WO2002006296A1

WO2002006296A1 - Processes for the preparation of 2,2'-anhydronucleic acid compound derivatives

Info

Publication number: WO2002006296A1
Application number: PCT/JP2001/006263
Authority: WO
Inventors: Tsuneji Suzuki; Hiroshi Nagase; Akiyoshi Kai; Hajime Iizuka
Original assignee: Mitsui Chemicals, Inc.
Priority date: 2000-07-19
Filing date: 2001-07-19
Publication date: 2002-01-24

Abstract

2,2'-Anhydronucleic acid compound derivatives useful as intermediates of drugs or agricultural chemicals or the like can be prepared from inexpensive starting compounds by reacting a compound of the general formula (2) with a compound of the general formula (3) to thereby obtain a 2,2'-anhydronucleic acid compound derivative: (3) (wherein R1, R2, R3, R4, Q, X, Y and Z represent specific groups respectively). Further, L-cytidine derivatives useful as intermediates of drugs or agricultural chemicals or the like can be prepared by synthesizing a 2'-alkoxycytidine directly from a 2,2'- anhydrocytidine derivative.

Description

Specification

Method for producing 2, 2'-anhydronucleic acid compound derivative

The present invention relates to a method for producing 2,2′-anhydronucleic acid compound derivatives and 2′-alkoxynucleic acid compound derivatives useful as intermediates for pharmaceuticals and agricultural chemicals, and 2′_ synthesized by these methods. The present invention relates to an alkoxy mono-L-cytidine derivative and a 2,2'-anhydro L-cytidine derivative. Background technology

Nucleic acids are important components of genes, and their use as pharmaceuticals has been studied in various ways. Non-natural nucleic acid derivatives, which are obtained by converting part of natural nucleic acids, which are often found in viral drugs and anticancer drugs, are used very often as pharmaceuticals. It is also being actively used in new therapeutic fields such as antisense drugs, in which non-natural nucleic acid derivatives that have been partially converted are used, and efficient synthesis of nucleic acid derivatives is achieved. And a conversion method is needed. Until now, various nucleic acid derivatives have been synthesized. Among them, many derivatives in which the 2′-position is variously converted have been synthesized and used extensively. 2,2'-Anhydronucleic acid compound derivatives have long been known as important synthetic intermediates for the 2'-position conversion. For example, the synthesis of 2, 2 — Anhyd ro— 1 -J3 -D—ar ab inosylcytosine and 2, 2 ′ — Anhyd ro— 1—] 3— D—ar ab inosyluraci 1 by Sanchez et al. (J. 〇. C, 38 (3), pp. 593-598 (1973)). The 2,2′-anhydronucleic acid derivative thus synthesized was a very useful substance for synthesizing the derivative at the 2′-position, but very expensive propiol on itri 1 e and me thy 1 The use of propiolate was a major problem in terms of a practical synthesis method for pharmaceuticals. Therefore, in order to produce 2,2'-anhydronucleic acid compound derivatives at lower cost, for example, A way was conceived.

(1) cytidine, natural nucleic acids the material to P0C1 ₃ such Urijin, ethylene force one Poneto, a method of cyclization with a Lewis acid such as (JP 48- 67286, JP 52- 5 9195)

(2) A method of converting propiol on itrile to 2-acrylonitrile and other acrylonitriles by the method of Sanchez et al. (Nuc1eosides Nucleotides 13 (1994) 6-7, 1647-16 54) are known. However, there have been no inexpensive synthetic methods that can be widely applied, despite various studies, except for derivatives that can be derived from cytidine peridine, which are readily available from nature.

Until now, most studies on nucleic acid synthesis have been conducted on D-forms, in which the steric nature of the sugar is natural, and there has been little research on L-form nucleic acid derivatives. However, in recent years, it has become clear that unnatural nucleic acid derivatives having an L-type sugar have an effect on viral diseases, particularly hepatitis B, and their importance is increasing. For example, it is known that L-type nucleic acids such as L-dT, L-dC, L-dA (WO 0009531) show a high therapeutic effect on hepatitis B. In addition, L-FMAU (Antimicro b. Agnnetts Chemoher. 1995, 39, 979) can significantly reduce toxicity by converting from D-type to L-enantiomer. It is expected to be used as a therapeutic agent for hepatitis. Therefore, there is a strong need for a method for inexpensively synthesizing L-type nucleic acid derivatives.

