CN105001301A - 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine synthesis method - Google Patents
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Abstract
The present invention provides a 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine synthesis method, which comprises: adopting a compound 6 to carry out a hydrogenation reduction reaction to prepare the 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine. According to the present invention, the chemical synthesis method can substitute the microorganism fermentation method, and the prepared 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine has characteristics of high yield, high purity and industrial mass production, can be used for preparation of gram-positive bacteria inhibition drugs, especially drugs for inhibiting Micrococcus luteus or Bacillus subtilis, and further has an aminopeptidase inhibition effect so as to be used as the aminopeptidase inhibitor. In addition, the pharmaceutical preparation containing an effective amount of the compound 7 can be used for tumor treatment, assisted tumor treatment or immunity enhancement.
Description
Technical field
The present invention relates to the preparation method of compound, particularly relate to a kind of preparation method of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine.
Background technology
Shanghai is come prebiotic thing drug research centered finite leading company (hereinafter referred to as carrying out beneficial bio-pharmaceutical) and carry out microorganism separation from the pedotheque gathered from physical environment, obtain a kind of novel streptomyces parvus (Streptomyces parvus) producing daptomycin, on July 20th, 2010 in the formal preservation in China Committee for Culture Collection of Microorganisms's common micro-organisms center, preserving number is CGMCC No.4027.At that time daptomycin compounds was only limitted to the secondary metabolite research of this streptomyces parvus CGMCC No.4027, carry out beneficial bio-pharmaceutical through further investigation, a kind of new compound 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine (3-amino-2-hydroxy-4-pheny butanoyl-valyl-isoleucine) (Chinese Patent Application No. 201110076554.6 is isolated secondarily in level meta-bolites, 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine and its preparation method and application), it has following structure:
This compound for the preparation of the medicine suppressing gram-positive microorganism, can especially suppress the medicine of micrococcus luteus or eel grass genus bacillus after deliberation.
Carry out beneficial bio-pharmaceutical to find through research extensive and deep further, in the secondary metabolite of little Streptomycin sulphate CGMCC No.4027, isolated new compound 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine has the effect (Chinese Patent Application No. 201110076555.0 suppressing aminopeptidase, the application of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine), can be used as amastatin.The pharmaceutical preparation of this compound containing significant quantity can be used for treatment tumour, adjuvant therapy of tumors or strengthens immunity.
But, the compound 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine limited amount that microbial fermentation processes obtains, be difficult to the demand meeting patient medication, therefore, adopting new chemical synthesis process to replace microbial fermentation processes is the very effective novel method of one, can obtain higher output to meet the demand of patient medication.
Summary of the invention
The object of the present invention is to provide the chemical synthesis process of compound 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine, this chemical synthesis process can substitute microbial fermentation processes, the 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine yield obtained is high, purity is high, and can industrialized mass production, the demand of patient can be met.
First object of the present invention is to provide the first chemical synthesis process of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine.
Another object of the present invention is to provide the second chemical synthesis process of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine.
The stereostructural formula of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine of the present invention is as shown in compound 7:
To achieve these goals, the present invention adopts following technical scheme:
A kind of synthetic method of 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine, comprise the steps, adopt compound 6 through hydro-reduction reaction obtained described 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine, i.e. compound 7, its chemical equation is:
Wherein R is Cbz-or H-.
Preferably, the hydrogenation catalyst being obtained described compound 7 by described compound 6 is Pd/C, and hydroborating reagent is H
2.
Preferably, the solvent obtaining described compound 7 by described compound 6 is methyl alcohol.
Further, when R is Cbz-, the synthesis of described 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine is as shown in synthetic route 1:
Further, the preparation of the compound 6 in said synthesis route 1: described compound 6 reacts through compound 4 and compound 5 and is prepared from the first solvent:
Preferably, described first reaction solvent is THF.
Preferably, when described compound 4 and compound 5 react, also add HOBt(1-hydroxybenzotriazole) and EDC(1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride), and the pH value of reaction solution is adjusted to 8-9.
Further, the preparation of the compound 4 in above-mentioned synthetic route 1: described compound 4 passes into dry hcl reaction through compound 3 and is prepared from the second solvent:
Preferably, described second reaction solvent is methylene dichloride.
Further, the preparation of the compound 3 in above-mentioned synthetic route 1: described compound 3 reacts through compound 1 and compound 2 and is prepared from the first solvent:
Preferably, described first reaction solvent is THF.
Preferably, when described compound 1 and compound 2 react, also add HOBt(1-hydroxybenzotriazole) and EDC(1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride), and the pH value of reaction solution is adjusted to 8-9.
Further, when R is H-, the preparation of described compound 6: described compound 6 passes into dry hcl reaction through compound 5 ' and is prepared from the 3rd solvent:
Preferably, described 3rd reaction solvent is ethyl acetate.
Further, the preparation of described compound 5 ': described compound 5 ' passes into dry hcl reaction through compound 4 and compound 2 ' and is prepared from the second solvent:
Preferably, described second reaction solvent is methylene dichloride.
Further, the preparation of described compound 4: described compound 4 passes into dry hcl reaction through compound 3 and is prepared from the second solvent:
Preferably, described second reaction solvent is methylene dichloride.
Further, the preparation of described compound 3: described compound 3 reacts through compound 1 and compound 2 and is prepared from the first solvent:
Preferably, described first reaction solvent is THF.
Further, the preparation of described compound 2 ': described compound 2 ' reacts through compound 1 ' and BOC acid anhydrides and is prepared from the 4th solvent:
Preferably, described 4th reaction solvent is the mixed solvent of water and tetrahydrofuran (THF).
The new compound that compound 7 obtained by chemical synthesis process of the present invention obtains with the microbial fermentation processes in Chinese Patent Application No. 201110076554.6 and Chinese Patent Application No. 201110076555.0 is after testing same compound, it is all 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine, and this 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine for the preparation of the medicine suppressing gram-positive microorganism, can especially suppress the medicine of micrococcus luteus or eel grass genus bacillus; Also there is the effect suppressing aminopeptidase, can be used as amastatin.The pharmaceutical preparation of this compound 7 containing significant quantity can be used for treatment tumour, adjuvant therapy of tumors or strengthens immunity.
The present invention can prepare finalization compound 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine through above-mentioned two chemical synthesis routes, these two kinds of chemical synthesis process can both substitute above-mentioned microbial fermentation processes of the prior art, the 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine yield obtained is high, purity is high, and can industrialized mass production, medication demand can be met.
Accompanying drawing explanation
Fig. 1 is the ESI-MS mass spectrum of compound 3 in Article 1 synthetic route.
Fig. 2 is the ESI-MS mass spectrum of compound 4 in Article 1 synthetic route.
Fig. 3 is the ESI-MS mass spectrum of compound 6 in Article 1 synthetic route.
Fig. 4 is the ESI-MS mass spectrum of compound 7 in Article 1 synthetic route.
Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of compound 7 in Article 1 synthetic route.
Fig. 6 is the automatic scale color atlas of compound 7 in Article 1 synthetic route.
Fig. 7 is the LC-MS spectrogram of compound 2 ' in Article 2 synthetic route.
Fig. 8 is the LC-MS spectrogram of compound 7 in Article 2 synthetic route.
Fig. 9 is the hydrogen nuclear magnetic resonance spectrogram of compound 7 in Article 2 synthetic route.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples only for illustration of the present invention but not for limiting protection scope of the present invention.
Embodiment 1
The first synthetic method of compound 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine (i.e. compound 7):
Wherein R is Cbz-.
1, the preparation of compound 3
3.77g (0.0173mol) compound 2 is in 250ml eggplant-shape bottle, add 200ml THF to dissolve, 2.34g (0.0173mol) HOBt(1-hydroxybenzotriazole is added under ice-water bath) and 3.64g (0.019mol) EDC(1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride), NMM(N-methyl agate beautiful jade) adjust pH is to 8-9, add 6.2g (0.0158mol) compound 1, adjust pH is to 8-9, r.t. stirring reaction again.4h point plate reacts completely.By the saturated NaHCO of reaction solution impouring 300ml
3in, EA250ml*3 extracts, and merges EA phase and uses saturated NaHCO successively
3200ml*2,5%KHSO4200ml*3, saturated NaCl200ml*1 washes, and anhydrous sodium sulfate drying is spin-dried for, and crosses post (EA:PE=1:20-1:6) and obtains pale yellow oil 4.4g.ESI-MS:443[M＋23]
+。The ESI-MS mass spectrum of compound 3 as shown in Figure 1.
2, the preparation of compound 4
4.4g compound 3 is in 250ml there-necked flask, and 100ml DCM dissolves, and ice-water bath stirs cooling, and pass into dry hydrogen chloride gas, namely 1h reacts completely.Reaction solution is proceeded in 250ml eggplant-shape bottle and be spin-dried for obtain white solid 2.9g.ESI-MS:321[M＋1]
+。The ESI-MS mass spectrum of compound 4 as shown in Figure 2.
3, the preparation of compound 6
3.29g (0.01mol) compound 5 and 1.49g (0.011mol) HOBt are in 250ml eggplant-shape bottle, add 150ml THF to dissolve, add 2.3g (0.012mol) EDC, NMM adjust pH is to 8-9, add 3.57g (0.01mol) compound 4, adjust pH is to 8-9, r.t. stirring reaction again.4h point plate reacts completely.By the saturated NaHCO of reaction solution impouring 300ml
3in, EA300ml*3 extracts, and merges EA phase and uses saturated NaHCO successively
3200ml*2,5%KHSO4200ml*3, saturated NaCl200ml*1 washes, anhydrous sodium sulfate drying, is spin-dried for obtain white solid 5g.Ether 100ml*1 grinds and washes, and obtains white solid 4.4g.ESI-MS:654[M＋23]
+。The ESI-MS mass spectrum of compound 6 as shown in Figure 3.
4, the preparation of compound 7
2.0g (0.003mol) compound 6, in 250ml eggplant-shape bottle, adds 85ml MeOH and dissolves, add 0.6g Pd/C afterwards, stirs lower water pump and vacuumizes, more logical H
2, repeatedly several times except net air, logical H afterwards
2stirring at room temperature is reacted.React completely to 55h point plate.Suction filtration removes Pd/C twice, and filtrate is revolved to steam and stopped in purees.Ether 30ml*2 grinds and washes to obtain white solid powder 0.96g.ESI-MS:408[M＋1]
+。
1H NMR(DMSO-d
6,D2O-d2,300MHz)δ=7.32-7.19(m,5H),4.16(d,J=6.6Hz,1H),4.00(d,J=5.4Hz,1H),3.88(d,J=3.0Hz,1H),3.35-3.29(m,1H),2.63-2.87(m,2H),2.02-2.09(m,1H),1.72-1.75(m,1H),1.37-1.42(m,1H),1.08-1.15(m,1H),0.78-0.88(m,12H)。As shown in Figure 4, as shown in Figure 5, its automatic scale color atlas as shown in Figure 6 for its hydrogen nuclear magnetic resonance spectrogram for the ESI-MS mass spectrum of compound 7.
Embodiment 2
The second synthetic method of compound 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine (i.e. compound 7):
Wherein R is H-.
1, the synthesis of compound 2 '
Add compound 1 ' (10g, 51.2mmol) and BOC acid anhydrides (12.3g, 56.3mmol) at 250mL there-necked flask, add 100mL water and 50ml tetrahydrofuran (THF).At 0 DEG C, slowly drip the NaOH aqueous solution (128ml, 1mol/L), rise to room temperature, stirring is spent the night.With citric acid regulating solution pH to 1, add ethyl acetate and water, separatory obtains organic phase, washing, and saturated common salt is washed, and adds anhydrous sodium sulphate, and for a moment, suction filtration is spin-dried for obtain compound 2 ' (15g, yield 99.0%) to standing and drying.LC-MS：296[M+1]
+。The LC-MS mass spectrum of compound 2 ' as shown in Figure 7.
2, the synthesis of compound 3
Add compound 1(30g, 76.2mmol at 500mL there-necked flask), compound 2(16.6g, 76.2mmol) and TBTU(24.5g, 76.2mmol), add 200ml methylene dichloride dissolve.By DIEA(17.5ml, 190.5mmol at 0 DEG C) be slowly added dropwise to reaction solution, rise to room temperature, stir 2 hours.Add methylene dichloride and moisture liquid, 1% phosphoric acid solution washing, 2% solution of potassium carbonate washing, washing, saturated common salt is washed, and adds anhydrous sodium sulphate, and for a moment, suction filtration is spin-dried for obtain crude product to standing and drying.Rapid column chromatography is separated to obtain sterling compound 3(27.7g, yield 86.5%).Compound 3 after testing, its ESI-MS:443 [M+1]
+.
3, the synthesis of compound 4
Compound 3(27.7g, 65.9mmol is added in 1000ml there-necked flask), add 400ml acetic acid ethyl dissolution.At-20 DEG C, pass into dry hydrogen chloride gas 1h, be spin-dried for obtain compound 4(22.5g, yield 95.6%).Compound 4 after testing, its ESI-MS:321 [M+1]
+.
4, the synthesis of compound 5 '
Compound 2 ' (15g, 50.1mmol), compound 4(18.1g, 50.1mmol is added at 500mL there-necked flask) and TBTU(16.1g, 50.1mmol), add 200ml methylene dichloride and dissolve.By DIEA(11.5ml, 125.3mmol at 0 DEG C) be slowly added dropwise to reaction solution, rise to room temperature, stir 2 hours.Add methylene dichloride and moisture liquid, 1% phosphoric acid solution washing, 2% solution of potassium carbonate washing, washing, saturated common salt is washed, and adds anhydrous sodium sulphate, and for a moment, suction filtration is spin-dried for obtain crude product to standing and drying.Rapid column chromatography is separated to obtain sterling compound 5 ' (26.2g, yield 87.4%).Compound 5 ' after testing, its ESI-MS:599 [M+1]
+.
5, the synthesis of compound 6
In 1000ml there-necked flask, add compound 5 ' (26.2g, 43.8mmol), add 300ml acetic acid ethyl dissolution.At-20 DEG C, pass into dry hydrogen chloride gas 1h, add ammoniacal liquor after reacting completely and regulate pH=8, washing, saturated common salt is washed, and adds anhydrous sodium sulfate drying, and leave standstill a moment, suction filtration is spin-dried for obtain compound 6(21.1g, yield 96.7%).Compound 6 after testing, its ESI-MS:499 [M+1]
+.
6, the synthesis of compound 7
Compound 6(21.1g, 42.4mmol is added in 500ml there-necked flask) and 10% palladium carbon (2g), add 200ml dissolve with methanol.Atmospheric pressure at room hydrogenation, stirring is spent the night, and suction filtration is spin-dried for obtain compound 7(16.9g, yield 97.8%).ESI-MS：408[M+1]
+。
1H NMR(DMSO-d
6,D2O-d2,300MHz)δ=7.32-7.19(m,5H),4.16(d,J=6.6Hz,1H),4.00(d,J=5.4Hz,1H),3.88(d,J=3.0Hz,1H),3.35-3.29(m,1H),2.63-2.87(m,2H),2.02-2.09(m,1H),1.72-1.75(m,1H),1.37-1.42(m,1H),1.08-1.15(m,1H),0.78-0.88(m,12H)。As shown in Figure 8, its hydrogen nuclear magnetic resonance spectrogram as shown in Figure 9 for the LC-MS mass spectrum of compound 7.
The present invention can prepare finalization compound 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine through above-mentioned two chemical synthesis routes, these two kinds of chemical synthesis process can both substitute above-mentioned microbial fermentation processes of the prior art, the 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine yield obtained is high, purity is high, and can industrialized mass production.
The new compound that compound 7 obtained by above-mentioned two kinds of chemical synthesis process of the present invention obtains with the microbial fermentation processes in Chinese Patent Application No. 201110076554.6 and Chinese Patent Application No. 201110076555.0 is after testing same compound, it is all 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine, and this 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine for the preparation of the medicine suppressing gram-positive microorganism, can especially suppress the medicine of micrococcus luteus or eel grass genus bacillus; Also there is the effect suppressing aminopeptidase, can be used as amastatin.The pharmaceutical preparation of this compound 7 containing significant quantity can be used for treatment tumour, adjuvant therapy of tumors or strengthens immunity.
Above-described embodiment is illustrative principle of the present invention and effect thereof only, but not for limiting the present invention.Any person skilled in the art scholar all without prejudice under spirit of the present invention and category, can modify above-described embodiment or changes.Therefore, such as have in art usually know the knowledgeable do not depart from complete under disclosed spirit and technological thought all equivalence modify or change, must be contained by claim of the present invention.
Claims (10)
1. the synthetic method of a 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine, comprise the steps, adopt compound 6 through hydro-reduction reaction obtained described 3-amino-2-hydroxy-4-phenylbutanoyl-valyl-isoleucine, i.e. compound 7, its chemical equation is:
Wherein R is Cbz-or H-.
2. synthetic method as claimed in claim 1, is characterized in that, the hydrogenation catalyst being obtained described compound 7 by described compound 6 is Pd/C, and hydroborating reagent is H2.
3. synthetic method as claimed in claim 1, is characterized in that, described synthetic method also comprises the preparation of compound 6, and when R is Cbz-, described compound 6 reacts through compound 4 and compound 5 and is prepared from the first solvent:
4. synthetic method as claimed in claim 1, is characterized in that, described synthetic method also comprises the preparation of compound 6, and when R is H-, described compound 6 passes into dry hcl reaction through compound 5 ' and is prepared from the 3rd solvent:
5. synthetic method as claimed in claim 4, is characterized in that, described synthetic method also comprises the preparation of compound 5 ', and described compound 5 ' passes into dry hcl reaction through compound 4 and compound 2 ' and is prepared from the second solvent:
6. synthetic method as claimed in claim 5, is characterized in that, described synthetic method also comprises the preparation of compound 2 ', and described compound 2 ' reacts through compound 1 ' and BOC acid anhydrides and is prepared from the 4th solvent:
7. as described in claim 3 or 5 synthetic method, it is characterized in that, described synthetic method also comprises the preparation of compound 4, and described compound 4 passes into dry hcl reaction through compound 3 and is prepared from the second solvent:
8. synthetic method as claimed in claim 7, is characterized in that, described synthetic method also comprises the preparation of compound 3, and described compound 3 reacts through compound 1 and compound 2 and is prepared from the first solvent:
9. as described in as arbitrary in claim 3-8 synthetic method, it is characterized in that, described first reaction solvent is THF; Described second reaction solvent is methylene dichloride; Described 3rd reaction solvent is ethyl acetate; Described 4th reaction solvent is the mixed solvent of water and tetrahydrofuran (THF).
10. as described in claim 3 or 8 synthetic method, it is characterized in that, also add HOBt and EDC when described compound 4 and compound 5 react, and the pH value of reaction solution is adjusted to 8-9; Described compound 1 and compound 2 also add HOBt and EDC when reacting, and the pH value of reaction solution is adjusted to 8-9.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102477067A (en) * | 2010-11-19 | 2012-05-30 | 上海来益生物药物研究开发中心有限责任公司 | 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine and preparation method and application thereof |
| CN102631664A (en) * | 2011-01-28 | 2012-08-15 | 上海来益生物药物研究开发中心有限责任公司 | Application of 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine |
| CN103319567A (en) * | 2012-03-20 | 2013-09-25 | 上海来益生物药物研究开发中心有限责任公司 | Tripeptide compound and preparation method and applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102477067A (en) * | 2010-11-19 | 2012-05-30 | 上海来益生物药物研究开发中心有限责任公司 | 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine and preparation method and application thereof |
| CN102631664A (en) * | 2011-01-28 | 2012-08-15 | 上海来益生物药物研究开发中心有限责任公司 | Application of 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine |
| CN103319567A (en) * | 2012-03-20 | 2013-09-25 | 上海来益生物药物研究开发中心有限责任公司 | Tripeptide compound and preparation method and applications thereof |
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