CN112358513A - Method for preparing Reidesciclovir intermediate by using continuous flow reactor - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- 239000000243 solution Substances 0.000 claims abstract description 51
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims abstract description 32
- -1 benzylmethyl Chemical group 0.000 claims abstract description 14
- 239000000463 material Substances 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 11
- WAUGGYPDCQZJKK-UHFFFAOYSA-N 1h-pyrrol-3-amine Chemical compound NC=1C=CNC=1 WAUGGYPDCQZJKK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 150000002500 ions Chemical class 0.000 claims abstract description 8
- 230000035484 reaction time Effects 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 150000001450 anions Chemical class 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 230000008569 process Effects 0.000 claims abstract description 4
- 150000003233 pyrroles Chemical class 0.000 claims abstract description 3
- 239000011259 mixed solution Substances 0.000 claims abstract 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 14
- JNODDICFTDYODH-UHFFFAOYSA-N 2-hydroxytetrahydrofuran Chemical compound OC1CCCO1 JNODDICFTDYODH-UHFFFAOYSA-N 0.000 claims description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 10
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 claims description 7
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 7
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- 239000007818 Grignard reagent Substances 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- ICAKDTKJOYSXGC-UHFFFAOYSA-K lanthanum(iii) chloride Chemical compound Cl[La](Cl)Cl ICAKDTKJOYSXGC-UHFFFAOYSA-K 0.000 claims description 3
- 229910002249 LaCl3 Inorganic materials 0.000 claims description 2
- 229910017544 NdCl3 Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 4
- 125000000129 anionic group Chemical group 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 5
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000005265 energy consumption Methods 0.000 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- ATINCSYRHURBSP-UHFFFAOYSA-K neodymium(iii) chloride Chemical compound Cl[Nd](Cl)Cl ATINCSYRHURBSP-UHFFFAOYSA-K 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 229950000077 iodol Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- CUOKHACJLGPRHD-BXXZVTAOSA-N D-ribono-1,4-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H]1O CUOKHACJLGPRHD-BXXZVTAOSA-N 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 239000012527 feed solution Substances 0.000 description 1
- 208000005098 feline infectious peritonitis Diseases 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 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
- 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
- 239000013589 supplement Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/06—Heterocyclic radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention provides a method for preparing a Rudexilvir intermediate (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triaza-7-yl) -3, 4-dibenzyl-5-benzylmethyl) tetrahydrofuran-2-alcohol (I) by using a continuous flow reactor. The method comprises the steps of taking a prepared negative ion solution of an intermediate pyrrole [2,1-f ] [1,2,4] triaza-4-amine (III) as a material 1, taking a mixed solution of (3R,4R,5R) -3, 4-dibenzyl-5- (benzylmethyl) dihydrofuran-2 (3H) -ketone (II) and a catalyst and a solvent as a material 2, and reacting and synthesizing the compound (I) through a continuous flow reactor at the reaction temperature of-20-0 ℃ for 50-150 s. Wherein, the anion solution of the intermediate pyrrole [2,1-f ] [1,2,4] triaza-4-amine (III) is prepared by taking 7-halogenated pyrrole [2,1-f ] [1,2,4] triaza-4-amine or pyrrole [2,1-f ] [1,2,4] triaza-4-amine (IV) as a raw material and metal reagents and the like through a kettle type or continuous flow reactor. Compared with the conventional kettle type reactor, the process has short reaction time and small liquid holding volume, is favorable for improving the temperature of low-temperature reaction, saves energy consumption, also improves the safety of the reaction and is convenient for continuous automatic control.
Description
Technical Field
The invention relates to the technical field of synthesis of Reidesciclovir, and more particularly relates to the technical field of an intermediate (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triaza-7-yl) -3, 4-dibenzyl-5-benzyl methyl) tetrahydrofuran-2-ol (I).
Background
Reidesciclovir (Remdesivir) is an antiviral drug developed by Gilidard Sciences, USA, code GS5742, first to prevent Ebola virus infection. In the context of a major outbreak of global new coronavirus in 2020, the U.S. FDA first approved the emergency use of redciclovir, and then officially approved that redciclovir is marketed 10 months in 2020.
The synthesis method of Reidesciclovir was originally developed by Gilidard and is generally formed by splicing two fragments. The intermediate 1, namely GS-441524, is a specific medicine for treating feline infectious peritonitis (transmissible abdominal disease), and the Reidesvir can be obtained by reacting with the phospholipid intermediate 2. The compound (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triaza-7-yl) -3, 4-dibenzyl-5-benzyl methyl) tetrahydrofuran-2-ol (I) is an important intermediate for synthesizing GS-441524.
Gilidard reported a second generation synthetic process for Redcisvir in Supplement Information of Nature, volume 531, pages 381-385 (2016), as shown below.
The method comprises the steps of taking 7-iodopyrrole [2,1-f ] [1,2,4] triaza-4-amine 1 as a raw material, carrying out hydrogen abstraction through phenyl magnesium chloride at the temperature of-20 ℃, protecting with TMS, carrying out iodine exchange with a Grignard reagent, and finally reacting with benzyl protected ribonolactone 2 to obtain a compound 3, namely (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triaza-7-yl) -3, 4-dibenzyl-5-benzyl methyl) tetrahydrofuran-2-ol (I) with the yield of 40%. The reaction is one of the key steps in the Rudeseivir process route, and the reaction involves the use of metal reagents for many times at low temperature due to the complex mechanism, and the traditional kettle type reaction method is difficult to accurately control the reaction conditions, so that the reaction yield is lower and is only 40%; meanwhile, because low-temperature reaction is involved, the reaction parameters of the pilot plant are difficult to amplify, and the pilot plant production is not facilitated.
Disclosure of Invention
In order to improve the reaction yield of (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triaza-7-yl) -3, 4-dibenzyl-5-benzylmethyl) tetrahydrofuran-2-ol (I) and overcome the problem of difficult amplification of low-temperature reaction, the invention provides a method for preparing (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triaza-7-yl) -3, 4-dibenzyl-5-benzylmethyl) tetrahydrofuran-2-ol (I) by hydrogenation in a continuous flow reactor. The method comprises the steps of taking negative ion solution of pyrrole [2,1-f ] [1,2,4] triaza-4-amine (III) as a material 1, taking mixed liquid of (3R,4R,5R) -3, 4-dibenzyl-5- (benzylmethyl) dihydrofuran-2 (3H) -ketone (II) and a catalyst and a solvent as a material 2, and reacting through a continuous flow reactor to synthesize the compound (I).
Wherein R is1Including trimethylsilyl and hydrogen atoms.
Wherein, the anion solution of pyrrole [2,1-f ] [1,2,4] triaza-4-amine (III) is prepared by taking 7-halogenated pyrrole [2,1-f ] [1,2,4] triaza-4-amine or pyrrole [2,1-f ] [1,2,4] triaza-4-amine (IV) as a raw material.
Wherein the catalyst comprises LaCl3、NdCl3Or their complex solutions with LiCl;
preferably, the solvent is an ether solvent, such as tetrahydrofuran;
preferably, the flow rate of the material 1 is 20-40 mL/min, and the flow rate of the material 2 is 5-15 mL/min;
preferably, the reaction temperature is-20 to 0 ℃, the reaction time is 50 to 150s, and the pressure is 0 to 3 bar.
The negative ion solution of pyrrole [2,1-f ] [1,2,4] triaza-4-amine (III) in the method can be prepared by two methods.
One of them, with 7-halogenopyrrole [2,1-f ]][1,2,4]Triaza-4-amines (IV, R)2Br or I) as raw material, in the presence of phenylmagnesium chloride solution and trimethylchlorosilane, reacting with C1～4And (3) reacting the alkyl Grignard reagent or the lithium chloride complex thereof to obtain the negative ion solution (III).
Wherein, the reaction can be carried out in a kettle type or continuous flow mode;
preferably, C1～4Alkyl grignard reagents include isopropyl magnesium chloride;
preferably, the reaction temperature is-20 to 0 ℃.
Secondly, pyrrole [2,1-f ]][1,2,4]Triaza-4-amines (IV, R)2Is H) as raw material, in the presence of Tetramethylethylenediamine (TMEDA) and trimethylchlorosilane, with C1～4And (3) reacting the alkyl lithium reagent to obtain the anion solution (III).
Wherein, the reaction can be carried out in a kettle type or continuous flow mode;
preferably, C1～4The alkyl lithium reagent is n-butyl lithium;
preferably, the reaction temperature is-78 to 0 ℃.
The invention has the advantages that:
1. compared with the conventional pressurized hydrogenation reactor, the continuous flow reactor is adopted for continuous flow synthesis, so that the reaction liquid holding volume is small, the reaction condition can be accurately controlled, the amplification effect is avoided, and the industrial production is facilitated.
2. The reaction time is greatly shortened from 2-4 hours of kettle type reaction to 60-120 seconds.
3. The reaction yield is improved from 40% to 66%, and the production cost is reduced.
Drawings
FIG. 1 is a schematic diagram of the micro-reaction process and system connection in example 1 of the present invention.
FIG. 2 is a schematic diagram of the micro-reaction process and system connection in example 2 of the present invention.
FIG. 3 is a schematic diagram of the micro-reaction process and system connection in example 3 of the present invention.
FIG. 4 is a schematic diagram of the micro-reaction process and system connection in example 4 of the present invention.
Detailed Description
For a better understanding of the present invention, reference will now be made to the following examples. It is to be understood that the following specific examples are illustrative of the invention only and are not limiting thereof.
Example 1:
1. flow path 1: adding 120g of 7-iodopyrrole [2,1-f ] [1,2,4] triaza-4-amine 1-1 into 2600mL of tetrahydrofuran, cooling to-5-10 ℃, dropwise adding 260g of phenylmagnesium chloride, finishing the addition for 30 minutes, carrying out heat preservation reaction for 30 minutes, dropwise adding 55g of trimethylchlorosilane, stirring for 60 minutes, then adding 260g of phenylmagnesium chloride, and preparing a solution with the concentration of about 0.14mol/L to serve as a flow path 1 for standby.
2. Flow path 2: 500mL of a 1.2mol/L isopropyl magnesium chloride lithium chloride solution was diluted with 400mL of anhydrous THF to prepare a solution of about 0.72mol/L, which was used as a flow path 2.
3. Flow path 3: 240g of (3R,4R,5R) -3, 4-dibenzyl-5- (benzylmethyl) dihydrofuran-2 (3H) -one 1-3 was added to 1100mL of a tetrahydrofuran solution of neodymium trichloride (0.58mol/L), and 200mL of tetrahydrofuran was added after stirring and dissolution to prepare a tetrahydrofuran solution as a flow path 3 for future use.
4. The reactor lines were connected as shown in FIG. 1. Connecting the flow path 1 and the flow path 2 into the reaction module 1, and setting a temperature zone 1 as a Grignard reagent exchange module; the outlet of the module 1 and the flow path 3 are connected into the reaction module 1, and the temperature setting area 2 is used as a coupling reaction module.
5. The temperature of the reaction block 1 was set to-10 ℃ and the temperature of the reaction block 2 was also set to-10 ℃, and after the temperature stabilized, stable feeding was started with the flow rate of the flow path 1 at 20.0mL/min, the flow rate of the flow path 2 at 5.0mL/min and the flow rate of the flow path 3 at 7.6 mL/min. Total reaction time of feed solution was 92 seconds.
6. When the raw material flow path 1 was completely transported for about two hours, the feeding was stopped and the system was replaced with THF, and the collected reaction solution was collectively treated.
7. The reaction solution was poured into 1200mL of an aqueous ammonium chloride solution (5%) at a temperature of 0 ℃ or lower, stirred for 30 minutes, extracted with 800mL of ethyl acetate, the ethyl acetate layers were combined, washed with 600mL of a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give about 280g of a crude viscous compound.
