ITRM20110418A1 - PROCESS FOR THE PREPARATION OF EPOXY WHICH INTERMEDIATES FOR THE SYNTHESIS OF NEBIVOLOL. - Google Patents

Description

Description of the industrial invention entitled: "Process for the preparation of epoxides as intermediates for the synthesis of Nebivolol"

FIELD OF THE INVENTION

The present invention relates to a new process for the synthesis of 6-fluoro-2- (oxiran-2-yl) chroman (1) epoxides, intermediates for the synthesis of Nebivolol.

Nebivolol is a racemic mixture of the two enantiomers [2S [2R [R [R]]]] Î ±, Î ± '- [imino-bis (methylene)] bis [6-fluoro-chroman-2-methanol] and [2R [2S [S [S]]]] Î ±, Î ± '- [imino-bis (methylene)] bis [6-fluoro-chroman-2-methanol] (Scheme 2).

OH H OH OH H OH O N OON O F F F F

d-nebivolol l-nebivolol

(SRRR) (RSSS)

Nebivolol

Pattern (2)

The 6-fluorochromano-2-carboxylate ester (2), by treatment at temperatures below -90 ° C with the organometal LiCH2Br, followed by low-temperature quenching with an aqueous solution and by treatment with a reducing agent, generates the diol (3) which, through tosylation and intramolecular substitution, leads to the epoxide (1) without altering the starting distereoisomeric composition.

This method is applicable to a racemic ester (2)

to obtain the mixture of the epoxides (1), or

optically active to obtain epoxides

semichirals.

STATE OF THE ART

US patent No. 4,654,362 (and its counterpart

EP 0145067) reports the reduction of the ester (2) ad

alcohol with Red-Al (NaAlH2 (OC2H4OCH3) 2), followed by

oxidation to obtain the corresponding aldehyde,

and by treatment with (Me3) 3SO <+> I <-> to have the

epoxides (1) (Scheme 3).

The same basic synthetic scheme, with modifications

improvements in terms of yield and purity, it comes

reported in WO 2010/089764 (Dr. Reddy's).

OR

Oa O CH2OH O OEt O CHO c

b O

F F F F

2 1

to. Red-Al; b. (COCl) 2, DMSO, CH2Cl2; c. (CH3) 3SO + I-, NaH, DMSO.

Pattern (3)

.

Also in US n ° 4,654,362 are reported as generic possibilities for this class of compounds, that of obtaining the epoxides (1) by elimination from the alpha substituted alcohols with a good leaving group (X) or by epoxidation of the corresponding olefin with base and acid metachloroperbenzoic acid (Scheme 4).

I HAVE

XaO b

O O O

F F F

1

Pattern (4)

Other methods to prepare the aldehyde and then the epoxides of type (1) are shown in Scheme 5. The aldehyde can be obtained by low temperature reduction of the imidazolide of the corresponding acid or of the same ester (2 ) with diisobutyl aluminum hydride. This is then converted into epoxide (1) by reaction with sodium hydride and trimethylsulfoxonium iodide into dimethylsulfoxide as previously described.

O to O

O O CHO c O OEtRR R

Or b

O OH

R.

Pattern (5)

The methodology of Scheme (5), which provides for the reduction of the ester to aldehyde, is explicitly reported for the 6-fluorine derived from EP 0334429 using the chiral ester and is aimed at preparing the single optical isomers separately (R , S; S, S) and (S, R; R, R) of nebivolol. In this case the 6-fluoro-chroman carboxylic acid is resolved in the single enantiomers by treatment with (+) - dehydroabietylamine. These enantiomers are converted separately to the corresponding epoxides in mixtures of two diastereomers. The following synthetic scheme (Scheme 6) describes the conversion of R acid.

FaF b F

O <CO> 2 <H> OCHO <O> O

to. carbonyl diimidazole, then DIBAL; b. Me3SO, tBuOK, DMSO

Pattern (6)

Chromane aldehyde is not particularly stable and prone to racemization if it is prepared in optically active form.

In Tetrahedron (2000), 56, 6339-6344 a synthesis of the aforementioned epoxides in chiral form is reported which starting from 4-fluoro phenol, through a fairly rich sequence of steps, provides type (3) glycols which are then transformed into epoxides passing through the tosylates (Scheme 7).

OH O OH OTBDMS OTBDMS OTBDMS

ab <c> d

OH e, f CO2Et

F F F F F F

g

F OTBDMS

<l> FiF h

OH O OH O OPNB O OH

OH OPNB OH F

m

F n F

O OTs O

OH O

to. allylbromide, K2CO3; b.210 ° C, c. TBDMSCl; d. borane-dimethylsulfide, H2O2, OH-; d. Dess Martin; And. Ph3P = CHCO2Et; f. DIBAL; g. TBAF; h. Sharpless oxidation followed by cyclization; the. PNB-OH, DEAD, TPP; L. NaOMe; m.TsCl, py; n. NaOMe.

Pattern (7)

This method, although it allows to obtain the epoxies in an optically pure form, is very long and laborious.

WO 2008/040528 (Zach System) reports the conversion of an ester of 6-fluoro-3,4-dihydro-2H-chromene-2-carboxylate into 2-halo-1- (6-fluoro-3,4-dihydro- 2H-cromen-2-yl) ethanone (alpha halo ketone) passing through the sulfoxonium ylide. The reduction of alpha halo ketone followed by cyclization in the presence of a base, provides the mixture of the four diastereomeric epoxides (Scheme 8).

FaF b F

O <CO> 2 <H> O

OS O O OMeMe

to. Me3SI, tBuOK, THF; b. LiCl, MeSO3H

Pattern (8)

WO 2008/010022 (Zach System) reports a synthesis (Scheme 9) in which the acid deriving from the ester (2) is reacted with the dimedone to then produce in two steps the corresponding alpha chlorine or alpha bromine ketone which it is reduced and cyclized to epoxide. The sequence is quite long and laborious.

O O O O O

O O O

OH O OR F F O O F

O OH O

O LG <O> LGO

F F F

Pattern (9)

WO 2010/034927 (Zach System) always reports the preparation of alpha halo ketones as precursors of the epoxides. In this case the alpha halo ketones are prepared as described in Scheme 10.

The ester (2) is treated at low temperature with LiCH2Cl to obtain, after quenching with acetic acid, the corresponding alpha-chlorine ketone which is then reduced to alpha chlorine alcohol and cyclized to epoxide.

O O O OH O Cl O OR O ClOF a b

Fc

F F

to. BuLi, CHBrCl, -80 ° C, then AcOH; b. NaBH4, EtOH, 0 ° C; c. i-PrOH, NaOH Scheme (10)

This method, although rather short, has the drawback of not eliminating the non-polar reaction by-products deriving from the organometallic species used, up to the final epoxide stage. These secondary products are aliphatic, numerous, of a slightly different nature, and are not visible to UV. For these reasons they are difficult to quantify. In addition, some are bromine or chlorine alkyls which can then affect the yields of the reactions used subsequently for the preparation of nebivolol, as well as the purity of the products obtained. It is not possible to purify the intermediate product, alcohol alcohol, by extraction or by partition.

SUMMARY OF THE INVENTION

Now surprisingly, a more efficient synthesis process of the epoxy intermediates (1), racemes or semichirals, has been found, which is summarized in Scheme 1. This process allows to eliminate the disadvantages already highlighted for the previously known synthesis pathways, namely:

â € ¢ length and complexity of the synthetic pathways â € ¢ need for chromatographic purifications to eliminate apolar aliphatic residues of secondary reactions given by the reagents used.

According to this process, the alkyl 6-fluorochromano-2-carboxylate (2), by treatment at a temperature below -90 ° C with the organometal LiCH2Br possibly generated in situ, followed by quenching, always done at a temperature lower than - 90 ° C with an aqueous solution, followed by treatment with a reducing agent such as NaBH4, generates the diol (3) which, by means of tosylation and intramolecular nucleophilic substitution, generates the epoxide (1) without altering the composition distereoisomeric starting point.

In a single step we pass from the ester (2) to the diol (3) from whose reaction crude the apolar aliphatic species produced during the reaction can be eliminated with simple washing: a solution of the crude in polar organic solvent is treated with an apolar solvent immiscible with the former, in which the diols are very poorly soluble. This method is therefore more suitable for a large-scale process synthesis. This synthesis allows to obtain the aforementioned epoxides (1) in racemic or semichiral form where by racemic form we mean a mixture of the 4 epoxides indicated in Figure 1, and by semichiral form we mean a mixture of only two diasteromeric epoxides of the RS RR type or SR SS, in which the asymmetrical center on the six-membered ring of the piran exhibits the same stereochemistry.

The mechanism of this reaction is not clear, but it should not be the classic one reported in the literature for the treatment of an ester with a metal organ, and preferably with an organolithium. In this case it would be expected that the intermediate initially formed, of the type:

LiO Br

OR

OEt

F.

evolved into alpha bromine ketone, stable under the reaction conditions.

On the other hand, what is observed after quenching at low temperature (below -90 ° C) with a 0.1M NaHSO4 solution is the alpha hydroxy-ketone (4), which we have isolated and characterized, which by reduction with NaBH4 provides the diol (3).

OR

O OH

F.

(4)

The object of the present invention is therefore a process for the preparation of the intermediate epoxides in the synthesis of nebivolol which includes:

to. The synthesis of type (3) diols starting from a chromane ester (2), both racemic and optically active, by treatment with LiCH2Br at a temperature below -90 ° C, aqueous quench at low temperature and subsequent treatment with a reducing agent such as NaBH4;

b. The purification of the diols thus obtained by partitioning between a polar and an apolar organic solvent that are immiscible from each other;

c. The transformation of diols (3) into epoxides (1), by means of tosylation or mesylation, and intramolecular nucleophilic substitution without altering the relationship between diastereoisomers. The epoxides thus obtained can be used for the preparation of nebivolol according to methods already well known in the art.

By way of example, the synthesis described in Scheme 11 can be used to obtain nebivolol.

OR

OR

1 (SR RS RR SS)

F.

OH OH

H H

ONON O O

Bn Bn O O F F F F

910 11 12

OH Bn OH OH Bn OH

O N O O N O

F F F F

13 14

OH Bn OH OH Bn OH

O N O O N O

15

F F F 16 F

OH H OH OH H OH O N OON O F F F F

Nebivolol (SRRR RSSS)

Scheme 11

This synthesis involves the treatment of the mixture of epoxies (1) with benzylamine in a solvent represented by a sterically encumbered alcohol, alone or in a mixture with an apolar solvent, to obtain a mycelia of four compounds (9, 10, 11, and 12 ), from which the 9/10 pair is separated from the 11/12 pair by crystallization or chromatography. This is followed by the reaction of the 9/10 amines with the 11/12 epoxides to obtain a mixture of four compounds (13, 14, 15 and 16). From this mixture the compounds 13 and 15 (RSSS SRRR) in mixture are separated from 14 and 16 by fractional crystallization by a suitable solvent. A catalytic hydrogenation reaction of the 13/15 mixture yields the nebivolol.

Methods are known to separate the enantiomers of an alkyl 6-fluorochromano-2-carboxylate, for example as described in EP334429 by forming the amide with the (+) - dehydroabiethylamine, or as reported in the Italian patent application RM2010A000622 dated 30 / 11/2010 by enzymatic hydrolysis by means of a mycote esterase.

When the starting alkyl 6-fluorochromano-2-carboxylate (2) is a defined isomer, the present synthesis gives rise to the semichiral epoxides, specifically to the RS / RR mixture or to the SS / SR mixture depending on whether the Starting ethyl carboxylate either the R isomer or the S isomer.

From the mixtures of semichiral epoxides it is possible to carry out the synthesis of nebivolol according to methods known in the art, for example the semichiral epoxides (RR RS) and (SS SR) are reacted separately with benzylamine under the conditions described above to obtain the compounds (9), (10), (11) and (12) separate. Then the amine (9) is reacted with the epoxide (12) to obtain only the enantiomer (15), while the amine (10) is reacted with the epoxide (11) to obtain only the enantiomer (13). The two benzylated derivatives of nebivolol (13) and (15) are joined in equal parts and subjected to catalytic hydrogenation to obtain nebivolol (Scheme 12).

O O

O O

RS

F F

(RR RS) (SS SR)

(R) -6-fluoro-2- (oxiran-2-yl) chroman (S) -6-fluoro-2- (oxiran-2-yl) chroman

S <OH> ROR OHSO NH OO

Bn O NHBn O

RR S

F F S F F

12

9 1110

OH OH OH OH

OSS N O

S O

RR <R> N O <R> S

F F F F

15 [(-) - SSSR] l-NBV Bn 13 [(+) - RRRS] d-NBVBn

NEBIVOLOL

Pattern (12)

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, type (1) epoxides,

O * O

*

F.

(1)

racemes or semichirals, are obtained with the method described in Scheme 1 starting from an ester (2) of 6-fluoroocroman 2-carboxylic acid, both in a racemic mixture and as an isolated enantiomer, where R is a C1- alkyl group C6, preferably an ethyl group.

OR

OR R

OR

F.

(2)

This conversion involves the transformation of the ester (2) into the diol (3) passing through the alpha hydroxy ketone (4).

OH O

O OHOOH

F F

(3) (4)

Alpha hydroxy ketone (4) is obtained by treatment of (2) with LiCH2Br, at low temperatures and in an inert organic solvent and subsequent quenching at low temperatures.

The organometal LiCH2Br can preferentially be obtained in situ by adding a solution of BuLi to a solution containing the ester (2) and the CH2Br2 in inert organic solvent. The temperature is lower than -90 ° C preferably between -130 ° C and -95 °, and even more preferentially - 105 ° C and -95 ° C.

The solvent belongs to the family of hydrocarbons or ethers, alone or in a mixture, preferably tetrahydrofuran alone or in a mixture.

At the completion of the reaction, keeping the mixture at the initial temperature, an aqueous solution is added, which can be neutral or acidic but in any case used in such a quantity as to keep the environment in alkaline conditions and preferably 0.1 M NaHSO4, and it is allowed to rise the temperature up to values between â € “50 and â €“ 10 ° C, preferably â € “30 ° C.

At this point a reducing agent (LiBH4, NaBH4) is added and preferably NaBH4e is kept under stirring until complete disappearance of the intermediate alpha hydroxyketone (4) to obtain the diol (3).

An aspect of the present invention relates to the procedure starting from the enantiopure chromane ester (2) according to which: the ester (2) is reacted as isomer under the same conditions described for the racemic ester (2) R or, alternatively as the S isomer, to provide a mixture of diols (5) consisting of the RS isomers

RR

OH OH

O O

OH OH

F F

(RS) (RR)

(<5>)

or, alternatively, from a mixture of diols (6)

consisting of the SR SS isomers

OHOH

O O

OH OH

F F

(SR) (SS)

(<6>)

Another characteristic aspect of the present

invention is the procedure that allows the purification of diols (3) or mixtures

semichirals (5) or (6) obtained with the method

previous one. This procedure involves the dissolution of the crude, obtained from the synthesis of the diols as described above, in an organic polar solvent, such as methanol, ethanol, acetonitrile, DMF, DMI, NMP, and preferably methanol, and the subsequent washing of the solution thus obtained with a C5-C10 alkane, immiscible with the former, and preferentially heptane. This washing allows to remove the aliphatic apolar secondary products generated during the reaction with the organometal, since the diol (3) or the corresponding mixtures of semichiral diols (5) and (6) are poorly soluble in apolar organic solvents.

Another characteristic aspect of the present invention is represented by the formation reaction of the epoxides (1), of the vicinal diols (3), carried out by means of tosylation or mesylation and subsequent intramolecular, bistadic or one-pot nucleophilic substitution, carried out in such a way as not to alter the initial diasteromeric ratio.

In this case it was surprisingly found that by treating the diol (3) with a base (chosen from LiH, NaH, KH, tBuOK and preferentially NaH), in an organic solvent (selected DMF, DMSO, NMP (N-methylpyrrolidone) and DMI (dimethylimidazolidone), preferably DMF, and leaving the system under agitation for times longer than one hour, followed by the addition of a mesylating or tosylating agent such as tosyl chloride, tosyl imidazole or mesyl chloride, and preferably tosyl chloride, in the in situ conversion to epoxide without altering the initial ratio between the diastereomers.

Alternatively, it was surprisingly discovered that by treating the diol (3) with a preformed solution of DMSO and NaH, or of imidazole and NaH in an organic solvent, followed by the addition of a tosylating agent, chosen from tosyl chloride or tosyl imidazole , preferably tosyl chloride, the in situ conversion into epoxide is obtained without altering the initial ratio between the diastereoisomers. Alternatively, the same result is obtained by treating the diols dissolved in an organic solvent immiscible with water, with a tosilating agent selected from tosyl chloride or tosyl imidazole, preferably tosyl chloride, under Schotten-Baumann conditions.

A further alternative is the treatment of a solution of the diol (3) in an organic solvent immiscible with water and containing an organic base, preferably diisopropylethylamine, cooled and maintained at a temperature below 25 ° C, preferably below the 4 ° C, with a solution of tosyl chloride in an organic solvent, followed by the addition of a 50% aqueous solution of NaOH.

It has been similarly demonstrated and therefore the object of the present invention is that by treating with the methods just described the â € ̃semichiralâ € mixture of diols (5) RS RR or, alternatively, the â € ̃semichiralâ € ™ mixture of diols (6 ) SR SS, the â € ̃semichiralâ € ™ mixture of epoxides (7) RS RR is obtained,

O O

O O

F F

(RS) (RR)

(<7>)

or, alternatively, the â € ̃semichiralâ € ™ mixture of epoxies (8) SR SS.

O O

O O

F F

(SR) (SS)

(8)

without alteration of the diasteromeric relationships.

By way of non-limiting example, starting from the diol (3) (mixture of RS + SR: RR + SS in a 1: 1 ratio) obtained starting from the racemic ester (2) by means of the organometallic reaction described, it is obtained by tosylation or base-catalyzed intramolecular mesylation and nucleophilic substitution, according to any of the methods described above, the mixture of epoxies (1) (RS + SR: RR + SS) in a 1: 1 diasteroisomeric ratio.

The synthesis of nebivolol in the form of a racemic mixture of the two enantiomers [2S [2R [R [R]]]] Î ±, Î ± â € ™ - [imino-bis (methylene)] bis [ 6-fluoro-chroman-2-methanol] and [2R [2S [S [S]]]] Î ±, Î ± â € ™ - [imino-bis (methylene)] bis [6-fluoro-chroman-2- methanol], having the following formulas

OH H OH OH H OH O N OON O F F F F

Nebivolol (SRRR RSSS)

which includes the following steps:

a) a mixture of the four isomers SR, RS, RR and SS of the epoxide is reacted (1)

O * O

*

F.

(<1>)

obtained according to one of the methods just described starting from the racemic ester (2), with benzylamine in a solvent represented by a sterically encumbered alcohol selected from tert-BuOH, 2-methyl-2-butanol, 2-methyl-2- pentanol, used alone or mixed with an apolar solvent, preferably cyclohexane, to obtain a mixture of the four compounds 9, 10, 11 and 12, from which the couple 9/10 is separated from the couple 11/12;

OH OH H HONON O O RRO O F F F F

9 <10> 11 12

b) the amines 9 and 10 are reacted, in mixture, with the couple of epoxides 11 and 12, in mixture, to obtain a mixture of four compounds (13, 14, 15 and 16);

OH Bn OH OH Bn OH

O N O O N O

F F F F

13 14

OH Bn OH OH Bn OH

O N O O N O

15

F F F 16 F

c) the compounds 13 and 15 (RSSS SRRR) are separated, in mixture, from 14 and 16 by fractional crystallization from 2-methyl-2-butanol, and subsequently from an ethyl acetate / cyclohexane mixture,

d) the benzyl protecting group is removed from the mixture 13 and 15, and optionally the hydrochloride salt is subsequently formed, to obtain the final product Nebivolol or Nebivolol hydrochloride.

Another aspect of the present invention is constituted by the synthesis of nebivolol, which includes the following steps:

a) the â € ̃semichiralâ € ™ mixture of epoxides (7), and / or separately the â € ̃semichiralâ € ™ mixture of epoxides (8), obtained according to the methods described above, starting respectively from the chromane ester R or S, by placing them to react with benzyl amine in a sterically encumbered alcohol selected from tert-BuOH, 2-methyl-2-butanol, 2-methyl-2-pentanol to obtain compounds (9) and (11) and / or respectively compounds (10) and (12).

b) the amino alcohol (9) is reacted with the epoxide (12) to obtain l-benzyl nebivolol (15) and / or the amino alcohol (10) with the epoxide (11) to obtain d-benzyl nebivolol (13)

c) the benzyl protecting group is removed with the formation of d- and / or l-nebivolol EXAMPLES

EXAMPLE 1: Synthesis of racemic diols

1- (6-fluorochroman-2-yl) ethane-1,2-diol

Oi. CH2Br2, MeLi, THF, -100 ° C OH O ii.0.1 N NaHSO4, -100 ° C O OH O iii. NaBH4, -30 ° C to 0 ° C

F F

A solution of racemic ethyl 6-fluorochrome-2-carboxylate (2.2 g, 10 mmol) and dibromomethane (1.35 mL) in anhydrous THF (40 mL) cooled to â € “100 ° C in a nitrogen atmosphere, is added dropwise to drop, in a time of about 30 minutes, a solution of 1.6M of MeLi in diethyl ether (11.2 mL), previously cooled to â € “78 ° C. The stirring is maintained at â € “100 ° C for about 1.0 h in total, until the ester substrate disappears (TLC control). At this point a 0.1N NaHSO4 solution (5 mL) is added at the same temperature. At the end of the addition the temperature is slowly brought to â € “30 / -20 ° C and the mixture mixed for 30 minutes. Then NaBH4 (0.3 g) is added and the resulting mixed mixture, after having removed the cooling bath, until complete reduction of the intermediate alpha hydroxy ketone to diol (about 0.5 h).

1N NaHSO4 is added to the mixture up to pH 5, the organic phase is separated and the aqueous phase extracted with EtOAc. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow and viscous liquid (2.05 g). The HPLC analysis indicates a purity of 97% of the two pairs of diastereomeric diols (in a substantially 1: 1 ratio).

For characterization purposes, the two diastereomeric pairs of diols were separated by flash chromatography on silica (1: 1 EtOAc / petroleum ether solvents).

Isomer (RS / SR)

1H NMR (400 MHz, DMSO-d6) Î ́ 6.98-6.82 (m, 2H); 6.75-6.67 (m, 1H), 4.92-4.90 (d, 1H, J = 6.0 Hz); 4.57 (t, 1H, J = 6.0 Hz); 3.95-3.88 (m, 1H); 3.60-3.50 (m, 2H); 3.50-3.40 (m, 1H); 2.80-2.60 (m, 2H); 2.10-1.98 (m, 1H); 1.76-1.63 (m, 1H).

Isomer (SS / RR):

1H NMR (400 MHz, DMSO-d6) Î ́ 6.98-6.80 (m, 2H);

6.75-6.67 (m, 1H), 4.80-4.76 (d, 1H, J = 6.0 Hz);

4.60 (t, 1H, J = 6.0 Hz); 4.00-3.94 (d, 1H, J =

14.0 Hz); 3.60-3.50 (m, 2H); 3.50-3.40 (m, 1H);

2.90-2.70 (m, 2H); 1.95-1.85 (m, 1H); 1.85-1.70 (m,

1H).

The configuration of the two pairs

diastereoisomeric diols has been attributed

on the basis of the pair of enantiomeric epoxides

produced by each of them.

EXAMPLE 2: synthesis of semichiral diols

(S) -1- (6-fluorochroman-2-yl) ethane-1,2-diol

Oi. CH2Br2, n-BuLi, THF, -100 ° C OH O ii. 0.1 N NaHSO4, -100 ° C O OH S O iii. NaBH4, r.t. S F F

(S)

To a solution of (S) -ethyl 6-fluorochrome-2-carboxylate) (18 g, 80.3 mmol) and dibromomethane (12.6 mL) in anhydrous THF (360 mL) cooled to â € “100 ° C in a nitrogen atmosphere, a solution of 1.6M of BuLi in hexane (101 mL), previously cooled to â € “78 ° C, is added drop by drop over a period of 30 minutes. The stirring is maintained at â € “100 ° C for 1.5 h in total, until the ester substrate disappears (TLC control). At this point a 0.1N NaHSO4 solution (40 mL) is added at the same temperature. At the end of the addition, the temperature is slowly brought to â € “30 / -20 ° C and mixed for 30-50 minutes. Then NaBH4 (2.5 g) is added and the resulting mixture mixed until complete reduction of the intermediate alpha hydroxy ketone to diol (about 0.5 h). 1N NaHSO4 is added to the mixture up to pH 5, the organic phase is separated and the aqueous phase extracted with EtOAc. The combined organic extracts are washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a yellow and viscous liquid (18 g). The HPLC analysis shows a ratio of 1.1: 1.0 of the two diastereoisomeric diols (6) (SR: SS).

In analogy to what is described in Example 2 i

diols 5 (RS: RR) are obtained starting from (R) -

ethyl 6-fluorochrome-2-carboxylate).

Example 3: Purification of the diols

The residue containing the resulting diols

from example 2 (18 g) is dissolved in CH3OH (2 volumes). The resulting solution is debated with heptane (10 volumes). After separation of the phases, the methanolic solution is concentrated under reduced pressure to obtain a viscous residue (15 g). The <1> H-NMR analysis indicates the absence of signals relating to the aliphatic impurities produced in the formation reaction of the diols themselves. The ratio of the two diastereoisoneric diols (RS: SS) remains unchanged following this purification step.

Example 4: isolation and characterization of the intermediate alpha-hydroxyketone

In order to demonstrate a possible reaction mechanism of the reaction described in Examples 1 and 2, we tried to isolate the alpha hydroxyketone intermediate (4) of the synthesis of the RS: RR diols described by analogy in Example 2

OR

O OH

R.

F.

(4)

The reaction solution still at â € “20 ° C after quenching with NaHSO4 and before adding the reducing agent was quickly deposited on a 2.5 mm thick preparative silica plate and run using EtOAc / hexane 1 as eluent : 1; Rf = 0.4, UV detection. The product was recovered by cutting the corresponding silica strip, subsequent washing with acetonitrile followed by removal of the solvent.

1H NMR (400 MHz, CD3CN) Î ́ 6.95-6.70 (m, 3H); 4.75-4.70 (m, 1H); 4.60-4.38 (AB system, 2H, J = 17 Hz); 2.90-2.60 (m, 2H); 2.20-2.00 (m, 1H); 1.90-1.60 (m, 1H) The reduction of alpha hydroxy ketone (4) with NaBH4 produces the pair of diols RS: RR.

Example 5: Synthesis of epoxides (1) from diols (3) Use of NaH and Tosyl chloride in DMF.

NaH (48 mg, 2.0 mmol, 2.5 eq) is added to a solution of the diols obtained according to example 1 in diastereoisomeric ratio 1.1 / 1.0 (200 mg, 0.80 mmol) in anhydrous DMF (6 mL, 30 volumes). The mixture is allowed to equilibrate (1 hour)

after which tosyl chloride is added (305 mg, 1.60

mmol, 2 eq). At the end of the reaction (8 hours), the

mixture is diluted with MTBE (15 mL) and treated

with NaHSO41M (10 mL). The organic phase comes

debated with H2O, dried on Na2SO4 and concentrated a

dryness giving a viscous residue. HPLC analysis

shows the presence of epoxides (1) (purity 75%)

in diastereoisomeric ratio 1.1 / 1.0.

Example 6: Synthesis of epoxides (1) from diols (3)

Use of NaH and DMSO in methyl t-butylether and TsCl

To a suspension of NaH (2.70 g, 0.07 mol, 4 eq) in MTBE (75 mL), anhydrous DMSO (10 mL, 0.14 mol, 8 eq) is added in an atmosphere of N2a 50 ° C. After 5-10 minutes, a solution of the diols (3) (5.00 g, 0.017 mol) in MTBE (75 mL) is added and the mixture is stirred at 50 ° C for 1 hour. After this period, a solution of tosyl chloride (5.00 g, 0.026 mol, 1.5 eq) in MTBE (50 mL) is added drop by drop and the mixture is stirred for 1 hour, checking the progress by HPLC. At the end of the reaction the mixture is filtered, the filtrate washed with MTBE (50 mL x 2) and the pooled filtrates washed with NaHSO41M (100 mL), NaHCO3 (2x50 mL), and water (50 mL) and dried over Na2SO4. The solvent is removed under reduced pressure to give a viscous residue (yield 90%, HPLC purity 95.5%, dystereomeric ratio between the epoxides unchanged).

Example 7: Synthesis of epoxides (1) from diols (3) Use of NaH and imidazole

To a suspension of imidazole (190.6 mg, 2.80 mmol, 3.5 eq) and NaH (58 mg, 2.4 mmol, 3.0 eq) in a solvent such as DMF, DCM, THF, MTBE (3 mL) left to stir for 10-15 minutes , the diols (200 mg, 0.80 mmol) are added (diastereoisomeric ratio 1.0: 1.0 dissolved in the solvent used (3 mL), and after about 10 minutes tosyl chloride (213 mg, 1.10 mmol, 1.4 eq) is added. (2-3 hours), the mixture is diluted with MTBE (15 mL) and treated with NaHSO41M (10 mL). The organic phase is debunked with H2O, dried over Na2SO4e concentrated to dryness giving a viscous residue. The HPLC analysis shows the presence of diastereoisomeric epoxides in the ratio 1.0 / 1.0 (purity 90%).

Example 8: Synthesis of epoxides (8) from diols (6) Use of Schotten Baumann conditions

A biphasic system consisting of diols (6, SR / SS, diastereoisomeric ratio 1.1 / 1.0) (100 mg, 0.40 mmol) in DCM (2.0 mL, 20 vol) and an aqueous solution of 50% NaOH (0.5 mL, 5 vol), is kept under vigorous stirring for 1 hour. A solution of tosylimidazole (115.6 mg, 0.52 mmol, 1.3 eq) in DCM (2.5 mL, 25 vol) is dropped to the suspension in 15 minutes at room temperature. At the end of the reaction (14 hours) the mixture is poured into water (2 mL), the organic phase separated, washed with water and dried over Na2SO4. The solvent is removed under reduced pressure giving a viscous residue. The HPLC analysis shows the presence of diastereomeric epoxides (8) (purity 73%) in the ratio 1.1 / 1.0.

Example 9: Synthesis of epoxides (8) from diols (6) Use of low temperature diisopropylethylamine and tosyl chloride

To a solution containing the SR / SS diols (10.15 g, 47.87 mmol) (1.1 / 1.0), diisopropylethylamine (10.65 mL, 61.11 mmol, 1.3 eq) and dimethylaminopyridine (0.17 g, 1.43 mmol, 0.03 eq) in DCM (250 mL ), tosyl chloride (10.9 g, 57.17 mmol, 1.2 eq) is added at 0 ° C. The mixture is left under stirring at 4 ° C and at the end of the reaction (12 hours), it is treated with 2- (diisopropylamino) ethylamine (2.0 mL, 11.43 mmol, 0.2 eq) for 15 minutes, then mixed with 0.1 M NaHSO4 and water. . Alternatively, the mixture can be treated with 8.5 g of (aminomethyl) polystyrene resin (1.5 mmol / g) for about 1 hour and then filtered. 50% aqueous NaOH (30 mL) is added to the separated organic phase and stirred vigorously until the epoxy formation reaction is complete (30 minutes). The mixture is diluted with water and the organic phase separated, washed with 1 M NaHSO4, with water and finally dried over Na2SO4. The solvent is removed under reduced pressure giving a viscous residue (11 g, yield 95%, diastereomeric ratio of the epoxides (8) 1.1 / 1.0).

EXAMPLE 10: Kinetic resolution on the epoxy mixture (SS SR).

A solution of the mixture of epoxies (SS SR) (4.50 g, 22.5 mmol) and benzylamine (3.8 mL, 35 mmol) in 2-methyl-2-butanol (38 mL) is mixed at room temperature for 12 hours. At the end of the reaction, the amine (10, SR) formed is filtered under vacuum and dried (1.90 g, 6.30 mmol). The filtered solution is poured into cyclohexane (250 mL) and the resulting solution is washed with 1M NaHSO4 (100 mL) and H2O (50 mL x 2) and then concentrated under reduced pressure to obtain 1.30 (6.00 mmol) g of epoxide (12) (SS).

The kinetic resolution on the epoxy mixture (RS RR) is carried out in the same way as described in the Example above.

EXAMPLE 11: Synthesis of benzyl l-nebivolol (SSSR) The compound (RS) -2-benzylamino-1- (6-fluoroocroman-2-yl, 9) ethanol and epoxide (12, SS) are dissolved in ethanol absolute (6 mL) and kept at reflux until the starting reagents disappear. At the end of the reaction the mixture is allowed to reach room temperature and the solvent is removed under reduced pressure.

EXAMPLE 12: Synthesis of d-benzyl nebivolol (RRRS) The compound (SR) -2-benzylamino-1- (6-fluoroocroman-2-yl, 10) ethanol and the epoxide (11, RR) are treated as in € ™ Example 11 to obtain dbenzyl nebivolol.

EXAMPLE 13: Synthesis of d, 1-benzyl nebivolol

The l-benzyl nebivolol described in Example 11 (3.00 g) and the d-benzyl nebivolol described in Example 12 (3.00 g) are combined and the mixture thus obtained (6.0 g) is taken up in 2- methyl-2-butanol (36 mL) heated until dissolved (80 ° C) and left at room temperature for 24 hours under gentle stirring. The solid obtained is filtered by taking up with 2-methyl-2-butanol (5 mL). It dries on the filter. 4.20 g of crystalline mixture with 99.6% purity are obtained

EXAMPLE 14: Synthesis of nebivolol hydrochloride The compound d, 1-benzyl nebivolol (2.0 g, 4.0 mmol) is dissolved in methanol (160 mL) together with 20% (1% by weight) Pd (OH) 2 / C. The mixture is stirred in a hydrogen atmosphere. At the end of the reaction, the catalyst is filtered on a porous septum and concentrated HCl (0.52 mL) is added to the filtrate. The solution is concentrated under reduced pressure and the residue obtained is heat treated with absolute ethanol (20 mL). The solid obtained is filtered and dried under vacuum (1.7 g).

Claims (24)

CLAIMS 1. Process for the preparation of a mixture of epoxides (1), through the intermediate diol (3), O OR * * F. (1) as intermediates in the synthesis of nebivolol, comprising the following synthetic steps: a) the ester (2) reacts, in which R is a C1-C6 alkyl group. OR OR OR * F. (2) with LiCH2Br, at a temperature lower than â € “90 ° C in inert solvent, an aqueous medium is subsequently added at the same temperature, and the aqueous mixture is then treated with a reducing agent to obtain the mixture of the diol (3); OH OR * * OH F. (3) b) the mixture of diol (3) thus obtained is transformed into the mixture of epoxides (1). Process according to claim 1, wherein step (b) comprises the following synthetic steps: the mixture of the diol (3) is treated with a mesylating or tosylating agent and subsequently, by means of an intramolecular substitution, the mixture of epoxides (1) is generated. 3. Process according to claim 1 or 2 in which the diols (3) obtained in step (a) are purified by partitioning between a polar organic solvent and an apolar solvent that are immiscible to each other, the thus purified diol is then subjected to the step (b). 4. Process according to any one of claims 1 to 3, wherein in step (a): the ester (2) reacts as the R isomer or, alternatively as the S isomer, obtaining a mixture of diols (5) consisting of the RS RR isomers OH OH O O OH OH F F (RS) (RR) (5) or, alternatively, a mixture of diols (6) consisting of the SR SS isomers OHOH O O OH OH F F (SR) (SS) (6) b) the mixture of diols (5) RS RR or, alternatively, the mixture of diols (6) SR SS, is treated with a mesylating or tosylating agent to give the â € ̃semichiralâ € ™ mixture of epoxides (7) RS RR OR OOO F F (RS) (RR) (7) or, alternatively, the â € ̃semichiralâ € ™ mixture of epoxies (8) SR SS. OR OO OR F F (SR) (SS) (8) 5. Process according to any one of claims 1 to 4 in which the synthetic step a) is carried out at a temperature ranging from -130 ° C to -95 ° C. 6. Process according to claim 5 wherein the temperature is between -105 ° C and -95 ° C. 7. Process according to any one of claims 1 to 6 wherein in the synthetic step a) the aqueous solution used for the treatment can be neutral or acidic but in any case used in such quantities as to maintain the environment in alkaline conditions. Process according to any one of claims 1 to 7 wherein the R group represents an ethyl. 9. Process according to any one of claims 1 to 8 in which the organometal LiCH2Br is generated in situ by adding a solution of BuLi to a solution containing the ester (2) and the CH2Br2 in an inert organic solvent at a temperature lower than â € “90 °. 10. Process according to any one of claims 1 to 9 wherein the reducing agent in the synthetic step a) is selected from NaBH4 or LiBH4, preferably NaBH4. 11. Process according to any one of claims 3 to 10 wherein, in the step of purification of the diols, the organic solvent p o l a r e à ̈ s c e l t o t r a methanol, ethanol, acetonitrile, DMF (dimethylformamide), DMI (dimethylimidazolidinone), NMP (N-methylpyrrolidone ), and preferably methanol and the non-polar solvent immiscible with the former is a C5-C10alkane or a mixture of C5-C10alkanes, preferably heptane. Process according to any one of claims 2 to 11, wherein in step (b) the mixture of diols is reacted in an organic solvent selected from dichloromethane, tertbutylmethyl ether, tetrahydrofuran, DMF, DMSO, NMP and DMI, and preferably DMF, with a base chosen from LiH, NaH, KH, tBuOK and preferentially NaH, optionally in the presence of a salt of lithium, potassium or cesium, and subsequently with a mesylating or tosylating agent selected from tosyl chloride (TsCl), tosyl imidazole and mesyl chloride, and preferably TsCl. 13. Process according to any one of claims 2 to 11 wherein, as an alternative to what is described in claim 12, the mixture of diols is reacted with a system composed of a pre-formed organic solvent solution selected from DMSO / NaH, or of imidazole / NaH and a tosylating agent selected from tosyl chloride (TsCl), tosyl imidazole and preferably TsCl. 14. Process according to any one of claims 2 to 11, in which, as an alternative to what is described in claims 12 and 13, the mixture of diols is reacted in an organic solvent that is not miscible with water, with an agent tosilant selected from tosyl chloride or tosyl imidazole, preferably tosyl chloride, with 50% NaOH in water, under the conditions foreseen for the Schotten-Baumann reaction. 15. Process according to any one of claims 2 to 11, wherein, as an alternative to what is described in claims 12, 13 and 14, the mixture of diols is reacted in an organic solvent that is immiscible with water, and containing an organic base, preferably diisopropylethylamine, cooled and maintained at a temperature below 25 ° C, preferably below 4 ° C, with a solution of tosyl chloride in an organic solvent, followed by the addition of an aqueous solution of NaOH. 16. Process comprising all the steps according to any one of claims 1 to 3 and 5 to 15 for the synthesis of nebivolol in the form of a racemic mixture of the two enantiomers [2S [2R [R [R]]]] Î ±, Î ± â € ™ - [imino-bis (methylene)] bis [6-fluoro-chroman-2-methanol] and [2R [2S [S [S]]]] Î ±, Î ± â € ™ - [imino- bis (m et h yle ne)] b is [6-fluoro-chroman-2-methanol], having the following formulas OH OHHOH OHH O N OON O F F F F Nebivolol (SRRR RSSS) which includes the further steps in which: a) a mixture of the four isomers SR, RS, RR and SS of the epoxide of formula (1) is reacted O * O * F. (1) with benzylamine in a solvent represented by a sterically encumbered alcohol selected from tert-B u O H, 2-methyl-2-butanol, 2-methyl-2-pentanol, used alone or mixed with a non-polar solvent, preferably cyclohexane, to obtain a mixture of the four compounds 9, 10, 11 and 12, from which the 9/10 pair is separated from the pair 11/12; OH OH H H ONON O O Bn Bn O <O> F F F F 91011 <12> b) the amines 9 and 10 are reacted, in mixture, with the pair of epoxides 11 and 12, in mixture, to obtain a mixture of four compounds (13, 14, 15 and 16); OH Bn OH OH Bn OH O N O O N O F F F F 13 14 OH Bn OH OH Bn OH O N O O N O 15 F F F16F c) the compounds 13 and 15 (RSSS SRRR) are separated, in mixture, from 14 and 16 by fractional crystallization from 2-methyl-2-butanol, and subsequently from an ethyl acetate / cyclohexane mixture, d) the benzyl protecting group is removed, and optionally the hydrochloride salt is subsequently formed, to obtain the final product Nebivolol or Nebivolol hydrochloride. 17. Process according to claims 4 to 15, for the synthesis of nebivolol, which includes the following steps: a) the â € ̃semichiralâ € ™ mixture of epoxides (7), and / or the â € ̃semichiralâ € ™ mixture of epoxides (8) are resolved kinetically by making them react with benzyl amine in a sterically encumbered alcohol chosen from tert-BuOH , 2-methyl-2-butanol, 2-methyl-2-pentanol to obtain compounds (9) and (11) and / or compounds (10) and (12) respectively; b) the amino alcohol (9) is reacted with the epoxide (12) to obtain l-benzyl nebivolol (15) and / or the amino alcohol (10) with the epoxide (11) to obtain d-benzyl nebivolol (13); c) the benzyl protecting group is removed with the formation of d- and / or l-nebivolol. 18. Purification process of diols of formula (3) OH OR * * OH F. (3) in which a raw mixture containing the diols is separated by partitioning between a polar organic solvent and an apolar solvent that are immiscible from each other. 19. Purification process according to claim 18 wherein the polar organic solvent is selected from methanol, ethanol, acetonitrile, DMF (dimethylformamide), DMI (dimethylimidazolidinone), NMP (N-methylpyrrolidone), and preferably methanol and the non-polar immiscible solvent with the former it is a C5-C10alkane or a mixture of C5-C10alkanes, preferentially heptane. 20. Process for the preparation of an epoxy mixture (1), OR OR * * F. (1) as intermediates in the synthesis of nebivolol, comprising the following synthetic steps: it is the mixture of the diol (3) OH OR * * OH F. (3) with a mesylating or tosylating agent and subsequently, by means of an intramolecular substitution, the mixture of epoxides (1) is generated. 21. Process according to claim 20, in which the mixture of diols is reacted in an organic solvent selected from dichloromethane, tertbutylmethyl ether, tetrahydrofuran, DMF, DMSO, NMP and DMI, and preferably DMF, with a base selected from LiH, NaH, KH, tBuOK and preferentially NaH, optionally in the presence of a lithium, potassium or cesium salt, and subsequently with a mesylating or tosylating agent selected from tosyl chloride (TsCl), tosyl imidazole and mesyl chloride, and preferably TsCl. 22. Process according to claim 20 wherein the mixture of diols is reacted with a system composed of a preformed organic solvent solution selected from DMSO / NaH, or of imidazole / NaH and a tosylating agent selected from tosyl chloride (TsCl) , tosyl imidazole and preferentially TsCl. 23. Process according to claim 20, in which the mixture of diols in an organic solvent immiscible with water is reacted with a tosylating agent selected from tosyl chloride or tosyl imidazole, preferably tosyl chloride, with 50% NaOH in water, under the conditions foreseen for the Schotten-Baumann reaction. 24. Process according to claim 20, in which the mixture of diols is reacted in an organic solvent that is not miscible with water, and contains an organic base, preferably diisopropylethylamine, cooled and maintained at a temperature below 25 ° C , preferably below 4 ° C, with a solution of tosyl chloride in an organic solvent, followed by the addition of an aqueous solution of NaOH.