# US 10,479,811 B1 · Process for preparing cyclophosphamide, intermediates, and monohydrate thereof

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- Number: US 10,479,811 B1
- Document ID: US10479811B1
- Status: Granted
- Kind: B1
- Application number: 16/210,066
- Filed: 2018-12-05
- Granted: 2019-11-19
- Earliest claimed: 2018-12-05
- Assignees: Pharmacore Biotech Co., Ltd.
- Applicants: Pharmacore Biotech Co., Ltd.
- Inventors: Wei-Hong Tseng; Vallapa Soong; Ko Hua Yu; Hsing Yu Chang; Chia-Yu Lin
- Web page: https://patentgrep.com/patent/US10479811B1

## CPC

- C07F 9/65846: {the phosphorus atom being part of a six-membered ring which may be condensed with another ring system}
- C07F 9/26: containing P-halide groups
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- 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)
- 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

The present disclosure provides a process for preparing cyclophosphamide, intermediate, and the monohydrate thereof.

## Claims

### Claim 1

A process for preparing cyclophosphamide monohydrate, comprising the steps of:
(a) providing bis (2-chloroethyl) amine hydrochloride;
(b) converting bis (2-chloroethyl) amine hydrochloride into cyclophosphamide monohydrate represented as formula I, and
wherein the converting comprises the step of reacting bis (2-chloroethyl) amine hydrochloride with phosphorus oxychloride in the presence of a base in toluene at a temperature ranging from 20° C. to 60° C. to form bis-(2-chloroethyl)-phosphoramidic dichloride represented as formula II:
wherein the bis-(2-chloroethyl)-phosphoramidic dichloride represented as formula II is converted into the cyclophosphamide represented as formula I by reacting with 3-amino-1-propanol in the presence of the base in a solvent and purifying and isolating to yield a crystalline of cyclophosphamide monohydrate represented as formula I.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the base in solid, liquid or aqueous form is selected from the group consisting of aliphatic amine, aromatic amine and a mixture thereof.

### Claim 3 (depends on 1)

The process according to claim 1, wherein a mole ratio of the base to the bis-(2-chloroethyl)-phosphoramidic dichloride represented as formula II is 1.0 to 1.5.

### Claim 4 (depends on 1)

The process according to claim 1, wherein the solvent is selected from the group consisting of halogenated solvent, ester and aromatic hydrocarbon.

### Claim 5 (depends on 1)

The process according to claim 1, wherein the bis-(2-chloroethyl)-phosphoramidic dichloride represented as formula II has a purity level greater than 98% by thin layer chromatography.

### Claim 6 (depends on 1)

The process according to claim 1, wherein the cyclophosphamide monohydrate represented as formula I has a purity of 99% or higher.

### Claim 7 (depends on 1)

The process according to claim 1, further comprising crystallizing a crystalline form A of the bis-(2-chloroethyl)-phosphoramidic dichloride represented as formula II by using a solution comprising toluene and n-heptane.

### Claim 8 (depends on 7)

The process according to claim 7, wherein the crystalline form A of the bis-(2-chloroethyl)-phosphoramidic dichloride represented as formula II is characterized by X-ray powder diffraction pattern comprising the characteristic 2θ° peaks of 13.8, 14.4, 15.4, 19.9, 23.6, 26.9, 29.0, 29.65, 31.0 and 31.9±0.2°, wherein peaks at 30.9 and 31.1±0.2° are un-split and 100% intensity peak is present at 23.6±0.2°, infrared absorption spectrum comprising the characteristic peaks approximately at 2959.5 cm−1, 1459.3 cm−1, 1263.3 cm−1, 1226.3 cm−1 and 980.3 cm−1, and differential scanning calorimetry (DSC) exhibits melting points ranging from 56-58° C.

### Claim 9 (depends on 8)

The process according to claim 8, wherein the X-ray powder diffraction pattern of the crystalline form A of the bis-(2-chloroethyl)-phosphoramidic dichloride represented as formula II is substantially in accordance with FIG. 1, and the infrared absorption spectrum of the crystalline form A of the bis-(2-chloroethyl)-phosphoramidic dichloride represented as formula II is substantially in accordance with FIG. 2.

### Claim 10 (depends on 1)

A process for preparing a sterile of the cyclophosphamide monohydrate represented as formula I, comprising dissolving the crystalline of cyclophosphamide monohydrate represented as formula I according to claim 1 in a crude solution comprising dichloromethane, tert-butyl methyl ether, and water.

### Claim 11 (depends on 10)

The process according to claim 10, wherein the sterile of the cyclophosphamide monohydrate represented as formula I is characterized by X-ray powder diffraction pattern comprising the characteristic 2θ° peaks of 7.0, 14.0, 14.8, 17.8, 22.0, 23.8, 26.8, 28.3 and 30.1±0.2°, wherein peaks at 26.8 and 26.9±0.2° are un-split and 100% intensity peak is present at 22.0±0.2°, and infrared absorption spectrum comprising the characteristic peaks approximately at 3432.9 cm−1, 3185.0 cm−1, 1453.7 cm−1, 1217.0 cm−1, 1179.7 cm−1, 1047.4 cm−1 and 950.5 cm−1, and differential scanning calorimetry (DSC) exhibits melting points ranging from 51-53° C.

### Claim 12 (depends on 11)

The process according to claim 11, wherein the X-ray powder diffraction pattern of the sterile of the cyclophosphamide monohydrate represented as formula I is substantially in accordance with FIG. 4, the infrared absorption spectrum of the sterile of the cyclophosphamide monohydrate represented as formula I is substantially in accordance with FIG. 5, and the differential scanning calorimetry (DSC) of the sterile of the cyclophosphamide monohydrate represented as formula I is substantially in accordance with FIG. 6.