JPH07233159A - Taxol derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound having strong antitumor activities. CONSTITUTION:This compound is expressed by formula I (X is a halogen; R<1> is amino having a protecting group, hydroxyl group having a protecting group, etc.; R<2> is an alkyl, an alkenyl, etc.; R'' is H, a halogen, etc.; R<4> and R<5> each is H or a protecting group of hydroxyl group), e.g. 13-[3-(tert- butoxycarbonylamino)-2,2-difluoro-3-phenylpropionyl]-10-deacetylbaccatin III. The compound is obtained by condensing, e.g. a compound expressed by formula II [R<11> is NHR<12> or OR<6> (R<12> is a protecting group of amino group; R<6> is an aryl, an alkyl, etc.), etc.; R<11> is a substituent group R<2>] with a compound expressed by formula III (R<41> and R<51> each is a protecting group of hydroxyl group) in the presence of a basic catalyst such as 4-dimethylaminopyridine in an inert solvent such as benzene at ambient temperature to the refluxing temperature using a carboxylic acid activator such as dicyclohexylcarbodiimide and, as necessary, deprotecting the resultant product.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel taxol derivative having an antitumor effect.

[0002]

2. Description of the Related Art Taxol is a natural product represented by the chemical structural formula shown in Chemical formula 7, and is obtained in trace amounts from the stems of the yew tree.

[0003]

[Chemical 7]

Taxol is known to have antitumor activity, and its mechanism of action is based on the inhibitory action of depolymerization of microtubules in cell division, which is different from conventional antitumor agents. Its clinical application is expected as an antitumor agent.

So far, taxol has been obtained from nature only in trace amounts. However, in recent years, 10-deacetylbaccatin, which is a taxol precursor represented by Chemical formula 8, which can be obtained in relatively large amounts from leaves of yew, etc.
III

[0006]

[Chemical 8]

A semi-synthesized taxol derivative using as a raw material has been reported (Japanese Patent Laid-Open No. 03-505725). Among them, a compound having a structure represented by Chemical formula 9 (Taxotere) has attracted attention as a compound having an antitumor activity equal to or higher than that of taxol, and is currently under development as an antitumor agent.

[0008]

[Chemical 9]

[0009]

However, taxol and its derivative taxotere are promising antitumor agents, but clinical studies have shown that they are not very effective against gastrointestinal cancer, especially colon cancer. A derivative having a stronger antitumor effect is desired.

[0010]

Conventionally, 2'of taxol has been used.
The hydroxyl group at the position has been considered to be essential for expressing a strong antitumor activity (Pharmac. Ther. 52, 1-34 (1991)). However, as a result of diligent studies, the present inventors have surprisingly found that a taxol derivative having a halogen atom at the 2′-position and having no hydroxyl group has a strong antitumor activity, and completed the present invention.

[0011]

The present invention has the general formula (I)

[0012]

[Chemical 10]

[Wherein X represents a halogen atom, and R ¹
Alkenyl having an amino group, a hydroxyl group having a protecting group or -Z-R groups (R ⁶ represented by ⁶ is a hydrogen atom, an alkyl group, an alkyl group having a substituent, alkenyl group, substituent having a protecting group Group, an alkynyl group, an alkynyl group having a substituent, an aryl group, an aryl group having a substituent, a cycloalkyl group, or a cycloalkyl group having a substituent, and Z is —NH—, —O—, — COO
-, -OCO-, -NHCO-, -CONH-, -NH
It means a group represented by COO-, -OCONH-, -NHCONH-, or -NHCOCONH-. ) Means

R ² is an alkyl group, an alkyl group having a substituent, an alkenyl group, an alkenyl group having a substituent, an alkynyl group, an alkynyl group having a substituent, an aryl group, an aryl group having a substituent, a cycloalkyl group, A cycloalkyl group having a substituent, or a saturated or unsaturated heterocyclic group (the heterocyclic group has a plurality of one or more atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as a constituent atom of the ring structure); The heterocyclic group may also include a hydroxyl group, a halogen atom, an alkyl group, an alkoxyl group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, an alkylcarbonyl group, an arylcarbonyl group, Alkyloxycarbonyl group, aryloxycarbonyl group, alkylcarbonyloxy group Arylcarbonyloxy group, a group selected from the group consisting of alkylcarbonylamino and arylcarbonylamino group which may have one or more as a substituent.) Means,

R ³ means a hydrogen atom, an alkyl group or a halogen atom, R ⁴ means a hydrogen atom or a hydroxyl-protecting group, and R ⁵ means a hydrogen atom or a hydroxyl-protecting group. ] The compound represented by these.

The substituents of the compound of the present invention will be described below.

In the present specification, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Similarly, the alkyl group means a straight or branched chain alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, octyl and the like having 1 to 8 carbon atoms. Means an alkyl group.

Similarly, an alkenyl group means a straight chain or branched chain alkenyl, for example, an alkenyl group having 2 to 7 carbon atoms such as vinyl, allyl, isopropenyl, butenyl and the like.

Similarly, an alkynyl group means a straight or branched chain alkynyl, such as ethynyl, 2-propynyl,
2 butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 2-hexynyl and the like having 2 carbon atoms
To 7 alkynyl groups.

Similarly, the aryl group means a group derived from an aromatic hydrocarbon such as phenyl, naphthyl and indanyl.

Similarly, a cycloalkyl group is, for example,
It means a cycloalkyl group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

The alkyl group, alkenyl group, alkynyl group, aryl group and cycloalkyl group may each have a substituent, and examples of the substituent include a phenyl group, an alkyl group, an alkoxyl group, Amino group, alkylamino group, aminoalkyl group, alkylaminoalkyl group, halogen atom, hydroxyl group, carboxyl group, alkyloxycarbonyl group, aryloxycarbonyl group, alkylcarbonyloxy group, arylcarbonyloxy group, alkylcarbonylamino group, aryl A carbonylamino group and the like can be mentioned.

The term "alkoxyl group" as used herein means a straight chain or branched chain alkoxyl, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy,
It means an alkoxyl group having 1 to 7 carbon atoms such as pentyloxy and hexyloxy.

The alkylamino group means an alkylamino group having 1 to 7 carbon atoms such as methylamino, ethylamino, n-propylamino, n-butylamino and dimethylamino.

The aminoalkyl group is, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl,
It means an alkylamino group having 1 to 7 carbon atoms such as 6-aminohexyl.

The alkylaminoalkyl group is, for example,
Methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl and the like can be mentioned.

The alkyl or aryloxycarbonyl group means a group -COO- having an oxygen atom bonded to an alkyl group or an aryl group.

The alkyl or arylcarbonyloxy group means a group --COO-- in which an alkyl group or an aryl group is bonded to a carbon atom.

The alkyl or arylcarbonylamino group means a group -NHCO- having an alkyl group or an aryl group bonded to a carbon atom.

Examples of the substituent R ² include a saturated or unsaturated heterocyclic group. The heterocyclic group is an atom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as a constituent atom of the ring structure. A substituent derived from a heterocyclic compound containing one or more of one or more kinds, and these heterocyclic substituents may be bonded at any position. The heterocyclic group may be monocyclic or bicyclic, and as the monocyclic heterocyclic group, pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, Oxadiazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, pyrazine,
4 such as piperazine, dioxane, pyran, morpholine
Substituents derived from a heterocyclic compound having a member ring to a 9-membered ring are mentioned.

Examples of the bicyclic heterocyclic group include substituents derived from benzofuran, indolizine, benzothiophene, indole, indazole, quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinosaline, quinazoline, chroman and the like.

Examples of the substituents R ¹ , R ⁴ and R ⁵ include a hydroxyl group-protecting group. Examples of the hydroxyl group-protecting group include tertiary butoxycarbonyl group, benzyloxycarbonyl group and p-methoxybenzyloxycarbonyl group. Group, trifluoroacetyl group, 2,2,2-trichloroethoxycarbonyl group, tertiary butyldimethylsilyl group, triethylsilyl group, benzyl group and the like.

Examples of the substituent R ¹ include an amino group-protecting group. Examples of the amino group-protecting group include tertiary butoxycarbonyl group, benzyloxycarbonyl group,
p-methoxybenzyloxycarbonyl group, phthaloyl group, acetyl group, trifluoroacetyl group or 2,
2,2-trichloroethoxycarbonyl group and the like can be mentioned.

The following are preferable substituents for the compound of the present invention.

The substituent X is preferably a fluorine atom.

As the substituent R ¹ , Z is —NHCO—,
In the case of —NHCOO—, that is, the substituent R ¹ is —NHCO.
-R ^6, preferably if a -NHCOO-R ^6, phenyl group, tertiary butyl group preferable as substituent R ^6. Particularly, it is preferable that Z is —NHCO—, R ⁶ is a phenyl group, Z is —NHCOO—, and R ⁶ is a tertiary butyl group.

As the substituent R ² , R ⁶ is preferably an aryl group or a heterocyclic group, and among the aryl groups, a phenyl group is particularly preferable.

Among the heterocyclic groups, monocyclic heterocyclic groups are preferred, and further monocyclic 5- to 6-membered heterocyclic groups such as pyrrole, furan, thiophene, pyrrolidine and tetrahydrofuran. , Tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, thiazole, oxadiazole, thiadiazole, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, dioxane, pyran, morpholine and other heterocyclic compounds Substituents derived from are preferred.

Among the heterocyclic groups, a monocyclic 5-membered to 6-membered heterocyclic group is particularly preferable, and 1 atom of an oxygen atom, a nitrogen atom and a sulfur atom is contained as a constituent atom of the ring structure.
Examples of the heterocyclic group include a substituent derived from a heterocyclic compound such as pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyridine, dihydropyridine, tetrahydropyran, piperidine, and pyran.

The most preferable heterocyclic group is a monocyclic 5-membered to 6-membered heterocyclic group, which contains 1 atom of an oxygen atom, a nitrogen atom and a sulfur atom as a constituent atom of the ring structure.
And a substituent derived from an unsaturated heterocyclic compound containing 1 unit.

The most preferable specific examples include 2-furyl, 3-furyl, 5-methylfuran-2-yl, 2-pyrrolyl, phenyl and p-methoxyphenyl.

A fluorine atom is preferred as the substituent R ³ .

The substituent R ⁴ is preferably a hydrogen atom or an acetyl group.

The substituent R ⁵ is preferably a hydrogen atom.

As the combination of the substituents, R ¹ is Z as --NHCO-- and R ⁶ is phenyl group, or Z is --NHCO--.
NHCOO- and R ⁶ is a tertiary butyl group, the other substituents are the substituent X is a fluorine atom and the substituent R, respectively.
^It is preferable that ³ is a fluorine atom, R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom.

The production method of the compound of the present invention will be described with reference to examples.

[0048]

[Chemical 11]

[In the formula, R ¹¹ is --NHR ¹² , --NR ⁶ R
¹² , -OR ¹³ , and -OR ⁶ are meant, and R ²¹ is a substituent R
² (when the substituent R ² has an amino group or a hydroxyl group as a substituent, these amino group and hydroxyl group are protected by a protecting group). R ⁴¹ represents a commonly used protective group for a hydroxyl group, and among these, a 2,2,2-trichloroethoxycarbonyl group, a triethylsilyl group or an acyl group (eg, acetyl group, propionyl group, oxalyl group, benzoyl group, etc.) ) Etc. are preferable. R ⁵¹ represents a commonly used protective group for a hydroxyl group, and of these, a 2,2,2-trichloroethoxycarbonyl group, a triethylsilyl group and the like are preferable. R ¹² represents a commonly used amino-protecting group, among which a benzyloxycarbonyl group, a tertiary butoxycarbonyl group, 2,2,2-
A trichloroethoxycarbonyl group and the like are preferable. R ¹³ means a commonly used protective group for a hydroxyl group, and among these, a 2,2,2-trichloroethoxycarbonyl group, a benzyl group and the like are preferable. X, R ² , R ³ and R ⁶ are the same as described above (provided that R ⁶ is hydrogen). ]

In the above reaction, an activator of a carboxylic acid such as di (2-pyridyl) carbonate (DPC) or dicyclohexylcarbodiimide (DCC) in the presence of a base catalyst such as 4-dimethylaminopyridine (DMAP) is used. It can be used for condensation in an inert solvent such as benzene or toluene at a temperature from room temperature to reflux. Alternatively, the carboxylic acid of the compound represented by formula (1) (hereinafter referred to as compound (1)) is reacted with oxalyl chloride, thionyl chloride or the like to convert into acid chloride, and then in the presence of a base such as DMAP, A compound represented by formula (2) (hereinafter referred to as compound (2)) is reacted with a baccatin derivative to obtain a compound represented by formula (3) (hereinafter referred to as compound (3)). You can also

Based on the compound (3) thus obtained,
Compounds of general formula I having different Z moieties of the substituent R ¹ can be synthesized.

First, the hydroxyl and amino protecting groups of R ¹¹ of compound (3) are removed, and in the compounds of the present invention, R ¹ is -N.
H ₂ (that is, Z is —NH— and R ⁶ is a hydrogen atom),
It is possible to obtain a compound in which R ¹ is —OH (that is, Z is —O— and R ⁶ is a hydrogen atom).

Removal of the protecting group is carried out by a method usually used in the field of organic chemistry corresponding to the protecting group used.
For example, in the case of a 2,2,2-trichloroethoxycarbonyl group, it can be removed by heat treatment with zinc powder in an acidic solvent such as acetic acid, and in the case of a triethylsilyl group, an acid such as hydrochloric acid in a solvent such as an aqueous ethanol solution. And can be removed by treating at low temperature.

By reacting a compound in which R ¹ is --OH with a carboxylic acid represented by R ⁶ COOH or an acid chloride represented by R ⁶ COCl, R ¹ is --OCO--R ⁶
(I.e., Z is -OCO-) is obtained.

By reacting a compound in which R ¹ is —NH ₂ with a carboxylic acid represented by R ⁶ COOH or an acid chloride represented by R ⁶ COCl, R ¹ is —NHCO—R ⁶
(I.e., Z is -NHCO-) is obtained.

Compounds in which R ¹ is --NH ₂ and R ⁶ OCOCl
Or by reaction with (R ⁶ OCO) compounds represented by ₂ O, R ¹ is -NHOCO-R ⁶ (i.e.,
A compound in which Z is -NHOCO-) is obtained.

Compounds in which R ¹ is --NH ₂ and R ⁶ NHCOC
By reacting with a compound represented by ¹ , R ¹ is
NHCONH-R ⁶ (i.e., Z is -NHCONH
A compound of −) is obtained. Further, R ¹ is -NHOCOR
It can also be obtained by reacting a compound represented by R ⁷ (R ⁷ is phenyl, paranitrophenyl or the like) with an amine represented by R ⁶ NH ₂ .

Compounds in which R ¹ is --NH ₂ and R ⁶ NHCOC
R ¹ by reacting with a compound represented by OCl
There -NHCOCONH-R ⁶ (i.e., Z is -NHC
A compound of OCONH-) is obtained.

R ⁴ or R ⁵ is a hydrogen atom, or R ⁴
A compound in which R ⁵ and R ⁵ are both hydrogen atoms is prepared by synthesizing the Z part of R ¹ and then removing the protecting groups of R ⁴¹ and R ⁵¹ .
The desired compound is obtained.

The compound (1) can be produced by the method shown in Chemical formula 12.

[0061]

[Chemical 12]

[Wherein R ¹⁴ represents a nitrogen-bonding protective group that is commonly used in the synthesis of beta-lactam compounds, and examples thereof include a paramethoxyphenyl group, a di (paramethoxyphenyl) methyl group, and a benzyl group. To be R ⁷¹ represents a protecting group for a carboxyl group, and examples thereof include methyl, ethyl, propyl, tertiary butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, acetylmethyl, trichloroethyl, acetoxymethyl, and the like. Of these, a methyl group, an ethyl group, a benzyl group, a paramethoxybenzyl group, a tertiary butyl group and the like are preferable. R ⁸ means an alkyl group or an aryl group, and the aryl group may have a substituent. X, R ³ , R ⁶ and R ²¹ are the same as above. ]

A compound represented by formula (4) (hereinafter referred to as compound (4)) or a compound represented by formula (5) (hereinafter referred to as compound (5)), which is a raw material for producing compound (1). Are manufactured as follows.

Compound (4) was prepared according to the literature (J. Org. Chem., 5
4, 661 (1989), etc.) and various aldehydes (R ²¹ —CHO) are reacted with, for example, ethyl bromodifluoroacetate (when X = R ³ = F) in the presence of zinc. .

The compound (5) was prepared according to the literature (Tetrahedron Lett.,
29, 5291 (1988), Tetrahedron Lett., 32, 5461 (1991)
Etc.), an imine (R ²¹ —CH═N—R ¹⁴ ) and ethyl bromodifluoroacetate (when X = R ³ = F) or fluoroacetyl chloride (X = F, R) that can be synthesized from an aldehyde and an amine according to ³ = H)) and the like can be reacted to react with each other. The compound (5) can also be synthesized by converting the ester of the compound (4) to an amide according to the method described in the literature (J. Med. Chem., 30, 1837 (1987) etc.) and then carrying out the Mitsunobu reaction. . When R ³ is an alkyl group, it can be synthesized by alkylating a compound of R ³ = H according to the method described in the literature (J. Org. Chem., 58, 2454 (1993) etc.).

The compound (2) can be obtained by protecting the hydroxyl groups of 10-deacetylbaccatin III extracted from yew leaves or bark.

In the above-mentioned production examples of the compound of the present invention, first, the compound (1) and the compound (2) are converted into the compound (3).
Was obtained, various Z moieties of the substituent R ¹ of the compound represented by the general formula I were synthesized.
Compound (1) before reacting with the baccatin derivative part of
After converting the R ¹¹ moiety of the compound and synthesizing various Z moieties, the compound may be reacted with the compound (2).

Next, a detailed description will be given with reference to Examples and Reference Examples. The compound names follow the nomenclature commonly used in the art. For example, the compound of Example 13 is
As used herein, 13- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-furyl) propionyl] -7,10-bis (2,2,2-trichloroethoxycarbonyl)- 10-deacetylbaccatin
Although described as III, this is also 13- [3- (tert
-Butoxycarbonylamino) -2,2-difluoro-
3- (2-furyl) propionyl] -7-O-, 10-
It can also be represented as O-bis (2,2,2-trichloroethoxycarbonyl) -10-deacetylbaccatin III.

[0069]

【Example】

Reference Example 1 Step 1: Ethyl 3-azido-2,2-difluoro-
3-Phenylpropionate 1.30 g of ethyl 2,2-difluoro-3-hydroxy-3-phenylpropionate derived from benzaldehyde and ethyl bromodifluoroacetate were dissolved in 20 ml of methylene chloride. To this solution was added triethylamine (1.02 ml) under ice-cooling, and then methanesulfonyl chloride 8
39 mg was slowly added and stirred for 30 minutes. The reaction solution was diluted with chloroform, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution in this order, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent; ethyl acetate: hexane = 1:10 (v / v)) to obtain 1.70 g of a colorless oil. This oily substance was dissolved in N, N-dimethylformamide (8 ml), sodium azide (735 mg) and tetra-n-butylammonium bromide (20 mg) were added, and the mixture was stirred at 65 ° C for 40 hr. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent; ethyl acetate: xane = 1:10 (v / v)) to give the title compound.
Obtained 559 mg as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.28 (t, 3H, J =
7Hz), 4.30 (q, 2H, J = 7Hz), 5.04-5.10 (m, 1H), 7.37-7.45
(m, 5H)

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluoro-3-phenylpropionate 559 mg of the compound obtained in the above Step 1 was dissolved in 10 ml of ethyl acetate.
Was dissolved in 100 mg of 10% palladium carbon (w / w), and catalytic reduction was carried out for 1 hour in a hydrogen stream. After the catalyst was filtered off and concentrated, the obtained residue was subjected to silica gel chromatography (developing solvent; ethyl acetate: hexane = 1: 4).
(v / v)) to give a colorless oily substance 485 mg. This oil was dissolved in 10 ml of tetrahydrofuran, and 264 mg of sodium hydrogen carbonate and di-tert-butyl dicarbonate 691 were added.
mg was added, and the mixture was stirred at room temperature for 14 hours. After concentrating, ethyl acetate and water were added, and the organic layer was washed with 1N hydrochloric acid and a saturated aqueous sodium hydrogencarbonate solution in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent; ethyl acetate: hexane = 1:10 (v / v)) to give 475 mg of the title compound.
Was obtained as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.27 (t, 3H, J =
7Hz), 1.42 (s, 9H), 4.21-4.30 (m, 2H), 5.36-5.44 (m, 2
H), 7.35-7.40 (m, 5H)

Step 3: 3- (tert-Butoxycarbonylamino) -2,2-difluoro-3-phenylpropionic acid 450 mg of the compound obtained in the above Step 2 is dissolved in 4 ml of ethanol and 2 ml of water, and then hydroxylated. Lithium (102 mg) was added, and the mixture was stirred at room temperature for 30 minutes. After ethanol was distilled off, the mixture was diluted with water and acidified with 1N hydrochloric acid under ice cooling. The precipitate was extracted with chloroform and the solvent was evaporated under reduced pressure to give the title compound.
337 mg was obtained as a colorless caramelized oil.

¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.37 (s, 9
H), 5.22-5.32 (m, 1H), 7.32-7.51 (m, 5H), 8.09 (d, 1H, J =
10Hz) MS-FAB: 302 (MH ⁺ )

Reference Example 2 (Alternative Method of Reference Example 1) Step 1: Ethyl 2,2-difluoro-3-[(p-
Methoxyphenyl) amino] -3-phenylpropionate 3,3-difluoro-1- (p-methoxyphenyl) -4 obtained by reacting imine derived from benzaldehyde and p-methoxyaniline with ethyl bromodifluoroacetate. 434 mg of -phenyl-2-azetidinone was dissolved in 3 ml of tetrahydrofuran, 1.65 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 30 minutes. Tetrahydrofuran was distilled off and the aqueous solution was freeze-dried. Suspend the obtained sodium salt in 20 ml of ethanol, and under ice cooling,
0.240 ml of thionyl chloride was added dropwise. After returning to room temperature,
The mixture was heated with stirring at 80 ° C. overnight. Ethanol was distilled off, the residue was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, hexane was added to the residue and the precipitated powder was collected by filtration and dried to obtain 437 mg of the title compound as a pale yellow powder.

Melting point: 116-117 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.26 (t, 3H, J = 7Hz), 3.69
(s, 3H), 4.28 (q, 2H, J = 7Hz), 5.00 (dd, 1H, J = 8Hz, 20Hz),
6.59 (d, 2H, J = 8Hz), 6.70 (d, 2H, J = 8Hz), 7.30-7.40 (m, 5H) IR (KBr): 3668, 3508, 3364, 3068, 2992, 2940, 291
6, 2836, 1980, 1876 1850, 1766, 1660, 1620, 1596, 1520 cm ^-1 MS-FAB: 336 (MH ⁺ )

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluoro-3-phenylpropionate 350 mg of the compound obtained in the above Step 1 was added to acetonitrile 10
2.29 g cerium (IV) ammonium nitrate
Was dissolved in 5 ml of water, added dropwise under ice cooling, and at the same temperature.
It was stirred for 30 minutes. A saturated multi-layered aqueous solution was added to the reaction solution, extracted three times with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 3).
(v / v)) to give 170 mg of a yellow oil. 92 mg of this oil was dissolved in 3 ml of tetrahydrofuran,
Sodium hydrogencarbonate (50.5 mg) and di-tert-butyl dicarbonate (132 mg) were added, and the mixture was stirred at room temperature for 24 hours. After concentration,
Ethyl acetate and water were added, the organic layer was washed with 1N hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution in this order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 10 (v / v)) to give the title compound.
104 mg was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ / TMS) was in full agreement with the compound of Step 2 of Reference Example 1.

