PROTECTED 3.5-DIHYDROXY-2,2-DIMETHYL-VALERONITRILES FOR THE SYNTHESIS OF EPOTHILONES AND EPOTHILONE DERIVATIVES AND PROCESS FOR THE PRODUCTION AND THE USE

CA 02455797 2004-01-27 WO 031014068 PCT/EP02/08730 Protected 3,5-Dihydroxay-2,2-dimethyl-valeronitrtles for the Synthesis of Epothilones and Epothilone Derivatives and Process for the Production and the Use The invention relates to the subject that ,s characterized in the claims, i.e., new intermediate products and process for their production and the use. The process for the production of new intermediate products starts from economical starting materials, yields the intermediate products in high enantiomer purities, in high chemical purity, in good yields, and it allows the industrial-scale production.

The invention is used in the synthesis of component A from natural and synthetically modified epothilones or derivatives. Epothilones are 16-membered macrolide rings that were isolated from the cultures ofMyxobacterium Sorangium Cellosttm and are representatives of a class of promising anti-tumor agents that were tested and found to be effective against a number of cancer lines. A surve/of the syntheses has been described by J. Mu]zer et al. in ]. Org.

Chem. 2000,65,7456-7467.

A-Component Fragment In the literature, in addition to the natural epothilones, a number of synthetic epothilone derivatives are described that vary for the most part within radicals M and T. In most cases, M CA 02455797 2004-01-27 stands for a heterocychc radical here. Most syntheses of the natural epothilones and the synthetic epothilone dérivative use the A-component fragment, which represent carbon atoms C5-CI0 in the macrolide. Within this component A (see below), CI is the C5 in the macrolide and C6 is the Ci0 in the macro|ide, etc.

T,v v,v !v:v,L..T In this connection, T stands for a CI-C4 alkyl or alkenyl radical, and Sgl and Sg2 stand for the protective groups that are famíliar to one skilled in the art, such as, e.g., the TBDMS group.

A possible production of the A-component is described in, for example, WO00/58254. A synthesis of ]3-keto esters, which cam be conversed into multistage sequences in component A, is disclosed thereto. The chiraIRy is introduced by an asymmetric hydrogenation ofa Ç-keto ester according to Noyorì:

)R In this connexion, the conversion of the ester group imo a ketone can only be done by meíìns of a multistage sequence. In this case, after a protecñon of the Iand 3-hydroxy group, the ester group (C-5 atom) is reduced to form alcohol, the oaidalion fo aldehyde is carried out, and the Crrignard addition of an alkyl radical with an alk'ylmagnesium or alkyllithium compound y,elds a secondary alcohol, hìch then is oxidized. To get from the ester to the ketone, a total of 8 steps are necessary. The direct reactìon ofím ester is not selective, since the intermediately produced product is further reacted, The following diagram shows the entire synthesis pathway:

CA 02455797 2004-01-27 o OH 0 $go oR RX B OR : SgO OH Se/l rn OR o $gO H MEMO! - Ozi do.

OR 0 R SgO B se A method for creating component A is descñbed by B. Paniker et al. in Tetrahedron 2000, 56, "/8-59-7868. If is described There that the aldol reaction with a chiral component yields a less selective reaction. By the round-about way of an N-methylthioacelyl-oxazolidinone, the symhesís of the chiral C3 atom in a multístage sequence with improved diastereoselectiviB' by means of boron enolate is d scríbed. To achieve usable dias e os¢lectivities, a me hyhhio subs im íon ís necessary; the thio ether is cleaved off aller the aldol reaction.

Further, a sequence can be found in the prior art (R. E. Taylor, Y. Chen, Org. Left, (2001), 3(14), 2221-2224) in which a phenyl ester is used for file Crdgnafd reaction. The yield that is achieved in this case is ind,cated with 77%, In the example that is described by A.

Fürsmer in Chem. Comm. 2001, I057-1059, a 67% yield is achieved. These yields of the Griffure reaction from the prior art are significantly less thon l.hose of this invention.

In J. Org. Chem, 2000, 65, 7456-7467, an asymmetrical symhesis ofa Ç-keto ester is further descñbed, whereby a variant in asymmetrical form is performed as an aldol reaction. In CA 02455797 2004-01-27 this method, D-Tsaline is used as a catalyst, which can be produced from the expensive amino acid D-valine. This method yields an ce-value of 90%. Another example m this regard is described by R. E. Taylor, Y. Chert, Org. Lett. (2001), 3(14), 2221-2224 as an asymmetrical a]dol reaction, in which the yield is 71%.

Another method for the production of a double TBDMS-protected A-component-ethyl ketone is finally described by Nicolaou in Chem. Ear. J. 2000, 6, 2783-2800.

This invention contains the object of being able to produce a universally usable starting intermediate compound of general formula 1 as well as the optically pure antipodes of general formulas In, lb, (I) (la) {lu) in which R1, R2 can be the same or different and, independently of one another, stand for an alcohol protective group 1bat is familiar o one skilled in the art, for example, benzyl,4merhoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, alkyl, or mtyl, or, in the case when R1 and R2 are bridged, stand for a metal protective group, such as, e,g., CA 02455797 2004-01-27 U1,U2 : ALOI, Pnenyl, JmWI U " 14 AI!{YI to produce #,-component fragments for epothilone total syntheses.

To this end, compounds of general formula I re reacted as described below:

M,,U Z o D O) AI( U-CH -T A The reactions of lhe compounds of general formula I, as well as their antipodes la, lb to form ketone AK are carried out with methyllithium or methyl-Grignard compounds according fo the standard process that is known to one skilled in the art; the aqueous vorking-up then yields the ketone. The subsequent alkylation with an alkyl or alkenyl-halide of formula T-Hal CA 02455797 2004-01-27 (Hal = CI, Be, 1 or tosylate, mesylate, tñflate, etc.) with the addition of a base yields the Acomponent fragments.

A can also be directly obtained, however, by the amides of general formula I beìng reacted directly with organometallic compounds, such as, e.g., the lithium compound/i-CH2-T, and then being worked up in aqueous form.

As a rule, the above-descñbed reactions run smoothly and produce the A-components in high yields.

There was therefore a need for an industrial-scale process that allows it to prepare a universally usable intermediate compound for the production of the A-comportent in the epothilone total synthesis.

In addiñon to the high yields Lu the conversion into the A-comporteras, the relatively easy accessibility of the compounds of general formula I from relatively inexpensive starting materials can be emphasized. Moreover, the compounds according to the invention are stable in storage in contrast to the esters and ketones that are known in the literature and can be reacted as needed during a contìnuous synthesis campaign. For the most part, the compounds of general formula I are crystalline solids and can be purified by crystallization. In this way, high chemical and opUcal yields (e.e. > 98%) can be achieved.

The object of the invention is achieved by the preparation of the new compounds of general formulas 1, la, Ib (I) 0a) (lb) CA 02455797 2004-01-27 in which R1, R2 can be the same or different, and, independently of one another, stand for an alcohol protective group, such as, e.g., benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, THP, TBDMS, TMS, TES, TIP, TBDPS, MEM, MOM, alkyl, or udtyl, or in the case when R1 and P.2 are bridged, stand for a metal protective group, such as, OEogo " "" ./ t\ Ul,UZ: Mlky|, Pn n tert u l For the production of the compounds according to the invention, a total of 4 variants can be indicated:

Variant I (General Access via Aldol Reaexions) a) In zhe case where R1 and R2 stand for a metal protective group, orR1 = R2, compounds of general formula I can be produced from compounds of formula II, 2,2-dimethyl3,5-dihyàroxy-valero-niIrile )H according fo the methods for protective group chemistry that are known to one skilled in the art; CA 02455797 2004-01-27 thus, for example, their production and cleavage are described by P..L Kocienskí in "Protecting Groups," Grorg Thieve Verlag Smtlgan, New York, 1994, as well as in Houben Weyl, 4th Edition, Volume VI/Ib, p. 737, Thieve Stuttgart 1984.

b) In the case that Rl and R2 do not represent any keta|-protective group but nevertheless can be the same or different, the production of the compounds of general formula I can be carried out directly from the compounds of general formula III, by projective group R.2 being introduced according to methods that are known in the literature.

Compounds of general formula II can be produced from compounds of general formula III {lit) in which R1 stands for a prot¢cnve group in the above-indicated meaning, by cleavage of protective group R1 according to the process, known to one skilled in the art, of the protective group cleavage of alcohols (P. J. Kocienski in "Protecting Groups,» Georg Thieve Verlag Stuttgart, New York 1994/Houben Weyl, 4th Edition Volume VUlb p. 737, Thieve Stuttgart 1984).

Compounds of general formula Ill can be produced from compounds of general fomatfla Iv (IV by reaction with the compound of formula V, 2-methylpropionitrile, CA 02455797 2004-01-27 in which R 1 is in the above-indicated meaning, in a way that is known to one skilled in the art by the techniques of the aldol condensation, The production of compounds of general formula IV are known to one skilled in he an, however:

R1 = THP in JOC, 1984, 49, 2301-2309 F.1 = benzyl in J. Chem. Soc. Perk, Trams 1, 2000, 2429-2454, RI = TBDMS in JOC, 2000, 65, 7456-7467.

The compound of formula V, 2-methylpmpionirrile, is a commercially available product.

Variant I1 (Production of Optically Active Intermediate Products of General Formula la) For the production of optically active compounds of general formula la {la) The procedure is analogous to that described under Variant i. Starting from the optically active intermediate stage of general formulas IIa and lIIa {,a) compounds of general formula la are produced.

Compounds of general formula lla are produced analogously from the optically active CA 02455797 2004-01-27 lo precursors of general formula Ia (llla} Optically active compounds of genera! formula Hla are accessible as follows:

i. Separation of the racemic compound of general formula III in the chiral phase (Lk.: G. Rousse|, P. Pires, Chìrabase, Pure and Applied Chemical, 1993, 65, 235-244), pñmañly by SMB technique: A. Seidel-Morgenstem et al., Chromat.

A. 1998, 827/2, 175-191.

2. By starting from the ra=emic alcohol of general formula III, esters of general formula VI O NI} in which R3 stands for a CI-C6 alkyl group or an alkyl, phenyl or benzyl group, are produced according to the process ofesterification tha! is known fo one skilled in the an.

And the latter is saponified enantiose]ec ively by en2ymíttic or microbiological methods.

The alcohol that is produced is clearly distinguished in ifs P,f value from the ester that is used so tha r.he two can easily be separated from another, e.g., by column chromatography.

3. By aldol condensation thí, is mediated with chìral catalysts, by compounds of general formulas IV and V being reacted wíth use of a catalytic or stoichiometñc amount of a chiral a|dol catalyst:

chiral catalyst or) (.iæ CA 02455797 2004-01-27 Il Literature: Sec, OE.g., J, Org. Chem. 2000, 65, 7456-7467 4. By a chiral reduction of the ketone of general formula VII O (ri0 being performed according to methods that arc known to one skilled in the art. Lit.: Noyori et al., 1. Am. Chem. Soc. 1987, 109, 5850; Noyoñ et al., 1. Am. Chem. Soc. 19ge, 110, 629, R. C.

La, rock in "Comprehensive Organic Transformations," VCH Publishers New York 1989, ISBN 0-g9573-710-8, pages 540-548.

Compounds of general formula VII, with R1 in the above-indicated meaning, can be obtained by reaction of the compound of tbrmula V with compotmds of general formula VIII v (VIII) in which Nu stands for a leaving group, such as CI, Bi, imidazole, -OPh, -O-C6H4NO2, -O-C1C4 alkyl, etc.

The reaction is caned out in a way that is basically known to one skilled m the art.

The production of compounds of general formula VIii is described in the literature. L Med. Chem. 1999, 706-721.

ha some cases, it has proven advantageous when compounds of general formula Vil are.

produced by oxidation from the racemic alcohols of general formula II according to the methods of oxidation that are known fo one skilled in thee art (e.g., Swern oxidation, PDC, PCC, etc.).

In some cases, it has proven advantageous when a compound of formula V is reacted with propiŒElactone to form a compound of IX:

CA 02455797 2004-01-27 (m3 The compound of formula IX can be convened very easily into compounds of general formula VIl by introducing protective groups according to the methods zhat are known to one skilled in the an (sec: P. J. Kocienski in "Pro ecrmg Groups," Gcorg Thieve Vcrlag Stuttgart, New York 1994, as well as m Houben Weyl, 4th Edition, Volume Vl/ib, p. 737, Thieme Bogart 1984).

Starting from compounds of formula IX, however, a compound of formula Ila OH OH (Ua) can be obtained by the keto group being reduced chirally with chemical or microbiological methods (e.g., according to: JOC19gS, 50, 127/J. Chem. Soc., Chem. Commun. 1987, 1368).

Variant III Compounds of general formula Ia (m) can also be produced by introducing protective groups according to methods that are known in CA 02455797 2004-01-27 the literature for introducing alcohol projective groups ri'oto the compounds of general formula X (x} (ser literature c ited abo ve for introducing protea ri ve group s).

Compounds of general forrn la X can be produced from compounds of general formula XI {xI) in which R4 stands tbr a methyl, ethyl or ben2yI group, by ester reduction according to methods that are known to one skilled in the an.

Compounds of general formula XI can be produced from compounds of general formula XII oR, OH (x,} in which R4 stands for a CI-C6 alk-'yl, methyl, ethyl, ten-butyl, phenyl or benzyl group, by introducing protective group R2 according to methods that are known to one skilled in the art (see above).

Compounds of general formula XII can be obtained from 13-ketoesters of general formula X.III CA 02455797 2004-01-27 (Xlll) by methods of chiral reduction (chemical or enzymatic).

Compounds of general formula XIII are obtained by reaction of compounds of general formula XIV with a compound of formula V (xtv iv} Compounds of general formula XIV are known in the literature or can also be obtained from the reaction of compounds of general formulas Xiii and XllIb.

{raltn) (Xlilb) ()al» Here, Nu is in the meaning of the leaving group that is already mentioned above, and Q stands for a hydrogen atom or a COOH group, lfQ is a hydrogen atom, Xiii is deprotonated with an organic base, such as, e.g., LDA and then is reacted with the activated acid derivative according m the method that is familiar to one skilled in the art.

In the case of Q being equal fo COOH, the procedure is performed with the methods of the masonic acid-semi-ester condensation, as descñbed in, e.g., J. Ara. Chem. Soc. 1999, 121, CA 02455797 2004-01-27 7050-7062, Synch. Commun. 1997, 27, 3227-3234, Compounds of general formula Xiii arc commercially available (e.g., Aldrich).

Compounds of general formula XJIIb are produced as described in g. C. Laroek in "Comprehensive Organic Transformations," VCH PublishersNew York 1989o ISBN 0-895737 0-8, pages 963-964.

in some cases, if has proven advantageous to run the diols of general formula lla ON t.

OH (lin) directly from the compounds of general formula XII OH (x.) by reduction of the ester group according to the above-mentioned process.

The product,on of racemic diol of general formula II can also use as starting compounds -keto esters of general formula X.III ix111) according to the commonly used methods for reduction of esters and ketones, Variant IV In some cases, for the production of optically acriv¢ diols of general formula IIa, it has proven advantageous to undertake a chromatographic separation or crystallization of the CA 02455797 2004-01-27 diast eomeñc k¢tals of general formulas X/Va and XIVb L :

(XlVa) (XIVb) in wh,ch A is taken for the radical of an optically active ketone, such as, e.g., (-) menthone, (-) camphor, etc., and then the kraal group is cleaved off according to be methods of protective group chemistry tha are known fo one skilled in the ar The production of diastcreomeñc 1,3 diol-ketals of general formulas XIVa and XIVb is carried out from the race, c diol of general formula Il by reaction with chiral ketones according to processes that are known iu zhe líteraturc. LIE.: T. Hafada cE al., I. Org. Chem. 1992, 57, 1412-1421.

Of course, the corresponding enamiorncr compounds of general formula lb L can also be produced with use of mirror-image catalysts or o hrr enzyme systems.

There is also the possibility of obtaining the corresponding enantiom rs in intermediate stages of general formula IHb OH .CN (lllb] CA 02455797 2004-01-27 by inversion of the hydroxyl group according to Mitsunobu (Lit.: Synthesis 1981, 1-28).

Ofproteeñve groups R1 and R2 that are used in the synthesis, the benzyl group and the TBDMS group are preferred, in the case that RI, R2 stands for a metal proteeñve group, especially -(C{CH3)2}- is preferred.

Of the different production variants here, the following partial sequences are especially preferred for the creation of chiral precursors:

l. Production of the compound of general formula VII from the intermediate stages of general formulas V and VIII R1 - benzyl, Nu = CI CN '0 €1 o o Production of the compound of general formula XIII from compounds of general formulas V and XIV R4 = ethyl, Nu = C1 O EIO CA 02455797 2004-01-27 Production of the compounds of general formula Vil by aldol condensation and subsequent oxidation Rl = benzyl, Nu = CI o H OH Oxidation 4. Production of the compounds of general formula IX (with Y = dimethylamino) 2.

1. IDA HO CA 02455797 2004-01-27 For the production of chiral precursors, especially the partial steps that are indicated below arc preferred:

I. Ch1 fal aldol condensation with a chiral ¢ata|ysl N GN 2. Enandoselecdve saponification of an acetate with the aid of an enzyme O enaatios¢lective enzymatic saponification 4chromatographic separation CA 02455797 2004-01-27 3. Chiral reduction of a 13-ketortitrile (Noyoñ type) S-Binap RuCIz OH %0" t" íCN 4. Chiral reduction of the l -keto ester with subsequent reduction O elation Reduction The production of the compounds according m the invention is carried out preferably in the sequences that re described below:

1, Production of acetone ketals OH O/ CN -- - C víl e °fR1 I (í / CN Rl = benzyl => hydrogenation R1 = THP => acidic cleavage R1 = TBDMS => TBAF • .r P7$ 2,- ----- CA 02455797 2004-01-27 2. Production of the Di-TBDMS-pro$ ¢rcd compound TBDM$D T DMSCI / DMF / Imìoaz l » TSDMSO CN TBDMSCI/DMF/imidazoI= The production of the compounds and processes according to the invention is to be explained in more detail in lhe embodiments below.

CA 02455797 2004-01-27 Example l:

Example la 5-B enzyloxy-2o2-díme hyl-3(R,S)-hydroxy-pentane-nitlile S.47 g (79.17 retool) of isobutyric acid nitrile is added in drops at -65°C to an LDA soluñon (produced from 33.64 g (79.17 retool) ofn-butyllithium 15% in hexane, (1,6 M) and g0. ] g (79.17 retool) ofdiisopropylamine), and it is stirred for 20 minutes ai -65°C. Then, a solution that consists of 10 g (60.9 re.mol) of 3-benzyloxy-1-propanaldehyde in 20 mi of THF is added in drops (over 60 minutes). The temperature is kept at -65°C1 Then, it is stirred for one more hour. It is now heated to -20°C, a solution that consists of 20% sulfuric acid is added in drops, and the temperature is allowed to reach +IO°C. Then, 50 ml ofMTB ether is added, and then the organic phase is separated. The organic phase is washed with water and then with saturated sodium bicarbonate. Finally, it is washed once more with water and then evaporated to the dry state in a vacuum.

Yield: 13,1 g (92% of theory) of a colorless oil.

Elernrma alysis:

C H N Cld. 72.07 8.21 6,00 Fnd. 72.34 g.43 5.85 ,,...;: y .. ,, , _ . = .....

Example lb 5-Benzyloxy-2,2-dimethyl-3 (R,S)-acetoxy-pentane-nirñle 14.56g (42.64 retool) of acetic acid anhydride is added at 0°C to a solution that consists of 25.6 g (109.7 retool) of 5-bermyloxy-2,2-dimethyl-3-hydroxy-pentane-nitrile of the title compound of Example la, 14.43 g (142.64 retool) of triethylamine and 200 mg of 4dimcthylaminopyridin¢ (DMAP), dissolved in 12g ml of MTB ether, and it is stirred for S hours at room temperature. The reaction mixture is poured into 2 1 of ice water and extracted twice CA 02455797 2004-01-27 with 300 ml each of MTB ether. The combined MTB phases are washed once Raith 300 ml of 5% hydrochloric acid and then with water. It is evaporated to the dry state in a vacuum.

Yield: 28.82 g (95% of theory) of a colorless oil.

Elementary analysis:

,. .... r" , 'I| • Cld.

Fnd.

,t ,. t, . , C H N 69,79 7.69 5.09 69.51 8,01 4.83 Example Ic 5-Benzyloxy-2,2-d methyl-3 (S)-hydroxy-pentane-nirrile g (36.31 retool) of 5-benzyloxy-2,2-dim¢thyl-3(R,S)-acetoxy-pentane-nilxile of the title compound of Example I b is added to a buffer solution, produced from 0.88 g of potassium dihydrogen phosphate and 1.82 g ofdisodium hydrogen phosphate in 250 mi of water. Then, 5 g ofhhe enzyme lipase AYS "A¢aano" (related to Amano) is added, and it is stirred for 24 hours at 40°C. The pli is brought fo 7 by adding 2.0õ2 g of disodium hydrogen phosphate, and then stirring is continued under HPLC monitoring a; intervals of 12 hours until The peak oflhe Racetate is smaller than I% of surface area. Working-up: If is extracted 2 times with 200 ml of ethyl acetate. The organic phases are combìned and evaporated to the dry state in a vacuum.

The purification is carried out by chromatography on silica ge] (hexane/ethyl acetate gradient).

4.2 g (45% of theory) of 5-benzy]oxy-2,2-dimethy]-3(R)-hydroxy-pentane-ninåle is obtained with the 1'+ fraction, and 4.8 g (4g% of theory) of 5-benzyloxy-2,2-dimethyl-3(s)-acetoxypentane-nitrile is obtained with the 20 fraction.

4.g g (17.5 retool) of 5-benzyloxy-2,2-dimethyl-3(S)-acetoxy-pentane-nitrile from the 2"d fraction is dissolved in 50 ml of methanol and mixed with 1.4 g (35 retool) of NaOH. It is stirred for 3 hours at 25°C, added to 200 ml of water, extracted with 2 x 200 ml of MTB ether, dried on sodium sulfate and concentrated by evaporation.

CA 02455797 2004-01-27 Yield: 4 g (47% of theory) of 5-be.zyloxy-2,2-dimethyl-3(S)-hydmxy-penmne-nimile as a colorless off.

Elementary analysis:

c H Cld. 72.07 8.21 Fnd. 71.85 8.41 N 6.00 5.g7 Example d 5-Hyàroxy-2,2-dimethyl-3(S)-hydroxy-pentane'nitrile 16 g of Pearlman's catalyst (Pd(OHh on carbon, 20%) is added to l 1.13 g (47.70 retool) of 5-benzyloxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile of the title compound of Example le, dissolved in 110 ml oftetrahydrofuran. It is now hydrogenated for 7.5 hours at 10 bar and at room temperature. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 6.73 g (98% of theory) of a colorless, viscous oil.

