CN114213455A - Chiral purification process of Rudesivir side chain intermediate - Google Patents
Chiral purification process of Rudesivir side chain intermediate Download PDFInfo
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- 238000000746 purification Methods 0.000 title claims abstract description 20
- 229940126062 Compound A Drugs 0.000 claims abstract description 29
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 239000012043 crude product Substances 0.000 claims abstract description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 239000012454 non-polar solvent Substances 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 230000009466 transformation Effects 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 239000008399 tap water Substances 0.000 claims description 3
- 235000020679 tap water Nutrition 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 238000005191 phase separation Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 10
- 239000000047 product Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000010606 normalization Methods 0.000 description 6
- 238000004537 pulping Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- -1 2, 3, 4, 5, 6-pentafluorophenoxy Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- DEAGOVGXNPHPIJ-FJXQXJEOSA-N 2-ethylbutyl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CCC(CC)COC(=O)[C@H](C)N DEAGOVGXNPHPIJ-FJXQXJEOSA-N 0.000 description 4
- 108060004795 Methyltransferase Proteins 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- ARKKGZQTGXJVKW-VPCXQMTMSA-N 1-[(2r,3r,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidine-2,4-dione Chemical compound C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 ARKKGZQTGXJVKW-VPCXQMTMSA-N 0.000 description 3
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 3
- 229960002063 sofosbuvir Drugs 0.000 description 3
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 3
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- 241000712891 Arenavirus Species 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- DFVPCNAMNAPBCX-LTGWCKQJSA-N GS-443902 Chemical compound C=1C=C2C(N)=NC=NN2C=1[C@]1(C#N)O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O DFVPCNAMNAPBCX-LTGWCKQJSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 206010023927 Lassa fever Diseases 0.000 description 1
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 1
- 108091034135 Vault RNA Proteins 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- BKXGIODZWZFNPV-UHFFFAOYSA-N benzene;dichlorophosphinic acid Chemical compound OP(Cl)(Cl)=O.C1=CC=CC=C1 BKXGIODZWZFNPV-UHFFFAOYSA-N 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect 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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
-
- 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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2429—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of arylalkanols
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- 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 discloses a chiral purification process of a Rudesevir side chain intermediate, which comprises the following two steps: s1, preparing a racemic mixture of crude Rudexilvir intermediates (A, B); s2, crystallizing and purifying to obtain the compound A. According to the chiral purification process of the Rudexiluwei side chain intermediate, the crude product racemic mixture of the Rudexiluwei intermediate is crystallized and converted into the required single chiral compound A, the possibility of simultaneously producing other compounds is effectively avoided, the purity of the compound A is effectively improved, the chiral purity of the compound A is over 99.7 percent, the yield of the compound A is also effectively improved, the yield of the compound A is 85-88 percent, the yield is stable, the reproducibility is good, the process steps are simple and stable, the product cost is effectively reduced, and the process is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a chiral purification process of a Rudesevir side chain intermediate.
Background
Reidesciclovir: remdesivir (GS-5734), developed by Gilidex corporation of America (Gilead Sciences), is a competitive inhibitor of nucleoside RNA-dependent RNA polymerase (RdRp), whose nucleotide triphosphate product, Remdesivir TP, competes with RdRp for substrate ATP and thus interferes with viral vRNA synthesis. While RdRp is an RNA polymerase widely distributed in both positive-stranded and double-stranded RNA viruses. Therefore, Remdesivir has a certain inhibitory effect on filamentous viruses (Ebola, etc.), arenaviruses (Lassa fever virus, etc.), coronaviruses (SARS, 2019-nCoV, etc.), and has a high inhibitory activity on CoV represented by MERS.
The structure of Remdesivir (GS-5734) is shown below:
and N- [ (S) - (2, 3, 4, 5, 6-pentafluorophenoxy) phenoxyphosphoryl ] -L-alanine isopropyl ester (compound A) is an important intermediate for synthesizing sofosbuvir. The structure is as follows:
for example, WO2016/69826 and EP3212174 report nucleophilic substitution of compound A with (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine (4) under tert-butyl magnesium chloride to obtain Sofosbuvir (Sofosbuvir). As shown in route one:
and (5) route one.
