JPH07196679A - Sugar derivative having o-n bond and its production - Google Patents

Abstract

PURPOSE:To obtain a new compound capable of producing hydantocidin in high yield without forming stereoisomers. CONSTITUTION:This sugar derivative is a compound of formula I [R<1> and R<2> each is H or together form a (substituted) alkylidene; R<3> and R<4> each is H or together form a (substituted) alkylidene; R<5> and R<6> each is H, COR<10> (R<10> is a lower alkyl, a lower alkoxy, an aryl, etc.) or SO2R<11> (R<11> is a lower alkyl, an aryl, etc.)], e.g. 1, 2:3,4-di-O-isopropyl idene-6-O-methoxycarbonylamino- D-psicofuranose. The compound of formula I can be produced by reacting a compound of formula II (X is an eliminable group) with a compound of formula H0NR<5>R<6>.

Description

Detailed Description of the Invention

[0001]

[Object of the Invention]

[0002]

The present invention relates to the following formula having excellent herbicidal activity.

[0003]

[Chemical 50]

Hydantosidin ([2R, 3
S, 4R, 5S] -2-Hydroxymethyl-3,4-dihydroxy-1-oxa-6,8-diazaspiro [4,4
4] Nonane-7,9-dione) novel production intermediate and production method.

[0005]

2. Description of the Related Art Hydantocidin, which is obtained as a metabolite of actinomycetes, is known as a compound having a strong herbicidal and growth inhibitory activity not only on annual cotyledons and dicotyledonous weeds but also on perennial weeds. .

JP-A-62-12789 M. Nakajima et al., J. Antibiot., 44 , 293 (199)
1) H. Haruyama et al., J. Chem. Soc. Perkin Tran
s.I., 1637 (1991) Hydantocidin has outstanding safety to animals, fish and microorganisms, and is rapidly decomposed in soil, so it has environmentally desirable properties. It is a compound that is useful as an excellent herbicide.

In addition to the above, the following methods are known as chemical methods for producing hydantosidine.

JP-A-2-85287 S. Mio et al., Tetrahedron 47 , 2111 (1991) S. Mio et al., Tetrahedron 47 , 2133 (1991) S. Mirza, DE 4,129,728A1 (1991) GWJ Fleet et al., Tetrahedron Lett., 34 ,
3327 (1993) S. Terashima et al., Tetrahedron Lett., 34 , 62
89 (1993) (A) Philippe Chemla, Tetr.
ahedron Lett. , 34 , 7391
(1993)

[0009]

In the industrial production of this hydantocidin, it is difficult to carry out fermentation from actinomycetes because the production amount is too small (the above-mentioned document).

In addition, industrially carrying out the methods (a) and (A) involve various difficult problems.

For example, in the methods (1) and (2), expensive tartaric acid or osmium tetroxide is used as a raw material or a reagent. Then, expensive reagents such as trimethylsilyltrifluoromethanesulfonic acid and trimethylsilylazide are used. , An expensive reagent such as trifluoromethanesulfonic acid anhydride or osmium tetroxide is used, and the yield of the target product is low. Then, many expensive reagents such as tetrapropyl pearl tenate and trifluoromethanesulfonic acid anhydride will be used. Further, the methods (1) and (2) are not an efficient method for producing hydantocidin itself, because the stereoisomers of the spiro moiety of hydantocidin, which has a herbicidal activity largely inferior to that of hydantocidin, are preferentially obtained.

Many reactions in the method (A) are reactions that can be used only at the laboratory level because reagents are expensive and highly toxic, and are industrially disadvantageous. It is impossible to carry out actual production (industrial production) by the method.

The inventors of the present invention have conducted extensive studies for a long time on the industrial production method of hydantocidin, and as a result, by the production method via a novel intermediate, hydantocidin is extremely preferentially compared with stereoisomers. , With high yield,
The present invention has been completed by finding that it can be manufactured inexpensively, easily and safely.

[0014]

[Constitution of the invention]

[0015]

The present invention has the general formula (I)

[0016]

[Chemical 51]

[In the formula, R ¹ and R ² represent a hydrogen atom or R ¹ and R ² together represent an optionally substituted alkylidene group, and R ³ and R ⁴ represent a hydrogen atom. Or R ³ and R ⁴ together represent an optionally substituted alkylidene group, R ⁵ and R ⁶ are the same or different, and are a hydrogen atom, a formula —COR ¹⁰ (R ¹⁰ is a lower alkyl group,
A lower alkoxy group, an aryl group, an aryloxy group, an aralkyloxy group, an amino group which may be substituted with 1 to 2 lower alkyl groups, or a lower alkenyloxy group is shown. Group represented by the formula (provided that R ⁵ and R ⁶ are not both hydrogen atoms) or the formula —SO ₂ R ¹¹ (R ¹¹ is a lower alkyl group, an aryl group or 1 to 2 lower alkyl groups) And optionally R ¹ and R ² together represent an alkylidene group, and R ³ and R ⁴ together. Represents an alkylidene group, R ⁵ represents a hydrogen atom, and R ⁶ represents a formula —C
OR ¹⁰ (R ¹⁰ is a lower alkoxy group, an aryloxy group,
An aralkyloxy group or a lower alkenyloxy group is shown. ) Represents a group represented by, more preferably, in the formula, R ¹
And R ² together represent an isopropylidene group, R ³
And R ⁴ together represent an isopropylidene group, R ⁵
Represents a hydrogen atom, and R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group). ] The compound represented by these, and its salt, General formula (II)

[0018]

[Chemical 52]

[In the formula, R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted; R ⁶ represents a hydrogen atom;
¹⁰ (R ¹⁰ is a lower alkyl group, a lower alkoxy group, aryl group, aryloxy group, aralkyloxy group, 1 shows two lower alkyl optionally substituted amino group or a lower alkenyloxy group.) In Represents a group represented by the formula or a group represented by formula —SO ₂ R ¹¹ (R ¹¹ represents a lower alkyl group, an aryl group or an amino group which may be substituted with 1 to 2 lower alkyls.), R ⁷ is the formula —CH
₂ OH group, formyl group, carboxyl group, lower alkoxycarbonyl group or formula CONHR ¹⁴ {R ¹⁴ is a hydrogen atom, a lower alkyl group, a phenyl group or an aralkyl group (the phenyl group and the aralkyl group are halogen atoms,
A lower alkoxy group or a nitro group may be substituted). } Represents a group represented by, preferably in the formula,
R ¹ and R ² together represent an alkylidene group, R ⁶
Represents a hydrogen atom or a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group), and R ⁷
Represents a group represented by the formula —CH ₂ OH, a formyl group, a carboxyl group or a group represented by the formula CONH ₂ , and more preferably, in the formula, R ¹ and R ² are taken together to form an isopropylidene group. R ⁶ represents a hydrogen atom or a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group), and R ⁷
Represents a group represented by the formula —CH ₂ OH, a formyl group, a carboxyl group or a group represented by the formula CONH ₂ , and even more preferably, in the formula, R ¹ and R ² together form isopropylidene. Represents a group, R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group), and R ⁷ represents a group represented by the formula —C.
A group represented by H ₂ OH, a formyl group, a carboxyl group or a group represented by the formula CONH ₂ is shown. ] The compound and its salt represented by these, and general formula (III)

[0020]

[Chemical 53]

[0021] [wherein, R ¹ and R ² represents an optionally alkylidene group optionally or R ¹ and R ² represents a hydrogen atom substituted together, preferably, wherein the R ¹ R ² together represents an isopropylidene group. ] The compound and its salt represented by these, and general formula (IV)

[0022]

[Chemical 54]

[0023] [wherein, R ¹ and R ² represents an optionally alkylidene group which may be substituted or R ¹ and R ² represents a hydrogen atom together, preferably, wherein, R ¹ and R ² represents a hydrogen atom or R ¹ and R ² together represent an isopropylidene group. ] The compound represented by the formula (V) is characterized by hydrogenation using a Raney catalyst, preferably in the presence of an acid, more preferably in the presence of acetic acid.

[0024]

[Chemical 55]

[In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these, General formula (VI)

[0026]

[Chemical 56]

[In the formula, X represents a leaving group, and R ¹ and R
² represents a hydrogen atom or R ¹ and R ² together represent an optionally substituted alkylidene group, and R ³ and R 2
⁴ represents a hydrogen atom, or R ³ and R ⁴ together represent an alkylidene group which may be substituted, and preferably,
In the formula, X represents a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a chlorine atom, a bromine atom or an iodine atom, R ¹ and R ² together represent an alkylidene group, and R ³ and R ⁴ are Together they represent an alkylidene group,
More preferably, in the formula, X represents a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a chlorine atom, a bromine atom or an iodine atom, and R ¹ and R ² together represent an isopropylidene group, R ³ and R ⁴ together represent an isopropylidene group. To a compound represented by the formula: HONR ⁵ R ⁶ [wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a formula —COR ¹⁰ (R ¹⁰ is a lower alkyl group, a lower alkoxy group, an aryl group, A group represented by an aryloxy group, an aralkyloxy group, an amino group which may be substituted with 1 to 2 lower alkyls or a lower alkenyloxy group, or a formula —SO ₂ R ¹¹ (R ¹¹
Represents a lower alkyl group, an aryl group or an amino group which may be substituted with 1 to 2 lower alkyl groups. ), In which R ⁵ represents a hydrogen atom, and R ⁶ represents a formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group. A group represented by the formula), more preferably in the formula, R ⁵ represents a hydrogen atom, and R ⁶ represents a formula —COR ¹⁰
(R ¹⁰ represents a lower alkoxy group). ] Reacting a compound represented by
General formula (I)

[0028]

[Chemical 57]

[In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above. ] The manufacturing method of the compound represented by these, General formula (I)

[0030]

[Chemical 58]

[In the formula, R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an optionally substituted alkylidene group, and R ³ and R ⁴ represent a hydrogen atom. Or R ³ and R ⁴ together represent an optionally substituted alkylidene group, R ⁵ and R ⁶ are the same or different, and are a hydrogen atom, a formula —COR ¹⁰ (R ¹⁰ is a lower alkyl group,
A lower alkoxy group, an aryl group, an aryloxy group, an aralkyloxy group, an amino group which may be substituted with 1 to 2 lower alkyl groups, or a lower alkenyloxy group is shown. ) Or a group represented by the formula —SO ₂ R ¹¹ (R ¹¹ represents a lower alkyl group, an aryl group or an amino group optionally substituted by 1 to 2 lower alkyl). In the formula, R ¹ and R ² together represent an alkylidene group, R ³ and R ⁴ together represent an alkylidene group, R ⁵ represents a hydrogen atom, and R ⁶ represents Expression −
COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group), and more preferably R in the formula.
¹ and R ² together represent an isopropylidene group, R
³ and R ⁴ together represent an isopropylidene group, R
⁵ represents a hydrogen atom, and R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group). ] In the presence of an acid catalyst, preferably in the presence of sulfonic acids or mineral acids as a catalyst, more preferably in the presence of sulfuric acid or methanesulfonic acid as a catalyst, General formula (IIa)

[0032]

[Chemical 59]

[In the formula, R ¹ , R ² and R ⁶ have the same meanings as described above. ] The manufacturing method of the compound represented by these, General formula (IIc)

[0034]

[Chemical 60]

[Wherein R¹ And R² Indicates a hydrogen atom
Or R¹ And R² May be replaced together.
Rylidene group, R⁶ Is the formula -COR^Ten(R^TenIs low
Alkoxy group, aryloxy group, aralkyloxy
Group optionally substituted with 1 to 2 lower alkyl
An amino group or a lower alkenyloxy group is shown. )
A group represented by R¹⁴Represents a hydrogen atom, and preferably has the formula
Medium, R¹ And R² Together represent an alkylidene group,
R⁶ Is the formula -COR^Ten(R^TenIs a lower alkoxy group, aryl
Ruoxy group, aralkyloxy group or lower alkenyl group
A xy group is shown. ) Is a group represented by¹⁴Is a hydrogen atom
And more preferably, in the formula, R¹ And R² Are together
Represents an isopropylidene group, R⁶ Is the formula -COR^Ten(R
^TenRepresents a lower alkoxy group. ) Represents a group represented by
R ¹⁴Represents a hydrogen atom. ] The compound represented by
In the presence of a base, preferably an alkali metal or
Rh earth metal hydroxide or lower alcohol alkali gold
Group salts, more preferably sodium hydroxide or potassium hydroxide
Formula (IV) characterized by being treated with um.

[0036]

[Chemical formula 61]

[In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by General formula (IIb)

[0038]

[Chemical formula 62]

[In the formula, R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an alkylidene group which may be substituted, and R ⁶ represents a formula —COR ¹⁰ (R ¹⁰ Represents a lower alkoxy group, an aryloxy group, an aralkyloxy group, an amino group which may be substituted with 1 to 2 lower alkyl groups, or a lower alkenyloxy group.), Preferably, In the formula, R ¹ and R ² together represent an alkylidene group, and R ⁶ is of the formula —COR ¹⁰ (R ¹⁰
Represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group. ), More preferably R ¹ and R ² together represent an isopropylidene group, and R ⁶ is of the formula —COR ¹⁰
(R ¹⁰ represents a lower alkoxy group). ] The compound represented by the formula is treated with ammonia in the presence of a solvent, represented by the general formula (III):

[0040]

[Chemical formula 63]

[In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by, and general formula (II
I)

[0042]

[Chemical 64]

[0043] [wherein, R ¹ and R ² represents an optionally alkylidene group optionally or R ¹ and R ² represents a hydrogen atom substituted together, preferably, wherein the R ¹ R ² together represents an alkylidene group, and more preferably, R ¹ and R ² together represent an isopropylidene group. ] The compound represented by the formula is preferably oxidized by using hypochlorites, chromic acid or chromate, and more preferably by using chromate. IV)

[0044]

[Chemical 65]

[In the formula, R ¹ and R ² have the same meanings as described above. ] It is a manufacturing method of the compound represented by these.

In R ¹ , R ² , R ³ and R ⁴ , "optionally substituted alkylidene group" means methylidene, ethylidene, n-propylidene, isopropylidene,
n-butylidene, isobutylidene, s-butylidene, t-butylidene, n-pentylidene, isopentylidene, 2-methylbutylidene, neopentylidene, 1-ethylpropylidene, n-hexylidene, 1-t-butylethylidene, 1 -C1 to C6 linear or branched alkylidene groups such as phenylethylidene and 2,2,2-trichloroethylidene, cyclic alkylidene groups such as cyclopentylidene, cyclohexylidene and cycloheptylidene, Benzylidene, 4-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,
4-dimethoxybenzylidene, 2-nitrobenzylidene, α
An aromatic-substituted alkylidene group such as methoxybenzylidene and an alkoxy-substituted alkylidene group such as methoxymethylene, ethoxymethylene, 1-methoxyethylidene, and 1-ethoxyethylidene, preferably a straight chain having 1 to 4 carbon atoms Or a branched chain alkylidene group, a cyclic alkylidene group, an aromatic substituted alkylidene group, more preferably methylidene, ethylidene, isopropylidene, n-butylidene, cyclopentylidene, cyclohexylidene, benzylidene, most preferably. It is an isopropylidene group.

In R ¹⁰ , R ¹¹ and R ¹⁴ , the "lower alkyl group" is, for example, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methyl Pentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2 -A linear or branched alkyl group having 1 to 6 carbon atoms such as ethylbutyl, preferably a methyl group or an ethyl group, and most preferably a methyl group.

In R ¹⁰ and R ¹⁴ , the “lower alkoxy group” is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, t-butoxy, n-pentoxy, isopentoxy. ,
2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy , 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, etc., wherein the above “lower alkyl group” is bonded to an oxygen atom, that is, a straight chain having 1 to 6 carbon atoms or It is a branched chain alkoxy group, preferably a linear or branched chain alkoxy group having 1 to 4 carbon atoms, more preferably a methoxy group or an ethoxy group, and most preferably an ethoxy group. .

In R ¹⁰ and R ¹¹ , the “aryl group” is, for example, phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl, and the like having 5 to 14 carbon atoms.
Aromatic hydrocarbon groups, preferably phenyl groups.

Further, the aryl group has 1 on the aryl ring.
May have 3 to 3 substituents, and examples of such a substituent include the above-mentioned "lower alkyl group", the above "lower alkoxy group", and the "halogen atom" described below, preferably a lower alkyl group. A group, and most preferably an aryl group having such a substituent is a p-toluyl group.

In R ¹⁰ , the "aryloxy group" means an oxygen atom in the above "aryl group" such as phenyloxy, indenyloxy, naphthyloxy, phenanthrenyloxy and anthracenyloxy. A bonded group, that is, an aromatic hydrocarbon oxy group having 5 to 14 carbon atoms, preferably a phenyloxy group.

The aryloxy group may also have the same substituents as the above "aryl group".

In R ¹⁴ , the “aralkyl group” is a group in which the above “lower alkyl group” is substituted with the above “aryl group” such as benzyl group, phenethyl group, α, α-dimethylbenzyl group. And preferably a benzyl group.

The "aralkyloxy group" for R ¹⁰ includes, for example, benzyloxy group, phenethyloxy group,
A group in which an oxygen atom is bonded to the above-mentioned "aralkyl group" such as α, α-dimethylbenzyloxy, and preferably a benzyloxy group.

In R ¹⁰ and R ¹¹ , the “amino group optionally substituted by 1 to 2 lower alkyl” is an unsubstituted amino group or 1 to 2 of the above “lower alkyl group” is substituted. And an unsubstituted amino group or a dimethylamino group.

The "lower alkenyloxy group" for R ¹⁰ is, for example, vinyloxy, allyloxy, 2-butenyloxy, 3-methyl-2-butenyloxy, 2-methyl.
-2-A straight-chain or branched alkenyloxy group having 2 to 6 carbon atoms such as butenyloxy, and preferably an allyloxy group.

In R ⁷ , the "lower alkoxycarbonyl group" is a group in which the above "lower alkoxy group" is bonded to a carbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group and a t-butoxycarbonyl group. And preferably a methoxycarbonyl group.

In the definition of R ¹⁴ , the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom.

In R ¹⁴ , "a phenyl group which may be substituted with a halogen atom, a lower alkoxy group or a nitro group" means an unsubstituted phenyl group or, for example, 4-methoxyphenyl, 2,4-dimethoxyphenyl, The "halogen atom" and the "lower alkoxy group" such as 3,4-dimethoxyphenyl, 4-chlorophenyl and 4-nitrophenyl
Or a phenyl group in which 1 to 3 nitro groups are substituted,
It is preferably an unsubstituted phenyl group.

In R ¹⁴ , "the aralkyl group which may be substituted with a halogen atom, a lower alkoxy group or a nitro group" means the unsubstituted "aralkyl group" or, for example, 4-methoxybenzyl, 2,4 -Dimethoxybenzyl, 3,
An aralkyl group in which 1 to 3 of the above "halogen atom", "lower alkoxy group" or nitro group is substituted, such as 4-dimethoxybenzyl, 4-chlorobenzyl, 4-nitrobenzyl, and preferably p- It is a methoxybenzyl group.

Compounds (I), (II) and (I of the present invention
II) can be salted. Such salts include alkali metal salts such as sodium salts and potassium salts, metal salts such as alkaline earth metal salts such as calcium salts and magnesium salts, and guanidine salts, triethylamine salts and dicyclohexylamine salts. Organic bases, preferably alkali metal salts, most preferably sodium salts.

Compounds (I), (II) and (I of the present invention
II) has stereoisomers each having an asymmetric carbon atom in its molecule and having an S-coordination and an R-coordination, and each of them or a mixture thereof can be included in the present invention. .

[0063] In the above, R ¹ and R ² is preferably a good alkylidene group optionally substituted R ¹ and R ² together, more preferably taken together R ¹ and R ² Is an alkylidene group, most preferably R ¹ and R ² together are an isopropylidene group.

[0064] R ³ and R ⁴ is preferably a good alkylidene group optionally substituted R ³ and R ⁴ together, further preferably alkylidene group is R ³ and R ⁴ together And most preferably R ³ and R ⁴ together are an isopropylidene group.

R ⁵ is preferably a hydrogen atom.

R ⁶ is preferably a hydrogen atom or the formula --CO
R ¹⁰ is a group represented by R ¹⁰ , and more preferably a group of the formula —COR ¹⁰
Is a group represented by.

R ¹⁰ is preferably a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group, more preferably a lower alkoxy group, and even more preferably a methoxy group or ethoxy group. It is a base.

R ⁷ is preferably a group represented by the formula —CH ₂ OH, a formyl group, a carboxyl group, or a formula —CONH ₂
Is a group represented by.

The method for producing hydantocidin will be described below.

[0070]

[Chemical formula 66]

[In the above formula, X represents a leaving group, and R ¹ ,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹⁴ have the same meanings as described above. ] In the above, the leaving group in the definition of X is
Usually, it is not particularly limited as long as it is a group capable of leaving as a nucleophilic residue, but preferably a halogen atom such as a chlorine atom, a bromine atom or an iodine atom; a lower alkane such as methanesulfonyloxy or ethanesulfonyloxy. Sulfonyloxy group; halogeno lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy, pentafluoroethanesulfonyloxy group; benzenesulfonyloxy group,
It is an arylsulfonyloxy group such as p-toluenesulfonyloxy, more preferably a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a chlorine atom, a bromine atom or an iodine atom.

Next, each step will be described in more detail.

In the following steps and reactions, the protective group for the hydroxyl group (including R ¹ , R ² , R ³ and R ⁴ ) and the protective group for the nitrogen atom (including R ⁵ , R ⁶ and R ¹⁴ ) are As long as it does not interfere with the subsequent reaction, protection and deprotection can be appropriately performed. That is, it is of course possible to convert the protecting group, and it can be subjected to each reaction in a protected state or an unprotected state.

Protecting groups for such hydroxyl groups and nitrogen atoms and methods for protecting and deprotecting are described in TW Green, "Protectiv.
e groups in Organic Synthesis "A Wiley-Interscienc
Choose according to the description in e Publication, New York, 1981,
It can be carried out.

(Step A) This step is a step of producing a compound represented by the general formula (VI) from fructose as a starting material. This step will be described in more detail below.

[0076]

[Chemical formula 67]

[In the above formula, R ²⁰ and R ²¹ represent an optionally substituted alkylidene group, and X, R ¹ , R ² and R
³ and R ⁴ are as defined above. ] Step A-1,
A-2, A-3 and A-4 are known methods, for example, J.
G. Moffatt et. Al., J. Org. Chem., 41 , 1836 (1976)
It can be performed according to the method described in.

Step A-5 is a step for producing a compound represented by the general formula (VI) from the compound represented by the general formula (X) obtained in steps A-1 to 4.

This step is carried out according to the method described in JG Moffatt et.
It can be produced according to the method described in J. Org. Chem., 41 , 1836 (1976), or according to the conventional method for producing a leaving group from a hydroxyl group known so far.

(Step B) This step is a step of producing a compound represented by the general formula (I) having an N—O bond from a compound represented by the general formula (VI).

Using a base in the presence of a solvent, a compound of the general formula HO
X is substituted by reacting with a compound represented by NR ⁵ R ⁶ (R ⁵ and R ⁶ are as defined above),
Compound (I) is produced.

The compound represented by the general formula HONR ⁵ R ⁶ is preferably a compound in which R ⁵ is a hydrogen atom and R ⁶ is a lower alkoxycarbonyl group.

Bases used include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide, potassium t-butoxide. Alkali metal salts of lower alcohols, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal hydrates such as sodium and potassium, sodium (bistrimethylsilyl) amide, alkali metal amides such as lithium diisopropylamide, Alkali metal carbonates such as potassium carbonate and sodium carbonate, preferably alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, sodium methoxide and sodium. Ethoxide, mosquito Lower alkali metal salts, sodium hydride alcohols such as um -t- butoxide,
It is an alkali metal hydride such as potassium hydride and an alkali metal such as sodium and potassium. The base is used in 1 to 10 equivalents based on the raw material.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably a lower solvent such as methanol, ethanol, isopropanol or t-butyl alcohol. Alcohols, aromatic hydrocarbons such as benzene, toluene and xylene, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ethers and ethers such as dimethoxyethane. , Ethyl acetate, esters such as butyl acetate, dimethyl sulfoxide, polar solvents such as dimethylformamide, methylene chloride, halogenated hydrocarbons such as dichloroethane, more preferably, methanol, ethanol, isopropanol,
Lower alcohols such as t-butyl alcohol, tetrahydrofuran, 1,4-dioxane, ethers, ethers such as dimethoxyethane, and polar solvents such as dimethyl sulfoxide and dimethylformamide.

The reaction temperature is usually -50 ° C to 200 ° C, preferably 0 ° C to 150 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually 1 to 120 hours.

In the general formula (I), R ⁵ is a hydrogen atom and R ⁶ is of the formula —COR ¹⁰ (R ¹⁰ is as defined above) or the formula —SO ₂ R ¹¹ (R ¹¹ is the above. Is a compound of the formula (I) wherein R ⁵ and R ⁶ are both hydrogen atoms (Philippe Chemla, T
etrahedron Lett., 34 , 7391 (1993)) and an acylating agent or sulfonylating agent in a suitable solvent in the presence of a base.

The acylating agent used is acetyl chloride,
Acid halides such as propionyl chloride and benzoyl chloride, acetic anhydride, propionic anhydride, acid anhydrides such as benzoic anhydride, methyl chlorocarbonate, ethyl chlorocarbonate,
Carbonic acid esters such as phenyl chlorocarbonate, benzyl chlorocarbonate, isobutyl chlorocarbonate, dimethyl carbonate, carbamic acid halides such as dimethylcarbamic acid chloride and diethylcarbamic acid chloride, and isocyanates such as methylisocyanate and trimethylsilylisocyanate. .

The sulfonylating agents used include methanesulfonyl chloride, sulfonyl chlorides such as paratoluenesulfonyl chloride, anhydrous methanesulfonic acid, anhydrous sulfonic acids such as benzenesulfonyl anhydride, dimethylaminosulfonyl chloride and diethylaminosulfonyl chloride. Such aminosulfonyl chlorides.

Bases used include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide, potassium t-butoxide. Alkali metal salts of lower alcohols, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal hydrates such as sodium and potassium, sodium (bistrimethylsilyl) amide, alkali metal amides such as lithium diisopropylamide, Alkali metal carbonates such as potassium carbonate and sodium carbonate, tri-lower alkylamines such as triethylamine and diisopropylamine, pyridine, heteroaromatic tertiary amines such as N, N-dimethylaminopyridine, D
Alicyclic amines such as BU, DBN and DABCO, and aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline, preferably triethylamine and diisopropylamine. Heteroaromatic tertiary amines such as lower alkyl amines, pyridine and N, N-dimethylaminopyridine.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aromatic hydrocarbons such as benzene, toluene and xylene, Acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, tetrahydrofuran, ethers such as 1,4-dioxane, ether and dimethoxyethane, esters such as ethyl acetate and butyl acetate, dimethyl sulfoxide, dimethylformamide. And a halogenated hydrocarbon such as methylene chloride or dichloroethane, more preferably a halogenated hydrocarbon such as methylene chloride or dichloroethane, or an ester such as ethyl acetate or butyl acetate. is there.

The reaction temperature is usually -60 ° C to 160 ° C, preferably 0 ° C to 100 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually 0.6 to 24 hours.

(Step C) In this step, the compound represented by the general formula (I) produced in step B is used as a starting material and reacted in a solvent in the presence of an acid catalyst to give a bicyclic compound (IIa).
Is a process of manufacturing.

In the compound (I) as a raw material, R ⁵ is preferably a hydrogen atom.

The acid catalyst to be used includes sulfonic acids such as methanesulfonic acid, paratoluenesulfonic acid and camphorsulfonic acid, carboxylic acids such as formic acid, acetic acid, propionic acid, benzoic acid and trifluoroacetic acid, hydrochloric acid,
Sulfuric acid, mineral acids such as perchloric acid, aluminum chloride, Lewis acids such as zinc chloride, phosphoric acids and the like, preferably methanesulfonic acid, paratoluenesulfonic acid, sulfonic acids such as camphorsulfonic acid, Hydrochloric acid, sulfuric acid,
Mineral acids such as perchloric acid, more preferably sulfuric acid and methanesulfonic acid. The acid catalyst is used in an amount of 0.001 to 100 equivalents, preferably 0.
It is 1 to 50 equivalents.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, it is an aliphatic hydrocarbon such as hexane or pentane, benzene, Toluene, aromatic hydrocarbons such as xylene, acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ether, ethers such as dimethoxyethane, ethyl acetate, acetic acid Esters such as butyl, polar solvents such as dimethyl sulfoxide, dimethylformamide, methylene chloride,
Halogenated hydrocarbons such as dichloroethane,
More preferred are halogenated hydrocarbons such as methylene chloride and dichloroethane, esters such as ethyl acetate and butyl acetate, and nitriles such as acetonitrile.

The reaction temperature is generally -50 ° C to 150 ° C, preferably 0 ° C to 50 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually 0.5 to 24 hours.

In this reaction, when R ³ and R ⁴ together in the starting compound (I) represent an optionally substituted alkylidene group, deprotection and cyclization reaction can be carried out simultaneously. , Convenient.

Further, the compound (IIa) can also be produced via a tricyclic compound having an oxazolidinone ring.

[0102]

[Chemical 68]

Step C-2 can be carried out in accordance with Step C using the above acid catalyst.

Step C-3 is a step of opening the oxazolidinone ring with an alkali in the presence of a solvent.

The alkali used may be an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide or calcium hydroxide, sodium methoxide, sodium ethoxide or potassium t-butoxide. Alkali metal salts of lower alcohols such as sodium hydroxide and potassium hydroxide are preferred.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but water and a mixed solvent thereof can be used.
The solvent of the mixing partner is preferably methanol,
Ethanol, alcohols such as propanol, acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, tetrahydrofuran, 1,
4-dioxane, ethers, ethers such as dimethoxyethane, esters such as ethyl acetate and butyl acetate, polar solvents such as dimethylsulfoxide and dimethylformamide, more preferably methanol, ethanol, propanol and the like. Alcohols, tetrahydrofuran, 1,4-dioxane, ethers, ethers such as dimethoxyethane, and more preferably methanol and tetrahydrofuran.

The reaction temperature is usually -50 ° C to 150 ° C, preferably 0 ° C to 100 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually 0.5 to 24 hours.

In the general formula (IIa), when R ⁶ is a hydrogen atom, it is further used as a starting material to react with an acylating agent or sulfonylating agent in a suitable solvent in the presence or absence of a base, R ⁶ is -COR ¹⁰ or -SO ₂ R
A compound which is ¹¹ (R ¹⁰ and R ¹¹ have the same meanings as described above.)
Can be manufactured.

The acylating agent used is preferably an acid halide such as acetyl chloride, propionyl chloride or benzoyl chloride, acetic anhydride or propionic anhydride.
Acid anhydrides such as benzoic anhydride, methyl chlorocarbonate,
Carbonic acid esters such as ethyl chlorocarbonate, phenyl chlorocarbonate, benzyl chlorocarbonate, isobutyl chlorocarbonate, dimethyl carbonate, carbamic acid halides such as dimethylcarbamic acid chloride, diethylcarbamic acid chloride, methylisocyanate, trimethylsilylisocyanate, etc. Isocyanates.

The sulfonylating agent used is preferably sulfonyl chlorides such as methanesulfonyl chloride and paratoluenesulfonyl chloride, anhydrous methanesulfonic acid, anhydrous sulfonic acids such as benzenesulfonyl anhydride, and dimethylaminosulfonyl chloride. And aminosulfonyl chlorides such as diethylaminosulfonyl chloride.

Examples of the base used include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide, sodium methoxide, sodium ethoxide and potassium t-butoxide. Alkali metal salts of lower alcohols, sodium hydride, alkali metal hydrides such as potassium hydride, alkali metal salts such as sodium and potassium,
Alkali metal amides such as sodium (bistrimethylsilyl) amide, lithium diisopropylamide,
Alkali metal carbonates such as potassium carbonate and sodium carbonate, tri-lower alkylamines such as triethylamine and diisopropylamine, pyridine, heteroaromatic tertiary amines such as N, N-dimethylaminopyridine, DBU, DBN, Alicyclic amines such as DABCO, aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline, and preferably tri-lower alkylamines such as triethylamine and diisopropylamine. , Pyridine, and heteroaromatic tertiary amines such as N, N-dimethylaminopyridine.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, it is an aliphatic hydrocarbon such as hexane or pentane, benzene, Toluene, aromatic hydrocarbons such as xylene, acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ether, ethers such as dimethoxyethane, ethyl acetate, acetic acid Esters such as butyl, polar solvents such as dimethyl sulfoxide, dimethylformamide, methylene chloride,
Halogenated hydrocarbons such as dichloroethane,
More preferred are nitriles such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ethers and ethers such as dimethoxyethane.

The reaction temperature is generally -50 ° C to 150 ° C, preferably 0 ° C to 50 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually 0.5 to 24 hours.

(Step D) In this step, the compound represented by the general formula (IIb) is produced by oxidizing the primary hydroxyl group of the compound represented by the general formula (IIa) produced by the step C into an aldehyde. It is a process.

The oxidizing agent used is not particularly limited as long as it is a relatively mild oxidizing agent capable of oxidizing a primary hydroxyl group to an aldehyde, but is preferably used for dimethyl sulfoxide oxidation (DMSO oxidation). Reagents (for dimethyl sulfoxide, dicyclohexylamide, oxalyl chloride, phosgene, chloroformic acid ester, acetic anhydride,
Phosphorus pentoxide, a complex of pyridine-sulfuric anhydride, a sulfonium salt formed from methyl sulfide and N-chlorosuccinimide, a chlorinating agent such as chlorine), a chromate salt such as chromic acid, a metal catalyst such as platinum Oxygen in the presence, permanganates such as potassium permanganate, sodium hypochlorite, hypochlorite compounds such as t-butyl hypochlorite, peroxysulfates such as oxone, ruthenium tetroxide and Ruthenium salts, sodium hypochlorite and TEMP that can generate it in the reaction system
It is an oxoammonium salt composed of a combination of O (2,2,6,6-tetramethyl-1-piperidinyloxy free radical). The equivalent of the oxidizing agent varies greatly depending on the conditions used, and for example, in the case of DMSO oxidation, 1 to 5 equivalents of oxalyl chloride and 1 to 10 equivalents of DMSO are used.

The reaction is carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably benzene, toluene, aromatic hydrocarbons such as xylene, methylene chloride, Chloroform, halogenated hydrocarbons such as dichloroethane, esters such as ethyl acetate and butyl acetate, ether, tetrahydrofuran,
1,4-dioxane, ethers such as dimethoxyethane, nitriles such as acetonitrile, acetone,
Ketones such as methyl ethyl ketone.

The reaction temperature is generally -70 ° C to 150 ° C, preferably -60 ° C to 50 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually 0.5 to 24 hours.

(Step E) In this step, the aldehyde group of the compound represented by the general formula (IIb) is oxidized to a carboxylic acid or ester and then amidated to give a compound represented by the general formula (II).
This is a step of producing the compound represented by c).

As a raw material for this step, R ⁶ is --COR ¹⁰
Alternatively, a compound which is —SO ₂ R ¹¹ (R ¹⁰ and R ¹¹ have the same meanings as described above) is preferable, and more preferably R ⁶ is −.
It is a compound that is COR ¹⁰ .

The oxidizing agent used in the oxidation reaction is not particularly limited as long as it is an oxidizing agent capable of oxidizing an aldehyde to a carboxylic acid, but silver oxide, copper oxide, copper acetate or nickel acetate is preferably present. Lower oxygen, oxygen in the presence of a metal catalyst such as platinum, chromate such as chromic acid, silver nitrate, silver salts such as silver oxide, chlorites such as sodium chlorite, potassium permanganate Such as permanganate, ruthenium tetroxide and ruthenium salts capable of generating it in a reaction system, sodium hypochlorite and TEM
An oxoammonium salt consisting of a combination of PO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical) and nickel oxide, more preferably silver oxide, copper oxide, copper acetate or acetic acid. Oxygen in the presence of nickel, oxygen in the presence of a metal catalyst such as platinum, chlorites such as sodium chlorite, ruthenium tetraoxide and ruthenium salts capable of generating it in the reaction system, sodium hypochlorite An oxoammonium salt consisting of a combination of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical), and more preferably sodium chlorite. The oxidizing agent is used in the amount of 1 to 10 equivalents based on the raw material.

The reaction is carried out in the presence or the absence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent,
Preferably, tertiary alcohols such as t-butyl alcohol, aromatic hydrocarbons such as benzene, toluene and xylene, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, tetrahydrofuran, 1, 4-dioxane, ethers, ethers such as dimethoxyethane, esters such as ethyl acetate and butyl acetate, polar solvents such as dimethyl sulfoxide and dimethylformamide, halogenated hydrocarbons such as methylene chloride and dichloroethane, and water And more preferably, tertiary alcohols such as t-butyl alcohol, nitriles such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ether, ethers such as dimethoxyethane, and water, and more preferably Has
1,4-dioxane, t-butyl alcohol and water.

The reaction temperature is generally -20 ° C to 150 ° C, preferably 20 ° C to 100 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually 0.5 to 24 hours.

The ester can be obtained by treating the carboxylic acid produced by oxidizing the aldehyde by the above method with the corresponding alcohol and acid.

The carboxylic acid or ester obtained above is reacted with ammonia to give the amide (I
Ic).

Ammonia used in this reaction is ammonia or ammonia gas dissolved in a solvent such as ethers, nitrites, alcohols and water, and is preferably ammonia gas.

In this reaction, it is desirable that the ester is directly reacted with ammonia or that the carboxylic acid is activated before the reaction with ammonia.

As the method for such activation, methyl chlorocarbonate, in the presence of a base such as triethylamine,
A method of treating with chlorocarbonic acid ester such as ethyl chlorocarbonate to obtain an acid anhydride, a method of treating with thionyl chloride, phosphorus oxychloride or the like to obtain an acid halide, 1-methyl-2
There are a method of treating with chloropyridiniodide, a method of treating with a phosphoric acid ester such as diethyl phosphate cyanide, and the like, and a method of treating with acid chloride such as thionyl chloride and phosphorus oxychloride is preferable. .

The reaction is carried out in the presence or absence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent,
Preferred are aliphatic hydrocarbons such as hexane and pentane, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, ethyl acetate and butyl acetate. Such as ethers, ethers, tetrahydrofuran, 1,4-dioxane, ethers such as dimethoxyethane, nitriles such as acetonitrile, acetone, ketones such as methyl ethyl ketone, and more preferably methylene chloride, Halogenated hydrocarbons such as chloroform and dichloroethane, esters such as ethyl acetate and butyl acetate, and more preferably halogenated hydrocarbons.

The reaction temperature is generally -50 ° C to 150 ° C, preferably 0 ° C to 50 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually 0.5 to 24 hours.

(Step F) In this step, in the compound represented by the general formula (IIc) produced in step E, R ⁶ is-.
A compound of COR ¹⁰ (R ¹⁰ has the same meaning as described above) is treated with a base in the presence of a solvent to cyclize to form a hydantoin ring, which is a compound represented by the general formula (IV). This is a step of producing a cyclic compound.

In the compound (IIc) which is the starting material for this step, R ¹ and R ² may be hydrogen atoms or optionally substituted alkylidene groups.

Bases used include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide, potassium t-butoxide. Alkali metal salts of lower alcohols, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal hydrates such as sodium and potassium, sodium (bistrimethylsilyl) amide, alkali metal amides such as lithium diisopropylamide, Alkali metal carbonates such as potassium carbonate and sodium carbonate, tri-lower alkylamines such as triethylamine and diisopropylamine, heteroaromatic tertiary amines such as pyridine and N, N-dimethylaminopyridine,
1,8-diazabicyclo [5.4.0] undecane-7
-Ene (DBU), 1,5-diazabicyclo [4.3.
Alicyclic amines such as 0] nonane-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), N, N-dimethylaniline, N, N
Aromatic amines such as diethylaniline, preferably alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide , An alkali metal salt of a lower alcohol such as potassium-t-butoxide. The base is used in 1 to 10 equivalents based on the raw material.

The reaction is carried out in the presence or the absence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent,
Preferably, lower alcohols such as methanol, ethanol, n-propanol, t-butyl alcohol,
Aromatic hydrocarbons such as benzene, toluene, xylene, ketones such as acetone, methyl ethyl ketone,
Nitriles such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ethers, ethers such as dimethoxyethane, ethyl acetate, esters such as butyl acetate, polar solvents such as dimethyl sulfoxide and dimethylformamide, methylene chloride, Halogenated hydrocarbons such as dichloroethane and water, more preferably methanol, ethanol, n-propanol, t-
Lower alcohols such as butyl alcohol, water.

The reaction temperature is usually -50 ° C to 100 ° C, preferably 0 ° C to 70 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually 0.1 to 24 hours.

(Step G) In this step, in the compound represented by the general formula (IIb) produced in step D, R ⁶ is-.
A compound which is COR ¹⁰ (R ¹⁰ has the same meaning as described above) is treated with ammonia in the presence of a solvent to add an amine to an aldehyde group to convert it into an amino alcohol and cyclize it to give a compound of the general formula It is a step of producing a compound represented by (III).

As the starting compound (IIb) of the present invention,
Preferred is a compound in which R ⁶ is a lower alkoxycarbonyl group.

