CN118206501A - Preparation method of rumorph - Google Patents
Preparation method of rumorph Download PDFInfo
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- CN118206501A CN118206501A CN202211612624.XA CN202211612624A CN118206501A CN 118206501 A CN118206501 A CN 118206501A CN 202211612624 A CN202211612624 A CN 202211612624A CN 118206501 A CN118206501 A CN 118206501A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 229940125782 compound 2 Drugs 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 229940125904 compound 1 Drugs 0.000 claims abstract description 17
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 lithium aluminum hydride Chemical compound 0.000 claims abstract description 11
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 10
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- 150000004678 hydrides Chemical class 0.000 claims abstract description 6
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000012280 lithium aluminium hydride Substances 0.000 claims abstract description 4
- 239000012448 Lithium borohydride Substances 0.000 claims abstract description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 3
- 229940126214 compound 3 Drugs 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- TUDHHJQPQZFEIH-UHFFFAOYSA-N piperidine-4,4-diol Chemical class OC1(O)CCNCC1 TUDHHJQPQZFEIH-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006783 Fischer indole synthesis reaction Methods 0.000 claims description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- GMLFPSKPTROTFV-UHFFFAOYSA-N dimethylborane Chemical group CBC GMLFPSKPTROTFV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- JQKIHHHTOFFTAM-UHFFFAOYSA-N piperidin-4-one;hydrate Chemical compound O.O=C1CCNCC1 JQKIHHHTOFFTAM-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 2
- RIFYBDSTDAXCRY-UHFFFAOYSA-N 2,2-dimethoxyethoxyalumane Chemical compound COC(CO[AlH2])OC RIFYBDSTDAXCRY-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 3
- PRPHBYLRCOEHOD-UHFFFAOYSA-N ethoxy(dimethoxy)alumane Chemical compound CCO[Al](OC)OC PRPHBYLRCOEHOD-UHFFFAOYSA-N 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000219053 Rumex Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- LHAPOGAFBLSJJQ-GUTACTQSSA-N iti007 Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.C([C@@H]1N2CCN(C=3C=CC=C(C2=3)[C@@H]1C1)C)CN1CCCC(=O)C1=CC=C(F)C=C1 LHAPOGAFBLSJJQ-GUTACTQSSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- PAEWLYMIIHHNKB-UHFFFAOYSA-N 1,9-diazatricyclo[6.3.1.04,12]dodeca-2,4(12),5,7,9-pentaene Chemical compound C1C=NC2=CC=CC3=C2N1C=C3 PAEWLYMIIHHNKB-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- RDMFHRSPDKWERA-UHFFFAOYSA-N 5H-Pyrido[4,3-b]indole Chemical compound C1=NC=C2C3=CC=CC=C3NC2=C1 RDMFHRSPDKWERA-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000002659 cell therapy Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000000848 glutamatergic effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- BQOLKFJNJCOALF-UHFFFAOYSA-N piperidin-1-ium-4,4-diol;chloride Chemical compound Cl.OC1(O)CCNCC1 BQOLKFJNJCOALF-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of rumorph, which comprises the following steps of: carrying out reduction reaction on the compound 1 and a hydride reducing agent to obtain a compound 2; the hydride reducing agent comprises at least one of lithium aluminum hydride, sodium borohydride, diisobutyl aluminum hydride, sodium cyanoborohydride, lithium borohydride, lithium triethylborohydride, triethylsilane, dimethoxy ethoxy aluminum hydride and borohydride complex. The invention has the advantages of easily obtained raw materials, mild reaction conditions and higher yield.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of rumorph.
Background
Rumex is a drug for treating adult schizophrenia, developed by the biopharmaceutical industry Intra-Cellular Therapies, which was approved by the United states Food and Drug Administration (FDA) for 12 months 2019 under the trade name Caplyta. Rumex is the first novel drug in the field of schizophrenia treatment, and exerts curative effects by synergistically regulating the central 5-HT, DA and glutamatergic systems.
Several synthetic methods of rumorph have been reported in the prior art. Such as:
Chinese patent CN101796051B discloses a method for preparing a heterocycle fused gamma-carboline which is condensed with a substituted heterocycle, and the method requires column chromatography purification in the subsequent closing process, has low yield, uses a large amount of toxic substances, is not beneficial to industrial production, and has the technical route as follows:
Chinese patent CN112062767B discloses a preparation method of lumepiquat chloride and an intermediate thereof, the key steps of the method are that asymmetric hydrogenation and tartaric acid crystallization are utilized to synthesize chiral o-bromooctahydro-gamma-carbazole, the chiral ligand JosiphosSL-J505-1 is expensive, the asymmetric catalytic conversion number (S/c=1000) is not high, the industrial application value is limited, and the technical route is as follows:
the inventors tried to further prepare rumolsidone by preparing intermediate compound 2 using compound 1 as a starting material, the structures of compound 1 and compound 2 are specifically as follows:
However, none of the current studies have successfully produced compound 2 from compound 1, such as the study of M.ty s Milen et al (NEW SYNTHESIS ofa late-STAGE TETRACYCLIC KEY INTERMEDIATE oflumateperone) clearly indicates that compound 2 cannot be produced from compound 1, as follows:
Therefore, it is necessary to develop a process for preparing rumorph which solves the above technical problems.
Disclosure of Invention
The invention aims to overcome the defects, and provides a brand-new preparation method of the rumorph, which has the advantages of easily available raw materials, mild reaction conditions, simplicity in operation, lower cost and higher yield, does not use a highly toxic reagent, is environment-friendly and has a good application prospect. The compound 2 is successfully prepared from the compound 1, the technical problem that the compound 2 cannot be prepared from the compound 1 is solved, the prepared compound 2 is stable in property, and the compound 3 and the rupulone can be further prepared.
The invention is realized by the following technical scheme:
a process for preparing compound 2 from compound 1 comprising the steps of:
In the presence of a solvent, carrying out a reduction reaction on the compound 1 and a hydride reducing agent to obtain a compound 2;
The structures of compound 1 and compound 2 are specifically as follows:
preferably, the hydride reducing agent is at least one selected from lithium aluminum hydride, sodium borohydride, diisobutyl aluminum hydride, sodium cyanoborohydride, lithium borohydride, lithium triethylborohydride, triethylsilane, dimethoxy ethoxy aluminum hydride, and borohydride complex; the borohydride complex is preferably dimethyl borane sulfide or THF borane.
Preferably, the reduction reaction is carried out at a temperature of less than 35 ℃, preferably less than 20 ℃, more preferably less than 10 ℃, most preferably less than 5 ℃, particularly preferably-20 ℃ to 5 ℃, most particularly preferably-10 ℃ to 5 ℃.
Preferably, the solvent is selected from the group of reaction inert solvents, preferably at least one of THF, diethyl ether, isopropyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, ethanol or isopropanol.
The invention also relates to a preparation method of the compound 3, which comprises the following steps:
in the presence of a solvent, carrying out Fischer indole synthesis reaction on the compound 2 and 4-piperidone or hydrate thereof and salt thereof to obtain a compound 3;
The structure of compound 3 is specifically as follows:
The compound 2 can be obtained from a commercially available product or can be prepared from the compound 1 by the preparation method.
Preferably, the 4-piperidone hydrate and its salt are selected from piperidine-4, 4-diol salts, preferably piperidine-4, 4-diol salts.
Preferably, the molar ratio of compound 2 to 4-piperidone or its hydrate and salt thereof is 1:1-5, preferably 1:1-3, more preferably 1:1.
Preferably, the solvent is selected from the group of reaction-inert solvents, preferably alcoholic solvents, more preferably C1-C6 alcohols, particularly preferably at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol.
Preferably, the reaction temperature is 50-120 ℃, preferably 60-100 ℃, more preferably 70-100 ℃, most preferably 90 ℃.
The invention also relates to a preparation method of the rumorph, which comprises the following steps:
(1) Carrying out reduction reaction on the compound 3 and a reducing agent to obtain a compound 4;
(2) Carrying out hydrocarbylation reaction on the compound 4 to obtain the rumopidone;
The reaction route is as follows:
the compound 3 can be obtained from a commercially available product or can be prepared from the compound 2 by the preparation method.
Preferably, the reducing agent is selected from at least one of triethylsilane, sodium cyanoborohydride and sodium triacetoxyborohydride.
Preferably, the reaction in step (1) is carried out at room temperature.
Preferably, the hydrocarbylation reaction feed material in step (2) is 4-halo-4 '-fluorobenzene butanone, preferably 4-chloro-4' -fluorobenzene butanone; the reaction is carried out in the presence of a base selected from at least one of potassium carbonate and sodium carbonate.
Preferably, step (2) is performed in the presence of a solvent selected from the group consisting of reaction-inert solvents, preferably at least one of DMF and DMSO.
Preferably, the temperature of the hydrocarbylation reaction in step (2) is from 60 to 150 ℃, preferably from 70 to 120 ℃, more preferably 100 ℃.
The invention also relates to application of the compound 2 or the compound 3 or the compound 2 prepared by the method or the compound 3 prepared by the method in preparing the rumolepdone.
The beneficial effects of the invention are as follows:
the compound 2 is successfully prepared by adopting the compound 1, and the reaction condition is mild and the operation is simple.
The method for preparing the rumorph by using the compound 1 as the initial raw material has the advantages of easily available raw materials, lower preparation cost, mild reaction conditions and higher yield, and is beneficial to industrial production.
