JP2969617B2 - Baccatin derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a baccatin derivative which is a synthetic intermediate of a taxol derivative useful as an antitumor agent, and a method for producing the same.

[0002]

2. Description of the Related Art Western yew (Taxus brevif)
taxa obtained from the bark of olia [chemical name: 4
α, 10β-diacetoxy-2α-benzoyloxy-
5β, 20-epoxy-1β, 7β-dihydroxy-1
3α-[(2R, 3S) -3-phenyl-3-benzoylamino-2-hydroxypropionyloxy] -tax-11-en-9-one] and its derivative N-
Debenzoyl-N- (t-butoxycarbonyl) -10
-Deacetyltaxol [chemical name: 4α-acetoxy-
2α-benzoyloxy-5β, 20-epoxy-1
β, 7β, 10β-trihydroxy-13α-[(2
[R, 3S) -3-phenyl-3- (t-butoxycarbonylamino) -2-hydroxypropionyloxy]-
Takis-11-en-9-one] is known to have an excellent antitumor action against ovarian cancer, thymus and other cancers [Annual Reports in Medicinal Chemistry (Anal Reports in Me).
(Digital Chemistry), Chapter 32, 3
05 (1993)].

[0003] Among the taxane derivatives, a compound in which the side chain at the 13-position of the taxane skeleton is a hydroxyl group is known as a baccatin compound, and is named as baccatin I-VII or the like by a substituent on the taxane skeleton. [Dictionary of Organic Compounds (Dic
Tionary of Organic Compou
nds), 4th edition (3rd supplementary edition), page 506 (1985)
Year)〕.

Baccatin compounds Taxol and N-debenzoyl- are introduced by introducing a side chain into the hydroxyl group substituted at the 13-position.
Various attempts have been made to produce N- (t-butoxycarbonyl) -10-deacetyltaxol. For example, (A) a baccatin compound and a hydroxyl-protected N-
A method of reacting benzoyl-3-phenyl isoserine in the presence of a condensing agent [Journal of American Chemical Society (Journal of Am)
erican Chemical Society),
110, 5917 (1988)], (B) a method of reacting a baccatin compound with a 4-phenylazetidinone compound (JP-A-6-1782), and (C) a method of reacting a baccatin compound with an oxazolidine compound. [Tetrahedron Letters
Letters), Vol. 36, 5185
(1992)], (D) a method of reacting baccatin with cinnamoyl chloride and osmium-oxidizing the resulting ester in the presence of sodium t-butylchlorocarbamate (JP-A-63-30478; 30479
No.) etc. are known.

However, the method (A) has a long reaction time and a low yield even when N-benzoyl-3-phenylisoserine is used in excess, and the methods (B) and (C) require a long reaction time. The steps of producing the 4-phenyl-azetidinone compound and the oxazolidine compound are complicated, and the method (D) allows the reaction to proceed only regioselectively (non-regioselective) and stereo-nonselectively (non-stereoselective). Therefore, there was a problem that the yield of taxol and the like was low.

[0006]

DISCLOSURE OF THE INVENTION The present invention provides an important synthetic intermediate for producing taxol and the like by efficiently introducing a side chain into a hydroxyl group at the 13-position of a baccatin compound using a raw material that can be synthesized by a simple method. It is intended to provide a method for efficiently producing a baccatin derivative, which is a body, and a novel synthetic intermediate produced in the course of its synthesis.

[0007]

According to the present invention, there are provided: (1) a general formula [II]

[0008]

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Wherein R ¹ represents a lower alkanoyl group or a hydroxyl-protecting group, R ² represents a hydroxyl-protecting group, R ³ represents a lower alkanoyl group, and R ⁴ represents a substituted or unsubstituted benzoyl group. Baccatin compound and general formula [I]

[0010]

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Wherein X represents a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkenyl group or an unsubstituted lower alkynyl group, or a reactive derivative thereof. General formula [III]

[0012]

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(Wherein the symbols have the same meanings as described above): (2) (i) Azide of this compound or
(Ii) halogenating this compound to give a compound of the general formula [IV]

[0014]

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(Wherein A represents a halogen atom, and other symbols have the same meanings as described above).
(3-halogeno-2-hydroxypropionyloxy)
By obtaining a baccatin compound and azideting this compound, a compound of the general formula [V]

[0016]

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(Wherein the symbols have the same meanings as above) to obtain a 13α- (3-azido-2-hydroxypropionyloxy) baccatin compound represented by the formula: (3) This compound is reduced, if necessary. By converting the product to a salt, the compound represented by the general formula [VI]

[0018]

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(Wherein the symbols have the same meanings as described above), and a 13α- (3-amino-2-hydroxypropionyloxy) baccatin derivative or a salt thereof can be produced.

The method of the present invention comprises the above general formulas [I] and [I
As the aryl group of II], [IV], [V] and [VI], an aromatic hydrocarbon cyclic group (for example, a phenyl group,
A naphthyl group) or an aromatic heterocyclic group (for example, a furyl group, a thienyl group, a pyridyl group) and the like. As the substituent on the lower alkenyl group or the lower alkynyl group, a lower alkoxy group (for example, methoxy group) Group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group) or a halogen atom.

Examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom, an iodine atom and the like.
As the hydroxyl-protecting group, a conventional hydroxyl-protecting group that can be easily removed by a conventional method can be used.

Specifically, the method of the present invention is characterized in that R ¹ is a lower alkanoyl group (for example, acetyl, propoxy,
Butyryl group, pentanoyl group), or a trihalo lower alkoxycarbonyl group (e.g., trichloroethoxycarbonyl group), a tri-lower alkylsilyl group (e.g., trimethylsilyl group, protecting groups such as hydroxyl groups of the triethylsilyl group); R ² is trihalo lower alkoxy A protecting group for a hydroxyl group such as a carbonyl group (eg, trichloroethoxycarbonyl group) and a tri-lower alkylsilyl group (eg, trimethylsilyl group, triethylsilyl group); R ³ is a lower alkanoyl group (eg, acetyl group, propionyl group, butyryl group); , pentanoyl group); R ⁴ is an unsubstituted benzoyl group or substituted benzoyl group (e.g., lower alkyl group, a lower alkoxy group, a benzoyl group substituted with halogen atom); X is an unsubstituted phenyl group, substituted phenyl group (e.g., Lower alkyl group A lower alkoxy group, a halogen phenyl group substituted with atoms) or unsubstituted lower alkenyl group (e.g., can be preferably applied when a vinyl group), R ¹ is acetyl group or trichloroethoxycarbonyl group, R ² is trichloroethoxycarbonyl It is particularly preferably applicable when a carbonyl group, R ³ is an acetyl group, R ⁴ is an unsubstituted benzoyl group, X is a halogenophenyl group or an unsubstituted phenyl group, and A is a bromine atom.

In the present invention, the epoxypropionic acid compound [I] has four stereoisomers [(2R, 3S) type or (2
(S, 3R) trans isomer and (2R, 3R)
R) type or (2S, 3S) type cis isomer], and 13α-epoxypropionyloxybaccatin compound [III], 13α- (3-halogeno-2)
-Hydroxypropionyloxy) baccatin compound [IV], 13α- (3-azido-2-hydroxypropionyloxy) baccatin compound [V] and 13α-
(3-Amino-2-hydroxypropionyloxy) baccatin derivative [VI] has a 2
Four stereoisomers [(2R, 3
S) type, (2S, 3R) type, (2R, 3R) type or (2S, 3S) type isomer]. The method of the present invention includes any isomer or a mixture thereof.

In the present invention, when the process (i) is carried out, the configuration of the (2R, 3R) or (2S, 3S) type epoxypropionic acid [I] and the side chain at the 13-position is (2R, 3R). 13α of the (3R) or (2S, 3S) type
-(Epoxypropionyloxy) baccatin compound [III], 13α-[(2R, 3S) or (2
(S, 3R) -3-azido-2-hydroxypropionyloxy] baccatin compound [V] and 13α-[(2
R, 3S) or (2S, 3R) -3-amino-2-
(Hydroxypropionyloxy) baccatin derivative [V
I]. Among them, the (2R, 3R) epoxypropionic acid compound [I], the 13α- (epoxypropionyloxy) baccatin compound [III], 13α- [(2R, 3S) -3-azido-2-hydroxypropionyloxy] baccatin compound [V] and 13α-[(2R, 3S) -3-amino-2-hydroxypropionyloxy] baccatin derivative [VI] It can be suitably implemented.

On the other hand, when going through the step (ii),
(2R, 3S) -type or (2S, 3R) -type epoxypropionic acid compound [I], 13α-having a configuration of side chain 13 at (2R, 3S) or (2S, 3R)
(Epoxypropionyloxy) baccatin compound [I
II], 13α-[(2S, 3R) or (2R, 3R
S) -3-halogeno-2-hydroxypropionyloxy] baccatin compound [IV], 13α-[(2R, 3
S) or (2S, 3R) -3-azido-2-hydroxypropionyloxy] baccatin compound [V] and 13α-[(2R, 3S) or (2S, 3R) -3
-Amino-2-hydroxypropionyloxy] baccatin derivative [VI]. Among them, the (2R, 3S) type epoxypropionic acid compound [I], and the configuration of the side chain at position 13 is (2R, 3S).
13α- (epoxypropionyloxy) which is 3S)
Baccatin compound [III], 13α-[(2S, 3
R) -3-halogeno-2-hydroxypropionyloxy] baccatin compound [IV], 13α-[(2R, 3
S) -3-Azido-2-hydroxypropionyloxy] baccatin compound [V] and 13α-[(2R, 3
S) -3-Amino-2-hydroxypropionyloxy] baccatin derivative [VI].

The condensation of the baccatin compound [II] with the epoxypropionic acid compound [I] or a reactive derivative thereof can be carried out in a suitable solvent. Examples of the solvent include aromatic solvents (eg, benzene, toluene, xylene, etc.), and examples of the reactive derivative include acid halides (eg, acid chloride, acid bromide, acid iodide), active esters (eg, p -Nitrophenyl ester) and mixed acid anhydrides (for example, mixed acid anhydrides with methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid). Baccatin compound [I
The condensation of the compound [I] with the epoxypropionic acid compound [I] can be carried out using a condensing agent. As the condensing agent, N, N'-dicyclohexylcarbodiimide, N, N '
-Carbonyldiimidazole, azodicarboxylic acid di-lower alkyl ester (for example, azodicarboxylic acid dimethyl ester), 1-methyl-2-halopyridinium iodide (for example, 1-methyl-2-bromopyridinium iodide) and the like are used. be able to. This condensation reaction is preferably performed in the presence of an organic base. As the organic base, an aromatic tertiary amine [eg, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline] is used. it can. On the other hand, the condensation of the baccatin compound [II] and the reactive derivative of the epoxypropionic acid compound [I] can be carried out in the presence or absence of a deoxidizing agent. As the deoxidizing agent, an organic base (for example, Pyridine, triethylamine, N-methylpiperidine, N-methylmorpholine, N-ethyl-N, N-diisopropylamine)
Can be used. This reaction can be carried out under cooling to heating, and is particularly preferably carried out at 18 ° C to 80 ° C.

The following (i) azidation of the 13α-epoxypropionyloxybaccatin compound [III] can be carried out by reacting with a metal azide in a suitable solvent or without a solvent. As the metal azide, alkali metal azide (eg, lithium azide, sodium azide, potassium azide) and tri-lower alkyltin azide (eg, tri-n-butyltin azide) are preferably used. Can be. When an alkali metal azide is used, water or a mixture of water and a hydrophilic solvent (eg, an alcohol solvent such as methanol, ethanol, propyl alcohol, butanol, or a ketone solvent such as acetone) is used as the solvent; Organic solvents (eg, dimethylsulfoxide, dimethylformamide, dimethylacetamide) can be used. The reaction is preferably performed in the presence of an abasic agent (for example, a formate such as methyl formate or an ammonium salt such as ammonium chloride). On the other hand, when a tri-lower alkyltin azide is used, the reaction can be carried out without solvent, and if necessary, an aprotic organic solvent (for example, dimethylsulfoxide, dimethylformamide, dimethylacetamide) can be added. Good. The reaction can be accelerated by adding a Lewis acid (eg, zinc bromide, zinc iodide, tin bromide, tin iodide). This reaction can be carried out under cooling to heating, and particularly preferably at 20 ° C to 60 ° C.

This azide reaction can be carried out regioselectively and stereoselectively. Since the 3-position of the epoxypropionyl group is substituted by an azide group by SN2 reaction, 13
(2S, 3R) type, (2R, 3S)
Type, (2S, 3S) type or (2R, 3R) type 13α
-If epoxypropionic acid [I] is used, the corresponding (2S, 3S) type, (2R, 3R) type, (2
(Α, 3R) type or (2R, 3S) type 13α- (3-
An azido-2-hydroxypropionyloxy) baccatin derivative [V] is obtained. (Ii) 13α-epoxypropionyloxybaccatin compound [III]
Can be carried out in a solvent in the presence of a Lewis acid and a halogenating agent. Examples of the Lewis acid include titanium halides (for example, titanium tetrachloride, titanium tetrabromide,
Titanium tetraiodide, tin halide (eg, tin tetrachloride, tin tetrabromide, tin tetraiodide), magnesium halide (eg, magnesium chloride, magnesium bromide,
Magnesium iodide), di-lower alkylaluminum halides (eg, diethylaluminum chloride) and the like. Examples of the halogenating agent include di-lower alkylamine / hydrohalide (eg, diethylamine hydrochloride, diethylamine hydrobromide, diethylamine hydroiodide) and the like.
When titanium halide, tin halide, magnesium halide or the like is used as the Lewis acid, these compounds also act as a halogenating agent, so that it is not necessary to separately add a halogenating agent. As the solvent, a halogenated hydrocarbon solvent (eg, dichloromethane, chloroform), an ether solvent (eg, tetrahydrofuran, diethyl ether) or an aromatic solvent (eg, toluene, nitrobenzene) and an aprotic polar solvent [eg, A mixed solvent of hexamethylphosphoric triamide (HMPA), dimethylformamide, and dimethylimidazolidinone] is preferably used, and a mixed solvent of a halogenated hydrocarbon solvent and HMPA is particularly preferable. The mixing ratio of the halogenated hydrocarbon solvent and HMPA is as follows: halogenated hydrocarbon solvent: HMPA
= 1: 0 to 0: 1, particularly 20: 1 to 5: 1. This reaction can be carried out under cooling to heating, and particularly preferably at -70 to 0 ° C.

