CN111995568B - Preparation method of poly-substituted fluorine-containing hexa-heterocyclic methylamine with protection groups - Google Patents

Preparation method of poly-substituted fluorine-containing hexa-heterocyclic methylamine with protection groups Download PDF

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CN111995568B
CN111995568B CN202010970379.4A CN202010970379A CN111995568B CN 111995568 B CN111995568 B CN 111995568B CN 202010970379 A CN202010970379 A CN 202010970379A CN 111995568 B CN111995568 B CN 111995568B
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bromopyridine
difluoromethoxy
extraction
drying
ring
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CN111995568A (en
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王海涛
张义勇
裴星先
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Beijing Liuhe Ningyuan Pharmaceutical Technology Co ltd
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Beijing Liuhe Ningyuan Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0419—Solvent extraction of solutions which are liquid in combination with an electric or magnetic field or with vibrations
    • B01D11/0423—Applying ultrasound
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pyridine Compounds (AREA)

Abstract

A preparation method of poly-substituted fluorine-containing hexa-membered nitrogen heterocyclic methylamine with protection is carried out by utilizing an ultrasonic extraction device, and is characterized by comprising the following steps: heating 2-hydroxy-5-bromopyridine-3-formic acid to 65 ℃ in methanol for refluxing, and dropwise adding thionyl chloride for reacting to obtain 2-hydroxy-5-bromopyridine-3-methyl formate; then the tert-butyl ((2- (difluoromethoxy) -5-hydroxypyridin-3-yl) methyl) carbamate is prepared through nine steps to obtain a final product; the extraction is implemented by using an ultrasonic extraction device, and comprises a preparation step, a covering step, a vibration and shaking step, a repeating step and a receiving step. The ultrasonic extraction device comprises an extraction part (1), a shell part (2), an ultrasonic part (3), a cross rod part (4), a left support part (5), a right support part (6), a glass device (7) and a demulsification component (8).

Description

Preparation method of poly-substituted fluorine-containing hexa-heterocyclic methylamine with protection groups
Technical Field
The invention relates to the technical field of preparation of a drug intermediate, in particular to a preparation method of a poly-substituted fluorine-containing hexa-membered nitrogen-containing heterocyclic methylamine with protection groups.
Background
4-hydroxybenzoic acid and derivatives thereof are important compounds, have strong biological activity, and are widely applied to the fields of medicines, pesticides and the like, so that the synthesis of the 4-hydroxybenzoic acid derivatives is widely concerned, and is particularly widely applied to medical intermediates. A preparation method of 3-chloro-4-hydroxybenzoic acid is given in CN110357773A, and a synthesis method of 3, 5-di-tert-butyl-4-hydroxybenzoic acid is given in CN109096099A, which are examples of the application and synthesis of 4-hydroxybenzoic acid derivatives, but the tert-butyl ((2-difluoromethoxy) -5-hydroxypyridin-3-yl) methyl) carbamate mentioned in the application rarely appears as an application of a medical intermediate, or documents or data are disclosed. 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.
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 addition, the prior art has the problem that the existing extraction device has the defects that the reaction dosage of the application far exceeds the dosage which is generally simple and qualitative, under the dosage, a simple extraction device is not used, if a common liquid separation extraction device is used, only 400ml of the organic solvent can be extracted at most each time, the extraction is divided for many times, the separation and combination are needed for many times, the time and labor are wasted, the energy consumption is wasted, and a great amount of time and energy are used for the synthesis personnel for the link, so that the application is not worth. Also there are some companies at present to order great extraction equipment, but only do extraction equipment greatly, can not solve the problem, because the extraction equipment is because the problem of dissolved matter nature, generally must be glass equipment just can be durable, but too big glass equipment rocks, it is all difficult to move, though can once take up a large amount of liquid mixture, nevertheless be difficult to grip in the extraction operation, it is inconvenient to rock the vibrations, it breaks easily to fall into, the degree of difficulty has been increased for actual operation again, do not have means among the prior art and solve both problems simultaneously, extraction device volume undersize that is the undersize, and the inconvenient problem of too big extraction device vibration operation, it is strong to provide a maneuverability, can once carry out the device of big hydrops extraction again.
The preparation of tert-butyl ((2-difluoromethoxy) -5-hydroxypyridin-3-yl) methyl) carbamate according to the present application has the problems that 500ml of the optical solvent is extracted once, small equipment cannot be loaded and is very troublesome in several times, a large equipment often makes a glass ware of several liters and cannot be taken and shaken, the whole experiment is scrapped after one time of error, and the preparation is dangerous and wasteful.
Disclosure of Invention
The invention aims to solve two specific problems in the prior art, namely, the problem of how to obtain tert-butyl ((2-difluoromethoxy) -5-hydroxypyridine-3-yl) methyl) carbamate through few and high-yield steps starting from 2, 3-difluoroaniline, and the scheme of the application perfectly solves the problem, and the problems of high implementation difficulty of an extraction link, small volume of an extraction device and inconvenient vibration operation of an overlarge extraction device are solved in the application.
The invention claims an ultrasonic extraction device, which is characterized in that: comprises an extraction part 1, a shell part 2, an ultrasonic part 3, a cross rod part 4, a left support part 5, a right support part 6, a glass device 7 and a demulsification component 8.
The extraction part 1 comprises a cylindrical part 11, an upper opening 12, an upper cover 13, a cone part 14, a liquid stop plug group 15 and a liquid outlet 16. The main part of extraction portion 1 is formed by last opening 12, cylinder portion 11, the concatenation of cone portion 14 from top to bottom, cylinder portion 11 is hollow cylinder type, the big-end-up of upper opening 12 and medial surface are dull polish portion 121, the outer fringe of upper cover 13 and dull polish portion 121 adaptation is the dull polish face, upper cover 13 top center has handle portion 131, cone portion 14 is hollow circular cone type, end liquid bolt group 15 has between cone portion 14 and liquid outlet 16, end liquid bolt group 15 has a end liquid chamber 153, end the horizontal through-hole that has one and liquid route looks vertically in the liquid chamber 153, wherein fill in and end liquid bolt 151, end liquid bolt handle 152 has on one side.
Outer shell 2 includes concave circle 21, main casing 22, observation groove 23, periphery 24, supporting portion 25 and the groove 27 of shaking the head down, concave circle 21 and the laminating of the top of vertebra body portion 14 down, main casing 22 and the laminating of cylinder portion 11, observation groove 23 is for opening a plurality of logical grooves on main casing (22) vertically, and these a plurality of logical grooves are the logical groove of the indefinite a plurality of rectangles of high-width unequal position, periphery 24 is the protruding edge of a week of supporting portion 25 lower part, the inboard bearing of supporting portion 25 go up opening 12. The main shell 22 has a concave recess matching the left side of the vibration head groove 27, and the vibration head groove 27 has a downward groove matching the vibration head 31.
The ultrasonic device 3 comprises a vibration head 31, a transducer 32, a generator 33, a power supply 34 and a reinforced cable 35, wherein the vibration head 31 and the transducer 32 are connected through the reinforced cable 35, a connecting line of the vibration head 31 and the transducer 32 is wrapped in the reinforced cable 35, the transducer 32 is connected with the generator 33, and the generator 33 is powered by the power supply 34. The vibrating head 31 is inserted into the groove and fixed by a groove screw 36.
The middle of the cross rod part 4 is provided with a circular ring part 42, the inner diameter of the circular ring part is matched with the outer diameter of the main shell 22, the periphery 24 can be supported by the upper part of the circular ring part 42, and the left and the right of the circular ring part 42 are respectively connected with a left cylindrical cross rod 41 and a right cylindrical cross rod 43 integrally.
The left support part 5 comprises a left rod 51, a left base 52, a left upper ring 53, a left hinge part 54, a left lower ring 55, a left flange 56 and a left bearing 57, the left support part 5 is positioned on the left side of the extraction part 1, the left base 52 is a cylindrical base with a screw hole in the middle, the lower end of the left rod 51 is screwed into the screw hole and fixed, the upper end of the left rod 51 is connected with the left lower ring 55 in a welding mode, the left lower ring 55 is buckled with the left upper ring 53 which is in a semi-annular shape, the left sides of the left lower ring 55 and the left upper ring 53 are hinged through the left hinge part 54, the right side of the left lower ring 55 and the left upper ring 53 is provided with a pair of left flanges 56 which are matched, the left flanges 56 are fixed through bolt groups, the left bearing 57 is fixed in the buckled left lower ring 55 and the left upper ring 53, and the inner hole of the left bearing 57 is inserted into the left cross rod 41.
Right support portion 6 includes right pole 61, right base 62, right upper ring 63, right articulated portion 64, right lower ring 65, right flange 66, right bearing 67, right support portion 6 is located extraction portion 1 right-hand, right base 62 is the cylindrical base that the centre has a screw, right pole 61 lower extreme is fixed to screwing in to this screw, right pole 61 upper end welded connection right lower ring 65, right lower ring 65 and the same semicircular right upper ring 63 lock that is in the top, right lower ring 65 and right upper ring 63 right side are articulated through right articulated portion 64, the left side has a pair of right flange 66 of looks adaptation, right flange 56 is fixed by bolt group, the right lower ring 65 and the right upper ring 63 internal fixation of lock have right bearing 67, right bearing 67 hole inserts right horizontal pole 43.
The glass unit 7 is located below the liquid outlet 16.
The demulsification assembly 8 includes a ball portion 81, a sheet portion 82 and a cone portion 83.
Preferably, the extraction part is made of glass. Vaseline is coated in the horizontal through holes.
The shell part is made of nylon PA66, polytetrafluoroethylene or engineering plastic.
The vibration head groove 27 is fixed on the main casing 22 by winding a plurality of turns of electrical tape.
The working power of the vibration head is between 60 and 100W, the working frequency is between 15KHZ and 100KHZ, and the head part of the vibration head is in a horn shape and is provided with an extended straight column.
The cross rod part 4, the left support part 5 and the right support part 6 are made of stainless steel.
The left bearing and the right bearing are ball bearings. The left bearing and the right bearing can be internally and externally provided with rubber gaskets.
The glass 7 is a combination of a large-volume wide-mouth container or a large-caliber funnel and other glassware.
The demulsification component 8 is made of polytetrafluoroethylene.
The preparation method of the poly-substituted fluorine-containing six-membered nitrogen-containing heterocyclic methylamine with the protection group is carried out by using the ultrasonic extraction device as described above due to the large amount of the required extraction agent, and is characterized by comprising the following steps.
(1) Dissolving 9-11g of 2-hydroxy-5-bromopyridine-3-formic acid in 105 ml of methanol, stirring until the system is colorless and transparent, heating to 65 ℃ for reflux, beginning to dropwise add 13-14g of thionyl chloride, after dropwise addition for 6-8min, gradually changing the system to be yellow and transparent, keeping the temperature at 65 ℃ until the reaction is monitored by HPLC, cooling the reaction mixture to room temperature, carrying out spin-drying concentration on the reaction mixture, adding 50ml of ethyl acetate for dilution, then adding 20ml of water for washing, separating out solids, carrying out suction filtration on the whole reaction mixture, pulping the solids by using 50ml of methyl tert-butyl ether, carrying out suction filtration, and drying to obtain the 2-hydroxy-5-bromopyridine-3-formic acid methyl ester.
(2) Dissolving 10-11g of 2-hydroxy-5-bromopyridine-3-methyl formate in 550ml of acetonitrile, cooling the system to 0 ℃ by using an external ice water bath, keeping the system stirred and kept in the external ice water bath, slowly adding 4.8-5.2g of 60% sodium hydride, dropwise adding 3.85-4.15g of 2-fluorosulfonyl difluoroacetic acid after the addition is finished, dropwise adding the 2-fluorosulfonyl difluoroacetic acid for at least 10min, removing the ice water bath, slowly raising the temperature to the normal temperature, continuously reacting until the reaction is finished by monitoring and reacting by using HPLC and LCMS, and dropwise adding 20ml of saturated NH4Cl solution with 30ml H2O quenching sodium hydride, gradually changing the solution into clear black brown liquid, separating out solid, performing suction filtration, adding 600ml ethyl acetate into the mixed solution for extraction, separating organic phase, and washing with 100ml saturated sodium chloride solution each timeAnd (3) drying and spin-drying the organic phase for 2 times, mixing the organic phase with 5 times of sample mixing mass, mixing petroleum ether and ethyl acetate, wherein the weight ratio of the petroleum ether to the ethyl acetate is 7: 1, passing 200-300 silica gel through a column to obtain 2-difluoromethoxy-5-bromopyridine-3-methyl formate.
(3) Dissolving 9.5-10.5g of 2-difluoromethoxy-5-bromopyridine-3-methyl formate in a mixed solution of 50ml of water and 50ml of tetrahydrofuran, cooling the system to about 10 ℃ by using an external ice water bath, slowly adding 4.25-4.75g of lithium hydroxide monohydrate into the system, after the addition is finished for at least 2-4min, reacting for at least 2.5-3.5h, dropwise adding 12N HCl into the system until the pH is adjusted to about 2 after the reaction is finished by monitoring HPLC and LCMS, then adding 100ml of dichloromethane each time to extract the mixture for 2 times, combining organic phases, drying and spin-drying to obtain the 2-difluoromethoxy-5-bromopyridine-3-carboxylic acid.
(4) Adding 8-9g of 2-difluoromethoxy-5-bromopyridine-3-formic acid into 80mL of trichloromethane, cooling the system to 0-5 ℃ by using an external ice water bath, then dripping 15-17mL of thionyl chloride, heating the system to 50 ℃ after dripping, reacting for 30 minutes, completely spin-drying the reaction mixture, dissolving the residue in 50mL of tetrahydrofuran, then dripping 100mL of ammonia water precooled to 0-10 ℃, naturally heating the system to room temperature, reacting for 8-16 hours, spinning off all the solvent, separating out the solid, performing suction filtration, leaching by using 50mL of water, and drying to obtain 2-difluoromethoxy-5-bromopyridine-3-formamide.
(5) Adding 7-7.5g of 2-difluoromethoxy-5-bromopyridine-3-formamide into 100mL of dichloromethane, then adding 20-22mL of triethylamine, cooling the reaction mixture to 0-5 ℃ by using an external ice water bath, dripping 13-15g of trifluoroacetic anhydride, naturally raising the reaction mixture to room temperature after dripping, reacting for 16 hours, pouring into 100mL of ice-water mixture, separating liquid, extracting the aqueous phase once with 50mL of dichloromethane, washing the organic phase once with 50mL of saturated salt, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain 2-difluoromethoxy-3-cyano-5-bromopyridine.
(6) Under the protection of nitrogen, 2.2 to 2.7g of 2-difluoromethoxy-3-cyano-5-bromopyridine is dissolved in 30mL of tetrahydrofuran, cooling the reaction mixture to 0 ℃ by using an external ice water bath, dropwise adding 40mL of borane tetrahydrofuran solution, naturally heating to room temperature after dropwise adding, carrying out heat preservation reaction for 1h, heating until reflux appears, keeping the reaction overnight, carrying out temperature reduction and sampling midway, slowly dropwise adding the taken sample into methanol and water, sending to HPLC-LCMS to monitor reaction, cooling the reaction mixture to 0 deg.C, slowly adding 70mL methanol dropwise, slowly heating to room temperature after dropwise addition, stirring for at least 1-2h, then refluxing for at least 1-2h, removing the solvent to obtain 2-difluoromethoxy-5-bromopyridine-3-methylamine as an oily liquid.
(7) Dissolving all the 2-difluoromethoxy-5-bromopyridine-3-methylamine obtained in the step 6 in 30mL of methyl tert-butyl ether, cooling the mixture to-10 ℃ by using an ice salt bath, dropwise adding at least 2.5eq of 7N dioxane/HCl, stirring for reacting for at least 1-2h, and performing suction filtration to obtain 2-difluoromethoxy-5-bromopyridine-3-methylamine hydrochloride solid.
(8) And (2) fully dispersing the 2-difluoromethoxy-5-bromopyridine-3-methylamine hydrochloride obtained in the step (7) in 20mL of dichloromethane, adding 2.7-3.3g of triethylamine under low-speed stirring, adding 3-3.6g of Boc anhydride in batches at normal temperature, reacting for 3h, adding 10mL of water, separating by 10mL of x3 dichloromethane, washing with brine, drying, removing the solvent, and carrying out column separation to obtain Boc protected 2-difluoromethoxy-5-bromopyridine-3-methylamine.
(9) Under stirring, 3.8-4.2g of Boc protected 2-difluoromethoxy-5-bromopyridine-3-methylamine is dissolved in 120mL of dioxane, 5.5-6.1g of boron bis valeryl and 3-3.5g of potassium acetate are slowly added into the system at room temperature, the system is fully dispersed while stirring, after the system is pumped and flushed with nitrogen for three times, 450 mg of Pd (dppf) Cl under nitrogen protection is added into the system2-CH2Cl2Heating to 85 ℃, refluxing, keeping the temperature, reacting for at least 10-14h, cooling to room temperature after HPLC monitoring reaction, adding 360mL of ethyl acetate for dilution, performing suction filtration, performing rotary drying and sample mixing, performing 5 times of sample mixing on 200-fold 300 silica gel column chromatography under the condition that the petroleum ether is ethyl acetate (20: 1) to obtain a product, pulping for 30min by using 30mL of petroleum ether, and performing suction filtration to obtain a pure product, namely ((2-difluoromethoxy-5-pinacol ester group) pyridine-3-yl) methyl) carbamic acid tert-butyl ester.
(10) 20-22g of NaBO3-4H2O in 40mL H2In O, the temperature is reduced to 0 ℃ by an external ice water bath, and 18 to 20g of ((2-difluoromethoxy-5-)Pinacol ester group) pyridine-3-yl) methyl) carbamic acid tert-butyl ester is dissolved in 360mL tetrahydrofuran and then is dripped into the system, the temperature is raised to room temperature after the dripping is finished, after at least 2-4h of reaction, 400mL saturated ammonium chloride and 400mL ethyl acetate are added into the system, after the liquid separation, the water phase is extracted again by 400mL ethyl acetate, and the organic phase is extracted by 400mL H2And (3) washing, drying, spin-drying and stirring, and passing a sample of 200-fold over 300 silica gel of 5 times of the sample under the conditions of petroleum ether and ethyl acetate of 10:1 to obtain a product, namely tert-butyl ((2- (difluoromethoxy) -5-hydroxypyridin-3-yl) methyl) carbamate.
The extraction in the above (1) to (10) is carried out by using the ultrasonic extraction device according to claim 2, and the specific steps are as follows.
(A) The preparation method comprises the following steps: the extraction portion is cleaned and aired, the extraction portion is completely sleeved into the outer shell portion to be fixed, the outer shell portion is sleeved into the circular ring portion, so that the periphery (24) can be supported by the upper portion of the circular ring portion (42), the left side of the vibration head groove (27) is pushed into a concave pit on the main shell (22), and the vibration head groove is wound for multiple circles at high temperature by using electrical adhesive tapes and is fixed on the main shell (22).
(B) Covering: the cover (13) is opened, the mixture to be extracted and the solvent are poured in, the demulsifying component is placed so that the ball part is outside the upper opening and the cone part is inward, and the cover is carefully closed.
(C) A vibration shaking step: pushing the shell part to enable the shell part to shake forwards and backwards for 10-20 times in a pendulum manner, enabling the manual idle straight shell part to be approximately static, starting the ultrasonic device and enabling the vibration head to vibrate for 1-2min at a frequency of more than 20KHz, and standing for 2-4 min.
(D) Repeating the steps: and C3-5 times of repetition.
(E) A receiving step: stopping extraction, opening the upper cover, taking out the demulsification component, respectively taking out the mixture of different phases below the liquid outlet by using different glassware, and pouring out the last phase of the extraction part from the upper opening.
Preferably, all of the foregoing reagents are chemically pure or purer. The water is deionized water, preferably double distilled water.
Compared with the prior art, the invention has the advantages that: the improvement on the device perfectly solves two problems; the problems that the implementation difficulty of an extraction link is high, the volume of an undersized extraction device is undersized, and the vibration operation of an oversized extraction device is inconvenient are solved; moreover, the ultrasonic device of this application combines the mode unique characteristic, if fixed in advance, then can't put into, and this kind of recess adds the mode of sticky tape, and fixed intensity is enough, easily dismantles again, and the fixed problem of large-scale glassware has been solved to the shape of shell 2. The problem of liquid level observation after fixing has been solved to the observation tank, can see through its degree of separation of observing the organic phase, and is very convenient, and is bulky more in addition, has the emulsion breaking difficult problem more, and the emulsion breaking subassembly that the polytetrafluoroethylene was done is cut with monoblock polytetrafluoroethylene, can solve the emulsion breaking problem effectively. And when the bearing pressure of the lower concave ring is high, the lower concave ring can be used for assisting in fixing the metal ring with the radian outside, and the lower concave ring can be detached when not used.
At present, no report of the preparation of the product exists in the prior art, compared with the preparation method of the same kind of substances, the method has the advantages that the steps are exquisite, the utilization rate of raw materials in each step is very high, the method has great value to realize industrial production, the synthesis is effectively realized through the exquisite design of the method, the yield is high, 1g of ((2-difluoromethoxy) -5-hydroxypyridine-3-yl) methyl) carbamic acid tert-butyl ester can be obtained from 2-hydroxy-5-bromopyridine-3-formic acid (10g), the method has certain industrial production value and great economic value, the application embodies the strong inventive concept and creativity through the exquisite design of an extraction link, the good preparation effect is obtained, no similar public information can be used for reference in the prior art, the scheme of the invention has originality. In contrast, the preparation by the traditional extraction method wastes at least one time in the extraction link, so that the method has no practical value. The traditional extraction equipment has insufficient volume, is difficult to extract under the condition of a large amount of solvents, is difficult to transfer materials, most of the materials are lost during each transfer, mixing and separation, and a large amount of substances are adhered to each neck of a glass container for many times when the materials are few, so that the yield is seriously influenced.
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 an overall schematic view of the apparatus.
Fig. 2 is a schematic side structure diagram of the left and right support parts.
Fig. 3 is a schematic top view of a cross bar portion of the present invention.
Figure 4 is a view of an ultrasound device of the present invention.
FIG. 5 is a schematic view of the composition of the extraction section.
Figure 6 is a schematic view of the housing portion composition.
FIG. 7 is a schematic lateral and forward view of the demulsification assembly.
FIG. 8 is a nuclear magnetic map of tert-butyl ((2-difluoromethoxy) -5-hydroxypyridin-3-yl) methyl) carbamate.
FIG. 9 is a scheme for the synthesis of tert-butyl ((2-difluoromethoxy) -5-hydroxypyridin-3-yl) methyl) carbamate.
Reference numerals: the extraction part 1, the cylindrical part 11, the upper opening 12, the frosted part 121, the upper cover 13, the handle part 131, the cone part 14, the liquid stop bolt group 15, the liquid stop bolt 151, the liquid stop bolt handle 152, the liquid stop cavity 153, the liquid outlet 16, the outer shell part 2, the lower concave ring 21, the main shell 22, the observation groove 23, the peripheral edge 24, the bearing part 25, the vibration head groove 27, the ultrasonic part 3, the vibration head 31, the transducer 32, the generator 33, the power supply 34, the reinforcing cable 35, the groove screw 36, the cross rod part 4, the left cross rod 41, the circular ring part 42, the right cross rod 43, the left support part 5, the left rod 51, the left base 52, the left upper ring 53, the left hinge part 54, the left lower ring 55, the left flange 56, the left bearing 57, the right support part 6, the right rod 61, the right base 62, the right upper ring 63, the right hinge part 64, the right lower ring 65, the right flange 66, the right bearing 67, the glass ware 7, the cone component 8, the ball part 81, the sheet part 82 and the emulsion breaking 83.
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
An ultrasonic extraction device is characterized in that: comprises an extraction part 1, a shell part 2, an ultrasonic part 3, a cross rod part 4, a left support part 5, a right support part 6, a glass device 7 and a demulsification component 8. The extraction device can be divided into a plurality of specifications, for example, the volume of the extraction part can be 1L, 2L, 3L, 4L and 5L to meet different requirements.
The extraction part 1 comprises a cylindrical part 11, an upper opening 12, an upper cover 13, a cone part 14, a liquid stop plug group 15 and a liquid outlet 16. The main part of extraction portion 1 is formed by last opening 12, cylinder portion 11, the concatenation of cone portion 14 from top to bottom, cylinder portion 11 is hollow cylinder type, the big-end-up of upper opening 12 and medial surface are dull polish portion 121, the outer fringe of upper cover 13 and dull polish portion 121 adaptation is the dull polish face, upper cover 13 top center has handle portion 131, cone portion 14 is hollow circular cone type, end liquid bolt group 15 has between cone portion 14 and liquid outlet 16, end liquid bolt group 15 has a end liquid chamber 153, end the horizontal through-hole that has one and liquid route looks vertically in the liquid chamber 153, wherein fill in and end liquid bolt 151, end liquid bolt handle 152 has on one side. To prevent the liquid from being ejected by excessive pressure, the liquid stop can be fitted with a rubber band or a special rubber retainer that is placed prior to the addition of liquid to retain the liquid stop stem 152 against ejection by excessive pressure.
Outer shell 2 includes concave circle 21, main casing 22, observation groove 23, periphery 24, supporting portion 25 and the groove 27 of shaking the head down, concave circle 21 and the laminating of the top of vertebra body portion 14 down, main casing 22 and the laminating of cylinder portion 11, observation groove 23 is for opening a plurality of logical grooves on main casing (22) vertically, and these a plurality of logical grooves are the logical groove of the indefinite a plurality of rectangles of high-width unequal position, periphery 24 is the protruding edge of a week of supporting portion 25 lower part, the inboard bearing of supporting portion 25 go up opening 12. The main shell 22 has a concave recess matching the left side of the vibration head groove 27, and the vibration head groove 27 has a downward groove matching the vibration head 31. The lower concave ring 21, the main shell 22, the observation groove 23, the periphery 24 and the bearing part 25 are integrally formed, and for the heavier situation, in order to prevent the lower concave ring 21 from deforming to cause the extraction part to slide out and break, a metal fixing belt can be arranged outside the lower concave ring 21, the lower concave ring can be made of aluminum alloy and is tightly fixed by a flange and a bolt, and the radian of the metal fixing belt is tightly attached to the outside of the lower concave ring.