Detailed Description
The invention will be further described with reference to specific embodiments, and advantages and features of the invention will become apparent from the description. These examples are merely exemplary and do not limit the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions of details and forms of the technical solution of the present invention may be made without departing from the spirit and scope of the present invention, but these changes and substitutions fall within the scope of the present invention.
Example 1
Compound 2: the preparation process of the 1-methyl-4-amino-1, 2,3, 4-tetrahydroquinoxaline comprises the following steps:
Compound 1 (1.5 g,8.44mmol,1 eq) was dissolved in 20mL of redistilled THF, and a solution of 1N lithium aluminum hydride in THF (20 mL) was added dropwise under nitrogen and ice-bath protection, and the ice-bath reaction was maintained for 1 hour. After completion of the reaction, the mixture was quenched with water dropwise, extracted with dichloromethane (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL. Times.2), and dried over anhydrous magnesium sulfate. Suction filtration and spin drying of the solvent gave compound 2 as a yellow oily liquid (0.66 g,48% yield).
The nuclear magnetic resonance spectrum of the produced compound 2 is as follows:
1H NMR(600MHz,DMSO-d6)δ6.97-6.99(m,1H),6.50-6.57(m,2H),6.37-6.39(m,1H),4.14(br s,2H),3.32-3.33(m,4H),2.74(s,3H).
Example 2
Compound 3: the preparation process of the 3-methyl-2,3,7,8,9,10-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline comprises the following steps:
compound 2 (0.3 g,1.84mmol,1 eq) and piperidine-4, 4-diol hydrochloride (0.28 g,1.84mmol,1 eq) were dissolved in 20mL isopropanol and reacted at 90℃under reflux for 2 hours. After the reaction of the raw materials is completed, the temperature is restored to the room temperature, 1mL of concentrated hydrochloric acid is added dropwise, and the reflux reaction is carried out for 3 hours at 90 ℃. After the reaction was completed, the reaction mixture was returned to room temperature, suction filtration, washing with cold isopropanol solution, and vacuum drying to obtain a pale yellow solid as hydrochloride of Compound 3 (0.24 g,57% yield).
The nuclear magnetic resonance spectrum of the produced compound 3 is as follows:
1H NMR(600MHz,DMSO-d6)δ6.51(m,1H),6.40(m,1H),6.22(m,1H),4.35(m,2H),4.15(m,2H),3.69(m,2H),3.30(m,2H),2.82(m,2H),2.75(s,3H),1.91(br s,1H).ESI-MS:m/z 228.1[M+H]+.
Example 3
Compound 4: the preparation process of the 3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline comprises the following steps:
Compound 3 hydrochloride (0.1 g,0.44mmol,1 eq) was dispersed in 20mL trifluoroacetic acid and triethylsilane (0.1 g,0.88mmol,2 eq) was added dropwise and reacted at room temperature for 12 hours. After the reaction is finished, spin-drying the solvent, adding n-hexane, pulping for 5 hours, discarding n-hexane to obtain light yellow oily liquid which is a compound 4, and directly putting into the next step in a racemization state.
ESI-MS:m/z 230.2[M+H]+.
Example 4
The preparation process of the rufoperazone (ITI-007) is as follows:
Compound 4 (0.1 g,0.44mmol,1 eq) was dissolved in 20mL of LDMF, 4-chloro-4' -fluorobenzene butanone (0.13 g,0.66mmol,1.5 eq), potassium carbonate (0.12 g,0.88mmol,2 eq), potassium iodide (6.64 mg,0.04mmol,0.1 eq) was added in sequence, and the mixture was reacted at 100℃for 12 hours. After completion of the reaction, the reaction mixture was returned to room temperature, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL. Times.2), and dried over anhydrous magnesium sulfate. Suction filtering, spin drying, adding cyclohexane, pulping for 12 hr, removing cyclohexane, spin drying to obtain yellow oily substance as racemized form of rumorph, and chiral preparing to obtain rumorph product by liquid phase separation.
The nuclear magnetic resonance spectrum of the prepared rumolsidone is as follows:
1H NMR(DMSO-d6,600MHz)δ9.10(br,1H),8.01-8.09(m,2H),7.48(m,2H),7.33-7.41(m,2H),7.11(m,2H),6.57-6.65(m,1H),6.51(d,J＝7.3Hz,1H),6.42(d,J＝7.9Hz,1H),3.59(dd,J＝12.2,6.5Hz,1H),3.41-3.52(m,3H),3.28-3.37(m,2H),3.20-3.25(m,1H),2.99-3.18(m,5H),2.81(s,3H),2.71(td,J＝10.2,3.0Hz,1H),2.52-2.62(m,1H),2.28(s,3H),2.22-2.27(m,1H),1.93-2.15(m,3H).13C NMR(DMSO-d6,150MHz)δ197.2,165.1,145.6,137.6,137.3,135.2,133.1,130.9,128.1,126.7,125.5,120.6,115.7,112.5,109.3,62.2,55.5,52.5,49.8,47.8,43.7,38.6,37.0,34.9,21.7,20.8,18.0.ESI-MS:m/z 394.2[M+H]+.HRMS(ESI)m/z calcd for C24H29FN3O[M+H]+,394.2216,found 394.2245.
