METHOD FOR PRODUCING CHIRAL AMINONITRILES

Abstract

The invention relates to a method for preparing an N-acyl- or N-sulfonyl--aminonitrile, comprising the following steps: a) condensation of an N-acyl- or N-sulfonyl--aminoaldehyde with hydroxylamine to give an aldoxime, and b) dehydration of the aldoxime obtained in step a) to give an N-acyl- or N-sulfonyl--aminonitrile. In an advantageous manner, the absolute configuration can be retained in the conversion to the N-acyl- or N-sulfonyl--aminonitrile.

Claims

1. Method for preparing an N-acyl- or N-sulfonyl--aminonitrile, comprising the following steps: a) condensation of an N-acyl- or N-sulfonyl--aminoaldehyde with hydroxylamine to give an aldoxime, and b) dehydration of the aldoxime obtained in step a) to give an N-acyl- or N-sulfonyl--aminonitrile.

2. The method according to claim 1, characterized in that in step a) an enantiomerically enriched or an enantiomerically pure N-acyl- or N-sulfonyl--aminoaldehyde is used, the absolute configuration of which is retained or substantially retained in the conversion to the N-acyl- or N-sulfonyl--aminonitrile.

3. The method according to claim 1, comprising the following steps: a) condensation of an N-acyl- or N-sulfonyl--aminoaldehyde according to the general formula (I) with hydroxylamine to give an aldoxime according to the general formula (II), and b) dehydration of the aldoxime obtained in step a) to give an N-acyl- or N-sulfonyl--aminonitrile according to the general formula (III): ##STR00011## in which: A is C or SO; R.sup.1 is selected from the group comprising branched or unbranched C.sub.1-C.sub.20-alkyl, C.sub.6-C.sub.10-aryl, C.sub.6-C.sub.16-heteroaryl, C.sub.7-C.sub.16-arylalkyl and/or C.sub.6-C.sub.16-heteroarylalkyl, wherein these are unsubstituted or monosubstituted or polysubstituted by at least one substituent selected from the group comprising OH, NH.sub.2, NHR.sup.4, NR.sup.4.sub.2, C.sub.1-4-alkyl, C.sub.7-C.sub.16-arylalkyl, C.sub.6-C.sub.16-heteroarylalkyl, carbonyl oxygen and/or C.sub.1-4-alkoxy; R.sup.2 is selected from the group comprising H, branched or unbranched C.sub.1-C.sub.20-alkyl, C.sub.6-C.sub.10-aryl, C.sub.6-C.sub.16-heteroaryl, C.sub.7-C.sub.16-arylalkyl and/or C.sub.6-C.sub.16-heteroarylalkyl, wherein these are unsubstituted or monosubstituted or polysubstituted by at least one substituent selected from the group comprising OH, NH.sub.2, NHR.sup.4, NR.sup.4.sub.2, C.sub.1-4-alkyl, C.sub.7-C.sub.16-arylalkyl, C.sub.6-C.sub.16-heteroarylalkyl, carbonyl oxygen and/or C.sub.1-4-alkoxy; or R.sup.1 and R.sup.2 together form a saturated 5- or 6-membered ring or a bicyclic ring system, wherein these may comprise at least one further heteroatom selected from N, O and/or S and/or these can be monosubstituted or polysubstituted by at least one substituent selected from the group comprising OH, NH.sub.2, NHR.sup.4, NR.sup.4.sub.2, C.sub.1-4-alkyl, carbonyl oxygen and/or C.sub.1-4-alkoxy; R.sup.3 is selected from the group comprising H, C.sub.1-6-alkoxy and/or C.sub.1-6-alkyl, wherein these are monosubstituted or polysubstituted by at least one substituent selected from the group comprising OH, OR.sup.4, NH.sub.2, NHR.sup.4, NR.sup.4.sub.2, NHY and/or halogen; or is selected from the group of the structural elements (IV), (V) and (VI) as follows: ##STR00012## R.sup.4 is in each case identical or each independently selected from the group comprising C.sub.1-C.sub.18-alkyl or C.sub.1-C.sub.18-acyl; X, Y are in each case identical or each independently H or a protecting group, especially selected from tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, acetyl, silyl, p-tolyl, trifluoromethyl and/or sulfonyl.

4. The method according to claim 1, characterized in that the substituents R.sup.1, R.sup.2 and R.sup.3 of the compounds according to the general formulae (I), (II) and (III) are the following: A is C; R.sup.1 is selected from the group comprising benzyl and/or C.sub.1-C.sub.2-alkyl, R.sup.2 is selected from the group comprising H, benzyl and/or C.sub.1-C.sub.2-alkyl, or R.sup.1 and R.sup.2 together form a saturated 5-membered ring or bicyclo[3.1.0]hexane, and R.sup.3 is selected from the group comprising H, tert-butoxy, chloromethyl, structural element (IV), (V) and/or (VI).

5. The method according to claim 1, characterized in that in step b) the dehydration of the aldoxime to give the N-acyl- or N-sulfonyl--aminonitrile is carried out in the presence of a transition metal catalyst, especially a Cu(II), Zn(II), Co(II) or Ni(II) catalyst.

6. The method according to claim 1, characterized in that the mole fraction of the catalyst is in the range from 0.1 mol % to 25 mol %, preferably in the range from 1 mol % to 10 mol %, preferably in the range from 2 mol % to 5 mol %.

7. The method according to claim 1, characterized in that the dehydration of the aldoxime to give the N-acyl- or N-sulfonyl--aminonitrile in step b) is carried out in the presence of a nitrile component preferably selected from the group comprising acetonitrile, propionitrile and/or butyronitrile, wherein the nitrile component is preferably present in the range of 10 eq., based on the aldoxime.

8. The method according to claim 1, characterized in that the dehydration of the aldoxime to give the N-acyl- or N-sulfonyl--aminonitrile in step b) is conducted at a temperature in the range from 20 C. to 150 C., preferably in the range from 50 C. to 100 C., preferably in the range from 80 C. to 85 C.

9. Method for preparing vildagliptin or salts thereof, comprising the following steps: a) condensing an aldehyde of the formula (1) with hydroxylamine to give an aldoxime of the formula (2): ##STR00013## in which R.sup.3 is CH.sub.2 substituted by a substituent selected from the group comprising OH, OR.sup.4, NH.sub.2, NHR.sup.4, NR.sup.4.sub.2, NHY and/or halogen or structural element (IV) as follows: ##STR00014## X, Y are identical or each independently H or a protecting group, especially selected from tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, acetyl, silyl, p-tolyl, trifluoromethyl and/or sulfonyl: R.sup.4 is identical or each independently selected from the group comprising C.sub.1-C.sub.18-alkyl or C.sub.1-C.sub.18-acyl; b) dehydration of the aldoxime of the formula (2) obtained in step a) to give an N-acyl--aminonitrile of the formula (3): ##STR00015## c) optional reaction of the N-acyl--aminonitrile of the formula (3), where R.sup.3 is CH.sub.2 substituted by a substituent selected from the group comprising OH, OR.sup.4, NH.sub.2, NHR.sup.4, NR.sup.4.sub.2, NHY and/or halogen, with 1-aminoadamantane-3-ol or a protected derivative of the formula (4) to give the compound of the formula (5): ##STR00016## and d) optional cleavage of the protecting group X to give vildagliptin of the formula (6): ##STR00017##

10. Method for preparing saxagliptin or salts thereof, comprising the following steps: a) condensation of an aldehyde of the formula (7) with hydroxylamine to give an aldoxime of the formula (8): ##STR00018## in which: X, Y are identical or each independently H or a protecting group, especially selected from tert-butyloxycarbonyl (Boc), benzyloxycarbonyl, acetyl, silyl, p-tolyl, trifluoromethyl and/or sulfonyl; b) dehydration of the aldoxime of the formula (8) obtained in step a) to give an N-acyl--aminonitrile of the formula (9): ##STR00019## c) optional cleavage of the protecting groups X, Y to give saxagliptin (10): ##STR00020##

Description

EXAMPLE 1

Preparation of (S)N-Boc-pyrrolidinecarbonitrile

1a) Preparation of E/ZN-Boc-1-proline Aldoxime

[0083] The synthesis was carried out analogously to the general procedure as described for step a). 104 mg of hydroxylamine hydrochloride (1.50 mmol) and 159 mg of sodium carbonate (1.50 mmol) were dissolved in 3 mL of water and 2 mL of ethanol at room temperature. After addition of 199 mg of N-Boc-1-prolinal (1.00 mmol), the solution was stirred at room temperature for 20 hours until the TLC reaction monitoring showed complete conversion. A colourless oil was obtained after work-up. The crude product was purified by column chromatography (cyclohexane/ethyl acetate 3:1, v/v). After removal of the solvent at 40 C. under reduced pressure, the product was obtained as a colourless oil with an E/Z ratio of 65:35. The E and Z isomers could not be separated. The isomers were confirmed by .sup.1H-NMR spectroscopy and GC. The yield of E/ZN-Boc-1-proline aldoxime was 143 mg (67%).

1b) Preparation of (S)N-Boc-pyrrolidinecarbonitrile

[0084] The synthesis was carried out analogously to the general procedure as described for step b). To a solution of 123 mg of E/ZN-Boc-1-proline aldoxime (570 mol) in 7 ml of acetonitrile were added 2.73 mg of copper(II) acetate (15.0 mol). The reaction mixture was heated to reflux for 7 hours and then stirred at room temperature for 16 hours. After work-up, the product was obtained as a colourless oil with an enantiomeric excess of 97%. The yield of (S)N-Boc-pyrrolidinecarbonitrile was 97 mg (86%).

EXAMPLE 2

Preparation of (R)N-Boc-pyrrolidinecarbonitrile

2a) Preparation of E/ZN-Boc-d-proline Aldoxime

[0085] The synthesis was carried out analogously to the general procedure as described for step a). 104 mg of hydroxylamine hydrochloride (1.5 mmol) and 159 mg of sodium carbonate (1.5 mmol) were dissolved in 3 mL of water and 2 mL of ethanol at room temperature. After addition of 199 mg of N-Boc-d-prolinal (1.0 mmol), the solution was stirred at room temperature for 24 hours until the TLC reaction monitoring showed complete conversion. A colourless oil was obtained after work-up. The crude product was purified by column chromatography (cyclohexane/ethyl acetate 2:1, v/v). After removal of the solvent at 40 C. under reduced pressure, the product was obtained as a colourless oil with an E/Z ratio of 72:28. The E and Z isomers could not be separated. The isomers were confirmed by .sup.1H-NMR spectroscopy and GC. The yield of E/ZN-Boc-d-proline aldoxime was 177 mg (81%).

2b) Preparation of (R)N-Boc-pyrrolidinecarbonitrile

[0086] The synthesis was carried out analogously to the general procedure as described for step b). To a solution of 161 mg of E/ZN-Boc-d-proline aldoxime (750 mol) in 7 ml of acetonitrile were added 2.73 mg of copper(II) acetate (15.0 mol). The reaction mixture was heated to reflux for 7 hours and then stirred at room temperature for 16 hours. After work-up, the product was obtained as a colourless oil with an enantiomeric excess of 99%. The yield of (R)N-Boc-pyrrolidinecarbonitrile was 130 mg (88%).

[0087] (R)N-Boc-pyrrolidinecarbonitrile, which can be used as nitrile product in the synthesis of vildagliptin, was obtained with an enantiomeric excess of 99%. The synthesis therefore shows the robustness of the method to potential racemization.

EXAMPLE 3

Preparation of (R)N-Boc-phenylalaninecarbonitrile

3a) Preparation of E/ZN-Boc-d-phenylalanine Oxime

[0088] The synthesis was carried out analogously to the general procedure as described for step a). 146 mg of hydroxylamine hydrochloride (2.11 mmol) and 223 mg of sodium carbonate (2.11 mmol) were dissolved in 5 mL of water and 5 mL of 1-propanol at room temperature. After addition of 350 mg of N-Boc-d-phenylalaninal (1.40 mmol), the solution was stirred for 18 hours and complete conversion was confirmed by TLC monitoring. Work-up afforded a mixture of E/Z isomers of the product as a colourless solid.

[0089] The isomers were separated by column chromatography (cyclohexane/ethyl acetate 3:1, v/v), freed from solvent at room temperature and obtained as colorless solids. The isomers E-N-Boc-d-phenylalaninal oxime and ZN-Boc-d-phenylalaninal oxime were confirmed by .sup.1H-NMR spectroscopy. The yield of E-N-Boc-d-phenylalaninal oxime was 200 mg (54%) and the yield of ZN-Boc-d-phenylalaninal oxime was 142 mg (38%).

3b) Preparation of (R)N-Boc-phenylalaninenitrile

[0090] The synthesis was carried out analogously to the general procedure as described for step b). 10.3 mg of copper(II) acetate (56.7 mol) were suspended in 1.5 mL of acetonitrile. 150 mg of E/ZN-Boc-d-phenylalaninal oxime (567 mol) obtained in step a) was added and the reaction mixture was heated to reflux for 60 min. Work-up (cyclohexane/ethyl acetate 2:1, v/v) afforded the product as a colourless solid. In order to determine the absolute configuration, measurements were conducted by chiral HPLC. The retention time by RP-HPLC was R.sub.t=9.0 min and the retention time by NP-HPLC was R.sub.t=23.3 min. The reaction conversion was determined by RP-HPLC. The yield of (R)N-Boc-phenylalaninenitrile was 116 mg (83%).

EXAMPLE 4

Preparation of (S)N-Boc-phenylalaninenitrile

4a) Preparation of E/ZN-Boc-1-phenylalanine Oxime

[0091] The synthesis was carried out analogously to the general procedure as described for step a). The synthesis was carried out according to SV1. 100 mg of hydroxylamine hydrochloride (1.43 mmol) and 152 mg of sodium carbonate (1.43 mmol) were dissolved in 5 mL of water and 5 mL of 1-propanol at room temperature. After addition of 238 mg of N-Boc-1-phenylalaninal (955 mol), the solution was stirred for 18 hours and complete conversion was confirmed by TLC monitoring. Work-up afforded a mixture of E/Z isomers of the product as a colourless solid. The isomers were confirmed by .sup.1H-NMR spectroscopy. The yield of E/ZN-Boc-1-phenylalanine oxime was 212 mg (84%).

4b) Preparation of (S)N-Boc-phenylalaninenitrile

[0092] The synthesis was carried out analogously to the general procedure as described for step b). 7.3 mg of copper(II) acetate (40.2 mol) were suspended in 1.0 mL of acetonitrile. 85.0 mg of E/ZN-Boc-1-phenylalaninal oxime (322 mol) obtained in step a) was added and the reaction mixture was heated to reflux for 60 min. Work-up (cyclohexane/ethyl acetate 2:1, v/v) afforded the product as a colourless solid. In order to determine the retention of the absolute configuration, measurements were conducted by chiral HPLC. The retention time by RP-HPLC was R.sub.t=9.0 min and the retention time by NP-HPLC was R.sub.t=20.9 min. The reaction conversion was determined by RP-HPLC. The yield of (S)N-Boc-phenylalaninenitrile was 73 mg (92%).

EXAMPLE 5

Investigation of the Reaction Parameters of the Cu(II)-Catalyzed Synthesis of (S)N-Boc-Pyrrolidinecarbonitrile

[0093] The Cu(II)-catalyzed synthesis of (S)N-Boc-pyrrolidinecarbonitrile by dehydrating E/ZN-Boc-1-proline aldoxime was carried out as has been described under example 1b) and the general procedure for step b), wherein the amount of acetonitrile and copper(II) acetate was in each case varied divergently or CH.sub.2Cl.sub.2 was added as co-solvent.

[0094] The results of the dehydrations are summarized in the following table:

TABLE-US-00001 TABLE 1 Amount of Solvent Amount of Reaction Conver- Entry CH.sub.3CN addition Cu(OAc).sub.2 time sion 1 >100 equiv. / 10 mol % 7 h at 80 quanti- C. + 16 h tative at 20 C. 2 >100 equiv. / 2 mol % 7 h at 80 quanti- C. + 16 h tative at 20 C. 3 10 equiv. CH.sub.2Cl.sub.2 >25 2 mol % 7 h at 80 quanti- equiv. C. + 16 h tative at 20 C.

[0095] As can be inferred from Table 1, complete conversion was achieved at a mole fraction of Cu(OAc).sub.2 as catalyst in a range from 2 to 10 mol %, based on the substrate. In addition, the amount of acetonitrile used could be reduced by using dichloromethane as co-solvent also with quantitative conversion.