CN116903616B - Ruimei gem Process for the preparation of intermediates - Google Patents
Ruimei gem Process for the preparation of intermediatesInfo
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- CN116903616B CN116903616B CN202310869300.2A CN202310869300A CN116903616B CN 116903616 B CN116903616 B CN 116903616B CN 202310869300 A CN202310869300 A CN 202310869300A CN 116903616 B CN116903616 B CN 116903616B
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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
- C07D471/02—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
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Abstract
本发明涉及药物中间体制备技术领域，提供了一种瑞美吉泮中间体的制备方法。本发明将具有式VII所示结构的化合物和尿素进行还原胺化反应，所得产物和具有式B所示结构的化合物进行环合，再经脱保护，并将所得脱保护产物、N,N′‑羰基二咪唑、无机碱和溶剂混合进行反应，得到瑞美吉泮中间体。本发明提供的方法采用的反应原料廉价易得，制备成本低，更有利于工业化生产。 The present invention relates to the technical field of pharmaceutical intermediate preparation and provides a method for preparing a remedipam intermediate. The method comprises subjecting a compound having a structure represented by Formula VII to a reductive amination reaction with urea, cyclizing the resulting product with a compound having a structure represented by Formula B, and then deprotecting the product. The deprotected product, N,N′-carbonyldiimidazole, an inorganic base, and a solvent are mixed and reacted to obtain the remedipam intermediate. The method provided by the present invention utilizes inexpensive and readily available reaction raw materials, has low preparation costs, and is more conducive to industrial production.
Description
Technical Field
The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a preparation method of a rui Mei Ji pam intermediate.
Background
Rametadiazepam (RIMEGEPANT, CAS: 1374024-48-2) is an oral drug belonging to the tricyclic class of tribenzamide (triptan) analogues for the treatment of migraine. Unlike triptans "triptan" drugs, RIMEGEPANT do not constrict blood vessels, but rather relieve migraine symptoms by blocking neurotransmitter calcium channels. RIMEGEPANT shows that it can relieve migraine symptoms within two hours and remain effective within 24 hours. The side effects of the ziram are relatively few, mainly including mild headache, nausea, dry mouth and the like.
Generally, RIMEGEPANT is a novel oral drug that is an effective and convenient treatment option for migraine sufferers.
The molecular structure of the Ruimei gem is shown as a formula I:
The literature jlabelcompdtradiophirm.2022; 65,126-139 discloses a preparation method comprising the steps of subjecting a compound a to reductive amination with a compound VII to form a compound VI, subjecting the compound VI to ring closure in the presence of CDI (N, N' -carbonyldiimidazole) to form a compound V, and then deprotecting the compound IV to form a compound IV, and reacting the compound IV with CDI and then with an intermediate II to form the final ramelteon I, wherein the synthetic route is as follows:
From the above route, it can be found that compound III is an intermediate for the synthesis of ramelteon, and the starting material of the above synthetic route, compound a, is expensive, which is disadvantageous in terms of cost reduction. Thus, there is a need to develop a low cost process for preparing the intermediate III of ramelteon.
Disclosure of Invention
In view of this, the present invention provides a process for the preparation of a ramelteon intermediate. The preparation method provided by the invention has low raw material cost, can obviously reduce the preparation cost of the Ruimei gem intermediate, and is more beneficial to industrial production.
In order to achieve the above object, the present invention provides the following technical solutions:
a method for preparing a ramelteon intermediate, comprising the following steps:
(1) Mixing a compound with a structure shown in a formula VII, urea, a catalyst, a reducing agent and a solvent for reductive amination reaction to obtain a compound with a structure shown in a formula C;
(2) Mixing the compound with the structure shown in the formula C, the compound with the structure shown in the formula B, a metal catalyst, an organic base and a solvent for cyclization reaction to obtain a compound with the structure shown in the formula V;
(3) Mixing the compound with the structure shown in the formula V with an ethanol solution of hydrogen chloride for deprotection reaction to obtain a deprotection product, wherein the structure of the deprotection product is shown in the formula IV;
(4) Mixing the deprotection product, N' -carbonyl diimidazole, inorganic base and a solvent for reaction to obtain a Ruimepam intermediate, wherein the structure of the Ruimepam intermediate is shown as a formula III;
Preferably, the catalyst in the step (1) is trimethylchlorosilane and hexamethylphosphoric triamide, the molar amount of the hexamethylphosphoric triamide is 1% -20% of the molar amount of the compound with the structure shown in the formula VII, and the molar amount of the trimethylchlorosilane is 0.5% -5 times of the molar amount of the compound with the structure shown in the formula VII.
