CN1309712C - Precursor of key intermediate of AG 7088 class compound and its sythetic process - Google Patents

Abstract

The invention relates to a synthetic method of a precursor of a synthetic intermediate of the AG7088 compound and a new class of compound. It has the following general structural formula: the synthetic route provided by the present invention is to couple N-protected aminoaldehyde and propiolate, and the resulting product is hydrogenated while converting the N-protecting group into Boc or other nucleophilic protecting groups. base. Then activate the hydroxyl group of the product, and generate an oxazolidinone compound through an intramolecular SN ₂ reaction. At the same time, the configuration of the hydroxyl group is reversed, and then a protecting group is placed on the N to open the oxazolidinone ring, and close the five oxazolidinone rings under acidic conditions. Lactone ring, the synthetic intermediates of AG7088 compounds are obtained. The invention provides a new synthesis method for the intermediates of AG7088 compounds. The synthesis uses natural amino acids as raw materials, has short synthesis route, high yield and good stereoselectivity.

Description

Precursor of key intermediate of AG7088 compound and its synthesis method

technical field

The invention relates to a precursor of a key intermediate of the AG7088 compound and a synthesis method thereof.

technical background

AG7088 compounds are inhibitors of rhinovirus protease, which are clinically used to treat common colds. And may have inhibitory effect on SARS virus. The AG7088 compound molecule contains two peptide bonds, which bind to the target protein in the form of hydrogen bonds. On the right side, the Michael addition receptor is covalently bonded to the sulfhydryl group of cysteine in the target protein. The amino acid structure in the middle is ketomethylene dipeptide isoesters.

Several main synthetic routes of its key intermediates are as follows:

1: J. Org. Chem. 2003, 5, 2042

2: Jean-Francios, etc, Tetrahedron Lett. 1995, 2757

3: Jeffrey A. Compbell, etc., J. Org. Chem. 1995, 14, 4602

Summarizing the synthetic routes of the above literatures, all have the defects of low selectivity and low yield.

Contents of the invention

The problem to be solved in the present invention is to provide a precursor synthesis method for the synthetic intermediate of a new AG7088 compound;

Another problem to be solved by the present invention is to provide a new type of precursor of a synthetic intermediate of AG7088.

The present invention provides a new type of precursor synthesis method for intermediates of AG7088; provides a new synthetic ketomethylene dipeptide isoesters (ketomethylene dipeptide isoesters), and hydroxymethylene dipeptide isoesters (hydroxyethylene The synthetic route of intermediates of dipeptide isoesters) is innovative, and several of them are new compounds.

The present invention provides a new class of precursors of synthetic intermediates of AG7088.

The precursor of the new synthetic intermediate of AG7088 provided by the present invention is a class of oxazolidinone compounds with the following general structural formula:

In the formula, _R1 is a hydrogen or nitrogen protecting group, and the nitrogen protecting group is recommended as: tert-butoxycarbonyl, benzyloxycarbonyl, trifluoromethylcarbonyl, benzyl;

R ₂ is alkyl or benzyl, preferably C ₁ -C ₆ alkyl or benzyl, more preferably Et, Me, Bn;

R ₃ ＝C ₁ ～C ₆ alkyl group,

Preferably R ₃ =Me, ⁱ Pr

In the formula, R ₄ , R ₅ , R ₆ or R ₈ ＝C ₁ ～C ₆ alkyl, preferably Me, Et; R ₇ is N protecting group, recommended as tert-butoxycarbonyl, benzyloxycarbonyl, trifluoromethyl Carbonyl, benzyl;

Or R ₁ and R ₃ are connected to form (CH ₂ ) ₃ ;

The recommended oxazolidinone compounds of the present invention have the following general structural formula:

In the formula, R ₂ and R ₃ are as described above.

For example:

The synthetic route provided by the present invention takes N-protected aminoaldehyde (recommended as dibenzyl-protected aminoaldehyde) as the starting material, and generates product (1) through coupling with ethyl propiolate, and (1) undergoes high-pressure hydrogenation Generate gamma-hydroxy acid ethyl ester, and at the same time change the protecting group to a nucleophilic protecting group R ⁹ such as Boc or Cbz, etc., to obtain the product (2). The oxazolidinone compound (3) was obtained by activating the hydroxyl group of the product (2) and then undergoing an intramolecular SN ₂ reaction. After adding a protecting group to (3), the oxazolidinone ring is opened under basic conditions, and then the ring is closed under acidic conditions to obtain the synthetic intermediate γ-ring lactone of AG7088 compounds.

Wherein _R is a hydrogen or nitrogen protecting group, and the nitrogen protecting group is recommended as: tert-butoxycarbonyl, benzyloxycarbonyl, trifluoromethylcarbonyl, benzyl;

R ₂ is alkyl or benzyl, preferably C ₁ -C ₆ alkyl or benzyl, more preferably Et, Me, Bn;

R ₃ is as described above; R ⁹ is a nucleophilic nitrogen protecting group such as Boc or Cbz.

The recommended reaction conditions can be specifically described as follows: at -78°C-40°C (further recommended -78°C), in an organic solvent such as THF, 1 to 2 equivalents of LDA pull out 1 to 2 equivalents of propiolate Active hydrogen, after adding 1 equivalent of N-protected aminoaldehyde, react for about 0.1-1h to obtain the coupling product (1).

The configuration of the hydroxyl C in the two chiral Cs of the product (1) is R, and the configuration of the amino C is S.

Compound (1) was conventionally hydrogenated under palladium catalysis in the presence of Boc anhydride to obtain the product (2) in which the triple bond was hydrogenated while the N protecting group became Boc, and the recommended solvent was EtOAc.

Compound (2) is activated into a sulfonyl ester by sulfonyl chloride under normal conditions, and then heated in an aprotic solvent such as DMF and CH ₂ Cl ₂ to obtain the ring-closing product (3). The sulfonyl chloride used is p Toluenesulfonyl chloride (TsCl), methanesulfonyl chloride (MsCl), p-nitrobenzenesulfonyl chloride (NsCl), etc. Its structure is:

The chirality of the C originally connected to the hydroxyl group in the product (3) was reversed, and it became the S configuration.

An example of a reaction is as follows:

Compound (3) puts a protecting group on N under normal conditions, then opens the oxazolidinone ring in the presence of a base in ethanol, and then closes the lactone ring in the presence of a weak acid to obtain the synthetic intermediate γ ring of AG7088 Lactones (4). Its structure is:

The recommended organic solvent is DMF, CH ₂ Cl ₂ , THF or dioxane, etc., and the recommended aprotic solvent is DMF, CH ₂ Cl ₂ , THF, DMSO, PhH, etc.

The inventor has created a new synthetic route through rational design, which avoids the shortcomings of the literature route and obtains synthetic intermediates of AG7088 compounds with better yields. The synthetic route involved in the present invention is innovative, and several intermediates therein are new compounds. The process has a short synthetic route, high yield in each step, simple operation, simple post-treatment, readily available raw materials and no environmental pollution.

This route is suitable for the synthetic design of analogues of AG7088, such as the obtained lactone compound can obtain different ketomethylene dipeptide isoesters (ketomethylene dipeptideisoesters) or hydroxymethylene dipeptide isoesters through different alkylation (hydroxyethylene dipeptide isoesters), so as to obtain different analogues. A series of lactone compounds can be obtained by different starting amino acids. This provides the possibility to synthesize a series of analogues of AG7088. Thereby it is possible to screen anti-SARS virus compounds.

Detailed ways

Example 1: Coupling

Under the protection of argon at -78°C, 2.5ml (4mmol) of BuLi was slowly added dropwise to 0.67ml (4.8mmol) of diisopropylamine dissolved in 6ml of THF, and after stirring for half an hour, 0.46ml was slowly added dropwise. (4mmol) of ethyl propiolate, reacted for half an hour, slowly added 593mg (2.1mmol) of N-dibenzyl-xynaldehyde dissolved in 4ml TFH, and added saturated NH ₄ Cl aqueous solution to quench the reaction for half an hour. extinction reaction. The temperature of the reaction system was allowed to slowly rise to room temperature. Then add 10ml of 1M aqueous citric acid solution, then extract the product with 15ml of ether, then wash the _organic phase with saturated _NaHCO3 and NaCl aqueous solution successively, separate the organic layer, dry over anhydrous _Na2SO4 , concentrate, and obtain a yellow viscous product by column chromatography. Thick liquid 489mg, yield 73%.

At the same time, 94 mg of another isomer was obtained, and the ratio between the two was about 5.2:1.

The spectrogram data is as follows:

¹ H NMR δ0.96(d, 3H, J=6.3), 1.26(t, 3H, J=7.6), 1.31(d, 3H, J=6.6), 2.39-2.49(m, 1H), 2.62(dd , 1H, J ₁ =4.2, J ₂ =10.5), 3.72(d, 2H, J=13.5), 4.11-4.23(m, 4H), 4.30-4.35(m, 2H).

ESI-MS: [M+1]=380

Optical rotation: CHCl ₃ , c=1.232, [α]=-133.4

Example 2: Hydrogenation

Dissolve 437 mg of the product obtained in the first step in 5 ml of EtOAc, add 512 mg of (Boc) ₂ O 175 mg of Pd(OH) ₂ , hydrogenate at 40 ° C for one day under 50 atm pressure, evaporate the solvent under reduced pressure, and quickly Column chromatography yielded 315 mg of product, yield 90%.

The spectrogram data is as follows:

¹ H NMR: δ0.93(d, 3H, J=6.6), 1.26(d, 3H, J=6.6), 1.26(t, 3H, J=7.2), 1.45(s, 9H), 1.56-1.67( m, 1H), 1.77-1.93 (m, 2H), 2.50-2.56 (ddd, J ₁ =2, 7, Jx = 6.9, J3 = 9.0), 2.92 (d, 1H, J = 6.3) 3.53-3.46 ( m, 1H), 3.61-3.71 (m, 1H), 4.14 (q, J=7.2), 4.45, (d, J=9.3).

ESI-Ms: [M+1]=304.2

Optical rotation: CHCl ₃ , c=1.070, [α]=-9.3

Example 3: Hydroxyl Flip Ring Closure

Dissolve 91 mg of the product from the previous step in 2.5 ml of CH ₂ Cl ₂ , then add 208 μl of NEt ₃ and 58 μl of MsCl to it in turn under the protection of argon and cooling in an ice-salt bath, react for half an hour, and add 5 ml of CH _2Cl2 diluted, washed successively with 1M HCl, saturated _NaHCO3 and NaCl aqueous solution, _the organic layer was separated, dried over anhydrous _NaSO4 , concentrated. The obtained product was dissolved in 4 ml of DMF and heated to 65° C. for one day without isolation. DMF was distilled off under reduced pressure and flash column chromatography was used to obtain 59 mg of the product, with a two-step yield of 86%.

The spectrogram data is as follows:

¹ H NMR δ0.93(d, 3H, J=5.4), 0.95(d, 3H, J=5.4), 1.27(t, 3H, J=7.2), 1.67-1.79(m, 1H), 1.92-2.04 (m, 2H), 2.53(t, 2H, J=4.2), 3.19(t, 1H, J=5.1), 4.15(q, 2H, J=7.2), 4.32-4.36(m, 1H), 6.80( s, 1H).

ESI-Ms: [M+1]=230.1

Optical rotation: CHCl ₃ , c=1.341, [α]=-59.8

Example 4: Upper Protection

Dissolve 1.174g of the product obtained in the previous step in 20ml of THF, add 1.68g of (Boc) ₂ , 0.97ml of NEt ₃ , and 125mg of DMAP, and react at room temperature for 4 hours. Washed successively with 1M HCl, saturated NaHCO ₃ and aqueous NaCl, the organic layer was separated, dried over anhydrous Na ₂ SO ₄ , and concentrated. Flash column chromatography gave 1.512 g of product, 89% yield.

The spectrogram data is as follows:

¹ H NMR δ0.90(d, 3H, J=7.2), 0.94(d, 3H, J=6.9), 1.27(t, 3H, J=7.5), 1.55(s, 9H), 1.85-2.04(m , 2H), 2.50 (t, 2H, J=7.8), 3.81 (dd, 2H, J ₁ =2.7, J ₂ =3.9), 4.16 (q, 2H, J=7.5), 4.28-4.34 (m, 1H ).

ESI-Ms: [M+ _NH4 ⁺ ] = 347.2

Optical rotation: CHCl ₃ , c=1.493, [α]=-25.5

Example 5: Opening and closing the lactone ring

Dissolve 629mg of the product from the previous step in 40ml of EtOH, add 1.77g of Cs ₂ CO ₃ , react at room temperature for 12 hours, stop the reaction, adjust the pH value of the solution to about 2, evaporate most of the EtOH under reduced pressure, and add 20ml 1M HCl and 40ml of EtOAc were extracted and separated, dried over anhydrous NaSO ₄ and concentrated. The product was dissolved in 30 ml of CH ₂ Cl ₂ , 109 mg of pTSA was added, and reacted at room temperature for 3 hours. Washed successively with 1M HCl, saturated NaHCO ₃ and aqueous NaCl, the organic layer was separated, dried over anhydrous NaSO ₄ and concentrated. Flash column chromatography gave 364 mg of product, 74% yield over two steps.

The spectrogram data is as follows:

¹ H NMR δ0.98(d, 3H, J=6.6), 1.02(d, 3H, J=6.6), 1.45(s, 9H), 1.79-1.90(m, 1H), 2.04-2.29(m, 2H ), 2.53 (dd, 2H, _J1 = 5.7, _J2 = 9.6), 3.45 (t, 1H, J = 9.6), 4.56 (d, 1H, J = 9.9), 4.74 (t, 1H, J = 6.9 ).

ESI-Ms: [M+ _NH4 ⁺ ] = 275.1

Optical rotation: CHCl ₃ , c=1.098, [α]=-48.3

Claims (10)

1. the precursor of the synthetic intermediate of an AG7088 compounds, its feature has following general structure:

R in the formula ₁Protecting group or hydrogen for N;

R ₂Be alkyl or benzyl, described alkyl is C ₁～C ₆Alkyl;

R ₃=C ₁～C ₆Alkyl,

R in the formula ₄, R ₅, R ₆Or R ₈=C ₁～C ₆Alkyl,

Perhaps R ₁, R ₃Be connected to (CH ₂) ₃

R ₇Be the N protecting group.

2. precursor as claimed in claim 1 is characterized in that described R ₃For Or

3. precursor as claimed in claim 1, its feature has following structural formula:

R in the formula ₂, R ₃According to claim 1.

4. precursor as claimed in claim 1 is characterized in that described N protecting group is: tertbutyloxycarbonyl, carbobenzoxy-(Cbz), trifluoromethyl carbonyl or benzyl.

5. the synthetic method of precursor as claimed in claim 3 is characterized in that the hydroxyl of (2) is activated, heats through intramolecularly SN in non-protonic solvent then ₂Reaction has just obtained precursor as claimed in claim 3 (3), and its general structure is:

R in the formula ₂Be alkyl or benzyl, described alkyl is C ₁～C ₆Alkyl;

R ₃=C ₁～C ₆Alkyl,

R in the formula ₄, R ₅, R ₆Or R ₈=C ₁～C ₆Alkyl,

R ₉, R ₇Be the N protecting group.

6. the synthetic method of precursor as claimed in claim 5 is characterized in that the hydroxyl of (2) activates into sulfonyl ester with SULPHURYL CHLORIDE, and this moment, one of the configuration of two chirality C was S, and another is R; Obtain hydroxyl activatory product and in non-protonic solvent, obtained precursor as claimed in claim 3 (3) in reacting by heating 1-12 hour.

7. the synthetic method of precursor as claimed in claim 5; the preparation method who it is characterized in that compound (2) obtains compound (1) with the amino-aldehyde of N protection and propiolate coupling just to obtain compound (2) through high-pressure hydrogenation, and the general structure of described amino-aldehyde, compound (1) and (2) is as follows:

R ₁Be protecting group or the hydrogen of N, R ₂, R ₃, R ₉As described in claim 5.

8. as claim 5 or 7 described synthetic methods, it is characterized in that described nitrogen-protecting group is: tertbutyloxycarbonyl, carbobenzoxy-(Cbz), trifluoromethyl carbonyl or benzyl.

9. synthetic method as claimed in claim 7; the preparation method who it is characterized in that compound (2) be with 2 equivalent diisopropylamine lithiums under-78 ℃; pull out the reactive hydrogen of 2 equivalent propiolates in the tetrahydrofuran (THF); amino-aldehyde reaction with 1 equivalent N protection just obtained coupled product (1) in 0.5-4 hour then; compound (1) high-pressure hydrogenation under the catalysis of Pa is changed protecting group simultaneously and has just been obtained compound (2).

10. synthetic method as claimed in claim 5 is characterized in that described non-protonic solvent is N, dinethylformamide, CH ₂Cl ₂, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or benzene.