MXPA06009399A - Chemical process - Google Patents

Abstract

Process for preparing compounds of Formula (I);and (IV);are described.

Description

CHEMICAL PROCESS The present invention relates to an improved chemical process for preparing intermediates. Certain of these intermediates are useful in the manufacture of compounds that are useful, for example, in the treatment of cancer, pain and cardiovascular diseases in a warm-blooded animal, such as a man; particularly, it refers to compounds that possess endothelin receptor antagonist activity. In particular, the present invention relates to a chemical process for preparing [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid, which is used in the manufacture of, N- (3-methoxy) -5-methylpyrazin-2-yl) -2- (4- [1, 3,4-oxadiazol-2-yl] pheny] pyridine-3-sulfonamide, which compound is described as Example 36 of the application of international patent WO96 / 40681. This compound possesses endothelin receptor antagonist activity, and accordingly it is useful wherever this antagonistic activity is seen, such as for research tools in pharmacological studies, diagnostics and related studies, or in the treatment of diseases and conditions. These include, but are not limited to, hypertension, pulmonary hypertension, cardiac or cerebral circulatory disease, and kidney disease. In addition, this compound is also useful in the treatment of cancer and pain in a warm-blooded animal, such as a man. A way to prepare N _- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1, 3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide is described in the applications International Patent WO 96/40681 and WO 98/40332. The route involves the use of the compound N _- (3-methoxy-5-methylpyrazin-2-yl) pyridine-3-sulfonamide as an intermediate product, with the formation of 1,4-oxadiazole at position 4 of the phenyl group at the end of the synthesis. This existing route is satisfactory for the synthesis of relatively small amounts of N- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1, 3,4-oxadiazole-2-yl] phenyl) pyridine-3-sulfonamide, but it is a linear rather than a convergent synthesis, and involves the isolation of a substantial amount of intermediate products. As such, the total yield of this synthesis is not high. Additionally, since the heteroaryl portion in the 4-position of the phenyl group is formed in the last step, it is necessary that a linear synthesis approach is first applied to the rest of the molecule. This is clearly undesirable when substituents in different parts of the molecule have to be varied in order to investigate structure-activity relationships. It would be highly desirable if a convergent approach for the synthesis of this type of compound could be conceived. This would be of significant benefit in the manufacturing efficiency of large-scale quantities of N _- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1, 3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide. Now we have devised a much improved process for the manufacture of heteroaryl-phenyl boronic acids, in particular, [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid. The process allows the exploitation of a more convergent route for the N _- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1, 3,4-oxadiazol-2-yl] phenyl) pyridine -3- sulfonamide than the previously described route, and allows a reduction in the amount of intermediate products that must be isolated. This provides significant advantages in manufacturing time and cost. In a further aspect of the present invention, one of the heteroaryl phenyl boronic acids, [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid, produced in accordance with the present invention, is used to prepare N .- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1, 3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamides? / - protected, in particular N- (isobuti I carbon il) N- (3-methoxy-5-methy1pyzin-2-yl) -2- (4- [1,3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide . These intermediates can then be deprotected to form N _- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1, 3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide . The process for the manufacture of the heteroaryl phenyl boronic acids of the present invention utilizes the increased acidity of the heteroaryl ring proton., and involves the sequential use of two bases. Initial attempts to add an equivalent of a base to a bromoaryl heteroaryl phenyl compound, in order to induce halogen-metal exchange lead to competitive deprotonation of the heteroaryl ring. Upon quenching the reaction with a borated ester, a negligible amount of the product was obtained, together with starting material and by-products. The present inventors found, surprisingly, that the sequential use of two bases results in good yields of the desired heteroaryl phenyl boronic acids. In the process of the present invention, the heteroaryl ring is initially deprotonated with a (typically) "weaker" base, before inducing the halogen-metal exchange with a (typically) "stronger" base. According to a first aspect of the present invention, there is provided a process for the preparation of a compound of Formula I wherein, Xi is selected from O, N R-i or S; and X2 is selected from CH or N; wherein F is a nitrogen protecting group, which comprises: the sequential reaction of a compound of the Formula (D with, (i) methyl- or an optionally substituted aryl, and then (ii) n-butyl-, s-butyl-, t-butyl or n-hexyl lithium, and then (iii) an ester For the process steps (i), (i) and (iii), the reactions can be conveniently carried out in an inert solvent or diluent or in an ethereal solvent, such as diethyl ether, tetrahydrofuran, diethoxymethane, and the like. , 2-dimethoxyethane or 1,4-dioxane.

