# US 2021/0277039 A1 · Preparation method of a cyclic phosphonate compound

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- Number: US 2021/0277039 A1
- Document ID: US20210277039A1
- Status: Published application
- Kind: A1
- Application number: 17/301,827
- Filed: 2021-04-15
- Published: 2021-09-09
- Earliest claimed: 2020-02-18
- Assignees: Gannex Pharma Co., Ltd.
- Applicants: Gannex Pharma Co., Ltd.
- Inventors: Jinzi Jason WU; Bailing YANG; Bin LIANG
- Web page: https://patentgrep.com/patent/US20210277039A1

## CPC

- C07F 9/657181: {the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative}
- C07F 9/65742: {non-condensed with carbocyclic rings or heterocyclic rings or ring systems}
- C07F 9/3808: {Acyclic saturated acids which can have further substituents on alkyl}
- C07F 9/42: Halides thereof
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

A method for preparing the cyclic phosphonate compound of Formula I is described. The method significantly improves the stereoselectivity of the compound with the required configuration.

## Claims

### Claim 1

A method for preparing a cyclic phosphonate compound shown in Formula I,
comprising the steps of:
(1) reacting a compound of Formula 9 with a chlorinating agent to obtain a phosphonyl chloride intermediate of Formula 11,
and dissolving the phosphonyl chloride intermediate of Formula 11 in a first organic solvent to form a solution of Formula 11;
(2) dissolving a compound of Formula 10 in a second organic solvent to form a solution of Formula 10
adding sequentially a Lewis acid and then an alkali to the solution of Formula 10 to form a reaction solution, wherein the Lewis acid is selected from the group consisting of TiCl4, SnCl4, FeCl3 and combinations thereof, and
(3) adding the reaction solution of step (2) into the solution of Formula 11 to produce the cyclic phosphonate compound of Formula I.

### Claim 2 (depends on 1)

The method of claim 1, wherein the first and the second organic solvent are selected from the group comprising dichloromethane, 1,2-dichloroethane and tetrahydrofuran, and
wherein the chlorinating agent is selected from the group comprising thionyl chloride, oxalyl chloride and triphosgene.

### Claim 3 (depends on 1)

The method of claim 1, wherein the molar ratio of chlorinated reagent to compound of Formula 9 in step (1) is in the range of 2:1 to 6:1.

### Claim 4 (depends on 1)

The method of claim 1, wherein the molar ratio of the compound of Formula 10 to the compound of Formula 9 in step (3) is in the range of 1.0:1-1.2:1.

### Claim 5 (depends on 1)

The method of claim 1, wherein the molar ratio of the Lewis acid to the compound of Formula 10 in step (2) is in the range of 1:1 to 2:1.

### Claim 6 (depends on 1)

The method of claim 1, wherein the alkali is an organic base.

### Claim 7 (depends on 6)

The method of claim 6, wherein the organic base is trimethylamine.

### Claim 8 (depends on 7)

The method of claim 7, wherein the molar ratio of triethylamine to the compound Formula 10 in step (2) is in the range of 1.5:1 to 8:1.

### Claim 9 (depends on 1)

The method of claim 1, wherein the chlorinating reagent is dripped into the solution of compound of Formula 9 at 15-25° C., and reacted with the compound of Formula 9 at 35-85° C. in step (1).

### Claim 10 (depends on 1)

The method of claim 1, wherein the Lewis acid is added dropwise to the solution of Formula 10 at −10° C. to 15° C. to form a first mixture, and then the alkali is added to the first mixture dropwise at −20° C. to 10° C. to form a second mixture, the second mixture is stirred for 10-60 minutes to form the reaction solution of step (2).

### Claim 11 (depends on 1)

The method of claim 1, wherein the reaction solution of step (2) is added dropwise into the solution of Formula 11 at −50° C. to 0° C., and is stirred at −50° C. to 0° C. to form the compound of Formula I.

### Claim 12 (depends on 1)

The method of claim 1, wherein the reaction solution of step (2) is added dropwise into the solution of Formula 11 at −40° C. to −30° C., and stirred at −40 to −30° C. to form the compound of Formula I.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound of Formula 9 reacts with the chlorinating agent in the presence of N,N-dimethylformamide in step (1).

### Claim 14 (depends on 13)

The method of claim 13, wherein the molar ratio of the N,N-dimethylformamide to the compound of Formula 9 is in the range of 0.02:1-0.5:1.