Efficient and environment friendly process for chloromethylation of substituted benzenes

Abstract

Disclosed herein is an efficient, environment friendly and commercially viable process for preparation of chloromethylated compound of formula I in substantially pure form and high yield, from the compound of formula II. The process includes contacting the compound of formula II with a chloromethylating agent generated in-situ by reaction of a formaldehyde precursor and hydrogen chloride, in a suitable solvent/contacting medium and in the presence of a catalytic amount of a short chain/low molecular weight carboxylic acid of formula III. I II III wherein, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined in the description. ##STR00001##

Claims

1. A process for preparing a compound of formula I, comprising contacting a compound of formula II with a chloromethylating agent generated in-situ by reaction of a formaldehyde precursor and hydrogen chloride, in a solvent and in presence of a catalytic amount of a carboxylic acid of formula III, ##STR00011## wherein R.sub.1, R.sub.2 and R.sub.3 are independent of each other, R.sub.1 represents H, R or —OR, wherein R is a substituted or unsubstituted C.sub.1-C.sub.4 alkyl group or substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl group; R.sub.2 represents hydroxy group —OH or alkoxy group —OR, wherein R is a substituted or unsubstituted C.sub.1-C.sub.4 alkyl group or substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl group; or R.sub.1 and R.sub.2 jointly form an alkylenedioxy group represented by —O—(CH.sub.2).sub.n—O— wherein n is 1, 2 or 3; R.sub.3 is a substituent at any position of the aromatic ring other than position 1, 3 and 4 and represents H, R, —OR, wherein R is a substituted or unsubstituted C.sub.1-C.sub.4 alkyl group, substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl group or SH; and R.sub.4 represents an alkyl group containing one to six carbon atoms; wherein the catalytic amount of the carboxylic acid of formula III is in a range of from 0.5% to 10% by weight of the compound of formula II.

2. The process as claimed in claim 1, wherein the formaldehyde precursor is paraformaldehyde.

3. The process as claimed in claim 1, wherein the formaldehyde precursor is metaformaldehyde.

4. The process as claimed in claim 1, wherein the solvent is selected from the group consisting of chlorinated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons and mixtures thereof.

5. The process as claimed in claim 1, wherein the solvent is toluene.

6. The process as claimed in claim 1, wherein the compound of formula II and the chloromethylating agent are contacted in presence of hydrogen chloride gas.

7. The process as claimed in claim 1, wherein the carboxylic acid is acetic acid.

8. The process as claimed in claim 1, wherein the carboxylic acid is propionic acid.

9. The process as claimed in claim 1, wherein the compound of formula II is 1,3-benzodioxole and the corresponding compound of formula I is 5-(chloromethyl)-1,3-benzodioxole.

10. The process as claimed in claim 9, wherein the 5-(chloromethyl)-1,3-benzodioxole is further converted to heliotropin.

11. The process as claimed in claim 1, wherein the compound of formula II is dihydrosafrole and the corresponding compound of formula I is 5-(chloromethyl)-6-propyl-1,3-benzodioxole.

12. The process as claimed in claim 11, wherein the 5-(chloromethyl)-6-propyl-1,3-benzodioxole is further converted to piperonylbutoxide.

13. The process of as claimed in claim 1, wherein the compound of formula II is anisole and the corresponding compound of formula I is 4-chloromethyl anisole.

14. The process as claimed in claim 13, wherein the 4-chloromethyl anisole is further converted to anisaldehyde.

Description

DETAILED DESCRIPTION OF THE PRESENT INVENTION

(1) The following is a detailed description of the embodiments of the present invention. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.

(2) Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”

(3) Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

(4) As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise.

(5) In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, process conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.

(6) The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

(7) All methods described herein can be performed in suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

(8) The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.

(9) Various terms are used herein. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.

(10) The term “first”, “second” and the like, herein do not denote any order, quantity or importance, but rather are used to distinguish one element from another, and the terms “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items.

(11) The term “contacting” used hereinbefore or hereinafter means reacting, mixing, combining and the like.

