CN105732630B - A kind of preparation method of CBZ- valganciclovir - Google Patents
A kind of preparation method of CBZ- valganciclovir Download PDFInfo
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- CN105732630B CN105732630B CN201610246694.6A CN201610246694A CN105732630B CN 105732630 B CN105732630 B CN 105732630B CN 201610246694 A CN201610246694 A CN 201610246694A CN 105732630 B CN105732630 B CN 105732630B
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- valganciclovir
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- 229960002149 valganciclovir Drugs 0.000 title claims abstract description 82
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000000706 filtrate Substances 0.000 claims abstract description 56
- 239000012065 filter cake Substances 0.000 claims abstract description 48
- 238000003825 pressing Methods 0.000 claims abstract description 41
- 239000012043 crude product Substances 0.000 claims abstract description 37
- 229960002963 ganciclovir Drugs 0.000 claims abstract description 37
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000002253 acid Substances 0.000 claims abstract description 30
- 150000002148 esters Chemical class 0.000 claims abstract description 30
- 239000007787 solid Substances 0.000 claims abstract description 28
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 239000004474 valine Substances 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims abstract description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims abstract description 9
- 238000010992 reflux Methods 0.000 claims abstract description 9
- 230000000630 rising effect Effects 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 11
- 238000012545 processing Methods 0.000 claims description 9
- 239000004744 fabric Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 claims 1
- 229910001948 sodium oxide Inorganic materials 0.000 claims 1
- 238000000926 separation method Methods 0.000 abstract description 10
- 239000000376 reactant Substances 0.000 abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 8
- 239000002699 waste material Substances 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 241000701022 Cytomegalovirus Species 0.000 description 7
- 229960004295 valine Drugs 0.000 description 7
- 239000002994 raw material Substances 0.000 description 6
- ZORWARFPXPVJLW-MTFPJWTKSA-N [2-[(2-amino-6-oxo-3h-purin-9-yl)methoxy]-3-hydroxypropyl] (2s)-2-amino-3-methylbutanoate;hydron;chloride Chemical compound Cl.N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 ZORWARFPXPVJLW-MTFPJWTKSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 229960004983 valganciclovir hydrochloride Drugs 0.000 description 5
- 208000030507 AIDS Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000003344 environmental pollutant Substances 0.000 description 3
- 231100000719 pollutant Toxicity 0.000 description 3
- -1 valyl ester Chemical class 0.000 description 3
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 2
- 230000002155 anti-virotic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000036737 immune function Effects 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 238000011017 operating method Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 206010048843 Cytomegalovirus chorioretinitis Diseases 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000001763 cytomegalovirus retinitis Diseases 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229950003188 isovaleryl diethylamide Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of CBZ- valganciclovir preparation methods, belong to the preparation field of valganciclovir.It includes the following steps, Ganciclovir, solvent one, DCC, DMAP and CBZ-L- valine are stirred to react Hou Jiashui at room temperature, stirring, it filters, obtained filtrate is concentrated to dryness, and one temperature rising reflux of reactant is added, 0 degree is cooled to hereinafter, aqueous slkali one is added dropwise, filters pressing obtains filter cake one and filtrate one；Filter cake one is dissolved in solvent two, is added water, white solid is precipitated and obtains CBZ- valganciclovir monoesters crude product two；Itself and reactant two are put into reaction kettle again and heated up, cooling, filters pressing obtains filter cake three i.e. sterling CBZ valganciclovir monoesters.Remaining dibasic acid esters is continued concentration and separation and generates monoesters by the present invention, is solved the waste of dibasic acid esters, is improved the conversion ratio and yield of monoesters, save the cost, so that the sterling CBZ- valganciclovir monoesters purity finally prepared is 98% or more.
Description
Technical field
The invention belongs to the preparation fields of valganciclovir, more specifically to a kind of system of CBZ- valganciclovir
Preparation Method.
Background technique
Valganciclovir is the left-handed valyl ester (pro-drug) of Ganciclovir, by the acyl enzyme in small intestine and liver after taking orally
It is converted to Ganciclovir rapidly, is used for acquired immunodeficiency syndrome (AIDS) patient cytomegalovirus (CMV) property retina
Cytomegalovirus (CMV) infection after inflammation and organ transplant, for international preferred prevention cmv infection drug.Cytomegalovirus
(CMV) belong to herpetoviridae, which is in quiescent condition in the individual for having normal immunological function, but when such as AIDS suffers from
Person, organ transplant are followed by the patient etc. by immunosuppressor, and when immune function depression, which will cause illness.?
The most common illness of CMV is the CMV retinitis in HIV/AIDS patient, this is a kind of ocular infection that can lead to blindness.
Valganciclovir hydrochloride mainly prepares generation method and has at present：1. using Ganciclovir as raw material, directly with N- benzyloxy
Base carbonyl-Valine-N- acetyl anhydride (or N- benzyloxycarbonyl group-L-- valine) condensation is obtained more by controlling reaction condition
VACV monoesters, then hydrogenated reduction synthesis valganciclovir hydrochloride；2. using Ganciclovir as raw material, first with orthoester-protected one
A hydroxyl, then with N- benzyloxy-oxo-L-valine and another hydroxyl condensation, obtain dibasic acid esters ester, then by hydrolysis and
Hydro-reduction reacts synthetic hydrochloric acid valganciclovir；3. reacting to obtain with active electrophilic reagent using purine compound as raw material
Valganciclovir hydrochloride is made in the mono-ester product of Ganciclovir, then hydrogenated and deprotection.1 reaction process of method has dibasic acid esters production
It is raw, and the separation of monoesters and dibasic acid esters is more difficult, is unfavorable for industrialized production.Ortho esters used in method 2 is expensive, and remove-insurance
It is more difficult to protect base.3 technique of method is cumbersome, and cost is too high, is unfavorable for industrialized production.
Therefore, in conclusion generally existing disadvantage of existing stage is to generate a large amount of dibasic acid esters and residual is a large amount of more
VACV forms more dibasic acid esters if Ganciclovir residual is few, and the content of monoesters further decreases, if reducing dibasic acid esters
Content, then Ganciclovir content significantly remains, and monoester content cannot be guaranteed and very low, and general patent document is all accomplished
In the ratio of 40-50%, then Ganciclovir and dibasic acid esters are divided one monoesters in the ratio of 50-60% with cumbersome separation method
From the separation of monoesters and dibasic acid esters is difficult to realize, and the dibasic acid esters after separation is useless, can only recycle hydrolysis Ganciclovir.So
Its processing step is simplified to the synthesis of CBZ- valganciclovir, reducing its raw material remaining, reducing cost is in industrialized production
Difficult point.
Therefore, it needs a kind of suitable for large-scale industrial production and simple process, production cost are low, yield is high CBZ-
The synthesis technology of valganciclovir, i.e., a kind of preparation method of CBZ- valganciclovir.
Summary of the invention
1, it to solve the problems, such as
For the above-mentioned problems in the prior art, the present invention provides a kind of Ganciclovir preparation method, will be remaining
Dibasic acid esters continues concentration and separation and generates monoesters, efficiently solves the waste of dibasic acid esters, and improve the conversion ratio and yield of monoesters, thus
The synthesis cost of CBZ- valganciclovir monoesters is reduced, reduces waste, the discharge of save the cost and pollutant, and ensure that conjunction
At monoesters quality so that the sterling CBZ- valganciclovir monoesters purity finally prepared is 98% or more.
2, technical solution
To solve the above-mentioned problems, the technical solution adopted in the present invention is as follows：
A kind of CBZ- valganciclovir preparation method, which is characterized in that the key intermediate being directed in preparation process
2- [(2- amino -1,6- dihydro -6- oxygen-purine -9-) methoxyl group] -3- hydroxyl -1- propyl N- (benzyloxycarbonyl group)-L-Val ester
The preparation method of (hereinafter referred to as " CBZ- valganciclovir monoesters ")；The preparation method of the CBZ- valganciclovir monoesters includes
Following steps：
(1) Ganciclovir or commercially available 50 parts by weight that 50 parts by weight are evaporated into after hydrolyzing filters pressing in Ganciclovir preparation are taken
The solvent one of 50-200 mass parts is added in Ganciclovir sterling, adds DCC, 2-3 mass parts of 90-120 mass parts
Reaction 5-12h is stirred at room temperature in the CBZ-L- valine of DMAP and 90-120 mass parts；
(2) water of 10 parts by weight is added in the product after being stirred to react to the step (1), stirs, filters, and will obtain
Filtrate be concentrated to dryness；
(3) reactant one that 150-200 mass parts are added into the step (2) products therefrom is warming up to reflux, cooling
To 0 DEG C or less；
(4) it is cooled to the aqueous slkali one that 8-10 parts by weight are added dropwise in 0 DEG C of product to the step (3), generates a large amount of white
Color solid, filters pressing obtain filter cake one i.e. CBZ- valganciclovir monoesters crude product one and filtrate one；
(5) filtrate one obtained by the step (4) is concentrated into half, then the aqueous slkali two of 2-5 parts by weight is added dropwise, be precipitated white
Color solid, filters pressing obtain filter cake two i.e. CBZ- valganciclovir monoesters crude product one and filtrate two；
(6) by the merging of filtrate two next group filtrate, processing returns to the step (5), the reaction was continued；
(7) filter cake two obtained by filter cake one obtained by step (4) and the step (5) is dissolved in the 2-4 times of solvent measured two,
The 10-20 times of water measured is added, white solid is precipitated and obtains CBZ- valganciclovir monoesters crude product two；
(8) reactant two of the CBZ- valganciclovir monoesters crude product two of 50 parts by weight and 80-100 parts by weight is thrown
Enter in reaction kettle and heat up, cooling, filters pressing obtains filter cake three i.e. sterling CBZ valganciclovir monoesters, remaining dibasic acid esters and is dissolved in molten
In agent two.
Preferably, the reactant one and reactant two are same substance.
Preferably, solvent one described in step (1) is at least one of DMF and DMSO.
Preferably, reactant one described in step (3) is the toluene and two of the chloroform of 150-200 parts by weight, 200 parts by weight
It is any in toluene.
Preferably, the sodium hydroxide water that aqueous slkali one described in step (4) is propylamine, methylamine, triethylamine, concentration are 20%
It is any in solution.
Preferably, aqueous slkali two described in step (4) is propylamine, propylamine, triethylamine, concentration are that 20% sodium hydroxide is water-soluble
It is any in liquid.
Preferably, the parts by weight of the aqueous slkali two are 0.4-0.8 times of aqueous slkali one.
Preferably, solvent two described in step (7) is any in ethanol solution, DMF and DMSO.
Preferably, reactant two described in step (8) is any in chloroform, toluene and dimethylbenzene.
3, beneficial effect
Compared with the prior art, beneficial effects of the present invention are：
(1) remaining dibasic acid esters is continued concentration and separation generation monoesters by the present invention, efficiently solves the waste of dibasic acid esters, and improve
The conversion ratio and yield of monoesters reduces waste to reduce the synthesis cost of CBZ- valganciclovir monoesters, save the cost and
The discharge of pollutant, and ensure that the monoesters quality of synthesis, so that the sterling CBZ- valganciclovir monoesters finally prepared is pure
Degree is 98% or more；
(2) present invention also has operating procedure few, and remaining dibasic acid esters is dissolved in solvent two, efficiently solves monoesters and double
The more difficult problem of separation of ester, is practically applicable to the synthesis of antivirus raw material medicine valganciclovir hydrochloride so that valganciclovir at
Originally it is greatly lowered, it can be achieved that the mode of Ganciclovir " treating different things alike " directly synthesizes CBZ- valganciclovir monoesters, greatly letter
Technique is changed, and monoesters quality obtained is improved, present approach reduces valganciclovir costs, are suitble to industrialization big
Large-scale production.
Detailed description of the invention
Fig. 1 is detection chromatogram of the resulting CBZ- valganciclovir monoesters of the embodiment of the present invention 1 under 254nm wavelength.
Specific embodiment
The present invention is further described below combined with specific embodiments below.
