Method for the preparation of beta-substituted gamma-amino carboxylic acids

Abstract

The present invention relates to the preparation of -substituted -amino carboxylic acids, preferably in enantiomerically enriched or even enantiomerically pure form, by a one-pot conversion of a -substituted -nitro dicarboxylic acid ester or of a -substituted -nitro dicarboxylate of general formula to a -substituted -nitro carboxylic acid and a subsequent reduction of the -nitro group to an amine group. In particular, the present invention relates to the preparation of (S)-pregabalin. In addition, the formation of enantiomerically enriched -substituted -amino carboxylic acids and -substituted -nitronate carboxylic acid salts are also described.

Claims

1. Method for the preparation of a (-substituted -amino carboxylic acid of general formula (I) ##STR00033## comprising a one-pot conversion of a -substituted -nitro dicarboxylate of general formula (II) to a -substituted -nitro carboxylic acid of general formula (III) ##STR00034## and a subsequent reduction of the -nitro group to an amine group, wherein R.sup.1 is selected from the group consisting of C.sub.1- to C.sub.12-alkyl, alkenyl, alkynyl, and aryl, and R.sup.2 and R.sup.3 are independently from one another selected from the group consisting of a C.sub.1- to C.sub.12-alkyl or aryl group, an alkali metal ion or a tetra-substituted ammonium ion, or R.sup.2 and R.sup.3 are together forming a C.sub.3- to C.sub.12-alkyl, alkenyl or aryl ring structure or are an alkaline earth metal ion, wherein the one-pot conversion of (II) to (III) involves the treatment of (II) with 0.2 to 10 equivalents of a strong Brnsted acid using a carboxylic acid as solvent, in the presence of 1 to 15 equivalents of water, at a temperature of between 90 C. and 120 C. and a concentration of less than 1 M, and wherein the strong Brnsted acid is MsOH (methanesulfonic acid) or H.sub.2SO.sub.4.

2. Method according to claim 1, wherein R.sup.1 is an alkyl group.

3. Method according to claim 1, wherein 0.5 to 6.0 equivalents of MsOH or 0.4 to 2.5 equivalents of H.sub.2SO.sub.4 are used as the strong Brnsted acid S.

4. Method according to claim 1, wherein the one-pot conversion of (II) to (III) is conducted in the presence of 5 to 10 equivalents of water.

5. Method according to claim 1, wherein the one-pot conversion of (II) to (III) is carried out at a concentration of 0.4 to 0.6 M.

6. Method according to claim 1, wherein enantiomerically enriched (S)-pregabalin (S-IV*) ##STR00035## is prepared.

7. Method according to claim 1, wherein the strong Brnsted acid is MsOH.

8. Method according to claim 1, wherein the strong Brnsted acid is H.sub.2SO.sub.4.

9. Method for the preparation of a -substituted -amino carboxylic acid of general formula (I) ##STR00036## comprising a one-pot conversion of a -substituted -nitro dicarboxylate late of general formula (II) to a -substituted -nitro carboxylic acid of general formula (III) ##STR00037## and a subsequent reduction of the -nitro group to an amine group, wherein R.sup.1 is selected from the group consisting of C.sub.1- to C.sub.12-alkyl, alkenyl, and aryl, and R.sup.2 and R.sup.3 are independently from one another selected from the group consisting of a C.sub.1- to C.sub.12-alkyl or aryl group, an alkali metal ion or a tetra-substituted ammonium ion, or R.sup.2 and R.sup.3 are together forming a C.sub.3- to C.sub.12-alkyl, alkenyl or aryl ring structure or are an alkaline earth metal ion, wherein the one-pot conversion of (II) to (III) involves the treatment of with 0.2 to 10 equivalents of a strong Brnsted acid using a carboxylic acid as solvent, in the presence of 1 to 15 equivalents of water, at a temperature of between 90 C. and 120 C. and a concentration of less than 1 M, wherein an enantiomerically enriched (-substituted -amino carboxylic acid of general formula (I*) ##STR00038## is prepared, the method further comprising a salt formation from a -substituted -nitro carboxylic acid of general formula (III) to obtain the corresponding enantiomerically enriched -substituted -nitro carboxylic acid salt of general formula (V*) ##STR00039## and subsequent crystallization or precipitation, wherein the -substituted -nitro carboxylic acid of general formula (III) is racemic or enantiomerically enriched, and M is an alkali metal cation, an alkaline earth metal cation or an organic amine.

10. Method according to claim 9, wherein the salt formation is performed using a base selected from the group consisting of triethanolamine, dibenzylamine, NaOH, quinidine, (S)-1-cyclohexyl-ethylamine, diisopropylamine, and tert-butylamine.

11. Method according to claim 9, wherein the carboxylic acid salt (V*) is further converted to a nitronate salt of general formula (XXI*) ##STR00040## by treatment with a strong base selected from the group consisting of NaOH and KOH.

Description

EXAMPLE 1

Optimization of One-Pot Hydrolysis and Decarboxylation of Dimethyl 2-(4-methyl-1-nitropentan-2-yl) malonate (XVI)

(1) ##STR00021##
See tables 1a-1b below.

(2) Due to previous non-satisfying results (entries 1-2), the one-pot hydrolysis/decarboxylation was investigated extensively. Optimization of the reaction started from HCl in water (entry 3) as described in WO 2009/147434. To reduce the formation of XVII, the amount of water was decreased by using AcOH as solvent instead, and also the amount of HCl was reduced (entry 4, 5). A slight increase of the amount of HCl from 6 to 8 did not improve the result. The amount of water was further decreased by using more concentrated HCl (entries 6 and 7), which improved the ratio of IX:XVII, but incomplete reaction was observed in entry 7 (HPLC: 44% of product with 10% of XVI).

(3) Increasing the reaction temperature to 110 C. significantly accelerated the reaction, although the concentration and water amount were lowered (comparing entry 8 with entries 6-7). The reaction rate comes to limit and low conversion (HPLC: 5% of product) was observed when only 2.5 equiv. of HCl were used (entry 9).

(4) To investigate the influence of acid amount without variation of the amount of water, MsOH was used as the strong acid S. Starting from 2.5 equiv., the ratio of IX:XVII was improved but about 10% of imide XVIII was also observed (entries 10 and 11). Although the reaction with 10 equiv. of water was carried out at 110 C., less than 10% of XVII was obtained. There was no by-product formation at 90 C. in the presence of various amounts of MsOH and water (entries 12, 13, and 14), however longer reaction time (1 d) was needed. Under these conditions (90 C., 8 equiv. of water, 0.5 M), XVII can be observed when using 4-6 equiv. of MsOH (comparing entry 14 with entries 18 and 19). Even though the reaction with a lower amount of MsOH (0.5-1.0 equiv.) was performed at a higher temperature (110 C.), still no XVII was formed (comparing entry 14 with entries 15 and 16). It comes to limit when the reaction is carried out with 2 equiv. of MsOH at 110 C. (comparing entry 15 with 17), where XVII was formed. Apparently, the amount of acid (0.5-2 equiv.) and temperature influence to the reaction rate: the higher the faster (entries 15-17 for acid amount and entries 11-12 for temperature). Using more than 3.5 equiv. of MsOH (entries 18-19) did not change the reaction rate significantly. The desired product can be obtained in >80% yield with 0.5-4 equiv. of MsOH (entries 15-18). The initial optimization shows that the formation of XVII and XVIII can be favorably suppressed.

(5) In order to get a more robust procedure, Taguchi experiment (L9 array; see table 2) was performed (entries 20-28). Four factors (acid amount (A), concentration (C), water amount (W), and temperature (T)), each at 3 levels were considered.

(6) TABLE-US-00001 TABLE 2 Unit MsOH (eq) Water (eq) T ( C.) Conc. (M) 1 2.5 6 90 0.25 2 3.0 8 100 0.5 3 3.5 10 110 1.0

(7) For most cases, the reaction gave high yield (>83%), except entry 24. For entries 25 and 28, low yield was obtained because of incomplete reaction (15% and 13%, respectively, as determined by .sup.1H NMR). As shown in entries 20, 25, and 27, long reaction time is needed at 90 C. XVII is always formed if the reaction is conducted at high concentration (1.0 M; entries 22, 23, and 27) and is never observed at low concentration (0.5 M; entries 20, 24, and 28). The best yield was obtained in entry 21, where 2.5 equiv. of MsOH were used.

(8) After performing statistical analysis of these results, the following significant process parameters were identified: Factors influencing the reaction rate: T>C>W>A Factors influencing the yield: A>W>C>T Factors influencing the amount of XVII: C>A>W>T

(9) Consequently, reaction with MsOH (2.5 equiv.), water (8 equiv.) at 0.5 M and 110 C. should provide the highest yield.

(10) A confirmation experiment (entries 29 with racemic substrate and 30 with enantiomerically enriched substrate) was conducted to verify the optimal process parameters obtained from the process parameter design.

(11) Scaling up economically by using crude Michael adduct under the same conditions (entries 31-32) gave product IX in about 70% yield over 2 steps (Michael addition and hydrolysis/dacarboxylation). Higher concentration showed again more by-product formation (entry 31).

(12) To get more cost effective, MsOH was replaced by H.sub.2SO.sub.4 (entries 33-43). The by-products were exclusively formed if water amount was very low (1.2 equiv., entry 33). Using the best condition found for MsOH with H.sub.2SO.sub.4 (entry 34), 7% of XVII was formed. To evaluate the factors (A, W, and T), design of experiment was again performed (entries 36-39).

(13) The best conditions (1.2 equiv. of H.sub.2SO.sub.4, 8 equiv. of water at 100 or 110 C., entries 40 and 41) were established by statistical analysis. This afforded the product IX in more than 80% yield over 2 steps (Michael addition and hydrolysis/dacarboxylation), which was higher than for MsOH (comparing entry 41 with entry 32). When using less H.sub.2SO.sub.4 (0.4 equiv.), the reaction time increased (entry 42), but almost the same result was obtained (comparing entry 41 with 42). Using recovered AcOH (5.8% water contained), the reaction successfully took place to afford product IX in up to 94% HPLC yield (entry 43).

(14) In conclusion, it was found that MsOH (0.5-6.0 equiv.) and H.sub.2SO.sub.4 (0.4-2.5 equiv.) can be used to perform the one-pot hydrolysis and decarboxylation reaction of XVI successfully. However, a significant amount of water (6-10 equiv.) is necessary to get gratifying results.

(15) The reaction rate and the product ratio were mainly influenced by the reaction temperature (110 C.) and the concentration (0.5 M). When applying this robust procedure, exclusively the desired product IX was formed in up to 94% yield for one step (using pure XVI) or 70-87% yield over two steps (using crude XVI).

EXAMPLE 2

Optimization of One-Pot Hydrolysis and Decarboxylation of Dipotassium 2-(4-methyl-1-nitropentan-2-yl) malonate (XIX)

(16) ##STR00022##

(17) In the case of dicarboxylate XIX, when using 4-6 equiv. of MsOH, XVII was still observed in 4-11%. Using low amounts of MsOH (1-3 equiv.), 12-100% of by-products were obtained, mostly XVIII.

(18) For enantiomerically enriched starting material, no erosion of enantiomeric ratio was observed.

EXAMPLE 3

Saponification of 5-Methyl-3-(nitromethyl) hexanoic Acid (IX) Using Various Bases

(19) ##STR00023##
See tables 3a-3b below.

(20) In all cases, crystallization or precipitation processes of XX* mono-salts using 1 equivalent of base have an essential influence on the separation of the enantiomers. The enantiomeric excess were upgraded from 86% ee to >90% ee. Especially, the best results were obtained by salt formation of (IX*) with NaOH (entry 6), diisopropylamine (entry 15), and (S)-1-cyclohexyl-ethylamine (entry 12).

(21) Enantiomeric excess was improved up to 99% ee (entry 15). However, purities of some salts are lower than those of the starting material, and XVIII was observed by HPLC as a major side product. These results seem to indicate the stability problem of the mono-salts.

(22) In contrast, purities of other salts were upgraded. However, those salts also decomposed to XVIII upon storage for a longer period. Therefore, these salts should be used immediately for hydrogenation.

EXAMPLE 4

Treatment of 5-Methyl-3-(nitromethyl) hexanoic Acid (IX) with 2 Equivalents of a Strong Base

(23) ##STR00024##

(24) TABLE-US-00002 TABLE 4 ee HPLC ee HPLC Base of purity of purity Yield (equiv.) IX of IX solvent t/T XXII of XXII [%] NaOH 85.9 86 EtOH 16 h at 83.7 90.7 79.0 (2.5) 20-25 C. KOH 86.0 79.0 EtOH/ 16 h at 83.8 97.2 96.2 (3.0) MeCN 20-25 C. 1:2 (only precipitation conditions shown; the starting material was prepared by extraction and concentration of organic layer)

(25) As shown in table 4, the enantiomeric excess was not improved by the disalt formation. However, the purity is significantly upgraded from 79% to >90%. In addition, these salts are very stable at room temperature.

EXAMPLE 5

Synthesis of 4-Methyl-1-nitro-pent-1-ene

(26) An aqueous 10 M NaOH solution (9 ml, 90 mmol, 1 equiv.) was added dropwise to a solution of isovaleraldehyde (9.70 ml, 90 mmol, 1 equiv.) and nitromethane (4.90 ml, 90 mmol, 1 equiv.) in EtOH (150 ml) at 0 C. After 10 min, the reaction mixture was warmed to room temperature. After 4 h, a pale yellow foam was observed. Then, acetic acid (5.2 ml, 90 mmol, 1 equiv.) was slowly added, followed by addition of water (50 ml). The aqueous layer was extracted with MTBE (250 ml). The extracts were washed with water until the pH of the washings was 6. The organic layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated in rotary evaporator affording a pale yellow crude oil of 3-methyl-1-(nitromethyl)-butanol (GC purity: 97.5%), which was used in the next step without further purification.

(27) To a solution of 3-methyl-1-(nitromethyl)-butanol (1 equiv.) in CH.sub.2Cl.sub.2 (100 ml) at 0 C. was added MsCl (7 ml, 90 mmol, 1 equiv.). Triethylamine (25 ml, 180 mmol, 2 equiv.) was then added dropwise. The reaction mixture was stirred for 30 min at 0 C., followed by pouring to a cold 10% HCl solution (30 ml) in separatory funnel. The organic layer was separated and washed with brine (50 ml), dried over Na.sub.2SO.sub.4, filtered, and concentrated in rotary evaporator. The residue was passed through a short Silica gel plug (eluent: 5% Et.sub.2O in cyclohexane) to afford 4-methyl-1-nitro-pent-1-ene as a yellow oil in 78-81% yield over 2 steps (GC purity: 98.5%).

EXAMPLE 6

Synthesis of 4-[(R)-(5-ethenyl-1-azabicyclo [2.2.2]octan-2-yl)-hydroxymethyl]quinolin-6-ol (Cupreidine)

(28) Under N.sub.2-atmosphere, dodecanethiol (9.6 ml, 40 mmol, 2.0 equiv.) was dissolved in DMF (40 ml). KO.sup.tBu (4.5 g, 40 mmol, 2.0 equiv.) was added (exothermic). The obtained white suspension was stirred for 5-10 min. Quinidine (6.49 g, 20 mmol, 1.0 equiv.) was added in one portion. The obtained yellow suspension was heated to 110 C. for 7 h and was monitored by HPLC. After cooling to room temperature, the reaction was quenched with saturated NH.sub.4Cl (100 ml, pH=8-9). The orange solution was extracted with CH.sub.2Cl.sub.2 (270 ml). The combined organic layers were extracted with 1N HCl (100 ml). The aqueous layer was washed with cyclohexane (40 ml) to remove dodecanethiol and methyl dodecanethiolate. The pH of aqueous layer was adjusted to 7.5-8 with 30% NaOH solution and then extracted with CH.sub.2Cl.sub.2 (2100 ml). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and completely concentrated in rotary evaporator to obtain an orange oil of crude product. This crude product was dissolved in CH.sub.2Cl.sub.2 (100 ml) and washed with brine (250 ml). The organic layer was dried over Na.sub.2SO.sub.4), filtered and completely concentrated in rotary evaporator to obtain an orange residue. The residue was then dissolved in 1N NaOH (80 ml). Sodium chloride (15 g) and water (20 ml) were added. After stirring for 30 min, 2N HCl (35 ml) was added and the pH was adjusted to 9.0-9.5. The beige suspension was stirred at room temperature for 3 h and was then filtered. The filter-cake was washed with water (310 ml). After drying at 60 C. for 18 h in vacuum, a beige powder of cupreidine was obtain in 85% yield (HPLC-purity: 85.9% along with dihydrocupreidine in 11.8%).

EXAMPLE 7

Synthesis of (S)-(3-Methyl-1-nitromethyl-butyl)-malonic acid dimethyl Ester (VI)

(29) At 15 C., to a solution of 4-methyl-1-nitro-pent-1-ene (13 g, 100 mmol, 1 equiv.) in MTBE (50 ml, 2M) was added catalyst cupreidine (2.8 g, 9 mol %), and dimethyl malonate (13 ml, 103 mmol, 1.03 equiv.). The resulting mixture was stirred at 10 C. and was monitored by GC. After 40 h, 2M HCl (40 ml) was added. Product was extracted with toluene (240 ml). The combined organic layers were washed with water (40 ml) and concentrated in rotary evaporator to give crude VI as yellow oil (86% ee, HPLC-purity: 97.3%)

(30) The aqueous phase containing upreidine was adjusted to a pH of 8.5-9.0 with NaOH palettes and 32% HCl. Catalyst was filtered and dried. The pale yellow powder was obtained in 91% yield (HPLC-purity: 85.1% along with dihydrocupreidine 12.5%).

EXAMPLE 8

Synthesis of Dipotassium-(3-methyl-1-nitro-methyl-butyl)-malonate (XIX)

(31) A solution of KOH (1.60 g, 28 mmol, 3.5 equiv.) in water (2 ml) and MeOH (32 ml) was introduced successively into a solution of VI (2.04 g, 8 mmol, 1 equiv.) in MeOH (4 ml). The mixture was stirred at room temperature for 16 h. The reaction was concentrated in rotary evaporator to give a yellow sticky solid. To this solid, acetone (15 ml) and MeOH (4 ml) was slowly added. A pale yellow solid was obtained and was filtered to get XIX in 95% yield (HPLC-purity: 88.0%).

EXAMPLE 9

Synthesis of (S)-5-methyl-3-nitromethyl-hexanoic Acid ((S)-IX)

(32) MsOH:

(33) To a solution of XVI (86.5% ee, 13.10 g, 50 mmol, 1 equiv.) in AcOH (100 ml) was added MsOH (8.20 ml, 125 mmol, 2.5 equiv.) and water (7.20 ml, 400 mmol, 8 equiv.). This mixture was heated to 110 C. and was monitored by HPLC. After 8 h, the reaction mixture was diluted with water (50 ml) and saturated NaCl (50 ml). Product was extracted with toluene (280 ml). The combined organic layers were concentrated in rotary evaporator. The residue was purified by flash column chromatography (5-10% EtOAc in CH.sub.2Cl.sub.2 with 0.1% AcOH) to give (S)-IX as yellow oil in 88% yield based on VI (HPLC-purity: 90.9%). To determine ee, esterification with 3M HCl in MeOH was carried out leading to ethyl 5-methyl-3-(nitromethyl)hexanoate in quantitative yield with 86.6% ee.

(34) Using the same procedure with crude XVI: IX* was obtained in 68% isolated yield based on 4-methyl-1-nitropent-1-ene with 86% ee (HPLC-purity: 93.0%).

(35) H.sub.2SO.sub.4:

(36) To a solution of crude XVI (86% ee, 15 mmol, 1 equiv.) in AcOH (30 ml, 0.5 M) was added 97% H.sub.2SO.sub.4 (1.0 ml, 18 mmol, 1.2 equiv.) and water (2.2 ml, 120 mmol, 8 equiv.). This mixture was heated to 110 C. and was monitored by HPLC (HPLC yield: 87.8%). After 9 h, the reaction mixture was concentrated in rotary evaporator (19% left by weight). Water was added to the obtained brown oil (13 ml) and the mixture was extracted with toluene (213 ml). The combined organic layers were concentrated in rotary evaporator to give crude (S)-IX as a brown oil (HPLC-purity: 86.7%). Some product was converted to ethyl 5-methyl-3-(nitromethyl)hexanoate with 3M HCl in MeOH to give quantitative yield with 86% ee.

(37) Starting from dipotassium-(3-methyl-1-nitromethyl-butyl)-malonate (XIX):

(38) To a solution of XIX (206 mg, 0.67 mmol, 1 equiv.) in AcOH (0.5 ml) was added MsOH (0.2 ml, 3.02 mmol, 4.5 equiv.) and water (0.1 ml, 5.36 mmol, 8 equiv.). This mixture was heated to 110 C. and was monitored by HPLC. After 3 h, the reaction was complete. Saturated NaCl solution (1 ml) and water (1 ml) were added. Product was extracted with toluene (31 ml). Solvents were evaporated to give a yellow crude oil with a 89:11 mixture of (S)-IX and XVII (HPLC-purity: 71.8%).

EXAMPLE 10

Synthesis of Pregabalin

(39) To a solution of (S)-IX (89% ee, 8.45 g, 44.7 mmol, 1 equiv.) in MeOH (45 ml) was added palladium on charcoal in water (5.43 g, 1.12 mmol, 2.5 mol %). The mixture was hydrogenated with Parr apparatus at 3.5-4 atm of hydrogen gas for 16 h at room temperature. Upon completion, the reaction mixture was filtered through a Celite plug and washed with MeOH (50 ml) and water (150-200 ml). The solvent was removed by rotary evaporator to afford pregabalin as white solid in 85% yield (HPLC-purity: 80.3%).

EXAMPLE 11

Synthesis of Nitro Acid Dibenzylammonium Salt (XXIII)

(40) ##STR00025##

(41) Dibenzylamine (96 l, 0.5 mmol) was added to a solution of nitro acid (S)-IX (95 mg, 0.5 mmol; ee: 85.4%, HPLC purity 91%) in THF (1 ml) was stirred. The clear solution was concentrated. The residue was cooled to 0 C. for 16 hours. THF (200 l) and .sup.iPr.sub.2O (150 l) were added to the residue and gave a suspension. The suspension was heated, then the mixture was cooled to room temperature and re-precipitated. After centrifugation of the suspension, mother liquor was removed and the solid was dried under vacuum at room temperature to give nitro acid dibenzylammonium salt XIX as a colorless solid (yield: 70 mg, 0.18 mmol; ee: 90.2%; HPLC purity: 62.4%).

EXAMPLE 12

Synthesis of Nitro Acid Sodium Salt (XXIV)

(42) ##STR00026##

(43) NaOH (20 mg, 0.5 mmol) was added to a solution of nitro acid (S)-IX (95 mg, 0.5 mmol; ee: 86.6%, HPLC purity: 90.9%) in MeOH (1 ml) and was stirred. The mixture was evaporated to dryness and .sup.iPrOH (1 ml) was added, stirred for 16 hours, and gave a suspension. The solid was separated by centrifugation of the suspension and washed with .sup.iPrOH (0.5 ml). After centrifugation of the suspension, the solid was separated and dried under vacuum at room temperature to give nitro acid sodium salt XXVI as a colorless solid (yield: 48 mg, 0.23 mmol; ee: 95.3%; HPLC purity: 96.7%).

EXAMPLE 13

Synthesis of Nitro Acid Quinidinium Salt (XXV)

(44) ##STR00027##

(45) Quinidine (162 mg, 0.5 mmol) was added to a solution of nitro acid (S)-IX (95 mg, 0.5 mmol; ee: 85.4%, HPLC purity 91%) in MTBE (1 ml) and was stirred for 16 hours to afford a suspension. The solid was separated by centrifugation of the suspension and MTBE (0.5 ml) was added to the solid. The suspension was centrifuged again, the solid was separated and dried under vacuum at room temperature to give nitro acid quinidinium salt XXV as a colorless solid (yield: 185 mg, 0.38 mmol; ee: 91.2%; HPLC purity: 85.3%).

EXAMPLE 14

Synthesis of Nitro Acid (S)-1-cyclohexyl-ethylammonium Salt (XXVI)

(46) ##STR00028##

(47) (S)-1-Cyclohexyl-ethylamine (0.35 ml, 2.33 mmol) was added to a solution of nitro acid (S)-IX (475 mg, 2.33 mmol; ee: 86.0%, HPLC purity 92.0%) in MTBE (5 ml) and was stirred for 0.75 hours to afford a thick suspension. The suspension was diluted with MTBE (2.5 ml). After filtration of suspension, the solid was dried under vacuum at room temperature to give nitro acid (S)-1-cyclohexyl-ethylammonium salt XXVI as a colorless solid (yield: 615 mg, 1.95 mmol; ee: 95.0%; HPLC purity: 99.6%).

EXAMPLE 15

Synthesis of Nitro Acid Diisopropylammonium Salt (XXVII)

(48) ##STR00029##

(49) Diisopropylamine (70 l, 0.5 mmol) was added to a solution of nitro acid (S)-IX (95 mg, 0.5 mmol, ee: 86.6%, HPLC purity: 90.9%) in MTBE (1 ml) and was stirred for 20 hours to afford a thick suspension. The suspension was diluted with MTBE (2.5 ml). After filtration of the suspension, the solid was dried under vacuum at room temperature to give nitro acid diisopropylammonium salt XXVII as a colorless solid (yield: 44 mg, 0.15 mmol; ee: 99.4%; HPLC purity: 82.3%).

EXAMPLE 16

Synthesis of Nitro Acid Tert-Butylammonium Salt (XXVIII)

(50) ##STR00030##
tert-Butylamine (52 l, 0.5 mmol) was added to a solution of nitro acid (S)-IX (95 mg, 0.5 mmol, ee: 85.4%, HPLC purity 91%) in EtOAc (1 ml) and was stirred for 21 hours to afford a suspension. The solid was separated by centrifugation of the suspension and EtOAc (0.5 ml) was added to the solid. The suspension was centrifuged again, the solid was separated and dried under vacuum at room temperature to give nitro acid tert-butylammonium salt XXVIII as colorless solid (yield: 44.5 mg, 0.17 mmol; ee: 95.5%; HPLC purity: 78.1%).

EXAMPLE 17

Synthesis of Nitronate Di-Sodium Salt (XXIX)

(51) ##STR00031##

(52) NaOH (396 mg, 4.95 mmol) was added to a solution of nitro acid (S)-IX (635 mg, 3.35 mmol, ee: 85.9%, HPLC purity: 86.0%) in EtOH (10 ml) and was stirred for 16 hours to afford a suspension. The solid was filtrated and washed with EtOH (4 ml) and then dried under vacuum at room temperature to give nitronate di-sodium salt XXIX as a pale yellow solid (yield: 617 mg, 2.26 mmol; ee: 83.7%; HPLC purity: 90.7%).

EXAMPLE 18

Synthesis of Nitronate Di-Potassium Salt (XXX)

(53) ##STR00032##

(54) A solution of nitro acid (S)-IX (496 mg, 2.62 mmol) in MeCN (10 ml) was added to a solution of potassium hydroxide (441 g, 7.87 mmol, ee: 86.0%, HPLC purity: 79%) in EtOH (0.5 ml) and was stirred for 16 hours to afford a suspension. The solid was filtrated and washed with absolute MeCN (0.3 ml) and then dried under vacuum at room temperature to give nitronate di-potassium salt XXX as a pale yellow solid (yield: 667 mg, 2.52 mmol; ee: 83.8%; HPLC purity: 97.2%).

(55) TABLE-US-00003 TABLE 1a XVI water T time % HPLC # (mmol) H.sup.+ (eq) AcOH (M) (eq) ( C.) (h) IX:XVII:XVIII.sup.a yield.sup.b 1 0.76 48% HBr (8.7) 42 115 16 0:100:0 2 0.76 30% HCl (8.7) 34 105 14 46:54:0 38 3 1 32% HCl (71) 530 100 8 33:67:0 4 0.50 32% HCl (6) 1.0 26 100 12 74:26:0 5 0.50 1M HCl/AcOH (2), 32% HCl (6) 0.5 26 100 12 65:35:0 6 0.50 1M HCl/AcOH (2), 37% HCl (6) 0.5 21 100 11 77:23:0 7 0.50 37% HCl (6) 1.0 21 100 11 80:20:0 90% conv. 8 1.0 37% HCl (5) 0.5 8 110 6 82:18:0 46.5 9 1.0 37% HCl (2.5) 0.5 8 110 10 nd 48% conv. 12 0.25 MsOH (2.5) 0.5 10 110 15 93:7:0 13 0.25 MsOH (3.0) 0.5 10 110 10 94:6:0 14 0.25 MsOH (3.0) 0.5 10 90 24 100:0:0 15 0.25 MsOH (3.0) 0.5 6 90 24 100:0:0 16 0.25 MsOH (3.5) 0.5 8 90 24 100:0:0 17 1.0 MsOH (0.5) 0.5 8 110 16 100:0:0 81.8 18 1.0 MsOH (1.0) 0.5 8 110 10 100:0:0 80.8 19 1.0 MsOH (2.0) 0.5 8 110 8 92:8:0 84.6 20 0.25 MsOH (4.0) 0.5 8 90 18 92:8:0 83.1 21 0.25 MsOH (6.0) 0.5 8 90 18 90:10:0 22 0.25 MsOH (2.5) 0.25 6 90 20 100:0:0 84.3 23 0.25 MsOH (2.5) 0.5 8 100 10 100:0:0 92.6 24 0.25 MsOH (2.5) 1.0 10 110 5 90:10:0 84.9 25 0.25 MsOH (3.0) 1.0 6 100 10 88:12:0 83.5 .sup.adetermined by 1H NMR spectrum; .sup.bdetermined by quantitative HPLC

(56) TABLE-US-00004 TABLE 1b XVI AcOH water T # (mmol) H.sup.+ (eq) (M) (eq) ( C.) time (h) IX:XVII:XVIII.sup.a % HPLC yield.sup.b 26 0.25 MsOH (3.0) 0.25 8 110 10 100:0:0 79.6 27 0.25 MsOH (3.0) 0.5 10 90 14 100:0:0 75.3 28 0.25 MsOH (3.5) 0.5 6 110 7.5 96:4:0 88.5 29 0.25 MsOH (3.5) 1.0 8 90 17 87:13:0 85.9 30 0.25 MsOH (3.5) 0.25 10 100 10 100:0:0 72.4 31 5 MsOH (2.5) 0.5 8 110 6 100:0:0 94.8 32 5.sup.c MsOH (2.5) 0.5 8 110 8 100:0:0 94.1 33 33.sup.c MsOH (2.5) 0.67 8 110 7 94:6:0 70.5 (2 steps) 34 50.sup.c MsOH (2.5) 0.5 8 110 8 100:0:0 68.3 (2 steps) 35 0.25 97% H.sub.2SO.sub.4 (8) 0.5 1.2 100 10 0:80:20 36 0.5 97% H.sub.2SO.sub.4 (2.5) 0.5 8 110 6 93:7:0 75.9 37 0.5 97% H.sub.2SO.sub.4 (1.5) 0.5 8 110 6 94:6:0 76.2 38 1.0 97% H.sub.2SO.sub.4 (1.2) 0.5 8 100 15 93:7:0 84.0 39 1.0 97% H.sub.2SO.sub.4 (1.2) 0.5 8 110 7 96:4:0 87.6 40 1.0 97% H.sub.2SO.sub.4 (1.5) 0.5 8 110 7 91:9:0 84.2 41 1.0 97% H.sub.2SO.sub.4 (1.5) 0.5 8 100 15 91:9:0 82.9 42 15.sup.c 97% H.sub.2SO.sub.4 (1.2) 0.5 8 100 18 (3 h at 110) 95:5:0 80.5 (2 steps) 43 15.sup.c 97% H.sub.2SO.sub.4 (1.2) 0.5 8 110 9 95:5:0 87.8 (2 steps) 44 4.sup.c 97% H.sub.2SO.sub.4 (0.4) 0.5 8 110 16 95:5:0 85.1 (2 steps) 45 3.9.sup.c 97% H.sub.2SO.sub.4 (1.2) 0.5 8 110 10 97:3:0 94.1 .sup.adetermined by 1H NMR spectrum; .sup.bdetermined by quantitative HPLC; .sup.cusing enantiomerically enriched (S)-XVI

(57) TABLE-US-00005 TABLE 3a ee of HPLC purity ee of HPLC purity Yield # IX of IX base (equiv.) solvent t/T XX of XX [%] 1 85.4 91 Triethanolamine EtOH 16 h at 0 C. 91.2 45.7 (1.0) 2 85.4 91 Triethanolamine EtOAc 16 h at 0 C. 91.7 63.1 (1.0) 3 85.4 91 Dibenzylamine (1.0) EtOH Heat gun .fwdarw. 20-25 C. 87.1 63.5 34 4 85.4 91 Dibenzylamine (1.0) THF/.sup.iPrOH 4:3 Heat gun .fwdarw. 20-25 C. 90.2 62.4 36 5 86.6 90.9 NaOH (1.0) NeOH .fwdarw. 16 h at 20-25 C. 95.1 96.7 45.6 .sup.iPrOH.sup.d 6 86.6 90.9 NaOH (1.0) NeOH .fwdarw. MeCN.sup.d 16 h at 20-25 C. 96.5 87.6 72.7 7 86.6 90.9 NaOH (1.0) NeOH .fwdarw. MTBE.sup.d 16 h at 20-25 C. 92.4 62.3 85.1 8 86.6 90.9 NaOH (1.0) NeOH .fwdarw. 16 h at 20-25 C. 95.3 96.7 24.1 acetone.sup.d 9 85.4 91 Quinidine (1.0) MTBE 16 h at 20-25 C. 91.2 85.3 76.2 .sup.dThe mono-sodium salt was prepared in MeOH, the sample was evaporated and organic solvents were added to residue

(58) TABLE-US-00006 TABLE 3b ee of HPLC purity ee of HPLC purity Yield # IX of IX base (equiv.) solvent t/T XX of XX [%] 10 86.6 90.9 (S)-1-cyclohexyl- MeCN 20 h at 20-25 C. 93.1 96.1 70.0 ethylamine (1.0) 11 86.0 92.0 (S)-1-cyclohexyl- MTBE 0.75 h at 20-25 C. 95.0 99.6 83.7 ethylamine (1.0) 12 86.6 90.9 (S)-1-cyclohexyl- PhMe 20 h at 20-25 C. 97.3 94.6 27.0 ethylamine (1.0) 13 86.6 90.9 (S)-1-cyclohexyl- EtOAc 20 h at 20-25 C. 96.0 96.6 58.0 ethylamine (1.0) 14 86.6 90.9 diisopropylamine EtOAc 20 h at 20-25 C. 98.6 90.9 19.0 (1.0) 15 86.6 90.9 diisopropylamine MTBE 20 h at 20-25 C. 99.4 82.3 30.5 (1.0) 16 86.6 90.9 diisopropylamine THF 20 h at 20-25 C. 95.9 74.6 53.0 (1.0) 17 85.4 91 tert-butylamine EtOAc 21 h at 20-25 C. 95.5 78.1 34.0 (1.0).sup.e 18 85.4 91 tert-butylamine PhMe 21 h at 20-25 C. 65.5 11.0 (1.0).sup.e .sup.eOnly precipitation conditions indicated