In the case of compound a, which is an intermediate for synthesizing ridciclovir, described above, the synthesis thereof is reported in patent document WO2020/247633 (shown in scheme two),
on the second route, the first route is,
the method uses the compound phenyl dichlorophosphate (5), L-alanine- (2-ethylbutyl) ester hydrochloride (6) and pentafluorophenol (3) to react under the action of triethylamine to obtain the compound A, but the yield is low and is only 21%. In the synthesis of compound a, the theoretical yield of compound 2, 1 was only 50% due to the formation of the same amount of diastereomer, whereas the actual yield was lower.
In the existing preparation method of the ridciclovir intermediate, although the compound A is obtained by refining with an organic solvent, the yield of the obtained compound A is still low, so that the reproducibility is poor, and the purity of the compound A is not high. For example, chinese patent publication No. CN111269263A, published 2020, 06, 12, discloses a reidexiwei side chain intermediate and a process for preparation thereof, wherein "the process comprises reacting phenyl dichlorophosphate with pentafluorophenol ester in an organic solvent under an alkaline condition to obtain an intermediate state, adding alanine (2-ethylbutyl) ester hydrochloride to perform a butt-joint reaction, washing with water to remove salts, and refining with an organic solvent to obtain a high-purity target product, N- [ (S) - (2, 3, 4, 5, 6-pentafluorophenoxy) phenoxyphosphoryl ] -L-alanine- (2-ethylbutyl) ester. "the crystallization process of the prior art reidesivir intermediate is to obtain the compound a by refining the compound a with an organic solvent under alkaline conditions, but the yield of the prior art compound a is only about 70%, the purity is only below 99.5%, the yield is still low, the reproducibility is poor, and the purity of the compound a is not high. For this reason, a new technical solution is needed to solve the above technical problems.
Disclosure of Invention
The invention aims to provide a chiral purification process of a Rudexiluwei side chain intermediate, which aims to solve the problems of low yield, poor reproducibility and low purity of an obtained compound A in the crystallization process of the Rudexiluwei side chain intermediate in the prior art.
In order to achieve the purpose, the invention provides the following technical scheme: the specific synthetic route of the chiral purification process of the Rudexiluwei side chain intermediate is as follows:
the specific process comprises the following steps:
s1, adding tap water into a mixture of the compound A and the compound B according to a mass ratio of 52:48, namely the crude product (A, B) of the Reidesciclovir intermediate, stirring, carrying out phase separation, carrying out vacuum concentration to dryness, then adding a single solvent, stirring and dissolving, washing with water, drying an organic phase with sodium sulfate, and carrying out vacuum concentration to dryness to obtain a racemic mixture of the crude product (A, B) of the Reidesciclovir intermediate, wherein the single solvent is one of isopropyl ether and methyl tert-butyl ether;
s2, adding a transformation solvent or a crystallization solvent into the racemic mixture of the crude Rudexilvir intermediate (A, B) obtained in the step S1, adding an organic base catalyst, reacting at 5-40 ℃ for 10-15 hours, cooling to-5 ℃, stirring, crystallizing for 5-10 hours, filtering, and drying to obtain the purified compound A.
Further, the volume ratio of the transformation solvent or the crystallization solvent to the organic base to the substrate is 20: 1-5: 1.
Further, the conversion solvent is one or more of n-hexane, petroleum ether, diethyl ether, toluene, ethyl acetate and isopropyl ether.
Further, the crystallization solvent is a mixed solvent of a polar solvent and a non-polar solvent or a single solvent; the volume ratio of the polar solvent to the non-polar solvent is 2: 1-1: 7, wherein the polar solvent is ethyl acetate; the nonpolar solvent is one or more of n-heptane, hexane or petroleum ether.
Further, the organic base is selected from one or more of dimethylamine, trimethylamine, triethylamine and pyridine.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the chiral purification process of the side chain intermediate of the ReideSewei, the racemic mixture of the crude product of the ReideSewei intermediate is crystallized and converted into the required single chiral compound A, the possibility of simultaneously producing other compounds is effectively avoided, the purity of the compound A is effectively improved, the chiral purity of the compound A reaches over 99.7 percent, the yield of the compound A is also effectively improved, the yield of the compound A reaches 85-88 percent, the yield is stable, and the reproducibility is good.
2. The chiral purification process of the Rudexiluwei side chain intermediate has simple and stable process steps, effectively reduces the cost of products and is suitable for industrial production.
Detailed Description
The following examples are intended to further illustrate the invention and are not intended to limit the application of the invention.
Preparation of crude (a, B) racemic mixture of the ridciclovir intermediate:
to a solution of L-alanine- (2-ethylbutyl) ester hydrochloride (10.0g,47.68mmol) in dichloromethane (140mL) was added benzene dichlorophosphate (PhOPOCl2) (7.82mL,52.45mmol) at-75 ℃ according to the procedure reported in document WO 2013013009; a solution of Et3N (13.96ml, 100mmol) in dichloromethane (50ml) was then added and stirred at-75 ℃ for 2 hours to give a mixture of Compound A and Compound B in a mass ratio of 52:48, to this mixture was then added pentafluorophenol (8.44 g, 45.86 mmoles, 0.96 eq.) and triethylamine (6.39 mL, 45.86 mmoles, 0.96 eq.) in 50mL dry dichloromethane, stirring at-5 deg.C overnight, adding 100ml tap water into the reaction mixture, stirring for 15 min, separating phases, concentrating the dichloromethane phase at 30 deg.C under reduced pressure to dryness, then adding about 150ml of methyl tert-butyl ether, stirring and dissolving, washing twice with 100ml of water, drying the organic phase with sodium sulfate, and concentrating under reduced pressure at 40 ℃ until the organic phase is dried to obtain 26.31g of semisolid, namely a racemic mixture of the crude Rudexilvir intermediate (A, B).
Example 1:
26.31g of racemic mixture of the crude Rudexilvir intermediate (A, B) is put into a 500ml clean and dry four-mouth reaction bottle, isopropyl ether (184ml) is added, the temperature is raised to 40 ℃, stirring and dissolving are carried out, triethylamine (2.63g) is added at the same time, stirring is carried out for 12 hours at 40 ℃, a large amount of white solid is separated out, stirring is carried out continuously, the temperature is reduced to 5 ℃, stirring is carried out for 10 hours, suction filtration is carried out to obtain a filter cake, vacuum drying is carried out for 12 hours at 40 ℃ to obtain 21.22g of white solid, namely the compound A, the yield is 93.5%, the purity is 99.95% (HPLC area normalization method), and de is more than 99%.
Example 2:
26.31g of a racemic mixture of a crude Reidesciclovir intermediate (A, B) is put into a 500ml clean and dry four-mouth reaction bottle, diethyl ether (263ml) is added, the temperature is increased to 40 ℃, stirring and dissolving are carried out, triethylamine (2.63g) is added, stirring is carried out continuously for 12 hours, a large amount of white solid is separated out, stirring is carried out continuously, the temperature is reduced to 0 ℃, stirring is carried out for 6 hours, a filter cake is obtained by suction filtration, vacuum drying is carried out for 12 hours at 40 ℃, 19.82g of white solid is obtained, namely the compound A, the yield is 87.3%, the purity is 99.89% (HPLC area normalization method), and de is more than 99%.
Example 3:
26.31g of a racemic mixture of a crude Reidesciclovir intermediate (A, B) is put into a 500ml clean and dry four-mouth reaction bottle, toluene (526ml) is added, the temperature is raised to 30 ℃ for basic dissolution, triethylamine (2.63g) is added at the same time, the mixture is continuously stirred at 30 ℃ for 12 hours, the temperature is lowered to 0 ℃ within 2 hours and then stirred for 8 hours, a filter cake is obtained by suction filtration, and then the mixture is dried in vacuum at 40 ℃ for 12 hours to obtain 20.36g of a white solid, namely a compound A, the yield is 89.7%, the purity is 99.92% (HPLC area normalization method), and the de is more than 99%.
Example 4:
26.31g of racemic mixture of crude Ruidexiwei intermediate (A, B) is put into a 500ml clean and dry four-mouth reaction bottle, a mixture of 10% ethyl acetate/n-heptane (263ml) is added, the temperature is increased to 15 ℃, reflux and pulping are carried out for 2 hours, then triethylamine (2.63g) is added, the temperature is continuously maintained at 15 ℃, pulping is carried out for 12 hours, the temperature is reduced to 0 ℃ within 3 hours, stirring and crystallization are carried out for 8 hours, suction filtration is carried out to obtain a filter cake, vacuum drying is carried out for 12 hours at 40 ℃ to obtain 19.55g of white solid (1), the yield is 86.1%, the purity is 99.79% (HPLC area normalization method), and de is more than 99%.
Example 5:
26.31g of racemic mixture of crude Reidesciclovir intermediate (A, B) is put into a 500ml clean and dry four-mouth reaction bottle, methyl tert-butyl ether (526ml) is added, the temperature is raised to reflux and pulping for 2 hours, triethylamine (2.63g) is added, then the reflux and pulping are continued for 15 hours, then the temperature is gradually lowered to 5 ℃, stirring and crystallization are carried out for 10 hours, suction filtration is carried out to obtain a filter cake, then vacuum drying is carried out for 12 hours at 40 ℃ to obtain 19.71g of white solid, namely compound A, the yield is 86.8%, the purity is 99.91% (HPLC area normalization method), and the de is more than 99%.
Example 6:
26.31g of racemic mixture of crude Ruidexiwei intermediate (A, B) is put into a 500ml clean and dry four-mouth reaction bottle, a mixture of 10% ethyl acetate/petroleum ether (263ml) is added, the temperature is increased to 15 ℃, reflux pulping is carried out for 2 hours, triethylamine (2.63g) is added, pulping is carried out for 12 hours at 15 ℃, the temperature is reduced to 0 ℃ within 3 hours, stirring and crystallization are carried out for 8 hours, suction filtration is carried out to obtain a filter cake, vacuum drying is carried out for 12 hours at 40 ℃ to obtain 19.79g of white solid, namely compound A, the yield is 87.2%, the purity is 99.89% (HPLC area normalization method), and de is more than 99%.
Claims (9)
1. A chiral purification process of a Rudeseivir side chain intermediate is characterized in that the specific synthetic route of the chiral purification process is as follows:
2. a chiral purification process of a ridciclovir side chain intermediate as claimed in claim 1, wherein the chiral purification process comprises the following steps:
s1, adding tap water into a mixture of the compound A and the compound B, namely the crude product (A, B) of the Reidesciclovir intermediate, stirring, carrying out phase separation, concentrating under reduced pressure to dryness, then adding a single solvent, stirring and dissolving, washing with water, drying an organic phase with sodium sulfate, and concentrating under reduced pressure to dryness to obtain a racemic mixture of the crude product (A, B) of the Reidesciclovir intermediate;
s2, adding a transformation solvent or a crystallization solvent into the racemic mixture of the crude Rudexilvir intermediate (A, B) obtained in the step S1, adding an organic base catalyst, reacting at 5-40 ℃ for 10-15 hours, cooling to-5 ℃, stirring, crystallizing for 5-10 hours, filtering, and drying to obtain the purified compound A.
3. A chiral purification process of a Rudexilawi side chain intermediate as claimed in claim 2, wherein in S1, the mass ratio of compound A and compound B is 52: 48.
4. The chiral purification process of a reideSivir side chain intermediate as claimed in claim 2, wherein in S2, the volume ratio of the transformation solvent or crystallization solvent to the organic base to the substrate is 20: 1-5: 1.
5. A chiral purification process of a Rudexilawi side chain intermediate as claimed in claim 4, wherein the conversion solvent is one or more of n-hexane, petroleum ether, diethyl ether, toluene, ethyl acetate and isopropyl ether.
6. A chiral purification process of a Rudexilawi side chain intermediate as claimed in claim 4, wherein the crystallization solvent is a mixed solvent of a polar solvent and a non-polar solvent or a single solvent; the volume ratio of the polar solvent to the non-polar solvent is 2: 1-1: 7.
7. A chiral purification process of a Rudexiluwei side chain intermediate as claimed in claim 6, wherein the polar solvent is ethyl acetate; the nonpolar solvent is one or more of n-heptane, hexane or petroleum ether.
8. A chiral purification process of a RudeSeivir side chain intermediate as claimed in claim 2 or 4, wherein the organic base is selected from one or more of dimethylamine, trimethylamine, triethylamine and pyridine.
9. A chiral purification process of a RudeSeivir side chain intermediate as claimed in claim 2 or 6, wherein the single solvent is one of isopropyl ether and methyl tert-butyl ether.
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