(12) In a general embodiment of the present invention, the compound of formula II is contacted with a chloromethylating agent generated in-situ from a formaldehyde precursor and hydrogen chloride, in a suitable solvent/contacting medium and in presence of a catalytic amount of a low molecular weight carboxylic acid of formula III till required conversion of the substituted benzene of formula II into desired product of formula I is achieved,

(13) ##STR00006## wherein R.sub.1, R.sub.2 and R.sub.3 are independent of each other, R.sub.1 represents H, R or —OR, wherein R is a substituted or unsubstituted C.sub.1-C.sub.4 alkyl group or substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl group; R.sub.2 represents hydroxy group —OH or alkoxy group —OR, wherein R is a substituted or unsubstituted C.sub.1-C.sub.4 alkyl group or substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl group; or R.sub.1 and R.sub.2 jointly form an alkylenedioxy group represented by —O—(CH.sub.2).sub.n—O— wherein n is 1, 2 or 3; R.sub.3 is a substituent at any position of the aromatic ring other than position 1, 3 and 4 and represents H, R, —OR, wherein R is a substituted or unsubstituted C.sub.1-C.sub.4 alkyl group, substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl group or SH; and R.sub.4 represents an alkyl group containing one to six carbon atoms.

(14) In many embodiments, the method for chloromethylation as disclosed herein can also be carried out under continuous addition of hydrogen chloride gas, which acts to stabilize the chloromethylating agent in the presence of water generated in the chloromethylation reaction.

(15) In various embodiments, the formaldehyde precursor that can used for the in-situ generation of the chloromethylating agent can be selected from paraformaldehyde and metaformaldehyde (1,3,5-trioxane).

(16) In various embodiments, the solvent/contacting medium can be selected based on its ability to retain the reagents and catalyst/promoter in a single phase to facilitate the reaction. Suitable solvent/contacting medium for the reaction of the compound of formula II with the chloromethylating agent generated in-situ can be selected from the group consisting of chlorinated hydrocarbons, aliphatic hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons and mixtures thereof.

(17) In one particularly preferred embodiment, the solvent/contacting medium is toluene.

(18) In certain preferred embodiments, the low molecular weight carboxylic acid of formula III represents acetic acid, propionic acid, butanoic acid, pentanoic acid or Hexenoic acid. The catalytic amount of the carboxylic acid of formula III is in a range of from 0.5% to 10% by weight of the compound of formula II.

(19) After the required conversion of the substituted benzene of formula II is achieved, excess hydrogen chloride, if any, can be substantially removed by conventional methods such as purging the reaction medium with nitrogen gas and/or applying vacuum, and any remaining hydrogen chloride can be further neutralized if required, to isolate the chloromethylated compound of formula I in high yield and high purity. In alternative embodiments, the chloromethylated compound of formula I thus obtained can be directly used in further reaction steps without isolation.

(20) The said general embodiment can be depicted as herein below: 1) Contacting paraformaldehyde or other suitable formaldehyde precursor with hydrogen chloride gas in a suitable solvent/contacting medium at a temperature to facilitate in-situ formation of the chloromethylating agent. When the solvent/contacting medium used was toluene, this temperature was typically in the range of from 30° C. to 60° C., and preferably in the range of from 40° C. to 50° C.; 2) Adjusting the temperature of the above mixture to the reaction temperature required for the chloromethylation reaction; 3) Contacting the substituted benzene compound of formula II with the chloromethylating agent generated in-situ in a suitable solvent/contacting medium at a required reaction temperature, in the presence of a catalytic quantity of a low molecular carboxylic acid of formula III acting as catalyst/promoter; 4) Optionally adding excess hydrogen chloride gas during the chloromethylation reaction, if required to stabilize the chloromethylating agent in the presence of water generated in the chloromethylation reaction; 5) Monitoring the progress of the reaction by conventional methods, such as GC, IR, etc, until desired conversion is achieved; 6) Substantially removing excess hydrogen chloride from the reaction mixture by conventional methods, such as purging the reaction medium with nitrogen gas and/or applying vacuum, if required; and 7) Isolating the chloromethyl derivative of formula I in high yield and high purity after conventional work-up techniques such as neutralization of balance hydrogen chloride, aqueous work-up etc., or directly using the chloromethyl derivative of formula I for further reaction without isolation.

