CN114573578A - Preparation method of alkyl substituted azaindole - Google Patents
Preparation method of alkyl substituted azaindole Download PDFInfo
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- CN114573578A CN114573578A CN202210142323.9A CN202210142323A CN114573578A CN 114573578 A CN114573578 A CN 114573578A CN 202210142323 A CN202210142323 A CN 202210142323A CN 114573578 A CN114573578 A CN 114573578A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 title description 3
- 125000005334 azaindolyl group Chemical class N1N=C(C2=CC=CC=C12)* 0.000 title description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 125
- 230000005540 biological transmission Effects 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 17
- YSXINNXWZFYHLV-UHFFFAOYSA-N CC(C1=C(C)NC2=CN=CC=C12)N Chemical compound CC(C1=C(C)NC2=CN=CC=C12)N YSXINNXWZFYHLV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 6
- XLKDJOPOOHHZAN-UHFFFAOYSA-N 1h-pyrrolo[2,3-c]pyridine Chemical compound C1=NC=C2NC=CC2=C1 XLKDJOPOOHHZAN-UHFFFAOYSA-N 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 129
- 238000003756 stirring Methods 0.000 claims description 114
- 239000007789 gas Substances 0.000 claims description 104
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 91
- 238000006243 chemical reaction Methods 0.000 claims description 59
- 229910052757 nitrogen Inorganic materials 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 36
- 238000005406 washing Methods 0.000 claims description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 25
- 239000011541 reaction mixture Substances 0.000 claims description 25
- -1 polytetrafluoroethylene Polymers 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 23
- 239000007787 solid Substances 0.000 claims description 23
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000002244 precipitate Substances 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- 238000010791 quenching Methods 0.000 claims description 15
- 230000000171 quenching effect Effects 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- 239000007832 Na2SO4 Substances 0.000 claims description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 235000019439 ethyl acetate Nutrition 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 239000005457 ice water Substances 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 238000010898 silica gel chromatography Methods 0.000 claims description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 238000007789 sealing Methods 0.000 claims description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 5
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 claims description 5
- TWLNVQNCJFIEEU-UHFFFAOYSA-N [N].CC(C)=O Chemical compound [N].CC(C)=O TWLNVQNCJFIEEU-UHFFFAOYSA-N 0.000 claims description 5
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 claims description 5
- 229940125782 compound 2 Drugs 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- 238000007865 diluting Methods 0.000 claims description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 5
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 5
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 229920001971 elastomer Polymers 0.000 claims description 4
- 239000011521 glass Substances 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- HYCQBQTZFINXQH-UHFFFAOYSA-N 1-(4-methylphenyl)sulfonylpyrrolo[2,3-c]pyridine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=CN=CC=C2C=C1 HYCQBQTZFINXQH-UHFFFAOYSA-N 0.000 claims description 3
- UVVMDRQBWSQEKC-UHFFFAOYSA-N 2-methyl-1h-pyrrolo[2,3-c]pyridine Chemical compound C1=NC=C2NC(C)=CC2=C1 UVVMDRQBWSQEKC-UHFFFAOYSA-N 0.000 claims description 3
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 claims description 3
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 3
- 229920002635 polyurethane Polymers 0.000 claims description 3
- 239000004814 polyurethane Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 229910001220 stainless steel Inorganic materials 0.000 claims description 3
- 239000010935 stainless steel Substances 0.000 claims description 3
- TVCXVUHHCUYLGX-UHFFFAOYSA-N 2-Methylpyrrole Chemical compound CC1=CC=CN1 TVCXVUHHCUYLGX-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 1
- 238000010626 work up procedure Methods 0.000 abstract 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 13
- 230000000694 effects Effects 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A synthesis device, comprising: four-mouth bottle (1), ladder groove (2), homothermal groove (3), gas transmission pipe (4), gas source (5), water bath portion (6). There is also a process for the preparation of 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine, which utilizes the aforementioned synthesis apparatus. It starts from 6-azaindole and proceeds by nine steps and work-up using the above described apparatus to give 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine.
Description
Technical Field
The invention relates to the technical field of preparation of drug intermediates, in particular to a preparation method of alkyl substituted azaindole.
Background
2-methyl-1H-pyrrole [2,3-c ] pyridine-3-yl and derivatives thereof are important compounds, have strong biological activity and can be applied to the field of medicine, but the methods mentioned in the application rarely appear as the application of medical intermediates, or are disclosed by documents or data. Due to the characteristics of the molecule, a unique synthetic route and a unique higher yield problem, the method cannot be popularized to the synthesis of other similar structures.
In the case of 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine, the skilled person can obtain it by a series of adjustments and changes of the preparation mode, but the preparation is not the most difficult problem, the high yield, whether the yield is stable and whether impurities exist are the more important problems, the substance is applied as an intermediate class, the core problem is the preparation cost problem, but the prior art does not have enough technical suggestion for the problem.
Temperature control was found to be of utmost importance by the preparation of 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine. The step of obtaining the product is to adopt a water bath mode for heat preservation, but in practice, multiple reactions are carried out, the yield is found to be unstable, the instability is found through reaction experiments, the main reason is that the reaction per se causes temperature change, the step of the application, particularly 1.4.6, has strict requirements on the temperature, the temperature of 0 ℃ is relatively difficult to control, the actual control of the water bath often fluctuates, the external regulation of the water bath often has insufficient response, the internal temperature also changes, and people try to introduce nitrogen, the reaction repeatability is improved, but the reaction repeatability still does not reach the expected degree, the adverse effect also generates a new variable, namely the temperature problem of the nitrogen, although the system is a water bath, the introduced nitrogen is room temperature, and sometimes has obvious difference with the temperature of 0 ℃, for example, winter and summer, in order to ensure that the introduced nitrogen does not influence the reaction, the nitrogen needs to be cooled to the system temperature or be raised to the system temperature, however, such a method requires extra cooling measures, and it is difficult to directly cool the nitrogen gas by using a water bath, and a nitrogen gas pipe with a large length must be buried in the water bath. There is also an additional problem with this application that requires repeated switching from 0-elevated temperature-0 degrees. Such as step 4.
Due to the nature of the molecule, this method cannot be generalized to the synthesis of other similar structures. This is determined by the originality of the preparation, the higher yields and the irreproducibility of the shorter reaction times obtained in numerous trials, other routes having substantially no higher yields or acceptable reaction times. In particular, the practical problems of temperature control of the present application are not noted, and the same or similar methods as the present application are not taken to perform the improvement of the apparatus.
Disclosure of Invention
The first purpose of the invention is to solve two specific problems in the prior art, namely, the reaction changes temperature per se to influence the water bath effect, and the nitrogen is introduced to stabilize the reaction. The cooling is not conservative, which is solved in the present application. We have solved this problem through designing one kind and can compromise the water bath portion that adjusts the entering gas temperature, and the actual effect is better.
