MXPA96003218A - Procedure for making inhibitors of human immunodeficiency and composite intermediate virus proteas - Google Patents

Abstract

The present invention relates to: A process for the racemization of piperazine-2-tert-butylcarboxamidaptically pure or enriched and its derivatives, the reaction comprising the piperazineptically pure compound or enriched with a racemising agent selected from a strong base, a salt of anhydrous metal or a carboxylic acid, in a solvent, on a temperature scale between room temperature and 250 ° C, the carboxamide derivatives of piperazine are the key intermediates in the preparation of the HIV protease inhibitor compounds, including the compound

Description

PROCEDURE PORO HQCER PROTEñSFl INHIBITORS OF VIRUSES IMMUNODEFICIENCIfl HUMflNR AND INTERIMEDiFlRIO COMPOUND í BACKGROUND OF THE INVENTION The present invention relates to a novel intermediate and method for synthesizing compounds that inhibit the protease encoded by a human deficiency virus (HIV), and in particular the compound described and known as "Compound 3" in EPO 541,168, which was published on May 12, 1993, or pharmaceutically acceptable salts thereof.

These compounds are valuable in the prevention of HIV infection, the treatment of HIV infection and the treatment of acquired immunodeficiency syndrome (SIDO). Very specifically, the process of the present invention involves the racemisation of optically pure and enriched piperazine-2-tert-butyl carboxamide and derivatives with strong base, anhydrous metal salts or carboxylic acids under moderate conditions. The piperazine-tert-butyl carboxamide derivatives are useful intermediates in the preparation of HIV protease compounds, including compound 3. A retrovirus known as human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes the progressive destruction of the immune system (acquired immunodeficiency syndrome, AIDS) and degeneration of the central and peripheral nervous system. The virus was previously known as LflV, HTLV-III or RR. A common feature of the duplication of the retrovirus is the extensive post-translation processing of polyprotein-containing proteins by a virally encoded protease to generate mature viral proteins required for the assembly and function of the virus. The inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N.E. and other Proc. Nat'l Rcad. Sci., 85, 4686 (1988), demonstrated that the genetic inactivation of the HIV-purified protease resulted in the production of immature, non-infectious viral particles. These results indicate that the inhibition of HIV protease represents a viable method for the treatment of AIDS and prevention by treatment of HIV infection. The sequence of HIV nucleotides shows the presence of a pol gene in an open reading frame CRatner, L. et al., Nature, 313,277 (1985) 3. The amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease CToh, H. et al., EHBO 3., 4, 1267 (1985); ? f *** 'er, M.D. and others, Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329,351 (1987)]. The compounds of the final product, including compound 3 that are shown in example 20 below, which can be made from the novel intermediates and method of this invention are HIV protease inhibitors, and are described in EPO 541,168 which was published on May 12, 1993. Previously, the synthesis of compound 3 and related compounds was achieved through a 12-step procedure using a dihydro-5- (s) -hydroxymethyl-3 (2H) furanone hydroxyprotected that was rented, and involved the replacement of a residual group of alcohol in the alkylated furanone with a piperidine moiety. The coupled product was then hydrolyzed to open the furanone ring in a portion of hydroxy acid, and the acid was finally coupled to 2 (R) -hydroxy-l (S) -aminoindane. This procedure is described in EPO 541,168. The end length of this path (12 steps), It is important that this procedure consumes time and is labor intensive, and requires the use of many expensive reagents and expensive starting material. A route that requires less reaction and reagent passage would yield desirable economic and time saving benefits. A modified pathway for compound 3 and related compounds was also shown in EPO 541,168 based on the diastereoselective alkylation of the enolate derivative of N- (2 (R) -hydroxy-l (S) -? Ndan-N, 0-isopro? l-ideno-yl) -3-phenyl-fT- ^ panoamide, in which the 3-carbon unit of C3-C5 was introduced as an allyl group and subsequently oxidized. Some problems with this pathway are: a) four steps are necessary to effect the introduction of the three carbon glycidyl fragment, b) 0s0? Highly toxic is used in the procedure and c) a low diastereoselectivity is obtained in the hydroxylation step. Therefore, a desirable procedure would directly introduce the 3-carbon unit in the oxidized form to the correct one. In addition, the synthesis of the chiral piperazine intermediate was effected from 2-pyrazinecarboxylic acid in a 6 step procedure and required the use of expensive reagents such as BOC-ON and EDC. Therefore, a shorter route for the piperazine intermediate is desired, which also does not use expensive reagents. Moreover, during the synthesis of the chiral piperazine intermediate, both the desired (S) -piperazine carboxylate enantio ero (ie the precursor of the piperazine intermediates of 2 (S) -carboxamide) co or the enantiomer (R) is formed by requiring the separation of the enantiomer (S) that is carried out to finally form compound 3. In the absence of the practical methodology to convert the antipode (R) to the antipode (S), it was discarded thus limiting the possible efficiency of this step to 50X. Therefore, a method for improving the recovery of the (S) -piperazine intermediate would be highly desirable.

Very recently, a shorter pathway has been found to prepare the compounds described in EPO 541,168, and in particular compound 3. In this new pathway, l- ((R) -2 ', 3'- Epoxypropyl- (S) -2-tert-butylcarbonyl-piperazine is prepared and reacted with N- (2 (R) -hydroxy-l (S) -indan-N, 0-isopropylidene-yl) -3-phenylpropanoamide to give the product trailer 8 After removal of the BOC protection group from the piperazine nitrogen, the unprotected piperazine compound is then reacted with 3-picolyl chloride to form the compound 3. As with the above-described procedure for preparing protease inhibitor compounds of HIV described in EPO 541,168, the preparation of the key chiral piperazine intermediate in this new procedure still results in a mixture of enantiomers that require the resolution of the (S) enantiomer which is then left to form the final product. In the absence of practical methodology to convert the unwanted antipode (R) to the antipode (S), it was discarded, thus limiting the possible efficiency of this step to 50% and resulting in considerable waste and expense. Therefore, a method to increase the yield of the (S) -piperazine intermediate would be highly desirable, resulting in a reduction in capital costs associated with the synthesis of compound 3 and a reduction in environmental problems caused by production of large quantities of unusable organic salt. The raceway of amides and peptides under the basic conditions is known, and can occur by means of "sprotonation of the asymmetric carbon atom to form an enolate, followed by reprotonation (eq 1).

With amides having a heterogeneous atom in the 2-position, nacemization is also known to occur through the elimination of the heterogeneous atom followed by the Michael-type readition of the heterogeneous atom to the unsaturated species (eq.2). Since this unsaturated species is a monomer susceptible to polymerization, low yields of racimized product are obtained.

X = OR, SR, NR'R ", ... See, Advances in Protein Chemistry, Anson, ML, Edsall, 3.T., ed. Volume IV, Academic Press, New York, 1948, 344-356. The conditions typically employed to racemize peptides, however, do not work in the case of the piperazin-2-tert-butylcarboxarnide derivatives of the present invention because the a-hydrogen, which is on the carbon atom of the piperazine ring It is very weakly acidic and therefore difficult to remove, so it was not expected and predictable that the racemization of piperazin-2-tert-butylcarboxylates could be efficiently and rapidly carried out under moderate conditions. The present invention provides a method for "increase the yield of desired intermediary X of (s) -piperazin, which is needed in the synthesis of compound 3, by raceifying optically pure piperazine-2-tert-butyl carboxamide or enriched in derivatives with strong base under moderate conditions. optically active p-perazin-2-tert-butylcarboxarnides are available through the resolution of the corresponding racemates, the subsequent racemization of the unwanted antipode provides a way of recirculating it to the desired antipode, thus increasing performance, eliminating waste and obtaining savings In this way, the present invention provides a more advantageous method for preparing HIV protease inhibitors containing the piperazine portion of 2 (S) -carboxamide which was previously known to allow synthesis with superior yield of the compounds useful in the treatment of HIV, and in particular compound 3, increasing the recovery of the piperazine of 2 (S) -carboxamide.

BRIEF DESCRIPTION OF THE INVENTION The present invention involves novel synthetic methods for making racemic piperazine-2-tert-butylcarboxamide derivatives, which are useful for the synthesis of HIV protease inhibitors. The present invention involves a process for racemization of optically pure or enriched piperazine-2-tert-butylcarboxamide substrate of formula IX or X, or a salt believed in itself.

IX which comprises reacting said substrate, or a salt of the metal, with a racemic agent selected from a strong base, an anhydrous metal salt or a carboxylic acid, in a solvent at a temperature-to-temperature scale. environment and 250 ° C, where Ri and R2 are each independently selected from the group consisting of hydrogen, R, , is selected from the group consisting of alkyl of c? -5, -CH2 aryl, -CH2-heteroaryl, aryl and trifluoromethyl. In one embodiment of the present invention is the process wherein R2 is selected from the group consisting of hydrogen and 0 ^ is selected from the group consisting of alkyl of cl-5, -CH2 aryl, -CH2-heteroaryl In one class is the process wherein said racemization agent is a strong base selected from the group consisting of lithium alkyl, a lithium amide, a hydroxide, an alkoxide and a Schwesinger base. The procedure in which this strong base is selected from the group consisting of lithium terbutoxide, sodium terbutoxide, potassium terbutoxide, lithium n-propoxide, sodium n-propoxide, np ^ potassium oxide, ethoxide is illustrated in this class. of sodium, potassium ethoxide, sodium ethoxide and potassium ethoxide. In a second class is the process wherein said racemizing agent is an anhydrous metal salt selected from magnesium chloride, magnesium bromide, zinc chloride, iron (III) chloride or titanium chloride.

(IV). In a third class is the process wherein said racemizing agent is a selected carboxylic acid of acetic acid, propionic acid, butyric acid or isobutyric acid. In a subclass of each of the above is the procedure wherein said temperature scale is between 50 and 120 ° C. Illustrative of this subclass is the process wherein said solvent is an ether, alkane, a cycloalkane, an alcohol or an aromatic compound or a mixture thereof. An additional illustration of this subclass is the process wherein said solvent is selected from THF, cyclohexane or propanol or a mixture thereof. In addition, this subclass illustrates the procedure wherein said substrate is selected from the group consisting of or a salt of them. In this class the procedure is illustrated where said substrate is selected from the group consisting of or a salt of them. In this class is further illustrated the process wherein said substrate salt is selected from a salt of pyroglutamic acid or a salt of phonorphsulphuric acid. A further example is the process wherein said substrate salt is the bis- (D-pyroglutamic acid salt.) In this embodiment, the process comprising the additional step of isolating the (S) enantiomer of the piperazin-2 compound is further illustrated. raceme-butylcarboxamide of the racemate Another example of the invention is a process for racemization of an optically pure or enriched piperazin-2-tert-butylcarboxa-roxy substrate of the formula IX, or a salt thereof, IX vue comprises reacting said substrate with an alkoxide in 1-proanol at a temperature range of between 50 and 120 ° C; wherein R * is hydrogen or tert-butyloxycarbonyl; and R2 is hydrogen. The invention specifically illustrates the process wherein said alkoxide is selected from sodium n-propoxide, potassium n-propoxide and lithium n-propoxide. The method in which the said sodium, potassium or lithium n-propoxide is prepared in situ by azeotropic drying of sodium, potassium or lithium hydroxide in 1-propanol is illustrated more specifically in the invention. The process in which said salt is the salt of (L) -pyrglutamic acid is illustrated in this invention.

A more specific illustration of the invention is the construction in which the temperature scale is between 85 and 120 ° C. Also included within the scope of the invention are compounds of the formula XI and salts thereof. 1 wherein R1 and R2 are independently selected from the group consisting of hydrogen, R, O R is selected from the group consisting of C 1-5 alkyl, -CH 2 -aryl, -CH α -heteroaryl, aryl, and trifluoroethyl. In a second embodiment of the invention are the compounds wherein R i is selected from the group consisting of hydrogen, R and R 2 is selected from the group consisting of hydrogen, R and R is selected from the group consisting of 5, -CH2 aryl, -CH2 ~ heteroaryl In one class of this embodiment are the compounds wherein R2 is hydrogen; and R is selected from alkyl of cl-5, -CH2 heteroaryl; provided that R1 and R2 are not both hydrogen and provided Ri is not t-butyloxycarbonyl. In a class are the compounds and salts thereof selected from the group consisting of Some abbreviations that appear in this application are the following: ABBREVIATIONS (~ Designation Protective group BOC (Boc) t-butyloxycarbonyl CBZ (Cbz) benzyloxycarbonyl (carbobenzoxy) TBS (TBDMS) t-butyl-dimethylsilyl Designation Protective group Ts or toeyl or tosylate p-toluenesulfonyl Ns or nosyl or nosylate 3-nitrobencensul fonyl Tf or triflyl or tri-tri-tri-fluoromethanesul-fonyl-sulphonyl or methanesulfonyl esylate Designation Reagent reactive coupling BOP benzotriazole-1-yloxytris- (di-ethylamino) -phosphonium hexafluorophosphate B0P-C1 bis (2-oxo-3-oxalidinyl) phosphinic acid chloride EDC l-ethyl-3- (3- dimethylaminopropycarbodiirnide hydrochloride O ros BOC-ON 2- (tert-butylcarbonyloxy) o) -2- phenylacetonitrile (BOC) 2? (BOC20 or Boc20) di-t-butyl dicarbonate n-Bu «N + F- tetrabutyl onium fluoride nBuLi (n-Buli) n-butyllithium (S) -CSA acid (lS - (+) - 10-camphor sulphonic DI deionized DIEA or DIPEA diisopropylethylamine DMAP dimethylaminopyride DME dimethoxyethane DMF dimethyl formanide Et3N triethylamine EtO c ethyl acetate h hours IPA 2-propanol KF Karl Fisher titration for water LDA diisopropylamide lithium '- ^ S hexameti lithium lysilazide L - > GA (L) pyroglutamic acid r.t. ambient temperature TFA rifluoroacetic acid TG thermal gravimetry: loss during heating THF tetrahydrofuran TLC thin layer chromatography DETAILED DESCRIPTION OF THE INVENTION During the synthesis of compounds that inhibit HIV protease and in particular compound 3, which is described , -n EPO 541,168, published on May 12, 1993, a key intermediate is the chiral piperazine compound of (s) -2-tert-butylcarboxarnide 11, eleven and its derivatives (ie, compounds of? to formula X), or salts thereof. The piperazine 11 is prepared from 2-pi-carboxylic acid 12 by first forming the acid chloride and then reacting the pi- raphine acid chloride with tert-butylamine to form pi-2-tert-butyl carboxyamide.

The pi-2-tert-carboxamide is then hydrogenated to form racemic 2-tert-butylcarboxamide-piperazine. At this point, the separation of the enantioses (S) and (R) is necessary for? "* J the antipode (S) is used to form the HIV protease inhibitor compounds described in EPO 541,168 and in particular compound 3 The separation of the enantiomers can be carried out according to methods well known to those skilled in the art, for example, chiral HPLC.Alternatively, the separation of the enantiomers (S) and (R) can be carried out by preparing the acid salts bis (s) sulphonic camphor 15 or (L) -pyroglutamic acid 16 of the carboxamide-piperazine compound of the 2-tert-butylcarboxamide-pi? erazine acrene 14. In the absence of practical methodology for converting the antipode ÍR) to the antipode ( S) was discarded, thus limiting the possible efficiency of this step to 50% The present invention provides a method for reacting the unwanted antipode (R) with a strong base, an anhydrous metal salt or a low carboxylic acid. moderate conditions according to scheme 1 to form a racemate in high yield. Once the racemate is formed, the desired antipode (S) can be recovered according to methods known to those skilled in the art (or by using the resolution described herein), thereby increasing the efficiency and performance of the process associated with the synthesis of compound 3.

SCHEME 1 IX Substrates that can be used for racemization include or a salt thereof, wherein R is Ci-s alkyl, -CH2-aryl, -CH2-heteroaryl, aryl or trifluoromethyl. Preferably the following substrates or a salt thereof are used in the present invention The most preferred substrates are or a salt of them. The racemization can be carried out using a racemising agent such as Mg, Zn, Fe or Ti anhydrous salts, carboxylic acids or strong bases. Some examples of salts of anhydrous metals that can be used in the present invention are anhydrous magnesium chloride, magnesium bromide, zinc chloride, iron (III) chloride or titanium (IV) chloride. Carboxylic acids that can be used include acetic acid, propionic acid, butyric acid and isobutyric acid. Preferably, strong bases such as lithium-alkyl (e.g., methyl-lithium, secbutyl-lithium, t-butyl-lithium), phenyl-lithium, lithium amides (e.g., LDA, LHMDS), hydroxides (e.g., lithium, sodium or potassium hydroxide), alkoxides or bases of '? weeinger are used. When the strong base is a hydroxide, it is preferable that solutions of aqueous hydroxides in alcohols are used to effect racemization. Examples of alkoxides that may be used include lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium n-propoxide, sodium n-propoxide, potassium n-propoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide. Very preferred is the use of lithium, sodium or potassium terbutoxide, lithium, sodium or potassium n-propoxide. Most notably, the alkoxide is generated in situ by azeotropic drying of solutions of sodium, potassium or lithium hydroxide in alcohol. See, e.g., German patent DRP 558469 (1932), which describes the preparation of sodium alkoxides by aceotropic drying of NaOH solutions in alcohol. Solvents, compatible with the reaction conditions, such as ethers, alkanes, alcohols, cycloalkanes and aromatics or a mixture thereof can be used. Preferably, ethers, alkanes and alcohols to a mixture thereof are used as the solvents. The most preferred solvents are THF, cyclohexane and propanol, or a mixture thereof. The racemization can be performed at a temperature scale that varies from room temperature to 250 ° C. Preferably, the temperature scale is between about 50 and 120 ° C. Most preferably, the temperature scale is between 85 and 120 ° C. - The racemisation process hereof can also be carried out on salts of the substrate. Salts of tartaric acid, dibenzoyltartaric acid, mandelic acid, lactic acid, camphor sulfonic acid and pyroglutamic acid can be used. Preferably, the (S) alkane-sulphonic acid salt or the (L) pyroglutamic acid salts are used. The (L) pyroglutamic acid salts are more preferred. The representative experimental procedures using the novel procedure are detailed below.

These procedures are illustrative only and should not be considered as limiting the novel process of the invention.

EXAMPLE 1 Pirazin-2-tert-butylcarboxamide 13 12 13 2-? irazinocarboxylic acid (12) 3.35 kg (27 moles) oxalyl chloride 3.46 kg (27.2 moles) tert-butylamine (KF = 460 μg / ml) 9.36 L (89 moles) EtOAc (KF = 56 μg / ml) 27 1 DMF 120 rnl- ^ ropanol 30 1 The carboxylic acid 12 was suspended in 20 1 of EtOAc and 120 ml of DMF in a three-neck flask of 72 1 with mechanical stirring under N 2 and the suspension was cooled to 2 ° C. The oxalyl chloride was added maintaining the temperature between 5 and 8 ° C. The addition was contemplated in 5 hours. During the exothermic addition, CO and CO2 were fired. The HCl that formed remained largely in solution. The acid chloride formation test was carried out by spreading an anhydrous sample of the reaction with t-butylamine. Upon completion, < 0.7% acid 12. The reaction can be monitored by CLAR: 25 cm Dupont Zorbax RXC8 column with a flow of 1 ml / min and detection at 250 nm; linear gradient of 98% aqueous H3PO4 at 0.1% and 2% H3CN at 50% CH3POÜ and 50% CH3CN at 30 minutes. Retention time: acid 12 = 10.7 min, amide 13 = 28.1 min. The reaction mixture is aged at 5 ° C for 1 hour. The resulting suspeneion was cooled to 0 ° C and the tert-butylamine was added at that speed to maintain the internal temperature below 20 ° C. The addition required 6 hours, since * the reaction was very exothermic. A small portion of the generated tert-butylammonium hydrochloride was removed from the reaction as a fluffy white solid.

The mixture was aged at 18 ° C for 30 minutes. The precipitated ammonium salts were removed by filtration. The filter cake was washed with 12 1 EtOAc. The combined organic phases were washed with 6 1 3% NaHC 3 and 2 X 2 L saturated aqueous NaCl. The organic phase was treated with 200 g of Darco G60 carbon and filtered through Solka Flok and the filter was washed with 4 1 EtOAc. The carbon treatment efficiently removed the purple color of the product. The EtOAc solution of 13 was concentrated at 10 bars at 25% of the original volume. 30 1 of 1-propanol was added and distillation was continued until a final volume of 20 1 was reached. The internal temperature in this change of solvent was < 30 ° C. A solution of 1-propanol / EtOAc of 13 was stable under reflux at atmospheric pressure for several days. Evaporation of an aliquot gave a tan solid, m.p. 87-88 ° C; 13c NMR (75 MHz, CDC13, ppm) 161.8, 146.8, 145.0, 143.8, 142.1, 51.0, 28.5.

EXAMPLE 2 rae-2-tert-butyl carboxamide pi erazine 14 Materials í > '* azine-2-tert-butylcarboxamide 13 (2.4 kg, 13.4 moles) in a solution of 12 1 of 1-proanol, Pd (0H) 2 at 20% / C 16% by weight, water 144 g. The solution of pyrazine-2-tert-butylcarboxamide 13/1-propanol was placed in an autoclave of 18.75 1. The catalyst was added and the mixture was hydrogenated at 65 ° C at 2.81 kg / cm2 (3 atmosphere) of H2. After 24 hours the reaction had absorbed the theoretical amount of hydrogen and CG (gas chromatography) indicated < 1% of 13. The mixture was cooled, purged with N2 and the catalyst was removed by filtration through Solka Flok.

The catalyst was washed with 2 1 of warm 1-propanol. The reaction was monitored by GC: 30 m Megabore column, 100 ° C at 160 ° C at 10 ° C / min, maintained for 5 minutes, then at 10 ° C / min 250 ° C, retention time. 13 = 7.0 min, 14 = 9.4 min. The reaction could also be monitored by CCD (thin layer chromatography) with EtOAc / MeOH (50:50) as solvent and Nin idrin as a revealing agent. Evaporation of an aliquot gave 14 as a white solid, m.p. 150-151 ° C; 13c NMR (75 MHz, D 2 O, ppm) 173.5, 59.8, 52.0, 48.7, 45.0, 44.8, 28.8.

EXAMPLE 3 (S) -2-tert-butylcarboxamide piperazine-bis- (S) -Canforsul phonic acid (S) -15 salt 14 15 naterals rac-2-tert-butyl-carboxamide-piperazine 14 4.10 kg (22.12 mole) in 1-propanol solution in 25.5 kg of solvent (S) - (+) -10-Phonic phorforsul 10.0 kg (43.2 moles) 1 - pro panol 12 L Acetonitrile 39L Water 2.4 L The solution of amine 14 in 1-propanol was charged to a 100 1 flask with an equipped batch concentrator. The solution was concentrated at 100 mbar and at a temperature of < 25 ° C to a volume approximately 12 1. At this point, the product had been precipitated from the solution, but was converted back to solution when the mixture was heated to 50 ° C. Acetonitrile (39 L) and water (2.4 L) were added to give a clear, slightly brown solution. -f The (S) -10 camphorsulfonic acid was charged for 30 minutes in 4 portions at 20 ° C. The temperature was raised to 40 ° C after C? A was added. After a few minutes a thick white precipitate formed. The white suspension was heated to 76 ° C to dissolve all solids, the slightly brown solution was then allowed to cool to 21 ° C for 8 hours. The product was precipitated at 62 ° C. The product was filtered without aging at 21 ° C, and the filter cake was washed with 5 liters of the solvent mixture of CH3CH / l-propanol / H2? 8/26/1. It was dried at 35 ° C in the vacuum oven with N 2 purge to give 15 as a white crystalline solid, p.f. 288-290 ° C (with decomposition.) Ca] D25 = i8.9 ° (c = 0.37, H2?). 13c NMR (75 MHz, D2O, ppm) 222.0, 164.0, 59.3.54.9.53.3,49.0,48.1,43.6, 43.5.43.1,40.6,40.4,28.5,27.2,25.4,19.9,19.8. The diastereomeric excess (d) of the material was 95% according to the following chiral HPLC test: an aliquot of 15 (33 mg) was suspended in 4 L of EtOH and 1 mL of Et3N. B0C2O (11 mg) was added and the reaction mixture was allowed to age for 1 hour. The solvent was removed completely in vacuo, and the residue was dissolved in approximately 1 L of EtOAc and filtered through a Pasteur SÍO2 pipette, using EtOAc as an eluent. The evaporated product fractions were dissolved in hexanes at about 1 mg / rnL. The enantiomers were separated on a column of Daicel Ciracell AS with a solvent system of hexane / IPA /: 3) at a speed t ^ r. flow of 1 rnL / min and detection at 228 nm. Retention time: antipode S = 7.4 min, R = 9.7 min.

EXAMPLE 4 (S) -2-tert-Butylcarboxamido-4-tert-butoxycarbonyl-iperazine 1 of the salt fifteen ? Materials (S) -2- tert-Butyl-carboxyamine piperazine Bis (S) - (+) - CSA salt 15, 95% ee 5.54 Kg (8.53 moles) Di-tert-Butyl Dicarbonate 1.86 Kg (8.53 moles) The beds Et3N 5.95L (42.6 moles) Aldrich EtOH Punctilious 200 grade 55 L EtOAc 2 L To the salt of (S) -CSA 22 in a 3-neck flask of I'C L with an addition funnel under N2 was added EtOH, followed by triethylamine at 25 ° C. The solid was easily dissolved by adding Et3N. The B0C2O was dissolved in EtOAc and charged to the addition funnel. The solution of B0C2O in EtOAc was added at a rate such as to maintain the temperature below 25 ° C. The addition required 3 hours. The reaction mixture is aged for 1 hour after the addition of the B002O solution is complete. The reaction can be monitored by CLAR: column of cm Dupont Zorbax RXC8 with a flow of 1 mL / minute and detection at 228 nm, (50/50) CH3CH / 0.I M KH2 O4 isocratic adjusted to? H = 6.8 with NaOH. Retention time of 1 = 7.2 min.

The chiral test was carried out using the same system as in the previous step. The reaction could also be monitored by CCD with 100% EtOAc as the solvent (Rf = 0.7). The solution was then concentrated to approximately 10 J_ at an internal temperature of > 20 ° C in a batch-type concentrator under a vacuum of 10 m bar. The solvent change was completed by slowly purging in 20 L EtOAc and re-concentrating to 10 1. The reaction mixture was washed in an extractor with 60 1 EtOAc. The organic phase was washed with 16% aqueous Na 2 C 3 solution, 2 X 10 1 DI deionized water and 2 X 6 1 saturated aqueous sodium chloride. The combined aqueous baths were again extracted with 20 1 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 EtOAc extracts. { The birates were concentrated under a vacuum of 10 bars with an internal temperature of <20 ° C in a batch-type concentrator of 100 1 to about 8 1. The change from solvent to cyclohexane was achieved by purging slowly in about 20 1 of cyclohexane and re-concentration to approximately 8 1. To the suspension was added 5 1 of cyclohexane and 280 ml of EtOAc and the mixture was heated to reflux, when everything was brought to solution.The solution was cooled and seed was added. g) at 58 ° C. The suspension was cooled to 22 ° C. for 4 hours and the product was isolated by filtration after one hour of aging at 22 ° C. The filter cake was washed with 1.8L of cyclohexane and dried in vacuum oven at 35 aC under N2 purge to give (% area> 99.9 per HPLC, R isomer below detection level) 1 as a lightly tan powder Ca] D25 = 22.0 ° (c = 0.20, MeOH), mp-107 ° C; 13Q NMR (75 MHz, CDC13, ppm) 170.1,154.5,79.8,58.7.50.6,46.6, 43.6,43.4,28,6,28.3.

EXAMPLE 5 Acid (S) -2-tert-Butyl-carboxamido-piperazine bis (L) Pyroglutamic 16 14 16 Materials rr "" - 2-tert-butyl-carboxamido- (0.11 moles) piperazine 14 in 1-propanol solution 155 ml, test = 21. lg L-pyroglutamic acid 28 g, (0.21 mole) water 5 ml The racemic-2-tert-butyl-carboxamide-piperazine 14 solution in 1-propanol was charged to a 500-milliliter round bottom flask with a reflux condenser, mechanical agitator and a nitrogen inlet. Water was added along with L-pyroglutamic acid and the resulting suspension was heated to reflux. The homogeneous yellow solution was cooled to 50 ° C and seeded with the bis- (L) -PGA salt of the amine R (50 rng). They began to form solids immediately. The solution was then further cooled to 25 ° C and aged for 16 hours. The solids were filtered at 22 ° C and the filter cake was washed with 35 ml of 1-pro-anol / cold 1% water. The filter cake was lowered to 35 ° C in a vacuum oven with 2 to give 23.75 g (48%) of (R) -2-tert-butyl-carboxamide-piperazine bis (D-pyroglutamic acid. material was 98% in accordance with the chiral HPLC test described above.The yellow mother liquors contained 22.6 g (45%) of (S) -2-tert-butyl-carboxamido-piperazine bis (L) -pyroglutamic acid salt 16 and ee was 95% according to the chiral HPLC test.The mother liquors were evaporated and used directly in the protection step shown in example 6.

EXAMPLE 6 (S) -2-tert-butyl-carboxamide-4-tert-butoxycarbonyl-piperazine 1-salt of (S) -2-tert-butyl-carboxamido-piperazine bis (D-pi-rogluthamic acid) 16 Materials Salt of (S) -2-te? -butyl-carboxamide-piperazine-Bis (L) -pyrglutamic acid 95% ee 22.6 g (50.1 moles) Di-tert-butyl dicarbonate 11.1 g (50.1 moles) Et3 N 35.5 mL (0.254 moles) 1-Propanol 226 ml • ^ OAc 24 ml To a salt of (S) -2-tert-butyl-carboxamido-piperazine-bis- (L) -pyroglutamic acid in a 500 ml 3 neck flask with low addition funnel N2 was added 1-? Ropanol. The gummy yellow solid dissolved rapidly upon addition of Et3N. A solution of B0C2 O in EtOAc was added for 2 hours at 22 ° C. The reaction mixture was aged for one hour after the addition was complete. The reaction can be monitored by HPLC (high performance liquid chromatography) and CCD using the same "-" "procedures as for the conversion of 15 to 1. The solution was then concentrated and the solvent was changed to acetate. ethyl (200) The reaction mixture was washed with 50 ml of aqueous a2C 3 solution to 7%, 2 x 30 ml of water and dried (Na 2 SO 3) and filtered, the EtOAc solution was concentrated and the solvent The mixture was heated to reflux to dissolve all solids The mixture was cooled and seeded (50 mg) at 52 ° C. The suspension was cooled to 22 ° C. C. for 2 hours and the product was isolated by filtration after 1 hour of aging at 22 ° C. The filter cake was washed with 8 ml of cyclohexane and dried in a vacuum oven at 35 ° C. N2 to give (% area of> 99.9 by HPLC analysis, R isomer below detection level) as a whitish powder.

EXAMPLE 7 Racernization of (S) -2-tert-butylcarboxamide-piperazine-tert-butoxycarbonyl-piperazine with a strong base formula on page 28"" "A racemization agent = potassium terbutoxide (S) -2-tert-butylcarboxamido-4-tert-butyloxycarbonyl-piperazine 1 (99.4% ee) 0.416 g potassium terbutoxide in terbutanol 1 M 0.04 rnL cyclohexane 7.3 LA a suspension of the enantiomeric pure piperazine derivative (1) in cyclohexane was added potassium terbutoxide and then heated to reflux for one hour.After cooling to room temperature a white precipitate was formed which was filtered to give 405 mg of racemic 2-tert-butylcarboxamido-4-tert-butyloxycarbonyl-piperazine.

B: Racemization agent = n-butyl lithium (S) -2-tert-butylcarboxamido-4-tert-butyloxycarbonyl-piperazine (99_4% ee) 0.421 g n-butyllithium in cyclohexane, 2.0 M 0.37 mL ^ iclohexane 7.5 mL To the paste of the piperazine derivative, which is purely pure (1) in cyclohexane, the lithium n-butyl solution was added slowly with ice cooling. The mixture was heated to reflux overnight. The removal of an aliquot and the analysis indicated that the ee had worn down to 50%. C; Racemization agent = base of Schwesinger (S) -2-tert-butylcarboxamide-4-tert-butyloxycarbonyl-piperazine (99.4% ee) 0.342 g l-tert-Octyl-4,4,4-Tris (dimethylamino) -2, 2-bisCtris- (dimethylamino) -phosphoranylideneamino3 * 2,4-catenadi- (phosphazene) 1M in hexane Dase from Schwesinger) 0.09 rnL Methylcyclohexane 6 mL The energetically pure piperazine enantio derivative (1) was heated to reflux with the Schwesinger base for 14 hours. The removal of an aliquot showed that the enantiomeric excess had worn out to 52%.

EXAMPLE 8 Racemization of (S) -2-tert-butylcarboxamide-4-tert-butoxycarbonyl-piperazine 1 with carboxylic acid.

Racemization agent = acetic acid. { ~ "- 2-tert-butyl lcaboxamide-4-te -. Jyloxycarbonyl-piperazine 1 (99.4% ee) 0.441 g Acetic acid 7.73 rnL The enantiomerically pure piperazine derivative (1) was heated in acetic acid at 100 ° C for 12 hours. After cooling to 22 ° C, the acetic acid was removed by evaporation in vacuo to give 430 mg of a white solid. The ee determination showed 68% wear.

EXAMPLE 9 Racemization of (S) -2-tert-butylcarboxamide-4-tert-butoxycarbonyl-piperazine 1 with anhydrous metal salt 1 Racemization agent = magnesium chloride (S) -2-tert-butylcarboxamide-4-tert-butyloxycarbonyl-piperazine 1 (99.4% ee) 0.430 g Anhydrous magnesium chloride 0.03 g Ethylene glycol diethyl ether 50 L The enantiomerically pure piperazine derivative (1) and the anhydrous magnesium chloride were heated for 12 hours at 100 ° C in ethylene glycol diethyl ether. The removal of an item and the analysis indicated that the ee had worn down to 97%.

EXAMPLE 10 Racemization of bisC (1S) -alphafor-10-sulphonic acid] of (S) -ter-butylcarboxamide-piperazine 15 with strong base 14 Racemization agent = potassium tert-butoxide Bis (lS) -alphafor-lO-sulfonic acid] of (S) -ter-butylcarboxamide-piperazine 15, 99.3% of 0.559 g ter-potassium butoxide in tetrahydrofuran 1.72 M 1.25 MI "" "Vethylcyclohexane 9 mL The diastereomerically pure piperazine camphor sulfur salt (15) was suspended in ethylcyclohexane and the potassium terbutoxide / THF solution was added. The reaction mixture was heated at 80 ° C for 12 hours. Removal of an aliquot indicated that the enantiomeric purity of the piperazine had worn to 32% EXAMPLE 11 Racemization of bisC (lS) -alphafor-lO-eulphonic acid] of (S) -2-tert-butylcarboxamide-piperazine 15 with carboxylic acid 14 Racemization agent = acetic acid BisC (lS) -alphafor-10-sulfonic acid] of (S) -ter-butylcarboxamide-piperazine 15, 99% of 2.14 g Glacial acetic acid 10 L The diastereomerically pure piperazine camphor salts salt (15) was heated in acetic acid at 16 ° C for 66 hours. After cooling to 25 ° C, the mixture was diluted with 30 ml of THF, adjusted to pH 9.5 with 50% NaOH, and extracted with ethyl acetate (3 x 50 ml). The organic phases were combined and dried with anhydrous magnesium sulfate and concentrated to give the free base of the piperazine amide (14). The determination of ee showed a wear to 71% by chiral HPLC assay.

EXAMPLE 12 Racemization of (R) -2-tert-butylcarboxarnide-4-furopicolyl-piperazine with strong base Racemization agent = potassium tert-butoxide (R) -2-tert-butylcarboxamide-4-furopicolyl-iperazine (99.3% ee) 1.87 g ter-potassium butoxide 1.7 M in THF 0.02 rnL THF 25 rnL The enantiomerically pure (R) -2-tert-butylcarboxamide-4-furopicolyl-piperazine is dissolved in THF and potassium tert-butoxide is added thereto. The solution is heated to reflux for 3 hours, when the analysis of an aliquot by chiral HPLC indicates that the material is racemic.

EXAMPLE 13 Racemization of (R) -2-tert-butylcarboxamide-4- (3-picolyl) -piperazine with strong base Racemization agent = potassium tert-butoxide *. - '* ^ 1-2-tert-butylcarboxamide-4- (3-picolyl) - r -' ^ erazine (99.3% ee) 0.67 g potassium tert-butoxide 1.7 M in THF 0.01 rnL THF 21 mL The enantiomerically pure (R) -2-tert-butylcarboxamide-4- (3-picolyl) -piperazine is dissolved in THF and potassium terbutoxide is added. The solution is heated to reflux for 4 hours, when the analysis of an aliquot by "** PLC chiral indicates that the material is racernic.

EXAMPLE 14 Combination of racemization of the bis- (L) -pi roglutámico acid salt of (R) -2-tert-butylcarboxamide-piperazine and resolution A: Racemization in cyclohexane / THF as solvent: Salt of bis (L) -pyroglutamic acid of (R) -2-tert-butylcarboxamide-piperazine (17) 97.9% R, 1.03% S, 3.4% TG (0.468 mol) 214.98 g 50% aqueous NaOH 80 rnL 1-Propanol 40 rnL / ua 65 rnL Tetrahydrofuran 700 rnL Watery sat. K2CO3 50 mL ter-butoxide-K 1M in ter-butanol 12.1 rnL The piperazine salt of bis (L) -pyroglutamic acid (undesired enantiomer (R) from Example 5) (17) was dissolved in 1-propanol, H2O and NaOH in a separating funnel. To the system ,; > When added, 700 ml of THF were added and the aqueous phase was separated. The organic phase was washed twice with 25 mL of saturated aqueous solution of K2CO3. The organic solution was transferred to a 1 L three neck flask with mechanical stirring and distillation head. The THF solvent was changed to cyclohexane at atmospheric pressure, concentrating to a total volume of approximately 250 mL followed by the addition of 700 rnL of cyclohexane and reconcentrating to 250 mL. After the addition of 150 ml of THF and potassium terbutoxide, the light paste was heated to reflux for 7 hours. The paste was cooled to 2 ° C for 2 hours, filtered and washed with 2 x 40 ml of cyclohexane. After drying, 82.94 g (96% recovery) of a white crystalline powder (99.7% p, 50.8% R, 49.2% S) were obtained. The racemic material can be resolved with 1.8 equivalents of (L) -pyroglutamic acid in a 1-propanol / water medium (see example 5).

B: Racemization in 1-propanol as solvent: - '^ 1, jß (R) -? Iperazm-2-ter- 29.62 g (TG = 3.4%) outyl-carboxamide of bis-L-pyroglutamic acid (17) (64.6 mMoles) Aqueous solution 50% NaOH (w / w) 11.7 L Water 11.7 rnL 1-Propanol 90 rnL Sol. Aqueous sat. K2CO3 10 L-tert-butoxide-K in THF, 1.72 M 1.15 rnL The amine salt (17) was dissolved in a separating funnel in the water / 1-propanol mixture by heating to 40 ° C. By addition of NaOH, a second phase was formed, which was divided. The aqueous phase was washed twice with 5 ml of saturated aqueous K2CO3 solution. An HPLC assay indicated that 95% of the amine was extracted into the organic phase. The solution of the amine in 1-propanol was charged to a distillation flask, and 200 ml of dry propanol was added. The solution was distilled at atmospheric pressure, until the solvent passed to 98 ° C and the KF of an aliquot had dropped to 0.350 mg / mL of solution. The distillation head was replaced with a reflux condenser and 1.15 ml of a 1.72 M solution of potassium terbutoxide was added. The solution was heated to reflux, and the chiral analysis of an aliquot indicated that the amine was racemic (50% R, 50% S) after 17 hours under reflux. The racernic material can be solved with 1.8"(L) -pyroglutamic acid jivalents in a 1-propanol / water medium (see example 5). It is also possible to achieve the same recernization by the addition of a sodium or sodium propoxide solution. potassium in 1-propanol.

EXAMPLE 15 Combination of racemization of the salt (R) -2-ter-j-utilcarboxamide-piperazine of bis (L) -pyroglutamic acid (17) and resolution Racemization in 1-propanol through the in situ preparation of the alkoxide: Salt (R) -piperazin-2-tert-butyl-188.9 g (TG = 3.4%) bis-L-pyroglutamic acid carboxamide (17) (0.42 ol ) 1-Propanol 950 rnL Aqueous solution 50% NaOH (w / w) 250 g? -? 300 g The amine salt (17) was dissolved in the mixture 1-propanol, NaOH, H 2 O in a separating funnel. A lower phase was formed that was separated. The lower aqueous phase contained the majority of L-PGA, while the upper phase of 1-propanol contained 79.0 g of piperazine (analysis by HPLC, 100% recovery). Also present in the organic phase were 4.5 mol% of L-PGA, and, by titration with HCl, 33 mol% of NaOH. The organic phase was dried azeotropically, until the KF of the solution had reached 0.259 mg / mL of solution. At this point an aliquot was removed and determined to be racemic (50% R, 50% S). 13.9 g of solid KHCO3 and 50 ml of H2O were added to the solution at 60 ° C and the solution was stirred for 30 minutes. A solid phase was separated and was removed by filtration. The permanent solution of 1-propanol was free from any strong base at this point and could be resolved using the conditions previously described (see for example, Example 5).

EXAMPLE 16 l- ((R) -2 ', 3'-Epoxypropyl) - (S) -2-tert-butylcarboximide-4-t r -butoxycarbonyl-piperazine 3 Materials (S) -2-tert-butylcarboximide-4-tert-butoxycarbonyl-piperazine 1 11.0 g (38.4 mmol) 3-Nitrobenzenesulfonate of (2S) - (+) - Glycidyl 2 9.96 g (38.4 mrnol) Diisopropylethylamine 5.5 mL (42.2 mmol) DMF 38 rnL Piperazine 1 and (2S) - (+) - glycidyl 2-nitrobenzenesulfonate 2 were dissolved in a 250 ml flask with magnetic stirring under N2 purge in DMF and DIEA. The resulting homogeneous solution was heated at 60-62 ° C for 9 hours. TLC (100% EtOAc as eluent, ninhydrin dye) indicated complete piperazine 1 consumption. The reaction was stopped with the addition of 30 rnl of a 5% aqueous solution of NaHC 3. The reaction mixture was extracted with 400 ml of isopropyl acetate. The organic phase '~' / 3 washed with water (3 x 50 rnl) and brine (1 x 50 ml), dried (Na 2 0 ') and evaporated to give a yellow oil. Flash chromatography (column 4 cm X 20 cm, SIO2, gradient elution with EtOAc: hexane 30:70 to EtOAc: hexane 60:40) and evaporation of the product containing the fractions gave 9.24 g (71% yield) ) of 3 as an oil. [a] D2S = -i7.7 ° (c = 0.12, MeOH); 13c NMR (100 MHz, CDCl 3, -25 ° C, ppm of the major rotamer) 170.0, 154.1, 80.2, 66.7, 56.3, 51.7, 50.8, 50.2, 47.0, 44.0, 41.9, 28.3, 28.1.

EXAMPLE 17 Preparation of epoxide 3 from piperazine 1 and (S) -Glycidol 4 1 Piperazine 1 (2.00 g, 7.00 mmol) and (S) -glycidol 4 (930 μL, 14.0 mmol) were heated at reflux in 19 ml of isopropanol for 17 hours, then the mixture was partitioned with 100 ml of ethyl acetate and 50 ml of water. The layers were separated, and the ethyl acetate layer was washed with saturated sodium chloride, dried with MgSO 4, and concentrated to 2.4 g of a gum. A portion of the gum (241 mg) was treated with 2 ml of pyridine and p-toluenesulfonyl chloride (130 mg, 0.68 mmol) overnight, then concentrated to an oil. The oil was partitioned with 25 ml of ethyl acetate and 10 ml of water. The ethyl acetate layer was washed with brine, dried (MgSO *) and concentrated to an oil. The crude oil was dissolved in 2 ml of THF and treated with 100 mg of a dispersion in 60% NaH oil. After 1 hour, the mixture was partitioned with ethyl acetate (50 ml), and 10 ml of water. The ethyl acetate layer was dried with MgSO * and concentrated to yield the desired epoxide 3 (see previous experiments for spectral data).

EXAMPLE IB Preparation of the coupled product 8 from the A solution of acetonide 7 (216 «v, 0.67 mmol) was cooled to -78 ° C, which can be made according to the procedure described in the patent of E.U.A. No. 5,169,952, issued December 8, 1992, and the epoxide N-Boc-piperazine 3 (229 g, 0.67 mmol, 1.0 eq. Iv.) In 3.5 ml of THF (KF = 22 μg / mL) (KF points) by Karl Fisher titration for water) in a 100 ml round bottom flask, equipped with a thermocouple, magnetic stirrer and under a nitrogen atmosphere. Then a solution of n'-butyl lithium in hexane (0.9 L, 1.6 M, 2.1 equiv.) Was added, keeping the internal temperature tint -78 ° C and -73 ° C. The reaction mixture was stirred at -76 ° C for 1 hour and then allowed to reach -25 ° C for 1 hour. The mixture was stirred between -25 and -22 ° C for 2.5 hours. Then, the reaction mixture was quenched with DI water (5 mL) at -15 ° C and partitioned with ethyl acetate (20 mL). The mixture was stirred and the layers were separated. The ethyl acetate extract was washed with saturated NaCl (10 ml) and ^ concentrated under reduced pressure (711 mm Hg) to produce a crude product which was subjected to chromatography on a column of silica gel with ethyl acetate / hexane (3: 2) to give the coupled product 8 (84 mg, 20% ) as a pale yellow syrup: 13c NMR (CDCl 3, 75.4 MHz) 6 172.6, 170.2, 154.6, 140.8, 140.4, 139.6, 129.5, 128.8, 128.1, 127.2, 126.8, 125.6, 124.1, 96.7, 8O.4, 79.2, 65.9, 65.8, 62.2, 51.3, 50.1, 45.3, 43.5, 39.5, 39.1, 36.2, 28.8, 28.4, 26.5, 24.2.

EXAMPLE 19 Preparing penultimate 9 To a solution of compound 8 (5.79 g, 8.73 mmol) in 25.5 ml of isopropanol at 0 ° C, 20 ml of 6N aqueous HCl were added, then, 15 minutes later, 10 ml of water was added.

Concentrated HCl. After 1 hour, the mixture was heated to ° C and left at rest for 4 hours. The mixture was then "** cooled to 0 ° C, and the pH was adjusted to 12.5 with 13 ml of 50% aqueous NaOH, keeping the temperature <29 ° C. The mixture was extracted with 2 x 80 ml of EtOAc, and the extracts were dried with MgSO4 and concentrated to yield 5.46 g of product 9 as a colorless foam: 13 C NMR (75.4 MHz, CDC13) 6 175.2, 170.5, 140.8, 140.5, 139.9, 129.1, 128.5, 127.9, 126.8, 126.5, 125.2, 124.2 , 73.0, 66.0, 64.8, 62.2, 57.5, 49., 47.9, 46.4, 45.3, 39.6, 38.2, 28.9.

EXAMPLE 20 Preparation of compound 3 monohydrate The solution of 9 in EtOAc (10.5 L, KF = 10 mg / mL) from the previous step was charged with 20 L of DMF dried on sieve (KF <30 mg / L) and the mixture was heated with a steam bath under vacuum of 762 mm Hg to remove by distillation mainly the water and / or any residual solvent of isopropanol or ethyl acetate. The volume of the final "" concentrate was 13.5 L (KF = 1.8 mg / mL) and then triethanola (2.86 L, 20.51 mol) was added to the solution at 25 ° C followed by 3-chloropicolyl hydrochloride (96%, 1287 g, 7.84 mol). The resulting part was heated to 6B ° C. The progress of the reaction was followed by HPLC analysis using the same conditions as in the previous step. Approximate retention times: Retention time (m n) Identity 2.7 DMF 4.2 3-picolyl chloride 4.8 Compound 3 9.1 penultimate 9 The mixture was allowed to stand at 68 ° C until the penultimate residual compound 9 was < 0.3% area by HPLC analysis. HPLC conditions: Column 25 cm Dupont C8-RX, 60:40 acetonitrile / (KH2PO4 / K2HPO4) 10 mM, 1.0 ml / min, detection = 220 nm. The mixture was stirred at 68 ° C for 4 hours, then cooled to 25 ° C and partitioned with ethyl acetate (80 L) and a mixture of 24 L saturated aqueous NaHC 3 and distilled water (14 L). The mixture was stirred at 55 ° C and the layers were separated. The ethyl acetate layer was washed 3 times with water (20 L) at 55 ° C. The washed layer of ethyl acetate was concentrated under atmospheric pressure to a final volume of 30 L. At the end of the atmospheric concentration, water (560 ml) was added to the hot solution and the mixture was cooled to 55 ° C and seeded with the monohydrate of compound J. The mixture was cooled to 4 ° C and filtered to collect the product. The product was washed with cold ethyl acetate (2 x 3 L), and dried under vacuum at 25 ° C to yield 2905 g (70.7%) of the monohydrate of compound J as a white solid. The differential scanning calorimetric curve (DSC) for the monohydrate of compound 3 at 10 ° C / min under a flow of trigene showed a relatively broad, shallow endotherm with a temperature peak of about 66 ° C followed by a combination a-exotherm endotherm on the temperature scale from 129 to 134 ° C and finally a higher melting endotherm with a peak temperature of 158 ° C, an extrapolated start temperature of 155 ° C and a corresponding heat of fusion of 59 J / g.

EXAMPLE 21 Kinetic resolution of (S / R) -2-tert-Butylcarboxamide-4-tert-butoxycarbonyl-piperazine 17 to 1 Materials (S / R) -2-tert-Butylcarboxamide-4-tert-butoxy- 1.40 g carbonyl piperazine 17 crude (S) -2-tert-Butylcarboxamide-4-tert-butoxycarbonyl-4x0.14g piperazine 1 (> 99.5 % ee) Methylcyclohexane with 2% EtOAc (vol / vol) 14 L The crude gummy product 17 was dissolved in 14 mL of the solvent mixture by heating to 90 ° C. The solution was allowed to cool, and at 10 ° C intervals the solution was seeded with 0.14 g of 1 (> 99.5% ee). At 55 ° C, the fourth batch of 0.14 g of seed was not further dissolved and subsequently by slow cooling to room temperature a white crystalline mass was formed. The reaction mixture was filtered, washed with 3 mL of the methylcyclohexane / EtOAc solvent mixture and dried in the vacuum oven under 2 to give 0.95 g of a white solid. The determination of the enantiomeric purity with a Chiracell AS column showed 93% ee. The methods and intermediates of this invention are useful for the preparation of final 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. These final compounds and their ability to inhibit HIV protease are described in J = PO 541,168 which was published on May 12, 1993. The treatment of AIDS or its prevention or treatment of HIV infection is defined as including, but not limited to, the treatment of a wide range of states of infection for HIV: AIDS, ARC (complex related to AIDS), both symptomatic and asymptomatic and actual or potential exposure to HIV. For example, the final compounds that can be made from the methods and intermediates of this invention are useful in the treatment of HIV infection after suspected exposure to HIV by, v. ~. ", blood transfusion, organ transplantation, exchange of bodily fluids, bites, accidental needle sticking, or exposure to the patient's blood during surgery.

HIV are also useful in the preparation and execution of screening tests for antiviral compounds. For example, the final compounds are useful for the isolation of enzymatic mutants, which are excellent selection tools for more potent antiviral compounds. In addition, compounds are useful for establishing or determining the binding site of other antivirals to the HIV protease, for example, by competitive inhibition. In this manner, the final compounds that are made from the methods and intermediates of this invention are commercial products to be sold for these purposes. The HIV protease inhibitor compounds which are to be made from the intermediates and processes of the present invention are described in EPO 541,164. The HIV protease inhibitor compounds may 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 describes suitable pharmaceutical formulations, routes of administration, salt forms and dosages for the compounds. The compounds of the present invention may have asymmetric centers and occur as recemates, racemic mixtures and as individual diastereomers or enantiomers with all isomeric forms being included in the present invention. When any variable (for example, aryl, heterocycle, R, R1, R2, n, X, etc.) occurs more than once in any constituent or in formulas I-XI, its definition of each occurrence is independent of its definition in every other occurrence Also, combinations of substituents and / or friables are permissible only if such combinations result in stable compounds. As used herein, except where indicated, "alkyl" is intended to include saturated aliphatic hydrocarbon groups of both straight and branched chain having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl; t-Bu is tert-butyl). As used herein, "aryl" is intended to describe phenyl (Ph) naphthyl. "Heteroaryl", as used herein is intended to describe a 6-membered aromatic heterocyclic ring or an unsaturated bicyclic stable heterocycle of 8 to 10 members wherein the mono- or bi-cyclic heterocycle consists of carbon atoms and 1 to 3 heteroatoms selected from the group consisting of N, 0, or S. For example, the term "heteroaryl" could include, but is not limited to, the following entities.

Although the above specifications teach the principles of the present invention, with the examples provided for purposes of illustration, it will be understood that the practice of the invention encompasses all variations, adaptations or - usual modifications, as they are included in the scope of the following claims and their equivalents.

Claims (22)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for the racemization of optically pure or enriched substrate of piperazine-2-tert-butylcarboxy acid of formula IX or X, or a salt thereof, xx comprising the reaction of said substrate, or a salt thereof, with a racemisation agent selected from a strong base, an anhydrous metal salt or a carboxylic acid, in a solvent on a temperature scale of between room temperature and 250 ° C; wherein R and R2 are each i independently selected from the group consisting of 0 0. , II II hydrogen, R, -C-R and -C-OR, - and R is selected from the group consisting of alkyls of 1 to 5 carbon atoms, -CH 2 -aryl, -CH 2 -heteroaryl, aryl and trifluoromethyl.

2. The process of claim 1, characterized in that R2 is selected from the group consisting of O and R is selected from the group consisting of alkyl of 1 to 5 carbon atoms, -CH2-aryl, and -CH2-heteroaryl .

3. The process of claim 2, characterized in that said racemization agent is a strong base selected from the group consisting of a lithium alkyl, a lithium amide, a hydroxide, an alkoxide and a Schwesinger base.

4. The method of claim 3, characterized in that said strong base is selected from the group consisting of lithium tert-butoxide, sodium tert-butoxide, potassium tert-utoxide, lithium n-propoxide, n-propoxide sodium, potassium n-propoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide.

5. The method of claim 2, characterized in that said racemisation agent is a salt of - «selected anhydrous neonate of magnesium chloride, magnesium bromide, zinc chloride, iron chloride, (III) or titanium chloride (IV).

6. The process of claim 2, characterized in that said racemisation agent is a carboxylic acid selected from acetic acid, propionic acid, butyric acid or isobutyric acid.

7. The method of claim 2, characterized in that said temperature scale is between 50 and 120 ° C.

8. The process of claim 2, characterized in that said solvent is an ether, an alkane, a cycloalkane, an alcohol or an aromatic compound, or a mixture thereof.

9. The process of claim 8, characterized in that said solvent is selected from THF, cyclohexane or propanol, or a mixture thereof.

10. The method of claim 2, characterized in that said substrate is selected from the group <; which consists of: or salts thereof.

11. - The method of claim 10, wherein said substrate is selected from the group consisting of or a salt of them.

12. The process of claim 11, comprising the additional isolation step of the S-enantiomer of the piperazin-2-tert-butylcarboxamide compound of the racemate.

13. The process of claim 2, characterized in that said salt is selected from a salt of pyroglutamic acid or a salt of phonorphsulphuric acid.

14. The process of claim 13, characterized in that said salt is the salt of bis- (D-rogluthanoic acid)

15. A process for the racemization of an optically pure or enriched substrate of piperazin-2-tert-butylcarboxamide of Formula IX or a salt thereof. IX comprising reacting said substrate, or a salt thereof, with an alkoxide in 1-propanol on a temperature scale of between 50 and 120 ° C; wherein R1 is hydrogen or tert-butyloxycarbonyl; and R2 is hydrogen.

16. The process of claim 15, characterized in that said alkoxide is selected from sodium n-propoxide, potassium n-propoxide and lithium n-propoxide.

17. The process of claim 16, characterized in that said sodium, potassium or lithium n-propoxide is prepared in situ by the azeotropic drying of sodium, potassium or lithium hydroxide in 1-propanol.

18. The process of claim 17, characterized in that said salt is the bis- (D-pyroglutamic acid salt.)

19. The process of claim 16, characterized in that said temperature scale is between 85 and 120 ° C.

20. A compound of formula XI and salts thereof. R1 XI wherein R * and R2 are each independently selected from the group consisting of hydrogen, 0 is selected from the group consisting of alkyl of 1 to 5"" carbon atoms, -CH2-aryl, -CH2-heteroaryl, aryl and trifluoromethyl.

21. The compound of claim 20, characterized in that * is selected from the group consisting of hydrogen, R and 0 -C-OR; R2 is selected from the group consisting of hydrogen and O -C-OR; and R is selected from the group consisting of alkyl of 1 to 5 carbon atoms, -CH 2 -aryl and -CH 2 -heteroaryl.

22. The compounds of claim 21, and the salts thereof, selected from the group consisting of