Reference Example 3 Step 1: p-Methoxybenzyl 2,2-difluoro-
3-hydroxy-3-phenylpropionate ethyl 2,2-difluoro-3-hydroxy-3-phenylpropionate 691 mg was dissolved in 9 ml of ethanol,
At room temperature, add 3 ml of 1N aqueous sodium hydroxide solution 2
Stir for hours. The solvent was distilled off under reduced pressure, and the residue was azeotropically distilled with ethanol three times and dried. Then, the residue was dissolved in 20 ml of N, N-dimethylformamide, 517 mg of p-methoxybenzyl chloride was added, and the mixture was heated with stirring at 80 ° C for 2 days. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to obtain 961 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 2.62 (d, 1H,
J = 4Hz), 3.82 (s, 3H), 5.11-5.18 (m, 1H), 5.20 (s, 2H), 6.
88 and 7.25 (each AB type d, 4H, J = 8Hz), 7.32-7.39 (m,
5H)

Step 2: p-Methoxybenzyl 2,2-
Difluoro-3- (2,2,2-trichloroethoxycarbonyloxy) -3-phenylpropionate 961 mg of the compound obtained in Step 1 above was dissolved in anhydrous dichloromethane
After dissolving in 10 ml, 0.27 ml of pyridine and 0.45 ml of 2,2,2-trichloroethyl chloroformate were added under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was poured into ice water and extracted with chloroform. It was washed with 10% hydrochloric acid (w / v), saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent; ethyl acetate: hexane = 1: 9 (v / v)) to obtain 1.45 g of the title compound as a colorless oil. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 3.83 (s, 3H), 4.65-4.72 (m,
2H), 5.20 (s, 2H), 6.06-6.11 (m, 1H), 6.88-6.91 (m, 2H),
7.26-7.29 (m, 2H), 7.32-7.42 (m, 5H)

Step 3: 2,2-difluoro-3- (2,
2,2-Trichloroethoxycarbonyl) oxy-3-phenylpropionic acid 1.45 g of the compound obtained in the above step 2 was added to trifluoroacetic acid 1
Dissolve in 5 ml, add 1.58 ml of anisole, and mix at room temperature for 3
Stir for 0 minutes. Trifluoroacetic acid was distilled off under reduced pressure, and the residue was azeotropically distilled with toluene. Ether was added to the residue and the crystals were collected by filtration. The crystals were washed with an ether-hexane (1: 1 (v / v)) mixed solvent to obtain 903 mg of the title compound as white crystals.

Melting point: 204-206 ° C. ¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 4.92 (s, 2H), 6.18-6.24
(m, 1H), 7.35-7.42 (m, 5H)

Reference Example 4 Step 1: Ethyl 3-benzoylamino-2,2-difluoro-3-phenylpropionate 280 mg of the compound obtained in Step 1 of Reference Example 1 was added to ethyl acetate 1
It was dissolved in 0 ml and 70% of 10% palladium carbon (w / w) was added, and catalytic reduction was performed for 1 hour under hydrogen stream. After removing the catalyst by filtration and concentrating, the residue was dissolved in 10 ml of dichloromethane, 0.183 ml of triethylamine and 16 mg of 4-dimethylaminopyridine were added, and benzoyl chloride 0.152 0.152 was added under ice cooling.
ml was added dropwise, and the mixture was stirred at room temperature for 20 minutes. After concentration, the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate in this order, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (developing solvent; ethyl acetate: hexane = 1: 2 (v / v)).
Purify with and crystallize with ether and hexane to give the title compound.
308 mg was obtained as white crystals.

Melting point: 104-105 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.24 (t, 3H, J = 7Hz), 4.22-
4.30 (m, 2H), 5.94 (dt, 1H, J = 16Hz, 10Hz), 6.94 (d, 1H, J = 9H
z), 7.36-7.55 (m, 8H), 7.78-7.80 (m, 2H) MS-FAB: 334 (MH ⁺ )

Step 2: 3-benzoylamino-2,2
-Difluoro-3-phenylpropionic acid 300 mg of the compound obtained in the above step 1 was added to 10 ml of ethanol.
And dissolved in 5 ml of water, 311 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. Ethanol was distilled off, diluted with water, and acidified with 1N hydrochloric acid under ice cooling. It was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The residue was crystallized from ether and hexane to give the title compound (252 mg) as white crystals.

Melting point: 170-171 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 5.93 (dd, 1H, J = 9Hz, 17Hz),
7.30-7.55 (m, 8H), 7.78-7.80 (m, 2H) MS-FAB: 306 (MH ⁺ )

Reference Example 5 Step 1: Ethyl 3-benzyloxy-2,2-difluoro-3-phenylpropionate 60% Sodium hydride (w / w) 104 mg was suspended in 8 ml of tetrahydrofuran, and ethyl 2,2 -Difluoro-3
A solution of 500 mg of -hydroxy-3-phenylpropionate in 4 ml of dimethyl sulfoxide was added dropwise under ice cooling. Benzyl bromide 0.309 m after hydrogen evolution stops
l was added, and the mixture was stirred for 30 minutes under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline in this order. The extract was dried over anhydrous magnesium sulfate, and the residue was purified by silica gel chromatography (developing solvent; ethyl acetate: hexane = 1: 9 (v / v)) to obtain 578 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.26 (t, 3H, J =
7Hz), 4.20-4.33 (m, 2H), 4.33 and 4.62 (2d, 2H, J = 12H
z), 4.85 (dd, 1H, J = 7Hz, 18Hz), 7.22-7.48 (m, 10H)

Step 2: 3-benzyloxy-2,2-
Difluoro-3-phenylpropionic acid 578 mg of the compound obtained in the above step 1 was added to 10 ml of ethanol.
The mixture was dissolved in, and 1N aqueous sodium hydroxide solution (3.60 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The ethanol was distilled off, diluted with water and washed with ether. The mixture was acidified with 1N hydrochloric acid under ice cooling and extracted with chloroform. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane to give the title compound (373 mg) as white crystals.

Melting point: 85-87 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 4.36 and 4.65 (2d, 2H, J = 12)
Hz), 4.87 (dd, 1H, J = 6Hz, 18Hz), 6.01 (br, 1H), 7.22-7.48
(m, 10H) IR (KBr): 3800, 3724, 3668, 3644, 3040, 2900, 257
2, 2340, 1756, 1608, 1590 cm ^-1 MS-FD: 292 (M ⁺ )

Reference Example 6 Step 1: Ethyl 3-benzoyloxy-2,2-difluoro-3-phenylpropionate Ethyl 2,2-difluoro-3-hydroxy-3-phenylpropionate 300 mg of dichloromethane 10 ml
The mixture was dissolved in water, 0.235 ml of triethylamine and 10 mg of 4-dimethylaminopyridine were added, 0.182 ml of benzoyl chloride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After concentration, the mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (developing solvent; ethyl acetate: hexane = 1
: 9 (v / v)) to give the title compound (416 mg) as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.23 (t, 3H, J =
7Hz), 4.24-4.32 (m, 2H), 6.45 (dd, 1H, J = 9Hz, 16Hz), 7.36
-7.63 (m, 8H), 8.09-8.11 (m, 2H)

Step 2: 3-benzoyloxy-2,2
-Difluoro-3-phenylpropionic acid The compound obtained in Step 1 above was hydrolyzed in the same manner as in Step 2 of Reference Example 4 to obtain the title compound as white crystals.

Melting point: 138-141 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 5.93 (br, 1H), 6.45 (dd, 1
H, J = 8Hz, 16Hz), 7.37-7.62 (m, 8H), 8.07-8.09 (m, 2H) IR (KBr): 3044, 2928, 2712, 2572, 1970, 1916, 175
2, 1734, 1602, 1588 cm ^-1 MS-FAB: 307 (MH ⁺ )

Reference Example 7 Step 1: Ethyl 3-cyclohexyl-2,2-difluoro-3-[(p-methoxyphenyl) amino] propionate Imine derived from cyclohexyl aldehyde and p-methoxyaniline and ethyl bromodifluoroacetate. 4-Cyclohexyl-3,3-difluoro-1- (p-methoxyphenyl) -2-azetidinone obtained by the reaction was reacted in the same manner as in Step 1 of Reference Example 2 to obtain the title compound as pale yellow crystals.

Melting point: 69-71 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.06-1.29 (m, 5H), 1.18 (t,
3H, J = 7Hz), 1.62-1.90 (m, 6H), 3.42 (br, 1H), 3.73 (s, 3
H), 3.81-3.88 (m, 1H), 4.08-4.17 (m, 2H), 6.59 (d, 2H, J =
9Hz), 6.74 (d, 2H, J = 8Hz) IR (KBr): 3668, 3504, 3420, 3044, 2972, 2932, 286
0, 2672, 2068, 1884, 1850, 1758, 1648, 1624, 1530 c
m ^-1 MS-FAB: 342 (MH ⁺ )

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -3-cyclohexyl-2,2-difluoropropionate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 2 to give the title compound. The compound was obtained as white crystals.

Melting point: 59-61 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.02-1.81 (m, 1H), 1.34 (t,
3H, J = 7Hz), 1.43 (s, 9H), 4.11-4.27 (m, 1H), 4.28-4.33
(m, 2H), 4.69 (d, 1H, J = 10.5Hz) MS-FD: 335 (M ⁺ )

Step 3: 3- (tert-Butoxycarbonylamino) -3-cyclohexyl-2,2-difluoropropionic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1 to give the title compound. Was obtained as white crystals.

Melting point: 139-142 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.02-1.40 (m, 5H), 1.44 (s,
9H), 1.65-1.84 (m, 6H), 4.14-4.20 (m, 1H), 4.86 (d, 1H, J =
10.5Hz) MS-FD: 308 (MH ⁺ )

Reference Example 8 Step 1: Ethyl 3-benzoylamino-3-cyclohexyl-2,2-difluoropropionate 500 mg of the compound obtained in Step 1 of Reference Example 7 was dissolved in 15 ml of acetonitrile, and cerium nitrate ( IV) Ammonium
A solution prepared by dissolving 3.20 g in 8 ml of water was added dropwise under ice cooling, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to give 220 mg of a yellow oil.
Got This oily substance and 0.156 ml of triethylamine were dissolved in 10 ml of dichloromethane, and 0.130 ml of benzoyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (developing solvent; ethyl acetate: hexane =
1: 4 (v / v)), hexane was added and the precipitated powder was collected by filtration and dried to obtain 288 mg of the title compound as a white powder.

Melting point: 90-92 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.06-1.34 (m, 5H), 1.30
(t, 3H, J = 7Hz), 1.64-1.91 (m, 6H), 4.27-4.33 (m, 2H), 4.7
3-4.84 (m, 1H), 6.24 (d, 1H, J = 10.5Hz), 7.44-7.56 (m, 3
H), 7.75-7.78 (m, 2H) MS-FD: 339 (M ⁺ )

Step 2: 3-benzoylamino-3-cyclohexyl-2,2-difluoropropionic acid The compound obtained in the above Step 1 was hydrolyzed in the same manner as in Step 2 of Reference Example 4 to obtain the title compound as white crystals. It was

Melting point: 128-130 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.03-1.35 (m, 5H), 1.64-2.
00 (m, 6H), 4.72-4.83 (m, 1H), 6.37 (d, 1H, J = 10.5Hz), 7.3
9-7.54 (m, 3H), 7.71 (d, 2H, J = 7Hz) MS-FD: 312 (MH ⁺ )

Reference Example 9 Step 1: N- (2,2-difluoro-3-hydroxyoctanoyl) -p-methoxyaniline n-hexyl aldehyde and ethyl 2,2-difluoro-3 derived from ethyl bromodifluoroacetate. -Dissolve 1.66 g of hydroxyoctanate in 15 ml of ethanol and then at room temperature 7.40 ml of 1N aqueous sodium hydroxide solution.
Was added and stirred for 2 hours. Ethanol was distilled off, diluted with water and washed with ether. The aqueous layer was evaporated under reduced pressure and azeotroped with ethanol to give a white powder. The obtained sodium salt was suspended in 40 ml of dichloromethane, 1.19 g of p-methoxyaniline and 1.25 g of N, N-diisopropylethylamine were added at room temperature, and bis (2-oxo-chloride) was further added.
Add 2.46 g of 3-oxazolidinyl) phosphine 15
Stir for hours. Dilute with dichloromethane, add 1N hydrochloric acid,
The extract was washed with saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (developing solvent; ethyl acetate: hexane = 1
: 2 (v / v)) and then crystallized from ethyl acetate and hexane to obtain 1.45 g of the title compound as white crystals.

Melting point: 120-122 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.88-0.92 (m, 3H), 1.30-
1.73 (m, 8H), 2.50 (br, 1H), 3.81 (s, 3H), 4.14-4.23 (m, 1
H), 6.90 (d, 2H, J = 9Hz), 7.47 (d, 2H, J = 9Hz), 7.48 (br, 1
H) IR (KBr): 3668, 3464, 3320, 3144, 3080, 3016, 295
6, 2928, 2860, 2044, 1886, 1682, 1616, 1544, 1516 c
m ^-1 MS-FAB: 302 (MH ⁺ )

Step 2: 3,3-difluoro-1- (p
-Methoxyphenyl) -4-pentyl-2-azetidinone 1.25 g of the compound obtained in the above step 1 and 1.31 g of triphenylphosphine were dissolved in 18 ml of tetrahydrofuran, and 795 mg of diethyl azodicarboxylate was dissolved in 6 ml of tetrahydrofuran. The above solution was added dropwise at room temperature under nitrogen over 10 minutes. Stir for 15 minutes at the same temperature,
The solvent was distilled off. After concentration, the residue was subjected to silica gel chromatography (developing solvent; ethyl acetate: hexane = 1: 9 (v
/ v)) to give 1.18 g of the title compound as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.90 (t, 3H, J =
7Hz), 1.31-1.50 (m, 6H), 1.67-1.77 (m, 1H), 1.98-2.05
(m, 1H), 3.81 (s, 3H), 4.31-4.37 (m, 1H), 6.92 (d, 2H, J = 9H
z), 7.34 (d, 2H, J = 9Hz) MS-FD: 283 (M ⁺ )

Step 3: Ethyl 2,2-difluoro-
3-[(p-Methoxyphenyl) amino] octanoate The compound obtained in Step 2 above was reacted in the same manner as in Step 1 of Reference Example 2 to obtain the title compound as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.84 (t, 3H, J =
7Hz), 1.22 (t, 3H, J = 7Hz), 1.18-1.35 (m, 5H), 1.45-1.56
(m, 2H), 1.77-1.84 (m, 1H), 3.73 (s, 3H), 3.91-4.02 (m, 1
H), 4.11-4.20 (m, 2H), 6.61 (d, 2H, J = 9Hz), 6.75 (d, 2H, J =
9Hz) MS-FD: 329 (M ⁺ )

Step 4: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluorooctanate The compound obtained in the above Step 3 was reacted in the same manner as in Step 2 of Reference Example 2 to give the title compound as a colorless oil. Got as.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.89 (t, 3H, J =
7Hz), 1.35 (t, 3H, J = 7Hz), 1.21-1.56 (m, 7H), 1.43 (s, 9
H), 1.66-1.73 (m, 1H), 4.20-4.34 (m, 3H), 4.53 (d, 1H, J = 1
0Hz) MS-FD: 323 (M ⁺ )

Step 5: 3- (tert-Butoxycarbonylamino) -2,2-difluorooctanoic acid The compound obtained in Step 4 above is hydrolyzed in the same manner as in Step 3 of Reference Example 1 to give the title compound as a white powder. Obtained.

Melting point: 84-85 ° C. ¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 0.85 (t, 3H, J = 7Hz), 1.20
-1.44 (m, 8H), 1.38 (s, 9H), 3.98-4.08 (m, 1H), 7.11 (d, 1
H, J = 10Hz) IR (KBr): 3340, 2968, 2940, 2876, 2664, 2500, 187
4, 1752, 1644, 1520 cm ^-1 MS-FD: 296 (MH ⁺ )

Reference Example 10 Step 1: Ethyl (threo) -2-fluoro-3-
(P-Methoxyphenylamino) -3-phenylpropionate (cis) -3-fluoro-1- (p-methoxyphenyl) -4-phenyl-2-azetidinone derived from fluoroacetyl chloride and p-methoxyaniline. The reaction was performed in the same manner as in Step 1 of Reference Example 1 to obtain the title compound as pale yellow crystals.

Melting point: 58-60 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.22 (t, 3H, J = 7Hz), 3.68
(s, 3H), 4.19-4.26 (m, 2H), 4.93 (dd, 1H, J = 3,27Hz), 5.14
(dd, 1H, J = 3,48Hz), 6.54 (d, 2H, J = 9Hz), 6.69 (d, 2H, J = 9H
z), 7.27-7.38 (m, 5H) IR (KBr): 3392, 3048, 2992, 2944, 2912, 2840, 2076,
1966, 1750,1620, 1596, 1516 cm ^-1 MS-FAB: 317 (M ⁺ )

Step 2: Ethyl (threo) -3- (te
rt-Butoxycarbonylamino) -2-fluoro-3-
Phenylpropionate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 2 to obtain the title compound as white crystals.

Melting point: 84-87 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.30 (t, 3H, J = 7Hz), 1.42
(s, 9H), 4.24-4.32 (m, 2H), 5.13 (d, 1H, J = 47Hz), 5.35 (d
d, 1H, J = 10,39Hz), 5.3 (br, 1H), 7.29-7.40 (m, 5H) IR (KBr): 3408, 3036, 2984, 2940, 2880, 2300, 1966,
1750, 1700, 1606 cm ^-1 MS-FD: 311 (M ⁺ )

Step 3: (Threo) -3- (tert-butoxycarbonylamino) -2-fluoro-3-phenylpropionic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1, The title compound was obtained as a colorless caramel oil.

¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.37 (s, 9
H), 5.14 (d, 1H, J = 44Hz), 5.13 (dd, 1H, J = 17,38Hz), 7.25-
7.40 (m, 5H), 7.69 (d, 1H, J = 9Hz), 13.3 (br, 1H) IR (KBr): 3320, 3068, 2984, 2940, 2544, 1728, 166
4, 1500 cm ^-1

Reference Example 11 Step 1: Ethyl 2-fluoro-3- (p-methoxyphenylamino) -2-methyl-3-phenylpropionate (cis) -3-fluoro-1- (p-methoxyphenyl)- (Cis) -3-fluoro-1- (p-methoxyphenyl) -3-methyl-4-phenyl-2-azetidinone obtained by methylating 4-phenyl-2-azetidinone was used as in Step 1 of Reference Example 2. To give the title compound as a pale yellow oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.25 (t, 3H, J =
7Hz), 1.39 (d, 3H, J = 22Hz), 3.66 (s, 3H), 4.25 (q, 2H, J = 7
Hz), 4.70 (d, 1H, J = 25Hz), 6.50-6.55 (m, 2H), 6.63-6.67
(m, 2H), 7.26-7.36 (m, 5H)

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -2-fluoro-2-methyl-3-
Phenylpropionate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 2 to obtain the title compound as white crystals.

Melting point: 67-70 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.30 (t, 3H, J = 7Hz), 1.37
(d, 3H, J = 22Hz), 1.38 (s, 9H), 4.28 (q, 2H, J = 7Hz), 5.07 (d
d, 1H, J = 10Hz, 26Hz), 5.57 (d, 1H, J = 10Hz), 7.31-7.38 (m,
5H) IR (KBr): 3804, 3668, 3400, 3072, 2984, 2948, 1900,
1752, 1712,1608 cm ^-1 MS-FD: 325 (M ⁺ )

Step 3: 3- (tert-Butoxycarbonylamino) -2-fluoro-3-phenylpropionic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1 to give the title compound as white. Obtained as a powder.

Melting point: 133-136 ° C. ¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.22 (d, 3H, J = 22Hz), 1.
33 (s, 9H), 5.00 (dd, 1H, J = 10Hz, 27Hz), 7.27-7.42 (m, 5H),
7.66 (d, 1H, J = 10Hz), 13.3 (br, 1H) IR (KBr): 3432, 3338, 3040, 2984, 2940, 2648, 1896,
1704, 1516 cm ^-1 MS-FAB: 298 (MH ⁺ )

Reference Example 12 Step 1: Ethyl 3-azido-2,2-difluoro-
3-p-Methoxyphenylpropionate An ethyl 2,2-difluoro-3-hydroxy-3- (p-methoxyphenyl) propionate derived from p-methoxybenzaldehyde and ethyl bromodifluoroacetate was used as in Step 1 of Reference Example 1. To give the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.29 (t, 3H, J
= 7Hz), 3.82 (s, 3H), 4.30 (q, 2H, J = 7Hz), 4.99-5.05 (m, 1
H), 6.93 (d, 2H, J = 9Hz), 7.34 (d, 2H, J = 9Hz)

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (p-
Methoxyphenyl) propionate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 1 to obtain the title compound as white crystals.

Melting point: 107-109 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.27 (t, 3H, J = 7Hz), 1.42
(s, 9H), 3.80 (s, 3H), 4.21-4.30 (m, 2H), 5.31-5.35 (m, 2
H), 6.89 (d, 2H, J = 9Hz), 7.26 (d, 2H, J = 9Hz) IR (KBr): 3524, 3376, 2988, 2944, 2920, 2844, 2408,
2060, 1902, 1766,1694, 1618, 1590, 1518 cm ^-1 MS-FD: 359 (M ⁺ )

Step 3: 3- (tert-Butoxycarbonylamino) -2,2-difluoro-3- (p-methoxyphenyl) propionic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1. Decomposition gave the title compound as a white powder.

Melting point: 114-115 ° C. ¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.37 (s, 9H), 3.75 (s, 3
H), 5.16-5.27 (m, 1H), 6.90 (d, 2H, J = 9Hz), 7.36 (d, 2H, J =
9Hz), 7.99 (d, 1H, J = 10Hz) IR (KBr): 3352, 2988, 2948, 2916, 2844, 2648, 1906,
1754, 1644,1616, 1588, 1518, 1458 cm ^-1 MS-FD: 331 (M ⁺ )

Reference Example 13 Step 1: Ethyl 3-azido-2,2-difluoro-
3- (o-Methoxyphenyl) propionate Ethyl 2,2-difluoro-3-hydroxy-3- (o-methoxyphenyl) propionate derived from o-methoxybenzaldehyde and ethyl bromodifluoroacetate was used as Step 1 of Reference Example 1. The reaction was performed similarly to give the title compound as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.28 (t, 3H, J =
7Hz), 3.86 (s, 3H), 4.29 (q, 2H, J = 7Hz), 5.70 (dd, 1H, J = 7H
z, 15Hz), 6.92-7.04 (m, 2H), 7.35-7.49 (m, 2H)

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (o-
Methoxyphenyl) propionate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 1 to obtain the title compound as white crystals.

Melting point: 76-78 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.30 (t, 3H, J = 7Hz), 1.42
(s, 9H), 3.86 (s, 3H), 4.20-4.32 (m, 2H), 5.66-5.75 (m, 1
H), 5.83 (d, 1H, J = 10Hz), 6.91-6.98 (m, 2H), 7.24-7.35
(m, 2H) IR (KBr): 3344, 2988, 2944, 2852, 2304, 1772, 169
2, 1606, 1592,1534 cm ^-1 MS-FD: 359 (M ⁺ )

Step 3: 3- (tert-Butoxycarbonylamino) -2,2-difluoro-3- (o-methoxyphenyl) propionic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1. Decomposition gave the title compound as a white powder.

Melting point: 124-125 ° C. ¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.37 (s, 9H), 3.79 (s, 3
H), 5.81-5.91 (m, 1H), 6.92-7.01 (m, 2H), 7.29-7.33 (m, 1
H), 7.54-7.56 (m, 2H), 7.85 (d, 1H, J = 10Hz) IR (KBr): 3456, 3316, 2988, 2948, 2916, 2844, 252
0, 1914, 1740, 1648, 1606, 1592, 1498 cm ^-1 MS-FD: 331 (M ⁺ )

Reference Example 14 Step 1: Ethyl 2,2-difluoro-3- (2-furyl) -3- (p-methoxyphenylamino) propionate Imine derived from furfural and p-methoxyaniline and ethyl bromodifluoroacetate. Was reacted in the same manner as in Step 1 of Reference Example 2 to obtain the title compound as pale yellow crystals.

Melting point: 46-48 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.29 (t, 3H, J = 7Hz), 3.72
(s, 3H), 3.96 (d, 1H, J = 11Hz), 4.31 (q, 2H, J = 7Hz), 5.07-
5.16 (m, 1H), 6.34 (dd, 1H, J = 2Hz, 3Hz), 6.38 (d, 1H, J = 3H
z), 6.68 (d, 2H, J = 9Hz), 6.75 (d, 2H, J = 9Hz), 7.40 (d, 1H, J
= 2Hz) IR (KBr): 3368, 3140, 3004, 2968, 2948, 2916, 284
4, 2552, 2320, 2064,1852, 1748, 1622, 1596, 1572,
1520, 1494, 1472 cm ^-1 MS-FD: 325 (M ⁺ )

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-
Furyl) propionate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 2 to obtain the title compound as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.31 (t, 3H, J =
7Hz), 1.44 (s, 9H), 4.30 (q, 2H, J = 7Hz), 5.29 (br, 1H, J = 10
Hz), 5.50-5.59 (m, 1H), 6.36-6.39 (m, 2H), 7.41 (d, 1H, J =
2Hz)

Step 3: 3- (tert-Butoxycarbonylamino) -2,2-difluoro-3- (2-furyl)
Propionic Acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1 to obtain the title compound as a colorless caramel oil.

¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.39 (s, 9
H), 5.36-5.46 (m, 1H), 6.45 (d, 1H, J = 3Hz), 6.49 (d, 1H, J
= 3Hz), 7.65 (s, 1H), 7.95 (d, 1H, J = 10Hz) MS-FAB: 292 (MH ⁺ )

Reference Example 15 Step 1: Imine derived from ethyl 2,2-difluoro-3- (3-furyl) -3-[(p-methoxyphenyl) amino] propionate 3-furaldehyde and p-methoxyaniline. The β-lactam compound obtained by reacting the derivative with ethyl bromodifluoroacetate was used in Step 1 of Reference Example 2.
The title compound was obtained as pale yellow crystals by reacting in the same manner as.

Melting point: 69-71 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.28 (t, 3H, J = 7Hz), 3.73
(s, 3H), 4.29 (q, 2H, J = 7Hz), 4.97-5.06 (m, 1H), 6.42 (s, 1
H), 6.64-6.66 (m, 2H), 6.74-6.77 (m, 2H), 7.39 (s, 1H),
7.44 (s, 1H) IR (KBr): 3512, 3340, 3152, 3132, 3088, 3048, 2992,
2948, 2908, 2832, 2552, 2496, 2316, 2080, 1862, 176
8, 1602, 1514 cm ^-1 MS-FD: 325 (M ⁺ )

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (3-
Furyl) propionate The compound of Step 1 was reacted in the same manner as in Step 2 of Reference Example 2 to obtain the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.30 (t, 3H, J =
7Hz), 1.44 (s, 9H), 4.26-4.32 (m, 2H), 5.06 (br, 1H, J = 9H
z), 5.37-5.46 (m, 1H), 6.42 (s, 1H), 7.41 (d, 1H, J = 2Hz),
7.47 (s, 1H)

Step 3: 3- (tert-Butoxycarbonylamino) -2,2-difluoro-3- (3-furyl)
Propionic acid The compound of step 2 was hydrolyzed in the same manner as in step 3 of Reference Example 1 to obtain the title compound as a colorless caramel oil.

¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.39 (s, 9
H), 5.23-5.33 (m, 1H), 6.60 (s, 1H), 7.61 (s, 1H), 7.71
(s, 1H), 7.80 (d, 1H, J = 10Hz) MS-FAB: 292 (MH ⁺ )

Reference Example 16 Step 1: Ethyl 2,2-difluoro-3- (5-methylfuran-2-yl) -3-[(p-methoxyphenyl) amino] propionate 5-methylfurfural and p-methoxyaniline The β-lactam compound obtained by reacting the imine derivative derived from ## STR1 ## with ethyl bromodifluoroacetate was reacted in the same manner as in Step 1 of Reference Example 2 to obtain the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.29 (t, 3H, J =
7Hz), 2.26 (s, 3H), 3.72 (s, 3H), 4.30 (q, 2H, J = 7Hz), 5.0
0-5.09 (m, 1H), 5.91 (d, 1H, J = 3Hz), 6.24 (d, 1H, J = 3Hz),
6.24-6.69 (m, 2H), 6.74-6.76 (m, 2H) MS-FD: 339 (M ⁺ )

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (5-
Methylfuran-2-yl) propionate The compound of Step 1 was reacted in the same manner as in Step 2 of Reference Example 2 to obtain the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.32 (t, 3H, J =
7Hz), 1.45 (s, 9H), 2.27 (s, 3H), 4.30 (q, 2H, J = 7Hz), 5.2
7 (brd, 1H, J = 10Hz), 5.42-5.51 (m, 1H), 5.93 (d, 1H, J = 3H
z), 6.24 (d, 1H, J = 3Hz)

Step 3: 3- (tert-Butoxycarbonylamino) -2,2-difluoro-3- (5-methylfuran-2-yl) propionic acid The compound of Step 2 was prepared in the same manner as Step 3 of Reference Example 1. Hydrolysis gave the title compound as white crystals.

Melting point: 86-88 ° C. ¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.39 (s, 9H), 2.23 (s, 3
H), 5.29-5.39 (m, 1H), 6.03 (d, 1H, J = 3Hz), 6.34 (d, 1H, J =
3Hz), 7.84 (d, 1H, J = 10Hz) IR (KBr): 3804, 3668, 3452, 3320, 2988, 2936, 2648,
2504, 1908, 1760, 1726, 1656, 1566, 1512 cm ^-1 MS-FD: 305 (M ⁺ )

Reference Example 17 Step 1: Ethyl 3-benzoylamino-2,2-difluoro-3- (2-furyl) propionate The compound obtained in Step 1 of Reference Example 14 was treated in the same manner as in Step 1 of Reference Example 8. The reaction was performed to obtain the title compound as a colorless oily substance.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.30 (t, 3H, J =
7Hz), 4.31 (q, 2H, J = 7Hz), 6.13 (dt, 1H, J = 10,14.5Hz), 6.
38-6.39 (m, 1H), 6.48 (d, 1H, J = 3Hz), 6.87 (d, 1H, J = 9Hz),
7.43-7.56 (m, 4H), 7.80-7.82 (m, 2H)

Step 2: 3-benzoylamino-2,2
-Difluoro-3- (2-furyl) propionic acid The compound of Step 1 was hydrolyzed in the same manner as in Step 2 of Reference Example 4 to obtain the title compound as white crystals.

Melting point: 123-125 ° C. ¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 6.04-6.13 (m, 1H), 6.49
(dd, 1H, J = 2,3Hz), 6.61 (d, 1H, J = 3Hz), 7.46-7.56 (m, 3H),
7.69 (d, 1H, J = 2Hz), 7.87-7.89 (m, 2H), 9.29 (d, 1H, J = 9H
z) IR (KBr): 3332, 3132, 2968, 1758, 1716, 1652, 1606,
1582,1530 cm ^-1 MS-FAB: 295 (MH ⁺ )

Reference Example 18 Step 1: Ethyl 2,2-difluoro-3- (p-methoxyphenylamino) -3- (tetrahydropyran-4-yl) propionate Tetrahydropyran-4-carboxaldehyde and p-methoxy The β-lactam obtained by reacting an imine derived from aniline with ethyl bromodifluoroacetate was reacted in the same manner as in Step 1 of Reference Example 2 to obtain the title compound as pale yellow crystals.

Melting point: 46-48 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.17 (t, 3H, J = 7Hz), 1.45-
1.76 (m, 4H), 2.06-2.12 (m, 1H), 3.36-3.42 (m, 3H), 3.73
(s, 3H), 3.82-3.91 (m, 1H), 3.92-3.99 (m, 2H), 4.05-4.1
8 (m, 2H), 6.58-6.62 (m, 2H), 6.73-6.77 (m, 2H) IR (KBr): 3540, 3376, 3044, 2996, 2960, 2916, 2848,
2772, 2708, 2600, 2428, 2072, 2008, 1908, 1874, 18
34, 1774, 1618 cm ^-1 MS-FD: 343 (M ⁺ )

Step 2: Ethyl 3-benzoylamino-2,2-difluoro-3- (tetrahydropyran-
4-yl) Propionate The compound obtained in Step 1 above was reacted in the same manner as in Step 1 of Reference Example 8 to obtain the title compound as white crystals.

Melting point: 100-101 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.29 (t, 3H, J = 7Hz), 1.48-
1.73 (m, 4H), 2.12-2.20 (m, 1H), 3.36-3.45 (m, 2H), 3.96-
4.01 (m, 2H), 4.24-4.34 (m, 2H), 4.79-4.90 (m, 1H), 6.27
(d, 1H, J = 11Hz), 7.44-7.66,7.74-7.76 (each m, total 5
H) IR (KBr): 3520, 3260, 3068, 2976, 2932, 2848, 2772,
2712, 1976, 1920,1762, 1654, 1606, 1582 cm ^-1 MS-FD: 341 (M ⁺ )

Step 3: 3-Benzoylamino-2,2
-Difluoro-3- (tetrahydropyran-4-yl) propionic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1 to obtain the title compound as white crystals.

Melting point: 223-226 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.33-1.46 (m, 2H), 1.57-1.
68 (m, 2H), 2.05-2.13 (m, 1H), 3.23-3.31 (m, 2H), 3.83-3.
86 (m, 2H), 4.60-4.72 (m, 1H), 7.45-7.57 and 7.82-7.84
(each m, total 5H), 8.53 (d, 1H, J = 10Hz) IR (KBr): 3304, 2964, 2916, 2868, 2528, 1958, 1768,
1656, 1622,1606 cm ^-1 MS-FD: 313 (M ⁺ )

Reference Example 19 Step 1: Ethyl 2,2-difluoro-3- (p-methoxyphenylamino) -3- (2-thienyl) propionate with an imine derived from 2-thiophenecarboxaldehyde and p-methoxyaniline. The β-lactam obtained by reacting ethyl bromodifluoroacetate was reacted in the same manner as in Step 1 of Reference Example 2 to obtain the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.27 (t, 3H, J =
7Hz), 3.72 (s, 3H), 3.93 (br, 1H), 4.30 (q, 2H, J = 7Hz), 5.
29 (dd, 1H, J = 7Hz, 19Hz), 6.63-6.67 (m, 2H), 6.72-6.76
(m, 2H), 6.99 (dd, 1H, J = 3Hz, 5Hz), 7.10 (d, 1H, J = 3Hz), 7.
28 (dd, 1H, J = 1Hz, 5Hz)

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-
Thienyl) propionate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 2 to give the title compound as a colorless oil.

3 ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.29 (t, 3H, J = 7Hz), 1.44
(s, 9H), 4.25-4.32 (m, 2H), 5.66-5.75 (m, 1H), 7.00 (dd, 1
H, J = 4Hz, 5Hz), 7.11 (d, 1H, J = 4Hz), 7.32 (dd, 1H, J = 1Hz, 5
Hz)

Step 3: 3- (tert-Butoxycarbonylamino) -2,2-difluoro-3- (2-thienyl)
Propionic Acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1 to obtain the title compound as a colorless caramel oil.

¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.39 (s, 9
H), 5.49-5.58 (m, 1H), 7.03 (dd, 1H, J = 3Hz, 5Hz), 7.20 (d,
1H, J = 3Hz), 7.50 (d, 1H, J = 5Hz), 8.09 (brd, 1H, J = 9Hz)

Reference Example 20 Step 1: Ethyl 3- (2-benzofuryl) -2,2
-Difluoro-3- (p-methoxyphenylamino) propionate A β-lactam obtained by reacting an imine derived from 2-benzofurylaldehyde and p-methoxyaniline with ethyl bromodifluoroacetate was used as in Step 1 of Reference Example 2. The same reaction was performed to obtain the title compound as a colorless oily substance. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.28 (t, 3H, J = 7Hz), 4.33
(q, 2H, J = 7Hz), 3.71 (s, 3H), 5.26 (m, 1H), 6.74 (m, 4H),
6.77 (s, 1H), 7.21 (m, 1H), 7.28 (m, 1H), 7.46 (m, 1H), 7.5
2 (m, 1H) MS-FD: 375 (M ⁺ )

Step 2: Ethyl 3- (2-benzofuryl) -2,2-difluoro-3- (tert-butoxycarbonylamino) propionate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 2. The title compound was obtained as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.30 (t, 3H, J
= 7Hz), 1.45 (s, 9H), 4.32 (q, 2H, J = 7Hz), 5.45 (br-d, 1H, J
= 10Hz), 5.70 (dd, 1H, J = 4.5Hz, J = 11Hz), 6.78 (s, 1H), 7.2
3 (m, 1H), 7.31 (m, 1H), 7.46 (d, 1H, J = 7.8Hz), 7.55 (d, 1
H, J = 7.3Hz) MS-FD: 369 (M ⁺ )

Step 3: 3- (2-benzofuryl)-
2,2-Difluoro-3- (tert-butoxycarbonylamino) propionic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1 to obtain the title compound as white crystals.

Melting point: 120-128 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.48 (s, 9H), 5.68 (bt, 1H,
J = 13Hz), 6.84 (s, 1H), 7.22 (m, 1H), 7.30 (m, 1H), 7.47
(d, 1H, J = 8Hz), 7.56 (d, 1H, J = 8Hz) IR (KBr): 3300, 3000, 1740, 1450, 1260, 1160, 1080,
850, 740 cm ^-1 MS-FD: 341 (M ⁺ )

Reference Example 21 Step 1: Ethyl 3-azido-3- (p-benzyloxyphenyl) -2,2-difluoropropionate Ethyl 3-(-) derived from p-benzyloxybenzaldehyde and ethyl bromodifluoroacetate p-Benzyloxyphenyl) -2,2-difluoro-3-hydroxypropionate was reacted in the same manner as in Step 1 of Reference Example 1 to obtain the title compound as white crystals.

Melting point: 42-43 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.28 (t, 3H, J = 7Hz), 4.30
(q, 2H, J = 7Hz), 5.01 (dd, 2H, J = 10Hz, 15Hz), 5.08 (s, 2H),
6.99-7.03 (m, 2H), 7.32-7.44 (m, 7H) IR (KBr): 3804, 3668, 3040, 2996, 2940, 2884, 2508,
2228, 2120, 1962, 1932, 1776, 1758, 1612, 1586 cm
^-1 MS-FD: 361 (M ⁺ )

Step 2: Ethyl 3- (p-benzyloxyphenyl) -3- (tert-butoxycarbonylamino) -2,2-difluoropropionate The compound obtained in Step 1 above was referred to as Step 2 of Reference Example 1. The reaction was performed similarly to give the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.26 (t, 3H, J =
7Hz), 1.42 (s, 9H), 4.19-4.30 (m, 2H), 5.05 (s, 2H), 5.31
-5.35 (m, 2H), 6.95-6.97 (m, 2H), 7.27-7.43 (m, 7H)

Step 3: 3- (p-benzyloxyphenyl) -3- (tert-butoxycarbonylamino)-
2,2-Difluoropropionic acid The compound obtained in the above Step 2 was hydrolyzed in the same manner as in Step 3 of Reference Example 1 to obtain the title compound as a caramel colorless oil.

¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.36 (s, 9
H), 5.08 (s, 2H), 5.16-5.26 (m, 1H), 6.96-6.98 (m, 2H),
7.31-7.44 (m, 7H), 7.98 (brd, 1H, J = 10Hz) MS-FD: 407 (M ⁺ )

Reference Example 22 Step 1: Ethyl 2,2-difluoro-3- (p-methoxyphenylamino) -3- (2-tetrahydrofuryl) propionate Ethyl 2,2-difluoro obtained in Step 1 of Reference Example 14 1.0 g of -3- (p-methoxyphenylamino) -3- (2-furyl) propionate was dissolved in 10 ml of a 1: 1 (v / v) solution of ethyl acetate and acetic acid, and 10% palladium hydroxide ( w / w) 432 mg was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere of 10 atm. After removing the catalyst by filtration and concentrating, it was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and concentrated, and then silica gel column chromatography (developing solvent: chloroform: acetone = 95:
5 (v / v)) to give 969 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.19 (m, 3H),
1.75-1.82 (m, 1H), 2.10 (m, 1H), 2.69 (m, 1H), 3.41 (m, 1
H), 3.58 and 3.64 (each m, total 1H), 3.73 (s, 3H), 3.8
6 (m, 1H), 4.10 (m, 4H), 6.61 (m, 2H), 6.76 (m, 2H) MS-FD: 329 (M ⁺ )

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-
Tetrahydrofuryl) propionate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 2 to give the title compound as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.35 (t, 3H, J
= 6.5Hz), 1.43 (s, 9H), 1.77 (m, 1H), 2.11 (m, 1H), 2.63
(m, 1H), 4.40 (m, 1H), 3.50 and 3.59 (each t, J = 8.5Hz, to
tal 1H), 3.74 (dd, 1H, J = 8Hz, J = 16Hz), 3.88 and 4.00 (ea
ch m, total 2H), 4.30 (m, 2H), 4.40 (m, 1H), 4.83 (m, 1H) MS-FD: 323 (M ⁺ )

Step 3: 3- (tert-Butoxycarbonylamino) -2,2-difluoro-3- (2-tetrahydrofuryl) propionic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1. Decomposition gave the title compound as a white oil.

Melting point: 133-135 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.43 and 1.48 (each brs,
total 9H), 1.80 (m, 1H), 2.15 (m, 1H), 2.66 (m, 1H), 3.60
(m, 1H), 3.77 (m, 1H), 3.91 (m, 2H), 4.20 and 4.43 (each
m, total 1H) IR (KBr): 3250, 2970, 1770, 1710, 1660, 1530, 137
0, 1250, 1160, 1040,890, 770, 690 cm ^-1 MS-FAB: 296 (M ⁺ )

Reference Example 23 Step 1: Ethyl 2,2-difluoro-3- (p-methoxyphenylamino) -3- [1- (p-toluenesulfonyl) imidazol-4-yl] propionate 1-tosylimidazole-4 -Β-lactam obtained by reacting imine derived from aldehyde and p-methoxyaniline with ethyl bromodifluoroacetate was reacted in the same manner as in Step 1 of Reference Example 2 to obtain the title compound as a colorless oily substance.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.25 (t, 3H, J
= 7Hz), 2.43 (s, 3H), 3.72 (s, 3H), 4.27 (m, 3H), 5.02 (m,
1H), 6.67 (m, 1H), 6.71 (m, 2H), 7.29 (s, 1H), 7.33 (d, 2H,
J = 8Hz), 7.78 (d, 2H, J = 8Hz), 7.95 (s, 1H) MS-FAB: 479 (M ⁺ )

Step 2: Ethyl 2,2-difluoro-
3- (tert-butoxycarbonylamino) -3- [1-
(P-toluenesulfonyl) imidazol-4-yl)
Propionate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 2 to give the title compound as a colorless oil.

Melting point: 135 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.29 (t, 3H, J = 7 Hz), 1.41
(s, 9H), 2.45 (s, 3H), 4.28 (q, 2H, J = 7Hz), 5.41 (m, 1H),
5.63 (d, 1H, J = 10Hz), 7.30 (s, 1H), 7.37 (d, 2H, J = 8Hz), 7.
82 (d, 2H, J = 8Hz), 7.96 (s, 1H) IR (KBr): 1775, 1718, 1540, 1885, 180, 1075, 680, 6
00 cm ^-1 MS-FAB: 474 (M ⁺ )

Step 3: 2,2-difluoro-3- (te
rt-Butoxycarbonylamino) -3- [1- (p-toluenesulfonyl) imidazol-4-yl) propionic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1 to give the title compound. Obtained as a white solid.

Melting point: 85 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.52 (s, 9H), 2.42 (brs, 3
H), 6.00 (m, 1H), 6.66 (m, 1H), 7.37 (m, 3H), 7.82 (d, 2H, J
= 8 Hz), 8.14 (brs, 1H) IR (KBr): 1720, 1515, 1370, 1180, 1060, 680, 600 cm
^-1 MS-FAB: 446 (M ⁺ )

Reference Example 24 Step 1: 3- (1-tert-butoxycarbonylpyro-
Lu-2-yl) -2,2-difluoro-3-hydroxy-N- (p-methoxyphenyl) propanamide 1- (tert-butoxycarbonyl) pyrrole-2-carboxaldehyde and ethyl derived from ethyl bromodifluoroacetate 3- (1-tert-Butoxycarbonylpyrrol-2-yl) -2,2-difluoro-3-hydroxypropionate was reacted in the same manner as in Step 1 of Reference Example 9 to obtain the title compound as a yellow oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.60 (s, 9H),
3.80 (s, 3H), 5.00 (d, 1H, J = 7Hz), 5.66-5.74 (m, 1H), 6.1
7 (t, 1H, J = 3Hz), 6.49 (brs, 1H), 6.87-6.90 (m, 2H), 7.25
(d, 1H, J = 2Hz), 7.47-7.49 (m, 2H), 8.12 (br, 1H)

Step 2: 4- (1-tert-butoxycarbonylpyrrol-2-yl) -3,3-difluoro-1-
(P-Methoxyphenyl) -2-azetidinone The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 9 to obtain the title compound as white crystals.

Melting point: 89-91 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.65 (s, 9H), 3.80 (s, 3H),
6.03-6.05 (m, 2H), 6.12 (t, 1H, J = 3Hz), 6.87-6.89 (m, 2H),
7.30 (brs, 1H), 7.38-7.40 (m, 2H) IR (KBr): 3548, 3180, 3088, 3064, 2980, 2940, 2844,
2632, 2024, 1876, 1852, 1776, 1744, 1616, 1590 cm
^-1 MS-FD: 378 (M ⁺ )

Step 3: Methyl 3- (1-tert-butoxycarbonylpyrrol-2-yl) -2,2-difluoro-
3- (p-Methoxyphenylamino) propionate 1.13 g of the compound of step 2 above is dissolved in 30 ml of methanol and 195 mg of sodium methoxide is added at room temperature.
Stir for minutes. After concentration, ethyl acetate and saturated aqueous ammonium chloride solution were added, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel chromatography (developing solvent; ethyl acetate: hexane = 1: 4 (v / v)) to obtain 1.14 g of the title compound as pale yellow crystals.

Melting point: 88-91 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.64 (s, 9H), 3.71 (s, 3H),
3.84 (s, 3H), 4.00 (br, 1H), 6.13 (t, 1H, J = 3.5Hz), 6.25-
6.30 (m, 1H), 6.34 (brs, 1H), 6.66-6.68 (m, 2H), 6.72-6.
75 (m, 2H), 7.27 (dd, 1H, J = 2Hz, 3.5Hz) IR (KBr): 3508, 3384, 3160, 3116, 3044, 3012, 2988,
2972, 2944, 2912,2840, 2600, 1762, 1746, 1616 cm
^-1 MS-FAB: 410 (MH ⁺ )

Step 4: Methyl 3- (tert-butoxycarbonylamino) -3- (1-tert-butoxycarbonylpyrrol-2-yl) -2,2-difluoropropionate Refer to the compound obtained in Step 3 above. The reaction was performed in the same manner as in Step 2 of Example 2 to obtain the title compound as white crystals.

Melting point: 124-125 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.43 (s, 9H), 1.62 (s, 9H),
3.84 (s, 3H), 5.55 (br, 1H), 6.15 (t, 1H, J = 3.5Hz), 6.28-
6.35 (m, 1H), 6.34 (brs, 1H), 7.30 (brs, 1H) IR (KBr): 3328, 2988, 2936, 2856, 1766, 1740, 1720,
1692, 1536 cm ^-1 MS-FD: 404 (M ⁺ )

Step 5: 3- (tert-Butoxycarbonylamino) -3- (1-tert-butoxycarbonylpyrrol-2-yl) -2,2-difluoropropionic acid The compound obtained in Step 4 above was used in Reference Example 1 Hydrolysis was performed in the same manner as in Step 3 of to give the title compound as white crystals.

Melting point: 135-137 ° C. (decomposition) ¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.36 (s, 9H), 1.56 (s, 9
H), 6.17 (t, 1H, J = 3Hz), 6.35-6.43 (m, 1H), 6.58 (brs, 1
H), 7.26 (brs, 1H), 7.74 (d, 1H, J = 10Hz) IR (KBr): 3320, 2988, 2944, 2520, 1748, 1648, 1480
cm ^-1 MS-FD: 390 (M ⁺ )

Reference Example 25 Step 1: Ethyl 2,2-difluoro-3- (p-methoxyphenylamino) -3- (2-thiazolyl) propionate 1.31 g of active zinc dust was suspended in 25 ml of tetrahydrofuran and refluxed. , An imine derived from thiazole-2-carboxaldehyde and p-methoxyaniline 2.18 g
And a mixture of 2.42 g of ethyl bromodifluoroacetate was added quickly. After stirring for 10 minutes, the insoluble material was filtered off and the solvent was distilled off under reduced pressure. The mixture was diluted with ethyl acetate, washed with a 1N aqueous hydrochloric acid solution, a saturated multi-layered aqueous solution and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel chromatography (developing solvent; ethyl acetate:
Purification with hexane = 1: 9 (v / v)) gave 1.87 g of the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.32 (t, 3H, J =
7Hz), 3.72 (s, 3H), 4.35 (q, 2H, J = 7Hz), 4.47 (d, 1H, J = 10
Hz), 5.38-5.47 (m, 1H), 6.71-6.77 (m, 4H), 7.37 (d, 1H, J =
3Hz), 7.82 (d, 1H, J = 3Hz)

Step 2: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-
Thiazolyl) propionate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 2 to obtain the title compound as white crystals.

Melting point: 91-94 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.35 (t, 3H, J = 7Hz), 1.47
(s, 9H), 4.32-4.38 (m, 2H), 5.74-5.84 (m, 2H), 7.39 (d, 1
H, J = 3Hz), 7.80 (d, 1H, J = 3Hz) IR (KBr): 3520, 3220, 3116, 3092, 2988, 2944, 2800,
2616, 1766,1720, 1534, 1504 cm ^-1 MS-FAB: 336 (MH ⁺ )

Step 3: Ethyl 3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-
Thiazolyl) propionic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1 to obtain the title compound as white crystals.

Melting point: 153-154 ° C. ¹ H-NMR (d ₆ -DMSO / TMS) δ (ppm): 1.42 (s, 9H), 5.68-5.78
(m, 1H), 7.76-7.80 (m, 2H), 8.41 (d, 1H, J = 10Hz) IR (KBr): 3300, 3144, 2984, 2824, 1914, 1758, 1716,
1538, 1514 cm ^-1 MS-FAB: 309 (MH ⁺ )

Reference Example 26 Step 1: Ethyl 2,2-difluoro-3- (p-methoxyphenylamino) -5-methylhexanate Refer to imine and ethyl bromodifluoroacetate derived from isobutyraldehyde and p-methoxyaniline. The reaction was performed in the same manner as in Step 1 of Example 25 to obtain the title compound as a colorless oily substance.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.87 (d, 3H, J =
7Hz), 0.92 (d, 3H, J = 7Hz), 1.02 (m, 2H), 1.23 (t, 3H, J = 7H
z), 1.53 (m, 1H), 3.20 (m, 1H), 3.73 (s, 3H), 4.12 (m, 3H),
6.61 (d, 2H, J = 9Hz), 6.74 (d, 2H, J = 9Hz)

Step 2: Ethyl 2,2-difluoro-
3- (tert-Butoxycarbonylamino) -5-methylhexanate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 2 to give the title compound as a colorless oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.95 (m, 6H),
1.34 (m, 3H), 1.41 (m, 11H), 1.52 (m, 1H), 4.31 (m, 3H), 4.
52 (m, 1H) .MS-FAB: 310 (MH ⁺ )

Step 3: 2,2-difluoro-3- (te
rt-Butoxycarbonylamino) -5-methylhexanoic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1 to obtain the title compound as white crystals.

Melting point: 202-205 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 0.93 (m, 6H), 1.43 (m, 11H),
1.69 (m, 1H), 3.45 (m, 1H), 4.16 (m, 1H) IR (KBr): 3400, 2970, 1700, 1660, 1460, 1270, 1170,
1050 cm ^-1

Reference Example 27 Step 1: Methyl 2,2-difluoro-3- (p-methoxyphenylamino) -5-methyl-4-hexenate Imines derived from isobutenyl aldehyde and p-methoxyaniline and bromodifluoro. The β-lactam obtained by reacting ethyl acetate was reacted in the same manner as in Step 1 of Reference Example 2 to obtain the title compound as a colorless oily substance.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.70 (s, 3H),
1.75 (s, 3H), 3.74 (s, 3H), 3.83 (s, 3H), 4.63 (m, 1H), 5.0
8 (d, 1H, J = 9Hz), 6.63 (d, 2H, J = 9Hz), 6.76 (d, 2H, J = 9Hz)

Step 2: Methyl 2,2-difluoro-
(3-tert-Butoxycarbonylamino) -5-methyl-4-hexenate The compound obtained in Step 1 above was reacted in the same manner as in Step 2 of Reference Example 2 to obtain the title compound as white crystals.

Melting point: 56 ° C. ¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.44 (s, 9H), 1.75 (s, 3H),
1.77 (s, 3H), 3.86 (s, 3H), 4.77 (m, 1H), 5.00 (m, 1H), 5.
06 (m, 1H) IR (KBr): 3400, 2950, 1770, 1680, 1520, 1440, 1290,
1200, 1080, 870, 580 cm ^-1 MS-FAB: 294 (MH ⁺ )

Step 3: 2,2-difluoro-3- (te
rt-Butoxycarbonylamino) -5-methyl-4-hexenoic acid The compound obtained in Step 2 above was hydrolyzed in the same manner as in Step 3 of Reference Example 1 to obtain the title compound as a white oil.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.45 (m, 9H),
1.75 (s, 3H), 1.77 (s, 3H), 5.05 (m, 2H), 6.32 (brs, 1H),
9.62 (brs, 1H) MS-FAB: 280 (MH ⁺ )

Example 1 Step 1: 13- [3- (tert-Butoxycarbonylamino) -2,2-difluoro-3-phenylpropionyl] -7,10-bis (2,2,2-trichloroethoxycarbonyl) -10-Deacetylbaccatin III 7,10-bis (2,2,2-trichloroethoxycarbonyl) -1 derived from deacetylbaccatin III
150 mg of 0-acetylbaccatin, 144 mg of di-2-pyridyl carbonate and 201 mg of the compound obtained in Step 3 of Reference Example 1 were dissolved in 5 ml of toluene. At room temperature, 4-
Dimethylaminopyridine (44.5 mg) was added, and the mixture was stirred for 15 minutes and then heated and stirred at 80 ° C for 60 hours. After toluene was distilled off from the reaction solution, chloroform was added to the residue, and the mixture was washed with 1N hydrochloric acid and a saturated aqueous solution of sodium bicarbonate in this order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel thin layer chromatography (developing solvent; chloroform:
Acetone = 30: 1 (v / v)) and the title compound 138 mg
Was obtained as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.18 (s, 3H),
1.23 and 1.24 (each s, total 3H), 1.41 and 1.43 (each
s, total 9H), 1.84 (s, 3H), 2.22 and 2.32 (each s, tota
l 3H), 2.60-2.63 (m, 1H), 3.85-3.89 (m, 1H), 4.12-4.16
(m, 1H), 4.30-4.33 (m, 1H), 4.59 and 4.90 (each d, 2H, J
= 12Hz), 4.77 (s, 2H), 4.93-4.95 (m, 1H), 5.53-5.57 (m, 4
H), 5.67 (d, 1H, J = 7Hz), 6.05 and 6.17 (each t, total 1
H, J = 8Hz), 6.20 and 6.21 (each s, total 1H), 7.31-7.66
and 8.05-8.09 (each m, total 10H)

Step 2: 13- [3- (tert-Butoxycarbonylamino) -2,2-difluoro-3-phenylpropionyl] -10-deacetylbaccatin III 138 mg of the compound obtained in Step 1 above was treated with acetic acid- methanol
(1: 1 (v / v)) Dissolve in 8 ml of mixed solvent and add active zinc powder.
300 mg was added, and the mixture was stirred at 60 ° C for 15 minutes. The insoluble material was filtered off, the toluene was distilled off, the residue was diluted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution. It was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 20: 1 (v / v)) to give a mixture of two diastereomers. 66.0 mg was obtained. Then, the obtained mixture was separated and purified by high performance liquid chromatography (used column; silica gel-based normal phase column, developing solvent: chloroform), and 30.0 mg of the fraction eluted earlier (isomer A),
27.4 mg of the later-eluting fraction (isomer B) was dissolved in dioxane and freeze-dried to obtain the title compound as a white powder.

Isomer A Melting point: 187-189 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.11 (s, 3H), 1.19 (s, 3H),
1.42 (s, 9H), 1.58 (s, 3H), 1.74 (s, 3H), 1.77-1.86 and
2.54-2.62 (each m, total 2H), 2.20 (s, 3H), 2.12-2.28
(m, 2H), 3.86 (d, 1H, J = 7Hz), 4.09-4.31 (m, 3H), 4.93 (d, 1
H, J = 8Hz), 5.16 (s, 1H), 5.35-5.45 (m, 2H), 5.66 (d, 1H,
J = 7Hz), 6.07 (t, 1H, J = 9Hz), 7.30-7.65 and 8.04-8.06 (e
ach m, total 10H) MS-FAB: 828 (MH ⁺ )

Isomer B Melting point: 183-186 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.11 (s, 3H), 1.20 (s, 3H),
1.40 (s, 9H), 1.70 (s, 3H), 1.74 (s, 3H), 1.70-1.85 and
2.54-2.62 (each m, total 2H), 2.28 (s, 3H), 2.19-2.22
(m, 2H), 3.87 (d, 1H, J = 7Hz), 4.17, 4.30 (2d, 2H, J = 8Hz),
4.22-4.26 (m, 1H), 4.94 (d, 1H, J = 8Hz), 5.16 (s, 1H), 5.4
0-5.58 (m, 2H), 5.66 (d, 1H, J = 7Hz), 6.15 (t, 1H, J = 9Hz), 7.
30-7.64 and 8.06-8.08 (each m, total 10H) MS-FAB: 828 (MH ⁺ )

Example 2 13- (2,2-Difluoro-3-hydroxy-3-phenylpropionyl) -10-deacetylbaccatin II
I 227 mg of the compound obtained in Step 3 of Reference Example 3 was added to benzene 10
suspended in 0.5 ml of oxalyl chloride and 0.523 ml of N, N-
20 mg of dimethylformamide was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was diluted with 5 ml of dichloromethane.
Dissolve in 7,10-bis (2,2,2-trichloroethoxycarbonyl) -10-deacetylbaccatin III 134 mg
And 4-dimethylaminopyridine (73 mg) were added, and the mixture was stirred at room temperature for 30 minutes. After diluting with dichloromethane, the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, 10% hydrochloric acid (w / v) and saturated brine in this order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel thin layer chromatography.
(Developing solvent; chloroform: methanol = 100: 1 (v /
Purified by v)) to obtain 152 mg of white powder. This powder was dissolved in 8 ml of a mixed solvent of acetic acid-methanol (1: 1 (v / v)), 300 mg of active zinc powder was added, and the mixture was stirred at 60 ° C for 15 minutes. The insoluble material was filtered off, concentrated, and then azeotropically distilled with toluene. The mixture was diluted with ethyl acetate, the insoluble material was filtered off, and washed with saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel thin layer chromatography (developing solvent; chloroform: methanol = 1
9: 1 (v / v)) to obtain 70.4 mg of a mixture of two diastereomers. Then, the obtained mixture is subjected to high performance liquid chromatography (used column; silica gel normal phase column, developing solvent; chloroform: methanol = 500).
: 1 (v / v)). 26.2 mg of the fraction eluting earlier (isomer A) and 36.9 mg of the fraction eluting later (isomer B) were each dissolved in dioxane and freeze-dried to obtain the title compound as a white powder.

Isomer A Melting point: 190-192 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.23 (s, 3H),
1.74 (s, 3H), 1.84 (s, 3H), 2.24-2.27 (m, 2H), 2.29 (s, 3
H), 2.48-2.55 (m, 1H), 3.87 (d, 1H, J = 7Hz), 4.19 and 4.2
9 (each d, each 1H, J = 8Hz), 4.19-4.22 (m, 1H), 4.96 (d, 1
H, J = 7Hz), 5.20 (s, 1H), 5.19-5.25 (m, 1H), 5.66 (d, 1H, J
= 7Hz), 6.26 (t, 1H, J = 9Hz), 7.35-7.64 and 8.06-8.08 (ea
ch m, total 10H) MS-FAB: 729 (MH ⁺ )

Isomer B Melting point: 158-162 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.23 (s, 3H),
1.74 (s, 3H), 1.90 (s, 3H), 2.18 (s, 3H), 2.24-2.27 (m, 2
H), 2.54-2.61 (m, 1H), 3.88 (d, 1H, J = 7Hz), 4.19 and 4.2
9 (each d, each 1H, J = 8Hz), 4.22-4.26 (m, 1H), 4.93 (d, 1
H, J = 8Hz), 5.20 (s, 1H), 5.24-5.31 (m, 1H), 5.66 (d, 1H, J
= 7Hz), 6.24 (t, 1H, J = 8Hz), 7.40-7.65 and 8.04-8.06 (ea
ch m, total 10H) MS-FAB: 729 (MH ⁺ )

Example 3 Step 1: 13- (3-benzoylamino-2,2-difluoro-3-phenylpropionyl) -7,10-bis (2,2,2-trichloroethoxycarbonyl) -1
0-Deacetylbaccatin III The compound obtained in Step 2 of Reference Example 4 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl _{3 /} TMS) δ (ppm): 1.17 (s, 3H),
1.23 (s, 3H), 1.84 (s, 3H), 2.17 and 2.35 (each s, total
3H), 2.18-2.30 (m, 2H), 2.57-2.65 (m, 1H), 3.86 (d, 1H, J
= 7Hz), 4.11-4.16 (m, 1H), 4.29-4.33 (m, 1H), 4.57-4.61
(m, 1H), 4.76 and 4.77 (each s, total 2H), 4.88-4.92
(m, 1H), 4.94-4.96 (m, 1H), 5.50-5.58 (m, 1H), 5.67 (d, 1
H, J = 7Hz), 5.99-6.13 (m, 2H), 6.16 and 6.20 (each s, tot
al 1H), 7.04 and 7.17 (each d, total 1H, J = 9Hz), 7.39-
7.66 (m, 11H), 7.79-7.82 (m, 2H), 8.03-8.09 (m, 2H)

Step 2: 13- (3-benzoylamino-2,2-difluoro-3-phenylpropionyl)-
10-Deacetylbaccatin III The compound obtained in the above step 1 was deprotected in the same manner as in step 2 of Example 1 and then purified by high performance liquid chromatography to obtain the title compound isomer A and isomer B as white powders, respectively. It was

Isomer A Melting point: 170-172 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.10 (s, 3H), 1.19 (s, 3H),
1.54 (s, 3H), 1.74 (s, 3H), 2.21-2.25 (m, 2H), 2.32 (s, 3
H), 2.53-2.61 (m, 1H), 3.85 (d, 1H, J = 7Hz), 4.15 and 4.3
0 (each d, each 1H, J = 9Hz), 4.16-4.20 (m, 1H), 4.93 (d, 1
H, J = 8Hz), 5.11 (s, 1H), 5.65 (d, 1H, J = 7Hz), 6.06 (dt, 1H,
J = 14Hz, 4Hz), 6.14 (t, 1H, J = 9Hz), 7.25 (d, 1H, J = 9Hz), 7.
37-7.64, 7.81-7.86 and 8.06-8.09 (each m, total 15H) MS-FAB: 832 (MH ⁺ )

Isomer B Melting point: 174-176 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.11 (s, 3H), 1.20 (s, 3H),
1.60 (s, 3H), 1.73 (s, 3H), 2.09-2.17 (m, 2H), 2.13 (s, 3
H), 2.53-2.61 (m, 1H), 3.85 (d, 1H, J = 7Hz), 4.14 and 4.2
9 (each d, each 1H, J = 9Hz), 4.15-4.26 (m, 1H), 4.92 (d, 1
H, J = 8Hz), 5.15 (s, 1H), 5.65 (d, 1H, J = 7Hz), 5.95-6.03
(m, 1H), 6.15 (t, 1H, J = 9Hz), 7.12 (d, 1H, J = 9Hz), 7.30-7.6
4, 7.79-7.83 and 8.04-8.09 (each m, total 15H) MS-FAB: 832 (MH ⁺ )

Example 4 13- (3-benzyloxy-2,2-difluoro-3
-Phenylpropionyl) -10-deacetylbaccatin III The compound obtained in Step 2 of Reference Example 5 was esterified in the same manner as in Example 2, deprotected, and then separated and purified by high performance liquid chromatography to give the title compound isomer A. , Isomer B were obtained as white powders.

Isomer A Melting point: 218-221 ° C. (decomposition) ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.25 (s, 3H),
1.74 (s, 3H), 1.86 (s, 3H), 2.15-2.28 (m, 2H), 2.18 (s, 3
H), 2.54-2.62 (m, 1H), 3.88 (d, 1H, J = 7Hz), 4.14 and 4.2
9 (each d, total 1H, J = 8Hz), 4.21-4.26 (m, 1H), 4.37 and
4.61 (each d, total 1H, J = 11Hz), 4.92-5.02 (m, 2H),
5.18 (s, 1H), 5.67 (d, 1H, J = 7Hz), 6.19 (t, 1H, J = 9Hz), 7.21
-7.64 and 8.04-8.07 (each m, total 15H) MS-FAB: 819 (MH ⁺ )

Isomer B Melting point: 207-209 ° C. (decomposition) ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.24 (s, 3H),
1.75 (s, 3H), 2.21-2.29 (m, 2H), 2.25 (s, 3H), 2.54-2.62
(m, 1H), 3.88 (d, 1H, J = 7Hz), 4.15 and 4.30 (each d, each
1H, J = 9Hz), 4.21-4.27 (m, 1H), 4.38 and 4.59 (each d, e
ach 1H, J = 11Hz), 4.93-5.02 (m, 2H), 5.16 (s, 1H), 5.67
(d, 1H, J = 7Hz), 6.24 (t, 1H, J = 9Hz), 7.22-7.64 and 8.05-
8.07 (each m, total 15H) MS-FAB: 819 (MH ⁺ )

Example 5 Step 1: 13- (3-Benzoyloxy-2,2-difluoro-3-phenylpropionyl) -7,10-bis (2,2,2-trichloroethoxycarbonyl) -1
0-Deacetylbaccatin III The compound obtained in Step 2 of Reference Example 6 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.17 (s, 3H),
1.22 and 1.23 (each s, total 3H), 1.74 and 1.75 (eac
hs, total 3H), 1.84 and 1.85 (each s, total 3H), 2.28
and 2.29 (each s, total 3H), 2.20-2.32 (m, 2H), 2.60-
2.67 (m, 1H), 3.86-3.89 (m, 1H), 4.13-4.16 (m, 1H), 4.32
(d, 1H, J = 8Hz), 4.57-4.62 and 4.89-4.93 (each m, total
2H), 4.76 (s, 2H), 4.94-4.97 (m, 1H), 5.52-5.59 (m, 1H),
5.68 (d, 1H, J = 7Hz), 6.14-6.25 (m, 1H), 6.18 and 6.19 (ea
ch s, total 1H), 7.42-7.66 (m, 11H), 8.05-8.13 (m, 4H)

Step 2: 13- (3-benzoyloxy-2,2-difluoro-3-phenylpropionyl)-
10-Deacetylbaccatin III The compound obtained in the above step 1 was deprotected in the same manner as in step 2 of Example 1 and then separated and purified by high performance liquid chromatography to give the title compound isomer A and isomer B as white powders, respectively. Obtained.