The foregoing detailed description is directed to one of the possible embodiments of the present invention, which is not intended to limit the scope of the invention, but is to be accorded the full scope of all such equivalents and modifications so as not to depart from the scope of the invention.
Claims (18)
1. A process for preparing compound 2 from compound 1, comprising the steps of:
In the presence of a solvent, carrying out a reduction reaction on the compound 1 and a hydride reducing agent to obtain a compound 2; wherein, the structures of the compound 1 and the compound 2 are specifically as follows:
2. The method according to claim 1, wherein the hydride reducing agent is at least one selected from the group consisting of lithium aluminum hydride, sodium borohydride, diisobutyl aluminum hydride, sodium cyanoborohydride, lithium borohydride, lithium triethylborohydride, triethylsilane, dimethoxyethoxy aluminum hydride, and borohydride complexes; the borohydride complex is preferably dimethyl borane sulfide or THF borane.
3. The preparation method according to claim 1, characterized in that the reduction reaction is carried out at a temperature below 35 ℃, preferably below 20 ℃, more preferably below 10 ℃, most preferably below 5 ℃, particularly preferably between-20 ℃ and 5 ℃, most particularly preferably between-10 ℃ and 5 ℃.
4. The preparation method according to claim 1, wherein the solvent is selected from the group consisting of reaction inert solvents, preferably at least one of THF, diethyl ether, isopropyl ether, methyl tert-butyl ether, 2-methyltetrahydrofuran, ethanol or isopropanol.
5. A process for the preparation of compound 3 comprising the steps of:
In the presence of a solvent, carrying out Fischer indole synthesis reaction on the compound 2 and 4-piperidone or hydrate thereof and salt thereof to obtain a compound 3; the structure of compound 3 is specifically as follows:
6. The process according to claim 5, wherein the 4-piperidone hydrate and the salt thereof are selected from piperidine-4, 4-diol salts, preferably piperidine-4, 4-diol salts.
7. The production method according to claim 5, further comprising the step of producing the compound 2 by the production method according to any one of claims 1 to 4.
8. The method according to claim 5, wherein the molar ratio of the compound 2 to 4-piperidone or its hydrate or its salt is 1:1-5, preferably 1:1-3, more preferably 1:1.
9. The preparation method according to claim 5, wherein the solvent is selected from the group consisting of reaction inert solvents, preferably alcoholic solvents, more preferably C1-C6 alcohols, particularly preferably at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol.
10. The preparation process according to claim 5, wherein the reaction temperature is 50-120 ℃, preferably 60-100 ℃, more preferably 70-100 ℃, most preferably 90 ℃.
11. A method for preparing rumolsidone, comprising the steps of:
(1) Carrying out reduction reaction on the compound 3 and a reducing agent to obtain a compound 4;
(2) Carrying out hydrocarbylation reaction on the compound 4 to obtain the rumopidone;
The reaction route is as follows:
12. The production method according to claim 11, further comprising the step of producing the compound 3 by the production method according to any one of claims 5 to 10.
13. The method according to claim 11, wherein the reducing agent is at least one selected from triethylsilane, sodium cyanoborohydride, and sodium triacetoxyborohydride.
14. The process of claim 11, wherein the reaction in step (1) is carried out at room temperature.
15. The process according to claim 11, wherein the hydrocarbylation reaction material in step (2) is 4-halo-4 '-fluorobenzene butanone, preferably 4-chloro-4' -fluorobenzene butanone; the reaction is carried out in the presence of a base selected from at least one of potassium carbonate and sodium carbonate.
16. The method of claim 15, wherein step (2) is performed in the presence of a solvent selected from the group consisting of a reaction-inert solvent, preferably at least one of DMF and DMSO.
17. The process according to claim 11, wherein the hydrocarbylation reaction temperature in step (2) is in the range of 60-150 ℃, preferably 70-120 ℃, more preferably 100 ℃.
18. Use of compound 2 or compound 3 or compound 2 prepared by the preparation method of any one of claims 1-4 or compound 3 prepared by the preparation method of any one of claims 5-10 in preparing rumolsidone.
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| CN202211612624.XA CN118206501A (en) | 2022-12-15 | 2022-12-15 | Preparation method of rumorph |
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