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Synthesis of BAY 86-9766 / RDEA119 via Chiral Sulfonate Intermediates

IP.com Disclosure Number: IPCOM000207423D
Publication Date: 2011-May-30
Document File: 10 page(s) / 92K

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Abstract

BAY 86-9766 / RDEA119 is a highly potent and selective MEK1/2 inhibitor currently under development in clinical trials for treatment of late stage cancer patients refractory or intolerant to other anticancer therapies [1]. The initial synthesis of BAY 86-9766 / RDEA119 comprises an osmium catalyzed dihydroxylation of the allyl sulfonamide substituted core followed by chromatographic separation of the enantiomers using a chiral stationary phase [2]. The present paper describes a chiral synthesis of sodium 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonate starting from (S)-epichlorohydrin and alternatively from enantiomerically pure glycidol derivatives. A process was developed for conversion of the chiral intermediates to BAY 86-9766 / RDEA119. The R-enantiomers have been prepared accordingly.

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Page 01 of 10

Synthesis of BAY 86-9766 / RDEA119 via Chiral Sulfonate Intermediates

Peter Fey,*[a] Lisa Harlow, Andrew Beevers[b]

Abstract

BAY 86-9766 / RDEA119 is a highly potent and selective MEK1/2 inhibitor currently under development in clinical trials for treatment of late stage cancer patients refractory or intolerant to other anticancer therapies [1].

The initial synthesis of BAY 86-9766 / RDEA119 comprises an osmium catalyzed dihydroxylation of the allyl sulfonamide substituted core followed by chromatographic separation of the enantiomers using a chiral stationary phase
[2]. The present paper describes a chiral synthesis of sodium 1-{[(4
S)-2,2- dimethyl-1,3-dioxolan-4-yl]methyl}cyclopropanesulfonate starting from (S)- epichlorohydrin and alternatively from enantiomerically pure glycidol derivatives. A process was developed for conversion of the chiral intermediates to BAY 86-9766 / RDEA119. The R-enantiomers have been prepared accordingly.

Introduction

BAY 86-9766 / RDEA119 is a highly potent and selective MEK1/2 inhibitor currently under development in clinical trials for treatment of late stage cancer patients refractory or intolerant to other anticancer therapies [1].

The initial synthesis of BAY 86-9766 / RDEA119 provides the target compound as a racemic mixture that needs to be separated by chiral chromatography [2].

Scheme 1: Racemic synthesis of BAY 86-9766 / RDEA119 (S)-9

F

S Cl

O O

H

O

NH2

O

F

H

N

O2S

OsO , NMO, THF, water

OH

O2S

NH

O

F

NH

O

F

pyridine

H

H

N

N

F

I

F

I

F

I

F

F

Chiral

Chromatography

S

R

H

O

H

O

OH

O2S

OH

O2S

NH

F

NH

O

F

H

+

H

O

N

N

F

I

F

I

F

F

BAY 86-9766 / RDEA 119 (S)-9

NMO: 4-methylmorpholine 4-oxide monohydrate

1



Page 02 of 10

Regarding costs, waste and productivity a stereoselective synthesis of BAY 86-9766 / RDEA119 is desirable. Starting from economically priced chiral epoxypropane derivatives 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclo propane sulfonyl chloride (S)-6 was prepared and converted to the final product.

Scheme 2: Stereoselective synthesis of BAY 86-9766 / RDEA119 (S)-9

F

O

O

(S)-6

S Cl

O O

O

O

H

NH2

O

F

H

N

O

O2S

OH

O2S

sulfolane, pyridine TBAB, 70°C

NH

F

NH

F

H

HClaq

H

O

N

O

N

F

I

F

I

F

I

F

F

(S)-8

BAY 86-9766 / RDEA 119 (S)-9

Synthesis of Butyl 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}cyclo propanesulfonates 4

Deprotonation of butyl cyclopropanesulfonate with n-butyllithium and reaction with (S)-epichlorohydrin provided the chloroalcohol 1a in good yield. 1a was converted quantitatively to the epoxide 2 with aqueous sodium hydroxide in tetrahydrofuran.

Scheme 3: Stereoselective synthesis of epoxides 2 starting from (S)-epichlorohydrine

S OBu

O O

1. n-BuLi, THF, -78°C
2. BF
3 etherate; HClaq

OH

O

NaOH

O

Cl

Cl S OBu

O O

+

S OBu

O O

(S)-1a

(S)-2

Performing the first step of the sequence without additives resulted in up to 65% by product formation caused by competitive self alkylation (scheme 4). Therefore several additives like TMEDA, DMI, DMPU, CuI, LiI were screened but sho...