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CN110511141B - Synthesis method of valproyl urea - Google Patents

Synthesis method of valproyl urea Download PDF

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CN110511141B
CN110511141B CN201910850010.7A CN201910850010A CN110511141B CN 110511141 B CN110511141 B CN 110511141B CN 201910850010 A CN201910850010 A CN 201910850010A CN 110511141 B CN110511141 B CN 110511141B
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isopropyl
urea
allylisopropylmalonic
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陆茜
李国华
匡逸
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Shanghai Lingkai Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
    • C07C273/1863—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety from urea
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
    • 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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Abstract

The invention discloses a synthesis method of valproyl urea, belonging to the technical field of drug synthesis. The method takes a commercialized raw material, namely, isopropyl malonic acid diester, as an initial raw material, and comprises the steps of reacting with allyl bromide or allyl chloride under an alkaline condition by adopting a one-pot method to generate dimethyl allyl isopropyl malonate, hydrolyzing to generate allyl isopropyl malonic acid, thermally decomposing the obtained allyl isopropyl malonic acid, further converting the allyl isopropyl malonic acid into acyl chloride, and reacting with urea to obtain valproyl urea; the synthetic route of the invention only needs two steps or three steps, the operation is simple in the whole process, the materials are easy to obtain, the cost is low, the yield is high, and the method is suitable for industrial production.

Description

Synthesis method of valproyl urea
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of valproyl urea.
Background
The iprodione is synthesized by Riedel J.D. for the first time in 1923, and is sold on the market in 1926 by Hoffmann-La Roche (Hoffmann Roche) with the hypnotic medicine of the formula of 'semaphorea';
in 2003, the japanese haloid pharmaceutical corporation (Shionogi ﹠ Co) introduced this component as a drug having antipyretic and analgesic effects. For example, the EVE Quick is added with the valproylurea and is matched with other components for use, so that the EVE Quick becomes an all-purpose analgesic, and has the effects of relieving physiological pain, headache, toothache, sore throat, arthralgia, myalgia, neuralgia, lumbago, shoulder pain, pain after tooth extraction, earache, fracture pain, traumatic pain, intolerance of cold and fever relieving. The demand is continuously enlarged, and a safe, environment-friendly and reliable synthesis route suitable for mass production is very necessary.
Currently, the synthetic routes for valproyl urea that have been reported are as follows:
route 1:
Figure BDA0002195531130000011
the route needs 3 steps to obtain a target product, the yield of the first step is only 43 percent, and the yield is low; in addition, the reflux is required to be performed for more than 30 hours in the first step, so that the energy consumption is high, the time consumption is long, and the cost is increased.
Route 2:
Figure BDA0002195531130000012
Figure BDA0002195531130000021
although the yield of the valproyl urea is improved compared with the yield of the valproyl urea in the route 1, the yield is only less than 60%, the price of isovaleric acid esterification serving as a substrate is expensive, the atom economy of allyl bromide is poor, and the overall cost is high.
Therefore, there is an urgent need to develop a method for synthesizing the valproyl urea with cheap and easily available raw materials and high efficiency.
Disclosure of Invention
The invention aims to solve the technical problem of providing the synthetic valproyl urea which has simple operation and route and high yield and can reduce the generation of three wastes, and the synthetic route is more suitable for large-scale production.
The purpose of the invention can be realized by the following technical scheme, and the reaction steps are as follows:
(1) mixing isopropyl malonic diester with an activating agent, then adding allyl chloride and an alkali reagent for reaction, and adding acid after the reaction is completed to obtain allyl isopropyl malonic acid;
(2) heating the allylisopropylmalonic acid obtained in the step (1) for decarboxylation to obtain 2-isopropyl-4-alkene valeric acid, then reacting with a chlorinating reagent under the action of a catalyst to obtain 2-isopropyl-4-alkene valeryl chloride, and reacting with urea to obtain valoyl urea; or, without adding a catalyst, directly reacting 2-isopropyl-4-alkene valeric acid obtained by heating and decarboxylation of the allylisopropylmalonic acid obtained in the step (1) with triphosgene to obtain 2-isopropyl-4-alkene valeryl chloride, and then reacting with urea to obtain the valyl urea.
In one embodiment of the invention, the molar fraction of the catalyst relative to allylisopropylmalonic acid is between 2% and 5%.
