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Asymmetric synthesis of esomeprazole

TETRAHEDRON:

ASYMMETRY

Tetrahedron:Asymmetry11(2000)3819–3825

Pergamon

Hanna Cotton,a Thomas Elebring,b Magnus Larsson,a Lanna Li,b Henrik So¨rensen b and

Sverker von Unge b,*

a Process Chemistry,AstraZeneca Process R&D So¨derta¨lje,S-15185So¨derta¨lje,Sweden

b Medicinal Chemistry,AstraZeneca R&D Mo¨lndal,S-43183Mo¨lndal,Sweden

Received7August2000;accepted1September2000

Abstract

A highly ef?cient synthesis of esomeprazole—the(S)-enantiomer of omeprazole—via asymmetric oxidation of prochiral sulphide1is described.The asymmetric oxidation was achieved by titanium-medi-ated oxidation with cumene hydroperoxide(CHP)in the presence of(S,S)-diethyl tartrate[(S,S)-DET]. The enantioselectivity was provided by preparing the titanium complex in the presence of1at an elevated temperature and/or during a prolonged preparation time and by performing the oxidation of1in the presence of an amine.An enantioselectivity of>94%ee was obtained using this method.?2000Elsevier Science Ltd.All rights reserved.

1.Introduction

5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulphinyl]-1H-benzimidazole,which has the generic name omeprazole,is the prototypical compound of a class of highly potent gastric acid secretion inhibitors.1Omeprazole—a racemic mixture—is successfully used against acid-related diseases.Unlike the histamine H2-receptor antagonists,such as cimetidine and ranitidine,omeprazole acts as an inhibitor of the gastric H+,K+-ATPase,the gastric acid pump.2

*Corresponding author.E-mail:sverker.vonunge@https://www.wendangku.net/doc/f112676918.html,

PII:S0957-4166(00)00352-9

H.Cotton et al./Tetrahedron:Asymmetry11(2000)3819–3825

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Esomeprazole—the generic name of the(S)-enantiomer3of omeprazole—is currently under registration as Nexium?,a new proton pump inhibitor.Consequently,we required an ef?cient synthesis of esomeprazole which could be used on a large scale.4Having considered different synthetic alternatives,we soon realised that the most attractive approach should be based on an enantioselective oxidation of sulphide1.5We also considered that asymmetric sulphoxidation would be even more desirable if a catalytic amount of a chiral catalyst could be employed rather than a stoichiometric amount of a chiral oxidant such as one of the Davis chiral oxaziridines.6 We were however,able to oxidise sulphide1and obtained40%ee using such a reagent7and the enantiomeric excess could be further enhanced to over94%ee by a crystallisation method.8In spite of this we did not consider the oxaziridines to be applicable in production scale. Having contemplated the different metal-catalysed chiral oxidations described in the literature9we regarded a modi?cation10of the Sharpless reagent11to be a good candidate for the ideal chiral catalyst.However,asymmetric sulphoxidation using the modi?ed Sharpless reagent has previously been associated with two fundamental limitations.Firstly,most of the highly enantioselective reactions so far reported in the literature employ stoichiometric amounts or near stoichiometric amounts of a chiral Ti-complex.12Secondly,oxidation of sulphides substi-tuted at sulphur with two large groups which is the case of sulphide1generally gives little or no asymmetric induction.13Indeed,our?rst attempt at applying a titanium-mediated oxidation to our speci?c case,following Kagan’s original method,10a gave very nearly racemic omepra-zole.14We persevered with the modi?ed Sharpless reagent despite the lack of success in the initial experiments.Eventually we were rewarded with a breakthrough when an amine was added to the oxidising system and the method for preparing the chiral titanium complex was altered as compared to state of the art.10

2.Results and discussion

Three alterations were introduced to the original procedures,10which taken together enabled an oxidation of sulphide1in over94%ee15(Scheme1).Firstly,the preparation of the titanium complex—including Ti(O i Pr)4,(S,S)-DET and water—was performed in the presence of sulphide1.Secondly,the solution of titanium complex was equilibrated at an elevated temperature and/or for a prolonged time.16Thirdly,the oxidation was performed in the presence of an amine,such as N,N-diisopropylethylamine.Each of the modi?cations enhances the enantioselectivity on their own.However,in order to ensure a very high enantiomeric excess of formed sulphoxide it was necessary to introduce all of the three alterations.The enantiomeric excess of the product could then be further enhanced by preparing a metal salt of crude esomeprazole and subsequently crystallising the salt from a suitable solvent.4c

Several striking features of the oxidation reaction are in very sharp contrast to what has been reported previously in the literature for titanium-mediated asymmetric sulphoxidations in general.One is that the enantiomeric excess of formed sulphoxide can still be high,in spite of the fact that the sulphur atom of sulphide1bears two seemingly similar-size groups.13Another feature is that we were able to obtain a high enantioselectivity even when catalytic quantities of titanium complex were employed.12Esomeprazole with over91%ee can be obtained when4 mol%catalyst is being used.We have observed however,that when using such a low amount of titanium complex the enantioselectivity occasionally is not reproducible and thus it is more

H.Cotton et al./Tetrahedron:Asymmetry11(2000)3819–38253821

Scheme 1.Reagents and conditions:(i)Ti(O i Pr)4/(S,S)-DET/H2O(0.3:0.6:0.1),PhCH3D;(ii)(i Pr)2NEt/ PhC(CH3)2OOH(0.3:1),30°C;(iii)NaOH(0.7),MIBK;(iv)crystallisation from MIBK and MeCN

preferable to use for instance30mol%of catalyst on a large scale.Still another feature of the method is that neither the choice of solvent17nor oxidation reaction temperature18affected the enantioselectivity dramatically.The oxidation reaction may thus be readily performed in non-chlorinated solvents,for instance toluene or ethyl acetate rather than dichloromethane (chlorinated solvents are less desirable with respect to environmental aspects),at or above room temperature with a high enantiomeric excess of esomeprazole still being obtained.

The reaction mechanism of the presented titanium mediated asymmetric oxidation of1is not understood in detail.The fact that catalytic quantities of titanium complex can be used without a dramatic decrease in enantioselectivity suggests a reaction mechanism involving a catalytic intermediate formed between the sulphide and the catalyst.Also in support of such a mechanism is the importance of equilibrating the titanium complex in the presence of the prochiral sulphide 1.Furthermore,we believe that the N H group of the imidazole moiety is important for the enantioselectivity.Hitherto we have not been able to demonstrate any enhancement of enan-tioselectivity using our new method for sulphide substrates containing an N-alkylated benz-imidazole or when the substrate simply lacks a benzimidazole or an imidazole moiety.Interest-ingly,we have been able to demonstrate that the ACAT enzyme inhibitor RP73163—an imidazole derivative—can be synthesised in92%ee by treating the prochiral sulphide2with CHP using our new method(Scheme2).It has previously been reported13b,c that treatment of sulphide2with Kagan’s modi?ed Sharpless reagent affords the corresponding sulphoxide as a racemic mixture.

The role of N,N-diisopropylethylamine in the oxidising system is unclear.Although other amines,such as triethylamine and4-methylmorpholine,could be used these generally gave lower enantioselectivity.We do not believe that the effect of the added amine on the enantioselectivity

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H.Cotton et al./Tetrahedron:Asymmetry11(2000)3819–3825

Scheme 2.Reagents and conditions:(i)Ti(O i Pr)4/(S,S)-DET/H2O(1:2.5:0.6),PhCH3,D;(ii)(i Pr)2NEt/ PhC(CH3)2OOH(1:1),rt

is due to a simple proton abstraction from the N H group of the benzimidazole moiety.We have observed that if a stronger base,such as DBU or1,1,3,3-tetramethylguanidine,is used the enantiomeric excess of formed sulphoxide is dramatically decreased.In the presence of such strong bases the(R)-enantiomer of omeprazole unexpectedly dominates in the sulphox-ide product in spite of the fact that(S,S)-DET is being used.One possibility that should not be excluded is that N,N-diisopropylethylamine and/or the N H group of the benzimidazole moiety may participate in the chiral titanium complex.Interestingly,a titanium mediated asymmetric oxidation of methyl p-tolyl sulphide has recently been developed where the titanium complex being used contains chiral trialkanolamines as ligands.19When the peroxo-titanium complex is formed in situ it has been suggested that titanium coordinates to four oxygen atoms as well as to the nitrogen atom of the alkanolamine.

Enantiomers of seven omeprazole analogues have also been prepared by the present method in our laboratories15(enantiomeric excess of crude sulphoxide is generally close to or above90%).

3.Conclusions

A highly ef?cient synthesis of esomeprazole has been developed.The synthesis,which is based upon a titanium mediated asymmetric oxidation of the corresponding prochiral sul-phide,is suitable for large-scale production.Our present?nding,that a benzimidazole or an imidazole group adjacent to sulphur seems to steer the stereochemistry of formed sulphoxide, suggests that this type of functionality could be utilised as directing groups when synthesising chiral sulphoxides as templates in asymmetric synthesis.

4.Experimental

4.1.General

All commercially available reagents and solvents were employed without prior puri?cation. The toluene,which in the experiment uses4mol%of titanium complex and is considered to

H.Cotton et al./Tetrahedron:Asymmetry11(2000)3819–38253823 be the source of water,had an analyzed water content of0.047%(w/w).The1H NMR spectrum was recorded on a Bruker AC-P300spectrometer(300.13MHz).The optical rotation was determined with a Perkin–Elmer241polarimeter(D line).Enantiomeric excess,the conversion of sulphide1and the sulphoxide:sulphone ratio were all determined by HPLC analysis on a Chiralpak?AD column(50×4.6mm),iso-hexane/ethanol/acetic acid(10:10:1)as eluent,UV detection at302nm,and a?ow rate of0.5ml/min.

https://www.wendangku.net/doc/f112676918.html,rge scale asymmetric synthesis of esomeprazole

Water(44ml, 2.4mol),(S,S)-diethyl tartrate(2.35kg,11.4mol)and titanium tetra-isopropoxide(1.60kg,5.6mol)were added to a suspension of15(6.2kg,18.8mol)in toluene (25L)at54°C.The mixture was stirred for50minutes at54°C,the temperature was then adjusted to30°C and subsequently N,N-diisopropylethylamine(0.72kg,5.6mol)and cumene hydroperoxide(84%in cumene,3.30kg,18.2mol)were added.After one hour at30°C the conversion of sulphide1was92%,the sulphoxide:sulphone ratio was76:1and the enantiomeric excess of crude sulphoxide was over94%.The solution was extracted three times with aqueous ammonium hydroxide(12.5%of NH3,3×20L).Subsequently,methyl isobutyl ketone(9L)was added to the combined aqueous extracts.Then the aqueous phase was pH-adjusted with acetic acid,separated and extracted with an additional portion of methyl isobutyl ketone(9L).To the combined organic solutions were added an aqueous solution of sodium hydroxide(49.6%of NaOH,1.07kg,13.2mol)and acetonitrile(70L).The solution was concentrated during which the product gradually precipitated.There was obtained3.83kg of esomeprazole sodium as a white solid:enantiomeric excess=>99.5%;[h]D20=+30.5(c0.01g/mL,H2O);1H NMR(DMSO-d6)l2.15(s,3H),2.20(s,3H),3.68(s,3H),3.71(s,3H),4.41and4.58(AB-system,J=12.9Hz, 2H),6.56(dd,J=8.5and2.4Hz,1H),7.00(d,J=2.4Hz,1H),7.34(d,J=8.5Hz),8.30(s,1H).

4.3.Asymmetric oxidation of sulphide1using4mol%of catalyst

(S,S)-Diethyl tartrate(171m L,1.0mmol)and titanium tetraisopropoxide(145m L,0.5mmol) were added to a suspension of15(4.0g,12.1mmol)in toluene(12mL)at50°C.The mixture was stirred for45minutes at50°C,the temperature was then adjusted to25°C and subsequently N,N-diisopropylethylamine(85m L,0.5mmol)and cumene hydroperoxide(84%in cumene,2.1 mL,12mmol)were added.After15minutes the conversion of sulphide1was96%,the sulphoxide:sulphone ratio was35:1and the enantiomeric excess of crude sulphoxide was over 91%.The product was not isolated.

Acknowledgements

We would like to acknowledge colleagues at Process Chemistry,AstraZeneca R&D, So¨derta¨lje,and Medicinal Chemistry,AstraZeneca R&D,Mo¨lndal,for fruitful discussions and helpful comments.We also would like to thank members of Substance Analysis,AstraZeneca R&D,Mo¨lndal and members of Process Analysis,AstraZeneca R&D,So¨derta¨lje for analyses. We are grateful to Dr.Graeme Semple for his helpful linguistic criticism.

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enantioselectivity when used in the oxidation of prochiral sulphides,two groups have independently developed modi?cations of the reagent that enantioselectively oxidise certain sulphides.Kagan and co-workers obtained aryl methyl sulphoxides with high enantiomeric excess by employing Ti(O i Pr)4/DET/ROOH(R=tert-butyl or cumyl)in a ratio of1:2:1in the presence of one crucial equivalent of water;see:(a)Pitchen,P.;Dun?ach,E.;

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12.Kagan and co-workers have for instance demonstrated that the enantiomeric excess for p-tolyl methyl sulphoxide

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H.Cotton et al./Tetrahedron:Asymmetry11(2000)3819–38253825

17.The choice of solvent has been reported earlier to have a pronounced in?uence on the enantiomeric excess of

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