IE42606B1 - 2,3-dihydrobenzofuran derivatives and a process for their preparation - Google Patents

Description

Ihe present invention relates to benzofuran derivatives and to a process, for their preparation. ..: Compounds of the general formula; £wherein. R^ and may be tlie sams ot different and each is . selected from hydrogen or an alkyl group (notably an alkyl group, containing from 1 to 6 carbon atoms, far exanple a methyl, an ethyl or a propyl group) or R, and it, together form an alkylene chain (e.g, one containing from 2 to 5 carbon, atoms} and Rj and R^.. may be the same or different and each is selected- from a lower. alkyl group or it, and Ra together with the i'i. atom form, a . heterocyclic ringZ7 find use as intermediates ia the production of herbicides. The term lower is used herein with respect to alkyl and alkoxy, groups to denote that these groups contain from 1 to 6 carbon atoms. ..It has been proposed that these compounds should be prepared by. reacting the appropriate -enamine, i.e. a confound of .. the general’formula .RjR^ = CH-NRjR^ . II with benrequinone. However,-herbicidal conpounds prepared from the . compounds of formula I produced in this way are unsatisfactory in - 25. that solutions of the herbicidal compounds develop precipitates, on ' - 3 standing. We have found that these precipitates are caused by the presence of hydroquinone derived materials in the intermediate compounds from which the final compounds are prepared. Surprisingly, the presence of an aldehyde of the formula R^CHCHO during reaction of the benzoquinone and the enamine reduces the amount of the hydroquinone materials in the product of formula I and hence in products prepared therefrom. It is thus possible to produce herbicidal compounds of the formula wherein and R2 have the values given above (notably methyl 15 or ethyl); M is an alkyl group containing from 1 to 6 carbon atoms (notably a methyl, ethyl, propyl or isopropyl group) and Rj is an alkyl group, preferably containing from 1 to 6 carbon atoms, e.g. a methyl, ethyl or propyl group) which are contaminated with less than 1 molar percent of hydroquinone derived impurities.

Accordingly, the present invention provides a compound of formula IV ΐ' 43605 (wherein is a group OM or NR^; Rjj_ is hydrogen or a group and Rp R2’ » R4’- RS }- have values above) characterised- in that the compound contains less - than 1 molar percent thereof Of hydroquinone derived impurities.

Ihe hydroquinone derived impurities which are present in less than 1 molar percent are hydroquinone itself in the case ox compounds of formula I and compound of the formula in the case of the compounds of formula III. lhe impurities are readily detected in the compounds of formula IV by gas/liquid IS chromatography. It is preferred that the impurities be present in less than O.S molar percent.

From another aspect, the-present invention provides a process for preparing a compound of formula I rfiidr comprises reacting benzoquinena with a compound of formula II characterised- in that the reaction is carried out in the presence of a_coimpoiBid o£fornula R^CHCKO wherein. Rj and Rj have the values given above.

Ihs precess of the invention is of especial use in the preparation of compounds of formula I in which R, and Rj are same lower alkyl (notably methyl or ethyl) and the group -NRjR^ is .. selected from piperidino, morpholino, and pyrrolidino. In this case the compound of formula R^CHCHO will be an aliphatic aldehyde, notably isobutyraldehyde. the process of the invention will usually be carried out in the presence of a liquid medium. Suitable liquid media for present use include aromatic hydrocarbons, e.g. benzene, toluene or xylene; aliphatic hydrocarbons, e.g. cyclohexane or petroleum ethers; haiogenated hydrocarbons; and aliphatic ketones, e.g. acetone and methyl ethyl ketone. If desired the liquid medium may be provided wholly or in part by the compound Rp^®®0» e,8· isobutyraldehyde is used. However, it is preferred to use a liquid medium in which the compound of formula I and water are only slightly soluble or miscible. Exemplary of such liquid media are the aromatic hydrocarbons.

Ihe benzoquinone and compound of formula II are conveniently used in the forms of solutions or slurries in one of the liquid media specified above and the reaction is preferably carried out with agitation and at a temperature of from 20 to 60°C, e.g. 40 to SO°C, although lower or higher tenperatures, e.g. up to the reflux temperature of the reaction mixture, may be used. Where the reaction is not carried out under reflux, it may be desirable to heat the reaction mixture, e.g. to 100-120°C, in the final stages to assist completion of the reaction.

