Synthesis of chiral &bgr;-amino acids

Details Synthesis of chiral &bgr;-amino acids Synthesis of chiral &bgr;-amino acids

1999-03-02

2002-07-02

Vollano, Jean F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S045000, C562S442000, C562S444000

Reexamination Certificate

active

06414180

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of chiral &bgr;-amino acids and esters of the formula
wherein X and Y are the same or different halo group, R
2
is H or lower alkyl; which process comprises reacting a 3,5-dihalosalicylaldehyde of the formula
with MEMCI or BnBr (Bn=benzyl) to obtain a protected 3,5-dihalosalicylaldehyde of the formula
wherein P is Bn or MEM; treating the protected 3,5-dihalosalicylaldehyde with (R) or (S) phenylglycinol in tetrahydrofuran (THF) or toluene to produce an iminoalcohol of the formula
reacting said imino alcohol with BrZnCH
2
CO
2
-t-Bu in N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO) or THF to produce an amino alcohol of the formula
reacting the amino alcohol with lead tetracetate (Pb(OAc)
4
) to form an imine of the formula
transesterifying, deprotecting, and hydrolyzing said imine in a one pot process to isolate a product of the formula
The reaction provides for the preparation of (R) or (S) isomers with enantiomeric excess (ee)>99%.
U.S. Ser. No. 08/890,907 discloses the following process for preparing &bgr;-amino acid esters.
Briefly in Scheme A, the chiral imine 1 derived from 3,5-dichlorobenzaldehyde and (S)-phenylglycinol is reacted with 2 equivalents of the Reformatsky reagent (BrZnCH
2
CO
2
tBu.THF) in NMP at −10° C. to afford the corresponding amino alcohol product 2 as one enantiomer (ee>96%). The amino alcohol 2 was then oxidatively cleaved with sodium periodate in ethanol in the presence of methyl amine to afford the corresponding phenyl imine 3. The &bgr;-amino ester 4 was then isolated as a PTSA salt from THF and heptane with an overall yield of 63%.
The chiral &bgr;-amino acids and esters produced by the process of the present invention are useful in preparing pharmaceutical agents known as &agr;
v
&bgr;
3
integrin antagonists disclosed in W097/08174. It is therefore desirable to provide a process for the preparation of said amino acids and esters which is amenable to scale-up, and which employs raw materials which are readily available, resulting in high yield and a high level of optical purity which doesn't require any chromatography and/or separation of diastereoisomers.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of chiral &bgr;-amino acids and esters of the formula
wherein X and Y are the same or different halo group, R
1
is H or methoxyethoxymethyl (MEM) and R
2
is H or lower alkyl; which process comprises reacting a 3,5-dihalosalicylaldehyde of the formula
with MEMCI or BnBr (Bn=benzyl) to obtain a protected 3,5-dihalosalicylaldehyde of the formula
wherein P is Bn or MEM; treating the protected 3,5-dihalosalicylaldehyde with (R) or (S) phenylglycinol in tetrahydrofuran (THF) or toluene to produce an iminoalcohol of the formula
reacting said imino alcohol with BrZnCH
2
CO
2
-t-Bu in N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO) or THF to produce an amino alcohol of the formula
reacting the amino alcohol with lead tetracetate (Pb(OAc)
4
) to form an imine of the formula
transesterifying, deprotecting, and hydrolyzing said imine in a one pot process to isolate a product of the formula
The reaction provides for the preparation of (R) or (S) isomers with enantiomeric excess (ee)>99%.
DETAILED DESCRIPTION OF THE INVENTION
The invention herein is directed to the preparation of &bgr;-amino acids and esters of the formula
and acid addition salts thereof wherein R
2
is H or lower alkyl and X and Y are the same or different halo groups.
Synthetic schemes for the most preferred synthetic methods are outlined in Schemes I-IV and the following descriptions thereof.
In Scheme I, 3,5-dihalosalicylaldehyde (A, X, Y=Cl, Br, I) was protected as a MEM derivative (B, P=MEM, X, Y=Cl, Br, I) or benzyl derivative (B, P=Bn, X, Y=Cl) by reaction, respectively, with MEMCI or benzyl bromine and potassium carbonate in DMF. The chiral imine C was formed from B and (S)-phenyl glycinol in THF in the presence of magnesium sulfate. C was reacted with two equivalents of Reformatsky reagent (BrZnCH
2
CO
2
tBu.THF) to stereoselectively form D (P=MEM, Bn, X, Y=Cl, Br, I). The amino alcohol residue of D (P=MEM, X, Y=Cl, Br, I) was oxidatively cleaved using lead acetate in methanol to form the imines E (P=MEM, X, Y=Cl, Br, I). Alternatively the oxidative cleavage can be performed with periodic acid in ethanol in the presence of methyl amine. The &bgr;-amino esters were then prepared refluxing E (P=MEM, X, Y=Cl, Br, I) in the presence of excess of p-toluenesulfonic acid in ethanol followed by precipitation in THF/heptane. F (X, Y=Cl, Br, I) was obtained with good overall yield and high optical purity and chemical purity. Intermediates C, D, E are not isolated and are used subsequently as prepared without purification.
In Scheme II, the chiral imines 6a (P=MEM) and 6b (P=Bn), were prepared by reaction of the corresponding protected 3,5-dichlorosalicylaldehyde 5a (P=MEM), 5b (P=Bn) with (S)-phenyl glycinol in THF in the presence of magnesium sulfate followed by filtration and distillation of the solvent. Imine 6a was reacted with 2 equivalents of Reformatsky reagent (BrZnCH
2
CO
2
tBu.THF) in NMP for 1 hour at −10° C. followed by quench with HCl/NH
4
Cl, extraction with MTBE and distillation of the solvents to obtain a crude product (100%) containing 7a as one diastereoisomer as determined by
1
H NMR and TLC. The same reaction performed in DMSO at 20° C. led to lower selectivity as 7a is isolated as a 95/5 mixture of diastereoisomer with 86% yield after chromatography. Reaction of imine 6b (P=Bn) in NMP was slower and was completed after 15 hours at −5° C. Compound 7b was isolated as one diastereoisomer as determined by
1
H NMR and TLC.
In Scheme III, the amino alcohol residue of 7a was oxidatively cleaved using lead tetra acetate in methanol to form the imine 8. 8 is refluxed in the presence of excess of p-toluenesulfonic acid in ethanol followed by precipitation in THF/heptane. The &bgr;-amino ester 9 was obtained with 49% overall yield and ee>99% as determined by chiral LC. Alternatively, the oxidative cleavage was performed with sodium periodate in ethanol in the presence of methyl amine or periodic acid in ethanol in the presence of methyl amine.
In Scheme IV, the chiral imine 11 was prepared by reaction of the corresponding protected 3-bromo-5-chlorosalicylaldehyde 10 with (S)-phenyl glycinol in THF in the presence of magnesium sulfate followed by filtration and distillation of the solvent. Imine 11 was reacted with 2 equivalents of Reformatsky reagent in NMP at −10° C. followed by quench with HCl/NH
4
Cl, extraction with MTBE and distillation of the solvents to obtain a crude product (100%) containing 12 as one diastereoisomer (as determined
1
H NMR). The amino alcohol residue of 12 was oxidatively cleaved using lead acetate in methanol to form the imine 13. 13 was refluxed in the presence of excess of p-toluenesulfonic acid in ethanol followed by precipitation in TF/heptane. The &bgr;-amino ester 14 was obtained with 45% overall yield (from unprotected salicylaldehyde) and ee>99% as determined by chiral LC.
In Scheme V, the chiral imine 16 was prepared by reaction of the corresponding protected 3-chloro-5-bromo salicylaldehyde 15 with (S)-phenyl glycinol in THF in the presence of magnesium sulfate followed by filtration and distillation of the solvent. Imine 16 was reacted with 2 equivalents of Reformatsky reagent in NMP at −10° C., followed by quench with HCl/NH
4
Cl, extraction with MTBE, and distillation of the solvents to obtain a crude product (100%) containing 17 as one diastereoisomer as determined by
1
H NMR. The amino alcohol residue of 17 was oxidatively cleaved using lead acetate in methanol to form the imine 18. 18 was refluxed in the presence of excess of p-toluenesulfonic acid in ethanol followed by precipi

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