CN117924314A - Preparation method of Rayleigh Lu Geli intermediate - Google Patents
Preparation method of Rayleigh Lu Geli intermediate Download PDFInfo
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- CN117924314A CN117924314A CN202311859234.7A CN202311859234A CN117924314A CN 117924314 A CN117924314 A CN 117924314A CN 202311859234 A CN202311859234 A CN 202311859234A CN 117924314 A CN117924314 A CN 117924314A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- YPWBPONDYDVMLX-UHFFFAOYSA-N 6-methoxypyridazin-3-amine Chemical compound COC1=CC=C(N)N=N1 YPWBPONDYDVMLX-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 238000007363 ring formation reaction Methods 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- MJXRENZUAQXZGJ-UHFFFAOYSA-N 2-(chloromethyl)-1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1CCl MJXRENZUAQXZGJ-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- CXRJNUVDWUINBY-UHFFFAOYSA-N ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate Chemical compound CCOC(=O)C1=C(N)SC(C=2C=CC(=CC=2)[N+]([O-])=O)=C1C CXRJNUVDWUINBY-UHFFFAOYSA-N 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 35
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 abstract description 10
- 239000012535 impurity Substances 0.000 abstract description 10
- 230000008901 benefit Effects 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 53
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000004821 distillation Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000013067 intermediate product Substances 0.000 description 7
- -1 (2, 6-difluorobenzyl) amino Chemical group 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 6
- 238000004537 pulping Methods 0.000 description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 3
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 125000006508 2,6-difluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C(F)=C1[H])C([H])([H])* 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102000008238 LHRH Receptors Human genes 0.000 description 2
- 108010021290 LHRH Receptors Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 229940090181 propyl acetate Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003021 water soluble solvent Substances 0.000 description 2
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- IEDZUWZMVFTGHG-UHFFFAOYSA-N ethyl acetate;ethyl formate Chemical compound CCOC=O.CCOC(C)=O IEDZUWZMVFTGHG-UHFFFAOYSA-N 0.000 description 1
- UDOUIRSXTJAWOV-UHFFFAOYSA-N ethyl acetate;propyl acetate Chemical compound CCOC(C)=O.CCCOC(C)=O UDOUIRSXTJAWOV-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- AJFDBNQQDYLMJN-UHFFFAOYSA-N n,n-diethylacetamide Chemical compound CCN(CC)C(C)=O AJFDBNQQDYLMJN-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a rui Lu Geli intermediate, belonging to the technical field of synthesis of pharmaceutical intermediates. In order to solve the problem of long and complex existing process route, a preparation method of a Rayleigh Lu Geli intermediate is provided, and the method comprises the steps of carrying out hydrolysis reaction on a compound of a formula III in the presence of an alkaline reagent I to obtain a compound of a formula IV; under the action of a condensing agent, carrying out condensation reaction on a compound shown in a formula IV and a compound shown in a formula V, namely 3-amino-6-methoxypyridazine, in an organic solvent to obtain a Rayleigh Lu Geli intermediate compound shown in a formula VI; reacting a compound of formula VI with a compound of formula VII in the presence of an acid-binding agent to obtain a compound of formula VIII, namely a Rayleigh Lu Geli intermediate. The method can effectively avoid impurities generated by introducing ethoxycarbonyl, has the advantages of simple specific route and easy operation, and the obtained intermediate has the advantages of high product yield and high purity and quality requirements and is environment-friendly.
Description
Technical Field
The invention relates to a preparation method of a rui Lu Geli intermediate, belonging to the technical field of synthesis of pharmaceutical intermediates.
Background
Rayleigh Lu Geli (Relugol ix) is developed by the Wuta-tsu corporation of Japan for the treatment of endometriosis and uterine fibroids, and is an oral gonadotropin-releasing hormone receptor antagonist which blocks gonadotropin-releasing hormone receptors and reduces testosterone production. The synthesis of a key intermediate (compound 6 in the following route) is also very important in the synthesis of rayleigh Lu Geli, and there is mainly the following route for the synthesis of the key intermediate involved, such as one of the rayleigh Lu Geli synthesis routes disclosed in chinese patent application (publication No. CN111423452 a), which is as follows:
In the reaction route, the ethoxycarbonyl is firstly introduced into N on the raw material and then hydrolyzed, and the ethoxycarbonyl introduced into the compound 2 is removed from the ethoxycarbonyl (or called ethyl group) in the ring closing step, but the raw material ethyl chloroacetate adopted in the process of introducing the ethoxycarbonyl has toxicity, has larger environmental pollution and is not beneficial to the production concept of green environmental protection; meanwhile, due to the presence of ethoxycarbonyl on N, partial hydrolysis can occur at the position in the hydrolysis process to generate impurities, so that the quality of an intermediate product is affected. In order to improve the above routes, there are also modifications of synthetic routes to avoid the use of raw materials such as ethyl chloroformate, such as the synthesis of compound 6 by a novel method disclosed in chinese patent application (publication No. CN110194776 a), which synthetic route is as follows:
Although the use of a starting material such as ethyl chloroformate is avoided in this synthetic route, compound 5 is a key intermediate in this process, and compound 6 is obtained by ring closure. The synthetic route of compound 5 is relatively complex in process and relatively long in route.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a preparation method of a Rayleigh Lu Geli intermediate, which solves the problems of simplifying a route, reducing impurities and improving the purity quality of a product.
The invention aims at realizing the following technical scheme, and discloses a preparation method of a Rayleigh Lu Geli intermediate, which is characterized by comprising the following steps of:
A. In the presence of an alkaline reagent I, carrying out hydrolysis reaction on a compound shown in a formula III to obtain a compound shown in a formula IV;
B. Under the action of a condensing agent, carrying out condensation reaction on a compound shown in a formula IV and a compound shown in a formula V, namely 3-amino-6-methoxypyridazine, in an organic solvent to obtain a Rayleigh Lu Geli intermediate compound shown in a formula VI;
C. reacting a compound of formula VI with a compound of formula VII in the presence of an acid-binding agent to obtain a compound of formula VIII, wherein R in the compound of formula VII is selected from hydrogen (H) or nitro (-NO 2);
The method is characterized in that the hydrolysis reaction is directly carried out on the raw material compound in the formula III under the action of an alkaline reagent, the carboxylic acid ethyl ester group is hydrolyzed into a carboxylic acid group, and H on NH in the compound in the formula III is not required to be substituted by ethyl chloroformate or the like to form ethoxycarbonyl before the hydrolysis, so that the process of subsequent hydrolysis after the ethoxycarbonyl is formed can be effectively avoided, and the ethoxycarbonyl on N is partially hydrolyzed to form the following impurities:
The presence of these impurities can affect the quality and purity of the intermediate product; the method has the advantages that the method effectively avoids the products of the impurities, has the advantages of simple specific route and easy operation, and the obtained intermediate has the advantages of high product yield, high purity and quality requirement and environmental friendliness; in the last step of ring closing process, R in the compound of the formula VII is selected from hydrogen or nitro, corresponding groups can be introduced and the ring closing is formed in the presence of an acid binding agent, the reaction is easy to carry out, the advantage of high intermediate product yield can be better realized, the single-step yield is high, the single-step product yield in the step A reaches 80%, the purity reaches more than 99%, and the total yield is also higher.
In the above preparation method of the intermediate of Rayleigh Lu Geli, preferably, the condensing agent in the step B is selected from one or more of N, N' -diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The reaction is more thorough by more effectively proceeding the reaction, and impurities in the reaction process are easy to remove, so that the method has the effects of high product yield and purity quality. Further preferably, the molar ratio of the compound of formula iv to the condensing agent is 1:1.5 to 2.5, preferably with a molar ratio of 1:1.8 to 2.0. The molar ratio of the compound of formula IV to the 3-amino-6-methoxypyridazine of formula V is 1:1.0 to 1.5, more preferably the molar ratio is 1:1.1 to 1.3.
In the above process for producing the intermediate of Rayleigh Lu Geli, the temperature of the condensation reaction in the step B is preferably 10 to 70 ℃.
In the preparation method of the intermediate of the Rayleigh Lu Geli, the organic solvent adopted in the condensation reaction can lead the reaction to be carried out more uniformly, wherein the organic solvent can be halogenated alkane, ether solvent, nitrile solvent, amide solvent, ester solvent and the like, the halogenated alkane can be methylene dichloride, chloroform and the like, the ether solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane and the like, the nitrile solvent can be acetonitrile, propionitrile and other amide solvents can be N, N-dimethylacetamide, N-dimethylformamide, N-diethylformamide or N, N-diethylacetamide and the like, and the ester solvent can be ethyl acetate ethyl formate, propyl acetate ethyl acetate, propyl acetate, isopropyl acetate and other solvents; preferably, the organic solvent in the step B is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, acetonitrile, N-dimethylacetamide, N-dimethylformamide, isopropyl acetate and ethyl acetate.
As a further preferable mode, the hydrolysis reaction in the step A further comprises post-treatment, wherein the post-treatment is to add acid into the reaction liquid to adjust the pH value to 6-7, then add a water-insoluble organic solvent for extraction and purification, and the intermediate product of the compound shown in the formula IV is obtained. The water-insoluble organic solvent is selected from ethyl acetate, propyl acetate, etc. The purification can be carried out by beating and purifying methyl tertiary butyl ether. The method can better remove water-soluble impurities, is favorable for reducing the introduction of the impurities into the next reaction, and improves the purity and quality of the product. The temperature of the hydrolysis reaction is controlled to be 40-70 ℃, preferably 50-60 ℃.
The hydrolysis reaction is preferably carried out by adding a water-soluble solvent, which is equivalent to the hydrolysis reaction in a system of mixing water and the water-soluble solvent, for example, one or more of methanol, ethanol, propanol and isopropanol in an alcohol solvent can be adopted; and can be selected from tetrahydrofuran or 2-methyltetrahydrofuran solvent, and nitrile solvent such as acetonitrile and propionitrile can be used. An alcohol solvent is preferably used as the reaction solvent.
In the above preparation method of the intermediate of rayleigh Lu Geli, preferably, the hydrolysis reaction in step a is performed in the presence of water, and the alkaline agent is one or more selected from sodium hydroxide, potassium hydroxide and carbonate. The carbonate herein may be sodium carbonate, potassium carbonate, or the like.
In the above preparation method of the intermediate of Rayleigh Lu Geli, preferably, the compound of formula III in the step A: the molar ratio of the alkaline reagent I is 1:1.2 to 1.6. The water consumption in the system is 2-7 times of the alkaline reagent mass consumption.
In the preparation method of the intermediate of the Rayleigh Lu Geli, preferably, the acid-binding agent in the step C is one or more selected from sodium hydroxide, potassium hydroxide and carbonate; the ring closure reaction is in the presence of water. The reaction can be more favorably carried out by neutralizing small molecular acid formed in the reaction process by the acid binding agent.
In the above preparation method of the intermediate of Rayleigh Lu Geli, preferably, the compound of formula III in the step A is synthesized by the following method:
In the presence of an alkaline reagent II, coupling reaction is carried out on a compound of formula I, namely 2-amino-4-methyl-5- (4-nitrophenyl) -3-thiophenecarboxylic acid ethyl ester, and a compound of formula II, namely 2, 6-difluorobenzyl chloride, so as to obtain an intermediate compound of formula III;
In the above preparation method of the intermediate of Rayleigh Lu Geli, preferably, the coupling reaction is carried out in a solvent, and the solvent is one or more selected from acetonitrile, toluene, N-dimethylformamide and N, N-dimethylacetamide. The amount of the solvent may be any amount according to the amount of the solvent required for general reaction in the art.
In the preparation method of the intermediate of the Rayleigh Lu Geli, preferably, the temperature of the coupling reaction is 70-110 ℃, preferably 80-100 ℃; the temperature of the ring closing reaction is 0-10 ℃.
In the preparation method of the intermediate of the above-mentioned Rayleigh Lu Geli, preferably, the alkaline reagent is one or more selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and carbonate. The carbonate in this case may be sodium carbonate, potassium carbonate or the like.
In the preparation method of the intermediate of the Rayleigh Lu Geli, preferably, the molar ratio of the compound of the formula I, namely the ethyl 2-amino-4-methyl-5- (4-nitrophenyl) -3-thiophenecarboxylate, to the compound of the formula II, namely the 2, 6-difluorobenzyl chloride, is 1:1.0 to 1.5, preferably 1:1.1 to 1.3. Further, it is preferable to make the molar ratio of the compound of formula I to the alkaline agent II be 1:1.4 to 2.0.
In the preparation method of the Rayleigh Lu Geli intermediate, the structural formula of the compound of the formula VII in the step C when R is H or-NO 2 is as follows:
The preparation method of the intermediate of the invention can be represented by the following reaction equation:
in summary, compared with the prior art, the invention has the following advantages:
1. According to the invention, through hydrolysis of raw materials, impurities generated by introducing ethoxycarbonyl can be effectively avoided, the specific route is simple and easy to operate, the obtained intermediate has the advantages of high product yield and high purity and quality requirements, the method is environment-friendly, and the purity of the intermediate IV compound in the step of hydrolysis reaction reaches more than 99%.
2. In the ring closing process, R in the compound of the formula VII is selected from hydrogen or nitro, corresponding groups can be introduced and the ring is formed in the presence of an acid binding agent, the reaction is easy to carry out, and the advantage of high yield of intermediate products can be better realized.
Drawings
FIG. 1 is a mass spectrum of a compound VI obtained in example 3 of the present invention.
Detailed Description
The technical scheme of the present invention will be further specifically described by means of specific examples and drawings, but the present invention is not limited to these examples.
Example 1
The specific preparation method of the compound III comprises the following steps:
400g of acetonitrile is added into a clean reaction bottle, 100g (0.327 mol,1.0 eq), 63.51g (0.3992 mol,1.2 eq) of 2, 6-difluorobenzyl chloride and 27.5g (0.49 mol,1.5 eq) of potassium hydroxide are added into the clean reaction bottle under stirring at room temperature, then the reaction is carried out for 18 hours under the conditions of heating to 80 ℃ and controlling the temperature to 75-80 ℃, TLC is adopted for monitoring the reaction, the reaction is confirmed to be complete, after the reaction is completed, the room temperature is reduced, the pH value of the reaction solution is regulated to 6-7 by using 6N hydrochloric acid solution under stirring, the reduced pressure distillation is carried out at 40 ℃ to remove the acetonitrile, then ethyl acetate and water are added for three times (500 g of ethyl acetate and 300g of water are added each time), the collected organic phases are combined, reduced pressure distillation is carried out at 40 ℃ to remove about 1380g of ethyl acetate, 360g of N-heptane is added, the mixed solution is heated to 60 ℃, the temperature is kept and stirred for 30min, the mixture is dissolved, then the temperature is slowly reduced to 10 ℃, stirring is carried out for 10h, full crystallization is carried out, solid is separated out, the mixed solution is filtered, a filter cake is washed by 120g of ethyl acetate and N-heptane with the same proportion, the obtained intermediate product wet product is dried for 12h under the vacuum condition of 70 ℃ to obtain a dry yellow crystal compound III, the yield is 120g, the yield is 85%, and the HPLC purity is 99.1%.
Example 2
The specific preparation method of the compound IV comprises the following steps:
Adding 330g of 95% ethanol solvent into a clean reaction bottle, sequentially adding 110g of compound III (0.255 mol,1.0 eq) under stirring, dropwise adding aqueous potassium hydroxide solution (60 g of water and 20g of potassium hydroxide are prepared into aqueous potassium hydroxide solution in advance), heating to 55 ℃ after the addition, carrying out heat preservation reaction for 16h, adopting a TLC plate to monitor the reaction in the reaction process, confirming that the reaction is complete, cooling the system to room temperature after the reaction is finished, regulating the pH of the reaction solution to about 7 by using 6N hydrochloric acid, carrying out normal pressure distillation at 80 ℃ to remove the ethanol solvent, adding 400g of ethyl acetate and 200g of water into the residues for each extraction, merging the organic phases collected each time, carrying out reduced pressure distillation to remove the ethyl acetate at 40 ℃, then adding 330g of methyl tert-butyl ether, carrying out pulping treatment at 45 ℃ for 6h, slowly cooling to room temperature, filtering after the completion, washing the obtained filter cake by using 110g of methyl tert-butyl ether, carrying out wet distillation at 60 ℃ to obtain a dry product with the purity of 98.87%, and carrying out vacuum drying at 60% of the dry product, wherein the purity is 98.87.95%.
