IE914396A1 - Process for preparing "syn" derivatives of propanamide - Google Patents

Process for preparing "syn" derivatives of propanamide

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Publication number
IE914396A1
IE914396A1 IE439691A IE439691A IE914396A1 IE 914396 A1 IE914396 A1 IE 914396A1 IE 439691 A IE439691 A IE 439691A IE 439691 A IE439691 A IE 439691A IE 914396 A1 IE914396 A1 IE 914396A1
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IE
Ireland
Prior art keywords
derivative
general formula
process according
syn
formula
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IE439691A
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Rhone Poulenc Rorer Sa
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Application filed by Rhone Poulenc Rorer Sa filed Critical Rhone Poulenc Rorer Sa
Publication of IE914396A1 publication Critical patent/IE914396A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

Method for preparing a 'syn' derivative of propanamide of forumula (I) by the action of a derivative of camphosultam of general formula (II) or (III) on aldehyde of formula (IV) in the presence of a Lewis acid and an organic base. In formulae (I) to (IV), X is a halogen atom, R is an alkyl, aryl or heteroaryl radical, R1? is the residue of one or other of the camphosultam enantiomers. The products obtained by the method may be used in the preparation of therapeutically active products.

Description

RHONE-POULENC RORER S.A., a French Body Corporate of 20 Avenue Raymond Aron, F 92165 Antony Cedex, France. - 1a The present invention provides a process for preparing a syn derivative of propanamide of general formula: OH 0 R (I) in which X represents a halogen atom, preferably a chlorine or bromine atom, R represents an alkyl, aryl or heteroaryl radical, and R^ represents the residue of one or other of the enantiomers of camphorsultam of formula: or (II) it being understood that, according to the nature of Rj, the syn derivative of propanamide of general formula (I) has the configuration: OH Ο or (IV) (V) which comprises condensing a camphorsultam derivative of 5 general formula: (VI) (VII) in which X is defined as above, with an aldehyde of general formula: R-CHO (VIII) in which R is defined as above, in the presence of a Lewis acid and an organic base, working in an inert organic solvent at a temperature of between -50 and +50°C, and preferably between -30 and 0°C.
Of special interest are the products of formula (I) in which R represents a phenyl radical, a 2- or 4- pyridyl - 3 radical, or a (l-trityl-lH-imidazol-4-yl) radical.
As the Lewis acid, titanium chloride (TiCl4) is preferably used. Generally, from 0.3 to 3 mol of Lewis acid are used per mol of starting material of general formula (VI) or (VII), and preferably 1 mol.
The organic base may be a tertiary aliphatic amine such as diisopropylethylamine or triethylamine.
Preferably, diisopropylethylamine is used. Generally, at least one mol of base is used per mol of starting material of general formula (VI) or VII).
As the inert organic solvent, it is especially advantageous to use a halogenated aliphatic hydrocarbon such as methylene chloride.
According to the camphorsultam derivative of 15 formula (VI) or (VII) used and the nature of the aldehyde of general formula (VIII), the syn derivative of formula (IV) or (V) is obtained, possibly in combination with the corresponding ‘'anti·· derivative. For a particular aldehyde of formula (VIII), if one of the forms (VI) or (VII) of the camphorsultam derivative yields one of the forms (IV) or (V) of the product of general formula (I), the other form of the camphorsultam derivative necessarily yields the other form (IV) or (V) of the product of general formula (I) · The practically pure syn derivative may be obtained from its mixture with the anti derivative by - 4 recrystallisation in a suitable solvent.
The starting material of general formula (VI) or (VII) may be obtained by the action of a haloacetic acid halide on a carophorsultam of formula (II) or (III) under the conditions described by W. Oppolzer et al., J. Amer. Chem. Soc., 112 . 2767-2772 (1990).