The reducing agent in the step (1) is one or more of sodium borohydride, potassium borohydride and sodium triacetoxyborohydride, and the molar amount of the reducing agent is 0.3-1.5 times of that of the compound with the structure shown in the formula VII.
Preferably, the molar amount of urea in the step (1) is 1 to 5 times the molar amount of the compound having the structure represented by formula VII.
Preferably, the temperature of the reductive amination reaction in the step (1) is-5-40 ℃ and the time is 0.5-5 h;
The solvent for the reductive amination reaction in the step (1) is one or more of dichloromethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, dimethylformamide and acetonitrile.
Preferably, the metal catalyst in the step (2) is one or more of cuprous iodide, cuprous chloride and palladium acetate, and the molar amount of the metal catalyst is 0.05% -10% of the molar amount of the compound with the structure shown in the formula C;
the organic alkali in the step (2) is one or more of potassium tert-butoxide, sodium tert-butoxide and sodium ethoxide, and the molar amount of the organic alkali is 2-5 times of that of the compound with the structure shown in the formula C;
The molar amount of the compound with the structure shown in the formula B in the step (2) is 1-1.5 times of the molar amount of the compound with the structure shown in the formula C.
Preferably, the temperature of the cyclization reaction in the step (2) is 50-150 ℃ and the time is 3-30 hours;
The solvent for the cyclization reaction in the step (2) is one or more of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile and 1, 4-dioxane.
Preferably, the temperature of the deprotection reaction in the step (3) is 10-60 ℃ and the time is 0.5-5 h, and the mass fraction of hydrogen chloride in the hydrogen chloride ethanol solution is 5-40%.
Preferably, the inorganic base in the step (4) is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, and the molar amount of the inorganic base is 1.5-5 times of the molar amount of the compound with the structure shown in the formula V.
Preferably, the molar amount of the N, N' -carbonyldiimidazole in the step (4) is 1 to 2 times the molar amount of the compound having the structure represented by formula V.
Preferably, the reaction temperature in the step (4) is 20-80 ℃ and the reaction time is 0.5-5 h;
The solvent for the reaction in the step (4) is one or more of acetone, acetonitrile, tetrahydrofuran, ethyl acetate and dichloromethane.
The invention provides a preparation method of a Ruimegem intermediate, which comprises the steps of mixing a compound with a structure shown in a formula VII, urea, a catalyst, a reducing agent and a solvent for reductive amination reaction to obtain a compound with a structure shown in a formula C, mixing the compound with the structure shown in the formula C, the compound with the structure shown in a formula B, a metal catalyst, an organic base and the solvent for cyclization reaction to obtain a compound with a structure shown in a formula V, mixing the compound with the structure shown in the formula V with a hydrogen chloride ethanol solution for deprotection reaction, and mixing the obtained deprotection product, N' -carbonyl diimidazole, inorganic base and the solvent for reaction to obtain the Ruimegem intermediate with the structure shown in a formula III. The method provided by the invention adopts the starting materials of the compound with the structure shown in the formula VII, urea and the compound with the structure shown in the formula B, the urea is cheap and easy to obtain, and meanwhile, compared with the compound A used in the prior art, the compound with the structure shown in the formula B is cheaper, so that the preparation cost of the Rametagepam intermediate with the structure shown in the formula III can be obviously reduced, and the method is more beneficial to industrial production.
Detailed Description
The invention provides a preparation method of a rui Mei Ji pam intermediate, which comprises the following steps:
(1) Mixing a compound with a structure shown in a formula VII, urea, a catalyst, a reducing agent and a solvent for reductive amination reaction to obtain a compound with a structure shown in a formula C;
(2) Mixing the compound with the structure shown in the formula C, the compound with the structure shown in the formula B, a metal catalyst, an organic base and a solvent for cyclization reaction to obtain a compound with the structure shown in the formula V;
(3) Mixing the compound with the structure shown in the formula V with an ethanol solution of hydrogen chloride for deprotection reaction to obtain a deprotection product, wherein the structure of the deprotection product is shown in the formula IV;
(4) Mixing the deprotection product, N' -carbonyl diimidazole, inorganic base and a solvent for reaction to obtain a Ruimepam intermediate, wherein the structure of the Ruimepam intermediate is shown as a formula III;
The synthetic route of the invention is as follows:
the process of the present invention will be described in detail with reference to the synthetic route.
The invention mixes the compound with the structure shown in the formula VII, the catalyst, the reducing agent and the solvent for reductive amination reaction to obtain the compound with the structure shown in the formula C. In the present invention, the catalyst in the step (1) is preferably trimethylchlorosilane and hexamethylphosphoric triamide, the molar amount of hexamethylphosphoric triamide is preferably 1% -20%, more preferably 2% -10% of the molar amount of the compound having the structure represented by the formula VII, and the molar amount of trimethylchlorosilane is preferably 0.5% -5%, more preferably 1% -3% of the molar amount of the compound having the structure represented by the formula VII.
In the invention, the reducing agent is preferably one or more of sodium borohydride, potassium borohydride and sodium triacetoxyborohydride, and the molar amount of the reducing agent is preferably 0.3-1.5 times, more preferably 0.5-1.2 times that of the compound with the structure shown in the formula VII.
In the present invention, the molar amount of urea is preferably 1 to 5 times, more preferably 1 to 2.5 times the molar amount of the compound having the structure represented by formula VII.
In the invention, the solvent for the reductive amination reaction is preferably one or more of dichloromethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, dimethylformamide and acetonitrile, more preferably dichloromethane, and the dosage of the solvent is not particularly required, so that the reductive amination reaction can be smoothly carried out.
In the present invention, the temperature of the reductive amination reaction is preferably-5 to 40 ℃, more preferably 0 to 30 ℃, and the time of the reductive amination reaction is preferably 0.5 to 5 hours, more preferably 1 to 2 hours.
In the specific embodiment of the invention, the compound with the structure shown in the formula VII, urea, solvent and hexamethylphosphoric triamide are preferably mixed, the temperature of the mixture is regulated to 0-5 ℃, then trimethylchlorosilane is added under the stirring condition, the mixture is reacted for 30min at the temperature of 0-5 ℃ after the addition, then a reducing agent is slowly added, and the reductive amination reaction is carried out at room temperature after the addition of the reducing agent is finished, wherein the addition time of the reducing agent is preferably 2h.
After the reductive amination reaction is finished, the product feed liquid is preferably subjected to liquid separation to obtain a water phase and an organic phase, the water phase is extracted by adopting methylene dichloride to obtain an extracted organic phase, the organic phase obtained by extracting the organic phase and the organic phase obtained by liquid separation are combined and sequentially subjected to water washing, anhydrous sodium sulfate drying, filtering and spin drying to obtain a crude product, the crude product is stirred and mixed with ethyl acetate and heptane, the mixture is filtered, the obtained solid product is dried to obtain a compound with a structure shown as a formula C, the volume ratio of the ethyl acetate to the heptane is preferably 1:4, the stirring and mixing temperature is preferably room temperature, and the stirring and mixing time is preferably 2h.
After the compound with the structure shown in the formula C is obtained, the compound with the structure shown in the formula C, the compound with the structure shown in the formula B, a metal catalyst, an organic base and a solvent are mixed for cyclization reaction, so that the compound with the structure shown in the formula V is obtained. In the invention, the metal catalyst is preferably one or more of cuprous iodide, cuprous chloride and palladium acetate, more preferably cuprous iodide, and the molar amount of the metal catalyst is preferably 0.05% -10%, more preferably 1% -6% of the molar amount of the compound with the structure shown in the formula C.
