CN115521337A - Synthetic method of Reidesciclovir intermediate - Google Patents
Synthetic method of Reidesciclovir intermediate Download PDFInfo
- Publication number
- CN115521337A CN115521337A CN202211176016.9A CN202211176016A CN115521337A CN 115521337 A CN115521337 A CN 115521337A CN 202211176016 A CN202211176016 A CN 202211176016A CN 115521337 A CN115521337 A CN 115521337A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- synthesis method
- intermediate according
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000010189 synthetic method Methods 0.000 title claims description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 18
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 claims abstract description 15
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000001308 synthesis method Methods 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000011230 binding agent Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- 239000007822 coupling agent Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 3
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NAQUAXSCBJPECG-NITSXXPLSA-N (3r,4r,5r)-3,4-bis(phenylmethoxy)-5-(phenylmethoxymethyl)oxolan-2-ol Chemical compound C([C@H]1OC([C@@H]([C@@H]1OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)O)OCC1=CC=CC=C1 NAQUAXSCBJPECG-NITSXXPLSA-N 0.000 description 1
- 241001115402 Ebolavirus Species 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical group C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of a Rudexilvir intermediate, which comprises the following steps: s1: adding a compound A1 and N, N' -carbonyldiimidazole into a first reaction solvent to react to prepare a compound A2; s2, adding the compound A2, the compound A3, an acid binding agent and a coupling agent into a second reaction solvent to react to prepare a compound A4; and S3, adding the compound A4 and alkali into a third reaction solvent for deprotection reaction to obtain a Reidcciclovir intermediate M. According to the synthesis method of the Reidesciclovir intermediate, the carbonate is formed to protect two active hydroxyl groups, and the two active hydroxyl groups are hydrolyzed under an alkaline condition, so that the generation of byproducts can be reduced, the reaction yield is improved, and the post-treatment steps are simplified.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a synthetic method of a Reidesciclovir intermediate.
Background
Reidcivir is a ribonucleoside analog produced by Gilead Biotechnology Inc. USA, mainly interferes with the RNA transcription process of virus, has broad-spectrum antiviral activity, and has the following chemical structural formula
Route 1: the route reported by patent WO2016069826 of the original research manufacturer giride: (3R, 4R, 5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-ol is used as a starting material, and the Rudexilvir is obtained by oxidation, addition, substitution, resolution, debenzylation, protection, substitution and final resolution. The route has poor selectivity, and is not suitable for industrial production because the purification is carried out by a chiral column.
Route 2: nature 2016 (Warren T K, jordan R, lo M K, et al. Therapeutic efficacy of the small molecule GS-5734against Ebola virus in rhesus mo keys J.,. Nature 2016,531 (7594): 381-385.) reports a second generation of synthesis, which can be scaled up to hectogram in the laboratory. The yield was 40%, 85%, 86%, 90%, 70% and 69% in total for 6 steps. The route is optimized to the route 1, during the cyano substitution step, the isomer ratio of the obtained product is 95% by adding trifluoromethanesulfonic acid, the trifluoromethanesulfonic acid greatly improves the ratio of the desired beta-anomer, and the chiral purity can be further improved by subsequent recrystallization.
In the scheme 2, two active hydroxyl groups need to be protected by ketal, and acidic conditions are usually adopted for deprotection, under which cyano groups are easily hydrolyzed to form amide to generate impurities, so that the reaction yield is reduced.
Disclosure of Invention
1. The technical problem to be solved is as follows:
aiming at the technical problem, the invention provides a synthetic method of a Reidesciclovir intermediate.
2. The technical scheme is as follows:
a synthetic method of a Reidesciclovir intermediate is characterized in that the route of the synthetic method is designed as follows:
the method comprises the following steps:
s1: adding a compound A1 and N, N' -carbonyldiimidazole into a first reaction solvent to react to prepare a compound A2;
s2, adding the compound A2, the compound A3, an acid binding agent and a coupling agent into a second reaction solvent to react to prepare a compound A4;
and S3, adding the compound A4 and alkali into a third reaction solvent to carry out deprotection reaction to obtain a Reideciclovir intermediate M.
Further, the first reaction solvent in step S1 is one or more of toluene, xylene, and cyclohexanone.
Further, the reaction temperature in the step S1 is 30-50 ℃, and the reaction time is 10-20 hours.
Further, the second reaction solvent in the step S2 is one or more of acetonitrile, tetrahydrofuran, dichloromethane and 1, 2-dichloroethane;
further, the coupling reagent of step S2 is magnesium chloride.
Further, the acid-binding agent in the step S2 is one or more of DIPEA, triethylamine, pyridine and 2, 6-dimethylpyridine;
further, the reaction temperature of the step S2 is 20-80 ℃;
further, the reaction time of the step S2 is 4-8h;
further, the molar ratio of the compound A2, the coupling reagent, the acid-binding agent and the compound A3 in the step S2 is 1: 1-5: 1-1.5; preferably, 1: 2.5: 1.2.
Further, the step S2 further includes a post-treatment step, wherein the post-treatment step includes adding a small amount of methanol to quench the reaction, concentrating under reduced pressure, and purifying the obtained concentrate by column chromatography to obtain a pure compound A4.
Further, the third solvent in step S3 is a mixed solvent of water and one of dichloromethane, 1, 2-dichloroethane, methanol and toluene.
Further, the alkali in step S3 is sodium carbonate, potassium carbonate, barium hydroxide, sodium hydroxide or potassium hydroxide.
Further, the reaction temperature of the step S3 is 20-45 ℃, and the reaction time is 1-24 hours.
3. Has the beneficial effects that:
according to the synthesis method of the ridciclovir intermediate, the carbonate is formed to protect two active hydroxyls, and the two active hydroxyls are hydrolyzed under an alkaline condition, so that the generation of byproducts can be reduced, the reaction yield is improved, and the post-treatment steps are simplified.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. Unless defined otherwise, technical or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the word "comprising" and similar words are intended to mean that the element or item listed before the word covers the element or item listed after the word and its equivalents, but does not exclude other elements or items.
Aiming at the problems in the prior art, the embodiment of the invention provides a synthetic method of a Reidesciclovir intermediate.
A synthetic method of a Reideciclovir intermediate comprises the following steps:
the method comprises the following steps:
s1: adding a compound A1 and N, N' -carbonyldiimidazole into a first reaction solvent to react to prepare a compound A2;
s2, adding the compound A2, the compound A3, an acid binding agent and a coupling agent into a second reaction solvent to react to prepare a compound A4;
and S3, adding the compound A4 and alkali into a third reaction solvent for deprotection reaction to obtain a Reidcciclovir intermediate M.
The first reaction solvent in the step S1 is one or more of toluene, xylene and cyclohexanone.
The reaction temperature in the step S1 is 30-50 ℃, and the reaction time is 10-20 hours.
The second reaction solvent in the step S2 is one or more of acetonitrile, tetrahydrofuran, dichloromethane and 1, 2-dichloroethane;
the coupling reagent of step S2 is magnesium chloride.
The acid-binding agent in the step S2 is one or more of DIPEA, triethylamine, pyridine and 2, 6-dimethylpyridine;
the reaction temperature of the step S2 is 20-80 ℃;
the reaction time of the step S2 is 4-8h;
the molar ratio of the compound A2, the coupling reagent, the acid-binding agent and the compound A3 in the step S2 is 1: 1-5: 1-1.5; preferably, 1: 2.5: 1.2.
Further, the step S2 further includes a post-treatment step, wherein the post-treatment step includes adding a small amount of methanol to quench the reaction, concentrating under reduced pressure, and purifying the obtained concentrate by column chromatography to obtain a pure compound A4.
The third solvent in the step S3 is a mixed solvent of water and one of dichloromethane, 1, 2-dichloroethane, methanol and toluene.
The alkali in the step S3 is sodium carbonate, potassium carbonate, barium hydroxide, sodium hydroxide or potassium hydroxide.
The reaction temperature of the step S3 is 20-45 ℃, and the reaction time is 1-24 hours.
According to the invention, the carbonate is formed to protect two active hydroxyls, and the hydrolysis is carried out under an alkaline condition, so that the generation of byproducts can be reduced, the reaction yield is improved, and the post-treatment steps are simplified.
Example 1
S1: adding compound A1 (50g, 0.172mol, 1.0eq) and N, N' -carbonyldiimidazole (27.8g, 0.171mol, 1.0eq) into 600ml of cyclohexanone, heating to 45 ℃, stirring for reacting for 16 hours, concentrating under reduced pressure, adding dichloromethane for dissolving, washing with saturated saline, drying with anhydrous magnesium sulfate, and performing spin-drying to obtain compound A2; directly used for the next reaction;
s2, under the protection of nitrogen, adding the compound A2, the compound A3 (93g, 0.206mol, 1.2eq) and the magnesium chloride (16.4g, 0.172mol,1.0 eq) obtained in the step S1 into acetonitrile 1.2L, heating to 60 ℃, and dropwise adding DIPEA (55.6g, 0.430mol,2.5 eq); reacting at room temperature for 6 hours, after HPLC detection reaction is completed, cooling ice water to 0 ℃, dropwise adding methanol for quenching reaction, concentrating under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound A4 (73.5g, 0.117mol) with the yield of two steps of 68%.