8. Adding the crude product into 280mL of isopropanol, stirring for dissolving, then dropwise adding 1680mL of isopropyl ether until the system is turbid, stirring for crystallization, filtering, rinsing the filter cake with a small amount of isopropyl ether, and drying to obtain a white solid (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ]][1,2,4]Triaza-7-yl) -3, 4-dibenzyl-5-benzylmethyl) tetrahydrofuran-2-ol 1-4167g, yield 65.5%.1H NMR(400MHz,DMSO-d6)δ8.05(s,2H), 7.96(s,1H),7.36–7.21(m,13H),7.14–7.07(m,3H),7.00–6.94(m,2H),6.91(d, J＝4.8Hz,1H),5.35(d,J＝5.9Hz,1H),5.04(d,J＝5.2Hz,1H),4.54(dd,J＝11.6, 2.6Hz,2H),4.47–4.35(m,4H),3.97(dd,J＝7.0,3.3Hz,1H),3.89(dd,J＝5.9,4.5 Hz,1H),3.65(dd,J＝10.1,3.4Hz,1H),3.44(dd,J＝10.0,6.4Hz,1H).MS(ESI) m/z＝553(M++1)。
According to the operation steps, different temperature zones, material flow rates, solvents and the like are changed, and the obtained experimental results are shown in the table I:
watch 1
Example 2:
1. flow path 1: adding 75.6g of 7-bromopyrrole [2,1-f ] [1,2,4] triaza-4-amine 2-1 into 2000mL of tetrahydrofuran, cooling to-15-20 ℃, dropwise adding 200g of phenylmagnesium chloride, finishing the addition for 30 minutes, carrying out heat preservation reaction for 30 minutes, dropwise adding 42.3g of trimethylchlorosilane, stirring for 60 minutes, then adding 200g of phenylmagnesium chloride, and preparing a solution with the concentration of about 0.14mol/L to be used as the solution A.
400mL of a 1.2mol/L solution of ethylmagnesium bromide and lithium chloride was diluted with 267mL of anhydrous THF to prepare a solution of about 0.72mol/L as solution B.
The solution B was slowly dropped into the solution A while maintaining the temperature of-15 to-20 ℃ and stirred for 60 minutes to prepare a flow path 1.
2. Flow path 2: 184.6g of (3R,4R,5R) -3, 4-dibenzyl-5- (benzylmethyl) dihydrofuran-2 (3H) -one 1-3 was added to 846mL of a tetrahydrofuran solution of lanthanum trichloride (0.58mol/L), and 154mL of tetrahydrofuran was added after stirring and dissolution to prepare a tetrahydrofuran solution as a flow path 2.
3. The reactor tubing was connected and flow 1 and flow 2 were connected to the reaction module as shown in FIG. 2.
4. The temperature of the reaction module was set at-10 ℃ and after the temperature stabilized, the feed was started to stabilize at a flow rate of 25.0mL/min for flow path 1 and at a flow rate of 7.6mL/min for flow path 2. The total reaction time of the feed liquid is 85 seconds.
5. When the raw material flow path 1 was completely transported for about 1.5 hours, the feeding was stopped and the system was replaced with THF, and the collected reaction solution was collectively treated.
6. The reaction solution was poured into 1000mL of an aqueous ammonium chloride solution (5%) at a temperature of 0 ℃ or lower, stirred for 30 minutes, extracted with 600mL of ethyl acetate, the ethyl acetate layers were combined, washed with 500mL of a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give about 215g of a crude viscous compound.
7. Adding the crude product into 215mL of isopropanol, stirring for dissolving, then dropwise adding 1290mL of isopropyl ether until the system is turbid, stirring for crystallization, filtering, rinsing a filter cake with a small amount of isopropyl ether, and drying to obtain 1-4118g of white solid (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triaza-7-yl) -3, 4-dibenzyl-5-benzyl methyl) tetrahydrofuran-2-ol with the yield of 60.3%. The spectral data are given in example 1.
According to the operation steps, different temperatures, material flow rates and the like are changed, and the obtained experimental results are shown in the second table: watch two
Example 3:
1. flow path 1: 100g of pyrrole [2,1-f ] [1,2,4] triaza-4-amine 1-1 is added into 1500mL of tetrahydrofuran, the temperature is reduced to-5-0 ℃, 86.5g of tetramethylethylenediamine is added, 81g of trimethylchlorosilane is slowly dropped, and the mixture is stirred for 60 minutes to serve as a flow path 1 for standby.
2. Flow path 2: 1000mL of a 2.5mol/L n-butyllithium tetrahydrofuran solution was used as a flow path 2.
3. Flow path 3: 312g of (3R,4R,5R) -3, 4-dibenzyl-5- (benzylmethyl) dihydrofuran-2 (3H) -one 1-3 was added to 1435mL of a tetrahydrofuran solution of neodymium trichloride (0.52mol/L), and the mixture was stirred at 20 to 25 ℃ for 60 minutes to prepare a flow path 3.
4. The reactor lines were connected as shown in FIG. 3. Connecting the flow path 1 and the flow path 2 into a reaction module 1, and setting a temperature zone 1 as an anion module; the outlet of the module 1 and the flow path 3 are connected into the reaction module 1, and the temperature setting area 2 is used as a coupling reaction module.
5. The temperature of the reaction module 1 was set to-40 ℃ and the temperature of the reaction module 2 was also set to-10 ℃, and after the temperature stabilized, stable feeding was started with the flow rate of the flow path 1 at 18.0mL/min, the flow rate of the flow path 2 at 10.0mL/min and the flow rate of the flow path 3 at 18.0 mL/min. Total reaction time of the feed liquid was 101 seconds.
6. When the raw material flow path 1 was completely transported for about 1.5 hours, the feeding was stopped and the system was replaced with THF, and the collected reaction solution was collectively treated.
7. The reaction solution was poured into 2000mL of an aqueous ammonium chloride solution (5%) at a temperature of 0 ℃ or lower, stirred for 30 minutes, extracted with 1200mL of ethyl acetate, the ethyl acetate layers were combined, washed with 900mL of a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give about 360g of a crude viscous compound.
8. And adding the crude product into 360mL of isopropanol, stirring and dissolving, then dropwise adding 2160mL of isopropyl ether until the system is turbid, stirring and crystallizing, filtering, rinsing a filter cake with a small amount of isopropyl ether, and drying to obtain 1-4245g of white solid (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triaza-7-yl) -3, 4-dibenzyl-5-benzyl methyl) tetrahydrofuran-2-ol, wherein the yield is 52.3%. The spectral data are given in example 1.
According to the operation steps, the temperature and the material flow rate of different temperature zones are changed, and the obtained experimental results are as shown in the third table:
watch III
Example 4:
1. flow path 1: adding 50g of pyrrole [2,1-f ] [1,2,4] triaza-4-amine 1-1 into 750mL of tetrahydrofuran, cooling to-5-0 ℃, adding 43.3g of tetramethylethylenediamine, slowly dropwise adding 40.5g of trimethylchlorosilane, and stirring for 60 minutes; the system was cooled to-60 ℃ and 500mL of a 2.5mol/L t-butyllithium solution in tetrahydrofuran was slowly dropped and stirred for 30 minutes to prepare a flow path 1.
2. Flow path 2: 156g of (3R,4R,5R) -3, 4-dibenzyl-5- (benzylmethyl) dihydrofuran-2 (3H) -one 1-3 was added to 718mL of a tetrahydrofuran solution of neodymium trichloride (0.52mol/L), and the mixture was stirred at 20 to 25 ℃ for 60 minutes to prepare a flow channel 2.
3. The reactor tubing was connected and flow 1 and flow 2 were connected to the reaction module as shown in FIG. 4.
4. The temperature of the reaction module was set at-20 ℃ and after the temperature stabilized, the feed was started to stabilize with the flow rate of flow path 1 at 28.0mL/min and the flow rate of flow path 2 at 18.0 mL/min. Total reaction time of feed liquid 88 seconds.
5. When the raw material flow path 1 was completely transported for about 1 hour, the feeding was stopped and the system was replaced with THF, and the collected reaction solution was collectively treated.
6. The reaction solution was poured into 500mL of an aqueous ammonium chloride solution (5%) at a temperature below 0 ℃, stirred for 30 minutes, extracted with 300mL of ethyl acetate, the ethyl acetate layers were combined, washed with 250mL of a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give about 110g of a crude viscous compound.
7. Adding the crude product into 110mL of isopropanol, stirring for dissolving, then dropwise adding 660mL of isopropyl ether until the system is turbid, stirring for crystallization, filtering, rinsing a filter cake with a small amount of isopropyl ether, and drying to obtain 1-4114g of white solid (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triaza-7-yl) -3, 4-dibenzyl-5-benzyl methyl) tetrahydrofuran-2-ol with the yield of 48.8%. The spectral data are given in example 1.
According to the operation steps, different temperatures, material flow rates and the like are changed, and the obtained experimental results are shown in the fourth table: watch four
In this specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense.
Claims (9)
1. A preparation method of a Ruidexiwei intermediate (3R,4R,5R) -2- (4-aminopyrrole [2,1-f ] [1,2,4] triaza-7-yl) -3, 4-dibenzyl-5-benzylmethyl) tetrahydrofuran-2-ol (I) comprises the steps of taking a negative ion solution of pyrrole [2,1-f ] [1,2,4] triaza-4-amine (III) as a material 1, taking a mixed solution of (3R,4R,5R) -3, 4-dibenzyl-5- (benzylmethyl) dihydrofuran-2 (3H) -ketone (II) and a catalyst and a solvent as a material 2, and carrying out reaction through a continuous flow reactor to synthesize the compound (I)
Wherein R is1Including trimethylsilyl and hydrogen atoms.
2. The method according to claim 1, wherein the negative ion solution of pyrrole [2,1-f ] [1,2,4] triaza-4-amine (III) is prepared from 7-halogenated pyrrole [2,1-f ] [1,2,4] triaza-4-amine or pyrrole [2,1-f ] [1,2,4] triaza-4-amine (IV).
3. The method of claim 1, wherein the catalyst comprises LaCl3、NdCl3Or their complex solutions with LiCl; the solvent includes an ether solvent such as tetrahydrofuran.
4. The method of claim 1, wherein the flow rate of material 1 is 20-40 mL/min and the flow rate of material 2 is 5-30 mL/min.
5. The method of claim 1, wherein the suitable reaction temperature is-20 to 0%oC, the reaction time is 50-150 s.
6. Preparation of pyrrole [2,1-f][1,2,4]Process for the preparation of a negative ion solution of triaza-4-amines (III) from 7-halogenopyrroles [2, 1-f)][1,2,4]Triaza-4-amines (IV, R)2Br or I) as raw material, in the presence of phenylmagnesium chloride solution and trimethylchlorosilaneC1~4And (3) reacting the alkyl Grignard reagent or the lithium chloride complex thereof to obtain the negative ion solution (III).
7. The method of claim 6, wherein the reaction can be carried out by a tank or continuous flow; c1~4The alkyl Grignard reagent comprises isopropyl magnesium chloride, and the reaction temperature is-20 to 0oC。
8. Preparation of pyrrole [2,1-f][1,2,4]Method for the anionic solution of triaza-4-amines (III) from pyrrole [2, 1-f)][1,2,4]Triaza-4-amines (IV, R)2Is H) as raw material, in the presence of Tetramethylethylenediamine (TMEDA) and trimethylchlorosilane, with C1~4And (3) reacting the alkyl lithium reagent to obtain the anion solution (III).
9. The method of claim 8, wherein the reaction can be carried out by a tank or continuous flow; c1~4The alkyl lithium reagent comprises n-butyl lithium, and the reaction temperature is-78-0oC。
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| US20160122356A1 (en) * | 2014-10-29 | 2016-05-05 | Gilead Sciences, Inc. | Methods for the preparation of ribosides |
| CN111484537A (en) * | 2020-05-19 | 2020-08-04 | 南京工业大学 | Method for preparing Rudesiwei key intermediate by using microchannel reaction device |
| CN111574523A (en) * | 2020-06-11 | 2020-08-25 | 玉林师范学院 | Method for preparing 1' -substituted carbon nucleoside analogue intermediate |
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| US20160122356A1 (en) * | 2014-10-29 | 2016-05-05 | Gilead Sciences, Inc. | Methods for the preparation of ribosides |
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