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KR-102964840-B1 - Method for preparing (R)-4-aminoindane and the corresponding amide

KR102964840B1KR 102964840 B1KR102964840 B1KR 102964840B1KR-102964840-B1

Abstract

The present invention relates to a method for preparing a 1,1,3-trimethylindane-4-amine of formula (I) or a salt thereof that is rich in one of two enantiomers, particularly the enantiomer (R), wherein (I) It includes the chiral separation of optionally substituted 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline of formula (III). (III) The present invention also relates to a method for producing an optically active amide of formula (II) starting from a compound of formula (I). (II)

Inventors

  • 차나르디 잠파올로
  • 메레게티 피에란젤로
  • 벨란디 파올로

Assignees

  • 에프엠씨 아그로 싱가포르 피티이. 엘티디.

Dates

Publication Date
20260513
Application Date
20200923
Priority Date
20190926

Claims (17)

  1. (R) A method for preparing a 1,1,3-trimethylindane-4-amine compound of formula (I) or a salt thereof that is rich in enantiomers (I) Method including the following steps: a) a step of providing a racemic mixture of the substituted 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline compound of formula (IIIa), (IIIa) The above racemic mixture comprises the (R) -enantiomer of formula (IVa) and the (S) -enantiomer of formula (Va), step (IVa) (Va) b) a step of treating a racemic mixture of the compound of formula (IIIa) according to work sequence A or work sequence B, where: - The above work sequence A includes the following steps: b1) A step of converting, by means of a protection reaction, a racemic mixture of the compound of formula (IIIa) into a racemic mixture of the compound of formula (IIIb) having a protection PG group attached to a nitrogen atom, (IIIb) A step in which the racemic mixture of the compound of formula (IIIb) comprises the (R) -enantiomer of formula (IVb) and the (S) -enantiomer of formula (Vb), (IVb) (Vb) b2) A step of separating the (R) -enantiomer of the formula (IVb) from the (S) -enantiomer of the formula (Vb); - The above work sequence B includes the following steps: b3) A step of separating the (R) -enantiomer of the formula (IVa) from the ( S) -enantiomer of the formula (Va); b4) A step of converting the (R) -enantiomer of formula (IVa) into the (R) -enantiomer of formula (IVb) by means of a protection reaction; c) a step of applying the (R) -enantiomer of Formula (IVb) obtained in step b2 or step b4 to an acid rearrangement reaction to obtain the compound of Formula (VI), (IVb) (VI) d) a step of obtaining the (R) -enantiomer of the compound of formula (I) by substituting the PG group of the compound of formula (VI) with a hydrogen atom; Here: * indicates an asymmetric carbon atom; X is a fluorine atom; n is 1 and; PG is -COR 1 period or -COOR 2 period, and R1 is a methyl group; R2 is a methyl group or a benzyl group.
  2. A method according to claim 1, further comprising the following steps in order: i) a step of obtaining a compound of formula (VII) by oxidizing the (S) -enantiomer of formula (Vb) obtained in step b2 with an oxidizing agent; (VII) ii) a step of dehydrating the compound of formula (VII) in an acidic environment to obtain the compound of formula (VIII); (VII); and iii) a step of hydrogenating the compound of formula (VIII) to obtain a racemic mixture of the compound of formula (IIIb) comprising the (R) -enantiomer of formula (IVb) and the (S) -enantiomer of formula (Vb).
  3. A method according to claim 1, further comprising the following steps in order: - A step of converting the (S) -enantiomer of formula (Va) obtained in step b3 into the (S) -enantiomer of formula (Vb) by means of a protective reaction; i) a step of obtaining a compound of formula (VII) by oxidizing the (S) -enantiomer of formula (Vb) with an oxidizing agent; (VII) ii) a step of dehydrating the compound of formula (VII) in an acidic environment to obtain the compound of formula (VIII); (VIII); and iii) a step of hydrogenating the compound of formula (VIII) to obtain a racemic mixture of the compound of formula (IIIb) containing the (R) -enantiomer of formula (IVb) and the (S) -enantiomer of formula (Vb).
  4. A method according to claim 2, wherein step iii is replaced in order by the following steps: ii-bis) A step of obtaining a compound of formula (IX) by converting the compound of formula (VIII) by a deprotection reaction; (IX); and iii-bis) A step of hydrogenating the compound of formula (IX) above to obtain a racemic mixture of the compound of formula (IIIa) containing the (R) -enantiomer of formula (IVa) and the (S) -enantiomer of formula (Va).
  5. A method according to either claim 2 or claim 3, wherein the racemic mixture of the compound of formula (IIIb) obtained in step iii is supplied to step b2.
  6. A method according to claim 4, wherein the racemic mixture of the compound of formula (IIIa) obtained in step iii-bis is supplied to step a.
  7. The method of claim 1, wherein step d for substituting a PG group with a hydrogen atom is performed by hydrolysis or catalytic hydrogenation.
  8. The method of claim 1, wherein step b2 or the separation step b3 is performed by chiral column chromatography technique.
  9. In claim 1, the separation step b3 of the racemic mixture of the compound of formula (IIIa) comprises the following steps: - A step of reacting the racemic mixture of formula (IIIa) with an optically active acid to obtain a mixture of the corresponding (R) -enantiomer salt and the corresponding (S) -enantiomer salt; - A step of separating the (R) -enantiomer salt from the (S) -enantiomer salt; - A step of applying the above (R) -enantiomer salt to basic hydrolysis to obtain the (R) -enantiomer of formula (IVa) to be supplied to step b4.
  10. A method according to claim 1, wherein the (R) -enantiomer of formula (IVb) applied in the acid rearrangement step c has an enantiomer excess rate (ee%) of greater than 90%, greater than 98%, or greater than 99.5% with respect to the (S) -enantiomer of formula (Vb).
  11. A method according to claim 1, wherein the acid rearrangement reaction comprises the step of reacting the (R) -enantiomer of formula (IVb) in the presence of an inorganic acid selected from sulfuric acid and orthophosphoric acid.
  12. A method according to claim 1, wherein the compound of formula (I) obtained from step d has an excess rate (ee %) of the (R) -enantiomer of greater than 97% or greater than 99% or greater than 99.5% for the (S)-enantiomer.
  13. In claim 1, in the compound of formula (IIIa) or (IIIb): X is a fluorine atom; n is 1 and; PG is a method in which it is an acetyl group or a carbobenzyl oxy group.
  14. (R) As a method for preparing an amide of formula (II) rich in enantiomers: (II) Method including the following steps: A step of preparing a 1,1,3-trimethylindane-4-amine of formula (I) or a salt thereof that is rich in (R) -enantiomer prepared according to claim 1; A step of condensing the compound of formula (I) with at least one compound of formula AC(O)Y, Here: A is A 1 and; R3 is methyl; R 4 is difluoromethyl; Y is a hydroxyl group or a halogen atom.
  15. In any one of claims 1 to 4, the compound of formula (I) is: The method.
  16. In claim 13, the method wherein PG is an acetyl group.
  17. In claim 14, the compound of formula (II) is: The method.

Description

Method for preparing (R)-4-aminoindane and the corresponding amide The present invention relates to a method for preparing a 1,1,3-trimethylindane-4-amine of formula (I) or a salt thereof that is rich in one of two enantiomers, particularly the enantiomer (R), wherein (I) It includes the chiral separation of optionally substituted 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline of formula (III). (III) The present invention also relates to a method for producing an optically active amide of formula (II) starting from a compound of formula (I) obtained by the above manufacturing method. (II) Indan derivatives having an amino group at position 4, their corresponding amides, and related methods of preparation are described in the literature, e.g., JP1070479, JP1117864, JP1313402, JP2157266, JP2249966, JP3077381, JP62096471, EP199822, EP256503, EP276177, EP280275, EP569912, US5093347, US5521317, WO01/53259, WO2004/018438, WO2004/039789, WO2004/072023, WO2004/103975, WO2005/075452, WO2011/162397, It is widely described in WO2012/084812, WO2013/186325, WO2015/118793 and WO2017/178868. The amides of the above-mentioned indan derivatives, in particular, have high fungicidal activity and can therefore be used for the control of plant pathogenic fungi in crops. However, there are few methods known in the art for providing an optically active form of 4-aminoindan. Patent US5521317 reports a method for preparing enantiomer-rich 4-aminoinganes in four steps, as reported in Schematic 1: i) a condensation reaction between a dihydroquinoline and a derivative of a carboxylic acid having a chiral center (indicated by * in the schematic below) and an LG leaving group; ii) catalytic hydrogenation to yield the corresponding tetrahydroquinoline; iii) addition of a strong acid to obtain the aminoingane derivative; and (iv) hydrolysis of the amide bond. Diagram 1 However, this method is unsatisfactory from an industrial perspective because it requires the use of different solvents at each step of the synthesis process, thereby increasing the processing and purification required at the end of each reaction. Furthermore, since acylated dihydroquinoline and the corresponding tetrahydroquinoline do not dissolve well in non-polar solvents, it is necessary to perform hydrogenation reactions at high temperatures, which can lead to racemization of the chiral center. Consequently, this strategy of introducing a chiral center generally leads to a mixture rich in one of the two enantiomers after extensive purification, but fails to achieve high optical purity. Patent application WO2011/162397 describes a method for obtaining a mixture rich in the enantiomer (R) of a 4-aminoindan in an 80/20 ratio to the corresponding enantiomer (S). This preparation can be carried out by using a chiral column or through the formation of a diastereomer salt with tartaric acid. Separation of enantiomers through the formation of a salt with an optically active organic acid generally entails sophisticated work and significant yield loss, as it is generally possible to reach high optical purity only after a certain number of fraction crystallizations. Furthermore, this method is applicable only to compounds having free amino groups capable of forming organic acids and salts added to the reaction mixture. In addition, the separation of the two enantiomers of the 4-aminoindan occurs in the final compound of the synthesis, that is, in the compound obtained after numerous synthesis steps, and consequently, costs increase due to the loss of high-value materials. Therefore, there is a need for a new method that can be easily industrialized to obtain 1,1,3-trimethylindane-4-amine rich in one of two enantiomers having high purity and greater synthesis efficiency, particularly the enantiomer (R) which is more effective than the enantiomer (S) as a fungicide in crops as is known. The applicant has now surprisingly discovered that in a method for synthesizing 4-aminoingan, optical resolution of a racemic mixture of synthetic intermediates of said compound, rather than the final product, is performed, and subsequently, synthesis is continued for only one of the two enantiomers of said intermediate, thereby overcoming the aforementioned disadvantages of the art. In particular, the optical resolution step is performed for an intermediate compound, e.g., an optionally substituted 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline. The enantiomer of interest, i.e., the enantiomer (R) of the intermediate, is then subjected to an acid rearrangement reaction and hydrolysis to obtain a final 4-aminoingan compound rich in the enantiomer (R). According to the present invention, it is possible to obtain a 4-aminoindane compound rich in enantiomers, that is, a 4-aminoindane compound in which enantiomer (R) exists in a dominant amount over enantiomer (S), with high yield and higher optical purity than can be obtained by the method of the prior art. Accordingly, according to the first aspect, the pre