CN101407513A - Method for synthesizing nucleoside analogue - Google Patents
Method for synthesizing nucleoside analogue Download PDFInfo
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- CN101407513A CN101407513A CNA2008101624543A CN200810162454A CN101407513A CN 101407513 A CN101407513 A CN 101407513A CN A2008101624543 A CNA2008101624543 A CN A2008101624543A CN 200810162454 A CN200810162454 A CN 200810162454A CN 101407513 A CN101407513 A CN 101407513A
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Abstract
The invention provides a method for synthesizing a nucleotide analogue, the structure of which is as shown in the formula (I), and the method comprises the following steps: the compound of the structure as shown in (V) is the reaction substrate, lithium ion is the reagent, preferred lithium nitrate, lithium chloride and lithium bromide are the catalyst, alkali metal borohydride acid salt is the reducing agent, and selective reduction is carried out in the mixed solvent of ethanol and water. After the reduction is finished, the reaction solution is isolated and purified, thus obtaining the nucleotide analogue as shown in the formula (I). The Lamivudine and Emtricitabine synthetic method has the advantages of safe and reliable operation, simple processing steps, low manufacturing cost and being environmental friendly, and the method is a more ideal synthetic method which is suitable for industrial production.
Description
(1) technical field
The present invention relates to a kind of synthetic method of nucleoside analog, be specially the synthetic method of lamivudine and emtricitabine.
(2) background technology
Nucleosides and their analogue and radical derivative are a kind of good curing agent.As shown in the formula cis nucleoside analog (X=H, lamivudine, Compound I A wherein; X=F, emtricitabine, Compound I B) be efabirenz, be the efficient selective inhibitor of hiv virus HIV and hepatitis b virus hbv, be widely used in the treatment of anti-AIDS and hepatitis B clinically.
X=H, lamivudine, Compound I A
X=F, emtricitabine, Compound I B
Relevant lamivudine synthetic bibliographical information is a lot, and main has: (1) Beach, J.et al, J.Org.Chem., 57 (8), 2217-19 (1992); (2) Humber, David C.et alTetrahedron Lett., 33 (32), 4625-28 (1992); (3) David C., et al, TetrahedronLett., 33 (32), 4625-28 (1992); (4) Haolun J.et al, J.Org.Chem., 60,2621-23 (1992); (5) Goodyear, M.et al, WO 9529174 (1995); (6) Shah, C.S.et al, WO03027106 (2003).
Relevant emtricitabine synthesizes main the having of bibliographical information: (1) Mansour T, et al EP:515157 (1992), (2) Jeong L., et al.J Med Chem, 36 (2): 181-195 (1993); (3) Keshava M., et al., US:6380388, (2002); (4) Cleary D., et al., WO:00/09494 (2000); (5) Goodyear, M.et al, WO 9529174 (1995); (6) Meng Jingfang etc., Chinese Journal of Pharmaceuticals, 589-591,36 (10), (2005).
Wherein, be chiral source with L-peppermint acid glyoxylic ester monohydrate (Compound I I), through asymmetric synthesis and must lamivudine and the route of emtricitabine be the most economical and the most practical at present, also be a method of normal use in the existing industrial production, process is as follows:
X=H, lamivudine, Compound I A
X=F, emtricitabine, Compound I B
" salicylic acid method " that this method is commonly referred to.In the existing industrial production, compound V[V-A:X=H, (2R, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester; V-B:X=F, (2R, 5S)-and 5-(5 '-fluoro-cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester] after the hydroboration reduction, because of its reductive poor selectivity, it is many to produce impurity in the process, the target product purity that generates is not high enough, influences separating out of product simultaneously, thereby all adopts earlier on producing through Whitfield's ointment salify (compound VI) [(Goodyear, M.et al, WO 9529174 (1995); Shah, C.S.et al, WO03027106 (2003); Gharpure, M.M., IN 2005MU01570 (2005)), then with triethylamine with the purge process that the salicylate of Compound I dissociates out, promptly pass through:
The first step: the crude product that makes Compound I by compound V earlier;
Second step: Compound I crude product and Whitfield's ointment salify, form salicylate compound VI, this process can be removed a part of impurity;
The 3rd step: through the triethylamine alkalization, dissociate obtains purity Compound I relatively preferably to compound VI in solvent.
(3) summary of the invention
The object of the invention provides a kind of the needs through Whitfield's ointment salify and triethylamine free process, directly under the effect of lithium ion reagent catalyzer, highly selective reducing compound V, products therefrom are directly by the synthetic method of a kind of nucleoside analog of separating out in the reaction system.
The technical solution used in the present invention is:
A kind of structure is suc as formula the synthetic method of the nucleoside analog shown in (I), described method comprises: with the compound of structure shown in (V) is reaction substrate, with lithium ion reagent is catalyzer, with basic metal boron hydrohalogenic acid salt is reductive agent, in the mixed solvent of second alcohol and water, carry out the selective reduction reaction, after reduction reaction finished, reaction solution obtained the nucleoside analog shown in the formula (I) through separation and purification;
Among formula (I), (V), X is H or F.
In the prior art, have compound (V) directly through LiAlH
4Reduction obtains the report of described compound (I), as Chinese patent CN200510015609.7, owing to adopt expensive LiAlH
4Be raw material, and because of LiAlH
4Active very good, very easily burning needs the anaerobic water-less environment, and the tetrahydrochysene furan that uses in this technology south price is much more expensive than ethanol, the production operation poor stability, and running cost and production cost height are unfavorable for suitability for industrialized production; And the present invention be boron hydrohalogenic acid salt with safety is a reductive agent, is catalyzer with lithium ion reagent, carries out the highly selective reduction reaction, obtains the nucleoside analog shown in the described formula (I), greatly reduces cost, is fit to suitability for industrialized production.
What play katalysis in the described lithium ion reagent is lithium ion, and its negatively charged ion is selected unrestricted, can be common lithium salts in this area and alkali thereof, mainly comprise: lithium nitrate, lithium chloride, lithiumbromide, lithium fluoride, Lithium Acetate, Lithium Sulphate, lithium perchlorate, Trilithium phosphate, monometallic, Quilonum Retard, lithium hydroxides etc. are preferably lithium nitrate, lithium chloride, lithiumbromide, described basic metal boron hydrohalogenic acid salt is preferably sodium borohydride.
Described reduction reaction is preferably carried out under 15～25 ℃.
The ratio of described compound (V), basic metal boron hydrohalogenic acid salt, lithium ion reagent quality is 100: 10～20: 0.05～0.2.
The ratio of described compound (V), ethanol, water consumption is: 100g: 600～800mL: 300～500g.
For preventing that basic metal boron hydrohalogenic acid salt from decomposing; usually also need add phosphate buffered saline buffer in the described reduction reaction; among the present invention; described damping fluid is dipotassium hydrogen phosphate-sodium hydrate buffer solution; described reduction reaction is carried out in the presence of dipotassium hydrogen phosphate and sodium hydroxide, and the ratio of described compound (V), dipotassium hydrogen phosphate, sodium hydroxide quality is 100: 100～150: 0.2～1.0.
Described separation and purification can be undertaken by this area ordinary method, the separation purification method of product described in the present invention is as follows: after reaction finishes, the reaction solution standing demix, getting upper strata organic layer (lower floor is the saturated salt water layer) accent pH is 4～5, stirred 0.5～2.0 hour, transferring pH again is 7.0, ethanol is reclaimed in distillation, and the raffinate behind the recovery ethanol is cooled to 20～30 ℃, extracts with toluene, separating and extracting liquid and water layer, extraction liquid washing, water lotion and water layer merge decompression inspissation contracts, and is cooled to 0～5 ℃ and spends the night (can add ethanol in its process separates out to promote crystal), separate out crystal and be dried to constant weight, obtain described nucleoside analog.
Concrete, described method is carried out as follows:
(1) in reaction vessel, adds and water, be stirred to dissolving, 10～20 ℃ add compound (V), ethanol and lithium ion reagent down, stirring fully disperses it, controlled temperature is 15～25 ℃, drip the aqueous solution that is dissolved with sodium hydroxide and sodium borohydride in 2 hours, carry out selective reduction and react to complete reaction under 15～25 ℃, described lithium ion reagent is lithium nitrate, lithiumbromide or lithium chloride;
The ratio of described compound (V), dipotassium hydrogen phosphate, lithium ion reagent, sodium hydroxide, sodium borohydride quality is 100: 100～150: 0.05～0.2: 0.2～1.0: 10～20; The ratio of described compound (V), ethanol, total water amount is: 100g: 600～800mL: 300～500g;
(2) after reaction finished, reaction solution was in 15 ℃ of standing demix, and it is 4～5 that the upper strata organic layer is transferred pH with hydrochloric acid soln, stirred 30 minutes, transferring pH with the sodium hydroxide solution of mass concentration 10% is 7, and ethanol is reclaimed in distillation, and the raffinate behind the recovery ethanol is cooled to 20～30 ℃, extract with toluene, the extraction liquid washing, the water lotion concentrating under reduced pressure is cooled to 0～5 ℃ and spends the night, separate out crystal and be dried to constant weight, obtain described nucleoside analog.
Compared with prior art, beneficial effect of the present invention is:
1) among the present invention the hydroboration reduction reaction in order to lithium ion reagent, preferred lithium nitrate, lithium chloride, lithiumbromide are that catalyzer reduces, and make the selectivity of reaction increase substantially, reaction yield and product purity increase substantially.
2) building-up process of the present invention foreshortens to single step reaction by original three-step reaction, makes reactions steps simplify, and has saved production cost, and is significant for industrial production.
3) the present invention has avoided using the triethylamine and the ester of irritating property smell when reducing material, has significantly reduced exhaust gas discharging in the workshop air, makes workman's operating environment obtain obvious improvement.
4) compare with CN 200510015609.7, owing to adopt stability high, easy to operate boron hydrohalogenic acid salt is a raw material, replaces tetrahydrofuran (THF) with low-cost ethanol simultaneously, greatly reduces cost, is beneficial to suitability for industrialized production.
To sum up, lamivudine of the present invention and emtricitabine synthetic method have that operational safety is reliable, processing step is simplified, characteristics such as production cost is low, environmental friendliness, are a kind of synthetic methods of even more ideal suitable suitability for industrialized production.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1: lamivudine (Compound I-A) synthetic
In three-necked flask, add dipotassium hydrogen phosphate 136 grams, water 250 grams, be stirred to dissolving, add 100 gram (2R below 20 ℃, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound V-A) and 750mL ethanol, lithium nitrate 0.1 gram, stir it is disperseed as far as possible, between 15～25 ℃ of the controlled temperature, drip the 150 gram aqueous solution that are dissolved with 0.5 gram sodium hydroxide and 20 gram sodium borohydrides in 2 hours, and under this temperature, react and disappeared to raw material point in about 2 hours.15 ℃ of left and right sides static layering, the upper strata organic layer is transferred pH=4 with dilute hydrochloric acid, stirred 30 minutes, and transferred about pH=7.0 with 10% sodium hydroxide then, steam ethanol to temperature and obviously raise, about surplus 300mL, be chilled to 20 ℃, divide reextraction with 800mL toluene, extraction liquid is washed with 30mL, combining water layer and water lotion, pressure reducing and steaming water 100mL is cooled to 0 ℃ and spends the night, and filters, be dried to constant weight, get white solid: 48.2 grams, HPLC purity: 99.56%, external standard content: 99.35%, yield: 80.20%, [α]
22 D=-143.2 ° (c 1.01, MeOH).
Embodiment 2: lamivudine (Compound I-A) synthetic
In three-necked flask, add dipotassium hydrogen phosphate 136 grams, water 250 grams, be stirred to dissolving, add 100 gram (2R below 20 ℃, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound V-A) and 750mL ethanol, lithiumbromide 0.1 gram, stir it is disperseed as far as possible, between 15～25 ℃ of the controlled temperature, drip the 150 gram aqueous solution that are dissolved with 0.5 gram sodium hydroxide and 20 gram sodium borohydrides in 2 hours, and under this temperature, react and disappeared to raw material point in about 1 hour.15 ℃ of left and right sides static layering, the upper strata organic layer is transferred pH=4 with dilute hydrochloric acid, stirred 30 minutes, and transferred about pH=7.0 with 10% sodium hydroxide then, steam ethanol to temperature and obviously raise, about surplus 300mL, be chilled to 30 ℃, divide reextraction with 800mL toluene, extraction liquid is washed with 30mL, combining water layer and water lotion, pressure reducing and steaming water 100mL is cooled to 5 ℃ and spends the night, and filters, be dried to constant weight, get white solid: 47.3 grams, HPLC purity: 99.51%, external standard content: 99.33%, yield: 78.70%, [α]
22 D=-143.0 ° (c 1.01, MeOH).
Embodiment 3: lamivudine (Compound I-A) synthetic
In three-necked flask, add dipotassium hydrogen phosphate 136 grams, water 250 grams, be stirred to dissolving, add 100 gram (2R below 20 ℃, 5S)-5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound V-A) and 750mL ethanol, lithium chloride 0.1 gram, stir it is disperseed as far as possible, between 15～25 ℃ of the controlled temperature, drip the 150 gram aqueous solution that are dissolved with 0.5 gram sodium hydroxide and 20 gram sodium borohydrides in 2 hours, and under this temperature, react and disappeared to raw material point in about 2 hours.15 ℃ of left and right sides static layering, the upper strata organic layer is transferred pH=5 with dilute hydrochloric acid, stirred 30 minutes, and transferred about pH=7.0 with 10% sodium hydroxide then, steam ethanol to temperature and obviously raise, about surplus 300mL, be chilled to 30 ℃, divide reextraction with 800mL toluene, extraction liquid is washed with 30mL, combining water layer and water lotion, pressure reducing and steaming water 100mL is cooled to 5 ℃ and spends the night, and filters, be dried to constant weight, get white solid: 47.8 grams, HPLC purity: 99.58%, external standard content: 99.51%, yield: 79.53%, [α]
22 D=-143.5 ° (c 1.01, MeOH).
Comparative Examples 1: lamivudine (synthetic (salicylic acid method) of Compound I-A)
In three-necked flask, add dipotassium hydrogen phosphate 136 grams, water 250 grams are stirred to dissolving, add 100 gram (2R below 20 ℃, 5S)-and 5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound V-A) and 750mL ethanol stirs and made its dispersion as far as possible in 30 minutes, between 15～25 ℃ of the controlled temperature, drip the 150 gram aqueous solution be dissolved with 0.5 gram sodium hydroxide and 20 gram sodium borohydrides in 2 hours, and under this temperature, react and disappeared to raw material point in about 3 hours.15 ℃ of left and right sides static layering, the upper strata organic layer is transferred pH=5 with hydrochloric acid, stirred 30 minutes, transfer about pH=7.0 with 10% sodium hydroxide then, steam ethanol to temperature and obviously raise, about surplus 300mL, be chilled to 20 ℃, divide reextraction with 800mL toluene, extraction liquid is washed with 30mL, combining water layer and water lotion, water layer heats up 75 ℃, add Whitfield's ointment 36 grams, reduce to about 55 ℃, add lamivudine salicylate crystal seed, spend the night about 5 ℃ then, filter, get the lamivudine salicylate of white solid, drying.
Last step product adds the 800mL ethyl acetate, be heated to backflow, drip triethylamine 30mL, continue to reflux 30 minutes, slowly being chilled to 30 ℃ stirred 1 hour, be cooled to 5 ℃ and spend the night, filter, get white solid: 44.3 grams, HPLC purity: 98.82%, external standard content: 98.75%, yield: 73.58%, [α]
22 D=-140.1 ° (c 1.01, MeOH).
Comparative Examples 2: lamivudine (synthetic (embodiment 1～3 does not add catalyzer) of Compound I-A)
In three-necked flask, add dipotassium hydrogen phosphate 136 grams, water 250 grams are stirred to dissolving, add 100 gram (2R below 20 ℃, 5S)-and 5-(cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound V-A) and 750mL ethanol stirs and made its dispersion as far as possible in 30 minutes, between 15～25 ℃ of the controlled temperature, drip the 150 gram aqueous solution be dissolved with 0.5 gram sodium hydroxide and 20 gram sodium borohydrides in 2 hours, and under this temperature, react and disappeared to raw material point in about 3 hours.15 ℃ of left and right sides static layering, the upper strata organic layer is transferred pH=5 with hydrochloric acid, stirred 30 minutes, and transferred about pH=7.0 with 10% sodium hydroxide then, steam ethanol to temperature and obviously raise, about surplus 300mL, be chilled to 30 ℃, divide reextraction with 800mL toluene, extraction liquid is washed with 30mL, combining water layer and water lotion, pressure reducing and steaming water 100mL is cooled to 5 ℃ and spends the night, and filters, be dried to constant weight, get white solid: 38.3 grams, HPLC purity: 98.12%, external standard content: 98.06%, yield: 63.62%, [α]
22 D=-138.3 ° (c 1.01, MeOH).
Embodiment 4: emtricitabine (Compound I-B) synthetic
In three-necked flask, add dipotassium hydrogen phosphate 136 grams, water 250 grams, be stirred to dissolving, add 100 gram (2R below 20 ℃, 5S)-5-(5 '-fluoro-cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound V-B) and 750mL ethanol, lithium nitrate 0.1 gram, stir it is disperseed as far as possible, between 15～25 ℃ of the controlled temperature, drip the 130 gram aqueous solution that are dissolved with 0.45 gram sodium hydroxide and 18 gram sodium borohydrides in 2 hours, and under this temperature, react and disappeared to raw material point in about 2 hours.15 ℃ of left and right sides static layering, the upper strata organic layer is transferred pH=4 with hydrochloric acid, stirs 30 minutes, transfers about pH=7.0 with 10% sodium hydroxide then, steaming ethanol to temperature obviously raises, about surplus 300mL, be chilled to 30 ℃, divide reextraction with 800mL toluene, extraction liquid is washed with 30mL, combining water layer and water lotion, pressure reducing and steaming water 200mL adds ethanol 800mL, being cooled to 5 ℃ spends the night, filter, be dried to constant weight, get white solid: 50.9 grams, HPLC purity: 99.38%, external standard content: 99.39%, yield: 78.52%, [α]
22 D=-133.0 ° (c 0.23, MeOH).
Embodiment 5: emtricitabine (Compound I-B) synthetic
In three-necked flask, add dipotassium hydrogen phosphate 136 grams, water 250 grams, be stirred to dissolving, add 100 gram (2R below 20 ℃, 5S)-5-(5 '-fluoro-cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound V-B) and 750mL ethanol, lithiumbromide 0.1 gram, stir it is disperseed as far as possible, between 15～25 ℃ of the controlled temperature, drip the 130 gram aqueous solution that are dissolved with 0.45 gram sodium hydroxide and 18 gram sodium borohydrides in 2 hours, and under this temperature, react and disappeared to raw material point in about 1 hour.15 ℃ of left and right sides static layering, the upper strata organic layer is transferred pH=4 with hydrochloric acid, stirs 30 minutes, transfers about pH=7.0 with 10% sodium hydroxide then, steaming ethanol to temperature obviously raises, about surplus 300mL, be chilled to 30 ℃, divide reextraction with 800mL toluene, extraction liquid is washed with 30mL, combining water layer and water lotion, pressure reducing and steaming water 200mL adds ethanol 800mL, being cooled to 5 ℃ spends the night, filter, be dried to constant weight, get white solid: 50.1 grams, HPLC purity: 99.29%, external standard content: 99.29%, yield: 77.28%, [α]
22 D=-132.8 ° (c 0.23, MeOH).
Embodiment 6: emtricitabine (Compound I-B) synthetic
In three-necked flask, add dipotassium hydrogen phosphate 136 grams, water 250 grams, be stirred to dissolving, add 100 gram (2R below 20 ℃, 5S)-5-(5 '-fluoro-cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound V-B) and 750mL ethanol, lithium chloride 0.1 gram, stir it is disperseed as far as possible, between 15～25 ℃ of the controlled temperature, drip the 130 gram aqueous solution that are dissolved with 0.45 gram sodium hydroxide and 18 gram sodium borohydrides in 2 hours, and under this temperature, react and disappeared to raw material point in about 2 hours.15 ℃ of left and right sides static layering, the upper strata organic layer is transferred pH=4 with hydrochloric acid, stirs 30 minutes, transfers about pH=7.0 with 10% sodium hydroxide then, steaming ethanol to temperature obviously raises, about surplus 300mL, be chilled to 20 ℃, divide reextraction with 800mL toluene, extraction liquid is washed with 30mL, combining water layer and water lotion, pressure reducing and steaming water 200mL adds ethanol 800mL, being cooled to 5 ℃ spends the night, filter, be dried to constant weight, get white solid: 49.2 grams, HPLC purity: 99.42%, external standard content: 99.35%, yield: 75.89%, [α]
22 D=-133.5 ° (c 0.23, MeOH).
Comparative Examples 3: emtricitabine (synthetic (salicylic acid method) of Compound I-B)
In three-necked flask, add dipotassium hydrogen phosphate 136 grams, water 250 grams are stirred to dissolving, add 100 gram (2R below 20 ℃, 5S)-and 5-(5 '-fluoro-cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound V-B) and 750mL ethanol stirs and made its dispersion as far as possible in 30 minutes, between 15～25 ℃ of the controlled temperature, drip the 130 gram aqueous solution be dissolved with 0.45 gram sodium hydroxide and 18 gram sodium borohydrides in 2 hours, and under this temperature, react and disappeared to raw material point in about 1 hour.15 ℃ of left and right sides static layering, the upper strata organic layer is transferred pH=4 with hydrochloric acid, stirred 30 minutes, and transferred about pH=7.0 with 10% sodium hydroxide then, steam ethanol to temperature and obviously raise, about surplus 300mL, be chilled to 20 ℃, divide reextraction with 800mL toluene, extraction liquid is washed with 30mL, combining water layer and water lotion, pressure reducing and steaming water 200mL, water layer is warming up to 65 ℃, adds Whitfield's ointment 34 grams, reduce to about 55 ℃, add emtricitabine salicylate crystal seed, spend the night about 0 ℃ then, filter, get the emtricitabine poplar hydrochlorate of white solid, drying.
Last step product adds the 800mL ethyl acetate, is heated to backflow, drips triethylamine 28mL, continue to reflux 30 minutes, slowly be chilled to 30 ℃ and stirred 1 hour, be cooled to 5 ℃ and spend the night, filter, get white solid: 42.5 grams, HPLC purity: 98.80%, external standard content: 98.91%, yield: 65.59%, [α]
22 D=-131.2 ° (c 0.23, MeOH).
Comparative Examples 4: emtricitabine (synthetic (embodiment 4～6 does not add catalyzer) of Compound I-B)
In three-necked flask, add dipotassium hydrogen phosphate 136 grams, water 250 grams are stirred to dissolving, add 100 gram (2R below 20 ℃, 5S)-and 5-(5 '-fluoro-cytosine(Cyt)-1-yl)-1,3-oxathiolane-2-carboxylic acid-L-menthyl ester (compound V-B) and 750mL ethanol stirs and made its dispersion as far as possible in 30 minutes, between 15～25 ℃ of the controlled temperature, drip the 130 gram aqueous solution be dissolved with 0.45 gram sodium hydroxide and 18 gram sodium borohydrides in 2 hours, and under this temperature, react and disappeared to raw material point in about 2 hours.15 ℃ of left and right sides static layering, the upper strata organic layer is transferred pH=4 with hydrochloric acid, stirs 30 minutes, transfers about pH=7.0 with 10% sodium hydroxide then, steaming ethanol to temperature obviously raises, about surplus 300mL, be chilled to 30 ℃, divide reextraction with 800mL toluene, extraction liquid is washed with 30mL, combining water layer and water lotion, pressure reducing and steaming water 200mL adds ethanol 800mL, being cooled to 0 ℃ spends the night, filter, be dried to constant weight, get white solid: 40.0 grams, HPLC purity: 98.36%, external standard content: 98.29%, yield: 61.71%, [α]
22 D=-131.1 ° (c 0.23, MeOH).
Claims (10)
1. a structure is suc as formula the synthetic method of the nucleoside analog shown in (I), and described method comprises:
With the compound of structure shown in (V) is reaction substrate, with lithium ion reagent is catalyzer, with basic metal boron hydrohalogenic acid salt is reductive agent, in the mixed solvent of second alcohol and water, carry out the selective reduction reaction, after reduction reaction finished, reaction solution obtained the nucleoside analog shown in the formula (I) through separation and purification;
Among formula (I), (V), X is H or F.
2. the method for claim 1 is characterized in that described lithium ion reagent is lithium nitrate.
3. the method for claim 1 is characterized in that described lithium ion reagent is lithiumbromide.
4. the method for claim 1 is characterized in that described lithium ion reagent is lithium chloride.
5. as the described method of one of claim 1～4, it is characterized in that described reduction reaction carries out under 15～25 ℃.
6. as the described method of one of claim 1～4, it is characterized in that the ratio of described compound (V), basic metal boron hydrohalogenic acid salt, lithium ion reagent quality is 100: 10～20: 0.05～0.2.
7. as the described method of one of claim 1～4, it is characterized in that the ratio of described compound (V), ethanol, water consumption is: 100g: 600～800mL: 300～500g.
8. as the described method of one of claim 1～4, it is characterized in that described reduction reaction carries out in the presence of dipotassium hydrogen phosphate and sodium hydroxide, the ratio of described compound (V), dipotassium hydrogen phosphate, sodium hydroxide quality is 100: 100～150: 0.2～1.0.
9. as the described method of one of claim 1～4, it is characterized in that described separation purification method is as follows: after reaction finishes, the reaction solution standing demix, getting upper strata organic layer accent pH is 4～5, stirs 0.5～2.0 hour, and transferring pH again is 7.0, ethanol is reclaimed in distillation, raffinate behind the recovery ethanol is cooled to 20～30 ℃, with the toluene extraction, and the extraction liquid washing, water lotion decompression inspissation contracts, be cooled to 0～5 ℃ and spend the night, separate out crystal and be dried to constant weight, obtain described nucleoside analog.
10. the method for claim 1 is characterized in that described method carries out as follows:
(1) in reaction vessel, adds and water, be stirred to dissolving, 10～20 ℃ add compound (V), ethanol and lithium ion reagent down, stirring fully disperses it, controlled temperature is 15～25 ℃, drip the aqueous solution that is dissolved with sodium hydroxide and sodium borohydride in 2 hours, carry out selective reduction and react to complete reaction under 15～25 ℃, described lithium ion reagent is lithium nitrate, lithiumbromide or lithium chloride;
The ratio of described compound (V), dipotassium hydrogen phosphate, lithium ion reagent, sodium hydroxide, sodium borohydride quality is 100: 100～150: 0.05～0.2: 0.2～1.0: 10～20; The ratio of described compound (V), ethanol, total water amount is: 100g: 600～800mL: 300～500g;
(2) after reaction finished, reaction solution was in 15 ℃ of standing demix, and it is 4～5 that the upper strata organic layer is transferred pH with hydrochloric acid soln, stirred 30 minutes, transferring pH with the sodium hydroxide solution of mass concentration 10% is 7, and ethanol is reclaimed in distillation, and the raffinate behind the recovery ethanol is cooled to 20～30 ℃, extract with toluene, the extraction liquid washing, the water lotion concentrating under reduced pressure is cooled to 0～5 ℃ and spends the night, separate out crystal and be dried to constant weight, obtain described nucleoside analog.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102010404A (en) * | 2010-12-29 | 2011-04-13 | 刘建红 | Method for purifying and refining lamivudine and emtricitabine |
| CN102153545A (en) * | 2011-03-04 | 2011-08-17 | 杭州科本药业有限公司 | Preparation method for lamivudine |
| WO2011120927A1 (en) | 2010-03-29 | 2011-10-06 | Esteve Química, S.A. | Process for obtaining emtricitabine |
| WO2012131541A1 (en) * | 2011-03-25 | 2012-10-04 | Piramal Healthcare Limited | A process for the isolation of emtricitabine |
| CN102746284A (en) * | 2012-07-05 | 2012-10-24 | 湖南千金湘江药业股份有限公司 | Preparation method for lamivudine |
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| CN109355328A (en) * | 2018-12-07 | 2019-02-19 | 武汉工程大学 | The enzymatic preparation method of Lamivudine |
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2008
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011120927A1 (en) | 2010-03-29 | 2011-10-06 | Esteve Química, S.A. | Process for obtaining emtricitabine |
| EP2377862A1 (en) | 2010-03-29 | 2011-10-19 | Esteve Química, S.A. | Process for obtaining emtricitabine |
| CN102010404A (en) * | 2010-12-29 | 2011-04-13 | 刘建红 | Method for purifying and refining lamivudine and emtricitabine |
| CN102153545A (en) * | 2011-03-04 | 2011-08-17 | 杭州科本药业有限公司 | Preparation method for lamivudine |
| CN102153545B (en) * | 2011-03-04 | 2012-11-21 | 杭州科本药业有限公司 | Preparation method for lamivudine |
| WO2012131541A1 (en) * | 2011-03-25 | 2012-10-04 | Piramal Healthcare Limited | A process for the isolation of emtricitabine |
| CN102746284A (en) * | 2012-07-05 | 2012-10-24 | 湖南千金湘江药业股份有限公司 | Preparation method for lamivudine |
| CN108409724A (en) * | 2018-06-04 | 2018-08-17 | 安徽帆香料有限公司 | A kind of emtricitabine separation method |
| CN109355328A (en) * | 2018-12-07 | 2019-02-19 | 武汉工程大学 | The enzymatic preparation method of Lamivudine |
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