The invention claims a synthesis device, which is characterized by comprising: four-mouth bottle, step groove, homothermal groove, gas pipe, gas source, water bath portion.
The stepped groove is divided into an upper top groove and a lower bottom groove, the cross sections of the top groove and the bottom groove are rectangular, and the area of the cross section of the top groove is at least 50 square centimeters larger than that of the cross section of the bottom groove; the bottom groove of the stepped groove is completely immersed in the liquid level in the water bath part.
The homothermal groove is in a shape of Jiong when viewed from top and can be placed in the top groove; with warm groove by the upper cover with down the groove piece together, upper cover edge straining in the groove upper portion outside down, the upper cover has air inlet and gas outlet near two tip, air inlet and gas outlet are cylindrical through-hole, the upper surface of upper cover has the counter weight arch that a plurality of appears in pairs, every protruding inside callipers of counter weight is equipped with the balancing weight of a long and thin cone.
The gas source comprises two parts of a gas cylinder and a flow meter, and the gas transmission pipes comprise a first gas transmission pipe, a second gas transmission pipe and a third gas transmission pipe; the first gas transmission pipe is connected with the outlet and the gas inlet of the gas cylinder and passes through the flowmeter; the second gas pipe is connected with the gas outlet and the gas inlet of the four-mouth bottle; the third gas pipe leads the gas out from the gas outlet of the four-mouth bottle.
Further, the gas inlet and the gas outlet of the four-mouth bottle are provided with a rubber plug with holes; the lower grooves of the stepped groove and the homothermal groove are made of glass, and the upper cover is made of polytetrafluoroethylene; the cross sections of the top groove and the bottom groove are square, the counterweight protrusions are at least three pairs, the counterweight block is a hollow or solid stainless steel product, and the longitudinal section of the counterweight block is square; the lower surface of the upper cover is provided with a plurality of baffle plates which vertically extend downwards, and all the baffle plates form a baffle plate group together; adjacent baffles alternately extend from one side or the other side of the upper cover; the inner sides of the air inlet and the air outlet are adhered with polyurethane thin layers for sealing; the gas cylinder is filled with high-pressure nitrogen, and the effective air supply flow of the flow meter comprises 0.3-5L/min; the section of the water containing part of the water bath part is larger than the section area of the bottom groove but smaller than the section area of the top groove.
A process for the preparation of 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine, carried out using a synthesis apparatus as previously described, characterized in that it comprises the following steps: (1) taking a clean 2L four-mouth bottle, adding 9.5-9.6g of NaH into 130mL of DCM, placing the bottle into the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing the same-temperature groove into the stepped groove, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 1-3L/min, keeping stirring, adding 24.5-25.5g of A1 into 100mL of DMF, uniformly mixing, adding into a four-mouth bottle, stirring at 0 ℃ for reaction for not less than 30min, adding 44-45g of TsCl, raising the temperature of the water bath part to 25 ℃ after completely adding, reacting for at least 50min, pouring the reaction mixture into not less than 500mL of ice-water mixture, filtering to obtain a precipitate, washing with 250mL of water for at least 3 times each time, and drying to obtain a white solid compound A2.
(2) Fully dissolving 29-31g of A2 in 800mL of THF, stirring in a four-neck bottle at-78 ℃ provided by a dry ice acetone bath or a liquid nitrogen acetone bath under the protection of nitrogen, dropwise adding 52-54mL2.5M n-BuLi, keeping the temperature and the nitrogen atmosphere after dropwise adding, stirring for at least 1 hour, keeping the temperature and the nitrogen atmosphere, adding 20-20.5g of methyl iodide, removing a low-temperature facility after adding, heating the mixture to room temperature, stirring for reaction for at least 100min, quenching the reaction mixture by using not less than 250mL of water, extracting for at least 2 times by using 300mL of EtOAc, combining organic phases, drying and concentrating to obtain a brown solid compound A3.
(3) Taking a four-mouth bottle, adding 300mL of MeOH, keeping stirring, adding a total of 29-31g of A3, keeping stirring after the addition is finished, adding 11.5-12g of KOH again keeping stirring, raising the system to 65 ℃, stirring for reacting for at least 12h, removing the solvent, diluting the residue with at least 200mL of water, filtering the precipitate, washing the precipitate with 100mL of water for at least 2 times each time, and drying to obtain A4 as a brown solid.
(4) Taking a clean 2L four-mouth bottle, adding 8-9g of A4 into 425mL of DCM, placing the bottle in the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing the bottle in the stepped groove at the same temperature, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 1-3L/min, keeping stirring, adding 25.5-26g of AlCl3, adding 11.6-12g of compound 4A into a four-opening bottle, increasing the temperature of the system to 50 ℃ by using the water bath part, stirring for reaction for not less than 50min, reducing the temperature of the system to 0 ℃, stirring for reaction for 1h, taking out the mixture, regulating the pH value to 8-10 by using a saturated NaHCO3 aqueous solution under the premise of keeping the temperature of 0 ℃, extracting the water phase by using 200mL of DCM after separation, filtering and precipitating, washing by using 1000mL of mixed solution of DCM/MeOH with the volume ratio of 10:1 for not less than 2 times each time, combining filtrates and carrying out vacuum concentration to obtain a crude product A5.
(5) Taking a clean 2L four-neck bottle, adding 7-7.5g of A5 into 300mL of DCM, then placing into the four-neck bottle, adding 7.5-8g of LiAlH4 while stirring, heating the system to 55 ℃, stirring for reacting for not less than 12h, quenching the reaction mixture by using 7-9mL of water, 7-9mL of NaOH aqueous solution with the mass percent of 15% and 22-26mL of water in sequence, drying by using sufficient Na2SO4, filtering the obtained suspension, washing a filter cake by using 500mL of mixed solution with DCM/MeOH in the volume ratio of 10:1 for each time for not less than 10 times, combining the filtrates, and concentrating to obtain a yellow solid compound A6.
(6) Taking a clean 2L four-mouth bottle, adding 3-3.5g of A6 into 100mL of DCM, placing into the four-mouth bottle, clamping, immersing the bottom into water in a stepped groove, immersing a homothermal groove into the stepped groove, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 1-3L/min, keeping stirring, sequentially adding a mixture of 6.5-7g of TEA, 228mg of DMAP, 8.94g of TsCl and 10mL of LCM into a four-mouth bottle, stirring and reacting at 0 ℃ for 30min, heating to 25 ℃, stirring and reacting for no less than 1.5h, removing the reaction mixture, quenching with no less than 50mL of water, extracting with no less than 50mL of DCM for no less than 2 times each time, combining organic phases, washing with 50mL of saline, drying with sufficient Na2SO4, and carrying out vacuum concentration to obtain a brown compound A7.
(7) Taking a clean 2L four-mouth bottle, adding 4-5g of A7 into a mixed solvent of 80mLMeOH and 240mL of methylbenzene, then placing the bottle into the four-mouth bottle, adding 2.9-3g of triphenyl phosphorus and 1.5-1.7g of phthalimide while stirring, cooling the system to 0 ℃, preserving the temperature by using an ice-water bath after the addition is finished, uniformly mixing the mixture by using 1.8-2g of DIAD in 20mL of methylbenzene, dropwise adding the mixture into the toluene, stirring for reacting for not less than 30min until the precipitation is finished, carrying out suction filtration on the reaction mixture, and washing a filter cake by using not less than 50mL of ethyl acetate to obtain a compound A8.
(8) Taking a clean 2L four-mouth bottle, adding 3.3-3.5g of A8 into 20mL of MeOH at room temperature, adding 3-3.1g of PPh3 into the MeOH, dissolving 1mL of 80% hydrazine hydrate into 10mL of methanol, dropwise adding the solution into the MeOH, stirring for reaction for more than 5min until the stirring is stopped, stirring the mixture at 60 ℃ for reaction for not less than 1.5h, performing 100-mesh 200-mesh silica gel column chromatography, using a proper amount of EA, and then using a proper amount of EA containing 0.5% by mass of triethylamine: MeOH ═ 10:1 mixed solvent, compound a9 was obtained.
(9) A clean 2L four-necked flask was taken, 3-3.2g of A9 was added to 30mL of MeOH, 900-1000mg of KOH were added with stirring, after which the mixture was warmed to 65 ℃ and stirred for not less than 12H to remove the solvent to give a residue, which was purified by silica gel column chromatography with DCM: MeOH ═ 20:1 to give compound 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine.
The compound corresponding to the aforementioned reference numeral is, a 1: 6-azaindole, A2: 1-p-toluenesulfonyl-6-azaindole, n-BuLi: n-butyllithium, a 3: 1-p-toluenesulfonyl-2-methyl-6-azaindole, a 4: 2-methyl-6-azaindole, 4A: oxalyl chloride monomethyl ester, a 5: 2- (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) -2-oxoacetic acid methyl ester, a 6: 2- (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethyl-1-ol, a 7: 2- (2-methyl-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethyl ester-4-methylbenzenesulfonate, A8: 2- (2- (2-methyl-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethyl) isoindole-1, 3-dione, A9:2- (2-methyl-1-p-benzenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine.
Compared with the prior art, the invention has the advantages that: reaction conditions, particularly reaction conditions of the first step, the fourth step and the sixth step, are obtained through multiple comparison and grope, but after multiple repetition, the reaction yield is unstable, and the comparison shows that whether the stability can reach 0 ℃ is crucial, the upper parts of four-mouth bottles are subjected to auxiliary cooling, such as ice coating, cooling coating and the like, so that the yield is improved, and the reaction repeatability is also improved, but the method is not reliable to implement, has operation risks, and needs to be filled with nitrogen, so that the complexity of the device is too high. Secondly, it is not necessary to inject nitrogen into the reaction of the present application, but it has been found in practice that the introduction of nitrogen brings part of the heat and helps to maintain the system particularly stable, with a good effect on the yield of the reaction, provided however that the nitrogen introduced should be at the desired temperature of the system, for example 0 ℃, and if the difference in the temperature of the nitrogen introduced is large, the donor is associated with a negative effect. However, how to cool the introduced nitrogen is a big problem, extra cooling measures are needed, the nitrogen cooling is difficult to operate by directly cooling the nitrogen by using a water bath, a nitrogen pipe with a large length needs to be buried in a water bath pool, but the pipeline is thin and easy to damage, and the risk of influencing the reaction is large. The main advantages of this application: firstly, the problem that the reaction temperature is unstable and the yield is also unstable is properly solved by introducing the temperature-regulated nitrogen, particularly, the first step, the fourth step and the sixth step are extremely sensitive to the temperature, and if the reaction temperature cannot be stably kept at the required specific temperature, the reaction yield has great adverse effect. Secondly, solved the problem of letting in nitrogen gas how to cool down properly, do not have extra extravagant energy moreover, the mode is also more positive more surely than directly putting into the water bath with the nitrogen gas pipe. From the results, the yield is improved, the repeatability of the reaction is improved, and the data of multiple experiments are stable.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
Fig. 1 is a schematic front and top view of the apparatus.
FIG. 2 is a schematic view of the structure of the upper cover and the lower tank of the isothermal tank.
FIG. 3 is a schematic view of the upper cover of the isothermal tank matching with the counterweight.
FIG. 4 is a schematic view of a gas flow path including a homothermal cell.
FIG. 5 is a schematic of the main preparation route.
FIG. 6 is a nuclear magnetic map of the final product.
Reference numerals: the gas conveying pipe comprises four bottles 1, a stepped groove 2, a top groove 21, a bottom groove 22, a homothermal groove 3, an upper cover 31, a lower groove 32, a gas inlet 311, a gas outlet 312, a counterweight protrusion 313, a counterweight block 314, a baffle group 315, a gas conveying pipe 4, a first gas conveying pipe 41, a second gas conveying pipe 42, a third gas conveying pipe 43, a gas source 5, a gas bottle 51 and a flow meter 52.
Detailed Description
The preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, and the scope of the present invention will be more clearly and clearly defined.
Example 1
A synthesis device, comprising: four-mouth bottle 1, ladder groove 2, homothermal groove 3, gas-supply pipe 4, air supply 5, water bath portion 6. Here, the inlet and outlet of the four-necked flask are placed on both sides for easy routing and handling, and a line for introducing nitrogen gas is commercially available, for example. Fitted with a sealing rubber plug, or other more corrosion resistant plug, to exclude air, such as a teflon plug. The nitrogen gas introduction speed can not be more than 10L/min for safety, and is reasonable, such as between 0.3 and 3L/min, or a specific value. The insuring speed of qi entering and exiting is basically the same.
The stepped groove 2 is divided into an upper top groove 21 and a lower bottom groove 22, the cross sections of the top groove and the bottom groove are rectangular, and the area of the cross section of the top groove is at least 50 square centimeters larger than that of the cross section of the bottom groove; the bottom groove of the stepped groove is completely immersed in the liquid level in the water bath part. The stepped trough is made of quartz glass or other chemical vessels are made of commercially available glass types, the rectangle is for example square, and the cross section of the bottom trough is at least 30 square centimeters larger than that of the four-mouth bottle.
The homothermal groove 3 is in a shape of Jiong in a top view and can be placed in the top groove; the homothermal groove is formed by splicing an upper cover 31 and a lower groove 32, the edge of the upper cover is fastened on the outer side of the upper part of the lower groove, the upper cover is provided with an air inlet 311 and an air outlet 312 near two end parts, the air inlet and the air outlet are cylindrical through holes, the upper surface of the upper cover is provided with a plurality of counterweight bulges which appear in pairs, and each counterweight bulge is internally provided with a counterweight block of a long and thin cone. With the setting of warm groove, nitrogen gas lets in from the gas outlet from the air inlet and leads to, receives the influence and the cooling wherein, and baffle group's setting makes the air current flow in inside tortuous, and the flow time is as long as possible, and the cooling that receives is abundant as far as possible. The lower groove is made of the same material as the stepped groove, the upper cover is made of polytetrafluoroethylene, the inner side of the outer edge of the upper cover can be made into a rough surface, sealing is convenient, and after part of water is soaked, the sealing effect is good. The isothermal tank has a problem of floating upwards, namely that the inside of the isothermal tank is gas, in order to ensure that the isothermal tank does not float, the three sides of the isothermal tank are squeezed by polytetrafluoroethylene gaskets, and the upper sides of the gaskets are slightly thick, so that the isothermal tank is always soaked in water.
The gas source comprises two parts of a gas cylinder 51 and a flow meter 52, and the gas transmission pipe 4 comprises a first gas transmission pipe 41, a second gas transmission pipe 42 and a third gas transmission pipe 43; the first gas transmission pipe is connected with the outlet and the gas inlet of the gas cylinder and passes through the flowmeter; the second gas pipe is connected with the gas outlet and the gas inlet of the four-mouth bottle; the third gas pipe leads the gas out from the gas outlet of the four-mouth bottle. Both gas cylinders and flow meters are commercially available products. The air pipe is also a commercial product, and the wall is selected to be thicker as much as possible.
Further, the gas inlet and the gas outlet of the four-mouth bottle are provided with a rubber plug with holes; the lower grooves of the stepped groove and the homothermal groove are made of glass, and the upper cover is made of polytetrafluoroethylene; the cross sections of the top groove and the bottom groove are square, the counterweight protrusions are at least three pairs, the counterweight block is a hollow or solid stainless steel product, and the longitudinal section of the counterweight block is square; the lower surface of the upper cover is provided with a plurality of baffle plates 3151 which extend vertically downwards, and all the baffle plates form a baffle plate group 315 together; adjacent baffles alternately extend from one side or the other side of the upper cover; the inner sides of the air inlet and the air outlet are adhered with polyurethane thin layers for sealing; the gas cylinder is filled with high-pressure nitrogen, and the effective air supply flow of the flow meter comprises 0.3-5L/min; the section of the water containing part of the water bath part is larger than the section area of the bottom groove but smaller than the section area of the top groove. For convenience of manufacture, the counterweight protrusion is for example integrally formed with the upper cover, or can be formed separately, the surface of the flat upper cover is glued by glue, and the slender conical counterweight block has a radius of the bottom surface of a, a height of h and 3-6 times of a of h. The baffle 3151 is basically pushed to the bottom of the lower groove after the upper cover is buckled, so as to ensure the tortuous of the air path.
Example 2
A process for the preparation of 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine comprising the steps of:
(1) taking a clean 2L four-mouth bottle, adding 9.52g of NaH into 130mL of DCM, placing the bottle into the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing a homothermal groove into the stepped groove, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 2L/min, keeping stirring, adding 25g of A1 into 100mL of DMF, uniformly mixing, adding into a four-mouth bottle, stirring at 0 ℃ for reaction for not less than 30min, adding 44.2g of TsCl, raising the temperature of the water bath part to 25 ℃ after completely adding, reacting for at least 60min, pouring the reaction mixture into not less than 600mL of ice-water mixture, filtering to obtain a precipitate, washing with 250mL of water for at least 4 times each time, and drying to obtain a white solid compound A2,58 g; in this step, the yield was relatively low and the value was unstable before the nitrogen gas was not introduced and the apparatus of the present application was not used, and the product obtained in the 1 st step, for example, in the case of 51.1g, 48.3g, 41.5g and 45.7g, was not substantially more than 52g, and was not suitable for practical production, and the product obtained by the reaction was about 52 to 54g after the nitrogen gas introduction, but was also unstable, and the product obtained in the 1 st step was generally 55g or more after the apparatus of the present application, and the yield was stable and was high or low.
(2) Fully dissolving 30g of A2 in 800mL of THF, stirring in a four-neck bottle at-78 ℃ provided by a dry ice acetone bath or a liquid nitrogen acetone bath under the protection of nitrogen, dropwise adding 53mL2.5M n-BuLi, keeping the temperature and the nitrogen atmosphere after dropwise adding, stirring for at least 1 hour, keeping the temperature and the nitrogen atmosphere, adding 20.29g of methyl iodide, removing a low-temperature facility after adding, heating the mixture to room temperature, stirring for reacting for at least 120min, quenching the reaction mixture by using not less than 300mL of water, extracting for at least 3 times by using 300mL of EtOAc, combining organic phases, drying and concentrating to obtain a brown solid compound A3, 30 g;
(3) adding 300mL of MeOH into a four-neck flask, keeping stirring, adding 30g of A3, keeping stirring, adding 11.77g of KOH after the addition is finished, raising the temperature of the system to 65 ℃, stirring for reacting for at least 15h, removing the solvent, diluting the residue with at least 200mL of water, filtering the precipitate, washing the precipitate with 100mL of water for at least 3 times each time, and drying to obtain A4 as a brown solid and 11.5g of A;
(4) taking a clean 2L four-mouth bottle, adding 8.5g of A4 into 425mL of DCM, placing the bottle in the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing the bottle in the stepped groove at the same temperature, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 2L/min, keeping stirring, adding 25.69g of AlCl3, adding 11.83g of compound 4A into a four-opening bottle, increasing the temperature of the system to 50 ℃ by using the water bath part, stirring for reaction for at least 60min, reducing the temperature of the system to 0 ℃, stirring for reaction for 1h, taking out the mixture, regulating the pH value to 9 by using a saturated 3 aqueous solution under the premise of keeping the temperature at 0 ℃, separating, extracting the water phase by using 200mL of DCM, filtering and precipitating, washing by using 1000mL of mixed solution of DCM/MeOH at the volume ratio of 10:1 for at least 4 times, combining the filtrates, and carrying out vacuum concentration to obtain crude product A5, 7.3 g; in this step, the yield was relatively low and the value was unstable before the nitrogen gas was not introduced and the apparatus of the present application was not used, and the product obtained in the 1 st step was, for example, 5.4g, 4.3g, 4.5g and 4.7g, and it was not substantially more than 6g, which was not suitable for practical production, and the product obtained in the reaction was about 7g after the nitrogen gas introduction, but it was also unstable, and the product obtained in the 1 st step was generally 7.2g or more after the apparatus of the present application, and the yield was stable, but was high or low.
