JP2020059693A - Method for preparing apronal and intermediate thereof - Google Patents

Abstract

To provide a simple, cost-effective and improved method for synthesizing apronal and an intermediate alkyl 2-isopropyl-4-pentenoate used in the synthesis of allylisopropylacetylurea of apronal.SOLUTION: There is provided a method including a step of reacting an alkyl 2-isopropyl-4-pentenoate with an alkali metal salt such as sodium urea in the presence of an aprotic polar solvent or a mixture of solvents to obtain apronal of the following formula (1). In addition, the present invention also includes a method for preparing the intermediate alkyl 2-isopropyl-4-pentenoate by dealkoxycarbonylation of dialkylallyl isopropyl malonate.SELECTED DRAWING: None

Description

  The present invention relates to an improved method for synthesizing Apronal (a compound of formula 1) and its intermediate alkyl 2-isopropyl-4-pentenoate of formula (4). The present invention further relates to appronal and a new, cost-effective method for synthesizing alkyl 2-isopropyl-4-pentenoate, a related intermediate used in the synthesis of appronal. The present invention provides a new synthetic route for the synthesis of apronal and its intermediate, alkyl 2-isopropyl-4-pentenoate of formula (4), which is simple and high yielding.

  The present invention relates to processes for preparing apronals (compounds of formula 1) and intermediates, ie alkyl 2-isopropyl-4-pentenoates of formula (4).

  Apronal (trade name Sedormid), or Apronalide, also known as allylisopropylacetylurea or aliisopropylacetylcarbamide, is a hypnotic / sedative. Apronal is allyl isopropyl acetylurea, known under the trade name Isodormid. Although not barbiturate, apronalide is similar in structure to barbiturate (an open-chain carbamide rather than having a heterocycle). It is therefore relatively milder, but similar in action to barbiturates (conventionally used as a daytime sedative at doses of 1-2 grams every 3-4 hours).

  The earliest method for synthesizing allyl isopropyl acetylurea is described in US Pat. No. 6,096,837 and by alkaline hydrolysis of 5-allyl-5-isopropyl barbituric acid as described by Equation 1.

  Disadvantages in the above invention are poor yields and longer reaction times.

  US Pat. No. 6,037,058 describes two different routes for synthesizing allylisopropylacetylurea, as described in Formula 2, starting from allylisopropylacetic acid. In the first route, allyl isopropyl acetic acid is converted to its acid chloride and then treated with urea to give allyl isopropyl acetyl urea.

  In the second route, allyl isopropyl acetic acid is converted to its amide and then treated with cyanic acid as follows (Equation 3).

  Both equations 2 and 3 have the disadvantage of leading to poor yields.

  U.S. Pat. No. 5,837,049 discloses a general method for making N-acylureas in which isovaleric acid is alkylated with an alkyl halide using the base lithium diisopropylamine with hexamethylphosphoramide. (Equation 4).

  The resulting acid was then converted to its acid chloride using thionyl chloride and the same was treated with excess urea in acetonitrile to give the acyl urea as described by Formula 4. The above method requires expensive reagents and low temperatures due to the intermediate, 2-isopropyl-4-pentenoate.

  U.S. Pat. No. 5,837,058 discloses a method for apronal, wherein under alkaline conditions ethyl isovalerate is reacted with allyl bromide to give ethyl 2-isopropyl-4-pentenoate, which is Hydrolyzed to isopropyl-4-pentenoate. 2-Isopropyl-4-pentenoate is then converted to its acyl chloride, which is then reacted with urea to give the apronal as described in Formula 5.

  The process described above involves many steps, results in poor yields and is not suitable for commercial operation.

German Patent Invention No. 459903 German Patent Invention No. 461814 U.S. Pat. No. 8,846,903 Chinese Patent Application Publication No. 107501129

  The main object of the invention is to provide a simple and cost-effective method for the synthesis of appronal (compounds of formula 1).

  Yet another object of the present invention is to provide another simple three-step method for appronal (compound of formula 1).

  An additional object of the present invention is to provide a process for preparing the intermediate alkyl 2-isopropyl-4-pentenoate of formula (4) by dealkoxy decarbonylation of dialkylallyl isopropyl malonate of formula (3). .

  An additional object of the present invention is to provide a process for preparing a dialkylallyl isopropyl malonate of formula (3) by allylation of a dialkyl isopropyl malonate of formula (2).

  Another object of the present invention is to provide a method of synthesizing an apronal of formula (1), that is, allylisopropylacetylurea, by reacting an alkyl 2-isopropyl-4-pentenoate with an alkali metal salt of urea.

  The present disclosure relates to methods of preparing compounds of Formula 1 and intermediates thereof.

を調製する方法であって、
非プロトン性極性溶媒または溶媒の混合物の存在下で、式（４）のアルキル２−イソプロピル−４−ペンテノエートを、尿素のアルカリ金属塩、好ましくは尿素ナトリウム（式５）と反応させ、式（１）のアプローナルを得る、
工程を含み、

アルキル基Ｒは、メチル（４ａ）またはエチル（４ｂ）から選択される、
方法を提供することにある。 A first aspect of the present invention is an appendage (compound of formula 1)

A method of preparing
An alkyl 2-isopropyl-4-pentenoate of formula (4) is reacted with an alkali metal salt of urea, preferably sodium urea (formula 5) in the presence of an aprotic polar solvent or mixture of solvents to give a compound of formula (1 ) Appronal,
Including steps,

The alkyl group R is selected from methyl (4a) or ethyl (4b),
To provide a method.

  Another aspect of the present invention is to provide a method for preparing an apronal of formula (1), wherein the aprotic polar solvent is selected from the group consisting of THF, methyl THF, dimethylacetamide, DMF, DMSO and sulfolane. To be selected.

  Another aspect of the present invention is to provide a method of preparing formula (1), wherein the alkali metal salt of urea used in this method is prepared in-situ or the substance thereof. Prepared and isolated in pure form.

  Another aspect of the invention is to provide a method of preparing formula (1), wherein the alkali metal is selected from the group consisting of sodium, lithium and potassium.

  Another aspect of the present invention is to provide a method for preparing the apronal of formula (1), wherein the reaction is carried out at a temperature of 0-55 ° C.

ここで、アルキル基またはＲは、メチル、エチルまたはイソプロピルから選択される、
（ｂ）非プロトン性極性溶媒の存在下で、アルカリ金属ハロゲン化物を用いて、式（３）のジアルキルアリルイソプロピルマロネートの脱アルコキシ脱カルボニル化により、式（４）のアルキル２−イソプロピル−４−ペンテノエートを調製する工程、
を含み、

ここで、Ｒは、メチル、エチル、イソプロピルから選択される、
方法を提供することにある。 Another aspect of the invention is a method of preparing an intermediate alkyl 2-isopropyl-4-pentenoate of formula (4):
(A) reacting a dialkyl-2-isopropylmalonate of formula (2) with an allyl halide in the presence of an aprotic polar solvent or mixture of solvents to obtain a dialkylallylisopropylmalonate of formula (3). ;

Wherein the alkyl group or R is selected from methyl, ethyl or isopropyl,
(B) Alkyl 2-isopropyl-4 of formula (4) by dealkoxy decarbonylation of dialkylallyl isopropyl malonate of formula (3) with an alkali metal halide in the presence of an aprotic polar solvent. -Preparing pentenoate,
Including,

Where R is selected from methyl, ethyl, isopropyl,
To provide a method.

  Another aspect of the present invention is to provide a method of preparing an intermediate alkyl 2-isopropyl-4-pentenoate of formula (4), wherein the allyl halide in step (a) is allyl bromide. Or selected from allyl chloride.

  Another aspect of the present invention is to provide a method of preparing an intermediate alkyl 2-isopropyl-4-pentenoate of formula (4), which comprises a step () for the preparation of a compound of formula (3): The base used in a) is selected from sodium hydride, potassium hydride and sodium methoxide.

  Another aspect of the present invention is to provide a method for preparing an intermediate alkyl 2-isopropyl-4-pentenoate of formula (4), wherein the reaction in step (a) is from 0 to 40 ° C. Done at temperature.

  Another aspect of the present invention is to provide a method of preparing an intermediate alkyl 2-isopropyl-4-pentenoate of formula (4), wherein The protic solvent is selected from the group comprising DMF, dimethylacetamide, DMSO and sulfolane.

  Another aspect of the present invention is to provide a method for preparing an intermediate alkyl 2-isopropyl-4-pentenoate of formula (4), wherein the aprotic solvent used in step (a) is DMF. And the aprotic solvent used in step (b) is DMSO.

  Another aspect of the invention is to provide a method for preparing an intermediate alkyl 2-isopropyl-4-pentenoate of formula (4), wherein the alkali metal halide used in step (b) is It is selected from the group consisting of sodium bromide, sodium chloride, potassium bromide, potassium chloride, lithium bromide, lithium chloride.

  Another aspect of the present invention is to provide a method of preparing an intermediate alkyl 2-isopropyl-4-pentenoate of formula (4), wherein the alkali metal halide used in step (b) comprises It is sodium bromide (NaBr).

  Another aspect of the present invention is to provide a method for preparing an intermediate alkyl 2-isopropyl-4-pentenoate of formula (4), wherein the reaction in step (b) is 100-200 ° C. Done at temperature.

  Another aspect of the present invention is to provide a method of preparing an intermediate alkyl 2-isopropyl-4-pentenoate of formula (4), wherein the dialkylallyl isopropyl malonate of formula (3) is diethyl It is selected from allyl isopropyl malonate or dimethyl allyl isopropyl malonate.

のアプローナル、すなわちアリルイソプロピルアセチル尿素を調製するための改良された方法を開示する。 A preferred embodiment of the present invention is the formula (1)

Discloses an improved method for preparing an apronal, i.e., allyl isopropyl acetyl urea.

Definitions For convenience, before further describing the present disclosure, certain terms and examples used herein are set forth herein. These definitions should be read in light of the remainder of this disclosure and should be understood as by one of ordinary skill in the art. Although the terms used herein have the meanings that will be recognized and known to those of skill in the art, for convenience and completeness, certain terms and their meanings are defined below.

  The term "alkyl" refers to a monovalent straight or branched chain of 1 to 24 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like. Refers to a radical.

  According to certain embodiments, the present disclosure relates to a simple process for the preparation of apronal, ie, allylisopropylacetylurea, represented herein as a compound of formula (1), alkyl 2-isopropyl-4-. Comprising reacting a pentenoate (Formula 4), wherein the alkyl group R is selected from methyl or ethyl and when reacted with an alkali metal salt of urea of Formula (5), the alkali metal is preferably lithium, sodium and It is selected from potassium, more preferably sodium, in the presence of an aprotic polar solvent at 0-55 ° C, preferably 5-30 ° C, most preferably 5-15 ° C.

ここで、アルカリ金属、Ｍ＝Ｎａ、Ｋ、Ｌｉ、かつ
アルキル基Ｒは、メチルまたはエチルから選択される。

Here, the alkali metal, M = Na, K, Li, and the alkyl group R are selected from methyl or ethyl.

In a preferred embodiment of the present invention, the compound of formula 4 is exemplified by R = CH ₃ (Compound 4a) and _{R =} C 2 _{H 5} (Compound 4b).

  Another embodiment of the present invention is an aprotic solvent or solvent selected from the group of solvents consisting of THF, DMF, DMSO, sulfolane, dimethylacetamide, preferably THF and DMF, most preferably DMF. Selection of mixture.

  A further embodiment of the present invention discloses a method for preparing the compound of formula 5, sodium urea, selected from the group consisting of THF, DMF, DMSO, dimethylacetamide, sulfolane, and toluene, preferably THF and Reacting sodium hydride with urea in the presence of an aprotic polar solvent or mixture of solvents, which is DMF, most preferably DMF.

  The third aspect of the present invention is that the alkali metal salt of urea of formula (5) used in the method of the present invention is prepared and used without isolation or is isolated only by the substance thereof. And is preferably used without isolation.

  A fourth aspect of the present invention is that the preparation of the alkali metal salt of urea may be selected from the group consisting of lithium urea, sodium urea and potassium urea, preferably sodium urea.

  A fifth aspect of the present invention is the preparation of a compound of formula 4, alkyl 2-isopropyl-4-pentenoate, which comprises the alkoxylation decarbonylation of a compound of formula 3, dialkylallyl isopropyl malonate, wherein the alkyl group or R is selected from methyl, ethyl or isopropyl and uses an alkali metal halide in the presence of an aprotic polar solvent at a temperature in the range 100 to 200 ° C. as described in formula 9.

  The alkali metal halide is selected from the group consisting of sodium chloride, sodium bromide, potassium chloride, potassium bromide, lithium chloride, lithium bromide and calcium chloride, and preferably lithium chloride, sodium bromide or potassium bromide. It is selected from the group consisting of and most preferably sodium bromide.

  An alkyl group in the alkyl 2-isopropyl-4-pentenoate of formula (4) especially means ethyl or methyl.

  The aprotic solvent used in step (a) is selected from the group consisting of THF, toluene, DMF, dimethylacetamide, DMSO and sulfolane, and in step (b) the group consisting of DMF, dimethylacetamide, DMSO and sulfolane. To be selected.

  Dialkylallyl isopropyl malonate of formula (3) especially means diethyl allyl isopropyl malonate or dimethyl allyl isopropyl malonate.

  Another embodiment of the present invention is the preparation of a compound of formula (3), dialkylallyl isopropyl malonate, which comprises alkylation of a commercially available dialkyl isopropyl malonate of formula (2), wherein alkyl is ethyl or methyl. Mean; preferably the base sodium hydride is used in the presence of an aprotic polar solvent at a temperature of preferably 0-40 ° C, more preferably 10-30 ° C.

  The aprotic solvent or mixture of solvents is preferably selected from the group of solvents consisting of THF, DMF, DMSO, sulfolane, dimethylacetamide, toluene, preferably THF and DMF, most preferably DMF.

  Reference is now made to the following examples, which together with the above description, illustrate the invention in a non limiting fashion. These provide details about the synthesis of compounds of the present disclosure. It should be understood that the following are representative only, and that the invention is not limited by the details shown in these examples.

Example 1
Preparation of dimethyl-2-allyl-2-isopropylmalonate (Formula 3a)
To a solution of 16.5 gm (0.688 mol) sodium hydride in 200 ml DMF was slowly added 100 gm (0.574 mol) dimethyl-2-isopropylmalonate at 20-25 ° C and stirred for 1 hour. Then, 83.3 gm (0.688 mol) of allyl bromide was added to this solution at 20 to 25 ° C, and the reaction product temperature was raised to 40 to 45 ° C and maintained for 3 to 4 hours. After completion of the reaction, the reaction product was cooled to 25-30 ° C. The sodium bromide was filtered. The filtered reaction product was added slowly to pre-chilled water. The top oil layer was separated and weighed 115 gm (yield 89.4%) and had a GC purity of 95%. This solution was used directly in the preparation of methyl-2-isopropyl-4-pentenoate.

Example 2
Preparation of methyl-2-isopropyl-4-pentenoate (Formula 4a)
To a solution of 8.4 gm of water (0.466 mol) and 96 gm of sodium bromide (0.932 mol) in 200 ml of dimethylformamide was added 115 gm of dimethyl 2-allyl-2-isopropylmalonate (crude product from above). added. The reaction mixture temperature was raised to 140-160 ° C. with stirring and maintained at that temperature for 12 hours. After completion of the reaction, the product was cooled to 40 ° C., diluted with 800 gm of water and stirred for about 30 minutes. The top oily layer was separated. Pure methyl-2-isopropyl-4-pentenoate was distilled under vacuum (at 10 mbar) at 75-80 ° C. yielding 65 gm and 99% GC purity.

Example 3
Preparation of allyl isopropyl acetyl urea (Formula 1):
To a precooled (10-15 ° C.) solution of 20 gm (0.833 mol) sodium hydride in 200 ml dimethylformamide, 57.6 gm (0.96 mol) urea was added slowly with stirring. The reaction temperature was maintained at 10-15 ° C for 4 hours. After the formation of sodium urea was completed, 100 gm (0.64 mol) was added into the reaction product with slow stirring at 10-15 ° C for 2 hours. Further, the temperature was maintained at 10 to 15 ° C for 8 hours. After completion of the reaction, the reaction product was added to pre-cooled water (5-10 ° C) to make 1400 ml. The precipitated allylisopropylacetylurea was filtered and washed with 100 ml of water. This wet compound was slurried in 500 ml of xylene, washed with 500 ml of xylene and dried at 100-110 ° C. to give allylisopropylacetylurea 90 gm (76.9% yield).

Example 4
Preparation of Sodium Urea (Formula 5):
Sodium urea was prepared according to the procedure described in Journal of the Korean Chemical Society 251; 4, 60; 2016 by treating urea with sodium hydride in xylene.

Example 5
Preparation of allyl isopropyl acetyl urea (Formula 1):
To a precooled slurry of 57.4 g (0.7 mol) sodium urea in 200 ml DMF was slowly added with stirring at 10-15 ° C. for 2 hours with 100 gm of methyl-2-isopropyl-4-pentenoate (0. 64 mol) was added to obtain a reaction product. In addition, the temperature of the reaction was maintained at 10-15 ° C for 6-8 hours. After completion of the reaction, the reaction product was transferred to pre-cooled water (5-10 ° C) to make 1400 ml. The precipitated allylisopropylacetylurea was filtered and washed with 100 ml of water. The wet compound was slurried with 500 ml of xylene, washed with 500 ml of water and dried at 100-110 ° C to give 90 gm (76.9% yield).

Example 6
Preparation of diethyl-2-allyl-2-isopropylmalonate (Formula 3b)
To a solution of 16.5 gm (0.688 mol) sodium hydride in 200 ml DMF was slowly added 116.5 gm (0.574 mol) dimethyl-2-isopropylmalonate at 20-25 ° C and stirred for 1 hour. . Then, 83.3 gm (0.688 mol) of allyl bromide was added to this solution at 20 to 25 ° C., and the reaction product temperature was raised to 40 to 45 ° C. and maintained for 3 to 4 hours. After completion of the reaction, the reaction product was cooled to 25-30 ° C. The sodium bromide was filtered. The filtered reaction product was added slowly to pre-chilled water. The top oily well was separated and weighed 120 gm. This solution was used directly in the preparation of ethyl-2-isopropyl-4-pentenoate.

Example 7
Preparation of ethyl-2-isopropyl-4-pentenoate (Formula 4b):
To a solution of 96 gm (0.932 mol) sodium bromide in 8.4 gm water (0.466 mol) and 200 ml dimethylsulfoxide (DMSO) 120 gm diethyl 2-allyl-2-isopropylmalonate (crude product from above) Stuff) was added. The reaction mixture temperature was raised to 140-160 ° C. with stirring and maintained at that temperature for 12 hours. After completion of the reaction, the product was cooled to 40 ° C., diluted with 800 gm of water and stirred for about 30 minutes. The top oily layer was separated. Pure ethyl-2-isopropyl-4-pentenoate was distilled under vacuum (10 mbar) at 75-80 ° C. to yield 68 grams (89.1% yield) and 99% GC purity.

Example 8
Preparation of allyl isopropyl acetyl urea (Formula 4)
To a precooled (10-15 ° C.) solution of 20 gm (0.833 mol) sodium hydride in 200 ml dimethylformamide, 57.6 gm (0.96 mol) urea was added slowly with stirring. The reaction temperature was maintained at 10-15 ° C for 4 hours. After the formation of sodium urea was completed, 100 gm (0.64 mol) of ethyl-2-isopropyl-4-pentenoate was added into the reaction product with slow stirring at 10-15 ° C for 2 hours. Further, the temperature was maintained at 10 to 15 ° C for 8 hours. After completion of the reaction, the reaction product was added to pre-cooled water (5-10 ° C) to make 1400 ml. The precipitated allylisopropylacetylurea was filtered and washed with 100 ml of water. The wet compound was slurried with 500 ml of xylene, washed with 500 ml and dried at 100-110 ° C. to give allylisopropylacetylurea 90 gm (76.9% yield).

Claims (16)

A method for preparing an appronal (compound of formula (1)), comprising:

The compound of formula (1) is reacted with an alkyl 2-isopropyl-4-pentenoate of formula (4) with an alkali metal salt of urea of formula (5) in the presence of an aprotic polar solvent or mixture of solvents. Process of obtaining

Including,
M = Li or Na or K,
The alkyl group R is selected from methyl or ethyl,
A method characterized by the following.   The apronal (compound of formula 1) according to claim 1, characterized in that the aprotic polar solvent is selected from the group consisting of THF, methyl THF, dimethylacetamide, DMF, DMSO and sulfolane. Method.   Process for preparing an apronal (compound of formula 1) according to claim 1, characterized in that the alkali metal salt is prepared and used without isolation or is prepared and isolated only with the substance. .   The method for preparing an apronal (compound of formula 1) according to claim 1, characterized in that the reaction is carried out at a temperature of 0-55 ° C. The compound of formula (4) is:
(A) reacting a compound of formula (2) dialkyl-2-isopropylmalonate with an allyl halide in the presence of a base in an aprotic polar solvent or mixture of solvents to form a dialkylallyl isopropyl formula (3). Obtaining malonate;

Wherein the alkyl group or R is selected from methyl, ethyl or isopropyl,
(B) Dealkylation of the dialkylallyl isopropyl malonate of formula (3) with an alkali metal halide in the presence of an aprotic polar solvent to give a compound of formula (4) alkyl 2-isopropyl- Preparing 4-pentenoate,

Where R is selected from methyl, ethyl, isopropyl,
A method for preparing an apronal (compound of formula 1) according to claim 1, characterized in that it is prepared by a method comprising.   Process for preparing a compound of formula (4) according to claim 5, characterized in that said allyl halide in step (a) is selected from allyl bromide or allyl chloride.   6. The method according to claim 5, characterized in that the base used in step (a) for the preparation of the compound of formula (3) is selected from sodium hydride, potassium hydride and sodium methoxide. A method of preparing a compound of formula (4).   Process for preparing a compound of formula (4) according to claim 5, characterized in that the reaction in step (a) is carried out at a temperature of 5-40 ° C.   Prepare a compound of formula (4) according to claim 5, characterized in that the aprotic solvent used in step (a) is selected from the group comprising DMF, dimethylacetamide, DMSO and sulfolane. Method.   Prepare the compound of formula (4) according to claim 5, characterized in that the aprotic solvent used in step (b) is selected from the group comprising DMF, dimethylacetamide, DMSO and sulfolane. Method.   Process for preparing a compound of formula (4) according to claim 5, characterized in that the aprotic solvent used in step (a) is DMF.   Process for preparing a compound of formula (4) according to claim 5, characterized in that the aprotic solvent used in step (b) is DMSO.   7. The alkali metal halide used in step (b) is selected from the group consisting of sodium bromide, sodium chloride, potassium bromide, potassium chloride, lithium bromide, lithium chloride. A method of preparing a compound of formula (4) as described in 1.   Process for preparing a compound of formula (4) according to claim 5, characterized in that the alkali metal halide used in step (b) is sodium bromide (NaBr).   Process for preparing a compound of formula (4) according to claim 5, characterized in that the reaction in step (b) is carried out at a temperature of 100-200 ° C.   Process for preparing a compound of formula (4) according to claim 5, characterized in that said dialkyl isopropyl malonate of formula (3) is selected from diethyl allyl isopropyl malonate or dimethyl allyl isopropyl malonate.