CN111362850A - Improved process for carrying out cyclization and continuous feed apparatus therefor - Google Patents
Improved process for carrying out cyclization and continuous feed apparatus therefor Download PDFInfo
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- CN111362850A CN111362850A CN202010179948.3A CN202010179948A CN111362850A CN 111362850 A CN111362850 A CN 111362850A CN 202010179948 A CN202010179948 A CN 202010179948A CN 111362850 A CN111362850 A CN 111362850A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J4/00—Feed or outlet devices; Feed or outlet control devices
- B01J4/001—Feed or outlet devices as such, e.g. feeding tubes
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2204/00—Aspects relating to feed or outlet devices; Regulating devices for feed or outlet devices
- B01J2204/002—Aspects relating to feed or outlet devices; Regulating devices for feed or outlet devices the feeding side being of particular interest
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/047—Standards external
Abstract
The present application relates to an improved process for carrying out a cyclization reaction, characterized in that the side reactions in the cyclization reaction are reduced by reducing the presence of free sodium methoxide in the reaction system. The application also relates to a continuous feeding device for implementing the improved method, wherein two feeding pipes are arranged in a nested structure of large pipe-in-pipe small pipes, a part of the small pipes are inserted into the large pipes, and the small pipe discharge opening is at a certain length away from the large pipe discharge opening.
Description
Technical Field
The invention relates to an improved method for carrying out the cyclization reaction and a continuous feed device for carrying out the method.
Background
In the prior art, the following cyclization reaction is reported to be carried out by taking dimethyl malonate, sodium methoxide and 6-ethylthio-3-hepten-2-one as raw materials, and the obtained product of the formula (1) is an important chemical intermediate.
Formula (1)
Cyclization reaction
In the formula, SEt represents an ethylthio group.
The mechanism of the cyclization reaction is shown in the following, namely, sodium methoxide firstly reacts with dimethyl malonate to generate sodium salt of dimethyl malonate, and the sodium salt reacts with 6-ethylthio-3-hepten-2-one to generate the compound shown in the formula (1).
Formula (1)
Disclosure of Invention
However, the inventors of the present invention have found that in the above reaction, methanol carried in sodium methoxide as a raw material and methanol generated by the reaction may undergo the following addition side reaction with 6-ethylthio-3-hepten-2-one under the action of sodium methoxide:
formula (2)
Side reactions
The above-mentioned side reactions and their solutions in the above-mentioned ring-closure reaction have not been reported so far.
Conventionally, when the above-mentioned cyclization reaction is continuously carried out, the above three raw materials are usually added to a reaction vessel at the same time. The sodium methoxide added in this way contacts dimethyl malonate and 6-ethylthio-3-hepten-2-one simultaneously, so that the sodium methoxide reacts with dimethyl malonate to generate dimethyl malonate sodium salt and the side reaction with 6-ethylthio-3-hepten-2-one. The present inventors have found that when the above ring-closure reaction is carried out by the above continuous feeding manner, the content of the impurity compound of formula (2) in the obtained product is 0.8% by weight or more.
In order to avoid the above side reaction, the present inventors tried to reduce the presence of free sodium methoxide in the reaction system.
The present invention has been made based on the above findings, and an object thereof is to provide an improved method for carrying out the above cyclization reaction, in order to reduce the above-mentioned side reactions in the reaction.
Specifically, the present invention relates to:
(1) the improved method for carrying out the cyclization reaction is characterized in that the side reaction in the cyclization reaction is reduced by reducing the existence of free sodium methoxide in the reaction system.
(2) The method described in (1) above, wherein the existence of free sodium methoxide in the reaction system is reduced by adjusting the feeding mode of three raw materials, namely dimethyl malonate, sodium methoxide and 6-ethylthio-3-hepten-2-one, in the reaction to ensure that the dimethyl malonate and the sodium methoxide are firstly mixed and reacted to generate dimethyl malonate sodium salt.
(3) The process according to the above (2), wherein the cyclization is carried out in a continuous manner, and the three raw materials are continuously introduced into the reaction vessel at the same time, so that dimethyl malonate and sodium methoxide therein are mixed just before entering the reaction vessel.
(4) The process according to any one of the above (1) to (3), wherein the three raw materials are fed through a continuous feeding apparatus characterized in that two feeding pipes are arranged in a nested structure of large sleeved small pipes, the large sleeved small pipes are a part of the small pipes inserted into the large pipes, and the small pipe discharge port is at a distance from the large pipe discharge port.
(5) The continuous feeding apparatus for carrying out the method according to any one of the above (1) to (3), wherein the two feeding pipes are arranged in a nested structure of large sleeved small pipes, the large sleeved small pipes are formed by inserting a part of the small pipes into the large pipes, and the small pipe discharge port is arranged at a certain length from the large pipe discharge port.
(6) The continuous feeding device in (5) above, wherein the length from the small pipe discharge port to the large pipe discharge port is 0.3 to 1.5m, and more preferably 0.5 to 1 m.
(7) The continuous feeding device in the above (5) or (6), wherein the inner diameter of the large pipe is 32 to 65 mm.
(8) The continuous feeding device according to any one of the above (5) to (7), wherein the small tube has an inner diameter of 15 to 32 mm.
(9) Use of a compound of formula (2) as a standard for controlling the amount of a compound of formula (1).
Drawings
FIG. 1 is a schematic diagram of a preferred configuration of a continuous feed apparatus for practicing the present invention.
Description of reference numerals:
1: a large pipe; 2: a small tube; 3: a small pipe discharge port; 4: a large pipe discharge port; 5: reaction kettle
Detailed Description
The above-mentioned ring-closure reaction may be carried out in a batch manner or a continuous manner. From the viewpoint of improving the production efficiency, the continuous embodiment is preferred.
However, in the continuous embodiment, it is necessary to continuously feed all three raw materials, and the three raw materials are usually introduced directly into the reaction vessel through three separate feed pipes, so that a large amount of free sodium methoxide is present in the system, and the above-mentioned side reaction cannot be avoided.
In the invention, the continuous feeding device shown in figure 1 is specially designed, which can ensure continuous feeding and avoid the existence of a large amount of free sodium methoxide in the reaction system.
The continuous feeding apparatus shown in fig. 1 comprises a reaction vessel 5 and a plurality of feeding pipes.
The structure of the reaction vessel 5 is not particularly limited, and may be a known conventional structure.
The number of the feed pipes is 3 in FIG. 1, but may be appropriately changed depending on the number of the reaction raw materials.
The continuous feeding device of the invention is characterized in that the two feeding pipes are nested structures of a large pipe 1 and a small pipe 2, and a part of the small pipe 2 is inserted into the large pipe 1.
The small pipe discharge port 3 needs to be away from the large pipe discharge port 4 by a certain length, in the length, the raw materials coming out of the small pipe 2 and the raw materials in the large pipe 1 react rapidly, and the reaction product immediately enters the kettle. The length of the reaction tube is adjusted according to the reaction rate of the raw materials in the small tube 2 and the large tube 1, as long as the reaction is as sufficient as possible, and is usually 0.3 to 1.5 m.
When the device is used for implementing the cyclization reaction, sodium methoxide and dimethyl malonate are introduced from two feeding pipes of a nested structure, the sodium methoxide and the dimethyl malonate are mixed at a part below a small pipe discharging port 3 and react quickly to generate sodium dimethyl malonate, and the sodium salt does not stay in the pipe and quickly enters a reaction kettle 5.
Sodium methoxide can be fed from the small pipe 2, dimethyl malonate can be fed from the large pipe 1, and vice versa.
When used in the above-mentioned cyclization reaction, the length of the small pipe discharge port 3 from the large pipe discharge port 4 is preferably 0.5m or more. Such a length can better ensure that sodium methoxide and dimethyl malonate react sufficiently, thereby reducing the presence of free sodium methoxide in the system. On the other hand, dimethyl malonate sodium salt generated by the reaction of sodium methoxide and dimethyl malonate is easily crystallized and adhered to the inside of the tube, and if the tube length through which the salt passes after the generation of the salt is long, the problem that the tube is clogged with the crystals is caused, and therefore, the length of the small tube discharge port 3 from the large tube discharge port 4 is preferably 1m or less.
More preferably, the pipe diameters of the small pipe 2 and the large pipe 1 are set to specific ranges, respectively. Specifically, the inner diameter of the large tube 1 is preferably 32-65 mm, and the inner diameter of the small tube 2 is preferably 15-32 mm. In the pipe diameter range, the problem of pipe blockage is not easy to occur, the feeding liquid can well form turbulent flow and be better mixed, and the sodium methoxide and the dimethyl malonate can fully react to generate dimethyl malonate sodium salt, so that the free sodium methoxide in a reaction system is reduced.
The continuous feeding apparatus of the present invention can be used not only in the above-mentioned cyclization reaction but also in other reactions which have a similar problem, i.e., in which it is necessary to avoid undesirable side reactions between the reaction raw materials.
Examples
The present invention will be described more specifically with reference to specific examples, but the present invention is not limited to these specific examples, and any modification or change that does not depart from the gist of the present invention falls within the scope of the present invention.
EXAMPLE 1 preparation of the impurity of formula (2)
Adding 8.9 g of methanol (0.275mol) and 1.4 g of sodium methoxide (0.025mol) into a four-mouth bottle, dropwise adding 120 g of 35.8% 6-ethylthio-3-hepten-2-one toluene solution (0.25mol) into the four-mouth bottle within 1h at 30-35 ℃, continuing to react for 2h after dropwise adding is finished, adding 50g of water, stirring for 10min for liquid separation, discarding the water phase, washing the organic phase with 50g of 10% hydrochloric acid and 50g of × 2 water respectively, evaporating the solvent by using a rotary evaporator to obtain a crude product, wherein the optimal absorption wavelength of the crude product is 270-280nm, purifying by using a column chromatography (petroleum ether: ethyl acetate: 5) to obtain a product, and measuring the purity of the product by using a high performance liquid chromatography to obtain 96.0%.
The conditions of the high performance liquid chromatography analysis are that an apparatus is an Agilent 1100LC liquid chromatograph, a UV detector, a chromatographic column is Kromasil 100-5-C18,4.6 × 250mm, a mobile phase is acetonitrile and water, the ratio of the acetonitrile to the water is 80: 20, the column temperature is 30 ℃, the flow rate is 1.0mL/min, and the wavelength is 280 nm.
Example 2
Using the continuous feeding apparatus shown in FIG. 1, dimethyl malonate, sodium methoxide, and 6-ethylthio-3-hepten-2-one were introduced as raw materials from large tube 1 and small tube 2, which were nested together, and at the same time, 6-ethylthio-3-hepten-2-one was introduced from a separate feeding tube, and the above-mentioned cyclization reaction was carried out continuously. The reaction temperature is 30-35 ℃, and the reaction time is 2 h.
After completion of the reaction, the content of the compound of formula (2) in the reaction product was measured by the above-mentioned high performance liquid chromatography to be 0.25% by weight, using the compound of formula (2) prepared in example 1 as an external standard.
Comparative example 1
The cyclization reaction is continuously carried out by using a conventional reaction kettle with three independent feed pipes and taking dimethyl malonate, sodium methoxide and 6-ethylthio-3-hepten-2-one as raw materials, and simultaneously introducing the three raw materials into the reaction kettle from the three feed pipes respectively. The reaction temperature is 30-35 ℃, and the reaction time is 2 h.
After completion of the reaction, the content of the compound of formula (2) in the reaction product was 0.83% by weight as measured by the above-mentioned high performance liquid chromatography using the compound of formula (2) prepared in example 1 as an external standard.
Industrial applicability
The improved implementation method and the continuous feeding device for implementing the method can effectively reduce the side reaction in the cyclization reaction, thereby improving the product quality and having high industrial application value.
Claims (9)
1. The following improved method for carrying out the cyclization reaction:
characterized in that the following side reactions in the cyclization reaction are reduced by reducing the presence of free sodium methoxide in the reaction system:
in the formula, SEt represents an ethylthio group.
2. The method of claim 1, wherein the presence of free sodium methoxide in the reaction system is reduced by adjusting the feeding modes of three raw materials of dimethyl malonate, sodium methoxide and 6-ethylthio-3-hepten-2-one in the reaction to ensure that the dimethyl malonate and the sodium methoxide are firstly mixed and reacted to generate dimethyl malonate sodium salt.
3. The process of claim 2 wherein said cyclization is carried out in a continuous mode by simultaneously and continuously introducing said three starting materials into the reactor such that the dimethyl malonate and sodium methoxide therein are mixed immediately prior to entering the reactor.
4. The process of any of claims 1-3, wherein the three feedstocks are fed through a continuous feed device characterized wherein the two feed pipes are arranged in a nested configuration of large sleeved small pipes, the large sleeved small pipes being a portion of the small pipes inserted into the large pipes, the small pipe discharge being a length from the large pipe discharge.
5. The continuous feeding device for carrying out the method according to any one of claims 1 to 3, wherein the two feeding pipes are arranged in a nested structure of a large pipe-in-pipe, the large pipe-in-pipe is a structure in which a part of a small pipe is inserted into a large pipe, and a small pipe outlet is arranged at a certain distance from a large pipe outlet.
6. A continuous feeder according to claim 5, wherein the length of the small pipe outlet from the large pipe outlet is 0.3 to 1.5m, more preferably 0.5 to 1 m.
7. A continuous feeder according to claim 5 or 6, wherein the large tube has an inner diameter of 32 to 65 mm.
8. A continuous feed apparatus as claimed in any one of claims 5 to 7, wherein the internal diameter of the small tubes is in the range of 15 to 32 mm.
9. Use of a compound of formula (2) as a standard for controlling the amount of a compound of formula (1).
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| CN202010179948.3A CN111362850B (en) | 2020-03-16 | 2020-03-16 | Improved process for carrying out cyclization and continuous feed apparatus therefor |
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Citations (6)
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| CN203227493U (en) * | 2013-01-30 | 2013-10-09 | 北京工商大学 | Gas-liquid mixing reactor |
| CN109865494A (en) * | 2019-02-26 | 2019-06-11 | 宁夏万香源生物科技有限公司 | Mixed liquor continuously neutralizes hierarchical system after a kind of chlorinated hydrolysis |
| CN209287552U (en) * | 2018-12-17 | 2019-08-23 | 宁夏神耀科技有限责任公司 | A kind of atomizer with mixed function |
| CN111217728A (en) * | 2018-11-23 | 2020-06-02 | 山东润博生物科技有限公司 | Synthetic method of clethodim intermediate |
| CN111217729A (en) * | 2018-11-23 | 2020-06-02 | 山东润博生物科技有限公司 | Preparation method and application of clethodim intermediate |
| CN111217730A (en) * | 2018-11-23 | 2020-06-02 | 山东润博生物科技有限公司 | Preparation method of clethodim and intermediate thereof |
-
2020
- 2020-03-16 CN CN202010179948.3A patent/CN111362850B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN203227493U (en) * | 2013-01-30 | 2013-10-09 | 北京工商大学 | Gas-liquid mixing reactor |
| CN111217728A (en) * | 2018-11-23 | 2020-06-02 | 山东润博生物科技有限公司 | Synthetic method of clethodim intermediate |
| CN111217729A (en) * | 2018-11-23 | 2020-06-02 | 山东润博生物科技有限公司 | Preparation method and application of clethodim intermediate |
| CN111217730A (en) * | 2018-11-23 | 2020-06-02 | 山东润博生物科技有限公司 | Preparation method of clethodim and intermediate thereof |
| CN209287552U (en) * | 2018-12-17 | 2019-08-23 | 宁夏神耀科技有限责任公司 | A kind of atomizer with mixed function |
| CN109865494A (en) * | 2019-02-26 | 2019-06-11 | 宁夏万香源生物科技有限公司 | Mixed liquor continuously neutralizes hierarchical system after a kind of chlorinated hydrolysis |
Non-Patent Citations (1)
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| 钱云: "烯草酮的合成及其工艺优化", 《南京理工大学硕士学位论文》 * |
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