WO2010024762A1 - PREPARATION OF β-PHENYL-ISOSERINE DERIVATIVES - Google Patents

PREPARATION OF β-PHENYL-ISOSERINE DERIVATIVES Download PDF

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WO2010024762A1
WO2010024762A1 PCT/SE2009/050962 SE2009050962W WO2010024762A1 WO 2010024762 A1 WO2010024762 A1 WO 2010024762A1 SE 2009050962 W SE2009050962 W SE 2009050962W WO 2010024762 A1 WO2010024762 A1 WO 2010024762A1
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general formula
alkyl
phenyl
mmol
amino
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French (fr)
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Armando Cordova
Pawel Dziedzic
Jan Vesely
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Organoclick Aktiebolag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a method of preparing ⁇ -isoserine derivatives.
  • the present invention relates to a catalytic asymmetric method for preparing carbamate-protected (BOC- or Cbz-protected) ⁇ -oxy- ⁇ -amino aldehydes and their transformation to corresponding carboxylic acids.
  • the present invention relates to the preparation of ⁇ -hydroxy- ⁇ - amino-acids useful in the selective esterification of the hydroxyl group at position 15 of baccatin III.
  • Docetaxel (TaxotereTM), a synthetic derivative of paclitaxel (TaxolTM), is an important anticancer agent. It is an ester of (2R,3S)-phenylisoserine with the hydroxyl group at position 15 of the tetracyclic heptadecane skeleton common to docetaxel, paclitaxel, and their derivatives.
  • Paclitaxel and docetaxel are used in the treatment of various cancer forms.
  • Paclitaxel and analogues thereof modified in the phenylisoserine side chain can be obtained by esterification of the corresponding (2R,3S)-phenylisoserine derivative with a protected baccatin III derivative: esterifi cation; deprotection paclitaxel Baccatin III derivative
  • PG Protective Group Baccatin III is obtained from Pacific yew (Taxus brevifolia).
  • Paclitaxel derivatives are modified in their isoserine side chain. They are of considerable interest since chemical modification of the side chain is a way to change the biological activity and/or other properties of paclitaxel with the aim to find better anti-cancer agents.
  • paclitaxel and derivatives thereof on an industrial scale employs chiral auxiliaries or toxic metal catalysts (see, for instance, U.S. Patents Nos. 6,114,550 and 6,307,064; A. M. Kanazawa, J.-N. Denis, A. E. Greene, J. Org. Chem. 59 (1994) 1238; references cited therein).
  • the present invention relates to a process for stereoselective synthesis of ⁇ -phenylisosehne derivatives of the general formula I:
  • R is aryl or R 2 ;
  • R 1 is C1-C10 non-branched or branched alkyl, C 2 -C 8 alkynyl, C 2 -C 8 alkenyl, C3-C6 cycloalkyl, C 4 -C ⁇ cycloalkenyl, C 4 -C 5 cycloalkenyl, or C 7 -Cn bicycloalkyl, R 1 being optionally substituted with one or more of the group consisting of: halogen, hydroxyl, alkoxy, aryl such as phenyl, cyano, carboxyl, CrC 7 alkyloxycarbonyl;
  • X 1 is H or a hydroxyl-protecting group selected from methoxymethyl, 1 - ethoxyethyl, bexyloxymethyl, 2,2,2-trichloroethoxymethyl, tetrahydrofuranyl, tetrahydropyranyl and ⁇ -(thmethylsilyl)ethoxymethyl, trialkylsilyl in which the alkyl contains from 1 to 4 carbon atoms, alkyldiphenylsilyl, -CH 2 -Ph in which Ph represents phenyl optionally substituted with one or more same or different atoms or groups chosen from halogen, alkyl containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms.
  • R is aryl, it is preferably phenyl or ⁇ - or ⁇ -naphthyl optionally substituted with one or more of halogen (fluorine, chlorine, bromine, iodine); alkyl, alkenyl, akynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro; trifluoromethyl; wherein alkyl or an alkyl portion of a substituent is any of CrC 4 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and wherein aryl
  • R is R 2 , it is preferably branched or non-branched C1-C10 alkyl, C2-C8 alkynyl, C 2 -C 8 alkenyl; C 3 -C 6 cycloalkyl; C 4 -C 6 cycloalkenyl; C 7 -Cn bicycloalkyl; optionally substituted with one or more of halogen; hydroxy; alkoxy; aryl, in particular phenyl; cyano; carboxyl; alkyloxycarbonyl in which alkyl is CrC 7, for instance benzyl; a carbon atom substituted by three halogen atoms, such as CF 3 , wherein aryl is optionally phenyl or phenyl substituted with one or more same or different substituents selected from: halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, trifluoromethyl.
  • R is phenyl
  • R 1 is te/t-butoxy
  • X 1 is benzyl or p-methoxybenzyl.
  • the ⁇ -phenylisosehne derivatives of the general formula I can be advantageously obtained directly by the process of the invention with excellent enantio- and diastereoselectivity.
  • the process of the invention comprises fewer steps than the non-catalytic processes known in the art.
  • the process of the invention includes a step similar to one described in WO2008/043798 directed to the preparation of precursors of compounds of general formula (I).
  • R, R 1 and X 1 have the same meaning as above, is oxidized to the corresponding carboxylic acid of the general formula I.
  • Suitable oxidants comprise NaCIO 2 , in particular in combination with butene.
  • the aldehyde of the general formula V is oxidized directly, that is, without purification, to the carboxylic acid of the general formula 1.
  • the process according to the invention is generally carried out by reaction the N-carbamate imine of the general formula Il with the protected ⁇ -oxyaldehyde of general formula III in the presence of a chiral amino acid or a derivative thereof of the general formula IV.
  • Suitable amino acids and derivatives thereof comprise (R)-proline, (R)-proline tetrazoles, (R)-proline amides, (R)-proline sulfoneamides.
  • (R)-proline is particularly preferred.
  • the desired enantiomeric form of the aldehyde of the general formula V is obtained in an enantiomeric excess of 99 % or more, that is, in essentially pure enantiomeric form.
  • the process of the invention is preferably carried out in a polar aprotic solvent, for instance acetonitrile, dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or /V-methyl pyrrolidone (NMP), at a temperature from -20 to 30 0 C, preferably at about room temperature (20-25 0 C).
  • a polar aprotic solvent for instance acetonitrile, dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or /V-methyl pyrrolidone (NMP)
  • the product of general formula (V) can be oxidized in, for instance, te/t-butanol:H 2 O 2:1 (v/v) at a concentration of from about 0.05 to about 0.5 M, preferably at about room temperature (20-25 0 C).
  • isobutene 6-7 eqvivalents
  • KH 2 PO 4 (1 ,5-2 eq)
  • NaCIO 2 (3-4 eq)
  • the compound of general formula I is used to prepare a methyl or other aliphatic or aromatic carboxylic ester of the general formula Vl
  • R, R 1 and X 1 are defined as above and Me is straight or branched CrC ⁇ alkyl, in particular methyl and ethyl.
  • Another preferred aspect of the invention comprises selective removal of the protecting group X 1 from a compound of the general formula Vl for preparing a ⁇ -amino- ⁇ -hydroxy carboxylic acid derivative of the general formula VII
  • Still another preferred aspect of the invention comprises selective removal of the protecting group R 1 from a compound of the general formula Vl to prepare a ⁇ - amino- ⁇ -hydroxy carboxylic acid derivative of the general formula VIII
  • reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 10 were combined, and the solvent evaporated under reduced pressure. The title compound 10 was recovered in form of a colourless oil; yield 12%, diastereomeric ratio (dr) >19:1 , enantiomeric excess (ee), 99%.
  • reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 12 were combined, and the solvent evaporated under reduced pressure. The title compound 12 was obtained as a colourless oil in 24 % yield; dr >19:1 ; ee 99 %.
  • reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 13 were combined, and the solvent evaporated under reduced pressure. The title compound 13 was obtained as a colourless oil in 56% yield; dr >19:1 ; ee 99%.
  • reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc). Fractions containing pure aldehyde 14 were combined, and the solvent removed under reduced pressure. The title compound 14 was obtained in 49% yield as a colourless oil; dr >19:1 dr; ee 99%.
  • Example 7 (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-phenyl- propanal (16).
  • /V-te/t-butoxycarbonylbenzylimine 1.0 equiv, 2.5 mmol
  • 2-benzyloxyacetaldehyde 1.1 equiv, 2.7 mmol
  • CH 3 CN 10 mL
  • R 2-proline
  • Example 9 (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3- phenylpropanal (18).
  • /V-te/t-butoxycarbonylbenzylimine 1.0 equiv, 50 mmol
  • 2-benzyloxyacetaldehyde 1.1 equiv, 55 mmol
  • (R)-proline 20 mol %)
  • reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 19 were combined, and the solvent evaporated. The title compound 19 was obtained as a colourless oil in 56% yield; dr 3:1 ; ee 99 %.
  • reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 20 were combined, and the solvent evaporated under reduced pressure. The title compound 20 was obtained as a colourless oil in 52% yield; dr 9:1 ; ee 99%.
  • reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions contaning pure aldehyde 22 were combined, and the solvent evaporated under reduced pressure. The title compound 22 was obtained as a colourless oil in 22 % yield; dr 3:1 ; ee 99%.
  • reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions contaning pure aldehyde 22 were combined, and the solvent evaporated under reduced pressure. The title compound 22 was obtained as a yellow oil in 45 % yield; dr 95:5; ee 99%.
  • Example 14 (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(3- methoxyphenyl)propanal (23).
  • reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 23 were combined, and the solvent evaporated under reduced pressure. The title compound 23 was obtained as a colourless oil in 67% yield; dr 93:7; ee 99%.
  • reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 24 were combined, and the solvent evaporated under reduced pressure.
  • Example 18 (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3- phenylpropanoic acid (27).
  • (2R,3S)-2-benzyloxy-3-te/t-butoxy- carbonylamino-3-phenylpropanal 16; 1 mmol
  • isobutene 0.1 ml_
  • te/t-butanol 4.0 ml_
  • H 2 O 2.0 ml_
  • KH 2 PO 4 54.4 mg, 4.0 mmol
  • NaCIO 2 36 mg, 4.0 mmol
  • Example 19 (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-phenyl- propanoic acid (28).
  • (2R,3S)-2-benzyloxy-3-te/t-butoxy- carbonylamino-3-phenylpropanal 16; 5 mmol
  • isobutene 0.5 ml_
  • te/t-butanol 20.0 ml_
  • H 2 O (10.0 ml_) was added sequentially KH 2 PO 4 (272 mg, 20.0 mmol) and NaCIO 2 (180 mg, 20.0 mmol) at 23 0 C.
  • Example 21 (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(3- methoxyphenyl)propanoic acid (30).
  • (2R,3S)-2-Benzyloxy-3- te/t-butoxy-carbonylamino-3-(3-methoxyphenyl)propanal 23; 1 mmol
  • isobutene 0.1 mL
  • te/t-butanol 4.0 mL
  • H 2 O 2.0 mL
  • KH 2 PO 4 54.4 mg, 4.0 mmol
  • NaCIO 2 36 mg, 4.0 mmol
  • Example 22 (2/?,3S)-2-Benzyloxy-3-benzyloxy-carbonylamino-3- (naphthalene-2-yl)propanoic acid (31).
  • (2R,3S)-2-Benzyloxy- 3-benzyloxy-carbonylamino-3-(naphthalene-2-yl)propanal 24; 1 mmol
  • isobutene 0.1 ml_
  • te/t-butanol 4.0 ml_
  • H 2 O 2.0 ml_
  • KH 2 PO 4 54.4 mg, 4.0 mmol
  • NaCIO 2 36 mg, 4.0 mmol
  • Example 23 Methyl (2R,3S)-2-benzyloxy-3-tert-butoxy-carbonylamino-3- phenylpropanoate (32).
  • (2R,3S)-2-benzyloxy-3-te/t-butoxy- carbonylamino-3-phenylpropanoic acid 26; 80 mg, 0.22 mmol
  • toluene:MeOH 4:1 , 2.5 ml_
  • thmethylsilyldiazometane 2.0 M in ether, 0.117 ml_, 0.23 mmol
  • Example 24 Methyl (2/?,3S)-2-hydroxy-3-fert-butoxy-carbonylamino-3- phenylpropanoate (33). To a solution of methyl (2R,3S)-2-benzyloxy-3-te/t- butoxy-carbonylamino-3-phenylpropanoate (32; 55 mg, 0.14 mmol) in MeOH (4 ml_), palladium on carbon (5 mg) was added. The reaction mixture was stirred under H 2 (90 psi) atmosphere. When the starting material could no longer be detected by TLC, the solution was filtered through celite and concentrated to give the title compound as white crystals in 99% yield (42 mg).
  • (2R, 3S)-2-(Benzyloxy)-3-(fe/t-butoxycarbonylamino)-3-phenylpropanoic acid 28 (1.40 g, 3.77 mmol) was dissolved in dry toluene (35 ml_) under nitrogen atmosphere in a single necked 100 ml round bottomed flask equipped with magnetic stirrer. Dicyclohexylcarbodiimide (0.778 g, 3.77 mmol) is added to the mixture which is left under stirring for 5 minutes at room temperature.
  • Example 27 4-Acetoxy-2 ⁇ -benzoyloxy-5 ⁇ ,20-epoxy-1,7 ⁇ ,10 ⁇ -trihydroxy-9- oxo-11 -taxen-13 ⁇ -y I ⁇ 2R, 3S)-3-terf-butoxycarbonylamino-3-phenyl-2- (benzyloxy)propionate (34).
  • Docetaxel derivative 33 (0.590 g, 0.471 mmol) was dissolved in glacial acetic acid (30 ml) under nitrogen atmosphere in a 100 ml single-necked flask equipped with magnetic stirrer. Methanol (30 ml) is then added followed by zinc/copper mixture (2.60 g, 2.2Og of zinc and 0.40 g of copper).
  • Example 28 4-Acetoxy-2 ⁇ -benzoyloxy-5 ⁇ ,20-epoxy-1,7 ⁇ ,10 ⁇ -trihydroxy-9- oxo-11-taxen-13 ⁇ -yl (2R, 3S)-3-tert-butoxycarbonylamino-3-phenyl-2- hydroxypropionate (docetaxel).

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Abstract

A process for stereoselective synthesis of a β-phenylisoserine comprises reacting a carbonyl imine R-C=N-CO-OR1 with a protected α- oxyaldehyde X1O-CH2CHO in the presence of a chiral amine catalyst and oxidizing aldehyde so obtained.

Description

PREPARATION OF β-PHENYL-ISOSERINE DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to a method of preparing β-isoserine derivatives. In particular, the present invention relates to a catalytic asymmetric method for preparing carbamate-protected (BOC- or Cbz-protected) α-oxy-β-amino aldehydes and their transformation to corresponding carboxylic acids. Most particularly, the present invention relates to the preparation of α-hydroxy-β- amino-acids useful in the selective esterification of the hydroxyl group at position 15 of baccatin III.
BACKGROUND OF THE INVENTION
The β-amino-α-hydroxy acid moiety is a common structural component in a vast group of naturally occurring pharmaceutically active molecules. Docetaxel (Taxotere™), a synthetic derivative of paclitaxel (Taxol™), is an important anticancer agent. It is an ester of (2R,3S)-phenylisoserine with the hydroxyl group at position 15 of the tetracyclic heptadecane skeleton common to docetaxel, paclitaxel, and their derivatives.
Figure imgf000002_0001
Paclitaxel and docetaxel are used in the treatment of various cancer forms. Paclitaxel and analogues thereof modified in the phenylisoserine side chain can be obtained by esterification of the corresponding (2R,3S)-phenylisoserine derivative with a protected baccatin III derivative: esterifi cation; deprotection paclitaxel
Figure imgf000003_0001
Baccatin III derivative
PG = Protective Group Baccatin III is obtained from Pacific yew (Taxus brevifolia).
Paclitaxel derivatives are modified in their isoserine side chain. They are of considerable interest since chemical modification of the side chain is a way to change the biological activity and/or other properties of paclitaxel with the aim to find better anti-cancer agents.
The synthesis of paclitaxel and derivatives thereof on an industrial scale employs chiral auxiliaries or toxic metal catalysts (see, for instance, U.S. Patents Nos. 6,114,550 and 6,307,064; A. M. Kanazawa, J.-N. Denis, A. E. Greene, J. Org. Chem. 59 (1994) 1238; references cited therein).
Thus, the provision of an improved method for the synthesis of paclitaxel derivatives is highly desirable.
Compounds of the general formula (I), especially those in which X1 is -CH2-Ph, are useful in the preparation of paclitaxel and its derivatives by direct estehfication with a 10-deacetyl baccatin III derivative comprising suitably protected hydroxyl groups, such as a 10-deacetyl baccatin III derivative disclosed in European Patents Nos. EP 0 336 840 and EP 0414 610.
Compounds of the general formula (I) in which X1 is H can be converted to the corresponding acetonide derivatives, which are useful in the preparation of paclitaxel and its analogues by esterification with a 10-deacetyl baccatin III derivative having suitably protected hydroxyl groups (A. M. Kanazawa, J.-N. Denis, A. E. Greene, J. Org. Chem. 1994, 59, 1238). Compounds of the general formula (I) can be prepared by using chiral technology described in U.S. Patent No. 6,114,550.
