(19)
(11)EP 3 429 352 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
05.05.2021 Bulletin 2021/18

(21)Application number: 17767401.7

(22)Date of filing:  15.03.2017
(51)International Patent Classification (IPC): 
C07C 231/12(2006.01)
C07C 233/24(2006.01)
C07C 211/60(2006.01)
A01N 37/24(2006.01)
C07C 233/15(2006.01)
C07C 209/62(2006.01)
C07C 209/70(2006.01)
(86)International application number:
PCT/US2017/022441
(87)International publication number:
WO 2017/160933 (21.09.2017 Gazette  2017/38)

(54)

PROCESS FOR CONVERTING S-ENANTIOMER TO ITS RACEMIC FORM

VERFAHREN ZUR UMWANDLUNG EINES S-ENANTIOMERS IN SEINE RACEMISCHE FORM

PROCÉDÉ DE CONVERSION DE S-ÉNANTIOMÈRE EN SA FORME RACÉMIQUE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 17.03.2016 US 201662309573 P

(43)Date of publication of application:
23.01.2019 Bulletin 2019/04

(60)Divisional application:
19173453.2 / 3560911

(73)Proprietor: FMC Corporation
Philadelphia, PA 19104 (US)

(72)Inventors:
  • SWAMY, Narayana
    Bangalore 560 094 (IN)
  • DEVARAJAN, Chokalingam
    Bangalore 560 086 (IN)
  • DATAR, Ravindra Vitthal
    Bangalore 560 064 (IN)

(74)Representative: Murgitroyd & Company 
Murgitroyd House 165-169 Scotland Street
Glasgow G5 8PL
Glasgow G5 8PL (GB)


(56)References cited: : 
WO-A1-2013/186325
US-A- 4 742 074
US-A- 5 476 964
US-A- 3 681 464
US-A- 5 093 347
US-A1- 2014 011 852
  
  • DAHL ET AL.: 'Route Scouting and Process Development of Lu AA26778' ORGANIC PROCESS RESEARCH & DEVELOPMENT vol. 12, 2008, pages 429 - 441, XP055421657
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

TECHNICAL FIELD



[0001] The present invention relates to the compound 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amine (the "Comp II"), an intermediate useful for the preparation of the fungicidal compound 3-difluoromethyl-N-(7-fluoro-1, 1, 3-trimethyl-4-indanyl)-1-methyl-4-pyrazolecarboxamide (the "Comp I"). More particularly, the present invention relates to the S enantiomer of Comp II and the preparation thereof. The formulas of Comp I and II are as follows:


BACKGROUND OF THE INVENTION



[0002] The Comp I is a recently discovered fungicidal molecule. The patent application WO2012084812 by Venturini, Isabella et al, first described the Comp I as a fungicide for agricultural use and the synthesis thereof. Structurally, the Comp I is an amide compound and thus can be easily obtained by the routine processes for making those amide compounds. For example, the Comp I can be obtained by condensing the Comp II and a corresponding pyrazole carboxylic acid or pyrazole carboxylic acid halide which provides the corresponding indane portion of the resultant Comp I. The synthesis route is showed as follows:



[0003] The Comp I is a chiral molecule with a chiral central on the 3'-carbon of the indane ring, which makes the Comp I have two enantiomer forms, namely R and S enantiomers. Further investigation found that the R enantiomer is the active component contributing to the fungicidal activity, while the S enantiomer shows no or less fungicidal activity.

[0004] Thus, there is a desire to synthesize in high yield the active component of R enantiomer without the formation of the unwanted inactive S enantiomer. One currently used approach to achieve this goal is using the R enantiomer of Comp II instead of the racemic form thereof as the starting material to react with the corresponding indane derivative to specifically yield the desired R enantiomer. With this approach, the R enantiomer of Comp II is useful while the S enantiomer is useless and wasted.

[0005] There is still a strong need to be met where the inactive S enantiomer can be recycled and the active R enantiomer can be synthesized in high yield.

[0006] WO2013/186325A1 also discloses the preparation of racemic 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine of formula (I). But the process of WO2013/186325A1 involves the reaction of 6-fluoro-2,2,4-trimethyl-1,2-dihydroquinoline with a carboxylic acid, followed by hydrogenation, acid isomerization and amide-hydrolysis.

SUMMARY OF THE INVENTION



[0007] That need is well fulfilled by the present invention. Thus, in one aspect of the present invention, it provides a novel process for the preparation of (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine, starting with (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine, or to say a process for converting (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine to its racemic form, namely (R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.

[0008] The presently claimed process mainly comprises the steps of:
  1. (a) acylating the (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine to obtain an indaneamide derivative;
  2. (b) oxidizing said indaneamide derivative to obtain 3-hydroxyl indaneamide derivative;
  3. (c) dehydrating said hydroxyl indaneamide derivative to obtain indeneamide derivative;
  4. (d) deacylating said indeneamide derivative to obtain indene amine derivative; and
  5. (e) hydrogenating said indene amine derivative to obtain the desired (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.


[0009] In another aspect of the present invention, it provides a process fully same to the aforesaid one except that the dehydration step (c) is carried out prior to subsequent to the deacylation step (d), or these two steps are carried out concurrently.

DETAILED DESCRIPTION OF THE INVENTION



[0010] The present invention provides a novel process for the preparation of (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine ("Formula I"), starting with (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine ("Formula II"). The Formula I and II as well as the entire synthesis route are shown below:

wherein, R is defined as below.

[0011] Thus, in one aspect, the present invention provides a process for the preparation of (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine, comprising the following steps of:
  1. (a) acylating the (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine to obtain an indaneamide derivative;
  2. (b) oxidizing said indaneamide derivative to obtain hydroxyl indaneamide derivative;
  3. (c) dehydrating said hydroxyl indaneamide derivative to obtain indeneamide derivative;
  4. (d) deacylating said indeneamide derivative to obtain indene amine derivative; and
  5. (e) hydrogenating said indene amine derivative to obtain the desired (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.


[0012] In another aspect, the present invention provides a process for the preparation of (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine having the following Formula I, comprising the following steps of:

  1. (a) acylating (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine having the following Formula (II) with an acylating agent of Formula RC(O)X to give a corresponding indaneamide derivative of Formula (III);

  2. (b) oxidization of said indaneamide derivative to give the corresponding hydroxyl indaneamide derivative of Formula (IV)

  3. (c) dehydration of said hydroxyl indaneamide derivative to give the corresponding indeneamide derivative of Formula (V);

  4. (d) deacylation of said indeneamide derivative to give the corresponding indeneamine derivative of Formula (VI); and

  5. (e) hydrogenation of said indeneamine derivative to obtain the desired (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine,

wherein,
  • R is selected from a C1-C6 alkyl group or a C6-C10 aryl group, these groups being optionally substituted with one or more of C1-C6 alkyl groups and/or halogen atoms;
  • X is a leaving group selected from: (i) a hydroxy group; (ii) a halogen atom; (iii) a C1-C6 alkylsulfonyloxy group; (iv) a C6-C10 arylsulfonyloxy group, (v) a RaCOO group wherein Ra is a C1-C6 alkyl group, the groups (iii)-(v) being optionally substituted with one or more halogen atoms.


[0013] Examples of a C1-C6 alkyl group are methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0014] Examples of a C6-C10 aryl group are phenyl, naphthyl.

[0015] Examples of halogen atoms are fluorine, chlorine, bromine, iodine.

[0016] The process of the present invention is carried out in the order as indicated above.

[0017] In one embodiment of the present processes, the order of the reactions between dehydration step (c) and deacylation step (d) can be changed. In another embodiment, step (c) is carried out prior to or subsequent to step (d). In a further embodiment, step (c) and step (d) are carried out concurrently.

[0018] In one embodiment, in step (a) of the present invention, the acylating agent RC(O)X for illustrative purpose is selected from acyl halide and anhydride, preferably acyl halide and anhydride of a lower alkanoic acid, more preferably selected from acetyl chloride, acetic anhydride or mixture thereof. However, one skilled in the art will appreciate that numerous alternative acylating agents can be used interchangeably in step (a) In another embodiment, the step (a) is carried out at elevated temperature, preferably ranging from 80°C to 120 °C, more preferably ranging from 80°C to 100°C. In another embodiment, step (a) comprises adding the compound of Formula (II) to freshly distilled acetic anhydride.

[0019] In one embodiment, in step (b) of the present invention, the oxidization comprises reacting the indaneamide derivative of Formula (III) in the presence of oxidizing agent to yield the corresponding hydroxyl indaneamide derivative of Formula (IV). In another embodiment, the oxidizing agent for illustrative purpose is selected from the group consisting of KMnO4, MnO2, SeO2, CrO3, or mixture thereof, preferably KMnO4. The skilled one in the art will appreciate numerous alternative oxidizing agent can be used interchangeably in step (b) of the present invention. In another embodiment, the reaction of step (b) is carried out at room temperature under stirring, preferably in the presence of MgSO4.



[0020] In one embodiment, in step (c) of the present invention, the dehydration comprises reacting said hydroxyl indaneamide derivative of Formula (IV) in the presence of a strong acid to yield indeneamide derivative of formula (V). In another embodiment, the reaction is carried out in an organic solvent, preferably selected from hexane, heptanes, methylene chloride, dichloroethane, methanol, ethanol, isopropanol, toluene, ethyl acetate and mixtures thereof. In another embodiment of step (c), the strong acid is selected from the group consisting of HCI, HBr, H2SO4 or mixtures thereof, with con. HCI and H2SO4 more preferred. In another embodiment, the reaction is carried out at room temperature, preferably ranging from 20°C to 40°C, more preferably 25°C. In another embodiment, the reaction is carried out at elevated temperature under stirring. In another embodiment, the reaction of step (c) is carried out without solvent.



[0021] In one embodiment, in step (d) of the present processes, the deacylating comprises contacting said indeneamide derivative with a strong acid, under elevated temperature to give an addition salt of indeneamine derivative; and then said indeneamine is treated with a base solution, to yield the indeneamine of Formula (VI). In another embodiment, for the illustrative example the strong acid is selected from the group consisting of HCI, HBr, H2SO4 or mixtures thereof, with con. HCI and H2SO4 more preferred. In another embodiment, the reaction is carried out at the elevated temperature ranging from 90°C to 120°C, preferably ranging from 100°C to 120°C. In another embodiment, the base is selected from NaOH, NaHCO3, KOH and mixtures thereof.



[0022] In one embodiment, in step (e) of the present invention, the hydrogenation comprises reacting said indeneamine derivative with gaseous hydrogen in the presence of a hydrogenation catalyst, to obtain the desired (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine. In another embodiment, the reaction is carried out in an organic solvent, preferably a polar solvent, more preferably selected from hexane, heptanes, methylene chloride, dichloroethane, methanol, ethanol, isopropanol, toluene, ethyl acetate and mixtures thereof. The illustrative examples of the hydrogenation catalyst include Group (X) metal catalysts, such as nickel, palladium and platinum, preferably Pd-C catalyst. In another embodiment, the reaction of step (e) is carried out without solvent.



[0023] Also disclosed herein is a racemate of (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amine which is prepared according to the present claimed processes.

[0024] Also disclosed herein is a compound of Formula V, where the R group is defined as above in the present application. In one embodiment, compound is N-(7-fluoro-1,1,3-trimethyl-1H-inden-4yl)acetamide.



[0025] Also disclosed herein is the use of the compound of Formula V for the preparation of (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amine. In one embodiment, it relates to use of N-(7-fluoro-1,1,3-trimethyl -1 H-inden-4yl)acetamide for the preparation of (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amine.

[0026] Also disclosed herein is a compound of Formula IV where the R group is defined as above in the present application. In one embodiment, the compound of Formula IV is (S)-N-(7-fluoro-1,1,3-trimethyl-3-hydroxy-1 H-indan-4-yl)acetamide.

[0027] Also disclosed herein is a compound of Formula VI, 7-fluoro-1,1,3-trimethyl-1 H-inden-4-amine.

[0028] The advantages of the presently claimed invention as described above are apparent to the skilled one in the art. With the processes of the present invention, the unwanted (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amine can be converted back to its raceme form and further recycled to produce the desired active form of R enantiomer. Therefore, the present process is more environmentally friendly and more cost effective which was never reported or envisioned before..

[0029] The following examples are provided for illustrative purpose, and shall not be construed in any way to restrict the scope of the presently claimed invention.

EXAMPLES


EXAMPLE 1


Step (a) - Acylation: Preparation of (S)-N-(7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)acetamide of Formula (III)



[0030] (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amine (6g, 31 mmol) was added to freshly distilled acetic anhydride (4 mL) and stirred at 90 °C for 30 min. Upon completion, reaction mixture was cooled to room temperature and was quenched by water (20 ml). The reaction mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over Na2S04 and concentrated in vacuo to leave a crude solid of (S)-N-(7-fluoro-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-yl)acetamide (7.1 g) that was analyzed by GC: 97.5 %.

Step (b) - Oxidization: Preparation of (S)-N-(7-fluoro-1,1,3-trimethyl-3-hydroxy-1 H-indan-4-yl)acetamide of Formula (IV)



[0031] 15% MgS04 solution was prepared (4.6g, 38 mmol). To this solution (S)-N-(7-fluoro-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-yl)acetamide (6g, 25.5 mmol) obtained from Step (a) dissolved in acetone (90 mL) was added at room temperature. To this solution KMnO4 (9.26g, 58.6 mmol) in solid form was added in portions and stirred at room temperature for 5 hours. Upon completion, reaction mixture was quenched by 1N NaOH solution to basic pH. The reaction mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to leave a crude solid of (S)-N-(7-fluoro-1,1,3-trimethyl-3-hydroxy-1 H-indan-4-yl)acetamide (5.1g) that was analyzed by GC: 83.5 %A.

Step (c) - Dehydration: Preparation of N-(7-fluoro-1,1,3-trimethyl-1 H-inden-4yl)acetamide of Formula (V)



[0032] Methanol (30 mL) was added to (S)-N-(7-fluoro-1,1,3-trimethyl-3-hydroxy-1 H-indan-4-yl)acetamide obtained from Step (b) (5g, 19.8 mmol). To this solution conc. HCI (10 mL) was added at room temperature and stirred for 90 min. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to leave a crude solid of N-(7-fluoro-1,1,3-trimethyl -1 H-inden-4yl)acetamide (4g) that was analyzed by GC: 90.8 %A.

Step d - Deacetylation: Preparation of 7-fluoro-1,1,3-trimethyl-1H-inden-4-amine of Formula (VI)



[0033] 25g of 50% H2SO4 was added to N-(7-fluoro-1,1,3-trimethyl -1 H-inden-4yl)acetamide obtained from Step (c) (4g, 17.2 mmol) at room temperature. The reaction mixture was stirred at 115 °C for 5 h. The reaction mixture was then diluted to 25% by adding water. Resulted solids were filtered, washed with water and then with hexane. The resulted solids were added to water (20 mL), basified with 10% NaOH solution (15 mL) and stirred at room temperature for 1 h. The reaction mixture extracted with ethyl acetate (20mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to leave a crude solid of 7-fluoro-1,1,3-trimethyl-1 H-inden-4-amine (2.2g) that was analyzed by GC: 95.5 %A.

Step e - Hydrogenation: Preparation of (R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amine of Formula (I)



[0034] Methanol (20 mL) was added to 7-fluoro-1,1,3-trimethyl-1 H-inden-4-amine obtained from Step (d) (1g, 7.6 mmol). To this solution 10% Pd-C (50 mg, 0.05 mmol) was added at room temperature. Dry hydrogen gas was bubbled through gas bubbler at room temperature under stirring for 2 h. The reaction mixture was filtered and concentrated in vacuo to leave a crude solid (0.9g) that was analyzed by GC: 83 %A. It was further purified through crystallization by dissolving in hexane (7mL) at 50 °C and allowed to stand at room temperature for 5 h. The resulted solids were filtered and dried in vacuo and the obtained solids of (R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amine (225 mg) was analyzed by GC: 95 %A. The racemic mixture was determined by chiral HPLC: 47:53 (R:S) and by specific rotation [α]D25 -1.45, C=0.15% in methanol.


Claims

1. A process for the preparation of (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amine having the following Formula (I), starting with (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine having the following Formula (II),

comprising the steps of:

(a) acylating the (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine to obtain an indaneamide derivative;

(b) oxidizing said indaneamide derivative to obtain 3-hydroxyl indaneamide derivative;

(c) dehydrating said 3-hydroxyl indaneamide derivative to obtain indeneamide derivative;

(d) deacylating said indeneamide derivative to obtain indene amine derivative; and

(e) hydrogenating said indene amine derivative to obtain the desired (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.


 
2. A process according to claim 1, which comprises:

(a) acylating the compound of Formula (II) with an acylating agent of Formula RC(O)X to give a corresponding indaneamide derivative of Formula (III) ;

(b) oxidization of said indaneamide derivative to give the corresponding 3-hydroxyl indaneamide derivative of Formula (IV)

(c) dehydration of said 3-hydroxyl indaneamide derivative to give the corresponding indeneamide derivative of Formula (V);

(d) deacylation of said indeneamide derivative to give the corresponding indeneamine derivative of Formula (VI); and

(e) hydrogenation of said indeneamine derivative to obtain the desired (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine,

wherein,

- R is selected from a C1-C6 alkyl group or a C6-C10 aryl group, these groups being optionally substituted with one or more of C1-C6 alkyl groups and/or halogen atoms;

- X is a leaving group selected from: (i) a hydroxy group; (ii) a halogen atom; (iii) a C1-C6 alkylsulfonyloxy group; (iv) a C6-C10 arylsulfonyloxy group, (v) a RaCOO group wherein Ra is a C1-C6 alkyl group, the groups (iii)-(v) being optionally substituted with one or more halogen atoms.


 
3. The process according to any of the preceding claims, wherein step (c) is carried out prior to or subsequent to step (d), or these two steps are carried out concurrently.
 
4. The process according to any of the preceding claims, wherein said acylating agent RC(O)X is selected from acyl halide and anhydride, preferably from acetyl chloride, acetic anhydride or mixture thereof.
 
5. The process according to any of the preceding claims, wherein said step (a) is carried out at elevated temperature, preferably ranging from 80°C to 120°C, more preferably from 80°C to 100°C.
 
6. The process according to any of the preceding claims, wherein oxidization step (b) comprises reacting said indaneamide derivative in the presence of oxidizing agent preferably selected from KMnO4, MnO2, SeO2, CrO3, or mixture thereof, to yield 3-hydroxyl indaneamide derivative.
 
7. The process according to any of the preceding claims, wherein dehydration step (c) comprises reacting said 3-hydroxyl indaneamide derivative dissolved in an organic solvent, preferably a polar solvent, and more preferably selected from hexane, heptanes, methylene chloride, dichloroethane, methanol, ethanol, isopropanol, toluene, ethyl acetate and mixtures thereof, in the presence of strong acid preferably selected from HCl, HBr, H2SO4 or mixture thereof, to yield indeneamide.
 
8. The process according to any of the preceding claims, wherein the dehydration step (c) is carried out at room temperature, preferably ranging from 25°C to 40°C.
 
9. The process according to any of the preceding claims, wherein deacylation step (d) comprises: contacting said indeneamide with a strong acid at elevated temperature to give an addition salt of indeneamine; and then said addition salt is treated with base solution to yield the desired (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.
 
10. The process according to any of the preceding claims, wherein the elevated temperature in step (d) is ranging from 90°C to 120°C, more preferably from 100°C to 120°C.
 
11. The process according to any of the preceding claims, wherein the strong acid in step (d) is selected from HCl, HBr, H2SO4 and mixtures thereof.
 
12. The process according to any of the preceding claims, wherein the base in step (d) is selected from NaOH, NaHCO3, KOH and mixtures thereof.
 
13. The process according to any of the preceding claims, wherein said hydrogenation step (e) comprises: contacting said indeneamine dissolved in an organic solvent with gaseous hydrogen in the presence of a hydrogenation catalyst, to obtain the desired (R,S)- 7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.
 
14. The process according to any of the preceding claims, wherein said organic solvent in step (e) is a polar solvent, and preferably selected from hexane, heptanes, methylene chloride, dichloroethane, methanol, ethanol, isopropanol, toluene, ethyl acetate and mixtures thereof.
 
15. The process according to any of the preceding claims, wherein said hydrogenation catalyst in step (e) is Group (X) metal catalysts, preferably selected from nickel, palladium and platinum and mixture thereof, more preferably Pd-C catalyst.
 


Ansprüche

1. Ein Verfahren zum Zubereiten von (R,S)-7-Fluor-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amin, das die folgende Formel (I) aufweist, das mit (S)-7-Fluor-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amin beginnt, das die folgende Formel (II) aufweist:

beinhaltend die folgenden Schritte:

(a) Acylieren des (S)-7-Fluor-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amins, um Indanamidderivat zu erhalten;

(b) Oxidieren des Indanamidderivats, um 3-Hydroxylindanamidderivat zu erhalten;

(c) Dehydratisieren des 3-Hydroxylindanamidderivats, um Indenamidderivat zu erhalten;

(d) Deacylieren des Indenamidderivats, um Indenaminderivat zu erhalten; und

(e) Hydrieren des Indenaminderivats, um das gewünschte (R,S)-7-Fluor-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amin zu erhalten.


 
2. Verfahren gemäß Anspruch 1, das Folgendes beinhaltet:

(a) Acylieren der Verbindung der Formel (II) mit einem Acylierungsmittel der Formel RC(O)X, um ein entsprechendes Indanamidderivat der Formel (III) zu ergeben;



(b) Oxidation des Indanamidderivats, um das entsprechende 3-Hydroxylindanamidderivat der Formel (IV) zu ergeben

(c) Dehydratisierung des 3-Hydroxylindanamidderivats, um das entsprechende Indenamidderivat der Formel (V) zu ergeben;

(d) Deacylierung des Indenamidderivats, um das entsprechende Indenaminderivat der Formel (VI) zu ergeben; und

(e) Hydrierung des Indenaminderivats, um das gewünschte (R,S)-7-Fluor-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amin zu erhalten:

wobei:

- R aus einer C1-C6-Alkylgruppe oder einer C6-C10-Arylgruppe ausgewählt ist, wobei diese Gruppen optional mit einem oder mehreren von C1-C6-Alkylgruppen und/oder Halogenatomen substituiert sind;

- X eine Abgangsgruppe ist, die aus Folgendem ausgewählt ist: (i) einer Hydroxygruppe; (ii) einem Halogenatom; (iii) einer C1-C6-Alkylsulfonyloxygruppe; (iv) einer C6-C10-Arylsulfonyloxygruppe, (v) einer RaCOO-Gruppe, wobei Ra eine C1-C6-Alkylgruppe ist, wobei die Gruppen (iii)-(v) optional mit einem oder mehreren Halogenatomen substituiert sind.


 
3. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei Schritt (c) vor oder im Anschluss an Schritt (d) ausgeführt wird oder diese zwei Schritte gleichzeitig ausgeführt werden.
 
4. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei das Acylierungsmittel RC(O)X ausgewählt ist aus Acylhalogenid und Anhydrid, vorzugsweise aus Acetylchlorid, Acetanhydrid oder Mischung davon.
 
5. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei der Schritt (a) bei erhöhter Temperatur, vorzugsweise im Bereich von 80 °C bis 120 °C, mehr bevorzugt von 80 °C bis 100 °C, ausgeführt wird.
 
6. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei Oxidationsschritt (b) das Zur-Reaktion-Bringen des Indanamidderivats in Gegenwart von Oxidationsmittel, vorzugsweise ausgewählt aus KMnO4, MnO2, SeO2, CrO3 oder Mischung davon, beinhaltet, um 3-Hydroxylindanamidderivat hervorzubringen.
 
7. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei Dehydratisierungsschritt (c) das Zur-Reaktion-Bringen des 3-Hydroxylindanamidderivats gelöst in einem organischen Lösungsmittel, vorzugsweise einem polaren Lösungsmittel und mehr bevorzugt ausgewählt aus Hexan, Heptanen, Methylenchlorid, Dichlorethan, Methanol, Ethanol, Isopropanol, Toluol, Ethylacetat und Mischungen davon, in Gegenwart starker Säure, vorzugsweise ausgewählt aus HCl, HBr, H2SO4 oder Mischung davon, beinhaltet, um Indenamid hervorzubringen.
 
8. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei Dehydratisierungsschritt (c) bei Raumtemperatur, vorzugsweise im Bereich von 25 °C bis 40 °C, ausgeführt wird.
 
9. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei Deacylierungsschritt (d) Folgendes beinhaltet: In-Kontakt-Bringen des Indenamids mit einer starken Säure bei erhöhter Temperatur, um ein Additionssalz von Indenamin zu ergeben; und wobei das Additionssalz anschließend mit einer Basenlösung behandelt wird, um das gewünschte (R,S)-7-Fluor-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amin hervorzubringen.
 
10. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei die erhöhte Temperatur in Schritt (d) im Bereich von 90 °C bis 120 °C, mehr bevorzugt von 100 °C bis 120 °C, liegt.
 
11. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei die starke Säure in Schritt (d) ausgewählt ist aus HCl, HBr, H2SO4 und Mischungen davon.
 
12. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei die Base in Schritt (d) ausgewählt ist aus NaOH, NaHCO3, KOH und Mischungen davon.
 
13. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei der Hydrierungsschritt (e) Folgendes beinhaltet: In-Kontakt-Bringen des Indenamins gelöst in einem organischen Lösungsmittel mit gasförmigem Wasserstoff in Gegenwart eines Hydrierungskatalysators, um das gewünschte (R,S)-7-Fluor-1,1,3-trimethyl-2,3-dihydro-1 H-inden-4-amin zu erhalten.
 
14. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei das organische Lösungsmittel in Schritt (e) ein polares Lösungsmittel ist und vorzugsweise ausgewählt aus Hexan, Heptanen, Methylenchlorid, Dichlorethan, Methanol, Ethanol, Isopropanol, Toluol, Ethylacetat und Mischungen davon.
 
15. Verfahren gemäß einem der vorhergehenden Ansprüche, wobei der Hydrierungskatalysator in Schritt (e) Gruppe-(X)-Metallkatalysatoren, vorzugsweise ausgewählt aus Nickel, Palladium und Platin und Mischung davon, mehr bevorzugt Pd-C-Katalysator ist.
 


Revendications

1. Un procédé pour la préparation de (R,S)-7-fluoro-1,1,3-triméthyl-2,3-dihydro-1 H-indèn-4-amine ayant la Formule (I) suivante, commençant par de la (S)-7-fluoro-1,1,3-triméthyl-2,3-dihydro-1 H-indèn-4-amine ayant la Formule (II) suivante,

comprenant les étapes :

(a) d'acylation de la (S)-7-fluoro-1,1,3-triméthyl-2,3-dihydro-1 H-indèn-4-amine afin d'obtenir un dérivé d'indaneamide ;

(b) d'oxydation dudit dérivé d'indaneamide afin d'obtenir du dérivé de 3-hydroxyle indaneamide ;

(c) de déshydratation dudit dérivé de 3-hydroxyle indaneamide afin d'obtenir du dérivé d'indèneamide ;

(d) de désacylation dudit dérivé d'indèneamide afin d'obtenir du dérivé d'indène aminé ; et

(e) d'hydrogénation dudit dérivé d'indène amine afin d'obtenir la (R,S)-7-fluoro-1,1,3-triméthyl-2,3-dihydro-1 H-indèn-4-amine souhaitée.


 
2. Un procédé selon la revendication 1, lequel comprend :

(a) l'acylation du composé de Formule (II) avec un agent d'acylation de Formule RC(O)X afin de donner un dérivé d'indaneamide correspondant de formule (III) ;

(b) l'oxydation dudit dérivé d'indaneamide afin de donner le dérivé de 3-hydroxyle indaneamide correspondant de formule (IV)

(c) la déshydratation dudit dérivé de 3-hydroxyle indaneamide afin de donner le dérivé d'indèneamide correspondant de Formule (V) ;

(d) la désacylation dudit dérivé d'indèneamide afin de donner le dérivé d'indènemaine correspondant de Formule (VI) ; et

(e) l'hydrogénation dudit dérivé d'indèneamine afin d'obtenir la (R,S)- 7-fluoro-1,1,3-triméthyl-2,3-dihydro-1 H-indèn-4-amine souhaitée,

où,

- R est sélectionné parmi un groupe alkyle en C1 à C6 ou un groupe aryle en C6 à C10, ces groupes étant facultativement substitués par un ou plusieurs éléments parmi des groupes alkyle en C1 à C6 et/ou des atomes d'halogène ;

- X est un groupe partant sélectionné parmi : (i) un groupe hydroxy ; (ii) un atome d'halogène ; (iii) un groupe alkylsulfonyloxy en C1 à C6 ; (iv) un groupe arylsulfonyloxy en C6 à C10, (v) un groupe RaCOO où Ra est un groupe alkyle en C1 à C6, les groupes (iii) à (v) étant facultativement substitués par un ou plusieurs atomes d'halogène.


 
3. Le procédé selon n'importe lesquelles des revendications précédentes, où l'étape (c) est menée préalablement ou postérieurement à l'étape (d), ou ces deux étapes sont menées simultanément.
 
4. Le procédé selon n'importe lesquelles des revendications précédentes, où ledit agent d'acylation RC(O)X est sélectionné parmi un halogénure d'acyle et un anhydride, préférablement parmi un chlorure d'acétyle, un anhydride acétique ou un mélange de ceux-ci.
 
5. Le procédé selon n'importe lesquelles des revendications précédentes, où ladite étape (a) est menée à température élevée, préférablement dans un intervalle allant de 80 °C à 120 °C, plus préférablement allant de 80 °C à 100 °C.
 
6. Le procédé selon n'importe lesquelles des revendications précédentes, où l'étape d'oxydation (b) comprend la mise en réaction dudit dérivé d'indaneamide en présence d'un agent oxydant préférablement sélectionné parmi KMnO4, MnO2, SeO2, CrO3, ou un mélange de ceux-ci, afin de fournir un dérivé de 3-hydroxyle indaneamide.
 
7. Le procédé selon n'importe lesquelles des revendications précédentes, où l'étape de déshydratation (c) comprend la mise en réaction dudit dérivé de 3-hydroxyle indaneamide dissous dans un solvant organique, préférablement un solvant polaire, et plus préférablement sélectionné parmi de l'hexane, des heptanes, du chlorure de méthylène, du dichloroéthane, du méthanol, de l'éthanol, de l'isopropanol, du toluène, de l'acétate d'éthyle et des mélanges de ceux-ci, en présence d'acide fort préférablement sélectionné parmi HCI, HBr, H2SO4 ou un mélange de ceux-ci, afin de fournir de l'indèneamide.
 
8. Le procédé selon n'importe lesquelles des revendications précédentes, où l'étape de déshydratation (c) est menée à température ambiante, préférablement dans un intervalle allant de 25 °C à 40 °C.
 
9. Le procédé selon n'importe lesquelles des revendications précédentes, où l'étape de désacylation (d) comprend : la mise en contact dudit indèneamide avec un acide fort à température élevée afin de donner un sel d'addition d'indèneamine ; et ensuite ledit sel d'addition est traité avec de la solution de base afin de fournir la (R,S)-7-fluoro-1,1,3-triméthyl-2,3-dihydro-1 H-indèn-4-amine souhaitée.
 
10. Le procédé selon n'importe lesquelles des revendications précédentes, où la température élevée à l'étape (d) est dans l'intervalle allant de 90 °C à 120 °C, plus préférablement allant de 100 °C à 120 °C.
 
11. Le procédé selon n'importe lesquelles des revendications précédentes, où l'acide fort à l'étape (d) est sélectionné parmi HCI, HBr, H2SO4 et des mélanges de ceux-ci.
 
12. Le procédé selon n'importe lesquelles des revendications précédentes, où la base à l'étape (d) est sélectionnée parmi NaOH, NaHCO3, KOH et des mélanges de ceux-ci.
 
13. Le procédé selon n'importe lesquelles des revendications précédentes, où ladite étape d'hydrogénation (e) comprend : la mise en contact de ladite indèneamine dissoute dans un solvant organique avec de l'hydrogène gazeux en présence d'un catalyseur d'hydrogénation, afin d'obtenir la (R,S)-7-fluoro-1,1,3-triméthyl-2,3-dihydro-1H-indèn-4-amine souhaitée.
 
14. Le procédé selon n'importe lesquelles des revendications précédentes, où ledit solvant organique à l'étape (e) est un solvant polaire, et préférablement sélectionné parmi de l'hexane, des heptanes, du chlorure de méthylène, du dichloroéthane, du méthanol, de l'éthanol, de l'isopropanol, du toluène, de l'acétate d'éthyle et des mélanges de ceux-ci.
 
15. Le procédé selon n'importe lesquelles des revendications précédentes, où ledit catalyseur d'hydrogénation à l'étape (e) est des catalyseurs métalliques du Groupe (X), préférablement sélectionnés parmi le nickel, le palladium et le platine et un mélange de ceux-ci, plus préférablement un catalyseur Pd-C.
 






Cited references

REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description