PROCESS FOR PREPARING HALOGENATED AZAINDOLE COMPOUNDS USING BOROXINE

Abstract

A process for preparing halogenated azaindole compounds makes use of stable reagents including a brominating reagent, a boroxine and a sulfonic anhydride to enhance the selectivity and yield of the final product. In addition, the process is associated with various other advantages, including the ability to recycle reagents, cost reduction, and improved manufacturability.

Claims

1. A process for preparing a compound of formula I, ##STR00051## said process comprising the steps of: (a) performing an oxidation reaction on the compound ##STR00052## to yield the compound ##STR00053## (b) performing a bromination reaction in the presence of one or more boroxine compounds on the compound obtained in step (a) to obtain the compound ##STR00054## and (c) performing a deprotection reaction on the compound obtained in step (b) to obtain the compound of formula I above; wherein X.sup.1 is selected from the group of H, ##STR00055## and Y is Br.

2. The process of claim 1, wherein said oxidation reaction is carried out using oxidizing agents selected from the group of catalytic methyltrioxorhenium (MTO) and hydrogen peroxide urea complex (UHP), m-CPBA, a mixture of Ac.sub.2O and H.sub.2O.sub.2, and a mixture of phthalic anhydride and H.sub.2O.sub.2.

3. The process of claim 1, wherein the compound ##STR00056## obtained in step (a) is treated with aqueous Na.sub.2SO.sub.3 followed by addition of aqueous K.sub.3PO.sub.4.

4. The process of claim 1, wherein the compound ##STR00057## obtained in step (a) is a crystalline solid with about 85% yield and >about 99% purity.

5. The process of claim 1, wherein said bromination is carried out in the presence of a bromide source such as tetraoctyl ammonium bromide, an activating agent such as methanesulfonic anhydride and a boroxine compound such as triphenylboroxine.

6. The process of claim 1, wherein said deprotection reaction is carried out using either substantially pure toluene, or toluene in combination with a solvent.

7. The process of claim 1, wherein the compound of formula I is obtained with a yield ranging from about 67.1% to 70.3% and purity ranging from about 98.5 to 99.7%.

8. A process for preparing a compound of formula II ##STR00058## said process comprising the steps of: (a) performing an oxidation reaction on the compound ##STR00059## using H.sub.2O.sub.2, phthalic anhydride, and a solvent to yield the compound ##STR00060## and (b) performing a bromination reaction on the compound obtained in step (a) using one or more boroxine compounds along with a bromide source and an activating agent to obtain the compound ##STR00061## and (c) performing a deprotection reaction on the compound obtained in step (b) using either substantially pure toluene, or toluene in combination with a solvent, followed by crystallization, to prepare the compound of formula II or its salts thereof.

9. A process for preparing a compound of formula III ##STR00062## said process comprising the steps of: (a) performing an oxidation reaction on the compound ##STR00063## using H.sub.2O.sub.2, phthalic anhydride and dichloromethane to yield the compound ##STR00064## and (b) performing a bromination reaction on the compound obtained in step (a) using one or more boroxine compounds, along with a bromide source and an activating agent, to obtain the compound ##STR00065## (c) performing a deprotection reaction on the compound obtained in step (b) using either substantially pure toluene or toluene in combination with a solvent, followed by crystallization, to obtain the compound ##STR00066## (d) reacting the compound obtained in step (c) to obtain the compound ##STR00067## followed by an activation reaction and coupling with compound ##STR00068## to produce the compound ##STR00069## and (e) adding the triazolyl compound ##STR00070## in the presence of Cu ion and a ligand to obtain the compound ##STR00071## wherein said ligand is selected from the group of 1,2-diaminocyclohexane, trans-1,2-diaminocyclohexane, cis-/trans-diaminocyclohexane, i-dimethyl-1,2-diaminocyclohexane, trans-N,N′-dimethyl-1,2-diaminocyclohexane, cis-/trans-N,N′-dimethyl-1,2-diaminocyclohexane, 1,2-diaminoethane, i-dimethyl-1,2-diaminoethane, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenantroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenantroline, and 5-nitro-1,10-phenanthroline; and (f) reacting the compound obtained in step (e) with (t-BuO).sub.2POOCH.sub.2Cl to produce the compound ##STR00072## and reacting the compound obtained in step (f) with an acid to yield the compound of formula III.

10. The process of claim 9, wherein said bromination is carried out in the presence of a bromide source which is tetraoctyl ammonium bromide, an activating agent which is methanesulfonic anhydride, and a boroxine compound which is triphenylboroxine.

11. The process of claim 10, wherein said acid is acetic acid.

12. The process of claim 11, wherein in step c) said solvent is isopropyl alcohol.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0032] It will be understood that any given exemplary embodiment can be combined with one or more additional exemplary embodiments. As used herein, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise.

[0033] Unless otherwise specifically set forth, many reagents have been identified herein by their commonly accepted letter abbreviations in the art for ease of reference.

[0034] In addition, unless otherwise specifically set forth elsewhere in the application, the following terms may be used herein, and shall have the following meanings:

[0035] An “alkyl” group refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g., “1-20”, is stated herein, it means that the group, in this case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted.

[0036] The term “C.sub.1-6 alkyl” as used herein and in the claims means straight or branched chain alkyl groups with up to and including 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and the like.

[0037] An “aryl” “Aryl” or “Ar” group refers to an all carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, napthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.

[0038] The abbreviations used in the present application are well-known to those skilled in the art. Some of the abbreviations used are as follows: [0039] Ac.sub.2O: acetic anhydride [0040] Boroxines: General term to refer to cyclic trimeric boronic acid anhydrides; these will [0041] include the trialkylboroxines such as trimethylboroxine, and also the triarylboroxines [0042] such as triphenylboroxine [0043] t-Bu: tert-butylK.sub.3PO.sub.4: potassium phosphate tribasic [0044] DCM: dichlormethance [0045] HCl: Hydrochloric acid [0046] H.sub.2O.sub.2: Hydrogen peroxide [0047] IPA: isopropyl alcohol [0048] mCPBA: m-Chloroperbenzoic acid [0049] Ms.sub.2O: methanosulfonic anhydride [0050] NaOH: sodium hydroxide [0051] Oct.sub.4NBr: Tetraoctylammonium bromide [0052] Tris: 2-amino-2-(hydroxymethyl)propane-1,3-diol

[0053] In a first aspect, the present invention provides a process for preparing a compound of formula I,

##STR00024##

[0054] said process comprising the steps of: [0055] (a) performing an oxidation reaction on the compound

##STR00025##

to yield the compound

##STR00026## [0056] (b) performing a bromination reaction in the presence of one or more boroxine compounds on the compound obtained in step (a) to obtain the compound

##STR00027##

and [0057] (c) performing a deprotection reaction on the compound obtained in step (b) to obtain the compound of formula I above;

[0058] wherein X.sup.1 is selected from the group of H,

##STR00028##

and Y

[0059] is Br.

[0060] In a first embodiment of the first aspect, the oxidation reaction is carried out using oxidizing agents selected from the group of catalytic methyltrioxorhenium (MTO) and hydrogen peroxide urea complex (UHP), m-CPBA (m-chloroperoxybenzoic acid), a mixture of Ac.sub.2O and H.sub.2O.sub.2, and a mixture of phthalic anhydride and H.sub.2O.sub.2.

[0061] In a second embodiment of the first aspect, the compound

##STR00029##

obtained in step (a) is treated with aqueous Na.sub.2SO.sub.3 followed by the addition of aqueous K.sub.3PO.sub.4.

[0062] In a third embodiment of the first aspect, the compound

##STR00030##

obtained in step (a) is a crystalline solid with about 85% yield and >about 99% purity.

[0063] In a third embodiment of the first aspect, the compound

##STR00031##

obtained in step (a) is a crystalline solid which is not isolated.

[0064] In a fourth embodiment of the first aspect, the bromination is carried out in the presence of a bromide source such as tetraoctyl ammonium bromide, an activating agent such as methanesulfonic anhydride, and a boroxine compound such as triphenylboroxine.

[0065] In a fifth embodiment of the first aspect, the deprotection reaction is carried out using toluene in conjunction with isopropyl alcohol (IPA).

[0066] In a sixth embodiment of the first aspect, the compound of formula I

##STR00032##

is obtained with a yield ranging from about 67.1% to 70.3%, and purity ranging from about 98.5 to 99.7%.

[0067] In a second aspect, the present invention provides a process for preparing a compound of formula II

##STR00033##

said process comprising the steps of: [0068] (a) performing an oxidation reaction on the compound

##STR00034##

using H.sub.2O.sub.2, phthalic anhydride, and a solvent to yield the compound

##STR00035##

and [0069] (b) performing a bromination reaction on the compound obtained in step (a) using one or more boroxine compounds, along with a bromide source and an activating agent to obtain the compound

##STR00036##

and [0070] (c) performing a deprotection reaction on the compound obtained in step (b) using either pure toluene or toluene in combination with a solvent, followed by crystallization, to prepare the compound of formula II or its salts thereof.

[0071] In a third aspect, the present invention provides a method of making a compound of formula III

##STR00037##

said process comprising the steps of: [0072] (a) performing an oxidation reaction on the compound

##STR00038##

using H.sub.2O.sub.2, phthalic anhydride and dichloromethane to yield the compound

##STR00039##

and [0073] (b) performing a bromination reaction on the compound obtained in step (a) using one or more boroxine compounds, along with a bromide source and an activating agent, to obtain the compound

##STR00040## [0074] (c) performing a deprotection reaction on the compound obtained in step (b) using either pure toluene or toluene in combination with a solvent, followed by crystallization, to obtain the compound

##STR00041## [0075] (d) reacting the compound obtained in step (c) to obtain the compound

##STR00042##

followed by an activation reaction and coupling with compound

##STR00043##

to produce compound

##STR00044##

and [0076] (e) adding the triazolyl compound

##STR00045##

in the presence of Cu ion and a ligand to obtain compound

##STR00046##

wherein said ligand is selected from the group of 1,2-diaminocyclohexane, trans-1,2-diaminocyclohexane, cis-/trans-diaminocyclohexane, cis-N,N′-dimethyl-1,2-diaminocyclohexane, trans-N,N′-dimethyl-1,2-diaminocyclohexane, cis-/trans-N,N′-dimethyl-1,2-diaminocyclohexane, 1,2-diaminoethane, N,N′-dimethyl-1,2-diaminoethane, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenantroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenantroline, and 5-nitro-1,10-phenanthroline; and [0077] (f) reacting the compound obtained in step (e) with (t-BuO).sub.2POOCH.sub.2Cl to produce the compound

##STR00047##

and reacting compound obtained in step (f) with an acid, such as acetic acid, to yield the compound of formula III above.

EXAMPLES

[0078] The present invention will now be described in connection with certain embodiments which are not intended to limit its scope. On the contrary, the present invention covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Thus, the following examples, which include specific embodiments, will illustrate one practice of the present invention, it being understood that the examples are for the purposes of illustration of certain embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.

[0079] The compounds of the present invention may be prepared using the reactions and techniques described in this section, as well as, other synthetic methods which may be available to those of ordinary skill in the art. The reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformation being affected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvents, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.

[0080] In a preferred embodiment of the invention, the synthesis of the halogenated azaindole compounds can be set forth in the following non-limiting schematic representation—Scheme I.

##STR00048##

[0081] All reagents were used as received without further purification. Reaction progress and final product purity was monitored using HPLC conditions, Table 1, using an Ascentis Express C18, 2.7 μm 4.6×150 mm column at 25° C. Mobile Phase A: 0.01M NH.sub.4OAc in H.sub.2O:MeOH (80:20), Mobile phase B: 0.01 NH.sub.4OAc in H.sub.2O:MeCN:MeOH (5:75:20), 1.0 mL/min. Gradient:

TABLE-US-00001 TABLE 1 HPLC Conditions Mobile Phase Time Composition (minutes) % A % B Gradient Profile 0.0 100.0 0.0 Initial 5.0 70.0 30.0 Linear 20.0 55.0 45.0 Linear 25.0 0.0 100.0 Linear 30.0 0.0 100.0 Hold

##STR00049## ##STR00050##

7-Bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridine hydrochloride monohydrate (id), CH.sub.2Cl.sub.2 (2660 L), Compound 1a (190 kg, 1.0 equiv) and phthalic anhydride (127.3 kg, 1.3 equiv) were charged to an 8000 L glass lined vessel, and the resulting mixture was heated to 35° C. A 30% w/w aqueous solution of hydrogen peroxide (76.8 kg, 1.2 equiv) was added via pump over 2 hours. The resulting suspension was stirred at 35-37° C. for an additional 2 hours, then sampled and analyzed by HPLC to determine the reaction progress. Once the oxidation reaction was deemed complete, the mixture was cooled to 10° C. The reaction was quenched by controlled addition of a solution of sodium sulfite (85.5 kg, 1 equiv) in water (1330 kg) such that the internal temperature remained below 20° C. The resulting biphasic mixture was stirred vigorously at 20° C. for 2 hours to ensure complete reduction of any residual oxidant. A solution of K.sub.3PO.sub.4 (353 kg) in water (1330 kg) was then added to the quenched reaction mixture and the biphasic mixture stirred at 20° C. for 2 hours. The top aqueous phase was discarded and the lower product-rich organic phase was washed with water (1330 kg). The bottom product-rich organic phase was transferred to a clean 8000 L reactor.

[0082] Toluene (1900 L) was added, and the batch was concentrated at ≦0.075 MPa while maintaining the jacket temperature below 40° C. to a final volume of 3000 L. Toluene was added (1900 L) two more times with similar concentrations to volume batch volume of 3000 L in order to meet the specifications for KF (<200 ppm) and DCM (dichloromethane) (<1 wt %). The batch was cooled to 20° C. and toluene (1900 L) was added. Tetraoctylammonium bromide (450.4 kg, 1.25 equiv) and triphenylboroxine (267 kg, 1.3 equiv) were added, and the mixture was agitated for 1 h. Methanesulfonic anhydride (275.5 kg, 2.4 equiv) and toluene (413 kg) were then added and the mixture agitated for 30 min. The slurry was heated to 75° C. for 10 h, then sampled and analyzed. During this time the reaction mixture transformed from a thick slurry to a homogenous solution. After completion of the bromination reaction, the batch was concentrated at ≦0.075 MPa while maintaining the jacket temperature below 40° C. to a final volume of 3000 L. The resulting slurry was cooled to 25° C. and acetonitrile (1200 kg) was added and agitated for 2 h. The slurry was filtered and the solids were rinsed with acetonitrile (450 kg). The solids were triphenylboroxine, and can be dried (50° C. under vacuum) and re-used in subsequent bromination reactions. Expected recovery is 60-70% of the input quantity of the triphenylboroxine. To the product-rich filtrate a solution of potassium phosphate tribasic (560 kg, 4 equiv) in water (1678 kg) was added to the reactor at such a rate that the internal temperature was maintained below 35° C. The resulting biphasic mixture was then heated to 40° C. for 2 hours. The batch was cooled to 20° C., the phases were allowed to split and were separated, and the aqueous layer was discarded. To the resulting mixture was added sodium hydroxide (106.4 kg, 4.0 equiv) in water (532 kg), and the mixture was then heated to 60° C. for 4 hours. After reaction completion the batch was cooled to 20° C., and water (950 kg) was added to dissolve solids. The biphasic mixture was polish filtered (1 μm) and then the phases were allowed to split and were separated. The top phase (product-rich) was sequentially washed with: a solution of NaOH (106.4 g, 4 equiv) in water (532 kg), a solution of KH.sub.2PO.sub.4 (105.9 kg) in water (950 kg), and water (950 kg).

[0083] The organic stream was transferred to an 8000 L glass lined vessel and toluene (950 L) was added. The mixture was then concentrated (T≦50° C., 40-90 mbar) to a final volume of 1300 L, at which point the water content of the toluene solution was <1.0 wt. Isopropanol (450 kg) was added and the batch was heated to 40° C. Aqueous HCl (162.5 kg, 35 w/w %, 2.5 equiv) was then added over 3 hours with high agitation. The resulting suspension was cooled to 20° C. over 1 hour and then stirred for 2 hours. The product was collected by centrifugation, washed with a mixture of toluene (400 L) and isopropanol (171 L), a mixture of toluene (752 L) and isopropanol (293 L), and toluene (570 L), and dried at 50° C. at <0.1 MPa to afford the brominated azaindole 1d as an off-white solid, 129.5 kg (99.64 AP, 99.79 wt %, 69.7% corrected yield).

[0084] Thus, the halogenated azaindole compounds and the reactions described above can be used in the production of the piperazine prodrug compound as shown further along in the scheme above. Also, in the scheme above, particularly 1e may be converted to 1i using the schemes described in PCT application number PCT/US2013/024880 filed Feb. 6, 2013, entitled “Methods for the Preparation of HIV Attachment Inhibitor Piperazine Prodrug Compound”, and incorporated herein in its entirety.

[0085] A Friedel-Crafts acylation followed by hydrolysis and amidation produced intermediate 1f. The triazole substituent was then incorporated via a copper-catalyzed Ullmann-Goldberg-Buchwald cross-coupling reaction of 1f and 2b leading to the formation of 1g. Attachment of the phosphate pro-drug by alkylation with 2c followed by hydrolysis and crystallization affords the drug substance 1i.

[0086] The effective preparation of the brominated intermediate 1d is an important step for the effective synthesis of compound 1i. The bromination process uses readily available and stable reagents such as triphenylboroxine, Oct.sub.4NBr and Ms.sub.2O and has several advantages. It provides high selectivity for the desired brominated azaindole and reduces the number of undesired impurities. This translates into higher yields and increased purity (average of 99 wt %). The ability to recycle and reuse the triphenylboroxine (˜60%) reagent results in a reduction of the cost of the overall process, and increases the sustainability of the manufacturing process. Initial cost estimations have shown that this process can be ˜20-35% less expensive than other preparations of compound 1e.

[0087] It will be evident to one skilled in the art that the present invention is not limited to the foregoing disclosure and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the instant disclosure be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing disclosure, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.