In one embodiment of the present invention, the activating agent in the step (1) is sodium alkoxide, n-butyllithium or sodium hydride.
In one embodiment of the invention, the sodium alkoxide is a sodium C1-C4 alkyl alkoxide.
In one embodiment of the present invention, the isopropyl malonate diester has the following structural formula:
Figure BDA0002195531130000022
whereinR is C1-C4 alkyl. Methyl group is more preferable.
In one embodiment of the present invention, the alkali agent in step (1) comprises one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.
In one embodiment of the present invention, the pH of the reaction system after the acid addition in the step (1) is 2 to 3.
In one embodiment of the invention, the acid is hydrochloric acid.
In one embodiment of the present invention, the reaction medium in step (1) is an aprotic organic solvent, and may be any one of tetrahydrofuran and 2-methyltetrahydrofuran.
In one embodiment of the present invention, the reaction temperature in the step (1) is 0 to 70 ℃.
In one embodiment of the present invention, the molar ratio of the isopropyl malonate to the activator in the step (1) is 1 (1.0 to 1.5).
In one embodiment of the present invention, the molar ratio of the isopropyl malonic acid diester to the allyl chloride in the step (1) is 1 (1.0 to 1.2).
In one embodiment of the present invention, the temperature of the decarboxylation in the step (2) is 140-180 ℃.
In one embodiment of the present invention, in the step (2), allylisopropylmalonic acid is directly heated at 140 ℃ and 180 ℃ for 15-20min to obtain the decarboxylation product 2-isopropyl-4-Envaleric acid.
In one embodiment of the present invention, the temperature of the reaction of the chlorinating agent or triphosgene with allylisopropylmalonic acid in step (2) is 30 to 50 ℃.
In one embodiment of the present invention, the molar ratio of the allylisopropylmalonic acid, the chlorinating agent and the catalyst in the step (2) is 1 (1.05-1.2) to 0.02-0.05.
In one embodiment of the invention, the molar ratio of the allylisopropylmalonic acid, the triphosgene and the catalyst in the step (2) is 1 (1.05-1.2) to 0.00-0.05.
In one embodiment of the present invention, the molar ratio of the allylisopropylmalonic acid to the urea in the step (2) is 1:1.0 to 1.1.
In one embodiment of the present invention, the chlorinating agent in step (2) comprises thionyl chloride or phosphorus pentachloride.
In one embodiment of the present invention, the catalyst in the step (2) is N, N-dimethylformamide.
In one embodiment of the present invention, the acid chloride reaction in the step (2) is carried out in an organic solvent, and the organic solvent is any one of aprotic reagents such as dichloromethane and 1, 2-dihaloethane.
In one embodiment of the present invention, the condensation reaction in step (2) further comprises adding an organic base. The organic base is triethylamine, pyridine or N, N-diisopropylethylamine.
In one embodiment of the present invention, the equivalent ratio of allyl isopropyl malonic acid, chlorinating agent (or triphosgene), urea and organic base in step (2) is 1:1.03:1.05: 1.05. Wherein the equivalent ratio refers to the molar ratio between the reactive functional groups.
In an embodiment of the present invention, the method specifically includes the following steps:
(1) synthesizing a compound 3 allyl isopropyl malonic acid by adopting a one-pot method:
dissolving isopropyl malonic acid diester (compound 1) and an activating agent in an aprotic organic solvent, adding allyl chloride at 20-70 ℃ for reaction for 150-160min, then adding an alkali reagent for reaction for 180-200min continuously at the temperature range, finally adding hydrochloric acid for adjusting the pH value to 2-3, and separating and removing inorganic sodium chloride to obtain the compound 3 allyl isopropyl malonic acid.
