CN115745997A - Preparation method of high-purity valaciclovir impurity H - Google Patents
Preparation method of high-purity valaciclovir impurity H Download PDFInfo
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- CN115745997A CN115745997A CN202211526395.XA CN202211526395A CN115745997A CN 115745997 A CN115745997 A CN 115745997A CN 202211526395 A CN202211526395 A CN 202211526395A CN 115745997 A CN115745997 A CN 115745997A
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- valacyclovir
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- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 title claims abstract description 30
- 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 title claims abstract description 18
- 229940093257 valacyclovir Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 34
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 229960004150 aciclovir Drugs 0.000 claims abstract description 20
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000012535 impurity Substances 0.000 claims abstract description 16
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims abstract description 15
- TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 4
- 238000001953 recrystallisation Methods 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000706 filtrate Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 238000004042 decolorization Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000002390 rotary evaporation Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000007670 refining Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- -1 L-valyl ester Chemical class 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives 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
- 239000013558 reference substance Substances 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229940108442 valtrex Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
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Classifications
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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
Abstract
The invention discloses a preparation method of high-purity valacyclovir impurity H, which comprises the steps of reacting acyclovir and CBZ-alanine in DMF at a low temperature, removing water generated in the reaction by using DCC, accelerating the reaction process by using DMAP, removing impurities in a product by using different solubilities of a target product and impurities such as DMAP in an ethanol solution in a recrystallization mode to obtain a high-purity impurity intermediate; and then high-purity impurity H is obtained after deprotection. Acyclovir and CBZ-alanine are reacted in DMF at a low temperature, the reaction is directionally converted, the post-treatment process is more convenient and simpler, and the impurity purity and the yield are high.
Description
Technical Field
The invention relates to the technical field of production of valxib impurity H, in particular to a production technology of high-purity valxib impurity H.
Background
Valacyclovir is the L-valyl ester prodrug of acyclovir. Acyclovir is an acyclic analogue of a natural nucleoside and has been found to have high antiviral activity. Acyclovir is widely used in The treatment and prevention of human viral infections, especially those caused by viruses of The herpes family, see Goodman and Gilman, the chemical name of The pharmaceutical Basis of Therapeutics 1193-1198 (9 th edition, 1996) Vaciclovir is 1-valine, 2- [ (2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy ] ethyl ester. (CAS registry number 124832-26-4). Valacyclovir is currently marketed under the trademark VALTREX. The chemical structure of valacyclovir is shown in structural formula I.
According to European pharmacopoeia, the impurity H in the finished product is required to be 0.1% at most, and therefore, the purity of the finished product as a reference substance is required to be more than 95%. The chemical structure of the impurity H is shown as a structural formula II
And structural formula II.
Disclosure of Invention
Based on the defects of the prior art, the technical problem solved by the invention is to provide a production technology of high-purity valdecoxib impurity H, which has the characteristics of safety, economy and environmental protection.
In order to solve the technical problem, the invention provides a preparation method of high-purity valacyclovir impurity H, which is synthesized according to the following reaction formula:
acyclovir and CBZ-alanine react in DMF at low temperature, DCC is used for removing water generated in the reaction, DMAP is used for accelerating the reaction process, and impurities in the target product and impurities such as DMAP and the like are removed in a recrystallization mode by utilizing the difference of the solubility of the target product and the impurities in ethanol solution to obtain an impurity intermediate with high purity; and then high-purity impurity H is obtained through deprotection.
Preferably, the preparation method of high-purity valacyclovir impurity H provided by the invention further comprises part or all of the following technical characteristics:
as an improvement of the technical scheme, the method comprises the following steps:
step (1), condensation reaction: cooling the solvent, adding acyclovir, CBZ-alanine and DMAP, adding half of DMF solution of DCC for reaction for 15h, adding the other half of DMF solution of DCC for continuous reaction for more than 15h, filtering, adding active carbon into the filtrate for decolorization, and performing suction filtration;
step (2) concentration: rotatably steaming the filtrate until no liquid flows out;
step (3) intermediate: adding 80-95% ethanol into the concentrated solution, heating to clear, cooling to 0-5 ℃, and filtering to obtain an intermediate, namely a CBZ-alanine acyclovir condensation compound;
and (4) hydrogenolysis reaction: putting the intermediate, 30-40% ethanol and palladium-carbon into a hydrogenation reactor, heating to 40-50 ℃, introducing hydrogen to react for 0.8-1.2H, filtering, and spin-drying the filtrate to obtain an impurity H.
As an improvement of the technical scheme, in the step (1), DMF is used as a solvent, and the temperature is kept at-5 ℃.
As an improvement of the above technical solution, in the condensation reaction in step (1), acyclovir: CBZ-alanine: DMAP: DCC: the mass ratio of DMF is 1:1 to 1.5:0.05 to 0.15:1 to 2: 5-10, wherein DMF is mixed with DCC according to the mass ratio of 1-3 to prepare a solution for standby, half of the solution is added at the beginning of the reaction, and the other half of the solution is added after the reaction is carried out for 15 hours.
As an improvement of the technical scheme, the rotary evaporation temperature in the step (2) is not more than 75 ℃ until no liquid flows out.
As an improvement of the technical scheme, in the purification of the intermediate in the step (3), 80-95% of ethanol which is 10-20 times of the weight of substrate acyclovir is added, the temperature is raised to be clear, and the crystallization temperature is 0-5 ℃.
As an improvement of the technical scheme, in the hydrogenolysis reaction in the step (4), the dosage of 30-40% ethanol is 5-7 times of the weight of the intermediate, the dosage of palladium-carbon is 0.05-0.2 of the weight of the intermediate, the reaction time is 1-4 h, and the concentration temperature of the filtrate after filtering out the palladium-carbon is less than 70 ℃.
Compared with the prior art:
the method comprises the steps of reacting acyclovir and CBZ-alanine in DMF at a low temperature, removing water generated in the reaction by using DCC, accelerating the reaction process by using DMAP, removing impurities in a product by using different solubilities of the target product and impurities such as DMAP in an ethanol solution in a recrystallization mode to obtain a high-purity impurity intermediate; and then high-purity impurity H is obtained through deprotection.
The beneficial effects of the invention are:
acyclovir and CBZ-alanine react in DMF at low temperature, the reaction is directionally converted, the post-treatment process is more convenient and simpler, and the impurity purity and the yield are high.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical means of the present invention more clearly understood, the present invention may be implemented in accordance with the contents of the description, and in order to make the above and other objects, features, and advantages of the present invention more clearly understood, the following detailed description is given in conjunction with the preferred embodiments.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings of the embodiments will be briefly described below.
FIG. 1 is a flow chart of a method of making high purity valacyclovir impurity H in accordance with the present invention;
FIG. 2 is a detection spectrum of related substances of an impurity H intermediate;
FIG. 3 is a detection spectrum of a substance related to impurity H.
Detailed Description
Other aspects, features and advantages of the present invention will become apparent from the following detailed description, which, when taken in conjunction with the drawings, illustrate by way of example the principles of the invention.
Example one
Step (1) reaction: and (3) cooling 140g of DMF to-5 ℃, and adding 24g of DCC into 55g of DMF for dissolving. And adding 20g of acyclovir, 24g of CBZ-alanine and 2.3g of DMAP into half of the DCC solution, reacting for 15h, adding the other half of the DCC solution, continuing to react for 20h, and filtering. Adding 0.6g of active carbon for decolorization
And (2) concentrating: the filtrate was concentrated at 75 ℃ under reduced pressure, and DMF was distilled off.
Step (3) intermediate: 340ml of 95 percent ethanol is added into the crude product, heated and dissolved, cooled to 0 to 5 ℃ and filtered to obtain 36g of intermediate.
And (4) refining: adding 219g of 35% ethanol into the intermediate, heating to 49 ℃, adding 5.1g of palladium-carbon, introducing hydrogen into the intermediate, reacting for 3 hours, performing suction filtration, and evaporating the filtrate to obtain a finished product.
FIG. 2 is a substance detection pattern of an intermediate of impurity H in example 1. The figure shows that the purity of the intermediate of the impurity H prepared by the method can reach more than 90%.
FIG. 3 is a spectrum of detection of substances related to impurity H in example 1. As can be seen in the figure, the purity of the impurity H prepared by the method can reach more than 95 percent, and other impurities are hardly generated
Example two
Step (1) reaction: and cooling 150g of DMF to-5 ℃, and adding 45g of DCC into 145g of DMF for dissolving. 30g of acyclovir, 44g of CBZ-alanine and 2.4g of DMAP are added into half of the DCC solution to react for 16h, the other half of the DCC solution is added, the reaction is continued for 18h, and the filtration is carried out. Adding 0.6g of active carbon for decolorization
Step (2) concentration: the filtrate is concentrated under low pressure at 75 ℃, and 1/3-2/3 DMF is evaporated.
Step (3) intermediate: 510ml of 95 percent ethanol is added into the concentrated solution, heated and dissolved, then the temperature is reduced to 0 to 5 ℃, and 43g of intermediate is obtained by suction filtration.
Refining in step (4): adding 284g 30% ethanol into the intermediate, heating to 45 ℃, introducing hydrogen to react for 1.1h, then carrying out suction filtration, and evaporating the filtrate to dryness to obtain a finished product.
EXAMPLE III
Step (1) reaction: and cooling 150g of DMF to-5 ℃, and adding 40g of DCC into 75g of DMF for dissolving. 25g of acyclovir, 37.5g of CBZ-alanine and 1.25g of DMAP are added into a half of DCC solution to react for 16h, the other half of DCC solution is added to continue to react for 18h, and then filtration is carried out. Adding 0.6g of active carbon for decolorization
And (2) concentrating: the filtrate is concentrated under low pressure at 75 ℃, and 1/3-2/3 DMF is evaporated.
Step (3), intermediate: 500ml of 95 percent ethanol is added into the concentrated solution, heated and dissolved, cooled to 0-5 ℃, and filtered to obtain 39g of intermediate.
And (4) refining: 234g of 30% ethanol is added into the intermediate, the temperature is raised to 48 ℃, hydrogen is introduced for reaction for 0.8h, then the filtration is carried out, and the filtrate is evaporated to dryness to obtain the finished product.
The raw materials listed in the invention, the upper and lower limits and interval values of the raw materials of the invention, and the upper and lower limits and interval values of the process parameters (such as temperature, time and the like) can all realize the invention, and the examples are not listed.
While the foregoing is directed to the preferred embodiment of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.
Claims (7)
1. A preparation method of high-purity valacyclovir impurity H is characterized by synthesizing according to the following reaction formula:
acyclovir and CBZ-alanine react in DMF at low temperature, DCC is used for removing water generated in the reaction, DMAP is used for accelerating the reaction process, and impurities in the target product and impurities such as DMAP and the like are removed in a recrystallization mode to obtain a high-purity impurity intermediate; and then high-purity impurity H is obtained after deprotection.
2. The method of preparing high purity valacyclovir impurity H of claim 1 comprising the steps of:
step (1), condensation reaction: cooling the solvent, adding acyclovir, CBZ-alanine and DMAP, adding half of DMF solution of DCC for reaction for 15h, adding the other half of DMF solution of DCC for continuous reaction for more than 15h, filtering, adding active carbon into the filtrate for decolorization, and performing suction filtration;
step (2) concentration: rotatably steaming the filtrate until no liquid flows out;
step (3), intermediate: adding 80-95% ethanol into the concentrated solution, heating to clear, cooling to 0-5 ℃, and filtering to obtain an intermediate, namely a CBZ-alanine acyclovir condensation compound;
and (4) hydrogenolysis reaction: putting the intermediate, 30-40% ethanol and palladium-carbon into a hydrogenation reactor, heating to 40-50 ℃, introducing hydrogen to react for 0.8-1.2H, filtering, and spin-drying the filtrate to obtain an impurity H.
3. The method of preparing high purity valacyclovir impurity H as claimed in claim 2 wherein: in the step (1), the solvent is DMF, and the temperature is reduced to-5 ℃.
4. The method of preparing high purity valacyclovir impurity H as claimed in claim 2 wherein: in the condensation reaction in the step (1), acyclovir: CBZ-alanine: DMAP: DCC: the mass ratio of DMF is 1:1 to 1.5:0.05 to 0.15:1 to 2: 5-10, wherein DMF is mixed with DCC according to the mass ratio of 1-3 to prepare a solution for standby, half of the solution is added at the beginning of the reaction, and the other half is added after the reaction is carried out for 15 h.
5. The method of preparing high purity valacyclovir impurity H as claimed in claim 2 wherein: and (3) carrying out rotary evaporation in the step (2) until no liquid flows out, wherein the rotary evaporation temperature is not more than 75 ℃.
6. The method of preparing high purity valacyclovir impurity H of claim 2 comprising: in the step (3), in the purification of the intermediate, 80-95% ethanol is added to be 10-20 times of the weight of substrate acyclovir, the temperature is raised to be clear, and the crystallization temperature is 0-5 ℃.
7. The method of preparing high purity valacyclovir impurity H as claimed in claim 2 wherein: in the hydrogenolysis reaction in the step (4), the dosage of 30-40% ethanol is 5-7 times of the weight of the intermediate, the dosage of palladium-carbon is 0.05-0.2 of the weight of the intermediate, the reaction time is 1-4 h, and the concentration temperature of the filtrate after filtering the palladium-carbon is less than 70 ℃.
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| CN202211526395.XA CN115745997A (en) | 2022-11-30 | 2022-11-30 | Preparation method of high-purity valaciclovir impurity H |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101068814A (en) * | 2004-09-04 | 2007-11-07 | 特瓦制药工业有限公司 | An isolated valacyclovir impurity, process for the preparation of valacyclovir impurity and use as a reference standard |
| WO2014094312A1 (en) * | 2012-12-21 | 2014-06-26 | 上海迪赛诺化学制药有限公司 | Method for synthesizing nucleoside amino acid derivatives through enzyme catalysis |
| CN110940754A (en) * | 2019-12-18 | 2020-03-31 | 湖北省宏源药业科技股份有限公司 | High performance liquid chromatography method for separating and measuring impurities in valacyclovir hydrochloride |
| CN111879868A (en) * | 2020-06-30 | 2020-11-03 | 辰欣药业股份有限公司 | Method for determining related substances of valacyclovir hydrochloride |
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2022
- 2022-11-30 CN CN202211526395.XA patent/CN115745997A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101068814A (en) * | 2004-09-04 | 2007-11-07 | 特瓦制药工业有限公司 | An isolated valacyclovir impurity, process for the preparation of valacyclovir impurity and use as a reference standard |
| WO2014094312A1 (en) * | 2012-12-21 | 2014-06-26 | 上海迪赛诺化学制药有限公司 | Method for synthesizing nucleoside amino acid derivatives through enzyme catalysis |
| CN110940754A (en) * | 2019-12-18 | 2020-03-31 | 湖北省宏源药业科技股份有限公司 | High performance liquid chromatography method for separating and measuring impurities in valacyclovir hydrochloride |
| CN111879868A (en) * | 2020-06-30 | 2020-11-03 | 辰欣药业股份有限公司 | Method for determining related substances of valacyclovir hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 蒲 通等: "盐酸伐昔洛韦有关物质的合成", 《中国医药工业杂志》, vol. 43, no. 12, pages 974 - 976 * |
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