JP3040847B2 - Lipid X analog - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[Object of the invention]

[0002]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel lipid X analog having an antitumor effect based on macrophage activation and a salt thereof.

[0003]

2. Description of the Related Art The outermost layer of the cell wall of Gram-negative bacteria obtained from intestinal bacteria contains toxic components (endotoxins) that are not secreted outside the cells. In addition, immunoadjuvant activity related to the self defense of the living body,
Macrophage activity, mitogen activity, exothermic effect,
It exhibits various biological activities such as tumor necrosis, antibody production enhancement, and TNF induction. Such endotoxins consist of lipopolysaccharide, and it has been found that the so-called lipid A moiety is the active center of endotoxin activity. On the other hand, as a lipid A biosynthesis precursor, lipids X and Y, which are monosaccharides, were isolated from the mutant strain of E. coli, and it was revealed that lipid A non-reducing terminal monosaccharide also showed the same activity as lipid A. .
Based on these results, an analog of lipid A, X, Y or lipid A non-reducing terminal monosaccharide was synthesized and its activity was examined (for example, Imoto et al., Tetrahedron Lett. ., 26, 1545 (1985
Year) or Kiso et al., Carbohydrate Research, 162, 127
1987). However, since it is a bacterial endotoxin itself, there remain problems such as lethal toxicity, pyrogenic action, leukopenia, and induction of autoimmune diseases.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies on the synthesis and pharmacological activity of lipid A monosaccharide analogs having macrophage activating activity, and as a result, have found that a known compound is obtained. The present inventors have found that a novel lipid X analog having a different structure from that of the above has an excellent macrophage activating effect and is useful as an immunostimulant or an antitumor agent, and thus completed the present invention.

[0005]

The novel lipid X analogs of the present invention have the general formula

[0006]

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In the formula, ^one of R ¹ and R ⁴ represents a hydrogen atom, a group having the formula —P (O) (OH) ₂ or a protecting group for a hydroxyl group, and the other represents a formula —P (O ) Represents a group having (OH) ₂ . R
² and R ³ are the same or different and are each an aliphatic acyl group having 6 to 20 carbon atoms or a group selected from the following [Substituent Group A], and having at least one substituted C 6 to C 20
Aliphatic acyl groups. R ⁵ represents a hydrogen atom or a protecting group for a hydroxyl group. However, R ² and R ³ are the same or different and are the same or different, and are an aliphatic acyl group having 6 to 20 carbon atoms, an aliphatic acyl group having 6 to 20 carbon atoms substituted with a hydroxyl group, or 6 to 20 carbon atoms. It does not show an aliphatic acyl group having 6 to 20 carbon atoms substituted with 2 aliphatic acyloxy groups. ]. [Substituent group A] a halogen atom, a hydroxyl group, an aliphatic acyloxy group having 6 to 20 carbon atoms and an aliphatic acyloxy group having 6 to 20 carbon atoms substituted with a halogen atom.

In the general formula (I), the term “protecting group for hydroxyl group” in the definition of R ¹ , R ⁴ and R ⁵ means a protecting group in the reaction and a protecting group for administration to a living body.
For example, alkylcarbonyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, myristoyl, tridecanoyl, palmitoyl, stearoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl An aliphatic acyl group such as a halogenated alkylcarbonyl group such as methoxyacetyl, a lower alkoxyalkylcarbonyl group such as methoxyacetyl, (E) -2-methyl-2-butenoyl and the like; benzoyl, α-
Arylcarbonyl groups such as naphthoyl and β-naphthoyl; halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl; lowers such as 2,4,6-trimethylbenzoyl and 4-toluoyl Alkylated arylcarbonyl group, lower alkoxylated arylcarbonyl group such as 4-anisoyl, nitrated arylcarbonyl group such as 4-nitrobenzoyl and 2-nitrobenzoyl, 2- (methoxycarbonyl) benzoyl Aromatic acyl groups such as lower alkoxycarbonylated arylcarbonyl groups such as, and arylated arylcarbonyl groups such as 4-phenylbenzoyl; tetrahydropyran-2-yl;
3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl
A tetrahydropyranyl or tetrahydrothiopyranyl group such as yl, 4-methoxytetrahydrothiopyran-4-yl; a tetrahydrofuranyl or tetrahydrothiofuranyl group such as tetrahydrofuran-2-yl or tetrahydrothiofuran-2-yl; Trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t
-Tri-lower alkylsilyl groups such as butylsilyl and triisopropylsilyl, and tri-lower alkyl substituted with one or two aryl groups such as diphenylmethylsilyl, diphenyl-t-butylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl. A silyl group such as a silyl group; a lower alkoxymethyl group such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, 2-methoxyethoxy Lower alkoxylated lower alkoxymethyl groups such as methyl,
Alkoxymethyl groups such as halogenated lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; 1-ethoxyethyl, 1-methyl
Lower alkoxylated ethyl group such as -1-methoxyethyl, 1- (isopropoxy) ethyl, halogenated ethyl group such as 2,2,2-trichloroethyl, arylzelenyl such as 2- (phenylphenylenyl) ethyl Substituted ethyl groups such as ethyl chloride; 1 such as benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl Lower alkyl group substituted with 3 to 3 aryl groups, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl , 2-nitrobenzyl, 4-nitrobenzyl,
Aryl with lower alkyl, lower alkoxy, nitro, halogen, cyano groups such as 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, piperonyl An aralkyl group such as a lower alkyl group substituted with 1 to 3 aryl groups having a substituted aryl ring; a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl; Alkoxycarbonyl groups such as halogen or lower alkoxycarbonyl groups substituted with tri-lower alkylsilyl groups such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; alkenyloxy groups such as vinyloxycarbonyl and allyloxycarbonyl Carbonyl group; benzyl Ruoxycarbonyl, 4-
Such as methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
1 or two aryl rings optionally substituted aralkyloxycarbonyl group with a lower alkoxy or a nitro group; protecting group in the reaction, such as alkenyl groups allyl group or the like; the formula -COCH ₂ CH ₂ COOH, - COCH ₂ CH (OH) COOH or -C
An acyl group having a terminal carboxy group such as a compound having OCH = CH-COOH or a protecting group for administration to a living body such as pivaloyloxymethyloxycarbonyl can be given.

"An aliphatic acyl group having 6 to 20 carbon atoms" in the definition of R ² and R ³ , "an aliphatic acyloxy group having 6 to 20 carbon atoms" in the definition of [Substituent group A]
And "an aliphatic acyl group having 6 to 20 carbon atoms" of "an aliphatic acyloxy group having 6 to 20 carbon atoms substituted with a halogen atom" includes, for example, pentylcarbonyl,
Hexylcarbonyl, heptylcarbonyl, octylcarbonyl, nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl, 3-
Ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl, dodecylcarbonyl,
Tridecylcarbonyl, tetradecylcarbonyl, pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl, 14-methylpentadecylcarbonyl, 13,13-dimethyltetradecylcarbonyl, heptadecylcarbonyl, 15-methylhexadecylcarbonyl, Octadecylcarbonyl, 1-methylheptadecylcarbonyl and nonadecylcarbonyl can be mentioned, and preferred is a linear or branched aliphatic acyl group having 10 to 16 carbon atoms.

The "halogen atom" in the definition of [Substituent group A] is fluorine, chlorine, bromine or iodine.

The compound (I) of the present invention may be in the form of a salt. The salt is preferably an alkali metal or alkaline earth metal such as a sodium, potassium or calcium salt. Salts: Salts of organic bases such as triethylamine salt and trimethylamine salt can be mentioned.

The compound (I) of the present invention has an asymmetric carbon in the molecule and has stereoisomers each having S-coordinate and R-coordination. Are also included in the present invention.

In the compound (I), preferred compounds include (1) compounds in which R ¹ and R ⁴ are the same or different and are a hydrogen atom or a group having the formula —P (O) (OH) ₂ ( 2) ^one of R ¹ and R ⁴ is a group having the formula —P (O) (OH) ₂ , and the other is a hydrogen atom or a group having the formula —P (O) (OH) ₂ Compound (3) One of R ² and R ³ represents a halogen atom, a hydroxyl group, an aliphatic acyloxy group having 10 to 16 carbon atoms or an aliphatic acyloxy group having 10 to 16 carbon atoms substituted with a halogen atom. An aliphatic acyl group having 10 to 16 carbon atoms which may have, and the other is a fatty acid having 10 to 16 carbon atoms having a halogen atom and a hydroxyl group or an aliphatic acyloxy group having 10 to 16 carbon atoms. compound is a family acyl group (4) R ² is a halogen atom, a hydroxyl group, 10 to 16 carbon atoms aliphatic acyloxy group or halogen Carbon number of 10 to 16 compounds is an aliphatic acyloxy group and optionally also a good number 10 to 16 carbon has an aliphatic acyl group substituted with atoms (5) R ⁵ is a hydrogen atom or the formula -COCH ₂ CH ₂ COOH, -COCH ₂ CH
Compounds which are acyl groups having a carboxy group at the terminal such as a group having (OH) COOH or -COCH = CH-COOH can be mentioned.

Representative compounds of the present invention include, for example,
The compounds described in Tables 1 and 2 can be mentioned, but the present invention is not limited to these compounds. Table 1

[0015]

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{Example Compound R ² R ³ } ─────────────────────────────── 1 -COCH ₂ CH (OH) C ₇ H ₁₅ -COCHFCH (OH) C _{11 H 23 2 -COCH 2 CH (OH} ) C 9 H 19 -COCHFCH (OH) C 11 H 23 3 -COCH 2 CH (OH) C 11 H 23 -COCHFCH (OH) C 11 H 23 4 -COCH 2 CH ( _{OH) C 13 H 27 -COCHFCH (} OH) C 11 H 23 5 -COCH 2 CH (OH) C 15 H 31 -COCHFCH (OH) C 11 H 23 6 -COCH 2 CH (OH) C 11 H 23 -COCHFCH _{(OH) C 7 H 15 7} -COCH 2 CH (OH) C 11 H 23 -COCHFCH (OH) C 9 H 19 8 -COCH 2 CH (OH) C 11 H 23 -COCHFCH (OH) C 11 H 23 9 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₃ H ₂₇ 10 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₅ H ₃₁ 11 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHClCH (OH) C ₁₁ H ₂₃ 12 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCHFCH (OH) C ₁₁ H ₂₃ 13 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₁ H ₂₃ 14 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ -COCHFCH (OH) C ₁₁ H ₂₃ 15 -COCH ₂ CH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₁ H ₂₃ 16 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₁ H ₂₃ 17 -COCH ₂ CH ( OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHClCH (OH) C ₁₁ H ₂₃ 18 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH (OH) CHFC ₁₁ H ₂₃ 19 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 20 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHFCH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ 21 -COCH ₂ CH (OH) C _{11 H 23 -COCHFCH (OCOC 13 H 27} ) C 11 H 23 22 -COCH 2 CH (OH) C 11 H 23 -COCHFCH (OCOC 11 H 23) C 9 H 19 23 -COCH 2 CH (OH) C 11 H 23 -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ 24 -COCH ₂ CH (OH) C ₉ H ₁₉ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 25 -COCH ₂ CH (OH) C ₁₃ H ₂₇ -COCHFCH _{(OCOC 11 H 23) C 11} H 23 26 -COCH 2 CH (OH) C 11 H 23 -COCHClCH (OCOC 11 H 23) C 11 H 23 27 -COCH 2 CH (OCOC 11 H 23) C 11 H 23 - COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 28 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ 29 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 30 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ 31 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ 32 -COCH ₂ CH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 33 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 34 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 35 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 36 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHClCH (OCOC _{11 H 23) C 11 H 23} 37 -COCH 2 CH (OH) C 11 H 23 -COCHF (CH 2) 2 CH (OH) C 9 H 19 38 -COCH 2 CH (OH) C 11 H 23 -COCHF ( CH ₂ ) ₃ CH (OH) C ₈ H ₁₇ 39 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHCl (CH ₂ ) ₄ CH (OH) C ₇ H ₁₅ 40 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHBr (CH ₂ ) ₅ CH (OH) C ₆ H ₁₃ 41 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHF (CH ₂ ) ₆ CH (OH) C ₅ H ₁₁ 42 -COCH ₂ CH (OH _{) C 11 H 23 -COCHCl (CH} 2) 7 CH (OH) C 4 H 9 43 -COCHFCH (OH) C 11 H 23 -COCH 2 CH (OH) C 11 H 23 44 -COCHFCH (OH) C 11 H ₂₃ -COCH ₂ CH (OH) C ₉ H ₁₉ 45 -COCHFCH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OH) C ₁₃ H ₂₇ 46 -COCHClCH (OH) C ₉ H ₁₉ -COCH ₂ CH (OH) C ₁₁ H ₂₃ 47 -COCHBrCH (OH) C ₁₃ H ₂₇ -COCH ₂ CH (OH) C _{11 H 23 48 -COCHFCH (OH)} C 9 H 19 -COCH 2 CH (OH) C 9 H 19 49 -COCHClCH (OH) C 13 H 27 -COCH 2 CH (OH) C 13 H 27 50 -COCHFCH (OH ) C ₉ H ₁₉ -COCH ₂ CH (OH) C ₁₃ H ₂₇ 51 -COCHFCH (OH) C ₁₃ H ₂₇ -COCH ₂ CH (OH) C ₉ H ₁₉ 52 -COCHFCH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 53 -COCHFCH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ 54 -COCHFCH (OH) C ₁₁ H ₂₃ -COCH ₂ CH ( OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 55 -COCHClCH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ 56 -COCHBrCH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ 57 -COCHFCH (OH) C ₉ H ₁₉ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 58 -COCHClCH (OH) C ₉ H ₁₉ -COCH ₂ CH (OCOC ₉ H _{19 ) C 11 H 23 59 -COCHFCH (} OH) C 9 H 19 -COCH 2 CH (OCOC 13 H 27) C 11 H 23 60 -COCHFCH (OH) C 9 H 19 -COCH 2 CH (OCOC 11 H 23) C ₉ H ₁₉ 61 -COCHFCH (OH) C ₉ H ₁₉ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ 62 -COCHClCH (OH) C ₁₃ H ₂₇ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 63 -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OH) C ₁₁ H ₂₃ 64 -COCHFCH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ -COCH ₂ CH (OH) C ₁₁ H ₂₃ 65 -COCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCH ₂ CH (OH) C ₁₁ H ₂₃ 66 -COCHClCH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ -COCH ₂ CH (OH) C ₁₁ H ₂₃ 67 -COCHBrCH (OCOC ₁₃ H ₂₇ ) C _{9 H 19 -COCH 2 CH (OH} ) C 11 H 23 68 -COCHFCH (OCOC 11 H 23) C 11 H 23 -COCH 2 CH (OH) C 9 H 19 69 -COCHClCH (OCOC 9 H 19) C 11 H ₂₃ -COCH ₂ CH (OH) C ₁₃ H ₂₇ 70 -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 71 -COCHFCH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ 72 -COCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 73 -COCHClCH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ 74 -COCHFCH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 75 -COCH ₂ CH ( _{OH) C 11 H 23 -COCH 2} CH (OCOCF 2 C 12 H 25) C 11 H 23 76 -COCH 2 CH (OCOC 13 H 27) C 11 H 23 -COCH 2 CH (OCOCF 2 C 12 H 25) C ₁₁ H ₂₃ 77 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ 78 -COCH ₂ CH (OH) C ₉ H ₁₉ -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ 79 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₉ H ₁₉ -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ 80 -COCH ₂ CH (OC OC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ 81 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C _{11 H 23 82 -COCH 2 CH (} OCOC 13 H 27) C 11 H 23 -COCH 2 CH (OCOCF 2 C 10 H 21) C 11 H 23 83 -COCH 2 CH (OCOC 11 H 23) C 11 H 23 - COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ 84 -COCH ₂ CH (OH) C ₉ H ₁₉ -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ 85 -COCH ₂ CH (OCOC _{13 H 27) C 9 H 19} -COCH 2 CH (OCOCF 2 C 10 H 21) C 11 H 23 86 -COCH 2 CH (OCOC 11 H 23) C 9 H 19 -COCH 2 CH (OCOCF 2 C 10 H 21 ) C ₁₁ H ₂₃ 87 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 88 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 89 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 90 -COCH ₂ CH (OH) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 91 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 92 -COCH ₂ CH ( OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 93 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 94 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 95 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 96 -COCH ₂ CH (OH) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 97 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 98 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 99 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 100 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 101 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 102 -COCH ₂ CH (OH) C ₉ H ₁₉ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 103 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₉ H ₁₉ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 104 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 105 -COCF ₂ CH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 106 -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 107 -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 108 -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 109 -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 110 -COCF ₂ CH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 111 -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 112 -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 113 -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 114 -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 115 -COCF ₂ CH (OH) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 116 -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 117 -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H _{23 118 -COCH 2 CH (OCOCF 2} C 12 H 25) C 11 H 23 -COCF 2 CH (OCOC 13 H 27) C 11 H 23 119 -COCH 2 CH (OCOCF 2 C 10 H 21) C 11 H 23 - COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 120 -COCF ₂ CH (OH) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 121 -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 122 -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 123 -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 124 -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 125 -COCF ₂ C ₁₂ H ₂₅ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 126 -COCF ₂ C ₁₂ H ₂₅ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 127 -COCH ₂ CHFC ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 128 -COCH ₂ CHFC ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 129 -COCH ₂ CHFC ₁₁ H ₂₃ -COCH ₂ CH (OH) C ₁₁ H ₂₃ 130 -COCH ₂ CHFC ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₅ H ₃₁ ) C ₁₁ H ₂₃ ─────────表 Table 2

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{Exemplary Compound R ² R ³ } ─────────────────────────────── 1 -COCH ₂ CH (OH) C ₇ H ₁₅ -COCHFCH (OH) C _{11 H 23 2 -COCH 2 CH (OH} ) C 9 H 19 -COCHFCH (OH) C 11 H 23 3 -COCH 2 CH (OH) C 11 H 23 -COCHFCH (OH) C 11 H 23 4 -COCH 2 CH ( _{OH) C 13 H 27 -COCHFCH (} OH) C 11 H 23 5 -COCH 2 CH (OH) C 15 H 31 -COCHFCH (OH) C 11 H 23 6 -COCH 2 CH (OH) C 11 H 23 -COCHFCH _{(OH) C 7 H 15 7} -COCH 2 CH (OH) C 11 H 23 -COCHFCH (OH) C 15 H 31 8 -COCH 2 CH (OH) C 11 H 23 -COCHClCH (OH) C 11 H 23 9 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCHFCH (OH) C ₁₁ H ₂₃ 10 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₁ H ₂₃ 11 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ -COCHFCH (OH) C ₁₁ H ₂₃ 12 -COCH ₂ CH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₁ H ₂₃ 13 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHFCH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ 14 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHFCH (OCO C ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 15 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ 16 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHClCH (OCOC _{11 H 23) C 11 H 23 17} -COCH 2 CH (OCOC 11 H 23) C 11 H 23 -COCHFCH (OCOC 11 H 23) C 11 H 23 18 -COCH 2 CH (OCOC 11 H 23) C 11 H 23 - COCHFCH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ 19 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 20 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ 21 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ 22 -COCH ₂ CH (OH) _{C 11 H 23 -COCHF (CH 2} ) 2 CH (OH) C 9 H 19 23 -COCH 2 CH (OH) C 11 H 23 -COCHF (CH 2) 3 CH (OH) C 8 H 17 24 -COCH 2 CH (OH) C ₁₁ H ₂₃ -COCHCl (CH ₂ ) ₄ CH (OH) C ₇ H ₁₅ 25 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHBr (CH ₂ ) ₅ CH (OH) C ₆ H ₁₃ 26 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHF (CH ₂ ) ₆ CH (OH) C ₅ H ₁₁ 27 -COCHFCH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OH) C ₁₁ H ₂₃ 28- COCHFCH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OH) C ₉ H ₁₉ 29 -COCHFCH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OH) C ₁₃ H ₂₇ 30 -COCHClCH (OH) C ₉ H ₁₉ -COCH ₂ CH (OH) C ₁₁ H ₂₃ 31 -COCHBrCH (OH) C _{1 3 H 27 -COCH 2 CH (OH} ) C 11 H 23 32 -COCHFCH (OH) C 9 H 19 -COCH 2 CH (OH) C 9 H 19 33 -COCHClCH (OH) C 13 H 27 -COCH 2 CH ( OH) C ₁₃ H ₂₇ 34 -COCHFCH (OH) C ₉ H ₁₉ -COCH ₂ CH (OH) C ₁₃ H ₂₇ 35 -COCHFCH (OH) C ₁₃ H ₂₇ -COCH ₂ CH (OH) C ₉ H ₁₉ 36- COCHFCH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 37 -COCHClCH (OH) C ₉ H ₁₉ -COCH ₂ CH (OCOC ₉ H ₁₉ ) C ₁₁ H ₂₃ 38 -COCHFCH ( _{OH) C 11 H 23 -COCH 2} CH (OCOC 13 H 27) C 11 H 23 39 -COCHFCH (OH) C 9 H 19 -COCH 2 CH (OCOC 11 H 23) C 9 H 19 40 -COCHFCH (OH) C ₉ H ₁₉ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ 41 -COCHClCH (OH) C ₁₃ H ₂₇ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 42 -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OH) C ₁₁ H ₂₃ 43 -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 44 -COCHFCH (OCOC ₉ H _{19) C 11 H 23 -COCH 2} CH (OCOC 9 H 19) C 11 H 23 45 -COCHFCH (OCOC 13 H 27) C 11 H 23 -COCH 2 CH (OCOC 13 H 27) C 11 H 23 46 -COCHClCH (OCOC ₁₁ H ₂₃ ) C ₁₃ H ₂₇ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ 47 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₁ H ₂₃ 48- COCH ₂ CH (OCO C ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 49 -COCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCH ₂ CH (OH) C ₁₁ H ₂₃ 50 -COCHFCH (OH ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 51 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHFCH (OH) C ₉ H ₁₉ 52 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₃ H ₂₇ 53 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₅ H ₃₁ ) C ₁₁ H ₂₃ 54 -COCHFCH (OH) C ₉ H ₁₉ -COCH ₂ CH ( OH) C ₁₁ H ₂₃ 55 -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 56 -COCHFCH (OH) C ₉ H ₁₉ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 57 -COCHFCH (OH) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₁ H ₂₃ 58 -COCHFCH (OH) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 59- COCHFCH (OH) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 60 -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₁ H ₂₃ 61 -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 62 -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 63 -COCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCHFCH (OH) C ₁₁ H ₂₃ 64 -COCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 65 -C OCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCHFCH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 66 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ 67 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ 68 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ 69 -COCH ₂ CH (OH) C ₉ H ₁₉ -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ 70 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₉ H ₁₉ -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ 71 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ 72 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ 73 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ 74 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ 75 -COCH ₂ CH (OH ) C ₉ H ₁₉ -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ 76 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₉ H ₁₉ -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ 77 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ 78 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCF ₂ CH ( OCOC ₁₁ H _{23 ) C 11 H 23 79 -COCH 2} CH (OCOC 13 H 27) C 11 H 23 -COCF 2 CH (OCOC 11 H 23) C 11 H 23 80 -COCH 2 CH (OCOC 11 H 23) C 11 H 23 - COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 81 -COCH ₂ CH (OH) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 82 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 83 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 84 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 85 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 86 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 87 -COCH ₂ CH (OH) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 88 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 89 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 90 -COCH ₂ CH (OH) C ₁₁ H ₂₃ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 91 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 92 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 93 -COCH ₂ CH (OH) C ₉ H ₁₉ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 94 -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₉ H ₁₉ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 95 -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₉ H ₁₉ -COCF ₂ CH (OH) C ₁₁ H ₂₃ 96 -COCF ₂ CH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 97 -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 98 -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 99 -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 100 -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 101- COCF ₂ CH (OH) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 102 -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C _{11 H 23 103 -COCF 2 CH (} OCOC 13 H 27) C 11 H 23 -COCH 2 CH (OCOC 11 H 23) C 11 H 23 104 -COCH 2 CH (OCOCF 2 C 12 H 25) C 11 H 23 - COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 105 -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 106 -COCF ₂ CH ( OH) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 107 -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 108 -C OCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 109 -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 110 -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 111 -COCF ₂ CH (OH) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 112 -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 113 -COCF ₂ CH ( OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 114 -COCH ₂ CH (OCOCF ₂ C ₁₂ H ₂₅ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 115 -COCH ₂ CH (OCOCF ₂ C ₁₀ H ₂₁ ) C ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 116 -COCF ₂ C ₁₂ H ₂₅ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 117 -COCF ₂ C ₁₂ H ₂₅ -COCH ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 118 -COCHFCH (OH) C ₁₁ H ₂₃ -COC ₁₃ H ₂₇ 119 -COCHF (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ -COC ₁₃ H ₂₇ 120 -COCH ₂ CHFC ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₃ H ₂₇ ) C ₁₁ H ₂₃ 121 -COCH ₂ CHFC ₁₁ H ₂₃ -COCF ₂ CH (OCOC ₁₁ H ₂₃ ) C ₁₁ H ₂₃ 122 -COCH ₂ CHFC ₁₁ H ₂₃ -COCH ₂ CH (OH) C ₁₁ H ₂₃ 123 -COCH ₂ CHFC ₁₁ H ₂₃ -COCH ₂ CH (OCOC ₁₅ H ₃₁ ) C ₁₁ H ₂₃のAmong them, preferred compounds include 1-8, 1
-16, 1-21, 1-22, 1-52, 1-54, 1-59, 1-65, 1-72, 1-7
4, 1-105, 1-106,1-107, 1-110, 1-111, 1-112, 1-115,
1-116, 1-117, 1-120, 1-121, 1-122, 1-125, 1-126,
1-127, 2-14, 2-15, 2-19, 2-36, 2-38, 2-59, 2-66, 2
-72, 2-78, 2-84, 2-87, 2-91, 2-93, 2-96, 2-97, 2-9
8, 2-99, 2-101, 2-102, 2-103, 2-104, 2-106, 2-107,
2-108, 2-111, 2-112, 2-113, 2-116, 2-117 and 2-120
Can be mentioned. Further, preferred compounds include 1-21, 1-54, 1-74, 1-105, 1-110, 1-115, 1
-120, 1-125, 1-126, 1-127, 2-14, 2-38, 2-59, 2-66,
2-72, 2-78, 2-84, 2-96, 2-101, 2-106, 2-111, 2-11
6, 2-117 and 2-120.

The lipid X analog of the present invention can be produced from the known compound glucosamine (II) as a starting material by the method described below.

[Method A]

[0021]

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[0022]

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[Method B]

[0024]

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[Method A] In the compound of the present invention, 1
This is a method for producing a compound in which a phosphoric acid residue is bonded at the position. [Method B] is a method for producing a compound of the present invention in which a phosphoric acid residue is bonded to the 4-position.

In the above formula, R ² and R ³ are as defined above. R ^{2 ′} and R ^{3 ′} are the same or different and each are an aliphatic acyl group having 6 to 20 carbon atoms or a group selected from the following [Substituent group A ′], wherein at least one or more carbon atoms are substituted. Represents from 20 to 20 aliphatic acyl groups. [Substituent group A '] A halogen atom, a hydroxyl group, a hydroxyl group protected by a "hydroxyl protecting group" in the definition of R ¹ , R ⁴ or R ⁵ , an aliphatic acyloxy group having 6 to 20 carbon atoms and a halogen atom A substituted aliphatic acyloxy group having 6 to 20 carbon atoms. R ⁶ is, for example, an aliphatic acyl group; an aromatic acyl group; an alkoxycarbonyl group; an alkenyloxycarbonyl group; an aralkyloxycarbonyl group; an amine protecting group such as the silyl group or the aralkyl group. Show. R ⁷ and R
¹¹ is the same or different and represents the same group as the “hydroxyl protecting group” in the definition of R ¹ , R ⁴ and R ⁵ . R ⁸ and R ⁹ are the same or different and are, for example, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, s-
Butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl , 1,1-dimethylbutyl,
A linear or branched alkyl group having 1 to 6 carbon atoms such as 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, or a carbon atom such as phenyl, naphthyl, etc. There may be mentioned 5 to 12 aryl groups. The aryl group may have 1 to 4 substituents selected from the following on the ring, and the substituent on the ring includes an amino group; a nitro group; and a cyano group. A carboxy group optionally substituted with the lower alkyl, a lower alkyl halide described below or the aralkyl, a carbamoyl group, the halogen atom, the lower alkyl group, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl. Halogenated lower alkyl groups such as, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-dibromoethyl And the above-mentioned aliphatic acyl groups, preferably a halogen atom or a halogenated lower alkyl group. R ¹⁰ and R ¹² are the same or different and each represents a protecting group for a phosphate group such as the aryl group or the aralkyl group.

In the first step , glucosamine hydrochloride (II) is
Trifluoroacetic acid and dicyclohexylcarbodiimide (D
CC), trifluoroacetic anhydride and triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, 1,5-diazabicyclo [ 4.3.
0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU)
And trifluoroacetate such as ethyl trifluoroacetate, and the above-mentioned organic base to produce an amide (III). 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 halogenated hydrocarbon such as methylene chloride or chloroform; Ethers such as tetrahydrofuran, dioxane and dimethoxyethane; methano-
, Ethanol, n-propanol, isopropanol,
alcohols such as n-butanol, isobutanol and isoamyl alcohol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; and sulfoxides such as dimethylsulfoxide. it can. Reaction temperature is 0 ° C to 100
C., preferably room temperature, and the reaction time is usually 0.1 hour to 24 hours, varying mainly depending on the reaction temperature, the type of the starting compound or the type of solvent used.

In the second step , the amide compound (III) is formed with an alcohol having the general formula R ⁷ OH (eg, methanol, ethanol, benzyl alcohol, allyl alcohol) under an acid catalyst to form a glycosidic bond, and the compound (IV) ). The solvent is a reagent represented by the general formula R ⁷
A large excess of alcohols with OH is used. The acid used is generally not particularly limited as long as it functions as an acid, but preferably includes hydrochloric acid, a mineral acid such as sulfuric acid, and an organic acid such as p-toluenesulfonic acid. The above-mentioned hydrous acids can also be used. Reaction temperature is 0 ℃ ~ 20
Carried out at 0 ° C., preferably at reflux temperature,
The reaction time varies depending mainly on the reaction temperature, the starting compound and the type of solvent used, but is usually from 0.1 hour to 24 hours.

In the third step , the alcohols at the 4- and 6-positions of the compound (IV) are converted to isopropylidene in a solvent under an acid catalyst,
This is a step of producing a compound (V) by protecting diols such as benzylidene and ethylidene. Geo-
The reagent used for the protection of the diol is not particularly limited as long as it is usually used for the protection of the diol.
Preferable examples include aldehyde derivatives such as benzaldehyde, ketone derivatives such as acetone, and dimethoxy compounds such as 2,2-dimethoxypropane and dimethoxybenzyl. The solvent is not particularly limited as long as it does not inhibit the reaction, but is preferably a halogenated hydrocarbon such as methylene chloride or chloroform, an ether such as dioxane or tetrahydrofuran, hexane or pentane. Hydrocarbons, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate, and polar solvents such as dimethylformamide and acetone. The acid catalyst to be used is not particularly limited as long as it is usually used as an acid. Inorganic acids or Lewis acids such as zinc chloride, aluminum chloride and tin chloride. The reaction temperature varies depending on the acid catalyst used, the starting compound, and the like, but is usually carried out at 0 to 100 ° C. , Usually 0.1 to 24 hours.

The fourth step is to remove the R ⁶ group of compound (V) to produce compound (VI). As the R ⁶ group,
When a silyl group is used, it is usually removed by treating with a compound which generates a fluorine anion such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferred. The reaction temperature and reaction time are not particularly limited, but are usually 10
Let react for minutes to 18 hours.

When R ⁶ is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating with a base in the presence of an aqueous solvent or by reduction. The base is not particularly limited as long as it does not affect the other parts of the compound,
It is preferably carried out using an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or concentrated ammonia-methanol. The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction. Water or water and alcohols such as methanol, ethanol, n-propanol or tetrahydrofuran is used. And a mixed solvent with an organic solvent such as ethers such as dioxane. The reaction temperature and the reaction time vary depending on the starting material, the base used, and the like, and are not particularly limited.
And 1 to 10 hours. The removal by reduction is performed using a reducing agent such as sodium borohydride according to a conventional method.

When the R ⁶ group is an aralkyl group or an aralkyloxycarbonyl group, a preferred method is to carry out catalytic reduction at room temperature using a catalyst such as platinum or palladium carbon. The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the present reaction, but may be methanol, ethanol,
Alcohols such as isopropanol, diethyl ether
Ethers such as ter, tetrahydrofuran, dioxane, aromatic hydrocarbons such as toluene, benzene, xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, Fatty acids such as acetic acid or a mixed solvent of these organic solvents and water is preferred. The catalyst to be used is not particularly limited as long as it is generally used for a catalytic reduction reaction, but preferably, palladium carbon, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide,
Triphenylphosphine-rhodium chloride, palladium-
Barium sulfate is used. The pressure is not particularly limited, but is usually 1 to 10 atm. The reaction temperature and reaction time vary depending on the type of the starting material and the catalyst, etc., but are usually carried out at 0 ° C. to 100 ° C. for 5 minutes to 24 hours.

When the R ⁶ group is an alkenyloxycarbonyl group, the same conditions as those for the removal reaction when the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group or a lower alkoxycarbonyl group are usually used. And can be eliminated by treating with a base. In the case of allyloxycarbonyl, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions.

The fifth step is a step of preparing the compound (VII) by acylating the 2-position amino group of the compound (VI). As an acylation method, a carboxylic acid having the general formula R ^{2 ′} OH (wherein R ^{2 ′} has the same meaning as described above) is converted to a condensate such as dicyclohexylcarbodiimide (DCC) or carbonyldiimidazole. Reacting in the presence of an agent, or an activated acylating agent R ^{2 ′} X wherein R ^{2 ′} has the same meaning as described above, and X is a group having the general formula OR ^{2 ′} ; chlorine, bromine,
Halogen atoms such as iodine; alkylcarbonyloxy groups such as acetoxy and propionyloxy; halogenated alkylcarbonyloxy groups such as chloroacetyloxy, dichloroacetyloxy, trichloroacetyloxy and trifluoroacetyloxy; and methoxyacetyloxy Aliphatic alkoxyoxy groups such as unsaturated alkoxycarbonyloxy groups such as (E) -2-methyl-2-butenoyloxy; arylcarbonyloxy groups such as benzoyloxy; 2-bromo Halogenated arylcarbonyloxy groups such as benzoyloxy and 4-chlorobenzoyloxy; lower alkylated arylcarbonyloxy groups such as 2,4,6-trimethylbenzoyloxy and 4-toluoyloxy; Anisoyloxy Lower alkoxy of ants, such as - ylcarbonyl group, 4-nitro-benzoyloxy, nitration, such as 2-nitro-benzoyloxy ants -
An aromatic acyloxy group such as a carbonyloxy group; a trihalogenomethyloxy group such as trichloromethyloxy; a lower alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy; And a leaving group such as an arylsulfonyloxy group such as benzenesulfonyloxy and p-toluenesulfonyloxy. ) With a solvent in the presence of a base. The solvent is not particularly limited as long as it does not inhibit the reaction, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride, or an ether such as ether, dioxane or tetrahydrofuran. Examples thereof include hydrocarbons such as ters and hexane, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate, and polar solvents such as dimethylsulfoxide and dimethylformamide. As the base used, preferably, an organic base can be mentioned, for example, triethylamine, pyridine, DBU, DBN, N, N-dimethylaniline, N, N-diethylaniline, N, N-dimethylaminopyridine is there. The reaction is carried out at a temperature of 0 ° C. to 100 ° C., preferably 20 ° C. to 50 ° C., and the reaction time varies mainly depending on the reaction temperature, the type of the starting compound or the type of the solvent used, but is usually 0.1%. Hours to 24 hours.

In the sixth step , the hydroxyl group at the 3-position of the compound (VII) is converted in the same manner as in the acylation of the amino group in the fifth step.
In this step, the compound (VIII) is produced by modifying with the R ^{3 ′} group.

The seventh step is a step for producing a compound (IX) by removing the protecting group R ^{7 at} the 1-position of the compound (VIII). R
^{In the case where the 7} group is a silyl group, an aralkyloxycarbonyl group, an aralkyl group, an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group, an alkoxymethyl group or a substituted ethyl group, R ⁶
It is carried out according to the removal method when the group is the corresponding group.

When the R ⁷ group is a tetrahydropyranyl group, a tetrahydrofuranyl group or the like, it can be usually removed by treating with an acid in a solvent. The acid used is preferably hydrochloric acid, sulfuric acid, paratoluenesulfonic acid or acetic acid. The solvent to be used is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; A mixed solvent of a solvent and water is preferred. The reaction temperature and the reaction time vary depending on the starting material and the kind of the acid used, but are usually 0 ° C. to 50 ° C. and 10 minutes to 18 hours.

When the R ⁷ group is an alkenyloxycarbonyl group, it is usually treated with a base in the same manner as in the removal reaction when the R ⁷ group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group. Can be desorbed. In the case of allyloxycarbonyl, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly simple and can be carried out with few side reactions.

When the R ⁷ group is an allyl group, preferably, the reaction is carried out in a solvent in the presence of a catalyst to transfer the double bond to an enol ether type, and immediately convert pyridine-iodine-water. By adding, it can be removed. The solvent is not particularly limited as long as it does not inhibit the reaction, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride, or an ether such as ether, dioxane or tetrahydrofuran. Examples thereof include hydrocarbons such as ters and hexane, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate, and polar solvents such as dimethylsulfoxide and dimethylformamide. Examples of the catalyst used include a palladium catalyst such as palladium chloride and palladium acetate, a rhodium catalyst such as 1,5-cyclooctadiene-bis (methyldiphenylphosphine) rhodium hexafluorophosphate, and rhodium acetate; Double bond transfer agents such as iridium catalysts such as cyclooctadiene-bis (methyldiphenylphosphine) iridium hexafluorophosphate may be mentioned. The reaction temperature varies depending on the catalyst, solvent, etc.
Performed at ~ 100 ° C. The reaction time varies depending on the reaction temperature in addition to the above, but is usually 1 to 5 hours.

The eighth step is a step of preparing the compound (X) by phosphorylating the 1-position hydroxyl group of the compound (IX) thus obtained. Phosphorylation is carried out by forming an anion with a base in a solvent and then reacting with a phosphorylating agent. The solvent is not particularly limited as long as it does not inhibit the reaction, but is preferably ether, dioxane,
Ethers such as tetrahydrofuran or halogenated hydrocarbons such as chloroform and methylene chloride can be mentioned. The base used is also not particularly limited as long as it normally forms an anion, but is preferably a lithium compound such as normal butyl lithium or phenyl lithium, or DBU, DBN, DMAP, triethylamine, or pyridine. Organic bases. As the phosphorylating agent, a reagent usually used for phosphorylation such as dibenzylchlorophosphate and diphenylchlorophosphate is used. Reaction temperature is -78 to
The reaction is carried out at 50 ° C., preferably at −78 ° C. to room temperature, and the reaction time is usually 10 minutes to 24 hours, although it depends mainly on the reaction temperature, the type of the starting compound or the solvent used. .

In the ninth step , the protecting group of the compound (X) is removed to produce the compound (XI), and if necessary, the protecting group of the R ^{3 ′} group is removed. In principle, the reaction for removing the protecting group for the phosphoric acid residue and the reaction for removing the protecting group for the hydroxyl group vary depending on the type of the protecting group, but the desired removal reaction can be carried out in any order and can be carried out sequentially. Although the protecting group of the phosphoric acid residue may be simultaneously removed by the operation of removing the protecting group, it is generally preferable to remove the protecting group R ¹⁰ of the phosphoric acid residue last. This is because of the ease of handling.
For example, when the R ¹⁰ group is an aralkyl group such as benzyl, the hydroxyl group is added to R ² and / or R ^{3 ′} by hydrogenolysis at −78 ° C. to room temperature under the catalyst of palladium carbon. All protecting groups can be removed at once, including the case where a protecting group is present, and when R ¹⁰ is an aryl group such as a phenyl group, hydrogenation under the catalyst of palladium carbon After the cracking, it is further carried out by carrying out a hydrogenolysis under the catalyst of platinum oxide. In some cases (for example, in the case of acetonide), the protecting group in which the R ⁸ and R ⁹ groups are partly removed by silica gel chromatography to remove the protecting group. Alternatively, in a solvent such as ethers such as tetrahydrofuran and dioxane, and alcohols such as ethanol and methanol, the temperature is raised to 0 to 100 ° C. by using dilute hydrochloric acid, dilute sulfuric acid, or hydrous paratoluenesulfonic acid as a catalyst. To remove. When a water-soluble salt of phosphoric acid is to be obtained, the salt is first washed with an inorganic acid diluted with water such as dilute hydrochloric acid, and then dissolved in an organic inert solvent such as chloroform and added with a base. Can be.

In the tenth step , the 4- and 6-positions of compound (VIII)
This is a step of producing a compound (XII) by removing the hydroxyl group at the 1-position, and is carried out according to the ninth step.

The eleventh step is a step of preparing the compound (XIII) by protecting the hydroxyl group at the 6-position of the compound (XII) with an R ¹¹ group. A compound having a 6-position primary hydroxyl group represented by the general formula R ¹¹ X
(Wherein, R ¹¹ and X have the same meanings as described above; for example, Cl 11
CH ₂ OCH ₃ , ClCH ₂ OCH ₂ C ₆ H ₅ , BrCH ₂ OCH ₂ C ₆ H ₅ , ClCO ₂ CH ₂
C ₆ H ₅ and ClCO ₂ CH ₂ CCl ₃ can be mentioned. ), -50
〜50 ° C. in a solvent (e.g., halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride,
Ethers such as ether, dioxane, tetrahydrofuran, hydrocarbons such as hexane, aromatic hydrocarbons such as benzene and toluene, esters such as ethyl acetate, dimethyl sulfoxide, dimethylformamide, acetone Polar solvents), bases (eg, DB
U, DBN, DMAP, DABCO, pyridine, triethylamine, aniline, N, N-dimethylaniline, N, N-diethylaniline) or in a solvent (eg, acetone, tetrahydrofuran, dioxane), base (eg, sodium hydroxide) , Potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate).

The twelfth step is a step of preparing the compound (XIV) by phosphorylating the 4-position hydroxyl group of the compound (XIII).
It is performed according to the process.

The thirteenth step is a step of preparing the compound (XV) by removing the protecting group of the compound (XIV). The removal of the protecting groups R ⁷ and R ¹¹ of the hydroxyl group is carried out according to the seventh step. And
When a protecting group for a hydroxyl group is present on R ^{2 ′} and / or R ^{3 ′} , removal of the protecting group and the protecting group R ^{12 for} a phosphoric acid residue are carried out according to the ninth step. As described in the step, it is preferable to carry out the method by devising conditions so that the protecting group R ¹² of the phosphoric acid residue is removed last.

In the fourteenth step , the protecting group for the hydroxyl group at the 1-position of the compound (XIV) is selectively removed in the same manner as in the seventh step.
After phosphorylating the 1-position hydroxyl group according to the step, if there is a hydroxyl-protecting group on the hydroxyl-protecting group R ¹¹ , R ^{2 ′} and / or R ^{3 ′} according to the thirteenth step, the protecting group is and removing the protecting group R ¹² of the phosphate residues, to produce compound (XVI).

[0047]

EFFECT OF THE INVENTION [ ¹⁴ C] Prostaglandin D ₂ release
Since there is a correlation between the measured macrophage activating action and the prostaglandin D ₂ releasing action, see [Zoela et al. (J. Biol.
m., Vol. 262, No. 35, pp. 17212-17220]], and a test was conducted on this. Cells were seeded at 5 × 10 ⁵ per well in 12-well culture dishes containing 1 ml of the culture solution, and cultured at 37 ° C. overnight. To this, 0.1 μCi / ml of [ ¹⁴ C] arachidonic acid was added, and labeling was performed for 18 hours. Wash each well three times with 0.5 ml of culture solution, add the test compound, and
Cultured for hours. The culture was collected and centrifuged for 5 minutes to remove cells. This culture solution was acidified, the liberated prostaglandin D ₂ chloroform: ethanol (2: 1,
(Volume ratio), followed by thin layer chromatography using a developing solvent system of chloroform, ethyl acetate, ethanol, and acetic acid (20: 20: 4: 1, volume ratio) to separate. Labeled prostaglandin D ₂ and O - autoradiography - was identified by the portion corresponding to the radioactivity scraped from the thin layer, liquid scintillation - Deployment counter - it was measured at.

[0048] The novel lipid X analogs of the present invention are excellent macrophages.
Since it has a diactivating effect and has low toxicity, it is useful as an immunostimulant or an antitumor agent. Compound of the present invention
As the administration form of (I), for example, tablets, capsules,
Oral administration by granules, powders, syrups, and the like, and parenteral administration by injections, suppositories, and the like can be mentioned. These preparations are manufactured by a known method using additives such as excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents. The amount used varies depending on symptoms, age, etc., but it can be usually administered to adults at a dose of 0.01 to 50 mg / kg body weight once or several times a day.

Hereinafter, the present invention will be described more specifically with reference to examples.

[0050]

Example 1 2-deoxy-2-[(3'R) -3'-hydroxymi
Ristoylamino] -3-O-[(2 "RS, 3" SR) -2 "-Fluoro
B-3 "-Hydroxymyristoyl] -α-D-glucopi
Lanosyl-1-phosphate

[0051]

Example 1a N-trifluoroacetylglucosamine

[0052]

Embedded image

160 g of D-(+)-glucosamine hydrochloride (0.742 mol
l) was dissolved in 2200 ml of methanol (99.6%), and 187.9 g (1.86 mol) of triethylamine was added. Further, 115.9 g of ethyl trifluoroacetate was added dropwise under ice-cooling, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, benzene (250 ml × 2) and ethyl acetate (250 ml) were sequentially added, concentrated under reduced pressure, and dried sufficiently with a vacuum pump. The crude trifluoroacetyl compound obtained here was advanced to the next step without purification.

[0054]

Example 1b Allyl 2-deoxy-2-trifluoroa
Cetamide-D-glucopyranoside

[0055]

Embedded image

To the crude trifluoroacetyl compound obtained in Example 1a was added 1850 ml of a 2% hydrochloric acid-allyl alcohol solution, and the mixture was heated under reflux for 30 minutes. The mixture was cooled to about 50 ° C. with ice water and filtered through celite. The filtrate was concentrated and dried sufficiently with a vacuum pump. The crude allyl ether obtained here proceeded to the next step without purification.

[0057]

Example 1c Allyl 2-deoxy-2-trifluoroa
Cetamide-4,6-O-isopropylidene-D-glucopi
Lanoside

[0058]

Embedded image

The crude allyl ether obtained in 1b was
Dissolve in 740 ml of N, N-dimethylformamide, add 370 ml of 2,2-dimethoxypropane, and further add pyridinium p.
-7.5 g of toluenesulfonate was added and the mixture was stirred at room temperature overnight. It concentrated under reduced pressure and diluted with ethyl acetate. The precipitate was removed by filtration, and the filtrate was washed with aqueous sodium hydrogen carbonate, water, and brine. The extract was dried over anhydrous magnesium sulfate, filtered using celite and activated carbon, and concentrated. The residue was applied to a silica gel column, and cyclohexane: ethyl acetate = 3: 2.
8 and 0.5, respectively, in which the ether bond at the 1-position is α and β.
g, 77.3 g, separated and purified. Both α-form and β-form can be used for the subsequent reaction. [Α-allyl form] mass spectrum M / Z; 356 [M ⁺ +1],
340, 298, 282, 256, 240, 222, 211, 193, 168, 126,
109, 101. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.44 (3H, s);
1.52 (3H, s); 2.50 (1H, br.s); 3.57-3.90 (5H, m); 3.99 (1
H, m); 4.15-4.24 (2H, m); 4.91 (1H, d, J = 4.0Hz); 5.23-5.
33 (2H, m); 5.79-5.93 (1H, m); 6.55 (1H, d, J = 8.8Hz). Infrared absorption spectrum ν max cm-1 (KBr): 3460-3300,
1733 (sh), 1716, 1560. Elemental analysis _{(C 14 H 20 NO 6 F} 3 = 355.3
As) [Β-allyl form] mass spectrum M / Z; 356 [M ⁺ +1],
340, 298, 280, 256, 240, 222, 211, 193, 168, 155,
145, 126, 114, 101. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.32 (3H, s);
1.50 (3H, s); 3.23 (1H, dt.J = 6.2,9.5Hz); 3.60 (1H, t, J =
9.2Hz); 3.74-3.87 (4H, m); 4.04 (1H, m); 4.27 (1Hm); 4.
65 (1H, d, J = 4.8Hz); 4.69 (1H, d, J = 8.1Hz); 5.11 (1H, m);
5.25 (1H, m); 5.78-5.92 (1H, m); 8.48 (1H, d, J = 7.0Hz). Infrared absorption spectrum ν max cm-1 (KBr): 3490, 3300,
1707, 1560. Elemental analysis (assuming C ₁₄ H ₂₀ NO ₆ F ₃ = 355.3)

[0060]

Example 1d Allyl 2-deoxy-2-amino-4,6-O
10 g of the β-allyl compound obtained with isopropylidene-β-D-glucopyranoside 1c was added to ethanol (99.
5%) in 200 ml, and add 1N aqueous sodium hydroxide solution to 10 ml.
0 ml was added and the mixture was heated under reflux for 4 hours. It concentrated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure, and the residual oil was applied to a silica gel column and purified with ethyl acetate to obtain 6.6 g (90.5%) of the desired compound. NMR spectrum (60 MHz, CDCl ₃ ) δ p
pm: 1.43 (3H, s); 1.52 (3H, s); 2.40 (3H, br.s); 2.6-4.6
(9H, m); 5.05-6.35 (3H, m). Elemental analysis (assuming C ₁₂ H ₂₁ NO ₅ = 259.302)

[0061]

Example 1e Allyl 2-deoxy-2-[(3'R) -3'-beta
Ndyloxymyristoylamino] -4,6-O-isopro
5 g (19.3 mmol) of the compound obtained with pyridene-β-D-glucopyranoside 1d was treated with methylene chloride.
After dissolving in 150 ml, 6.8 g of (R) -3-benzyloxymyristate was added, and further, 4.79 g of N, N'-dicyclohexylcarbodiimide was added, followed by stirring at room temperature for 1 hour. filtration,
It concentrated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure. The residue was applied to a silica gel column and purified with cyclohexane: ethyl acetate = 1: 1 to obtain 5.33 g of the desired compound.
(48%). Infrared absorption spectrum ν max cm-1 (KBr): 3510, 3280,
1643, 1550. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (3H, t, J =
6.9Hz); 1.20-1.41 (18H, m); 1.45 (3H, s); 1.52 (3H, s);
1.56-1.70 (2H, m); 2.43 (1H, dd, J = 6.9,15.4Hz); 2.56 (1
H, dd, J = 3.7,15.0Hz); 3.19-3.29 (1H, m); 3.46-3.63 (2H,
m); 3.75-3.94 (5H, m); 4.18-4.24 (1H, m); 4.36 (1H, d, J =
2.6Hz); 4.45-4.62 (3H, m); 5.12-5.26 (2H, m); 5.70-5.8
8 (1H, m); 6.72 (1H, d, J = 5.9Hz); 7.30-7.37 (5H, m).

[0062]

Example 1f Allyl 2-deoxy-2-[(3'R) -3'-beta
Ndyloxymyristoylamino] -3-O-[(2 "RS, 3"
SR) -2 "-Fluoro-3"-(benzyloxycarbonyloxy
B) Myristoyl] -4,6-O-isopropylidene-β-
1 g (1.74 mmol) of the N-acyl compound obtained with D-glucopyranoside 1e was dissolved in 80 ml of methylene chloride, and (±) -syn-2-fluoro-3-benzyloxycarbonyloxymyristic acid 828 was dissolved. mg,
359 mg of N, N'-dicyclohexylcarbodiimide,
255 mg of 4-dimethylaminopyridine was sequentially added, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, concentrated under reduced pressure, and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure. The residue was applied to a silica gel column, and cyclohexane: ethyl acetate =
Purification was performed at 5: 1 to obtain the desired compound in a yield of 1.22 g (73.6%). Elemental analysis (as _{C 55 H 84 FNO 11 · H} 2 O = 972.286) Infrared absorption spectrum ν max cm-1 (film): 329
0, 1750, 1655. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.66-2.43 (57
H, m); 3.12-6.53 {17H, m [including 4.98 (2H, s)]}; 7.28 (1
0H, s).

[0063]

Example 1g 2-deoxy-2-[(3'R) -3 '-(benzylo
Xy) myristoylamino] -3-O-[(2 "RS, 3" SR) -2 "
-Fluoro-3 "-(benzyloxycarbonyloxy) mi
Ristoyl] -4,6-O-isopropylidene-D-glucose
380 mg of the compound obtained with pyranose 1f was dissolved in 20 ml of dried tetrahydrofuran, and 17 mg (5% mol) of 1,5-cyclooctadiene-bis [methyldiphenylphosphine] iridium hexafluorophosphate was dissolved. Then, the inside of the reaction vessel is replaced with nitrogen and further replaced with hydrogen. After confirming that the color of the solution had changed from red to colorless, it was immediately replaced with nitrogen. After stirring at room temperature for 3 hours, water 2 ml, iodine 200 mg,
0.2 ml of pyridine was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with 5% aqueous sodium thiosulfate, aqueous sodium hydrogen carbonate, and aqueous sodium chloride. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was applied to a silica gel chromatography column and purified with cyclohexane: ethyl acetate = 3: 1 to give the desired compound 28
0 mg (76.9%) was obtained. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.53-2.78
(58H, m); 3.48-5.43 {11H, m [including 5.12 (2H, s)]}; 6.
25 (1H, d, J = 8Hz); 7.28-7.48 (10H, m). Elemental analysis (as C ₅₂ H ₈₀ FNO ₁₁ = 914.206)

[0064]

Example 1h 2-deoxy-2-[(3′R) -3′-hydroxy
Myristoylamino] -3-O-[(2 "RS, 3" SR) -2 "-full
Oro-3 "-hydroxymyristoyl] -α-D-gluco
550 mg of the compound obtained with 1 g of pyranosyl- 1 -phosphate is dissolved in 20 ml of dried tetrahydrofuran, and the solution is heated at -78 ° C. in a nitrogen stream.
Slowly add 0.4 ml of normal butyllithium (1.6M hexane solution), and after 2 minutes dibenzyl phosphorochloride
5 ml dried tetrahydrofuran solution containing 231 mg
Was added dropwise. Five minutes later, at the same temperature, 1 g of 10% palladium carbon was added, and hydrogenolysis was performed. After 15 minutes, the temperature was returned from -78 ° C to room temperature, and the mixture was stirred for 3 hours. After filtration, tetrahydrofuran was distilled off under reduced pressure, and the residue was applied to a silica gel chromatography column and purified with chloroform: methanol = 5: 1.
The 6-O-isopropylidene group was also removed, and the target compound was
g (22.3%). Mass spectrum (FAB / MS):
728 [M −H] ⁻

[0065]

Embodiment 22-deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3'-Hydroxymyristoylamino] -3-O-[(3 "
R) -3 "-Hydroxymyristoyl] -α-D-glucopi
Lanosyl-1-phosphate

[0066]

Example 2a Allyl 2-deoxy-2-[(2'R, 3'S) and
Beauty (2'S, 3'R) -2'- fluoro-3 '- (benzylidene Ruokishikarubo
Nyloxy) myristoylamino] -4,6-O-isopro
10 g (38.56 mmol) of the compound obtained with pyridene-β-D-glucopyranoside 1d are dissolved in 200 ml of methylene chloride and (±) -syn-2-fluoro-3- (benzyloxycarbonyloxy) 16.06 g of myristic acid was added, and N5N-dicyclohexylcarbodiimide was added to 955 g.
Was added and stirred at room temperature for 1 hour. The mixture was filtered, concentrated under reduced pressure, and diluted with ethyl acetate. The ethyl acetate layer was washed with sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure.
9.6 g (39.03%) of (R, 3'S) and (2'S, 3'R)
In a yield of 9.67 g (39.31%). [(2'R, 3'S) compound] NMR spectrum (270MHz, CDCl ₃₎
δ ppm: 0.88 (3H, t, J = 6.9Hz); 1.18-1.43 (18H, m); 1.47
(3H, s); 1.53 (3H, s); 1.67-1.98 (2H, m); 3.15-3.24 (1H,
m); 3.57-3.84 (5H, m); 3.91 (1H, dd, J = 5.5,10.6Hz); 4.0
2 (1H, dd, J = 6.2,12.8Hz); 4.23-4.30 (1H, m); 4.39 (1H, d,
J = 8.06Hz); 4.94 (1H, dd, J = 2.2,47.6Hz); 5.14-5.28 (5H,
m); 6.45 (1H, t, J = 5.4Hz); 7.34-7.41 (5H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1750,168
5, 1535. [(2'S, 3'R) compound] NMR spectrum (270 MHz, CDCl ₃ )
δ ppm: 0.88 (3H, t, J = 6.9Hz); 1.18-1.43 (18H, m); 1.45
(3H, s); 1.53 (3H, s); 1.54-2.01 (2H, m); 3.30-3.36 (3H,
m); 3.55 (1H, t, J = 9.5Hz); 3.80 (1H, t, J = 10.3Hz); 3.93
(1H, dd, J = 5.5,11.0Hz); 4.01-4.14 (2H, m); 4.27 (1H, dd,
J = 5.5,18.3Hz); 4.87 (1H, d, J = 8.4Hz); 4.91 (1H, dd, J = 2.
2,48.0Hz); 5.09-5.30 (5H, m); 5.78-5.93 (1H, m); 6.60 (1
H, t, J = 5.1Hz); 7.26-7.38 (5H, m). Elemental analysis (as C ₃₄ H ₅₂ FNO ₉ = 637.786) Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1750, 168
5, 1535.

[0067]

Example 2b Allyl 2-deoxy-2-[(2'R, 3'S) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O-[(3 "R) -3" -benzyloxy
Shimiristoyl] -4,6-O-isopropylidene-β-D
-3.5 g (5.49 mmol) of the (2'R, 3'S) compound obtained with glucopyranoside 2a,
Dissolve in 150 ml of methylene chloride, add 1.93 g of (R) -3-benzyloxymyristic acid, further add 0.7 g of 4-dimethylaminopyridine, 1.36 g of N, N'-dicyclohexylcarbodiimide, and add room temperature. For 1 hour. The mixture was filtered, concentrated under reduced pressure, and diluted with ethyl acetate. The ethyl acetate layer was washed with sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, ethyl acetate was distilled off under reduced pressure, and the residue was subjected to cyclohexane: ethyl acetate = 5: 1.
And the target compound was obtained in a yield of 3.54 g (67.6%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (6H,
t, J = 6.6Hz); 1.25-1.73 (46H, m); 2.42-2.61 (2H, m); 3.3
5-3.42 (1H, m); 3.56-4.08 (6H, m); 4.21-4.28 (1H, m); 4.4
0-4.98 (4H, m); 5.07-5.36 (6H, m); 5.72-5.86 (1H, m); 6.
44-6.48 (1H, m); 7.14-7.35 (10H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1743, 169
5, 1530.

[0068]

Example 2c 2-Deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3 '-(Benzyloxycarbonyloxy) myristoy
Ruamino] -3-O-[(3 "R) -3" -benzyloxymyris
Toyl] -4,6-O-isopropylidene-D-glucopyra
The compound obtained in Node 2b was treated in the same manner as 1 g to give 2.69 g (79.3%) of the desired compound. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (6H, t, J =
6.2Hz); 1.23-1.73 (46H, m); 2.42-2.54 (3H, m); 3.60-4.
02 (6H, m); 4.42-5.27 (9H, m); 7.16-7.46 (10H, m) .Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1745, 1685, 153
Five.

[0069]

Example 2d2-deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3'-Hydroxymyristoylamino] -3-O-[(3 "
R) -3 "-Hydroxymyristoyl] -α-D-glucopi
Lanosyl-1-phosphate The compound obtained in 2c was treated in the same manner as in 1h,
The compound was obtained in a yield of 91 mg (11%). Mass spectrum (FAB / MS): 728 [M-H]^-

[0070]

Embodiment 32-deoxy-2-[(2'S, 3'R) -2'-fluoro-
3'-Hydroxymyristoylamino] -3-O-[(3 "R)-
3 "-Hydroxymyristoyl] -α-D-glucopyrano
Sil-1-phosphate

[0071]

Example 3a Allyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O-[(3 "R) -3" -benzyloxy
Cicarbonyloxy myristoyl] -4,6-O-isopro
3.5 g of the (2 ′S, 3′R) compound obtained with pyridene-β-D-glucopyranoside 3a was treated in the same manner as 2b to give the desired compound in a yield of 2.7 g ( 49.3 %). Was.

[0072]

Example 3b 2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3 '-(Benzyloxycarbonyloxy) myristoy
Ruamino] -3-O-[(3 "R) -3"-(benzyloxycarbo
Nyloxy) myristoyl] -4,6-O-isopropylide
The compound obtained with 1 -D-glucopyranose 3a was treated in the same manner as in 1 g to obtain the desired compound in a yield of 1.75 g (67.5%). NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.81-2.34 (52
H, m); 2.47-2.78 (2H, m); 3.00 (1H, br.); 3.45-5.51 {14H,
m [including 5.12 (4H, s)]}; 6.65 (1H, br.s); 7.35 (10H,
s). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1745, 167
0, 1545.

[0073]

Example 3c 2-Deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3'-Hydroxymyristoylamino] -3-O-[(3 "R)-
3 "-Hydroxymyristoyl] -α-D-glucopyrano
The compound obtained with sil-1-phosphate 3b was treated in the same manner as in 1h to give the desired compound in a yield of 190 mg (29.3%).

[0074]

Embodiment 42-deoxy-2-[(2'R, 3'S) -2'-fluoro-
3'-Hydroxymyristoylamino] -3-O-[(3 "R)-
3 "-Hydroxymyristol] -D-glucopyranosyl-
4-phosphate

[0075]

Example 4a Allyl 2-deoxy-2-[(2'R, 3'S) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O-[(3 "R) -3"-(benzyloxy
Cicarbonyloxy) myristoyl] -4,6-O-isop
The (2′R, 3 ′S) compound obtained with lopylidene-β-D-glucopyranoside 2a was treated in the same manner as in 3a to give the desired compound in a yield of 6.1 g (77.9%). NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.86-2.23 (52
H, m); 2.45-2.84 (2H, m); 3.17-6.30 {19H, m [5.12 (4H, s)
6.58 (1H, br.s); 7.33 (10H, s). Infrared absorption spectrum ν max cm-1 (KBr): 1745, 1671, 1545.

[0076]

Example 4b Allyl 2-deoxy-2-[(2'R, 3'S) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O-[(3 "R) -3"-(benzyloxy
Cycarbonyloxy) myristoyl] -β-D-gluco
5 g (5.24 mmol) of the compound obtained with pyranoside 4a was added to 50 ml of 80%
It was suspended in acetic acid and stirred at 50 ° C. for 30 minutes. Acetic acid was distilled off under reduced pressure.
(94.8%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (6H, t, J =
6.9Hz); 1.08-1.84 (40H, m); 2.47 (1H, dd, J = 8.1,15.0H
z); 2.58 (1H, dd, J = 3.7,15.0Hz); 3.26 (1H, br.s); 3.40-
3.45 (1H, m); 3.61 (1H, t, J = 9.2Hz); 3.75-3.94 (3H, m);
4.00-4.31 (2H, m); 4.63 (1H, d, J = 8.4Hz); 4.82-5.28 (11
H, m); 5.75-5.88 (1H, m); 6.00 (1H, dd, J = 4.4,8.4Hz); 7.
33-7.38 (10H, m). Elemental analysis (as C ₅₃ H ₈₀ FNO ₁₃ = 958.215) Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1745, 169
5, 1535.

[0077]

Example 4c Allyl 2-deoxy-2-[(2'R, 3'S) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O-[(3 "R) -3"-(benzyloxy
Cicarbonyloxy) myristoyl] -6-O-benzyl
Oxycarbonyl - beta-D-Group Kopiranosaido compound obtained in 4b 4.3 g (4.5 mmol) in methylene chloride
The solution was dissolved in 100 ml, 822 mg of 4-dimethylaminopyridine was added, and 916 mg of benzyloxychloroformate was added dropwise, followed by stirring at room temperature for 1 hour. It concentrated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, ethyl acetate was distilled off under reduced pressure. The residue was applied to a silica gel column, and cyclohexane: ethyl acetate = 5: 1.
And the target compound was obtained in a yield of 2.43 g (49.6%). NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.64-1.89 (46
H, m); 2.37-2.64 (2H, m); 3.09-6.20 {22H, m [5.09 (4H,
s), 5.13 (2H, s)]]; 6.49 (1H, br.s); 7.32 (15H,
s). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1745, 169
5, 1533.

[0078]

Example 4d Allyl 2-deoxy-2-[(2'R, 3'S) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O-[(3 "R) -3"-(benzyloxy
Cicarbonyloxy) myristoyl] -4-O-diphenyl
Ruphosphoryl-6-O-benzyloxycarbonyl-β-
2.2 g (2.01 mmol) of the compound obtained with D-glucopyranoside 4c was methylene chloride.
The solution was dissolved in 30 ml, and 1.47 g of 4-dimethylaminopyridine was added, and 1.62 g of diphenylchlorophosphate was added dropwise, followed by stirring at room temperature for 1 hour. It concentrated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure. The residue was applied to a silica gel column, and cyclohexane: ethyl acetate was added.
= 3: 1 to give 2.65 g (99.3%) of the desired compound. NMR spectrum (60MHz, CDC
l ₃ ) δ ppm: 0.64-2.05 (46H, m); 2.25-2.51 (2H, m); 3.00-
6.15 {21H, m [including 5.08 (6H, s)]}; 6.63 (1H, br.s);
7.18-7.33 (25H, m) .Infrared absorption spectrum ν max
_{cm-1 (CHCl 3):} 1747, 1690,
1590, 1530.

[0079]

Example 4e 2-deoxy-2-[(2′R, 3 ′S) -2′-fur
Oro-3 '-(benzyloxycarbonyloxy) myristo
Ilamino] -3-O-[(3 "R) -3"-(benzyloxycal
Bonyloxy) myristoyl] -4-O-diphenylphos
Holyl-6-O-benzyloxycarbonyl-D-gluco
The compound obtained with pyranose 4d was treated in the same manner as 1 g to give the desired compound in a yield of 1.6 g (69.3%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (6H, t, J =
6.2Hz); 1.13-1.71 (40H, m); 2.37 (1H, dd, J = 7.33,17.22H
z); 2.55 (1H, dd, J = 5.13,17.22Hz); 3.61 (1H, br.); 3.83
-3.90 (1H, m); 4.16-4.37 (3H, m); 4.64-4.81 (2H, m); 4.9
6-5.28 (9H, m); 5.56 (1H, dd, J = 9.2,11.0Hz); 6.84 (1H, d
d, J = 3.3,7.7Hz); 7.09-7.37 (25H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1743, 168
5, 1590.

[0080]

Example 4f2-deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3'-Hydroxymyristoylamino] -3-O-[(3 "
R) -3 "-Hydroxymyristol]-D-glucopyranosyl
-4-phosphate 1.3 g (1.01 mmol) of the compound obtained in
Dissolve in 30 ml of lofuran and add 1 g of 10% palladium carb
And hydrogenolysis was performed at room temperature for 3 hours. Filter, filter
Add 200 mg of platinum oxide to the solution and hydrogenate again at room temperature for 2 hours
Decomposed. Filter and distill off tetrahydrofuran under reduced pressure
The residue is applied to a silica gel column and chloroform:
After 9: 1 methanol, chloroform: methanol = 5: 1
Purification gave the desired compound in a yield of 490 mg (66.3%). Infrared absorption spectrum ν max cm-1 (KBr): 1710, 1660. Mass spectrum (FAB / MS): 728 [M-H]^-

[0081]

Embodiment 52-deoxy-2-[(2'S, 3'R) -2'-fluoro-
3'-Hydroxymyristoylamino] -3-O-[(3 "R)-
3 "-Hydroxymyristoyl] -D-glucopyranosyl
-4-phosphate

[0082]

Example 5a Allyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O-[(3 "R) -3" -benzyloxy
Shimiristoyl] -4,6-O-isopropylidene-β-D
-4.5 g (7.06 mmol) of the (2S, 3R) compound obtained with glucopyranoside 2a,
Dissolve in 100 ml of tetrahydrofuran and add triethylamine
857 ml was added, and 2.86 g of 3-benzyloxymyristate chloride was further added dropwise, followed by stirring at room temperature for 1 hour.
It concentrated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure, the residue was applied to a silica gel column, and purified with cyclohexane: ethyl acetate = 5: 1 to obtain the desired compound in 5.
Obtained in 1 g (75.7%) yield. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.65-2.08 {52
H, m [including 1.43 (3H, s)]}; 2.43-2.72 (2H, m); 3.05-
6.21 {19H, m [4.48 (2H, s); including 5.12 (2H, s)]}; 6.31-
6.67 (1H, m); 7.28 (5H, s); 7.30 (5H, s). Infrared absorption spectrum ν max cm-1 (KBr): 1745, 1670,
1545, 1268, 1089.

[0083]

Example 5b Allyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O-[(3 "R) -3" -benzyloxy
Compound obtained with [ Simiristoyl] -β-D-glucopyranoside 5a was treated in the same manner as 4b to give 4.14 g (96%) of the desired compound. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.62-2.18 (46
H, m); 2.32-2.91 (4H, m); 3.20-4.25 (8H, m); 4.28-4.71 {3
H, m [including 4.48, (2H, s)]}; 4.86-6.19 (8H, m); 6.45
-6.85 (1H, m); 7.28 (5H, s); 7.31 (5H, s). Infrared absorption spectrum ν max cm-1 (KB
r): 1742, 1669, 1578, 127
1.

[0084]

Example 5c: Allyl 2-deoxy-2-[(2'S, 3'R)-
2'-fluoro-3 '-(benzyloxycarbonyloxy)
Myristoylamino] -3-O-[(3 "R) -3" -benzylo
Ximiristoyl] -6-O-benzyloxycarbonyl
The compound obtained with -β-D-glucopyranoside 5b was treated in the same manner as in 4c to give 2.85 g (65.4%) of the desired compound. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.85-2.08 (46
H, m); 2.41-2.64 (2H, m); 3.00 (1H, br.s); 3.48-6.08 {21
H, m [including 4.45 (2H, s), 5.15 (4H, s)]}; 6.18-6.72 (1
H, m); 7.26-7.56 (15H, m). Infrared absorption spectrum ν max cm-1 (KBr): 1750, 1727,
1676, 1548.

[0085]

Example 5d Allyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3'-benzyloxycarbonyloxymyris
Toylamino] -3-O-[(3 "R) -3" -benzyloxime
Ristoyl] -4-O-diphenylphosphoryl-6-O-be
The compound obtained with benzyloxycarbonyl-β-D-glucopyranoside 5c was treated in the same manner as 4d to give the desired compound in a yield of 3.16 g (99.5%). NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.72-1.87 (46
H, m); 2.26-2.49 (2H, m); 3.45-6.05 {21H, m [4.30 (2H, s),
5.05 (4H, s)]}; 6.18-6.50 (1H, m); 6.89-7.49 (2
5H, m). Infrared absorption spectrum ν max cm-1 (KBr): 1743, 1679,
1541, 1494.

[0086]

Example 5e 2-Deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3 '-(Benzyloxycarbonyloxy) myristoy
Ruamino] -3-O-[(3 "R) -3" -benzyloxymyris
Toyl] -4-O-diphenylphosphoryl-6-O-benzyl
The compound obtained with luoxycarbonyl-D-glucopyranose 5d was treated in the same manner as in 1 g to give the desired compound in a yield of 1.8 g (66.4%). NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.66-2.01 (46
H, m); 2.16-2.56 (2H, m); 2.89 (1H, d, J = 5Hz); 3.38-5.71
{16H, m [including 4.32 (2H, s), 5.10 (4H, s)]}; 6.45-6.81
(1H, m); 7.08-7.45 (25H, m). Infrared absorption spectrum ν max cm-1 (KBr): 1747, 1685,
1590.

[0087]

Example 5f2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3'-Hydroxymyristoylamino] -3-O-[(3 "
R) -3 "-Hydroxymyristoyl] -4-O-diphenyl
Phosphoryl-D-glucopyranose 880 mg (0.6 mmol) of the compound obtained in 5e was added to 30 ml
Dissolved in hydrofuran, 1 g of 10% palladium on carbon
Was added and hydrogenolysis was performed at room temperature for 2 hours. Filtered, tet
Lahydrofuran is distilled off under reduced pressure.
And purified with ethyl acetate to give 340 mg of the target compound.
(56.2%). Elemental analysis (C₄₆H₇₃FNO₁₂(As P = 882.057)

[0088]

Example 5g2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3'-Hydroxymyristoylamino] -3-O-[(3 "
R) -3 "-Hydroxymyristoyl]-D-glucopyrano
Syl-4-phosphate 490 mg (0.56 mmol) of the compound obtained in 5f
Dissolve in 30 ml of furan, add 80 mg of platinum oxide and bring to room temperature.
For 3 hours. Filter and remove under reduced pressure
Drofuran is distilled off, and 380 mg (93.7%) of the target compound
In the yield. Elemental analysis (C₃₄H₆₅FNO₁₂(Assuming P = 729.861)Mass spectrum (FAB / MS) 728 [M-H]^- , 502.

[0089]

Example 6 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-
3'-Myristoyloxymyristoylamino] -3-O-
Myristoyl-D-glucopyranosyl-4-phosphate
G

[0090]

Example 6a Allyl 2-deoxy-2-[(2'R, 3'S) and
Beauty (2'S, 3'R)-2'-fluoro-3 '- (Millis Toiruokishi)
Myristoylamino] -4,6-O-isopropylidene-β
5.18 g (20 mmol) of the compound obtained with 1-d -D-glucopyranoside was added to 150 ml of methylene chloride.
Then, 9.93 g of (±) -syn-2-fluoro-3-myristoyloxymyristic acid was added, and 4.95 g of N, N′-dicyclohexylcarbodiimide was further added, followed by stirring at room temperature for 1 hour. Filter, concentrate under reduced pressure and dilute with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, the residue was subjected to silica gel chromatography, and purified with cyclohexane: ethyl acetate = 3: 1, to give an N-acyl compound (2′R, 3 ′S) compound as a target compound, (2'S, 3'R)
The bodies were obtained in yields of 5.65 g (39.6%) and 5.55 g (38.9%), respectively. [(2'R, 3'S) compound] NMR spectrum (270MHz, CDCl ₃₎
δ ppm: 0.88 (6H, t, J = 6.9Hz); 1.20-1.38 (38H, m); 1.44
(3H, s); 1.52 (3H, s); 1.60-1.84 (5H, m); 2.30 (2H, m);
3.23-3.33 (1H, m); 3.58-3.85 (4H, m); 3.93 (1H, dd, J = 5.
5,10.6Hz); 4.07 (1H, dd, J = 6.2,12.8Hz); 4.30-4.37 (1H,
m); 4.76 (1H, d, J = 7.7Hz); 4.93 (1H, dd, J = 2.9,48.0Hz);
5.20-5.36 (3H, m); 5.79-5.94 (1H, m); 6.44 (1H, t, J = 5.5H
z). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1735, 168
0, 1535. [(2'S, 3'R) compound] NMR spectrum (270 MHz, CDCl ₃ )
δ ppm: 0.88 (6H, t, J = 6.9Hz); 1.20-1.38 (38H, m); 1.45
(3H, s); 1.52 (3H, s); 1.56-1.76 (5H, m); 2.29 (2H, m);
3.30-3.41 (2H, m); 3.57 (1H, t, J = 9.2Hz); 3.80 (1H, t, J = 1
0.6Hz); 3.93 (1H, dd, J = 5.5,11.0Hz); 4.05-4.16 (2H, m);
4.29-4.36 (1H, m); 4.77 (1H, d, J = 8.1Hz); 4.89 (1H, dd, J
= 2.2,48.0Hz); 5.20-5.34 (3H, m); 5.80-5.89 (1H, m); 6.
52 (1H, t, J = 5.5Hz). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1735, 168
0, 1535.

[0091]

Example 6b Allyl 2-deoxy-2-[(2'R, 3'S) -2 '
-Fluoro-3 '-(myristoyloxy) myristoyl
Mino] -3-O-myristoyl-4,6-O-isopropylide
2 g (2.8 mmol) of the compound (2′R, 3 ′S) obtained with 1 -β-D-glucopyranoside 6a
Dissolve in 30 ml of methylene chloride and add myristic acid chloride.
After adding 728 mg, add 313 mg of triethylamine,
Stirred at room temperature for 1 hour. It was concentrated, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure, the residue was applied to a silica gel column, and purified with cyclohexane: ethyl acetate = 5: 1 to obtain 1.35 of the desired compound.
g (52.1%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (9H, t, J =
6.6Hz); 1.13-1.67 {70H, m [including 1.36 (3H, s), 1.46 (3H, s)]}; 2.25-2.35 (4H, m); 3.32-3.41 (1H, m); 3.66- 3.
85 (3H, m); 3.95 (1H, dd, J = 5.5,10.6Hz); 4.05 (1H, dd, J =
6.2,12.8Hz); 4.26-4.34 (1H, m); 4.74-4.93 (2H, m); 5.1
6-5.29 (4H, m); 5.75-5.89 (1H, m); 6.34 (1H, dd, J = 4.4,8.
8 Hz). Elemental analysis (as C ₅₄ H ₉₈ FNO ₉ = 924.374) Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1740, 169
5. Mass spectrum (FAB / MS) 924 (M ⁺ +1), 909,
883, 867, 737, 724, 655,
638, 610, 526, 513, 452.

[0092]

Example 6c Allyl 2-deoxy-2-[(2'R, 3'S)-
2'-Fluoro-3'-myristoyloxymyristoylami
No] -3-O-myristoyl-β-D-glucopyranosy
The compound obtained in step 6a was treated in the same manner as in 4b to give the desired compound in a yield of 2 g (80.4%). NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.66-1.91 (74
H, m); 2.09-2.55 (4H, m); 2.87-6.16 (15H, m); 6.54 (1H,
m). Infrared absorption spectrum ν max cm-1 (KBr): 1739, 1668,
1553, 1468, 1175.

[0093]

Example 6dAllyl 2-deoxy-2-[(2'R, 3'S) -2 '
-Fluoro-3'-myristoyloxymyristoylami
No] -3-O- myristoyl-6-O-benzyloxycar
Bonyl-β-D-glucopyranoside 1.9 g (2.15 mmol) of the compound obtained in 6c was treated with methyl chloride
Dissolved in 20 ml of benzyloxychloroform
Mate and then 327 mg of triethylamine.
And stirred at room temperature for 5 hours. Concentrate with ethyl acetate
Diluted. Ethyl acetate layer was washed with aqueous sodium bicarbonate
The extract was washed with brine and dried over anhydrous magnesium sulfate. Filtration
And ethyl acetate was distilled off under reduced pressure.
Cyclohexane: ethyl acetate = 3: 1
Purification gave the desired compound in a yield of 660 mg (30.2%). NMR spectrum (270 MHz, CDCl_Three) δ ppm: 0.88 (9H, t, J =
6.9Hz); 1.25-1.65 (66H, m); 2.25-2.36 (4H, m); 2.82 (1
H, s); 3.59-3.66 (2H, m); 4.03 (1H, dd, J = 6.2,12.8Hz);
4.27 (1H, dd, J = 5.1,12.8Hz); 4.42-4.52 (1H, m); 4.81 (1
H, dd, J = 3.7,47.6Hz); 4.84 (1H, d, J = 8.1Hz); 5.14-5.27 (6
H, m); 5.76-5.89 (1H, m); 6.37 (1H, dd, J = 4.4,8.1Hz);
7.34-7.40 (5H, m). Infrared absorption spectrum ν max cm-1 (KB
r): 1737, 1673, 1550, 128
5.

[0094]

Example 6e Allyl 2-deoxy-2-[(2'R, 3'S)-
2'-Fluoro-3'-myristoyloxymyristoylami
No] -3-O- myristoyl-4-O-diphenyl phosphoryl
6-O-benzyloxycarbonyl-β-D-gluco
600 mg (0.589 mmol) of the compound obtained from pyranoside 6d was dissolved in 20 ml of methylene chloride, and diphenyl chlorophosphate was dissolved.
474.8 mg was added, and 62.6 mg of triethylamine was further added, followed by stirring at room temperature overnight. It concentrated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, ethyl acetate was distilled off under reduced pressure. The residue was applied to a silica gel column, and cyclohexane: ethyl acetate = 5: 1.
The target compound was obtained in a yield of 600 mg (81.4%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (9H, t, J =
6.9Hz); 1.05-1.73 (64H, m); 2.11-2.30 (4H, m); 3.46-3.
56 (1H, m); 3.77-3.82 (1H, m); 4.03 (1H, dd, J = 6.2,12.8H
z); 4.19-4.38 (3H, m); 4.63-4.89 (2H, m); 5.01-5.26 (6
H, m); 5.64-5.87 (2H, m); 6.37 (1H, dd, J = 4.4,7.7Hz); 7.
11-7.34 (15H, m). Elemental analysis (as C ₇₁ H ₁₀₉ FNO ₁₄ P = 1250.618) Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1743, 169
0.

[0095]

Example 6f 2-deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3'-Myristoyloxymyristoylamino] -3-O
-Myristoyl-4-O-diphenylphosphoryl-6-O-
The compound obtained with benzyloxycarbonyl-D-glucopyranose 6e was treated in the same manner as in 1 g to give the desired compound in a yield of 490 mg (84.3%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (9H, t, J =
7.0Hz); 1.11-1.66 (64H, m); 2.11-2.29 (4H, m); 3.36 (1
H, s); 4.13-4.39 (4H, m); 4.71-5.56 (7H, m); 6.70 (1H, d
d, J = 3.3,8.1Hz); 7.11-7.35 (15H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1751, 171
1, 1658.

[0096]

Example 6g 2-deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3'-Myristoyloxymyristoylamino] -3-O
-Myristoyl-4-O-diphenylphosphoryl-D-g
The compound obtained with leukopyranose 6f was treated in the same manner as 5f to give the desired compound in a yield of 270 mg (75.9%). Elemental analysis (as C ₆₀ H ₉₉ FNO ₁₂ P = 1076.419) Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1735, 168
Five.

[0097]

Example 6h 2-deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3'-Myristoyloxymyristoylamino] -3-O
-Myristoyl-D-glucopyranosyl-4-phosphate
The compound obtained with 6 g of the salt was treated in the same manner as with 5 g to give the target compound in a yield of 190 mg (96.2%). Mass spectrum (FAB / MS) 922 [M-H] ^-

[0098]

Example 7 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-
3'-Myristoyloxymyristoylamino] -3-O-
Myristoyl-D-glucopyranosyl-4-phosphate
G

[0099]

Example 7aAllyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3'-myristoyloxymyristoylami
No] -3-O- myristoyl-4,6-O-isopropylidene
-β- D- Glucopyranoside 2.9 g (4.06 mmol) of the (2 ′S, 3′R) form obtained in 6a
Dissolve in 30 ml of methylene, add 1.02 g of myristic acid,
Further, 1 g of N, N'-dicyclohexylcarbodiimide was added.
Then, the mixture was stirred at room temperature for 1 hour.
Added 50 mg of 4-dimethylaminopyridine.
Then, the mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure and add ethyl acetate
And the ethyl acetate layer was diluted with aqueous sodium hydrogen carbonate,
The extract was washed with brine and dried over anhydrous magnesium sulfate.
After filtration, the ethyl acetate was distilled off under reduced pressure.
Apply to the column and elute with cyclohexane: ethyl acetate = 5: 1.
To obtain the desired compound quantitatively. NMR spectrum (60MHz, CDCl_Three) δ ppm: 0.66-2.01 (79
H, m); 2.05-2.61 (4H, m); 3.30-6.23 (14H, m); 6.85 (1H,
m). Infrared absorption spectrum ν max cm-1 (KBr): 1741, 1666,
 1544, 1468.

[0100]

Example 7bAllyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3'-myristoyloxymyristoylami
No] -3-O-myristoyl-β-D-glucopyranosy
Do The compound obtained in 7a was treated in the same manner as 4b,
The compound was obtained in a yield of 3.08 g (84.7%). Infrared absorption spectrum ν max cm-1 (KBr): 1736, 1671,
 1553, 1467.

[0101]

Example 7cAllyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3'-myristoyloxymyristoylami
No] -3-O- myristoyl-6-O-benzyloxymethyl
Le-β-D-glucopyranoside 2.7 g (3.05 mmol) of the compound obtained in Step 7b
Dissolved in 50 ml of benzylchloromethyl ether 0.52
5 g, then 0.355 g of tetramethylurea, and 6
Heated to reflux for an hour. The methylene chloride is distilled off under reduced pressure, and the residue is
Apply to a silica gel column and add cyclohexane: ethyl acetate
= 3: 1 to yield 2.08 g (67.8%) of the desired compound.
Was. NMR spectrum (270 MHz, CDCl_Three) δ ppm: 0.88 (9H, t, J =
6.9Hz); 1.20-1.73 (65H, m); 2.24-2.37 (4H, m); 3.47-3.
51 (1H, m); 3.74 (1H, t, J = 9.5Hz); 3.89-4.11 (4H, m); 4.2
6-4.33 (1H, m); 4.59 (1H, d, J = 8.4Hz); 4.63 (2H, s); 4.79
(1H, dd, J = 4.3,48.4Hz); 4.81 (2H, s); 5.03 (1H, dd, J = 9.
(2,10.6Hz); 5.15-5.30 (3H, m); 5.80-5.88 (1H, m); 6.36
(1H, dd, J = 4.4,9.2Hz); 7.29-7.36 (5H, m) .Infrared absorption spectrum ν max cm-1 (CHCl_Three): 3430, 173
8, 1695. Mass spectrum (M / Z): 986, 928, 834, 775, 717, 59
6, 509, 456, 383, 354,298,285, 268.

[0102]

Example 7dAllyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3'-myristoyloxymyristoylami
No] -3-O- myristoyl-4-O-diphenyl phosphoryl
6-O-benzyloxymethyl-β-D-glucopyr
Nocide The compound obtained in 7c was treated in the same manner as in 6e,
The compound was obtained quantitatively. NMR spectrum (270 MHz, CDCl_Three) δ ppm: 0.88 (9H, t, J =
6.9Hz); 1.10-1.68 (65H, m); 2.08-2.31 (3H, m); 3.65-3.
69 (2H, m); 3.78-3.84 (1H, m); 4.03-4.11 (2H, m); 4.25-4.
32 (1H, m); 4.50-4.85 (7H, m); 5.15-5.39 (4H, m); 5.76-
5.83 (1H, m); 6.38 (1H, dd, J = 4.8,9.2Hz); 7.13-7.44 (15
H, m). Infrared absorption spectrum ν max cm-1 (CHCl_Three): 3430, 174
0, 1695. Mass spectrum (M / Z): 1014, 994, 758, 670, 580, 4
40, 322, 268.

[0103]

Example 7e 2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3'-Myristoyloxymyristoylamino] -3-O
-Myristoyl-4-O-diphenylphosphoryl-6-O-
The compound obtained with benzyloxymethyl-D-glucopyranose 7d was treated in the same manner as in 1 g to obtain the desired compound in a yield of 1.58 g (71%). NMR spectrum (60MHz
, CDCl ₃ ) δ ppm: 0.63-2.42 (77H, m); 3.55-5.78 {14H, m
[Including 4.54 (2H, s), 4.66 (2H, s)]}; 6.70 (1H, m); 7.0
0-7.53 (15H, m).

[0104]

Example 7f 2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3'-Myristoyloxymyristoylamino] -3-O
-Myristoyl-4-O-diphenylphosphoryl-D-g
1.44 g (1.2 mmol) of the compound obtained with leukopyranose 7e was added to methanol
Dissolve in 30 ml, add 1 g of 10% palladium carbon,
The catalytic reduction was carried out at 40 to 45 ° C for 3 hours. After filtration, methanol was distilled off under reduced pressure. The residue was applied to a silica gel column and purified with cyclohexane: ethyl acetate = 1: 1 to obtain the desired compound.
Obtained in a yield of 715 mg (55.2%). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 3440, 174
0, 1690. Elemental analysis (as C ₆₀ H ₉₉ FNO ₁₂ P = 1076.419)

[0105]

Example 7g 2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3'-Myristoyloxymyristoylamino] -3-O
-Myristoyl-D-glucopyranosyl-4-phosphate
The compound obtained in 7f was treated in the same manner as 5 g to give the desired compound in a yield of 420 mg (89%). Mass spectrum (FAB / MS): 922 [M-H] ^-

[0106]

Embodiment 82-deoxy-2-[(2'S, 3'R) -2'-fluoro-
3'-Hydroxymyristoylamino] -3-O-[(3 "R)-
3 "-(myristoyloxy) myristoyl] -D-gluco
Pyranosyl-4-phosphate

[0107]

Embodiment 8 (a)Allyl 2-deoxy-2-[(2'S, 3 '
R) -2'-Fluoro-3 '-(benzyloxycarbonyloxy
B) Myristoylamino] -3-O- [(3 "R) -3"-(myris
Toyloxy) myristoyl] -4,6-O-isopropylate
Den-α-D-glucopyranoside 33.1 g of the (2 ′S, 3′R) compound obtained in 2a was added to 700 ml of methyl
Dissolve in lenchloride and add 25.9 g of 3-myristoyloxy
Add myristic acid and add another 7 g of 4-dimethylaminopyridine.
Gin, 12.8 g of N, N'-dicyclohexylcarbodiimide
Was added and stirred at room temperature for 2 hours. After filtration, concentrate under reduced pressure
And then diluted with ethyl acetate. The ethyl acetate layer was
Washed with aqueous sodium hydrogen and brine, dried over anhydrous magnesium sulfate
Dried with sodium. Filter and evaporate ethyl acetate under reduced pressure
And the residue was chromatographed on silica gel.
: Ethyl acetate = 5: 1, and 47.7 g (8
5.5%). NMR spectrum (CDCl_Three) δ ppm: 0.86-0.90 (9H, m); 1.2
5-1.77 {68H, m, [including 1.37 (3H, s); 1.48 (3H, s)]};
2.26 (2H, m); 2.49 (1H, dd, J = 6.3,15.1Hz); 2.62 (1H, dd, J
= 6.3,15.1Hz); 3.70-3.86 (5H, m); 3.93-3.98 (1H, m); 4.
21-4.27 (1H, m); 4.63 (1H, d, J = 3.9Hz); 4.90 (1H, dd, J = 2.
4,47.4Hz); 5.09-5.21 (7H, m); 5.74-5.84 (1H, m); 6.63
(1H, dd, J = 3.9,9.8Hz); 7.26-7.36 (5H, m) .Infrared absorption spectrum ν max cm-1 (CHCl_Three); 3440, 174
5, 1690, 1530. Elemental analysis: C₆₂H₁₀₄NFO₁₂As

[0108]

Example 8b Allyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O- [(3 "R) -3"-(myristoyl
4.6 g of the compound obtained with [oxy) myristoyl] -α-D-glucopyranoside 8a was treated in the same manner as 4b,
The target compound was obtained in a yield of 4.2 g (94.8%). NMR spectrum (CDCl ₃ ) δ ppm: 0.85-0.90 (9H, m); 1.0
4-1.78 (64H, m); 2.26-2.31 (2H, m); 2.47-2.59 (2H, m);
3.63-3.88 (5H, m); 3.96-4.02 (1H, m); 4.16-4.23 (1H, m);
4.66 (1H, d, J = 3.7Hz); 4.89 (1H, dd, J = 2.2,47.6Hz); 5.0
9-5.21 (7H, m); 5.73-5.87 (1H, m), 6.66 (1H, dd, J = 3.7,9.
5Hz); 7.26-7.37 (5H, m). Infrared absorption spectrum ν max cm-1 (KBr); 1741, 1719,
1703, 1670, 1545, 1468. Elemental analysis: C ₅₉ H _{100 as} NFO _12.

[0109]

Example 8c Allyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O- [(3 "R) -3"-(myristoyl
Oxy) myristoyl] -6-O-benzyloxycarbo
23.1 g of the compound obtained with nil-α-D-glucopyranoside 8d were treated in the same manner as 4c,
The target compound was obtained in a yield of 10.6 g (40.6%). NMR spectrum (CDCl ₃ ) δ ppm: 0.85-0.90 (9H, m); 1.0
2-1.77 (62H, m); 2.25-2.31 (2H, m); 2.46-2.59 (2H, m);
3.31 (1H, d, J = 4.2Hz); 3.61 (1H, td, J = 9.3,4.2Hz); 3.76-
3.86 (2H, m); 3.93-4.00 (1H, m); 4.16-4.24 (1H, m); 4.38
-4.48 (1H, m); 4.88 (1H, dd, J = 2.2,47.6Hz); 5.07-5.19 (9
H, m); 5.70-5.85 (1H, m); 6.62 (1H, dd, J = 3.7,9.5Hz); 7.
26-7.40 (10H, m). Infrared absorption spectrum ν max cm-1 (KBr); 1747, 1738,
1724, 1712, 1678, 1547. Elemental analysis: C ₆₇ H ₁₀₆ NFO ₁₄

[0110]

Example 8d Allyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O- [(3 "R) -3"-(myristoyl
Oxy) myristoyl] -4-O-diphenylphosphoryl
-6-O-benzyloxycarbonyl-α-D-glucopyra
10.47 g of the compound obtained with Nocide 8c was treated in the same manner as for 4d to give 11.46 g (91.3%) of the desired compound. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-0.90 (9H, m); 1.0
3-1.80 (62H, m); 2.13-2.19 (2H, m); 2.33 (1H, dd, J = 7.3,1
5.8Hz); 2.42 (1H, dd, J = 5.1,15.8Hz); 3.75-3.82 (1H, m);
3.89-4.02 (2H, m); 4.17-4.36 (3H, m); 4.64 (1H, d, J = 3.7
Hz); 4.72 (1H, dd, J = 9.2,18.7Hz); 4.85-5.22 (9H, m); 5.
42 (1H, dd, J = 9.2,11.0Hz); 5.70-5.84 (1H, m); 6.56 (1H, d
d, J = 3.7,9.5Hz); 7.12-7.65 (20H, m). Infrared absorption spectrum ν max cm-1 (film): 175
0, 1690, 1590.

[0111]

Example 8e 2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3 '-(Benzyloxycarbonyloxy) myristoy
Ruamino] -3-O- [(3 "R) -3"-(myristoyloxy)
Myristoyl] -4-O-diphenylphosphoryl-6-O-
1.4 g of the compound obtained with benzyloxycarbonyl-D-glucopyranose 8d was treated in the same manner as 1 g to give 0.77 g (56.6%) of the desired compound. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-0.90 (9H, m); 1.1
8-1.82 (62H, m); 2.12-2.18 (2H, m); 2.32 (1H, dd, J = 7.3,1
5.8Hz); 2.41 (1H, dd, J = 5.5,15.8Hz); 2.70 (1H, dd, J = 1.
5,4.8Hz); 4.09-4.18 (3H, m); 4.29-4.34 (1H, m); 4.67 (1
H, dd, J = 9.2,18.7Hz); 4.87 (1H, m); 4.89 (1H, dd, J = 1.8,4
7.3Hz); 5.61-5.25 (6H, m); 5.46 (1H, dd, J = 9.2,11.0Hz);
6.63 (1H, dd, J = 3.3,8.8Hz); 7.12-7.38 (20H, m). Infrared absorption spectrum ν max cm-1 (KB
r); 1739, 1660, 1290, 126
6, 1250, 1195. Elemental analysis: as C ₇₆ H ₁₁₁ FNO ₁₇ P

[0112]

Example 8f2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3'-Hydroxymyristoylamino] -3-O-[(3 "
R) -3 "-(Myristoyloxy) myristoyl] -4-O-
Diphenylphosphoryl-D-glucopyranose 6.5 g of the compound obtained in 8e was treated in the same manner as 5f,
The target compound was obtained in a yield of 4.89 g (93.7%). NMR spectrum (CDCl_Three) δ ppm: 0.85-0.90 (9H, m); 1.1
8-1.80 (62H, m); 2.13-2.21 (2H, m); 2.37-2.39 (2H, m);
3.50-3.61 (4H, m); 3.97-4.06 (2H, m); 4.21-4.28 (1H, m);
 4.65-4.83 (2H, m); 5.04-5.13 (1H, m); 5.24-5.28 (2H, m
m); 5.49-5.57 (1H, m); 6.80-6.85 (1H, m); 7.14-7.38 (1
0H, m). Infrared absorption spectrum ν max cm-1 (KBr); 1735, 1671,
 1289, 1202, 1060. Elemental analysis: C₆₀H₉₉FNO₁₃As P

[0113]

Example 8g2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3'-Hydroxymyristoylamino] -3-O-[(3 "
R) -3 "-(Myristoyloxy) myristoyl] -D-
Lucopyranosyl-4-phosphate 4.59 g of the compound obtained in 8f were treated in the same way as 5 g,
The target compound was obtained in a yield of 3.9 g (98.7%). NMR spectrum (270 MHz, heavy pyridine) δ ppm: 0.85-
0.90 (9H, m), 1.03-2.15 (62H, m), 2.43-2.49 (2H, m), 3.0
8-3.25 (2H, m), 4.09-4.13 (1H, m), 4.52-4.56 (2H, m), 4.6
2-4.65 (1H, m), 4.99-5.08 (1H, m), 5.21-5.49 (2H, m), 5.
63-5.74 (2H, m), 6.24-6.31 (1H, m), 8.03-8.72 (6H, m) .Infrared absorption spectrum ν max cm-1 (KBr); 1734, 1661,
 1550, 1465, 1224, 1182, 1171, 1063. Elemental analysis: C₄₈H₉₁FNO₁₃As P

[0114]

Embodiment 92-deoxy-2-[(2'R, 3'S) -2'-fluoro-
3'-Hydroxymyristoylamino] -3-O-[(3 "R)-
3 "-(myristoyloxy) myristoyl] -D-gluco
Pyranosyl-4-phosphate

[0115]

Example 9a Allyl 2-deoxy-2-[(2'R, 3'S) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamide] -3-O- [(3 "R) -3"-(myristoyl
Oxy) myristoyl] -4,6-O-isopropylidene-
1.1 g of the (2′R, 3 ′S) compound obtained with α-D-glucopyranoside 2a was treated in the same manner as for 8a to give 1.36 g (73.8%) of the target compound. Infrared absorption spectrum ν max cm-1 (film): 174
0, 1685, 1530, 1460. Elemental analysis: C ₆₂ H _{104 as} FNO _12.

[0116]

Example 9b Allyl 2-deoxy-2-[(2'R, 3'S) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O- [(3 "R) -3"-(myristoyl
Oxy) myristoyl] -α-D-glucopyranoside 9a, 57.6 g of compound obtained in the same manner as 4b,
42.6 g (76.8%) of the target compound was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.86-0.90 (9H, m); 1.2
5-1.76 (64H, m); 2.25-2.45 (4H, m), 3.64-3.76 (3H, m),
3.85-3.90 (2H, m); 3.95-4.00 (1H, m); 4.14-4.21 (2H, m);
4.84-5.32 (8H, m); 5.83-5.87 (1H, m); 7.07-7.10 (1H, m
. m); 7.26-7.38 (5H, m) Elementary analysis: as C ₅₉ H ₁₀₀ O ₁₂ NF

[0117]

Example 9c Allyl 2-deoxy-2-[(2'R, 3'S) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O- [(3 "R) -3"-(myristoyl
Oxy) myristoyl] -6-O-benzyloxycarbo
0.83 g of the compound obtained with nyl-α-D-glucopyranoside 9b was treated in the same manner as 4c,
0.6 g (63.6%) of the target compound was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.86-0.90 (9H, m); 1.2
5-1.76 (63H, m); 2.23-2.45 (4H, m); 3.63-3.65 (2H, m);
3.85-3.98 (2H, m); 4.11-4.19 (2H, m); 4.43-4.93 (2H, m);
4.89 (1H, dd, J = 2.6,47.3Hz); 4.93 (1H, d, J = 3.3Hz); 5.0
1-5.30 (8H, m); 5.76-5.92 (1H, m); 7.03-7.07 (1H, m); 7.
26-7.41 (10H, m). Infrared absorption spectrum ν max cm-1 (film): 175
0, 1690. Elemental analysis: C ₆₇ H ₁₀₆ O ₁₄ NF

[0118]

Example 9d Allyl 2-deoxy-2-[(2'R, 3'S) -2 '
-Fluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O- [(3 "R) -3"-(myristoyl
Oxy) myristoyl] -4-O-diphenylphosphoryl
-6-O-benzyloxycarbonyl-α-D-glucopyra
30.5 g of the compound obtained with nocide 9c was treated in the same manner as 4d,
31 g (96%) of the target compound was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-0.90 (9H, m); 1.1
2-1.72 (62H, m); 2.06-2.12 (2H, m), 2.35 (1H, dd, J = 7.7,1
7.6Hz); 2.52 (1H, dd, J = 5.5,17.6Hz); 3.90-4.35 (6H, m);
4.73 (1H, dd, J = 9.2,18.7Hz); 4.89 (1H, dd, J = 2.6,47.6H
z); 4.95 (1H, d, J = 3.7Hz); 5.04-5.29 (8H, m); 5.47 (1H, d
d, J = 9.2,11.0Hz); 5.77-5.84 (1H, m); 6.81 (1H, dd, J = 3.
7.11-7.37 (20H, m). Infrared absorption spectrum ν max cm-1 (film): 174
5, 1690, 1590, 1530. Elemental analysis: C ₇₉ H ₁₁₅ O _{17 as} NFP

[0119]

Example 9e 2-deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3 '-(Benzyloxycarbonyloxy) myristoy
Ruamino] -3-O- [(3 "R) -3"-(myristoyloxy)
Myristoyl] -4-O-diphenylphosphoryl-6-O-
15 g of the compound obtained with benzyloxycarbonyl-D-glucopyranose 9d was treated in the same manner as 1 g to give 11.6 g (79.6%) of the desired compound. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-0.90 (9H, m); 1.1
4-1.75 (62H, m); 2.08-2.13 (2H, m); 2.33 (1H, dd, J = 7.7,1
6.9Hz); 2.51 (1H, dd, J = 4.8,16.9Hz); 3.63 (1H, dd, J = 1.
1,4.03Hz); 3.97 (1H, m); 4.14-4.36 (3H, m); 4.66-4.77
(1H, m); 4.89 (1H, dd, J = 2.7,47.6Hz); 5.02-5.20 (6H, m);
5.30 (1H, t, J = 3.7Hz); 5.53 (1H, dd, J = 9.2,11.0Hz); 6.9
2 (1H, dd, J = 2.9,7.7Hz); 7.12-7.34 (20H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ); 3420, 175
0, 1690, 1590, 1530, 1490, 960. Elemental analysis: as C ₇₆ H ₁₁₁ NO ₁₇ FP

[0120]

Example 9f2-deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3'-Hydroxymyristoylamino] -3-O-[(3 "
R) -3 "-(Myristoyloxy) myristoyl] -4-O-
Diphenylphosphoryl-D-glucopyranose 11.6 g of the compound obtained in 9e was treated in the same manner as 5f,
8.14 g (87.4%) of the target compound was obtained. NMR spectrum (CDCl_Three) δ ppm: 0.85-0.90 (9H, m); 1.1
9-1.63 (62H, m); 2.15-2.20 (2H, m); 2.37 (1H, dd, J = 8.4,1
7.2Hz); 2.68 (1H, d, J = 8.8Hz); 3.38 (1H, m); 3.59-3.62
(2H, m); 4.02-4.05 (3H, m); 4.33-4.40 (1H, m); 4.74 (1H,
(dd, J = 1.1,48.0Hz); 4.77 (1H, dd, J = 9.5,19.1Hz); 5.11-5.
15 (1H, m); 5.30 (1H, t, J = 3.7Hz); 5.54 (1H, dd, J = 9.5,10.
3Hz); 6.83 (1H, dd, J = 3.3,9.2Hz); 7.15-7.39 (10H, m) .Infrared absorption spectrum ν max cm-1 (KBr); 1736, 1661,
 1585, 1560, 1492.

[0121]

Example 9g2-deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3'-Hydroxymyristoylamino] -3-O-[(3 "
R) -3 "-(Myristoyloxy) myristoyl] -D-
Lucopyranosyl-4-phosphate 7.72 g of the compound obtained in 9f were treated in the same manner as 5 g,
6.7 g of the target compound was obtained quantitatively. NMR spectrum (CDCl_Three) δ ppm: 0.85-0.91 (9H, m); 1.2
5-2.01 (62H, m); 2.38-2.44 (2H, m); 3.19 (2H, d, J = 5.86H
z); 4.11-4.18 (1H, m); 4.43-4.59 (3H, m); 4.99-5.07 (1
H, m); 5.15-5.33 {(2H, m) [5.24 (1H, dd, J = 2.0,48.8Hz)
Including}; 5.74-5.81 (2H, m); 6.28 (1H, t, J = 9.8Hz); 8.02
(1H, dd, J = 2.7,9.8Hz); 8.61 (5H, br.s) .Infrared absorption spectrum ν max cm-1 (KBr): 1753, 1716,
 1657, 1184, 1138, 1117, 1068. Elemental analysis: C₄₈H₉₁FNO₁₃As P

[0122]

Example 10 2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3 '-(Myristoyloxy) myristoylamino] -3
-O- [(3 "R) -3" -hydroxymyristoyl] -D-glu
Copyranosyl-4-phosphate

[0123]

Example 10a Allyl 2-deoxy-2-[(2'S, 3'R)-
2'-Fluoro-3 '-(myristoyloxy) myristoyl
Amino] -3-O-[(3 "R) -3" -benzyloxy myristo
Yl] -4,6-O-isopropylidene-β-D-glucopyr
3.2 g of the (2'S, 3'R) compound obtained with nocide 6a was treated in the same manner as 2b to give the desired compound in a yield of 4.12 g (89.2%).

[0124]

Example 10b Allyl 2-deoxy-2-[(2'S, 3'R)-
2'-Fluoro-3 '-(myristoyloxy) myristoyl
Amino] -3-O-[(3 "R) -3" -benzyloxy myristo
Yl] -β-D-glucopyranoside 10a was treated in the same manner as 4b,
2.94 g (75.4%) of the target compound was obtained. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.5-2.0 (71H,
m); 2.1-2.8 (4H, m); 3.0-5.9 (18H, m); 6.3-6.6 (2H, m);
7.1-7.3 (5H, m).

[0125]

Example 10c Allyl 2-deoxy-2-[(2'S, 3'R)-
2'-Fluoro-3 '-(myristoyloxy) myristoyl
Amino] -3-O-[(3 "R) -3" -benzyloxy myristo
Yl] -6-O-benzyloxymethyl-β-D-glucopi
2.73 g of the compound obtained with lanocide 10b was treated in the same manner as for 7c to give 1.7 g (55.5%) of the desired compound. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.7-2.0 (71H,
m); 2.1-2.7 (4H, m); 2.90 (1H, br.s); 3.4-5.5 (20H, m);
6.2-6.6 (2H, m); 7.1-7.4 (10H, m).

[0126]

Example 10d: Allyl 2-deoxy-2-[(2 ' S, 3'R)-
2'-fluoro-3 '- (myristoyloxy oxy) millimeter Sutoiru
Amino] -3-O-[(3 "R) -3" -benzyloxy myristo
Yl] -4-O-diphenylphosphoryl-6-O- benzyl
1.65 g of the compound obtained with oxymethyl-β-D-glucopyranoside 10c was treated in the same manner as in 4d to quantitatively obtain 2.0 g of the target compound. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.5-2.0 (71H,
m); 2.1-2.7 (4H, m); 3.5-5.6 (20H, m); 6.2-6.7 (2H, m);
7.1-7.5 (20H, m).

[0127]

Example 10e 2-Deoxy-2-[(2'S, 3'R) -2'-fur
Oro-3 '-(myristoyloxy) myristoylamino]
-3-O-[(3 "R) -3" -benzyloxymyristoyl] -4
-O-diphenylphosphoryl-6-O-benzyloxime
1.9 g of the compound obtained with chill-D-β-glucopyranose 10d was treated in the same manner as 1 g to give 0.88 g (47.5%) of the target compound. NMR spectrum (CDCl ₃ ) δ ppm: 0.88 (9H, t, J = 6.2-7.0H
z); 1.15-1.70 (62H, m); 2.20-2.45 (4H, m); 3.07 (1H, m);
3.60-3.82 (3H, m); 4.20-4.90 (10H, m); 5.17 (1H, m); 5.3
0 (1H, t, J = 3.3-3.7Hz); 5.57 (1H, dd, J = 9.4,10.8Hz); 6.6
8 (1H, dd, J = 3.5,8.6Hz); 7.10-7.35 (20H, m). Infrared absorption spectrum ν max cm-1 (film): 345
0-3300, 2920, 2860, 1740, 1680.

[0128]

Example 10f 2-deoxy-2-[(2'S, 3'R) -2'-fur
Oro-3 '-(myristoyloxy) myristoylamino]
-3-O- [(3 "R) -3" -hydroxymyristoyl] -4-O
0.78 g of the compound obtained with 10 -diphenylphosphoryl-D-glucopyranose 10e was treated in the same manner as for 7f to give 0.37 g (51.4%) of the desired compound. NMR spectrum (CDCl ₃ ) δ ppm: 0.88 (9H, t, J = 6.2-7.0H
z); 1.10-1.30 (58H, m); 1.40-1.75 (4H, m); 2.10-2.33 (4
H, m); 3.50-4.10 (7H, m); 4.70-4.98 (3H, m); 5.13-5.40
(2H, m); 5.56 (1H, t, J = 9.5-10.3Hz); 6.77 (1H, dd, J = 3.7,
9.2Hz); 7.15-7.38 (10H, m).

[0129]

Example 10g 2-deoxy-2-[(2'S, 3'R) -2'-fur
Oro-3 '-(myristoyloxy) myristoylamino]
-3-O-[(3 "R) -3" -hydroxymyristoyl] -D-g
0.29 g of the compound obtained with 10 f of lucopyranosyl-4-phosphate was treated in the same manner as 5 g to give 0.25 g of the desired compound quantitatively. NMR spectrum (CF ₃ COOD) δ ppm: 0.87-0.98 (9H, m);
1.20-1.55 (58H, m); 1.55-2.00 (4H, m); 2.43-2.64 (2H,
m); 2.73-2.94 (2H, m); 4.14-4.65 (5H, m); 4.79 (1H, dd, J
= 9.3,18.5Hz); 5.15 (1H, dd, J = 1.0,46.9Hz); 5.40-5.78
(3H, m). Mass spectrum (FAB / MS): 938 [MH] ^- .

[0130]

Example 11 2-deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3 '-(Myristoyloxy) myristoylamino] -3
-O- [(3 "R) -3" -hydroxymyristoyl] -D-glu
Copyranosyl-4-phosphate

[0131]

Example 11a Allyl 2-deoxy-2-[(2'R, 3'S)-
2'-Fluoro-3 '-(myristoyloxy) myristoyl
Amino] -3-O-[(3 "R) -3" -benzyloxy myristo
Yl] -4,6-O-isopropylidene-β-D-glucopyr
3.4 g of the (2′R, 3 ′S) compound obtained with nocide 6a was treated in the same manner as in 2b to give the desired compound in a yield of 3.8 g (77.4%). NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.5-2.0 (77H,
m); 2.0-2.8 (4H, m); 3.2-5.6 (16H, m); 6.1-6.4 (2H, m);
7.1-7.4 (5H, m).

[0132]

Example 11b Allyl 2-deoxy-2-[(2'R, 3'S)-
2'-Fluoro-3 '-(myristoyloxy) myristoyl
Amino] -3-O-[(3 "R) -3" -benzyloxy myristo
3.68 g of the compound obtained with yl] -β-D-glucopyranoside 11a was treated in the same manner as 4b to give 2.97 g (84%) of the desired compound.

[0133]

Example 11c Allyl 2-deoxy-2-[(2'R, 3'S)-
2'-Fluoro-3 '-(myristoyloxy) myristoyl
Amino] -3-O-[(3 "R) -3" -benzyloxy myristo
Yl] -6-O-benzyloxymethyl-β-D-glucopi
2.77 g of the compound obtained with lanocide 11b was treated in the same manner as for 7c to give 2.36 g (76%) of the desired compound. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.6
-2.0 (71H, m); 2.0-2.7 (4H,
m); 3.4-6.2 (21H, m); 6.2-
6.6 (2H, m); 7.1-7.5 (10H,
m).

[0134]

Example 11dAllyl 2-deoxy-2-[(2'R,
3'S) -2'-Fluoro-3 '-(myristoyloxy) myris
Toylamino] -3-O-[(3 "R) -3" -benzyloxime
Ristoyl] -4-O-diphenylphosphoryl-6-O-be
Ndyloxymethyl-β-D-glucopyranoside 2.25 g of the compound obtained in 11c were treated in the same manner as 4d
Thus, 2.36 g (86.4%) of the target compound was obtained. NMR spectrum (60MHz, CDCl_Three) δ ppm: 0.6-2.0 (71H,
m); 2.1-2.4 (4H, m); 3.5-6.1 (20H, m); 6.1-6.6 (2H, m);
7.1-7.5 (20H, m).

[0135]

Example 11e 2-deoxy-2-[(2'R, 3'S) -2'-fur
Oro-3 '-(myristoyloxy) myristoylamino]
-3-O-[(3 "R) -3" -benzyloxymyristoyl] -4
-O-diphenylphosphoryl-6-O-benzyloxime
2.2 g of the compound obtained with chill-D-glucopyranose 11d was treated in the same manner as 1 g to give 1.83 g (85.7%) of the target compound. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.5-2.0 (71H,
m); 2.1-2.6 (4H, m); 3.6-5.9 (17H, m); 6.75 (1H, br.s);
7.1-7.4 (20H, m).

[0136]

Example 11f 2-deoxy-2-[(2′R, 3 ′S) -2′-fur
Oro-3 '-(myristoyloxy) myristoylamino]
-3-O- [(3 "R) -3" -hydroxymyristoyl] -4-O
1.7 g of the compound obtained with -diphenylphosphoryl-β-D-glucopyranose 11e was treated in the same manner as for 7f to give 0.6 g (42.1%) of the desired compound.

[0137]

Example 11g 2-deoxy-2-[(2'R, 3'S) -2'-fur
Oro-3 '-(myristoyloxy) myristoylamino]
-3-O-[(3 "R) -3" -hydroxymyristoyl] -D-g
0.54 g of the compound obtained with lucopyranosyl-4-phosphate 11f was treated in the same manner as for 5 g to obtain 0.45 g (96.8%) of the desired compound. NMR spectrum (CF ₃ COOD) δ ppm: 0.87-0.98 (9H, m);
1.27-1.60 (58H, m); 1.65-1.93 (4H, m); 2.50-2.60 (2H, m
m); 2.80-2.90 (2H, m); 4.12-4.62 (5H, m); 4.80 (1H, dd, J
= 9.5,18.3Hz); 5.18 (1H, dd, J = 2.7,48.6Hz); 5.40-5.93
(3H, m). Mass spectrum (FAB / MS): 938 [MH] ^- .

[0138]

Example 12 2-deoxy-2-[(2'R, 3'S) -2'-fluoro
B-3'-Myristoyloxymyristoylamino] -3-O
-Myristoyl-D-glucopyranosyl-4-phosphate
G

[0139]

Example 12a Allyl 2-deoxy-2-[(2'R, 3'S)-
2'-fluoro-3'-myristoyloxymyristoylua
Mino] -4,6-O-isopropylidene-β-D-glucopi
Lanoside and allyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3'-myristoyloxymyristoylami
No] -4,6-O-isopropylidene-β-D-glucopyr
5.18 g (20 mmol) of the compound obtained in Nocide 1d was treated with 150 ml of methylene chloride.
Then, 9.93 g of (±) -syn-2-fluoro-3-myristoyloxymyristinic acid was added, 4.95 g of N, N'-dicyclohexylcarbodiimide was further added, and the mixture was stirred at room temperature for 1 hour. Filter, concentrate under reduced pressure and dilute with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, the residue was subjected to silica gel chromatography, and purified with cyclohexane: ethyl acetate = 3: 1 to obtain the desired compound (2′R, 3 ′S) and (2 ′S, 3′R). ) Body
The yields were 5.65 g (39.6%) and 5.55 g (38.9%). [(2′R, 3 ′S) form] NMR spectrum (270 MHz, CDCl ₃ ) δ p
pm: 0.88 (6H, t, J = 6.9Hz), 1.20-1.38 (38H, m), 1.44 (3H,
s), 1.52 (3H, s), 1.60-1.84 (5H, m), 2.30 (2H, m), 3.23-
3.33 (1H, m), 3.58-3.85 (4H, m), 3.93 (1H, dd, J = 5.5,10.6
Hz), 4.07 (1H, dd, J = 6.2,12.8Hz), 4.30-4.37 (1H, m), 4.
76 (1H, d, J = 7.7Hz), 4.93 (1H, dd, J = 2.9,48.0Hz), 5.20-
5.36 (3H, m), 5.79-5.94 (1H, m), 6.44 (1H, t, J = 5.5Hz). [(2'S, 3'R) form] 0.88 (6H, t, J = 6.9Hz), 1.20-1.38 (38H,
m), 1.45 (3H, s), 1.52 (3H, s), 1.56-1.76 (5H, m), 2.29
(2H, m), 3.30-3.41 (2H, m), 3.57 (1H, t, J = 9.2Hz), 3.80 (1
(H, t, J = 10.6Hz), 3.93 (1H, dd, J = 5.5,11.0Hz), 4.05-4.16
(2H, m), 4.29-4.36 (1H, m), 4.77 (1H, d, J = 8.1Hz), 4.89
(1H, dd, J = 2.2,48.0Hz), 5.20-5.34 (3H, m), 5.80-5.89 (1
H, m), 6.52 (1H, t, J = 5.5Hz).

[0140]

Example 12b Allyl 2-deoxy-2-[(2'R, 3'S)-
2'-Fluoro-3 '-(myristoyloxy) myristoyl
Amino] -3-O- myristoyl-4,6-O-isopropyl
Compound (2'R, 3'S) obtained with den-β-D-glucopyranoside 12a 2 g (2.8 mmol)
Was dissolved in 30 ml of methylene chloride, 728 mg of myristic acid chloride was added, and then 313 mg of triethylamine was added, followed by stirring at room temperature for 1 hour. It was concentrated, diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure, and the residue was applied to a silica gel column and purified with cyclohexane: ethyl acetate = 5: 1 to obtain 1.35 g (52.1%) of the desired compound in a yield. Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1740, 169
5. Mass spectrum (M / Z): 924 (M ⁺ +1), 909, 883, 867, 73
7, 724, 655, 638, 610, 526, 513, 452. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (9H, t, J =
6.6Hz), 1.13-1.67 {70H, m [including 1.36 (3H, s), 1.46 (3H, s)]}, 2.25-2.35 (4H, m), 3.
32-3.41 (1H, m), 3.66-3.85
(3H, m), 3.95 (1H, dd, J = 5.5,
10.6 Hz), 4.05 (1H, dd, J = 6.
2,12.8 Hz), 4.26-4.34 (1H,
m), 4.74-4.93 (2H, m), 5.16
−5.29 (4H, m), 5.75−5.89 (1
H, m), 6.34 (1H, dd, J = 4.4,8.
8 Hz). As _C 54 _H 96 FNO _9: Elemental analysis

[0141]

Example 12c Allyl 2-deoxy-2-[(2'R, 3'S)-
2'-fluoro-3'-myristoyloxymyristoylua
Mino] -3-O-myristoyl-β-D-glucopyranosa
The compound obtained in Id 12b was treated in the same manner as in 4b,
It was obtained in a yield of 2 g (80.4%) of the desired compound. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.66-1.91 (74
H, m), 2.09-2.55 (4H, m), 2.87-6.16 (15H, m), 6.54 (1H,
m).

[0142]

Example 12d Allyl 2-deoxy-2-[(2'R, 3'S)-
2'-fluoro-3'-myristoyloxymyristoylua
Mino] -3-O-myristoyl-6-O-benzyloxyca
Dissolve 1.9 g (2.15 mmol) of the compound obtained with rubonyl-β-D-glucopyranoside 12c in 20 ml of methylene chloride, add 550 mg of benzyloxychloroformate, and further add 327 mg of triethylamine. And stirred at room temperature for 5 hours. It was concentrated and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure. The residue was applied to a silica gel column and purified with cyclohexane: ethyl acetate = 3: 1 to obtain 660 mg (30.2%) of the desired compound. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.8
8 (9H, t, J = 6.9 Hz), 1.25-1.6
5 (66H, m), 2.25-2.36 (4H,
m), 2.82 (1H, s), 3.59-3.66.
(2H, m), 4.03 (1H, dd, J = 6.2,
12.8 Hz), 4.27 (1H, dd, J = 5.
1,12.8 Hz), 4.42-4.52 (1H,
m), 4.81 (1H, dd, J = 3.7, 47.6)
Hz), 4.84 (1H, d, J = 8.1 Hz),
5.14-5.27 (6H, m), 5.76-5.8
9 (1H, m), 6.37 (1H, dd, J = 4.
4,8.1 Hz), 7.34-7.40 (5H,
m).

[0143]

Embodiment 12eAllyl 2-deoxy-2-[(2'R,
3'S) -2'-Fluoro-3'-myristoyl oximyrist
Ilamino] -3-O- myristoyl-4-O-diphenyl
Phosphoryl-6-O-benzyloxycarbonyl-β-D-
Glucopyranoside 600 mg (0.589 mmol) of the compound obtained in 12d was treated with methyl chloride.
Dissolve in 20 ml of diene and diphenylchlorophosphate 47
4.8 mg, and then 62.6 mg of triethylamine.
And stirred overnight at room temperature. Concentrate under reduced pressure and add ethyl acetate
Diluted with water. Ethyl acetate layer with sodium bicarbonate
Wash with water and saline and dry with anhydrous magnesium sulfate
did. After filtration, the ethyl acetate was distilled off under reduced pressure.
Apply to Kagel column, cyclohexane: ethyl acetate = 5: 1
The target compound was obtained in a yield of 600 mg (81.4%).
Was. Infrared absorption spectrum ν max cm-1 (CHCl_Three): 1743, 169
0. NMR spectrum (270MHz, CDCl_Three) δ ppm: 0.88 (9H, t, J =
6.9Hz), 1.05-1.73 (64H, m), 2.11-2.30 (4H, m), 3.46-3.
56 (1H, m), 3.77-3.82 (1H, m), 4.03 (1H, dd, J = 6.2,12.8H
z), 4.19-4.38 (3H, m), 4.63-4.89 (2H, m), 5.01-5.26 (6
H, m), 5.64-5.87 (2H, m), 6.37 (1H, dd, J = 4.4,7.7Hz), 7.
11-7.34 (15H, m). Elemental analysis: C₇₁H₁₀₉FNO₁₄As P

[0144]

Example 12f 2-deoxy-2-[(2′R, 3 ′S) -2′-fur
Oro-3'-myristoyloxymyristoylamino] -3-
O-myristoyl-4-O-diphenylphosphoryl-6-O
-The compound obtained with benzyloxycarbonyl-D-glucopyranose 12e was treated in the same manner as for 1 g to give the desired compound in a yield of 490 mg (84.3%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (9H, t, J =
7.0Hz), 1.11-1.66 (64H, m), 2.11-2.29 (4H, m), 3.36 (1
H, s), 4.13-4.39 (4H, m), 4.71-5.56 (7H, m), 6.70 (1H, d
d, J = 3.3,8.1Hz), 7.11-7.35 (15H, m).

[0145]

Example 12g 2-deoxy-2-[(2'R, 3'S) -2'-fur
Oro-3'-myristoyloxymyristoylamino] -3-
O-myristoyl-4-O-diphenylphosphoryl-D-
490 mg of the compound obtained with glucopyranose 12f was dissolved in 30 ml of tetrahydrofuran, 1 g of 10% palladium carbon was added, and hydrogenolysis was performed at room temperature for 2 hours. After filtration, tetrahydrofuran was distilled off under reduced pressure, and the residue was applied to a silica gel column.
Purification with ethyl acetate gave the desired compound in a yield of 270 mg (75.9%). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1735, 168
5. Elemental analysis: as C ₆₀ H ₉₉ FNO ₁₂ P

[0146]

Example 12h 2-deoxy-2-[(2'R, 3'S) -2'-fur
Oro-3'-myristoyloxymyristoylamino] -3-
O-myristoyl-D-glucopyranosyl-4-phosphate
The compound obtained with 12 g of the salt was treated in the same manner as with 5 g to give the target compound in a yield of 190 mg (96.2%). Mass spectrum (FAB / MS): 922 (MH) ^- .

[0147]

Example 13 2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3'-Myristoyloxymyristoylamino] -3-O
-Myristoyl-D-glucopyranosyl-4-phosphate
G

[0148]

Example 13a Allyl 2-deoxy-2-[(2'S, 3'R)-
2'-Fluoro-3'-myristoyloxymyristoylami
No] -3-O- myristoyl-4,6-O-isopropylidene
-Compound (2'S, 3'R) obtained with β-D-glucopyranoside 12a 2.9 g (4.06 mmol)
Was dissolved in 30 ml of methylene chloride, and 1.02 g of myristic acid was dissolved.
And N, N'-dicyclohexylcarbodiimide
1 g was added, and the mixture was stirred at room temperature for 1 hour. However, since the reaction did not proceed, 4-dimethylaminopyridine was further added.
50 mg was added, and the mixture was stirred at room temperature for 1 hour. Concentrate under reduced pressure,
The mixture was diluted with ethyl acetate, and the ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure. The residue was applied to a silica gel column, and cyclohexane: ethyl acetate =
Purification was performed at a ratio of 5: 1 to quantitatively obtain the target compound. NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.66-2.01 (79
H, m), 2.05-2.61 (4H, m), 3.30-6.23 (14H, m), 6.85 (1H,
m).

[0149]

Example 13b Allyl 2-deoxy-2-[(2'S, 3'R)-
2'-fluoro-3'-myristoyloxymyristoylua
Mino] -3-O-myristoyl-β-D-glucopyranosa
The compound obtained with Id 13a was treated in the same manner as 4b to give 3.08 g (84.7%) of the desired compound.

[0150]

Example 13c Allyl 2-deoxy-2-[(2'S, 3'R)-
2'-Fluoro-3'-myristoyloxymyristoylami
No] -3-O- myristoyl-6-O-benzyloxymethyl
2.7 g (3.05 mmol) of the compound obtained with 13-b -D-glucopyranoside 13b was dissolved in 50 ml of methylene chloride and benzyl chloromethyl ether was dissolved in 0.5 ml of methylene chloride.
Add 525 g, then add 0.355 g of tetramethylurea,
Reflux for 6 hours. The methylene chloride is distilled off under reduced pressure,
The residue was applied to a silica gel column and purified with cyclohexane: ethyl acetate = 3: 1 to obtain 2.08 g (67.8%) of the target compound. Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 3430, 173
8, 1695. Mass spectrum (M / Z): 986, 928, 834, 775, 717, 59
6, 509, 456, 383, 354,298,285, 268. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (9H, t, J =
6.9Hz), 1.20-1.73 (65H, m), 2.24-2.37 (4H, m), 3.47-3.
51 (1H, m), 3.74 (1H, t, J = 9.5Hz), 3.89-4.11 (4H, m), 4.2
6-4.33 (1H, m), 4.59 (1H, d, J = 8.4Hz), 4.63 (2H, s), 4.79
(1H, dd, J = 4.3,48.4Hz), 4.81 (2H, s), 5.03 (1H, dd, J = 9.
2,10.6Hz), 5.15-5.30 (3H, m), 5.80-5.88 (1H, m), 6.36
(1H, dd, J = 4.4,9.2Hz), 7.29-7.36 (5H, m).

[0151]

Example 13dAllyl 2-deoxy-2-[(2'S, 3'R) -2 '
-Fluoro-3'-myristoyloxymyristoylami
No] -3-O- myristoyl-4-O-diphenyl phosphoryl
6-O-benzyloxymethyl-β-D-glucopyr
Nocide The compound obtained in 13c was treated in the same manner as 12e,
Target compound was obtained quantitatively. Infrared absorption spectrum ν max cm-1 (CHCl_Three): 3430,
 1740, 1695. Mass spectrum (M / Z): 1014, 994, 758, 670, 580, 4
40, 322, 268. NMR spectrum (270MHz, CDCl_Three) δ ppm: 0.88 (9H, t, J =
6.9Hz), 1.10-1.68 (65H, m), 2.08-2.31 (3H, m), 3.65-3.
69 (2H, m), 3.78-3.84 (1H, m), 4.03-4.11 (2H, m), 4.25-4.
32 (1H, m), 4.50-4.85 (7H, m), 5.15-5.39 (4H, m), 5.76-
5.83 (1H, m), 6.38 (1H, dd, J = 4.8,9.2Hz), 7.13-7.44 (15
H, m).

[0152]

Example 13e 2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3'-Myristoyloxymyristoylamino] -3-O
-Myristoyl-4-O-diphenylphosphoryl-6-O-
The compound obtained with benzyloxymethyl-D-glucopyranose 13d was treated in the same manner as in 1 g to obtain the desired compound in a yield of 1.58 g (71%). NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 0.63-2.42 (77
H, m), 3.55-5.78 {14H, m [including 4.54 (2H, s), 4.66 (2H, s)]}, 6.70 (1H, m), 7.00-7.53 (15H, m).

[0153]

Example 13f 2-deoxy-2-[(2'S, 3'R) -2'-fluoro
B-3'-Myristoyloxymyristoylamino] -3-O
-Myristoyl-4-O-diphenylphosphoryl-D-g
1.44 g (1.2 mmol) of the compound obtained with lucopyranose 13e was dissolved in 30 ml of methanol, 1 g of 10% palladium carbon was added, and hydrogenolysis was performed at 40-45 ° C. for 3 hours. After filtration, methanol was distilled off under reduced pressure, and the residue was applied to a silica gel column and purified with cyclohexane: ethyl acetate = 1: 1 to obtain the desired compound in a yield of 715 mg (55.2%). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 3440, 174
0, 1690. Elemental analysis: as C ₆₀ H ₉₉ FNO ₁₂ P

[0154]

Example 13g 2-deoxy-2-[(2'S, 3'R) -2'- fluoro
B-3'-Myristoyloxymyristoylamino] -3-O
- myristoyl - D- glucopyranosyl-4-phosphate
The compound obtained in Preparative 13f, were processed as 5g, to obtain the desired compound in a yield of 420 mg (89%). Mass spectrum (FAB / MS): 922 (MH) ^- .

[0155]

Example 14 2-deoxy-2-[(R or S) -2 ′, 2′-diflu
Oro-3'-hydroxymyristoylamino] -3-O-[(R) -3
-Myristoyloxymyristoyl]-D-Glucopyra
Nosyl-4-phosphate

[0156]

Example 14a Allyl 2-deoxy-2-[(RS) -2 ', 2'-
Difluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -4,6-O-isopropylidene-β-
Dissolve 2.2 g of D-glucopyranoside (±) -3-benzyloxycarbonyloxy-2,2-difluoromyristic acid in 20 ml of dry dichloromethane, add 2 ml of oxalic acid chloride, and add N, N-
One drop of dimethylformamide was added, and the mixture was stirred at room temperature for 1 hour. Dichloromethane was distilled off under reduced pressure to obtain an acid chloride. Allyl 2-deoxy-2-amino-4,6 obtained in 1d
-O-Isopropylidene-β-D-glucopyranoside
1.51 g was dissolved in 20 ml of dry dichloromethane, 700 mg of triethylamine was added, and acid chloride was added under ice cooling. After stirring at room temperature for 1 hour, dichloromethane was distilled off under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure,
The residue was subjected to silica gel chromatography and purified with cyclohexane: ethyl acetate = 2: 1 to give 2.64 g (75.8 g) of the desired compound.
%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (3H, t, J =
6.2-7.0Hz), 1.25-1.61 {24H, m [1.45 (3H, s), 1.52 (3H,
s)]}, 1.72-1.79 (2H, m), 2.95 (0.5H, d, J = 3.3H
z), 3.11 (0.5H, d, J = 3.3Hz), 3.21-3.60 (3H, m), 3.76-4.
13 (4H, m), 4.23-4.33 (1H, m), 4.70 (0.5H, d, J = 8.4Hz),
4.81 (0.5H, d, J = 8.4Hz), 5.14-5.31 (5H, m), 5.75-5.91 (1
H, m), 6.47-6.54 (1H, m), 7.30-7.40 (5H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 3430, 292
5, 2850, 1755, 1705, 1535, 1380, 1263. Mass spectrum (M / Z): 655 (M ⁺ ), 640, 597, 532, 46
8, 385, 360, 242, 227,184, 143, 108, 101, 91, 69,
43. Elemental analysis: as C ₃₄ H ₅₁ F ₂ NO ₉

[0157]

Example 14b Allyl 2-deoxy-2-[(RS) -2 ', 2'-
Difluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -4,6-O-isopropylidene-3-O
-[(R) -3 "-Myristoyloxymyristoyl]-β-D
- glucopyranoside (R)-3-myristoyl oxy myristate 230 mg (0.5 mmo
l) with oxalyl chloride 0.5 ml, dichloromethane 4 ml
After treating with acid for 2 hours, excess oxalyl chloride and solvent were removed under reduced pressure and dried. Compound 262 mg (0.4 mmol) obtained in 14a, triethylamine 50 m
g in dichloromethane (5 ml) and sufficiently cooled on ice.
5 ml of the dichloromethane solution of the above acid chloride was added dropwise. In about 3 hours, the raw materials disappear, and the solvent is removed under reduced pressure.
Dilute with ethyl acetate, 5% aqueous sodium bicarbonate,
After treatment with a saturated saline solution, purification was performed by column chromatography (silica gel 20 g, cyclohexane: ethyl acetate = 5: 1), and the yield was 325.8 mg (74.3%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.85-0.90 (9
H, m), 1.20-1.80 (68H, m), 2.20-2.31 (2H, m), 2.43-2.66
(2H, m), 3.35 (1H, m), 3.68-4.07 (5H, m), 4.26 (1H, m),
4.58 (1H, m), 5.11-5.41 (7H, m), 5.74 (1H, m), 6.58 (1H, m
m), 7.29-7.38 (5H, m). Infrared absorption spectrum ν max cm-1 (liquid film): 3350,29
25, 2850, 1780, 1710.

[0158]

Example 14c Allyl 2-deoxy-2-[(RS) -2 ', 2'-
Difluoro-3 '-(benzyloxycarbonyloxy) mi
Ristoylamino] -3-O-[(R) -3 "-myristoyloxy
Myristoyl] -β-D-glucopyranoside 14b was added to 0.2 g of the obtained compound, and 50 ml of 85% acetic acid was added.
Stirred at 60 ° C. for 50 minutes. The acetic acid was removed under reduced pressure, dried with a vacuum pump, and purified by column chromatography [silica gel 15 g, cyclohexane: ethyl acetate = 2: 1]. Yield 0.11 g
(57.9%). In this reaction, it is better to complete the reaction quickly by using as much acetic acid as possible. If the amount of acetic acid is small, a by-product is formed and the yield is reduced. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.85-0.90 (9
H, t, J = 6.4-6.8Hz), 1.18-1.42 (47H, m), 1.43-1.80 (14H,
m), 1.90-2.00 (1H, m), 2.09 (1H, t, J = 5.9-6.4Hz), 2.25-
2.32 (2H, m), 2.41-2.50 (2H, m), 3.37-3.53 (1H, m), 3.63
-3.70 (2H, m), 3.78-4.08 (4H, m), 4.21-4.34 (1H, m), 4.5
3 (0.4H, d, J = 8.3Hz), 4.59 (0.6H, d, J = 8.3Hz), 4.92-5.36
(7H, m), 5.74-5.88 (1H, m), 6.59 (0.6H, d, J = 8.8Hz), 6.6
9 (0.4H, d, J = 8.8Hz), 7.35-7.39 (5H, m). Infrared absorption spectrum ν max cm-1 (Nujol): 3
350, 3450, 3300, 2950,1760, 1690, 1620, 1550. Elemental analysis: as C ₅₉ H ₉₉ F ₂ NO _12.

[0159]

Example 14d Allyl 6-O-benzyloxycarbo
Nyl-2-deoxy-2-[(RS) -2 ', 2'-difluoro-3'-(be
Ndyloxycarbonyloxy) myristoylamino]-
3-O-[(R) -3 "-myristoyloxymyristoyl] -β-
120 mg (0.11 mmol) of the compound obtained from D-glucopyranoside 14c and 25.4 mg (1.3 equivalents) of benzyloxycarbonyl chloride were dissolved in 20 ml of dichloromethane and cooled with ice. After adding 17.2 mg (1.5 equivalents) of dimethylaminopyridine and stirring for 30 minutes, the mixture was returned to room temperature and stirred for 2 hours. Column chromatography (silica gel 100 g, cyclohexane: ethyl acetate = 2:
The target compound was purified in 1) in a yield of 80 mg (59.2%)
A protected material was obtained in both positions 6 and 6 in a yield of 36 mg (26.7%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (9H, t, J =
6.35-6.83Hz), 1.25-1.73 (62H, m), 2.24-2.31 (2H, m),
2.41-2.48 (2H, m), 3.52-3.69 (4H, m), 3.90-4.02 (3H, m),
4.18-4.30 (1H, m), 4.42-4.57 (3H, m), 5.02-5.25 (7H, m
m), 5.68-5.85 (1H, m), 6.48-6.65 (1H, m), 7.32-7.40 (10
H, m). Infrared absorption spectrum ν max cm-1 (Nujol): 3
500, 3300, 2900, 2850,1720, 1690, 1540. Elemental analysis: as C ₆₇ H ₁₀₅ F ₂ NO _14.

[0160]

Example 14e Allyl 6-O-benzyloxycarbo
Nyl-2-[(RS) -2 ', 2'-difluoro-3'-(benzyloxy
Carbonyloxy) myristoylamino] -4-O-diphen
Nylphosphoryl-2-deoxy-3-O-[(R) -3-myristoy
Loximyristoyl] -β-D-glucopyranoside 14 g of the compound obtained in 14d, diphenylphosphoryl chloride and dimethylaminopyridine were added in excess of 1 g each, and the mixture was heated under reflux for 3 hours using 50 ml of tetrahydrofuran as a solvent. . After removing the solvent under reduced pressure, the mixture was diluted with ethyl acetate, and then treated with a 5% aqueous sodium hydrogen carbonate solution and a saturated saline solution. Column chromatography (silica gel 30
g, cyclohexane: ethyl acetate = 3: 1) to obtain 0.62 g (97.5%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.90 (9H, t, J =
6.8Hz), 1.14-1.75 (62H, m), 2.12-2.41 (3H, m), 3.61-3.
83 (3H, m), 3.91-4.04 (1H, m), 4.13-4.23 (2H, m), 4.30-4.
38 (1H, m), 4.69 (1H, ddd, J = 9.0,9.0,18.0Hz), 4.85 (1H,
d, J = 7.0Hz), 4.99-5.39 (7H, m), 5.47-5.63 (2H, m), 5.67
-5.85 (1H, m), 6.80 (0.5H, d, J = 7.0Hz), 6.95 (0.5H, d, J =
7.0Hz), 7.10-7.36 (20H, m). Infrared absorption spectrum ν max cm-1 (liquid film): 3300,29
00, 2850, 1750, 1700,1590, 1540. Elemental analysis: as C ₇₉ H ₁₁₄ F ₂ NO ₁₇ P

[0161]

Example 14f 6-O-benzyloxycarbonyl-4-
O-diphenylphosphoryl-2-deoxy-2-[(RS) -2 ', 2'
-Difluoro-3 '-(benzyloxycarbonyloxy)
Myristoylamino] -3-O-[(R) -3- myristoyloki
30 mg (5% mol) of 1,5-cyclooctadiene bis [methyldiphenylphosphine] iridium hexafluorophosphate was added to 50 mg of the compound obtained from [ Simiristoyl] -D-glucopyranoside 14e, and 5 ml of tetrahydrofuran. And then replaced with nitrogen and then replaced with hydrogen. When the color of the solution changed, it was quickly replaced with nitrogen and stirred at room temperature for 3 hours. 1 ml of concentrated hydrochloric acid was added, the mixture was stirred at 50 ° C for 2 hours, and purified by preparative thin-layer chromatography (1 mm) to obtain 40 mg (82.1%) of the target compound. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm (R, S mixed): 0.
83-0.90 (9H, t, J = 6.5-6.8Hz), 1.16-1.74 (62H, m), 2.09-
2.18 (2H, m), 2.32-2.49 (2H, m), 2.73-2.74 (0.5H, d, J = 3.
9Hz), 3.28-3.29 (0.5H, d, J = 3.9Hz), 4.01-4.38 (4H, m),
4.63-4.74 (1H, m), 4.89-5.23 (7H, m), 5.33-5.47 (1H, m),
6.72-6.73 (1H, m), 7.12-7.37 (20H, m). Infrared absorption spectrum ν max cm-1 (liquid film): 3350,29
25, 2850, 1750, 1710, 1590, 1540, 1490, 1460. Elemental analysis: as C ₇₆ H ₁₁₀ F ₂ NO ₁₇ P

[0162]

Example 14g 4-O-diphenylphosphoryl-2-deo
Xy-2-[(RS) -2 ', 2'-difluoro-3'-hydroxymyris
Toylamino] -3-O-[(R) -3- myristoyloxymilli
[Stoyl] -D-glucopyranoside in 2 ml of tetrahydrofuran
After 30 mg and 20 mg of 10% palladium carbon were added, the atmosphere was replaced with hydrogen using an aspirator, stirred at room temperature for 6 hours, and left overnight. Preparative thin-layer chromatography (1 mm, cyclohexane:
The mixture was developed with ethyl acetate = 1: 1) to obtain 10 mg (41.2%) of two target compounds each having a substituent at the 2-position represented by R or S. [2R form (lower Rf)] NMR spectrum (270 MHz
z, CDCl ₃ ) δ ppm: 0.85-0.90 (9H, t, J = 6.34-6.36Hz), 1.
20-1.68 (62H, m), 2.17-2.23 (2H, m), 2.34-2.47 (2H, m),
3.10 (1H, d, J = 4.5Hz), 3.18-3.27 (2H, m), 3.54-3.61 (1H,
m), 3.92-4.03 (3H, m), 4.27-4.36 (1H, m), 4.78 (1H, q, J =
9.2Hz), 5.02-5.11 (1H, m), 5.36 (1H, t, J = 3.4Hz), 5.53
(1H, t, J = 9.3Hz), 6.87-6.91 (1H, m), 7.14-7.39 (10H, m). Infrared absorption spectrum ν max cm-1 (Nujol): 3
500, 3450, 3375, 2900, 2850, 1730, 1680, 1600. [2S-form (Rf is the upper one)] NMR spectrum (270MH
z, CDCl ₃ ) δ ppm: 0.85-0.90 (9H, t, J = 6.3-6.41Hz), 1.2
1-1.68 (62H, m), 2.17-2.23 (2H, m), 2.34-2.50 (2H, m),
3.08 (1H, d, J = 4.4Hz), 3.18-3.29 (2H, m), 3.54-3.61 (1H,
m), 3.94-4.00 (3H, m), 4.27-4.36 (1H, m), 4.79 (1H, q, J =
9.4Hz), 5.02-5.12 (1H, m), 5.36 (1H, t, J = 3.4Hz), 5.53
(1H, t, J = 9.7Hz), 6.92-7.01 (1H, m), 7.14-7.39 (10H, m). Infrared absorption spectrum ν max cm-1 (Nujol): 3
500, 3450, 3375, 2900, 2850, 1730, 1680, 1600.

[0163]

Example 14h 2-Deoxy-2-[(R or S) -2 ′, 2′-dif
Luoro-3'-hydroxymyristoylamino] -3-O-[(R)
-3- Myristoyloxymyristoyl] -D-Glucopyra
To 2 ml of nosyl-4-phosphate tetrahydrofuran, 60 mg of each compound obtained in 14 g and 5 mg of platinum oxide were added, the mixture was replaced with hydrogen using an aspirator, and the mixture was stirred at room temperature for 3 hours. Platinum oxide was removed by filtration, tetrahydrofuran was removed under reduced pressure, and the two target compounds were R or S. Of the two target compounds, those having a higher Rf value from the starting compound having a higher Rf value were 50 mg. (95%), 52 mg (97%) of the starting compound having the lower Rf value was obtained from the lower starting compound [developing solvent (chloroform: ethanol: ethyl acetate: water = 8: 5: 2: 1)]. [2R form (Rf is lower)] NMR spectrum (270MH
z, d ₅ -pyridine + heavy water) δ ppm: 0.85-0.90 (9H, m), 1.
14-2.04 (62H, m), 2.39-2.48 (2H, m), 3.05-3.14 (1H, m),
3.28-3.37 (1H, m), 4.07-4.11 (1H, m), 4.49-4.66 (3H, m),
4.88-4.98 (1H, m), 5.18-5.29 (1H, m), 5.71-5.81 (2H, m
m), 6.17-6.32 (1H, m). Infrared absorption spectrum ν max cm-1 (Nujol): 3
500, 3350, 2900, 2850,1720, 1680, 1590, 1540, 149
0, 1460. [2S form (Rf is the upper one)] NMR spectrum (270MH
z, d ₅ -pyridine + heavy water) δ ppm: 0.88-0.97 (9H, m), 1.
24-2.02 (62H, m), 2.33-2.48 (2H, m), 2.92-3.01 (1H, m),
3.36-3.59 (1H, m), 4.11-4.22 (1H, m), 4.53-4.69 (3H, m),
4.93-5.04 (1H, m), 5.49-5.56 (1H, m), 5.68-5.74 (1H,
m), 5.82-5.83 (1H, m), 6.26-6.38 (1H, m). Infrared absorption spectrum ν max cm-1 (Nujol): 3
500, 3350, 2900, 2850,1720, 1680, 1590, 1540, 149
0, 1460.

[0164]

Example 15 2-deoxy-2-[(R) -3′-hydroxymilli
Styramino] -3-O-[(R) -3 "-(2,2-difluoromilli
Stoyloxy) myristoyl] -D-glucopyranosyl-4
-Phosphate

[0165]

Example 15a Allyl 2-deoxy-2-[(R) -3'-ben
Diloxymyristoylamino] -3-O-[(R) -3 "-(2,2-
Difluoromyristoyloxy) myristoyl] -4,6-O
Allyl 2-deoxy-2-[(R) -3′-benzyloxymyristoylamino] -4,6-O-isopropylidene- β-isopropylidene-β-D-glucopyranoside 1e 4.1 g (7.12 mmol) of D-glucopyranoside
Dissolve in 100 ml of diethyl ether, 4.54 g (9.26 mmol)
Of R-3- (2 ', 2'-difluoromyristoyloxy) myristic acid, and 1.9 g (9.26 mmol) of N, N'-dicyclohexylcarbodiimide 0.087 g (0.71 mmol) of 4-dimethylaminopyridine Was added and stirred at room temperature for 1 hour. It concentrated under reduced pressure and diluted with ethyl acetate. The precipitate was removed by filtration, and the ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate.
After filtration, the ethyl acetate was distilled off under reduced pressure, and the residue was applied to a silica gel column and purified with cyclohexane: ethyl acetate = 5: 1 to obtain the target compound in a yield of 5.5 g (74%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (9H, t, J =
6.6Hz); 1.16-1.72 [66H, m {including 1.36 (3H, s), 1.45 (3H, s)}]; 1.93-2.08 (2H, m); 2.32-2.45 (2H, m); 2.55 ( 1H, d
d, J = 5.9,16.1Hz); 2.69 (1H, dd, J = 7.3,16.1Hz); 3.18-3.
28 (1H, m); 3.64-3.82 (4H, m); 3.85-3.99 (3H, m); 4.18-
4.17 (1H, m); 4.34 (1H, d, J = 8.1Hz); 4.47 (1H, d, J = 11.7H
z); 4.59 (1H, d, J = 11.7Hz); 5.05-5.36 (3H, m); 5.71-5.8
3 (1H, m); 6.33 (1H, d, J = 9.5Hz); 7.23-7.41 (5H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1765, 167
5. Mass spectrum (M / Z): 1048 (M ⁺ +1), 1032, 1006, 941,
822, 806, 780, 742, 715, 677, 657, 634, 596, 558,
516, 502,472, 388, 361, 334, 318, 276, 250, 209,
151, 101, 91, 55, 41. Elemental analysis: C ₆₁ H ₁₀₃ F ₂ NO ₁₀ : 1048.5

[0166]

Example 15b Allyl 2-deoxy-2-[(R) -3'-ben
Diloxymyristoylamino] -3-O-[(R) -3 "-(2,2-
Difluoromyristoyloxy) myristoyl] -β-D-
4.8 g (4.58 mmol) of the compound obtained with glucopyranoside 15a was added to 200 ml of 90
The mixture was suspended in 50% acetic acid and stirred at 50 ° C. for 2 hours. Acetic acid was distilled off under reduced pressure, and the residue was applied to a silica gel column and purified with cyclohexane: ethyl acetate = 1: 1 to obtain the desired compound in a yield of 3.1 g (67%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.82-0.95 (9
H, m); 1.15-1.77 (60H, m); 1.91-2.12 (3H, m); 2.31-2.48
(2H, m); 2.55 (1H, dd, J = 4.4,16.1Hz); 2.68 (1H, dd, J = 8.
3,16.1Hz); 2.73 (1H, d, J = 4.4Hz); 3.29-3.38 (1H, m); 3.
66 (1H, ddd, J = 4.4,9.3,9.3Hz); 3.70-4.00 (5H, m); 4.18-
4.28 (1H, m); 4.35 (1H, d, J = 8.3Hz); 4.47 (1H, d, J = 11.7H
z); 4.60 (1H, d, J = 11.7Hz); 4.97-5.33 (4H, m); 5.71-5.8
8 (1H, m); 6.34 (1H, d, J = 8.8Hz), 7.28-7.41 (5H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1760, 167
3. Elemental analysis value C ₅₈ H ₉₉ F ₂ NO ₁₀ : 1008.4

[0167]

Example 15c Allyl 2-deoxy-2-[(R) -3'-ben
Diloxymyristoylamino] -3-O-[(R) -3 "-(2,2-
Difluoromyristoyloxy) myristoyl] -6-O-
2.5 g (2.48 mmol) of the compound obtained with benzyloxymethyl-β-D-glucopyranoside 15b was dissolved in 50 ml of dichloromethane, and 500 mg (3.22 mmol) of benzyl chloromethyl ether was added. mg (3.22 mm
ol) was added and stirred at room temperature overnight. It concentrated under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and brine,
It was dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure, and the residue was applied to a silica gel column and purified with cyclohexane: ethyl acetate = 3: 1 to obtain the desired compound in a yield of 1.65 g (59%). Further, 0.95 g of the raw material was recovered. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.84-0.94 (9
H, m); 1.16-1.75 (60H, m); 1.91-2.11 (2H, m); 2.32-2.46
(2H, m); 2.51-2.73 (3H, m); 3.35-3.46 (1H, m); 3.60-3.9
9 (6H, m); 4.18-4.30 (1H, m); 4.34 (1H, d, J = 8.3Hz); 4.44
-4.66 (4H, m); 4.79 (2H, s); 4.98-5.38 (4H, m); 5.69-5.8
7 (1H, m); 6.89 (1H, d, J = 8.8Hz); 7.23-7.43 (10H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1760, 167
5. Elemental analysis value C ₆₆ H ₁₀₇ F ₂ NO ₁₁ = 1128.6

[0168]

Example 15d Allyl 2-deoxy-2-[(R) -3'-ben
Diloxymyristoylamino] -3-O-[(R) -3 "-(2,2-
Difluoromyristoyloxy) myristoyl] -4-O-
Diphenylphosphoryl-6-O-benzyloxymethyl-
610 mg (0.54 mmol) of the compound obtained with β-D-glucopyranoside 15c was dissolved in 20 ml of dichloromethane, and 100 mg (0.59 mmol) of diphenyl chlorophosphate was added, followed by 33 mg (0.27 mmol).
Was added and stirred at room temperature for 3 hours. While confirming the progress of the reaction, finally 640 mg (2.38 mmol) of diphenyl chlorophosphate,
198 mg (1.62 mmol) of 4-dimethylaminopyridine was added in four portions. The reaction solution was washed with 1 N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, and dried over sodium sulfate. After filtration, dichloromethane was concentrated under reduced pressure, the residue was subjected to silica gel chromatography, and cyclohexane: ethyl acetate was added.
= 4: 1 to give the desired compound in a yield of 530 mg (72%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.83-0.94 (9
H, m); 1.08-1.75 (60H, m); 1.87-2.09 (2H, m); 2.29-2.55
(4H, m); 3.56-3.87 (4H, m); 3.94 (1H, dd, J = 6.4,12.7Hz);
4.24 (1H, dd, J = 5.4,12.7Hz); 4.43-4.81 (8H, m); 5.03-
5.29 (4H, m), 5.50 (1H, dd, J = 9.3,9.8Hz); 5.69-5.87 (1H,
m), 6.34 (1H, d, J = 8.3Hz), 7.18-7.39 (20H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1760, 167
8, 1597, 1496, 960. Elemental analysis: C ₇₈ H ₁₁₆ F ₂ NO ₁₄ P: 1360.7

[0169]

Example 15e 2-Deoxy-2-[(R) -3′-benzyloxy
Simiristoylamino] -3-O-[(R) -3 "-(2,2-difluoro
Lomiristoyloxy) myristoyl] -4-O-diphenyl
530 mg (0.39 mmol) of the compound obtained in the form of l-phosphoryl-D-glucopyranose 15d was dissolved in 5 ml of tetrahydrofuran, and 33 mg (10% mol) of 1,5-cyclooctadiene-bis (methyldiphenylphosphine) was dissolved. Iridium hexafluorophosphate was added.
The inside of the reaction vessel was replaced with nitrogen and further replaced with hydrogen. After confirming that the catalyst was activated and turned from red to colorless, it was immediately replaced with nitrogen. After stirring at room temperature for 3 hours, 2 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 24 hours. It concentrated under reduced pressure and diluted with ethyl acetate. The extract was washed with water, aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography.
= 2: 1 to give the target compound in a yield of 258 mg (55%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.82-0.98 (9
H, m); 1.07-1.77 (60H, m); 1.84-2.09 (2H, m); 2.21-2.50
(5H, m); 3.26 (1H, t, J = 7.3Hz); 3.52-3.62 (2H, m); 3.81-
3.91 (2H, m); 4.19-4.30 (1H, m); 4.39 (1H, d, J = 11.2Hz);
4.61 (1H, d, J = 11.2Hz); 4.67-4.78 (1H, m); 4.98 (1H, t, J =
3.9Hz); 5.19-5.29 (1H, m); 5.41 (1H, dd, J = 9.3,10.7Hz);
6.23 (1H, d, J = 9.3Hz); 7.13-7.38 (15H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 1750, 166
0. Elemental analysis _{C 67 H 104 FNO 13 P:} 1200.5 as CHNFP theory 67.03 8.73 1.17 3.16 2.58 (%) analysis 66.91 8.61 1.13 3.04 2.46 (%)

[0170]

Example 15f 2-deoxy-2-[(R) -3′-hydroxy
Myristoylamino] -3-O-[(R) -3 "-(2,2-difluoro
Myristoyloxy) myristoyl] -4-O-diphenyl
250 mg (0.21 mmol) of the compound obtained with phosphoryl-D-glucopyranose 15e was dissolved in 10 ml of methyl alcohol, 100 mg of 10% palladium on carbon was added, and the mixture was subjected to catalytic reduction at room temperature for 3 hours. Filtered,
Methyl alcohol was distilled off under reduced pressure, the residue was subjected to silica gel chromatography, and purified with ethyl acetate to obtain the desired compound in 12%.
Obtained in 2 mg (53%) yield. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.82-0.95 (9
H, m); 1.07-1.63 (60H, m); 1.80-2.11 (2H, m); 2.17-2.53
(4H, m); 3.20-3.39 (2H, m); 3.55-3.66 (2H, m); 3.70 (1H,
d, J = 3.4Hz); 3.38-4.04 (2H, m); 4.21-4.33 (1H, m); 4.76
(1H, dd, J = 9.3,9.8Hz); 5.18-5.28 (1H, m); 5.31 (1H, dd, J
= 3.4,3.9Hz); 5.48 (1H, dd, J = 9.8,10.3Hz); 6.25 (1H, d, J =
8.8Hz); 7.13-7.42 (10H, m). Infrared absorption spectrum ν max cm-1 (CHCl ₃ ): 3425, 292
5, 2855, 1760, 1660, 1590, 1490, 1180, 1157, 965.

[0171]

Example 15g 2-Deoxy-2-[(R) -3'-hydroxymi
Ristoylamino] -3-O-[(R) -3 "-(2,2-difluoromi
Ristoyloxy) myristoyl] -D-glucopyranosyl
85 mg (0.08 mmol) of the compound obtained with 4-phosphate 15f was dissolved in 10 ml of tetrahydrofuran, 15 mg of platinum oxide was added, and the mixture was subjected to catalytic reduction at room temperature for 5 hours. After filtration, tetrahydrofuran was distilled off under reduced pressure to obtain the desired compound in a yield of 72 mg (98%). Infrared absorption spectrum ν max cm-1 (KBr): 2956, 2923,
2853, 1761, 1644, 1549, 1467, 1188, 1128, 1058, 9
72.

[0172]

Example 16 2-Deoxy-2-[(S) -3′-fluoromyris
Toylamino] -3-O-[(R) -3 "-myristoyloxymilli
STYL] -D-Glucopyranosyl-4-phosphate

[0173]

Example 16a Diphenylmethyl (S) -3-fluoromi
5 g of (R) -3-hydroxymyristate protected with a carboxyl group was dissolved in 50 ml of dichloromethane with listit diphenyldiazomethane, and 8 g of diethylaminosulfur trifluoride was added under ice-cooling, followed by stirring for 3 hours. Then, the mixture was returned to room temperature and stirred for 2 hours. The reaction solution was evaporated to dryness, diluted with ethyl acetate, and washed with a 5% aqueous sodium hydrogen carbonate solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was again evaporated to dryness. Silica gel chromatography (silica gel 30 g, cyclohexane: ethyl acetate = 5: 1)
And 4.71 g (80%) of the target compound was obtained. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (3H, t, J
= 6.59Hz); 1.25-1.47 (20H, m); 2.56-2.83 (2H, m); 4.96
(1H, dm, J = 48.3Hz); 6.94 (1H, s); 7.29-7.34 (10H, m). Infrared absorption spectrum ν max cm-1 (nujol): 29
00, 2850, 1740, 1460. Mass spectrum (M / Z): 412
(As _{C 27 H 37 FO 2 = 412} ) 43. Elemental ^{analysis; (M +); 412;} 392; 209; 184; 166; 152; 105

[0174]

Example 16b 4.71 g of the compound prepared with (S) -3-fluoromyristic acid 16a was added to dichloromethane 20m
and 50 ml of trifluoroacetic acid was added dropwise at room temperature. After stirring for 3 hours at room temperature, the reaction was evaporated to dryness and diluted with ethyl acetate. The extract was washed with saturated saline, the organic layer was dried over anhydrous magnesium sulfate, the solvent was again evaporated to dryness, and then silica gel chromatography (silica gel 100 g)
, Cyclohexane: ethyl acetate = 5: 1, then, after elution of the impurities, the residue was purified by ethyl acetate) to give 2.79 g of the desired compound
(99%). NMR spectrum (270 MHz, CDCl ₃ + D ₂ O) δ ppm: 0.88 (3H,
t, J = 6.5Hz); 1.26-1.75 (20H, m); 2.65-2.74 (2H, m); 4.9
7 (1H, dm, J = 48.4Hz). Infrared absorption spectrum ν max cm-1 (nujol): 34
00, 1680, 1540, 1460. Mass spectrum (M / Z): 247
(M ⁺ ); 226; 208; 172; 166; 151; 140. Elemental analysis (assuming C ₁₄ H ₂₇ FO ₂ = 246.2)

[0175]

Example 16c Allyl 2-deoxy-2-[(S) -3′-fur
Olomiristoylamino] -4,6-O-isopropylidene-
0.1 g (0.386 mmol) of β-D-glucopyranoside allyl 2-deoxy-2-amino-4,6-O-isopropylidene-β-D-glucopyranoside,
0.11 g of (S) -3-fluoromyristic acid prepared in 16b
(1.2 equivalents) was dissolved in 10 ml of dichloromethane, and N, N'-
0.09 g (1.2 equivalents) of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature overnight. The reaction was evaporated to dryness, diluted with ethyl acetate, and 5% aqueous sodium hydrogen carbonate,
After washing with saturated saline and drying the organic layer with anhydrous magnesium sulfate, the solvent was again evaporated to dryness and silica gel chromatography (silica gel 100 g, cyclohexane: ethyl acetate)
= 3: 2) to give 0.13 g (69%) of the desired compound. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.8
8 (3H, t, J = 6.4 Hz); 1.21-1.3
5 (20H, m); 1.44 (3H, s); 1.5
2.49-2.60 (2H, m); 3 (3H, s);
3.29-3.35 (1H, m); 3.44-3.
47 (1H, m); 3.70 (2H, m); 3.9
0-4.01 (3H, m); 4.21 (2H, dm,
4.67 (1H, d, J = 8. J = 51.3 Hz);
4.90 (1H, dm, J = 40.5H)
z); 5.19-5.33 (2H, m); 5.81
-5.98 (2H, m). Elemental analysis (assuming C ₂₆ H ₄₆ FNO ₆ = 487.5)

[0176]

Example 16d Allyl 2-deoxy-2-[(S) -3′-fur
Oromiristoylamino] -3-O-[(R) -3 "-myristoyl
Oxymyristoyl] -4,6-O-isopropylidene-β-
1 g (2.05 mmol) of the compound obtained with D-glucopyranoside 16c and 1.1 g (1.2 equivalents) of (R) -3-tetradecanoyloxytetradecanoic acid were dissolved in 30 ml of dichloromethane, and N, N'-dicyclohexyl was dissolved. 0.51 g (1.2 equivalents) of carbodiimide and 0.3 g (1.2 equivalents) of 4-dimethylaminopyridine were added at room temperature. After stirring at room temperature for 1 hour, the reaction solution was evaporated to dryness and diluted with ethyl acetate. Five
% Aqueous sodium bicarbonate solution and saturated saline,
The organic layer was dried over anhydrous magnesium sulfate. After removing anhydrous magnesium sulfate by filtration and evaporating the solvent to dryness, silica gel chromatography (silica gel 50 g, cyclohexane:
Purification by ethyl acetate = 5: 1), 1.46 g (77%) of the target compound
I got it. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.85-0.90 (9
H, m); 1.26-1.36 (62H, m); 1.37 (3H, s); 1.47 (3H, s); 2.2
2-2.64 (6H, m); 3.28-3.38 (1H, m); 3.68-3.84 (2H, m); 3.
91-4.09 (3H, m); 4.27-4.34 (1H, m); 4.62 (1H, d, J = 8.3H
z); 4.87 (1H, dm, J = 45.9Hz); 5.12-5.29 (4H, m); 5.72-5.
88 (2H, m). Infrared absorption spectrum ν max cm-1 (chloroform):
3440, 2900, 2850, 1740, 1680, 1540. Elemental analysis (assuming C ₅₄ H ₉₈ FNO ₉ = 924.4)

[0177]

Example 16e Allyl 2-deoxy-2-[(S) -3-f
Luoromiristoylamino] -3-O-[(R) -3 "-myristoy
1.35 g (1.46 mmol) of the compound obtained with [ loximyristoyl] -β-D-glucopyranoside 16d was dissolved in 100 ml of a 90% aqueous acetic acid solution and stirred at 60 ° C for 1 hour. The reaction solution was evaporated to dryness, diluted with ethyl acetate, and washed with a 5% aqueous sodium hydrogen carbonate solution and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was again evaporated to dryness, and the residue was purified by column chromatography (silica gel 100 g, cyclohexane: ethyl acetate = 2: 1) to give the target compound, 0.1%.
97 g (75%) were obtained. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.85-0.91 (9
H, m); 1.19-1.69 (62H, m); 2.26-2.52 (6H, m); 3.68-4.01
(6H, m); 4.15-4.28 (2H, m); 4.74-4.99 (2H, m); 5.11-5.3
4. (5H, m); 5.83-5.93 (1H, m); 6.09 (1H, d, J = 9.3Hz). Infrared absorption spectrum ν max cm-1 (Nujol): 34
50, 3300, 1740, 1720, 1550. Elemental analysis (as C ₅₁ H ₉₄ FNO ₉ = 884.3)

[0178]

Example 16fAllyl 6-O-benzyloxymethyl
-2-deoxy-2-[(S) -3'-fluoromyristoylamido
ノ] -3-O-[(R) -3 "-myristoyloxymyristoyl]-
β-D-glucopyranoside 0.1 g (0.113 mmol) of the compound obtained in 16e and benzene
0.4 g (4 equivalents) of ruchloromethyl ether
Dissolved in 6 ml, and added tetramethylurea at room temperature.
Stirred overnight. The reaction mixture is evaporated to dryness and diluted with ethyl acetate.
After washing, wash with 5% aqueous sodium hydrogen carbonate solution and saturated saline
Was cleaned. The organic layer was dried with anhydrous magnesium sulfate
After that, column chromatography (silica gel 10 g, cyclohexa
(Ethyl acetate = 2: 1) to give 71 mg (62%) of the desired compound
I got NMR spectrum (270MHz, CDCl_Three) δ ppm: 0.85-0.90 (9
H, m); 1.25-1.61 (62H, m); 2.26-2.54 (6H, m); 3.32 (1H, d,
J = 3.4Hz); 3.47-3.53 (1H, m); 3.64-3.71 (1H, m); 3.90-3.
92 (2H, m); 4.03-4.09 (2H, m); 4.29-4.37 (1H, m); 4.66 (2
H, s); 4.78-5.29 (7H, m); 5.73-5.89 (2H, m); 7.26-7.37
(5H, m). Infrared absorption spectrum ν max cm-1 (Nujol): 34
00, 3300, 1750, 1730,1680. Elemental analysis (C₅₉H₁₀₁NO_Ten(Assuming F = 1003.4)

[0179]

Example 16g Allyl 6-O-benzyloxymethyl
-2-deoxy-4-O-diphenylphosphoryl-2-[(S) -3 '
-Fluoromiristoylamino] -3-O-[(R) -3 "-myris
Toyloxymyristoyl] -β-D-glucopyranoside 30 mg (0.0 mg
298 mmol) and 30 mg (3.75 equivalents) of diphenylphosphoric acid chloride were dissolved in 1 ml of dichloromethane, 10 mg (2.75 equivalents) of 4-dimethylaminopyridine was added at room temperature, and the mixture was stirred overnight. The reaction solution was evaporated to dryness, diluted with ethyl acetate, washed with a 5% aqueous sodium hydrogen carbonate solution and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration, evaporated to dryness,
Purification by preparative thin-layer chromatography (1 mm, cyclohexane: ethyl acetate = 2: 1) gave 29 mg (81%) of the target compound. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88-0.90 (9
H, m); 1.25-1.74 (62H, m); 2.13-2.47 (6H, m); 3.62-3.83
(4H, m); 4.02-4.11 (1H, m); 4.28-4.34 (1H, m); 4.54-4.8
1 (5H, m); 4.87 (1H, dm, J = 34.2Hz); 4.93 (1H, d, J = 8.3Hz);
5.13-5.28 (3H, m); 5.32 (1H, dd, J = 1.5,9.3Hz); 5.77-5.9
1 (1H, m); 6.04 (1H, d, J = 8.3Hz); 7.13-7.35 (15H, m). Infrared absorption spectrum ν max cm-1 (chloroform):
3450, 2950, 2850, 1725, 1680, 1520.

[0180]

Example 16h 2-deoxy-4-O-diphenylphospho
Lil-2-[(S) -3'-fluoromyristoylamino] -3-O-
[ (R) -3 "-Myristoyloxymyristoyl] -D-glucopi
Compound obtained in Ranosu 16g 0.1 g of (0.081 mmol) was dissolved in tetrahydrofuran 10 ml, 1,5-cyclooctadiene - bis (methylphenyl phosphine) iridium hexafluorophosphate 4 mg was added, and the mixture was purged with nitrogen, After the reaction mixture was replaced with hydrogen and the color of the reaction solution changed, the mixture was replaced with nitrogen again, stirred at room temperature for 3 hours, added with 5 ml of concentrated hydrochloric acid, and stirred overnight as it was. The reaction solution was evaporated to dryness, diluted with ethyl acetate, washed with a 5% aqueous sodium hydrogen carbonate solution and saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. After removing anhydrous magnesium sulfate by filtration and evaporating to dryness, the residue was purified by column chromatography (silica gel 50 g, cyclohexane: ethyl acetate = 1: 1) to obtain 86 m of the desired compound.
g (98%) was obtained. Infrared absorption spectrum ν max cm-1 (chloroform):
3550, 3050, 2925, 2850, 1710.

[0181]

Example 16i 2-Deoxy-2-[(R) -3′-fluoromilli
Stoylamino] -3-O-[(R) -3 "-myristoyloxime
After dissolving 20 mg (0.0186 mmol) of the compound obtained with [ristoyl ] -D-glucopyranosyl-4-phosphate in 16 h in 10 ml of tetrahydrofuran, 20 mg of platinum oxide was added, and the mixture was replaced with hydrogen and stirred at room temperature for 5 hours. The reaction solution was filtered to remove platinum oxide, and evaporated to dryness to obtain 12 mg (70%) of the desired compound as a powder. Infrared absorption spectrum ν max cm-1 (Nujol): 3
350, 1720, 1660.

[0182]

Example 17 2-deoxy-2- (2,2-difluorotetrade
(Canoylamino) -3-O-[(R) -3-tetradecanoyloxy
Citetradecanoyl] -D-glucopyranose 4-phosphate
Site

[0183]

Example 17a Allyl 2-deoxy-2- (2,2-difluoro
Rotetradecanoylamino) -4,6-O-isopropylidene
-Β-D-glucopyranoside 2,2-difluorotetradecanoic acid (7.5 g) in methylene chloride
(50 ml) To the solution was added 5 ml of oxalyl chloride and one drop of dimethylformamide. After stirring at room temperature for 1 hour, the mixture was concentrated, 150 ml of methylene chloride was added, and the solution was added to allyl 2-amino-2-deoxy-4,6-O-isopropylidene-β-D-glucopyranoside (5.44 g) of triethylamine (2.5 g) was added dropwise to a methylene chloride solution (50 ml). The mixture was stirred at room temperature for 1 hour, concentrated, and the residue was diluted with ethyl acetate. Wash with aqueous sodium bicarbonate and saline,
The extract was dried over magnesium sulfate, filtered, concentrated, and purified by a silica gel column to obtain 8.1 g of the target compound 1.

[0184]

Example 17bAllyl 2-deoxy-2- (2,2-difluoro
Rotetradecanoylamino) -4,6-O-isopropylidene
-3-O-[(R) -3-tetradecanoyloxytetradecanoy
Le] -β-D-glucopyranoside Methyle chloride of the compound (8.0 g) obtained in Example 17a
(R) -3-tetradecanoyloxytetate
Radecanoic acid (6.0 g) and dimethylaminopyridine (1.6 g)
 And further DCC (3.2 g). Stir at room temperature for 1 hour and filter
After passing through, concentrate and purify by silica gel column chromatography.
did. Elution with cyclohexane-ethyl acetate (5: 1)
9.0 g of the desired compound was obtained.

[0185]

Example 17c Allyl 2-deoxy-2- (2,2-difluoro
Rotetradecanoylamino) -3-O-[(R) -3-tetradeca
Noyloxytetradecanoyl] -β-D-glucopyranosa
The compound (9.0 g) obtained in Example 17b was treated with 85% aqueous acetic acid (9%).
(00 ml) was warmed at 60 ° C. for 1 hour. After concentration, the residue was subjected to silica gel column chromatography and eluted with cyclohexane-ethyl acetate (2: 1) to obtain 4.3 g of the desired compound.

[0186]

Example 17d Allyl 6-O-benzyloxycarbo
Nyl-2-deoxy-2- (2,2-difluorotetradecanoyl
Amino) -3-O-[(R) -3-tetradecanoyloxytetra
Decanoyl] -β-D-glucopyranoside A solution of the compound obtained in Example 17c (4.2 g) and benzyl chloroformate (350 mg) in methylene chloride (100 ml) was prepared.
300 mg of dimethylaminopyridine was added under ice cooling. The temperature was slowly raised to room temperature and stirred for 1 hour. The reaction solution was concentrated, ethyl acetate was added, washed with brine, and dried over magnesium sulfate. After filtration, the mixture was concentrated, and the residue was purified by silica gel column chromatography. Elution with cyclohexane-ethyl acetate gave the target compound.

[0187]

Example 17e Allyl 6-O-benzyloxycarbo
Nyl-2-deoxy-2- (2,2-difluorotetradecanoyl
Amino) -4-O- (diphenylphosphoryl) -3-O-[(R) -3-
Tetradecanoyloxytetradecanoyl] -β-D-glu
Copyranoside Diphenylchlorophosphate was added to a solution of the compound (1.5 g) obtained in Example 17d in tetrahydrofuran (150 ml).
(3.2 g) and dimethylaminopyridine (1.6 g).
Refluxed for hours. After concentration and addition of ethyl acetate, the mixture was washed with dilute sulfuric acid and aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography. Cyclohexane-ethyl acetate
Elution with (3: 1) gave the desired compound.

[0188]

Example 17f 6-O-benzyloxycarbonyl-2-
Deoxy-2- (2,2-difluorotetradecanoylamino)-
4-O-diphenylphosphoryl-3-O-[(R) -3-tetradecano
Iloxytetradecanoyl] -D-glucopyranose In a solution of the compound (1.0 g) obtained in Example 17e in tetrahydrofuran (40 ml), 1,5-cyclooctadienebis [methyldiphenylphosphine] iridium hexafluorophosphate ( 20 mg), and the iridium complex was activated with hydrogen. Immediately, the hydrogen was replaced with nitrogen, and the mixture was stirred at room temperature for 3 hours. Further, add 10 ml of concentrated hydrochloric acid, and add
For 3 hours. The mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and purified by silica gel column chromatography. Elution with cyclohexane-ethyl acetate (3: 1) afforded the desired compound.

[0189]

Example 17g2-deoxy-2- (2,2-difluorotetra
(Decanoylamino) -4-O-diphenylphosphoryl-3-O-
[(R) -3-tetradecanoyloxytetradecanoyl] -D-
Glucopyranose Tetrahydro of the compound (300 mg) obtained in Example 17f
To a furan (20 ml) solution was added 100 mg of 10% palladium on carbon.
Then, hydrogenolysis was carried out. After filtration and concentration, silica gel
Purification by column chromatography gives the desired compound.
Was.

[0190]

Example 17h 2-deoxy-2- (2,2-difluorotetra
Decanoylamino) -3-O-[(R) -3-tetradecanoyloxy
Citetradecanoyl] -D-glucopyranose-4-phosphate
The compound (60 mg) obtained in Example 17 g was dissolved in tetrahydrofuran (6 ml), and 6 mg of platinum oxide was added.
Hydrogenolysis was performed for a time. Filtration and concentration gave the desired compound.

[0191]

Example 18 Triethylamine salt of phosphoric acid compound 1h, 2d, 3c, 4f, 5g, 6h, 7g, 8g, 9
g, 10 g, 11 g, 12 h, 13 g, 14 h, 15
When it is necessary to obtain the water-soluble triethylamine salt of the phosphoric acid compound obtained in g, 16i and 17h, the following operation is performed. 30 mg of phosphoric acid was suspended in 8 ml of 0.1 N hydrochloric acid, and 30 ml of chloroform-methanol (1: 2) was added thereto, followed by dissolving by applying ultrasonic waves. To this solution is added chloroform 10
When 10 ml of 0.1 N hydrochloric acid and 10 ml of 0.1 N hydrochloric acid were added, the mixture was separated into two layers, and the chloroform layer was separated. Chloroform was removed under reduced pressure and dissolved in 0.1% triethylamine water, and this aqueous solution was used as a sample for activity measurement.

────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Tomoo Kobayashi 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Tetsuo Hiraoka 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo (72) Inventor Masahiro Nishijima 1-4-29-A-101, Miyamadaira, Miyamae-ku, Kawasaki-shi, Kanagawa (72) Inventor Minoru Akamatsu 1-26-21, Shimizu, Suginami-ku, Tokyo (56) Reference Patent 2839921 (JP, B2) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07H 13/06 CA (STN) CAOLD (STN) CAPLUS (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula [In the formula, ^one of R ¹ and R ⁴ is a hydrogen atom, and the formula —P (O)
It represents a group having (OH) ₂ or a protecting group for a hydroxyl group, and the other represents a group having the formula —P (O) (OH) ₂ . R ² and R ³ are the same or different and each are an aliphatic acyl group having 6 to 20 carbon atoms or a group selected from the following [Substituent Group A], and having at least one substituted with 6 to 20 carbon atoms. Represents an aliphatic acyl group. R ⁵ represents a hydrogen atom or a protecting group for a hydroxyl group. However, R ² and R ³ are the same or different and are the same or different, and are an aliphatic acyl group having 6 to 20 carbon atoms, an aliphatic acyl group having 6 to 20 carbon atoms substituted with a hydroxyl group, or 6 to 20 carbon atoms. It does not show an aliphatic acyl group having 6 to 20 carbon atoms substituted with 2 aliphatic acyloxy groups. Further
R ³ is a group having 6 to 2 carbon atoms substituted with a halogen atom.
It does not show 0 aliphatic acyl groups. And a salt thereof. [Substituent group A] halogen atom, hydroxyl group, 6 to 2 carbon atoms
0 aliphatic acyloxy groups and an aliphatic acyloxy group having 6 to 20 carbon atoms substituted with a halogen atom.