CN114315749B - Method for synthesizing aliskiren intermediate by continuous flow microreactor - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 46
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 title abstract description 18
- 229960004601 aliskiren Drugs 0.000 title abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 136
- 238000002360 preparation method Methods 0.000 claims abstract description 39
- ISULZYQDGYXDFW-UHFFFAOYSA-N 3-methylbutanoyl chloride Chemical compound CC(C)CC(Cl)=O ISULZYQDGYXDFW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 72
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- OAHNTYYIALLVPB-UHFFFAOYSA-N 6-(1-piperidin-4-yl-3-pyridin-4-ylpyrazol-4-yl)-1,4-dihydroindeno[1,2-c]pyrazole Chemical compound C1=C2CC3=CNN=C3C2=CC=C1C1=CN(C2CCNCC2)N=C1C1=CC=NC=C1 OAHNTYYIALLVPB-UHFFFAOYSA-N 0.000 claims description 16
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Substances [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 14
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 8
- RMXLHIUHKIVPAB-OWOJBTEDSA-N (e)-1,4-dibromobut-2-ene Chemical compound BrC\C=C\CBr RMXLHIUHKIVPAB-OWOJBTEDSA-N 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- XPOIQAIBZGSIDD-UHFFFAOYSA-M 2-[4-(dimethylamino)styryl]-1-methylpyridinium iodide Chemical compound [I-].C1=CC(N(C)C)=CC=C1\C=C\C1=CC=CC=[N+]1C XPOIQAIBZGSIDD-UHFFFAOYSA-M 0.000 claims description 3
- GGVFBUYNEPBFQT-UHFFFAOYSA-N 2-hydroxy-6-(2-naphthalen-2-ylethyl)benzoic acid Chemical compound OC(=O)C1=C(O)C=CC=C1CCC1=CC=C(C=CC=C2)C2=C1 GGVFBUYNEPBFQT-UHFFFAOYSA-N 0.000 claims description 3
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
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- IIGCYQPNZRSCLY-UHFFFAOYSA-N 1,1-dimethyl-3-prop-1-enylurea Chemical compound CC=CNC(=O)N(C)C IIGCYQPNZRSCLY-UHFFFAOYSA-N 0.000 description 1
- MMVUZMIOJNPDME-UHFFFAOYSA-N 4-methylbenzenesulfonate;triethylazanium Chemical compound CC[NH+](CC)CC.CC1=CC=C(S([O-])(=O)=O)C=C1 MMVUZMIOJNPDME-UHFFFAOYSA-N 0.000 description 1
- 101000579218 Homo sapiens Renin Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
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- CYUJPKOZIGBPOO-IGRGDXOOSA-N tert-butyl n-[(1s,3s)-3-[[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl]-4-methyl-1-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]pentyl]carbamate Chemical compound C1=C(OC)C(OCCCOC)=CC(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H]2OC(=O)[C@H](C(C)C)C2)C(C)C)=C1 CYUJPKOZIGBPOO-IGRGDXOOSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
Abstract
The invention relates to a continuous flow micro-reaction synthesis method of an aliskiren intermediate, and belongs to the technical field of medicine preparation. The preparation method adopts a continuous flow microreactor technology to carry out technical optimization on key intermediates of aliskiren raw material medicines, takes S-4-benzyl-2-oxazolidone and isovaleryl chloride as starting materials, and synthesizes the aliskiren intermediates through substitution reaction, addition reaction and other reactions. Meanwhile, the influence of factors related to the molar ratio of materials, the reaction residence time, the reaction temperature and the like in the process flow on the yield and the purity is examined, and the optimal process condition is determined. The optimization process has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor cost, low project total cost and capacity improvement.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a method for synthesizing aliskiren intermediate by a continuous flow microreactor.
Background
Aliskiren (aliskiren), CAS number: 173334-57-1, which is a non-peptide inhibitor of human renin developed by North China, has a long chain structure similar to that of a peptide chain of natural renin, and has good renin inhibition activity and IC50 reaching nanomole. Aliskiren was approved by the FDA in the united states for the treatment of hypertension in month 5 of 2007. The chemical structural formula is shown as the following formula I:
The compound shown as a formula SM8 is a key intermediate of aliskiren, and the chemical structural formula of the compound is shown as follows:
the reported preparation processes of SM8 are numerous, and most of the processes are batch processes of a traditional kettle type reactor. The preparation process has many challenges, the synthesis route is complicated, the overall yield is low, column chromatography or column chromatography is needed for separating and purifying a plurality of core intermediates, the production and preparation process often involves dangerous highly toxic chemicals and high-risk chemical reactions, and simultaneously generates a plurality of waste water and byproducts, thereby being very easy to cause environmental pollution.
The patent WO2007045420, in the name of Yuanyanghua, discloses the following synthetic route:
The route uses hydrogenation and lactam ring closure reaction, pd/C is used as a catalyst in the hydrogenation reaction, and heavy metals in the finished product are difficult to control. Chinese patent CN101679213 reports the following route:
The reagent tetra-n-propyl ammonium perruthenate (TPAP) used in this route is expensive and the yield is not high because the reaction product is a mixture of two major stereoisomers.
The research application field of the micro-channel reaction technology is gradually expanded from micro-processing to a new subject with independent concepts, and compared with the conventional kettle reaction, the micro-channel reactor has the following advantages: a) By arranging the preheating device, the temperature of the materials is raised in advance before the materials enter the reactor, and the materials reach the reaction temperature after the materials enter the reactor, so that the time is saved compared with the kettle type reactor, and the reaction efficiency is improved by more than 5 times; b) The reaction device adopts a continuous flow pipeline which is communicated through a baffle box, the volume is reduced to 10% of that of a kettle type, and the occupied area and the factory investment are greatly reduced; c) The reaction tube is spirally wound, and reactants form spiral tangential motion along the spiral tube, so that the reactants can obtain high Reynolds number (Reynolds number is more than 5500) under the condition of low flow rate, and side reactions caused by long-time stay in a reaction system are avoided; d) When the chemical reaction is carried out, the materials in the micro-channel reactor are 1% of those in the kettle type reactor, and the micro-channel reactor can resist 4Mpa high pressure, which is 20 times of that in the kettle type reactor. The method solves the dangerous problem of the reaction of inflammable, explosive, high-toxicity and strong-corrosion (such as NaN 3, hydrogen peroxide, cyclopentene, tetrazole and concentrated sulfuric acid) from two aspects; e) The pipeline is an integral pipeline, has good tightness, is not connected with various valves and flanges of a kettle type, realizes zero emission of harmful gas sulfur dioxide and hydrogen chloride, and avoids the problems of environmental pollution and personal health damage; f) The chemical reaction result is monitored in real time through online monitoring equipment such as an online gas phase detector and a liquid phase online monitor, so that the reaction temperature and the reaction pressure can be regulated and controlled within 1 min; g) The multi-stage feeding device, the mixing device, the preheating device and the reaction device are communicated through continuous flow pipelines, so that the continuous process of multi-stage reaction is realized, the steps of repeated stock and feeding are reduced, the waste heat of the previous stage reaction can be fully utilized, the production efficiency is improved, and the energy consumption is reduced; h) And water is used as a cleaning agent, and the water can efficiently remove the material residues in the last reaction in the system at high temperature and high pressure, so that the cleaning agent is green, low-carbon and environment-friendly. Thus, the synthesis process completed in the microchannel reactor always allows to obtain a product of higher purity in a shorter time frame.
The gradual popularization and application of the microreactor lead to the obvious improvement of the research of efficient preparation of chemical substances, high-throughput screening of cells and proteins, reaction kinetics and the like.
The invention develops a set of continuous flow microreactor and a new process route, and simultaneously applies the continuous flow microreaction technology to a new preparation process of a key intermediate compound SM8 of aliskiren so as to solve the problems of low raw material conversion rate, high risk, environmental pollution and the like in the process.
Disclosure of Invention
Aiming at the technical problems of low raw material conversion rate, high risk, environmental pollution and the like in the preparation method of the key intermediate compound SM8 of aliskiren, the invention provides a continuous flow micro-reaction synthesis method of the key intermediate compound SM8 of aliskiren, and the method has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor cost, low project total cost and high productivity by using a continuous flow process compared with a batch process using a traditional kettle reactor.
The invention provides a continuous flow micro-reaction synthesis method of a key intermediate compound SM8 of aliskiren. An aliskiren intermediate, termed compound SM8, has the structure shown below:
The method provided by the invention can take S-4-benzyl-2-oxazolidone and isovaleryl chloride as starting materials, and the compound SM2 is obtained through substitution reaction in a microreactor; carrying out substitution reaction on the compound SM2 in a microreactor to obtain a compound SM3, and optionally carrying out aftertreatment; carrying out addition reaction on the compound SM3 in a micro-reactor to obtain a compound SM4, and optionally carrying out aftertreatment; carrying out substitution reaction on the compound SM4 in a microreactor to obtain a compound SM5, and optionally carrying out aftertreatment; carrying out addition reaction on the compound SM5 in a micro-reactor to obtain a compound SM6, and optionally carrying out aftertreatment; carrying out substitution reaction on the compound SM6 in a micro-reactor to obtain a compound SM7, and optionally carrying out aftertreatment; carrying out substitution reaction on the compound SM7 in a microreactor to obtain a compound SM8, and optionally carrying out aftertreatment; the specific reaction route is as follows:
The specific process route is shown in figure 1.
In one aspect, the present invention provides a process for the preparation of compound SM2, comprising step a: s-4-benzyl-2-oxazolidone, dimethylaminopyridine, triethylamine and solvent are mixed to prepare solution A-1 for standby, the solution A-1 and isovaleryl chloride are input into a microreactor system by a metering pump, the reaction solution is quenched after flowing out and enters a post-treatment system to obtain SM2,
The solvent in the step a is selected from at least one of toluene, xylene, THF and dichloromethane. Preferably, the solvent in the step a is toluene.
The reaction temperature in the microreactor of the step a is-10 ℃ to 20 ℃. In some embodiments, the reaction temperature in the microreactor of step a is from 0 ℃ to-5 ℃.
The flow rate in the micro-channel reactor in the step a is 1 ml/min-50 ml/min.
The molar ratio of S-4-benzyl-2-oxazolidinone to isovaleryl chloride in the microchannel reactor in step a is 0.5:1 to 1.5:1.
The reaction residence time in the microchannel reactor in step a is from 10 seconds to 120 seconds.
The reaction solution in the step a is quenched by a 1% sodium hydroxide aqueous solution after flowing out.
The preparation method of the compound SM2 comprises the step of optionally carrying out post-treatment after the reaction of the step a is completed.
In some embodiments, the method for preparing compound SM2, step a post-treatment comprises: the organic phases are extracted, combined, washed with water, dried and the solvent is removed to give compound SM2.
In some embodiments, a method of preparing compound SM2, comprises step a: s-4-benzyl-2-oxazolidone, dimethylaminopyridine, triethylamine and toluene are mixed to prepare a solution A-1 for later use, the solution A-1 and isovaleryl chloride are input into a microreactor system by two plunger metering pumps at a set flow rate of 1 ml/min-50 ml/min, and after the reaction solution flows out, the reaction solution is quenched by a 1% sodium hydroxide aqueous solution and enters a post-treatment system to obtain SM2.
Compared with the traditional kettle type reaction, the preparation method of the continuous flow micro-reactor adopted in the step a has the technical effects of avoiding the overflow of isovaleryl chloride, reducing ring-opening byproducts and reducing post-treatment wastewater.
In some embodiments, a method of preparing compound SM3, comprises step b: SM2, N-dimethyl propenyl urea is prepared into solution A-2, the solution A-2, lithium bis (trimethylsilyl) amide and trans-1, 4-dibromo-2-butene are input into a microreactor system by a metering pump, reaction liquid flows out and is quenched, the reaction liquid enters a post-treatment system to obtain SM3,
The reaction temperature in the microreactor of the step b is-10 ℃ to 90 ℃.
In some embodiments, the reaction temperature in the microreactor of step b is from 0 ℃ to 50 ℃. In some embodiments, the reaction temperature in the microreactor of step b is 30 ℃.
The flow rate in the micro-channel reactor in the step b is 1 ml/min-50 ml/min.
The molar ratio of SM2 to trans 1, 4-dibromo-2-butene in the microchannel reactor in step b is 0.5:1 to 1.5:1.
The reaction residence time in the microchannel reactor in step b is from 10 seconds to 100 seconds.
The reaction solution in the step b is quenched by a 10% hydrochloric acid aqueous solution after flowing out.
The preparation method of the compound SM3 comprises the step of optionally carrying out post-treatment after the reaction in the step b is completed. In some embodiments, the method for preparing compound SM3, step b post-treatment comprises: after the reaction was completed, the organic phases were combined, washed with water, dried, and the solvent was removed to obtain compound SM3.
In some embodiments, a method of preparing compound SM3, comprises step b: SM2, N-dimethyl propenyl urea is prepared into solution A-2, lithium bis (trimethylsilyl) amide and trans-1, 4-dibromo-2-butene are input into a microreactor system by a metering pump at a set flow rate of 1 ml/min-50 ml/min, and after the reaction solution flows out, the reaction solution is quenched by 10% hydrochloric acid aqueous solution and enters a post-treatment system to obtain SM3.
The preparation method of the continuous flow micro-reactor is adopted in the step b, and compared with the traditional kettle type reaction, the preparation method has the technical effect of avoiding ultralow temperature reaction.
In some embodiments, a method of preparing compound SM4, comprises step c: preparing solution A-3 from N-bromosuccinimide and water, inputting SM3 and solution A-3 into a microreactor system by a metering pump, separating reaction liquid after flowing out, entering a post-treatment system to obtain SM4,
The reaction temperature in the microreactor of the step c is 10-40 ℃. In some embodiments, the reaction temperature in the microreactor of step c is from 20 ℃ to 35 ℃.
The flow rate in the micro-channel reactor in the step c is 1 ml/min-50 ml/min.
The molar ratio of SM3 to N-bromosuccinimide in the microchannel reactor in step c is 0.5:1 to 1.5:1.
The reaction residence time in the microchannel reactor in step c is from 10 seconds to 100 seconds.
The preparation method of the compound SM4 comprises the step of optionally carrying out post-treatment after the reaction in the step c is completed. In some embodiments, the method for preparing compound SM4, the step c post-treatment comprises: after the reaction was completed, the organic phases were combined, washed with water, dried, and the solvent was removed to obtain compound SM4.
In some embodiments, a method of preparing compound SM4, comprises step c: preparing N-bromosuccinimide and water into a solution A-3, inputting SM3 and the solution A-3 into a microreactor system by a metering pump at a set flow rate of 1 ml/min-50 ml/min, separating the reaction solution after the reaction solution flows out, and then, entering a post-treatment system to obtain SM4.
And step c adopts a preparation method of a continuous flow micro-reactor, and compared with the traditional kettle type reaction, the preparation method has the technical effects of reducing the by-products of the hydrogen bromide elimination reaction and reducing the post-treatment wastewater.
In some embodiments, a method of preparing compound SM5, comprises step d: SM4, 2-methylimidazole and toluene are prepared into solution A-4, sodium azide, sodium bicarbonate and purified water are prepared into solution A-4-2, the solution A-4 and the solution A-4-2 are input into a microreactor system by a metering pump, reaction liquid flows out and then enters a post-treatment system after being separated to obtain SM5,
The reaction temperature in the microreactor of step d is 60-90 ℃. In some embodiments, the reaction temperature in the microreactor of step d is from 75 ℃ to 85 ℃.
The flow rate in the micro-channel reactor in the step d is 1 ml/min-50 ml/min.
The molar ratio of SM4 to sodium azide in the microchannel reactor in step d is 0.5:1 to 1.5:1.
The reaction residence time in the microchannel reactor in step d is from 10 seconds to 100 seconds.
The preparation method of the compound SM5 comprises the step of optionally carrying out post-treatment after the reaction of the step d is completed. In some embodiments, the method for preparing compound SM5, the post-treatment of step d comprises: after the reaction was completed, extraction was performed, the organic phases were combined, washed with water, dried, and the solvent was removed to obtain compound SM5.
In some embodiments, a method of preparing compound SM5, comprises step d: SM4, 2-methylimidazole and toluene are prepared into solution A-4, sodium azide, sodium bicarbonate and purified water are prepared into solution A-4-2, SM3 and solution A-3 are input into a microreactor system by a metering pump at a set flow rate of 1 ml/min-50 ml/min, and after the reaction solution flows out, the reaction solution is separated and enters a post-treatment system to obtain SM5.
The preparation method of the continuous flow micro-reactor is adopted in the step d, and compared with the traditional kettle type reaction, the preparation method has the technical effect of avoiding the explosion hazard of sodium azide. In some embodiments, a method of preparing compound SM6, comprises step e: preparing SM5, palladium carbon and methanol into solution A-5, inputting the solution A-5 and hydrogen into a microreactor system by using a metering pump, allowing the reaction solution to flow out and enter a post-treatment system to obtain SM6,
The reaction temperature in the microreactor of the step e is 10-40 ℃. In some embodiments, the reaction temperature in the microreactor of step e is from 15 ℃ to 35 ℃.
And e, the flow rate in the micro-channel reactor in the step is 1 ml/min-50 ml/min.
The reaction residence time in the microchannel reactor in step e is from 10 seconds to 100 seconds.
The preparation method of the compound SM6 comprises the step of optionally carrying out post-treatment after the reaction in the step e is completed. In some embodiments, the method for preparing compound SM6, the step e post-treatment comprises: after the reaction was completed, the organic phases were combined, washed with water, dried, and the solvent was removed to obtain compound SM6.
In some embodiments, a method of preparing compound SM6, comprises step e: preparing SM5, palladium carbon and methanol into a solution A-5, inputting the solution A-5 and hydrogen into a micro-reactor system by a metering pump at a set flow rate of 1 ml/min-50 ml/min, and after the reaction solution flows out, entering a post-treatment system to obtain SM6.
Step e adopts a preparation method of a continuous flow micro-reactor, and has the technical effect of avoiding explosion hazard in the hydrogenation process compared with the traditional kettle-type reaction.
In some embodiments, a method of preparing compound SM7, comprises step f: preparing SM6 and p-toluenesulfonic acid into solution A-6, inputting the solution A-6 into a microreactor system by a metering pump, allowing the reaction solution to flow out and enter a post-treatment system to obtain SM7,
The reaction temperature in the microreactor of the step f is 30-100 ℃. In some embodiments, the reaction temperature in the microreactor of step f is from 45 ℃ to 55 ℃.
And f, the flow rate in the micro-channel reactor in the step is 1 ml/min-50 ml/min.
The molar ratio of SM6 to p-toluene sulfonic acid in the microchannel reactor in step f is 0.5:1 to 1.5:1.
The reaction residence time in the microchannel reactor in step f is from 10 seconds to 100 seconds.
The preparation method of the compound SM7 comprises the step of optionally carrying out post-treatment after the reaction in the step f is completed. In some embodiments, the method of preparing compound SM7, step f post-treatment comprises: after the reaction was completed, the organic phases were combined, washed with water, dried, and the solvent was removed to obtain compound SM7.
In some embodiments, a method of preparing compound SM7, comprises step f: and (3) preparing SM6 and p-toluenesulfonic acid into a solution A-6, inputting the solution A-6 into a microreactor system at a set flow rate of 1 ml/min-50 ml/min by using a metering pump, and after the reaction solution flows out, entering a post-treatment system to obtain SM7.
Step f adopts a preparation method of a continuous flow microreactor, and compared with the traditional kettle-type reaction, the preparation method has the technical effect of reducing the generation of ring-opening byproducts.
In some embodiments, a method of preparing compound SM8, comprises step g: SM7, dimethylaminopyridine, triethylamine and toluene are prepared into solution A-7, di-tert-butyl dicarbonate and toluene are prepared into solution A-7-2, the solution A-7 and the solution A-7-2 are input into a microreactor system by a metering pump, after the reaction solution flows out, the reaction solution enters a post-treatment system to obtain SM8,
The reaction temperature in the microreactor of step g is from 30℃to 100 ℃. In some embodiments, the reaction temperature in the microreactor of step g is from 45 ℃ to 55 ℃.
The flow rate in the micro-channel reactor in the step g is 1 ml/min-50 ml/min.
The molar ratio of SM7 to di-tert-butyl dicarbonate in the microchannel reactor in step g) was 0.5:1 to 1.5:1.
The reaction residence time in the microchannel reactor in step g is from 10 seconds to 100 seconds.
The preparation method of the compound SM8 comprises the step of optionally carrying out post-treatment after the reaction of the step g is completed. In some embodiments, the method of preparing compound SM8, step g post-treatment comprises: after the reaction was completed, extraction was performed, the organic phases were combined, washed with water, dried, and the solvent was removed to obtain compound SM8.
In some embodiments, a method of preparing compound SM8, comprises step g: SM7, dimethylaminopyridine, triethylamine and toluene are prepared into solution A-7, di-tert-butyl dicarbonate and toluene are prepared into solution A-7-2, the solution A-7 and the solution A-7-2 are input into a microreactor system by a metering pump at a set flow rate of 1 ml/min-50 ml/min, and after the reaction solution flows out, the reaction solution enters a post-treatment system to obtain SM8.
Step g adopts a preparation method of a continuous flow micro-reactor, and compared with the traditional kettle-type reaction, the preparation method has the technical effect of reducing the generation of ring-opening byproducts.
The preparation method of the compound SM8 comprises at least one of the steps a, b, c, d, e, f and g.
In some embodiments, the method of preparing compound SM8 of the present invention comprises one or at least 2 of steps a-g; or at least 3 steps; or at least 4 steps; or at least 5 steps; or at least 6 steps; or 7 steps.
In the technical scheme of the invention, a continuous flow microreactor is creatively adopted, an improved method is adopted to synthesize the aliskiren key intermediate compound SM8, and the optimal process condition is determined by examining the influence of factors such as the molar ratio of materials, the reaction residence time, the reaction temperature and the like on the yield and the purity, so that the compound SM8 prepared by the optimized process has high purity, high yield and less three wastes, and meets the requirements of registration and marketing. The preparation process of the key intermediate has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor cost, low project total cost and capacity improvement.
In summary, the invention has the following beneficial technical effects:
1. Compared with the traditional kettle type reaction, in the step a, the continuous flow micro-reactor is adopted to avoid the overflow of isovaleryl chloride, reduce the ring-opening byproducts and reduce the post-treatment wastewater; in step b, avoiding an ultra-low temperature reaction; in step c, the hydrogen bromide elimination reaction by-product is reduced, and the post-treatment wastewater is reduced; in step d, the explosion hazard of sodium azide is avoided; in step e, the explosion hazard of the hydrogenation process is avoided; in step f or g, the production of ring-opened byproducts is reduced. Meanwhile, the continuous flow micro-reactor can meet the higher requirements of the step based on environmental protection and safety and stable process parameters due to a relatively closed reaction system and high-efficiency mass transfer, heat transfer and exchange performance.
2. According to the continuous flow micro-reaction synthesis method of the aliskiren intermediate compound SM8, provided by the invention, the optimal process condition is determined by examining the influence of factors such as the molar ratio of materials, the reaction residence time, the reaction temperature and the like on the yield and the purity, and the method has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor cost, low project total cost and capacity improvement.
In the description of the present invention, it should be understood that the terms "first," "second," and the like are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
In the present invention, the expressions "compound a" and "compound represented by formula a" and "formula a" mean the same compound.
In the present invention, "optional" or "optionally" means that there may or may not be; or may not be performed; the term "optionally adding a reaction solvent to the crude product obtained in the step (C)" means that the reaction solvent may be added to the crude product obtained in the step (C) or not.
Drawings
Fig. 1 is a continuous flow process scheme for the key intermediate compound SM8 of aliskiren.
Detailed Description
In order to better understand the technical solution of the present invention, the following further discloses some non-limiting examples, which are further described in detail.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
In the present invention, min represents minutes; h represents hours; g represents gram; ml represents milliliters; kg indicates Kg.
In the present invention, HPLC means high performance liquid chromatography.
EXAMPLE 1 preparation of Compound SM2
1Mol of S-4-benzyl-2-oxazolidinone, 0.2mol of dimethylaminopyridine, 0.5mol of triethylamine and 15mL of toluene are mixed to prepare a solution A-1, the solution A-1 is placed in a liquid storage bottle A, 1.5mol of isovaleryl chloride and 5mL of toluene are mixed and placed in a liquid storage bottle B, the reaction temperature is set to be 0 ℃, materials in A, B bottles are pumped into a microchannel reactor by two plunger metering pumps according to a flow rate of 1:2, the residence time is 20 seconds, liquid products are collected, HPLC monitoring reaction is completed, the reaction liquid is quenched by a 1% sodium hydroxide aqueous solution after flowing out, enters a post-treatment system, and after extraction and drying, the organic solvent is removed, SM2 is obtained, the purity is 99.5%, and the yield is 95%.
EXAMPLE 2 preparation of Compound SM3
1Mol of SM2 and 0.3mol of N, N-dimethyl propenyl urea are mixed to prepare a solution A-2, the solution A-2 is placed in a liquid storage bottle C, 0.2mol of lithium bis (trimethylsilyl) amide and 1.2mol of trans-1, 4-dibromo-2-butene are mixed and placed in a liquid storage bottle D, the reaction temperature is set to be 30 ℃, materials in C, D bottles are respectively pumped into a microchannel reactor by two plunger metering pumps according to a flow rate of 1:1, the residence time is 40 seconds, liquid products are collected, HPLC monitoring reaction is completed, the reaction liquid is quenched by a 10% hydrochloric acid aqueous solution after flowing out, enters a post-treatment system, and the SM3 is obtained after the organic solvent is removed by extraction and drying, the purity is 96.5%, and the yield is 91%.
EXAMPLE 3 preparation of Compound SM4
2Mol of N-bromosuccinimide and 20mL of water are mixed to prepare a solution A-3, the solution A-3 is placed in a liquid storage bottle E, 1mol of SM3 is placed in the liquid storage bottle F, the reaction temperature is set to be 20 ℃, materials in E, F bottles are respectively pumped into a microchannel reactor by two plunger metering pumps according to the flow rate of 1:1, the residence time is 10 seconds, liquid products are collected, HPLC monitoring reaction is completed, the reaction liquid flows out and then enters a post-treatment system, and after extraction and drying, the organic solvent is removed, SM4 with the purity of 99.6% and the yield of 83% is obtained.
EXAMPLE 4 preparation of Compound SM5
1Mol of SM4, 0.2mol of 2-methylimidazole and 15mL of toluene are mixed to prepare a solution A-4, the solution A-4 is placed in a liquid storage bottle G, 1.5mol of sodium azide, 0.2mol of sodium bicarbonate and 15mL of purified water are mixed and placed in a liquid storage bottle H, the reaction temperature is set to be 80 ℃, materials in G, H bottles are respectively pumped into a microchannel reactor by two plunger metering pumps at a flow rate of 1:1, the retention time is 30 seconds, liquid products are collected, HPLC monitors that the reaction is complete, after the reaction liquid flows out, the separated liquid enters a post-treatment system, and after the extraction and drying are carried out, the organic solvent is removed, SM5 with the purity of 95.6% and the yield of 96% is obtained.
EXAMPLE 5 preparation of Compound SM6
1Mol of SM5, 0.1mol of palladium-carbon and 10mL of methanol are mixed to prepare a solution A-5, the solution A-5 is placed in a liquid storage bottle I, the reaction temperature is set to 25 ℃, materials and hydrogen in the bottle I are respectively pumped into a micro-channel reactor by two plunger metering pumps according to the flow rate of 1:1.2, the residence time is 40 seconds, liquid products are collected, the HPLC monitoring reaction is complete, the reaction liquid flows out and then enters a post-treatment system, and after extraction and drying, the organic solvent is removed, SM6 is obtained, the purity is 98.6%, and the yield is 92%.
EXAMPLE 6 preparation of Compound SM7
1Mol of SM6 and 0.1mol of p-toluenesulfonic acid are mixed to prepare a solution A-6, the solution A-6 is placed in a liquid storage bottle J, the reaction temperature is set to be 50 ℃, materials in the J bottle are pumped into a micro-channel reactor by a plunger type metering pump according to the flow rate of 1ml/min, the residence time is 10 seconds, liquid products are collected, the HPLC monitoring reaction is complete, the reaction liquid flows out and then enters a post-treatment system, and after extraction and drying, the organic solvent is removed, SM7 is obtained, the purity is 99%, and the yield is 82%.
EXAMPLE 7 preparation of Compound SM8
1Mol of SM7SM6, 0.1mol of dimethylaminopyridine, 0.1mol of triethylamine-p-toluenesulfonic acid and 20mL of toluene are mixed to prepare a solution A-67, the solution A-67 is placed in a liquid storage bottle JK, 2mol of di-tert-butyl dicarbonate and 10mL of toluene are mixed to prepare a solution A-7-2, the solution A-7 is placed in a liquid storage bottle L, the reaction temperature is set to be 50 ℃, materials in K, L bottles are pumped into a microchannel reactor by a plunger metering pump according to a flow rate of 1:1.2, the residence time is 10 seconds, liquid products are collected, HPLC monitoring reaction is completed, the reaction liquid flows out and then enters a post-treatment system, and after extraction and drying, the organic solvent is removed, SM8 is obtained, the purity is 99%, and the yield is 99.5%.
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.
Claims (2)
1. The preparation method of the compound SM8 comprises the following reaction processes:
The method is characterized by comprising the following steps of:
step a: mixing S-4-benzyl-2-oxazolidinone, dimethylaminopyridine, triethylamine and a solvent to prepare a solution A-1 for later use, inputting the solution A-1 and isovaleryl chloride into a microreactor system by using a metering pump, setting the reaction temperature of the microreactor to react, quenching the reaction solution after flowing out, entering a post-treatment system to obtain SM2,
Wherein the reaction temperature of the microreactor is-10 ℃ to 20 ℃;
Step b: SM2, N-dimethyl propenyl urea is prepared into solution A-2, the solution A-2, lithium bis (trimethylsilyl) amide and trans-1, 4-dibromo-2-butene are input into a microreactor system by a metering pump, the reaction temperature of the microreactor is set for reaction, the reaction solution is quenched after flowing out, the solution enters a post-treatment system to obtain SM3,
Wherein the reaction temperature of the microreactor is between-10 ℃ and 90 ℃;
Step c: preparing solution A-3 from N-bromosuccinimide and water, inputting SM3 and solution A-3 into a microreactor system by a metering pump, setting the reaction temperature of the microreactor to react, separating the reaction solution after flowing out, entering a post-treatment system to obtain SM4,
Wherein the reaction temperature of the microreactor is 10-40 ℃;
Step d: SM4, 2-methylimidazole and toluene are prepared into solution A-4, sodium azide, sodium bicarbonate and purified water are prepared into solution A-4-2, the solution A-4 and the solution A-4-2 are input into a microreactor system by a metering pump, the reaction temperature of the microreactor is set for reaction, the reaction solution flows out and then is separated into a post-treatment system to obtain SM5,
Wherein the reaction temperature of the microreactor is 60-90 ℃;
Step e: preparing SM5, palladium carbon and methanol into solution A-5, inputting the solution A-5 and hydrogen into a microreactor system by a metering pump, setting the reaction temperature of the microreactor to react, introducing the reaction solution into a post-treatment system after flowing out to obtain SM6,
Wherein the reaction temperature of the microreactor is 10-40 ℃;
Step f: preparing SM6 and p-toluenesulfonic acid into solution A-6, inputting the solution A-6 into a microreactor system by a metering pump, setting the reaction temperature of the microreactor to react, introducing the reaction solution into a post-treatment system after flowing out to obtain SM7,
Wherein the reaction temperature of the microreactor is 30-100 ℃;
Step g: SM7, dimethylaminopyridine, triethylamine and toluene are prepared into solution A-7, di-tert-butyl dicarbonate and toluene are prepared into solution A-7-2, the solution A-7 and the solution A-7-2 are input into a microreactor system by a metering pump, the reaction temperature of the microreactor is set for reaction, after the reaction solution flows out, the solution enters a post-treatment system to obtain SM8,
Wherein the reaction temperature of the microreactor is 30-100 ℃.
2. The production process according to claim 1, wherein in step a to step g, the reaction residence time in the microchannel reactor is from 10 seconds to 100 seconds; and/or in the steps a to g, the flow rate in the microchannel reactor is 1ml/min to 50ml/min.
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