EP2663563A1

EP2663563A1 - Vinyl quinuclidine useful as a synthesis intermediate in the preparation of (r)-mequitazine

Info

Publication number: EP2663563A1
Application number: EP12700225.1A
Authority: EP
Inventors: Marc Nicolas; Laurent Larquetoux; Sébastien LEROUX; Eric Doris
Original assignee: Commissariat a lEnergie Atomique CEA; Pierre Fabre Medicament SA; Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
Current assignee: Pierre Fabre Medicament SA; Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
Priority date: 2011-01-10
Filing date: 2012-01-10
Publication date: 2013-11-20
Also published as: FR2970255A1; WO2012095418A1; US8754074B2; JP2014506256A; US20130296553A1; FR2970255B1

Abstract

The present invention relates to the use of the vinyl quinuclidine enantiomer (R) of the following formula 2 as a synthesis intermediate in the preparation of (R)-mequitazine.

Description

Quinuclidine vinyl useful as a synthetic intermediate in the preparation of (R) - mequitazine

The present invention relates to the optically pure vinyl quinuclidine of the following formula 2 as a synthetic intermediate in the preparation of the enantiomer (R), dextrorotatory, mequitazine of the following formula:

"D" mequitazine 1 to "L" mequitazine 1 b racemic mequitazine 1 vinyl quinuclidine 2

(R enantiomer) (S enantiomer)

Diagram 1

Mequitazine 1 is an active ingredient developed pa r Pierre Fa laboratories fiber and commercialized in its racemic version of (mixture of 2 enantiomers Ia and Ib, Scheme 1) as the Primalan ^®. This medicine is used as an antihistamine for the treatment of, for example, urticaria, hay fever or certain allergies. Its preparation in its racemic form 1 and in its levorotatory form lb has been described in patents FR 2 522 660 and EP 0 089 860. The disadvantage of the synthesis protocol for mequitazine in optically active form (la or lb) is that it involves a step of splitting the racemic, via the formation of a complex with tartaric acid. This splitting involves the loss of at least 50% of product (loss of the undesired enantiomer) and leads to an optically enriched compound.

The inventors of the present invention have thus developed a novel process for synthesizing mequitazine la using vinyl quinuclidine 2 as a synthesis intermediate thus making it possible to avoid a step of splitting a racemic mixture.

The present invention thus relates to the enantiomer (R) of the vinyl quinuclidine of formula 2 below:

and pharmaceutically acceptable salts thereof.

This compound 2 will have in particular an enantiomeric excess (ee) greater than 95%, especially greater than 96%, in particular greater than 97%, more particularly greater than 98%, and advantageously greater than 99%.

For the purposes of the present invention, the term "enantiomeric excess" means the difference between the molar fraction of the major enantiomer (enantiomer (R) in the case of vinyl quinuclidine) and the molar fraction of the minority enantiomer ( enantiomer (S) in the case of vinyl quinuclidine).

By "molar fraction" is meant, in the sense of the present invention, the ratio between the molar amount of the enantiomer in question and the molar amount of the two enantiomers. By "pharmaceutically acceptable" is meant, within the meaning of the present invention all that is useful in the preparation of a pharmaceutical composition, which is generally non-toxic and which is acceptable for veterinary and / or human pharmaceutical use.

For the purposes of the present invention, the term "pharmaceutically acceptable salts" means the salts which are pharmaceutically acceptable, as defined above, and which have the desired pharmacological activity of the parent compound. Such salts include:

(1) acid addition salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, bromic acid, phosphoric acid and the like or formed with organic acids such as ascorbic acid, benzoic acid, aspartic acid, oxalic acid, benzene sulfonic acid, tartaric acid, glutamic acid, lactic acid, maleic acid, succinic acid fumaric acid, citric acid, malic acid, mandelic acid, methanesulfonic acid, pantothenic acid, para-toluenesulfonic acid, acetic acid, gluconic acid, ethanesulfonic acid, propionic acid, salicylic acid, trifluoroacetic acid and the like; advantageously it is trifluoroacetic acid; or

(2) salts formed when the acidic proton present in the parent compound is either replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or is coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Advantageously, the pharmaceutically acceptable salt is an acid addition salt, advantageously formed with trifluoroacetic acid.

