CA2271974A1 - 2, 2-dibromo-azasteroids and their use in a method for introducing a 1, 2-double bond into azasteroids - Google Patents

Abstract

A process for introducing a 1,2-double bond into 17.beta.-substituted-3-oxo-4-azasteroids includes the preparation of novel 2,2-dibromo-4-azasteroids by a three step process comprising oxalylation, reaction with excess bromine, and removal of the oxalyl group.
This process is preferably carried out at temperatures at or above -20°C and results in a high yield of the 2,2-dibromo-4-azasteroid. The 2,2-dibromo-4-azasteroid can be converted to the corresponding 17.beta.-substituted-4-aza-5.alpha.-androst-1-ene-3-one by at least two processes, one of which involves correcting the oxidation state at the 2-carbon and then introducing the 1,2-double bond, and the other of which involves introducing the unsaturation to produce a vinyl bromide followed by correcting the oxidation state of the 2-carbon. Preferably, the dibromo compound is reacted with thiophenol to produce a 2-phenylthio intermediate, followed by oxidation of the phenylthio group to a sulfoxide and 1,2-elimination of the sulfoxide group to create the 1,2-double bond.

Description

2,2-DIBROMO-AZASTEROIDS AND THEIR USE IN A METHOD FOR INTRODUCING
A 1,2-DOUBLE BOND INTO AZASTEROIDS
FIELD OF THE INVENTION
The invention relates to a process for dehydrogenating azasteroids, and to novel intermediates for use in the dehydrogenation of azasteroids. In particular, the invention relates to processes for introducing a 1,2-double bond into 17-~3-substituted-3-oxo-4-azasteroids, to novel 2,2-dibromo-4-azasteroids which are intermediates in the process, and to processes for preparing novel 2,2-dibromo-4-azasteroids.
BACKGROUND OF THE INVENTION
Numerous methods have been proposed for introducing a 1,2-double bond into 4-azasteroids. One such process is disclosed in U.S. Patent No. 5,021,575 issued to King et al. on June 4, 1991. The process disclosed by this patent is a four step process comprising: (a) reacting a 17-(3-substituted-3-oxo-4-azasteroid with oxalyl chloride; (b) monobrominating the oxalylated intermediate at the 2-position; (c) reacting the brominated product with ethylenediamine or 2-(N-methylamino) ethanol to produce a and ~3 2-monobrominated isomers; followed by (d) dehydrobromination of the product of (c) which results in the introduction of a double bond at the 1,2-position.

The process disclosed by King et al. suffers from the disadvantage that the monobromination reaction (b) must be performed at a very low temperature (-70°C in Example 1 ) and with very gradual addition of a stoichiometrically precise quantity of bromine to prevent contamination of the product due to undesired side reaction products. The very low reaction temperature and slow addition of bromine in this step hinder and restrict the King et al. process from being useful on a large scale. Therefore, there is a need for a more industrially applicable process for introducing a 1,2-double bond into a 3-oxo-4-azasteroid.
SUMMARY OF THE INVENTION
The present invention overcomes the above-noted disadvantages by providing a novel process for introducing a 1,2-double bond into 17-~3-substituted-3-oxo-4-azasteroids. In the process of the present invention, a 17-~3-3-oxo-4-azasteroid is reacted with oxalyl chloride as in the above-mentioned King et al. process. However, the subsequent step in the process of the present invention involves reacting the oxalyl intermediate with a non-critical excess of bromine, and leads to the formation of a 2,2-dibromo-4-azasteroid rather than the 2-monobromo-4-azasteroids which result from the bromination step in the King et al. process.
The 2,2-dibromo-azasteroids formed in the process of the present invention are novel compounds. These dibromo compounds, which possess at C-2 a state of oxidation apparently inappropriate for conversion to unsubstituted 1,2-unsaturated steroids, are surprisingly useful as intermediates in this conversion.
The claimed process whereby these a,a-dibromolactams are converted to a,~3-unsaturated lactams is also unknown.

The inventors have usefully found that bromination of the oxalyl intermediate with excess bromine is much less temperature-sensitive than the monobromination of the King et al. process.
This permits the bromination in the process of the present invention to be performed at temperatures at or above -25 ° C, resulting in clean addition of two bromine atoms at the 2-position, so that removal of the protecting oxalyl group results in formation of the 2,2-dibromo-4-azasteroid cleanly and in excellent yield. Furthermore, the bromine can be added in one portion over a short period of time with only a rough regard for the quantity of bromine which, in combination with the more moderate reaction temperature which can be conveniently achieved in a wide range of processing equipment, makes the process of the invention more industrially useful than the King et al. process.
The process of the present invention contemplates two variants for converting the dibromo intermediates to the final simple 1,2-unsaturated steroids. In one variant the oxidation state at carbon 2 is first corrected and then the unsaturation is introduced.
In the second variant, the unsaturation is introduced to produce a vinyl bromide and then the oxidation state of carbon 2 is corrected. Preferred examples of both variants of the present invention are provided. One of these preferred examples of the first variant comprises reaction of the 2,2-dibromo compound with a thiophenolic compound in the presence of a base to produce a mixture of 2a and 2(3 phenylthio-azasteroids, followed by elimination of a phenylsulfenic acid to introduce a double bond at the 1,2-position. A preferred route of the second variant comprises dehydrohalogenation of the 2,2-dibromo-azasteroid to introduce a 1,2-double bond while removing one equivalent of HBr, followed either by removal of the remaining bromine atom by metallation/protonation with for example buyllithium and a proton source, or reduction with an appropriate reagent such as triethyl aluminum/palladium chloride.
Accordingly, in one aspect, the present invention provides a compound of the formula:
O
II
(IV) Qf ~r H
H
wherein R is (i) a straight or branched chain alkyl group having 1 to 12 carbons;
(ii) a straight or branched chain alkyl group having 1 to 12 carbons in which a hydrogen is substituted with an alkyl ester having 1 to 4 carbons;
(iii) a cycloalkyl group having 4 to 8 carbons;
(iv) phenyl;
(v) ORl where Rl is a C,_g straight or branched chain alkyl group or benzyl;
or (vi) NHRZ R3, where Rz and R3 are each independently selected from hydrogen, C,_lz straight or branched chain alkyl, C1_lz straight or branched chain alkyl having a hydrogen substituted with a C1_4 alkyl ester, C3_lo cycloalkyl, phenyl, or Rz and R3 taken together with the nitrogen to which they are attached represent a 5 or 6 member saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen.
In another aspect, the present invention provides a process for preparing a compound of the formula:

t G- (Z
L~
(IV) ~r ' H
H
the process comprising:
(a) reacting the compound of the formula R_~
(I) H
N

with oxalyl chloride to produce a compound of the formula:
O

Z
(II) H

(b) bromination of the compound of formula II with an excess of bromine to produce a compound of the formula: o G- fZ
H
Br,~ ~ H ~H (III) p O
(c) de-oxalylation of the compound of formula III to produce a compound of said formula (IV).
In yet another aspect, the present invention provides a process for producing a 17~3-substituted 4-aza-Sa-androst-1-ene-3-one, comprising:
(a) reacting a compound having the formula:

O
G--R
(IV) r3 Br H
H
with thiophenol to produce a compound of the formula:
O
II
G- fZ
s ~ r (V) ~I
c~'Ni H
H
(b) oxidation of the phenylthio moiety to a sulfoxide, followed by 1,2-elimination to produce a compound of the formula:
G -- CZ
(vI) H
H
In yet another aspect, the present invention provides a process for producing a 17~3-substituted 4-aza-Sa-androst-1-ene-3-one, comprising:
(a) reacting a compound having the formula:

