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KR-20260066043-A - Selective preparation method for single-axis asymmetric compounds

KR20260066043AKR 20260066043 AKR20260066043 AKR 20260066043AKR-20260066043-A

Abstract

The present invention relates, in one embodiment thereof, to a method for preparing a compound of formula (I) or a salt thereof as defined in the specification. The method for preparing said method comprises a process of obtaining a compound of formula (I) or a salt thereof by reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, or by reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof. In the compound of formula (I), it is suitable that R₄ is formula (VI) or (VII) and R₅ is formula (VIII) or (IX) (each of the above formulas and R₄ and R₅ are all defined in the specification).

Inventors

  • 요시나리, 도모히로
  • 이마다, 스나오
  • 이시오카, 히로키
  • 가와구치, 겐이치
  • 가와미나미, 에이지
  • 오타카, 준페이
  • 히로세, 유키

Assignees

  • 아스텔라스세이야쿠 가부시키가이샤

Dates

Publication Date
20260512
Application Date
20240906
Priority Date
20230908

Claims (13)

  1. Compound of the following formula (I) or its salt: [During the meal, A is N or CH, and Y is bonded to -CH 2 -, -O-, -S- or -NR Y -, and RY is a C 1-3 alkyl that may be H or substituted, and R 1 is the following expression (IV) or (V), and Ring A is a cross-linked heterocycloalkane that may be substituted with 7 to 9 members containing 1 to 2 nitrogen atoms, or a heterocycloalkane that may be substituted with 4 to 6 members containing 1 to 2 nitrogen atoms, and Z is bonded to -CH2- , -O-, -S- or -N( RZ1 )-, and R Z1 is a C 1-3 alkyl that may be H or substituted, and PG 1 is the protector of NH included in ring A, and PG2 is the protecting group of OH, and R2 is a C1-15 alkyl that may be substituted or a heterocycloalkyl that may be substituted, and R3 is a halogen, a C3-6 cycloalkyl, a vinyl, or a C1-3 alkyl that may be substituted, and R 4 is the following expression (VI) or (VII), and R 4A is a C 1-3 alkyl, and R 4B is a naphthyl, phenanthrenyl, or a phenyl that may be substituted, and R 5 is the following formula (VIII) or (IX), and PG 3 is the protector of NH, and R 5A is H, methyl, F, or Cl, and R 5B is Cl, methyl, ethyl, or vinyl, and * indicates an asymmetric axis], It is a method of manufacturing, and A process for obtaining the compound of formula (I) or its salt by reacting the compound of formula (IIA) or its salt with the compound of formula (IIIA) or its salt, or by reacting the compound of formula (IIB) or its salt with the compound of formula (IIIB) or its salt: [During the meal, A, Y, R Y , R 1 , Hwan A, Z, R Z1 , PG 1 , PG 2 , R 2 , R 3 , R 4 , R 4A , R 4B , R 5 , PG 3 , R 5A , R 5B and * are as defined above, and X is Cl, Br, I, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and BLG is a boronic acid group, a boronic acid ester group, a trifluoroborate group, or a triolborate base. Includes, Herein, a method for selectively preparing an axially asymmetric compound or its salt of one of the compounds of formula (I) or its salts having axial asymmetry.
  2. In paragraph 1, the reaction comprises reacting a compound of formula (IIA) or its salt with a compound of formula (IIIA) or its salt, and Here, X is Cl or Br, and Y is -O- or -S- and, R 1 is the following equations (IV-1), (IV-2), (IV-3) and (V): It is a group selected from the group consisting of, and R2 is a C1-3 alkyl that may be substituted with tetrahydropyranyl or -OCH3 , and R 3 is cyclopropyl, and R 4 a, the following equations (VI-1), (VI-2) and (VI-3): It is a group selected from the group consisting of, and R 5 a, the following equations (VIII-1) and (IX-1): The cause selected from the group consisting of, method.
  3. In paragraph 2, the reaction of a compound of formula (IIA) or its salt with a compound of formula (IIIA) or its salt is included, Here, A is N and, R 1 is the following equations (IV-1), (IV-2) and (V): It is a group selected from the group consisting of, and R 5 a, the following equation (VIII-1): The cause, method indicated by.
  4. In paragraph 3, the compound of formula (IIA) or its salt is the following formula (IIA-1): It is a compound represented by, A compound of formula (IIIA) or its salt is of the following formula (IIIA-1): It is a compound represented by, The following process: A method comprising a process for obtaining a compound represented by formula (I-1) by means of
  5. In Paragraph 4, the following process: A method comprising obtaining a compound (1) or its salt by means of.
  6. In paragraph 5, the following process from the following compounds (16) and the following compounds (17): A method comprising obtaining the above compound (14) by means of.
  7. In paragraph 5, the following process from the following compound (2): A method comprising obtaining a compound of formula (IIA-1) by means of
  8. In paragraph 6, from the following compound (24) and the following compound (25), the following process: A method comprising obtaining compound (20) by means of.
  9. In any one of paragraphs 4 to 8, from the following compound (27), the following process: A method comprising obtaining a compound of formula (IIIA-1) by means of
  10. In paragraph 3, the compound of formula (IIA) or its salt is of the following formula (IIA-2): It is a compound represented by, A compound of formula (IIIA) or its salt is of the following formula (IIIA-1): It is a compound represented by, The following process: A method comprising a process for obtaining a compound represented by formula (I-1) by means of
  11. In Item 10, the following process: A method comprising obtaining a compound (1) or its salt by means of.
  12. In Clause 10 or 11, the following process: A method comprising obtaining a compound of formula (IIA-2) by means of.
  13. A compound or its salt represented by any of the following.

Description

Selective preparation method for single-axis asymmetric compounds The present invention relates to a method for selectively preparing one axially asymmetric compound among compounds having axial asymmetry. More specifically, the invention relates to a method for selectively preparing one axially asymmetric compound or its salt among a compound of formula (I) having axial asymmetry or a salt thereof. In addition, the present invention relates to a method for efficiently preparing a compound for use in a selective preparation method of an axially asymmetric compound, and to an axially asymmetric compound obtained by the selective preparation method of an axially asymmetric compound. Patent Document 1 (International Publication No. 2022/173032) describes a quinazoline compound for inducing degradation of G12D mutant KRAS protein, a compound represented by the following formula (A) or a salt thereof, and a method for preparing the same. (Also, refer to Patent Document 1 for the definitions of each element in the formula.) The present invention will be described in detail below. 1. Definition As described above, in one embodiment, the present invention relates to a method for selectively obtaining a compound with one axis of asymmetry or a salt thereof. In this specification, the expression “selectively obtaining a compound with one axis of asymmetry or a salt thereof” means that a compound with one axis of asymmetry or a salt thereof is obtained in a higher proportion than a compound with the other axis of asymmetry or a salt thereof, such that the ratio of M bodies to P bodies (M:P ratio) is not 1:1. In one embodiment, in the method of the present invention, M is obtained in a higher proportion than P, and the ratio (M:P ratio) is not particularly limited, but is, for example, 1.3:1 or higher, 1.4:1 or higher, 1.5:1 or higher, 1.6:1 or higher, 2:1 or higher, 3:1 or higher, 4:1 or higher, 5:1 or higher, 6:1 or higher, 7:1 or higher, 8:1 or higher, 10:1 or higher, 20:1 or higher, 40:1 or higher, 60:1 or higher, 80:1 or higher, 90:1 or higher. Furthermore, when M is obtained in a higher proportion than P, the description "1.3:1 or higher" means that 1.3 units or more of M is obtained for every 1 unit (gram or molar amount) of P. For example, it means that 1.3 g or more of M is obtained for every 1 g of P. In addition, in the present invention, since the molecular weights of the M body and the P body are the same, the M:P ratio as a gram ratio matches the M:P ratio as a molar ratio. In addition, in one embodiment, in the method of the present invention, the P body is obtained in a higher proportion than the M body, and the ratio (M:P ratio) is not particularly limited, but is, for example, 1:1.3 or higher, 1:1.4 or higher, 1:1.5 or higher, 1:1.6 or higher, 1:2 or higher, 1:5 or higher. Also, in the case where the P body is obtained in a higher proportion than the M body, as described above, the description "1:1.3 or higher" means that 1.3 units or more of the P body are obtained for every 1 unit of the M body. In addition, in a method for preparing an axially asymmetric compound that does not use a chiral auxiliary, the target compound is obtained as a stereoisomer mixture with an M:P ratio of about 1:1. Compared to this method, the method of the present invention is advantageous in that it can increase the selectivity of stereoisomers when obtaining a desired axially asymmetric compound. Furthermore, in one embodiment, the present invention relates to a method for producing an axially asymmetric compound using a chiral auxiliary group, thereby obtaining an axially asymmetric compound having a chiral auxiliary group. The inventors also discovered that an axially asymmetric compound having a chiral auxiliary group is easier to separate and fractionate compared to one not having a chiral auxiliary group. That is, the mixture of axially asymmetric compounds having a chiral auxiliary group (M body and P body) obtained by the manufacturing method of the present invention allows one axially asymmetric compound to be purified to high purity by simple operations such as recrystallization. In addition, one axially asymmetric compound can also be purified to high purity by fractionation operations such as conventional column chromatography. In other words, the manufacturing method of the present invention can achieve both an improvement in the yield of a target compound having a predetermined stereoisomorphism and a reduction in processes such as separation and fractionation, and furthermore, can contribute to a reduction in manufacturing costs. The analysis of the obtained axially asymmetric compound or its salt can be performed using known methods such as HPLC or NMR. Furthermore, there is no substantial difference between the M:P ratio calculated by HPLC analysis and the M:P ratio calculated by NMR analysis. In this specification, the HPLC analysis conditions used are the following conditions, but are not limited to thes