JP2003502401A - C-2 hydroxyl protected-N-acyl (2R, 3S) -3-phenyl isoserine activated esters and methods for their preparation - Google Patents

Abstract

(57) Abstract: The present invention is useful for the production of paclitaxel, paclitaxel analogs and intermediates thereof, wherein the following formula (wherein P ₁ is a hydroxyl protecting group, R ₁ is an alkyl group, an olefin group, an aromatic group) Which is an aromatic group, an O-alkyl group, an O-olefin group, or an O-aromatic group, wherein Z is a substituted phenyl residue or an N-imide residue. Also provided are methods of forming the compounds of the present invention.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates generally to the synthesis of paclitaxel from its precursor compound.
More specifically, however, the present invention relates to the semi-synthesis of paclitaxel using a protected baccatin III backbone esterified with an appropriately protected side chain activated ester, producing an intermediate that is converted to paclitaxel.

BACKGROUND OF THE INVENTION The compound referred to as taxol in the literature, recently as “paclitaxel”, is a compound that has gained attention in the scientific and medical communities due to its proven antitumor activity. Is. Paclitaxel has been approved for chemotherapeutic treatment of several different tumors and clinical trials have shown promise for a broad spectrum of potent anti-leukemic and tumor-inhibiting activities. As is well known, paclitaxel is a naturally occurring taxane diterpenoid having the following formula and numbering system.

The paclitaxel molecule is found in several species of yew (Genus Taxus, Taxaceae), but the concentration of this compound is very low. Moreover, these evergreen trees are slow growing. Thus, the increasing use of paclitaxel as an effective anti-cancer agent can deplete natural resources in the form of yew trees. In fact, yew bark usually shows the highest concentration of paclitaxel, but about 16,000 pounds of bark is required to produce 1 kg of paclitaxel. That is, the long-term prospects for paclitaxel availability by isolation are disappointing.

Paclitaxel compounds are, of course, constructed from the baccatin III backbone and include various other taxane compounds such as baccatin III, cephalomannine, 10-deacetylbaccatin III and the like. Some of it is more easily and more efficiently extracted from yew trees. In fact, 10-deacetylbaccarin III can be extracted from yew leaves as a renewable resource in relatively high yields. However, these other taxane compounds normally present in yew trees do not show the antitumor activity to the extent that paclitaxel compounds exhibit.

Since paclitaxel compounds are extremely promising as chemotherapeutic agents, organic chemists have spent a lot of time and energy trying to synthesize the paclitaxel molecule. A more promising route to the creation of significant amounts of paclitaxel compounds is to attach an A-ring side chain to the C-13 position of the naturally occurring baccatin III backbone derived from various taxanes present in yew. Proposed by semi-synthesis of paclitaxel. Denis et al., “Highly Efficient”
ient, Practical Approach to Natural T
axol ”, Journal of the American Chemical
See al Society, page 5917 (1988). This document describes the partial synthesis of paclitaxel from 10-deacetylbaccarin III.

The simplest way to carry out the partial synthesis of paclitaxel is to provide a derivative with a chiral, non-racemic side chain, baccatin III, which is rich in natural resources, or a closely similar diterpenoid substance, and the effect of conjugating the two. Means are required. Of particular interest in this case is the condensation of baccatin III or 10-deacetylbaccarin III with the side chain of the A-ring of paclitaxel. However, the esterification of these two units is difficult due to the occluded C-13 hydroxyl of III being located within the recess of the hemispherical taxane skeleton. For example, G
reene & Gueritete-Voegelen reported only 50% conversion after 100 hours in a partial synthesis of paclitaxel (J. Am.
． Chem. Soc. 1988, 110: 5917).

[0007]   "Process for," issued to Denis et al. On May 8, 1990.
U.S. Pat. No. 4,929,011 entitled "Preparing Taxol"
General formula: (In the formula, P₁Is a hydroxyl protecting group) of the (2R, 3S) side chain acid
: (In the formula, P_TwoIs a hydroxyl protecting group)
A semi-synthesis of clitaxel is described, followed by treatment of the condensation product to give P₁And P_Two
Methods for removing protecting groups are described. The method of Denis et al.₁Protecting group
Except for (2R, 3S) 3-phenylisoserine derivative, A of paclitaxel molecule
A ring side chain. P on the baccatin III skeleton_TwoThe protecting group is, for example, trimethyl
It is a silyl or trialkylsilyl radical.

Another semisynthesis of paclitaxel is described by Swindell et al., US Pat. No. 5,770,7.
45. Swindell et al. From the Baccatin III backbone have the general formula: Where R ₁ is alkyl, olefin or aromatic or PhCH ₂ ,
P ₂ is a hydroxyl protecting group) discloses the semi-synthesis of paclitaxel by condensation with a side chain bearing.

The side chain in the method of Swindell et al. Differs from the side chain bond used by Denis et al. Above in that the nitrogen is protected as a carbamate. Preferably,
The A-ring side chain is protected with benzyloxycarbonyl (CBZ). After esterification, the CBZ protecting group is removed and replaced with PhCO leading to paclitaxel. This method gives higher yields than described by Denis. Swindell
In these methods, the preferred masking group was selected from trichloroethoxymethyl or trichloroethoxycarbonyl. Benzyloxymethyl (BOM) is 3
-Disclosed as a possible hydroxyl protecting group for the phenyl isoserine side chain, however, in the method described therein, the BOM protecting group does not interfere with the even greater interference of C-2 in the bound 3-phenyl isoserine side chain. It could not be removed from the hydroxyl. For that reason, the use of BOM-protected side chains was not considered further.

Thereafter, US Pat. No. 5,67, Sisti et al. Issued October 7, 1997.
5,025 shows that the BOM group could be removed from the C-2 hydroxyl, which is a major hindrance in the bound 3-phenylisoserine side chain.

US Pat. No. 4,924,012 issued to Colin et al. On May 8, 1990
In a method for producing a derivative of baccatin III and 10-deacetylbaccatin III, wherein an acid is condensed with a derivative of baccatin III and 10-deacetylbaccatin III, and then the protecting group is removed by acid hydrolysis. Is disclosed. TAXOTERE (registered trademark, Rhone-Poulenc
Sanle) and several syntheses of related compounds are described in Journal o
f Organic Chemistry 1986, 51:46; 1990, 5
5: 1957; 1991, 56: 1681; 1991, 56: 6939; 199.
2, 57: 4320; 1992, 57: 6387; and 1993, 58:25.
5 is reported. Also, Holton US Pat. No. 5,015,744, issued May 14, 1991, describes such a synthesis. Other techniques for the synthesis of paclitaxel and paclitaxel analogs are described in US Pat. No. 5,688,977 to Sisi et al., US Pat. No. 5,750,737 to Sisi et al .; Si.
US Pat. No. 5,684,175 to Sti et al .; US Pat.
736.

[0012] Despite the advances in semi-synthesis of paclitaxel molecules in the above methods, there remains a need for more efficient protocols for the synthesis of paclitaxel due to increased efficiency in yield and product ratio. . There remains a need for semi-synthesis that meets the requirements of commercial-based methods. There remains a further need for efficient protocols for the synthesis of paclitaxel analogs, intermediates and various A-ring side chain structures.

DISCLOSURE OF THE INVENTION It is an object of the present invention to provide novel C-2 hydroxyl protected-N-acyl (2R, 3S) -3-phenylisoserine activated esters and their useful for semi-synthesis of paclitaxel. It is to provide a manufacturing method.

Another object of the invention is baccatin II protected during the semi-synthesis of paclitaxel.
It is to provide a new and useful method for the preparation of hydrogenatable benzylic protected side chains that can be easily attached to the I backbone.

Yet another object of the present invention is to provide N-CBZ protected C-2 hydroxyl-benzyl protected (2R, 3S) -3-phenylisoserine activated esters and processes for their preparation.

Yet another object of the present invention is an efficient, cost-effective process for the preparation of N-CBZ protected C-2 hydroxyl-benzyl protected (2R, 3S) -3-phenylisoserine activated ester. To develop.

Therefore, according to the invention, the formula: (In the formula, P ₁ is a hydroxyl protecting group, R ₁ is an alkyl group, an olefin group,
An aromatic group, an O-alkyl group, an O-olefin group, or an O-aromatic group, Z
Are substituted phenyl residues or N-imide residues) are provided. R ₁ is preferably Ph, PhCH ₂ , O—Ph or O—CH ₂ Ph, and P ₁ is preferably benzyl, benzyloxymethyl or benzoyl.

Z is the formula: Is a phenyl residue having the formula: (Wherein R _{2 to} R ₆ are each H or an electron-withdrawing group). Examples of electron withdrawing groups include NO ₂ or halogen such as F. At least one of R _{2 to} R ₆ is preferably halogen or NO ₂ .

In a preferred embodiment P ₁ is benzyloxymethyl and R ₂ , R
₃ , R ₅ and R ₆ are H; R ₄ is NO ₂ ; R ₁ is OCH ₂ Ph. Similarly, it is also preferred that P ₁ is benzyloxymethyl, R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are F; R ₁ is OCH ₂ Ph. It is also preferred that P ₁ is benzyloxymethyl, R ₂ and R ₄ are NO ₂ , R ₃ , R ₅ and R ₆ are H, and R ₁ is OCH ₂ Ph.

Z is also a heterocyclic N-imide residue having preferably 5 to 7 atoms in the ring, and Z is substituted with at least one electron withdrawing group such as a nitro or halogen group. . The N-imide residue may be substituted with a plurality of same or different electron withdrawing groups. In particular Z is a succinimide, phthalimide, 5-norbornene-2,3-dicarboximide and maleimide residue and substituted derivatives thereof.

The present invention also contemplates methods of making ester derivatives useful in the manufacture of paclitaxel, paclitaxel analogs and intermediates thereof. The method of the present invention has the general formula: [Wherein R ₁ is an alkyl group, an olefin group, an aromatic group, an O-alkyl group, an O-olefin group, or an O-aromatic group; P ₁ is a hydroxyl protecting group;
₁₀ is a first compound of H or CO ₂ X (X is an alkyl group, an olefin group or an aromatic group), represented by the general formula: HO-Z (wherein Z is a substituted phenyl residue and an N-imide residue). A compound of the general formula: (Wherein R ₁ is an alkyl group, an olefin group, an aromatic group, an O-alkyl group, an O-olefin group, or an O-aromatic group; P ₁ is a hydroxyl protecting group; Z
Is selected from substituted phenyl residues and N-imide residues). When R ₁₀ is H, the reaction step can be carried out in the presence of THF and a carbodiimide such as dicyclohexylcarbodiimide. R _{1
When 0} is CO ₂ X, X is especially —CH ₂ CH (CH ₃ ) ₂ and the reaction step can be carried out in the presence of N-methylmorpholine and THF.