(21) It will be understood that the detailed procedure of these embodiments can be varied. Thus, the chloromethylation reaction temperature and/or the ratio of the compound of formula II to the chloromethylating species and/or the quantity of carboxylic acid catalyst may be varied depending on the desired conversion to be achieved, and other polymeric formaldehyde precursors such as 1,3,5-trioxane (metaformaldehyde) may be used instead of paraformaldehyde.

(22) In a specific embodiment of the present invention, this method can be advantageously used to react the compound of the formula II wherein R.sub.1 and R.sub.2 together jointly form an alkylenedioxy group represented by —O—(CH2).sub.n-O— wherein n is 1, 2 or 3, wherein the alkylenedioxy group is highly susceptible to decomposition at higher temperatures under acidic conditions, to obtain the corresponding chloromethylated compound of formula I in high yield and high purity.

(23) ##STR00007##

(24) In a further embodiment of the present invention, wherein R.sub.1 and R.sub.2 together jointly form an alkylenedioxy group represented by —O—(CH2).sub.n-O— wherein n is 1, and R.sub.3 is a substituent at the 5.sup.th position of aromatic ring and represents H, the substituted benzene compound of formula II is methylene dioxybenzene (1,3-benzodioxole) and the corresponding chloromethylated derivative of formula I (i.e. 5-(chloromethyl)-1,3-benzodioxole) is used as an intermediate in the manufacture of heliotropin, which has wide use in fragrance & flavour applications as well as is a key starting material for pharmaceutical intermediates.

(25) ##STR00008##

(26) In yet another embodiment of the present invention, wherein R.sub.1 and R.sub.2 together jointly form an alkylenedioxy group represented by —O—(CH2).sub.n-O— wherein n is 1, and R.sub.3 is a substituent at the 5.sup.th position of aromatic ring and represents the propyl group, the substituted benzene compound of formula II is dihydrosafrole, and the corresponding chloromethylated derivative of formula I (5-(chloromethyl)-6-propyl-1,3-benzodioxole) is used as an intermediate in the manufacture of piperonylbutoxide, which finds wide application as an insecticide synergist.

(27) ##STR00009##

(28) In yet another embodiment of the present invention, wherein R.sub.1 and R.sub.3═H, and R.sub.2═—OCH3, the substituted benzene compound of formula II is anisole, and the corresponding chloromethylated derivative of Formula I (i.e. 4-chloromethyl anisole) can be used as an intermediate in the manufacture of anisaldehyde.

(29) ##STR00010##

EXAMPLES

(30) The present disclosure is further explained in the form of following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

Example-1: Preparation of 5-(Chloromethyl)-1,3-benzodioxole

(31) Toluene (122 g) and Paraformaldehyde (30 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 0° C. and Acetic acid (3.0 g) and Methylene dioxybenzene (122 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 0° C. and 5° C. for 12 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water, and the organic layer obtained contained 5-(Chloromethyl)-1,3-benzodioxole ˜75.9% and unreacted Methylene dioxybenzene ˜19.2% and impurity formation ˜5% by GC (excluding solvent).

Example-2: Preparation of 5-(Chloromethyl)-1,3-benzodioxole

(32) Toluene (122 g) and Paraformaldehyde (30 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 0° C. and Acetic acid (6.0 g) and Methylene dioxybenzene (122 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 0° C. and 5° C. for 12 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 5-(Chloromethyl)-1,3-benzodioxole ˜83.5% and unreacted Methylene dioxybenzene ˜9.9% and impurity formation ˜6% by GC (excluding solvent).

Example-3: Preparation of 5-(Chloromethyl)-1,3-benzodioxole

(33) Toluene (122 g) and Paraformaldehyde (45 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 5° C. and Acetic acid (12.0 g) and Methylene dioxybenzene (122 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 5° C. and 10° C. for 6 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 5-(Chloromethyl)-1,3-benzodioxole ˜77.6% and unreacted Methylene dioxybenzene ˜18.9% and impurity formation ˜4% by GC (excluding solvent).

