PROCESS OF PREPARATION OF APRONAL AND ITS INTERMEDIATE FIELD OF THE INVENTION
The present invention relates to an improved process for the synthesis of Apronal (compound of Formula 1) and its intermediate alky] 2-isopropyl-4-pentenoate of Formula (4). The invention further relates to cost effective new process for the synthesis of Apronal and of a related intermediate alkyl 2-isopropyl-4-pentenoate used in the synthesis of Apronal. The present invention provides a new synthesis route for synthesis of Apronal and its intermediate alkyl 2-isopropyl-4-pentenoate of Formula (4), which is simple and efficient high in yield.
BACK GROUND OF THE INVENTION
The present invention relates to process of manufacture of Apronal (compound of Formula-1) and the intermediate namely alkyl 2-isopropyl-4-pentenoate of Formula (4).
Apronal (brand name Sedormid), or Apronalide, also known as allylisopropylacetylurea or allylisopropylacetylcarbamide is, a hypnotic /sedative drug. Apronal is allylisopropylacetylurea and known by brand names Isodormid.. Though it is not a barbiturate, apronalide is similar in structure to the barbiturates (being an open-chain carbamide instead of having a heterocyclic ring). In accordance, it is similar in action to the barbiturates, although considerably milder in comparison (formerly used as a daytime sedative at doses of 1 to 2 grams every

3 to 4 hours).
The earliest process for the synthesis of allyl isopropyl acetyl urea was described in DE Patent 459903 by the alkaline hydrolysis of 5-allyl-5-isopropyl barbituric acid as described by the Scheme-1. Scheme-1

The disadvantages in the above invention are yield is poor and takes longer reaction time.
DE461814 describes two different routes for the synthesis of allyl isopropyl acetylurea as described in the scheme-2 starting from allyl isopropyl acetic acid. In the first route allyl isopropyl acetic acid is converted its acid chloride then treated with urea to get allyl isopropyl acetylurea.

Scheme-2

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

Both scheme 2 and scheme 3 are disadvantageous resulting in poor yield.
US8846903B2 discloses a generalized method of making N-acyl urea in which isovalaric acid was alkylated with alkyl halide using base lithium diisopropyl amine with hexamethylphosphoramide (Scheme-4)


The resulting acid was then converted to its acid chloride, using thionylchloride and same was treated with large excess of urea in acetonitrile to get acylurea as described by the scheme 4. The process described above involves costly reagents and low temperature for the preparation of intermediate namely 2-isopropyl-4-pentenoic acid.

CN107501129A discloses a process for apronal in which ethyl isopentanoate is reacted with allyl bromide, under alkaline condition to give ethyl 2-isopropyl-4-pentenoate which was then hydrolysis to 2-isopropyl-4-pentenoic acid. Then 2-isopropyl-4-pentenoic acid is converted its acyl chloride which was then reacted with urea to obtain the Apronal as described in the scheme-5. Scheme-5


The above method described involves a number of steps, results in poor yield, and not suitable for commercial operation.
OBJECT OF THE INVENTION
It is a primary object of the present invention is to provide simple and cost -effective method for synthesis of Apronal (compound of Formula-1).
It is yet another object of the present invention to provide an alternate simple three step process for Apronal (compound of formula 1).
It is an additional objective of the present invention to provide a process of preparation of the intermediate alkyl 2-isopropyl-4-pentenoate of formula (4) by dealkoxy decarbonylation of dialkyl allylisopropylmalonate of formula (3).
It is an additional object of the present invention to provide a process of preparation of dialkyl allylisopropylmalonate of formula-3 by allylation of dialkyl isopropylmalonate of formula (2).
It is another object of the present invention to provide a process of synthesis of Apronal namely allyl isopropyl acetyl urea formula (1) by reacting alkyl 2-isopropyl-4-pentanoate of formula (4) with alkali metal salt of urea.

SUMMARY OF THE INVENTION
The present disclosure relates to the process of preparation of a compound of the formula 1 and it's intermediate.
It is a primary aspect of the present invention to provide a process for preparation of Apronal (compound of Formula -1) comprising of:

reacting alky] 2-isopropyl-4-pentenoate of formula (4) with alkali metal salt of urea preferably sodium urea (Formula 5) in the presence of an aprotic polar solvent or mixture of solvents to get Apronal of Formula (1); Scheme-6

Formula (4) Formula (1)
wherein the alkyl group R is selected from Methyl (4a) or Ethyl (4b).

