CN113336758B - Novel synthesis method of compound 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine - Google Patents
Novel synthesis method of compound 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine Download PDFInfo
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- CN113336758B CN113336758B CN202010150266.XA CN202010150266A CN113336758B CN 113336758 B CN113336758 B CN 113336758B CN 202010150266 A CN202010150266 A CN 202010150266A CN 113336758 B CN113336758 B CN 113336758B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 49
- ZEBGLCLVPCOXIV-UHFFFAOYSA-N 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound NC1=NC=NN2C(I)=CC=C12 ZEBGLCLVPCOXIV-UHFFFAOYSA-N 0.000 title description 13
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 13
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940107700 pyruvic acid Drugs 0.000 claims abstract description 4
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims abstract description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 5
- 125000002346 iodo group Chemical group I* 0.000 claims description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical class CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000003918 triazines Chemical class 0.000 claims description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 239000007858 starting material Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- -1 triazine compound Chemical class 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000001241 acetals Chemical class 0.000 description 4
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- NMPVEAUIHMEAQP-UHFFFAOYSA-N 2-Bromoacetaldehyde Chemical compound BrCC=O NMPVEAUIHMEAQP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000026045 iodination Effects 0.000 description 2
- 238000006192 iodination reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- VYEHSYWBLDTUHX-UHFFFAOYSA-N 1h-pyrrolo[2,1-f][1,2,4]triazin-4-one Chemical compound O=C1NC=NN2C=CC=C12 VYEHSYWBLDTUHX-UHFFFAOYSA-N 0.000 description 1
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 description 1
- FUSNOPLQVRUIIM-UHFFFAOYSA-N 4-amino-2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-n-[3-(trifluoromethyl)phenyl]pyrimidine-5-carboxamide Chemical compound O=C1NC(C)(C)CN1C(N=C1N)=NC=C1C(=O)NC1=CC=CC(C(F)(F)F)=C1 FUSNOPLQVRUIIM-UHFFFAOYSA-N 0.000 description 1
- MFALBWSBIOLNCA-UHFFFAOYSA-N 4-chloro-7-iodopyrrolo[2,1-f][1,2,4]triazine Chemical compound ClC1=NC=NN2C(I)=CC=C12 MFALBWSBIOLNCA-UHFFFAOYSA-N 0.000 description 1
- ONTLBVKRDUFQFP-UHFFFAOYSA-N 4-chloropyrrolo[2,1-f][1,2,4]triazine Chemical compound ClC1=NC=NN2C=CC=C12 ONTLBVKRDUFQFP-UHFFFAOYSA-N 0.000 description 1
- PDWZJMKDSKSWMD-UHFFFAOYSA-N 6-methyl-2h-1,2,4-triazin-5-one Chemical compound CC1=NNC=NC1=O PDWZJMKDSKSWMD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 1
- 206010023927 Lassa fever Diseases 0.000 description 1
- 208000030156 Marburg disease Diseases 0.000 description 1
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- YFHNDHXQDJQEEE-UHFFFAOYSA-N acetic acid;hydrazine Chemical compound NN.CC(O)=O YFHNDHXQDJQEEE-UHFFFAOYSA-N 0.000 description 1
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012493 hydrazine sulfate Substances 0.000 description 1
- 229910000377 hydrazine sulfate Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012336 iodinating agent Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- VSPXQZSDPSOPRO-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound NC1=NC=NN2C=CC=C12 VSPXQZSDPSOPRO-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- QQOWHRYOXYEMTL-UHFFFAOYSA-N triazin-4-amine Chemical class N=C1C=CN=NN1 QQOWHRYOXYEMTL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a method for preparing a triazine compound shown as a formula (I). The invention uses pyruvic acid andusing formamidine as a starting material to synthesize an intermediate
The compound shown in the formula (I) can be obtained through two steps of reaction. The method provided by the invention has mild conditions, is simple and convenient to operate, greatly reduces the cost, and is suitable for industrial mass production.
Description
Technical Field
The invention relates to a new synthesis and purification method of a compound 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazine-4-amine, belonging to the fields of chemistry and medicine.
Background
7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine (CAS number 1770840-43-1) is an important intermediate, the structure of which is a key starting material for Reidesciclovir and has the formula:
redysivir was used initially for the treatment of ebola virus disease and marburg virus infection and was later found to exhibit reasonable antiviral activity against more distantly related viruses such as respiratory syncytial virus, hunin virus, lassa fever virus and MERS. Therefore, the synthesis of the precursor fragment 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine is key for further reducing the cost and improving the productivity.
At present, the synthesis method of 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazine-4-amine is mainly a small-amount synthesis route reported by a patent (WO2007064931), wherein a compound 01 and Boc hydrazine are used as starting materials, ring closure is carried out to obtain an intermediate 02, further sulfonyl chloride isocyanate is used for cyano group on pyrrole 2 position to obtain a compound 03, further Boc protecting group is removed under acidic condition to obtain a compound 04, and ring closure is carried out with methyl ether and iodine on NIS is used for obtaining a product compound 06 (7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazine-4-amine). The detailed reaction route is shown as the following formula.
As can be seen from the above routes, the ring closing step 1 has a yield of less than 60%, and chlorosulfonic acid isocyanate used in step 2 is highly toxic and requires column chromatography for purification, so the routes are not suitable for industrial scale-up. From the viewpoint of cost, due to the compound 01 and BocN 2 H 4 The cost is large and the yield of step 1 is low, resulting in high overall route cost. Furthermore, we have developed the compound 7-iodopyrrolo [2, 1-f][1，2，4]The new route for triazin-4-amines is of the formula:
we used pyruvic acid and formamidine hydrochloride as starting materials, and hydrazine hydrate in ethanol under reflux to obtain triazine fragment (compound 03), and then further with bromo diethyl acetal to obtain compound 04, completing the construction of main ring. Further conversion of the hydroxyl group to chlorine using phosphorus oxychloride gives the key intermediate compound 05. Subsequently, preferential ammonolysis using compound 05 as starting material affords compound 06 with further iodination to afford product 07 (scheme A). At the same time, starting from compound 05, it is also possible to obtain compound 08 by preferential iodination and subsequent ammonolysis to obtain compound 07 (scheme B).
The method has the advantages that the yield of each step is high, the intermediate is easy to recrystallize and purify, isomers can be avoided, and accordingly, the yield and the purification difficulty are improved, and the method is favorable for industrial production. In addition, the raw materials of the route are basic chemicals, so that the price is low and easy to obtain, and the production cost of the product 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazine-4-amine is greatly reduced.
Disclosure of Invention
The invention aims to develop a novel method for preparing 7-iodopyrrolo- [2, 1-f ] [1, 2, 4] triazin-4-amine, and the method can improve the yield and reduce the production cost, so that the method is suitable for industrial mass production.
The invention provides a novel method for preparing 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine. The method comprises the following steps:
1) the intermediate shown in (II) is formed by the ring closure of pyruvic acid and formamidine under the participation of hydrazine:
2) reacting the intermediate obtained in the step 1) as shown in the formula (II) with halogenated acetaldehyde or halogenated acetal to obtain an intermediate as shown in the formula (III):
3) carrying out dehydroxylation and chlorination on the intermediate obtained in the step 2) as shown in the formula (III) to obtain an intermediate as shown in the formula (IV):
4) converting the intermediate obtained in the step 3) as shown in the formula (IV) to obtain a target compound as shown in the formula (I):
in the step 1), formamidine hydrochloride or formamidine acetate can be used.
The solubility of hydrazine hydrate used in the step 1) may be 40% to 80%, or a salt of hydrazine such as hydrazine acetate, hydrazine hydrochloride, hydrazine sulfate, or the like may be used.
In the step 1), an alcohol solvent such as ethanol, isopropanol or tert-butanol is preferably used.
The reaction temperature of the step 1) is-20 ℃ to 100 ℃.
The step 2) uses halogenated acetaldehyde or halogenated acetal.
Further, chloroacetaldehyde or bromoacetaldehyde is preferably selected.
If halogenated acetal is used in the step 2), a catalytic amount of acid is added into the reaction system.
Further, the acid may be selected from hydrochloric acid, sulfuric acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, or the like.
Further, the amount of the acid is 1 to 50% by mass of the halogenated acetal.
The dehydroxylation and chlorination reagent used in the step 3) is phosphorus oxychloride or thionyl chloride.
Further, phosphorus oxychloride is preferably used.
In the step 4), the compound (IV) can be iodo to obtain a compound (I):
further, the iodinating agent may be selected from iodine, N-iodosuccinimide, or iodine chloride.
Further, the amination reaction may use aqueous ammonia or an alcoholic solution of ammonia, preferably an alcoholic solution of ammonia.
The invention provides a method for preparing triazine compounds. The preparation method is simple and convenient, has low cost and is suitable for industrial production. Obviously, many modifications, substitutions, and alterations are possible in light of the above teachings of the invention, without departing from the basic technical ideas of the invention, as defined by the following general technical knowledge and conventional practices of the art.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The starting materials and equipment used in the embodiment of the present invention are known products and are obtained by purchasing commercially available products.
Example 1: synthesis of compound 6-methyl-1, 2, 4-triazin-5 (4H) -one.
Adding an ethanol solution of formamidine hydrochloride (compound 02) and hydrazine hydrate into a reaction bottle, cooling the system to-10 ℃, then adding the compound 01 into the reaction system, and adding a trace amount of acetic acid for catalysis. And heating and refluxing the system for 5 hours, cooling and filtering after the reaction is finished, and concentrating the filtrate to be dry to obtain a crude product of the compound 03, wherein the crude product is directly used for the next reaction without purification.
Example 2: synthesis of the compound pyrrolo [2, 1-f ] [1, 2, 4] triazin-4 (3H) -one.
Adding the crude product of the compound 03 into water, then adding 2-bromo-diglycal into the system, adding trace hydrochloric acid into the system, then heating to 90 ℃ to react for 3 hours, cooling the system to room temperature after the raw materials disappear, filtering, and washing a filter cake with cold water to obtain a compound 04 (the yield of the two steps is 65%).
Example 3: synthesis of 4-chloropyrrolo [2, 1-f ] [1, 2, 4] triazine.
DIPEA and phosphorus oxychloride are added into a toluene solution of a compound 04, a system is heated to 120 ℃ to react for 24 hours, after raw materials disappear, the reaction liquid is added into ice water to be quenched, then sodium bicarbonate is added to adjust the pH value to be neutral, the system is subjected to liquid separation, an aqueous phase is extracted for 2 times by toluene, organic phases are combined, dried, filtered and concentrated to obtain the compound 05 (the yield is 93%).
Example 4: synthesis of compound 4-aminopyrrolo [2, 1-f ] [1, 2, 4] triazine
Compound 05 was dissolved in tetrahydrofuran, and then, an amine methanol solution was added to the system, the system was stirred at room temperature for 0.5 hour, then, at 50 ℃ overnight, after TLC showed disappearance of the starting material, water was added to quench the reaction, the mixture was stirred at room temperature for 2 hours, and filtered, and the cake was collected to give compound 06 (yield: 82%).
Example 5: synthesis of compound 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine
Dissolving the compound 06 in dimethyl sulfoxide, adding NIS in batches, stirring the system at room temperature for 16 hours, adding water into the system to quench the reaction after TLC identification of the disappearance of the raw materials, continuing stirring for 2 hours, filtering the system, and collecting a filter cake to obtain a compound 07 (yield: 75%)
Example 6: synthesis of compound 4-chloro-7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazine
Dissolving Compound 05 in anhydrous dichloromethane, adding NIS, stirring at room temperature for 16 hr, TLC monitoring for disappearance of raw material, filtering, collecting filtrate, washing filtrate with sodium sulfite aqueous solution twice, collecting organic phase, drying organic phase, filtering, collecting filtrate, and concentrating to obtain Compound 06 (yield: 75%)
Example 7: synthesis of compound 7-iodopyrrolo [2, 1-f ] [1, 2, 4] triazin-4-amine
Dissolving the compound 05 in tetrahydrofuran, adding an amine methanol solution, stirring the reaction at room temperature for 2 hours after the addition is finished, heating to 55 ℃ for reaction for 16 hours, adding water to quench the reaction after TLC (thin layer chromatography) monitors that raw materials disappear, removing an organic phase by concentrating the mixture under reduced pressure, adding ethanol into the system, pulping for 2 hours, filtering, and collecting a filter cake to obtain the compound 07 (yield: 81%).
Claims (2)
1. A preparation method of triazine compounds shown in formula (I),
the method is characterized by comprising the following steps:
1) the intermediate shown in (II) is formed by the ring closure of pyruvic acid and formamidine under the participation of hydrazine:
2) reacting the intermediate obtained in the step 1) and shown in the formula (II) with halogenated acetaldehyde or halogenated acetal to obtain an intermediate shown in the formula (III):
3) carrying out dehydroxylation and chlorination on the intermediate obtained in the step 2) as shown in the formula (III) to obtain an intermediate as shown in the formula (IV):
4) converting the intermediate obtained in the step 3) as shown in the formula (IV) to obtain a target compound as shown in the formula (I):
in the step 4), the compound (IV) can be converted into an amino intermediate and then iodo to obtain a compound (I):
or the compound (IV) is iodo firstly and then is ammonolyzed to obtain the compound (I):
2. the method as set forth in claim 1, wherein the dehydroxychlorination reagent used in step 3) is phosphorus oxychloride or thionyl chloride.
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|---|---|---|---|---|
| WO2017184668A1 (en) * | 2016-04-20 | 2017-10-26 | Gilead Sciences, Inc. | Methods for treating flaviviridae virus infections |
| CN108348526A (en) * | 2015-09-16 | 2018-07-31 | 吉利德科学公司 | Method of treating arenaviridae and coronaviridae viral infections |
| CN109348715A (en) * | 2016-03-28 | 2019-02-15 | 因赛特公司 | Pyrrolotriazine compounds as TAM inhibitors |
| CN110003215A (en) * | 2013-11-11 | 2019-07-12 | 吉利德科学公司 | It can be used for treating pyrrolo- [1,2-f] [1,2,4] triazine of respiratory syncytial virus infection |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110003215A (en) * | 2013-11-11 | 2019-07-12 | 吉利德科学公司 | It can be used for treating pyrrolo- [1,2-f] [1,2,4] triazine of respiratory syncytial virus infection |
| CN108348526A (en) * | 2015-09-16 | 2018-07-31 | 吉利德科学公司 | Method of treating arenaviridae and coronaviridae viral infections |
| CN109348715A (en) * | 2016-03-28 | 2019-02-15 | 因赛特公司 | Pyrrolotriazine compounds as TAM inhibitors |
| WO2017184668A1 (en) * | 2016-04-20 | 2017-10-26 | Gilead Sciences, Inc. | Methods for treating flaviviridae virus infections |
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