Furthermore, the reaction of ring opening with a metal alkoxide to convert the 2'-position of a 2,2'-anhydronucleic acid compound derivative synthesized by various methods into an alkoxy group is a very useful reaction. J. Chem. Soc., Perkin Tran sl (1982), 1171 and raser et al., J. Heterocycle C. hem., 30, 1277 (1993)), it was not known that L-type 2'-alkoxycytidine derivatives could be directly synthesized. Disclosure of the invention

The problem to be solved by the present invention is to provide a method for producing a 2,2'-anhydride nucleic acid compound derivative which is useful as an intermediate of a medicinal and agricultural chemical using a less expensive compound as a starting material. Another object of the present invention is to provide a method for directly synthesizing 2'-alkoxy-L-cytidine from a 2,2'-anhydro-L-cytidine derivative. Another object of the present invention is to provide an L-type cytidine derivative which has been recognized as important in recent years.

The present inventors have conducted intensive studies on the problem and found that a compound represented by the general formula (2), which is a starting material that can be easily synthesized from sugar and cyanamide, is less expensive than an acrylic acid derivative or an acrylonitrile derivative. The present inventors have found that the compound represented by the general formula (1) can be synthesized by reacting with the compound represented by the general formula (3) which can be synthesized, and have completed the present invention. We have also found a method for directly synthesizing 2'-alkoxy-1-L-cytidine from 2,2'-anhydro-L-cytidine derivatives. Furthermore, they have found that useful L-type cytidine derivatives can be synthesized by these methods.

That is, the present invention includes the following embodiments. '

[1] General formula (1)

(1)

(Wherein, R 1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 2 carbon atoms or a protected hydroxyalkyl group having 1 to 2 carbon atoms, and R 2 represents a hydrogen atom. , A hydroxy group, a protected hydroxy group, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, wherein R 3 and R 4 are each independently a hydrogen atom or 1 carbon atom. Represents an alkyl group having 1 to 4 carbon atoms, a fluoroalkyl group having 1 to 4 carbon atoms, and Q represents an oxygen atom or an imino group.) The method for producing a 2,2′-anhydronucleic acid compound derivative represented by the following formula: So, General formula (2)

(Wherein, R1 and R2 have the same meanings as described above), and an aminooxazoline derivative represented by the following general formula (3):

(In the formula, X and Y each independently represent a halogen atom, Z represents a cyano group, a carbonyl group, or an alkyloxy propyl group having 1 to 4 carbon atoms, and R and R have the same meanings as described above. A process for producing a compound represented by the general formula (1) by reacting a compound represented by the formula (1) as a raw material, and a method for producing a 2,2'-anhydronucleic acid compound derivative and a salt thereof. .

[2] In the general formula (1), R 1 is a hydroxyalkyl group having 1 to 2 carbon atoms or a protected hydroxyalkyl group having 1 to 2 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and R 2 is The production method of the above-mentioned [1], wherein R 3 is a hydrogen atom, a hydroxy group, a protected hydroxy group or an alkoxy group having 1 to 4 carbon atoms, and R 3 is a hydrogen atom.

[3] — In the general formula (1), R1 is a hydroxymethyl group, R2 is a hydroxy group, R4 is a hydrogen atom, a methyl group or a trifluoromethyl group, and in the general formula (3), X And Y are each independently a chlorine atom or a bromine atom, and Z is a cyano group, a carboxyl group, a methoxycarbonyl group or an ethoxy group. The production method of the above-mentioned [2], which is a cycarponyl group.

[4] The above-mentioned item [3], wherein, in the general formula (1), R4 is a methyl group, Q is an oxygen atom, and in the general formula (3), Z is a methoxycarbonyl group or an ethoxycarbonyl group. Manufacturing method.

[5] The production method of the above-mentioned [3], wherein in the general formula (1), R4 is a hydrogen atom, Q is an imino group, and in the general formula (3), Z is a cyano group.

[6] General formula (6)

(Wherein, R4, R5 and R6 have the same meanings as described above.) A method for producing a 2,2′-anhydro-L-cytidine derivative and a salt thereof,

General formula (4)

(Four)

(Wherein, R5 and R6 represent a hydrogen atom or a protecting group for a hydroxyl group.) An L-aminooxazoline derivative represented by the general formula (5)

(Wherein, R 4 and X have the same meanings as described above). The step of reacting the compound represented by the formula (1) to obtain a 2,2′-anhydro-L-cytidine derivative represented by the above general formula (6) A process for producing a 2,2′-anhydro-L-cytidine derivative and an acceptable salt thereof, characterized by having:

[7] General formula (8)

(8)

(Wherein R4, R5, R6 and R7 have the same meanings as described above.) A method for producing an L-cytidine derivative represented by the formula:

The compound represented by the general formula (6) and the compound represented by the general formula (7)

(R7-0) n-M (7)

(R7 is an alkyl group having 1 to 4 carbon atoms, an aralkyl group having 1 to 10 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, and an alkylaminoalkyl having 1 to 10 carbon atoms.) Represents an alkoxyalkyl group having 1 to 10 carbon atoms, n represents an integer of 1 to 3, and M represents a metal.) To form an L-cytidine derivative represented by the general formula (8). A method for producing an L-cytidine derivative and a salt thereof, comprising the step of:

[8] The production method according to the above item [7], wherein R4, R5 and R6 in the general formula (8) are hydrogen atoms.

[9] A 2,2′-anhydro-L-cytidine derivative represented by the general formula (6) and a salt thereof synthesized by the production method of the above item [6], and synthesized by the method of the above item [7]. A 2′-alkoxy-L-cytidine derivative represented by the general formula (8) and a salt thereof.

[10] —The 2,2′-anhydro-L-cytidine derivative of the above-mentioned [9] represented by the general formula (6) and a salt thereof. [11] The 2,2′-anhydro-L-cytidine derivative of the above-mentioned [10], wherein R 4, R 5 and R 6 in the general formula (6) are hydrogen atoms, and salts thereof.

[12] The 2′-alkoxy-1-L-cytidine derivative of the above-mentioned [9] represented by the general formula (8) and a salt thereof.

[13] —The 2′-alkoxy-L-cytidine derivative of the above-mentioned [12], wherein R 5 and R 6 in the general formula (8) are hydrogen atoms, and salts thereof. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail, but the present invention is not limited to these descriptions.

In the present invention, the alkyl group having 1 to 4 carbon atoms includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group.

Examples of the hydroxyalkyl group having 1 to 2 carbon atoms include a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, and a 1,2-dihydroxyethyl group.

Examples of the perfluoroalkyl group having 1 to 4 carbon atoms include a trifluoromethyl group, a penfluorofluoroethyl group, a hepturofluoropropyl group, and a nonafluorobutyl group.

Polyhydroxyalkyl groups having 2 to 4 carbon atoms include 1,2-dihydroxyethyl, 1,2-dihydroxypropyl, 2,3-dihydroxypropyl, 1,2,3-trihydroxypropyl, Examples thereof include a 2-dihydroxybutyl group, a 1,3-dihydroxybutyl group, and a 2,3-dihydroxybutyl group.

Halogen atoms include fluorine, chlorine, bromine and iodine.

The alkoxy group having 1 to 4 carbon atoms includes a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group and a tert-butoxy group.

An alkylthio group having 1 to 4 carbon atoms means a methylthio group, an ethylthio group, n-propyl Thio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio.

Alkoxycarbonyl groups having 1 to 4 carbon atoms are methoxycarbonyl, ethoxycarbonyl, n_propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl And a tert-butoxycarbonyl group.

Protected means a structure in which a hydroxyl group is protected by an easily deprotectable protecting group.A protecting group generally known in synthetic chemistry can be used, and two hydroxyl groups are simultaneously protected. It can also have an annular structure. More specifically, it is represented by an ether-based protecting group represented by a benzyl group derivative, a silyl-based protecting group represented by a TBDMS group, an acyl-based protecting group represented by a benzoyl derivative, and a CIPS group. Cyclic protecting groups.

Examples of the aralkyl group having 1 to 10 carbon atoms include a substituted benzyl derivative represented by a benzyl group, an aryl substituted alkyl group, and a heterocyclic substituted alkyl group represented by a pyridylmethyl group.

An alkylaminoalkyl group having 1 to 10 carbon atoms means N, N-dimethylaminoethyl, N, N-dimethylaminoethyl, N, N-dimethylaminopropyl, N-methyl-N-phenyl. Enylaminopropyl group and the like.

Examples of the alkoxyalkyl group having 1 to 10 carbon atoms include a methoxyethyl group, an ethoxyxyl group, a methoxypropyl group, and a benzyloxethyl group. Metal alkoxides include lithium alkoxide, sodium alkoxide, potassium alkoxide, cesium alkoxide, aluminum alkoxide, magnesium alkoxide, calcium alkoxide, barium alkoxide, and borane alkoxide (trimethylporanate). It can be synthesized using the method described above.

In addition, the salts of the compounds represented by the general formulas (1), (6) and (8) refer to those that can form a salt, and specifically include, for example, hydrochloride, hydrogen bromide Inorganic acids or acetates such as acid salts, hydrofluorates, sulfates and phosphates, trifluoroacetic acid Salts formed using organic acids such as salts, oxalates and formates are exemplified. In addition, depending on the intended use of the compound, a salt is formed which is acceptable for the purpose, for example, for pharmaceuticals or agricultural chemicals.

The compounds represented by the general formulas (1), (4), (6) and (8) can contain possible optical isomers.

Specific examples of the compound include compounds represented by the general formula (1): 2,2'-anhydro-1-0-D-arabinofuranosylcytosine, 2,2'-anhydro-11-) 3—L—arabinofuranosylcytosine, 2, 2 ′ _anhydro-1-yl) 3—D-arapinofuranosyl-1-5-methylcytosine, 2,2′_anhydro-1-jS—L-arapinofuranosyl-1 5-Methylcytosine, 2, 2'-anhydro-D-ara

2,2'-anhydro-1 11) 3-L-arabinofuranosyl-5-trifluoromethyrucytosine, 2, 2'-anhydro-1 1 -3 -D-arabinofuranosylperacyl,

2,2'-anhydro-1-3-D-arabinofuranosyl thymine, 2,2'-anhydro-1-3-L-arabinofuranosyl thymine, 2,2'-anhydro-1-jS 1-D-arapinofuranosyl 5-5-trifluoromethylperacyl, 2,2'-anhydro 1-L-arabinofuranosyl 5-5-trifluoromethylperacyl, 2,2'-anhydro-1 _ 1 D-lipofuranosylcytosine, 2, 2'-anhydro — 1 α-L-lipofuranosylcytosine, 2, 2'-anhydro-1 D-lipofuranosyl-1 5-methylcytosine, 2, 2'-anhydro- 1-α-L-ribofuranosyl-5-methylcytosine, 2,2'_anhydro-I-a-D-ribofuranosyl-5-trifluoromethylcytosine, 2,2'-anhydro-11-α-L-uri Pofuranosyl 5-—trifluoromethylcytosine, 2, 2′-anhydride 1 1 1 1 D-lipofuranosylperacyl, 2, 2'-anhydro- 1 α-L-ribofuranosylperacyl, 2, 2'-anhydro 1 1-D-lipofuranosyl thymine, 2, 2'- Anhydro-1-1-L-lipofuranosyl thymine, 2,2'-Anhydro-1-1 α-D-lipofuranosyl-5 _trifluoromethylperacyl, 2,2'-an Hydro-1-Hi-L-Lipofuranosyl _ 5 -Trifluoromethylperacyl, 2,2'-Anhydro-3,5-di-1-benzyl-1-] 3-L-arabinofuranosyl cytosine, 2,2 '—Anhydro-1,5-di-1-acetyl-1-1 / 3-L-ara-pinofuranosylcytosine, 2, 2' —anhydro-3,5-di-t-butyl-methylsilyl-1-1 i8— L-arabinofuranosylcytosine, 2,2'-anhydro-1D-galactofuranosylcytosine, 2,2'-anhydro-111; 8-D

, 2 '-anhydro-5-doxy-1-| 3-L

2,2'-anhydro-3-deoxy-1 11) 3-L-arapinofuranosylcytosine and the like.

The compounds represented by the general formula (3) include 2,3-dichloropropionitrile, 2,3-dibromopropionitrile, 3-bromo-2-chloropropionitrile, and 2-bromo-3— 2,3-Dichloro-2-methylpropionitrile, 2,3-Dibutorum 2-Methylpropionitrile, 3-Bromo-2-cyclo-1,2-methylpropionitrile, 2-Bromo-3 —Chloro-2-methylthiopropionitrile, 2,3-Dichloro-2-trifluoromethylpropionitrile, 2,3-Dibutorum 2-Methyltrifluoromethylpropionitrile, 3-Bromo2-chloro-2 _Trifluoromethylpropionitrile, 2-promo 3- 3-chloro-2-propriomethyl nitrile, 2,3-dichloropropionic acid, 2,3-dibromopropionic acid, 3- 2-bromo-3-propionic acid, 2-bromo-3-propionic acid, 2,3-dichloro-2-methylpropionic acid, 2,3-dibutyl 2-methylpropionic acid, 3-bromo-2-propionic acid — 2-Methylpropionic acid, 2-Bromo-3-cyclo- 2-Methylpropionic acid, 2,3-dichloro-2 —.Trifluoromethylpropionic acid, 2,3-Dibuto 2- (trifluoromethyl) Propionic acid, 3-bromo-2-chloro-2-trifluoromethylpropionic acid, 2-bromo-3-chloro-2-propionic acid, 2,3-dichloropropionic acid methyl ester, 2,3-dibromopropion Acid methyl ester, 3-bromo-2-methyl propionate methyl ester, 2-bromo-3-methyl propionate methyl ester, 2,3-dichloro mouth — 2-Methylpropionic acid methyl ester, 2,3-dibutene 2-methyl 2-propionic acid methyl ester, 3-promo-2-chloro-2-methylpropionic acid methyl ester, 2-promo 3-chloro-2-methyl methyl propionate Ester, 2,3-dichloro-2-methyl trifluoromethylpropionate, 2,3-dibutamate 2-Methyl trifluoromethylpropionate, 3-bromo_2-chloro-2- Methyl trifluoromethylpropionate, 2-promo 3- chloro-2-methyl trifluoromethylpropionate,

2,3-dichloropropionic acid ethyl ester, 2,3-dibromopropionic acid ethyl ester, 3-bromo-2-chloropropionic acid ethyl ester, 2-butane-mo 3--3-chloropropionic acid ethyl ester, 2,3-dichloro-2- Ethyl methyl propionate, 2,3-dibutoxy 2-ethyl methyl propionate, 3-bromo-2-chloro-2-methyl propionate, 2-bromo-3-ethyl-2-ethyl propionate, 2,3-Dichloro-methyl-2-ethyl trifluoromethylpropionate, 2,3-Dibutyl-methyl 2-ethyltrifluoromethylpropionate, 3-Promo 2-chloro-1-2-trifluoromethylpropion Ethyl ester, 2-bromo-3-chloro-2-trifluoromethylpropio Such as acid Echiruesuteru and the like. Examples of the compound represented by the general formula (2) include 2-amino-D-lipofurano [1 ', 2': 3, 4] -2-oxazoline, 2-amino-α-L-lipofurano [1 ', 2' : 3, 4] -1-oxazoline, 2-amino-D-arabinofurano [, 2 ,:

3, 4] — 2-oxazoline, 2-amino-1 / 3—L-arabinofurano [Γ, 2 ': 3, 4] -1-oxazoline, 2-amino-1) 3-D-galactofurano [1', 2 ': 3, 4] -1-oxazoline and the like.

The compounds represented by the general formula (6) include 2,2'-anhydro-11-S | L-arabinofuranosylcytosine, 2,2'-anhydro-1--arapinofuranosyl 5-methylcytosine, 2'-Anhydro-1-] 3-L-arabinofurano sylure 5-trifluoromethylcytosine, 2,2'-anhydro-3 ', 5, di-O-benzyl-1-j3-L-arabinofurano Silcytosine, 2, 2'—: Raw 3, 5, 5, O-Acetyl-1] 3—L—

2,2'-anhydro-3 ', 5, -di-t-butyldimethylsilyl-1-1j3 Also, as the compound of the general formula (8), 2'-〇-methyl-1--1] -L-arabino Furanosylcytosine, 2'-Hymethoxyethyl-1-) 3-L-arabinofuranosylcytosine, 2'-O-Methoxyethyl-1'8] -L-arapinofuranosylcytosine, 2'-〇ethyl-1-11 jS—L-arabinofuranosylcytosine, 2'-〇-propyl-1 11] 3-L-arabinofuranosylcytosine, 2'-O-methoxypropyl-11-β-L-arapino Furanosylcytosine, 2'-Ο-benzyl-1-1S-L-trifluoromethyl-1-1J3-L-arabi

CHIRU 1 / 3-L-arabinofuranosyl-5-methylcytosine, 2'-〇-Methoxyethyl-11-L-arabinofuranosyl-5-methylcytosine, 2'-〇1-methyl-1 1-i3— L-arabinofuranosyl-5-trifluoromethylcytosine, 2'-O-methoxyethyl-1-j8-L-arabinofuranosyl-5-trifluoromethylcytosine, 2'-O-methyl-3,, 5, —Di-O—Benziru 1 _ —L—arabinofuranosylcytosine, 2′— Ο—methoxchetyl-3 ′, 5 ′ —di—〇—benzyl-1—) 3— L—arabinofuranosylcytosine , 2'-〇-methyl-3 ', 5'-di-O-t-butyldimethylsilyl-1-iS_L-arabinofuranosylcytosine, 2'-'- methoxyethyl-3 ', 5'-〇-t —Butyldimethylsilyl-1- (1-) 3—L-arabinofuranosylcytosine, 2, -P-methyl-3 ', 5, Z-O-acetyl- 1- / 3-L-arabinofuranosylcytosine, 2'-〇-methoxyethyl-3', 5'-O-acetyl

L-arabinofuranosylcytosine, 2'-methyl-1--3 ', 5, Z-O-benzoyl-1-jS-L-arabinofuranosylcytosine, 2, -0-methoxyethyl-3', 5, ji-1 0-benzoyl-11 / 3-L-arabinofuranosylcytosine.

According to the present invention, the target compound, the 2,2′-anhydronucleic acid compound derivative, is obtained by converting the compounds represented by the general formulas (2) and (3) in a solvent under the conditions described below. It can be synthesized by reacting. Further, the 2′-alkoxycytidine derivative can be synthesized by reacting the compounds represented by the general formulas (6) and (7).

The reaction solvent used in the present invention may be any solvent that is inert to the reaction (except when the reaction substrate is also used as a solvent), and aromatic hydrocarbons such as benzene, toluene, and xylene, and getyl. Ethers, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, ethers such as ethylene glycol dimethyl ether, alcohols such as methanol, ethanol and propanol, dimethylformamide, dimethylsulfoxide, dimethylimidazolidinone, dimethyl Aprotic polar solvents such as acetamide; halogen-containing solvents such as methylene chloride, chloroform, and dichloroethane; nitro compounds such as nitromethane and nitroethane; and carboxylic esters such as ethyl acetate and ethyl propionate. , Pyridine, picoline, le Amines such as gin, phenols such as phenol, cresol and xylenol, carboxylic acids such as formic acid, acetic acid, and propionic acid, acetone, methyl ethyl ketone, acetonitrile, pyridine, and water alone or in combination of two or more. Can be used.

The reaction temperature varies depending on the solvent used, and is not particularly limited. The reaction temperature is preferably from 0 ° C to the boiling point of the solvent used or lower, and preferably from room temperature to 150 ° C.

The reaction pressure is not particularly limited, but is preferably normal pressure to 3 OMPa.

The reaction may be carried out by adding a commonly used acid or alkali in order to carry out the reaction efficiently, and in some cases, the reaction may be carried out by appropriately combining them. In addition, the time, amount, method, and the like for adding are not limited.

Examples of the alkali used include inorganic bases such as calcium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tert-butoxy potassium, sodium hydrogen carbonate, magnesium oxide, and the like, triethylamine, morpholine, N —Methylmorpholine, pyridine, organic bases such as N, N-dimethylaminopyridine and the like. Examples of the acid used include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, and oxalic acid. Organic acids such as an And solid acids such as bar list 15 and the like.

The reaction may be performed in the presence of a phase transfer catalyst. Examples of the phase transfer catalyst used include triethylbenzylammonium chloride (or bromide), tetramethylammonium chloride (or bromide), tetraethylammonium chloride (or bromide), and tetra-n_ Quaternary ammonium salts such as butylammonium chloride (or bromide), tetra-n-butylammonium hydrogen sulfide, etc., 18_crown-16-ether, 12-crown-16ether, dibenzo-24 —Crown-18-ether, dicyclohexano—24-crown-18-ether and other crown ethers.

The reaction time is not particularly limited, but is preferably 1 hour to 72 hours.

As a treatment method after the above reaction, for example, a conventional purification method such as column chromatography and recrystallization can be used.

Example

Hereinafter, examples of the compound of the present invention will be described, but the present invention is not limited thereto.

(Example 1) 2,2,1-Anhydro-1-j3-D-arabinofuranosylcytosine hydrobromide

2-Amino-i3-D-arabinofurano [, 2 ': 3,4] 1-2-year-old xazoline (0.50 g, 2.87 mmo 1) and 2,3-dibromopropionitrile (0.

Triethylamine (0.33 g, 3.26 mmol 1) was added to a methanol solution (2 OmL) of 74 g, 3.48 mmol 1), and the mixture was stirred at 70 for 5 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The obtained residue was washed with a mixed solvent of methanol and chloroform (form = 1: 2) to obtain 0.14 g (0.622 mmo 1, 22%) of white crystals as a target compound.

'H-NMR (400MHz, D 2 0) δ ppm: 3.59 (dd, 1H, J = 3.2Hz, J-12.9Hz), 3.62 (dd, 1H,

J = 3.2Hz, J = 12.9Hz), 4.45 (dd, 1H, J = 3.2Hz, J = 4.8Hz), 4.71 (s, 1H), 5.57 (d,

1H, J = 6.1Hz), 6.59 (d, 1H, J = 7.3Hz), 6.65 (d, 1H, J = 6.1Hz), 8.13 (d, 1H,

(J = 7.3Hz) (Example 2) 2,2, _anhydro_1-jS-L-arabinofuranosylcytosine hydrobromide

2-Amino] 3—L-arapinofurano-1 ': 3,4] —Methanol of 2-oxazoline (5.30 g, 88.3 mmo 1) and triethylamine (10.74 g, 106 mmo 1) The solution was heated to 50 ° C. Over 6 hours, a methanol solution (8 OmL) of 2,3-dibromopropionitrile (25 g, 11.75 mmol 1) was added dropwise. Further, the mixture was heated and stirred at 5 Ot for 3.5 hours. The reaction solution was concentrated under reduced pressure until a solid was precipitated, and 50 Om 1 of chloroform was added, and the precipitated crystals were collected by filtration. The crystals were dried under reduced pressure at 50 ° C to obtain 8.73 g (32%) of the desired product as yellow crystals.

Melting point: 217 ° C (decomposition)

_{^ -NMR (400MHz, D 2 0} ) δ ppm: 3.59 (dd, 1H, J = 3.2Hz, J = 12.9Hz), 3.62 (dd, 1H, J = 3.2Hz, J = 12.9Hz), 4.45 (dd , 1H, J-3.2Hz, J = 4.8Hz), 4.71 (s, 1H), 5.57 (d, 1H, J = 6.1Hz), 6.59 (d, 1H, J = 7.3Hz), 6.65 (d, 1H) , J = 6.1Hz), 8.13 (d, 1H, J = 7.3Hz)

I (KBr) v _Mx 1677, 1501, 1201, 1110, 1030, mcm

(Example 3) 2,1-Methyl-L-cytidine hydrochloride (4-amino-11- (2-O-methyl-i3-L-lipofuranosyl) -2 (1H) monopyrimidinone hydrochloride)

1.0 g of 2,2'-anhydro-1-3-L-arabinofuranosylcytosine hydrobromide was dissolved in 2 Om1 of N, N-dimethylformamide. At room temperature, 7. Om 1 of magnesium methoxide (10% methanol solution) was added. After reacting at 100 for 5 hours, it was left overnight at room temperature. After addition of 0.7 ml of acetic acid, the mixture was concentrated and dried to give a brown oil. Purification was performed by silica gel column chromatography using a mixed solvent of black form: methanol = 2: 1. The fraction containing the target substance was concentrated and dried to obtain 0.54 g of an amorphous target substance. This was dissolved in ethanol and acidified with 4N hydrochloric acid-dioxane. Then, when condensed, insolubles were precipitated. The concentration was stopped, isopropyl alcohol was added, and the mixture was stirred under ice cooling. The crystals were collected by filtration to obtain 0.31 g of the title compound. Melting point: 204 ° C (decomposition)

-NMR (DMS0-d6, 400MHz) ά ppm: 3.424 (s, 3H), 3.568-3.623 (m, IH),

3.717-3.755 (m, IH), 3.813-3.831 (m, IH), 3.879-3.908 (m, IH),

4.074-4.103 (m, lH), 5.776 (d, IH, J-3Hz), 6.192 (d, IH, J = 7Hz),

8.372 (d, IH, J-7Hz), 8.687 (s, lH), 9.835 (s, IH)

IR (KBr) v _max 3414, 1720, 1672, 1275, 1102cm " ¹ _o

(Example 4) 2,1-O- (2-methoxyethyl) 1 L-cytidine hydrochloride (4-amino-1- [2 _- (1-methoxyethyl) 1 / S-L-lipofuranosyl] -2 (1H) Monopyrimidinone hydrochloride)

20 Omg of aluminum foil strips were mixed with 4 Om 1 of 2-methoxyethanol and gradually heated. 1 The reaction started around 30 ° C, and the aluminum foil dissolved in about 10 minutes. After the solution was cooled to room temperature, 0.5 g of 2,2, _anhydro-l-) 3-L-arapinofuranosylcytosine hydrobromide was added. The mixture was reacted under reflux for 5 hours, cooled to room temperature, added with 0.5 ml of acetic acid, concentrated and dried to obtain a brown amorphous. Purification was performed by silica gel column chromatography using a mixed solvent of black form: methanol = 2: 1. The fraction containing the desired product was concentrated and dried to give 0.27 g of the desired product as an oil. This product was dissolved in a small amount of ethanol and acidified with 4N hydrochloric acid-dioxane. It was then concentrated to give a brown oil. Isopropyl alcohol was added to dissolve and concentrated until a little solvent remained. The mixture was stirred for about 1 hour, and the precipitated insolubles were collected by filtration and washed with a small amount of isopropyl alcohol to obtain 0.19 g of the title compound.

Melting point: 1 94 ° C (decomposition)

^[ HNMR (DMS0-d6, 400MHz) 5 pm: 3.249 (s, 3H), 3.467-3.492 (a, 2H),

3.584-3.621 (m, IH), 3.693-3.75 (m, 3H), 3.769-3.975 (m, 2H), 4.054-4.082 (m, IH)

5.757 (d, IH, J = 3Hz), 6.171 (d, IH, J = 8Hz), 8.360 (d, IH, J = 8Hz), 8.669 (s, lH),

9.791 (s, lH)

I (Br) v _max 3398, 1726, 1683, 1279, 1107cm— ¹ Industrial applicability

According to the present invention, a 2,2′-anehydronucleic acid compound derivative useful as an intermediate for medical and agricultural chemicals can be produced from inexpensive starting materials. Also, 2′-alkoxy-L-L-directly derived from the 2,2′-anhydro-L-cytidine derivative produced according to the present invention.

'Can be synthesized.

Claims

The scope of the claims

General formula (1)

(In the formula, R 1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 2 carbon atoms or a protected hydroxyalkyl group having 1 to 2 carbon atoms, and R 2 represents a hydrogen atom. , A hydroxy group, a protected hydroxy group, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, wherein R 3 and R 4 are each independently a hydrogen atom or a carbon atom 4 represents an alkyl group or a perfluoroalkyl group having 1 to 4 carbon atoms, and Q represents an oxygen atom or an imino group.) A method for producing a 2,2′_anhydride-containing nucleic acid compound derivative represented by the following formula: And the general formula (2)

(2)

(Wherein R 1 and R 2 have the same meanings as described above), and an aminooxazoline derivative represented by the following general formula (3):

(In the formula, X and Y each independently represent a halogen atom, Ζ represents a cyano group, a carboxyl group or an alkyloxycarbonyl group having 1 to 4 carbon atoms, and R3 and R4 have the same meaning as described above. 2,2'-anhydronucleic acid compound derivative, which comprises a step of reacting the compound represented by the formula (1) to obtain a 2,2'-anhydride nucleic acid compound derivative represented by the general formula (1). And a method for producing the salt thereof.

'2. In the general formula (1), R 1 is a hydroxyalkyl group having 1 to 2 carbon atoms, a protected hydroxyalkyl group having 1 to 2 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. The method according to claim 1, wherein R 2 is a hydrogen atom, a hydroxy group, a protected hydroxy group or an alkoxy group having 1 to 4 carbon atoms, and R 3 is a hydrogen atom.

3. In the general formula (1), R 1 is a hydroxymethyl group, R2 is a hydroxy group, R 4 is a hydrogen atom, a methyl group or a trifluoromethyl group; 3. The production method according to claim 2, wherein X, Y are each independently a chlorine atom or a bromine atom, and Z is a cyano group, a carboxyl group, a methoxycarbonyl group or an ethoxycarbonyl group.

4. The production method according to claim 3, wherein, in the general formula (1), R4 is a methyl group, Q is an oxygen atom, and in the general formula (3), Z is a methoxycarbonyl group or an ethoxycarbonyl group.

5. The production method according to claim 3, wherein, in the general formula (1), R 4 is a hydrogen atom, Q is an imino group, and in the general formula (3), Z is a cyano group.

6. General formula (6)

(In the formula, R 4 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a perfluoroalkyl group having 1 to 4 carbon atoms, and R 5 and R 6 each independently represent a hydrogen atom or a protecting group for a hydroxyl group. And a method for producing 2, 2′-anhydro-L-cytidine and a salt thereof represented by the formula:

General formula (4)

(Wherein, R5 and R6 have the same meanings as described above) and a general formula (5)

7 \ (5)

CN

R4

(Wherein, R 4 and X have the same meanings as described above.) A compound represented by the following formula is reacted to obtain a 2,2′-anhydro-L-cytidine derivative represented by the general formula (6). A process for producing a 2,2′-anhydro-L-cytidine derivative or a salt thereof, characterized by having:

7. General formula (8)

(In the formula, R 4 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a perfluoroalkyl group having 1 to 4 carbon atoms, and R 5 and R 6 each independently represent a hydrogen atom or a hydroxyl group. Represents a protecting group, and R7 is an alkyl group having 1 to 4 carbon atoms, an aralkyl group having 1 to 10 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, an alkylaminoalkyl group having 1 to 10 carbon atoms or carbon atom. A method for producing an L-cytidine derivative represented by the following formula (1):

General formula (6)

(Wherein, R4, R5 and R6 have the same meanings as described above), and a 2,2-anhydro-L-cytidine derivative represented by the following general formula (7):

(R 7_〇) _n -M (7) A metal alkoxide represented by the formula (R 7 has the same meaning as described above, n represents an integer of 1 to 3, and M represents a metal). , L-Si expressed by the above general formula (8) A method for producing an L-cytidine derivative and a salt thereof, comprising a step of obtaining a thiidine derivative.

8. The method according to claim 7, wherein in the general formula (8), R4, R5 and R6 are hydrogen atoms.

9. General formula (6)

(In the formula, R 4 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a perfluoroalkyl group having 1 to 4 carbon atoms, and R 5 and R 6 each independently represent a hydrogen atom or a protecting group for a hydroxyl group. 2, 2'-anhydro-L-cytidine derivative and a salt thereof.

10. General formula (8)

(In the formula, R 4 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a perfluoroalkyl group having 1 to 4 carbon atoms, and R 5 and R 6 each independently represent a hydrogen atom or a protecting group for a hydroxyl group. R7 represents an alkyl group having 1 to 4 carbon atoms, an aralkyl group having 1 to 10 carbon atoms, a perfluoroalkyl group having 1 to 4 carbon atoms, an alkylaminoalkyl group having 1 to 10 carbon atoms or 1 to 10 carbon atoms. An L-cytidine derivative represented by the formula: or a salt thereof.

11. The method according to claim 9, wherein R4, R5 and R6 in the general formula (6) are hydrogen atoms. 2, 2'-anhydro-L-cytidine derivatives and acceptable salts thereof.

12. The 2′-alkoxy-L-cytidine derivative according to claim 10, wherein R 5 and R 6 in the general formula (8) are a hydrogen atom, and an acceptable salt thereof.