Example 3
The specific preparation method of the compound VI is as follows:
340g of acetonitrile, 85g (0.21 mol,1.0 eq) of compound IV and 34.14g (0.273 mol,1.3 eq) of 3-amino-6-methoxypyridazine are sequentially weighed and put into a clean reaction bottle, replaced by nitrogen for 2 times, under the protection of nitrogen, 53g (0.42 mol,2.0 eq) of condensing agent N, N' -diisopropylcarbodiimide is dropwise added, the nitrogen is replaced once after the dropwise addition, the temperature is raised to 60 ℃ and controlled to react for 12h, TLC monitoring reaction is carried out to confirm that the reaction is completed, the temperature is reduced to 40 ℃ after the reaction is completed, acetonitrile is removed by reduced pressure distillation, and 85g of 95% ethanol and 340g of water are added into residues, then pulping for 3h at 50 ℃, cooling to 10 ℃, stirring for 2h, filtering the mixed solution, washing the obtained filter cake with 50g of mixed solvent of water and ethanol in the same proportion, putting the wet product into a vacuum dryer at 75 ℃ for drying treatment for 18h to obtain a dry white solid compound VI 2- ((2, 6-difluorobenzyl) amino) -N- (6-methoxypyridazin-3-yl) -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxamide, wherein the yield is 96g, the yield is 89.4%, and the HPLC purity is 98.8%.
The obtained product of the compound VI is subjected to mass spectrum analysis, and the mass spectrum result shows that the molecular weight of [ M+/-1 ] is 512.15[ M+H +],520.90[M-H- ] and the molecular weight of the compound VI is 511.11, respectively, as shown in the figure 1.
Example 4
Synthesis of Rayleigh Lu Geli intermediate Compound of formula VIII:
Adding 50g of water and 100g of acetone into a clean reaction bottle, adding 51.1g (0.1 mol) of a compound shown in a formula VI, 18.8g (0.12 mol) of phenyl chloroformate and 12.7g (0.12 mol) of sodium carbonate, carrying out a ring closing reaction for 5 hours under the condition of 0-5 ℃ under stirring and cooling control temperature, removing solvent acetone through reduced pressure distillation after the reaction is finished, adding 400g of ethyl acetate and 200g of water for extraction, washing the obtained organic phase sequentially with 300ml of 1N hydrochloric acid and 300ml of saturated saline, adding anhydrous sodium sulfate into the organic phase for drying, filtering, concentrating and drying the obtained filtrate to obtain a crude product, pulping and purifying with 500ml of methyl tertiary butyl ether for 3 hours, filtering, and drying a filter cake to obtain a corresponding Rayleigh Lu Geli-methyl-6- (4-nitrophenyl) thiophene [2,3-d ] pyrimidine-2, 4H-1 g with the yield of 1- (2, 6-difluorobenzyl) -3- (6-methoxypyridin-3-yl) thiophene as an intermediate compound, wherein the yield is 77.1.3.1 g, and the purity is 77.41%.
Example 5
The specific preparation method of the compound IV comprises the following steps:
Adding 330g of methanol solvent into a clean reaction bottle, sequentially adding 110g (0.255 mol,1.0 eq) of compound III under stirring, dropwise adding aqueous sodium hydroxide solution (70 g of water and 22g of potassium hydroxide are weighed and prepared into aqueous sodium hydroxide solution in advance), heating to 60 ℃ after the addition is finished, keeping the temperature for reaction for 14 hours, adopting a TLC plate to monitor the reaction in the reaction process, confirming that the reaction is complete, cooling the system to room temperature after the reaction is finished, regulating the pH value of the reaction solution to be about 7 by using 6N hydrochloric acid, performing normal pressure distillation at 80 ℃ to remove the methanol solvent, adding 350g of ethyl acetate and 300g of water into the residues for extraction, merging the organic phases collected each time, performing reduced pressure distillation at 40 ℃ to remove the ethyl acetate, adding 350g of methyl tert-butyl ether, pulping at 45 ℃ for 6 hours, slowly cooling to room temperature, stirring for 3 hours, filtering, washing the obtained methyl tert-butyl ether 100g, obtaining an intermediate compound, controlling the wet filter cake at 60 ℃ and performing vacuum drying at 89 ℃ for 98.8% of dry yield, and obtaining the product with the purity of 98.8% by using HPLC.
