FI124449B - Preparation process for endothelin receptor antagonists - Google Patents

Description

FIELD OF THE INVENTION OF THE MANUFACTURING PROCESS OF THE ENDOTHELINE RECEPTOR

The invention described relates to the preparation of 6- (2-hydroxyethoxy) -pyrimidines by Mit-5 sunobu coupling. The invention described thus falls within the field of chemistry.

BACKGROUND OF THE INVENTION

Monohydrate bosentan is the active ingredient in Tracleer®, an oral endothelin receptor antagonist used to treat pulmonary hypertension. Bosentan is a sulfonamide derivative with the chemical name 4-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yl] benzenesulfonamide and having the structural formula (I).

o ^ P

fj ^ r ^ 'nh oP

y ^ vys' j-vv ^ o ^ M k OH (I)

Bosentan was first described in EP0526708-A1. The same document also describes the various processes by which it was formed. One of these processes illustrates the reaction of 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yl] benzenesulfonamide with Scheme 1, sodium ethylene glycol.

W rl n / 0 ^ 0 ^ 11 UU 2 [fr NH ° "H ° Na °" 9 ϊ ηΥί —_- ν \ ° Λ

CV fi T <r · * τ ^ Ν Cl {T

LI ί ϋ m l X rvu ι-j-

f Monohahdi I

OH

00 o Diagram 1

LO

CV

^ 20 From an industrial point of view, such a reaction is quite impractical since, except that sodium ethylene glycol is toxic and irritating to the body, it is produced by the process of combining ethylene glycol with sodium metal, a hazardous and explosive substance due to its high reactivity with water . On the other hand, extreme reaction conditions such as high temperature, a very basic reaction pH, the use of highly reactive sodium ethylene glycol and long reaction times are required. In addition, these extreme conditions required to replace the chlorine make it difficult to separate by-products or impurities.

For example, complex purification systems are required to remove dimerization products of the 1,2-diheteroethylene-bis-sulfonamide type. It should also be remembered that the level of impurities in pharmaceutical compounds must be extremely low. For example, the highest level of impurity 10 for a product acceptable for human use is 0.10%. It should also be noted that a highly corrosive gas such as HCl gas is produced as a by-product of the reaction.

WO 2001055120 discloses a modification of this synthetic route as shown in Scheme 2 which solves the problems of dimerization with mono-protected ethylene glycol.

v r o- ^ f & L o '

irX ° Tj —_- nVyS - ^ n <V ° yS

Dihalidi ,,, ....>

a e- Mononahdi I

15 OH

Figure 2

The major problem with this bosentan preparation process is the same as in the proposed process EP 0526708-A1, that is, the use of reagents that are potentially sensitizing agents, such as the dihalide and mononium halide shown in Schemes 1 and 2. The same extreme reaction conditions mentioned in EP 0526708-A1 are also required.

i. Patent applications WO 2009095933 and WO 2009112954 disclose different types

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00 processes for the preparation of bosentan. However, they use the same formula the process shown in Part 3 consisting of 4-tert-butyl-N- [6-hydroxy-5- (2-methoxy-phenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yl] benzenesulfonamide and 2-halo - co g ethanol reaction.

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δ

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3 Q ^ p Ovv /, ° rt ^ i ^ S'NH θ '/ _J3H [i ^ 5 ^ S'NH O' '

n * V ° yS _-_- n ^ y ° yS

^? · Ν X: Halogen \ ί? · Ν ^

OH

Figure 3

The synthetic route has the advantage of avoiding the use of sensitive substances such as the dihalide and monohalide of Schemes 1 and 2. However, problem 5 of this alternative process is the complexity of the technical solution, since in the starting material, 4-tert-butyl-N- [6-hydroxy-5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yl] benzenesulfonamide has at least two nucleophilic atoms which may react equally with 2-haloethanol: OH group O and pyrimidone N. In addition, the alcohol liberated upon formation of bosentan may react with the halogen derivative. As a result of this competitive reaction, large amounts of impurities are formed, such as a compound of formula (V).

The structural similarity of this impurity to bosentan also renders its physico-chemical behavior similar, which makes its removal extremely complex and requires expensive purification processes.

The process for the preparation of bosentan i £ 5, as described in WO 2010015623, is chemically very similar to that described in WO 2009095933 and WO 2009112954 except that it introduces a hydroxyethylene group when 4-tert-butyl-N- [6-hydroxy-5- (2-Methoxy-phenoxy) -2- (2-pyrimidinyl) -20-pyrimidin-4-yl] -benzenesulfonamide reacts with an ethylene glycol derivative which c8 replaces one of the OH groups as a good leaving group according to Scheme 4, m

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δ

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4

cw, ° cuP

'NH θ' ^ ΟΗ 'NH θ' k ^ N GS: Outgoing group \ jj.N k ^

OH

Figure 4

Although the reaction mechanism of this process is very similar to that of WO 2009095933 and WO 2009112954, it has the same technical disadvantage, i.e. the formation of impurity (V).

SUMMARY OF THE INVENTION The present invention solves the problem by providing an effective way to produce 6- (2-hydroxyethoxy) pyrimidines, particularly bosentan.

The process used in the present invention allows the preparation of very pure 6- (2-10 hydroxyethoxy) pyrimidines, particularly bosentan, under very selective and non-extreme conditions, such as moderate temperatures, very short reaction times and very neutral pH values, without producing corrosive gases. formation of a significant impurity (V) without the need for the use of strong and sensitive materials such as the dihalide and monohalide shown in Schemes 1 and 2, which is based on a Mitsunobu-type coupling between two OH groups. a compound of formula (I), or a salt or solvate thereof, including a hydrate:? a * J> o "NH o 'ί x (|)

CL

^ 20 wherein: o m ^ R 1 is -CH 2 CH 2 OH or -CH 2 CH 2 R 2, preferably R 1 is -CH 2 CH 2 OH;

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R 2 is -O-Rprot, -OH precursor or -O-Rprot precursor and Rprot is a protecting group for alcohols; 5 which is formed by a Mitsunobu-type coupling between the compound of formula HO-R-i, preferably HOCH2CH2OH and a compound of formula (II) or a salt of a compound of formula (II):

n ^ ° yS

(II) 5 wherein R 3 is a 4-tert-butylbenzenesulfonamide group or a precursor of a 4-tert-butylbenzenesulfonamide group. Alternatively, if desired or necessary, CH 2 CH 2 R 2 -CH 2 CH 2 OH and / or R 3 can be converted to 4-tert-butylbenzenesulfonamide.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned in the first part of the invention, the compounds of formula (II) contain a substituent R 3 wherein R 3 is a 4-tert-butylbenzenesulfonamide group or a group which is convertible to a 4-tert-butylbenzenesulfonamide group. For the purposes of this invention, a group which is convertible to a 4-tert-butylbenzenesulfonamide group means a group which produces a 4-tert-butylbenzenesulfonamide group in a conventional chemical process. The state of the art describes various processes for producing compounds of formula (II). Scheme 5 illustrates various processes for the preparation of compounds of formula (Ma) corresponding to compounds of formula (II) wherein R 3 is a 4-tert-butyl-benzenesulfonamide group.

As mentioned in the first part of the invention, CH2CH2R2 can be converted to -CH2CH2OH and / or R3 to 4-tert-butylbenzenesulfonamide.

o C \ l

CM

X

cc

CL

C/O

C/O

o m

CM

δ

CM

6 OH θ '

iVyS

.N, Λ; · A AA

if C) H

(Mb) Ο.Α

rj ^ Y 'ΝΗ cA

y ^ ArS

A- A AA

if η N ΟΗ

/ ^ "X

V0 ^ νη2 ο '

(Χχ "νη ο '1 ex X

Art X "0

IxN ("d> Α ^ · Ν (Mc)

Figure 5

the first aspect of the invention in a further preferred embodiment, R is CH2CH2OH.

the first side 5 of the invention in a preferred embodiment, R 3 is 4-fe / f-butyylibentseenisulfonamidiryhmä.

In another embodiment, the invention relates to a process for the preparation of a compound of formula (I) or a salt or solvate thereof, including a hydrate wherein R 1 is CH 2 CH 2 OH; a Mitsunobu-type coupling between the following: A compound of formula Ηθ-R 1 and a compound of formula (II) or a salt thereof, wherein R 3 is a group 9 or a group of 4-tert-butylbenzenesulfonamide, which is convertible to a 4-tert-butylbenzenesulfonamide group.

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x Mitsunobu type coupling preferably uses at least one phosphine and

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at least one azodicarboxylate.

C/O

C/O

The phosphines useful for the invention are primarily of formula (III)

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g compounds:

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f

R 4 -R 4 (lii) 7 wherein each of the three R 4 groups may be the same or different and are independently selected from aryl, substituted aryl, O-aryl, O-substituted aryl, C 1 -C 7 alkyl, C 1 -C 7 substituted alkyl , O (C 1 -C 7 alkyl) and O (C 1 -C 7 substituted alkyl). The most preferred compounds of formula (III) are triphenylphosphine, tributylphosphine and diphenylpyridylphosphine.

