Title of Invention	PROCESS FOR THE PREPARATION OF METHYL-METHYL-3, 4-DIHYDRO-2H-PYRAN-5-CARBOXYLATE
Abstract	The present invention provides an improved process for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV), comprising the steps of: (i) alkylating l-Bromo-3-chloropropane of formula (I) with Methylacetoacetate of formula (II) to prepare haloketone of formula (VII) in presence of an alcoholic solvent; (ii) O-alkylating the compound of formula (VII) with sodium methoxide to obtain the desired molecule methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV) in its crude form; (iii) Purifying the content of step (ii) above by fractional distillation to obtain the purified molecule of formula (IV).

Title of Invention

PROCESS FOR THE PREPARATION OF METHYL-METHYL-3, 4-DIHYDRO-2H-PYRAN-5-CARBOXYLATE

Abstract

The present invention provides an improved process for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV), comprising the steps of: (i) alkylating l-Bromo-3-chloropropane of formula (I) with Methylacetoacetate of formula (II) to prepare haloketone of formula (VII) in presence of an alcoholic solvent; (ii) O-alkylating the compound of formula (VII) with sodium methoxide to obtain the desired molecule methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV) in its crude form; (iii) Purifying the content of step (ii) above by fractional distillation to obtain the purified molecule of formula (IV).