SHORT DESCRIPTION OF THE INVENTION
The present invention relates to a process for stereoselective synthesis of β-phenylisosehne derivatives of the general formula I:
O
Jl
R1-O^NH O
(I)
R" >^ OH
OX1
wherein
R is aryl or R2;
R1 is C1-C10 non-branched or branched alkyl, C2-C8 alkynyl, C2-C8 alkenyl, C3-C6 cycloalkyl, C4-Cβ cycloalkenyl, C4-C5 cycloalkenyl, or C7-Cn bicycloalkyl, R1 being optionally substituted with one or more of the group consisting of: halogen, hydroxyl, alkoxy, aryl such as phenyl, cyano, carboxyl, CrC7 alkyloxycarbonyl;
X1 is H or a hydroxyl-protecting group selected from methoxymethyl, 1 - ethoxyethyl, bexyloxymethyl, 2,2,2-trichloroethoxymethyl, tetrahydrofuranyl, tetrahydropyranyl and β-(thmethylsilyl)ethoxymethyl, trialkylsilyl in which the alkyl contains from 1 to 4 carbon atoms, alkyldiphenylsilyl, -CH2-Ph in which Ph represents phenyl optionally substituted with one or more same or different atoms or groups chosen from halogen, alkyl containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms.
If R is aryl, it is preferably phenyl or α- or β-naphthyl optionally substituted with one or more of halogen (fluorine, chlorine, bromine, iodine); alkyl, alkenyl, akynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro; trifluoromethyl; wherein alkyl or an alkyl portion of a substituent is any of CrC4 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and wherein aryl comprises any of phenyl, α- or β-naphthyl, 2- or 3-furfuryl, thiophenyl, 2- or 3-pyridyl, indolyl, 2- or 3-pyridyl, imidazolyl.
If R is R2, it is preferably branched or non-branched C1-C10 alkyl, C2-C8 alkynyl, C2-C8 alkenyl; C3-C6 cycloalkyl; C4-C6 cycloalkenyl; C7-Cn bicycloalkyl; optionally substituted with one or more of halogen; hydroxy; alkoxy; aryl, in particular phenyl; cyano; carboxyl; alkyloxycarbonyl in which alkyl is CrC7, for instance benzyl; a carbon atom substituted by three halogen atoms, such as CF3, wherein aryl is optionally phenyl or phenyl substituted with one or more same or different substituents selected from: halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, trifluoromethyl.
Particularly preferred is a compound of the general formula (I) in which R is phenyl, R1 is te/t-butoxy, and X1 is benzyl or p-methoxybenzyl.
According to the present invention the β-phenylisosehne derivatives of the general formula I can be advantageously obtained directly by the process of the invention with excellent enantio- and diastereoselectivity. The process of the invention comprises fewer steps than the non-catalytic processes known in the art. The process of the invention includes a step similar to one described in WO2008/043798 directed to the preparation of precursors of compounds of general formula (I).
The process of the present invention comprises a first step comprising the reaction between a N-carbonyl imine of the general formula II, R-C=N-CO-OR1, in which Ar and R1 have the same meaning as above, with a protected α- oxyaldehyde of the general formula III, X1O-CH2CHO, in which X1 has the same meaning as above, in the presence of a chiral amine catalyst of the general formula IV R2
O ,γ2
N " o wrι H2 .N}' Ύ ' 2 (IV)
H 2
wherein Y2 is any Of CO2H, Ar2OSiR3, tetrazole, O=C-NHR, O=C-NH-SO2R, and the most preferred catalysts is (R)-proline,
and a second step, in which the β-amino-α-hydroxyaldhyde of the general formula V formed in the first step,
Figure imgf000006_0001
OX1
in which R, R1 and X1 have the same meaning as above, is oxidized to the corresponding carboxylic acid of the general formula I. Suitable oxidants comprise NaCIO2, in particular in combination with butene. In a preferred embodiment the aldehyde of the general formula V is oxidized directly, that is, without purification, to the carboxylic acid of the general formula 1.
The process according to the invention is generally carried out by reaction the N-carbamate imine of the general formula Il with the protected α-oxyaldehyde of general formula III in the presence of a chiral amino acid or a derivative thereof of the general formula IV. Suitable amino acids and derivatives thereof comprise (R)-proline, (R)-proline tetrazoles, (R)-proline amides, (R)-proline sulfoneamides. (R)-proline is particularly preferred. In the process of the invention the desired enantiomeric form of the aldehyde of the general formula V is obtained in an enantiomeric excess of 99 % or more, that is, in essentially pure enantiomeric form.
The process of the invention is preferably carried out in a polar aprotic solvent, for instance acetonitrile, dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or /V-methyl pyrrolidone (NMP), at a temperature from -20 to 30 0C, preferably at about room temperature (20-25 0C). A catalyst loading of 5-30 mol-%, in particular of about 20 mol%, is preferred.
The product of general formula (V) can be oxidized in, for instance, te/t-butanol:H2O 2:1 (v/v) at a concentration of from about 0.05 to about 0.5 M, preferably at about room temperature (20-25 0C). To the stirred solution isobutene (6-7 eqvivalents), KH2PO4 (1 ,5-2 eq), and NaCIO2 (3-4 eq) are added sequentially. The resulting mixture is stirred at room temperature to form the desired product of the general formula (I) for a time sufficient to consume 95 % or more of compound V..
According to a preferred aspect of the invention, the compound of general formula I is used to prepare a methyl or other aliphatic or aromatic carboxylic ester of the general formula Vl
Figure imgf000007_0001
wherein R, R1 and X1 are defined as above and Me is straight or branched CrCβ alkyl, in particular methyl and ethyl.
Another preferred aspect of the invention comprises selective removal of the protecting group X1 from a compound of the general formula Vl for preparing a β-amino-α-hydroxy carboxylic acid derivative of the general formula VII
Figure imgf000007_0002
wherein R and R1 are defined as above. Still another preferred aspect of the invention comprises selective removal of the protecting group R1 from a compound of the general formula Vl to prepare a β- amino-α-hydroxy carboxylic acid derivative of the general formula VIII
NH2 O
(VIM)
R OMe
OX1
wherein R is defined as above and X1 is H.
The invention will now be explained in greater detail by reference to a number of preferred embodiments.
DESCRIPTION OF PREFERRED EMBODIMENTS
A. Stereoselective preparation of aldehyde derivatives of β-isosehne
Example 1. (2R,3S)-2-fert-Butyldimethylsilyloxy-3-fert-butoxycarbonyl- amino-3-phenylpropanal (10). To a stirred solution of /V-te/t-butoxycarbonyl- benzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in DMF (10 ml_) at 4 0C was added (R)-proline (20 mol%), and the resulting reaction mixture vigorously stirred for 48 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 10 were combined, and the solvent evaporated under reduced pressure. The title compound 10 was recovered in form of a colourless oil; yield 12%, diastereomeric ratio (dr) >19:1 , enantiomeric excess (ee), 99%. 1H NMR (400 MHz, CDCI3): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d, J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), -0.14 (s, 3H), -0.34 (s, 3H); 13C NMR (100 MHz, CDCI3): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, - 5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C20H33NO4Si) requires m/z 402.2071 , found 402.2074. The ratio of enantiomers was determined by HPLC with an AD column n-hexane: /-PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, tR = 16.6 min; minor enantiomer, tR = 24.1 min; [α]D 25 = + 10.5 (c=1.0, CHCI3). Example 2. (2/?,3S)-2-fert-Butyldimethylsilyloxy-3-tert-butoxycarbonyl- amino-3-phenylpropanal (11). To a stirred solution of /V-te/t-butoxycarbonyl- benzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 4 0C was added (R)-proline (20 mol %), and the resulting reaction mixture vigorously stirred for 48 h. Next, the reaction was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 11 were combined, and the solvent evaporated under reduced pressure. The title compound 11 was obtained as a colourless oil in 36% yield; dr >19:1 ; ee >99%l. 1H NMR (400 MHz, CDCI3): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d, J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), -0.14 (s, 3H), -0.34 (s, 3H); 13C NMR (100 MHz, CDCI3): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, -5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C20H33NO4Si) requires m/z 402.2071 , found 402.2074. The enantiomeric excess was determined by HPLC with an AD column n-hexane: /-PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, tR = 16.6 min; minor enantiomer, tR = 24.1 min; [α]D 25 = + 10.5 (c=1.0, CHCI3).
Example 3: (2/?,3S)-2-fert-Butyldimethylsilyloxy-3-tert-butoxycarbonyl- amino-3-phenylpropanal (12). To a stirred solution of /V-te/t-butoxycarbonyl- benzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in NMP (10 ml_) at 4 0C was added (R)-proline (20 mol %), and the resulting reaction mixture vigorously stirred for 48 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 12 were combined, and the solvent evaporated under reduced pressure. The title compound 12 was obtained as a colourless oil in 24 % yield; dr >19:1 ; ee 99 %. 1H NMR (400 MHz, CDCI3): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d, J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), - 0.14 (s, 3H), -0.34 (s, 3H); 13C NMR (100 MHz, CDCI3): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, -5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C20H33NO4Si) requires m/z 402.2071 , found 402.2074. The enantiomeric excess was determined by HPLC with an AD column n-hexane: /- PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, tR = 16.6 min; minor enantiomer, tR = 24.1 min; [α]D 25 = + 10.5 (c=1.0, CHCI3).
Example 4. (2R,3S)-2-tert-Butyldimethylsilyloxy-3-tert-butoxycarbonyl- amino-3-phenylpropanal (13). To a stirred solution of /V-te/t-butoxycarbonyl- benzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyl-oxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 23 0C was added (R)-proline (20 mol %), and the resulting reaction mixture vigorously stirred for 48 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 13 were combined, and the solvent evaporated under reduced pressure. The title compound 13 was obtained as a colourless oil in 56% yield; dr >19:1 ; ee 99%. 1H NMR (400 MHz, CDCI3): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d, J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), -0.14 (s, 3H), -0.34 (s, 3H); 13C NMR (100 MHz, CDCI3): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, -5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C20H33NO4Si) requires m/z 402.2071 , found 402.2074. The enantiomeric excess was determined by HPLC with an AD column n-hexane: /-PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, tR = 16.6 min; minor enantiomer, tR = 24.1 min; [α]D 25 = + 10.5 (c=1.0, CHCI3).
Example 5. (2S,3/?)-2-tert-Butyldimethylsilyloxy-3-fert-butoxy-carbonyl- amino-3-phenylpropanal (14). To a stirred solution of /V-te/t-butoxycarbonyl- benzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 23 0C was added (S)-proline (20 mol %), and the reaction mixture vigorously stirred for 48 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc). Fractions containing pure aldehyde 14 were combined, and the solvent removed under reduced pressure. The title compound 14 was obtained in 49% yield as a colourless oil; dr >19:1 dr; ee 99%. 1H NMR (400 MHz, CDCI3): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d, J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), -0.14 (s, 3H), -0.34 (s, 3H); 13C NMR (100 MHz, CDCI3): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, -5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C20H33NO4Si) requires m/z 402.2071 , found 402.2074. The enantiomeric excess was determined by HPLC with an AD column n-hexane: /-PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, tR = 16.6 min; minor enantiomer, tR = 24.1 min; [α]D 25 = -10.5 (c=1.0, CHCI3).
Example 6. (2S,3/?)-2-fert-Butyldimethylsilyloxy-3-tert-butoxy- carbonylamino-3-phenylpropanal (15). To a stirred solution of N-tert- butoxycarbonylbenzylimine (1.0 equiv, 2.5 mmol) and 2-te/t-butyldimethylsilyl- oxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 23 0C was added frans-hydroxy-(S)-proline (20 mol %), and the resulting reaction mixture vigorously stirred for 48 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 15 were combined, and the solvent evaporated. The title compound 15 was obtained as a colourless oil in 6 % yield: dr >19:1 ; ee 99 %. 1H NMR (400 MHz, CDCI3): δ = 9.70 (bs, 1 H), 7.36-7.24 (m, 5H), 5.43 (d,
J=8.0Hz, 1 H), 5.21 (d, J=8.0Hz, 1 H), 4.22 (bs, 1 H), 1.41 (s, 9H), 0.78 (s, 9H), - 0.14 (s, 3H), -0.34 (s, 3H); 13C NMR (100 MHz, CDCI3): 201.7, 155.2, 139.5, 128.7, 127.8, 126.6, 81.7, 80.3, 55.6, 28.5, 25.8, -5.1 , -5.5; HRMS (ESI): calcd for [M+Na] (C20H33NO4Si) requires m/z 402.2071 , found 402.2074. The enantiomeric excess was determined by HPLC with an AD column n-hexane: /- PrOH = 98:2, λ = 220 nm), 0.5 ml/min; major enantiomer, tR = 16.6 min; minor enantiomer, tR = 24.1 min; [α]D 25 = -10.5 (c=1.0, CHCI3).
Example 7. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-phenyl- propanal (16). To a stirred solution of /V-te/t-butoxycarbonylbenzylimine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 mL) at 23 0C was added (R)-proline (20 mol%), and the reaction mixture vigorously stirred for 7 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 16 were combined, and the solvent evaporated. The title compound 16 was obtained as a colourless oil in 60% yield; dr >19:1 dr; ee 99%. 1H NMR (400 MHz): δ = 9.73-9.72 (m, 1 H), 7.37-7.23 (m, 8H), 7.10-7.06 (m, 2H), 5.52 (bs, 1 H), 5.24 (bs, 1 H), 4.60 (d, J=11.6Hz, 1 H), 4.39 (d, J=11.6Hz, 1 H), 4.04 (bs, 1 H), 1.40 (s, 9H); 13C NMR (100 MHz): 201.2, 155.2, 139.4, 136.7, 128.8, 128.7, 128.4, 128.3, 127.9, 126.8, 86.0, 80.3, 73.6, 54.3, 28.5; HRMS (ESI): calcd for [M+Na] (C2IH25NO4) requires m/z 378.1676, found 378.1671. The enantiomeric excess was determined by HPLC with an AD column (n-hexane: /-PrOH = 90:10, λ = 220 nm), 0.5 ml/min; major enantiomer, tR = 15.9 min; minor enantiomer, tR = 28.2 min; [α]D 25 = + 29.0 (c=1.0, CHCI3).
Example 8. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-
(naphthalene-2-yl)propanal (17). To a stirred solution of N-tert- butoxycarbonylnaphthylimine (1.0 equiv, 2.5 mmol) and 2- benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 23 0C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 17 were combined, and the solvent evaporated under reduced pressure. The title compound 17 was obtained as a yellow oil in 60% yield; dr 95:5 dr; ee 99%. 1H NMR (400MHz, CDCI3): δ - 9.79 (s, 1 H), 7.87-7.77 (m, 4H), 7.54-7.44 (m, 3H), 7.26-7.14 (m, 3H), 7.05 (d, J=7.6Hz, 2H), 5.78 (d, J=8.8Hz, 1 H), 5.48 (d, J=8.8Hz, 1 H), 4.60 (d, J=11.6Hz, 1 H), 4.37 (d, J=11.6Hz, 1 H), 4.15 (bs, 1 H), 1.42 (s, 9H); 13C NMR (100MHz, CDCI3): 201.3, 155.4, 136.9, 136.7, 133,5, 133.1 , 128.7, 128.6, 128.4, 128.4, 128.3, 127.9, 126.6, 126.3, 125.8, 124.9, 86.0, 80.4, 73.7, 54.5, 28.5; HRMS (ESI): calcd. for [M+Na] (C25H27NO4) requires m/z 428.1832, found 428.1842. The enantiomeric excess was determined by chiral HPLC with an AD column (n-hexane:/-PrOH = 90:10, λ = 254 nm) 1.0 ml/min, syn-diastereomer: tR major enantiomer = 9.4 min, tR minor enantiomer = 19.3 min; [α]D = + 40.0 (c=1.0, CHCI3).
Example 9. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3- phenylpropanal (18). To a stirred solution of /V-te/t-butoxycarbonylbenzylimine (1.0 equiv, 50 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 55 mmol) in CH3CN (200 mL) at 23 0C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 10 h. The reaction was quenched by extraction with EtOAc and H2O. The combined organic layers were dried with Na2SO4, concentrated under reduced pressure, loaded on a silica-gel column, and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 18 were combined, and the solvent evaporated under reduced pressure. The title compound 18 was obtained as a colourless oil in 61 % yield; dr >19:1 ; ee 99%. 1H NMR (400 MHz): δ = 9.73-9.72 (m, 1 H), 7.37-7.23 (m, 8H), 7.10-7.06 (m, 2H), 5.52 (bs, 1 H), 5.24 (bs, 1 H), 4.60 (d, J=11.6Hz, 1 H), 4.39 (d, J=11.6Hz, 1 H), 4.04 (bs, 1 H), 1.40 (s, 9H); 13C NMR (100 MHz): 201.2, 155.2, 139.4, 136.7, 128.8, 128.7, 128.4, 128.3, 127.9, 126.8, 86.0, 80.3, 73.6, 54.3, 28.5; HRMS (ESI): calcd for [M+Na] (C2iH25NO4) requires m/z 378.1676, found 378.1671. The enantiomeric excess was determined by HPLC with an AD column (n-hexane:/-PrOH = 90:10, λ = 220 nm), 0.5 mL/min; major enantiomer, tR = 15.9 min; minor enantiomer, tR = 28.2 min; [α]D 25 = + 29.0 (c=1.0, CHCI3).
Example 10. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(4- methylphenyl)propanal (19). To a stirred solution of /V-te/t-butoxycarbonyl-4- methylbenzylimine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 23 0C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 19 were combined, and the solvent evaporated. The title compound 19 was obtained as a colourless oil in 56% yield; dr 3:1 ; ee 99 %. 1H NMR (400 MHz, CDCI3): δ(antf) = 9.70 (s, 1 H), 9.48*(bs, 0.3H), 7.36-7.08 (m, 12H), 5.50 (bs, 1 H), 5.20 (bs, 0.3H), 5.14*(bs, 0.3H), 5.04*(bs, 0.3H), 4.70*(d, J=11.6 hz, 0.3H), 4.60 (d, J=11.2Hz, 1 H), 4.52*(d, J=12Hz, 0.3H), 4.42 (d, J=12Hz, 1 H), 4.10*(m, 0.3H), 4.02 (bs, 1 H), 2.36 (s, 3H), 2.33*(s, 1 H), 1.40(s, 12H); 13C (100MHz, CDCI3): 21.3, 28.5, 54.1 , 73.6, 80.2, 86.1 , 126.7, 127.9, 128.3, 128.4, 128.7, 128.8, 129.4, 136.8, 137.5, 155.2, 201.3; HRMS (ESI): calcd for [M+Na] (C22H27NO4) requires m/z 392.1839, found 392.1832; The enantiomeric excess was determined by chiral HPLC with an AD column ( n-hexane:/-PrOH = 90:10, λ = 220 nm) 0.5 ml/min; syn-diastereomer: major enantiomer, tR = 14.60 min; minor enantiomer, tR = 23.25 min; [α]D = +22.0 for dr 3:1 (symanti) (c=1.0, CHCI3).
Example 11. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(4- methoxyphenyl)propanal (20). To a stirred solution of /V-te/t-butoxycarbonyl-4- methoxybenzyl-imine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 23 0C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 20 were combined, and the solvent evaporated under reduced pressure. The title compound 20 was obtained as a colourless oil in 52% yield; dr 9:1 ; ee 99%. 1H NMR (400 MHz, CDCI3): δ= 9.70 (s, 1 H), 7.40-7.20 (m, 6H), 7.16-7.11 (m, 1 H), 6.89-6.86 (d, J=8.4Hz, 2H), 5.48 (bs, 1 H), 5.18 (bs, 1 H), 4.60 (d, J=11.6Hz, 1 H), 4.42 (d, J=11.6Hz, 1 H), 4.00 (bs, 1 H), 3.82 (s, 3H),1.40 (s, 9H); 13C NMR (100 MHz, CDCI3): 28.3, 35.5, 73.4, 80.0, 85.9, 113.9, 127.8, 128.0, 128.1 , 128.2, 128.2, 128.5, 128.6, 136.6, 155.0, 201.3; HRMS (ESI): calcd for [M+Na] (C22H27NO5) requires m/z 408.1781 , found 408.1785; The enantiomeric excess was determined by chiral HPLC with an AD column (n-hexane:/-PrOH = 90:10, λ = 220 nm) 0.5 ml/min. Syn-diastereomer: major enantiomer, tR = 20.34 min; minor enantiomer, tR = 36.04 min; [α]D = +28.0 (c=1.0, CHCI3).
Example 12. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(4-chloro- phenyl)propanal (21). To a stirred solution of /V-te/t-butoxycarbonyl-4- chlorobenzylimine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 23 0C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions contaning pure aldehyde 22 were combined, and the solvent evaporated under reduced pressure. The title compound 22 was obtained as a colourless oil in 22 % yield; dr 3:1 ; ee 99%. 1H NMR (400 MHz, CDCI3): δ(antι ) - 9.71 (s, 1 H), 9.46* (bs, 1 H), 7.40-7.20 (m, 16H), 7.10-7.06 (m, 2H), 5.56 (bs, 1 H), 5.20 (bs, 1 H), 5.16* (d, J=11.2Hz, 1 H), 5.04* (bs, 1 H), 4.72* (d, J=12Hz, 1 H), 4.63 (d, J=12Hz, 1 H), 4.52*(d, J=12Hz, 1 H), 4.40 (d, J=12Hz, 1 H), 4.06* (bs, 1 H), 3.98 (bs, 1 H), 1.40 (s, 18H); 13C NMR (100MHz, CDCI3)(syn- diastereomer): 200.9, 154.9, 136.2, 133.5, 129.3, 128.7, 128.5, 128.3, 128.2, 128.0, 127.0, 85.3, 80.3, 73.4, 53.7, 28.3; HRMS (ESI): calcd for [M+Na] (C2iH24NO4CI) requires m/z 412.1286, found 412.1290; The enantiomeric excess was determined by chiral HPLC with an AD column (n-hexane:/-PrOH = 93:7, λ = 220 nm) 0.5 mL/min; syn-diastereomer: major enantiomer, tR = 18.60 min; minor enantiomer, tR = 41.88 min. [a]D = +31.0 for dr 2:1 (syrr.anti) (c=1.0, CHCI3).
Example 13. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(2-nitro- phenyl)propanal (22). To a stirred solution of /V-te/t-butoxycarbonyl-2- nitrobenzylimine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 23 0C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions contaning pure aldehyde 22 were combined, and the solvent evaporated under reduced pressure. The title compound 22 was obtained as a yellow oil in 45 % yield; dr 95:5; ee 99%.1H NMR (400MHz, CDCI3): δ - 9.81 (s, 1 H), 8.04 (d, J=7.6Hz, 1 H), 7.67-7.57 (m, 2H), 7.51 -7.45 (m, 1 H), 7.25-7.16 (m, 3H), 6.97 (d, J=6.4Hz, 2H), 6.00 (d, J=8.0Hz, 1 H), 5.70 (d, J=8.0Hz, 1 H), 4.70 (d, J=11.6Hz, 1 H), 4.34 (s, 1 H), 4.27 (d, J=7.2Hz, 1 H), 1.37 (s, 9H); 13C NMR (100MHz, CDCI3): 199.0, 154.9, 147.8, 136.4, 136.0, 133.6, 129.6, 128.8, 128.7, 128.5, 128.4, 125.5, 90.0, 80.7, 73.7, 49.9, 28.4; HRMS (ESI): calcd. for [M+Na] (C2iH24N2O6) requires m/z 423.1527, found 423.1525. The enantiomeric excess was determined by chiral HPLC with an AD column ( n-hexane:/-PrOH = 92:8, λ = 254 nm) 0.5 ml/min, syn-diastereomer: tR major enantiomer = 21.2 min, tR minor enantiomer = 25.8 min; [ά\o = - 13.0 (c=1.0, CHCI3).
Example 14. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(3- methoxyphenyl)propanal (23). To a stirred solution of /V-te/t-butoxycarbonyl-3- methoxybenzyl-imine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 23 0C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 23 were combined, and the solvent evaporated under reduced pressure. The title compound 23 was obtained as a colourless oil in 67% yield; dr 93:7; ee 99%.1H NMR (400MHz, CDCI3): δ - 9.71 (s, 1 H), 7.28-7.23 (m, 4H), 7.11 -7.07 (m, 2H), 6.91 -6.88 (m, 1 H), 6.86-6.82 (m, 2H), 5.50 (d, J=7.6Hz, 1 H), 5.22 (d, J=7.6Hz, 1 H), 4.04 (s, 1 H), 3.77 (s, 3H), 1.40 (s, 9H); 13C NMR (100MHz, CDCI3): 201.2, 160.0, 155.2, 141.1 , 136.7, 129.8, 128.7, 128.4, 128.3, 119.0, 113.4, 112.5, 86.0, 80.3, 73.7, 55.4, 28.5; HRMS (ESI): calcd. for [M+Na] (C22H27NO5) requires m/z 408.1781 , found 408.1790; The enantiomeric excess was determined by chiral HPLC with an AD column ( n-hexane:/-PrOH = 90:10, λ = 254 nm) 1.0 ml/min, syn- diastereomer: tR major enantiomer = 10.1 min, tR minor enantiomer = 17.9 min; [α]D = + 24.0 (c=1.0, CHCI3).
Example 15. (2/?,3S)-2-Benzyloxy-3-benzyloxy-carbonylamino-3- (naphthalene-2-yl)propanal (24). To a stirred solution of N- benzyloxycarbonylnaphthylimine (1.0 equiv, 2.5 mmol) and 2- benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 23 0C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 24 were combined, and the solvent evaporated under reduced pressure. The title compound 24 was obtained as a colourless oil in 48% yield; dr 98:2 dr; ee 93%.[CC]D25 = + 30.7 (c = 1.0, CHCI3); 1H NMR (400 MHz, CDCI3) δ 9.76 (d, J = 1.2 Hz, 1 H), 7.83-7.76 (m, 5H), 7.52-7.15 (m, 10H), 7.06-7.04 (m, 2H), 5.90 (d, J = 8.4 Hz, 1 H), 5.46 (d, J = 8.4 Hz, 1 H), 5.11 -5.08 (m, 2H),4.61 -4.58 (m, 1 H), 4.40 (d, J = 11.6 Hz, 1 H), 4.14 (br s, 1 H); 13C NMR (100 MHz, CDCI3) δ 201.3, 155.7, 136.4, 136.2, 133.3, 133.1 , 128.7, 128.67, 128.65, 128.62, 128.57, 128.4, 128.3, 128.1 , 127.8, 126.5, 126.3, 125.7, 124.6, 116.2, 85.6, 73.8, 67.3, 55.0; The enantiomeric excess was determined by HPLC with an Ad column, (n- hexane: /-PrOH = 80:20, λ =220 nm), 1.0 mL/min; tR = major enantiomer 23.5 min, minor enantiomer 13.6 min. HRMS (ESI): calcd. for
[M+Na]+(C28H25NO4Na) requires m/z 462.1676, found 462.1689.
Example 16. (2/?,3S)-2-Benzyloxy-3-benzyloxy-carbonylamino-3- phenylpropanal (25). To a stirred solution of /V-benzyloxycarbonyl benzyl imine (1.0 equiv, 50 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 55 mmol) in CH3CN (200 mL) at 23 0C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 10 h. The reaction was quenched by extraction with EtOAc and H2O. The combined organic layers were dried with Na2SO4, concentrated under reduced pressure, loaded on a silica-gel column, and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 25 were combined, and the solvent evaporated under reduced pressure. The title compound 25 was obtained as a colourless oil in 72% yield; dr 75:25; ee 98%.[CC]D25 = + 16.6 (c = 1.0, CHCI3); 1H NMR (400 MHz, CDCI3) δ 9.72 (s, 1 H), 7.73-7.08 (m, 15H), 5.80 (d, J = 8.8 Hz, 1 H), 5.30 (d, J = 8.8 Hz, 1 H), 5.11 -5.07 (m, 2H),4.61 -4.58 (m, 1 H), 4.42 (d, J = 12.0 Hz, 1 H), 4.05 (br s, 1 H); 13C NMR (100 MHz, CDCI3) δ 201.3, 155.7, 136.4, 133.3, 128.7, 128.6, 128.5, 128.3, 127.8, 126.5, 126.3, 125.7, 124.6, 116.2, 85.6, 73.8, 67.3, 55.0; The enantiomeric excess was determined by HPLC with an Ad column, (n-hexane: /- PrOH = 80:20, λ =220 nm), 1.0 mL/min; tR = major enantiomer 11.4 min, minor enantiomer 24.9 min. HRMS (ESI): calcd. for [M+Na]+(C24H23NO4Na) requires m/z 412.1519, found 412.1518.
Example 17. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3- (cinnamoyl)propanal (26). To a stirred solution of /V-te/t-butoxycarbonyl-3- cinnamoyl-imine (1.0 equiv, 2.5 mmol) and 2-benzyloxyacetaldehyde (1.1 equiv, 2.7 mmol) in CH3CN (10 ml_) at 23 0C was added (R)-proline (20 mol %), and the reaction mixture vigorously stirred for 16 h. The reaction mixture was directly loaded on a silica-gel column and eluted with pentane:EtOAc or toluene:EtOAc. Fractions containing pure aldehyde 26 were combined, and the solvent evaporated under reduced pressure. The title compound 26 was obtained as a colourless oil in 52% yield; dr 67:33; ee 98%. Compound 26 was reduced to the corresponding alcohol 26a with NaBH4. Data for compound 26a: white solid. 1H NMR (400MHz, CDCI3): δ - 7.36-7.26 (m, 10H), 6.59 (dd, J=1.2Hz, J'=15.6Hz, J"=2.0Hz, 1 H), 6.19 (dd, J=6.4Hz, J'=12Hz, J" =6.0Hz, 1 H), 5.0 (d, J=8.8Hz, 1 H), 4.60 (ddd, J=11.6Hz, J'=9.6Hz, J" =11.2Hz, 2H), 3.78-3.66 (m, 1 H), 3.58- 3.48 (m, 1 H), 3.18 (bs, 1 H), 1.47 (s, 9H); 13C NMR (100MHz, CDCI3): 156.9, 138.1 , 136.9, 131.4, 128.8, 128.7, 128.3, 128.2, 127.9, 126.6, 81.4, 80.5, 73.6, 61.2, 52.6, 28.6; HRMS (ESI): calcd. for [M+Na] (C23H29NO4) requires m/z 406.1989, found 406.1979; The enantiomeric excess was determined by chiral HPLC with an AD column ( n-hexane:/-PrOH = 90:10, λ = 254 nm) 0.5 ml/min, syn-diastereomer: tR minor enantiomer = 14.3 min, tR major enantiomer = 16.9 min; anf/'-diastereomer: tR minor enantiomer = 21.8 min, tR major enantiomer = 30.4 min [α]D = +19.5 (c=1.0, CHCI3).
B. Oxidation of β-isoserine aldehydes to carboxylic acids
Example 18. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3- phenylpropanoic acid (27). To a mixture of (2R,3S)-2-benzyloxy-3-te/t-butoxy- carbonylamino-3-phenylpropanal (16; 1 mmol), isobutene (0.1 ml_), te/t-butanol (4.0 ml_) and H2O (2.0 ml_) was added sequentially KH2PO4 (54.4 mg, 4.0 mmol) and NaCIO2 (36 mg, 4.0 mmol) at 23 0C. After 16 h, the crude product was purified by column chromatography (pentane/EtOAc) to afford 320 mg (85%) of the title compound 27 as a colorless oil. 1H NMR (400 MHz, CDCI3): δ = 7.37- 7.19 (m, 8H), 7.04-7.00 (m, 2H), 5.80 (d, J=8Hz, 1 H), 5.30 (d, J=8.8Hz, 1 H), 4.70 (d, J=1 OHz, 1 H), 4.32 (d, J=1 OHz, 1 H), 4.20 (bs, 1 H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCI3): 173.4, 155.9, 139.5, 136.6, 128.8, 128.6, 128.2, 128.0, 127.8, 126.9, 80.6, 80.1 , 73.2, 56.0, 28.5; HRMS (ESI): calcd for [M+Na] (C2IH25NO5) requires m/z 394.1625, found 394.1635. [α]D 25 = +19.0 (c=1.0, CHCI3).
Example 19. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-phenyl- propanoic acid (28). To a mixture of (2R,3S)-2-benzyloxy-3-te/t-butoxy- carbonylamino-3-phenylpropanal (16; 5 mmol), isobutene (0.5 ml_), te/t-butanol (20.0 ml_) and H2O (10.0 ml_) was added sequentially KH2PO4 (272 mg, 20.0 mmol) and NaCIO2 (180 mg, 20.0 mmol) at 23 0C. After 16 h, the crude product was purified by column chromatography (pentane/EtOAc) to afford 1.5g (80%) of the title compound 28 as a colorless oil. 1H NMR (400 MHz, CDCI3): δ = 7.37- 7.19 (m, 8H), 7.04-7.00 (m, 2H), 5.80 (d, J=8Hz, 1 H), 5.30 (d, J=8.8Hz, 1 H), 4.70 (d, J=1 OHz, 1 H), 4.32 (d, J=1 OHz, 1 H), 4.20 (bs, 1 H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCI3): 173.4, 155.9, 139.5, 136.6, 128.8, 128.6, 128.2, 128.0, 127.8, 126.9, 80.6, 80.1 , 73.2, 56.0, 28.5; HRMS (ESI): calcd for [M+Na] (C2IH25NO5) requires m/z 394.1625, found 394.1635. [α]D 25 = +19.0 (c=1.0, CHCI3). Example 20. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(4- methylphenyl)propanoic acid (29). To a mixture of (2R,3S)-2-Benzyloxy-3-te/t- butoxy-carbonylamino-3-(4-nnethylphenyl)propanal (19; 1 mmol), isobutene (0.1 ml_), te/t-butanol (4.0 mL) and H2O (2.0 ml_) was added sequentially KH2PO4 (54.4 mg, 4.0 mmol) and NaCIO2 (36 mg, 4.0 mmol) at 23 0C. After 16 h, the crude product was purified by column chromatography (pentane/EtOAc) to afford the title compound 29 as a colorless oil in 64% yield. 1H NMR (400MHz, CDCI3): δ - 10.0 (bs, 1 H), 7.25-7.20 (m, 5H), 7.15 (d, J=11.6Hz, 2H), 7.07 (d, J=5.2Hz, 2H), 5.80 (d, J=8.8Hz, 1 H), 5.28 (d, J=9.2Hz, 1 H), 4.70 (d, J=10.8Hz, 1 H), 4.34 (d, J=8.0Hz, 1 H), 4.20 (s, 1 H), 2.36 (s, 3H), 1.43 (s, 9H); 13C NMR
(100MHz, CDCI3): 173.5, 155.9, 137.4, 136.8, 136.6, 129.3, 128.5, 128.3, 128.2, 126.8, 80.6, 80.2, 73.2, 55.8, 28.5, 21.3; HRMS (ESI): calcd. for [M+Na] (C22H27NO5) requires m/z 408.1781 , found 408.1778; [α]D = + 17.0 (c=1.0, CHCI3).
