WO2001058872A1

WO2001058872A1 - Method for diastereoselective preparation of piperidines functionalised in positions 2 and 4 for use as synthesis intermediates

Info

Publication number: WO2001058872A1
Application number: PCT/FR2001/000370
Authority: WO
Inventors: Janine Cossy; Damien Belloti; Jean-Roger Desmurs
Original assignee: Rhodia Chimie
Priority date: 2000-02-09
Filing date: 2001-02-08
Publication date: 2001-08-16
Also published as: FR2804682A1; AU2001235633A1; FR2804682B1

Abstract

The invention concerns a method for preparing, with diastereoselective induction, a piperidine monosubstituted in position 4 and functionalised in position 2, comprising steps which consist in: (i) reacting the corresponding N-protected piperidine, monosubstituted in position 4 and non-functionalised in position 2, with a strong base so as to form the negatively charged corresponding carbanion in position 2; then (ii) reacting said carbanion with an electrophilic reagent, with a volume less than 80 Å3 or more than 100 Å3.

Description

Process for the diastereoselective preparation of piperidines functionalized in positions 2 and 4 usable as synthesis intermediates

The invention relates to a process for the diastereoselective functionalization in position 2 of monosubstituted piperidines in position 4. The process of the invention leads to the preparation of racemic mixtures of piperidines disubstituted in positions 2 and 4 which, due to the functionalization in position 2, constitute reaction intermediaries of choice in the preparation of numerous biologically active molecules. These racemic mixtures are all the more interesting as they mainly comprise certain diastereoisomers, the relative stereochemistry of the substituents of which is determined.

An example of a target biologically active molecule is the argatroban of formula:

in which the piperidine nucleus comprises two centers of well-defined absolute configuration and in which a substituent attached to one of these centers is a methyl substituent. The synthesis of this compound, which is a powerful antithrombotic agent, is greatly simplified starting from a piperidine having the appropriate relative trans stereochemistry at the level of the carbons in positions 2 and 4. The process of the invention allows the preparation of cis compounds or trans of such a piperidine from a piperidine monosubstituted by a methyl group in position 4. More precisely, the process of the invention, which allows the diastereoselective preparation of a monosubstituted piperidine in position 4 and functionalized in position 2, comprises the steps consisting in:

(i) reacting the corresponding N-protected piperidine, monosubstituted in position 4 and non-functionalized in position 2, with a strong base, so as to form the corresponding negatively charged carbanion in position 2; then

(ii) reacting said carbanion with an electrophilic reagent, of a volume of less than 80 A ³ or greater than 100 A ³ .

Preferably, the method of the invention comprises the steps consisting in:

(i) reacting the corresponding piperidine monosubstituted in position 4, not functionalized in position 2, of formula I:

in which

P represents a protecting group for the amino function, R 1 is chosen from an alkyl group optionally substituted by one or more halogen atoms; an alkoxy group; hydroxy; aryloxy; aryl; heteroaryl; heteroaryloxy; arylalkyl; arylalkoxy; heteroarylalkyl; heteroarylalkoxy; amino; alkylamino and dialkylamino, with a strong base, so as to form the corresponding anion of formula II:

wherein Ri and P are as defined above; (ii) reacting on the anion of formula II obtained in the preceding step an electrophilic reagent with a volume of less than 80 Å ³ or greater than 1 10 A ³ . The N-protected piperidine monosubstituted in position 4 and functionalized in position 2, obtained according to the process of the invention, comprises, as substituent of the piperidine nucleus:

- the group grafted in position 2 by functionalization, and - the substituent initially present on the piperidine ring of formula I, for example the substituent R-i defined above.

In the context of the invention, the term “alkyl” means a linear or branched hydrocarbon chain preferably comprising 1 to 15 carbon atoms, better still 1 or 2 to 10 carbon atoms, for example 1 or 2 to 6. Examples alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1 - ethylpropyl, hexyl, isohexyl, neohexyl, 1 -methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1-methyl-1 -ethylpropyl. Most preferably, the alkyl radical contains 1 to 4 carbon atoms. By aryl is meant a mono- or polycyclic aromatic radical, preferably mono- or bicyclic (C ₆ -C ₁₂ ), such as phenyl or naphthyl.

By heteroaryl is meant according to the invention, a heterocyclic, mono- or polycyclic, preferably mono- or bicyclic, aromatic radical of 4 to 12 carbon atoms and one or more heteroatoms chosen from O, S and N. Such heterocycles aromatics are, for example pyridine, furan, thiophene, pyrrole, pyrrazole, imidazole, thiazole, isoxazole, isothiazole, pyridazine, pyrimidine, pyrazine, t azines, indolizine, indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzothiazole, purine, quinoline, isoquinoline, cinnoline, phthalizine, quinazoline, quinoxaline, pteridine , naphthyridines, carbazole, phenothiazine, phenoxazine, acridine, phenazine, oxazole, pyrazole, oxadiazole, triazole and thiadiazole. It is preferred that heteroaryl represents a quinoline, indolyl, isoquinoline, isoindole, furan, thiophene, pyrrole, imidazole, pyridine, oxazole, thiazole, benzofuran or benzothiophene ring.

Protective groups for the amino function are acyl groups of R-CO type (where R is a hydrogen atom, an alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl radical, R being optionally substituted by alkyl, alkoxy or halogen), the urea groups of formula -CO- NA ₂ B ₂ or the urethane groups of formula -CO-OA ₂ (in which A ₂ and B ₂ are independently alkyl, aryl, arylalkyl or cycloalkyl - optionally substituted by alkyl, alkoxy or halogen - or A ₂ and B ₂ together form with the nitrogen atom which carries them a heterocycle, mono- or polynuclear - preferably mono- or binuclear - saturated, unsaturated or aromatic optionally substituted by alkyl, alkoxy or halogen), thiourethane groups of formula -CS-NA ₂ B ₂ (where A ₂ and B ₂ are as defined above), tetrahydropyranyl groups, and more rarely alkyl, alkenyl groups (allyl or isopropenyl), arylalkyl such as trityl or benzyl and groups of the benzylidene type.

As examples of an amino group protecting group, there may be mentioned the formyl group, the acetyl group, the chloroacetyl group, the dichloroacetyl group, the phenylacetyl group, the thienylacetyl group, the tert-butoxycarbonyl group and the benzyloxycarbonyl group. Particularly preferred protective groups are in particular (CC ₆ ) alkoxycarbonyl and (C ₆ -C ₁₀ ) aryl- (CrC ₆ ) alkoxycarbonyl such as tert-butyloxycarbonyl and benzyloxycarbonyl.

By halogen atom is meant chlorine, bromine, iodine or fluorine, chlorine and bromine being preferred.

The term “cycloalkyl” is understood to mean, according to the invention, a cyclic hydrocarbon radical, preferably of (C ₃ -C ₈ ) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

By alkenyl is meant according to the invention a hydrocarbon group, linear or branched, preferably comprising from 2 to 15 carbon atoms and comprising one or more double bonds, preferably 1 to 2 double bonds.

Preferred alkenyls are those comprising 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. When -NA ₂ B ₂ forms a saturated heterocycle, it preferably has from 4 to 12 carbon atoms and optionally 1 to 2 additional heteroatoms chosen from O, N and S. Examples of saturated heterocycles are pyrrolidine, l ' imidazoline, pyrazoline, piperidine, morpholine, thiomorpholine, piperazine, quinuclidine and saturated derivatives of the following radicals: indolizine, indole, isoindole, indazole, benzimidazole, benzothiazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline , pteridines, acridine, phenazine, phenothiazine and phenoxazine.

When -NA ₂ B ₂ forms an unsaturated heterocycle, this preferably has from 4 to 12 carbon atoms and optionally 1 to 2 additional heteroatoms chosen from O, N and S. Examples of unsaturated heterocycles are pyrroline, l ' imidazoline, pyrazoiine, and the unsaturated derivatives comprising a double bond of the following radicals: piperidine, morpholine, thiomorpholine and piperazine.

The starting piperidine is not substituted in position 2. It includes a prochiral center in position 4.

By functionalization of position 2 of the piperidine nucleus, two chiral centers are then created.

A preferred subgroup of compounds of formula I consists of those for which Ri represents an optionally halogenated (Cι-C ₆ ) alkyl, (CC ₆ ) alkoxy, (C ₆ -C ₁₀ ) aryl, (C ₆ -C ₁₀ ) aryloxy, (C ₆ -C ₁₀ ) aryl- (Cι-C ₆ ) alkyl, (C ₆ - Cι ₀ ) aryl- (Cι-C ₆ ) alkoxy or di (Cι-Ce) alkylamino. Among these compounds, preference is given to those in which Ri represents (d-

C ₆ ) optionally halogenated alkyl (such as ethyl) or (C ₆ -Cιo) aryl- (C-ι-C ₆ ) alkyl (such as benzyl).

Better still, Ri represents (CC ₆ ) alkyl (and in particular ethyl) or (C ₆ - C-ιo) aryl- (C-ι-C6) alkyl (and in particular benzyl). According to yet another embodiment of the invention, the method of the invention is implemented starting from 4-methylpiperidine protected at the endocyclic nitrogen level by a group P.

In step (i), the corresponding carbanion of the starting piperidine is formed, which carries a negative charge in position 2. From the piperidine I, the carbanion of formula II is obtained:

in which Ri and P are as defined above by pulling out a proton in position 2. To do this, the piperidine of formula I is reacted with a strong base, preferably a base having a pKa greater than 30.

When the starting piperidine comprises a halogen atom, the base is chosen so as not to react with these halogen atoms.

Examples of suitable bases are in particular an alkali metal amide, a lithiated base, an arylsodium or hexamethyldisilazane. It is particularly preferred to conduct step (i) in the presence of a base chosen from n-butyllithium, phenyllithium, phenylsodium, tert-butyllithium, sec-butyllithium and diisipropyllithium amide.

Advantageously, it is also possible to use M ₀ N (SiMe ₃ ) ₂ where M ₀ represents an alkali metal such as potassium and Me represents methyl.

Another particularly preferred base consists of the butyllithium / alkali metal alcoholate system, for example n-butyllithium / potassium tert-butoxide.

In the case of bases of the alkali metal amide, lithiated base or arylsodium type, it is preferable to add to the reaction medium a complexing agent capable of complexing the metal cation. Such complexing agents are in particular tetramethylethylenediamine, [(CH ₃ ) ₂ N] ₃ PO and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1 H) pyrimidinone.

Step (i) is preferably carried out in a solvent and in particular an ether such as, for example, a cyclic or alicyclic aliphatic ether (diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane), a mono- or diether derived from ethylene glycol (dimethoxyethane) or a polyether such as diethylene glycol dimethyl ether. The temperature at which the reaction is carried out depends on the base used. Generally, the temperature is maintained between -100 and 10 ° C, preferably between -100 ° C and -50 ° C.

Generally, from 1 to 3 molar equivalents of the base are used relative to the starting piperidine, preferably from 1, 2 to 1, 8 equivalents.

In step (ii), the carbanion is reacted with an electrophilic reagent. The electrophilic reaction takes place diastereoselectively, which means that the attack of the electrophilic reagent preferably takes place in a given direction.

After functionalization of position 2 of the piperidine nucleus, that is to say after reaction of the electrophile with the carbanion, two chiral centers (the starting piperidine being prochiral) are created.

However, insofar as there is diastereoselectivity, the number or the proportion of enantiomers present in the final mixture does not correspond to the number or the theoretical proportion of possible enantiomers. Certain enantiomers are absent or in the minority in the final mixture.

More precisely, the majority of the enantiomers are observed, the relative stereochemistry of the asymmetric centers of which is fixed.

In theory, the electrophilic attack leads to four enantiomers, two of which have a relative configuration of the cis type and the other two have a relative configuration of the trans type.

According to the invention, a diastereoselectivity is obtained, that is to say that a pair of enantiomers (the cis couple or the trans couple) is predominantly obtained. Generally, the majority torque constitutes at least 60% of the total mixture obtained, preferably at least 70, better still at least 90%. It has been found that a small electrophile promotes the formation of the pair of cis enantiomers. Conversely, a large electrophile promotes the formation of the pair of trans enantiomers.

In order to ensure diastereoselectivity, the electrophile must have either a volume greater than 1 10 A ³ , or a volume less than 80 A ³ . Preferably, the volume of the electrophile is greater than 200 A ³ , better still 300 A ³ , or less than 75 A ³ , better still 70 A ³ .

According to a still more preferred embodiment, the volume of the electrophile is greater than 400 A ³ or less than 66 A ³ . Numerous methods for calculating the volumes of molecules are known in the art. Those skilled in the art may refer in this connection to the methods described in "Molecular Physics, 1987, vol. 62, no. 5, 1247-1265";"J.

Am. Chem. Soc. 1983, 105, 5220-5225 "; or" Ann. Rev. Biophys. Bioeng., 1977, 6, 151-176 ".

According to the invention, the volumes of the electrophilic reagents are calculated using the MOPAC software, version 6, for the optimization of the structures, which is commonly available commercially from suppliers of scientific software, by implementing the PM3 method, the Van der Waals surfaces being calculated using Cerius software from Molecular Simulation Inc.

The nature of the electrophile is arbitrary according to the invention, provided that the volume conditions set out above are observed.

The electrophilic reagent is for example chosen from a haloformate, a halothioformate, an amide, a ketone, an aldehyde and an electrophile, the electrofuge part of which is chosen from -S0 ₂ -Y, a trisubstituted silyl group, a trisubstituted stannyl group or a group -Se-Y, it being understood that Y represents an alkyl group optionally substituted by alkoxy; an aryl group optionally substituted by halogen, alkyl or alkoxy; or an arylalkyl group in which the alkyl part is optionally substituted by alkoxy or halogen and in which the aryl part is optionally substituted by alkyl, alkoxy or halogen. Examples of substituents of the silyl and stannyl group are in particular the group Y defined above.

The nature of the amides, ketones and aldehydes which can be used in the process of the invention is not critical according to the invention.

Mention may be made, for example, of aromatic, aliphatic and / or cyclic amides, ketones and aldehydes.

As electrophile having an electrofuge part of formula -SO ₂ -Y, there may be mentioned sulfonyl halides, and more preferably sulfonyl chlorides.

Other examples are the derivatives of formula E-SO ₂ Y where E represents cyano; alkoxy; aryloxy optionally substituted with alkyl or alkoxy; or arylalkyloxy optionally substituted by alkyl or alkoxy. As haloformate and halogenothioformate, chloroformates and chlorothioformates are preferred.

As examples of electrophilic reagents having an electrofuge part of formula alkylthio or arylthio, one can quote: • the compounds of formula:

G-S0 ₂ -SJ in which G and J are independently alkyl optionally substituted by alkoxy or halogen; and aryl optionally substituted with alkyl, alkoxy or halogen; • the compounds of formula:

G-S-S-J

II o in which G and J are as defined above; and • the disulfides of formula:

GSSJ in which G and J are as defined above. As electrophilic reagents having an electrofuge part of formula -Se-Y, a distinction is made between the compounds of formula G-S0 ₂ -Se-Y; the compounds of formula G-SO-Se-Y; and the compounds of formula G-Se-Se-Y where G and Y are as defined above.

A first group of preferred electrophilic reagents consists of sulfonyl halides, haloformates, halothioformates, carbon dioxide (CO ₂ ) and carbon sulfide (CS ₂ ). Among these, sulfonyl chlorides are preferred; chloroformates; chlorothioformiates; carbon dioxide and carbon sulfide.

Another group of preferred electrophilic reagents consists of the electrophilic reagents of formula C0 ₂ , CS ₂ , R _a S0 ₂ CI, R _b OCOCI, in which: R _a represents (CC ₆ ) alkyl optionally substituted by (Ci-Cβ) alkoxy (preferably (C ₂ -C ₆ ) alkyl optionally substituted by (Cι-C ₆ ) alkoxy) or halogen; (C ₆ -C-ιo) aryl optionally substituted by (CC _δ ) alkyl, (CC ₆ ) alkoxy or halogen; or (C ₆ -Cιo) aryl- (Cι-C ₆ ) alkyl in which the aryl part is optionally substituted by (CrC ₆ ) alkyl, (CC ₆ ) alkoxy or halogen and the alkyl part is optionally substituted by (CrC ₆ ) alkoxy or halogen; and Rb represents (C] -C ₆ ) alkyl optionally substituted by (Cι-C ₆ ) alkoxy (preferably (C ₂ -C ₆ ) a kyle optionally substituted by (Cι-C ₆ ) alkoxy); (C ₆ - C-ιo) aryl optionally substituted by (CrC ₆ ) alkyl or (CC ₆ ) alkoxy; or (C ₆ -Cιo) aryl- (C-ι-C ₆ ) alkyl in which the aryl part is optionally substituted by (CrC ₆ ) alkyl or (Cι-C ₆ ) alkoxy and the alkyl part is optionally substituted by (C -ι-C ₆ ) alkoxy.

Another example of an electrophilic reagent is RR _c N-CS-CI in which R is as defined above and R _c takes any of the meanings given above for R _b . Advantageously, the electrophilic reagent is R _a -S0 ₂ -Cl in which R _a is (C ₆ -Cι ₀ ) aryl- (C ₁ -C ₆ ) alkyl or (C ₃ -C ₆ ) alkyl.

According to another preferred embodiment, the electrophile is C0 ₂ . The reaction of the electrophilic reagent on the carbanion in step ii) can be carried out in the absence or in the presence of a solvent. According to a preferred variant of the process of the invention, the procedure is carried out in the presence of the same solvent as used in step (i), namely in the presence of an ether as defined above.

The implementation of step (ii) does not necessarily require the isolation of the anion II formed in step (i) but can be carried out in situ. The reaction temperature is, during step (ii), between -100 °

C and 50 ° C.

According to a preferred embodiment, the addition of the electrophilic reagent is carried out at a temperature maintained between -100 ° C and -10 ° C, preferably between -100 ° C and -50 ° C. In a second step, the the temperature of the reaction medium rise until reaching the range from 0 ° C to 50 ° C, preferably from 10 ° C to 30 ° C.

Usually, a molar ratio of the electrophilic reagent to the carbanion is used between 1 and 3 equivalents, preferably between 1, 2 and 1, 8.

The starting piperidines are easily obtained from the corresponding unprotected piperidines (that is to say having a free endocyclic amino function) by implementing conventional methods of organic chemistry. To do this, the skilled person can draw inspiration from the works cited above by Greene and Kocienski. Unprotected piperidines are commercial products or conventionally prepared from commercial products.

Advantageously, the method of the invention further comprises the step of deprotecting the endocyclic amino function of the compound resulting from step (ii) by removing the protective group.

Deprotection is carried out in a conventional manner using methods known from organic chemistry.

The deprotection conditions are easily determined by a person skilled in the art. They are described in particular in "Protective Groups in Organic Synthesis, Greene T.W. and Wuts P.G.M., Ed. John Wiley and Sons, 1991; and in Protecting Groups, Kocienski P.J., 1994, Georg Thieme Verlag".

For a protective group of the arylalkyloxycarbonyl type, the elimination can be carried out by catalytic hydrogenation, for example in the presence of palladium on carbon. For a protective group of the alkoxycarbonyl type, the deprotection can be carried out by treatment in an acid medium, for example by the action of trifluoroacetic acid or hydrochloric acid.

The cyclic amines obtained by the process of the invention are used as synthesis intermediates in the preparation of various molecules. The following diagram 1 illustrates in particular the preparation of argatroban starting from the racemic trans-2-benzyloxycarbonyl-4-methyl! Piperidine of formula III.

Diagram 1

VIII

Boc: tert-butoxycarbonyl i-Bu: isobutyl

NEt ₃ : triethylamine

AcOEt: ethyl acetate

Bn: benzyl

HCI: hydrochloric acid. In step A, compound IV is reacted with a molar equivalent of isobutyl chloroformate in the presence of triethylamine (1 equivalent) in tetrahydrofuran as solvent at -25 ° C.

Then the compound of formula III is added to the reaction medium maintained at -35 ° C. Compound V is thus obtained, which is a mixture of two trans diastereomers. In each diastereoisomer, the two methyl and benzyloxycarbonyl groups are trans from one another.

The least polar diastereoisomer is separated by chromatography on silica gel (step B1)). In step B.2), the protective group -Boc is removed by the action of dry hydrochloric acid in ethyl acetate. Compound VI is isolated in the form of a hydrochloride. This compound VI is reacted with 3-methyl-quinol-8-ylsulfonyl chloride (1, 2 molar equivalent) in the presence of triethylamine (10 equivalents) in CH ₂ CI ₂ as solvent, at 0 ° C (step C.1)). After hydrolysis between 0 ° C and room temperature, the compound VII is recovered (step C.2)). The hydrogenation, at room temperature, of this compound in the presence of 10% palladium on carbon in a mixture of ethanol and acetic acid, leads to the argatroban of formula VIII (step D).

The following examples illustrate the implementation of the process of the invention.

Boc denotes the tert-butoxycarbonyl group.

CPG stands for gas chromatography.

EXAMPLE 1 Preparation of 2-ethoxycarbonyl-4-methylpiperidine using ethyl chloroformate as electrophilic reagent

The reactions are carried out under an inert atmosphere using anhydrous reagents and solvents and using perfectly dry equipment.

N, N, N ', N' are added to a stirred solution of N-Boc-4-methyl-piperidine 1 (4 g; 20 mmol) in dry ether (40 ml) at -90 ° C - tetramethylethylenediamine (TMEDA) (3.5 g; 30 mmol), then sec-butyllithium 1, 3 M in a cyclohexane / hexane 92/8 mixture (23 ml of solution;

30 mmol) drop by drop (in 20 min). The resulting cloudy yellow solution is stirred at -90 ° C for 5 h. Ethyl chloroformate (32 mmol) is then added quickly (the temperature rises to around -70 ° C, then drops back to -90 ° C). The temperature rose slowly (in 4 h) to ambient, then the reaction mixture is left under stirring for 13 h. The reaction mixture is diluted with water (100 ml) then extracted with ethyl acetate (100 ml, then 2 x 50 ml). The combined organic phases are dried over MgS0, filtered and evaporated. The reaction product mixture is separated from the remaining starting product 1 (50-60% recyclable) by flash chromatography on a silica column (petroleum ether / ethyl acetate 95/5, then 90/10). The reaction product mixture is dissolved in dry dichloromethane (30 ml), then treated at 0 ° C with trifluoroacetic acid (13.7 g; 120 mmol) added dropwise (release of apparent CO ₂ ). The resulting solution is stirred at 0 ° C for 10 min, then at room temperature for 24 h. The reaction mixture is neutralized by addition of a saturated solution of NaHCO ₃ in water, then extracted with dichloromethane (4 x 100 ml). The combined organic phases are dried over MgS0, filtered and evaporated. The crude product obtained is purified by flash chromatography on a silica column (dichloromethane / ethanol 95/5) to give ethyl 4-methyl-pipecolate (oil) in the form of a mixture of trans and cis stereoisomers. The trans / cis ratio is determined by GPC / Mass and by ¹ H NMR. The trans and cis ethyl 4-methyl-pipecolates can be separated by another flash chromatography on a silica column (dichloromethane / ethanol 95/5).

A mixture of diastereoisomers of 2-ethoxycarbonyl-4-methylpiperidine is thus isolated in which the ratio of trans isomers to cis isomers is 65/35 (overall yield = 29%).

Trans isomers

Characterization data of trans isomers:

¹ H NMR (300 MHz, CDCI ₃ ): δ (ppm) 0.94 (3H, d, J = 6.5 Hz); 1.10-1.25 (1H, m); 1.28 (3H, t, J = 7.2 Hz); 1.47 (1 H, qd, J = 12.3 and 3.2 Hz); 1.50-1.65 (2H, m); 2.00-2.10 (1H, m); 2.23 (1H, br s); 2.77-2.90 (2H, m); 3.65 (1H, m); 4.20 (2H, q, J = 7.2 Hz).

¹³ C NMR (75 MHz, CDCI ₃ ): δ (ppm) 14.3 (q); 21, 6 (q); 27.6 (d); 33.7 (t); 35.0 (t)

; 42.3 (t); 55.6 (d); 60.7 (t); 174.3 (s).

SM-IE (relative intensity): m / z 171 (M ⁺ , 1%); 98 (100%); 56 (17%).

Cis isomers

Characterization data for cis isomers:

¹ H NMR (300 MHz, CDCI3): δ (ppm) 0.95 (3H, d, J = 6.5 Hz); 1.07 (2H, qd, J = 12.5 and

3 Hz); 1.27 (3H, t, J = 7.2 Hz); 1.45-1.65 (2H, m); 1.97 (1H, br s); 2.00 (1H, m);

2.62 (1 H, td, J = 12.2 and 2.3 Hz); 3.15 (1H, m); 3.30 (1 H, dd, J = 11.6 and 2.7 Hz);

4.18 (2H, q, J = 7.2 Hz). ¹³ C NMR (75 MHz, CDCI3): δ (ppm) 14.2 (q); 22.4 (q); 31, 3 (d); 34.6 (t); 38.0 (t)

; 45.9 (t); 59.1 (d); 60.7 (t); 173.4 (s).

SM-IE (relative intensity): m / z 171 (M ⁺ , 1%); 98 (100%); 56 (17%).

EXAMPLE 2 Preparation of 2-benzyloxycarbonyl-4-methyl-piperidine using benzyl chloroformate as electrophilic reagent.

The title compound is prepared by carrying out the procedure illustrated in Example 1, except that the ethyl chloroformate is replaced by benzyl chlorofomate. A mixture of the 2-benzyloxycarbonyl-4-methylpiperidine diastereoisomers is isolated in this way, in which the ratio of trans isomers to cis isomers is 95/5 (overall yield = 15%). Characterization data for trans isomers of formula:

¹ H NMR (300 MHz, CDCI ₃ ): δ (ppm) 0.93 (3H, d, J = 6.5 Hz); 1.10-1.25 (1H, m); 1.48 (1 H, qd, J = 12.2 and 3.5 Hz); 1.50-1.63 (2H, m); 2.08 (m, 1H); 2.23 (1H, br s); 2.76-2.88 (2H, m); 3.69 (1H, m); 5.16 (2H, s); 7.25-7.40 (5H, m).

SM-IE (relative intensity): m / z 233 (M ⁺ , 1%); 98 (100%); 91 (13%); 56 (18%).

EXAMPLE 3

Preparation of 2-ethoxycarbonyl-4-methyl-piperidine using carbon dioxide as an electrophilic reagent.

To a stirred solution of N-Boc-4-methyl-piperidine (2.5 g; 12.5 mmol) in dry ether (25 ml) at -78 ° C are added TMEDA (2.18 g ; 18.75 mmol) then sec-butyllithium 1, 3M in a cyclohexane / hexane 92/8 mixture (14.42 ml of solution; 18.75 mmol) drop by drop (in 15 min). The resulting cloudy yellow solution is stirred at -78 ° C for 1.5 h. Then dry CO ₂ (g) is bubbled into the solution for 1 h at -78 ° C.

The temperature rose slowly to room temperature (in 2 h), then left for 17 h. Water is added (50 ml) and the mixture is neutralized with H ₃ P0 / H ₂ 0 1 M. The mixture is extracted with CH ₂ CI ₂ (3 x 75 ml) and the combined organic phases are dried over MgS0 ₄ , filtered and evaporated. The crude product is purified by flash chromatography on a silica column (dichloromethane / ethyl acetate 70/30, then 50/50, then pure ACOEt) to give 0.6 g of starting N-Boc-4-methyl-piperidine ( 24%) and 0.91 g of N-Boc-4-methyl-pipecolic acid (30%) in the form of a single stereoisomer. 0.5 g of the N-Boc-4-methyl-pipecolic acid obtained is treated with a saturated solution of HCl in ethanol (5 ml) at 0 ° C. The solution is then stirred at room temperature for 22 h , then is neutralized with a saturated solution of NaHC0 ₃ in water. The mixture is extracted with chloroform (3 x 25 ml). The combined organic phases are dried over MgSO ₄ , filtered and evaporated to give ethyl cis-4-methyl-pipecolate with a yield of 96% (0.34 g). Only the cis stereoisomer is observed. The overall yield of the title compound is 29%. This product is characterized as in Example 1.

EXAMPLE 4

Preparation of 2-methoxycarbonyl-4-methyl-piperidine using methyl chloroformate as an electrophilic reagent. The title compound is prepared by carrying out the procedure illustrated in Example 1, except that the ethyl chloroformate is replaced by methyl chloroformate. A mixture of the 2-methoxycarbonyl-4-methyl-piperidine diastereoisomers is isolated in this way in which the ratio of trans isomers to cis isomers is 65/35 (overall yield = 30%).

Claims

1. Method of diastereoselective synthesis for the preparation of a monosubstituted piperidine in position 4 and functionalized in position 2, comprising the steps consisting in: (i) reacting the corresponding N-protected piperidine, monosubstituted in position 4 and not functionalized in position 2, with a strong base, so as to form the corresponding negatively charged carbanion in position 2; then

(ii) reacting said carbanion with an electrophilic reagent, of a volume less than 80 A ³ or greater than 100 A ³ .

2. Method according to claim 1, characterized in that the piperidine monosubstituted in position 4, not functionalized in position 2 starting, has the formula I:

in which P represents a protective group for the amino function,

R-, is chosen from an alkyl group optionally substituted by one or more halogen atoms; an alkoxy group; hydroxy; aryloxy; aryl; heteroaryl; heteroaryloxy; arylalkyl; arylalkoxy; heteroarylalkyl; heteroarylalkoxy; amino; alkylamino and dialkylamino.

3. Method according to claim 2, characterized in that Ri represents a group (C-ι-C ₆ ) optionally halogenated alkyl, (C-ι-C ₆ ) alkoxy,

(C ₆ -Cιo) aryl, (C ₆ -C ₁₀ ) aryloxy, (C ₆ -C ₁₀ ) aryl- (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl- (Cι-

C ₆ ) alkoxy or di (C-ι-C ₆ ) alkylamino.

4. Method according to any one of claims 2 or 3, characterized in that Ri represents (CrCe) optionally halogenated alkyl or

(C ₆ -Cι ₀ ) aryl- (CrC ₆ ) alkyl.

5. Method according to any one of claims 2 to 4, characterized in that Ri represents (CC ₆ ) alkyl or (C6-C ₁₀ ) aryl- (Cι-C ₆ ) alkyl.

6. Method according to claim 5, characterized in that in the piperidine of formula I, R 1 represents methyl and P is as defined in claim 2.

7. Method according to any one of the preceding claims, characterized in that the electrophilic reagent is chosen from a sulfonyl halide; a haloformate; halothioformate; carbon dioxide or carbon sulfide.

8. Method according to claim 7, characterized in that the electrophilic reagent is chosen from a sulfonyl chloride; a chloroformate; a chlorothioformate; carbon dioxide or carbon sulfide.

9. Method according to claim 8, characterized in that the electrophilic reagent has the formula C0 ₂ , CS ₂ , R _a -S0 ₂ -Cl, or R _b O-CO-CI, in which

R _a represents (dC ₆ ) alkyl optionally substituted by (CC ₆ ) alkoxy or halogen; (Ce-C-io) aryl optionally substituted by (CiC _δ ) alkyl, (Cι-C ₆ ) alkoxy or halogen; or (C ₆ -Cι ₀ ) aryl- (Cι-C ₆ ) alkyl, the aryl part of which is optionally substituted with (C-ι-C ₆ ) alkyl, (CC ₆ ) alkoxy or halogen and the alkyl part is optionally substituted by (Cι-C ₆ ) alkoxy or halogen; and

R represents (Cι-Ce) alkyl optionally substituted by (d- Ce) alkoxy; (C ₆ -C ₁₀ ) aryl optionally substituted by (CrCe) alkyl or (CC ₆ ) alkoxy; or else (C ₆ -Cι ₀ ) aryl- (CrC ₆ ) alkyl, the aryl part of which is optionally substituted by (Cι-C ₆ ) alkyl or (CrC ₆ ) alkoxy and the alkyl part is optionally substituted with (CrC ₆ ) alkoxy .

10. Method according to any one of the preceding claims, characterized in that the electrophilic reagent is R _a -S0 ₂ -Cl in which R _a is (CQ- C ₁₀ ) aryl- (CrC ₆ ) alkyl or (C ₃ - C ₆ ) alkyl; or the electrophile is C0 ₂ .

11. Method according to any one of the preceding claims, characterized in that the protecting group for the endocyclic nitrogen atom is (CrC ₆ ) alkoxycarbonyl or (C ₆ -C ₁₀ ) aryl- (Cι-C ₆ ) alkoxycarbonyl .

12. Method according to any one of the preceding claims, characterized in that, in step (i) the base is chosen from an alkali metal amide, a lithiated base, an arylsodium or hexamethyldisilazane.

13. Method according to claim 12, characterized in that in step i), the reaction of the strong base on the piperidine is carried out in the presence of a complexing agent.

14. Method according to claim 13, characterized in that the complexing agent is chosen from tetramethylethylenediamine, hexamethylphosphotriamide and 1, 3-dimethyl-3,4,5,6-tetrahydro-

2 (1 H) pyrimidinone.

15. Method according to any one of claims 12 to 14, characterized in that the strong base is chosen from n-butyllithium, phenyllithium, phenylsodium, tert-butyllithium, sec-butyllithium, diisopropyllithium amide , the n-butyllithium / alkali metal alcoholate system, and M ₀ N (SiMe ₃ ) ₂ where M ₀ represents an alkali metal and Me represents methyl.

16. Method according to any one of the preceding claims, characterized in that step (i) is carried out at a temperature between - 100 and 10 ° C, preferably between -100 and -50 ° C.

17. Method according to any one of the preceding claims, characterized in that step (ii) is carried out at a temperature between - 100 and 50 ° C.

18. The method of claim 17, characterized in that the addition of the electrophilic reagent to the carbanion takes place at a temperature between -100 and -50 ° C, the reaction being continued at a temperature between 0 and 50 ° C.

19. Method according to any one of the preceding claims, characterized in that it further comprises the step consisting in deprotecting the endocyclic amino function by elimination of the protective group.