Example-4: Preparation of 5-(Chloromethyl)-1,3-benzodioxole

(34) Toluene (122 g) and Paraformaldehyde (30 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 0° C. and Propionic acid (7.4 g) and Methylene dioxybenzene (122 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 0° C. and 5° C. for 12 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 5-(Chloromethyl)-1,3-benzodioxole ˜85.2% and unreacted Methylene dioxybenzene ˜11.6% and impurity formation ˜3% by GC (excluding solvent).

Example-5: Preparation of 5-(Chloromethyl)-1,3-benzodioxole

(35) Toluene (122 g) and Paraformaldehyde (30 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 0° C. and Hexanoic acid (6.0 g) and Methylene dioxybenzene (122 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 0° C. and 5° C. for 11 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 5-(Chloromethyl)-1,3-benzodioxole ˜75.3% and unreacted Methylene dioxybenzene ˜18.5% and impurity formation ˜6% by GC (excluding solvent).

Example-6: Preparation of 5-(Chloromethyl)-1,3-benzodioxole (without Carboxylic Acid Catalyst)

(36) Toluene (122 g) and Paraformaldehyde (30 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 0° C. and Methylene dioxybenzene (122 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 0° C. and 5° C. for 12 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 5-(Chloromethyl)-1,3-benzodioxole ˜73.2% and unreacted Methylene dioxybenzene ˜19.6% and impurity formation ˜7% by GC (excluding solvent).

Example-7: Preparation of 5-(Chloromethyl)-1,3-benzodioxole

(37) Toluene (122 g) and Paraformaldehyde (30 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 0° C. and Formic acid (6.0 g) and Methylene dioxybenzene (122 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 0° C. and 5° C. for 10 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 5-(Chloromethyl)-1,3-benzodioxole ˜52.2% and unreacted Methylene dioxybenzene ˜33.3% and impurity formation ˜15% by GC (excluding solvent).

Example-8: Preparation of 5-(Chloromethyl)-1,3-benzodioxole

(38) Toluene (122 g) and Paraformaldehyde (15 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 5° C. and Acetic acid (6.0 g) and Methylene dioxybenzene (122 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 5° C. and 6° C. for 6 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 5-(Chloromethyl)-1,3-benzodioxole ˜40.8% and unreacted Methylene dioxybenzene ˜56.6% and impurity formation ˜3% by GC (excluding solvent).

Example-9: Preparation of 5-(Chloromethyl)-1,3-benzodioxole

(39) Toluene (122 g) and Paraformaldehyde (30 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 5° C. and Acetic acid (6.0 g) and Methylene dioxybenzene (122 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 5° C. and 10° C. for 8 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 5-(Chloromethyl)-1,3-benzodioxole ˜74.4% and unreacted Methylene dioxybenzene ˜20% and impurity formation ˜5% by GC (excluding solvent).

Example-10: Preparation of Heliotropin

(40) Toluene (122 g) and Paraformaldehyde (45 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 5° C. and Acetic acid (6.0 g) and Methylene dioxybenzene (122 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 5° C. and 6° C. for 6 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. At the end of the reaction the organic layer contained 5-(Chloromethyl)-1,3-benzodioxole ˜82.1% and unreacted Methylene dioxybenzene ˜13.5% and impurity formation ˜4% by GC (excluding solvent). 150 g of Hexamine was added under stirring and the temperature of the reaction mass was increased to about 80° C. and maintained at this temperature under stirring for about 4 hour, till the content of the chloromethyl derivative was less than 0.5% by GC analysis. 360 g of 50% aqueous acetic acid was added to the resulting hexamine complex and the reaction mass was digested at about 90° C. for about 6 hours. After completion of the reaction, the reaction mass was diluted with water to separate the organic layer, and product and unreacted Methylene dioxybenzene was further extracted from the aqueous layer using Toluene. The organic layer together with the Toluene extracts was distilled to separate a fraction containing unreacted 19 g of Methylene dioxybenzene and 91 g of Heliotropin (GC purity >98%, yield 88.3% w/w on Methylene dioxybenzene consumed).

