AU3471199A

AU3471199A - Oxidation process using tempo

Info

Publication number: AU3471199A
Application number: AU34711/99A
Authority: AU
Inventors: Jing Li; Zhiguo Song; David M Tschaen; Mangzu Zhao
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1998-04-09
Filing date: 1999-04-05
Publication date: 1999-11-01
Anticipated expiration: 2019-04-05
Also published as: CA2327890A1; JP2002511440A; WO1999052849A1; EP1070039A1; AU748207B2

Description

WO 99/52849 PCT/US99/07466 TITLE OF THE INVENTION OXIDATION PROCESS USING TEMPO BACKGROUND OF THE INVENTION 5 Oxidation is one of the most fundamental transformations in organic synthesis and there are numerous methods reported in the literature. (Hudlicky, M. "Oxidations In Organic Chemistry", ACS Monograph No. 186 American Chemical Society Washington D.C. (1990).) However, relatively few methods exist for the oxidation of 10 primary alcohols to the corresponding carboxylic acids. The most commonly used ones are CrO 3

H

2

SO

4 (Bowden; Heilbron; Jones; Weedon J. Chem. Soc., 1946, 39; Bowers; H.; Jones; L. J. Chem. Soc., 1953, 2548; Millar, J. G.; Oehlschlager, A. C.; Wong, J. W. J. Org. Chem. 1983,48, 4404.), RuCl 3 HO,10 6 (Carlsen, P. H. J.; Katsuki, T.; Martin V. S.; 15 Sharpless, K. B. J. Org. Chem. 1981, 46, 3936.) and TEMPO/NaCO10 (Nooy, A. E. J. de; Besemer, A. C.; Bekkum, H. v. Synthesis, 1996, 1153.; Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559.; Miyazawa, T.; Endo, T.; Shiihashi, S.; Okawara, M. J. Org. Chem. 1985, 50, 1332). A two-step process involving Swern oxidation 20 (Mancuso, A. J.; Huang, S-L., Swern, D. J. Org. Chem. 1978, 43, 2480.; Mancuso, A. J.; Brownfan, D. S.; Swern, D. J. Org. Chem. 1979,44, 4148.; Ireland, R.; Norbeck, D. J. Org. Chem. 1985, 50, 2198.) followed by oxidation of the resulting aldehyde with NaCO10 2 (Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.; Dalcanale,.E.; Montanari, 25 F. J. Org. Chem. 1986, 51, 567) is another option. All of these procedures have some limitations and disadvantages and new methods for the oxidation of primary alcohols to the carboxylic acids are still desired. (Schroder, M.; Griffith, W. P. J. Chem. Soc. Chem. Comm. 1979, 58.; and Paquette, L. A.; Dressel, J.; Pansegrau, P. D. Tetrahedron Lett. 30 1987, 28, 4965.) The present invention relates to an oxidation using sodium chlorite in the presence of a catalytic amount of TEMPO and sodium hypochlorite which converts a primary alcohol to a carboxylic acid. This oxidation method avoids the disposal issues associated with running a 35 Jones oxidation (CrO 3

/H

2

SO

4 ) reaction, as well as reducing the WO 99/52849 PCT/US99/07466 2 epimerization of any ac-chiral centers and is a one step procedure. For substrates prone to chlorination with the TEMPO-NaC10 protocol, the present invention reduces this problem. 5 SUMMARY OF THE INVENTION The present invention discloses a process for preparing a compound of Formula I:

R

1-C O 2 H I wherein: 10 R 1 is: a) H, b) Cl-C8 alkyl, c) C2-C8 alkynyl, d) C3-C7 cycloalkyl, 15 e) aryl, f) heteroaryl, or g) heterocyclyl; C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three 20 substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, and CO(CH2)nCH3, aryl is defined as phenyl or naphthyl , which is unsubstituted or substituted with one, two or three substituents selected from 25 the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, or when aryl is substituted on adjacent carbons they can form a 5- or 6-membered fused ring having one, two or three heteroatoms selected from O, N, 30 and S, this ring is unsubstituted or substituted on carbon or nitrogen with one, two or three substituents selected from WO 99/52849 PCT/US99/07466 3 the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and CO(CH2)nCH3; heteroaryl is defined as a 5- or 6-membered aromatic ring 5 containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and additionally 10 the 5- or 6-membered aromatic ring can be benzofused and unsubstituted or substituted with one, two or three substituents as described above; heterocyclyl is defined as a 5- or 6-membered, non-aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S , 15 which may contain one or two double bonds and which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and 20 additionally the 5- or 6-membered ring can be benzofused and unsubstituted or substituted with one, two or three substituents as described above; n is: 0 to 5; 25 t is: 0, 1 or 2;

R

4 is: H, or C1-C8 alkyl; or 30 comprising the following steps: 1) adding to a compound of Formula II in a solvent, WO 99/52849 PCT/US99/07466 4

R'-CH

2 OH II a solution of phosphate buffer to maintain a pH of about 4.0 to about 8.0; 5 2) maintaining the phosphate-buffered biphasic mixture of the compound of Formula II at about 0oC to about 50 0 C; 3) adding a catalytic amount of TEMPO to the mixture; and 10 4) charging the TEMPO/phosphate-buffered biphasic mixture with a solution of sodium chlorite and a catalytic amount of sodium hypochlorite to oxidize to the compound of Formula I. DETAILED DESCRIPTION OF THE INVENTION 15 The present invention discloses a process for preparing a compound of Formula I:

R

1-C O 2 H I wherein:

R

1 is: 20 a) H, b) C1-C8 alkyl, c) C2-C8 alkynyl, d) C3-C7 cycloalkyl, e) aryl, 25 f) heteroaryl, or g) heterocyclyl; C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, WO 99/52849 PCT/US99/07466 5 CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, and CO(CH2)nCH3, aryl is defined as phenyl or naphthyl , which is unsubstituted or substituted with one, two or three substituents selected from 5 the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, or when aryl is substituted on adjacent carbons they can form a 5- or 6-membered fused ring having one, two or three heteroatoms selected from O, N, 10 and S, this ring is unsubstituted or substituted on carbon or nitrogen with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and CO(CH2)nCH3; 15 heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 20 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and additionally the 5- or 6-membered aromatic ring can be benzofused and unsubstituted or substituted with one, two or three substituents as described above; heterocyclyl is defined as a 5- or 6-membered, non-aromatic ring 25 containing 1, 2 or 3 heteroatoms selected from O, N and S , which may contain one or two double bonds and which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 30 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and additionally the 5- or 6-membered ring can be benzofused and WO 99/52849 PCT/US99/07466 6 unsubstituted or substituted with one, two or three substituents as described above; n is: 0 to 5; 5 t is: 0, 1 or 2;

R

4 is: H, or C1-C8 alkyl; or 10 comprising the following steps: 1) adding to a compound of Formula II in a solvent,

R'-CH

2 OH 11 II a solution of phosphate buffer to maintain a pH of about 4.0 to about 8.0; 15 2) maintaining the phosphate-buffered biphasic mixture of the compound of Formula II at about 0 0 C to about 50 0 C; 3) adding a catalytic amount of TEMPO to the mixture; and 20 4) charging the TEMPO/phosphate-buffered biphasic mixture with a solution of sodium chlorite and a catalytic amount of sodium hypochlorite to oxidize to the compound of Formula I. 25 The process as recited above, wherein the solvent is selected from the group consisting of: acetonitrile, tetrahydrofuran, acetone, tertiary C 4

-C

8 -alcohol, diethyl ether, DME (dimethyl ether), diglyme, triglyme, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, dioxane, dichloromethane, chloroform, carbon tetrachloride, 30 or a mixture of said solvents. The process as recited above, wherein the phosphate buffer comprises an aqueous mixture of NaOH, KOH, NaH 2

PO

4 , KH 2

PO

4

,

WO 99/52849 PCT/US99/07466 7 Na 2

HPO

4 , and K 2

HPO

4 , sufficient to maintain a pH of about 4.0 to about 8.0, and preferably a pH of about 6.5 to about 7.0. The process as recited above, wherein TEMPO (2,2,6,6 tetramethyl-1-piperidinyloxy, free radical) is used in about 1.0 to about 5 10.0 mole percent, preferably about 5.0 to about 7.0 mole percent. The process as recited above, wherein sodium chlorite is used in about 1.0 to about 3.0 equivalents, and preferably about 2.0 equivalents relative to the compound of Formula II. The process as recited above, wherein sodium hypochlorite 10 is used in about 1.0 to about 7.0 mole percent, preferably about 2.0 to about 5.0 mole percent. The process as recited above, wherein the reaction temperature is about 0OC to about 50oC, and preferably about 35 0 C to about 40 0 C. 15 The process as recited above, wherein the reaction time is up to about 24 hours, and preferably between about 2 and about 4 hours. It is further understood that the substituents recited above would include the definitions recited below. 20 The alkyl substituents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, tert-butyl, neopentyl, isopentyl, etc. Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each of which may be substituted or unsubstituted with other 25 hydrocarbon substituents, and include for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl. The alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge. The aryl substituent represents phenyl and 1-naphthyl or 2 30 naphthyl, including aryls substituted with a 5- or 6-membered fused ring, such as an unsubstituted and substituted methylenedioxy, oxazolyl, imidazolyl, or thiazolyl ring. The heteroaryl substituent represents a carbazolyl, furanyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, 35 pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl.

WO 99/52849 PCT/US99/07466 8 The heterocyclyl substituent represents, oxazolidinyl, thiazolidinyl, thiazolidinyl, oxadiazolyl, or thiadiazolyl. Each of the above substituents (alkyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl) can be either 5 unsubstituted or substituted as defined within the description. Recently, in an attempt to oxidize primary alcohols, such as Im: O Bu CO 2 H OH Bu OMe 1m to the corresponding carboxylic acid, we found that RuClJHIO 6 protocol offered low yield of the desired products. See Carlsen, P. H. et al. J. Org. 10 Chem. 1981, 46, 3936. It was probably due to the destruction of electron rich aromatic ring. TEMPO catalyzed oxidation with bleach also gave low yield due to significant chlorination of the aromatic rings. See A. E. J. de Nooy, et al. Synthesis, 1996, 1153.; P. L. Anelli, et al. S. J. Org. Chem. 1987, 52, 2559. and T. Miyazawa, et al. J. Org. Chem. 1985, 50, 1332. The synthesis 15 of Im is decribed in Merck Case No. 20127PV, entitled "Oxidation Process Using TEMPO" which is being filed simultaneously with this application. In order to eliminate the chlorination problem, a few other oxidants (H 2 0 2 , AcO 2 H, t-BuO 2 H etc.) were examined, but no satisfactory 20 results was obtained. Finally, when sodium chlorite (NaC10 2 ) was used as the oxidant, the product were obtained in 70-90% yield. The reaction appeared to be very slow (1-2%/hour) but generally went to completion overnight (-20 hours). More careful monitoring of the reaction indicated WO 99/52849 PCT/US99/07466 9 that it was self accelerating process e.g. the conversion was less than 5% after one hour but reached -90% in only 6 hours. Apparently, some more active species was generated as the reaction progress. Sodium hypochlorite (NaClO, bleach) was believed to be the most likely 5 candidate. Indeed, when 10mol% of bleach was added to the reaction mixture, the reaction was accelerate dramatically. It reached >50% conversion in one hour and finished in approximately three hours. SCHEME 1 R I OH Formula II TEMPO, NaCIO 2 , NaCIO

R

1 C0 2 H 10 Formula I The reaction was then optimized regard to further reduce the chlorination and enhance the safety for scale up. The reaction was faster at lower pH, but it was accompanied by increased chlorination. It was slower at lower temperature as expected, but surprisingly, the 15 chlorination level appeared to be slightly elevated. Increasing the amount of TEMPO and bleach increased the reaction rate, but the TEMPO/NaC10 ratio should be >2 to reduce the chances of chlorination. The bleach was added slowly and simultaneously with NaCO10 2 to the batch at 35 oC to prevent build up of the oxidant and the risk of a run 20 away reaction. It should be noted that mixing of bleach and NaC10 2 prior to the addition is not advised since some toxic and potentially explosive chlorine dioxide (C10 2 ) may be generated. Next, a number of primary alcohols were oxidized to the carboxylic acids and the results are summarized in Table 1. In general, 25 the reaction were very smooth and the yield were excellent (85-100%).

WO 99/52849 PCT/US99/07466 10 Chiral alcohols 1g, lj, and 1k were oxidized to the corresponding carboxylic acid without any racemization of the labile chiral centers. Mostly notably, for substrates prone to chlorination (lc-lh), our new procedure gave much better yields. The most dramatic 5 demonstration of the superiority of our new procedure was revealed in entry 5. When le was treated with NaCO10 and catalytic TEMPO, the desired product was obtained in less than 5% yield. One of the major side product was isolated and identified to be the chlorinated compound 4, CI

CO

2 H OMe 4 10 based on NMR studies. On the other hand, our TEMPO/NaC1O 2 protocol offered essentially quantitative yield of 2e.

WO 99/52849 PCT/US99/07466 11 Table 1: TEMPO Catalyzed Oxidation of Primary Alcohols to Carboxylic Acids 5 Substrate Product Yield Yield (NaCIO 2 ) (NaCIO) Ph OH Ph"CO2H 98% la 2a Ph - OH Ph - CO 2 H 100% lb 2b OH CO2H 99% 65% OMe OMe lc 2c OH MCO 2 H 100% 86% MeOMeO 2d ld OH CO 2 H 96% <5% OMe le OMe 2e Br Br 96% 80% OH If O CO 2 H OMe if OMe 2f WO 99/52849 PCT/US99/07466 12 Table 1: (Cont.) TEMPO Catalyzed Oxidation of Primary Alcohols to Carboxylic Acids 5 Substrate Product Yield Yield (NaCIO,) (NaCIO) Br Br 92% 60% OH CO 2 H OMe 1g OMe 2g OH Ph CO 2 H 90% 20% Ph 2h 1h OH . 95% Ph ii Ph

CO

2 H 2i HO 0 H0 2 0 95% N N Ph'" Ph"" 0 0 1j 2j Ph ," OH Ph ' CO 2 H 85% NHCBZ NHCBZ 1k 2k 2OH 2CO 2 H 100% 0 2 N 0 2 N 1 21 In conclusion, an efficient and environmentally benign procedure for the oxidation of primary alcohols to the carboxylic acids 10 has been developed. In this procedure, NaC10 2 is used as the stoichiometric oxidant in the presence of catalytic amount of TEMPO WO 99/52849 PCT/US99/07466 13 and bleach (NaCIO). Most primary alcohols were oxidized in essentially quantitative yield. Compared with TEMPO/NaCO10/CH 2 Cl 2 protocol, the amount of chlorination of electron rich aromatic rings in the substrates were dramatically reduced and the yield and purity of the products 5 improved. Additionally, no chlorinated solvent is used. The instant invention can be understood further by the following examples, which do not constitute a limitation of the invention. General: All substrates and reagents were obtained 10 commercially, except 1g (See Examples 2-5 decribing the preparation of this primary alcohol) and used without purification. 'H and 13C NMR spectra were recorded at 250 and 62.5 MHz respectively. The products were identified by comparing their NMR spectra with those of commercial materials except for 2g and 2j. The yields were determined 15 by reverse phase HPLC with Zorbax SB-Phenyl or YMC ODS-AM columns and MeCN/0.1% HPO 4 as the mobile phase. EXAMPLE 1 20 Oxidation of Primary Alcohol-TEMPO Oxidation NaCIO 2 R1 OH TEMPO R 1

CO

2 H Formula II NaCIO Formula I A mixture of the primary alcohol 1 (40 mmol) in MeCN (200 mL) and sodium phosphate buffer (0.67 M, pH= 6.7 ) was 25 heated to 35 oC. TEMPO (436 mg, 2.8 mmol) was added then a solution of sodium chlorite (9.14 g 80%, 80.0 mmol in 40 mL water) and a solution of dilute bleach (1.06 mL 5.25% bleach diluted into 20 mL, 2.0mol%) were added simultaneously in 2 hours.* *Do not mix the sodium chlorite solution and bleach prior to 30 the addition since the mixture appears to be unstable. The addition should be carried out as follows: approximately 20% of the sodium chlorite solution is added followed by 20% WO 99/52849 PCT/US99/07466 14 of the dilute bleach. Then the rest of the NaC10 2 solution and dilute bleach are added simultaneously in 2 hours. The reaction is slightly exothermic. The mixture was stirred at 35 oC until the reaction is 5 complete (<2A% SM, 2-4 h) then cooled to rt. Water (300 mL) was added and the pH was adjusted to 8.0 with 2.0 N NaOH (~48 mL). The reaction was quenched by pouring into cold (0 oC) Na 2

SO

3 solution (12.2 g in 200 mL water) maintained < 20 oC. The pH of the aqueous layer should be 8.5-9.0 After stirring for 0.5 hour at rt, MTBE (200 mL) was added with 10 stirring. The organic layer was separated discarded. More MTBE (300 mL) was added and aqueous layer was acidified with 2.0 N HCI (~100 mL) with stirring to pH = 3-4. The organic layer was washed with water (2 x 100 mL), brine (150 mL) to give a solution of the crude carboxylic acid 2 in 90-95% yield. 15 EXAMPLE 2 Preparation of 2-bromo-5-methoxybenzyl alcohol Br Br C0 2 H OH OMe OMe 20 Sodium borohydride (8.6 g) is slurried in THF (150mL KF=150 gg/mL) in a round bottom flask equipped with a thermocouple, an addition funnel, a nitrogen inlet a mechanical stirrer and a cooling bath. 2-Bromo-5-methoxybenzoic acid (50 g) is dissolved in THF (100mL KF= 150 gg/mL) is added to the sodium borohydride slurry over 45 min 25 while maintaining the temperature at 20-25oC. The reaction must be controlled with intermittent cooling and by careful monitoring of the addition rate. The mixture is aged for 30 min at 20-25oC. Boron trifluoride etherate (36.9 g) is added over a period of 30 min at 30-35'C. The addition of boron trifluoride etherate produces a delayed 30 exotherm and should be added slowly in order to control the reaction WO 99/52849 PCT/US99/07466 15 temperature. The resulting white slurry is aged for 1 h at 30-35 0 C and then sampled for HPLC assay. A peak at RT = 8.7 min is an impurity related to the starting material. The acid is at RT = 9.1min. The reaction mixture is cooled to 15 0 C and carefully 5 quenched into a cold (10 oC) saturated ammonium chloride solution (150 mL) while maintaining the temperature < 25 0 C. Ethyl acetate (500 mL) is added and the layers are separated. The organic layer is washed with water (100 mL) and then transfered to a 1L round bottom flask equipped for distillation. The 10 solution was concentrated and charged with fresh ethyl acetate. This is repeated until a solution with a volume of 200 mL has KF<200 gg/mL.The solvent is then switched to DMF to give the final volume of 200 mL with a KF<200 gg/mL. 15 EXAMPLE 3 Preparation of 2-bromo-5-methoxybenzyl chloride Br Br OH ________CI OMe OMe 20 The DMF solution of the benzyl alcohol (91.3 g in 400mL KF=300 gg/mL) is charged to a 2 L flask equipped with a mechanical stirrer, thermocouple, N 2 inlet, and cooling bath. The solution is cooled to 0-5 0 C and the addition funnel is charged with thionyl chloride (55.0 g). The thionyl chloride is added over a period of 45 min while maintaining 25 the temperture 5-10oC. The mixture is aged for 1 h at 50C and assayed by HPLC. The addition funnel is charged with water (400 mL) which is added dropwise to the reaction mixture over a period of 30 min. while maintaining the temperture < 15'C. The temperature is controlled by WO 99/52849 PCT/US99/07466 16 cooling and monitoring the rate of addition. The initial addition of water is highly exothermic. Using large excess of thionyl chloride results in a more exothermic quench. If the quench temperture is not controlled, hydrolysis of the benzyl chloride back to the alcohol may result. 5 The resulting thick white slurry is aged for 1 h at 0-5°C. The benzyl chloride is isolated by filtration. The cake is washed with (1:1) DMF:H 2 0 (100mL) and then water (200 mL). The solid is dried in vacuo to give 93 g of the benzyl chloride( 94% yield, 96 A%). HPLC assay: Column: Waters Symmetry C8, 4.6 x 250mm; UV 10 Detection: 220 nm; Column Temp: 25 oC; Flow rate: 1 mL / min.; Eluent:

CH

3

CN:H

2 0:0.1% H 3

PO

4 (70:30); RT (benzyl alcohol) = 3.9 min; RT (benzyl chloride) = 7.3 min.; and RT (DMF) = 2.6 min. EXAMPLE 4 15 Preparation of the Acetonide of N-propanoyl (1R,2S)-cis-aminoindanol 0

H

2 N, 7 N H0 1 ,,. O O1.. A 5 L 3-neck round bottom flask equipped with a mechanical stirrer, N2 inlet, thermocouple probe, heating mantle, and 20 addition funnel is charged with (1R,2S)-cis-aminoindanol (100 g), tetrahydrofuran (1.2 L, KF 120 Rg/mL), and triethylamine (96 mL, KF 500 gg/mL). The resulting slurry is heated under a N 2 atmosphere to 40 45oC giving a yellow solution. Propionyl chloride (59 mL) is charged to an addition funnel and added to the solution while maintaining the 25 temperature at 45-50'C. The temperature is controlled by rate of propionyl chloride addition and a cooling bath. HPLC assay shows >99% amide formed. Methanesulfonic acid (3 mL) is added to the reaction slurry. 2- WO 99/52849 PCT/US99/07466 17 Methoxypropene (140 mL) is charged to an addition funnel and added over 30 minutes at a temperature of 50'C. The addition of 2-methoxypropene is mildly exothermic. The temperature is maintained by the rate of addition and a heating 5 mantle. The reaction remains a slurry but does become less thick. The reaction slurry is aged for 1-2 hours at 50 0 C. HPLC assay at this point shows <0.5A% of the amide remaining. The amide is not removed in the isolation so it is important to push the reaction to completion. The reaction slurry is cooled to 0-5oC and quenched by 10 addition of 5% aqueous sodium carbonate solution (1 L) and heptane (1 L). The layers are stirred and separated and the organic is washed with water (300 mL). HPLC assay at this point shows the acetonide in >98A% and >90% yield. The acetonide/THF/heptane solution is filtered into a 2 L 15 round bottom flask and the solution is distilled to a final volume of 700mL. Heptane (UL) is added and the solution is distilled to a final volume of 700mL. The distillation is done under partial vacuum at -50'C. NMR assay at this point shows < 2 mol% THF. The solution is allowed to cool and is seeded with acetonide at 35-40 0 C. The thick slurry 20 is aged for 1 hour at ambient temperature then cooled to 0-5oC and aged for 1 hour. The slurry is filtered and the cake is washed with cold heptane (200 mL) and air dried to yield acetonide as a crystalline white solid (141.1 g, 85% yield, 99.6 A%). 25 EXAMPLE 5 Alkylation of the Acetonide with 2 -bromo-5-methoxybenzyl chloride. Br 1) Cl Br N OH 0,, OMe LiHMDS, THF, -100C e 2) HOMeI 2) HCI WO 99/52849 PCT/US99/07466 18 A THF solution (2L, KF< 200 gg/mL) of the acetonide (252 g) and the benzyl chloride (255 g) is cooled to -10oC. Lithium bis(trimethylsilyl)amide (1.45 L) is added dropwise over 5 h at 0-2oC. The mixture is then aged for 1.5 h and assayed by HPLC. 5 The reaction is quenched by adding aqueous saturated ammonium chloride solution (1 L). The initial addition of the ammonium chloride should be slow in order to control the foaming. The rate can be increased when the foaming subsides. The quenched reaction is then transfered into a mixture of 10 aqueous ammonium chloride (1.5 L), water (0.5 L), and ethyl acetate (3 L). The mixture is then agitated for 15 min and the layers are separated. The organic layer is washed with water (1 L) and brine (0.5 L). The ethyl acetate solution is concentrated to a low volume and solvent switched to 1,4-dioxane. The dioxane solution is adjusted to a final volume of 1.8 L. 15 The dioxane solution of the coupled product is charged to a 12 L round bottom flask and 6 M HC1 (1.5 L) is charged. The mixture is heated to reflux and monitored by HPLC. The mixture is cooled to 20 0 C and MTBE (3 L) is added. The mixture is agitated for 15 min and the layers are separated. The organic 20 layer is washed with water (1 L). The MTBE solution of the crude acid is extracted with 0.6 M sodium hydroxide (2 L). The aqueous solution of the sodium salt of the acid is combined with MTBE (2.5 L) and cooled to 10C. The two phase mixture is acidified with 5.4 M sulfuric acid (250 mL), agitated for 15 min, settled and the layers separated. The 25 MTBE solution of the acid is washed with water (0.5 L). The MTBE solution of the acid is dried by distilation and then solvent switched to THF. The final volume of the THF is 2 L with a KF < 250 gg/mL. HPLC assay: column: Waters Symmetry; Eluent: acetontrile: water: phosphoric acid (70:30:0.1); Flow rate: 1 mL/min.; RT (acetonide)= 4.5 30 min.; RT (benzyl chloride) = 7.5 min.; RT (coupled product) = 11.5 min.; RT (aminondanol) = 1.7 min.; RT (hydroxyamide) = 1.7 min.; and RT (acid) = 4.5 min.

WO 99/52849 PCT/US99/07466 19 EXAMPLE 6 Preparation of 3-(2-bromo-5-methoxyphenyl)-2-methylpropanol Br 0 Br OH NaBH 4

/BF

3 (Et 2 O) OH THF OMe OMe Sodium borohydride (33 g) is slurried in THF (0.5 L KF=200 5 tg/mL) in a round bottom flask. The THF solution (2 L) of the acid is added to the sodium borohydride slurry over 1 h while maintaining the temperature at 20-25 0 C. The reaction is controlled with a cooling bath and by carefully monitoring the addition rate. A nitrogen sweep and proper 10 venting of the hydrogen is also important. The mixture is aged for 30 min at 20-25 'C. Boron trifluoride etherate (152 g) is added over 1 h at 30-35 oC. The addition produces a delayed exotherm and should be carefully monitored in order to control the reaction temperature. The resulting milky white slurry is aged for 1 15 h at 30 °C and sampled for HPLC assay. The reaction mixture is cooled to 15 oC and carefully quenched in a cold (10C) ammonium chloride solution (1.5 L) while maintaing the temperature at 25 oC. The rate of hydrogen evolution is controlled by the rate of the addition of the mixture into the ammonium 20 chloride. The quenched mixture is distilled in vacuo to remove the THF. The aqueous layer is extracted with MTBE (1.5 L) and the organic layer is dried by flushing with additional MTBE. The MTBE solution is then solvent switched to hexanes and adjusted to a volume of 350 mL and seeded. The slurry is aged for 2 h at 20 oC and then cooled to 0-5 oC aged 25 for 1 h and filtered. The cake is washed with cold hexanes (200 mL). The solid is dried under a nitrogen sweep. The isolated solid (164 g) is > 99A% by HPLC and > 99%ee.

WO 99/52849 PCT/US99/07466 20 HPLC: Column: Waters Symmetry C8; Solvent: acetonitrile:water: phosphoric acid (50:50:0.1); Flow rate: lmL /min.; Detection: 220 nm; RT (acid) = 10.2 min.; RT (alcohol) = 10.7min. Chiral HPLC: Column: Chiracel OD-H; Hexane:2-propanol (97:3); Flow 5 rate: 1 mL/ min.; Detection: 220 nm; RT minor isomer = 21 min.; and RT major isomer = 23 min. EXAMPLE 7 Preparation of 3

-(

2 -bromo-5-methoxyphenyl)-2-methylpropanoic acid Br Br 0 OH TEMPO, NaCIO 2 , OH NaCIO / 10 OMe OMe The acid was prepared following the general procedure recited in Example 1. 2g: 1 H NMR (CDCla) L8: 7.44 (d, J=8.7 Hz, 1H), 6.78 (d, J=3.1 Hz, 15 1H), 6.66 (dd, J=8.7, 3.1 Hz, 1H), 3.75 (s, 3H), 3.13 (dd, J=13.1, 6.8 Hz, 1H), 2.98-2.84 (m, 1H), 2.77 (dd, J=13.1, 7.4 Hz, 1H), 1.23 (d, J=6.9 Hz, 3H). 2j: 'H NMR (CDCla): 9.0-8.0 (broad, 1 H), 7.47-7.30 (m, 5H), 5.71 (d, J = 7.7 Hz, 1H), 4.43 (d, J = 7.7 Hz, 1H), 2.70-2.40 (m, 2H), 2.33 20 2.27 (m, 1H), 2.17-1.80 (m, 3H), 1.58 (s, 3H). UC NMR (CDC) 8: 172.04, 169.48, 137.52, 128.73, 126.16, 94.66, 77.05, 64.34, 34.52, 29.91, 23.45, 17.28. Anal. Calcd for CH:NO C, 65.44; H, 6.22; N, 5.09. Found C, 65.31; H, 6.15; N, 4.98. 25

Claims

1. A process for preparing a compound of Formula I: R 1 -C0 2 H wherein: 5 R 1 is: a) H, b) C1-C8 alkyl, c) C2-C8 alkynyl, d) C3-C7 cycloalkyl, 10 e) aryl, f) heteroaryl, or g) heterocyclyl; C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three 15 substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, and CO(CH2)nCH3, aryl is defined as phenyl or naphthyl , which is unsubstituted or substituted with one, two or three substituents selected from 20 the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, or when aryl is substituted on adjacent carbons they can form a 5- or 6-membered fused ring having one, two or three heteroatoms selected from O, N, 25 and S, this ring is unsubstituted or substituted on carbon or nitrogen with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, and CO(CH2)nCH3; 30 heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, WO 99/52849 PCT/US99/07466 22 which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and additionally 5 the 5- or 6-membered aromatic ring can be benzofused and unsubstituted or substituted with one, two or three substituents as described above; heterocyclyl is defined as a 5- or 6-membered, non-aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, 10 which may contain one or two double bonds and which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 , Br, Cl, F, I, CF3, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and additionally 15 the 5- or 6-membered ring can be benzofused and unsubstituted or substituted with one, two or three substituents as described above; n is: 0 to 5; 20 t is: 0, 1 or 2; R 4 is: H, or C1-C8 alkyl; or 25 comprising the following steps: 1) adding to a compound of Formula II in a solvent, R'-CH 2 OH II a solution of phosphate buffer to maintain a pH of about 4.0 to about 8.0; 30 2) maintaining the phosphate-buffered biphasic mixture of the compound of Formula II at about 0oC to about 50'C; WO 99/52849 PCT/US99/07466 23 3) adding a catalytic amount of TEMPO to the mixture; and 4) charging the TEMPO/phosphate-buffered biphasic mixture 5 with a solution of sodium chlorite and a catalytic amount of sodium hypochlorite to oxidize to the compound of Formula I.

2. The process as recited in Claim 1, wherein the solvent is selected from the group consisting of: acetonitrile, 10 tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), DME (dimethoxyethane), DIGLYME (2-methoxyethyl ether), TRIGLYME (triethylene glycol dimethyl ether), toluene, benzene, hexane, pentane, dioxane, or a mixture of said solvents, including a mixture of said solvents with water. 15

3. The process as recited in Claim 2, wherein the phosphate buffer comprises an aqueous mixture of NaOH, KOH, NaH 2 PO 4 , KH 2 PO 4 , Na 2 HP0 4 , and K 2 HPO 4 , sufficient to maintain a pH of about 4.0 to about 8.0. 20

4. The process as recited in Claim 3, wherein TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) is used in about 1.0 to about 10.0 mole percent. 25

5. The process as recited in Claim 4, wherein sodium chlorite is used in about 1.0 to about 3.0 equivalents.

6. The process as recited in Claim 5, wherein sodium hypochlorite is used in about 1.0 to about 7.0 mole percent. 30

7. The process as recited in Claim 6, wherein the reaction temperature is about 0 0 C to about 50 0 C.

8. The process as recited in Claim 7, wherein the 35 phosphate buffer comprises an aqueous mixtureof NaOH, KOH, WO 99/52849 PCT/US99/07466 24 NaH 2 PO4, KH 2 PO 4 , Na 2 HPO4, and K 2 HPO 4 , sufficient to maintain a pH of about 6.5 to about 7.0.

9. The process as recited Claim 8, wherein TEMPO 5 (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) is used in about 5.0 to about 7.0 mole percent.

10. The process as recited in Claim 9, wherein sodium chlorite is used in about 2.0 equivalents relative to the compound of 10 Formula II.

11. The process as recited in Claim 10, wherein sodium hypochlorite is used in about 2.0 to about 5.0 mole percent.

12. The process as recited in Claim 11, wherein the 15 reaction temperature is about 35oC to about 40 0 C.

13. The process as recited in Claim 12, wherein the reaction time is about 2 hours to about 4 hours. 20