EP0619822A1 - Procede de preparation de glycosides de peracyle steroides - Google Patents

Procede de preparation de glycosides de peracyle steroides

Info

Publication number
EP0619822A1
EP0619822A1 EP92921860A EP92921860A EP0619822A1 EP 0619822 A1 EP0619822 A1 EP 0619822A1 EP 92921860 A EP92921860 A EP 92921860A EP 92921860 A EP92921860 A EP 92921860A EP 0619822 A1 EP0619822 A1 EP 0619822A1
Authority
EP
European Patent Office
Prior art keywords
zinc
tigogenin
cellobioside
recited
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92921860A
Other languages
German (de)
English (en)
Inventor
Douglas John M. Allen
Frank Robert Busch
John Francis Lambert
Russell James Shine
Stanley Walter Walinsky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Inc
Original Assignee
Pfizer Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc filed Critical Pfizer Inc
Publication of EP0619822A1 publication Critical patent/EP0619822A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring

Definitions

  • Tigogenin beta-O-cellobioside is a known compound having utility in the treatment of hypercholesterolemia and atherosclerosis (Malinow, U.S. Patents 4,602,003 and 4,602,005; Malinow et al., Steroids, vol. 48, pp. 197-211 , 1986).
  • Each patent discloses a different synthesis of this compound from alpha-D-cellobiose octaacetate; the first via the glycosyl bromide heptaacetate which is coupled with tigogenin in the presence of silver carbonate, and finally hydrolyzed; and the second via direct stannic chloride catalyzed coupling of the cellobiose octaacetate with tigogenin in methylene chloride, again followed by hydrolysis.
  • This invention is directed to a process for the synthesis of tigogenin ⁇ -O, 11- ketotigogenin ⁇ -O, hecogenin ⁇ -O, or diosgenin ⁇ -O cellobioside heptaalkanoate that provides greater ⁇ -anomeric selectivity and increased yields.
  • the process is particularly useful for preparing tigogenin ⁇ -O-cellobioside heptaalkanoate, which is an intermediate for the known hypocholesterolemic agent tigogenin ⁇ -O-cellobioside.
  • the process comprises reacting ⁇ -cellobiosyl bromide heptaalkanoate and ⁇ -tigogenin, 11- ⁇ - ketotigogenin, ⁇ -hecogenin or ⁇ -diosgenin in the presence of zinc fluoride or zinc cyanide under conditions suitable for forming the tigogenin ⁇ -O-, 11-ketotigogenin ⁇ -O, hecogenin ⁇ -O-, or diosgenin ⁇ -O-cellobioside heptaalkanoate.
  • the metal salt used in the stereospecific reaction of ⁇ -cellobiosyl bromide heptaalkanoate and ⁇ -tigogenin, 11-keto- ⁇ -tigogenin, ⁇ -hecogenin or ⁇ - diosgenin is zinc fluoride or zinc cyanide. It is especially preferred that the metal salt Is zinc fluoride. It is preferred that about 0.5 equivalents to about 4 equivalents and especially preferred that about 1.5 equivalents to about 2.25 equivalents metal salt is used.
  • zinc fluoride or zinc cyanide-activated coupling may also be preferred to conduct the zinc fluoride or zinc cyanide-activated coupling in the presence of additional zinc salts such as zinc halides (e.g., zinc bromide, zinc chloride, zinc iodide) or basic salts of zinc (zinc oxide, zinc hydroxide, zinc hydroxy fluoride, zinc carbonate, etc.) to buffer or to activate the promoter (i.e., zinc fluoride or zinc cyanide metal salt).
  • zinc halides e.g., zinc bromide, zinc chloride, zinc iodide
  • basic salts of zinc zinc oxide, zinc hydroxide, zinc hydroxy fluoride, zinc carbonate, etc.
  • Trialkyl tertiary amines e.g., diisopropylethyl amine, triethyiamine, tributylamine
  • tetraalkylureas e.g., tetramethyl urea, tetraethyi urea
  • dialkylanilines e.g., diisopropyl aniline, dibutyianiline
  • the above additives are generally used at 10-50% mole equivalents of the promoters.
  • alkanoate (C ⁇ C 4 ) substituted alpha-cellobiosyl bromides may be used it is preferred that acetate (i.e., C,) is used. They may be prepared from conventional starting materials according to methods described in K. Freudenberg and W. Nagai, Ann., 494,63 (1932) (e.g. Example 3). It is preferred that about 0.5 equiva ⁇ lents to about 3 equivalents, and especially preferred that about 1 equivalent to about 2 equivalents alkanoate (C C 4 ) substituted alpha-cellobiosyl bromides are used.
  • reaction-inert solvent refers to a solvent which does not react or decompose with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
  • the solvent can comprise a single entity, or contain multiple components.
  • the solvent is a non-protic reaction inert solvent and it is especially preferred that the solvent is acetonitrile because of the excellent stereoselectivity it provides.
  • Other solvents include methylene chloride, ethyl acetate and nitromethane.
  • the reaction is acid catalyzed as this can increase the selectivity of the ⁇ -cellobioside product over the ⁇ -cellobioside anomeric product.
  • mineral acids are used.
  • Hydrobromic acid has been shown to be particularly effective in increasing the ⁇ -cellobioside product yield.
  • Other preferred acids include hydrochloric, hydrofluoric and sulfuric acid. It is preferred that about 0.05 equivalents to about 2 equivalents, and especially preferred that about 0.1 equivalents to about 0.5 equivalents acid catalyst is used.
  • ⁇ -Tigogenin's preparation is described by Rubin in U.S. Patents Nos. 2,991 ,282 and 3,303,187, by B. L ⁇ ken in U.S. Patent No. 3,935,194 and Caglioti et al., Tetrahedron 19, 1127 (1963). Its structure is depicted below.
  • 11-Keto- ⁇ -tigogenin switches the carbonyl group from the 12 position to the 11 position of the structure depicted above.
  • 11-Keto- ⁇ -tigogenin is prepared from hecogenin by the following procedure. According to the procedure of Conforth, et al., (J. Chem. Soc, 1954. 907), hecogenin is acetylated, brominated, treated with sodium hydroxide and reduced with zinc to give the 12-hydroxy-11-keto analog. Then 12- hydroxy-11-keto analog is acetylated and reduced with calcium and ammonia to give 11-ketotigogenin.
  • ⁇ -Diosgenin's preparation is described in "Diosgenin and Other Steroidal Drug Precursors" by Asolkar, L.V., Chadha, Y.R., and Rawat, P.S., Council of Scientific and Industrial Research, New Delhi, India, 183 pages, 1979 and also in T. Kawasaki et al., Chem, Pharm. Bull., Japan 10 698 (1962). Its structure is depicted below.
  • any environment or conditions suitable for (i.e., capable of) forming the desired tigogenin, 11-ketotigogenin, hecogenin- or diosgenin- beta-O-cellobioside heptaalkanoate may be used.
  • the reaction occurs at a temperature of about 20 °C to about 100°C and preferably from about 50 °C to about 65 °C. Below about 20 °C the reaction can be slow and above about 100°C undesired side reactions (e.g. anomerization) can occur. This reaction is conveniently carried out at ambient pressure however, pressures from about 0.5 to about 3 atmospheres may be used.
  • the steroid, metal salt and solvent are heated to reflux and sufficient solvent is. azeotropically distilled to remove substantially all the water. Then the cellobiosyl bromide heptaacetate is added to the above mixture and heated for about
  • the glycosides may be precipitated from the crude filtered reaction mixture (e.g. acetonitrile product solution) by the addition of about 25% to 75% water and the remainder alcohol (e.g. methanol). Precipitation of the product from aqueou methanol/acetonitrile requires less processing than an extractive isolation, and provide a product of greater purity.
  • the crude filtered reaction mixture e.g. acetonitrile product solution
  • the remainder alcohol e.g. methanol
  • the steroidal peracyl glycosides may be deacetylated by conventional method such as treatment with triethyiamine in methanol, basic anion exchange resins o sodium methoxide in methanol or methanol THF solvents (e.g. Example 2 below).
  • the deacetylated product may be prepared by refluxing in methanol/THF using a non-catalytic amount of sodium methoxide followed by conventional work-up. The excess methoxide is used to decompose the fluoro sugar, if any ⁇ -cellobiosyl fluoride heptaacetate is present, otherwise the deacetylation would be catalytic in sodium methoxide.
  • the ttgogenyl- ⁇ -O-cellobioside or analogs are then isolated by conventional methods such as filtration.
  • tigogenyl ⁇ -O- cellobioside heptaalkanoate can be prepared from tigogenyl ⁇ -O-cellobioside heptaalkanoate by heating the ⁇ -glycoside in a methylene chloride solution containing hydrogen bromide.
  • This invention makes a significant advance in the field of steroidal glycosides by providing efficient methods of preparing steroidal peracyl glycosides.
  • the deacetylated end products are useful as antihypercholesterolemic agents. It should be understood that the invention is not limited to the particular embodiments shown and described herein, but that various changes and modifications may be made without departing from the spirit and scope of this novel concept as defined by the following claims.
  • Thin-layer chromatography 7 and high pressure liquid chromatography 2 show that the product contains 77% (w/w) tigogenyl ⁇ -O-cellobioside heptaacetate and 15% (w/w) ⁇ -cellobiosyl fluoride heptaacetate.
  • the ⁇ -cellobiosyl fluoride heptaacetate is most easily removed from the product during the deacetylation step.
  • the slurry was concentrated by removing 200 ml of distillate and then 200 mi of water was added to the refluxing slurry. Another 200 ml of distillate was removed, and additional water (200 ml) was added. The slurry was cooled to ambient temperature and filtered. The product cake was washed with water (50 ml) and then pulled dry on the filter. The water-wet cake was heated to reflux (65° C in 600 mis of THF and 92 mis of water). DARCO G-60 (1.53 grams) was added to the solution, stirred for 15 minutes, and then the mixture was filtered through Celite. The solution was concentrated by removing 460 ml of distillates and 460 ml of methanol was then added.
  • the methanol addition and concentration sequence was repeated twice again removing an addition 800 mis of distillate and 800 mis of fresh methanol was added.
  • the resulting slurry was cooled 5 to 20°C and then granulated for one hour.
  • the product was filtered, rinse with fresh methanol (50 ml), and then the wet cake was reslurried in 300 mis of fresh methanol (24° C).
  • the product was filtered and then dried at40°C / 7 vacuo overnight.
  • Tigogenyl ⁇ -O-cellobioside (24.4g; 0.036 moles) was isolated in 74% overall yield. Spectral and physical properties were identical to an authentic sample.
  • the millequivalents of HBracid contained in the ⁇ -cellobiosyl bromide heptaacetate solution before and after the azeotropic strip are reported below.
  • the azeotropic strip increase the tetratable acid approximately 8-10 fold depending upon the water content.
  • Example 1 When the azeotropic distillation was used in Example 1 to dry the glycosyl bromide solution and to increase its acid content, the reaction time was decreased to 1.0 hour at 65°C. In addition, high yields and high ⁇ -anomeric selectivity were maintained.
  • the crude reaction mixture was filtered through Celite to afford approximately 20 liters of a golden colored filtrate.
  • the filtrate was heated (55-60° C) and concentrated at reduced pressure to about 10 liters.
  • the concentrated solution was cooled to 50° C and 5.0 liters of methanol was added.
  • 7.5 liters of deionized water was slowly added over 30 minutes.
  • a solid precipitated from solution once about 2 liters of water was charged.
  • the mixture was heated to reflux (73°C) and then maintained at reflux for 2 hours.
  • the slurry was cooled to 25° C and granulated overnight.
  • the crude product was filtered, washed with methanol (2 x 1.5 liters), and then dried in vacuo at 40°C.
  • the crude solid (1.01 kg) was 95.5% pure by a hplc assay.
  • the crude product contained only 1.3% of tigogenyl ⁇ -O-cellobioside heptaacetate and no ⁇ -cellobiosyl fluoride heptaacetate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

Procédés de synthèse d'heptaalcanoate de bêta-O-cellobioside de tigogénine, qui est un intermédiaire de l'agent hypocholestérolémique connu, le bêta-cellobioside de tigogénine. Le procédé consiste à faire réagir de l'heptaalcanoate de bromure de alpha-cellobioside et de la beta-tigogénine en présence de fluorure de zinc ou de cyanure de zinc dans des conditions permettant la formation de l'heptaalcanoate de beta-O-cellobioside de tigogényle. Des procédés de préparation analogues d'heptaalcanoate de beta-O-cellobioside d'hécagénine, d'heptaalcanoate de beta-O-cellobioside de 11-cetotigogénine et d'heptaalcanoate de beta-O-cellobioside de diosgénine sont également décrits. Le procédé permet d'obtenir à la fois des rendements élevés et une sélectivité élevée beta-anomérique.
EP92921860A 1991-11-25 1992-10-15 Procede de preparation de glycosides de peracyle steroides Withdrawn EP0619822A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US79757491A 1991-11-25 1991-11-25
US797574 1991-11-25
PCT/US1992/008638 WO1993011150A1 (fr) 1991-11-25 1992-10-15 Procede de preparation de glycosides de peracyle steroides

Publications (1)

Publication Number Publication Date
EP0619822A1 true EP0619822A1 (fr) 1994-10-19

Family

ID=25171219

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92921860A Withdrawn EP0619822A1 (fr) 1991-11-25 1992-10-15 Procede de preparation de glycosides de peracyle steroides

Country Status (13)

Country Link
EP (1) EP0619822A1 (fr)
JP (1) JPH0826064B2 (fr)
AU (1) AU659506B2 (fr)
CA (1) CA2123684A1 (fr)
FI (1) FI942394A0 (fr)
HU (1) HUT67035A (fr)
IL (1) IL103797A0 (fr)
MX (1) MX9206761A (fr)
NZ (1) NZ245244A (fr)
PT (1) PT101088A (fr)
TW (1) TW232699B (fr)
WO (1) WO1993011150A1 (fr)
ZA (1) ZA929081B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4226593A (en) * 1992-06-26 1994-01-24 Pfizer Inc. Steroidal glycosides for treating hypercholesterolemia
US5563259A (en) * 1992-06-26 1996-10-08 Pfizer Inc. Process for making β-O-cellobiosyl steroid derivatives and trimethyl silyl steroid intermediates used therein
DE69314031T2 (de) * 1992-06-26 1998-01-22 Pfizer Verfahren zur herstellung von per-acylierten glykosiden
CA2161239A1 (fr) * 1993-04-28 1994-11-10 Douglas J.M. Allen Spirostanyl-glycosidal monohydrate cristallise
US5502038A (en) * 1993-06-21 1996-03-26 Medical Research Foundation Of Oregon Cholesterol sequestrant glycosides that inhibit intestinal cholesterol absorption
JPH09500906A (ja) * 1993-12-28 1997-01-28 ファイザー・インク． 血中コレステロール低下薬
WO1996038466A1 (fr) * 1995-05-29 1996-12-05 Pfizer Inc. Glycosides steroidiques
US5756470A (en) * 1996-10-29 1998-05-26 Schering Corporation Sugar-substituted 2-azetidinones useful as hypocholesterolemic agents

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4602005A (en) * 1982-05-17 1986-07-22 Medical Research Foundation Of Oregon Tigogenin cellobioside for treating hypercholesterolemia and atherosclerosis
US4602003A (en) * 1982-05-17 1986-07-22 Medical Research Foundation Of Oregon Synthetic compounds to inhibit intestinal absorption of cholesterol in the treatment of hypercholesterolemia

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9311150A1 *

Also Published As

Publication number Publication date
FI942394A (fi) 1994-05-24
NZ245244A (en) 1995-04-27
ZA929081B (en) 1994-05-24
HU9401374D0 (en) 1994-08-29
HUT67035A (en) 1995-01-30
MX9206761A (es) 1995-01-31
AU2775892A (en) 1993-06-28
JPH06510794A (ja) 1994-12-01
PT101088A (pt) 1994-02-28
TW232699B (fr) 1994-10-21
AU659506B2 (en) 1995-05-18
WO1993011150A1 (fr) 1993-06-10
IL103797A0 (en) 1993-04-04
FI942394A0 (fi) 1994-05-24
CA2123684A1 (fr) 1993-06-10
JPH0826064B2 (ja) 1996-03-13

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