CN116041181A - A kind of method for preparing 4-halo-2-methyl-2-butenoic acid alkyl ester - Google Patents

Abstract

The invention discloses a method for preparing 4-halogeno-2-methyl-2-butenoic acid alkyl ester, which takes halogeno acetaldehyde and 2-zinc bromide propionate as raw materials and prepares the 4-halogeno-2-methyl-2-butenoic acid alkyl ester through a Reformatsky reaction. The reaction has mild condition, good economy, basically no toxicity or harm and high safety coefficient, and is suitable for industrialized mass production. The Reformatsky S reaction and the subsequent dehydration reaction, the products are mainly solid waste inorganic salt zinc halide except main products and a small amount of organic byproducts, can be conveniently recovered, and the reaction solvent can be recycled with very little pollution.

Description

A kind of method for preparing 4-halo-2-methyl-2-butenoic acid alkyl ester

technical field

The invention relates to the technical field of fine organic synthesis, in particular to a method for preparing 4-halo-2-methyl-2-butenoic acid alkyl ester.

Background technique

Carotenoids are a general term for a class of important natural pigments, which are commonly found in yellow, orange-red or red pigments of animals, higher plants, fungi, and algae. Carotenoids are the main source of vitamin A in the body, and also have anti-oxidation, immune regulation, anti-cancer, and anti-aging effects. 4-Halo-2-methyl-2-butenoic acid alkyl esters are important intermediates for the preparation of carotenoid carboxylates. For example, crocin acid diester, β-apo-8'-carotene acid ester and β-apo-4'-carotene acid ester, etc.; in addition, it can also be used to prepare other compounds.

Synthetic 4-chloro/bromo-2-methyl-2-butenoic acid ester mainly has following method at present:

(1) Addition and elimination method: suitable for the preparation of chloride and bromide. See the following reaction formula for details:

(2) Alcohol halogenation method: suitable for the preparation of chloride and bromide. See the following reaction formula for details:

(3) Radical substitution method: suitable for bromide preparation. See the following reaction formula for details:

(4) Wittig method: suitable for the preparation of chloride and bromide. See the following reaction formula for details:

However, each of the above-mentioned methods has its own disadvantages. For example, in method (1), the main raw material is not directly available, it needs to be prepared from more basic raw materials through several steps, and halogen is directly used as the reaction reagent, which is not only dangerous and polluting, but also has poor atom economy , because the theoretical utilization rate of halogen is only half; in method (2), except that the degree of danger is reduced, other situations are similar to method (1); in method (3), the main raw material is not easy to obtain, and the cost of NBS Higher, after the reaction, a large amount of NHS is difficult to handle, and there are a large amount of isomers (I') in the product, and the economy is very poor; finally, in method (4), compared with the first three methods, no matter It is undoubtedly the best method in terms of raw material source, reaction effect and economy, but as far as the current production environment is concerned, there are also fatal drawbacks. The reaction involves organophosphorus reagents, and a large amount of oxidation produced in the product Organic phosphorus recovery and regeneration is difficult, polluting and costly, improper treatment will cause great harm to the environment.

Contents of the invention

In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a method for preparing 4-halo-2-methyl-2-butenoic acid alkyl ester, the raw material is cheap and easy to get, the reaction is stable and reliable, and the reaction conditions are mild. Environmentally friendly and other advantages, it is very suitable for industrial production.

The purpose of the present invention adopts following technical scheme to realize:

A method for preparing 4-halo-2-methyl-2-butenoic acid alkyl esters, comprising the steps of: making a Reformatsky (Reformatsky) reaction between a compound of formula A and a compound of formula B, followed by performing the original Position dehydration reaction, obtains general formula (I) compound:

其中，X为卤素，R为烃基。

Wherein, X is a halogen, and R is a hydrocarbon group.

Further, the compound of formula A reacts with the compound of formula B in the form of anhydrous haloacetaldehyde solution; the preparation method of anhydrous haloacetaldehyde solution comprises the following steps: Calcium is mixed, and the oil phase and the water phase are separated by standing; the oil phase is collected, and a solvent is added to the water phase for extraction, and the oil phases are combined, dried, and filtered to obtain an anhydrous haloacetaldehyde solution. Specifically, the drying steps are: drying through anhydrous calcium chloride and drying with 4A molecular sieves in sequence.

