FORM 2
The Patent Act 1970,
(39 of 1970)
&
The Patent rule 2003
Complete Specification
(See Section 10 and Rule 13)
1. TITLE OF THE INVENTION
Process for synthesizing Heliotropin and its Derivatives
2. APPLICANT (S)
(a) Name; GHARDA HORMUSJI KEKI
(b) Nationality: INDIAN
(c) Address: GHARDA HOUSE, 48 HILL ROAD, BANDRA (WEST), MUMBAI 400 050, INDIA
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to the synthesis of aldehyde derivatives of benzodioxoles or dialkoxybenzenes.
PRIOR ART
3,4-methylenedioxy benzaldehyde (also known as Heliotropine or piperonal) is a compound contained in tropical and subtropical plant etheric oils. It is principally used in the fragrance industry and for the production of perfumes.
Many Heliotropine synthesis pathways are known. Some of the synthesis pathways start from 1,2 methylenedioxybenzene. For example, it is known to treat this compound with gaseous HCI, ZnCI2 and formaldehyde in benzene, forming Piperonyl chloride; Piperonyl chloride is then made to react with a hexamine in alcohol (Sommelet reaction) and then hydrolysed, thus obtaining Heliotropine. The reaction of 1,2 methylenedioxybenzene with formaldehyde, HCI and m-Nitrobenzenesulfonic acid, and an Aluminium catalyst, to obtain Heliotropine is also known. Other authors (GB 1,591,268) propose a transformylation process (Vilsmeier-Haack reaction), in which 1,2 methylenedioxybenzene, treated with N-alkylformanilide and phophorus oxychloride, is converted to Heliotropin. All these processes are not entirely satisfactory in that they are considerably non-specific, and/or require intermediate purification passages or give inadequate yields.
In other processes 1,2 methylenedioxybenzene is treated with Glyoxylic acid and alkali: the 3,4 Methylenedioxymandelic acid thus obtained is converted into Heliotropin by oxidative decarboxylation, achieved with HN03 and HCI (U.S. Pat. No. 5,095,128) or with phosphoric acid (DE 2,754,490).

Currently, there is a lack of an industrially viable process starting from 1,2 methylenedioxybenzene or its derivatives, which have high specificity, excellent yields and avoid the need for intermediate purifications. The present invention is a response to this need.
SUMMARY OF THE INVENTION
The present invention provides a process for obtaining a compound of formula (111)

in which,
Xi and X2, the same or different, are linear or branched C1-C8 alkyls;
n and m are 0, 1 or 2, with the proviso that n and m are not simultaneously 0; or
(OX1) n and (OX2)m taken together to form an -O-T-O- group,
where T is chosen from -CH2-, -CH2CH2-, -CH2CH2CH2-, -C(CH3)2--
The said process comprises of the following passages:
(i) treating a chloromethyl derivative of formula (I) with an alkaline earth metal hydroxide and thus hydrolyzing compound (I) to form the alcohol (II), where X1, X2, m and n have the aforesaid meanings;


DETAILED DESCRIPTION OF THE INVENTION
In all the formulae given in the present application, Xi and X2, the same or different, are linear or branched C1-C8 alkyls, n and m are 0, 1 or 2, with the proviso that n and m are not simultaneously 0; or (OXi)n and (OX2)m taken together form an -O-T-0 group, where T is chosen from -CH2-, -CH2CH2-, -CH2CH2CH2-, -C(CH3)2-. Preferably the substituents X1 and X2 are chosen from C1-C4 alkyl, or, taken together, correspond to the -O-CH2-O- group; in this latter case, the structure of the final product (III) corresponds to heliotropin. This compound is the preferred substance, synthesizable with the process of the present invention.
The chloromethyl derivative of formula (I), the starting product of the present process, is commercially available, or can be easily synthesized by known methods.

A preferred method for synthesizing the compound (I) consists of chloromethylating a compound of formula (IV), where Xi, X2, n and m have the previously given meaning: chloromethylation is carried out with aqueous formaldehyde or paraformaldehyde and hydrochloric acid in the absence or presence of an inert organic solvent; this latter method is preferred in that it gives rise to a product (I) with less impurities.

The hydrochloric acid used can be gaseous or in aqueous solution; hydrochloric acid as a 36-37% aqueous solution is preferred. The organic solvent is chosen from an aromatic, alicyclic or chlorinated solvent; toluene, cyclohexane and methylene chloride are preferred. Toluene and methylene chloride are particularly 1:5 preferred. The volumes of solvent in relation to substrate (IV) are between 1:1 and 1:5 (v/v); a ratio of 1:2 (v/v) is particularly preferred.
The hydrochloric acid in solution is used in quantities of between 1 and 10 equivalents in relation to the substrate, and more preferably from 2 to 4 equivalents, the best results being obtained with 3 equivalents.
The paraformaldehyde is used in quantities of between 0.5 and 2 equivalents in relation to the substrate (IV), and more preferably from 0.95 to 1.3 equivalents.
The reaction temperature varies between 10°C and 80°C., more preferably between 15°C and 50°C, the best results being obtained between 20°C and 25°C. Reaction times vary generally from 30 minutes to 24 hours. Considering

that the selectivity of the reaction decreases over time at the expense of substrate conversion, a reaction time of between 4 and 5 hours is expedient.
At the end of the reaction, the organic phase is separated from the aqueous phase. The aqueous phase, containing essentially acid at a lower concentration and formaldehyde, can be re-used in the next cycle after re-saturating with gaseous hydrochloric acid. The organic phase, containing the chloromethylated product (I), is directly usable, as the crude product, in the subsequent aldehyde synthesis reaction.
US 2007100167 (A1) describes a process for making the compound (III) starting from the chloromethyl derivative (I) and passing via the ester intermediate (A); Patent also claims that this synthesis pathway is a suitable alternative to directly hydrolysing the chloromethyl derivative with NaOH because the yield of the alcohol (II) using direct hydrolysis technique has never been greater than 80%; moreover, Patent says that the such hydrolysis leads to byproducts which hinders the subsequent oxidation passage due to inactivation of catalyst by the by product. Patent claims an Oxidation process in the liquid phase using air as the oxidant and Ru and Pt supported on carbon as preferred catalysts.
A distinctive characteristic of the present process for making the compound (III) is: starting from the chloromethyl derivative (I) without passing via the ester intermediate (A) directly synthesize the alcohol derivative (II) in quantitative yield. This synthesis pathway is suitable as it resorts to directly hydrolysing the chloromethyl derivative with Alkaline Metal Hydroxide and is relatively faster and in near quantitative yields. The subsequent oxidation passage also uses relatively simple Hypohalite and not using any Noble metal catalyst, which requires recycle to be cost effective. The overall yield of the Compound (III) obtained here after the oxidation is 74 %. Thus the process described here is more users friendly and can be easily implemented as a large scale manufacturing process in the Plant.


The process of the present invention consists in hydrolysing the compound (I) to form the alcohol (II),

The reaction can be advantageously conducted directly in the biphasic system derived from chloromethylation process, without the need for purification. The reaction is achieved by adding chloromethyl derivative to aqueous alkaline hydroxide preferably Calcium hydroxide solution at reflux. The molar ratio of alkaline earth metal hydroxide to chloromethyl derivative (I) is between 3:1 and 1:1, preferably 1:1.
The reaction is conducted between 60°C and 85°C., preferably at 80°C. The hydrolysis is completed after about 1 hour, and the yield of alcohol (II) is between 90 and 96% in relation to the chloromethyl derivative.
The second passage of the process of the invention consists of oxidizing the compound of formula (II) to give the final compound of formula (III).


The oxidation reaction can also be favorably conducted on the crude product from the preceding reaction, without the need for intermediate purification. Oxidation of the alcohol (II) takes place in the crude organic mixture.
The process comprises reacting by contacting:
A) a water-immiscible, liquid Organic Phase comprising of Alcohol (II); With
B) an aqueous phase containing Hypohalite ion; And
C) a catalytic amount of a quaternary ammonium salt and/or a quaternary phosphonium salt.
The novel process proceeds under mild conditions in high yields and in reduced reaction time.
Oxidation of the alcohol (II) takes place in the crude organic mixture. The weight ratio of water to organic solvent is preferably between 5:1 and 2:1, being preferably 1:1. Practical considerations of reaction vessel size, product recovery, etc. are the only limitations upon the maximum amount of solvent that can be used.
The reaction takes place in the presence of Hypohalites. The hypohalites here used are hypochlorite, hypobromite, hypoiodite, or any combination thereof. Any suitable source of hypohalite ion can be used in the practice of this invention, but

typically the alkali metal hypohalites are used. Due to reasons of familiarity and general availability, hypochlorite is preferred over the other hypohalites. Sodium hypohalite is particularly preferred.
Oxidation occurs in a biphasic system using a phase transfer catalyst. The catalysts here used are quaternary ammonium and phosphonium salts and are known in the art as phase transfer catalysts. The ammonium salts are preferred over the phosphonium salts and benzyltrimethyl-, benzyltriethyl-, and tetra-n-butylammonium chlorides and bromides are most preferred.
Catalytic amount of the onium salt is required in the practice of this oxidation. Again, the concentration will vary with particular reagents employed. However, best results are generally achieved when the onium salt concentration is from about 1 mole percent to about 30 mole percent based upon the organic compound to be oxidized. Concentrations between about 2 mole percent and about 10 mole percent are preferred.
Although stoichiometric amounts of oxidisable organic compound and hypohalite ion are necessary, preferably an excess of hypohalite ion is employed to promote a quantitative reaction. Of course, the particular ratio of organic compound to hypohalite ion will vary with the particular reagents.
Temperature and pressure are not critical for oxidation as long as the biphasic mixture remains a liquid. Best results are obtained when the reaction temperatures range from about 0°C to about 35°C with ambient temperature and pressure preferred.
Although the reaction can be conducted neat, it is preferably conducted in the presence of an inert, water-immiscible organic solvent. Typical solvents include benzene, chlorobenzene, o-dichlorobenzene, hexane, methylene chloride, chloroform, carbon tetrachloride, and the like. Not only do these solvents

contribute to the formation of a biphasic reaction mixture, but they also aid in moderating reaction rate and temperature.
Generally, at least sufficient solvent to dissolve the oxidisable organic compound is used and preferably the amount of solvent used is equal in volume to the amount of aqueous hypohalite used.
The following non-limiting examples serve to illustrate the present invention.
Experimental Part
Synthesis of 5-carboxaldehyde benzo[1.3]dioxole
(a) Synthesis of chloromethyl-benzodioxole
The following are introduced into a 3 liter flask:
121 g p-CH20 (97%) (3.9 moles)
369 g 1,3-benzodioxole (99.1%) (3 moles)
680 ml of toluene 990 ml HCI (10N) (9.9 moles).
The mixture is allowed to react for 5 hours under a head of N2, maintaining the temperature at 25-30°C. with an ice bath. After separating the phases and extraction of aqueous phase twice with 200 ml of toluene, a crude product of 1354.0 g is obtained with the following composition:
1,3-benzodioxole 11.82% w/w (160.1 g) (1.31 moles)
5-chloromethyl-1, 3-benzodioxole 19.50% w/w (264.24g) (1.55 moles)
Conversion of 1,3-benzodioxole: 62%
Selectivity of 5-chloromethyl-1, 3-benzodioxole: 92%
Yield of 5-chloromethyl-1,3-benzodioxole: 52%
(b) Synthesis of piperonyl alcohol from 5-chloromethyl-1,3-benzodioxole
148 g of Slaked lime (88%) (1.76 moles) and 700 ml H20 are introduced into a 5 liter flask. The flask is placed under agitation and the temperature of the mixture

is brought to 80°C to 85°C under a head of N2. The previously prepared crude product of the 5-chloromethyl-1,3-benzodioxole synthesis is fed drop-wise into the mixture over 2 hour. The mixture is allowed to react for another 1 hour following the drop-wise addition.
After cooling, the mixture is filtered. The phases are separated and the aqueous is extracted with toluene, which is then mixed with main organic phase. This gives a crude product weighing 1522 g, with the following composition:
Piperonyl alcohol 15.1% w/w (230 g) (1.513 moles)
1,3-benzodioxole 10.3% w/w (156.6 g) (1.284 moles)
Conversion of 5-chloromethyl-1,3-benzodioxole: 100%
Yield of piperonyl alcohol relative to 5-chloromethyl-1,3-benzodioxole: 97.6%
(c) Oxidation of the piperonyl alcohol/1,3-benzodioxole mixture
The previously obtained crude piperonyl alcohol synthesis product is introduced into a 3 liter flask. Tetra-n-butylammonium bromide (22.7 g, 0.0704 mole) was added.
1580 ml of 160-gpl aqueous sodium hypochlorite solution (3.39 mole) was then introduced into the flask at 25 - 30°C over 1.5 hours.
The reaction mixture was occasionally cooled by an external water bath to keep the reaction temperature from exceeding 30°C. The reaction was monitored by gas chromatography. At 8 hours reaction time, 99% of the piperonyl aJcohoJ bad been converted to heliotropin.
Layers are separated and aqueous layer is extracted with toluene, which is mixed with main organic layer. Combined organic layer is then washed with water and taken for distillation to recover solvent.

A crude product weighing 1791 g, composed of the following, is obtained:
piperonyl alcohol 0.06% w/w (1.035 g)
heliotropin 10.47 % w/w (187.5 g)
1,3-benzodioxole 8.6 % w/w (154.02 g)
Conversion of piperonyl alcohol=99.5%
Yield of heliotropin =82.6%
(d) Purification of the Crude Product and Crystallization of Heliotropin The crude reaction product is distilled separating firstly the unreacted 1,3-benzodioxole at 40°C/1.5 mbar (152.24 g) and then the heliotropin or 5-carboxaldehyde-1,3-benzodioxole at 91°C /1.5 mbar, to obtain 182 g heliotropin at 96% (% a/a)
Heliotropin yield by distillation: 92.7%
Heliotropin thus obtained can be suitably crystallized by using an ethanol/H20 mixture.
After drying at 30°C/23 mbar, 164 g of crystalline Heliotropin is obtained with Purity: 99.2% (% w/w) Crystallization yield 90%.

I claim,
1) Process for obtaining a compound of formula (III)

in which,
Xi and X2, the same or different, are linear or branched C1-C8 alkyls;
n and m are 0, 1 or 2, with the proviso that n and m cannot be simultaneously 0;
or (OXi)n and (OX2)m taken together form an O-T-0 group, where T is chosen
from -CH2-, -CH2CH2-, -CH2CH2CH2-, -C(CH3)2-,
said process comprising the following passages:
(i) hydrolysis of chloromethyl derivative of formula (I) with an aqueous solution of alkaline earth metal hydroxide to form the corresponding afcohol of formufa (II), where X1, X2, m and n have the aforesaid meanings;

(ii) Oxidation of the alcohol (II) to form the compound (III) wherein the passage (ii) is conducted by treating in the liquid phase the product

of passage (i) with aqueous solution of Hypohalite usually used jn excess to effect quantitative conversion of the alcohol to the aldehyde, in the presence of a suitable Phase transfer catalyst.

2) Process as claimed in claim 1, wherein Xi and X2 are chosen from a C1-C4
alkyl or taken together correspond to the -0-CH2-0- group.
3) Process as claimed in claim 1, wherein the passage (i) is conducted by adding
an organic solution of the derivative (I) to an aqueous solution containing an
alkaline earth Metal hydroxide at reflux.
4) Process as claimed in claim 1, wherein in the passage (i) the alkaline earth Metal Hydroxide is preferably Calcium Hydroxide.
5) Process as claimed in claim 1, wherein in the passage (i), the molar ratios of Calcium Hydroxide to chloromethyl derivative (I) are between 1:1 and 3:1 and the reaction temperature is between 40°C and 85°C.
6) Process as claimed in claim 5, wherein in the passage (i) the molar ratios of
Calcium Hydroxide to chloromethyl derivative (I) are between 1.1:1 and 1.5:1.
7) Process as claimed in claim 5, wherein in the passage (i) the reaction
temperature is between 75°C and 85°C.

8) Process as claimed in claim 1, wherein the passage (ii) is conducted by adding aqueous Hypohalite to the product of passage (i) and a phase transfer catalyst, of the ammonium salts group, at temperature of 0°C to about 35°C.
9) Process as claimed in claim 8, wherein the Hypohalite used is preferably Sodium Hypochlorite.

10) Process as claimed in claim 8, wherein the passage (ii) is conducted in a water: organic solvent mixture, in which the weight ratio of water to organic solvent present is between 5:1 and 2:1, being preferably 1:1.
11) Process as claimed in claim 8, wherein in passage (ii) an excess of Sodium Hypochlorite is employed to promote a quantitative reaction.
M) Process as claimed in claim 8, wherein in passage (ii) Sodium Hypochlorite used is 2 to 7 m/m of Alcohol (II).
13) Process as claimed in claim 8, wherein in passage (ii) Phase Transfer catalyst used is about 1 mole percent to about 30 mole percent based on Alcohol (II).
14) Process as claimed in claim 8, wherein in passage (ii) the concentration of the catalyst is about 2 mole percent to about 10 mole percent based on alcohol (II).
15) Process as claimed in claim 8, wherein in passage (ii) phase transfer catalysts used are quaternary ammonium or phosphonium salt.
16) Process as claimed in claim 8, wherein in passage (ii) benzyltrimethyl-, benzyltriethyl-, and tetra-n-butylammonium chlorides and bromides are most preferred.

17) Process as claimed in claim 8, wherein in passage (ii) reaction temperatures range from about 0°C to about 35°C.
18) Process as claimed in claim 8, wherein in passage (ii) ambient temperatures and pressures are preferred.