METHODS OF MAKING l-(2-AMINOPROPYL)-6-HYD OXYINDAZOLE
This application claims the benefit under 35 U.S.C. §119(e) of prior U.S. Provisional Patent Application No. 60/295,427 filed June 1, 2001, and is incorporated in its 5 entirety by reference herein.
BACKfflROTTND OF THE ΪNVENTTON
The present invention relates specifically to methods of making l-(2-aminopropyl)- i o 6-hydroxyindazole which avoid^undesired side products.
WO 98/30548 (Yamanouchi) shows the utility of l-(aminoalkyl)indazoles for treating CNS diseases. The route of synthesis involves the reaction of various indazoles, having substituents only in the benzene ring, with alkylating agents. It is well known that such alkylation of indazoles always gives about a 1:1 mixture of isomeric 1- and 2-
15 alkylindazoles. See, generally, Song and Yee, Organic Letters, vol. 2, page 519 (2000). Therefore about half of the reaction material is wasted due to the formation of the undesired 2-alkylindazole which must be separated by chromatography or other technique. The isolated 1-alkylindazole is then further modified to provide the target 1- (aminoalkyl)indazole.
20 Fischer and Tafel, Justus Liebigs Annalen der Chemie, vol. 227, p. 334 (1885) report nitrosation of 2'-ethylaminoacetophenone with sodium nitrite and the reduction of the resulting nitrosamine with zinc to yield l-ethyl-3-methylindazole. Use of isoamyl nitrite instead of sodium nitrite for an analogous nitrosation is discussed in Applegate and Turnbull, Synthesis, p. 1011 (1988). McGeachin, Canadian Journal of Chemistry, vol. 44,
25 p. 2323 (1966) reports nitrosation of a 2-aminobenzaldehyde wherein the amino group is substituted with a nonhydroxylic C 3H|8N30 group, for the purpose of verification of chemical structure. The resulting nitrosamine was reduced with zinc forming a very specific indazole, for the purpose of further verification of chemical structure.
Monoalkylhydrazines react with benzophenones or acetophenones having ortho leaving groups (e.g., halide or mesylate) to give l-alkylindazoles substituted at the 3- position as reported in Caron and Vazquez, Synthesis, p. 588 (1999). The analogous conversion of benzaldehydes o 3-unsubstituted indazoles requires forcing conditions unsuitable for scaleup. See Halley and Sava, Synthetic Communications, vol. 27, p.
1 199 (1997).
Suwinski and Walczak, Polish Journal of Chemistry, vol. 59, p. 521 (1985), report cyclization of 2-aminobenzaldoxime hemisulfate to give indazole. The inventors attempted to extend this method to a 2-alkylaminobenzaldoxime hemisulfate, but the desired 1-alkylindazole was not obtained and instead the unwanted nitrile or the free oxime was obtained. An analogous cyclization of oxime acetates, demonstrated only for forming 3 -substituted indazoles, employs conditions poorly suited for scaleup as shown in Brown et al., Journal of Medicinal Chemistry, vol. 35, p. 2419 (1992). Cyclization of 2-acylaminobenzaldoxime derivatives yields 1-acylindazoles (von Auwers and Frese, Justus Liebigs Annalen der Chemie, vol. 450, p. 290 (1926)) but these do not provide 1- alkylindazoles upon reduction, the 1-unsubstituted indazole being formed instead. See Al-Khamees and Grayshan, Journal of the Chemical Society, Perkin Trans. I, p. 2001 (1985). A known synthesis of 1,3-dialkylindazoles from .l,3-dialkylindoles involves (1) oxidative cleavage of the 1,3-dialkylindazole to give the 2-(N-alkylformamido)aryl"alkyl ketone; (2) ketoxime formation with concurrent N-deformylation; (3) O-acetylation; and (4) heating the resulting ketoxime acetate at 170-200 °C in the melt, under vacuum. See Matassa et al., J. Med. Chem., vol. 33, page 1781 (1990); and Brown et al., J. Med. Chem., vol. 35, page 2419 (1992). This method has not been demonstrated for aldoximes, required for the synthesis of 3-unsubstituted indazoles. Furthermore, the in
vacuo thermolysis step has been reported on a maximal 1.3-gram scale, and would present experimental difficulties on a larger preparative scale.
