CN115873002A - Synthesis method of Reidesciclovir intermediate - Google Patents
Synthesis method of Reidesciclovir intermediate Download PDFInfo
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- CN115873002A CN115873002A CN202211586921.1A CN202211586921A CN115873002A CN 115873002 A CN115873002 A CN 115873002A CN 202211586921 A CN202211586921 A CN 202211586921A CN 115873002 A CN115873002 A CN 115873002A
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- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 170
- 238000006243 chemical reaction Methods 0.000 claims abstract description 159
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract description 128
- 238000000034 method Methods 0.000 claims abstract description 40
- 239000002253 acid Substances 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 69
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 claims description 52
- 239000002904 solvent Substances 0.000 claims description 51
- 239000007795 chemical reaction product Substances 0.000 claims description 43
- 238000002360 preparation method Methods 0.000 claims description 43
- 239000000203 mixture Substances 0.000 claims description 36
- 238000010791 quenching Methods 0.000 claims description 34
- 238000002156 mixing Methods 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 230000000171 quenching effect Effects 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 150000002825 nitriles Chemical class 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 238000010626 work up procedure Methods 0.000 claims 2
- 238000005520 cutting process Methods 0.000 claims 1
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- 239000002699 waste material Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 239000002351 wastewater Substances 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- -1 cyano compound Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing 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
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000010887 waste solvent Substances 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of a Reidesciclovir intermediate. Which comprises the following steps: in the presence of protonic acid, the compound shown in the formula III and formamide react to obtain the compound shown in the formula V. When the method is used for preparing the Ruidexilvir intermediate, the continuous reaction feeding is controllable, the conversion rate is high, the reaction steps are short, the production period is short, and the method is environment-friendly.
Description
Technical Field
The invention relates to a synthesis method of a Ruidexilvir intermediate, belonging to the field of chemistry.
Background
The Reidesciclovir is an antiviral drug on the market recently, and in order to reduce cost, the synthesis method is continuously improved, but with the increasing environmental protection requirements of China, the discharge of three wastes (waste gas, waste water and waste residues) for synthesizing the drug is increased, and the problem that the three wastes (waste water, waste residues and waste residues) are extremely high in treatment cost and even cannot be produced due to excessive waste water, waste residues and waste residues is caused is solved. This problem exists in the production of one of the pyrrole ring-containing intermediates, which have the following structure:
the synthesis process of the Redsevir pyrrole ring segment is relatively fixed, the target compound is obtained mainly by closing a ring with a cyano compound in the last step, and the synthesis documents are more but the main method is as follows:
in the first step of the method, dioxane is taken as a solvent, and is refluxed and closed under the catalysis of acid, the solvent dioxane is recovered after the reaction is finished, and the compound 2-1 is obtained by ethanol crystallization.
In the second step, acetonitrile is used as a reaction solvent, chlorosulfonyl isocyanate and excessive DMF act together to form the cyano group, the reaction is better, but the post-treatment is carried out by quenching with a large amount of water and extracting with a hydrophobic solvent, so that a large amount of high ammonia nitrogen and high COD (chemical oxygen demand) wastewater is generated, the treatment is difficult, the cost of three wastes is high, the solvent of the extraction product is a mixed solvent of the acetonitrile and the hydrophobic solvent, the mixed solvent is basically not applicable, and a large amount of waste solvents are generated. Is very disadvantageous for mass production.
And in the third step, BOC removal is carried out by using a large amount of concentrated hydrochloric acid, the concentrated hydrochloric acid is corroded on equipment and is not friendly to operation, the concentrated hydrochloric acid cannot be used mechanically after reaction, neutralization is needed in post-treatment, a large amount of high-salinity wastewater is generated, and the treatment is difficult and the treatment cost is high.
The formamidine in the fourth step can obtain a product with better yield and high purity, but the aftertreatment is purified by a reaction solvent ethanol and a large amount of water, so that a large amount of high-salt high-phosphorus high-COD waste liquid is generated, and the method is extremely unfriendly to the environment. High cost processing is necessary.
The synthesis of the pyrrolo [2,1-F ] [1,2,4] triazin-4-amine (Compound 5) fragment, as described above for its synthesis, produces, starting from the second step, large amounts of waste water effluents which are difficult to treat.
Disclosure of Invention
The invention aims to overcome the defect of high three wastes in the prior art. Therefore, the invention provides a method for synthesizing an intermediate of the Reidesciclovir, which has short steps, is environment-friendly, is beneficial to safe production and is suitable for industrialization.
The invention provides a preparation method of a compound shown as a formula V, which comprises the following steps: in the presence of protonic acid, the compound shown in the formula III and formamide react to obtain the compound shown in the formula V,
wherein ring A is a 5-to 6-membered heteroaromatic ring, a 6-to 10-membered aromatic ring, substituted with 1,2 or 3R a Substituted 5-to 6-membered heteroaromatic rings or substituted by 1,2 or 3R a A substituted 6-to 10-membered aromatic ring; the R is a Are each independently C 1 ～C 4 An alkyl group;
R D is-CN, -COOCH 3 -COOH or-CHO;
when R is D When is-CN, R d is-NH 2 (ii) a When R is D is-COOCH 3 When R is d is-C = O; when R is D When it is-COOH, R d is-C = O; when R is D When it is-CHO, R d Is H;
z is N or C;
r is-NR 1 R 2 ，R 1 And R 2 Are each independently H or COOR 3 ；R 3 Is C 1 ～C 4 An alkyl group;
x is N.
In the preparation method of the compound shown in the formula V, the reaction can also be carried out in the presence of a solvent which is conventional in the reaction; preferably under nitrile group as reaction solvent; more preferably in acetonitrile as reaction solvent.
In the method for producing the compound represented by the formula V, when a nitrile is added as a reaction solvent, the mass ratio of the nitrile solvent to the compound represented by the formula III may be conventional in such reactions in the art.
In the method for preparing the compound represented by the formula V, the reaction can be carried out in an open system.
In the method for producing the compound represented by the formula V, the ring a is preferably a 5-to 6-membered heteroaromatic ring or a 6-to 10-membered aromatic ring. More preferably a 5-to 6-membered heteroaromatic ring. More preferably, the pyrrole ring.
In the preparation method of the compound shown as the formula V, R is a Preferably methyl, ethyl, propyl or butyl.
In the preparation method of the compound shown as the formula V, R is D preferably-CN.
In the preparation method of the compound shown as the formula V, in the R, R 1 And R 2 Preferably at least one is H. More preferably, R is-NH 2 or-NHBoc.
In the method for producing the compound represented by the formula V, Z is preferably N.
In the preparation method of the compound shown in the formula V, X is preferably N.
In the preparation of the compound of formula V, the protic acid may be conventional in the art for such reactions. Aqueous solutions of mineral acids are preferred. More preferably an aqueous solution of sulfuric acid, hydrochloric acid, nitric acid or phosphoric acid. Further preferred is an aqueous solution of sulfuric acid.
In the process for the preparation of the compound of formula V, the molar ratio of the compound of formula III to formamide may be conventional in the art for such reactions. Preferably 1. More preferably 1.
In the process for the preparation of the compound of formula V, the molar ratio of the compound of formula III to protic acid may be conventional in such reactions in the art. When the reaction is carried out in the presence of an aqueous solution of a mineral acid, the molar ratio of the compound represented by the formula III to the total amount of water and acid is preferably 1 to 1. More preferably, the molar ratio of the compound represented by formula III to the total amount of water and acid is 1.5.
In the process for the preparation of the compound of formula V, the temperature of the reaction may be conventional in the art for such reactions. Preferably 80 to 120 ℃. More preferably 85 to 115 ℃. Further preferably 90 ℃,100 ℃ or 110 ℃.
In the process for preparing the compound of formula V, the reaction time may be conventional in the art for such reactions. Preferably 5 to 16 hours. More preferably 8 to 10 hours. Further preferably 8 or 10 hours.
In the method for producing the compound represented by the formula V, the reaction is preferably carried out at 85 to 95 ℃ C (e.g., 90 ℃ C.) for 0.5 to 2 hours (e.g., 1 hour), at 95 to 105 ℃ C (e.g., 100 ℃ C.) for 0.5 to 2 hours (e.g., 1 hour), and at the end at 105 to 115 ℃ C (e.g., 110 ℃ C.) for 4 to 12 hours (e.g., 8 hours).
In the preparation method of the compound shown in the formula V, after the reaction is completed, the post-treatment can be included, and the post-treatment operation can be conventional in the field of such reactions. Preferably, the reaction product is concentrated under reduced pressure, cooled and recrystallized. The temperature of the reduced pressure concentration is preferably 70-90 ℃. Further preferably 80 ℃. The time for the concentration under reduced pressure is preferably 1 to 6 hours. Further preferably 3 hours. The pressure for the concentration under reduced pressure is preferably 150 to 450Pa. Further preferably 300Pa. The cooling is preferably to 60 ℃ to 80 ℃. More preferably to 70 deg.c. The recrystallization is preferably in alcohols. More preferably by recrystallization from ethanol. Preferably, the recrystallization is performed by adding ethanol, cooling to-5 ℃ to 5 ℃ (for example, 0 ℃), stirring for 0.5 to 2 hours (for example, 1 hour), and then performing suction filtration, wherein the mass ratio of the compound represented by the formula III to ethanol is preferably 1: 6-2: 3; more preferably 105:300.
in some embodiments, in the method for preparing the compound represented by formula V, the reaction is preferably performed in an open system; a is preferably pyrrole; the R is D preferably-CN; said R is preferably-NHBoc; z is preferablyN; said X is preferably N; the acid is preferably sulfuric acid; the molar ratio of the compound represented by the formula III to formamide is preferably 1:3; the molar ratio of the compound represented by the formula III to the acid is preferably 1:1.5; the reaction is preferably carried out at 90 ℃ for 1 hour, then at 100 ℃ for 1 hour and finally at 110 ℃ for 8 hours. After the reaction is completed, preferably, the reaction product is subjected to reduced pressure concentration for 3 hours at the temperature of 80 ℃ and the pressure of 300Pa, the reaction product is cooled to 70 ℃, ethanol is added, the reaction product is cooled to 0 ℃, the reaction product is stirred for 1 hour and then is subjected to suction filtration, and the mass ratio of the compound shown in the formula III to the ethanol is preferably 105:300.
in some embodiments, in the method of preparing the compound of formula V, the R is D preferably-CN; also included is a method for preparing a compound of formula 3, comprising the steps of: in a solvent, reacting a compound shown in a formula 2 with chlorosulfonyl isocyanate and formamide to obtain a compound shown in a formula 3,
wherein the rings A, R and Z are as defined above.
In the preparation method of the compound represented by the formula 3, the solvent may be a solvent that is conventional in such a reaction in the art. One or more of an ester solvent, an ether solvent, or a nitrile solvent is preferred. More preferably one or more of ethyl acetate, methyl tert-butyl ether or acetonitrile. Further preferred is acetonitrile.
In the method for preparing the compound represented by the formula 3, the reaction may be performed in an open system.
In the preparation method of the compound represented by the formula 3, the molar ratio of the compound represented by the formula 2 to formamide may be conventional in such reactions in the art. Preferably 1:2 to 1:5. more preferably 1:3.
in the method for preparing the compound represented by formula 3, the molar ratio of the compound represented by formula 2 to chlorosulfonyl isocyanate may be conventional in such reactions in the art. Preferably 1:1.0 to 1:2.0. more preferably 1:1.1.
in the preparation method of the compound represented by the formula 3, the mass ratio of the compound represented by the formula 2 to the solvent may be conventional in such reactions in the art. Preferably 1: 5.0-1: 20.0. more preferably 1:5.0.
in the preparation method of the compound represented by the formula 3, the temperature of the reaction may be conventional in such reactions in the art. Preferably-5 to 5 ℃. More preferably from-5 to 0 ℃. Further preferably-5 ℃ or 0 ℃.
In the preparation method of the compound represented by the formula 3, the reaction time may be conventional in the art for such a reaction. Preferably 0.5 to 24 hours. More preferably 2 to 6 hours. Further preferably 3 hours.
In the preparation method of the compound represented by the formula 3, the reaction operation may be conventional in the art for such a reaction. The following are preferred: step 1: firstly, mixing the compound shown in the formula 2 with chlorosulfonyl isocyanate; step 2: and (3) reacting the mixture obtained in the step 1 with formamide.
In the method for preparing the compound represented by formula 3, when the compound represented by formula 2 is mixed with chlorosulfonyl isocyanate in step 1, the operation may be conventional in such reactions in the art. The following are preferred: firstly, dissolving the compound shown in the formula 2 in a solvent, and then adding chlorosulfonyl isocyanate for mixing. The compound represented by formula 2 is preferably dissolved in a solvent at room temperature (e.g., 25 ℃). The chlorosulfonyl isocyanate is preferably added dropwise. The chlorosulfonyl isocyanate is preferably added while controlling the temperature at-5 to 5 ℃. More preferably, chlorosulfonyl isocyanate is added while controlling the temperature at 0 ℃. The mixing is preferably temperature-controlled mixing, and the mixing temperature is preferably-5 ℃. More preferably from-5 to 0 ℃. Further preferably-5 ℃. The mixing time is preferably 1 to 3 hours. More preferably 1 hour.
In the method for preparing the compound represented by the formula 3, when the mixture obtained in the step 1 is reacted with formamide in the step 2, the reaction operation may be a conventional one in the art. The following are preferred: formamide is added into the mixture obtained in the step 1 to carry out reaction. Formamide is preferably added dropwise to the mixture obtained in step 1. The dropwise addition is preferably completed within 0.5 to 2 hours. More preferably 1 hour. Formamide is added to the reaction product, preferably at a controlled temperature of-5 to 5 ℃. More preferably, formamide is added to the reaction product at a controlled temperature of-5 to 0 ℃. Further preferably formamide is added to the reaction product at-5 ℃. The reaction is preferably temperature-controlled, and the reaction temperature is preferably-5-0 ℃. More preferably-5 ℃. The reaction time is preferably 1 to 3 hours. More preferably 2 hours.
In the preparation method of the compound shown in the formula 3, a quenching reagent can be added to quench the reaction after the reaction is finished. The quenching reagent may be conventional in the art for such reactions. Water is preferred. The molar ratio of the compound of formula 2 to the quenching reagent may be conventional in such reactions in the art. Preferably 1:2. more preferably 1. The quenching reagent may also be added followed by stirring for 0.5-2 hours. Preferably 1 hour. Preferably, the stirring temperature is from-5 to 0 ℃. More preferably, the stirring temperature is-5 ℃.
In the preparation method of the compound shown in the formula 3, after the reaction quenching, the obtained reaction product can be subjected to reduced pressure concentration to obtain a crude reaction product, and the reduced pressure concentration condition can be conventional in the field of such reactions. The temperature of the reduced pressure concentration is preferably 30-40 ℃. Further preferably 30 ℃. The pressure for the concentration under reduced pressure is preferably-0.15 MPa to-0.05 MPa. Further preferably-0.09 MPa. The time for the concentration under reduced pressure is preferably 1 to 6 hours. Further preferably 3 hours.
In the preparation method of the compound represented by the formula 3, the reaction product crude product obtained after quenching and vacuum concentration of the reaction can be directly used for the next reaction.
In some embodiments, in the method for preparing the compound represented by formula 3, the reaction is preferably performed in an open system; ring a is preferably pyrrole; said R is preferably-NHBoc; z is preferably N; the solvent is acetonitrile; the reaction operation is preferably as follows: step 1: firstly, mixing the compound shown in the formula 2 with chlorosulfonyl isocyanate; step 2: reacting the mixture obtained in the step 1 with formamide; in the step 1, when the compound represented by formula 2 is mixed with chlorosulfonyl isocyanate, the operation is preferably as follows: firstly dissolving the compound shown in the formula 2 in a solvent at the temperature of 25 ℃, then dropwise adding chlorosulfonyl isocyanate at the temperature of 0 ℃, and then controlling the temperature to be-5 ℃ for reaction for 1 hour; in the step 2, when the mixture obtained in the step 1 reacts with formamide, the reaction operation is preferably as follows: controlling the temperature to be minus 5 ℃, dropwise adding formamide into the reaction product, preferably completing dropwise adding within 1 hour, and then controlling the temperature to be minus 5-0 ℃ to react for 2 hours; after the reaction is finished, adding water to quench the reaction, stirring the mixture for 1 hour at the temperature of minus 5 ℃, and then concentrating the mixture for 3 hours under the conditions of the temperature of 30 ℃ and the pressure of minus 0.09MPa to obtain a crude reaction product which is directly used for the next reaction; the molar ratio of the compound represented by the formula 2 to formamide is preferably 1:3; the molar ratio of the compound represented by formula 2 to chlorosulfonyl isocyanate is preferably 1:1.1; the mass ratio of the compound represented by the formula 2 to acetonitrile is preferably 1:5.0; the molar ratio of the compound represented by formula 2 to water is preferably 1.5.
The invention provides a preparation method of a compound shown as a formula III-1, which comprises the following steps: in a solvent, reacting a compound shown as a formula II with chlorosulfonyl isocyanate and formamide to obtain a compound shown as a formula III-1,
wherein ring B is a 5-to 6-membered heteroaromatic ring, a 6-to 10-membered aromatic ring, substituted with 1,2 or 3R b Substituted 5-to 6-membered heteroaromatic rings or substituted by 1,2 or 3R b A substituted 6-to 10-membered aromatic ring; the R is b Are each independently C 1 -C 4 An alkyl group;
R y is hydroxy or-NR 1 R 2 ，R 1 And R 2 Are each independently H or COOR 3 ；R 3 Is C 1 -C 4 An alkyl group;
y is O, N or C.