Elementary analysis:

C Cld. 58.72 Fnd. 58.64 H N 9.15 9.78 9.23 9,69 Example le 31S)-(3,5) Acetone dimethylketal-2,2-dimethyl-pentane-nirrile 6.73 g (47 retool) of 5-hydroxyl-2,2-dimethyl-3(S)-hydroxy-pentane-nirrile of the title compound of Example ld is dissolved in 27 ml of acetone dimethylketal, and 546 mg of CA 02455797 2004-01-27 camphor-lO-sulfonic acid ,s added. If is heated for 15 hours fo 50°C. It is evaporated fo the dry state in a vacuum. The residue is taken up in 200 ml ofmelhylene chloride and washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution. The organic phase is dríed on sodium sulfate and evaporated to the dry state in a vacuum. The oil that is obtained crystallizes while standing.

Yield: 5.55 g, (-/7% of theory) of colorless crystalline solid.

Elementary analysis - , c H N Cld. 65.54 9.35 7.64 Fnd. 65.38 9.29 7,58 Example 2 3(S)-3,5-Di-;er -buty ldimethylsilyloxy-2,2-dimethyl-pentane-nirrile 7.13 g (104.75 retool) of imidazo]e and 7.9 g (52.37 retool) of tert-b tyldimethylsilyl chloride are added to a solution that consists of 3 g (20.95 retool) of 5-hydroxy-2,2-dim¢thyl3(S)-hydroxy-penrane-nit¢iloe of the title compound of Example l d, in 20 ml of dim¢ hylformamid¢, and it is stirred for 16 hours at room temperature. The solution is poured into 200 ml of water and extracted twice with 50 ml each ofcycl'ohexane. The organic phases are combined and evaporated to the dry state in a vacuum. The residue is purified by flash chromatography on silica gel (hexane/MTB ether).

Yield: 7.39 g, (95% of theory) of a colorless, viscous oil.

CA 02455797 2004-01-27 Elemem .a analysis:

C H Old.

Fnd.

, ..... , ,,,. a 61.39 11.12 62.00 ] 1.30 N 3.77 3.80 Example 3 3(S)-3,5-Cyclohexanone-dimethylketal-2,2-dim¢thyl-pentane-nitrile I0 mg ofp-toluenesuifonic acid is added to a solution that consists of 3 g (20.95 retool) of 5-hydroxyl-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile of the title compound of Example 1 fin 30.21 g (0.2095 mol) ofcyclohexanone-dimethylketal, and it is stirred for 6 hours at lO0°C. The solution is poured into 200 ml of water and extracted twice with 50 ml each of ethyl acetate. The orgamc phases are combined and evaporated to the dry state in a vacuum. The rcsidae is purified by flash chromatography on silica gel (hexane/MTB ether).

Yield: 4.21 g (90% of theory) of a colorless, viscous oil.

El menW), : alySis:

Cld.

Fnd.

C H N 69.92 9.48 6.27 69.81 9.62 6.15 I =, I. , I i ii . , ] III I --..ç Example 4 3 (S)-3,5-Benzaldehyde-dimethylacetal-2,2-dimethyl-penmne-nitrile 31.9 g (0,2095 mol) of benzaldehyde-dimethylacetal and 50 mg of p-toluenesulfonic acid are added to a solution that consists of 3 g (20.95 retool) of 5-hydroxy-2,2-dimelthyl-3(S)- hydroxy-pentane-nitrile of the title compound of Example 1 f, in 20 ml of dimethylformamide, and it is stirred for 16 hot4rs at 100°C. The solution is poured into 200 ml of water and extracted CA 02455797 2004-01-27 twice with 50 ml each of ethyl acetate. The organic phases are combined and evaporated to the dry state in a vacuum. The residue is punfi¢d by flash chromatography on silica gel (hexane/IV[TB ether).

Yield: 4.26 g (88% of theory) of a colorless, viscous oil.

Elementary analysis! ..........

I C H N ] k Cld, 69.92 9.48 6.27 Fnd. 69.81 9.62 6,15 Example 3(S)-3,5-Diehlor diphenylsilane-2,2-dimethyl-penmn -nirrile 3.14 g ( }6.09 retool} ofimidazole and 5,83 g (23.05 retool) of diehlor liphenylsi]ane are added to a solution thal consists of 3 g (20.95 retool) of 5-hydroxy-2,2-dime hyl-3(S)-hydroxypentane-nitrile of the fille compound of Example If, in 20 ml of dimethylfonnamide, and it is stirred for 16 hours at room temperature. The solution is poured into 200 ml of water and extracted twice with 50 ml each ofmelhylrne chloride. The organic phases are combined and evaporated to the dry state in a vacuum. The residue is purified by flash chromatography on sihca gel (h¢xane/MTB ether).

Yield: 5.76 g (85% oflheory) of a colorless, viscous oil.

Elcmenta.r'y anal ms: .........

C H N i Cld. 70.55 6.54 4.33 Fnd. 70.41 6.71 4.25 CA 02455797 2004-01-27 Example óa 5-tert-Bu yldìmethylsilyl-2,2-dimethyl-3(R,S)-hydroxy-penmne-nimle 4.62 g (66.99 retool) of isobutyric acid nítrile is added in drops at -65°C to an LDA solution (produced from 28.6 g (66.99 retool) of n-butyllithium 15% (1.6 M) and 6.82 g, 66.99 retool, diisopropylamine}, and it is stirred for 20 minutes at -65"C. Then, a solution that consists of l 1.47 g (60.9 retool) of 5-tert-butyldimethylsilyl-l-propanaldehyde in 20 ml of THF is added in drops (over 60 minutes). The temperature is held at -65°C1 Then, il is sñrred for one more hour. Il is no v heated fo -20°C, and a solution of 130 ml of IN hydrochloric acid is added in drops, and the temperature is allowed to come to +10°C. Then, 50 ml of MTB ether is added, and then the organic phase is separated. The organic phase is washed with water and then satmated sodium bicarbonate solution. Finally, it is washed once more with water and then evaporated to the dry state ìn a vacuum.

