CA1189069A - Preparation of protected 3'deoxynucleosides - Google Patents
Preparation of protected 3'deoxynucleosidesInfo
- Publication number
- CA1189069A CA1189069A CA000422144A CA422144A CA1189069A CA 1189069 A CA1189069 A CA 1189069A CA 000422144 A CA000422144 A CA 000422144A CA 422144 A CA422144 A CA 422144A CA 1189069 A CA1189069 A CA 1189069A
- Authority
- CA
- Canada
- Prior art keywords
- thiocarbonyl
- diprotected
- hydroxyl
- compound
- group
- 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.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Saccharide Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
3'-deoxynucleosides are prepared from 2',5'-diprotected ribonucleosides by a process in which the 3'-hydroxy of the 2',5'-diprotected ribonucleoside is replaced with a substituted thiocarbonyl group, e.g. by reaction with phenylchlorothionocarbonate, and then reduced e.g. with tri(n-butyl)tin monohydride, to form the 3'-deoxy compound.
3'-deoxynucleosides are prepared from 2',5'-diprotected ribonucleosides by a process in which the 3'-hydroxy of the 2',5'-diprotected ribonucleoside is replaced with a substituted thiocarbonyl group, e.g. by reaction with phenylchlorothionocarbonate, and then reduced e.g. with tri(n-butyl)tin monohydride, to form the 3'-deoxy compound.
Description
This invention relates to 3'-deoxyribonucleosides and derivatives thereof. More particularly, it relates to a process for the conversion of ribonucleosi~es to 3'-deoxyribonucleosides and their protected derivatives.
One example of a known 3'-deoxyribonucleoside which has known and proven utility is the pharmaceutical compound cordycepin which is 3'-deoxyadenosine of formula:
~L
~o~,/ ~I
~1 0~1 However, known synthetic methods for producing such compounds containing the 3'-deoxyribose ring are complicated, involving a substantial number of chemical synthetic steps required to be conducted sequentially.
The chemical conversion of ribonucleosides to 3'-deoxynucleosides has not been easy to accomplish. Procedures usually involve halogenation of the carbohydrate ring followed by replacement of halogen with hydrogen. Alternatively, the desulfurization of thioanhydronucleosides leads to deoxynucleosides. 3'-deoxynucleosides such as cordycepin are of considerable interest for their biological activity, but there is a need for a general procedure for the conversion of ribonucleosides into protected 3'-deoxynucleosides, both for preparation of cordycepin and known compounds and for preparation of novel compounds for investigation.
According to the present invention~ there is provided a process for preparing a 3'-deoxynucleoside, which comprises:
reacting a 2',5'-diprotected ribonucleoside having a 3'-hydroxyl group with a thiocarbonyl compound so as to replace the hydrogen atom of the 3'-hydroxyl with a substituted thiocarbonyl group;
removing the substituted thiocarbonyl group from the 3'-position of the 2',5'-diprotected, 3'-(substituted-thiocarbonyl) ribonucleoside so prepared by chemical reduction, to form therefrom a 2',5'-diprotected, 3'-deoxyribonucleoside;
and optionally deprotecting one or both of the 2' and 5'-positions.
One example of a known 3'-deoxyribonucleoside which has known and proven utility is the pharmaceutical compound cordycepin which is 3'-deoxyadenosine of formula:
~L
~o~,/ ~I
~1 0~1 However, known synthetic methods for producing such compounds containing the 3'-deoxyribose ring are complicated, involving a substantial number of chemical synthetic steps required to be conducted sequentially.
The chemical conversion of ribonucleosides to 3'-deoxynucleosides has not been easy to accomplish. Procedures usually involve halogenation of the carbohydrate ring followed by replacement of halogen with hydrogen. Alternatively, the desulfurization of thioanhydronucleosides leads to deoxynucleosides. 3'-deoxynucleosides such as cordycepin are of considerable interest for their biological activity, but there is a need for a general procedure for the conversion of ribonucleosides into protected 3'-deoxynucleosides, both for preparation of cordycepin and known compounds and for preparation of novel compounds for investigation.
According to the present invention~ there is provided a process for preparing a 3'-deoxynucleoside, which comprises:
reacting a 2',5'-diprotected ribonucleoside having a 3'-hydroxyl group with a thiocarbonyl compound so as to replace the hydrogen atom of the 3'-hydroxyl with a substituted thiocarbonyl group;
removing the substituted thiocarbonyl group from the 3'-position of the 2',5'-diprotected, 3'-(substituted-thiocarbonyl) ribonucleoside so prepared by chemical reduction, to form therefrom a 2',5'-diprotected, 3'-deoxyribonucleoside;
and optionally deprotecting one or both of the 2' and 5'-positions.
2',5'-Diprotected ribonucleosides and their processes of preparation are known. They are described, for example, in "Tetrahedron Letters" 4775-4778 (1981), and in "Canadian Journal of Chemistry" 60, 1106-1113 (1982~, both articles by G.H.
Hakimelahi, Z.A. Proba and K.K. Ogilvie. By means of such processes, one may obtain compounds of general formula ~0~
( I ) ~ o.5i 1 in which B represents a purine or pyrimidine group, e.g. uracil or adenine, R represents a traditional nucleoside blocking group such as dimethoxytrityl, and Sil represents a silyl or loweralkyl-sllyl group such as t.butyldimethylsilyl. In the present invention, such products are reacted and reduced at their
Hakimelahi, Z.A. Proba and K.K. Ogilvie. By means of such processes, one may obtain compounds of general formula ~0~
( I ) ~ o.5i 1 in which B represents a purine or pyrimidine group, e.g. uracil or adenine, R represents a traditional nucleoside blocking group such as dimethoxytrityl, and Sil represents a silyl or loweralkyl-sllyl group such as t.butyldimethylsilyl. In the present invention, such products are reacted and reduced at their
3'-position, to proauce 3'-deoxynucleoside derivatives, which may then be deprotected.
A suitable reagent to react at the 3'-hydroxyl is phenyl chlorothionocarbonate, which reacts readily with the 2',5'-protected derivatives of formula I, thus:
Ro~ ~o~c.c~
~o ~.S;) ~ o o,s;l When the base B is N-protected, however, the yield of clesired product is low~ The resultant product II may then be reduced, to replacQ the oxy-thiocarbonyl group with hydrogen, thus producing a 3'-deoxynucleotide. Suitable reducing agents are tri(n-butyl)tin monohydride in 2,2'-azobis (2-methylpropionitrile), thus:
k~ (n l3~)3 S~, ~ > ~>~
~O-C-O ~,Sil (~
The silyl protecting group at position 2' is compound III can be removed by known methods, e.g. reaction with tetrabutylammonium fluoride (T~AF~. When B représents an N-protec~ed base group, j - 4 -e.g. N-benzoyl protected purines and pyrimidines, the N-protecting groups are substantially unaffected by TBAF.
An alternative reagent to phenyl chlorothionocarbonate is (thiocarbonyl) diimidazole. This reacts with compounds of formula I as follows:
Ro o ~ o c~ ~
M - C~
Uo O,S;l 1~ . C - O O,S;~
(1 ~ s where IM represents imidazole. Compound IV can be reduced similarly to compound II, e.g. with (n-Bu)3SnH and 2,2'-azobis (2-methylpropionitrile) to give a compound of formula III
above. This reaction proceeds well with both N-protected and N-unprotected nucleosides, although in the case of N-benzoyl-adenosine and N-benzoylguanosine derivatives, the reaction is relatively slow.
The end products, of formula V:
R~< \,~1 (V ) o~
can be used directly in nucleotide synthesis. They can be completely deprotected by standard procedures, to give 3'-deoxynucleosides, such as cordycepin, of pharmacological interest.
The invention is further described in the following specific examples:
Example l:
1 m.mole of a protected nucleoside of formula I above, in which R represented dimethoxytrityl DMT and B represented uracil, was dissolved in 20ml acetonitrile and 6m.mole
A suitable reagent to react at the 3'-hydroxyl is phenyl chlorothionocarbonate, which reacts readily with the 2',5'-protected derivatives of formula I, thus:
Ro~ ~o~c.c~
~o ~.S;) ~ o o,s;l When the base B is N-protected, however, the yield of clesired product is low~ The resultant product II may then be reduced, to replacQ the oxy-thiocarbonyl group with hydrogen, thus producing a 3'-deoxynucleotide. Suitable reducing agents are tri(n-butyl)tin monohydride in 2,2'-azobis (2-methylpropionitrile), thus:
k~ (n l3~)3 S~, ~ > ~>~
~O-C-O ~,Sil (~
The silyl protecting group at position 2' is compound III can be removed by known methods, e.g. reaction with tetrabutylammonium fluoride (T~AF~. When B représents an N-protec~ed base group, j - 4 -e.g. N-benzoyl protected purines and pyrimidines, the N-protecting groups are substantially unaffected by TBAF.
An alternative reagent to phenyl chlorothionocarbonate is (thiocarbonyl) diimidazole. This reacts with compounds of formula I as follows:
Ro o ~ o c~ ~
M - C~
Uo O,S;l 1~ . C - O O,S;~
(1 ~ s where IM represents imidazole. Compound IV can be reduced similarly to compound II, e.g. with (n-Bu)3SnH and 2,2'-azobis (2-methylpropionitrile) to give a compound of formula III
above. This reaction proceeds well with both N-protected and N-unprotected nucleosides, although in the case of N-benzoyl-adenosine and N-benzoylguanosine derivatives, the reaction is relatively slow.
The end products, of formula V:
R~< \,~1 (V ) o~
can be used directly in nucleotide synthesis. They can be completely deprotected by standard procedures, to give 3'-deoxynucleosides, such as cordycepin, of pharmacological interest.
The invention is further described in the following specific examples:
Example l:
1 m.mole of a protected nucleoside of formula I above, in which R represented dimethoxytrityl DMT and B represented uracil, was dissolved in 20ml acetonitrile and 6m.mole
4 (dimethylamino)pyridine, and 5m.mole phenyl chlorothionocarbonate added. After stirring at room temperature for six hours the solution was diluted with 40ml ethyl acetate.
The organic layer was washed three times with water, dried over magnesium sulphate, and evaporated to leave the crude product.
The product was purified by silica gel chromatography. Similar procedures were adopted and pursued with other starting materials of formula I, but in which B represented adenine, N-benzoyladenine, N-benzoylcytosine and N-benzoylguanine.
Results are shown in table I below.
Example 2:
1.1 m.mole of protected nucleoside was dissolved in lOml dimethyl formamide (DMF) and 3 m.mole (thiocarbonyl) ~iimidazole was added. After stirring at room temperature for times ranging from 1-85 hours, depending on the starting material the solution was diluted with lOOml ethyl acetate and 50ml water. The organic layer was separated and was shecl with water (3 x 50 ml), ~ried over MgSO4 and evaporated at reduced pressure, the residue was purified by silica gel chromatography.
Reactions were generally over in 4 h except when the starting material was N-ben~oyladenosine and N-benzoylguanine derivatives ~hich required 85 h and 70 h respeccively. During this long reaction period, isomerization of the silyl groups occurred and mixtures of the 2'- and 3'-derivatives were obtained. These mixtures were only resolved after reduction and desilylation~ at which point they were readily separated.
The various starting materials, products, and the results obtalned, according to Examples 1 and 2 are given in the following Table 1. The compounds so obtained correspond to general formuLa IV given above.
TABL~ I
Expt.No. Com~ound of Compound OL Reaction Yielcl Melting formula II formula IV Time (~)Point PrepareclPrepared (h) (C) B R B R
1 Uracil DMT 6 6076-78 2 Uracil D~lT 4 5096-78 3 Adenine DMT 6 60 80-83 4 Adenine DMT 4 56 103-105 . . _ N-benzoyl DMT 85 4051-60 adenine 6 N-benzoyl DMT 4 5288-91 cYtosine .. , . . . _ _ _ . ...
7 N-benzoyl MMT 70 50 42-49 quanine . .
DMT represents ~imethoxytrityl, ~T represents monomethoxytrityl.
In each compound the silyl group Si is t-butyldimethylsilyl. In Experiments 5 and 7 mixtures of 2'- and 3'- isomers were obtained.
~e~
Compounds prepared according to the previous examples and listed in Table I were reduced, and the 3'-deoxyderivatives isolated.
In each case, a mixture of 6 m.mole of the compound, lg of 2,2'-azobis ~2-methylpropionitrile) and 27 m.mole (n-Bu)3SnH were heated at reflux in toluene for 3-4 hours.
Solvents were removed and products isolated by silica yel chromatography. In some cases, the product so obtained, of general formula III was subsequently de-silylated with tetrabutylammonium fluoride (TBAF) to obtain product of formula V. The results are given in Table II below.
TABLE II
Expt.No. Compound of Compound of Reaction Yield Melting formula III formula V Time (~) Point PreparedPrepared (hours) 1C) B R B R
.
8 Uracil DMT 3 55 78-80 9 Uracil DMT 1 95 100-102 . . . _ 10 Adenine DMT 4 42 69-72 .
11 Adenine DMT 1 93 123-126 12 N-benzoyl ~iT 4 35 35-45 adenine 13 N-benzoyl MMT 1 50111-112 adenine . . _ _ . _ 14 N benzoyl DMT 4 40 96-98 _ cytosine N-benzoyl DMT 1 90119-122 cYtosine -16 N-benzoyl MMT 4 4135-42 a~uanine 17 N-benzoyl MMT 1 40140-141 auanine In experiments 12 and 16, mixtures of 2'- and 3'- isomers were obtained. The isomers were readily separable by TLC after desilylation.
_ g
The organic layer was washed three times with water, dried over magnesium sulphate, and evaporated to leave the crude product.
The product was purified by silica gel chromatography. Similar procedures were adopted and pursued with other starting materials of formula I, but in which B represented adenine, N-benzoyladenine, N-benzoylcytosine and N-benzoylguanine.
Results are shown in table I below.
Example 2:
1.1 m.mole of protected nucleoside was dissolved in lOml dimethyl formamide (DMF) and 3 m.mole (thiocarbonyl) ~iimidazole was added. After stirring at room temperature for times ranging from 1-85 hours, depending on the starting material the solution was diluted with lOOml ethyl acetate and 50ml water. The organic layer was separated and was shecl with water (3 x 50 ml), ~ried over MgSO4 and evaporated at reduced pressure, the residue was purified by silica gel chromatography.
Reactions were generally over in 4 h except when the starting material was N-ben~oyladenosine and N-benzoylguanine derivatives ~hich required 85 h and 70 h respeccively. During this long reaction period, isomerization of the silyl groups occurred and mixtures of the 2'- and 3'-derivatives were obtained. These mixtures were only resolved after reduction and desilylation~ at which point they were readily separated.
The various starting materials, products, and the results obtalned, according to Examples 1 and 2 are given in the following Table 1. The compounds so obtained correspond to general formuLa IV given above.
TABL~ I
Expt.No. Com~ound of Compound OL Reaction Yielcl Melting formula II formula IV Time (~)Point PrepareclPrepared (h) (C) B R B R
1 Uracil DMT 6 6076-78 2 Uracil D~lT 4 5096-78 3 Adenine DMT 6 60 80-83 4 Adenine DMT 4 56 103-105 . . _ N-benzoyl DMT 85 4051-60 adenine 6 N-benzoyl DMT 4 5288-91 cYtosine .. , . . . _ _ _ . ...
7 N-benzoyl MMT 70 50 42-49 quanine . .
DMT represents ~imethoxytrityl, ~T represents monomethoxytrityl.
In each compound the silyl group Si is t-butyldimethylsilyl. In Experiments 5 and 7 mixtures of 2'- and 3'- isomers were obtained.
~e~
Compounds prepared according to the previous examples and listed in Table I were reduced, and the 3'-deoxyderivatives isolated.
In each case, a mixture of 6 m.mole of the compound, lg of 2,2'-azobis ~2-methylpropionitrile) and 27 m.mole (n-Bu)3SnH were heated at reflux in toluene for 3-4 hours.
Solvents were removed and products isolated by silica yel chromatography. In some cases, the product so obtained, of general formula III was subsequently de-silylated with tetrabutylammonium fluoride (TBAF) to obtain product of formula V. The results are given in Table II below.
TABLE II
Expt.No. Compound of Compound of Reaction Yield Melting formula III formula V Time (~) Point PreparedPrepared (hours) 1C) B R B R
.
8 Uracil DMT 3 55 78-80 9 Uracil DMT 1 95 100-102 . . . _ 10 Adenine DMT 4 42 69-72 .
11 Adenine DMT 1 93 123-126 12 N-benzoyl ~iT 4 35 35-45 adenine 13 N-benzoyl MMT 1 50111-112 adenine . . _ _ . _ 14 N benzoyl DMT 4 40 96-98 _ cytosine N-benzoyl DMT 1 90119-122 cYtosine -16 N-benzoyl MMT 4 4135-42 a~uanine 17 N-benzoyl MMT 1 40140-141 auanine In experiments 12 and 16, mixtures of 2'- and 3'- isomers were obtained. The isomers were readily separable by TLC after desilylation.
_ g
Claims (4)
OR PRIVILEGE IS CLAIMEDD ARE DEFINED AS FOLLOWS:
1. A process for preparing a 3'-deoxynucleoside, which comprises:
reacting a 2',5'-diprotected ribonucleoside having a 3'-hydroxyl group with a thiocarbonyl compound so as to replace the hydrogen atom of the 3'-hydroxyl with a substituted thiocarbonyl group;
removing the substituted thiocarbonyl group from the 3'-position of the 2',5'-diprotected, 3'-(substituted-thiocarbonyl) ribonucleoside so prepared by chemical reduction, to form therefrom a 2',5'-diprotected, 3'-deoxyribonucleoside;
and optionally deprotecting one or both of the 2' and 5'-positions.
reacting a 2',5'-diprotected ribonucleoside having a 3'-hydroxyl group with a thiocarbonyl compound so as to replace the hydrogen atom of the 3'-hydroxyl with a substituted thiocarbonyl group;
removing the substituted thiocarbonyl group from the 3'-position of the 2',5'-diprotected, 3'-(substituted-thiocarbonyl) ribonucleoside so prepared by chemical reduction, to form therefrom a 2',5'-diprotected, 3'-deoxyribonucleoside;
and optionally deprotecting one or both of the 2' and 5'-positions.
2. The process of claim 1 said replacement of the hydrogen atom of the 3'-hydroxyl is conducted using phenyl chlorothiono-carbonate.
3. The process of claim 1 wherein said replacement of the hydrogen atom of the 3'-hydroxyl is conducted using (thiocarbonyl)diimidazole.
4. The process of claim 1, claim 2 or claim 3 wherein reduction to the 3'-deoxyribonucleoside is conducted using an organo-tin compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000422144A CA1189069A (en) | 1983-02-22 | 1983-02-22 | Preparation of protected 3'deoxynucleosides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000422144A CA1189069A (en) | 1983-02-22 | 1983-02-22 | Preparation of protected 3'deoxynucleosides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1189069A true CA1189069A (en) | 1985-06-18 |
Family
ID=4124614
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000422144A Expired CA1189069A (en) | 1983-02-22 | 1983-02-22 | Preparation of protected 3'deoxynucleosides |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1189069A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6500946B1 (en) * | 1998-03-17 | 2002-12-31 | Ajinomoto Co., Inc. | Methods for producing nucleoside derivatives and intermediates therefor |
-
1983
- 1983-02-22 CA CA000422144A patent/CA1189069A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6500946B1 (en) * | 1998-03-17 | 2002-12-31 | Ajinomoto Co., Inc. | Methods for producing nucleoside derivatives and intermediates therefor |
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