CN111333633A - Rugosril intermediate compound and preparation method and application thereof - Google Patents
Rugosril intermediate compound and preparation method and application thereof Download PDFInfo
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a new intermediate compound of Ruogeli and a preparation method thereof, wherein the intermediate compound has high purity and can be used for preparing Ruogeli and salt, derivatives or analogues thereof; the invention also discloses a preparation method of Ruogeli, and the obtained finished product has high yield and high purity, and the condensed urea by-product is not detected.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and relates to a Ruogeli intermediate compound, and a preparation method and application thereof.
Background
Ruogeli is a gonadotropin releasing hormone antagonist (GnRH) developed by Wutian, Japan and marketed in Japan in 2018 for bleeding and pain caused by uterine fibroids. Clinical trials in phase iii intended for endometriosis-related pain and prostate cancer are also in progress.
Only 2 synthetic routes to relogeli are currently disclosed. Med. chem.2011,54, 4998-:
the route is a compound route, the yield of the last step is only 44%, and the yield is low.
The original patent CN104703992B discloses another synthetic route, which is as follows:
the overall yield of the route is high, but the route has a great defect that urea is formed in the last step to react, urea condensation byproducts with the content of about 2.0% are generated, the impurities are difficult to remove, and in addition, the impurities have a tendency to increase along with the scale-up of the feeding materials, and the removal difficulty is further increased, so that the development of a Ruugeli process route with high yield and less urea condensation byproducts has important significance.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention discloses a brand-new Ruugeli intermediate compound and a preparation method thereof, and a preparation method of Ruugeli and salts or analogues thereof, wherein a condensed urea byproduct is not detected in the prepared Ruugeli finished product, and the yield and the purity are high.
The present invention provides a compound of formula G,
wherein the content of the first and second substances,
R2is C1-6A linear or branched alkyl group; preferably, R2Is ethyl or isobutyl.
The present invention also provides a process for the preparation of compound formula G comprising the steps of: in an organic solvent, carrying out condensation reaction on the intermediate F and 3-amino-6-methoxypyridazine or salt thereof under the action of a condensing agent to obtain a compound G;
wherein R is2Is C1-6A linear or branched alkyl group;
preferably, R2Is ethyl or isobutyl;
preferably, the organic solvent is selected from the group consisting of N, N-Dimethylacetamide (DMA), N-dimethylformamide, acetonitrile, tetrahydrofuran, N-methylpyrrolidone, preferably N, N-Dimethylacetamide (DMA), N-dimethylformamide, and acetonitrile;
preferably, the condensing agent is selected from the group consisting of propylphosphoric anhydride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/4-dimethylaminopyridine or 1-hydroxybenzotriazole and carbonyldiimidazole, preferably propylphosphoric anhydride;
preferably, the condensation reaction temperature is 25-85 ℃, preferably 40-60 ℃;
preferably, the reaction is carried out under the condition of an organic base, wherein the organic base is preferably DIPEA (N, N-diisopropylethylamine) or triethylamine;
preferably, the method further comprises a post-treatment step;
preferably, the steps include: dissolving a compound F in an organic solvent, adding 3-amino-6-methoxypyridazine hydrochloride, organic base and a condensing agent, stirring the mixture, heating to 40-60 ℃, and reacting for 1-10 h; the method can further comprise the following post-treatment steps: cooling the reaction solution to room temperature, adjusting pH to 5-6, adding water for dilution, extracting, combining organic phases, drying, filtering, concentrating the filtrate, and purifying; the reaction time is preferably 1-2 h; the pH is preferably adjusted using an inorganic base (e.g., sodium carbonate); the solvent used for extraction is preferably ethyl acetate; the concentration is preferably carried out under reduced pressure.
The invention also provides a preparation method of the compound shown in the formula F, which comprises the following steps: carrying out a reduction reaction on the compound shown in the formula E in a mixed solvent of an organic solvent and water under the action of alkali to obtain a compound shown in the formula F; the reaction equation is as follows:
wherein R is1、R2Each independently represents C1-6A linear or branched alkyl group;
preferably, R1Is ethyl; r2Is ethyl or isobutyl;
preferably, the alkali is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide and sodium ethoxide, and more preferably potassium hydroxide or lithium hydroxide;
preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol and tetrahydrofuran, and more preferably ethanol and methanol;
preferably, the method further comprises a post-treatment step;
preferably, it comprises the steps of: dissolving the compound shown in the formula E in an organic solvent, adding an alkaline solution, and stirring at room temperature for reaction for 24-72 h; the method can further comprise the following post-treatment steps: adding water into the reaction solution, concentrating under reduced pressure, adjusting pH to 6-7 with acid, extracting, mixing organic phases, drying, filtering, and concentrating; adjusting the pH value and optimizing ice bath conditions; the acid is preferably hydrochloric acid (e.g., 1M hydrochloric acid); the solvent used for extraction is preferably dichloromethane; the reaction time is preferably 20-48 h; the concentration is preferably carried out under reduced pressure.
The present invention also provides a process for the preparation of compound formula E, comprising the steps of: the compound formula D and methoxyamino benzoate are subjected to condensation reaction in an organic solvent to obtain a compound formula E, and the reaction equation is as follows:
wherein R is1、R2Each independently represents C1-6A linear or branched alkyl group;
preferably, R1Is ethyl; r2Is ethyl or isobutyl;
preferably, the organic solvent is one or more of acetonitrile, toluene, chlorobenzene, isopropyl acetate and tetrahydrofuran; more preferably toluene or acetonitrile;
preferably, the reaction temperature is 50-110 ℃, preferably 70-108 ℃;
preferably, the method further comprises a post-treatment step;
preferably, the steps include: dissolving a compound formula D and methoxy amino phenyl formate in an organic solvent, stirring and heating to 70-108 ℃; the method can further comprise the following post-treatment steps: cooling, adding an alkali solution, stirring, separating, washing, drying the organic phase, filtering and concentrating; cooling, preferably to room temperature; the base is preferably potassium carbonate solution (such as 1M potassium carbonate solution); water is preferably adopted for washing; the concentration is preferably carried out under reduced pressure.
The present invention also provides a process for the preparation of compound formula D, comprising the steps of:
wherein X represents Cl, Br or I;
wherein R is1、R2Each independently represents C1-6A linear or branched alkyl group;
preferably, R1Is ethyl; r2Is ethyl or isobutyl;
preferably, steps A-B: reacting the compound shown in the formula A with a halogenating reagent in an organic solvent to generate a compound shown in the formula B;
more preferably, the organic solvent is selected from one or more of chloroform, dichloromethane, ethyl acetate, isopropyl acetate and chlorobenzene, and ethyl acetate or chloroform is preferred;
more preferably, the initiator used in the halogenation reaction is one or more selected from Azobisisobutyronitrile (AIBN), Azobisisoheptonitrile (AIBN) or benzoyl peroxide;
more preferably, the halogenating agent is selected from the group consisting of N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), N-chlorosuccinimide (NCS), dibromohydantoin;
more preferably, the temperature of the halogenation reaction is 50 to 100 ℃, preferably 60 to 70 ℃;
more preferably, the method also comprises a post-treatment step;
more preferably, the steps comprise: dissolving a compound A in an organic solvent, adding a halogenated reagent and an initiator, stirring and heating to 50-100 ℃, and reacting for 15-30 h (such as 15-18 h); optionally further comprises post-treatment step, cooling, adding saturated sodium sulfite solution and water into the reaction solution, stirring, separating, washing, concentrating the organic phase, crystallizing, washing and drying; the temperature is preferably reduced to room temperature; water is preferably adopted for washing; concentrating preferably under reduced pressure; the concentration preferably adopts a mode of adding ethanol and heptane for fractional concentration; drying preferably under reduced pressure; washing is preferably carried out by using an ethanol/heptane mixed solvent, and more preferably, the volume ratio of ethanol to heptane is 1: 2;
preferably, steps B-C: carrying out an alkylation reaction on the compound shown in the formula B and dimethylamine hydrochloride in an organic solvent under the action of alkali to obtain a compound shown in a formula C;
more preferably, the base used in the alkylation reaction is one or more selected from triethylamine, N-diisopropylethylamine, N-methylmorpholine, sodium carbonate, potassium carbonate and sodium bicarbonate, preferably triethylamine or potassium carbonate;
more preferably, the organic solvent is methanol, ethanol, isopropanol, acetonitrile, preferably ethanol;
more preferably, the temperature of the reaction is-10-40 ℃, preferably room temperature;
more preferably, the crude product of the compound formula C generated by the reaction is added into a solvent (preferably tetrahydrofuran), and then acid is added to precipitate out, so that a high-purity intermediate C is obtained; the acid is selected from hydrochloric acid, phosphoric acid, sulfuric acid, oxalic acid, acetic acid or malic acid;
more preferably, the base is selected from one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and triethylamine;
more preferably, the method also comprises a post-treatment step;
more preferably, the steps comprise: dissolving the compound shown in the formula B in an organic solvent, adding alkali, adding dimethylamine hydrochloride in batches, and stirring at room temperature for reacting for 2-10 h (such as 3-6 h); the method can further comprise the following post-treatment steps: heating the reaction solution to 30-60 deg.C (such as 40-50 deg.C), adding water, stirring for 1-5 hr, stirring at 25-35 deg.C for 1-5 hr, filtering, washing, and drying; the washing solvent is preferably an ethanol/water solution, more preferably the volume ratio of ethanol to water is 4: 1; the drying method is preferably drying under reduced pressure.
Preferably, steps C-D: carrying out reduction reaction on the compound formula C in an organic solvent under the action of palladium carbon hydrogen to obtain a compound formula D;
more preferably, the organic solvent is one or more of alcohol (such as methanol, ethanol, etc.), dichloromethane, and ethyl acetate; methanol and dichloromethane, ethanol are preferred.
More preferably, the temperature of the reduction reaction is 20-50 ℃, preferably room temperature;
more preferably, the steps comprise: dissolving a compound C in an organic solvent, placing the system in a nitrogen environment, adding Pd/C, placing the system in a hydrogen environment, and stirring and reacting at 20-50 ℃ for 2-5 h; the method can further comprise the following post-treatment steps: filtering the reaction solution, concentrating the filtrate to dryness, adding an organic solvent for dissolving, adding acid, stirring, filtering, washing, drying to obtain crystals, dissolving the crystals in the organic solvent and water, adding alkali, stirring, separating liquid, washing an organic phase, drying, filtering and concentrating; the concentration is preferably reduced pressure concentration; the organic solvent is preferably ethyl acetate; the solvent adopted for washing is ethyl acetate; the drying is preferably drying under reduced pressure; the acid is preferably one of hydrochloric acid, phosphoric acid, sulfuric acid, oxalic acid, acetic acid and malic acid, and is more preferably hydrochloric acid (such as 20% (V/V) hydrochloric acid isopropanol solution); the alkali used is preferably one of sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, and more preferably sodium carbonate.
Preferably, compound formula D can further prepare compound formula G, the process comprising the steps of: D-E, E-F and/or F-G as described above.
The invention also provides a preparation method of Ruogeli (formula I), which comprises the following steps: in an organic solvent, a compound shown in the formula G undergoes a cyclization reaction under the action of alkali to obtain Ruogeli (shown in the formula I), and the reaction equation is as follows:
wherein R is2Represents C1-6A linear or branched alkyl group;
preferably, the first and second liquid crystal materials are,R2is ethyl or isobutyl;
preferably, the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide, preferably sodium methoxide, sodium ethoxide or sodium tert-butoxide;
preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, tert-butanol and tetrahydrofuran; methanol and tetrahydrofuran, isopropanol are preferred.
Preferably, the temperature of the cyclization reaction is 20-80 ℃, preferably 60-70 ℃;
preferably, the method further comprises a post-treatment step;
preferably, the steps include: dissolving a compound shown in the formula G in an organic solvent, adding alkali, stirring the mixture, heating to 20-80 ℃, and reacting for 1-12 h; the method can further comprise the following post-treatment steps: adjusting pH to 7-10 with acid, concentrating to dry, adding organic solvent, filtering, adding solvent to precipitate a large amount of solid, filtering, pulping, filtering, and drying; the acid is preferably 6M hydrochloric acid; the pH is preferably 8 to 9; the solvent is preferably ethyl acetate; the solvent adopted by the pulping is preferably a mixed solvent of ethyl acetate and dichloromethane, and more preferably the volume ratio of the ethyl acetate to the dichloromethane is 1: 1.
Preferably, the preparation method comprises the following steps:
wherein R is1、R2Each independently represents C1-6A linear or branched alkyl group;
preferably, R1Is ethyl; r2Is ethyl or isobutyl;
more preferably, each step A-B, B-C, C-D, D-E, E-F, F-G in the reaction equation is as described above.
The present invention also provides a compound of the formula,
wherein R is1、R2Each independently represents C1-6A linear or branched alkyl group; preferably, R1Is ethyl; r2Is ethyl or isobutyl.
The invention also provides the use of a compound of formula D, formula E, formula F or formula G for the preparation of relogelide and salts, derivatives or analogues thereof.
In the present invention, the post-treatment step includes, but is not limited to, stirring, liquid or solid transferring, water washing, alkali washing, acid washing, PH value adjusting, filtering, ultrafiltration, circulating ultrafiltration, suction filtration, dilution, concentration, drying, recrystallization, freeze-drying, or one or more of stirring, liquid or solid transferring, water washing, alkali washing, acid washing, PH value adjusting, filtering, ultrafiltration, circulating ultrafiltration, suction filtration, dilution, concentration, drying, recrystallization, freeze-drying, and the like.
The invention has the beneficial technical effects that:
1. the brand new Ruugeli intermediate compound shown in the formula D, the formula E, the formula F or the formula G has higher purity, particularly the compound shown in the formula G has high purity, and a favorable basis is provided for preparing high-purity Ruugeli.
2. According to the synthetic method of Ruugeli, the structure of urea is introduced in the previous step, and the urea condensation byproduct formed in the process is not detected in the Ruugeli finished product through a plurality of subsequent steps; and the seven-step reaction has the total molar yield of over 45 percent and the purity of over 99 percent.
Detailed Description
The present invention is further illustrated below with reference to specific examples, wherein the operating parameters are given by way of illustration only and are not intended to limit the full scope of the present invention.
Examples 1 to 2: formula B (wherein R1Is ethyl, R2Is isobutyl and X is bromo) intermediates
Example 1
30.14g of the compound of the formula A are weighed into a 1000mL three-necked flask, 240mL of ethyl acetate, 15.11g of NBS (N-bromosuccinimide) and 0.93g of AIBN (azobisisobutyronitrile) are added, the mixture is stirred and heated to 70 ℃, the temperature is reduced to room temperature after 18 hours of reaction, 60mL of saturated sodium sulfite solution is added, 200mL of water is added, the aqueous phase is separated after 10 minutes of stirring, and the organic phase is washed twice with 100mL of water. The organic phase was concentrated under pressure to about 120mL, 90mL of ethanol was added, and the mixture was concentrated to about 120mL, further 90mL of ethanol was added, further 120mL was concentrated, heptane 50mL was added, and the mixture was stirred at 20 to 30 ℃ for 30 minutes, n-heptane was again added, stirring was performed at 0 to 10 ℃ for 1 hour, crystals were collected by filtration and washed with ethanol/heptane 1/2, and after drying under reduced pressure, 31.64g of pale yellow crystal form B was obtained with a yield of 91.45% and a chemical purity of 97.80%.
The nuclear magnetic data are as follows: CDCl3,400MHz,0.77-0.94(m,6H),1.32-1.35(t,3H),1.81(m,1H),3.87-3.96(d,2H),4.26-4.31(q,2H),4.68(s,2H),4.96(s,2H),6.81-6.87(dd,2H),7.21-7.28(q,1H),7.66-7.69(dd,2H),8.27-8.30(dd,2H)；ESI+,[M+H]+:611.07.