The amount of the compound of formula R^CHCHO which is present is preferably at least 10, e.g. 10 to 200, molar percent, based on the amount of the compound of formula II, and is typically 2 606 ..... - 6 - ...... in the range 20 to 100 molar percent. The presence of the compound RjRjCHffiO may be achieved by separate addition of the compound to the reaction mixture or by the use of tlie conpound as a solvent or carrier for either or both of the other reagents. However, a convenient method for incorporating the conpound is to use the reaction.mixture in which the conpound of formula II is prepared; Thus, the conpound of formula II may be prepared by reacting a conpound H-NRjR, with gn excess, e.g. 10 to'2005, notably 20-1005, molar excess, of the conpound I^RgCHCHO and the reaction product used directly in the process of the invention without purification, although it will usually bs necessary to remove water . therefrom, e.g. by distillation. The present invention-therefore also provides a process for preparing a compound of formula I or a . derivative thereof-which comprises: reacting a conpound of formula 15 H-NRgR^ with an excess of a conpound of formula RjS^GHGK) to give a reaction mixture containing a conpound of formula II and the eonpound R^RjCHCKO: and reacting this reaction mixture with.’ - benzoquinona; . ..

Khilst the preparation of the conpound of formula I may.be carried out by adding a solution of the enamine of formula II to a .. solution or slurry of the-benzoquinone, we have found that the product of such a reaction may be discoloured due to side reactions and surprisingly that these side reactions -are suppressed if the ..enamine is present for most or ail of the reaction period in rare . ..than the. stoichiometric amount: required to react with the benzoquinone 2 6 0 6 Whilst the preparation of the compound of formula I may be carried out by adding a solution of the enamine of formula II to a solution or slurry of the benzoquinone, we have found that the product of such a reaction may be discoloured due to side reactions and surprisingly that these side reactions are suppressed if the enamine is present for most or all of the reaction period in more than the stoichiometric amount required to react with the benzoquinone.

The presence of the requisite amount of enamine in the reaction mixture can be achieved by, for example, adding the benzoquinone either as a single addition or progressively over a period of time to a reaction mixture containing the desired amount of enamine; or by adding the benzoquinone and enamine in the desired proportions to a continuously operated process. Preferably, the overall excess of the enamine employed is from 1 to 101, notably 1 to 41, molar although higher excesses may be used if desired and during the initial stages of a batch process where benzoquinone is added progressively to the enamine much larger excesses may occur.

Thus, the present invention also provides a process for preparing a compound of formula I which comprises reacting a compound of formula with an excess of a conpound of formula R^t^CHCHO in the presence of an organic solvent to form a reaction mixture containing a conpound of formula II; and reacting this reaction mixture with benzoquinone, the conpound of formula II being present • ¢2606 _in the reaction mixture at substantially all times in more than the . stoichiometric amount required to react with the benzoquinone present in. the reaction mixture. The invention also comprises a process for preparing a compound of formula I- which process 5 comprises reacting bsnzcquinone with a compound of formula II characterised in that the reaction is carried out in the presence of a compound of formula R^GICHE) and in that at substantially all times during the reaction the compound of formula II is present in more than the stoichiometric amount required to react with the benzoquinons present in the reaction mixture, The processes of the invention-may be carried out batchwise or as a continuous process' and the product of formula I may be recovered using customary techniques, e.g'. by filtering the reaction mixture-in which it is produced to recover the solid product which may thereafter be washed. However, where the compound of formula I is used as an intermediate in the production of other conpoimds, e.g. of formulae HI or IV, it may not be necessary to separate it from the reaction mixture. ’ -Ihe intermediate cospounds of formula IV are of especial use in the preparation of the herbicidal compounds of formula III, that is conpounds of formula IV where R^q is CM and is RgSO^· ..From another aspect the invention provides a process for preparing a compound of formula III which comprises treating a . compound of formula IV £wherein_R,Q is CM or NR^R^ when Rq is.. .. hydrogen or ί^θ is KRjR^ when R^ is R.SOZ and which compound is 43606 ~ 9 contaminated with less than 1 molar percent of hydroquinone based inpurities27 so as to convert a 2-NRjR^ group to a 2-OM group and/or a 5-OH group to a 5-RjS020- group.

This is conveniently done by reacting a compound of formula IV 5 with a conpound RgSO^l (where Hal is halogen - notably chlorine) to convert the 5-OH group into a 5-SO3Rg group; and/or converting the 2-NRjR^ group into an -OM group by hydrolysis and alkoxylation. These conversions may be carried out in either order. Preferably the conpound of formula IV has itself been prepared from a conpound of formula I obtained by a process described above.

The present invention therefore also provides a process for preparing a compound of formula /^wherein R^ and R£ may be the same or different and each is selected from an alkyl group or R^ and Rg together form an alkylene chain; M is an alkyl group; and Rg is selected from hydrogen or a group RgSOgwhere Rj is an alkyl groupJ7 which comprises: Stage (a) reacting benzoquinone with an enamine of formula: r1r2c-ch-nr3r4 II /^wherein and Rj have the values given above and Rj and R^ may be the same or different and each is selected from a lower alkyl group ‘'dSSC® - or Rg and together with ..the N atom form a heterocyclic ring27 in the presence of a compound of formula RjI^CHCHO, the enamine preferably being present at substantially all times during the reaction period, in iaore than the stoichiometric amount required - 5 to react with the bensoquinone; whereby there is produced a cosoouad of formula and optionally converting this compound into a compound of formula IV where RjQ is NR3R4 and Rjj is RgSQg by reaction with a compound of. formula Hal’SO^Rg' 15 Stage (b) reacting a conpound of fonnula with an acid as hereinafter defined and a compound.of formula HOM (where M has the values given above), preferably in a single stage, whereby there is produced, a compound of fomila VI, Ihe conversion of. the NRgR^ group to an CM group, e.g. is 25 suitably achieved by treatanentwith an acid and.an alkanol. This - 11 4260G treatment may be carried out in a single stage and preferably Stage (b) is carried out in a single stage by using a mixture of acid and alkanol as is described and claimed in Patent Specification No' Z/'/i S The term acid as used herein in respect of Stage (b) is to denote a strong acid, which may be a mineral acid or an organic acid; which does not take part in deleterious side reactions during the Stage (b) of the process, apart from forming a salt with the amine HNRjR^ released during the process; and which preferably dissociates in water to give at least 1 gram equivalent of H+ per gram mol of acid. Thus, suitable acids for present use include hydrochloric, sulphuric and phosphoric acids, but do not include nitric acid which may oxidise the reagents and/or products. The acid may be used in the form of an aqueous IS solution thereof or in an anhydrous form. Ihe mineral acid for present use is preferably hydrochloric acid which desirably provides not less than 20 parts by weight of HCl per 80 parts of water in the reaction mixture.

The compound HCM is, as indicated in the preferred conpounds which it is desired to produce, preferably a lower alkanol, notably methanol, ethanol, propanol or iso-propanol.

Stage (b) is preferably carried out in a liquid medium, which may be merely an excess of the alkanol reagent. However, the process is conveniently carried out by adding the solution of the conpound of formula I produced in Stage (a) of the process 2 6 0 6 - 12 to an agitated mixture of the-acid and alkanol so as to-fern a two phase reaction mixture. The addition may take place in one or more stages, or may he on a continuous, basis where the process is operated continously^ The reaction, may be carried out at elevated temperatures, although it is preferred to use temperatures -. below 40°C.. ’ We have found that the relative proportions of acid, alkanol, and conpound of formula I affect the yield and quality of the product. We prefer to employ more than 1.5 molar proportions of alkanol and mare than 1.2 molar equivalent proportions of acid per molar proportion of compound of formula I.. Whilst.the process may ; be carried out under substantially anhydrous conditions, as when H,SO4 is used as the acid, water my be preferred with some acids, e.g. when HCl is present. In this case we prefer to use more than IS 0.35 parts by weight of HCl per part of water ia the reaction .mixture. · It is preferred to agitate the reaction mixture and it will be appreciated that all weights ahd proportions-are in respect of the total reactioh mixture not just the organic or aqueous phase.

Apart from the reagents and solvents, the reaction mixture may contain minor amounts of other, non-deleterio.us materials.

Thus, the compound of formula II need not be in pure form but -may be. used in the . form, of the reaction product from an earlier . process step as outlined below. · - ' 25 Tne compound of formula VI may be recovered, from the reaction - 13 42506 mixture by allowing the mixture to separate into organic and aqueous phases, removing the organic layer and recovering the product therefrom, e.g. by distillation (to remove excess alkanol and solvent when present), washing with a mild alkali (e.g. sodium S carbonate) and further distillation, preferably under reduced pressure, to remove final amounts of solvent. The isolated product may then be purified by conventional techniques.

As indicated by formula VI, the product of the above process may have the 5-position in the form of a 5-OH group or a derivative thereof. However, it is preferred that the 5-position be in the form of an RjSO2O- group, ie that the product be of the general formula III. This group is preferably a CHjSO2O- group and is preferably introduced into the intermediate compound of formula I by reacting this conpound with HalSO^Rj in the presence of an acid acceptor (Hal being halogen, notably chlorine) between Stages (a) and (b). Alternatively, the RgSO2O- group may be introduced by reacting a conpound of formula VI wherein Rg is hydrogen with Hal SO2Rg after Stage (b) of the invention has been carried out. in reacting a conpound of formula I or VI with Hal SC^Rg, the reaction is carried out in the presence of an acid acceptor which term includes tertiary amines, notably trialkylamines, e.g. trimethylamine or triethylamine; tertiary aromatic amines, e.g. dimethyl-aniline; and pyridine and its homologues. Whilst the reagents may be used in substantially the stoichiometric amounts, 2.6 0 6 is prefer to use a small excess, e.g, up to 20J molar excess, of the co:iwund R^SO^al based on the compound of formula I or VI and an excess, e.g: 10 to 501 molar excess, of acid acceptor based on the amount of H-Hal which would theoretically be liberated.

- Itie reaction may be carried out merely by mixing together the R-SO2fel and compound-of formula I or VI sioltsucously or sequentially and in one or- more stages* Desirably the reaction temperature is less than 100°C, preferably within the range 30 to EO°C. However, to aid uniform reaction \:s prefer to carry cut the .reaction in an organic solvent as reaction asdiisa, or in an excess th© acid acesotnre Sui.t®ble solvent? 3.π.^1·ϋ.^*3Τΐθ!ΐ*?χ?ΐ3? or^snic solvents, e.g. benzene, toluene, xylene or hexane. liken the reaction is substantially ccmalets·, as evidsnesd byanalysis of a sample showing little or so reaaining initial conpound 15 of formula I or VI, the product may be recovered using conventional techniques. However, where 'die pic&ici-hts not been subjected- to Stage fo) of the process of the-invention, i.e. is a compound of fofiuula VII where Sg is EgS9?-, we prefer-not ts iselato the product but merely to extract the halogen salt of the acid acceptor from the reaction. raixture by water extraction and ts separate off the organic layer containing the co:m>ound of fbmula VII for use in preparing tlie compound of formula VI where is R*S32~ ^*e‘ a conpound of formula III) as described above.

From the above, it will be seen that the stages of the process ‘dle inVentioa ilsay bg SiffSliarised SS:;' ΐ RRRRR URRlRRRUR - 15 42606 Stage 1 R^CHCHO Stage 3A + HNR^ H RjSO^Ial + acid acceptor acid + alkanol Stage 5B IX Stage 4B RgSOgHal + acid acceptor R5so2< «1 R-, III as?®6 . ? l.G - - - ·, ....... ··' · · The above process stages say be carries out as distinct aid separate steps bat, as indicated above, readily lend themselves to sequential operation in that reaction products from -one stage may be- used directly in a later stage. Itetherraore, ifc is possible to recover excess reagents and solvents for rs-use.

Tnus, acid acceptor way be recovered item tiie -aqusauB phase frost stage 3A or 4B by treatment of the halogen salt with alkali (e.g. HaOH) and subsequent distillation; the organic phase of the reaction mLsturas from stages 3£. snd/or 4A way be fractionally. distilled to recover .alkanol and solvent, and the aquions paas&S may be distilled to recover alkanol and, possibly, acid, the residue then being treated with alkali ro liberate the amine HMRjR^ and the acid acceptor nb.ich may have best carried over in the organic phase from stage SA to stage 4A ana this residue is fractionally distilled to recover amine for use in stage 1 and acid accepter for uso In stages 3A or 4B.

Tne process of the invention will naw be illustrated by the following Examples, in which all parts and percentages are given by weight unless stated otherwise: . Exanple -1 Preparation of enamine of formula II ·' - To a stirred mixture of 332 parts of isobutvraldshyds (100% molar percent excess) with 867.5 parts of toluene were added 200.3 parts of morpholine. The temperature rose from 20°C to 4I°C. The mixture was refluxed with continuous separation and removal of tlie 3 β Ο 6 aqueous phase from the returning solvent stream. To complete the water removal, the final stages were carried out with a fractionation column. The total time at reflux was 4.8 hours. Preparation of 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-norpholino5 benzofuran of formula I To 54 parts of technical benzoquinone were added 51.5 parts of toluene and to this slurry was added sufficient of the enamine solution as prepared above to be equal to a 4i molar excess of enamine to technical benzoquinone. The tine of addition was 0.7 hours, reaction temperature 4O-45°C during addition. After a further 0.7 hours the reaction mixture was raised to the boiling point and maintained at reflux for 0.25 hours. After cooling to 25°C the insoluble product was filtered off, washed with toluene, and air dried to constant weight giving 2,3-dihydro-3,3-dimethyl15 5-hydroxy-2-morpholino-benzofuran.

The yield of 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-morpholinobenzofuran was 89.31 based on the benzoquinone starting material and the purity was 98.71 by analysis. The hydroquinone impurity ί in the product was 0.21.

Comparative example The above steps were repeated, except that the enamine solution was fractionally distilled to remove unreacted isobutyraldehyde so that no significant amount of isobutyraldehyde should be present during reaction of the enamine with the benzoquinone. In this case the 2,3-dihydn>-3,3-dimethyl-S-hydroxy-2-norpholino-benzofiiran was jtgQOS ; - is - produced in 89.2ί yield and at a purity of 96.li. Tne hydroquinone content was 1.6¾.

Example Z ’ . _ The process of the Oonparative Example was repeated, except that iscbutyraldehyde in an equimolar amount based on the-enamine used, was added as a separate feed to the reaction vessel in which the 2,5-dihydro-3,3-di1’isthyl“3“liydTOxy“2“iB3iph01ino-beuzo£i.’r2n was being prepared. The product was produced in 901 yield, at a purity of 97-.8¾ and with a hydroquinone content of 0.2¾. .....

Sample 3 ..... .

To a stirred-mixture of 332 parts of isobutyraldshyde (ICO? irnlar per cent excess) with 867.5 parts of toluene were added 200.5 parts of morpholine. Tne temperature rose from 20°C to 4I°C. The mixture was refluxed with continuous, separation and removal of tlie aque.ous phase from the returning solvent stream. To conslete' the water removal, the final stages were carried out with a fractionation column. Hie total time at reflux was 4.3 hours. To this enamine solution was added a total of 238.2 parts of technical fcenroquinone (95.7¾ molar on the naipholihs assuming 1001 :0 conversion to enandne) over a period of 1.2 hours, ’’he Temperature was maintained ar 35-45¾ throughout the addition by heating or cooling as required. When the heat of reaction was no longer observed, the reaction mixture was raised to the boiling point ananaintained at reflux for 0.5 hours. After cooling to 2S°C the 5 . insoluble product was filtered- off, washed with 670 parts of toluene, 4200β and air dried to constant weight giving 50S.1 parts of 2,3-dihydro3,3-dimethyl-5-hydroxy-2-morpholino-benzofuran, yield 91.7¾ based on the technical benzoquinone used.

Example 4 To a slurry of 108 parts of benzoquinone in 104 parts of toluene was added 0.52 molar equivalents of enamine dissolved in toluene and isobutyraldehyde and prepared in a similar manner to the enamine solution used in Exanple 3. The addition time was 0.75 hours, reaction temperature 4O-45°C. The reaction mixture was left agitating for 16 hours before a further 0.52 molar equivalents of enamine solution was added. After refluxing the reaction mixture and isolating the product as described in Exanple 1, 208.3 parts were obtained, equivalent to an 83.6¾ yield based on the technical benzoquinone used.

Whereas the product obtained in Exanple 3 was light tan in colour, the product from this Exanple was grey.

Example 5 Preparation of 2,3-dihydro-3,3-dinBthyl-2-morpholino-benzofuran-5yl methane sulphonate of formula VIII The product from Exanple 1 (112.5 parts) was reslurried in 350 parts of toluene and heated to 40°C with agitation. Methane sulphonyl chloride (56.5 parts) and triethylamine (50.5 parts) were added simultaneously but separately to the reaction mixture, which was maintained at 40-46°C, over a period of 0.35 hours. A further 5 parts of triethylamine were added, followed by 110 parts of •ξ .-w·--,-.-.-.::?:y-··· <.- :ftΐί-ί :-·· 'ί-ι-'-'ΐι:!·-'/:-,yiyisy7--- =<- ': ΐ··. ιιιτ.ιαα-' - <----- -Υ- ·?<<<:λ-~-:-·-·,:: · ·-->; water. Tne two phase reaction mixture was Iieaied to 5G-S5°C and then allowed to separate. Ihe lower, triethylamisie hydrochloride layer 'was removed. The upper organic layer was evaporated to dryness to give solid 2,3-dihydro-3,3-dimethyl-2--morpholinoS·. b.enzo£uran-S~yl. methane sulphonate, < - Preparation of- 2, S-ciliydro-S-diirs'dtyl-Z-etlieay-bs-na-sfur.Hi-S-ylBiethane sulphonate of fomaila III Ihe product from the above stags (24.9 parts) was- suspended in water (SO parts) and aidiydiOus hydrochloric scia (22,4 parts), The suspension was rapidly heated to 90-100°C and- then-cooled after 2 minutes, Ihe crude product was extracted into ether (3 x 60 parts) and the extracts washed with water (2 x SO parts), Tire extracts were dried with sodium sulphate and evaporated to give a gum which crystallised to give 253-dihydrQ-=3c3»dirstoyl-2IS hydrcxy“benzofura&-5“yi--!iEthane sulphonate crystals. Ihe crystals were dissolved in ethanol containing 2 drops of sulphuric acid and refluxed for one .hour, Tne mixture was then cooled, - neutralised with triethylamine and evaporated to about-one quarter '22-/222 v 2:/2 '222:1 222:2'222222-2:252222:2- 222:2 2: 22::2 /:/2:2-22-222'' of its volume, ’fetor was added to precipitate 2„3-dijiydra“3,320 dia3thyl“2-ethoxy“benzofuran”5=yl-irathanc sulphonate, Tris product contained 0.41 diirssylquinol isrpurity as compared to 21 in a product produced from material derived from the Coriicnrativs Example . to .Example-1-. - · _-. - ...........- . = - .--- 25 3 SOC Exanple 6 Stage (a) Preparation of enamine of formula II and its conversion to a compound of formula I To a stirred mixture of 332 parts of isobutyraldehyde (1001 5 molar per cent excess) with 867.5 parts of toluene were added 200.5 parts of morpholine. The tenperature rose from 20°C to 41°C. The mixture was refluxed rath continuous separation and removal of the aqueous phase from the returning solvent stream.

To complete the water removal, the final stages were carried out with a fractionation column. The total time at reflux was 4.8 hours. To the enamine solution thus produced was added a total of 238.2 parts of technical benzoquinone over a period of 1.2 hours.

The tenperature was maintained at 35-45°C throughout by heating or cooling as required. When the heat of reaction was no longer IS observed, the reaction mixture was raised to the boiling point and maintained at reflux for O.S hours. After cooling to 25°C the insoluble product was filtered off, washed with 670 parts of toluene, and air dried to constant weight giving 505.1 gms of 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-morpholino-benzofuran.

Yield 91.71 on the technical benzoquinone used.

Stage (b) Preparation of compound of formula VIII and its conversion to a compound of formula III Preparation of 2,3-dihydro-3,3-dimethyl-2-morpholino-benzofuran-5yl-methane sulphonate Stage 3A) The product from Stage (a) (505.1 parts) was reslurried in <33606 1083 parts of toluene and heated ta 40 C with agitation, Msthais sulphonyl chloride (253 parts) and triothylamine (228 parts) tiers added simultaneously but separately to the reaction mixture, wnich vias maintained at. 40-46¾ over a period o£0.35 hours, A _ S further.23 parts, of triethylamine. were added, followed by 585 parts of water. Ihe two phase reaction mixture was heated to 50-55¾ and then aliened to separate. Tne lower, triethylamine hydrochloride, layer was removed and the upper organic was passed to-stage 4A-. -- .......

Preparation of 2,3-dihydro-3,3-dinsthyl-2-etho2y-benzofaran-£-yl nrtliane sulphonate (Stage 4A) - ' .

Tc- the solution from stage 3A were added 350 parts of ethyl -. - alcohol, 43 parts of water, and 655 parts of 301 w/w hydrochloric acid. The temperature rose to 47VC._ The two-phase reaction mixture wss agitated for 16 hours with cooling to 20°C and after settling, the lower aqueous layer was removed.

The upper solvent layer was distilled to remove the bulk of ///th® solution to remove traces of hydrochloric acid. The solution was 20 then distilled to remove the remaining- toluene xsaving 564 pasts of product - yisld 87.Si on the technical, bensequinone used in - Stage (a). . '- - '< ....... ... . -23 4 3S06 Example 7 Alternative method for carrying out Stage (b) in Exanple 6 Preparation of 2,3-dihydro-3,3-dimethyl-5-hydroxy-2-ethoxybenzofuran of formula IX - (Stage 3B) Parts of 2,3-dihydro-3,3-dimethyl-S-hydroxy-2-morpholinobenzofuran prepared as in Stage (a) of Exanple 6 were allowed to air-dry after filtration and were added to 513 parts of ethyl alcohol and 32.5 parts of water. To this were added 72 parts of concentrated sulphuric acid and the mixture was refluxed for 4 hours.

The reaction mixture was cooled and poured into 3200 parts of ice and water to give an oil which solidified on seeding with previously prepared product. This product was filtered off and air dried. Yield: 57.7 parts, purity by GLC 95%, equivalent to a molar yield of 67.51. Continuous ether extraction of the filtrate showed that a further 5.5% of product had remained in solution.

Stage 4B - Preparation of 2,3-dihydro-3,5-dimethyl-2-ethoxybenzofuran-5-yl methane sulphonate of formula III 8.32 parts of the product from stage 3B were dissolved in 20 parts of toluene and 6 parts of triethylamine. To this were added 6.3 parts of methane sulphonyl chloride over 0.2 hours, the tenperature being maintained at 4O-45°C. 15 parts of water were added with agitation, and after separation of the lower layer and evaporation to dryness, 11.7 parts of product were obtained, purity 911 by GLC, equivalent to a 981 molar yield.

