GB2096596A - 8-quinolinesulfonyl derivatives and their synthesis and use as coupling agents in nucleotide chemistry - Google Patents
8-quinolinesulfonyl derivatives and their synthesis and use as coupling agents in nucleotide chemistry Download PDFInfo
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- GB2096596A GB2096596A GB8200577A GB8200577A GB2096596A GB 2096596 A GB2096596 A GB 2096596A GB 8200577 A GB8200577 A GB 8200577A GB 8200577 A GB8200577 A GB 8200577A GB 2096596 A GB2096596 A GB 2096596A
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- Prior art keywords
- quinolinesulfonyl
- group
- derivative
- synthesis
- derivatives
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Classifications
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
-
- 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
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
Abstract
N-(2-Thiazolyl)carbamate derivatives represented by the general formula (1): (FORMULA) (wherein R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a thienyl group, a furyl group, or a pyridyl group), a process for their preparation, and an immunity-controlling medicinal composition containing same, effective against chronic articular rheumatism, viral diseases, cancer, etc.
Description
SPECIFICATION 8-quinolinesulfonyl derivatives and their synthesis and use as coupling agents
The present invention relates to coupling agents for the synthesis of oligonucleotides, and particularly to novel improved coupling agents and a process for preparation thereof.
A known oligonucleotide synthesis is represented by the equation:
by-product by-product by-product wherein B and B' which may be the same or different, each represents N6-benzoyladenine, N4benzoylcytosine, N2-benzoylguanine, uracil, thymine, etc., R represents a hydrogen atom, tetrahydropyranyl group, etc., R'represents 5-chloro-8-quinolyl group, etc., R" represents 4chlorophenyl group etc, and R"' represents a triazoyl group, etc, and Sub represents other substituents.
Various coupling agents have been known for the synthesis of oligonucleotides by the phosphotriester approach, as shown in the above reaction scheme. For example, 2,4,6triisopropylbenzenesulfonyl chloride (TPS) as described in R. Lohrman, H.G. Khorana, J. Amer.
Chem. Soc. (JACS), Vol. 88, p. 829 (1966); 2,4,6-triisopropoylbenzenesulfonyltriazolide [N.
Katagiri, K. Itakura, S.A. Narang, JACS, 97,7332(1975)]; 2,4,6-triisoprpoylbenzenesulfonyltetrazolide [J. Stawinski, T. Hozumi, S.A. Narang, C.P. Bahi, R. Wu, Nucleic Acids Res., 4,353 (1977)]; and 8-quinolinesulfonyl chloride [H. Takaku, M. Kato, M. Yoshida, T. Hata, Chemistry
Letters, p. 811(1979)] are particularly known.
However, these coupling agents causes extensive sulfonation at the 5'-hydroxyl group of nucleosides and guanine during the coupling reactions. Arylsulfonyltriazolides are extremely slow in coupling reactions, much slower than the corresponding chlorides. On the other hand, arylsulfonyltetrazolides afford very rapid coupling rates but the sulfonylation at the 5'-hydroxyl group occurs during the coupling reactions. Furthermore, arylsulfonic acids formed during the coupling reactions are not able to be separated from the reaction mixture. 8-Quinolinesulfonyl chloride does not synthesize oligonucleotides in high yields and produces hydrochloric acid upon the coupling reactions which cause cleavage of a protecting group for the 5'-hydroxyl group of nucleosides.
We have now discovered novel coupling agents for the synthesis of oligonucleotides, and a process for their preparation. The compounds are 8-quinolinesulfonyl compounds having the formula (I)
wherin A is a tetrazolyl group, or a triazolyl or imidazolyl group which is unsubstituted or substituted by an electrophilic group.
The use of the 8-quinolinesulfonyl derivative (I) as a new coupling agent in the synthesis of oligonucleotides by the phosphotriester approach provides a much reduced time period for the reaction with much higher yields without by-products such as the above described. Further, the 8-quinolinesulfonyl derivative is converted to a neutral inner salt having the chemical structure shown below upon the coupling reaction and is easily separated as a precipitate from the reaction mixture.
The neutral inner salt does not cause cleavage of acid-sensitive protecting groups such as a dimethoxytrityl group as a protecting group for the 5'-hydroxy group of the nucleosides. In the case of arylsulfonic acids, the cleavage takes place during the coupling reactions.
The 8-quinolinesulfonyl derivatives (I) according to the present invention can be prepared by reacting an 8-quinolinesulfonyl halide represented by formula (II)
wherein X represents a halogen atom, with a tetrazole compound, or a triazole or imidazole compound which may be substituted by an electrophilic group such as a halogen atom, a nitro group or a cyano group. More specifically, a 8-quinolinesulfonyl halide (II) (I equiv.) is treated with a tetrazole compound, or a triazole or imidazole compound which may be substituted by an electrophilic group (I equiv.) in the presence of a tertiary amine (1 equiv] in a nonpolar solvent at room temperature for 1 to 3 hours to provide the 8-quinolinesulfonyl derivative (I) in yields of over 80%. In formula (II), bromine, chlorine, iodine or fluorine can be used as halogen atom.
These 8-quinolinesulfonyl halides can be prepared by a conventional method and are commercially available from Aldorich Co.
A mononitro group, dinitro group, halogen groups such as chlorine, bromine, iodine or fluorine, and cyano group can be used as the electrophilic (electron-attracting) group(s) on triazole or imidazole in the formula (I).
Suitable tertiary amines in the reaction are triethylamine and pyridine. Suitable solvents are tetrahydrofuran (THF), methylene chloride, d ioxane and acetonitrile.
The 8-quinolinesulfonyl derivatives (I) of the present invention can be effectively used as a coupling agent in the synthesis of oligonucleotides by the reaction of nucleoside 3'-phosphate and 5'-hydroxylnucleotide or 5'-hydroxylnucleoside and provide excellent results under the following conditions:
A 2',5'-protected nucleoside 3'-phosphodiester (A) (1 to 1.5 equiv.) is treated with 3'phosphotriester (B) (2 to 3 equiv.) in the presence of an 8-quinolinesulfonyl derivative (1) (2 to 3 equiv.) in dry pyridine to give the corresponding dinucleotides (C). In these reactions, the corresponding oligonucleotides (C) can be rapidly produced without the sulfonylated by-products and easily isolated from the reaction mixture.The use of 8-quinolinesulfonyl derivatives, and especially 8-quinolinesulfonyltetrazolide (QS-te), in the synthesis of oligonucleotides by the phosphotriester approach gives a much reduced reaction time period (0.5 to 2 hours) with much higher yields (over 80%) compared to conventional methods.
In order to obtain a longer-chain oligonucleotide, the condensation reactions using the 8quinolinesulfonyl derivative (I) as described above are repeated after removing protecting groups of a previously formed oligonucleotide (for example, the dimethoxytrityl group and the chlorophenyl group (R") in the dinucleotide (C)) using, e.g. ptoluenesulfonic acid or pyridinaldoxime, in a conventional manner as described in, for example, Chemistry Letters, pp.
543-546 (1981).
The synthetic method of the present invention and the utilization of the product are illustrated in the following Examples.
EXAMPLE 1
To a solution of 8-quinolinesulfonyl chloride produced by Aldorich Co. (2.28 g) in dry THF (20 ml) was added tetrazole (0.7 g) at 0 C. Subsequently a solution of triethylamine (1.39 ml) in THF (2 ml) was added and the reaction was conducted for 2 hours at room temperature. The precipitated triethylammonium chloride was removed by filtration, and the filtrate was concentrated in vacuo. The residue was extracted with CH2CI2 (100 ml), washed with water (30 ml) three times, and dried over Na2SO4. The CH2CI2 extract was concentrated in vacuo and the resulting crystalline product was washed with small amount of CH2CI2, and 2.09 g (80% yield) of 8-quinolinesulfonyltetrazolide was thus obtained.
Melting point: 210"C (decomposed)
Elemental Analysis:
Calcd.: C,45.97%; H,-2.71%; N,26.81%
Found: C,45.60%; H, 2.77%; N,26.71% H-NMR(DMSO-d6, ppm from TMS Standard): 9.9(1 H, s, CH in tetrazole)
EXAMPLE 2
To a solution of 8-quinolinesulfonyl chloride (2.28 g) and triazole (0.69 9) in dry CH2CI2 (20 ml) was added a solution of triethylamine (1.39 ml) in CH2CI2 (2 ml). The reaction mixture was maintained for 2 hours at 0 C, and then the mixture was processed as described in Example 1, providing 2.00 g of 8-quinolinesulfonyltriazolide (81% yield).
Melting point: 226-229"C Elemental Analysis:
Calcd.: C,50.76%; H,3.10%; N,21.53%
Found: C,50.08%; N,3.12%; N,21.58%
H-NMR (CDCl3, ppm from TMS Standard): 8.90(H5), 8.08(H3)
EXAMPLE 3
To a solution of 8-quinolinesulfonyl chloride (2.28 g) and imidazole (0.69 g) in dry CH2CI2 (20 ml) was added a solution of triethylamine (1.39 ml) in dry CH2CI2 (2 ml). The reaction mixture was maintained for 3 hours at 0 C, and the mixture was processed as described in
Example 1, providing 1.94 g of 8-quinolinesulfonylimidazolide (87% yield).
Melting Point: 180-182"C Elemental Analysis:
Calcd: C,55.59%; H,3.49%; N,16.21%
Found: C,55.48%; H,3.51%; N,16.39%
EXAMPLE 4
To a solution of 8-quinolinesulfonyl chloride (2.28 g) and 3-nitro-1,2,4-triazole (1.14 g) in dry
THF (20 ml) was added a solution of triethylamine (1.4 ml) in dry THF (2 ml) at O"C. After 2 hours, the precipitate was removed by filtration, and the filtrate was evaporated in vacuo. The crystalline residue was dissolved in CH2CI2, which was washed with water. The CH2CI2 solution was then dried over Na2SO4, filtered, and evaporated in vacuo. The resulting crystalline product was washed with a small amount of benzene, yielding 2.6 g (85% yield) of a white crystalline solid, 8-quinolinesulfonyl-3-nitro- 1 , 2,4-triazole.
Melting Point: 227-229"C Elemental Analysis:
Found: C,43.13%; H,2.31%; N,22.78%
Calculated: C,43.28%; H,2.31%; N,22.94%
EXAMPLE 5
A reaction similar to that in Example 1 was performed, except for the use of 8-quinolinesulfonyl bromide in place of the chloride, providing 8-quinolinesulfonyltetrazoline in an 80% yield.
EXAMPLE 6
5'-0-Di methoxytrityl-2'-0-tetrahydropyranyluridine 3 '-(5-chloro-8-qu inolyl) phosphate (3.75 mmol) and 2'-O-tetrahydropyranyl-N6-benzoyladenosine 3'-(4-chlorophenyl, 5-chloro-8-quinolyl) phosphate (2.5 mmol) were dissolved in dry pyridine t10 ml) and rendered anhydrous by removing water in the form of azetrope with the dry pyridine. The water-removal step was repeated three times. The residue was dissolved in dry pyridine (12.5 ml) and then 8quinolinesulfonyltetrazolide (2.45 9, 9.37 mmol) was added thereto at room temperature. After 1 hour, 8-quinolinesulfonic acid was removed by filtration. The filtrate was quenched with icewater and extracted with methylene chloride (CN2CI2) (120 ml X 3).The CH2CI2 extract was washed with 0.1 M triethylammonium bicarbonate solution, dried over Na2SO4, filtered, and under reduced pressure evaporated to obtain a gum. The residue was dissolved in CH2Cl2, and applied to a silica gel column. The column was eluted with a mixture of CH2CI2 MeOH (98:2 v/v). The obtained fractions were evaporated to provide 4.06 g (9796 yield) 5'-0-dimethoxytrityl-2'-0-tetrahydropyranyluridylyl (3'-5') 2'-O-tetrahydropyranyl-N6-benzoyladenosine-3 '-p-(5chloro-8-quinolyl)phosphate-p2-(4-chlorophenyl, 5-chloro-8-quinolyl)-phosphate shown below as a solid by precipitation from a nhexane ether (10:1 v/v) mixture.
Rf = 0.42 (CH2Cl2:CH3OH = 9:1 v/v)
UV = Amax(MeOH) 276, 234 nm; Amin(MeOH) 254 nm
The structure of the olionucleotide was confirmed by a conventional enzymatic hydrolysis after removal of the protecting groups of the fully protected oligonucleotide.
In a similar manner, other oligonucleotides were obtained in good yields, as shown in Table 1.
Table 1
Synthesis of Oligonucleotides
Nucleoside 5'hydroxyl- 8-quinolinesulfonyl
3'-phosphate nucleotide or derivatives
Example (mmol) nucleoside (mmol) (mmol) Oligonucleotides Yield (%) 7 d-DMTrTpQCl d-tpQCl(PhCl) 8-quinolinesulfonyl- d-DMTrTp(QCl)- 92
(3.0) (1.5) tetrazolide TpQCl(PhCl)
(7.5) 8 d-DMTrTp(QCl)- d-Tp(QCl)TpQCl- 8-quinolinesulfonyl- d-DMTrTp(QCl)- 91
TpQCl (PhCl) tetrazolide Tp(QCl)Tp(QCl)
(0.53) (0.35) (1.3) TpQCl(PhCl) 9 DMTrUp(QCl)- Utp(QCl)bzAtp- 8-quinolinesulfonyl- DMTr{Utp(QCl)- 80
bz-AtpQCl (QCl)-Utp(QCl)bzA- tetrazolide bzAtpQCl}2Utp
(0.48) (OBz)2 (QCl)bzA(OBz)2
(0.32) 10 DMTrUtp(QCl) U(OBz)2 8-quinolinesulfonyl- DMTrUtp(QCl)- 88
3-nitro-1,2,4- U(OBz)2
triazole
Claims (11)
1. An 8-quinolinesulfonyl derivative represented by formula (I)
wherein A represents a tetrazolyl group, or a triazolyl or imidazolyl group which is unsubstituted or substituted by an electrophilic group.
2. An 8-quinolinesulfonyl derivative as claimed in Claim 1, wherein A represents a tetrazolyl group.
3. An 8-quinolinesulfonyl derivative as claimed in Claim 1, wherein A represents a triazolyl group.
4. An 8-quinolinesulfonyl derivative as claimed in Claim 1, wherein said electrophilic group is a nitro, dinitro or cyano group or a halogen atom.
5. An 8-quinolinesulfonyl derivative as claimed in Claim 4, wherein A represents a 3-nitro1,2,4-triazolyl group.
6. A process of synthesizing an 8-quinolinesulfonyl derivative as claimed in any preceding claim, comprising reacting an 8-quinolinesulfonyl halide represented by formula (II)
wherein X represents a halogen atom, with a tetrazole compound or a triazole or imidazole compound which is unsubstituted or substituted by an electrophilic group.
7. A process as claimed in Claim 6, which is carried out in a nonpolar solvent in the presence of a tertiary amine.
8. A synthesis process as claimed in Claim 6, substantially as hereinbefore described in any of Examples 1 to 4.
9. A process of producing an oligonucleotide which comprises reacting a nucleoside 3'phosphate and a 5'-hydroxy nucleotide or nucleoside in the presence as coupling agent of an 8quinolinesulfonyl derivative as claimed in any of Claims 1 to 5 or made by a process as claimed in any of Claims 6 to 8.
10. A process as claimed in Claim 9, wherein the 8-quinolinesulfonyl derivative is used in an amount of 2 to 3 equivalents per equivalent of the phosphodiester.
11. A process as claimed in Claim 9, substantially as hereinbefore described in any of
Examples 6 to 10.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56003000A JPS57116067A (en) | 1981-01-12 | 1981-01-12 | Novel 8-quinolinesulfonyl derivative, its synthesis and use |
| JP213481A JPS57118573A (en) | 1981-01-12 | 1981-01-12 | N-(2-thiazolyl)carbamate derivative, its preparation, and drug composition comprising it |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2096596A true GB2096596A (en) | 1982-10-20 |
Family
ID=26335456
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8200577A Withdrawn GB2096596A (en) | 1981-01-12 | 1982-01-08 | 8-quinolinesulfonyl derivatives and their synthesis and use as coupling agents in nucleotide chemistry |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JPS57116067A (en) |
| GB (1) | GB2096596A (en) |
| WO (1) | WO1982002385A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201506024A (en) | 2013-07-02 | 2015-02-16 | 必治妥美雅史谷比公司 | Tricyclic carboxamide derivatives as potent ROCK inhibitors |
| JP6522602B2 (en) | 2013-07-02 | 2019-05-29 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | Tricyclic pyrido-carboxamide derivatives as ROCK inhibitors |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1068607A (en) * | 1976-04-14 | 1979-12-25 | Don R. Baker | 2-cyclopropanecarboxamido-5-halothiazole as anti-inflammatory agents |
| FR2406634A1 (en) * | 1977-10-19 | 1979-05-18 | Fabre Sa Pierre | IMMUNOSTIMULANTS DERIVED FROM AMINO THIAZOLES |
| US4217355A (en) * | 1978-04-24 | 1980-08-12 | Pfizer Inc. | Amide therapeutic agents |
| DK150068C (en) * | 1978-06-02 | 1987-06-29 | Pfizer | METHOD OF ANALOGUE FOR THE PREPARATION OF AMINOTHIAZOLES |
-
1981
- 1981-01-12 JP JP56003000A patent/JPS57116067A/en active Pending
-
1982
- 1982-01-08 GB GB8200577A patent/GB2096596A/en not_active Withdrawn
- 1982-01-12 WO PCT/JP1982/000009 patent/WO1982002385A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57116067A (en) | 1982-07-19 |
| WO1982002385A1 (en) | 1982-07-22 |
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| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |