CN109762040A - A kind of preparation method of ucleosides NS5B polymerase inhibitors - Google Patents
A kind of preparation method of ucleosides NS5B polymerase inhibitors Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 title claims abstract description 13
- 239000003112 inhibitor Substances 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims abstract description 20
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 19
- 238000001914 filtration Methods 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 17
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 238000013019 agitation Methods 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000002777 nucleoside Substances 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003835 nucleoside group Chemical group 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- 229940087646 methanolamine Drugs 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims 2
- 150000002240 furans Chemical class 0.000 claims 1
- 235000019260 propionic acid Nutrition 0.000 claims 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims 1
- 238000003908 quality control method Methods 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000012065 filter cake Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000012071 phase Substances 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 241000711549 Hepacivirus C Species 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 6
- 229940011051 isopropyl acetate Drugs 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000013517 stratification Methods 0.000 description 6
- -1 4- toluyl Chemical group 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
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- 238000011017 operating method Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- IJMWOMHMDSDKGK-UHFFFAOYSA-N Isopropyl propionate Chemical compound CCC(=O)OC(C)C IJMWOMHMDSDKGK-UHFFFAOYSA-N 0.000 description 3
- 108060004795 Methyltransferase Proteins 0.000 description 3
- 125000005340 bisphosphate group Chemical group 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- 230000036632 reaction speed Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- ASPYPCXTOWJMTI-UHFFFAOYSA-N 2-fluorooxolan-3-ol Chemical compound FC1OCCC1O ASPYPCXTOWJMTI-UHFFFAOYSA-N 0.000 description 2
- 206010008909 Chronic Hepatitis Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 208000012839 conversion disease Diseases 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000000845 uracil-1-yl group Chemical group [*]N1C(=O)N([H])C(=O)C([H])=C1[H] 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- LTKOYWPELWFYHK-UHFFFAOYSA-N 1-$l^{1}-oxidanyl-4-methylbenzene Chemical compound CC1=CC=C([O])C=C1 LTKOYWPELWFYHK-UHFFFAOYSA-N 0.000 description 1
- 206010057573 Chronic hepatic failure Diseases 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 208000010334 End Stage Liver Disease Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 241000710781 Flaviviridae Species 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- CKMFSCALVULGRX-UHFFFAOYSA-M [Cl-].CC(C)(C)[Mg+].C1CCOC1 Chemical compound [Cl-].CC(C)(C)[Mg+].C1CCOC1 CKMFSCALVULGRX-UHFFFAOYSA-M 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
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- XBDUZBHKKUFFRH-UHFFFAOYSA-N n-(2-oxo-1h-pyrimidin-6-yl)benzamide Chemical compound OC1=NC=CC(NC(=O)C=2C=CC=CC=2)=N1 XBDUZBHKKUFFRH-UHFFFAOYSA-N 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
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Abstract
The present invention provides a kind of preparation methods of ucleosides NS5B polymerase inhibitors, include the following steps: 1. in presence of an acid, and reaction is hydrolyzed in compound shown in formula ASC21-RM1, obtains compound shown in formula ASC21-A；2. in the presence of a base, formula ASC21-A compound represented is hydrolyzed reaction and obtains compound shown in formula ASC21-B；3. in the presence of tert-butyl magnesium chloride, compound shown in formula ASC21-B reacts at 10~15 DEG C with formula ASC21-RM2, obtains compound shown in formula ASC21 under conditions of not using DMPU.Compared with prior art, preparation method provided by the present application it is at low cost, it is easy to operate, be easy to quality control and be suitble to industrialization.
Description
Technical field
The invention belongs to pharmaceutical fields, specifically, the present invention relates to have medicative ucleosides to HCV infection
NS5B polymerase inhibitors (2S) -2- ((((the chloro- 5- of (2R, 3R, 4S, 5R) -4- (2,4- dioxo -3,4- dihydro-pyrimidin -1
(2H)-yl) the fluoro- 3- hydroxyl tetrahydrofuran -2- base of -4-) methoxyl group) (phenoxy group) phosphoryl) amino) isopropyl propionate
(ASC21) preparation method.
Background technique
Hepatitis C Virus (HCV) is single stranded positive-sense RNA virus, belong to virus flavivirus (Flaviviridae) section,
Hepatitis virus category.The polygenic NS5B regional code RNA Dependent RNA polymerase (RdRp) of RNA, for virus replication be to
It closes important.After initial acute infection, since preferentially duplication is without directly causing cytopathy in liver cell by HCV, greatly
The individual development of majority infection is chronic hepatitis.Particularly, lack strong T lymphocyte response and high virus mutation tendency seemingly
Facilitate the chronic infection of height ratio.Chronic hepatitis can progress to liver fibrosis, lead to cirrhosis, end-stage liver disease and HCC
(hepatocellular carcinoma), the main reason for becoming liver transfer operation.
