CN115703796A - Preparation method of important intermediate of Reidesciclovir - Google Patents
Preparation method of important intermediate of Reidesciclovir Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 9
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical group N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 6
- 239000005695 Ammonium acetate Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 229940043376 ammonium acetate Drugs 0.000 claims description 6
- 235000019257 ammonium acetate Nutrition 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 6
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 5
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 5
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 3
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 claims description 3
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 3
- 239000001099 ammonium carbonate Substances 0.000 claims description 3
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 3
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 230000001681 protective effect Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- BNHFWQQYLUPDOG-UHFFFAOYSA-N lithium;1,2,2,3-tetramethylpiperidine Chemical compound [Li].CC1CCCN(C)C1(C)C BNHFWQQYLUPDOG-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000001816 cooling Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 238000006264 debenzylation reaction Methods 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- VRIAKQCGLJNRLZ-OJYYSWAESA-N C1=CC=C(C=C1)COC([C@@H]2[C@]([C@](C(=O)O2)(O)OCC3=CC=CC=C3)(O)OCC4=CC=CC=C4)O Chemical compound C1=CC=C(C=C1)COC([C@@H]2[C@]([C@](C(=O)O2)(O)OCC3=CC=CC=C3)(O)OCC4=CC=CC=C4)O VRIAKQCGLJNRLZ-OJYYSWAESA-N 0.000 description 2
- 241001115402 Ebolavirus Species 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- IJCOKJGMVJGKBB-CGEWXTDFSA-N (3ar,4r,6r,6ar)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyl-6,6a-dihydro-3ah-furo[3,4-d][1,3]dioxole-4-carbonitrile Chemical compound NC1=NC=NN2C([C@]3(C#N)O[C@H](CO)[C@H]4OC(O[C@H]43)(C)C)=CC=C21 IJCOKJGMVJGKBB-CGEWXTDFSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000013504 emergency use authorization Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- YTJXGDYAEOTOCG-UHFFFAOYSA-N lithium;di(propan-2-yl)azanide;oxolane Chemical compound [Li+].C1CCOC1.CC(C)[N-]C(C)C YTJXGDYAEOTOCG-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 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 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
- 238000000926 separation method Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a new synthetic route of a Rudexilevir important intermediate compound I (3aR, 4R,6 aR) -4- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxolane-4-carbonitrile, and relates to a new intermediate compound III and a compound II. Firstly, reacting a compound VI with a compound VII under the action of high-steric-hindrance strong base to generate a compound V, then, substituting hydroxyl in the compound V into cyano under the action of Lewis acid to obtain a compound IV, carrying out deprotection reaction to obtain a compound III, carrying out upper protection to generate a compound II, and finally carrying out substitution reaction to obtain a compound I.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of an important intermediate of Reideciclovir and two new compounds thereof.
Background
Reidesciclovir (Remdesivir) was developed by Gilider, USA, and was originally developed against Ebola virus. However, as the research progresses, it has been found that the antiviral effect of Reidesvir is not limited to filamentous viruses such as Ebola virus, but is also effective in inhibiting various viruses such as coronavirus. The FDA issued reidecivir as an emergency use authorization for treating new coronary pneumonia at 1/5 of 2020.
The document jmed. Chem.2017,60,1648-1661 reports a synthetic route to reidcisvir.
The first generation route is as follows
The second generation route is as follows
Through the two generations of reactions, the addition of the amino group on the heterocyclic compound to the sugar ring is found to have the problem of low yield, which causes the restriction of the subsequent route. The lower yield is mainly due to the influence of the exposed amino group on the heterocycle. Including the subsequent cyanidation reaction, the debenzylation reaction has low yield because of the active hydrogen of amino. It is imperative to use new reaction substrates.
Disclosure of Invention
In one aspect, the invention provides a new synthetic route of a Rudexilvir important intermediate compound I (3aR, 4R,6R, 6aR) -4- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (hydroxymethyl) -2, 2-dimethyltetrahydrofuro [3,4-d ] [1,3] dioxolane-4-carbonitrile.
The invention provides a preparation method of a Rudexilvir intermediate I, which comprises the following steps:
the invention also provides a preparation method of the Rudexilvir intermediate II, which comprises the following steps:
the invention also provides a preparation method of the Rudexilvir intermediate III, which comprises the following steps:
as an alternative embodiment of the present invention, the present invention also provides a preparation method of the following ridciclovir intermediate I, which comprises the following steps:
the specific scheme is as follows:
firstly, in the step a, a compound VI reacts with a compound VII under the action of large steric hindrance strong base to generate a compound V,
preferably, in step a, the strong sterically hindered base is lithium diisopropylamide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, or lithium tetramethylpiperidine, etc.
