OA17076A - Process for the stereoselective preparation of a pyrazole carboxamide. - Google Patents

Process for the stereoselective preparation of a pyrazole carboxamide. Download PDF

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Publication number
OA17076A
OA17076A OA1201400365 OA17076A OA 17076 A OA17076 A OA 17076A OA 1201400365 OA1201400365 OA 1201400365 OA 17076 A OA17076 A OA 17076A
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formula
compound
enantloselective
process according
reagent
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OA1201400365
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Tomas Smejkal
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Syngenta Participations Ag
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Abstract

The present invention relates to a process for the enantioselective preparation of 3difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ((1S,4R)-9-dichloromethylene-1,2,3,4tetrahydro-1,4-methano-naphthalen-5-yl)-amide of formula Ib.

Description

Process for the stereoseiective préparation of a pyrazole carboxamlde
The présent invention relates to a process for the stereoseiective (enantioselective) préparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxyl!c add ((1S,4R)-9dlchloromethyiene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yi)-amlde.
The compound 3-difluoromethyl-1-methyHH-pyrazole-4-carboxyiic acid (9dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthaien-5-yi)-amide Is described for exampie in WO 2007/048556. Said compound shows an excellent fungicidal activity and is for example effective for the réduction of mycotoxin contamination In plants. Mycotoxlns (aflatoxins, ochratoxlns, patulin, fumonisins, zearalenones, trichothecenes, in particular deoxynivalenol) are produced for example by different Fusarium and Asperglllus, Pénicillium and Altemaria species as described in WO 2012/072575.
Said compound can occur in two enantiomeric forms, ia
(la),
which chemical désignation Is 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ((IR^S^-dichioromethylene-I^.S^-tetrahydro-M-methano-naphthalen-S-yiï-amide, and Ib
(lb),
which chemical désignation is 3-difluoromethyi-1-methyl-1H-pyrazole-4-carboxylic acid ((1S,4R)-9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide.
The enantiomer of formula Ib shows a more prominent fonglcidal activity. A fongicide with an excess of the fongicidally more active enantiomer can be applied In Iower concentrations with the same efficiency as the racemate which ls economlcally advantageous. It is therefore highly desired to selectlvely prépare the Ib-enantiomer of said compound.
It ls known from WO 2011/015416 to prépare the racemic form of 3-dichloromethyl-1-methyl1 H-pyrazole-4-carboxylic acid (9-dlchloromethylene-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl)-amide by
a) reduclng the compound of formula II
In the presence of a reduclng agent to the compound of formula III
(III).
b) dehydrating the compound of formula III in the presence of an add to the compound of formula IV
c) reactlng the compound of formula IV with hydroxylamlne to the compound of formula V
HO
and
d) acylating the oxlme oxygen of the compound of formula V In the presence of a solvent and an acylating agent and finally reacting the obtained product with the compound of formula VI
(VI), or
e) reacting the compound of formula V with an excess of the compound of formula VI. The product of this process is 3-dlfluoromethyl-1-methyi-1 H-pyrazole-4-carboxylic acid (9dichloromethylene-1l2l3,4-tetrahydro-1,4-methano-naphthaien-5-y!)-amlde in form ofthe racemate.
The two enantiomers of 3-difluoromethyl-1-methy1-1H-pyrazole-4-carboxytic acid (9dichloromethy1ene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide can be separated for exemple by chiral chromatography of the racemate. However, said method Is expensive and unsultable for large-scale production of said compound.
The compound of formula III was prepared according to WO 2011/015416 in racemic form as a mixture of Isomers as shown below as compounds II la, lllb, il le and llld:
(llld),
It has surprlslngly been found that the 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ((1S,4R)-9-dlchloromethyIene-1,2>3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide (enantiomer of formula Ib) can be produced by this process ln excess to 3-difluoromethyl-1methyl-1 H-pyrazole-4-carboxyllc acid ((1 R,4S>9-dlchloromethylene-1,2,3,4-tetrahydro-l ,4methano-naphthalen-5-yl)-amide (enantiomer of formula la) If the enantioselective step Is the enantloselective synthesls of the compound of formula III, so that the enantiomer (1S,4R)-95 dichloromethylene-8-hydroxy-octahydro-1,4-methano-naphthalen-5-one of formula I Ile
Is obtained ln excess. Oie enantloselective synthesis of the compound of formula III allows a very cost effective préparation of the fongicide 3-difluoromethyl-1-methyMH-pyrazole-4carboxyllc acid ((1 S,4R)-9-dlchloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-510 yl)-amide with high yields.
The compound of formula llle can occur ln form of the following Isomers of formulae llif-lllm:
(îllh),
This Invention encompasses the préparation of ail Isomers of formula llle.
-5It has further been found that the 3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxylic add ((1S,4R)-9-dichloiOmethylene-1,2I3,4-tetrahydro-'l,4-methano-naphthalen-5-yi)-amide (enantlomer of formula Ib) can be produced In higher yields If the compound of formula II le can be prepared selectively ln form of Its Isomer of formula iiif. The préparation of the compound of formula II If In enantiomerlcally enriched form, i.e. ln an excess to the Isomers of formulae lllg-ilim, allows a higher yield ln the déhydration step, which résulte ln a higher yield of enantlomer of formula Ib.
The aim of the présent Invention Is therefore to provide a novel process for the enantioseiectlve préparation of 3-difluoromethyl-1-mathyi-1H-pyrazole-4-carboxylic add ((1 S,4R)-9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide of formula Ib
(ib).
which process comprises a) reduclng a compound of formula II
I
with an enantioseiectlve reagent to a compound of formula llle
(Hle),
b) dehydrating the compound of formula llle ln the presence of an acid to the compound of formula IVa (S)
(IVa),
c) reacting the compound of formula IVa with hydroxylamine to the compound of formula Va (S)
and
d) acylatlng the oxlme oxygen of the compound of formula Va ln the presence of a solvent and an acylatlng agent and finally reacting the obtained product with the compound of formula VI
e) reacting the compound of formula V with an excess of the compound of formula VI.
The product of this process is 3-dlfluoromethyf-1-methyl-1H-pyrazole-4-carboxylic acid (9dichtoromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide l ln form of a mixture of formula la and Ib, wherein 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxyllc acid ((1 S,4R)-9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide (Ib) is présent in the mixture in an excess of 55 - 99% to the compound of formula la.
The alkyl groups occurring ln the définitions of the substituents can be stralght-chaln or branched and are, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, feo-propyl, sec-butyl, /so-butyl or fert-butyl.
-7The alkoxy groups occurrlng in the définitions of the substituents can be straight-chain or branched and are, for example, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, nhexyloxy, fco-propoxy, n-butoxy, sec-butoxy, /so-butoxy or tert-butoxy.
According to the présent invention, préparation in enantiomerically enriched form or In excess means that the molar proportion of the desired product (formula ille, formula ilif and formula Ib) Is greaterthan 50% (for example greater than 55, 60,65,70,75,80,85, 90,95, 96, 97,98 or 99%) of the total amount of ail Isomers présent in the reaction mixture.
Reaction step a):
The réduction of carbonyi compounds to alcohols Is a reaction of considérable practical Interest. From both economical and ecologlcal point of view, catalytic methods are more bénéficiai than stolchiometric réduction Systems. Good results hâve been obtained using catalytic Systems based on transition metals e.g. Ir, Rh, Pd, NI and Ru. in addition, with a suitable chiral catalyst, enantioselective hydrogénation of carbonyi compounds can be achleved with the formation of optically active alcohols with high enantiomeric excesses. (Catalytic asymmetric synthesls, Iwao Ojlma, third Edition, Wlley-VCH 2010, pp 384-413 and the iiterature cited therein.) in this respect, ruthénium dérivatives of the type [Rufphosphine or diphosphine)~(amlne or dlamine)] in a basic environment hâve been shown as excellent catalysts for the sélective hydrogénation, In homogeneous phase, of varying types of ketones. The reactions are generally conducted with hydrogen under pressure at moderato températures. (R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed. Engl. 2001,40,40-73)
As an alternative, catalytic réduction methods based on hydrogen transfer reactions hâve aiso been established. in these processes 2-propanol or formic acid Is normaliy used as hydrogen source, in this respect, ruthénium dérivatives of the type [Ru(arene)~(diamlne dérivative)] but also rhodium and Iridium dérivatives hâve been shown as excellent catalysts for the sélective hydrogénation, In homogeneous phase, of varying types of ketones. (T. ikariya, A. J. Blacker, Acc. Chem. Res. 2007,40,1300-1308)
Regarding both hydrogénation and transfer hydrogénation, it has been found however, that one spécifie catalyst or a ciass of catalysts cannot be used equaliy well in ail hydrogénations, but that each réduction problem has to be Investlgated separateiy with regard to the catalyst
-8use and tha conditions. This is ail the more so In the case of hydrogénations that take place with catalysts that conslst not only of a ligand and a transition métal but that, as outlined In the above cases, requlre two different ligands and the transition métal In order to be sufflclently active.
