Specification
PROCESS AND INTERMEDIATES FOR THE PREPARATION OF BILASTINE
Field of the Invention
The invention relates to a process for the preparation of key intermediates in the synthesis of Bilastine and to new intermediates in said process.
Background of the Invention
Bilastine is a second-generation antihistamine medication which is used in the treatment of allergic rhinoconjunctivitis and urticaria.
Bilastine
Several synthesis of Bilastine has been disclosed in the last years using a compound of formula (III) as key intermediate as it provides a straightforward synthetic route for Bilastine, minimizing protecting group chemistry.
For instance, WO 2009/102155 discloses the preparation of this key intermediate by reacting compound 4 and methyltrimethylsilyl dimethylketene acetal (5) in the presence of a Palladium catalyst, t-BusP and ZnF2. This key intermediate is then converted into Bilastine by either reaction with 1-(2-ethoxyethyl)-2-piperidin-4-yl-1 H-benzoimidazole (3a) followed by hydrolysis of the ester group or by reaction with 2-(4-piperidinyl)-1 H-benzoimidazole (7), followed by alkylation of the benzimidazole nitrogen and hydrolysis of the ester group. However, this cross coupling approach lacks industrial interest due to the instability, availability and cost of the ketene acetal and the phosphine used in the key step of the synthesis.
CN 104151 160 A refers to the synthesis of compounds similar to key intermediate (III), but which lack a leaving group. The compound is synthesized through the alkylation of the halobenzene compound (2) in the presence of a palladium catalyst and a lithium amide. Then again, this approach uses organometallic reagents and an amide base, which is highly unstable and expensive.
The process for preparing Bilastine disclosed in Synthetic Communications 201 1 , 41 (9), 1394-1402 includes palladium catalyzed vinylation of aryl bromide (3) with vinyl tributylstannane or with vinylboronic anhydride followed by hydroboration of the resulting styrene (1 1 ). This alternative cross coupling approach uses in the first step high cost and low available vinyl synthons (and highly toxic in the case of the tin compound). Besides, the anti-Markovnikov hydroxylation step is performed using the well-known and undesirable borane (highly toxic and flammable gas), which also undermines its industrial applicability.
CN 104326909 A and CN 102675101 A refer to a process for the synthesis of key intermediate (III) which comprises acylation of 2-methyl-2-phenyl-propanoic acid or an ester thereof in the presence of a Lewis acid and subsequent reduction of the oxo group. This approach, even if industrially applicable, uses stoichiometric reagents both in the acylation and the reduction step and involves the generation of high amounts of residues.
In general, the methods disclosed in the prior art for the preparation of compounds of formula (III) according to the present invention, require the use of organometallic reagents, toxic reagents, harsh reaction conditions or have a low productivity and, therefore, are not suitable for industrial production.
It is therefore necessary to develop a new process for obtaining compounds of formula (III), which are key intermediates in the synthesis of Bilastine, which overcome all or part of the problems associated with the known processes belonging to the state of the art.
Summary of the Invention
The invention faces the problem of providing a new process for the preparation of formula (III) and to intermediates thereof.
In contrast to processes of the prior art, the process of the invention meets the needs of industrial production. It allows preparing compounds of formula (III) in the absence of organometallic and toxic reagents, in short reaction times, is a simple and low cost process and gives rise to the desired product with a very high productivity.
The inventors have found that compounds of formula (III) can be obtained in a very straightforward manner by acylation and subsequent oxidative rearrangement of readily available and economical starting materials. As shown in the experimental section, this process not only avoids the use of highly toxic, unstable and/or expensive reagents, but also leads to the compounds of formula (III) in shorter reaction times and with higher productivity than prior art processes. All these features make the process of the invention very cost-efficient and therefore highly suitable for industrial scale production.
The compounds of formula (III) obtained by the process of the invention already include the leaving group required for subsequent reaction with the piperidinyl compound and so does not require additional reaction steps for its use in the preparation of Bilastine.
Thus, in a first aspect the invention is directed to a process for preparing a compound of formula (III)
or a solvate thereof wherein
X is a leaving group; and
R1 is Ci-C6 alkyl;
which comprises oxidative rearrangement of a compound of formula (II) or a solvate thereof
(II).
In a second aspect the invention is directed to the use of a compound of formula
(II)
or a solvate thereof wherein X is a leaving group as an intermediate in the preparation of Bilastine.
In a third aspect, the invention is directed to a compound of formula (II’)
or a solvate thereof wherein X is selected from Cl, I, OMs, OTs and OTf.
Detailed Description of the Invention
The term“alkyl” refers to a linear or branched alkane derivative containing from 1 to 6 (“Ci-C6 alkyl”), preferably from 1 to 3 (“C1-C3 alkyl”), carbon atoms and which is bound to the rest of the molecule through a single bond. Illustrative examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl. Preferably, it is methyl.
The term“aryl” refers to an aromatic group having between 6 and 10 (“C6-C10 aryl”), preferably 6 or 10 carbon atoms, comprising 1 or 2 aromatic nuclei fused to one another. Illustrative examples of aryl groups include phenyl, naphthyl, indenyl, phenanthryl, etc. Preferably, it is phenyl.
The term “(C6-Cio)aryl(Ci-C6)alkyl” refers to an alkyl group as defined above substituted with an aryl group as defined above. Examples of such groups include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, etc. Preferably, it is benzyl.
The term“haloalkyl” refers to an alkyl group as defined above containing from 1 to 6 (“C1-C6 haloalkyl”), preferably from 1 to 3 (“C1-C3 haloalkyl”), carbon atoms wherein at least one hydrogen atom has been replaced by halogen. Examples of haloalkyl groups include but are not limited to CF3, CCI3, CHF2, CF2CF3. Preferably, it is -CF3.
The term“halogen” refers to bromine, chlorine, iodine or fluorine.
The term “leaving group” refers to a functional group or an atom that can be displaced by another functional group in a substitution reaction, such as a nucleophilic substitution reaction. Suitable leaving groups are well known in the art. In a particular embodiment, the leaving group is selected from halogen, C1-C6 alkylsulfonates, C1-C6 haloalkylsulfonates and (Ci-C6)alkyl(C6-Cio)arylsulfonates, such as chloro, bromo, iodo, mesylate (OMs), triflate (OTf), tosylate (OTs) and the like.
The invention also refers to“salts” of the compounds described in the present description. By way of illustration, said salts can be acid addition salts, base addition salts or metal salts, and can be synthesized from the parent compounds containing a basic or acid moiety by means of conventional chemical processes known in the art. Such salts are generally prepared, for example, by reacting the free acid or base forms of said compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of the two. Non-aqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol or acetonitrile are generally preferred. Illustrative examples of said acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc., organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, trifluoroacetate, camphorsulfonate, etc. Illustrative examples of base addition salts include inorganic base salts such as, for example, ammonium salts and organic base salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glutamine, amino acid basic salts, etc. Illustrative examples of metal salts include, for example, sodium, potassium, calcium, magnesium, aluminum and lithium salts. In a particular embodiment, the salt is an acid addition salt, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, trifluoroacetate or camphorsulfonate. Preferably, it is selected from HCI, HBr, H3PO4, H2SO4, MsOH, pTsOH, TFA, citrate and fumarate salt.
Likewise, the compounds described in the present description can be obtained or used both as free compounds or as solvates (e.g., hydrates, alcoholates, etc.), both forms being included within the scope of the present invention. The solvation methods are generally known in the state of the art. Preferably, the solvate is a hydrate.
The term“organic solvent” includes for example cyclic and acyclic ethers (e.g. Et24 and hydrates or solvate thereof, HCI, H2SO4, H3PO4, HCIO4, HBF4, CISO3H, MsOH and TfOH. Preferably, the acid is AICI3- In a particular embodiment, the acid is present in an amount of from 0.1 to 10.0 molar equivalents with respect to the compound of formula (I); preferably from 0.1 to 5.0, more preferably from 0.5 to 3.0 molar equivalents.