Claims (3)

1. A process for preparing a compound of tlie formula NR_R. 4 4 £uherein Rj -and R? may be 'die sans or different and each is selected fiou! hydrogen or an allyl group or and Ih together form 10 si alkylene chain: and R^ snd R, may be die sane, or different and each is selected from a lower allcvl tjroun or it. nnd R, together ’ R^OCH-MR^ Ills ^wherein R., s ih? Hi - QSVS ®- e values given above/ - characterised in that the reaction is carried out in the 0^! a compound of formula R-R-ffiffiO wherein It cad hsi r e -* e values - given above. -.. - ( - 2. A process as claimed in claim 1 wherein tlie compound Κ,ί^ΟΐίΉΰ 20 is present in at least 10 molar percent based on the confound of formula II, - -- - l· 3. A process as - claimed-in claim 1 wherein the-compound R^R^CHGiO is present in from 10 to 200 volar percent based on the compound of formula II, ' - - . 23 4, A process as claimed iir-any one-of the preceding-claims - 25 wherein the compound of formula II is prepared by reacting a compound of formula HNRjR^ with an excess of the conpound R^CHCHO to give a reaction mixture containing the compounds of formula II and R^I^GICHO, and reacting this reaction mixture with 5 benzoquinone. 5. A process as claimed in any one of the preceding claims characterised in that in the reaction between the benzoquinone and the conpound of formula II the conpound of fornula II is present at substantially all times in more than the stoichiometric amount 10 required to react with the benzoquinone present in the reaction mixture. 6. A process as claimed in any one of the preceding claims for preparing a conpound of formula I or a derivative wherein the conpound of formula II is prepared by reacting a conpound of fornula 15 H-NRjRj with an excess of a conpound of fornula R^CHGIO in the presence of an organic solvent to form a reaction mixture containing a conpound of fornula II; and reacting this reaction mixture with benzoquinone, the conpound of fornula II being present in the reaction mixture at substantially all times in more than the stoichiometric 20 amount required to react with the benzoquinone present in the reaction mixture. 7. A process as claimed in claim 6 wherein water is removed from the reaction mixture containing the conpound of fornula II before it is reacted with benzoquinone. 25 8. A process according to either of claims 5 or 6 wherein tlie 3.6 ο ..θ compound of formula II is employed in sn overall excess _of from 1 to 10-molar percent. 9. Λ process for preparing a compound of the fomila Vo 2 c. /. R. I ri —H. in /wherein R, and R, may he the same or different and each is -. X Λ - 10 selected from hydrogen or an alkyl group or R, and together form an alkylene chain; M is a lower allyl group; and Rg is air ailyl .greup27 which comprises treating a compound of formula *11 ,/ IV /wherein Rgg is a group G'-i or WR^R^ when R,, is hydrogen or i NR-Jt, when R,, is R-SO,- and which ccEcound is conhjjnina'tedιάϊ&20 less than 1 molar percent of hydroquinone based inpuritieO' ? ° 33 to convert a 2-fS^R. group to a 3-GM group and/or s-5-63’group to: lO. A process as 1 ΰίείίΕΰ ίη οΐΩηι 9 1Α©Γδϊη £ng. ccuU’ersion O£-£ne 5-QR group is achieved by reaction with, a «wound of formula nalSO^RgHterelnKsi/denotesfislogen, 42506 11. A process as claimed in either of claims 9 or 10 wherein conversion of the Z-NRjR^ group is achieved by hydrolysis and alkoxylation. 12. A process as claimed in any one of claims 9 to 11 wherein the compound of formula IV has been produced by a process as claimed in any one of claims 1 to 8. 13. A process as claimed in any one of claims 9 to 12 wherein the “NRjR^ group is hydrolysed and alkoxylated before conversion of the 5-OH group is carried out. 14. A process for preparing a conpound of formula: /^wherein R^ and R2 may be the same or different and each is selected from hydrogen or an alkyl group or R^ and R2 together form an alkylene chain; M is an alkyl group; and is selected from hydrogen or a group Rj^- where Rg is an alkyl group_7 which conprises: Stage (a) reacting benzoquinone with an enamine of formula: R 1 R 2 C=ffl-NR 3 R 4 II ^wherein Rj and R2 have the values given above and Rj and R 4 may be the same or different and each is selected from a lower alkyl group or R- and S, togsthsr with the N atom fora-a heterocyclic ring!? in the presence of a cospatrid a£ fontula R-R^SCHO, whereby there is produced a coapound of fomiila; .: and optionally converting this compound into a compound or .10 formula- .· ......- . Rg-SGnG -“-γ/· Tv -.-, -r,- _Q Ί Ipj rbb O VyR'RSRuWEr VXII IS by reaction with a compound of formula fiaiSOjK; ttotsin-Hal. -Stage fo) reacting s «wound of fortiula: ' _ , vn with' an acid (as hereinbefore defined) and- a csffiporad of foxeDfe HS (where M has tba valwis given above), whereby there is produced a conpound of formula VI. IS. Λ process as claimed in claim 14 wherein the product compound of formula VI is reacted with a conpound of formula RgS0 2 Hal (Hal being halogen) to give a compound of formula III 16. A process according to claim 14 wherein the compound of formula I is reacted with a conpound of formula RgSO 2 Hal (Hal being halogen) to give a compound of formula VII wherein Rg is a group R^SC^-. 17. A process according to any one of claims 14, 15 or 16 wherein the reaction with the conpound R-S0 2 Hal is carried out in the presence of an acid acceptor. 18. A process according to any one of claims 10 and 14 to 17 therein the compound RjSO^Ial is used in up to 20ί molar excess based on the amount of the conpound of formula I, IV, VI or VII. 19. A process as claimed in any one of the preceding claims therein and Rj are the same and are both selected from a methyl, ethyl or propyl group. 20. A process as claimed in any one of the preceding claims wherein R$ is selected from methyl, ethyl or propyl. 21. A process as claimed in any one of the preceding claims wherein M is selected from methyl, ethyl or propyl. Γ·5β-·ί-ί:-ν— 30 21. A process as claimed in any oris ox the preceding elaisis .. wherein -NR^ represents a vo^holino, piperidino or pyrrAJidiaQ ®W- - 23. A process aecerding to claia i for prewring & ctapdyndlff 5 fenaila ΐ substantially as heteinhefooss desctfiR&«. ; , - 24, A process according to claim 1 for prapariiig a coHwuaa-ef ftenarls 1 gcistgftti i ’ily as her^-®hofere dsserissdriS's^-GK&'Si Examples 1 ta 4-.' ' - ~ . 25, A process as clgtaed in any one o£ deal® I ’ta 5 tSieraial£x 9s© exanporaai of forwila ϊ is k^S-diJ^ropS^S-’ihKridiyl-S-sSigiteXxSv·' 5-hydrcxy bsnfofuran. - - ' _ - 26. A process as ciainsa ia any oas fi£ dlaiiis J ti 22 ijhexSfe Άε conpound of fem-ls HI is 2 , benzsforaa-5-yX neshaae sulphonate- 15 27. A cispataa of fernule I tfenever produced fey o process'ai clsimad in any cos s£ daisss 1 to Saad It co Iff28, A process aeeo’xS.ng te clsiicS &r produclrsgla s&spas&ikQfi , foTcda IF! sthstaiidd ly os fesilrfewsa dfescw.-ed, -- -H ye. 4 process -ter producing n cospaiss of fextsila Hi - ' .

2. C substantially as tereirfoeibre described ift ary 'aft£ox SEffl^ss'STjp 3f* A stoi-ws for ^repaying ? setesMd of ifei fe»ial,f 4 8 6 0 6 which comprises reacting p-benzoquinone with from 1 to 4¾ molar overall excess of the enamine (QIg) 2 c?-O in the presence of from 10 to 200 molar Ϊ of isobutyraldehyde (based on the enamine) in an aromatic hydrocarbon medium; reacting the reaction product 5 with CHj SO 2 C1 in the presence of an acid acceptor; and reacting the reaction product in separate stages with ethyl alcohol and a mineral acid selected from sulphuric acid, hydrochloric acid and phosphoric acid. 31. A conpound of formula III whenever produced by a process as 10 claimed in any one of claims 9 to 22, 28, 29 and 30. 32. A conpound of fornula £wherein and may be the same or different and each is selected from hydrogen or an alkyl group or Rj and together form an alkylene chain; R^ o is a group OM or NRgR^; R^j is a group RgSOg or is hydrogen; M is an alkyl group containing from 1 to 6 carbon atoms; and may be the same or different and each is selected from a lower alkyl group or Rg and together with the N atom form a heterocyclic ring; and Rg is an alkyl groupJ7 which is contaminated with less than 1 molar percent of hydroquinone derived inpurities. 33. A conpound as claimed in claim 32 wherein R^ and R2 are the 25 same and both are selected from methyl, ethyl or propyl groups.

3. Ί ~A, Λ roBKojnd ss ciaissd In inditr (a elaiifc- 5?,£nd 33'istsrs&r. Rjg is a Icyer -siXojq? group- „ , 35. A r»taQiffw a. clain/d sa v# -QOn- d cialss 32 ta 3£*ii8g£Khi Rj. is a sstbyi ethyl oy proryi >7303, 36, A copgijiBia ss claL’ed m say one ai claias 1 3?. 33 or 35 'Sseteia represents £ κοηώβΗηο, ριρ&Α&τ,ο or eyrnolidi» ^βφ·,.. eU.rSr’nais -S csgtassinapgd s^ieh Isss ¢33,1 'gaifix pgrsfafr afcetdnoi. ~ ~ ~ -'”