Meso-diketones of formula VII
wherein A Is a methylene group which can be substituted, for example, A Is the group
wherein R1 and R2 are each, Independently from each other, hydrogen, halo, Ci-Cialkyl, Cr C4alkoxy, Ci-C4haloalkyl or CrC4haloalkoxy; or A Is the group
wherein R3 and R4 are each, Independently, hydrogen, halo, CrC4aikyl, CrC4alkoxy, Cr C4haloalkyl or CrC4haloalkoxy; are easlly prepared from Dlels-Alder adducts of pbenzoqulnone and optionally substituted cyclopentadiene, optionally followed by réduction of double bonds.
In contrast to the readily synthetic avallablli ty, there hâve been only few studles toward an enantioselectlve desymmetrizing réduction ofthe compound offormula VII. S. Brâse and coworkers (C. F. Nislng, U. K. Ohnemüller, S. B rase, Synthesis 2006,16,2643-2645) reported on an ennatioselectlve desymetrlzatlon of the compound of formula Vlia using Corey-Bakshl-Shlbata (CBS)-feductlon, but the low température (-30 to -78*C) and high cost of catecholborane reagent llmit Its practlcal use.
(Vlla)
Marchand and co-workers (Marchand, A. P.; Xing, D.; Wang, Y.; Bott, S. G.Tetrahedron: Asymmetry 1995,6,2709-2714) developed asymmetric réduction of the compound of formula Vlla utillsing Baker’s yeast, but extremely long reaction times (60h), low yield and low volume yield make this method unsuitable for scale up. It should be also noted that these catalysts do not in general allow access to both enantlomers.
Noyori and co-workers (S. Hashlguchi, A. Fujii, J.K. Haack, K. Matsumura, T. Ikariya, R. Noyori, Angew. Chem. Int. Ed. Engl. 1997,36,288-290) reported on an enantloselective synthesis If hydroxyketone (VIII) via Ru-catalysed hydrogen transfer but only ln the direction of oxidatlon (starting from the corresponding meso-dlol).
ln the abstract: ‘This methodprovides access to alcohols that are not available from the corresponding ketones by standard enantloselective réduction/ and ln the text regarding enantloselective réduction of prochiral ketones using 2-propanol as a hydrogen source ...high enantloselectlvlty Is not possible ln the préparation of alcohols having a high réduction potential such as 2,3-benzo-2-cyclenols and 1-phenyiethanols with an electron-donatlng group on the aromatlc ring.
Mclntosh and co-workers (D. R. Clay, A. G. Rosenberg, M. C. Mclntosh, Tetrahedron:Asymmetry 2011,22,713-716.) reported on an enantloselective and diastereoselective transfer hydrogénation (no hydrogénation reported) of tetracyclic epoxy diketone (XX). However, person skilled in the art would Immedlately recognise that the α,β epoxy ring brings about an alteration of the steric and electronlc properties of the carbonyl
-10moiety. Therefore, It could not be expected that a tricycllc compound without the epoxy ring would react analogously In a stéréo sélective way.
Therefore, In the light of the teaching of the references mentioned above, a person skilled in the art could not expect the stereoselective réduction of a compound of formula II via hydrogénation or transfer hydrogénation to proceed with high enantioselectivity and/or diastereoselectivlty.
Preferred enantioselective reagents are ruthénium complexes selected from the following group consisting of the compounds of formulae IX to XIV:
wherein
X and Y are equal or different and represent a halogen, hydrogen, or an anionic group, for example BHZ :
Z represents an anlon, for example BF4‘, [B(C6F5)4]', TfO’, CiCV, SbF6* or PFe‘,
L represents an aryl, In particular a phenyl group, which can be substituted by CrC4alkyl, C1-C4alkoxy or trialkyfsllyl. Spécifie examples Include, but are not limited to benzene, pcymene, mesitylene and hexamethylbenzene.
-11 The catalysts according to the invention must be chiral. For example, non-chlrai catalysts like RuCI2(PPh3)2(en) (described for example In JP 11189600A2 and CN1680412, CAS Number 212210-86-1 or 83438-00-0)
RuCI2(PPh3>2(en),
RuCIXPPthbtpica) (described for example, InWO 2005/105819, CAS Number 850346-91-7 or 850424-31-6)
RuCL2(PPh3)2(plca) and the catalyst (CAS Number 850424-32-7,850346-92-8 and
850424-33-8) lead to racemic products.
The group of formula (XV)
représente In the compounds of formulae IX - XII a phosphorus-contalnlng ligand, preferably a chiral phosphorus-contalnlng ligand, more preferably a chiral blphosphlne or blphosphite, orthelr mlxed forms. Chiral phosporus-contanlng ligands are known In the art and may used In the présent Invention, examples are glven In .Catalytlc asymmetric synthesis, Iwao Ojima, third Edition, Wiley-VCH 2010, pp 344-357 and the llterature cited thereln; and In STREM catalog of phosphorus ligands and compounds:
-12http://www.strem.com/uDloads/resourees/documents/DhosDhorusllaands.Ddf
Preferred diphosphlne ligands represented by formula (XV) of the invention are selected from the group consisting of
2,2'-b1s(dlpheny1phosphino-1,r-blnaphtyl(blnap);
2,2,-bls[di(p-to1yl)phosphlno]-1 ,T-b1naphthyl(to1blnap);
2,2'-bis[di(3,5-xyly1)phosphlno]- 1,T-binaphthyl (xytbinap);
2,2'-bls[di(p-t-buty1phenyl)phosphlno]-1 ,Γ-blnaphthyl;
2,2'-bls[di(p-methoxyphenyl)phosphlno]-1 ,Γ-blnaphthyl;
2,2’-bls(diphenyiphosphino)- 5,5', 6,6',7,7',8,8’-octahydro-1,1 ’-blnaphthyl;
2,2'-b1s(dl-p-tolylphosphino)-5,5', 6,6’,7,7',8(8’-octahydro-1,r-blnaphthyl;
2,2'-b1s(di-3,5-xy1yl phosphino)- 5,5’, e.e'.yj’.e.e'-octahydro-l.r-blnaphthyltxylyl-HB-blnap);
((4,4’-bi-1,3-benzodioxol)-5,5'-<liyl)bis(diphenylphosph1ne)(segphos);
(4,4'-bl-1 .S-benzodloxolJ-S.S’-dlylJblsidlÎS.S-xylyOphosphlne) (dm-segphos); (4,4'-bi-1,34)enzodÎoxol)-5l5*-<liyl)bls(dl(3l5-di-t-butyl-4-methoxypheny1)phosphine);
2,2’-bls(dipheny1phosphino)-6,6’-dÎmethoxy-1,V-blphenyi (MeO-biphep); 2,2’-bis(di-p-tolylphosphino)-6l6’-<llmethoxy-1,r-blphenyl(tolyl-MeO-biphep); 2,2’-bls(di-3,5-xyiy1phosphino)-6,6,-<limethoxy-1, Γ-blphenyl (xylyl-MeO-blphep); 2,2'-bls(dipheny1phosphino)-6l6’-<limethyl-1,r-blphenyl;
