# US 12,006,324 B1 · Preparation method of trilaciclib and precursors of trilaciclib

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- Number: US 12,006,324 B1
- Document ID: US12006324B1
- Status: Granted
- Kind: B1
- Application number: 18/084,179
- Filed: 2022-12-19
- Published: 2024-07-04
- Granted: 2024-06-11
- Earliest claimed: 2022-12-15
- Assignees: Chunghwa Chemical Synthesis & Biotech Co. Ltd.
- Applicants: Chunghwa Chemical Synthesis & Biotech Co. Ltd.
- Inventors: Satyanarayana Kamani; Hsin-Yun Chang; Tzu-Chiang Lu; Chin-Cheng Mai
- Web page: https://patentgrep.com/patent/US12006324B1

## CPC

- C07D 487/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed herein is a specific method of preparation of Trilaciclib. The said method is to provide an efficacy of a protection free synthetic method of Trilaciclib with less steps and good yields.

## Claims

### Claim 1

A method for preparing Trilaciclib of formula (I),
comprising:
(a) oxidizing a compound of formula (VII) to afford a compound of formula (VI-1) or (VI-2);
(b) reacting a compound of formula (V) and the compound of formula (VI-1) or (VI-2) under a strong alkali to afford a compound of formula (IV);
(c) conducting an intramolecular cyclization of the compound of formula (IV) in presence of a base to afford a compound of formula (III);
(d) activating a hydroxyl group of the compound of formula III to become a leaving group to afford a compound of Formula II;
(e) conducting a reductive elimination of the compound of formula II to afford Trilaciclib of formula (I);
wherein
R1 is selected from hydrogen or C1˜C4 alkyl, aryl;
R2 is selected from hydrogen, silyl, halo alkyl, —C(O) alkyl, —S(O)2 alkyl, —S(O)2 halo alkyl, —S(O)2 aryl or —S(O)2 aryl-alkyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein an oxidizing agent used in the step (a) is selected from the group consisting of oxone, hydrogen peroxide, meta-chloroperoxybenzoic acid, sodium hypochlorite and sodium chlorite.

### Claim 3 (depends on 1)

The method of claim 1, wherein a solvent used in the step (a) is selected from the group consisting of acetonitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, water and dioxane.

### Claim 4 (depends on 1)

The method of claim 1, wherein the step (a) is carried out at a temperature of −20 to 80° C.

### Claim 5 (depends on 1)

The method of claim 1, wherein the strong alkali in the step (b) is alkali metal hexamethyldisilazane.

### Claim 6 (depends on 5)

The method of claim 5, wherein the alkali metal hexamethyldisilazane is selected from a group consisting of lithium hexamethyldisilazane, sodium hexamethyldisilazane and potassium hexamethyldisilazane.

### Claim 7 (depends on 1)

The method of claim 1, wherein a solvent used in the step (b) is selected from a group consisting of tetrahydrofuran, 1,4-dioxane and toluene.

### Claim 8 (depends on 1)

The method of claim 1, wherein the step (b) is carried out at a temperature of −40 to 60° C.

### Claim 9 (depends on 1)

The method of claim 1, wherein the base used in the step (c) is selected from a group consisting of lithium hydroxide, sodium hydroxide, magnesium hydroxide, aluminum hydroxide, sodium methoxide, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium tert-butoxide and sodium tert-butoxide.

### Claim 10 (depends on 1)

The method of claim 1, wherein the intramolecular cyclization in the step (c) is carried out at a temperature of 50 to 100° C.

### Claim 11 (depends on 1)

The method of claim 1, wherein a reagent used to activate the hydroxyl group in the step (d) is selected from the group consisting of p-toluensulfonyl chloride, p-oluensulfonyl anhydride, trifloromethane sulfonylchloride, trifloromethane sulfonic anhydride, methane sulfonyl chloride and methane sulfonyl anhydride.

### Claim 12 (depends on 11)

The method of claim 11, wherein the equivalent of the reagent is 1.0 to 20 equiv.

### Claim 13 (depends on 1)

The method of claim 1, wherein a solvent used in the step (d) is selected from a group consisting of dichloromathane, dimethylformamide, acetonitrile and tetrahydrofuran.

### Claim 14 (depends on 1)

The method of claim 1, wherein the activation of hydroxyl group in the step (d) is carried out at a temperature of −20 to 90° C.

### Claim 15 (depends on 1)

The method of claim 1, wherein the reductive elimination in the step (e) is carried out in presence of a palladium catalyst with a reducing agent.

### Claim 16 (depends on 15)

The method of claim 15, wherein the palladium catalyst is selected from a group of 10% Pd/C, tetrakis(triphenylphosphine)palladium (0), palladium acetate, palladium chloride, trans-dichlorobis(acetonitrile)palladium (II), 1,1-bis(diphenylphosphino)ferrocene)dichloropalladium-dichloromethane (1:1), 1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium, tris(dibenzyllideneacetone)dipalladium, and bis(triphenylphosphine)palladium (II) dichloride.

### Claim 17 (depends on 16)

The method of claim 16, wherein the reducing agent is selected from a group consisting of hydrogen gas, triethyl silane, trimethyl silane, ammonium formate and formic acid.

### Claim 18 (depends on 1)

The method of claim 1, wherein the solvent used in the step (e) for the reductive elimination is selected from a group consisting of alcohols, ethers and esters.

### Claim 19

A compound of formula (II),
wherein R2 is selected from hydrogen, silyl, halo alkyl, —C(O) alkyl, —S(O)2 alkyl, —S(O)2 halo alkyl, —S(O)2 aryl or —S(O)2 aryl-alkyl.

### Claim 20

A compound of formula (III),

### Claim 21

A compound of formula (IV),
wherein R1 is selected from hydrogen or C1˜C4 alkyl.