CN112778224A - Method for synthesizing ganciclovir analogue - Google Patents
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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Abstract
The invention discloses a method for synthesizing ganciclovir analogues, and belongs to the technical field of synthesis of medical intermediates. The acyclic nucleoside analogue 3 is obtained by taking N-aryl heterocyclic ring 1 and D-A ethylene oxide 2 as raw materials, taking Lewis acid as a catalyst, adding a molecular sieve and reacting. The reaction has relatively single chemical selectivity, high regioselectivity and good to excellent yield. Further reduction of acyclic purine nucleoside 3 gave ganciclovir analogue 4. The method has the advantages of easily obtained raw materials and simple operation, and provides a new way for synthesizing ganciclovir analogues.
Description
Technical Field
The invention relates to a method for synthesizing Ganciclovir (Ganciclovir) analogue, belonging to the technical field of synthesis of medical intermediates.
Background
Acyclic nucleosides have received increasing attention for their important antiviral activity, for example, ganciclovir is a nucleoside antiviral agent commonly used to treat infections with the cytomegavirus (cytomegalovirus). Preventing cytomegalovirus disease that may occur in organ transplant recipients at risk for cytomegalovirus infection. Treating cytomegalovirus retinitis of patients with immunodeficiency (including AIDS). Therefore, the method for synthesizing Ganciclovir (Ganciclovir) analogue has wide application prospect and significance.
The traditional method for synthesizing penciclovir mainly comprises the following two methods: 1) the method comprises the steps of firstly carrying out esterification reaction on hydroxymethyl dioxolane as an initial substrate, then carrying out esterification reaction on acetyl chloride and acetic anhydride, carrying out reduced pressure fractionation, then carrying out condensation on the product and diacetyl guanine, and carrying out purification, hydrolysis and refining on the product to obtain ganciclovir, wherein the total yield of the method is 18%. 2) 1, 3-dichloro-2-propanol is used as an initial substrate, paraformaldehyde is firstly reacted, then the initial substrate is treated with acetic anhydride, and then the initial substrate is condensed with diacetyl guanine, and then the initial substrate is mixed with carboxylate to obtain a ganciclovir derivative, and finally the ganciclovir derivative is obtained by hydrolysis, wherein the total yield of the method is 22.6%. However, the above methods for synthesizing antiviral ganciclovir all require a large amount of silylation reagent, the catalyst for condensation reaction is highly toxic mercuric cyanide, and column chromatography separation of foreign body is very inconvenient and the yield is not high.
Therefore, the method for preparing ganciclovir analogues by selecting cheap and easily available D-A ethylene oxide and adopting catalytic amount of Lewis acid is not sufficiently researched, and a new synthetic method still needs to be developed.
Disclosure of Invention
In order to overcome the defects, the invention discloses a method for synthesizing ganciclovir analogues. Taking N-aryl heterocyclic ring 1 and D-A ethylene oxide 2 as raw materials, and reacting under the action of Lewis acid catalyst to obtain the acyclic nucleoside 3. The acyclic nucleoside 3 is then reduced to give ganciclovir analogue 4. The invention provides a simple, convenient, cheap and efficient way for synthesizing ganciclovir analogues.
The invention relates to a method for synthesizing ganciclovir analogues, which adopts the technical scheme that the reaction equation is expressed as follows:
the method comprises the following steps: taking N-aryl heterocycle 1 and D-A ethylene oxide 2 as raw materials, reacting in an organic solvent in the presence of a Lewis acid catalyst to obtain acyclic nucleoside 3, and then carrying out reduction reaction to generate ganciclovir analogue 4.
Wherein: x is a carbon or nitrogen atom; r is C1-C4 alkoxy or phenyl (wherein, in the second reaction step, phenyl is not included); r1Is one or more of halogen, C1-C6 alkyl, C1-C4 alkoxy and benzyloxy. More specifically, the N-aryl heterocyclic ring 1 comprises benzotriazole compounds, purine compounds and substituted imidazole compounds, and Ar comprises phenyl groups substituted at different positions and naphthyl groups substituted at different positions.
Further, in the technical scheme, the Lewis acid catalyst is selected from Sc (OTf)3、Y(OTf)3Or Gd (OTf)3。
Further, in the above technical scheme, the first step of adding molecular sieve is favorable for improving the reaction yield, and the molecular sieve is selected from
Molecular sieve,
Molecular sieves or
And (3) a molecular sieve.
Further, in the above technical solution, the first step organic solvent is selected from 1, 2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran or toluene.
Further, in the above technical scheme, the first step reaction temperature is selected from 40 ℃ to 100 ℃.
Further, in the above technical scheme, the molar ratio of the first step N-aryl heterocyclic ring 1 to the D-A ethylene oxide 2 is 1: 1-2.
Further, in the above technical scheme, the molar ratio of the first step Lewis acid catalyst to the N-aryl heterocyclic ring 1 is 0.03-0.10: 1.
Further, in the above technical solution, the second step reducing agent is selected from sodium borohydride or potassium borohydride, and is performed in a methanol solvent.
The invention has the beneficial effects that:
the method has the advantages of easily obtained reaction raw materials, relatively single reaction chemical selectivity, high regioselectivity, good to excellent yield of the acyclic nucleoside compound 3 obtained after the reaction. The non-cyclic purine nucleoside 3 is reduced to obtain a Ganciclovir analogue 4, and a new way is provided for the synthesis of Ganciclovir (Ganciclovir) analogues.
Detailed Description
Example 1
Examination of reaction conditions (taking entry 5 as an example):
in a reaction tube, benzotriazole 1a (0.1mmol,12mg), phenyl oxirane gem-diethoxylate compound 2a (0.1mmol,26.4mg), Y (OTf)3(5 mol%, 2.7mg) and
MS (30mg) was added to the reaction tube, 2mL of 1, 2-dichloroethane was added to the reaction system, and the reaction tube was placed in an oil bath at 80 ℃ for reaction for 10 hours. TLC detection, reaction termination, concentration and column chromatography to obtain compound 3a with 94% yield.
aReaction conditions:1a(0.1mmol),2a(0.1mmol),catalyst(xmol％),
MS(30mg)and solvent for 10h in the pressure tube.bThe yield was determined by 1H NMR using CH2Br2as an internal standard.cThe ratio was determined by 1H NMR analysis of crude product.dIsolated yield of 3a in parentheses.
In the process of screening the reaction conditions, the influence of different Lewis acid catalysts on the reaction is firstly examined (entries 1-5), and finally Y (OTf) is determined3Is the best catalyst. Meanwhile, considering the influence of the solvent, the solvent dosage, the catalyst dosage and the temperature on the reaction, the DCE is finally selected as the solvent, the volume is 2mL, the reaction temperature is 80 ℃, and the catalyst dosage is 5 mol%.
Under the condition of other fixed conditions, only the influence of different molecular sieves is examined, and the addition is finally confirmed through the examination of the molecular sieves
The optimum condition is 30mg of molecular sieve.
The specific screening results are as follows:
aReaction conditions:1a(0.1mmol),2a(0.1mmol),Y(OTf)3(5mol％),MS(30mg)and DCE(2mL)at 80℃ for 10h in the pressure tube.bThe yield was determined by 1H NMR using CH2Br2as an internal standard.cThe ratio was determined by 1H NMR analysis of the crude product.dIsolated yield of 3a in parentheses.
example 2:
in a reaction tube, benzotriazole 1a (0.1mmol,12mg), o-tolyl oxirane gem-diethoxylate compound 2b (0.1mmol,27.8mg), Y (OTf)3(5 mol%, 2.7mg) and
MS (30mg) was added to the reaction tube2mL of 1, 2-dichloroethane was added to the reaction system, and the reaction tube was placed in an oil bath at 80 ℃ for reaction for 10 hours. TLC detection, reaction termination, concentration and column chromatography to obtain compound 3b with 84% yield. Colorless solid,33.4mg, m.p.:65.6-70.3 ℃.1H NMR(400MHz,CDCl3)δ8.21(d,J＝8.0Hz,1H),8.03(d,J＝8.0Hz,1H),7.44(s,1H),7.42-7.25(m,4H),7.12-7.09(m,2H),4.81(s,1H),4.35-4.27(m,2H),3.92(q,J＝7.2Hz,2H),1.93(s,3H),1.30(t,J＝7.2Hz,3H),1.02(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.8,165.1,147.0,136.2,132.4,131.5,131.3,129.8,128.0,126.7,126.3,124.5,120.1,111.7,87.2,76.4,62.6,62.2,19.0,14.2,13.8.HRMS(ESI)m/z:[M+Na]+Calcd for C21H23N3NaO5 420.1530；Found 420.1524.
Example 3:
benzotriazole 1a (0.1mmol,12mg), p-tolyl oxirane gem-diethoxylate compound 2c (0.1mmol,27.8mg), Y (OTf)3(5 mol%, 2.7mg) and
MS (30mg) was added to the reaction tube, 2mL of 1, 2-dichloroethane was added to the reaction system, and the reaction tube was placed in an oil bath at 80 ℃ for reaction for 10 hours. TLC detection, reaction termination, concentration and column chromatography to obtain compound 3c with 87% yield. Colorless oil,34.6mg,1H NMR(400MHz,CDCl3)δ8.07-8.05(m,1H),7.37-7.29(m,5H),7.25-7.22(m,1H),7.18(d,J＝8Hz,2H),4.68(s,1H),4.36-4.27(m,2H),3.92(q,J＝7.2Hz,2H),2.35(s,3H),1.31(t,J＝7.2Hz,3H),1.00(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ165.9,165.0,147.2,139.5,131.8,131.4,129.5,127.9,126.2,124.6,120.0,112.2,89.5,76.5,62.6,62.2,21.4,14.2,13.7.HRMS(ESI)m/z:[M+Na]+Calcd for C21H23N3NaO5 420.1530；Found 420.1530.
example 4:
in a reaction tube, benzotriazole 1a (0.1mmol,12mg), 2g of 2-naphthyl oxirane gem-diethyl ester compound (0.1mmol,31.4mg)，Y(OTf)3(5 mol%, 2.7mg) and
MS (30mg) was added to the reaction tube, 2mL of 1, 2-dichloroethane was added to the reaction system, and the reaction tube was placed in an oil bath at 80 ℃ for reaction for 10 hours. TLC detection, reaction termination, concentration and column chromatography to obtain 3g of compound with 90% yield. Colorless soild,39.0mg, m.p. 94.2-98.4 ℃.1H NMR(400MHz,CDCl3)δ8.14(s,1H),8.08(d,J＝8.0Hz,1H),7.88-7.80(m,3H),7.57(s,1H),7.53-7.51(m,2H),7.41-7.39(m,1H),7.35-7.30(m,1H),7.27-7.20(m,2H),4.77(s,1H),4.39-4.30(m,2H),3.94(q,J＝7.2Hz,2H),1.33(t,J＝7.2Hz,3H),1.03(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ165.9,165.0,147.3,133.7,133.0,132.0,131.5,128.9,128.7,128.0,127.8,127.1,126.8,126.0,124.7,123.4,120.1,112.1,89.4,76.5,62.7,62.3 14.2,13.7.HRMS(ESI)m/z:[M+Na]+Calcd for C24H23N3NaO5 456.1530；Found 456.1530.
Example 5:
in a reaction tube, benzotriazole 1a (0.1mmol,12mg), phenyl oxirane geminal dimethyl ester compound 2k (0.1mmol,23.6mg), Y (OTf)3(5 mol%, 2.7mg) and
MS (30mg) was added to the reaction tube, 2mL of 1, 2-dichloroethane was added to the reaction system, and the reaction tube was placed in an oil bath at 80 ℃ for reaction for 10 hours. TLC detection, reaction termination, concentration and column chromatography to obtain compound 3k with 70% yield. Colorless oil,24.9mg,1H NMR(400MHz,CDCl3)δ8.08-8.06(m,1H),7.49-7.47(m,2H),7.41-7.36(m,4H),7.35-7.30(m,2H),7.20-7.17(m,1H),4.74(s,1H),3.87(s,1H),4.46(s,1H).13C NMR(100MHz,CDCl3)δ166.2,165.3,147.2,134.6,131.4,129.7,128.9,128.0,126.3,124.7,120.1,112.1,89.2,76.2,53.4,53.0.HRMS(ESI)m/z:[M+Na]+Calcd for C18H17N3NaO5 378.1060；Found 378.1060.
example 6:
in a reaction tube, 5, 6-dimethyl benzotriazole 1b (0.1mmol,14.7mg), phenyl oxirane gem-diethoxylate compound 2a (0.1mmol,26.4mg), Y (OTf)3(5 mol%, 2.7mg) and
MS (30mg) was added to the reaction tube, 2mL of 1, 2-dichloroethane was added to the reaction system, and the reaction tube was placed in an oil bath at 80 ℃ for reaction for 10 hours. TLC detection, reaction termination, concentration and column chromatography to obtain 3m compound with 91% yield. Colorless soild,37.4mg, m.p.:67.9-76.0 ℃.1H NMR(600MHz,CDCl3)δ7.78(s,1H),7.46-7.44(m,2H),7.36(t,J＝3.6Hz,3H),7.34(s,1H),6.95(s,1H),4.67(s,1H),4.33-4.29(m,2H),3.94(q,J＝7.2Hz,2H),2.33(s,3H),2.23(s,3H),1.30(t,J＝7.2Hz,3H),1.03(t,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.9,164.9,146.4,138.3,134.9,134.4,130.4,129.4,128.7,126.3,119.1,111.3,89.1,76.3,62.5,62.2,20.9,20.5,14.1,13.7.HRMS(ESI)m/z:[M+Na]+Calcd for C22H25N3NaO5 434.1686；Found 434.1678.
Example 7:
in a reaction tube, 6-chloropurine 1c (0.1mmol,15.4mg), phenyloxirane gem-diethanolate compound 2a (0.1mmol,26.4mg), Y (OTf)3(5 mol%, 2.7mg) and
MS (30mg) was added to the reaction tube, 2mL of 1, 2-dichloroethane was added to the reaction system, and the reaction tube was placed in an oil bath at 80 ℃ for reaction for 10 hours. TLC detection, reaction termination, concentration and column chromatography to obtain compound 3n with 65% yield. Colorless soild,27.2mg, m.p.:77.3-86.7 ℃.1H NMR(400MHz,CDCl3)δ8.79(s,1H),8.12(s,1H),7.52-7.50(m,2H),7.42(t,J＝3.2Hz,3H),7.18(s,1H),4.81(s,1H),4.34-4.25(m,2H),4.10-4.01(m,2H),1.29(t,J＝7.2Hz,3H),1.13(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ165.4,165.0,152.6,152.3,151.6,144.0,135.2,131.4,130.1,129.2,126.3,84.1,77.5,62.7,62.6,14.1,13.9.HRMS(ESI)m/z:[M+Na]+Calcd for C19H19ClN4NaO5 441.0936；Found 441.0927.
Example 8:
in a reaction tube, 2-amino-6-benzyloxypurine 1d (0.1mmol,24.1mg), phenyloxirane gem-diethoxylate compound 2a (0.1mmol,26.4mg), Y (OTf)3(5 mol%, 2.7mg) and
MS (30mg) was added to the reaction tube, 2mL of 1, 2-dichloroethane was added to the reaction system, and the reaction tube was placed in an oil bath at 80 ℃ for reaction for 10 hours. TLC detection, reaction termination, concentration and column chromatography to obtain the compound 3s with 40% yield. Colorless oil,20.2mg,1H NMR(400MHz,CDCl3)δ7.57(s,1H),7.52-7.46(m,4H),7.40-7.30(m,6H),6.93(s,1H),5.57(s,2H),4.95(s,2H),4.81(s,1H),4.35-4.26(m,2H),4.06(q,J＝7.2Hz,2H).1.29(t,J＝7.2Hz,3H),1.14(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ166.0,165.4,161.2,159.7,154.8,138.0,136.4,136.1,129.5,128.8,128.5,128.4,128.2,126.4,115.0,83.0,77.1,68.3,62.5,62.4,14.2,13.9.HRMS(ESI)m/z:[M+H]+Calcd for C26H28N5O6 506.2034；Found 506.2050.
example 9:
only the reaction substrate was changed according to the reaction conditions in examples 2 to 9, N-heteroaromatic ring (0.1mmol), D-A oxirane (0.1mmol), Y (OTf)3(5mol％),
MS (30mg), DCE (2mL) was reacted at 80 ℃ for 10h to obtain the following reaction results:
example 10:
in a reaction tube, the acyclic nucleoside compound 3s (50.5mg,0.1mmol) and 2mL of methanol were added, the reaction was left at 30 ℃ and then sodium borohydride (27mg,0.7mmol,7equiv) was added to the reaction system in portions. And (5) detecting by TLC, and quenching the reaction by saturated ammonium chloride after the reaction is complete. Extraction with ethyl acetate, combination of the organic phases, drying of the organic phase over anhydrous sodium sulphate and concentration in vacuo, column chromatography (dichloromethane/methanol 10:1) afforded compound 4s (38.3mg, 91% yield). Colorless oil,38.3mg,1H NMR(600MHz,CDCl3)δ7.55-7.54(m,2H),7.48-7.45(m,5H),7.35-7.32(m,2H),7.31-7.28(m,1H),7.10(s,1H),6.83(s,1H),5.55(s,2H),5.08(s,2H),3.88(dd,J＝3.0,12.6Hz,2H),3.80-3.73(m,2H),3.69(dd,J＝1.8,4.2Hz,2H).13C NMR(150MHz,CDCl3)δ161.6,159.3,153.9,137.8,136.3,135.1,130.3,129.4,128.6,128.4,128.2,127.4,116.1,83.9,79.0,68.4,62.9,62.5.HRMS(ESI)m/z:[M+Na]+Calcd for C22H23N5NaO4444.1642；Found 444.1641.
example 11:
in a reaction tube, a mixture of compound 4s (42.1mg,0.1mmol) and 10% Pd/C (8.5mg) was added in 2mL of methanol, and the reaction was stirred at room temperature under a hydrogen atmosphere. TLC, when the reaction was complete, the mixture was filtered over celite and the crude product was subjected to column chromatography (dichloromethane/methanol ═ 2:1) to give 30.8mg of compound 5s (30.8mg, 93% yield) as a colourless oily liquid.1H NMR(600MHz,DMSO-d6)δ10.85(s,1H),7.74(s,1H),7.40-7.34(m,5H),6.84(s,1H),6.84(s,2H),4.86(s,1H),4.66(s,1H),3.68-3.65(m,1H),3.58-3.51(m,2H),3.38-3.36(m,2H).13C NMR(150MHz,DMSO-d6)δ156.9,154.1,151.3,138.8,135.1,128.7,128.5,126.0,116.3,82.8,79.9,61.0,60.8.HRMS(ESI)m/z:[M+Na]+Calcd for C15H17N5NaO4354.1173；Found 354.1173.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (9)
1. A method of synthesizing an acyclic nucleoside analog 3, comprising the steps of:
n-aryl heterocyclic ring 1 and D-A epoxy ethane 2 are taken as raw materials and react in an organic solvent in the presence of a Lewis acid catalyst to obtain acyclic nucleoside 3; wherein: x is a carbon or nitrogen atom; r is C1-C4 alkoxy or phenyl; r1Is one or more of halogen, C1-C6 alkyl, C1-C4 alkoxy and benzyloxy.
2. The method of synthesizing an acyclic nucleoside analog 3 according to claim 1, wherein: the Lewis acid catalyst is selected from Sc (OTf)3、Y(OTf)3Or Gd (OTf)3。
3. The method of synthesizing an acyclic nucleoside analog 3 according to claim 1, wherein: the reaction is carried out under the condition of adding molecular sieve selected from
Molecular sieve,
Molecular sieves or
And (3) a molecular sieve.
4. The method of synthesizing an acyclic nucleoside analog 3 according to claim 1, wherein: the molar ratio of the N-aryl heterocyclic ring 1 to the D-A ethylene oxide 2 is 1: 1-2.
5. The method of synthesizing an acyclic nucleoside analog 3 according to claim 2, wherein: the molar ratio of the Lewis acid catalyst to the N-aryl heterocyclic ring 1 is 0.03-0.10: 1.
6. The method of synthesizing an acyclic nucleoside analog 3 according to claim 1, wherein: the organic solvent is selected from 1, 2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran or toluene.
7. The method of synthesizing an acyclic nucleoside analog 3 according to claim 1, wherein: the reaction temperature is selected from 40 ℃ to 100 ℃.
8. A method of synthesizing ganciclovir analog 4, comprising the steps of:
synthesizing an acyclic nucleoside analogue 3 by the method of any one of claims 1 to 7, followed by reacting the acyclic nucleoside analogue 3 in the presence of a reducing agent to form ganciclovir analogue 4; wherein: x is a carbon or nitrogen atom; r is C1-C4 alkoxy; r1Is one or more of halogen, C1-C6 alkyl, C1-C4 alkoxy and benzyloxy.
9. The method of synthesizing a ganciclovir analog according to claim 8, wherein: the reducing agent is selected from sodium borohydride or potassium borohydride, and the reaction is carried out in a methanol solvent.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2001354672A (en) * | 2001-05-31 | 2001-12-25 | Ajinomoto Co Inc | Method for producing acyclic nucleosides |
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