Further, the solvent used for extraction is one or more compositions of toluene, xylene, methylene chloride, and 2-methyltetrahydrofuran, preferably 2-methyltetrahydrofuran; the anhydrous halogenated acetaldehyde solution The mass percentage is 4-25%.

Further, the halogen is chlorine or bromine; the compound of formula A is chloroacetaldehyde or bromoacetaldehyde.

Further, the hydrocarbon group is one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or vinyl, preferably methyl or ethyl.

Further, the compound of formula B is prepared by in-situ reaction of metal zinc powder and 2-bromopropionate, the molar ratio of metal zinc powder to 2-bromopropionate is (2:1)～(1:1), The priority is 1.1:1; since the compound of formula B is not suitable to be isolated and used alone, it is represented by the molar ratio of compound of formula A to 2-bromopropionate. The molar ratio of the compound of formula A to 2-bromopropionate is (2:1)-(0.5:1), preferably 1:1.

Further, the temperature of the in-situ reaction is 0-100°C, preferably 70°C; the reaction time is 20min-10h, preferably 0.5h.

Further, titanocene dichloride can be added as a catalyst during the reaction between the compound of formula A and the compound of formula B, and the molar dosage of the catalyst is 0.5-2% of the molar dosage of 2-bromopropionate, preferably 0.8% . It should be noted that the reaction between the compound of formula A and the compound of formula B may not add titanocene dichloride as a catalyst.

Further, after mixing and reacting the compound of formula A and the compound of formula B, a mixed solution is obtained, then adding H ₂ SO ₄ aqueous solution for hydrolysis, separating the filtrate and solid, and distilling the filtrate to obtain the compound of general formula (I).

Further, the reaction temperature is 0-100°C, preferably 70-76°C, more preferably 70°C; the reaction time is 20min-10h, preferably 0.5h.

Compared with the prior art, the beneficial effects of the present invention are:

(1) The preparation method of the present invention uses haloacetaldehyde and 2-zinc bromide propionate as raw materials to prepare 4-halo-2-methyl - Hydrocarbyl 2-butenoate. The condition is mild, the economy is good, and it is basically non-toxic and harmless, with a high safety factor, and is suitable for large-scale industrial production. In the Reformatsky S reaction itself and the subsequent dehydration reaction, in addition to the main product and a small amount of organic by-products, the product is mainly solid waste inorganic salt zinc halide, which can be easily recycled, and the reaction solvent can be recycled, and the pollution is very small.

(2) The compound of formula B of the present invention is prepared by reacting metal zinc powder and 2-bromopropionate in situ, and the raw materials used are cheap and easy to obtain.

(3) In the process of preparing the compound of general formula (I), a catalyst can be added to the reaction, or no catalyst can be added. The difference is that the catalyst can make the reaction milder, easier to carry out and improve the reaction effect.

Detailed ways

In the following, the present invention will be further described in conjunction with specific implementation methods. It should be noted that, on the premise of not conflicting, the various embodiments or technical features described below can be combined arbitrarily to form new embodiments.

Some of the raw materials or reagents involved in the following examples are supplemented as follows:

The 40% chloroacetaldehyde aqueous solution is industrial grade, and the chloroacetaldehyde dry solution is self-made, and the method is as follows:

In a separatory funnel, add 500ml of chloroacetaldehyde aqueous solution with a mass percentage of 40% into 300ml of solvent 2-methyltetrahydrofuran, then add 140g of anhydrous calcium chloride to fully dissolve, promote the precipitation of the water phase, let it stand, and separate the water 60g of anhydrous calcium chloride was added to the oil phase to fully dissolve, to promote the precipitation of the water phase, let it stand, and separate the water phase; combine the water phase, and use 2X100ml solvent 2-methyltetrahydrofuran to fully extract twice. Combine the oil phases, and then fully dry them through 100g of anhydrous calcium chloride and 100g of molecular sieves (4A). After filtering, you can obtain a dry solution of chloroacetaldehyde 2-methyltetrahydrofuran. The content of GC normalization method is 21.4%, and the water content is <0.06%. .

The above-mentioned extraction solvents are replaced by dichloromethane and xylene in turn, and the dry solution of chloroacetaldehyde dichloromethane and the dry solution of chloroacetaldehyde xylene can be obtained respectively, wherein the content of the dried solution of chloroacetaldehyde dichloromethane by GC normalization method is 8.7 %, moisture <0.03%; chloroacetaldehyde xylene dry solution, GC normalized content 4.6%, moisture <0.03%.

10% bromoacetaldehyde dichloromethane dry solution is a reagent purchased directly.

The solvents used, the raw materials of methyl 2-bromopropionate and ethyl 2-bromopropionate, and titanocene dichloride (Cp ₂ TiCl ₂ ) used as a catalyst are all industrial grades.

Example 1

The preparation method of 4-chloro-2-methyl-2-butenoic acid ethyl ester comprises the following steps:

Under nitrogen protection, disperse 8.1g (90%) metal zinc powder in 100ml solvent 2-methyltetrahydrofuran, then add 18.5g (99%) of ethyl 2-bromopropionate and mix well, stir and heat up to 70°C to trigger During the reaction, the internal temperature rose to 75°C due to the exothermic reaction, and the reaction continued for 0.5h, and the internal temperature returned to 70°C. 37.0 g (21.4%) of chloroacetaldehyde 2-methyltetrahydrofuran was added dropwise to dry the solution for 10 min. After dropping, continue to react for 0.5h and cool down to room temperature naturally. Under stirring, 20ml of 10% by mass H ₂ SO ₄ aqueous solution was added to fully hydrolyze, and the cloudy reaction liquid became clear and transparent after precipitation of muddy solids. At this time, the solid formed a solid mass at the bottom of the bottle, and the filtrate was separated by decantation directly, and the surface of the solid was washed with a small amount of reaction solvent, and then merged into the filtrate. The solvent was recovered by distillation under reduced pressure, and 16.7 g of the crude product was distilled off to obtain 4-chloro-2-methyl-2-butenoic acid ethyl ester. GC normalized content 68.3%. The main impurities of the crude product are unremoved solvents and low boilers, and the content of the GC normalization method can be increased to 87.2% through redistillation. The sample was purified by silica gel column (ethyl acetate/petroleum ether=1:50), and the NMR and mass spectrometry data of the product are as follows:

UV (MeOH) absorption: λmax=218nm;

IR (KBr) absorption: 2984, 1717, 1651, 1273, 756 (cm ^-1 );

MS (EI): m/z 162 (M+, 6%), 134 (45%), 117 (73%), 113 (72%), 99 (58%), 89 (64%), 82 (17%) ), 69 (14%), 53 (100%), 39 (23%);

¹ H-NMR (CDCl ₃ , 600MHz): δ6.79(qt, J=1.54, 7.79Hz,=CH-), 4.19(q, J=7.17Hz, -OCH ₂ -), 4.13(d, J= 7.79 Hz, -CH ₂ Cl), 1.88 (d, J=1.71, -CH3), 1.27 (t, J=7.2 Hz, -OCH ₂ -CH ₃ ).

Example 2

The preparation method of 4-chloro-2-methyl-2-butenoic acid methyl ester comprises the following steps:

Under nitrogen protection, disperse 8.1g (90%) metal zinc powder in 100ml solvent 2-methyltetrahydrofuran, then add 17.1g (99%) of methyl 2-bromopropionate and mix well, stir and heat up to 68°C to trigger During the reaction, the internal temperature rose to 74°C due to the exothermic reaction, and the reaction continued for 0.5h, and the internal temperature returned to 70°C. 37.0 g (21.4%) of chloroacetaldehyde 2-methyltetrahydrofuran was added dropwise to dry the solution for 10 min. After dropping, continue to react for 0.5h and cool down to room temperature naturally. Under stirring, 20ml of 10% by mass H ₂ SO ₄ aqueous solution was added to fully hydrolyze, and the cloudy reaction liquid became clear and transparent after precipitation of muddy solids. The filtrate was separated by decantation directly, the solid surface was washed with a small amount of reaction solvent, and combined into the filtrate. The solvent was recovered by distillation under reduced pressure, and 14.6 g of the crude product was distilled off to obtain 4-chloro-2-methyl-2-butenoic acid methyl ester. GC normalized content 70.7%. Re-distilled once again, the GC normalized content is 83.4%. The sample was purified by silica gel column (ethyl acetate/petroleum ether=1:50), and the NMR and mass spectrometry data of the product are as follows:

UV (MeOH) absorption: λmax=218nm;

IR (KBr) absorption: 2987, 1716, 1652, 1280, 757 (cm ^-1 );

MS (EI): m/z 148 (M+, 12%), 117 (69%), 113 (57%), 99 (64%), 89 (71%), 82 (23%), 69 (17%) ), 53 (100%), 39 (24%);

¹ H-NMR (CDCl ₃ , 600MHz): δ6.80(qt, J=1.55, 7.99Hz,=CH-), 4.14(d, J=7.97Hz, -CH ₂ Cl), 3.74(s, -OCH ₃ ), 1.90 (d, J=1.71 Hz, -CH ₃ ).

Example 3

The preparation method of 4-chloro-2-methyl-2-butenoic acid ethyl ester comprises the following steps:

Under nitrogen protection, disperse 8.1g (90%) metal zinc powder in 100ml solvent 2-methyltetrahydrofuran, then add 18.5g (99%) of ethyl 2-bromopropionate and mix well, stir and heat up to 72°C to trigger During the reaction, the internal temperature rose to 76°C due to the exothermic reaction, and the reaction continued for 0.5h, and the internal temperature returned to 70°C. The temperature was lowered to 60°C, and 91.0 g (8.7%) of chloroacetaldehyde dichloromethane dry solution was added dropwise, and part of the dichloromethane was recovered by atmospheric distillation for 30 minutes. After dropping, continue to react for 0.5h and cool down to room temperature naturally. Under stirring, 20ml of 10% by mass H ₂ SO ₄ aqueous solution was added to fully hydrolyze, and the cloudy reaction liquid became clear and transparent after precipitation of muddy solids. The filtrate was separated by decantation directly, the solid surface was washed with a small amount of reaction solvent, and combined into the filtrate. The solvent was recovered by distillation under reduced pressure, and 13.2 g of the crude product was distilled off to obtain 4-chloro-2-methyl-2-butenoic acid ethyl ester. GC normalized content 53.4%.

Example 4

The preparation method of 4-chloro-2-methyl-2-butenoic acid ethyl ester comprises the following steps:

Under nitrogen protection, disperse 8.1g (90%) metal zinc powder in 100ml solvent 2-methyltetrahydrofuran, then add 18.5g (99%) of ethyl 2-bromopropionate and mix well, stir and heat up to 69°C to trigger During the reaction, the internal temperature rose to 75°C due to the exothermic reaction, and the reaction continued for 0.5h, and the internal temperature returned to 70°C. 173.0 g (4.6%) of chloroacetaldehyde xylene drying solution was added dropwise for 15 min. After dropping, continue to react for 0.5h and cool down to room temperature naturally. Under stirring, 20ml of 10% by mass H ₂ SO ₄ aqueous solution was added to fully hydrolyze, and the cloudy reaction liquid became clear and transparent after precipitation of muddy solids. The filtrate was separated by decantation directly, the solid surface was washed with a small amount of reaction solvent, and combined into the filtrate. The solvent was recovered by distillation under reduced pressure, and 7.9 g of the crude product was distilled off to obtain 4-chloro-2-methyl-2-butenoic acid ethyl ester. GC normalized content 84.1%.

Example 5

The preparation method of 4-bromo-2-methyl-2-butenoic acid ethyl ester comprises the following steps:

Under nitrogen protection, disperse 8.1g (90%) metal zinc powder in 100ml solvent 2-methyltetrahydrofuran, then add 18.5g (99%) of ethyl 2-bromopropionate and mix well, stir and heat up to 71°C to trigger During the reaction, the internal temperature rose to 74°C due to the exothermic reaction, and the reaction continued for 0.5h, and the internal temperature returned to 70°C. The temperature was lowered to 60°C, and 125.0 g (10%) of bromoacetaldehyde dichloromethane dry solution was added dropwise, and part of the dichloromethane was recovered by atmospheric distillation for 30 minutes. After dropping, continue to react for 0.5h and cool down to room temperature naturally. Under stirring, 20ml of 10% by mass H ₂ SO ₄ aqueous solution was added to fully hydrolyze, and the cloudy reaction liquid became clear and transparent after precipitation of muddy solids. At this time, the solid formed a solid mass at the bottom of the bottle, and the filtrate was separated by decantation directly, and the surface of the solid was washed with a small amount of reaction solvent, and then merged into the filtrate. The solvent was recovered by distillation under reduced pressure, and 21.7 g of the crude product was distilled off to obtain 4-bromo-2-methyl-2-butenoic acid ethyl ester. GC normalized content 55.5%. After re-distillation, the content of GC normalization method can be increased to 76.2%. The sample was purified by silica gel column (ethyl acetate/petroleum ether=1:30), and the NMR and mass spectrometry data of the product are as follows:

UV (MeOH) absorption: λmax=225nm;

IR (KBr) absorption: 2991, 1713, 1646, 1276, 757 (cm-1);

MS(EI): m/z 206(M+,3%),161(9%),133(2%),127(18%),117(73%),113(1%),99(100% ), 82 (10%), 71 (19%), 53 (32%), 39 (12%);

¹ H-NMR (CDCl ₃ , 600MHz): δ6.92(qt, J=1.21, 8.38Hz,=CH-), 4.21(q, J=7.19Hz, -OCH ₂ -), 4.03(d, J= 8.39 Hz, -CH ₂ Br), 1.92 (d, J=1.22, -CH ₃ ), 1.31 (t, J=7.20 Hz, -OCH ₂ -CH ₃ ).

Example 6

The preparation method of 4-bromo-2-methyl-2-butenoic acid methyl ester comprises the following steps:

Under nitrogen protection, disperse 8.1g (90%) metal zinc powder in 100ml solvent 2-methyltetrahydrofuran, then add 17.1g (99%) of methyl 2-bromopropionate and mix well, stir and heat up to 68°C to trigger During the reaction, the internal temperature rose to 73°C due to the exothermic reaction, and the reaction was continued for 0.5h, and the internal temperature returned to 70°C. Cool down to 60°C, add 125.0g (10%) bromoacetaldehyde dichloromethane dry solution dropwise, and recover part of the dichloromethane by atmospheric distillation for 30 minutes. After dropping, continue to react for 0.5h, and cool down to room temperature naturally. Under stirring, 20ml of 10% by mass H ₂ SO ₄ aqueous solution was added to fully hydrolyze, and the cloudy reaction solution precipitated a muddy solid and became clear and transparent. The filtrate was separated by decantation directly, the solid surface was washed with a small amount of reaction solvent, and combined into the filtrate. The solvent was recovered by distillation under reduced pressure, and 19.6 g of the crude product was distilled off to obtain 4-bromo-2-methyl-2-butenoic acid methyl ester. GC normalized content 60.7%. Re-distilled again, the GC normalized content is 78.4%. The sample was purified by silica gel column (ethyl acetate/petroleum ether=1:30), and the NMR and mass spectrometry data of the product are as follows:

UV (MeOH) absorption: λmax=225nm;

IR (KBr) absorption: 2990, 1714, 1647, 1279, 760 (cm-1);

MS(EI): m/z 192(M+,7%),161(7%),133(3%),113(4%),99(100%),82(11%),59(2% ), 53 (100%), 39 (22%);

¹ H-NMR (CDCl ₃ , 600MHz): δ6.83 (qt, J=1.72, 8.29Hz, =CH-), 4.02 (d, J=8.30Hz, -CH ₂ Br), 3.73 (s, -OCH ₃ ), 1.89 (d, J = 1.70 Hz, -CH ₃ ).

Example 7

The preparation method of 4-chloro-2-methyl-2-butenoic acid ethyl ester comprises the following steps:

Under nitrogen protection, disperse 8.1g (90%) metal zinc powder in 100ml solvent 2-methyltetrahydrofuran, then add 18.5g (99%) of ethyl 2-bromopropionate and titanium dichloride (Cp ₂ TiCl ₂ ) 0.2g (97%) was mixed thoroughly and evenly, and when the temperature was raised to higher than 50°C with stirring, the reaction started to start smoothly, no obvious exotherm was observed, and finally raised to 70°C to continue the reaction for 0.5h. 37.0 g (21.4%) of chloroacetaldehyde 2-methyltetrahydrofuran was added dropwise to dry the solution for 10 min. After dropping, continue to react for 0.5h and cool down to room temperature naturally. Under stirring, 20ml of 10% by mass H ₂ SO ₄ aqueous solution was added to fully hydrolyze, and the cloudy reaction liquid became clear and transparent after precipitation of muddy solids. The filtrate was separated by decantation directly, the solid surface was washed with a small amount of reaction solvent, and combined into the filtrate. The solvent was recovered by distillation under reduced pressure, and 15.1 g of the crude product was distilled off to obtain 4-chloro-2-methyl-2-butenoic acid ethyl ester. GC normalized content 86.5%. After re-distillation, the content of GC normalization method can be increased to 92.0%.

The above-mentioned embodiment is only a preferred embodiment of the present invention, and cannot be used to limit the protection scope of the present invention. Any insubstantial changes and substitutions made by those skilled in the art on the basis of the present invention belong to the scope of the present invention. Scope of protection claimed.

Claims (10)

1. A process for preparing a hydrocarbyl 4-halo-2-methyl-2-butenoate comprising the steps of: subjecting a compound of formula a to a Reformatsky reaction with a compound of formula B, followed by in situ dehydration reaction, to give a compound of formula (I):

wherein X is halogen and R is hydrocarbyl.

2. The process for preparing a 4-halo-2-methyl-2-butenoic acid hydrocarbyl ester according to claim 1, wherein the compound of formula a is reacted with the compound of formula B in the form of an anhydrous haloacetaldehyde solution; the preparation method of the anhydrous halogenated acetaldehyde solution comprises the following steps: mixing the aqueous solution of halogenated acetaldehyde with anhydrous calcium chloride, and standing to separate an oil phase and a water phase; collecting an oil phase, adding a solvent into the water phase for extraction, combining the oil phases, drying, and filtering to obtain the anhydrous halogenated acetaldehyde solution.

3. The process for producing a hydrocarbon 4-halo-2-methyl-2-butenoic acid ester according to claim 2, wherein the solvent used for the extraction is one or a combination of two or more of toluene, xylene, methylene chloride and 2-methyltetrahydrofuran; the mass percentage of the anhydrous halogenated acetaldehyde solution is 4-25%.

4. The process for preparing a hydrocarbon-4-halo-2-methyl-2-butenoate according to claim 1 or 2, wherein the halogen is chlorine or bromine; the compound of the formula A is chloroacetaldehyde or bromoacetaldehyde.

5. The method for producing a hydrocarbon-based 4-halo-2-methyl-2-butenoic acid ester according to claim 1, wherein said hydrocarbon group is one or two or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or vinyl.

6. The process for preparing a 4-halo-2-methyl-2-butenoic acid hydrocarbyl ester according to claim 1, wherein the compound of formula B is prepared from metallic zinc powder by in situ reaction with 2-bromopropionate; the molar ratio of the compound of the formula A to the 2-bromopropionate is (2:1) to (0.5:1); the molar ratio of the metal zinc powder to the 2-bromopropionate is (2:1) - (1:1).

7. The method for preparing 4-halo-2-methyl-2-butenoic acid alkyl ester according to claim 6, wherein the in-situ reaction temperature is 0-100 ℃ and the reaction time is 20 min-10 h.

8. The process for preparing a hydrocarbon 4-halo-2-methyl-2-butenoate according to claim 1, wherein titanocene dichloride is added as a catalyst during the reaction of the compound of formula a with the compound of formula B; the molar dosage of the catalyst is 0.5-2% of the molar dosage of the 2-bromopropionate.

9. The process for preparing hydrocarbon 4-halogeno-2-methyl-2-butenoate according to claim 1, wherein the compound of the formula A is mixed with the compound of the formula B to give a mixed solution, and H is added ₂ SO ₄ The aqueous solution is hydrolyzed, filtrate and solid are separated, and the filtrate is distilled to obtain the compound of the general formula (I).

10. The method for preparing 4-halogeno-2-methyl-2-butenoic acid alkyl ester according to claim 1, wherein the reaction temperature is 0-100 ℃ and the reaction time is 20 min-10 h.