Thus, for example, the reaction can be carried out by sequential treatment of 2- (4-bromophenyl) -1, 3,4-oxadiazole with 4-methylphenyllithium, followed by n-hexylthio, and finally triisopropylborate in a solvent or diluent. suitable, for example, an ethereal solvent such as tetrahydrofuran, for example at a temperature in the range from -90 to -50 ° C, more particularly from -70 to -55 ° C, conveniently at or near -70 ° C. Optionally, the bromo heteroaryl phenyl compound of formula II can be charged to a solution of the first base to allow deprotonation, followed by the addition of the second base to induce transmetallation. This method, although it is slightly less efficient in performance and quality, has advantages in cases where the first base has to be generated in situ due to the lack of stability at ambient temperatures. In this case, only a cryogenic vessel is required to complete the processing. The molar proportions of the reagents used in steps (i), (ii) and (iii) of the process are preferably in the range of 1.0-1.5: 1.0-1.5: 2.1-3 respectively, but more preferably in the range of 1.06-1.3: 1.07-1.1: 2.2-2.3 respectively. Conveniently, the lithiated intermediates formed during the conversion of the compounds of Formula II into the compounds of Formula I are not isolated as such, but each is prepared and used as a solution in an organic solvent. Therefore, the compounds of Formula I can be manufactured from compounds of Formula II in a single container process. An aryl lithium, for example, is phenyl- or n-aft I-lithium. An optional substituent for an aryl lithium, for example, is methyl. Particularly preferred optionally substituted aryl lithiums are, for example, phenyl-, 2-methylphenyl, 4-methylphenyl-, mesityl- or naphthyl-lithium. A borated ester is an alkyl, alkenyl or aryl boronic ester, for example, trimethyl-, triethyl- or triisopropyl-borate. When R1 is a nitrogen protecting group, then, for example, the appropriate methods for protection are those that are familiar to those skilled in the art. Conventional protecting groups can be used in accordance with standard practice (for further illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). An appropriate nitrogen protecting group, R, for example, is an alkyl protecting group of 1 to 6 carbon atoms, phenyl, allyl, methoxymethyl, benzyl, triphenylmethyl or diphenylphosphinyl. This first aspect of the present invention provides compounds of Formula I in commercially acceptable and high quality yields. Additional values of X1 and X2 are as follows. Such values may be used where appropriate with any definitions, claims or modalities defined hereinbefore or later.

X2 is CH X2 is N.

X! is NR1 and X2 is CH. X-, is NR1 and X2 is N.

R-i is allyl or benzyl. R-i is benzyl. Therefore, in a further aspect of the invention, a process for the preparation of compounds of the formula I is provided. wherein, X-i is selected from O, R-¡or S; and X2 is selected from CH or N; wherein Ri is a nitrogen protecting group; Which comprises: the sequential reaction of compounds of the Formula with, (i) 4-methylphenyllithium; and then (ii) n-hexyl lithium; and then (ii) triisopropylborate. In a further aspect of the invention, a process for the preparation of compounds of Formula I is provided where Xi is selected from O, NRi or S; and X2 is selected from CH or N; wherein R-, is a nitrogen protecting group; which comprises: the sequential reaction of compounds of Formula II with, (i) 4-methylphenyl lithium; and then (ii) n-hexyl lithium; and then (ii) triisopropylborate. In a further aspect of the invention there is provided a process for the preparation of compounds of Formula I where, X2 is N; which comprises: the sequential reaction of compounds of the Formula with (i) methyl lithium; and then (ii) n-butyllithium; and then (ii) triisopropylborate. In a further aspect of the invention, it is provided for the preparation of compounds of Formula I, where Xi is O; and X2 is N; which comprises: the sequential reaction of the compounds of the Formula with, (i) 4-methylphenyllithium; and then (ii) n-butyllithium; and then (ii) triisopropylborate.

The compounds of Formula II can be prepared according to the experimental methods and procedures described in Bioorganic & Medicinal Chemistry Letters, 2002, 12 (20), 2879-2882; Eur. J. Med. Chem., 2000, 35, 157-162; Helvetica Chimica Acta, 1950, 33, 1271-1276; Eur .J. Med. Chem., 1985, 20 (3), 257-66 and J. Het. Chem., 1989, 26, 1341. A further aspect of the present invention provides the use of [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid, prepared according to the present invention, for the preparation of compounds of Formula IV, which are useful intermediates for the preparation of N- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1,3,4-oxadiazole- 2-yl] phenyl) pyridine-3-sulfonamide, N - (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1, 3,4-oxadiazol-2-yl] phenyl) pyridine -3-sulfonamide is prepared by deprotecting the compounds of formula IV. In this aspect of the invention, [4- (1,3,4-oxadiazol-2-yl) phenyl] boronic acid is coupled with the compounds of Formula III to form compounds of Formula IV.

Particularly, this reaction takes place in an aqueous solvent, for example methanol, ethanol, isopropanol, industrial methylated spirit (IMS), isobutanol, NMP (N-methylpyrrolidinone), DMF; with or without an organic phase, for example toluene or xylenes at a temperature for example in the range from 60 to 100 ° C, more particularly from 75 to 85 ° C, in the presence of: (i) boronic acid (ii) an appropriate source of palladium (0), for example PdCI2, Pd (Ph3P) 4 or Pd (OAc) 2; (iii) an appropriate ligand, for example triphenylphosphine or trisodium salt of 3,3'3"-phosphidyne tris (benzenesulfonic acid); (iv) a base, for example triethylamine, benzyldimethylamine, N-methylmorpholine, N-methylpiperidine, triethanolamine, ethyldiethanolamine, diisopropylethylamine, potassium acetate, cesium fluoride or potassium fluoride Particularly, the palladium source is palladium acetate Particularly, the base is N-methylmorpholine In another aspect, particularly the base is triethylamine. it takes place in an aqueous solvent without an organic phase In another aspect, particularly this reaction takes place in an aqueous solvent with an organic phase Where this reaction takes place in an aqueous solvent with an organic phase, particularly the organic phase contains toluene In another aspect of the present invention, wherein this reaction takes place in an aqueous solvent with an organic phase, particularly the organic phase. a contains xylene. In another aspect, this reaction takes place more specifically in the presence of palladium acetate, trisodium salt of 3,3'3"-phosphidin tris (benzenesulfonic acid), N-methylmorpholine in water and isopropanol In another aspect, this reaction has place more specifically in the presence of palladium acetate, trisodium acid salt 3, 3'3"-fosfidino tris (benzenesulfonic), triethylamine, xylene, water and IMS The molar proportions of the reagents used in process steps (i), (ii), (iii) and (iv) are preferably in the range of 1.0-2.0: 0.02-0.3: 0.06-0.9: 1.5-5.0 respectively, but more preferably in the range of 1.4-1.6: 0.03-0.1: 0.09-0.3: 2.0-3.0, respectively. Formula III or Formula IV, P is a nitrogen protecting group Appropriate methods for protection are those familiar to those skilled in the art Conventional protecting groups can be used in accordance with standard practice (for greater illustration, see TW Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991.) An appropriate value for P, for example, is an acyl group, for example an alkanoyl group of 1 to 6 carbon atoms, such as acetyl.; an aroyl group, for example benzoyl; an alkoxycarbonyl group having 1 to 6 carbon atoms, for example a methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl; an arylmethoxycarbonyl group, for example benzyloxycarbonyl; a phosphinyl group, for example diphenylphosphilnil; a benzyl group or an alkenyl group of 2 to 6 carbon atoms, such as allyl. An appropriate value for P is an alkoxycarbonyl group of 1 to 6 carbon atoms. Most appropriate values for P are a methoxycarbonyl, ethoxycarbonyl or isobutoxycarbonyl group. More specifically, a value for P is isobutoxycarbonyl. The deprotection conditions for the nitrogen protecting groups described herein, necessarily vary with the choice of the protecting group. Thus, for example, an acyl group such as an alkanoyl group of 1 to 6 carbon atoms or an alkoxycarbonyl group of 1 to 6 carbon atoms or an aroyl group can be removed, for example, by hydrolysis with an appropriate base such as an alkali metal hydroxide, for example lithium or sodium hydroxide or an amine, for example ammonia. Alternatively, an alkoxycarbonyl group such as a t-butoxycarbonyl group can be removed, for example, by treatment with an appropriate acid such as hydrochloric, sulfuric or phosphoric acid, or a trifluoroacetic acid and an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group, can be removed. , for example, by hydrogenation on a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example boron tris (trifluoroacetate). A phosphinyl group can be removed by basic hydrolysis, such as an alkali metal hydroxide, for example lithium or sodium hydroxide or an amine, for example ammonia. A benzyl group can be removed by hydrogenation on a catalyst such as palladium on carbon. An alkenyl group of 2 to 6 carbon atoms such as allyl can be removed by hydrolysis assisted by palladium. In a further aspect of the invention, there is provided a process for preparing a compound of Formula IV, which comprises reacting [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid, with a compound of Formula III. In a further aspect of the invention, there is provided a process for preparing a compound of Formula IV, which comprises reacting [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid, prepared in accordance with the present invention, with a compound of Formula III. In this aspect of the invention, more specifically, the invention provides the use of [4- (1, 3,4-oxadiazoI-2-yl) phenyl] boronic acid, prepared according to the present invention, for the preparation of N _- (isobutoxycarbonyl) N _- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1,3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide, a compound of the formula IV and an intermediate useful in the preparation of j \ |- (3-methoxy-5-methylpyrrazin-2-yl) -2- (4- [1, 3,4- oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide. In this aspect of the invention, [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid is coupled with h- (isobutoxycarbonyl) -2-chloro-j ^ - (3-methoxy) -5-methylpyrazin-2-yl) pyridine-3-sulfonamide, to form N- (isobutoxycarbonyl) N _- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1, 3,4 -oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide. The preparation of N _- (isobutoxycarbonyl) -2-chloro-N- (3-methoxy-5-methylpyrazin-2-yl) -pyridine-3-sulfonamide is described in Example 1 of WO96 / 40681. Thus, according to this aspect of the invention, there is provided a process for preparing N- (isobutoxycarbonyl) - (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1 , 3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide, which comprises coupling [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid, with JN- (isobutoxycarbonyl) -2-chloro-j \ J _- (3-methoxy-5-methylpyrazin-2-yl) pyridine-3-sulfonamide. Therefore, in a further aspect of the invention, the use of [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid is provided., in the preparation of j \ - (isobutoxycarbonyl) jNj .- (3-methoxy-5-methylprazrazin-2-yl) -2- (4- [1, 3,4-oxadiazol- 2-yl] phenyl) pyridine-3-sulfonamide. In a further aspect of the invention, there is provided the use of [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid, prepared according to the process of the present invention, in the preparation of N .- (isobutoxycarbonyl) hJ- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1, 3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide. In a further aspect of the invention, a compound of Formula IV is provided. In a further aspect of the invention, a compound of Formula IV is provided. In a further aspect of the invention, it is provided I - (isobutoxycarbonyl) j - (3-methoxy-5-methypyrazin-2-yl) -2- (4- [1, 3,4-oxadiazol-2-yl] phenyl) pyridine- 3-sulfonamide. In a further aspect of the invention, there is provided the use of N _- (isobutoxycarbonyl) j ^ .- (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1, 3,4-oxadiazole- 2-yl] phenyl) pyridine-3-sulfonamide in the preparation of N _- (3-methoxy-5-methy1-pyrazin-2-yl) -2- (4- [1, 3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide. The invention will now be illustrated by the following non-limiting examples, in which, unless otherwise specified: (i) the returns are directed to the reader's assistance only, and are not necessarily the maximum obtainable through the diligent development process; (ii) NMR spectra with 1H were determined at 270 MHz or 400 MHz in DMSOd6 using tetramethylsilane (TMS) as internal standard, and are expressed as chemical changes (delta values) in parts per million in relation to TMS using conventional abbreviations for the designation of principal peaks; s, singlet; m, multiplet; t, triplet; br, broad; d, duplete.

EXAMPLE 1 ACID r4- (1.3.4-OXAD1AZOL-2-IL, PHENYL, BORONIC) A solution of methyllithium (8% w / w in diethoxymethane) (65 mL) was added to a suspension of 2- (4-bromophenyl) - 1, 3,4-oxadiazole (40 g) in tetrahydrofuran (THF) (425 mL at -65 ° C. After one hour, a solution of n-butyllithium (2.5M in hexanes) (78 mL) was added to -65 ° C. After one hour, triisopropylborate (90 mL) was added, keeping the reaction mixture at -65 ° C. The reaction mixture was maintained at -65 ° C. for one hour, and then The mixture was heated to -20 ° C and was poured into a mixture of acetic acid (28 mL) in water (222 mL), the resulting solid was isolated, washed with THF and water, and dried to give the base compound (28.96 ga 95.1%, weight / weight, 82%). NMR spectrum at 400 MHz: (DMSOd.) 8.00 (s, 4H), 8.31 (s, 2H), 9. 35 (s, 1H); Mass spectrum MH + 191.0628 (calculated using 11-B). Found 191.0633. The 2- (4-bromophenyl-1, 3,4-oxadiazole used as starting material was prepared as follows: To a 4-bromobenzoic hydrazide suspension (200 g) in industrial methylated spirit (700 mL), triethyl ortho-formate (309) was added. mL), methylated industrial spirit (100 mL), and sulfuric acid (0.8 mL) The reaction mixture was heated to reflux for 1 hour, the reaction mixture was cooled to 0.5 ° C and the product was crystallized. The product was isolated, washed and dried to give 2- (4-bromophenyl-1,3,4-oxadiazole (186.1 g, 89.9%) NMR spectrum with 400 MHz: (DMSOd6) 9.35 (s, 1H), 7.98 (d, 1H), 7.95 (d, 1H), 7.84 (d, 1H), 7.81 (d, 1H); Mass spectrum MH + 224.9663 (calculated using 79-Br) Found 224.9701.

EXAMPLE 2 ACID .4-M, 3.4-OXADIAZOL-2-IDFENIL. BORÓNICO Lithium (8.2 g) and tetrahydrofuran (670 g) granules were charged to a reactor under an argon atmosphere, and the mixture was cooled to -35 ° C. 4-Chlorotoluene (74.3 g) was added at -35 ° C and the mixture was kept at this temperature for 6 hours. The resulting solution was added to a suspension of 2- (4-bromophenyl) -1,3,4-oxadiazole (124.4 g) in tetrahydrofuran (800 g) at -65 ° C. After 30 minutes, a solution of n-hexyl lithium (33% w / w in hexanes) (240 mL) was added at -65 ° C. After an additional 30 min, triisopropylborate (230.8 g) was added, maintaining the reaction mixture at -65 ° C. The reaction mixture was allowed to warm to -35 ° C and was emptied into a solution of acetic acid (91.5 g) in water (688 g). The resulting solid was isolated, washed with THF and water, and dried to yield the base compound (92.2 g, 88%).

EXAMPLE 3 ACID T4- (1.3.4-OXADIAZOL-2-IDFENIL1 BORÓNICO Example 2 was repeated, but the charge of 4-chlorotoluene was increased from 1.06 moles to 1.30 moles. The yield of the base compound increased to 89.3%.

EXAMPLE 4 ACID .4-.1.3.4-OXADIAZOL-2-IL.FENIL1 BORÓNICO Tetrahydrofuran (250 g) was charged to a mixture of lithium granules (3.02 g) and biphenyl (0.01 g) under an argon atmosphere and the mixture was cooled to -30"C. 2-chlorotoluene (27.55 g) was slowly added. ) at -30 ° C. The reaction was maintained at -30 ° C for 6 hours, and then cooled to -65 ° C. A mixture of 2- (4-bromophenyl-1, 3,4-oxadiazole (50 g) in THF (300 g) was added slowly at -65 ° C. The reaction was maintained at -65 ° C for 30 minutes , then a solution of n-hexyllithium (33% w / w in hexanes, 86 mL) was added at -65 ° C. The reaction was maintained at 65 ° C for 30 minutes, and then trimethyl borate (48.7 g) was added. at -65 ° C. The reaction was maintained at -65 ° C. for 10 minutes, then methanol (55.3 g) was added followed by 4-methyl-2-pentanone (240 g). The reaction mixture was heated and The solvents were distilled with low boiling point under vacuum, up to a maximum temperature of 55 ° C. The residual mixture was cooled to 0 ° C. and 10% w / w sulfuric acid (92 g) was added followed by water ( 92 g), while maintaining the temperature below 7 ° C. The product was precipitated, the pH was adjusted to 6.5 by the addition of more than 10% w / w of sulfuric acid (85.3 g). up to 40 ° C, then cooled again to 5-10 ° C. The product was isolated and washed with THF (56 g) and water (60 g), yielding the wet base compound (25.2 g, 60%).

EXAMPLE 5 ACID T4- (1.3.4-OXADIAZOL-2-IDFENIL1 BORÓNICO Tetrahydrofuran was charged to lithium pellets (7.6 g) under an argon atmosphere, and the mixture was cooled to -30 ° C. 2-Chlorotoluene (69.4 g) was slowly added at -30 ° C. The reaction was maintained at -30 ° C for 6 hours, then it was added to a suspension of 2- (4-bromophenyl) -1,4,4-oxadiazole (124.4 g) in tetrahydrofuran (800 g) at -65 ° C. . The reaction was maintained at -65 ° C for 30 minutes, and then a solution of n-hexyl lithium (33% w / w in hexanes, 245 mL) was added at -65 ° C. The reaction was maintained at -65 ° C for 30 minutes, and then trimethyl borate (230.8 g) was added at -65 ° C. The reaction was maintained at -65 ° C for 30 minutes, then methanol (175 mL) was added followed by 4-methyI-2-pentanone (600 g). The reaction mixture was heated and the solvents were distilled at low boiling point, under vacuum, at a maximum temperature of 50 ° C. The reaction mixture was cooled to 5-10 ° C, and the pH was adjusted to 6.5 by the addition of 5% w / w sulfuric acid (990.5 g). The product was precipitated. The mixture was heated to 40 ° C, then cooled again to 10 ° C. The product was isolated, washed with THF and water, and dried, yielding the base compound (79.3 g, 75.5%).

EXAMPLE 6 ACID _4- (1, 3,4-OXAPIAZOL-2-BORONIC IL-PHENYL 1 Example 4 was repeated but chlorobenzene (61.6 g) was used in place of 2-chlorotoluene The isolated yield of the base compound was 87.8 g (83.8 g) %).

EXAMPLE 7 N- (ISOBUTOXICARBONIL N- (3-METOXY-3-METLLPIRAZIN-2-IL) -2.4- p.3.4-OXADIAZOL-2-FENIL ILT) PYRIDINE-3-SULFON AMIDE Palladium acetate (0.4144 g) and trisodium salt of 3,3'3"-phosphidine tris (benzenesulfonic acid) 30% w / w were dissolved in aqueous solution (3.26 g), in water (35 mL), for 6 minutes in an ultrasonic bath.The yellow solution was added to a stirred suspension of [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid (10 g) and [(2-chloropyridin-3-yl) sulfonyl] ] 3-methoxy-5-methylpyrazin-2-yl) isobutyl carbamate (16.86 g) in xylene (100 mL), methylated spirit (50 mL) and triethylamine (17 mL), then the bottle was washed with the solution of The reaction mixture was refluxed (80 ° C) in an oil bath (105 ° C) and stirred under reflux for 24.5 hours. The reaction was filtered to 30 ° C and filtered through a Whatman GF / B glass fiber filter paper, and the aqueous phase was separated.The reaction flask and the filter cake were washed with xylene (20 mL). The washing of xylene was used to r e-extract the aqueous phase The combined organic phases were stirred and heated by reflux (85 ° C) in a clean 500 mL flask with 4 necks, equipped with overhead stirrer, water condenser and nitrogen atmosphere. Essochem 30 solvent (Bp hydrocarbons 100-130 ° C) (100 mL) was added dropwise, for 6 minutes and the mixture was allowed to cool on its own to room temperature and then further cooled to 5 ° C for 1 hour. The product was filtered and washed with Essochem 30 solvent (50 mL). The cake was dried on the filter for 3 hours to give 15.20 g with 100% strength, yield of 76.8%. NMR spectrum with 1H at 270 MHz: 0.70 (d, 6H), 1.72 (m, 1H), 2.51 (s, 3H), 3.84 (d, 2H), 4.00 (s, 3H), 7.59 (m, 1H); 7.80 (d, 2H), 7.90 (s, 1H), 8.17 (d, 2H), 8.50 (s, 1H), 8.90 (m, 1H) and 9.00 (d, 1H). Mass spectrum MH + = 525.2 (C24H25N6O6S = 525.16).

EXAMPLE 8 N- (ISOBUTOXICARBONYL N- (3-METOXY-5-MEYLPYLZZIN-2-IL, -2 (4- p.3.4-OXADIAZOL-2-FINE ILL) PIRI DIN A-3-SULFON AMIDE To a 500 mL flask with multiple necks equipped with an overhead stirrer, purged with nitrogen, was charged [(2-chloropyridin-3-yl) sulfonyl] (3-methoxy-5-methylpyrazin-2-yl) carbamate from isobutyl (22.15 g), [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid (12.26 g), isopropanol (60 mL), water (140 mL) and trisodium acid salt 3.3 '3' -phosphidin tris (benzenesulfonic) 30% w / w in aqueous solution (13.7 g) The stirring was started and palladium acetate (0.541 g) was added after 10 minutes N-methylmorpholine (13.25 mL) was added. ) and the temperature was adjusted to 60 ° C.

After an additional 45 minutes, the mixture was filtered through a 1 μm glass fiber filter paper, and the aqueous phase was separated. The reaction flask and the filter cake were washed with toluene (22 mL). The toluene wash was used to re-extract the aqueous phase, and the organic layers were combined. These contained the base compound 822.8 g, 90%), which was not isolated.

EXAMPLE 9 N- (ISOBUTOXICARBONYL) N- (3-METOXY-5-METHYLPIRAZZ) N-2-IL) -2,4- M.3.4-OXADIAZOL-2-IL1 PHENYL) PIRI DIN A-3-SULFON AMIDA To a 150 mL flask with multiple necks equipped with an overhead stirrer, purged with nitrogen, was charged [(2-chloropyridin-3-yl) sulfonyl] (3-methoxy-5-methylpyrazin-2-yl) carbamate from! sobutyl (7.75 g), [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid (4.29 g), isopropanol (21 mL), water (49 mL) and 3-trisodium acid salt, 3'3"-phosphidine tris (benzenesulfonic) 30% w / w in aqueous solution (2.88 g) The stirring was started and palladium acetate (0.114 g) was added after 10 minutes, potassium fluoride (2.48 g) was added. g) and the temperature was adjusted to 60 ° C. After an additional 10 minutes, the mixture was filtered through a 1 μm glass fiber filter paper, and the aqueous phase was separated, the organic phase contained the base compound (7.36 g, 86%), which was not isolated.

Claims (13)

1. A process for the preparation of a compound of the Formula I where Xi is selected from O, NRi or S; and X2 is selected from CH or N; wherein R-t, is a nitrogen protecting group, which comprises: the sequential reaction of a compound of the Formula with, (i) methyl- or aryl-lithium optionally substituted; and then (ii) n-butyl-, s-butyl-, t-butyl or n-hexyl lithium; and then (ii) a borated ester.

2. The process according to claim 1, further characterized in that Xi is O.

3. The process according to claim 1 or 2, further characterized in that X2 is N.

4. The process according to any of claims 1 to 3, further characterized in that said methyl or substituted alkyl optionally is 4-methylphenyllithium or methyllithium.

5. The process according to any of claims 1 to 4, further characterized in that said n-butyl-, s-butyl-, t-butyl- or n-hexyl lithium is n-hexylityl or n-butyl lithium.

6. The process according to any of claims 1 to 5, further characterized in that said borated ester is triisopropylborate.

7. [4- (1, 3,4-Oxadiazol-2-yl) phenyl] boronic acid prepared by the process described in any of claims 1 to 6.

8. A process for preparing compounds of Formula IV: (IV) which comprises coupling [4- (1, 3,4-oxadiazol-2-yl) phenyl] boronic acid with a compound of Formula III: (ffl) wherein P is a nitrogen protecting group.

9. The process according to claim 8, which takes place in the presence of (i) an appropriate source of palladium (0), for example PdCI2, Pd (Ph3P) 4 or Pd (OAc) 2; (I) an appropriate ligand selected from triphenylphosphine or trisodium salt of 3,3'3"-phosphidino tris (benzenesulfonic acid); (iii) a base, for example triethylamine, benzyldimethylamine, N-methylmorpholine, N-methylpiperidine, triethanolamine, ethyldiethanolamine, diisopropylethylamine, potassium acetate, cesium fluoride or potassium fluoride 10.

The process according to claim 8 or claim 9, further characterized in that said acid [4- (1,3,4-oxadiazole-2) -il) phenyl] boronic acid is prepared according to the process described in any of claims 1 to 7.

The process according to any of claims 8 to 10, further characterized in that P is isobutoxycarbonyl.

12. A compound of Formula IV: wherein P is a nitrogen protecting group.

13. A compound of Formula IV as described in claim 11, which is Js [- (isobutoxycarbonyl) j - (3-methoxy-5-methylpyrazin-2-yl) -2- (4- [1, 3,4-oxadiazol-2-yl] phenyl) pyridine-3-sulfonamide.