FIELD OF THE INVENTION
The present invention relates to a process for 4-chlorobutyraldehyde diethyl acetal, which comprises of reacting 4-chlorobutyraldehyde with triethyl orthoformate in presence of ethanol and tetrabutyll ammonium bromide at room temeperature with ease and safety at low costs. The process finds its scope in the synthesis of triptans such as sumatriptan, almotriptan and zolmetriptan etc.
BACKGROUND OF THE INVENTION
The synthesis of 4-chlorobutyraldehyde diethyl acetal was first reported by Loftfield et al (JACS, 1951, 73, 1356) which involves reaction of 4-chlorobutyraldehyde with ethanol in presence of CaCl2 to obtain the diacetal. Further the preparation was reported by Grandberg et al. (Izvestiya Timiryazevskoi Sel''skokhozyaistvennoi Akademii (1974), (6), 198-204).
U.S. Pat. Appl. Publ. 20040192958 describes a process for prepg. an enol ester of a 4-halobutyraldehyde (e.g., 1-acetoxy-4-chloro-1-butene), which comprises contacting cyclopropanecarboxaldehyde and a carboxylic acid halide (e.g., acetyl chloride) in the presence of a Lewis acid catalyst (e.g., zinc chloride). Acetals of 4-halobutyraldehyde (e.g., 4-chlorobutyraldehyde di-Me acetal) are prepd. by contacting an enol ester of a 4-halobutyraldehyde with an alc. (e.g., methanol) in the presence of a acid cation-exchanger catalyst (e.g., Amberlyst 15).

Hyatt et al have further reported in Organic Preparations and Procedures International (2004), 36(5), 487-490 that 4-Halobutyraldehyde acetals, X(CH2)3CH(OR)2 (X = Cl, R = Me, Et; X = Br, R = Me), were prepd. via a coupling reaction of cyclopropanecarboxaldehyde with the corresponding acetyl halides, MeCOX, using ZnCl2 in EtOAc to form the intermediate acetates, X(CH2)2CH:CHOCOMe, and subsequent reaction of the acetates with the corresponding alcs. ROH and Amberlyst-15 acidic ion-exchange resin catalyst to give the desired acetals in 74%, 71% and 65% yields, respectively.

Sarma et al. have reported an improved manufg. Process, which was developed by performing the reaction of 4-chloro butaraldehyde generated in situ from com. available starting material sodium salt of 4-chloro-1-hydroxy butane sulfonic acid with methanol or ethanol and further on displacement of alkyl chloride with aq. di-Me amine furnished dialkyl 4-dimethylaminobutaraldehyde acetals. The improved process allows to manufacturing the intermediates, dialkyl 4-dimethylaminobutaraldehyde acetals, at considerably low cost and in higher yield.

OBJECTIVES OF THE PRESENT INVENTION

An objective of the present invention is to provide a facile and easy to operate process for 4-chlorobutyraldehyde diethyl acetal in high yields.The inventors of this invention carried out extensive researches on industrially advantageous processes to achieve the foregoing objects and found that triethyl orthoformate is reacted with 4-chlorobutyraldehyde in the presence of an solvent such as ethanol and a quaternary ammonium halide compound as phase transfer catalyst. According to the present invention, there is provided a process for preparing 4-chlorobutyraldehyde diethyl acetal represented by the formula I,

the process comprising of reacting 4-chlorobutyraldehyde represented of formula II

with triethyl orthoformate in the presence of an solvent such as ethanol and a quaternary ammonium halide compound as phase transfer catalyst.

Yet another objective of the present invention is development of a process for for 4-chlorobutyraldehyde diethyl acetal with high purity of 95 % by GC.
SUMMARY OF THE INVENTION
A process for 4-chlorobutyraldehyde diethyl acetal, which comprises of reacting 4-chlorobutyraldehyde with triethyl orthoformate in presence of ethanol and tetrabutyll ammonium bromide at room temeperature is disclosed. The process finds its scope in the synthesis of triptans such as sumatriptan, almotriptan and zolmetriptan etc.
DESCRIPTION OF THE INVENTION
There has been research interest not only on the development easy to operate process for triptans such as zolmitriptan, sumatriptan and almotriptan etc. One of the key intermediates for many of the triptan is 4-chlorobutyraldehyde diethyl acetal. However the existing route for the aforementioned intermediate are neither cost effective nor environmentally benign. Herewith we present a cost effective, easy operate and environmentally benign process for 4-chlorobutyraldehyde diethyl acetal.
The present process involves the reaction of 4-chlorobutyraldehyde with triethyl othofomate. The amount of the inorganic triethyl orthoformate used is 1 to 6 moles, preferably 1 to 2 molesper mole of aldehyde of the formula II. Desirably the orthoformate is used in higher molar amount relative to an aldehyde.
In many instances acetalizations are acid catalyzed and stiochoiometric HBr or HCl has been used for completion of the reaction. However the present process doesnot require any external acid source for the reaction.
The phase transfer catalyst used for the invention are quaternary ammonium halides selected from the group of tetrabutyl ammonium bromide and tetrabutyl ammonium chloride. The amount of the phase transfer catalyst used is sufficient if it is a minimum amount required for the progress of the reaction.The amount of phase transfer catalyst used is 0.0001 to 0.01, preferably 0.001, mole equivalent to the compound of formula II.Solvents preferred in the reaction include alcoholic solvent. Solvents which are industrially suitable and proper for the reaction are, for example, ethanol, methanol, iospropanol, t-butanol and n-butanol etc. among which ethanol and methanol, are preferred. A mixture of at least two of these aromatic hydrocarbons can be used in the reaction. The amount of the solvent used may be a minimum amount which allows the reaction to proceed. In many instances, it is assisted by a co-solvent of aprotic dipolar nature. In the present process the co-solvent is selected from the group dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone, dimethyl sulfoxide and sulfolane either singly or in a combination of two or more of the solvent. More preferably dimethyl formamide is used. The amount of co-solvent used is is 0.0001 to 0.01, preferably 0.001, mole equivalent to the compound of formula II.

The reaction was carried out by stirring a mixture of aldehyde of formula II, with triethyl orthoformate in the presence of an solvent such as ethanol and a quaternary ammonium halide compound as phase transfer catalyst at 30-32 0C for 1 to 5h, preferably 1-2h. The reaction temperature is 30 – 32 0C in order to control the formation of impurities.If the reaction temperature is above 32 0C, it resulted in formation of impurities.

The product was purified by distillation. The product can collect at the vapour temperature of 65 – 70 0C under 16 mm pressure. The vapour temperature at < 65 0C or at > 70 0C under 16 mm pressure resulted more impure product.

ADVANTAGES OF THE PRESENT INVENTION

1. The reagent does not have to be prepared in advance;
2. The yields are higher overall;
3. The work-up procedure is simple;
4. The products are purer and do not need to be chromatographed before they are used;
5. The reaction times are shorter;
6. The reagents are cheaper;

The following examples illustrate the invention, which should not be construed in limiting the scope of the present invention.

EXAMPLE 1

4-chlorobutyraldehyde diethyl acetal

21kg of 4-chlorobutyraldehyde, 189 Lts of absolute ethanol, 26.1 kg of triethyl orthoformate and 0.77 kg of TBAB were charges to a 500 Lts flask and the whole was stirred at 30-32 0C for 1hour. It was followed by addition of aqueous solution of 10 hg of sodium bicarbonate in 200 ml of water. The product was extracted with 2×75 Lts of ethyl acetate. The organic layer was washed with 2×25 Lts of water. The organic layer was dried over anhydrous sodium sulphate and was concentrated below 500C under 16 mm pressure to obtain a crude weight of 33 kg. The crude mass was subjected to distillation and the fractions below 63 0C vapour temperature was discarded. The main fraction was collected at the vapour temperature of 65-70 0C under 16 mm pressure.

CLAIMS
We claim
1. A process for preparing 4-chlorobutyraldehyde diethyl acetal represented by the formula I,

the process comprising of reacting 4-chlorobutyraldehyde represented of formula II

with triethyl orthoformate in the presence of an solvent such as ethanol and a quaternary ammonium halide compound as phase transfer catalyst.

2. The process of claim 1, wherein the synthesis 4-chlorobutyraldehyde diethyl acetal of formula I comprises
a. reacting a compound of formula II,

with triethyl orthoformate in the presence of an solvent such as ethanol and a quaternary ammonium halide compound as phase transfer catalyst at a temperature of 30-32oC for 1-2 hours

b. neutralizing with a aqueous solution of sodium bicarbonate,
c. washing the aqueous layer with an organic solvent,
d. concentrating the organic layer by solvent evaporation below 500C,
e. distilling the crude mass under 16 mm pressure
f. discarding the fraction below 63 0C vapour temperature
g. Collecting the main fraction at the vapour temperature of 65 – 70 0C under 16 mm pressure with 95% GC purity.

3. The process of claim 2a, wherein the phase transfer catalyst is a quaternary ammonium halide selected from the group of tetrabutyl ammonium bromide and tetrabutyl ammonium chloride, more preferably tetrabutyl ammonium bromide.

4. The process of claim 2a, wherein the phase transfer catalyst is 0.0001 to 0.01, preferably 0.001, mole equivalent to the compound of formula I.

5. The process of claim 2a, wherein the organic solvent is selected from the group ethanol, methanol, iospropanol, t-butanol and n-butanol etc. among which ethanol and methanol, are preferred.

6. The process of claim 2a, wherein the co-solvent is selected from the group dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone, dimethyl sulfoxide and sulfolane either singly or in a combination of two or more of the solvent.

7. The process of claim 2a, wherein the reaction mixture was stirred for 1 to 4 h, preferably 1-2h.

8. The process of claim 2a, wherein the reaction mixture was stirred at 30-32 0C.

9. The process of claim 2b, wherein the reaction mixture neutralized with a aqueous solution of sodium bicarbonate.

10. The process of claim 2e, wherein the crude mass was purified by distillation under 16 mm pressure.

11. The process of claim 2f, wherein the fraction below 63 0C vapour temperature was discarded.

12. The process of claim 2g, wherein the main fraction was collected at the vapour temperature of 65 – 70 0C under 16 mm pressure

13. The process of claim 2g, wherein the main fraction collected at the vapour temperature of 65 – 70 0C under 16 mm pressure rendered 95% of GC purity.