Example 2
30.14g of the compound of the formula A are weighed into a 1000mL three-necked flask, 240mL of chloroform, 15.11g of NBS (N-bromosuccinimide) and 0.93g of AIBN (azobisisobutyronitrile) are added, the mixture is stirred and heated to 60 ℃, the temperature is reduced to room temperature after 15 hours of reaction, 60mL of saturated sodium sulfite solution is added, 200mL of water is added, the aqueous phase is separated after 10 minutes of stirring, and the organic phase is washed twice with 100mL of water. The organic phase was concentrated under pressure to about 120mL, 90mL of ethanol was added, and the mixture was concentrated to about 120mL, further 90mL of ethanol was added, further 120mL was concentrated, heptane 50mL was added, and the mixture was stirred at 20 to 30 ℃ for 30 minutes, n-heptane was again added, stirring was performed at 0 to 10 ℃ for 1 hour, crystals were collected by filtration and washed with ethanol/heptane-1/2, and after drying under reduced pressure, 31.95g of pale yellow crystals of formula B was obtained with a yield of 92.33% and a chemical purity of 97.35%.
Examples 3 to 4: formula C (wherein R1Is ethyl, R2Is isobutyl and X is bromo) intermediates
Example 3
Weighing 25.50g of light yellow crystal B obtained in example 1, adding the light yellow crystal B into a 1000mL three-necked bottle, adding 250mL of ethanol and 25.33g of triethylamine, adding 17.35g of dimethylamine hydrochloride in batches in ice bath, stirring at room temperature for reaction for 3 hours, raising the temperature to 40 ℃, adding 300mL of tap water, stirring at the temperature for 1 hour, stirring at 25 ℃ for 1 hour, filtering and collecting crystals, washing with 200mL of ethanol/tap water (4/1), and drying at 45 ℃ under reduced pressure to obtain 21.22g of light yellow solid, namely intermediate C, the yield of 88.40% and the chemical purity of 93.73%.
And (3) crude product purification: 20.0g of the crude product was added to 100ml of tetrahydrofuran, 6.8g of oxalic acid solid was added with stirring, the solid was gradually precipitated at room temperature, filtered, and the filter cake was washed with tetrahydrofuran to obtain a pale yellow powder. The chemical purity is 99.56%.
The nuclear magnetic data are as follows: CDCl3,400MHz,0.82-0.97(m,6H),1.31-1.35(t,3H),1.85(m,1H),2.04-2.07(s,6H),3.53(s,2H),3.92(d,2H),4.27-4.42(q,2H),5.03(s,2H),6.83-6.89(dd,2H),7.23-7.34(q,1H),7.65-7.67(dd,2H),8.24-8.29(dd,2H)；ESI+,[M+H]+:576.24.
Example 4
Weighing 25.50g of light yellow crystal B obtained in example 2, adding the light yellow crystal B into a 1000mL three-necked bottle, adding 250mL of ethanol and 30.50g of potassium carbonate, adding 17.35g of dimethylamine hydrochloride in batches in an ice bath, stirring at room temperature for reaction for 3 hours, raising the temperature to 50 ℃, adding 300mL of tap water, stirring at the temperature for 1 hour, stirring at 25 ℃ for 2 hours, filtering and collecting crystals, washing with 200mL of ethanol/tap water (4/1), and drying at 45 ℃ under reduced pressure to obtain 21.01g of light yellow crystals, namely the compound of the formula C, wherein the yield is 87.57%, and the chemical purity is 91.33%.
Examples 5 to 6: formula D (wherein R1Is aRadical, R2Is isobutyl) intermediate preparation
Example 5
21.22g of the compound of the formula C obtained in example 3 was weighed and charged into a 500mL three-necked flask, 210mL of ethanol was further added, the system was replaced with a nitrogen atmosphere, 1.01g of Pd/C containing 10% water was then added, and finally, the system was replaced with a hydrogen atmosphere and stirred at room temperature for reaction for 5 hours. Pd/C was filtered off through celite, the filtrate was concentrated to dryness under reduced pressure, then the concentrate was dissolved with 350mL of ethyl acetate, 10mL of 20% (V/V) isopropanol hydrochloride solution was added dropwise to the resulting solution at room temperature, after stirring for 1 hour, crystals collected by filtration were washed with 100mL of ethyl acetate, and dried under reduced pressure at 45 ℃ to give 19.87g of white crystal D.HCl, yield 92.60%, chemical purity 99.17%.
The nuclear magnetic data are as follows: DMSO-d6,400MHz,0.73-0.87(d,6H),1.26-1.30(t,3H),1.75-1.88(m,1H),2.53(s,6H),3.82(d,2H),4.23-4.25(q,2H),4.40(s,2H),4.93(s,2H),7.08-7.12(m,2H), delta 7.42-7.48 (m,5H),9.49-9.64(d, 2H); ESI +, [ M + H ] +:546.22.
