# US 9,040,699 B2 · Method for preparing cyclopropane derivatives

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- Number: US 9,040,699 B2
- Document ID: US9040699B2
- Status: Granted
- Kind: B2
- Application number: 14/349,648
- Filed: 2011-11-10
- Published: 2015-02-19
- Granted: 2015-05-26
- Earliest claimed: 2011-11-10
- Assignees: Aratana Therapeutics, Inc.
- Applicants: Eleonora Kiss; Erwin Blomsma; Serge De Bruijn; E. J. N. Remy Litjens
- Inventors: Eleonora Kiss; Erwin Blomsma; Serge De Bruijn; E. J. N. Remy Litjens
- Web page: https://patentgrep.com/patent/US9040699B2

## CPC

- C07D 473/18: one oxygen and one nitrogen atom, e.g. guanine
- C07D 321/10: condensed with carbocyclic rings or ring systems
- C07D 473/40: with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to the preparation of cyclopropane derivatives, in particular 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-4,8-dihydro-1H-purin-6-one, especially via the [(1S,7R)-4-phenyl-3,5-dioxabicyclo[5.1.0]octan-1-yl]methanol intermediate.

## Claims

### Claim 1

A compound of the formula (5):
or a tautomer, racemate or stereoisomer thereof,
wherein n is an integer from 0 to 5, X is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, hydroxyl, C1-6alkoxy or amino; and R11 is hydroxyl or amino.

### Claim 2 (depends on 1)

The compound according to claim 1, which is an compound of formula (5′):

### Claim 3 (depends on 1)

A method for the preparation of a compound of formula (5) or a tautomer, racemate or stereoisomer thereof, according to claim 1:
wherein n, X and R11 have the same meaning as that defined in claim 1,
comprising the step of transforming the —COR12 moiety of a compound of formula (4) thereby obtaining the compound of formula (5);
wherein R12 is —OR3 or amino and R3 is selected from C1-6alkyl, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-6haloalkyl or C6-10haloarylC1-6alkylene.

### Claim 4 (depends on 3)

The method according to claim 3, wherein the preparation of said compound of formula (4) comprises reacting a compound of formula (2) with a compound of formula (3):
thereby obtaining a compound (4a)
wherein R19 is OR23 and R23 is selected from C1-6alkyl, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-6haloalkyl or C6-10haloarylC1-6alkylene, and R4 and R5 are each independently selected from C1-6alkyl, C6-10arylC1-6alkylene or C6-10aryl.

### Claim 5 (depends on 4)

The method according to claim 4, further comprising the step of transforming the ester moiety of compound (4a) into an amide moiety, thereby obtaining a compound of formula (4b),

### Claim 6

A method for the production of a compound of formula (A):
or a tautomer, a racemate, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, or solvate thereof,
wherein B is selected from the group comprising purinyl, pyrimidyl, or aza or deaza analog thereof, or —NR1R2; each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C1-6alkyl, aminoC1-6alkyl, nitro, formamido, —NHR18 or OR7; and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R7 is selected from C1-4alkyl, C6-10arylC1-6alkylene or C6-10aryl, R18 is selected from C6-10arylC1-6alkylene, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C1-6alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C6-10arylC1-6alkyloxycarbonyl; and
R1 is selected from hydrogen, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
R2 is selected from C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
comprising the step of hydrolyzing or reducing a compound of formula (8);
wherein n is an integer from 0 to 5 and X is C1-6alkyl, C1-6haloalkyl C2-6alkenyl, C2-6alkynyl, halogen, hydroxyl, C1-6alkoxy or amino; and
wherein B′ is B or selected from the group consisting of purinyl, pyrimidyl, or aza or deaza analog thereof, or —NR1R2; each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C1-6alkyl, aminoC1-6alkyl, nitro, formamido, —NHR18, —NR24R25 or OR7; and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R7 is selected from C1-4alkyl, C6-10arylC1-6alkylene or C6-10aryl, R18 is selected from C6-10arylC1-6alkylene, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C1-6alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C6-10arylC1-6alkyloxycarbonyl, R24 and R25 are independently hydrogen or C1-6alkyl; and
R1 is selected from hydrogen, C6-10aryl, C6-10arylC1-6alkylene, C1-4alkyl, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
R2 is selected from C6-10aryl, C6-10arylC1-6alkylene, C1-4alkyl, C6-10haloaryl, C1-4haloalkyl or C6-10halo arylC1-6alkylene.

