CN115650950A - Rui Lu Geli intermediate and preparation method thereof, and amide condensation method - Google Patents
Rui Lu Geli intermediate and preparation method thereof, and amide condensation method Download PDFInfo
- Publication number
- CN115650950A CN115650950A CN202211368606.1A CN202211368606A CN115650950A CN 115650950 A CN115650950 A CN 115650950A CN 202211368606 A CN202211368606 A CN 202211368606A CN 115650950 A CN115650950 A CN 115650950A
- Authority
- CN
- China
- Prior art keywords
- formula
- geli
- rui
- structure shown
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 150000001408 amides Chemical class 0.000 title claims abstract description 23
- 238000009833 condensation Methods 0.000 title claims abstract description 17
- 230000005494 condensation Effects 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 239000000543 intermediate Substances 0.000 claims abstract description 53
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000006482 condensation reaction Methods 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 16
- 239000004202 carbamide Substances 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 14
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 13
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- YPWBPONDYDVMLX-UHFFFAOYSA-N 6-methoxypyridazin-3-amine Chemical compound COC1=CC=C(N)N=N1 YPWBPONDYDVMLX-UHFFFAOYSA-N 0.000 claims description 11
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 9
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- -1 amine ester Chemical class 0.000 abstract description 3
- 125000003277 amino group Chemical group 0.000 abstract description 3
- FWVCSXWHVOOTFJ-UHFFFAOYSA-N 1-(2-chloroethylsulfanyl)-2-[2-(2-chloroethylsulfanyl)ethoxy]ethane Chemical compound ClCCSCCOCCSCCCl FWVCSXWHVOOTFJ-UHFFFAOYSA-N 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 238000003756 stirring Methods 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 5
- 229940011051 isopropyl acetate Drugs 0.000 description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000002585 base Substances 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- AOMXMOCNKJTRQP-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN(C)C)C(C(=O)N(C=2N=NC(OC)=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 AOMXMOCNKJTRQP-UHFFFAOYSA-N 0.000 description 2
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 229950004238 relugolix Drugs 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 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 relates to the technical field of drug intermediates, and provides a Rui Lu Geli intermediate, a preparation method thereof and an amide condensation method. According to the invention, the hydrolysis reaction in the conventional synthetic route of Rui Lu Geli is carried out in the front position, namely the compound with the structure shown in formula II is directly hydrolyzed to obtain the Rui Lu Geli intermediate with the structure shown in formula I, and because the amino group has an extremely strong electron-donating effect, the activity of the amine ester in the compound with the structure shown in formula II can be reduced, so that the amine ester is not easily influenced by hydrolysis. In addition, the invention also provides acylThe invention relates to a method for condensing amines, which uses the expensive condensing agent T used in the traditional method 3 P is replaced by a condensing agent with low price, so that the cost can be obviously reduced, and the method is more favorable for industrial production.
Description
Technical Field
The invention relates to the technical field of drug intermediates, in particular to a Rui Lu Geli intermediate, a preparation method thereof and an amide condensation method.
Background
Rui Lu Geli (Relugolix, CAS: 737789-87-6), chemical name: n- [4- [1- [ (2,6-difluorophenyl) methyl ] -5- [ (dimethylamino) methyl ] -1,2,3,4-tetrahydro-3- (6-methoxy-3-pyridazinyl) -2,4-dioxothieno [2,3-D ] pyrimidin-6-yl ] phenyl ] -N' -methoxyurea, having the structural formula shown in formula A, was developed by Wutian pharmaceuticals and ASKA Pharmaceutical for the treatment of uterine fibroids and advanced prostate cancer, and is currently the first and only oral gonadotropin releasing hormone (GnRH) receptor antagonist therapy. Myovant Sciences and Sunovion Pharmaceuticals signed a distribution agreement of Rui Lu Geli for prostate cancer in the United states on 08/05 of 2020.
The Chinese patent CN114230576A discloses the following method: the amino group of the compound 1 is protected by BOC to obtain a compound 2 with the yield of 93.5 percent; heating the compound 2 in an ethanol and potassium hydroxide aqueous solution at 40 ℃ for 24 hours to react to prepare a compound 3 with a yield of 91.7 percent; compound 3 in condensing agent 1-propylphosphoric cyclic anhydride (T) 3 P) and 3-amino-6-methoxypyridazine react by amide condensation in the presence of P) to generate a compound 4 with the yield of 86.5 percent; deprotection of compound 4 gave compound 5 in 90.1% yield; compound 5 is prepared into compound 6 through urea condensation reaction, and the yield is 93.1%; cyclizing the compound 6 under the alkaline condition to obtain Rui Lu Geli with the yield of 94.9%. In the route, a strong alkaline system exists, the reaction is carried out by heating for a long time at 40 ℃, and the amine ester group in the compound B is partially hydrolyzed, so that the yield is reduced; on the other hand, when compound E is used for synthesizing intermediate F of Ry Lu Geli, the condensing agent used is expensive T 3 P, which is not beneficial to reducing the cost; and this method requires protection of the amino group firstThen deprotection, protection and deprotection are carried out, so that the reaction steps are more complicated, and the yield of the target product is reduced.
In conclusion, the existing preparation method of Rui Lu Geli has the problems of low yield, high cost and complicated steps, and a new preparation method of Rui Lu Geli is urgently to be developed, so that the yield is improved, and the preparation cost is reduced.
Disclosure of Invention
In view of the above, the invention provides a Rui Lu Geli intermediate, a preparation method thereof and an amide condensation method. The Rui Lu Geli synthesized by the Rui Lu Geli intermediate provided by the invention has the advantages of high product yield, low cost and short synthetic route.
In order to achieve the above object, the present invention provides the following technical solutions:
a Rui Lu Geli intermediate having a structure according to formula I:
in formula I: r 1 Is C 1 ～C 6 An alkyl group.
The invention also provides a preparation method of the Rui Lu Geli intermediate in the scheme, which comprises the following steps:
mixing a compound with a structure shown in a formula II, alkali and a solvent for hydrolysis reaction to obtain a Rui Lu Geli intermediate with a structure shown in a formula I;
in formula II: r is 1 Is C 1 ～C 6 Alkyl radical, R 2 Is C 1 ～C 6 An alkyl group.
Preferably, the alkali is one or two of sodium hydroxide and potassium hydroxide; the molar ratio of the compound with the structure shown in the formula II to the alkali is 1 (1-3).
Preferably, the solvent is a mixed solvent of water and an organic solvent, and the volume ratio of the organic solvent to the water in the mixed solvent is (0.1-10): 1.
Preferably, the temperature of the hydrolysis reaction is 10-100 ℃, and the time is 2-30 h.
The invention also provides a method for synthesizing a Rui Lu Geli intermediate with a structure shown in a formula III by using the Rui Lu Geli intermediate with the structure shown in the formula I, which comprises the following steps:
mixing a Rui Lu Geli intermediate with a structure shown in a formula I, methoxylamine hydrochloride, N' -carbonyl diimidazole, alkali and a solvent to perform a urea condensation reaction to obtain a Rui Lu Geli intermediate with a structure shown in a formula III;
in formula III: r is 1 Is C 1 ～C 6 An alkyl group.
Preferably, the molar ratio of the N, N' -carbonyldiimidazole to the intermediate Ruyi Lu Geli having the structure shown in formula I is (1-4): 1; the molar ratio of the methoxylamine hydrochloride to the intermediate of Rui Lu Geli with the structure shown in the formula I is (1-4) to 1; the alkali is one or more of triethylamine, N-methylmorpholine, N-methylpyrrolidine, pyridine and triethylene diamine; the molar ratio of the alkali to the intermediate of Rui Lu Geli with the structure shown in formula I is (1-4): 1.
The invention also provides an amide condensation method, which comprises the following steps:
mixing a compound with a structure shown in a formula IV, 3-amino-6-methoxypyridazine, a condensing agent and a solvent to perform an amide condensation reaction to obtain a compound with a structure shown in a formula V; the condensing agent is one or more of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, diisopropylcarbodiimide and dicyclohexylcarbodiimide;
in formulas IV to V: r is 1 Is C 1 ～C 6 An alkyl group; r 3 Is H, C 1 ～C 3 Alkyl or-CH 2 N(CH 3 ) 2 ，R 4 is-NO 2 or-NHCONHOCH 3 。
Preferably, the molar ratio of the compound having the structure represented by formula IV to the condensing agent is 1 (1-5).
The invention also provides a synthetic method of the Rui Lu Geli, which comprises the following steps:
preparing a Rui Lu Geli intermediate having the structure of formula III according to the method of claim 6;
the method of claim 8 or 9 for preparing R from a Rui Lu Geli intermediate having a structure shown in formula III 4 is-NHCONHOCH 3 、R 3 is-CH 2 N(CH 3 ) 2 、R 1 Is C 1 ～C 6 A compound having a structure represented by formula V;
and (3) carrying out cyclization reaction on the compound with the structure shown in the formula V under alkaline conditions to obtain Rui Lu Geli.
The invention provides a Rui Lu Geli intermediate, the structural formula is shown as formula I; when the intermediate of Rui Lu Geli shown in formula I is used for synthesizing Rui Lu Geli, the target product can be obtained only by three reactions of urea condensation, amide condensation and cyclization, and the synthesis method is short in synthesis route and low in cost.
The invention also provides a preparation method of the Rui Lu Geli intermediate in the scheme, the Rui Lu Geli intermediate with the structure shown in formula I is obtained by hydrolysis reaction of a compound with the structure shown in formula II, in a synthesis route of Rui Lu Geli commonly used in the field, urea condensation is usually carried out on the compound with the structure shown in formula I, and then hydrolysis reaction is carried out, or amino is protected by a protective group and then hydrolyzed, the hydrolysis reaction is carried out in the invention, namely the compound with the structure shown in formula II is directly hydrolyzed to obtain the Rui Lu Geli intermediate with the structure shown in formula I, because the amino has a strong electron donating effect, the activity of the aminoester in the compound with the structure shown in formula II can be reduced, so that the aminoester is not easily influenced by hydrolysis, and in addition, compared with a urea group, the amino is not influenced by hydrolysis, and under the two reasons, the yield of the hydrolysis reaction is remarkably improved.
The invention also provides an amide condensation method, the compound with the structure shown in the formula IV and 3-amino-6-methoxypyridazine are subjected to amide condensation to obtain the compound with the structure shown in the formula V, and the condensing agent adopted in the condensation reaction is one or more of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, diisopropylcarbodiimide and dicyclohexylcarbodiimide. The invention uses the expensive condensing agent T adopted in the traditional method 3 The P is replaced by the condensing agent with low price, so that the cost can be obviously reduced, and the industrial production is more facilitated.
Detailed Description
The invention provides a Rui Lu Geli intermediate, which has a structure shown in a formula I:
in formula I: r 1 Is C 1 ～C 6 Alkyl, preferably C 1 ～C 3 Alkyl, more preferably methyl, ethyl or propyl; the propyl group is preferably an n-propyl group.
The invention also provides a preparation method of the Rui Lu Geli intermediate in the scheme, which comprises the following steps:
mixing a compound with a structure shown in a formula II, alkali and a solvent for hydrolysis reaction to obtain a intermediate of the Rui Lu Geli with the structure shown in the formula I;
in formula II: r 1 Is C 1 ～C 6 Alkyl radical, R 2 Is C 1 ～C 6 An alkyl group.
In the present invention, R in the formula II 1 And R in the formula I 1 R in formula II, which is not described in detail herein 2 Preferably C 1 ～C 3 Alkyl, more preferably methyl or ethyl.
In the present invention, the alkali is preferably one or both of sodium hydroxide and potassium hydroxide; the molar ratio of the compound having the structure represented by formula II to the base is preferably 1 (1-3), more preferably 1 (1-2).
In the present invention, the solvent is preferably a mixed solvent of water and an organic solvent, and the volume ratio of the organic solvent to the water in the mixed solvent is (0.1-10): 1, more preferably (0.2-5): 1; the organic solvent is preferably one or more selected from tetrahydrofuran, dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), acetonitrile, methanol, ethanol and 1,4-dioxane, and more preferably tetrahydrofuran.
In the present invention, the temperature of the hydrolysis reaction is preferably 10 to 100 ℃, more preferably 20 to 50 ℃; in the embodiment of the present invention, the reaction is preferably performed at room temperature, and the hydrolysis reaction time is preferably 2 to 30 hours, and more preferably 3 to 20 hours.
In the present invention, the reaction formula of the hydrolysis reaction is as follows:
after the hydrolysis reaction is finished, preferably, the obtained product liquid is subjected to rotary evaporation to remove the solvent, then the residue is mixed with water, the obtained mixed liquid is cooled to 10 ℃, then the pH value of the mixed liquid is adjusted to 5-6 by hydrochloric acid, the mixed liquid is stirred for 30min and then filtered, and the obtained product is sequentially subjected to water washing and drying to obtain the intermediate of Rui Lu Geli with the structure shown in formula I.
The invention also provides a method for synthesizing a Rui Lu Geli intermediate with a structure shown in a formula III by using the Rui Lu Geli intermediate with the structure shown in the formula I, which comprises the following steps:
mixing a Rui Lu Geli intermediate with a structure shown in a formula I, methoxylamine hydrochloride, N' -carbonyldiimidazole, alkali and a solvent to perform a urea condensation reaction to obtain a Rui Lu Geli intermediate with a structure shown in a formula III;
in formula III: r 1 Is C 1 ～C 6 An alkyl group.
In the present invention, the R1 group in formula III is the same as that in formula I, and is not described herein again.
In the present invention, the molar ratio of the N, N' -Carbonyldiimidazole (CDI) to the intermediate of formula I, i.e., rayleigh Lu Geli, is preferably (1-4): 1, more preferably (1-2.5): 1; the molar ratio of the methoxylamine hydrochloride to the intermediate of the Rui Lu Geli with the structure shown in the formula I is preferably (1-4): 1, and more preferably (1-2.5): 1.
In the present invention, the base used in the urea condensation reaction is preferably one or more of triethylamine, N-methylmorpholine, N-methylpyrrolidine, pyridine and triethylenediamine; the molar ratio of the base to the Rui Lu Geli intermediate having the structure of formula I is (1-4): 1, more preferably (1-2.5): 1.
In the present invention, the solvent for urea condensation reaction is preferably one or more of dichloromethane, tetrahydrofuran, ethyl acetate, acetone, methanol, ethanol, isopropanol, acetonitrile and toluene, and more preferably dichloromethane.
In the present invention, the temperature of the urea condensation reaction is preferably 10 to 80 ℃, more preferably 30 to 60 ℃, and the time of the urea condensation reaction is preferably 2 to 20 hours, more preferably 3 to 15 hours.
In the specific embodiment of the invention, the solvent, CDI and alkali are preferably mixed, then the temperature is reduced to 10 ℃, then methoxylamine hydrochloride is added in batches, then the temperature is increased to 30-40 ℃, the reaction is carried out for 20-40 min, preferably for 30min, and then the intermediate of Rui Lu Geli with the structure shown in formula I is added for urea condensation reaction.
In the present invention, the reaction formula of the urea condensation reaction is as follows:
after the urea condensation reaction is finished, the obtained product feed liquid and water are preferably stirred and mixed (marked as first stirring and mixing), and then liquid separation is carried out to obtain a water phase and an organic phase; extracting the water phase with ethyl acetate to obtain an extracted organic phase; combining the extracted organic phase with the organic phase obtained by liquid separation, and then performing rotary evaporation to remove the solvent; cooling the residual product after rotary evaporation to 0-10 ℃, stirring and mixing the product with heptane (recording as second stirring and mixing), and then sequentially filtering and drying to obtain a Rui Lu Geli intermediate with a structure shown in a formula III; the first stirring and mixing temperature is preferably 20-30 ℃, and the time is preferably 30min; the time for the second stirring and mixing is preferably 2h.
The invention also provides an amide condensation method, which comprises the following steps:
mixing a compound with a structure shown in a formula IV, 3-amino-6-methoxypyridazine, a condensing agent and a solvent to perform an amide condensation reaction to obtain a compound with a structure shown in a formula V; the condensing agent is one or more of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), diisopropylcarbodiimide (DIC) and Dicyclohexylcarbodiimide (DCC);
in formulas IV to V: r is 1 Is C 1 ～C 6 An alkyl group; r 3 Is H, C 1 ～C 3 Alkyl or-CH 2 N(CH 3 ) 2 ，R 4 is-NO 2 or-NHCONHOCH 3 。
In the present invention, R in formula VI and formula V 1 The radicals correspond to those of formula I and are not described in detail here.
In the present invention, the condensing agent is preferably EDCl or DIC; the condensing agent adopted by the invention has low price, is beneficial to reducing the production cost, and is more suitable for industrial production.
In the present invention, the molar ratio of the compound having the structure represented by formula IV to the condensing agent is preferably 1 (1 to 5), more preferably 1 (1 to 2.5).
In the present invention, the molar ratio of the compound having the structure represented by formula IV to 3-amino-6-methoxypyridazine is preferably 1 (1 to 1.5), more preferably 1 (1 to 1.2).
In the present invention, the solvent for amide condensation reaction is preferably one or more of dichloromethane, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, acetone, dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), and toluene, and more preferably dichloromethane.
In the present invention, the temperature of the amide condensation reaction is preferably 0 to 100 ℃, more preferably 20 to 60 ℃, and the time of the amide condensation reaction is preferably 2 to 20 hours, more preferably 3 to 12 hours.
In the present invention, the reaction formula of the amide condensation reaction is as follows:
in the present invention, R in the structure of formula IV 3 is-CH 2 N(CH 3 ) 2 ，R 4 is-NHCONHOCH 3 Then, the obtained structure is the compound with the structure shown in the formula III, and the reaction formula of the amide condensation reaction is as follows (the product structure is marked as V-a):
in the present invention, when R in formula IV 3 Is H or C 1 -C 3 Alkyl radical, R 4 is-NO 2 or-NHCONHOCH 3 When, or in the formula IV R 3 Is H, C 1 -C 3 Alkyl or-CH 2 N(CH 3 ) 2 ，R 4 is-NO 2 The invention has no special requirements on the preparation method of the compound with the structure shown in the formula IV, and the synthesis method which is well known to the technical personnel in the field can be adopted, in particular, when R in the formula IV 3 is-CH 2 N(CH 3 ) 2 ，R 4 is-NO 2 In this case, the synthesis is preferably performed by the method disclosed in chinese patent CN104703992 a.
The invention also provides a synthetic method of Rui Lu Geli, which comprises the following steps:
preparing a Rui Lu Geli intermediate having a structure shown in formula III according to the method in the scheme;
r is prepared by taking a Rui Lu Geli intermediate with a structure shown in formula III as a raw material according to the method in the scheme 4 is-NHCONHOCH 3 、R 3 is-CH 2 N(CH 3 ) 2 、R 1 Is C 1 ～C 6 A compound having a structure represented by formula V (i.e., V-a) for an alkyl group;
and (3) carrying out cyclization reaction on the compound with the structure shown in the formula V under alkaline conditions to obtain Rui Lu Geli.
The present invention has no special requirement on the specific operation method of the cyclization reaction, and a method well known to those skilled in the art can be adopted, in the specific embodiment of the present invention, the base adopted in the cyclization reaction is preferably sodium hydroxide or potassium hydroxide, and the solvent adopted in the cyclization reaction is preferably methanol; the temperature of the cyclization reaction is preferably 50-70 ℃, more preferably 60 ℃, and the time of the cyclization reaction is preferably 4-6 h, more preferably 5h.
In the present invention, the specific synthesis process of the rayl Lu Geli is shown in scheme 1:
according to the route 1, when the method is used for synthesizing Rui Lu Geli, rui Lu Geli can be obtained by using a compound with a structure shown in formula II as an initial material through hydrolysis, urea condensation, amide condensation and cyclization, the synthesis route is short, the yield is high, and a condensing agent adopted in the amide condensation reaction is low in price and is more suitable for industrial production.
The technical solutions in the present invention will be described clearly and completely with reference to the following embodiments in the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
EXAMPLE 1 preparation of Compounds of formula I-1
4.90g (10.0 mmol) of compound II-1, 15mL of water, 30mL of tetrahydrofuran and 1.00g (18.0 mmol) of potassium hydroxide are added into a bottle, and the mixture is stirred and reacted for 12 hours at room temperature; removing tetrahydrofuran, adding 15mL of water, cooling to 10 ℃, adjusting the pH of the reaction solution to 5-6 with hydrochloric acid, stirring for 30min, and filtering; the product was washed once with 20mL of water and dried to give 4.66g of compound I1 as a white solid in 98% yield and 98% purity. 1 H-NMR(400M,CDCl 3 )：7.28-7.21(3H，m)，6.82(2H，d)，6.65(2H，d)，5.07(2H，s)，3.88(2H，br)，3.72(3H，s)，3.67(2H，s)，2.18(6H，s)。