19.87g of D.HCl is weighed and added into a 500mL three-necked bottle, 100mL of water and 100mL of ethyl acetate are added, 10.85g of sodium carbonate is finally added, stirring is carried out for 2 hours at room temperature, a water phase is separated, an organic phase is washed twice by 25mL of tap water, the organic phase is dried by anhydrous sodium sulfate and filtered, and filtrate is decompressed and concentrated to obtain 18.35g of light yellow solid, namely a compound shown as a formula D, wherein the free yield is 98.52%, and the chemical purity is 99.12%; the nuclear magnetic data are as follows: DMSO-d6,400MHz, 0.77-0.90(d,6H),1.22-1.25(t,3H),1.77(m,1H),1.94(s,6H), 3.39(s,2H)3.82(d,2H),4.09-4.14(q,2H),4.92(s,2H),5.39(s,2H),6.59-6.61(dd,2H),7.00-7.07(m,4H),7.37-7.45(m,1H),; ESI +, [ M + H ] +:546.22.
Example 6
21.22g of the compound of the formula C obtained in example 4 was weighed and charged in a 500mL three-necked flask, 100mL of methanol and 100mL of methylene chloride were further added, the system was replaced with a nitrogen atmosphere, 1.01g of Pd/C containing 10% water was then added, and finally the system was replaced with a hydrogen atmosphere and stirred at room temperature for 2 hours. Pd/C was filtered off through celite, the filtrate was concentrated to dryness under reduced pressure, then the concentrate was dissolved with 350mL of ethyl acetate, 10mL of 20% (V/V) isopropanol hydrochloride solution was added dropwise to the resulting solution at room temperature, after stirring for 1 hour, crystals collected by filtration were washed with 100mL of ethyl acetate, and after drying under reduced pressure at 45 ℃ 20.53g of white crystal D.HCl was obtained with a yield of 95.67% and a chemical purity of 99.35%.
Weighing 20.00g of D.HCl, adding the D.HCl into a 500mL three-necked flask, adding 100mL of water and 150mL of ethyl acetate, finally adding 8.0g of sodium carbonate, stirring at room temperature for 1.0 hour, separating out a water phase, washing an organic phase twice with 50mL of tap water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating a filtrate under reduced pressure to obtain 18.95g of a light yellow solid, namely a compound shown in formula D, wherein the free yield is 97.83%, and the chemical purity is 99.29%.
Examples 7-8 formula E (wherein R1Is ethyl, R2Is isobutyl) intermediate preparation
Example 7
3.95g of the compound shown in the formula D and 1.82g of phenyl methoxycarbamate obtained in example 6 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 stirring reaction, 20mL of 1M potassium carbonate solution is added, 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 filtered, and the filtrate is concentrated under reduced pressure to obtain 4.34g of yellow solid, namely the compound shown in the formula E, wherein the yield is 93.05 percent, and the chemical purity is 96.95 percent.
The nuclear magnetic data are 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)；ESI+,[M+H]+:619.23.
Example 8
3.95g of the compound shown in the formula D and 1.82g of phenyl methoxycarbamate obtained in example 5 are weighed and added into a 250mL three-necked flask, 20mL of acetonitrile is added, the mixture is stirred and heated to 70 ℃, stirred for reaction for 2 hours, then cooled to room temperature, 20mL of 1M potassium carbonate solution is added, stirring is continued for 0.5 hour, an organic phase and a water phase are separated, the organic phase is washed twice with 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 4.47g of yellow solid, namely the compound shown in the formula E, the yield is 95.67%, and the chemical purity is 97.23%.
Examples 9-10 preparation of intermediates of formula F wherein R2 is isobutyl
Example 9
Weighing 2.43g of the compound shown in the formula E obtained in example 7, adding the compound into a 250mL three-necked flask, adding 24mL of ethanol and 4mL of water and 5.8mL of 20% KOH solution, stirring at room temperature for 48 hours, adding 24mL of tap water into the solution, concentrating the solution under reduced pressure to about 30mL, adding 1M hydrochloric acid into the solution under ice bath to adjust the pH value to 6, extracting the solution twice with 20mL of DCM (dichloromethane), combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering the solution, and concentrating the filtrate under reduced pressure to obtain 2.35g of a white solid, namely the compound shown in the formula F, wherein the yield is 91.91% and the chemical purity is 95.40%.
The nuclear magnetic data are as follows: DMSO-d6,,400MHz,0.75-0.91(m,6H),1.71-1.78(m,1H),2.44(s,6H),3.35(s,2H),3.63(s,3H),3.78-3.80(d,2H),4.95(s,2H),7.02-7.06(dd,2H)，7.14-7.16(dd,2H),7.35-7.43(m,1H),7.69-7.71(dd,2H),9.18(s,1H),9.71(s,1H),16.65(s,1H)；ESI+,[M+H]+:591.21.
Example 10
Weighing 2.43g of the compound shown in the formula E obtained in example 8, adding the compound into a 250mL three-necked flask, adding 24mL of methanol and 4mL of water and 5.8mL of 20% LiOH solution, stirring at room temperature for reaction for 20 hours, adding 24mL of tap water into the solution, concentrating the solution under reduced pressure to about 30mL, adding 1M hydrochloric acid into the solution under ice bath to adjust the pH to 7, extracting the solution twice with 20mL of DCM (dichloromethane), combining the organic phases, drying the combined organic phases with anhydrous sodium sulfate, filtering the solution, and concentrating the filtrate under reduced pressure to obtain 2.41g of a white solid, namely the compound shown in the formula F, wherein the yield is 94.38% and the chemical purity is 95.70%.
Examples 11-12 preparation of Compounds of formula G
Example 11
Weighing 2.30G of the compound shown in the formula F in example 9, adding the compound into a 250mL three-necked flask, adding 23mL of DMA (N, N-dimethylacetamide), 0.97G of 3-amino-6-methoxypyridazine hydrochloride, 1.26G of DIPEA (N, N-diisopropylethylamine), 7.43G of 50% ethyl propyl phosphate anhydride acetate solution, stirring the mixture, heating the mixture to 60 ℃, reacting for 1 hour, cooling to room temperature, adjusting the pH to 5-6 with 1M sodium carbonate solution at 0 ℃, adding 200mL of water for dilution, extracting with 20mL of ethyl acetate for three times, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain 2.81G of white crystals, namely the compound shown in the formula G, wherein the yield is 96.54%, and the chemical purity is 95.66%.
The nuclear magnetic data are as follows: CDCl3,400MHz,0.77-1.05(m,6H),1.79-1.82(m,1H),2.20(s,6H),3.50(s,2H),3.82(s,3H),3.91-3.93(d,2H),4.10(s,3H),5.02(s,2H),6.71-6.77(dd,2H),7.09-7.16(dd,1H),7.22-7.24(d,2H),7.27-7.33(dd,2H),7.48(s,1H),7.54-7.56(d,2H),7.70(s,1H),14.05(s,1H)；ESI+,[M+H]+:698.26.
Example 12
Weighing 2.30G of the compound F obtained in example 10, adding the compound F into a 250mL three-necked flask, adding 23mL of acetonitrile, 0.97G of 3-amino-6-methoxypyridazine hydrochloride, 1.08G of triethylamine and 7.43G of a 50% propyl phosphoric anhydride acetonitrile solution, stirring the mixture, heating the mixture to 40 ℃, reacting for 2 hours, cooling to room temperature, adjusting the pH to 5-6 with 1M sodium carbonate solution at 0 ℃, adding 200mL of water for dilution, extracting with 20mL of ethyl acetate for three times, drying an organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain 2.85G of white crystals, namely the compound G, wherein the yield is 97.89% and the chemical purity is 97.35%.
Examples 13-14 preparation of Rulugol
Example 13
Weighing 1.59g of the compound of the formula G1 obtained in example 11, adding the compound into a 100mL three-necked flask, adding 40mL of methanol, 2.7mL of tetrahydrofuran and 0.90g of 28% sodium methoxide solution in methanol, stirring the mixture, heating to 60 ℃, reacting for 2 hours, cooling to room temperature, adjusting pH to 9 with 6M hydrochloric acid at 0 ℃ under reduced pressure, concentrating under reduced pressure to dryness, 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. The yield is 94.89%, the chemical purity is 99.45%, and the condensed urea by-product is not detected.
The nuclear magnetic data are 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)；ESI+,[M+H]+:624.18.
Example 14
Weighing 1.59g of the compound shown in the formula of example 12, adding the compound into a 100mL three-necked flask, adding 40mL of isopropanol and 0.50g of sodium ethoxide solid, stirring the mixture, heating to 70 ℃, reacting for 2 hours, cooling to room temperature, adjusting the pH to 8 with 6M hydrochloric acid at 0 ℃ under reduced pressure, concentrating under reduced pressure to dryness, adding 10mL of methanol, filtering to remove salts, adding 100mL of ethyl acetate, precipitating a large amount of solid, filtering, scraping filter cakes, 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 1.31g of white crystal, namely Ruogeli. The yield was 92.38%, the chemical purity was 99.58%, and the condensed urea by-product was not detected.
Claims (8)
1. A compound of the formula G,
wherein the content of the first and second substances,
R2is C1-6A linear or branched alkyl group; preferably, R2Is ethyl or isobutyl.
2. A process for the preparation of a compound of formula G comprising the steps of: in an organic solvent, carrying out condensation reaction on the intermediate F and 3-amino-6-methoxypyridazine or salt thereof under the action of a condensing agent to obtain a compound G;
wherein R is2Is C1-6A linear or branched alkyl group;
preferably, R2Is ethyl or isobutyl;
preferably, the organic solvent is selected from the group consisting of N, N-Dimethylacetamide (DMA), N-dimethylformamide, acetonitrile, tetrahydrofuran, N-methylpyrrolidone, preferably N, N-Dimethylacetamide (DMA), N-dimethylformamide, and acetonitrile;
preferably, the condensing agent is selected from the group consisting of propylphosphoric anhydride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/4-dimethylaminopyridine or 1-hydroxybenzotriazole and carbonyldiimidazole, preferably propylphosphoric anhydride;
preferably, the condensation reaction temperature is 25-85 ℃, preferably 40-60 ℃;
preferably, the reaction is carried out under the condition of an organic base, wherein the organic base is preferably DIPEA (N, N-diisopropylethylamine) or triethylamine;
preferably, the method further comprises a post-treatment step;
preferably, the steps include: dissolving a compound F in an organic solvent, adding 3-amino-6-methoxypyridazine hydrochloride, organic base and a condensing agent, stirring the mixture, heating to 40-60 ℃, and reacting for 1-10 h; the method can further comprise the following post-treatment steps: cooling the reaction solution to room temperature, adjusting pH to 5-6, adding water for dilution, extracting, combining organic phases, drying, filtering, concentrating the filtrate, and purifying; the reaction time is preferably 1-2 h; the pH is preferably adjusted using an inorganic base (e.g., sodium carbonate); the solvent used for extraction is preferably ethyl acetate; the concentration is preferably carried out under reduced pressure.
3. A process for the preparation of a compound of formula F comprising the steps of: carrying out a reduction reaction on the compound shown in the formula E in a mixed solvent of an organic solvent and water under the action of alkali to obtain a compound shown in the formula F; the reaction equation is as follows:
wherein R is1、R2Each independently represents C1-6A linear or branched alkyl group;
preferably, R1Is ethyl; r2Is ethyl or isobutyl;
preferably, the alkali is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide and sodium ethoxide, and more preferably potassium hydroxide or lithium hydroxide;
preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol and tetrahydrofuran, and more preferably ethanol and methanol;
preferably, the method further comprises a post-treatment step;
preferably, it comprises the steps of: dissolving the compound shown in the formula E in an organic solvent, adding an alkaline solution, and stirring at room temperature for reaction for 24-72 h; the method can further comprise the following post-treatment steps: adding water into the reaction solution, concentrating under reduced pressure, adjusting pH to 6-7 with acid, extracting, mixing organic phases, drying, filtering, and concentrating; adjusting the pH value and optimizing ice bath conditions; the acid is preferably hydrochloric acid (e.g., 1M hydrochloric acid); the solvent used for extraction is preferably dichloromethane; the reaction time is preferably 20-48 h; the concentration is preferably carried out under reduced pressure.
4. A process for the preparation of a compound of formula E comprising the steps of: the compound formula D and methoxyamino benzoate are subjected to condensation reaction in an organic solvent to obtain a compound formula E, and the reaction equation is as follows:
wherein R is1、R2Each independently represents C1-6A linear or branched alkyl group;
preferably, R1Is ethyl; r2Is ethyl or isobutyl;
preferably, the organic solvent is one or more of acetonitrile, toluene, chlorobenzene, isopropyl acetate and tetrahydrofuran; more preferably toluene or acetonitrile;
preferably, the reaction temperature is 50-110 ℃, preferably 70-108 ℃;
preferably, the method further comprises a post-treatment step;
preferably, the steps include: dissolving a compound formula D and methoxy amino phenyl formate in an organic solvent, stirring and heating to 70-108 ℃; the method can further comprise the following post-treatment steps: cooling, adding an alkali solution, stirring, separating, washing, drying the organic phase, filtering and concentrating; cooling, preferably to room temperature; the base is preferably potassium carbonate solution (such as 1M potassium carbonate solution); water is preferably adopted for washing; the concentration is preferably carried out under reduced pressure.
5. A process for the preparation of a compound of formula D comprising the steps of:
wherein X represents Cl, Br or I;
wherein R is1、R2Each independently represents C1-6A linear or branched alkyl group;
preferably, R1Is ethyl; r2Is ethyl or isobutyl;
preferably, steps A-B: reacting the compound shown in the formula A with a halogenating reagent in an organic solvent to generate a compound shown in the formula B;
more preferably, the organic solvent is selected from one or more of chloroform, dichloromethane, ethyl acetate, isopropyl acetate and chlorobenzene, and ethyl acetate or chloroform is preferred;
more preferably, the initiator used in the halogenation reaction is one or more selected from Azobisisobutyronitrile (AIBN), Azobisisoheptonitrile (AIBN) or benzoyl peroxide;
more preferably, the halogenating agent is selected from the group consisting of N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), N-chlorosuccinimide (NCS), dibromohydantoin;
more preferably, the temperature of the halogenation reaction is 50 to 100 ℃, preferably 60 to 70 ℃;
more preferably, the method also comprises a post-treatment step;
more preferably, the steps comprise: dissolving a compound A in an organic solvent, adding a halogenated reagent and an initiator, stirring and heating to 50-100 ℃, and reacting for 15-30 h (such as 15-18 h); optionally further comprises post-treatment step, cooling, adding saturated sodium sulfite solution and water into the reaction solution, stirring, separating, washing, concentrating the organic phase, crystallizing, washing and drying; the temperature is preferably reduced to room temperature; water is preferably adopted for washing; concentrating preferably under reduced pressure; the concentration preferably adopts a mode of adding ethanol and heptane for fractional concentration; drying preferably under reduced pressure; washing is preferably carried out by using an ethanol/heptane mixed solvent, and more preferably, the volume ratio of ethanol to heptane is 1: 2;
preferably, steps B-C: carrying out an alkylation reaction on the compound shown in the formula B and dimethylamine hydrochloride in an organic solvent under the action of alkali to obtain a compound shown in a formula C;
more preferably, the base used in the alkylation reaction is one or more selected from triethylamine, N-diisopropylethylamine, N-methylmorpholine, sodium carbonate, potassium carbonate and sodium bicarbonate, preferably triethylamine or potassium carbonate;
more preferably, the organic solvent is methanol, ethanol, isopropanol, acetonitrile, preferably ethanol;
more preferably, the temperature of the reaction is-10-40 ℃, preferably room temperature;
more preferably, the crude compound of formula C produced by the reaction is added to a solvent (preferably tetrahydrofuran), and an acid is added to precipitate out to obtain a high-purity intermediate C; the acid is selected from hydrochloric acid, phosphoric acid, sulfuric acid, oxalic acid, acetic acid or malic acid;
more preferably, the base is selected from one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and triethylamine;
more preferably, the method also comprises a post-treatment step;
more preferably, the steps comprise: dissolving the compound shown in the formula B in an organic solvent, adding alkali, adding dimethylamine hydrochloride in batches, and stirring at room temperature for reacting for 2-10 h (such as 3-6 h); the method can further comprise the following post-treatment steps: heating the reaction solution to 30-60 deg.C (such as 40-50 deg.C), adding water, stirring for 1-5 hr, stirring at 25-35 deg.C for 1-5 hr, filtering, washing, and drying; the washing solvent is preferably an ethanol/water solution, more preferably the volume ratio of ethanol to water is 4: 1; the drying mode is preferably drying under reduced pressure;
preferably, steps C-D: carrying out reduction reaction on the compound formula C in an organic solvent under the action of palladium carbon hydrogen to obtain a compound formula D;
more preferably, the organic solvent is one or more of alcohol (such as methanol, ethanol, etc.), dichloromethane, and ethyl acetate; methanol and dichloromethane, ethanol are preferred;
more preferably, the temperature of the reduction reaction is 20-50 ℃, preferably room temperature;
more preferably, the steps comprise: dissolving a compound C in an organic solvent, placing the system in a nitrogen environment, adding Pd/C, placing the system in a hydrogen environment, and stirring and reacting at 20-50 ℃ for 2-5 h; the method can further comprise the following post-treatment steps: filtering the reaction solution, concentrating the filtrate to dryness, adding an organic solvent for dissolving, adding acid, stirring, filtering, washing, drying to obtain crystals, dissolving the crystals in the organic solvent and water, adding alkali, stirring, separating liquid, washing an organic phase, drying, filtering and concentrating; the concentration is preferably reduced pressure concentration; the organic solvent is preferably ethyl acetate; the solvent adopted for washing is ethyl acetate; the drying is preferably drying under reduced pressure; the acid is preferably one of hydrochloric acid, phosphoric acid, sulfuric acid, oxalic acid, acetic acid and malic acid, and is more preferably hydrochloric acid (such as 20% (V/V) hydrochloric acid isopropanol solution); the alkali used is preferably one of sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, and is more preferably sodium carbonate;
preferably, compound formula D can further prepare compound formula G, the process comprising the steps of: D-E according to claim 4, E-F according to claim 3 and/or F-G according to claim 2.
6. A preparation method of Ruogeli (formula I) comprises the following steps: in an organic solvent, a compound shown in the formula G undergoes a cyclization reaction under the action of alkali to obtain Ruogeli (shown in the formula I), and the reaction equation is as follows:
wherein R is2Represents C1-6A linear or branched alkyl group;
preferably, R2Is ethyl or isobutyl;
preferably, the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide, preferably sodium methoxide, sodium ethoxide or sodium tert-butoxide;
preferably, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, tert-butanol and tetrahydrofuran; methanol and tetrahydrofuran, isopropanol are preferred;
preferably, the temperature of the cyclization reaction is 20-80 ℃, preferably 60-70 ℃;
preferably, the method further comprises a post-treatment step;
preferably, the steps include: dissolving a compound shown in the formula G in an organic solvent, adding alkali, stirring the mixture, heating to 20-80 ℃, and reacting for 1-12 h; the method can further comprise the following post-treatment steps: adjusting pH to 7-10 with acid, concentrating to dry, adding organic solvent, filtering, adding solvent to precipitate a large amount of solid, filtering, pulping, filtering, and drying; the acid is preferably 6M hydrochloric acid; the pH is preferably 8 to 9; the solvent is preferably ethyl acetate; the solvent adopted by the pulping is preferably a mixed solvent of ethyl acetate and dichloromethane, and more preferably the volume ratio of the ethyl acetate to the dichloromethane is 1: 1;
preferably, the method comprises the following steps:
wherein R is1、R2Each independently represents C1-6A linear or branched alkyl group;
preferably, R1Is ethyl; r2Is ethyl or isobutyl;
more preferably, the reaction equation comprises steps A-B, B-C, C-D, D-E, E-F, F-G as described in claims 5, 4, 3, and 2, respectively.
7. The following compounds are described in detail below with reference to,
wherein R is1、R2Each independently represents C1-6A linear or branched alkyl group; preferably, R1Is ethyl; r2Is ethyl or isobutyl.
8. Use of a compound of formula D, formula E, formula F or formula G for the preparation of rilogelide and salts, derivatives or analogues thereof.
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| CN115073490A (en) * | 2021-03-12 | 2022-09-20 | 上海医药工业研究院 | Preparation method of Ruogeli and intermediate thereof |
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| CN114805326A (en) * | 2022-06-06 | 2022-07-29 | 南京方生和医药科技有限公司 | Preparation process of Ruogeli impurity |
| WO2024069492A1 (en) * | 2022-09-29 | 2024-04-04 | Macfarlan Smith Limited | Processes for the preparation and manufacture of relugolix |
| CN115650950A (en) * | 2022-11-03 | 2023-01-31 | 江西同和药业股份有限公司 | Rui Lu Geli intermediate and preparation method thereof, and amide condensation method |
| CN115785062A (en) * | 2022-12-27 | 2023-03-14 | 常州制药厂有限公司 | Method for preparing intermediate of Rui Lu Geli by continuous hydrogenation |
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