Total synthesis method of pactalactam

Patent metadata

Field	Value
Publication number	US-11345667-B2
Application number	US-202016852820-A
Country	US
Kind code	B2
Filing date	Apr 20, 2020
Priority date	Apr 18, 2019
Publication date	May 31, 2022
Grant date	May 31, 2022

Abstract

The present invention relates to a method of preparing pactalactam represented by Formula 5 below using a total synthesis method:

First claim

The invention claimed is:

1. A method of preparing pactalactam, the method comprising:
a first step of preparing a cyclopentenone derivative compound represented by Formula 2 from a phenyloxazoline derivative compound represented by Formula 1;
a second step of preparing an N-PMB aziridine (N-para-methoxybenzylamine aziridine) derivative compound represented by Formula 3 from the cyclopentenone derivative compound;
a third step of preparing an oxazoline derivative compound containing a cyclopentane core represented by Formula 4 from the N-PMB aziridine derivative compound; and
a fourth step of preparing pactalactam represented by Formula 5 from the oxazoline derivative compound containing the cyclopentane core:

wherein, in Formula 2 above, R 1 is H or I.

2. The method of claim 1 , wherein the first step comprises:
a first-first step of adding a compound of enolated Formula 1 above using lithium diisopropylamide (LDA) to the compound represented by Formula 1-1 to form a compound represented by Formula 1-2 below;
a first-second step of first adding tert-butyldimethylsilyl chloride (TBSCl) to the compound of Formula 1-2 above to react, second diisobutylaluminium hydride (DIBAL-H) to the resulting mixture to react, third adding Dess-Martin periodinane (DMP) to the resulting mixture to react, fourth adding Ph 3 PMeBr and n-BuLi to the resulting mixture to react, fifth adding ZnBr 2 to the resulting mixture to react, and sixth adding DMP to the resulting mixture to form a compound represented by Formula 1-3 below;
a first-third step of first adding vinyl magnesium bromide to the compound of Formula 1-3 above to react, second second-generation Grubbs catalyst to the resulting mixture to form a compound represented by Formula 1-4 below; and
a first-fourth step of first adding DMP to the compound of Formula 1-4 above to react, second Iodine (I 2 ) to the resulting mixture to form a compound represented by Formula 2:

3. The method of claim 2 , wherein the compound of Formula 1-2 above is a mixture of stereoisomers represented by Formula 1-2-a and 1-2-b below, and the method further comprises a step of adding DMP and NaBH 4 to the compound of Formula 1-2-a to convert the compound of Formula 1-2-a into the compound of Formula 1-2-b:

4. The method of claim 1 , wherein the second step comprises a second-first step of adding PMBNH 2 , and a compound represented by Formula 2-1 below to the compound of Formula 2 above to form the compound of Formula 3 above:

wherein, in Formula 2-1 above, R 2 is OTBS (O-tert-Butyldimethylsilyl).

5. The method of claim 1 , wherein the second step comprises a second-first step of adding I 2 to the compound of Formula 2 above to form a compound of Formula 2-1 below; a second-second step of adding PMBNH 2 to the compound of Formula 2-1 above to form the compound of Formula 3

wherein, in Formula 2-1 above, R 2 is OTBS (O-tert-Butyldimethylsilyl).

6. The method of claim 1 , wherein the third step comprises:
a third-first step of adding MePPh 3 Br and n-BuLi to the compound of Formula 3 above to form a compound of Formula 3-1 below;
a third-second step of first adding OsO 4 and NMO to the compound of Formula 3-1 above to react, second adding 2,2-dimethoxypropane, and TsOH-H 2 O to the resulting mixture to react, third adding tetrabutylammonium bromide (TBAF) to the resulting mixture to react, and fourth adding Dess-Martin periodinane (DMP) to the resulting mixture to form a compound of Formula 3-2 below;
a third-third step of adding MeMgBr to the compound of Formula 3-2 above to form a compound of Formula 3-3 below;
a third-fourth step of first adding CAN to the compound of Formula 3-3 above to react, second adding NsCl to the resulting mixture to form a compound of Formula 3-4 below; and
a third-fifth step of adding NaN 3 to the compound of Formula 3-4 above to form the compound of Formula 4:

7. The method of claim 1 , wherein the fourth step comprises:
a fourth-first step of first adding NaBH 3 CN and AcOH to the compound of Formula 4 above to react, and second adding TIPSOTf to the resulting mixture to form a compound of Formula 4-1 below;
a fourth-second step of first adding diisopropyl azodicarboxylate (DIAD) to the compound of Formula 4-1 above to react, second adding aqueous HCl solution to the resulting mixture to react, and third adding triphosgene to the resulting mixture to form a compound of Formula 4-2 below;
a fourth-third step of first adding 2-mercaptoacetic acid and DBU to the compound of Formula 4-2 above to react, and second adding Zn powder and NH 4 Cl to the resulting mixture to form a compound of Formula 4-3 below;
a fourth-fourth step of adding a compound represented by Formula 4-4 below, Cu(OAc) 2 , DBU, DMAP, and MeCN to the compound of Formula 4-3 above to form a compound of Formula 4-5 below;
a fourth-fifth step of first adding tetrabutylammonium bromide (TBAF) to the comp to the compound of Formula 4-5 above to react, and second adding AcOH—H 2 O to the resulting mixture to form a compound of Formula 4-6 below; and
a fourth-sixth step of adding a compound represented by Formula 4-7 below and K 2 CO 3 to the compound of Formula 4-6:

wherein, in Formula 4-1 above, R is Bn or H; and in Formula 4-5 above R is TIPS (triisopropylsilyl) or H.

Assignees

• Korea Inst Sci & Tech

Inventors

• Kim Taejung
• Ham Jungyeob
• Park Young Tae

Classifications

• C07D235/02 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• C07D263/52

  condensed with carbocyclic rings or ring systems · CPC title

• C07D498/10

  Spiro-condensed systems · CPC title