Hypotype there are six kinds of main HCV genotype and more than 50 kinds, geographical distribution are different.HCV genotype 1 is Europe
The main genotypes in continent and the U.S..The extensive genetic heterogeneity of HCV has important diagnosis and clinical definition, perhaps can explain
Difficulty in vaccine development and response is lacked to current treatment.
NS5B RdRp be to the duplication of single stranded positive-sense HCV rna gene group it is indispensable, this becomes disease-resistant poison
Close the attractive target of object exploitation.There is two major classes NS5B inhibitor: non-nucleosidic inhibitors (NNI) and nucleoside analog.NNI
It is integrated to the allosteric region of albumen, and nucleosidic inhibitors anabolism (anabolize) is corresponding nucleotide and serves as polymerization
The selective substrate of enzyme.The nucleotide subsequently formed mixes nascent RNA polymer chain and can terminate the polymer chain
Growth.Currently, the nucleosides and non-nucleosidic inhibitors of NS5B are known.
Application No. is the patent applications of WO 2016140615 to disclose a kind of ucleosides that can be used for treating HCV infection
NS5B polymerase inhibitors (2S) -2- ((((the chloro- 5- of (2R, 3R, 4S, 5R) -4- (2,4- dioxo -3,4- dihydro-pyrimidin -1
(2H)-yl) the fluoro- 3- hydroxyl tetrahydrofuran -2- base of -4-) methoxyl group) (phenoxy group) phosphoryl) amino) isopropyl propionate, structure
As shown in following formula ASC21；It in the present invention for convenience, is ASC21 by the Compound nomenclature, chemical formula is
C21H26ClFN3O9P, ucleosides NS5B polymerase inhibitors are suitble to prepare the therapeutic agent of HCV infection.
Application No. is the patent applications of WO 2016140615 to also disclose a kind of be used to prepare as described in above formula
The method of ASC21, the technique preparation provided with reference to the patent.The route has the disadvantages that industrialization higher cost, subsequent ring
Border pollution is larger, and uses a large amount of DMPU (1,3- dimethyl -3,4,5,6- tetrahydro -2- pyrimidones), and easy residual, which arrives, to be produced
It in product, and is difficult to be detected with TLC and react, the subsequent inverted column purification removal of need is with high costs.
Summary of the invention
Therefore, it is an object of the present invention to overcome the disadvantages of the prior art and insufficient, provides one kind and is used to prepare nucleosides
There is quality at low cost, easy to operate, easy to control and be suitble to extensive for the method for class NS5B polymerase inhibitors ASC21, this method
The advantages of industrial operation.
In the present invention, unless stated otherwise, the chemical name of the formula ASC21-RM1 compound represented be (2R,
3R, 4S, 5R) -5- (- 1 (2H)-yl of 4- benzamido -2- oxopyrimidin) the fluoro- 2- of the chloro- 4- of -4- ((4- toluyl oxygen
Base) methyl) -3- methyl-methyl 4 methylbenzoate:
The chemical name of the formula ASC21-A compound represented is (2R, 3R, 4S, 5S) -4- chloro- 5- (2,4- dioxy
Generation -3,4- dihydro-pyrimidin -1 (2H)-yl) the fluoro- 2- of -4- ((4- toluyl oxygroup) methyl) tetrahydrofuran -3- base 4- methyl
Benzoic ether:
The chemical name of the formula ASC21-B compound represented is 1- (the fluoro- 4- hydroxyl of the chloro- 3- of (2R, 3S, 4R, 5R) -3-
Base -5- (methylol) tetrahydrofuran -2- base) pyrimidine -2,4 (1H, 3H)-diketone:
The chemical name of the formula ASC21-RM2 compound represented is (S)-isopropyl 2- ((S)-(phenyl-pentafluoride oxygroup)
(phenoxy group) phosphoryl amino) isopropyl propionate:
On the one hand, the present invention provides a kind of preparation method of nucleosides NS5B polymerase inhibitors shown in formula ASC21, packets
Include following step:
In presence of an acid, reaction is hydrolyzed in compound shown in formula ASC21-RM1 to step 1., obtains shown in formula ASC21-A
Compound；
In the presence of a base, reaction is hydrolyzed in formula ASC21-A compound represented to step 2., obtains shown in formula ASC21-B
Compound；
Step 3. do not use DMPU under conditions of, in the presence of tert-butyl magnesium chloride, compound shown in formula ASC21-B with
Formula ASC21-RM2 reacts at 10~15 DEG C, obtains compound shown in formula ASC21；
Method according to the present invention, wherein in the step 3, under conditions of not using DMPU, -15~-
Tert-butyl magnesium chloride is added dropwise at 10 DEG C and is dripped off in 1~2 hour, is then to slowly warm up to 10~15 DEG C, shown in formula ASC21-B
Compound reacted with formula ASC21-RM2 compound represented, obtain compound shown in formula ASC21；
The reaction equation of above-mentioned preparation method is as follows:
Method according to the present invention, wherein in step 1, the acid is organic acid, preferably acetic acid, formic acid, third
Acid or trifluoroacetic acid；
Preferably, the reaction carries out in water；
Preferably, the temperature of the reaction is 110~120 DEG C；
Preferably, the time of the reaction is 18~20h.