Example-11: Preparation of Heliotropin

(41) Toluene (122 g) and Paraformaldehyde (60 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 5° C. and Acetic acid (6.0 g) and Methylene dioxybenzene (122 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 5° C. and 10° C. for 6 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. At the end of the reaction the organic layer contained 5-(Chloromethyl)-1,3-benzodioxole ˜87.7% and unreacted Methylene dioxybenzene ˜6.7% and impurity formation ˜5% by GC (excluding solvent). 150 g of Hexamine was added under stirring and the temperature of the reaction mass was increased to about 80° C. and maintained at this temperature under stirring for about 4 hour, till the content of the chloromethyl derivative was less than 0.5% by GC analysis. 360 g of 50% aqueous acetic acid was added to the resulting hexamine complex and the reaction mass was digested at about 90° C. for about 6 hours. After completion of the reaction, the reaction mass was diluted with water to separate the organic layer, and product and unreacted Methylene dioxybenzene was further extracted from the aqueous layer using Toluene. The organic layer together with the Toluene extracts was distilled to separate a fraction containing unreacted 16 g of Methylene dioxybenzene and 91 g of Heliotropin (GC purity >98%, yield 85.8% w/w on Methylene dioxybenzene consumed).

Example-12: Preparation of Piperonyl Butoxide

(42) Toluene (122 g) and Paraformaldehyde (45 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 15° C. and Acetic acid (6.0 g) and Dihydrosafrole (164 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 15° C. and 20° C. for 6 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 5-(Chloromethyl)-6-propyl-1,3-benzodioxole ˜79.0% and unreacted Dihydrosafrole 11.0% (excluding solvent). This was reacted with butyl carbitol (178 g) and sodium hydroxide (60.0 g) at 30° C. for 5 hours under stirring. After completion of the reaction, the reaction mass was diluted with water to separate the organic layer. The organic layer was distilled to separate a fraction containing unreacted 20 g of Dihydrosafrole and 230 g of Piperonyl Butoxide (GC purity >96%, yield 159.7% w/w on Dihydrosafrole consumed).

Example-13: Preparation of Chloromethyl Anisole

(43) Hexane (122 g) and Paraformaldehyde (45 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 15° C. and Acetic acid (6.0 g) and Anisole (108 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 15° C. and 20° C. for 5 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 4-(Chloromethyl)-anisole ˜58.5%, 2-(Chloromethyl)-anisole ˜19.8% and unreacted anisole ˜2.3%.

Example-14: Preparation of Chloromethyl Anisole

(44) Cyclohexane (122 g) and Paraformaldehyde (45 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 15° C. and Acetic acid (6.0 g) and Anisole (108 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 15° C. and 20° C. for 5 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 4-(Chloromethyl)-anisole ˜60.5%, 2-(Chloromethyl)-anisole ˜20.8% and unreacted anisole ˜6.8%.

Example-15: Preparation of 4-Anisaldehyde

(45) Toluene (122 g) and Paraformaldehyde (45 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 15° C. and Acetic acid (6.0 g) and Anisole (108 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 15° C. and 20° C. for 5 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. At the end of the reaction the organic layer contained 4-(Chloromethyl)-anisole ˜64.1%, 2-(Chloromethyl)-anisole ˜20.3% and unreacted anisole ˜5.2%. 150 g of Hexamine was added under stirring and the temperature of the reaction mass was increased to about 80° C. and maintained at this temperature under stirring for about 4 hour, till the content of the chloromethyl derivative was less than 0.5% by GC analysis. 360 g of 50% aqueous acetic acid was added to the resulting hexamine complex and the reaction mass was digested at about 90° C. for about 6 hours. After completion of the reaction, the reaction mass was diluted with water to separate the organic layer, and product and unreacted anisole was further extracted from the aqueous layer using Toluene. The organic layer together with the Toluene extracts was distilled to separate a fraction containing unreacted 10 g of Anisole and 75 g of Anisaldehyde (GC purity >98% (sum of both isomers), yield 76.5% w/w on Anisole consumed).

Example-16: Preparation of 4-(Chloromethyl)-1,2-dimethoxybenzene

(46) Toluene (122 g) and Paraformaldehyde (30 g) were charged into a 500 ml reaction flask and the mixture was heated to about 40° C. under stirring and maintained at this temperature under stirring with simultaneous passing of hydrogen chloride gas for about 1 hour, until a clear solution was obtained. The reaction mass was then cooled to about 15° C. and Acetic acid (6.0 g) and 1,2-Dimethoxybenzene (138 g) were charged into the reactor under stirring. The reaction mass was then maintained at between 15° C. and 20° C. for 6 hours under stirring with continuous addition of hydrogen chloride gas. The hydrogen chloride addition was stopped and the reaction mass was purged with nitrogen gas for one hour. The reaction mass was washed with water and the organic layer obtained contained 4-(Chloromethyl)-1,2-dimethoxybenzene ˜57.0% and unreacted 1,2-Dimethoxybenzene ˜27.1%.