The product of general formula (I) in the form (IV) in which X represents a halogen atom, preferably a bromine atom, and R represents a phenyl radical, is especially useful for preparing taxol or a derivative thereof of general formula: 3'S in which R2 represents a hydrogen atom or an acetyl radical and R3 represents a benzoyl or t-butoxycarbonyl radical, which possess noteworthy antitumor properties. The products of general formula (IX) in which R2 represents a hydrogen atom or an acetyl radical and R3 represents a benzoyl radical are 10-deacetyltaxol and taxol, respectively. of general formula: - 5 The products of general formula (IX) in which R2 represents a hydrogen atom or an acetyl radical and R3 represents a t-butyoxycarbonyl radical are described in European Patent EP-B-0,253,738.
The product of general formula (I) in the form (IV) in which R represents a phenyl radical and X preferably represents a bromine atom, when treated with a base such as sodium methylate or lithium benzylate, yields a cis-βphenylglycidic acid ester c6h5_ 3R^ H in which R4 represents an (benzyl) radical.
The products of general formula (X), by the action of an azide, yield the products of general formula: /\ coor4 H (X) alkyl (methyl) or aralkyl N< COOR4 (xi) in which R4 is defined as above. The hydroxyl function of the products of general formula XI is then protected with a group R5 so as to produce a product of general formula: - 6 IE 914396 C6H5 ZaR5 3S >—^2R N? COOR, (XII) in which R4 is defined as above and R5 represents a group protecting the hydroxyl function, which is reduced to a product of general formula: C6H5 o-r5 5 asV- —ς 2R (XIII) NHf coor4 in which R4 and R5 are defined as above. The product of general formula XIII is treated with a reactant enabling a benzoyl or t-butoxycarbonyl radical to be introduced, to produce a product of general formula: c6h5 3S nh-r3 p-% 2R COORj (XIV) in which R3, R4 and R5 are as defined above, which is then saponified to give a product of general formula: NH-R3 COOH (XV) in which R3 and R5 are as defined above. The compound of general formula XV is then condensed with baccatine III or -deacetylbaccatine III, the hydroxyl functions of which at position 7 and, where appropriate, at position 10 are protected by a protective group chosen from 2,2,2trichloroethoxycarbonyl or trialkylsilyl radicals, to give a product of general formula (IX) after replacement of the protective groups present by hydrogen atoms.
The products of general formula (I) in the form (IV) in which R represents a l-trityl-lH-imidazol-4-yl radical and X represents halogen, particularly chlorine, are especially useful for preparing (IS,2S)-3-amino-l- (215 amino-lH-imidazol-4-yl)-2-chloro-l-propanol, which is described in European Patent EP-B-0,215,687 and which possesses advantageous antitumor properties.
The action of ammonia on a product of general formula (I) in the form (IV) in which R represents a 120 trityl-lH-imidazol-4-yl radical and X represents a chlorine atom, gives the imidazolpropanamide derivative of formula: in which Zj is trityl.
Reduction of the product of formula (XVI) by means of, e.g., a boron hydride, gives a product of formula: (XVII) in which Zj is as defined above.
By the action of an agent for blocking the amine function on the product of formula (XVII), there is obtained a product of formula: QH (XVIII) in which is defined as above and Z represents a group protecting the amine function which is readily replaceable by a hydrogen atom on hydrolysis in an acid medium.
Selective removal of the protective group Zj from the product of formula (XVIII) gives a product of formula: NH-Z (XIX) in which Z is defined as above.
By diazotisation of the product of formula (XIX) with a diazonium salt, there is obtained a product of formula: in which Ar represents an optionally substituted phenyl radical and Z is defined as above.
Reduction of the product of formula (XX) with hydrogen in the presence of a catalyst gives a product of formula: - 10 OH I H in which Z is as defined above.
Replacement of the protective group Z in the product of formula (XXI) by a hydrogen atom gives (1S,2S)5 3-amino-l-(2-amino-lH-imidazol-4-yl)-2-chloro-l-propanol which can optionally be isolated in salt form.
The product of general formula (I) in which X represents halogen, especially a bromine atom, and R represents a l-trityl-lH-imidazolyl-4-radical may be used for preparing erythro-B-hydroxy-L-histidine, which is an amino acid constituent of bleomycins, under the conditions described by T. OWA et al, Chemistry Letters, 1873 (1988).
The examples which follow show how the invention may be put into practice.
EXAMPLE 1 (-)-N-Chloroacetyl-10,2-bornanesultam (1.55 g; 5.31 mmol) in dichloromethane (20 cc) is introduced under an argon atmosphere into a 100-cc round-bottomed flask. The mixture is cooled to -30°C, and titanium chloride (0.584 cc; 5.31 mmol) is then added in the course of 5 minutes.
After 30 minutes’ stirring, a light yellow solution is - 11 obtained.
Diisopropylethylamine (0.925 cc; 5.31 mmol) is then added at -30°C in the course of 10 minutes. The reaction mixture becomes red. It is stirred for 30 minutes at -30°C. 5 Benzaldehyde (0.486 cc; 4.78 mmol) is then added at -30°C in the course of 10 minutes. The mixture is stirred for 30 minutes at -30°C, the temperature is then allowed to rise to approximately 0°C and the mixture is stirred again for 45 minutes at this temperature. An orange-yellow solution is obtained.
A pH 7 buffer solution (1.1 cc) is added. After settling has taken place, the organic face is washed and then dried over sodium sulphate. After filtration and concentration to dryness, a whitish solid (1.71 g) is obtained.
After recrystallisation in boiling ether acetate (40 cc), (2'R,3’S)-N-(3'-hydroxy-2'-chloro-3·phenylpropanoyl)-10-2-bornanesultam (0.959 g) is obtained. The yield is 50.4%.
EXAMPLE 2 (-)-N-Chloroacetyl-10,2-bornanesultam (19.8 g; 67.9 mmol) dissolved in dichloromethane (200 cc) is introduced at -30°C under an argon atmosphere into a 500-cc threenecked round bottomed flask. A 1M solution (66 cc) of titanium chloride in dichloromethane is added in the course - 12 of 10 minutes at a temperature of between -31 and -33°C.
The mixture is stirred for 30 minutes.
Diisopropylethylamine (11.8 co) is then added in the course of 10 minutes at -30°C. The mixture is stirred again for 30 minutes at this temperature. l-trityl-4-imidazolecarbaldehyde (22.95 g) in dichloromethane (75 cc) is added in the course of 10 minutes to the black reaction mixture.
After 45 minutes' stirring, a pH 7 buffer solution (100 cc) is added at 0°C.
After settling has taken place, the organic phase is washed with saturated bicarbonate solution (60 cc) and with water (2 x 100 cc) and then dried over magnesium sulphate. After filtration and evaporation to dryness, the product (39.36 g is obtained in a 95% yield in the form of a froth, the analysis of which shows it to contain the (2'R,3'S) syn isomer (71%), (2'S,3'R) syn isomer (12%) and (2'S,3'S) anti isomer (17%).
On recrystallisation in ethyl acetate (1140 cc), (2'R,3'S)-N-[3'-hydroxy-2'-chloro-3'-(1-trityl-lH-imidazol4-yl)propanoyl]-10,2-bornanesultam (18.13 g) is obtained in the form of white crystals.
Analysis by proton nuclear magnetic resonance shows that it contains more than 95% of the (2'R,3'S) syn isomer. - 13 EXAMPLE 3 (+)-N-Chloroacety1-10,2-bornanesultam (1.5 g; 5.14 mmol) dissolved in dichlororoethane (20 cc) is introduced at -30°C under an argon atmosphere into a 250-cc round5 bottomed flask. Titanium chloride (0.57 cc; 5.14 mmol) is added in the course of 10 minutes at a temperature in the region of -30°C. The mixture is stirred for 30 minutes and diisopropylethylamine (0.9 cc; 5.14 mmol) is then added at -30°C. The mixture is stirred for 30 minutes at -30°C and 2-pyridinecarbaldehyde (0.44 cc; 4.61 mmol) is then added. The mixture is stirred for 1 hour at -30°C and the temperature is then allowed to rise to approximately 0°C.
A pH 7 buffer (10 cc) is added. After settling has taken place, the organic phase is dried over magnesium sulphate. After filtration and concentration to dryness in a rotary evaporator, a product (1.71 g) is obtained in the form of a froth, which is recrystallised in an ethyl acetate/diisopropyl ether (6-1 by volume) mixture. N-[3·hydroxy-2’-chloro-3'-(2-pyridyl)propanoyl]-10,220 bornanesultam (0.25 g), containing, on the basis of the proton nuclear magnetic resonance spectrum, a mixture (95:5) of (2'R,3'S) syn and (2’S,3'S) anti isomers, is thereby obtained with a degree of conversion of 97%.
EXAMPLE 4 Working as in Example 3, but using 4-pyridineIE 914396 -14carbaldehyde (1.5 g) , N-[3'-hydroxy-2'-chloro-3'-(4pyridyl)propanoyl]-10,2-bornanesultam (0.7 g), containing, on the basis of the proton nuclear magnetic resonance spectrum, more than 95% of (2'R,3'S) syn isomer, is obtained with a degree of conversion of 85%.