Method according to the present invention, wherein in step 2, the alkali is organic base, preferably triethylamine, N, N-
Diisopropylethylamine, n-propylamine or n-butylamine；
Preferably, the reaction carries out in organic solvent；It is highly preferred that the organic solvent is methanol, ethyl alcohol or different
Butanol；
Preferably, the temperature of the reaction is 65 DEG C~70 DEG C；
Preferably, the time of the reaction is 18~20h.
Method according to the present invention, wherein in step 3, the time of the heating is 2~3 hours, and per hour
5 DEG C of heating；
Preferably, the reaction carries out in organic solvent；It is highly preferred that the organic solvent is tetrahydrofuran, methyl
Tetrahydrofuran or dioxane；
Preferably, after heating, the time of the reaction is 8 hours.
It was found by the inventors of the present invention that by means of the present invention, under the premise of not using DMPU, by properly increasing
Reaction temperature accelerates reaction speed, and reduces the inventory of tBuMgCl, so that the reaction conversion ratio is reached expected, simultaneously also
It can be by bisphosphate Control of Impurities in an acceptable range (9%~15% in reaction solution)；
In a specific embodiment, the inventory of t-BuMgCl drops to 1.3 equivalents from 2.2 original equivalents.
In a preferred embodiment, the reaction equation of each step of the preparation method is as follows:
Wherein, it the described method comprises the following steps:
Compound shown in formula ASC21-RM1, glacial acetic acid and water, magnetic agitation, heating are added into reaction vessel for step 1.
Reaction 18h is carried out to 110~120 DEG C, is filtered, it is dry, obtain compound shown in formula ASC21-A；
Formula ASC21-A compound, methanol and triethylamine, magnetic agitation are added into reaction vessel and is heated to 65 for step 2.
~70 DEG C carry out reaction 18h, are concentrated, and extract, and filter, and crystallize, dry, obtain compound shown in formula ASC21-B；
Step 3. is under the protection of nitrogen, and under conditions of not using DMPU, formula ASC21-B institute is added into reaction vessel
Show that compound shown in compound, tetrahydrofuran and formula ASC21-RM2, stirring, revolving speed are 250~300r/min, is cooled to -15
Tert-butyl magnesium chloride is added dropwise into reaction vessel and drips off in 1~2 hour, then at -15~-10 DEG C for~-10 DEG C and temperature control
Be to slowly warm up to 10~15 DEG C, react 8 hours, be quenched, extract, concentration, column chromatography, filtering, it is dry to get.
Wherein, the column chromatography uses silica gel column chromatography.
Wherein, it in the reaction process, is detected using TLC.
Compared with prior art, preparation method provided by the present application has the advantage that
Cost is relatively low, and operation is easy, and reaction detection is easy, and subsequent product purifying is easier to, and is easy to quality control, subsequent ring
Border degradation is easy, and environmental pollution is smaller, is more suitable for large-scale industrial production.
Specific embodiment
The synthetic route of embodiment 1WO 2016140615
1.1 process route
1.2 preparation method
The preparation of step 1:ASC21-A
1. acetic acid (26.05kg, 434mol, 70.8eq) is added into cleaned glass reaction kettle, water (13.35kg,
741mol, 120eq) and 3.8kg ASC21-RM1 (3.8kg, 6.13mol, 1.0eq), agitating and heating flow back (110~120 DEG C)
React 18h.
