DK172858B1 - Process for preparing a naphthalene derivative, and a naphthalene derivative which can be used as an intermediate in this process - Google Patents

Description

DK 172858 B1

Compounds of formula I are known and have HMG-CoA reductase inhibitory properties.

zx / 1 οί''Ύ ^ ° io

They include the natural fermentation products mevinolin (R = CH3, U.S. Patent No. 4,231,938) and compactin (R = H, U.S. Patent No. 3,983,140) and derivatives thereof all with the natural 2-methylbutyrate side chain. Compounds of formula II with the 2,2-dimethylbutyrate side chain and R = CH3 are known to be more active inhibitors of HMG-CoA reductase than their 2-methylbutyrate analogs.

20 0 Ύ 11 0 <S „i"? * C «! CH, r SJL ^ CH3

Some compounds of formula II and processes for their preparation are disclosed in U.S. Pat.

30 4 444 784 and published EPO Application No. 33 538. However, the methods disclosed therein involve four different chemical steps: (1) de-esterification of the 2-methylbutyrate side chain, (2) protection of the 4-hydroxyl group in the pyra non-ring, ( 3) re-esterification to form the desired 2,2-dimethyl butyrate, and (4) deprotection of the 4- 2 hydroxyl group. This road was long and yielded low total yields.

U.S. Patent No. 4,582,915 discloses a novel pathway to the dimethylbutyrate side chain via direct alkylation of the α-carbon atom in the naturally occurring methylbutyrate side chain using a metal alkyl amide and a metal halide. However, this process has been found to have certain disadvantages in the commercial manufacture of a drug. In order to obtain a high transfer of starting material, it is necessary to use a repeated addition of the amide base and the methyl halide. Of course, this results in reduced yields and is time consuming. Furthermore, selective hydrolysis is still necessary to reduce the amount of unmethylated starting material to less than 0.7%. This step is time consuming as the hydrolysis of unreacted starting material is very slow and usually requires 20 hours. The overall yield for this process is moderate when the starting material is mevinolin. In addition to unreacted starting material, a number of other impurities are formed during the methylation and hydrolysis steps. These include when the starting material is mevinolin, des-butyrate quinoline and bis-methylated compounds wherein the α-lactone carbon atom is methylated in addition to the carbon atom of the 8'-c ester side chain, and a methyl ether wherein the ring oxygen atom of the lactone is now in the open form. has been methylated. The purity of the final product isolated from the whole process is near the limit of use as a product in human treatment.

A method with a less pronounced impurity spectrum 30 would ensure less change in batch-to-batch variations, causing problems in obtaining an acceptable final drug purity, without resorting to repeated recrystallizations with consequent loss.

The present invention thus relates to a novel process for preparing a naphthalene derivative Vi by alkylating the α-position in an acyl group, which is outlined by the following reaction scheme: 5 tc, H, tne> eSitw | T CONHR, o 0 ν / 5ί ("·> ί'-Γ, Μ,

RlX ^ o ch ”* u 'j $ r ~' X £ r- R · r R '«

] 1] IV

15 o 0 'X & r *' l * «,

20 V VI

Specifically, the process can be used to methylate methanol to produce a product which is a more reactive inhibitor of HMG-CoA reductase than mevinolin.

The reaction proceeds using just a single portion of base and methyl halide to form a product of pharmaceutically acceptable purity.

In practicing the process of the present invention, the product (VI) achieves substantially higher yields and, more importantly, with a higher purity than a similar product prepared according to the process of U.S. Patent No. 4,582,915.