The present invention also provides a process for synthesizing compound 2. The approach used is based on the use, as starting material, of a family of molecules extracted from cinchona bark: Cinchona alkaloids. These alkaloids have a structural homology that will be used for the construction of the skeleton of (R) - mequitazine.

The alkaloids of Cinchona 3 are characterized by a quinuclidine nucleus (homologous to that of mequitazine) substituted by two pendant groups: a "benzyl alcohol" side chain and a vinylic unit, both of defined stereochemistry (Scheme 2) . The strategy put in place enhances the stereochemistry of the vinyl motif for the creation of the stereogenic center of the domain (R) of the meq u ita z i n e. It is necessary to break down the side chain of the Cinchona backbone in order to create an optically pure alkaline quinuclidine 2 nucleus which is the key intermediate in the synthesis. The vinyl quinuclidine intermediate 2 can then serve as a precursor for the synthesis of mequitazine via an oxidizing coumpre of the double bond, the reduction of the aldehyde obtained u, the activation of the alcohol obtained and the cou lage with phenothiazine.

"D" Mequitazine 1a

Chinchona alkaloids 3 Vinyl quinuclidine 2

(R enantiomer)

Figure 2 The advantages of this approach via Cinchona alkaloids are:

no "random" creation of the stereogenic center carried by the quinuclidine nucleus because it is already present on the starting alkaloid with absolute optical purity (this center will be preserved throughout the synthesis), no loss of half of the raw material committed for duplication, and

an abundant and inexpensive starting material from biomass.

The family of Cinchona alkaloids has different members that differ in nature and stereochemistry of the side chain (eg quinine, cinchonidine, quinidine, cinchonine) but whose stereochemistry of the "vinyl" motif is constant. The synthesis process developed works indifferently from the different members of the family of Cinchona alkaloids. The present invention therefore also relates to a process for synthesizing the enantiomer (R) of vinyl quinuclidine from a Cinchona alkaloid of formula 3 below:

wherein the carbon atom marked by a star is of configuration (R) and R represents a hydrogen atom, a (C ₁ -C ₆ ) alkoxy group such as methoxy, or an R 4 -OH group in which R 4 represents alkyl, Ci-C _6.

For the purposes of the present invention, the term "C ₁ -C ₆ alkyl group" means a saturated linear or branched hydrocarbon-based chain comprising 1 to 6, preferably 1 to 4, carbon atoms. It may be a methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, isobutyl, ter-butyl, pentyl or hexyl group.

For the purposes of the present invention, the term "(C ₁ -C ₆ ) alkoxy" means a linear or branched saturated hydrocarbon-based chain comprising 1 to 6, preferably 1 to 4, carbon atoms, linked to the remainder of the molecule through an oxygen atom. It may be a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, ter-butoxy, pentoxy or hexoxy group. This will be in particular a methoxy or ieri-butoxy group.

The Cinchona alkaloid of formula 3 may be chosen more particularly from quinine, cinchonidine, quinidine and cinchonine, and in particular will be quinine.

The process for synthesizing the enantiomer (R) of vinyl quinuclidine will more particularly comprise the following successive steps:

(i) oxidation of the alcohol function carried by the Cinchona alkaloid of formula 3 as defined above to give the following ketone of formula 4:

for which the carbon atom marked by a star is of configuration (R) and R is as defined previously,

(ii) auto-oxidation of the ketone of formula 4 obtained in step (i) above to give the ester of formula 5 below:

for which the carbon atom marked by a star is of (R) configuration and RI represents a (C ₁ -C ₆ ) alkyl group such as tert-butyl,

(iii) reducing the ester of formula 5 obtained in the preceding step (ii) to give an alcohol of the following formula 6:

for which the star-labeled carbon atom is of configuration (R), and (iv) cyclization of the alcohol of formula 6 obtained u at step (iii) above to give the enantiomer (R) of vinyl quinuclidine of formula 2 as defined above.

Step (i):

The stage (i) can be carried out especially in the presence of imethylsulfoxide.

(DMSO) and oxalyl chloride, i.e. under Swern oxidation conditions.

The reaction will be carried out especially at a temperature between -60 and -80 ° C, especially at about -78 ° C. The dichloromethane may be used as a solvent.

Step (ii):

Step (ii) may be carried out in the presence of oxygen (the oxygen being in particular bubbled in the reaction medium) and a base of formula R 1 -CO-M such that f-BuOK, R 1 being as defined above and especially representing an iron-b utyl group and M representing an alkali metal such as sodium or potassium, and in particular potassium. The reaction may be carried out in the presence of the alcohol of formula R 1 -OH corresponding to the base, such as ieri-butanol. Tetrahydrofuran may be used as a solvent.

Step (iii):

Step (iii) may be carried out in the presence of a hydride such as lithium aluminum hydride (LAH). Tetrahydrofuran may be used as a solvent. Step (iv):

The cyclization step (iv) will comprise in particular the following two successive steps: (iv-1) activation of the OH function of the alcohol of formula 6 as defined above to give the compound of formula 7 below:

wherein the u-star-labeled carbon atom is of (R) configuration and R2 is a leaving group such as a chlorine atom, and

(iv-2) cyclization of the compound of formula 7 in the presence of a base to give the (R) enantiomer of vinyl quinuclidine formula 2 as defined above.

By "leaving group" is meant, in the sense of the present invention, a chemical group that can be easily moved by a nucleophile during a nucleophilic substitution reaction, the nucleophile being more particularly an amine, and in particular a secondary amine. Such a leaving group may be more particularly a halogen atom such as a chlorine atom, a mesylate (CH ₃ -S (O ₂ ) O-), triflate (CF ₃ -S (O) ₂ O-) or another tosylate (p-Me-C ₆ H ₄ -S (O) ₂ O-).

· Step (iv-1) may be performed in the presence of SOCI ₂ lo rs R 2 = Cl. The dichloromethane may be used as a solvent.

• Step (iv-2) may be carried out in the presence of K ₂ CO ₃ as a base. Acetonitrile may be used as a solvent. A catalytic amount of sodium iodide may also be added.

The compound 2 thus obtained can be separated from the reaction medium by methods well known to those skilled in the art, for example by extraction, evaporation of the solvent or again by precipitation and filtration. It may also be purified if necessary by techniques well known to those skilled in the art, such as by recrystallization, distillation, column chromatography on silica gel or by high performance liquid chromatography (HPLC).

The present invention thus provides for the use of the enantiomer (R) of vinyl quinuclidine 2 as a synthetic intermediate in the preparation of the enantiomer (R) of mequitazine.

The present invention therefore also relates to a process for synthesizing the enantiomer (R) of mequitazine from the enantiomer (R) of vinyl quinuclidine 2.

This process may more particularly include the following successive steps:

(a) oxidative cleavage of the double bond of the enantiomer (R) of vinyl quinuclidine of formula 2 as defined above to give the aldehyde of formula 8 below:

for which the carbon atom marked by a star is of configuration (R),

(b) reducing the aldehyde of formula 8 obtained in the preceding step (a) to give the alcohol of the following formula 9:

for which the carbon atom marked by a star is of configuration (R), activation of the OH function of the alcohol of formula 9 obtained in step (b) above, give a compound of formula 10 below:

for which the carbon atom marked with a star is of (R) configuration and R3 represents a leaving group such as a mesylate (Oms or CH ₃ -S (O ₂ ) O-), and

(d) coupling the compound of formula 10 obtained in step (c) above with phenothiazine to give the enantiomer (R) of mequitazine.

Step (a) Step (a) may be performed by ozonolysis, that is to say in the presence of 0 ₃ , the methanol may be used as a solvent. This reaction may be carried out starting from an acid addition salt of the enantiomer (R) of vinyl quinuclidine of formula 2 as defined above, the acid may be more particularly trifluoroacetic acid. . The advantage of using such a salt and that it protects the basic nitrogen from oxidizing conditions.

Step (b):

Step (b) may be carried out in the presence of a hydride such as NaBH ₄ .

Step (c):

Step (c) may be carried out in the presence of mesyl chloride (MsCl), also called methanesulfonyl chloride, and a base such as pyridine, when R3 = OMs. Chloroform may be used as a solvent.

Step (d):

Step (d) is carried out in the presence of a base such as potassium ferf-butoxylate. Tetrahydrofuran may be used as a solvent.

The mequitazine thus obtained may have an enantiomeric excess (ee) greater than 95%, especially greater than 96%, in particular greater than 97%, more particularly greater than 98%, and advantageously greater than 99%.

EXAMPLES

The following abbreviations have been used:

TLC Thin Layer Chromatography

DMSO Dimethylsulfoxide

ESI Ionisation by electrospray

LAH Lithium aluminum hydride (LiAI

Ms Mesyl

NMP N-Methyl-2-pyrrolidone

Pyr Pyridine

Rf Front Report

Rfx Reflux

NMR Nuclear Magnetic Resonance

MS mass spectrometry

TFA trifluoroacetic acid

THF Tetrahydrofuran

TOF Flight Time

By way of example, quinine 3i has been converted to vinyl quinuclidine 2 according to the reaction scheme below (Scheme 3).

Figure 3

Synthesis of ketone 4i:

In a previously dried 250 mL flask, anhydrous DMSO (1.6 mL, 22.5 mmol, 5.2 eq) is added dropwise into a solution of oxalyl chloride (770 μl, 9.1 mmol, 2.1 eq) in 20 mL of anhydrous CH ₂ Cl ₂ at -78 ° C under a nitrogen atmosphere. The medium is left stirring for 20 minutes at this temperature and then a solution of quinine 3i (1.4 g, 4.32 mmol, 1 eq) in 20 ml of CH ₂ Cl ₂ is added dropwise to the medium on a period of 15 minutes. After stirring for 1 hour at -78 ° C., anhydrous triethylamine (5.35 mL, 38.4 mmol, 8.9 eq) is added dropwise, the medium is left for 15 minutes at -78 ° C. C then 1 h at room temperature. The reaction is stopped by adding 25 ml of a saturated solution of NaCl and 10 ml of water. The medium is extracted with 3 × 25 ml of CH ₂ Cl ₂ . The combined organic phases are dried over Na ₂ SO ₄ , filtered and then evaporated under vacuum. The crude is purified by chromatography on silica gel (eluent: CH ₂ Cl ₂ / MeOH / H ₄ OH 95 / 4.5 / 0.5) to give a quininone fraction 4i which solidifies with difficulty. The fraction is taken up in a few ml of water to precipitate the quininone which is filtered and then dried overnight under vacuum on P ₂ 0 ₅ to give 1.25 g (90%) of 4i in the form of a yellow solid. clear.

C ₂₀ H ₂₂ N ₂ O ₂ , M = 322.40 gmol ^-1 , R / 0.3 (CH ₂ Cl ₂ / MeOH / NH ₄ OH 90/9/1).

NMR H (400 MHz, CDCl ₃ ): 8.84 (1H, d, J = 4.4 Hz), 8.03 (1H, d, J = 9.2 Hz), 7.65-7, 64 (2H, m), 7.40 (1H, dd, J = 9.2Hz, J = 2.8Hz), 5.97 (1H, ddd, J = 17.2Hz, J = 10.3 Hz, J = 7.4Hz), 5.05 (1H, ddd, J = 10.3Hz, J = 1.6Hz, J = 1.2Hz), 5.03 (1H). , ddd, J = 17.2 Hz, J = 1.6 Hz, J = 1.3 Hz), 4.19 (1H, t, J = 9.0 Hz), 3.93 (3H, s, ), 3.16-3.08 (1H, m), 2.95-2.84 (2H, m), 2.62 (1H, ddd, J = 14.0Hz, J = 7, 5 Hz, J = 2.1 Hz), 2.40-2.33 (1H, m), 2.26 (1H, ddd, J = 13.5Hz, J = 7.5Hz, J = 1.0 Hz), 1.89 (1H, m), 1.73-1.65 (2H, m), 1.58-1.50 (1H, m). ¹³ C NMR (100 MHz, CDCl ₃ ): 203.0; 159.0; 146.9; 145.5; 141.4; 140.2; 131.4; 125.7; 122.6; 119.9; 114.8; 102.6; 62.9; 55.4; 49.6; 48.7; 27.6; 27.3; 22.0; 21.6.

MS (ESI + TOF): 323 [M + H] ⁺ (100).

Synthesis of f-butyl ester 5i:

In a previously dried 10 mL flask, anhydrous f-BuOH (0.4 mL) is added to a freshly sublimed f-BuOK solution (174 mg, 1.55 mmol, 2.5 eq) in 1 mL of THF anhydrous. The solution is saturated by bubbling with oxygen for 10 minutes at 0 ° C. and then left under an atmosphere of 0 ₂ . A solution of 4i (200 mg, 0.62 mmol, 1 eq) in 1 mL of anhydrous THF is added dropwise. The medium turns to dark orange. After 30 minutes at 0 ° C, TLC shows that quininone 4i has been fully consumed, the medium has turned yellow. Stirring is stopped then 5 ml of Et ₂ 0 is added leading to the precipitation a yellow solid which is removed by filtration. The solid is rinsed with 5 ml of Et ₂ O, and then the mother liquors are concentrated under vacuum. Precipitation with ether is repeated 4 times and the filtrate is finally evaporated to yield 86 mg (60%) of 5i as a viscous yellow oil.

C ₁₃ H ₂₃ N O ₂ , M = 225.33 gmol ¹ .

H NMR (400 MHz, CDCl ₃ ): 6.06 (1H, ddd, J = 17.0Hz, J = 10.5Hz, J = 9.0Hz), 5.12 (1H, ddd, J = 10.5 Hz, J = 1.6 Hz, J = 1.2 Hz), 5.05 (1H, ddd, J = 17.0 Hz, J = 1.6 Hz, J = 1.2 Hz), 3.04 (1H, ddd, J = 12.5Hz, J = 4.5Hz, J = 3.0Hz), 2.94 (1H, dd, J = 12.4Hz, J = 3.2 Hz), 2.87 (1H, dd, J = 12.4Hz, J = 3.2Hz), 2.70 (1H, ddd, J = 12.5Hz, J = 10.9 Hz, J = 3.2 Hz), 2.29 (1H, m), 2.20-2.05 (3H, m), 1.49-1.36 (2H, m) , 1.44 (9H, s).

¹³ C NMR (100 MHz, CDCl ₃ ): 172.3; 137.1; 116.6; 79.8; 51.2; 46.1; 43.0; 38.9; 35.7; 28.9; 28.1.

MS (ESI + TOF): 226 [M + H] ⁺ (100).

[α] _β = + 45.4 ° (c = 0.099, CHCl ₃ ).

Synthesis of alcohol 6:

In a previously dried 10 mL flask, LiAIH (LAH) (33.7 mg, 0.89 mmol, 4 eq) is added in portions to a solution of 5 i (50 mg, 0.22 mmol, 1 eq) in 1 5 mL of anhydrous THF at 0 ° C. The reaction is stopped after 4 hours stirring at room temperature under a nitrogen atmosphere. 1.5 ml of 1M sodium hydroxide and 2 ml of water are added successively in the medium which is stirred for 20 minutes. The alumina formed is filtered on celite which is rinsed abundantly with THF and then with THF / MeOH 3: 1. The filtrate is evaporated under concentrated vacuum to yield 30.8 mg (90%) of 6 as a yellow oil which is directly engaged in the next step.

C ₉ H ₁₇ NO, M = 155.24 gmol ¹ , fy: 0.1 (CH ₂ Cl ₂ / MeOH / NH ₄ OH 90/9/1).

1 H NMR (400 MHz, CDCl ₃ ): 6.12 (1H, ddd, J = 17.1Hz, J = 10.2Hz, J = 9.0Hz), 5.26 (1H, ddd) , J = 10.2 Hz, J = 1.6 Hz, J = 0.9 Hz), 5.14 (1H, ddd, J = 17.1Hz, J = 1.6Hz, J = 1, 1 Hz), 3.66 (2H, J = 6.4 Hz), 3.07 (1H, ddd, J = 12.4Hz, J = 4.6Hz, J = 2.9Hz), 2.97 (1H, dd, J = 12.4Hz, J = 3.2Hz), 2.88 (1H, dd, J = 12.4Hz, J = 3.2Hz), 2, 68 (1H, ddd, J = 12.4Hz, J = 10.5Hz, J = 3.6Hz), 2.25 (1H, m), 1.82-1.74 (1H, m), 1.63-1.39 (4H, m).

¹³ C NMR (100 MHz, CDCl ₃ ): 137.6; 116.4; 60.4; 51.9; 46.3; 43.1; 36.3; 35.0; 29.1.

Synthesis of chloride 7i:

In a previously dried 25 mL flask, thionyl chloride (94 μl, 1.28 mmol, 2 eq) is added dropwise to a solution of 6 (100 mg, 0.64 mmol, 1 eq) in 5 mL of anhydrous CH ₂ Cl ₂ under a nitrogen atmosphere and at 0 ° C. The medium is then refluxed for 2 hours. The medium is cooled to 0 ° C., neutralized with 6 ml of a saturated aqueous solution of K ₂ CO ₃ and then extracted with 4 × 10 ml of CH ₂ Cl ₂ . The combined organic phases are dried over Na ₂ SO ₄ , filtered and then evaporated under vacuum to yield 7i in the form of a brown oil which is directly engaged in the next step.

C ₉ H ₁₆ CIN, M = 173.68 gmol ¹ , R /: 0.27 (CH ₂ Cl ₂ / MeOH / NH ₄ OH 90/9/1).

1 H NMR (400 MHz, CDCl ₃ ): 6.09 (1H, ddd, J = 17.0Hz, J = 10.3Hz, J = 8.9Hz), 5.16-5.07 ( 2H, m), 3.56 (2H, J = 6.8Hz), 3.10 (1H, ddd, J = 12.2Hz, J = 5.0Hz, J = 2.8Hz ), 3.00 (1H, dd, J = 12.4Hz, J = 2.8Hz), 2.90 (1H, dd, J = 12.4Hz, J = 2.8Hz), 2.71 (1H, ddd, J = 12.2Hz, J = 10.5Hz, J = 3.3Hz), 2.27 (1H, m), 1.87 (1H, m) 1.79-1.61 (2H, m), 1.58-1.42 (2H, m).

¹³ C NMR (100 MHz, CDCl ₃ ): 137.1; 115.8; 51.8; 46.4; 45.2; 42.4; 34.2; 33.8; 28.9.

Synthesis of vinyl quinuclidine 2:

In a previously dried 25 mL flask, potassium carbonate (120 mg, 0.87 mmol, 1.5 eq) is added all at once to a solution of 7 (100 mg, 0.58 mmol, 1 eq. ) in 10 mL of anhydrous acetonitrile. A spatula tip of sodium iodide is introduced before refluxing the medium for 2 hours. The reaction is stopped and the acetonitrile is evaporated under vacuum. The medium is taken up in 10 ml of water, extracted with 4 × 10 ml of chloroform. The combined organic phases are dried over Na ₂ SO ₄ , filtered and then evaporated under vacuum. The crude is purified by chromatography on silica gel (eluent: CH ₂ Cl ₂ / MeOH / H ₄ OH 90/9/1) to yield 58 mg (75%) of 2 in the form of a yellow oil.

C ₉ H ₁₅ N, M = 137.22 gmol ^-1 , R / 0.20 (CH ₂ Cl ₂ / MeOH / NH ₄ OH 90/9/1). 1 H NMR (400 MHz, CDCl ₃ ): 5.89 (1H, ddd, J = 16.8Hz, J = 9.9Hz, J = 8.2Hz), 5.07-4.99 (2H NMR (CDCl3):? H, m), 3.04 (1H, ddd, J = 13.2Hz, J = 10.0Hz, J = 2.0Hz), 2.89-2.71 (4H, m), 2.71 (1H, ddd, J = 13.2Hz, J = 6.4Hz, J = 2.0Hz), 2.35-2.26 (1H, m), 1.77-1. , 54 (4H, m), 1.43-1.33 (1H, m).

¹³ C NMR (100 MHz, CDCl ₃ ): 141.2; 114.3; 51.2; 47.5; 46.8; 40.0; 27.4; 26.6; 21.2.

MS (ESI + TOF): 138 [M + H] ⁺ (100).

[a] ² ° = + 54.7 ° (c = 0.098, CHC _3!).

Vinyl quinuclidine 2 has been used for the synthesis of mequitazine of stereochemistry (RJ, dextrogy

Figure 4

Synthesis of quinuclidine-methanol 9:

In a 10 ml flask, TFA (30 μl, 0.38 mmol, 1.1 eq) is added to a solution of vinyl quinuclidine 2 (48 mg, 0.35 mmol, 1 eq) in THF (1 mL). ). The medium is left stirring for 10 minutes, then the THF is evaporated under vacuum. The vinyl quinuclidine salt is taken up in 2 mL of MeOH and the temperature of the medium is raised to -78 ° C. Ozone is bubbled into the solution until saturation (appearance of a violet color after 5 min). The excess of ozone is then removed by bubbling nitrogen in the medium for 10 minutes. Solid NaBH ₄ (106 mg, 2.8 mmol, 8 eq) is then introduced in one time at a time when the mixture is gradually brought to room temperature. After 16 h, the reaction is stopped by adding 4 mL of a saturated aqueous solution of K ₂ CO ₃ . The aqueous phase is extracted with 4 × 5 mL of ethyl acetate. The combined organic phases are dried over Na ₂ SO ₄ , filtered, and then evaporated under vacuum. The crude reaction product (31 mg, 63%) is directly engaged in the next step (yellow oil).

C ₈ H ₁₅ NO, M = 141.21 gmol ¹ , R /: 0.05 (CH ₂ Cl ₂ / MeOH / NH ₄ OH 90/9/1).

1 H NMR (400 MHz, CDCl ₃ ): 3.51 (2H, d, J = 8.4 Hz), 2.97 (1H, dd, J = 13.4Hz, J = 9.9Hz. ), 2.84-2.70 (4H, m), 2.30 (1H, ddd, J = 13.4Hz, J = 6.5Hz, J = 2.0Hz), 1.85 -1.76 (2H, m), 1.70-1.56 (2H, m), 1.56-1.48 (1H, m), 1.42-1.33 (1H, m.p. m).

¹³ C NMR (100 MHz, CDCl ₃ ): 64.4; 51.6; 47.6; 47.2; 38.4; 27.7; 21.9; 21.3.

MS (ESI + TOF): 142 [M + H] ⁺ (100).

[α] ² ° = + 50.2 ° (c = 0.1, CHCl ₃ ).

Synthesis of mesylate 10:

In a 5 mL flask, a solution of alcohol 9 (22 mg, 0.16 mmol, 1 eq) in 1 mL of CHCl ₃ is cooled to 0 ° C. Pyridine (15 μl, 0.19 mol, 1.2 eq) and methanesulfonyl chloride (15 μl, 0.19 mmol, 1.25 eq) are added dropwise. At the end of the addition, the medium is brought to room temperature. After stirring for 4 hours, the precipitate obtained is filtered, rinsed 3 times with acetone and then dried under vacuum. The mesylate 10 (24.2 mg, 61%) is obtained in its hydrochloride form (pale yellow solid).

C ₉ H ₁₈ CINO ₃ S, M = 255.76 gmol ¹ , R /: 0.25 (CH ₂ Cl ₂ / MeOH / NH ₄ OH 80/18/2) (developer KMnO ₄ ). The spectral data ( ¹ H and ¹³ C NMR) are in agreement with those of the mesylate described by Imbert et al. (Guminski, Y., Fabre, V., Lesimple, P., Imbert, T. Organic Preparations and International Procedures 1999, 31, 319-323).