2. HPLC detection is controlled in after completion of the reaction, reaction solution is cooled to 60 DEG C, and the water of 13.35kg is added, and room is down in stirring
Temperature stirs 2h.Filtering, filter cake 12.5kg water washing collect filter cake.
3. dry: filter cake drying at 40 DEG C of aeration cabinet for 24 hours, obtains 2.7kg pale solid.HPLC purity
91.4%, yield 85%.
Step 2: the preparation (using n-propylamine) of intermediate A SC21-B
1. reaction: ASC21-A (2.72kg, 5.26mol, 1.0eq), 21.3kg first being added into cleaned glass reaction kettle
Then n-propylamine (3.1kg 52.4mol, 10eq) is added in alcohol, reacts 22h at 28 DEG C.
2. concentration: after middle control is qualified, reaction solution is concentrated under reduced pressure into condenser substantially without fraction at 40 DEG C.
3. extraction: 6.4kg water and 16.9kg methylene chloride is added, after stirring, extraction, stratification collects water phase, water phase
It repeats to be extracted twice with methylene chloride again, organic phase is washed with 1.5kg again, merges water phase.Then pH is adjusted to 3mol/L hydrochloric acid
=1.12, then extracted with 11kg 2- methyltetrahydrofuran, it is difficult to it is layered.
4. filtering: padding diatomite on funnel, crude product solution is filtered, wash filter cake with 2- methyltetrahydrofuran, then
Standing separates organic phase.
5. crystallization: filtrate is evaporated under reduced pressure at 60 DEG C, and then concentrate is carried secretly with isopropyl acetate repeatedly, until range estimation is precipitated greatly
Measure solid.It is cooled to 20-25 DEG C of stirring 10-15 minutes.Filtering, filter cake are washed with isopropyl acetate, obtain pale solid.
6. dry: filter cake is dried under reduced pressure 15.5h at 35 DEG C, obtains 1123.9g pale solid.HPLC purity 99%, yield
76%.
The preparation of step 3:ASC21
1. reaction: be added into cleaned glass reaction kettle 1 16.55kg tetrahydrofuran and ASC21-RM2 (22.119kg,
4.67mol, 1.25eq), DMPU (4.526kg, 35.3mol, 9.5eq) is stand-by in 18-23 DEG C of stirring, is added into reaction kettle 2
ASC21-B (1044g, 3.72mol, 1.0eq), 22.15kg tetrahydrofuran, nitrogen protection are cooled to -9 DEG C, temperature control -8~-10
DEG C, 20.7% tert-butyl magnesium chloride-tetrahydrofuran solution (4.45kg, 7.88mol, 2.1eq) is instilled into substrate, is dripped within 67 minutes
It is complete.Drop finishes, and -10 DEG C or so are stirred 42 minutes.Material in reaction kettle 1 is slowly added into reaction kettle 2 by temperature control -8~-10 DEG C
In, react 15h.
2. being quenched: after middle control is qualified, instilling 9.92kg 1mol/L hydrochloric acid, temperature control≤8 DEG C.
3. extraction: 21.3kg toluene is added, is warming up to 20 DEG C, stratification collects upper organic layer.Organic layer is used
9.93kg 1mol/L salt acid elution, is then washed 3 times (10kg/ times) with 5wt% sodium carbonate, collects upper organic layer.Merge alkali
Water layer is extracted with toluene/tetrahydrofuran mixed liquor (8.25kg toluene+8.25kg tetrahydrofuran), collects upper organic layer.Merge
Organic layer is successively washed with the 25wt%NaCl aqueous solution of 8.25kg HCl containing 0.1mol/L, 8.25kg 25wt%NaCl aqueous solution
It washs.
4. concentration: organic layer is concentrated under reduced pressure at 50 DEG C then carries removal toluene secretly with methanol, forms the solution of methanol.
5. column chromatographs: the methanol solution of residue is pure with homemade reverse-phase chromatographic column (BP-C, 18.4um, 0.15%TFA)
Change.Eluant, eluent is methanol/water (from 1/1 to 3:2 to 4:1, V/V),
6. extraction: gained object eluent, which is concentrated under reduced pressure, removes a large amount of methanol, and water phase is extracted with dichloromethane, is associated with
Machine phase, organic phase are dried, filtered with magnesium sulfate
7. concentration: filtrate decompression is concentrated into no fraction, and 4kg acetone is added into residue and is concentrated again, repeats this operation 2
It is secondary.
8. dry: white solid vacuum drying at 50 DEG C obtains 1432.2g off-white powder, and (HPLC purity 98.4% is received
Rate 70%).