The first compound has the formula: A compound having the thereby formed by obtaining a first compound is reacted with a compound having the formula Cl-CO 2 _X. The second compound has the formula: (Wherein R _{2 to} R ₆ are each selected from the group consisting of H and an electron-withdrawing group). Particularly, R _{2 to} R ₆ are each a H, halogen or NO ₂ group, and at least one of R _{2 to} R ₆ is halogen or NO.
_{There are two} . R ₁ is particularly Ph, PhCH _2, O-Ph or _O-CH 2 Ph, _{P 1} is benzyl, benzyloxymethyl or benzoyl. Alternatively, the second compound is a heterocycle N-, wherein Z has 5 to 7 atoms in the ring.
The compound may be an imide residue. In particular, Z can be succinimide, phthalimide, 5-norbornene-2,3-dicarboximide, or maleimide residues and their substituted derivatives.

These and other objects of the invention will be more readily appreciated and understood in view of the detailed description of the exemplary embodiments which follow.

The present disclosure broadly contemplates an efficient method of making paclitaxel, intermediates and precursors thereof. More specifically, the present invention provides a 7-O-protected baccatin I
It relates to the semisynthesis of paclitaxel by esterifying a suitably protected 3-phenylisoserine activated ester having a protecting group at the C-2 to C-13 hydroxyl position of II. More particularly, the present invention is preferably baccatin III
Utilizes CBZ protection at the C-7 site of E. coli. The general methods described herein include the preparation of C-7CBZ baccatin III, the preparation of an appropriately protected 3-phenylisoserine activated ester having a suitable protecting group at C-2, the two compounds Condensation and subsequent deprotection, acylation, deprotection of condensation products to form paclitaxel is included.

A. Preparation of C7-CBZ Protected Baccatin III According to the present invention, to prepare C7-CBZ protected Baccatin III, 2
Two alternative routes are described, which are co-filed by Sisti et al., Application no. 0.
8 / 922,684, now found in U.S. Patents X, XXX, XXX. On the one hand, baccatin III is protected at the C-7 site to give rise to C-7CBZ baccatin III. On the other hand, 10-deacetylbaccatin III (10-DAB
) Is C-7CBZ baccatin III directly without going through the baccatin III intermediate
Can be converted to. The production from baccatin III is advantageous in terms of its yield and simplicity. The method using 10-deacetylbaccatin III is 10-
Deacetylbaccatin III is advantageous because it is much more naturally abundant and therefore cheaper than baccatin III, but the yield of this alternative is low.

Route 1 (Use of Baccatin III) C-7CBZ Baccatin III has the formula: And can be synthesized from baccatin III by the following reaction. Baccatin III is dissolved in THF (tetrahydrofuran) to form a first solution, which is cooled under a nitrogen atmosphere to reduce the temperature below -20 ° C. Then, n-butyllithium (1.6M in hexane) is added dropwise to the first solution to form a second solution and stirred at low temperature for about 5 minutes. This is C-7 of baccatin III
Create lithium alkoxide. Chloroformic acid benzyl ester (CBZ-Cl
) Is added dropwise to the second solution to form a third solution, which is then warmed to 0 ° C. with stirring for about 1 hour. Cold saturated ammonium chloride is added to the third solution to quench excess butyllithium and CBZ-Cl to quench the reaction, and the mixture is concentrated in vacuo to give a first residue. The first residue is then taken up in ethyl acetate and washed once with water to remove unwanted salts. Then the organic layer is washed with brine. The organic layer is then dried and concentrated under vacuum to give a second residue. Recrystallization of the second residue with ethyl acetate: hexane or chromatography gives C-7CBZ baccatin III as a white solid.

It will be appreciated by those of ordinary skill in the art that other alkaline bases, particularly potassium hydride and sodium hydride, may be used in place of n-butyllithium to form the C-7 metal alkoxide of baccatin III. Is the range to be understood.

Route 2 (Use of 10-Deacetylbaccatin III) Alternatively, C-7CBZ baccatin III can be synthesized directly from 10-deacetylbaccatin III as follows. In this case, 10-DABIII is dissolved in THF to form a first solution, which is cooled under a nitrogen atmosphere to reduce the temperature below 20 ° C, preferably -40 ° C. Then at least 2 equivalents of n-butyllithium (1.6M in hexane) are added dropwise to the first solution to form a second solution, which is then stirred at low temperature for about 5 minutes. Acetyl chloride (1 equivalent) is preferably added to the second solution to form a third solution, which is stirred at low temperature for about 30 minutes. Alternatively, 10-DABI
It is also possible to use acetic anhydride (1 equivalent) instead of acetyl chloride for the acetylation of II. In each case, chloroformic acid benzyl ester (1 eq.) Was then added and this fourth solution was stirred at low temperature for a further 30 minutes, then 30
Warm to 0 ° C. in minutes. Cold saturated ammonium chloride is added to the fourth solution at low temperature to remove excess n-butyllithium, acetyl chloride and CBZ-Cl to quench the reaction. The mixture is warmed to room temperature. Removal of the solvent under vacuum gives the first residue, which is taken up in ethyl acetate and washed with water to remove the unwanted salts. The organic layer is then washed with brine, dried and concentrated under vacuum to give the final residue. Chromatography of the final residue (silica gel, hexane:
When added to ethyl acetate), C-7CBZ baccatin III is produced. This method
It provides a direct synthesis of C-7CBZ baccatin III from 10-DABIII, noting that the intermediate formed in this reaction is the C-7 lithium alkoxide of baccatin III, ie the intermediate is not baccatin III itself. Is important.

Both routes 1 and 2 are specifically intended for the production of derivatives of baccatin III, but as will be apparent to one of ordinary skill in the art, the baccatin III analog is It can be easily prepared from the two methods by substituting the appropriate acid chloride with the second solution in Route 2. This results, for example, in the formation of analogs with different alkyl groups at C-10.

Both Route 1 and Route 2 leading to the production of C-7CBZ baccatin III are
It can be expressed as a general method. The method starts with the step of dissolving a starting material selected from the group consisting of baccatin III and 10-deacetylbaccatin III in a first solvent to form a first solution. The first solution is then cooled to reduce the temperature to -20 ° C or below. An alkyllithium base is then added to the first solution to form an intermediate compound having a lithium alkoxide at the C-7 position. The method then involves selective acylation at the C-10 position, as required for the 10-DAB III starting material. If the first intermediate compound present in the first solution is an intermediate compound that does not yet have an acyl at the C-10 position, a second solution consisting of C-7 lithium alkoxide of baccatin III is prepared. To do. Of course, when the starting compound is baccatin III, there is already an acetyl group at the C-10 position. In any case, the method then involves adding CBZ-Cl to the second solution to form a third solution of C-7CBZ baccatin III.

[0031] B. N-acyl C-2 hydroxyl protected (2R, 3S) -3-phenyliso
Preparation of Serine A-Ring Side Chain Activated Ester The second precursor required for the semisynthesis of paclitaxel according to the present invention has the general formula: (In the formula, R ₁ is an alkyl group, an olefin group, an aromatic group, Ph, PhCH ₂ , O-
Alkyl group, O-olefin group, or O-aromatic group, O-Ph, or OC
H ₂ Ph, P ₁ is a hydroxyl protecting group, R ₂ is an N-imido group or a phenyl ring substituted by one or more electron withdrawing groups, and imide groups contemplated in the present invention include: For example, succinimide, phthalimide, 5-
Norbornene-2,3-dicarboximide, or a derivative thereof such as a maleimide group or a succinimide group substituted in the 3 and / or 4 position or having 5 to 7 atoms in the ring, chloro, fluoro, Other heterocyclic imido groups substituted with nitro or other groups are included). N-acyl C-2 hydroxyl protected (2R, 3S) -3-phenyl isoserine side chain activated ester.

A preferred hydroxyl protecting group is the benzyloxymethytyl (BOM) protecting group. Benzyl has also proven suitable with benzoyl, and other protecting groups are believed to be suitable as well. A preferred N-acyl group is benzyloxycarbonyl (CBZ). Other protecting groups and acyl groups (with alkyl, olefin and aromatic substituents and variants thereof) can be substituted within the range understood by those skilled in the art.

The starting compound for preparing the desired side chain is the preferred N-CBZ protection (2R,
(2R, 3S) -3-Phenylisoserine ethyl ester for producing 3S) -3-phenylisoserine ethyl ester by the reaction of the following formula.

In this case, (2R, 3S) -3-phenylisoserine ethyl ester was separately dissolved in an equal part of diethyl ether: water or an equal part of methyl t-butyl ether: water, and the solution was adjusted to 0 ° C. Cooled. Then sodium carbonate was added to this solution, benzyl chloroformate was added dropwise over a period of about 5 minutes, and the resulting mixture was stirred at 0 ° C. for about 1 hour. After stirring for 1 hour, the solution was poured into water and optionally extracted with methylene chloride or ethyl acetate. The organic layer was separated, dried and concentrated under vacuum to give a residue. The residue was then recrystallized from ethyl acetate: hexane to give N-CBZ (2R, 3S) -3-phenylisoserine ethyl ester having the formula:

The N-CBZ (2R, 3S) -3-phenylisoserine ethyl ester was then protected in several ways with a hydrogenatable benzylic protecting group. For example, one route to the desired hydrogenatable benzyl protected side chain is as follows. In this case, CBZ (2R, 3S) -3-phenylisoserine ethyl ester is dissolved in anhydrous THF under a nitrogen atmosphere and cooled to a low temperature such as -40 ° C or -70 ° C in a dry ice / acetone bath. Then, an alkyllithium agent such as n-butyllithium is added dropwise. However, the alkyllithium agent must be linear alkyl. In any case, the reaction is best performed at temperatures below 0 ° C. The resulting mixture was stirred for about 10 minutes. Benzyloxymethyl chloride (BOM-Cl) was then added dropwise over about 5 minutes and the mixture was added at low temperature for about 2 minutes.
Stir for ~ 5 hours. The solution was then warmed to 0 ° C. and water was added to stop the reaction.
The resulting mixture was concentrated under vacuum to form a residue which was then taken up in ethyl acetate and washed with water and brine. The organic layer is then dried, concentrated in vacuo and the residue recrystallized from ethyl acetate: hexane or ethyl acetate:
Chromatography with hexane gave the compound: Is obtained.

Another route to prepare the compound of formula 6 is accomplished by dissolving N-CBZ (2R, 3S) -3-phenylisoserine ethyl ester in anhydrous methylene chloride. Then a tertiary amine base such as diisopropylethylamine is added to the B
Add with OM-Cl and reflux the mixture for 24 hours. In this reaction, N-
CBZ, C-2 [hydroxyl] protected (2R, 3S) -3-phenylisoserine ethyl ester is produced, but the reaction proceeds much slower than the preferred route described above.