Synthesis of (R) -equitazine, dextrorotatory:

In a 5 mL flask, a solution of t-BuOK (13.2 mg, 0.12 mmol, 3 eq) in 0.5 mL of NMP is added to the reaction medium containing mesylate hydrochloride 10 (10 mg, 39 mg). μηηοΙ, 1 eq), phenothiazine (15.6 mg, 78 μηηοΙ, 2 eq) in 1 mL of anhydrous THF heated to 60 ° C. The medium becomes dark red after 2 h 30 at this temperature. The reaction is brought to ambient temperature, hydrolysed and extracted with 3 × 3 ml of Et ₂ O. The organic phases are combined and then washed with water. The organic phase is extracted twice with an aqueous solution at pH 2. The aqueous phase is then washed with Et ₂ and concentrated. The solid is taken up in 1.5 mL H ₂ O / Et ₂ O (1 / 0.5) in an ice bath. The precipitate was filtered, rinsed with Et ₂ 0 and taken up in 4 mL of saturated K ₂ C0 _3. The aqueous phase is extracted with 3 x 3 mL of CHCl ₃ . The organic phases are dried over Na ₂ SO ₄ , filtered or concentrated in vacuo. Mequitazine la (9.1 mg, 72%) is obtained as a white solid.

C ₂₀ H ₂₂ N ₂ S, M = 322.47 gmol ¹ , R /: 0.50 (CH ₂ Cl ₂ / MeOH / NH ₄ OH 80/18/2) (UV developer). The spectral data (NMR) of mequitazine are in agreement with the authentic product. Absolute stereochemistry of (R) the -méquitazine was determined by measuring the specific rotation ([o;] ^ ⁰ = + 43.4 (c = 0.098, EtOH)) and the enantiomeric excess by chiral HPLC:

OD column 256 x 4.6 mm

flow rate: 1 mL.min ^"1

Eluent: Hexane / EtOH 97: 3 + 0.5% hNET _2, t _r (S) -méquitazine (control): 10.3 min, t _r (R) - mequitazine: 12.2 min. The enantiomeric excess of (R) -equitazine is greater than 99%.

Claims

1. Use of the enantiomer (R) of the vinyl quinuclidine of formula 2 below:

as a synthetic intermediate in the preparation of the enantiomer (R) of mequitazine.

2. Process for synthesizing the enantiomer (R) of mequitazine from the enantiomer (R) of vinyl quinuclidine of formula 2 as defined in claim 1.

3. Method according to claim 2 comprising the following successive steps:

(a) oxidative cleavage of the double bond of the enantiomer (R) of vinyl quinuclidine as defined in claim 1 to give the aldehyde of formula 8 below:

for which the carbon atom marked by a star is of configuration (R),

for which the carbon atom marked with a star is of configuration (R), (c) activation of the OH function of the alcohol of formula 9 obtained in step (b) above to give a compound of formula 10 below :

for which the carbon atom marked with a star is of configuration (R) and R3 represents a leaving group, and (d) coupling the compound of formula 10 obtained in step (c) above with phenothiazine to give the enantiomer (R) of mequitazine.

4. Method according to claim 3, characterized in that step (a) is carried out by ozonolysis.

5. Process according to claim 4, characterized in that step (a) is carried out starting from an acid addition salt of the enantiomer (R) of vinyl quinuclidine of formula 2 as defined in claim 1.

6. Method according to any one of claims 3 to 5, characterized in that step (b) is carried out in the presence of a hydride.

7. Process according to claim 6, characterized in that the hydride is NaBH ₄ .

8. Process according to any one of claims 3 to 7, characterized in that R3 represents a mesylate (OMs).

9. Process according to claim 8, characterized in that step (c) is carried out in the presence of mesyl chloride (MsCl) and a base.

10. The method of claim 9, characterized in that the base is pyridine.

11. Method according to any one of claims 3 to 10, characterized in that step (d) is carried out in the presence of a base.

12. Process according to claim 11, characterized in that the base is potassium ieri-butoxylate.