Example 21. (2/?,3S)-2-Benzyloxy-3-fert-butoxy-carbonylamino-3-(3- methoxyphenyl)propanoic acid (30). To a mixture of (2R,3S)-2-Benzyloxy-3- te/t-butoxy-carbonylamino-3-(3-methoxyphenyl)propanal (23; 1 mmol), isobutene (0.1 mL), te/t-butanol (4.0 mL) and H2O (2.0 mL) was added sequentially KH2PO4 (54.4 mg, 4.0 mmol) and NaCIO2 (36 mg, 4.0 mmol) at 23 0C. After 16 h, the crude product was purified by column chromatography (pentane/EtOAc) to afford the title compound 30 as a colorless oil in 74% yield. 1H NMR (400MHz, CDCI3): δ - 9.00 (bs, 1 H), 7.25-7.19 (m, 4H), 7.04 (d, J=2.8Hz, 2H), 6.92 (d, J=7.6Hz, 1 H), 6.88-6.81 (m, 2H), 5.80 (d, J=9.2Hz, 1 H), 5.28 (d, J=8.8Hz, 1 H), 4.70 (d, J=7.6Hz, 1 H), 4.32 (d, J=7.6Hz, 1 H), 4.20 (s, 1 H), 3.76 (s, 3H), 1.43 (s, 9H); 13C NMR (100MHz, CDCI3): 173.5, 159.9, 155.9, 136.8, 129.6, 128.5, 128.5, 128.3, 128.2, 119.2, 113.4, 112.4, 80.1 , 73.1 , 55.4, 28.5; HRMS (ESI): calcd. for [M+Na] (C22H27NO6) requires m/z 424.1731 , found 424.1726; [α]D = + 36.7 (c=1.0, CHCI3).
Example 22. (2/?,3S)-2-Benzyloxy-3-benzyloxy-carbonylamino-3- (naphthalene-2-yl)propanoic acid (31). To a mixture of (2R,3S)-2-Benzyloxy- 3-benzyloxy-carbonylamino-3-(naphthalene-2-yl)propanal (24; 1 mmol), isobutene (0.1 ml_), te/t-butanol (4.0 ml_) and H2O (2.0 ml_) was added sequentially KH2PO4 (54.4 mg, 4.0 mmol) and NaCIO2 (36 mg, 4.0 mmol) at 23 0C. After 16 h, the crude product was purified by column chromatography (pentane/EtOAc) to afford the title compound 31 as a yellow oil in 80% yield. 1H NMR (400MHz, CDCI3): δ - 8.80-8.20 (bs, 1 H), 7.86-7.76 (m, 4H), 7.52-7.42 (m, 3H), 7.20-7.04 (m, 3H), 6.98 (d, J=7.6Hz, 2H), 5.91 (d, J=9.6Hz, 1 H), 5.48 (d, J=9.2Hz, 1 H), 4.70 (d, J=7.6Hz, 1 H), 4.30 (d, J=8.8Hz, 1 H), 1.44 (s, 9H); 13C NMR (100MHz, CDCI3): 173.4, 156.0, 137.0, 136.5, 133.4, 133.1 , 128.9, 128.5, 128.4, 128.3, 127.8, 126.4, 126.2, 125.8, 125.0, 79.9, 73.3, 56.2, 28.5; HRMS (ESI):calcd for [M+Na] (C25H27NO5) requires m/z 444.1781 , found 444.1790. [α]D = + 37.5 (c=1.0, CHCI3) .
C. Esterification of β-isoserine derivatives
Example 23. Methyl (2R,3S)-2-benzyloxy-3-tert-butoxy-carbonylamino-3- phenylpropanoate (32). To a solution of (2R,3S)-2-benzyloxy-3-te/t-butoxy- carbonylamino-3-phenylpropanoic acid (26; 80 mg, 0.22 mmol) in toluene:MeOH (4:1 , 2.5 ml_) was added slowly thmethylsilyldiazometane (2.0 M in ether, 0.117 ml_, 0.23 mmol). After 30 min of vigorous stirring the reaction was quenched with acetic acid, and the solution evaporated. The residue was purified by silica-gel chromatography, eluant pentane/EtOAc (3:1 ). The title compound 32 was obtained as yellow oil in 95% yield (80 mg). 1H NMR (400 MHz, CDCI3): δ = 7.36-7.18 (m, 8H), 7.02-6.98 (m, 2H), 4.68 (d, J= 11.6Hz, 1 H), 4.26 (d, J= 12Hz, 1 H), 4.14 (bs, 1 H), 3.78 (s, 3H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCI3): 170.9, 155.4, 139.7, 136.9, 128.6, 128.5, 128.1 , 127.7, 126.9, 80.4, 80.2, 73.0, 56.3, 52.5, 28.5; HRMS (ESI): calcd. for [M+Na] (C22H27NO5) requires m/z 408.1781 , found 408.1788; [α]D = +25.0 (c=1.0, CHCI3).
D. Selective removal of protective groups from β-isoserine esters
Example 24. Methyl (2/?,3S)-2-hydroxy-3-fert-butoxy-carbonylamino-3- phenylpropanoate (33).To a solution of methyl (2R,3S)-2-benzyloxy-3-te/t- butoxy-carbonylamino-3-phenylpropanoate (32; 55 mg, 0.14 mmol) in MeOH (4 ml_), palladium on carbon (5 mg) was added. The reaction mixture was stirred under H2 (90 psi) atmosphere. When the starting material could no longer be detected by TLC, the solution was filtered through celite and concentrated to give the title compound as white crystals in 99% yield (42 mg). 1H NMR (400 MHz, CDCI3): δ = 7.38-7.18 (m, 5H), 5.44 (d, J=9.6Hz, 1 H), 5.22 (d, J=8.8Hz, 1 H), 4.46 (bs, 1 H), 3.83 (s, 3H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCI3): 173.6, 155.4, 139.3, 128.8, 128.0, 126.9, 80.2, 73.8, 56.3, 53.3, 28.5; HRMS (ESI): calcd for [M+Na] (Ci5H2iNO5) requires m/z 318.1312, found 318.1313; [α]D = + 13.2 (c=1.0, CHCI3).
Example 25. Methyl (2R,3S)-2-benzyloxy-3-amino-3-phenyl-propanoate (32).
A solution of methyl (2R,3S)-2-benzyloxy-3-te/t-butoxy-carbonylamino-3- phenylpropanoate (32; 35 mg, 0.9 mmol) in CH2CI2/HCOOH (1 :1 ;1 ml_) was stirred overnight. The reaction mixture was neutralized with aqueous NaHCO3, and the aqueous phase extracted with CH2CI2. The organic phase was dried with Na2SO4 and evaporated. The residue was purified by silica-gel chromatography to give 20 mg (78 %) of the title compound 32 in form of white crystals. 1H NMR (400 MHz, CDCI3): δ = 7.35-7.25 (m, 8H), 7.20-7.16 (m, 2H), 4.65 (d, J= 11.6Hz, 1 H), 4.44 (d, J= 11.6Hz, 1 H), 4.32 (d, J=5.2Hz, 1 H), 4.06 (d, J=5.2Hz, 1 H), 3.61 (s, 3H), 2.25 (bs, 2H); 13C NMR (100 MHz, CDCI3): 171.7, 141.3, 137.2, 128.6, 128.6, 128.3, 128.1 , 128.0, 127.4, 83.5, 73.2, 58.4, 52.1 ; HRMS (ESI): calcd for [M+H] (Ci7Hi9NO3) requires m/z 286.1438, found 286.1439; [α]D = + 78.4 (c=1.0, CHCI3).
E. Preparation of protected docetaxel derivative 33.
Figure imgf000021_0001
33 Example 26. 4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1,13α-dihydroxy-9-oxo- 7β,10β-bis(2,2,2-trichloroethoxycarbonyloxy)-11 -taxen-13α-yl (2R, 3S)-3- (fert-butoxycarbonylamino)-3-phenyl-2-(benzyloxy)-propionate (33). (2R, 3S)-2-(Benzyloxy)-3-(fe/t-butoxycarbonylamino)-3-phenylpropanoic acid 28 (1.40 g, 3.77 mmol) was dissolved in dry toluene (35 ml_) under nitrogen atmosphere in a single necked 100 ml round bottomed flask equipped with magnetic stirrer. Dicyclohexylcarbodiimide (0.778 g, 3.77 mmol) is added to the mixture which is left under stirring for 5 minutes at room temperature. Then 4- (N,N-dimethylamino)pyhdine (0.087 g, 0.71 mmol) and 4-acetoxy-2α- benzoyloxy-5β,20-epoxy-1 ,13α-dihydroxy-9-oxo-7β,10β-bis(2,2,2- trichloroethoxycarbonyloxy)-11-taxene (0.650 g, 0.73 mmol) are added at once. The mixture is left under stirring for 26 hours at room temperature. Then ethyl acetate (200 ml) is added and the organic phase is washed with water (30 ml), sodium hydrogen carbonate (2x30 ml), and saturated sodium chloride solution (30 ml) and finally dried with anhydrous sodium sulphate. The organic phase is filtered and evaporated to give a residue which is purified by silica gel chromatography to give 0.660 g (73% yield) of 4-acetoxy-2α-benzoyloxy-5β,20- epoxy-1 ,13α-dihydroxy-9-oxo-7β,10β-bis(2,2,2-thchloroethoxycarbonyloxy)-11 - taxen-13α-yl (2R, 3S)-3-(te/t-butoxycarbonylamino)-3-phenyl-2-(benzyloxy)- propionate 33.
E. Preparation of protected docetaxel derivative 34.
Figure imgf000022_0001
34
Example 27. 4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β,10β-trihydroxy-9- oxo-11 -taxen-13α-y I {2R, 3S)-3-terf-butoxycarbonylamino-3-phenyl-2- (benzyloxy)propionate (34). Docetaxel derivative 33 (0.590 g, 0.471 mmol) was dissolved in glacial acetic acid (30 ml) under nitrogen atmosphere in a 100 ml single-necked flask equipped with magnetic stirrer. Methanol (30 ml) is then added followed by zinc/copper mixture (2.60 g, 2.2Og of zinc and 0.40 g of copper). The solution is heated for 2 hours at 65 0C then cooled to room temperature, diluted with ethyl acetate (40 ml) and filtered through Celite which is washed afterwards with ethyl acetate (4x40ml). The solvent is evaporated and the residue is purified by silica gel chromatography to give 0.230 g (55 % yield) of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1 ,7β,10β-thhydroxy-9-oxo-11 -taxen- 13α-yl (2R, 3S)-3-terf-butoxycarbonylamino-3-phenyl-2-(benzyloxy)propionate 34. 1H NMR (400 MHz, CDCI3): δ - 8.10-8.04 (d, J=8.0Hz, 2H), 7.62-7.57 (m, 1 H), 7.51-7.45 (m, 2H), 7.40-7.20 (m, 10H), 7.04 (bs, 1 H), 6.26 (m, 1 H), 5.66 (d, J=7.2Hz, 1 H), 5.58 (d, J=9.2Hz, 1 H), 5.24 (s, 1 H), 4.92 (d, J=8.8Hz, 1 H), 4.68 (d, J=7.6Hz, 1 H), 4.34-4.10 (m, 5H), 3.90 (d, J=6.8Hz, 1 H), 2.60-2.45 (m, 1 H), 2.23 (s, 3H), 1.89 (s, 3H), 1.88-1.80 (m, 3H), 1.72 (s, 3H), 1.33 (s, 9H), 1.25 (s, 3H), 1.11 (s, 3H); 13C NMR (I OOMHz, CDCI3): 211.6, 170.7, 170.1 , 167.3, 138.9, 136.3, 136.0, 133.9, 130.4, 129.5, 128.9, 128.8, 128.5, 128.1 , 128.0, 126.8, 84.5, 81.2, 80.2, 79.1 , 76.8, 75.3, 74.7, 72.9, 72.1 , 71.8, 57.8, 56.1 , 46.6, 43.4, 37.0, 35.8, 28.5, 28.4, 26.6, 22.7, 21.2, 14.7, 10.2; HRMS (ESI): calcd. for [M+Na] (C50H59NO14) requires 920.3828, found 920.3805; [α]D = -36.0 (c=1.0, CHCI3).
F. Preparation of protected docetaxel
Figure imgf000023_0001
docetaxel
Example 28. 4-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1,7β,10β-trihydroxy-9- oxo-11-taxen-13α-yl (2R, 3S)-3-tert-butoxycarbonylamino-3-phenyl-2- hydroxypropionate (docetaxel). 4-acetoxy-2α-benzoyloxy-5β,20-epoxy- 1 ,7β,10β-thhydroxy-9-oxo-11-taxen-13α-yl (2R, 3S)-3-te/t-butoxycarbonylamino- 3-phenyl-2-(benzyloxy)propionate 34 (0.03 g, 0.037 mmol) was dissolved in methanol (3 ml) in a 10 ml single-necked round bottomed flask equipped with magnetic stirrer. Then palladium hydroxide (0.03 g, 0.21 mmol) was added and the reaction mixture was stirred under hydrogen atmosphere (100 psi) at room temperature for 66 hours. The solution was then filtered through Celite and the solids were washed with methanol (5x1 OmI). Evaporation of the solvent gave white solid purified by silica gel chromatography to give 0.025 g (84% yield) of 4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1 ,7β,10β-thhydroxy-9-oxo-11-taxen-13α- yl (2R, 3S)-3-fe/t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate (docetaxel).

Claims

C l a i m s
1. A process for stereoselective synthesis of a β-phenylisoserine derivative of the general formula I:
O JJ R1-O^NH O
R-^OH (l) OX1
wherein
R is aryl (Ar) or R2; R1 is C1-C10 non-branched or branched alkyl, C2-C8 alkynyl, C2-C8 alkenyl, C3-C6 cycloalkyl, C4-C6 cycloalkenyl, C4-C5 cycloalkenyl, or C7-Cn bicycloalkyl, R1 being optionally substituted with one or more of the group consisting of: halogen, hydroxyl, alkoxy, aryl such as phenyl, cyano, carboxyl, CrC7 alkyloxycarbonyl; X1 is H or a hydroxyl-protecting group selected from methoxymethyl, 1 - ethoxyethyl, bexyloxymethyl, 2,2,2-trichloroethoxymethyl, tetrahydrofuranyl, tetrahydropyranyl and β-(thmethylsilyl)ethoxymethyl, trialkylsilyl in which the alkyl contains from 1 to 4 carbon atoms, alkyldiphenylsilyl, -CH2-Ph in which Ph represents phenyl optionally substituted with one or more same or different atoms or groups chosen from halogen, alkyl containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms; the process comprising a first step comprising the reaction between a N- carbonyl imine of the general formula II, R-C=N-CO-OR1 (II), in which Ar and R1 have the same meaning as above, with a protected α-oxyaldehyde of the general formula III, X1O-CH2CHO (III), in which X1 has the same meaning as above, in the presence of a chiral amine catalyst of the general formula IV
Figure imgf000025_0001
and a consecutive second step, in which the β-amino-α-hydroxyaldehyde of the general formula V,
o
R1-O^NH O
(V)
R
OX1
formed in the first step, in which R, R1 and X1 have the same meaning as above, is oxidized to the corresponding carboxylic acid of the general formula I.
2. The process of claim 1 , wherein the intermediate β-amino-α-hydroxy- aldehyde of the general formula V is oxidized without purification to the carboxylic acid of the general formula I.
3. The process of claim 1 or 2, wherein the oxidant comprises NaCIO2.
4. The process of claim 3, wherein the oxidant further comprises isobutene.
5. The process of any of claims 1 to 4, wherein Y2 is any of CO2H, Ar2OSiR3, tetrazole, O=C-NHR, O=C-NH-SO2R.
6. The process of any of claims 1 to 4, wherein the catalyst is (R)-proline.
7. The process of any of claims 1 to 6, wherein, if R is aryl, it is any of: phenyl or α- or β-naphthyl optionally substituted with one or more of halogen (fluorine, chlorine, bromine, iodine); alkyl, alkenyl, akynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro; trifluoromethyl; and wherein alkyl or an alkyl portion of a substituent is any of CrC4 alkyl, C2-C8 alkenyl, C2-C8 alkynyl and wherein aryl comprises any of phenyl, α- or β-naphthyl, 2- or
3-furfuryl, thiophenyl, 2- or 3-pyridyl, indolyl, 2- or 3-pyridyl, imidazolyl.
8. The process of any of claims 1 to 6, wherein R2 is branched or non- branched C1-C10 alkyl, C2-C8 alkynyl, C2-C8 alkenyl; C3-C6 cycloalkyl; C4- Cβ cycloalkenyl; C7-Cn bicycloalkyl; optionally substituted with one or more of halogen; hydroxy; alkoxy; aryl, in particular phenyl; cyano; carboxyl; alkyloxycarbonyl in which alkyl is CrC7, for instance benzyl; a carbon atom substituted by three halogen atoms, such as CF3, wherein aryl is optionally phenyl or phenyl substituted with one or more same or different substituents selected from: halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, trifluoromethyl.
9. The method of any of claims 1 to 8, further comprising transforming the compound of general formula 1 to an ester of the general formula Vl,
0
Jl
R1-O^NH O
(Vl)
R' OMe
OX1
wherein R, R1 and X1 are defined as above and Me is straight or branched CrCβ alkyl, in particular methyl or ethyl.
10. The method of claim 9, comprising selective removal of the protecting group X1 from a compound of the general formula Vl for preparing a β- amino-α-hydroxy carboxylic ester derivative of the general formula VII
Figure imgf000027_0001
wherein R and R1 are defined as above.
11. The method of claim 9, comprising selective removal of the protecting group R1 from a compound of the general formula Vl for preparing a β- amino-α-hydroxy carboxylic ester derivative of the general formula VIII
NH2 O
(VIM)
R OMe
OX1
wherein R is defined as above and X1 is H.
12. The process of claim 1 , wherein the aldehyde of the general formula V is obtained in an enantiomeric purity of at least 99 %.
PCT/SE2009/050962 2008-08-26 2009-08-26 PREPARATION OF β-PHENYL-ISOSERINE DERIVATIVES WO2010024762A1 (en)

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EP2697211A1 (en) * 2011-04-01 2014-02-19 Shilpa Medicare Limited Process for preparing docetaxel and its hydrate
EP2697211A4 (en) * 2011-04-01 2014-08-13 Shilpa Medicare Ltd Process for preparing docetaxel and its hydrate
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