CN112062767B - Preparation method and intermediate of rumepilone - Google Patents
Preparation method and intermediate of rumepilone Download PDFInfo
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- CN112062767B CN112062767B CN202011124359.1A CN202011124359A CN112062767B CN 112062767 B CN112062767 B CN 112062767B CN 202011124359 A CN202011124359 A CN 202011124359A CN 112062767 B CN112062767 B CN 112062767B
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention provides a preparation method of rumepilone and an intermediate thereof, which comprises the step of using 6-bromo-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ]]Indole compound 1 is used as an initial raw material to obtain a compound 2, then Boc protection is carried out to obtain a compound 3, then the compound 3 and 2-chloro-N-methylacetamide are firstly carried out to obtain a compound 4, and then intramolecular Ullmann coupling reaction is carried out to cyclize the compound to obtain a compound 5; reducing the compound 5 by using borane to obtain a compound 6, then removing Boc protection and salifying to obtain a mepiquat chloride key intermediate compound 7, or reducing and deprotecting by a one-pot method and salifying to obtain an intermediate compound 7; an intermediate compound 7 and a compound 8 are subjected to reductive amination condensation to obtain a compound 9, and finally the compound is reacted with a 4-fluorophenyl Grignard reagent to obtain a Lumepigron product compound 10, wherein the reaction route is as follows:
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a preparation method of a new drug, namely rumepilone, for treating schizophrenia.
Background
Lumamepilone (Lumateperone, code ITI-007) is a new drug developed by Intra-Cellular therapeutics biopharmaceutical company, which combines a potent 5-HT2A receptor antagonist, a dopamine receptor phosphorylation modulator (DPPM), a glutamate modulator and a 5-hydroxytryptamine reuptake inhibitor into a whole, can be used for treating acute and residual schizophrenia, also has the effect of improving sleep quality, can reduce the negative symptoms of schizophrenia, also has certain effects on depression, anxiety and other symptoms related to impaired social functions, and is expected to become a breakthrough in the field of multi-target anti-schizophrenia drugs and bring new hopes to vast schizophrenia patients if the drug is finally sold in the market.
The chemical name of the rumepilone is as follows: 1- (4-fluorophenyl) -4- [ (6bR,10aS) -3-methyl-2, 3,6b,7,10,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (9H) -yl ] -1-butanone having the following structural formula:
J.Med.chem.J.2014 57 vol 2670-page 2682 reviews a synthetic route of a generation of Lumeperirone by using 3, 4-dihydroquinoxalin-2 (1H) -one as a starting material, carrying out nitrosation and zinc powder reduction reaction, then carrying out cyclization reaction with N-ethoxycarbonyl-4-piperidone to obtain 2-oxo-2, 3,9, 10-tetrahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline-8 (7H) -ethyl formate, reducing double bond by using sodium cyanoborohydride, carrying out methylation under the action of methyl iodide, reducing amidocarbonyl by using borane, and then carrying out hydrolysis and removal of ethoxycarbonyl to obtain a key mother ring intermediate cis-2,3,6b,7,8,9,10,10 a-octahydro-3-methyl-1H-pyrido [3',4', 4,5] pyrrolo [1,2,3-de ] quinoxaline. Then condensing the intermediate with 4-chloro-1- (4-fluorophenyl) -1-butanone to obtain cis-rumepilone, separating by a preparation column to obtain a rumepilone product, and finally purifying and separating the rumepilone product in a form of p-rumepilone p-toluenesulfonate, wherein the reaction route is shown as follows:
the article also reports a second-generation synthetic route of rumepilone, firstly 2-bromophenylhydrazine hydrochloride and 4-piperidone hydrate hydrochloride are subjected to cyclization reaction, then double bonds are subjected to silicon hydrogen reduction and amino protection reaction and then subjected to palladium-catalyzed coupling reaction with benzophenone imine, then the double bonds are condensed with ethyl bromoacetate, the condensed product is subjected to acidolysis and deprotection cyclization by a one-pot method to obtain cis-2-oxo-2, 3,6b,7,10,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline-8 (9H) -ethyl formate, and key mother ring intermediates cis-2,3,6b,7,8,9,10,10 a-octahydro-3-methyl-1H-pyrido [3',4', 4,5] pyrrolo [1,2,3-de ] quinoxaline, and finally condensing with-chloro-1- (4-fluorophenyl) -1-butanone and preparing and separating to obtain a rumepilone and rumepilone p-toluenesulfonic acid product, wherein the reaction route is as follows:
generally, the two methods for synthesizing the rumepilone have overlong steps, the route intermediates are racemate final products and need to be prepared and separated, the selectivity is poor, the yield is low, and the route cost is high; the condensation reaction yield of the key intermediate of the amine alkylation reaction and 4-chloro-1- (4-fluorophenyl) -1-butanone in the last step is low, and because of the influence of higher activity of benzyl carbonyl, side reactions are more and impurities are easy to generate; in general, the method still has certain limitations and lacks competitiveness when used for process production, and a method which is simple in process route, low in cost and suitable for industrial production still needs to be found.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for preparing the rumepilone, and the preparation method has the advantages of simple process route, low cost and suitability for industrial production.
One of the purposes of the invention is to provide a preparation method of a rumepilone intermediate compound 3, which adopts the following technical scheme:
a preparation method of a rumepilone intermediate compound 3 comprises the following steps:
(1) reducing double bonds of the compound 1 through asymmetric hydrogenation or enzyme catalytic reduction reaction, and then salifying with acid by a one-pot method to obtain a compound 2;
the acid is D or L-mandelic acid, D or L-malic acid, D or L-camphorsulfonic acid, D or L-tartaric acid or D or L-DTTA;
(2) selectively Boc protecting the amino group of the compound 2 to obtain an intermediate compound 3;
further, in the hydrogenation reduction reaction in the step (1), the catalyst is selected from dichloro (p-cymene) ruthenium (II), diiodo (p-cymene) ruthenium (II) or rhodium acetate, and the ligand is selected from S-BINAP, (S) -XylbINAP, S-Sunphos, Josiphos SL-J505-1 or Josiphos SL-J505-2; the added alkali is selected from triethylamine, diisopropylethylamine or N-methylmorpholine; the reaction solvent is selected from methanol, ethanol or isopropanol; the hydrogen pressure is 0.1-20.0 Mpa; the reaction temperature is 20-90 ℃.
Further, in the step (1), the type of the olefin reductase used in the enzyme-catalyzed reduction reaction is selected from OYEs, OPR1 or OPR 3; the coenzyme is NADP; the reducing agent reagent is selected from ethanol, glucose or isopropanol; the selected reaction system is DMSO, ethanol, isopropanol or water and the mixed solution thereof; the selected buffer is phosphoric acid, hydrochloric acid, sodium hydroxide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, Tris-HCl or a mixed solution formed by the phosphoric acid, the hydrochloric acid, the sodium hydroxide, the potassium dihydrogen phosphate, the dipotassium hydrogen phosphate, the sodium dihydrogen phosphate, the disodium hydrogen phosphate and the Tris-HCl; the reaction temperature is 20-35 ℃.
Further, in the Boc protection reaction in the step (2), the base is selected from triethylamine, diisopropylethylamine or N-methylmorpholine; the reaction solvent is selected from methanol, ethanol, isopropanol, dimethylformamide, dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, dichloromethane or toluene; the reaction temperature is-15 to 90 ℃.
The second purpose of the invention is to provide a preparation method of the intermediate compound 7 of rumepilone, which adopts the following technical scheme:
the preparation method of the rumepilone intermediate compound 7 comprises the following steps:
(1) condensing the compound 3 with 2-chloro-N-methylacetamide under the action of alkali to obtain a compound 4;
(2) carrying out intramolecular Ullmann coupling reaction on the compound 4 under the action of copper salt and ligand to obtain a compound 5;
(3) reducing the compound 5 under the action of a reducing agent to obtain a compound 6;
(4) deprotecting the compound 6 under the action of acid and salifying to obtain an intermediate compound 7;
further, in the step (1), the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; no catalyst is added or the catalyst is selected from benzyltriethylammonium chloride, sodium iodide, potassium iodide or TBAB; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or 1, 4-dioxane; the reaction temperature is-15 to 110 ℃.
Further, in the ullmann coupling reaction in the step (2), the selected catalyst is cuprous chloride, cuprous bromide or cuprous iodide; the ligand is not added or is selected from TMEDA, N' -dimethylethylenediamine, acetylacetone or dibenzoylmethane; the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine or DBU; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene; the reaction temperature is 20-180 ℃.
Further, in the reduction reaction in the step (3), the reducing agent is selected from borane or borane dimethyl sulfide complex; the reaction solvent is selected from dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran or toluene; the reaction temperature is-15 to 110 ℃.
Further, in the deprotection and salt formation reaction in the step (4), a deprotection reagent is selected from hydrochloric acid or thionyl chloride; the reaction solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile or toluene; the reaction temperature is 0-110 ℃.
The invention also aims to provide another preparation method of the intermediate compound 7 of the rumepilone, which adopts the following technical scheme:
the preparation method of the rumepilone intermediate compound 7 comprises the steps of reducing the compound 5 under the action of a reducing agent, carrying out BOC removal reaction by a one-pot method, and then salifying to obtain the compound 7;
further, the step reducing agent is selected from borane, borane dimethyl sulfide complex, lithium borohydride, sodium borohydride or potassium borohydride; the additive is selected from boron trifluoride diethyl etherate, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, zinc dichloride or ferric trichloride; the reaction solvent is selected from acetonitrile, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran or toluene; the reaction temperature is-15 to 110 ℃. The salt-forming solvent is selected from methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, toluene, tetrahydrofuran or 2-methyltetrahydrofuran; the salifying temperature is selected to be-20-90 ℃.
The fourth purpose of the invention is to provide a preparation method of rumepilone, which adopts the following technical scheme:
a preparation method of rumepilone comprises the following steps
(1) Carrying out reductive amination reaction on the compound 7 and the compound 8 in a solvent to obtain a compound 9;
(2) carrying out addition reaction on the compound 9 and 4-fluorophenyl magnesium bromide in a solvent to obtain a rumepilone compound 10;
further, in the reductive amination reaction in the step (1), the acid-binding agent is selected from triethylamine, diisopropylethylamine, DBU or DABCO; the reducing agent is selected from sodium borohydride, potassium borohydride, sodium acetate borohydride or sodium cyanoborohydride; the additive is selected from acetic acid, trifluoroacetic acid and p-toluenesulfonic acid; the solvent is selected from dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran or toluene; the reaction temperature is 0-60 ℃.
Further, in the step (2), the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, toluene or trifluorotoluene; the reaction temperature is-30 to 60 ℃.
The fifth purpose of the invention is to provide a new intermediate compound of rumepilone, the structural formula is as follows:
the invention aims at providing a preparation method of rumepilone, which adopts the following technical scheme:
a preparation method of Lumepilone takes a 6-bromo-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indole compound 1 as an initial raw material, firstly, a chiral intermediate is obtained by asymmetric hydrogenation reaction or alkene reductase catalytic reduction reaction, organic acid salifying is further purified to obtain a compound 2, then, the compound 3 is protected by Boc to obtain a compound 3, then, the compound 3 is firstly cyclized with 2-chloro-N-methylacetamide by intramolecular Ullmann coupling reaction to obtain a compound 5; reducing the compound 5 by using borane to obtain a compound 6, then removing Boc protection and salifying to obtain a mepiquat chloride key intermediate compound 7, or reducing and deprotecting by a one-pot method and salifying to obtain an intermediate compound 7; an intermediate compound 7 and a compound 8 are subjected to reductive amination condensation to obtain a compound 9, and finally the compound is reacted with a 4-fluorophenyl Grignard reagent to obtain a Lumepigron product compound 10, wherein the reaction route is as follows:
the method utilizes enzyme catalysis or asymmetric hydrogenation to obtain a chiral intermediate for synthesizing the rumepilone, has high yield and good chiral selectivity, effectively improves the route efficiency, and reduces the process cost; the intermediate 2 is modified by using the Boc protecting group, so that the subsequent crystallization performance of the intermediate is better, the purification and separation are facilitated, the reaction condition for removing the Boc is mild, and the operation is simple and convenient; the intermediate 3 can be subjected to condensation, Ullmann cyclization, carbonyl reduction and other reactions to obtain an intermediate 7, the reaction operation is simple, and the intermediate is easy to separate and purify; the Ullmann cyclization catalyst has low price and low route cost; the intermediate 2 is separated and purified by utilizing the chiral acid to form salt, so that the optical purity of the intermediate and the product can be greatly improved, and the subsequent purification means such as resolution or chiral column preparation and separation are avoided; in addition, the amide intermediate 9 and the Grignard reagent are used for high-efficiency selective reaction, the reaction is clean, high-efficiency and quick, and the purity of the obtained product is high. In general, the method reduces the experimental steps, is simple to operate, has mild reaction conditions, high total yield and low route cost, and is suitable for large-scale production.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
The hydrogenation vessel was charged with Compound 1(25.11g,100mmol), triethylamine (20.24g,200mmol) and methanol (125mL), dissolved by stirring, and [ Ru (C) was added rapidly after 3 nitrogen purges in vacuo6H6)Cl2]2(50.0mg,0.10mmol) and Josiphos SL-J505-1(113mg,0.20mmol), after the addition, the hydrogen is switched for three times, and then the mixture is pressurized to 8-10 Mpa and heated to 55-60 ℃ for reaction for 36 hours. Filtering with diatomite after the reaction is finished, removing part of methanol by spinning, dropping water (250mL), adding ethyl acetate for extraction (125mL × 2), discarding the water phase, combining organic phases, washing with water (125mL) for 1 time, adding anhydrous sodium sulfate for drying, filtering, heating to 55-66 ℃, adding a methanol (70mL) solution of L-tartaric acid (14.26g,95mmol), adding a small amount of seed crystals, slowly cooling to 0-10 ℃, precipitating a large amount of solid, filtering, collecting the solid, and drying to obtain a product 2a (33.59g, the yield is 83.3%, ee. is more than or equal to 99.5%)).
In example 1, [ Ru (C)6H6)Cl2]2That is, the dichloro (p-cymene) ruthenium can be replaced by diiodo (p-cymene) ruthenium (II) or rhodium acetate; the triethylamine can be replaced by diisopropylethylamine or N-methylmorpholine; the methanol can be replaced by ethanol or isopropanol; l-tartaric acid can be replaced by D or L-malic acid, D or L-camphorsulfonic acid, D-tartaric acid or D or L-DTTA.
Example 2
Adding a compound shown in the formula 1(25.11g,100mmol) into a three-neck flask under the protection of nitrogen, adding isopropanol (125mL) and water (250mL), stirring and fully dissolving, adding a buffer solution (0.2M) formed by mixing potassium dihydrogen phosphate and sodium hydroxide to adjust the pH value to 6.7-6.9, adding OPR3 enzyme (50mg) and NADH (0.6g) after the addition is finished, and reacting for 24-30 hours at 33 +/-0.5 ℃ by keeping the temperature. After the reaction is finished, 0.5M dilute hydrochloric acid (50mL) is added and stirred, ethyl acetate (75mL) is added and extracted once, the aqueous phase is separated, 0.5M sodium hydroxide is added to be used for regulating the pH value to 12-13, ethyl acetate (75mL 3) is added and extracted, the organic phase is collected and washed for 1 time, L-mandelic acid (15.21g,100mmol) is added and heated to 50-55 ℃ and stirred, the temperature is slowly cooled to 0-5 ℃, and the product 2b (31.94g,78.8 percent, ee. is more than or equal to 99.7 percent) is obtained by filtering and drying.
In the embodiment 2, isopropanol is a reducing agent and a solvent, when the reducing agent is glucose, the solvent can also be DMSO, ethanol, isopropanol or water and a mixed solution of the DMSO and the ethanol and the isopropanol, and when the solvent is replaced by DMSO, the reducing agent glucose is also added; the buffer solution of potassium dihydrogen phosphate and sodium hydroxide can be replaced by phosphoric acid, hydrochloric acid, sodium hydroxide, potassium hydroxide, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, Tris-HCl or their mixture; OPR3 can be replaced by OYEs or OPR 1; l-mandelic acid can be replaced by D-mandelic acid, D or L-malic acid, D or L-camphorsulfonic acid, D or L-tartaric acid, or D or L-DTTA
Example 3
Compound 2a (40.32g,100mmol) was charged into a three-necked flask, methylene chloride (200mL) was added thereto, the mixture was dissolved with stirring, Boc anhydride (100mmol) was added, triethylamine (18.33g,150mmol) was added thereto, and the mixture was reacted at room temperature for 6 to 8 hours. After the reaction, 5% potassium dihydrogen phosphate solution (200mL) was added and the mixture was stirred for liquid separation, the aqueous phase was extracted with dichloromethane (200mL) 2 times, the organic phase was washed with saturated brine (200mL) 1 time, concentrated, slurried with petroleum ether (200mL), filtered and dried to obtain Compound 3(32.25g, yield 91.3%).
MS(ESI)m/z＝354.1[M+H]+
1H NMR(400MHz,CDCl3)δ7.19(d,J＝8.0Hz,1H),7.04(d,J＝7.2Hz,1H),6.60(t,J＝7.6Hz,1H),3.95-4.06(m,2H),3.08-3.95(m,5H),1.86–1.96(m,1H),1.69–1.84(m,1H),1.46(s,9H).
In example 3, triethylamine can be replaced by diisopropylethylamine or N-methylmorpholine; the reaction solvent dichloromethane can be replaced by methanol, ethanol, isopropanol, dimethylformamide, dimethylacetamide, tetrahydrofuran, 1, 4-dioxane or toluene.
Example 4
Compound 3(35.33g,100mmol) was charged into a three-necked flask, DMF (106mL) was added and stirred to dissolve it, potassium carbonate (27.64g,200mmol) was added, N-methyl-2-chloroacetamide (12.90g,120mmol) and potassium iodide (332mg,2mmol) were added, and the mixture was heated to 55 to 60 ℃ and reacted for 10 to 16 hours. After the reaction, water (353mL) was added, dichloromethane (176mL) was added, the mixture was stirred and separated, the aqueous phase was extracted 2 times with dichloromethane (78mL), the organic phases were combined, washed with water (176mL) 1 time, concentrated, slurried with petroleum ether (176mL), filtered and dried to give compound 4(37.13g, 87.5% yield).
MS(ESI)m/z＝424.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.85(br,1H),7.18(d,J＝8.0Hz,1H),7.09(d,J＝7.2Hz,1H),6.61(t,J＝7.6Hz,1H),3.90-4.25(m,2H),3.75-3.85(m,1H),3.45-3.74(m,3H),3.28-3.40(m,1H),3.12-3.26(m,1H),2.63(d,J＝4.4Hz,3H)1.82–1.93(m,1H),1.68–1.81(m,1H),1.36(s,9H).
In example 4, potassium carbonate can be replaced by sodium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; the potassium iodide can be replaced by benzyltriethylammonium chloride, sodium iodide or TBAB, or not added; the reaction solvent N, N-dimethylformamide DMF may be replaced by N, N-dimethylacetamide, N-methylpyrrolidone or 1, 4-dioxane.
Example 5
Adding compound 4(42.43g,100mmol) into a three-neck flask, adding DMAC (126mL), stirring and dissolving, adding potassium carbonate (27.64g,200mmol), adding cuprous iodide (381mg,2.0mmol), adding dibenzoyl methane (449mg,2mmol), and heating to 85-90 ℃ for reaction for 10-16 hours. After the reaction, water (420mL) was added, ethyl acetate (210mL) was added, the mixture was stirred and separated, the aqueous phase was extracted with ethyl acetate (105mL) 2 times, the organic phases were washed with water (210mL) 1 time, concentrated, slurried with petroleum ether (210mL), filtered and dried to give Compound 5(28.78g, 83.8% yield).
MS(ESI)m/z＝344.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ6.90(d,J＝7.2Hz,1H),6.85(d,J＝7.2Hz,1H),6.77(t,J＝7.6Hz,1H),3.98(t,J＝14.4Hz,1H),3.87(br,1H),3.53-3.67(m,1H),3.40–3.52(m,2H),3.24–3.32(m,1H),3.22(s,3H),3.04–3.13(m,1H),2.54–3.00(m,1H),1.89–1.98(m,1H),1.72–1.84(m,1H),1.39(s,9H).
In example 5, cuprous iodide can be replaced by cuprous chloride or cuprous bromide; the ligand is not added or is selected from dibenzoylmethane, and can be replaced by TMEDA, N' -dimethylethylenediamine or acetylacetone, or is not added; the potassium carbonate can be replaced by sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine or DBU; the reaction solvent N, N-dimethylacetamide DMAC may be replaced by N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene or chlorobenzene.
Example 6
The compound 5(34.34g,100mmol) is added into a three-neck flask, tetrahydrofuran (172mL) is added and stirred to dissolve, a 1M borane tetrahydrofuran solution (200mL,200mmol) is slowly dropped, and the mixture is heated to reflux reaction for 12-15 hours. After the reaction is finished, cooling to 0-5 ℃, adding methanol (100mL) to quench the reaction, concentrating under reduced pressure, adding methanol (100mL) to concentrate under reduced pressure, adding methanol (50mL), adding water (343mL), slowly cooling, stirring, crystallizing, filtering and drying to obtain the compound 6(30.01g, yield 91.1%).
MS(ESI)m/z＝330.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ6.55(t,J＝7.6Hz,1H),6.45(d,J＝7.2Hz,1H),6.37(d,J＝8.0Hz,1H),3.70-3.98(m,1H),3.52-3.69(m,1H),3.40–3.52(m,1H),3.26–3.49(m,3H),2.99–3.13(m,2H),2.54–2.99(m,2H),2.80(s,3H),1.79–1.93(m,1H),1.68–1.78(m,1H),1.42(s,9H).
In example 6, the borane may be replaced with borane dimethylsulfide complex; the tetrahydrofuran may be replaced by dichloromethane, 1, 2-dichloroethane, 2-methyltetrahydrofuran or toluene.
Example 7
The compound 6(32.94g,100mmol) was added to a three-necked flask, and absolute ethanol (165mL) was added thereto, and stirred to dissolve the compound, and concentrated hydrochloric acid (30.4g,300mmol) was slowly added dropwise thereto, followed by heating to reflux and reacting for 12 to 15 hours. After the reaction, part of ethanol was removed, ethyl acetate (165mL) was added, the mixture was slowly cooled to 0-5 ℃ and filtered and dried to obtain compound 7(28.17g, yield 93.2%).
In example 7, concentrated hydrochloric acid may be replaced with thionyl chloride; the reaction solvent ethanol can be replaced by methanol, isopropanol, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, acetone, acetonitrile or toluene.
Example 8
Adding compound 5(34.34g,100mmol) into a three-neck flask, adding acetonitrile (172mL), stirring and dissolving, slowly and dropwise adding a 47% boron trifluoride diethyl etherate solution (90.6g,300mmol), heating to 55-60 ℃ for reaction, adding sodium borohydride (56.75g,150mmol) in batches, and then keeping the temperature for reaction for 10-12 hours. After the reaction is finished, cooling to 0-5 ℃, slowly adding a 5% sodium hydroxide solution to quench the reaction (343mL), concentrating to remove most of acetonitrile, extracting the water phase for 3 times by using ethyl acetate (172mL), combining the organic phases, washing with saturated salt water for 2 times (86mL), drying with sodium sulfate, concentrating, dropwise adding a hydrochloric acid methanol solution (30%, 24.3g and 200mmol), cooling to room temperature for crystallization, filtering, and drying to obtain a compound 7(26.66g and 88.2%).
In example 8, the sodium borohydride reducing agent can be replaced by borane, borane dimethylsulfide complex, lithium borohydride, or potassium borohydride; the additive boron trifluoride diethyl etherate can be replaced by trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid zinc dichloride or ferric trichloride; the reaction solvent acetonitrile can be replaced by dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran or toluene; the salifying methanol can be replaced by ethanol, isopropanol, ethyl acetate, acetonitrile, toluene, tetrahydrofuran or 2-methyltetrahydrofuran.
Example 9
Adding a compound 7(30.22g,100mmol), a compound 8(18.83g,110mmol) and tetrahydrofuran (150mL) into a three-neck flask, slowly adding triethylamine (10.12g,100mmol), stirring for reacting for 2-3 hours, adding acetic acid (9.01g,150mmol), adding sodium borohydride acetate (7.57g,200mmol) in batches, reacting for 6-8 hours at room temperature, adding 100mL of water to quench the reaction, adding a 10% sodium hydroxide solution to adjust the pH value to 9-10, separating, extracting the water phase for 3 times with ethyl acetate (150mL), combining the organic phases, washing with saturated saline water for 2 times (75mL), drying with sodium sulfate, concentrating, adding a small amount of seed crystals, cooling to room temperature for crystallization, filtering, and drying to obtain a compound 9(34.53g, 89.8%).
MS(ESI)m/z＝385.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ6.57(t,J＝7.2Hz,1H),6.43(d,J＝7.2Hz,1H),6.39(d,J＝8.0Hz,1H),3.61-4.02(m,10H),3.40–3.52(m,1H),3.26–3.49(m,3H),2.52–3.13(m,7H),2.34-2.42(m,4H),1.68–1.93(m,4H).
In example 9, the reducing agent sodium borohydride acetate can be replaced by sodium borohydride, potassium borohydride or sodium cyanoborohydride; the acetic acid can be replaced by trifluoroacetic acid or p-toluenesulfonic acid; the solvent tetrahydrofuran can be replaced by dichloromethane, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran or toluene; the triethylamine may be replaced by diisopropylethylamine, DBU or DABCO.
Example 10
The compound 9(38.45g,100mmol) is added into a three-neck flask, tetrahydrofuran (190mL) is added and stirred to dissolve, the temperature is cooled to 0-5 ℃, a 1M 4-fluorophenyl magnesium bromide solution (105mL,105mmol) is slowly dropped, and the temperature is slowly raised to room temperature for reaction for 2-4 hours. And after the reaction is finished, adding saturated ammonium chloride (190mL) to quench the reaction, separating the solution, extracting the water phase for 3 times by using ethyl acetate (150mL), combining the organic phases, washing the organic phases for 2 times (75mL), concentrating, adding p-toluenesulfonic acid (100mmol), cooling to room temperature for crystallization, filtering, adding water into the solid, slowly dropwise adding 1N sodium hydroxide solution to adjust the pH value to 11-12, slowly cooling for crystallization, filtering, and drying to obtain a product 10(35.61g, 90.5%, the purity is more than 99.8%).
In example 10, tetrahydrofuran may be replaced by 2-methyltetrahydrofuran, toluene or trifluorotoluene.
Claims (4)
1. The new intermediate compound of rumepilone is characterized by the following structural formula:
2. a preparation method of rumepilone is characterized by comprising the following steps:
(1) carrying out reductive amination reaction on the compound 7 and the compound 8 in a solvent to obtain a compound 9;
(2) carrying out addition reaction on the compound 9 and 4-fluorophenyl magnesium bromide in a solvent to obtain a rumepilone compound 10;
3. the method for preparing lumeplerenone according to claim 2, wherein in the reductive amination in the step (1), the acid-binding agent is selected from triethylamine, diisopropylethylamine, DBU, or DABCO; the reducing agent is selected from sodium borohydride, potassium borohydride, sodium acetate borohydride or sodium cyanoborohydride; the additive is selected from acetic acid, trifluoroacetic acid and p-toluenesulfonic acid; the solvent is selected from dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran or toluene; the reaction temperature is 0-60 ℃; in the reaction of the step (2), the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, toluene or trifluorotoluene; the reaction temperature is-30 to 60 ℃.
4. A preparation method of rumepilone is characterized in that a 6-bromo-2, 3,4, 5-tetrahydro-1H-pyrido [4,3-b ] indole compound 1 is used as an initial raw material, firstly, an asymmetric hydrogenation reaction or an alkene reductase catalytic reduction reaction is utilized to obtain a chiral intermediate, and an organic acid is utilized to form a salt for further purification to obtain a compound 2, then, Boc protection is carried out to obtain a compound 3, then, the compound 3 and 2-chloro-N-methylacetamide are firstly used to obtain a compound 4, and then, intramolecular Ullmann coupling reaction is firstly carried out to cyclize to obtain a compound 5; reducing the compound 5 by using borane to obtain a compound 6, then removing Boc protection and salifying to obtain a mepiquat chloride key intermediate compound 7, or reducing and deprotecting by a one-pot method and salifying to obtain an intermediate compound 7; an intermediate compound 7 and a compound 8 are subjected to reductive amination condensation to obtain a compound 9, and finally the compound is reacted with a 4-fluorophenyl Grignard reagent to obtain a Lumepigron product compound 10, wherein the reaction route is as follows:
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000077010A2 (en) * | 1999-06-15 | 2000-12-21 | Du Pont Pharmaceuticals Company | Substituted heterocycle fused gamma-carbolines |
| CN101528937A (en) * | 2006-11-15 | 2009-09-09 | 巴斯夫欧洲公司 | Process for enzymatic reduction of alkene derivatives |
| CN101796051A (en) * | 2007-03-12 | 2010-08-04 | 细胞内治疗公司 | substituted heterocycle fused gamma-carbolines synthesis |
| CN102858987A (en) * | 2010-02-01 | 2013-01-02 | 巴斯夫欧洲公司 | Process for the reduction of cinnamaldehyde derivative employing enoate reductases |
| CN110831941A (en) * | 2018-06-11 | 2020-02-21 | 细胞内治疗公司 | Synthesis of substituted heterocycle fused gamma-carboline compound |
| CN110862355A (en) * | 2019-12-03 | 2020-03-06 | 济南大学 | Synthetic method of efinaconazole intermediate |
| WO2020112941A3 (en) * | 2018-11-27 | 2020-07-09 | Teva Czech Industries S.R.O | Solid state forms of lumateperone salts and processes for preparation of lumateperone and salts thereof |
-
2020
- 2020-10-20 CN CN202011124359.1A patent/CN112062767B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000077010A2 (en) * | 1999-06-15 | 2000-12-21 | Du Pont Pharmaceuticals Company | Substituted heterocycle fused gamma-carbolines |
| CN101528937A (en) * | 2006-11-15 | 2009-09-09 | 巴斯夫欧洲公司 | Process for enzymatic reduction of alkene derivatives |
| CN101796051A (en) * | 2007-03-12 | 2010-08-04 | 细胞内治疗公司 | substituted heterocycle fused gamma-carbolines synthesis |
| CN102858987A (en) * | 2010-02-01 | 2013-01-02 | 巴斯夫欧洲公司 | Process for the reduction of cinnamaldehyde derivative employing enoate reductases |
| CN110831941A (en) * | 2018-06-11 | 2020-02-21 | 细胞内治疗公司 | Synthesis of substituted heterocycle fused gamma-carboline compound |
| WO2020112941A3 (en) * | 2018-11-27 | 2020-07-09 | Teva Czech Industries S.R.O | Solid state forms of lumateperone salts and processes for preparation of lumateperone and salts thereof |
| CN110862355A (en) * | 2019-12-03 | 2020-03-06 | 济南大学 | Synthetic method of efinaconazole intermediate |
Non-Patent Citations (2)
| Title |
|---|
| Discovery of a Tetracyclic Quinoxaline Derivative as a Potent and Orally Active Multifunctional Drug Candidate for the Treatment of Neuropsychiatric and Neurological Disorders;Peng Li et al.;《J. Med. Chem.》;20140221;第57卷;第2670-2682页 * |
| Simple and Efficient Preparation of Ketones from Morpholine Amides;R.Martin et al.;《SYNLETT》;19971231;第1414-1416页 * |
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