2,2’-bls(di-o-to1ylphosphino)-6l6,-<limethy1-1,r-b1phenyl;
2,2'-bls(dl-m-fluoropheny1phosphino)-6(6,-<llmethyl-1,r-b1phenyl;
2,2’,6,6,-tetramethoxy-4,4,-bls(diphenylphosphlno)-3>3,-blpyridine (p-phos);
2,2',6,6’-tetramethoxy-4,4'-bls(di-p-to1y1phosphlno)-3,3,-bipyr1dlne (p-tolyl-p-phos);
2,2',6,6'-tetramethoxy-4,4'-bis(di-o-to1ylphosphlno)-3,3,-blpyrldine (o-tolyl-p-phos);
2,2',6,6'-tetramethoxy-4,4'-bîs(di-3,5-xyiylphosphlno)-313,-blpyridlne (xyiyl-p-phos);
4.12- bls(di-3,5-xylylphosphino)42.2]-paracyc1ophane;
4.12- bls(diphenylphosphino)-[2.2]-paracyclophane;
4.12- bis(dï-p-toiylphosphlno)-[2.2]-paracyciophane;
4.12- bls(d1-o-toiylphosphino)-[2.2]-paracyciophane;
N.N-dimethyl-1 -[1\2-bis(diphenylphosphino)ferrocenyl]ethylamine;
2.3- bls(diphenylphosphlno)butane (chlraphos);
-cyclohexyl-1,2-bis(blsdlphenylphosphlno)ethane;
2.3- O-lsopropylldene-2,3-dlhydroxy-1,4-bls(dlphenylphosphlno)butane;
1.2- bls[(o-methoxyphenyl)phenylphosphlno]ethane (dlpamp);
1.2- bls(2,5-dlmethylphosphorano)ethane;
N.N'-bisidiphenylphosphlnoJ-N.N’-bistl-phenylethylJethylenedamÎne;
1.2- bis(diphenylphosphlno)propane (prophos);
2.4- bls(dlphenylphosphlno)pentane;
cyclohexyianlsylmethytphosphine;
2.3- bls(diphenylphosphlno)-5-norbomene;
3.4- bls(diphenylphosphlno)-1-benzylpyrrolidine;
1-[r,2-bis(dlphenylphosphlno)ferrocenyl]ethyl alcohol;
4.5- bls(dlphenylphosphlnomethyl)-2,2-dimethyl-1,3-dloxolan (diop); 4-(i-propyl)-2-{(S)-2-(dlphenylphosphlno)ferrocenyl}oxazoline;
3,4-bls(dlphenylphosphlno)-1-benzylpyrrolldine (deguphos),
2.3- bls(diphenylphosphlno)- blcyclo[2.2.1]hepto-5-ene (NORPHOS); l-tertiary-butoxycarbonyl-4-diphenyiphosphlno-2-(diphenylphosphinomethyl)pyrroiidine (BPPM);
2.3- bls(tertlary-butylmethylphosphlno) quinoxaline (QuinoxP*);
2.4- bis(diphenylphosphlno)pentane (SKEWPHOS);
2.4- bls(dl(3,5-xylyl)phosphlno)pentane (XylSKEWPHOS); 4,4’-bls(dlphenylphosphlno)-2,2',5,5,-tetramethyl-3,3,-bithiophene (TMBTP); xylyl-C3-tunephos ;
xylyt-synphos ; Joslphos type ligands; Garphos type ligands; Deguphos ; PhanePHOS ; BDPP ; Norphos ; ProPhos ;
1,r-bis(dlphenylphosphino)ferrocene (DPPF); bls(2-dlphenyiphosphinophenyl) ether (DPEphos); bls(diphenylphosphlno)methane;
1,2-bis(dlphenylphosphino)ethane; 1,3-bis(dlphenylphosphino)propane; and 1,4bls(dlphenylphosphlno)butane; 1,5-bis(diphenylphosphlno)pentane.
The diphosphine as specifîcally exemplified In the above may be an optically active diphosphine.
The group of formula ΝΛ (XVI), represents in the compounds of formulae IX - X an amino group-containing ligand, preferably a chiral amino group-containing ligand, more preferably a chiral diamine ligand. Chiral amino group-containing ligands are known In the art and may used In the présent invention, examples are given In R. Noyor, T. Ohkuma, Angew. Chem., Int. Ed. Engl. 2001,40,40-73; In W02004/007506 and In STREM catalog of other ligands: httD://www.strem.com/uDloads/resources/documents/other liqands.pdf
Spécifie examples of the diamine ligands represented by formula (XVI) of the invention include
1.2- dlphenylethylenedlamine (DPEN);
1.2- bls(naphthyi)ethylenedlamine;
1.1- bls(4-methoxyphenyl)-3-methyl-1,2-butanediamlne (DAIPEN);
1.2- bls(2-methoxyphenyl)ethane-1,2-diamlne;
spiro[4.4]nonane-1,6-diamlne;
l-pyrrolidinecarboxylicacid, 4-amino-2-(aminomethyl)-,1,1-dimethylethyl ester;
1.3- diphenyl-1,3-propanediamine;
1.4- diphenyl-1,4-butanedlamlne;
1-phenyl-1,2-ethanedi amine;
2-pyrrolidinemethanamlne;
3.4- O-isopropylldenehexane-2,5-diamine (IPHAN);
2.3- O-isopropylldenebutane-1,4-dlamine (IPBAN);
1.2- cyclohexanediamlne (DACH);
1.2- ethanediamine (en);
1,2-propanediamine;
2.4- pentanediamlne;
2.5- hexanedlamlne;
1.2- benzenediamlne;
N1,N2-dimethy!-1,2-ethanediamine and
DMDPEN.
The diamlne ligands as specifically exemplified in the above may be optically active.
The group of formula
represents in the compound of formula Xli a amino group-containlng ligand with a second donor group, D is preferably representing a nitrogen, sulphur or phosphores. XVII is optionally a chiral ligand.
A range of chiral amino group-contalning ligands is known and may used In the présent Invention, examples are given in STR EM catalog of other ligands: httD://www.strem.com/uDloads/resources/documents/other lioands-pdf
Spécifie exemples of the amino group-containlng iigands represented by formula (XVii) of the invention Include
2-(a-methyimethanamine)-1 H-benzimidazole (Me-BiMAH);
2-(a-(i-propyl)methanamlne)-1 H-benzimldazole (i-Pr-BIMAH); 2-(a-(i-butyi)methanamine)-1 H-benzimidazole (l-Bu-BiMAH);
2-(a-(t-butyl) methanamine}-1 Η-benzlmldazole (t-Bu-BiMAH); 2-(di-l-propylphosphlno)ethanamine:
2-(diphenylphosphino)ethylamine;
2-Pyridinemethanamine (PICA);
-(2-pyri dy I )eth anami ne;
2-(diphenylphosphino)-1,2-diphenylethanamine;
2- amino-1 -phenylpropyldiphenylphosphlne and
3- (diphenylphosphino]propylamine.
The ligands as specifically exemplified in the above may be optically active.
The group of formula
(χνιιΐ).
représente In the compound of formula XIII a amino sulfonamlde ligand, more preferably a chiral amino sulfonamlde ligand. A range of chiral amino sulfonamlde ligands ls known and may used In the présent Invention, examples are glven in T. ikarlya, A J. Blacker, Acc. Chem. Res. 2007,40,1300-1308.
Spécifie examples ofthe amino sulfonamlde ligand represented by the compound of formula XVIII comprise
N-(4-toluenesulfonyl)-1,2-diphenylethylenediamlne (TsDPEN); N-(methanesulfonyl)-1,2-diphenylethylenediamine (MsDPEN) and N-pentafluorophenylsulfonyl-1,2-dlphenylethylenediamine (FsDPEN).
The group of formula
(XIX).
SOjR représente in the compound of formula XIV an aryl-amlno-sulfonamlde ligand, more preferably a chiral ligand containing L (définition above) and N Π N-SO2R (VIII, définition above) which are connected by a C^ bridge which may be optionally Interrupted by a heteroatom.