Isomer A Melting point: 209-211 ° C. (decomposition) ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.10 (s, 3H), 1.19 (s, 3H),
1.62 (s, 3H), 1.73 (s, 3H), 2.21-2.24 (m, 2H), 2.28 (s, 3
H), 2.54-2.61 (m, 1H), 3.86 (d, 1H, J = 7Hz), 4.15 and 4.3
1 (each d, each 1H, J = 8Hz), 4.16-4.23 (m, 1H), 4.94 (d, 1
H, J = 8Hz), 5.12 (s, 1H), 5.65 (d, 1H, J = 7Hz), 6.17 (t, 1H,
J = 8Hz), 6.54 (t, 1H, J = 12Hz), 7.40-7.65 and 8.06-8.15
(each m, total 15H) MS-FAB: 833 (MH ⁺ )

Isomer B Melting point: 218-221 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.10 (s, 3H), 1.17 (s, 3H),
1.74 (s, 3H), 1.84 (s, 3H), 2.17-2.22 (m, 1H), 2.25 (s, 3
H), 2.55-2.63 (m, 2H), 3.89 (d, 1H, J = 7Hz), 4.16 and 4.3
0 (each d, each 1H, J = 8Hz), 4.17-4.25 (m, 1H), 4.95 (d, 1
H, J = 7Hz), 5.15 (s, 1H), 5.66 (d, 1H, J = 7Hz), 6.21 (t, 1H,
J = 8Hz), 6.61 (dd, 1H, J = 8,16Hz), 7.41-7.65 and 8.05-8.
11 (each m, total 15H) MS-FAB: 833 (MH ⁺ )

Example 6 Step 1: 13- [3- (tert-Butoxycarbonylamino) -3-cyclohexyl-2,2-difluoropropionyl) -7,10-bis (2,2,2-trichloroethoxycarbonyl) -10-deacetylbaccatin II
I The compound obtained in Step 3 of Reference Example 7 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.05-1.89
(m, 11H), 1.20 (s, 3H), 1.27 (s, 3H), 1.37 and 1.42 (each
s, total 9H), 1.86 (s, 3H), 2.05 and 2.13 (each s, tota
l 3H), 2.26-2.44 (m, 2H), 2.31 and 2.37 (each s, total
3H), 2.59-2.67 (m, 1H), 3.92-3.94 (m, 1H), 4.14-4.22 (m,
2H), 4.33 (d, 1H, J = 8Hz), 4.58-4.62 (m, 1H), 4.74-4.81
(m, 3H), 4.90 (d, 1H, J = 12Hz), 4.96 (d, 1H, J = 9Hz), 5.56-
5.62 (m, 1H), 5.70 (d, 1H, J = 7Hz), 6.14 and 6.26 (each t,
total 1H, J = 9Hz), 6.26 and 6.27 (each s, total1H), 7.48
-7.52, 7.61-7.65 and 8.06-8.11 (each m, total 5H)

Step 2: 13- [3- (tert-butoxycarbonylamino) -3-cyclohexyl-2,2-difluoropropionyl) -10-deacetylbaccatin
III The compound obtained in Step 1 above was deprotected in the same manner as in Step 2 of Example 1 and then separated and purified by high performance liquid chromatography to obtain the title compound isomer A and isomer B as white powders.

Isomer A Melting point: 184-188 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (s, 3H), 1.06-1.88
(m, 11H), 1.23 (s, 3H), 1.42 (s, 9H), 1.76 (s, 3H), 2.04
(s, 3H), 2.28 (s, 3H), 2.20-2.38 (m, 2H), 2.56-2.63 (m, 1
H), 3.93 (d, 1H, J = 7Hz), 4.17 and 4.32 (each d, each 1H,
J = 8Hz), 4.14-4.29 (m, 2H), 4.75 (d, 1H, J = 11Hz), 4.95 (d,
1H, J = 8Hz), 5.23 (s, 1H), 5.69 (d, 1H, J = 7Hz), 6.13 (t, 1H,
J = 8Hz), 7.47-7.64 and 8.06-8.08 (each m, total 5H) MS-FAB: 834 (MH ⁺ )

Isomer B Melting point: 187-192 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.06-1.88
(m, 11H), 1.24 (s, 3H), 1.38 (s, 9H), 1.76 (s, 3H), 1.96
(s, 3H), 2.34 (s, 3H), 2.29-2.31 (m, 2H), 2.56-2.63 (m, 1
H), 3.93 (d, 1H, J = 7Hz), 4.18 and 4.32 (each d, each 1H,
J = 9Hz), 4.21-4.28 (m, 2H), 4.76 (d, 1H, J = 11Hz), 4.96 (d,
1H, J = 9Hz), 5.22 (s, 1H), 5.69 (d, 1H, J = 7Hz), 6.25 (t, 1H,
J = 8Hz), 7.47-7.63 and 8.09-8.11 (each m, total 5H) MS-FAB: 834 (MH ⁺ )

Example 7 Step 1: 13- (3-benzoylamino-3-cyclohexyl-2,2-difluoropropionyl) -7,1
0-bis (2,2,2-trichloroethoxycarbonyl) -10-deacetylbaccatin III The compound obtained in Step 2 of Reference Example 8 was esterified in the same manner as in Step 1 of Example 1 to give the title compound as a white powder. Got as.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.10-1.84
(m, 11H), 1.19 (s, 3H), 1.24 and 1.27 (each s, total 3
H), 1.86 (s, 3H), 2.02 and 2.16 (each s, total 3H), 2.32
and 2.41 (each s, total 3H), 2.24-2.39 (m, 2H), 2.59-
2.67 (m, 1H), 3.93 (d, 1H, J = 7Hz), 4.18 and 4.33 (each d,
total 2H, J = 8Hz), 4.60 (d, 1H, J = 12Hz), 4.77-4.78 (m, 2
H), 4.74-4.78 (m, 2H), 4.74-4.98 (m, 1H), 4.89-4.93 (m, 1
H), 4.96 (d, 1H, J = 9Hz), 5.56-5.62 (m, 1H), 5.70 (d, 1H, J =
7Hz), 6.19 and 6.25 (each t, total 1H, J = 8Hz), 6.24 and
6.27 (each s, total 1H), 6.32 and 6.39 (each d, total
1H, J = 11Hz), 7.41-7.77 and 8.05-8.11 (each m, total 10
H)

Step 2: 13- (3-Benzoylamino-3-cyclohexyl-2,2-difluoropropionyl) -10-deacetylbaccatin III The compound obtained in Step 1 above was treated in the same manner as in Step 2 of Example 1. After deprotection, the product was separated and purified by high performance liquid chromatography to obtain the title compound isomer A and isomer B as white powders, respectively.

Isomer A Melting point: 170-174 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.12-1.88
(m, 1H), 1.21 (s, 3H), 1.76 (s, 3H), 1.93 (s, 3H), 2.21-2.
36 (m, 2H), 2.37 (s, 3H), 2.45-2.63 (m, 1H), 3.93 (d, 1H, J
= 7Hz), 4.19 and 4.32 (each d, each 1H, J = 8Hz), 4.26 (m,
1H), 4.83-4.89 (m, 1H), 4.95 (d, 1H, J = 8Hz), 5.19 (s, 1H),
5.68 (d, 1H, J = 7Hz), 6.26 (t, 1H, J = 9Hz), 6.41 (d, 1H, J = 10)
Hz), 7.41-7.76 and 8.10-8.12 (each m, total 10H) MS-FAB: 838 (MH ⁺ )

Isomer B Melting point: 172-176 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.13-1.88
(m, 1H), 1.24 (s, 3H), 1.76 (s, 3H), 2.01 (s, 3H), 2.171-
2.34 (m, 2H), 2.31 (s, 3H), 2.56-2.64 (m, 1H), 3.93 (d, 1
H, J = 7Hz), 4.19 and 4.32 (each d, each 1H, J = 8Hz), 4.2
7 (m, 1H), 4.79-4.88 (m, 1H), 4.95 (d, 1H, J = 8Hz), 5.22 (s,
1H), 5.69 (d, 1H, J = 7Hz), 6.20 (t, 1H, J = 9Hz), 6.34 (d, 1H,
J = 10Hz), 7.44-7.78 and 8.06-8.08 (each m, total 10H) MS-FAB: 838 (MH ⁺ ).

Example 8 Step 1: 13- [3- (tert-Butoxycarbonylamino) -2,2-difluorooctanoyl] -7,10
-Bis (2,2,2-trichloroethoxycarbonyl)
-10-Deacetylbaccatin III The compound obtained in Step 5 of Reference Example 9 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.88-0.93
(m, 3H), 1.20 (s, 3H), 1.16-1.48 (m, 8H), 1.26 and 1.27
(each s, total 3H), 1.38 and 1.42 (each s, total 9H),
1.86 (s, 3H), 2.05 and 2.14 (each s, total 3H), 2.30 an
d 2.36 (each s, total 3H), 2.24-2.41 (m, 2H), 2.59-2.6
7 (m, 1H), 3.93 (d, 1H, J = 7Hz), 4.14-4.17 (m, 1H), 4.33 (d,
1H, J = 8Hz), 4.24-4.33 (m, 1H), 4.60 and 4.90 (each d, to
tal 2H, J = 12Hz), 4.77 and 4.78 (each s, total 2H), 4.9
6 (d, 1H, J = 9Hz), 5.56-5.61 (m, 1H), 5.70 (d, 1H, J = 7Hz),
6.14 and 6.25 (each t, total 1H, J = 8Hz), 6.26 and 6.28
(each s, total 1H), 7.48-7.52, 7.60-7.64 and 8.06-8.
10 (each m, total 5H)

Step 2: 13- [3- (tert-Butoxycarbonylamino) -2,2-difluorooctanoyl] -10-deacetylbaccatin III The compound obtained in Step 1 above was used as Step 2 of Example 1. Similarly, after deprotection, the product was separated and purified by high performance liquid chromatography to obtain the title compound isomer A and isomer B as white powders.

Isomer A Melting point: 142-146 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.90 (t, 3H, J = 7Hz), 1.13
(s, 3H), 1.25-1.54 (m, 8H), 1.23 (s, 3H), 1.41 (s, 9H), 1.
76 (s, 3H), 2.04 (s, 3H), 2.27 (s, 3H), 2.21-2.39 (m, 2H),
2.56-2.63 (m, 1H), 3.93 (d, 1H, J = 7Hz), 4.17 and 4.32 (ea
ch d, each 1H, J = 8Hz), 4.23-4.29 (m, 2H), 4.58 (d, 1H, J = 1
0Hz), 4.95 (d, 1H, J = 8Hz), 5.23 (s, 1H), 5.69 (d, 1H, J = 7H
z), 6.13 (t, 1H, J = 8Hz), 7.47-7.64 and 8.06-8.08 (each
m, total 5H) MS-FAB: 822 (MH ⁺ )

Isomer B Melting point: 144-150 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.91 (t, 3H, J = 7Hz), 1.13
(s, 3H), 1.25-1.54 (m, 8H), 1.23 (s, 3H), 1.38 (s, 9H), 1.
76 (s, 3H), 1.96 (s, 3H), 2.33 (s, 3H), 2.30 (m, 2H), 2.56-
2.63 (m, 1H), 3.94 (d, 1H, J = 7Hz), 4.18 and 4.32 (2d, 2H,
J = 8Hz), 4.21-4.28 (m, 2H), 4.62 (d, 1H, J = 10Hz), 4.96 (d,
1H, J = 8Hz), 5.22 (s, 1H), 5.69 (d, 1H, J = 7Hz), 6.25 (t, 1H,
J = 8Hz), 7.47-7.63 and 8.09-8.11 (each m, total 5H) MS-FAB: 822 (MH ⁺ )

Example 9 Step 1: 13- [3- (tert-Butoxycarbonylamino) -2-fluoro-3-phenylpropionyl]-
7,10-Bis (2,2,2-trichloroethoxycarbonyl) -10-deacetylbaccatin III The compound obtained in Step 3 of Reference Example 10 was esterified in the same manner as in Step 1 of Example 1 to give the title compound. Obtained as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.19 (s, 3
H), 1.26 (s, 3H), 1.40 (s, 9H), 1.84 and 1.87 (each s, to
tal 3H), 2.06 (s, 3H), 2.13 and 2.33 (each s, total 3
H), 2.60-2.63 (m, 1H), 3.88 (d, 1H, J = 7Hz), 4.13-4.17 (m,
1H), 4.29-4.33 (m, 1H), 4.58 and 4.90 (each d, total 2
H, J = 12Hz), 4.78 (s, 2H), 4.92-4.94 (m, 1H), 5.19-5.56
(m, 3H), 5.54-5.59 (m, 1H), 5.67-5.70 (m, 1H), 6.20-6.25
(m, 2H), 7.35-7.66 and 8.04-8.08 (each m, total 10H)

Step 2: 13- [3- (tert-Butoxycarbonylamino) -2-fluoro-3-phenylpropionyl] -10-deacetylbaccatin III The compound obtained in Step 1 above was processed in Step 2 of Example 1. After deprotection in the same manner as described above, the product was separated and purified by high performance liquid chromatography to obtain the title compound isomer A and isomer B as white powders.

Isomer A Melting point: 179-182 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.22 (s, 3
H), 1.39 (s, 9H), 1.74 (s, 3H), 1.97 (s, 3H), 2.11 (s, 3H),
2.06-2.22 (m, 2H), 2.55-2.62 (m, 1H), 3.90 (d, 1H, J = 7H
z), 4.16 and 4.29 (each d, each 1H, J = 8Hz), 4.22-4.26
(m, 1H), 4.93 (d, 1H, J = 8Hz), 5.22 (s, 1H), 5.22 (d, 1H, J = 4
8Hz), 5.32 (dd, 1H, J = 9Hz, 24Hz), 5.54 (br, 1H), 5.66 (d, 1
H, J = 7Hz), 6.22 (t, 1H, J = 8Hz), 7.27-7.65 and 8.04-8.06
(each m, total 10H) IR (KBr): 3452, 3072, 2984, 2940, 1722, 1606, 1498
cm ^-1 MS-FAB: 810 (MH ⁺ )

Isomer B Melting point: 181-184 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.22 (s, 3
H), 1.40 (s, 9H), 1.73 (s, 3H), 1.75 (s, 3H), 2.29 (s, 3H),
2.20-2.31 (m, 2H), 2.54-2.62 (m, 1H), 3.90 (d, 1H, J = 7H
z), 4.17 and 4.30 (each d, total 1H, J = 8Hz), 4.22-4.28
(m, 1H), 4.94 (d, 1H, J = 8Hz), 5.19 (s, 1H), 5.28 (d, 1H, J = 4
7Hz), 5.42 (dd, 1H, J = 9Hz, 24Hz), 5.62 (d, 1H, J = 9Hz), 5.6
7 (d, 1H, J = 7Hz), 6.20 (t, 1H, J = 8Hz), 7.28-7.62 and 8.04
-8.08 (each m, total 10H) IR (KBr): 3456, 3072, 2984, 2944, 1718, 1606, 1498
cm ^-1 MS-FAB: 810 (MH ⁺ )

Example 10 Step 1: 13- [3- (tert-Butoxycarbonylamino) -2-fluoro-2-methyl-3-phenylpropionyl] -7,10-bis (2,2,2-trichloroethoxy) Carbonyl) -10-deacetylbaccatin II
I The compound obtained in Step 3 of Reference Example 11 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.18 (s, 3
H), 1.28 (s, 3H), 1.39 (br, 12H), 1.82 (s, 3H), 1.98 (s, 3
H), 1.99 and 2.38 (each s, 4: 1, total 12H), 2.54-2.6
2 (m, 1H), 3.90 (d, 1H, J = 7Hz), 4.13-4.27 (2d, 2H, J = 8Hz),
4.58 and 4.89 (each d, toal 2H, J = 12Hz), 4.77 (d, 2H, J =
2Hz), 4.92-4.94 (m, 1H), 5.08-5.15 (m, 1H), 5.51-5.66
(m, 1H), 5.65 (d, 1H, J = 7Hz), 5.83 (d, 1H, J = 7Hz), 6.22 (s,
1H), 6.27 (t, 1H, J = 8Hz), 7.28-7.69 and 8.04-8.06 (each
m, total 10H)

Step 2: 13- [3- (tert-butoxycarbonylamino) -2-fluoro-2-methyl-3-
Phenylpropionyl] -10-deacetylbaccatin
III The compound obtained in Step 1 above was deprotected in the same manner as in Step 2 of Example 1, and then separated and purified by high performance liquid chromatography to obtain the title compound isomer A and isomer B as white powders, respectively.

Isomer A Melting point: 180-186 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.25 (s, 3
H), 1.35 (br, 12H), 1.68 (s, 3H), 1.75 (s, 3H), 2.38 (s, 3
H), 2.55-2.63 (m, 1H), 3.90 (d, 1H, J = 7Hz), 4.17 and 4.3
2 (each d, each 1H, J = 9Hz), 4.20 (m, 1H), 4.96 (d, 1H, J = 9
Hz), 5.11 (d, 1H, J = 10Hz), 5.17 (s, 1H), 5.68 (d, 1H, J = 7H
z), 5.73 (d, 1H, J = 7Hz), 6.25 (t, 1H, J = 8Hz), 7.32-7.62 a
nd 8.08-8.10 (each m, total 10H) MS-FAB: 824 (MH ⁺ )

Isomer B Melting point: 176-180 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.11 (s, 3H), 1.24 (s, 3
H), 1.39 (br, 12H), 1.72 (s, 3H), 1.89 (s, 3H), 1.93 (s, 3
H), 2.51-2.59 (m, 1H), 3.82 (d, 1H, J = 7Hz), 4.12 and 4.2
7 (each d, each 1H, J = 9Hz), 4.19 (m, 1H), 4.89 (d, 1H, J = 9
Hz), 5.07 (t, 1H, J = 13Hz), 5.16 (s, 1H), 5.64 (d, 1H, J = 7H
z), 5.88 (d, 1H, J = 9Hz), 6.25 (t, 1H, J = 8Hz), 7.27-7.68 a
nd 8.03-8.05 (each m, total 10H) MS-FAB: 824 (MH ⁺ )

Example 11 Step 1: 13- [3- (tert-butoxycarbonylamino)
-2,2-Difluoro-3- (p-methoxyphenyl) propionyl] -7,10-bis (2,2,2-trichloroethoxycarbonyl) -10-deacetylbaccatin III Obtained in Step 3 of Reference Example 12 The compound was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.18 (s, 3
H), 1.22 and 1.24 (each s, total 3H), 1.40 and 1.42 (e
ach s, total 9H), 1.87 (s, 3H), 2.02-2.08 (m, 1H), 2.25
and 2.34 (each s, total 3H), 2.58-2.65 (m, 1H), 3.78 an
d 3.79 (each s, total 3H), 3.88 (t, 1H, J = 7Hz), 4.13-4.
16 (m, 1H), 4.31-4.33 (m, 1H), 4.59 and 4.60 (each d, tot
al 1H, J = 12Hz), 4.77 (s, 2H), 4.90 (d, 1H, J = 12Hz), 4.95
(d, 1H, J = 12Hz), 5.35 (br, 1H), 5.41 (br, 1H), 5.53-5.57
(m, 1H), 5.68 (d, 1H, J = 6Hz), 6.07 and 6.17 (each t, tota
l1H, J = 8Hz), 6.20 and 6.21 (each s, total 1H), 6.90-6.
93 (m, 2H), 7.28-7.31 (m, 2H), 7.48-7.65 and 8.05-8.09
(each m, total 5H)

Step 2: 13- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (p-
Methoxyphenyl) propionyl] -10-deacetylbaccatin III The compound obtained in the above step 1 was deprotected in the same manner as in step 2 of Example 1 and then separated and purified by high performance liquid chromatography to give the title compound isomer A and isomer B. Were obtained as white powders, respectively.

Isomer A Melting point: 189-192 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.11 (s, 3H), 1.19 (s, 3
H), 1.42 (s, 9H), 1.73 (s, 3H), 1.74 (s, 3H), 2.14-2.29
(m, 2H), 2.22 (s, 3H), 2.54-2.62 (m, 1H), 3.78 (s, 3H), 3.
88 (d, 1H, J = 7Hz), 4.15 and 4.30 (each d, each 1H, J = 8H
z), 4.16-4.19 (m, 1H), 4.94 (d, 1H, J = 8Hz), 5.17 (s, 1H),
5.37 (br, 2H), 5.67 (d, 1H, J = 7Hz), 6.08 (t, 1H, J = 8Hz), 6.
90 (d, 2H, J = 9Hz), 7.29 (d, 2H, J = 9Hz), 7.48-7.52, 7.61-7.
64 and 8.04-8.06 (each m, total 5H) IR (KBr): 3456, 2984, 2944, 1764, 1724, 1616, 1588,
1516, 1454 cm ^-1 MS-FAB: 858 (MH ⁺ )

Isomer B Melting point: 190-193 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.20 (s, 3
H), 1.40 (s, 9H), 1.73 (s, 3H), 1.74 (s, 3H), 2.22 (d, 2H, J
= 8Hz), 2.30 (s, 3H), 2.55-2.62 (m, 1H), 3.77 (s, 3H), 3.8
8 (d, 1H, J = 7Hz), 4.16 and 4.31 (each d, each 1H, J = 8H
z), 4.22-4.30 (m, 1H), 4.94 (d, 1H, J = 8Hz), 5.17 (s, 1H),
5.30-5.49 (m, 1H), 5.47 (d, 1H, J = 10Hz), 5.67 (d, 1H, J = 7H
z), 6.16 (t, 1H, J = 8Hz), 6.91 (d, 2H, J = 9Hz), 7.29 (d, 2H, J
= 9Hz), 7.48-7.52, 7.60-7.64 and 8.06-8.08 (each m, to
tal 5H) IR (KBr): 3464, 2984, 2944, 1764, 1724, 1616, 158
8, 1516, 1456 cm ^-1 MS-FAB: 858 (MH ⁺ )

Example 12 Step 1: 13- [3- (tert-Butoxycarbonylamino) -2,2-difluoro-3- (o-methoxyphenyl) propionyl] -7,10-bis (2,2,2) −
Trichloroethoxycarbonyl) -10-deacetylbaccatin III The compound obtained in Step 3 of Reference Example 13 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.19 (s, 3
H), 1.24 and 1.26 (each s, total 3H), 1.38 and 1.43 (e
ach s, total 9H), 1.85 (s, 3H), 2.23 and 2.36 (each s, t
otal 3H), 2.58-2.65 (m, 1H), 3.90 (s, 3H), 3.90 (m, 1H),
4.13-4.17 (m, 1H), 4.31-4.33 (m, 1H), 4.59 (d, 1H, J = 12H
z), 4.78 (s, 2H), 4.89 and 4.90 (each d, total 1H, J = 12H
z), 4.93-4.97 (m, 1H), 5.55-5.59 (m, 1H), 5.69 (d, 1H, J = 7
Hz), 5.78-5.80 (m, 2H), 6.07 and 6.18 (each t, 1H, J = 8H
z), 6.24 (s, 1H), 6.94-7.02 (m, 2H), 7.28-7.65 (m, 2H),
8.05-8.10 (m, 5H)

Step 2: 13- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (o-
Methoxyphenyl) propionyl] -10-deacetylbaccatin III The compound obtained in the above step 1 was deprotected in the same manner as in step 2 of Example 1 and then separated and purified by high performance liquid chromatography to give the title compound isomer A and isomer B. Were obtained as white powders, respectively.

Isomer A Melting point: 195-198 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.12 (s, 3H), 1.22 (s, 3H), 1.
42 (s, 9H), 1.74 (s, 3H), 1.89 (s, 3H), 2.17-2.34 (m, 2H),
2.20 (s, 3H), 2.55-2.62 (m, 1H), 3.89 (s, 3H), 3.89 (d, 1H,
J = 7Hz), 4.16 and 4.30 (each d, each 1H, J = 9Hz), 4.22-
4.29 (m, 1H), 4.94 (d, 1H, J = 8Hz), 5.20 (s, 1H), 5.68 (d, 1
H, J = 7Hz), 5.70-5.81 (m, 2H), 6.07 (t, 1H, J = 8Hz), 6.93-
7.00 (m, 2H), 7.28-7.37 (m, 2H), 7.48-7.52, 7.60-7.65 an
d 8.05-8.07 (each m, total 5H) IR (KBr): 3464, 2984, 2944, 1768, 1722, 1606, 1496,
1456, 1442 cm ^-1 MS-FAB: 858 (MH ⁺ )

Isomer B Melting point: 196-198 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.23 (s, 3
H), 1.39 (s, 9H), 1.75 (s, 3H), 1.87 (s, 3H), 2.20-2.32
(m, 2H), 2.32 (s, 3H), 2.54-2.62 (m, 1H), 3.88 (s, 3H), 3.
89 (d, 1H, J = 7Hz), 4.17 and 4.31 (each d, total 1H, J = 8H
z), 4.22-4.28 (m, 1H), 4.95 (d, 1H, J = 8Hz), 5.20 (s, 1H),
5.68 (d, 1H, J = 7Hz), 5.74-5.84 (m, 2H), 6.15 (t, 1H, J = 8H
z), 6.93-7.02 (m, 2H), 7.28-7.37 (m, 2H), 7.48-7.52, 7.6
0-7.64 and 8.08-8.10 (each m, total 5H) IR (KBr): 3464, 2984, 2944, 1768, 1724, 1606, 1496,
1456, 1444 cm ^-1 MS-FAB: 858 (MH ⁺ )

Example 13 Step 1: 13- [3- (tert-Butoxycarbonylamino) -2,2-difluoro-3- (2-furyl) propionyl] -7,10-bis (2,2,2- Trichloroethoxycarbonyl) -10-deacetylbaccatin II
I The compound obtained in Step 3 of Reference Example 14 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.20 (s, 3
H), 1.25 and 1.26 (each s, total 3H), 1.43 and 1.45 (e
ach s, total 9H), 1.85 (s, 3H), 1.94 and 1.97 (each s, t
otal 3H), 2.02-2.09 (m, 1H), 2.28 and 2.35 (each s, tot
al 3H), 2.25-2.30 (m, 1H), 2.62-2.64 (m, 1H), 3.91 (m, 1
H), 4.11-4.17 (m, 1H), 4.33 (d, 1H, J = 9Hz), 4.59 (d, 1H, J
= 12Hz), 4.77 and 4.78 (2s, 2H), 4.90 (d, 1H, J = 12Hz), 4.
94-4.97 (m, 1H), 5.35 (d, 1H, J = 9Hz), 5.55-5.60 (m, 2H),
5.69 (d, 1H, J = 7Hz), 6.17 and 6.26 (each t, total 1H, J = 8
Hz), 6.24 (s, 1H), 6.39-6.41 (m, 1H), 6.43-6.44 (m, 1H),
7.44-7.65 and 8.06-8.10 (each m, total 6H)

Step 2: 13- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-
Furyl) propionyl] -10-deacetylbaccatin
III The compound obtained in Step 1 above was deprotected in the same manner as in Step 2 of Example 1, and then separated and purified by high performance liquid chromatography to obtain the title compound isomer A and isomer B as white powders, respectively.

Isomer A Melting point: 190-192 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.22 (s, 3
H), 1.44 (s, 9H), 1.75 (s, 3H), 1.89 (s, 3H), 2.19-2.34
(m, 2H), 2.25 (s, 3H), 2.55-2.62 (m, 1H), 3.91 (d, 1H, J = 7
Hz), 4.16 and 4.31 (each d, each 1H, J = 8Hz), 4.22-4.27
(m, 1H), 4.94 (d, 1H, J = 8Hz), 5.20 (s, 1H), 5.38 (br, 1H, J =
10Hz), 5.56-5.64 (m, 1H), 5.68 (d, 1H, J = 7Hz), 6.16 (t, 1
H, J = 8Hz), 6.39 (dd, 1H, J = 2Hz, 3Hz), 6.43 (d, 1H, J = 3Hz),
7.43 (d, 1H, J = 2Hz), 7.47-7.52, 7.60-7.65 and 8.06-8.0
8 (each m, total 5H) IR (KBr): 3760, 3464, 2984, 2944, 1764, 1722, 1628,
1604, 1588, 1500 cm ^-1 MS-FAB: 818 (MH ⁺ )

Isomer B Melting point: 188-191 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.22 (s, 3
H), 1.42 (s, 9H), 1.75 (s, 3H), 1.85 (s, 3H), 2.26-2.31
(m, 2H), 2.31 (s, 3H), 2.55-2.63 (m, 1H), 3.92 (d, 1H, J = 7
Hz), 4.17 and 4.32 (each d, each 1H, J = 9Hz), 4.21-4.26
(m, 1H), 4.95 (d, 1H, J = 8Hz), 5.19 (s, 1H), 5.39 (br, 1H, J =
10Hz), 5.62-5.69 (m, 1H), 5.68 (d, 1H, J = 7Hz), 6.23 (t, 1
H, J = 8Hz), 6.39 (dd, 1H, J = 2Hz, 3Hz), 6.43 (d, 1H, J = 3Hz),
7.44 (d, 1H, J = 2Hz), 7.47-7.51, 7.60-7.64 and 8.07-8.0
9 (each m, total 5H) IR (KBr): 3460, 2984, 2940, 1768, 1724, 1606, 1586,
1500 cm ^-1 MS-FAB: 818 (MH ⁺ )

Example 14 Step 1: 13- [3- (tert-Butoxycarbonylamino) -2,2-difluoro-3- (3-furyl) propionyl] -7,10-bis (2,2,2- Trichloroethoxycarbonyl) -10-deacetylbaccatin I
II The compound of Step 3 of Reference Example 15 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.19 (s, 3H),
1.24 and 1.25 (each s, total 3H), 1.42 and 1.45 (each
s, total 9H), 1.85 (s, 3H), 1.92 (s, 3H), 2.03-2.09 (m, 1
H), 2.28 and 2.36 (each s, total 3H), 2.21-2.32 (m, 2
H), 2.59-2.66 (m, 1H), 3.89-3.93 (m, 1H), 4.14-4.17 (m, 1
H), 4.33 (d, 1H, J = 8Hz), 4.60 (d, 1H, J = 12Hz), 4.91 (d, 1H,
J = 12Hz), 4.95-4.97 (m, 1H), 5.09-5.12 and 5.47-5.50 (e
ach m, total 1H), 5.55-5.59 (m, 1H) ,. 5.69 (d, 1H, J = 7Hz),
6.14 and 6.24 (each t, total 1H, J = 7Hz), 6.23 (s, 1H),
6.45 (s, 1H), 7.44 and 7.45 (each s, total 1H), 7.48 (s,
1H), 7.50-7.65 and 8.06-8.09 (each m, total 5H)

Step 2: 13- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (3-
Furyl) propionyl] -10-deacetylbaccatin
III The compound obtained in Step 1 above was deprotected in the same manner as in Step 2 of Example 1 and then separated and purified by high performance liquid chromatography to obtain the title compounds isomer A and isomer B as white powders.

Isomer A Melting point: 183-186 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.21 (s, 3H),
1.44 (s, 9H), 1.75 (s, 3H), 1.90 (s, 3H), 2.25 (s, 3H), 2.
18-2.33 (m, 2H), 2.55-2.63 (m, 1H), 3.91 (d, 1H, J = 7Hz),
4.17 and 4.31 (each d, total 2H, J = 8Hz), 4.22-4.29 (m,
1H), 4.94 (d, 1H, J = 8Hz), 5.13 (brd, 1H, J = 8Hz), 5.20 (s, 1
H), 5.41-5.47 (m, 1H), 5.68 (d, 1H, J = 7Hz), 6.14 (t, 1H, J =
8Hz), 6.45 (s, 1H), 7.43 (s, 1H), 7.50 (s, 1H), 7.48-7.64
and 8.06-8.07 (each m, total 5H) IR (KBr): 3464, 2984, 2904, 1764, 1726, 1604, 1
506, 1454 cm ^-1 MS-FAB: 818 (MH ⁺ )

Isomer B Melting point: 185-190 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.21 (s, 3H),
1.42 (s, 9H), 1.75 (s, 3H), 1.83 (s, 3H), 2.27-2.32 (m, 2
H), 2.32 (s, 3H), 2.55-2.63 (m, 1H), 3.91 (d, 1H, J = 7Hz),
4.17 and 4.32 (each d, total 2H, J = 8Hz), 4.21-4.28 (m,
1H), 4.95 (d, 1H, J = 7Hz), 5.19 (s, 1H), 5.23 (d, 1H, J = 10H
z), 5.41-5.53 (m, 1H), 5.68 (d, 1H, J = 7Hz), 6.21 (t, 1H, J =
9Hz), 6.44 (s, 1H), 7.44 (s, 1H), 7.52 (s, 1H), 7.48-7.64
and 8.07-8.09 (each m, total 5H) IR (KBr): 3464, 2984, 2908, 1768, 1724, 1604, 1
506, 1454 cm ^-1 MS-FAB: 818 (MH ⁺ )

Example 15 Step 1: 13- [3- (tert-Butoxycarbonylamino) -2,2-fluoro-3- (5-methylfuran-
2-yl) propionyl] -7,10-bis (2,2,2)
2-Trichloroethoxycarbonyl) -10-deacetylbaccatin III The compound of step 3 of Reference Example 16 was esterified in the same manner as in step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.20 (s, 3H),
1.25 and 1.26 (each s, total 3H), 1.43 and 1.45 (each
s, total 9H), 1.85 (s, 3H), 1.94 and 1.97 (each s, tota
l 3H), 2.02-2.09 (m, 1H), 2.27 and 2.36 (each s, total
3H), 2.29 (s, 3H), 2.19-2.39 (m, 2H), 2.58-2.67 (m, 1H),
3.73-3.93 (m, 1H), 4.14-4.17 (m, 1H), 4.33 (d, 1H, J = 8Hz),
4.59 (d, 1H, J = 12Hz), 4.78 (s, 2Hz), 4.89 (d, 1H, J = 12H
z), 4.95-4.98 (m, 1H), 5.32 (br, 1H, J = 9Hz), 5.52-5.59
(m, 2H), 5.69 (d, 1H, J = 7Hz), 5.96 (s, 1H), 6.15 and 6.24
(each t, total 1H, J = 8Hz), 6.24 (s, 1H), 6.29 (d, 1H, J = 3
Hz), 7.48-7.65 and 8.06-8.09 (each m, total 5H)

Step 2: 13- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (5-
Methylfuran-2-yl) propionyl] -10-deacetylbaccatin III The compound obtained in Step 1 above was deprotected in the same manner as in Step 2 of Example 1, and then separated and purified by high performance liquid chromatography to give the title compound isomer. A and isomer B were obtained as white powders, respectively.

Isomer A Melting point: 187-190 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.21 (s, 3H),
1.45 (s, 9H), 1.75 (s, 3H), 1.89 (s, 3H), 1.80-1.90 (m, 1
H), 2.26 (s, 6H), 2.19-2.33 (m, 2H), 2.55-2.63 (m, 1H),
3.91 (d, 1H, J = 7Hz), 4.16 and 4.31 (each d, total 2H, J =
8Hz), 4.23-4.29 (m, 1H), 4.94 (d, 1H, J = 8Hz), 5.20 (s, 1
H), 5.34 (br, 1H, J = 10Hz), 5.47-5.56 (m, 1H), 5.68 (d, 1H,
J = 7Hz), 5.96 (d, 1H, J = 3Hz), 6.13 (t, 1H, J = 8Hz), 6.29 (d,
1H, J = 3Hz), 7.48-7.64 and 8.06-8.07 (each m, total 5H) IR (KBr): 3464, 2984, 1980, 1766, 1726, 1604, 1564,
1504 cm ^-1 MS-FAB: 832 (MH ⁺ )

Isomer B Melting point: 190-194 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.22 (s, 3H),
1.42 (s, 9H), 1.75 (s, 3H), 1.85 (s, 3H), 2.28 (s, 3H), 2.
26-2.32 (m, 2H), 2.32 (s, 3H), 2.56-2.63 (m, 1H), 3.92 (d,
1H, J = 7Hz), 4.17 and 4.32 (each d, total 2H, J = 8Hz), 4.
24-4.28 (m, 1H), 4.96 (d, 1H, J = 7Hz), 5.21 (s, 1H), 5.37
(d, 1H, J = 10Hz), 5.51-5.60 (m, 1H), 5.68 (d, 1H, J = 7Hz),
5.96 (d, 1H, J = 3Hz), 6.21 (t, 1H, J = 9Hz), 6.28 (d, 1H, J = 3H
z), 7.47-7.64 and 8.07-8.09 (each m, total 5H) IR (KBr): 3468, 2984, 2940, 1768, 1724, 1604, 1584,
1564 cm ^-1 MS-FAB: 832 (MH ⁺ )

Example 16 Step 1: 13- [3-Benzoylamino-2,2-difluoro-3- (2-furyl) propionyl] -7-triethylsilyl baccatin III 7-triethylsilyl derived from baccatin III
Baccatin III 78.5 mg, compound 2 from step 2 of Reference Example 17
mg and di-2-pyridyl carbonate 121 mg were dissolved in toluene 5 ml, 4-dimethylaminopyridine 27.4 mg was added at room temperature, and the mixture was stirred for 15 minutes and then heated and stirred at 70 ° C. for 24 hours. Toluene was distilled off, ethyl acetate was added to the residue, and the mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
The residue was subjected to silica gel thin layer chromatography (developing solvent;
Chloroform: Acetone = 40: 1 (v / v)) to give the title compound (58.4 mg) as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.53-0.61
(m, 6H), 0.90-0.94 (m, 9H), 1.19 and 1.20 (each s, tota
l 3H), 1.23 (s, 3H), 1.68 and 1.69 (each s, total 3H),
1.89 and 1.98 (each s, total 3H), 2.17 and 2.18 (each
s, total 3H), 2.22 and 2.35 (each s, total 3H), 2.25-
2.33 (m, 2H), 2.48-2.56 (m, 1H), 3.79-3.82 (m, 1H), 4.12-
4.16 (m, 1H), 4.28-4.31 (m, 1H), 4.44-4.49 (m, 1H), 4.91-
4.94 (m, 1H), 5.68 (d, 1H, J = 7Hz), 6.16-6.24 (m, 2H), 6.41
(s, 1H), 6.40-6.44 (m, 1H), 6.50-6.52 (m, 1H), 6.97-7.04
(m, 1H), 7.43-7.64 (m, 7H), 7.80-7.82 (m, 2H), 8.06-8.1
1 (m, 2H)

Step 2: 13- [3-Benzoylamino-2,2-difluoro-3- (2-furyl) propionyl] baccatin III 54 mg of the compound obtained in the above Step 1 was dissolved in 20 ml of ethanol and cooled on ice. , 0.5% aqueous hydrochloric acid solution (10 ml) was added, and the mixture was stirred for 48 hours. After neutralization with sodium hydrogen carbonate, ethanol was distilled off, the residue was diluted with water, extracted with ethyl acetate and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Silica gel thin layer chromatography of the residue (developing solvent; chloroform: methanol = 4
0: 1 (v / v)) purified mixture of two diastereomers
42 mg was obtained. Then, the obtained mixture was separated and purified by high performance liquid chromatography (used column; ODS-based reverse phase column, developing solvent; ethanol: water = 2: 1 (v / v)),
The first-eluting fraction (isomer A) (19.3 mg) and the later-eluting fraction (isomer B) (19.5 mg) were each dissolved in dioxane and lyophilized to give the title compound as a white powder.

Isomer A Melting point: 172-174 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.15 (s, 3H), 1.26 (s, 3H),
1.67 (s, 3H), 1.88 (s, 3H), 2.23 (s, 3H), 2.24 (s, 3H), 2.
23-2.31 (m, 2H), 2.46 (d, 1H, J = 4Hz), 2.52-2.59 (m, 1H),
3.79 (d, 1H, J = 7Hz), 4.14 and 4.30 (each d, total 2H, J =
8Hz), 4.41-4.46 (m, 1H), 4.95 (d, 1H, J = 8Hz), 5.67 (d, 1H,
J = 7Hz), 6.14-6.26 (m, 1H), 6.24 (t, 1H, J = 7Hz), 6.28 (s, 1
H), 6.43 (dd, 1H, J = 2,3Hz), 6.52 (d, 1H, J = 3Hz), 6.94 (d, 1
H, J = 9Hz), 7.48-7.64 (m, 7H), 7.80-7.82 (m, 2H), 8.06-8.
08 (m, 2H) IR (KBr): 3464, 3068, 2944, 2860, 1728, 1674, 1604,
1584,1518 cm ^-1 MS-FAB: 864 (MH ⁺ )

Isomer B Melting point: 174-176 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.15 (s, 3H), 1.25 (s, 3H),
1.68 (s, 3H), 1.77 (s, 3H), 1.84-1.91 (m, 1H), 2.24 (s, 3
H), 2.28-2.32 (m, 2H), 2.35 (s, 3H), 2.44 (d, 1H, J = 4H
z), 2.52-2.60 (m, 1H), 3.80 (d, 1H, J = 7Hz), 4.16 and 4.31
(each d, total 2H, J = 8Hz), 4.40-4.45 (m, 1H), 4.96 (d, 1
H, J = 8Hz), 5.67 (d, 1H, J = 7Hz), 6.19-6.30 (m, 1H), 6.26
(s, 1H), 6.28 (t, 1H, J = 7Hz), 6.41 (dd, 1H, J = 2,3Hz), 6.51
(d, 1H, J = 3Hz), 6.98 (d, 1H, J = 10Hz), 7.43-7.64 (m, 7H),
7.80-7.82 (m, 2H), 8.09-8.11 (m, 2H) .IR (KBr): 3464, 3072, 2956, 2904, 1970, 1768, 1728,
1678, 1604, 1584, 1518 cm ^-1 MS-FAB: 864 (MH ⁺ )

Example 17 Step 1: 13-O- [3-benzoylamino-2,2
-Difluoro-3- (tetrahydropyran-4-yl) propionyl] -7-O-triethylsilylbaccatin III The compound obtained in Step 3 of Reference Example 18 was used in Step 1 of Example 16.
Esterification was carried out in the same manner as to give the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.53-0.61
(m, 6H), 0.90-0.95 (m, 9H), 1.17 and 1.20 (each s, tota
l 3H), 1.23 (s, 3H), 1.54-1.79 (m, 4H), 1.69 (s, 3H), 1.8
6-1.92 (m, 1H), 2.01 and 2.10 (each s, total 3H), 2.17
(s, 3H), 2.18 (s, 3H), 2.19-2.28 (m, 3H), 2.29 and 2.38
(each s, total 3H), 2.50-2.56 (m, 1H), 3.38-3.47 (m, 2
H), 3.82 (d, 1H, J = 7Hz), 4.00-4.17 (m, 2H), 4.13-4.17
(m, 1H), 4.31 (d, 1H, J = 8Hz), 4.44-4.50 (m, 1H), 4.85-4.9
8 (m, 1H), 4.93 (d, 1H, J = 10Hz), 5.67-5.70 (m, 1H), 6.18 an
d 6.24 (each t, total 1H, J = 7Hz), 6.34 and 6.42 (each
d, total 1H, J = 11Hz), 6.42 and 6.46 (each s, total 1H),
7.41-7.64, 7.72-7.77 and 8.06-8.12 (each m, total 10
H)

Step 2: 13-O- [3-Benzoylamino-2,2-difluoro-3- (tetrahydropyran-4-yl) propionyl] baccatin III The compound obtained in Step 1 above was processed in Example 16 After deprotection in the same manner as in 2, the product was separated and purified by high performance liquid chromatography to obtain the title compound isomer A and isomer B as white powders.

Isomer A Melting point: 179-182 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (s, 3H), 1.24 (s, 3H),
1.67 (s, 3H), 1.53-1.77 (m, 4H), 1.84-1.91 (m, 1H), 2.01
(s, 3H), 2.23 (s, 3H), 2.19-2.36 (m, 3H), 2.29 (s, 3H), 2.
50 (d, 1H, J = 4Hz), 2.53-2.59 (m, 1H), 3.39-3.49 (m, 2H),
3.81 (d, 1H, J = 7Hz), 3.99-4.04 (m, 2H), 4.14 and 4.30 (ea
ch d, total 2H, J = 8Hz), 4.42-4.47 (m, 1H), 4.81-4.92 (m,
1H), 4.95 (d, 1H, J = 8Hz), 5.67 (d, 1H, J = 7Hz), 6.17 (t, 1H,
J = 9Hz), 6.30 (s, 1H), 6.32 (d, 1H, J = 10Hz), 7.43-7.64,
7.73-7.75 and 8.05-8.07 (each m, total 10H) IR (KBr): 3448, 3072, 2960, 2856, 1728, 1676, 1606,
1584, 1518 cm ^-1 MS-FAB: 882 (MH ⁺ )

Isomer B Melting point: 180-183 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (s, 3H), 1.22 (s, 3H),
1.68 (s, 3H), 1.51-1.76 (m, 4H), 1.84-1.91 (m, 1H), 1.88
(s, 3H), 2.23 (s, 3H), 2.18-2.26 (m, 3H), 2.32-2.37 (m, 1
H), 2.39 (s, 3H), 2.44 (d, 1H, J = 4Hz), 2.51-2.59 (m, 1H),
3.39-3.47 (m, 2H), 3.80 (d, 1H, J = 7Hz), 4.00-4.03 (m, 2
H), 4.17 and 4.31 (each d, total 2H, J = 8Hz), 4.39-4.45
(m, 1H), 4.87-4.91 (m, 1H), 4.96 (d, 1H, J = 8Hz), 5.67 (d, 1
H, J = 7Hz), 6.26 (t, 1H, J = 9Hz), 6.26 (s, 1H), 6.37 (d, 1H, J
= 10Hz), 7.40-7.63, 7.71-7.73 and 8.11-8.13 (each m, t
otal 10H) IR (KBr): 3464, 3068, 2964, 2856, 1728, 1676, 1604,
1584, 1518 cm ^-1 MS-FAB: 882 (MH ⁺ )

Example 18 Step 1: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-thienyl) propionyl] -7,10-bis-O- (2 , 2,
2-Trichloroethoxycarbonyl) -10-deacetylbaccatin III The compound obtained in Step 3 of Reference Example 15 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.18 (s, 3H),
1.23 and 1.24 (each s, total 3H), 1.42 and 1.45 (each
s, total 9H), 1.85 (s, 3H), 1.90 (s, 3H), 2.02-2.09 (m, 1
H), 2.29 and 2.36 (each s, total 3H), 2.23-2.36 (m, 2
H), 2.59-2.66 (m, 1H), 3.88-3.92 (m, 1H), 4.13-4.16 (m, 1
H), 4.32 (d, 1H, J = 8Hz), 4.58-4.61 (m, 1H), 4.77 (s, 2H),
4.91 (d, 1H, J = 12Hz), 4.96 (d, 1H, J = 10Hz), 5.29 and 5.40
(each brd, total 1H, J = 9Hz), 5.54-5.59 (m, 1H), 5.69 (d,
1H, J = 7Hz), 5.74-5.80 (m, 1H), 6.14 and 6.23 (each t, to
tal 1H, J = 8Hz), 6.21 and 6.22 (each s, total 1H), 7.02
-7.05 (m, 1H), 7.15 (d, 1H, J = 3.5Hz), 7.34-7.36 (m, 1H),
7.49-7.53, 7.62-7.66 and 8.05-8.09 (each m, total 5
H)

Step 2: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3-
(2-thienyl) propionyl] -10-deacetylbaccatin III The compound obtained in the above Step 1 was deprotected in the same manner as in Step 2 of Example 1, and then separated and purified by high performance liquid chromatography to give the title compound isomer A. , Isomer B were obtained as white powders.