35 4 DK 172858 B1

The process of the invention can be more precisely illustrated by the following reaction scheme: 5 HVV '-c * H' ("5ity - coNHR, 0 0 k ^ DSifllle ^ t-CUH,

<E> l-C4H, (ne) 2SiCl <4) R5X

10 R (R, 2 R * g III IV.

i-c4H, <».> lsias ^ CMH)! (lv ^ 0Si (t1e> et-C4H, o 15 n 7 (5) aq.Hr _ II? V ^ o CHfHz (ΤΓνΤοη * X ^ p ch'CH * R3nr5 T · X. ch3 <moo ° c r3 r®AXX-ch3

20 V VI

wherein R 1 is alkyl of 1 to 5 carbon atoms, R 2 is H, CH 3, OH or CH 2 OH, R 3 is H or alkyl of 1 to 3 carbon atoms, R 4 is alkyl of 3 to 5 carbon atoms, R 1 is identical to R 2 except that where R2 is OH or CH2OH, R'2 is OSi (Me) 2t-C «H9 or CH2OSi (Me) 2t-C4H5,

R 5 is alkyl of 1 to 3 carbon atoms, R 6 and R 7 are independently (i) alkyl of 1 to 3 carbon atoms or (ii) R 6 and R are attached to the nitrogen atom to which they are attached to form a 5 or 6 membered heterocyclic group such as pyrrolidine or piperidine, 5Re is selected from H, OH and CH; OH, provided that at least one of the groups R2 and Re is H, R'e is identical to Re except that where Re is OH or CH2OH, R'a is OSi (Me) 2t-C2 H9 or CH2OSi (Me): tC; H ?, 10 X is chlorine, bromine or iodine, M * is a cation derived from lithium, sodium or potassium, and 15a, b and c each represent single bonds, or a, b or c denotes a double bond, or both a and c denote double bonds.

Unless otherwise indicated, the term alkyl includes both straight chain and branched chain alkyl.

The preparation of compounds of formula VI from compounds of formula V wherein R 1 is ethyl, R 3 is methyl, 25 and R 5 is methyl are preferred.

This applies, inter alia, to the preparation of compounds of formula VI from compounds of formula V wherein R'2 is H, CH3 or CH2OSi (Me) jt-C3 Hg. This is especially true for the preparation of the compounds of formula V wherein a and c both represent double bonds. Examples thereof are the preparation of compounds of formula VI from compounds of formula V wherein 35 R 1 = ethyl, R 3 = methyl, = n-butyl, R 5 = methyl and a. R 1 = 2 CH 3, and R 1 = H, or 6 DK 172858 B1 b. R'2 = CH2OSi (Me) 2t-C «Hj, and R'B = H, or C.R'2 = H, and R'e = CH2OSi (Me) 2t-C4H9.

This also applies to the preparation of compounds of formula VI from compounds of formula V, wherein a, b and c are all single bonds. Examples thereof are the preparation of compounds of formula VI from compounds of formula V wherein 10

R 1 = ethyl, R 3 = methyl, R 4 = n-butyl, R 5 = methyl, and a. R 2 is CH 3 and R 1 is H or 15 b. R 2 is CH 2 Si (Me) 2t-C 4 H 9, and R's is H, or c. R'2 is H and R'B is CH2 Si (Me) 2t-C4H9.

It is preferred to prepare compounds of formula 20 VI wherein R 1 is ethyl, R 3 is methyl and R 3 is methyl.

In a class of this embodiment are those compounds wherein R 2 is CH 3 or CH 2 OH. In a subclass are those compounds in which a and c both represent double bonds.

Examples of this subclass are the compounds: (1) 6R- [2- [8 (S) - (2,2-dimethylburyryloxy) -2 (S), 6 (R) -dimethyl-1,2,6, 7,8,8a (R) -hexahydronaphthyl-1 (S)] ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, and (2) 6R - [2- [8 (S) - (2,2-dimethylbutyryloxy) -2 (S) -methyl-6 (R) -hydroxymethyl-1,2,6,7,8,8a (R) -hexahydronaphthyl-1 (S)] ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

In another subclass are those compounds in which a, b and c are all single bonds. Examples of this subclass are the compounds: 5 (1) 6 (R) - [2- [8 (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 (S) -dimethyl-1,2 3,4,4a (S), 5, 6, 7,8, 8a (S) -decahydronaphthyl-1 (S)] ethyl: -4 (R) -hydroxy-3,4,5,6-tetrahydro-2 2H-pyran-2-one, and 10 (2) 6R- [2- [8 (S) - (2,2-dimethylbutyryloxy) -2 (S) -methyl-6 (R) -hydroxymethyl-1,2, 3,4,4a (S), 5,6,7,8,8a (S) -decahydro-naphthyl-1 (S)] ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro -2H-pyran-2-one.

