CN114230576A - Preparation method of Ruogeli - Google Patents
Preparation method of Ruogeli Download PDFInfo
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- CN114230576A CN114230576A CN202111573117.5A CN202111573117A CN114230576A CN 114230576 A CN114230576 A CN 114230576A CN 202111573117 A CN202111573117 A CN 202111573117A CN 114230576 A CN114230576 A CN 114230576A
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- ruugeli
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- palladium carbon
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 18
- 229940125898 compound 5 Drugs 0.000 claims abstract description 15
- 229940126214 compound 3 Drugs 0.000 claims abstract description 14
- 229940125782 compound 2 Drugs 0.000 claims abstract description 12
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 12
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 6
- YPWBPONDYDVMLX-UHFFFAOYSA-N 6-methoxypyridazin-3-amine Chemical compound COC1=CC=C(N)N=N1 YPWBPONDYDVMLX-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000006239 protecting group Chemical group 0.000 claims abstract description 5
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims abstract description 5
- 229940125904 compound 1 Drugs 0.000 claims abstract description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 235000019253 formic acid Nutrition 0.000 claims abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- NJTZSWLQBQJUHK-UHFFFAOYSA-N CCCP(=O)=O Chemical compound CCCP(=O)=O NJTZSWLQBQJUHK-UHFFFAOYSA-N 0.000 claims description 2
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 claims description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- -1 t-butyloxycarbonyl Chemical group 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000006722 reduction reaction Methods 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000003595 spectral effect Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 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 4
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-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
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 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 1
- SMQXTAFGVWBZDG-UHFFFAOYSA-N 6-methoxypyridazin-3-amine hydrochloride Chemical compound Cl.COc1ccc(N)nn1 SMQXTAFGVWBZDG-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- MNKNAPFEXFDRAP-UHFFFAOYSA-M ethyl propyl phosphate Chemical compound CCCOP([O-])(=O)OCC MNKNAPFEXFDRAP-UHFFFAOYSA-M 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- WCMDBGGJBGZLDL-UHFFFAOYSA-N phenyl n-methoxycarbamate Chemical compound CONC(=O)OC1=CC=CC=C1 WCMDBGGJBGZLDL-UHFFFAOYSA-N 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- QQKDTTWZXHEGAQ-UHFFFAOYSA-N propyl carbonochloridate Chemical compound CCCOC(Cl)=O QQKDTTWZXHEGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 229950004238 relugolix Drugs 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a preparation method of Ruogeli, which comprises the following steps: s1: the compound 1 is reduced under the condition of palladium carbon/formic acid or palladium carbon/hydrazine hydrate to obtain a compound 2; s2: reacting the compound 2 with tert-butyloxycarbonyl or trifluoroacetyl to obtain a compound 3; s3: hydrolyzing the compound 3 to obtain a compound 4; s4: reacting the compound 4 with 3-amino-6-methoxypyridazine to obtain a compound 5; the method has fewer synthesis steps and higher synthesis efficiency, can safely obtain a high-quality Ruugeli intermediate with high yield, leads the reduction reaction catalyzed by palladium carbon to be preposed, effectively controls the Ruugeli to be used as the index of the heavy metal content of the bulk drug, adopts a non-hydrogen mode for reduction, is more beneficial to industrial production, avoids the production risk brought by the use of a high-pressure reaction kettle, skillfully adopts the protection of amino, and removes a protecting group after introducing a pyridazine ring, so that the route has higher yield.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of Ruogeli.
Background
Relogelix (Relugolix) was the first oral gonadotropin releasing hormone (GnRH) receptor antagonist to be used in the treatment of endometriosis and advanced prostate cancer. Is a small molecular gonadotropin releasing hormone (GnRH) receptor antagonist, and is used for treating hysteromyoma and relieving symptoms in 2019. Since it rapidly achieves simultaneous suppression of LH and FSH release from the pituitary gland over a short period of time and is shown to reduce testosterone levels by a number of clinical phase i and phase ii studies, it is later approved for the treatment of advanced prostate cancer.
So far, there are few reports on the synthetic process of Ruugeli at home and abroad, and the former company, Wutian chemical company, first discloses the synthetic method (WO0056739& WO 2004067535). The specific synthetic route is as follows:
an additionally published synthesis method (WO2014051164) was originally developed, and the specific synthesis route is as follows:
the second method is obviously superior to the first method, reduces the reaction steps, adopts dimethylamine to directly react with bromide to reduce the corresponding steps, but also uses a highly toxic substance, ethyl chloroformate and a high-pressure hydrogenation step, and causes environmental pollution problems and dangerous reactions during production.
The domestic patent (CN112321602) only changes ethyl chloroformate into propyl chloroformate, and the route and the reaction conditions are not changed greatly. The problems in the process are still not solved.
At present, a multi-step mode is adopted in the preparation process of Ruogeli, the multi-step mode comprises the steps of reducing nitro by palladium carbon hydrogen and producing with low efficiency, and for the production of bulk drugs with high dosage specifications, a safer production condition and a method more suitable for industrialization need to be found.
Disclosure of Invention
The invention aims to provide a preparation method of Rugoside, which can be used for obtaining a high-quality Rugoside intermediate with high yield more safely.
In order to achieve the above purpose, the invention provides the following technical scheme: a preparation method of Ruogeli comprises the following steps:
s1: the compound 1 is reduced under the condition of palladium carbon/formic acid or palladium carbon/hydrazine hydrate to obtain a compound 2;
s2: reacting the compound 2 with tert-butyloxycarbonyl or trifluoroacetyl to obtain a compound 3;
s3: hydrolyzing the compound 3 to obtain a compound 4;
s4: reacting the compound 4 with 3-amino-6-methoxypyridazine to obtain a compound 5;
s5: removing the protecting group of the compound 5 to obtain a compound 6
S6: reacting the compound 6 with a compound 9 to obtain a compound 7, wherein the compound 9 is 1, 1-carbonyl diimidazole or salt thereof, methoxylamine or salt thereof;
s7: intramolecular cyclization of the compound 7 under alkaline conditions to obtain a compound 8;
further, in the invention, in S1, hydrazine hydrate is used as a hydrogen source, palladium carbon is used as a catalyst, the proportion of the hydrazine hydrate is 1-3eq, a reaction solvent is alcohol, and the reaction temperature ranges from 0 ℃ to 60 ℃.
Further, in the present invention, in S2, compound 2 is reacted with t-butyloxycarbonyl group or trifluoroacetyl group under basic conditions to protect the amino group, and compound 3 is obtained.
Further, in the present invention, in S3, compound 3 is hydrolyzed with a strong base, which is KOH, NaOH, or LiOH, to give compound 4.
Further, in the invention, in S4, compound 4 reacts with 3-amino-6-methoxypyridazine under the conditions of propyl phosphoric anhydride and alkali to obtain compound 5, the reaction solvent is selected to be an aprotic polar solvent, and the reaction temperature is selected to be 0-80 ℃.
Further, in the present invention, the aprotic polar solvent is DMF, DMAc, DMSO, toluene, or tetrahydrofuran, and the base is diisopropylethylamine or triethylamine.
Further, in the present invention, in S5, compound 5 is deprotected under acidic conditions at a temperature of 0 to 50 ℃ and the acid is hydrochloric acid, trifluoroacetic acid or phosphoric acid.
Further, in the present invention, in S6, the amount of the compound 6, 1, 1-carbonyldiimidazole used is 1.0 to 3.0 equivalents, the amount of methoxylamine hydrochloride used is 1.0 to 3.0 equivalents, the reaction is carried out under basic conditions, the base is triethylamine or diisopropylethylamine, and the amount of the base used is 0.8 to 0.9 equivalents.
Further, in the present invention, in S7, compound 7 is reacted in a solvent, which is methanol, ethanol, acetonitrile, tetrahydrofuran or a mixed solvent thereof, and a base is sodium methoxide or sodium ethoxide, the amount of the base used is 0.01 to 2.0 equivalents, preferably 0.1 to 0.2 equivalents, of compound 7.
The beneficial effects are that the technical scheme of this application possesses following technological effect:
the method has fewer synthesis steps and higher synthesis efficiency, can safely obtain a high-quality Ruugeli intermediate with high yield, leads the reduction reaction catalyzed by palladium carbon to be preposed, effectively controls the Ruugeli to be used as the index of the heavy metal content of the bulk drug, adopts a non-hydrogen mode for reduction, is more beneficial to industrial production, avoids the production risk brought by the use of a high-pressure reaction kettle, skillfully adopts the protection of amino, and removes a protecting group after introducing a pyridazine ring, so that the route has higher yield.
Drawings
The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 is a schematic diagram of the synthetic route of the present invention.
Detailed Description
In order to better understand the technical content of the present invention, specific embodiments are described below with reference to the accompanying drawings.
In this disclosure, aspects of the present invention are described with reference to the accompanying drawings, in which a number of illustrative embodiments are shown. Embodiments of the present disclosure are not necessarily defined to include all aspects of the invention. It should be appreciated that the various concepts and embodiments described above, as well as those described in greater detail below, may be implemented in any of numerous ways, as the disclosed concepts and embodiments are not limited to any one implementation. In addition, some aspects of the present disclosure may be used alone, or in any suitable combination with other aspects of the present disclosure.
The embodiment discloses a preparation method of Ruogeli, which comprises the following steps:
preparation of compound 2:
3000ml of methanol, 110.1g of hydrazine hydrate (85%) and 300g of Compound 1 were put into a 5L reactor, and 15g of 10% palladium on carbon was added thereto, followed by reaction with stirring at room temperature for 10 hours. Pd/C was filtered off through celite, the filtrate was concentrated to dryness under reduced pressure, then the concentrate was dissolved in 500mL of ethyl acetate, 1000mL of n-heptane was added dropwise to the resulting solution at room temperature, after crystallization for 1 hour under stirring, the crystals were collected by filtration, washed with 300mL of ethyl acetate and n-heptane (1:2) solution, and dried under reduced pressure at 45 ℃ to obtain 266.9g of off-white crystals 2 with yield 93.98% and chemical purity 98.67%.
Nuclear magnetic data for compound 2: DMSO-d6, 400MHz, 0.93-1.10(t, 3H), 1.26-1.30(t, 3H), 1.79(m, 2H), 2.08(s, 6H), 3.50(d, 2H), 3.73-3.77(q, 2H), 3.82(d, 2H), 4.23-4.25(q, 2H), 4.40(s, 2H), 5.23(s, 2H), 7.08-7.12(m, 2H), delta 7.42-7.48 (m, 3H);
mass spectral data for compound 2: ESI+，[M+H]+:532.57。
Preparation of compound 3 (tert-butoxycarbonyl protection):
123.1g of di-tert-butyl dicarbonate is weighed and added into 500ml of dichloromethane; 1500ml of dichloromethane, 200g of compound 2, 114.2g of triethylamine and 5ml of DMF are added into a 5L reaction kettle, the temperature is reduced to 10 ℃, a dichloromethane solution of di-tert-butyl dicarbonate is slowly dripped, and after the dripping is finished, the reaction solution is heated to room temperature for reaction for 2 to 3 hours. Cooling the reaction solution to 10 ℃, adding 1000ml of purified water, stirring uniformly, standing, separating, adding 500ml of 0.2mol/L hydrochloric acid into the organic phase, washing with 500ml of 5% sodium bicarbonate once, washing with 500ml of purified water, and drying the organic phase with anhydrous sodium sulfate. Concentration under reduced pressure gave about 222.3g of a semi-solid product in 93.55% yield. The product is not refined and is directly put into the next reaction step.
Nuclear magnetic data for compound 3: DMSO-d6, 400MHz, 0.93-1.10(t, 3H), 1.26-1.30(t, 3H), 1.59(s, 9H), 2.08(s, 6H), 3.50(d, 2H), 3.73-3.77(q, 2H), 3.82(d, 2H), 4.23-4.25(q, 2H), 4.40(s, 2H), 5.23(s, 2H), 7.08-7.12(m, 2H), delta 7.42-7.48 (m, 3H), 9.78(s, 1H);
mass spectral data for compound 3: ESI+，[M+H]+:532.88。
Preparation of compound 4:
suspending 300g of compound 3 in 3000ml of ethanol and 750ml of purified water, adding 48% potassium hydroxide aqueous solution, stirring and reacting at the temperature of 40 ℃ for 24 hours, after the reaction is finished, concentrating under reduced pressure to remove the ethanol, adding 1500ml of water into the residue, cooling to 10 ℃, adding 1M hydrochloric acid to adjust the pH value to be 6-7, adding 1500ml of dichloromethane 3 for extraction, drying the organic phase by using anhydrous sodium sulfate, and filtering. After concentration under reduced pressure, about 262.8g of a white solid product was obtained with a yield of 91.72%.
Nuclear magnetic data for compound 4: (DMSO-d6, 400MHz0.97-1.05(t, 3H), 1.56(s, 9H), 2.28(s, 6H), 3.46(d, 2H), 3.86(d, 2H), 4.13-4.15(q, 2H), 4.44(s, 2H), 5.23(s, 2H), 7.08-7.14(m, 2H), delta 7.41-7.48 (m, 3H), 9.76(s, 1H);
mass spectral data for compound 4: ESI+，[M+H]+:604.28。
Preparation of compound 5:
240.30g of compound is weighed and added into a 3L three-necked bottle, 2.4L DMAc (N, N-dimethylacetamide), 77.1g 3-amino-6-methoxypyridazine hydrochloride are added, nitrogen protection is carried out, 77.2g DIPEA (N, N-diisopropylethylamine) is added dropwise at the temperature controlled within 30 ℃, the temperature is raised to 50-60 ℃ after dropping, stirring is carried out for 1 hour, 303.5g 50% ethyl propyl phosphate anhydride acetate solution is added, the mixture is reacted for 1 hour at 50-60 ℃, then the temperature is reduced to room temperature, the pH is adjusted to 5-6 with 1M sodium carbonate solution at the temperature controlled within 30 ℃, then 200mL water is added for dilution, 20mL ethyl acetate is used for extraction for three times, the organic phase is dried by anhydrous sodium sulfate and then filtered, and the filtrate is concentrated under reduced pressure to obtain a light yellow solid. Vacuum drying at 45 deg.C gave 244.7g of off-white solid, Compound 5, in 86.5% yield and 95.66% chemical purity.
Preparation of compound 6:
240.0g of compound 5 is weighed and added into a 3L three-necked flask, then 2L of ethyl acetate is added,76.0g of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 2 to 3 hours, and the end of the reaction was monitored by TLC. Adding 1N sodium hydroxide solution into the reaction solution, adjusting the pH value to 8-9, separating the solution, extracting the water phase twice by using 1L 2 ethyl acetate, drying the organic phase by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a light yellow solid. 600ml of methanol were added, stirred at room temperature for 2 hours, filtered and the filter cake rinsed with a little methanol. The filter cake was dried under vacuum at 45 ℃ to give 183.6g of off-white solid, compound 5, in 90.14% yield and 98.86% chemical purity. The nuclear magnetic data for compound 6 are as follows: CDCl3，400MHz 0.85-1.09(m，3H)，1.49-1.85(m，2H)，2.20(s，6H)，3.51(s，2H)，3.99-4.37(m，5H)，5.04(s，2H)，6.75(t，2H)，7.00(d，1H)，7.07-7.20(m，1H)，7.45-7.56(m，2H)，8.29(d，2H)，8.55(d，1H)，13.87(s，1H)；
Mass spectral data for compound 6: [ M + H ]]+＝611.54。
Preparation of compound 7:
3.95g of the compound 6 and 1.82g of phenyl methoxycarbamate are weighed and added into a 250mL three-necked flask, 20mL of toluene is added, the temperature is raised to 108 ℃ by stirring, the temperature is reduced to room temperature after 3 hours of reaction by stirring, 20mL of 1M potassium carbonate solution is added, the stirring is continued for 0.5 hour, an organic phase and a water phase are separated, the organic phase is washed twice by 10mL of tap water, the organic phase is dried by anhydrous sodium sulfate and then filtered, and the filtrate is decompressed and concentrated to obtain 4.34g of yellow solid, namely the compound 7, the yield is 93.1%, and the chemical purity is 96.95%.
The nuclear magnetic data for compound 7 is as follows: DMSO-d6, 400MHz, 0.76-0.93(m, 6H), 1.21-1.25(t, 3H), 1.72-1.78(m, 1H), 1.93(s, 6H), 3.42(s, 2H), 3.64(s, 3H), 3.79-3.83(d, 2H), 4.09-4.14(q, 2H), 4.92(s, 2H), 7.03-7.07(dd, 2H), 7.24-7.27(dd, 2H), 7.37-7.43(m, 1H), 7.66-7.69(dd, 2H), 9.05(s, 1H), 9.62(s, 1H);
mass spectral data for compound 7: [ M + H ]]+:619.23。
Preparation of compound 8:
weighing 1.59g of compound 7 by weight, adding the compound into a 100mL three-necked flask, adding 40mL of methanol, 2.7mL of tetrahydrofuran and 0.90g of 28% sodium methoxide methanol solution, stirring the mixture, heating the mixture to 60 ℃, reacting for 2 hours, cooling to room temperature, adjusting the pH to 9 with 6M hydrochloric acid at 0 ℃ under reduced pressure, concentrating under reduced pressure until the mixture is dry, adding 10mL of methanol, filtering to remove salts, adding 100mL of ethyl acetate, precipitating a large amount of solid, scraping the filter cake after filtering, drying under reduced pressure to obtain 1.20g of light yellow solid, adding 5mL of ethyl acetate and 5mL of dichloromethane, pulping for 24 hours, filtering, adding ethyl acetate/dichloromethane 1: 1 washing the filter cake with the mixed solution, and drying to obtain 1.35g of white crystal, namely Ruogeli, with the yield of 94.89%, the chemical purity of 99.65% and the maximum unknown single impurity of 0.04%.
The nuclear magnetic data for compound 8 (rilogeli) is as follows: CDCl3, 400MHz, 2.13(s, 6H), 3.54-3.77(m, 2H), 3.79(s, 3H), 4.18(s, 3H), 5.29-5.35(brs, 2H), 6.88-6.94(t, 2H), 7.12-7.15(d, 1H), 7.29-7.34(m, 1H), 7.43-7.47(d, 3H), 7.54-7.56(d, 2H), 7.75-7.80(d, 2H);
mass spectral data of relugeli: [ M + H ]]+:624.18。
The method has fewer synthesis steps and higher synthesis efficiency, can safely obtain a high-quality Ruugeli intermediate with high yield, leads the reduction reaction catalyzed by palladium-carbon to be preposed, effectively controls the Ruugeli to be used as the index of the heavy metal content of the bulk drug, adopts a non-hydrogen mode for reduction, is more beneficial to industrial production, avoids the production risk brought by the use of a high-pressure reaction kettle, skillfully adopts the protection of amino, and removes a protecting group after introducing a pyridazine ring, so that the route has higher yield
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.
Claims (9)
1. A preparation method of Ruogeli is characterized in that: the method comprises the following steps:
s1: the compound 1 is reduced under the condition of palladium carbon/formic acid or palladium carbon/hydrazine hydrate to obtain a compound 2;
s2: reacting the compound 2 with tert-butyloxycarbonyl or trifluoroacetyl to obtain a compound 3;
s3: hydrolyzing the compound 3 to obtain a compound 4;
s4: reacting the compound 4 with 3-amino-6-methoxypyridazine to obtain a compound 5;
s5: removing the protecting group of the compound 5 to obtain a compound 6
S6: reacting the compound 6 with a compound 9 to obtain a compound 7, wherein the compound 9 is 1, 1-carbonyl diimidazole or salt thereof, methoxylamine or salt thereof;
s7: intramolecular cyclization of compound 7 under basic conditions gives compound 8.
2. A method of producing Ruugeli according to claim 1, wherein: in S1, hydrazine hydrate is used as hydrogen source, palladium carbon is used as catalyst, the proportion of hydrazine hydrate is 1-3eq, reaction solvent alcohol is used, and the reaction temperature is 0-60 ℃.
3. A method of producing Ruugeli according to claim 2, wherein: in S2, compound 2 is reacted with t-butyloxycarbonyl or trifluoroacetyl group under basic conditions to protect the amino group, and compound 3 is obtained.
4. A method of producing Ruugeli according to claim 1, wherein: in S3, compound 3 is hydrolyzed with strong base, such as KOH, NaOH or LiOH, to obtain compound 4.
5. A method of producing Ruugeli according to claim 1, wherein: in S4, reacting a compound 4 with 3-amino-6-methoxypyridazine under the conditions of propylphosphoric anhydride and alkali to obtain a compound 5, wherein the reaction solvent is selected to be an aprotic polar solvent, and the reaction temperature is selected to be 0-80 ℃.
6. A method of producing Ruugeli according to claim 4, wherein the method further comprises: the aprotic polar solvent is DMF, DMAc, DMSO, toluene or tetrahydrofuran, and the base is diisopropylethylamine or triethylamine.
7. A method of producing Ruugeli according to claim 1, wherein: in S5, compound 5 is deprotected under acidic condition, the temperature is 0-50 deg.C, and the acid is hydrochloric acid, trifluoroacetic acid or phosphoric acid.
8. A method of producing Ruugeli according to claim 1, wherein: in S6, the amount of the compound 6, 1, 1-carbonyldiimidazole used is 1.0 to 3.0 equivalents, the amount of the methoxylamine hydrochloride used is 1.0 to 3.0 equivalents, the reaction is carried out under basic conditions, the base is triethylamine or diisopropylethylamine, and the amount of the base used is 0.8 to 0.9 equivalents.
9. A method of producing Ruugeli according to claim 1, wherein: in S7, compound 7 is reacted in a solvent selected from methanol, ethanol, acetonitrile, tetrahydrofuran, and mixtures thereof, the base is sodium methoxide or sodium ethoxide, and the amount of compound 7 used is 0.01 to 2.0 equivalents, preferably 0.1 to 0.2 equivalents.
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