PH26336A - Optically active-3-demethylmevalonic and derivatives and intermediates - Google Patents

Description

: ; : Lo vo ET

OF1ICALLY ACTIVE 3-DEMETHYLMEVALONIC

ACID DERIVATIVES, AND INTERMEDIATES

Derivatives of 3_demethylmevalonic : acid, such as, for example, mevinolin, are of great interest as inhibitors of 3-hydroxy-%-methylglutaryl-coenzyme A reductase (HIIG-CoA reductase). This enzymes catalyzes the formation of meve- lonic acid from 3-hydroxy-3-methylgluta- i ~ ryl-coenzyme A (HIC-CoA) and, as rate- determining enzyme, plays a central part : : . in the biosynthesis of cholesterol. Co

Hence derivatives of 3-demethylmevalonic are suitable for lowering high cholesterol - levels, which are associated with numerous : disorders (M.S. Brown, J.L. Goldstein, :

Science 232, 34 (1986)). Besides the natu- ral substance mevinolin there is a number of .. structurally simpler analogs (Drugs of the co

Future 12, 437 (1987)), which like mevinolin, - contain the demethyl-mevalonic acid structural . .. : moiety. These compounds are obtained by syntheshs. : The demethylmevalonic acid structural moiety =

Co Lo | _ 3 _ CL | ;

is a central element of the structure of these compounds, and there is a number of processes "for the s:nthesis thereof, as shown by the publications listed by way of example herein- : after: D. E. Lynch, R.P. Volante, R.V. Wattley,

I. “hinakai, Tetrahedron Lett. 28, 1385 (1987)),

T. Rosen, C. H. Heathcock, Tetrahedron 42, 4909 (1986). J.D. Prugh, C.S. Rooney, A.'A. Deans,

H. G. Remjit. J. Org. Chem. 51, 648 (1988), Y.

Guindon, C. Yoakim, M.A. Bernstein, H. E.

Horton, Tetrahedron Lett 26, 1185 (1985), M.

Sletzinger, T. R. Verhoeven, R.P. Volante, J. ~ M. McNamara, E.G. Corley, T.M. H. Liu, Tetra- hedron Lett. 25, 2951 (1985), J. D. Frugh, A. Deans,

Tetrahedron Lett. 23,281 (1982), Y.L. Yang, J.

R. Falck, Tetrahedron Lett. 23, 4705 (1982).

Depending on the process, the demethylmeva- lonic acid structural moiety is produced in two different but synthetically equivalent . forms: as 3,5-dbhydroxy carboxylic acid derivative I / -4 - : | . pe

LT | CEES cee : Sn wa eH wel aay i

Co : CE « . ‘ r 0 i. . , A n WL 26336

Co H OH H OH | Co EE . N \ ‘ oo 2 : Lo : : AI co : Co ~~ : or as p-hydroxy lactone II } )

H

HO BT =z 0 oo PE

S . .

Co ITOH

Co | N\ . . . R Co :

The two formulae I and II can be inter- yoo converted by known processes. Of pharmacologi- . "cal interest are the compounds- which have = ‘the sbsolute configurations indicated in the To formulae I and II. : SE oo The invention relates to a new process for : N the préparation of compounds having the deme- : : [a .

S55 ~ Co BR Co

Ie } : E . ) . . .

oo thylmevalonic acid structural moiety in the form of pure enantiomers of the formulae I and

II, in which Y is the -CH=CH- or ~CH,—CH- group, R is a radical of the formula ol

TN ro «

RS EE in which 7 denotes a radical of the formula -CH or a nitrogen atom, Rr, rt and Rr’ denote, independently of one another, hydrogen,a straight-chain or branched hydrocarbon radical which up to 6 ~ carton atoms and can optionally be substituted at the terminal carbon by Te a saturated or unsaturated cyclic hydro- carbon radical having 3 to 6 carbon . atoms, or denote a cyclic saturated or up to doubly unsaturated hydrocarbon radical having 3 to 7 carbon atoms, : ; “ra | - 6 -

. . Cn Ss an aromatic radical selected from oo the group comprising phenyl, furyl, theinyl and pyridinyl, which cen optionally carry oo in the nucleus 1 to 3 identical pr diffe- : rent substituents from the following oo groups: halogen, trifluoromethyl, alkyl or alkenyl, having up to 6 carbon atoms - in each case, hydroxyl, alkoxy having 41 to 6 carbon atoms, carboxyl, or carbael-. koxy having 1 to 6 carbon atoms in the alkoxy moiety, : or is a radical of the formula B . !

R® Le : NC A pd P , - in which Co h ..

A-B represents the -CH-CH- or -0=C- Co group - -

R® and R’, with R® and R/ being identical or different, represent a saturated or : unsaturated alkyl radical which has gp -

A 7 - :

to 20 carton atoms and can be subs- tituted by an alkoxy graup having 1 to 6 carbon atoms or the group 0 0 - ; - Rr’, where Rr denotes alkyl having 1 to 8 carbon atoms, or represent a cycloalkyl radical ha- ving 3 to 7 carbon atoms, a phenyl, thienyl, A : furyl or naphthyl radical, it being possible for the aromatic radicals to be substituted in the nucleus 1 to 3 times by halogen, alkyl or . alkoxy, having 1 to 6 carbon atoms in each case, cycloalkyl having 3 to 7 carbon atoms or the group 0 Nn 0 - I _ Rr | " : where Rr’ denotes alkyl having 1 to 8 carbon atoms, or a pyridinyl radical which can be substituted in the nucleus 1 to 2 times by alkyl having 4 to 4 carbon atcms, : ! ,

Ee - 8 -

SR

' ) Pe

RS rej resents a saturated or unsatu- rated alkyl radical having up to 8 Co oo carbon atoms, a benzyl radical . : which can be gubgtituted in the nucleus 1 to 3 times by halogen, alkoxy or alkyty having 1 to 4 carbon atoms in each case, a phenyl, thienyl, furyl -. or naphthyl radical, it being possible for the aromatic, radicals to be subs- tituted in the nucleus 1 to 3 times by hslogen, alkoxy or alkyl, having 1 to 4 carbon atoms in each case, or a oo } cycloakkyl radical having 3 to 7 carbon atoms, and ) :

R' is hydrogen, a metal cation or alkyl - Co having 1 to 8 carbon atoms. ' : Suitable groups R are proposed in German

Patent Application Nos. 37 22°807:2; “eorrespon- 8 ding to U.S. patent application Ser. No. 216,331 20 . (formula B)s and P 38 23 045.3, corresponding : to U.3. patent application Ser. No. 216,458 . : (formula Q , priority date: July 10,1987 Co [Patent Application No. P 37 22 808.07 . | J ’

Co | ~9-

To | ! Co oo : -

, filing date July 7, 1988).

Compared with the processes described, the process according to the invention represents a considerable simplication and shortening of the synthetic route.

A central intermediate for carrying out the process according to the invention is the compound of the formula III . } . } »

M- ITI wo » 1 ~~ ~~ COR in which IM is a protective group suitable . for 4,3-diols, such as, for examplé, the .

Hz0-C~CHy group, or a radical of the follo- wing formulae

AE , Co CL vl CTR NSERC Ee

Pel oo | CURRED edie poo Co EEE a . : : . | 26334 \ oo s CL { . : } : Cy ’ or . $ 3 H : , . : ) 0

Co and R denotes C,-Cg-alkyl, for example t-butyl, : ~ which can be converted into a very wide variety Co - . - ( .

Co > of derivatives of the formula I or II. . Co . The process according to the invention com- Co . P prises } (1) converting a diol ester of the formula. AER

H OH @ Cov o 0 . SE nt . ' : . 1 . . . . Lo . : | OR Co . ! . . , . 1 . * . a | - 11 - SE ~ | So \ " VS in which R denotes C, ~Cq-alkyl, by introduction of customary protective group by methods known per se into a compound of the formula VII which is protected on the primary alcohol group

H 0 VII

R20 p.& il ~~ Na

OR and in which R' denotes C,~Cg-alkyl and R° repre- . . ] sents a customary alcohol protective group, : (2) converting a resulting compound of the : formula VII, or the corresponding alcoholate thereof, by customary condensation with t-butyl acetate, or a suitable equivalent such as, for example, malonic ester, into a compound of the formula VIII . : H QH 0 0 2S PPR VIII oR’

. ' ' : . CT meas oe . i Co BU

E | Lo < Cy } . , 1 2 1 oo in which BR and R have the meanings indicated Ca for formula VII, ) . (3) reducing a resulting hydroxy keto ester CL )

VIII by methods known per se to the 1,3-diol

S ester of the formula IX > I OH H oH . 2 1 IX ‘ ! cA Ee R 2 . . i i 1 2 i I in which R' and R™ have the meanings indicated So for formula VII, : ‘ Co ( So (4) converting a resulting 1,3-diol ester : nN of the formula IX by introduction of a protective group suitable for 1,3-diols into a compound of } the formula X . Co , . Lp mrt ee ml . !

M Co Y, ' . ~~ :

Ho” po - xo \ 1 . tr : ~~ 2 in which M is a protective group suitable for

J oo 4a a - 13 - ! :

’ i f : 1 2 , 3 1,%3-diols, and R and RR" have the meanings indica- ted for formula VII, (5) converting a resulting compound of the i formula ‘X by customary methods with eliminatéon of the protective group rR into a compound of the : ? ! formula III ! i : 1 III

ANG . . i

HO H ’

Ho Ny co_R’ ~~ 2 : Lo i in which M is a protective group suitable for ! 1 1,%3-diols, and R denotes a C, ~Cgalkyl radi cal, (6) converting a resulting compound of the formula III into an olefin derivative of the formula XI \ ..

MH ’ og a XI : I co Rr

A rR” : J oo . - 1

PE v ‘ } : ’ Co (Y of formula I = CH = CH) and i CL Co ) ! . (7) hydrolyzing a resulting compound of the formula XI to give a compound of the formula I . 1 - . in which Y denotes the CH = CH group, and R . oo represemts a C ~Cg-alkyl radi cal , (8) where appropriate hydrogenating ‘a Co resulting compound of the formula I in which Y represents a Cli=CH group to give a compound of I the formula I in which Y is the CH,-CH, group, SA (9) where appropriate converting a rem lting . 1 ’ . compound into the acid (R = fl) or a salt (r' = metal cation), and (10) where appropriate converting a resal- ’ ting compound of the formula I into a compound co . - of the formuka II. iE nom ’ ve i

Where R denotes an alkyl radical having 1 to 8 carbon atoms, the alkyl radical is oo straight-chain or branched. ; oh ©

J

Co - 15 = : 2 p ) ! }

Ce oo

‘ . i ) .

The starting compounds of the formula VI are known or can be prepared by customary . methods. The preparation expediently starts : from L(-)-malic acid /3(-)-2-hydroxysuccinic acid/of the formula IV

H OH oo ~ CO_H Iv

A 2

HO,

This is a converted by known methods into .

A C,-Cg-alkyl ester of the formula V oo . H OH i . 1 2

R 05C in which R' denotes C,-Cg-alkyl, preferably - . methyl or ethyl, preferably by treatment with alcohol under acidic conditions.

Compounds V is reduced to the diol ester

VI, preferably with borane/dimethyl sulfide i. ' Co , . Ca eget be gL SE ERAT it 3 | i. Ge cli ; 3 a : - PL MR ul . ’ . - : Lo . ot Fa ie : complex using n catalytic umount of sodium Lo , } borohydride by a process of T. Moriwake et al. | v; (Chemistry, Letters 1984, 1379).

In. the process according to the invention, the diol ester VI is, in the first step, protected 1 on the primary alcohol group, R in the formula .

VII denotes an alcohol protective group (cf. Bro- Co ‘ tective Groups in Organic Synthesis, Wiley, New - :

York 1981), preferably t-butyldiphenylsilyl.

The condensation in step 2 is carried out .. : oo with, for example, t-butyl acetate, preferably : with the lithium enolate of t-butyl acetate, in a solvent at -78°c. to room temperature, preferab- SURE ly between -30°c, and -10°c., preferably in ; . : Co tetrahydrofuran (THF). 2 to 5 equivalent of the Co - enolate are used. The lithium enolate is pre- . oo CL pared by the customary methods, pieferably °° CL wh on using lithium diisopropylamide (LDA) at - 70°C. Lo Bo : to -50°C. One possible version of the process . | ) Ch comprises the use of the compound VII in the . Les oo form of its alcoholate, specificallyas, for I J ST oo example, the lithium, sodium or magnesium | oo i. : J | . ; } ’ . - 17 = oo ~ | N .

Ya | Cy vo | oo Ce alcoholate. }

The hydroxy keto ester VIII is reduced to the 1,3-diol ester IX, specifically in such a way that the configuration indicated in formula

IX is produced preferentially or exclusivelyo

Preferably used for this purpose is an alkylborane or alkoxyalkylborane in conjunct on with sodium borohydride at temperatures between i -110°c. and o°c., specifically based on processes known from the literature (K. Narasaka, H.C. Pai,

Chem. lett. 19%, 1115, Tetrahedron Jett. 28, 155 (1987) '

Compound IX is expediently converted into : the acetonide X :

CH tr \ J

M = N Dy

J cH 3 preferably using 2,2-dimethoxypropane in acetone } ' a - 18 - .

Co | BAD ORIGINAL J v y - . te ‘ with the addition of an acid catalyst such as, for example, p-toluenesulfonic acid. : \ .

The acetonide X is converted into the alcohol III } CH : 3 \ / Co . ’ (1 = /N\ ), [a

CH

3 ° . } Processes known per se are used to eliminate . 2 N : } the protective groups R . t-Butyldiphenyl-~ silyl is preferably eliminated with flouride Co jons, for example with tetrabutylammonium oo fluoride in TIIF. : ' -

The alcohol III is a valuable synthon for I i the preparation of demethylmevalonic acid So ! derivatives. ‘ oo ‘. E

To prepare the olefin derivatives of the - } { . .. "formula XI, III is oxidized to the akdehyde XII, for example using dimethyl sulfoxide.oxalyl chlo- Co ride/triethylamine (SYnthesis 1981, 165) »

. . : «

H No XII

N > 1 0c) (R' = c(cH,),)

E OHC 3°3 '

The linkage of XII in which M is, for example,

CH ’

NJ

. Cc “1

CH

3 with a suitable halide XTII, for example for the preparation of compounds corresponding to German

Patent Application No. P 38 23 045.3

F Tt

CH_X 2 CH

Cl ~ CH 3 >

XIII X = Cl, Br

XIV X = PPh; +Br ©

Xv X = PO(0AK), ’ !

Ak = C4-Cj-Alkyl . “a , !

i oo Ca ; SESE . . . SE is preferably carried out by a Wittig or -

Wittig-llorner reaction via the appropriate : phosphonium hal ides XIV or alkyl phospho- "nates XV to give the compound XI' of the formula . , F ’

XI

H.C cH : 3 3 . . oc ><, co_c(cH,) . 2

AN AX 3°33 .

N

~ocH > 3

It is possible to prepare further compounds ' '

XI in an analogous manner. Compounds XI are ; iE ’ hydrolyzed by methods known per se to give com- * poiinas I" @1th Y-="CA = CH. The conversion. of Co a compound XI into a desired final product.is .. Lo illustrated hereinafter by the reaction with CU compound XI', Hydrolysis of the acetonide of . ; the formula XI' under acidic conditions results : Cs in compound 1! ,

J } } . a - 21 ~ H . . . : 1 LC

F . i H OH H OH - S C0,G (CH, ) 5

NX x ”

N z hi 3

Cl CH 3 .

Lo I' is converted by standard processes into the corresponding lactone

H 0 . 7 0 2 II

F = 7 . ;

CH : Te

TL 3

XX = H . | 3 . ] h

NN

. _ | ) . -*

So Can

. . . St wv lh. iad ERAS ca td EEN he “ . . . ’ iw rn on ‘ Anas EN te . ' EAS vo ‘ Ge Sen Sy Fl : . Vv 1 . i \ Lt . A aan . } : . : ERE | Ll bo “ " = ! . . : SU preferably with trifluoroacetic acid in methylene chloride. co ' The conversion of compounds I into lactones : II is carried out either directly from the 1 J esters (R = C,-Cgmnlkyl) or from the correspon- . 9 . ER ding free acid (R = H), Furthermore, lactones \ ‘ : of acid-sensitive compounds are prepared from the Co , » free acids by use of lactonization reagents such , . t i . as, for example, carbodiimides. So . . a :

N 0 E

The aldehydes of the formila XII in which M ’ J : : denotes a radical of the formula oo t . . . : ! . \ ya | ~

SF \ ’ Sr 1 . ,

CH AN Ea : 3 - } . . : \ " oo . ~ . oie ..

Co 1 y or ML Se CL oY ] ] - . } . ‘ ; i - Co : : } Co, ' oa oo . CL Ce Ce ty Ce : . : } ) R -— 23 - : . Sr " - . ! \ TL ce . . ’ . . ; ) ] ' . . Lo : . LL T i

. ‘ : b are new.

Hence the invention also relates to these compounds, and to processes for the preparation . thereof. The aldehydes are, for example, valuable intermediates for the prevaration of compound. of the formula I and of the formula IT, which rep- : resent valuable pharmaceuticals. © .

EXAMPLE 1

Hethyl 0 §-3-hydroxy--(t-butyldiphenylsilyloxy)butyrate (formula VII) : 64.05 g (0.233 mol) of t-butyldiphenylchlo~- rosilane were added dropwise, at o°c., to a solution of 31.1 g (0.233 mol) of methyl (38)-3,4-dihydroxy- : 15 but yrate (formula VI), Chem. Lett. 1984, 1389, and 31,7 g (0.466 mol) of imidazole in 400 ml of dry . dimethylformamide. The mixture was stirred at room temperature for 2 h, then 1000 ml of water were added, and the mixture was extracted with - ether (2x). The combined organic phhses were ’ dried (11g50,,) and evaporated in a rotary evaporator, . J ’ [ . - 24 - : Co wo Cee TRIRENRERI TR RR © Flash chromatography on silica gel (cyclo- Co hexane/ethylacetate = 3:1 + 1% KEt,) yielded . a. - 77.4 g (0.208 mol, 89%) of Example 1. Co - . SA CL / o« 75° = -9.6° (c = 10.2 in methanol) ~~. ' : H-NHR (CDCl), 60 iliz): § =7.80~7.20. (m, 10H), 4.20 - 3.60 (m, 6H), 2.5 (d, 2H); 1.05 . (sy 911). Co oo EXAMPLE 2 ~ a : t-Butyl “. Co Co : (53) -5-hydroxy-3-oxo-6-(t-butyldiphenylsilyloxy) oo : : hexanoate (formula VIII) ~~ °° co " 225 ml (0.36 mol) of n-butyllithium (hexane) : oo | were added dropwise at 0°C. .undér argon, to a IEE : - solution of 41.0 g (0.405 mol) of diisopropyl- Lo © 15 _ ° amine in 400 ml of dry THF.

After.30 min.at— --4. - SEEN ~ pe A Cn o°c., the mixture was cooled to -70%., and Co Ca co oo " 36.7 ml (0.27 mol) of t-butyl acétate wers =~ Coat . . o = __- - Se added dropwise, After 1 h at -70 C., 27.9 g . LL (0 Le Cg . : (0.075 mol) of the compound from Example 14 . sl oo 20 dissolved in a little THF, were added dropwise Ct i ] , \ ’ te } ’ ) no i . | - 25 - So Son . : . : : > . / oo Co Lon

After 1.5 h at - 720%¢. , the temperature was allowed to rise slowly to -15°¢C. The mixture waa finally stirred at -15%¢, for 15 min and then } poured onto cold 500 ml of 2N HCl, 500 ml of ether. The aqueous phase was extracted 2X with ether, and the combined organic phases were washed to neutrality with saturated sodium chlo- ride solution (3x). Drying with Hg sO, and‘ removal of the solvent in vacuo yielded 36 g (quantitative) of the title compound. It was transferred without further purification to the next stage. / 7 =-9.8° (c=10.6 in methanol) for the crude product.

EXAMPLE 3 t-Butyl 3R,53-dihydroxy-6-(t-butyldiphenylsilyloxy)hexa- anoate (formula 1X) .. 32 ml (0.032 mol) of triethylborane solution (THF) were added dropwise, at room temperature, under argon, to 9.13 g (0.02 mol) of the compound from kxample 2 $n 200 ml of dry THF. After the

Co : | ST . ER = Co | | DRIP ot Ce oo 26336 mixture had been stirred at room tempe rature qo 7 for 15 min it was cooled to -70°C., and 1.51 g (0.04 mol) of sodium borohydride were added, ’ : ’ and then 15 ml of dry methanol were added. : | ; " 5 The mixture was left to stir at - 70 C. for : 2.5 h and was then poured into a cold solution oo i of 35 ml of 35 percent hydrogen peroxide in 300 "ml of waler. Extraction was with ethyl gcetate (3x). The combined organic phases were washed . with saturated sodium bicarbonate solution (3x) Co Co and dried (Mgso,). Removal of the solvent in vacuo yielded 9.48 g (quant.) of the title Co compound. : ’ : vo Sa

An analytical sample was purified by flash ’ chromatography on silica gel (ethyl acetate/- oo " cyclohexane = 2:1 + 1% NEt,). So [750 =-6.6° (C=10.4 in"methanoi)” © “

H-NMR (CDC1,, 270 Milz): § = 7.15 and AE 8,40 (each m, together 104), 4,21 (m, 1H), se © 4,0 (my, M), 3.51 (m, 28), 2.40 (m, 21); 1.70 = oo - 27 - oo Co oo i ! ‘ Lo y to . ) BU

SU

1.40 and 1.05 (several m, together 20H). ;

EXAMPLE 4 t-butyl (3R,58)-6-(t-butyldiphenylsilyloxy)-3,5-0~ isopropylidene=-3,5-dihydroxyhexanoate (formula X) 6.88 g (0.015 mol) of the compound from

Example 3 (crude product) were dissolved in 200 ml of acetone/2.75 ml of 2,2-dimethoxypropane and, at room temperature, 250 mg of p-toluene- sulfonic acid were added. After 2 h at room temperature, , ml of triethylamine were added, and the solvent was removed in vacuo. The residue was partitioned between ether and water. The aqueous phase was extracted once with ether. The combined organic phases were washed with sodium : _ bicarbonate solution and dried (Mg50,) « Rerioval of the solvent in vacuo, and flash chromato graphy on silica gel (cyclohexane/ethyl acetate = 5:1) yielded 5.2 g (0.010 mol, 70%) of the title compounds ! « oo - 28 -

CL | | CTT EE

L Co vo ‘ ’ . . - 0 7 ==#.0% (c=24.6 in methanol)

H-NMR (270 tidz, CDC1,) 5 6 = 7.20 and 7.40 (each m, together 10H), 4.25 (m, WH), 4.00 (m, 1H), : 3.70 (dd, MW), 3.52 (dd, MH), 2.45 (dd, Mm), 2.30 ’ 5 (dd, 1), 1.70 fdt, 1H), 1.50 « 1.00 (different m, together 25H). oo

EXAMPLE 5 } : t-Butyl i (38,55) -6-hyd roxy-3,5-0-160propyLidetie=3,5- Co dihydroxyhexanoate (formula (111) 1.89 g (6 mmol) of tetrabutylammonium fluoride . trihydrate were added, at 0°c., to a solution of 2.49 g (5 mmol) of the compound from Example h : in 20 ml of THF. After 3 h at 0°C., the mixture vas diluted with 100 ml of ether, dhd ths solution ‘was washed with 100 ml of saturated sod ium chloride | - solution. The aqueous phase was re-extracted once oo . with ether, and the combined organic phases vere | .. dried (Mg50y,) « The solvent was removed in vacuo, . 20 | and the residue was flash chromato graphed on ) . . silica gel (cyclohexane/ethyl acetate = 13). . j : , . | | Co [7 } :

Yield 1.04 g (4.0 mmol, 80%). - 20 0 / 75 ==%.7 {c = 14.9 methanol) ,

H-NIR (Diis0O-dg, 270 HHz); d =4.61 (t, 1H), } 4.20 (m, 1H), 3.88 (m, MH), 3.40 - 3.20 (m, 2H), 2.38 (dd, 1H), 2.22 (dd, 1H), 1.55 (dt, 1H), 1.40 (sy, 121), 1.25 (8s, 3H), 1.15 (m, 1H). \ +

MS: C4300, 2617 (M + He : EXAIIPLE 6 : t-Butyl . oo (3R, 53) -6-0x0-3,5-0-isopropylidene-3,5-dihydro- : xyhexanoate (formula XII) 0.43 g (5.50 mmol) of dimethyl sulfoxide was added dropwise, at -789C,, to a solution of 0.235 ) ml (2.75 mmol) of oxalyl chloride in 10 ml of dichlorometh ane, ‘and the mixture was stirred at .. the same temperature for 5 min. Then 0.65 g (2.5 mmol) of the compound from Example 5 was added dropwised After stirring fer 5 minutes, 1.70 ml of triethylamine were added, and the reaction mix- - ture was raised to room temperature in 2 h. For j 1 + ~ }

Ce. - 20 =

ER oo { working-up, the mixture was poured onto water E “and extracted by shaking 3x with 50 ml of ether ’ each time. The combined organic extracts were dried over Mg 30, and evaporated. Volatile cons~ . tituents were removed from the remgining oil : oo under high vacuum and it was immediately reacted further,

Rf (cyclohexane/ethyl acetate = 1:1): 0.24, : | EXALPLE 7

E~63-2=(4-(4=F luorophe nyl)-2-(1-methylethyl)- ) 6-phenylpyridin-3-yl)-ethenyl-4R-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one (formula 11)

Step a: (formula XI) « . = 1.6 ml (2.5 mmol) of a 1.6M solution of n- } butyllithium in hexane were added dropwise, at 0°C., | } to a solution of 0.26 g (2.5 mmol) of diisopropyl- : ,. amine in 10 ml of THF, and the mixture was stirred EE ] at the same teuperature for 15 min. To this solution a - were added dropwise 1.10 g (2.5 mmol) of diethyl’ b= (k=f1norophe nyl)-2=(1-me th ylé thyl)-6-phe nylpyri-

Co o din-3-ylmethylhosphonate (formula XV, prepared Cl % by heating the appropriate bromide with triethyl f

J * , _ 31 _ . i ’ . : : n

. ' phosphite in tolucne for 8 h and purification by chromatography (cyclohexane/ethyl acetate = 2:1, silica gel)) in 5 ml of THF. The resul=- ting deep green reaction solution was stirred at o’c., for 1 h, and then 0.65 g of the crude product from Example 6 was added, and the mixture was stirred for 3 h to reach room temperature. For working-up, the mixture was added to 100 ml of water and extracted 3X with 100 ml of ether each time. ’ : 10 The combined organic phases were washed with satu- . rated brine, dried (Fgs0,,) and evaporated. Flash chromatography on silica pel (cyclohexane/ethyl acetate = 3:1+ 1% NEE).

H-NHR (Dit30-dg 270 iz); § - 0.93 (mc, 2H), 1.25 (5s, 3H), 1.31 (d, J=7Hz, 6H), 1.41 (s, 9H), 1.43 (s, 3), 2.48 (mc, 2H), 3.52(h, J = 7 Hz, 1H), 4,30 (me, 1), 4.47 (mc, 1M), 5.33 (dd, J = 16 Hz,

GHz, 1), 6.56 (4, J=16Hz, 1H), 7.25 (mc, 2H), 7.h0 - . 253% (m, SH), 7.66 (s, 1), 8.16 (mc, 2i) PPMeo

HS (DCL): m/e= 546 (i +H)e . . f .

ER - 32 - | .

i. 3 § 26336 step b t-Butyl

E-3R,55~3,5~dihydroxy-7-(4-(4-fluorophenyl)-2~ (1-methylethyl)-6-phenylpyridin-3-yl)hept-6-enoate (formula 1) 107 mg (0.19 mmol) of compound from step 7a were dissolved in 10 ml of THF, and 5 ml of 2N HCl were added. After 1.5 h at room temperature, the mivture was neutralized with saturated sodium bicar- Cn . bonate solution and extracted with ether. The com=- bined ether phases were washed once with saturated sodium chloride solution and aried (0). Removal i of the solvent in vacuo and crystallization from diisopropyl ether/n~pentane yielded 78 mg (0.15 mmol, 79%). oo h-tR (CDC, 270 iz); 6 = 1.36 (4, J = 7 Hz, 6H), 1.43-1.5%5 (m, 1M), 2.35(s, MH), 2.37 .. (dy J = 2 Hz, 1H), 3.30 (brs, 1H), 3.46 (hy J =7

Hz, 1H), 3.73 (brs, 1H), 4.11 (mc, 1H), 4.41 (nc,

MH), 5.38(dd, J = 16 Hz, 7 Hz, MM), 6.62 (dd, J = 16 Hz, 2 Hz, 1H), 7.08 (mc, 2H), 7.25 - 7.49 (m, 6H), 8.10 (mc, 2H). / : , . wn i SY - 33 = - BAD ORIGINAL 9 case mown io

Hg: (FAB): w/e = 506 (M5 +). step ¢

BG? ~(4-(4~fluoronhenyl)-2-(1-methylethyl)-6- phenylpsridin-3-yl)ethenyl-UR-hydroxy-3,4,5,6-tetra- hydro-2il-pyran-2-one (formula 11)

A solution of "1 mg (0.0% mmol) of compound from step b in 2 ml of dich loromethane and 0,10 ml (0.59 mmol) of trifluoroacetic acid was stirred i at room temperature, monitoring the progress of the reaction by thin-layer chromatography (silica pel, cyclohexane/ethyl acetate = 2:1). Precursor was no longer present after 2 h. The reaction soluton was added to saturated HallCO solution and extracted several times with ether. The combined organic extracts were washed with water, dried (1g 50,,) and evaporated. The residue was ko mg (100%) of Example 7, which agrees in al characteristics with authen- .. tic mineral (cf. German Patent Application No. P 38 23 0b5. 4).

Step d

The correponding sodium salts are obt ai ned ! - 3h 1

BAD ORIGINAL P))

oo from the esters from step b

Sodium

E-3R,54-3,5-dihydroxy-7-(4=(4-Tluorophenyl)-2- (1-methylethyl)-6-phenylpuridin-3-~yl)hept-6~enocate 1 mmol of ester from step b is hydrolyzed with 1 minol of sodium hydroxide solution in ethanol/water } at room temperature. The solvent is removed in vacuo, and the residue is azeotroped several times Co with toluene, . - . 10 The residue is triturated with ether/hexane.

The following compounds of the formula I or

II can be prepared in an analogous manner: sodium B-3R,55-9,9-di (4-Tluorophenyl)-3,5-dihydro- oo xy-8-isopropyl-6,8-nonadienoate To a . sodium E-3R,55-9,9-di(4-fluoro-3-methylphenyl)- 3,5-dihydroxy-8-isopro pyl-6,8-nonadienoate : sodium E=3R, 5559, 9-di (4-fluoro-2-me th ylphenyl)-3 ,5= dihydroxy-8-isopropyl-6,8-nonadienoate oo sodium E-3R,5R-9,9~di(4-fluoro-3-methylphenyl)-3,5- dihydroxy -8-isopropyl-8-nonenoate " : fi

Ce : - 35 - . Ci | BAD ORiGiNAL g])

v ‘ Cw sodium E-3R,%R-9,9-di(4~-fluorophenyl)-3,5-dihydroxy~ A 8-isopropyl-8-nonenoate vo

E-65-(2-(4-(4-fluorophenyl)-2-(1-methylethyl)~6- oo phenylpyridin-3-yl)ethgnyl)-4R-hydroxy=3,4,- 5,6-tetrahydro-2li-pyran-2-one

B-653-(2-(2,6-bis(1-methylethyl)-4-(4-fluorophenyl)~

Jyridin-3-yl)ethenyl)-4R-hydroxy-3,8,5,6 tetrahydro-2H~pyran-2-one ’ a

B-63-(2-(6-(1,1-dime th ylethyl) -b~(k-fluorophenyl)- 2-(1-methylethyl)pyridin-3-yl)ethenyl)-4R- . i hydroxy-3,4,5,6-tetranydro-2H-pyran-2-one 5-65-(2-(,6-bis(h-fluorophenyl) -2-(1-methylethyl)~ oo . | byridin-3-y1)ethenyl)-4Rehydroxy=3,4,5,6= tetrahydro-2H-pyran-2-one

B68 (2-(2-(-f luorophenyl)-k-(1-methylethyl) -6- phenylpyridin-3-yl)ethenyl)-4R-hydroxy=-3,4 ,- 5,6-tetrahydro-2H-pyran-2-one

B-63-(2-(6-(2,5-dimethylphenyl) -4-(4-fluorophenyl)= 2-(1-methylethyl)pyridi n-3-y1)ethenyl)<4R-hydro- . xy=-3,4,5,6-tetrahydro-2i-pyran-2-one - 65- (2 (2-e tliyL-b~ (hf Luorophenyl) ~6-phe nylpyridin=3= y1)-ethyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H- oo : pyran-2-one } . . ’ i | '

So LL . - 36 =

E-63-(2-(2-cyclohexyl-b-(4-fluorophenyl)-6-(1~ methylethyl)pyridin-3-y1l)ethenyl)-4R-hyd roxy 3,4,5,6~tetrahydro-2H-pyran-2-one

E-653-(2-(4-(-fluorophenyl)=-2-(1-methylethylj-6- phenylpyrididin-3-yl)ethenyl)-4R-hydroxy=- 3.h,5,6-tetrahydro-2ll-pyran-2-one

E-65-(2-(2,6-bis(1-methylethyl)-b-(4-fluorophenyl)- pyrimidin-3-yl)ethgnyl)-4R-hydroxy-3,4,5,6~ tetrahydro-2li-pyran-2-one

E~63-(2-(6~cyclohexyl-l-(4-fluorophenyl)-2-(1-methyl- ethyl)pyrimidin-3-yl)ethenyl)-4R-hydroxy-3,4,5- 6-tetrahydro-2ll-pyran-2-one -

E-65-(2-(h ,6-bis(4-fluorophenyl)-2-(1-methylethyl)- pyrimidin-3-yllethenyl)-4#-hyd roxy-3,4,5,6~ | tetrahydro-2li-pyran-2-one .

J

Cd : - vl .

EE - 37 -

Claims (4)

. “ | . * ' . . WE CLAIM:

1. A process for the preparation of optically active 3~demethylmevalonic acid derivatives of the . formula I y H CH H H N ® cor’ 1 2 Y , rR” (3,5-dihydroxy earboxylic acid derivatives) or of . the formula II ’ ’ . H = 0 HO : ’ 0 II oC TVH Y CL (B-hydroxy lactones) in which ve Y is the ~CH=CH~or -CH,=CH,-group, : R is a radical of the formula } } . - oo Las

\ . ’ oo i oo BAD ORIGINA, L F AL

~ » ’ 2633¢

4 . RS R hd of rR’ , in which 7 denotes a radical of the formula -CH or a nitrogen atom, : l 5 Rr, R' and R° denote, independently of one another, hydrogen, a straight-chain or branched hydrocarbon radical which has up to 6 carbon atoms and can optically be subs- tituted at the terminal carbon by a saturated. or unsaturated cyclic hydrocarbon radical having 3 to 6 carbon atoms,.or denote a : cyclic saturated or up to doubly unsaturated IRA hydrocarbon radical having 3 to 7 carbon atoms, on aromatic radical selected from : the group consisting phenyl, furyl, thienyl and pyridinyl, which can optionally carry / oo ~ 39 -

. : . 26 - 6336 in the nucleus 1 to 3 identical or different substituents from the following groups: halogen, trifluoromdthyl, alkyl or alkenyl, having up to 6 carbon atoms in each case, hydroxyl, alkoxy having 1 to 6 carbon atoms, carboxyl, or carbalkoxy having 1 to 6 carbon atoms in the alkoxy moiety, or is a radical of the formula P gC BR : . NC pd A

R’ . in which A-B represents the -CH-CH- or -C=C= group RO and Rr’, with r6 and R’ being identical or different, represent a satvrated or unsaturated alkyl radical which has up to 20 carbon atoms and tr can be substituted by an alkoxy group having 41 to 6 carbon atoms or the group . : 0 . . 0-¢C-R, ) - FR f ! Ce - ho -

¥ . * Co ' 26336 0 where R° denotes alkyl having 1 to 8. carhon atoms, or represents a cycloalkyl radical having 3 to 7 carbon atoms, a phenyl, thienyl, furyl or naphthyl radical, it being possible for the aromatic radicals to be substituted in the nucleus 1 to 3 times by halogen, alkyl or alkoxy, having 1 to 6 carbon atoms, in each case, cycloalkyl having 3 to 7 carbon atoms or the group. ( - 10 ob . where rR? denotes alkyl having 1 to 8 carbon atoms, or a pyridinyl radical which can be substituted in the nucleus 1 to 3 times by alkyl having 1 to & carbon atoms. 2 R™ represents a saturated or unsaturated alkyl radical having up to 8 carbon atoms, a benzyl .. ! radical which can be substituted in the nucleus 1 to 3 times by halogen, alkoxy or alkyl, having 1 to 4 carbon atoms in each mase, a phenyl, thienyl, furyl or naphthyl radical, it being possible for

J . e

. . 26336 : 6 the aromatic radicals to be substituted in phe nucleus 1 to 3 times by halogen, alkoxy ot alkyl, having 1 to 4 carbon atoms in each case, or a cycloalkyl raidcal having 3 to 7 carbon atoms, and 1 R is hydrogen, a metal cation or alkyl having 1 to 8 carbon atoms, which comprises . (1) converting a diol ester of the formula VI H H 0 ‘ . LN ? : ; HO pb PR VI ; ~ 1 OR in which R' denotes C,~Cg-alkyl, by introduc- . tion of a customary protective group by methods known per se into a compound of the formula VII which is protected on the primary alcohol group .. : ) H OH 0 VII “ J ~~ ox!

+ . . 1 2 : : and in which R denotes C,-Cg-alkyl and R + ! oY ; >

‘. /, \ .

Ct ' . ro. Lo . ° C ! oo oo EA . Co i 9 6 33 . ’ NC ' : : represents a customary alcohol protective : ’ ; groups, (2) converting a resulting compound of the formula . VII, or the corresponding alccholate thereof, by customary condensation with t-butyl acetate, , ) or a suitable equivalent into a compound of the formula VIII oo - H OH Co R20 SA ver ~N or” oo : ’ in which R! and R° have the meanings indicated for formula VII, ‘ (30 reducing a resulting hydroxy keto ester VIII by methods known per se to the 1,3-diol ester } " of the formula IX ST mm : H Oo" goog a . RO COR xX -

2 . in which R' and R? have the meanings indicated oo : . : \ : . oo a ; - cor : ci - 43.

. t ' .

j . . J. . rh oo 2633¢ . “| ’ .. 2633 + for formula VII, (4) converting a resulting 1,3-diol ester of the formula IX by introduction of a protective group suitable for 1,%-diols into a compound : of the formula X : oN ‘ kw 5 mY X r%0 ~ N co ]?! ~~ ~~ 2 in which M is a protective group suitable for 1,3-diols, and rR and R® have the meanings indicated for formula VII, (5) converting a resulting compound of the formula X by customary methods with elimination of the protective group R® into a compound of the . formula III : M ~~ 1 «Hy : HO Lol III in which M is a protective group suitable for ;

- . fe “ - bl - .

. . } 2633¢g 1,3-diols, and R' denotes a €,~Cg-alkyl radical, (6) converting a resulting compound of the formula III into an olefin derivative of : the formula XI H H > > con! ~~ 2 : : .

cH . oo J )

R . : (Y of formula I = CH = CH) and (7) hydrolyzing a resulting compound of the for- mula XI to give a compound of the formula I : 10 i. in which Y denotes the CH = CH group, and R' represents a C,~Cg-alkyl radical, .. (8) where appropriate hydrogenating a resulting compound of the formula I in which Y repre- oo oo sents a CH = CH group to give a compound .. of the formula I in which Y is the CH, - CH, ,

+ pnt a ro | | HL Co - : v 2633 ON . , ¥ To , ) . group, (9) where appropriate converting a resulting com- pound into the acid (rR = H) or a salt (r" = . metal cation) and (10) where appropriate converting a resulting com=- . pound of the formula I into a compound of the : formula II. . Gunther Wess ’ Kurt Kesseler Ekkehard Baader ‘ Gerhard Beck ————————————_r Uf © Inventors , -

{ . 7 ’ : : ot . . oy - U6 = : = - Le ~ . J ‘ . a J : . ¥ - : . ; J