# US 10,479,810 B2 · Crystal form of tenofovir alafenamide salt, preparation method and use thereof

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- Number: US 10,479,810 B2
- Document ID: US10479810B2
- Status: Granted
- Kind: B2
- Application number: 16/208,721
- Filed: 2018-12-04
- Published: 2019-04-04
- Granted: 2019-11-19
- Earliest claimed: 2016-06-05
- Assignees: Shanghai Begreat Pharmatech
- Applicants: Shanghai Begreat Pharmatech
- Inventors: Xiaoming Meng
- Web page: https://patentgrep.com/patent/US10479810B2

## CPC

- C07F 9/65616: {containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs}
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Disclosed are a new polymorph II, crystal form A and B of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate, and preparation methods and pharmaceutical use thereof. The crystal form II is a hemi-fumarate; the crystal form A is a mono-fumarate; and the crystal form B is a sesqui-fumarate. Compared with the existing crystal form, the new crystal forms have obvious advantages in solubility, stability and preparation process.

## Claims

### Claim 1

A crystalline form of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate designated as crystalline form A, having an X-ray powder diffraction pattern comprising diffraction peaks at at least one 2θ value of: 23.8±0.2, 10.5±0.2, 28.5±0.2, 21.2±0.2, or 19.5±0.2.

### Claim 2 (depends on 1)

A process for the preparation of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form A according to claim 1, comprising:
(i) dissolving 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine free base in an organic solution;
(ii) adding a fumaric acid in a molar amount no less than the free base into the solution prepared in the step (i) to precipitate a 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate salt; and
(iii) obtaining 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form A after liquid-solid separation.

### Claim 3

A crystalline form of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate designated as crystalline form B, having an X-ray powder diffraction pattern comprising diffraction peaks at at least one 2θ value of: 10.5±0.2, 21.0±0.2, 10.9±0.2, 27.2±0.2, or 22.5±0.2.

### Claim 4 (depends on 3)

A process for the preparation of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form B according to claim 3, comprising:
(i) dissolving 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine free base in an organic solution;
(ii) adding a fumaric acid in a molar amount greater than the free base into the solution prepared in the step (i) to precipitate a 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate salt; and
(iii) obtaining 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form B after liquid-solid separation.

### Claim 5

A crystalline form of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate designated as crystalline form II, having an X-ray powder diffraction pattern comprising diffraction peaks at at least one 2θ value of: 26.6±0.2, 21.3±0.2, 27.1±0.2, 19.6±0.2, or 18.7±0.2.

### Claim 6 (depends on 5)

The 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form II according to claim 5 having a melting point of 106.6±2° C.

### Claim 7 (depends on 5)

A process for the preparation of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form II according to claim 5, comprising:
(i) dissolving 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine free base in an organic solution;
(ii) adding a fumaric acid in a molar amount into the solution prepared in the step (i) to precipitate a 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate salt; and
(iii) obtaining 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form II after liquid-solid separation.

### Claim 8 (depends on 1)

The 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form A according to claim 1, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ value of: 15.1±0.2, 23.2±0.2, 17.0±0.2, 9.8±0.2, 20.8±0.2, or 17.6±0.2.

### Claim 9 (depends on 1)

The 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form A according to claim 1, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ value of: 15.7±0.2, 27.1±0.2, 25.2±0.2, 33.5±0.2, 22.4±0.2, or 19.0±0.2.

### Claim 10 (depends on 1)

The 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form A according to claim 1, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ value of: 13.3±0.2, 4.8±0.2, 9.6±0.2, 26.7±0.2, 5.3±0.2, 11.4±0.2, 14.0±0.2, 30.2±0.2, 8.5±0.2, 31.3±0.2, 21.9±0.2, or 12.5±0.2.

### Claim 11 (depends on 3)

The 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form B according to claim 3, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ value of: 28.9±0.2, 27.7±0.2, 24.1±0.2, 18.7±0.2, 13.5±0.2, or 20.6±0.2.

### Claim 12 (depends on 3)

The 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form B according to claim 3, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ value of: 4.9±0.2, 14.1±0.2, 11.2±0.2, 16.4±0.2, 23.3±0.2, or 19.6±0.2.

### Claim 13 (depends on 3)

The 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form B according to claim 3, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ value of: 11.8±0.2, 15.1±0.2, 12.3±0.2, 38.0±0.2, 17.3±0.2, 15.7±0.2, 18.1±0.2, 21.8±0.2, 31.8±0.2, 35.0±0.2, 41.7±0.2, or 40.0±0.2.

### Claim 14 (depends on 5)

The 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form II according to claim 5, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ value of: 32.1±0.2, 21.9±0.2, 5.4±0.2, 22.4±0.2, 11.1±0.2, or 17.8±0.2.

### Claim 15 (depends on 5)

The 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form II according to claim 5, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ value of: 12.9±0.2, 24.5±0.2, 24.9±0.2, 19.0±0.2, 23.6±0.2, or 30.0±0.2.

### Claim 16 (depends on 5)

The 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form II according to claim 5, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ value of: 32.4±0.2, 37.5±0.2, 10.5±0.2, 14.5±0.2, 16.7±0.2, or 40.3±0.2.

### Claim 17 (depends on 5)

The 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form II according to claim 5, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at at least one 2θ value of: 23.9±0.2, 12.3±0.2, 38.6±0.2, 43.0±0.2, 27.8±0.2, or 35.8±0.2.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising the 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form A according to claim 1 as an active ingredient to treat hepatitis B virus (HBV) infection or human immunodeficiency virus (HIV) infection.

### Claim 19 (depends on 3)

A pharmaceutical composition comprising the 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form B according to claim 3 as an active ingredient to treat hepatitis B virus (HBV) infection or human immunodeficiency virus (HIV) infection.

### Claim 20 (depends on 5)

A pharmaceutical composition comprising the 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine fumarate crystalline form II according to claim 5 as an active ingredient to treat hepatitis B virus (HBV) infection or human immunodeficiency virus (HIV) infection.