JPH0826064B2 - Method for producing steroid peracyl glycosides - Google Patents

Description

Description: BACKGROUND OF THE INVENTION The present invention relates to a method of synthesizing steroid glycosides, and in particular to the preparation of steroid peracyl glycosides for use as intermediates therein.

Tigogenin β-O-cellobioside is a known compound with utility in the treatment of hypercholesterolemia and atherosclerosis (Malinow, US Pat. No. 4,602,003).
And No. 4,602,005; Malinow et al., Steroids, 48, 197-
211 pages, 1986). Each patent describes the α-
A different synthetic method starting from D-cellobiose octaacetate, namely the first patent is the combination of the former with tigogenin in the presence of silver carbonate via glycosyl bromide heptaacetate and the final hydrolysis; the second patent is the chloride. Disclosed is a method for direct re-hydrolysis via the direct binding of tin tetrachloride in methylene to the bond of cellobiose octaacetate with tigogenin. According to Malinow et al., The reaction of cellobiose octaacetate with titanium tetrabromide produces cellobiosyl bromide heptaacetate, which is bound to tigogenin by mercuric cyanide and then hydrolyzed. Both of these methods have significant drawbacks with respect to mass production for use as a pharmaceutical. The desirable goals met by the present invention are:
By avoiding toxic and / or expensive reagents, and avoiding time-consuming and expensive purification steps, the desired Tigogenin β-O
-It was to devise a synthetic method for the pure production of cellobioside.

Schmidt, Angew. Chem. Int. Ed. Engl., 25, pp 212-235 (1986), 1-, in the presence of a base (where other hydroxy groups are protected, for example by benzyl or acetyl). It outlines the reaction and synthesis of O-glycosyltrichloroacetimidates formed by the reaction of sugars having a hydroxy group with trichloroacetonitrile. When using sodium hydride as the base α
The anomer is predominantly formed and the β-anomer is predominantly formed when the base is potassium carbonate. The α-anomer of tetrabenzyl glycosyltrichloroacetimidate, when bound to cholesterol, produces a mixture of anomers that varies with catalyst (p-toluenesulfonic acid or boron trifluoride etherate) and temperature (-40 ° C to + 20 ° C). did. On the other hand, both the a- and β-anomers of tetraacetylglycosyl analogs are β-
It is reported to produce only the anomeric product.

Accordingly, there is ongoing research in this field of technology for improved stereocontrolled synthesis of steroid glycosides.

SUMMARY OF THE INVENTION The present invention provides tigogenin β-O, 11-keto tigogenin β-O, hecogenin β-O or diosgenin β-, which provides higher β-anomer selectivity and increased yield.
O cellobioside heptaalkanoate synthesis method. This method is particularly useful for preparing Tigogenin β-O cellobioside heptaalkanoates, which are intermediates of the known anticholesterolemic drug Tigogenin β-O cellobioside. This method is based on Tigogenin β-O,
Α-cellobiosyl bromide hepta in the presence of zinc fluoride or zinc cyanide under suitable conditions to form 11-ketotigogenin β-O, hecogenin β-O or diosgenin β-O cellobioside heptaalkanoate. Alkanoate and β-tigogenin, 11-β-ketotigogenin,
It is characterized by reacting with β-hacogenin or β-diosgenin.

Other features and advantages will be apparent from the specification and claims.

DETAILED DESCRIPTION OF THE INVENTION α-Cellobiosyl bromide heptaalkanoate and β
The metal salt used for stereospecific reaction with -tigogenin, 11-keto-β-tigogenin, β-hemogenin or β-diosgenin is preferably zinc fluoride or zinc cyanide. The metal salt is particularly preferably zinc fluoride. about
Preferably 0.5 to about 4 equivalents of metal salt are used,
Particularly preferred is about 1.5 equivalents to about 2.25 equivalents.

Also, zinc halides (eg, zinc bromide, zinc chloride, zinc iodide) or basic salts of zinc (zinc oxide) to buffer or activate promoters (ie, zinc fluoride or zinc cyanide metal salts). , Zinc hydroxide, zinc hydroxyfluoride, zinc carbonate, etc.), preferably the coupling activated with zinc fluoride or zinc cyanide is carried out in the presence of a further zinc salt. Trialkyl tertiary amines (eg, diisopropylethylamine, triethylamine, tributylamine), tetraalkylureas (eg, tetramethylware, tetraethylurea) or dialkylanilines (eg, diisopropylaniline, dibutylaniline) are also useful reaction buffers. Is.
The above additives are usually used at 10-50% molar equivalents of the accelerator.

Although any of the alkanoate (C1-C4) substituted α-cellobiosyl bromides may be used, it is preferred to use the acetate salt (ie C1). These are K. Freudenberg and W.
It can be prepared from conventional starting materials by the method described in Nagai. Ann., 494, 63 (1932) (eg Example 3). About 0.5 to about 3 equivalents of alkanoate (C1-C
4) Substituted α-cellobiosyl bromides are preferably used, with about 1 to about 2 equivalents being particularly preferred.

Any reaction inert solvent can be used. The term "reactive inert solvent" as used above and elsewhere herein means that it does not react with starting materials, reagents, intermediates or products to adversely affect the yield of the desired product. , Or a solvent that does not decompose them. In general, the solvent may consist of a single component or may contain multiple components. Preferably the solvent is an aprotic reaction inert solvent, with acetonitrile being particularly preferred as it provides excellent stereoselectivity. Other solvents include methylene chloride, ethyl acetate and nitromethane.

The reaction is preferably acid catalyzed because of the increased selectivity of the β-cellobioside product over the α-cellobioside anomeric product. A mineral acid is preferably used. Hydrobromic acid has been shown to be particularly effective in increasing the yield of β-cellobioside product. Other preferred acids include hydrochloric acid, hydrofluoric acid and sulfuric acid. It is preferred to use about 0.05 to about 2 equivalents of the acid catalyst, with about 0.1 to about 0.5 equivalents being particularly preferred.

For the preparation of β-tigogenin, Rubin, U.S. Pat.Nos. 2,991,282 and 3,303,187, B. Loken, U.S. Pat.No. 3,935,194, and Caglioti et al., Tetra.
It is described in hedron 19,1127 (1963). The structure is described below.

For the preparation of β-hemogenin, see Russell E. Marker.
J. Amer. Chem. Soc., 69, 2167-2211 (1947) in the report on steroid sapogenins. The structure is described below.

In 11-keto-β-tigogenin, the carbonyl group is changed from the 12-position to the 11-position in the above structure. 11-keto-β-tigogenin is prepared from hecogenin by the following procedure.
By the method of Conforth et al. (J. Chem. Soc., 1954, 907),
Hecogenin is acetylated, brominated, treated with sodium hydroxide and reduced with zinc to produce the 12-hydroxy-11-keto analog. The 12-hydroxy-11-keto analog is then acetylated and reduced with calcium and ammonia to produce 11-ketotigogenin.

For the preparation of β-diosgenin, see Asolkar, L, V., C.
hadha, YR, and Rawat, PS, by ″ Diosgenin and
Other Steroidal Drug Precursosrs ″ Council of Scien
tific and Industrial Research, New Delhi, India, 183 pages, 1979 and T. Kawasaki et al., Chem. Phar.
m. Bull., Japan 10698 (1962). The structure is described below.

Preferably about 1 to about 2 equivalents of steroid are used. It is particularly preferred to use about 1 to about 1.5 equivalents of steroid.

Uses any environment or condition (eg, temperature, time, solvent) suitable (i.e., formable) for formation of the desired Tigogenin, 11-keto Tigogenin, Hecogenin- or Diosgenin-β-O-cellobioside heptaalkanoate be able to. However, the reaction preferably occurs at a temperature of about 20 ° C to about 100 ° C, preferably about 50 ° C.
℃ to about 65 ℃. Below about 20 ° C the reaction is slow, and above about 100 ° C undesired side reactions (eg anomerization) occur. The reaction is easily carried out at normal pressure, although pressures of about 0.5 to about 3 atmospheres can be used.

Preferably the steroid, metal salt and solvent are heated at reflux and sufficient solvent is azeotropically distilled to remove substantially all of the water. Cellobiosyl bromide heptaalkanoate is then added to the above mixture and heated, typically under nitrogen for about 0.5 to about 6.0 hours. The desired compound is then isolated by conventional methods.

For example, glycosides can be precipitated from a crude reaction mixture (eg, acetonitrile producing solution) that has been filtered by the addition of about 25% to 75% water and residual alcohol (eg, methanol). Precipitation of the product from aqueous methanol / acetonitrile provides a product that requires less processing and is more pure than isolation by extraction.

Steroid peracyl glycosides can be deacetylated by conventional methods such as treatment with triethylamine in methanol, treatment with basic anion exchange resin or sodium methoxide in methanol or methanol / THF solvent. (For example, Example 2 below). For example, the deacetylated product can be prepared by refluxing in methanol / THF with a non-catalytic amount of sodium methoxide followed by conventional workup steps.
If some β-cellobiosylfluoride heptaacetate is present, excess methoxide is used to cleave the fluorosugar. Otherwise, deacetylation is catalyzed in sodium methoxide. The Tigogenyl-β-O-cellobioside or analog is then isolated by conventional methods such as filtration.

The above method is designed for the synthesis of β-form steroid glycosides, but the more thermodynamically stable α-
Anomers are easily obtained by acid-catalyzed isomerization of β-glycosides. For example, Tigogenin α-O-cellobioside heptaalkanoate can be prepared from Tigogenin β-O-cellobioside heptaalkanoate by heating β-glycoside in a methylene chloride solution containing hydrogen bromide. it can.

The effect of reaction stoichiometry, temperature, solvent, molecular sieves and traces of hydrogen bromide on stereoselectivity and yield of tigogenyl β-O-cellobioside heptaacetate (using the method of Example 1) is shown. Put together in 1.

The zinc fluoride activated glycoside coupling was repeated using hecogenin and diosgenin in a similar manner to the β-tigogenin glycoside coupling of Example 1 below. The results using these other sterols are summarized in Table 2.

The present invention greatly advances the field of steroid glycosides by providing an efficient method of preparing steroid peracyl glycosides. The deacetylated end product is useful as an antihypercholesterolemic agent.

The present invention is not limited to the particular embodiments described herein, but is subject to various modifications and alterations without departing from the spirit and scope of this novel concept, as defined by the following claims. It goes without saying that you can build

Example 1 Tigogenyl β-O-cellobioside heptaacetate β-Tigogenin (4.16 g; 0.01 mol) and anhydrous zinc fluoride (4.13 g; 0.04 mol) in a dry flask equipped with a mechanical stirrer, thermometer and distillation head. And 160 ml of dry acetonitrile were added. The slurry is heated at reflux (85
C.), 90 ml of fraction was removed over the head, while 60 ml of fresh dry acetonitrile was added to the slurry. The mixture
After cooling to 25 ° C., a sample was taken for the Karl Fischer method measurement (KF = 0.02% H20).

α-cellobiosyl bromide heptaacetate (14.00
g; 0.02 mol) was added to the flask and the slurry was then heated to 65 ° C under a nitrogen atmosphere with stirring. The mixture was maintained at 65 ° C for 2.5 hours until thin layer chromatography (TLC) showed the reaction was complete. The reaction was cooled to room temperature and 130 ml methylene chloride was added. The dilute slurry was filtered through Celite and the filtrate (300 ml) was washed with saturated sodium bicarbonate solution (70 ml) followed by water wash (70 ml).
did. The organic layer was dried over anhydrous sodium sulfate (20 grams), filtered and then the solution was distilled at atmospheric pressure.
Concentrated to 50 ml. 200 ml of 2B-ethanol was added to the warm concentrate and the suspension was concentrated to about 50 ml. 25 diluted slurry
After cooling to ℃, it was granulated for 90 minutes at room temperature. After filtering the crude product and washing the cake with 25 ml of 2B-ethanol,
After drying at 40 ° C. under vacuum for 17 hours, 10.8 g of white crystalline solid (mp = 226-231 ° C.) was obtained.

After dissolving the solid in 25 ml of methylene chloride, 75 ml of 2B-
Ethanol was added. Heat the dilute slurry at reflux (76
0 mm), 35 ml fraction was removed over the head. The resulting slurry was cooled to room temperature and then granulated for 90 minutes. The β-glycoside was filtered and dried under vacuum at 40 ° C. for 18 hours to obtain 9.65 g of white crystalline solid (mp = 229-234).
° C). Thin layer chromatography 1 and high pressure liquid chromatography 2 (HPLC) showed 77% product (w /
w) containing Tigogenyl β-O-cellobioside heptaacetate and 15% (w / w) α-cellobiosyl fluoride heptaacetate. Alpha-cellobiosyl fluoride heptaacetate is most easily removed from the product during the deacetylation step.

Example 2 Tigogenin β-O-cellobioside 250 ml of crude Tigogenyl β-O-cellobioside heptaacetate (50.0 g; 0.048 mol) while maintaining under a nitrogen atmosphere.
Of tetrahydrofuran and 250 ml of methanol. The turbid solution was filtered through a Celite bed,
A solution of sodium methoxide (0.46g; 0.008mol) in methanol (10ml) was then added to the filtrate. The solution was heated at reflux (60 ° C) and maintained at reflux for 1.25 hours to give a thick white slurry. The reaction was removed and analyzed by thin layer chromatography which indicated the reaction was complete. The slurry was concentrated by removing 200 ml of distillate and then 200 ml of water was added to the slurry at reflux.
An additional 200 ml fraction was removed and more water (200 ml) was added. The slurry was cooled to room temperature and filtered. The cake formed was washed with water (50 ml) and then suction dried on the filter. The damp cake was heated at reflux (600 ml THF and 92 ml water at 65 ° C). DARCO G-60 (1.5
3 grams) was added and stirred for 15 minutes, then the mixture was filtered through Celite. The solution was concentrated by removing 460 ml of fraction and then 460 ml of methanol was added. Repeat methanol addition and concentration twice
The 800 ml fraction was removed again and 800 ml fresh methanol was added. The resulting slurry was cooled to 20 ° C and then granulated for 1 hour. The product was filtered, washed with fresh methanol (50 ml) and then the wet cake was reslurried in 300 ml fresh methanol (24 ° C.). The product was filtered then dried at 40 ° C. in vacuo overnight. Tigogenyl β-O-cellobioside (24.4 g; 0.036 mol) was added to the total amount of 7
Isolated in 4% yield. The spectrum and physical properties were identical to the reference sample.

Example 3 α-D-cellobiosyl bromide heptaacetate
Prepared from α-D-cellobiose-octaacetate and hydrogen bromide added to glacial acetic acid using a modified method of Freudenberg and Nagari ³ .

 Hydrogen bromide gas in glacial acetic acid until a density of 1.212 is obtained.
20% (w / w) hydrogen bromide in glacial acetic acid by blowing
A solution (178.7 g; 0.44 mol HBr) was prepared. Nitrogen atmosphere
Α-D-cellobio in a separate drying reactor maintained below
Sucrose octaacetate (50.0g; 0.074mol) 408ml salt
It was dissolved in methylene chloride. Add HBr / HOAC solution to this disaccharide solution.
Was added to give a yellow solution. Stir the solution at 17-25 ° C for 2 hours
And then a small amount to confirm in the analysis that the reaction is complete.
An amount of solution was taken. The thin layer chroma indicates that the reaction is complete.
If tography 2 shows, cool the solution to 10 ° C,
0.5 liter of water was added. Stir the mixture for 10 minutes and mix.
The stirring was stopped and the layers were separated. Decant the methylene chloride layer
Then 7.5% w / w sodium bicarbonate solution (0.5 liter
And then washed with water (0.5 liter). Finally,
Methylene chloride solution over 8 grams of anhydrous magnesium sulfate
It was dried with and filtered. MgSO_Four・ 50 ml of hydrate cake
Wash with fresh methylene chloride and combine the filtrate and wash solution.
I let you. About 0.15 liter of methylene chloride solution by atmospheric distillation
Concentrated to room temperature and then cooled to room temperature. 15 minutes with stirring
Add diisopropyl ether (0.6 liter) slowly over
In addition to each other, a thick slurry was obtained. Product at 25 ° C for 1 hour
The mixture was granulated, filtered, and dried under vacuum at 40 ° C. for 4.5 hours. α
-Cellobiosyl bromide heptaacetate (47.6g; 92%
Yield) as white crystalline solid (m.p. = 192-194 ° C)
Get this¹HNMR spectrum (CDCl₃) Is consistent with its structure
Was. ¹ K. Freudenberg and W. Ann., 494, 63 (1932).² Merck Pleco with toluene / acetic acid (4: 1) eluate
TLC silica gel 60F-254 plate. Unfold plate
And then dissolved in water 10% (w / w) H₂SO_FourSquirt on the plate
It was heated so that the fog would come out and the spot would come out.

Example 4 11-ketotigogenyl-β-O-cellobioside heptaacetate A 1 liter 3-neck round bottom flask equipped appropriately with acetonitrile (305 ml), 11-ketotigogenin (5.00 g; 0.00 g;
11 mol) and rhombohedral crystal zinc fluoride (1.65 g;
016 mol) was added. Heat the slurry at reflux (80 ° C),
A 100 ml fraction was then removed over the head. The slurry was cooled to room temperature and then 15.39 grams (0.022 moles) of α
-Cellobiosyl bromide heptaacetate was added. The reaction mixture was reheated at 60-65 ° C and then maintained at 60-65 ° C for 2 hours. A reaction sample was taken to confirm that the reaction was complete by analysis. Thin layer chromatographic analysis (Et
OAc / hexane: 1.5 / 1) showed complete disappearance of the glycosyl bromide starting material, so the reaction was cooled to 25 ° C.,
152 ml of methylene chloride was added. After stirring for 10 minutes, the mixture was filtered through Celite and the filter cake was washed with 25 ml of CH 2.
_It was washed with ₂ Cl ₂ . Combine the combined reaction filtrate and wash with water (81 ml), saturated sodium bicarbonate (75 ml) and water (13 ml).
7 ml) and washed. Finally the organic layer was dried over 11 grams of anhydrous magnesium sulfate. The MgSO ₄ is filtered and washed with 16 ml fresh CH ₂ Cl ₂ . The filtrate and washings were combined and then concentrated under reduced pressure to 1/4 of the original volume (300 ml). 2B-Ethanol (250 ml) was added and the resulting solution was concentrated to 1/2 volume (170 ml). Cool the slurry to 20-25 ° C,
It was then granulated for 1 hour. Filtering the white waxy solid,
It was washed with fresh 2B-ethanol (50 ml) and then dried at 40 ° C. under vacuum overnight. 11-ketotigogenin-β-O-cellobioside heptaacetate (9.7 grams; mp = 205-2
19 ° C.) was isolated in a yield of 84% overall. The chromatographic and spectral properties are shown to be 11-ketotigogenyl-β
It was the same as the reference sample of -O-cellobioside heptaacetate. Crude 11-ketotigogenin-β-O-cellobioside could also be isolated in 64% yield by the following aqueous isolation procedure: The crude reaction mixture was added to fresh fresh acetonitrile (50
ml) and then filtered through Celite. Methanol (290 ml) was added to the filtrate and the resulting solution was heated at reflux (65 ° C) for 1 hour. 100 ml of deionized water was slowly added to the reflux solution to obtain a turbid mixture. After refluxing (72 ° C) for 20 minutes, the mixture was gradually cooled to room temperature,
It was then granulated at 23-25 ° C for 1 hour. The crude product was filtered and washed with water. Filter cake with 2B-ethanol (75m
l) and the mixture was heated at reflux. The mixture was then cooled to room temperature, filtered and the solid dried at 40 ° C. under vacuum overnight. 11-ketotigogenyl-β-O-cellobioside heptaacetate was isolated in a yield of 64% of the whole.

Example 5 11-Ketotigogenyl-β-O-cellobioside 11-ketotigogenyl-β-O-cellobioside heptaacetate (9.7 g; 9.2 mmol) was suspended in 50 ml of methanol and 50 ml of tetrahydrofuran. After filling the system with nitrogen, a solution of sodium methoxide (0.10 g; 1.9 mmol) in methanol (1 ml) was added. The solution was heated at reflux (61 ° C) and then maintained at reflux for 1 hour.
Thin layer chromatography of the resulting slurry (CH
₂ Cl ₂ / methanol 4: 1) showed the reaction was complete. Tetrahydrofuran was removed from the reaction solution by atmospheric distillation and finally by replacing with methanol (220 ml). A total of 180 ml of distillate was collected. The slurry was cooled to 20-25 ° C and then granulated overnight. The product is filtered and washed with methanol (2x20ml) then 100ml of the wet cake.
Re-slurried with deionized water (20 hours). After filtration and drying under vacuum at 25 ° C. overnight, 4.7 grams of 11-ketotigogenyl-β-O-cellobioside was isolated in 65.5% overall yield. The product was homogeneous by TLC and the analytical properties were structurally consistent with the product.

Example 6 In-Situ Hydrobromic Acid Generation In a 75 ml round bottom flask equipped with mechanical stirrer, thermometer and vacuum distillation head, α-cellobiosyl bromide heptaacetate (5.00 g; 7.15 mmol) and 50 ml acetonitrile. Was added. After filling the system with nitrogen, the pressure was reduced to about 425 mm Hg. The solution was heated to 56-58 ° C and about 13 ml of distillate was removed through the head. The solution was cooled to room temperature and the vacuum was gradually released. Methylene chloride (37 ml) was added to the glycosyl bromide solution and the solution was then extracted with water (2x25 ml). After combining the aqueous phases, 0.1005 N N
The aOH solution was used to titrate to the end point of phenolphthalene.

The milliequivalents of HBr acid contained in the α-cellobiosyl bromide heptaacetate solution before and after azeotropic stripping are reported below. Azeotropic stripping increases titratable acid by about 8-10 fold depending on the water content.

When azeotropic distillation was used in Example 1 to dry the glycosyl bromide solution and increase its acid content, the reaction time was reduced to 1.0 hour at 65 ° C. Furthermore, high yields and high β-anomer selectivity were maintained.

Example 7 Aqueous Isolation of Tigogenyl β-O-Cellobioside Heptaacetate Fluorination of α-cellobiosyl bromide heptaacetate (1.830 mol) and β-tigogenin (0.915 mol) in acetonitrile by the procedure of Example 1. Zinc mediated glycoside coupling was performed. Once the reaction was complete, the crude reaction mixture was worked up by the aqueous method and the following procedure gave high quality β-O-cellobioside heptaceate.

The crude reaction mixture was filtered through Celite to give about 20 liters of golden filtrate. The filtrate was heated (55-60 ° C) and concentrated under reduced pressure to about 10 liters. The concentrated solution was cooled to 50 ° C. and 5.0 liter of methanol was added. After that, 7.5
L of deionized water was added slowly over 30 minutes. Once about 2 liters of water had been added, a solid precipitated out of solution. Heat the mixture at reflux (73 ° C) and then at reflux 2
Maintained for hours. The slurry was cooled to 25 ° C and granulated overnight. The crude product was filtered, washed with methanol (2x1.5 liters) and then dried under vacuum at 40 ° C. Coarse solids (1.
01 kg) was 95.5% pure by HPLC analysis. Moreover, the crude product contained only 1.3% of Tigogen α-O-cellobioside heptaacetate and no β-cellobiosylfluoride heptaacetate.

Under nitrogen, crude Tigogenyl β-O-cellobioside heptaacetate (1.0 kg) was slurried in 10.2 liters of 2B ethanol, then the mixture was heated at reflux (78
° C). After maintaining the slurry at reflux for 1.5 hours, the mixture was washed with 2
Cooled to 5 ° C and then granulated for 12 hours. The product is filtered, washed with fresh ethanol (2x300ml) and finally 40
Dry under vacuum at 0 ° C. overnight. Tigogenyl β-O-cellobioside heptaacetate (0.89 kg) was isolated from tigogenin in 74% overall yield. The white crystalline product is 98.9% pure by high pressure liquid chromatography and is only 0.
It contained only 5% (w / w) α-anomeric isomer.

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Claims (12)

[Claims] 1. A method for synthesizing tigogenin-, 11-keto tigogenin-, hecogenin- or diosgenin-β-O-cellobioside heptaalkanoate, which comprises α-cellobiosyl bromide heptaalkanoate. (Wherein, R is C ₁ -C ₄₎ and β- tigogenin, 11-
A steroid selected from the group consisting of keto-β-tigogenin, β-hemogenin and β-diosgenin is capable of forming the said tigogenin-, 11-ketotigogenin-, hecogenin- or diosgenin-β-O-cellobioside heptaalkanoate. The method as described above, characterized in that the reaction is carried out in the presence of zinc fluoride or zinc cyanide under various conditions. 2. The method of claim 1 wherein the metal salt is zinc fluoride, R is methyl and the reaction occurs in an aprotic reaction inert solvent. 3. The method according to claim 2, wherein the steroid is β-tigogenin or 11-keto-β-tigogenin. 4. The method of claim 3, wherein the reaction is acid catalyzed. 5. The method according to claim 4, wherein the acid catalyst is hydrobromic acid or hydrofluoric acid. 6. The reaction is zinc bromide, zinc chloride, zinc iodide, zinc hydroxyfluoride, zinc oxide, zinc carbonate, zinc hydroxide, trialkyl tertiary amine, tetraalkylurea or N, N-dialkylaniline. The method of claim 5, which occurs in the further presence of 7. The reaction occurs at about 20 ° C. to about 100 ° C., using about 1 to about 2 equivalents of 11-keto-β-tigogenin,
7. The method of claim 6, wherein 0.5 to about 4 equivalents of zinc fluoride is used and about 0.5 to about 3 equivalents of α-cellobiosyl bromide heptaalkanoate. 8. The solvent is acetonitrile and is about 0.05.
8. The method of claim 7, wherein from about 2 equivalents of hydrobromic acid is used. 9. The method of claim 2 wherein the 1-O-steroid peracyl-β-glycosides are precipitated from acetonitrile by the addition of about 25% to 75% water and residual alcohol. 10. The method of claim 2, further comprising the step of deacetylating Tigogenyl β-O-cellobioside heptaalkanoate to form Tigogenyl β-O-cellobioside. 11. The method according to claim 10, wherein deacetylation occurs by treatment with sodium methoxide in methanol. 12. The method of claim 2, wherein the steroid is 11-ketotigogenin.