcarboxaldehyde according to claim 1, characterized in that: In the process of synthesizing the acetal intermediate by dehydrating trimethyl orthoformate, the molar ratio of p-chlorobenzaldehyde, ethylene glycol, trimethyl orthoformate and trifluoromethanesulfonic acid is 1:(1.1-10):(1.1-4):0.

1.

3. A novel synthesis process of 4-biphenylcarboxaldehyde according to claim 2, characterized in that: The process of synthesizing the acetal intermediate by dehydration of trimethyl orthoformate has a reaction temperature of 30-110°C.

4. A novel synthesis process of 4-biphenylcarboxaldehyde according to claim 3, characterized in that: The invention discloses a process for synthesizing an acetal intermediate by dehydration using a water separator, wherein the molar ratio of p-chlorobenzaldehyde, ethylene glycol and trifluoromethanesulfonic acid is 1:(1.1-3):0.

1.

5. The method for preparing 4-biphenylcarboxaldehyde according to claim 4, characterized in that: The process of synthesizing acetal intermediates by dehydration using a water separator has a reaction temperature of 50-130°C.

6. The method for preparing 4-biphenylcarboxaldehyde according to claim 5, characterized in that: The Lewis acid catalyst used in the reaction of phenylmagnesium chloride and acetal intermediate is one of zinc chloride, manganese chloride and magnesium chloride.

7. The method for preparing 4-biphenylcarboxaldehyde according to claim 6, characterized in that: Phenyl magnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate, and the molar ratio of 2-(4-chlorophenyl)-1,3-dioxane, phenyl magnesium chloride and the catalyst is 1:(1.05-2):(0-0.05).

8. The method for preparing 4-biphenylcarboxaldehyde according to claim 7, characterized in that: Phenyl magnesium chloride reacts with the acetal intermediate to form a biphenyl acetal intermediate, and the reaction temperature is -5-50°C.

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