S3: adding the compound A4 (73.5g, 0.117mmol, 1.0eq) into a mixed solvent of 500ml of 1, 2-dichloroethane and 100ml of water, adding sodium hydroxide (11.7g, 0.293mol, 2.5eq), stirring at room temperature for reaction for 3 hours, detecting by HPLC to complete the reaction, separating liquid, extracting an aqueous phase by dichloromethane, combining organic phases, concentrating, and purifying by column chromatography to obtain a Redcisvir intermediate M (61.4g, 0.102mol); the yield thereof was found to be 87.1%.
Example 2
S1: adding compound A1 (50g, 0.172mol, 1.0eq) and N, N' -carbonyldiimidazole (27.8g, 0.171mol, 1.0eq) into 600ml of toluene, heating to 50 ℃, stirring for reacting for 16 hours, concentrating under reduced pressure, adding dichloromethane for dissolving, washing with saturated saline, drying with anhydrous magnesium sulfate, and performing spin-drying to obtain compound A2; directly used for the next reaction;
s2, under the protection of nitrogen, adding the compound A2, the compound A3 (93g, 0.206mol, 1.2eq) and the magnesium chloride (16.4g, 0.172mol, 1.0eq) obtained in the step S1 into 1.2L of 1, 2-dichloroethane, heating to 60 ℃, and dropwise adding triethylamine (43.5 g,0.430mol, 2.5eq); reacting for 6 hours at room temperature, after HPLC detection reaction is completed, cooling ice water to 0 ℃, dropwise adding methanol to quench reaction, decompressing and concentrating to obtain a crude product, and purifying the crude product by column chromatography to obtain a compound A4 (70.6 g, 0.112mol), wherein the yield of two steps is 65.3%.
S3: adding the compound A4 (70.6g, 0.112mmol and 1.0eq) into a mixed solvent of 500ml of acetonitrile and 100ml of water, adding sodium hydroxide (11.2g, 0.280mol and 2.5eq), stirring at room temperature for reaction for 3 hours, detecting by HPLC that the reaction is complete, separating liquid, extracting a water phase by using dichloromethane, combining organic phases, concentrating, and purifying by column chromatography to obtain a Reidcisvir intermediate M (60.1g and 0.100mol); the yield thereof was found to be 89%.
Although the embodiments of the present invention have been described in detail hereinabove, it is apparent to those skilled in the art that various modifications and variations can be made to the embodiments. However, it is to be understood that such modifications and variations are within the scope and spirit of the present invention as set forth in the following claims. Moreover, the invention as described herein is capable of other embodiments and of being practiced or of being carried out in various ways.
Claims (10)
1. A synthetic method of a Reideciclovir intermediate is characterized in that the synthetic method has the following route design:
the method comprises the following steps:
s1: adding a compound A1 and N, N' -carbonyldiimidazole into a first reaction solvent to react to prepare a compound A2;
s2, adding the compound A2, the compound A3, an acid-binding agent and a coupling agent into a second reaction solvent to react to prepare a compound A4;
and S3, adding the compound A4 and alkali into a third reaction solvent for deprotection reaction to obtain a Reidcciclovir intermediate M.
2. A synthesis method of a ridciclovir intermediate according to claim 1, characterized in that the first reaction solvent in step S1 is one or more of toluene, xylene and cyclohexanone; the reaction temperature is 30-50 ℃, and the reaction time is 10-20 hours.
3. A synthesis method of a ridciclovir intermediate according to claim 2, characterized in that the second reaction solvent in step S2 is one or more of acetonitrile, tetrahydrofuran, dichloromethane and 1, 2-dichloroethane.
4. A synthesis method of a ridciclovir intermediate according to claim 2, characterized in that the coupling reagent in step S2 is magnesium chloride.
5. A synthesis method of a ridciclovir intermediate according to claim 2, characterized in that the acid-binding agent of step S2 is one or more of DIPEA, triethylamine, pyridine, 2, 6-lutidine.
6. A synthesis method of a ridciclovir intermediate according to claim 2, characterized in that the reaction temperature of step S2 is 20-80 ℃; the reaction time of the step S2 is 4-8h.
7. A synthesis method of a Rudeciclovir intermediate according to claim 2, characterized in that the molar ratio of the compound A2, the coupling reagent, the acid-binding agent and the compound A3 in the step S2 is 1: 1-5: 1-1.5.
8. A synthesis method of a ridciclovir intermediate according to claim 2, characterized in that the step S2 further comprises a post-treatment step, wherein the post-treatment step comprises adding a small amount of methanol to quench the reaction, concentrating under reduced pressure, and purifying the obtained concentrate by column chromatography to obtain pure compound A4.
9. A synthesis method of a ridciclovir intermediate according to claim 8, wherein the third solvent in step S3 is a mixed solvent of water and one of dichloromethane, 1, 2-dichloroethane, methanol and toluene; the alkali is sodium carbonate, potassium carbonate, barium hydroxide, sodium hydroxide or potassium hydroxide.
10. A synthesis method of a Rudexilvir intermediate as claimed in claim 8, wherein the reaction temperature of step S3 is 20-45 ℃ and the reaction time is 1-24 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211176016.9A CN115521337A (en) | 2022-09-26 | 2022-09-26 | Synthetic method of Reidesciclovir intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211176016.9A CN115521337A (en) | 2022-09-26 | 2022-09-26 | Synthetic method of Reidesciclovir intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115521337A true CN115521337A (en) | 2022-12-27 |
Family
ID=84699701
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211176016.9A Pending CN115521337A (en) | 2022-09-26 | 2022-09-26 | Synthetic method of Reidesciclovir intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115521337A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023197791A1 (en) * | 2022-04-11 | 2023-10-19 | 广东晨康生物科技有限公司 | Cyclic carbonate nucleoside compound and use thereof |
| US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
-
2022
- 2022-09-26 CN CN202211176016.9A patent/CN115521337A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
| WO2023197791A1 (en) * | 2022-04-11 | 2023-10-19 | 广东晨康生物科技有限公司 | Cyclic carbonate nucleoside compound and use thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN115521337A (en) | Synthetic method of Reidesciclovir intermediate | |
| CN110903248B (en) | Synthesis method of 5-chloro-4-aminopyridazine | |
| CN112125805B (en) | Water-soluble magnolol derivative, preparation method of honokiol derivative and intermediate thereof, and related monohydroxy protected intermediate | |
| CN107540685B (en) | Preparation method and intermediate of Sotagliflozin | |
| CN108503610A (en) | A kind of preparation method of optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one | |
| EP2852583A1 (en) | Sulfilimine and sulphoxide methods for producing festinavir | |
| CN112645833A (en) | Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid | |
| US5780677A (en) | Process for producing glutamine derivative | |
| CN115806543A (en) | Articaine hydrochloride intermediate and preparation method and application thereof | |
| CN112225647A (en) | Method for synthesizing 5-bromo-2-methoxyphenol | |
| CN115651022A (en) | Synthetic method of high-purity Reidesvir intermediate | |
| CN104987325B (en) | A kind of preparation method of voriconazole | |
| Pal et al. | Synthesis of chiral pyranocyclohexane, oxepanocyclohexane, and furylpyran and-oxepane systems by the application of intramolecular nitrone and nitrile oxide cycloaddition of carbohydrate derivatives | |
| CN114717280A (en) | Synthesis method of monopilavir | |
| CN103694291A (en) | Synthesis method for valrubicin | |
| Zong et al. | Highly efficient removal of allyloxycarbonyl (Alloc) function provides a practical orthogonal protective strategy for carbohydrates | |
| CN108314613B (en) | Preparation method of dapagliflozin isomer impurity I | |
| CA2748954A1 (en) | Process for the recovery of beta-acetylfuranoside | |
| CN112979736B (en) | Preparation method of Reidesciclovir | |
| KR102486535B1 (en) | Method for prearation of kanamycin X from kanamycin A by chemical synthesis | |
| CN114773405B (en) | Preparation method of monatiravir | |
| CA2266473A1 (en) | A method for producing optically active erythro-3-amino-2-hydroxybutyric esters and acids thereof | |
| CN113480453B (en) | Synthesis method of NH2-PEG5-NHBoc | |
| JP5636692B2 (en) | Method for producing 5-hydroxy-1,3-dioxane and method for producing branched glycerol trimer using 5-hydroxy-1,3-dioxane obtained by the method as a raw material | |
| CN108276456A (en) | The preparation method of one kind (2S, 3R, 4S) -2,3,4,5- tetrahydroxys-valeral |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |