METHOD FOR PREPARING METHIONINE ANALOGUES

Abstract

The invention relates to a method for preparing a compound (I) or one of the salts thereof, and the uses of said method, R.sup.1OOCC(X)CHR.sup.2R.sup.3(I), wherein X is selected among O; NR, wherein R is H or a C1-C6 alkyl; and NOR wherein R is H, or a C1-C6 alkyl or an alkylaryl; R.sup.1 is H or a C1-C6 alkyl group; R.sup.2 is H, a C1-C6 alkyl, or an alkylaryl; and R.sup.3 is CH.sub.2SR.sup.4 or CH.sub.2SeR.sup.4, where R.sup.4 is H or a C1-C6 alkyl from a compound (II), or one of the salts thereof, R.sup.1OOCC(X)CHR.sup.2R.sup.5 and R.sup.5 is H or COOR.sup.6, where R.sup.6 is H or a C1-C6 alkyl, said method being carried out in the presence of a compound (III) CH.sub.2(Y)(Z). Wherein Y is H; OR.sup.7, where R.sup.7 is H, a C1-C6 alkyl or an acyl with formula COR.sup.4; SR.sup.4 or SeR.sup.4 where R.sup.4 matches the preceding definition; or 1 NR.sup.8R.sup.9, where R.sup.8 and R.sup.9, identical or different, each or together are a C1-C6 alkyl, or an alkylaryl; Z, identical or different to Y, is OR.sup.10 where R.sup.10 is H, a C1-C6 alkyl or COR.sup.4; a cyclic or acyclic N(COR.sup.4)(COR.sup.4) group; or NR.sup.11R.sup.12, where R.sup.11 and R.sup.12, identical or different, each or together are a C1-C6 alkyl or an alkylaryl; wherein Y and Z together are O; said method involving an intermediate product (IV) R.sup.1OOCC(X)CHR.sup.2CH.sub.2Z.

Claims

1. A method for preparing a compound or a salt thereof, the compound having the formula (I),
R.sup.1OOCC(X)CHR.sup.2R.sup.3(I) wherein X is O; NR wherein R represents H or a C1-C6 alkyl group; or NOR wherein R represents H, a C1-C6 alkyl group or an alkylaryl group; R.sup.1 represents H or a C1-C6 alkyl group; R.sup.2 represents H, a C1-C6 alkyl group, or an alkylaryl group; and R.sup.3 represents CH.sub.2SR.sup.4 or CH.sub.2SeR.sup.4 with R.sup.4 representing H or a C1-C6 alkyl group from a compound of formula (II), or a salt thereof,
R.sup.1OOCC(X)CHR.sup.2R.sup.5(II) wherein R.sup.1, R.sup.2 and X are as previously defined; and R.sup.5 represents H or COOR.sup.6 with R.sup.6 representing H or a C1-C6 alkyl group, the method being carried out in the presence of a compound of formula (III)
CH.sub.2(Y)(Z)(III) wherein Y represents H; OR.sup.7 with R.sup.7 representing H, a C1-C6 alkyl group or an acyl group of formula COR.sup.4 with R.sup.4 as previously defined; SR.sup.4 or SeR.sup.4 with R.sup.4 as previously defined; or NR.sup.8R.sup.9, with R.sup.8 and R.sup.9 are identical or different, each representing a C1-C6 alkyl group; or an alkylaryl group, or R.sup.8 and R.sup.9 together represent a C1-C6 alkyl group or an alkylaryl group; Z is identical to or different from Y and represents OR.sup.10 with R.sup.10 representing H, a C1-C6 alkyl group, or COR.sup.4 with R.sup.4 as previously defined; a cyclic or acyclic N(COR.sup.4)(COR.sup.4) group, with R.sup.4 as previously defined; or NR.sup.11R.sup.12, with R.sup.11 and R.sup.12; are identical or different, each representing a C1-C6 alkyl group or an alkylaryl group, or R.sup.11 and R.sup.12 together represent a C1-C6 alkyl group or an alkylaryl group; or Y and Z together represent O; the method wherein the compound (II) is reacted with the compound (III) to lead to an intermediate compound of formula (IV)
R.sup.1OOCC(X)CHR.sup.2CH.sub.2Z(IV) wherein R.sup.1, R.sup.2, X and Z are as previously defined, the compound (IV) is reacted with R.sup.4SH or a salt thereof, or R.sup.4SeH or a salt thereof, with R.sup.4 as previously defined, already present in the reaction medium or added during the method, and upon completion of the reaction, the compound (I) or a salt thereof is isolated.

2. The method according to claim 1, wherein the reaction of the compound (IV) with R.sup.4SH or a salt thereof or R.sup.4SeH or a salt thereof, already present in the reaction medium or added during the method, leads to a compound of formula (V)
R.sup.1OOCC(A)(B)CHR.sup.2CH.sub.2Z(V) wherein, R.sup.2 and Z are as previously defined; A represents OH, HNR where R represents H, a C1-C6 alkyl group, or HNOR where R represents H, a C1-C6 alkyl group, or an alkylaryl group; and B represents SR.sup.4 or SeR.sup.4 with R.sup.4 as previously defined.

3. The method according to claim 1, wherein the compound (II) is reacted with hydrated or non-hydrated formaldehyde or paraformaldehyde, in a basic medium and in the presence of MeSH or a salt thereof.

4. The method according to claim 1, wherein the compound of formula (II) is reacted with the compound of formula (III), wherein the compound of formula (III) is 1-[(methylsulfanyl)methyl]-piperidine, 1-[(methylsulfanyl)methyl]-pyrrolidine, or 1-[(methylsulfanyl)methyl]-diethylamine.

5. The method according to claim 1, wherein the compound of formula (II) is reacted with the compound of formula (III), wherein the compound of formula (III) is methylenedipiperidine, methylenedipyrrolidine, or methylenedi(diethylamine).

6. The method according to claim 1, wherein the compound of formula (II) is oxaloacetic acid or pyruvic acid.

7. The method according to claim 1, wherein 2-oxo-4-methylthiobutanoic acid (KMB) or a salt thereof is obtained.

8. A compound of formula (IV)
R.sup.1OOCC(X)CHR.sup.2CH.sub.2Z(IV) wherein X is O; NR wherein R represents H or a C1-C6 alkyl group; or NOR where R represents H, a C1-C6 alkyl group, or an aryl group, R.sup.1 represents H or a C1-C6 alkyl group; R.sup.2 represents H, a C1-C6 alkyl group or an alkylaryl group; and Z represents OR.sup.10 with R.sup.10 representing H; a C1-C6 alkyl group or COR.sup.4 with R.sup.4 representing H or a C1-C6 alkyl group, a cyclic or acyclic N(COR.sup.4)(COR.sup.4) group, with R.sup.4 representing H or a C1-C6 alkyl group; or NR.sup.11R.sup.12, with R.sup.11 and R.sup.12 are identical or different, each representing a C1-C6 alkyl group; or an alkylaryl group, or R.sup.11 and R.sup.12 together represent a C1-C6 alkyl group or an alkylaryl group.

9. The compound according to claim 8, wherein X represents O, R.sup.2 represents H, and Z represents the piperidinyl group.

10. A compound of formula (V):
R.sup.1OOCC(A)(B)CHR.sup.2CH.sub.2Z(V) wherein R.sup.1 represents H or a C1-C6 alkyl group; R.sup.2 represents H, a C1-C6 alkyl group or an alkylaryl group; A represents OH; HNR where R represents H or a C1-C6 alkyl group; or HNOR where R represents H, a C1-C6 alkyl group, or an alkylaryl group; B represents SR.sup.4 or SeR.sup.4 with R.sup.4 representing H or a C1-C6 alkyl group; and Z represents OR.sup.10 with R.sup.10 representing H or a C1-C6 alkyl group or COR.sup.4 with R.sup.4 representing H or a C1-C6 alkyl group; or NR.sup.11R.sup.12, with R.sup.11 and R.sup.12 are; identical or different, each representing a C1-C6 alkyl group; or an alkylaryl group, or R.sup.11 and R.sup.12 together represent a C1-C6 alkyl group or an alkylaryl group.

11. The compound according to claim 10, wherein A represents OH, B represents SCH.sub.3, R.sup.2 represents H, and Z represents a piperidinyl group.

12. The compound of formula (IV) according to claim 9, wherein R.sup.1 represents H.

13. The method according to claim 1, wherein 2-oxo-4-methylthiobutanoic acid (KMB) is prepared, and further comprising chemically or biologically transforming 2-oxo-4-methylthiobutanoic acid (KMB) to D,L-methionine, D-methionine, L-methionine, D,L-2-hydroxy-4-methylthiobutanoic acid (HMTBA), D-2-hydroxy-4-methylthiobutanoic acid, or L-2-hydroxy-4-methylthiobutanoic acid.

14. The method according to claim 7, wherein the salt is a calcium, sodium, ammonium, manganese, copper, zinc, or magnesium salt of 2-oxo-4-methylthiobutanoic acid (KMB).

15. The method according to claim 2, wherein the compound of formula (II) is oxaloacetic acid or pyruvic acid.

16. The method according to claim 2, wherein 2-oxo-4-methylthiobutanoic acid (KMB) or a salt thereof is obtained.

17. The method according to claim 16, wherein the salt is a calcium, sodium, ammonium, manganese, copper, zinc, or magnesium salt of 2-oxo-4-methylthiobutanoic acid (KMB).

18. The method according to claim 2, wherein 2-oxo-4-methylthiobutanoic acid (KMB) is prepared, and further comprising chemically or biologically transforming 2-oxo-4-methylthiobutanoic acid (KMB) to D,L-methionine, D-methionine, L-methionine, D,L-2-hydroxy-4-methylthiobutanoic acid (HMTBA), D-2-hydroxy-4-methylthiobutanoic acid, or L-2-hydroxy-4-methylthiobutanoic acid.

19. The compound of formula (V) according to claim 11, wherein R.sup.1 represents H.

Description

EXAMPLE 1: PREPARATION OF KMB BY THE FIRST ROUTE IN THE PRESENCE OF NAOH, HCHO AND MESNA

[0051] The general scheme of the synthesis is the following:

##STR00001##

[0052] In a reactor, 100 mg of oxaloacetic acid are placed and a solution of NaOH 1 M is added (2 eq.). The reactor is placed at 30 C. and the dissolution of the oxaloacetic acid is immediate. After 2 minutes, the 37% w/w formaldehyde solution is added (1 eq). The stirring is maintained for 2 minutes at 30 C. then the MeSNa (2 eq., 108 mg) is added in one portion and the reaction medium is stirred at 30 C.

[0053] A monitoring of the reaction by HPLC-UV (column C18 Hydro-RP) is performed after 10 minutes of contact then every 20 minutes. The best performances were measured after 30 minutes of contact at 30 C. with the following results: [0054] Conversion.sub.oxaloacetic acid=100% [0055] Dosed yield in KMB=75% [0056] Selectivity in KMB=75%

EXAMPLE 2: PREPARATION OF KMB BY THE SECOND ROUTE BY USING THE ACTIVATED THIOMETHYL DERIVATIVE AND THE OXALOACETIC ACID

[0057] The general scheme of the synthesis is the following:

##STR00002##

1.SUP.st .Step: Synthesis of the Activated Thiomethyl Derivative [Compound (III)]

[0058] ##STR00003##

[0059] In a 1 L reactor under argon, are introduced successively under stirring at 20 C.: [0060] 90.0 g of piperidine [0061] 180 ml of THF [0062] 34.4 g of paraformaldehyde

[0063] The reaction medium is cooled to 10 C. then MeSH is added by bubbling into the reaction medium, at 10 C., until the required amount (1 eq.). The addition is completed in 4 hours then the set temperature is raised to 20 C. The reaction medium is stirred for 3 h at this temperature. A GC-FID control (column Equity-1) indicates that the conversion of piperidine is complete and the RR.sub.dosed in activated thiomethyl species is of 97%.

[0064] 180 ml of methyl tert-butyl ether (MTBE) then 180 ml of a NaCl saturated aqueous solution are added to the reaction medium, the two phases are stirred for 5 min and then separated. The organic phase is washed twice with 180 ml of NaCl saturated aqueous solution then dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure (10 mbar, 30 C.). The activated thiomethyl derivative is obtained in the form of a colorless liquid without additional purification (150.4 g). The following performances were obtained: [0065] Complete conversion of piperidine [0066] Isolated yield of activated thiomethyl derivative=95% [0067] Titer=94% (dosed by NMR .sup.1H vs 3,5-dimethylanisole)

2.SUP.nd .Step: Synthesis of KMB Piperidinium

[0068] ##STR00004##

[0069] In a 100 mL reactor under argon, provided with a thermostatically controlled bath, 3 g (1 eq.) of oxaloacetic acid and 30 ml of ethanol are introduced. After dissolution at 20 C. (about 1 minute), the activated thiomethyl derivative is added (1 eq.) then, the medium is heated up to 60 C. in 30 minutes then the temperature is maintained for 1 h.

[0070] A monitoring of the reaction by HPLC-UV (column C18 Hydro-RP) is performed after 10 minutes of contact then every 20 minutes. The best performances were measured after 1 hour of contact at 60 C. with: [0071] Complete conversion of oxaloacetic acid [0072] Dosed yield in KMB=78% [0073] Selectivity in KMB=78%

[0074] The reaction medium is withdrawn then concentrated under reduced pressure (10 mbar, 20 C., 6 h). The KMB piperidinium is obtained in the form of a yellow oil without additional purification. [0075] Isolated yield in KMB piperidinium=60% [0076] Titer=60% (dosed by HPLC vs standard)

EXAMPLE 3: PREPARATION OF KMB BY THE SECOND ROUTE BY USING THE ACTIVATED THIOMETHYL DERIVATIVE AND THE PYRUVIC ACID

[0077] The general scheme of the synthesis is the following:

##STR00005##

1.SUP.st .Step: Synthesis of the Activated Thiomethyl Derivative

[0078] It is described in the first step of Example 2.

2.SUP.nd .Step: Condensation with the Pyruvic Acid

[0079] ##STR00006##

[0080] In a Vial, 300 mg (1 eq.) of pyruvic acid and 3 mL of ethanol are introduced. After dissolution at 20 C., the activated thiomethyl derivative (TMA) is added (1 eq.) then the vial is placed in a plate previously heated to 60 C. The reaction medium is stirred at this temperature for 1 hour.

[0081] A monitoring of the reaction by HPLC-UV (column C18 Hydro-RP) is performed after 15 minutes of contact then every 15 minutes. The best performances were measured after 15 min of contact at 60 C. with: [0082] Conversion of the pyruvic acid=57% [0083] Yield dosed in KMB=42% [0084] Selectivity in KMB=74%

EXAMPLE 4: PREPARATION OF KMB BY THE THIRD ROUTE IN A SEQUENCED MANNER VIA METHYLENEDIPIPERIDINE SPECIES

[0085] The general scheme of the synthesis is as follows:

##STR00007##

1.SUP.st .Step: Synthesis of the Intermediate (IV)

[0086] ##STR00008##

[0087] In a 10 mL reactor under argon equipped with a temperature probe, are introduced successively at C. [0088] 500 mg of oxaloacetic acid [0089] 10-5 mL of EtOH [0090] 209 mg of acetic acid

[0091] After dissolution of the acid (about 5 minutes of stirring), dipiperidinomethane (0.95 eq.) is added in 50 minutes via a syringe pump. After the end of the addition, the medium is heated to 60 C. in 1 hour then stirred at this 15 temperature for 10 minutes. A control by HPLC-MS (ESI.sup.+) confirms the formation of the intermediate IV.

[0092] The reaction medium is cooled to 20 C. then the solvent is evaporated under reduced pressure (10 mbar, 20 C., 1 h) to lead to (IV) in the form of a pale-yellow oil (1.2 g). [0093] Complete TT.sub.oxaloacetic acid [0094] RR.sub.isolated of the activated thiomethyl derivative=60% [0095] Titer=35% (dosed by NMR .sup.1H vs 3,5-dimethylanisole)

2.SUP.nd .Step: Synthesis of KMB Piperidinium

[0096] ##STR00009##

[0097] In a 10 mL reactor under argon provided with a temperature probe, are introduced successively under stirring at 0 C.: [0098] 300 mg of intermediate (IV) [0099] 5 mL of EtOH

[0100] Once the reaction medium at a temperature lower than 5 C., the MeSH gas is introduced in 1 hour (via a syringe pump). The reaction medium is then heated to 60 C. in 1 hour then this temperature is maintained for 30 minutes.

[0101] An HPLC control indicates a complete transformation of the intermediate and the majority formation of KMB piperidinium.

[0102] The reaction medium is withdrawn then concentrated under reduced pressure (10 mbar, 20 C., 1 h). The KMB piperidinium is obtained in the form of a yellow oil without additional purification (260 mg) [0103] Complete TT.sub.intermediate IV [0104] RR.sub.isolated of the KMB piperidinium=90% [0105] Titer=45% (dosed by HPLC vs standard)