Embodiment 1
The Ganciclovir for being evaporated into 50Kg after hydrolyzing filters pressing in Ganciclovir preparation is taken, 200kgDMF, 100K g is added
DCC and 3.0Kg DMAP adds 110.0Kg CBZ-L- valine, and 9h is stirred at room temperature, and 10Kg water is added, and stirs, and takes out
Filter, obtained filtrate is concentrated to dryness, and 200Kg chloroform temperature rising reflux is added, and is cooled to 0 degree hereinafter, 10Kg propylamine is then added dropwise, raw
At a large amount of white solids, filters pressing obtains filter cake one i.e. CBZ- valganciclovir monoesters crude product one and filtrate one, then by filtrate one
It is concentrated into half, then 5Kg propylamine is added dropwise, white solid is precipitated, filters pressing obtains filter cake two i.e. CBZ- valganciclovir monoesters crude product
One and filtrate two, continue the merging next group filtrate of filtrate two that filters pressing processing is concentrated.Obtained filter cake one and filter cake two are dissolved
In 4 times of ethanol solutions, the water of 10 times of amounts is added, white solid is precipitated, this step reduces the residual Ganciclovir in monoesters
To 1% hereinafter, obtaining CBZ- valganciclovir monoesters crude product two.By two He of CBZ- valganciclovir monoesters crude product of 50Kg
It heats up in the chloroform investment reaction kettle of 100Kg, cooling, filters pressing obtains filter cake three i.e. sterling CBZ- valganciclovir monoesters, remains
Dibasic acid esters be dissolved in chloroform so that the sterling CBZ- valganciclovir monoesters purity finally prepared is 98% or more.
Table 1 is CBZ- valganciclovir monoesters finished product purity table, as follows：
It can be seen that CBZ- valganciclovir monoesters finished product purity alreadys exceed 98% from table 1 and Fig. 1, Ganciclovir residual
And 1% hereinafter, CBZ- valganciclovir dibasic acid esters does not detect, therefore can do the hydrochloric acid figured silk fabrics more former times Lip river of mass review USP
Wei bulk pharmaceutical chemicals.
Embodiment 2
The Ganciclovir for being evaporated into 50Kg after hydrolyzing filters pressing in Ganciclovir preparation is taken, 100kgDMF, 150K g is added
DCC and 3.0Kg DMAP adds 120.0Kg CBZ-L- valine, and 8h is stirred at room temperature, and 10Kg water is added, and stirs, and takes out
Filter, obtained filtrate is concentrated to dryness, and 150Kg chloroform is added and is warming up to reflux, is cooled to 0 degree hereinafter, then dropwise addition 8Kg methylamine,
Generate a large amount of white solids, filters pressing obtains filter cake one i.e. CBZ valganciclovir monoesters crude product one and filtrate one, then by filtrate one
It is concentrated into half, then 5Kg propylamine is added dropwise, white solid is precipitated, filters pressing obtains filter cake two i.e. CBZ valganciclovir monoesters crude product one
With filtrate two, continue the merging next group filtrate of filtrate two that filters pressing processing is concentrated.Then obtained filter cake one and filter cake two is molten
The water of 20 times of amounts is added in 2 times of DMF solutions in solution, and white solid is precipitated, this step reduces the residual Ganciclovir in monoesters
To 1% hereinafter, obtaining CBZ- valganciclovir monoesters crude product two.By the CBZ- valganciclovir monoesters crude product two and 80Kg of 50Kg
It heats up in chloroform investment reaction kettle, cooling, it is molten that filters pressing obtains filter cake three i.e. sterling CBZ- valganciclovir monoesters, remaining dibasic acid esters
Solution is in chloroform, so that the sterling CBZ- valganciclovir monoesters purity finally prepared is 98% or more.
Embodiment 3
The Ganciclovir sterling of commercially available 50Kg is taken, 50kgDMSO, 90K g DCC and 3.0Kg DMAP is added, adds
5h is stirred at room temperature in 110.0Kg CBZ-L- valine, and 10Kg water is added, and stirs, and filters, and obtained filtrate is concentrated to dryness,
Be added 200Kg toluene be warming up to reflux, be cooled to 0 degree hereinafter, then be added dropwise 10Kg triethylamine, generate a large amount of white solids, pressure
Filter, obtains filter cake one i.e. CBZ valganciclovir monoesters crude product one and filtrate one, filtrate one is concentrated into half, then 2Kg tri- is added dropwise
Ethamine, is precipitated white solid, and filters pressing obtains filter cake two i.e. CBZ valganciclovir monoesters crude product one and filtrate two, filtrate two is closed
And next group filtrate continues that filters pressing processing is concentrated.Then obtained filter cake one and filter cake two are dissolved in 2 times of DMSO solutions, are added
Enter the water of 15 times of amounts, white solid is precipitated, the residual Ganciclovir in monoesters is reduced to 1% hereinafter, obtaining CBZ- by this step
Valganciclovir monoesters crude product two.It will be in CBZ- valganciclovir monoesters crude product two and 100Kg toluene the investment reaction kettle of 50Kg
Heating, cooling, filters pressing obtains filter cake three i.e. sterling CBZ- valganciclovir monoesters, remaining dibasic acid esters and is dissolved in toluene, so that
The sterling CBZ- valganciclovir monoesters purity finally prepared is 98% or more.
Embodiment 4
The Ganciclovir sterling of commercially available 50Kg is taken, 100kgDMSO, 50KgDMF, 120K g DCC and 2.0Kg is added
12h is stirred at room temperature in DMAP, then 90.0Kg CBZ-L- valine, and 10Kg water is added, and stirs, and filters, and obtained filtrate is dense
Be reduced to it is dry, be added 200Kg dimethylbenzene be warming up to reflux, be cooled to 0 degree hereinafter, then be added dropwise 10Kg concentration for 20% hydroxide
Sodium water solution generates a large amount of white solids, and filters pressing obtains filter cake one i.e. CBZ valganciclovir monoesters crude product one and filtrate one, then
Filtrate one is concentrated into half, then the sodium hydrate aqueous solution that 2Kg concentration is 20% is added dropwise, white solid is precipitated, filters pressing obtains
Filter cake two is CBZ valganciclovir monoesters crude product one and filtrate two, and the merging next group filtrate of filtrate two is continued to be concentrated at filters pressing
Reason.Then obtained filter cake one and filter cake two are dissolved in 2 times of DMSO solutions, the water of 15 times of amounts are added, white solid is precipitated,
Residual Ganciclovir in monoesters is reduced to 1% hereinafter, obtaining CBZ- valganciclovir monoesters crude product two by this step.By 50Kg
CBZ- valganciclovir monoesters crude product two and 100Kg dimethylbenzene investment reaction kettle in heat up, cooling, filters pressing obtains filter cake three i.e.
Sterling CBZ- valganciclovir monoesters, remaining dibasic acid esters are dissolved in dimethylbenzene, so that the sterling CBZ- figured silk fabrics more former times finally prepared
Lip river Wei monoesters purity is 98% or more.
Based on above-mentioned, remaining dibasic acid esters is continued concentration and separation and generates monoesters by the present invention, efficiently solves the waste of dibasic acid esters,
And the conversion ratio and yield of monoesters are improved, to reduce the synthesis cost of CBZ- valganciclovir monoesters, waste is reduced, is saved
The discharge of cost and pollutant, and ensure that the monoesters quality of synthesis, so that the sterling CBZ- valganciclovir finally prepared
Monoesters purity is 98% or more；The present invention also has operating procedure few, and remaining dibasic acid esters is dissolved in solvent two, efficiently solves
The more difficult problem of the separation of monoesters and dibasic acid esters, simple process are practically applicable to the synthesis of antivirus raw material medicine valganciclovir hydrochloride,
So that valganciclovir cost is greatly lowered, Quality advance, present approach reduces valganciclovir costs, are suitble to industrialization big
Large-scale production.
Schematically the present invention and embodiments thereof are described above, description is not limiting, institute in attached drawing
What is shown is also one of embodiments of the present invention, and actual structure is not limited to this.So if the common skill of this field
Art personnel are enlightened by it, without departing from the spirit of the invention, are not inventively designed and the technical solution
Similar frame mode and embodiment, are within the scope of protection of the invention.
