WO2004096830A1 - Synthesis of solanum glycosides - Google Patents

Synthesis of solanum glycosides Download PDF

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Publication number
WO2004096830A1
WO2004096830A1 PCT/EP2004/004629 EP2004004629W WO2004096830A1 WO 2004096830 A1 WO2004096830 A1 WO 2004096830A1 EP 2004004629 W EP2004004629 W EP 2004004629W WO 2004096830 A1 WO2004096830 A1 WO 2004096830A1
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Prior art keywords
formula
benzoyl
acetyl
sph
halogen
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PCT/EP2004/004629
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French (fr)
Inventor
Mohammed Shahid
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Glycomed Sciences (Uk) Limited
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Priority to EP04730531A priority Critical patent/EP1618122A1/en
Priority to CA002524131A priority patent/CA2524131A1/en
Priority to AU2004234071A priority patent/AU2004234071A1/en
Priority to JP2006505349A priority patent/JP2006524664A/en
Priority to US10/555,038 priority patent/US7435816B2/en
Publication of WO2004096830A1 publication Critical patent/WO2004096830A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the chemical synthesis of solanum giycosides, in particular to the synthesis of solasonine as well as to novel ⁇ -monosaccharide intermediate compounds.
  • Solasodine and its giycosides are of considerable interest clinically. They are widely used as starting products for the synthesis of various steroidal drugs, the aglycon solasodine is a source for synthetic cortisone and progesterone.
  • solasodine giycosides have potent antineoplastic properties.
  • solasonine 22R, 25R
  • solasonine 22R, 25R
  • solamargine 22R, 25R
  • solamargine 22R, 25R
  • solamargine 22R, 25R
  • the above triglycosides are conventionally obtained by extraction from a plant source.
  • a commercially available extract of S. sodomaeum commonly referred to as BEC (Drug Future, 1988, vol. 13.8, pages 714-716) is a crude mixture of solamargine, solasonine and their isomeric diglycosides.
  • the extraction process for making BEC involves homogenizing the fruits of S. sodomaeum in a large volume of acetic acid, filtering off the liquid through muslin followed by precipitation of the giycosides with ammonia (Drugs of today (1990), Vol. 26 No. 1, p. 55-58, cancer letters (1991), Vol. 59, p. 183-192).
  • the yield of the solasodine glycoside mixture is very low (approx. 1%).
  • the individual process steps are not defined to GMP in terms of scale up, definition of yield, composition and product quality.
  • the steroid skeleton of solasodine contains a very labile nitrogen-containing ring. This aglycon cannot readily be chemically modified while keeping the steroid skeleton intact.
  • the prior art does not disclose the synthesis of the solasonine using the aglycon material as starting material.
  • solasonine requires the stereoselective glycosylation of solasodine at the relatively unreactive hydroxyl group.
  • solasodine is not compatible with the conventional steroid glycosylation technique. No glycosylation was observed following the treatment of solasodine with tetrabenzoyl -D-glucopyranosyl trichloroacetimidate and trimethyl-silyl triflate or boron trifluoride dietherate (unpublished results).
  • the problem underlying the present invention is to provide a cost effective method for the preparation of solasonine.
  • the present invention resides in the finding that the stereoselective ⁇ -glycosylation of solasodine may be achieved in high yields using specific galacto-pyranosyl donors.
  • the reaction is carried out in the presence of a promoter.
  • R Benzylidine, 4-nitrobenzylidine or 4-methoxybenzylidine
  • R 2 Benzoyl, acetyl or pivolyl
  • R 3 Halogen, SEt or SPh
  • each R-j is the same or different and independently represents a benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene group
  • each R2 is the same or different and independently represents a benzoyl, acetyl or pivaloyl group and
  • R 3 is halogen, SPh or SEt
  • each Ri is the same or different and independently represents a benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene group and each R 2 is the same or different and independently represents a benzoyl, acetyl or pivaloyl group.
  • reaction is carried out in the presence of a promoter.
  • Any conventional promoter as used in carbohydrate chemistry may be used.
  • the reaction is preferably carried out using dichloromethane as the solvent.
  • the reaction time is 30 min.-1 hr.
  • the desired end product solasonine may be prepared by partially deprotecting the ⁇ -glycoside of formula 2 to give intermediate formula 3(1) and then selectively silylating one of the hydroxyl groups (OH-2 and OH-3) using tert-butyldimethylsilyl chloride, imidazole in DMF at 50°C.
  • R1 Benzylidine, 4-nitrobenzylidine or 4-methoxybenzylidine
  • each of Ri is the same or different and represent independently from each other benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene,
  • R 2 is tert-butylsilyl or H and R 3 is H.
  • the OH-3 protected galactose-solasodine adduct is then glycosylated at the OH-2 with a suitable ⁇ -L-rhamnopyranosyl donor.
  • Suitable rhamnose donors include tri-O-benzolyl- -rhamnopyranosly, tri-O- pivoloyl-L-rhamnopyranosyl, or tri-O-acetyl- 4- L-rhamnopyranosyl bromides of formula 4
  • R, Acetyl, benzoyl or pivolyl
  • R 2 Halogen, SEt or SPh
  • each of Ri is the same or different and independently represents acetyl, benzoyl or pivaloyl, and R 2 is halogen or SEt, SPh
  • R., Acetyl, benzoyl or pivolyl
  • R 2 Halogen, SEt or SPh
  • each of Ri is the same or different an independently represents acetyl, benzoyl or pivaloyl and R 2 is halogen, SEt, SPh gives a fully protected solasonine of formula 6(1).
  • each Ri is the same or different and independently represents benzylidene, 4-nitrobenzyilidene or 4-methoxybenzylidene and each R 2 are the same or different and independently represent acetyl, benzoyl or pivaloyl.
  • the protected solasonine formula 6(1) may be de-acetalised using aqueous acetic acid at 70°C and de-esterified using sodium methoxide in methanol/dichloromethane mixture to give the fully deprotected solasonine formula 6(2) where in R and R 2 are H.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