_g_ (IV) C3~
Cir i h H
with a hindered amine base to produce a compound of the formula:
c ~-R
(VII) H "
(b) removal of bromine from the compound of formula VII to produce a compound of the formula:
G-(Z
(VI) i h N
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described, by way of example only, with reference to the accompanying drawings in which:

_9_ Figure 1 shows the process for the preparation of a preferred compound of formula IV in which R is -NH-tent-butyl;
Figure 2 shows a first preferred process by which the product of Figure 1 is converted to the corresponding 173-substituted-4-aza-Sa-androst-1-ene-3-one of formula VI;
and Figure 3 shows a second preferred process by which the product of Figure 1 is converted to the corresponding 173-substituted-4-aza-Sa-androst-1-ene-3-one of formula VI.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Some of the 4-azasteroid compounds which can be prepared by the process of the present invention are testosterone-Sa-reductase inhibitors useful for treating hyperandrogenic conditions such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia including male pattern alopecia, prostatic carcinoma and benign prostatic hypertrophy by topical or systemic administration.
One preferred embodiment of the invention relates to a process for preparing the compound 173-(N-tert-butyl-carbamoyl)-4-aza-Sa-androst-1-ene-3-one, also known as finasteride, a Sa-reductase inhibitor. The preferred process includes preparation of finasteride from the corresponding 2,2-dibromo intermediate, as well as preparation of the 2,2-dibromo intermediate from the starting material dihydrofinasteride. For greater certainty, finasteride, dihydrofinasteride and the corresponding 2,2-dibromo intermediate correspond to compounds of the above formulas VI, I and IV, respectively, in which R is -NH-tent-butyl.
The 2,2-dibromo-4-azasteroids of the invention (compounds of formula IV) are produced from 4-azasteroids (compounds of formula I) by a three step process, comprising oxalylation to protect the 4-amino group, followed by bromination and deprotection steps.
The oxalylation comprises reaction of a 4-azasteroid with oxalyl chloride in the presence of an amine base as a hydrogen chloride trapping agent. The reaction is preferably conducted in a dry, inert organic solvent at a temperature of from about -25°C to about 25 ° C, resulting in the compound of formula II. In a particularly preferred embodiment, the organic solvent is methylene chloride and the amine base is pyridine. Most preferably, the oxalyl chloride is added to a solution of dihydrofinasteride and pyridine in methylene chloride at a temperature of about -20 ° C and, following addition of oxalyl chloride, the reaction mixture is warmed or allowed to warm to 20 to 25°C with stirring.
The oxalyl intermediate is preferably not isolated, and is reacted in situ with an excess of bromine, preferably at least 2 molar equivalents of molecular bromine (Brz) based on the amount of 4-azasteroid starting material, and more preferably about 3 to 4 molar equivalents of molecular bromine. Preferably, the reaction mixture is cooled to about -20 ° C to about -25 ° C prior to addition of the bromine, which may be added in one portion or more gradually, and the temperature is then allowed to rise to about 20 to 25 ° C. Bromination of the oxalylated intermediate results in the production of an intermediate which may be envisioned to be the compound of formula III, and which is preferably not isolated. Any excess bromine in the reaction mixture may preferably be consumed by addition of formic acid.
The deprotection step comprises the removal of the oxalyl group, for example by adding to the reaction mixture 2- (N-methylamino) ethanol or ethylenediamine in portions until the oxalyl compound has been completely converted to the 2,2-dibromo compound of formula IV. A
reaction scheme showing the preferred conversion of dihydrofinasteride to the 2,2-dibromo precursor of finasteride is shown in Figure 1.
The novel 2,2-dibromo-4-azasteroids of formula IV may be isolated and optionally purified before further reaction but preferably they are reacted further without substantial purification other than removal of water soluble or volatile contaminants. The inventors have found that the process described above can produce an almost quantitative crude yield of 2,2-dibromo compound from the 4-azasteroid starting material.
The present invention provides two preferred processes for conversion of the 2,2-dibromo azasteroid intermediate to the product containing a double bond at the 1,2-position, namely the 173-substituted-4-aza-5a-androst-1-ene-3-one of formula VI. The more preferred of these processes involves reaction of the 2,2-dibromo intermediate with thiophenol in the presence of a strong base to produce a mixture of a and ~3 isomers of 2-phenylthio-4-azasteroid (compound of formula V), followed by oxidation of the phenylthio moiety to a sulfoxide and 1,2-elimination of the sulfoxide to produce the compound of formula VI.
The reaction with thiophenol is preferably conducted in sodium methoxide/methanol, with the addition of at least three molar equivalents of thiophenol to produce the compound of formula V. This intermediate may also be isolated and optionally purified prior to further reaction. The 1,2-double bond is then introduced by a conventional process in which the phenylthio group is oxidized to a sulfoxide by treatment with sodium periodate, followed by application of sufl'lcient heat to achieve 1,2-elimination of the sulfoxide. A preferred example of this process is illustrated in Figure 2, showing the preparation of finasteride from its 2,2-dibromo precursor.
In an alternate preferred process, the 2,2-dibromo-4-azasteroid is first dehydrobrominated by reaction with a hindered base such as 2,4,6-trimethylpyridine, thereby producing a monobrominated intermediate having a double bond at the 1,2-position (compound of formula VII). The remaining bromine is replaced by hydrogen in a conventional manner, for example by reaction of the compound of formula VII with n-butyllithium, followed by quenching with a proton donor (W.E. Parham, Lawrence D. Jones and Yousry Sayed, J. Org. Chem.