(5) Taking a clean 2L four-neck bottle, adding 7.3g of A5 into 300mL of DCM, then placing into the four-neck bottle, adding 7.65g of LiAlH4 while stirring, after the addition is finished, heating the system to 55 ℃, stirring for reacting for not less than 15h, sequentially quenching the reaction mixture by 8mL of water, 8mL of NaOH aqueous solution with the mass percent of 15% and 24mL of water, drying by using sufficient Na2SO4, filtering the obtained suspension, washing the filter cake by 500mL of mixed solution of DCM/MeOH with the volume ratio of 10:1 for not less than 10 times, combining the filtrates, and concentrating to obtain yellow solid compound A6, 7.26 g;
(6) taking a clean 2L four-mouth bottle, adding 3.3g of A6 into 100mL of DCM, placing the bottle into the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing the same-temperature groove into the stepped groove, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 2L/min, keeping stirring, sequentially adding a mixture of 6.6g of TEA, 228mg of DMAP, 8.94g of TsCl and 10mL of LCM into a four-port bottle, stirring at 0 ℃ for reaction for 30min, heating to 25 ℃, stirring for reaction for not less than 2h, removing the reaction mixture, quenching with not less than 50mL of water, extracting with not less than 50mL of DCM for not less than 3 times each time, combining organic phases, washing with 50mL of saline, drying with enough Na2SO4, and carrying out vacuum concentration to obtain brown compounds A7 and 4.5 g; in this step, the yield was relatively low and the value was unstable before the nitrogen gas was not introduced and the apparatus of the present application was not used, and the product obtained in the 1 st step was, for example, 3.4g, 4.3g, 4.5g and 3.7g, and it was not substantially more than 4g, which was not suitable for practical production, and the product obtained in the reaction was about 4.3g after the nitrogen gas introduction, but was also unstable, and the product obtained in the 1 st step was generally 4.4g or more after the apparatus of the present application, and the yield was stable and was only high or low.
(7) Taking a clean 2L four-mouth bottle, adding 4.5g of A7 into a mixed solvent of 80mLMeOH and 240mL of methylbenzene, then placing the bottle into the four-mouth bottle, adding 2.92g of triphenylphosphine and 1.6g of phthalimide while stirring, after the addition is finished, cooling the system to 0 ℃, preserving the temperature by using an ice-water bath, uniformly mixing 1.9g of DIAD into 20mL of methylbenzene, dropwise adding the mixture, stirring for reaction for not less than 30min after the dropwise addition is finished, filtering the reaction mixture until the precipitation is finished, washing a filter cake by using not less than 50mL of ethyl acetate to obtain a compound A8,3.4 g;
(8) taking a clean 2L four-mouth bottle, adding 3.4g of A8 into 20mL of MeOH at room temperature, adding 3.02g of PPh3, dissolving 1mL of 80% hydrazine hydrate into 10mL of methanol, dropwise adding the solution, stirring for reaction for more than 10min until the solution is completely clarified after stirring is stopped, stirring the mixture at 60 ℃ for reaction for not less than 2h, performing 100-mesh 200-mesh silica gel column chromatography, using proper amount of EA, and then using EA containing 0.5% by mass of triethylamine: MeOH ═ 10:1 mixed solvent to give compound a9,1.9 g;
(9) a clean 2L four-necked flask was taken, 3.1g of a9 was added to 30mL of MeOH, 923mg of KOH were added with stirring, the mixture was heated to 65 ℃ and stirred for not less than 15H, the solvent was removed to give a residue, and the residue was purified by silica gel column chromatography with DCM: MeOH ═ 20:1 to give compound 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine, 500 mg.
The compounds corresponding to the reference numerals are, a 1: 6-azaindole, A2: 1-p-toluenesulfonyl-6-azaindole, n-BuLi: n-butyllithium, a 3: 1-p-toluenesulfonyl-2-methyl-6-azaindole, a 4: 2-methyl-6-azaindole, 4A: oxalyl chloride monomethyl ester, a 5: 2- (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) -2-oxoacetic acid methyl ester, a 6: 2- (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethyl-1-ol, a 7: 2- (2-methyl-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethyl ester-4-methylbenzenesulfonate, A8: 2- (2- (2-methyl-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethyl) isoindole-1, 3-dione, A9:2- (2-methyl-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine.
Example 3
A process for the preparation of 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine comprising the steps of:
(1) taking a clean 2L four-mouth bottle, adding 9.54g of NaH into 130mL of DCM, then placing the bottle into the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing the bottle into the stepped groove at the same temperature, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 2.5L/min, keeping stirring, adding 25.2g of A1 into 100mL of DMF, uniformly mixing, adding into a four-mouth bottle, stirring at 0 ℃ for reaction for not less than 40min, adding 44.7g of TsCl, raising the temperature of the water bath part to 25 ℃ after completely adding, reacting for at least 70min, pouring the reaction mixture into not less than 700mL of ice-water mixture, filtering to obtain a precipitate, washing with 350mL of water for at least 5 times each time, and drying to obtain white solid compounds A2 and 58.7 g;
(2) fully dissolving 30.5g of A2 in 800mL of THF, stirring in a four-mouth bottle at-78 ℃ under the protection of nitrogen and provided by a dry ice acetone bath or a liquid nitrogen acetone bath, dropwise adding 53.5mL of 2.5M n-BuLi, keeping the temperature and the nitrogen atmosphere after the dropwise adding is finished, stirring for at least 1 hour, keeping the temperature and the nitrogen atmosphere, adding 20.4g of methyl iodide, removing a low-temperature facility after the dropwise adding is finished, heating the mixture to room temperature, stirring for reacting for at least 120min, quenching the reaction mixture by using not less than 350mL of water, extracting for at least 4 times by using 300mL of EtOAc, combining organic phases, drying and concentrating to obtain a brown solid compound A3, 30.3 g;
(3) adding 300mL of MeOH into a four-neck flask, keeping stirring, adding 30.5g of A3, keeping stirring, adding 11.9g of KOH after the addition is finished, raising the temperature of the system to 65 ℃, stirring for reacting for at least 18h, removing the solvent, diluting the residue with at least 200mL of water, filtering the precipitate, washing the precipitate with 100mL of water for at least 4 times, and drying to obtain A4 as a brown solid, wherein the weight of A4 is 11.97 g;
(4) taking a clean 2L four-mouth bottle, adding 8.7g of A4 into 425mL of DCM, placing the bottle in the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing the bottle in the stepped groove at the same temperature, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 2.5L/min, keeping stirring, adding 25.8g of AlCl3, adding 11.9g of compound 4A into four bottles, increasing the temperature of the system to 50 ℃ by using the water bath part, stirring for reaction for not less than 70min, reducing the temperature of the system to 0 ℃, stirring for reaction for 1h, taking out the mixture, regulating the pH value to 9.2 by using a saturated aqueous solution 3 under the premise of keeping the temperature at 0 ℃, extracting the water phase by using 200mL of DCM after separation, filtering and precipitating, washing by using 1000mL of mixed solution of DCM/MeOH at the volume ratio of 10:1 for not less than 5 times, merging filtrate and carrying out vacuum concentration to obtain crude product A5,7.47 g;
(5) taking a clean 2L four-neck bottle, adding 7.47g of A5 into 300mL of DCM, then placing into the four-neck bottle, adding 7.95g of LiAlH4 while stirring, heating the system to 55 ℃, stirring for reacting for not less than 18h, quenching the reaction mixture by using 9mL of water, 9mL of NaOH aqueous solution with the mass percent of 15% and 25mL of water in sequence, and then using sufficient Na2SO4Drying, filtering the obtained suspension, washing the filter cake for not less than 111 times by 500mL of mixed solution with DCM/MeOH in a volume ratio of 10:1, combining the filtrates, and concentrating to obtain yellow solid compound A6,7.38 g;
(6) taking a clean 2L four-mouth bottle, adding 3.4g of A6 into 100mL of DCM, placing the bottle into the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing the same-temperature groove into the stepped groove, and immersing the lower part of the stepped groove into a water bath part; the temperature of the water bath part is kept at 0 ℃, the isothermal tank, the gas cylinder, the flow meter and three gas transmission pipes are connected, nitrogen is introduced into the flow meter at the speed of 2.5L/min, stirring is kept, and then 6.77g of TEA, 247mg of DMAP, ethanol and water are sequentially added,Adding a mixture of 9g of TsCl and 10mL of CCM into a four-mouth bottle, stirring at 0 ℃ for reaction for 30min, heating to 25 ℃, stirring for reaction for at least 3h, removing the reaction mixture, quenching with at least 60mL of water, extracting with at least 60mL of DCM for at least 4 times, combining the organic phases, washing with 50mL of brine, and adding a sufficient amount of Na2SO4Drying and vacuum concentrating to obtain brown compound A7,4.83 g;
(7) taking a clean 2L four-mouth bottle, adding 4.7g of A7 into a mixed solvent of 80mLMeOH and 240mL of methylbenzene, then placing the bottle into the four-mouth bottle, adding 3g of triphenylphosphine and 1.6g of phthalimide while stirring, after the addition is finished, cooling the system to 0 ℃, preserving the temperature by using an ice-water bath, uniformly mixing 2g of DIAD in 20mL of methylbenzene, dropwise adding the mixture, stirring for reaction for not less than 30min after the dropwise addition is finished, filtering the reaction mixture until the precipitation is finished, and washing a filter cake by using not less than 60mL of ethyl acetate to obtain a compound A8,3.53 g;
(8) taking a clean 2L four-mouth bottle, adding 3.4g of A8 into 20mL of MeOH at room temperature, adding 3.02g of PPh3, dissolving 1mL of 80% hydrazine hydrate into 10mL of methanol, dropwise adding the solution, stirring for reaction for more than 10min until the solution is completely clarified after stirring is stopped, stirring the mixture at 60 ℃ for reaction for not less than 2h, performing 100-mesh 200-mesh silica gel column chromatography, using proper amount of EA, and then using EA containing 0.5% by mass of triethylamine: MeOH ═ 10:1 mixed solvent to give compound a9,1.98 g;
(9) a clean 2L four-necked flask was taken, 3.1g of a9 was added to 30mL of MeOH, 923mg of KOH were added with stirring, the mixture was warmed to 65 ℃ with stirring for not less than 15H after addition, the solvent was removed to give a residue, and the residue was purified by silica gel column chromatography with DCM: MeOH ═ 20:1 to give compound 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine, 589 mg.
Preferably, all of the foregoing reagents are chemically pure or purer. The water is deionized water, preferably double distilled water.
At present, no report of the preparation of the product exists in the prior art, compared with a preparation method of similar substances, the method disclosed by the invention has the advantages that the steps are delicate, the utilization rate of raw materials in each step is very high, the method has great value for realizing industrial production, the method disclosed by the invention is finely designed, the synthesis is effectively realized, the yield is higher, certain industrial production value is realized, and the economic value is higher. Compared with the method, the yield is reduced by at least 10%, and the method has the advantages that the first, fourth and sixth steps are relatively large risk and cannot be carried out correctly.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that are not thought of through the inventive work should be included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope defined by the claims.
Claims (4)
1. A synthesis device, comprising:
a four-mouth bottle (1), a step groove (2), a homothermal groove (3), a gas pipe (4), a gas source (5) and a water bath part (6);
the stepped groove (2) is divided into an upper top groove (21) and a lower bottom groove (22), the cross sections of the top groove and the bottom groove are rectangular, and the cross section area of the top groove is at least 50 square centimeters larger than that of the bottom groove; the bottom groove of the stepped groove is completely immersed in the liquid level in the water bath part;
the homothermal groove (3) is in a shape of Jiong in a top view and can be placed in the top groove; the isothermal groove is formed by splicing an upper cover (31) and a lower groove (32), the edge of the upper cover is fastened on the outer side of the upper part of the lower groove, the upper cover is provided with an air inlet (311) and an air outlet (312) close to two end parts, the air inlet and the air outlet are cylindrical through holes, the upper surface of the upper cover is provided with a plurality of counterweight bulges which appear in pairs, and a counterweight block of a slender cone is clamped in each counterweight bulge;
the gas source comprises two parts, namely a gas cylinder (51) and a flow meter (52), and the gas conveying pipe (4) comprises a first gas conveying pipe (41), a second gas conveying pipe (42) and a third gas conveying pipe (43); the first gas transmission pipe is connected with the outlet and the gas inlet of the gas cylinder and passes through the flowmeter; the second gas pipe is connected with the gas outlet and the gas inlet of the four-mouth bottle; the third gas pipe leads the gas out from the gas outlet of the four-mouth bottle.
2. A synthesis device according to claim 1, characterized in that:
the gas inlet and the gas outlet of the four-mouth bottle are provided with a rubber plug with a hole;
the lower grooves of the stepped groove and the homothermal groove are made of glass, and the upper cover is made of polytetrafluoroethylene;
the cross sections of the top groove and the bottom groove are square, the counterweight protrusions are at least three pairs, the counterweight block is a hollow or solid stainless steel product, and the longitudinal section of the counterweight block is circular;
the lower surface of the upper cover is provided with a plurality of baffle plates (3151) which extend vertically downwards, and all the baffle plates form a baffle plate group (315) together; adjacent baffles alternately extend from one side or the other side of the upper cover;
the inner sides of the air inlet and the air outlet are adhered with polyurethane thin layers for sealing;
the gas cylinder is filled with high-pressure nitrogen, and the effective air flow of the flowmeter is 0.3-5L/min;
the section of the water containing part of the water bath part is larger than the section area of the bottom groove but smaller than the section area of the top groove.
3. A process for the preparation of 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine using a synthesis apparatus according to claim 2, characterized by comprising the steps of:
(1) taking a clean 2L four-mouth bottle, adding 9.5-9.6g of NaH into 130mL of DCM, placing the bottle into the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing the same-temperature groove into the stepped groove, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 1-3L/min, keeping stirring, adding 24.5-25.5g of A1 into 100mL of DMF, uniformly mixing, adding into a four-mouth bottle, stirring at 0 ℃ for reaction for not less than 30min, adding 44-45g of TsCl, raising the temperature of the water bath part to 25 ℃ after completely adding, reacting for at least 50min, pouring the reaction mixture into not less than 500mL of ice-water mixture, filtering to obtain a precipitate, washing with 250mL of water for at least 3 times each time, and drying to obtain a white solid compound A2;
(2) fully dissolving 29-31g of A2 in 800mL of THF, stirring in a four-mouth bottle at-78 ℃ provided by a dry ice acetone bath or a liquid nitrogen acetone bath under the protection of nitrogen, dropwise adding 52-54mL2.5M n-BuLi, keeping the temperature and the nitrogen atmosphere after dropwise adding, stirring for at least 1 hour, keeping the temperature and the nitrogen atmosphere, adding 20-20.5g of methyl iodide, removing a low-temperature facility after adding, heating the mixture to room temperature, stirring for reaction for at least 100min, quenching the reaction mixture by using not less than 250mL of water, extracting for at least 2 times by using 300mL of EtOAc, combining organic phases, drying and concentrating to obtain a brown solid compound A3;
(3) adding 300mL of MeOH into a four-neck flask, keeping stirring, adding 29-31g of A3, keeping stirring after the addition is finished, adding 11.5-12g of KOH, raising the temperature of the system to 65 ℃, stirring for reacting for at least 12h, removing the solvent, diluting the residue with at least 200mL of water, filtering the precipitate, washing the precipitate with 100mL of water for at least 2 times each time, and drying to obtain A4 as a brown solid;
(4) taking a clean 2L four-mouth bottle, adding 8-9g of A4 into 425mL of DCM, placing the bottle in the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing the bottle in the stepped groove at the same temperature, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 1-3L/min, keeping stirring, adding 25.5-26g of AlCl3, adding 11.6-12g of compound 4A into a four-opening bottle, increasing the temperature of a system to 50 ℃ by using the water bath part, stirring for reaction for not less than 50min, reducing the temperature of the system to 0 ℃, stirring for reaction for 1h, taking out a mixture, regulating the pH value to 8-10 by using a saturated NaHCO3 aqueous solution under the premise of keeping the temperature of 0 ℃, extracting a water phase by using 200mL of DCM after separation, filtering and precipitating, washing by using 1000mL of mixed solution of DCM/MeOH with the volume ratio of 10:1 for not less than 2 times each time, combining filtrates and carrying out vacuum concentration to obtain a crude product A5;
(5) taking a clean 2L four-mouth bottle, adding 7-7.5g of A5 into 300mL of DCM, then placing into the four-mouth bottle, adding 7.5-8g of LiAlH4 while stirring, heating the system to 55 ℃, stirring for reaction for not less than 12h, quenching the reaction mixture by using 7-9mL of water, 7-9mL of NaOH aqueous solution with the mass percent of 15% and 22-26mL of water in sequence, and then using sufficient Na2SO4Drying, filtering the obtained suspension, washing the filter cake with 500mL of mixed solution with DCM/MeOH in a volume ratio of 10:1 for not less than 10 times, combining the filtrates, and concentrating to obtain a yellow solid compound A6;
(6) taking a clean 2L four-mouth bottle, adding 3-3.5g of A6 into 100mL of DCM, placing into the four-mouth bottle, clamping, immersing the bottom into water in a stepped groove, immersing a homothermal groove into the stepped groove, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 1-3L/min, keeping stirring, sequentially adding a mixture of 6.5-7g of TEA, 228mg of DMAP, 8.94g of TsCl and 10mL of LCM into a four-mouth bottle, stirring and reacting at 0 ℃ for 30min, heating to 25 ℃, stirring and reacting for no less than 1.5h, removing the reaction mixture, quenching with no less than 50mL of water, extracting with no less than 50mL of DCM for no less than 2 times each time, combining organic phases, washing with 50mL of saline, and washing with sufficient Na2SO4Drying and vacuum concentrating to obtain brown compound A7;
(7) taking a clean 2L four-mouth bottle, adding 4-5g of A7 into a mixed solvent of 80mLMeOH and 240mL of methylbenzene, then placing the bottle into the four-mouth bottle, adding 2.9-3g of triphenyl phosphorus and 1.5-1.7g of phthalimide while stirring, cooling the system to 0 ℃, preserving the temperature by using an ice-water bath after the addition is finished, uniformly mixing 1.8-2g of DIAD in 20mL of methylbenzene, dropwise adding the mixture into the toluene, stirring for reacting for not less than 30min until the precipitation is finished, carrying out suction filtration on the reaction mixture, and washing a filter cake by using not less than 50mL of ethyl acetate to obtain a compound A8;
(8) taking a clean 2L four-mouth bottle, adding 3.3-3.5g of A8 into 20mL of MeOH at room temperature, adding 3-3.1g of PPh3 into the MeOH, dissolving 1mL of 80% hydrazine hydrate into 10mL of methanol, dropwise adding the solution into the MeOH, stirring for reaction for more than 5min until the stirring is stopped, stirring the mixture at 60 ℃ for reaction for not less than 1.5h, performing 100-mesh 200-mesh silica gel column chromatography, using a proper amount of EA, and then using a proper amount of EA containing 0.5% by mass of triethylamine: MeOH ═ 10:1 mixed solvent to give compound a 9;
(9) taking a clean 2L four-mouth bottle, adding 3-3.2g of A9 into 30mL of MeOH, adding 900-1000mg of KOH while stirring, after the addition is finished, heating the mixture to 65 ℃, stirring for reaction for not less than 12H, removing the solvent to obtain a residue, and purifying the residue by silica gel column chromatography, wherein DCM is 20:1, so as to obtain the compound 2 (2-methyl-1H-pyrrole [2,3-c ] pyridin-3-yl) ethane-1-amine;
the compounds corresponding to the aforementioned reference numbers are, a 1: 6-azaindole, A2: 1-p-toluenesulfonyl-6-azaindole, n-BuLi: n-butyllithium, a 3: 1-p-toluenesulfonyl-2-methyl-6-azaindole, a 4: 2-methyl-6-azaindole, 4A: oxalyl chloride monomethyl ester, a 5: 2- (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) -2-oxoacetic acid methyl ester, a 6: 2- (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethyl-1-ol, a 7: 2- (2-methyl-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethyl ester-4-methylbenzenesulfonate, A8: 2- (2- (2-methyl-1-p-toluenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethyl) isoindole-1, 3-dione, A9:2- (2-methyl-1-p-benzenesulfonyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine.
4. A process for the preparation of 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine according to claim 3, characterized by comprising the following steps:
(1) taking a clean 2L four-mouth bottle, adding 9.52g of NaH into 130mL of DCM, then placing the bottle into the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing a homothermal groove into the stepped groove, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 2L/min, keeping stirring, adding 25g of A1 into 100mL of DMF, uniformly mixing, adding into a four-mouth bottle, stirring at 0 ℃ for reaction for not less than 30min, adding 44.2g of TsCl, raising the temperature of the water bath part to 25 ℃ after completely adding, reacting for at least 60min, pouring the reaction mixture into not less than 600mL of ice-water mixture, filtering to obtain a precipitate, washing with 250mL of water for at least 4 times each time, and drying to obtain a white solid compound A2;
(2) fully dissolving 30g of A2 in 800mL of THF, stirring in a four-neck bottle at-78 ℃ provided by a dry ice acetone bath or a liquid nitrogen acetone bath under the protection of nitrogen, dropwise adding 53mL2.5M n-BuLi, keeping the temperature and the nitrogen atmosphere after dropwise adding, stirring for at least 1 hour, keeping the temperature and the nitrogen atmosphere, adding 20.29g of methyl iodide, removing a low-temperature facility after adding, heating the mixture to room temperature, stirring for reacting for at least 120min, quenching the reaction mixture by using not less than 300mL of water, extracting for at least 3 times by using 300mL of EtOAc, combining organic phases, drying and concentrating to obtain a brown solid compound A3;
(3) adding 300mL of MeOH into a four-neck flask, keeping stirring, adding 30g of A3, keeping stirring, adding 11.77g of KOH after the addition is finished, raising the temperature of the system to 65 ℃, stirring for reacting for at least 15h, removing the solvent, diluting the residue with at least 200mL of water, filtering the precipitate, washing the precipitate with 100mL of water for at least 3 times each time, and drying to obtain A4 as a brown solid;
(4) taking a clean 2L four-mouth bottle, adding 8.5g of A4 into 425mL of DCM, placing the bottle in the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing the bottle in the stepped groove at the same temperature, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 2L/min, keeping stirring, adding 25.69g of AlCl3, adding 11.83g of compound 4A into a four-opening bottle, increasing the temperature of the system to 50 ℃ by using the water bath part, stirring for reaction for at least 60min, reducing the temperature of the system to 0 ℃, stirring for reaction for 1h, taking out the mixture, regulating the pH value to 9 by using a saturated 3 aqueous solution under the premise of keeping the temperature at 0 ℃, separating, extracting the water phase by using 200mL of DCM, filtering and precipitating, washing by using 1000mL of mixed solution of DCM/MeOH at the volume ratio of 10:1 for at least 4 times, combining the filtrates, and carrying out vacuum concentration to obtain a crude product A5;
(5) taking a clean 2L four-neck bottle, adding 7.3g of A5 into 300mL of DCM, then placing into the four-neck bottle, adding 7.65g of LiAlH4 while stirring, after the addition is finished, heating the system to 55 ℃, stirring for reaction for not less than 15h, quenching the reaction mixture by using 8mL of water, 8mL of NaOH aqueous solution with the mass percent of 15% and 24mL of water in sequence, and then using sufficient Na2SO4Drying, filtering the obtained suspension, washing the filter cake with 500mL of mixed solution with DCM/MeOH in a volume ratio of 10:1 for not less than 10 times, combining the filtrates, and concentrating to obtain a yellow solid compound A6;
(6) taking a clean 2L four-mouth bottle, adding 3.3g of A6 into 100mL of DCM, placing the bottle into the four-mouth bottle, clamping the bottle, immersing the bottom of the bottle into water in a stepped groove, immersing the same-temperature groove into the stepped groove, and immersing the lower part of the stepped groove into a water bath part; keeping the temperature of a water bath part at 0 ℃, connecting a homothermal tank, a gas cylinder, a flowmeter and three gas transmission pipes, introducing nitrogen into the flowmeter at the speed of 2L/min, keeping stirring, sequentially adding a mixture of 6.6g of TEA, 228mg of DMAP, 8.94g of TsCl and 10mL of LCM into a four-port bottle, stirring and reacting at 0 ℃ for 30min, heating to 25 ℃, stirring and reacting for not less than 2h, removing the reaction mixture, quenching with not less than 50mL of water, extracting with not less than 50mL of DCM for not less than 3 times each time, combining organic phases, washing with 50mL of saline, and sufficiently Na2SO4Drying and vacuum concentrating to obtain brown compound A7;
(7) taking a clean 2L four-mouth bottle, adding 4.5g of A7 into a mixed solvent of 80mLMeOH and 240mL of methylbenzene, then placing the bottle into the four-mouth bottle, adding 2.92g of triphenylphosphine and 1.6g of phthalimide while stirring, after the addition is finished, cooling the system to 0 ℃, preserving the temperature by using an ice-water bath, uniformly mixing 1.9g of DIAD in 20mL of methylbenzene, dropwise adding the mixture, stirring for reaction for not less than 30min after the dropwise addition is finished, filtering the reaction mixture until the precipitation is finished, and washing a filter cake by using not less than 50mL of ethyl acetate to obtain a compound A8;
(8) taking a clean 2L four-mouth bottle, adding 3.4g of A8 into 20mL of MeOH at room temperature, adding 3.02g of PPh3, dissolving 1mL of 80% hydrazine hydrate into 10mL of methanol, dropwise adding the solution, stirring for reaction for more than 10min until the solution is completely clarified after stirring is stopped, stirring the mixture at 60 ℃ for reaction for not less than 2h, performing 100-mesh 200-mesh silica gel column chromatography, using proper amount of EA, and then using EA containing 0.5% by mass of triethylamine: MeOH ═ 10:1 mixed solvent to give compound a 9;
(9) a clean 2L four-necked flask was taken, 3.1g of a9 was added to 30mL of MeOH, 923mg of KOH was added with stirring, the mixture was warmed to 65 ℃ with stirring for not less than 15H after addition, the solvent was removed to give a residue, and the residue was purified by silica gel column chromatography with DCM: MeOH ═ 20:1 to give compound 2 (2-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) ethan-1-amine.
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