In a particular embodiment, the acylation reaction is carried out in the presence of an organic solvent. Suitable solvents include, for example, ethers, hydrocarbon solvents, halogenated solvents, aromatic solvents, ketones, esters, and mixtures thereof. In an embodiment, the solvent is a hydrocarbon solvent, such as pentane, hexane or heptane. In an embodiment, the reaction is carried out in the presence of a non-polar organic solvent, such as an ether (e.g. Et23, K2CO3, CS2CO3, L12CO3, NaHCCh, KHCO3, CsHCCh, L1HCO3), an alkali metal phosphate (e.g. Na3P04, K3PO4, Na2HP04, K2HP04, NaH2P04, KH2P04), an alkali metal alkoxide (e.g. NaOMe, KOMe, NaOEt, KOEt, NaOtBu, KOtBu), an alkali metal hydroxide (e.g. NaOH, KOH, LiOH, CsOH), an aliphatic or aromatic amine (e.g. Me2NH, Et2NH, iP^NH, BU2NH, MesN, EtsN, BU3N, iPr2EtN, N-methylmorpholine, pyridine, DMAP, aniline, N,N-dimethylaniline). Preferably, the base is an inorganic base, more preferably it is an alkali metal carbonate, bicarbonate or phosphate.
In an embodiment, the organic solvent is a polar organic solvent, such as THF, a ketone (e.g. acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), an ester (e.g. EtOAc, iPrOAc), a nitrile (e.g. acetonitrile, benzonitrile), an amide (e.g. DMF, DMA, HMPA, NMP), a sulfoxide (DMSO), alcohol (e.g. methanol, ethanol, propanol, isopropanol, sec-butanol, t-butanol), or mixtures thereof. In a further embodiment, the organic solvent is a polar aprotic organic solvent, such as THF, a ketone (e.g. acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), an ester (e.g. EtOAc, iPrOAc), a nitrile (e.g. acetonitrile, benzonitrile), an amide (e.g. DMF, DMA, HMPA, NMP), a sulfoxide (DMSO), or mixtures thereof.
In a preferred embodiment, the reaction is carried out in the presence of an inorganic base and a polar aprotic organic solvent.
In an embodiment, the reaction is performed at a temperature between 20°C and 180°C, preferably at a temperature between 20°C and 160°C, preferably between 50°C and 150°C.
Reaction of a compound of formula (V) or (V) wherein R2 is H with a compound of formula (VI)
Reaction of a compound of formula (V) or (V’) wherein R2 is H with a compound of formula (VI) to provide a compound of formula (V) wherein R2 is -CFhCFhOEt or Bilastine, respectively, can be carried out as disclosed previously in the prior art.
In a particular embodiment of the invention, the reaction is carried out in the presence of a base and an organic solvent.
Suitable bases include inorganic and organic bases, such as an alkali metal carbonate or bicarbonate (e.g. Na2CC>3, K2CO3, CS2CO3, U2CO3, NaHCC>3, KHCO3, n alkali metal phosphate (e.g. Na3P04, K3PO4, Na2HP04, K2HP04, an alkali metal alkoxide (e.g. NaOMe, KOMe, NaOEt, KOEt,
n alkali metal hydroxide (e.g. NaOH, KOH, LiOH, CsOH), an aliphatic or aromatic amine (e.g. Me2NH, Et2NH, iP^NH, BU2NH, MesN, EtsN, BU3N, iPr2EtN, N-methylmorpholine, pyridine, DMAP, aniline, N,N-dimethylaniline). Preferably, the base is an inorganic base; more preferably an alkali metal hydroxide or alkoxide; even more preferably an alkali metal hydroxide such as NaOH, KOH, LiOH or CsOH.
In an embodiment, the organic solvent is a polar organic solvent, such as THF, a ketone (e.g. acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), an ester (e.g. EtOAc, iPrOAc), a nitrile (e.g. acetonitrile, benzonitrile), an amide (e.g. DMF, DMA, HMPA, NMP), a sulfoxide (DMSO), alcohol (e.g. methanol, ethanol, propanol, isopropanol, sec-butanol, t-butanol), or mixtures thereof. In a further embodiment, the organic solvent is a polar aprotic organic solvent, such as THF, a ketone (e.g. acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), an ester (e.g. EtOAc, iPrOAc), a nitrile (e.g. acetonitrile, benzonitrile), an amide (e.g. DMF, DMA, HMPA, NMP), a sulfoxide (DMSO), or mixtures thereof.
In a preferred embodiment, the reaction is carried out in the presence of an
inorganic base, preferably an alkali metal hydroxide, and a polar organic solvent.
In an embodiment, the reaction is performed at a temperature between 0°C and 180°C, preferably at a temperature between 20°C and 160°C, preferably between 30°C and 100°C.
In a preferred embodiment of the invention, hydrolysis of the ester group to the carboxylic acid takes place under the reaction conditions for reacting the compound of formula (V) wherein R2 is H with a compound of formula (VI). In this case, Bilastine or a salt or solvate thereof is directly obtained without the need of an additional reaction step. In a particular embodiment, this is carried out in the presence of an inorganic base, preferably an alkali metal hydroxide (e.g. KOH or NaOH), and a polar organic solvent (e.g. DMSO).
Hydrolysis of the ester group
Hydrolysis of the ester group in a compound of formula (V) wherein R2 is -CH2CH20Et or in a compound of formula (III) to provide Bilastine or a compound of formula (III’), respectively, can be carried out as disclosed previously in the prior art.
In an embodiment, the reaction is carried out by acid or basic hydrolysis. In a particular embodiment, hydrolysis is carried out by treatment with an acid or a base under heat. Suitable acids include acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, HCI, HBr, HF, HCI04, H2SO4, HNO3, H3PO4, formic acid, propionic acid, butyric acid, malic acid, citric acid, benzoic acid, p-toluenesulfonic acid, oxalic acid and succinic acid, preferably HCI, HBr and H2SO4. Suitable bases include alkali metal carbonates or bicarbonates (e.g. Na2CC>3, K2CO3, CS2CO3, U2CO3, NaHCCh, KHCO3, CsHCCh, UHCO3), alkali metal phosphates (e.g. NasPCU, K3PO4, Na2HPC>4, K2HPO4, NaH2PC>4, KH2PO4), alkali metal alkoxides (e.g. NaOMe, KOMe, NaOEt, KOEt, NaOtBu, KOtBu), and alkali metal hydroxides (e.g. NaOH, KOH, LiOH, CsOH). Preferably, the base is an alkali metal hydroxide or alkoxide; more preferably an alkali metal hydroxide such as NaOH, KOH, LiOH or CsOH.
In an embodiment, the reaction is carried out in the presence of water, an organic solvent, or mixtures thereof.
In a particular embodiment, the reaction is carried out in the presence of an organic solvent, preferably a polar organic solvent such as THF, a ketone (e.g. acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), an ester (e.g. EtOAc, iPrOAc), a nitrile (e.g. acetonitrile, benzonitrile), an amide (e.g. DMF, DMA, HMPA, NMP), a sulfoxide (DMSO), alcohol (e.g. methanol, ethanol, propanol, isopropanol, sec-butanol, t-butanol), or mixtures thereof.
In a preferred embodiment, the reaction is carried out in the presence of an inorganic base, preferably an alkali metal hydroxide, and a polar organic solvent.
In an embodiment, the reaction is performed at a temperature between 0°C and 180°C, preferably at a temperature between 20°C and 160°C, preferably between 30°C and 100°C.
In a preferred embodiment, hydrolysis of the ester group takes place under the basic conditions used of the reaction of the compound of formula (V) wherein R2 is H with a compound of formula (VI), so that Bilastine, or a salt or solvate thereof, is directly obtained in a single reaction step from the compound of formula (V) wherein R2 is H, or a salt or solvate thereof.
In another aspect, the invention is directed to the use of a compound of formula
(II)
or a solvate thereof wherein X is a leaving group as an intermediate in the preparation of Bilastine.
In an embodiment, X is selected from Cl, Br, I, OMs, OTs and OTf; preferably X is Cl or Br; more preferably X is Cl.
In a further aspect, the invention is directed to a compound of formula (II’)
or a solvate thereof wherein X is selected from Cl, I, OMs, OTs and OTf.
In a preferred embodiment, X is Cl.
It should be understood that the scope of the present disclosure includes all the possible combinations of embodiments disclosed herein.
EXAMPLES
Example 1 : Preparation of 1 -(4-(2-chloroethyl)phenyl)-2-methylpropan-1 -one
In a reaction vessel iPrCOCI (8.2 g) was cooled to 9°C and mixed with AlC (5.2 g). 2-Chloroethylbenzene (4.3 g) was added dropwise and the mixture was stirred for 60 minutes, poured over HCI 1 M (50 ml.) at 0°C. TBME (10 ml.) was added and the mixture was stirred. The organic layer was washed with NaOH 1 M (25 ml_), separated, dehydrated with anhydrous sodium sulfate and then condensed and the solvent was removed under vacuum. 7.4 g of 1-(4-(2-chloroethyl)phenyl)-2-methylpropan-1-one were obtained in a 100% yield and a 90% purity.
Example 2: Preparation of 2-[4-(2-Chloro-ethyl)-phenyl]-2-methyl-propionic acid methyl ester
In a round-bottom flask with a reflux condenser, ICI (9.6 ml.) was added to a solution of 1-[4-(2-chloro-ethyl)-phenyl]-2-methyl-propan-1-one (13.42 g) in TMOF (55 ml_). The mixture reacted fairly vigorously in an exothermic reaction. After few minutes, when the bubbling and the reflux had stopped, the mixture was cooled down and the workup was performed as follows: it was quenched with a saturated solution of sodium bicarbonate (120 ml.) and extracted with dichloromethane (80 ml. x 3). The organic layer was washed with a solution of Na2S203 (10%, 150 ml_), dried with anhydrous sodium sulfate and concentrated. 15.03 g of 2-[4-(2-chloro-ethyl)-phenyl]-2-methyl-propionic acid methyl ester were obtained in a 98% yield and 85% purity.
Example 3: Preparation of 2-[4-(2-Chloro-ethyl)-phenyl]-2-methyl-propionic acid methyl ester
I2 (794 mg) was added to a round-bottom flask with 1-[4-(2-chloro-ethyl)-phenyl]-2-methyl-propan-1 -one (200 mg) in TMOF (913 pl_). The mixture was stirred for five minutes before sulphuric acid (22 pl_) was added. At this point, the vessel was heated at 80 °C. After 1 hour, workup was accomplished by the addition of a solution of NaHCOs (5 ml.) and then extraction with dichloromethane (5 ml. x 3). The organic layer was washed with a solution of Na2S203 (20 ml_), dried with anhydrous sodium sulfate and concentrated under vacuum. 0.226 g of 2-[4-(2-Chloro-ethyl)-phenyl]-2-methyl-propionic acid methyl ester were obtained in a 99% yield and 86% purity.
Example 4: Preparation of 2-[4-(2-Chloro-ethyl)-phenyl]-2-methyl-propionic acid methyl ester
l2 (290 mg) was dissolved in 1.65 ml. of a 0.23M solution of HCI in MeOH. It was mixed with 1-[4-(2-chloro-ethyl)-phenyl]-2-methyl-propan-1-one (200 mg) and with TMOF (400 mg). The mixture was heated at 100°C for 10 minutes, cooled to room temperature and poured over 5 mL of a Na2S2C>3 solution. The mixture was extracted with DCM (2 x 5 ml_). The organic layer was washed with a solution of Na2S2C>3 (5 mL), dried with anhydrous sodium sulfate and concentrated under vacuum. 0.220 g of 2-[4-(2-chloro-ethyl)-phenyl]-2-methyl-propionic acid methyl ester were obtained in a 96% yield and 70% purity.
Alternatively, [4-(2-Chloro-ethyl)-phenyl]-2-methyl-propionic acid methyl ester was also obtained as in Example 4 but using ethyl chloroformate as the acid source instead of the solution of HCI in MeOH.
Productivity comparison
In the following table, the productivity and process cycle times of the process of the invention is compared to those of the best or closest examples from the prior art. The productivity refers to the amount of product of formula (III) obtained based on the total amount of starting materials, reagents and solvents used in the process. This is a measure of the cost-efficiency of a process and so is of great importance for industrial scale production.
[al Patent CN 102675101 A does not contain a detailed experimental procedure.
[bl Measuring of the sum of the amounts of starting materials, reagents and solvents used in the reaction steps. Solvents and solutions used during the work up are not taken into account.
[cl Considering reaction times, without workup.
[dl Considering 1 M concentration in toluene (typical commercial presentation) as there is no data of solvent volume.
As shown above, the process of the invention allows the preparation of compounds of formula (III) in a very high productivity and short reaction times. Consequently, this process is very cost-efficient and so very suitable for industrial production. Additionally, the process does not require the use or organometallic or highly toxic reagents, as in other prior art processes. Finally, the resulting compounds of formula (III) already include the leaving group required for subsequent reaction with the piperidinyl compound and so does not require additional reaction steps for its use in the preparation of Bilastine.
CLAIMS
1. A process for preparing a compound of formula (III)
or a solvate thereof wherein
X is a leaving group; and
R1 is Ci-C6 alkyl;
which comprises oxidative rearrangement of a compound of formula (II) or a solvate thereof
2. Process according to claim 1 , which comprises:
(a) acylation of a compound of formula (I)
or a solvate thereof wherein X is a leaving group, to provide a compound of formula (II)
or a solvate thereof, and
(b) oxidative rearrangement of a compound of formula (II), or a solvate thereof, to provide a compound of formula (III)
or a solvate thereof, wherein R1 is C1-C6 alkyl.
3. Process according to claim 1 , wherein X is selected from Cl, Br, I, OMs, OTs and
OTf.
4. Process according to anyone of claims 1 to 3, wherein oxidative rearrangement is carried out in the presence of a tri(Ci-C6)alkyl orthoester, a (Ci-C6)alkanol or a mixture thereof, an oxidizing agent and an acid catalyst.
5. Process according to any one of claim 4, wherein the oxidizing agent is an iodine oxidizing agent, such as h, ICI, ICI3, HIO3, Phl(OAc)2, Phl(OCOCF3)2, Phl(OTf)2, Phl(OH)OTs, PhIO, NIS, IBX or DMP.
6. Process according to any one of claims 4 or 5, wherein the acid catalyst is selected from sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, camphorsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, fumaric acid, citric acid, oxalic acid, succinic acid, tartaric acid and malic acid.
7. Process according to any one of claims 2 to 6, wherein acylation is carried out in the presence of an acylating agent selected from (iPrCO)20 and a compound of formula iPrCO-Z, wherein Z is selected from OH, Cl, Br and I.
8. Process according to any one of claims 2 to 7, wherein acylation is carried out in the presence of a protic acid and/or a Lewis acid.
9. Process according to any one of claims 1 to 8, which comprises converting the compound of formula (III), or a solvate thereof, into Bilastine, or a salt or solvate thereof.
10. Process according to any one of claims 1 to 9, which further comprises:
(c) reacting a compound of formula (III)
or a solvate thereof wherein
X is a leaving group; and
R1 is C1-C6 alkyl;
with a compound of formula (IV)
or a salt or solvate thereof wherein R2 is selected from H and -ChhCI-hOEt; to provide a compound of formula (V)
or a salt or solvate thereof; and
(d) converting the compound of formula (V), or a salt or solvate thereof, into Bilastine, or a salt or solvate thereof.
1 1. Process according to claim 10, wherein R2 in the compounds of formula (IV) and (V) is -ChhCI-hOEt and step (d) comprises hydrolysis of the ester group in the compound of formula (V), or a salt or solvate thereof, to provide Bilastine, or a salt or solvate thereof.
12. Process according to claim 10, wherein R2 in the compounds of formula (IV) and (V) is H and step (d) comprises:
(d1 ) reacting a compound of formula (V), or a salt or solvate thereof, wherein R2 is H, with a compound of formula (VI)
Y^\^0Et
(VI)
wherein Y is a leaving group,
to provide a compound of formula (V), or a salt or solvate thereof, wherein R2 is -ChhCI-hOEt; and
(d2) hydrolysis of the ester group in the compound of formula (V), or a salt or solvate thereof, wherein R2 is -ChhCI-hOEt to provide Bilastine or a salt or solvate thereof.
13. Process according to any one of claims 10 or 12, wherein step (d) comprises reacting a compound of formula (V), or a salt or solvate thereof, wherein R2 is H with a compound of formula (VI)
Y^\^0Et
(VI)
wherein Y is a leaving group,
and hydrolysis of the ester group in a compound of formula (V), or a salt or solvate thereof, to provide Bilastine or a salt or solvate thereof in a single reaction step.
14. Process according to any one of claims 1 to 9, which further comprises:
(c’) hydrolysis of a compound of formula (III)
or a solvate thereof wherein
X is a leaving group; and
R1 is Ci-C6 alkyl;
to provide a compound of formula (IN’)
or a salt or solvate thereof;
(d’) reacting a compound of formula (IN’), or a salt or solvate thereof, with a compound of formula (
or a salt or solvate thereof wherein R2 is selected from H and -ChhCI-hOEt; to provide a compound of formula (V’)
(V)
or a salt or solvate thereof; and
(e’) if needed, converting the compound of formula (V’), or a salt or solvate thereof, into Bilastine, or a salt or solvate thereof.
15. A compound of formula (IG)
or a solvate thereof wherein X is selected from Cl, I, OMs, OTs and OTf.