Then b, under the action of Lewis acid, substituting hydroxyl in the compound V into cyano to obtain a compound IV,
preferably, in step b, the Lewis acid is boron trifluoride etherate, TMSOTf, TBSOTf
Step c, carrying out deprotection reaction to obtain a compound III,
preferably, in step c, the deprotection reagent is a combination of palladium carbon and palladium hydroxide carbon, and the ratio of palladium carbon: the mass ratio of palladium hydroxide to carbon =1.0: 0.5-1.0, and the used solvent is methanol or ethanol.
The protection in the step d generates a compound II,
preferably, in step d, the catalyst is boron trifluoride diethyl etherate, p-toluenesulfonic acid, benzenesulfonic acid and copper sulfate, and the protective reagent is acetone and 2, 2-dimethoxypropane.
And e, finally carrying out substitution reaction to obtain the compound I.
Preferably, in step e, the ammonia source is ammonium acetate, ammonia methanol solution, ammonium sulfate, ammonium bicarbonate.
Further, in step b, the lewis acid is boron trifluoride diethyl etherate, TMSOTf, TBSOTf.
Further, in step c, the deprotection reagent is a combination of palladium carbon and palladium hydroxide carbon, and the ratio of palladium carbon: the mass ratio of palladium hydroxide to carbon =1.0: 0.5-1.0, and the used solvent is methanol or ethanol.
Further, in the step d, the catalyst is boron trifluoride diethyl etherate, p-toluenesulfonic acid, benzenesulfonic acid and copper sulfate, and the protective reagent is acetone and 2, 2-dimethoxypropane.
Further, in step e, the ammonia source is ammonium acetate, ammonia methanol solution, ammonium sulfate, ammonium bicarbonate.
In another aspect, the present invention also provides novel ridciclovir intermediate compounds III and II:
in conclusion, the invention provides a novel method for synthesizing a ridciclovir intermediate, which takes a methylthio-substituted heterocycle as a starting material, and can efficiently take the intermediate I of the ridciclovir through steric hindrance strong base hydrogen abstraction and sugar ring reaction, cyanidation reaction, debenzylation reaction, acetonide protection and final substitution ammonolysis reaction. Because the amino containing active hydrogen is not used as a reactant, the first step of addition of the heterocyclic ring and the sugar ring, the second step of cyanidation and the third step of debenzylation are all higher than the yield of directly using the naked amino in the literature report. And in the fourth step, acetone fork protection is performed, acetone is used as a protection source, the cost is low, the reaction yield is high, and the operation is simple. In the fifth step of ammonolysis, ammonium acetate and ammonia methanol solution are used as ammonia sources, the treatment after the reaction is simple and convenient, and the reaction conversion rate is high. Therefore, the whole route is very efficient and concise, and is very suitable for industrial production.
Detailed Description
In order that those skilled in the art may better understand the present invention, the following embodiments further illustrate the present invention. It should be understood that the following examples are given for better illustration of the present invention and are not intended to limit the present invention.
Example 1:
synthesis of Compound V
N 2 Under protection, adding compound VI (21g, 127mmol) and 500mL THF, stirring for dissolving, cooling to about-70 ℃, adding 2M LDA THF solution (95mL, 190mmol), stirring for dissolving, slightly heating, continuously cooling to-70 ℃, slowly dropping compound VII (2, 3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone)/THF (54g, 129mmol/420 mL), after dropping, keeping the temperature for 3 hours, detecting by TLC, adding ammonium chloride aqueous solution, adjusting pH to 8, stirring for 30 minutes, layering, extracting the lower water layer twice with 250mL ethyl acetate, combining the organic layers, adding anhydrous sodium sulfate for drying, filtering, spin-drying the filtrate, performing silica gel column chromatography (ethyl acetate/petroleum ether for elution), concentrating to obtain 70.3g yellow oily compound V with purity of HPLC 98%, and yield of 95%.
ESI-HRMS theoretical values: c 33 H 33 N 3 O 5 S[M+H] + 584.2141, found 584.2143.
Example 2:
synthesis of Compound V
N 2 Adding compound VI (40g, 242mmol), 600mL THF, stirring to dissolve, cooling to-78 deg.C, adding 1M THF solution of bis (trimethylsilyl) lithium amide (266mL, 266mmol), stirring to dissolve, slightly heating, continuously cooling to-78 deg.C, slowly adding compound VII (2, 3, 5-tribenzyloxy-D-ribono-1, 4-lactone)/THF (92g, 220mmol/500 mL), dropping, keeping the temperature for 2.5 hr, detecting by TLC, adding ammonium chloride waterAdjusting pH of the solution to 7, stirring for 1 hour, demixing, extracting a lower water layer twice with 300mL ethyl acetate, combining organic layers, adding anhydrous sodium sulfate, drying, filtering, spin-drying filtrate, performing silica gel column chromatography (ethyl acetate/petroleum ether elution), and concentrating to obtain 119g of yellow oily compound V with HPLC purity of 97% and yield of 93%.
ESI-HRMS theory: c 33 H 33 N 3 O 5 S[M+H] + 584.2141, found 584.2143.
Example 3:
synthesis of Compound V
N 2 Under protection, adding compound VI (35g, 212mmol), stirring 100mL of THF for dissolving, cooling to about-78 ℃, adding 1M THF solution (266mL, 233mmol) of bis (trimethylsilyl) sodium amide, stirring for dissolving, slightly heating, continuously cooling to-78 ℃, slowly dropping compound VII (2, 3, 5-tribenzyloxy-D-ribono-1, 4-lactone)/THF (83.6 g,200mmol/200 mL), after dropping, keeping the temperature for 2 hours, detecting by TLC, adding ammonium chloride aqueous solution, adjusting pH to 7, stirring for 1 hour, demixing, extracting the lower layer twice by 220mL ethyl acetate, combining organic layers, adding anhydrous sodium sulfate for drying, filtering, spin-drying the filtrate, performing silica gel column chromatography (ethyl acetate/petroleum ether elution) to obtain 106g of yellow oily compound V, with HPLC purity of 97% and yield of 91%.
ESI-HRMS theory: c 33 H 33 N 3 O 5 S[M+H] + 584.2141, found 584.2143.
Example 4:
synthesis of Compound IV
Dissolving compound V (40g, 68.5 mmol) in 300mL of DCM under stirring, cooling to-20 deg.C, slowly adding boron trifluoride diethyl ether (1.95g, 13.7mmol, 0.2equiv) dropwise, maintaining the temperature at-20 deg.C, keeping the temperature for 30 min, slowly adding TMSCN (8.1g, 82.2mmol, 1.2equiv) dropwise, and keeping the temperature for 1h. Triethylamine (20 mL) was added, the temperature was slowly raised to room temperature, a saturated aqueous solution of sodium bicarbonate (150 mL) was added to quench the liquid, 150mL was washed with water, stirred for 30 minutes, filtered and separated, the aqueous phase was extracted twice with 200mL dichloromethane, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried, subjected to silica gel column chromatography (ethyl acetate/petroleum ether elution), and concentrated to 39.4 g, HPLC purity 99%, yield 97%.
ESI-HRMS theoretical values: c 34 H 32 N 4 O 4 S[M+H] + 593.2144, found 593.2142.1H-NMR (400mhz, cdcl3) δ 8.18 (s, 1H), 7.43-7.21 (m, 15H), 6.80 (d, J =4.7hz, 1h), 6.68 (d, J =4.7hz, 1h), 4.71 (s, 2H), 4.65-4.37 (m, 5H), 4.35-4.13 (m, 2H), 3.88 (dd, J =10.5,2.9hz, 1h), 3.74 (dd, J =10.5,3.5hz, 1h), 2.65 (s, 3H).
Example 5:
synthesis of Compound IV
Dissolving compound V (40g, 68.5 mmol) and 300mL of LPCM under stirring, cooling to about-78 deg.C, slowly adding TMSOTf (31.3g, 140.8 mmol) dropwise, maintaining the temperature at-78 deg.C, keeping the temperature for 30 minutes, slowly adding TMSCN (29.3g, 294.7 mmol) dropwise, and keeping the temperature for 2 hours. Triethylamine (36 mL) was added, the temperature was slowly raised to room temperature, sodium bicarbonate (55 g), 150mL water were added, stirring was carried out for 30 minutes, filtration was carried out for layer separation, the aqueous phase was extracted twice with 250mL dichloromethane, the organic phases were combined, anhydrous sodium sulfate was added for drying, filtration was carried out, the filtrate was dried by spinning, silica gel column chromatography (ethyl acetate/petroleum ether elution) was carried out, and 36.9 g was obtained by concentration, with HPLC purity of 98%, yield of 91%.
ESI-HRMS theory: c 34 H 32 N 4 O 4 S[M+H] + 593.2144, found 593.2142.1H-NMR (400MHz, CDCl3) delta 8.18 (s, 1H), 7.43-7.21 (m, 15H), 6.80 (d, J =4.7Hz, 1H), 6.68 (d, J =4.7Hz, 1H), 4.71 (s, 2H), 4.65-4.37 (m, 5H), 4.35-4.13 (m, 2H), 3.88 (dd),J＝10.5,2.9Hz,1H),3.74(dd,J＝10.5,3.5Hz,1H),2.65(s,3H)。
Example 6:
synthesis of Compound III
Compound IV (31g, 52.3 mmol) was dissolved in methanol (100 mL) with stirring, 3.1g palladium on carbon (5%) and 3.1g palladium on carbon (20%) were added and stirred under 0.4MPa hydrogen for 1.5 h, TLC indicated that the starting material was reacted, filtered and concentrated to give 36.4 g, HPLC purity 96%, yield 99%.
ESI-HRMS theoretical values: c 13 H 14 N 4 O 4 S[M+H] + 323.0736, found 323.0740.
Example 7:
synthesis of Compound III
Compound IV (31g, 52.3 mmol) was dissolved in methanol (100 mL) with stirring, 3.1g palladium on carbon (5%) and 1.55g palladium on carbon (20%) were added and stirred under 0.4MPa for 2h, TLC indicated that the starting material was reacted completely, filtered and concentrated to give 34.9 g, HPLC purity 95%, yield 95%.
ESI-HRMS theoretical values: c 13 H 14 N 4 O 4 S[M+H] + 323.0736, found 323.0740.
Example 8:
synthesis of Compound II
Uniformly stirring compound III (10g, 31mmol), acetone (2.2g, 37.2mmol) and DCM (50 mL), cooling to 0 ℃, adding boron fluoride ethyl ether (0.44g, 3.1mmol), keeping the temperature at 0 ℃ for reaction for 1h, detecting by TLC, allowing the raw materials to disappear, adding a saturated aqueous solution of sodium bicarbonate and proper water, stirring, standing and layering. The aqueous phase was extracted with DCM. The combined DCM phases were spin-dried, subjected to silica gel column chromatography (ethyl acetate/petroleum ether elution), and concentrated to obtain 11.2g of II, the HPLC purity was 99%, and the yield was 99%.
ESI-HRMS theoretical values: c 16 H 18 N 4 O 4 S[M+H] + 363.1049, found 362.1046.
Example 9:
synthesis of Compound II
And (3) uniformly stirring the compound III (10g, 31mmol) and DCM (100 mL), adding 2, 2-dimethoxypropane (18g, 172.8mmol) and p-toluenesulfonic acid (0.8g, 4.2mmol), gradually dissolving, keeping the temperature at 20-22 ℃, keeping the temperature for reaction for 2h, carrying out TLC detection after the temperature is kept, allowing the raw materials to disappear, cooling to 10 ℃, adding a saturated aqueous solution of sodium bicarbonate and proper water, stirring, standing and layering. DCM was added to extract the aqueous phase. The combined DCM phases were spin-dried, subjected to silica gel column chromatography (ethyl acetate/petroleum ether elution), and concentrated to give 10.6g of II, 95% pure by HPLC, 94% yield.
ESI-HRMS theory: c 16 H 18 N 4 O 4 S[M+H] + 363.1049, found 362.1046.
Example 10:
synthesis of Compound I
Dissolving compound II (10g, 27.6 mmol) in 100mL of methanol, adding ammonium acetate (21.3g, 276 mmol) into an autoclave, heating to 120 ℃, stirring overnight, spin-drying, performing silica gel column chromatography (eluting with ethyl acetate/petroleum ether), and spin-drying to obtain 9.04g of I, wherein the HPLC purity is 98%, and the yield is 99%.
ESI-HRMS theory: c 15 H 17 N 5 O 4 [M+H] + 332.1281, found 332.1284.1H-NMR (400MHz, CD3OD): delta 7.94 (s, 1)H),7.09(d,J＝4.6Hz,1H),6.65(d,J＝4.6Hz,1H),5.80(s,2H),5.43(d,J＝6.6Hz,1H),5.24(dd,J＝6.6,2.4Hz,1H),4.69–4.65(m,1H),4.53(s,1H),3.99(dd,J＝12.5,1.8Hz,1H),3.85(d,J＝12.5Hz,1H),1.81(s,3H),1.40(s,3H)。
Example 11:
synthesis of Compound I
Compound II (10g, 27.6 mmol) was dissolved in 100mL of methanol, ammonium acetate (21.3g, 276 mmol) was added to the autoclave, the temperature was raised to 120 ℃ and stirred overnight, followed by spin-drying, silica gel column chromatography (ethyl acetate/petroleum ether elution) to obtain 8.68g of I, purity by HPLC of 96% and yield of 95%.
ESI-HRMS theoretical values: c 15 H 17 N 5 O 4 [M+H] + 332.1281, found 332.1284.1H-NMR (400MHz, CD3OD): δ 7.94 (s, 1H), 7.09 (d, J =4.6Hz, 1H), 6.65 (d, J =4.6Hz, 1H), 5.80 (s, 2H), 5.43 (d, J =6.6Hz, 1H), 5.24 (dd, J =6.6,2.4Hz, 1H), 4.69-4.65 (m, 1H), 4.53 (s, 1H), 3.99 (dd, J =12.5,1.8Hz, 1H), 3.85 (d, J =12.5Hz, 1H), 1.81 (s, 3H), 1.40 (s, 3H).
Example 12:
synthesis of Compound I
Compound II (10g, 27.6mmol) was dissolved in 100mL of methanol, and 7M ammonia solution (169mL, 112mmol) was added to the solution, the mixture was brought into an autoclave, heated to 110 ℃, stirred overnight, spin-dried, subjected to silica gel column chromatography (ethyl acetate/petroleum ether elution), and spin-dried to obtain 8.40g of I, which had an HPLC purity of 96% and a yield of 92%.
ESI-HRMS theoretical values: c 15 H 17 N 5 O 4 [M+H] + 332.1281, found 332.1284.1H-NMR (400MHz, CD3OD): delta 7.94 (s, 1H), 7.09 (d, J =4.6Hz, 1H), 6.65 (d, J =4.6Hz, 1H), 5.80 (s, 2H), 5.43 (d, J =6.6Hz, 1H), 5.24 (dd, J = d =: (d, J =): D, J =: (1H): D, J: (1H): S, 1H), 3.6.6,2.4Hz,1H),4.69–4.65(m,1H),4.53(s,1H),3.99(dd,J＝12.5,1.8Hz,1H),3.85(d,J＝12.5Hz,1H),1.81(s,3H),1.40(s,3H)。
Claims (10)
1. A preparation method of an important intermediate I of Reidesciclovir comprises the following steps:
2. a preparation method of a Rudeciclovir intermediate I comprises the following steps:
3. a preparation method of a Rudexilvir intermediate II comprises the following steps:
4. a preparation method of a Reidesciclovir intermediate III comprises the following steps:
5. the method of claim 1, wherein: in the step a, a compound VI reacts with a compound VII under the action of strong steric hindrance base to generate a compound V, wherein the strong steric hindrance base is lithium diisopropylamide, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide or lithium tetramethylpiperidine.
6. The method of claim 1, wherein: in the step b, under the action of Lewis acid, hydroxyl in the compound V is substituted into cyano to obtain a compound IV, wherein the Lewis acid is boron trifluoride diethyl etherate, TMSOTf or TBSOTf.
7. The production method according to claim 1 or 4, characterized in that: in the step c, carrying out deprotection reaction on the compound IV to obtain a compound III, wherein the deprotection reagent is a combination of palladium carbon and palladium hydroxide carbon, and the ratio of the palladium carbon to the palladium carbon is as follows: the mass ratio of palladium hydroxide to carbon =1.0:0.5 to 1.0, and the used solvent is methanol or ethanol.
8. The production method according to claim 1 or 3, characterized in that: in the step d, a compound II is generated by protecting the compound III, the catalyst is boron trifluoride diethyl etherate, p-toluenesulfonic acid, benzenesulfonic acid or copper sulfate, and the protective reagent is acetone or 2, 2-dimethoxypropane.
9. The production method according to claim 1 or 2, characterized in that: in the step e, the compound II is subjected to substitution reaction to obtain the compound I, and the ammonia source is ammonium acetate, ammonia methanol solution ammonium sulfate or ammonium bicarbonate.
10. Novel intermediate compounds III with compounds II:
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