In each case, the resulting protected (2R, 3S) -3-phenylisoserine ethyl ester compound of formula 6 was simply reacted: Can be converted to the N-CBZ C-2 O-BOM protected (2R, 3S) phenyl isoserine intermediate.

In this case, the protected (2R, 3S) -3-phenylisoserine ethyl ester is dissolved in ethanol / water (ratio 8: 1). Lithium hydroxide (or other suitable alkali hydroxide) is added to the solution and the resulting mixture is stirred for about 3 hours for saponification of the compound. The mixture is then acidified (1N HCl) and extracted with ethyl acetate. The organic layer obtained is separated, dried and concentrated under vacuum. The residual acid is then isolated and used without further purification. This is the general formula: To produce the desired side chain having

Benzyl itself is an example of a hydrogenatable benzyl protecting group that can be used instead of BOM. formula: Was thus prepared by the following reaction using benzyl bromide instead of BOM-Cl in Reaction IV as described above.

Here, CBZ-protected (2R, 3S) -3-phenylisoserine ethyl ester is dissolved in anhydrous THF under a nitrogen atmosphere, and, for example, in a dry ice / acetone bath.
Cool to a lower temperature such as 40 ° C or -78 ° C, then add an alkyllithium agent such as n-butyllithium dropwise. However, it is desirable that the alkyllithium agent is linear alkyl. The resulting mixture was stirred for about 10 minutes. Benzyl bromide (BnBr) was then added dropwise over about 5 minutes and the mixture was stirred at the reduced temperature for about 2-5 hours. The solution was then warmed to 0 ° C. and quenched with water. The resulting mixture was evacuated under vacuum until a residue was formed, then the residue was taken up in ethyl acetate, washed with water and with brine. The organic layer is then dried, evacuated under vacuum and the residue
Recrystallization from ethyl acetate: hexane or chromatography with ethyl acetate: hexane gave the compound of formula 8.

Alternatively, the compound of formula 8 was obtained by the following reaction:

Here, to a stirred solution of NaH in anhydrous DMF under N ₂ , Formula 5 dissolved in DMF
Was added over 5 minutes. The mixture was then stirred at 0 ° C. for 1.5 hours, after which time benzyl bromide (1.1 eq) was added dropwise over 5 minutes and the reaction was stirred for 2 hours. Then, the mixture was quenched with H _{2 O.} Then, one kind was selected from diethyl ether and methyl t-butyl ether and added. The organic layer was then washed with 4 parts of water, brine and then dried and reduced under vacuum to give the compound of formula 8. The compound of Formula 8 was then converted to the following formula by the method of Reaction V above:

The N-CBZ-C-2-OBOM protected (2R, 3S) -3-phenylisoserine (Formula 7) may be converted to the corresponding activated ester by one of two routes. . However, it should be appreciated that other esterification methods known in the scientific literature and well understood by those skilled in the art may be used to make the activated ester. Furthermore, it should be appreciated that these methods are applicable to the C-2 and C-3N variants of Formula 7, as is well understood by those skilled in the art.

In the first path, N-CBZ-C-2-OBOM protection (2R, 3S) -3
-Phenylisoserine was added to 1.2 equivalents of dicyclohexylcarbodiimide or other suitable carbodiimide in THF and P-nitrophenol, pentaflurophenol, 2,4-dinitrophenol (or widely understood by those skilled in the art). Other substituted phenols) or N-hydroxysuccinimide (or other N-hydroxyimides well understood by those skilled in the art) and mixed for several hours at room temperature. A preferred substituted phenol is P-nitrophenol. A preferred N-hydroxyimide is N-hydroxysuccinimide. Substituted phenols and N-hydroxyimides contemplated by this invention are either readily available or can be synthesized from readily available starting materials by procedures known to those skilled in the art. .

The resulting mixture was diluted with ethyl acetate, cooled to 0 ° C. for a few hours, stirred for a few more minutes and filtered. The filtrate is then treated with 1N HCl, water, 20% Na.
It was washed with aqueous HCO ₃ solution, water, brine, dried over sodium sulphate and vacuumed to a residue. The residue was then subjected to column chromatography and / or recrystallized from ethyl acetate: heptane.

An exemplary reaction in the first pathway is as follows:

In the second route, a mixed anhydride of N-CBZ-C-2-OBOM 3-phenylisoserine was added to P-nitrophenol, pentaflurophenol, 2,4-
Reacted with either dinitrophenol (or a substituted phenol, which is also well understood by those skilled in the art) or N-hydroxysuccinimide (or other N-hydroxyimides, which are also widely understood by those skilled in the art), and correspondingly activated. The ester was obtained. It is contemplated that mixed anhydrides having alkyl, olefin, aromatic or other suitable groups may be used, as is well understood by those skilled in the art.

N-CBZ-C-2-OBOM-3 cooled to −15 ° C. to −20 ° C. under nitrogen
To a solution of phenyl isoserine in THF was added 1.5 equivalents of isobutyl chloroformate followed by 1.5 equivalents of N-methylmorpholine. The resulting mixture was stirred for a few minutes, then P-nitrophenol, pentaflurophenol, 2
, 4-dinitrophenol (or other substituted phenol well understood by those skilled in the art) or N-hydroxysuccinimide (or other N-hydroxyimide also well understood by those skilled in the art). 5 equivalents were added. The mixture is then stirred for a few minutes at -15 ° C to -20 ° C, then 0
Stirred at 1 ° C to 25 ° C for 1 hour. After that time, the mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulphate and vacuumed down to a residue. The residue is then subjected to column chromatography,
And / or heptane: recrystallized from ethyl acetate.

Reactions VIII, IX, X, XI and XII may be generalized by the following reaction XIII:

Where P ₁ is a hydroxyl protecting group such as BOM or benzyl; R 1 is an alkyl group, an olefin group, an aromatic group (eg Ph, PhCH ₂ ), an O-alkyl group, O-olefin group, or O-aromatic group (for example, O-Ph or OC)
H ₂ Ph); R ₁₀ is H or CO ₂ X (wherein X is an alkyl group, an olefin group, or an aromatic group); and Z is

A substituted phenyl moiety such as where each of R _{2 to} R ₆ is selected from the group consisting of H and an electron withdrawing group (eg, halogen or NO ₂ ), or Z
Is an N-imide moiety (including succinimide, phthalimide, 5-norbornene-2,3-dicarboximide, maleimide or derivatives thereof, such as maleimide groups or succinimide substituted at the 3 and / or 4 sites. Groups, or other heterocyclic imide groups preferably having from 5 to 7 atoms in the ring, chloro, fluoro, nitro, or heterocyclic imide groups substituted with other groups, including It is not limited to).

C. C-7 CBZ Condensation of Baccatin III with side chain activated ester Side chain activated ester (Formula 10, 11, 12 or 13 or variants well understood by those skilled in the art), as well as C-7 The CBZ Baccatin III may be condensed. This condensation proceeds by the following reaction at 0 ° C. in the presence of a suitable lithium base in THF (eg lithium hexamethyldisalizan or n-BuLi):

(In the formula, R ₁ is p-nitrophenyl (Formula 10), 2,4-dinitrophenyl (
Formula 11), pentaflurophenyl (Formula 12), or another substituted phenyl group, or N-succinimide (Formula 13), or another N-imide group.

Here, C-7 CBZ Baccatin III (1.0 eq) and activated ester (Formulas 10, 11, 12, 13 or other compound as described above, 1.5 eq) under anhydrous nitrogen under anhydrous THF. , And cooled to 0 ° C. It should be noted that other temperatures, including ambient temperature, have been shown to be suitable as well. To this was then added the appropriate lithium base, in this case lithium hexamethyldisalizan. However, it is also possible to use n-butyllithium. This will probably result in C-7 as described by Holton (US Pat. No. 5,229,526 and US Pat. No. 5,274,124).
The C-13 CBZ baccatin III C-13 lithium alkoxide is produced in a manner similar to the TES baccatin III C-13 lithium alkoxide. The mixture is then preferably stirred for a few hours, although short times such as 30 minutes were used. The mixture was then made up with ethyl acetate and 1N HCl at 1: 3.
Dilute with 1 mixture, collect the organic phase, wash with water and brine, dry over sodium sulphate and apply a vacuum to give a residue. The residue is then purified by column chromatography (ethyl acetate / heptane) or recrystallisation (diethyl ether or methyl 1-butyl ether or ethyl acetate / heptane),
The coupled product was obtained.

Alternatively, Formula 15 can be made using C-7 TES Baccatin III instead of C-7-CBZ Baccatin III.

The synthesis of C-7 TES Baccatin III has been described [Dennis et al. (De
nis et al) “A Highly Efficient, Practical Approach Two Natural Taxol (A Highly Efficien)
t, Practical Approach to Natural Taxo
l) ", J. Am . Chem . Soc ., 1988, p . 5917 and Kant et al ., " Achemoselective Approach, Twf Functionalization The Shi-10 Position of 10-Deacetylbaccatin III. Synthesis and Biological Properties of Novel Taxol Analogs (A Chemoselective Appr
och to Functionize the the C-10 Positi
on of 10-deacyl Acceleration III. Synt
hesis and Biological Properties of N
over Tax Analogs) ", Tetrahesron Let
ters Vol. 35, No 31, 1994, p5543]. Other C-7 protected baccatin III compounds, which are well understood by those skilled in the art, may also be used.

The conversion of formula 14 to paclitaxel has been previously described (Site e.
t al. , S. N. 08 / 719,488, now US Pat. No. 5,750,7
37), and as follows:

D. Deprotection and Acylation to Make Paclitaxel from Formula 14 The compound according to Formula 14 was prepared by removing the nitrogen and C-7 CBZ groups, leaving the benzoyl group on the nitrogen, and finally a protecting group of the C-2'benzyl type. Was converted to paclitaxel by removing the. Removal of the CBZ group and then addition of the benzoyl group to the nitrogen was carried out as follows (BOM is shown as a protecting group at the C-2 'hydroxyl site, but a benzyl group can also be used). ):

Here, the ligation product of Formula 14 was dissolved in isopropanol and to it was added Pearlman's catalyst. The resulting mixture was hydrogenated at 40 psi for 24 hours. Alternatively, mix the mixture with 1 part of hydrogen.
It is also possible to stir under atmospheric pressure. Further alternatively, the mixture can be hydrogenated at 1 atm of hydrogen in the presence of at least 1 equivalent of trifluroacetic acid, resulting in the TFA salt of the resulting amine. The mixture was then filtered through diatomaceous earth and reduced in vacuo to give a residue. Preferably, the residue was taken up in toluene and anhydrous potassium carbonate was added. Alternatively, the residue may be taken up in ethyl acetate or toluene and a tertiary amine such as triethylamine added. In each case, benzoyl chloride was then added dropwise and the mixture was washed with water and finally with brine. The resulting organic phase was then separated, dried and concentrated under vacuum to give C-2'-BOM paclitaxel (Formula 16). Finally, C-2'-BOM was removed by the next reaction.

