HU213393B - Process for preparing new intermediates for use to prepare castanospermine - Google Patents

Abstract

The following cpds. are new: ethyl 5,7-dideoxy-5- (Boc-amino)-1,2-0- isopropylidene-alpha-D-gluco-6-octulo-1,4:6,3-difu ranuronate (I); ethyl 5,7-dideoxy-5-(Boc-amino)-1,2-0- isopropylidene-L-glycero-alpha-D-gluco-octofuranuronate (II); (3aR-(3aalpha, 5alpha(4Sasterisk, 5R asterisk), 6alpha,6aalpha)) -4-hydroxy-5-(tetrahydro-6 -hydroxy-2,2- dimethyl-furo(2,3,-d) (1,3)dioxol-5-yl)-2-pyrrolidinone (III); (3aR-(aalpha, 5alpha(3R asterisk, 3Sasterisk), 6alpha,6aalpha)) -2-(tetrahydro-6-hydroxy-2,2 -dimethyl-furo (2,3-d)(1,3)dioxol-5-yl)-3-pyrrolidinol (IV). - Castanospermine (V) is produced by (a) reacting 5-(Boc-amino)5-deoxy-1,2-0- isopropylidene-alpha-D-glucuronolactone (VI) with EtOAc and a strong base in an inert solvent to low temp. to form (I); (b) hydrogenating (I) in the presenc of a Pt catalyst in EtOAc to form (II); (c) treating (II) with HCOOH in an inert solvent with cooling to remove the protecting gp., followed by basification and cyclisation to form (III); (d) reducing (III) with an Al hydride to form (IV); and (e) treating (IV) with CF3OOH with cooling and then hydrogenating in the presence of a Pt catalyst under pressure to form (V).

Description

The present invention relates to the preparation of intermediates of general formula (A) used in the process for the preparation of castanpospermin, wherein R is hydrogen or = O.

Castanospermin is a naturally occurring indolizidine alkaloid that inhibits the enzymatic hydrolysis of glycosides, and has anti-cancer, anti-viral and anti-AIDS effects. In addition, ester and glycosyl derivatives of castanospermin are mentioned in the literature (see European Patent Application 0297 534) as inhibitors of digestive enzymes and used in the treatment of diabetes.

Castanospermin was originally obtained from natural sources in kilograms. But the process is costly and limited by the availability of plant resources. More recently, castanospermine has been synthesized by various methods, as described by Bemotas et al., Tetrahedron Letters, 25, 165 (1984); Setol et al., Tetrahedron Letters, 26, 4617 (1985); Hamana et al., J. Med. Org. Chem., 52, 5492 (1987)]; and Reymond et al., 1989, Tetrahedron Letters, 30, 705. The various processes are either quite lengthy and of low productivity and / or are non-specific in that they require the separation of a significant amount of the intermediate in undesired stereochemical configuration or have other drawbacks.

Thus, although Reymond et al., For example, claim that their process is "very stereoselective," the yield is poor in many steps of the process. Further, although Hamana et al. Describe their process as "most efficient at this time," the process requires the introduction of an oznolysis step that limits its application on an industrial scale.

The present invention relates to a process for the preparation of new intermediates of general formula (A) which can be used in the preparation of castanospermine according to Scheme 1 wherein R is hydrogen or = O. Formula A includes compounds of formulas IV and V.

In the process of the scheme, castanospermin is prepared starting from 5- (tert-BOC) amino-5-deoxy-1,2-O-isopropylidene-α-D-glucuronolactone. The term tert-BOC or BOC refers to a tert-butoxycarbonyl group.

The conversion of 5- (tert-BOC-amino) -5-deoxy-1,2-O-isopropylidene-α-D-glucuronolactone to castanospermine comprises the following steps; (a) reacting 5- (tert-BOC-amino) -5-deoxy-1,2-O-isopropylidene-α-D-glucorono-lactone of formula (I) in ethyl acetate and a strong base with ethyl acetate and a strong base -acetate is added to the carbonyl group of the lactone to give the cyclic hemiketal of the β-keto ester (compound of formula II); (b) hydrogenating the hemiketal in ethyl acetate under pressure in the presence of a platinum catalyst to reduce the β-keto group; (c) treating the resulting β-hydroxy ester of formula (III) with anhydrous cooling to remove the protecting group in an inert solution, followed by the alkalization and internal cyclization of the amine to give the lactam (IV); (d) reducing lactam with aluminum hydride; and (e) the resulting pyrrolidine of formula (V) is first treated with trifluoroacetic acid under cooling and then hydrogenated over platinum catalyst to form castanospermin of formula (VI).

In the process of the present invention, the compound of formula (III) wherein R is = O is deprotected, followed by internal cyclization with a base and, if desired, a compound of formula (A) wherein R is hydrogen, the resulting compound of formula IV is treated with a reducing agent.

The hydrolysis of the compound of formula (III) to remove the tert-butoxycarbonyl protecting group from the amino group is preferably carried out with formic acid, as other conventional hydrolyzers do not function well here. By hydrolysis, the amine is in fact obtained in the form of its formate salt, and its solution is rendered alkaline to the free amine. The alkaline base is preferably a column-shaped basic ion exchange resin. The formation of the free amine results in cyclization with the ester group to give the corresponding γ-lactam of formula IV.

The lactam (TV) is reduced in aluminum solvent with aluminum hydride to the corresponding cyclic amine (V) (pyrrolidine). Preferably, lithium aluminum hydride is used in an ethereal solution such as tetrahydrofuran.

The following examples illustrate the process of the invention and the preparation of starting compounds without limiting the scope of the invention.

Example I 1,2-O-Isopropylidene-5-oxo-CL-D-glucuronolactone hydrate

Dimethyl sulfoxide (10.7 g, 0.14 mol) was dissolved in methylene chloride (200 mL) and oxalyl chloride (8.0 mL, 0.09 mol) in methylene chloride (50 mL) was added dropwise at -70 the reaction temperature should be below -55 ° C. After stirring for half an hour at -70 ° C, 10.0 g (0.046 mol) of 1,2-isopropylidene-α-D-glucuronolactone dissolved in 100 ml of methylene chloride are added dropwise over 10 minutes and also kept below -55 ° C. reaction temperature. After stirring for 3 hours at -70 ° C, triethylamine (18.0 ml, 0.13 mol) was added dropwise over 5-10 minutes, again keeping the temperature below -55 ° C. After another 15 minutes, the cooling bath was removed, water (2.0 mL) was added and the mixture was allowed to warm to room temperature. Ethyl acetate (350 mL) was added, the resulting slurry was added dropwise to silica gel (250 mL) and eluted with ethyl acetate (500 mL). Evaporation of the eluate gave 10.0 g (94%) of crude product. If its sample amount is 1; Recrystallization from 1: ethyl acetate / hexane gave pure 1,2-O-isopropylidene-5-oxo-αD-glucuronolactone as colorless needles: mp 145-148 ° C; 1 H NMR (acetone-d 6 δ 1.41 (s, 3, CH ₃ ) 1.57 (s, 3, CH ₃ ), 4.62 (d, 1, J = 3.1 Hz, H-3), 4.91 (d, 1, J = 3.7 Hz, H-2), 4.98 (d, 1, J = 3.1 Hz, H-4), 5.26 (s, 1, OH) , 5.50 (s, 1,

HU 213 393 Β

OH), 6.03 (d, 1, J = 3.7 Hz, 1H); mass spectrum, m / z (relative intensity) 215 (MH ⁺ -H ₂ O, 100), 185 (15), 157 (12).

Example 2A

1.2-O-Isopropylidene-5-oxo-α-D-glucurono-lactone-O-benzyloxime in ml benzene 1.85 g (7.9 mmol) of 1,2-O-isopropylidene-5-oxo-α-D-glucurono- The lactone hydrate was suspended, O-benzylhydroxylamine hydrochloride (1.28 g, 7.9 mmol) was added and the resulting mixture was refluxed for 3 hours. (During this time, the hydroxylamine and the starting material are completely dissolved.) The solution is cooled and the solvent removed. The residual viscous oil was purified by chromatography on 100 ml of silica gel with ethyl acetate / hexane 1: 3 as eluent to give 2.51 g (99%).

1.2-O-isopropylidene-5-oxo-αD-glucuronolactone O-benzyloxime is obtained in the form of a colorless viscous oil which slowly solidifies on standing. NMR analysis showed that only one oxime isomer was present. An analytical sample was recrystallized from benzene-hexane (1: 1) to give colorless prisms: mp 83-85 ° C; 1 H NMR (CDCl ₃ ) δ, 36 (s, 3, CH ₃ ) 1.52 (s, 3, CH ₃ ), 4.86 (d, 1, J = 3.5 Hz, H-2), 4.91 (d, 1, J = 4.4 Hz, H-3), 5.42 ("AB" sub-spectrum, 2 J _AB = 13.7 Hz, CH ₂ ), 5.51 (d, 1, J = 4.4 Hz, H-4), 6.00 (d, 1, J = 3.5 Hz, H 1), 7.37 (m, 5, C ₆ H ₅ ) ¹³ C NMR (CDCl ₃ ) 0 26.66, 27.34, 60.02, 72.22, 79.60, 83.15, 83.23, 107.07, 113.71, 128.54, 128.62, 128.74, 128 , 83, 135.46 144.52, 162.96; mass spectrum, m / z (relative intensity) 320 (MH +, 100), 262 (15), 91 (90).

Example 2B

1.2-O-Isopropylidene-5-oxo-α-D-glucurono-lactone-O- (trimethylsilyl) oxime Dissolve 0.45 g (1.9 mmol) of 1,2-O-isopropylidene-5 in 1 ml of benzene. A mixture of -oxo-αD-glucuronolactone hydrate and 0.24 g (2.3 mmol) of O- (trimethylsilyl) hydroxylamine was heated to reflux under nitrogen stirring with vigorous stirring and heated to reflux. for hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residual thick oil was dissolved in about 35 mL of ethyl acetate and filtered through a celite pad to remove insoluble material. The filtrate was evaporated to give crude 0.6 g (about 100%)

1.2-O-isopropylidene-5-oxo-α-D-glucuronolactone-O-trimethylsilyl oxide is obtained as a grayish amorphous solid. This is a mixture of oxime stereoisomers of about 3: 2 by 1 H NMR, which is not investigated further. The crude oxime was used without further purification in the following reactions: 1 H NMR (DMSO-d 6) δ 6.03 (d, 1, J = 4.0 Hz) 5.42 (d, 1, J = 4.3 Hz) δ , 05 (d, 1, J = 4.3 Hz), 4.90 (d, 1, J = 4.0 Hz), 1.44 (s, 1), 1.29 (s, 1,) 0 , 00 (s, 9); mass spectrum (CL / CH 4), m / z (relative intensity) 302 (MH ⁺ , 4) 258 (12), 230 (100), 172 (40), 95 (60).

