MXPA96004007A - Regioespecifico procedure to make cis-1-amino-2-alcanol from epox - Google Patents

Abstract

The present invention relates to a regioselective process for synthesizing any enantiomer of cis-1-amino-2-indanol or mixture of said eniantomers, said method substantially retaining the stereochemical integrity of the carbon-oxygen bond in C-2 in the starting material indenodeoxide, characterized in that the method comprises the steps of: (a) providing an equivalent of indene oxide dissolved in a solvent and optionally a cosolvent, said solvent selected from alkylnitrile or arylnitrile, (b) mixing therein approximately two equivalents of an acid, said acid selected from a strong protic acid or a Lewis acid or an organic acid, and subsequently maintaining the temperature of the resulting mixture between about -70 ° C and about + 30 ° C for a period of between about 0.25 hours and about 6.0 hours; (c) add excess water to effect hydrolysis, and stir for a period of between about 0.5 hours and about 8.0 hours, at a temperature between about 25 ° C and about 100 ° C, to give the corresponding enantiomer of cis-1-amino-2-indanol, or a mixture of said enantiomers

Description

REGIOESPECIFIC PROCEDURE TO MAKE CIS-1-AMIN0-2-ALCAN0L FROM EPQXIDO BACKGROUND OF THE INVENTION The present application is related to Mere! 18996, U.S.S.IM. 8 / 059,038, filed May 7, 1993, and Mere! Case 19115 The present invention relates to a novel intermediate for synthesizing io compounds which inhibit the protease encoded by human virus mmunode íciencia íVIH), and in particular certain analogs ol i igapep two, such as Compound J in the Examples below. These compounds are of value in the prevention of HIV infection, treating INFECTION n HIV and the treatment of immunodeficient íciencia acquired (resulting SID. Syndrome These compounds are also useful for inhibiting renin and other prsteasas. The invenci n here describes relates to a process for carrying out the regiospeci? c generation of a cis -l-am? no-2-ainnal, particularly c? s-1? a? po-2-y-anol (compound B), from a Specifically, the stereochemical integrity of the carbonaceous bond in L-2 in the starting material of indene is retained, so that there is a substantially complete conversion to the product c? sl- am? no-2-? ndanol complete. '-or example, the ?;; of i.1S, 2R) -indeed oroduce sij & wtancialmente 33-1 - am no-2P ndanol, and oxide (1P, 2S >? -inoeno produces substantial body lP ~ l ~ am ~ no 2S- ndanoi mixtures of enantiomers of eoOxido produce?. The process described is superior to the prior art in that the process is shorter, more productive and has higher yields with less environmental impact. retrovirus called human immunodeficiency virus <vTH> is the etiological agent of the complex disease and includes the praqresive destruction of the immune system (acquired immunodeficiency syndrome: GIDA) and degeneration of the central and peripheral nervous system. previously known as LAV, HTLV-III or APV.A common feature of replication of retroviruses is the post-translational processing of precursor polyproteins by a vrartual pratease encoded to generate protein mature virals required for the assembly of virus viruses »The inhibition of this procedure prevents the production of normally infected viruses. Par eiemola, lohl, N.E., and others, Proc Nat'I Acad. Sci. 35. 4686 < 19Q8) showed that qenet t inactivation of the HIV-encoded protein resulted in the production of non-infectious viral particles. These results indicate that inhibition of HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of HIV infection.

- The nucleotide sequence of HIV shows the presence of a pol qene in an open reading frame CPatner, L. et al., Mature, 313, 277 (1985) 1. The amino acid sequence homology provides evidence that the pol sequence encodes the reverse transcriptase, an endonuclease and an HIV protease CToh, H. et al., EMBO J .. 4. 1267 (1985); Power, M.D. and others, Science. 231, 1567 U987); Pearl, L.H., et al., Nature, 329, 351 (1987) 1. The compounds of the final product, including certain oligopeptide analogues which are *. < can be made from the novel intermediates and methods of this invention, on HIV protease inhibitors. and are described in EPO 541,168, which were published on May 12, 1993. See, for example. Compound J in it. In the past, the synthesis of compound J and related compounds was lacquered through a 12 step procedure. This procedure is described in EPD 541,168. The longitude of this '12 steps' route makes this procedure time intensive, and requires the use of many expensive reagents and costly starting material. A route that requires fewer reaction steps and reagents would provide desirable economic and time saving benefits. Specifically, the invention provides a process for the synthesis of 13-l ~ am? No -2P-? ndanol (Compound 8) from uM or from (1S, 2P5-mdeno (Compound A). The epoxide A is treated with a strong acid and a nitrile, then hydrolyzed with water to give the target Compound B. The method of the invention is a one-step procedure, and avoids the isolation of any intermediate. The preparation of l-amino-2-indanol was previously achieved through a sequence of multiple steps. The sequence involved the treatment of an indene oxide with aqueous ammonia to produce trans-1-amino-indanol (compound C).

Cpd C Cpd D Cpd E Cpd F * Intermediate C is then treated with an acyl halide, thus converting the amine to an intermediate amide (compound D) The hydroxyl group of the hydroxyaline D is activated by conversion to esylate (Compound E) , which is then induced to cyclize and form oxazoline F. The α-tazsilene F produced by this method of the above technique is purified, then subjected to conditions similar to those described above by converting it to a In previous attempts, it was reported that epoxides give only deficient yields of oxidation when subjected to the conditions of strong acid solvents. Bishop, "Comprehens ve Qrqanic Synthesis", ed. BM Trost et al, Pergamon Press, New Yorl 1991, Vol 6 p 7, Oda v. Others Bu 11 Chem. Ac "Jpn., 35, 1219 (1962) Unlike the present invention, epoxides < When they are treated with acid and a nitrophoid is reported to produce alphanumeric, it is trans diabal and not a <; azoi? nas CG. Bsurgery et al., Tetrahedron ,, 28, 1377 < 1972); P.J. Pyan et al., Tetrahedron, 29, 3649 (1973) 1. Also, unlike the present invention, methyl trans-2-epoxy-etearate is reported to produce an entro-beta aminoalcohol and not a Qxazoiin CE.N. Z ^ aniova and PP Evstiqneeva,? H. Urq. I- hi .. JO, 078, '1974) 3. Therefore, the related technique teaches that the The amount of an epoxid under the conditions described by this invention would not only be expected to produce low yields but also a wrong product. The method of the present invention provides a route with fewer chemical steps to achieve the same overall synthesis of iS-amino-2R-indanol. In addition, the isolation of intermediates is not necessary in the present invention. Also, the present process uses more quantities of organic solvents and proceeds at a greater overall yield than the previous methods, a result which provides a lower environmental impact than the previous methods.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides novel methods for carrying out the reqiospecific generation of an iS-1P) -ano- ,. "•, 2S) -alkanol, particularly lS-apuna-2R-? ndanol The method of the present invention substantially retains the stereochemical integrity of the carbon-or ienne bond of the starting material of < LS, IR) -ami no- < 2R, 2S) -alcanoi. The product compounds are intermediates for compounds useful in the synthesis of HIV protease inhibitors, renin and other proteases.