The specific preparation method of the compound VI comprises the following steps:
330g of N, N-dimethylformamide solvent, 85g (0.21 mol,1.0 eq) of compound IV and 39.39g (0.315 mol,1.5 eq) of 3-amino-6-methoxypyridazine are sequentially weighed and put into a clean reaction bottle, replaced by nitrogen for 2 times, under the protection of nitrogen, 81.5g (0.53 mol,2.5 eq) of condensing agent 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide is dropwise added, after the dropwise addition, the nitrogen is replaced once, the temperature is raised to 70 ℃ and controlled to be within the range of 65-70 ℃ for reaction for 10 hours, TLC monitoring reaction is carried out, after the reaction is finished, the temperature is reduced to 40 ℃, the N, N-dimethylformamide solvent is removed by reduced pressure distillation, 100g of propanol and 300g of water are added into the residue, pulping is carried out for 3h at 50 ℃, the temperature is reduced to 10 ℃ and stirring is carried out for 3h, then filtering is carried out, the obtained filter cake is washed by 50g of mixed solvent of water and propanol with the same proportion, the obtained wet product is put into a vacuum dryer at 75 ℃ and is dried for 18h under vacuum, and the dry white solid compound VI 2- ((2, 6-difluorobenzyl) amino) -N- (6-methoxypyridazin-3-yl) -4-methyl-5- (4-nitrophenyl) thiophene-3-carboxamide is obtained, the yield is 96.8g, the yield is 90.1%, and the HPLC purity is 98.4%.
Synthesis of Rayleigh Lu Geli intermediate Compound of formula VIII:
Adding 50g of water and 100g of acetone into a clean reaction bottle, adding 51.1g (0.1 mol) of the synthesized compound shown in the formula VI, 26.2g (0.13 mol) of p-nitrophenyl chloroformate and 15.9g (0.15 mol) of sodium carbonate, carrying out a ring closing reaction for 5 hours under the condition of stirring and cooling control temperature of 0-5 ℃, removing solvent acetone through reduced pressure distillation after the reaction is finished, adding 400g of ethyl acetate and 200g of water for extraction, washing the obtained organic phase sequentially with 300ml of 1N hydrochloric acid and 300ml of saturated saline solution, adding anhydrous sodium sulfate into the organic phase for drying, filtering, concentrating the obtained filtrate to obtain a crude product, pulping and purifying with 500ml of methyl tertiary butyl ether for 3 hours, filtering, and drying a filter cake to obtain the corresponding intermediate compound shown in the formula VIII 1- (2, 6-difluorobenzyl) -3- (6-methoxypyridazin-3-yl) -5-methyl-6- (4-nitrophenyl) thiophene [2,3-d ] pyrimidine (2, 3-d ] pyrimidine-2, 4, 2, 4H-7.80%, wherein the purity is 98.80%, and the yield is 3.80.8%.
Example 6
The specific preparation method of the compound III comprises the following steps:
400g of toluene solvent and 100g (0.327 mol,1.0 eq), 69g (0.425 mol,1.3 eq) of 2, 6-difluorobenzyl chloride and 51.9g (0.49 mol,1.5 eq) of sodium carbonate are added into a clean reaction bottle under stirring at room temperature, then the reaction is carried out under the conditions of heating to 65 ℃ and controlling the temperature to 65 ℃ to 70 ℃ for 16h, TLC is adopted to monitor the reaction, after the reaction is completed, the temperature is reduced to room temperature, the pH value of the reaction solution is regulated to 6 to 7 by using a 6N hydrochloric acid solution under stirring, toluene is removed by reduced pressure distillation, then ethyl acetate and water are added into the reaction solution for three times (500 g of ethyl acetate and 300g of water are added each time), the collected organic phases are combined, reduced pressure distillation is carried out at 40 ℃ to remove about 1400g of ethyl acetate, 360g of N-heptane is added, the mixture is heated to 60 ℃, the temperature is kept and stirred for 30min, the mixture is dissolved, then the temperature is slowly reduced to 10 ℃, stirring is carried out for 10h, full crystallization is carried out, solids are separated out, filtration is carried out, a filter cake is washed by 120g of mixed solvent of ethyl acetate and N-heptane (volume ratio is 1:1), the obtained intermediate product wet product is dried for 12h under the vacuum condition of 70 ℃, and the dry product yellow crystal compound III is obtained, the yield is 118.7g, the yield is 84.1%, and the HPLC purity is 99.2%.
