Carbonylation reaction ester forming method for micropacked bed reactor

Abstract

The invention relates to a method for carbonylation esterification reaction of an immobilized Pd-catalyzed halogenated (hetero) aryl compound, CO and alcohols, organic alkali is used as an auxiliary agent and is applied to a micro-packed bed reaction system, the step of removing a catalyst in a Batch process after-treatment process using a homogeneous catalyst is avoided, the operation steps are simplified, the selectivity is high, the cost is low, and the method is suitable for industrial production. And the yield can reach 96% or above. Organic alkali needs to be added in the reaction to enrich the generated halogen anions, so that catalyst deactivation and equipment corrosion caused by the halogen anions are prevented; the micro-packed bed reaction system comprises a feeding system, a preheater, a micro-reactor, a gas-liquid separation device and a pressure reduction and back pressure system. The reaction system is a combination of continuous flow chemistry and a microreactor technology, the gas-liquid-solid three-phase interface contact area is increased by utilizing the advantages of a microchannel, multiphase mass transfer and heat transfer are greatly enhanced, the reaction time is remarkably shortened, the retention time distribution of the gas phase and the liquid phase is narrower, and side reactions can be reduced.

Description

Technical Field

[0001] The invention relates to the fields of medicine and chemical synthesis, and in particular to a method for carbonylation reaction to produce esters in a micro-packed bed reactor. Background Art

[0002] Carbonyl derivatives are widely used in the fields of coating production, fragrance processing and drug synthesis. Carbonyl-containing aromatic compounds obtained by carbonylation reaction with halogenated aromatic compounds as substrates are important organic chemical raw materials and indispensable reaction intermediates in fine chemical synthesis.

[0003] The most common carbonylation method is to use homogeneous noble metal (palladium, rhodium) catalysts to construct carbonyl compounds and their derivatives using metal carbonyl compounds as carbonyl sources. Due to the molecular-level active site distribution and high mass transfer efficiency of homogeneous catalysts, they show high conversion rates and directional selectivity. However, the difficulty in recycling the catalysts and the need for expensive phosphorus-containing ligands in the reaction system have greatly hindered their industrial application.

[0004] Carbon monoxide (CO) is considered to be the most ideal carbonyl source due to its 100% atomic efficiency and economy, and solid-supported catalysts have also been developed for the construction of carbonyl compounds. However, in traditional batch processes, the long contact time between reactants and catalysts often leads to overreaction, low selectivity, rapid catalyst deactivation, equipment corrosion and other problems. Not only that, it is difficult to achieve an ideal mass transfer and heat transfer process relying on the stirring paddle of a traditional intermittent reactor, which greatly limits the reaction process. Therefore, it is of great significance to develop a green and efficient carbonylation reaction system. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides a method for carbonylation reaction to produce esters using a micro-packed bed, characterized in that it comprises the following steps:

[0006] (1) mixing a reaction substrate, a reaction solvent and a reaction aid to prepare a raw material solution;

[0007] (2) introducing the raw material liquid and carbon monoxide into a microreactor for reaction, wherein the reaction tube of the microreactor is filled with a solid-supported catalyst;

[0008] The catalyst active component of the solid-supported catalyst is Pd;

[0009] (3) After the reaction is completed, the gas-liquid mixture obtained is subjected to gas-liquid separation and purification to obtain a reaction product.

[0010] In certain embodiments, the reaction substrate is a bromine-substituted aryl or heteroaryl compound, wherein the aryl or heteroaryl may be substituted with one or more substituents. The substituents are independently selected from hydrogen, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halogen, cyano, nitro, -C(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-C(O)C(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O) 2 R a or a 3-10 membered cycloalkyl, heterocyclic, aryl or heteroaryl group containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, 3-10 membered cycloalkyl, heterocyclic, aryl or heteroaryl group containing 0-3 heteroatoms may be optionally replaced by 1-3 R a replace;

[0011] Each R a , R b are independently selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halogen, hydroxy, cyano, nitro, benzyl, -C(O)NR c R d 、-C(O)R c 、-C(O)OR c 、-OR c 、-OC(O)R c 、-OC(O)OR c 、-OC(O)NR c R d 、-NR c R d 、-SRc 、-S(O)R c 、-S(O) 2 R c or a 3-10 membered cycloalkyl, heterocyclic, aryl or heteroaryl group containing 0-3 heteroatoms, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl or benzyl group may be optionally replaced by 1-3 R c replace;

[0012] Each R c , R d are independently selected from hydrogen, halogen, carbonyl, hydroxyl, cyano, nitro, phenyl, benzyl, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogenated C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl or halogenated C 3 -C 6 Cycloalkyl.

[0013] In certain embodiments, the aryl or heteroaryl group is selected from one of pyrimidine, pyridine, indole or a benzene ring.

[0014] In certain embodiments, the reaction substrate is selected from

[0015] In certain embodiments, the reaction solvent is one of methanol or ethanol.

[0016] In certain embodiments, when preparing the raw material solution in step (1), a co-solvent may be selectively added according to the type of ester to be generated, and the co-solvent is selected from one or more of DMF or THF.

[0017] In certain embodiments, the reaction aid is selected from one or more of triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicycloundec-7-ene.

[0018] In certain embodiments, the catalyst used in step (2) is a solid-supported DPPF-PdCl 2 The catalyst has an active component of Pd, and the noble metal accounts for 2-5% of the total weight of the catalyst.

[0019] In certain embodiments, the immobilized DPPF-PdCl used in step (2) 2 The noble metal in the catalyst accounts for 2.5-3.5% of the total weight of the catalyst.

[0020] In certain embodiments, the reaction temperature in step (2) is 100-150°C, preferably 110-130°C; the reaction pressure is 1-5 MPa, preferably 2.5-3.5 MPa; the reaction space velocity is 1-5 h -1 ; The gas-liquid ratio is 20 to 150; The reactant concentration is 1 to 10 wt%.

[0021] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0022] The term "alkenyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, the term "C 2-6 The term "alkenyl" refers to straight or branched unsaturated groups of 2 to 6 carbon atoms (having at least one carbon-carbon double bond), including but not limited to vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

[0023] The term "alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group has 2 to 20, 2 to 10, 2 to 6, or 3 to 6 carbon atoms. For example, "C 2-6 The term "alkynyl" includes straight or branched hydrocarbon chain alkynyl groups as defined above having 2 to 6 carbon atoms.

[0024] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0025] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl group comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms (e.g., 3, 4, 5 or 6 carbon atoms), and most preferably 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include cycloalkyl groups of spirocyclic, condensed and bridged rings.

[0026] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl.

[0027] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl.

[0028] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. It is preferably 6-14 members, and more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.

[0029] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. The non-limiting examples of monocyclic heterocyclic radicals include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl. Polycyclic heterocyclic radicals include spiro heterocyclic radicals, condensed heterocyclic radicals and bridged heterocyclic radicals.

[0030] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between rings, the spiro heterocyclic group is divided into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably, it is a 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 5-yuan or 5-yuan / 6-yuan single spiro heterocyclic group.

[0031] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group.

[0032] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.

[0033] The heterocyclic group includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:

[0034]

[0035] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0036] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5 or 6-membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and pyridazinyl.

[0037] The heteroaryl group includes a heteroaryl group as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0038]

[0039] The abbreviations of some reaction reagents involved in the present invention are as follows:

[0040] CO: Carbon monoxide

[0041] DIEA: N,N-diisopropylethylamine

[0042] DBU: 1,8-diazabicycloundec-7-ene

[0043] DMF: N,N-dimethylformamide

[0044] THF: Tetrahydrofuran

[0045] TEA: triethylamine

[0046] Beneficial Effects

[0047] The present invention combines a micro-packed bed with a supported catalyst, utilizes the advantages of the micro-packed bed to increase the gas-liquid-solid three-phase interface contact area, strengthens multiphase mass transfer and heat transfer, significantly improves reaction efficiency and shortens reaction time, and the reaction process is continuous, stable, safer and more reliable. By accurately adjusting the micro-packed bed reaction process parameters and utilizing the catalytic performance of the catalyst, the selectivity of the target carbonylation can be improved to more than 96%. DETAILED DESCRIPTION

[0048] The present invention is further illustrated below in conjunction with specific embodiments. The embodiments are implemented based on the technical solutions of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0049] Example 1

[0050] Weigh the raw material SM1 (10.0 g) and dissolve it in ethanol (375.4 g). Heat and ultrasonicate at 40°C for 30 min to remove the dissolved air in the solution, then add triethylamine (14.6 g) to prepare a raw material solution with a concentration of 2.5 wt%. Use a measuring cylinder to measure the catalyst immobilized type DPP-Pd R390-100 (6.5 ml, manufacturer: SiliCycle) was loaded into a micro-packed bed reaction tube. The reaction conditions were: temperature 130°C; reaction pressure 3.0 MPa; carbon monoxide flow rate 3.0 ml / min; liquid inlet flow rate 0.2 ml / min. After 2 hours of reaction, samples were taken and the components and contents in the reaction product were measured by gas chromatography. The chromatographic measurement results are shown in Table 2.

[0051] Example 2

[0052] Weigh the raw material SM2 (10.0 g) and dissolve it in a mixed solution of methanol (281 g) and tetrahydrofuran (92.3 g). Heat at 40°C for 30 min to remove the dissolved air in the solution, then add DBU (3.2 g) and DIEA (13.5 g) to prepare a raw material solution with a concentration of 2.5 wt%. Use a measuring cylinder to measure the catalyst immobilized type DPP-Pd R390-100 (6.5 ml, manufacturer: SiliCycle) was loaded into a micro-packed bed reaction tube. The reaction conditions were: temperature 110°C; reaction pressure 3.0 MPa; carbon monoxide flow rate 6.0 ml / min; liquid inlet flow rate 0.2 ml / min. After 2 hours of reaction, samples were taken and the components and contents in the reaction product were measured by liquid chromatography. The chromatographic measurement results are shown in Table 2.

[0053] Example 3

[0054] Weigh the raw material SM3 (10.0 g) and dissolve it in methanol (372.8 g). Heat and ultrasonicate at 40°C for 30 min to remove the dissolved air in the solution, then add DIEA (17.2 g) to prepare a raw material solution with a concentration of 2.5 wt%. DPP-Pd R390-100 (6.5 ml, manufacturer: SiliCycle) was loaded into a micro-packed bed reaction tube. The reaction conditions were: temperature 130°C; reaction pressure 3.0 MPa; carbon monoxide flow rate 8.0 ml / min; liquid inlet flow rate 0.3 ml / min. After 2 hours of reaction, samples were taken and the components and contents in the reaction product were measured by gas chromatography. The chromatographic measurement results are shown in Table 2.

[0055] Comparative Example 1

[0056] The comparative example is a batch carbonylation process.

[0057] Take the raw material SM1 (10.0 g), dissolve it in ethanol (100 ml), and then add the homogeneous catalyst DPPF-PdCl 2 (1.06g) and triethylamine (7.3g), then carbon monoxide gas was charged to 3.0MPa, the temperature was raised to 90°C and the reaction was continued for 24h, and the components and contents in the reaction product were measured by gas chromatography. The chromatographic measurement results are shown in Table 2.

[0058] Comparative Example 2

[0059] Take the raw material SM2 (10.0g), dissolve it in a mixed solution of DMF (100ml) and methanol (20ml), then add palladium acetate (0.47g), 1,3-bis(diphenylphosphine)propane (0.86g) and potassium carbonate (11.56g), then fill carbon monoxide gas to 3.0MPa, heat to 80℃ and react for 24h, take samples and measure the components and contents in the reaction product by gas chromatography. The chromatographic measurement results are shown in Table 2.

[0060] Comparative Example 3

[0061] Weigh the raw material SM3 (10.0 g), dissolve it in methanol (400 ml), and then add the homogeneous catalyst DPPF-PdCl 2 (1.3g) and triethylamine (17.2g), then carbon monoxide gas was charged to 3.0MPa, the temperature was raised to 100℃ and the reaction was carried out for 24h, and the components and contents in the reaction product were measured by gas chromatography. The chromatographic measurement results are shown in Table 2.

[0062] Table 1

[0063]

[0064] Table 2

[0065]

[0066] The results in Table 2 show that the method of the present invention for carbonylation reaction to produce esters using a micro-packed bed and the use of a solid-supported catalyst can reduce catalyst costs, improve reaction selectivity and reaction efficiency, and facilitate post-processing compared to the use of conventional precious metal catalysts and reactors.

Claims

1. A method for carbonylation reaction to produce esters using a micro-packed bed reactor, characterized in that: The following steps are involved: (1) mixing a reaction substrate, a reaction solvent and a reaction aid to prepare a raw material solution; (2) introducing the raw material liquid and carbon monoxide into a microreactor for reaction, wherein the reaction tube of the microreactor is filled with a solid-supported catalyst; The catalyst active component of the solid-supported catalyst is Pd; (3) After the reaction is completed, the gas-liquid mixture obtained is subjected to gas-liquid separation and purification to obtain a reaction product.

2. The method according to claim 1, characterized in that: The reaction substrate is a bromine-substituted aryl or heteroaryl compound, wherein the aryl or heteroaryl group may be substituted with one or more substituents.

3. The method according to claim 1 or claim 2, characterized in that: The aryl or heteroaryl group is selected from one of pyrimidine, pyridine, quinoline, indole or benzene ring.

4. The method according to claim 1, characterized in that The reaction substrate is selected from 5. The method according to claim 1, characterized in that The reaction solvent is one of methanol or ethanol.

6. The method according to claim 1, characterized in that In step (1), a co-solvent may be added when preparing the raw material solution, and the co-solvent is selected from one or more of N,N-dimethylformamide and tetrahydrofuran.

7. The method according to claim 1, characterized in that The reaction aid is selected from one or more of triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicycloundec-7-ene.

8. The method according to claim 1, characterized in that: The catalyst used in step (2) is a solid-supported DPPF-PdCl2 catalyst, the active component of which is Pd, and the catalyst precious metal accounts for 2 to 5% of the total weight of the catalyst.

9. The method according to claim 8, characterized in that The catalyst noble metal accounts for 2.5-3.5% of the total weight of the catalyst.

10. The method according to claim 1, characterized in that The reaction temperature in step (2) is 100-150°C; the reaction pressure is 1.0-5.0 MPa; the reaction space velocity is 1-5 h -1 ; The gas-liquid ratio is 20 to 150; The reactant concentration is 1 to 10 wt%.

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