In the invention, the organic base is preferably one or more of potassium tert-butoxide, sodium tert-butoxide and sodium ethoxide, more preferably potassium tert-butoxide, and the molar amount of the organic base is preferably 2-5 times, more preferably 2.5-3.5 times the molar amount of the compound with the structure shown in the formula C.
In the present invention, the molar amount of the compound having the structure represented by formula B is preferably 1 to 1.5 times, more preferably 1 to 1.2 times the molar amount of the compound having the structure represented by formula C.
In the present invention, the solvent for the cyclization reaction is preferably one or more of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile and 1, 4-dioxane, more preferably dimethyl sulfoxide, and the amount of the solvent is not particularly limited, so that the cyclization reaction can be smoothly performed.
In the present invention, the temperature of the cyclization reaction is preferably 50 to 150 ℃, more preferably 60 to 120 ℃, the time of the cyclization reaction is preferably 3 to 30 hours, the cyclization reaction is preferably performed under a protective atmosphere, the protective atmosphere is preferably nitrogen, in a specific embodiment of the present invention, the cyclization reaction preferably includes a first stage and a second stage which are sequentially performed, the temperature of the first stage is preferably 50 to 90 ℃, more preferably 70 to 80 ℃, the time is preferably 3 to 10 hours, more preferably 5 to 6 hours, the temperature of the second stage is preferably 90 to 120 ℃, more preferably 100 to 110 ℃, the time is preferably 5 to 20 hours, and the present invention divides the cyclization reaction into two stages, performs an intermolecular substitution reaction in the first stage, and performs an intramolecular coupling reaction in the second stage, thereby improving the selectivity of the intermolecular substitution reaction through the two-stage reaction.
In a specific embodiment of the present invention, the compound having the structure represented by formula C, the compound having the structure represented by formula B, the metal catalyst, the organic base, and the solvent are preferably mixed, and the mixture is heated to the reaction temperature of the first stage under the protection of nitrogen to perform the reaction, and after the reaction of the first stage is completed, the mixture is heated to the reaction temperature of the second stage to perform the reaction.
After the cyclization reaction is finished, the obtained product feed liquid is preferably cooled to room temperature and then filtered, the obtained filtrate is mixed with water, the pH value of the mixed liquid is regulated to 6-7 by hydrochloric acid to precipitate a product, the mixed liquid is stirred for 30min and then filtered again, and the obtained solid product is washed with water and then dried, so that the compound with the structure shown in the formula V is obtained.
After the compound with the structure shown in the formula V is obtained, the compound with the structure shown in the formula V and the hydrogen chloride ethanol solution are mixed for deprotection reaction to obtain a deprotection product, wherein the structure of the deprotection product is shown in the formula IV. In the invention, the mass fraction of hydrogen chloride in the hydrogen chloride ethanol solution is preferably 5% -40%, more preferably 30%, the dosage ratio of the compound with the structure shown in the formula V to the hydrogen chloride ethanol solution is preferably 1 mmol/1 mL, the temperature of the deprotection reaction is preferably 10-60 ℃, more preferably 20-25 ℃ and the time is preferably 0.5-5 h, more preferably 2h, after the deprotection reaction is finished, the solvent in the product feed liquid is preferably spin-dried, and the residual product and acetone are mixed and then spin-dried again to obtain the deprotection product.
After a deprotection product is obtained, the deprotection product, N' -carbonyl diimidazole, inorganic base and a solvent are mixed for reaction, so that the rui-Mei-Ji-pam intermediate is obtained, and the structure of the rui-Mei-Ji-pam intermediate is shown as a formula III. In the present invention, the inorganic base is preferably one or more of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, more preferably potassium carbonate, and the molar amount of the inorganic base is preferably 1.5 to 5 times, more preferably 2 to 3 times the molar amount of the compound having the structure represented by formula V.
In the present invention, the molar amount of the N, N' -Carbonyldiimidazole (CDI) is preferably 1 to 2 times, more preferably 1.2 to 1.6 times the molar amount of the compound having the structure represented by formula V.
In the present invention, the solvent used in the reaction in the step (4) is preferably one or more of acetone, acetonitrile, tetrahydrofuran, ethyl acetate and dichloromethane, more preferably acetone, and the amount of the solvent used in the present invention is not particularly limited, so that the reaction can be smoothly performed.
In the present invention, the reaction temperature in the step (4) is preferably 20 to 80 ℃, more preferably 50 to 60 ℃, and the time is preferably 0.5 to 5 hours, more preferably 2 hours.
In a specific embodiment of the present invention, the deprotected product, solvent, CDI, and inorganic base are preferably mixed and then heated to the temperature of the reaction to conduct the reaction.
After the reaction is completed, the solvent in the obtained product feed liquid is preferably removed by rotary evaporation, then the rest product and water are mixed and extracted by methylene dichloride, the obtained organic phase is dried by anhydrous sodium sulfate and filtered, and the filtrate is dried by rotary evaporation to obtain the compound with the structure shown in the formula III.
The following description of the embodiments of the present invention will clearly and fully describe the technical solutions of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the following examples, the compounds having the structures shown in formula VII, formula C, formula B, formula V and formula III are denoted as compound VII, compound C, compound B, compound V and compound III, respectively.
EXAMPLE 1 preparation of Compound C
Adding 20.0g of compound VII, 9.0g of urea, 200mL of dichloromethane and 0.90g of hexamethylphosphoric triamide into a bottle, cooling to 0-5 ℃ in an ice water bath, gradually adding 16.3g of trimethylchlorosilane under stirring, keeping the temperature of 0-5 ℃ after the addition is finished, continuously stirring for 30min, slowly adding 3.8g of sodium borohydride in batches for about 2h, removing the ice water bath, stirring at room temperature for reacting for 1h, adding 200mL of water, stirring for 30min, separating liquid, extracting the water phase with 100mL of dichloromethane, merging organic phases, washing with 50mL of water, drying with anhydrous sodium sulfate, filtering, spinning, adding 20mL of ethyl acetate and 80mL of heptane into the obtained crude product, stirring at room temperature for 2h, filtering, and drying to obtain 22.4g of white solid compound C, wherein the yield is 92%.
The nuclear magnetic hydrogen spectrum data of the product are ：1H-NMR(400M,CDCl3)：8.95(1H,brs),4.25(2H,brs),3.26(1H,brs),2.75(2H,brs),2.08(4H,brs),1.78(2H,brs),1.49(9H,s).
EXAMPLE 2 preparation of Compound C
20.0G of compound VII, 7.2g of urea, 200mL of tetrahydrofuran and 0.54g of hexamethylphosphoric triamide are added into a bottle, the temperature is reduced to 0-5 ℃ by an ice water bath, 21.7g of trimethylchlorosilane is gradually added under stirring, the stirring is continued for 30min at 0-5 ℃ after the addition, 27.6g of sodium triacetoxyborohydride is slowly added in batches, the addition is completed approximately for 2h, the ice water bath is removed, the stirring reaction is carried out for 2h at room temperature, the solvent is removed, 200mL of water is added, the stirring is carried out for 30min, the filtration and the washing with 50mL of water are carried out, the drying is carried out, 20mL of ethyl acetate and 80mL of heptane are added into the obtained crude product, the stirring is carried out at room temperature for 2h, the filtration and the drying are carried out, and 22.7g of white solid compound C is obtained, and the yield is 93%.
EXAMPLE 3 preparation of Compound V
4.87G of compound C, 3.26g of compound B, 0.12g of cuprous iodide, 6.73g of potassium tert-butoxide and 50mL of DMSO are added into a bottle, nitrogen protection is carried out, the temperature is raised to 80 ℃ for reaction for 6 hours, then the temperature is raised to 110 ℃ for reaction for 10 hours, the temperature is lowered to room temperature, filtration is carried out, the filtrate is poured into 200mL of water, the pH of the filtrate is regulated to 6-7 by hydrochloric acid, stirring is carried out for 30 minutes, filtration is carried out again, 20mL of water is used for washing, and drying is carried out, thus obtaining 5.67g of white solid compound V, and the yield is 89%.
The nuclear magnetic hydrogen spectrum data of the product are ：1H-NMR(400M,DMSO)：11.59(1H,brs),7.90(1H,d),7.53(1H,d),6.96(1H,m),4.37(1H,m),4.12(2H,brs),2.88(2H,brs),2.15(2H,m),1.75(2H,brs),1.44(9H,s).
EXAMPLE 4 preparation of Compound V
4.87G of compound C, 3.56g of compound B, 45mg of palladium acetate, 7.40g of potassium tert-butoxide and 50mL of DMF are added into a bottle, nitrogen protection is adopted, the temperature is raised to 70 ℃ for reaction for 5 hours, the temperature is raised to 100 ℃ for reaction for 8 hours, the temperature is reduced to room temperature, the filtration is carried out, the filtrate is poured into 200mL of water, the pH of the hydrochloric acid is regulated to 6-7, the stirring is carried out for 30 minutes, the filtration is carried out again, 20mL of water is used for washing, and the 5.92g of white solid compound V is obtained after drying, and the yield is 93%.
EXAMPLE 5 preparation of Compound III
3.18G of compound V and 10mL of ethanol solution of hydrogen chloride (30% mass fraction) are added into a bottle, the mixture is stirred at room temperature for reaction for 2 hours, 10mL of acetone is added after the solvent is removed, the mixture is dried again by spinning, 30mL of acetone, 2.43g of CDI and 2.90g of potassium carbonate powder are added into the obtained product, the mixture is heated to 50 ℃ for reaction for 2 hours, the solvent is removed by spinning, 30mL of cold water is added, dichloromethane is used for extraction (3 times, 30mL each time), anhydrous sodium sulfate is dried, filtered and dried by spinning, and 3.0g of white solid compound III is obtained, and the yield is 96%.
The nuclear magnetic hydrogen spectrum data of the product are ：1H-NMR(400M,DMSO)：11.62(1H,brs),8.11(1H,s),7.93(1H,dd),7.76(1H,d),7.56(1H,t),6.97-7.12(2H,m),4.54(1H,t),4.06(2H,d),3.25(2H,t),2.26-2.43(2H,m),1.83(2H,d).
EXAMPLE 6 preparation of Compound III
3.18G of Compound V and 10mL of ethanol solution of hydrogen chloride (30% mass fraction) are added into a bottle, the mixture is stirred at room temperature for reaction for 2 hours, 10mL of acetonitrile is added after the solvent is removed, the mixture is dried again by spinning, 30mL of acetonitrile, 2.11g of CDI and 3.18g of sodium carbonate powder are added into the obtained product, the mixture is heated to 60 ℃ for reaction for 2 hours, the solvent is removed by spinning, 30mL of cold water is added, dichloromethane is used for extraction (3 times, 30mL of each time), anhydrous sodium sulfate is dried, filtered and dried by spinning, and 2.94g of white solid compound III is obtained, and the yield is 94%.
EXAMPLE 7 preparation of Rametagempam (Compound I)
Adding 2.90g of compound II, 50mL of tetrahydrofuran and 2.58g of potassium tert-butoxide into a flask, stirring at room temperature for 10min, adding 3.44g of compound III, stirring at room temperature for reaction for 1h, screwing off a solvent, adding 50mL of water, adjusting pH to 12 with liquid alkali, stirring at room temperature for 2h, adjusting pH to neutrality with hydrochloric acid, stirring at room temperature for 1h, filtering, washing with 20mL of water, drying, adding 20mL of ethyl acetate into the obtained crude product, heating to 50 ℃ for 10min, keeping 50 ℃ and gradually adding 60mL of heptane, removing the heating after the addition, stirring at room temperature for reaction for 3h, filtering, and drying to obtain 4.81g of yellow solid compound I, wherein the yield is 90%.
The nuclear magnetic hydrogen spectrum data of the product are ：1H-NMR(400M,DMSO)：11.61(1H,brs),8.51(1H,brs),8.08(1H,d),7.94(1H,d),7.55(1H,brs),7.17–7.47(4H,m),7.05(1H,brs),6.02(1H,dd),4.31–4.58(3H,m),4.12(1H,brs),3.10(1H,brs),2.98(1H,brs),2.79–2.92(1H,m),2.04–2.33(4H,m),1.61–1.83(6H,m).
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. A method for preparing a ramipam intermediate, which is characterized by comprising the following steps:
(1) Mixing a compound with a structure shown in a formula VII, urea, a catalyst, a reducing agent and a solvent for reductive amination reaction to obtain a compound with a structure shown in a formula C, wherein the catalyst is trimethyl chlorosilane and hexamethylphosphoric triamide;
(2) Mixing the compound with the structure shown in the formula C, a compound with the structure shown in the formula B, a metal catalyst, an organic base and a solvent for cyclization reaction to obtain the compound with the structure shown in the formula V, wherein the metal catalyst is one or more of cuprous iodide, cuprous chloride and palladium acetate, and the organic base is one or more of potassium tert-butoxide, sodium tert-butoxide and sodium ethoxide;
(3) Mixing the compound with the structure shown in the formula V with an ethanol solution of hydrogen chloride for deprotection reaction to obtain a deprotection product, wherein the structure of the deprotection product is shown in the formula IV;
(4) Mixing the deprotection product, N' -carbonyl diimidazole, inorganic base and a solvent for reaction to obtain a Ruimepam intermediate, wherein the structure of the Ruimepam intermediate is shown as a formula III;
2. The preparation method of claim 1, wherein the molar amount of hexamethylphosphoric triamide is 1% -20% of the molar amount of the compound having the structure shown in formula VII, and the molar amount of trimethylchlorosilane is 0.5-5 times of the molar amount of the compound having the structure shown in formula VII;
The molar amount of the reducing agent is 0.3-1.5 times the molar amount of the compound with the structure shown in the formula VII.
3. The method according to claim 1, wherein the molar amount of urea in the step (1) is 1 to 5 times the molar amount of the compound having the structure represented by formula VII.
4. The preparation method according to claim 1, wherein the reductive amination reaction in the step (1) is carried out at a temperature of-5 to 40 ℃ for 0.5 to 5 hours;
The solvent for the reductive amination reaction in the step (1) is one or more of dichloromethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, dimethylformamide and acetonitrile.
5. The production method according to claim 1, wherein the molar amount of the metal catalyst is 0.05% to 10% of the molar amount of the compound having the structure represented by formula C;
the molar quantity of the organic base is 2-5 times of that of the compound with the structure shown in the formula C;
The molar amount of the compound with the structure shown in the formula B in the step (2) is 1-1.5 times of that of the compound with the structure shown in the formula C.
6. The preparation method according to claim 1, wherein the temperature of the cyclization reaction in the step (2) is 50-150 ℃ and the time is 3-30 hours;
the solvent for the cyclization reaction in the step (2) is one or more of dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetonitrile and 1, 4-dioxane.
7. The preparation method of claim 1, wherein the deprotection reaction in the step (3) is performed at a temperature of 10-60 ℃ for 0.5-5 hours, and the mass fraction of hydrogen chloride in the hydrogen chloride ethanol solution is 5-40%.
8. The preparation method of claim 1, wherein the inorganic base in the step (4) is one or more of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, and the molar amount of the inorganic base is 1.5-5 times the molar amount of the compound having the structure shown in formula V.
9. The preparation method according to claim 1, wherein the molar amount of N, N' -carbonyldiimidazole in the step (4) is 1 to 2 times the molar amount of the compound having the structure represented by formula V.
10. The preparation method according to claim 1, wherein the reaction temperature in the step (4) is 20-80 ℃ and the reaction time is 0.5-5 h;
The solvent for the reaction in the step (4) is one or more of acetone, acetonitrile, tetrahydrofuran, ethyl acetate and dichloromethane.
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