Useful azodicarboxylates for use in the invention include compounds of formula (IV): wherein R 2 may be the same or different, and each R 5 may be the same or different and is independently selected from 0 (C 1 -C 7 alkyl), 0 (C 1 -C 7 substituted alkyl). , O-aryl, O-substituted aryl, OCH2-aryl, OCH2-substituted aryl, N (C1-C7 alkyl) 2 and N (C1-C7 substituted alkyl) 2.

The compound of formula (IV) is selected from diethyl azodicarboxylate, disopropyl azodicarboxylate, di-tert-butyl azodicarboxylate and 1,1 '- (azodicarbonyl) dipiperidine, preferably diisopropyl azodicarboxylate.

In another embodiment, the invention relates to a process for the preparation of a compound of formula (I) or a salt or solvate thereof, including a hydrate wherein R 1 is CH 2 CH 2 OH; consisting of a Mitsunobu-type linkage between: A compound of formula HO-R 1 and a compound of formula (II) or a salt thereof wherein R 3 is a 4-tert-butylbenzenesulfonamide group o or a group convertible to a 4-tert-butylbenzenesulfonamide group.

At least one phosphine and one azodioxo carbonyl are used for the I'L Mitsunobu type coupling.

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In another embodiment, the invention relates to a process for the preparation of qo compound of formula (I) or a salt or solvate thereof, including a hydrate wherein R 1 is CH 2 CH 2 OH; consisting of a Mitsunobu-type linkage between the compound of formula HO-R 1 and a compound of formula (II) or a salt thereof, wherein R 3 is a 4-tert-butylbenzenesulfonamide group 30 or a group, which is convertible to a 4-tert-butylbenzenesulfonamide group; wherein at least one phosphine and one 8 azodicarbonyl are used for the Mitsunobu-type coupling; and wherein the phosphine is a compound of formula (III) wherein each of the three R 4 groups is independently an aryl group, substituted aryl, O-aryl, O-substituted aryl, C 1 -C 7 alkyl, C 1 -C 7 substituted alkyl, O (C 1 -C 7) C7 alkyl) or O (C1-C7 substituted alkyl).

In another embodiment, the invention relates to a process for the preparation of a compound of formula (I) or a salt or solvate thereof, including a hydrate wherein R 1 is CH 2 CH 2 OH; consisting of a Mitsunobu-type linkage between: A compound of formula HO-R 1 and a compound of formula (II) or a salt thereof wherein R 3 is a 4-tert-butylbenzenesulfonamide group 10 or a group which is convertible 4-fe / t-butyylibentseenisulfonamidiryhmäksi; wherein at least one phosphine and one azodicarbonyl are used for the Mitsunobu-type coupling; wherein the phosphine is a compound of formula (III) wherein each of the three R 4 groups is independently an aryl group, substituted aryl, O-aryl, O-substituted aryl, C 1 -C 7 alkyl, C 1 -C 7 substituted alkyl, O (C 1 -C 7) -15 alkyl) or O (C 1 -C 7 substituted alkyl); and wherein azodicarbonyl is a compound of formula (IV) wherein each R 5 group is independently O (C 1 -C 7 alkyl), O (C 1 -C 7 substituted alkyl), O-aryl, O-substituted aryl, OCH 2 -aryl, OCH 2-substituted aryl, N (C 1 -C 7 alkyl) 2 or N (C 1 -C 7 substituted alkyl) 2.

Mitsunobu-type coupling generally uses at least one organic solvent. Solvents useful for the present invention include: acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, Ν, Ν-dimethylformamide, and dichloromethane and mixtures thereof. Preferably, acetonitrile is used.

In another embodiment, the invention relates to a process for the preparation of a compound of formula (I) or a salt or solvate thereof, including a hydrate wherein R 1 is CH 2 CH 2 OH; formed by a Mitsunobu-type coupling between the compound of formula HO-R 1 and a compound of formula (II) or a salt thereof wherein R 3 is a 4-tert-butylbenzenesulfonamide group w or a group which is convertible 4-tert-butyylibentseenisulfonamidiryhmäksi; x wherein at least one phosphine and one azodicarbonyl are used for the Mitsunobu-type coupling; wherein the phosphine is a compound of formula (III) wherein each g of the three R 4 groups is independently an aryl group, substituted aryl, O-n aryl, O-substituted aryl, C 1 -C 7 alkyl, C 1 -C 7 substituted alkyl, 0 ( C 1 -C 7 alkyl) or O (C 1 -C 7 substituted alkyl); wherein azodicarbonyl is a compound of formula (IV) wherein each R5 group is independently 0 (Cycalkyl), 35O (C1-C7 substituted alkyl), O-aryl, O-substituted aryl, OCH2-aryl, OCH2-substituted aryl, N (C 1 -C 7 alkyl) 2 or N (C 1 -C 7 substituted alkyl) 2; and wherein the Mitsun sunobu type coupling preferably uses at least one organic solvent selected from acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, Ν, Ν-dimethylformamide or dichloromethane, or a mixture thereof, preferably acetonitrile.

the first side 5 of the invention in a preferred embodiment, the protecting group Rproton alcohols, preferably selected from alcohols such protecting groups as acetals, piieetterit, ethers, esters, carbonates, and derivatives of sulfonic acids.

The reaction heat at which the Mitsunobu-type coupling occurs may range from about 10 ° C to about 150 ° C. A more suitable temperature for the coupling is about 40 ° C to 120 ° C, and most suitable is 60 ° C to 90 ° C.

In another embodiment, the invention relates to a process for the preparation of a compound of formula (I) or a salt or solvate thereof, including a hydrate wherein R 1 is CH 2 CH 2 OH; consisting of a Mitsunobu-type coupling between the compound of formula HO-R 1 and a compound of formula (II) or a salt thereof, wherein R 3 is a 4-tert-butylbenzenesulfonamide group; wherein at least one phosphine and at least one azodicarboxylate are used for the Mitsunobu-type coupling; and wherein the Mitsunobu-type coupling is carried out at a temperature of from about 20 ° C to 150 ° C, preferably from about 40 ° C to 120 ° C, and most preferably from about 60 ° C to 90 ° C.

The process used in the invention is particularly useful in the synthesis of bosentan, i.e., when the compound of formula (I) is bosentan. It is of particular benefit in the synthesis of bosentan monohydrate.

In yet another embodiment, the invention relates to a process for the preparation of bosentan, preferably bosen- tannan monohydrate, which consists of a Mitsunobu-type 9 coupling between the compounds of formula HO-R

C \ J

a compound of formula (II) or a salt thereof, wherein R3 is a 4-tert-butylbenzenesulfonamide group or a group which is convertible to a 4-tert-butylbenzenesulfonamide group; and wherein at least one phosphine and one azodicarbonyl are used for the Mitsunobu-type coupling.

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The process is not limited to a Mitsunobu-type reaction, but may also include additional steps such as reducing the average particle diameter of bosentan monohydrate to less than 100 µm. The par 10 particle size of bosentan monohydrate can be adjusted by techniques known to those skilled in the art, such as milling or micronization.

In another embodiment, the invention relates to a process for the preparation of bosentan monohydrate consisting of a Mitsunobu-type coupling between the following compounds: A compound of formula HO-R 1 and a compound of formula (II) or a salt thereof wherein R 3 is 4-tert-butylbenzenesulfonamide which is convertible to a 4-tert-butylbenzenesulfonamide group; optionally converting, respectively, -CH 2 CH 2 R 2 -CH 2 CH 2 OH and R 3 into 4-tert-butylbenzenesulfonamide; wherein at least one phosphine and one azodicarbonyl are used for the Mitsunobu-type coupling; and including the step of reducing the particle size of bosentan monohydrate to less than 100 µm.

In another embodiment, the invention relates to a process for the preparation of bosentan monohydrate consisting of a Mitsunobu-type coupling between: A compound of formula HO-R 1 and a compound of formula (II) or a salt thereof wherein R 3 is a 4-tert-butylbenzenesulfonamide group or group which is convertible to a 4-tert-butylbenzenesulfonamide group; optionally converting, in either order only, -CH 2 CH 2 R 2 -ChhChhOl + and R 3 into 4-tert-t-butylbenzenesulfonamide; wherein at least one phosphine and one azodicarbonyl are used for the Mitsunobu-type coupling; including the step of reducing the particle size of 20 bosentan monohydrate to less than 100 prl; and wherein the bosentan prepared is mixed with an acceptable carrier for the preparation of the pharmaceutical compound.

In another embodiment, the invention relates to a process for the preparation of bosentan monohydrate consisting of a Mitsunobu-type coupling between the following compounds: A compound of formula HO-R 1 and a compound of formula (II) or a salt thereof wherein R 3 is 4-tert-butylbenzenesulfonamide which is 0 convertible to a 4-tert-butylbenzenesulfonamide group; wherein, optionally, j is converted, respectively, to -CH 2 CH 2 R 2 -CH 2 CH 2 OH and R 3 to 4-tert-butylbenzenesulfonamide; wherein the Mitsunobu-type coupling utilizes at least one phosphine and one azodicarbonyl; wherein the phosphine is a compound of formula (III) 00 g wherein each of the three R 4 groups is independently K aryl, substituted aryl, O-aryl, O-substituted aryl, C 1 -C 7 alkyl, C 1 -C 7 substituted alkyl, O (C 1 -C 7 alkyl) or O (C 1 -C 7 substituted alkyl); wherein azodicarbonyl is a compound of formula (IV) wherein each R 5 group is independently 0 (C 1 -C 7 alkyl), 0 (C 1 -C 7 substituted alkyl), O-aryl, O-substituted aryl, OCH 2 -aryl, OChh-substituted aryl, N (C 1 -C 7 alkyl) 2 or N (Cr 11).

C1-substituted alkyl) 2; wherein the Mitsunobu type coupling utilizes at least one organic solvent, preferably acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, Ν, Ν-dimethylformamide or dichloromethane, or a mixture thereof, preferably acetonitrile; wherein the Mitsunobu-type coupling is carried out at a temperature of from about 5 ° C to about 150 ° C, preferably from about 40 ° C to about 120 ° C, and most preferably from about 60 ° C to about 90 ° C; including the step of reducing the particle size of Bosen Danish monohydrate to less than 100 µm; and wherein the bosentan prepared is mixed with an acceptable carrier for the preparation of the pharmaceutical compound.

Bosentan and its hydrates, in particular bosentan monohydrate, are suitable for the preparation of a pharmaceutical compound. The most preferred form is the oral tablet, preferably the coated tablet. The tablet core may be prepared by methods known to those skilled in the art, such as direct compression or granulation, either dry or wet. Therefore, the process of the invention may also include the step of mixing the prepared bosentan monohydrate with an acceptable carrier in the preparation of the pharmaceutical compound.

Furthermore, the invention encompasses all possible variations of the above descriptions. In yet another embodiment, the invention also relates to the processes described in Examples 1-5.

In the present invention, bosentan refers to 4-tert-butyl-N- [6-hydroxy-5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yl] benzenesulfonamide, including its hydrates and salts; it primarily refers to Bosen Danish monohydrate.

In the present invention, a "Mitsunobu-type coupling" refers to an organic reaction which allows the alkylation of acidic compounds such as carboxylic acids, phenols, imides, oximes and active methylenes by using alcohols as alkylating agents in the organic environment. with an azodicarb ™ oxylate system. The phosphine / azodicarboxylate system may be considered as an oxidation-reduction system wherein the azodicarboxylate is reduced and the phosphine is oxidized to the corresponding oxide (Mitsunobu, O.; Yamada, Y. Hierve. Chem. Zoco.

° Japan 1967, 40, 2380-2382).

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In the context of this invention, the "" protecting group for alcohols "refers to those organic groups which serve to protect the alcohol groups from undesired reactions of synthetic processes. These include e.g. acetals, silicon ethers, ethers, esters, carbonate esters and sulfonic acid derivatives. More specific examples of protecting groups for alcohols are (trimethylsilicon) ethoxymethyl (SEM) and tert-methoxymethylbutyl (MOM).

By "-OH precursor" is meant any group which can be converted to the -OH group by the required chemical reactions and may be, in addition to the above examples, an ester group, an aldehyde, a carbonate, an Amine or an amide.

The "-0-RProt precursor" means a group which can be converted to the -0-Rprot group by the required chemical reactions.

"Precursor of the 4-tert-butylbenzenesulfonamide group" means any of the 10 groups which can be converted to 4-tert-butylbenzenesulfonamide by the required chemical reactions; such groups may include e.g. -OR6, -NR7R8, -NRgSAr, with an N-leaving group or halogen; wherein R e is H, R 10, -COOR 10, -COR 10, -SO 2 R 10, or -C (= NRh) NR 12 R 13; R 7 and R 8 are independently H or R 10, R 11, R 12 and R 13 are each independently H or R 10; R-ιοοη group 15 C 1 -C 7 alkyl, C 1 -C 7 substituted alkyl, aryl group or substituted aryl group.

In the invention, a C 1 -C 7 alkyl group means a linear or branched alkyl group having up to seven carbon atoms. Thus, it includes e.g. methyl group, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1,2-dimethylbutyl. 1,1-dimethylpropyl, 2,2-dimethylprop-20-yl, 2-ethylpropyl, n-hexyl, 1,2-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1-ethyl-2-methylpropyl and 1-methyl-2-ethylpropyl. They can also occur as cyclic radicals. These groups may optionally be substituted.

The use of the term "aryl" (Ar) is defined in each case as such containing from 3 to 12 carbon atoms, preferably from 6 to 12 carbon atoms, such as, for example, cyclopropyl 9 penyl, phenyl, tropyl, indenyl, naphthyl, azalenyl, biphenyl, fluorenyl, ant

C \ J

cvj racenyl, etc., preferably phenyl. The aryl group may optionally be substituted.

CC

In the invention, the term '' optionally substituted 'refers to a group such as C 1-10 g C 7 alkyl, aryl or halogen, which may be substituted with one or more K 30 substituents; with one, two, three or four substituents, preferably one, two or three substituents, or more preferably one or two substituents, provided that there are sufficient substituents on the group. The substituents may be the same or different and may be placed at any free position.

13

In the present invention, halogen means an element selected from the group consisting of F, Cl, Br or I. Phosphine refers to those substituted phosphorus derivatives of the oxidation stage III having the structure P (R) 3 wherein the substituents may be independently of, but not limited to, said groups; A C 1 -C 2 alkyl or 5 aryl group.

In the present invention, azodicarboxylate refers to those compounds which have the functional group of azodicarbonyl -CO-N = N-CO-. The chemical processes known are those routine chemical changes that are generally known in the art.

10 Moderate temperatures refer to temperatures below 100 ° C.

The term "organic solvent" as used herein refers to any organic compound or mixture of organic compounds capable of Mitsunobu-type coupling. Examples include alcohols such as ethanol and isopropanol, hydrocarbons, halogenated compounds, ethers and acetone. Organic solvents include 15 mm. benzene, toluene, diethyl ether, chloroform, ethyl acetate, 1,4-dioxane, tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile (MeCN), dimethylformamide (DMF), dimethylsulfoxide (DMSO), polar protic solvents nanol, isopropanol (IPA), n-propanol, ethanol, methanol and dichloromethane.

EXAMPLES

20 Process for the manufacture of the starting product; Preparation of 4-tert-Butyl-N- [6-hydroxy-5- (2-methoxy-phenoxy) -2- (2-pyrimidinyl) -pyrimidin-4-yl] -benzenesulfonamide In a 250 mL ball flask was charged 5 g (9.51 mmol) 4-tert-Butyl-N- [6-hydroxy-5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yl] benzenesulfonamide and 90 mL toluene. The contents were shaken for 5 minutes and 7.60 g of NaOH (190.1 £ 25 mmol) and 2.45 g of tetrabutylammonium bromide (7.60 mmol) were added. The mixture was maintained at room temperature for 48 hours. Thereafter, 45 ml of toluene were distilled off and 17 ml x Fe 2 O was added. After the addition of H2O, the mixture was refluxed for one hour,

CC

Followed by the addition of 33 ml of 6 M HCl. The suspension thus obtained was filtered. The resultant solid was dissolved in 30 mL of H 2 O for 30 minutes at 50 ° C at 30 ° C. The dissolved solid was purified by a mixture of acetonitrile and toluene.

3.71 g of material with a purity above 95% by HPLC were obtained.

14

Example 1: Preparation of 4-tert-butyl-N- [6-hydroxy-5- (2-methoxyphenoxy) -2- (2-pyrimidin-yl) pyrimidin-4-yl] benzenesulfonamide, bosentan.

To a suspension of 10 g (1.97 mmol) of 4-tert-butyl-N- [6-hydroxy-5- (2-methoxy-phenoxy) -2- (2-pyrimidinyl) -pyrimidin-4-yl] -benzenesulfonamide; 7.75 g (29.6 5 mmol) triphenylphosphine in 60 mL acetonitrile was added 2.2 mL (39.5 mmol) ethylene glycol and heated to reflux temperature. Subsequently, 5.8 ml of isopropyl azodicarboxylate (29.6 mmol) was added, after which the reaction mixture was left on the shaker at the same temperature for 2 hours. After 2 hours, the mixture was evaporated to dryness. The residue was crystallized from 10 ml of ethanol to give 3.3 g of a solid yellow solid (81.3% bosentan, 0.8% impurity V by HPLC).

Example 2: Preparation of 4-tert-butyl-N- [6-hydroxy-5- (2-methoxyphenoxy) -2- (2-pyrimidin-yl) pyrimidin-4-yl] benzenesulfonamide, bosentan.

To a suspension of 1 g (1.97 mmol) of 4-tert-butyl-N- [6-hydroxy-5- (2-methoxy-15-phenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yl] benzenesulfonamide In 6 mL of dichloromethane, 0.6 mL (2.36 mmol) of tributylphosphine and 0.1 mL of ethylene glycol (1.97 mmol) were added and heated to reflux temperature. At this temperature, 0.60 g (2.36 mmol, 1.2 eq) of 1,1 '- (azodicarbonyl) dipiperidine was added. After the addition, the reaction mixture was kept at the same temperature for 20 hours, after which it was evaporated to dryness. The material was 24.5% bosentan and 0.9% impurity by HPLC.

Example 3: Preparation of 4-tert-butyl-N- [6-hydroxy-5- (2-methoxyphenoxy) -2- (2-pyrimidin-1-yl) pyrimidin-4-yl] benzenesulfonamide, bosentan.

Into a balloon flask was charged 2 g (3.94 mmol) of 4-tert-butyl-N- [6-hydroxy-5- (2-methoxyphenyl) oxy] -2- (2-pyrimidinyl) pyrimidin-4-yl] benzenesulfonamide, , 55 g (5.91 mmol) of 9 triphenylphosphine and 1 g (3.94 mmol) of bis- (2-hydroxyethyl) terephthalate in 8 mL

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of acetonitrile and heated to reflux temperature, then 1.16 mL of DIAD (5.91 mmol) was added. The solution thus obtained was left on the shaker at the same temperature for 24 hours. Thereafter, 3 ml of water was added, the mixture was cooled to 0 ° C and 3 ml of a 2N aqueous KOH solution were added. The mixture was shaken for 30 min.

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noodles, 6 ml of toluene was added and the mixture was left on a shaker. The phases were separated, the organic phase was brought to room temperature and extracted with 24 ml of a 5: 1 solution of H2O: acetonitrile. The aqueous phase was treated with 20 mL of toluene and 6N aqueous HCl at 40 ° C for 30 minutes. The resulting toluene phase was evaporated to dryness to give an impure residue containing 7.3% bosentan by HPLC.

Example 4: Preparation of 4-tert-butyl-N- [6-hydroxy-5- (2-methoxyphenoxy) -2- (2-pyrimidin-yl) pyrimidin-4-yl] benzenesulfonamide, bosentan.

To a suspension of 1 g (1.97 mmol) of 4-tert-butyl-N- [6-hydroxy-5- (2-methoxy-phenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yl of benzenesulfonamide in 6 mL of acetonitrile, 0.62 mL (2.36 mmol) triphenylphosphine and 0.1 mL ethylene glycol (1.97 mmol) were added and heated to reflux temperature. At this temperature, 1.1 ml (2.35 mmol) of diethyl azodicarboxylate was added. After the addition, the reaction mixture was kept at the same temperature for 20 hours. The mixture was then evaporated to dryness to give a material which was 49.3% bosentan by HPLC and 1.4% impurity.

Example 5: Preparation of 4-tert-Butyl-N- [6-hydroxy-5- (2-methoxyphenoxy) -2- (2-pyrimidin-1-yl) pyrimidin-4-yl] benzenesulfonamide, bosentan monohydrate.

(a) Manufacture of bosentan technical

To a suspension of 800 g (1.58 mol) of 4-tert-butyl-N- [6-hydroxy-5- (2-methoxy-phenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yl] Benzenesulfonamide In 2.4 L of acetonitrile, 620 g (2.36 mol) triphenylphosphine and 176 ml ethylene glycol (3.15 mol) were added and heated to reflux temperature. 480 ml (2.44 mol) of isopropyl azodicarboxylate were then added, after which the reaction mixture was left on the shaker at the same temperature for 10 minutes and then cooled by shaking for 1.5 hours. The resulting solid was removed by filtration and the filtered liquid made basic with 1N KOH. Two → 25 extractions were performed with toluene and the aqueous phase thus obtained was treated with 6N HCl. The aqueous solution was left on the shaker 9 for 12 hours, during which time it precipitated strongly. The solid thus obtained

CNJ

The filtrate was filtered and rinsed with water and subsequently dried at 30 ° C.

| This gave 337 g of bosentan technical (74.3% bosentan and 7.2% impurity by HPLC).

C/O

o cu 30 (b) Preparation of bosentan monohydrate δ

CVJ

The material produced in a) was recrystallized three times in ethanol-water (1: 1) to give 190 g of bosentan monohydrate (94.2% bosentan and 0.1% impurity by HPLC). Karl-Fisher: 2.5-3.5% H2O. 1 H-NMR

16 (CDCl 3, 300 MHz) δ 9.04, d, 2H, J = 4.9 Hz; 8.43, d, 2H, J = 8.1 Hz; 7.40-7.50, m; 7.44, d, 2H, J = 8.4 Hz; 7.13, t, J = 7.7 Hz; 7.07, d, J = 8 Hz; 6.99, d, J = 7.6 Hz; 6.88, t, J = 7.5 Hz; 4.61, t, 2H J = 3.9 Hz; 3.94: s: 3H; 3.86, t, 2H J = 3.9 Hz; 1.29, s, 9H.

Example 6: Pharmaceutical composition of bosentan monohydrate, coated tablet

One possible composition of a bosentan coated tablet may be formulated with the following excipients in the ranges mentioned below.

Compound __% of tablet weight

Maissitärkkelys__25-35_

Pregelatinised starch__7-15_

Natriumglykolaattitärkkelys __ ^ 8_

Povidoni__1-5_

Glyserolidibehenaatti__1-5_

Magnesiumstearaatti__0,2-1,0_

Bosentan Monohydrate The coating may be formulated with conventional excipients such as hypromellose, glycerol triacetate, talc, titanium dioxide, iron (III) oxide or ethyl cellulose, and is estimated at 1-4% by weight.

The average particle diameter of the bosentan monohydrate used may be less than 100 μιτι. This pharmaceutical composition can be produced by methods known to the person skilled in the art, such as dry granulation.

Particle Size Distribution Analysis: The size distribution of the bosentan particle was observed on a Malvern laser diffraction apparatus (Malvern Mastersizer 2000): R 1 = (1.529, o ^ 1), dispersant R 1 = 1.330 (Water); Position: General Purpose; Speed: 00 2,500 rpm; Dispersant: Water + 0.2% Nonidet P40 (20: 0.5).

CC

CL

20

C/O

C/O

o m c \ j δ c \ j

Claims (14)

A process for the preparation of a compound of formula (I), or a salt or solvate thereof, including a hydrate: ????????? NH? , preferably R 1 is -CH 2 CH 2 OH, R 2 is -O-Rprot, -OH precursor -O-Rprot precursor, and Rprot is a protecting group for alcohols, which is formed by a Mitsunobu-type linkage between a compound of formula HO -R 1 and a compound of formula (II) or a salt thereof: wherein R 3 is a 4-tert-butylbenzenesulfonamide group, a precursor of a 4-tert-butylbenzene sulphonamide group, or a group that is convertible to a 4-tert-butylbenzene-cis sulfonamide group. CC The process of claim 1, wherein R 1 is -CH 2 CH 2 OH. The process according to claim 3 or 2, wherein R 3 is a benzenesulfonamide group of 4-tert-butyl-CVJ 5. CVJ The process of any one of claims 1 to 3, wherein the Mitsu-Nobu-type coupling takes place in the presence of at least one phosphine and at least one azodicarbonyl. The process of claim 4 wherein the phosphine is a compound of formula (III): R 4 (III) wherein each of the three R 4 groups is independently an aryl group, substituted aryl, O-aryl, O-substituted aryl, Cyalkyl, C 1 -C 7 substituted al-10 alkyl, O (C 1 -C 7 alkyl) or O (C 1 -C 7 substituted alkyl). The process of claim 5, wherein the compound of formula (III) is triphenylphosphine, tributylphosphine or diphenylpyridylphosphine, preferably triphenylphosphine. The process of any one of claims 4 to 6, wherein the azodicarbonyl is a compound of formula (IV): R5An'-V5O 2 CV) δ 4 each of which R 5 is independently O (C 1 -C 7 alkyl), O (C 1 -C 7 substituted alkyl), O-aryl, O-substituted aryl, OCH 2 -aryl, OCH 2-substituted c 1 aryl, N (C 1 -C 7 alkyl) 2 or N (C 1 -C 7 substituted alkyl) 2. CC A process according to claim 7, wherein the compound of formula (IV) is diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate or 1,1 '- (azodicarbonyl) dipiperidine, preferably azodicarboxylate. The process of any one of claims 1 to 8, wherein coupling to the Mitsu-Nobu type occurs in the presence of at least one organic solvent. The process according to claim 9, wherein the organic solvent is aceto-nitrile, tetrahydrofuran, 2-methyltetrahydrofuran, Ν, Ν-dimethylformamide, dichloromethane or any mixture thereof, preferably acetonitrile. The process of any one of claims 1-3 or 10, wherein Rprot is one of the following groups: acetal, silicon ether, ester, carbonate or sulfonic acid derivative. The process according to any one of claims 1 to 11, wherein the Mitsunobu-type coupling is carried out at a temperature of about 20 ° C to 150 ° C, preferably 40 ° C to 120 ° C and more preferably 60 ° C to 90 ° C. C temperature. A process according to any one of claims 1 to 12, wherein the compound of formula (I) is bosentan, preferably bosentan monohydrate. The process of any one of claims 13, further comprising the step of reducing the mean diameter of the bosentan particle to less than 100 µm. 't δ c \ j o C \ l CM X cc CL CO CO o m CM δ CM