? ^ DETAILED DESCRIPTION OF THE INVENTION The invention provides novel methods for making the enantiomeric intermediates l-amine-2-alkanoi, particularly lS-amino-2P-indanoi or iR-amino-2S ~? Pdanol. These intermediates are useful for the preparation of HIV protease inhibitors. In this invention, a regioselect method is described to synthesize any enantioses of c? Si ~ am? No ~ -3 ndanol or mixture of said enanthos, said process substantially retaining the stereochemical integrity of the carbon-oxycarbon bond in C-2 in the starting material of Indene Oxide, wherein the process comprises the steps of (a) providing an equivalent of indene oxide dissolved in a solvent and preferably a casolvent, said solvent being purified from lithium or nitrous oxide.; B) mixing therein approximately two equivalents of an acid, said acid selected from a strong protic acid or a Lewis acid or an organic acid, and subsequently maintaining the temperature of the resulting mixture between about -70 ° C and;; at + 30 ° C for a period of between about 25 hours and about 6.0 hours, (c) adding excess water to effect hydrolysis, stir for a period of about 0.5 hours and about 8 hours. hours, at a temperature of between dt 25 ° C and approximately 100 ° C, to give the corresponding enantomerous of c? s-l? am? no-2-? ndanal, or a mixture of said eniantomeros. In this particular application, the nitric oxide starting material (compound A sample ol eniantomer 13, 2R) is easily synthesized by a variety of methods. The nitric oxide starting material, in any mixture of enantiomers including racemic and optically pure forms, is treated with a strong protic acid, such as sulfuric acid or H3S0 * -503, or Lewis acid such as boron fluoride, or an organic acid such as p-toluenesulfonic acid, methansulonic acid, trifluoroacetic acid or t-fluoro-methane-phonic acid. The reaction can be carried out in a mixture of a solvent and optionally a cosolvent, the solvent consisting of an alkyl nitrite or an ap lnit, eg, acetonitrile, propionitrile, or ben pnyl. . The cosolvent does not, but is not limited to hydrocarbons, such as 'Tolines to toluene, or hydrocarbons such as diclaroethane or clearbenzene. Other conditions include a temperature between about ~ 70 ° C to approximately + 30 ° C, and an incubation period that ranges from about 0.25 to about 6 hours. The presence of water in these steps,, a) and < b), it is not necessary and in some cases it gives unwanted results. The product of step ib) appears to be the axazoline < TO? general structure F (here the form 13, 2P) in a performance within the scale of approximately 50-B57 ..

/ * - "" Although it is possible, it is unnecessary to isolate the oxazoLine intermediate F. Preferably, the non-isolated axazolme F is treated directly with water for a period of about 0.5 to about 8 hours at a temperature on the scale of about 25- 1 0 ° C. This affects the hydrolysis of the oxazoline and produces lS-am? No-2P ~? Ndanol (compound B). The isolation of this product is either its crystalline free base (i.e., amino-indanol) or as a flepvado of amine salt i and g., A sai of tartaric acid) is achieved directly from the reaction medium by pH adjustment to provide the iintermediate ID of a inoindanol. The overall performance, that is, the performance of steps (a) to (c) above, ranges from about 50% to about 80 ° / .. In a regioselect procedure modality The present invention, the (1S, 2R) oxide and i-indene is ei-itastancly converted to iS ~ am ~ no ~ 2R -? Ndanal by the steps wa1- (a; provide an equivalent of (13, 2R) -Oxy of the dissolved in a solvent and optionally a solvent, said solvent selected from alkyl or ally, &b; b) mixing therein approximately two equivalents of an acid, said acid selected from an acid A strong product or a Lewis acid or an organic acid, and maintaining the temperature of the resulting mixture between about ~ 70 ° C and about + -30 ° C during a period of < V- > re about 0.25 hours and about 6.0 hours; (c) adding excess water to effect hydrolysis, and depositing for a period of between about 0.5 hours and about 8.0 hours, at a temperature between about 25 ° C and about 10 ° C, to give the IS -am? no-2P-índanol substencial entity free from any other enantOmero. In another embodiment of the regiaselective process of the present invention, (IR, 2S) -oxid of indena is substantially converted to IP-amino-23 -indanal, by the steps of: (a) providing an equivalent of (IR, 23) ) -Ipdeps oxide dissolved in acetonitop and optionally a cosolvent; (b) mixing therein about two equivalents of a selected acid of methanesulfonic acid or H2S? 4.303,. subsequently maintaining the appropriate temperature; 10 - 25"C for a period of between about I hours and ap or immately 5 hours; <c) add excess water to effect hydrolysis, and add during a period of < = > of 2 hours and approximately 5 hours, on a temperature scale of between about 45 ° C and about 100 ° C, to give the 1R-am? no-2S-? ndanol substanc to the free entity of any other plant. Another embodiment of the present invention is the reqiaselective process of synthesis of J S-am? Na-2P ~ ndanol, which consists of the steps of: '< a) provide an equivalent of < 13, 2R) -indenoxide dissolved in acetsmtpla and optionally a cosolvent; ib) mixing therein about two equivalents of an acid selected from ethersulonic acid or HaSO ^ -SOs, and subsequently maintaining the temperature at about -10-25 ° C for a period of between about 2 hours and about 5 hours; (c) adding excess water to effect hydrolysis, and jumping for a period of between about 2 hours about 5 hours, at a temperature range of between about 45 ° C and about L00 ° C, to give the . S-am? No-2P-? Ndanol substantial entity free from any other eniantomero. Another embodiment of the present invention is the regioselect method of synthesis of iR-amine 23-n ndanol, which consists of the steps of:, (a) providing an equivalent of > iP, 3) - Oxide of indene or dissolved in acetanitpla v apcisnalmento a cosolvent; < b) mixing in the same approximately two equivalents of a selected acid of methansulfunic acid or H = SQ - * - thi? 3, and maintaining the temperature again at approximately -10- 25 ° C during a period of time between about 2 hours and about 5 hours; ? c > add e > water for hydrolysis, and stir for a period of between about 2 hours and about 5 hours, at a temperature range of between a ^ - ededo of 45 ° C and approximately 100 ° C, to give the IR-am? no ~ 2S-? Substantial freedom free of any other emanator. The methods and intermediates of this invention are useful for the preparation of end-product compounds that are useful in the inhibition of HIV protease, the prevention or treatment of infection by the human immunodeficiency virus (HIV), and the treatment of pathological conditions. Consequences such as AIDS. The treatment of ADD or the prevention or treatment of HIV infection is defined as, including < but not limited to) the treatment of a wide variety of states of HIV infection: AIDS, CRS (AIDS-related complex), both symptomatic and asymptotic, and actual or potential exposure to HIV. For example, the final product compounds that can be made from the methods and intermediates of this invention are useful in the treatment of HIV infection after exposure to HIV, v. g., by blood transfusion, Orqan transplantation, exchange of body fluids, stings, punctures of accidental needles or exposure to patient's blood during surgery. The final product HIV protease inhibitors are also useful in the preparation and execution of screening tests for antiviral compounds. For example, the final product compounds are useful for isolating enzyme mutants, which are excellent selection tools for ? f more powerful antiviraies. Furthermore, said compounds are useful for establishing or determining the binding site of other antivirals for HIV protease, e.g., by competitive inhibition. Therefore, the final product compounds that are made from the methods and intermediates of this invention are commercial products that are to be sold for those purposes. The HIV protease inhibitor compounds that can be made from the intermediates and methods of the present invention are described in EPO 541,164. The HIV pratease inhibitor compounds can be administered to patients in need of such treatment in pharmaceutical compositions comprising a pharmaceutical carrier and therapeutically effective amounts of the compound or a pharmaceutically acceptable salt thereof. EPO 541,164 discloses suitable pharmaceutical formulations, v. Of administration, salts and v dose re-compounds for the compounds. The compounds of the present invention can have asymmetric centers and occur as racemates, racemic mixtures / as individual diastereomers, or eniaptomers with all isomeric forms being included in the present invention. When any / apbale occurs (v.gr ,, ari Lo) more than once in any constituent, its definition in each occurrence is independent of its definition in each other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result stable compounds. As used herein, except where indicated, or "alkyl" includes straight and branched chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl Bu is butyl, t ~ Bu is tertbutyl); as used herein, "aryl" is understood to be phenyl (Ph) or naphthyl. Representative experimental procedures using the novel procedure are detailed below. These methods are illustrative only and are not limitations on the novel process of this invention.

EXAMPLE 1 Conversion of indene oxide to cis-l-atnino-2-i ndanol r1í "_c? R i al es Peso Bramos My molecular limolium or milliliter Oxide of indene 11 T '~ f - 1 mi 8.33 Acetonitr i lo 41 10 me 244 Water 18 2.15 mi 119.4 H-.5Q. * Cans. 98 0.92 m1. 16.6 KOH at 5 N 57 3.0 i. 15 Dowex 50;; 4 (H +) 1.9 meg / l 15 mi wet res 28.5 eq Methane! 17 50 mi. fifty To 1 ml of Mdeno Oxide (8.33 mM) dissolved in 10 ml of acetonitop, 0.15 ml of water (8.33 mmoles) was added. The mixture was cooled to u-5 ° in an ice bath. Soluble sulfuric acid was added dropwise to qota while the loading temperature was maintained below 10 °. When all the acid was added and the temperature was raised to 20-25 °, the clear solution aged for 30 minutes. To this mixture 2 ml of water were added and the solution »heated for 30 minutes. When met loxazole ina converted to ammoindanol was complete, the reaction mixture was cooled to room temperature. A solution of I-OH at 5 N (3 ml, 15 mmole) was added. This is 907. of theory for sulfuric acid. The solution remained acid to the litmus. If the pH rises above, reacilaciop 2 occurs and the aminoindanal yield is reduced. The solid planed ü -.30. *) Was removed by operation. 15 ml of Dowex resin (moistened with aceton tr i lo) was added with stirring. The stirred resin was added for 15 minutes and sampled for liquid chromatography (d lx 50).

When the peak liquid chromatography for aminoindanal disappeared, the resin was collected by filtration, washed with acetonite and then with methane !. The wet resin was treated with a solution of 50 ml of JN in methanol. The suspension was added at room temperature for 30 minutes. l.

The resin was collected again by filtration and the methanol / NH3 was saved. Another charge of H ^ / MeOH at 1 N (20 ml) was added and the ream was put back into suspension. After removing the resin. The methanol / NHs solutions of am oindanol were combined and concentrated to remove the NH3. Analysis of the final MeOH solution showed 1.0 g (yield of 817.) of cis-α -am? No-2-mdanol ready for the tartaric acid resolving agent.

EXAMPLE 2 Preparation of Racemic Indene Oxide Indene (957., L22 mL) was dissolved in ethanal (812 mL) and acetopitoplo (348 mL), then filtered. The filtrate was diluted with sodium dibasic phosphate to 0.05 M (116 ml), then adjusted to pH of LO.5 with aqueous sodium hydroxide to pH. ? or aqueous hydrogen (357., 105 ml) was diluted with water C53 ml) and added for 3 hours, while maintaining the temperature at 25 ° C and the internal pH at 10.5 with H aqueous sodium oxide ai M ( total of 120 mi). After 6 hours, aqueous sodium metabisui is added at 1 M (26 ml), while the pH was maintained above 3.3 by the addition of 1 M aqueous NauH (39 ml). Water was added < 700 ml) and the mixture was extracted with methylene chloride (580 ml and 300 ml). The combined organic extracts containing i ndene oxide (L17 mg) were concentrated to a volume EXAMPLE 5 Preparation of < 1S.2R) - indene oxide The substrate, (1S, 2P) - Indena oxide was prepared according to the method described by D.J. O'Oonnell, and others J. Qrqan c Chem stry, 43, 4540 (1778), incorporated herein by reference to these purposes.

EXAMPLE 4 Preparation of is-l-amino-2-indapol Oxide of ipdene (117 g) diluted to a total volume of? ? Mi in full met chloride was diluted with acetanitide (600 ml) and cooled to -20 ° C. Then methansulfonic acid was added. The mixture was heated to 25 ° C and aged for 2 hours. Ge added water (600 mL) and the mixture was heated at 45 ° C for 5 hours. The organic phase was separated and the aqueous phase was then heated at reflux for 4 hrs with a concentration at approximately 200 q / i. The solution was adjusted to a pH of 12.5 with a 50% aqueous sodium hydroxide solution, and then cooled to 5 ° C. and mixed, dried under vacuum to provide cis-am-po-2? ndanol "; EXAMPLE 5 Preparation of lS-amino-2R-indanol (1, S, 2R) -medenoxide (857.ee), (259 g, 0.185 mole) was dissolved in chlorobenzene (300 ml) and heptapos (1200 ml) and added slowly to a solution of methanesulfunic acid (250 ml, 0.375 moles) in acetanitide (1250 ml) at a temperature of less than about -10 ° C. The reaction mixture was heated to 22 ° C and aged for 1.0 hours. Water was added to the mixture and concentrated by distillation until an internal temperature of 100 ° C was attained. The reaction mixture was heated at 100 ° C for 2-3 hours and then cooled to room temperature. Chlorobenzene (1000 ml) was added, the mixture was stirred, the organic phase was separated. The remaining aqueous phase containing iS-amino, 2R-nndane (857. t? E, L65 g, 607.) was adjusted to a pH of 12 with aqueous sodium hydroxide, and the product was collected by -Miltration. and SPCO at vacuum at 4 ("> ° C to produce IS-amino, 2R-? ndanol (857.ee, L60 q).

EXAMPLE 6 Preparation of 1S-amino-2R-indanol (1S, 2P) -oxide of indene (857.ee> "(259 q, o.85 moles) was dissolved in chlorobenzene '300 ml) and heptapas (1200 mi) v was added slowly to a solution of fuming sulfuric acid (50-3 21%, 134 mi) in acetonitr (1250 ml) at one The reaction mixture was heated to 22 ° C and dyed to 1.0 hours, water was added to the mixture and it was concentrated by distillation until an internal temperature of 0.5 ml was reached. C. The reaction mixture was heated at 0 ° C for 2-3 hours and then cooled to room temperature, chlorobenzene (1000 ml) was added, the mixture was stirred, the organic phase was separated. The remaining aqueous phase containing lS-a ino, 2R-? ndanol (357. ee, 205 r '747.) was diluted with an equal volume of acetonitrile. The pH was adjusted to 12.5 with 507 aqueous sodium hydroxide. and the organic phase was separated The remaining aqueous phase was extracted with additional acetonitop.The combined acetonitoplo extracts were concentrated in vacuo to provide IS-amino, 2R-indanol (857.ee, 205 g) .Alternatively, the remaining aqueous phase containing lS-am? no-2P-? ndanol «857. ee, 205 q, 4" /. ? e diluted with u? ~ equal volume of butanoi and the pH was adjusted to 12.5 with aqueous sodium hydroxide to 507. and the organic phase was separated. The organic phase was washed with chlorobenzene. L-tartaric acid was added and water was removed by distillation to crystallize the tartaric acid salt of the ino-ndanol.

EXAMPLE 7 Use of benzonitrile Indens (5 o) oxide was dissolved in benzonitides Lo \ 50 2. 25 mi). The mixture was diluted with a 5M aqueous sodium hydroxide solution (50 ml) and extracted with methylene chloride. The organic extracts were concentrated to the bed to give 5.03 g of oxazole.

EXAMPLE 8 Redissolution of cis-l-amino-2-indanol C? S-l-am? No-2-? ndanoi (100 g) was dissolved in methanol (1500 ml) and a solution of L-tartaric acid (110 g) in methanol (1500 ml) was added.The mixture was heated to 60 ° C and cooled to 20 ° C, filtered and dried in vacuo to allow give 13-amin, 2P-indanol a salt of L-tartaric acid of 13-amine, 2P-? ndanal as a solvate of methanol (38 q).

EXAMPLE 9 Preparation of lS-amino-2R-indanol The methane solvate! of salt of acid (..- tartaric acid from l-ammonium, 2R-? ndanol (88 g) was dissolved in water (180 ml) and heated to 55 ~ 60 ° C. The solution was clarified by filtration and the pH was adjusted to 12.5 with 507 aqueous sodium hydroxide. The mixture was cooled to (-5 ° C du before 2 hours, then aged at a temperature for 1 hour, filtered, washed with water cold and dry at 4 ° c to produce IS-ammo, 2P- \ ndanol (1007. ee, 997. pure, 37 g ' EXAMPLE 10 Preparation of Amide 1 A solution of (-) -c? S-l-a? No? Ndan-2-ol (884 q, 5.93 moles) in 17.8 1 of dry THF < r F = 55 mq / ml) Ü F Siqnica titration of Fischer I for aqua 'and tpe i lamina (868 ml, ^ .2 moles) in a 50 1 round-bottomed flask equipped with a thermocouple probe , mechanical stirrer and a nitroqene inlet adapter and bubbling! ", cooled to 15 ° C. Then, 3-phepoyl opium chloride (loo q, 5.93 moles) was added during ~ * 5 minutes, while the internal temperature between 14 ~ 24 ° C was cooled with an aqua cooling bath with After the addition, the mixture was aged at 18 to 20 ° C for 30 minutes and by high performance chromatography chromatography analysis for the disappearance of (-> -c? s-l? a? n? ndan-2-ol.

The progress of the reaction was monitored by high performance liquid chromatography analysis < CLAR): Dupont column C8-PX 25 cm, «- > < "> : 40 acetonitri io / iOmM (HaPQ. '/ = HP04), 1.0 ml / rnin, injection volume = 20 ml, detection = 200 nm, sample preparation = dilution at 500 X. The approximate retention times were : Retention time (min. > Identity "6.3 c? S ~ am noindanol The reaction was treated with pipdinium p-toluenesulfonate (241 g, 0.96 moles, 0.16 equiv.) And stirred for 10 minutes (the pH of the mixture after diluting 1 ml of sample with an equal volume of aqua is between 4.3-4.6). Then, 2-metax? Propene was added (1.27 i, 13.24 moles, 2.2 equi / J reaction was heated at 38-4 ° C for 2 hours.

. Nezcis reaction was cooled to 20 ° C and was partitioned with ethyl acetate (32 ml) aHCO: aqueous at 57. (10 ml). The mixture was added, the layers separated. The ethyl acetate extract was washed with aqueous NaHC03 at 57. < 10 mi) and aqua < 4 mi). The ethyl acetate extract was dried by atmospheric distillation - the solvent was changed to cyclohexane ivolu in total of 30mL). At the end of the distillation and concentration (20 ° C. in volume of the extraction volume of ethyl acetate), the hot cyclohexane solution was allowed to cool slowly to 25 ° C. to crystallize the product. The suspension resuLtante it was subsequently cooled to i? ßC and aged for 1 hour. The product was isolated by filtration and the wet cake was washed with cold cyclohexane (10 ° C) (2 X 300 mL). The washed cake was dried under vacuum (66 cm Hg) at 40 ° C to give 1.65 ka of acetonide 1 (86.47., 987. in area per CLAR), * H PMN \ 300.13 MHz, CDC13, main rotamer) 6 7.36 -714 ', 9H > , 5.03 (d, 0 = 4.4, 1H), 4.66 a, 1H) 3.15 (m, 2H), 3.06 (br, 2H), 2.97, 2H), 1.62 (s, 3H), 1.37 (s, 3H) ) s l3C PMN (75.5 MHz, CDC13 main rotary) 6 c 168.8, 140.9, 140.8, 140.6, L28.6, 128.5, 128.4, 127.1, 126.3, 125.8, 124.1, < * 6.5, 78.6, 65.9, 38.4, 36.2, 31.9, 26.5, 24.1. Anal. Cale for Ca? Ha3N0a! C, 78.47; H, 7.21; N, 4.36. Found C, 78.65; H, 7.24; M, 4.4o.

EXAMPLE 11 Preparation of epoxy tosylate method A solution of acetonide 1 J J OO q, 3.11 moles) and tosylate of 2'3) ~ qididy '853 q,. 4 evils, 1.2 equiv. ) in . 6 1 THF (r F = 22 mg / ml) in a 50-necked 4-necked round bottom flask, equipped with a thermocoupler, mechanical stirrer, addition funnel and adapter for nitrogen inlet was degassed 3 times through of nitrogen purge to vacuum and cooled to -56 ° C. Then lithium hexamethylethyl azide (L? NCCH3) 3S was added? ] 2) (2.6 1, 1.38 M, 1.15 eguiv.) For 2 hours, while maintaining the internal temperature between -50 to -45 ° C. The reaction mixture was stirred at -45 to -40 ° C for 1 hour and then allowed to warm to -25 ° C for 1 hour. The mixture was stirred between -25 and ~ 22 ° C for 4 hours (or until the acetanide was 3.07 in area). The progress of the reaction was monitored by CLAF analysis: silica column of X 4.6 nm Zorbax of 25 cm, ethyl acetate to 207. in hexane, 2.0 ml / rn n, volume of? Nyecc ?ón-20 ml, detecc ? n = 254 nm, sample preparation = d? 100 X.

The approximate retention times were as follows: Retention time (min.) Identity cr-r amide i 6.5 glycidyl tosylate 13.5 epoxide 3 The reaction mixture was quenched with deionized (6.7 1) at -15 ° and partitioned with ethyl acetate (10 1). The mixture was added and the layers separated. Ei Ethyl acetate extract was washed with a mixture of aqueous NaHCO3 at 17. (5 1) and saturated Naül (0.5 1). The ethyl acetate extract (28.3 1) was concentrated by vacuum distillation (71.12 cm Hg) and additional ethyl acetate was added to complete the solvent changed to ethyl acetate (final volume = 11.7 i). The ethyl acetate concentrate was changed from solvent to MeQH to crystallize the product and concentrate to a final volume of 3.2 1. The residual ethyl acetate solvent was removed by charging 10 1 of metapol and collecting 10 1 of distillate. The resulting suspension was stirred at 22 ° C for 1 hour, then cooled to 5 ° C and aged for 0.5 hours. The product was isolated by filtration and the wet cake was washed with methanol po (2 X 250 mL). The wet cake was dried under vacuum (66 cm Hg) at 25 ° C to give 727 g of epizoxide 3 (61.27., 0.7 in area of the main epoxide by CLAP): 1 C h'MN COO MHz,? _DCl-s > & 171. J, L40.6, 140.5, 139.6, 129.6, 128.8, 127.1, 126. Ü, 125.6, 124.1, .0, 79.2, 65.8, 50.0, 48.0, 44.8, 39.2, 37.4, 36.2, 26.6, 24.1.

EXAMPLE 12 Preparation of penultimate 6 A suspension of 2 (S) -t-but i lcarbaxamido-4 ~ N-Boc-piperazine 4 (1950 g "- 6.83 moles,> 99.57 .ee) (ee = excess eniantomeric) and epoxide 3 (2456 g, 97"5.2.5 mixture of epoxides 4S / R, 6.51 moles) in isopropanol (2-prapanol, 18.6 1) in a 72-liter round bottom flask with 4 inlets.

With mechanical agitator, reflux condenser, steam bath, Teflon-coated thermocoupler and nitrogen inlet, it was heated to reflux (the internal temperature was 84-85 ° C). After 40 minutes, a homogeneous solution was obtained. The mixture was refluxed for 28 hours. The internal temperature during reflux was 84-85 ° C. The progress of the reaction was monitored by CLAR analysis: Dupant CS-FX 25 cm column, 60:40 aceton? Tplo / 10 nM < "Hs-P0 * / KaHP0. *, 1.0 ml / mm, detection = 220 nm, sample preparation = 2 and 1, reaction mixture diluted in 1 ml in acetopitrol. they were appro- priately: Retention time < 'm? n.) Identity 4.8 iperazma 4 8.9 epó ids Z compiled product After 28 hours, the remaining epoxide 3 and the coupled product 5 to the CLAP analysis) were 1.57. in Area and 91-937. in area, respectively .. The mixture was cooled to 0 to 5 ° C and 20.9 1 of NC1 to 6 N was added while maintaining the temperature below L5 ° C. After the addition was complete, the mixture was heated to 22 ° C. The evolution of gas was observed at this point < isobut i log) "The mixture was aged at 20 to 22" C for 6 hours.

The progress of the reaction was monitored by CLAR analysis; the same conditions as before. The approximate retention times were the following: Retention time (mm.) Identity 7.0 cis-aminaindanal 11.9 penulti ato 6 15.1 coupled product 5 The mixture was cooled to OßC and 7.5 1 of IMaOH to 507. were added slowly to adjust the pH of the mixture to pH = 11.6 while maintaining the temperature at less than 25 ° C during the addition. The mixture was partitioned with ethyl acetate '40 1) and water 3 1). The mixture was stirred and the layers separated. The organic phase (60 1) was concentrated under reduced pressure (73.6 cm and Hq> the solvent was changed to DMF / concentrated to a final volume of 30.5 1 (IF = LS mq / ml). CLAR test of 6 in the ethyl acetate t-ue of 86.57 .. The compound of penuiti ato 6 in DMF was used directly in the next step without further purification For 6 isolated: 13 C NMR C / 5.4 MHz, CDC13) 6 175.2, 170.5, 140.8, 140.5, 139.9, 329.1, 128.5, 127.9, 126.8, 126.5, 125.2, 124.2, 73.0, 66., 64.8, 62.2, 57.5, 49.5, 47.9, 46.4, 45.3, 39.6, 39.3, 38.2, EXAMPLE 13 Prepopulation of compound J mopohydrate The solution of 6 in DMF (1.5 1, IF = 10 mg / ml) from the previous step was dropped with 8 1 of sieved DMF (r F. 30 mg / 1) and the mixture warmed with a low steam ac ?? of 76.2 cm Hg to distill mainly aqua v / or any residual isopropanal or ethyl acetate solvent. The volume of final concentrate was 13.5 1 (I F = 1.0 mg / ml) and La tpeti lamina < 2.86 i, 20.51 moles) was added to the solution at 25 ° C followed by 3-p-cal chloride chloride hydrochloride (967., 1287 g, 7"84 moles) The resulting suspension was heated to 68 ° C. The progress of the reaction was followed by analysis of ? J ^ _AP using the same conditions as the previous step. The retention times were the following: Retention time < m? n) Identity DMF 4.7 chloride 3-p? col? lo 4.8 compound J 9.1 penultimate 6 The mixture was aged at 68 ° C until the compound 6 of residual penultimate was 0.3 7. in Area by CLAP analysis. The mixture was stirred at 68 ° C for 4 hr, then cooled to 25 ° C and partitioned with ethyl acetate (80 1) and a mixture of 24 1 saturated aqueous NaHCO and distilled water (14 i). The mixture was stirred at 55 ° C and the layers were separated. The ethyl acetate layer was washed three times with water (20 ° C at 55 ° C.) The washed ethyl acetate layer was concentrated at atmospheric pressure to a final vessel volume of 30 1. At the end of the The atmospheric concentration, the water (560 ml) was added to the hot solution and the mixture was cooled to C and then seeded with a monophonic compound, the mixture was cooled to 4 ° C and filtered to collect the product. it was washed with cold ethyl acetate (2 X 3 1), and dried in vacuo at 25 ° C to give 05 to 70% of compound J monohydrate or white solid.

EXAMPLE 14 Piperazin-2-terbu i lcarboxamide 9 8 9 Acid 2-? perazipcarooxi 1 ico 8) 3.35 Ig (27 moles) Oxalyl Chloride 3.46 g (27.2 moles) Terbuti sheet ü F = 460yg / ml) 9.36 1 (89 moles) EtOAc < ü F = 56í.g / ml) 27 1 DMF 120 mi 1- opanol 30 1 The carboxylic acid 8 was suspended in i of EtOAc / i2 ml of DMF in a 3-necked flask of 72 1 with mechanical stirring under N2 and the suspension was cooled to 2 ° C. Oxalyl chloride was added, maintaining the temperature between 5 and 8 ° C. The addition was completed in 5 hr. During the exothermic addition, CO and C0-? HCl was formed by remaining partly in solution. A precipitate was present which is probably the HCl salt of the pyrazine acid chloride. The acid chloride formation test was carried out by quenching an anhydrous sample of the reaction with t-butylamine. When completed, they were 0"77. of acid 8" The test to complete the formation of acid chloride is important because the incomplete reaction leads to the formation of an impurity of bis-tert-butyloxa ida. The reaction can be monitored by CLAR: 25 cm Dupont Zarbax RXC8 column with i ml / rnin, flow and detection at 250 nm, H P0 ^. water to 507. and CH3CN at 507. to 30 in. The retention times were: acid 8 = 10.7 min, amide 9 = 28.1 min. The reaction mixture was aged at 5 ° C for 1 hr. The resulting suspension was cooled to 0 ° C and the terbuti sheet was added at a rate such as to maintain the internal temperature below 20 ° C. The addition required 6 hr, since the reaction was very exothermic. A small portion of the generated terbutyl ammonium hydrochloride was swept out of the reaction as a fluffy white solid. The mixture is aged at 1S ° C for an additional 3 min. The precipitated ammonium salts were removed by filtration. The filter cake was washed with 12 1 EtOAc. The organic phases were washed with 6 1 of 37% NaHCO 3 and 2 × 2 1 of saturated aqueous NaCl. The organic phase was treated with 200 g of charcoal Darco 860 and filtered through Soli Flol and the cake was washed with 4 1 of EtOAc. The carbonation treatment efficiently removed some purple color in the product. The EtOAc solution of 9 was concentrated at 10 mbar as l5 ° C of the original volume. 30 1 of 1-prapanal was added, and the distillation was continued until a final volume of 20 1 was reached. At this point, the EtOAc was lower than the detection limit in the 1H PMN (17), the internal temperature in this solvent change was 30 ° C. A solution of 1-propanol / EtOAc of 3 was stable at atmospheric reflux pressure for several days. Evaporation of an aliquot gave a tan solid, m.p. 07-88 ° C. ? a: NMR (75 MHz, CD13, ppm) 161.8, 146.8, 145.0, 143.8, 142.1, 51.0, 28.5.

EXAMPLE 15 rac-2-tert-butylcarboxamide-p-perazine 10 Materials Piraz? No ~ - -ter-but i icarboxamida 9, 2.4 ig (13.4 moles) in J-propanoi solution 12 1 of 2? 7. of Pd (OH) -; 167. by weight of water, 144 q. The solution of p? Raz? Na ~ _2 - + - er-but i lcarbaxa i da / 1- The catalyst was added to the autoclave of 18.75 1. The catalyst was added and the mixture was hydrogenated at 65 ° C to 2.8 g / cm2 (3 atm) of Ha. After 24 hr the reaction had collected the rich amount. of hydrogen and gas chromatography indicated 17. of 9, The mixture was cooled, purged with Na and the catalyst was removed by filtration through Soll-a Flac.

The catalyst was washed with 2 l of warm l-propanol. It was found that the use of warm 1-propanol during the washing of the filter cake improved the filtration and reduced the product losses of the filter cake. The reaction was monitored by gas chromatography: 30 m Megabore column, from 10u ° C to 160 ° C at 10 ° C / m ?n, for 5 in, then at L 0 ° C / m ?n, at 250 ° C, retention times: = 7"or mm, 10 - 9" 4 in. The reaction could be monitored by thin layer chromatography with CtOAc / MeOH (5 ?: 50 > as solvent and nmhidpna as a revealing agent.) Evaporation from one to the other indicated that the yield with amidation and hydrogenated On is 887. and that the concentration of 10 is 133 g / 1. an aliquot gave 10 as a white solid, mp 150-151 aC; 13PMN (75 MHz, D ^ 0, ppm) 173.5, 59.8, EXAMPLE 16 Acid salt (SJ -alkan-phenylsiloxane < S) -11 of (S) -2-tert -butylcarboxamido-4-tert-butoxycarbonyl l-piperazine 4 11 Rac ~ 2 ~ te? -butylcarbaxamidopiperazine materials 4.10 \ q (22.12 mol) in 1-propanol solution in 25.5 g of Acid solvent (S) - < +) -10 -alcanfor ico 10.0 g (43.2 moles) i-F'ropanal 12 1 Acet on tp lo 39 i Water 2.4 1 The solution of amine 10 in i-prop nol was charged to a 1 1 flask with a connected intermittent concentrator. The solution was concentrated at 10 bars and at a temperature of 25 ° C at a volume of approx. 12. At this point, the product had precipitated from the solution, but passed back to solution when the mixture was heated to 50 ° C. The analysis of a homogeneous aliquot indicated that the Concentration of 10 was 341 q / 1. The concentration was determined by CLAR: Dupont column 2orbax PXC8 of 25 cm with 1.5 l / mip, flow and detection at 21o nm, (98/2) isocytic CH3CN / aqueous H3P0 l 0.17 .. Retention time of 10: 2.5 min. Acryonitrile (391) and water (2.4 1) were added to give a slightly brown, clear solution. The determination of the water content by titration of I F and the ratio of CH3CN / i-propanal by integration of 1H PMN showed that the ratio of CH3CN / l-propanol / water was 26/8 / 1.6. The concentration in the solution was 72.2 q / l "The (S) -10-camphor-sulfonic acid was charged during 30 min, in 4 portions at 20 ° C. The temperature was raised to 4 ° C after the CSA was added. After a few minutes a thick white precipitate formed. The white suspension was heated to 76 ° C to dissolve all the solids, the slightly brown solution was then cooled to 21 ° C for 8 hr. The product was precipitated at 62 ° C. The product was filtered without aging at 21 ° C, and the filter cake was washed with 5 1 of the solvent mixture of CH 3 CN / 1-prapanal / Ha 0 26/8 / 1.6. It was dried at 35 ° C in the vacuum oven cpm purqa of Ña to give 5.6 I q (397.) of il as a white crystalline solid, m.p. 288-290 ° C (with decomposition »CoiliD255 = 18.9 ° (c = 0.37, HaQ)" 1? TPMN (75 MHz, Da0"ppm) 222.0, 164.0, 59.3, 54.9, 53.3, 49.0, 48.1, 43.6, 43.5, 43.1, 4D.6, 40.4, 28.5, 27.2, 25.4, 19.9, 19"8. The ee of the material was 5 according to the Next chiral CLAP test; an aliquot of 11 (33 mg) was suspended in 4 ml EtOH and i ml Et3N. BacaO (11 mg > and the reaction mixture was allowed to age for 1 hr.) The solvent was completely removed in vacuo, and the residue was dissolved in about 1 ml of EtOAc and filtered through a Pasteur pipette. 3 ° O., using EtOAc as eluent The evaporated product fractions were redissolved in hexanes to ca. 1 mq / ml.The epantiomers were separated on a Daicel Chiracell AS column with a hexane / IPA solvent system (9 '; 3) at a flow rate of 1 ml / mm, and detection at 228 nm The retention times were: ant ipode S = 7.4 min, R = 9.7 min.

EXAMPLE 17 < S) -2-tert-butylcarboxamido-4-tert-butoxycarbonyl-4-salt 1 1 11 4 Materials (S) -2-tert-but i lcarbaxa idopipera ina Bis (S) - (+) - salt of CSA 11, 957. ee 5.54 Hg (8.53 moles) Dicarbopato Di-ter-but i lo 1.86 r (8.53 moles) H.H . 9 1 (42.6 moles) Punctual EtOH of purity degree 200 5 1 EtOAc 2 1 To the salt of (S) -CSA 11 in a 3 neck flask of 100 1 with an addition funnel under Na was added EtOH, followed by triethylamine at 25 ° C. The solid was easily dissolved by adding Et3N. The Boca0 was dissolved in EtOAc and charged to the addition funnel. The solution of Boca0 in EtOAc was added at a rate such that the temperature was maintained below 25 ° C. The addition was made for 3 hr. The reaction mixture is aged for 1 hr after the addition of the E > oca0 The reaction can be monitored by CLARs Dupont Zorbax F * C8 column of 25 cm with i l / mm, flow and detection at 220 nm, < 50/50) LH3 N? Socrátco co / 1 HrF0? at 0.1M, adjusted to pH = j.8 with NaOH. The retention time was 4 = 7.2 in. The chiral test was carried out using the same system as in the previous step. The reaction could also be monitored by thin layer chromatography with EtQAc to Loo ?, as the solvent (R ^ = = - 0.7). The solution was then concentrated to approximately 10 1 at an internal temperature of 20 ° C in an intermittent type concentrator under a vacuum of i-baps. The solvent change was completed by purging slowly in 20 ml of EtOAc and reconcentrating to approx. L. The reaction mixture was washed in a _Vt ractor with 60 1 EtOAc. The organic phase was washed with 16 1 of an aqueous solution of NaaC0 at 57., 2 X 10 1 of deionized water and 2 x 6 1 of saturated aqueous sodium chloride. The combined aqueous baths were again extracted with 20 1 of EtOAc and the organic phase was washed with 2 X 3 1 of water and 2 X 4 1 of saturated aqueous sodium chloride. The combined EtQAc extracts were concentrated under a vacuum of 10 m bap at an internal temperature of 20 ° C in an intermittent concentrator of 100 1 to approx. 8 1. The change from solvent to cyclohexane was achieved by purging slowly in approximately 20 1 of cyclohexane, and re-concentrating to approximately 8 1. To the suspension were added 5 1 of cyclohexane and 280 ml of EtOAc and the mixture was heated to reflux , when everything was put in solution. The solution was cooled and the seed (10 q) was added at 5S ° C. The suspension was cooled to 22 ° C in 4 hr the product was isolated by filtration after 1 hr of aged at 22 ° C. The filter cake was washed with 1..8 1 of cyclohexane and dried in the oven. it lay at 35 ° C ba or purqa with Na to give 1.87 I g (777., 99.9 7. in ea by CLAR, isomer P below the detection level) of 4 as a light tan powder, CocIID3"15 = 22.? ° < c = • 0.2O, MeOH), pf ,,, l 7 ° C; * 3PMN (75 MHz, CD13, ppm) 170.1, L54.5, 79.8, 58.7, 50.6, 46.6, 43.6 43.4, 28.6, 28.3 Although the above description teaches the principles of the present invention, with examples provided for the purpose of lustration, ~ and will understand that the practice The invention encompasses all customary variations, adaptations and modifications that fall within the scope of the following claims and their equivalents.

Claims (5)

1. NOVELTY OF THE INVENTION
2. CLAIMS 1.- A regioselective procedure for synthesizing any enantiomer of c? S-l? Am? No-2-? Ndanal or mixture of said enantiomers, said procedure substantially retaining the stereoguimic integrity of the link _ Carbanese-oxygenate in C-2 in the oxide starting material of
3. Also, characterized in that the method comprises the steps of: (a) providing an equivalent of dissolved methylene oxide in a solvent and optionally a cosolvent, said solvent selected from alkyl or arylmotrila; (b) mixing therein approximately two equivalents of an acid, said acid selected from a strong protic acid or a Lewis acid or an organic acid, and subsequently maintaining the temperature of the resulting mixture between * around -70 ° C and above or + 30 ° C for a period of between about 0.25 hours and rapidly < "> 0 hours, (c) adding excess water to effect hydrolysis, and stirring for a period of between about 0.5 hours and approximately 8.0 hours, at a temperature between about 25 ° C and about 100 '. C, to give the corresponding excimer of c s- L -am? No - 2-? Ndana L, or a mixture of said enantiomers 2.- A regioselect procedure 1 / o, characterized because the '1G, 2Í < 1 ndeno oxide is substantially the same .jnverted to lS-am? no-2P-? ndana L, which consists of the steps of: (a) providing an equivalent of (1S, 2R) -node of dissolved hydrogen in an optional solvent between a cosolvent, said solvent selected from alnitr i lo or arilnitpla; (b) mixing therein approximately two equivalents of an acid, said acid selected from a strong pric acid or a Le is acid or an organic acid, and subsequently maintaining the temperature of the resulting mixture between about -70 ° C and approximately r-30oC for a period of between about 0.25 hours and about 6.0 hours; (c) adding excess water to effect hydrolysis, and stirring for a period of between about 0.5 hours / about 8.0 hours, at a temperature between about 25 ° C about 100 ° C, to give the lS-amine -2P ~? Ndanoi substantially free of any other eniantó ei o. 3. A regioselective procedure, characterized by Jorque the (1P, 2S) ndene oxide is substantially converted to lP-am? No-2S-? Pdanol, which consists of the steps of: (a) providing an equivalent of < IR, ZS) -nodium oxide dissolved in a solvent and optionally a solvent, said solvent selected from an initial initiation or application; (b) mixing therein approximately two eguivalents of an acid, said acid selected from a strong protic acid or a Leis acid or an organic acid, and subsequently maintaining the temperature of the resulting mixture between about -70 ° C. and approximately + -30"C during a period of between around j. 25 hours and approximately 6.0 hours; (c) adding excess water to effect hydrolysis, and stirring for a period of between about 0.5 hours and about 8.0 hours, at a temperature between about 25 ° C and about 100 ° C, to give the iR-am? na-25-? ndanal substantial entity free of any other antimerous eni.
4. 4.- A procedure regióse! Synthesis ectivo of 1 S-am? no ~ 2R-? ndanol, which consists of the steps of: a) providing an equivalent of (1S, 2R) -methodine dissolved in acetanitp and optionally a cosolvent; (b) mixing therein approximately two equivalents of an acid selected from methanesulphonic acid or Ha50. * ~ SQ3, and subsequently maintaining the temperature at approximately ~ 10-25: > C for a period of between about 2 hours and about 5 hours; > c) adding excess water to effect hydrolysis, and stirring for a period of between about 2 hours and approximately 5 hours, at a temperature range between about 45 ° C and about L00 ° C, to give the IS-am? No ~ 2P-? Ndapol substantially free of any other emanator.
5. 5. A reqioselective procedure for the synthesis of LR-am no-SP-i ndanol, which consists of the steps of: (a) providing an equivalent to (IR, 2S) -? "Of dissolved solution in acetomtplo and optionally a cosolvent; ib) mixing therein approximately two equivalents of a selected acid of methanesulfonic acid. and maintaining subsequently the temperature at about -10-25 ° C for a period of between about 2 hours and about 5 hours; (c) adding excess water to effect hydrolysis, and stirring for a period of between about 2 hours and about 5 hours, at a temperature range of between about 45 ° C and about 100 ° C, to give the 1R- amino-2S-indanol substantially free of any other eniantómers.