CN107973830B - Total synthesis method of neooxytocin - Google Patents

Total synthesis method of neooxytocin Download PDF

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CN107973830B
CN107973830B CN201711180837.9A CN201711180837A CN107973830B CN 107973830 B CN107973830 B CN 107973830B CN 201711180837 A CN201711180837 A CN 201711180837A CN 107973830 B CN107973830 B CN 107973830B
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deoxy
benzoyl
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uridine
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邵华武
沈旭东
梁鹏
潘阳
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Chengdu Institute of Biology of CAS
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Abstract

The invention belongs to the technical field of medicinal chemistry and organic synthesis, and aims to provide a method for chemically and completely synthesizing neoaomycin, which specifically comprises the following steps: using D-galactose and the like as raw materials, firstly carrying out 8-step reaction to obtain a compound 14, then carrying out condensation with uracil to obtain a compound 15, then carrying out 4-step reaction to obtain a compound 19, then carrying out condensation with a compound 6 to obtain a compound 20, finally sequentially removing ester protecting groups, and then removing Cbz protecting groups to obtain a natural product neooxytocin. The invention relates to a method for synthesizing a natural product neooxytocin for the first time. The method has the advantages of high product purity, low cost, simple operation and the like.

Description

Total synthesis method of neooxytocin
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry and organic synthesis, and particularly relates to a chemical synthesis method of neooxytocin.
Background
As a novel pesticide, biopesticides have been rapidly developed in recent decades due to their characteristics of environmental protection, safety, high efficiency, etc. (Trends in Biotechnology 2012,30, 250-. Among them, nucleoside antibiotics have attracted considerable interest to chemosynthesizers for their broad biological activity (J.Antibiott.1988, 41, 1711-1739; pharm.Therap.1991, 52, 269-286; Nat.Prod.Rep.2010,27, 279-304; Trends in microbiology 2015,23,110-119, etc.). Many documents report the good application prospects of some nucleoside antibiotics in crop protection (chem.Rev.1992,92, 1745-1768; chem.Rev.1995,95, 1859-1876; hetrocycles 2005,65, 667-695; Pest Manag.Sci.2007,63,524-554, etc.).
Neooxytocin (Xinnaomycin) is a polypeptide nucleoside agricultural antibiotic, and is separated from fermentation liquor of streptomyces norsii xinao-4 (CN 200910060121). Neomycin has antibacterial, antifungal and antiviral activity as a broad-spectrum nucleoside agricultural antibiotic. The field efficacy test shows that the 4% neomycin aqueous solution has good effect on preventing and treating tobacco mosaic virus diseases, and is obviously higher than 20% moroxydine-copper acetate wettable powder (Mod. agrochem.2011,10,50-52) of a commercial control medicament; the composition has good control effect on tomato mosaic virus diseases, and is safe to tomato growth (J.Henan agric.Sci.2013,42, 86-88); it also has preventing and treating effect on bacterial diseases such as bacterial leaf blight, bacterial wilt, soft rot and the like of rice. In addition, neomycin exhibits strong inhibitory activity against sclerotinia sclerotiorum and rhizoctonia cerealis, and the bacteriostatic effect is equivalent to that of polyoxin (agrichemicals 2013,52, 293-294).
However, the yield of neooxytocin obtained by microbial fermentation is low. In order to improve the yield of neomycin, several studies on the biosynthetic gene cluster of neomycin have been conducted. Although some progress has been made in the study of the Streptomyces norsleri xinao-4 gene manipulation system, the problem of low yield of biosynthetic neoornithromycin is still not solved (int.J.mol.Sci.2014,15, 12217-. In addition, because the polarity of neomycin is high, the fermentation liquor contains a large amount of amino acids and saccharides, the components are complex, and the number of homologues is large, so that the separation and purification are difficult. Therefore, it is very significant how to obtain neooxytocin with high purity in large quantity.
Chemical total synthesis is an important technical idea for obtaining a large amount of natural products with high purity. However, no complete synthesis of neooxytocin is reported at present.
Disclosure of Invention
The invention aims to provide a method for chemically and completely synthesizing neoaomycin, namely, the method takes D-galactose and the like as raw materials and realizes the chemical and complete synthesis of neoaomycin through a series of reactions.
In order to achieve the above purpose, the invention synthesizes a new chemical substance: compound 18 and further reacting with compound 18 to synthesize neooxytocin.
The compound 18 is named as 2 ', 3' -di-O-benzoyl-4 '-azido-4' -deoxy- α -D-glucuronic acid methyl ester uridine and has the chemical structural formula:
Figure BDA0001479137150000021
correspondingly, the preparation method of the compound 18 specifically comprises the following steps:
1) adding 2 ', 3' -di-O-benzoyl-4 '-azido-4' -deoxy- α -D-glucosyluridine, compound 16 for short, and TEMPO into CH3Adding iodobenzene acetate into CN, reacting completely, adding anhydrous EtOH for quenching reaction, and concentrating to obtain a solid crude product, which is named as: compound 17;
2) said compound 17 being soluble in anhydrous CH3OH, addition of H2SO4After the reaction is completed, NaHCO is added3Carrying out quenching reaction and concentrating; extracting the reaction solution with ethyl acetate, drying, filtering, and concentrating under reduced pressure to obtain compound 18.
Preferably, in the preparation method of the compound 18, the synthesis method of the compound 14 is as follows:
1) refluxing compound 14 and uracil under TMSOTf/BSA/acetonitrile condition to obtain compound 15, and reacting compound 15 in Et3N/CH3Hydrolyzing in OH to obtain a compound 16, wherein the names of the compounds 14 and 15 are respectively 1, 6-di-O-acetyl-2, 3-di-O-benzoyl-4-azido-4-deoxy- α -D-glucose and 2 ', 3 ' -di-O-benzoyl-4 ' -azido-6 ' -O-acetyl-4 ' -deoxy- α -D-uridine glucose;
2) the synthesis method of the compound 14 comprises the following steps:
reacting compound 13 with H2SO4/AcOH/Ac2Reacting under the condition of O to obtain a compound 14, wherein the compound 13 is named as 2, 3-di-O-benzoyl-4-azido-6-O-tert-butyldimethylsilyl-4-deoxy- α -D-glucosylformic acid glucoside;
3) the synthesis method of the compound 13 comprises the following steps: compound 11 in CH3ONa/CH3Hydrolyzing OH, adding imidazole and TBSCl into DMF for reaction to obtain a compound 12, and reacting the compound 12 with BzCl in pyridine to obtain a compound 13; the nomenclature of the compounds 11 and 12 is respectively: compound 11: 4-azido-2, 3, 6-tri-O-benzoyl-4-deOxygen- α -D-glucoside, compound 12 is 4-azido-6-O-tert-butyldimethylsilyl-4-deoxy- α -D-glucoside.
Further, compound 19 synthesized by using compound 18 is named as 2 ', 3' -di-O-benzoyl-4 '-amino-4' -deoxy- α -D-glucuronic acid methyl ester uridine and has the chemical structural formula as follows:
Figure BDA0001479137150000031
correspondingly, the preparation method of the compound 19 comprises the following steps: reacting said compound 18 with SnCl2·H2O, p-methylthiophenol, CHCl3And Et3And N, and separating to obtain the compound 19.
Further, compound 20 synthesized from compound 19, named as (R) -2 ', 3 ' -di-O-benzoyl-4 ' - (2 "- (2" ' - (N-methyl, N-Cbz) amino) acetamido-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronic acid methyl ester uridine, has the chemical structural formula:
Figure BDA0001479137150000041
correspondingly, the preparation method of the compound 20 comprises the following steps: the compound 19, (R) -2- [ 2' - (N-methyl, N-Cbz) amino ] acetamido-3-hydroxypropionic acid is used as a raw material, HATU is used as a condensing agent, 2, 6-lutidine is used as alkali, the mixture is fully reacted, and after extraction, washing, drying, filtering and concentration, the compound 20 is obtained by separation.
Further, compound 21 synthesized from compound 20 is named as (R) -4 ' - (2 "- (2 '" - (N-methyl, N-Cbz) amino) acetamido-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronide uridine, and has the chemical structural formula:
Figure BDA0001479137150000042
correspondingly, the preparation method of the compound 21 comprises the following steps: the compound 20 was hydrolyzed in aqueous methanol of LiOH at 0 ℃, concentrated and prepared by HPLC to give compound 21.
Further, the total synthesis method for synthesizing the neooxytocin by using the compound 21 comprises the following steps: adding the compound 21 and Pd/C with the content of 10% into EtOH and water, completely reacting at room temperature under the condition of hydrogen, filtering and concentrating to obtain the neoaomycin.
Accordingly, the intermediates of the fully synthetic neoaomycin obtained and utilized by the invention are novel, have independent use and protection values and are claimed.
The invention has the beneficial effects that:
1. the invention is a method for synthesizing the neooxytocin which is a natural product for the first time, and truly realizes the artificial total synthesis of the neooxytocin;
2. the invention takes cheap and easily obtained D-galactose and the like as starting raw materials, and has the characteristics of low cost, simple operation and extremely high product purity;
3. the synthetic route of the invention can carry out multiple modifications at multiple positions of the neoaomycin chemical structure, and lays a foundation for synthesizing neoaomycin structural analogues and developing new high-efficiency low-toxicity biological pesticides.
Drawings
FIG. 1 is a full synthetic scheme for neooxytocin;
FIG. 2 is a NMR spectrum of 2 ', 3' -di-O-benzoyl-4 '-azido-4' -deoxy- α -D-glucuronic acid methyl ester uridine, a compound 18;
FIG. 3 is a NMR carbon spectrum of 2 ', 3' -di-O-benzoyl-4 '-azido-4' -deoxy- α -D-glucuronic acid methyl ester uridine, a compound 18;
FIG. 4 is a NMR spectrum of 2 ', 3' -di-O-benzoyl-4 '-amino-4' -deoxy- α -D-glucuronic acid methyl ester uridine, compound 19;
FIG. 5 is a NMR carbon spectrum of 2 ', 3' -di-O-benzoyl-4 '-amino-4' -deoxy- α -D-glucuronic acid methyl ester uridine, compound 19;
FIG. 6 is a NMR spectrum of (R) -2 ', 3 ' -di-O-benzoyl-4 ' - (2 "- (2 '" - (N-methyl, N-Cbz) amino) acetamido-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronic acid methyl ester uridine, compound 20;
FIG. 7 is a NMR carbon spectrum of compound 20 (R) -2 ', 3 ' -di-O-benzoyl-4 ' - (2 "- (2 '" - (N-methyl, N-Cbz) amino) acetamido-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronic acid methyl ester uridine;
FIG. 8 is a NMR spectrum of uridine (R) -4 ' - (2 "- (2 '" - (N-methyl, N-Cbz) amino) acetamido-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronide of compound 21;
FIG. 9 is a NMR carbon spectrum of compound 21 (R) -4 ' - (2 "- (2 '" - (N-methyl, N-Cbz) amino) acetamido-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronide;
FIG. 10 is a NMR spectrum of compound 22 (R) -4 ' - (2 "- (2 '" - (N-methyl) amino) acetylamino-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronic acid uridine (neomycin);
FIG. 11 is a NMR carbon spectrum of compound 22 (R) -4 ' - (2 "- (2" ' - (N-methyl) amino) acetylamino-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronic acid uridine (neomycin);
FIG. 12 is a NMR spectrum of the natural product neomycin (R) -4 ' - (2 "- (2" ' - (N-methyl) amino) acetamido-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronic acid uridine (natural product neomycin);
FIG. 13 shows the NMR carbon spectrum of the natural product neomycin (R) -4 '- (2' - (N-methyl) amino) acetamido-3 '-hydroxy) propionamido-4' -deoxy- α -D-glucuronic acid uridine (natural product neomycin).
Detailed Description
Since the present invention relates to a series of chemical reactions, a detailed example is provided to enable those skilled in the art to understand the technical scheme of the present invention. It should be clear to those skilled in the art that, on the basis of the present example, the synthesis raw materials, the process methods and the parameters are properly adjusted to achieve the same purpose, and all are within the protection scope of the present invention.
1. Synthesizing: d-serine methyl ester hydrochloride (Compound 2)
The chemical reaction equation is as follows:
Figure BDA0001479137150000061
because the present invention relates to a large number of compounds and chemical reaction equations, for more convenient explanation and exposition, all important intermediates in the synthesis steps are labeled in the following manner: compound + number, as shown in this example, D-serine methyl ester hydrochloride is abbreviated as: a compound 2; and corresponding numbers are noted below the chemical structural formula in the chemical reaction equation, as shown in this example, below the structural formula of D-serine methyl ester hydrochloride: 2.
thionyl chloride (18.68g,157.00mmol) was added to N2Slowly dropwise adding the anhydrous CH cooled by ice salt bath under protection3After completion of the dropwise addition, the reaction mixture was warmed to room temperature and stirred for half an hour. Then, compound 1(5.00g,47.58mmol) was added as described in the above reaction equation, and the reaction mixture was clarified from turbidity at room temperature for 12 hours. The reaction was concentrated and dried in vacuo to give a white solid: compound 2(7.10g, 96%).
The compound 2 belongs to the existing raw materials and can be directly purchased.
2. Synthesizing: 2- (N-methyl, N-Cbz) aminoacetic acid (Compound 4)
The chemical reaction equation is as follows:
Figure BDA0001479137150000071
compound 3 sarcosine (3.00g,33.67mmol) was added to an aqueous solution (100mL) of NaOH (3.24g,80.90 mmol), and stirred in an ice-water bath to be homogeneous. CbzCl (6.89g, 40.39mmol) was added dropwise. After stirring at room temperature for 16 h, TLC monitored the starting material reaction to completion. The reaction solution was washed with ethyl acetate (2X 100mL), and the aqueous layer was washed with 1M hydrochloric acid to pH 2, followed by washing with ethyl acetateExtraction with ethyl acetate (2X 150 mL). The combined ethyl acetate solutions were washed with saturated NaCl solution (100mL) and anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain colorless oily matter N-Cbz-sarcosine: compound 4(7.11g, 94%).
3. Synthesizing: (R) -methyl 2- [ 2' - (N-methyl, N-Cbz) amino ] acetamido-3-hydroxypropionate (Compound 5)
The chemical reaction equation is as follows:
Figure BDA0001479137150000072
compound 4(6.00g,26.88mmol) was dissolved in dry DMF (80mL) followed by the addition of HATU (18.33g,48.21mmol) and 2, 6-lutidine (10.14g,94.62 mmol) in that order and stirring at room temperature for 2 h. Compound 2(5.80g,37.30mmol) above was added and after 14 hours of stirring at room temperature, TLC monitored the completion of the starting material reaction. Saturated NaCl solution (250mL) was added, and the reaction solution was extracted with ethyl acetate (3X 200 mL). The combined ethyl acetate solutions were washed with saturated NaCl solution (2X 200mL) and anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure. The resulting concentrate was separated by silica gel column Chromatography (CH)2Cl2MeOH, 50:1) to give a colorless oil: compound 5(6.45g, 74%).
4. Synthesizing: (R) -2- [ 2' - (N-methyl, N-Cbz) amino ] acetamido-3-hydroxypropionic acid (Compound 6)
The chemical reaction equation is as follows:
Figure BDA0001479137150000081
compound 5(3.80g,11.72mmol) is dissolved in CH3In OH (30mL), LiOH & H was added dropwise at 0 deg.C2O (639.3mg,15.24mmol) in water (10 mL). After stirring for 1 hour, TLC monitored the starting material reaction to completion. 1M hydrochloric acid was added dropwise to adjust the pH to 1. Water (100mL) was added and extracted with ethyl acetate (2X 150 mL). The combined ethyl acetate solutions were washed with saturated NaCl solution (100mL) and anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain a white solid:compound 6(2.76g, 76%).
5. Synthesis of 4-hydroxy-2, 3, 6-tri-O-benzoyl- α -D-galactobioside (Compound 9)
The chemical reaction equation is as follows:
Figure BDA0001479137150000082
acetyl chloride (7.5mL) was added dropwise to anhydrous methanol (350mL) cooled in an ice-water bath, and after the addition was complete, the reaction was warmed to room temperature and stirred for half an hour. Compound 7 was then added as described in the reaction equation above: d-galactose (25.00g,0.14mol) was heated under nitrogen reflux for 12 hours, and the reaction turned from cloudy to clear. The reaction was cooled to room temperature and solid NaHCO was added3The pH was adjusted to 8. Filtering, concentrating the filtrate, and pumping the solvent by an oil pump to obtain a crude product: compound 8(34.3g) was used and was directly subjected to the next reaction. Compound 8(34.3g) was dissolved in pyridine (300mL) and cooled at-20 ℃. BzCl (68.39g,0.49mol) was added dropwise and stirred slowly to room temperature for 18 h. The reaction was quenched dropwise with methanol (50 mL). After concentration, water (800mL) was added, and the reaction mixture was extracted with ethyl acetate (3X 500 mL). The combined ethyl acetate solutions were washed with 1M hydrochloric acid to pH 2 and then with saturated NaCl solution (2 × 400mL), anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure the concentrate obtained was chromatographed on silica gel (petroleum ether/ethyl acetate, 8:1) to give the compound 9: 4-hydroxy-2, 3, 6-tri-O-benzoyl- α -D-galactobioside (35.90g, 51%, twosteps) as a colorless oil.1H NMR(400MHz,CDCl3)δ8.10–7.97(m,6H), 7.64–7.37(m,9H),5.78(dd,J＝10.7,2.9Hz,1H),5.72(dd,J＝10.7,3.5 Hz,1H),5.24(d,J＝3.4Hz,1H),4.70(dd,J＝11.4,5.8Hz,1H),4.59(dd,J ＝11.4,6.9Hz,1H),4.43(d,J＝1.6Hz,1H),4.38(t,J＝6.3Hz,1H),3.47(s, 3H),2.84–2.50(br,1H)；13C NMR(100MHz,CDCl3)δ166.5,166.1,165.8, 133.5,133.3,129.9,129.8,129.7,129.6,129.3,128.5,128.4,97.5,70.8, 68.9,68.2,67.7,63.4,55.5。
6. Synthesis of 4-azido-2, 3, 6-tri-O-benzoyl-4-deoxy- α -D-glucomethyl glycoside (Compound 11)
The chemical reaction equation is as follows:
Figure BDA0001479137150000091
compound 9(10.00g,19.74mmol) and pyridine (6.25g,78.96mmol) were dissolved in CH2Cl2(100mL) at-10 ℃ Tf2O (5.57g,19.74 mmol). After 1.5 hours at-10 ℃ the starting material was monitored by TLC for completion. The reaction solution was washed with 1M hydrochloric acid to pH 2, then with water (2 × 100mL), anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain a crude product: compound 10, was directly subjected to the next reaction. The crude compound was dissolved in DMF (80mL) and NaN was added3(2.57g,39.48 mmol). After 16 hours at room temperature, TLC monitored the starting material reaction to completion. To the reaction mixture was added a saturated NaCl solution (300mL), and the mixture was extracted with ethyl acetate (3X 200 mL). The combined ethyl acetate solutions were washed with saturated NaCl solution (2X 200mL) and anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the obtained concentrate by silica gel column chromatography (petroleum ether/ethyl acetate, 12:1) to obtain colorless oily substance, compound 11: 4-azido-2, 3, 6-tri-O-benzoyl-4-deoxy- α -D-glucosylmethane glycoside (7.87g, 75%, twostes).1H NMR(600MHz,CDCl3)δ8.11(d,J＝7.4Hz,2H),8.00(d,J＝7.4Hz,2H), 7.97(d,J＝7.4Hz,2H),7.61(t,J＝7.4Hz,1H),7.54–7.48(m,4H),7.38(q, J＝7.5Hz,4H),6.00(t,J＝9.9Hz,1H),5.20(dd,J＝10.0,3.6Hz,1H), 5.17(d,J＝3.6Hz,1H),4.71(dd,J＝12.1,2.1Hz,1H),4.63(dd,J＝12.1, 4.7Hz,1H),4.09–4.03(m,1H),3.86(t,J＝10.1Hz,1H),3.44(s,3H)；13C NMR(100MHz,CDCl3)δ166.2,160.0,165.6,133.5,133.4,130.0,129.9, 129.8,129.6,129.1,128.9,128.6,128.5,97.2,71.9,71.0,68.0,63.4,61.0, 55.7.
7. Synthesis of 4-azido-6-O-tert-butyldimethylsilyl-4-deoxy- α -D-glucoside A (Compound 12)
The chemical reaction equation is as follows:
Figure BDA0001479137150000101
compound 11(20.00g,37.63mmol) was dissolved in CH3OH (100mL), CH was added3ONa (0.61g,11.29 mmol). After 15 hours at room temperature, the reaction was monitored by TLC for completion. Concentrating, and vacuumizing to constant weight to obtain crude product. The crude product was dissolved in DMF (80mL), imidazole (7.69g,11mmol) was added and TBSCl (8.51g,56.44mmol) was added portionwise at 0 ℃. After slowly warming to room temperature for 16 hours, the reaction was monitored by TLC for completion. To the reaction mixture was added a saturated NaCl solution (300mL), and the mixture was extracted with ethyl acetate (4X 200 mL). The combined ethyl acetate solutions were washed with saturated NaCl solution (2X 200mL) and anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure. The resulting concentrate was chromatographed on silica gel (petroleum ether/ethyl acetate, 5:1-1:1) to give a colorless oil: compound 12(7.90g, 63%).1H NMR(400MHz, CDCl3)δ4.79(d,J＝3.8Hz,1H),3.84(d,J＝1.0Hz,2H),3.81(t,J＝9.3 Hz,1H),3.55(dd,J＝9.5,3.8Hz,1H),3.51–3.46(m,2H),3.41(s,3H), 3.33–3.10(br,2H),0.93(s,9H),0.10(s,6H)；13CNMR(100MHz,CDCl3)δ 99.2,73.4,72.5,70.8,62.5,61.5,55.3,25.9,18.4,-5.3,-5.4.
8. Synthesis of 2, 3-di-O-benzoyl-4-azido-6-O-tert-butyldimethylsilyl-4-deoxy- α -D-glucomethyl glycoside (Compound 13)
The chemical reaction equation is as follows:
Figure BDA0001479137150000111
compound 12(7.50g,22.49mmol) was dissolved in pyridine (80mL) and BzCl (7.59g,53.98mmol) was added dropwise at 0 ℃. After 16 hours at room temperature, the reaction was monitored by TLC for completion. The reaction was quenched dropwise with methanol (10 mL). After concentration, water (200mL) was added, and the reaction mixture was extracted with methylene chloride (3X 200 mL). The combined dichloromethane solutions were washed with 1M hydrochloric acid to pH 2, saturated NaCl solution (2 × 200mL), anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure. The resulting concentrate was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 20:1) to give a colorless oil: compound (I)13(11.01g,90％)。1HNMR(400MHz,CDCl3)δ8.09–7.96 (m,4H),7.57–7.48(m,2H),7.44–7.36(m,4H),5.96(dd,J＝15.6,5.6Hz, 1H),5.20–5.14(m,2H),4.01–3.90(m,3H),3.76(dd,J＝10.2,1.5Hz,1H), 3.42(s,3H),1.00(s,9H),0.18(s,3H),0.17(s,3H)；13CNMR(100MHz, CDCl3)δ166.0,165.7,133.4,133.3,130.0,129.9,129.8,129.3,129.1,128.4, 97.1,72.1,71.1,70.4,62.2,60.3,55.4,26.0,18.5,-5.2,-5.4.
9. Synthesis of 1, 6-di-O-acetyl-2, 3-di-O-benzoyl-4-azido-4-deoxy- α -D-glucose (Compound 14)
The chemical reaction equation is as follows:
Figure BDA0001479137150000112
compound 13(10.00g,18.46mmol) was added to AcOH (33mL) and Ac2O (67 mL), H was added dropwise at 0 deg.C2SO4(2.0 mL). After 2 days at 0 ℃, the reaction was monitored by TLC for completion. The reaction mixture was poured into ice water (400mL) and extracted with dichloromethane (3X 200 mL). The combined dichloromethane solutions were washed with water (2X 400mL), saturated NaHCO3The solution was washed to pH 8, saturated NaCl solution (2 × 300mL), anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure. The resulting concentrate was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 3:1) to give a white solid: compound 14(5.41g, 59%).1HNMR(400MHz,CDCl3)δ8.03 (d,J＝7.6Hz,2H),7.92(d,J＝7.5Hz,2H),7.60–7.49(m,2H),7.46–7.36 (m,4H),6.54(d,J＝3.6Hz,1H),5.96(t,J＝10.0Hz,1H),5.42(dd,J＝ 10.2,3.6Hz,1H),4.48–4.36(m,2H),4.05(d,J＝10.3Hz,1H),3.94(t,J＝ 10.2Hz,1H),2.20(s,6H)；13CNMR(100MHz,CDCl3)δ170.5,168.6, 165.6,165.4,133.7,133.6,129.8,128.7,128.5,89.3,70.8,70.4,70.1,62.5, 60.3,20.8.
10. Synthesis of 2 ', 3 ' -di-O-benzoyl-4 ' -azido-6 ' -O-acetyl-4 ' -deoxy- α -D-glucosyluridine (Compound 15)
The chemical reaction equation is as follows:
Figure BDA0001479137150000121
uracil (1.38g,12.33mmol), BSA (7.53g,37.00mmol) were added to CH3CN (40mL), the reaction mixture was stirred at room temperature for 10 minutes, and the reaction mixture was changed from cloudy to clear. Compound 14(4.09g,8.22mmol) was added followed by TMSOTf (12.79g,57.55 mmol). N is a radical of2After heating to reflux for 16 h under protection, TLC monitored the reaction was complete. After concentration, water (200mL) was added, and the reaction mixture was extracted with ethyl acetate (3X 200 mL). The combined ethyl acetate solutions were washed with saturated NaCl solution (2X 200mL) and anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure. The obtained crude product is subjected to CH3OH is recrystallized to obtain a light yellow solid: compound 15(3.58g, 79%).1HNMR(400MHz,DMSO-d6)δ11.37(s,1H),7.92(d,J＝8.1Hz, 3H),7.77(d,J＝7.3Hz,2H),7.71–7.58(m,2H),7.55–7.42(m,4H),6.33(d, J＝9.1Hz,1H),6.05(t,J＝9.5Hz,1H),5.80–5.69(m,2H),4.41(d,J＝ 11.8Hz,1H),4.34–4.28(m,1H),4.26–4.13(m,2H),2.11(s,3H).
11. Synthesis of 2 ', 3' -di-O-benzoyl-4 '-azido-4' -deoxy- α -D-glucosyluridine (Compound 16)
The chemical reaction equation is as follows:
Figure BDA0001479137150000131
compound 15(3.14g,5.71mmol) was dissolved in anhydrous CH3OH (200mL), Et was added3N (4.04g,40.00 mmol). After 48 hours at room temperature, the reaction turned from turbid to clear and the reaction was monitored by TLC for completion. The reaction solution was concentrated at 40 ℃ to obtain a crude solid. Washed with ether to give a pale yellow solid: compound 16(2.47g, 85%).
12. Synthesis of 2 ', 3' -di-O-benzoyl-4 '-azido-4' -deoxy- α -D-glucuronic acid methyl ester uridine (Compound 18)
The chemical reaction equation is as follows:
Figure BDA0001479137150000132
compound 16(1.20g,2.37mmol), TEMPO (73.9mg,0.47mmol) were added to CH3CN (15mL) and water (12 mL). Iodobenzene acetate (1.90g,5.91 mmol) was added portionwise and after stirring at room temperature for 6 h, the reaction was monitored by TLC for completion. The reaction was quenched by the addition of anhydrous EtOH (5mL) and concentrated. And (3) obtaining a crude product: compound 17, was directly subjected to the next reaction. Dissolving the crude product in anhydrous CH3To OH (20mL), H was added2SO4(0.4 mL). After heating to reflux for 4 hours, the reaction was monitored by TLC for completion. Adding NaHCO3The reaction was quenched and concentrated. Water (40mL) was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (3X 40 mL). The combined ethyl acetate solutions were washed with saturated NaCl solution (2X 50mL) and anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure. The resulting concentrate was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 1:1) to give a white solid: compound 18 (558.1mg, 44%, twosteps).1H NMR(400MHz,CDCl3)δ8.27(s,1H), 7.97(d,J＝7.2Hz,2H),7.87(d,J＝7.2Hz,2H),7.60–7.46(m,3H), 7.45–7.34(m,4H),6.15(d,J＝9.5Hz,1H),5.90–5.74(m,2H),5.57(t,J＝ 9.5Hz,1H),4.30–4.13(m,2H),3.92(s,3H，OCH3).13C NMR(101MHz,CDCl3)δ166.86,165.27,165.24,162.66,162.63,150.17,139.21,134.00, 133.84,130.19,130.01,129.87,128.59,128.44,128.34,127.62,103.88, 80.71,77.26,75.84,72.80,69.50,61.40,53.51.ESI-HRMS:m/zcalcdfor C25H22N5O9[M+H]+:536.1412；found:536.1419.
13. Synthesis of 2 ', 3' -di-O-benzoyl-4 '-amino-4' -deoxy- α -D-glucuronic acid methyl ester uridine (Compound 19)
The chemical reaction equation is as follows:
Figure BDA0001479137150000141
SnCl2·H2O (295.0mg,1.31mmol), p-methylthiophenol (324.9mg,2.62 mmol) were added to CHCl3(5mL) of the mixture was added,et was added dropwise at room temperature3N (396.3mg,3.92 mmol). After stirring for 5 min, compound 18(350.0mg,0.65mmol) was added. After 2 hours at room temperature, the reaction was monitored by TLC for completion. Adding silica gel, mixing, and separating by silica gel column Chromatography (CH)2Cl2/CH3OH, 40:1) to give a white solid: compound 19(288.1mg, 86%).1H NMR(400MHz, DMSO-d6)δ11.39(s,1H),7.99(d,J＝8.1Hz,1H),7.90(d,J＝7.3Hz,2H), 7.75(d,J＝7.3Hz,2H),7.61(t,J＝7.4Hz,2H),7.46(q,J＝8.0Hz,4H), 6.17(d,J＝8.3Hz,1H),5.78–5.62(m,3H),4.50(d,J＝10.1Hz,1H),3.73 (s,3H),1.93–1.61(br,2H，NH2).13CNMR(101MHz,DMSO)δ168.71,165.95,165.03,163.09,150.81,141.46,134.37,133.94,129.74,129.55, 129.31,129.10,128.70,103.14,78.56,76.12,71.36,53.70,52.75,29.48. ESI-HRMS:m/zcalcdforC25H23N3O9[M+H]+:509.1434；found: 510.1514.
14. Synthesis of (R) -2 ', 3 ' -di-O-benzoyl-4 ' - (2 "- (2 '" - (N-methyl, N-Cbz) amino) acetamido-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronic acid methyl ester uridine (Compound 20)
The chemical reaction equation is as follows:
Figure BDA0001479137150000151
compound 6(200mg,0.65mmol) above was dissolved in dry DMF (5mL), followed by the addition of HATU (490.0mg,1.29mmol) and 2, 6-lutidine (172.5mg, 1.61mmol) in that order and stirring at room temperature for 2 hours. Additional compound 19(164.1mg,0.32 mmol) was added and after 14 hours of continued stirring at room temperature, TLC monitored the completion of the starting material reaction. Saturated NaCl solution (30mL) was added, and the reaction solution was extracted with ethyl acetate (3X 30 mL). The combined ethyl acetate solutions were washed with saturated NaCl solution (2X 30mL) and anhydrous Na2SO4Drying, filtering, and concentrating under reduced pressure. The resulting concentrate was separated by silica gel column Chromatography (CH)2Cl2/CH3OH, 50:1) to give a white solid: compound 20(178.0mg, 69%).1HNMR(400MHz,DMSO-d6)δ11.40(s,1H),8.24(t,J＝7.4Hz,1H),8.15(d,J＝8.1Hz,1H),8.03(d,J＝ 7.9Hz,1H),7.77(d,J＝7.3Hz,4H),7.66–7.57(m,2H),7.50–7.41(m,4H), 7.39–7.26(m,5H),6.21(d,J＝8.5Hz,1H),5.89–5.77(m,2H),5.74(d,J＝ 8.1Hz,1H),5.08(s,1H),5.02(dd,J＝21.3,8.4Hz,1H),4.73–4.61(m,3H), 4.33–4.22(m,1H),3.99–3.80(m,2H),3.57(d,J＝16.9Hz,3H，O-CH3), 3.31–3.15(m,2H),2.84(d,J＝16.4Hz,3H，N-CH3).13CNMR(150MHz, D2O)δ170.72,168.49,167.54,165.75,164.93,163.10,156.42,156.11, 150.81,141.64,137.41,134.42,129.65,129.62,129.48,129.33,129.05, 128.87,128.66,128.26,127.85,127.57,103.16,75.24,73.27,71.26,66.73, 60.29,52.86,51.42,51.07,50.27,29.46,27.01.ESI-HRMS:m/zcalcdfor C39H40N5O14[M+H]+:802.2513；found:802.2586.
15. Synthesis of (R) -4 ' - (2 "- (2" ' - (N-methyl, N-Cbz) amino) acetylamino-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronic acid uridine (Compound 21)
The chemical reaction equation is as follows:
Figure BDA0001479137150000161
compound 20(200mg,0.25mmol) is dissolved in CH3In OH (5mL), LiOH & H was added dropwise at 0 deg.C2O (41.9mg,1.00mmol) in water (3 mL). After stirring for 3 hours at 0 ℃, TLC monitored the starting material reaction was complete. AcOH was added dropwise to adjust the pH of the solution to 2. The reaction was concentrated and HPLC preparation gave a white solid: compound 21(43.3mg, 30%).1H NMR(400MHz,D2O)δ7.74(d,J＝7.2Hz,1H),7.40–7.16(m,5H),5.80(d,J＝7.6 Hz,1H),5.56–5.42(m,1H),5.17–4.90(m,2H),4.32(d,J＝34.1Hz,1H), 4.02–3.87(m,2H),3.85–3.74(m,2H),3.72–3.52(m,3H),2.95–2.74(m, 3H).13CNMR(150MHz,D2O)δ171.70,171.66,165.81,158.32,157.83, 151.85,141.81,136.14,128.78,128.41,127.72,103.15,82.33,73.51,71.22, 67.89,61.48,55.55,53.08,51.59,35.94.ESI-HRMS:m/z calcd for C24H30N5O12[M+H]+:580.1813；found:580.1885.
16. Synthesis of (R) -4 ' - (2 "- (2" ' - (N-methyl) amino) acetylamino-3 "-hydroxy) propionamido-4 ' -deoxy- α -D-glucuronic acid uridine (neomycin)
The chemical reaction equation is as follows:
Figure BDA0001479137150000162
compound 21(25.0mg,0.0431mmol), Pd/C10% (10.0mg) was added to EtOH (3mL) and water (3mL) and reacted under hydrogen at room temperature for 15 minutes, after which TLC monitored completion of the reaction, filtration and concentration to give compound 22, the desired neomycin (19.2mg, 100%) [ α ] as a white solid]20 D+37.0(c0.74,H2O)；1HNMR(600MHz, D2O)δ7.81(d,J＝7.9Hz,1H),5.89(d,J＝7.9Hz,1H),5.57(s,1H),4.48 (t,J＝5.3Hz,1H),3.96(s,2H),3.83–3.77(m,3H),3.76–3.70(m,2H),2.64 (s,3H)；13CNMR(150MHz,D2O)δ174.0,171.4,168.1,166.4,152.3, 142.0,103.1,82.4,77.9,73.6,71.6,61.4,55.7,53.4,50.2,33.2；ESI-HRMS: m/zcalcdforC16H23N5NaO10[M+Na]+:468.1337；found:468.1324。

Claims (10)

1. The compound 18 is named as 2 ', 3' -di-O-benzoyl-4 '-azido-4' -deoxy- α -D-glucuronic acid methyl ester uridine and has a chemical structural formula as follows:
Figure FDA0001479137140000011
2. a process for the preparation of compound 18 according to claim 1, characterized in that: the method specifically comprises the following steps:
1) adding 2 ', 3' -di-O-benzoyl-4 '-azido-4' -deoxy- α -D-glucosyluridine, compound 16 for short, and TEMPO into CH3Adding into CNIodobenzene acetate reacts completely, then anhydrous EtOH is added for quenching reaction, and a solid crude product is obtained by concentration, and is named as: compound 17;
2) said compound 17 being soluble in anhydrous CH3OH, addition of H2SO4After the reaction is completed, NaHCO is added3Carrying out quenching reaction and concentrating; extracting the reaction solution with ethyl acetate, drying, filtering, and concentrating under reduced pressure to obtain compound 18.
3. The process for the preparation of compound 18 according to claim 2, characterized in that: the synthesis method of the compound 16 comprises the following steps: refluxing compound 14 with uracil under TMSOTf/BSA/acetonitrile conditions to give compound 15, compound 15 in Et3N/CH3And (3) hydrolyzing OH to obtain a compound 16, wherein the names of the compounds 14 and 15 are respectively 1, 6-di-O-acetyl-2, 3-di-O-benzoyl-4-azido-4-deoxy- α -D-glucose and 2 ', 3 ' -di-O-benzoyl-4 ' -azido-6 ' -O-acetyl-4 ' -deoxy- α -D-uridine.
4. The compound 19 synthesized by using the compound 18 is characterized by being named as 2 ', 3' -di-O-benzoyl-4 '-amino-4' -deoxy- α -D-glucuronic acid methyl ester uridine and having a chemical structural formula as follows:
Figure FDA0001479137140000021
5. a process for the preparation of compound 19 according to claim 4, characterized in that: reacting said compound 18 with SnCl2·H2O, p-methylthiophenol, CHCl3And Et3And N, and separating to obtain the compound 19.
6. The compound 20 synthesized by the compound 19 is characterized by being named as (R) -2 ', 3' -di-O-benzoyl-4 '- (2' - (N-methyl, N-Cbz) amino) acetamido-3 '-hydroxy) propionamido-4' -deoxy- α -D-glucuronic acid methyl ester uridine, and the chemical structural formula is as follows:
Figure FDA0001479137140000022
7. a process for the preparation of compound 20 as claimed in claim 6, characterized in that: the compound 19, (R) -2- [ 2' - (N-methyl, N-Cbz) amino ] acetamido-3-hydroxypropionic acid is used as a raw material, HATU is used as a condensing agent, 2, 6-lutidine is used as alkali, the mixture is fully reacted, and after extraction, washing, drying, filtering and concentration, the compound 20 is obtained by separation.
8. The compound 21 synthesized by the compound 20 is characterized by being named as (R) -4 '- (2' - (N-methyl, N-Cbz) amino) acetamido-3 '-hydroxy) propionamido-4' -deoxy- α -D-glucuronic acid uridine and having a chemical structural formula as follows:
Figure FDA0001479137140000023
9. a process for the preparation of compound 21 according to claim 8, characterized in that: the compound 20 was hydrolyzed in aqueous methanol of LiOH at 0 ℃, concentrated and prepared by HPLC to give compound 21.
10. A total synthesis process for the synthesis of neoornithromycin using compound 21 according to claim 8, characterized in that: adding the compound 21 and Pd/C with the content of 10% into EtOH and water, completely reacting at room temperature under the condition of hydrogen, filtering and concentrating to obtain the neoaomycin.
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