CN1309712C - Precursor of key intermediate of AG 7088 class compound and its sythetic process - Google Patents
Precursor of key intermediate of AG 7088 class compound and its sythetic process Download PDFInfo
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- CN1309712C CN1309712C CNB2004100174349A CN200410017434A CN1309712C CN 1309712 C CN1309712 C CN 1309712C CN B2004100174349 A CNB2004100174349 A CN B2004100174349A CN 200410017434 A CN200410017434 A CN 200410017434A CN 1309712 C CN1309712 C CN 1309712C
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- protecting group
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Abstract
The present invention relates to a synthetic method of a precursor of a synthetic intermediate body of an AG 7088 compound and a novel compound. The present invention has the following structure general formula. The present invention provides the following synthetic route: aminoaldehyde protected by N and propargylic acid ester carry out coupling operation; an obtained product is hydrogenized, and simultaneously, a protecting group of N is converted into a Boc protecting group or other protecting groups which have nucleophilicity; hydroxy of a product is activated; through intramolecular SN2 reaction, an oxazolon ane compound is generated; simultaneously, conformation of the hydroxy is turned, a protecting group is supplied for N, and an oxazolon ane ring is opened; under the acid condition, a five-member lactone ring is closed, and a synthetic intermediate body of an AG 7088 compound is obtained. The present invention provides the novel synthetic method of the intermediate body of the AG 7088 compound. The synthesis uses natural amino acid as raw material, the synthetic route is short, the yield is high, and the stereoselectivity is good.
Description
Technical field
The present invention relates to the precursor and the synthetic method thereof of the key intermediate of AG7088 compounds.
Technical background
The AG7088 compounds is the inhibitor of rhinovirus albumen (rhinovirus protease), is used for the treatment of the medicine of general flu clinically.And may have inhibition effectiveness to SARS virus.Contain two peptide bonds in the AG7088 compounds molecule, combine with the mode of target protein with hydrogen bond.And its right side be Michael addition acceptor with target protein in the sulfydryl of halfcystine combine in the mode of covalent linkage.And the amino acid structure of its intermediary is the different ester of ketone methylene radical dipeptides (ketomethylene dipeptide isoesters).
Several main synthetic routes of its key intermediate 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
Sum up above document synthetic route, all selective not high, the defective that productive rate is low excessively.
Summary of the invention
The problem to be solved in the present invention provides a kind of precursor synthesis method of synthetic intermediate of new AG7088 compounds;
Another problem that the present invention will solve provides the precursor of the synthetic intermediate of the new AG7088 of a class.
The invention provides the precursor synthesis method of the intermediate of the new AG7088 of a class; A kind of new different ester of synthetic ketone methylene radical dipeptides (ketomethylene dipeptide isoesters) is provided, and the synthetic route of the intermediate of the different ester of hydroxyl methylene radical dipeptides (hydroxyethylene dipeptide isoesters), have novelty, wherein several compounds are new compound.
The invention provides the precursor of the synthetic intermediate of the new AG7088 of a class.
The precursor of the synthetic intermediate of new AG7088 provided by the invention is a class oxazolidone compounds, has following general structure:
R in the formula
1Be hydrogen or nitrogen-protecting group, described nitrogen-protecting group is recommended as: tertbutyloxycarbonyl, carbobenzoxy-(Cbz), trifluoromethyl carbonyl, benzyl;
R
2Be alkyl or benzyl, preferred C
1～C
6Alkyl or benzyl, Et more preferably, Me, Bn;
R
3=C
1～C
6Alkyl,
Preferred R
3=Me,
iPr
R in the formula
4, R
5, R
6Or R
8=C
1～C
6Alkyl, preferred Me, Et; R
7Be the protecting group of N, be recommended as tertbutyloxycarbonyl, carbobenzoxy-(Cbz), trifluoromethyl carbonyl, benzyl;
Perhaps R
1, R
3Be connected to (CH
2)
3
The oxazolidone compounds of recommending of the present invention has following general structure:
R in the formula
2, R
3As previously mentioned.
For example:
Synthetic route provided by the invention is that the amino-aldehyde of protecting with N (being recommended as the amino-aldehyde of dibenzyl protection) is a starting raw material; through generating product (1) with the ethyl propiolate coupling; (1) generates γ-alcohol acid ethyl ester through high-pressure hydrogenation, simultaneously protecting group is changed into protecting group R with nucleophilicity
9As Boc or Cbz etc., obtain product (2).Product (2) activates hydroxyl then through intramolecular SN
2Reaction has obtained oxazolidone compound (3).To after (3) last protecting group the oxazolidone ring be opened under alkaline condition, just obtained the synthetic intermediate γ cyclic lactone of AG7088 compounds then at acidic conditions ShiShimonoseki ring.
R wherein
1Be hydrogen or nitrogen-protecting group, described nitrogen-protecting group is recommended as: tertbutyloxycarbonyl, carbobenzoxy-(Cbz), trifluoromethyl carbonyl, benzyl;
R
2Be alkyl or benzyl, preferred C
1～C
6Alkyl or benzyl, Et more preferably, Me, Bn;
R
3As previously mentioned; R
9Nitrogen-protecting group such as Boc or Cbz etc. for nucleophilicity.
The reaction conditions of recommending can specifically describe as follows: (further recommend-78 ℃) under-78 ℃-40 ℃; in organic solvent such as THF; 1～2 normal LDA pulls out the reactive hydrogen on 1～2 normal propiolate; amino-aldehyde adding 1 normal N protection reacts about 0.1～1h and just obtains coupled product (1).
Among two chirality C of product (1) hydroxyl C be configured as R, and amino C be configured as S.
Compound (1) has under the condition that the Boc acid anhydrides exists through conventional hydrogenation to be hydrogenated the product (2) that the protecting group of N simultaneously becomes Boc with regard to having obtained three key under palladium catalysis, and solvent is recommended as EtOAc.
Compound (2) hydroxyl under normal condition activates into sulfonyl ester with SULPHURYL CHLORIDE, then in non-protonic solvent as DMF, CH
2Cl
2Middle heating has just obtained closing ring product (3), and used SULPHURYL CHLORIDE is Tosyl chloride (TsCl), methylsulfonyl chloride (MsCl), p-nitrophenyl SULPHURYL CHLORIDE (NsCl) etc.Its structure is:
Originally the chirality upset of the C that linked to each other with hydroxyl in the product (3) becomes the S configuration.
Be exemplified below with reaction formula:
Compound (3) under normal condition on the N protecting group, in ethanol, have again and open the oxazolidone ring in the presence of the alkali, in the presence of weak acid, shut the synthetic intermediate γ cyclic lactone (4) that lactonic ring has just obtained AG7088 then.Its structure is:
It is DMF that described organic solvent is recommended, CH
2Cl
2, THF or dioxane etc., described non-protonic solvent is recommended as DMF, CH
2Cl
2, THF, DMSO, PhH etc.
The contriver has created a new synthetic route by reasonably design, has avoided the shortcoming of document route and the synthetic intermediate of the AG7088 compounds that obtains with productive rate preferably.Synthetic route involved in the present invention has novelty, and several intermediates wherein are new compound.The synthetic route of this technology is short, the yield height in each step, and easy and simple to handle, aftertreatment is simple, and employed raw material is easy to get, and does not cause environmental pollution.
This route is applicable to the synthetic design of the analogue of AG7088, can obtain different different esters of ketone methylene radical dipeptides (ketomethylene dipeptideisoesters) or the different ester of hydroxyl methylene radical dipeptides (hydroxyethylene dipeptide isoesters) as resulting lactone compound through different alkylations, thereby obtain different analogues.Initial amino acid whose difference can obtain a series of lactone compound.This just provides possibility for a series of analogue of synthetic AG7088.Thereby for screening anti-SARS virus compound provides possibility.
Embodiment
Embodiment 1: coupling
Under-78 ℃ of argon shields with 2.5ml (4mmol;) BuLi slowly be added drop-wise in 0.67ml (4.8mmol) Diisopropylamine among the THF that is dissolved in 6ml; stirring slowly drips the ethyl propiolate of 0.46ml (4mmol) after half an hour; reaction will be dissolved in the N-dibenzyl a word used in person's names ammonium aldehyde of 593mg among the 4ml TFH (2.1mmol) half an hour adds at leisure, and reaction adds saturated NH after half an hour
4Cl aqueous solution quencher reaction.Allow the temperature of reaction system slowly rise to room temperature.The aqueous citric acid solution that adds 10ml 1M is then used 15ml extracted with diethyl ether product again, uses saturated NaHCO more successively
3With NaCl solution washing organic phase, separate organic layer, anhydrous Na
2SO
4Drying concentrates, and column chromatography obtains yellow thick liquid 489mg, productive rate 73%.
Obtain another isomer 94mg simultaneously, about 5.2: 1 of both ratios.
Spectral data is as follows:
1H?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
Optically-active: CHCl
3, c=1.232, [α]=-133.4
Embodiment 2: hydrogenation
The resulting product of the first step of 437mg is dissolved among the 5ml EtOAc, adds (Boc) of 512mg again
2The Pd of O 175mg (OH)
2, at 40 ℃, hydrogenation is one day under the 50atm pressure, and pressure reducing and steaming solvent, rapid column chromatography just obtain the product of 315mg, productive rate 90%.
Spectral data is as follows:
1H?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
Optically-active: CHCl
3, c=1.070, [α]=-9.3
Embodiment 3: ring is closed in the hydroxyl upset
The previous step product of 91mg is dissolved in the CH of 2.5ml
2Cl
2In, cryosel is bathed under the cooling successively NEt with 208 μ l under argon shield then
3, the MsCl of 58 μ l joins wherein, reacts half an hour, adds the CH of 5ml
2Cl
2Dilute, use the HCl of 1M successively, saturated NaHCO
3With the NaCl solution washing, separate organic layer, anhydrous Na SO
4Drying concentrates.The product that obtains is without separation, is dissolved among the DMF of 4ml and is heated to 65 ℃ of reactions one day.Pressure reducing and steaming DMF rapid column chromatography obtains the 59mg product, two step productive rates 86%.
Spectral data is as follows:
1H?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
Optically-active: CHCl
3, c=1.341, [α]=-59.8
Embodiment 4: go up protection
1.174g is got the previous step product be dissolved in 20ml and get among the THF, add (Boc) of 1.68g
2, the NEt of 0.97ml
3, the DMAP of 125mg, room temperature reaction 4 hours.Use the HCl of 1M successively, saturated NaHCO
3With the NaCl solution washing, separate organic layer, anhydrous Na
2SO
4Drying concentrates.Rapid column chromatography obtains the product of 1.512g, productive rate 89%.
Spectral data is as follows:
1H?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+NH
4 +]＝347.2
Optically-active: CHCl
3, c=1.493, [α]=-25.5
Embodiment 5: lactonic ring is closed in open loop
The previous step product of 629mg is dissolved in the Cs that adds 1.77g among the EtOH of 40ml
2CO
3, room temperature reaction 12 hours, stopped reaction transfer to the pH value of solution and are about 2, and the most EtOH of pressure reducing and steaming adds the 1M HCl of 20ml and the EtOAc extracting and separating of 40ml, anhydrous Na SO
4Drying concentrates.Product is dissolved in the CH of 30ml
2Cl
2In, the pTSA of adding 109mg, room temperature reaction 3 hours.Use the HCl of 1M successively, saturated NaHCO
3With the NaCl solution washing, separate organic layer, anhydrous Na SO
4Drying concentrates.Rapid column chromatography obtains the 364mg product, two step productive rates 74%.
Spectral data is as follows:
1H?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，J
1＝5.7，J
2＝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+NH
4 +]＝275.1
Optically-active: 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.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100174349A CN1309712C (en) | 2004-04-02 | 2004-04-02 | Precursor of key intermediate of AG 7088 class compound and its sythetic process |
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|---|---|---|---|
| CNB2004100174349A CN1309712C (en) | 2004-04-02 | 2004-04-02 | Precursor of key intermediate of AG 7088 class compound and its sythetic process |
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|---|---|
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| CN1309712C true CN1309712C (en) | 2007-04-11 |
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|---|---|---|---|
| CNB2004100174349A Expired - Fee Related CN1309712C (en) | 2004-04-02 | 2004-04-02 | Precursor of key intermediate of AG 7088 class compound and its sythetic process |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001014329A1 (en) * | 1999-08-24 | 2001-03-01 | Agouron Pharmaceuticals, Inc. | Synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates |
-
2004
- 2004-04-02 CN CNB2004100174349A patent/CN1309712C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001014329A1 (en) * | 1999-08-24 | 2001-03-01 | Agouron Pharmaceuticals, Inc. | Synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates |
Non-Patent Citations (3)
| Title |
|---|
| A Formal Stereoselective Synthesis of a HydroxyethyleneDipeptide Isostere Jean.Francois etc.,Tetrahedron Lett.,Vol.36 No.16 1995 * |
| Chirosprcific Syntheses of Precursors of CyclopentaneandCyclopentene Carbocyclic Nucleosides by[3+3]-Coupling andTransannular Alkylation Jeffrey A. Campbell etc.,J.Org.Chem.,Vol.60 1995 * |
| One-Step Highly Diastereoselective Synthesis of-Aminoalkyl-Sunstituted-Butyrolactones by an AsymmetricSamarium-Mediated Ketyl-Alkene Coupling Reaction Shin.ichi Fukuzawa etc.,J.Org.Chem.,Vol.68 2003 * |
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