Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2003-06-03
2004-11-16
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S472000
Reexamination Certificate
active
06818764
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method of manufacturing substance GM-95, which has an anti-cancer activity, and also relates to intermediates in the manufacture of substance GM-95.
BACKGROUND ART
Regarding substance GM-95, which has an anti-cancer activity, International Publication No. WO00/24747 discloses isolation from a culture. The structure of substance GM-95 is unique; it is a macrocyclic compound comprising seven oxazole rings and a thiazoline ring connected together. No chemical manufacturing method has been known for these macrocyclic compounds comprising sequential 5-membered hetero-cyclic rings, such as substance GM-95 so far.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide a method of manufacturing substance GM-95, and intermediates in the manufacture of substance GM-95.
That is, the present invention relates to a method of manufacturing substance GM-95 having general formula [I]
characterized by (a) deprotecting a macrocyclic compound having general formula [II]
(wherein, R
1
's are the same or different and each represents a lower alkyl group, and R
2
represents a thiol protecting group) by removing acetal protecting groups (the R
1
's) thereof, and forming an oxazole ring through an intramolecular cyclization reaction between the thus produced formyl group and an amide group, and (b) deprotecting the resulting macrocyclic compound represented by general formula [III]
(wherein, R
2
is as mentioned above) by removing the thiol protecting group (R
2
) thereof, and forming a thiazoline ring through an intramolecular cyclization reaction between a thiol group thus produced and an amide group. Moreover, the present invention relates to the macrocyclic compounds represented by above-mentioned general formulae [II] and [III], which are useful as intermediates in the manufacture of substance GM-95.
Specifically, the present specification provides the following inventions.
Item 1: A method of manufacturing substance GM-95 having general formula [I], characterized by deprotecting the thiol protecting group (R
2
) of the macrocyclic compound having general formula [III] and forming a thiazoline ring through an intramolecular cyclization reaction between a thiol group thus produced and an amide group.
Item 2: A method of manufacturing substance GM-95 having general formula [I], characterized by (a) deprotecting acetal protecting groups (the R
1
's) of the macrocyclic compound having general formula [II] and forming an oxazole ring through an intramolecular cyclization reaction between a formyl group thus produced and an amide group, and
(b) deprotecting the thiol protecting group (R
2
) of the resulting macrocyclic compound having general formula [III] and forming a thiazoline ring through an intramolecular cyclization reaction between a thiol group thus produced and an amide group.
Item 3: The macrocyclic compound having general formula [II].
Item 4: The macrocyclic compound having general formula [III].
Item 5: A method of manufacturing the macrocyclic compound having general formula [II], characterized by (a) carrying out dehydration condensation between an acetal derivative having general formula [IV-a]
(wherein, the R
1
's are as mentioned above, and R
3
represents a carboxyl protecting group) and a thiol derivative having general formula [V-a]
(wherein, R
2
is as mentioned above, and R
4
represents an amino protecting group), and
(b) deprotecting the amino protecting group (R
4
) and the carboxyl protecting group (R
3
) of the resulting amide derivative having general formula [VI]
(wherein, the R
1
's, R
2
, R
3
and R
4
are as mentioned above) and then carrying out intramolecular cyclization.
Item 6: A method of manufacturing the macrocyclic compound having general formula [II], characterized by (a) carrying out dehydration condensation between an acetal derivative having general formula [IV-b]
(wherein, the R
1
's are as mentioned above, and R
5
represents an amino protecting group) and a thiol derivative having general formula [V-b]
(wherein, R
2
is as mentioned above, and R
6
represents a carboxyl protecting group), and
(b) deprotecting the amino protecting group (R
5
) and the carboxyl protecting group (R
6
) of the resulting amide derivative having general formula [VII]
(wherein, the R
1
's, R
2
, R
5
and R
6
are as mentioned above) and then carrying out intramolecular cyclization.
The scheme of the method of manufacturing GM-95 according to the present invention is shown below.
In the present invention, examples of the lower alkyl groups represented by the R
1
's are straight-chain or branched lower alkyl groups having 1 to 6 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group, and an s-butyl group, with a methyl group or an ethyl group being preferable, and a methyl group being more preferable.
Examples of the thiol protecting group represented by R
2
are protecting groups mentioned in ‘Protective Groups in Organic Synthesis’ (published 1981) by Greene, for example unsubstituted or substituted benzyl groups such as a benzyl group, a p-methoxybenzyl group, a 4-methylbenzyl group, a 3,4-dimethylbenzyl group, a p-hydroxybenzyl group, a p-acetoxybenzyl group and a p-nitrobenzyl group, a diphenylmethyl group, a trityl group, a t-butyl group, an acetyl group, a benzoyl group, and so on, with an unsubstituted or substituted benzyl group such as a benzyl group, a p-methoxybenzyl group, a 4-methylbenzyl group, a 3,4-dimethylbenzyl group, a p-hydroxybenzyl group, a p-acetoxybenzyl group or a p-nitrobenzyl group, or a diphenylmethyl group, a trityl group, or a t-butyl group being preferable, and a benzyl group, a trityl group, or a t-butyl group being more preferable.
In the present invention, examples of the carboxyl protecting group represented by R
3
or R
6
are protecting groups mentioned in the above-mentioned ‘Protective Groups in Organic Synthesis’ by Greene, for example straight-chain or branched lower alkyl groups having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an n-butyl group, an isobutyl group, an s-butyl group and a t-butyl group, and an allyl group, a benzyl group, a diphenylmethyl group, and so on, with a methyl group or an ethyl group being preferable for either R
3
or R
6
.
Examples of the amino protecting group represented by R
4
or R
5
are again protecting groups mentioned in the above-mentioned ‘Protective Groups in Organic Synthesis’ by Greene, for example a methoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a cyclopropylmethoxycarbonyl group, a diisopropylmethoxycarbonyl group, a 2-furanylmethoxycarbonyl group, an isobutoxycarbonyl group, a t-butoxycarbonyl group, a benzyloxycarbonyl group, a formyl group, and so on, with a t-butoxycarbonyl group or a benzyloxycarbonyl group being preferable for either R
4
or R
5
.
Steps of Manufacturing Compound [I] (Substance GM-95) from Compound [II]
(a) Manufacture of Compound [III] from Compound [II]
The present step is a step of deprotecting the macrocyclic compound having general formula [II] by removing the acetal protecting groups (the R
1
's) thereof, and forming an oxazole ring through an intramolecular cyclization reaction between the produced formyl group and an amide group.
i) In the above reaction, removing the acetal protecting groups (the R
1
's) is carried out in the presence of an acid in a suitable solvent. The solvent may be any solvent so long as it is inert to the reaction; examples are tetrahydrofuran, dioxane, ethyl acetate, and so on. Such solvents may be used alone, or a mixture thereof may be used. Examples of the acid are organic acids such as trifluoroacetic acid and formic acid, and minera
Asao Tetsuji
Kitagawa Kazuhiro
Okajima Shigeo
Shigeno Kazuhiko
Yamada Shozo
Kifle Bruck
Rader & Fishman & Grauer, PLLC
Taiho Pharmaceutical Co. Ltd.
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