CN113831377A - Molnbupiravir related substance, and preparation method and application thereof - Google Patents
Molnbupiravir related substance, and preparation method and application thereof Download PDFInfo
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- 239000000126 substance Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000012535 impurity Substances 0.000 claims abstract description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 10
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 239000012445 acidic reagent Substances 0.000 claims abstract description 7
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 4
- 239000010452 phosphate Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 22
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 11
- 235000019253 formic acid Nutrition 0.000 claims description 11
- HTNPEHXGEKVIHG-ZJTJHKMLSA-N molnupiravir Chemical compound CC(C)C(=O)OC[C@H]1O[C@H](C(O)C1O)N1C=C\C(NC1=O)=N\O HTNPEHXGEKVIHG-ZJTJHKMLSA-N 0.000 claims description 11
- 229940075124 molnupiravir Drugs 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 239000003814 drug Substances 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 claims description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- HMNQNULAYXDEEQ-UHFFFAOYSA-N acetic acid;hydroxylamine Chemical compound ON.CC(O)=O HMNQNULAYXDEEQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- -1 n-butyl anhydride Chemical class 0.000 claims description 3
- 150000003222 pyridines Chemical class 0.000 claims description 3
- 229910000030 sodium bicarbonate Chemical class 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 239000013558 reference substance Substances 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 238000003908 quality control method Methods 0.000 description 4
- 208000025721 COVID-19 Diseases 0.000 description 3
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- HTNPEHXGEKVIHG-QCNRFFRDSA-N molnupiravir Chemical compound C(OC(=O)C(C)C)[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C(=O)N=C(NO)C=C1 HTNPEHXGEKVIHG-QCNRFFRDSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 1
- XCUAIINAJCDIPM-XVFCMESISA-N N(4)-hydroxycytidine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=NO)C=C1 XCUAIINAJCDIPM-XVFCMESISA-N 0.000 description 1
- 241000315672 SARS coronavirus Species 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940126587 biotherapeutics Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000004199 lung function Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention provides a Molnbupiravir related substance, a preparation method and an application thereof, wherein the related substance has a structure shown in a formula 1, and comprises the following specific steps: 1. the compound of formula 2 or sulfate, hydrochloride and phosphate thereof are condensed with acylating agent in solvent and catalyst 4-dimethylaminopyridine and alkaline condition to obtain compound of formula 3; 2. adding a hydroxylamine reagent into the compound of the formula 3 in a solvent, and reacting to obtain a compound of a formula 4; 3. the compound of formula 4 is subjected to acetone removal protection in a solvent under the action of an acid reagent to obtain the compound of formula 1. The preparation method provided by the invention has mild conditions and simple treatment, and can be used for preparing the compound of the formula 1 with purity meeting the requirement in a large scale. The invention also discloses application of the compound shown in the formula 1 as a Molnuprivir impurity reference substance.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a Molnopiravir related substance, a preparation method and application thereof.
Background
Molnupiarvir (MK-4482 or EIDD-2801) is an effective oral broad spectrum antiviral drug. It is an improved version of its active nucleoside analogue EIDD-1931, with improved pharmaceutical properties. In mice infected with SARS-CoV or MERS-CoV, prophylactic and therapeutic administration of Molnupiarvir can improve lung function, reduce viral titer and weight loss. Reidesciclovir is an option for COVID-19 treatment; however, this preliminary solution still remains to be improved, and the process of meeting the demand is complicated by the problems of raw material supply, price, length of the synthesis route, and the like. Molnupiravir is an interesting supplement to the treatment of COVID-19 by ridciclovir, and compared with the Molnupiravir, the Molnupiravir is simple in structure and made of abundant raw materials, and is expected to relieve supply chain difficulty and reduce cost. Meanwhile, Molnupiravir shows potential for treatment of mice with the pharmaceutical strain COVID-19 of reed-ciclovir, and can be used orally. These advantages have prompted merck to obtain drug candidate approval from ridge back Biotherapeutics.
The structural formula of Molnupiravir is shown below:
the quality control of raw material drugs and preparations is always the key and difficult point in the process of drug development, and the research on impurities is the key point in the quality control. Starting materials, intermediates, reaction by-products, degradation impurities, etc. in the synthesis process of Molnupiravir may become impurities remaining in the final product (Molnupiravir), thereby affecting the quality of the medicine. At present, researches on related substances of Molnnupiravir and researches on quality control analysis methods are rarely reported.
Disclosure of Invention
Aiming at the problems, the invention aims to research the synthesis process of the Molnopiravir and provides a related substance generated in the synthesis process of the Molnopiravir; another object of the present invention is to disclose a method for preparing the related substance. The invention also aims to indicate the application of the related substances in the Molnupiravir bulk drug and the impurity reference substance of the preparation thereof.
The technical scheme of the invention is as follows: a Molnbupiravir related substance, the structure of which is shown in formula I:
further, the preparation method of the Molnnupiravir related substance comprises the following steps:
further, a preparation method of the Molnnupiravir related substance comprises the following specific operation steps:
step (1): the compound of formula 2 or sulfate, hydrochloride and phosphate thereof are condensed with acylating agent in solvent and catalyst 4-dimethylaminopyridine and alkaline condition to obtain compound of formula 3;
step (2): adding a hydroxylamine reagent into the compound of the formula 3 in a solvent, and reacting to obtain a compound of a formula 4;
and (3): the compound of formula 4 is subjected to acetone removal protection in a solvent under the action of an acid reagent to obtain the compound of formula 1.
Further, in the step (1), the acylation reagent is selected from n-butyl anhydride and n-butyl chloride; preferably, the method comprises the following steps: n-butyric anhydride;
the solvent is one or two of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile, acetone, N-methylpyrrolidone, N-dimethylformamide and N, N-dimethylacetamide; preferably, the method comprises the following steps: acetonitrile;
under the alkaline condition, the base is one or two of 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylamine, N-diisopropylethylamine, pyridine, substituted pyridine, sodium carbonate and sodium bicarbonate; preferably, the method comprises the following steps: triethylamine.
Further, in the step (2), the solvent is selected from one or two of methanol, ethanol, isopropanol, n-butanol and a mixture thereof with water; preferably, the method comprises the following steps: a mixed solvent of isopropyl alcohol and water;
the hydroxylamine reagent is selected from one or two of hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine acetate or hydroxylamine aqueous solution; preferably, the method comprises the following steps: hydroxylamine sulfate.
Further, in the step (3), the solvent is one or two selected from acetone, isopropanol, formic acid, water, trifluoroacetic acid, aqueous hydrochloric acid solution, aqueous phosphoric acid solution and any mixed solution thereof; preferably, the method comprises the following steps: a mixed solvent of formic acid and water;
the acid reagent is selected from one or two of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and mixed acid thereof; preferably, the method comprises the following steps: formic acid.
Further, an application of the Molnopiravir related substance in a Molnopiravir bulk drug and a preparation impurity reference substance thereof.
The invention has the beneficial effects that: the impurities prepared by the method can be used as impurity reference substances in the quality research of Molnuprivir raw material medicines or preparations, the content of the impurities in the finished product Molnuprivir is convenient to control to be lower than 0.15%, and the method has important significance for quality control and research of Molnuprivir raw material medicines and preparations.
Description of the drawings:
FIG. 1 shows a hydrogen spectrum of a compound of formula 1 of the present invention: (1H NMR)；
FIG. 2 shows a carbon spectrum of a compound of formula 1 of the present invention: (13C NMR)；
FIG. 3 is a mass spectrum of a compound of formula 1 according to the present invention;
FIG. 4 is a liquid chromatography profile of a compound of formula 1 of the present invention;
FIG. 5 is an HPLC chromatogram of a compound of formula 1 in a finished product of the invention.
Detailed Description
In order to more clearly illustrate the technical solution of the present invention, the present invention will be further described below;
a Molnbupiravir related substance, the structure of which is shown in formula I:
further, the preparation method of the Molnnupiravir related substance comprises the following steps:
further, a preparation method of the Molnnupiravir related substance comprises the following specific operation steps:
step (1): the compound of formula 2 or sulfate, hydrochloride and phosphate thereof are condensed with acylating agent in solvent and catalyst 4-dimethylaminopyridine and alkaline condition to obtain compound of formula 3;
step (2): adding a hydroxylamine reagent into the compound of the formula 3 in a solvent, and reacting to obtain a compound of a formula 4;
and (3): the compound of formula 4 is subjected to acetone removal protection in a solvent under the action of an acid reagent to obtain the compound of formula 1.
Further, in the step (1), the acylation reagent is selected from n-butyl anhydride and n-butyl chloride; preferably, the method comprises the following steps: n-butyric anhydride;
the solvent is one or two of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile, acetone, N-methylpyrrolidone, N-dimethylformamide and N, N-dimethylacetamide; preferably, the method comprises the following steps: acetonitrile;
under the alkaline condition, the base is one or two of 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylamine, N-diisopropylethylamine, pyridine, substituted pyridine, sodium carbonate and sodium bicarbonate; preferably, the method comprises the following steps: triethylamine.
Further, in the step (2), the solvent is selected from one or two of methanol, ethanol, isopropanol, n-butanol and a mixture thereof with water; preferably, the method comprises the following steps: a mixed solvent of isopropyl alcohol and water;
the hydroxylamine reagent is selected from one or two of hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine acetate or hydroxylamine aqueous solution; preferably, the method comprises the following steps: hydroxylamine sulfate.
Further, in the step (3), the solvent is one or two selected from acetone, isopropanol, formic acid, water, trifluoroacetic acid, aqueous hydrochloric acid solution, aqueous phosphoric acid solution and any mixed solution thereof; preferably, the method comprises the following steps: a mixed solvent of formic acid and water;
the acid reagent is selected from one or two of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and mixed acid thereof; preferably, the method comprises the following steps: formic acid.
Further, an application of the Molnopiravir related substance in a Molnopiravir bulk drug and a preparation impurity reference substance thereof.
