PROCESS FOR PRODUCING SUBSTITUTED 4-AMINOINDANE DERIVATIVES FROM 2-(HYDROXYALKYL)-ANILINES

Abstract

The present invention relates to a method for preparing substituted 4-aminoindane derivatives from 2-(hydroxyalkyl)-anilines by cyclization,

##STR00001##

in which the substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the definitions as specified in the description.

Claims

1. A process for preparation of a compound of formula (I) ##STR00009## 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, comprising reacting a compound of formula (IIa) or (IIb) or (IIc) ##STR00010## with aqueous sulfuric acid or anhydrous hydrogen fluoride at a temperature in a range of from of −80° C. to 70° C.

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

3. 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.

4. The process according to claim 1, wherein the process is carried out at a temperature in a range of from 1° C. to 30° C., optionally at a temperature in a range of from 1° C. to 20° C.; optionally at a temperature in a range of from 1° C. to 15° C.

5. The process according to claim 1, wherein the process is carried out at a temperature in a range of from 5° C. to 15° C.

6. The process according to claim 1, wherein an aqueous sulfuric acid having a concentration of at least 85w % is used.

7. The process according to claim 1, wherein an aqueous sulfuric acid is used that has a concentration in a range of from 85w % to 97w %, optionally that has a concentration in a range of from 88 w % to 92 w %, optionally the concentration of the aqueous sulfuric acid is 90 w %.

8. The process according to claim 1, wherein the amount of used aqueous sulfuric acid or anhydrous hydrogen fluoride 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 a total amount of the compound of formula (IIa) or (Ib) or (IIc).

9. The process according to claim 1, wherein the reaction can be conducted in the presence or absence of a solvent, optionally the reaction is conducted in absence of a solvent.

10. Process for preparation of a compound of formula (V) ##STR00011## comprising the process of claim 1, and further comprising reacting the compound of formula (I) with a compound of formula (VI). ##STR00012## to obtain the compound of formula (V).

Description

DETAILED DESCRIPTION OF THE PROCESS

[0053] According to the invention, substituted 4-aminoindane derivatives of the formula (I) may be prepared by the reaction of an alcohol of the formula (IIa) or (IIb) or (IIc) with sulfuric acid or anhydrous hydrogen fluoride, as shown in scheme (1):

##STR00004##

[0054] In scheme 1, the substituents R.sup.1, R.sup.2, R.sup.3 and R of the formulae (I), (IIa), (IIb) or (IIc) 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), (IIa), (IIb) or (IIc).

[0055] The compounds of the formulae (IIa), (IIb) or (IIc) used as starting materials may be prepared analogously to known methods (WO 2002/38542, WO 2006/120031). Furthermore, the compound of the formula (IIa) can also be prepared by the two-fold reaction of appropriately substituted aminobenzonitriles of the formula (III) with Grignard reagents of the formulae (IVa) and (IVb) via the intermediately formed ketones of the formulae (Va) or (Vb) as shown in scheme (2).

##STR00005##

[0056] In scheme 2, the substituents R.sup.1, R.sup.2, R.sup.3 and R.sup.4 of the formulae (III), (IVa), (IVb), (Va), (Vb) and (IIa) 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), (IIa), (IIb) or (IIc). In the formulae (IVa) and (IVb), X is preferably chlorine, bromine or iodine and particularly preferably chlorine or bromine.

[0057] The aminobenzonitriles of the formula (III) are known and in some cases commercially available.

[0058] The Grignard reagents of the formulae (IVa) and (IVb) are either commercially available or can be prepared from the corresponding chlorides, bromides or iodides by reaction with magnesium turnings by known literature methods.

[0059] To obtain the compound of the formula (I) according to the invention and as shown in scheme 1, the compound of the formula (IIa) or (IIb) or (IIc) 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 (I), (IIa), (IIb) and (IIc) 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 above description of these compounds.

[0060] The process according to the invention is preferably carried out without a solvent or in one or more of the following solvents: ethers such as dioxane, diglyme, methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME); nitriles such as acetonitrile (ACN) or butyronitrile; aromatic hydrocarbons such as toluene, anisole, xylenes, mesitylene; halohydrocarbons and halogenated aromatic hydrocarbons, particularly chlorohydrocarbons such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride (dichloromethane, DCM), dichlorobutane, chloroform, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, especially 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene; fluorinated aliphatic and aromatic compounds such as trichlorotrifluoroethane, benzotrifluoride, 4-chlorobenzotrifluoride and water. It is also possible to use solvent mixtures.

[0061] Furthermore, the process according to the invention is particularly preferably carried out in pure aqueous sulfuric acid or anhydrous hydrogen fluoride without solvent.

[0062] Preferably, the process according to the invention is carried out at a temperature in the range of from −80° C. to 70° C., particularly preferably at a temperature in the range of from −50° C. to 30° C., more preferably at a temperature in the range of from −30° C. to 15° C.

[0063] 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 70° C.

[0064] 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.

[0065] 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 1° C. to 70° C.

[0066] Particularly 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 1° C. to 30° C.

[0067] More 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 1° C. to 20° C.

[0068] Even more 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 1° C. to 15° C.

[0069] Most 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 5° C. to 15° C.

[0070] 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 (IIa) or (IIb) or (IIc).

[0071] 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 (IIa) or (IIb) or (IIc).

[0072] 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 (IIa) or (lIb) or (IIc).

[0073] The process according to the invention is generally conducted at standard pressure but may be carried out either under reduced pressure or at elevated pressure—generally between 0.1 and 100 bar.

[0074] 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).

[0075] Depending on the type of substituents, the compound of the formula (I) 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.

[0076] The desired compound of the formula (I) can be isolated and purified by diluting the reaction mixture with water with subsequent crystallization and release of the free 4-aminoindane derivative. Such methods are known to those skilled in the art and particularly include the crystallization of the 4-aminoindane derivative ammonium salt from water and liberation of the free 4-aminoindane derivative via neutralization and extraction with an organic solvent.

[0077] 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 (a): Preparation of rac-1,1-dimethyl-3-propyl-indan-4-amine

[0078] ##STR00006##

[0079] In a 25 mL three-necked reaction flask equipped with a thermometer was placed 15.4 mL of concentrated sulfuric acid (97% purity). To the acid was added 6.43 g (97% purity, 28.18 mmol, 1.0 eq) of rac-4-(2-aminophenyl)-2-methyl-heptan-4-ol dropwise at 15° C. internal temperature. After the first dissolution of the substrate a jelly-like solid separates, which then slowly dissolves again. The solution was allowed to reach 22° C. and was stirred for 8 hours at this temperature until full conversion was obtained according to HPLC analysis. The solution was then added to 80 mL of deionized water. A white solid precipitated, which was filtered off. The wet solid was then suspended in 50 mL of deionized water and sodium hydroxide was used to adjust pH 7. The solid transformed into an oily layer, which was extracted with 50 mL of ethyl acetate. After phase separation, the organic phase was washed with 50 mL of saturated brine and dried over magnesium sulfate. After filtration of the drying agent, the organic phase was concentrated via distillation at 40° C. down to a vacuum of 5 mbar to leave 5.37 g (81% purity, 21.3 mmol, 75% yield) of rac-1,1-dimethyl-3-propyl-indan-4-amine as a dark red oil. .sup.1H-NMR (600 MHz; CDCl.sub.3)=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 (b) Preparation of rac-1,1-dimethyl-3-propyl-indan-4-amine (Comparative Example)

[0080] ##STR00007##

[0081] In a 8 mL screw-capped vial was placed 0.5 g (87% purity, 2.06 mmol, 1.0 eq) of rac-4-(2-aminophenyl)-2-methyl-heptan-4-ol and heated to the temperature, which is indicated in the table. To the starting material was added 2.0 g (97% purity, 19.7 mmol, 9.6 eq) of concentrated sulfuric acid. The reaction was mixed at the indicated temperature until full conversion of starting material was observed via HPLC monitoring. The yield was determined via quantitative .sup.1H-NMR spectroscopy of the reaction mixture using dibromomethane as internal standard.

TABLE-US-00001 No. Temperature/° C. Time/h Yield 1 30 8 71% 2 50 6 65% 3 70 6 61% 4 90 6 52% 5 120 4 41% 6 140 4 40% 7 180 4 28%

[0082] .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 (c): Preparation of rac-1,1-dimethyl-3-propyl-indan-4-amine Using Anhydrous HF

[0083] ##STR00008##

[0084] To a 20 mL Nalgene® laboratory bottle charged with 0.5 g of 4-(2-amino-phenyl)-2-methyl-heptan-4-ol (87.1% purity, 2.25 mmol) at −30° C. was added 1 g (1 mL, 50 mmol, 22 eq) of precooled (+5° C.) anhydrous hydrogen fluoride (b.p. 19.5° C., m.p −83.6° C.). The bottle was sealed via stopper, the reaction mixture was allowed to warm to room temperature (25° C.) and stirred at this conditions for 24 hrs.

[0085] After the reaction was complete, the bottle was cooled down to +5° C. and opened. The excess of hydrogen fluoride was allowed to evaporate at open air under the fume hood. The oily residue was then treated with 10% aqueous solution of NaHCO.sub.3 (10 mL) until a pH value of 7 was obtained (CO.sub.2 evolution occurred) and extracted with CH.sub.2Cl.sub.2 (2×10 mL). The combined dichloromethane extracts were washed with H.sub.2O (10 mL), dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to leave 0.46 g (68% purity, 1.62 mmol, 72% yield) of rac-1,1-dimethyl-3-propyl-indan-4-amine as a yellow oil.

[0086] NMR (400 MHz; CDCl.sub.3)=7.05 (t, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.51 (d, J=8.0 Hz, 1H), 3.62 (bs, 2H), 3.07-3.02 (m, 1H), 2.12 (dd, J=12.0 Hz, 24.0 Hz, 1H), 1.91-1.80 (m, 2H), 1.78 (dd, J=6.0 Hz, 12.0 Hz, 1H), 1.56-1.34 (m, 2H), 1.33 (s, 3H), 1.24 (s, 3H), 0.99 (t, J=8.0 Hz, 3H).