# US 10,927,113 B2 · Process for preparing purine derivatives

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- Number: US 10,927,113 B2
- Document ID: US10927113B2
- Status: Granted
- Kind: B2
- Application number: 16/480,858
- Filed: 2018-01-25
- Published: 2019-12-26
- Granted: 2021-02-23
- Earliest claimed: 2017-01-26
- Assignees: Cyclacel Limited
- Applicants: Cyclacel Limited
- Inventors: Benjamin Mark Skead; Robert Westwood; Derek Londesbrough; Julian Scott Northen; Jonathan Charles Christian Atherton
- Web page: https://patentgrep.com/patent/US10927113B2

## CPC

- C07D 473/16: two nitrogen atoms
- A61P 35/00: Antineoplastic agents
- C07D 473/40: with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a process for preparing a compound of formula [I], said process comprising the steps of: formula [II]+formula [III]→formula [I] (i) forming a reaction mixture comprising (a) a compound of formula [II], (b) a compound of formula [III] and (c) 1,2-propanediol or polyethylene glycol, or a mixture thereof, and optionally (d) a base; (ii) heating said reaction mixture to a temperature of at least about 150° C. to form a compound of formula [I]; (iii) isolating said compound of formula [I]; and (iv) optionally converting said compound of formula [I] into salt form; wherein: R1 and R2 are each independently H, alkyl or haloalkyl; R3 and R4 are each independently H, alkyl, haloalkyl or aryl; R5 is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and formula (A) where one of X, Y and Z is N and the remainder are CR9; R7, R8 and each R9 are independently H, alkyl or haloalkyl, wherein at least one of R7, R8 and R9 is other than H. Further aspects of the invention relate to a highly diastereoselective process for the preparation of compounds of formula [III], a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I], and to a process for preparing the crystalline tartrate salt and free base of compounds of formula [I].

## Claims

### Claim 1

A process for preparing a compound of formula [I],
wherein:
R1 and R2 are each independently H, alkyl or haloalkyl;
R3 and R4 are each independently H, alkyl, haloalkyl or aryl;
R5 is alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups;
R6 is selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and
where one of X, Y and Z is N and the remainder are CR9;
R7, R8 and each R9 are independently H, alkyl or haloalkyl, wherein at least one of R7, R8 and R9 is other than H;
said process comprising the steps of:
(i) forming a reaction mixture comprising (a) a compound of formula [II], (b) a compound of formula [III] and (c) 1,2-propanediol or polyethylene glycol, or a mixture thereof;
(ii) heating said reaction mixture to a temperature of at least about 150° C. to form a compound of formula [I]; and
(iii) isolating said compound of formula [I].

### Claim 2 (depends on 1)

A process according to claim 1 wherein the reaction mixture in step (i) further comprises a base.

### Claim 3 (depends on 1)

A process according to claim 1 wherein the reaction mixture comprises from about 2 to about 3 mole equivalents of compound [III] relative to compound [II].

### Claim 4 (depends on 1)

A process according to claim 1 wherein step (iii) comprises extracting the reaction mixture from step (ii) into water and ethyl acetate, separating the ethyl acetate phase and drying with a drying agent, filtering and concentrating the filtrate.

### Claim 5 (depends on 1)

A process according to claim 1 which comprises converting said compound of formula [I] into the L-tartrate salt.

### Claim 6 (depends on 1)

A process according claim 1 which comprises the steps of:
(i) forming a reaction mixture comprising (a) a compound of formula [2], (b) a compound of formula [3] and (c) 1,2-propanediol or polyethylene glycol, or a mixture thereof;
(ii) heating said reaction mixture to a temperature of at least about 150° C. to form a compound of formula [1]; and
(iii) isolating said compound of formula [1].

### Claim 7 (depends on 6)

A process according to claim 6 wherein the reaction mixture in step (i) further comprises a base selected from N,N-diisopropylethylamine (DIEA), tri-Npropylamine, and tri-Nbutylamine.

### Claim 8 (depends on 6)

A process according to claim 6 wherein compound [2] has a purity of at least 97%.

### Claim 9 (depends on 6)

A process according to claim 6 wherein compound [3] has a diastereomeric excess of at least 85%.

### Claim 10 (depends on 1)

A process according to claim 1 wherein compound [III] is prepared by the steps of:
(a) treating a compound [V] with (S)-2-Me-CBS-oxazoborolidine and borane-N,N-diethylaniline complex in a solvent comprising THF to form a compound [IV]; and
(b) removing the protecting group PG from said compound [IV] to give compound [III], wherein PG is a protecting group, preferably Boc, R1 is alkyl or haloalkyl, and R3 is alkyl, haloalkyl or aryl.

### Claim 11 (depends on 10)

A process according to claim 10 which comprises the steps of:
(a) treating a compound [5] with (S)-2-Me-CBS-oxazoborolidine and borane-N,N-diethylaniline complex in a solvent comprising THF to form a compound [4]; and
(b) removing the protecting group PG from said compound [4] to give compound [3], where PG is a protecting group, preferably Boc.

### Claim 12 (depends on 1)

A process according to claim 1 which comprises preparing a compound of formula [II] by the steps of:
(i) treating a compound of formula [VI] with HF, pyridine and tBuONO to form a compound of formula [VII]; and
(ii) treating said compound of formula [VII] with R5Br in DMSO and K2CO3 to form a compound of formula [II];
where R5 and R6 are as defined in claim 1.

### Claim 13 (depends on 12)

A process according to claim 12 which comprises the steps of:
(i) treating compound [6] with HF, pyridine and tBuONO to form compound [7]; and
(ii) treating said compound [7] with isopropyl bromide in DMSO and K2CO3 to form compound [2].

### Claim 14

A process for preparing the crystalline L-tartrate salt of compound [1], said process comprising the steps of refluxing a solution of compound [1] in ethanol and adding dropwise thereto a solution of L-tartaric acid in a mixture of water and ethanol, wherein the ratio of ethanol:water in the final mixture after addition of the L-tartaric acid solution is at least about 15:1