Full Text	FORM - 2 THE PATENTS ACT, 1970 (39 of 1970} COMPLETE SPECIFICATION (See section 10; rule 13) A PROCESS FOR THE PREPARATION OF METHYL-METHYL-3, 4-DIHYDRO-2H-PYRAN-5-CARBOXYLATE SPC Lifesciences Pvt. Ltd., A Company Incorporated Under The Indian Companies Act, Having its registered address at 284/1, 2, 3 GIDC, Makarpura, Vadodara- 390 010, Gujarat, INDIA. The following specification particularly describes the nature of the invention and the manner in which it is to be performed: FIELD OF THE INVENTION The present invention relates to a simple, economical, environment friendly and improved process for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV) which finds use as an intermediate in the synthesis of the main compound 6-chlorohexanone of formula (V). BACKGROUND OF INVENTION Methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV) is alternatively named as methyl 3,4-dihydro-6-methyl-2H-pyran-5-carboxylate or 2H-pyran-5-carboxylic acid, 3,4-dihydro-6-methyl-, methyl ester or 5,6-dihydro-3-methoxycarbonyl-2-methyl-4H-pyran. There has not been much research carried out in the field for the preparation of the said compound. However, such a compound finds extensive use as an intermediate in the in the synthesis of the main compound 6-chlorohexanone of formula (V) which is an important component in the preparation of pharmaceutically active ingredient pentoxyfyline. PRIOR ART The US Pat. No. 3422107 discloses a process for the preparation of the said compound of formula (IV) under the title "certain oxoalkyldimethylxanthines and a process for the preparation thereof. The said prior art discloses and claims a process of production of a compound oxoalkyldimethylxanthines which is distinguished by a marked vaso-dilatory effect with low toxicity. The said compound as produced by the process is readily soluble in water and lipids. Thus, the said product has wide applications in the therapeutic uses. As a part of the whole reaction scheme in the said prior art, the said compound of formula (IV) is produced as an intermediate compound from mixing of the reactants 560.0g of potassium carbonate, 700.0ml of ethanol, 404.0g of 1,3-dibromo propane and 260.0g of ethylacetoacetate and heated at 60°C. After the reaction subsides, the reaction mixture is refluxed for 5 hours. The bulk of alcohol is distilled under ordinary pressure. The residue is mixed with 1500.0 ml of water. The resulting oily layer is separated, and the aqueous phase is extracted with benzene. The benzene layer obtained is mixed with the oil. After drying with sodium sulphate, benzene is distilled off and the residue is fractionally distilled. Hence, 250.0g of 2-methyi-3-carbethoxy-5, 6-dihydropyrane is obtained. Keeping in view the viability of the above mentioned process for the preparation of compound of formula (IV), and recognizing the importance of this compound as an important intermediate in the synthesis of compound of formula (V), certainly a need was felt for meeting the requirements of lowering the cost, and protecting the ecology from pollution, as caused in the prior art during the process of preparation of the compound of formula (IV). DISADVANTAGES OF THE PRIOR ART (i) The major disadvantage of the prior art invention is that vigorous treatments have to be given to the effluent to make it free from all hazardous chemicals which make the it less efficient; (ii) The effluent is produced in large quantities and it becomes very cumbersome to dispose off the same; (iii) Large amount of water is required during the reaction so as to dissolve the salts that are formed during the reaction; (iv) There is no recovery of the solvent after use; (v) The raw materials used are costly and not easily available; (vi) To perform the reaction steps at commercial level becomes very-expensive and time consuming; and (vii) The use of class-I solvent (benzene) for the extraction of the desired compound of formula (IV) which is highly carcinogenic and environmentally unsafe. OBJECTS OF THE PRESENT INVENTION The main object of the present invention is to devise a method for the preparation of methyl-methyl-3,4-dihydro-2H- pyran-5- carboxylate which produces four times lesser effluent. The other object of the present invention is to invent a method for the preparation of methyl-methyl-3, 4-dihydro-2H- pyran-5-carboxylate which utilizes sodium methoxide requiring very less quantity of water for dissolving the salts produced during the reaction. The other object of the present invention is to design a method for the preparation of methyl-methyl-3, 4-dihydro-2H- pyran-5-carboxylate during which the solvent used is recovered and reused. The other object of the present invention is to develop a method for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate without using any solvent during its extraction which makes the process simple, economical and eco- friendly. The other object of the present invention is to propose a method for the preparation of methylmethyl-3,4-dihydro-2H-pyran-5-carboxylate which uses readily and easily available raw materials. The other object of the present invention is to propose a method for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate that can be suitable for commercial manufacturing. ADVANTAGES OF THE PRESENT INVENTION i. The process for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate in accordance to present invention is carried out in the presence of sodium methoxide instead of potassium carbonate, which is having lower molecular weight that requires less quantities of water for dissolving the same. It is also proposed that, sodium methoxide which is used as a reactant having molecular weight which is 2.5 times less than Potassium carbonate, thus less salt is formed during the present invention process. The quantity of sodium methoxide of formula (III) required is significantly less than that of potassium carbonate making the process economical. ii. Again in the process of the present invention, the generated solvent along with the final product is recovered by distillation and reused further in next batch of the process in production of compound of formula (IV) thus making the process more efficient and economical. iii. In the present invention less salt is produced which requires less water for dissolving these salts and thus generates almost four times less effluent in comparison with the process involving potassium carbonate making the process environment friendly. The various aspects of the proposed process make it novel, simpler and easier to handle on commercial scale. iv. In the present invention, there is no catalyst required to drive the reaction in forward direction, as the addition of