CN1176096C

CN1176096C - Technology for producing AR with IR as initiation material by liquid ammonia process

Info

Publication number: CN1176096C
Application number: CNB011238860A
Authority: CN
Inventors: 张光兴; 陆锦康
Original assignee: Individual
Current assignee: Individual
Priority date: 2001-08-10
Filing date: 2001-08-10
Publication date: 2004-11-17
Anticipated expiration: 2021-08-10
Also published as: CN1406946A

Abstract

The present invention discloses a preparation method. Inosine (IR) is used as an initial raw material and is acetylated by excessive acetic oxide. Obtained acetylated inosine is chlorinated by a Vilsmeier reagent to obtain chlorine-acetylated inosine. Through deacetylation, chlorinated inosine is obtained from chlorine-acetylated inosine. Liquid ammonia is introduced into the chlorinated inosine to carry out amination, and the inosine (IR) is converted into adenosine (AR), wherein through deacetylation, chlorinated inosine can be obtained from the chlorine-acetylated inosine. The chlorinated inosine as a product can be separated, liquid ammonia is introduced for amination, and adenosine (AR) as a product can be obtained, or through deacetylation, chlorinated inosine is obtained from chlorine-acetylated inosine. Without separation, amination is carried out by direct heating, and in this way, inosine (IR) is converted into the adenosine (AR). In the present invention, a high efficiency chlorinating reagent (Vilsmeier reagent) is used for chlorination. Liquid ammonia is used for ammoniation. The product which has the advantages of high yield, low cost and good quality is suitable for industrial production.

Description

With inosine (IR) is the technology that initiation material by liquid ammonia is produced adenosine (AR)

Invention field

The present invention relates to a kind of is starting raw material with inosine (IR), with the novel process that liquid ammonia process for caustic soda purification is produced adenosine (AR), is starting raw material with inosine (IR) particularly, prepares the novel process of adenosine (AR) through acetylize, chlorination, deacetylation, liquid ammonia amination.

Background technology

The similar of adenosine (AR) and inosine (IR), difference only are that place, 6-position adenosine is-NH2 that inosine is=O on its purine skeleton.They all are the important source material of Nucleotide industry, itself also all are medicines.By certain method, adenosine (AR) and easily conversion mutually of inosine (IR).J.Amer.Chem.Soc.Vol.80 for example, 1669-1675 has delivered inosine (IR) after the phenylating protection in 1958, by thio reaction, connects on the 6-position-the SH base, and first sulfuration then generates adenosine (AR) through reaction under high pressure again in methanol ammonia.This processing step is many, yield is low, quality product does not reach requirement, and suitability for industrialized production has difficulties.And adenosine (AR) can obtain inosine (IR) by deamination (chemical deamination or desaminase deamination).

Before the eighties, mainly from Yeast Nucleic Acid (RNA) degraded, dephosphorization obtains adenosine (AR) then.After the eighties, Japan begins with producing adenosine through zymotechnics (AR).But at present domestic because of no stable yields bacterial strain, producing adenosine through zymotechnics (AR) is in China's not industrialization as yet.Produce adenosine (AR) with above two kinds of methods, cost is all higher, and making with adenosine (AR) is other follow-up ucleotides product of raw material, as ATP, and cAMP, CoA, Ara-A etc. lack competitive capacity on market.

Adenosine (AR) all was that inosine (IR) is higher than adenosine (AR) with the market value of these two products of inosine (IR) in the past.But since domestic employing large-scale industry of the early 1990s inosine produced by fermentation (IR), the price of inosine reduces year by year, reduces to present Renminbi 130-150 unit/kilogram from the Renminbi 2400-2600 unit/kilogram of the seventies.So, can not be to adopted adenosine (AR) to obtain inosine (IR) like that in the past by deamination; And, then become possibility by inosine (IR) preparation adenosine (AR) because inosine (IR) is cheap.The price of adenosine (AR) is reduced greatly, and will make it have competitive capacity in the international market.

Summary of the invention

The object of the present invention is to provide with domestic inosine cheap and easy to get (IR) is starting raw material; produce the novel process of adenosine (AR) with liquid ammonia process for caustic soda purification; be starting raw material particularly, carry out the novel process that amination prepares adenosine (AR) through acetylize, chlorination, deacetylation, feeding liquid ammonia with inosine (IR).This technology is simple, production cost is low, productive rate is high, good product quality.

To achieve these goals, the technical solution used in the present invention is: with inosine (IR) is starting raw material, and with inosine acetylize in the presence of excessive aceticanhydride, the acetylize inosine that obtains obtains chloro-acetylize inosine through chlorination; Behind the chloro-acetylize inosine deacetylation, the chlorination inosine that obtains adopts the liquefied ammonia ammonification, obtains product adenosine (AR).

Another technical scheme of the present invention is: (IR) is starting raw material with inosine, makes inosine acetylize in the presence of excessive aceticanhydride, and the acetylize inosine that obtains obtains chloro-acetylize inosine through chlorination; Chloro-acetylize inosine is through deacetylation, and intermediate product chlorination inosine directly obtains the product adenosine with the liquefied ammonia ammonification without separating.

Concrete steps are as follows:

A). with inosine (IR) is raw material, under alkaline condition with inosine (IR) with excessive aceticanhydride acetylize, from reaction mixture, collect resultant acetylize inosine;

B). with resultant acetylize inosine be dissolved in Vilsmeier reagent/(chlorine methylene radical)-alkyl dimethyl ammonium chloride in the solvent and add in the reactor that fills above-mentioned solvent and reflux, after the cooling, this reaction solution is neutralized with alkaline aqueous solution, with solvent extraction at least once, solvent layer merge, dry, concentrate chloro-acetylize inosine;

C). above-mentioned chloro-acetylize inosine is dissolved in advance under 0 ℃ by in the saturated alcoholic solvent of ammonia, and reaction solution was sealed in 0 ℃ of following placing response 5-30 hour; The reaction back discharges remaining ammonia, through concentrated, dry, obtains chlorination inosine crystallisate; Described alcoholic solvent can be methyl alcohol, ethanol and be fit to other alcohols of the present invention;

D). the chlorination inosine that obtains is dissolved in the liquefied ammonia, in the high pressure resistant reactor of a sealing, is warming up to 90--130 ℃ of reaction 10--50 hour gradually; After reaction was finished, slowly excess of ammonia was emitted in decompression under room temperature, got pale brown-white solid; Solid is dissolved in recrystallization gets product adenosine (AR) in an amount of pure water.

Above-mentioned reaction is called the four-step reaction method.

In the aforesaid method, the deacetylation of chloroacetylation inosine and ammonification also can be carried out continuously.The chloro-acetylize inosine that above-mentioned a-b step is obtained is dissolved in advance under 0 ℃ by in the saturated methyl alcohol of ammonia, ethanol or other alcoholic solvents exactly, and reaction solution was sealed in 0 ℃ of following placing response 10--50 hour; After deacetylated reaction is finished, reaction solution is warming up to 90--130 ℃ of reaction 10-50 hour gradually, reaction mixture is through obtaining product adenosine (AR) except that ammonia, neutralization, crystallization.This reactive mode is called the three-step reaction method.

In one step of inosine among the present invention (IR) acetylize, described alkaline condition can and be fit to other organic basess of the present invention for arsenic pyridine, sodium alkoxide.

The chlorination of acetylize inosine is in the reaction of chloro-acetylize inosine among the present invention; described solvent can be one or more the combination of chloroform, tetracol phenixin, methylene dichloride, benzene, toluene, THF, DMF equal solvent, also can adopt to be fit to other solvents of the present invention.

The preparation method of above-mentioned adenosine can describe with following reaction formula:

With inosine (IR) is the reaction scheme of starting raw material synthesizing adenosine (AR):

Among the present invention, adopt solvent and reactant recovery system, with used solvent and excessive reactant in the preparation adenosine process, as all recyclings such as chloroform, benzene, alcohol, methyl alcohol, pyridine, aceticanhydride, ammonia, to reduce production costs, to reduce environmental pollution.Described solvent and reactant recovery system can adopt technology commonly used and method.

Describe the present invention in detail below in conjunction with the drawings and specific embodiments, described embodiment is used to describe the present invention, rather than restriction the present invention.

Description of drawings

The mass spectrum of the product that Fig. 1 four-step reaction obtains (E) adenosine (AR)

The infrared spectrogram of Fig. 2 a adenosine (AR) standard substance

The infrared spectrogram of product (E) adenosine (AR) that Fig. 2 b four-step reaction obtains

Fig. 3 a schemes through the chromatogram (HPLC) of product (E) adenosine (AR) that four-step reaction obtains

Fig. 3 b schemes through the chromatogram (HPLC) of product (E) adenosine (AR) that three-step reaction obtains

The potentiometric titration figure of the product that Fig. 4 four-step reaction obtains (E) adenosine (AR)

Specific embodiments

Embodiment 1

Adopt the four-step reaction legal system to be equipped with adenosine:

A). acetylization reaction: with 20 kilograms of reactant (A) inosines (IR) (74.56mol), aceticanhydride adds in the retort that fills 48 liters of pyridines for 32 liters, 130 ℃ of-131 ℃ of following stirring and refluxing.Thin-layer chromatography (TLC) monitoring reaction with silica gel coating thickness 0.25mm reacted about 1 hour, after treating that the reactant inosine disappears substantially in the thin-layer chromatography, after reaction solution vacuum concentration to pyridine and excessive aceticanhydride eliminated substantially, be placed under less than 5 ℃ environment and separate out precipitation.Filter the collecting precipitation thing and, get 24 kilograms of acetylize inosine (B) crude products with absolute ethanol washing, drying.Fusing point 234-239 ℃.Weight yield 120%.

The exhibition layer system of TLC is a chloroform: methyl alcohol=9: 1; Product (B) acetylize inosine Rf ≈ 0.5.

B). chlorination reaction: react product (B) the acetylize inosine that a) obtains and 16.32 kilograms of Vilsmeier reagent that are dissolved in 62.93 liters of chloroforms with 24 kilograms: (chlorine methylene radical)-alkyl dimethyl ammonium chloride adds in the retort that fills 64.25 liters of chloroforms, refluxes down at 61 ℃ ± 1 ℃.The thin-layer chromatography monitoring reaction, react about 1 hour after, question response thing (B) acetylize inosine disappears substantially.After the cooling, this reaction mixture solution under agitation is added drop-wise in 132 liters of saturated sodium bicarbonate solutions, room temperature dripped off in following 1 hour.At this moment, reaction solution layering.Water layer with twice of 33 liters of chloroform extracting after, the combined chloroform layer adds 4.8 kilograms of anhydrous magnesium sulfates (MgSO4) drying at least 0.5 hour under room temperature; Then, under 30 ℃, vacuum concentration gets 44.15 kilograms of flaxen soup compound (C) chloro-acetylize inosine crude products.

The exhibition layer system of TLC is a chloroform: methyl alcohol=9: 1; Product (C) chloro-acetylize inosine Rf ≈ 0.8.

C). deacetylation reaction: with product (C) chloro-acetylize inosine be dissolved in 100 liters in advance under 0 ℃ by in the saturated methyl alcohol of about 30 kilograms of liquefied ammonia, the reaction solution sealing was also placed 15 hours down at 0 ℃.After decompression discharges and reclaims remaining ammonia, eliminate substantially to ammonia and methyl alcohol at 30-32 ℃ of following vacuum concentration, product (D) chlorination inosine crystallizes out.With the vacuum-drying at room temperature of chlorination inosine crystallisate, get the spot that thin-layer chromatography shows homogeneous down, i.e. 12.619 kilograms of crude product (D) chlorination inosines.Fusing point 182-183.5 ℃.Weight yield to product B is 52.58%.This product can be in methyl alcohol recrystallization.

The exhibition layer system of TLC is a chloroform: methyl alcohol=4: 1.

D). aminating reaction: 12.619 kilograms of reaction product (D) chlorination inosines are dissolved in (the chlorination inosine: the liquefied ammonia mol ratio is 1: 33) in 25 kilograms of liquefied ammonia, in the high pressure resistant reactor of a sealing, are warming up to 110 ℃ gradually, kept 30 hours.Tank pressure is 79 kilograms of-74 kilograms of variations.After reaction was finished, slowly decompression discharged ammonia to eliminating substantially under room temperature, pale brown-white solid.Solid is dissolved in recrystallize gets 10.44 kilograms of product (E) adenosines (AR) in an amount of pure water.Fusing point 233-234 ℃.Weight yield 82.73%.The mass spectroscopy proof meets the molecular weight of adenosine (AR); The infrared measurement proof has the characteristic peak of adenosine, and consistent with the infrared spectrogram of standard adenosine (AR); Chromatogram (HPLC) is measured purity:＞99.50%; Potentiometric titration proof content＞98% is shown in accompanying drawing 1-4.Above leading indicator meets " American Pharmacopeia " USP24, version quality standard in 2000.

The weight total recovery of reaction is: 10.44/20 * 100%=52.2%.

Adopt solvent and reactant recovery system: will prepare solvent used in the adenosine process and excessive reactant, as all recyclings such as chloroform, methyl alcohol, pyridine, aceticanhydride, ammonia, to reduce production costs, to reduce environmental pollution.Described solvent and reactant recovery system can adopt technology commonly used and method.

Embodiment 2

Adopt the three-step approach synthesizing adenosine:

A)-b) technology of reaction is identical with embodiment 1, and different is will reaction c) and the reaction of deacetylation d) merge into a step with two steps of aminating reaction and finish reaction c) product need not separation, concrete operations are as follows:

With 44.15 kilograms of products (C) chloro-acetylize inosine be dissolved in 65.8 liters in advance under 0 ℃ by in the saturated methyl alcohol of about 30 kilograms of liquefied ammonia, the reaction solution of sealing was 0 ℃ of following placing response 15 hours.After reaction is finished, be warming up to 110 ℃ gradually, kept 30 hours.Tank pressure maintains 74 kilograms--and-79 kilograms.After reaction is finished, be cooled to room temperature, slowly decompression discharges ammonia to eliminating substantially, 12.86 kilograms of pale brown-white solid product (E) adenosines (AR).Fusing point: 233 ℃.Chromatogram (HPLC) purity: 99.15%.Content (potentiometric titration): 93-95%.Weight yield with respect to product (B) is 53.58%; Total recovery is: 12.86/20 * 100%=64.3%.

The adenosine that present embodiment 1 and 2 obtains can be further purified by recrystallization, and concrete grammar is as follows:

Behind the thorough Ex-all ammonia of product (E) adenosine (AR), add an amount of pure water dissolving.Then, transfer PH 2.0-3.0 with 6N hydrochloric acid, add activated carbon decolorizing after, filter; Filtrate is transferred PH 4.5-5.0 again, cold placement, precipitation to be separated out.The elimination throw out.Supernatant liquor transfers PH 11 placement freezers to spend the night, and has a large amount of adenosines (AR) crystallization to separate out.Filter and collect crystallization, drying.Mother liquor reclaims.The adenosine that is met 24,2000 years version quality standards of " American Pharmacopeia " USP.

Comparing embodiment 1 and 2 as can be seen,, " three-step approach " yield is higher about 12 percentage points than " four step rule ", but adenosine product (E) purity that " three-step approach " obtains is not as " four step rule ".The adenosine product that " three-step approach " obtains behind the palpus recrystallizing and refining, just can reach 24,2000 years version quality standards of " American Pharmacopeia " USP.

Embodiment 3

Adopt the four-step reaction legal system to be equipped with adenosine:

A) acetylization reaction: with 20 kilograms of reactant (A) inosines (IR), aceticanhydride adds to for 20 liters in the retort that fills 2 kilograms of sodium ethylates, and stirring and refluxing was also used the thin-layer chromatography monitoring reaction, to about 2 hours.After reactant disappears substantially in the thin-layer chromatography, the reaction solution vacuum concentration to after excessive aceticanhydride eliminates substantially, is placed under less than 5 ℃ environment and separates out precipitation.Filter the collecting precipitation thing and, get 25 kilograms of product (B) acetylize inosines with absolute ethanol washing, drying.Fusing point 234-238 ℃.Weight yield 125%

B) chlorination reaction: 25 kilograms of reactions product (B) acetylize inosine that a) obtains and the 12 kilograms of Vilsmeier reagent [(chlorine methylene radical)-alkyl dimethyl ammonium chloride] that are dissolved in 50 liters of benzene are added in the retort that fills 50 liters of benzene; reflux; the thin-layer chromatography monitoring reaction; after about 2 hours, reactant (B) acetylize inosine disappears substantially.After the cooling, this reaction solution under agitation is added drop-wise in the saturated sodium bicarbonate solution, water layer with twice of chloroform extracting after, the combined chloroform layer, it is dry under room temperature to add anhydrous magnesium sulfate; Then, vacuum concentration gets 46.95 kilograms of flaxen soup compound (C) chloro-acetylize inosines.

C) deacetylation reaction: with product (C) chloro-acetylize inosine be dissolved in 80 liters in advance under-5 ℃ by in the saturated ethanol of liquefied ammonia, the reaction solution sealing was also being placed 30 hours down less than-5 ℃.After decompression discharged and reclaims remaining ammonia, vacuum concentration eliminated substantially to ammonia and methyl alcohol, and product (D) chlorination inosine crystallizes out.With the vacuum-drying at room temperature of chlorination inosine crystallisate, get 14.1 kilograms of product (D) chlorination inosines.Fusing point 182-183 ℃.Weight yield to product B is 56.4%.This product can be in methyl alcohol recrystallize.

D) aminating reaction: according to the chlorination inosine: the liquefied ammonia mol ratio is reaction product chlorination inosine to be dissolved in the liquefied ammonia for 14.1 kilograms in 1: 25, is warming up to 130 ℃ gradually in the high pressure resistant reactor of a sealing, keeps 10 hours.After reaction was finished, slowly decompression discharged ammonia to eliminating substantially under room temperature, pale brown-white solid.Solid is dissolved in recrystallization gets 11.22 kilograms of product (E) adenosines (AR) in an amount of pure water.Fusing point 233-234 ℃.Weight yield 86.66%.Meet 24,2000 years version quality standards of " American Pharmacopeia " USP after measured.

E) weight total recovery: 11.22/20 * 100%=56.1%.

Embodiment 4

Adopt the three-step approach synthesizing adenosine:

A)-b) technology of reaction is identical with embodiment 3, and different is will reaction c) and the reaction of deacetylation d) merge into a step with two steps of aminating reaction and finish reaction c) product need not separation, concrete operations are as follows:

With 46.95 kilograms of products (C) chloro-acetylize inosine be dissolved in 50 liters in advance under 0 ℃ by in the saturated methyl alcohol of liquefied ammonia, the reaction solution of sealing after reaction is finished, is warming up to 90 ℃ 0 ℃ of following placing response 5 hours gradually, keeps 50 hours.After reaction is finished, be cooled to room temperature, slowly decompression discharges ammonia to eliminating substantially, 14.55 kilograms of pale brown-white solid product (E) adenosines (AR).Fusing point: 233 ℃.Chromatogram (HPLC) purity: 99.15%.Content (potentiometric titration): 93-95%.Weight yield with respect to product (B) is: 58.2%; The weight total recovery is: 14.55/20 * 100%=72.75%.

Present embodiment 3,4The adenosine that obtains can be further purified by recrystallization, and concrete grammar is as follows:

Among the embodiment, the method for potentiometric titration is: claim adenosine sample (AR) 0.1996 gram, be dissolved in a certain amount of acetic acid solution under fully stirring, with acetate standardized solution (0.02642mol./L) titration of perchloric acid to terminal.27.5ml perchloric acid acetate standardized solution is equivalent to 98.28% finished product adenosine (AR) content (in dry product).

The present invention is a raw material with domestic inosine cheap and easy to get (IR), and through acetylize, the acetylize inosine that obtains obtains chloro-acetylize inosine through chlorination; Chloro-acetylize inosine obtains adenosine (AR) through deacetylation, ammonification; This production craft step is simple and direct, the productive rate height, and AR/IR weight yield＞50% is guaranteed to make 1 kilogram of AR with being lower than 2 kilograms of IR, and good product quality reduces the production cost of adenosine (AR) greatly.

Claims

1. be the technology that starting raw material, liquid ammonia process for caustic soda purification are produced adenosine with the inosine, it is characterized in that with inosine in the presence of alkali with excessive aceticanhydride acetylize, the acetylize inosine that obtains obtains chloro-acetylize inosine through chlorination; Behind the chloro-acetylize inosine deacetylation, the chlorination inosine that obtains adopts the liquefied ammonia ammonification to obtain the product adenosine.

2. be the technology that starting raw material, liquid ammonia process for caustic soda purification are produced adenosine with the inosine, it is characterized in that making inosine in the presence of alkali with excessive aceticanhydride acetylize, the acetylize inosine that obtains obtains chloro-acetylize inosine through chlorination; Behind the chloro-acetylize inosine deacetylation, intermediate product chlorination inosine directly obtains the product adenosine with the liquefied ammonia ammonification without separating.

According to claim 1,2 one of them described be the technology that starting raw material, liquid ammonia process for caustic soda purification are produced adenosine with the inosine, it is characterized in that alkali used in the described acetylization reaction is pyridine or sodium alkoxide.

4. according to claim 3 is the technology that starting raw material, liquid ammonia process for caustic soda purification are produced adenosine with the inosine, it is characterized in that the preferred pyridine of alkali used in the described acetylization reaction.

According to claim 1,2 one of them described be the technology that starting raw material, liquid ammonia process for caustic soda purification are produced adenosine with the inosine, it is characterized in that be chloro-acetylize inosine with the acetylize inosine with the chlorination of Vilsmeier reagent; The temperature of chlorination reaction is controlled at 61 ℃ ± 1 ℃.

6. according to claim 1 is the technology that starting raw material, liquid ammonia process for caustic soda purification are produced adenosine with the inosine, it is characterized in that chloro-acetylize inosine is dissolved in advance under 0 ℃ by in the saturated alcohol of ammonia, and the reaction solution sealing is less than 0 ℃ of following placing response 5-30 hour; The reaction back discharges remaining ammonia, through concentrated, dry, obtains chlorination inosine crystallisate.

7. according to claim 1 is the technology that starting raw material, liquid ammonia process for caustic soda purification are produced adenosine with the inosine, it is characterized in that the chlorination inosine is dissolved in the liquefied ammonia, is warming up to 90-130 ℃ of reaction 10-50 hour in the high pressure resistant reactor of a sealing gradually; After reaction was finished, slowly excess of ammonia was emitted in decompression under room temperature, got pale brown-white solid product adenosine.

8. according to claim 2 is the technology that starting raw material, liquid ammonia process for caustic soda purification are produced adenosine with the inosine, the deacetylation and the aminating reaction that it is characterized in that the acetylize inosine carry out continuously, step is: chloro-acetylize inosine is dissolved in advance under 0 ℃ by in the saturated methyl alcohol of ammonia, the reaction solution sealing is after following placing response 10-50 hour less than 0 ℃; Reaction solution is warming up to 90-130 ℃ gradually, reacted 10-50 hour, reaction mixture is through obtaining product except that ammonia, neutralization, recrystallization

9. according to claim 1 is the technology that starting raw material, liquid ammonia process for caustic soda purification are produced adenosine with the inosine, it is characterized in that reactions steps is as follows:

A). acetylization reaction: with 20 kilograms of reactant inosines, aceticanhydride adds in the retort of containing 48 liters of pyridines for 32 liters, 130 ℃ of-131 ℃ of following stirring and refluxing, use the thin-layer chromatography monitoring reaction, after reactant disappeared substantially to about 1 hour thin-layer chromatography, after reaction solution vacuum concentration to pyridine and excessive aceticanhydride eliminated substantially, be placed under less than 5 ℃ environment and separate out precipitation; Filter the collecting precipitation thing and, get 24 kilograms of acetylize inosine crude products, fusing point 234-239 ℃ with absolute ethanol washing, drying;

B). chlorination reaction: with 24 kilograms of acetylize inosines be dissolved in 16.32 kilograms of Vilsmeier reagent in 62.93 liters the chloroform and add in the retort that fills 64.25 liters of chloroforms and reflux, thin-layer chromatography monitoring reaction to reactant acetylize inosine disappears substantially; After the cooling, under agitation be added drop-wise to this reaction solution in the saturated sodium bicarbonate solution; After twice of the water layer usefulness chloroform extracting, the combined chloroform layer, it is dry under room temperature to add anhydrous magnesium sulfate, and then, vacuum concentration gets 44.15 kilograms of flaxen soup compound chloro-acetylize inosine crude products;

C). deacetylation reaction: with product chloro-acetylize inosine be dissolved in 100 liters in advance under 0 ℃ by in the saturated methyl alcohol of about 30 kilograms of liquefied ammonia, the reaction solution sealing was also being placed 15 hours down less than 0 ℃; After decompression discharged and reclaims remaining ammonia, vacuum concentration eliminated substantially to ammonia and methyl alcohol, and product chlorination inosine crystallizes out; With the vacuum-drying at room temperature of chlorination inosine crystallisate, get 12.619 kilograms of crude product chlorination inosines; Fusing point 182-183.5 ℃;

D). aminating reaction: 12.619 kilograms of reaction product chlorination inosines are dissolved in 25 kilograms of liquefied ammonia, in the high pressure resistant reactor of a sealing, be warming up to 110 ℃ gradually, kept 30 hours, after reaction is finished, slowly decompression discharges ammonia to eliminating substantially under room temperature, pale brown-10.44 kilograms of white solid adenosines, fusing point 233-234 ℃; Total weight yield: 52.2%.

10. according to claim 2 is the technology that starting raw material, liquid ammonia process for caustic soda purification are produced adenosine with the inosine, it is characterized in that comprising the steps:

A). acetylization reaction: with 20 kilograms of reactant inosines, aceticanhydride adds in the retort that fills 48 liters of pyridines for 32 liters, 130 ℃ of-131 ℃ of following stirring and refluxing, uses the thin-layer chromatography monitoring reaction, disappears substantially to reactant; After reaction solution vacuum concentration to pyridine and excessive aceticanhydride eliminated substantially, be placed under less than 5 ℃ environment and separate out precipitation; Filter the collecting precipitation thing and, get 24 kilograms of acetylize inosine crude products, fusing point 234-239 ℃ with absolute ethanol washing, drying;

B). chlorination reaction: with 24 kilograms of acetylize inosines be dissolved in 16.32 kilograms of Vilsmeier reagent in 62.93 liters the chloroform, add in the retort that fills 64.25 liters of chloroforms and reflux, thin-layer chromatography monitoring reaction to reactant acetylize inosine disappears substantially; After the cooling, this reaction solution is added drop-wise in the saturated sodium bicarbonate solution; After twice of the water layer usefulness chloroform extracting, the combined chloroform layer adds anhydrous magnesium sulfate drying; Then, vacuum concentration gets 44.15 kilograms of flaxen soup compound chloro-acetylize inosine crude products;

C). deacetylation-aminating reaction merges and carries out: 44.15 kilograms of product chloro-acetylize inosines are dissolved in 65.8 liters and give earlier under 0 ℃ and to be used approximately in the saturated methyl alcohol of 30 kilograms of liquefied ammonia; The reaction solution of sealing after 15 hours, is being warming up to 110 ℃ less than 0 ℃ of following placing response gradually, keeps 30 hours; Be cooled to room temperature, slowly decompression discharges ammonia to eliminating substantially, pale brown-12.86 kilograms of white solid product adenosines; Fusing point: 233 ℃; Total weight yield 64.3%;

11. according to claim 10 is the technology that starting raw material, liquid ammonia process for caustic soda purification are produced adenosine with the inosine, it is characterized in that behind the thorough Ex-all ammonia of product adenosine, adds an amount of pure water dissolving; Transfer to PH 2.0-3.0 with hydrochloric acid, add activated carbon decolorizing after, filter; Filtrate transfers to PH 4.5-5.0 again, cold placement, precipitation to be separated out, elimination throw out; Supernatant liquor transfers PH 11 spending the night less than 0 ℃ of placement, and the adenosine crystallization is separated out.