BOM-protected paclitaxel was dissolved in isopropanol and Pearlman's catalyst was added to it. This mixture was hydrogenated under 40 psi hydrogen for 24 hours or 1 atmosphere hydrogenation in the presence of trifluroacetic acid for 24 hours to give paclitaxel.

The conversion of Formula 15 to paclitaxel has been previously described (Sisli et al.
li et al. ,), U.S. Pat. No. 5,675.025, Oct. 7, 1997), performed as follows:

E. Deprotection and Acylation to Create Paclitaxel from Formula 15 The compound according to Formula 15 was prepared by removing the CBZ protecting group and acylating the side chain to produce T
It was converted to paclitaxel by removing the ES protecting group and the hydrogenatable benzyl protecting group. Here, some advantageous routes have been found,
Generally, before deprotecting C-2 'with a hydrogenatable benzyl protecting group, T
It is necessary to deprotect the C-7 site by removing the ES protecting group.
If the TES protecting group is not removed first, it may seem difficult to remove the hydrogenatable protecting group in later processing steps.

In any case, the preferred route for producing paclitaxel is to first remove the CBZ protecting group by the following reaction:

Here, the ligation product of formula 15 was dissolved in isopropanol and to which Pearlman's catalyst was added. The resulting mixture was stirred under 1 atmosphere of hydrogen for 24 hours.
The mixture was then filtered through diatomaceous earth and reduced in vacuo to give a residue. The residue was then taken up in ethyl acetate or toluene and a tertiary amine base such as triethylamine was added. Benzoyl chloride was added dropwise and the mixture was stirred for 2 hours. The resulting mixture was then washed with dilute solution of NaHCO ₃ and finally with brine. The resulting organic phase was then separated, dried and reduced in vacuo to give the CBZ deprotected / acylated compound:

The compound of formula 17 was then deprotected at C-7 by the following reaction:

Here, the compound of formula 17 was dissolved in acetonitrile (CH ₃ CN) at 0 ° C. Then, hydrofluoric acid (40% aqueous solution) was added, and the mixture was stirred for 10 hours while keeping it at 0 ° C. The mixture was then diluted with ethyl acetate, a saturated aqueous solution of NaHCO ₃ , water and finally brine. The organic phase was separated, dried and reduced in vacuo to give the product deprotected at the C-7 site according to the formula:

Finally, the compound of formula 18 is deprotected at C-2 ′ to remove the hydrogenatable benzylic (BOM) protecting group and liberate the C-2 ′ hydroxyl, thereby providing the desired I got paclitaxel. This was done by the following reaction:

Alternatively, the compound of formula 15 was first dissolved in CH ₃ CN at 0 ° C. and hydrofluoric acid (40% aqueous solution) was added to remove the TES protecting group at the C-7 site. The compound was deprotected. This provided the compound of formula 19.

The CBZ protecting group may then be removed in a manner similar to that described above. Here, the compound of Formula 19 was dissolved in isopropanol and Pearlman's catalyst was added along with trifluoroacetic acid (TEA) (1 equivalent). The mixture was kept at room temperature at 40 psi of hydrogen for about 4 days. This removes the CBZ protecting group,
The C-2'BOM protected paclitaxel compound was produced as the FA salt. The mixture was filtered through diatomaceous earth and vacuum was applied. Base plus acylating agent was then added to the residue. In particular, the TFA salt of the C-2'BOM protected compound was dissolved in pyridine and either benzoyl chloride or benzoic anhydride was added. The resulting product has the formula:

The compound of formula 16 was dissolved in isopropyl alcohol and mixed in a pearl bottle (Parr).
bottle) and Pearlman's catalyst was added. 40 ps of hydrogen in this mixture
Hydrogenated at i for 24 hours. The mixture was then filtered through diatomaceous earth and the eluent was evacuated under vacuum. The residue was then chromatographed by the desired technique or recrystallized from ethyl acetate: hexane for the final paclitaxel product.

Consequently, the present invention has been described in relation to certain features directed to exemplary aspects of the invention. However, the present invention is defined by the claims of the present specification interpreted in view of the prior art, and is typical of the present invention without departing from the inventive idea contained in the present specification. It should be appreciated that changes or changes may be made in various aspects.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 207/46 C07D 207/46 209/48 209/76 209/76 209/48 Z (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI) , CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, C , CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG , SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Chandler, Madavi, Sea USA Colorado, Boulder, Desert Mountain Court 5342 F Term (reference) 4C069 AC36 AD10 BC06 BC12 CC15 4C204 AB01 BB01 BB04 CB04 CB19 DB16 EB03 FB34 GB01 4H006 AA01 AA02 AA03 AB28 AC48 BB23 BB25 BJ50 BT16 BV22 BV53 RA10

Claims (29)

