CN111205176B - Synthetic method of 3, 5-dihalogen-2-pentanone - Google Patents
Synthetic method of 3, 5-dihalogen-2-pentanone Download PDFInfo
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- CN111205176B CN111205176B CN202010038462.8A CN202010038462A CN111205176B CN 111205176 B CN111205176 B CN 111205176B CN 202010038462 A CN202010038462 A CN 202010038462A CN 111205176 B CN111205176 B CN 111205176B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
- C07C45/676—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton by elimination of carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Abstract
The invention discloses a synthetic method of 3, 5-dihalogen-2-pentanone, belonging to the technical field of organic chemistry. The 3, 5-dihalogen-2-pentanone is obtained by taking acetoacetate as a raw material and sequentially carrying out cyclopropanation, ring-opening halogenation and hydrolysis decarboxylation reactions. The method has the advantages of simple and easily obtained raw materials, high atom utilization rate of the halogenation step and less waste. The method has simple reaction conditions in each step, does not need purification in the middle, can continuously feed materials, can realize cyclic application of the cyclopropanation catalyst, and has potential industrial amplification prospect.
Description
The technical field is as follows:
the invention belongs to the field of organic chemistry, and particularly relates to a synthetic method of 3, 5-dihalogen-2-pentanone.
Background art:
3, 5-dihalogen-2-pentanone has wide application in the fields of medicine and pesticide. For example, the compound can be used for preparing 1-acetyl-1-chlorocyclopropane through further intramolecular cyclization, and the compound is an important intermediate for synthesizing the bactericide prothioconazole (see: CN 106278850); further cyclizing with potassium thiocyanate to prepare clomephiazole serving as a sedative-hypnotic drug (see: China journal of pharmaceutical industry, 2006, 37 and 441).
Synthetic methods have been reported in the literature: 1) acetyl-gamma-butyrolactone is used as a raw material, and is subjected to chlorination and esterification, and then further subjected to decarboxylation reaction under the action of concentrated hydrochloric acid to obtain a target product, namely 3, 5-dihalogen-2-pentanone. The route has the defects of higher raw material price and generation of byproducts such as hydrogen chloride, sulfur dioxide and the like in the chlorination and esterification processes (see CN 103709023). 2) Methyl vinyl ketone is used as a raw material and reacts with dichloromethane under the catalysis of CuCl and illumination to obtain a target product 3, 5-dihalogen-2-pentanone. The raw material methyl vinyl ketone used in the route is a highly toxic product and has high production safety risk (see: J.chem.Soc., chem.Commun.,1983,1446).
Therefore, it is necessary to find a synthetic method which is more environment-friendly and suitable for industrial amplification.
The invention content is as follows:
in order to solve the problems, the invention provides a novel synthesis route of 3, 5-dihalogen-2-pentanone. Performing cyclopropanation, ring-opening halogenation and hydrolysis decarboxylation on acetoacetic ester serving as a raw material in sequence to obtain the 3, 5-dihalogen-2-pentanone. The method has the advantages of simple and easily obtained raw materials, high atom utilization rate of the halogenation step and less waste. The method has simple reaction conditions in each step, does not need purification in the middle, can continuously feed materials, can realize cyclic application of the cyclopropanation catalyst, and has potential industrial amplification prospect.
The invention relates to a method for synthesizing 3, 5-dihalogen-2-pentanone, which adopts the technical means that the method comprises the following steps: using acetoacetate ester as a raw material to sequentially carry out cyclopropanation (first step), ring-opening halogenation (second step) and hydrolysis decarboxylation (third step) reactions to obtain the 3, 5-dihalogen-2-pentanone. The reaction scheme is represented as follows:
wherein R is C1-C4 alkyl, X2Is Cl2、Br2Or I2。
Further, cyclopropanation (the first step) reaction is carried out by taking acetoacetate (1) and dichloroethane as raw materials and beta-cyclodextrin as a catalyst, heating, dripping alkali liquor, and keeping the temperature after dripping to generate an intermediate (2).
Further, cyclopropanizing (the first step) reaction, wherein the alkali liquor is 30-50% of sodium hydroxide aqueous solution, and the reaction temperature is 30-50 ℃; after the heat preservation is finished, separating out an alkali liquor layer containing beta-cyclodextrin for recycling, then separating out dichloroethane solution of the intermediate (2), washing the dichloroethane solution to be neutral by using water, and directly using the dichloroethane solution for ring-opening halogenation reaction.
Further, the cyclopropanation (the first step) is carried out, wherein the molar ratio of the acetoacetate (1), the dichloroethane, the beta-cyclodextrin and the alkali liquor is 1:1.0-3.0:0.01-0.05: 1.0-3.0.