Isomer A Melting point: 189-193 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.11 (s, 3H), 1.20 (s, 3H),
1.44 (s, 9H), 1.74 (s, 3H), 1.83 (s, 3H), 2.26 (s, 3H), 2.
19-2.29 (m, 2H), 2.55-2.62 (m, 1H), 3.90 (d, 1H, J = 7Hz),
4.16 and 4.31 (each d, total 2H, J = 8Hz), 4.21-4.28 (m,
1H), 4.94 (d, 1H, J = 8Hz), 5.31 (brd, 1H, J = 8Hz), 5.18 (s, 1
H), 5.74-5.77 (m, 1H), 5.67 (d, 1H, J = 7Hz), 6.14 (t, 1H, J =
8Hz), 7.02 (dd, 1H, J = 4Hz, 5Hz), 7.15 (d, 1H, J = 4Hz), 7.34
(d, 1H, J = 5Hz), 7.48-7.64 and 8.06-8.07 (each m, total
5H) IR (KBr): 3800, 3688, 3668, 3452, 2984, 2944, 1764,
1722, 1604 cm ^-1 MS-FAB: 834 (MH ⁺ )

Isomer B Melting point: 191-195 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.20 (s, 3H),
1.41 (s, 9H), 1.74 (s, 3H), 1.80 (s, 3H), 2.32 (s, 3H), 2.
25-2.27 (m, 2H), 2.55-2.62 (m, 1H), 3.90 (d, 1H, J = 7Hz),
4.16 and 4.31 (each d, total 2H, J = 8Hz), 4.17-4.26 (m,
1H), 4.95 (d, 1H, J = 8Hz), 5.19 (s, 1H), 5.47 (d, 1H, J = 10H
z), 5.74-5.79 (m, 1H), 5.67 (d, 1H, J = 7Hz), 6.20 (t, 1H, J =
8Hz), 7.03 (dd, 1H, J = 4Hz, 5Hz), 7.14 (d, 1H, J = 4Hz), 7.34
(d, 1H, J = 5Hz), 7.48-7.64 and 8.07-8.09 (each m, total
5H) IR (KBr): 3800, 3464, 2984, 2944, 1766, 1722, 1604
cm ^-1 MS-FAB: 834 (MH ⁺ )

Example 19 Step 1: 13-O- [3- (2-benzofuryl) -3
-(Tert-butoxycarbonylamino) -2,2-difluoropropionyl] -7,10-bis-O- (2,
2,2-Trichloroethoxycarbonyl) -10-deacetylbaccatin III The compound obtained in Step 3 of Reference Example 20 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.19 (s, 3
H), 1.25 (s, 3H), 1.44 and 1.46 (each s, total 9H), 1.
74 (m, 1H), 1.84 (s, 3H), 1.97 (m, 3H), 2.27 and 2.34 (eac
hs, total 3H), 2.62 (m, 1H), 3.91 (m, 1H), 4.14 (m, 1H),
4.32 (m, 1H), 4.59 (d, 1H, J = 12Hz), 4.89 (d, 1H, J = 12Hz),
4.78 (m, 2H), 4.96 (m, 1H), 5.49 (m, 1H), 5.57 (m, 1H), 5.6
9 (d, 1H, J = 7Hz), 5.77 (m, 1H), 6.22 (m, 2H), 6.84 (d, 1H, J
= 3Hz), 7.30-8.07 (m, 9H) MS-FAB: 1220 (M ⁺ )

Step 2: 13-O- [3- (2-benzofuryl) -3- (tert-butoxycarbonylamino)-
2,2-Difluoropropionyl] -10-deacetylbaccatin III The compound obtained in Step 1 above was deprotected in the same manner as in Step 2 of Example 1 and then separated and purified by high performance liquid chromatography to give the title compound isomer A , Isomer B were obtained as white powders.

Isomer A Melting point: 185-187 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.22 (s, 3
H), 1.43 (s, 9H), 1.59 (m, 1H), 1.75 (s, 3H), 1.84 (s, 3H),
2.26 (m, 2H), 2.32 (s, 3H), 2.59 (m, 1H), 3.91 (d, 1H, J = 7
Hz), 4.16 (d, 1H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.24 (m, 1
H), 4.95 (d, 1H, J = 8Hz), 5.18 (s, 1H), 5.50 (d, 1H), 5.67
(d, 1H, J = 7Hz), 5.77 (m, 1H), 6.25 (t, 1H, J = 9Hz), 6.82 (s,
1H), 7.26 (m, 1H), 7.31 (m, 1H), 7.46 (m, 1H), 7.57 (m, 1
H), 7.48 (m, 2H), 7.63 (m, 1H), 8.06 (m, 2H) IR (KBr): 3460, 2960, 1730, 1458, 1375, 1245, 1160,
1070, 720 cm ^-1 MS-FAB: 868 (M ⁺ )

Isomer B Melting point: 183-185 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.22 (s, 3
H), 1.46 (s, 9H), 1.76 (s, 3H), 1.83 (m, 1H), 1.88 (s, 3H),
2.25 (m, 5H), 2.59 (m, 1H), 3.91 (d, 1H, J = 7Hz), 4.16 (d, 1
H, J = 8Hz), 4.31 (d, 1H, J = 8Hz), 4.26 (m, 1H), 4.94 (d, 1H,
J = 8Hz), 5.18 (s, 1H), 5.49 (m, 1H), 5.68 (d, 1H, J = 7Hz),
5.74 (m, 1H), 6.19 (m, 1H), 6.82 (s, 1H), 7.24 (m, 1H), 7.3
0 (m, 1H), 7.46 (m, 1H), 7.57 (m, 1H), 7.48 (m, 2H), 7.63
(m, 1H), 8.06 (m, 2H) IR (KBr): 3460, 2960, 1730, 1458, 1375, 1245, 1160,
1070, 720 cm ^-1 MS-FAB: 868 (M ⁺ )

Example 20 Step 1: 13-O- [3- (p-benzyloxyphenyl) -3- (tert-butoxycarbonylamino)
-2,2-Difluoropropionyl] -7,10-bis-O- (2,2,2-trichloroethoxycarbonyl)
-10-Deacetylbaccatin III The compound obtained in Step 3 of Reference Example 21 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.18 (s, 3H),
1.22 and 1.24 (each s, total 3H), 1.40 and 1.42 (each
s, total 9H), 1.85 (s, 3H), 1.86 (s, 3H), 2.02-2.08 (m, 1
H), 2.24 and 2.33 (each s, total 3H), 2.19-2.33 (m, 2
H), 2.58-2.65 (m, 1H), 3.86-3.90 (m, 1H), 4.13-4.16 (m, 1
H), 4.31-4.33 (m, 1H), 4.57-4.61 (m, 1H), 4.77 (s, 2H),
4.87-4.91 (m, 1H), 4.95 (d, 1H, J = 10Hz), 5.05 and 5.06 (e
ach s, total 2H), 5.36-5.42 (m, 2H), 5.53-5.58 (m, 1H),
5.68 (d, 1H, J = 7Hz), 6.06 and 6.16 (each t, total 1H, J =
8Hz), 6.21 and 6.22 (each s, total 1H), 6.98-7.01 (m, 2
H), 7.28-7.42, 7.47-7.62 and 8.06-8.08 (each m, total
5H)

Step 2: 13-O- [3- (p-benzyloxyphenyl) -3- (tert-butoxycarbonylamino) -2,2-difluoropropionyl] -10-
Deacetylbaccatin III The compound obtained in the above step 1 was deprotected in the same manner as in step 2 of Example 1, and then separated and purified by high performance liquid chromatography to obtain the title compound isomer A and isomer B as white powders, respectively. .

Isomer A Melting point: 184-190 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.11 (s, 3H), 1.19 (s, 3H),
1.41 (s, 9H), 1.73 (s, 3H), 1.74 (s, 3H), 2.20 (s, 3H), 2.
14-2.28 (m, 2H), 2.54-2.62 (m, 1H), 3.87 (d, 1H, J = 7Hz),
4.16 and 4.30 (each d, total 2H, J = 9Hz), 4.21-4.29 (m,
2H), 4.94 (d, 1H, J = 8Hz), 5.05 (s, 2H), 5.17 (s, 1H), 5.37
(br, 2H), 5.66 (d, 1H, J = 7Hz), 6.08 (t, 1H, J = 8Hz), 6.97-
6.99 (m, 2H), 7.28-7.61 and 8.04-8.06 (each m, total 12
H) IR (KBr): 3468, 2984, 2904, 1762, 1724, 1614, 1586,
1514 cm ^-1 MS-FAB: 934 (MH ⁺ )

Isomer B Melting point: 186-192 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.12 (s, 3H), 1.20 (s, 3H),
1.40 (s, 9H), 1.74 (s, 3H), 1.75 (s, 3H), 2.30 (s, 3H), 2.
22-2.24 (m, 2H), 2.54-2.60 (m, 1H), 3.88 (d, 1H, J = 7Hz),
4.19 and 4.31 (each d, total 2H, J = 9Hz), 4.22-4.29 (m,
2H), 4.94 (d, 1H, J = 8Hz), 5.04 (s, 2H), 5.17 (s, 1H), 5.40
-5.49 (m, 2H), 5.67 (d, 1H, J = 7Hz), 6.15 (t, 1H, J = 8Hz), 6.
97-7.00 (m, 2H), 7.28-7.61 and 8.06-8.08 (each m, total
12H) IR (KBr): 3468, 2984, 2904, 1766, 1724, 1614, 1586
cm ^-1 MS-FAB: 934 (MH ⁺ )

Example 21 13-O- [3- (tert-butoxycarbonylamino)
-2,2-difluoro-3- (p-hydroxyphenyl) propionyl] -10-deacetylbaccatin III A mixture (65.7 mg) of isomers A and B before separation obtained in Step 2 of Example 20 was treated with ethyl acetate. Dissolve in 4 ml and 10% (w
/ w) Palladium on carbon (66 mg) was added and catalytic reduction was carried out for 8 hours in a hydrogen stream. After removing the catalyst by filtration and concentrating, the obtained residue was purified by silica gel thin layer chromatography (developing solvent; chloroform: methanol = 20: 1 (v / v)) to obtain 50 mg of a mixture of two diastereomers. Obtained. Then, the obtained mixture was subjected to high performance liquid chromatography (used column;
C ₁₈ reverse phase column, developing solvent; methanol: water = 17: 13 (v
/ v)), and the fraction that elutes first (isomer A) (21.8 mg) and the fraction that elutes later (isomer B) (22.0 mg) are dissolved in dioxane and freeze-dried to give the title compound. Was obtained as a white powder.

Isomer A Melting point: 193-198 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.09 (s, 3H), 1.16 (s, 3H),
1.42 (s, 9H), 1.71 (s, 3H), 1.73 (s, 3H), 2.30 (s, 3H), 2.
19-2.23 (m, 2H), 2.52-2.58 (m, 1H), 3.85 (d, 1H, J = 7Hz),
4.17 and 4.31 (each d, total 2H, J = 8Hz), 4.22-4.25 (m,
1H), 4.95 (d, 1H, J = 8Hz), 5.21 (s, 1H), 5.39-5.42 (m, 1H),
5.62-5.66 (m, 2H), 6.11 (t, 1H, J = 8Hz), 6.24 (br, 1H), 6.
80-6.82 (m, 2H), 7.20-7.22 (m, 2H), 7.48-7.64 and 8.05-
8.07 (each m, total 5H) IR (KBr): 3836, 3460, 2984, 2908, 1762, 1718, 1616,
1602, 1518 cm ^-1 MS-FAB: 844 (MH ⁺ )

Isomer B Melting point: 190-195 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.10 (s, 3H), 1.18 (s, 3H),
1.43 (s, 9H), 1.73 (s, 3H), 1.84 (s, 3H), 2.22 (s, 3H), 2.
12-2.19 (m, 2H), 2.52-2.58 (m, 1H), 3.83 (d, 1H, J = 7Hz),
4.16 and 4.31 (each d, total 2H, J = 8Hz), 4.17-4.28 (m,
1H), 4.37 (br, 1H), 4.95 (d, 1H, J = 8Hz), 5.18 (s, 1H), 5.3
0-5.42 (m, 2H), 5.65 (d, 1H, J = 7Hz), 6.05 (t, 1H, J = 8Hz),
6.08 (br, 1H), 6.80-6.82 (m, 2H), 7.21-7.23 (m, 2H), 7.48
-7.64 and 8.04-8.06 (each m, total 5H) IR (KBr): 3448, 2984, 2904, 1762, 1720, 1618, 1602,
1518 cm ^-1 MS-FAB: 844 (MH ⁺ )

Example 22 Step 1: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-tetrahydrofuryl) propionyl] -7,10-bis-O-
(2,2,2-trichloroethoxycarbonyl) -10
-Deacetylbaccatin III The compound obtained in Step 3 of Reference Example 22 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.21 (s, 3
H), 1.26 (s, 3H), 1.39 (m, 9H), 1.76 (m, 1H), 1.87 (s, 3
H), 1.91 (m, 1H), 2.04 (s, 3H), 2.10 (m, 1H), 2.14 (m, 1H),
2.30 (brs, 1H), 2.36 (m, 3H), 2.63 (m, 1H), 2.71 (m, 1H),
3.54 (m, 1H), 3.65 (m, 1H), 3.76 (m, 1H), 3.92 (m, 2H), 4.1
7 (d, 1H, J = 8Hz), 4.33 (d, 1H, J = 8Hz), 4.41 (m, 1H), 4.61
(d, 1H, J = 12Hz), 4.89 (d, 1H, J = 12Hz), 4.79 (m, 2H), 4.98
(brd, 1H, J = 12Hz), 5.59 (m, 1H), 5.57 (m, 1H), 5.69 (d, 1
H, J = 7Hz), 6.13 and 6.25 (each m, total 1H), 6.27 (m, 1
H), 7.51 (m, 2H), 7.63 (m, 1H), 8.08 (m, 2H) MS-FAB: 1172 (M ⁺ )

Step 2: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3-
(2-Tetrahydrofuryl) propionyl] -10-deacetylbaccatin III The compound obtained in the above Step 1 was deprotected in the same manner as in Step 2 of Example 1 and then separated and purified by high performance liquid chromatography to give the title compound isomer. A, a mixture of isomer B and isomer C, and isomer D were obtained as white powders, respectively.

Isomer A Melting point: 190 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.23 (s, 3
H), 1.42 (s, 9H), 1.85 (m, 1H), 1.77 (s, 3H), 2.04 (s, 3H),
2.27 (s, 3H), 2.33 (m, 1H), 2.60 (m, 1H), 2.65 (m, 1H), 3.
55 (t, 1H, J = 8.5Hz), 3.72 (m, 1H), 3.76 (m, 1H), 3.90 (m, 1
H), 3.92 (m, 1H), 4.02 (m, 1H), 4.18 (d, 1H, J = 8Hz), 4.26
(m, 1H), 4.32 (d, 1H, J = 8Hz), 4.83 (d, 1H, J = 11Hz), 4.95
(d, 1H, J = 8Hz), 5.23 (s, 1H), 5.69 (d, 1H, J = 7Hz), 6.13 (m,
1H), 7.49 (m, 2H), 7.62 (m, 1H), 8.08 (m, 2H) IR (KBr): 3450, 2980, 1720, 1460, 1370, 1250, 1170,
1070, 990,710 cm ^-1 MS-FAB: 822 (M ⁺ )

Mixture of isomer B and isomer C Melting point: 195 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.23 (s, 3
H), 1.37 and 1.40 (each s, total 9H), 1.85 (m, 1H), 1.7
7 (s, 3H), 1.96 and 2.05 (each s, total 3H), 2.28 and
2.32 (each s, total 3H), 2.72 (m, 1H), 3.53 (m, 1H), 3.6
6 (m, 1H), 3.76 (m, 1H), 3.90 (m, 1H), 4.01 (m, 2H), 4.40
(m, 2H), 4.18 (d, 1H, J = 8Hz), 4.26 (m, 1H), 4.32 (d, 1H, J = 8
Hz), 4.87 (m, 1H), 4.95 (d, 1H, J = 8Hz), 5.21 and 5.24 (ea
ch s, total 1H), 5.69 (m, 1H), 6.11 and 6.24 (each m, to
tal 1H), 7.49 (m, 2H), 7.62 (m, 1H), 8.08 (m, 2H) IR (KBr): 3450, 2980, 1720, 1460, 1370, 1250, 1170,
1070, 990,710 cm ^-1 MS-FAB: 822 (M ⁺ )

Isomer D Melting point: 196-198 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (s, 3H), 1.21 (s, 3
H), 1.39 (s, 9H), 1.89 (m, 1H), 1.75 (s, 3H), 1.96 (s, 3H),
2.31 (m, 2H), 2.34 (s, 3H), 2.52 (m, 1H), 2.71 (m, 1H), 3.
66 (m, 2H), 3.79 (m, 3H), 3.92 (m, 1H), 4.22 (m, 2H), 4.32
(d, 1H, J = 8Hz), 4.46 (m, 1H), 4.97 (d, 1H, J = 7Hz), 5.23 (s,
1H), 5.68 (d, 1H, J = 7Hz), 6.23 (t, 1H, J = 8.5Hz), 7.50 (t, 1
H, J = 7.5Hz), 7.62 (t, 1H, J = 7.5Hz), 8.09 (d, 1H, J = 7.5Hz) IR (KBr): 3450, 2980, 1720, 1460, 1370, 1250, 1170,
1070, 990,710 cm ^-1 MS-FAB: 822 (M ⁺ )

Example 23 13-O- {3- (tert-butoxycarbonylamino)
-2,2-difluoro-3- [1- (p-toluenesulfonyl) imidazol-4-yl] propionyl} -1
0-Deacetylbaccatin III The compound (143 mg) obtained in Step 3 of Reference Example 23 was esterified in the same manner as in Step 1 of Example 1 to give 13-O- {3- (tert.
-Butoxycarbonylamino) -2,2-difluoro-
3- [1- (p-toluenesulfonyl) imidazole-
4-yl] propionyl} -7,10-bis-O-
(2,2,2-trichloroethoxycarbonyl) -10
-After obtaining 128 mg of deacetylbaccatin III, it was deprotected in the same manner as in step 2 of Example 1, separated and purified by high performance liquid chromatography to give 9 mg of the title compound isomer A,
9 mg of each isomer B was obtained as a white powder.

Isomer A Melting point: 200 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.22 (s, 3
H), 1.41 (s, 9H), 1.76 (s, 3H), 1.82 (brs, 3H), 1.87 (m, 1
H), 2.28 (s, 3H), 2.29 (m, 2H), 2.45 (s, 3H), 2.59 (m, 1
H), 3.90 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 8Hz), 4.25 (m, 1H),
4.31 (d, 1H, J = 8Hz), 4.94 (d, 1H, J = 8Hz), 5.19 (s, 1H), 5.
52 (m, 2H), 5.69 (d, 1H, J = 8Hz), 6.19 (m, 1H), 7.33 (s, 1H),
7.39 (d, 2H, J = 9Hz), 7.82 (d, 2H, J = 9Hz), 7.50 (t, 2H, J = 7.
5Hz), 7.62 (t, 1H, J = 7.5Hz), 7.94 (d, 1H, J = 1Hz), 8.07 (d,
2H, J = 7.5Hz) MS-FAB: 972 (M ⁺ )

Isomer B Melting point: 200 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.22 (s, 3
H), 1.42 (s, 9H), 1.77 (s, 3H), 1.84 (m, 1H), 1.89 (brs, 3
H), 2.23 (s, 3H), 2.33 (m, 2H), 2.46 (s, 3H), 2.60 (m, 1
H), 3.90 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 8Hz), 4.22 (m, 1H),
4.31 (d, 1H, J = 8Hz), 4.95 (d, 1H, J = 8Hz), 5.19 (s, 1H), 5.
46 (m, 1H), 5.58 (m, 1H), 5.69 (d, 1H, J = 8Hz), 6.13 (t, 1H, J
= 8.5Hz), 7.34 (s, 1H), 7.39 (d, 2H, J = 8Hz), 7.82 (d, 2H, J =
8Hz), 7.51 (t, 2H, J = 7.5Hz), 7.63 (t, 1H, J = 7.5Hz), 7.94
(d, 1H, J = 1Hz), 8.07 (d, 1H, J = 7.5Hz) MS-FAB: 972 (M ⁺ )

Example 24 Step 1: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (imidazol-4-yl) propionyl] -7,10-bis-O-
(2,2,2-trichloroethoxycarbonyl) -10
-Deacetylbaccatin III 143 mg of the compound obtained in Step 3 of Reference Example 23 was esterified in the same manner as in Step 1 of Example 1 to give 13-O- {3- (tert.
-Butoxycarbonylamino) -2,2-difluoro-
3- [1- (p-toluenesulfonyl) imidazole-
4-yl] propionyl} -7,10-bis-O-
(2,2,2-trichloroethoxycarbonyl) -10
-Deacetylbaccatin III 128 mg was obtained. This compound was dissolved in 3 ml of toluene and triethylamine 45
μl and 88 mg of 1-hydroxybenzotriazole were added, and the mixture was reacted at 70 ° C. for 3 hours. The product was dissolved in 10 ml of ethyl acetate, washed with saturated multi-layer water, washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and subjected to silica gel thin layer chromatography (Whatman PLK-5F, developing solvent chloroform: Methanol = 98: 2 (v / v)),
33 mg of the title compound was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.20 (s, 3
H), 1.27 (s, 3H), 1.42 and 1.44 (each s, total 9H), 1.
85 (s, 3H), 1.97 (m, 3H), 2.05 (m, 1H), 2.30 and 2.34 (eac
hs, total 3H), 2.40 (m, 2H), 2.62 (m, 1H), 3.91 (brd, 1H,
J = 6Hz), 4.15 (d, 1H, J = 8Hz), 4.32 (d, 1H, J = 8Hz), 4.60 (d,
1H, J = 12Hz), 4.89 (d, 1H, J = 12Hz), 4.78 (m, 2H), 4.95 (br
d, 1H, J = 9Hz), 5.58 (m, 2H), 5.70 (d, 1H, J = 6Hz), 5.82 (m,
1H), 6.20 (m, 2H), 6.24 (s, 1H), 7.10 (m, 1H), 7.50 (m, 2
H), 7.63 (m, 2H), 8.07 (m, 2H) MS-FAB: 1163 (M ⁺ )

Step 2: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3-
(Imidazol-4-yl) propionyl] -10-deacetylbaccatin III The compound obtained in the above Step 1 was deprotected in the same manner as in Step 2 of Example 1 and then separated and purified by high performance liquid chromatography to give the title compound. Isomer A and isomer B were obtained as white powders, respectively.

Isomer A Melting point: 200-205 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (s, 3H), 1.20 (s, 3
H), 1.46 (s, 9H), 1.74 (s, 3H), 1.86 (brs, 3H), 1.91 (m, 1
H), 2.28 (s, 3H), 2.34 (m, 2H), 2.50 (m, 1H), 3.87 (d, 1H,
J = 7Hz), 4.25 (m, 3H), 4.90 (d, 1H, J = 8Hz), 5.25 (s, 1H),
5.53 (m, 1H), 5.69 (d, 1H, J = 6.5Hz), 6.16 (m, 1H), 7.16 (s,
1H), 7.52 (m, 2H), 7.62 (m, 2H), 8.09 (m, 2H) MS-FAB: 818 (M ⁺ )

Isomer B Melting point: 200-205 ° C ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.16 (s, 3H), 1.22 (s, 3
H), 1.44 (s, 9H), 1.74 (s, 3H), 1.89 (m, 1H), 1.91 (s, 3H),
2.30 (s, 3H), 2.32 (brs, 2H), 2.50 (m, 1H), 3.89 (d, 1H, J
= 7Hz), 4.25 (m, 3H), 4.99 (d, 1H, J = 8Hz), 5.37 (s, 1H), 5.
55 (m, 1H), 5.69 (d, 1H, J = 7Hz), 6.23 (t, 1H, J = 8.5Hz), 7.1
7 (s, 1H), 7.52 (m, 2H), 7.63 (m, 2H), 8.10 (d, 2H) MS-FAB: 818 (M ⁺ )

Example 25 Step 1: 13-O- [3- (tert-butoxycarbonylamino) -3- [1- (tert-butoxycarbonyl))
Pyrrol-2-yl] -2,2-difluoropropionyl] -7,10-bis-O- (2,2,2-trichloroethoxycarbonyl) -10-deacetylbaccatin I
II The compound obtained in Step 5 of Reference Example 24 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.19 (s, 3H),
1.24 and 1.25 (each s, total 3H), 1.41 and 1.44 (each
s, total 9H), 1.61 and 1.63 (each s, total 9H), 1.85
(s, 3H), 1.93 and 2.04 (each s, total 3H), 2.27 and 2.
37 (each s, total 3H), 2.20-2.40 (m, 2H), 2.57-2.64 (m,
1H), 3.90-3.93 (m, 1H), 4.13-4.16 (m, 1H), 4.31-4.34 (m,
1H), 4.58-4.62 (m, 1H), 4.77 and 4.78 (each s, total 2
H), 4.91 (d, 1H, J = 12Hz), 4.96 (d, 1H, J = 10Hz), 5.55-5.60
(m, 2H), 5.69 (d, 1H, J = 7Hz), 6.12-6.17 (m, 1H), 6.16-6.1
8 (m, 1H), 6.24 and 6.25 (each s, total 1H), 6.38 (brs, 1
H), 6.30-6.39 (m, 1H), 7.28-7.31 (m, 1H), 7.48-7.53, 7.
61-7.65 and 8.06-8.10 (each m, total 5H)

Step 2: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3-
(2-Pyrrolyl) propionyl] -7,10-bis-O
-(2,2,2-trichloroethoxycarbonyl) -1
0-Deacetylbaccatin III 112 mg of the compound obtained in the above step 1 was dissolved in 5 ml of formic acid and stirred at room temperature for 7 hours. After concentration, saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel thin-layer chromatography (developing solvent; chloroform: methanol = 20: 1 (v / v)), and the compound was dissolved in 4 ml of tetrahydrofuran and di-tert-butyl dicarbonate was added. 100 mg was added, and the mixture was stirred at room temperature for 16 hours and further at 70 ° C for 4 hours. After concentration, the residue was subjected to silica gel thin layer chromatography (developing solvent; ethyl acetate: hexane = 1: 2 (v /
v)) and the title compound (44.8 mg) was obtained as a white powder.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.17 (s, 3H),
1.24 and 1.26 (each s, total 3H), 1.44 (s, 9H), 1.85
(s, 6H), 2.27 and 2.39 (each s, total 3H), 2.20-2.39
(m, 2H), 2.57-2.64 (m, 1H), 3.89 (d, 1H, J = 7Hz), 4.13-4.1
7 (m, 1H), 4.33 (d, 1H, J = 8Hz), 4.60 (d, 1H, J = 12Hz), 4.76
and 4.77 (each s, total 2H), 4.91 (d, 1H, J = 12Hz), 4.94-
4.99 (m, 1H), 5.27 (br, 1H), 5.51-5.58 (m, 2H), 5.68 (d, 1
H, J = 7Hz), 6.13-6.24 (m, 4H), 6.78-6.80 (m, 1H), 7.48-7.
52, 7.61-7.65 and 8.07-8.08 (each m, total 5H), 8.72
and 8.77 (each br, total 1H)

Step 3: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3-
(2-Pyrrolyl) propionyl] -10-deacetylbaccatin III After deprotecting the compound of the above Step 2 in the same manner as in Step 2 of Example 1, the compound was separated and purified by high performance liquid chromatography to give the title compound isomer A and isomer. Each B was obtained as a white powder.

Isomer A Melting point: 189-193 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.11 (s, 3H), 1.18 (s, 3H),
1.44 (s, 9H), 1.75 (s, 3H), 1.84 (s, 3H), 2.24 (s, 3H), 2.
55-2.63 (m, 1H), 3.90 (d, 1H, J = 7Hz), 4.16 and 4.31 (each
d, total 2H, J = 8Hz), 4.24-4.27 (m, 2H), 4.95 (d, 1H, J = 8H
z), 5.20 (s, 1H), 5.24 (d, 1H, J = 10Hz), 5.51-5.60 (m, 1
H), 5.67 (d, 1H, J = 7Hz), 6.13 (t, 1H, J = 8Hz), 6.16-6.19
(m, 1H), 6.25 (brs, 1H), 6.77-6.79 (m, 1H), 7.48-7.67 an
d 8.05-8.07 (each m, total 5H), 8.74 (br, 1H) MS-FAB: 817 (MH ⁺ )

Isomer B Melting point: 189-193 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.11 (s, 3H), 1.19 (s, 3H),
1.46 (s, 9H), 1.76 (s, 6H), 1.88-1.95 (m, 1H), 2.17-2.28
(m, 1H), 2.32 (s, 3H), 2.74-2.81 (m, 1H), 2.88 (br, 1H),
3.93 (d, 1H, J = 7Hz), 4.19 and 4.32 (each d, total 2H, J =
8Hz), 4.24-4.33 (m, 2H), 4.95 (d, 1H, J = 8Hz), 5.25 (s, 1
H), 5.26 (brd, 1H, J = 10Hz), 5.51-5.58 (m, 1H), 5.68 (d, 1
H, J = 7Hz), 6.14 (brs, 1H), 6.18 (t, 1H, J = 8Hz), 6.22 (brs,
1H), 6.83 (brs, 1H), 7.47-7.64 and 8.05-8.08 (each m, t
otal 5H), 9.07 (br, 1H) MS-FAB: 817 (MH ⁺ )

Example 26 Step 1: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-thiazolyl) propionyl] -7,10-bis-O- (2 , Two,
2-Trichloroethoxycarbonyl) -10-deacetylbaccatin III The compound obtained in Step 3 of Reference Example 25 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as white crystals.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.20 (s, 3H),
1.27 and 1.28 (each s, total 3H), 1.47 and 1.49 (each
s, total 9H), 1.86 (s, 3H), 2.02 and 2.09 (each s, tota
l 3H), 2.29 and 2.30 (each s, total 3H), 2.39-2.45
(m, 1H), 2.58-2.66 (m, 1H), 3.94 (d, 1H, J = 7Hz), 4.16 and
4.33 (each d, total 2H, J = 8Hz), 4.59 and 4.60 (each d,
total 1H, J = 12Hz), 4.78 (s, 2H), 4.91 (d, 1H, J = 12Hz), 4.
96 (d, 1H, J = 8Hz), 5.56-5.62 (m, 1H), 5.71 (d, 1H, J = 7Hz),
5.75-5.82 and 5.88-5.93 (each m, total 1H), 6.25-6.32
(m, 1H), 7.40-7.42 (m, 1H), 7.48-7.52, 7.61-7.65 and
8.01-8.10 (each m, total 5H), 7.75-7.78 (m, 1H)

Step 2: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3-
(2-thiazolyl) propionyl] -10-deacetylbaccatin III The compound obtained in the above step 1 was deprotected in the same manner as in step 2 of Example 1 and then purified by high performance liquid chromatography to give the title compound isomer A. , Isomer B were obtained as white powders.

Isomer A Melting point: 178-183 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (s, 3H), 1.24 (s, 3H),
1.47 (s, 9H), 1.75 (s, 3H), 1.93 (s, 3H), 2.27 (s, 3H), 2.
24-2.41 (m, 2H), 2.55-2.63 (m, 1H), 3.94 (d, 1H, J = 7Hz),
4.17 and 4.32 (each d, total 2H, J = 8Hz), 4.22-4.32 (m,
2H), 4.95 (d, 1H, J = 8Hz), 5.21 (s, 1H), 5.69 (d, 1H, J = 7H
z), 5.81-5.92 (m, 2H), 6.26 (t, 1H, J = 8Hz), 7.41 (d, 1H, J =
3Hz), 7.77 (d, 1H, J = 3Hz), 7.48-7.65 and 8.08-8.10 (eac
hm, total 5H) IR (KBr): 3460, 2984, 2904, 1766, 1722, 1604, 150
2, 1454 cm ^-1 MS-FAB: 835 (MH ⁺ )

Isomer B Melting point: 182-185 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.14 (s, 3H), 1.24 (s, 3H),
1.48 (s, 9H), 1.75 (s, 3H), 1.99 (s, 3H), 2.23-2.40 (m, 2
H), 2.26 (s, 3H), 2.55-2.63 (m, 1H), 3.94 (d, 1H, J = 7Hz),
4.17 and 4.32 (each d, total 2H, J = 8Hz), 4.24-4.32 (m,
2H), 4.95 (d, 1H, J = 8Hz), 5.23 (s, 1H), 5.69 (d, 1H, J = 7H
z), 5.78 (brd, 1H, J = 10Hz), 5.86-5.91 (m, 1H), 6.22 (t, 1
H, J = 8Hz), 7.40 (d, 1H, J = 3Hz), 7.76 (d, 1H, J = 3Hz), 7.48-
7.65 and 8.07-8.09 (each m, total 5H) IR (KBr): 3452, 2984, 1962, 1764, 1728, 1604, 158
6, 1502 cm ^-1 MS-FAB: 835 (MH ⁺ )

Example 27 Step 1: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-5-methylhexanoyl] -7,10-bis-O- (2,2,2 2-Trichloroethoxycarbonyl) -10-deacetylbaccatin
III The compound obtained in Step 3 of Reference Example 26 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.98 (m, 6
H), 1.20 (s, 3H), 1.27 (s, 3H), 1.37 and 1.42 (each s, t
otal 9H), 1.47 (m, 2H), 1.74 (m, 2H), 1.86 (s, 3H), 2.04
(m, 3H), 2.31 and 2.37 (each s, total 3H), 2.36 (m, 2H),
2.63 (m, 1H), 3.93 (d, 1H, J = 7.5Hz), 4.16 (m, 1H), 4.33
(d, 1H, J = 8Hz), 4.34 (m, 1H), 4.59 (m, 1H), 4.79 (m, 2H),
4.92 (m, 1H), 4.96 (d, 1H, J = 9Hz), 5.59 (m, 1H), 5.70 (d, 1
H, J = 7Hz), 6.13 and 6.26 (each m, total 1H), 6.26 and
6.28 (each s, total 1H), 7.50 (m, 2H), 7.63 (m, 1H), 8.0
7 (m, 2H) MS-FAB: 1159 (M ⁺ )

Step 2: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-5-methylhexanoyl] -10-deacetylbaccatin III The compound obtained in Step 1 above is carried out. After deprotection in the same manner as in Step 2 of Example 1, the product was isolated and purified by high performance liquid chromatography to obtain the title compound isomer A and isomer B as white powders.

Isomer A Melting point: 135 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.98 (m, 6H), 1.14 (s, 3
H), 1.23 (s, 3H), 1.24 (m, 2H), 1.39 (m, 1H), 1.41 (s, 9H),
1.77 (s, 3H), 1.84 (m, 1H), 1.96 (s, 3H), 2.32 (m, 2H), 2.
28 (s, 3H), 2.60 (m, 1H), 3.93 (d, 1H, J = 7Hz), 4.17 (d, 1H,
J = 8.5Hz), 4.22 (m, 1H), 4.32 (d, 1H, J = 8.5Hz), 4.39 (m, 1
H), 4.95 (d, 1H, J = 8Hz), 5.23 (s, 1H), 5.69 (d, 1H, J = 7Hz),
6.14 (m, 1H), 7.49 (t, 2H, J = 7.5Hz), 7.61 (t, 1H, J = 7.5H
z), 8.07 (d, 2H, J = 7.5Hz) MS-FAB: 808 (M ⁺ )

Isomer B Melting point: 135 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 0.99 (m, 6H), 1.14 (s, 3
H), 1.24 (s, 3H), 1.25 (m, 2H), 1.39 (m, 1H), 1.55 (s, 9H),
1.76 (s, 3H), 1.84 (m, 1H), 1.96 (s, 3H), 2.32 (m, 2H), 2.
34 (s, 3H), 2.61 (m, 1H), 3.94 (d, 1H, J = 7Hz), 4.18 (m, 2
H), 4.32 (d, 1H, J = 8Hz), 4.38 (m, 1H), 4.56 (d, 1H, J = 10H
z), 4.96 (d, 1H, J = 10Hz), 5.21 (s, 1H), 5.68 (d, 1H, J = 7H
z), 6.26 (m, 1H), 7.51 (m, 2H), 7.60 (m, 1H), 8.10 (m, 2H) MS-FAB: 808 (M ⁺ )

Example 28 Step 1: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-5-methyl-4-hexenyl] -7,10-bis-O- (trichloroethoxy Carbonyl) -10-deacetylbaccatin III The compound obtained in Step 3 of Reference Example 27 was esterified in the same manner as in Step 1 of Example 1 to obtain the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.20 (s, 3
H), 1.26 (s, 3H), 1.41 and 1.43 (each s, total 9H), 1.
79 (s, 3H), 1.80 (s, 3H), 1.86 (s, 3H), 2.04 (m, 3H), 2.06
(m, 1H), 2.31 and 2.37 (each s, total 3H), 2.35 (m, 2H),
2.63 (m, 1H), 3.93 (d, 1H, J = 7Hz), 4.16 (d, 1H, J = 9Hz), 4.
33 (d, 1H, J = 9Hz), 4.59 (d, 1H, J = 12Hz), 4.79 (m, 2H), 4.90
(m, 1H), 4.96 (brd, 1H, J = 10Hz), 5.11 (m, 2H), 5.39 (m, 1
H), 5.70 (d, 1H, J = 7Hz), 6.16 and 6.29 (each m, total 1
H), 6.26 and 6.27 (each s, total 1H), 7.50 (m, 2H), 7.6
3 (m, 1H), 8.08 (m, 2H) MS-FAB: 1157 (M ⁺ )

Step 2: 13-O- [3- (tert-butoxycarbonylamino) -2,2-difluoro-5-methyl-4-hexenyl] -10 deacetylbaccatin I
II The compound obtained in Step 1 above was deprotected in the same manner as in Step 2 of Example 1, and then separated and purified by high performance liquid chromatography to obtain the title compound isomer A and isomer B as white powders.

Isomer A Melting point: 155 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.24 (s, 3
H), 1.42 (s, 9H), 1.76 (s, 3H), 1.78 (s, 3H), 1.79 (s, 3H),
1.84 (m, 1H), 1.94 (s, 3H), 2.29 (s, 3H), 2.30 (m, 2H), 2.
60 (m, 1H), 3.93 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 9Hz), 4.32
(d, 1H, J = 9Hz), 4.21 (s, 1H), 4.26 (m, 1H), 4.83 (m, 1H),
4.95 (d, 1H, J = 8Hz), 5.12 (m, 2H), 5.21 (s, 1H), 5.68 (d, 1
H, J = 7Hz), 6.25 (t, 1H, J = 8.5Hz), 7.45 (t, 2H, J = 7.5Hz),
7.62 (t, 1H, J = 7.5Hz), 8.08 (d, 2H, J = 7.5Hz) MS-FAB: 806 (M ⁺ )

Isomer B Melting point: 155 ° C. ¹ H-NMR (CDCl ₃ / TMS) δ (ppm): 1.13 (s, 3H), 1.23 (s, 3
H), 1.43 (s, 9H), 1.76 (s, 3H), 1.79 (m, 6H), 1.85 (m, 1H),
2.01 (s, 3H), 2.28 (s, 3H), 2.30 (m, 2H), 2.60 (m, 1H), 3.
93 (d, 1H, J = 7Hz), 4.17 (d, 1H, J = 9Hz), 4.32 (d, 1H, J = 9H
z), 4.27 (m, 1H), 4.78 (m, 1H), 4.95 (d, 1H, J = 8Hz), 5.10
(m, 2H), 5.23 (s, 1H), 5.69 (d, 1H, J = 7Hz), 6.16 (t, 1H, J = 8
Hz), 7.50 (t, 2H, J = 7.5Hz), 7.62 (t, 1H, J = 7.5Hz), 8.07
(d, 2H, J = 7.5Hz) MS-FAB: 806 (M ⁺ )

[0359]

[Table 1]

[0360]

[Table 2]

^T Bu; tertiary butyl group, Ph; phenyl group,
Ac; Acetyl group.

[0362]

The following experimental examples show the antitumor effect of the compounds of the present invention.

Experimental Example Three types of tumor cells, PC-12, PC-6 and P388, were each used as PC.
-12 is 1.0 × 10 ³ cells / 150 μl / well, PC-6 is 5.0 × 10
³ cells / 150 μl / well, P388 5.0 × 10 ² cells / 150
96 well-microplates were seeded so as to have a volume of μl / well, and P388 was added after 2 hours and the other two were added after 24 hours at 50 μl / well. Then, cultivate for 3 days,
4 hours before the end of drug contact, MTT [3- (4,5-Dimethylthiazol
-2-yl) -2,5-diphenyl-2H-tetrazolium bromide] 5 m
20 μl / well of g / ml solution was added. Then, after removing the culture solution, 150 μl / well of dimethyl sulfoxide was added, and the absorbance was measured at 540 nm. The antitumor effect was shown as a GI ₅₀ value at a drug concentration at which the cell growth in the drug-added group was halved compared to the control group.

[0364]

[Table 3] GI ₅₀ ; 50% growth inhibitory concentration (ng / ml)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07D 407/12 305 // A61K 31/335 ADU 31/34

Claims (16)

[Claims] 1. A compound represented by the general formula (I): [In the formula, X represents a halogen atom, R ¹ is an amino group having a protecting group, a hydroxyl group having a protecting group, or a group represented by —Z—R ⁶ (R ⁶ is a hydrogen atom, an alkyl group, a substituent Alkyl group having a group, alkenyl group, alkenyl group having a substituent, alkynyl group, alkynyl group having a substituent, aryl group, aryl group having a substituent, cycloalkyl group, or cycloalkyl group having a substituent Z is -NH-, -O-, -COO-, -OCO-, -NHCO-, -CONH-, -NHCOO-, -OC.
It means a group represented by ONH-, -NHCONH-, or -NHCOCONH-. R ² is an alkyl group, an alkyl group having a substituent, an alkenyl group, an alkenyl group having a substituent, an alkynyl group, an alkynyl group having a substituent, an aryl group, an aryl group having a substituent, cycloalkyl Group, a cycloalkyl group having a substituent, or a saturated or unsaturated heterocyclic group (wherein the heterocyclic group is at least one atom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as a constituent atom of the ring structure). The heterocyclic group may contain a plurality of groups, and the heterocyclic group is a hydroxyl group, a halogen atom, an alkyl group, an alkoxyl group, a phenyl group, an amino group, an alkylamino group,
Aminoalkyl group, alkylaminoalkyl group, alkylcarbonyl group, arylcarbonyl group, alkyloxycarbonyl group, aryloxycarbonyl group, alkylcarbonyloxy group, arylcarbonyloxy group,
It may have one or more groups selected from the group consisting of an alkylcarbonylamino group and an arylcarbonylamino group as a substituent. ), R ³ means a hydrogen atom, an alkyl group or a halogen atom, R ⁴ means a hydrogen atom or a hydroxyl-protecting group, and R ⁵ means a hydrogen atom or a hydroxyl-protecting group. ] Compound represented by 2. The compound according to claim 1, wherein X is a fluorine atom. ^3. The compound according to claim 1 or 2, wherein R ³ is a fluorine atom. 4. The compound according to claim 1, 2 or 3, wherein R ⁴ is a hydrogen atom or an acetyl group. 5. R ¹ is a group The compound according to claim 1, claim 2, claim 3 or claim 4 which is 6. R ¹ is a group The compound according to claim 1, claim 2, claim 3 or claim 4 which is 7. The compound and salt thereof according to claim 1, wherein R ² is an aryl group. 8. The compound and salt thereof according to claim 1, wherein R ² is a phenyl group. 9. The compound according to any one of claims 1 to 6 and a salt thereof, wherein R ² is a heterocyclic group. 10. The compound or salt thereof according to claim 9, wherein the heterocyclic group is a monocyclic heterocyclic group. 11. The compound or a salt thereof according to claim 9, wherein the heterocyclic group is a monocyclic heterocyclic group having a size of 5 to 6 membered rings. 12. The heterocyclic group having a size of a monocyclic 5- to 6-membered ring and containing one oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure. Item 9
Described compounds and salts thereof 13. The unsaturated heterocyclic group wherein the heterocyclic group is a monocyclic 5- to 6-membered ring and contains one oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure. 10. The compound according to claim 9 and a salt thereof 14. Formula (II): Compounds with the structure 15. A compound represented by the formula (III): Compounds with the structure 16. A compound of formula (IV): Compounds with the structure