# US 2023/0271908 A1 · Methods, processes, and compositions for improved preparation of hu308 and hu433

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- Number: US 2023/0271908 A1
- Document ID: US20230271908A1
- Status: Published application
- Kind: A1
- Application number: 18/027,897
- Filed: 2021-09-23
- Published: 2023-08-31
- Earliest claimed: 2020-09-24
- Assignees: Tetra Bio-Pharma Inc.
- Applicants: Tetra Bio-Pharma Inc.
- Inventors: Harpreet Kaur; Xuejun Liu; Prabin Nepal; Subakar Paramanantham; Monika Garg; Zemin Li; Andy Tjeng; Moises Rodriguez; Laura Jong; Azam Mirzahossein; Ofer Yifrach-Stav; Erin Bassett; Randy Ringuette; Charles Campbell; Melanie Kelly
- Web page: https://patentgrep.com/patent/US20230271908A1

## CPC

- C07C 41/26: by introduction of hydroxy or O-metal groups
- C07C 271/22: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07C 29/48: by oxidation reactions with formation of hydroxy groups
- C07C 67/08: by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
- C07C 67/29: by introduction of oxygen-containing functional groups
- C07C 67/293: by isomerisation; by change of size of the carbon skeleton
- C07C 269/06: by reactions not involving the formation of carbamate groups
- C07B 2200/07: Optical isomers
- C07C 2602/42: the bicyclo ring system containing seven carbon atoms
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Disclosed herein are methods, processes and compositions for preparing a compound of formula 8: (8), and formula 18: (18). The methods and processes comprise performing a first allylic oxidation, a protection reaction, a second allylic oxidation, a reduction reaction, performing an acid-catalyzed coupling reaction, a methylation reaction and a deprotection reaction. Disclosed herein are methods, processes and compositions for enantioselectively preparing compounds of formulae 8 and 18. Also disclosed herein are compositions comprising compounds of formulae 8, 18 and/or intermediates and/or starting material thereof.

## Claims

### Claim at position 1

1-27. (canceled)

### Claim 28

A method of enantioselectively preparing a compound of formula 8:
the method comprising:
providing a first reactant of formula 12,
performing a first allylic oxidation comprising compound 12, SeO2, and peroxide to yield a compound of formula 13:
performing a protection reaction comprising compound 13, acid chloride, dichloromethane (DCM), and a first base to yield a compound of formula 14:
performing a second allylic oxidation comprising compound 14, CrO3, tert-butyl hydroperoxide (TBHP), a first solvent to yield a compound of formula 15:
performing a reduction reaction comprising compound 15, sodium borohydride (NaBH4) and ethanol to yield a compound of formula 16:
performing an acid-catalyzed coupling reaction comprising compound 16, an acid, DCM, and a compound of formula 2:
to yield a first mixture comprising a compound of formula 6:
and a compound of formula 17:
performing a coupling reaction comprising the first mixture, Boc-alanine, N,N′-dicyclohexylcarbodiimide (DCC), and 4-dimethylaminopyridine (DMAP) to yield a second mixture comprising a compound of formula 10:
and a compound of formula 11:
purifying the second mixture to yield enantiomerically purified compound 10;
performing a hydrolysis reaction comprising enantiomerically purified compound 10, a third base and a third solvent, to yield enantiomerically purified compound 6;
performing a methylation reaction comprising enantiomerically purified compound 6, dimethyl sulfate (Me2SO4), potassium carbonate (K2CO3) and acetone to yield an enantiomerically purified compound of formula 7:
performing a deprotection reaction comprising enantiomerically purified compound 7, a second base and a second solvent to yield the enantiomerically purified compound 8; and
isolating the enantiomerically purified compound 8.

### Claim 29 (depends on 28)

The method of claim 28, wherein the peroxide is tert-butyl hydroperoxide (TBHP).

### Claim 30 (depends on 29)

The method of claim 29, wherein the first allylic oxidation comprises 1 eq. compound 12, 0.036-1.19 eq. SeO2, and 0-3.5 eq. peroxide.

### Claim 31 (depends on 30)

The method of claim 30, wherein the first allylic oxidation comprises 0.036 eq. SeO2, 2.0 eq. TBHP, 0.45 eq. NaBH4, and is conducted at room temperature.

### Claim 32 (depends on 31)

The method of claim 31, wherein the acid chloride is pivaloyl chloride.

### Claim 33 (depends on 32)

The method of claim 32, wherein the first base is trimethylamine (TEA), 4-dimethylaminopyridine (DMAP) or pyridine.

### Claim 34 (depends on 33)

The method of claim 33, wherein the protection reaction comprises 1 eq. compound 13, 1.2-2.0 eq. acid chloride, 6 vol. of dichloromethane (DCM), and 1.5-6 eq. of the first base.

### Claim 35 (depends on 34)

The method of claim 34, wherein the acid chloride is pivaloyl chloride, the base is pyridine, and the protection reaction comprises 1.2 eq. pivaloyl chloride, 1.5 eq. base and 6 vol. of DCM.

### Claim 36 (depends on 35)

The method of claim 35, wherein the second allylic oxidation comprises 1 eq. compound 14, 0.05-0.5 eq. CrO3, 3.15-7 eq. tert-butyl hydroperoxide (TBHP), and 14.6-16 vol. of the first solvent.

### Claim 37 (depends on 36)

The method of claim 36, wherein the first solvent is acetonitrile (ACN) or DCM.

### Claim 38 (depends on 37)

The method of claim 37, wherein the second allylic oxidation comprises 0.5 eq. CrO3, 3.15 eq. TBHP, 14.6 vol. of solvent and the second allylic oxidation occurs at an initial temperature of 0° C. and a final temperature of room temperature; and wherein the solvent is ACN.

### Claim 39 (depends on 37)

The method of claim 37, wherein the second allylic oxidation comprises 0.05 eq. CrO3, 7 eq. TBHP, 16 vol. of solvent and the second allylic oxidation occurs at room temperature; and wherein the solvent is DCM.

### Claim 40 (depends on 39)

The method of claim 39, wherein the reduction reaction comprises 1 eq. of compound 15, 1.05-1.32 eq. of sodium borohydride (NaBH4) and 10-18 vol. of ethanol (EtOH) and is conducted at room temperature.

### Claim 41 (depends on 40)

The method of claim 40, wherein the reduction reaction comprises 1.1 eq. of NaBH4, 10 vol. of EtOH and is conducted at room temperature over a period of 30 minutes.

### Claim 42 (depends on 41)

The method of claim 41, wherein the acid is para-toluenesulfonic acid (pTSA) or MeSO3H.

### Claim 43 (depends on 42)

The method of claim 42, wherein the acid-catalyzed coupling reaction comprises 1.02-1.1 eq. of compound 16, 0.05-0.28 eq. of pTSA, 35-112 vol. of DCM, and 1 eq. of the compound of formula 2.

### Claim 44 (depends on 43)

The method of claim 43, wherein the acid-catalyzed coupling reaction comprises 1.02 eq. of compound 1, 0.1 eq. of pTSA, 35 vol. of DCM, and 1 eq. of the compound of formula 2.

### Claim 45 (depends on 42)

The method of claim 42, wherein the acid-catalyzed coupling reaction comprises 0.05-0.2 eq. of MeSO3H, 1.02 eq. of compound 1, 112 vol. of DCM and 1 eq. of the compound of formula 2.

### Claim 46 (depends on 45)

The method of claim 45, wherein the acid-catalyzed coupling reaction comprises 0.2 eq. of MeSO3H, 1.02 eq. of compound 1, 112 vol. of DCM and 1 eq. of the compound of formula 2.

### Claim 47 (depends on 46)

The method of claim 46, wherein the methylation reaction comprises 1 eq. of enantiomerically purified compound 6, 2.5-5 eq. dimethyl sulfate (Me2SO4), 5.3-6.7 eq. of potassium carbonate (K2CO3) and 5-20 vol. of acetone and is conducted at room temperature.

### Claim at position 22

48-67. (canceled)