A range of chiral aryl-amlno-sulfonamlde ligands ls known and may used In the présent Invention, examples are glven In T. Touge, T. Hakamata, H. Nara, T. Kobayashl, N. Sayo, T. Salto, Y.Kayakl, T. Ikarlya J. Am. Chem. Soc. 2011,133,14960-14963 and In Hannedouche, J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2004,126,986-987.
Spécifie examples of the aryl-amlno-sulfonamlde ligand represented by formula (XIX) of the Invention comprise
-17N-[2-(phenethyloxymethylamino)-1.2-diphenyl-ethyl]benzenesulfonamide;
N-[1,2-diphenyl-2-(3-phenylpropylamino)ethyl]benzenesulfonamÎde and N-II^-dipheny^-^-phenylbutylaminoJethyljbenzenesulfonamide.
The ligands as specifically exemplified ln the above may be optlcally active.
The group of formula
represents ln the compound of formula XI a tridentate diamine ligand, more preferably a chiral tridentate diamine ligand. R“, Rb and Rc each Independently represent a hydrogen atom, an optionally substituted Ci-Cîoalkyl group, an optionally substituted Cz-Cîoalkenyl group, an optionally substituted CrCa cycloalkyl group, an optionally substituted C7-C20 aralkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group, and Rb and R” may form an alkylene group or alkylenedioxy group; RN1, RN2, Rra, and RM each independently represent a hydrogen atom, an optionally substituted C1-C20 alkyl group, an optionally substituted Cz-Cnalkeny group, an optionally substituted CrCa cycloalkyl group, an optionally substituted C7-C20 aralkyl group, an optionally substituted C3Ce cycloalkyl group, at least one of RN1, RN2, RN3, and Rw represents a hydrogen atom, and RN1 and R may form an alkylene group; n represents an Integer 0 to 3, and Ar represents an optionally substituted arylene group. Preferred optional substituents are described In WO 2011/135753. A range of suitable tridentate diamine ligands and the corresponding ruthénium complexes (XI) Is known and may used In the présent Invention, examples are given in WO2011/135753.
A spécifie tridentate diamine ligand represented by formula (XXI) of the Invention Is 1-(4 methoxyphenyl)-1 ’-(4-methoxyphenyl-kC)-3-methyl-1,2-butanediamine.
Spécifie examples of ruthénium complexes represented by formula (IX) of the Invention Include:
-18RuCI2[(R)-xylblnap][(R.R)-dpen] CAS= [220114-38-5 ] : dichloro{(R}-(+}-2l2,-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl0}[(1 R,2R}-(+}-1,2dlphenylethylenediamlne]njthenium(ll): and
RuCl2[(R}-xylbinap][(R)-dalpen] CAS = [220114-32-9]: Dichloro{(R)-(+)-2l2,-bis[di(3,5-xyiyl)phosphtno]-1,1 *-blnaphthyi}[(2R>-(->-1,1 -bls(4melhoxyphenyl)-3-methyl-1,2-butanediamine]njthenium(ll) :
RuCI2[(R}-xylbinap][(R,R)-dpen. CAS = [220114-38-5] ; and RuCI2[(R}-xyl-P-Phos][(R)4phan], CAS = [832117-89-2].
A preferred example of ruthénium complexes represented by formula (XI) of the Invention Is (R>RUCY™-XylBINAP, Strem catalog 44-0217, chloro{(R}-(+>-2,2,-bis[di(3,5-xylyl)phosphIno]-1ir-blnaphthylX(2R>-(->-1-(4-methoxyphenyl}· 1 *-(4-methoxyphenyl-kC}-3-methyl-1,2-butanediamine]ruthenium(ll).
A preferred example of ruthénium complexes represented by formula (XII) of the Invention Is: RuCI2[(S,S}-DIOP](S}-Me-BIMAH (STREM catalog Nr. = 44-0955) Dichloro[(4S,5S)-(+)-4t5-bls(diphenylphosphlnomethyi)-2,2-dimethyl-1t3-dloxolane][(S)-(-)-2(a-methylmethanamine)-1 H-benzlmidazole]njthenium(ll).
An example of ruthénium complexes represented by formula (XIII) of the Invention Is RuCI[(S,S)-Tsdpen](p-cymene) CAS = [192139-90-5], chloro{[(1S,2S>-(+}-2-amino-1,2-diphenylethyi](4-toluenesulfonyl)amldo}(pcymenejruthenlum (II ).
An example of ruthénium complexes represented by formula (XIV) of the Invention is (S,S)-Ts-DENEB™, CAS = [1384974-37-1], N-[(1 S.2SJ-1,2-dîphenyl-2-(2-(4methylbenzyloxy)ethylamino)-ethyl]-4-methylbenzene sulfonamide(chloro)ruthenium(ll).
It Is known to carry out enantioselective catalytic hydrogénations by two process variants that differ In principle (with molecular hydrogen or by transfer hydrogénation). Also, the process of the subject matter of the Invention may be carried out either in the presence of molecular hydrogen or by means of transfer hydrogénation. Both types of process hâve been evaluated
-19in the prior art and may be used analogously. (Catalytic asymmetric synthesis, Iwao Ojima, third Edition, Wiley-VCH 2010, pp 384-413)
It has been found that acid resldues affect the présent reaction In that on the one hand they lead to a low yieid and on the other hand cause a low enantiomer enrichment of the products. Therefore, It has proved advantageous If a base Is présent In the reaction step a) according to the Invention. Suitable bases are for example aîkali métal alcohoiates, such as for example sodium methanolate, sodium ethanolate or potassium tert.-butyiate or potassium Isopropylate or carbonates or hydroxldes of alkall or alkaline earth matais. Also advantageous are organic nitrogen bases such as pyridine, DMAP, triethylamine, Hunig base, 1,2-ethyienediamine, dlphenylenediamine, 1,2-dl-(4-anisyi)-2-lsobutyl-1,2ethylenediamlne and 1,2-di-(4-anlsyl)-2-isopropyl-1,2-ethylenediamine. A particulariy preferred base Is potassium tert.-butyiate.
A person skilled In the art Is able to détermine a sultably adéquate excess of base. A molar excess of base referred to the catalyst used of between 1:1 and 1000:11s advantageous, an excess of > 10 :1 being particulariy preferred and an excess of > 2:1 being most particulariy preferred. One of the bases mentioned above Is accordingly added to the substrate In an amount of 0.1-50 mol%, particulariy preferably 0.1-10 % and most particulariy preferably 0.1-5 % referred to the latter.
Ail Inert solvents known to the person skilled In the art for this purpose may be used, also mixtures of these solvents In any composition may be used. Preferred classes of solvents Include alcohols, ethers, esters, nltriles, amines, amides, hydrocarbons, aromatic hydrocarbons and chlorînated hydrocarbons. Particulariy referred solvents and solvent mixture according to the Invention Include: methanol, éthanol, isopropanol, tert.-butanol, ethylacetate,Isopropyl acetate, acetonitril, triethylamine, tetrahydrofurane, 2-methyltetrahydrofurane, letrahydrofuran-2-ylmethanol, toluene, xylene, chlorobenzene, dimethylacetamlde, dimethylformamlde N-methyl-2-pyiTolidone.
The hydrogénation or transfer hydrogénation catalyst comprising is advantageously used In a concentration of 0.001-5 mol% referred to the substrate to be hydrogenated. It Is particulariy preferred to use the catalyst In, a concentration that Is as low as possible while ensuring the
-20optimum possible conversion rate. The catalyst Is particularly preferably used ln a concentration of 0.01-1 mol%.
The température during the hydrogénation or transfer hydrogénation reaction may in princlple be chosen arbltrarily by the person skilled ln the art as long as a sufflclently qulck and sélective reaction is achieved. The reaction is accordingly preferably carried out at températures between -10’ and 100eC, more preferably between 0e and 80“C and particularly preferably between 0* and 60’0.
Reaction time of hydrogénation or transfer hydrogénation Is between 10 minutes and 48 hours, preferably between 30 minutes and 24 hours, most preferably between 1 hour and 12 hours.
Hydrogénation of the présent invention is carried out ln the presence of molecular hydrogen, then a hydrogen pressure of 0.1 - 20, preferably 0.2 -10 and particularly preferably between 1-8 MPa should be adjusted.
The transfer hydrogénation of the présent invention is carried out In the presence of a hydrogen donor, such as formic acid or a sait thereof, or 2-propanoi or other alcohols having a hydrogen atom in α-posltlon. Among combinations of the hydrogen donor and base, when the hydrogen donor Is formic acid, It is préférable to use an amine as a base, ln this case, formic acid and the amine may be added separateiy into the reaction System, or It is aiso acceptable to use a mixture of formic acid and an amine (e.g. the azeotroplc mixture of formic acid and triethylamine) prepared in advance. If the hydrogen donor 1s a liquid it may be used as the réaction solvent or co-solvent.
The compound of formula il le
and Its Isomers of formulae lllf - Hlm
are novel and especlally developed for the process according to the Invention and therefore constltute a further object of the Invention.
In a preferred embodiment of the présent Invention the enantloselective réduction of the compound of formula II is done via hydrogénation in presence of a transition métal catalyst, preferably a ruthénium catalyst
In another preferred embodiment of the présent Invention the enantloselective réduction of the compound of formula II Is done via transfer hydrogénation In presence of a transition métal catalyst, preferably a ruthénium catalyst.
In an especlally preferred embodiment of the présent invention the enantloselective reagent is chloro{(R)-(+)-2,2’-bis[di(3,5-xylyl)phosphlno]-1,1,-blnaphthyl}[(2RH-)-1-(4methoxyphenyl)-1 '-(4-πιβΙήοχνρΚβη^4<Ο)-3-πΐθϋψΙ-1,2-butanediamlne]ruthenium(l I ).
Réaction step b) can be performed as described in WO 2011/015416. Suitable acids for reaction step b) are strong acids like phosphoric acid, polyphosphoric acids, concentrated H2SO4, methanesulfonlc acid, p-toluenesulfonic acid, Immobllized acids (fixed on polymeric carriers) e.g. like Amberiyst™, preferably concentrated H2SO4. Dépendent on the used acid,
-22the reaction can be performed at températures from 10’C to 150 ’C. A preferred température range for the use of concentrated H2SO4 as solvent is from 10 to 25’C. For concentrated H2SO4, the weight ratio of startlng material to the concentrated H2SO4 is from 1 :0.2 to 1 :10, preferably 1 :1 or less in which case a soivent Is requlred and the preferred température range Is 70-90‘C. The compound of formula IVa Is added to the acid ln solid form or the acid Is added to a solution of compound of formula IVa ln an organic solvent. The reaction can be supported by azeotroplc distillation of water, optionally under reduced pressure, especlally If a catalytic amount of acid Is used.
Suitable organic solvents for reaction step b) are for example toluene, xylene, methyl cyclohexane, chiorobenzene or dichlorobenzene, preferably toluene. As any élimination, this reaction can be donc by converting the hydroxy! to a suitable leavlng group such as for example halogen (Br, Cl, by reaction for example with PCIS. PBr3, SOCI2) or sulfonate (by reaction for example with methansuifonyichlorlde in presence of base) or acetate followed by treatment with a base, acid or iewis acid (for example KOH, NaOH NaO'Bu, KO'Bu or tertlary amines including aromatic such as for exampie pyridine).
The compound of formula IVa (S)
can occur ln the following isomers or mixtures thereof:
(S) (S) (S)
(S)
-23The Isolation or purification of a spécifie Isomer or a isomer mixture of formula IVa Is not necessary. The compound of formula IVa and its isomers are novel and especially developed for the process according to the Invention and therefore constitute a further object of the Invention.
Reaction step c) can be performed as described ln WO 2011/015416. Hydroxylamine can be used as free base ln water (50% solution is commercially avallable) or generated in situ from Its salts such as for example hydrochloride or sulfate by treatment with a base (for example triethylamine, pyridine, NaOH or KOH, sodium acetate, potassium or sodium carbonate). Hydroxylamine is preferably used ln form of Its sulfate or hydrochloride and ln an amount of 1 to 2 équivalents, In particular 1.1 to 1.3 équivalents with regard to the compound of formula IVa. Suitable bases for this reaction step are for example pyridine, tertiary amines like triethylamine, NaOH or KOH, sodium acetate, potassium or sodium carbonate Especlally preferred is sodium acetate and NaOH. The base Is used ln an amount of 1 to 2 équivalents, preferably 1-1.5 équivalents with regard to the compound of formula IVa. Suitable solvents are alcohols (preferred anhydrous), dimethylformamlde, N-methyl-2-pyrrolldone, or CH3CN , In particular anhydrous éthanol or anhydrous methanol. An especlally preferred solvent Is anhydrous éthanol. Réaction step e) can be advantageously performed at températures of from 10 to 40’C preferably at 25’C or ambient température. The reaction can be also performed ln a two phase system (organic solvent/water, organic solvent for example are: toluene, xylene, methylcyclohexane) at températures of from 50 -100’C using the above mentioned hydroxylamine sources and bases ln the presence of phase transfer catalysts selected from carboxylic acids (for example acetlc, propionlc, isobutyric, plvallc, valeric, isovaleric, benzolc, 2-ethylhexanolc) used ln amount 2-50 mol%. A preferred amount of catalyst Is 5-10 mol%, a preferred température Is 80-90‘C, preferred catalysts are benzolc add and 2-ethylhexanolc acid.
With sodium acetate as base, a phase transfer catalyst Is not required. This Is a preferred embodiment of the process.
The compound of formula Va can occur ln the following Isomers or mixtures thereof:
-24(S) (S) (S)
The Isolation or purification of a spécifie Isomer or a Isomer mixture of formula Va Is not necessary. The compound of formula Va and Its Isomers are novel and especially developed for the process according to the Invention and therefore constltute a further object of the Invention.
Reaction step d) can be performed as described In WO 2011/015416 or In W02012/101139.
A prefened embodiment of reaction step d) comprises acylating the oxlme oxygen of the compound of formula Va (S)
In the presence of a solvent and an acylating agent of formula XXIIa
Ri-C(X)-CI (XXIIa), whereln X Is oxygen or sulfur, preferably oxygen; Ri Is CrCealkoxy, CH3-C(=CH2)-Ophenoxy or trichloromethoxy; preferably Ci-Cealkoxy, phenoxy or trichloromethoxy; and reacting the so obtained product of formula XXIIla
whereln X is oxygen or sulfur, preferably oxygen, Ri Is CrC6alkoxy, CH3-C(=CH2)-O-, phenoxy or trichloromethoxy;
Preferred acylating agents of formula XXIIa are those, whereln Ri Is methoxy, ethoxy, isopropoxy, phenoxy or Isopropenyloxy and X is oxygen, more preferably Ri Is methoxy, ethoxy, isopropoxy or phenoxy and X Is oxygen, in particular Ri is ethoxy.
The compounds of formula XXIlia are novei, were espedally developed for the process according to the Invention and therefore constitute a further object of the Invention. Preferred compounds formula XXIIla are those, wherein Ri Is methoxy, ethoxy, Isopropoxy, phenoxy or Isopropenyloxy and X Is oxygen, more preferably Ri Is methoxy, ethoxy, Isopropoxy or phenoxy and X Is oxygen, In particular Ri is ethoxy.
The process according to the invention consiste of two chemical transformations: reaction of the oxime oxygen with the acylating agent followed by in situ transformation of the acylated dérivative to the compound of formula lb by reaction with 1.0 to 1.3 équivalents preferably 1.05 équivalants of the compound of formula Vi advantageousiy In the présence of an acid (preferably HCl, H2SO4 or CH3SO3H, most preferred CH3SO3H). The addition of the acid accelerates the formation of the compound of formula ib and therefore significantly reduces the reaction time.
-26The acylation Is advantageously performed In the presence of a base. The base Is used In an amount of 1 to 1.5 équivalents with respect to the compound of formula Va, in particular in an amount of 1.2 équivalents. Suitable bases for the acylation are pyridine or tertiary amines like triethylamine. Trlethyiamlne Is espedally preferred as a base. Preferred reaction températures for the process are from 60 to 150“C, in particular 85-125 ’C, most preferably 95 to 115 *C. In another preferred embodiment ofthe présent invention the reaction Is performed at a température from 130 to 135’C with an acylation agent of the formula XXIla wherein Ri is ethoxy and X is oxygen.