Ammonia used in this reaction is ammonia or ammonia gas dissolved in a solvent such as ethers, nitrites, alcohols and water, and preferably ammonia water. Ammonia is used in the amount of 1 equivalent to a large excess amount based on compound (IIb).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but it is preferably methanol, ethanol, n-propanol or t-butyl alcohol. Of lower alcohols, aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ethers, ethers such as dimethoxyethane, ethyl acetate and butyl acetate. Such esters, polar solvents such as dimethylsulfoxide and dimethylformamide, methylene chloride, halogenated hydrocarbons such as dichloroethane, and water, more preferably methanol, ethanol, n-propanol and t-butyl alcohol. Lower alcohols such as Emissions, 1,4-dioxane, ethers such as ether and dimethoxyethane, water.

The reaction temperature is generally -50 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

The reaction time varies depending mainly on the reaction temperature, the starting compound or the type of solvent used, but is usually 0.1
Hours to 24 hours.

(Step H) This step is represented by the general formula (IV) by oxidizing the secondary hydroxyl group of the dihydrohydantoin ring of the compound represented by the general formula (III) produced by the step G. It is a step of producing a compound.

The oxidizing agent used is not particularly limited as long as it can oxidize a secondary hydroxyl group to convert it to a carbonyl group, but preferably, it is a reagent used for DMSO oxidation (for dimethyl sulfoxide, Dicyclohexylamide, oxalyl chloride, phosgene, chloroformic acid ester, acetic anhydride, phosphorus pentoxide, pyridine-sulfuric acid anhydride complex, sulfonium salt formed from methyl sulfide and N-chlorosuccinimide, and a chlorinating agent such as chlorine. ), Manganese such as manganese dioxide, permanganates such as potassium permanganate, oxygen in the presence of silver oxide, copper oxide, copper acetate or nickel acetate, oxygen in the presence of a metal catalyst such as platinum, chromium. Chromates such as acids, silver nitrate,
Silver salts such as silver oxide, ruthenium tetraoxide and ruthenium salts capable of generating it in the reaction system, sodium hypochlorite, hypochlorites such as calcium hypochlorite, chlorine, bromine, etc. Molecular halogens, more preferably hypochlorites such as sodium hypochlorite and calcium hypochlorite, and chromic acid, and even more preferably chromic acid. The oxidizing agent is used in the amount of 1 to 10 equivalents based on compound (III).

The reaction is carried out in the presence or the absence of a solvent. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent,
Preferably, aromatic hydrocarbons such as benzene, toluene and xylene, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ether and ether such as dimethoxyethane. , Ethyl acetate, esters such as butyl acetate, polar solvents such as dimethyl sulfoxide and dimethylformamide, methylene chloride, halogenated hydrocarbons such as dichloroethane, water,
Further preferred are ketones such as acetone and methyl ethyl ketone, and water.

The reaction temperature is generally -50 ° C to 100 ° C, preferably 0 ° C to 70 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually 0.1 to 24 hours.

(Step I) In this step, the N—O bond of the tricyclic compound represented by the general formula (IV) produced by the steps F and H is cleaved and, if desired, a hydroxyl group-protecting group. This is a process of producing hydantocidin by removing R ¹ and R ² .

When R ¹ and R ² are both hydrogen atoms, the reaction for removing the protecting group is unnecessary.

The order of cleavage of the N--O bond and removal of the protecting group can be appropriately changed.

Cleavage of the N--O bond is carried out by Raney catalyst (Na--
Ni) is used to carry out a hydrogenation reaction in the presence of a solvent.

The Raney catalyst is used in an amount of 0.01 to 10 times the amount of the compound (IV).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably lower alcohols such as methanol, ethanol and n-butanol, Acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, tetrahydrofuran, 1,4-dioxane, ethers, ethers such as dimethoxyethane,
Ethyl acetate, esters such as butyl acetate, dimethyl sulfoxide, polar solvents such as dimethylformamide, water, and mixed solvents thereof, and more preferably,
Tetrahydrofuran, 1,4-dioxane, ether,
Ethers such as dimethoxyethane, lower alcohols such as methanol, ethanol, n-butanol,
Water and a mixed solvent thereof, and even more preferably,
Lower alcohols such as methanol, ethanol, n-butanol, water, and mixed solvents thereof.

This reaction is preferably carried out under pressure rather than atmospheric pressure. When pressurizing, preferably 1 to 100 kg /
cm ² , more preferably 3 to 6 kg / cm ² .

Since the reaction does not proceed at room temperature, heating is desirable. The reaction temperature is usually 30 ° C to 150 ° C.
The temperature is preferably 40 ° C. to 100 ° C., more preferably 45 ° C. to 70 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
It is usually 0.5 to 72 hours.

When R ¹ and R ² are both hydrogen atoms,
In order to lower the pH in the reaction system, it is desirable to add an additive. This is because, if the additive is not added, the product hydantosidine is decomposed in the reaction system and the yield is reduced, so that the extreme alkalinity in the reaction system, which is considered to be the cause, is prevented. On the other hand, however, the Raney catalyst has a catalytic activity only when it is slightly alkaline, so that it is necessary to add an additive within a range in which the catalytic activity is not lost. With this additive, the yield is dramatically improved and the isomerization of the spiro moiety can be suppressed as much as possible.

Examples of such additives include sulfonic acids such as methanesulfonic acid, paratoluenesulfonic acid and camphorsulfonic acid, carboxylic acids such as formic acid, acetic acid, propionic acid and benzoic acid, hydrochloric acid, sulfuric acid and perchlorine. Mineral acids such as acids, Lewis acids such as aluminum chloride and zinc chloride, phosphoric acid and the like, preferably sulfonic acids such as methanesulfonic acid, paratoluenesulfonic acid and camphorsulfonic acid, formic acid, acetic acid and propione. Acids, organic acids such as carboxylic acids such as benzoic acid, and more preferably methanesulfonic acid or acetic acid.

This additive is used in 0.01 to 0.2 equivalents, preferably 0.1 to 0.2 equivalents, relative to compound (IV).

In this step, when the protective group for the hydroxyl group is deprotected after the cleavage reaction of the N--O bond, the stereoisomer of spiro carbon may be mixed if the nitrogen atom at the 7-position of hydantosidine is not protected. Therefore, it is preferable to protect the nitrogen atom after the N—O bond cleavage reaction and before deprotecting the hydroxyl-protecting group. The protecting group for the nitrogen atom is deprotected after the protecting group for the hydroxyl group is deprotected.

Examples of the protecting group for the nitrogen atom include acetyl group, propionyl group, benzoyl group, methoxycarbonyl group, acyl group such as dimethylaminocarbonyl group, methylsulfonyl group, sulfonyl group such as paratoluenesulfonyl group. Etc., preferably an acetyl group, a propionyl group, an acyl group such as a benzoyl group,
An alkoxycarbonyl group such as a methoxycarbonyl group, an aryloxycarbonyl group such as a phenoxycarbonyl group, a (substituted) aminocarbonyl group such as a dimethylaminocarbonyl group, and more preferably an acetyl group.

The above steps and reactions can be carried out stepwise, and in some cases, they can be carried out at once in combination with successive steps and reactions. In this case, it is possible to carry out only the purification process at once, or to carry out each reaction in one reaction vessel.

After completion of each of the above reactions, the desired product of the reaction is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the mixture is washed with water.
The organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

If necessary, the obtained target compound can be obtained by a conventional method,
It can be further purified by, for example, recrystallization, reprecipitation or chromatography.

[0170]

EXAMPLES The present invention will be described in more detail below with reference to examples.

[0171]

[Chemical 69]

[0172]

[Chemical 70]

[0173]

[Chemical 71]

[0174]

[Chemical 72]

[0175]

[Chemical formula 73]

[0176]

[Chemical 74]

[0177]

[Chemical 75]

[0178]

[Chemical 76]

[0179]

[Chemical 77]

[0180]

[Chemical 78]

[0181]

[Chemical 79]

[0182]

[Chemical 80]

[0183]

[Chemical 81]

[0184]

[Chemical formula 82]

[0185]

[Chemical 83]

[0186]

[Chemical 84]

[0187]

[Chemical 85]

[0188]

[Chemical 86]

[0189]

[Chemical 87]

[0190]

[Chemical 88]

[0191]

Example 1 Fructose (573.96 g, 3.19 mol) was suspended in acetone (5.74 L), concentrated sulfuric acid (28.7 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. 28% ammonia water (6
0 ml) was added, and the formed precipitate was filtered off with Celite. The filtrate was concentrated, the concentrate was dissolved in methylene chloride, and washed with water and half-saturated saline. After concentrating the organic layer, hexane-
Crystallize from a mixed solvent of methylene chloride to obtain the target compounds 1 and 2:
371.70 g (yield 45%) of 4,5-di-O-isopropylidene-D-fructopyranose was obtained.

[0192]

Example 2 1,2: 4,5-di-O-obtained in Example 1
Isopropylidene-D-fructopyranose (352.14 g,
1.35mol), tetra-n-butylammonium chloride
(12.65 g, 45.5 mol) and ruthenium trichloride (10.00 g) were dissolved in methylene chloride (1.5 L), and an aqueous sodium hypochlorite solution [1.2 M, 1.3 L] was gradually added at room temperature. The reaction temperature rose to the reflux temperature. After the reaction was completed, the reaction solution was filtered through Celite, and the filtrate was extracted with methylene chloride three times.
The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crystals were washed with ether-hexane (1:
After washing with 1) and drying, the desired product 1,2: 4,5-di-O
313.76 g (yield 90%) of isopropylidene-D-erythro-2,3-hexodiuro-2,6-pyranose were obtained.

[0193]

Example 3 1,2: 4,5-di-O-obtained in Example 2
Isopropylidene-D-erythro-2,3-hexodiuro-2,6-pyranose (313.76g, 1.21mol) was dissolved in ethanol (2.75L), and sodium borohydride was cooled with ice.
(13.79g, 0.364mol) was added and stirred for 1 hour. The reaction mixture was concentrated, saturated aqueous ammonium chloride solution was added, and the mixture was stirred for 30 minutes. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired product 1, 2: 4.
312.91 g (yield 99%) of 5-di-O-isopropylidene-D-psicopyranose was obtained.

[0194]

Example 4 1,2: 4,5-di-O-obtained in Example 3
Isopropylidene-D-psicopyranose (312.91 g, 1.2
0 mol) was dissolved in acetone (3.0 L), concentrated sulfuric acid (16.6 ml) was added at room temperature, and the mixture was stirred for 10 hours. Aqueous ammonia (40 ml) was added to the reaction solution, and the generated ammonium sulfate was filtered off with Celite. The filtrate was concentrated under reduced pressure, and the obtained concentrate was partitioned between water and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography (ethyl acetate: hexane 1: 3). : 193.53 g (yield 63%) of 3,4-di-O-isopropylidene-D-psicofuranose was obtained.

[0195]

Example 5 1,2,3,4-di-O-obtained in Example 4
Isopropylidene-D-psicofuranose (17.4g, 66.9m
mol) in methylene chloride solution (200 ml) at 0 ° C. with triethylamine (20.5 ml, 147 mmol) and methanesulfonyl chloride.
(5.7 ml, 74 mmol) was sequentially added dropwise, and the mixture was stirred for 20 minutes. The reaction was stopped by pouring water, the mixture was extracted 3 times with methylene chloride, the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain the desired product 1,2,3,4-di-.
O-isopropylidene-6-O-methanesulfonyl-D
20.9 g (yield 92%) of psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.76 (d, 1H, J = 5.
8Hz), 4.62 (d, 1H, J = 5.8Hz), 4.31 (d, 1H, J = 9.9Hz), 4.39-4.
23 (m, 3H), 4.06 (d, 1H, J = 9.9Hz), 3.07 (s, 3H), 1.45 (s, 6H),
1.38 (s, 3H), 1.33 (s, 3H) .MS (m / z) 338 (M ⁺ ), 323,279,263,229,205,149,113.

[0197]

[Sixth Embodiment] With the same operations as in the fifth embodiment, 1, 2, 3, and 4 are performed.
-Di-O-isopropylidene-D-psicofuranose (1
33 mg, 511 μmol), triethylamine (0.36 ml, 2.6 mmol) and tosyl chloride (244 mg, 1.28 mmol),
2: 3,4-di-O-isopropylidene-6-O-p-
Toluenesulfonyl-D-psicofuranose 193 mg
(Yield 91%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.80 (d, 2H, J = 8.
4Hz), 7.36 (d, 2H, J = 8.4Hz), 4.68 (d, 1H, J = 5.8Hz), 4.56 (d,
1H, J = 5.8Hz), 4.26 (d, 1H, J = 9.9Hz), 4.21 (q, 1H, J = 8.0Hz),
4.10 (dd, 1H, J = 10.0,8.0Hz), 4.05 (dd, 1H, J = 10.0,8.0Hz),
4.01 (d, 1H, J = 9.9Hz), 2.45 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3
H), 1.35 (s, 3H), 1.29 (s, 3H). MS (m / z) 414 (M ⁺ ), 399,356,298,240,229,205,155.

[0199]

Example 7 1,2,3,4-di-O-obtained in Example 4
Isopropylidene-D-Psychofuranose (1.02g, 3.92m
triphenylphosphine (1.23 g, 4.70 mmol) and N-chlorosuccinimide (NCS) (628 mg, 4.70 mmol) were sequentially added to 20 ml of tetrahydrofuran (THF) solution (mol).
Stir at room temperature for 40 minutes. The reaction was stopped by adding water, extracted three times with ethyl acetate, the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to obtain the desired product 6-chloro-6-deoxy-1,2,3,4.
-Di-O-isopropylidene-D-psicofuranose 9
30 mg (yield 85.1%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.80 (dd, 1H, J =
5.8,1.0Hz), 4.61 (d, 1H, J = 5.8Hz), 4.28 (dd, 1H, J = 9.8Hz),
4.23 (ddd, 1H, J = 9.3,6.4,1.0Hz), 4.04 (d, 1H, J = 9.8Hz), 3.
59 (dd, 1H, J = 9.8,6.4Hz), 3.54 (dd, 1H, J = 9.8,9.3Hz), 1.44
(s, 6H), 1.37 (s, 3H), 1.32 (s, 3H) .MS (m / z) 279 (M + 1), 263,221,203,185,162,147.

[0201]

Example 8 Similar to Example 7, 1,2: 3,4-di-
O-isopropylidene-D-psicofuranose (1.02 g,
3.92 mmol) and triphenylphosphine (1.23 g, 4.70 mmol)
And N-bromosuccinimide (NBS) (837mg, 4.70mmo
l) to the desired product 6-bromo-6-deoxy-1,2,3
903 mg (yield 71%) of 4-di-O-isopropylidene-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.82 (d, 1H, J = 5.
8Hz), 4.62 (d, 1H, J = 5.8Hz), 4.30 (dd, 1H, J = 9.6,6.4Hz), 4.
27 (d, 1H, J = 10.2Hz), 4.04 (d, 1H, J = 10.2Hz), 3.44 (dd, 1H, J
= 10.2,6.4Hz), 3.38 (dd, 1H, J = 10.2,9.6Hz), 1.45 (s, 3H),
1.44 (s, 3H), 1.37 (s, 3H), 1.32 (s, 3H) .MS (m / z) 323 (M ⁺ ), 309,265,249,206,191,163.

[0203]

Example 9 1,2,3,4-di-O-obtained in Example 4
Isopropylidene-D-psicofuranose (1.06g, 4.07m
mol), chlorodiphenylphosphine (1.17 g, 5.29 mmol) and imidazole (610 mg, 8.96 mmol) in toluene solution 10 ml
Iodine (1.34 g, 5.29 mmol) was added little by little, and the mixture was stirred at room temperature for 10 minutes. The reaction was stopped by adding 10 ml of a 1N sodium hydroxide (NaOH) aqueous solution, and after stirring well, the aqueous layer was separated. The organic layer was washed twice with a saturated aqueous solution of sodium thiosulfate, and when it was confirmed that the color of iodine had disappeared, it was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to obtain the desired product 6-deoxy-1,2: 3,4-di-O. -Isopropylidene-
1.14 g of 6-iodo-D-psicofuranose (yield 75%)
Got

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.82 (dd, 1H, J =
5.8,1.0Hz), 4.64 (d, 1H, J = 5.8Hz), 4.37 (ddd, 1H, J = 9.8,6.
4,1.0Hz), 4.28 (d, 1H, J = 9.8Hz), 4.04 (d, 1H, J = 9.8Hz), 3.3
0 (dd, 1H, J = 10.0,6.4Hz), 3.22 (dd, 1H, J = 10.0,9.8Hz), 1.4
8 (s, 3H), 1.44 (s, 3H), 1.38 (s, 3H), 1.33 (s, 3H) .MS (m / z) 371 (M + 1), 355,313,295,255,237,170.

[0205]

Example 10 Methyl N-hydroxycarbamate
(2.89 g, 31.7 mmol) was dissolved in 30 ml of dimethylformamide and potassium t-butoxide (3.56 g, 31.7 mmol) was added at room temperature.
And a dimethylformamide solution (6.5 ml) of 1,2,3,4-di-O-isopropylidene-6-O-methanesulfonyl-D-psicofuranose (3.50 g, 10.3 mmol) obtained in Example 5 was added. added. After stirring at 80 ° C for 7 hours, the mixture was poured into ice water and extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried (Na ₂ SO ₄ ), concentrated and then subjected to silica gel chromatography (ethyl acetate: hexane =
1: 3) and the desired product 1,2,3,4-di-O-isopropylidene-6-O-methoxycarbonylamino-
1.4553 g (yield 42%) of D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.86 (1 H, br.s),
4.81 (1H, dd, J = 1.1,5.8Hz), 4.61 (1H, d, J = 5.8Hz), 4.31 (1
H, dt, J = 1.1,5.8Hz), 4.28 (1H, d, J = 9.8Hz), 4.03 (1H, d, J =
9.8Hz), 4.05-3.88 (2H, m), 3.75 (3H, s), 1.44 (3H, s), 1.43
(3H, s), 1.36 (3H, s), 1.31 (3H, s) .MS (m / z) 333 (M ⁺ ), 316,275,260,229,217,200,159,109,6
9,59,44.

[0207]

Example 11 Methyl N-hydroxycarbamate (2
45mg, 2.69mmol), and sodium hydride (108mg, 2.69mmo
l) in dimethylformamide (DMF) solution (3 ml) at 0 ° C
Then, 3 ml of a DMF solution of 1,2,3,4-di-O-isopropylidene-6-O-methanesulfonyl-D-psicofuranose (607 mg, 1.79 mmol) obtained in Example 5 was added, and 60
Stir for 3 1/2 hours at ° C. After air cooling at room temperature,
Methyl N-hydroxycarbamate (817mg, 8.95mmol)
2 ml of DMF solution and sodium hydride (358 mg, 8.95 mmol)
Were sequentially added, and the mixture was stirred at 60 ° C. for 3 hours. The reaction was stopped by pouring water, the mixture was extracted 3 times with diethyl ether, the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 7).
5:25) and then the desired product 1,2,3,4-di-O
301 mg (yield 50%) of -isopropylidene-6-O-methoxycarbonylamino-D-psicofuranose was obtained.

The equipment data were in agreement with those of Example 10.

[0209]

Example 12 1,2,3,4-di-O obtained in Example 5
-Isopropylidene-6-O-methanesulfonyl-D-
Psychofuranose (1.15 g, 3.40 mmol) was added to t-butanol 2
It was dissolved in 0 ml and at room temperature ethyl N-hydroxycarbamate (0.71 g, 6.80 mmol) and potassium hydroxide (85
%) (0.67 g, 10.2 mmol) was added and the mixture was refluxed for 3 hours. The reaction solution was cooled, water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated brine and dried (Na ₂ SO
₄ ), after concentration, purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to obtain the desired product 1,2:
865.5 mg of 3,4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose
(Yield 73%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.69 (1 H, br.s),
4.83 (1H, d, J = 5.9Hz), 4.62 (1H, d, J = 5.9Hz), 4.33 (1H, t, J =
6.4Hz), 4.30 (1H, d, J = 10.0Hz), 4.21 (2H, ABq, J = 7.5Hz), 4.
04 (1H, d, J = 10.0Hz), 4.02 (1H, dd, J = 5.8,11.4Hz), 3.95 (1
H, dd, J = 7.4,11.4Hz), 1.46 (3H, s), 1.44 (3H, s), 1.37 (3H,
s), 1.32 (3H, s), 1.29 (3H, t, J = 7.3Hz) .MS (m / z) 347 (M ⁺ ), 332,289,126,109,69,59,44.

[0211]

Example 13 1,2,3,4-di-O obtained in Example 5
-Isopropylidene-6-O-methanesulfonyl-D-
Psychofuranose (1.27 g, 3.75 mmol) was added to t-butanol.
(25.0 ml), ethyl N-hydroxycarbamate (0.79 g, 7.50 mmol), and potassium t-butoxide (1.2
6 g, 11.25 mmol) was added and the mixture was heated under reflux for 5 hours. After cooling the reaction mixture, water was added and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated brine and dried (Na ₂ SO
₄ ), after concentration, purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to obtain the desired product 1,2:
1.08 g (yield 83%) of 3,4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose was obtained.

The equipment data were in agreement with those of Example 12.

[0213]

Example 14 1,2,3,4-di-O obtained in Example 5
-Isopropylidene-6-O-methanesulfonyl-D-
Psychofuranose (9.70 g, 28.7 mmol) was dissolved in isopropanol (200 ml), ethyl N-hydroxycarbamate (6.00 g, 57.3 mmol) and potassium t-butoxide (9.65 g, 86.0 mmol) were added, and the mixture was heated under reflux for 4 hours. did. After cooling the reaction mixture, water was added and the mixture was extracted 3 times with ethyl acetate.
The combined organic layers were washed with water and saturated brine and dried (N
a ₂ SO ₄ ), after concentration, purified by silica gel chromatography (ethyl acetate: hexane = 1: 3), 1,2,3,
4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose (6.62 g, yield 67
%) And 1,2: 3,4-di-O-isopropylidene-
6-O-isopropyloxycarbonylamino-D-psicofuranose (2.67 g, 26%) was obtained.

Instrumental data for 1,2: 3,4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose was in agreement with that of Example 12.

1,2,3,4-di-O-isopropylidene-6-O-isopropyloxycarbonylamino-D
-Psychofuranose ¹ H-NMR (200MHz, CDCl ₃ ) δ: 7.62 (1H, br.s), 4.99 (1H, qq, J
= 6.3,6.3Hz), 4.83 (1H, dd, J = 1.1,5.8Hz), 4.62 (1H, d, J = 5.
8Hz), 4.33 (1H, dt, J = 1.1,6.0Hz), 4.29 (1H, d, J = 9.7Hz), 4.
04 (1H, d, J = 9.7Hz), 4.05-3.89 (2H, m), 1.46 (3H, s), 1.44 (3
H, s), 1.37 (3H, s), 1.31 (3H, s), 1.27 (3H, d, J = 6.3Hz) .MS (m / z) 361 (M ⁺ ), 346,332,303,268,260,244,229,186,15
9,142,126,69,59,44.

[0216]

Example 15 1,2,3,4-di-O obtained in Example 5
-Isopropylidene-6-O-methanesulfonyl-D-
Psychofuranose (1.25 g, 3.81 mmol) and ethyl N-hydroxycarbamate (0.80 g, 7.6 mmol) were dissolved in a mixed solvent of 16.0 ml of t-butanol and 8.0 ml of dimethyl sulfoxide, and potassium t-butoxide (1.28 g, 11.4 mmol). ) Was added and the mixture was refluxed for 2 hours. The reaction solution was poured into ice water and extracted 3 times with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to obtain the desired product 1,2: 3. 841.8 mg (yield 64%) of 4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose was obtained.

The device data were in agreement with those of Example 12.

[0218]

Example 16 1,2,3,4-di-O obtained in Example 5
-Isopropylidene-6-O-methanesulfonyl-D-
Psychofuranose (296.2 mg, 0.8753 mmol) was dissolved in 6 ml of isopropanol, and at room temperature, isobutyl N-hydroxycarbamate 350 mg, potassium hydroxide (KOH) 1
73 mg was added, and the mixture was stirred at the same temperature for 30 minutes, heated to 70 to 80 ° C, and stirred for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with brine, dried and concentrated. The obtained crude product was subjected to silica gel chromatography (hexane:
Purified with ethyl acetate = 6: 1 → 4: 1)
167.6 mg (yield 51%) of 2: 3,4-di-O-isopropylidene-6-O-isobutyloxycarbonylamino-D-psicofuranose was obtained, and 92.7 mg (31%) of the raw material was recovered.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.74 (1 H, s), 4.8
3 (1H, dd, J = 1.1,5.8Hz), 4.62 (1H, d, J = 5.8Hz), 4.33 (1H, t
d, J = 1.1,6.8Hz), 4.30 (1H, d, J = 9.8Hz), 4.04 (1H, d, J = 9.8H
z), 4.05-3.90 (4H, m), 1.95 (1H, qq, J = 6.7,6.7Hz), 1.46 (3
H, s), 1.44 (3H, s), 1.37 (3H, s), 1.32 (3H, s), 0.93 (6H, d, J =
6.7Hz) .MS (m / z) 375 (M ⁺ ), 360,317,186,126,109,69,57,44.

[0220]

Example 17 1,2: 3,4-di-O obtained in Example 6
-Isopropylidene-6-O-p-toluenesulfonyl-D-psicofuranose (516 mg, 1.25 mmol) in 6 ml of t-butanol solution, ethyl N-hydroxycarbamate
4 ml of a solution of (262 mg, 2.49 mmol) in ^t BuOH and potassium t-butoxide (419 mg, 3.74 mmol) were sequentially added, and the mixture was refluxed for 6 hours.
The reaction was stopped by pouring water and extracted with ethyl acetate three times,
The organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to obtain the desired product 1,2,3,4-di-O-isopropylidene- 326 mg (yield 75%) of 6-O-ethoxycarbonylamino-D-psicofuranose was obtained.

The equipment data were in agreement with those of Example 12.

[0222]

Example 18 6-Bromo-6-deoxy-1,2: 3,4-di-O-isopropylidene-D-obtained in Example 8
Ethoxy solution 1 of Psychofuranose (528mg, 1.63mmol)
In 0 ml, ethyl N-hydroxycarbamate (343 mg,
3.26 mmol) and potassium hydroxide (183 mg, 3.26 mmol) were added, and the mixture was refluxed for 9 hours. The reaction was stopped by pouring water, the mixture was extracted 3 times with ethyl acetate, the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1),
Target compound 1,2: 3,4-di-O-isopropylidene-6
61.2 mg (yield 11%) of -O-ethoxycarbonylamino-D-psicofuranose was obtained.

The equipment data were in agreement with those of Example 12.

[0224]

Example 19 By the same procedure as in Example 18, 6-deoxy-1,2: 3,4-di-O-isopropylidene-6-iodo-D-psicofuranose (557 mg, obtained in Example 9)
1.50mmol), ethyl N-hydroxycarbamate (474m
g, 4.51 mmol) and potassium hydroxide (253 mg, 4.51 mmol), the target compound 1,2: 3,4-di-O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose 54.1 mg (yield: Rate 10%).

The equipment data were in agreement with those of Example 12.

[0226]

Example 20 Acetoxime (163 mg, 2.22 mmol) and sodium hydride (NaH) (60%) (89.0 mg, 2.22 mmol) in D
1,2: 3,4 obtained in Example 5 at 0 ° C. in 5 ml of MF solution
-Di-O-isopropylidene-6-O-methanesulfonyl-D-psicofuranose (503 mg, 1.49 mmol) was added and 6
Stir at 0 ° C. for 3 hours. Water was poured into the reaction solution at 0 ° C. to stop the reaction, the mixture was extracted 3 times with diethyl ether, the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate =
9: 1) to obtain the desired product 1,2: 3,4-di-O-
Isopropylidene-6-O-isopropylideneamino-
353 mg (75% yield) of D-psicofuranose and 7,7-dimethyl-3,4-isopropylidenedioxy-2-methylidene-1,6,8-trioxaspiro [4.4] nonane as a by-product. 30.3 mg (yield 8.4%) was obtained.

1,2,3,4-di-O-isopropylidene-6-O-isopropylideneamino-D-psicofuranose ¹ H NMR (200 MHz, CDCl ₃ ) δ: 4.80 (d, 1H, J = 5.9 Hz) ), 4.63 (d, 1
H, J = 5.9Hz), 4.35 (dd, 1H, J = 8.6,6.1Hz), 4.26 (d, 1H, J = 9.6
Hz), 4.12 (dd, 1H, J = 11.2,6.1Hz), 4.05 (dd, 1H, J = 11.2,8.6
Hz), 4.05 (d, 1H, J = 9.6Hz), 1.86 (s, 6H), 1.44 (s, 6H), 1.36
(s, 3H), 1.32 (s, 3H) .MS (m / z) 315 (M ⁺ ), 300,257,242,229,200,171,141.7,7-Dimethyl-3,4-isopropylidenedioxy-2-methylidene-1,6,6. 8-Trioxaspiro [4.4] nonane ¹ H NMR (200 MHz, CDCl ₃ ) δ: 5.12 (d, 1H, J =
5.6 Hz), 4.58 (d, 1H, J = 1.9H)
z), 4.56 (d, 1H, J = 5.6 Hz), 4.3
6 (d, 1H, J = 1.9 Hz), 4.36 (d, 1
H, J = 9.9 Hz), 4.16 (d, 1H, J = 9.
9Hz), 1.51 (s, 3H), 1.44 (s, 3)
H), 1.41 (s, 3H), 1.36 (s, 3H). MS (m / z) 242 (M ⁺ ), 227, 203, 1
84,169,141,113.

[0228]

Example 21 1,2,3,4-di-O obtained in Example 4
-Isopropylidene-D-psicofuranose (24.0
g, 92.3 mmol), triphenylphosphine (29.
1g, 111mmol), N-hydroxyphthalimide (18.1g, 111
Diethyl azodicarboxylate (DEAD) (17.4 ml, 111 mmol) was added dropwise to 500 ml of a THF solution of (mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. After distilling off the solvent under reduced pressure, hexane-
Diethyl ether mixed solvent (1: 1) was poured to precipitate crystals, and the crystals were separated by filtration using Celite and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3),
Target compound 1,2: 3,4-di-O-isopropylidene-6
35.4 g (yield 95%) of -O-phthalimido-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.88-7.74 (m, 4
H), 5.04 (d, 1H, J = 5.8Hz), 4.65 (d, 1H, J = 5.8Hz), 4.51-4.14
(m, 3H), 4.29 (d, 1H, J = 9.8Hz), 4.05 (d, 1H, J = 9.8Hz), 1.46
(s, 3H), 1.40 (s, 3H), 1.36 (s, 6H) .MS (m / z) 405 (M ⁺ ), 390,347,332,289,272,231,202,185,16
3.

[0230]

Example 22 1,2,3,4-di-obtained in Example 21
O-isopropylidene-6-O-phthalimido-D-psicofuranose (35.4 g, 87.4 mmol) in ethanol solution 35
Add hydrazine hydrate (4.5 ml, 92 mmol) to 0 ml and add 9
Heated to reflux for 0 minutes. After the reaction solution has cooled to room temperature,
White crystals generated during the reaction were filtered off using Celite, and the filtrate was concentrated. Ethyl acetate and water are poured into the obtained residue,
The mixture was extracted 3 times with ethyl acetate, the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain the desired product 1,2,3,4-di-O-isopropylidene- 22.1 g of 6-O-amino-D-psicofuranose (yield
92%).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.50 (br.s, 2H),
4.73 (d, 1H, J = 5.8Hz), 4.53 (d, 1H, J = 5.8Hz), 4.31 (dd, 1H, J
= 7.6,5.4Hz), 4.25 (d, 1H, J = 9.6Hz), 4.02 (d, 1H, J = 9.6Hz),
3.76 (dd, 1H, J = 10.2,5.4Hz), 3.67 (dd, 1H, J = 10.2,7.6Hz),
1.43 (s, 6H), 1.35 (s, 3H), 1.30 (s, 3H) .MS (m / z) 318 (M ⁺ ), 303,279,260,243,229,217,159.

[0232]

[Example 23] 1,2,3,4-di-
2 ml of triethyl orthoacetate was added to 13 ml of a toluene solution of O-isopropylidene-6-O-amino-D-psicofuranose (1.34 g, 4.87 mmol), and the mixture was heated under reflux for 2 hours.
The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 4:
The product of interest 1,2: 3,4-di-O-isopropylidene-6- (1-ethoxyethylidene) -D-
1.55 g (yield 92%) of psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.80 (d, 1H, J = 5.
8Hz), 4.63 (d, 1H, J = 5.8Hz), 4.39 (dd, 1H, J = 8.4,7.2Hz), 4.
28 (d, 1H, J = 9.7Hz), 4.05 (d, 1H, J = 9.7Hz), 4.06-3.88 (m, 3
H), 4.00 (q, 2H, J = 7.1Hz), 1.94 (s, 3H), 1.45 (s, 6H), 1.38
(s, 3H), 1.33 (s, 3H), 1.26 (t, 3H, J = 7.1Hz) .MS (m / z) 345 (M ⁺ ), 330,287,272,243,230,216,171.

[0234]

Example 24 1,2,3,4-di-obtained in Example 22
O-isopropylidene-6-O-amino-D-psicofuranose (5.00 g, 18.2 mmol) was dissolved in 100 ml of dichloroethane, and pyridine (1.33 ml, 18.16 mmol) and methyl chlorocarbonate (1.47 ml, 19.1 mmol) were added at 0 ° C. ) Was added and the mixture was stirred at the same temperature for 1 hour. Water and saline were added to this reaction solution, which was extracted with dichloromethane, dried, concentrated, and purified by silica gel column chromatography (hexane: ethyl acetate = 5: 2 → 1: 1) to obtain the desired product 1,2,3. 5.75 g (94% yield) of 4-di-O-isopropylidene-6-O-methoxycarbonylamino-D-psicofuranose was obtained.

The device data were in agreement with those of Example 10.

[0236]

Example 25 1,2,3,4-di-obtained in Example 22
O-isopropylidene-6-O-amino-D-psicofuranose (0.71 g, 2.6 mmol) was added to methylene chloride (14 ml).
Pyridine (0.25 ml, 3.1 mmol) and phenyl chlorocarbonate (0.36 ml, 2.8 mmol) were added at 0 ° C., and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The combined organic layers were washed with dilute hydrochloric acid and semi-saturated saline, dried (Na ₂ SO ₄ ) and concentrated, and the resulting crude product was purified by silica gel chromatography to obtain the desired product 1.
2: 3,4-di-O-isopropylidene-6-O-phenoxycarbonylamino-D-psicofuranose 979.
4 mg (yield 96%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.27 (1 H, br.s),
7.41-7.33 (2H, m), 7.26-7.13 (3H, m), 4.87 (1H, dd, J = 1.0,
5.8Hz), 4.65 (1H, d, J = 5.8Hz), 4.38 (1H, br.t, J = 5.6Hz), 4.
32 (1H, d, J = 9.8Hz), 4.18-4.00 (3H, m), 1.49 (3H, s), 1.46 (3
H, s), 1.39 (3H, s), 1.32 (3H, s) .MS (m / z) 395 (M ⁺ ), 360,337,262,244,109,94,59,44.

[0238]

Example 26 1,2,3,4-di-obtained in Example 22
O-isopropylidene-6-O-amino-D-psicofuranose (4.62 g, 16.8 mmol) was added to methylene chloride (60 ml).
And was added to pyridine (1.5 ml, 18 mmol) and benzyl chlorocarbonate (2.6 ml, 18 mmol) at 0 ° C. It was brought to room temperature and stirred for 1 hour. Water was added and the mixture was extracted 3 times with methylene chloride.
The organic layers were combined, washed with diluted hydrochloric acid and saturated brine, dried (Na ₂ SO ₄ ) and concentrated. The obtained crude product is subjected to silica gel chromatography (ethyl acetate: hexane = 1: 3).
The desired product 6-O-benzyloxycarbonylamino-1,2: 3,4-di-O-isopropylidene-
6.18 g (yield 90%) of D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.81 (1 H, br.s),
7.36 (5H, br.s), 5.19 (2H, s), 4.80 (1H, d, J = 5.8Hz), 4.60 (1
H, d, J = 5.8Hz), 4.35-4.26 (2H, m), 4.08-3.91 (3H, m), 1.44
(6H, s), 1.36 (3H, s), 1.30 (3H, s) .MS (m / z) 409 (M ⁺ ), 394,350,307,229,149,127,113,91,69,
59,44.

[0240]

Example 27 1,2,3,4-di-obtained in Example 22
O-isopropylidene-6-O-amino-D-psicofuranose (1.69 g, 6.14 mmol) was added to dichloroethane solution 17
ml, pyridine (0.52 ml, 6.4 mmol) and acetic anhydride at 0 ° C.
(0.61 ml, 6.4 mmol) were sequentially added, and the mixture was stirred at the same temperature for 30 minutes. The reaction was stopped by adding water, the mixture was extracted with methylene chloride three times, the organic layer was washed once with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate =
3: 7) and then the desired product 6-O-acetamide-1,
1.71 g (yield 88%) of 2: 3,4-di-O-isopropylidene-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, DHSO-d ₆ ) δ: 11.08 (br.s, 1
H), 4.86 (d, 1H, J = 5.8Hz), 4.64 (d, 1H, J = 5.8Hz), 4.19 (dd, 1
H, J = 8.2,5.7Hz), 4.15 (d, 1H, J = 9.6Hz), 3.94 (d, 1H, J = 9.6H
z), 3.83 (dd, 1H, J = 9.8,5.7Hz), 3.77 (dd, 1H, J = 9.8,8.2H
z), 1.74 (s, 3H), 1.38 (s, 3H), 1.33 (s, 3H), 1.29 (s, 3H) .MS (m / z) 317 (M ⁺ ), 302,259,229,202,184,159,127.

[0242]

[Embodiment 28] The operation of Embodiment 22 is performed in the same manner as in Embodiment 27.
1,2,3,4-di-O-isopropylidene-6 obtained in
-O-amino-D-psicofuranose (1.12g, 4.07mmo
l), pyridine (0.35 ml, 4.3 mmol) and benzoyl chloride (0.50 ml, 4.3 mmol) to give the desired product 6-O-benzamide-1,2: 3,4-di-O-isopropylidene-D-psicofuranose. 1.50 g (97% yield) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.19 (br.s, 1H),
7.77-7.73 (m, 2H), 7.56-7.39 (m, 3H), 4.93 (d, 1H, J = 5.8H
z), 4.70 (d, 1H, J = 5.8Hz), 4.41 (dd, 1H, J = 7.2,5.1Hz), 4.34
(d, 1H, J = 9.7Hz), 4.25 (dd, 1H, J = 11.4,5.1Hz), 4.12 (dd, 1
H, J = 11.4,7.2Hz), 4.04 (d, 1H, J = 9.7Hz), 1.47 (s, 3H), 1.41
(s, 3H), 1.39 (s, 3H), 1.34 (s, 3H) .MS (m / z) 379 (M ⁺ ), 364,321,306,263,229,205,163.

[0244]

Example 29 1,2,3,4-di-obtained in Example 22
To 30 ml of a THF solution of O-isopropylidene-6-O-amino-D-psicofuranose (3.00 g, 10.9 mmol) was added trimethylsilylisocyanate (4.4 ml, 33 mmol) and 1 drop of triethylamine, and the mixture was stirred at room temperature for 30 minutes. . The reaction was stopped by pouring water, the mixture was extracted 3 times with ethyl acetate, the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 4) and the desired product 1,2,3,4-di-O-
3.02 g (yield 87%) of isopropylidene-6-O-ureido-D-psicofuranose was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.34 (br.s, 1H),
5.67 (br.s, 2H), 4.68 (dd, 1H, J = 5.8,1.1Hz), 4.62 (d, 1H, J =
5.8Hz), 4.41 (ddd, 1H, J = 7.8,4.5,1.1Hz), 4.32 (d, 1H, J = 9.
8Hz), 4.05 (d, 1H, J = 9.8Hz), 4.00 (dd, 1H, J = 11.4,7.8Hz),
3.89 (dd, 1H, J = 11.4,4.5Hz), 1.47 (s, 3H), 1.46 (s, 3H), 1.3
8 (s, 3H), 1.32 (s, 3H) .MS (m / z) 318 (M ⁺ ), 303,279,260,217,202,185,159.

[0246]

Example 30 1,2,3,4-di-obtained in Example 22
10 ml of a solution of O-isopropylidene-6-O-amino-D-psicofuranose (1.07 g, 3.89 mmol) in dichloroethane
To this, pyridine (0.38 ml, 4.7 mmol) and dimethylcarbamoyl chloride (0.43 ml, 4.7 mmol) were added at 0 ° C.
Heated and stirred for 2 hours. The reaction was stopped by pouring water, the mixture was extracted 3 times with methylene chloride, the organic layer was washed once with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to obtain the desired product 1,
2: 3,4-di-O-isopropylidene-6-O-
(3,3-Dimethylureido) -D-psicofuranose
1.18 g (yield 87%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.31 (br.s, 1H),
4.85 (d, 1H, J = 5.8Hz), 4.63 (d, 1H, J = 5.8Hz), 4.37 (dd, 1H, J
= 7.7,5.8Hz), 4.29 (d, 1H, J = 9.7Hz), 4.03 (d, 1H, J = 9.7Hz),
3.99 (dd, 1H, J = 11.2,5.8Hz), 3.93 (dd, 1H, J = 11.2,7.7Hz),
2.89 (s, 6H), 1.44 (s, 6H), 1.36 (s, 3H), 1.32 (s, 3H) .MS (m / z) 346 (M ⁺ ), 331,273,229,213,172,147.

