CN108373471A - A kind of synthetic method of high-purity single acetyl Ganciclovir - Google Patents
A kind of synthetic method of high-purity single acetyl Ganciclovir Download PDFInfo
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- CN108373471A CN108373471A CN201810405248.4A CN201810405248A CN108373471A CN 108373471 A CN108373471 A CN 108373471A CN 201810405248 A CN201810405248 A CN 201810405248A CN 108373471 A CN108373471 A CN 108373471A
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- ganciclovir
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- 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 kind of synthetic methods of high-purity single acetyl Ganciclovir, include the following steps：Using Ganciclovir as raw material, alcoholic extract hydroxyl group is protected through three ester of boric acid, and acetylation reagent is then added and carries out highly selective acylation, obtains single acetyl Ganciclovir.Preparation method feed stock conversion that the present invention announces is high, acetylation is selectively good, and gained single acetyl Ganciclovir content reaches 99% or more, improves the synthesis quality of follow-up valganciclovir class product, and production efficiency is high, is suitble to large-scale industrial production.
Description
Technical field
The invention belongs to pharmaceutical intermediates to synthesize field, and in particular to a kind of synthesis side of high-purity single acetyl Ganciclovir
Method.
Background technology
Valganciclovir (valganciclovir) is the prodrug of Ganciclovir, for treat AIDS patient by big and small
The long-term treatment of the kidney transplant patients of the retinitis caused by cellular virus (CMV) and cytomegalovirus (CMV) disease risks,
Ganciclovir can be hydrolyzed by phosphate in enteron aisle and liver after oral and play antivirus action, but its bioavilability is aobvious
It writes and is higher than Ganciclovir, be 10 times of Ganciclovir, toxicity substantially reduces, and is administered orally conveniently, in recent years figured silk fabrics more former times Lip river
The market share of Wei improves year by year, wide market.
Single acetyl Ganciclovir, entitled 9- (1- acetoxy-3s-the third oxygen of the hydroxyl -2- methyl) guanine of chemistry are synthesis
The important intermediate of valganciclovir, at present the preparation method of document report mainly have following two：
(1) using triacetyl Ganciclovir as raw material, organic amine effect under hydrolysis obtain single acetyl Ganciclovir (Europe specially
Sharp EP1837336).This method needs stir 48 hours at 50-75 DEG C, and reaction time is long, and raw material converts incomplete and diethyl
The generation of acyl Ganciclovir is that the purification of subsequent product valganciclovir increases difficulty.
(2) it is reacted under the conditions of acidic catalyst with trimethyl orthoacetate as raw material using Ganciclovir and generates single acetyl more former times
Luo Wei (Nucleosides and Nucleotides, 1994,13,903-913 and Magnetic Resonance in
Chemistry 2000,38,696-700).This method major defect is that have the generation of diacetyl Ganciclovir, diacetyl more former times Lip river
The content of Wei accounts for 17-21%, and the separation of single acetyl and diacetyl product is more difficult, and the single acetyl Ganciclovir caused is pure
Degree is in 90-95% or so, the final quality for influencing valganciclovir.
In conclusion it is single acetyl Ganciclovir and pair that the existing stage, which prepares the shortcomings that single acetyl Ganciclovir generally existing,
Difficult problem is isolated and purified between product diacetyl Ganciclovir and remaining raw material Ganciclovir or triacetyl Ganciclovir,
Product single acetyl Ganciclovir purity is caused to be difficult to reach ideal quality.
Invention content
It is an object of the invention to overcome defect existing for above-mentioned technology, a kind of high-purity single acetyl Ganciclovir is provided
Synthetic method, this method reduce the remaining of raw material, effectively reduce the ratio of diacetyl Ganciclovir, the product of reaction easily divides
From life cycle of the product shortens, and purity is up to 99% or more, is conducive to industrialized production.
The technical solution adopted in the present invention, reaction equation are as follows：
A kind of synthetic method of high-purity single acetyl Ganciclovir, includes the following steps：
Ganciclovir and protection reagent carry out hydroxyl protection reaction in organic solvent, and acetylation examination is added after reaction
Agent, through being quenched and obtaining after purification single acetyl Ganciclovir.
Further, the organic solvent is selected from tetrahydrofuran, 2- methyltetrahydrofurans, ethyl acetate or toluene.
Further, the protection reagent is selected from Dibutyltin oxide, three ester of boric acid, methyl-boric acid, sulfite, alkyl
The molar ratio of any one in methoxyl group silicon, Ganciclovir and protection reagent is 1:0.5-1.5.Preferably for dibutyl
It is 1 that tin oxide, which protects reagent, the two molar ratio,:0.1-0.5；For borate, methyl-boric acid, sulfite, alkyl methoxyl group
It is 1 that silicon, which protects reagent, the two molar ratio,:1-1.5.
In addition it is also possible to protect glycol under the conditions of selective chlorination sulfoxide and alkali (such as pyridine), high-purity production can be also obtained
Product, but yield is substantially reduced.
Wherein, three ester of boric acid includes trimethylborate, triethyl borate, triisopropyl borate ester and butyl borate.Sulfurous
Acid esters includes dimethyl sulfite and sulfurous acid diethyl ester, can be bought with market, can also be by thionyl chloride and methanol or ethyl alcohol
It is used after reaction purification.Alkyl methoxyl group silicon includes dimethylformamide dimethyl oxygroup silicon and methyl trimethoxy oxygroup silicon.
Selection dihydroxy protection is easy reaction when needing in view of upper protecting group, and does not make with the group on purine ring
Also want relatively mild with condition when, deprotection.In above-mentioned protecting group, preferably methyl-boric acid, sulfite and dibutyl oxidation
Tin, since itself aqueous solvent is good, reaction terminates methyl-boric acid, can be removed completely by way of washing.
Further, the acetylation reagent is selected from vinyl acetate or 1- acetyl imidazoles, Ganciclovir and acetylation examination
The molar ratio of agent is 1:1-4.
Experiment is found：When the selection of acetylation reagent is using common chloroacetic chloride, acetic anhydride, 1- when acetylation reagent excess
When 1.5 equivalent, Main By product is hydroxyl diacetyl (O, O), and acetylation reagent is in 0.8-0.95 equivalents, in addition to raw material is anti-
Answer it is endless except, still have apparent hydroxyl diacetyl by-product.
Use vinyl acetate or 1- acetyl imidazoles for acetylation reagent, reaction speed is slower, but it is double that hydroxyl is not detected
Acetylation by-product, when acetylation reagent excess, raw material can with the reaction was complete, only occur can with 6% N below of controlled quentity controlled variable,
O- diacetyl by-products, can be removed by ethyl alcohol recrystallization.
Further, the reagent that is quenched is alcohols solvent, is selected from methanol or ethyl alcohol.When deprotection is quenched, catalysis is added
Amount imidazoles can be accelerated to deprotect speed.
Experiment is found：When deprotection, optimize Dibutyltin oxide and dimethylformamide dimethyl oxygroup silicon, methyl trimethoxy oxygroup silicon shape
At protecting group it is the quickest.
Further, acetyl is added after carrying out hydroxyl protection reaction in organic solvent in the Ganciclovir and protection reagent
Change reagent, carry out highly selective acylation, the ratio of single acetyl Ganciclovir and diacetyl Ganciclovir in reaction solution is controlled in experiment
For 92-95：3-6, diacetyl product are N, O- diacetyl Ganciclovir through structural confirmation.
Invention advantageous effect
(1) synthesis of the prior art to single acetyl Ganciclovir, products obtained therefrom content only have 90-95%, the present invention with it is existing
There is technology to compare, good reaction selectivity greatly reduces the ratio of diacetyl Ganciclovir, and improves raw material Ganciclovir
Conversion ratio and yield so that the single acetyl Ganciclovir purity finally prepared is up to 99% or more, to ensure that the follow-up production of synthesis
The quality of product valganciclovir.
(2) present invention is easy to operate, and multistep reaction can be completed by " one kettle way ", and intermediate is without isolating and purifying, product
Disposably detached with impurity and can reach acceptable quality, improve efficiency, and is few using solvent, reduce valganciclovir at
Sheet and environmental pollution are suitble to industrialization large-scale production.
Specific implementation mode
Embodiment 1
By Ganciclovir 500.0g (1.96mol, 1.0eq), Dibutyltin oxide 244.0g (0.98mol, 0.5eq), four
Hydrogen furans 5.0kg is added in reaction kettle, is heated to back flow reaction 3 hours, and raw material is controlled in TLC, and the reaction was complete, is down to room temperature, is added
Iodine 49.7g (0.196mol, 0.1eq) is then added dropwise to vinyl acetate 337.5g (3.92mol, 2.0eq), it is small to be stirred at room temperature 5
When, control single acetyl Ganciclovir and the ratio of impurity are 95/3 in HPLC, are cooled down 0~10 DEG C, and 2.0kg methanol is added dropwise, and drop finishes, room
Temperature stirring 2 hours, is concentrated under reduced pressure out solvent, and 3.0kg ethyl acetate is added, and crosses and filters out insoluble matter, and filtrate is primary with 500g washings,
Layering, water layer are extracted with 500g ethyl acetate, and organic layer merges, and are concentrated under reduced pressure, and ethyl alcohol recrystallization obtains clear crystal 434.5g, are received
Rate 74.6%, purity 99.3%, mp 133.6-134.2 DEG C, MS (m/z) 298.2 (M+H)+, H NMR (400MHz, DMSO-
d6)：10.56(s,1H),7.76(s,1H),6.45(s,2H),5.37(s,2H),4.80-4.84(d,1H),3.82-3.86(d,
1H),3.75-3.80(m,1H),3.21-3.41(m,3H),1.83(s,3H)；A small amount of reaction solution is taken, by preparing liquid phase separation
Go out impurity, carries out qualitative analysis, MS (m/z) 340.3 (M+H)+, H NMR (400MHz, DMSO-d6)：12.10(s,1H),
11.86(bs,1H),8.14(s,1H),5.53(s,1H),3.81-4.17(m,3H),3.16(bs,1H),2.19(s,3H),
1.81 (s, 3H) confirm that the impurity structure is N, O- diacetyl Ganciclovir.
It is 0.1mol Ganciclovir below, is operated according to embodiment 1, from the Dibutyltin oxide of different equivalents, acetylation
The experimental result of reagent reaction：
Remarks：1. TM/IM is single acetyl Ganciclovir/N, O- diacetyl Ganciclovir
Embodiment 2
By Ganciclovir 500.0g (1.96mol, 1.0eq), trimethylborate 244.4g (2.35mol, 1.2eq), toluene
7.5kg is added in reaction kettle, is heated to back flow reaction 5 hours, and raw material is controlled in TLC, and the reaction was complete, is down to room temperature, and triethylamine is added
396.7g (3.93mol, 2.0eq) is then added 1- acetyl imidazoles 323.7g (2.94mol, 1.5eq), it is small to be stirred at room temperature 6
When, the ratio of control single acetyl Ganciclovir and N, O- diacetyl Ganciclovir is 94/4 in HPLC, is cooled down 0~10 DEG C, is added dropwise
2.0kg methanol, drop finish, are stirred at room temperature 2 hours, and solvent is concentrated under reduced pressure out, and 3.0kg ethyl acetate is added, and are washed once with 500g,
Layering, water layer are extracted with 500g ethyl acetate, and organic layer merges, and are concentrated under reduced pressure, and ethyl alcohol recrystallization obtains clear crystal 440.9g, are received
Rate 75.7%, purity 99.2%, mp 133.9-134.6 DEG C, MS (m/z) 298.2 (M+H)+。
Embodiment 3
By Ganciclovir 500.0g (1.96mol, 1.0eq), triethyl borate 314.7g (2.15mol, 1.1eq), 2- first
Base tetrahydrofuran 5.0kg is added in reaction kettle, is heated to back flow reaction 3 hours, and raw material is controlled in TLC, and the reaction was complete, is down to room temperature,
Triethylamine 595.0g (5.88mol, 3.0eq) is added, vinyl acetate 421.8g (4.9mol, 2.5eq) is then added, is stirred at room temperature
6 hours, the ratio that single acetyl Ganciclovir and N, O- diacetyl Ganciclovir are controlled in HPLC was 93/5, cools down 0~10 DEG C, is added dropwise
2.0kg ethyl alcohol, drop finish, are stirred at room temperature 3 hours, and solvent is concentrated under reduced pressure out, and 3.0kg ethyl acetate is added, and are washed once with 500g,
Layering, water layer are extracted with 500g ethyl acetate, and organic layer merges, and are concentrated under reduced pressure, and ethyl alcohol recrystallization obtains clear crystal 438.0g, are received
Rate 75.2%, purity 99.1%, mp 133.6-134.5 DEG C, MS (m/z) 298.2 (M+H)+。
Embodiment 4
By Ganciclovir 500.0g (1.96mol, 1.0eq), methyl-boric acid 140.7g (2.35mol, 1.2eq), tetrahydrochysene furan
The 5.0kg that mutters is added in reaction kettle, is heated to back flow reaction 3 hours, and raw material is controlled in TLC, and the reaction was complete, is down to room temperature, and three second are added
Amine 595.0g (5.88mol, 3.0eq) is then added vinyl acetate 421.8g (4.9mol, 2.5eq), is stirred at room temperature 6 hours,
The ratio that single acetyl Ganciclovir and N, O- diacetyl Ganciclovir are controlled in HPLC is 93/5, cools down 0~10 DEG C, 2.0kg is added dropwise
Methanol, drop finish, are stirred at room temperature 3 hours, and solvent is concentrated under reduced pressure out, and 3.0kg ethyl acetate is added, and primary, layering is washed with 500g,
Water layer is extracted with 500g ethyl acetate, and organic layer merges, and is concentrated under reduced pressure, and ethyl alcohol recrystallization obtains clear crystal 421.1g, yield
72.3%, purity 99.3%, mp 133.7-134.7 DEG C, MS (m/z) 298.2 (M+H)+。
It is 0.1mol Ganciclovir below, is operated according to embodiment 4, it is anti-from the borane reagent of different equivalents, acetylation reagent
The experimental result answered：
Remarks：1. TM/IM is single acetyl Ganciclovir/N, O- diacetyl Ganciclovir
Embodiment 5
By Ganciclovir 500.0g (1.96mol, 1.0eq), pyridine 232.6g, 2- methyltetrahydrofuran 5.0kg is added anti-
It answers in kettle, thionyl chloride 349.8g (2.94mol, 1.5eq) is added dropwise, drop, which finishes, is heated to back flow reaction 4 hours, and raw material is controlled in TLC
The reaction was complete, and solvent and remaining thionyl chloride are concentrated under reduced pressure out after cooling, and triethylamine 495.8g (4.9mol, 2.5eq) is added,
Then 1- acetyl imidazoles 431.6g (3.92mol, 2.0eq) is added, is stirred at room temperature 6 hours, single acetyl more former times Lip river is controlled in HPLC
The ratio of Wei and N, O- diacetyl Ganciclovir are 94/4, are cooled down 0~10 DEG C, and 2.0kg ethyl alcohol is added dropwise, and drop finishes, and it is small to be stirred at room temperature 4
When, solvent is concentrated under reduced pressure out, 3.0kg ethyl acetate is added, primary, layering, water layer 500g vinyl alcohols extraction are washed with 500g
It takes, organic layer merges, and is concentrated under reduced pressure, and ethyl alcohol recrystallization obtains clear crystal 268.5g, yield 46.1%, purity 97.3%, mp
133.5-135.6 DEG C, MS (m/z) 298.2 (M+H)+。
Embodiment 6
By Ganciclovir 500.0g (1.96mo, 1.0eq), dimethyl sulfite 215.8g (1.96mol, 1.0eq), toluene
8.0kg is added in reaction kettle, is heated to back flow reaction 4 hours, and raw material is controlled in TLC, and the reaction was complete, is down to room temperature, and triethylamine is added
595.0g (5.88mol, 3.0eq) is then added 1- acetyl imidazoles 539.5g (4.9mol, 2.5eq), is stirred at room temperature 6 hours,
The ratio that single acetyl Ganciclovir and N, O- diacetyl Ganciclovir are controlled in HPLC is 93/5, cools down 0~10 DEG C, imidazoles is added
2.0kg methanol is then added dropwise in 25g, and drop finishes, is stirred at room temperature 3 hours, and solvent is concentrated under reduced pressure out, and 3.0kg ethyl acetate is added, and uses
500g washings are primary, and layering, water layer is extracted with 500g ethyl acetate, and organic layer merges, and are concentrated under reduced pressure, ethyl alcohol recrystallization obtains colourless
Crystal 419.4g, yield 72.0%, purity 99.2%, mp 133.7-134.5 DEG C, MS (m/z) 298.2 (M+H)+。
It is 0.1mol Ganciclovir below, is operated according to embodiment 6, from the dimethyl sulfite of different equivalents, acetylation
The experimental result of reagent reaction：
Remarks：1. TM/IM is single acetyl Ganciclovir/N, O- diacetyl Ganciclovir
Embodiment 7
By Ganciclovir 500.0g (1.96mol, 1.0eq), dimethylformamide dimethyl oxygroup silicon 259.2g (2.16mol,
1.1eq), tetrahydrofuran 5.0kg is added in reaction kettle, is heated to back flow reaction 4 hours, and raw material is controlled in TLC, and the reaction was complete, is down to
Pyridine 310.0g (3.92mol, 2.0eq) is added in room temperature, and 1- acetyl imidazoles 431.6g (3.92mol, 2.0eq) is then added,
It being stirred at room temperature 6 hours, the ratio that single acetyl Ganciclovir and N, O- diacetyl Ganciclovir are controlled in HPLC is 95/3, cooling 0~
10 DEG C, 2.0kg methanol is added dropwise, drop finishes, is stirred at room temperature 3 hours, and solvent is concentrated under reduced pressure out, and 3.0kg ethyl acetate is added, uses 500g
Washing is primary, and layering, water layer is extracted with 500g ethyl acetate, and organic layer merges, and is concentrated under reduced pressure, and ethyl alcohol recrystallization obtains clear crystal
433.3g, yield 74.4%, purity 99.4%, mp 133.9-134.6 DEG C, MS (m/z) 298.2 (M+H)+。
Embodiment 8
By Ganciclovir 500.0g (1.96mol, 1.0eq), methyl trimethoxy oxygroup silicon 267.0g (1.96mol, 1.0eq),
Toluene 8.0kg is added in reaction kettle, is heated to back flow reaction 5 hours, and raw material is controlled in TLC, and the reaction was complete, is down to room temperature, and pyrrole is added
Pyridine 542.6g (6.86mol, 3.5eq) is then added vinyl acetate 506.2g (5.88mol, 3.0eq), is stirred at room temperature 5 hours,
The ratio that single acetyl Ganciclovir and N, O- diacetyl Ganciclovir are controlled in HPLC is 94/4, cools down 0~10 DEG C, 2.0kg is added dropwise
Ethyl alcohol, drop finish, are stirred at room temperature 3 hours, and solvent is concentrated under reduced pressure out, and 3.0kg ethyl acetate is added, and primary, layering is washed with 500g,
Water layer is extracted with 500g ethyl acetate, and organic layer merges, and is concentrated under reduced pressure, and ethyl alcohol recrystallization obtains clear crystal 430.5g, yield
73.9%, purity 99.3%, mp 133.8-134.7 DEG C, MS (m/z) 298.2 (M+H)+。
It is 0.1mol Ganciclovir below, is operated according to embodiment 7, it is anti-from the silica reagent of different equivalents, acetylation reagent
The experimental result answered：
Remarks：1. TM/IM is single acetyl Ganciclovir/N, O- diacetyl Ganciclovir
The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (7)
1. a kind of synthetic method of high-purity single acetyl Ganciclovir, which is characterized in that include the following steps：Ganciclovir and boron
Sour three esters carry out hydroxyl protection reaction in organic solvent, and acetylation reagent is added after reaction, through being quenched and obtaining after purification
Single acetyl Ganciclovir.
2. a kind of synthetic method of high-purity single acetyl Ganciclovir according to claim 1, it is characterised in that：It is described to have
Solvent is selected from tetrahydrofuran, 2- methyltetrahydrofurans or toluene.
3. a kind of synthetic method of high-purity single acetyl Ganciclovir according to claim 1, it is characterised in that：The boron
Sour three esters are selected from trimethylborate, three n-butyl of triethyl borate, triisopropyl borate ester and boric acid.
4. a kind of synthetic method of high-purity single acetyl Ganciclovir according to claim 1, it is characterised in that：It is described more
The molar ratio of three ester of VACV and boric acid is 1:1.0-1.5.
5. a kind of synthetic method of high-purity single acetyl Ganciclovir according to claim 1, it is characterised in that：The second
Acylating reagent is selected from vinyl acetate or 1- acetyl imidazoles.
6. a kind of synthetic method of high-purity single acetyl Ganciclovir according to claim 1, it is characterised in that：It is described more
VACV and the molar ratio of acetylation reagent are 1:1-4.
7. a kind of synthetic method of high-purity single acetyl Ganciclovir according to claim 1, it is characterised in that：It is described to quench
The reagent that goes out is alcohols solvent, is selected from methanol or ethyl alcohol.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1397233B1 (en) * | 2010-01-08 | 2013-01-04 | Fidia Farmaceutici | IMPROVEMENT PROCEDURE FOR THE SYNTHESIS OF MONO-ACETIL GANCICLOVIR, INTERMEDIATE KEY FOR THE SYNTHESIS OF VALGANCICLOVIR. |
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2018
- 2018-04-29 CN CN201810405248.4A patent/CN108373471A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1397233B1 (en) * | 2010-01-08 | 2013-01-04 | Fidia Farmaceutici | IMPROVEMENT PROCEDURE FOR THE SYNTHESIS OF MONO-ACETIL GANCICLOVIR, INTERMEDIATE KEY FOR THE SYNTHESIS OF VALGANCICLOVIR. |
Non-Patent Citations (2)
| Title |
|---|
| TSUTOMU YOKOMATSU等: "Lipase-Catalyzed Enantioselective Acylation of Prochiral 2-(0~-Phosphono)alkyl-l,3-Propanediols: Application to the Enantioselective Synthesis of o~-Phosphono-~-Amino Acids", 《TETRAHEDRON: ASYMMETRY》 * |
| 高永辉等: "硼酸保护羟基法合成甘油单月桂酸酯", 《合成化学》 * |
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Application publication date: 20180807 |