Suitable solvents are toluene, dioxane, tetrahydrofurane, xylene, chlorobenzene or acetonitrile. Most preferred solvent Is xylene.
If the acylation agent is phosgen or thiophosgen, the structure of the compound obtained from the reaction of the oxime of formula Va with phosgen or thiophosgen dépends on the order of addition of the reactants.
If the compound of formula XXIla, wherein Ri Is chloro and X Is oxygen or sulfur Is added to the compound of formula Va; the compound of formula XXIVa (S)
(XXIVa), wherein X Is oxygen or sulfur; is obtained.
If the compound of formula Va Is added to the compound of formula XXIIa wherein R, Is chloro and X Is oxygen or sulfur; the compound of formula XXVa
-27(S)
wherein X Is oxygen or sulfur and Ri Is chloro; is obtained.
For compounds of formula XXllla, wherein Ri Is Ci-C6alkoxy, CHrC(=CH2)-O-, phenoxy or trtchloromethoxy If X Is oxygen; the compound of formula XVIa was obtained Independently from the order of addition of the reactants.
The compounds of formula XXIVa and XXVa are novel, were especlally developed for the process according to the Invention and therefore constitute a further object of the invention, ln a preferred compound of formula XXVa, X is oxygen.
It was also found that the addition of CH3SO3H accelerates the formation of the compound of formula Ib and therefore signlficantly reduces the reaction time.
The compound of formula VI Is known and commercialiy available. The compound is disclosed, for example, ln US-5,093,347.
Preparatorv examples;
HPLC Waters Alliance 2695
UV détecter Waters 996 DAD
Example P1 : préparation of enantiomertcallv enriched (1S, 4Rb9-dichloromethvlene-8hvdroxy-octahydro-1.4-methano-naphthalen-5-one of formula lllf:
(lllf).
-28ln a 100ml Hastelloy autoclave equipped with a magnetic stirring bar under argon, a mixture ofthe compound of formula II (1.00 g, 3.86 mmol), chloro((R)-(+)-2,2’-bis[di(3,5xylyl)phosphino]-1,1’-binaphthyîX(2R)-(-)-1-(4-methoxyphenyl)-T-(4-methoxyphenyl-kC)-3methyl-1,2-butanediamlne]ruthenium(ll) ((R)-RUCY™-XylBINAP, Strem catalog 44-0217) (0.0183 g, 0.0154 mmoi), dichloromethane (10.0 mi) and Iso-propanol (8.0 ml) was treated with potassium fert-butoxlde (0.0223 g, 0.193 mmoi) dissolved In Iso-propanol (2.0 mi). The autoclave was purged with 0.5 MPa hydrogen (3-times), pressurized with 5 MPa hydrogen and vlgorously stirred at 25-28’C for 22 hours. The crude reaction mixture was evaporated and the product was isoiated via column chromatography (silica, heptanes -> 30% ethyl acetate In heptanes gradient) glving 900 mg of (1S, 4R)-9-dichloromethylene-8-hydroxyoctahydro-1,4-methano-naphthalen-5-one in form of a white solid.
Chiral HPLC analysis (Chiralpack ID, 0.46cm x 25cm, heptane:lso-propanol = 90:10, 1ml/min, Detection:220nm): rétention time 8.83 minutes (major enantiomer, 83.4%), 12.93 minutes (mlnor enantiomer 16.6%). The sign of the optical rotation in CHCI3 is(+).
’H NMR analysis Indicated that the product diastereopurity (ratio of major diastereoisomer lllf / sum of ali diastereoisomers (formulae llie - ilim)) is 96%.
’H NMR (CDCi3, 400 MHz) δ (major isomer) 1.58 -1.72 (m, 3H), 1.84 (bs, 1 H), 2.04 (m, 2H), 2.20 - 2.35 (m, 2H), 2.48 - 2.55 (m, 1H), 2.74 (m, 2H), 3.12 (m, 1 H), 3.28 (m, 1H), 4.41 (m, 1H).
Example P2: préparation oftheenantiomerlcallvenriched compound offormula IVa:
(S)
Finely powdered compound of formula lllf (0.50 g, 1.915 mmol) was added to an intensiveiy stirred 96% sulphurlc acid (2.5 ml) at 0°C. The reaction mixture was stirred 10 min at the same température and at amblent température for 1 hour (orange solution). The reaction mixture was poured Into water and extracted with dichloromethane. The organic phase was dried over Na2SO4 and evaporated in vacuum giving 417 mg of brown solid.
-29Chiraî HPLC analysis (Chiralpack ID, 0.46cm x 25cm, heptane:iso-propanol = 90:10, 1ml/min, Détection: 240nm): rétention time 7.61 minutes (mlnor enantiomer, 14.5%), 8.16 minutes (major enantiomer, 85.5%).
1H NMR (CDCh, 400 MHz) δ 1.23 -1.32 (m, 2H), 1.88 - 2.14 (m, 4H), 2.23 - 2.30 (m, 1 H), 2.35 - 2.57 (m, 3H), 3.49 (m, 1 H), 3.87 (m, 1 H).
Example P3: préparation of enantlomerically enriched compound of formula Va:
(S)
Cl
Cl (Va).
A mixture of compound of formula IVa (0.385 g, 1.584 mmol), hydroxylamine hydrochloride (0.132 g, 1.900 mmol), pyridine (0.1879g, 2.376 mmol) and absolute éthanol (3.0 ml) was stirred at ambient température for 4.5 hours. Water was added to the reaction mixture and the solid formed was filtered and dried glvlng 313 mg of the desired product.
1H-NMR (CDCI3, 400 MHz,): δ 1.36-1.26(m, 2H); 2.03-1.78(m, 4H); 2.27-2.17(m, 1H); 2.492.33(m, 2H); 2.78-2.68(m, 1H); 3.40(d, 1H, J=2.6Hz); 3.80(d, 1H, J=3.3Hz);
Example P4: préparation of enantiomericailv enriched 3-dlfluoromethyl-1-methvl-1Hovrazole-4-carboxvlic acid (H S,4F?)-9-dlchloromethvlene-1,2,3.4-tetrahvdro-1,4-methanonaphthalen-5-vl>amlde of formula Ib:
CH3
To a stirred solution ofthe compound of formula Va (0.100 g, 0.3874 mmol) in dioxane (0.5 mL) was added triethylamine (0.0392 g, 0.3874 mmol) and then 4-(difluoromethyl)-1-methylpyrazole-3-carbonyl chioride (0.1508 g, 0.775 mmol) slowly. The reaction mixture was heated slowly to a température of 82e and kept at this température for 3 hours and at ambient température for 18 hours. After cooling to ambient température most of the solvent was removed by rotary évaporation and the residue was stirred with dlethyl ether and water. A solution of NaOH (48 mg) in water (0.2 ml) was added and the mixture was stirred for additional 10 min. The water phase was separated and the organic phase was extracted with 1M NaOH, 1M HCl, water, dried over NaiSO4 and evaporated In vacuum. The crude product was purified via column chromatography (silica, heptanes/ethyl acetate 2:1->1:1 ) giving 75 mg of the desired product as a yellow solid.
Chiral HPLC analysis (Chiralpack ID, 0.46cm x 25cm, heptaneJso-propanol = 90:10, 1ml/mln, Détection: 260nm): rétention time 10.04 minutes (major enantlomer, 85.4%), 14.14 minutes (minor enantiomer, 14.6%). The sign ofthe optical rotation In CHCI3 Is (-).
1H NMR (CDCb, 400 MHz) δ 1.37 (m, 1H), 1.49 (m, 1H), 2.09 (m, 2H), 3.90 (s, 3H), 3.94 (m, 1 H), 4.07 (m, 1 H), 6.91 (t, Jh-f = 54.2 Hz, 1 H), 7.02 (d, J = 7.3 Hz, 1 H), 7.16 (t, J = 7.8 Hz, 1H), 7.79 (d, J- 8.2 Hz, 1H), 8.01 (s, 1H), 8.15 (m, 1H).