The present invention relates to the chemical synthesis of solanum glycosides, in particular to the synthesis of solasonine as well as to novel β-monosaccharide intermediate compounds, of Formula (II), where each R1 is the same or different and independently represents a benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene group and each R2 is the same or different and independently represents a benzoyl, acetyl or pivaloyl group.

Description

Synthesis of Solanum Giycosides
The present invention relates to the chemical synthesis of solanum giycosides, in particular to the synthesis of solasonine as well as to novel β-monosaccharide intermediate compounds.
Solasodine and its giycosides are of considerable interest clinically. They are widely used as starting products for the synthesis of various steroidal drugs, the aglycon solasodine is a source for synthetic cortisone and progesterone.
It is moreover well established that certain naturally occurring conjugate solasodine giycosides have potent antineoplastic properties. Of particular interest are the triglycosides solasonine (22R, 25R)-spiro-5-en-3β-yl-α-L-rhamno- pyranosyl-(1 ->2 gal)-O-p-D-glucopyranosyl-(1 ->3 gal)-β-D-galactopyranose and solamargine (22R, 25R)-spiro-5-en-3β-yl-α-L-rhamnopyranosyl-(1 ->2 glu)-α-L- rhamnopyranosyl- (1->4 glu)-β-D-gluco-pyranose. The structures of these triglycosides are shown below:
Figure imgf000002_0001
Solamargine
W:\DOCUMENTY1177030.DOC
Figure imgf000003_0001
Solasonine
The above triglycosides are conventionally obtained by extraction from a plant source. A commercially available extract of S. sodomaeum, commonly referred to as BEC (Drug Future, 1988, vol. 13.8, pages 714-716) is a crude mixture of solamargine, solasonine and their isomeric diglycosides. The extraction process for making BEC involves homogenizing the fruits of S. sodomaeum in a large volume of acetic acid, filtering off the liquid through muslin followed by precipitation of the giycosides with ammonia (Drugs of today (1990), Vol. 26 No. 1, p. 55-58, cancer letters (1991), Vol. 59, p. 183-192). The yield of the solasodine glycoside mixture is very low (approx. 1%). Moreover the individual process steps are not defined to GMP in terms of scale up, definition of yield, composition and product quality.
There is a great need for a cost efficient process that provides the antineoplastically active triglycoside solasonine at high yield with little or no impurities.
Contrary to other steroid ring systems, the steroid skeleton of solasodine contains a very labile nitrogen-containing ring. This aglycon cannot readily be chemically modified while keeping the steroid skeleton intact. In spite of the fact that the aglycon solasodine is readily available, the prior art does not disclose the synthesis of the solasonine using the aglycon material as starting material.
The synthesis of solasonine requires the stereoselective glycosylation of solasodine at the relatively unreactive hydroxyl group.
It has been found that solasodine is not compatible with the conventional steroid glycosylation technique. No glycosylation was observed following the treatment of solasodine with tetrabenzoyl -D-glucopyranosyl trichloroacetimidate and trimethyl-silyl triflate or boron trifluoride dietherate (unpublished results).
The problem underlying the present invention is to provide a cost effective method for the preparation of solasonine.
The present invention resides in the finding that the stereoselective β-glycosylation of solasodine may be achieved in high yields using specific galacto-pyranosyl donors. Preferably the reaction is carried out in the presence of a promoter.
Detailed description of the invention
It was unexpectedly found that by reacting a D-galacto-pyranosyl donor of the following formula 1
Formula 1
R, = Benzylidine, 4-nitrobenzylidine or 4-methoxybenzylidine
R2 = Benzoyl, acetyl or pivolyl
Figure imgf000004_0001
R3 = Halogen, SEt or SPh
Formula 1
wherein each R-j is the same or different and independently represents a benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene group each R2 is the same or different and independently represents a benzoyl, acetyl or pivaloyl group and
R3 is halogen, SPh or SEt
with solasodine the correspondingly protected β-glycoside of formula 2 could be obtained in high yield.
Formula 2
or 4-methoxybenzylidine
Figure imgf000005_0001
wherein each Ri is the same or different and independently represents a benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene group and each R2 is the same or different and independently represents a benzoyl, acetyl or pivaloyl group.
Preferably the reaction is carried out in the presence of a promoter.
Any conventional promoter as used in carbohydrate chemistry may be used.
The following promoters are particularly preferred:
Silver triflate, boron trifluoride diethyl etherate (-10°C), trimethylsilyl triflate bromide, N-iodosuccinimide, thiomethyl sulfonium triflate.
The reaction is preferably carried out using dichloromethane as the solvent. Preferably the reaction time is 30 min.-1 hr.
The desired end product solasonine may be prepared by partially deprotecting the β-glycoside of formula 2 to give intermediate formula 3(1) and then selectively silylating one of the hydroxyl groups (OH-2 and OH-3) using tert-butyldimethylsilyl chloride, imidazole in DMF at 50°C.
However, due to the small selectivity between the OH-2 and OH-3 hydroxyl groups a mixture of OH-2 and OH-3 silylated protected β-glycosides are formed. The OH-3 silylated protected β-glycoside can mostly be precipitated from the mixture in methanol of the formula 3(2).
Formula 3
or 4-methoxybenzyIidine
Figure imgf000006_0001
R1 = Benzylidine, 4-nitrobenzylidine or 4-methoxybenzylidine
3(2) R2 = Tert butyl silyl R3 = H
wherein each of Ri is the same or different and represent independently from each other benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene,
R2 is tert-butylsilyl or H and R3 is H.
The OH-3 protected galactose-solasodine adduct is then glycosylated at the OH-2 with a suitable α-L-rhamnopyranosyl donor.
Suitable rhamnose donors include tri-O-benzolyl- -rhamnopyranosly, tri-O- pivoloyl-L-rhamnopyranosyl, or tri-O-acetyl- 4- L-rhamnopyranosyl bromides of formula 4
Formula 4 R, = Acetyl, benzoyl or pivolyl R2 = Halogen, SEt or SPh
Figure imgf000007_0001
wherein each of Ri is the same or different and independently represents acetyl, benzoyl or pivaloyl, and R2 is halogen or SEt, SPh
Deprotection of the tert-butylsilyl group at the OH-3 position using tetrabutylammonium flouride in THF and glycosidation with a suitable α-D- glucopyranosly donor, wherein the D-gluco-pyranosyl donor is tetra-O-benzoyl- -D-glucopyranosyl bromide, tetra-O-acetyl- -D-glucopyranosyl bromide or tetra-O-pivoloyl-α-D- glucopyranosyl bromide, or a thio-glycoside of the general formula 5
Formula 5
R., = Acetyl, benzoyl or pivolyl R2 = Halogen, SEt or SPh
Figure imgf000007_0002
wherein each of Ri is the same or different an independently represents acetyl, benzoyl or pivaloyl and R2 is halogen, SEt, SPh gives a fully protected solasonine of formula 6(1). Formula 6
Figure imgf000008_0001
wherein each Ri is the same or different and independently represents benzylidene, 4-nitrobenzyilidene or 4-methoxybenzylidene and each R2 are the same or different and independently represent acetyl, benzoyl or pivaloyl.
The protected solasonine formula 6(1) may be de-acetalised using aqueous acetic acid at 70°C and de-esterified using sodium methoxide in methanol/dichloromethane mixture to give the fully deprotected solasonine formula 6(2) where in R and R2 are H.

Claims

Claims
1. A galactose-solasodine conjugate of the general formula 2 or a derivative thereof
Formula 2
or 4-methoxybenzylidine
Figure imgf000009_0001
wherein each R-| is the same or different and represents benzylidene, 4- nitro benzylidene or 4-methoxybenzylidene and each R2 is the same or different and represents benzoyl, acetyl or pivaloyl.
2. A method for the preparation of the galactose-solasodine conjugate as defined in claim 1 , comprising the reaction of solasodine with a galactopyranosyl donor of general formula 1 Formula 1
Benzylidine, 4-nitrobenzylidine or 4-methoxybenzylidine
Benzoyl, acetyl or pivolyl
Figure imgf000010_0001
Halogen, SEt or SPh
wherein each R2 independently represents a benzoyl, acetyl or pivaloyl group, and Ri is benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene and R3 is halogen, SE or SPh .
3. A method for the preparation of solasonine comprising the silylation of the diol of formula 3(1) to give a selectively silylated product in the OH-3 position 3(2)
Formula 3
or 4-methoxybenzylidine
Figure imgf000010_0002
R3 = H
R1 = Benzylidine, 4-nitrobenzylidine or 4-methoxybenzylidine
3(2) R2 = Tert butyl silyl
R3 = H wherein R^ is represents either benzilidene, 4-nitrobenzilidene, or 4- methoxybenzylidene acetal protecting group by gylcosylation of OH-2 with an α-L-rhamnopyranosyl donor, followed by deprotection of the group on the hydroxyl (OH-3) and a further glycosylation of the hydroxyl (OH-3) with -D-glucopyranosyl donor to yield the protected solasonine of formula 6(1 ) which is de-acetalised and de-esterified to yield a solasonine of formula 6(2).
Formula 6
or 4-methoxybenzylidine
Figure imgf000011_0001
The method according to claim 3, wherein the D-gluco-pyranosyl donor is tetra-O-benzoyl- -D-glucopyranosyl bromide, tetra-O-acetyl- -D-gluco- pyranosyl bromide or tetra-O-pivoloyl-α-D-glucopyranosyl bromide.
The method according to claim 2-4, wherein the glycosylation reaction is carried out in the presence of a promoter selected from silver triflate, boron trifluoride diethyl etherate, trimethylsilyl triflate bromide, N-iodosuccinimide or dimethyl thiomethyl sulfonium triflate.
6. The method of claim 3, wherein the protected glycoside is deprotected in methanol-dichloromethane solution by treatment with sodium methoxide, followed by neutralization with a mild acid ion-exchange resin.
7. The method of claim 3-6, wherein the hydroxyl groups (OH-4 and OH-6) are protected by acetalisation with Benzaldehyde dimethoxy acetal in DMF and a catalytic amount of para-toluene sulphonic acid.
8. The method of claim 3-7, wherein the rhamnose donor is tri-O-benzoyl-α-L- rhamnopyranosyl bromide, or a thio-giycoside of the general formula 4
Formula 4
R., = Acetyl, benzoyl or pivolyl R2 = Halogen, SEt or SPh
Figure imgf000012_0001
wherein each of the Ri is the same or different and each independently represent benzoyl, acetyl or pivaloyl and
R2 is halogen, SEt or SPh.
9. The method of claim 3-8, wherein the glucose donor is tetra-O-benzoyl- α-D-glucopyranosyl bromide, or a thio-glycoside of the general formula 5
Formula 5
R., = Acetyl, benzoyl or pivolyl R2 = Halogen, SEt or SPh
Figure imgf000012_0002
wherein each of Ri is the same or different and independently represents benzoyl, acetyl or pivaloyl and R2 is SEt, SPh or halogen
10. The method of claim 3-9, wherein the protected solasonine is de-acetalised and de-esterified by treatment with 80% acetic and then sodium methoxide solution in methanol-dichloromethane, followed by neutralization mild acid ion-exchange resin.
PCT/EP2004/004629 2003-04-30 2004-04-30 Synthesis of solanum glycosides WO2004096830A1 (en)

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EP04730531A EP1618122A1 (en) 2003-04-30 2004-04-30 Synthesis of solanum glycosides
CA002524131A CA2524131A1 (en) 2003-04-30 2004-04-30 Synthesis of solanum glycosides
AU2004234071A AU2004234071A1 (en) 2003-04-30 2004-04-30 Synthesis of solanum glycosides
JP2006505349A JP2006524664A (en) 2003-04-30 2004-04-30 Synthesis of solanam glycoside.
US10/555,038 US7435816B2 (en) 2003-04-30 2004-04-30 Synthesis of solanum glycosides

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EP03009725.7 2003-04-30
EP03009725 2003-04-30

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2005005454A1 (en) * 2003-07-08 2005-01-20 Glycomed Sciences Limited Steroid modified chacotrioses and solatrioses
WO2005005449A2 (en) * 2003-07-08 2005-01-20 Glycomed Sciences Limited Steroid modified solatrioses

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BR112019026102A2 (en) * 2017-06-12 2020-06-30 Lignamed, Llc processes for preparing a compound and a mixture of compounds

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005005454A1 (en) * 2003-07-08 2005-01-20 Glycomed Sciences Limited Steroid modified chacotrioses and solatrioses
WO2005005449A2 (en) * 2003-07-08 2005-01-20 Glycomed Sciences Limited Steroid modified solatrioses
WO2005005449A3 (en) * 2003-07-08 2005-04-21 Glycomed Sciences Ltd Steroid modified solatrioses

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AU2004234071A1 (en) 2004-11-11
EP1618122A1 (en) 2006-01-25

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