Accordingly, there is a need to provide processes to manufacture l-(2- aminopropyl)-6-hydroxyindazole which avoid undesired isomers and which are capable of producing scaleup quantities of the desired compound.
All patents, patent applications, and publications referenced in this application are incorporated in their entirety and form a part of the present application.
STIMMAKV OF TffF. PRFSFNT TNWNTTON
A feature of, the present invention is to provide a method to make l-(2- aminopropyl)-6-hydroxyindazole.
A further feature of the present invention is to provide a method to make l-(2- aminopropyl)-6-hydroxyindazole in large quantities and with avoiding large quantities of undesired isomers.
Additional features and advantages of the present invention will be set forth in part in the description that follows, and in part will be apparent from the description, or may be learned by practice of the present invention. The objectives and other advantages of the present invention will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims.
To achieve these and other advantages, and in accordance with the purposes of the present invention, as embodied and broadly described herein, the present invention relates to a method of making l-(2-aminopropyl)-6-hydroxyindazole. involving a) nitrosating 4-benzyloxy-2-(2-hydroxypropyI)aminobenzaldehyde to produce 4-benzyloxy-2-(2-hydroxypropyl)nitrosaminobenzaldehyde; b) reacting said 4-benzylόxy-2-(2-hydroxypropyI)nitrosaminobenzaldehyde with a reducing agent to convert NO to NH2 with concomitant cyclization to form 6- benzyloxy- 1 -(2-hydroxypropyl)indazole;
c) reacting said 6-benzyloxy-l-(2-hydroxypropyl)indazole with a sulfonyl halide or sulfonic anhydride to form the corresponding sulfonic ester which is reacted with a metal azide to yield l-(2-azidopropyl)-6-benzyloxyindazole; and d) reacting said l-(2-azidopropyl)-6-benzyloxyindazole with a hydrogen source and a catalyst to yield l-(2-aminopropyl)-6-hydroxyindazole.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide a further explanation of the present invention, as claimed. DF AΠ FT TIFSCTCΓPTTON OF TTTF. PKFSFNT TNVF.NTTON The present invention relates to. methods of making l-(2-aminopropyl)-6- hydroxyindazole. The methods of the present invention preferably permit the making of 1- (2-aminopropyl)-6-hydroxyindazole on a large scale and preferably avoiding the formation of undesirable isomers. In more detail, Yamanouchi in WO 98/30548, in Reference Example 35, describes a preparation of compound 10, wherein 6-benzyloxyindazole is reacted with propylene oxide and a base to give, after chromatographic purification, 6- benzyloxy-l-(2-hydroxypropyl)indazole (8). It is well known in the art that alkylation reactions of N-unsubstituted indazoles produce mixtures of isomeric 1-alkylated and 2- alkylated products, which must then be separated chromatpgraphically or by other means. See, generally, Song and Yee, Organic Letters, vol. 2, page 519 (2000). The loss of material in the form of the undesired 2-alkylated product, for instance, is especially undesirable when enantiomerically enriched- or enantiomerically pure final pharmaceutically active product (10) is desired.
For instance, a method for producing 6-benzyloxy-lr(2-hydroxypropyl)indazole (8) and its enantiomerically enriched or enantiomerically pure R or S forms, free of the isomeric 6-benzyloxy-2-(2-hydroxypropyl)indazole, is desired for use in the production
on .a multigram or larger scale of l-(2-aminopropyl)-6-hydroxyindazole (10) and its enantiomerically enriched or enantiomerically pure S or R forms.
In the methods of the present invention, the process can begin with 4-benzyloxy
(2-hydroxypropyl)aminobenzaldehyde which is subjected to a nitrosation in order to form
5 4-benzyloxy-(2-hydroxypropyl)nitrosaminobenzaldehyde. Referring to the reactions being set forth in Scheme 1, various preferred compounds are referenced by their numerals in bold in Scheme 1. The 4-benzyloxy-(2- hydroxypropyl)nitrosaminobenzaldehyde (l), which is formed is then reacted with a reducing agent to convert NO to NH2 with concomitant cyclization. The resulting
10 compound, 6-benzyloxy-l-(2-hydroxypropyl)indazole (8) is formed to the exclusion of the isomeric 6-benzyloxy-2-(2-hydroxypropyl)indazole.
The described conversion of 6 to 7 to 8 can be effected using racemic compounds, or using entantiomerically enriched or enantiomerically pure compounds of either the R or the S absolute configuration.
15 The following sequences are provided to set forth preferred methods of making the compounds of the present invention. Furthermore, preliminary steps to the formation of the starting material, namely, the starting 4-benzyloxy-(2- hydroxypropyl)aminobenzaldehyde are also provided. For purposes of the present invention, the starting material can be formed by various methods and the methods set
20. forth below are simply offered as examples of reaction schemes that can be used to produce the starting material for the methods of the present invention! Those skilled in the art will recognize, from a review of the present application, that other reaction schemes can be used to form the starting materials for use in the methods of the present . invention.
Sequence A:
Step 1. 6-Benzyloxyindole (1) (Batcho and Leimgruber, Organic Syntheses,. Collective Vol. 7, p. 34 (1990)) is reacted with (+)-propylene oxide and 'a base in an organic solvent to yield (+)-l-(2-hydroxyρropyl)-6-benzyloxyindole (2). Preferably the base is sodium hydride and the solvent is tetrahydrofuran. The temperature is 0 °C to 25 °C,. preferably about 10 °C. Preferably an inert atmosphere, e.g., nitrogen or argon, is maintained.
Alternatively, compound 1 is reacted with (R)-propylene oxide according to the foregoing method to yield (R)-l-(2-hydroxypropyl)-6-benzyloxyindole (R-2). Alternatively, compound 1 is reacted with (S)-propylene oxide according to the foregoing method to yield (S)- 1 -(2-hydroxyprόpyl)-6-benzyloxyindole (S-2) . Step 2. Compound 2 is reacted with ozone in an organic solvent, preferably dichloromethane, at -80 to -40 °C, preferably -55 to -70 °C, followed by addition of a reducing agent, preferably dimethyl sulfide. The temperature is then allowed to increase to about 25 °C, to yield (+)-4-benzyloxy-2-(N-(2- hydroxypropyl)formamido)benzaldehyde (3).
Alternatively, compound R-2 is reacted according to the foregoing method to yield (i?)-4-benzyloxy-2-(N-(2-hydroxypropyl)formamido)benzaldehyde (&-$)• Alternatively, compound S-2 is reacted according to the foregoing method to yield (S)-4- benzyloxy-2-(N-(2-hydroxypropyl)formamido)benzaldehyde (S-3).
Step 3. Compound 3 is reacted with a base or an acid in the presence of water and an organic solvent, to yield (+)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzaldehyde (6). Preferably, base, is used and the preferred base is sodium hydroxide or potassium hydroxide and the preferred solvent is tetrahydrofuran and the temperature is 0 to.35 °C, preferably 20 to 25 °C. Preferably, an- inert atmosphere, e.g., nitrogen or argon, is maintained.
Alternatively, compound R-3 is reacted according to the foregoing method to yield (i?)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzaldehyde (R-6). Alternatively, compound 5-3 is reacted according to the foregoing"method to yield (ιS)-4-benzyloxy-2-
(2-hydroxypropyl)aminobenzardehyde (-S'-6). Sequence B:
Step 1. 4-Benzyloxy-2-fluorobenzonitrile (4) is reacted with (+)-l-amino-2-propanol in an organic solvent, to yield (+)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzonitrile (5).
At least two molar equivalents of l-amino-2^propanol are used, as one molar equivalent is consumed as the amine hydrofluoride. Alternatively an auxiliary base is employed, for example a tertiary amine such as triethylamine or N,N-disopropylethylamine, an alkali metal carbonate such as sodium carbonate or potassium carbonate, or basic alumina.
When the auxiliary base is employed, less than two molar equivalents of (±)-l-amino-2- propanol can be used, preferably about 1.5 molar equivalents. Preferably an auxiliary base is employed, most preferably basic alumina. The solvent is preferably a dipolar aprotic solvent, for example dimethyl sulfoxide or N-methylpyrrolidone. The temperature is 80 to 140 °C, preferably 100 to 120 °C. Optionally, a drying agent; e.g., zeolite molecular sieves, is present.
Alternatively, compound 4 is reacted with (R)-l-amino-2-propanol according to the foregoing method to yield (i?)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzohitrile (R-5). Alternatively, compound 4 is reacted with (S)-l-amino-2-propanol according to the foregoing method to yield (5)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzonitrile
(S-5).
Step 2. Compound 5 is reacted with a hydrogen source and a catalyst in a solvent mixture containing water, an acidic component and an organic solvent, to yield (±)-4- benzyloxy-2-(2-hydroxypropyl)aminobenzaldehyde (6). The organic solvent can be
formic acid, which also serves as the acidic component and hydrogen source, or acetic acid, which also serves as the acidic component. Optionally an organic co solvent can be used, for example pyridine. The hydrogen source an be, "for example, hydrogen gas, hypophosphorous acid, or ' an inorganic hypophosphite salt such as sodium hypophosphite. Preferably the solvent is a mixture of pyridine, acetic acid, and water in a ratio of about 2:1:1 parts by volume. Preferably, the hydrogen source is sodium hypophosphite and preferably the catalyst is Raney nickel. The temperature is 20 to 60 °C, preferably 40 to 45 °C. [This method is generally described in Fieser and Fieser, Reagents for Organic Synthesis, Volume 1, page 726 (1967).]
Alternatively, compound R~5 is reacted according to the foregoing method to yield (i?)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzaldehyde (R-6). Alternatively, compound S-5 is reacted according to the foregoing method to yield (5)-4-benzyloxy-2- (2-hydroxypropyl)aminobenzaldehyde (S-6) . Compound 6 is reacted with an organic nitrite, e.g., isoamyl nitrite, in an organic solvent (e^g., tetrahydrofuran), or with an inorganic nitrite, e.g., sodium nitrite, in an organic solvent (e.g., acetic acid), or organic-aqueous solvent pair (e.g., acetic acid- water; tetrahydrofuran -dilute aqueous HC1) to • yield (+)-4-benzyloxy-2-(2- hydroxypropyl)nitrosaminobenzaldehyde (7). Preferably the nitrite is sodium nitrite and the solvent is acetic acid-water. Preferably the temperature is kept between about 0 °C and 35 °C. Preferably an inert atmosphere, e.g., nitrogen or argon, is maintained.. The preferred method is to react 6 with about 1.2 molar equivalents of NaN0 in acetic acid- water (about 4: 1 parts by volume) at 15 to 25 °C. The resulting compound 7 can be isolated, but it is preferable instead to convert 7 without isolation to 8 e.g., by a one-flask method as described herein.
Alternatively, compound R~6 is reacted according to the foregoing method to yield (i?):4-benzyloxy-2-(2-hydroxypropyl)nitrosaminobenzaldehyde (R-7)-
Alternatively, compound S-6 is reacted according to the foregoing method to yield (<S)-4- benzyloxy-2-(2-hydroxypropyl)nitrosaminobenzaldehyde (5'-7). Compound 7 is reacted with a reducing agent in an organic solvent optionally containing water to yield (+)-6-benzyloxy-l-(2-hydroxypropyl) indazole (8). Preferably the reducing agent is zinc and the solvent is a mixture of acetic acid and water in a ratio of about 4: 1 parts by volume. Most preferably, the reduction is carried out by adding zinc to the reaction mixture in which compound 7 was prepared from compound 6, without isolation of compound 7.
The desired reduction-cyclization reaction of 7 to 8 can be accompanied by a competing denitrosation reaction to regenerate 6. When zinc dust is used as the reducing agent, the ratio of 8 to 6 is about 5:1. The nitrosation-reduction sequence can be repeated on the crude reaction mixture to effect nearly complete conversion of 6 to 8. Alternatively, removal of 6 from the crude product can be effected by chromatography. Alternatively, 6 is removed as a water-soluble hydrazone derivative which is formed by treating the crude product with, e.g., .Girard's Reagent T or Girard's Reagent P. Alternatively, 6 is removed as a polymer-bound hydrazone derivative by treating the crude product with a polymer-bound arenesulfonylhydrazide resin. Alternatively, compound R-l is reacted according to the foregoing method to yield (i?)-6-benzyloxy-l-(2-hydroxypropyl)indazole (R-S). Alternatively, compound SV7 is reacted according to the foregoing method to yield (5)-6-benzyloxy-l-(2- hydroxypropyl)indazole (S-S).
Compound 8 is reacted with an alkanesulfonyl halide or anhydride, or with an arenesulfonyl halide or anhydride, in an organic solvent in the presence of a base, to form
the corresponding sulfonic ester. Preferably an alkanesulfonyl halide is used, most preferably methanesulfonyl chloride. The organic solvent can be pyridine which also serves as the base. Preferably the solvent is dichloromethane and the base is triethylamine. Preferably an inert atmosphere, e.g., nitrogen or argon, is maintained. The sulfonic ester thus obtained is reacted with an alkali metal azide in an organic, solvent, to yield (+)-l-(2-azidopropyl)-6-benzyloxyindazole (9). Preferably the alkali metal azide is sodium azide and the solvent is preferably a dipolar aprotic solvent, most preferably N,N- dimethylformamide. The temperature can b7e 25 to 80 °C, preferably about 60 °C, and other temperatures are possible. Alternatively, compound R-S is reacted according to the foregoing method to yield (5)-l-(2-azidopropyl)-6-benzyloxyindazole (S-9). Alternatively, compound S-S is reacted according to the foregoing method to yield (R)-l-(2-azidopropyl)-6- benzyloxyindazole (R-9).
Compound 9 is reacted with a hydrogen source and a catalyst in an organic solvent, to yield (±)-l-(2-aminopropyl)-6-hydroxy indazole (10). Preferably the hydrogen source is ammonium formate, the catalyst is palladium on charcoal and the solvent is ethanol.
Alternatively, compound S-9 is reacted according to the foregoing method to yield (5)-l-(2-aminopropyl)-6-hydroxy indazole (£-10). Alternatively, compound R-9 is reacted according to the foregoing method to yield (R)-l-(2-aminopropyl)-6-hydroxy indazole (R-IQ).
The following examples are given to illustrate the preparation of compounds that are the subject of this invention but should not be construed as implying any limitations to the claims.
FXAMPT F.S
Preparation of (+)-6-benzyloxy-l-(2-hydroxypropyI)indole (2). To a stirred, cooled
(10 °C) suspension of NaH (80.7 g of a 60% dispersion in mineral oil, 2.02 mol) in anhydrous THF (1.9 L) was added a solution of 6-benzyloxyindole (1) (375 g, 1.68 mol) in anhydrous THF (1.9 L) keeping the temperature below 25 °C. After 2 h at 10 °C, (+)- propylene oxide (140 L, 2.0 mol) was added dropwise keeping the temperature below
25 °C. After 48 h at 10 °C, (±)-propylene oxide (71 mL, 1.0 mol) was added. After 96 h at 10 °C , saturated aqueous KH2P04 (3.8 Jf) and ethyl acetate (3.8 L) were carefully added, the layers were separated and the aqueous solution was extracted with 3.8 L of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to yield 2 (520 g, 110%, contains mineral oil). Preparation of (+)-4-Benzyloxy-2-(N-(2-hydroxypropyI)formamido)benzaIdehyde (3). A solution of 172 g of 2 in 1.5 L of dichloromethane was cooled to 78 °C and ozonized (4% ozone in oxygen). Excess ozone was displaced with oxygen for 5 min, followed by addition of 78 mL of dimethyl sulfide and warming to 25 °C. The solution was concentrated to half volume, eluted through Florisil rinsing with ethyl ether-ethyl acetate and concentrated in vacuo. One additional run on 172 g scale and three runs on 58-g scale were performed. The combined products were eluted through silica (2.5 kg) with a gradient of 10%-80% ethyl acetate-hexane to yield, after concentration in vacuo, 3 (351 g, 70%) as an oil.
Preparation of (+)-4-BenzyIoxy-2-(2-hydroxypropy.)aminobenzaldehyde (6). An ice-cooled solution of 3 (298 g, 0.95 mol) in THF (3 L) Was treated with 1M aq NaOH (1.95 L, 1.9 mol) keeping the temperature below 8° C. After 3 was consumed, the mixture, was diluted with brine and extracted twice with ethyl ether. The organic solution was washed with water until neutral and with brine, dried over sodium sulfate, treated
with charcoal and eluted through silica (1 kg) with ether and with 1:1 ethyl acetate- hexane to yield, after concentration in vacuo, 6 (207 g, 76%) as a yellow solid. Preparation of 4-BenzyIoxy-2-fluorobenzonitriIe (4). Benzyl bromide (467 mL, 3.93 mol) and potassium carbonate' (1.4 kg, 10.1 mol) were added to a solution of 2-fluoro-4- hydroxybenzonitrile (490 g, 3.57 mol) in 3.4 L of acetone. The stirred mixture was heated at 60 °C for 20 h, then cooled and filtered. The filtrate was concentrated and the resulting solid was triturated with 10% ethyl acetate-hexane (5 L) and vacuum dried at 35 °C to yield 4 (787 g, 97%). Preparation of (R -4-Benzyloxy-2-(2-hydroxypropyl)aminobenzonitrile (R-5). A solution of (R)-(-)-lramino-2-propanol (389 g, 5.19 mol) in DMSO (600 mL) was added to a solution of 4 (786 g, 3.46 mol), basic alumina (786 g), and 4A molecular sieves (131 g). The stirred mixture was heated at 110-140 °C for 24 h, cooled' and filtered through Celite, washing with 10 L of 4:1 ether-ethyl acetate followed by 4 L of 3:2 ethyl acetate- hexane. The organic washes were extracted with water (5 L) and the aqueous phase was extracted with four 2-L. portions of 25% ethyl acetate-hexane'. The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated to about 4 L and allowed to stand for 48 h. The precipitated solid was collected by . • filtration, washed with hexane and vacuum dried to provide R-5 (first crop 613 g, second crop, 86 g). The concentated supernatant was applied to a 5 kg silica gel pad and eluted with a gradient of 10-50% ethyl acetate-hexane to give, after concentration in vacuo, 119 g of 5, for a total yield of 791 g (81%) ofΛ-5.
Preparation of 2? 4-Benzyloxy-2-(2-hydroxypropyl)aminobenzaIdehyde (R-6).
Sodium hypophosphite hydrate (986 g, 11.2 mol) and Raney nickel (500 g of a 50% aqueous suspension) were added to a solution of R-5 (790 g, 2.8 mol) in 7 L of 2:1:1 pyridine-acetic acid-water. The mixture was stirred at 45 °C for 7 h, then cooled to 25
°C overnight and filtered through Celite rinsing with water and ethyl acetate. The filtrate was washed with saturated Na2HP04 to pH 5, with water and brine, dried over sodium sulfate and concentrated. During concentration, 4 L "of heptane was added to azeotropically remove pyridine. After 8 L of solvent had been removed the product solidified. Heptane (5 L) was added and the solid was triturated, isolated by filtration and vacuum dried at 35 °C to yield R-6 (722 g, 90%).
Preparation of (^)-6-benzyloxy-l-(2-hydroxypropyl)indazole (R-8). Sodium nitrite
(209 g, 3.03 mol) was added over 25 min to a stirred solution of R-6 (720 g, 0.2.53 mol) in acetic acid (5.6 L) and water (1.4 L), keeping the temperature below 25° C. The resulting solution of nitrosamine R-1 was cooled in ice, and zinc dust (595 g, 9.10 mol) was added in 25-g portions over 3.5 h, keeping the temperature below 35°C. Ethyl acetate (7 L) was added and the thick suspension was filtered on a sintered glass funnel, washing with ethyl acetate (7.5 L). To the filtrate containing a 5:1 mixture of R-8 and regenerated R-6 was added Girard's Reagent T (98 g, 0.58 mol). After stirring at 25° C for 1 day, another 150 g (0.90 mol) of Girard's Reagent T was added. After 3 more days R-6 was consumed. The mixture was extracted twice with water, with aqueous Na2HP0 to remove acetic acid, with water and brine, dried over sodium sulfate, filtered through Florisil and concentrated. The residue was eluted through 5 kg of silica with 1 : 1 ethyl acetate-hexane. Clean fractions were concentrated and 4 L of heptane was added to precipitate R-8. The solid was collected by filtration, washed with 1:1 ethyl acetate- hexane and vacuum dried at 35°C to yield (417 g, 58%) of a yellow solid, composed of 96.7% R-8, 0.3% S-8 and 3% R-6 by HPLC. Concentration of the supernatant afforded an additional 141 g (20%) of R-8. Preparation of (+)-6-benzyloxy-l-(2-hydroxypropyl)lndazoIe (8). The procedure described for R-8 was followed, beginning with (±)-6 (202.7 g, 0.71 mol). After
nitrosamine 7 had been converted to a mixture of 8 and 6 (5:1), sodium nitrite (29.5 g,
0.43 mol) was added to renitrosate 6. Zinc dust (84 g, 1.28 mol) was then added in portions with cooling as described above. When the formation of 8 was. complete, the reaction mixture was worked up as described above and combined with the product from another run that started with 176 g of 6. The combined crude product was purified by chromatography on a Biotage Kiloprep-250 instrument, eluting with ethyl acetate- hexane, to yield 8 (226 g, 60%) of 99% HPLC purity.
Preparation of (S^-l-(2-Azidopropyl)-6-benzyloxyindazole (S-9). A solution of R-8 (415 g, 1.47 mol) in dichloromethane (4 L) was treated with triethylamine (224 mL, 1.6 mol) and cooled to 0 °C. Methanesulfonyl chloride (125 mL, 1.6 mol) was added keeping the temperature below 25 °C. The mixture was stirred at 25 °C until complete and was then quenched with water (4 L) and stirred vigorously. The layers were separated and the aqueous layer was extracted with an additional 4 L of dichloromethane. The combined organic solutions were dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in DMF (4 L), sodium azide (191 g, 2.94 mol) was added and the mixture was stirred and heated to 70 °C for 16 h, then allowed to cool to 25 °C. Water (16 L) and diethyl ether (5.5 L) were added, the mixture was stirred vigorously and the layers were allowed to separated The aqueous layer was extracted with diethyl ether (2x7 L), and the combined organic solutions were concentrated and the residue was eluted through silica (6 kg) with 1:3 ethyl acetate/hexane. Product containing fractions were concentrated in vacuo to' yield S-9 (380 g, 84%) as an oil. Preparation of (3> -l-(2-Aminopropyl)-6-hydroxyindazole (S-10). Ammonium formate (312 g, 4.96 mol) and 10% Pd(C) (38 g) were added to a stirred solution of S-9 (380 g, 1.24 mol) in 4 L of EtOH. After 2 h, another 38 g of 10% Pd(C) was added. The mixture was stirred for 2 h, then filtered through Celite, rinsing with EtOH, and the
filtrate was concentrated. The residue was partitioned between saturated NaHC03 (4 L) and 1:1 ethyl acetate-THF (5 L). The aqueous phase was treated with 200 g of NaCl and extracted with 2:1 ethyl acetate-THF (3 x 4 L). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The solid residue was suspended in ethyl acetate (3 L), stirred for 0.5 h and filtered to give 200 g of a solid.
This material was suspended in THF (1 L) and the mixture was stirred for several minutes and filtered to give a solid, which was washed with cold THF (200 mL), air dried, and then dried for 16 h in vacuo at 45 °C to yield S-10 (183 g, 77%).
SCTTF.MF. T
HO. lA C> H, NH„
NaH, THF CH3 Al,0,, DMSO
Other embodiments of the present invention will be apparent to those skilled in the art from consideration of the present specification and practice of the present invention disclosed herein. It is intended that the present specification and examples be considered as- exemplary only, with a true scope and spirit of the invention being indicated by the following claims and equivalents thereof.