Example P5: préparation of the single enantiomer of (1 S, 4R)-9-dichloromethvlene-8hvdroxv-octahydro-1.4-methano-naphthalen-5-one of formula lllf:
A 500 ml Hastelloy autoclave was charged with compound of formula II (20.00 g, 74.9 mmol). Under argon, dry and degassed toluene (80.0 ml) was added, followed by a degassed solution of dichloro[(4S,5S)-(-)-4,5-bis(diphenylphosphinomethyl)-212-dimethyl1,3-dloxolane][(S)-(+)-2-(a-methylmethanamine)-1H-benzlmldazole]ruthenlum(ll), min. 98% , Strem catalog 44-0955 (0.05g, 0.060mmol) and triphenylphosphlne (0.098g, 0.375mmol) In toluene (11.0 ml) and a solution of potassium tert-butoxide (0.433 g, 3.75 mmol) In isopropanol (10 ml). The autoclave was purged with 0,5 MPa hydrogen (3-times), pressurized with 5 MPa hydrogen and vlgorously stirred at 25-28’C for 2 hours. The crude reaction mixture was evaporated, dissolved In ethylacetate, filtratered over a plug of silica and evaporated giving 18.32 g of (1S, 4R)-9-dlchloromethylene-8-hydroxy-octahydro-1,4methano-naphthalen-5-one as a brown gum.
Chiral HPLC analysis (Chiralpack ID, 0.46cm x 25cm, heptane:lso-propanol = 90:10, 1ml/min, Detection:220nm): rétention time 8.83 minutes (major enantiomer, 98.9%), 12.93 minutes (minor enantiomer 1.1%). The sign of the optical rotation in CHCh is (+).
The product was further recrystalilzed from toiuene (35ml) to give 15g (77%) of lllf as a white solid.
Chiral HPLC analysis (Chiralpack ID, 0.46cm x 25cm, heptane:iso-propanol - 90:10, 1ml/mln, Détection:220nm): rétention time 8.83 minutes (major enantiomer, 100%), minor enantiomer not detected (<0.1%).
’H NMR (CDCh, 400 MHz) δ (major isomer) 1.58 - 1.72 (m, 3H), 1.84 (bs, 1H), 2.04 (m, 2H), 2.20 - 2.35 (m, 2H), 2.48 - 2.55 (m, 1H), 2.74 (m, 2H), 3.12 (m, 1H), 3.28 (m, 1H), 4.41 (m, 1H).
Exampie P6: préparation ofthe singleenantiomerofthe compound offormula IVa:
-32(S)
Finely powdered compound of formula lllf (14 g, 53.6 mmol) was added to an Intenslvely stirred 96% sulphuric acid (50 ml) at O’C. The reaction mixture was stirred 10 min at the same température and at ambient température for 1 hour (orange solution). The reaction mixture was poured into ice/water and extracted with tert-butyl methyi ether. The organic phasewas dried over Na2SO< and evaporated in vacuum glvlng 12.7g (84%) ofthe title compound as a brown solid
Chiral HPLC analysis (Chlralpack ID, 0.46cm x 25cm, heptane:iso-propanol - 90:10, 1ml/min, Détection: 240nm): rétention time 7.61 minutes (major enantlomer, 100%), minor enantlomer not detected (<0.1%).
1H NMR (CDClj, 400 MHz) δ 1.23 - 1.32 (m, 2H), 1.88 - 2.14 (m, 4H), 2.23 - 2.30 (m, 1H), 2.35 - 2.57 (m, 3H), 3.49 (m, 1 H), 3.87 (m, 1 H).
Exemple P7: préparation of single enantlomer of compound of formula Va:
(S)
A mixture of compound of formula IVa (10.7 g, 44.0 mmol), hydroxylamlne hydrochloride (3.67g, 52.8 mmol), pyridlne (5.22 g, 66.0 mmol) and absolute éthanol (80 ml) was stirred at ambient température for 3.5 hours. Water/ïce was added to the reaction mixture and the solid formed was filtered and dried glvlng 10.75 g (95% yleld) of the of the title compound.
1H-NMR (CDCI3, 400 MHz,): δ 1.36-1.26(m, 2H); 2.03-1.78(m, 4H); 2.27-2.17(m, 1 H); 2.492.33(m, 2H); 2.78-2.68(m, 1 H): 3.40(d, 1H, J=2.6Hz); 3.80(d, 1H, J=3.3Hz);
-33Example PS: préparation of the single enantlomer of 3-difluoromethvl-1 -methvl-1 H-ovrazole-
4- carboxvllc acid ((1 S.4R>9-dlchloromethvlene-1.2,3,4-tetrahvdro-1.4-methano-naphthalen-
5- vl)-amlde of formula Ib:
ci ci (Ib).
To a stirred solution of the compound of formula Va (10.7 g, 41.5 mmol) in dioxane (50 mL) was added triethyl amine (4.20 g, 41.5 mmol) and then 4-(difluoromethyl}-1-methyl-pyrazole3-carbonyl chloride (16.1 g, 82.9 mmol) slowly. The reaction mixture was heated slowly to a température of 82° and kept at this température for 3 hours. After cooling to ambient température most of the solvent was removed by rotary évaporation and the residue was stirred with diethyl ether and water. A solution of NaOH (4.8 g) in water (20 ml) was added and the mixture was stirred for additional 30 min. The water phase was separated and the organic phase was extracted with 1M NaOH, 1M HCl, water, dried over Na2SO4 and evaporated in vacuum. The crude product was purifîed crystallization: the product was stirred for 2 hours In a mixture of ether and pentane; then it was filtered and washed with cold ether to give 11g (65%) of the title compound as a white solid.
Chiral HPLC analysis (Chlralpack ID, 0.46cm x 25cm, heptane:iso-propanol = 90:10, 1ml/min, Détection: 260nm): rétention time 10.04 minutes (major enantiomer, 100%), mlnor enantiomernot detected (<0.1 %). The slgn ofthe optical rotation In CHCI3 is (-).
1H NMR (CDCIs, 400 MHz) δ 1.37 (m, 1 H), 1.49 (m, 1 H), 2.09 (m, 2H), 3.90 (s, 3H), 3.94 (m.
H), 4.07 (m, 1 H), 6.91 (t, J^f =54.2 Hz, 1 H), 7.02 (d, J = 7.3 Hz, 1 H), 7.16 (t, J = 7.8 Hz,
1H), 7.79 (d, J - 8.2 Hz, 1H), 8.01 (s, 1H), 8.15 (m, 1H).
Mp=146C.
Example P9: Enantioselective réduction ofthe compound of formula II via hydrogénation:
(II)
(ΙΙΙΐ)
A mixture ofthe compound of formula II (0.1 g - 4.00 g), catalyst, base, additive and solvent (1.3-3 mL/mmol) was added into a 100ml hastelloy autoclave equipped with a magnetic stirring bar under argon. The autoclave was purged with 0.5 MPa hydrogen (3-times), pressurized with hydrogen and vlgorously stirred under the conditions specified In the table below. The crude reaction mixture was evaporated and the crude product was analysed.
Chiral HPLC analysis (Chiralpack ID, 0.46cm x 25cm, heptane:iso-propanol = 90:10, 1ml/min, Détection:220nm): rétention time 8,83 minutes (major enantiomer), 12.93 minutes 10 (mlnor enantiomer). The sign of the optical rotation for the major enantiomer In CHCIa is (+).
Conversion and selectivity (ratio of major diastereolsomer / sum of ail diastereoisomers and by-products) was determined by ’H NMR analysis.