In the preparation method of the compound represented by the formula III-1, the solvent may be a solvent conventional in such reactions in the art. One or more of an ester solvent, an ether solvent, or a nitrile solvent is preferred. More preferably one or more of ethyl acetate, methyl tert-butyl ether or acetonitrile. Further preferred is acetonitrile.
In the method for preparing the compound represented by the formula III-1, the reaction may be carried out in an open system.
In the process for producing the compound represented by the formula III-1, the ring B is preferably a 5-to 6-membered heteroaromatic ring or a 6-to 10-membered aromatic ring. More preferably a 5-to 6-membered heteroaromatic ring. More preferably, the pyrrole ring.
In the preparation method of the compound shown as the formula III-1, R is b Preferably methyl, ethyl, propyl or butyl.
In the preparation method of the compound shown as the formula III-1, R is y Is preferably-NR 1 R 2 Wherein R is 1 And R 2 At least one is H. The R is y More preferably-NH 2 or-NHBoc.
In the process for producing the compound represented by the formula III-1, Y is preferably N.
In the process for the preparation of the compound of formula III-1, the molar ratio of the compound of formula II to formamide may be conventional in the art for such reactions. Preferably 1:2 to 1:5. more preferably 1:3.
in the process for preparing the compound of formula III-1, the molar ratio of the compound of formula II to chlorosulfonyl isocyanate may be conventional in such reactions in the art. Preferably 1:1.0 to 1:2.0. more preferably 1:1.1.
in the preparation method of the compound represented by the formula III-1, the mass ratio of the compound represented by the formula II to the solvent may be conventional in such reactions in the art. Preferably 1:5.0 to 1:20.0. more preferably 1:5.0.
in the preparation method of the compound represented by the formula III-1, the temperature of the reaction may be conventional in the art for such a reaction. Preferably-5 to 5 ℃. More preferably from-5 to 0 ℃. Further preferably-5 ℃ or 0 ℃.
In the preparation method of the compound represented by the formula III-1, the reaction time may be conventional in the art for such reactions. Preferably 0.5 to 24 hours. More preferably 2 to 6 hours. Further preferably 3 hours.
In the preparation method of the compound represented by the formula III-1, the reaction operation may be conventional in the art for such a reaction. The following are preferred: step 1: firstly, mixing the compound shown in the formula II with chlorosulfonyl isocyanate; step 2: and (2) reacting the mixture obtained in the step (1) with formamide.
In the preparation method of the compound represented by the formula III-1, when the compound represented by the formula II is mixed with chlorosulfonyl isocyanate in the step 1, the operation may be conventional in such reactions in the art. The following are preferred: firstly, dissolving the compound shown in the formula II in a solvent, and then adding chlorosulfonyl isocyanate for mixing. The compound of formula II is preferably dissolved in a solvent at room temperature (e.g., 25 ℃). The chlorosulfonyl isocyanate is preferably added dropwise. The chlorosulfonyl isocyanate is preferably added while controlling the temperature at-5 to 5 ℃. More preferably, chlorosulfonyl isocyanate is added while controlling the temperature at 0 ℃. The mixing is preferably temperature-controlled mixing, and the mixing temperature is preferably-5 ℃. More preferably from-5 to 0 ℃. Further preferably-5 ℃. The mixing time is preferably 1 to 3 hours. More preferably 1 hour.
In the method for preparing the compound represented by the formula III-1, when the mixture obtained in the step 1 is reacted with formamide in the step 2, the reaction operation may be conventional in the art. The following are preferred: formamide is added into the mixture obtained in the step 1 to carry out reaction. Formamide is preferably added dropwise to the mixture obtained in step 1. The dropwise addition is preferably completed within 0.5 to 2 hours. More preferably 1 hour. Formamide is added to the reaction product, preferably at a controlled temperature of-5 to 5 ℃. More preferably, formamide is added to the reaction product at a controlled temperature of-5 to 0 ℃. Further preferably formamide is added to the reaction product at-5 ℃. The reaction is preferably temperature-controlled, and the reaction temperature is preferably-5-0 ℃. More preferably-5 ℃. The reaction time is preferably 1 to 3 hours. More preferably 2 hours.
In the preparation method of the compound shown in the formula III-1, a quenching reagent can be added to quench the reaction after the reaction is finished. The quenching reagent may be conventional in the art for such reactions. Water is preferred. The molar ratio of the compound of formula 2 to quenching reagent may be conventional in such reactions in the art. Preferably 1:2. more preferably 1. The quenching reagent can be added and then stirred for 0.5 to 2 hours. Preferably 1 hour. Preferably, the stirring temperature is from-5 to 0 ℃. More preferably, the stirring temperature is-5 ℃.
In the preparation method of the compound shown in the formula III-1, after the reaction quenching, the obtained reaction product can be subjected to reduced pressure concentration to obtain a crude reaction product, wherein the reduced pressure concentration condition can be conventional in the field of such reactions. The temperature of the reduced pressure concentration is preferably 30-40 ℃. Further preferably 30 ℃. The pressure for the concentration under reduced pressure is preferably-0.15 MPa to-0.05 MPa. Further preferably-0.09 MPa. The time for the concentration under reduced pressure is preferably 1 to 6 hours. Further preferably 3 hours.
In the preparation method of the compound shown in the formula III-1, the reaction is quenched and decompressed and concentrated to obtain a crude reaction product which can be directly used for the next reaction.
In some embodiments, in the method for preparing the compound represented by the formula III-1, the reaction is preferably carried out in an open system; ring a is preferably pyrrole; said R is preferably-NHBoc; z is preferably N; the solvent is acetonitrile; the reaction operation is preferably as follows: step 1: firstly, mixing the compound shown in the formula II with chlorosulfonyl isocyanate; step 2: reacting the mixture obtained in the step 1 with formamide; in the step 1, when the compound represented by the formula II is mixed with chlorosulfonyl isocyanate, the operation is preferably as follows: firstly dissolving the compound shown in the formula II in a solvent at the temperature of 25 ℃, then dropwise adding chlorosulfonyl isocyanate at the temperature of 0 ℃, and then controlling the temperature to be-5 ℃ for reaction for 1 hour; in the step 2, when the mixture obtained in the step 1 reacts with formamide, the reaction operation is preferably as follows: controlling the temperature to be minus 5 ℃, dropwise adding formamide into the reaction product, preferably completing dropwise adding within 1 hour, and then controlling the temperature to be minus 5-0 ℃ to react for 2 hours; after the reaction is finished, adding water to quench the reaction, stirring the mixture for 1 hour at the temperature of minus 5 ℃, and then concentrating the mixture for 3 hours under the conditions of the temperature of 30 ℃ and minus 0.09MPa to obtain a crude product of the reaction product, wherein the crude product is directly used for the next reaction; the molar ratio of the compound of formula II to formamide is preferably 1:3; the molar ratio of the compound represented by the formula II to chlorosulfonyl isocyanate is preferably 1:1.1; the mass ratio of the compound represented by the formula II to acetonitrile is preferably 1:5.0; the molar ratio of the compound of formula II to water is preferably 1.5.
The invention provides a preparation method of a Rudexilvir intermediate compound shown in a formula 5, which comprises the following steps:
(1) In a solvent, reacting a compound shown in a formula 2 with chlorosulfonyl isocyanate and formamide to obtain a compound shown in a formula 3;
(2) Carrying out the following reaction on the crude product of the reaction product obtained in the step (1) to obtain a compound shown in a formula 5;
wherein, in the step (1), water quenching is added after the reaction is finished to perform reaction; the definitions of A, R and Z are the same as those of the preparation method of the compound shown in the formula V; the reaction conditions such as the solvent, the amount ratio of each reactant, the reaction temperature, the reaction time, the feeding sequence and the post-treatment are the same as those described in the preparation method of the compound represented by the formula 3; in the (2), the A, R and Z are defined as in the preparation method of the compound shown in the formula V; the reaction conditions such as the solvent, the amount ratio of the reactants, the reaction temperature, the reaction time, the order of addition, and the post-treatment are the same as those described in the above-mentioned method for preparing the compound represented by the formula V.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the synthetic method is novel, after the compound shown in the formula III is reacted, the acetonitrile is recovered through decompression and concentration, an oily crude product is obtained, and the temperature is directly raised to close the ring; and the reaction design of the invention has the following technical advantages:
1. carrying out the next reaction by using excessive formamide for obtaining the compound shown in the formula III by using the compound shown in the formula II for reaction;
2. BOC is removed by using the heat instability heating of the BOC, and then amino is closed;
3. the acetonitrile can be recycled, and no wastewater is generated in the whole synthesis process;
4. the continuous feeding of the reaction is controllable, the conversion rate is high, the reaction steps are short, the production period is short, and the method is environment-friendly.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The reagent information used in the examples is shown in the following table:
example 1: synthesis of Compound 3-1
At 25 deg.C, adding 100g of compound 2-1 (0.548mol, 1.0eq) and 500g of acetonitrile into a reaction bottle, stirring to dissolve, cooling the reaction system to-5 deg.C, adding 85.44g of chlorosulfonyl isocyanate (0.603mol, 1.1eq) into the reaction bottle, dropping at 0 deg.C, holding at-5 deg.C, reacting for 1 hr, and reacting until the raw materials disappear. 74.1g of formamide (1.64mol, 3eq) is added dropwise at the temperature of-5 ℃, the temperature is controlled for 1 hour and the reaction is carried out for 2 hours at the temperature of-5 ℃. 14.8g (0.822mol, 1.5eq.) of water was added dropwise thereto, and the mixture was stirred at 5 ℃ for 1 hour. After stirring, the mixture is concentrated under reduced pressure for 3 hours under the conditions of 30 ℃ and-0.09 MPa to obtain 213g of a compound 3-1 dark crude product (the same batch of the same amount of the crude product is washed and extracted by water to obtain 105g of a product, the yield is 93 percent), and the product is directly used for the next step. 1 HNMR(400MHz,CDCl 3 )δ7.54(s,1H),6.89(d,1H)，6.78(dd,1H)，6.17(dd,1H)，1.49(s,9H).MS(+)：M+1208.11
Example 2: synthesis of Compound 5-1
The crude product of the compound 3-1 prepared in the example 1 is reacted with stirring, the temperature is slowly raised to 90 ℃ for reaction for one hour, the temperature is 100 ℃ for reaction for one hour, the temperature is 110 ℃ for reaction for 8 hours until the raw materials disappear, the crude product is decompressed and concentrated for 3 hours under the conditions of 80 ℃ and 300Pa, the residual formamide is recovered, the temperature is cooled to 70 ℃,300 g of ethanol is added, the temperature is cooled to 0 ℃, the mixture is stirred for one hour and filtered, 52.2g (0.39 mol, the yield is 74.4 percent, the liquid phase purity is 99 percent) of the pure compound 5-1 is obtained, and the yield in two steps is 69.2 percent. 1 HNMR(400MHz,CDCl 3 )δ7.51(s,1H),6.77(d,1H)，6.76(d,1H)，6.30(dd,1H)，1.49(s,9H).MS(+)：M+1135.14。
Claims (10)
1. A process for preparing a compound of formula V, comprising the steps of: in the presence of protonic acid, reacting a compound shown as a formula III with formamide to obtain a compound shown as a formula V,
wherein ring A is a 5-to 6-membered heteroaromatic ring, a 6-to 10-membered aromatic ring, substituted with 1,2 or 3R a Substituted 5-to 6-membered heteroaromatic rings or substituted by 1,2 or 3R a A substituted 6-to 10-membered aromatic ring; said R is a Are each independently C 1 ～C 4 An alkyl group;
R D is-CN, -COOCH 3 -COOH or-CHO;
when R is D When is-CN, R d is-NH 2 (ii) a When R is D is-COOCH 3 When R is d is-C = O; when R is D When it is-COOH, R d is-C = O; when R is D When it is-CHO, R d Is H;
z is N or C;
r is-NR 1 R 2 ，R 1 And R 2 Are each independently H or COOR 3 ；R 3 Is C 1 ～C 4 An alkyl group;
x is N.
2. A process for the preparation of a compound of formula V according to claim 1, wherein the process satisfies one or more of the following conditions:
a) The reaction is carried out under the condition that nitrile is used as a reaction solvent; preferably under the condition of taking acetonitrile as a reaction solvent;
b) The reaction is carried out in an open system;
c) The ring A is a 5-to 6-membered heteroaromatic ring or a 6-to 10-membered aromatic ring; preferably a 5-to 6-membered heteroaromatic ring;
further preferably a pyrrole ring;
d) The R is a Is methyl, ethyl, propyl or butyl;
e) The R is D is-CN;
f) In the R, R 1 And R 2 At least one is H; said R is preferably-NH 2 or-NHBoc;
g) Z is N;
h) The X is N;
i) The protonic acid is an aqueous solution of inorganic acid; preferably an aqueous solution of sulfuric acid, hydrochloric acid, nitric acid or phosphoric acid; further preferably an aqueous solution of sulfuric acid;
j) The molar ratio of the compound shown in the formula III to formamide is 1; preferably 1;
k) The reaction temperature is 80-120 ℃; preferably 85 to 115 ℃; further preferably 90 ℃,100 ℃ or 110 ℃;
l) the reaction time is 5 to 16 hours; preferably 8 to 10 hours; further preferably 8 or 10 hours;
m) after the reaction is completed, post-treatment is also included, and the post-treatment operation comprises the steps of decompressing and concentrating, cooling and recrystallizing the reaction product.
3. A process for the preparation of a compound of formula V according to claim 2, wherein the process satisfies one or more of the following conditions:
n) when the reaction is carried out in the presence of an aqueous solution of a mineral acid, the molar ratio of the compound represented by the formula III to the total amount of water and acid is 1 to 1; preferably the molar ratio of the compound of formula III to the total amount of water and acid is 1.5;
o) the reaction is first carried out at 85 ℃ to 95 ℃ (e.g., 90 ℃) for 0.5 to 2 hours (e.g., 1 hour), then at 95 ℃ to 105 ℃ (e.g., 100 ℃) for 0.5 to 2 hours (e.g., 1 hour), and finally at 105 ℃ to 115 ℃ (e.g., 110 ℃) for 4 to 12 hours (e.g., 8 hours);
p) in the post-treatment, the temperature of the reduced pressure concentration is 70-90 ℃; preferably 80 ℃; the pressure of the reduced pressure concentration is 150 Pa-450 Pa; preferably 300Pa; the time of the decompression concentration is 1 to 6 hours; preferably 3 hours; the cooling is to 60-80 ℃; preferably to 70 ℃; the recrystallization is recrystallization in alcohols; preferably in ethanol; and the recrystallization operation is to add ethanol, cool the mixture to a temperature of between-5 and 5 ℃ (for example, 0 ℃), stir the mixture for 0.5 to 2 hours (for example, 1 hour), and then perform suction filtration, wherein the mass ratio of the compound shown in the formula III to the ethanol is 1: 6-2: 3; preferably, the ratio of 105:300, and (c) a step of cutting;
q) the reaction is carried out in an open system; a is pyrrole; the R is D is-CN; the R is-NHBoc; z is N; the X is N; the acid is preferably sulfuric acid; the molar ratio of the compound shown in the formula III to formamide is 1:3; the molar ratio of the compound shown in the formula III to the acid is 1:1.5; the reaction is firstly carried out for 1 hour at 90 ℃, then carried out for 1 hour at 100 ℃, and finally carried out for 8 hours at 110 ℃; after the reaction is completed, reducing the pressure of the reaction product at 80 ℃ and 300PaConcentrating under pressure for 3 hours, cooling to 70 ℃, adding ethanol, cooling to 0 ℃, stirring for 1 hour, and performing suction filtration, wherein the mass ratio of the compound shown in the formula III to the ethanol is 105:300.
4. a process for the preparation of a compound of formula V according to any one of claims 1 to 3, wherein R is D is-CN; also included is a method for preparing a compound of formula 3, comprising the steps of: in a solvent, reacting a compound shown in a formula 2 with chlorosulfonyl isocyanate and formamide to obtain a compound shown in a formula 3,
wherein rings A, R and Z are as defined in any one of claims 1 to 3.
5. The process for preparing a compound of formula V according to claim 4, wherein in the process for preparing a compound of formula 3, one or more of the following conditions are satisfied:
r) the solvent is one or more of an ester solvent, an ether solvent or a nitrile solvent; preferably one or more of ethyl acetate, methyl tert-butyl ether or acetonitrile; further preferably acetonitrile;
s) the reaction is carried out in an open system;
t) the molar ratio of the compound represented by the formula 2 to formamide is 1:2 to 1:5; preferably 1:3;
u) the molar ratio of the compound represented by the formula 2 to chlorosulfonyl isocyanate is 1:1.0 to 1:2.0; preferably 1:1.1;
v) the mass ratio of the compound represented by the formula 2 to the solvent is 1: 5.0-1: 20.0; preferably 1:5.0;
w) the temperature of the reaction is-5 to 5 ℃; preferably-5 to 0 ℃; further preferably-5 ℃ or 0 ℃;
x) the reaction time is 0.5 to 24 hours; preferably 2 to 6 hours; further preferably 3 hours;
y) the reaction is operated as: step 1: firstly, mixing the compound shown in the formula 2 with chlorosulfonyl isocyanate; step 2: reacting the mixture obtained in the step 1 with formamide;
z) in the preparation method of the compound shown in the formula 3, adding a quenching reagent to quench the reaction after the reaction is finished; the quenching reagent is water; the mol ratio of the compound shown in the formula 2 to the quenching reagent is 1:2; preferably 1; adding the quenching reagent and stirring for 0.5-2 hours; preferably 1 hour; the stirring temperature is-5 to 0 ℃; preferably, the stirring temperature is-5 ℃.
6. The process for preparing a compound of formula V according to claim 5, wherein in the process for preparing a compound of formula 3, one or more of the following conditions are satisfied:
aa) mixing the compound represented by formula 2 with chlorosulfonyl isocyanate in step 1, as follows: dissolving a compound shown as a formula 2 in a solvent, and adding chlorosulfonyl isocyanate for mixing; wherein the compound represented by the formula 2 is dissolved in a solvent at room temperature (e.g., 25 ℃); preferably, chlorosulfonyl isocyanate is added dropwise; controlling the temperature to be-5 ℃, and adding chlorosulfonyl isocyanate; preferably, chlorosulfonyl isocyanate is added while controlling the temperature at 0 ℃; the mixing is temperature-controlled mixing, and the mixing temperature is-5 to 5 ℃; preferably-5 to 0 ℃; further preferably-5 ℃; the mixing time is 1 to 3 hours; preferably 1 hour;
ab) in step 2, the reaction of the mixture obtained in step 1 with formamide is carried out as follows: adding formamide into the mixture obtained in the step 1 for reaction; wherein, formamide is added dropwise into the mixture obtained in the step 1; the dropwise addition is completed within 0.5-2 hours; preferably, the dropwise addition is completed within 1 hour; controlling the temperature to be-5 ℃, and adding formamide into the reaction product; preferably controlling the temperature to be-5-0 ℃, and adding formamide into the reaction product; further preferably, formamide is added into the reaction product at the temperature of-5 ℃; the reaction is temperature-controlled reaction, and the reaction temperature is-5-0 ℃; preferably-5 ℃; the reaction time is 1 to 3 hours; preferably 2 hours;
ac) after the reaction quenching, carrying out reduced pressure concentration on the obtained reaction product to obtain a reaction product crude product, wherein the temperature of the reduced pressure concentration is 30-40 ℃; preferably 30 ℃; the pressure of the reduced pressure concentration is-0.15 MPa to-0.05 MPa; preferably-0.09 MPa; the time for decompression concentration is 1 to 6 hours; preferably 3 hours;
ad) quenching the reaction, and concentrating under reduced pressure to obtain a crude reaction product which is directly used for the next reaction;
ae) the reaction is carried out in an open system; ring a is pyrrole; the R is-NHBoc; z is N; the solvent is acetonitrile; the reaction was carried out as follows: step 1: firstly, mixing the compound shown in the formula 2 with chlorosulfonyl isocyanate; step 2: reacting the mixture obtained in the step 1 with formamide; in the step 1, when the compound represented by the formula 2 is mixed with chlorosulfonyl isocyanate, the operation is as follows: dissolving the compound shown in the formula 2 in a solvent at the temperature of 25 ℃, then dropwise adding chlorosulfonyl isocyanate at the temperature of 0 ℃, and then controlling the temperature to be-5 ℃ for reaction for 1 hour; in the step 2, when the mixture obtained in the step 1 reacts with formamide, the reaction is carried out as follows: controlling the temperature to be minus 5 ℃, dropwise adding formamide into the reaction product, wherein the dropwise adding is completed within 1 hour, and then controlling the temperature to be minus 5-0 ℃ for reacting for 2 hours; after the reaction is finished, adding water to quench the reaction, stirring the mixture for 1 hour at the temperature of minus 5 ℃, and then decompressing and concentrating the reaction product for 3 hours at the temperature of 30 ℃ and under the pressure of minus 0.09MPa to obtain a crude product of the reaction product which is directly used for the next reaction; the molar ratio of the compound shown in the formula 2 to formamide is 1:3; the molar ratio of the compound shown in the formula 2 to chlorosulfonyl isocyanate is 1:1.1; the mass ratio of the compound shown in the formula 2 to acetonitrile is 1:5.0; the molar ratio of the compound represented by the formula 2 to water is 1.5.
7. A method for preparing a compound represented by formula III-1, comprising the steps of: in a solvent, reacting a compound shown as a formula II with chlorosulfonyl isocyanate and formamide to obtain a compound shown as a formula III-1,
wherein ring B is a 5-to 6-membered heteroaromatic ring, a 6-to 10-membered aromatic ring, substituted with 1,2 or 3R b Substituted 5-to 6-membered heteroaromatic rings or substituted by 1,2 or 3R b A substituted 6-to 10-membered aromatic ring; said R is b Are each independently C 1 -C 4 An alkyl group;
R y is hydroxy or-NR 1 R 2 ，R 1 And R 2 Are each independently H or COOR 3 ；R 3 Is C 1 -C 4 An alkyl group;
y is O, N or C.
8. A process for the preparation of a compound of formula III-1 according to claim 7, wherein the process satisfies one or more of the following conditions:
af) the solvent is one or more of ester solvent, ether solvent or nitrile solvent; preferably one or more of ethyl acetate, methyl tert-butyl ether or acetonitrile; further preferably acetonitrile;
ag) the reaction is carried out in an open system;
ah) said ring B is a 5-to 6-membered heteroaromatic ring or a 6-to 10-membered aromatic ring; preferably a 5-to 6-membered heteroaromatic ring; further preferred is a pyrrole ring;
ai) said R b Is methyl, ethyl, propyl or butyl;
aj) said R y is-NR 1 R 2 Wherein R is 1 And R 2 At least one is H; said R is y preferably-NH 2 or-NHBoc;
ak) said Y is N;
al) the molar ratio of the compound of formula II to formamide is 1:2 to 1:5; preferably 1:3;
am) the molar ratio of the compound of formula II to chlorosulfonyl isocyanate is 1:1.0 to 1:2.0 of the total weight of the mixture;
preferably 1:1.1;
an) the mass ratio of the compound shown in the formula II to the solvent is 1:5.0 to 1:20.0; preferably 1:5.0;
ao) the reaction temperature is-5 to 5 ℃; preferably-5 to 0 ℃; further preferably-5 ℃ or 0 ℃;
ap) the reaction time is 0.5 to 24 hours; preferably 2 to 6 hours; further preferably 3 hours;
aq) the reaction was operated as: step 1: firstly, mixing the compound shown in the formula II with chlorosulfonyl isocyanate; and 2, step: reacting the mixture obtained in the step 1 with formamide;
ar) adding a quenching reagent to quench the reaction after the reaction is finished; the quenching reagent is water; the mol ratio of the compound shown in the formula 2 to the quenching reagent is 1:2; preferably 1; adding the quenching reagent and stirring for 0.5-2 hours; preferably 1 hour; the stirring temperature is-5 to 0 ℃; preferably, the stirring temperature is-5 ℃.
9. A process for the preparation of a compound of formula III-1 according to claim 8, wherein the process satisfies one or more of the following conditions:
as) in step 1, the compound of formula II is mixed with chlorosulfonyl isocyanate in the following manner: dissolving a compound shown as a formula II in a solvent, and adding chlorosulfonyl isocyanate for mixing; wherein the compound of formula II is dissolved in a solvent at room temperature (e.g., 25 ℃); preferably, chlorosulfonyl isocyanate is added dropwise; controlling the temperature to be between 5 ℃ below zero and 5 ℃, and adding chlorosulfonyl isocyanate; preferably, chlorosulfonyl isocyanate is added at the temperature of 0 ℃; the mixing is temperature-controlled mixing, and the mixing temperature is-5 ℃; preferably-5 to 0 ℃; further preferably-5 ℃; the mixing time is 1 to 3 hours; preferably 1 hour;
at) in the step 2, when the mixture obtained in the step 1 reacts with formamide, the reaction is carried out as follows: adding formamide into the mixture obtained in the step 1 for reaction; wherein, formamide is added dropwise into the mixture obtained in the step 1; the dropwise addition is completed within 0.5-2 hours; preferably, the dropwise addition is completed within 1 hour; controlling the temperature to be-5 ℃, and adding formamide into the reaction product; preferably controlling the temperature to be-5-0 ℃, and adding formamide into the reaction product; further preferably, formamide is added into the reaction product at the temperature of-5 ℃; the reaction is temperature-controlled reaction, and the reaction temperature is-5-0 ℃; preferably-5 ℃; the reaction time is 1 to 3 hours; preferably 2 hours;
au) after the reaction quenching, carrying out reduced pressure concentration on the obtained reaction product to obtain a reaction product crude product, wherein the temperature of the reduced pressure concentration is 30-40 ℃; preferably 30 ℃; the pressure of the reduced pressure concentration is-0.15 MPa to-0.05 MPa; preferably-0.09 MPa; the time of the decompression concentration is 1 to 6 hours; preferably for 3 hours;
av) quenching the reaction, and concentrating under reduced pressure to obtain a crude reaction product which is directly used for the next reaction;
aw) the reaction is carried out in an open system; ring a is pyrrole; the R is-NHBoc; z is N; the solvent is acetonitrile; the reaction was carried out as follows: step 1: firstly, mixing the compound shown in the formula II with chlorosulfonyl isocyanate; step 2: reacting the mixture obtained in the step 1 with formamide; in the step 1, when the compound represented by the formula II is mixed with chlorosulfonyl isocyanate, the operation is as follows: dissolving the compound shown in the formula II in a solvent at the temperature of 25 ℃, then dropwise adding chlorosulfonyl isocyanate at the temperature of 0 ℃, and then controlling the temperature to be-5 ℃ for reaction for 1 hour; in the step 2, when the mixture obtained in the step 1 reacts with formamide, the reaction is carried out as follows: controlling the temperature to be minus 5 ℃, dropwise adding formamide into the reaction product, wherein the dropwise adding is completed within 1 hour, and then controlling the temperature to be minus 5-0 ℃ for reacting for 2 hours; after the reaction is finished, adding water to quench the reaction, stirring the mixture for 1 hour at the temperature of minus 5 ℃, and then decompressing and concentrating the reaction product for 3 hours at the temperature of 30 ℃ and under the pressure of minus 0.09MPa to obtain a crude product of the reaction product which is directly used for the next reaction; the molar ratio of the compound shown in the formula II to formamide is 1:3; the molar ratio of the compound shown in the formula II to chlorosulfonyl isocyanate is 1:1.1; the mass ratio of the compound shown in the formula II to acetonitrile is 1:5.0; the molar ratio of the compound shown in the formula II to water is 1.5.
10. A method for preparing a compound represented by formula 5, comprising the steps of:
(1) In a solvent, reacting a compound shown in a formula 2 with chlorosulfonyl isocyanate and formamide as follows to obtain a compound shown in a formula 3;
(2) Carrying out the following reaction on the crude product of the reaction product obtained in the step (1) to obtain a compound shown in a formula 5;
wherein, in the step (1), water quenching is added after the reaction is finished to perform reaction; the definitions of A, R and Z are defined in any one of claims 1-6; the reaction conditions such as the solvent, the amount ratio between the reactants, the reaction temperature, the reaction time, the order of addition and the work-up are as defined in any one of claims 4 to 6; in said (2), said A, R and Z are as defined in any one of claims 1 to 6; the reaction conditions such as solvents, the amount ratio between the reactants, the reaction temperature, the reaction time, the order of addition and the work-up are as defined in any one of claims 1 to 3.
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