This halogenation reaction is also regioselective and
In order to proceed stereoselectively and to always cleave the 3-position of the epoxypropionyloxy group by SN2 reaction, the configuration of the side chain at the 13-position is (2R, 3S) type, (2
(S, 3R) type, (2R, 3R) type or (2S, 3S)
When the 13α- (epoxypropionyloxy) baccatin compound [III] is used, the corresponding (2S, 3R) type, (2R, 3S) type, (2S, 3S)
Type or (2R, 3R) type 13α- (3-halogeno-
2-hydroxypropionyloxy) baccatin compound [IV] is obtained.

The obtained 13α- (3-halogeno-2-hydroxypropionyloxy) baccatin compound [I
V] is optionally protected by protecting the 2-position hydroxyl group in the 13-position side chain and reacting with a metal azide in a suitable solvent in the presence or absence of a metal clathrate (metal chelating agent); When the hydroxyl group is protected, it can be carried out by removing the protecting group.

When protecting the 2-position hydroxyl group in the 13-position side chain, a conventional hydroxyl-protecting group which can be easily removed by a conventional method can be used as the protecting group. For example, a tri-lower alkylsilyl group ( Examples thereof include a trimethylsilyl group and a triethylsilyl group). As the metal clathrate, crown ethers (for example, 1,
4,7,10-tetraoxacyclododecane, 1,4
7,10,13-pentaoxacyclopentadecane,
1,4,7,10,13,16-hexaoxacyclooctadodecane);
4,7,10,13-Pentaoxacyclopentadecane is preferred. As the metal azide, the solvent and the reaction conditions,
The same metal azide and solvent can be used as in the case of azifying 13α-epoxypropionyloxybaccatin compound [III], and the reaction can be performed under the same reaction conditions.

This azidation reaction can also be carried out stereoselectively, and the 3-halogeno-2-propionyloxy group can be used.
Position is substituted with an azide group by SN2 reaction, so that the configuration of the side chain at position 13 is (2S, 3R) type, (2R, 3S)
Type, (2S, 3S) type or (2R, 3R) type 13α
When-(3-halogeno-2-hydroxypropionyloxy) baccatin compound [IV] is used, the corresponding (2R, 3S) type, (2S, 3R) type, (2
R, 3R) type or (2S, 3S) type 13α- (3-
An azido-2-hydroxypropionyloxy) baccatin derivative [V] is obtained.

The thus obtained 13α- (3-azido-
2-Hydroxypropionyloxy) baccatin compound [V] is subjected to (1) reduction reaction to give a compound of the general formula [VI]

[0034]

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(Wherein the symbols have the same meanings as described above), to give a 13α- (3-amino-2-hydroxypropionyloxy) baccatin compound represented by the general formula [VII]:

[0036]

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Wherein R ⁵ is a substituted or unsubstituted phenyl-
Represents a lower alkoxycarbonyl group, a substituted or unsubstituted lower alkoxycarbonyl group or a substituted or unsubstituted benzoyl group. ), A salt thereof or a reactive derivative thereof, to give a compound of the general formula [VIII]

[0038]

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(Wherein the symbols have the same meanings as described above), thereby obtaining a 13α- (3-acylamino-2-hydroxypropionyloxy) baccatin compound represented by the formula:
The protecting group is removed from this compound, or (2) a 13α- (3-acylamino-2-hydroxypropionyloxy) baccatin compound [VIII is subjected to a reduction reaction in the presence of a reactive derivative of compound [VII]. ]
By removing the protecting group from this compound, the compound represented by the general formula [IX]

[0040]

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(In the formula, R ¹¹ represents a lower alkanoyl group or a hydrogen atom, and other symbols have the same meanings as described above.)
Can be produced.
The taxol derivative represented by the general formula [IX] is useful as an antitumor agent or as a synthetic intermediate of the antitumor agent, such as taxol, N-debenzoyl-N- (t-butoxycarbonyl) -10-deacetyltaxol and the like. JP-A-63-30479, JP-A-6-1782, French Patent Publication FR2698363, International Patent Application Publication WO 92/09589, Bio-Organic and Medicinal Chemistry Letters (B
ioorganic & Medicinal Chemistry Letters), Volume 4,
2631 (1994).

The reduction of 13α- (3-azido-2-hydroxypropionyloxy) baccatin compound [V]
It can be carried out in a suitable solvent, and as the solvent, use is made of an alcohol-based solvent (eg, methanol, ethanol, propanol, butanol), an ether-based solvent (eg, tetrahydrofuran, dioxane), acetic acid, and a mixed solvent thereof. Can be. The reduction reaction may be carried out by catalytic reduction in the presence of a metal catalyst (e.g., palladium-carbon) or by using a reducing agent (e.g., triphenylphosphine). When triphenylphosphine is used, Preferably, a small amount of water is added.

The resulting 13α- (3-amino-2)
-Hydroxypropionyloxy) baccatin derivative [VI] can be treated with a suitable acid (for example, formic acid) according to a conventional method to give an acid addition salt, if necessary.

The condensation of 13α- (3-amino-2-hydroxypropionyloxy) baccatin derivative [VI] or a salt thereof with compound [VII], a salt thereof or a reactive derivative thereof is carried out in a suitable solvent or without a solvent. Can be implemented. As the solvent, an organic solvent (eg, a halogenated hydrocarbon solvent such as methylene chloride, an ether solvent such as tetrahydrofuran, or an aprotic organic solvent such as dimethylformamide) can be used. The same acid halides and mixed acid anhydrides as in the case of the propionic acid compound [I] can be used.
The condensation of 13α- (3-amino-2-hydroxypropionyloxy) baccatin derivative [VI] or a salt thereof with compound [VII] is the same as the condensation of baccatin compound [II] with epoxypropionic acid compound [I]. The reaction can be carried out under the same conditions as a condensing agent, the same organic base, and the same conditions. Condensation is performed using the same condensing agent, the same organic base as the condensation of the baccatin compound [II] and the reactive derivative of the epoxypropionic acid compound [I],
It can be carried out under similar reaction conditions.

The resulting 13α- (3-acylamino-2)
-Hydroxypropionyloxy) baccatin compound [VIII] can be appropriately removed according to a conventional method according to the type of the protecting group. When the protecting group is a trihalo lower alkoxycarbonyl group, zinc-
It can be easily removed by acetic acid treatment or the like.

The reduction of 13α- (3-azido-2-hydroxypropionyloxy) baccatin compound [V] in the presence of a reactive derivative of compound [VII] can be carried out in a suitable solvent. As the reactive derivative of [VII], an acid anhydride, a mixed acid anhydride with carbonic acid and the like can be suitably used, and as a solvent, a halogenated hydrocarbon solvent (eg, methylene chloride, chloroform), an aromatic solvent Solvents (eg, toluene, benzene) can be suitably used. The reduction reaction can be carried out using a reducing agent (for example, triphenylphosphine), and it is preferable to add a small amount of water.

The epoxypropionic acid compound [I], which is the starting compound of the present invention, can be produced by hydrolyzing the corresponding epoxypropionic acid ester with a base (for example, an alkali metal hydroxide) by a conventional method. . Among the corresponding epoxypropionates, the trans ester is, for example, a substituted or unsubstituted aryl aldehyde, a substituted or unsubstituted lower alkenyl aldehyde, a substituted or unsubstituted lower alkynyl aldehyde and a haloacetic acid ester, Darzens (Darzen).
s) The reaction can be carried out according to a conventional method and, if necessary, can be produced by optical resolution [JP-A-60-13775 and JP-A-13776, JP-A-3-15398, Journal of Organic Kennistry (Journ)
al. Organic Chemistry), vol. 58, p. 1287 (1993) and the like]. On the other hand, a cis-type ester is produced by, for example, converting a trans-substituted or unsubstituted cinnamate into a dihydroxy form by Shaless oxidation, forming a reactive monoester, and then subjecting the ring to intramolecular ring closure by base treatment [ Journal of Organic Chemistry (Journa
l of Organic Chemistry), 5
1, page 46 (1986), or according to the method described in International Patent Application Publication WO 92/09589, substituted or unsubstituted aryl aldehyde, substituted or unsubstituted lower alkenyl aldehyde, or substituted or unsubstituted lower alkynyl aldehyde And if necessary optically active N-
The (2-halogenopropionyl) -2-oxazolidinone derivative is subjected to aldol condensation according to a conventional method, and the obtained compound is subjected to a dehydrohalogenation reaction to form an oxirane ring. Can be manufactured.

In the present specification, the taxane skeleton represents a diterpene skeleton represented by the following formula, and a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group and a lower alkanoyl group each have a carbon number of It means an alkyl group having 1-5, a lower alkenyl group having 2-6 carbon atoms, a lower alkynyl group having 2-6 carbon atoms, an alkoxy group having 1-5 carbon atoms, and an alkanoyl group having 2-6 carbon atoms.

[0049]

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[0050]

【Example】

Example 1 (1) A solution of 1.78 g of (2R, 3R) -3-phenyl-2,3-epoxypropionic acid methyl ester in 50 ml of methanol was added with 0.1 ml of lithium hydroxide monohydrate under ice-cooling.
A solution of 504 g in 25 ml of water is added dropwise. The mixture is warmed to room temperature and stirred at the same temperature for 1 hour. The methanol was distilled off from the reaction solution, and the residue was adjusted to pH 3-4 by adding a 5% aqueous citric acid solution under ice-cooling. The residue was extracted with chloroform, the chloroform layer was washed with brine, and dried over magnesium sulfate. I do. The solvent was distilled off under reduced pressure, hexane was added to the residue, and the precipitated crystals were collected by filtration, washed with hexane, and dried to give (2R, 3R) -3-phenyl-2,3.
1.32 g of epoxypropionic acid are obtained. Yield: 80
%.

M. p. 81.5-83.0 ° C IR (nujol) ν _max (cm ^-1 ): 3140, 17
50, 1720, 1460, 1200 FAB-MS (m / z): 165 (MH ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 3.83 (1H, d,
J = 4.7 Hz), 4.31 (1 H, d, J = 4.7 H)
z), 7.1-7.4 (5H, m), 8.2 (1H, b
load s).

(2) (2R, 3R) -3-phenyl-
1.376 g of 2,3-epoxypropionic acid and 4α-
Acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 13α-dihydroxy-7β, 10β-
4.998 g of di (2,2,2-trichloroethoxycarbonyloxy) -tax-11-en-9-one are dissolved in 250 ml of toluene. In this solution, N, N'-
1.844 g of dicyclohexylcarbodiimide and 4-
0.34 g of (N, N-dimethylamino) pyridine are added and the mixture is stirred at 80 ° C. for 1 hour 30 minutes. After cooling the reaction mixture to room temperature, insolubles are removed by filtration, and the solvent is distilled off from the filtrate under reduced pressure. The residue was subjected to silica gel flash column chromatography [solvent: ethyl acetate-hexane (2:
5)] to give 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-
7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3R) -3-phenyl-2,3-epoxypropionyloxy] -tax-11-en-9-one 5 0.734 g are obtained. yield:
99%.

[Α] (20, D) =-15.77 ° (c
= 0.9, chloroform) IR (nujol) ν _max (cm ^-1 ): 3500, 17
60, 1730, 1460, 1380, 1250, 10
60 FAB-MS (m / z): 1039 (MH ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 1.14 (6H,
s), 1.58 (1H, s), 1.83 (6H, s),
1.95-2.1 (3H, m), 2.39 (3H,
s), 2.63 (1H, m), 3.87 (1H, d, J
= 7 Hz), 3.97 (1H, d, J = 4.5 Hz),
4.14 (1H, d, J = 9 Hz), 4.30 (1H,
d, J = 9 Hz), 4.33 (1 H, d, J = 4.5 H)
z), 4.60 (1H, d, J = 11.8 Hz);
76 (2H, s), 4.92 (1H, d, J = 11.8)
Hz), 4.97 (1H, m), 5.55 (1H, d
d, J = 7, 11 Hz), 5.63 (1H, d, J =
7Hz), 6.03 (1H, m), 6.19 (1H,
s), 7.3-7.5 (7H, m), 7.64 (1H,
m), 8.00 (2H, m).

(3-1) 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R , 3R) -3
-Phenyl-2,3-epoxypropionyloxy]-
105 mg of Takis-11-en-9-one in 0.3 m of water
and 2.7 ml of methanol in a mixed solvent. To this solution 0.3 ml of methyl formate and 195 mg of sodium azide are added and the mixture is stirred at 50 ° C. for 40 hours. After cooling the reaction mixture to room temperature, it is poured into cold water, and the water mixture is extracted with ethyl acetate. The extract is washed with a 5% aqueous citric acid solution and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography [solvent: ethyl acetate-chloroform (1:
20)] to give 4α-acetoxy-2
α-benzoyloxy-5β, 20-epoxy-1β-
Hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3
S) -3-Phenyl-3-azido-2-hydroxypropionyloxy] -tax-11-en-9-one 92
mg. Yield: 85%.

[Α] (22, D) = − 16.43 ° (c
= 1, chloroform) IR (nujol) ν _max (cm ⁻¹ ): 3480, 21
10, 1760, 1730, 1460, 1380, 12
50 FAB-MS (m / z): 1082 (MH ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H,
s), 1.27 (3H, s), 1.70 (1H, s),
1.86 (3H, s), 2.09 (3H, d, J = 1H
z), 2.0-2.2 (3H, m), 2.30 (3H,
s), 2.63 (1H, m), 3.12 (1H, d, J
= 8 Hz), 3.90 (1H, d, J = 7 Hz), 4.
16 (1H, d, J = 8 Hz), 4.32 (1H, d,
J = 8 Hz), 4.44 (1H, dd, J = 4, 8H)
z), 4.61 (1H, d, J = 12 Hz), 4.7
6 (1H, d, J = 12 Hz), 4.82 (1H, d,
J = 12 Hz), 4.92 (1H, d, J = 12H)
z), 4.95 (1H, m), 5.01 (1H, d, J
= 4 Hz), 5.56 (1H, dd, J = 7, 11H
z), 5.68 (1H, d, J = 7 Hz), 6.22
(1H, m), 6.27 (1H, s), 7.46 (5
H, m), 7.51 (2H, m), 7.64 (1H,
m), 8.06 (2H, m).

(3-2) 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R , 3R) -3
-Phenyl-2,3-epoxypropionyloxy]-
104 mg of Taki-11-en-9-one was dissolved in 1 ml of tri-n-butyltin azide at 50 ° C., and zinc iodide 6
Add mg and stir at 50 ° C for 5 days. The reaction mixture was returned to room temperature and subjected to silica gel chromatography [solvent:
Chloroform], followed by thin layer chromatography [solvent: ethyl acetate-chloroform (1:20)] to give 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-
7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3S) -3-phenyl-3-azido-2-hydroxypropionyloxy] -tax-11-en-9- 73 mg are obtained.
Yield: 67%.

(4-1) 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R , 3S) -3
-Phenyl-3-azido-2-hydroxypropionyloxy] -tax-11-en-9-one (92 mg) was dissolved in methanol (4 ml), and 10% palladium-carbon 47 was dissolved.
The mixture is stirred for 2 hours at room temperature under a hydrogen atmosphere of 1 atm. The inorganic substance was removed by filtration from the reaction solution, and the filtrate was concentrated under reduced pressure to obtain crude 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β,
10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3S) -3-phenyl-3-amino-2-hydroxypropionyloxy]-
90 mg of Takis-11-en-9-one are obtained. This was dissolved in 4 ml of tetrahydrofuran, 39.7 mg of t-butoxycarboxylic anhydride and 25.25 kg of potassium hydrogen carbonate.
Add 5 mg and stir at room temperature for 19 hours. The reaction mixture is diluted with ethyl acetate, washed with water and saturated saline, dried, and then the organic layer is concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography [solvent: ethyl acetate-hexane (2: 3)] to give 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1.
β-hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2
[R, 3S) -3-phenyl-3- (t-butoxycarbonylamino) -2-hydroxypropionyloxy]-
69 mg of Takis-11-en-9-one are obtained. yield:
70%.

[Α] (20, D) = − 39.0 ° (c =
1, chloroform) IR (nujol) ν _max (cm ⁻¹ ): 3440, 17
60, 1720 FAB-MS (m / z): 1156 (MH ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H,
s), 1.28 (3H, s), 1.35 (9H, s),
1.71 (1H, s), 1.86 (3H, s), 1.9
6 (3H, s), 2.01-2.12 (1H, m),
2.33 (2H, m), 2.39 (3H, s), 2.5
6-2.69 (1H, m), 3.33 (1H, d, J =
5.4 Hz), 3.91 (1H, d, J = 6.9H)
z), 4.18 (1H, d, J = 8 Hz), 4.34
(1H, d, J = 8 Hz), 4.60 (1H, d, J =
12Hz), 4.62-4.67 (1H, m), 4.7
8 (2H, m), 4.91 (1H, d, J = 12H
z), 4.93-4.98 (1H, m), 5.22-
5.39 (1H, m), 5.38 (1H, d, J = 9.
4Hz), 5.55 (1H, dd, J = 7, 11H)
z), 5.70 (1H, d, J = 6.9 Hz), 6.1
7-6.25 (1H, m), 6.25 (1H, s),
7.29-7.45 (5H, m), 7.46-7.54
(2H, m), 7.59-7.66 (1H, m), 8.
08-8.13 (2H, m).

(4-2) 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R , 3S) -3
-Phenyl-3-azido-2-hydroxypropionyloxy] -tax-11-en-9-one (92 mg) was dissolved in a mixture of tetrahydrofuran (5 ml) and water (0.2 ml), and triphenylphosphine (25 mg) was added.
After stirring for 8 hours, 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-
7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3S) -3-phenyl-3-amino-2-hydroxypropionyloxy] -tax-11-en-9- A reaction solution containing ON is obtained. T-butoxycarboxylic anhydride 39.7 was added to the reaction mixture.
mg and 25.5 mg of potassium bicarbonate are added and stirred at room temperature for 19 hours. The solvent was distilled off from the reaction solution under reduced pressure,
The residue was purified by silica gel thin-layer chromatography [solvent: ethyl acetate-hexane (2: 3)] to give
4α-acetoxy-2α-benzoyloxy-5β, 2
0-epoxy-1β-hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy)
-13α-[(2R, 3S) -3-phenyl-3- (t
-Butoxycarbonylamino) -2-hydroxypropionyloxy] -tax-11-en-9-one 75m
g. Yield: 76%.

(4-3) 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R , 3S) -3
-Phenyl-3-azido-2-hydroxypropionyloxy] -tax-11-en-9-one 57.3 mg
Was dissolved in methylene chloride (2 ml), t-butoxycarboxylic acid anhydride (36.3 mg), potassium hydrogen carbonate (26 mg), triphenylphosphine (28.5 mg) and water (0.05 ml)
And stirred at room temperature for 20 hours. The solvent was distilled off from the reaction mixture, and the residue was purified by silica gel thin layer chromatography [solvent: ethyl acetate-hexane (2: 3)] to give 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy- 1β-hydroxy-7
β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3S) -3-phenyl-3- (t-butoxycarbonylamino) -2-hydroxypropionyloxy] -tax- 11-en-
46 mg of 9-one are obtained. Yield: 75%.

(5) 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-
7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3S) -3-phenyl-3- (t-butoxycarbonylamino) -2-
273 mg of [hydroxypropionyloxy] -tax-11-en-9-one is dissolved in a mixture of 1.2 ml of acetic acid and 10.8 ml of methanol, and 544 mg of zinc powder is added. The mixture is stirred at 60 ° C. for 2 hours. The insolubles are removed from the reaction solution by filtration, and the filtrate is concentrated. After dissolving the residue in ethyl acetate, the organic layer is dried and concentrated. The residue was purified by silica gel chromatography [solvent: ethyl acetate-hexane (3: 2)] to give 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 7β,
10β-trihydroxy-13α-[(2R, 3S)-
3-phenyl-3- (t-butoxycarbonylamino)
-2-hydroxypropionyloxy] -tax-11
156 mg of -en-9-one are obtained. Yield: 82%.

[Α] (20, D) = − 48.37 ° (c
= 0.74, chloroform) IR (nujol) ν _max (cm ^-1 ): 3440, 17
20 FAB-MS (m / z): 808 (MH ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H,
s), 1.24 (3H, s), 1.34 (9H, s),
1.58 (1H, brs), 1.69 (1H, s),
1.77 (3H, s), 1.85 (4H, s + m),
2.27 (2H, d, J = 8.7 Hz), 2.37 (3
H, s), 2.54-2.62 (1H, m), 3.37.
(1H, d, J = 5.5 Hz), 3.91 (1H, d,
J = 7.0 Hz), 4.19 and 4.32 (each2
H, d, J = 8.5 Hz), 4.21-4.26 (2
H, m), 4.61 (1H, brs), 4.94 (1
H, d, J = 7.7 Hz), 5.21 (1H, d, J)
= 1.7Hz), 5.27 (1H, brd, J = 9H)
z), 5.43 (1H, d, J = 9.3 Hz), 5.6
8 (1H, d, J = 7.0 Hz), 6.21 (1H,
t, J = 9 Hz), 7.3-7.4 (5H, m), 7.
50 (2H, t, J = 7.4 Hz), 7.61 (1H,
d, J = 7.4 Hz), 8.10 (2H, d, J = 7.
4 Hz).

Example 2 (1) 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 13α in an argon atmosphere
4.92 g of dihydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -tax-11-en-9-one are dissolved in 70 ml of toluene. To this solution, 1.79 g of (2R, 3S) -3-phenylepoxypropionic acid, 2.38 g of N, N′-dicyclohexylcarbodiimide and 342 mg of 4- (N, N-dimethylamino) pyridine were added at room temperature, and the mixture was added for 10 minutes. Stir. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography [solvent: toluene-ethyl acetate (15: 1)] to give 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-. Hydroxy-7β, 10β-di (2,2,2-
Trichloroethoxycarbonyloxy) -13α-
5.55 g of [(2R, 3S) -3-phenyl-2,3-epoxypropionyloxy] -tax-11-en-9-one are obtained. Yield: 97%.

IR (nujol) ν _max (cm ^-1 ): 3
520, 1760, 1730 FAB-MS (m / z): 1039 (MH ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H,
s), 1.28 (3H, s), 1.73 (1H, s),
1.86 (3H, s), 2.01-2.13 (1H,
m), 2.09 (3H, s), 2.20-2.41 (2
H, m), 2.22 (3H, s), 2.63 (1H,
m), 3.64 (1H, d, J = 1.7 Hz), 3.9
2 (1H, d, J = 6.9 Hz), 4.16 (1H,
d, J = 8.2 Hz), 4.22 (1H, d, J = 1.
7Hz), 4.32 (1H, d, J = 8.2Hz),
4.61 (1H, d, J = 11.8 Hz), 4.79
(2H, s), 4.92 (1H, d, J = 11.8H)
z), 4.94 (1H, m), 5.57 (1H, dd,
J = 7.1, 10.7 Hz), 5.69 (1H, d,
J = 6.9 Hz), 6.27 (1H, s), 6.31
(1H, m), 7.30-7.66 (8H, m), 8.
07 (2H, m).

(2) Under an argon atmosphere, 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-
1β-hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2
R, 3S) -3-Phenyl-2,3-epoxypropionyloxy] -tax-11-en-9-one 2.70
g was dissolved in a mixed solvent of 50 ml of dichloromethane and 5 ml of hexamethylphosphoric triamide. The solution is cooled in a dry ice-acetone bath, 2.80 g of titanium tetrabromide is added, and then stirred for 18 hours while cooling in an ice bath. After adding 100 ml of water to the reaction solution and stirring for 10 minutes, the organic layer is separated and concentrated under reduced pressure. 50 ml of ethyl acetate, 25 ml of hexane and 50 ml of water are added to the residue, and the organic layer is separated. The organic layer was further washed with water and dried, and the solvent was distilled off. The residue was subjected to silica gel flash column chromatography [solvent: hexane-ethyl acetate (2:
1)] and purified by 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-
7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2S, 3R) -3-phenyl-3-bromo-2-hydroxypropionyloxy] -tax-11-en-9- 2.22 g of on are obtained. Yield: 76%.

IR (nujol) ν _max (cm ^-1 ): 3
440, 1760, 1720 FAB-MS (m / z): 1119, 1121 (M
H ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H,
s), 1.25 (3H, s), 1.74 (1H, s),
1.81 (3H, d, J = 1 Hz), 1.85 (3H,
s), 2.06 (1H.m), 2.28 (2H, m),
2.39 (3H, s), 2.63 (1H, m), 2.9
9 (1H, d, J = 7 Hz), 3.90 (1H, d, J)
= 7 Hz), 4.16 (1H, d, J = 8 Hz), 4.
34 (1H, d, J = 8 Hz), 4.60 (1H, d,
J = 12 Hz), 4.77 (2H, s), 4.78 (1
H, dd, J = 6, 7 Hz), 4.91 (1H, d, J)
= 12 Hz), 4.97 (1H, m), 5.27 (1
H, d, J = 6 Hz), 5.53 (1H, dd, J =
7,11 Hz), 5.68 (1H, d, J = 7 Hz),
6.17 (1H, m), 6.21 (1H, s), 7.4
-7.5 (7H, m), 7.64 (1H, m), 8.0
7 (2H, m).

(3) 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-
7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2S, 3R) -3-phenyl-3-bromo-2-hydroxypropionyloxy] -tax-11-en-9- On 112 mg dissolved in dimethylformamide 2 ml, 1,4,7,10,
2 mg of 13-pentaoxacyclopentadecane are added. The mixture is cooled in an external bath at -15 to -10 ° C, 65 mg of sodium azide is added, and the mixture is stirred for 18 hours while cooling in an ice bath. Pour the reaction into cold water and extract with ethyl acetate. The organic layer is washed with saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography [solvent: ethyl acetate-hexane (2:
3)] to give 4α-acetoxy-2α
-Benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3
S) -3-Phenyl-3-azido-2-hydroxypropionyloxy] -tax-11-en-9-one 77
mg. Yield: 71%.

The physical properties were the same as those of the compound obtained in Example 1 (3).

Example 3 4α-acetoxy-2α-benzoyloxy-5β, 2
0-epoxy-1β-hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy)
-13α-[(2S, 3R) -3-phenyl-3-bromo-2-hydroxypropionyloxy] -tax-1
100 mg of 1-en-9-one was dissolved in 2 ml of dimethylformamide, and 0.12 ml of azidotrimethylsilane was dissolved.
And stirred at 50 ° C. for 2 hours in an external bath. 29 mg of sodium azide is added to the reaction solution, and the mixture is further stirred at 50 ° C. in an external bath for 18 hours. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in 5 ml of ethanol, and about 15% hydrogen chloride-ethanol solution is added while cooling in an ice bath, followed by stirring for 10 minutes. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography [solvent: ethyl acetate-hexane (2: 3)] to give 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 10β-diene. (2,2,2
-Trichloroethoxycarbonyloxy) -13α-
[(2R, 3S) -3-phenyl-3-azido-2-hydroxypropionyloxy] -tax-11-ene-
63 mg of 9-one are obtained. Yield: 65%. Physical properties were the same as those of the compound obtained in Example 1 (3).

Example 4 (1) In an argon atmosphere, ( 2R, 3S ) -3- (4-
Fluorophenyl) -2,3-dihydroxypropionic acid methyl ester 3.95 g of dichloromethane 100 m
The solution was cooled to -3 to -5 ° C and triethylamine was added.
86 ml and p-toluenesulfonyl chloride 3.62
Add g. After stirring at −3 to −5 ° C. for 44 hours, the reaction solution is washed with water and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel flash column chromatography [solvent: ethyl acetate-hexane (1: 2)] to give ( 2R, 3
5.64 g of S ) -3- (4-fluorophenyl) -3-hydroxy-2-p-toluenesulfonyloxypropionic acid methyl ester are obtained.

M. p. 122.5-123.5 ° C IR (nujol) ν _max (cm ^-1 ): 3500, 17
70, 1140, 730 FAB-MS (with NaCl added) (m / z): 391 (M
⁺ + Na) ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.4
3 (3H, s), 2.66 (1H, d, J = 6 Hz),
3.64 (3H, s), 4.88 (1H, d, J = 4H)
z), 5.11 (1H, t-like), 6.87-
6.95 (2H, m), 7.17-7.25 (4H,
m), 7.55-7.60 (2H, m).

(2) Dissolve 5.48 g of (2R, 3S) -3- (4-fluorophenyl) -3-hydroxy-2-p-toluenesulfonyloxypropionic acid methyl ester in 75 ml of dimethylformamide, and add 1. 4ml
Add. The reaction mixture was cooled in an ice bath, and after adding 6.16 g of potassium carbonate, the mixture was stirred at room temperature for 22 hours. The reaction mixture is cooled again in an ice bath, 100 ml of water are added and extracted with ethyl acetate. After washing the organic layer with saturated saline,
Dry over anhydrous sodium sulfate. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (solvent: ethanol-hexane (1: 3)), and (2)
R, 3R) -3- (4-Fluorophenyl) -2,3-
2.69 g of epoxypropionic acid methyl ester are obtained.

IR (nujol) ν _max (cm ^-1 ): 1
740, 1510 EI-MS (m / z): 196 (M ⁺ ) ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.5
7 (3H, s), 3.82 (1H, d, J = 5 Hz),
4.24 (1H, d, J = 5 Hz), 6.99-7.0
7 (2H, m), 7.36-7.44 (2H, m) (3) (2R, 3R) -3- (4-fluorophenyl)
-2,3-epoxypropionic acid methyl ester 0.2
A solution of 0.03 g of lithium hydroxide in 3 ml of water is added dropwise to a solution of 06 g of methanol in 5 ml of ice under cooling with ice. The mixture is warmed to room temperature and stirred at the same temperature for 1.5 hours. Methanol was distilled off from the reaction solution, and a 5% aqueous citric acid solution was added to the residue under ice-cooling, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to obtain (2R, 3R) -3- (4-fluorophenyl) -2,3-epoxypropionic acid. The obtained (2R, 3R) -3- (4-fluorophenyl)
-2,3-epoxypropionic acid and 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1
β, 13α-dihydroxy-7β, 10β-di (2,
0.235 g of 2,2-trichloroethoxycarbonyloxy) -tax-11-en-9-one toluene 10
To the ml solution are added 0.227 g of N, N'-dicyclohexylcarbodiimide and 0.014 g of 4- (N, N-dimethylamino) pyridine and the mixture is stirred at 80 DEG C. for 2 hours. The insolubles are removed by filtration, and the solvent is distilled off from the filtrate under reduced pressure.

The residue was subjected to silica gel flash column chromatography [solvent: ethyl acetate-toluene (1: 1)
6)], and 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7
β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3R) -3- (4
-Fluorophenyl) -2,3-epoxypropionyloxy] -tax-11-en-9-one 0.167 g
Get. Yield: 60%.

IR (nujol) ν _max (cm ^-1 ): 1
760, 1720, 1240, 720 FAB-MS (m / z): 1057 (MH ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H,
s), 1.16 (3H, s), 1.61 (1H, s),
1.83 (3H, s), 1.87 (3H, d, J = 1H
z), 2.0-2.1 (3H, m), 2.36 (3H,
s), 2.63 (1H, m), 3.87 (1H, d, J
= 7 Hz), 3.95 (1H, d, J = 4 Hz), 4.
14 (1H, d, J = 9 Hz), 4.30 (1H, d,
J = 4 Hz), 4.31 (1H, d, J = 9 Hz),
4.61 (1H, d, J = 12 Hz), 4.77 (2
H, s), 4.92 (1H, d, J = 12 Hz);
97 (1H, m), 5.56 (1H, dd, J = 7, 1
5.63 (1H, d, J = 7 Hz), 6.
01-6.08 (1H, m), 6.20 (1H, s),
7.07 (2H, m), 7.39-7.52 (4H,
m), 7.60-7.68 (1H, m), 8.00 (2
H, m).

(4) 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-
7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3R) -3-
(4-Fluorophenyl) -2,3-epoxypropionyloxy] -tax-11-en-9-one 235 m
g is dissolved in 7 ml of 11% aqueous methanol. To this solution are added 0.7 ml of methyl formate and 4 ml of sodium azide.
32 mg are added and the mixture is stirred at 50 ° C. for 24 hours. Pour the reaction mixture into cold water and extract with ethyl acetate. The organic layer is washed with a 5% aqueous citric acid solution and saturated saline, dried over sodium sulfate, and the solvent is distilled off. The residue was purified by preparative thin-layer chromatography to give 4α-acetoxy-2α-benzoyloxy-
5β, 20-epoxy-1β-hydroxy-7β, 10
β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3S) -3- (4-fluorophenyl) -3-azido-2-hydroxypropionyloxy] -tax-11-ene 162 mg of -9-one
Get. Yield: 67%.

IR (nujol) ν _max (cm ^-1 ): 3
480,2110,1760,1720 FAB-MS (m / z ): 1122 (M + + Na) 1 H-NMR (CDCl 3) δ: 1.22 (3H,
s), 1.28 (3H, s), 1.74 (1H, s),
1.87 (3H, s), 2.12 (3H, d, J = 1H
z), 2.0-2.3 (3H, m), 2.31 (3H,
s), 2.65 (1H, m), 3.21 (1H, d, J
= 8 Hz), 3.92 (1H, d, J = 7 Hz), 4.
18 (1H, d, J = 8 Hz), 4.33 (1H, d,
J = 8 Hz), 4.42 (1H, dd, J = 3, 8H)
z), 4.61 (1H, d, J = 12 Hz), 4.7
6 (1H, d, J = 12 Hz), 4.81 (1H, d,
J = 12 Hz), 4.93 (1H, d, J = 12H)
z), 4.96 (1H, m), 5.03 (1H, d, J
= 3 Hz), 5.56 (1H, dd, J = 7, 11H)
z), 5.69 (1H, d, J = 7 Hz), 6.26
(1H, m), 6.28 (1H, s), 7.15 (2
H, m), 7.47 (4H, m), 7.63 (1H,
m), 8.06 (2H, m).

(5) 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-
7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3S) -3-
81 mg of (4-fluorophenyl) -3-azido-2-hydroxypropionyloxy] -tax-11-en-9-one was dissolved in 3 ml of dichloromethane, and 39 mg of triphenylphosphine, 0.05 ml of water and di-t-carbonate were dissolved.
-Butyl 48 mg and potassium bicarbonate 37 mg were added,
Stir at room temperature for 22 hours. The reaction mixture is diluted with chloroform and washed with water and saturated saline. After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was purified by preparative thin-layer chromatography.
α-acetoxy-2α-benzoyloxy-5β, 20
-Epoxy-1β-hydroxy-7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy)
-13α-[(2R, 3S) -3- (4-fluorophenyl) -3- (t-butoxycarbonylamino) -2-
33 mg of [hydroxypropionyloxy] -tax-11-en-9-one are obtained. Yield: 39%.

IR (nujol) ν _max (cm ^-1 ): 3
400, 1760, 1730 FAB-MS (m / z): 1174 (MH ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H,
s), 1.28 (3H, s), 1.35 (9H, s),
1.73 (1H, s), 1.86 (3H, s), 1.9
6 (3H, s), 2.1 (1H, m), 2.3 (2H,
m), 2.36 (3H, s), 2.6 (1H, m),
3.41 (1H, d, J = 5 Hz), 3.91 (1H,
d, J = 7 Hz), 4.18 (1H, d, J = 8H)
z), 4.34 (1H, d, J = 8 Hz), 4.60
(1H, m), 4.60 (1H, d, J = 12 Hz),
4.78 (2H, s), 4.91 (1H, d, J = 12
Hz), 4.96 (1H, m), 5.26 (1H, b
r) 5.36 (1H, m), 5.54 (1H, m),
5.70 (1H, d, J = 7 Hz), 6.23 (1H,
m), 6.25 (1H, s), 7.05-7.40 (4
H, m), 7.50 (2H, m), 7.63 (1H,
m), 8.10 (2H, m).

(6) 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-
7β, 10β-di (2,2,2-trichloroethoxycarbonyloxy) -13α-[(2R, 3S) -3-
(4-Fluorophenyl) -3- (t-butoxycarbonylamino) -2-hydroxypropionyloxy]-
Takis-11-en-9-one 6.42 g of acetic acid 50 m
1) To a solution of 200 ml of methanol, add 15 g of zinc powder and stir at 60 ° C for 30 minutes. The zinc dust is removed from the reaction solution by filtration, and the filtrate is concentrated. The residue is dissolved in ethyl acetate, and washed with a 1% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. After drying the organic layer over sodium sulfate, the solvent is distilled off. The residue was purified by silica gel flash column chromatography [solvent: ethyl acetate-hexane (3: 2)] to give 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 7β,
10β-trihydroxy-13α-[(2R, 3S)-
2.61 g of 3- (4-fluorophenyl) -3- (t-butoxycarbonylamino) -2-hydroxypropionyloxy] -tax-11-en-9-one are obtained. Yield: 58%.

M. p. 159 ° C (gradual decomposition) IR (nujol) ν _max (cm ^-1 ): 3440, 17
10, 1460 FAB-MS (m / z): 826 (MH ⁺ ) ¹ H-NMR (CDCl ₃ ) δ: 1.13 (3H,
s), 1.24 (3H, s), 1.34 (9H, s),
1.73 (1H, s), 1.75 (1H, d), 1.7
6 (3H, s), 1.83 (1H, m), 1.86 (3
H, d, J = 1 Hz), 2.29 (2H, m), 2.3
6 (3H, s), 2.58 (1H, m), 3.49 (1
H, d, J = 5 Hz), 3.92 (1H, d, J = 7H)
z), 4.19 (1H, d, J = 8 Hz), 4.22
(1H, m), 4.23 (1H, d, J = 2 Hz),
4.32 (1H, d, J = 8 Hz), 4.58 (1H,
m), 4.94 (1H, m), 5.21 (1H, d, J
= 2 Hz), 5.25 (1H, br), 5.43 (1
H, br), 5.68 (1H, d, J = 7 Hz), 6.
24 (1H, m), 7.08 (2H, m), 7.38
(2H, m), 7.49 (2H, m), 7.61 (1
H, m), 8.10 (2H, m).

[0082]

According to the method of the present invention, the reaction time reported so far is long, and the yield of the hydroxyl-protected N-type is low.
The method using benzoyl-3-phenylisoserine [method (A)], the method using an azetidinone compound or an oxazolidine compound that is complicated to synthesize [methods (B) and (C)], and lacks regioselectivity. Unlike any of the methods using osmium oxidation with low yield [Method (D)], an epoxypropionyl group in which the 3-position is first substituted with an aryl group or the like at the 13-position hydroxyl group of the baccatin compound [II] is quantitatively determined. And the product oxirane ring is regioselectively and stereoselectively cleaved with the metal azide, or is cleaved and halogenated, and then the halogen atom is regioselectively and stereoselectively substituted, 13α- (3
-Azido-2-hydroxypropionyloxy) baccatin derivative [V] and further reducing the azide group gave 13α- (3-amino-2-hydroxy-3
-Phenylpropionyloxy) baccatin derivative [V
I] can be efficiently produced.

The thus obtained 13α- (3-amino-
2-Hydroxy-3-phenylpropionyloxy) baccatin derivative [VI] is a synthetic intermediate such as taxol and N-debenzoyl-N- (t-butoxycarbonyl) -10-deacetyltaxol which are useful as antitumor agents. By utilizing the method of the present invention, a taxol derivative [IX] can be efficiently produced.

Further, 13 generated in the course of the method of the present invention.
α- (Epoxypropionyloxy) baccatin compound [III], 13α- (3-halogeno-2-hydroxypropionyloxy) baccatin compound [IV] and 1
The 3α- (3-azido-2-hydroxypropionyloxy) baccatin compound [V] is a novel compound, and the efficient taxol and N-debenzoyl-N- (t-butoxycarbonyl) -10-deacetyl of the present invention. It has important significance in the asymmetric synthesis of taxol and the like.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification code FI C07D 303: 40 305: 14) (72) Inventor Kenji Tsujihara 1149, Omaki, Oaza, Urawa City, Saitama Prefecture 133 (56) References JP Hei 3-83956 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 305/14 C07D 407/12 303 A61K 31/335 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A compound of the general formula [III] (Wherein R ¹ is a lower alkanoyl group , a trihalo lower alk
A oxycarbonyl group or a tri-lower alkylsilyl group , R
² is a trihalo lower alkoxycarbonyl group or a tri lower
An alkylsilyl group , R ³ represents a lower alkanoyl group, R ⁴ represents a substituted or unsubstituted benzoyl group, X represents a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkenyl group or an unsubstituted lower alkynyl group. 13α-
Epoxy propionyloxy baccatin compound. 2. A compound of the general formula [IV] (Wherein R ¹ is a lower alkanoyl group , a trihalo lower alk
A oxycarbonyl group or a tri-lower alkylsilyl group , R
² is a trihalo lower alkoxycarbonyl group or a tri lower
An alkylsilyl group , R ³ is a lower alkanoyl group, R ⁴ is a substituted or unsubstituted benzoyl group, X is a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkenyl group or an unsubstituted lower alkynyl group, and A is a halogen atom . )
13α- (3-halogeno-2-hydroxypropionyloxy) baccatin compound represented by the formula: 3. A compound of the general formula [V] (Wherein R ¹ is a lower alkanoyl group , a trihalo lower alk
A oxycarbonyl group or a tri-lower alkylsilyl group , R
² is a trihalo lower alkoxycarbonyl group or a tri lower
An alkylsilyl group , R ³ represents a lower alkanoyl group, R ⁴ represents a substituted or unsubstituted benzoyl group, X represents a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkenyl group or an unsubstituted lower alkynyl group. 13α-
(2R, 3S-3-azido-2-hydroxypropionyloxy) baccatin compound.