Catalyst Conditions Conversion /Selectivity Ration of major : mlnor enantiomer
(R)-RUCY™-XylBlNAP (0.4 mol%) 50 bar H2. RTZ20h, KOtBu (0.05), IPA/DCM (1:1), 1 gscale 100%/96% 83:17
Ru Cl2(( R)-xylbi nap][(R)daipen (1 mol%) 50 bar H2, RTZ20h, KOtBu (0.05), IPA/TOL (1:1), 1 gscale 75%/100% 84:16
RuCl2[(R)xylbinap][(R,R)-dpen (1 mol%) 50 bar H2,RT/3h. KOtBu (0.1), IPA/DCM (1:1), 100 mg scale 100% /87% 69:33
RuCl2[(R)-xyl-PPhos]((R)-lphan] (1 mol%) 10 bar H2, RT/22h, KOtBu (0.05), IPA/TOL (1:1), 100 mg scale 100%/87% 94:6
RuCla[(S.S)-DIOPJ(S)- Me-BIMAH (1mol%) 10 bar H2, RT/18h, KOtBu (0.05), TOL/tBuOH (9:1), 250 mg scale 100%/98% 96:4
RuCI2[(S,S)-DIOP|(S)- 50 bar H2, RT/1h, KOtBu (0.05), 08% /98% 97:3
Me-BIMAH (0.5 mol%) PPh3 (1.5mol%), TOL/tBuOH (9:1), 500 mg scale
RuCI2[(S,S)-DIOP](S)Me-BIMAH (0.1 mol%) 50 bar H2, RT/1h, KOtBu (0.05), PPh3 (0.5mol%), TOL/tBuOH (9:1), 2 q scale 97% /98% 97:3
RuCI2[(S,S)-DIOP](S)- Me-BIMAH (0.05 mol%) 50 bar H2. RT/16h, KOtBu (0.05), PPh3 (0.5mol%), TOL/tBuOH (9:1), 4 g scale 100%/93% 98:2
ΙΡΑ = 2-propanol, DCM = dichloromethane, TOL = toluene
RuCI2[(R>xylbinap][(R,R)-dpen], CAS= [220114-38-5]
RuCI2[(R)-xylblnap][(R)-dalpen], CAS = [220114-32-9] (R>RUCY™-XylBINAP (STREM catalogue Nr. = 44-0217)
Chioro{(R)-(+)-2,2,-bis[dl(3,5-xylyl)phosphlno]-1,r-blnaphthyl}[(2R)-(-)-1-(4-methoxyphenyi)1'-(4-methoxyphenyl-kC)-3-methyi-1,2-butanedîamlne]ruthenium(ll)
RuCI2[(R)-xylbinap][(R,R)-dpen, CAS = [220114-38-5]
RuCi2[(R)-xyl-P-Phos][(R)-lphan], CAS - [832117-89-2]
RuCI2[(S,S)-DIOP](S)-Me-BIMAH (STREM catalogue Nr. = 44-0955)
Dlchloro[(4S,5S )-(+)-4,5-bls(diphenylphosphlnomethyl)-2,2-dimethyl-1,3-dioxolane][(S)-(-)-2(a-methylmethanamlne)-1H-benzimidazole]ruthenium(ll).
Example P10: Enantloselective réduction ofthe compound of formula II via transfer hydrogénation:
(II)
(lllf)
A mixture of the compound of formula II (0.25 g), catalyst (1 mol%) was vlgorously stirred under the conditions specified in the table below. The crude reaction mixture was evaporated
-36and the crude product was analysed. Conversion and selectivity (ratio of major diastereoisomer / sum of ail diastereoisomers and by-products) was determined by 1H NMR analysis.
Chiral HPLC analysis (Chiraipack ID, 0.46cm x 25cm, heptane:iso-propanol = 90:10, 1ml/min, Detectlon220nm): rétention time 8.83 minutes (major enantiomer), 12.93 minutes (minor enantiomer). The sign of the optlcal rotation for the major enantiomer in CHO3 Is (+).
Catalyst Conditions Conversion/ Selectivity Ration of major : minor enantiomer
(S,S)-TsDPEN-Ru-(pcymene)-CI (1 mol%) KOtBu (0.025), IPA (0.2M), 60’C/20h 100%/71% 67:33
(S,S)-Ts-DENEB™ (1 moi%) KOtBu (0.025). IPA(0.2M), 4O’C/2Oh 96% /97% 77:23
(S,S)-Ts-DENEBIM (1mol%) HCOOH (2.0), Et3N (1.7), acetonitrile (8 mL), 0’C to RT/16h 99%/99% 92:8
(S,S)-TsDPEN-Ru-(p-cymene}-CI, CAS = [192139-90-5] (S,S)-Ts-DENEB™, CAS = [1384974-37-1]

Claims (13)

  1. What is dalmed is:
    1. A process for the enantioselective préparation of 3-difluoromethyl-1-methyl*1 H-pyrazole-4carboxylic acid ((1S,4R)-9-dichloromethylene-1,2,3,4-tetrahydro-1,4-methano-naphthalen-55 yl>amlde of formula Ib (S) (Ib), which process comprises
    a) reducing a compound of formula II
    10 with an enantioselective reagent to a compound of formula llle (llle),
    b) dehydratlng the compound of formula llle ln the presence of an acid to the compound of formula IVa (S)
    c) reactlng the compound of formula IVa with hydroxylamine to the compound of formula Va (S) CCH (Va).
    X <*>
    hct and
    5 d) acylatlng the oxlme oxygen of the compound of formula Va In the presence of a solvent and an acylatlng agent and finally reacting the obtained product with the compound of formula VI
    e) reactlng the compound of formula V with an excess ofthe compound of formula VI.
  2. 2. A process according to claim 1, wherein the enantloselective réduction ofthe compound of formula II Is done via hydrogénation In the presence of a transition métal catalyst.
  3. 3. A process according to claim 1,wherein the enantloselective réduction ofthe compound of 15 formula II Is done via transfer hydrogénation In the presence of a transition métal catalyst.
  4. 4. A process according to claim 1, wherein the enantloselective reagent is a ruthénium catalyst.
  5. 5. A process according to claim 2, wherein the enantloselective reagent Is a ruthénium catalyst.
  6. 6. A process according to claim 3, wherein the enantloselective reagent Is a ruthénium cataiyst.
  7. 7. A process according to daim 1, wherein the enantloselective reagent Is chloroitRJ-t+J-Z.Z'bis[di(3,5-xylyl)phosphino]-1,T-binaphthytX(2R)-(-)-1-(4-methoxyphenyl)-r-(4methoxypheny^kC)-3-methyl-1,2-butanediamine]ruthθnlum(ll).
  8. 8. A process according to claim 1, wherein the enantloselective reagent Is dichloro[(4S,5S)(+)-4,5-bis(diphenylphosphlnomethyl)-2,2-dimethyl-1,3-dioxolane][ (S )-(-)-2- (amethylmethanamlne)-1 H-benzimldazole]ruthenium(ll)
  9. 9. The compound (1S,4R)-9-dichloromethylene-8-hydroxy-octahydro-1,4-methano- and Its Isomers.
  10. 10. The compound (1S,4R)-9-dichloromethylene-2,3l4l6,7l8-hexahydro-1H-1,4-methanonaphthalen-5-one of formula (S) and Its Isomers.
  11. 11. The compound (1 S,4R)-9-dichloromethylene-2,3l4,6l7l8-hexahydro-1 H-1,4-methanonaphthalen-5-one oxime of formula Va and Its Isomers.
  12. 12. A compound of formula XXIIIa (XXIIIa), wherein X Is oxygen or sulfur, R, Is Ci-Cealkoxy, CH3-C(=CH2)-O-, phenoxy or trichloromethoxy; and Its Isomers.
  13. 13. A compound of formula XXIVa (XXIVa), wherein X is oxygen or sulfur, and its isomers.
    Process for the stereoselective préparation of a pvrazole carboxamlde
    Abstract:
    The présent Invention relates to a process for the enantioselective préparation of 35 difluoromethyl-1 -methyl-1 H-pyrazole-4-carboxylic acid ((1 S,4R)-9-dichloromethy1ene-1,2,3,4tetrahydro-1,4-methano-naphthalen-5-yl)-amide of formula Ib (S) (Ib).
OA1201400365 2012-02-15 2013-02-13 Process for the stereoselective preparation of a pyrazole carboxamide. OA17076A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP12155526.2 2012-02-15
EP12173642.5 2012-06-26
EP12177606.6 2012-07-24
EP12182799.2 2012-09-03

Publications (1)

Publication Number Publication Date
OA17076A true OA17076A (en) 2016-03-23

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