(1975) or by reduction with a reducing agent such as triethylaluminum with palladium chloride (Kosaku Hirota, Yukia Kitade, Yoshitake Kanbe and Yoshia Kilsobe and Yoshifmi Maki, Synthesis (2), 213-215 (1993) , resulting in the compound of formula VI.
Figure 3 illustrates the preparation of finasteride from the 2,2-dibromo precursor according to this preferred process.
The following examples should be considered as not limiting the invention and will serve to illustrate the manner in which the present invention is accomplished.
EXAMPLE 1 - Preparation of 2,2-dibromo-dihydrofinasteride(IV) 4.0 g of dihydrofinasteride was dissolved in 80 ml of methylene chloride and 5.4 ml of pyridine and the mixture refluxed under a Dean-Stark trap for the removal of water. The solution was cooled to -20 ° C and 1.0 ml of oxalyl chloride added. The slurry was allowed to warm to 20-25°C and stirred for 16 hours. The brown solution was cooled to -20°C giving a slurry and 2.4 ml of bromine added by syringe. The slurry dissolved and the mixture was allowed to warm to 20-25°C and stirred for 16-24 hours. To this mixture was added cautiously 1.6 ml of 95-97%
formic acid causing strong gas evolution and an exotherm. When gas evolution has effectively ceased three portions of 6.0 g of 2-methylaminoethanol were added sequentially. When the mixture became cloudy, 20 ml of ethanol was added. The reaction was followed by thin layer chromatography and was continued until the spot attributed to the oxalyl protected compound faded away. The reaction mixture was then quenched with 50 ml of 1:10 v/v 85%
phosphoric acid:water. The phases were cleanly separated. The organic layer was extracted twice more with 50 ml portions of the same aqueous acid and then once with SO ml of water. The organic layer was dried with magnesium sulfate, filtered and concentrated to dryness to give a crude product 5.87 g (103% of theory). A sample of pure 2,2-dibromodihydrofinasteride was isolated by chromatography.
NMR(CDC13) 0.75(s,3H), 1.15(s,3H), 1.35 (s,9H), 3.03 (d,1H vicinal coupling), 3.25 (m,lH Sa), 3.50 (d, 1H vicinal coupling), 5.05(br s 1H amide) 6.1(br s, 1H, amide).
Hydrogenation of the compound gave back dihydrofinasteride. Incomplete hydrogenation gave two diastereomeric monobromides.
EXAMPLE 2 - Preparation of 2a and ~3-phenylthio-dihydrofinasteride(V) All the material (5.87 g) produced in Example 1 was stirred and dissolved in 57 ml of methanol in a 200 ml flask. To this was added 3.9 g of thiophenol and 5.1 g of 25% sodium methoxide in methanol. The mixture was stirred for 16-24 hours. The reaction was worked up by adding 30 ml of methylene chloride and 60 ml of water. The two phase mixture was cut and the organic layer washed with four times 60 ml of 10% aq. sodium hydroxide and finally with 60 ml of water. Then 60 ml of hexanes were added and the mixture distilled to a low volume and then hexanes volume replaced with fresh hexanes until the internal temperature reached about 68 ° C. This procedure caused a solid to precipitate. The hexane slurry was filtered and the product washed with more hexanes. The yield of crude 2a and ~3-phenylthio-dihydrofinasteride was 4 gm (77.6%) from dihydrofinasteride.
EXAMPLE 3 - Preparation of Finasteride(VI) A mixture of 0.482 (1 mmol) of 2-phenylthiodihydrofinasteride dissolved in 5 ml of methanol was mixed with 0.248(115 mmol) of sodium periodate dissolved in 1.2 ml of water and the mixture stirred overnight and part of the next day. Although the starting material spot became weak by TLC (silica gel, ethylacetate) it did not vanish even when the mixture was warmed gently. The mixture was diluted with methylene chloride and water and the organic phase separated and washed with water. The methylene chloride was removed under vacuum also drying the sample. Methyl isobutyl ketone (MIBK) was added and the temperature raised to 115°C. Some calcium carbonate was added and the heating was continued at reflux for about an hour and then left overnight at room temperature. The mixture was then heated to reflux and filtered through celite to remove solids. The solution was cooled in ice and the precipitated solid filtered and washed with cold MIBK. The yield was 0.17 g of finasteride and its identity was confirmed by NMR and TLC Rf EXAMPLE 4 - Preparation of phenylthiodihydrofinasteride(V) from dihydrofinasteride(I) without isolation of intermediates In a 200 ml three-necked bottomed flask normally equipped was placed 4 g of dihydrofinasteride, 5.4 ml of pyridine and 100 ml of methylene chloride. 20 ml of solvent was distilled out to dry the mixture and the residue cooled to -20°C, after which 0.95 ml of 99+~~0 oxalyl chloride was added by syringe over about 5 minutes. The cold slurry was stirred for 15 monutes and then warmed to room temperature and stirred overnight. The mixture was cooled to -20°C and 2.4 ml of bromine was added in one portion. There was an exotherm of 15-20°C.

Warming was continued to room temperature and the reaction mixture was then aged for 19 hours. The reaction mixture was again cooled to -20 ° C and 18 ml of 2-(N-methylamino) ethanol was added, after which the reaction mixture was allowed to warm to room temperature and aged for a few hours. The mixture was worked up with several washes with 1:9 phosphoric acid/water and then several brine washes. The methylene chloride solution was then cooled to -20°C and 3.8 g of thiophenol was added, followed by addition of 2.4 g of triethylamine. The original homogeneous solution at -20°C became a stirrable mush on warming to room temperature. By TLC (silica gel/ethyl acetate) the phenylthiodihydrofinasteride product can be seen forming with sulfur-containing by-products near the solvent front. After stirring overnight, 2. S ml of water was added and the layers separated. The organic layer was washed with 1:10 v/v phosphoric acid/water, then brine, and was then azeotropically dried. The solvent was changed to heptane, giving a sticky insoluble slurry. Addition of acetonitrile gave two cleanly separable phases with the product in the acetonitrile. Cooling the acetonitrile solution in an ice bath gave crystals. The solid was triturated with refluxing acetonitrile followed by cooling in ice and reisolating the solid, which was filtered and dried to give 2.46 g (47.7% overall) of a single spot material. The NMR
indicates that this is a single diastereomer of phenylthiodihydrofinasteride(V). NMR (CDC13) 0.70 (s,3H), 0.92(2,3H), 1.4-(s,9H), 1.87(dbl of tr, 1H), 1.97(m,1H), 2.
I3(t,1H), 2.24(dbl of dbl 1H), 2.90 (dbl of dbl, 1H), 3.75(dbl of dbl, IH) 5.04(s,1H), 5.90(s,1H), 7.3(m,3H), 7.55(m,2H).
EXAMPLE 5 - Preparation of 2-Bromofinasteride(VII) 2 ml. of redistilled collidine was brought to reflux and 200 mg. of 2,2-dibromodihydrofinasteride added. The reflux was maintained overnight under a nitrogen atmosphere. The reaction mixture was diluted with benzene and extracted with 2N HCl four times. The organic solution was evaporated. The product was predominantly a single material by TLC (silica gel/ethyl acetate). NMR and MS are consistent with the assigned structure. The NMR shows a vinyl singlet at 5.7ppm and has a shifted methyl singlet at 1.03.
The characteristic geminal methylene signals are gone. The MS showed 450(6.3), 451(3.2), 452(7.0), 453(2.7), 435(2.3), 437(2.3), 408(1.1), 395(1.8), 397(1.5), 379(1.2), 381(1.1), 370(2.4), 371(8.4), 372(14.6), 373(7.1), 374(5.7), 375(2.0), 357(5.5), 350(3.6), 352(3.6), 128(19.3), 110(18.5), 79(30.3), 81(27.9), 59(100).
Although the invention has been described in relation to certain preferred embodiments, it is not limited thereto. Rather, the invention includes all embodiments which may fall within the scope of the following claims.

Claims (17)

1. A compound of the formula:
wherein R is (i) a straight or branched chain alkyl group having 1 to 12 carbons;
(ii) a straight or branched chain alkyl group having 1 to 12 carbons in which a hydrogen is substituted with an alkyl ester having 1 to 4 carbons;
(iii) a cycloalkyl group having 4 to 8 carbons;
(iv) phenyl;
(v) OR1 where R1 is a C1-8 straight or branched chain alkyl group or benzyl;
or (vi) NHR2R3, where R2 and R3 are each independently selected from hydrogen, C1-12 straight or branched chain alkyl, C1-12 straight or branched chain alkyl having a hydrogen substituted with a C1-4 alkyl ester, C3-10 cycloalkyl, phenyl, or R2 and R3 taken together with the nitrogen to which they are attached represent a 5 or 6 member saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen.

2. The compound of claim 1, wherein R is an -NH-tert-butyl group and the compound of formula IV is 2,2-dibromo dihydrofinasteride.

3. A process for producing a 17.beta.-substituted 4-aza-5.alpha.-androst-1-ene-3-one, comprising:
(a) reacting a compound having the formula:
with thiophenol to produce a compound of the formula:
(b) oxidation of the phenylthio moiety to a sulfoxide, followed by 1,2-elimination to produce a compound of the formula:
wherein R is (i) a straight or branched chain alkyl group having 1 to 12 carbons;
(ii) a straight or branched chain alkyl group having 1 to 12 carbons in which a hydrogen is substituted with an alkyl ester having 1 to 4 carbons;
(iii) a cycloalkyl group having 4 to 8 carbons;
(iv) phenyl;
(v) OR1 where R1 is a C1-8 straight or branched chain alkyl group or benzyl;
or (vi) NHR2R3, where R2 and R3 are each independently selected from hydrogen, C1-12 straight or branched chain alkyl, C1-12 straight or branched chain alkyl having a hydrogen substituted with a C1-4 alkyl ester, C3-10 cycloalkyl, phenyl, or R2 and R3 taken together with the nitrogen to which they are attached represent a 5 or 6 member saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen.

4. The process of claim 3, wherein step (a) comprises reacting the compound of formula IV
with a least 3 molar equivalents of thiophenol and sodium methoxide in methanol to produce the compound of formula V.

5. The process of claim 3 or 4, wherein step (a) comprises reacting the compound of formula V with sodium periodate to oxidize the phenythio group, followed by heating at a temperature sufficient to achieve elimination of the oxidized phenylthio group and thereby produce the compound of formula VI.

6. The process of any one of claims 3 to 5, wherein R is -NH-tert-butyl.

7. A process for producing a 17.beta.-substituted 4-aza-5.alpha.-androst-1-ene-3-one, comprising:
(a) reacting a compound having the formula:
with a hindered amine base to produce a compound of the formula:
(b) removal of bromine from the compound of formula VII to produce a compound of the formula:
wherein R is (i) a straight or branched chain alkyl group having 1 to 12 carbons;
(ii) a straight or branched chain alkyl group having 1 to 12 carbons in which a hydrogen is substituted with an alkyl ester having 1 to 4 carbons;

(iii) a cycloalkyl group having 4 to 8 carbons;
(iv) phenyl;
(v) OR1 where R1 is a C1-g straight or branched chain alkyl group or benzyl;
or (vi) NHR2R3, where R2 and R3 are each independently selected from hydrogen, C1-12 straight or branched chain alkyl, C1-12 straight or branched chain alkyl having a hydrogen substituted with a C1-4 alkyl ester, C3-10 cycloalkyl, phenyl, or R2 and R3 taken together with the nitrogen to which they are attached represent a 5 or 6 member saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen.

8. The process of claim 7, wherein the hindered amine base is 2,4,6-trimethylpyridine.

9. The process of claim 7 or 8, wherein removal of bromine comprises reaction of the compound of formula VII with n-butyllithium, followed by quenching the reaction mixture with a protic solvent.

10. The process of claim 7 or 8, wherein removal of bromine comprises reaction of the compound of formula VII with triethylaluminum and a palladium chloride catalyst.

11. The process of any one of claims 7 to 10, wherein R is -NH-tert-butyl.

12. A process for preparing a compound of the formula:
wherein R is (i) a straight or branched chain alkyl group having 1 to 12 carbons;
(ii) a straight or branched chain alkyl group having 1 to 12 carbons in which a hydrogen is substituted with an alkyl ester having 1 to 4 carbons;
(iii) a cycloalkyl group having 4 to 8 carbons;
(iv) phenyl;
(v) OR1 where R1 is a C1-8 straight or branched chain alkyl group of benzyl;
(vi) NHR2R3, where R2 and R3 are each independently selected from hydrogen, C1-12 straight or branched chain alkyl, C1-12 straight or branched chain alkyl having a hydrogen substituted with a C1-4 alkyl ester, C3-10 cycloalkyl, phenyl, or R2 and R3 taken together with the nitrogen to which they are attached represent a 5 or 6 member saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen;
the process comprising:
(a) reacting a compound of the formula with oxalyl chloride to produce a compound of the formula:
(b) bromination or the compound of formula II with an excess of bromine;
(c) de-oxalylation of the product of step (b) to produce a compound of the formula:

13. The process of claim 12, wherein step (a) comprises reacting the compound of formula I
with oxalyl chloride in a dry, inert organic solvent in the presence of an amine base at a temperature of from about -25°C to about 25°C to produce the compound of formula II.

14. The process of claim 12 or 13, wherein step (b) comprises reacting the compound of formula II with at least about 3 molar equivalents of bromine in a dry organic solvent at a temperature of from about -25°C to about 25°C.

15. The process of claim 14, wherein the compound of formula II is reacted with about 3 to 4 molar equivalents of bromine.

16. The process of any one of claims 12 to 15, wherein step (c) comprises reacting the product of step (b) with ethylenediamine or 2-(N-methylamino)ethanol in a dry, inert organic solvent to produce the compound of formula IV.

17. The process of any one of claims 12 to 16, wherein R is -NH-tert-butyl.