Example 7
The specific preparation method of the compound VI comprises the following steps:
340g of acetonitrile, 85g (0.21 mol,1.0 eq) of compound IV and 28.87g (0.231 mol,1.1 eq) of 3-amino-6-methoxypyridazine are sequentially weighed and put into a clean reaction bottle, replaced by nitrogen for 2 times, under the protection of nitrogen, 53g (0.42 mol,2.0 eq) of condensing agent N, N' -diisopropylcarbodiimide is dropwise added, nitrogen is replaced once after the dropwise addition, the temperature is raised to 60 ℃ and controlled to react for 12 hours, TLC monitors the reaction, the temperature is reduced to 40 ℃, reduced pressure distillation is carried out to remove acetonitrile, 90g of methanol and 340g of water are added into the residue, then the temperature is controlled to pulp for 3 hours at 50 ℃, the temperature is reduced to 10 ℃, the mixture is stirred for 2 hours, then filtered, the obtained filter cake is washed by 50g of mixed solvent of the same proportion of water and methanol, the wet product is put into a vacuum drier at 75 ℃ for drying treatment for 18 hours, and the dry white solid compound VI 2- ((2, 6-difluorobenzyl) -N- (6-methoxy) -pyridazine with the purity of 4-3.98-4-3.87% and the yield of thiophene is high purity of 3.98%.
The specific embodiments described herein are offered by way of illustration only. Those skilled in the art may make various modifications or additions to the described embodiments or substitutions thereof without departing from the spirit of the invention or exceeding the scope of the invention as defined in the accompanying claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (10)
1. A method for preparing a rayleigh Lu Geli intermediate, which is characterized by comprising the following steps:
A. In the presence of an alkaline reagent I, carrying out hydrolysis reaction on a compound shown in a formula III to obtain a compound shown in a formula IV;
B. Under the action of a condensing agent, carrying out condensation reaction on a compound in the formula IV and a compound in the formula V, namely 3-amino-6-methoxypyridazine, in an organic solvent to obtain an intermediate compound in the formula VI;
C. in the presence of an acid binding agent, carrying out ring closure reaction on a compound of a formula VI and a compound of a formula VII to obtain an intermediate compound of a formula VIII, wherein R in the compound of the formula VII is selected from hydrogen or nitro;
2. The method for preparing a Rayleigh Lu Geli intermediate according to claim 1, wherein the condensing agent in step B is selected from one or more of N, N' -diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
3. The process for preparing a Rayleigh Lu Geli intermediate according to claim 2, wherein the temperature of the condensation reaction in step B is 10℃to 70 ℃.
4. The method for preparing a Rayleigh Lu Geli intermediate according to claim 1, wherein the organic solvent in the step B is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, acetonitrile, N-dimethylacetamide, N-dimethylformamide, isopropyl acetate and ethyl acetate.
5. The method for preparing a Rayleigh Lu Geli intermediate according to claim 1, wherein the hydrolysis reaction in step a is carried out in the presence of water, and the alkaline agent is one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide and carbonate.
6. The method for preparing a Rayleigh Lu Geli intermediate according to claim 1, wherein the acid-binding agent in step C is one or more selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide and carbonate; the ring closure reaction is in the presence of water.
7. The process for the preparation of the intermediate of claim Lu Geli according to any one of claims 1 to 6, wherein the compound of formula iii in step a is synthesized by:
In the presence of an alkaline reagent II, coupling reaction is carried out on a compound of formula I, namely 2-amino-4-methyl-5- (4-nitrophenyl) -3-thiophenecarboxylic acid ethyl ester, and a compound of formula II, namely 2, 6-difluorobenzyl chloride, so as to obtain an intermediate compound of formula III;
8. The method for preparing the intermediate of claim 7, wherein the coupling reaction is performed in a solvent selected from one or more of acetonitrile, toluene, N-dimethylformamide and N, N-dimethylacetamide.
9. The method for preparing a Rayleigh Lu Geli intermediate according to claim 8, wherein the temperature of the coupling reaction is 70-110 ℃; the temperature of the ring closing reaction is 0-10 ℃.
10. The method for preparing a Rayleigh Lu Geli intermediate according to claim 7, wherein the alkaline reagent II is one or more selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and carbonate.
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