(47) The above Examples are further summarized in table-1 below:

(48) TABLE-US-00001 TABLE 1 Mole Mole per Para- per Ex- mole formal- mole Sub- ample Qty Carboxylic Qty of dehyde of Temp Time Product strate No. Substrate (g) Acid (g) substrate (g) substrate Solvent (° C.) (h) Product (GC %) (GC %) 1 MDB 122 Acetic 3 0.05 30 1.0 Toluene 0 to 5 12 5-(Chloromethyl)- 75.9 19.2 Acid 1,3-benzodioxole 2 MDB 122 Acetic 6 0.10 30 1.0 Toluene 0 to 5 12 5-(Chloromethyl)- 83.5 9.9 Acid 1,3-benzodioxole 3 MDB 122 Acetic 12 0.20 45 1.5 Toluene  5 to 10 6 5-(Chloromethyl)- 77.6 18.9 Acid 1,3-benzodioxole 4 MDB 122 Propionic 7.4 0.10 30 1.0 Toluene 0 to 5 12 5-(Chloromethyl)- 85.2 11.6 Acid 1,3-benzodioxole 5 MDB 122 Hexanoic 6 0.05 30 1.0 Toluene 0 to 5 11 5-(Chloromethyl)- 75.3 18.5 acid 1,3-benzodioxole 6 MDB 122 — 0 0.00 30 1.0 Toluene 0 to 5 12 5-(Chloromethyl)- 73.2 19.6 1,3-benzodioxole 7 MDB 122 Formic 6 0.13 30 1.0 Toluene 0 to 5 10 5-(Chloromethyl)- 52.2 33.0 acid 1,3-benzodioxole 8 MDB 122 Acetic 6 0.10 15 0.5 Toluene  5 to 10 6 5-(Chloromethyl)- 40.8 56.6 Acid 1,3-benzodioxole 9 MDB 122 Acetic 6 0.10 30 1.0 Toluene  5 to 10 8 5-(Chloromethyl)- 74.4 20.0 Acid 1,3-benzodioxole 10 MDB 122 Acetic 6 0.10 45 1.5 Toluene  5 to 10 6 5-(Chloromethyl)- 82.1 13.5 Acid 1,3-benzodioxole 11 MDB 122 Acetic 6 0.10 60 2.0 Toluene  5 to 10 6 5-(Chloromethyl)- 87.7 6.7 Acid 1,3-benzodioxole 12 DHS 164 Acetic 6 0.10 45 1.5 Toluene 15 to 20 6 5-(Chloromethyl)- 79.0 11.0 Acid 6-propyl-1,3- benzodioxole 13 Anisole 108 Acetic 6 0.10 45 1.5 Hexane 15 to 20 5 2 & 4- 19.8/ 2.3 Acid (Chloromethyl) 58.5 anisole 14 Anisole 108 Acetic 6 0.10 45 1.5 Cyclo- 15 to 20 5 2 & 4- 20.8/ 6.8 Acid hexane (Chloromethyl) 60.5 anisole 15 Anisole 108 Acetic 6 0.10 45 1.5 Toluene 15 to 20 5 2 & 4- 20.3/ 5.2 Acid (Chloromethyl) 64.1 anisole 16 1,2- 138 Acetic 6 0.10 30 1.0 Toluene 15 to 20 6 4- 57.0 27.1 DMB Acid (Chloromethyl)- 1,2- dimethoxybenzene

TECHNICAL ADVANTAGE OF THE PRESENT INVENTION

(49) The inventors of present invention have herein provided a solution to the shortcomings of the prior art by developing an efficient process for carrying out the said reaction comprising the in-situ generation of the chloromethylating agent in a suitable solvent by the reaction of hydrogen chloride with a formaldehyde precursor, and carrying out the chloromethylation reaction in the presence of a catalytic amount of low molecular weight carboxylic acid which acts as a catalyst/promoter of the reaction.