In preparation method according to this embodiment, the amount that DMPU is used is more, remained in product it is larger, in final products
Contain 0.15% DMPU；And DMPU, ASC21, bisphosphate impurity the three discovery when TLC is monitored and reacted are difficult to separate.
The synthetic route of the invention of embodiment 2
2.1 process route
2.2 preparation method
The preparation of step 1:ASC21-A
1 material proportion of table
Operating procedure:
1. reaction: 43.0g ASC21-RM1,294.8g glacial acetic acid and 151.1g being added into the 1L there-necked flask of clean dried
Water, magnetic agitation are heated to 110 DEG C of reactions.React 18h.
2. filtering: after middle control is qualified, being cooled to 60 DEG C, instill 150.5g water, stir 30 minutes.It is cooled to 15 DEG C again, stirs
Mix 1h.Filtering, filter cake 150.5g water washing collect filter cake.
3. dry: filter cake is dried under reduced pressure 12h under 40 DEG C, -0.085~-0.098MPa, obtains 31.8g pale solid.
HPLC purity 87.8%, yield 88.8%.
Step 2: the preparation of intermediate A SC21-B
2 material proportion of table
Operating procedure:
1. reaction: 30.6g ASC21-A, 192.8g methanol and 59.9g tri- being added into the 500ml there-necked flask of clean dried
Ethamine, magnetic agitation are heated to 70 DEG C of reactions.React 18h.
2. concentration: after middle control is qualified, reaction solution is rotated to condenser under 50 DEG C of water-baths, -0.070MPa substantially without fraction.
3. extraction: 120g water and 100g normal heptane is added, stirs stratification after five minutes, collects lower layer.It uses again on upper layer
100g washing, collects lower layer.Merge lower layer, adjusts pH=2 with 3mol/L hydrochloric acid, then extracted 3 times with 2- methyltetrahydrofuran
(103g/ times) collects upper layer.
4. filtering: padding 2.0g diatomite on a buchner funnel, crude product solution is filtered, is washed with 31g 2- methyltetrahydrofuran
Filter cake is washed, filtrate is collected.
5. crystallization: filtrate is rotated under 50 DEG C of water-baths, -0.098MPa to surplus 100ml residue, instills 89g acetic acid while hot
Solid is gradually precipitated in isopropyl ester.Continue revolving to surplus 100ml residue, 178g isopropyl acetate is added.Continue to rotate to surplus
150ml residue is cooled to 15 DEG C of stirring 0.5h.Filtering, filter cake are washed with 18g isopropyl acetate, obtain pale solid.
6. dry: filter cake is dried under reduced pressure 8h under 40 DEG C, -0.098MPa, obtains 10.8g pale solid.HPLC purity
99.5%, yield 65.6%.
The preparation of step 3:ASC21
3 material proportion of table
1. reaction: under nitrogen protection, into the 500ml glass reaction kettle of clean dried be added 12.6g ASC21-B,
189.5g tetrahydrofuran and 26.5g ASC21-RM2, open stirring, and revolving speed 250r/min is cooled to -10 DEG C.- 10 DEG C of temperature control,
59ml tert-butyl magnesium chloride is instilled into substrate, 2h is dripped off.Drop finishes, and is to slowly warm up to 15 DEG C of reactions (about heating up 5 DEG C per hour).
8h is reacted, sampling about 0.3ml control in HPLC, and raw material A SC21-B≤5.0% is controlled.If unqualified, -10 DEG C are cooled to,
Then according to the surplus of ASC21-B, the ASC21-RM2 of 1.3 equivalents and the tert-butyl magnesium chloride of 1.3 equivalents are successively added.Drop finishes,
It is to slowly warm up to 10 DEG C of reactions (about heating up 5 DEG C per hour), then sub-sampling.
2. being quenched: after middle control is qualified, being cooled to -5 DEG C, instill 88.4g 1mol/L hydrochloric acid, temperature control≤12 DEG C.
3. extraction: 253g toluene is added, is warming up to 25 DEG C, stratification collects upper organic layer.Organic layer 126g
Then 1mol/L salt acid elution is washed 3 times (126g/ times) with 5wt% sodium carbonate, collect upper organic layer.Merge buck layer, uses
Toluene/tetrahydrofuran mixed liquor (110g toluene+110g tetrahydrofuran) extraction, collects upper organic layer.Merge organic layer, successively
It is washed with 25wt%NaCl aqueous solution, the 160g 25wt%NaCl aqueous solution that 160g includes 0.1mol/L HCl.
4. concentration: organic layer is rotated to condenser under 65 DEG C of water-baths, -0.098MPa without fraction.
5. column chromatographs: residue column chromatographic purifying.200~300 mesh silica gel dosages are 200g, and eluant, eluent is dichloromethane
Rf is collected in alkane/methanol (30/1, V/V), TLC monitoring (solvent: methylene chloride/methanol (10/1, V/V), 254nm UV colour developing)
About 0.5 principal point.Gained object eluent is rotated to condenser under 35 DEG C of water-baths, -0.098MPa without fraction, obtains 11.9g
Off-white powder.HPLC purity 98.2%, yield 63.9%.
6. filtering: off-white powder being dissolved in 160.0g acetone, is filtered, filtrate is collected.
7. concentration: filtrate rotates to condenser under 40 DEG C of water-baths, -0.070MPa without fraction.
8. dissolution: 3.8g acetone and 124.9g methyl tertiary butyl ether(MTBE) being added into residue, stirring is molten to ask, and adds
25.2g methyl tertiary butyl ether(MTBE), for use.
9. crystallization: 457.4g normal heptane being added into 1L there-necked flask, opens mechanical stirring, revolving speed 450r/min is cooled to 5
~10 DEG C.The above-mentioned reaction mixture prepared is instilled in normal heptane, white solid is precipitated, drips off within about 1 hour.Drop finishes, and continues to stir
It mixes 30 minutes.
10. filtering: filtering, wash filter cake with 25.2g normal heptane.
11. dry: filter cake is at 45 DEG C, under -0.098MPa after dry 16h, sample detection residual solvent, it is desirable that normal heptane≤
5000ppm.If unqualified, continue drying.Sample detection residual solvent again after 4 hours, until qualified.It is white to obtain 11.3g class
Color solid.HPLC purity 98.2%, yield 60.7%.
The synthetic route of the invention of embodiment 3
3.1 process route
3.2 preparation method
The preparation of step 1:ASC21-A
4 material proportion of table
Operating procedure:
1. reaction: into the 1L there-necked flask of clean dried be added 43.0g ASC21-RM1,294.8g trifluoroacetic acid and
151.1g water, magnetic agitation are heated to 120 DEG C of reactions.React 20h.
2. filtering: after middle control is qualified, being cooled to 65 DEG C, instill 150.5g water, stir 30 minutes.It is cooled to 5 DEG C again, stirring
1h.Filtering, filter cake 150.5g water washing collect filter cake.
3. dry: filter cake is dried under reduced pressure 12h under 50 DEG C, -0.085~-0.098MPa, obtains 31.8g pale solid.
HPLC purity: 80.2%, yield: 62.4%.
Step 2: the preparation of intermediate A SC21-B
5 material proportion of table
Operating procedure:
1. reaction: into the 500ml there-necked flask of clean dried be added 30.6g ASC21-A, 192.8g isopropanol and
76.36g DIEA, magnetic agitation are heated to 65 DEG C of reactions.React 20h.
2. concentration: after middle control is qualified, reaction solution is rotated to condenser under 60 DEG C of water-baths, -0.098MPa substantially without fraction.
3. extraction: 120g water and 100g normal heptane is added, stirs stratification after ten minutes, collects lower layer.It uses again on upper layer
100g washing, collects lower layer.Merge lower layer, adjusts pH=1 with 3mol/L hydrochloric acid, then extracted 3 times with 2- methyltetrahydrofuran
(103g/ times) collects upper layer.
4. filtering: padding 2.0g diatomite on a buchner funnel, crude product solution is filtered, is washed with 31g 2- methyltetrahydrofuran
Filter cake is washed, filtrate is collected.
5. crystallization: filtrate is rotated under 60 DEG C of water-baths, -0.070MPa to surplus 90ml residue, and it is different to instill 89g acetic acid while hot
Solid is gradually precipitated in propyl ester.Continue revolving to surplus 90ml residue, 178g isopropyl acetate is added.Continue revolving to surplus 150ml
Residue is cooled to 5 DEG C of stirring 0.5h.Filtering, filter cake are washed with 18g isopropyl acetate, obtain pale solid.
6. dry: filter cake is dried under reduced pressure 8h under 50 DEG C, -0.085~MPa, obtains 10.8g pale solid.HPLC purity
98.3%, yield 56.2%.