Figure BDA0002195531130000041
Wherein R is C1-C8 alkyl;
(2) synthesis of compound 6 valproyl urea:
adding the compound 3 into a reaction kettle, heating to 140-180 ℃, reacting for 15-20min to obtain an intermediate compound 4, cooling to below 40 ℃, adding 1, 2-dichloroethane, a catalytic amount of N, N-dimethylformamide and a proper amount of a chlorination reagent, and reacting for 120-130min to obtain an intermediate 5; then adding the intermediate 5 into a premixed 1, 2-dichloroethane solution of urea and organic base, and reacting at 80-83 ℃ for 150-;
or adding the compound 3 into a reaction kettle, heating to 140-180 ℃, reacting for 15-20min to obtain an intermediate compound 4, cooling to below 40 ℃, adding 1, 2-dichloroethane and a proper amount of triphosgene, and reacting for 120-130min to obtain an intermediate 5; then adding the intermediate 5 into a premixed 1, 2-dichloroethane solution of urea and organic base, and reacting at 80-83 ℃ for 150-;
Figure BDA0002195531130000042
the invention has the beneficial effects that:
the method of the invention starts from easily obtained industrial raw materials, reduces the production treatment process by adopting a one-pot method, and has good atom economy; meanwhile, a certain amount of organic three wastes are prevented from being generated through a solvent-free chemical reaction in a local step; meanwhile, the yield of the substitution product in the first step in the method is over 72.2 percent and is higher than 87.6 percent; the yield of the amidation process in the second step is over 75 percent and can reach 85 percent higher, the total yield of the valproyl urea can reach 54.2 percent and can reach 74.5 percent higher, and the yield is greatly improved.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of valproate;
FIG. 2 is a scheme showing the synthesis of valproate;
FIG. 3 is a FTIR spectrum of valproyl urea.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
(1) preparation of allylisopropylmalonic acid:
Figure BDA0002195531130000051
dissolving dimethyl isopropylmalonate (100g, 574mmol) and sodium methoxide (40.3g,746mmol) in 300mL tetrahydrofuran, heating to 60-66 ℃, reacting for 150min, cooling to 40-46 ℃, adding allyl chloride (52.7g,688.9mmol) for reacting for 70-80min, adding sodium hydroxide aqueous solution (87g) for reacting for 180-200min at 40-45 ℃, adding hydrochloric acid for adjusting the pH value to 3-4 at room temperature, separating phases, and extracting the aqueous phase with ethyl acetate for three times; ethyl acetate and tetrahydrofuran were concentrated to give allylisopropylmalonic acid (93.5g) in 87.6% overall yield.
The structural characterization data for the compounds 2, 3 obtained are as follows:
compound 2:1HNMR(400M CDCl3)δ5.74-5.76(m,1H),5.04-5.10(d,J＝16Hz,2H),3.72(s,6H),2.65-2.66(d,J＝4Hz,2H),2.31-2.35(m,1H),0.99(s,3H),0.97(s,3H)ppm.
compound 3:1HNMR(400M dMSO-d6)δ13.0(br,2H),5.65-5.75(m,1H),4.99-5.10(dd,J1＝20Hz,J2＝12Hz,2H),2.50-2.51(d,J＝4Hz,2H),2.1-2.17(m,1H),0.92-0.94(d,J＝8Hz,6H)ppm.
(2) preparation of the valproyl urea:
Figure BDA0002195531130000052
adding the compound 3(60g,322mmol) into a reaction kettle, heating to 140-180 ℃, reacting for 15-20min to obtain an intermediate compound 4(44.8g,315mmol), cooling to below 40 ℃, adding a catalytic amount of N, N-dimethylformamide (0.6mL, 8.1mmol) and thionyl chloride (39.2g,330mmol), and reacting for 120-130min to obtain an intermediate 5; the intermediate 5 is added with a mixed solution of premixed urea (18.9g,315mmol) and 1, 2-dichloroethane (57mL), then pyridine (26.1g,330mmol) is added to react at 80-83 ℃ for 180min, after the solid is collected by filtration, the solid is pulped with water, and the solid is washed with water during centrifugation, so that 46.8g of the valproyl urea can be obtained with the yield of 79%.
The structural characterization data for compounds 4, 6 are as follows:
compound 4:1HNMR(400M DMSO-d6)δ12.1(br,1H),5.68-5.78(m,1H),4.96-5.06(dd,J1＝8Hz,J2＝6Hz,2H),2.18-2.22(t,J＝6Hz,2H),2.07-2.11(m,1H),1.75-1.80(m,1H),0.88-0.92(dd,J1＝J2＝8Hz,6H)ppm.
compound 6:1HNMR(400M DMSO-d6)δ10.15(br,1H),7.86(br,1H),7.21(br,1H),5.63-5.74(m，1H),5.04(s,1H),4.95-5.00(m,1H),2.31-2.51(m,1H),2.20-2.27(m,2H),1.74-1.79(m,1H),0.86-0.90(ddt,J1＝8Hz,J2＝4H,6H)ppm.
example 2
With reference to example 1, by replacing dimethyl isopropylmalonate in step (1) with diethyl isopropylmalonate (120g, 593.7mmol), 79.8g of allylisopropylmalonic acid was obtained with a yield of 72.2% without changing the other conditions.
Referring to example 1, 50.5g of propionylurea was obtained in 85% yield under the same conditions except that N, N-dimethylformamide was not added in place of thionyl chloride in the step (2) where triphosgene (32.62g, 110mmol) was added.
Example 3
Referring to example 1, the sodium methoxide in step (1) was replaced with 60% sodium hydride (25.3g,631mmol) and the other conditions were unchanged to give 94.4g of allylisopropylmalonic acid in 85.4% yield.
Referring to example 1, when triethylamine (33.3g,330mmol) was added in step (2) in place of pyridine, 44.5g of propylvaleryl urea was obtained in 75% yield without changing the conditions.
Example 4
Step (1) Allylisopropylmalonic acid was obtained with reference to example 1.
Referring to example 1, the thionyl chloride in step (2) was replaced with phosphorus pentachloride (68.7g,330mmol) carbonyl activator and other conditions were not changed to give 47.5g of alanyl urea amidated product in 80% yield.
Comparative example 1
Referring to example 1, sodium methoxide in step (1) was replaced with potassium hydroxide (48.3g,861mmol), and the other conditions were not changed to obtain 33.2g of allylisopropylmalonic acid in 30% yield.
Comparative example 2
Step (1) Allylisopropylmalonic acid was obtained with reference to the examples.
Referring to example 1, DMF (2.5mL,32mmol) was added to step (2) and the remaining conditions were changed to give 41.0g of propionylurea as an amidation product in 65% yield.
The preferred embodiments of the invention disclosed above are intended to be illustrative only. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise embodiments disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims (8)

1. A synthetic method of the valproate is characterized by comprising the following steps:
(1) dissolving isopropyl malonic diester and an activating agent in an aprotic organic solvent, adding allyl chloride at 20-70 ℃ for reacting for 150-160min, then adding an alkali reagent for continuing to react for 180-200min at the temperature range, finally adding hydrochloric acid for adjusting the pH value to be 2-3, and separating and removing inorganic sodium chloride to obtain allyl isopropyl malonic acid; the activating agent is C1-C4 sodium alkyl alkoxide or sodium hydride;
(2) heating and decarboxylating the allylisopropylmalonic acid obtained in the step (1) to obtain 2-isopropyl-4-alkene valeric acid, then reacting the 2-isopropyl-4-alkene valeryl chloride with a chlorinating reagent under the action of a catalyst to obtain 2-isopropyl-4-alkene valeryl chloride, and reacting the 2-isopropyl-4-alkene valeryl chloride with urea under the action of an organic base to obtain valoyl urea; the mole fraction of the catalyst relative to the allylisopropylmalonic acid is 2-5%; the chlorination reagent comprises thionyl chloride and phosphorus pentachloride;
the catalyst is N, N-dimethylformamide; the organic base is triethylamine, pyridine or N, N-diisopropylethylamine.
2. The method of claim 1, wherein the isopropylmalonic acid diester has a formula as follows:
Figure FDA0003528451200000011
wherein R is C1-C4 alkyl.
3. The method of claim 2, wherein R is methyl.
4. The method according to claim 1, wherein the molar ratio of the isopropyl malonate to the activator in the step (1) is 1 (1.0-1.5).
5. The method as claimed in claim 1, wherein in the step (2), the allylisopropylmalonic acid is directly heated at 140 ℃ and 180 ℃ for 15-20min to obtain the decarboxylated 2-isopropyl-4-Envaleric acid.
6. The method according to claim 1, wherein the temperature at which the allylisopropylmalonic acid is reacted with the chlorinating agent in the step (2) is 30 to 50 ℃.
7. The method according to claim 1, wherein the molar ratio of the chlorinating agent to the allylisopropylmalonic acid in the step (2) (1.05-1.2): 1.
8. The method according to any one of claims 1 to 7, wherein the aprotic organic solvent in step (1) is any one of tetrahydrofuran and 2-methyltetrahydrofuran.
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