JPS58150556A - Preparation of optically active alpha-aminoaldehyde - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as a synthetic intermediate of bestatin, etc., with a simple operation, in high yield and optical purity, by oxidizing an optically active beta-aminoalcohol under specific condition. CONSTITUTION:The objective compound can be prepared by reacting the optically active beta-aminoalcohol of formula (R1 is amino-protecting group, etc.; R2 and R4 are H or alkyl; R3 is H, alkyl or aryl) with a sulfur trioxide complex in dimethyl sulfoxide in the presence of triethylamine for several minutes - ten-odd minutes. The sulfur trioxide complex is e.g. the complex of sulfur trioxide with pyridine, dioxane, DMF, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing optically active α-amino aldehydes and peptide aldehydes by oxidizing optically active β-amino alcohols as raw materials. Optically active α-amino aldehydes are bestatin,
It is a useful compound as a synthetic intermediate for pepstatin, amastatin, etc. On the other hand, among optically active peptide aldehydes, leupeptin, antipain, chymostatin, and elastatinal have been discovered as enzyme inhibitors produced by microorganisms.

These contain argininal, phenylalaninal, and alaninal as C-terminal residues, respectively. These optically active peptide aldehydes include various proteases such as plasmin.

Strongly inhibits trypsin, papain, chymotrypsin, esterase, etc. ``In addition, these enzyme inhibitors have been in the spotlight in recent years as they have been reported to have anti-inflammatory effects, anti-ulcer effects, inhibition of mutation induction, inhibition of ascites accumulation, inhibition of carcinogenesis, and inhibition of cancer metastasis, and are effective against many diseases.

Conventional methods for synthesizing α-aminoaltehydes can be roughly divided into methods for reducing α-amino acid derivatives and methods for oxidizing β-amino alcohols derived from α-amino acids. As a reduction method, sodium amalgam reduction of N-protected α-amino acid ester (J, Biol, Ohem, Vol. 217,
817 pages, 1955).

Diisobutylaluminum hydride reduction (0herrl.

Pharm, Bull, vol. 28, p. 8081,
1975), Rosenmund reduction of N-phthaloyl-α-amino acid chlorides (J. Org.
Volume 18, page 297, 19L3).

Lithium aluminum hydride reduction (A
nn,, vol. 640, IIIJ, 1961,
J.

Antibiotics, Volume 29, 600Q 197
6th year, J, Med.

Chem, vol. 20, p. 510, 1977), diisobutylaluminum hydride reduction of N-protected α-amino acid imidazolides (J, O,S, Ohem,
Oomm,, 79 pages.

(1979) and catalytic reduction of N-protected α-amino acid mixed acid anhydrides (Chem, Pharm, Bull, 2003).
Volume 0, page 361, 1972) are known, but
All of these are obtained as a mixture of raw materials and by-products.

Since α-aminoaldehydes are unstable to purification methods such as silica gel and racemize, α-aminoaldehydes are used as a single optically pure product.
-Aminoaldehyde has not yet been obtained. For this reason, the known reduction method requires a two-step operation of protecting and purifying the aldehyde moiety of α-aminoaldehyde and deprotecting it.

It also has the disadvantage of low yield. In addition, as an oxidation method, there is a method of oxidation of β-amino alcohols (Ohem, Pharm, Bull, Vol. 20,
361, 1972), chromic acid-pyridine oxidation (
J, Org, Ohem, vol. 46, 4797
Page, 1981), but all of these methods only yield mostly racemized α-aminoaldehydes. There are also examples of optically active forms obtained by glycol oxidative cleavage using periodic acid of 3-amino-1,2-diols derived from α-amino acids.
-The number of steps from amino acids is long and impractical, and-
Membrane properties have not been confirmed (J, C, S, Chem
, Oomm, p. 875, 1979).

As described above, the known methods are unsatisfactory due to drawbacks such as low yields, the need to protect aldehyde groups for purification, or a long number of steps. For this reason, the physical properties of optically pure α-aminoaldehydes are largely unknown to date. As a result of various studies, the present inventors found that sulfur trioxide complex and dimethyl sulfoxide were allowed to act on optically active β-amino alcohols or peptide alcohols in the presence of triethylamine to oxidize them for a short period of time, resulting in optical activity with good yield. The present invention was completed by discovering a simple manufacturing method for obtaining optically pure α-amino altehydes or peptide aldehydes. In addition, J, A, 0.8. , 86 volumes.

5505, 1967, there are known reports of oxidizing alcohols to form aldehydes. No report has been found yet, and by carrying out the method of the present invention, it has become possible to produce excellent optically active α-ruamino aldehydes or peptide aldehydes as described below.

The method of the present invention can be expressed as a chemical formula as shown below.

(2) (In the formula, amino protecting group, amino acid residue, peptide residue, amino acid residue or peptide residue with all or part of the functional group protected, R2 and R1 are hydrogen atoms or alkyl groups, R3 is A hydrogen atom, an alkyl group, or an aryl group, and the alkyl group and aryl group may be unsubstituted or substituted.) The amino protecting group for R1 is a group commonly used in peptide synthesis, etc. Tert-butoxycarbonyl group, carbobenzoxy group, benzyl group, tosyl group, etc. can be used. Regarding RA, specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, carboxymethyl, 0-benzyl, i-xymethyl, β-carphokidiethyl, β-methylthioethyl, benzyl, S -Hensylthiomethyl.

4-hensyloxybenzyl, 3,4-dimethoxybenzyl, imidasolylmethyl, 3,4-methylenedioxybenzyl, phenyl, 4-hensyloxyphenyl, N
Y-Nitroquanidinoprohil, N'-Boc-7
Mi/butyl, NY-BOC-aminopropyl, indolylmethyl group, etc.

Next, the method of the present invention will be explained.

Various synthetic methods can be applied to the synthesis method of the β-amino alcohol or peptide alcohol shown by the above-mentioned formula (1).

After dissolving in nor-benzene mixed solvent and reacting with trimethylsilyldiazomethane at room temperature.

After distilling off the reaction solvent under reduced pressure and replacing the reaction vessel with argon gas, etc., dissolve in tetrahydrofuran/ethanol solvent, add lithium chloride and sodium borohydride, and allow to react at room temperature. β-amino alcohol can be added. The product can be isolated by distilling off the solvent from the reaction solution, followed by extraction with a solvent such as methylene chloride, washing, drying, and then distilling off the solvent to easily obtain it as a crystal or oil. I can do it. On the other hand, peptide alcohol can be obtained by obtaining a methyl ester of a peptide by a conventional method, adding tetrahydrofuran, lithium chloride, sodium borohydride, and ethanol to this and reacting it under argon gas. The obtained product can be used as it is in the next σ reaction, but with a suitable solvent.

For example, it is preferable to carry out recrystallization purification using n-hexane, ethyl acetate, methylene chloride, ether/n-hexane, ethyl acetate-n-hexane, etc., or purify by vacuum distillation or column chromatography before use in the next reaction. Next, if this β-amino alcohol or peptide alcohol and triethylamine are mixed in anhydrous dimethyl sulfokind and oxidized by adding a solution of sulfur trioxide complex in anhydrous dimethyl sulfoxide, an optically active α-amino aldehyde or peptide alcohol is produced. . Although it is sufficient to use 25 equivalents of each of triethylamine and sulfur trioxide complex, it is appropriate to use about 3 equivalents. As the sulfur trioxide complex, a complex of sulfur trioxide and virison, oxane, trimethylamine, DMF, etc. can be used. A reaction time of several minutes to several minutes is sufficient, and the reaction temperature can be at room temperature. Anhydrous dimethyl sulfoxide acts as a solvent, but benzene, methylene chloride, etc. can also be used if necessary.

After the reaction is complete, the reaction mixture is poured into ice water and the product is dissolved in an appropriate solvent such as ether or ethyl acetate-benzene (4
:l) etc.

After washing with an aqueous citric acid solution, water, a saturated sodium bicarbonate solution, etc., the mixture is dried and the solvent is distilled off to obtain optically active α-amino aldehydes and peptide alcohols as products. The obtained optically active α-amino aldehydes and peptide aldehydes can be used as enzyme inhibitors, etc. without any purification, but crystalline ones can be recrystallized from a suitable solvent.

As described above, the method of the present invention provides a novel method for producing α-aminoartechite in high yield and high optical purity using simple operations from β-amino alcohol which is easily obtained from α-amino acid.

The present invention will be explained below using reference examples and examples.

shall be.

Ala: Alanine residue Val: Valine residue Leu: Leucine residue Pro: Prolife residue Met + Methionine residue Trp: Tryptophan residue Tyr
: Tyrosine residue Lys : Lysine residue Glu ; Glutamic acid residue Cys
: Cystine residue Arg : Arginine residue Phe : Phenylalanine residue o+y
: Glycine residue Boc : Tertiary butquine carbonyl group Z
: Carbobenzoxy group Bzl : Benzyl group No. : Nitro group 24-DNP : 2,4-dinitrophenylhydrazone derivative py-so : Sulfur trioxide/pyridine complex OMe : Methyl ester Reference Example 1. Synthesis of Boc-L-Lys(Z)-ol 0.7 m of 2M-trimethylsilyldiazomethane-hexane solution in 20% methanol-benzene solution of 380m9 (1 mmol) of oc-L-Lys(Z)-OH
1 over 5 minutes and stirred at room temperature for 20 minutes. The reaction solution was distilled off under reduced pressure, and the reaction vessel was replaced with alcon gas, and 85m9 (2m mo+) of lithium chloride, 76mp (2 mmol) of sodium borohydride, and 9ml of tetrahydrofuran-ethanol (1:2 volume tut) were added. , come to room temperature - stir overnight. The reaction solution was distilled off under reduced pressure, and 10%
Add 10 ml of citric acid aqueous solution, extract 8 times with 80 ml of methylene chloride, and dry the methylene chloride layer with anhydrous sodium sulfate. After evaporating the solvent.

Boc-L-Lys(Z)-of is obtained as colorless crystals. Yield: 858 m9 (98%) This was recrystallized from ether-〇-hexane to obtain colorless needle crystals.

Melting point: 69-710C, Cα 0-9.25 (C==
1, methanol) Reference Examples 2 to 12 Boc-L-Lys (Z
)-OH to Boc-L-Ala-OH (Reference Example 2)
, Boc-L-Vat-OH (8), Boc-L-
Leu-OH (4), Boc-L-Pro-OT ((
5), Z-L-Pro-OH (6), Boc-L-
Met-OH (7), Z-L-Phe-OH (8),
Z-L-Oys(Bzl)-0H(9), Boc-
L-Tyr)-OH(10), Boc-L-Tyr
(Bzl)-OH(11), Boc-L-Arg(
No. 2) Various amino alcohols were synthesized in place of -014(1,2).

2. Boc-L-Ala-ol 9B
54~6℃ -109G>l, MeOHlA
Boc-L-Vat-ol 90 (105vO
,5m+yt1g) -16,4(0-1,Me(l(
) 4, Boc-L-Leu-of 95 (11
0℃70.5mmHg) -28,8(s, tt
)5, Boc-L-Pro-of 92 (9
0V0.4mml(g) -55,1(p, tr
)6, Z-L-Pro-of Ql
−46,8(rr, /l
)? , Boc-L-Met-of 82 47-
8℃ -21(〃,〃)8, Z-L-Phe-of
90 89~92℃ -4],,?
(0-1 EtOH) 9, Z-L-Cys (Bzl
)-ol 77 61~a℃ -135,5 (0=
1. MeOI()+0. Hoc-L-Trp-ol
91 118~120℃ -29,7(n, #
) 11, Hoe-L-Tyr(Bzl)-ol
89 98-100℃ -19,7(1,71)12,
Hoc-L-Arg(Not)-ol 5! l 1
82-4°C-7,45 (rr, n) Example 1.
Synthesis of Z-L-Phe-al Z-L-Phe-o1
5701Q (2 mmol), i. ethylamine 607
Py-803955 #1p (6 mmol) and 6 ml of anhydrous dimethyl sulfoxide were added to a 6 ml solution of anhydrous dimethyl sulfoxide under stirring at room temperature, stirred for 10 minutes, and the reaction solution was poured into 6 oml of ice water and the aqueous layer was evaporated with ether. Extracted 3 times with +oml, the ether layer was 10%
Each was washed twice with 80 ml of citric acid, water, and saturated sodium bicarbonate solution in that order, and dried with anhydrous sodium sulfate. After distillation of the solvent, 2-L-Phe-al is obtained as a product as hot-colored crystals. The yield was 567 mg (1,00%), and this product was recrystallized from ether-〇/'\xane to obtain colorless needle crystals. Yield 4
80■ (85%), melting point; 77-9°C9 [α] +4
4.5 (C=1, methylene chloride) Examples 2 to 18 Bo
c-L-Ala-of (Example 2), Boc-
L-Val-at(s), Boc-L-Leu-ol
(4), Boc-L-Pro-0l (5), Z-L
-Pro-ol(a), Boc-L-Met-of
(7).

Boc-L-Trp-of(8), Boc-L-
Tyr(Bzl)-of(9), Boc-L-L
ys(Z)-of(10), Z-L-Cys(Bz
l)-of(11), Boc-L-Arg(No2
) -ol(12).

Various α-amino aldehydes were synthesized in place of Boc-L-Glu(Bzl)-ol (18).

0 Example Yield (to) Melting point Recrystallization solvent
[α]02Boc-L-Ala
j--chill” n +88.9-at 66
90-2℃ -Hexane (O-1, Methyl chloride)
) a Boc-L-V a I s a *15.6
℃ +198-@I
(#, l)4B0cm
To L-Leu86 61~3℃ +184
-11 (
/7. tt)5Boc-L-Pr.

−, + 84 (oily) (0=1, / 9/
-Jl/)6Z-L-Pro96*18B~5℃
-781-1 (Q-1, chloride) 7Boc-L-Me to o*14 to 2℃
+278-at
(#, #)8 ””
"p85, 84-7℃ Aete J"n +42
U-・1-hexane (n,y)
, Boc-L-Tyr
+46.2 (Bzl) - 轡, 8198″″10
0℃ " (□, 〃)l,, Boc-L
-Lys +24.
9(Z)-at 77 78-80℃
(#, tr)llZ-L-Cys-L
-101 (Bzl)-sl+ 78 105-112℃
” (#, /I)lzBoc-L-Arg (NO2)-al gI21a8~1411: Acetic acid x%vx-7'b +27.9-n-hexane (
C-+, ρMF)18Boc-L-Glu (Bzl)-al ss 111-113℃x-fpv
-n-64+24.11 suns (C=
1. Chloride No f-F//) *mark is the melting point when it is made from 2.4 to DNP.

Claims (1)

[Claims] (1) General formula (in the formula, amine protecting group, amino acid residue, peptide residue, amino acid residue or peptide residue with all or part of the functional group protected, R2 and R4 are hydrogen atoms or alkyl groups, R3 is a hydrogen atom, an alkyl group, or an aryl group, and the alkyl group and the aryl group may be unsubstituted or substituted) in the presence of triethylamine in dimethyl sulfoxide. A method for producing optically active α-aminoaldehydes F represented by the general formula, which comprises reacting a sulfur trioxide complex.