EXAMPLE 2 preparation of Compounds of formula I-2
Adding 5.18g (10 mmol) of compound II-2, 20mL of water, 20mL of DMF and 0.80g (20 mmol) of sodium hydroxide into a bottle, heating to 40 ℃ and reacting for 6h; cooling to 10 deg.C, adjusting pH of the reaction solution to 5-6 with hydrochloric acid, adding 80mL water, maintaining at 10 deg.C, stirring for 30min, and filtering; the resulting product was washed once with 20mL of water and dried to give 4.71g of compound I-2 as a white solid in 96% yield and 98% purity. 1 H-NMR(400M,CDCl 3 )：7.27-7.20(3H，m)，6.83(2H，d)，6.66(2H，d)，5.05(2H，s)，4.12(2H，t)，3.85(2H，br)，3.66(2H，s)，2.16(6H，s)，1.35(3H，t)。
EXAMPLE 3 preparation of Compounds of formula I-3
5.32g (10 mmol) of compound II-3, 20mL of water, 20mL of DMSO and 0.80g (20 mmol) of sodium hydroxide are added into a bottle, and the mixture is stirred at room temperature for reaction for 10 hours; cooling to 10 deg.C, adjusting pH of the reaction solution to 5-6 with hydrochloric acid, adding 80mL water, maintaining at 10 deg.C, stirring for 30min, and filtering; the resulting product was washed once with 20mL of water and dried to give 4.83g of compound I-3 as a white solid in 96% yield and 98% purity. 1 H-NMR(400M,CDCl 3 )：7.27-7.21(3H，m)，6.81(2H，d)，6.68(2H，d)，5.04(2H，s)，4.09(2H，t)，3.86(2H，br)，3.66(2H，s)，2.15(6H，s)，1.55(2H，m)，0.90(3H，t)。
EXAMPLE 4 preparation of the Compound of formula III-1
Adding 100mL of dichloromethane, 7.0g (43.26 mmol) of CDI and 2.63g (26.0 mmol) of triethylamine into a bottle, cooling to 10 ℃, adding 4.0g (47.6 mmol) of methoxyamine hydrochloride in batches, heating to 30 ℃ after adding, reacting for 30min, adding 10.3g (21.63 mmol) of the compound of the structural formula I-1, and keeping the temperature at 40 ℃ after adding, and reacting for 6h; adding 100mL of water, keeping the temperature of 20-30 ℃, stirring for 30min, separating liquid, and extracting the water phase once by using 100mL of dichloromethane; combining organic phases, carrying out rotary evaporation until about 20mL of residual organic phase is obtained, cooling to 0-10 ℃, dropwise adding 100mL of heptane, and stirring for 2h after the addition is finished; filtration and drying were carried out to obtain 11.5g of a white solid compound of the formula III-1 in 97% yield and 98% purity. 1 H-NMR(400M，CDCl 3 )：8.05(1H，br)，7.58(1H，br)，7.46-7.40(4H，m)，7.22(1H，m)，6.82(2H，t)，5.03(2H，br)，3.83(3H，s)，3.72(3H，s)，3.65(2H，s)，2.09(6H，s)。
EXAMPLE 5 preparation of Compound of formula III-2
Adding 100mL of ethyl acetate, 8.75g (54.1 mmol) of CDI and 2.6g (33.0 mmol) of pyridine into a bottle, cooling to 10 ℃, adding 4.2g (50.0 mmol) of methoxyamine hydrochloride in batches, heating to 40 ℃ after adding, reacting for 30min, adding 10.6g (21.63 mmol) of the compound of the structural formula I-2, and keeping at 50 ℃ after adding, and reacting for 5h; adding 100mL of water, keeping the temperature at 20-30 ℃, stirring for 30min, separating liquid, and extracting the water phase once by using 100mL of ethyl acetate; combining organic phases, carrying out rotary evaporation until about 20mL of residual organic phase is obtained, cooling to 0-10 ℃, dropwise adding 100mL of heptane, and stirring for 2h after the addition is finished; filtration and drying were carried out to obtain 11.7g of a white solid compound of the formula III-2 in a yield of 96% and a purity of 98%. 1 H-NMR(400M，CDCl 3 )：8.01(1H，br)，7.57(1H，br)，7.46-7.40(4H，m)，7.21(1H，m)，6.81(2H，t)，5.01(2H，br)，4.15(2H，q)，3.83(3H，s)，3.65(2H，s)，2.09(6H，s)，1.36(3H，t)。
EXAMPLE 6 preparation of the Compound of formula III-3
Adding 100mL of tetrahydrofuran, 8.1g (50.0 mmol) of CDI and 3.0g (30.0 mmol) of N-methylmorpholine into a bottle, cooling to 10 ℃, adding 4.2g (50.0 mmol) of methoxyamine hydrochloride in batches, heating to 35 ℃ after adding, reacting for 30min, adding 10.9g (21.63 mmol) of the compound of the structural formula I-3, and keeping at 45 ℃ after adding, reacting for 5h; spin-drying the solvent, adding 50mL of water and 100mL of isopropyl acetate, stirring at 20-30 ℃ for 30min, separating the liquid, and extracting the water phase once with 100mL of isopropyl acetate; combining organic phases, carrying out rotary evaporation until about 20mL of residual organic phase is obtained, cooling to 0-10 ℃, dropwise adding 100mL of heptane, and stirring for 2h after the addition is finished; filtering and drying to obtain 12.0g of a white solid compound of the structural formula III-3, wherein the yield is 96 percent and the purity is 98 percent. 1 H-NMR(400M，CDCl 3 )：8.02(1H，br)，7.56(1H，br)，7.46-7.40(4H，m)，7.21(1H，m)，6.81(2H，t)，5.00(2H，br)，4.15(2H，q)，3.82(3H，s)，3.64(2H，s)，2.09(6H，s)，1.54(2H，m)，0.95(3H，t)。
EXAMPLE 7 preparation of Compound of formula V-1
A flask was charged with 5.06g (10 mmol) of Compound IV-1, 1.38g (11 mmol) of 3-amino-6-methoxypyridazine and 50mL of dichloromethane, and 2.89g (15 mmol) of EDCl was added thereto with stirring and reacted at room temperature for 5 hours with stirring; dichloromethane was removed by rotation, 50mL water was added, stirred for 30min, filtered, washed with 30mL water and dried to give 5.95g of yellow solid compound V-1 in 97% yield and 98% purity. 1 H-NMR(400M,CDCl 3 )：11.55(1H，s)，8.29(2H，d)，7.51(2H，d)，7.38(1H，s)，7.22-7.18(2H，m)，6.87(2H，d)，5.05(2H，s)，4.10(3H，s)，3.87(3H，s)，3.65(2H，s)，2.19(6H，s)。
EXAMPLE 8 preparation of Compound of formula V-2
5.34g (10 mmol) of compound IV-2, 1.63g (13 mmol) of 3-amino-6-methoxypyridazine and 50mL of ethyl acetate were put into a flask, and 1.90g (15 mmol) of DIC were added thereto with stirring and the mixture was reacted at 40 ℃ for 4 hours; ethyl acetate was spun off, 60mL of water and 20mL of ethanol were added, stirred for 30min, filtered, washed with 30mL of water, and dried to give 5.56g of yellow solid compound V-2, yield 87%, purity 95%. 1 H-NMR(400M,CDCl 3 )：11.39(1H，s)，8.28(2H，d)，7.52(2H，d)，7.37(1H，s)，7.22-7.18(2H，m)，6.85(2H，d)，5.03(2H，s)，4.13-4.09(5H，m)，3.64(2H，s)，2.18(6H，s)，1.58(2H，m)，0.91(3H，t)。
EXAMPLE 9 preparation of Compound of formula V-a-1
5.49g (10 mmol) of Compound III-1, 1.50g (12 mmol) of 3-amino-6-methoxypyridazine and 50mL of isopropyl acetate were charged in a flask, and 3.84g (20 mmol) of EDCl was added thereto under stirring, and the reaction was stirred at 50 ℃ for 3 hours; the isopropyl acetate was removed by spinning off, 60mL of water and 20mL of ethanol were added, stirred for 30min, filtered, washed with 30mL of water, and dried to obtain 5.97g of a yellow solid compound V-a-1, yield 91%, purity 98%. 1 H-NMR(400M,CDCl 3 )：10.88(1H，s)，8.05(1H，s)，7.58(1H，s)，7.46-7.40(4H，m)，7.23-7.18(3H，m)，6.85(2H，d)，5.02(2H，s)，4.09(3H，s)，3.85(3H，s)，3.76(3H，s)，3.63(2H，s)，2.18(6H，s)。
EXAMPLE 10 preparation of Compound of formula V-a-2
5.77g (10 mmol) of Compound III-3, 1.38g (11 mmol) of 3-amino-6-methoxypyridazine and 60mL of dichloromethane were charged in a flask, and 4.13g (20 mmol) of DCC was added thereto under stirring, followed by reaction with stirring at room temperature for 8 hours; dichloromethane was spun off, 50mL water and 20mL ethanol were added, stirred for 30min, filtered, washed with 30mL water, and dried to obtain 5.69g yellow solid compound V-a-2, yield 83%, purity 96%. 1 H-NMR(400M,CDCl 3 )：10.75(1H，s)，8.04(1H，s)，7.59(1H，s)，7.45-7.40(4H，m)，7.24-7.19(3H，m)，6.86(2H，d)，5.00(2H，s)，4.11-4.06(5H，m)，3.80(3H，s)，3.63(2H，s)，2.18(6H，s)，1.56(2H，m)，0.93(3H，t)。
EXAMPLE 11 preparation of Compounds of formula III-c
Into a bottle were charged 4.49g (10 mmol) of Compound IV-3, 1.50g (12 mmol) of 3-amino-6-methoxypyridazineAnd 50mL of dichloromethane, adding 2.89g (15 mmol) of EDCl under stirring, and stirring at room temperature for reaction for 5h; dichloromethane was removed by rotation, 50mL of water was added, stirred for 30min, filtered, washed with 30mL of water, and dried to obtain 5.45g of yellow solid compound V-3, with a yield of 98% and a purity of 98%. 1 H-NMR(400M,CDCl 3 )：12.06(1H，s)，8.26(2H，d)，7.69(1H，s)，7.58(2H，d)，7.40(1H，s)，7.23-7.18(2H，m)，6.89(2H，d)，5.03(2H，s)，4.11(3H，s)，3.89(3H，s)。
EXAMPLE 12 preparation of Compound of formula V-4
A flask was charged with 4.63g (10 mmol) of Compound IV-4, 1.50g (12 mmol) of 3-amino-6-methoxypyridazine and 50mL of dichloromethane, and 2.53g (20 mmol) of DIC was added thereto under stirring to react at room temperature for 8 hours with stirring; dichloromethane was spun off, 60mL of water and 20mL of ethanol were added, stirred for 30min, filtered, washed with 30mL of water, and dried to give 5.02g of yellow solid compound V-4 in 88% yield and 96% purity. 1 H-NMR(400M,CDCl 3 )：12.03(1H，s)，8.25(2H，d)，7.57(2H，d)，7.39(1H，s)，7.23-7.18(2H，m)，6.89(2H，d)，5.03(2H，s)，4.11(3H，s)，3.89(3H，s)，2.46(3H，s)。
Example 13 preparation of Rui Lu Geli
60ml of methanol and 0.25g (6.10 mmol) of sodium hydroxide were added to the flask and dissolved by stirring; then 5.0g (7.63 mmol) of compound V-a-1 is added, and the temperature is raised to 60 ℃ for reaction for 5 hours; spin-drying solvent, adding 60ml water, adjusting pH to 8-9 with 6M hydrochloric acid, cooling to 0-10 deg.C, standing for 30min, filtering, and washing with 20ml water; pulping the obtained solid with 50ml ethyl acetate, and filtering again; drying to obtain Rui Lu Geli, white solid 4.61g, yield 97% and purity 99%. 1 H-NMR(400M，CDCl 3 )：7.64-7.12(8H，m)，6.91(2H，t)，6.80(1H，br)，5.33(2H，br)，4.17(3H，s)，3.81(3H，s)，3.69(2H，s)，2.13(6H，s)。
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. An intermediate of Lu Geli, having the structure of formula I:
in formula I: r 1 Is C 1 ～C 6 An alkyl group.
2. A process for preparing intermediates of rayl Lu Geli as claimed in claim 1 comprising the steps of:
mixing a compound with a structure shown in a formula II, alkali and a solvent for hydrolysis reaction to obtain a Rui Lu Geli intermediate with a structure shown in a formula I;
in formula II: r 1 Is C 1 ～C 6 Alkyl radical, R 2 Is C 1 ～C 6 An alkyl group.
3. The production method according to claim 2, wherein the alkali is one or both of sodium hydroxide and potassium hydroxide; the molar ratio of the compound with the structure shown in the formula II to the alkali is 1 (1-3).
4. The production method according to claim 2, wherein the solvent is a mixed solvent of water and an organic solvent, and the volume ratio of the organic solvent to water in the mixed solvent is (0.1-10): 1.
5. The method according to claim 2, wherein the hydrolysis reaction is carried out at a temperature of 10 to 100 ℃ for 2 to 30 hours.
6. A method for synthesizing a Rui Lu Geli intermediate with a structure shown in formula III by using the Rui Lu Geli intermediate with the structure shown in formula I is characterized by comprising the following steps:
mixing a Rui Lu Geli intermediate with a structure shown in a formula I, methoxylamine hydrochloride, N' -carbonyldiimidazole, alkali and a solvent to perform a urea condensation reaction to obtain a Rui Lu Geli intermediate with a structure shown in a formula III;
in formula III: r 1 Is C 1 ～C 6 An alkyl group.
7. The preparation method according to claim 6, wherein the molar ratio of the N, N' -carbonyldiimidazole to the intermediate Ruiz Lu Geli having the structure of formula I is (1-4): 1; the molar ratio of the methoxylamine hydrochloride to the intermediate of Rui Lu Geli with the structure shown in the formula I is (1-4) to 1; the alkali is one or more of triethylamine, N-methylmorpholine, N-methylpyrrolidine, pyridine and triethylene diamine; the molar ratio of the alkali to the Rui Lu Geli intermediate with the structure shown in formula I is (1-4): 1.
8. An amide condensation process, comprising the steps of:
mixing a compound with a structure shown in a formula IV, 3-amino-6-methoxypyridazine, a condensing agent and a solvent to perform an amide condensation reaction to obtain a compound with a structure shown in a formula V; the condensing agent is one or more of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, diisopropylcarbodiimide and dicyclohexylcarbodiimide;
in formulas IV to V: r 1 Is C 1 ～C 6 An alkyl group; r 3 Is H, C 1 ～C 3 Alkyl or-CH 2 N(CH 3 ) 2 ，R 4 is-NO 2 or-NHCONHOCH 3 。
9. The amide condensation method according to claim 8, wherein the molar ratio of the compound having the structure represented by formula IV to the condensing agent is 1 (1-5).
10. A synthetic method of Rui Lu Geli is characterized by comprising the following steps:
preparing a Rui Lu Geli intermediate having the structure of formula III according to the method of claim 6;
the method of claim 8 or 9 for preparing R from a Rui Lu Geli intermediate having a structure shown in formula III 4 is-NHCONHOCH 3 、R 3 is-CH 2 N(CH 3 ) 2 、R 1 Is C 1 ～C 6 A compound having a structure represented by formula V;
and (3) carrying out cyclization reaction on the compound with the structure shown in the formula V under alkaline conditions to obtain Rui Lu Geli.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211368606.1A CN115650950A (en) | 2022-11-03 | 2022-11-03 | Rui Lu Geli intermediate and preparation method thereof, and amide condensation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211368606.1A CN115650950A (en) | 2022-11-03 | 2022-11-03 | Rui Lu Geli intermediate and preparation method thereof, and amide condensation method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115650950A true CN115650950A (en) | 2023-01-31 |
Family
ID=84995800
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211368606.1A Pending CN115650950A (en) | 2022-11-03 | 2022-11-03 | Rui Lu Geli intermediate and preparation method thereof, and amide condensation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115650950A (en) |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104703992A (en) * | 2012-09-28 | 2015-06-10 | 武田药品工业株式会社 | Production method of thienopyrimidine derivative |
| CN111333633A (en) * | 2020-04-01 | 2020-06-26 | 江西青峰药业有限公司 | Rugosril intermediate compound and preparation method and application thereof |
| CN111423452A (en) * | 2020-03-26 | 2020-07-17 | 江西青峰药业有限公司 | Rugoside intermediate, preparation method and application thereof |
| CN112321602A (en) * | 2019-08-05 | 2021-02-05 | 苏州鹏旭医药科技有限公司 | Preparation method of Ruogeli drug intermediate |
| CN112552312A (en) * | 2020-12-07 | 2021-03-26 | 杭州科巢生物科技有限公司 | Synthetic method of Ruogeli or salt thereof |
| CN112745304A (en) * | 2019-10-29 | 2021-05-04 | 上海度德医药科技有限公司 | Preparation method of Relugolix and intermediate compound |
| CN113444105A (en) * | 2020-03-27 | 2021-09-28 | 南京海润医药有限公司 | Preparation method of Relugolix |
| CN113501830A (en) * | 2021-07-14 | 2021-10-15 | 山东百诺医药股份有限公司 | Preparation method of Ruogeli |
| CN114230576A (en) * | 2021-12-21 | 2022-03-25 | 伊诺药物研究(南京)有限公司 | Preparation method of Ruogeli |
| CN114380810A (en) * | 2021-12-27 | 2022-04-22 | 南京方生和医药科技有限公司 | Rugosril intermediate impurity and preparation method thereof |
| CN114907370A (en) * | 2021-02-10 | 2022-08-16 | 奥锐特药业(天津)有限公司 | High-purity thienopyrimidine compound and preparation method thereof |
| CN114989134A (en) * | 2022-07-14 | 2022-09-02 | 江西同和药业股份有限公司 | Thiophene compound and preparation method and application thereof |
-
2022
- 2022-11-03 CN CN202211368606.1A patent/CN115650950A/en active Pending
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104703992A (en) * | 2012-09-28 | 2015-06-10 | 武田药品工业株式会社 | Production method of thienopyrimidine derivative |
| CN112321602A (en) * | 2019-08-05 | 2021-02-05 | 苏州鹏旭医药科技有限公司 | Preparation method of Ruogeli drug intermediate |
| CN112745304A (en) * | 2019-10-29 | 2021-05-04 | 上海度德医药科技有限公司 | Preparation method of Relugolix and intermediate compound |
| CN111423452A (en) * | 2020-03-26 | 2020-07-17 | 江西青峰药业有限公司 | Rugoside intermediate, preparation method and application thereof |
| CN113444105A (en) * | 2020-03-27 | 2021-09-28 | 南京海润医药有限公司 | Preparation method of Relugolix |
| CN111333633A (en) * | 2020-04-01 | 2020-06-26 | 江西青峰药业有限公司 | Rugosril intermediate compound and preparation method and application thereof |
| CN112552312A (en) * | 2020-12-07 | 2021-03-26 | 杭州科巢生物科技有限公司 | Synthetic method of Ruogeli or salt thereof |
| CN114907370A (en) * | 2021-02-10 | 2022-08-16 | 奥锐特药业(天津)有限公司 | High-purity thienopyrimidine compound and preparation method thereof |
| CN113501830A (en) * | 2021-07-14 | 2021-10-15 | 山东百诺医药股份有限公司 | Preparation method of Ruogeli |
| CN114230576A (en) * | 2021-12-21 | 2022-03-25 | 伊诺药物研究(南京)有限公司 | Preparation method of Ruogeli |
| CN114380810A (en) * | 2021-12-27 | 2022-04-22 | 南京方生和医药科技有限公司 | Rugosril intermediate impurity and preparation method thereof |
| CN114989134A (en) * | 2022-07-14 | 2022-09-02 | 江西同和药业股份有限公司 | Thiophene compound and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108718527B (en) | Process for preparing compounds | |
| CN110526859B (en) | Revinanexin intermediate, preparation method thereof and preparation method of Revinanexin | |
| WO2022018625A1 (en) | Process for the preparation of an intermediate used in the synthesis of letermovir | |
| CN114478690A (en) | Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane derivative | |
| PL213231B1 (en) | Process for preparing substituted cyclopentane derivatives and novel crystalline structures thereof | |
| EP3413891B1 (en) | Processes for the preparation of highly pure prucalopride succinate | |
| CN110655517A (en) | Preparation method of doriravir open-loop impurities and impurities thereof | |
| TWI541235B (en) | Process of preparing a quinazoline derivative | |
| JP2023536207A (en) | Process for preparing phthalazinone derivatives and intermediates thereof | |
| CN115650950A (en) | Rui Lu Geli intermediate and preparation method thereof, and amide condensation method | |
| JP6781030B2 (en) | L-carnosine derivative or salt thereof, and method for producing L-carnosine or salt thereof | |
| EP1212321A2 (en) | Intermediates for the production of naphthyridine-3-carboxylic acid derivatives | |
| JP4908706B2 (en) | Benzofuran derivatives | |
| WO2021238962A1 (en) | Method for preparing glp-1 receptor agonist | |
| CN112272665A (en) | Process for preparing sitagliptin | |
| US20040138232A1 (en) | Acyl derivatives of 5-(2-(4-(1,2 benzisothiazole-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2h-indol-2-one having neuroleptic activity | |
| KR20220018486A (en) | 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro- Alternative method for preparing 1H-imidazo[1,5-a]pyrazin-2-yl]-carboxylic acid | |
| WO2020115200A1 (en) | Improved process for preparing ozanimod | |
| Benedini et al. | New organic nitrates. I. Synthesis of 1, 3‐benzoxazine‐2, 4‐dione, 1, 3‐benzoxazine‐2‐thion‐4‐one, 1, 3‐benzothiazine‐2, 4‐dione and quinazoline‐2, 4‐dione derivatives | |
| CN110483470B (en) | Method for preparing landiolol hydrochloride | |
| JP3204368B2 (en) | Preparation of optically active amides | |
| JP7279134B2 (en) | Method for producing prolinamide compound | |
| JP5919270B2 (en) | Method for producing dimiracetam | |
| JP2935515B2 (en) | 1-Azabicyclo [m, n, 0] alkane derivatives and salts thereof and methods for producing them | |
| CN115572264A (en) | Preparation method of enzalutamide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |