CN101372487A - Preparation of valaciclovir hydrochloride and pharmaceutically acceptable salt thereof - Google Patents

Preparation of valaciclovir hydrochloride and pharmaceutically acceptable salt thereof Download PDF

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Publication number
CN101372487A
CN101372487A CNA2007100925924A CN200710092592A CN101372487A CN 101372487 A CN101372487 A CN 101372487A CN A2007100925924 A CNA2007100925924 A CN A2007100925924A CN 200710092592 A CN200710092592 A CN 200710092592A CN 101372487 A CN101372487 A CN 101372487A
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China
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valacyclovir
carbodiimide
deprotection
xie ansuan
acyclovir
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Inventor
孟文学
李跃芬
冉咏梅
邹鑫
彭良臣
卿勇
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Shanghai Fosun Pharmaceutical Group Co Ltd
Chongqing Carelife Pharmaceutical Co Ltd
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Shanghai Fosun Pharmaceutical Group Co Ltd
Chongqing Carelife Pharmaceutical Co Ltd
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Priority to CNA2007100925924A priority Critical patent/CN101372487A/en
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to protected Valaciclovir which is N-(9-fluorine methoxycarbonyl)-L-valine 2-((amino group-1, 6-dihydro-6-oxo-9H-purine-9-group) methoxyl group) methyl ethyl oxalate and a method for preparing the protected Valaciclovir. The invention also relates to a method for preparing Valaciclovir, which comprises the steps: FMOC-L-valine and Acyclovir are coupled by using a coupling agent to form the protected Valaciclovir which is then caused to get rid of the protection, so that the Valaciclovir and salt of the Valaciclovir that can be accepted on pharmacy. The invention also relates to the preparation and the purification of valaciclovir hydrochloride.

Description

The preparation of valacyclovir or its pharmaceutically-acceptable salts
Invention field
The present invention relates to protected valacyclovir, i.e. N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan 2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl) methoxyl group] ethyl ester and preparation method thereof.The present invention also relates to a kind of new synthetic and purification process of valaciclovir hydrochlordide
Background of invention
Valacyclovir is the L-L-valine ester prodrug of acyclovir.Acyclovir---2-amino-1,9-dihydro-9-[(2-hydroxy ethoxy) methyl]-the 6H-purine-6-one, be a kind of purine biosynthesis nucleoside analog derived from guanine; Chemical structural formula shown in the figure I below having:
Figure A200710092592D00041
Figure I
Found that acyclovir has high antiviral active, and be widely used in treatment and prevention human viral infection, the particularly infection that causes by the simplexvirus group.Referring to " therapeutic pharmacological basis " (The Pharmacological Basis ofTherapeutics) of Goodman and Gilman, 1193-1198 (the 9th edition, 1996).Acyclovir is commercially available as its sodium salt, and trade mark is
Figure A200710092592D00042
United States Patent (USP) the 4th, 199 discloses with acyclovir for No. 574 and to have treated virus infection.
Valacyclovir---L-Xie Ansuan 2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl) methoxyl group] ethyl ester, the chemical structural formula shown in the figure II below having:
Figure A200710092592D00051
Figure II
FDA approved valacyclovir is used for the treatment of zoster and reproduction bleb.Valaciclovir hydrochlordide is commercially available, and trade mark is
Figure A200710092592D00052
For oral administration, give valacyclovir but not acyclovir then is more favourable; Because not only in animal but also in the people, seldom by the acyclovir of gastrointestinal absorption.By comparison, valacyclovir is after oral, rapidly by gastrointestinal absorption.In addition, behind oral administration, valacyclovir is converted into acyclovir rapidly in health adult's body.Someone thinks that the conversion of valacyclovir results from first outpost of the tax office intestines and liver because enzymically hydrolyse and metabolism.
United States Patent (USP) the 4th, 957, the preparation method of amino acid ester, its pharmacy acceptable salt and this compounds that discloses the purine nucleoside analogs acyclovir No. 924.Also disclose medicinal preparations and used disclosed compounds for treating herpesvirus infection.Valacyclovir and salt thereof (comprising hydrochloride) all belong to the row of disclosed compound.
Particularly, described ' No. 924 patent disclosures prepare the method for valacyclovir by the protected Xie Ansuan of condensation; In the method, the 4-Dimethylamino pyridine and the coupling reagent dicyclohexylcarbodiimide that in the dimethyl formamide solution of acyclovir, add CBZ-Xie Ansuan, catalytic amount.The CBZ group is removed by catalytic hydrogenation, and this reaction will be used hydrogen and special equipment (for example autoclave).The urea by product that this method also needs to remove is resulting, produced by the dicyclohexylcarbodiimide coupling agent.Because the relevant problem of described ' No. 924 patented method, thereby obviously need to use less difficult deprotection steps and be easier to remove method by product, that prepare valacyclovir.
Summary of the invention
The present invention relates to protected valacyclovir (N-FMOC-valacyclovir) and preparation method thereof.The invention still further relates to a kind of method for preparing valacyclovir or its pharmaceutically-acceptable salts that comprises coupling step and deprotection (deblocking) step.The invention still further relates to the preparation and the purifying of valaciclovir hydrochlordide.
On the one hand, the present invention relates to N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan 2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl) methoxyl group] ethyl ester (N-FMOC-valacyclovir).
On the other hand, the present invention relates to a kind of method of the N-FMOC-of preparation valacyclovir, comprise making N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan (FMOC-L-Xie Ansuan) and acyclovir that the link coupled step take place in the presence of coupling agent.One concrete aspect, this coupling agent is a for example dicyclohexylcarbodiimide of carbodiimide, or water-soluble carbodiimide N-(3-dimethylamino-propyl)-N-ethyl carbodiimide for example.
Chemical structural formula shown in the figure III below said N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan has:
Figure A200710092592D00071
Figure III
Said N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan 2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl) methoxyl group] ethyl ester have below the structural formula shown in the figure IV:
Figure A200710092592D00072
Figure IV
On the other hand; the present invention relates to a kind of method of the N-FMOC-of preparation valacyclovir; described method comprises the steps: to make amino shielded Xie Ansuan and acyclovir generation coupling; form protected valacyclovir; make protected valacyclovir deprotection then, form valacyclovir or its pharmacy acceptable salt.The specific examples of amino shielded Xie Ansuan is the FMOC-L-Xie Ansuan.One concrete aspect, be for example dicyclohexylcarbodiimide or N-(3-dimethylamino-propyl)-N-ethyl carbodiimide of carbodiimide with coupling agent, realize coupling.
On the other hand; the present invention relates to a kind of method for preparing valaciclovir hydrochlordide; said method comprising the steps of: make FMOC-L-Xie Ansuan and acyclovir generation coupling; form protected valacyclovir; wherein with the carbodiimide that is selected from dicyclohexylcarbodiimide and N-(3-dimethylamino-propyl)-N-ethyl carbodiimide; realize coupling, further make protected valacyclovir deprotection, form valaciclovir hydrochlordide with hydrochloric acid at last with organic bases.Being fit to be used for the example of organic bases of deprotection comprises pyridine, triethylamine, piperidines etc.Piperidines is preferred organic bases.
On the other hand, the present invention relates to a kind of method for preparing the valaciclovir hydrochlordide of pure form, said method comprising the steps of: form the valaciclovir hydrochlordide aqueous solution, this solution is mixed with Virahol, form suspension, from gained suspension, isolate the valaciclovir hydrochlordide of pure form then.
Detailed Description Of The Invention
The term " about " of this paper and the coupling of quantitative measurement value is represented to expect will be by the deviation of determination of technical staff or definite quantitative measurement value aspect, the attention standard techniques personnel that described technician promptly measures or measures and the precision of utilization and measuring result and used surveying instrument matches.
Unless this paper has explanation in addition, phrase used herein " valaciclovir hydrochlordide " comprises its anhydrous form, hydrate and solvate.
N-described in the present invention (9-fluorenes methoxycarbonyl)-L-Xie Ansuan (FMOC-L-Xie Ansuan) is commercially available, also can prepare by technology well known in the art.
In one embodiment, the invention provides the N-FMOC-valacyclovir.Just as discussed below, can in the presence of carbodiimide coupling take place by making FMOC-L-Xie Ansuan and acyclovir, prepare this protected valacyclovir.
In another embodiment, the invention provides a kind of method of the N-FMOC-of preparation valacyclovir, described method comprises makes FMOC-L-Xie Ansuan and acyclovir that the link coupled step take place in the presence of carbodiimide.
In coupling step of the present invention, make the hydroxy esterification of acyclovir (figure I) with the FMOC-L-Xie Ansuan, form protected valacyclovir---the N-FMOC-valacyclovir.This esterification can be adopted technology known in the art, in solvent, preferably in non-protonic solvent, most preferably at N, in the dinethylformamide, uses for example triethylamine of alkaline catalysts, coupling agent and optional fatty amine, carries out this coupling step.Preferred alkaline catalysts is 4-(dimethylamino) pyridine.
Though be not limited to any concrete theory of operation, it is believed that coupling agent forms a kind of active group that reacts the formation ester with the hydroxyl of alcohol in position that is inclined to.The structural characteristics of carbodiimide are-part of N=C=N-, and carbodiimide is an example that can be used for implementing coupling agent of the present invention.Preferred coupling agent comprises dicyclohexylcarbodiimide and N-(3-dimethylamino-propyl)-N-ethyl carbodiimide, and both are commercially available for they.
Protected valacyclovir of the present invention---the N-FMOC-valacyclovir is different from valacyclovir, because the part of this Xie Ansuan has a N-FMOC close and protect base.Can be in deprotection of the present invention (deblocking) step by removing protecting group, and make protected valacyclovir be converted into valacyclovir or its pharmacy acceptable salt.
In another embodiment; the invention provides a kind of method for preparing valacyclovir; said method comprising the steps of: make FMOC-L-Xie Ansuan and acyclovir generation coupling form protected valacyclovir; make protected valacyclovir deprotection then, form valacyclovir or its pharmacy acceptable salt.Adopt carbodiimide coupling agent for example dicyclohexylcarbodiimide and N-(3-dimethylamino-propyl)-N-ethyl carbodiimide at last, finish described coupling step.
As discussed above, the FMOC-L-Xie Ansuan is 2-amino-3 Methylbutanoic acid that N-replaces; In this compound, the sealing of described substituting group is amino, thereby this amino is not participated in or does not disturb or do not compete linked reaction of the present invention, but after linked reaction, can remove described substituting group from this amino.
The deprotection steps for preparing valacyclovir by the N-FMOC-valacyclovir among the present invention can be under mild conditions be implemented by the organic bases that adds 2～8 times excessive (based on molar weights of N-FMOC-valacyclovir), and preferred organic bases is a piperidines.
Preferably be-10 ℃ to about 50 ℃ approximately, more preferably from about-10 ℃ extremely about 25 ℃, most preferably from about 20 ℃ to about 25 ℃, carry out described deprotection steps in temperature.
In another embodiment, the invention provides a kind of method for preparing valaciclovir hydrochlordide: in valacyclovir, add concentrated hydrochloric acid and be selected from C 1-6Alkyl alcohol; From the solution of final formation, be settled out valaciclovir hydrochlordide; Adopt the known any technology of organic synthesis those skilled in the art,, reclaim precipitated product for example by filtration (gravity or suction) or centrifugal.Preferred alkyl alcohol is a Virahol.Preferably, the precipitated product that is recovered to is carried out vacuum-drying.
In another embodiment, the invention provides a kind of method for preparing the valaciclovir hydrochlordide of pure form, this method comprises the steps: to make valaciclovir hydrochlordide to form the valaciclovir hydrochlordide aqueous solution, in this aqueous solution, add Virahol, from gained suspension, isolate the valaciclovir hydrochlordide of pure form.
The present invention has following advantage:
Compared with prior art the present invention has adopted FMOC-L-Xie Ansuan and acyclovir prepared in reaction valacyclovir or its pharmacy acceptable salt, makes reacted deprotection can take gentle condition to carry out rather than existingly comes deprotection by hydrogenation and special equipment.Method of the present invention can not produce by products such as urea, the easier purifying of product when coupling simultaneously.
Further illustrate this invention with the following examples.
Embodiment 1
N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan 2-[(2-amino-1,6-dihydro-6-oxo-9H- Purine-9-yl) methoxyl group] ethyl ester
With the FMOC-L-Xie Ansuan (45.2g, 133.2mmol), 4-(dimethylamino) pyridine (1.63g 13.32mmol) is dissolved in 20ml N, in the dinethylformamide, add acyclovir (20.0g, 88.8mmol).Nitrogen protection about 25 ℃ of following stir abouts 1 hour, drips the gained mixture under about 20～25 ℃ and is dissolved in N, 1 of dinethylformamide (40ml), 3-dicyclohexylcarbodiimide (36.6g, solution 177.7mmol) to this reaction solution.20～25 ℃ were reacted 12 hours down, added 10ml water stopped reaction, and filtering and concentrating adds extremely dissolving of methyl alcohol to doing.Be cooled to-10 ℃ approximately under stirring, stirring is spent the night.Filter, vacuum-drying gets N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan 2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl) methoxyl group] ethyl ester (46.6g, 96%), to measure through HPLC, its purity is 97.9%.
1HNMR(DMSO-d6，d，ppm)：0.84(d，6H)；1.94-2.08(m，1H)；3.70(s，2H)；3.90(m，1H)；4.10-4.30(m，5H)；5.35(s，2H)；6.54(s，2H)；7.29-7.43(m，4H)；7.73-7.94(m，6H)；10.68(s，1H).
Embodiment 2
N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan 2-[(2-amino-1,6-dihydro-6-oxo-9H- Purine-9-yl) methoxyl group] ethyl ester
With FMOC-L-Xie Ansuan (4.4g, 13.0mmol), acyclovir (2.3g, 10mmol), N-(3-dimethylamino-propyl)-N-ethyl-carbodiimide hydrochloride (3.0g, 15mmol), 4-(dimethylamino) pyridine (0.2g, 1.6mmol) and triethylamine (1.4g, 13.9mmol) at N, the suspension in the dinethylformamide (15ml) at room temperature stirs then and spends the night about 0 ℃ of following stir about 4 hours.0.3N hydrochloric acid soln (53ml) is joined in the above-mentioned solution under about 0 ℃, obtains white precipitate, then with gained suspension about 0 ℃ of following stir about 1 hour.Leach precipitation and drying under reduced pressure, obtain N-FMOC-valacyclovir (5.3g, 97%).HPLC purity 98.5%.
Embodiment 3
Prepare valacyclovir by N-FMOC-valacyclovir deprotection
(5g 9.1mmol) joins 50mlN, in the dinethylformamide, stirs molten clearly under the room temperature, adds the 5ml piperidines, stirring at room reaction 4 hours with the N-FMOC-valacyclovir.Be evaporated to dried.Do not separate and be directly used in the next step.
Embodiment 4
Prepare valaciclovir hydrochlordide by valacyclovir
In the residue of above-mentioned embodiment 3, add concentrated hydrochloric acid 5ml, continue to stir 0.5 hour, add Virahol 150ml, being cooled to-10 ℃ of stirrings spends the night, filter, obtain white solid, vacuum-drying gets valaciclovir hydrochlordide crude product (about 3.2g, yield is to N-FMOC-valacyclovir meter 98%), censorship HPLC surveys purity (99.2%).
Embodiment 5
The valaciclovir hydrochlordide of pure form
Valaciclovir hydrochlordide 6g and water 24g are added there-necked flask in about 40 ℃ of stirrings, dissolve fully until solid, filter, at about 40 ℃ this filtrate joined in the Virahol (90g), then gained suspension was stirred 2 hours down at about 20 ℃, be cooled to restir below-5 ℃ 8 hours, leach solid, with about 12g washed with isopropyl alcohol and in about 25 ℃ of drying under reduced pressure to constant weight, obtain valaciclovir hydrochlordide (5.32g, 88.7%) the HPLC purity 99.6% of pure form.

Claims (22)

  1. (1.N-9-fluorenes methoxycarbonyl)-L-Xie Ansuan 2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl) methoxyl group] ethyl ester.
  2. 2. one kind prepares N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan 2-[(2-amino-1,6-dihydro-6-oxo-9H-purine-9-yl) methoxyl group] method of ethyl ester, described method comprises makes N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan and acyclovir that the link coupled step take place in the presence of coupling agent.
  3. 3. the method for claim 2 is characterized in that being coupled at 0 ℃ and carries out.
  4. 4. the method for claim 2 is characterized in that being coupled at-5 ℃ and carries out.
  5. 5. the method for claim 2 is characterized in that being coupled at 25 ℃ and carries out.
  6. 6. the method for claim 2 is characterized in that coupling agent is a carbodiimide.
  7. 7. the method for claim 6 is characterized in that described carbodiimide is a dicyclohexylcarbodiimide.
  8. 8. the method for claim 6 is characterized in that described carbodiimide is water miscible.
  9. 9. the method for claim 8 is characterized in that described water-soluble carbodiimide is N-(3-dimethylamino-propyl)-N-ethyl carbodiimide.
  10. 10. method for preparing valacyclovir or its pharmaceutically-acceptable salts, described method comprises the steps:
    Make N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan and acyclovir generation coupling, form protected valacyclovir; Then
    Make protected valacyclovir deprotection, form valacyclovir or its pharmacy acceptable salt.
  11. 11. the method for claim 10 is characterized in that realizing described coupling with coupling agent.
  12. 12. the method for claim 11 is characterized in that used coupling agent is a carbodiimide.
  13. 13. the method for claim 12 is characterized in that described carbodiimide is a dicyclohexylcarbodiimide.
  14. 14. the method for claim 13 is characterized in that described carbodiimide is water miscible.
  15. 15. the method for claim 14 is characterized in that described water-soluble carbodiimide is N-(3-dimethylamino-propyl)-N-ethyl carbodiimide.
  16. 16. the method for claim 10 is characterized in that realizing described deprotection under 20～25 ℃ temperature.
  17. 17. the method for claim 10 is characterized in that at N, realizes described deprotection in the dinethylformamide.
  18. 18. the method for claim 10 is characterized in that realizing deprotection with organic bases.
  19. 19. the method for claim 18 is characterized in that described organic bases is a piperidines.
  20. 20. a method for preparing valaciclovir hydrochlordide said method comprising the steps of:
    Make N-(9-fluorenes methoxycarbonyl)-L-Xie Ansuan and acyclovir generation coupling; form protected valacyclovir; wherein realize described coupling with the coupling agent of a kind of N-of being selected from (3-dimethylamino-propyl)-N-ethyl carbodiimide and dicyclohexylcarbodiimide; and then make protected valacyclovir deprotection with organic bases, then
    Make the valacyclovir of deprotection form valaciclovir hydrochlordide with hydrochloric acid.
  21. 21. the method for claim 20 is characterized in that described organic bases is a piperidines.
  22. 22. the method for claim 20 is characterized in that realizing described deprotection under 20～25 ℃ temperature.
CNA2007100925924A 2007-08-20 2007-08-20 Preparation of valaciclovir hydrochloride and pharmaceutically acceptable salt thereof Pending CN101372487A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101787027A (en) * 2010-03-19 2010-07-28 常州康丽制药有限公司 Preparation method of high-purity carbamazepine (CBZ)-valaciclovir

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101787027A (en) * 2010-03-19 2010-07-28 常州康丽制药有限公司 Preparation method of high-purity carbamazepine (CBZ)-valaciclovir
CN101787027B (en) * 2010-03-19 2011-12-14 常州康丽制药有限公司 Preparation method of high-purity carbamazepine (CBZ)-valaciclovir

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