6(R)-(2-(8'-acyloxy-2'-methyl-6'-methyl (or hydrogen)-polyhydronaphthyl-1')-ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones, the hydroxy acid form of said pyranones, the pharmaceutically acceptable salts of said hydroxy acids, and the lower alkyl, and phenyl, dimethylamino or acetylamino substituted lower alkyl esters of said hydroxy acid, processes for preparing the same, and a pharmaceutical antihypercholesterolemic composition containing the same.

(54) Process for preparation i

The present invention relates to a process for the preparation of antihypercholesterolemic compounds, with general formulas I and to:

<img file="RO82367A_D0001.tif" />

<img file="RO82367A_D0002.tif" />

wherein R 'represents hydrogen or methyl, R' represents an alkyl group of 1 ... 10 carbon atoms with a straight or branched chain, except for 2- (S) -butyl, a cycloalkyl group of 3 ... 10 atoms. of carbon, alkenyl with 2 ... 10 carbon atoms, alkyl with 1 ... ... 10 carbon atoms, substituted: with CF₃, the phenyl, halophenyl, phenyl-alkyl group with 1 ... ... 3 carbon atoms, substituted phenyl-alkyl with 1 ... 3 carbon atoms, wherein the substituent is halogen or an alkyl group of 1 ... 3 carbon atoms or alkoxys with 1 ... 3 carbon atoms, the dotted lines for emicylcholinesterase compounds denoted by X, Y, Z represent possible double bonds, and if these double bonds are present, they will be both X and Z concomitantly, either X, Y, Z each.

Certain 3,5-dihydroxy-3-methylpentanoic acid derivatives are known to inhibit cholesterol biosynthesis, according to FM Singer et al. Proc. Shock. Exper. Biol. Med. 102, 370 (1959) 'and FH Hulcher, Arch. Bio10 chem. Biophys., 146, 422 (1971).

However, the activity of these known compounds has not been found satisfactory, that is, they have practical application.

Also known is the extraction of fermentation products, active in the inhibition of cholesterol biosynthesis (Patents,

USA, no. 4049495) 4137322).

The most active component of this group of natural products, now called Com20 pactin, III a (R '= CH₃) in table 1, it was isolated from a completely different fermentation (Patent, USA, no. 4231938) Albers-Schonberg et al. USSN 154, 157 - dated May 28, 1980), described a dihydro MK-803, specified c. III d (R '= CIi₃) in table 1, with efficiency equal to MK-803, isolated as MK -803 '

MK-803 dihydro and tetrahydro derivatives of different structures (III, b, c and e (R '= CH) are also known₃) in Table 1), prepared by catalytic hydrogenation of MK-803.

82307

THE PRICE OF LAW 1: 21.35

The process of the invention broadens the range of antihypercholesterolemia derivatives, in that a compound of general formula III:

<img file="RO82367A_D0003.tif" />

wherein R 'has the above meanings, it is heated under reflux, under nitrogen atmosphere, with an alkali metal hydroxide in a protic solvent, preferably water, followed by acidification at a temperature of 0 ... 3 ° C, then by lactonization by heating in toluene solution, to obtain the compound of general formula IV:

<img file="RO82367A_D0004.tif" />

wherein R 'has the above meanings, the obtained compound is treated with tert-butyldimethylsilyl chloride and imidazole in dimethylformamide as an aprotic solvent, at ambient temperature, under nitrogen atmosphere, to obtain the 4-tert-butyldimethylsilyloxy compound of formula V :

CH₃ ch₃CH₃~ C-SrO

CH₃CH₃ be

<img file="RO82367A_D0005.tif" />

wherein R 'has the above meanings to which the double bonds present in the polyhydronaphilic molecule part are optionally reduced, by hydrogenation in the presence of PtO catalyst₂, under pressure up to 100 at ambient temperature, followed by silica gel column chromatography to isolate the desired product, after which the resulting 4-yl / r-butyldimethylsilyloxy compound is acylated, either by treatment with RCOC1 acid chloride, in which R has the meaning indicated above, in pyridine under nitrogen atmosphere, possibly in the presence of an aeration catalyst, selected from 4-pyrrolidinopyridine, 4-dimethylaminopyridine and 4-hydroxybenztriazole, either by treating the solution in dichloromethane with an RCOOH acid, wherein R has the significance indicated above, and N, N-dicyclohexylcarbodiimide in the presence of the above-mentioned aeration catalyst, preferably under a nitrogen atmosphere, and the protecting group 4 is removed. Osilil, by treating with about 3 equivalents of tetrabutylammonium fluoride trihydrate and about 4 equivalents of glacial acetic acid for an equivalent of 4-O-silyl, in tetrahydrofuran, ether or 1,2-dimethioxyethane, at ambient temperature, under a nitrogen atmosphere, to obtain the compound of formula I, followed, if desired, by transformation, by known methods, into a pharmaceutically acceptable salt of compound Ia, or by conversion to methyl, ethyl or "J / rt-monoglyceride.

Examples of carrying out the process according to the invention are given below.

Example 1 Preparation 6 (R) - (2- (8 '(S) -hydroxy-2' (S), 6 \ R) -dimethyl-1 '-, 2', 6 ', 7', 8 ', 8'a (R} -hexahydrone f -ethyl) -4 {R) -hydroxy-3,4,

5,6-tetrahydro-2H-pyran-2-one, IVa (R '- = CH +

A mixture of 8 g (19.78 mmol) of MK-803 (III ", R '- CH₃) and 8.31 g (197.8 mmol) of LiOH.IRO in 600 ml of water was stirred at reflux under nitrogen for 56 h. The reaction mixture was cooled to 0 ° C under stirring with 20 ml hydrochloric acid. The mixture was then extracted with three portions of 250 ml of ether and the combined extracts were washed successively with three portions of 200 ml of water and then 200 ml of saturated brine. After drying over MgSO₄, this organic solution is filtered and the solvent evaporated to obtain an oily residue. This residue was dissolved in 200 ml of toluene and heated under reflux in a nitrogen atmosphere for 2 h, with continuous separation of the water, to make the relactonization. Evaporation of toluene and trituration of the residue with hexane gave 5.15 g (81%) of compound IV "(R '~ CH₃) as a white solid, which does not require further purification.

An analytical sample was prepared by recrystallizing a portion of this material with butyl chloride, a white agglomerate, m.p. 128-113 ° C (vacuum); NMR (CDC1)₃) S 0.87 (d, 3, J = 7Hz, CH,), 1.16 (d, 3, J = 7Hz, CH;,), 2.64 (m, 2 piran C₃ H's), 4.27 (bnn, 1, naphthalene C_SI1), 4.37 (m, l piran C., H), 4.71 (iu, 1 piran C_UH), 5.56 (m, l, C-naphthalene C), 5.79 (dd, l, J = 36.10 Hz, naphthalene C₃H), 6.03 (d, 1 J-1 Hz, 82367 talen C, H); IR (CHC1₃) 3400 (OH) 1725 (C-O), 1240, 1120, 1080 cm '.

Analysis%: calculated for C_i9H,₃A₄. O.IC, H., C1: C = 70.67; H, 8.84; found:

C = 7O, 77, H = 8.75.

Alternative Preparation for 6 (R) - {2- [8 '(S) -hydroxy -2' (S), 6 '(R) -dimethyl-1', 2 ', 6', · 7 ', 8', 8'a (R} -hexahydronaptil-1 '(S)') - 4 (R} -hydroxy-3,4,5,6-tetrahydro-2II -2- pyranone, 7I \ (Ă "= CH₃)

A suspension of 188 mg (0.463 mmol) of MK 803 (III _of, R '= CH₃) in 5 ml (5 mmol) of LiOH solution IN is stirred, for 12 hours, at 135 ° C, in a pressure vessel of 30 ml, of very clean steel. The cooled reaction mixture is acidified with H₃PO₄ IM and extract with ethyl acetate. The ethyl acetate solution is dried (MgSO₄), filtered and the solvent evaporated. The residue is dissolved in 20 ml of toluene, which is heated at reflux for 4 hours, in a Dean-Stark apparatus, for relactonization. Evaporation of toluene gives the compounds mentioned in the title.

Preparation of alcohols IV "(R '= H) and IV" IV _c, IV, and IV, (R '^ II or CH₃)

Using, essentially, the conditions described above, but substituting an equivalent amount of lilac (R'-H) or Illb, Ily or lily (R '= H or CH esters)_S) for lilac (R '~ = CH₃ corresponding alcohols are obtained IV "(R '= H), IVIB_e, IV. and IV, (R'-H or CH₃).

The 8'-hydroxy compounds with structure IV can be acylated to give a new class of 8-acyloxy compounds with the structure defined in formulas I and II and with the definitions below. These new compounds are inhibitors of cholesterol synthesis in vivo.

Example 2. 6 (R) - {2- [8 '(S) -2.2^,'-dimethylpropanoyloxy-2' (S), 6 '(R} -dimethyl-P, 2', 6 ', 7', 8 ', 8' a (R) -hexahydronaphthyl-1 '(S} -ethyls \\ -4 (R} -hi-hydroxy-3,4,5,6-tetrahydro-2H-2 pyranone

Step A: Preparation 6 [R) ~ {2 - [6 "- (S) hydroxy-2 '(S) -6' (li) -dimethyl-V, 2 ', 6^,, 7 ', 8'a (li') - hexahydronajiyl-1 '(S)] - ethyl} - 4 (R) - dimethyl-tert-butyloxyloxy) -3,4,5, G-tetrahydro-2H-2 pyranone , V „(R '- CHf)

A mixture of alcohol IV "(R '= CH₃) (18.3 g, 57.1 mmol), 21.5 g (142.8 mmol) of r / Cbufildimethylchlorosilane and 19.4 g (285.6 mmol) of imidazole in 200 ml of N, N-dimethylformamide were Knead at 20 ° C in a nitrogen atmosphere for 18 li. The reaction mixture was then diluted with 1500 ml of ether and washed successively with water, 2% aqueous hydrochloric acid, water and saturated sodium bicarbonate. The ether solution was dried over MgSO₄, filtered and reduced to a volume of 11. After adding 600 ml of hexane, the volume was reduced to 600 ml on a steam bath. The product crystallized at room temperature; after isolation and drying with ether, 13.7 g of product are obtained - solid, with a cotton breast. The mother liquid was reduced to 250 ml and a second crop of crystals was isolated, after which the same solution was at 0 ° C overnight.