sodium methoxide itself makes the reaction an exothermic reaction. SUMMARY OF THE INVENTION In order to achieve the foregoing objects, the present invention provides an improved process for the preparation of methyI-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV), comprising the steps of: (i) alkylating l-Bromo-3-chloropropane of formula (I) with Methylacetoacetate of formula (II) to prepare haloketone of formula (VII) in presence of an alcoholic solvent; (ii) O-alkylating the compound of formula (VII) with sodium methoxide to obtain the desired molecule methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV) in its crude form; (iii) Purifying the content of step (ii) above by fractional distillation to obtain the purified molecule of formula (IV). DETAIL DESCRIPTION OF THE INVENTION With extensive research, the applicant has come out with a path breaking technology which is a simple and economical process for the preparation of compound of formula (IV) taking into account the key features like: a. avoiding the usage of excess quantity of potassium carbonate; b. minimizing the effluents; c. using readily and easily available raw materials; d. developing a process, which can be suitable and feasible for commercial manufacturing. The present invention for which the applicant sought protection is an improved and novel process for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-Carboxylate of Formula (IV) which is a useful intermediate in the synthesis of 6-chlorohexanone of Formula (V). Accordingly, we have developed an improved process for the preparation of the compound of formula (IV), which is schematically illustrated in the Scheme-I as given below: Here, l-Bromo-3-chloropropane is the key raw material for carrying out the condensation reaction. Methyl acetoacetate is used as an active methylene compound for the condensation reaction. Also sodium methoxide is used as the reactant. The reaction steps involved in the present invention can be summarized as: (1) Preparation of the requisite side chain starting with condensation of l-Bromo-3-chloropropane of formula (I) with methylacetoacetate of formula (II) to prepare haloketone of formula (VII). (2) The haloketone of formula (VII) undergoes 0-alkylation with sodium methoxide under variable reaction conditions to give the desired molecule methyl-methyl-3, 4-dihydro-2H-pyran-5-carboxylate of formula (IV) in crude form, with simultaneous production of methanol. (3) The crude molecule Methyl-methyl-3, 4-dihydro-2H-pyran-5-carboxylate of Formula (IV) is then purified by fractional distillation. In this improved process, the reaction is carried out in the presence of alcoholic solvent selected from the groups of methyl alcohol, ethyl alcohol, isopropyl alcohol or n-propanol, pentanol, hexanol, propanol and preferably methyl alcohol. The said improved process can be carried out using sodium methoxide (Na-O-CH3) in solution suitably selected from aliphatic alcohols with C1 to C6 carbon atoms and preferably methyl alcohol as well as in powder form. During the condensation of compound of formula [I) and compound of formula (II) and cyclisation of the haloketone of formula (VII) in the presence of sodium methoxide of formula (III), methanol is also produced stoichiometrically. This amount of methanol is recovered back along with the initial amount of methanol that was used at the start of the reaction. The recovered methanol as produced at the end of each batch is distilled and is reused in the next batches, so that there is no requirement of methanol to be added in further batches. This makes the reaction significantly economical and eco-friendly. In this process, the temperature of the reaction is maintained between the ranges 0°C- 95°C. Sodium methoxide is used in the present invention which has 2.5 times lower molecular weight than potassium carbonate (K2CO3) used in the prior art. Thus the salts formed are also less, resulting into a decreased water requirement for dissolving the salts. Hence, the quantity of effluent generated is also minimized. The reaction need not be always operated under a nitrogen atmosphere except while adding sodium methoxide to the reaction vessel. It is also seen that the reaction is operated in absence of catalyst due to the exothermic condition of the reaction while adding sodium methoxide to the reactants during the course of the reaction. The present invention does not require any solvent for the extraction of compound of formula (IV) that makes the process simple, economical and eco-friendly. The instant invention [an improved process for preparation of a compound of formula (IV)] and the manner in which it is to be performed is described in details below with working examples and is by way of illustration only. Therefore, these examples should not be construed to limit the scope of invention as illustrated below. EXAMPLE - 1 To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 160.0g (2.96mol) of sodium methoxide in powder form is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C (limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is EXAMPLE-2 To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 184.0g (3.4mol) of sodium methoxide in powder form is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C(limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is reaction. Finally, 205.0g of purified compound of formula (IV) is obtained. The end product obtained in the present invented process is in liquid state having relative density of 1.1. EXAMPLE-3 To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 208.0g (3.84mol) of sodium methoxide in powder form is slowly added in installments 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C (limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is EXAMPLE-4 To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 240.0g (4.44mol) of sodium methoxide in powder form is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C (limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is EXAMPLE-5 To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 280.0g (5.18mol) of sodium methoxide in powder form is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70cC(limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is EXAMPLE-6 To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315,0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 800.0g of 20% sodium methoxide (2.96mol) in alcoholic solvent like Methyl alcohol is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C (limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is <:90 thus before reusing the solvent it is obtained in pure form of nlt again by fractional distillation for next batch reaction. finally purified compound formula obtained. end product present invented process liquid state having relative density> EXAMPLE-7 To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chIoropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 640.0g of 25% sodium methoxide (2.96mol) in alcoholic solvent like Methyl alcohol is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C (limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is EXAMPLE-8 To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 290.0g (2.5mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 160.0g (2.96mol) of sodium methoxide in powder form is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C(limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is We would like to draw a generalized data sheet on the above experiments by varying the amount of the reactants and solvents, in a tabular form as a means of optimization of the process parameters for large scale manufacture of the compound of formula (IV) in industrial scale. Exampl Alcoholic 1-Bromo- Methyl Sodium Water Purified es solution 3- acetoace methoxide product chloropro pane tate Example 780.0 ml 315.0g or 250.0g or 160.0g or 315.0g 250.0g - 1 2mol. 2.15mol 2.96mol Example 780.0 ml 315.0g 250.0g/ 184.0g or 315.0g 205.0g -2 3.4mol Example 780.0 ml 315.0g 250.0g/ 208.0g or 315.0g 196.0g -3 3.84mol Example 780.0 ml 315.0g 250.0g/ 240.0g or 315.0g 188.0g -4 4.44mol Example 780.0 ml 315.0g 250.0g/ 280.0g or 315.0g 164.0g -5 5.l8mol Example 780.0 ml 315.0g 250.0g/ 800.0g of 315.0g 248.0g -6 20% or 2.96mol Example 780.0 ml 315.0g 250.0g/ 640.0g of 315.0g 247.0g -7 25% or 2.96mol Example 780.0 ml 315.0g 290.0g/2. 160.0g or 315.0g 238.0g -8 5mol 2.96mol From all the experiments performed in examples 1-8, by varying the reaction parameters, we observed that increase in amount/loading of sodium methoxide (as shown in examples 1 to 6) compared to other reactants has a negative impact (i.e. decrease) on the yield of the final product. The same trend is also observed in case of the reactant methyl acetoacetate as observed in example 8. Also the impact of additional solvent (during addition of sodium methoxide in alcoholic solvent) as seen from examples 6 and 7 has nothing to do with the yield of the final product. The best yield of the final purified product is obtained in examples 1, 6 and 7. In our large scale/commercial manufacturing process the ratios of the reactants in examples 1, 6 and 7, most preferably in example 1 will be adhered to. We have drawn a comparative result on the process of the prior art invention US3422107 and our instant invention in a tabular form and find a marked difference between these two processes. COMPARATIVE TABLE Patented prior art process Raw material Input qty Product Effluent generation l-Bromo-3-chloropropane 315g. 250g. 1900g. Methyl-acetoacetate 250g. Potassium carbonate 560g. Water 1500ml Instant invented process l-Bromo-3-chloropropane 315g. 250g. 450g. Methyl- ace toace tate 250g. Sodium methoxide 160g. Water 315ml In this process generated solvent is re used in further batches. From this comparison we establish that the instant invention is improved and effective in many aspects over the prior art process. The prior art process requires vigorous treatments to the effluent to make it free from all hazardous chemicals which makes the process less efficient. The effluent is produced in large quantities and it becomes very cumbersome to dispose off the same if the process is operated in commercial scale. Large amount of water is required during the reaction so as to dissolve the salts that are formed during the reaction and there is there is no recovery of the solvent after use. The present invention for which protection is sought does not require any additional solvent for the extraction of the desired compound/product that makes the process simple, economical and eco-friendly. In the prior art the alcoholic solvent used in the reaction is not mentioned to be reused further. In contrast, the solvent is generated in the present invention due to the compound of formula (III) i.e. sodium methoxide, thereby reducing the consumption of solvent and consequently making the process cost effective. The disclosed invention does not suffer from any drawbacks and is very environment friendly. WE CLAIM: 1. An improved process for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV), comprising the steps of: (i) alkylating l-Bromo-3-chloropropane of formula (I) with Methylacetoacetate of formula (II) to prepare haloketone of formula (VII) in presence of an alcoholic solvent; (ii) O-alkylating the compound of formula (VII) with sodium methoxide to obtain the desired molecule methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV) in its crude form; (iii) Purifying the content of step (ii) above by fractional distillation to obtain the purified molecule of formula (IV). 2. The process as claimed in claim 1, wherein the alcoholic solvents are selected from the groups of methyl alcohol, ethyl alcohol, isopropyl alcohol or n-propanol. 3. The process as claimed in claim 1 or 2, wherein the alcoholic solvent is most preferably, methyl alcohol. 4. The process as claimed above, wherein sodium methoxide is employed in step (ii) of claim 1 as dry powder or in solution suitably selected from aliphatic alcohols with C1 to C6 carbon atoms. 5. The process as claimed in claim 1, wherein the molar ratios of the reactants l-Bromo-3-chloropropane, methylacetoacetate and sodium methoxide are maintained in the ratios of 1: 1.07: 1.48 to 1: 1.25: 2.59. 6. The process as claimed in any of the proceeding claims, wherein sodium methoxide added in step (ii) of claim 1 is preferably employed in powder form. 7. The process as claimed in claim 1, wherein a nitrogen atmosphere is maintained only during addition of sodium methoxide. 8. The process as claimed in claim 1, which comprises fractional distillation of the crude product wherein the solvent is regenerated for its reuse in further batches. 9. The process as claimed in claim 1, wherein the solvent is produced stoichiometrically during the condensation and cyclisation of formula [I) and compound of formula (II) and cyclisation of the haloketone of formula (VII) in the presence of sodium methoxide of formula (III), is recovered back along with the initial amount of methanol, is distilled and reused in the further batches. 10. The process as claimed in claim 1, wherein the temperature of the reaction in each step is maintained between the ranges 0°C- 95°C. 11. The process as claimed in claim 1, wherein the end product obtained after fractional distillation is in liquid state having a relative density of 1.1.