Claims (4)
1. a kind of CBZ- valganciclovir preparation method, it is characterised in that：It takes and is evaporated into after hydrolyzing filters pressing in Ganciclovir preparation
The Ganciclovir of 50Kg is added 200kgDMF, 100K gDCC and 3.0Kg DMAP, adds 110.0Kg CBZ-L- valine,
9h is stirred at room temperature, 10Kg water is added, stirs, filters, obtained filtrate is concentrated to dryness, 200Kg chloroform temperature rising reflux is added,
Be cooled to 0 degree hereinafter, then be added dropwise 10Kg propylamine, generate a large amount of white solids, filters pressing obtains filter cake one i.e. CBZ- figured silk fabrics more former times Lip river
Wei monoesters crude product one and filtrate one, are then concentrated into half for filtrate one, then 5Kg propylamine is added dropwise, and white solid is precipitated, and filters pressing obtains
It is CBZ- valganciclovir monoesters crude product one and filtrate two to filter cake two, continues the merging next group filtrate of filtrate two that filters pressing is concentrated
Processing；Obtained filter cake one and filter cake two are dissolved in 4 times of ethanol solutions, the water of 10 times of amounts is added, white solid is precipitated, this
Residual Ganciclovir in monoesters is reduced to 1% hereinafter, obtaining CBZ- valganciclovir monoesters crude product two by one step；By 50Kg's
It heats up in the chloroform of CBZ- valganciclovir monoesters crude product two and 100Kg investment reaction kettle, cooling, it is i.e. pure that filters pressing obtains filter cake three
Product CBZ- valganciclovir monoesters, remaining dibasic acid esters are dissolved in chloroform, so that the sterling CBZ- valganciclovir finally prepared
Monoesters purity is 98% or more.
2. a kind of CBZ- valganciclovir preparation method, it is characterised in that：It takes and is evaporated into after hydrolyzing filters pressing in Ganciclovir preparation
The Ganciclovir of 50Kg is added 100kgDMF, 150KgDCC and 3.0Kg DMAP, adds 120.0Kg CBZ-L- valine,
8h is stirred at room temperature, 10Kg water is added, stirs, filters, obtained filtrate is concentrated to dryness, and 150Kg chloroform is added and is warming up to back
Stream, be cooled to 0 degree hereinafter, then be added dropwise 8Kg methylamine, generate a large amount of white solids, filters pressing obtains filter cake one i.e. CBZ figured silk fabrics more former times
Lip river Wei monoesters crude product one and filtrate one, then filtrate one is concentrated into half, then 5Kg propylamine is added dropwise, white solid is precipitated, filters pressing obtains
It is CBZ valganciclovir monoesters crude product one and filtrate two to filter cake two, continues the merging next group filtrate of filtrate two that filters pressing is concentrated
Processing；Then obtained filter cake one and filter cake two are dissolved in 2 times of DMF solutions, the water of 20 times of amounts is added, it is solid that white is precipitated
Residual Ganciclovir in monoesters is reduced to 1% hereinafter, obtaining CBZ- valganciclovir monoesters crude product two by body, this step；It will
It heats up in CBZ- valganciclovir monoesters crude product two and 80Kg chloroform the investment reaction kettle of 50Kg, cooling, filters pressing obtains filter cake three
I.e. sterling CBZ- valganciclovir monoesters, remaining dibasic acid esters are dissolved in chloroform, so that the sterling CBZ- figured silk fabrics more former times finally prepared
Lip river Wei monoesters purity is 98% or more.
3. a kind of CBZ- valganciclovir preparation method, it is characterised in that：The Ganciclovir sterling of commercially available 50Kg is taken, is added
50kgDMSO, 90K g DCC and 3.0Kg DMAP, add 110.0Kg CBZ-L- valine, 5h are stirred at room temperature, and are added
10Kg water stirs, and filters, and obtained filtrate is concentrated to dryness, and 200Kg toluene is added and is warming up to reflux, is cooled to 0 degree hereinafter, so
10Kg triethylamine is added dropwise afterwards, generates a large amount of white solids, filters pressing obtains filter cake one i.e. one He of CBZ valganciclovir monoesters crude product
Filtrate one is concentrated into half, then 2Kg triethylamine is added dropwise by filtrate one, and white solid is precipitated, and filters pressing obtains filter cake two i.e. CBZ figured silk fabrics
Ganciclovir monoesters crude product one and filtrate two continue the merging next group filtrate of filtrate two that filters pressing processing is concentrated；Then it will obtain
Filter cake one and filter cake two be dissolved in 2 times of DMSO solutions, the water of 15 times of amounts are added, white solid is precipitated, this step is by monoesters
In residual Ganciclovir be reduced to 1% hereinafter, obtaining CBZ- valganciclovir monoesters crude product two；By the CBZ- figured silk fabrics more former times of 50Kg
It heats up in Lip river Wei monoesters crude product two and 100Kg toluene investment reaction kettle, cooling, filters pressing obtains filter cake three i.e. sterling CBZ- figured silk fabrics more former times
Lip river Wei monoesters, remaining dibasic acid esters are dissolved in toluene, so that the sterling CBZ- valganciclovir monoesters purity finally prepared exists
98% or more.
4. a kind of CBZ- valganciclovir preparation method, it is characterised in that：The Ganciclovir sterling of commercially available 50Kg is taken, is added
100kgDMSO, 50KgDMF, 120Kg DCC and 2.0KgDMAP, then 90.0Kg CBZ-L- valine, are stirred at room temperature 12h,
10Kg water is added, stirs, filters, obtained filtrate is concentrated to dryness, and 200Kg dimethylbenzene is added and is warming up to reflux, be cooled to 0 degree with
Under, the sodium hydrate aqueous solution that 10Kg concentration is 20% is then added dropwise, generates a large amount of white solids, filters pressing obtains filter cake one i.e.
CBZ valganciclovir monoesters crude product one and filtrate one, then filtrate one is concentrated into half, then the hydrogen that 2Kg concentration is 20% is added dropwise
White solid is precipitated in aqueous solution of sodium oxide, and filters pressing obtains filter cake two i.e. CBZ valganciclovir monoesters crude product one and filtrate two, will
Filtrate two merges next group filtrate and continues that filters pressing processing is concentrated；Then obtained filter cake one and filter cake two are dissolved in 2 times of DMSO
In solution, be added 15 times amount water, be precipitated white solid, this step by the residual Ganciclovir in monoesters be reduced to 1% hereinafter,
Obtain CBZ- valganciclovir monoesters crude product two；The CBZ- valganciclovir monoesters crude product two and 100Kg dimethylbenzene of 50Kg are thrown
Enter in reaction kettle and heat up, cooling, filters pressing obtains filter cake three i.e. sterling CBZ- valganciclovir monoesters, remaining dibasic acid esters and is dissolved in two
In toluene, so that the sterling CBZ- valganciclovir monoesters purity finally prepared is 98% or more.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5840890A (en) * | 1996-01-26 | 1998-11-24 | Syntex (U.S.A.) Inc. | Process for preparing a 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative |
| CN102070635A (en) * | 2009-11-19 | 2011-05-25 | 浙江车头制药有限公司 | Preparation method for ganciclovir valine ester derivative |
| CN102702199A (en) * | 2012-06-13 | 2012-10-03 | 湖北葛店人福药业有限责任公司 | Method for preparing ganciclovir |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5840890A (en) * | 1996-01-26 | 1998-11-24 | Syntex (U.S.A.) Inc. | Process for preparing a 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative |
| CN102070635A (en) * | 2009-11-19 | 2011-05-25 | 浙江车头制药有限公司 | Preparation method for ganciclovir valine ester derivative |
| CN102702199A (en) * | 2012-06-13 | 2012-10-03 | 湖北葛店人福药业有限责任公司 | Method for preparing ganciclovir |
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Denomination of invention: A Preparation Method of CBZ Valganciclovir Granted publication date: 20181130 Pledgee: China Postal Savings Bank Limited by Share Ltd. Anqing branch Pledgor: ANHUI HAIKANG PHARMACEUTICAL Co.,Ltd. Registration number: Y2024980000631 |
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Address after: 246000 No.21, Huancheng West Road, Daguan District, Anqing City, Anhui Province Patentee after: Anhui Haikang Pharmaceutical Co.,Ltd. Country or region after: China Address before: 246000 No.21, Huancheng West Road, Daguan District, Anqing City, Anhui Province Patentee before: ANHUI HAIKANG PHARMACEUTICAL Co.,Ltd. Country or region before: China |