The combined product was 17.13 g (69%) of the main compound, with the appearance of a fluffy white solid: m.p. 14S, .. 144 ° C (in vacuo); NMR (CDC1)₃) δ 0.10 [s, 6, (CH₃)₂Si], 0.9 [O (CH₃)_sCSi); 1,19] (d, 3, j - 7Hz, CH₃); 2.58 (d, 2, j = 4Hz, piran C₃H's); 4.3 (m, 2 piran C₄N and naphthalene C_ofH), 4.70 (m, l, pyran, C₆H), 5.57 (m, 1, CH naphthalene); 5.58 (dd, 1, j = 6, 10 Hz, naphthalene C₃H); 6.03 (d, 1, j = = lOPIz, naphthalene C₄H).

Analysis for C₂₅H₄₃A₄Yes,%: calculated: C - 69.08; H - 9.74; found: C, 69.46; H - 9.83.

Stage B; Preparal G (R} - {2- [8 \ S) -2 '', 2-dimethylpropanoyloxy-2 '(S), 6' (R) -dimethyl-7 2 ', 6', 8 ', 8'a ( R) -hexahydronaphthyl -1 '(S) -ethyl-4 (R) -dimethyl - tert-butyl $ yloxy} -3,4,5,6-tetrahydro-2H-pyran-2-one, VI_of (R '- CII₃).

A solution of 6.0 g (13.8 mmol) of alcohol Va (R '== CH₃) from step A and 200 mg of 4 dimethylamino-pyridine in 50 ml of pyridine was cooled to 0 ° C under a nitrogen atmosphere. To this stirred solution, 6.8 ml (6.65 g, 55.2 mmol) of dc pivaolil chloride was added for 15 min. The reaction mixture was stirred at 0 ° C for 1 h and then at 20 ° C for 4 days. The reaction mixture was diluted with 750 ml of ether and washed with hydrochloric acid diluted in 2% water, until the washing liquid became acidic; and then with saturated NaHCO solution₃. After drying with MgSOj, the solution was filtered and evaporated to give 7.81 g of the parent compound, as the appearance of a light orange oil: NMR (CDC1)₃) 80.09 [s, 6 (CH₃)₂And] ; 0.88 [s, 9, (CH₃)₃CSi]; 1.28 [s, 9, (CH₃)₃COD₂-]; 2.57 (d, 2, J = - 4Hz, pyran C₃H's); 4.32 (m, l, pyran C.jH); 4.63 (in, l, pyran C_eH); 5.34 (m, 1, naphthalene C_SH); 5.54 (m, 1, naphthalene C₅H); 5.78 (dd, l J - 6, 10Hz naphthalene C_ofH); 6.03 (d, l, J = 10 Hz, naphthalene C₄H).

Using the effective technological process, as described in example 1, step B, but replacing pivaloyl chloride used with an equimolecular amount of acid chloride of structure R-COC1, described in table 1, are prepared esters of structure VI of (IU = CH₃) also described in table 1.

Table 1

<td>a II RCO</td><td>NMR (CDC1₃, 8)</td>

<td> 1</td><td> 2</td>

<td>CY^m‘</td><td>7.10 (1, 2, j - 8Hz, μ- Fph-)</td>

<td>_F/ V</td><td>8.03 (dd, 2, J = 5, 8Hz, p-Fpli)</td>

<td>CH₃CO₂-</td><td>2.02 (s, 3, CK, CO, ·)</td>

<td>2 cw₃? S ^, _ ch₃</td><td>1.19 (d, J -7Hz, s-CH₃ ester) 1.21 (d, J -7Hz, s-CH₃ ester) Total 3H</td>

<td>(CfTJjCHCHaCO -</td><td>0.83 (d, 6, J-6Hz, (CH₃)_ofCÎI-)</td>

<td>{CH₃)₂CHCO₃—</td><td>1.13 (d, 6,, | Mlz {CH₃)₂CH)</td>

<td>CH₃(CH₃)₃CO₂-</td><td>0.95 {t, 8, | / Hz, CH₃- (CH₂)₃—</td>

<td>&lt;X_;-</td><td>1.60 - 2.08 {ra, 15, adamantyl)</td>

<td>€ Η₃(ΰΗ₂)₀€ Ο ,, -</td><td></td>

<td>Czech CO ^ '-</td><td></td>

<td>CH₂ = CH-CO, -</td><td></td>

<td>WHAT THE₃(CH_of).₂CO₂—</td><td></td>

<td>C_eH₅CO₃-</td><td></td>

<td>4-CLC₀H₄CO₂-</td><td></td>

<td>A LD R-C ··· O</td><td></td>

<td>2,4-F₂C_gH₃CO₂ —</td><td></td>

<td>C₆H₅(CH₂)_âCO₂—</td><td></td>

<td>4-FC₆H₄CH₂CO₂—</td><td></td>

<td>2,4-F₂C₆CH₂CO₃-</td><td></td>

<td>4-CLC₀H₄CH₂CO₂ —</td><td></td>

<td>4-FC₆H₄(CH_s)_;!CO₂-</td><td></td>

CH_ofCH-CH₂CQ₂—

10

Tabehtl 1 (continued)

<td> 1</td><td> 2</td>

<td>CH₃\ yCO, - CH / ~</td><td></td>

<td>CH II Co., - ch / \ /^COJ</td><td></td>

<td>CH₃(CH₂)_sCO&gt; -</td><td></td>

<td>&gt; 02- CHsțjX ..... * CH;</td><td></td>

Step C: Preparation &lt;? (/?) - {2 - [&lt;S "(S) -2,2 '' - dimethylpropanoyloxy - 2 '(- S), 6 \ R) -dimethyl-7', 2 ', 6 ', 7', S ', 8'a' (R) -hexahydronaphthyl-T (S)] -ethyl) -4 (R) -hydroxy-3,4,5,6-letrahydro-2H-pyran-2 -onei, l _of (R '= C7i₃).

To a solution of 10.0 g (31.7 moles) of Bu ^ N -t-F '- 3H₂O and 2.4 ml (2.5g, 42.3 mmol) of acetic acid in 50 ml of tetrahydrofuran 7.81 g (13.8 mmol) of silyl ether VI were added. _of (R 'CH₃) from step B in 50 ml tetrahydrofuran. This mixture was stirred at 2 (V'C in a nitrogen atmosphere for 18 h. The reaction mixture was diluted with 700 ml of ether and washed successively with 2% hydrochloric acid diluted with water, then with water and then with saturated dc NaHCO solution₃. The organic solution was dried (MgSCh) and filtered. Evaporation of the solvent deposited 6.45 g of a white solid. This substance was crystallized in 100 ml of butyl chloride and the isolated crystals were

I dried at 35 ° C / 0.01 mm, for 4 h, to provide 4 g (72%) of the parent compound as needles, almost white: melting point 167.5 ... 170.5 ^ 6 (in vacuum); NMR (CDC1)₃) S0.88 (d, 3, J - 7Hz, CH₃) ;

1.08 (d, 3, [= 7Hz, CH₃); 1.19 (s, 9, (CH₃)₃C) 2.67 (d, 2, J = 4Hz, piran C_ofH "s) 4.39 (m, l, pyran C₄H), 4.65 (m, l, pyran C₆H), 5.36 (, 1, naphthalene C_SH), 5.55 (m, l, C-H-naphthalene), 5.80 (dd, l, J = 6, 10Hz, naphthine C-tine₃H); 6.04 (d, 1, J = 1θΉζ, naphthalene C₄H); HPLC (4.6 mm x 25 cm Particle 10 PAC, 10% isopropanol / hexane 4 ml / min), retention time 4.4 min.

Analysis calculated for C ^ H ^ Oj,%:

C, 71.25; 14 = 8.97; found: "C = 71.40; H - = 8.93.

under the same conditions as in Example 1, step C, but substituting for 2,2-dimethylpropenoyloxy-silyl ether compound VI _u (R '= = CH₃), an equimolecular quantity of other esters of the formula Via (R '= CH₃), described in table 2, are prepared esters of structure I, (R '= CH₃) described in Table 2.

Tabehtl 2

<td>1ÎCO₂-</td><td>Formula</td><td>Melting point, ° C</td>

<td> 1</td><td> 2</td><td> □</td>

<td>CH / \ /^C°²· ch₃</td><td>Csiha_itA₅</td><td> 139... 148</td>

<td>ΧΓ</td><td></td><td>119.5 ... 120.5 (vacuum)</td>

<td>(CH₃)₂CHCH₂CO₂-</td><td></td><td> 126... 128</td>

<td>(CH_of)₂hCG₂-</td><td></td><td> 144... 147</td>

12

Table 2 (continued)

<td> 1</td><td> 2</td><td> 3</td>

<td>0H₃(CH₈) CO₂-</td><td>^ 21% 6θ5</td><td></td>

<td>gh₃co₂- </td><td>C_3IH₃₀O -... D, ic₄h₉</td><td>T53 ... T56 (vacuum)</td>

<td></td><td>ε₃₀Η₄2 ··· Ο₅0₁05€_(ΐΗ₁₀</td><td>1.5.5 ... US (vacuum)</td>

<td>CH₃(CH₂)₆CO₂-</td><td>1 i</td><td></td>

<td></td><td></td><td></td>

<td>. rCHv- CH-CO;, -</td><td></td><td></td>

<td>CK (CK_of)₃CO₂-</td><td></td><td></td>

<td>• C_eK₅CO₂ —</td><td></td><td></td>

<td>4-C1C₆H₄CQ₂—</td><td></td><td></td>

<td>2,4-Τ₂% Η₃ςθ_£~ ' :</td><td></td><td></td>

<td>C_eH₅(OH₂)_ofCO₂—</td><td></td><td></td>

<td>4— FC₆-H₄C £ -I₂CO_of-</td><td></td><td></td>

<td>2'3-F₂C₆H ^ CH₂CO₂ - ·,</td><td></td><td></td>

<td> 4-ClLŞHjCHJ.O.,</td><td></td><td></td>

<td>4-I^:C₆H₄(CH₂)₃CO₂—</td><td></td><td></td>

<td>BUT.₃CH3-CLL / OG., -</td><td></td><td></td>

<td>CH_3s^ '^ / CO₂ - ch /</td><td></td><td></td>

<td>CHIJ. II cq</td><td></td><td></td>

<td>CH₃(CH₂)₈CO₂-</td><td></td><td></td>

<td>C ° 2</td><td></td><td></td>

Table 3 (continued) • Example 3. 6 (/ 2) - {2 - [&lt;5 "(S) - fcnilacetoxy-2 \ S), 6 '(R) -dimelyl-1', 2 ', 6', T, 8 'a (K) -hexahydrone.ftil-l' (S) -ethyl) -4- (R) -hydroxy-3,4,

5,6-tdrah hydro-2 H-pira.n-2-οη ă

Step A: Preparation of 6TR) - {2- [8 '(S} -phenylacetoxy-2' (S), 6 '(K) -dimethyl - V, 2', 6 ', 7', 8 ', 8'a (R) - Hexahulronaflyl-1 '(S) -dyl \} -4 (R) -dimethyl-tert-butylsilyloxy-3,4,5,6- tetrahydro-2II-pyran-2-one, VI J, R' - CII_t)

The solution of 434 mg (1.0 min) alcohol V, (Ii = CH₃) from Example 1, flap A, 204 mg (1.5 mmol) of phenylacetic acid and 309 mg (1.5 mmol) of Ν, Ν'-dicyclohexylcarhodiimide in 10 mL dichloromethane was treated with 22 mg (0.15 mmol) of pyrrolidinopyridyl and stirred at 20 ° C in a nitrogen atmosphere. After 3 days, the solvent was removed in vacuo and the residue was suspended in 25 ml ether and filtered. Evaporation of the filtrate gave an oily substance, which was chromatographed (here on a column with 3 x 15 cm silica gel (230, 400 mesh),

Elution (under air pressure) with ether-hexane (1: 1, vol: vol) gave 460 mg (83%) of the main compound, with the appearance of a viscous oil. NMR (CDC1,) S 0.10 (s, 6, (CHj), Si), 0.90 [s, 9, CH₃)₃CSI], 3.58 (s, 2, PhCH-—), 5.34 (in, 1, CJ1 naphthalene), 7.30 (s, 5, Eh).

Using the dc method in Example 3, step A, but replacing the phenylacetic acid used with an equimolecular amount of organic acids of R-COOH structure, described in table 3, are esters of structure VI. _of(R '= CHj) also described in Table 3.

Table 3

<td>A II li-CO-</td><td>KMN (CDCl 8)</td>

<td> 1</td><td> 2</td>

<td>l&gt; "^co-</td><td>0.78-l, 02 (ni, 4, cyclopropun)</td>

<td>Cl₃CHjCH-CH, CO₂ —</td><td>1.04 (4.33 = - ^, (_.Η₃ΕΗΟ '₃)</td>

<td>ch₃^ / co * - ch / .....</td><td>l, 8S (s,.&gt;, CH₃C = q 2.17 (d, 3, J = 2Mz, uy c, 5, fi8 (bi's, 1, C — CH—)</td>

<td>ch₂II QQ CH / \ / ³</td><td>l, 80 (s, 3, CH₃C = C) 4.86, 4.92 (s, 2, CH, = C)</td>

<td>CH₃(CH₂)_KCO₂—</td><td>0.87 (111.3, CHj (CH „gCO₂ -) l, 23 (m, m, CH₃(CH₂)₇CH₂C0₂—)</td>

<td> 602</td><td></td>

<td> 1 </td><td> 2 .</td>

<td>I</td><td></td>

<td>CH₃CO₂-</td><td></td>

<td rowspan="2">0 CH₃^ Y ^ 0. ch₃</td><td></td>

<td rowspan="2"></td>

<td rowspan="2">(£ H₃)₂CHCH₂CO₂—</td>

<td rowspan="2"></td>

<td>(CH₃), CHCO2 ~</td>

<td>CH₃(CH₂)₃CO ^ _</td><td></td>

<td>3c-Co ^₂-</td><td></td>

<td>\ \ CC% _ /</td><td></td>

<td>"Ί 5-C-Co.,⁷ \</td><td></td>

<td>! - C —- CO₂— 1</td><td></td>

<td>CH₃(CH₂)₀CO₂~</td><td></td>

<td>c_gh_uco -</td><td></td>

<td>ch₂= CH-CO₂-</td><td> • \ ...</td>

<td>CF₃(CH,) JCA₂ -</td><td></td>

<td></td><td></td>

<td>4-C [C₆H₄CO₂-</td><td></td>

<td>2.4 Î'gC ^ H.jCQg -</td><td></td>

<td>%% | CH)₃CO₂</td><td></td>

<td>4-FC₆H₄CO₂ —</td><td></td>

<td>2,4 -FgCgHgCH ^ CO ^</td><td></td>

<td>4-CLC_eH₄C.III₂CO_s~</td><td></td>

<td>4FC₃H₄(CH₂)₃CO, -</td><td></td>

Step Β: Preparation of 6 (R} - {2- [2 '{S) &lt;- phenylacetbxi-2' (S} ', 6' (Ry-dimethyl '- T, 2 *, 6', 7 ', 8' , 8'a (R) - hexahydronatyl-1 '(Sj-elyl]} -4- (R) -hydroxy-3,4,5,6 - tetrahydro-2H-pyran ·,.-3-one, I' (IT = CHf).

Using the method, essentially, as described in step C, from the example. 1, but. replacing the compound, propanoyl! The oxide used above with an eclimolar amount of phenylacetoxy, composed of excmpliil 2) step A, sc produces the main compound with the mp 109, 112 ° C.

Using the other esters, VI _of(R '= CH₃) described in example 2, step A; table IV and following the method of the example 3, step.-B, is realized, esters.of structure I_e(R '= CH₃) described in table · 4;

Table 4

<td>RCO₂</td><td>Formula</td><td>Pnnct of melting, ° C</td>

<td> 1</td><td> 2</td><td> 3</td>

<td>|&gt; -Co₂-</td><td> ^23^32*^5</td><td> 116..119</td>

<td>CF ". 1 ClîjCnCIIjCO »·</td><td>WA</td><td> 110.. 113</td>

<td>CH »^ _ZC (.)₂CH / ~</td><td>c₂₁h₃₁a_s</td><td> ' 113..118</td>

<td>ch₂J¹. CO₂CH / \ /</td><td></td><td> 116..119</td>

<td>CH_â(CH₂)_sCO₃-</td><td>C »₉H₄₆A_S</td><td></td>

<td>CH / X ^H CH</td><td>C₂₁H₃₀A-</td><td> 126. . 129</td>

<td>ΧΓ</td><td></td><td></td>

<td>CH₃CO, -</td><td></td><td></td>

<td>Q Y ^ O ^ CH ch₃</td><td></td><td></td>

<td>^! (CH₃)_ofCHCH₂CO₂-</td><td></td><td></td>

<td>. (CH₃)₂CHCO₂—</td><td></td><td></td>

Table 4 (cotyledons / countries)

<td> 1</td><td> 2</td><td> 3</td>

<td>CH₃{CH₃)₃CO₂ —</td><td></td><td></td>

<td>^&gt; C-CO₂-</td><td></td><td></td>

<td>0 - CO »-</td><td></td><td></td>

<td>/ - c— co »- ^z 1</td><td></td><td></td>

<td>|. - c — co, - 1</td><td></td><td></td>

<td>co ^ CT-ycn -</td><td></td><td></td>

<td></td><td></td><td></td>

<td>Cyl, = CH-CO »-</td><td></td><td></td>

<td>: cf₃(ch₂)₂co₂~</td><td></td><td></td>

<td>g_ch_bco₂-</td><td></td><td></td>

<td>4-CLC₆H "CO -</td><td></td><td></td>

<td>2,4-F, C_cH₃CO, -</td><td></td><td></td>

<td>C_tut.H₅(CH,)., CO »-</td><td></td><td></td>

<td>4 FC „H.₄CH₂CO₂-</td><td></td><td></td>

<td> 2_ţ4-F₂C₍₁II₃CH₂CO₂-</td><td></td><td></td>

<td> 4-010(.14.^:14200,^</td><td></td><td></td>

<td>4-FC₃H₄(CI-I₂)₃CO₂^</td><td></td><td></td>

Example 4. 6 (R) - {[8 '(S) -2 "-ethyl-2-tetylbutyryloxy' - 2 '(S} -6' (R) -dimethyl-T, 2 ', 6', 7 ' , 8'R'a (R) -hexahydronaphthyl-1'S}} - ethyl] -4 (R) -hydroxy-3,4,3., 6-tetrahydro-2H-piratyne-2-step Step A. · Preparation of 6 (Ii) - (S) -2-ethyl-2 "- methylbtitIryloxy-2 '(S} z6' (R) -dimethyl-Γ, 2 ', 6', 7 ', 8', 8'a (R) - Haxahydronaphthyl-1 '(S) -ethyl and 4 (R) - (dirtethyltetrabutylsilyloxy-3,4,3,6 - tetrahydro-2H-pyran2-one) Vl "W - C //,) ....... ...

3.0 g of 2-ethyl-2-methylbutyryl chloride (20 mmol) were added to a magnetically stirred solution of 2.17 g (5 mmol) dc alcohol V 'fR' = / CH_e) and 74: mg of 4-pyrrolidinopyridine in 20 ml of pyridine. This reaction mixture was suspended at^it10D ° C₁ 'Get an atmosphere of N ,. The mixture was diluted with 500-ml ether and washed with 1N hydrochloric acid until the washing liquid became acidic and then with sodium chloride (3 x X 50 ml). After drying with demagium-non-sulphate sulphate, the solution was filtered and evaporated to 4.2 g, / having a brown oily appearance. This oily residue was chromatographed on a silica gel column of 4 x15 ages (230 ... 400-stains). The elution of 'with air pressure with hexane-hexane' (1; 1, vdl: vol] gave 2.6 g (95%) -of-the main compound as a yellow oily Substance: NMR {CDC1₃) S 0.08 '(s,' 6, (CH₃)₂If), 0; 9 (s; 9; (CH₃) jCSi), 2.57 (d, 2, J 4Hz, pyran C₃H's), 4.30 (s, 1, pyran 'CJd), 4, -63 (m,' l, -pyran QH), 5.42, -naphthalene CH), 5.53 (m, l, -naphthalene

C, H); 5.78 (dd, l, 'j =' 6, Ήζ, 10 Hz,-naphthalene C.jH), 6.03 (d, 'l, J == 10' Hz, naphthalene C, H).

Using essentially the procedure as described in Example 3, step A, but replacing 2- (ethyl-2-methylbutyryl olorhydraflu

- previously used with an amount of 'edhiradlecu1 acid chloride-structure of the structure -RCOCI, the compounds described in table 5, are esteric products (of structure VI ₍(R^J ^^!ΕΗ₃) also described in Table 5.

Table 5

<td>and a them R-CO</td><td>NMR (CDCbi</td>

<td></td><td>8.67 (ni. 9, CH_ţCH, CH, (CHjCH.h OCCy</td>

<td></td><td rowspan="2">0.78 (t, 9, J - 7Hz, (CHjCH,) ₃COCX) · 1 ·, 48 (ψ · 6, J - 7Hz, (CHiCH ^ CCOJ</td>

<td>C-CO z</td>

<td>-x 1 c-xa- ⁷ 1 ' 1</td><td>1.28 (s, 6, (CH₃)₂CCOJ 2.20. (S, 3, .CHj: C-CHj)</td>

<td>Î</td><td>3.86 (in, 2, CH₂"C)</td>

<td>-C-C © -.1</td><td>1, 12 (s, -6, (CHjbCCO, 0; 83 (l, 3, (CHjCHoCCOd</td>

Step .13: Preparation of 6 {R) - {2 -, [i (5) -2 "-ethyl-2 '' -melyl-butyryloxy - 2 '(S} -6' (, 2 ', 6', 7 ', 8', 8'a - (R) -hexahydronaphthyl-, 7 '. (5)] - φ7} -Î (R) -hydroxy-3, d, 5,6-tctrahydro' -.211-py a ii-2-one

Essentially, using the process as described in Example 1, Step C, or Example 2, Step B, but using as a suspension material the silyl ether compound of Example 3, Step A, the compound with melting point; TÎ3⁰C '(C₂H₄'/ Oj). Similarly, structure I esters described in Table 6 are prepared.

T.vbeM 6

<td>RCO₂-</td><td>Formula ¹</td><td>Melting point (° C)</td>

<td></td><td></td><td> 81..,'83</td>

<td>\ O CO ,, ·· Z</td><td>c₂₇h₄₂a₅</td><td> 129..132</td>

<td>^ -C-CO, - i "</td><td>&lt;· ΆΛ </td><td> 75..78</td>

<td>c-Co., - 1</td><td></td><td> 135..138</td>

Using the method of example 1, step A, following example 1, steps B or C or examples 2 or 3, steps A and B, but substituting for diol with. structure IV "(R '= CH_â) in example 1, step A, the corresponding structure diol, (R '= Bl) or IV_6li, or _t(R '= H, -or -CH ·,), silyl esters of¹ structures V. "(R '= H) or V ₆, _c, or, (R '- H) or CH₃), esters of structures VI ,, {R '= -H) or Vie Șl v (R' - H) or -CH_b) and esters-, originals. of structure I "(R '= H) or, 1 and- iCR' - * = - H or CH₃), according to technique ©

The manufacturing IL Α, bearing in mind that R - Ό © of the 8'-alkanoyl group is:

<td></td><td>4-CLC_eH₄C0₂—</td>

<td>CH_ofCO_of — '</td><td> 2.11-./-,41.,00,- ‘</td>

<td>0 II CH ./ \^ZX O · , -CH₃</td><td>CftiCH ^ OO ·</td>

<td>. (CH₃) JCHOH ^ CO₂— · ·</td><td>- 4-RC_e^:H4OH_âCO₂- i</td>

<td>(CH₃)₂CHCO₂~</td><td>^ d-FATRCI ^ CO, -.</td>

<td> .(4^((41.,)0(^- ·.· ·.</td><td>4.ac ^ CMCO₃-</td>

Table [eontioua-re)

<td>Zs / &lt;\ 1A! _Co₂-</td><td>4.FC_eH '(CH,)_complicatedCO₂-</td>

<td>CH₃(CH₂)₆CO, -</td><td>/ ν-Ί -c0₂-</td>

<td>c₆h_uco₃-</td><td>-'N C-CO ~ X</td>

<td>CH = CH-CO₂ —</td><td>^ -ILco,^Z 1</td>

<td>CF (CK), CO₂-</td><td>f c-co₂1</td>

<td>c₃h₅co₂-</td><td>----- co - _ /</td>

<td>CF . 1 CF₃CH — CH₂CO₂~</td><td>CH₃ (CHjjJgCOg -</td>

<td>CH ,,, CO „- CH / CH 11 with ch / \ /^C°*</td><td>G'j ?. X - / , ···.&gt; Ζ / ·&gt; ...^v'.V -evu</td>

Example 5. Preparation 6 (R) - [2-8 (S) (2 "~ '-ethyl-2' '- methylbutyryloxy} ~ 2' (S), 6 '(S) -dimethyl-r, 2', 3 ', 4', 4'a {S), 5 ', 6', 7 \ 8'a (S} -decahydronaftiP1 '(S) -etiî) - 4 (R) hydro xi-3,4,5, 6-teirahydro-2H-pyran-2-onei, I, (R '= CH_S)

Step A. Preparation 6 (R) - {2- [8 \ S) hydroxy-2 '(S), 6' (S) dimethyl - Γ, 2 ', 3', 4 ', 4'a (S), 5 ', 6', 7 ', 8', 8'a (S) - dccahydronaphthyl - 7 '(. S)' -ethyl} - 4 (H) -hydroxy-3,4,5.6-tetrahydro-2II * - piran-2-ounce IV _r(R '= CHf).

, A solution of 2.0 g (6.2 mmol) of alcohol r. IV "(R '= CH_S) in 100 ml of ethyl acetate was hydrogenated, in the presence of platinum oxide (1 g), at 0.24 at pressure, until the equivalent of 2 mol H was taken; The catalyst was removed by filtration, and the filtrate was evaporated to dryness to afford it; convert to a white solid (1.9 g), which. was chromatographed on a column of 'cagel' sili (230 ..; 400 mesh) of 6 χ 20 cm. Elution under atmospheric pressure with acetone: methylene chloride (3: 7, vol: vol) gave - 1.0 g (50%), a compound as a colorless solid. , ί An analytical example was prepared by recrystallizing * a portion of the substance from chloroform, to give a sub-20 fluffy white solid, mp 166 ... 168 ° C.

Step B: Preparation 6 (R) - {2- [P '(S) hydroxy-2' (S), 6 '(S) -dimethyl-P, 2', 3 ', 4'a (S), 5 '6', 7 ', 8', 8'a (S) - dccahydronaphthyl t '(S) -ct'T) 4 (R) -dimethyl-tert-buiylsilyloxy) -3,4,5,6-tetr ahidro -2H-pyran-2-onei, V e (R '- CH₃).

A solution of dc 1.0 g: 3.1 mmol alcohol IV, (R '= CH₃) imidazole (1.0 g, 15.4 mmol) and 1.16 g, 7.7 mmol tert-butyldimethylchlorosilane in 20 Ν, Ν-dimethylformamide was stirred at 20 ° C in a nitrogen atmosphere for 18 hours. li. The reaction solution was diluted with 200 ml dc ether and washed successively with water, 2% hydrochloric acid diluted in aqueous solution and brine. The solution in ether was dried with MgSO 2 and evaporated to give a white solid (1.8 g), which was chromatographed on a column of silica of 6 χ 20 cm (230 ... 400 mesh).

Air pressure elution with acetone / methylene chloride (1: 19, vol: vol) gave 1.0 g (74%) of the main compound, as a white solid, with the melting point

136 ... 138 ° C.

Step C Preparation 6 (R} - [2- [8 '(S) -2-elyl-2' '- methylbutyryloxy} -2' (S} 6 "(S) - dimethyl 1 '' 2'3 ', 4 'a (S}, 5', 6 ', 7', 8 ', 8'a {S) -decahydronaphthyl) P (S)} - ethyl y4 (R} (methyl-terpbutylsilyloxy) 3,4,5,6 -tetrahydro-2H-pyran-2-onei VI, (R '~ =.

replacing an equimolar amount of alcohol V_t (R '= CH₃) for alcohol. V, (R '= CH₃) in step A of example 3 and following the technology for step A, an adequate amount of the main compound VI was obtained _f(R '= CII₃) as a yellow oil. NMR (CDC1₃), 0.08 [S, 6, (CH₃)₂And],

O, 90 [S, 9, {CH₃)₃CSi], 1.13 [S, 6, (CH₈)₂COJ,

2.63 (m, 2, C-pyran₃H's), 4.33 (m, 1, CJI pyran), 4.60 (m, 1, C piran)₀H), 5.23 (m, 1, naphthalene C_SH). . ..

Step P: Preparation of 6 (R} -2- [8 '- (S} (2 "ethyl-2" -methylbutyryloxy) -2' - (S), 6 (S) -dimethylP. 2 ', 3', 4 ', 4'a (S), 5', 6 ', 7', 8 ', 8'a (S) -decahydrone f 1' (.S)] ethyl-4 (H) -hydroxy-3, 4,5,6-tetrahydro-2H pyran-2-one I _C(R '

Substituting an equimolar amount of silyl ether VI, (R '^ CII_:)) from example 4, step C, for the silyl ether in step C of example 1 and following the methodology for step C of example 1, a corresponding amount of the above mentioned compound was obtained in solid form.

An analytical sample was prepared by recrystallizing the hexane material to obtain the white needles with a melting point 146., 147 ° C,

Using, essentially, the procedure described in example 4, step A, up to D, but substituting for the diol in structure IV "(R 'CII)₃) in step A, an equimolecular amount of the diol of structure IV "(R '= H), the compounds are made: IV, (R' = H) in e823G7 tap A; V in step Β; VI in stage C and I_C(R '= H) in step 1).

Example 6. 5 (R) - {2- [Ă '' (- S) - (2-cA / -2 "methylbutyryloxy) -2 '(S), 6' (R) -dimethyl-Γ, 2 ', 3 ', 4', 6 ', 7', 8'a (S) -octahydronaphthyl-ona (S)] -ethyl} 4 (R) -hydro-xi-3,4,5,6-tetrahydro-2H- piran-2ona, I _b(R '= CH₃)

Stage A; Preparation 6 (R) ~ [2 - (&lt;? '(. S) hydr or xi-2' (S), 6 '(R} ~ dimethyl-Γ, 2', 3 ', 4', 6 ', 7 ', 8' a (S) -octahydronap tH-Γ (S) -ethyl] -4 (R) -hydroxy

3,4,5,6-tetrahydro- 2H- pyran- 2-one, IV ,, (R'-CIIf

Using the technology described for the preparation of the starting material IV "(R '= CH₃), by hydrolysis of MK 803 with LiOH reflux, H.₂O for 56 h, but replacing MK-803 with an equimolecular amount of compound III b (RCH)₃), the main compound IV is produced with comparable efficiency _t(R '- CH₃), with melting point 136 ... 139 ° C. Following the methodology from example R^r, step B, C and D, but substituting for compound IV "(R —CH₃) used in step R an equimolecular amount of compound IV b (R '= CH_S) from step A of this example, sc produces, in productions comparable to those experienced in example 4, the following compounds:

Step 13 \ 6 (R) - [2- (8 '(S) -hydroxy-2' (S), 6 '(R} -dimethyl-Γ, 2', 3 ', 4', 6 ', 7' , 8'a IS) - octahydronaphthyl-Γ (S) -eiyl] -4 (R) - (dimethyl-tert-butylsilyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-one, V "(R '= CII_s) 9, mp-140 ... 142 ° C.

Step C: 6 (R) -2- (8 '(S) - (2' '- ethyl-2 "-melylbutyryloxy-2' (S), 6 '(R) -dimethiPT, 2', 3 ', 4 ', 6', 7 '3'a (S) -cetahydronaphthyl-Γ (S)) -ethyl-4 (R) - (dimethyltert-butylsilyloxy) -3,4,5,6-telrahydro-2Hpyran-2 -one, VI „(R '~ CH₃)

O __

H \ pn_ where R — C — O is _ / ^{c 2}

Step D: 6 (R} - {2- [&lt;V (S) - (2 "-ethyl-2" methylbutyryloxy) -2 '(S}, 6' (R) -dimethyl-Γ, 2 ', 3' , 4 ', 6', 7 ', 8'a (S) -octahydronaphthyl-Γ (S)] -ethyl} 4 (R) -hydro xi-3,4,5,6-telrahydro-2H - pyran-2-one , I / R '= CH_of}

The _ _A ϋ \ (() _ where R — C — O is / ^v following the technology, essentially, as described in Example 6, but using III _t(R '= H), or III_t, III times III _e(R '= H or CH₃) as starting material, instead of III i, (R '= CH₃), is produced, instead of compound IV _t(R '- H), or IV_C, JR' — H ori CH_of), V_t(R '= H) or V_{c&gt; and},_e(R '= H or CHa), VI₆(R '= H) or VI _c,, (R '= H or CH_S) and I »(R '= H) or I _e,_e(R '= H or CH₃),

The _

II \ ΓΠ where R-C-O is

Example 7. Preparation of the compound having the structural formula:

<img file="RO82367A_D0006.tif" />

Step 1: Preparation of 6 (R) - {2- [? ($) Hydroxy-2 (S}, 6 (R) -dimethyl - Ί, 2.6,7 8.8α (Κ) ΐ hexahydrone onaf til-1 (S) -ethyl]} -4 (R) -hydroxP3,

4,5,6-tetrahydro-2H-pyran-2-one

Mix with magnetic stirrer, under reflux, under nitrogen atmosphere, for 72 h, a mixture of 50.2 g (0.124 mol) mevinolin and 52.0 g 61.24 mol ΕίΟΗ.Η, Ο in 3 1 water. The mixture, under stirring, is cooled to 0 ° C with an ice bath / acetone and treated with 120 ml (1.44 mol) of 12 N hydrochloric acid at such a rate so that the temperature of 3 ° C is not exceeded . This mixture is saturated with solid sodium chloride and extracted four times with 500 ml of ether. The combined extracts were washed twice with 250 ml NaCl solution, dried over MgSO₄ and evaporate to obtain 31.7 g of orange oil. This oil is dissolved in 250 ml toluene and the solution is refluxed, for four hours, under a nitrogen atmosphere, continuously separating the water in a Dean-Stark defense, to make the relactonization. By evaporation of toluene, an oily residue is obtained, which is dissolved in 1.5 1 ether. This solution was washed with 250 ml saturated sodium bicarbonate solution, 250 ml water and 250 ml NaCl solution, dried and evaporated to give a solid residue. By crushing this solid substance with 200 ml of hexane, the title compound is obtained as a cream-colored solid (29.7 g 75%), which does not require further purification for synthesis purposes. An analytical sample is prepared by recrystallizing a portion of this solid substance from «-butyl chloride, obtaining colorless agglomerates, with a melting point

128...131ⁿC.

Step 2: Preparation 6 (R) - [2 - (&lt;? (S) / zyloxyZ-2 (S), d (R) -dimethyl-Ί, 2,6,7,8,8a (R) hexahydronaphthyl-ί (S) ethyl] -4 (R) -tert-butylmethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one (.3)

Mix with a magnetic stirrer, at room temperature, for 18 hours, a solution of 18.3 g (0.057 mol) of alcohol III, 10.3 g (0.068 mol) Zcr / -butyldimethylsilyl chloride 9.3 g (0.137 mol) imidazole in 200 ml dimethylformamide. The reaction mixture is diluted with 1500 ml ether and washed successively with 200 ml water, 200 ml hydrochloric acid. 2% aqueous, 200 ml water, 200 ml

02307 saturated sodium bicarbonate solution, and twice 200 ml of water, then dried over MgSO₄. The filtered ethereal solution is concentrated to one liter, diluted with 600 ml of hexane and the resulting solution is concentrated to 600 ml of hexane to afford 13.7 g of a white solid. By reducing the solution to 250 ml and resting at 0 ° C overnight, a second crystal yield of 3.4 g is obtained. The combined yield is 17.1 g (69%) and the solid substance melts at 142. .. 144 ° C.

Step 3: Preparation 6 (li) - i {2 -. [&lt;5? (S) hydroxy-2 (S), 6 (S) Aime.til-l, 2,3,4,4a (S), 5,6, 7,8,8a (S) -decahydronaf.til-t (S) -.ethyl]} - &lt;//?). Tert-boli1dimethylsilylloxy-3,4,5; 6-tetr.aMdro-2Ilpiran -2-onei (4)

A 5.0 g mixture (0₍0115 mol) -of IV silyl ether and 1.0.g PtO₂ In 200 ml of ethyl acetate is hydrogenated overnight in the Pair of hydrogenation apparatus. Take Low / Pressure. The catalyst is removed by filtration and the filtrate is concentrated to dryness, leaving a solid, white substance. This solid substance is chromatographed on an 80 mm column, containing silica gel of sieve dimensions of 90, 457 mesh / cm.⁴. iElution under air pressure 'with 4,5 1 methylene chloride / acetone- (98: 2 vol .: vol) gives a head (forehead) which is discarded, the next dilution with the same' eluent, in 'Quantity of 2 1 gives the title compound - in the form of 3.4 g solid substance (67%), melting point 4 46 ... 147 ^ 0.

Step 4: Preparation of 6 (di) - [2-; [&lt;7 (5) :( 2,2-dimethylthiothir-yloxy] -2 (S), 6 (S) -dimethyl-1,2 3,4 ·. , 4α (5), 5,6,7,8,8a (S) -dccahidrona.ftU-l (-S) ethyl} -4 (di) -tertUmtildimethylsilyloxy-3,4,5,6-tedrahydro-2H- pyran-2-one '(5). 0; 067 g (0.005: .mol) chloride "dc -2,2 + dimethylbutifyl" is added to a solution, magnetically stirred at 0, bl g (0.00025 mol). of the alcohol ViiiiO, 0074 g (Q, 0005 mol) 4 (pyrrolidinopyridine in 2 ml pyridine). After "heating this solution to 4O0" C, itime; of orc, under the atmosphere. Of nitrogen, it is stirred: add 0.0335 g of 2,2-tdimethylbutyl chloride 610,003.9 g "of 1-pyro lidinopyridine : and (heating is continued for three more hours.

The reaction mixture is stirred, sc «diluted with 50 ml of ether and washed with sc, twice or with 5-ml .acidroloEhidfic (3N and (twice with. Each (10 ml). NaCl solution / Ethereal solution. .sees 'over' 'M'gSQr,' is filtered and, 'evaporates, retaining' 0.4.36 g of wing (yellow. This oil is chromatographed for a coJoan of -30 mm, containing: gel- « of «silica of the dimensions« of the sieve of «90 ... 4 57 stems / cm⁴. Column: eluted under «air pressure with 300 nil dermdtilene chloride, then« with 100: nil .mixture of «unethylene chloride / acetone - (98: 2&gt; v uv) · for« a «yes. «Cap.-care« c. In coritination,: - elute with 50 ml «mixture of methylene / acetone (98 2« -voi: vol), to obtain «0.81 ig ((60%) of the desired compound, sub-form.de pale-oil-.galben.

Step 5. dSparing 6 (K) - {[2 -. 7 (5) (2,2-dimeylbutyryloxy) -2 (S.), 6 (S) -dimethyl-J, 2,3,4,4a ( S), 5,6,7,8,8a (S) -decahydronaphthyl) 7 (S)] -ethyl} -4 (R) -hydroxT3,4,5,6-tert-2-yl-pi-2-one They

Add 0.5 g (0.00093 mol) of the silyl ether obtained above: to a solution of .30. ml tetrahydrofuran, containing 0.224 g (0.00372 mol) glacial acetic acid and 0.8.8-g (0; 002-79 mol) tetrabutyl ammonium hydride fluoride. This solution is stirred .magnetically: under a nitrogen atmosphere, .48 hours. The reaction solution is diluted with 450 ml of ether and washed with 25 ml of water and twice with 75 ml of NaCl solution. The ethereal solution is dried over, iIgSO₄, filter and evaporate to give 0.45 g of viscous oil. This oil is chromatographed on a column of 40 mm dc containing silica gel of «sieve dimensions of 90 ... 157 mesh / cm. Column sc is eluted with methylcn chloride / acetone (85: 15 vol: vol) under air pressure and fractions of .20 ml are collected. Sc reunites fractions 21—-37 and is concentrated to dryness, to obtain the title compound, in the form of 0.37 g solid substance (94%). An analytical sample is prepared_:by 'recrystallization from ether / hexane of the solid substance, obtaining colorless plates, with a melting point 159 ... 160 ° C.

Exemplul.'8. 3 (R), 5 (R) -d, hydroxy ox7 [8 (S) (2,2-diethylbutyryloxy) -.2 (S), 6 (S) - dimethyl-1,2,. 3,4,4a (S), 5,6,7,8,8a (S) -dehydrohydronaphthyl-4 (5j] ethyl heptanoate

- Add, under a nitrogen atmosphere, 30 ml of sodium methoxide to a suspension, under stirring, of 3.0 g of the compound of formula I in 50 ml of ethanol. The resulting solution is stirred at room temperature for 1/2 l, then diluted with 300 ml of ether. The ethereal solution is washed three times with one SOmlapa, dried over Mg.SO₄ and.they filter. The filtrate is evaporated in vacuo, leaving an oil which is chromatographed on a 60 mm column containing silica gel of sieve dimensions of -90 ... 157 mesh / cm. Elocarbon -with 250 ml, methylene chloride / ethanol (96: -4 vol: vol), under air pressure, the title compound is obtained as dc -substance-solid.

Exemplul'9. .7 (/ 2), 5 (R) -dihydroxy-7 - '[8iS) (2,2-dimethylbutyryloxy) -2 (S), (S) -dimethyl-1,2,4,4 (4a ($ ); 2,3-dihydroxypropyl heptanoate 5 (6,7,8,8a (S) -decahydronaphthyl-d (S)] heptanoate.

The sodium salt of the compound of the formula Ia is prepared by adding 0.55 ml of sodium hydroxide IN to a solution of 0.22 g of compound '1 in 2 ml of dimethylformamide. After stirring this solution for 15 minutes, 0.2 g l-i &lt;l-2, udihydrr oxypropane is added and the solution, under stirring, is heated for 6 h at SO^BUTC (oil bath). After cooling to ambient temperature, the reaction solution is poured into 100 ml ether. This ethereal solution is washed twice with 25 ml of salt solution, dried over MgSO₄and filter. The filtrate is evaporated in vacuo, leaving an oil which sc chromatographs on a 20 mm column containing silica gel of sieve dimensions of 90 ... 157 eyelets / cm. Elution with acetylene / methylene chloride (60.40 vol: vol) under air pressure gives the title compound as an oil that solidifies by letting it rest in the refrigerator overnight.

Preparation of lilac and lilac compounds (R ^ CII₃)

A. Fermentation

A freeze-dried MF-4845 culture tube was opened aseptically and the contents were suspended in an Erlcnmcjmr (germ culture vial) vial, containing approximately 10 ml of the medium having the following composition:

Environment - solution (extract) of wheat under pressure ........................... 5 g;

- tomato paste ............... 10 g;

- oat broth .......: 10 g;

- glucose ........................... 10 g;

- trace element solution ... 10 g;

- distilled water ..................... 1000 g;

- pH - 6.8 with NaOH Solution of trace elements - FeSCl,. 7H, 0 .................. 1000mg;

- MnSO₄.4H »O ............ 1000 mg;

- CuClș ,. 2H_ofO ............... 25 mg;

- H.₃BO_of ........................ 56 mg;

- CaCR. 2H, 0 ............... 100 mg;

- · (NH₄)_eMo₇b₂₁. 4H, 0 ...... 19 mg;

- ZnSO₄. 7H₂O ............... 200 mg;

- deionized distilled water ... 1000 ml.

The vial was inoculated for 24 h

28 ° C, on a shaker of 220 / min. An Erlenmeyer bottle of 21, containing 500 ml of medium, was then inoculated with 10 ml of the first phase of fermentation growth, from the germ mixture, and this was stirred 24 h at 28 ° C.

In a stainless steel fermentation tank, 485 1 dc medium- were introduced, containing:

- D-Glucose ...... 4.5% by weight / vol;

- peptonised milk ......

..................... 2.5% by weight / vol;

- brewer's yeast ... 0.25 weight / vol;

- polyglycol 2000 ............ 0.25 vol / vol;

whose / HT was adjusted to 7.0. It was sterilized for 15 minutes at 121 ° C. One liter of phase II fermentation · was then introduced and the mixture was incubated at 85 rpm for 12 h and then at 130 rpm for 84 h, at -28 ° C, with air ventilation. of · 5 x 30.4793 cm³ for 12 hours and then for 84 hours.

B. Isolation. 1. Extraction

Two batches of 375 1 complete broth were combined, acidified and homogenized to an H = 4.1, carefully adding 800 ml of concentrated HCl and extraction by adding 281 1 of ethyl acetate, continuing with stirring for another two hours.

About 25 x 453.6 g of auxiliary filter material was then added and the entire paste was pumped through a press filter. Additionally, 281 1 ethyl acetate was used to wash the press cake and continue the extraction, reversing the pumping direction by the press, 4 times. Then all the washing solvent was removed from the press and combined with the first filtrate.

The filtrate from the 2 phases was allowed to be clarified and the water layer removed. The ethyl acetate layer was washed with 37.5 1 deionized water, the phases were allowed to separate and the extract of ethyl acetate was concentrated in vacuo to a residue of about 37.5 1.

2. lactonization

Extracts by ethyl acetate from an additional broth of 1125 1 were added to the above extract and the volume was reduced to about 112.5 1 by vacuum distillation. About 186 1 toluene was added and the lot was concentrated in vacuo to a volume of 120 1. This ctafft was repeated; then enough toluene was added to bring the volume to 312 1. Without vacuum, the batch was brought to reflux and kept there for 2 h, with a temperature above 106 ° C. This solution was concentrated in vacuo at a small volume, which was further concentrated to an oily residue on a rotary evaporator, in vacuo.

3. Chromatography on silica gel

The extract obtained above was washed with a stream of liquid, to remove other solvents, by adding dc 4 1 of methylene chloride and re-concentrating it as oil.

The oily residue was dissolved in about 20 1 mixture of ethyl acetate and methylene chloride (30/70; vol: vol) and a paste was formed, by the addition of 2.8 kg of silica gel.

The paste (suspension) in the same solvent mixture was loaded in a horizontal layer on top of a silica gel column. The elution was made with ethyl acetate / methyl chloride light fractions, then further collected in fractions of 1 l each. Fractions 6–10 inclusive were concentrated in vacuo to an oily residue, which was dissolved in hot ethyl acetate, treated with carbon for, discoloration, hot filtrate and cooled. Compound III crystals "(R^!= CH₃) were sons.

82 307 treats in the mum solutions, were concentrated to the oil for subsequent chromatography. III "pure (R'— CH₃) arc melting point 17O ... 17PC.

4. Chromatography or silica gel Mummy solution residues from the similar broth extract, equivalent to an additional fermentation capacity of 2400 1, were combined as above, in methylene chloride solution. Half of this solution was taken for chromatography on silica gel.

A small aliquot showed a total solid residue content of 325 g. The solution was treated with 40 g decolorized coal, filtered and the cake rinsed with methylene chloride. The combined filtrate and the washing liquid were concentrated in vacuo to the oily residue. This was redissolved in 800 ml of ethyl acetate / methylene chloride (30/70 vol / vol) and 225 g of silica gel was added. The suspension was introduced into a column of cm x cm silica gel, with filling of the same solvent mixture. The ethyl acetate / methylene chloride (30/70 vol / vol) was further used.

An amount of 3 1a was initially taken separately. Subsequently, fractions of 200 ml each were collected.

Chromatography as phase reversal of the filling

5J) ml from fraction 10 of the previous chromatography were concentrated to the oily stage, weighing 500 mg, and the oily component, redissolved in 5 ml acetonitrile. This acetonitrile solution was introduced into a stainless steel column by chromatography, and the filling was made for chromatography with phase reversal of the liquid column. The column was eluted with a mixture, consisting of 55% vol / vol acetonitrile and 45% -0.05 Al dcamonium phosphate,&gt; 11 = 3.

The elution volume, between 1360 and 1700 ml, was combined based on the identification of the refractive index. The organic solvent was the basis for identifying the refractive index. The organic solvent was removed in vacuo and the residual aqueous solution extracted with ethyl acetate.

In vacuo, ethyl acetate-eliminated gave 120 g of compound which crystallized from a concentrated solution of acetonitrile, yielding crystals of compound III _a(R '= CH_of), melting point 129O ... 131 ° C.

Preparation of compounds III,_llClC

Starting substances 11%, Iile, III, (R '- CH₃) is prepared in accordance with the following technological scheme and methods of preparation:

Demethylated analogues 11%, III ,, III_C, (R '= R) are obtained starting with 11% (R' = H) in each case.

For the preparation of III _e it is advantageous to reduce III j, given that i2.S the perhydronaphthalene ring present in the starting substances is retained in the final product, as desired, and there is still a need to separate the isomers.

Reactions and reagents

1. Hydrogenation at about 2O ... 75 ° C and at atmospheric pressure, up to about 4 at, on Zrfs- {trifcnylphosphine) -chlor-rhodium, in an aromatic solvent, such as benzene, xylene or especially toluene.

In the case of toluene, the preferable conditions are 40 ° C and about 2 ... 7 at.

2. Hydrogenation at about 2O, 25^aC and at atmospheric pressure of 5% palladium c-carbonium carbonate in a lower alkanol, especially ethanol.

3. Hydrogenation at about 2O ... 25 ° C and atmospheric pressure on 10% palladium pc wood charcoal in ethyl acetate.

50 dc mixture (0.1236 mole) of 11% compound (R '= CH₃) and an equimolar amount (114.35 mg; 0.1236 mmol) of iris- (triphenylphosphine) -chlor-rhodium in 10 ml of toluene was hydrogenated at room temperature for 6 days, with a total take-off of 14.6 ml of hydrogen.

The mixture was evaporated in vacuo to dryness. The red residue was subjected to thin layer chromatography on silica sheets impregnated with silver nitrate and was carried out 2 times in 10% ethyl acetate-ethyl acetate. The product of compound II% (R '= CH₃) at 22.3 mg.

Spectral mass (M / c) 406 (nrj; 304 (m-102); 286 (m-102-18). NMR (CDC% 300 MHz) 54.37 (m, (H), 4.60 (m, H), 5.34 (doft, J 2.5 Hz, IM, 55.41 (m, IN),

A solution of 80.71 mg (0.2 mmol) of compound III '(R' = CH_of) in 10 nil of absolute ethanol, in the presence · of an equal weight of 5% Pd on CaCO₃ was hydrogenated at 1 h until a molar equivalent of hydrogen was observed. The catalyst was then removed by filtration and the filtrate evaporated to dryness (81 mg). After purification by thin layer chromatography, to remove a small amount of the dc tetrahydrocomputer by-product, 72 mg of the 1,4-reaction product II% (R '= CH) was isolated₃).

Spectral mass (Me) 406 (ni +), 304 (m-102), 186 (304-H, O). NMR (CDC 300% MHz) 4.38 (m, 1H), 4.64 (rn, IH), 5.28 (d of t, J = 3.5 Hz, IH), 5.48 (m, IH) ).

A solution of 80.91 (0.2 mmol) dc composed of 11% (R '= CH₃) in 10 ml of ethyl acetate was hydrogenated in the presence of the same amount of platinum dc oxide at 1 atm. An exact amount of 2 moles of hydrogen equivalent was consumed in the range of 1 li. The catalyst was removed by filtration and the filtrate was concentrated to dryness and passage into an oily substance. The cis and trans isomers were separated by sub-layer chromatography of 82367 on silica gel plates in the 10% ethyl acetate-benzyl acetate system detected. by spraying water. The trans isomer III_of(R '= CH₃) appears as a more polar spot, compared to the cis isomer, and 10 mg were isolated. Spectral mass (M / e) 4 () 8 (m +), 323 (m-85), 306 (m-102). NMR (CDC1)_S, 300 MHz) 4.36 (broud singlet), III), 4.59 (m, 1H), 5.19 (d or * t, J = 2.5 Hz, III).

Fermentation production of compound III "

A. Fermentation

A natural isolate of Penicillium citriitm, NRRL 6082, was used to prepare a malt yeast extract (YMR), which was incubated for 5 weeks at 28 ° C.

1/5 of the mixture (MF 4870 a) was used to incubate each of the 5 seedless (250 ml) vials without filter, containing germs, containing 44 ml of KF, germline medium with CaCb . These were incubated for 3 days at 28 ° C and 220 rpm. 0 part of the grown germs (about 1.5 ml) was used to incubate each of the 100 vials with medium, containing 40 ml of LM medium product without malt extract, The product vials were incubated 4 days at 25 ° C.

Another group of vials produced by rredium (140), each containing 40 ml of unaltered LM product medium, were incubated under the same conditions, as described above. The broths in both fermentations were combined. Great environments. in the previous fermentation are:

- dextrose ........................ 4 g / 1;

- malt extract ..................... 10 g / 1;

- yeast .................. 4 g / 1;

- agar .............................. 20 g / 1;

- distilled water ..................... 1 1;

- pH .............................. 7.0.

B. Isolation

The combined broths in total (10.3 1) were filtered and the micelle cake was washed with 2.5 L of distilled water. The mixture between the filtrate and the wash was adjusted to pP = = 4.0 with 1N hydrochloric acid. The aqueous solution was extracted with 7 1 of ethyl acetate and the extract was re-extracted with 3 χ 2 1 of aqueous sodium hydroxide solution.

The combination of the extract with the sodium dioxide was adjusted to a 3.8 pill with 1 N hydrochloric acid and then extraction of 2 1 and J 1 of ethyl acetate. The combined solution of ethyl acetate was dried with Na₂SO₄ anhydrous, filtered and concentrated to: 1a drying. The oily residue was dissolved in toluene shaken for 1 h. The toluene solution was concentrated to dryness and the residue was dissolved in 18 ml of w-hexane / toluene / methanol (4/1/1 per well). -The solution was introduced in an e30

Sephadex LH-20 30 mm (ID) .X 40 cm and balanced in the same solvent system. After elution with 300 ml of solvent, a fraction of 10 ml was obtained and concentrated to the oil stage. High performance liquid chromatography (HPLC) on a column (9mm χ 50 cin), using a mixture of acetonitrile / water (60/40 by volume), and the elution solvent provides 45 mg of dihydrocompactil. Compound III ¢, (Rb-H), mw 392, 2560 per mass spectrum (calculated for C_Q3H₃₆A₅, 392, 2558).

In KBr, most IR peaks obtained are Ia 1724, 1704, 1858, 1078 and 1070 cm.¹ significant is a peak of 3005 ..cm¹and.the absence of a peak At 3030 cm^-1.

A nuclear magnetic resonance spectrum was obtained in CDC1₃ (3 mg / 0.5 ml) on a spectrometer _:MRI superconductor. The peak positions given in ppm relative to teramethylsilane are as follows:

<td>â</td><td>Indicator group</td>

<td>5.62d, d, d (2.17, 4.5, 10.0)</td><td>H₃(or 4 ')</td>

<td> 5,43(1 (10)</td><td>(or 3 ')</td>

<td>5.20 m</td><td></td>

<td>4.65 m</td><td>h₆</td>

<td>4.39 m</td><td>^hand</td>

<td>2.75 d, d (17.5 / 5.5)</td><td rowspan="2">3-CH₂</td>

<td>2.63 d, d, d (17.5; 4.0; 1.5)</td>

<td>2.39 ni</td><td>ch₃CHC = a</td>

<td>2.29 in d, dm, from, multiple m, 1.5, 100)</td><td>I44a '+ H₂</td>

<td> 1,14 &lt;1</td><td>ch₃CHC = a</td>

<td>0.90 t</td><td>ch₃gh.</td>

<td>0.84 d</td><td>CÎÎgCHg</td>

d = doublet, tn = multiple, t- —.two

823G7

There is evidence that the structure is;

<img file="RO82367A_D0007.tif" />

It was found that the α-methylbutyryl group in field III_H (R '= CH₃) and the hydro-derivatives, III can be removed to produce a family of 6 (R) - (2,8-hydroxy-2,6-diethylpolyhydronaphthyl-1) -ethyl-4 (R) -hydroxy3,4,5,6-tetrahydro- 2H-pyran-2, which are but anti-hypercholesterolemic agents themselves and which are extremely useful as intermediates for the preparation of esters, which are even more potent in this use.

The preparation of the new alcohols of this invention is carried out by heating the esters III _a„ _and(R '= CH_s) with an alkali metal hydroxide, such as lithium hydroxide potassium hydroxide or sodium hydroxide in a protic solvent, such as water or alcohols, for a long time. Lithium hydroxide, lithium hydroxide in water is preferred at a reflux of about 50 ... 72 h or under pressure, at a higher temperature of 120 ... 180 ° C, for a shorter time, from 8. to 24 h.

The pyranonic cycle is ready, but the removal of the acyl group is not easy. heating must be prolonged and / or pressure must be used. An inert atmosphere is also useful. It is quite unexpected that molecules with so many highly sensitive functional centers can withstand the harsh conditions required for the removal of methylbutyric ester. In particular, high yields are not expected.

in the case of compounds III ȚK' — Π), the saponification of the esters is much easier, proceeding to completion in about 20 h, to obtain IV _f(R '= H).

Compound IV "(R '= H) is known as ML-236A, as mentioned in US Pat. 3.98314 million.

The products are isolated by acidification and extraction with organic solvents that produce the trihydroxyacid form of compounds IV "__e. These trihydroxy acids can be relactonized by heating an acid solution in a suitable organic solvent, such as toluene or benzene, in an apparatus allowing continuous separation of the formed water.

The alcohols that are part of this invention have the structures IV "_, (R '= CH_of), like trihydroxy acids, and results from the opening of lactone cycles.

An alternative synthetic route for compounds IV_t,_{[I (} it comprises the steps of hydrolysis dc to III "Ia IV", as described above, urinated by the hydrogenation of IV "under the conditions described previously for the preparation ΙΠ"._{£&gt; ί}, to produce IV * IV _c, or IV "depending on those reaction conditions.

Preparation of compounds IV

Raw materials, compounds 8'a-hydroxy IV_u__e (R '= CH₃) are prepared from esters (III ,, R '= CH₃), (III ,, R '= CH₃) and (III *, *, *, R '= CH₃), by heating them with lithium hydroxide solution for a long time, the pyranonic cycle is ready to open, but the removal of the so-called acyl group is not easy. The heating must be extended and / or added pressure. An inert atmosphere is also useful. In the case of compounds III, (R '= H) the saponification of the esters is much easier, proceeding to completion in about 20 h.

The 8'-hydroxy products are isolated by acidification and extraction with organic solvents which produce the hydroxyacid form, in which the pyranonic ring is still open. These hydroxyacids are re-contacted by heating an acid solution in a suitable organic solvent, such as benzene or toluene, in an apparatus which allows the continuous separation of the formed water.

Compound IV * (R '= H) is known as ML-236A, as shown in US Pat. 3.98314 million.

In their lactone form, these alcohols are compounds of formula IV_a__t in Table 7 and are prepared as described below.

The absolute configuration of these compounds is known by X-ray diffraction. Table 7 gives a convenient overview of this structure and their stereochemical connections. The reference numbers of the various compounds, including those of the different series of polyhydronaphilic structures, remain the same as in this description and are used as such. Each of the esters l_a_, (R '= CH₃) of this invention contain 7-8 chiral centers. The relative and absolute configuration of these asymmetric centers is shown in table 1. More specifically, for the ester I "(R '= CHj), the Calm, Ingold, Prelog designations for the absolute configurations are 4 (R), 6 (R), l' (S), 2 (S), 6 '(H), 8' (S) and 8a '(R) (R, S, Cahn, C. Ingold and V. Prelog, Andcw, Chem. Int, Ed. 5382 (1966);

<img file="RO82367A_D0008.tif" />

The compounds of this invention and

As indicated in formula I _c, all these compounds have the same spatial orientation of the groups at each asymmetric carbon atom, and therefore belong to the same stereochemical series. The R-S designation for each center may not be identical to that found for the ester Ϊ "(R '= CH₃) due to the details of the sequence rules used to determine this name. In the two esters% and I, which have an additional asymmetrical carbon atom, non-existent in ester 1 «, the hydrogen atom at 4a^J is in the bottom orientation (or st) in the transcyclic table 7.

Tabehtl 7 their stereo links:

<img file="RO82367A_D0009.tif" />

<img file="RO82367A_D0010.tif" />

<img file="RO82367A_D0011.tif" />

<img file="RO82367A_D0012.tif" />

R / = H or CH3 Stereochemistry of hydrophilic series

<td>write</td><td>Double links present</td><td>Structure</td>

<td>of</td><td>X and Z</td><td>1 1 i_Rz \ ^ \ z</td>

<td>b</td><td>X</td><td>ΤΊΠ_RZ \ Z \ Z</td>

<td>c</td><td>Y</td><td>Ί ii _RZ \ Z \ Z</td>

<td>tt</td><td> 7.</td><td>_Rxp D</td>

<td>c</td><td>nothing</td><td>AP</td>

<td> ·*</td><td></td><td></td>

82307

The 8'-acyloxy compounds of this invention are used as antihypercholesterolemic agents for the treatment of stereosclerosis, hyperlipcnia and other similar human diseases. They may be administered orally or by administration in the form of a capsule, tablet or injection or similar preparation. It is usually preferable for oral use. The doses may vary depending on the age, severity, body weight or 10 other conditions of human patients, but a daily dosage for adults is in the range of about 2 mg to 2000 mg (preferably 10 to 100 mg}, given in three or four divided doses, larger doses may be favorably applied as required.

The compounds of this invention also have useful antifungal activities.

For example, they can be used to control Penicillium sp., Aspergillus niger 20 Cladosporium sp., Cochliobolus miyabeanus and Helminthosporium cynodnotis. For these uses, they are mixed with suitable formulation agents, powders, emulsifying agents or solvents, such as aqueous ethanol 25, and administered in spray or dust on the plants to be protected.

The preparation of these compounds of the invention is described below:

<img file="RO82367A_D0013.tif" />

ch₃ eh₃ ch₃ch₃ J5V_LQ_l§tîI_of._e

R-CO-O

<img file="RO82367A_D0014.tif" />

vl_of-it's yours

IV_Q-&gt; I^vbc, and eo

Definitions: - X, Y, Z, R and R_s as defined in the description, and the e-series as defined in Table 7. 65

Reactions: I) sodium hydroxide, heating, acidification and lactonization;

2) Z-Butyldimethylc Iorsilane and imidazole in dimethylformamide at. ambient temperature and inert atmosphere;

3} treatment with RCOC1 and 4-dimethylanhnopyridine in pyridine solution, preferably in an inert atmosphere;

4) treatment with RCOOH and Ν, Χ'-dicyclohexylcarbodiimide and 4-pyrrolidinpyridine in dichloromethane, preferably in an inert atmosphere;

5) three equivalents of tetrabutylammonium fluoride and 4 equivalents of acetic acid on the ester equivalent in THE, preferably in an inert atmosphere;

6) alkaline aqueous solution, followed by careful acidification with dilute acid.

7} see reactions and reagents and description for synthesis III in the process of this invention, 4-hydroxyl on the pyranane ring of IV alcohols ", _e it is first protected with a t-butyldimethylsilyl group by reaction with t-butyldimethylchlorosilane in an inert atmosphere, at ambient temperature, in the presence of an acid acceptor, such as xmidazole, to produce protected Nas alcohols. 8-Hydroxyl on the polyhydronaphthyl ring is then acidified in one or two pathways. The first comprises treating with the chlorine acid the desired acyl group, in pyridine, in the presence of 4-dimethylaminophidine as a catalyst. The second comprises treating S-polyhydronaphthol with free acid of the desired acid group and a carbodiimide, such as Ν, Ν'-dicyclohexylcarbodiiinide with 4-pyrrolidinpyridine, as a catalyst, in dichloromethane. These procedures give protected VI esters. Removal of the 4-hydroxyl protecting silyl group in the pyranone ring is then performed using three equivalents of tetra-butylammonium fluoride and to give the desired compounds I. The proportion of reagents in the latter reaction is critical to process efficiency and product purity.

The acyl groups thus placed on 8'-hydroxyl are those wherein R in I is:

1) alkyl chain, linear or branched, except (S) -2-butyl;

2) C cycloalkyl₃_₁₀;

3) C alkenyl₂_₁₀;

4) CF₃ alkyl ί'ι_₁₀ replaced;

5) phenyl, '

6) halophenyl, wherein halogen is chlorine, bromine or iodine;

7) phenyl (C, _₃) alkyl;

8) phenyl (C._₃) substituted alkyl, wherein the substituent is halogen, for example, chlorine, fluorine, bromine or iodine, C 1-6 alkyl₃ or C alkoxy

It is preferred that R- is CH₃.

The preferred definitions for R are:

-, as linear alkyl C₂_₅;

823G7 - C-branched alkyl chain₃„_]0 except (S) 2-butyl;

- cycloalkyl Τ₃__ι0;

- C alkenyl₃__lib wherein the unsaturation is not in conjunction with carbonyl, in particular;

- C-branched alkyl chain_ta, ^withthe exception (S) -2-butyl-propyl or 1-ethyl-1-methylpropyl. It is also preferred that none of the X, Y, Z be a double bond.

Compounds I _c they can be hydrolyzed with bases, such as NaOH, to produce salts, such as sodium salt of Compounds II_a__r. Using the bases with other pharmaceutically acceptable cations produces salts of these cations. Carefully acidifying the salts produces hydroxyacids that change into compounds I_c. at acid pH.

Treatment of compound I, in acid or basic catalysis with methanol, ethanol, propanol, or butanol or with phenyldimethylamino-, or acetylamino-alkanol, or acetylainino-alkanols, forms the appropriate esters of the compounds

Pharmaceutically acceptable salts of this invention include those consisting of cations, such as: sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as amine salts such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, Ν, Ν'-dibenzylethylenediamine, chlorprocaine procaine, diethanolamine, N-benzylphenylethylamine, 1-&gt; chlorobenzyl-2-pyrrolidine-1-yl-inethylbenzimidazole, diethylamine-piperazine and iris- (hydroxymethyl) -aminomethane.

Typical formulations to fill a size C dc hard gelatin capsules contain: 3,125; 6.25; 12.5; 25 or 50 mg of one of the compounds of this invention, such as, for example, the product of example 3, step b, example 1 step C or example 2 step b and sufficiently finely ground lactose to provide a total content of capsule of 580 ... 590 mg.

The process according to the invention therefore has the advantage of obtaining compounds with superior pharmacological activity.