The novel process of the invention comprises selective C-alkylation of the α-position of the 8'-acyl side chain of the polyhydronaphthyl moiety of formula III. The C-alkylation takes place in the presence of α-hydroxyvalerolacone masked as alkylamide bis (tert-butyldimethylsilyl) -20 ether. Good yields are obtained with a single portion of base and alkyl halide. After C-alkylation, the alkyl amide is transferred pure into the valerolactone without affecting the C-alkylated acyl side chain. The entire process of protecting, C-alkylating and removing protecting groups 25 is carried out in a single container.

The starting lactone is transferred into an amide by reaction with an alkylamine, preferably n-butylamine, under an inert atmosphere such as nitrogen. The hydroxyl groups are protected with 30 tert-butyldimethylsilyl chloride or a similar reagent and a base such as imidazole.

The alkali metal amide is formed by combining a hydrocarbon solution of an n-butyl alkali metal wherein the alkali metal is lithium, sodium or potassium, preferably lithium, with a dried solution of R6R: NH where R6R-, NH is diethylamine. , dimethylamine, diisopropylamine or pyrrolidine, preferably pyrrolidine in an ethereal solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, preferably tetrahydrofuran at a temperature of about 5 -20 ° C.

The solution of hydroxyl protected alkylamide formed precooled to ca. -35 ° C, and the solution of alkali metal amide is added at such a rate to keep the temperature below -30 ° C. The solution is left at approx. -35 ° C for approx. 2 hours. Alkyl halide, preferably methyl chloride, methyl bromide or methyl iodide, especially preferred methyl iodide, is added to the mixture at once. The mixture is re-cooled to ca. -30 ° C for approx. 1 hour after the alkyl halide addition, it is heated to ca. -10 ° C over a period of approx. 20 minutes and leave for approx. 20 minutes at approx. -10 ° C. The reaction mixture is quenched with an excess of water and extracted with a hydrocarbon solvent such as cyclohexane or the like.

20

The tert-butyldimethylsilyl protecting groups are removed by treatment with an acid such as aqueous hydrofluoric acid. Aqueous sodium hydroxide is added to bring the pH of the solution to exactly 6.5 without allowing the temperature to rise to 25 above 10 ° C.

The above solution is added 2.0 N NaOH and refluxed for 1 to 6 hours, preferably 3 hours. The mixture is cooled to 25 ° C, diluted with water and the solvent is distilled off under vacuum. The mixture is cooled to ca. 10 ° C and carefully acidified with 3.0 N HCl to pH 7.0. Ethyl acetate is added and the layers are separated. The ethyl acetate layer is washed with water. Methanol is added and the mixture is heated to ca. 20 ° C with the addition of 35 aqueous NH 3 to crystallize the ΝΗ² - salt of the lactone over a period of approx. 15 minutes. When the crystallization is underway, the mixture is heated to 35-50 ° C for 5-60 minutes, preferably 45 ° C for 15 minutes, and then cooled to 10 to -20 ° C for 0.5 to 12 hours. preferably -10 ° C for 2.5 hours. The ammonium salt is washed with ethyl acetate / methanol and dried in vacuo with a stream of nitrogen.

The crude ammonium salt is suspended in a hydrocarbon solvent such as toluene and heated at 90-110 ° C for 2 to 12 hours, preferably 100 ° C for 3.5 hours, under a stream of nitrogen. The mixture is cooled to 25 ° C, filtered, and the filtrate is concentrated in vacuo while maintaining the internal temperature below 40 ° C. A hydrocarbon solvent such as cyclohexane is added and the mixture is heated under reflux for 0.1 to 1 hour, preferably 0.25 hours, then cooled for 1 to 12 hours at 25 to 10 ° C, preferably 2 hours at 10 ° C. to 15 eC. The product lactone is filtered and washed with cold hydrocarbon solvent, such as cyclohexane, then dried in vacuo to give a high purity product.

The product obtained above is recrystallized from aqueous methanol to give a product of pharmaceutically acceptable purity as determined by HPLC.

25

The starting material lovastatin, wherein R1 = ethyl, R- = CH3 / R3 = CH3 and a and c are double bonds, is readily available or can be prepared according to the fermentation procedures described in U.S. Patent No. 4,231,938.

30 Lovastatin hydrogenation derivatives are prepared according to the procedures outlined in U.S. Pat.

4,444,784. The starting material compactin, wherein R 1 = ethyl, R 2 = H, and R 3 = CH 3, and a and c are double bonds, are prepared according to the fermentation procedure outlined in U.S. Patent No. 4,231,938. wherein R 2 = CH 2 OH is prepared according to the procedure outlined in USSN 048 136. The compounds in which R 2 or R 9 are OH are prepared according to the methods described in U.S. Patent Nos. 4,537,859 and 4,517,373.

5

The invention is further explained by the following examples.

Example 1 10

Preparation of 6 (R) - [2- [8 (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 (R) -dimethyl-1,2,3,6,7,8,8a (R) -hexahydro-1 (S)] - ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (1a) 3,5-bis (tert-butyldimethylsilyl) lovastatin-butylamide (A compound of formula IV wherein Rx = ethyl, R'2 = methyl, R3 = methyl, R4 = n-butyl, R'e = H, and a and c are double bonds).

All manipulations are performed under a nitrogen atmosphere.

53.0 g (0.128 mol) of lovastatin was dissolved in 210 ml (2.12 mol) of n-butylamine at 25 ° C and heated to gentle reflux at 80 ° C. After 1 hour, the solution was cooled to 25 ° C, the pressure was reduced to 120 mm Hg and the butylamine was distilled off at a bath temperature of 60 ° C. The concentrated solution was cooled to 25 ° C and 263 ml of dimethylformamide (sieve dried, K.F.

= 43) was added (apparent volume = 373 ml).

The pressure was again reduced to 120 mm Hg and the mixture was heated at 110 ° C (bath temperature) for 45 minutes while collecting 17 ml of distillate. The mixture was then cooled to 25 ° C and 19.59 g (0.288 mol) of imidazole and then 44.4 g (0.288 mol) of tert-butyl dimethylsilyl chloride were added. The mixture was then heated at 60 ° C for 8 to 14 hours until the silylation was complete.

11 DK 172858 B1

The mixture was cooled to 12 ° C and 5.8 ml (0.143 mol) of anhydrous methanol were added and the mixture was allowed to stand at 10-15 ° C for 0.5 hour. The mixture was then partitioned between 1.5 liters of cyclohexane and 750 ml of distilled water and stirred vigorously. The layers were separated and the upper layer (cyclohexane) washed with 750 ml of saturated aqueous sodium bicarbonate and 750 ml of distilled water.

The cyclohexane layer was distilled at ambient pressure.

After collecting 1320 ml of distillate (vessel volume = 580 ml), the solution was distilled with 600 ml of screen-dried THF and then 110 ml of distillate was collected under distillation of the mixture at ambient pressure. The solution was then cooled to 25 ° C for use in the next 15 steps.

(Ib) 3,5-bis- (tert-butyldimethylsilyl) synvinoline-butyl amide (a compound of formula V wherein R 1 = ethyl, R 2 = methyl, R 3 = methyl, R 1 = n-butyl, R 1 e = H, and a and c 20 are double bonds).

A solution of 25.13 ml of sieve-dried pyrrolidone and 192 ml of sieve-dried THF was cooled to -18 ° C. 182.5 ml of a 1.65 M solution of n-butyl lithium (0.301 mol) in hexane was added at such a rate that the temperature was kept below -10 ° C (about 15 minutes). After complete addition, the mixture was allowed to stand at -20 ° C for 15 minutes.

A solution of 3,5-bis- (tert-butyldimethylsilyl) lovastatin-butylamide in THF / cyclohexane was cooled to -35 ° C. The solution of lithium pyrrolidide at -20 ° C was then rapidly added to the stirred mixture at such a rate that the temperature was kept below -30 ° C during the addition. The solution was then left at -35 ° C for 2 hours. 12.2 ml (0.196 mol) of dried methyl iodide was then added to the mixture at one time. The mixture was then cooled to -30 ° C and left for 1 hour after the methyl iodide addition, then heated to -10 ° C over 23 minutes and left at -10 ° C for 20 minutes.

The mixture was quenched with 550 ml of water and quickly stirred for 10 minutes. The phases were separated and the lower (aqueous) phase was re-extracted with 465 ml of cyclohexane.

The combined organic phase was washed with 500 ml of 1 N HCl and 500 ml of 10% Ts aqueous sodium bisulfite (NaOHSO3).

The combined organic phase was concentrated at 120 mm Hg to a volume of 300 ml. This concentrated solution was used directly in the next step.

(lc) Synvinolin-butylamide 15

The concentrated solution of the previous step was diluted with 600 ml of acetonitrile and the mixture was again concentrated at 120 mm Hg to a volume of 300 ml. The mixture was cooled to 25 ° C and 20 300 ml of acetonitrile was added. The resulting solution was cooled to 7 ° C. 79 ml of 50% aqueous solution of hydrofluoric acid was added. The mixture was then heated to 25 ° C over 1 hour. The mixture was allowed to stand at 25 ° C for 1.5 hours, then cooled to 5 ° C. Aqueous 3 N sodium hydroxide (NaOH) was carefully added to the rapidly stirred mixture to bring the pH of the solution to exactly 6.5. At no time during the base addition was the temperature allowed to rise above 10 ° C. The layers were separated and the lower (aqueous) phase was extracted back with 30 788 ml of THF / cyclohexane solution (563 ml of THF / 225 ml of cyclo hexane). The THF / cyclohexane extract was combined with the original acetonitrile layer and the combined extracts were concentrated at 120 mm Hg to a volume of 290 ml.

1000 ml of anhydrous ethanol was added and the volume 35 was reduced to 788 ml by distillation at 120 mm Hg.

This solution was used directly in the next step.

13 DK 172858 B1 (ld) Ammonium salt of synvinoline

To the ethanol solution of synvinoline-butylamine from the previous step, 164 ml of 2N sodium hydroxide (NaOH) was added at 25 ° C and the resulting solution was brought to gentle reflux (81 ° C). After 3 hours, the mixture was cooled to 25 ° C and diluted with 789 ml of distilled water. The pressure was reduced to 120 mm Hg and ethanol was distilled off. The vessel volume was reduced to 788 ml by collecting 840 ml distillate. The mixture was cooled to 11 ° C and carefully acidified with 3.0 N HCl to pH = 7.0. 925 ml of ethyl acetate was added and the aqueous phase was further acidified to pH = 2.5. The lower (aqueous) phase was re-extracted with 463 ml of ethyl acetate and combined with the first ethyl acetate layer. The combined ethyl acetate layer was washed with 360 ml of water. 533 ml of anhydrous methanol was added and the mixture was heated to 20 ° C while adding 18.0 ml of 28% aqueous NH 4 OH over 15 minutes. When crystallization was underway, the mixture was heated to 45 ° C, allowed to stand for 15 minutes, then cooled to -10 ° C for 2.5 hours. After standing for 1 hour, the product was filtered off and washed with 3: 1 ethyl acetate / methanol (338 ml EtOAc / 112 ml MeOH, -10 ° C). The product was dried in vacuo with a nitrogen stream at 30-35 ° C to give the title compound from step (ld).

(Le) 6 (R) - [2- [8 (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 (R) -dimethyl-1,2,6,6,7,8, 8a (R) -hexahydro-1 (S)] ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one

Lactonization 25.0 g (52.35 mmol) of the crude ammonium salt of step 1 (d) was suspended in 500 ml of toluene and heated at 100 ° C under a constant stream of nitrogen for 3.5 hours.

The solution was cooled to 25 ° C and 1.25 g of "Darco KB" (activated carbon) was added. The mixture was stirred at 25 ° C for 0.5 hour and filtered through "SuperCel" 10 (diatomaceous earth), and the filtrate was concentrated in vacuo to a volume of 50 ml, maintaining an internal temperature of less than 40 ° C. 300 ml of cyciohexane was added and the mixture was heated at reflux for 0.25 hours, then cooled over 2 hours to 10-15 15 ° C and left for 1 hour. The product was filtered and washed with 115 ml of cold cyciohexane and then dried in vacuo at 30-35 ° C to give the desired compound as a crystalline solid.

Recrystallization

The lactonized product (20.0 g) was dissolved in 240 ml of methanol at 25 ° C under N 2, then filtered through a 15 g disc of "Ecosorb-C" (homogeneous mixture of activated carbon 25 on fiber supports over 0 ° C). 25 hours). "Ecosorb-C" was rinsed with an additional 40 ml of methanol. The combined filtrate was heated to 35 ° C and 90 ml of water was added over 0.25 hours. The mixture was cooled gradually at a rate of 5 ° C / 0.25 hours until crystallization began.

The mixture was allowed to stand for 0.5 hours, then reheated to 40 ° C, and the remaining 190 ml of water was slowly added over 1 hour. The mixture was cooled to 35 ° C over 1.5 hours, allowed to stand for 1 hour, filtered and the product washed with 90 ml of equal volume methanol and water. The product was dried in vacuo at 30-35 ° C under a stream of nitrogen to give the title compound in pharmaceutically acceptable purity as white elongated bars. The title compound was identified by HPLC.

Examples 2-4

By following the procedure essentially as described in Example 1, but instead of lovastatin as used therein, using approx. Equimolar amounts of the compounds of formula III as described below were also prepared in the following, 2,2-dimethylbutyrate products 15

Ri Ri R3 and b c R5

Example 2 CH 3 CH 2 CH 3 CH 3 - - - CH 3

Example 3 CH3CH2 CH2OH CH3 db - db CH3 Example 4 CH3CH2 CH20H CH3 CH3

Claims (19)