The preparation of step 3:ASC21
Table 6
1. reaction: under nitrogen protection, into the 500ml glass reaction kettle of clean dried be added 12.6g ASC21-B,
189.5g tetrahydrofuran and 26.5g ASC21-RM2, open stirring, and revolving speed 300r/min is cooled to -15 DEG C.- 15 DEG C of temperature control,
59ml tert-butyl magnesium chloride is instilled into substrate, 1h is dripped off.Drop finishes, and is to slowly warm up to 10 DEG C of reactions (about heating up 5 DEG C per hour).
8h is reacted, sampling about 0.3ml control in HPLC, and raw material A SC21-B≤5.0% is controlled.If unqualified, -15 DEG C are cooled to,
Then according to the surplus of ASC21-B, the ASC21-RM2 of 1.3 equivalents and the tert-butyl magnesium chloride of 1.3 equivalents are successively added.Drop finishes,
It is to slowly warm up to 15 DEG C of reactions (about heating up 5 DEG C per hour), then sub-sampling.
2. being quenched: after middle control is qualified, being cooled to 5 DEG C, instill 88.4g 1mol/L hydrochloric acid, temperature control≤12 DEG C.
3. extraction: 253g toluene is added, is warming up to 15 DEG C, stratification collects upper organic layer.Organic layer 126g
Then 1mol/L salt acid elution is washed 3 times (126g/ times) with 5wt% sodium carbonate, collect upper organic layer.Merge buck layer, uses
Toluene/tetrahydrofuran mixed liquor (110g toluene+110g tetrahydrofuran) extraction, collects upper organic layer.Merge organic layer, successively
It is washed with 25wt%NaCl aqueous solution, the 160g 25wt%NaCl aqueous solution that 160g includes 0.1mol/L HCl.
4. concentration: organic layer is rotated to condenser under 50 DEG C of water-baths, -0.070MPa without fraction.
5. column chromatographs: residue column chromatographic purifying.200~300 mesh silica gel dosages are 200g, and eluant, eluent is dichloromethane
Rf is collected in alkane/methanol (30/1, V/V), TLC monitoring (solvent: methylene chloride/methanol (10/1, V/V), 254nm UV colour developing)
About 0.5 principal point.Gained object eluent is rotated to condenser under 55 DEG C of water-baths, -0.070MPa without fraction, obtains 11.9g
Off-white powder.HPLC purity is 97.1%, yield 63.2%.
6. filtering: off-white powder being dissolved in 160.0g acetone, is filtered, filtrate is collected.
7. concentration: filtrate rotates to condenser under 50 DEG C of water-baths, -0.098MPa without fraction.
8. dissolution: 3.8g acetone and 124.9g methyl tertiary butyl ether(MTBE) being added into residue, stirring is molten to ask, and adds
25.2g methyl tertiary butyl ether(MTBE), for use.
9. crystallization: 457.4g normal heptane being added into 1L there-necked flask, opens mechanical stirring, revolving speed 350r/min is cooled to 5
~10 DEG C.The above-mentioned reaction mixture prepared is instilled in normal heptane, white solid is precipitated, drips off within about 1 hour.Drop finishes, and continues to stir
It mixes 30 minutes.
10. filtering: filtering, wash filter cake with 25.2g normal heptane.
11. dry: filter cake is at 40 DEG C, under -0.085MPa after dry 16h, sample detection residual solvent, it is desirable that normal heptane≤
5000ppm.If unqualified, continue drying.Sample detection residual solvent again after 4 hours, until qualified.Obtain 9.7g off-white color
Solid, HPLC purity 98.2%, yield 52.1%.
The screening of the reaction condition of the invention of embodiment 4
It was found by the inventors of the present invention that obtaining the product of the application in the prior art, the reaction using DMPU hydrotropy is needed
It is carried out in a low temperature of -10~-20 DEG C, making reaction solution is in homogeneously, to accelerate reaction speed.But DMPU is equal in water phase and organic phase
Still there are a large amount of DMPU residuals into product after thering is preferable dissolubility, post-processing to complete.And DMPU, ASC21, diphosphonic acid
Ester impurity three discovery when TLC is monitored and reacted is difficult to separate, it is difficult to be separated with common purification on normal-phase silica gel, and need to use C-
18 reverse phase silica gels are separated.Although fine using reverse phase silica gel separation separating effect, also have disadvantages that.Reverse phase first
Silica gel is expensive, is 200~300 times of common silica gel price.Secondly, product exists in view of reverse phase silica gel needs Reusability
It must strictly be handled before upper prop, other foreign matters cannot be brought into reverse phase silica gel, subsequent use be influenced, after this is substantially increased
The difficulty of reason.Finally, reversed-phase silica gel column chromatography must be strictly controlled residual solvent, in order to avoid influencing column effect, this also gives post-processing band
Carry out certain difficulty.
Unexpectedly, inventors have found that not using DMPU, accelerate reaction speed by properly increasing reaction temperature.
By reducing tBuMgCl inventory, 1.3 equivalents are dropped to from 2.2 original equivalents and improve reaction temperature, can make reaction conversion ratio
Reach expected, it also can be by bisphosphate Control of Impurities in an acceptable range (9%~15% in reaction solution).
Specifically, compare the method for the application and the prior art, inventors have found that meeting using method of the invention
It under the premise of the quality index of target product, avoids using the DMPU for being difficult to remove, so that product is easier to purify.
Finally it should be noted that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting.Although reference
Embodiment describes the invention in detail, those skilled in the art should understand that, to technical solution of the present invention
It is modified or replaced equivalently, without departure from the spirit and scope of technical solution of the present invention, should all cover of the invention
In scope of the claims.
Claims (8)
1. the preparation method of nucleosides NS5B polymerase inhibitors, includes the following steps: shown in a kind of formula ASC21
In presence of an acid, reaction is hydrolyzed in compound shown in formula ASC21-RM1 to step 1., obtains chemical combination shown in formula ASC21-A
Object；
In the presence of a base, reaction is hydrolyzed in formula ASC21-A compound represented to step 2., obtains chemical combination shown in formula ASC21-B
Object；
Step 3. is not under conditions of using DMPU, in the presence of tert-butyl magnesium chloride, compound shown in formula ASC21-B and formula
ASC21-RM2 reacts at 10~15 DEG C, obtains compound shown in formula ASC21；
2. preparation method according to claim 1, wherein in the step 3, under conditions of not using DMPU ,-
Tert-butyl magnesium chloride is added dropwise at 15~-10 DEG C and is dripped off in 1~2 hour, is then to slowly warm up to 10~15 DEG C, formula ASC21-
B compound represented is reacted with formula ASC21-RM2 compound represented, obtains compound shown in formula ASC21.
3. preparation method according to claim 1 or 2, wherein in step 1, the acid is organic acid, preferably vinegar
Acid, formic acid, propionic acid or trifluoroacetic acid；
Preferably, the reaction carries out in water；
Preferably, the temperature of the reaction is 110~120 DEG C；
Preferably, the time of the reaction is 18~20h.
4. preparation method according to any one of claim 1-3, wherein in step 2, the alkali is organic base, excellent
It is selected as triethylamine, N, N- diisopropylethylamine, n-propylamine or n-butylamine；
Preferably, the reaction carries out in organic solvent；It is highly preferred that the organic solvent is methanol, ethyl alcohol or isobutanol；
Preferably, the temperature of the reaction is 65 DEG C~70 DEG C；
Preferably, the time of the reaction is 18~20h.
5. preparation method described in any one of -4 according to claim 1, wherein in step 3, the time of the heating is 2
~3 hours, and heat up 5 DEG C per hour；
Preferably, the reaction carries out in organic solvent；It is highly preferred that the organic solvent is tetrahydrofuran, methyl tetrahydro
Furans or dioxane；
Preferably, after heating, the time of the reaction is 8 hours.
6. preparation method according to any one of claims 1-5, the method comprise the steps that
Compound shown in formula ASC21-RM1, glacial acetic acid and water are added into reaction vessel for step 1., and magnetic agitation is heated to 110
~120 DEG C carry out reaction 18h, filter, dry, obtain compound shown in formula ASC21-A；
Formula ASC21-A compound, methanol and triethylamine, magnetic agitation are added into reaction vessel and is heated to 65~70 for step 2.
DEG C reaction 18h is carried out, be concentrated, extracted, filtered, crystallized, it is dry, obtain compound shown in formula ASC21-B；
Step 3. is under the protection of nitrogen, under conditions of not using DMPU, is added shown in formula ASC21-B and changes into reaction vessel
Compound shown in conjunction object, tetrahydrofuran and formula ASC21-RM2, stirring, revolving speed are 250~300r/min, are cooled to -15~-10
DEG C and temperature control at -15~-10 DEG C, be added dropwise and tert-butyl magnesium chloride and drip off in 1~2 hour into reaction vessel, then slowly
Be warming up to 10~15 DEG C, react 8 hours, be quenched, extract, concentration, column chromatography, filtering, it is dry to get.
7. preparation method according to claim 6, wherein the column chromatography uses silica gel column chromatography.
8. method according to any one of claims 1-7, wherein in the reaction process, detected using HPLC.
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Application publication date: 20190517 |