### Claim 7 (depends on 6)

The method according to claim 6, wherein said compound of formula (8) is prepared by coupling a compound of formula (5a) with a compound of formula B′—H,
wherein n is an integer from 0 to 5, X is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halogen, hydroxyl, C1-6alkoxy or amino; and R11 is hydroxyl or amino;
B′ has the same meaning as that defined in claim 6; and
H is hydrogen.

### Claim 8 (depends on 7)

The method according to claim 7, wherein prior to coupling compound of formula (5a) with compound B′—H, the hydroxyl moiety of the compound of formula (5) is transformed to obtain a compound of formula (6):
wherein LG represents a leaving group selected from halo, mesylate, tosylate, azide, nosylate, triflate, cyano or imidazolyl.

### Claim 9 (depends on 6)

The method according to claim 6, wherein the preparation of said compound of formula (8) comprises reacting a compound of formula (5b) with a compound of formula (13),
wherein R15 is —OR27 or R28, R16 is selected from the group consisting of amino, nitro, formamido and hydrogen, R17 is selected from halo, C1-6alkoxy, C1-6aryloxy, C6-10arylC1-6alkyleneoxy, C1-6alkylsulfinyl, C6-10arylsulfinyl, C6-10arylC1-6alkylenesulfinyl, C1-6alkylsulfonyl, C6-10arylsulfinyl, C6-10arylC1-6alkylenesulfonyl, C1-6alkylthio, C6-10arylthio, C6-10arylC1-6alkylenethio, C1-6alkylsulfonate, C6-10arylsulfonate, haloC1-4alkylsulfonate, C1-6alkylphosphonate and C6-10arylphosphonate;
R27 is selected from the group consisting of hydrogen, C1-6alkyl, C6-10aryl and C1-10arylC1-6alkylene,
R28 is selected from halo, C1-6alkoxy, C1-6aryloxy, C6-10arylC1-6alkyleneoxy, C1-6alkylsulfinyl, C6-10arylsulfinyl, C6-10arylC1-6alkylenesulfinyl, C1-6alkylsulfonyl, C6-10arylsulfinyl, C6-10arylC1-6alkylenesulfonyl, C1-6alkylthio, C6-10arylthio, C6-10arylC1-6alkylenethio, C1-6alkylsulfonate, C6-10arylsulfonate, haloC1-4alkylsulfonate, C1-6alkylphosphonate and C6-10arylphosphonate; and
R26 is selected from, hydrogen, C6-10arylC1-6alkylene or COR30, wherein R30 is selected from C1-6alkyl, haloC1-6alkyl, C1-6alkyloxy, 9-fluorenylmethyloxy, or C6-10arylC1-6alkyloxy.

### Claim 10 (depends on 7)

The method according to claim 7, wherein compound (5a) is prepared using a method comprising the step of transforming the —COR12 moiety of a compound of formula (4) thereby obtaining the compound of formula (5a),
wherein R12 is —OR3 or amino and R3 is selected from C1-6alkyl, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-6haloalkyl or C6-10haloarylC1-6alkylene.

### Claim 11 (depends on 10)

The method according to claim 10, further comprising the step of crystallizing and purifying said compound of formula (5a) or (5b).

### Claim 12 (depends on 6)

The method according to claim 6, wherein the compound of formula (A) is a compound of formula (A′):

### Claim 13

A method for the preparation of a compound of formula (A)
or a tautomer, a racemate, a stereoisomer, a pharmaceutically acceptable salt, a hydrate, or solvate thereof,
wherein B is selected from the group comprising purinyl, pyrimidyl, or aza or deaza analog thereof, or —NR1R2; each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C1-6alkyl, aminoC1-6alkyl, nitro, formamido, —NHR18 or OR7; and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R7 is selected from C1-4alkyl, C6-10arylC1-6alkylene or C6-10aryl, R18 is selected from C6-10arylC1-6alkylene, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C1-6alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C6-10arylC1-6alkyloxycarbonyl; and
R1 is selected from hydrogen, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
R2 is selected from C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
comprising the step of coupling a compound of formula (10) or (12),
with a with a compound of formula B′—H under Mitsunobu conditions,
wherein H is hydrogen,
wherein B′ is B or selected from the group consisting of purinyl, pyrimidyl, or aza or deaza analog thereof, or —NR1R2; each group being optionally substituted by one or more substituents independently selected from halo, amino, hydroxyl, C1-6 alkyl, aminoC1-6alkyl, nitro, formamido, —NHR18, —NR24R25 or OR7; and wherein a carbon atom of said purinyl or pyrimidyl can be oxidized to form a C═O, wherein R7 is selected from C1-4alkyl, C6-10arylC1-6alkylene or C6-10aryl, R18 is selected from C6-10arylC1-6alkylene, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C1-6alkyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, or C6-10arylC1-6alkyloxycarbonyl, R24 and R25 are independently hydrogen or C1-6alkyl; and
R1 is selected from hydrogen, C6-10aryl, C6-10arylC1-6alkylene, C1-4alkyl, C6-10haloaryl, C1-4haloalkyl or C6-10haloarylC1-6alkylene;
R2 is selected from C6-10aryl, C6-10arylC1-6alkylene, C1-4alkyl, C6-10haloaryl, C1-4haloalkyl or C6-10halo arylC1-6 alkylene;
R13 is selected from the group consisting of hydrogen, C1-6alkyl, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-6haloalkyl, C6-10haloarylC1-6alkylene, C6-10aminoaryl, C1-6aminoalkyl, C6-10aminoarylC1-6alkylene and C1-6alkoxy, and R14 is a group selected from C1-6alkyl, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl C1-6haloalkyl, C6-10haloarylC1-6alkylene, C6-10aminoaryl, C1-6aminoalkyl, C6-10aminoarylC1-6alkylene and C1-6alkoxy, each group being optionally substituted with one or more substituents each independently selected from C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, halogen, hydroxyl, C1-6alkoxy or amino.

### Claim 14 (depends on 13)

The method according to claim 13, wherein said compound of formula (10) is a compound of formula (5a) or (14)
wherein n is an integer from 0 to 5, X is selected from C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, halogen, hydroxyl, C1-6alkoxy or amino.

### Claim 15 (depends on 9)

The method according to claim 9, wherein compound (5b) is prepared using a method comprising the step of transforming the —COR12 moiety of a compound of formula (4) thereby obtaining the compound of formula (5b);
wherein R12 is —OR3 or amino and R3 is selected from C1-6alkyl, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-6haloalkyl or C6-10haloarylC1-6alkylene.

### Claim 16 (depends on 9)

The method according to claim 9, wherein compound (5b) is prepared using a method comprising reacting a compound of formula (2) with a compound of formula (3):
thereby obtaining a compound (4a)
wherein R19 is OR23 and R23 is selected from C1-6alkyl, C6-10aryl, C6-10arylC1-6alkylene, C6-10haloaryl, C1-6haloalkyl or C6-10haloarylC1-6alkylene, and R4 and R5 are each independently selected from C1-6alkyl, C6-10arylC1-6alkylene or C6-10aryl;
followed by transforming the ester moiety of compound (4a) into an amide moiety, thereby obtaining a compound of formula (5b).