A process for the preparation of a naphthalene derivative 5 of the general formula VI .xr ·% φ. Wherein R 1 is alkyl of 1 to 5 carbon atoms, R 2 is H, CH 3, OH or CH; OH, R 3 is H or alkyl of 1 to 3 carbon atoms, R 5 is alkyl of 1 to 3 carbon atoms, Re is selected from H, OH and CH 2 OH, provided that at least one of the groups R 2 and Re is H, and a, b and c each represents single bonds, or a, b or c denotes a double bond, or both a and c denote double bonds, characterized by treating a compound of the general formula V1 t-C4H, (r, e> 2Si (v ^ coNHR <L .OSi (ne) et-C4H, '> Λ ~ c »f> 5 R3 R4 ^ JULy # CH3 R'e V R'e V 10 wherein Rf R3, R5 and a, b and c have the meaning given above and R <is alkyl having 3 to 5 carbon atoms, R'2 is selected from H, CH3, OSi (Me); t-C4H; and CH 2 Si (Me) jt-C 2 Ho, and R 1e are selected from H, OS 1 (Me) 2t-C 4 H 9 and CH-OS 1 (Me) 2 t-C 4 H 9, with at least one of the groups R'2 and R ' e is H, 20 with (A) acid in a polar solvent to remove the silyl protecting groups, then (B) treats the diluted base deprotected product for hydrolysis of the alkylamide, and then (C) heats the carboxylate salt of the lactone in a hydrocarbon. dridopløsningsmiddel. Process according to claim 1, characterized in that the acid in step (A) is hydrofluoric acid and the polar solvent is acetonitrile, that the diluted base in step (B) is 2.0 N NaOH and that the carboxyl salt in step (A) C) is heated at 100 ° C in toluene. DK 172858 B1 Process according to claim 2, characterized in that, after treatment of the deprotected product with NaOH, the hydrolyzate is contacted with aqueous ammonia to form the ammonium salt of the lactone. 5 Process according to claim 3, characterized in that a and c both represent double bonds. Process according to claim 4, characterized in that the compound prepared is selected from: (a) 6 (R) - [2- [8 (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 ( R) -dimethyl-1,2,6,7,8,8a (R) -hexahydronaphthyl-1 (S)] ethyl] 4- (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran -2-one, or (b) 6 (R) - [2- [8 (s) - (2,2-dimethylbutyryloxy) -2 (S) -methyl-6 (R) -hydroxymethyl-1,2, 6,7,8,8a (R) -hexahydronaphthyl-1 (S)] ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one. 20 A process for preparing a naphthalene derivative of general formula VI. V 'A cif «C V 30. Rb VI wherein R 1 is alkyl of 1 to 5 carbon atoms, R 2 is H, CH 3, OH or CH: OH, DK 172858 B1 R-3 is H or alkyl of 1 to 3 carbon atoms, R 5 is alkyl of 1 to 3 carbon atoms, Re is selected from H, OH and CH 2 OH, provided that at least one of the groups R; and Re is H, and a, b and c each represent single bonds, or a, b or c denote a double bond, or both a and c denote double bonds, characterized by treating a compound with an inert atmosphere. the general formula HVY 15 0 k <ζχΤ 20 * · III wherein R 1, R 3, R 3, Re, a, b and c have the meaning given above, with A) an alkylamine, R 4 NH 2, wherein R 1 is alkyl of 3 to 5 carbon atoms, followed by protection with tert-butyldimethylsilyl chloride and imidazole, and B) is treated with an alkali metal amide of the formula M Wherein M 'is a cation selected from sodium, potassium and lithium and R6 and R7 are independently alkyl of 1 to 3 carbon atoms, or R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring of 5 or 6 link, followed by contact with R, X, where X is chlorine, bromine or iodine and R5 has the meaning given in the preceding paragraph to form an intermediate of the general formula V ----- ------------------ 5 l -0Si <He> 2l-C «H9 o R1 JL, CHe X ^ O CHe 2 R 10, wherein R 1, R 3, R 4, R 5 and a, b and c are as defined above, and R 2 is selected from H, CH 3 / OSi (Me) 2t-C 4 H 3 and CH 2 OSi (Me) 2t-C4H + and R'b is selected from H, OSi (Me) 2t-C4H9 and CH: OSi (Me) 2t-C4H9, with at least one of the groups R'2 and R'b being H, C) followed by 25 (i). ) treating compound V with acid in a polar solvent to remove the silyl protecting groups, (ii) treating the deprotected product with diluted base for hydrolysis of the alkylamide, and (iii) heating the carboxylate salt of the lactone in a hydrocarbon solvent. . DK 172858 B1 Naphthalene derivative usable as an intermediate in the process of claim 1, characterized in that it has the general formula V 5 t-C-H 2 neipSiCW +. 4. e ^ Y ^^ CONHR4 L -CBi (Me) 2t-C4H, 0 Y o CH, e; \ whii "3 K5 f · I" ru 10 ^ ssL ^ lvv ^ CH3 r '* 2 V c D »" 8 V 15 wherein R 1 is alkyl of 1 to 5 carbon atoms, R 3 is H or alkyl of 1 to 3 carbon atoms, R 4 is alkyl of 3 to 5 carbon atoms, R 5 is alkyl of 1 to 3 carbon atoms, R '2 is selected from H, CH3, OSi (Me) 2t-C. | H9 and CH2OSi (Me) 2t-C' H9, R'e is selected from H, OSi (Me) jt-C4H9 and CH2OSi ( Me) 2t-C4H9, however, at least one of the groups R'2 and R'e is H, and 30a, b and c each represent single bonds, or a, b or c denote a double bond, or both a and c denote double bonds.