Claims (11)

1. A process for preparing a ’'syn·' derivative of propanamide of general formula: X in which X represents a halogen atom, R represents an 5 alkyl, aryl or heteroaryl radical and R x represents the residue of one or other of the enantiomers of camphorsultam of formula: it being understood that, according to the nature of R 1# 10 the H syn” derivative of propanamide has the configuration: which comprises reacting a camphorsultam derivative of in which X is as defined above, with an aldehyde of general formula: 5 R-CHO in which R is as defined above, in the presence of a Lewis acid and an organic base in an inert organic solvent at a temperature of between -50 and +50°C.
2. Process according to claim 1, wherein the 10 Lewis acid is titanium chloride (TiCl 4 ).
3. Process according to claim 1 or 2, wherein from 0.3 to 3 mol of Lewis acid are used per mol of camphorsultam derivative.
4. Process according to any one of claims 1 to 3 15 wherein the organic base is a tertiary aliphatic amine.
5. Process according to claim 4, wherein the base is diisopropylethylamine or triethylamine.
6. Process according to any one of claims 1 to 5 wherein at least one mol of organic base is used per mol of - 17 camphorsultam derivative.
7. Process according to any one of claims 1 to 6 wherein R is phenyl or l-trityl-lH-imidazol-4-yl.
8. Use of a product obtained by the process 5 according to any one of claims 1 to 7 in which R is phenyl for the preparation of taxol or a derivative thereof.
9. Use of a product obtained by the process according to any one of claims 1 to 7 in which R is l-trityl-lH-imidazol-4-yl for the preparation of (1S,2S)10 3-amino-l-(2-amino-H-imidazol-4-yl)-2-chloro-l-propanol or erythro-B-hydroxy-L-histidine.
10. A process according to claim 1 substantially as described in any one of Examples 1 to 4.
11. A syn derivative of propanamide as defined 15 in claim l when prepared by a process as claimed in any one of claims 1 to 7 or 10.
IE439691A 1990-12-18 1991-12-17 Process for preparing "syn" derivatives of propanamide IE914396A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR9015814A FR2670490B1 (en) 1990-12-18 1990-12-18 PROCESS FOR THE PREPARATION OF "SYN" DERIVATIVES OF PROPANAMIDE.

Publications (1)

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IE914396A1 true IE914396A1 (en) 1992-07-01

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IE439691A IE914396A1 (en) 1990-12-18 1991-12-17 Process for preparing "syn" derivatives of propanamide

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EP (1) EP0563219B1 (en)
JP (1) JPH06503572A (en)
KR (1) KR930703277A (en)
AT (1) ATE114646T1 (en)
AU (1) AU652018B2 (en)
CA (1) CA2098583A1 (en)
CZ (1) CZ115393A3 (en)
DE (1) DE69105524D1 (en)
ES (1) ES2065163T3 (en)
FI (1) FI932812A0 (en)
FR (1) FR2670490B1 (en)
GR (1) GR3014892T3 (en)
HU (1) HUT68144A (en)
IE (1) IE914396A1 (en)
MX (1) MX9102629A (en)
NO (1) NO931918D0 (en)
NZ (1) NZ241025A (en)
PT (1) PT99854A (en)
SK (1) SK62093A3 (en)
WO (1) WO1992011250A1 (en)
YU (1) YU195391A (en)
ZA (1) ZA919882B (en)

Also Published As

Publication number Publication date
ATE114646T1 (en) 1994-12-15
AU652018B2 (en) 1994-08-11
NZ241025A (en) 1993-04-28
HUT68144A (en) 1995-05-29
CZ115393A3 (en) 1994-02-16
KR930703277A (en) 1993-11-29
NO931918L (en) 1993-05-26
EP0563219B1 (en) 1994-11-30
FR2670490B1 (en) 1994-09-23
NO931918D0 (en) 1993-05-26
CA2098583A1 (en) 1992-06-19
FI932812A (en) 1993-06-17
FR2670490A1 (en) 1992-06-19
WO1992011250A1 (en) 1992-07-09
AU9144491A (en) 1992-07-22
HU9301770D0 (en) 1993-09-28
GR3014892T3 (en) 1995-05-31
ZA919882B (en) 1992-09-30
YU195391A (en) 1994-01-20
MX9102629A (en) 1992-10-01
DE69105524D1 (en) 1995-01-12
SK62093A3 (en) 1993-11-10
FI932812A0 (en) 1993-06-17
EP0563219A1 (en) 1993-10-06
JPH06503572A (en) 1994-04-21
PT99854A (en) 1992-12-31
ES2065163T3 (en) 1995-02-01

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