Example 1
A clean and dry 250mL reaction flask was charged with 7.62g of the compound of formula 2, 43.74g of acetonitrile, 0.24g of 4-dimethylaminopyridine and 2.03g of triethylamine in this order, stirred to dissolve, and then kept at 0-10 ℃ and 3.2g of n-butyric anhydride was added dropwise. The reaction was monitored until after substantial disappearance of starting material and concentrated. 48.2g of ethyl acetate and 15.1g of water are added. After concentration, column chromatography is carried out to obtain 6.1g of the compound of the formula 3, the yield is 86.7 percent, and the purity is 97.3 percent.
Example 2
2.88g of the compound of formula 3, 28.9g of isopropanol, 17.33g of purified water, 4.28g of hydroxylamine sulfate were added to a reaction flask, and heated to 70 to 75 ℃ with stirring. The reaction was monitored until the starting material had substantially disappeared, after removal of isopropanol by rotary evaporation, 18.9g of ethyl acetate was added, stirring was carried out, liquid separation was carried out by standing, the organic phase was concentrated, and column chromatography was carried out to obtain 2.5g of the compound of formula 4, with a yield of 83.2% and a purity of 91.7%.
Example 3
A reaction flask was charged with 1.04g of the compound of formula 4, 5.11g of formic acid, and 0.27g of purified water, and heated to 40 to 50 ℃ with stirring. The reaction was monitored until the raw materials were substantially disappeared, the solvent was removed by rotary evaporation, 6.31g of 2-methyltetrahydrofuran was added, and after stirring, standing and liquid separation, 10.3g of 18% potassium hydrogencarbonate solution was added to the organic phase, and after stirring, standing and liquid separation, the reaction mixture was stirred and liquid separated. The organic phase was evaporated to dryness and 8.13g of methyl tert-butyl ether was added, stirred and washed, and after filtration, the filter cake was vacuum dried to give 0.74g of the compound of formula 1 in 79.8% yield and 98.2% purity.
1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.53(s,1H),6.83(d,J＝8.2Hz,1H),5.71(d,J＝5.5Hz,1H),5.59(d,J＝8.2Hz,1H),5.35(d,J＝5.7Hz,1H),5.22(d,J＝5.0Hz,1H),4.24-4.10(m,2H),4.00(m,1H),3.93-3.89(m,2H),2.33(t,J＝7.2Hz,2H),1.58-1.52(m,2H),0.89(t,J＝7.3Hz,3H).MS:352.1(M+H)+,328.2(M-H)-.
Finally, it should be understood that the embodiments described herein are merely illustrative of the principles of embodiments of the present invention; other variations are possible within the scope of the invention; thus, by way of example, and not limitation, alternative configurations of embodiments of the invention may be considered consistent with the teachings of the present invention; accordingly, the embodiments of the invention are not limited to the embodiments explicitly described and depicted.
Claims (7)
1. A Molnnupiravir related substance is characterized in that the structure is shown as formula I:
2. the method of claim 1, wherein the method comprises the following steps:
3. the method for preparing a Molnupiravir related substance as claimed in claim 2, wherein the specific operation steps are as follows:
step (1): the compound of formula 2 or sulfate, hydrochloride and phosphate thereof are condensed with acylating agent in solvent and catalyst 4-dimethylaminopyridine and alkaline condition to obtain compound of formula 3;
step (2): adding a hydroxylamine reagent into the compound of the formula 3 in a solvent, and reacting to obtain a compound of a formula 4;
and (3): the compound of formula 4 is subjected to acetone removal protection in a solvent under the action of an acid reagent to obtain the compound of formula 1.
4. The method according to claim 3, wherein the Molnnupiravir-related substance is a compound selected from the group consisting of,
in the step (1), the acylation reagent is selected from n-butyl anhydride and n-butyl chloride;
the solvent is one or two of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile, acetone, N-methylpyrrolidone, N-dimethylformamide and N, N-dimethylacetamide;
under alkaline conditions, the base is one or two selected from 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylamine, N-diisopropylethylamine, pyridine, substituted pyridine, sodium carbonate and sodium bicarbonate.
5. The method according to claim 3, wherein the Molnnupiravir-related substance is a compound selected from the group consisting of,
in the step (2), the solvent is one or two selected from methanol, ethanol, isopropanol, n-butanol and a mixture of the n-butanol and water;
the hydroxylamine reagent is selected from one or two of hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine acetate or hydroxylamine aqueous solution.
6. The method according to claim 3, wherein the Molnnupiravir-related substance is a compound selected from the group consisting of,
in the step (3), the solvent is one or two selected from acetone, isopropanol, formic acid, water, trifluoroacetic acid, hydrochloric acid aqueous solution, phosphoric acid aqueous solution and any mixed solution thereof;
the acid reagent is selected from one or two of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and mixed acids thereof.
7. The use of a Molnupiravir related substance as recited in claim 1 in a Molnupiravir bulk drug and a formulation impurity control thereof.
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| CN115785181B (en) * | 2022-11-30 | 2023-08-29 | 山东诚汇双达药业有限公司 | Method for preparing Mo Pila-wei intermediate by one-pot method |
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