CN112552259A - Preparation method of 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone - Google Patents
Preparation method of 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- -1 4-substituted phenyl Chemical group 0.000 title claims abstract description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 title claims abstract description 19
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 140
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 239000007864 aqueous solution Substances 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 37
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 239000002253 acid Substances 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 102
- 239000000047 product Substances 0.000 claims description 54
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 32
- 239000002585 base Substances 0.000 claims description 25
- 150000004820 halides Chemical class 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 238000004821 distillation Methods 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000007795 chemical reaction product Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 4
- 239000012454 non-polar solvent Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000007142 ring opening reaction Methods 0.000 abstract description 22
- 238000006467 substitution reaction Methods 0.000 abstract description 19
- 239000004927 clay Substances 0.000 abstract description 15
- 238000006735 epoxidation reaction Methods 0.000 abstract description 14
- 239000003054 catalyst Substances 0.000 abstract description 13
- 238000001914 filtration Methods 0.000 abstract description 8
- 238000011084 recovery Methods 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 239000004593 Epoxy Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000001308 synthesis method Methods 0.000 description 5
- NNAHKQUHXJHBIV-UHFFFAOYSA-N 2-methyl-1-(4-methylthiophen-2-yl)-2-morpholin-4-ylpropan-1-one Chemical compound CC1=CSC(C(=O)C(C)(C)N2CCOCC2)=C1 NNAHKQUHXJHBIV-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000003999 initiator Substances 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 150000002367 halogens Chemical group 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 150000001649 bromium compounds Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000012840 feeding operation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229910052901 montmorillonite Inorganic materials 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000009489 vacuum treatment Methods 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone; the preparation method comprises two steps of epoxidation reaction and morpholine substitution reaction; in the morpholine substitution reaction, a proper amount of auxiliary agent is added, wherein the auxiliary agent is selected from at least one of water, strong acid, weak base salt and salt aqueous solution and strong base, weak acid and salt aqueous solution, so that the ring opening rate and the ring opening selectivity in the morpholine substitution reaction process can be obviously accelerated, the overall reaction rate and yield are further improved, the problems of difficult subsequent catalyst filtration and recovery and product purification caused by adding catalysts such as clay in the traditional process are solved, the high-purity 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone can be more favorably obtained, the process cost and the post-treatment operation risk are reduced, and the economic benefit is improved.
Description
Technical Field
The invention belongs to the field of organic synthesis, and relates to a preparation method of 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone, in particular to a preparation method of high-purity 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone.
Background
2-methyl-1- (4-methylthiophenyl) -2-morpholinyl-1-acetone (ultraviolet initiator 907) can absorb ultraviolet radiation energy to form free radicals or cations in the ink curing process, initiate monomers and oligomers to perform polymerization, crosslinking and grafting reactions, and cure the ink into a high molecular polymer with a three-dimensional network structure in a short time; the molecular structure of the uv initiator 907 is shown below:
regarding the synthesis method of the ultraviolet initiator 907, CN101633647A discloses a method for synthesizing α -amino aryl alkyl ketone compounds with high selectivity and high yield, the synthesis method comprises friedel-crafts reaction, bromination reaction, epoxidation reaction and amine substitution ring-opening reaction, and a catalyst is added when epoxide reacts with organic amine, the catalyst is obtained by taking any one or more of montmorillonite, kaolin, clay, bentonite or carclazyte as raw materials; the synthesis method has the problems of difficult catalyst separation after subsequent ring-opening reaction, high operation cost and dark product color generated by the reaction, and 5-10% of activated carbon is required for decolorization.
CN102659717A discloses a synthesis method of 2-methyl-1- (4-methylthiophenyl) -2-morpholinyl-1-propanone, wherein hydrochloric acid is adopted for acidification in the ring opening process to obtain 1- (4-chlorophenyl) -2-methyl-2-morpholinyl-1-propanol hydrochloride, and then the hydrochloride is oxidized and substituted to obtain a target product 2-methyl-1- (4-methylthiophenyl) -2-morpholinyl-1-propanone; the synthesis method adds an oxidation step, and has complex process and high cost. CN110563671A discloses a preparation method of a photoinitiator 2-methyl-1- (4-methylthiophenyl) -2-morpholinyl-1-acetone, which comprises the steps of friedel-crafts acylation reaction, chlorination, epoxidation, morpholinyl substitution, methylthio substitution and refining; in addition to the risk of strong corrosion in the operation process, more importantly, in the nucleophilic reaction process with the epoxy intermediate, a large amount of hydroxide anions exist in high-concentration liquid alkali, and a strong competitive relationship exists with the substitution reaction of morpholine, and meanwhile, the possibility of elimination reaction is increased due to the strong alkalinity of the reaction system, and the elimination product can further react with the morpholine, so that the product has poor purity and is not easy to purify.
Therefore, the development of the preparation method of the 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone, which has the advantages of high ring opening efficiency in the morpholine substitution reaction process, simple post-treatment process and low operation risk, is still of great significance.
Disclosure of Invention
The invention aims to provide a preparation method of 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone; the preparation method comprises two steps of epoxidation reaction and morpholine substitution reaction; in the morpholine substitution reaction, a proper amount of auxiliary agent is added, wherein the auxiliary agent is selected from at least one of water, strong acid, weak base salt and salt aqueous solution and strong base, weak acid and salt aqueous solution, so that the ring opening rate and the ring opening selectivity in the morpholine substitution reaction process can be obviously accelerated, the overall reaction rate and yield are further improved, the problems of difficult subsequent catalyst filtration and recovery and product purification caused by adding catalysts such as clay in the traditional process are solved, the high-purity 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone can be more favorably obtained, the process cost and the post-treatment operation risk are reduced, and the economic benefit is improved.
The high purity of the invention means that the purity of the product is more than or equal to 99 percent.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone, which comprises the following steps:
(1) adding halide into a mixed solution of methanol and sodium methoxide, controlling the temperature to react, and heating and distilling the methanol to obtain a reaction product; the molecular formula of the halide is shown as a formula I);
wherein R is selected from halogen and R1S, H or R2Any one of (1), R1And R2Selected from C1-C4 alkyl, X is selected from Cl or Br;
preferably R1And R2Can be methyl, ethyl, propyl, butyl or tert-butyl;
(2) morpholine and an auxiliary agent are added into the reaction product obtained in the step (1), and temperature control reaction is carried out to obtain the 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone;
wherein the auxiliary agent is selected from at least one of water, a strong acid and weak base salt aqueous solution and a strong base and weak acid salt aqueous solution.
In the traditional morpholine substitution reaction, auxiliaries such as argil and the like are required to be added as catalysts to promote the ring opening reaction, improve the ring opening selectivity and reduce the generation of impurities, but the post-treatment of the reaction is complicated, firstly, the auxiliaries such as argil and the like are introduced, and the auxiliaries need to be filtered out in the post-treatment; secondly, the clay is fine, so that the viscosity of the material is high, the filtering is difficult, and a small amount of clay enters the filtrate due to the fact that the clay easily penetrates through the filter paper, so that the quality of the final product is unqualified. Again, filtering the clay increases operational risks (such as dust ingestion, etc.); aiming at the technical problems, the prior art does not give out what the main function of the additives such as the argil and the like in the process of epoxy ring opening and does not give out corresponding mechanism explanation, and the invention discovers that the argil (the main component of the argil is SiO) in the process of taking the traditional argil and the like as the catalyst through research2:(50-70)w％；Al2O3:(10-16)w％；、Fe2O32-4 w%; MgO (1-6) w%, etc.) has relatively complicated effect in the epoxy ring-opening process, but the research of the application finds that the existence of water, strong acid and weak base salt aqueous solution or strong base and weak acid salt aqueous solution can play a similar role to that of the carclazyte, and even has better effect than that of the carclazyte; compared with the traditional argil process, the preparation method disclosed by the invention has the advantages that the specific auxiliary agent is added in the morpholine substitution reaction, the reaction rate is increased, the reaction process can be completed within about 12 hours, the side reaction is reduced, the selectivity of the ring-opening reaction is improved, the post-treatment process does not need to be filtered, the operation risk is reduced, the operation time is reduced, the argil is prevented from entering the product, the product clarity is improved, the feeding operation is simplified, the argil does not need to be manually fed, and the cost is saved.
The auxiliary agent disclosed by the invention has the characteristics of economy, environmental friendliness, no generation of too much waste and low operation risk.
The preparation method avoids the product from containing argil impurities, improves the reaction selectivity, and obtains the product with higher purity which can reach more than 99 percent.
In the present invention, the reaction equation of the preparation method of 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-propanone is as follows:
wherein R is selected from halogen and R1S, H or R2Any one of the above; r1And R2Selected from C1-C4 alkyl; x is Cl or Br.
In the reaction equation, the halide shown in the formula I) and sodium methoxide are subjected to epoxidation reaction in a methanol solvent to obtain a compound shown in the formula II), and then morpholine and a proper amount of auxiliary agent are added to obtain a target product 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone shown in the formula 3); by adopting the synthesis process, the introduction of catalysts such as argil and the like is avoided, the difficulty and risk of post-treatment are reduced, the process cost is reduced, the ring opening speed is high, the reaction time is saved, the process efficiency is improved, the product purity is high, and the waste is less.
Preferably, the halide is added in step (1) in a dropwise manner.
Preferably, morpholine is further added to the mixture of methanol and sodium methoxide before the halide is added in step (1), to obtain a mixture of methanol, morpholine and sodium methoxide. The corresponding reaction equation is as follows:
in the preparation method, a certain amount of morpholine is added in the epoxidation reaction in the step (1), so that the solubility of a reaction intermediate can be improved, the epoxidation reaction is promoted, and the cyclization reaction rate and yield are improved; experiments prove that morpholine is added in the epoxidation reaction in the step (1), so that the epoxidation reaction can be completed within 1 h; and morpholine is added in the steps, so that adverse effects on the reaction in the subsequent process are avoided.
Preferably, the mass ratio of morpholine to halide in the mixed solution of methanol, morpholine and sodium methoxide is (4.5-6): 10, for example, 4.6:10, 4.7:10, 4.8:10, 4.9:10, 5.0:10, 5.1:10, 5.2:10, 5.3:10, 5.4:10, 5.5:10, 5.6:10, 5.7:10, 5.8:10 or 5.9: 10.
Preferably, the mass ratio of sodium methoxide to halide in step (1) is (6.5-8): 10, such as 6.6:10, 6.7:10, 6.8:10, 6.9:10, 7:10, 7.1:10, 7.2:10, 7.3:10, 7.4:10, 7.5:10, 7.6:10, 7.7:10, 7.8:10, or 7.9: 10.
Preferably, the ratio of the volume of methanol to the mass of halide in step (1) is (1.5-2.5): 1L/kg, for example 1.6:1L/kg, 1.7:1L/kg, 1.8:1L/kg, 1.9:1L/kg, 2:1L/kg, 2.1:1L/kg, 2.2:1L/kg, 2.3:1L/kg or 2.4: 1L/kg.
According to the preparation method disclosed by the invention, the ratio of the methanol to the sodium methoxide to the halide meets the conditions, so that the epoxidation reaction is promoted, the reaction efficiency and the conversion rate are improved, and the problem of overlarge energy consumption in subsequent distillation caused by excessive solvent is avoided.
Preferably, the temperature-controlled reaction in step (1) is at 25-32 deg.C, such as 26 deg.C, 27 deg.C, 28 deg.C, 29 deg.C, 30 deg.C or 31 deg.C.
Preferably, the temperature-controlled reaction time in step (1) is 0.5-1 h, such as 0.6h, 0.7h, 0.8h or 0.9 h.
In the step (1) of the method, a proper amount of morpholine is added in the epoxidation reaction, so that the reaction can be promoted to be carried out at the temperature, and the reaction efficiency is further improved.
Preferably, the final temperature of the temperature-rising methanol distillation in the step (1) is 80 to 85 ℃, for example, 81 ℃, 82 ℃, 83 ℃ or 84 ℃.
Preferably, the distillation of methanol at elevated temperature in step (1) is carried out under atmospheric conditions.
Here, the atmospheric pressure means a condition where no pressurization or vacuum treatment is performed.
Preferably, the temperature of the mixed solution is controlled to be less than 30 ℃, for example, 15 ℃, 20 ℃ or 25 ℃ before the halide is added dropwise in step (1).
Preferably, the mass ratio of morpholine added in step (2) to halide added in step (1) is 1 (0.45-0.75), such as 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65 or 1: 0.7.
Preferably, the adjuvant is selected from water, and the amount of the adjuvant added in step (2) is 2% to 20% of the total added mass of morpholine, such as 3%, 5%, 7%, 9%, 11%, 13%, 15%, 17%, 19%, etc., preferably 5% to 15%.
In the invention, when the auxiliary agent is selected from water, if the addition amount of the auxiliary agent is too small, the reaction cannot be effectively catalyzed, the reaction is very slow, and conversely, if the addition amount of the auxiliary agent is too large, the recovery difficulty and recovery rate of morpholine are increased, and the recovery of methanol is also influenced. The total morpholine added mass refers to the sum of the masses of morpholine added in the step (1) and the step (2); if morpholine is added in the step (1), the total addition amount of morpholine is the sum of the addition amounts of the step (1) and the step (2), and if no morpholine is added in the step (1), the total addition amount of morpholine is the addition amount of morpholine in the step (2).
Preferably, the solute of the strong alkali weak acid salt aqueous solution is at least one selected from sodium carbonate, sodium bisulfite and sodium bicarbonate.
Preferably, the solute of the aqueous solution of a strong acid and a weak base salt is selected from alkaline earth metal salts, preferably calcium chloride and/or magnesium chloride.
Preferably, the concentration of the strong and weak acid salt aqueous solution is 0.01-0.15 mol/L, such as 0.02mol/L, 0.03mol/L, 0.04mol/L, 0.05mol/L, 0.06mol/L, 0.07mol/L, 0.08mol/L, 0.09mol/L, 0.1mol/L, 0.11mol/L, 0.12mol/L, 0.13mol/L, 0.14mol/L, 0.15mol/L, etc., preferably 0.05 mol/L-0.1 mol/L.
Preferably, the concentration of the aqueous solution of the strong acid and weak base salt is 0.001-0.01 mol/L, such as 0.002mol/L, 0.003mol/L, 0.004mol/L, 0.005mol/L, 0.006mol/L, 0.007mol/L, 0.008mol/L, 0.009mol/L, 0.01mol/L, etc.; the concentration of the aqueous solution of the strong acid and the weak base salt is not excessively high.
According to the invention, researches show that the assistant adopts the strong base weak acid salt aqueous solution or the strong acid weak base salt aqueous solution, so that the ring-opening reaction is promoted, the liquid addition amount can be effectively reduced, the water consumption amount is reduced, the waste water generation amount is reduced, and the morpholine and methanol can be conveniently recycled.
According to the invention, researches show that the concentration of the strong base weak acid salt aqueous solution or the strong acid weak base salt aqueous solution serving as the auxiliary agent cannot be too high, otherwise, the ring-opening reaction is not facilitated, and the purity of the target product is reduced.
Preferably, the auxiliary agent is selected from strong base weak acid salt aqueous solution, and the amount of the auxiliary agent added in the step (2) is 0.1-10% of the total added mass of the morpholine, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% or 9%, and the like, and preferably 0.5-7%.
Preferably, the auxiliary agent is selected from strong acid and weak base salt aqueous solution, and the amount of the auxiliary agent added in step (2) is 0.1-10% of the total added mass of morpholine, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% or 9%, and the like, preferably 0.5-5%.
The invention adopts the strong base weak acid salt aqueous solution or the strong acid weak base salt aqueous solution with lower concentration as the auxiliary agent, and the usage amount of the solution is obviously reduced compared with the case of simply adding water as the auxiliary agent.
Preferably, the temperature of the temperature-controlled reaction in the step (2) is 102-110 ℃; for example, 103 ℃, 104 ℃, 105 ℃, 106 ℃, 107 ℃, 108 ℃, 109 ℃ or the like.
Preferably, the temperature-controlled reaction time in step (2) is 4-16h, such as 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h or 15h, and preferably 10-14 h.
Preferably, the preparation method further comprises the step of recovering morpholine by reduced pressure distillation after the temperature-controlled reaction in the step (2) is finished.
Preferably, the vacuum pressure of the reduced pressure distillation morpholine is less than-0.01 MPa, such as-0.02 MPa, -0.03MPa, -0.04MPa, -0.05MPa, -0.06MPa, -0.07MPa, -0.08MPa, -0.09MPa or-0.095 MPa, etc.
The vacuum pressure is the difference between the absolute pressure and the atmospheric pressure.
Preferably, the final temperature of the morpholine obtained by reduced pressure distillation is 90-110 ℃, such as 95 ℃, 100 ℃ or 105 ℃.
Preferably, the preparation method further comprises adding a non-polar solvent into the product after distilling the morpholine under reduced pressure, then washing with water, and separating to obtain an organic phase.
Preferably, the non-polar solvent is selected from toluene.
Preferably, the preparation method further comprises subjecting the organic phase to vacuum concentration; preferably, the vacuum pressure is less than-0.01 MPa, e.g., -0.02MPa, -0.03MPa, -0.04MPa, -0.05MPa, -0.06MPa, -0.07MPa, -0.08MPa, -0.09MPa, or-0.095 MPa, etc.
Preferably, the end point temperature of the vacuum concentration is 115-125 ℃, such as 118 ℃, 120 ℃ or 122 ℃.
Preferably, the preparation method further comprises recrystallizing the vacuum-concentrated product.
Preferably, the solvent for recrystallization comprises methanol.
As a preferable technical scheme of the invention, the preparation method of the 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone comprises the following steps:
(a) adding methanol, morpholine and sodium methoxide into a reaction kettle, cooling to a temperature of less than 30 ℃, then dropwise adding halide, and controlling the temperature in the reaction kettle to be 25-35 ℃ to react for 0.5-1 h; heating to 80-85 ℃ under normal pressure, and distilling methanol to obtain a reaction product;
(b) adding morpholine and an auxiliary agent into the reaction product obtained in the step (a), and reacting at the temperature of 102-110 ℃ for 4-16 hours; then, distilling morpholine under reduced pressure at the vacuum pressure of less than-0.01 MPa and at the temperature of 90-110 ℃;
(c) adding toluene into the distillation product in the step (b), washing with water for 2-4 times, and separating liquid to obtain an upper organic phase;
(d) and (c) heating the upper organic phase in the step (c) to 115-125 ℃ under the vacuum pressure of less than-0.01 MPa, concentrating in vacuum, and recrystallizing with methanol to obtain the 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone.
Compared with the prior art, the invention has the following beneficial effects:
(1) according to the preparation method, the specific auxiliary agent is added in the morpholine substitution reaction, so that the ring-opening reaction rate can be obviously promoted, the morpholine substitution reaction is further promoted, and compared with the traditional clay process, the reaction efficiency is obviously improved;
(2) the preparation method of the invention adopts the auxiliary agent, and the subsequent treatment does not need to filter clay, thereby reducing the operation risk, simultaneously avoiding the clay from entering the product in the filtering process and improving the clarity of the product;
(3) the preparation method has simple feeding, does not need to manually feed argil, and saves the cost;
(4) the preparation method of the invention adopts the auxiliary agent, improves the selectivity of ring-opening reaction, reduces or avoids side reaction, improves the purity and yield of the product, and reduces the cost.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1
The embodiment provides a preparation method of 2-methyl-1- (4-methylthiophenyl) -2-morpholinyl-1-propanone, which specifically comprises the following steps:
(a) adding 2000L of methanol, 535kg of morpholine and 710kg of sodium methoxide into a reaction kettle to obtain a mixed solution of the methanol, the morpholine and the sodium methoxide; cooling to 28 ℃, slowly dripping 1000kg of bromide into the mixed solution, and controlling the temperature to 28 ℃ for reaction for 0.5h after dripping is finished; then, under the condition of normal pressure, the temperature is increased to 85 ℃ and methanol is distilled; the bromide has the formula shown below:
(b) 1450kg of morpholine and 140kg of water are added into the reaction kettle in the step (a); keeping the temperature at 105 ℃ and reacting for 12 h;
(c) distilling the product in step (b) under vacuum pressure of-0.05 MPa at a temperature of 100 ℃ under reduced pressure to obtain morpholine; then adding 3000L of toluene, washing twice with 350L of water, and separating liquid to obtain an upper organic phase;
(d) vacuum concentrating the upper organic phase obtained in step (c) at-0.08 MPa and 120 deg.C; the product was then recrystallized from 3500L methanol to give 2-methyl-1- (4-methylthiophenyl) -2-morpholinyl-1-propanone.
The purity of the product was tested and the product GC purity was 99.4% with a yield of 89.5%.
The total yield of the crystallization mother liquor can be improved to 94 percent by further concentrating and crystallizing.
The following yields refer to yields obtained from recrystallization of the product.
Example 2
This example differs from example 1 in that 140kg of water was replaced in step (b) with 50L of an aqueous solution of sodium carbonate having a concentration of 0.1mol/L, the other parameters and conditions being exactly the same as in example 1.
The purity of the product is tested, and the product purity is 99.0%, and the yield is 90%.
Example 3
This example differs from example 1 in that 140kg of water was replaced in step (b) with 30L of an aqueous solution of sodium bicarbonate with a concentration of 0.1mol/L, and the other parameters and conditions were exactly the same as in example 1.
The purity of the product is tested, and the product purity is 99.1%, and the yield is 91%.
Example 4
This example differs from example 1 in that 140kg of water was replaced in step (b) with 20L of an aqueous solution of calcium chloride having a concentration of 0.002mol/L, and the other parameters and conditions were exactly the same as in example 1.
The purity of the product is tested, and the product purity is 99.0%, and the yield is 89.8%.
Example 5
This example differs from example 1 in that 140kg of water was replaced in step (b) with 10L of an aqueous magnesium chloride solution having a concentration of 0.001mol/L, and the other parameters and conditions were exactly the same as in example 1.
The purity of the product is tested, and the product purity is 99.2%, and the yield is 90%.
It can be seen from comparison of examples 1 and 2-5 that water, an aqueous solution of sodium carbonate, an aqueous solution of sodium bicarbonate, an aqueous solution of calcium chloride and an aqueous solution of magnesium chloride are used as the auxiliary agents, which can effectively promote the ring-opening substitution reaction, and the product purity and yield are high, and it can be seen from comparison of the above examples that the addition amount of the aqueous solution of strong acid, weak base salt or strong base, weak acid salt is used as the auxiliary agent, on the premise of achieving similar effects, the addition amount can be obviously reduced, thereby reducing the yield of wastewater in the process, and further facilitating the cost reduction.
Example 6
This example differs from example 1 in that 140kg of water was replaced in step (b) with 15L of a 0.2mol/L sodium bicarbonate solution, the other parameters and conditions being exactly the same as in example 1. The reaction time is obviously prolonged, the reaction time is prolonged by one time and is still not completely reacted, and then the reaction is stopped.
The reaction solution was subjected to GC test, and the purity was 85%, 10% of epoxy intermediate, 5% of impurities.
Example 7
This example differs from example 1 in that 140kg of water was replaced in step (b) with 70L of a 0.05mol/L sodium bicarbonate solution, and the other parameters and conditions were exactly the same as in example 1.
The purity of the product is tested, and the product purity is 99.3%, and the yield is 91.5%.
As can be seen from comparison of examples 3 and 6 to 7, the concentration of the aqueous sodium bicarbonate solution as an auxiliary is not too high, and is too high, which is disadvantageous in terms of purity and yield of the product.
Example 8
This example differs from example 1 in that the amount of water added in step (b) was replaced by 10kg and the other parameters and conditions were exactly the same as in example 1. The raw materials still remain after the reaction time is prolonged by 1 time, and the residual amount of the epoxy intermediate is more than 30 percent through GC detection of the reaction liquid.
Example 9
This example differs from example 1 in that the amount of water added in step (b) was replaced by 90kg and the other parameters and conditions were exactly the same as in example 1.
The purity of the product is tested, and the product purity is 98.4%, and the yield is 85%.
Example 10
This example differs from example 1 in that the amount of water added in step (b) was replaced by 200kg and the other parameters and conditions were exactly the same as in example 1.
The purity of the product is tested, and the product purity is 99.4%, and the yield is 93%. The reaction time was not significantly increased compared to example 1, while also affecting the recovery of methanol and morpholine.
As can be seen from comparison of examples 1 and 8 to 10, when the amount of water added as an auxiliary is too small, the effect of promoting the ring-opening reaction is not significant, and when the amount of water added is too large, the effect of promoting the ring-opening reaction is not further increased, and the energy consumption for the subsequent recovery of methanol and morpholine is increased.
Example 11
This example differs from example 1 only in that no morpholine was added in step (a) and in that the amount of morpholine added in step (b) was 1985 kg;
the time for completing the epoxidation reaction in step (a) of this example was 3 hours, and other parameters and conditions were exactly the same as those in example 1.
The purity of the product is tested, and the product purity is 99.2%, and the yield is 91.5%.
Comparing example 1 with example 11, it can be seen that the addition of morpholine in step (a) in the process of the present invention is beneficial to promote the reaction rate of epoxidation, thereby saving reaction time and causing no adverse effect on the subsequent reaction.
Example 12
This example differs from example 1 in that the bromide was replaced by an equimolar amount of chloride, the other parameters and conditions being exactly the same as in example 1; the molecular formula of the chloride is shown as follows:
the purity of the product is tested, and the product purity is 99.0%, and the yield is 90%.
Comparative example 1
This comparative example is different from example 1 in that no water was added in step (2) and other parameters and conditions were exactly the same as those in example 1.
In the comparative example, the epoxidation product in the morpholine substitution reaction could not undergo a ring-opening reaction, and the target product could not be obtained.
Comparative example 2
This comparative example differs from example 1 in that no water was added in step (2) and 20kg of clay catalyst was added, and the other parameters and conditions were exactly the same as in example 1.
The clay catalyst is obtained by soaking clay in 20 wt% sulfuric acid for 12h, washing, filtering, and activating at 450 deg.C for 5h, wherein the mesh number is 60-80 mesh.
In the comparative example, 20 hours are needed for completing the morpholine substitution reaction, the reaction time is long, the subsequent filtering operation is needed for separating the clay catalyst, the efficiency is low, the product still contains a small amount of clay, the clarity of the product is insufficient, and the clarity is improved by subsequent adsorption or secondary filtering treatment.
The purity of the product is tested, and the product purity is 92%, and the yield is 85%.
Comparative example 3
This comparative example differs from example 1 in that 140kg of water was replaced in step (b) with 20L of a 0.1mol/L sodium chloride solution, the other parameters and conditions were exactly the same as in example 1, the reaction rate was not significantly increased, the reaction time was extended by 1 time, and 35% of the epoxy intermediate remained.
And (3) performance testing:
the purity of the products obtained in the above examples and comparative examples was tested by GC.
The applicant declares that the above description is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be understood by those skilled in the art that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are within the scope and disclosure of the present invention.
Claims (10)
1. A preparation method of 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone is characterized by comprising the following steps:
(1) adding halide into a mixed solution of methanol and sodium methoxide, controlling the temperature to react, and heating and distilling the methanol to obtain a reaction product; the molecular formula of the halide is shown as a formula I);
wherein R is selected from halogen and R1S, H or R2Any one of the above; r1And R2Selected from C1-C4 alkyl;
x is Cl or Br;
(2) morpholine and an auxiliary agent are added into the reaction product obtained in the step (1), and temperature control reaction is carried out to obtain the 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone;
wherein the auxiliary agent is selected from at least one of water, a strong acid and weak base salt aqueous solution and a strong base and weak acid salt aqueous solution.
2. The method according to claim 1, wherein the halide is added in step (1) by dropwise addition;
preferably, morpholine is further added to the mixed solution of methanol and sodium methoxide before the halide is added in the step (1), so as to obtain a mixed solution of methanol, morpholine and sodium methoxide;
preferably, the mass ratio of morpholine to halide in the mixed solution of methanol, morpholine and sodium methoxide is (4.5-6): 10.
3. The preparation method according to claim 1 or 2, wherein the mass ratio of sodium methoxide to halide in step (1) is (6.5-8): 10;
preferably, the ratio of the volume of the methanol to the mass of the halide in the step (1) is (1.5-2.5): 1L/kg.
4. The method according to any one of claims 1 to 3, wherein the temperature-controlled reaction in step (1) is controlled at a temperature of 25 to 32 ℃;
preferably, the temperature-controlled reaction time in the step (1) is 0.5-1 h;
preferably, the end point temperature of the temperature rise and distillation of the methanol in the step (1) is 80-85 ℃;
preferably, the distillation of methanol at elevated temperature in step (1) is carried out at atmospheric pressure;
preferably, the temperature of the mixed solution is controlled to be less than 30 ℃ before the halide is added dropwise in the step (1).
5. The process according to any one of claims 1 to 4, wherein the ratio of the mass of morpholine added in step (2) to the mass of halide added in step (1) is 1 (0.45 to 0.75);
preferably, the auxiliary agent is selected from water, and the amount of the auxiliary agent added in the step (2) is 2-20% of the total added mass of the morpholine, preferably 5-15%;
preferably, the solute of the strong alkali weak acid salt aqueous solution is at least one selected from sodium carbonate, sodium bisulfite and sodium bicarbonate;
preferably, the solute of the aqueous solution of a strong acid and weak base salt is selected from alkaline earth metal salts, preferably calcium chloride and/or magnesium chloride;
preferably, the concentration of the strong alkali weak acid salt aqueous solution is 0.01-0.15 mol/L, preferably 0.05-0.1 mol/L;
preferably, the concentration of the strong acid weak base salt aqueous solution is 0.001-0.01 mol/L;
preferably, the auxiliary agent is selected from strong base weak acid salt aqueous solution, and the amount of the auxiliary agent added in the step (2) is 0.1-10%, preferably 0.5-7% of the total added mass of the morpholine.
Preferably, the auxiliary agent is selected from strong acid and weak base salt aqueous solution, and the amount of the auxiliary agent added in the step (2) is 0.1-10%, preferably 0.5-5% of the total added mass of the morpholine.
6. The method according to any one of claims 1 to 5, wherein the temperature-controlled reaction in step (2) is controlled at a temperature of 102 to 110 ℃;
preferably, the temperature-controlled reaction time in the step (2) is 4-16h, preferably 10-14 h.
7. The process according to any one of claims 1 to 6, wherein the process further comprises recovering morpholine by distillation under reduced pressure after the temperature-controlled reaction in step (2) is completed;
preferably, the vacuum pressure of the reduced pressure distillation morpholine is less than-0.01 MPa;
preferably, the final temperature of the morpholine distilled under reduced pressure is 90-110 ℃.
8. The process according to claim 7, further comprising adding a nonpolar solvent to the product after distilling morpholine under reduced pressure, followed by washing with water and separating the liquid to obtain an organic phase;
preferably, the non-polar solvent is selected from toluene;
preferably, the preparation method further comprises subjecting the organic phase to vacuum concentration; preferably the vacuum pressure is less than-0.01 MPa.
9. The method of claim 8, further comprising recrystallizing the vacuum-concentrated product;
preferably, the solvent for recrystallization comprises methanol.
10. The method of any one of claims 1 to 9, comprising the steps of:
(a) adding methanol, morpholine and sodium methoxide into a reaction kettle, cooling to a temperature of less than 30 ℃, then dropwise adding halide, and controlling the temperature in the reaction kettle to be 25-35 ℃ to react for 0.5-1 h; heating to 80-85 ℃ under normal pressure, and distilling methanol to obtain a reaction product;
(b) adding morpholine and an auxiliary agent into the reaction product obtained in the step (a), and reacting at the temperature of 102-110 ℃ for 4-16 hours; then, distilling morpholine under reduced pressure at the vacuum pressure of less than-0.01 MPa and at the temperature of 90-110 ℃;
(c) adding toluene into the distillation product in the step (b), washing with water for 2-4 times, and separating liquid to obtain an upper organic phase;
(d) and (c) heating the upper organic phase in the step (c) to 115-125 ℃ under the vacuum pressure of less than-0.01 MPa, concentrating in vacuum, and recrystallizing with methanol to obtain the 2-methyl-1- (4-substituted phenyl) -2-morpholinyl-1-acetone.
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