Full Text

FORM - 2
THE PATENTS ACT, 1970 (39 of 1970}
COMPLETE SPECIFICATION
(See section 10; rule 13)
A PROCESS FOR THE PREPARATION OF METHYL-METHYL-3, 4-DIHYDRO-2H-PYRAN-5-CARBOXYLATE
SPC Lifesciences Pvt. Ltd.,
A Company Incorporated Under The Indian Companies Act,
Having its registered address at 284/1, 2, 3 GIDC, Makarpura,
Vadodara- 390 010, Gujarat, INDIA.
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to a simple, economical, environment friendly and improved process for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV) which finds use as an intermediate in the synthesis of the main compound 6-chlorohexanone of formula (V).

BACKGROUND OF INVENTION
Methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV) is alternatively named as methyl 3,4-dihydro-6-methyl-2H-pyran-5-carboxylate or 2H-pyran-5-carboxylic acid, 3,4-dihydro-6-methyl-, methyl ester or 5,6-dihydro-3-methoxycarbonyl-2-methyl-4H-pyran. There has not been much research carried out in the field for the preparation of the said compound. However, such a compound finds extensive use as an intermediate in the in the synthesis of the main compound 6-chlorohexanone of formula (V) which is an important component in the preparation of pharmaceutically active ingredient pentoxyfyline.
PRIOR ART
The US Pat. No. 3422107 discloses a process for the preparation of the said compound of formula (IV) under the title "certain oxoalkyldimethylxanthines and a process for the preparation thereof. The said prior art discloses and claims a process of production of a

compound oxoalkyldimethylxanthines which is distinguished by a marked vaso-dilatory effect with low toxicity. The said compound as produced by the process is readily soluble in water and lipids. Thus, the said product has wide applications in the therapeutic uses.
As a part of the whole reaction scheme in the said prior art, the said compound of formula (IV) is produced as an intermediate compound from mixing of the reactants 560.0g of potassium carbonate, 700.0ml of ethanol, 404.0g of 1,3-dibromo propane and 260.0g of ethylacetoacetate and heated at 60°C. After the reaction subsides, the reaction mixture is refluxed for 5 hours. The bulk of alcohol is distilled under ordinary pressure. The residue is mixed with 1500.0 ml of water. The resulting oily layer is separated, and the aqueous phase is extracted with benzene. The benzene layer obtained is mixed with the oil. After drying with sodium sulphate, benzene is distilled off and the residue is fractionally distilled. Hence, 250.0g of 2-methyi-3-carbethoxy-5, 6-dihydropyrane is obtained.
Keeping in view the viability of the above mentioned process for the preparation of compound of formula (IV), and recognizing the importance of this compound as an important intermediate in the synthesis of compound of formula (V), certainly a need was felt for meeting the requirements of lowering the cost, and protecting the ecology from pollution, as caused in the prior art during the process of preparation of the compound of formula (IV).
DISADVANTAGES OF THE PRIOR ART
(i) The major disadvantage of the prior art invention is that vigorous treatments have to be given to the effluent to make it free from all hazardous chemicals which make the it less efficient;

(ii) The effluent is produced in large quantities and it becomes very cumbersome to dispose off the same;
(iii) Large amount of water is required during the reaction so as to dissolve the salts that are formed during the reaction; (iv) There is no recovery of the solvent after use; (v) The raw materials used are costly and not easily available; (vi) To perform the reaction steps at commercial level becomes very-expensive and time consuming; and
(vii) The use of class-I solvent (benzene) for the extraction of the desired compound of formula (IV) which is highly carcinogenic and environmentally unsafe.
OBJECTS OF THE PRESENT INVENTION
The main object of the present invention is to devise a method for the preparation of methyl-methyl-3,4-dihydro-2H- pyran-5- carboxylate which produces four times lesser effluent.
The other object of the present invention is to invent a method for the preparation of methyl-methyl-3, 4-dihydro-2H- pyran-5-carboxylate which utilizes sodium methoxide requiring very less quantity of water for dissolving the salts produced during the reaction.
The other object of the present invention is to design a method for the preparation of methyl-methyl-3, 4-dihydro-2H- pyran-5-carboxylate during which the solvent used is recovered and reused.
The other object of the present invention is to develop a method for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate without using any solvent during its extraction which makes the process simple, economical and eco- friendly.

The other object of the present invention is to propose a method for the preparation of methylmethyl-3,4-dihydro-2H-pyran-5-carboxylate which uses readily and easily available raw materials.
The other object of the present invention is to propose a method for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate that can be suitable for commercial manufacturing.
ADVANTAGES OF THE PRESENT INVENTION
i. The process for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate in accordance to present invention is carried out in the presence of sodium methoxide instead of potassium carbonate, which is having lower molecular weight that requires less quantities of water for dissolving the same. It is also proposed that, sodium methoxide which is used as a reactant having molecular weight which is 2.5 times less than Potassium carbonate, thus less salt is formed during the present invention process. The quantity of sodium methoxide of formula (III) required is significantly less than that of potassium carbonate making the process economical.
ii. Again in the process of the present invention, the generated solvent along with the final product is recovered by distillation and reused further in next batch of the process in production of compound of formula (IV) thus making the process more efficient and economical.
iii. In the present invention less salt is produced which requires less water for dissolving these salts and thus generates almost four times less effluent in comparison with the process involving potassium carbonate making the process environment friendly. The various aspects of the proposed process make it novel, simpler and easier to handle on commercial scale.

iv. In the present invention, there is no catalyst required to drive the reaction in forward direction, as the addition of sodium methoxide itself makes the reaction an exothermic reaction.
SUMMARY OF THE INVENTION
In order to achieve the foregoing objects, the present invention provides an improved process for the preparation of methyI-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV), comprising the steps of:

(i) alkylating l-Bromo-3-chloropropane of formula (I) with Methylacetoacetate of formula (II) to prepare haloketone of formula (VII) in presence of an alcoholic solvent;

(ii) O-alkylating the compound of formula (VII) with sodium methoxide to obtain the desired molecule methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV) in its crude form;

(iii) Purifying the content of step (ii) above by fractional distillation to obtain the purified molecule of formula (IV).

DETAIL DESCRIPTION OF THE INVENTION
With extensive research, the applicant has come out with a path breaking technology which is a simple and economical process for the preparation of compound of formula (IV) taking into account the key features like:
a. avoiding the usage of excess quantity of potassium carbonate;
b. minimizing the effluents;
c. using readily and easily available raw materials;
d. developing a process, which can be suitable and feasible for
commercial manufacturing.
The present invention for which the applicant sought protection is an improved and novel process for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-Carboxylate of Formula (IV) which is a useful intermediate in the synthesis of 6-chlorohexanone of Formula (V).

Accordingly, we have developed an improved process for the preparation of the compound of formula (IV), which is schematically illustrated in the Scheme-I as given below:

Here, l-Bromo-3-chloropropane is the key raw material for carrying out the condensation reaction. Methyl acetoacetate is used as an active methylene compound for the condensation reaction. Also sodium methoxide is used as the reactant.
The reaction steps involved in the present invention can be summarized as:
(1) Preparation of the requisite side chain starting with condensation of l-Bromo-3-chloropropane of formula (I) with methylacetoacetate of formula (II) to prepare haloketone of formula (VII).

(2) The haloketone of formula (VII) undergoes 0-alkylation with sodium methoxide under variable reaction conditions to give the desired molecule methyl-methyl-3, 4-dihydro-2H-pyran-5-carboxylate of formula (IV) in crude form, with simultaneous production of methanol.

(3) The crude molecule Methyl-methyl-3, 4-dihydro-2H-pyran-5-carboxylate of Formula (IV) is then purified by fractional distillation.

In this improved process, the reaction is carried out in the presence of alcoholic solvent selected from the groups of methyl alcohol, ethyl alcohol, isopropyl alcohol or n-propanol, pentanol, hexanol, propanol and preferably methyl alcohol. The said improved process can be carried out using sodium methoxide (Na-O-CH3) in solution suitably selected from aliphatic alcohols with C1 to C6 carbon atoms and preferably methyl alcohol as well as in powder form. During the condensation of compound of formula [I) and compound of formula (II) and cyclisation of the haloketone of formula (VII) in the presence of sodium methoxide of formula (III), methanol is also produced stoichiometrically. This amount of methanol is recovered back along with the initial amount of methanol that was used at the start of the reaction. The recovered methanol as produced at the end of each batch is distilled and is reused in the next

batches, so that there is no requirement of methanol to be added in further batches. This makes the reaction significantly economical and eco-friendly.
In this process, the temperature of the reaction is maintained between the ranges 0°C- 95°C. Sodium methoxide is used in the present invention which has 2.5 times lower molecular weight than potassium carbonate (K2CO3) used in the prior art. Thus the salts formed are also less, resulting into a decreased water requirement for dissolving the salts. Hence, the quantity of effluent generated is also minimized. The reaction need not be always operated under a nitrogen atmosphere except while adding sodium methoxide to the reaction vessel. It is also seen that the reaction is operated in absence of catalyst due to the exothermic condition of the reaction while adding sodium methoxide to the reactants during the course of the reaction. The present invention does not require any solvent for the extraction of compound of formula (IV) that makes the process simple, economical and eco-friendly.
The instant invention [an improved process for preparation of a compound of formula (IV)] and the manner in which it is to be performed is described in details below with working examples and is by way of illustration only. Therefore, these examples should not be construed to limit the scope of invention as illustrated below.
EXAMPLE - 1
To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 160.0g (2.96mol) of sodium methoxide in powder form is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction

mass immediately increases. The reaction is maintained at a reflux temperature of 70°C (limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is EXAMPLE-2
To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 184.0g (3.4mol) of sodium methoxide in powder form is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C(limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is
reaction. Finally, 205.0g of purified compound of formula (IV) is obtained. The end product obtained in the present invented process is in liquid state having relative density of 1.1.
EXAMPLE-3
To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 208.0g (3.84mol) of sodium methoxide in powder form is slowly added in installments 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C (limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is EXAMPLE-4
To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 240.0g (4.44mol) of sodium methoxide in powder form is slowly added in installments at 30-40°C under

nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C (limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is EXAMPLE-5
To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 280.0g (5.18mol) of sodium methoxide in powder form is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70cC(limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity

is EXAMPLE-6
To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315,0g (2.0mol) of l-bromo-3-chloropropane and 250.0g (2.15mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 800.0g of 20% sodium methoxide (2.96mol) in alcoholic solvent like Methyl alcohol is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C (limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is <:90 thus before reusing the solvent it is obtained in pure form of nlt again by fractional distillation for next batch reaction. finally purified compound formula obtained. end product present invented process liquid state having relative density> EXAMPLE-7
To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chIoropropane and 250.0g (2.15mol) of methyl

acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 640.0g of 25% sodium methoxide (2.96mol) in alcoholic solvent like Methyl alcohol is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C (limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is EXAMPLE-8
To 780.0 ml of alcoholic solvent preferably methyl alcohol, 315.0g (2.0mol) of l-bromo-3-chloropropane and 290.0g (2.5mol) of methyl acetoacetate is charged at 30-40°C without maintaining nitrogen atmosphere. To the said content, 160.0g (2.96mol) of sodium methoxide in powder form is slowly added in installments at 30-40°C under nitrogen atmosphere. Maintaining a nitrogen atmosphere has been necessary since the reaction is exothermic, temperature of the reaction mass immediately increases. The reaction is maintained at a reflux temperature of 70°C(limit) for 10-12 hours, preferably 6-8 hour and the reaction mass is cooled to 55-60°C. About 315.0g of water is charged at this stage at atmospheric pressure so as to dissolve all the salts in water

that are formed at the time of reaction. Fractional distillation of the crude product gives unreacted compound of formula (I) and the solvent used in the reaction which is methyl alcohol. The solvent methyl alcohol recovered by fractional distillation is not in the pure form and its purity is We would like to draw a generalized data sheet on the above experiments by varying the amount of the reactants and solvents, in a tabular form as a means of optimization of the process parameters for large scale manufacture of the compound of formula (IV) in industrial scale.

Exampl Alcoholic 1-Bromo- Methyl Sodium Water Purified
es solution 3- acetoace methoxide product
chloropro pane tate
Example 780.0 ml 315.0g or 250.0g or 160.0g or 315.0g 250.0g
- 1 2mol. 2.15mol 2.96mol
Example 780.0 ml 315.0g 250.0g/ 184.0g or 315.0g 205.0g
-2 3.4mol
Example 780.0 ml 315.0g 250.0g/ 208.0g or 315.0g 196.0g
-3 3.84mol
Example 780.0 ml 315.0g 250.0g/ 240.0g or 315.0g 188.0g
-4 4.44mol
Example 780.0 ml 315.0g 250.0g/ 280.0g or 315.0g 164.0g
-5 5.l8mol
Example 780.0 ml 315.0g 250.0g/ 800.0g of 315.0g 248.0g
-6 20% or

2.96mol
Example 780.0 ml 315.0g 250.0g/ 640.0g of 315.0g 247.0g
-7 25% or 2.96mol
Example 780.0 ml 315.0g 290.0g/2. 160.0g or 315.0g 238.0g
-8 5mol 2.96mol
From all the experiments performed in examples 1-8, by varying the reaction parameters, we observed that increase in amount/loading of sodium methoxide (as shown in examples 1 to 6) compared to other reactants has a negative impact (i.e. decrease) on the yield of the final product. The same trend is also observed in case of the reactant methyl acetoacetate as observed in example 8. Also the impact of additional solvent (during addition of sodium methoxide in alcoholic solvent) as seen from examples 6 and 7 has nothing to do with the yield of the final product. The best yield of the final purified product is obtained in examples 1, 6 and 7. In our large scale/commercial manufacturing process the ratios of the reactants in examples 1, 6 and 7, most preferably in example 1 will be adhered to.
We have drawn a comparative result on the process of the prior art invention US3422107 and our instant invention in a tabular form and find a marked difference between these two processes.
COMPARATIVE TABLE

Patented prior art process
Raw material Input
qty Product Effluent generation
l-Bromo-3-chloropropane 315g. 250g. 1900g.
Methyl-acetoacetate 250g.

Potassium carbonate 560g.
Water 1500ml

Instant invented process
l-Bromo-3-chloropropane 315g. 250g. 450g.
Methyl- ace toace tate 250g.

Sodium methoxide 160g.

Water 315ml

In this process generated solvent is re used in further batches.
From this comparison we establish that the instant invention is improved and effective in many aspects over the prior art process. The prior art process requires vigorous treatments to the effluent to make it free from all hazardous chemicals which makes the process less efficient. The effluent is produced in large quantities and it becomes very cumbersome to dispose off the same if the process is operated in commercial scale. Large amount of water is required during the reaction so as to dissolve the salts that are formed during the reaction and there is there is no recovery of the solvent after use. The present invention for which protection is sought does not require any additional solvent for the extraction of the desired compound/product that makes the process simple, economical and eco-friendly. In the prior art the alcoholic solvent used in the reaction is not mentioned to be reused further. In contrast, the solvent is generated in the present invention due to the compound of formula (III) i.e. sodium methoxide, thereby reducing the consumption of solvent and consequently making the process cost effective. The disclosed invention does not suffer from any drawbacks and is very environment friendly.

WE CLAIM:
1. An improved process for the preparation of methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV), comprising the steps of:

(i) alkylating l-Bromo-3-chloropropane of formula (I) with Methylacetoacetate of formula (II) to prepare haloketone of formula (VII) in presence of an alcoholic solvent;

(ii) O-alkylating the compound of formula (VII) with sodium methoxide to obtain the desired molecule methyl-methyl-3,4-dihydro-2H-pyran-5-carboxylate of formula (IV) in its crude form;

(iii) Purifying the content of step (ii) above by fractional distillation to obtain the purified molecule of formula (IV).

2. The process as claimed in claim 1, wherein the alcoholic solvents are
selected from the groups of methyl alcohol, ethyl alcohol, isopropyl
alcohol or n-propanol.
3. The process as claimed in claim 1 or 2, wherein the alcoholic solvent is most preferably, methyl alcohol.
4. The process as claimed above, wherein sodium methoxide is employed in step (ii) of claim 1 as dry powder or in solution suitably selected from aliphatic alcohols with C1 to C6 carbon atoms.
5. The process as claimed in claim 1, wherein the molar ratios of the reactants l-Bromo-3-chloropropane, methylacetoacetate and sodium methoxide are maintained in the ratios of 1: 1.07: 1.48 to 1: 1.25: 2.59.
6. The process as claimed in any of the proceeding claims, wherein sodium methoxide added in step (ii) of claim 1 is preferably employed in powder form.
7. The process as claimed in claim 1, wherein a nitrogen atmosphere is
maintained only during addition of sodium methoxide.
8. The process as claimed in claim 1, which comprises fractional distillation of the crude product wherein the solvent is regenerated for its reuse in further batches.
9. The process as claimed in claim 1, wherein the solvent is produced stoichiometrically during the condensation and cyclisation of formula [I) and compound of formula (II) and cyclisation of the haloketone of formula (VII) in the presence of sodium methoxide of formula (III), is

recovered back along with the initial amount of methanol, is distilled and reused in the further batches.
10. The process as claimed in claim 1, wherein the temperature of the reaction in each step is maintained between the ranges 0°C- 95°C.
11. The process as claimed in claim 1, wherein the end product obtained after fractional distillation is in liquid state having a relative density of 1.1.

PROCESS FOR THE PREPARATION OF METHYL-METHYL-3, 4-DIHYDRO-2H-PYRAN-5-CARBOXYLATE

Documents:

Inventors:

PCT Conventions: