PROCESS FOR PRODUCING SUBSTITUTED 2-ALLYLANILINES AND SUBSTITUTED 4-AMINOINDANES

Abstract

The present invention primarily relates to a process for producing certain substituted 2-allylanilines of the hereinbelow-defined formula (I) and their use in a process for producing substituted 4-aminoindane derivatives of the hereinbelow-defined formula (V). The present invention further relates to a process for producing fungicidal indanyl carboxamides. In particular, the present invention relates to a process for producing 2-(difluoromethyl)-N-(1,1-dimethyl-3-propyl-2,3-dihydro-1H-inden-4-yl)nicotinamide and/or 3-(difluoromethyl)-N-[(R)-2,3-dihydro-1,1,3-trimethyl-1H-inden-4-yl]-1-methylpyrazole-4-carboxamide.

Claims

1. Process for preparation of a compound of the formula (V) ##STR00045## in which R.sup.1 represents (C.sub.1-C.sub.4)alkyl; R.sup.2 represents hydrogen or (C.sub.1-C.sub.8)alkyl; R.sup.3 represents hydrogen or (C.sub.1-C.sub.8)alkyl, provided that R.sup.2 and R.sup.3 are not hydrogen at the same time; R.sup.4 represents hydrogen, halogen, (C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)haloalkyl, comprising (d) reacting a compound of Formula (I) ##STR00046## wherein the definitions of the substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 listed in the formula (I) are the same as in the formula (V), is reacted with aqueous sulfuric acid or anhydrous HF.

2. The process for the preparation of a compound of formula(V) according to claim 1 comprising (b), (c) and (d), wherein in (b) a compound of formula (III) ##STR00047## in which X represents a halogen or O—SO.sub.2R wherein R is a methyl, phenyl or tolyl group is reacted with a compound of formula (IIIa) ##STR00048## to obtain a compound of formula (IV) ##STR00049## and wherein in (c) a compound of formula (IV), is rearranged in the presence of an acid to obtain a compound of formula (I) ##STR00050## and wherein in (d) a compound of formula (I) is reacted with aqueous sulfuric acid or anhydrous hydrogen fluoride (HF), to yield a compound of formula (V).

3. The process according to claim 1, wherein R.sup.1 is n-propyl, R.sup.2 and R.sup.3 are methyl and R.sup.4 is hydrogen.

4. The process according to claim 1, wherein R.sup.1, R.sup.2 and R.sup.3 are methyl and R.sup.4 is hydrogen.

5. The process according to claim 1, wherein in (a) a compound of formula (II) ##STR00051## is converted in the presence of an activating agent to a compound of formula (III).

6. The process according to claim 1, wherein a solvent in (a) and/or (b) and/or (c) is selected from the group consisting of chlorobenzene, toluene, xylene, anisole and trifluorobenzene, optionally the solvent is chlorobenzene.

7. The process according to claim 1, wherein (a) is carried out at a temperature in a range of from −5° C. to 120° C.; and/or (b) is carried out at a temperature in a range of from 10° C. to 90° C.; and/or (c) is carried out at a temperature in a range of from 80° C. to 140° C.

8. The process according to claim 1, wherein (b) is conducted in the presence of an additional base, wherein the additional base is selected from the group consisting of N-methylmorpholine, diisopropylethylamine, N,N,N′,N′-tetramethylguanidine, tri-n-butylamine, triethylamine, 1,4-Diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-undec-7-ene, N-Methylimidazole, potassium tert-butoxide, sodium tert-butoxide and lithium tert-butoxide, optionally the base used in (b) is selected from the group consisting of N-methylmorpholine, diisopropylethylamine, N,N,N′,N′-tetramethylguanidine, tri-n-butylamine and triethylamine, optionally the base used in (b) is selected from the group consisting of N-methylmorpholine and diisopropylethylamine.

9. The process according to claim 1, wherein the acid in (c) is selected from the group consisting of 4-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, Zn(OTf).sub.2, Cu(OTf).sub.2, Ni(OTf).sub.2, Fe(OTf).sub.2, Fe(OTf).sub.3, benzenesulfonic acid, sulfuric acid, sulfamic acid, phenylphosphonic acid, ethylphosphonic acid, phosphoric acid, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid and trifluoroacetic acid, optionally the acid in (c) is methanesulfonic acid, optionally the acid in (c) is 4-toluenesulfonic acid.

10. The process according to claim 1, wherein (d) is carried out at a temperature in a range of from −80° C. to 30° C., optionally at a temperature in a range of from −50° C. to 20° C.; optionally at a temperature in a range of from −30° C. to 20° C.

11. The process according to claim 1, wherein in (d) the aqueous sulfuric acid having a concentration of at least 85 w % is used.

12. The process according to claim 1, wherein an amount of used aqueous sulfuric acid or anhydrous HF is in a range of from 3-45 molar equivalents, optionally of from 6 to 40 molar equivalents, optionally of from 9 to 35 molar equivalents based on the total amount of the compound of the formula (II).

13. A process for preparation of a compound of the formula (VII) ##STR00052## wherein in formula (VII), comprising the process according to claim 1 and further comprising (e), wherein a compound of the formula (V) is reacted with a compound of formula (VI) ##STR00053## to obtain a compound of formula (VII).

14. Compound of formula (III) ##STR00054## wherein R.sup.1 represents (C.sub.1-C.sub.4)alkyl; R.sup.2 represents hydrogen or (C.sub.1-C.sub.8)alkyl; R.sup.3 represents hydrogen or (C.sub.1-C.sub.8)alkyl, provided that R.sup.2 and R.sup.3 are not hydrogen at the same time; R.sup.4 represents hydrogen, halogen, (C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)haloalkyl.

15. Compound of formula (IV) ##STR00055## Wherein R.sup.1 represents (C.sub.1-C.sub.4)alkyl; R.sup.2 represents hydrogen or (C.sub.1-C.sub.8)alkyl; R.sup.3 represents hydrogen or (C.sub.1-C.sub.8)alkyl, provided that R.sup.2 and R.sup.3 are not hydrogen at the same time; and R.sup.4 represents hydrogen.

Description

DETAILED DESCRIPTION OF THE PROCESS

[0063] The process according to the invention can be conducted as shown in schemes (1) to (3):

##STR00027##

##STR00028##

##STR00029##

[0064] In scheme 1 the substituents X, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 of the formulae (I)-(IV) each have the general, preferred, particularly preferred, more preferred or most preferred meanings which have already been defined for these substituents in connection with the description of the compounds of the formulae (I) to (IV).

[0065] In scheme 2 the substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 of the formulae (II), (IIIa) and (I) each have the general, preferred, particularly preferred, more preferred or most preferred meanings which have already been defined for these substituents in connection with the description of the compounds of the formulae (I) to (IV).

[0066] In scheme 3 the substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 of the formulae (I) and (V) each have the general, preferred, particularly preferred, more preferred or most preferred meanings which have already been defined for these substituents in connection with the description of the compounds of the formulae (I) and (V).

[0067] The process shown in scheme 1 is the process according to the invention when conducted stepwise, i.e. the steps (a), (b) and (c) are performed consecutively.

[0068] The process shown in scheme 2 is the process according to the invention when conducted as a telescoping synthesis. This means, the process is worked as a sequential one-pot synthesis with reagents added to a reactor one at a time and wherein minimal work-up procedures are performed during the process.

[0069] The reagents used and reaction conditions applied in the processes shown in scheme 1 and 2 are both the same.

[0070] To obtain the compound of the formula (II), an alkyl- or alkenylaldehyde is dosed neat or diluted to a stirred Grignard solution containing an C.sub.1-C.sub.4-alkenyl- or C.sub.1-C.sub.4-alkylmagnesium halide. The principle of this reaction is known from the literature, e. g. Adam's protocol and is applicable also in this case (W. Adam, V. R. Stegmann, Synthesis 2001, p 1203-1214).

Step (a)

[0071] In step (a) an allylalcohol of the formula (II) is activated via transformation of the hydroxyl group into a suitable leaving group X, generating a compound of the formula (III). This is achieved by addition of an activating reagent to the diluted or undiluted allylalcohol at a suitable temperature.

[0072] Preferably, the activating reagent is added to the diluted or undiluted allylalcohol in stoichiometric amounts.

[0073] Preferably, the activating agent in step (a) is selected from anhydrous hydrogen chloride, anhydrous hydrogen bromide, thionyl chloride, phosphoroxychloride, phosphorus trichloride, phosphorus tribromide (PBr.sub.3), methanesulphonic chloride, methanesulphonic anhydride, 4-toluenesulphonic chloride and 4-toluenesulphonic anhydride.

[0074] Particularly preferably, the activating agent is selected from anhydrous hydrogen chloride, anhydrous hydrogen bromide, thionyl chloride, phosphoroxychloride, phosphorus trichloride, and phosphorus tribromide.

[0075] More preferably, the activating agent is phosphorus tribromide.

[0076] Generally, step (a) can be conducted without the presence of a solvent or in one or more of the following solvents: ethers such as tetrahydrofuran (THF), dioxane, diethyl ether, diglyme, methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME), dimethyl ether, 2-methyl-THF; alkanes or cycloalkanes or alkyl-substituted cycloalkanes, for example n-hexane, n-heptane, cyclohexane, isooctane or methylcyclohexane; nitriles such as acetonitrile (ACN) or butyronitrile; aromatic hydrocarbons such as toluene, xylenes, anisole, mesitylene; esters such as ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate; halogenated aromatic hydrocarbons, particularly chlorohydrocarbons such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride (dichloromethane, DCM), dichlorobutane, chloroform, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, trifluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, especially 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene; fluorinated aliphatic and aromatic compounds such as trichlorotrifluoroethane, benzotrifluoride and 4-chlorobenzotrifluoride. It is also possible to use solvent mixtures.

[0077] Preferably, the solvent is an aromatic solvent.

[0078] Also preferably, the solvent is selected from tetrahydrofuran, n-heptane, toluene, xylenes, anisole, trifluorobenzene and chlorobenzene.

[0079] Particularly preferably, the solvent is selected from chlorobenzene, toluene, xylene, anisole and trifluorobenzene.

[0080] More preferably, the solvent is selected from xylenes, anisole, and chlorobenzene.

[0081] Most preferably, the solvent is chlorobenzene.

[0082] Preferably, step (a) of the process according to the invention is carried out at a temperature in the range of from −5° C. to 120° C.

[0083] Particularly preferably, step (a) of the process according to the invention is carried out at a temperature in the range of from 0° C. to 60° C.

[0084] More preferably, step (a) of the process according to the invention is carried out at a temperature in the range of from 0° C. to 40° C.

[0085] Most preferably, step (a) of the process according to the invention is carried out at a temperature in the range of from 0° C. to 20° C.

Step (b)

[0086] To obtain the compound of the formula (IV) via step (b), the compound of the formula (III) is generally reacted with the compound of the formula (IIIa) in the presence of a base and a solvent at a suitable temperature.

[0087] Preferably, the compound of the formula (III) is reacted with the compound of the formula (IIIa) in stoichiometric amounts.

[0088] Suitable bases are all customary inorganic or organic bases. These preferably include alkaline earth metal or alkali metal hydrides, hydroxides, amides, alkoholates, acetates, carbonates or bicarbonates, such as, for example, sodium acetate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate or ammonium carbonate, and also tertiary amines, such as trimethylamine, triethylamine, tri-n-butylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N,N-dimethylaminopyridine, 1,4-Diazabicyclo[2.2.2]octane (DABCO), 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), N,N-diisopropylethylamine, N,N,N′,N′-tetramethylguanidine, N-Methylimidazole.

[0089] Particularly preferably, the base in step (b) is selected from N-methylmorpholine, N,N-diisopropylethylamine, N,N,N′,N′-tetramethylguanidine, tri-n-butylamine, triethylamine, DABCO, DBU and N-Methylimidazole.

[0090] More preferably, the base used in step (b) is selected from N-methylmorpholine, N,N-diisopropylethylamine, N,N,N′,N′-tetramethylguanidine, tri-n-butylamine and triethylamine.

[0091] Most preferably, the base used in step (b) is N-methylmorpholine or N,N-diisopropylethylamine.

Step (b) is preferably conducted in one or more of the solvents listed in the general solvent definition of step (a).

[0092] Particularly preferably, the solvent is selected from tetrahydrofuran, n-heptane, chlorobenzene, toluene, xylenes, anisole and trifluorobenzene.

[0093] More preferably, the solvent is selected from chlorobenzene, toluene, xylene, anisole and trifluorobenzene.

[0094] Even more preferably, the solvent is selected from chlorobenzene, xylenes and anisole.

[0095] Most preferably, the solvent is chlorobenzene.

[0096] Preferably, step (b) of the process according to the invention is carried out at a temperature in the range of from 10° C. to 90° C.

[0097] Particularly preferably, step (b) of the process according to the invention is carried out at a temperature in the range of from 15° C. to 50° C.

[0098] More preferably, step (b) of the process according to the invention is carried out at a temperature in the range of from 20° C. to 30° C.

[0099] Step (c) To obtain the compound of the formula (I) via step (c), the compound of the formula (IV) is generally reacted in the presence of a Lewis or Brønsted acid and a solvent at a suitable temperature.

[0100] Preferably, the compound of the formula (IV) is reacted in the presence of catalytic to stoichiometric amounts of the Lewis or Brønsted acid.

[0101] Generally, step (c) according to the invention is carried out in the presence of a suitable Lewis acid, for example metal halides like AlCl.sub.3, BF.sub.3 and other Lewis acids known in literature; or triflates, for example silver triflate, zinc trifluoromethanesulfonate (Zn(OTf).sub.2), Copper(II)trifluoromethanesulfonate (Cu(OTf).sub.2), nickel(II)trifluoromethanesulfonate (Ni(OTf).sub.2), Iron(II) trifluoromethanesulfonate (Fe(OTf).sub.2,), Iron(III) trifluoromethanesulfonate (Fe(OTf).sub.3) and other triflates described in the literature. The process may also be carried out in the presence of Bronstedt acids like e.g. HCl, HBr, HF, H.sub.2SO.sub.4, KHSO.sub.4, AcOH, H.sub.3NSO.sub.3, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, methansulfonic acid, benzenesulfonic acid, trifluoromethansulfonic acid, polyphosphoric acid, phosphoric acid, phenylphosphonic acid, ethylphosphonic acid, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid and trifluoroacetic acid.

[0102] Preferably, in the process according to the invention the acid in step (c) is selected from 4-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, zinc trifluoromethanesulfonate (Zn(OTf).sub.2), Copper(II)trifluoromethanesulfonate (Cu(OTf).sub.2), nickel(II)trifluoromethanesulfonate (Ni(OTf).sub.2), Iron(II) trifluoromethanesulfonate (Fe(OTf).sub.2,), Iron(III) trifluoromethanesulfonate (Fe(OTf).sub.3), benzenesulfonic acid, H.sub.2SO.sub.4, H.sub.3NSO.sub.3, phenylphosphonic acid, ethylphosphonic acid, phosphoric acid, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid and trifluoroacetic acid.

[0103] More preferably the acid in step (c) is methanesulfonic acid or 4-toluenesulphonic acid.

[0104] Most preferably the acid in step (c) is 4-toluenesulphonic acid.

[0105] Step (c) is conducted in one or more of the solvents listed in the general solvent definition of step (a).

[0106] Preferably, the solvent is selected from chlorobenzene, toluene, xylenes, anisole and trifluorobenzene.

[0107] Particularly preferably, the solvent is selected from chlorobenzene, xylenes and anisole.

[0108] More preferably, the solvent is chlorobenzene.

[0109] Preferably, step (c) of the process according to the invention is carried out at a temperature in the range of from 80° C. to 140° C.

[0110] During the condensation of the substituted aniline of the formula (IIIa) and the activated allylalcohol of the formula (III), desired and undesired regioisomers of the N-allylated intermediates are generated, wherein the compound of the formula (IV) is the desired N-allylated intermediate. During the subsequent ACR only the N-allylated intermediate of the formula (IV) rearranges to the compound of the formula (I) but not the undesired regioisomer. After the ACR, the undesired regioisomers can be eliminated by a temperature-controlled degradation, preferably into the separable organic compounds aniline and diene.

[0111] Therefore particularly preferably, step (c) is carried out consecutively first at a temperature in the range of from 80° C. to 95° C. and second at a temperature in the range of from 115° C. to 140° C. The first temperature range is ideal for the ACR to generate the compound of the formula (I). The second temperature range is ideal for the degradation of the undesired regioisomer into organic compounds such as aniline and diene. Those are easily separable from the final product (i.e. the compound of the formula (I)) as aniline can easily be washed off the product phase with acidic water. The diene can also be simply removed via distillation due to its much lower boiling point compared to the final product.

[0112] More preferably step (c) is carried out consecutively first at a temperature in the range of 85 to 90° C. and second at a temperature in the range of 125° C. to 130° C.

[0113] In a preferred embodiment of the invention, the steps (a), (b) and (c) of the process according to the invention are conducted consecutively in a telescoping synthesis as defined above by utilizing the same solvent for all of the steps (a), (b) and (c). Particularly preferably, the solvent used in the telescoping synthesis is chlorobenzene.

[0114] In a further preferred embodiment, during the process according to the invention the product of step (a) is not isolated before conducting step (b) and/or the product of step (b) is not isolated before conducting step (c).

[0115] The present invention further relates to a process for producing a compound of the formula (V)

##STR00030##

wherein in formula (V) the substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each have the general, preferred, particularly preferred, more preferred or most preferred meanings which have already been defined for these substituents in connection with the description of the compounds of the formulae (I)-(IV) as defined above, comprising the steps (b) and (c) or comprising the steps (a), (b) and (c) as defined above and further comprising step (d), wherein the compound of the formula (I) is cyclized in the presence of an acid to obtain the compound of the formula (V).

[0116] Suitable acids for step (d) are sulphonic acids, in particular trifluoromethanesulphonic acid (TfOH), methanesulphonic acid (MsOH) and polyphosphoric acid as known from WO 2017/133981.

Step (d)

[0117] To obtain the compound of the formula (V) according to the invention and as shown in scheme 3, the compound of the formula (I) is reacted with aqueous sulfuric acid or anhydrous hydrogen fluoride (HF), wherein the definitions of the substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 of the formulae (V) and (I) each have the general, preferred, particularly preferred, more preferred or most preferred meanings which have already been defined for these substituents in connection with the description of the compounds of the formulae (V) and (I).

[0118] Preferably, when aqueous sulfuric acid is utilized as the mediator, the compound of the formula (I) and the aqueous sulfuric acid are dosed simultaneously into an empty reaction vessel. If said reaction vessel requires a minimum filling level, it can be filled with aqueous sulfuric acid up to this level. Simultaneous dosing of the substrate (i.e. the compound of the formula (I)) and aqueous sulfuric acid maintains high chemoselectivity throughout the entire reaction due to keeping the substrate concentration at a constant level. Advantageously, this prevents oligo- and polymerization of the substrate. When anhydrous hydrogen fluoride is utilized as the mediator this tendency towards oligo- and polymerization is not observed. Preferably the substrate is dosed to anhydrous hydrogen fluoride in this case.

[0119] Preferably, the process according to the invention is carried out at a temperature in the range of from −80° C. to 30° C., particularly preferably at a temperature in the range of from −50° C. to 20° C., more preferably at a temperature in the range of from −30° C. to 20° C.

[0120] Also preferably, if aqueous sulfuric acid is used as cyclization mediator, the process according to the invention is carried out at a temperature in the range of from 0° C. to 25° C., particularly preferably, at a temperature in the range of from 0° C. to 20° C., more preferably, at a temperature in the range of from 0° C. to 15° C.

[0121] Also preferably, if anhydrous hydrogen fluoride is used as cyclization mediator, the process according to the invention is carried out at a temperature in the range of from −80° C. to 20° C., particularly preferably at a temperature in the range of from −50° C. to 20° C., more preferably at a temperature in the range of from −30° C. to 20° C.

[0122] The process is generally conducted at normal pressure or at elevated pressure in an autoclave.

[0123] Preferably, the aqueous sulfuric acid used in the process according to the invention has a concentration of at least 85 w %. Particularly preferably, the aqueous sulfuric acid used in the process according to the invention has a concentration in the range of from 85 w % to 95 w %, more preferably in the range of from 88 w % to 92 w %, most preferably the concentration of the aqueous sulfuric acid is 90 w %.

[0124] The amount of the employed cyclization mediator may be varied over a wide range but is preferably in the range of from 3-45 molar equivalents, preferably of from 6 to 40 molar equivalents, especially preferably of from 9 to 35 molar equivalents based on the total amount of the compound of the formula (I).

[0125] If aqueous sulfuric acid is used as cyclization mediator, its used amount may be varied over a wide range but is preferably in the range of from 3-18 molar equivalents, preferably of from 6 to 15 molar equivalents, especially preferably of from 9 to 12 molar equivalents based on the total amount of the compound of the formula (II).

[0126] If anhydrous hydrogen fluoride is used as cyclization mediator, its used amount may be varied over a wide range but is preferably in the range of from 15-45 molar equivalents, preferably of from 20-40 molar equivalents, especially preferably of from 25-35 molar equivalents based on the total amount of the compound of the formula (I).

[0127] Generally, the process according to the invention can be conducted in the absence of a solvent or in the presence of one or more of the following solvents: alkanes or cycloalkanes or alkyl-substituted cycloalkanes, for example n-hexane, n-heptane, cyclohexane, isooctane or methylcyclohexane; aromatic hydrocarbons such as toluene, xylenes, mesitylene; amides such as N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidone; halohydrocarbons and halogenated aromatic hydrocarbons, particularly chlorohydrocarbons such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride (dichloromethane, DCM), dichlorobutane, chloroform, trichloroethane, pentachloroethane, difluorobenzene, trifluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, especially 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene; fluorinated aliphatic and aromatic compounds such as trichlorotrifluoroethane, benzotrifluoride, 4-chlorobenzotrifluoride. It is also possible to use solvent mixtures.

[0128] Preferably, the process is carried out in the absence of a solvent, using aqueous sulfuric acid or anhydrous HF as a mediator of the cyclization reaction and as solvent.

[0129] Preferably, when HF is used as the cyclization mediator in the process according to the invention, HF is used in anhydrous form, optionally as solution in organic solvents, more preferably HF is used in anhydrous form with a boiling point of 20° C. (i.e. without any organic solvents and free of water).

[0130] The reaction time in aqueous sulfuric acid or anhydrous HF is not critical and it can generally be varied from 1 to 30 hours (h), preferably from 3 to 24 h.

[0131] According to the invention the starting material, i.e. the compound of the formula (I), is mixed with aqueous sulfuric acid or anhydrous HF and stirred for a certain time at a certain temperature as defined above. For the isolation of the product, the excess of sulfuric acid is removed via addition of water leading to precipitation of the ammonium hydrogensulfate salt of (I), subsequent filtration and washing the salt with water. In order to recycle the sulfuric acid, the filtrate can be subjected to a distillation to obtain the required acid concentration. Advantageously, anhydrous hydrogen fluoride can be recycled more easily as it can be distilled from the reaction solution directly, leaving the ammonium fluoride salt of (V). Said salts are neutralized with a suitable base and extracted into a suitable organic solvent, from which compound (V) is isolated via removal of the solvent by distillation followed by purification via high vacuum distillation.

[0132] The present invention further relates to a process for producing a compound of the formula (VII)

##STR00031##

wherein in formula (VII) the substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each have the general, preferred, particularly preferred, more preferred or most preferred meanings which have already been defined for these substituents in connection with the description of the compounds of the formulae (I)-(IV) as defined above, comprising the steps (b) to (d) or comprising the steps (a) to (d) as defined above and further comprising step (e), wherein the compound of the formula (V) is reacted with a compound of the formula (VI)

##STR00032##

to obtain the compound of the formula (VII). The reaction according to step (e) is in principle known from e.g. WO 2014/095675 A1.

[0133] Depending on the type of substituents, the compounds according to the invention can occur as geometric and/or optical isomers or as their corresponding isomeric mixtures in various compositions. These isomers are, for example, enantiomers, diastereomers or geometric isomers. As a consequence, the invention described herein includes both the pure stereoisomers and every mixture of these isomers.

[0134] Another object of the present invention is the compound of the formula (III)

##STR00033##

wherein in formula (III) the substituents R.sup.1, R.sup.2 and R.sup.3 each have the general, preferred, particularly preferred, more preferred or most preferred meanings which have already been defined for these substituents in connection with the description of the compounds of the formulae (I)-(IV) as defined above.

[0135] Another object of the present invention is the compound of the formula (IV)

##STR00034##

wherein in formula (IV) the substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each have the general, preferred, particularly preferred, more preferred or most preferred meanings which have already been defined for these substituents in connection with the description of the compounds of the formulae (I)-(IV) as defined above.

[0136] The present invention is elucidated in detail by the examples which follow, although the examples should not be interpreted in such a manner that they restrict the invention.

PREPARATION EXAMPLES

Example 1

Preparation of rac-4-bromo-2-methyl-hept-2-ene (a compound according to formula (III))

[0137] ##STR00035##

[0138] In a 25 mL three-necked reaction flask equipped with a thermometer was placed 2 mL of anhydrous THF under a gentle stream of argon. 5.0 g (90% purity, 35.1 mmol, 1.0 eq) of rac-2-methylhept-2-en-4-ol were added in one portion. The solution was cooled to 0° C. Then 1.1 mL (3.17 g, 11.6 mmol, 0.33 eq) of phosphorus tribromide were dosed to the solution at 0° C. for 10 minutes via syringe pump. Afterwards the reaction mixture was allowed to reach 22° C. To the mixture was added another 2 mL of anhydrous THF. The resulting two liquid phases were separated and the lower one was discarded. The upper phase was liberated from volatile components via distillation at 40° C. down to a vacuum of 20 mbar to leave 6.27 g (92% purity, 30.2 mmol, 86% yield) of rac-4-bromo-2-methyl-hept-2-ene as a dark yellow liquid. .sup.1H-NMR (400 MHz; CDCl.sub.3) δ=5.43-5.39 (m, 1H), 4.88-4.82 (m, 1H), 1.88-1.77 (m, 2H, H5), 1.75 (s, 3H), 1.71 (s, 3H), 1.45-1.35 (m, 2H), 0.93 (t, J=7.4 Hz, 3H).

Example 2

Preparation of N-[(E)-1,1-dimethylhex-2-enyl]aniline (a compound according to formula (IV))

[0139] ##STR00036##

[0140] In a 500 mL four-necked reaction flask equipped with a thermometer was placed 150.0 g (88% purity, 1.03 mol, 1.0 eq) of rac-2-methylhept-2-en-4-ol under a gentle stream of argon. Then 33.5 mL (95.6 g, 0.35 mol, 0.34 eq) of phosphorus tribromide were dosed to the solution at 5° C. over a period of 3 hours via syringe pump. Afterwards the reaction mixture was allowed to reach 22° C. To the mixture was added 60 mL of anhydrous THF. The resulting two liquid phases were separated and the lower one was discarded. The upper phase was dosed to a solution comprising 94.7 mL (96.7 g, 1.03 mol, 1.0 eq) of aniline, 125.6 mL (115.6 g, 1.13 mol, 1.1 eq) of 4-methylmorpholine in 920 mL anhydrous THF at 22° C. over a period of 1.5 hours. A yellow solution with white precipitate was obtained. After completed dosing the mixture was diluted with 100 mL of deionized water. Afterwards the volatiles of this mixture were removed via distillation at 40° C. down to a vacuum of 50 mbar. The distillation residue was diluted with 900 mL of MTBE and 1200 mL of deionized water. Phases were separated and the organic phase was dried with 1000 mL of saturated brine and over magnesium sulphate. The drying agent was filtered off and the filtrate was concentrated at 40° C. down to a vacuum of 4 mbar to leave 193.1 g (87.5% purity, 0.83 mol, 81% yield) of a red oil containing N-[(E)-1,1-dimethylhex-2-enyl]aniline and rac-N-(3-methyl-1-propyl-but-2-enyl)aniline in a regioisomeric ratio of 84:16. Spectral data of the major regioisomer N-[(E)-1,1-dimethylhex-2-enyl]aniline: .sup.1H-NMR (400 MHz; CDCl.sub.3) δ=7.11-7.07 (m, 2H), 6.71-6.69 (m, 3H), 5.58-5.57 (m, 2H), 3.63 (bs, 1H), 2.03-2.01 (m, 2H), 1.40 (q, J=8.0 Hz, 2H), 1.37 (s, 6H), 0.89 (t, J=8.0 Hz, 3H). The regioisomeric ratio of 84:16 was determined independently via HPLC analysis and via comparison of the integration values of the major isomer's singulett of the geminal methyl groups (singulett at 1.37 ppm) with the two singletts of the geminal methyl groups of the minor isomer rac-N-(3-methyl-1-propyl-but-2-enyl)aniline (singuletts at 1.74 ppm and 1.70 ppm) in .sup.1H-NMR.

Example 3

Preparation of rac-2-(3-methyl-1-propyl-but-2-enyl)aniline (a compound according to formula (I))

[0141] ##STR00037##

[0142] To a 100 mL four-necked round-bottomed flask equipped with a thermometer was added 36.1 mL of chlorobenzene and 10.0 g (88.5% purity, 43.53 mmol, 1.0 eq) of a regioisomeric mixture of N-[(E)-1,1-dimethylhex-2-enyl]aniline and rac-N-(3-methyl-1-propyl-but-2-enyl)aniline with an isomeric ratio of 84:16. The resulting solution was degassed via argon-bubbling for 15 minutes at 22° C. Afterwards 2.1 g (10.88 mmol, 0.25 eq) of 4-toluenesulphonic acid monohydrate was added in one portion. The mixture was heated to 90° C. internal temperature to form a solution, which was stirred for 5 hours at this temperature until a HPLC measurement indicated complete conversion of N-[(E)-1,1-dimethylhex-2-enyl]aniline. Afterwards the temperature was increased until reflux at 130° C. internal temperature was obtained. After further stirring for 1.5 hours a HPLC measurement indicated complete degradation of rac-N-(3-methyl-1-propyl-but-2-enyl)aniline. The reaction mixture was cooled down to 22° C. A white precipitate was formed. To the reaction mixture was then added 50 mL of chlorobenzene and 100 mL of deionized water. The phases were separated and the organic phase was washed with 20 mL of deionized water. Afterwards the organic phase was concentrated at 60° C. and down to a vacuum of 5 mbar to leave 7.1 g (74% purity, 25.80 mmol, 59% yield) of a clear orange oil. .sup.1H-NMR (400 MHz; CDCl.sub.3) δ=7.12 (d, J=7.7 Hz, 1H), 7.01 (dd, J=7.5, 7.7 Hz, 1H), 6.77 (dd, J=7.5, 7.7 Hz, 1H), 6.65 (d, J=7.7 Hz, 1H), 5.12-5.08 (m, 1H), 3.56 (bs, 2H), 3.47-3.41 (m, 1H), 1.71 (s, 6H), 1.65-1.56 (m, 2H), 1.40-1.26 (m, 2H), 0.93 (t, J=8.0 Hz, 3H).

Example 4

Preparation of rac-2-(3-methyl-1-propyl-but-2-enyl)aniline (a Compound According to Formula (I)) Via a Telescoped Reaction

[0143] ##STR00038##

[0144] In a 1000 mL four-necked reaction flask equipped with a thermometer was dissolved 250.0 g (89% purity, 1.73 mol, 1.0 eq) of rac-2-methylhept-2-en-4-ol in 250.0 g of chlorobenzene under a gentle stream of argon. Then 54.8 mL (156.06 g, 0.57 mol, 0.33 eq) of phosphorus tribromide were dosed to the solution at 3° C. over a period of 4 hours via syringe pump. Afterwards the reaction mixture was allowed to reach 22° C. Phases were separated and the lower, dark phase was discarded. The yellow-greenish upper phase was then dosed to a 4000 mL jacketed reactor containing a stirred solution of 151.2 mL (154.6 g, 1.64 mol, 0.95 eq) of aniline and 182.5 mL (167.9 g, 1.64 mol, 0.95 eq) of 4-methylmorpholine in 1031 mL chlorobenzene at 24° C. under argon over a period of 2 hours. The resulting suspension was then stirred for 1 hour at 24° C. To the reaction mixture were then added 1800 mL of saturated brine and 600 ml of deionized water. The resulting two liquid phases were mixed and separated. The lower phase was drained off and discarded. Afterwards the organic phase was degassed via argon bubbling for 0.5 hours. To the reaction solution was then added 82.3 g (0.43 mol, 0.25 eq) of 4-toluenesulphonic acid monohydrate in one portion. The mixture was heated to 90° C. internal temperature to form a solution, which was stirred for 5 hours at this temperature until a HPLC measurement indicated complete conversion of N-[(E)-1,1-dimethylhex-2-enyl]aniline. Afterwards the temperature was increased until reflux at 130° C. internal temperature was obtained. After further stirring for 1.5 hours a HPLC measurement indicated complete degradation of rac-N-(3-methyl-1-propyl-but-2-enyl)aniline. The reaction mixture was cooled down to 22° C. A white precipitate was formed. To the reaction mixture was then added 1000 mL of deionized water. The phases were mixed and separated The lower phase was drained off and discarded. Afterwards the organic phase was concentrated at 60° C. and down to a vacuum of 5 mbar to leave 258.0 g (76% purity, 0.96 mol, 55% yield) of a dark red oil. .sup.1H-NMR (400 MHz; CDCl.sub.3) δ=7.12 (d, J=7.7 Hz, 1H), 7.01 (dd, J=7.5, 7.7 Hz, 1H), 6.77 (dd, J=7.5, 7.7 Hz, 1H), 6.65 (d, J=7.7 Hz, 1H), 5.12-5.08 (m, 1H), 3.56 (bs, 2H), 3.47-3.41 (m, 1H), 1.71 (s, 6H), 1.65-1.56 (m, 2H), 1.40-1.26 (m, 2H), 0.93 (t, J=8.0 Hz, 3H).

Example 5

Preparation of rac-2-(1,3-dimethyl-but-2-enyl)aniline (a Compound According to Formula (I)) Via a Telescoped Reaction

[0145] ##STR00039##

[0146] In a 100 mL four-necked reaction flask equipped with a thermometer was placed 20.00 g (98.5% purity, 196.69 mmol, 1.00 eq) of rac-4-methylpent-3-en-2-ol and 50 mL of chlorobenzene. The solution was cooled to 0° C. and inertized via Argon. To the solution was dosed 17.75 g (99% purity, 64.91 mmol, 0.33 eq) of phosphorus tribromide at 0-4° C. over a period of 90 minutes. After 15 minutes of post-stirring at 0° C. the reaction mixture was allowed to warm up to 22° C. and was subsequently transferred into a dropping funnel. Of the two separated phases the dark viscous lower layer was discarded. A second 100 mL four-necked reaction flask was equipped with a thermometer and with the dropping funnel containing the product phase of the first reaction. Then 17.58 g (99% purity, 186.85 mmol, 0.95 eq) of aniline and 19.09 g (99% purity, 186.85 mmol, 1.00 eq) of N-methylmorpholine were dissolved in 50 mL of chlorobenzene at 22° C. To this solution was dosed the product solution of the first reaction within 2 hours maintaining an internal temperature of 22-24° C. via waterbath cooling. After 1 hour of post-stirring at 22° C. the organic phase was washed with 2×200 mL deionized water and was subsequently degassed with Argon for 1 hour. To the organic phase was then added 1.23 g (99% purity, 6.39 mmol, 3.3 mol %) of 4-toluenesulfonic acid monohydrate in one portion at 22° C. Afterwards the reaction mixture was heated to 90° C. internal temperature and stirred for 6 hours until HPLC monitoring revealed complete conversion of one regioisomer. This was followed by elevating the internal temperature to 130° C. and further stirring for 2 hours at this temperature level until HPLC monitoring indicated complete conversion of the other regioisomer. Afterwards the reaction solution was cooled down to 22° C. and washed with 2×100 mL deionized water. The aqueous phase was extracted with 2×50 mL of chlorobenzene. The combined organic phases were then dried over MgSO.sub.4, the drying agent was filtered off and the filtrate was concentrated to dryness at 60° C. and down to 13 mbar to leave 20.80 g (66.1% purity, 78.45 mmol, 40% yield) of rac-2-(1,3-dimethylbut-2-enyl)aniline as a clear, red oil. .sup.1H-NMR (600 MHz; CDCl.sub.3) δ=7.17-7.14 (m, 1H), 7.05-7.01 (m, 1H), 6.79-6.75 (m, 1H), 6.66 (dd, J=6.0 Hz, 12.0 Hz, 1H), 5.11 (d, J=6.0 Hz, 1H), 3.64-3.54 (m, 3H), 1.75 (s, 3H), 1.71 (s, 3H), 1.33 (d, J=9.0 Hz, 3H).

Example 6

Preparation of rac-2-(1,3-dimethylbut-2-enyl)-4-fluoroaniline (a Compound According to Formula (I)) Via a Telescoped Reaction

[0147] ##STR00040##

[0148] In a 100 mL four-necked reaction flask equipped with a thermometer was placed 20.00 g (98.5% purity, 196.69 mmol, 1.00 eq) of rac-4-methylpent-3-en-2-ol and 50 mL of chlorobenzene. The solution was cooled to 0° C. and inertized via Argon. To the solution was dosed 17.75 g (99% purity, 64.91 mmol, 0.33 eq) of phosphorus tribromide at 0-4° C. over a period of 1 hour. After 30 minutes of post-stirring at 0° C. the reaction mixture was allowed to warm up to 22° C. and was subsequently transferred into a dropping funnel. Of the two separated phases the dark viscous lower layer was discarded. A second 100 mL four-necked reaction flask was equipped with a thermometer and with the dropping funnel containing the product phase of the first reaction. Then 20.97 g (99% purity, 186.85 mmol, 0.95 eq) of aniline and 19.09 g (99% purity, 186.85 mmol, 1.00 eq) of N-methylmorpholine were dissolved in 35 mL of chlorobenzene at 22° C. To this solution was dosed the product solution of the first reaction within 4 hours maintaining an internal temperature of 22-24° C. via waterbath cooling. After 1 hour of post-stirring at 22° C. the organic phase was washed with 2×200 mL deionized water and was subsequently degassed with Argon for 1 hour. To the organic phase was then added 1.23 g (99% purity, 6.39 mmol, 3.3 mol %) of 4-toluenesulfonic acid monohydrate in one portion at 22° C. Afterwards the reaction mixture was heated to 95° C. internal temperature and stirred for 6 hours until HPLC monitoring revealed complete conversion of one regioisomer. This was followed by elevating the internal temperature to 130° C. and further stirring for 2 hours at this temperature level until HPLC monitoring indicated complete conversion of the other regioisomer. Afterwards the reaction solution was cooled down to 22° C. and washed with 2×100 mL deionized water. The aqueous phase was extracted with 2×50 mL of chlorobenzene. The combined organic phases were then dried over MgSO.sub.4, the drying agent was filtered off and the filtrate was concentrated to dryness at 40° C. and down to 10 mbar to leave 18.10 g (50.8% purity, 47.60 mmol, 24% yield) of rac-2-(1,3-dimethylbut-2-enyl)-4-fluoroaniline as a clear, red oil. .sup.1H-NMR (600 MHz; CDCl.sub.3) δ=6.78-6.70 (m, 1H), 6.63-6.56 (m, 2H), 5.05 (d, J=6.0 Hz, 1H), 3.61-3.56 (m, 1H), 3.43 (bs, 2H), 1.72 (s, 3H), 1.69 (s, 3H), 1.27 (d, J=9.0 Hz, 3H).

Example 7

Preparation of rac-1,1-dimethyl-3-propyl-indan-4-amine Using Aqueous Sulfuric Acid

[0149] ##STR00041##

[0150] To a 1000 mL four-necked round-bottomed flask equipped with a thermometer, a mechanical stirrer and two dropping funnels was dosed a mixture comprising 350.0 g of recycled sulfuric acid (90% purity) and 44.0 g fresh sulfuric acid (90% purity) simultaneously with 100.0 g (74% purity, 0.36 mol, 1.0 eq) of rac-1,1-dimethyl-3-propyl-indan-4-amine at 0-10° C. internal temperature over a period of 3 hours under vigorous stirring. Some jelly-like solids were formed intermediary, which dissolved completely during the end of the addition. After completed dosing, the dark red reaction solution was added onto 800.0 g of deionized icy water under vigorous stirring. The solid was filtered off and washed with a total of 400 mL of deionized water. The combined filtrate was subjected to distillation at 20 mbar and 150° C. in order to concentrate the sulfuric acid back to 90% purity. The solid was suspended in 500 mL of deionized water and 150 mL of methylcyclohexane. To this suspension was added 86.8 g (1.08 mol, 3.0 eq) of 50 w % soda lye. Two liquid phases were formed, of which the lower phase was separated. The aqueous phase was extracted once with another 150 mL of methylcyclohexane. The combined organic phases were then washed with 100 mL of saturated brine. After phase separation the organic phase was concentrated via distillation at 40° C. down to a vacuum of 25 mbar to leave 88.4 g (67% purity, 0.29 mol, 81% yield) of rac-1,1-dimethyl-3-propyl-indan-4-amine as a dark red oil. .sup.1H-NMR (600 MHz; CDCl.sub.3) δ=7.02 (t, J=7.5 Hz, 1H), 6.59 (d, J=7.5 Hz, 1H), 6.47 (d, J=7.5 Hz, 1H), 3.56 (bs, 2H), 3.11-3.06 (m, 1H), 2.09 (dd, J=12.0 Hz, 24.0 Hz, 1H), 1.92-1.86 (m, 2H), 1.76 (dd, J=6.0 Hz, 12.0 Hz, 1H), 1.55-1.32 (m, 2H), 1.30 (s, 3H), 1.21 (s, 3H), 0.97 (t, J=8.0 Hz, 3H).

Example 8

Preparation of rac-1,1-dimethyl-3-propyl-indan-4-amine Using Anhydrous HF

[0151] ##STR00042##

[0152] In a 30 mL Nalgene® laboratory bottle were placed 10.0 g (10 mL) of anhydrous hydrogen fluoride (b.p. 19.5° C., m.p. −83.6° C.). The content was cooled to −30° C. and 5.0 g (71% purity, 17.39 mmol, 1.0 eq) of rac-1,1-dimethyl-3-propyl-indan-4-amine was added to the reaction mixture in small portions. The bottle was sealed by a stopper and the reaction mixture was allowed to warm to 25° C. Afterwards stirring was prolonged for 24 hours under the same conditions. The content of the bottle was then poured into a 250 mL plastic beaker, and excess of hydrogen fluoride was evaporated at open air within the fumehood. The oily residue was treated with 20 mL of 10 w % aqueous solution of sodium bicarbonate until pH 7 was obtained (ceasing CO.sub.2 gas formation) and extracted with 2×50 mL of dichloromethane. The combined dichloromethane extracts were then washed with 30 mL of concentrated brine, dried over sodium sulfate and evaporated via distillation to leave 4.88 g (62% purity, 14.88 mmol, 86% yield) of rac-1,1-dimethyl-3-propyl-indan-4-amine as a dark red oil. .sup.1H-NMR (600 MHz; CDCl.sub.3) δ=7.02 (t, J=7.5 Hz, 1H), 6.59 (d, J=7.5 Hz, 1H), 6.47 (d, J=7.5 Hz, 1H), 3.56 (bs, 2H), 3.11-3.06 (m, 1H), 2.09 (dd, J=12.0 Hz, 24.0 Hz, 1H), 1.92-1.86 (m, 2H), 1.76 (dd, J=6.0 Hz, 12.0 Hz, 1H), 1.55-1.32 (m, 2H), 1.30 (s, 3H), 1.21 (s, 3H), 0.97 (t, J=8.0 Hz, 3H).

Example 9

Preparation of rac-1,1,3-trimethyl-indan-4-amine Using Aqueous Sulfuric Acid

[0153] ##STR00043##

[0154] To a 100 mL four-necked round-bottomed flask equipped with a thermometer was added 91.00 g (90% purity, 835.05 mmol, 10.66 eq) of aqueous sulfuric acid. To the acid were then dosed 20.80 g (66% purity, 78.32 mmol, 1.0 eq) of rac-2-(1,3-dimethylbut-2-enyl)aniline at 5-10° C. internal temperature over a period of 1 hour under vigorous stirring. Some jelly-like solids were formed intermediary, which dissolved completely during the end of the addition. The reaction mixture was stirred for further 3 hours at 22° C. until HPLC monitoring indicated complete conversion. Afterwards the reaction solution was added onto 160.0 g of deionized icy water under vigorous stirring. The resulting mixture was then completely neutralized until pH 10 via addition of aqueous sodium hydroxide (20 w %). The resulting solid material was filtered off and was discarded. The filtrate was extracted with 2×100 mL t-butylmethylether. The combined organic phases were then dried over MgSO.sub.4. The drying agent was filtered off and the organic phase was concentrated via distillation at 40° C. down to a vacuum of 10 mbar to leave 17.10 g (45% purity, 43.86 mmol, 56% yield) of rac-1,1,3-trimethylindan-4-amine as a red oil. .sup.1H-NMR (600 MHz; CDCl.sub.3) δ=7.03 (t, J=7.0 Hz, 1H), 6.60 (d, J=7.0 Hz, 1H), 6.50 (d, J=7.0 Hz, 1H), 3.59 (bs, 2H), 3.23-3.21 (m, 1H), 2.21 (dd, J=8.0 Hz, 12.0 Hz, 1H), 1.62 (dd, J=8.0 Hz, 12.0 Hz, 1H), 1.34 (d, J=8.0 Hz, 3H), 1.31 (s, 3H), 1.23 (s, 3H).

Example 10

Preparation of rac-7-fluoro-1,1,3-trimethyl-indan-4-amine Using Aqueous Sulfuric Acid

[0155] ##STR00044##

[0156] To a 250 mL four-necked round-bottomed flask equipped with a thermometer was added 226.32 g (90% purity, 2238.33 mmol, 47.05 eq) of aqueous sulfuric acid. To the acid were then dosed 18.10 g (51% purity, 47.58 mmol, 1.00 eq) of rac-2-(1,3-dimethylbut-2-enyl)-4-fluoroaniline at 5-10° C. internal temperature over a period of 1 hour under vigorous stirring. Some jelly-like solids were formed intermediary, which dissolved completely during the end of the addition. The reaction mixture was stirred for 1 hour at 15° C. until HPLC monitoring indicated complete conversion. Afterwards the reaction solution was added onto 150.0 g of deionized icy water under vigorous stirring. The resulting suspension was filtered and the filtrate was discarded. The solid was re-suspended in 100 mL of deionized water and the resulting mixture was neutralized with 25 mL of aqueous sodium hydroxide (20 w %). The resulting suspension was again filtered. The solid was then washed with 1×25 mL deionized water. After drying at 40° C. and 70 mbar 8.00 g (67% purity, 27.60 mmol, 58% yield) of rac-7-fluoro-1,1,3-trimethyl-indan-4-amine were obtained as an off-white solid. .sup.1H-NMR (600 MHz; CDCl.sub.3) δ=6.68-6.65 (m, 1H), 6.44-6.41 (m, 1H), 3.25-3.16 (m, 3H), 2.22 (dd, J=8.0 Hz, 12.0 Hz, 1H), 1.65 (dd, J=8.0 Hz, 12.0 Hz, 1H), 1.43 (s, 3H), 1.35 (s, 3H), 1.32 (d, J=8.0 Hz, 3H).