SK62093A3 - Method of preparing "syn" derivatives of propanamide - Google Patents

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

The invention relates to a process for the preparation of a syn propanamide derivative of the formula I

(I) in which a halogen atom, preferably a chlorine atom or a bromine atom, represents an alkyl group, an aryl group or a heteroaryl group and represents a residue of one or the other of the enantiomers of camphosultam of formula II or III

wherein according to the nature of R < 1 >

(IV)

TEXT

FOR

NATIONAL PHASE

Particularly interesting compounds are those compounds of formula I wherein R is phenyl or - trityl -

4 (1H) -imidazolyl.

SUMMARY OF THE INVENTION

The compounds of the formula I according to the invention are obtained by condensation of a camphosultam derivative of the formula VI or VII

of formula VIII

meaning, with the aldehyde of general

R-CHO (VIII) wherein R is as defined above, in the presence of titanium tetrachloride and an organic base in an inert organic solvent at a temperature of -50 to 50 ° C, preferably at a temperature of -30 to 50 ° C

Low: 14 ° C.

Typically, 0.3 to 3 moles of Lewis acid is used per mole of compound of formula (VI) or (VII), preferably 1 mole of Lewis acid per mole of compound of formula (VI) or (VII).

As organic bases, aliphatic tertiary amines such as di-propylethylamine or triethylamine can be used. Preferably, di isopropylethylamines are used.

Usually at least one mole of base is used per mole of compound of formula VI or VII.

As an inert organic solvent, it is particularly preferred to use a halogenated aliphatic hydrocarbon such as methylene chloride.

Depending on the camphosultam derivative of formula (VI) or (VII) used and the nature of the aldehyde of formula (VIII), a syn derivative of formula (IV) or (V) is obtained, optionally accompanied by the corresponding anti-derivative. For a given aldehyde of formula VIII, when one of the forms VI or VII of the camphosultam derivative leads to one of the forms IV or V of the compound of formula I, then the other form of the camphosultam derivative necessarily leads to the other form IV or V of the compound of formula I.

A practically pure syn derivative can be obtained from its mixture with an anti derivative by crystallization in a suitable solvent.

The compound of formula (VI) or (VII) may be obtained by treating a camphorate with a haloacetic acid haline.

suitám formulas II or III under conditions, described W.Ορρό 1zer-a al. v J. Amer. Chem. Soc., 112 , 2767-2772 (1990). compound of of formula I in the form of

of formula

IV, in which X represents a halogen atom, preferably an atom, is particularly suitable for bromine and R represents a phenyl

preparing taxol or derivatives thereof of formula IX r ₂ o 0 OH coo --- ( I (IX) 2'R CH-OH . 1 1 | OH £ OCOCH-j c ₆ h ₃ -ch-nh-r ₃ - oococ ₆ h ₅ 3'S wherein R ₂ is H or acetyl and R

represents a benzoyl group or tert. butoxycarbonyl group having remarkable antitumor activity.

Compounds of formula (IX) in which R @ 1 is hydrogen or acetyl and R @ 1 is benzoyl are 10-deacetyltaxol, respectively. taxol.

Compounds of formula (IX) wherein R 5 is hydrogen or acetyl and R 1 is t-butoxycarbonyl are described in European patent P - B - 0 2 5 3 7 3 8.

If a compound of formula I in the form of formula IV in which R is a phenyl group and X is preferably a bromine atom is treated with a base such as sodium methoxide or lithium benzoxide, then a cis -beta-phenyl ester of 1-gylic acid of the formula X

(X) wherein R _Λ is alkyl (methyl) or aralkyl (benzyl) group. The reaction product of formula X with an azide to produce the compound of formula XI ^C 6 ^H 5

OH

C (XI)

COOR ₄ wherein R a is as defined above, their hydroxy function e is then protected with R 5 to form a compound of formula XII

coor ₄ (XII) wherein R 1 is as defined above and R 5 is a hydroxy protecting group that is reduced to a compound of formula XIII

(XIII) wherein R 1 and R 5 are as defined above, treated with a reagent to introduce a benzoyl or t-butoxycarbonyl group to form a compound of formula

XIV

NH-R ₃ coor ₄ (XIV) wherein R 5, R a and R 5 have the above meanings, which are then saponified to form a compound of formula XV

COOH (XV) nh-r ₃ which is condensed with baccatin III or 10-deacetylbaccatin III, whose hydroxy function in position 7 and optionally in position 10 are protected with a protecting group selected from the group consisting of 2,2,2-trichloroethoxycarbones 1 and a trialkylsilyl group, the replacement of the protecting groups present with hydrogen atoms to give a compound of formula IX.

Compound of formula (I) in the form of formula (VI) wherein R is 1-yl-1-4 (1H) -imidazolyl

group and X represents a chlorine atom, is particularly suitable for training 3-Amino-1- (2-amino-4 (1H) -imidazolyl) -2-chloro-1-propa- no 1 u vo isomer (1S, 2S), which is described in European Patent EP-B-0 2 1 568 7 and which has an interesting anti-tumor effect

1.

Treatment of a compound of Formula I in the form of Formula IV wherein R 2 is treated with ammonia

and i-idazolyl and / X is 1-trityl-4 (1H) chloro, the i-idazolepropanamide derivative of formula XVI is obtained

(XVI) wherein Zt is as defined above.

Reduction of a compound of formula XVI, for example with boron hydride, provides a compound of formula XVII

(XVII) wherein Z 1 is trityl.

Treatment of a compound of formula XVII with an amine blocking agent provides a compound of formula XVIII

OH

(XVIII) wherein Z 1 is as defined above and Z represents an amino function protecting group which is readily replaced by an oxygen atom when hydrolyzed in an acidic environment.

Selective deprotection of Z, a compound of formula XVIII, yields a compound of formula XIX

OH (XIX) N i H OR H in which Z has higher as defined above. diazotization general compounds formula XIX using

of the diazonium salt, a compound of formula XX is obtained

(XX) wherein Ar is optionally substituted phenyl and Z is as defined above.

Reduction of a compound of formula XX with hydrogen in the presence of a hydrogenation catalyst gives a compound of formula XXI

(XXI) wherein Z is as defined above.

Replacement of the protecting group of a compound of formula (XXI) with a hydrogen atom gives 3-amino-1- (2'-amino-4 '(1H) -imidazol-1-yl) -2-chloro-1- (1S, 2-ol). S) -1-propanol, which may optionally be isolated in the form of a salt.

A compound of formula I wherein X is bromine and R is 1-tri-1-4 (1H) -imidazolyl may be used to prepare an erythro-beta-L-histidine amino acid which is part of bleomycins , under the conditions described

T. Owa et al.

in Chemistry Letters,

1873 (1988).

In the following, the invention will be described in more detail by means of specific examples thereof, which, however, are intended to be illustrative only and do not limit the scope of the invention, which is clearly defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Into a 100 cm ³ were introduced under argon atmosphere 1.55 g (-) - N-ch1óracety1 - 10.2 bornansu1tamu (5.31 mmol in 1) in 20 cm ³ of dichloromethane. The mixture is cooled to -30 ° C and 0.584 cm ³ of titanium tetrachloride (5.31 mmol) are added over 5 minutes. After stirring for 30 minutes, a light yellow solution was obtained. To this solution is added 0.925 cm ^{3 of} diisopropylethylamine (5.31 mmol) at -30 ° C over 10 minutes. The reaction mixture turns red. The reaction mixture is then stirred for a period of time at the temperature of benzaldehyde (4 r.p. at -30 [deg.] C., with cm ³ for 30 minutes at

The mixture was m

-30 ° C mmo1).

30 ° C.

while rising to the heart rate for 1 second for 45 seconds then close to 0 ° C and minutes. The reaction mixture is stirred for 30 minutes at room temperature

then

Leave the mixture to mix with a yellow-orange solution at this temperature for 0.486 minutes.

1.1 cm ³ of pH = 7 buffer solution are added. After decantation, the organic phase is washed and then dried over sodium sulphate. After filtration and concentration of the filtrate to dryness, 1.71 g of an off-white solid is obtained. After recrystallization from 40 cm @ ^{3 of} boiling ethyl acetate, 0.959 g of N- (3'-hydroxy-2'-chloro-3'-phenylpropanoyl) - (2'R, 3'S) -10,2-bornansulfamate is obtained.

Yield: 50.4%.

Example 2

19.8 g of (-) - N-chloroacetyl, 2-bornansu 1 tamu (67.9 mmol) in solution in 200 cm ^{3 of} dichloromethane are introduced into a 500 cm ³ three-necked flask at -30 ° C under an argon atmosphere. . Then 66 cm ^{3 of a} 1M solution of titanium tetrachloride in dichloromethane are added at -31 to -33 ° C over 10 minutes. The mixture was stirred for 30 minutes. 11.8 cm @ ^{3 of} diisopropylethylamine are then added at -30 DEG C. over 10 minutes. The mixture was then stirred at this temperature for an additional 30 minutes. 22.95 g of 1-trityl-4-imidazolecarboxaldehyde in 75 cm ^{3 of} dichloromethane are added to the black reaction mixture over 10 minutes. After stirring for 45 minutes at 100C, 100 cm @ ³ of pH = 7 buffer solution are added. After decantation, the organic phase is washed with 60 cm @ ^{3 of a} saturated aqueous solution of sodium bicarbonate and then with 2.times.100 cm @ ^{3 of} water, and then dried over magnesium sulphate. Filtration and evaporation of the filtrate to dryness afforded the product as a solid foam, which analysis showed that it contained 71% syn (2'R, 3'S), 12% syn (2'S, 3'R) and 17% isomer anti (2'S, 3'S). Recrystallization from 1140 cm ^{3 of} ethyl acetate gave 18.13 g of N- (3'-hydroxy-2'-chloro-3 '- (1-trityl-4 (1H) -imidazolyl) propanoyl) - (2'R, 3'S) - Of 10,2-bornansultam in the form of white crystals. Using nuclear magnetic resonance spectroscopy, the product was shown to contain 95% of the syn (2'R, 3'S) isomer.

Example 3

To a flask of 250 cm ³ at a temperature; -30 ° C and under argon atmosphere introduced 1.5 g of (+) - N -chloroacetyl-10,2-benzanesultam (5.14 mmol) in solution in 20 cm ³ of dichloromethane. 0.57 cm ³ of titanium tetrachloride (5.14 mmol) are then added over 10 minutes at a temperature close to -30 ° C. The mixture is stirred for 30 minutes and then 0.9 cm ^{3 of} diisopropylethylamine (5.14 mmol) is added at -30 ° C. The mixture is stirred for 30 minutes at -30 DEG C. and 0.44 cm @ ^{3 of} 2-pyridinecarboxaldehyde (4.61 mmol) are added. The mixture was stirred for one hour at -30 ° C and then allowed to warm to near 0 ° C. Add 10 cm ^{3 of} buffer with H = 7. After decantation, the organic phase is dried over magnesium sulphate. After filtration and concentration of the filtrate to dryness by rotary evaporation, 1.71 g of the desired product are obtained in the form of a solid foam which is recrystallized with a 6: 1 by volume mixture of ethyl acetate and isopropyl ether. In this way, 0.25 g of N- (3'-hydroxy-2'-chloro-3 '- (2-pyridyl) propanoyl) -1,2,2-boronan tamu (conversion degree: 97%) is obtained, which according to the ¹ H-nuclear magnetic resonance spectroscopy, it comprises a 95: 5 mixture of syn (2'R, 3'S) and anti (2'S, 3'S) isomer.

Example 4

The procedure is as in Example 3, but using 1.5 g of 4-pyridinecarboxaldehyde to give 0.7 g of N- (3'-hydroxy-2'-chloro-3 '- (4-pyridyl) propanoyl). -10,2-bornansultam (conversion degree: 85%), which, according to ¹ H-NMR spectroscopy, contains more than 95% of the syn (2'R, 3'S) isomer.

Claims (6)

A process for the preparation of a syn propanamide derivative of the general formula I wherein X represents a halogen atom, R represents an alkyl group, an aryl group or a heteroaryl group and R 1 represents a residue of one or the other of the enantiomers of camphosultam of formula II or III IV or V OH 0 OH 0 J II R ^^ V ^ R _£ R ^ Y ^ R, X X (IV) (IN) characterized in that the camphosultam derivative of the general formula VI or VII is used Ktorom in which X is as defined above, is reacted with an aldehyde of formula VIII R-CHO (VIII) wherein R is as defined above, in the presence of titanium tetrachloride and an organic base in an inert organic solvent at a temperature of -50 to 50 ° C. The process according to claim 1, characterized in that 0.3 to 3 moles of titanium tetrachloride are used per mole of camphos derivative. 3. The process according to claim organic base is selected tertiary and min. characterized by a set comprising aliphatic 3. The process of claim 3 wherein the organic base is di-propylethylamine or The method of claim 3 or 4, wherein at least one mole of base is used per mole of camphos derivative. A process according to any one of claims 1 to 5 for the preparation of the syn propanamide derivative of the general formula X wherein X and R 1 are as defined in claim 1. A process according to any one of claims 1 to 5 for the preparation of a syn propanamide derivative of the general formula in which X and R 1 have the meanings given in claim 3. and Z i represents Use of a compound obtained by the process of claim 6 for the preparation of taxol and derivatives thereof. The use of a compound obtained by the method of claim 7 for the preparation of 3-amino-1- (2-amino-4 (1H) -imidazolyl) -2-chloro- (1S, 2S) 1-propanol. Use of a compound obtained by the method of claim 7 for the preparation of erythro-beta-hydroxy-L-histidine.