[Claims] 1. The formula: (In the formula, P ₁ is a hydroxyl protecting group, R ₁ is an alkyl group, an olefin group,
An aromatic group, an O-alkyl group, an O-olefin group, or an O-aromatic group, Z
Is selected from the group consisting of substituted phenyl residues and N-imide residues). 2. The compound according to claim 1, wherein R ₁ is selected from the group consisting of Ph, PhCH ₂ , O-Ph and O-CH ₂ Ph. 3. The compound according to claim 1, wherein P ₁ is selected from the group consisting of benzyl, benzyloxymethyl and benzoyl. 4. The compound according to claim ₁ , wherein R ₁ is O—CH ₂ Ph and P ₁ is benzyloxymethyl. 5. Z is of the formula: (In the formula, R _{2 to} R ₆ are each selected from the group consisting of H and an electron-withdrawing group.)
The compound according to claim 1, which is a substituted phenyl residue having: 6. R _{2 to} R ₆ are each selected from the group consisting of H, halogen and NO ₂ , and at least one of R _{2 to} R ₆ is one of the group consisting of halogen and NO _2. 5 ". 7. The compound according to claim 6, wherein the halogen is F. 8. P₁Is benzyl, benzyloxymethyl and benzoyl?
Selected from the group consisting of; R_Two, R_Three, R₅And R₆Is H; R_FourIs NO_Two
And R₁Is OCH_TwoThe compound according to claim 6, which is Ph. 9. P ₁ is selected from the group consisting of benzyl, benzyloxymethyl and benzoyl; R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are F; R ₁ is OCH ₂ Ph. The compound according to claim 6. 10. P ₁ is selected from the group consisting of benzyl, benzyloxymethyl and benzoyl; R ₂ and R ₄ are NO ₂ ; R ₃ , R ₅ and R
The compound according to claim 6, wherein ₆ is H; R ₁ is OCH ₂ Ph. 11. The compound according to claim 1, wherein Z is a heterocyclic N-imide residue having 5 to 7 atoms in the ring. 12. Z is a heterocycle N substituted with at least one electron withdrawing group.
-The compound according to claim 1, which is an imide residue. 13. The compound according to claim 12, wherein the electron withdrawing group is selected from the group consisting of halogen and nitro group. 14. The heterocyclic N-imide residue is substituted with a plurality of electron withdrawing groups, and the first electron withdrawing group substituted on the heterocyclic N-imide residue is the heterocyclic N-imide. 13. The compound according to claim 12, which is of a different type from the second electron-withdrawing group substituted on the residue. 15. Z is succinimide, phthalimide, 5-norbornene-
The compound according to claim 1, which is selected from the group consisting of 2,3-dicarboximide and maleimide residues and substituted derivatives thereof. 16. Z is an N-imide residue selected from the group consisting of the following formulas 1-5, and has the formulas 1-5: The compound of claim 1, wherein R _{2 to} R ₉ and Y are each selected from the group consisting of H and an electron-withdrawing group, and n is an integer. 17. The compound according to claim 16, wherein Z is an N-imide residue of the formula 5, and n is an integer of 2-4. 18. The compound according to claim 16, wherein R _{2 to} R ₉ and Y are electron withdrawing groups selected from the group consisting of halogen and nitro group, respectively. 19. The general formula: [Wherein R ₁ is an alkyl group, an olefin group, an aromatic group, an O-alkyl group, an O-olefin group, or an O-aromatic group; P ₁ is a hydroxyl protecting group;
₁₀ is a first compound of H or CO ₂ X (X is an alkyl group, an olefin group or an aromatic group) and has the general formula: HO-Z (wherein Z is a substituted phenyl residue and an N-imide residue). A compound of the general formula: (Wherein R ₁ is an alkyl group, an olefin group, an aromatic group, an O-alkyl group, an O-olefin group, or an O-aromatic group; P ₁ is a hydroxyl protecting group; Z
Are selected from substituted phenyl residues and N-imide residues) to form a paclitaxel, paclitaxel analogs and ester derivatives useful for the production of their intermediates. 20. The chemical method according to claim 19, wherein R ₁₀ is H, and the reaction step is performed in the presence of THF and carbodiimide. 21. The chemical method according to claim 20, wherein the carbodiimide is dicyclohexylcarbodiimide. 22. The chemical method according to claim 19, wherein R ₁₀ is CO ₂ X, and X is an alkyl group, an olefin group or an aromatic group. 23. The chemical method according to claim 22, wherein X is —CH ₂ CH (CH ₃ ) ₂ . 24. The chemical method according to claim 22, wherein the reaction step is performed in the presence of N-methylmorpholine and THF. 25. The first compound has the formula: Compound of the formula Cl-CO 2 first compound "claim 22" is formed by obtaining and _X is reacted with a compound having the chemical method described with. 26. The second compound has the formula: (In the formula, R _{2 to} R ₆ are each selected from the group consisting of H and an electron-withdrawing group.)
The chemical method according to claim 19, which comprises: 27. R _{2 to} R ₆ are each selected from the group consisting of H, halogen and NO ₂ groups, wherein at least one of R _{2 to} R ₆ is one of the group consisting of halogen and NO ₂ groups. , R ₁ is Ph, PhCH ₂ , O-Ph and O-CH _2.
27. The chemical process according to claim 26, wherein P ₁ is selected from the group consisting of Ph and P ₁ is selected from the group consisting of benzyl, benzyloxymethyl and benzoyl. 28. The chemical method according to claim 19, wherein Z is a heterocyclic N-imide residue having 5 to 7 atoms in the ring. 29. Z is succinimide, phthalimide, 5-norbornene-
The chemical method according to claim 19, which is selected from the group consisting of 2,3-dicarboximide and maleimide residues and substituted derivatives thereof.