(50) The inventors of the present invention have provided a solution wherein the chloromethylating agent is generated in-situ by passing hydrogen chloride gas into a mixture of paraformaldehyde and the solvent/contacting medium at a temperature typically in the range 30° C. to 50° C., and the reaction mass is then adjusted to the reaction temperature required for carrying out the chloromethylation reaction, which is typically lower than the above temperature range, before the addition of the substituted benzene compound of formula II. In this way the inventors of the present invention have provided a method to limit the exposure of the substituted benzene compound to higher temperatures, thereby minimising the formation of by-products, and obtaining the target aryl methyl chloride compound of formula I in high yield and purity.

(51) The inventors of the present invention have observed that chloromethylation of substituted benzene by the reaction with the chloromethylating agent generated in-situ is accelerated in the presence of short chain/low molecular weight carboxylic acid present in catalytic quantities. Although the prior art discloses use of anhydrous mixture of zinc chloride in combination with low molecular weight carboxylic acid like acetic or propionic acid is extremely active in promoting the chloromethylation, the ratio of zinc chloride and carboxylic acid used was very high, typically in the range 1:2 to 4 moles of zinc chloride to carboxylic acid). Moreover, none of the prior art teach the standalone use of carboxylic acids such as acetic acid, present in catalytic quantities acting as catalyst/promoter to accelerate the chloromethylation reaction in the absence of the Lewis acid.

(52) The inventors of the present invention have also observed that after completion of the chloromethylation reaction, the excess hydrogen chloride can be substantially removed by conventional methods such as purging the reaction medium with nitrogen gas and/or applying vacuum, and the remaining hydrogen chloride can be further neutralized if required, resulting in a clean and simple workup with minimum effluent generation, and the resulting aryl methyl chloride with minimal workup can be further functionalized to the desired product(s).

(53) For example, after carrying out the chloromethylation of methylene dioxybenzene, the excess hydrogen chloride can be substantially removed by purging the reaction medium with nitrogen gas, and the chloromethyl species without isolation can be converted to the target compound heliotropin by proceeding for the Sommlet reaction without workup and generation of any liquid effluent in the chloromethylation step.

(54) The advantages of the present invention over the prior art may be summarized as follows: 1) The process of the present invention uses catalytic quantity of low molecular weight carboxylic acid, and eliminates the use of Lewis acids and/or mineral acids such as sulfuric acid, thereby minimising effluent problems and making the process industrially viable and environmentally friendly. 2) The process of the present invention avoids biphasic reaction typically associated with the Blanc reaction by carrying out the reaction in a solvent/contacting medium suitable for the in-situ generation of the chloromethylating agent and the subsequent reaction with the substituted benzene substrate. 3) The process of the invention can be carried out without the chlorinated solvents typically used for chloromethylation reaction and without usage of the conventional halomethylation catalysts. 4) The chloromethylation reaction can be carried out at relatively low temperatures thereby minimizing the decomposition of the substituted benzene compounds at high temperatures under acidic conditions, and obtaining the target aryl methyl chloride compound of Formula I in high purity and yield. 5) The process of the present invention provides for easy work up and high purity and yield of the chloromethylated product. The excess hydrogen chloride can be substantially removed by conventional methods such as purging the reaction medium with nitrogen gas and/or applying vacuum, and the remaining hydrogen chloride can be further neutralized if required, resulting in a clean and simple workup with minimum effluent generation, and the resulting aryl methyl chloride without isolation and/or with minimal workup can be further functionalized to the desired product (s).

(55) In view of the above, the present invention provides a novel method for chloromethylation of the substituted benzene in high purity and yield, while minimizing the generation of large quantities of effluent typically associated with this reaction.

(56) The method disclosed in the present invention may be advantageously used for the industrial manufacture of several industrially important products such as heliotropin (from 5-(chloromethyl)-1,3-benzodioxole), piperonylbutoxide (from 5-(chloromethyl)-6-propyl-1,3-benzodioxole) and anisaldehyde (from 4-chloromethyl anisole), among others.