Further, the ring-opening halogenation (second step) reaction is carried out by adding halogen to a dichloroethane solution of the intermediate (2) to effect ring-opening, thereby producing the intermediate (3).
Further, the ring-opening halogenation (second step) is carried out, the molar ratio of the intermediate (2) to the halogen is 1.0:1.0-2.0, and the reaction temperature is 0-5 ℃.
Further, in the hydrolysis decarboxylation (third step), the dichloroethane solution of the intermediate (3) is dropped into preheated 15-25% hydrochloric acid to perform hydrolysis decarboxylation reaction, so as to obtain 3, 5-dihalo-2-pentanone.
Further, the hydrolysis decarboxylation (third step) is carried out, the molar ratio of the intermediate (3) to the hydrochloric acid is 1.0:1.0-1.5, and the reaction temperature is 70-90 ℃.
The invention has the following advantages:
1. the method has the advantages of simple and easily obtained raw materials, high atom utilization rate of the halogenation step and less waste.
2. The reaction conditions of each step are simple, the purification is not needed in the middle, and the materials can be continuously fed.
3. The cyclopropanation catalyst can be recycled.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Firstly, adding methyl acetoacetate 1a (116.1g, 1.0mol), dichloroethane (247.4g, 2.5eq) and beta-cyclodextrin (22.7g, 0.02eq) into a 2L reaction bottle, heating and stirring to 40 ℃, slowly adding 40% sodium hydroxide solution (400.0g, 4.0eq) from a dropping funnel, dripping for 1.0h, controlling the temperature in the dripping process to be 40-45 ℃, and continuing to stir for 2.0h under heat preservation after dripping.
Stopping heating and cooling to room temperature, separating an alkali solution layer containing beta-cyclodextrin for recycling, separating a dichloroethane layer, adding water for washing to neutrality, and directly using for ring-opening halogenation reaction, wherein the purity of the intermediate (2a) is 97% by gas chromatography (after dichloroethane is subtracted).
Secondly, chlorine (85.1g, 1.2mol) is introduced into the dichloroethane solution of the intermediate (2a) for 2.0h, the temperature is controlled between 0 and 5 ℃ in the introduction process, and then the heat preservation and stirring are continued for 2.0h after the introduction is finished. The dichloroethane solution of the intermediate (3a) obtained was used directly for the hydrolysis decarboxylation reaction, and the gas chromatography purity of the intermediate (3a) was 95% (minus dichloroethane).
Thirdly, the dichloroethane solution of the intermediate (3a) is transferred to a dropping funnel, slowly dropped into a reaction flask preheated to 80 ℃ and filled with 20% hydrochloric acid (182.5g, 1.0eq), the dropping is finished for 1.0h, and then the mixture is stirred for 2.0h under heat preservation.
Stopping heating, cooling to room temperature, separating out dichloroethane layer, concentrating and recovering dichloroethane, continuing negative pressure distillation, collecting 86-88 deg.C (20mmHg) boiling range product 4a to obtain 141.1g of 3, 5-dichloro-2-pentanone with GC purity > 99.0% and total yield of 91% in three steps.
Example 2
The first step is the same as in example 1.
And secondly, dropwise adding bromine (175.8g, 1.1mol) into the dichloroethane solution of the intermediate (2a) obtained in the first step, wherein the dropwise adding is finished within 2.0h, the temperature is controlled to be 0-5 ℃ in the dropwise adding process, and after the dropwise adding is finished, continuously stirring for 1.0h under heat preservation. The dichloroethane solution of the intermediate (3b) obtained was used directly for the hydrolytic decarboxylation reaction, and the gas chromatography purity of the intermediate (3b) was 93% (minus dichloroethane).
Thirdly, the dichloroethane solution of the intermediate (3b) is transferred to a dropping funnel, slowly dropped into a reaction flask preheated to 80 ℃ and filled with 20% hydrochloric acid (182.5g, 1.0eq), the dropping is finished for 1.0h, and then the mixture is stirred for 2.0h under heat preservation.
Stopping heating, cooling to room temperature, separating out dichloroethane layer, concentrating and recovering dichloroethane, continuing negative pressure distillation, collecting boiling range product 4b with 90-92 deg.C (3mmHg) boiling range to obtain 214.7g of 3, 5-dibromo-2-pentanone with GC purity > 98.4% and total yield of 88% in three steps.
Example 3
The first step is the same as in example 1.
And secondly, dripping a solution prepared from iodine (279.2g, 1.1mol) and 300g of dichloroethane into the dichloroethane solution of the intermediate (2a) obtained in the first step, wherein the dripping takes about 2.0 hours, controlling the temperature in the dripping process to be 0-5 ℃, and continuing to keep the temperature and stir for 1.0 hour after the dripping is finished. The dichloroethane solution of the intermediate (3c) obtained was used directly for the hydrolytic decarboxylation reaction, and the gas chromatography purity of the intermediate (3c) was 81% (minus dichloroethane).
Thirdly, the dichloroethane solution of the intermediate (3c) is transferred to a dropping funnel, slowly dropped into a reaction flask preheated to 80 ℃ and filled with 20% hydrochloric acid (182.5g, 1.0eq), the dropping is finished for 1.0h, and then the mixture is stirred for 2.0h under heat preservation.
Stopping heating and returning to room temperature, separating a dichloroethane layer, concentrating and recovering dichloroethane to obtain 4c, namely 257.6g of 3, 5-diiodo-2-pentanone, the GC purity is 80 percent, and the total yield of the three steps is 61 percent (pure yield).
Example 4
The first step is as follows:
referring to the operation of the first step of example 1, the reaction conditions were changed to obtain the results of tables 1 and 2.
TABLE 1
TABLE 2
The second step:
referring to the operation of the second step of example 1, the reaction conditions were changed to obtain the results of Table 3.
TABLE 3
| Experiment number | Chlorine gas | Reaction temperature | Reaction time | The purity of the intermediate 3a is GCA% |
| 1 | 1.0 | 0-5℃ | 6h | 92％ |
| 2 | 1.2eq | 0-5℃ | 4h | 95％ |
| 3 | 1.5eq | 0-5℃ | 4h | 92％ |
| 4 | 1.2eq | -5-0℃ | 8h | 89％ |
The third step:
referring to the operation of the third step of example 1, the reaction conditions were changed to obtain the results of Table 4.
TABLE 4
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (5)
1. A method for synthesizing 3, 5-dihalogen-2-pentanone is characterized by comprising the following steps: taking acetoacetate (1) as a raw material, and sequentially carrying out cyclopropanation, ring-opening halogenation and hydrolysis decarboxylation reactions to obtain 3, 5-dihalogen-2-pentanone (4), wherein the reaction equation is as follows:
wherein R is C1-C4 alkyl, and X is Cl or Br;
the cyclopropanation reaction is carried out by taking acetoacetic ester (1) and dichloroethane as raw materials and beta-cyclodextrin as a catalyst, heating, dripping alkali liquor, and preserving heat after dripping to generate an intermediate (2); the alkali liquor is 40-50% sodium hydroxide aqueous solution, and the reaction temperature is 40-50 ℃; after the heat preservation is finished, separating an alkali liquor layer containing beta-cyclodextrin for recycling, separating a dichloroethane solution of the intermediate (2), washing the dichloroethane solution to be neutral by using water, and directly using the dichloroethane solution for ring-opening halogenation reaction; the molar ratio of the acetoacetate (1), the dichloroethane, the beta-cyclodextrin and the alkali liquor is 1:2.5-3.0:0.01-0.05: 1.0-3.0.
2. Process for the synthesis of 3, 5-dihalo-2-pentanone according to claim 1, characterized in that: the ring-opening halogenation reaction is carried out by adding halogen into dichloroethane solution of the intermediate (2) to carry out ring-opening reaction to generate the intermediate (3).
3. Process for the synthesis of 3, 5-dihalo-2-pentanone according to claim 2, characterized in that: in the ring-opening halogenation reaction, the molar ratio of the intermediate (2) to the halogen is 1.0:1.0-2.0, and the reaction temperature is 0-5 ℃.
4. Process for the synthesis of 3, 5-dihalo-2-pentanone according to claim 1, characterized in that: the hydrolysis decarboxylation reaction is carried out by dropping dichloroethane solution of the intermediate (3) into preheated 15-25% hydrochloric acid to carry out hydrolysis decarboxylation reaction to obtain 3, 5-dihalo-2-pentanone.
5. Process for the synthesis of 3, 5-dihalo-2-pentanone according to claim 4, characterized in that: in the hydrolysis decarboxylation reaction, the molar ratio of the intermediate (3) to the hydrochloric acid is 1.0:1.0-1.5, and the reaction temperature is 70-90 ℃.
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| CN111792987A (en) * | 2020-07-19 | 2020-10-20 | 江苏云帆化工有限公司 | Synthetic method for preparing 3, 5-dichloro-2-pentanone from methyl acetoacetate |
| CN112794803B (en) * | 2020-12-01 | 2023-03-24 | 山东国邦药业有限公司 | Preparation method of cyclopropylamine intermediate methyl cyclopropanecarboxylate |
| CN115124440A (en) * | 2022-06-27 | 2022-09-30 | 江苏七洲绿色科技研究院有限公司 | Preparation method of prothioconazole intermediate |
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