It is another aspect of the present invention to provide a process for preparation of Apronal of Formula (1) wherein the aprotic polar solvent is selected from a group consisting of THF, methyl THF, dimethyl acetamide, DMF, DMSO and sulfolane.
It is another aspect of the present invention to provide a process for preparation of Formula (1) wherein the alkali metal salt of urea used in the process is prepared in-situ or prepared and isolated in pure form.
It is another aspect of the present invention to provide a process for preparation of Formula (1) wherein alkali metal is selected from the group consisting up sodium, lithium and potassium.
It is another aspect of the present invention to provide a process for preparation of apronal of Formula (1), wherein the reaction is carried out at a temperature of 0-
55°C.
It is another aspect of the present invention to provide a process for preparation of
the intermediate, alkyl 2-isopropyl-4-pentenoate of formula (4) comprising of
steps:
(a) reacting dialkyl-2-isopropyl malonate of formula (2) with an allyl halide in the
presence of base in an aprotic polar solvent or mixture of solvents to get dialkyl
allylisopropylmalonate of formula (3);

Scheme-7

Formula (2) Formula (3)
wherein, the alkyl group or R is selected from methyl, ethyl or Isopropyl, (b) dealkoxy decarbonylation of dialkyl allylisopropylmalonate of formula (3) to prepare alkyl 2-isopropyl-4-pentenoate of formula (4) using an alkali metal halide in the presence of aprotic polar solvents;
Scheme-8

Formula (3) Formula (4)
wherein R is selected from group methyl, ethyl, isopropyl
It is another aspect of the present invention to provide a process for preparation of its intermediate, alkyl 2-isopropyl-4-pentenoate of formula (4) wherein the allyl

halide in step (a), is selected from allyl bromide or allyl chloride.
It is another aspect of the present invention to provide a process for preparation of its intermediate, alkyl-2-isopropyl-4-pentenoate of formula (4) wherein the base used in step (a) for preparation of compound of formula (3) is selected from sodium hydride, potassium hydride, and sodium methoxide.
It is another aspect of the present invention to provide a process for preparation of intermediate, alkyl-2-isopropy-4-pentenoate of formula (4) wherein the reaction in step (a) is carried out at a temperature of 0-40°C.
It is another aspect of the present invention to provide a process for preparation of its intermediate, alkyl 2-isopropyl-4-pentenoate of formula (4) wherein the aprotic solvent used in step (a) and step (b) is selected from the group comprising DMF, dimethylacetamide, DMSO and Sulfolane.
It is another aspect of the present invention to provide a process for preparation of its intermediate, alkyl 2-isopropyl-4-pentenoate of formula (4) the aprotic solvent used in step (a) is DMF and the aprotic solvent used in step (b) is DMSO.
It is another aspect of the present invention to provide a process for preparation is intermediate, alkyl 2-isopropyl-4-pentenoate of formula (4) wherein 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.
It is another aspect of the present invention to provide a process for preparation its intermediate, alkyl 2-isopropyl-4-pentenoate of formula (4) the alkali metal halide used in step (b) is sodium bromide (NaBr).
It is another aspect of the present invention to provide a process for preparation of its intermediate, alkyl 2-isopropyl-4-pentenoate of formula (4) wherein the reaction in step (b) is carried out at a temperature of 100-200°C.
It is another aspect of the present invention to provide a process for preparation its intermediate, alkyl 2-isopropyl-4-pentenoate of formula (4) wherein the dialkyl allylisopropylmalonate of formula (3) is selected from diethyl allylisopropylmalonate or dimethyl allylisopropylmalonate.
DETAILED DESCRIPTION OF THE INVENTION ?
A preferred embodiment of the present invention discloses an improved process for the preparation of Apronal namely allyl isopropyl acetyl urea of Formula (1)


Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are described here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person skilled in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The term "alkyl" refers to a monovalent straight or branched chain radical of from one to twenty-four carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.
According to an embodiment, the present disclosure relates to a simple process for the manufacture of Apronal, namely ally! isopropyl acetyl urea, represented herein as a compound of formula (1) which comprise of reacting alkyl 2-isopropyl-4-pentenoate formuIa-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), wherein the alkali metal is preferably selected from lithum, sodium and potassium, more preferably sodium, and in the presence of an aprotic polar solvent at 0-55°C preferably at 5-30°C most preferably 5-15°C.

Scheme-9

wherein the alkali metal, M = Na, K, Li, and
wherein the alkyl group R is selected from Methyl or Ethyl.
Preferred embodiments of the present invention, wherein the compound of Formula 4 is exemplified by R= CH3 (compound 4a) and R=C2H5 (compound 4b).

Another embodiment of the present invention is selection of Aprotic solvent or mixture of solvents selected from the group of solvents consisting of THF, DMF, DMSO, sulfolone ,dimethyl acetamide preferably TPTF and DMF most preferably

DMF.
Further embodiment of the present invention discloses a method for the preparation of sodium urea, a compound of formula-5 which comprises of reacting sodium hydride with urea in the presence of aprotic polar solvent or a mixture of solvent selected from the group consists THF DMF, DMSO, dimethylacetamide sulfolone, and toluene preferably THF and DMF most preferably DMF.
Third aspect of the present invention is that the alkali metal salt of urea of formula (5) used in the process is prepared and used without isolation or isolated in pure form and used in the process, preferably used without isolation.
The fourth aspect of the present invention is the preparation alkali metal salt of urea can be selected from the group consist of lithium urea, sodium urea and potassium urea preferably sodium urea.
The fifth aspect of the present invention is the preparation of alkyl 2-isopropyl-4-pentenoate a compound of formula-4 comprise of dealkoxy decarbonylation of dialkyl allylisopropylmalonate a compound of formula-3, wherein, the alkyl group or R is selected from methyl, ethyl or isopropyl, and using alkali metal halide in the presence of aprotic polar solvents at temperature ranging from 100-200°C as described in scheme-9.

Scheme-10

wherein the alkali metal halide selected from a group consist of sodium chloride, sodium bromide, potassium chloride, potassium bromide, lithium chloride, lithium bromide, calcium chloride, preferably selected from a group consist of lithium chloride, sodium bromide, potassium bromide most preferably sodium bromide.
wherein alkyl group in alkyl 2-isopropyl-4-pentenoate formula(4) means particularly ethyl or methyl.

wherein the aprotic solvent used in the step (a) is selected from the group comprising of THF, Toluene, DMF, dimethylacetamide, DMSO and Sulfolane and the step (b) is selected from the group comprisng of DMF, dimethylacetamide, DMSO and Sulfolane.
wherein dialkyl allylisopropylmalonate Formula (3) means particularly, diethyl allylisopropylmalonate or dimethyl allylisopropylmalonate.
Another embodiment of the present invention is the preparation of dialkyl allylisopropylmalonate, a compound of Formula (3), comprising of alkylating commercially available dialkylisopropylmalonate of Formula (2), wherein alkyl means ethyl or methyl; using a base sodium hydride in the presence of aprotic polar solvents at temperature preferably 0-40C more preferably 10-30°C. Scheme-11

Wherein aprotic solvent or mixture of solvents preferably selected from group of solvent consist THF DMF, DMSO, sulfolone, dimethyl acetamide, toluene preferably THF and DMF most preferably DMF.

EXAMPLES
Reference is now made to the following examples, which together with the above descriptions; illustrate the invention in a non limiting fashion. They provide the details about the synthesis of the compounds of the present disclosure. Tt should be understood the following is representative only, and that the invention is not limited by the details set forth in these examples.
EXAMPLE 1
Preparation of dimethyl-2-allyl-2-isopropylmalonte (Formula 3a)
To a solution of Sodium Hydridel6.5 gm (0.688 mole), in DMF 200ml, Dimethyl-
2-isopropylmalonte 100 gm (0.574 mole) was added slowly at 20-25C and the
stirred for 1 hour. To this solution Ally! bromide 83.3 gm (0.688 mole) was then
added at 20-25C and reaction mass temperature was increased to 40-45°C and was
maintained for 3-4 hours. On completion of the reaction, the reaction mass was
cooled to 25-30C. Sodium bromide was filtered. The filtered reaction mass slowly
added to pre-child water. The top oil layer was separated and weighed 115 gm
(yield 89.4%) GC purity 95%. This solution was directly taken to preparation of
methyl-2-isopropyl-4-pentenoate
EXAMPLE 2
Preparation of methyl-2-isopropyl-4-pentenoate (Formula 4a)
To a solution of Sodium bromide 96 gm (0.932 mole), in water 8.4 gm (0.466
mole) and dimethylformamide 200ml, dimethyl 2-allyl-2-isopropylmalonate 115

gm (crude from above) of was added. The reaction mixture temperature was raised to 140-160°C under stirring and maintained at that temperature for 12 hours. On completion of the reaction, the mass was cooled to 40°C, diluted with water 800gm and stirred for about 30 minutes. The top oily layer was separated. The pure methyl-2-isopropyl-4-pentenoatewas distilled under vacuum (at 10 mbar) at 75 - 80°C to yield 65 gm GC purity 99%.
EXAMPLE 3
Preparation of allyl isopropyl acetylurea (formula 1):
To a pre cooled (10-15C) solution Sodium Hydride 20 gm (0.833 mole) in dimethylformamide 200 ml, urea 57.6 gm (0.96 mole) was added slowly under stirring. The reaction temperature was maintained for 4 Hrs at 10 - 15°C. After complete formation sodium urea, 100 gm (0.64 mole) was added into the reaction mass under stirring slowly over a period of 2 hours at 10 - 15°C. Further the temperature was maintained at 10 - 15°C for 8 hours. After completion of the reaction, the reaction mass was added to pre cooled water (5 - 10°C) of 1400 ml. The precipitated allyl isopropyl acetyl urea was filtered out and washed with water 100 ml. This wet compound was slurred with xylene 500 ml, washed with 500 ml, of xylene and dried at 100 - 110°C to yield allyl isopropyl acetyl urea 90 gm (76.9% yield).

EXAMPLE 4
Preparation sodium urea (Formula 5):
Sodium urea was prepared as per 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 pre-cooled slurry of sodium urea 57.4g (0.7mole), in DMF 200ml, methyl-2-isopropyl-4-pentenoate100 gm (0.64 mole) was added into the reaction mass slowly under stirring over 2 hrs at 10 - 15°C. Further the temperature of the reaction was maintained at 10 - 15°C for 6-8 hours. After completion of the reaction, the reaction mass was transferred to pre cooled water (5-10°C) into 1400 ml. The precipitated allyl isopropyl acetyl urea was filtered out and washed with water 100 ml. This wet compound was slurred with xylene 500 ml, washed with water 500 ml, and dried at 100 - 110°C to yield 90 gm (76.9% yield).
EXAMPLE 6
Preparation of diethyl-2-allyl-2-isopropylmalonte (formula 3b)
To a solution of Sodium Hydride 16.5 gm (0.688 mole), in DMF 200ml, Dimethyl-2-isopropylmalonte 116.5 gm (0.574 mole) was added slowly at 20-25C and the stirred for 1 hour. To this solution Allyl bromide 83.3 gm (0.688 mole) was then added at 20-25C and reaction mass temperature was increased to 40-45°C and was

maintained for 3-4 hours. On completion of the reaction, the reaction mass was cooled to 25-30C. Sodium bromide was filtered. The filtered reaction mass slowly added to pre-chilled water. The top oil layer was separated, weighed 120 gm This solution was directly taken to preparation of ethyl-2-isopropyl-4-pentenoate.
EXAMPLE 7:
Preparation of ethyl-2-isopropyl-4-pentenoate (Formula 4b): To a solution of Sodium bromide 96 gm (0.932 mole), in water 8.4 gm (0.466 mole) and Dimethyl sulfoxide (DMSO) 200ml, diethyl 2-allyl-2-isopropylmalonate 120 gm (crude from above) of was added. The reaction mixture temperature was raised to 140-160°C under stirring and maintained at that temperature for 12 hr. On completion of the reaction, the mass was cooled to 40°C, diluted with water 800gm and stirred for about 30 minutes. The top oily layer was separated. The pure ethyl-2-isopropyl-4-pentenoatewas distilled under vacuum (at 10 mbar) at 75 - 80°C to yield 68 grams (89.1% in yield). GC purity 99%.
EXAMPLE 8:
Preparation of allyl isopropyl acetyl urea (formula 4):
To a pre cooled (10-15C) solution Sodium Hydride 20 gm (0.833 mole) in dimethyl formamide 200 ml, urea 57.6 gm (0.96 mole) was added slowly under stirring. The reaction temperature was maintained for 4 Hrs at 10-15°C. After complete formation sodium urea, ethyl-2-isopropyl-4-pentenoatel00 gm (0.64

mole) was added into the reaction mass under stirring slowly over a period of 2 hours at 10 - 15°C. Further the temperature was maintained at 10-15°C for 8 hours. After completion of the reaction, the reaction mass was transferred to pre cooled water (5 - 10°C) into 1400 ml. The precipitated allyl isopropyl acetyl urea was filtered out and washed with water 100 ml. This wet compound was slurried xylene 500 ml, washed with 500 ml,and dried at 100-110°C to yield allyl isopropyl acetyl urea 90 gm (76.9% yield).

WE CLAIM:
1. A process for preparation of Apronal (compound of Formula (1));

comprising of reacting 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 to get compound of Formula (1);

wherein M=Li or Na, or K, and wherein
wherein the alkyl group R is selected from Methyl or Ethyl.

2. The process for preparation of Apronal of (compound of Formula 1) as claimed in claim 1, wherein the aprotic polar solvent is selected from a group consisting of THF, methyl THF, dimethylacetamide, DMF, DMSO and Sulfolane.
3. The process for preparation of Apronal (compound of Formula 1) as claimed in claim 1, wherein the alkali metal salt is prepared and used without isolation or prepared and isolated in pure form.
4. The process for preparation of Apronal (compound of Formula 1) as claimed in claim 1, wherein the reaction is carried out at a temperature 0-55°C.
5. The process for preparation of Apronal (compound of Formula 1) as claimed in claim 1, wherein the compound of Formula (4) is prepared by a process comprising of following steps:
(a) reacting a compound dialkyl-2-isopropyl malonate of Formula (2) with ally] halide in the presence of base in aprotic polar solvent or mixture of solvents to get dialkyl allylisopropylmalonate Formula (3);

wherein, the alkyl group or R is selected from methyl, ethyl or Isopropyl,

(b) dealkoxy decarbonylation of dialkyl allylisopropylmalonate of formula (3) to prepare the compound alkyl 2-isopropyl-4-pentenoate formula (4) using an alkali metal halide in the presence of aprotic polar solvents;

wherein R is selected from group methyl, ethyl, isopropyl.
6. The process for preparation of the compound of Formula (4) as claimed in
claim 5, wherein the allyl halide in step (a), is selected from allyl bromide or allyl
chloride.
7. The process for preparation of the compound of Formula (4) as claimed in claim 5, wherein the base used in step (a) for preparation of compound of formula (3) is selected from sodium hydride, potassium hydride, and sodium methoxide.
8. The process for preparation of the compound of Formula (4) as claimed in claim 5, wherein the reaction in step (a) is carried out at a temperature of 5-40°C.

9. The process for preparation of the compound of Formula (4) as claimed in claim 5, wherein the aprotic solvent used in step (a) is selected from the group comprising DMF, dimethylacetamide, DMSO and Sulfolane.
10. The process for preparation of the compound of Formula (4) as claimed in claim 5, wherein the aprotic solvent used in step (b) is selected from the group comprising of DMF, dimethylacetamide, DMSO and Sulfolane.
11. The process for preparation of the compound of Formula (4) as claimed in claim 5, wherein the aprotic solvent used in step (a) is DMF.
12. The process for preparation of the compound of Formula (4) as claimed in claim 5, wherein the aprotic solvent used in step (b) is DMSO.
13. The process for preparation of the compound of Formula (4) as claimed in claim 5, wherein 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.
14. The process for preparation of the compound of Formula (4) as claimed in claim 5, wherein the alkali metal halide used in step (b) is sodium bromide (NaBr).

15. The process for preparation of the compound of Formula (4) as claimed in claim 5, wherein the reaction in step (b) is carried out at a temperature of 100-200°C.
16. The process for preparation of the compound of Formula (4) as claimed in claim 5, wherein the dialkyl allylisopropylmalonate of formula (3) is selected from diethyl allylisopropylmalonate or dimethyl ally] isopropylmalonate.