# US 2026/0092040 A1 · Synthesis of cyclopropane carboxylic acids

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- Number: US 2026/0092040 A1
- Document ID: US20260092040A1
- Status: Published application
- Kind: A1
- Application number: 19/113,778
- Filed: 2023-09-20
- Published: 2026-04-02
- Earliest claimed: 2022-09-21
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Takeda Pharmaceutical Company Limited
- Inventors: Nikolaos Papaioannou; Michael Jonathan Fray; Andreas Rennhack; Sarah Jocelyn Fink
- Web page: https://patentgrep.com/patent/US20260092040A1

## CPC

- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present disclosure provides methods of preparing substituted cyclopropane compounds.

## Claims

### Claim 1

A process for the preparation of a trans racemate of formula (I)
wherein
P1 is a protecting group (such as tert-butyl)
R1 is H or optionally substituted C1-C6 alkyl,
said process comprising reacting a compound of formula (II):
wherein R1 is defined above for compounds of formula (I)
with a nitrogen ylid, optionally formed in situ, prepared by
reacting an α halo ester, (such as methyl chloroacetate and tert-butyl bromoacetate)
with a tertiary amine, (such as DABCO),
to form a quaternary ammonium salt,
followed by treatment with an alkali metal base (such as Cs2CO3 or K2CO3) and/or an organic base (such as DBU),
in a polar aprotic solvent (such as acetonitrile)
at an elevated temperature, (such as 70-80° C.)
such that the compound of formula (I) is formed (for example with high diastereoselectivity, such as 50:1, over the corresponding cis racemate)

### Claim 2 (depends on 1)

A process according to claim 1, wherein the α halo ester is tert-butyl bromoacetate.

### Claim 3 (depends on 1, 2)

A process according to claim 1 or 2, wherein the tertiary amine is DABCO.

### Claim 4

A process according to any preceding claim wherein the alkali metal base is Cs2CO3.

### Claim 5

A process according to any preceding claim, wherein the polar aprotic solvent is acetonitrile.

### Claim 6

A process according to any preceding claim wherein the elevated temperature is 70-80° C.

### Claim 7

A process according to any preceding claim, wherein the reaction is performed for 12 to 30 hours, such as 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30, such as 20 hours.

### Claim 8 (depends on 1)

A process according to claim 1, wherein the steps, reagents and conditions are:
wherein R1 and P1 are defined above for compounds of formula (I).

### Claim 9 (depends on 1)

A process according to any preceding claim 1, wherein a compound of formula (II) is prepared by reacting an intermediate of formula (III)
wherein R1 is defined above for compounds of formula (I) and L1 represents a leaving group, such as a halogen, in particular Cl
with a vinyltrihaloborate (such as vinyltrifluoroborate, in particular a salt thereof such as potassium).

### Claim 10

A process according to any preceding claim wherein the protecting group P1 is removed from compounds of formula (I) to liberate the free carboxylic acid of formula (IV):
as a trans racemate (for example in high diastereomeric purity, in particular that is essentially free of the cis racemate) by:
a) acidolysis using an organic acid (such as TFA) in a chlorinated solvent (such as DCM); or
b) saponification using an alkali metal hydroxide (such as sodium hydroxide) in an aqueous medium (such THF and water),
followed by acidification with (for example aqueous hydrochloric acid), to liberate the free acid from the salt so formed.

### Claim 11

A process for the resolution of a compound of formula (IV) into essentially one or other of its enantiomeric forms, for example to provide a compound of formula (V) (such as absolute as drawn):
for example wherein the resolution is effected by reaction with an optically pure chiral amine (such as(S)-1-(naphthalen-2-yl) ethanamine or(S)-1-(naphthalen-1-yl) ethanamine),
in a suitable solvent (such as ethyl acetate, isopropanol and dimethyl carbonate) to form a mixture of diastereomeric salts from which the preferred diastereomeric salt crystallises and is collected by filtration.

### Claim 12 (depends on 11)

A process according to claim 11, wherein the free acid is recovered from said salt by treating the latter with an excess of an aqueous solution of an alkali metal hydroxide (such sodium hydroxide or potassium hydroxide),
in the presence of an immiscible organic solvent (such as toluene or MTBE) to remove the organic base, and retain the aqueous solution.

### Claim 13 (depends on 12)

A process according to claim 12, wherein the aqueous solution is acidified to pH 3-4 with an inorganic acid (such as hydrochloric acid) to precipitate the free acid as a solid which is collected by filtration.

### Claim 14 (depends on 11, 12, 13)

A process according to any one of claims 11 to 13, wherein the compound of formula (V) is enantiomerically enriched and in particular having an enantiomeric purity (ee value) of 90% or more, such 91, 92, 93, 94, 95, 96, 96, 97, 98, 99 or 100%, especially 99%.

### Claim 15

A process according to any preceding claim wherein R1 is C1-3 alkyl, such as methyl, ethyl, propyl or isopropyl, in particular methyl.

### Claim 16

A process according to any preceding claim wherein P1 is C1-4 alkyl such as t-butyl.

### Claim 17 (depends on 11, 12, 13, 14, 15, 16)

A process according to any one of claims 11 to 16, wherein a compound of formula (V) is reacted with an aryl amine of formula (VI):
wherein R2 is H, or C1-3 alkyl and L2, is a leaving group such as a halogen, in particular Cl, to provide a compound of formula (VII):

### Claim 18 (depends on 17)

A process according to claim 17, wherein the compound of formula (VII) is compound (VIIa):

### Claim 19 (depends on 17)

A process according to claim 17, wherein the compound of formula (VII) is compound (VIIb):

### Claim 20

A process wherein the compound of formula (VII) is reacted with a compound of formula (VIII)
to provide a compound of formula (IX)
or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are defined above.

### Claim 21 (depends on 20)

A process according to claim 20, wherein the compound of formula (VII) is compound (VIIa) and the compound of formula (IX) is compound (IXa):

### Claim 22 (depends on 20)

A process according to claim 20, wherein the compound of formula (VII) is compound (VIIb) and the compound of formula (IX) is compound (IXb):

### Claim 23

A compound obtained or obtainable from any one of the preceding claims.

### Claim 24

A compound of formula (I), (II), (IV), (V), (VI), (VII), (VIIa) (VIII), (IX), (IXa) or (LXb).

### Claim 25 (depends on 22, 23)

A pharmaceutical composition comprising a compound according to claim 22 or 23 and an excipient, diluent or carrier.

### Claim 26 (depends on 23, 24, 25)

A compound according to claim 23 or 24 or a pharmaceutical composition according to claim 25, for use in treatment, particularly as a pKAL inhibitor.