Yield: 13.65 g (87% of theory) Elemem. aaa! ,SiS! .....

Cld.

Fnd.

c 60.65 60.48 H 10.57 10.65 N 5.44 5.37 Example 6b 5-Hydroxyl-2,2-dimethyl-3(R,S)-hydroxy-pentane-nitñle 12.18 g (46,61 retool) of tel,,-abutylammonium fluoride hydrate is added to a solution that consists of 3 g (l 1.65 retool) of 5-tert-butyldimethylsilyl-2,2+dimethyl-3(R,S)-hydroxy-penmnenitrile of the title compound of Example 6a, dissolved in 40 ml of terrahydrofuran, and it is stirred for 16 hours at room temperature. Then, it is evaporated to the dry state in a vacuum.

The residue is purified by RP-18 chromatography (mobile solvent: acetonitrile/water gradient).

Yield: 1.41 g (g5% of theory) of a colorless, viscous oil.

CA 02455797 2004-01-27 Elem¢nmz-/ana.l sis:

C _ . | .....

Cld. 58.72 Fnd. 58.51 ........ ,q» ..

H 9.15 9.23 N 9.78 , n 9.64 Example 6c, (-)-Camphor keml 3(SY(3,5} Camphordimeth ylketal-2,2-dimethyl-pentane-nitrile 6.73 g (47 mmol of 5-hydroxyl-2,2-dimelhy[-3(R,S)-hydroxy-penmne-nitrile of the title compound of Example ób is dissolved in 27 ml of methylene chloride with 93 g of (I S)-(-)- camphor keml (produced from (I S)-[-)-camphor, methanol and p-toluenesulfonic acid), and 546 mg of camphor-10-sulfonic acid is added. If is refluxed for 15 hours. The hatch ìs diluted in 200 ml of methylene chloride and washed with saturated sodium bicarbonate solution, then with saturamd sodium chloride solution. The organic phase is dried on sodium su|rate and evaporated to the dry state in a vacuum. The residue is purified, chromatographed in a chiral phase (mobile solvent: acetonirri]e/waler gradient). The off that is obtained crystallizes while standing.

Yield: I0 g, (77% of theory) of a colorless, crystalline solid.

Elememar[ analysis:

C H N Cld. 73.61 9.81 5.05 . , m Fad. 73.40 9.79 5.00 Example 6d 5-Hydroxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitrile Cleavage of the camphor ketal 13 g (47 retool) of 3(S)-(3,5) camphordimethylketal-2,2-dimethyl-pentane-nitrile of the CA 02455797 2004-01-27 compound of Example 6c is dissolved m 40 ml of errahydrofuran, 12.18 g (46.61 mmol) of erraburylammonium fluoride hydrate is added, and it is stirred tbr 16 hours at room temperature, then i is evaporated o the dry state in a vacuum. The residue is purified by RP-I 8 chromamÆ4phy (mobile solves: acetonitrile/water gradiem).

Yield: 5.72 g (85% of theory) of a colorless, viscous oil.

Elementary analysis:

C H Cld. 58.72 9.15 Fnd. 58.60 9,00 ,,ç , , N ......... L1 9-78 • 960, j Example 7 5-Benzyloxy-2,2-dìmethyl-3(S)-hydroxy-pemane-nitrile and 5-Benzyloxy-2,2-dimethyl-3(R)-hydroxy-pentane-nitrile The title compound of Example la, 5-ben.zyloxy-2,2-dimethyl-3(R,S)-hydroxy-pemaneni ñle, is chromatographed in a chiral phase (I0 g on Chiralpak AD 20 ldeluam: hexímelethano[ 98:2, wavelength: 20g nm)_ The following are obtained:

R-Isomer, yield3.g g (38% of theory) of a colorless, viscous oil.

Elementaœe analysis:

Cld.

Fnd.

C H N 58.72 9.15 9.78 58.59 9.31 9,7l S-Isomer, yield: 4.1 g (41% of theory) of a colorless, viscous oil.

CA 02455797 2004-01-27 3! Elementary analysis" C Cld. 58.72 ........... i H N 9.15 9.7g Fnd. 58.61 9.27 _. , . , , _ 9.69 Example Sa 5_tert-Buryldimethylsilyl-2,2-dimethyl-3 (K,S)acetoxy-pentane-nitrile 14.43 g 042-64 retool) of uåethylamine and 200 mg of 4-dirnethylaminopyñdine (DMAP), dissolved in 128 ml of MTB ether, and, at 0°C, 14.56 g (142.64 retool) of acetic acid anhydride are added to 28.24 g (109.7 retool) of 5-tert-butyldimethylsilyl-2,2-dimethyl-3(tLS)- hydroxy-pentarte-nitrile, the title compound ofExample 6a, and it is stirred for 5 hours at room temperature. It is poured into 2 1 of ice water and extracted twice with 300 m! each of MTB ether. The combined MTB phases are washed once with 300 ml of 5% hydrochloñc acid and then with water, h is evaporated to the dry state in a vacuum. The residue is purified by flash chromatography on silica gel (hexane/MTB ether).

Yield: 31,21 g (95% of theory) of a colorless oil.

Elementary analysis:

C Cld. 60.16 Fnd. 60.02 H 9.76 9.85 N 4.68 4.59 Example 8b 5-tert-Butyldimethylsilyl-2,2-dimethyl-3(S)hydroxy-pentane-nitrile g (33.39 retool) of 5-tert-buryldimethylsilyl-2,2-dimethyl-3(P-.,S)-acetoxy-pentanenit'rile of the title compound of Example ça is added to a buffer solution, produced from 0.88 g CA 02455797 2004-01-27 of potassium dihydrogen phosphate and 1.82 g of disodium hydrogen phosphate in 250 ml of waler. Then, 5 g of the enzyme lipase AYS "Amano" {related m Amåno) is added, and if is stirred for 42,5 hoars ai room temperature. The pli is brought to 7 by adding 2.062 g of sodium hydrogen phosphate, and then stirring is continued for 44.5 hours. Working-up: If is extracted 3 times with 200 ml of ethyl acetate. The organic phases are combined and evaporated to the dry state in a vacuum. The purification is carded out by chromatography on silica gel (hexane/ethyl acrtasr gradient), 3.8 g (45%) of 5-ten-buryldimethylsilyl-2,2-dimethyl-3(R)-hydroxy-pemane-nitrile and 4.8 g (4g%) of 5-terFbutyldìmethylsilyl-2,2-dimethyl-3(S}-aceIoxy-prntane-nitrile are obtained.

4.8 g (I 6 mmo[) of 5-terFb tryldimethylsilyl-2,2-dimethyl.3(S)-acetoxy-pentane-nitrile is dissolved in 50 ml of ethanol and mixed with 1.28 g of NaOH (32 retool). Il is s n'ed for 3 hours ai 25°C, added to 200 ml of water, extracted with 2 x 200 ml of MTB ether, dried on sodium sulfate and concentrated by evaporation.

Yield: 3.43 g (40% of theory) Elementary analysis!` '1 12 Cld. 60.65 Fnd. 60.54 H 1o.57 .- . a. . =, , 10.64 N 5.44 5.37 Example 8c 3(S)-3,5-Di-ten-butyldimethylsilyloxy-2,2-dimelhyl-pentane-nitrile 2.37 g (34.95 retool) ofimidazole and 2.63 g (17.47 mol) of tert-butyldimethylsilyl chloride are added to a solution that consists of 3 g {11.65 retool) of 5-tert-butyldimethylsilyl2,2-dimethyl-3(S)-hydroxy-penm,ne-nitrile of the title compound of Example 8b, dissolved in mi of dimethylformamide, and it is stirred tbr 16 hours at room temperature, The solution is poured into 100 ml of water and extracted twice with 50 ml each of MTB ether. The organic CA 02455797 2004-01-27 phases axe combined and evaporated to the dry state in a vacuum. The residue is purified by flash chromatography on silica gel (hex ne/MTB ether), Yield: 4. l I g (95% of theory) of a colorless, viscous oil.

Elementary analysis: ....................

C H Cld. 61.39 II.12 Fnd. 61.3 ] 11.25 . - ,,1, t ....

N 3.77 3.64 Example 9 5-Hyàroxy-2,2-dimethyl-3(S)-hydroxy-pentane-nitñle 12. I 8 g (46.61 retool) of tetrabu lammonium fluoride hyd,,'ate is added to a solution lhat consists of 3 g (I 1.65 retool) of 5-tert-buryldimethylsilyl-2,2-dimethyl-3(S)hydroxy-pentaneni(file of the title compound of Example 8b, dissolved in 40 ml ofte rahydrofuran, and k is stirred for 16 hours al room temperature. Then, if is evaporated to the dry state in a vacuum.

The residue is purified by RP-18 chromatography (mobile solvent: acetonitrile/water gradient).

Yield: 1.41 g (85% of theory) of a colorless, viscous oil.

£lemenlarYana!!, s!s:

Cld.

Fnd.

i C H N 58.72 9,15 9.78 58.61 9.23 9.69 , . j.

Example 10a 5-Benzyloxy-2,2-dimethyl-3-keto-penmne-nitrile 5.47 g (79.17 retool) of isobutyric acid nitrile is added in drops at -65°C to an LDA solution (produced from 33.64 g (79.17 rnmol) of n-butyllithium (15%, 1.6M) and 80,1 g (79.17 CA 02455797 2004-01-27 retool) of diisopropylamine), and it is stirred for 20 minutes at -65°C. Then, a solution that consists of 14.29 g (71.97 retool) of 3-benzyloxy-l-propionic acid chloride in 20 ml of THF is added in drops (60 minutes). The temperature is held al -65°C! Then, stirring is continued for one hour. If is heated to -20°C, and a solution that consists of 20% sulfuric acid is added in drops, and the temperature is allowed to reach +10°C. Thela, 50 ml of MTB ether is added, and then the organic phase is separated. The organic phase is washed with water and then with saturated sodium bicarbonate solution. Finally, it is washed once more with water and then evaporated to the dry state in a vacuum. The residue is puñfied by flash chromatography on silica gel (hexane/MTB ether).

Yield: 14.15 g (85% of theory) of a colorless, viscous oil.

fìlemeatar Cld.

Fnd.

analysis: .........

t.

C H N O [1 72.70 7.ql 6.06 13.83 t . .,, 72.54 7.58 5.87 Example 10b 5-Hydroxyl-2,2-dimezhyl-3-keto-pentane-nitñle 3 g of Peadman's catalyst (Pd(OH)2 on carbon, 20%) is added to 10 g (43.23 retool) of Sbenzyloxy-2,2-dimethyl-3-keto-pentane-nilrile of the title compound of Example 10a, dissolved in 100 ml of methanoL It is now hydrogenated for 7.5 hours at 10 bar and at room temperature.

Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 5.98 g (98% of theory) of a colorless, viscous oil.

CA 02455797 2004-01-27 Elementary analysis:

C H N CId. 59.56 7.85 9.92 Fnd. 59.47 7.94 9.85 Example lOc 3(S),5-Dihydroxy-2,2-dimethyl-pentane-nitrile g (35.41 mmol) of 5-hydroxyl-2,2-dimethyl-3-k¢to-pentan¢-nirrile of the title compound of Example 10b is hydrogenated wifla a catalyst (produced from 233 mg of RuCb.(Phh and 626 mg of R-BINAP according to 1L Selkè, Angew. Chem. [Applied Chem.] 1998, 110, pp. 19271930) (at 40°C and 100 bar). Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.

Yield: 4.96 g (98% of theory} of a colorless, viscous oil.

Elementary_ analysis:

_. _ ........ ., C H N Cld. 58.72 9.15 9.78 Fnd. 58.65 9.26 9.71 . o. . .............

Example 11 S-3-(2,2-Dimethyl-[1,3]dioxan-4-yl)-3-methyl-butan-2-one 35.6 ml of methyllithium-lithium bromide complex (1.5 M in diethyl ether) is added in drops at -20"C to 3.26 g (17.79 retool) of the title compound of Example le, 3(S)-(3,5)-acetone dimethylketal-2,2-dimethyl-penmn¢-nirrile, dissolved in 5 ml of diethyl ether. Then, it is stirred for 30 minutes at -20°C and then heated to room temperature. It is stirred overnight at room temperature. 10 ml of saturated ammonium chloride solution is added, and it is stirred for 6 ....... , - , .... ,_.

CA 02455797 2004-01-27 hours at room Icmpcrature. Thr organic phase ,s separated and washed twice with water. The organic phase is evaporated to ,he dry state in a vacuum. The purification is carded out by chromatography on silica gel (hexanc/ethyl acetate gradient).

Yield: 2.77 g (78% of theory) of an oil.

Elementary analysis: , C Cld. 65.97 Fad. 65.84 H 10.07 10.19 Example 12 SI 1,3-Bis-(tcn-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentan-5-one 40.35 ml of lithium methylate (i M solution in THF) is added in drops ai -20°C to 5 g (l 3.45 retool) of the title compound of Example 2, 3(S)-3,5-di-tert-butyldimrthy]si]yloxy-2,2dim lhyl-pentane-nitrile, dissolved in 5 ml of diethyl ether. Then, it is stirred for 30 minutes at -20°C, and thon heated fo room.temperature. If is stirred overnight at room temperature. I0 ml of saturated ammonium chloride solution is added, and it is stin'cd for 6 hours at room temperature. The organic phase is separated and washed twice with water. The organic phase is evaporated to the dry state in a vacuum. The purification is carried out by chromatography on silica gel (h¢xane/ethyl acetate gradient).

Yield: 4.06 g (75% of theory) of an oil E!ementary analysis: .. .............

C C]d. 62.63 Fnd. 62.51 H 11.51 11.64 .... J . .. . .....

CA 02455797 2004-01-27 Example 13 S-2-(2,2-Di methyl- [ 1,3 ] di oxan-4-yl )-2 -methyl -heptan-3-one 34 ml of n-buryllír.hium, 15% (1.6 M in hexane) is added in drops at -65°C 3.26 g (17.79 retool) of the tide compound of Example I¢, 3(S)-(3,5)-acetone dimelhylketal-2,2dimethyl-pentane-nitrfle, dissolved in 5 ml of THF. Then, il is stirred for rive hours at -65°C, and then it is heated to room temperanare. If is stirred overnight at room temperature, fo ml of saturated ammonium chloride solution is added, and il is stirred fbr 6 hours a room lemper'amre.

The organic phase is separated and washed twice with water. The organic phase is evaporated to the dry state in a vacuum. The purification is carried oul by chromatography on silica gel (hexane/elhyl aceŒEte gradient).

Yield: 4,13 g (96% oftheoD,) ofím oil Elementary analysis:

_. |l ....... ,,,, _.

C Cld. 69.38 A Fnd. 69.27 l _ ,\ H 10.81 10.96 Example 14 (4S)-4-(2-Methyl-3-oxo-hepI-6-en-2-yl)-2,2-dìmethyl-(1,3)dio íme ml of 3-bulenyllithium solution (produced from 4-promo-I-butenes and lithium wire of tert-butyllithium, according to ]. Org. Chem., Vol. 56, No. 21, pp. 6094-6103 (1991) or J.

Chem. Soc. Perkin Trains, I, pp. 2937 (1988)) is added in drops ai -90°C to 3.26 g 417.79 retool) of the title compound of Example I e, 3(S)-(3,5)-acetone diraethylketal-2,2-d,methyl-penlanenilrile, dissolved in 5 ml of diethyl ether. Then, if is stirred for 17 hours ai -90°C and then heated to room temperature. R is snrred overnight at room temperature/br 17 hours. I0 ml of saturated ammonìum chloñde solution is added, and it is stirred for 6 hours al room temperature. The organic phase is separated and washed twice wi h water. The organic phase is evaporated to the ...... - , -. _ ,._ CA 02455797 2004-01-27 dry state in a vacuum. The purification is carried out by chromatography on silica gel (hexane/ethyl acetate gradient).

Yield: 2.74 g (70% of theory) of a colorless oil, Elemen, .ar analysis: .......

c H Cld. 69.96 10.06 Fad. 69.90 10.00 Abbreviatioas of the Ether Protective Groups That are Used:

TES = Triethylsilyl TMS = Trímethylsilyl TIP = Triisopropyl TBDPS = tert-Buty[-dimethylsi]y! ME M = Methyle hoxymethyl MOM - M thyloxymethyl THP = Tetrahydropymnyl-(ether) CA 02455797 2009-05-05 The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A compound of general formula I:

CN in which:

Ri, R2 are the same or different and, independently of one another, stand for an alcohol protective group, or, in the case when Ri and R2 are bridged, stand for a ketal protective group.

A compound of general formula la:

OR, ORz eN (la) in which:

R1, R2 are the same or different and, independently of one another, stand for an alcohol protective group, or, in the case when Ri and Rz are bridged, stand for a ketal protective group.

3. A compound of general formula Ib:

ç (lb)