[0248]

Example 31 1,2,3,4-di-obtained in Example 22
11 ml of a methylene chloride solution of O-isopropylidene-6-O-amino-D-psicofuranose (1.14 g, 4.14 mmol)
To the above, triethylamine (0.61 ml, 4.3 mmol) and methanesulfonyl chloride (0.34 ml, 4.3 mmol) were added at 0 ° C., and the mixture was stirred at room temperature overnight. The reaction was stopped by pouring water, the mixture was extracted 3 times with methylene chloride, the organic layer was washed once with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give 1,2: 3,4-di-O-isopropylidene-6-. O-methanesulfonylamino-D
-1.29 g of psicofuranose (88% yield) and 1,2:
3,4-di-O-isopropylidene-6-O-dimethanesulfonylamino-D-psicofuranose 94.1 mg (yield
5.3%).

1,2,3,4-di-O-isopropylidene-6-O-methanesulfonylamino-D-psicofuranose ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.19 (br.s, 1H) , 4.75 (d, 1H, J =
5.8Hz), 4.62 (d, 1H, J = 5.8Hz), 4.35 (dd, 1H, J = 7.0,5.2Hz),
4.30 (d, 1H, J = 9.7Hz), 4.14 (dd, 1H, J = 12.0,5.2Hz), 4.10 (d
d, 1H, J = 12.0,7.0Hz), 4.06 (d, 1H, J = 9.7Hz), 3.08 (s, 3H),
1.46 (s, 6H), 1.38 (s, 3H), 1.33 (s, 3H) .MS (m / z) 353 (M ⁺ ), 338,295,229,208,166.1,2: 3,4-di-O-isopropylidene- 6-O-
Dimethanesulfonylamino-D-psicofuranose ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.87 (d, 1 H, J = 5.8 Hz), 4.62 (d,
1H, J = 5.8Hz), 4.40-4.16 (m, 3H), 4.30 (d, 1H, J = 9.4Hz), 4.0
4 (d, 1H, J = 9.4Hz), 3.35 (s, 6H), 1.45 (s, 6H), 1.38 (s, 3H),
1.33 (s, 3H) .MS (m / z) 432 (M + 1), 416,373,338,315,298,257,229,185.

[0250]

[Embodiment 32] The operation of the embodiment
1,2,3,4-di-O-isopropylidene-6 obtained in
-O-amino-D-psicofuranose (1.03g, 3.74mmol)
And triethylamine (0.57 ml, 4.1 mmol) and p-toluenesulfonyl chloride (785 mg, 4.11 mol) from 1,2,3,4
-Di-O-isopropylidene-6-O-p-toluenesulfonylamino-D-psicofuranose 775 mg (yield 48
%) And 6-O- [bis (p-toluenesulfonyl) amino] -1,2: 3,4-di-O-isopropylidene-
741 mg (34% yield) of D-psicofuranose was obtained.

1,2,3,4-di-O-isopropylidene-6-Op-toluenesulfonylamino-D-psicofuranose ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.81 (d, 2H, J = 8.3Hz), 7.35 (d,
2H, J = 8.3Hz), 7.24 (br.s, 1H), 4.72 (dd, 1H, J = 5.8,1.1Hz),
4.56 (d, 1H, J = 5.8Hz), 4.52 (ddd, 1H, J = 7.6,5.8,1.1Hz), 4.
27 (d, 1H, J = 9.8Hz), 4.12 (dd, 1H, J = 11.2,5.8Hz), 4.05 (dd,
1H, J = 11.2,7.6Hz), 4.02 (d, 1H, J = 9.8Hz), 2.45 (s, 3H), 1.4
3 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H), 1.30 (s, 3H) .MS (m / z) 429 (M ⁺ ), 414,371,356,313,296,242,216,198,17
1. 6-O- [bis (p-toluenesulfonyl) amino]-
1,2: 3,4-di-O-isopropylidene-D-psicofuranose ¹ H-NMR (200MHz, CDCl ₃ ) δ: 7.66 (d, 4H, J = 8.4Hz), 7.19 (d,
4H, J = 8.4Hz), 4.84 (d, 1H, J = 5.8Hz), 4.62 (d, 1H, J = 5.8Hz),
4.29 (d, 1H, J = 9.8Hz), 4.32-4.21 (m, 3H), 4.05 (d, 1H, J = 9.8
Hz), 2.42 (s, 6H), 1.46 (s, 3H), 1.42 (s, 3H), 1.38 (s, 3H), 1.
34 (s, 3H) .MS (m / z) 583 (M ⁺ ), 568,525,411,370,299,270,238,185.

[0252]

Example 33 1,2: 3,4-di-
12 ml of a solution of O-isopropylidene-6-O-amino-D-psicofuranose (1.22 g, 4.43 mmol) in dichloroethane
To this, pyridine (0.43 ml, 5.3 mmol) and dimethylsulfamoyl chloride (0.57 ml, 5.3 mmol) were added at 0 ° C, and the mixture was heated to 70 ° C and stirred for 9 hours. The reaction was stopped by pouring water, the mixture was extracted 3 times with methylene chloride, the organic layer was washed once with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain the desired product 1,
2: 3,4-di-O-isopropylidene-6-O-dimethylaminosulfonylamino-D-psicofuranose 1.
18 g (70% yield) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.45 (br.s, 1H),
4.75 (d, 1H, J = 5.8Hz), 4.61 (d, 1H, J = 5.8Hz), 4.30 (dd, 1H, J
= 7.2,5.9Hz), 4.30 (d, 1H, J = 9.9Hz), 4.08 (dd, 1H, J = 11.2,
5.9Hz), 4.04 (d, 1H, J = 9.9Hz), 4.02 (dd, 1H, J = 11.2,7.2H
z), 2.99 (s, 6H), 1.45 (s, 6H), 1.38 (s, 3H), 1.32 (s, 3H) .MS (m / z) 382 (M ⁺ ), 367,324,309,266,229,208,168.

[0254]

Example 34 1,2,3,4-di-obtained in Example 22
O-isopropylidene-6-O-amino-D-psicofuranose (121.4 mg, 0.441 mmol) was added to acetonitrile (4.
This was dissolved in 0 ml), methanesulfonic acid (14 μl, 0.22 mmol) was added, and the mixture was stirred at room temperature for 14 hours. Dilute aqueous ammonia was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate three times.
The combined organic layer was washed with saturated brine and dried (Na ₂ SO ₄ ).
After concentration, the product was purified by silica gel chromatography (ethyl acetate: hexane = 1: 1) to obtain the desired product [1R, 5
R, 6R, 7R] -2-Aza-3,8-dioxa-1-
6.5 mg of hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (yield 7%)
Obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.94 (d, 1H, J = 5.
8Hz), 4.92 (d, 1H, J = 5.8Hz), 4.35 (s, 1H), 3.95 (d, 1H, J = 11.
0Hz), 3.82 (d, 1H, J = 11.8Hz), 3.76 (d, 1H, J = 11.8Hz), 3.70
(d, 1H, J = 11.0Hz), 3.02 (br.s, 2H), 1.50 (s, 3H), 1.37 (s, 3
H) .MS (m / z) 217 (M ⁺ ), 202,159,149,126.

[0256]

Example 35 [1R, 5R, 6R, obtained in Example 34,
7R] -2-Aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (115 mg, 530 μmol) in acetonitrile (1 ml) was added with chloro at 0 ° C. Add 1 ml of methyl formate,
Stir at room temperature for 24 hours. The reaction was stopped by adding water, the mixture was extracted with ethyl acetate three times, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product [1R, 5R, 6
R, 7R] -2-Aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-
65.7 mg (yield 45%) of N-methoxycarbonylbicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.97 (1 H, d, J = 5.
6Hz), 4.91 (1H, d, J = 5.6Hz), 4.39 (1H, m), 4.26 (1H, dd, J = 6.
5,12.6Hz), 4.19 (1H, dd, J = 1.4,11.5Hz), 4.03 (1H, dd, J = 9.
7,12.6Hz), 3.84 (3H, s), 3.72 (1H, dd, J = 1.2,11.5Hz), 3.32
. (1H, dd, J = 6.5,9.7Hz), 1.51 (3H, s), 1.40 (3H, s) 1 H-NMR (200MHz, CDCl 3 + D 2 O) δ: 4.96 (1H, d ，
J = 5.6 Hz), 4.91 (1H, d, J = 5.6H)
z), 4.39 (1H, m), 4.25 (1H, d, J
= 12.6 Hz), 4.19 (1H, dd, J = 1.
4, 11.5 Hz), 4.02 (1H, d, J = 12.
6 Hz), 3.84 (3H, s), 3.72 (1H, d
d, J = 1.2, 11.5 Hz), 1.51 (3H,
s), 1.39 (3H, s). MS (m / z) 275 (M ⁺ ), 260, 217, 1
59, 126, 69, 59, 44.

[0258]

Example 36 1,2: 3,4-di-obtained in Example 25
O-isopropylidene-6-O-phenoxycarbonylamino-D-psicofuranose (481.0 mg, 1.
216 mmol) in 5 ml of acetonitrile, concentrated sulfuric acid (7 μl, 10 mmol) was added at room temperature, and at the same temperature, 2.5
Stir for time. Water was added to the reaction solution, extracted with ethyl acetate, washed with brine, dried and concentrated, and silica gel column chromatography (hexane: ethyl acetate = 4: 1).
And then the desired product [4R, 5R, 6R, 7R] -1-
Aza-5,6-isopropylidenedioxy-2,9,1
1-trioxatridecane cyclo [5.3.0.1 ^{4, 7]} undecane-10-one to give 243.4mg (82.3% yield).

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.07 (d, 1H, J = 5.
3Hz), 4.95 (d, 1H, J = 5.3Hz), 4.46 (d, 1H, J = 10.3Hz), 4.33
(t, 1H, J = 1.8Hz), 4.31 (d, 1H, J = 10.3Hz), 4.30 (dd, 1H, J = 1
2.2,1.8Hz), 3.81 (dd, 1H, J = 12.2,1.8Hz), 1.48 (s, 3H), 1.3
8 (s, 3H) .MS (m / z) 244 (M + 1), 228,205,185,175,149,126.

[0260]

Example 37 1,2: 3,4-di-obtained in Example 30
To 5 ml of a solution of O-isopropylidene-6-O- (3,3-dimethylureido) -D-psicofuranose (188 mg, 542 μmol) in dichloroethane was added methanesulfonic acid (18 μl, 0.2 μl).
27 mmol) was added, and the mixture was stirred at 70 ° C. for 7 hours and a half. The reaction was stopped by pouring water, the mixture was extracted 3 times with methylene chloride, the organic layer was washed once with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired product [4R, 5R, 6R, 7R] -1-aza-5. , 6-isopropylidenedioxy-2,9,11-
Trioxatridecane cyclo [5.3.0.1 ^{4, 7]} to obtain undecane-10-one 43.4 mg (33% yield).

The instrument data were in agreement with those of Example 36.

[0262]

Example 38 [4R, 5R, 6R, obtained in Example 36,
7R] -1-Aza-5,6-isopropylidenedioxy-2,9,11-trioxatricyclo [5.3.0.
1 ^4,7 ] undecan-10-one (1.14 g, 4.70 mol) in methanol (MeOH) (10 ml) was added with 10 ml of 1N NaOH aqueous solution.
l was added and the mixture was stirred at 50 ° C. for 1 hour and a half. 1N hydrochloric acid (HCl)
An aqueous solution was added to neutralize the reaction solution, which was extracted 5 times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4) to obtain the desired product [1R, 5R, 6R, 7R] -2-aza-3. , 8-Dioxa-1-hydroxymethyl-6,7-
873 mg (yield 86%) of isopropylidenedioxybicyclo [3.2.1] octane was obtained.

The instrument data were in agreement with those of Example 34.

[0264]

Example 39 1,2,3,4-di-obtained in Example 10
O-isopropylidene-6-O-methoxycarbonylamino-D-psicofuranose (4.33 g, 13.0 mmol) was dissolved in dichloroethane, and methanesulfonic acid (0.42 ml) was added at room temperature.
Was added and stirred for 30 minutes. Water was added to this reaction solution,
Extract with methylene chloride, wash with brine, dry and concentrate, then silica gel column chromatography (hexane:
Purify with ethyl acetate = 2: 1 → 2: 3) to obtain the desired product [1
R, 5R, 6R, 7R] -2-Aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo [3.
2.1] Octane (3.215 g, yield 90%) was obtained.

The equipment data were in agreement with those of Example 35.

[0266]

Example 40 1,2,3,4-di-obtained in Example 12
O-isopropylidene-6-O-ethoxycarbonylamino-D-psicofuranose (5.26 g, 15.1 mmol) was dissolved in acetonitrile (50 ml), 0.04 ml of concentrated sulfuric acid was added at room temperature, and the mixture was stirred for 4 hours. Water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to obtain the desired product [1R, 5R, 6R, 7R] -2-aza-3,8-
3.00 g (yield 68%) of dioxa-2-N-ethoxycarbonyl-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.97 (1 H, d, J = 5.
6Hz), 4.91 (1H, d, J = 5.6Hz), 4.39 (1H, m), 4.29 (2H, q, J = 7.1
Hz), 4.25 (1H, dd, J = 6.4,12.6Hz), 4.20 (1H, dd, J = 1.4,11.6
Hz), 4.03 (1H, dd, J = 9.7,12.6Hz), 3.72 (1H, dd, J = 1.2,11.6
Hz), 3.35 (1H, dd, J = 6.4,9.7Hz), 1.52 (3H, s), 1.40 (3H, s),
1.35 (3H, t, J = 7.1Hz). ¹ H-NMR (200MHz, CDCl ₃ + D ₂ O) δ: 4.96 (1H, d, J = 5.6Hz), 4.9
1 (1H, d, J = 5.6Hz), 4.39 (1H, m), 4.29 (2H, q, J = 7.1Hz), 4.24
(1H, d, J = 12.6Hz), 4.20 (1H, dd, J = 1.4,11.5Hz), 4.02 (1H,
d, J = 12.6Hz), 3.72 (1H, dd, J = 1.2,11.5Hz), 1.51 (3H, s), 1.
40 (3H, s), 1.35 (3H, t, J = 7.1Hz) .MS (m / z) 289 (M ⁺ ), 274,231,173,126,69,59,44.

[0268]

Example 41 1,2,3,4-di-obtained in Example 14
O-isopropylidene-6-O-isopropyloxycarbonylamino-D-psicofuranose (1.58 g, 4.37 mmo
l) was dissolved in acetonitrile (16.0 mL), concentrated sulfuric acid (0.02 ml, 0.9 mmol) was added at room temperature, and the mixture was stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ) and concentrated, and the crude product was purified by silica gel chromatography (ethyl acetate: hexane = 1: 3) to give the desired product [1R , 5
R, 6R, 7R] -2-Aza-3,8-dioxa-1-
0.93 g (yield 70%) of hydroxymethyl-6,7-isopropylidenedioxy-2-N-isopropyloxycarbonylbicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ + D ₂ O) δ: 5.06 (1 H, q
q, J = 6.3,6.3Hz), 4.95 (1H, d, J = 5.6Hz), 4.90 (1H, d, J = 5.6H
z), 4.38 (1H, brd.s), 4.23 (1H, d, J = 12.5Hz), 4.17 (1H, dd, J
= 1.3,12.6Hz), 4.01 (1H, d, J = 12.6Hz), 3.70 (1H, dd, J = 1.3,
12.6Hz), 1.51 (3H, s), 1.40 (3H, s), 1.34 (3H, d, J = 6.3Hz),
1.32 (3H, d, J = 6.3Hz) .MS (m / z) 303 (M ⁺ ), 288,244,217,159,149,126,69,59,44.

[0270]

Example 42 1,2,3,4-di-obtained in Example 16
O-isopropylidene-6-O-isobutyloxycarbonylamino-D-psicofuranose (147.9 mg, 0.394 mm
To a solution of dichloroethane (5 ml) in which ol) was dissolved, methanesulfonic acid (13 μl, 0.20 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to this reaction solution, which was extracted with ethyl acetate, washed with brine, dried and concentrated, and then subjected to silica gel column chromatography (hexane: ethyl acetate = 4:
1 → 3: 1) and then the desired product [1R, 5R, 6R,
7R] -2-Aza-3,8-dioxa-1-hydroxymethyl-2-N-isobutyloxycarbonyl-6,7
77.0 mg (yield 62%) of isopropylidenedioxybicyclo [3.2.1] octane were obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.97 (1 H, d, J = 5.
6Hz), 4.91 (1H, d, J = 5.6Hz), 4.39 (1H, br.s), 4.29-4.16 (2
H, m), 4.08-3.93 (3H, m), 3.72 (1H, br.d, J = 11.6Hz), 3.34 (1
H, dd, J = 6.5,9.8Hz), 2.02 (1H, qq, J = 6.6Hz), 1.51 (3H, s),
1.40 (3H, s), 0.97 (6H, d, J = 6.6Hz). ¹ H-NMR (200MHz, CDCl ₃ + D ₂ O) δ: 4.97 (1H, d, J = 5.6Hz), 4.9
1 (1H, d, J = 5.6Hz), 4.39 (1H, br.s), 4.23 (1H, d, J = 12.5Hz),
4.19 (1H, br.d, J = 11.7Hz), 4.06-3.93 (2H, m), 4.01 (1H, d, J
= 12.5Hz), 3.72 (1H, br.d, J = 11.7Hz), 2.02 (1H, qq, J = 6.6H
z), 1.51 (3H, s), 1.40 (3H, s), 0.96 (6H, d, J = 6.6Hz) .MS (m / z) 317 (M ⁺ ), 302,259,167,149,126,69,57,42.

[0272]

Example 43 6-O-benzyloxycarbonylamino-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (6.18 g, 15.1 mmol) obtained in Example 26 was added to acetonitrile (100 ml). ), And add concentrated sulfuric acid at room temperature.
(0.20 mL) was added and the mixture was stirred for 5 hours. Add water to the reaction mixture,
Extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ) and concentrated, and then silica gel column chromatography (ethyl acetate: hexane = 1: 3).
And then the desired product [1R, 5R, 6R, 7R] -2-
4.59 g of aza-2-N-benzyloxycarbonyl-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane
(Yield 80%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ + D ₂ O) δ: 7.38 (5 H,
s), 5.32-5.17 (2H, m), 4.97 (1H, d, J = 5.5Hz), 4.90 (1H, d, J =
5.5Hz), 4.38 (1H, m), 4.26 (1H, d, J = 12.5Hz), 4.18 (1H, d, J =
11.6Hz), 4.02 (1H, d, J = 12.5Hz), 3.71 (1H, d, J = 11.6Hz), 1.
51 (3H, s), 1.39 (3H, s) .MS (m / z) 349 (M ⁺ ), 334,290,260,216,113,92,69,59,44.

[0274]

[Embodiment 44] The procedure of embodiment 27 is repeated in the same manner as that of embodiment 39.
6-O-acetamido-1,2: 3,4-di-O obtained in
-Isopropylidene-D-psicofuranose (192 mg, 604
μmol) to the desired product [1R, 5R, 6R, 7R] -2-
8.6 mg (yield 5.5%) of aza-2-N-acetyl-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.93 (d, 1H, J = 5.
6Hz), 4.91 (d, 1H, J = 5.6Hz), 4.36 (t, 1H, J = 0.7Hz), 4.35 (d,
1H, J = 8.1Hz), 4.21 (d, 1H, J = 8.1Hz), 3.96 (dd, 1H, J = 11.0,
0.7Hz), 3.69 (dd, 1H, J = 11.0,0.7Hz), 2.11 (s, 3H), 1.88 (1
H, br.s), 1.49 (s, 3H), 1.37 (s, 3H) .MS (m / z) 259 (M ⁺ ), 244,219,201,175,149,126.

[0276]

[Embodiment 45] The operation of embodiment 28 is carried out in the same manner as in embodiment 39.
6-O-benzamide-1,2: 3,4-di-O obtained in
-Isopropylidene-D-psicofuranose (241 mg, 635
μmol) to the desired product [1R, 5R, 6R, 7R] -2-
Aza-2-N-benzoyl-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane 42.7 mg (yield 21%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.08-8.03 (m, 2
H), 7.62-7.41 (m, 3H), 5.01 (d, 1H, J = 5.6Hz), 4.94 (d, 1H, J =
5.6Hz), 4.62 (d, 1H, J = 12.2Hz), 4.47 (d, 1H, J = 12.2Hz), 4.3
9 (t, 1H, J = 1.4Hz), 3.98 (dd, 1H, J = 11.6,1.4Hz), 3.96 (br.
s, 1H), 3.72 (dd, 1H, J = 11.6,1.4Hz), 1.52 (s, 3H), 1.39 (s, 3
H) .MS (m / z) 321 (M ⁺ ), 306,279,263,216,163,149.

[0278]

Example 46 1,2: 3,4-di-obtained in Example 31
A solution of O-isopropylidene-6-O-methanesulfonylamino-D-psicofuranose (209 mg, 592 μmol) in dichloroethane (5 ml) was added with methanesulfonic acid (19 μl, 0.30).
mmol) was added dropwise, and the mixture was stirred at room temperature for 90 minutes. The reaction was stopped by pouring water, the mixture was extracted 3 times with methylene chloride, the organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel chromatography (hexane: ethyl acetate = 2: 3).
And then the desired product [1R, 5R, 6R, 7R] -2-
Aza-3,8-dioxa-1-hydroxymethyl-6,
135 mg of 7-isopropylidenedioxy-2-N-methanesulfonylbicyclo [3.2.1] octane (yield 77
%) Was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.97 (d, 1H, J = 5.
5Hz), 4.89 (d, 1H, J = 5.5Hz), 4.80 (dd, 1H, J = 11.4,0.9Hz),
4.46 (t, 1H, J = 0.9Hz), 4.30 (d, 1H, J = 13.2Hz), 4.03 (d, 1H, J
= 13.2Hz), 3.71 (dd, 1H, J = 11.4,0.9Hz), 3.16 (s, 3H), 2.61
(br.s, 1H), 1.50 (s, 3H), 1.39 (s, 3H) .MS (m / z) 295 (M ⁺ ), 280,266,237,216,179,149,126.

[0280]

[Example 47] The same operation as Example 39 was carried out to obtain Example 32.
1,2,3,4-di-O-isopropylidene-6 obtained in
From —O-p-toluenesulfonylamino-D-psicofuranose (121 mg, 281 μmol), the target compound [1R, 5R, 6
R, 7R] -2-Aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-
73.5 mg (71% yield) of Np-toluenesulfonylbicyclo [3.2.1] octane were obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.84 (d, 2H, J = 8.
4Hz), 7.35 (d, 2H, J = 8.4Hz), 4.93 (d, 1H, J = 5.6Hz), 4.79 (d,
1H, J = 5.6Hz), 4.62 (dd, 1H, J = 11.5,1.1Hz), 4.47 (d, 1H, J = 1
2.9Hz), 4.39 (t, 1H, J = 1.1Hz), 4.12 (d, 1H, J = 12.9Hz), 4.08
(br.s, 1H), 3.52 (dd, 1H, J = 11.5,1.1Hz), 2.46 (s, 3H), 1.51
(s, 3H), 1.36 (s, 3H) .MS (m / z) 371 (M ⁺ ), 356,313,295,279,252,216,155,126.

[0282]

[Embodiment 48] The procedure of embodiment 33 is repeated in the same manner as that of embodiment 39.
1,2,3,4-di-O-isopropylidene-6 obtained in
From -O-dimethylaminosulfonylamino-D-psicofuranose (407 mg, 1.06 mmol), the target compound [1R, 5R,
6R, 7R] -2-Aza-2-N-dimethylaminosulfonyl-3,8-dioxa-1-hydroxymethyl-
6,7-Isopropylidene dioxybicyclo [3.2.
1] Octane (296 mg, yield 86%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.00 (d, 1 H, J = 5.
6Hz), 4.86 (d, 1H, J = 5.6Hz), 4.79 (dd, 1H ,, J = 11.4,0.9Hz),
4.42 (t, 1H, J = 0.9Hz), 4.16 (d, 1H, J = 12.9Hz), 3.99 (d, 1H, J
= 12.9Hz), 3.59 (dd, 1H, J = 11.4,0.9Hz), 2.96 (s, 6H), 2.74
(br.s, 1H), 1.51 (s, 3H), 1.39 (s, 3H) .MS (m / z) 324 (M ⁺ ), 309,266,216,166,126.

[0284]

Example 49 Methylene chloride (100 ml) containing oxalyl chloride (4.0 ml, 45.5 mmol) was cooled to -50 ° C or lower, and a solution of dimethyl sulfoxide (6.46 ml, 91 mmol) in methylene chloride (120 ml) was added. [1R, 5R, 6R, 7R] -2 obtained in Example 39 after stirring at the same temperature for 20 minutes
-Aza-3,8-dioxa-1-hydroxymethyl-
6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo [3.2.1] octane (5.01 g, 18.
125 ml of a methylene chloride solution containing 2 mmol) was added.
Stir for 30 minutes at the same temperature, triethylamine (20.3 ml, 145 m
mol) was added, the temperature was gradually raised, and the mixture was stirred at 0 ° C. for 30 minutes. Aqueous ammonium chloride (NH ₄ Cl aq) was added to this reaction solution, extracted with methylene chloride, washed with 1N-HCl and brine, dried and concentrated to obtain 5.86 g of a crude product. This was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 2) to obtain the desired product [1S, 5
R, 6R, 7R] -2-Aza-3,8-dioxa-1-
3.928 g (yield 77%) of formyl-2-N-methoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.38 (1 H, s), 5.2
5 (1H, d, J = 5.5Hz), 4.97 (1H, d, J = 5.5Hz), 4.55 (1H, m), 4.22
(1H, dd, J = 1.5,11.9Hz), 3.85 (3H, s), 3.72 (1H, dd, J = 1.2,1
1.9Hz), 1.44 (3H, s), 1.34 (3H, s) .MS (m / z) 273 (M ⁺ ), 258,157,142,85,73,59,44.

[0286]

Example 50 Oxalyl chloride (4.0 ml, 46.1 mmol)
Was dissolved in methylene chloride (110 ml) at -60 ° C,
A solution of dimethyl sulfoxide (5.4 ml, 77 mmol) in methylene chloride (5 ml) was added dropwise. After stirring for 15 minutes,
[1R, 5R, 6R, 7R] -2-aza-3,8-dioxa-2-N-ethoxycarbonyl-obtained in Example 40
1-Hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (11.12g, 38.4mmo
A solution of l) in methylene chloride (15 ml) is -60
The mixture was added dropwise at 0 ° C. and stirred for 30 minutes. Triethylamine (16.
1 ml, 115 mmol) was added at −60 ° C. and stirred for 15 minutes, then 0
The temperature was raised to ℃ and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The combined organic layers were washed with diluted hydrochloric acid and half-saturated saline, dried (Na ₂ SO ₄ ), concentrated, and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain the desired product [1S, 5R, 6
R, 7R] -2-Aza-2-N-ethoxycarbonyl-
3,8-dioxa-1-formyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane was added to 10.8
2 g (yield 98%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.39 (1 H, s), 5.6
2 (1H, d, J = 5.5Hz), 4.97 (1H, d, J = 5.5Hz), 4.55 (1H, br.s),
4.30 (2H, q, J = 7.1Hz), 4.23 (1H, dd, J = 1.5,11.9Hz), 3.72 (1
H, dd, J = 1.1,11.9Hz), 1.45 (3H, s), 1.35 (3H, s), 1.32 (3H,
t, J = 7.1Hz) .MS (m / z) 287 (M ⁺ ), 272,171,98,85,71,59,44.

[0288]

Example 51 Oxalyl chloride (1.1 ml, 13 mmol)
Dissolve in methylene chloride (50 ml), and at -60 ° C, a solution of dimethyl sulfoxide (1.7 ml, 23 mmol) in methylene chloride (3.7
ml) was added. After stirring for 15 minutes, the product obtained in Example 43 [1
R, 5R, 6R, 7R] -2-Aza-2-N-benzyloxycarbonyl-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane ( A solution of 4.12 g (11.7 mmol) in methylene chloride (14 ml) was added at -60 ° C, and the mixture was stirred for 30 minutes. Triethylamine (5.4 ml, 39 mmol) was added at -60 ° C, and the mixture was stirred for 15 minutes, then heated to 0 ° C and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The combined organic layers were washed with diluted hydrochloric acid and half-saturated saline,
After drying (Na ₂ SO ₄ ), concentration, purification by silica gel column chromatography (ethyl acetate: hexane = 1: 2),
Target [1S, 5R, 6R, 7R] -2-Aza-2-N
-Benzyloxycarbonyl-3,8-dioxa-1-
Formyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (3.77 g, yield 92%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.38 (1 H, s), 7.3
6 (5H, s), 5.25 (2H, ABq, J = 12.7Hz), 5.25 (1H, d, J = 5.4Hz),
4.96 (1H, d, J = 5.4Hz), 4.54 (1H, br.s), 4.17 (1H, dd, J = 1.3,
11.6Hz), 3.69 (1H, br.d, J = 11.6Hz), 1.44 (3H, s), 1.34 (3H,
s).

[0290]

Example 52: Oxalyl chloride (0.80 ml, 9.1 mmol)
Was dissolved in methylene chloride (25 ml), and a solution of dimethyl sulfoxide (1.10 ml, 15.2 mmol) in methylene chloride (2.0 ml) was added at -60 ° C. After stirring for 15 minutes, [1R, 5R, 6R, 7R] -2-aza-3,8-obtained in Example 46.
A solution of dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-N-methanesulfonylbicyclo [3.2.1] octane (2.24 g, 7.58 mmol) in methylene chloride (5 ml) was added, and the mixture was added for 15 minutes. Stirred. Furthermore, −
Triethylamine (3.20 ml, 22.7 mmol) was added at 60 ° C., and the mixture was stirred for 15 minutes, then the temperature was raised to 0 ° C. and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The combined organic layers were washed with diluted hydrochloric acid and half-saturated saline,
After drying (Na ₂ SO ₄ ), concentration, purification by silica gel column chromatography (ethyl acetate: hexane = 1: 1),
Object [1S, 5R, 6R, 7R] -2-aza-3,8
-Dioxa-1-formyl-6,7-isopropylidenedioxy-2-N-methanesulfonylbicyclo [3.
2.1] Octane (2.41 g, yield 90%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 9.39 (1 H, s), 5.1
8 (1H, d, J = 5.4Hz), 5.00 (1H, dd, J = 1.9,11.8Hz), 4.94 (1H,
d, J = 5.4Hz), 4.65 (1H, dd, J = 1.0,1.9Hz), 3.70 (1H, dd, J = 1.
0,11.8Hz), 3.09 (3H, s), 1.44 (3H, s), 1.34 (3H, s) .MS (m / z) 294 (M ⁺ +1), 278,214,162,149,79,59,44.

[0292]

[Example 53] [1R, 5R, 6R, obtained in Example 40]
7R] -2-aza-3,8-dioxa-2-N-ethoxycarbonyl-1-hydroxymethyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane
(1.0018g, 3.463mmol) and 2,2,6,6, -tetramethyl-1-piperidinyloxy free radical (TEMP
O) (10 mg) dissolved in 10 ml of methylene chloride, potassium bromide 37.9 mg, tetra-n-butylammonium chloride
Saturated sodium hydrogencarbonate solution in which 50.6 mg was dissolved was added, and sodium hypochlorite aqueous solution [1.2M] 3.5 ml was added at 0 ° C.
1.7 ml of saturated aqueous sodium hydrogen carbonate solution and saturated saline 3.
5 ml of the mixed solution was added over 9 minutes. After stirring at 0 ° C for 40 minutes, the mixture was stirred at room temperature for 40 minutes, 1.7 ml of an aqueous solution of sodium hypochlorite was added, and the mixture was stirred at the same temperature for 45 minutes. The reaction solution was adjusted to pH 2 with 1N-NCl, extracted with ethyl acetate, dried, concentrated, and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product [1S, 5R, 6R, 7R]- 2-aza-2-N-ethoxycarbonyl-3,8-dioxa-1-formyl-
6,7-Isopropylidene dioxybicyclo [3.2.
1] Octane (637.6 mg, yield 64%) was obtained.

The equipment data were in agreement with those of Example 50.

[0294]

Example 54 [1R, 5R, 6R, obtained in Example 39
7R] -2-Aza-3,8-dioxa-1-hydroxymethyl-6,7-isopropylidenedioxy-2-N-
Methoxycarbonylbicyclo [3.2.1] octane (4
52.6mg, 1.644mmol) and TEMPO (10mg) dissolved in methylene chloride (4ml), potassium bromide (18mg), tetra-n-butylammonium chloride (24.2mg) in saturated sodium hydrogen carbonate solution (3.3ml) Then, a mixed solution of an aqueous solution of sodium hypochlorite ([1.2M] 4.5 ml), a saturated aqueous solution of sodium hydrogencarbonate (2.25 ml) and saturated saline solution (4.5 ml) was added at 0 ° C over 15 minutes. After stirring at 0 ° C. for 40 minutes, the mixture was stirred at room temperature for 20 minutes, an aqueous sodium sulfite solution was added, and the mixture was adjusted to pH 2 with 1N-NCl and extracted with ethyl acetate. The obtained ethyl acetate layer was dried, concentrated, and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product [1S, 5R, 6R, 7R] -2-aza-
272.6 mg (yield 61%) of 3,8-dioxa-1-formyl-2-N-methoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane were obtained.

Instrument data were consistent with that of Example 49.

[0296]

Example 55 [1S, 5R, 6R, obtained in Example 49
7R] -2-aza-3,8-dioxa-1-formyl-
2-N-methoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (1.0025 g,
3.669 mmol) of water (5 ml) -1,4-dioxane (20 m
dissolved in a mixed solvent of l), sodium dihydrogen phosphate dihydrate at _{55 ℃ (NaH 2 PO 4 ·} 2H 2 O) (1.171g), sodium chlorite (NaClO ₂₎ (1.659g) Add 15 ml of aqueous solution,
The mixture was stirred at the same temperature for 5 hours. Furthermore, NaH ₂ PO ₄・ 2H ₂ O (859m
g) and 5 ml of an aqueous solution of NaClO ₂ (829 mg) were added, and the mixture was stirred with heating for 1.5 hours. Sodium sulfite (Na
₂ SO ₃ ) aqueous solution was added to adjust pH to 3 with 1N-NCl, extracted with ethyl acetate, dried and concentrated to give the desired product [1S, 5R, 6R, 7R].
-2-aza-1-carboxy-3,8-dioxa-6,
1.01 g (yield 95%) of a crude product of 7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.25 (1 H, d, J = 5.
5Hz), 4.96 (1H, d, J = 5.5Hz), 4.59 (1H, m), 4.20 (1H, dd, J = 1.
5,11.9Hz), 3.85 (3H, s), 3.69 (1H, dd, J = 0.9,11.9Hz), 1.49
(3H, s), 1.38 (3H, s) .MS (m / z) 289 (M ⁺ ), 274,214,142,73,69,59,44.

[0298]

Example 56 [1S, 5R, 6R, obtained in Example 50]
7R] -2-aza-2-N-ethoxycarbonyl-3,
8-Dioxa-1-formyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (3.41 g, 11.
9 mmol) was dissolved in 1,4-dioxane (20 ml), and an aqueous solution of sodium chlorite (4.83 ml, 53.4 mmol) and sodium dihydrogen phosphate dihydrate (4.45 g, 29.7 mmol) at room temperature ( 15 ml) was added. After stirring at 55 ° C. for 1 hour, saturated sodium sulfite aqueous solution was added to decompose generated chlorine. After concentrating the reaction solution, [1N] sodium hydride aqueous solution (15 ml) was added, and the aqueous layer was ether (50 ml × 2).
Washed with. The aqueous layer was adjusted to pH 3 with [4N] hydrochloric acid, 10 g of sodium chloride was further added, and the mixture was stirred. The aqueous layer was extracted 6 times with ethyl acetate, the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give the desired product [1S, 5R, 6R, 7R] -2-aza-1-carboxy-3, 8-dioxa-2-N-ethoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.
2.1] Octane (2.75 g, yield 76%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.36 (1 H, br.),
5.23 (1H, d, J = 4.8Hz), 4.96 (1H, dd, J = 0.9,5.4Hz), 4.58 (1
H, br.s), 4.29 (2H, q, J = 7.6Hz), 4.20 (1H, d, J = 11.9Hz), 3.6
8 (1H, d, J = 11.9Hz), 1.47 (3H, s), 1.37 (3H, s), 1.25 (3H, t, J
= 7.6Hz) .MS (m / z) 303 (M ⁺ ), 268,173,142,126,83,69,59,44.

[0300]

Example 57 [1S, 5R, 6R, obtained in Example 51
7R] -2-aza-2-N-benzyloxycarbonyl-3,8-dioxa-1-formyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (3.7
7 g, 10.8 mmol) was dissolved in 1,4-dioxane (40 ml) and sodium dihydrogen phosphate dihydrate (3.24 g, 21.6 mmo)
l) and an aqueous solution (38 ml) of sodium chlorite (4.40 g, 48.6 mmol) were added. After stirring at 60 ° C. for 2 hours, a saturated sodium sulfite aqueous solution was added to decompose generated chlorine.
After concentrating the reaction solution, [1N] sodium hydroxide aqueous solution (1
5 ml) was added and the aqueous layer was washed with ether (50 ml). The aqueous layer was adjusted to pH 3 with diluted hydrochloric acid, and the aqueous layer was adjusted to 6 with ethyl acetate.
Extracted twice, the combined organic layers were dried (Na ₂ SO ₄ ), concentrated, and the desired product [1S, 5R, 6R, 7R] -2-aza-2-N-
Benzyloxycarbonyl-1-carboxy-3,8-
3.65 g (yield 92%) of dioxa-6,7-isopropylidenedioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.38-7.31 (5H,
m), 6.40 (1H, br.s), 5.24 (2H, ABq, J = 12.0Hz), 5.24 (1H, d, J
= 5.5Hz), 4.95 (1H, d, J = 5.5Hz), 4.57 (1H, m), 4.14 (1H, dd, J
= 1.1,12.0Hz), 3.66 (1H, br.d, J = 12.0Hz), 1.47 (3H, s), 1.3
6 (3H, s) .MS (m / z) 365 (M ⁺ ), 350,321,234,176,91,69,59.

[0302]

Example 58 [1S, 5R, 6R, obtained in Example 52]
7R] -2-aza-3,8-dioxa-1-formyl-
6,7-Isopropylidenedioxy-2-N-methanesulfonylbicyclo [3.2.1] octane (2.14g, 7.30m
mol) in 1,4-dioxane (10 ml), sodium dihydrogen phosphate dihydrate (2.27 g, 15.2 mmol), and an aqueous solution of sodium chlorite (3.30 g, 36.5 mmol) (10 m
l) was added. After stirring at 55 ° C. for 2 hours, saturated sodium sulfite aqueous solution was added to decompose generated chlorine. After concentrating the reaction solution, [1N] sodium hydroxide aqueous solution (10 ml)
Was added and the aqueous layer was washed with ether (50 ml). The aqueous layer was adjusted to pH 3 with diluted hydrochloric acid, extracted 6 times with ethyl acetate from the aqueous layer, the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give the desired product [1S, 5R, 6R, 7R] -2-aza. -1-Carboxy-3,8-dioxa-6,7-isopropylidenedioxy-2-N-methanesulfonylbicyclo [3.2.
1] Octane (2.02 g, yield 89%) was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.15 (1 H, d, J = 5.
4Hz), 4.96 (1H, dd, J = 1.6,13.5Hz), 4.93 (1H, d, J = 5.4Hz),
5.05-4.75 (1H, br.), 4.70 (1H, br.s), 3.68 (1H, d, J = 13.5H
z), 3.11 (3H, s), 1.48 (3H, s), 1.37 (3H, s) .MS (m / z) 309 (M ⁺ ), 294,279,250,230,145,85,79,59,44.

[0304]

Example 59 [1S, 5R, 6R, obtained in Example 55
7R] -2-Aza-1-carboxy-3,8-dioxa-6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo [3.2.1] octane (1.70 g,
5.62 mmol) is dissolved in methylene chloride (35.0 ml) and the temperature is 0 ° C.
, Pyridine (0.94 ml, 13 mmol), and thionyl chloride (0.7
4 ml, 10 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the concentrate was dissolved in methylene chloride (30 ml), and ammonia gas was introduced at 0 ° C. for 10 minutes. After stirring at room temperature for 1 hour, water was added to the reaction solution, and the mixture was mixed with ethyl acetate to 3 times.
Extracted twice. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ) and concentrated. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to obtain the desired product [1S, 5R, 6R, 7R] -2-aza-1-carbamoyl-3,8-dioxa-6,7-isopropyi. Ridenedioxy-2-N-methoxycarbonylbicyclo [3.
2.1] Octane (1.49 g, yield 92%) was obtained.

¹ H-NMR (200 MHz, DMSOd ₆ ) δ: 7.31 (1H, br.
s), 7.04 (1H, br.s), 5.00 (1H, d, J = 5.5Hz), 4.95 (1H, d, J = 5.
5Hz), 4.65 (1H, br.s), 3.95 (1H, dd, J = 1.4,11.8Hz), 3.82 (1
H, br.d, J = 11.8Hz), 3.72 (3H, s), 1.38 (3H, s), 1.30 (3H, s) .MS (m / z) 288 (M ⁺ ), 273,200,142,127,85,73 , 69,59,44.

[0306]

[Example 60] [1S, 5R, 6R, obtained in Example 56]
7R] -2-aza-1-carboxy-3,8-dioxa-2-N-ethoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (9.35 g, 3
0.8 mmol) is dissolved in ethyl acetate (100 ml) and the temperature is 0 ° C.
, Pyridine (4.5 ml, 62 mmol), and thionyl chloride (2.7 m
l, 37 mmol) was added. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The concentrate obtained here was suspended in methylene chloride (100 ml), and ammonia gas was introduced at 0 ° C. The reaction solution was further stirred at room temperature for 1 hour, water was added to the reaction solution, and the mixture was extracted 3 times with methylene chloride. The combined organic layers were washed with half-saturated saline, dried (Na ₂ SO ₄ ) and concentrated to give the desired product [1S, 5R, 6R, 7R] -2-aza-1-carbamoyl-3,8-dioxa-. 7.79 g (yield 84%) of 2-N-ethoxycarbonyl-6,7-isopropylidene dioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, DMSOd ₆ ) δ: 7.29
(1H, br.s), 7.04 (1H, br.s),
4.99 (1H, d, J = 5.5Hz), 4.94 (1
H, d, J = 5.5 Hz), 4.56 (1H, br.
s), 4.17 (2H, q, J = 7.0Hz), 3.9.
5 (1H, br.d, J = 11.5Hz), 3.82
(1H, br.d, J = 11.5Hz), 1.38 (3
H, s), 1.30 (3H, s), 1.23 (3H,
t, J = 7.0 Hz). MS (m / z) 303 (M ⁺ +1), 287, 23
0,172,99,85,70,57,44.

[0308]

Example 61 [1S, 5R, 6R, obtained in Example 57]
7R] -2-Aza-2-N-benzyloxycarbonyl-1-carboxy-3,8-dioxa-6,7-isopropylidenedioxybicyclo [3.2.1] octane (3.32 g, 9.09 mmol ) To ethyl acetate (5
0 ml) and at 0 ° C. pyridine (0.90 ml, 11 mmol),
And thionyl chloride (1.3 ml, 11 mmol) were added, and the mixture was stirred for 10 minutes. The mixture was brought to room temperature and stirred for 1.5 hours, ethyl acetate (100 ml) was added to the reaction solution, the temperature was brought to 0 ° C., and ammonia gas was introduced for 5 minutes. The mixture was brought to room temperature, stirred for 5 hours, water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with diluted hydrochloric acid and saturated brine, dried (Na ₂ SO ₄ ), concentrated, and then the desired product [1S, 5R, 6R, 7R] -2-aza-2-N-
Benzoyloxycarbonyl-1-carbamoyl-3,
2.52 g (yield 76%) of 8-dioxa-6,7-isopropylidenedioxybicyclo [3.2.1] octane was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.39-7.32 (5H,
m), 6.30 (1H, br.s), 5.52 (1H, br.s), 5.26 (1H, d, J = 5.4Hz),
5.25 (2H, s), 4.91 (1H, d, J = 5.4Hz), 4.53 (1H, m), 4.13 (1H, d
d, J = 1.4,12.0Hz), 3.67 (1H, dd, J = 1.1,12.0Hz), 1.47 (3H,
s), 1.37 (3H, s) .MS (m / z) 365 (M ⁺ +1), 349,232,203,190,177,132,106,91,6
9,59.

[0310]

Example 62 [1S, 5R, 6R, obtained in Example 58]
7R] -2-Aza-1-carboxy-3,8-dioxa-6,7-isopropylidenedioxy-2-N-methanesulfonylbicyclo [3.2.1] octane (1.87 g, 6.0
4 mmol) was dissolved in ethyl acetate (30 ml) and thionyl chloride (0.53 ml, 7.2 mmol) and pyridine (0.98 ml, 1) were added at 0 ° C.
2.8 mmol) was added, the mixture was brought to room temperature and stirred for 1 hour. Subsequently, ammonia gas was introduced into the reaction solution for 10 minutes and further stirred for 2 hours. Water was added to the reaction solution, and the aqueous layer was extracted 6 times with ethyl acetate. The combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ) and concentrated to give the desired product [1S, 5R, 6
R, 7R] -2-Aza-1-carbamoyl-3,8-dioxa-6,7-isopropylidenedioxy-2-N-
Add methanesulfonylbicyclo [3.2.1] octane to 0.
76 g (yield 41%) was obtained.

¹ H-NMR (200 MHz, DMSOd ₆ ) δ: 7.45 (1H, br.
s), 7.27 (1H, br.s), 4.95 (2H, s), 4.64 (1H, br.s), 4.58 (1H,
br.d, J = 11.7Hz), 3.86 (1H, br.d, J = 11.7Hz), 3.16 (3H, s),
1.38 (3H, s), 1.30 (3H, s) .MS (m / z) 308 (M ⁺ ), 293,276,250,129,123,65,69,59,44.

[0312]

Example 63 [1S, 5R, 6R, obtained in Example 61]
7R] -2-Aza-2-N-benzyloxycarbonyl-1-carbamoyl-3,8-dioxa-6,7-isopropylidenedioxybicyclo [3.2.1] octane
(296.3 mg) was dissolved in 6 ml of methanol and Pd /
30 mg of C (10%) was added, and hydrogenation reaction was carried out at 40 ° C. under normal pressure. The reaction solution was filtered through Celite and concentrated to give the desired product [1S, 5R, 6R, 7R] -2-aza-1.
18-carbamoyl-3,8-dioxa-6,7-isopropylidenedioxybicyclo [3.2.1] octane
0.0 mg (yield 96%) was obtained.

¹ H-NMR (200 MHz, DMSOd ₆ ) δ: 7.35 (1H, br.
s), 7.18 (1H, br.s), 6.90 (1H, s), 4.83 (2H, br.s), 4.33 (1H,
br.s), 3.80 (1H, d, J = 10.8Hz), 3.63 (1H, d, J = 10.8Hz), 1.37
(3H, s), 1.28 (3H, s) .MS (m / z) 230 (M ⁺ ), 215,172,125,85,69,59,44.

[0314]

Example 64 [1S, 5R, 6R, obtained in Example 63,
7S] -2-Aza-1-carbamoyl-3,8-dioxa-6,7-isopropylidenedioxybicyclo [3.
2.1] Octane (30.0 mg, 0.130 mmo
l) is dissolved in acetonitrile (1.0 ml) and the temperature is 0 ° C.
At, methyl chlorocarbonate (0.12 ml) and pyridine (0.12 ml) were added. The mixture was heated to 50 ° C., stirred for 3 hours, potassium hydroxide (85%) (0.10 g) dissolved in methanol (1.0 ml) was added, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was neutralized with water and diluted hydrochloric acid. The aqueous layer was extracted 3 times with ethyl acetate, the combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ) and concentrated, and the resulting crude product was subjected to silica gel chromatography (ethyl acetate: hexane). = 6: 1), the desired product [4R, 5R, 6R, 7
S] -1,9-diaza-2,11-dioxa-5,6-
Isopropylidene dioxytricyclo [5.3.0.1
1,5.9 mg (yield 48%) of ^4,7 ] undecane-8,10-dione was obtained.

¹ H-NMR (200 MHz, CD ₃ OD) δ: 5.12 (1 H, d, J = 5.
4Hz), 5.03 (1H, d, J = 5.4Hz), 4.44 (1H, dd, J = 1.4,1.6Hz), 4.
19 (1H, dd, J = 1.6,11.4Hz), 4.02 (1H, dd, J = 1.4,11.4Hz), 1.
15 (3H, s), 1.39 (3H, s) .MS (m / z) 256 (M ⁺ ), 241,166,155,125,110,85,69,59,54,4
Four.

[0316]

Example 65 [1S, 5R, 6R, obtained in Example 49
7R] -2-aza-2-N-methoxycarbonyl-3,
8-dioxa-1-formyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (108.8 mg,
0.398 mmol) was dissolved in 1,4-dioxane (2.0 ml), aqueous ammonia (28%, 0.5 ml) was added at room temperature, and the mixture was stirred for 1 hr. The reaction mixture is concentrated and purified by silica gel chromatography (ethyl acetate) to give the desired product [4R, 5
R, 6R, 7S] -1,9-diaza-2,11-dioxa-8-hydroxy-5,6-isopropylidenedioxytricyclo [5.3.0.1 ^4,7 ] undecane-10
59.7 mg (58%) of -one was obtained.

¹ H-NMR (200 MHz, CD ₃ OD) δ: 5.10 (1 H, d, J = 5.
4Hz), 4.99 (1H, d, J = 5.4Hz), 4.91 (1H, S), 4.25 (1H, br.t),
4.06 (1H, dd, J = 1.6,11.2Hz), 3.79 (1H, dd, J = 1.6,11.2Hz),
1.47 (3H, s), 1.39 (3H, s) .MS (m / z) 258 (M ⁺ ), 243,225,200,183,129,69,59,44.

[0318]

Example 66 [4R, 5R, 6R, obtained in Example 65,
7S] -1,9-diaza-2,11-dioxa-8-hydroxy-5,6-isopropylidenedioxytricyclo [5.3.0.1 ^4,7 ] undecan-10-one (0.5
7 g, 2.2 mmol) in acetone (10.0 ml), at room temperature,
Jones reagent (1.5 ml) was added, and the mixture was stirred at 40 ° C for 1 hr.
Ethyl acetate was added to the reaction solution, and the resulting insoluble material was filtered off. The filtrate was extracted three times with ethyl acetate, the combined organic layers were washed with saturated brine, dried (Na ₂ SO ₄ ) and concentrated.
The obtained crude product was purified by silica gel chromatography (ethyl acetate: hexane = 6: 1) to obtain the desired product [4
R, 5R, 6R, 7S] -1,9-diaza-2,11-
The dioxa-5,6-isopropylidenedioxy tricyclo [5.3.0.1 ^{4, 7]} undecane-8,10-dione 297.8mg (53% yield).

The instrument data matched that of Example 64.

[0320]

Example 67 [1S, 5R, 6R, obtained in Example 59]
7R] -2-aza-1-carbamoyl-3,8-dioxa-6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo [3.2.1] octane (200.2
mg, 0.6945 mmol) was dissolved in 4 ml of MeOH, and a solution of sodium methoxide in methanol [2M] (0.52 ml, 1.04) was added at room temperature.
mmol) was added, and the mixture was stirred at room temperature for 10 minutes and at 50 ° C. for 1 hour. Saturated saline was added to this reaction solution, which was neutralized with 1N-hydrochloric acid, extracted with ethyl acetate, dried and concentrated to give the desired product [4R,
5R, 6R, 7S] -1,9-diaza-2,11-dioxa-5,6-isopropylidenedioxytricyclo [5.3.0.1 ^4,7 ] undecane-8,10-dione was added to 160.0 mg (yield 90%) was obtained.

The instrument data matched that of Example 64.

[0322]

Example 68 [1S, 5R, 6R, obtained in Example 60]
7R] -2-aza-1-carbamoyl-3,8-dioxa-2-N-ethoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (6.12
g, 20.2 mmol) in methanol (65 ml), potassium hydroxide (85%) (1.47 g, 22.3 mmol) is added, and the temperature is 50 ° C.
At room temperature for 3 hours. The reaction mixture was concentrated, water was added, and the mixture was neutralized with diluted hydrochloric acid. The aqueous layer was extracted 3 times with ethyl acetate, the combined organic layers were washed with saturated brine, and dried (N
a ₂ SO ₄ ), concentrated. The obtained crude product was purified by silica gel chromatography (ethyl acetate: hexane = 6: 1) to obtain the desired product [4R, 5R, 6R, 7S] -1,9-diaza-2,11-dioxa-5. 6-isopropylidenedioxy tricyclo [5.3.0.1 ^{4, 7]} undecane-8,10-dione 4.52 g (87% yield).

The instrument data matched that of Example 64.

[0324]

Example 69 [4R, 5R, 6R, obtained in Example 64,
7S] -1,9-diaza-2,11-dioxa-5,6
-Isopropylidene dioxytricyclo [5.3.0.
1 ^4,7 ] Undecane-8,10-dione (1.4701g, 5.738m
mol) in 300 ml of ethanol, Raney nickel (5.2 g) is added, and hydrogen gas (4.5 kg / cm ² ) and 55
React at 5.5 ° C for 5.5 hours, filter through Celite, and concentrate to obtain the desired product [2R, 3R, 4R, 5S] -6,8-diaza-2.
1.0443 g (yield 95%) of -hydroxymethyl-3,4-isopropylidenedioxy-1-oxaspiro [4.4] nonane-7,9-dione was obtained.

¹ H-NMR (270 MHz, DMSO-d ₆ ) δ: 10.81 (1 H, s),
8.34 (1H, s), 5.06 (1H, t, J = 5.5Hz), 4.78-4.72 (2H, m), 4.32
-4.28 (1H, m), 3.51-3.46 (2H, m), 1.44 (3H, s), 1.25 (3H, s) .MS (m / z) 258 (M ⁺ ), 229,149,85,68,59 , 44.

[0326]

Example 70 [2R, 3R, 4R, obtained in Example 69,
5S] -6,8-diaza-2-hydroxymethyl-3,
4-Isopropylidenedioxy-1-oxaspiro [4.4] nonane-7,9-dione (480.9 mg, 1.862 mmo
l) is dissolved in acetonitrile (16 ml) at room temperature,
Acetic anhydride (0.60 ml, 4.7 mmol), pyridine (0.41 ml, 5.6 mmo
l) and dimethylaminopyridine (0.10g) were added, and 1 at the same temperature
Stir for time. Further, acetic anhydride (0.36 ml, 2.8 mmol) and pyridine (0.27 ml, 3.7 mmol) were added, and the mixture was stirred for 40 minutes. to this
1N-NCl was added, extracted with ethyl acetate, washed with brine, dried,
Concentrate and purify by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product [2R, 3
R, 4R, 5S] -2-Acetoxymethyl-6-N-acetyl-6,8-diaza-3,4-isopropylidenedioxy-1-oxaspiro [4.4] nonane-7,9-
593.0 mg (yield 93%) of dione was obtained.

¹ H-NMR (200 MHz, CDCl ₃ ) δ: 5.30 (1 H, d, J = 7.
0Hz), 4.93 (1H, dd, J = 4.3,7.0Hz), 4.68-4.61 (1H, m), 4.49
(1H, dd, J = 4.3,11.8Hz), 4.19 (1H, dd, J = 7.0,11.8Hz), 2.54
(3H, s), 2.10 (3H, s), 1.58 (3H, s), 1.32 (3H, s) .MS (m / z) 343 (M ⁺ +1), 327,243,183,126,86,69,44.

[0328]

Example 71 [2R, 3R, 4R, obtained in Example 70]
5S] -2-acetoxymethyl-6-N-acetyl-
6,8-diaza-3,4-isopropylidenedioxy-
1-oxaspiro [4.4] nonane-7,9-dione (2
54.0mg, 0.742mmol) was dissolved in methanol-water (5ml-2.5ml), Dowex 50W (H ⁺ ) (762mg) was added at room temperature, and the temperature was 50 ° C.
The mixture was heated to 40 ° C. and stirred at 70 ° C. for 2 hours for 40 minutes. The reaction solution was filtered through Celite, concentrated, and subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 5 →
Purification with ethyl acetate → ethyl acetate: methanol = 10: 1), [2R, 3S, 4R, 5S] -2-acetoxymethyl-6-N-acetyl-6,8-diaza-3,4-
Dihydroxy-1-oxaspiro [4.4] nonane-
8,9-dione 88.7 mg (yield 40%), [2R, 3S,
4R, 5S] -6-N-acetyl-6,8-diaza-
3,4-Dihydroxy-2-hydroxymethyl-1-oxaspiro [4.4] nonane-7,9-dione 72.1 mg
(Yield 37%) was obtained.

[2R, 3S, 4R, 5S] -2-acetoxymethyl-6-N-acetyl-6,8-diaza-3,
4-dihydroxy-1-oxaspiro [4.4] nonane-7,9-dione ¹ H-NMR (270 MHz, CD ₃ OD) δ: 5.06 (1 H, d, J = 6.5 Hz), 4.42-4.
36 (2H, m), 4.19-4.10 (2H, m), 2.49 (3H, s), 2.05 (3H, s) .MS (m / z) 302 (M ⁺ ), 260,182,157,145,128,86,57,44. [2R, 3S, 4R, 5S] -6-N-acetyl-6,6
8-Diaza-3,4-dihydroxy-2-hydroxymethyl-1-oxaspiro [4.4] nonane-7,9-dione ¹ H-NMR (200MHz, CD ₃ OD) δ: 5.03 (1H, d, J = 6.8Hz), 4.39-4.
32 (1H, m), 4.19-4.14 (1H, m), 3.76 (1H, dd, J = 4.3,12.1Hz),
3.67 (1H, dd, J = 5.2,12.1Hz), 2.54 (3H, s) .MS (m / z) 260 (M ⁺ ), 242,218,200,129,116,86,73,57,44.

[0330]

Example 72 [2R, 3S, 4R, obtained in Example 71
5S] -2-acetoxymethyl-6-N-acetyl-
6,8-Diaza-3,4-dihydroxy-1-oxaspiro [4.4] nonane-7,9-dione (190.0 mg, 0.69 m
hydrazine monohydrate (61 mol) in water (1.9 ml)
μl) was stirred at room temperature under pressure for 1 hour. The reaction solution was concentrated and purified with Diaion CHP-20P (water) to obtain 95 mg of hydantosidine (yield 69.3%).

[0331]

Example 73 [1S, 5R, 6R, obtained in Example 59]
7R] -2-Aza-1-carbamoyl-3,8-dioxa-6,7-isopropylidenedioxy-2-N-methoxycarbonylbicyclo [3.2.1] octane (234.8
mg, 1.029 mmol) in methanol (4 ml) -purified water (2 ml)
Dissolve in, add 1.17g of Dowex 50W (H ⁺ ), and add 1.
Add 0.7 g of Dowex 50W (H ⁺ ) for 5 hours, and add at 80 ℃ for 7.
Stir for 5 hours. The reaction solution was filtered through Celite and concentrated to give the desired product [1S, 5R, 6S, 7R] -2-aza-
1-carbamoyl-6,7-dihydroxy-3,8-dioxa-2-N-methoxycarbonylbicyclo [3.
2.1] octane was obtained in an amount of 248 mg (yield 97%).

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 7.22 (1 H, br.
s), 7.21 (1H, br.s), 5.35 (1H, br.d, J = 4.8Hz), 5.20 (1H, br.
d, J = 7.0Hz), 4.50 (1H, br.t), 4.38-4.31 (2H, m), 3.86 (1H, b
rd, J = 11.4Hz), 3.77 (1H, br.d, J = 11.4Hz), 3.70 (3H, s) .MS (m / z) 249 (M ⁺ +1), 218,162,115,91,59,44 .

[0333]

Example 74 [1S, 5R, 6R, obtained in Example 60]
7R] -2-Aza-1-carbamoyl-3,8-dioxa-2-N-ethoxycarbonyl-6,7-isopropylidenedioxybicyclo [3.2.1] octane (14.75
g, 48.79 mol) in methanol (290 ml) -purified water (14
5 ml), add Dowex 50W (H ⁺ ) (73.75 g) and add 8
Heat to 0 ° C and stir for 20 hours, then Dowex 50W (H ⁺ ) 3
2.8 g was added and the mixture was stirred at 100 ° C. for 8 hours. The reaction solution was filtered through Celite and concentrated to obtain the desired product [1S, 5
R, 6S, 7R] -2-Aza-1-carbamoyl-6,6
7.-Dihydroxy-3,8-dioxa-2-N-ethoxycarbonylbicyclo [3.2.1] octane was added to 12.
The yield was 55 g (yield 98%).

¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 7.21 (1 H, br.
s), 6.84 (1H, br.s), 4.49 (1H, d, J = 6.1Hz), 4.38 (1H, br, s),
4.38-4.09 (2H, br), 4.33 (1H, d, J = 6.1Hz), 4.15 (2H, q, J = 7.
0Hz), 3.85 (1H, br.d, J = 11.6Hz), 3.77 (1H, br.d, J = 11.6H
z), 1.22 (3H, t, J = 7.0Hz) .MS (m / z) 263 (M ⁺ +1), 217,161,115,104,69,57,44.

[0335]

EXAMPLE 75 [1S, 5R, 6S, obtained in Example 74,
7R] -2-Aza-1-carbamoyl-6,7-dihydroxy-3,8-dioxa-2-N-ethoxycarbonylbicyclo [3.2.1] octane (499.4 mg, 2.01 mmol)
In a suspension of ethanol (10 ml) at 60 ° C in sodium methoxide in methanol (2M) (1.3 ml, 2.6 mm
ol) was added and the mixture was stirred at the same temperature for 3 hours. This reaction solution was filtered through Celite to obtain 64 out of 1.6345 g of the obtained crystals.
3.4 mg was purified with Diaion CHP20P (water) to obtain the desired product [1S, 2R, 3S, 4R] -7,9-diaza-2,3.
-Dihydroxy-6,11-dioxatricyclo [5.
3.0.1 ^1,4 ] Undecane-8,10-dione 111.
3 mg was obtained.

¹ H-NMR (200 MHz, D ₂ O) δ: 4.67 (1H, d, J = 6.2H
z), 4.55 (1H, d, J = 6.2Hz), 4.45 (1H, br.s), 4.08 (1H, br.d, J
= 11.4Hz), 3.76 (1H, br.d, J = 11.4Hz).

[0337]

[Example 76] [1S, 5R, 6S, obtained in Example 74]
7R] -2-Aza-1-carbamoyl-6,7-dihydroxy-3,8-dioxa-2-N-ethoxycarbonylbicyclo [3.2.1] octane (3.0175 g, 11.51 mmo
l) was dissolved in methanol (60 ml), and 7.5 ml of a solution of sodium methoxide in methanol (2M) was added at 50 ° C., and the mixture was stirred at the same temperature for 1 hour and at 55 ° C. for 3 hours, and then methanesulfone at room temperature. Acid (0.75 ml) was added. Purified water (15 ml) and ethanol (250 ml) were added to the obtained reaction solution,
Raney nickel 10.4g was added, and under hydrogen pressure (6kg / cm ² ).
Stir at 55 ° C. for 7 hours. This is filtered through Celite, concentrated, purified with Diaion CHP-20P (water), and hydantocidin and epihydantosaidin (7.5: 1).
As a mixture, 1.8847 g (yield 75%) was obtained. Epihydantosidine is the optical isomer of the spiro carbon of hydantosidine.

[0338]

Example 77 [1S, 5R, 6S, obtained in Example 74]
7R] -2-Aza-1-carbamoyl-6,7-dihydroxy-3,8-dioxa-2-N-ethoxycarbonylbicyclo [3.2.1] octane (996.0 mg, 3.80 mmol)
Was dissolved in 20 ml of methanol, 206 mg of sodium hydroxide (96%) was added at 55 ° C., the mixture was stirred at the same temperature for 2.5 hours, and 0.22 ml of acetic acid was added at room temperature. Purified water 3
ml, ethanol 80 ml, and Raney nickel 2.6 g were added, and the mixture was stirred under hydrogen pressure (5.3 kg / cm ² ) at 55 ° C. for 8 hours. The obtained reaction solution was filtered through Celite, concentrated, and purified with Diaion CHP-20P (water) to prepare a mixture of hydantosidine and epihydantosidine (20: 1).
481.9 mg (yield 58%) was obtained.

[0339]

INDUSTRIAL APPLICABILITY In general, it is easy to introduce a nitrogen atom into the anomeric position of sugar while controlling the stericity because the stereoisomers at the anomeric position are mixed and it is necessary to use a dangerous reagent. is not.

On the other hand, in the method of passing through the intermediate (I) of the present invention, since the intermediate (I) has an O—N bond, the reactivity of the nitrogen atom can be appropriately increased, and further, in the molecule. Since the reaction is performed, the anomeric position can be easily and stereospecifically reacted, and stereoisomers are not mixed.

The bicyclic compound (II) and the tricyclic compounds (III) and (IV) are equivalent to those in which the hydroxyl group of the hydroxymethyl group at the 2-position of hydantosidine and the nitrogen atom at the 6-position are simultaneously protected. Yes, it is convenient. Further, in the compound (II), when R ⁶ represents —COR ¹⁰ (R ¹⁰ has the same meaning as described above), it is convenient not only as a protecting group for the reaction to the anomeric position, but also in the future for hydantosidine. Since it already has a structure that can be a carbonyl group at the 7-position, it is possible to improve the yield and shorten the process.

Since the compound (II) has a bicyclo system which is sterically undistorted, it is considered to exist stably regardless of the kind of the substituent of R ⁷ , and the yield of the subsequent reaction is high. .

Furthermore, in the reaction for obtaining the compound (V) from the tricyclo compound (IV), O of the compound (IV)
Even though the electron-withdrawing carbonyl group is bonded to the nitrogen atom of the —N bond and the reactivity is lowered, by heating under hydrogen pressure condition in the presence of Raney catalyst, the O—N
The bond can be broken. Moreover, the three-dimensional arrangement of the spiro portion can be maintained in a desired arrangement.

In addition, since the starting materials and reagents used are inexpensive and easy to handle throughout the entire process, and the molecular weight of each intermediate is relatively small, the volume efficiency is excellent even on an industrial scale.

[0345] The following is the above-mentioned prior art Philippe.
Chemla, Tetrahedron Lett., 34 , 7391 (1993) (hereinafter referred to as Document A), the following invention.

[0346]

[Chemical 89]

The present invention is compared with the present invention to explain that the present invention cannot be easily conceived from the invention described in the document A.

First, when the reactions in the invention described in Document A are individually examined, many of them are reactions that can be used only at the laboratory level and are industrially disadvantageous. It is impossible to actually produce by the method.

Specifically, in the step 2 → 3 (the so-called Mitsunobu reaction), purification such as diethylazodicarboxylic acid (DEAD) or triphenylphosphine (Ph ₃ P) is relatively expensive and the purification after the reaction is performed. Uses reagents that are problematic to the law. That is, since it is a by-product after the reaction derived from DEAD or Ph ₃ P, it is necessary to use column chromatography or the like when separating and purifying the target product, which is not an industrially easy method.

In the step 5 → 6 , expensive trimethylsilyl triflate (TMSOTf) is used.

In the process of 6 → 7 , highly toxic Na ₂ Cr is used.
I am using O ₇ .

In the process of 7 → 8 , expensive ceric ammonium nitrate ((NH ₄ ) ₂ Ce (NO ₃ ) ₆ ,
CAN) is used.

In the process of 8 → 9 , expensive and highly toxic Mo (CO) ₆ is used.

The method described in Document A has a plurality of problems as described above in the industrial production of hytantosidine, and moreover, via the intermediate described in Document A, the reagent of each step It is extremely difficult to adapt to industrial production by improving reaction conditions and the like.

Next, when the reaction in the invention described in Document A was examined as a whole, it was a stereospecific production method of hydantosidine by passing through a bridged ring derivative such as compound 6 , and Points There is no difference from the present invention.

Further, in the invention described in Document A, the nitrogen atom which will form the hydantosidine ring in the future is treated at the initial stage (compound
It has been introduced with a PMB-protected nitrogen atom in 5 ) and appears efficient (at least at the laboratory level). However, in finding a method that can be industrially produced based on the method of Document A, the method of introducing a nitrogen atom in the initial stage is rather an obstacle. That is, the production of a compound having a hydroxyurea partial structure, such as compound 5 , which is a raw material of the bridged ring derivative 6 , requires multiple steps, and inevitably uses an industrially unsuitable method such as the Mitsunobu reaction. Nevertheless, the method of the present invention cannot be conceived because it sticks to the introduction of nitrogen atoms in the initial stage. In the present invention, the nitrogen atom is not introduced at the initial stage, and the compound (I) which is a raw material of the bridged ring derivative is a short-stage, simple and inexpensive method suitable for industrial production [having a leaving group at the 6-position. The psicose derivative (VI) is reacted with hydroxylamine having a nitrogen atom protected (for example, HO—NHCOOCH ₂ CH ₃ ) under alkaline conditions].

Further, as an effect of the difference between the compound 5 of Document A and the compound (I) of the present invention, improvement of reaction conditions for producing a cross-linked compound can be mentioned. In Document A, expensive trimethylsilyl triflate (TMSOTf) is used in the step 5 → 6 , which is a ring-closing reaction. An inexpensive acid can be used for

Also in the hydantoin ring forming reaction, the present invention is superior to the invention described in Document A. In Document A, highly toxic Na ₂ CrO ₇ is used in the hydantoin ring formation reaction (steps 6 → 7 ), but in the hydantoin ring formation reaction (steps F and G) of the present invention, step F is used. Since an inexpensive base is used in step G and aqueous ammonia is used in step G, it is excellent as an industrial manufacturing method.

In addition, in the method of cleaving the ON bond of the important synthetic intermediate 8 of hydantosidine, the expensive and highly toxic Mo (CO) ₆ is used in Reference A, but in the present invention, The ON-N bond can be cleaved by a hydrogenation reaction with a Raney catalyst. Literature A
However, in the present invention, as described above, the ON-N bond can be cleaved by heating under hydrogen pressure conditions in the presence of a Raney catalyst, as described above. It is found that the present invention cannot be easily conceived from Document A also from this point.

As described above, by using the compound (I) as an intermediate in the present invention instead of the compound 5 in the document A, all the above-mentioned problems of the method of the document A can be solved at once.

As described above, according to the present invention, hydantocidin can be specifically produced in a high yield, simply, inexpensively and safely on an industrial scale without formation of stereoisomers. It provides a method.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07H 15/04 E // A01N 47/38 B (C07D 491/107 233: 72 307: 20) ( (C07D 498/08 273: 01 307: 20) (C07D 498/20 233: 72 273: 01 307: 20)

Claims (29)

[Claims] 1. A compound represented by the general formula (I): [Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R 2
² together represents an optionally substituted alkylidene group, R ³ and R ⁴ represent a hydrogen atom, or R ³ and R 4
⁴ together represents an optionally substituted alkylidene group, R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom,
Formula -COR ¹⁰ (R ¹⁰ represents a lower alkyl group, a lower alkoxy group, an aryl group, an aryloxy group, an aralkyloxy group, an amino group which may be substituted with 1 to 2 lower alkyl groups, or a lower alkenyloxy group. .) (Provided that R ⁵ and R ⁶ are both hydrogen atoms) or the formula —SO ₂ R ¹¹ (R ¹¹ is a lower alkyl group, an aryl group or 1 or 2 lower alkyl groups). Represents an optionally substituted amino group). ] The compound and its salt represented by these. 2. A compound represented by the general formula (I): [In the formula, R ¹ and R ² together represent an alkylidene group, R ³ and R ⁴ together represent an alkylidene group,
R ⁵ represents a hydrogen atom, and R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group.). ] The compound and its salt represented by these. 3. A compound represented by the general formula (I): [In the formula, R ¹ and R ² together represent an isopropylidene group, R ³ and R ⁴ together represent an isopropylidene group, R ⁵ represents a hydrogen atom, and R ⁶ represents a formula-COR
¹⁰ represents a group represented by ¹⁰ (R ¹⁰ represents a lower alkoxy group). ] The compound and its salt represented by these. 4. A compound represented by the general formula (II): [Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R 2
² together represents an optionally substituted alkylidene group, R ⁶ is a hydrogen atom, formula —COR ¹⁰ (R ¹⁰ is a lower alkyl group, a lower alkoxy group, an aryl group, an aryloxy group, an aralkyloxy group, A group represented by an amino group or a lower alkenyloxy group which may be substituted with 1 to 2 lower alkyls) or a formula —SO ₂ R
¹¹ (R ¹¹ represents a lower alkyl group, an aryl group or an amino group which may be substituted with 1 or 2 lower alkyl groups), and R ⁷ represents a group of the formula —CH ₂ OH. Group, a formyl group, a carboxyl group, a lower alkoxycarbonyl group or a formula CONHR ¹⁴ {R ¹⁴ is a hydrogen atom,
A lower alkyl group, a phenyl group or an aralkyl group (the phenyl group and the aralkyl group may be substituted with a halogen atom, a lower alkoxy group or a nitro group). } Shows group represented by. ] The compound and its salt represented by these. 5. A compound represented by the general formula (II): [In the formula, R ¹ and R ² together represent an alkylidene group, R ⁶ represents a hydrogen atom or a formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group. Is represented by the formula), R ⁷ is a group represented by the formula —CH ₂ OH, a formyl group,
A carboxyl group or a group represented by the formula CONH ₂ is shown. ] The compound and its salt represented by these. 6. A compound represented by the general formula (II):[In the formula, R¹ And R² Together are isopropylidene groups
Indicates R⁶ Is a hydrogen atom or the formula -COR^Ten(R^TenIs low
Indicates an alkoxy group. ) Is a group represented by ⁷ Is an expression
-CH₂ OH group, formyl group, carboxyl
Group or formula CONH₂ Represents a group represented by. ]]
Compounds and their salts. 7. A compound represented by the general formula (II): [Wherein R ¹ and R ² together represent an isopropylidene group, R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group), and R ⁷ represents a group represented by the formula: -CH ₂ OH
A group represented by, a formyl group, a carboxyl group or a formula CO
A group represented by NH ₂ is shown. ] The compound and its salt represented by these. 8. A compound represented by the general formula (III): [Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R 2
² together represents an optionally substituted alkylidene group. ] The compound and its salt represented by these. 9. A compound represented by the general formula (III): [In the formula, R ¹ and R ² together represent an isopropylidene group. ] The compound and its salt represented by these. 10. A compound represented by the general formula (IV): [Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R 2
² together represents an optionally substituted alkylidene group. ] The compound represented by the formula [V] is characterized by hydrogenating using a Raney catalyst. [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 11. A compound represented by the general formula (IV): [In the formula, R ¹ and R ² represent a hydrogen atom. ] The compound represented by the formula [V] is characterized by hydrogenating using a Raney catalyst. [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 12. A compound represented by the general formula (IV): [In the formula, R ¹ and R ² represent a hydrogen atom. ] The compound represented by the formula [V] is characterized by hydrogenating using a Raney catalyst in the presence of an acid. [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 13. A compound represented by the general formula (IV): [In the formula, R ¹ and R ² represent a hydrogen atom. ] The compound represented by the general formula (V) is characterized in that it is hydrogenated using a Raney catalyst in the presence of acetic acid. [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 14. A compound represented by the general formula (IV): [In the formula, R ¹ and R ² together represent an isopropylidene group. ] The compound represented by the formula [V] is characterized by hydrogenating using a Raney catalyst. [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 15. A compound represented by the general formula (VI): [Wherein, X represents a leaving group, R ¹ and R ² represent a hydrogen atom, or R ¹ and R ² together represent an optionally substituted alkylidene group, and R ³ and R 2 ⁴ represents a hydrogen atom, or R ³ and R ⁴ together represent an alkylidene group which may be substituted. To a compound represented by the formula: HONR ⁵ R ⁶ [wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a formula —COR ¹⁰ (R ¹⁰ is a lower alkyl group, a lower alkoxy group, an aryl group, A group represented by an aryloxy group, an aralkyloxy group, an amino group which may be substituted with 1 to 2 lower alkyl groups or a lower alkenyloxy group, or a formula —SO ₂ R
¹¹ (R ¹¹ represents a lower alkyl group, an aryl group or an amino group which may be substituted with 1 to 2 lower alkyl groups). ] The compound represented by the general formula (I): [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above. ] The manufacturing method of the compound represented by these. 16. A compound represented by the general formula (VI): [In the formula, X represents a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a chlorine atom, a bromine atom or an iodine atom, R ¹ and R ² together represent an alkylidene group, and R ³ and R ⁴ Together represent an alkylidene group. ] To the compound represented by the general formula HONR ⁵ R ⁶
[In the formula, R ⁵ represents a hydrogen atom, and R ⁶ represents a formula-COR.
¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group.)
Represents a group represented by. ] The compound represented by the general formula (I): [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above. ] The manufacturing method of the compound represented by these. 17. A compound represented by the general formula (VI): [In the formula, X represents a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a chlorine atom, a bromine atom or an iodine atom, R ¹ and R ² together represent an isopropylidene group, and R ³ and R 2 ⁴ together represents an isopropylidene group. ] To the compound represented by the general formula HONR ⁵ R
⁶ [In the formula, R ⁵ represents a hydrogen atom, and R ⁶ represents a formula —COR ¹⁰
(R ¹⁰ represents a lower alkoxy group). ] Reacting a compound represented by
General formula (I) [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above. ] The manufacturing method of the compound represented by these. 18. A compound represented by the general formula (I): [Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R 2
² together represents an optionally substituted alkylidene group, R ³ and R ⁴ represent a hydrogen atom, or R ³ and R 4
⁴ together represents an optionally substituted alkylidene group, R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom,
Formula -COR ¹⁰ (R ¹⁰ represents a lower alkyl group, a lower alkoxy group, an aryl group, an aryloxy group, an aralkyloxy group, an amino group which may be substituted with 1 to 2 lower alkyl groups, or a lower alkenyloxy group. .) Or a group represented by the formula —SO ₂ R ¹¹ (R ¹¹ represents a lower alkyl group, an aryl group or an amino group optionally substituted by 1 to 2 lower alkyl). Indicates. ] The compound represented by the general formula (IIa) is characterized by reacting the compound represented by the formula (IIa): [In the formula, R ¹ , R ² and R ⁶ have the same meanings as described above. ] The manufacturing method of the compound represented by these. 19. A compound represented by the general formula (I): [In the formula, R ¹ and R ² together represent an alkylidene group, R ³ and R ⁴ together represent an alkylidene group,
R ⁵ represents a hydrogen atom, and R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group.). ] The compound represented by the general formula (IIa) embedded image characterized by reacting a compound represented by the formula [II] in the presence of sulfonic acids or mineral acids as a catalyst. [In the formula, R ¹ , R ² and R ⁶ have the same meanings as described above. ] The manufacturing method of the compound represented by these. 20. General formula (I): [In the formula, R ¹ and R ² together represent an isopropylidene group, R ³ and R ⁴ together represent an isopropylidene group, R ⁵ represents a hydrogen atom, and R ⁶ represents a formula-COR
¹⁰ represents a group represented by ¹⁰ (R ¹⁰ represents a lower alkoxy group). ] The compound represented by the formula is reacted in the presence of sulfuric acid or methanesulfonic acid as a catalyst, and is represented by the general formula (IIa): [In the formula, R ¹ , R ² and R ⁶ have the same meanings as described above. ] The manufacturing method of the compound represented by these. 21. A compound represented by the general formula (IIc): [Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R 2
² together represents an optionally substituted alkylidene group, R ⁶ is of the formula —COR ¹⁰ (R ¹⁰ is a lower alkoxy group, an aryloxy group, an aralkyloxy group, 1 to 2
Represents an amino group or a lower alkenyloxy group which may be substituted with one lower alkyl. ) And R ¹⁴ represents a hydrogen atom. ] The compound represented by the formula is treated with a base in the presence of a solvent, represented by the general formula (IV): [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 22. General formula (IIc): [In the formula, R ¹ and R ² together represent an alkylidene group, and R ⁶ is a formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group.) Represents a group represented by and R ¹⁴ represents a hydrogen atom. ] The compound represented by the formula [IV] is treated with a hydroxide of an alkali metal or an alkaline earth metal or an alkali metal salt of a lower alcohol in the presence of a solvent. [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 23. A compound represented by the general formula (IIc): [In the formula, R ¹ and R ² together represent an isopropylidene group, R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group), and R ¹⁴ represents hydrogen. Indicates an atom. ] The compound represented by the formula is treated with sodium hydroxide or potassium hydroxide in the presence of a solvent. [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 24. A compound represented by the general formula (IIb): [Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R 2
² together represents an optionally substituted alkylidene group, R ⁶ is of the formula —COR ¹⁰ (R ¹⁰ is a lower alkoxy group, an aryloxy group, an aralkyloxy group, 1 to 2
Represents an amino group or a lower alkenyloxy group which may be substituted with one lower alkyl. ) Represents a group represented by. ] The compound represented by the general formula (III) embedded image characterized by treating the compound represented by the formula with ammonia in the presence of a solvent. [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 25. A compound represented by the general formula (IIb): [In the formula, R ¹ and R ² together represent an alkylidene group, and R ⁶ is a formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group, an aryloxy group, an aralkyloxy group or a lower alkenyloxy group.) Represents a group represented by. ] The compound represented by the general formula (III) embedded image characterized by treating with ammonia in the presence of a solvent. [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 26. A compound represented by the general formula (IIb): [In the formula, R ¹ and R ² together represent an isopropylidene group, and R ⁶ represents a group represented by the formula —COR ¹⁰ (R ¹⁰ represents a lower alkoxy group). ] The compound represented by the general formula (III) embedded image characterized by treating with ammonia in the presence of a solvent [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 27. A compound represented by the general formula (III): [Wherein R ¹ and R ² represent a hydrogen atom, or R ¹ and R 2
² together represents an optionally substituted alkylidene group. ] The compound represented by the general formula (IV): [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 28. A compound represented by the general formula (III): [In the formula, R ¹ and R ² together represent an alkylidene group. ] The compound represented by general formula (I) characterized by oxidizing the compound represented by hypochlorite or chromate.
V) [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these. 29. A compound represented by the general formula (III): [In the formula, R ¹ and R ² together represent an isopropylidene group. ] The compound represented by the general formula (IV) embedded image characterized by oxidizing the compound represented by the formula: [In the formula, R ¹ and R ² have the same meanings as described above. ] The manufacturing method of the compound represented by these.