JPH03501966A - Glycosylamines and their N-alkylidene derivatives; their preparation and their use in particular in the diastereoselective synthesis of α-amino acids and their derivatives. - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Glycodylamine and its N-alkylidene conductor; its preparation and especially α-amino Its use in diastereoselective synthesis of acids and their derivatives The present invention provides a compound of the following formula (I) in which R-N-Q (1) Here, Q represents a dihydrogen atom or the following group, R represents a carbohydrate residue, Preferred are hexose and bendose residues, the hydroxyl functional group of which is acyl protected. having a group and bonded to the nitrogen functional group via the anomeric carbon atom, R represents an aliphatic residue of 1 to 18 C atoms, oxygen-blocked or sulfur-blocked, and can be substituted with CN-, CONH2- or sulfonyl, or aromatic residues, in some cases halogen-substituted, lower-alkyl-substituted, lower-alcohol-substituted Indicates an xy-, cyano-, or nitro-substituted residue, or O, S, Hetero containing at least one hetero atom selected from the group N as a ring member Indicates an aromatic residue, or in some cases a lower alkyl substituted C-c alicyclic residue. , the present invention also provides diastereoselective synthesis of chiral amino compounds of the following formula This paper relates to the application of Compound I.

Aromatics include phenyl and naphthyl, and heteroaromatics include phenyl and naphthyl. Thiophene, furan, and pyridine, pyrimidine, pyrazine, pyridazine N-containing aromatic compounds such as

"Lower alkyl" or "lower alkoxy" may include up to 4 carbon atoms or We can list the branched groups in . "Halogen" means fluorine, chlorine, bromine, iodine, Especially chlorine.

Acyl protecting groups for the hydroxyl functionality of carbohydrates contain aliphatic or aromatic hydrocarbon residues. can have. Branched aliphatic groups such as pivaloyl are preferred.

Compounds of formula I are used in the diasteroselective synthesis of chiral amino compounds of formula .

Here, R and R1 have the above meanings, and R2 is a derived carboxyl group, meaning especially -CN and -CONHR4, R means hydrogen or aliphatic C1-C6-acyl group, R is C-C-alkyl, C 3-C7 cycloalkyl or cycloalkenyl or optionally substituted means an aromatic residue.

As long as R3 means aliphatic acyl, formyl and acetyl can be mentioned. . When R4 means alkyl, tertiary butyl is preferred, the aromatic residue of R4 include in particular phenyl and naphthyl, in which case the substituents include R1 The things listed above can exist.

The (acylated) carbohydrates R of formulas l and m and of the formulas below are preferably glucosyl derived from arabinosyl, mannosyl or galactosyl residues , in particular the 5-D-galactopyranosyl residue.

There is increasing interest in the synthesis of chiral compounds. Selectivity of action of chemical agents This is because the demands related to this are increasing. In this regard, amino acids and A special meaning is given to the made bebutidine. 'These are, so to speak, natural because it is an active substance and is particularly useful as an additive in medicines, recreational products, and feedstuffs .

Various methods have been developed in recent years for the diastereoselective synthesis of α-amino acid derivatives.

Most of these methods are carried out via metallized and lithiated intermediates. In that case, expensive metal materials such as n-butyllithium are used, and moisture and oxygen are must be ensured.

As an example of this method, a rough chimney of a diketopiperazine with a shell tip is used. (U, Sinilkop, Pure Appl, Ch. ea+, 55 (1983), 1799).

The economical and industrially used amino acid synthesis method is Schdrecker synthesis (for example, A. Klemann et al.'s overview, Ullmann's Encyclopedia of India Strial Chemistry, Bd, A2, 57.5 edition, VCH Publishing, Wine, Ha Im 1988).

In that case, a racemic mixture is obtained, which has to be separated in a special treatment step. do not have.

The asymmetric Strecker synthesis was developed by Weinges and his collaborators (Liebig and n, Chem, 191!0.212: 1985゜566), 4S, 5S- (+)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane It was carried out. According to this method, optical guidance is moderate.

However, in many cases pure diastereomers are crystallized. Other researchers In the Schdrecker synthesis using dipebutidine as a derivative, low conversion Although the surplus of one diastereomer is high in the conversion rate, this surplus decreases as the conversion rate increases. We observed that the surplus decreased significantly (S, Inouuni, et al., J, C, S, Chei , Commun, 1981.229).

Compound I, which is the object of the present invention, can be used in Schdrecker synthesis with high High asymmetric induction is achieved with conversion. Tested O-acetyl and 2. 3゜4.6-tetra -0-pivaloyl β-D-galactopyranosylamine l (Synthesis Example 1) most effective.

Therefore, in the following, high-yield synthesis using pivaloyl-protected galactosylamine I Explain the formation. Conversions proceed similarly when other glycodylamines are used. However, as a general rule, diasteroselectivity is low.

To prepare compound I, venter O-pivaloyl β- D-galactopyranose was obtained. This is trimethylsilyl azide/tetrachloride. With tin, 2.3.4.6-tetra-0-pivaloyl β-D-galactopi Converted to lanosyl-azide. From now on, reduction or platinum or lanenique Amine 1 was obtained by catalytic hydrogen conversion on the silica (Example 1): In exactly the same way, the corresponding β-glucosyl-1α-mannosyl- (Example 2) , and D- and L-arabinosyl-amines were obtained.

〇-protected glycosylamine such as compound 1 with aldehyde and sodium cyanide/ If acetic acid is converted using the Schdrecker synthesis method, the corresponding N-glycosyl α- Aminonitriles are obtained in high yields. At that time, for example, galactosylamine 1 As seen in the reaction below, there is an interesting dependence of the direction of optical guidance on the solvent. be observed.

R'-CH solvent: CHCL3. 3ゝ (R): (S)-1: 5, yield 72% R'-0CH3, solvent: I・-propyl Tool (R): (S)-7: 2, yield 95% Preferentially ( α-aminonitrile of the structure S) occurs, preferentially in isopropanol (R )-diastereomers are formed. Furthermore, for example, other 01-04 alcohols is also available.

However, in both cases considerable reaction time is required. in isoproper tool The reaction in chloroform requires 24 hours, and the reaction in chloroform requires 15 days.

Therefore, it has been demonstrated that a method other than the above is desirable.

First, from glycosylamine and aldebide, the corresponding Schiff base (Formula 1. Q is ■ and ), which is then treated with a salt in a solvent that acts in the desired direction of induction. Lewis acids such as zinc chloride (■), aluminum chloride, or zinc chloride (TV) in the presence of trimethylsilyl cyanide. charged lewis acid The reaction proceeds quantitatively in 10 minutes to 24 hours, depending on the amount of Asteroselectivity was obtained. Regarding the case of m-chloro-benzylaldehyde, These steps are illustrated (Example 3.4.5).

(R):(S)-7:1 (Example 4) (R):(S)-1:5 (actual Example 5) Using equimolar amounts of ZnCl2, the L reaction in the same direction of induction has already been It ended after 10 minutes. In one isopropanol (Example 4) during the purification of the charge. The (R)-diastereomer precipitates out in pure form. This gives a yield of about 65%. Can be isolated.

(R)-diastereomer was extracted from the charge in which (S)-diastereomer was produced in excess. Omer crystallizes slowly and pure from methanol/water from 4 or n-hebutane. 1. In this way, the (S)-diastereomer is highly enriched. Worth it.

Aliphatic aldehydes as well as aromatic aldehydes can be treated with α-huminonitrile in this way. It can be used for diastero selective synthesis. This is an example of pivalaldehyde Its reaction with compound 1 produces the corresponding azomethine 4, which is α-aminonitrile with high cyastereoselectivity together with lymethylsilyl cyanide 5 is born. It is a derivative of D-tertiary-leucine. This 9th example Therefore, it is possible to replace ZnC12 with SnCl4 (it has been shown that results can be obtained). (Example 6).

anti hand, Te too thing and others in, transformation A. From the mixture 5 above, the main shear stereomer is purified using aqueous methanol. It was neatly precipitated. It can be isolated with a yield of 80%. THF Alternatively, other ring 4 ethers can be used, such as dioxane.

2 The diastereomer ratios described in Fa, L7) KB HPLC system with iode array detector) , an RP-column (ODS n-column) in a methanol/water mixture with a flow rate of 1 mρ/min. ram 83μ).

To confirm the structure of the diastereomer, compound 1 was prepared with benzaldehyde. The product mixture produced in isopropanol is diluted with water-dioxane by hydrochloric acid. It was produced as an excess enantiomer in Instead of dioxane, other miscible with water Solvents such as alcohols can be used, and acids such as other strong acids such as alcohols can be used. For example, sulfuric acid can be used. Is it the retention time of a diastereomer similar to compound 6? The structure of the α-aminonitrile moiety in this excess product is deduced.

(R): (S) > 12: 1 (a) “2--152.2 (c-0, 5゜1　nHC1) (R) -72 Elk') C>: (a) 22--155. ’: (cm 1, 5.1696 aqueous, HC1) Reactions 6→7 are also performed simultaneously with N-glycosylamide Figure 2 shows the conversion of non-nitriles to amino acids. As a rule, pivaloylated glycerin The codyl compound is regenerated. Type 1 glycosylamine is a type of glycosylamine in which amino compounds participate. Other reactions that involve a high degree of asymmetry induction also occur.

As an example, four-component synthesis using UGI was carried out.

For example, galactosylamine 1 is p-nitrobenzaldehyde, zinc chloride, formic acid , and tertiary-butyl isocyanide to form diastereotate by reacting virtually quantitatively at 0°C. omer p-nitrophenylglycine derivative 8, in this case about 12.5: A diasteroselectivity of 1 was achieved.

Yield is almost quantitative: (R): (S)-12,571, n-hebutane CH2C Yield of pure (R)-diastereomer: 81% after crystallization from Later on, the pure (R)-diastereomer 8 was already isolated in a yield of 8196 (performed). Example 7). Results similar to this reaction were obtained (Example 8). For example, cycloaliphatic aldehyde If pivalaldehyde of Only diastereomer 9 of the derivative was obtained (Example 9).

Even in HPLC, in the high region -1H- and -13c-NMR- spectra. However, the second diastereomer was not detected. NMR of 8/9 type compound- The spectrum shows signal multiplexing, which is attributed to the rotamers of the formyl group. .

The pure diastereomer 8 was prepared in methanol with the catalyst mixture Na-methyl,-t If treated with It can be observed in roughy and NMR spectra.

As in the case of the reaction with thiophene-2-aldehyde, the group corresponding to compound 1 The reaction of 4 components (components with the same structure as compound 8) with lucosyl-amine 10 It proceeded with virtually quantitative diasteroselectivity (Example 10).

(R); (S)-11: 1 Overall, glycosylamines are very effective optical (auxiliary) derivatives. , which can be used to perform amine participation such as Schdrecker synthesis and Ugi-reaction. In the case of reactions with It is achieved by Diastereomers are often obtained directly by crystallization. It was. The glycosyl residue as an auxiliary group can be separated by an acidic agent of the N-glycosidic bond. be separated.

Compounds with interesting optical activity, such as α-amino acids, β-amino acids, can be extracted from the product. No-alcohol and 1,2-diamine are obtained.

5.5 g (10 mmol) of 2. 3.4.　6-Chitler〇-Pivaloiru β-D-galactopyranosyl-azide Melting point 92°C [α)”--20,7(C-1 ゜CHCl3)) in 200rrl of ethanol to 0.4g of platinum dioxide Hydrogen conversion is carried out using After evaporating the solvent in vacuo, the remaining galactosylamine 1 Crystallize from methanol. Yield 4.95g, 96%, [α]22-+10.3 (c=1.CHCl3), melting point 88°C.

IR-spectrum and IH-NMR-spectrum and elemental analysis correspond to structure 1. ing.

0.55g (1 mmol) of 2. 3.4.　6-Chitler〇-Pivaloiru α-D-mannopyranosyl-azide (pentapivaloyl-mannobyranose) Obtained from: Melting point 86-87°C [α)''-+84.5 (c-A.

CHCl3)) was added to 40 mj) of ethanol in the same manner as in Example 1. mg of PtO2 is hydrogenated and the reaction solution is treated in the same manner. Yield: 0 ．． 5g.

9826° [α) + 4.1 (c-2, CHCl 3); Elemental analysis and IH -NMR- spectrum corresponds to this structure (Den) -2,3,4,6-Chitler O- Pivaloyl β-D-galactopyranosyl-amine 210g (20 mmol) of pivaloyl-protected galactosylamine 1 and 5.6 g (40 mmol) of 30 drops of m-chlorobenzaldehyde in 60mj2 isopropanol of glacial acetic acid. After 30 minutes, precipitated Schiff's base 2 (quantitative amount) was filtered off. , crystallized from isopropanol. Yield 10.6g (84%); Melting point 135 °C: [α) 2'-14,1 (c-1, CHCl3) 13 cm and "H-N The MR-spectrum confirms the structure of compound 2.

13C-NMR, δ-159.8 (C-N), 92.8 (C-1).

Example 4 Schdrecker synthesis with glucosylamine - reaction method to (R) diastereomer Synthesis of ■-type compounds with directional properties.

1 g (1.55 mmol) of Schiff's base 2 was added to 25 ml of Impropate at a temperature of 0°C in a 0. 5mj? of trimethylsilylanide (3,75 mm mol) and 10 mg of ZnC12 and stirred for 14 hours with exclusion of water. Ta. It is then concentrated in vacuo (approx. 10 ml) and 50 ml of dichloromethane is added. The charge was shaken out twice with 50 mfl of water and the organic phase was dried over Na2SO4. Dry and evaporate the solvent in vacuo. According to HPLC analysis, the residue Reomer ratio (R): (S) shows -7:1 (1.1 g to constant ik). n-hebuta A clear HPLC of the pure (R)-diastereomer was obtained after crystallization from . Melting point 136°C, [α) 22=+1'2. 1 (c-1, CHCl3), Holding time t-3' 50' (methanol/water ratio 85:15, flow rate 1 mfI/min ).

The 13 cm and "H-NMR spectra confirm this structure.

13C-NMR: δ-118,7 (c-n), 87.25 (C-1), 49. 7 (α-C).

Example 5 Schdrecker synthesis with galactosylamine 1 as in Example 4. However, (S ) - diastereomer unidirectional.

In a similar charge as described in Example 4, but with the exception of 25 ml as solvent. Quantitative (Ig) N-glycosylamino A diastereomeric mixture of nitriles (3b) was obtained, with clear HPLC (S)-diastereomer predominates: (R):(S)-1:5° mixture remains oily.

The (R)-diastereomer present in a small amount is very slowly separated from water-methanol. Put it on display.

The (S)-diastereomer was prepared at t-4'34 after standard conditions (see Example 4). ’ indicates the retention time.

13C-NMR; δ-118,6 (C-N), 86.4 (C-1), 49.3 (α-C) Example 6 Schdrecker synthesis with pivalaldehyde and galactosylamine 1: 1: N-(2,3,4,6-tetra-0-pivaloyl-β-D-galactopi Lanosyl - 1 g (2 mmol) of 30th isine nitrile and 1 g of glycodylamine 1 ml of pivalaldehyde in 20 ml of n-heptane, 1 ml of pivalaldehyde Stirred with acidic ion exchange material 1R200.

After 15 minutes, water-free MgSO4 was added and after stirring for 5 minutes it was filtered off. filter Heptane was distilled from the liquid, and 10 rrJ of doluol was extracted twice from the residue in vacuo. Evaporated. Dissolve the remaining Schiff's base ■ in 15 mR of tetrahydrofuran. Dissolved, cooled to 78°C, added 0.3 mg of trimethylsilyl cyanide and then 0.3 mg of trimethylsilyl cyanide. It was reacted with 2 ml of SnCl4. Stir for 2 hours and then as described in Example 4. Processed as described. The mixture is (R):(S)-15:1 diastereomer The ratio was shown. After crystallization from water/methanol, the main diastereomers are purified in pure form. It was obtained with a yield of 82%. Melting point: 178°C, [α]22-+32.8 (c=1. CHCl3): methanol/water, 13 Retention time: t-4'15. C-NMR-11,9,6 (C-N), 90. 2 (C-1), 58. Four-component reaction using OUgi - Synthesis example of the compound of general formula (■) 2N-Formyru N-(2,3,4,6-Chitler〇-Pivaloyru β-D- galactosylamine 1 of (galactopyranosyl)-p-nidomole) and 0. 32 g (2.1 mmol) of p-nitrobenzaldehyde and 0.37 g (2.1 mmol) of p-nitrobenzaldehyde. for Zn C12 of (2.1 mmol) and formic acid of O,Ig (2.1 mmol) , 0.174 g (2.14 lmol) of tert-butyl isocyanide were mixed at 0°C. , 1 hour at 0° C. and then an additional 12 hours at ambient temperature. 50mfI of dichloromethane are added and the mixture is extracted with 200 rJ of 2N hydrochloric acid.

This is then washed with water, the organic phase is dried over MgSO4 and the solvent is distilled off in vacuo. fruit The product was obtained practically quantitatively. Obvious HPLC diastereomer ratio: 12 ．． The pure main product (R )-diastereomer was obtained in 81% yield.

Melting point = 138°C; [α) 27-35.6 (c-1°CHCl3).

Elemental analysis and C- and IH-NMR spectra are consistent with structure 8. Faith The overlap in numbers is a result of the rotamers of the formyl group.

Example 8 The four-component reaction of Ugi using heteroaromatic aldehydes, two N-formyl N-(2,3,4,6-tetra-0-pivaloyl β-D-galactopyranosyl )-2-chenyl-glycine-N'-tert-butyramide by the method described in Example 7. The reaction is carried out, but in this case instead of p-nitrobenzaldehyde, thio Phen-2-carparcht is used. The diastereomer ratio of the crude product is (R) : (S)-25:2. in petroleum ether/acetate (3:1) The pure (R)-diastereomer was isolated by silica gel chromatography. % yield. Melting point = 124°C, [α] 25--29. 7 (c -1, C HC1B).

Elemental analysis and IH-NMR spectra are consistent with the structure and indicate the use of aliphatic aldehydes. Four-component reaction by Ugi: N-formyl-N-(2,3,4,6-tetra- 0-pivaloyl β-D-galactopyranosyl)-30th isine-N'-3rd block Tyramide In this reaction, instead of p-nitro-benzaldehyde, a corresponding amount of Viva Raldehyde was used. Otherwise, reactions and treatments were carried out as described in Example 7. provided. An oily product was obtained which solidified amorphously and showed clear HPLC of structure 9. Only diastereomers are shown. There is an apparent α-structure by-product with a proportion of about 10%. Ru.

Yield (HPLC): 80%; [α) 22--4.9 (c-1, CHCI 3), Retention time: 1mf in 0DSS1 column! /min flow rate of methanol 2,3.4.6-Chitler O-pivaloyl-β-D-g in Le/water (87/13) Four-component reaction using lucopyranosylamine 10; N-formyl-N-(2 ,3,4,6-chitler O-pivaloyl β-D-glucopyranosyl)-2-thi Phenyl-glycine-N'-tert-butylamide 1120 mfl anhydrous tetrahydride 2. of Ig (2.1 mmol) in Lofuran. 3.4. 6-Chitler O-Piva Royleux β-D-glucopyranocyamine 10 and 0.24 g (2.1 mmol ) of thiophene-2-carbaldehyde and 0.37 g (2 mmol) of Zn Cl 2 and 0.1 g (2.1 mmol) of formic acid (100%) at 0°C 0.174 g (2.1 mmol) of tert-butyl isocyanide was added at 1 Stir at 0° C. for 1 hour and then at room temperature for 24 hours. As described in Example 7 Processing yields an oily mixture of diastereomer-11 in 88% yield. 0DS In explicit HPLC on II column (3 μ), methanol flow rate 1 ml/min Analysis result in water/water (86/14): diastereomer ratio (R) = (S)-1 1: 1° holding time: (S)-3' 43': (R)-4' 15'.

If! ! Kaikan report □A″””””’PCT/EP　!17100371　-2--inside--^-both- 肱PCT/EP　87100371　-3-

Claims (11)

[Claims] 1. A compound of the following formula (I). RN=Q(I) Here, Q represents a dihydrogen atom or the group below, and there are ▲mathematical formulas, chemical formulas, tables, etc. ▼(II) R represents a carbohydrate residue, preferably hexose and pentose is a residue whose hydroxyl function has an acyl protecting group and is is bonded to the nitrogen functional group, R1 represents an aliphatic residue of 1 to 18 C atoms, oxygen-blocked or sulfur-blocked, or can be substituted with CN-, CONH2 or sulfonyl, or aromatic residues, in some cases halogen-substituted, lower-alkyl-substituted, lower-alcohol-substituted Indicates an xy-substituted, cyano-substituted, or nitro-substituted residue, or O, S, Hetero containing at least one hetero atom selected from the group N as a ring member Indicates an aromatic residue or, in some cases, a lower alkyl substituted C3-C7 alicyclic residue. vinegar. 2. Claim 1, wherein the acyl protecting group for the hydroxyl group is a pivaloyl residue. Compounds listed. 3. Carbohydrate residues are β-D-glucopyranosyl series or β-D-galactopyra The compound according to claim 1 or 2, characterized in that it belongs to the nosyl series. 4. Converting the corresponding O-acyl protected glycosyl azide to the amine by reduction A method for producing a compound according to any one of claims 1, 2, or 3, characterized by: 5. Carbohydrates are first converted into pent-O-pivaloyl derivatives, which are then converted into tet-O-pivaloyl derivatives. is converted into O-glycosyl azide, which is then reduced to claim 1 , 2 or 3, wherein the compound according to claim 1, 2 or 3 is produced A method for producing any of the compounds described above. 6. The compound according to any one of claims 1, 2, or 3, in which Q represents two hydrogen atoms. is reacted with an aldehyde of the following formula (IV), O=CH-R1(IV) Here, R1 has the above meaning A process for the preparation of a compound of formula I (Q equals a residue of formula II), characterized in that: 7. The reaction of an aldehyde with a compound of formula I can be carried out under Schdretzker synthesis conditions or under UG 7. The method according to claim 6, wherein the method is carried out under four-component synthesis conditions of I. 8. Compound of the following formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) Here, R and R1 have the above meanings. and R2 has a derived carboxyl group, especially -CN and CONHR4. means, R3 represents hydrogen or an aliphatic C1-C6-acyl group; R4 represents a C1-C10-acyl group; C3-C7 cycloalkyl or cycloalkenyl, or optionally means a substituted aromatic residue. 9. 9. The compound according to claim 8, wherein R2 represents a cyano group. 10. R2 is an N-substituted carboxamide group, and R3 is an acyl residue. 9. A compound according to claim 8, characterized in that 11. Claims 1, 2 or 2 in the diastereoselective synthesis of the compound according to claim 7. or 3. Application of the compound described in any one of 3.