Example 3A

Preparation of 5- (tert-BOC) -amino-5-deoxy-1,2-O-isopropylidene-α-D-glucuronolactone from O-benzyloxime

1,2-O-Isopropylidene-5-oxo-α-D-glucurono-lactone-O-benzyloxime (3.16 g, 9.9 mmol) and 2.38 g (10.9 mmol) of (BOC) ₂ O in 20 mL of ethyl dissolved in acetate, 0.5 g of 10% palladium on charcoal (Pd / C) was added and the mixture was stirred for half an hour under nitrogen. The catalyst was filtered off and washed with 10 mL of ethyl acetate. To the filtrate was added 0.9 g of fresh Pd / C and hydrogenated on a Parr apparatus at 3 atmospheric pressure for 60 hours. The catalyst was filtered off, washed with ethyl acetate (15 mL) and the filtrate was evaporated. The residue was purified by chromatography on silica gel (80 mL), eluting with ethyl acetate: hexane (1: 3), to give 1.85 g (59%) of 5- (tert-BOC) amino-5-deoxy-1,2,2-O. -isopropylidene-αD-glucuronolactone is obtained. An analytical sample was recrystallized from ethyl acetate / hexane (1: 1) to give colorless needles; mp 157-159 ° C;

1 HNMR (CDCl 3) δ, 35 (s, 3, CH ₃ ) 1.46 (s, 9, C ₄ H _e ), 1.52 (s, 3, CH ₃ ), 4.78 (dd, 1, J = 8.8, 4.2 Hz, H-5), 4.82 (d, 1, J = 3.7 Hz, H-2), 4.84 (d, 1, J = 3.0 Hz) , H-3), 4.95 (dd, 1, J = 4.2, 3.0 Hz, H-4), 5.10 (d, 1, J = 8.8 Hz, NH), 5, 93 (d, 1, J = 3.7 Hz, 1H); mass spectrum, m / z (relative intensity) 316 (MH ⁺ , 5), 288 (20), 260 (100), 216 (40).

Example 3B

Formula (1)

Preparation of 5- (tert-BOC) amino-5-deoxy-1,2-O-isopropylidene-α-D-glucuronolactone from O- (trimethylsilyl) oxime

If Example 3A is repeated using 1,2-O-isopropylidene-5-oxo-αD-glucuronolactone-O- (trimethylsilyl) oxime instead of O-benzyloxime, with an average yield of 5-60%. (tert-BOC) amino-5-deoxy-1,2-O-isopropylidene-αD-glucuronolactone is obtained.

Example 4

Ethyl-5,7-dideoxy-5 - {[(tert-butoxy) carbonyl] amino}

1,2-O- (1-methylethylidene) -α-D-gluco-6-octulo-1,4: 6,3-difuranuronate

To a solution of diisopropylamine (7.7 mL, 55.0 mmol) in anhydrous tetrahydrofuran and cooled to -78 ° C under dry nitrogen, 34.4 mL (55.0 mmol) was added dropwise over 5 minutes under vigorous stirring. 1.6M solution of n-butyllithium in hexane. The resulting solution was stirred for 20 minutes at -78 ° C and then

Ethyl acetate (5.5 mL, 56.2 mmol) was added dropwise over 10 to 15 minutes maintaining the reaction temperature below -70 ° C. After 20 min, 5.3 g (16.8 mmol) of 5- (tert-BOC) amino-5-deoxy-1,2-O-isopropylidene-α-D-glucuronolactone in 50 ml of tetrahydrofuran are added. Dropwise over 20 minutes, also keeping the reaction temperature below -70 ° C. The reaction mixture was stirred for an additional 2 hours at -78 ° C, then allowed to warm to -10 ° C and poured into a mixture of 100 mL of IN hydrochloric acid and about 100 g of ice. This mixture is 3 x 100 ml

Extract with ethyl acetate and wash the combined extracts with 100 mL of unsaturated sodium bicarbonate and 100 mL of brine, then dry over magnesium sulfate and concentrate under reduced pressure. The oily residue was purified by flash chromatography on 100 ml of silica gel using 3% methylene chloride in acetone as eluent. 6.6 g (97%) of pure ethyl 5,7-dideoxy-5 - {[(tert-butoxy) carbonyl] amino} -1,2-O- (1-methyl) as a colorless oil are obtained. ethylidene) -α-gluco-6-octulo-1,4: 6,3-difuranuronate, which according to 1 H NMR analysis is the pure isomer in which the N-BOC and acetate groups are trans [α] D 20 = + 10.7 ° (c 2.3, CHCl 3); 1 H NMR (CDCl 3) δ 6.03 (d, 1, J = 3.7 Hz, H 1), 5.5 ^ (s, 1, OH) 5.38 (d, 1d, J = 9.5 Hz) , NH), 4.88 (dd, 1, J = 5.4, 5.4 Hz, H-4), 4.68 (d, 1, J = 3.7 Hz, H-2), 4, 67 (d, 1, J = 5.4 Hz, H-3), 4.21 (q; 2, J = 7.2 Hz, CH ₂ CH ₃ ), 3.84 (dd, 1, J = 9.5,5.4 Hz, H-5), 2.82 (d, 1, J = 16.3 Hz, H-7), 2.59 (d, 1, J = 16.3 Hz, H -7 '), 1.46 (s, 3, CH ₃ ) 1.45 (s, 9, t C ₄ H ₉ ), 1.34 (s, 3, CH ₃ ) 1.29 (t, 3, J = 7.2 Hz, CH ₂ CH ₃ ); ¹³ C NMR (CDCl 3) δ 13.9, 27.1, 27.6, 28.2, 40.8, 59.1, 61.3, 78.8, 80.8, 84.0, 86.7 , 101.9, 107.1, 113.0, 155.3, 172.3; mass spectrum, m / z (relative intensity) 404 (MH ⁺ , 80), 386 (MH ⁺ -H ₂ O, 30), 330 (MH ⁺ -C ₃ H ₆ O ₂ , 100), 286 (40), 215 (25 ).

Example 5 Ethyl 5,7-Dideoxy-5 - {[(tert-butoxy) carbonyl] amino} -1,2-O- (1-methylethylidene) -L-glycero-α-D-gluco -oktofurán uronic a solution of 150 ml of ethyl acetate, 10.0 g (24.8 mmol) of ketol-ester II 3 x 10 ⁵ psi over 4.0 g of PtO2 catalyst was hydrogenated in a Parr apparatus for 20 hours. The catalyst was filtered through a pad of celite and washed with ethyl acetate (50 mL). The combined hairs were evaporated under reduced pressure to give 10.0 g (100%) of an oily mixture of two isomers (a and b), which was subjected to high performance liquid chromatography (250 x 4.6 mm Waters Hypersil ODS (Cl8, 5μ) column and CH3CN ( 60) / H 2 O (40) at a flow rate of 1.5 ml / min, ca. It determined 10 ⁷ Pa to 7 of the two isomers: 2 mixture, wherein a predominating. The retention time of the desired isomer is 3.4 minutes and that of the b isomer 2.9 minutes. The mixture was purified by flash chromatography on silica gel (750 mL), eluting with 4% methylene chloride in acetone. After a 500 ml pre-run, 25 125 ml fractions were collected. 10-17. Fraction 5.0 g pure at, 18-23. distillate contains 3.5 g of a mixture of a and old, distillates 24 and 25 b. 18-23. distillation of the product by distillation of the material by chromatography on an additional 2.9 g of ethyl 5,7-dideoxy-5 - {[(tert-butoxy) carbonyl] amino} -1,2-0- (1-methylethylidene) ) -L-Glycero-αD-glucooctofuran uronate is obtained in an isomer yield of 79%. The isolated isomer slowly crystallizes upon standing. An analytical sample was recrystallized from a 1: 4 mixture of ether / petroleum ether to give colorless prismic crystals having a boiling point of 35-60 ° C and a melting point of 102-104 ° C; [α] D 20 = + 21.8 ° (c 2.3, CHCl ₃ ); 1 HNMR (CDCl ₃ ) 65.93 (d, J = 3.7 Hz, H 1), 5.32 (d, 1, J = 9.1 Hz, NH), 4.85 (br s, 1, OH) , 4.56 (d, 1, J = 3.7 Hz, H-2), 4.56 (m, 1, H-6), 4.17 (q, 2, J = 7.2 Hz CH ₂ , CH ₃ ), 4.13 (m, 1, H-4), 4.05 (d, 1, J = 2.2 Hz, H-3), 3.61 (dd, 1, J = 9.4 , 9.1 Hz, H-5), 3.44 (br s, 1, OH), 2.7 (dd, 1, J = 16.2.9.5 Hz, H-7), 2.44 (dd, 1, J = 16.2, 3.6 Hz, H-7), 1.50 (s, 3, CH 3), 1.45 (s, 9, tert-C ₄ H ₉ ), 1, 32 (s, 3, CH ₃ ), 1.27 (t, 3, J = 7.2 Hz, CH ₂ CH ₃ ); ¹³ C NMR (CDCl ₃ ) δ 14.2, 26.2, 26.8, 28.2,

38.6, 51.9, 60.9, 65.4, 74.1, 80.1, 81.1, 84.5, 105.1,

111.6, 157.6, 172.6; MS m / z (relative intensity) 406 (MH ⁺ -C4H8,35), 334 (MH ⁺ -C4H ₈ O, 25), 306 (MH ⁺ -C ₅ H ₉ O _2, 100), 292 (13) , 100 (46).

Example 3a {3aR- [3a (t, 5a (4S *, 5R *), 6a, 6aa]} - 4-Hydroxy-5- (tetrahydro-6-hydroxy-2,2-dimethylfuro [2,3- d] -1,3-dioxol-5-yl) -2-pyrrolidinone Compound IV

To a solution of 13.3 g (32.7 mmol) of BOC-aminodiol III in 135 ml of methylene chloride is added dropwise over a period of 10 minutes under stirring at 0-5 ° C under nitrogen, 400 ml of 98% formic acid. . The resulting solution was stirred for 1 hour at 0-5 ° C, then for 6 hours at room temperature and finally evaporated to dryness under vacuum at 30 ° C to give 12.3 g of a thick viscous oil. This was dissolved in 50 mL of water and adsorbed on a column of 11x2 Dowex-based ion exchange resin (prewashed with 1.5 L of IN sodium hydroxide followed by about 5.01 water to neutrality) and eluted with water. After 500 ml in run 5 ^χ 125 ml and 10x300 mL fractions were collected. 13-36. fraction

6.3 g of crystalline {3aR- [3aa, 5a- (4S ', 5R *), 6a, 6aa]} - 4-hydroxy-5- (tetrahydro-6) (73% in total in both steps) were obtained. Hydroxy-2,2-dimethylfuro [2,3-d] -1,3-dioxol-5-yl) -2-pyrrolidinone is obtained. An analytical sample was recrystallized from methanol to give colorless needle crystals, m.p. 263-265 ° C; [α] _"Η = -39.3 ° (C 0.67, _H2 O); ¹ H NMR (DMSO-d ₆ ) 7.34 (br s, 1, NH), 5.82 (d, 1, J = 3.7 Hz, H 1), 5.10 (d, 1, J = 4 , 7 Hz, 3-OH), 5.00 (d, 1, J = 4.9 Hz,

6-OH), 4.40 (d, 1, J = 3.7 Hz, H-2), 4.23 (ddd, 1, J = 5.4, 4.2.1, OHz, H-6 ), 4.18 (dd, 1, J = 9.6.2.7 Hz, H-4), 4.11 (dd, 1, J = 4.7, 2.7 Hz, H-3), 3.60 (dd, 1, J = 9.6,4.2 Hz, H-5), 2.48 (dd, 1, J = 16.6, 5.4 Hz, H-7), 1, 95 (dd, 1, J = 16.6, 1.0 Hz, H-7), 1.37 (s, 3, CH ₃ ), 1.24 (s, 3, CH ₃ ); ¹³ CNMR (DMSO-d6) 26.3,26,8,41,3,56,9,66,5,73.3, 77.4, 84.9 104.5,110,6,175.8; mass spectrum, m / z (relative intensity) 260 (MH ⁺ , 100), 202 (MH ⁺ -C ₃ H ₆ 0.23).

Example 7 {3aR- [3a <x, 5a (2R *, 3S *), 6a, 6av.]} -2- (Tetrahydro-6-hydroxy-2,2-dimethylfuro [2,3-d] -1,3-Dioxol-5-yl) -3-pyrrolidinol (Compound V)

To a solution of 2.3 g (60.0 mmol) of lithium aluminum hydride in 150 ml of anhydrous tetrahydrofuran under nitrogen at 25 ° C with vigorous stirring over a period of 3 to 5 minutes, add 3.0 g (11.5 mmol) of several portions (IV). lactam. Foaming and H ₂ development occur. The mixture was refluxed for 20 hours, cooled to 0-5 ° C, and water (2.5 mL) was treated with IN NaOH (2.5 mL) and

7.5 ml of water was added successively by the careful addition of the reaction

HU213 393 B is frozen. This mixture was stirred for 20 minutes at 5 ° C and then filtered through a pad of celite. The collected aluminate salts were washed with 200 mL of tetrahydrofuran, and the combined filtrate and washings were evaporated to dryness under reduced pressure to give 1.7 g of {3aR- [3aa, 5a- (2R ', 3S'), 6a (V) as a white powder. 6a]} -2- (tetrahydro-6-hydroxy-2,2-dimethylfuro [2,3-d] -1,3-dioxol-5-yl) -3-pyrrolidinol is obtained. The collected aluminate salts were refluxed with 100 mL of 9: 1 tetrahydrofuran / water for 45 minutes. The salts were filtered off, washed with tetrahydrofuran (50 mL), and the combined filtrates were evaporated to dryness to give an additional 0.5 g of V and the yield increased to 77%. An analytical sample was recrystallized from methanol to give colorless needle crystals, m.p. 223-225 ° C; [α] _ο2! = -5.0 (c 0.32, H ₂ O); 1 H NMR (CDCl ₃ ) δ 5.92 (d, 1, J = 3.8 Hz, H 1), 4.55 (d, 1, J = 3.8 Hz, H-2), 4.40 ( ddd, J = 5.3,3,6,1,6 Hz, H-6), 4.25 (d, 1, J = 2.6 Hz, H-3), 4.13 (dd, 1, J = 7.8,2,6 Hz, H-4), 3,50 (m, 3, OH, NH), 3,18 (ddd, 1, J = 11,2,7,8, 7,6 Hz) , H-8 '), 3.12 (dd, 1, J = 7.8, 3.6 Hz, H-5), 2.86 (ddd, 1, J = 11.2,

9.5 5.1 Hz, H-8), 2.05 (dddd, J = 13.8, 9.5, 7.6, 5.3 Hz,

H-7), 1.86 (dddd, J = 13.8, 7.8, 5.1.1.6 Hz, H-7), 1.50 (s, 3, CH ₃ ), 1.32 (s, 3, CH ₃ ); ¹³ C NMR 26.1, 26.6, 35.4, 43.2, 61.6, 70.6, 75.6, 77.9, 85.3, 103.8, 110.1; mass spectrum, m / z (rel intensity) 246 (MH ⁺ , 100), 188 (MH ⁺ -C ₃ H ₆ O, 52).

Claims (1)

Patent Claim Point A process for the preparation of a compound of formula (A) wherein: R is hydrogen or = O, characterized in that the compound of formula (A) wherein R is = O is deprotected from the β-hydroxyester of formula (III) and treated with a base, and optionally treating the resulting compound of formula IV with a reducing agent to produce a compound of formula A wherein R is hydrogen.