The ultrasonic device 3 comprises a vibration head 31, a transducer 32, a generator 33, a power supply 34 and a reinforced cable 35, wherein the vibration head 31 and the transducer 32 are connected through the reinforced cable 35, a connecting line of the vibration head 31 and the transducer 32 is wrapped in the reinforced cable 35, the transducer 32 is connected with the generator 33, and the generator 33 is powered by the power supply 34. The vibrating head 31 is inserted into the groove and fixed by a groove screw 36. The power of the vibration head is between 60 and 100W, the frequency is an integer between 15KHZ and 100KHZ, a certain section of the vibration head is in a horn shape and is provided with an extended straight column, the groove is matched with the same type of the vibration head, and the groove is further provided with at least two symmetrical through holes for the groove screw 36 to penetrate through and penetrate through the screw hole on the vibration head for fixation.
The middle of the cross rod part 4 is provided with a circular ring part 42, the inner diameter of the circular ring part is matched with the outer diameter of the main shell 22, the periphery 24 can be supported by the upper part of the circular ring part 42, and the left and the right of the circular ring part 42 are respectively connected with a left cylindrical cross rod 41 and a right cylindrical cross rod 43 integrally. The circular ring portion 42, the left cross bar 41 and the right cross bar 43 may be formed by integrally molding stainless steel or by welding.
The left support part 5 comprises a left rod 51, a left base 52, a left upper ring 53, a left hinge part 54, a left lower ring 55, a left flange 56 and a left bearing 57, the left support part 5 is positioned on the left side of the extraction part 1, the left base 52 is a cylindrical base with a screw hole in the middle, the lower end of the left rod 51 is screwed into the screw hole and fixed, the upper end of the left rod 51 is connected with the left lower ring 55 in a welding mode, the left lower ring 55 is buckled with the left upper ring 53 which is in a semi-annular shape, the left sides of the left lower ring 55 and the left upper ring 53 are hinged through the left hinge part 54, the right side of the left lower ring 55 and the left upper ring 53 is provided with a pair of left flanges 56 which are matched, the left flanges 56 are fixed through bolt groups, the left bearing 57 is fixed in the buckled left lower ring 55 and the left upper ring 53, and the inner hole of the left bearing 57 is inserted into the left cross rod 41. The left bearing is a ball bearing, and a circle of balls are arranged between the inner ring and the outer ring.
Right support portion 6 includes right pole 61, right base 62, right upper ring 63, right articulated portion 64, right lower ring 65, right flange 66, right bearing 67, right support portion 6 is located extraction portion 1 right-hand, right base 62 is the cylindrical base that the centre has a screw, right pole 61 lower extreme is fixed to screwing in to this screw, right pole 61 upper end welded connection right lower ring 65, right lower ring 65 and the same semicircular right upper ring 63 lock that is in the top, right lower ring 65 and right upper ring 63 right side are articulated through right articulated portion 64, the left side has a pair of right flange 66 of looks adaptation, right flange 56 is fixed by bolt group, the right lower ring 65 and the right upper ring 63 internal fixation of lock have right bearing 67, right bearing 67 hole inserts right horizontal pole 43. The left bearing is a ball bearing, and a circle of balls are arranged between the inner ring and the outer ring.
The glass unit 7 is located below the liquid outlet 16. The demulsification assembly 8 includes a ball portion 81, a sheet portion 82 and a cone portion 83. The demulsification assembly made of polytetrafluoroethylene is cut into polytetrafluoroethylene in one piece, the ball part is used for dropping the whole assembly, the piece part is very thin, the cone part is very thin, and the tip is needle-shaped. The demulsification assembly may in practice be arranged in a plurality of different cone heights.
Preferably, the extraction part is made of glass. Vaseline is coated in the horizontal through holes. The shell part is made of nylon PA66, polytetrafluoroethylene or engineering plastic. The vibration head groove 27 is fixed on the main casing 22 by winding a plurality of turns of electrical tape. The working power of the vibration head is between 60 and 100W, the working frequency is between 15KHZ and 100KHZ, and the head part of the vibration head is in a horn shape and is provided with an extended straight column. The cross rod part 4, the left support part 5 and the right support part 6 are made of stainless steel. The left bearing and the right bearing are ball bearings. The left bearing and the right bearing can be internally and externally provided with rubber gaskets. The glass 7 is a large volume wide mouth container or a combination of a large bore funnel and other glassware, such as a large beaker, or a jar. The demulsification component 8 is made of polytetrafluoroethylene.
Example 2
The preparation method of the poly-substituted fluorine-containing six-membered nitrogen-containing heterocyclic methylamine with the protection group is carried out by using the ultrasonic extraction device as described above due to the large amount of the required extraction agent, and is characterized by comprising the following steps.
(1) Dissolving 9-11g of 2-hydroxy-5-bromopyridine-3-formic acid in 105 ml of methanol, stirring until the system is colorless and transparent, heating to 65 ℃ for reflux, beginning to dropwise add 13-14g of thionyl chloride, after dropwise addition for 6-8min, gradually changing the system to be yellow and transparent, keeping the temperature at 65 ℃ until the reaction is monitored by HPLC, cooling the reaction mixture to room temperature, carrying out spin-drying concentration on the reaction mixture, adding 50ml of ethyl acetate for dilution, then adding 20ml of water for washing, separating out solids, carrying out suction filtration on the whole reaction mixture, pulping the solids by using 50ml of methyl tert-butyl ether, carrying out suction filtration, and drying to obtain the 2-hydroxy-5-bromopyridine-3-formic acid methyl ester.
(2) Dissolving 10-11g of 2-hydroxy-5-bromopyridine-3-methyl formate in 550ml of acetonitrile, cooling the system to 0 ℃ by using an external ice water bath, keeping the system stirred and kept in the external ice water bath, slowly adding 4.8-5.2g of 60% sodium hydride, dropwise adding 3.85-4.15g of 2-fluorosulfonyl difluoroacetic acid after the addition is finished, dropwise adding the 2-fluorosulfonyl difluoroacetic acid for at least 10min, removing the ice water bath, slowly raising the temperature to the normal temperature, continuously reacting until the reaction is finished by monitoring and reacting by using HPLC and LCMS, and dropwise adding 20ml of saturated NH4Cl solution with 30ml H2Quenching sodium hydride by using O, gradually changing the solution into clear black brown liquid, separating out solids, completely filtering, adding 600ml of ethyl acetate into the mixed solution for extraction, separating an organic phase, washing the organic phase for 2 times by using 100ml of saturated sodium chloride solution each time, drying and spinning the organic phase, mixing the organic phase with 5 times of sample mixing mass, and mixing petroleum ether, ethyl acetate which is 7: 1, passing 200-300 silica gel through a column to obtain 2-difluoromethoxy-5-bromopyridine-3-methyl formate.
(3) Dissolving 9.5-10.5g of 2-difluoromethoxy-5-bromopyridine-3-methyl formate in a mixed solution of 50ml of water and 50ml of tetrahydrofuran, cooling the system to about 10 ℃ by using an external ice water bath, slowly adding 4.25-4.75g of lithium hydroxide monohydrate into the system, after the addition is finished for at least 2-4min, reacting for at least 2.5-3.5h, dropwise adding 12N HCl into the system until the pH is adjusted to about 2 after the reaction is finished by monitoring HPLC and LCMS, then adding 100ml of dichloromethane each time to extract the mixture for 2 times, combining organic phases, drying and spin-drying to obtain the 2-difluoromethoxy-5-bromopyridine-3-carboxylic acid.
(4) Adding 8-9g of 2-difluoromethoxy-5-bromopyridine-3-formic acid into 80mL of trichloromethane, cooling the system to 0-5 ℃ by using an external ice water bath, then dripping 15-17mL of thionyl chloride, heating the system to 50 ℃ after dripping, reacting for 30 minutes, completely spin-drying the reaction mixture, dissolving the residue in 50mL of tetrahydrofuran, then dripping 100mL of ammonia water precooled to 0-10 ℃, naturally heating the system to room temperature, reacting for 8-16 hours, spinning off all the solvent, separating out the solid, performing suction filtration, leaching by using 50mL of water, and drying to obtain 2-difluoromethoxy-5-bromopyridine-3-formamide.
(5) Adding 7-7.5g of 2-difluoromethoxy-5-bromopyridine-3-formamide into 100mL of dichloromethane, then adding 20-22mL of triethylamine, cooling the reaction mixture to 0-5 ℃ by using an external ice water bath, dripping 13-15g of trifluoroacetic anhydride, naturally raising the reaction mixture to room temperature after dripping, reacting for 16 hours, pouring into 100mL of ice-water mixture, separating liquid, extracting the aqueous phase once with 50mL of dichloromethane, washing the organic phase once with 50mL of saturated salt, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain 2-difluoromethoxy-3-cyano-5-bromopyridine.
(6) Under the protection of nitrogen, 2.2 to 2.7g of 2-difluoromethoxy-3-cyano-5-bromopyridine is dissolved in 30mL of tetrahydrofuran, cooling the reaction mixture to 0 ℃ by using an external ice water bath, dropwise adding 40mL of borane tetrahydrofuran solution, naturally heating to room temperature after dropwise adding, carrying out heat preservation reaction for 1h, heating until reflux appears, keeping the reaction overnight, carrying out temperature reduction and sampling midway, slowly dropwise adding the taken sample into methanol and water, sending to HPLC-LCMS to monitor reaction, cooling the reaction mixture to 0 deg.C, slowly adding 70mL methanol dropwise, slowly heating to room temperature after dropwise addition, stirring for at least 1-2h, then refluxing for at least 1-2h, removing the solvent to obtain 2-difluoromethoxy-5-bromopyridine-3-methylamine as an oily liquid.
(7) Dissolving all the 2-difluoromethoxy-5-bromopyridine-3-methylamine obtained in the step 6 in 30mL of methyl tert-butyl ether, cooling the mixture to-10 ℃ by using an ice salt bath, dropwise adding at least 2.5eq of 7N dioxane/HCl, stirring for reacting for at least 1-2h, and performing suction filtration to obtain 2-difluoromethoxy-5-bromopyridine-3-methylamine hydrochloride solid.
(8) And (2) fully dispersing the 2-difluoromethoxy-5-bromopyridine-3-methylamine hydrochloride obtained in the step (7) in 20mL of dichloromethane, adding 2.7-3.3g of triethylamine under low-speed stirring, adding 3-3.6g of Boc anhydride in batches at normal temperature, reacting for 3h, adding 10mL of water, separating by 10mL of x3 dichloromethane, washing with brine, drying, removing the solvent, and carrying out column separation to obtain Boc protected 2-difluoromethoxy-5-bromopyridine-3-methylamine.
(9) Under stirring, 3.8-4.2g of Boc protected 2-difluoromethoxy-5-bromopyridine-3-methylamine is dissolved in 120mL of dioxane, 5.5-6.1g of boron bis valeryl and 3-3.5g of potassium acetate are slowly added into the system at room temperature, the system is fully dispersed while stirring, after the system is pumped and flushed with nitrogen for three times, 450 mg of Pd (dppf) Cl under nitrogen protection is added into the system2-CH2Cl2Heating to 85 ℃, refluxing, keeping the temperature, reacting for at least 10-14h, cooling to room temperature after HPLC monitoring reaction, adding 360mL of ethyl acetate for dilution, performing suction filtration, performing rotary drying and sample mixing, performing 5 times of sample mixing on 200-fold 300 silica gel column chromatography under the condition that the petroleum ether is ethyl acetate (20: 1) to obtain a product, pulping for 30min by using 30mL of petroleum ether, and performing suction filtration to obtain a pure product, namely ((2-difluoromethoxy-5-pinacol ester group) pyridine-3-yl) methyl) carbamic acid tert-butyl ester.
(10) 20-22g of NaBO3-4H2O in 40mL H2Cooling to 0 ℃ by using an external ice water bath, dissolving 18-20g of tert-butyl ((2-difluoromethoxy-5-pinacol ester group) pyridine-3-yl) methyl) carbamate in 360mL of tetrahydrofuran, dropwise adding the tetrahydrofuran into the system, heating to room temperature after dropwise adding, reacting for at least 2-4 hours, adding 400mL of saturated ammonium chloride and 400mL of ethyl acetate into the system, separating the liquid, extracting the water phase with 400mL of ethyl acetate again, and extracting the organic phase with 400mL of H2And (3) washing, drying, spin-drying and stirring, and passing a sample of 200-fold over 300 silica gel of 5 times of the sample under the conditions of petroleum ether and ethyl acetate of 10:1 to obtain a product, namely tert-butyl ((2- (difluoromethoxy) -5-hydroxypyridin-3-yl) methyl) carbamate.
Example 3
The preparation method of the poly-substituted fluorine-containing six-membered nitrogen-containing heterocyclic methylamine with the protection group is carried out by using the ultrasonic extraction device as described above due to the large amount of the required extraction agent, and is characterized by comprising the following steps.
(1) Dissolving 11g of 2-hydroxy-5-bromopyridine-3-formic acid in 115ml of methanol, stirring until the system is colorless and transparent, heating to 65 ℃ for reflux, beginning to dropwise add 14g of thionyl chloride, after 8min of dropwise addition, gradually changing the system into yellow and transparent, keeping the temperature at 65 ℃ until the reaction is monitored by HPLC, cooling the reaction mixture to room temperature, carrying out rotary drying and concentration on the reaction mixture, adding 50ml of ethyl acetate for dilution, then adding 20ml of water for washing, separating out a solid, carrying out suction filtration on the reaction mixture, pulping the solid by using 50ml of methyl tert-butyl ether, carrying out suction filtration again, and drying to obtain the 2-hydroxy-5-bromopyridine-3-methyl formate, wherein the yield is 76.3%.
(2) Dissolving 11g of methyl 2-hydroxy-5-bromopyridine-3-carboxylate in 550ml of acetonitrile, cooling the system to 0 ℃ by using an external ice water bath, keeping the system stirred and kept in the external ice water bath, slowly adding 5.2g of 60% sodium hydride, dropwise adding 4.15g of 2-fluorosulfonyl difluoroacetic acid after the addition is finished, dropwise adding for at least 10min, removing the ice water bath, slowly raising the temperature to normal temperature, continuously reacting until the reaction is finished by monitoring HPLC and LCMS, and dropwise adding 20ml of saturated NH4Cl solution with 30ml H2Quenching sodium hydride by using O, gradually changing the solution into clear black brown liquid, separating out solids, completely filtering, adding 600ml of ethyl acetate into the mixed solution for extraction, separating an organic phase, washing the organic phase for 2 times by using 100ml of saturated sodium chloride solution each time, drying and spinning the organic phase, mixing the organic phase with 5 times of sample mixing mass, and mixing petroleum ether, ethyl acetate which is 7: 1, 200-300 silica gel is passed through the column to obtain 2-difluoromethoxy-5-bromopyridine-3-methyl formate with the yield of 73.4 percent.
(3) Dissolving 10.5g of methyl 2-difluoromethoxy-5-bromopyridine-3-carboxylate in a mixed solution of 50ml of water and 50ml of tetrahydrofuran, cooling the system to about 10 ℃ by using an external ice water bath, slowly adding 4.75g of lithium hydroxide monohydrate into the system, after the addition is finished for at least 3min, after the reaction is carried out for at least 3h, monitoring the reaction by HPLC and LCMS, dropwise adding 12N HCl into the system until the pH is adjusted to about 2, then adding 100ml of dichloromethane each time to extract the mixture for 2 times, combining organic phases, drying and spin-drying to obtain the 2-difluoromethoxy-5-bromopyridine-3-carboxylic acid, wherein the yield is 85.8%.
(4) Adding 9g of 2-difluoromethoxy-5-bromopyridine-3-formic acid into 80mL of trichloromethane, cooling the system to 0-5 ℃ by using an external ice water bath, then dripping 17mL of thionyl chloride, heating the system to 50 ℃ after dripping is finished, reacting for 30 minutes, completely spinning off the reaction mixture, dissolving the residue in 50mL of tetrahydrofuran, then dripping 100mL of ammonia water precooled to 0-10 ℃, naturally heating the system to room temperature, reacting for 14 hours, spinning off all solvents, separating out solids, performing suction filtration, rinsing with 50mL of water, and drying to obtain 2-difluoromethoxy-5-bromopyridine-3-formamide with the yield of 85.1%.
(5) Adding 7.5g of 2-difluoromethoxy-5-bromopyridine-3-formamide into 100mL of dichloromethane, then adding 22mL of triethylamine, cooling the reaction mixture to 0-5 ℃ by using an external ice water bath, dripping 15g of trifluoroacetic anhydride, naturally heating the reaction mixture to room temperature after dripping, reacting for 16 hours, pouring the mixture into 100mL of ice water mixture, separating liquid, extracting the aqueous phase once by using 50mL of dichloromethane, then washing the organic phase once by using 50mL of saturated salt, drying by using anhydrous sodium sulfate, carrying out suction filtration, and carrying out spin drying to obtain 2-difluoromethoxy-3-cyano-5-bromopyridine with the yield of 51%.
(6) Under the protection of nitrogen, 2.7g of 2-difluoromethoxy-3-cyano-5-bromopyridine is dissolved in 30mL of tetrahydrofuran, the reaction mixture is cooled to 0 ℃ by an external ice water bath, 40mL of borane tetrahydrofuran solution is dropwise added, the temperature is naturally raised to room temperature after the dropwise addition is finished, the reaction is kept for 1h, the reaction is further heated until reflux appears, the reaction is kept overnight, the temperature is lowered and the sample is taken out in the middle, the taken sample is slowly and dropwise added into methanol and water, after the HPLC-LCMS monitoring reaction is finished, the reaction mixture is cooled to 0 ℃, 70mL of methanol is slowly and dropwise added, after the dropwise addition is finished, the temperature is slowly raised to room temperature, the stirring is carried out for at least 1.5h, then the reflux is carried out for at least 1.5h, and the solvent is removed to obtain the oily liquid 2-difluoromethoxy-5-bromopyridine-3-methylamine.
(7) And (3) dissolving the 2-difluoromethoxy-5-bromopyridine-3-methylamine obtained in the step (6) in 30mL of methyl tert-butyl ether, cooling the mixture to-10 ℃ by using an ice salt bath, dropwise adding 2.5eq of 7N dioxane/HCl, stirring for reacting for at least 1.5h, and performing suction filtration to obtain 2-difluoromethoxy-5-bromopyridine-3-methylamine hydrochloride solid.
(8) Fully dispersing the 2-difluoromethoxy-5-bromopyridine-3-methylamine hydrochloride obtained in the step 7 in 20mL of dichloromethane, adding 3.3g of triethylamine under low-speed stirring, adding 3.6g of Boc acid anhydride in batches at normal temperature, reacting for 3h, adding 10mL of water, separating with 10mL of dichloromethane containing 10mL of x3, washing with brine, drying, removing the solvent, and separating by using a column to obtain Boc-protected 2-difluoromethoxy-5-bromopyridine-3-methylamine, wherein the total yield of the steps from (6) to (8) is 27.3%.
(9) 4.2g of Boc protected 2-difluoromethoxy-5-bromopyridine-3-methylamine are dissolved in 120mL of dioxane under stirring, 6.05g of boron diamsecurity and 3.5g of potassium acetate are slowly added into the system at room temperature, the system is fully dispersed while stirring, the system is pumped with nitrogen for three times, 487mg of Pd (dppf) Cl is added into the system under the protection of nitrogen2-CH2Cl2Heating to 85 ℃, refluxing, keeping the temperature, reacting for at least 14h, cooling to room temperature after HPLC monitoring reaction, adding 360mL of ethyl acetate for dilution, performing suction filtration, performing rotary drying and sample mixing, performing 5-time sample mixing on 200-fold 300 silica gel column chromatography under the condition that the ratio of petroleum ether to ethyl acetate is 20:1 to obtain a product, pulping for 30min by using 30mL of petroleum ether, and performing suction filtration to obtain a pure product, namely tert-butyl ((2-difluoromethoxy-5-pinacol ester group) pyridin-3-yl) methyl) carbamate, wherein the yield is 55.8%, and the pure product is a white solid.
(10) 22g of NaBO3-4H2O in 40mL H2Cooling to 0 ℃ by using an external ice water bath, dissolving 19g of tert-butyl ((2-difluoromethoxy-5-pinacolato) pyridin-3-yl) methyl) carbamate in 360mL of tetrahydrofuran, dropwise adding the tetrahydrofuran into the system, heating to room temperature after dropwise adding, reacting for at least 3 hours, adding 400mL of saturated ammonium chloride and 400mL of ethyl acetate into the system, separating the liquid, extracting the water phase with 400mL of ethyl acetate again, and extracting the organic phase with 400mL of H2After O washing, drying and spin-drying, under the conditions of petroleum ether and ethyl acetate of 10:1, a sample of 200-fold stirring is 5 times and the sample is passed through a silica gel column of 300 times to obtain 10.583g of tert-butyl ((2- (difluoromethoxy) -5-hydroxypyridin-3-yl) methyl) carbamate, and the yield is 76.9%.
The total yield is 2.44% by calculation, the same conditions are used, only a common vessel is used for extraction, other conditions are completely the same, the result yield is only 1.93%, the yield is obviously lower, and the time is about half longer.
Example 4
The preparation method of the poly-substituted fluorine-containing six-membered nitrogen-containing heterocyclic methylamine with the protection group is carried out by using the ultrasonic extraction device as described above due to the large amount of the required extraction agent, and is characterized by comprising the following steps.
(1) Dissolving 10.0g of 2-hydroxy-5-bromopyridine-3-formic acid (45.9mmol) in 110ml of methanol, stirring until the system is colorless and transparent, heating to 65 ℃ for reflux, beginning to dropwise add 13.7g of thionyl chloride (114.8mmol, 2.5eq) after 7min of dropwise addition, gradually changing the system to be yellow and transparent, keeping the temperature at 65 ℃ until the reaction is monitored by HPLC, cooling the reaction mixture to room temperature, spin-drying and concentrating the reaction mixture, adding 50ml of ethyl acetate for dilution, adding 20ml of water for washing, separating out a solid, completely filtering the reaction mixture, pulping the solid by using 50ml of methyl tert-butyl ether, filtering, and drying to obtain 8.0g of methyl 2-hydroxy-5-bromopyridine-3-formate with the yield of 75.2%, wherein the solid is light brown.
The detection data are 1HNMR (400Hz, CDCl3): delta ppm 11.49(brs, 1H), 8.30-8.34(M, 2H), LCMS (extension time:2.407min):233.0[ M +1 ].
(2) Dissolving 10.5g of methyl 2-hydroxy-5-bromopyridine-3-carboxylate (45.3mmol) in 550ml of acetonitrile, cooling the system to 0 ℃ by using an external ice water bath, keeping the system stirred and kept in the external ice water bath, slowly adding 5.0g of 60% sodium hydride (124.6mmol, 2.75eq), dropwise adding 4.0g of 2-fluorosulfonyl difluoroacetic acid (16.1mmol, 2eq) after the addition is finished, dropwise adding for at least 10min, removing the ice water bath, slowly raising the temperature to the normal temperature, continuously reacting until the reaction is finished by HPLC and LCMS monitoring, dropwise adding 20ml of saturated NH4Cl solution and 30ml of H2O to quench sodium hydride, gradually changing the solution into clear black brown liquid and separating out solids, carrying out suction filtration, adding 600ml of ethyl acetate into the mixed solution for extraction and separating an organic phase, washing the organic phase by 100ml of saturated sodium chloride solution for 2 times, drying and spin-drying the organic phase, mixing the organic phase with 5 times of sample mixing mass, and mixing the organic phase with petroleum ether and ethyl acetate, wherein the ratio of the petroleum ether to the ethyl acetate is 7: 1, 200-300 silica gel is passed through the column to obtain 9.2g of methyl 2-difluoromethoxy-5-bromopyridine-3-carboxylate, the yield is 72.1 percent, and the product is white powdery solid.
The assay data are 1HNMR (400Hz, DMSO): delta ppm 8.63(d, J ═ 2.0Hz, 1H), 8.47(d, J ═ 2.0Hz, 1H), 7.72(t, JH-F ═ 71.6Hz, 1H), 3.86(s, 3H). LCMS (extension time:3.908min):283.0[ M +1 ].
(3) Dissolving 10.0g of methyl 2-difluoromethoxy-5-bromopyridine-3-carboxylate in a mixed solution of 50ml of water and 50ml of tetrahydrofuran, cooling the system to about 10 ℃ by using an external ice water bath, slowly adding 4.5g of lithium hydroxide monohydrate (106.5mmol, 3eq) into the system, after the addition is finished for at least 2min, after the reaction is finished for at least 2.5h, monitoring the completion of the reaction by HPLC and LCMS, dropwise adding 12N HCl into the system until the pH is adjusted to about 2, then adding 100ml of dichloromethane into the system each time to extract the mixture for 2 times, combining organic phases, drying and spin-drying to obtain 8.5g of 2-difluoromethoxy-5-bromopyridine-3-carboxylate, wherein the yield is 85.3%, and the mixture is a white solid.
The detection data is LCMS (coverage time:3.223min):268.0[ M +1 ].
(4) Adding 8.5g of 2-difluoromethoxy-5-bromopyridine-3-formic acid into 80mL of trichloromethane, cooling the system to 0-5 ℃ by using an external ice water bath, then dripping 16mL of thionyl chloride, heating the system to 50 ℃ after dripping, reacting for 30 minutes, completely spin-drying the reaction mixture, dissolving the residue in 50mL of tetrahydrofuran, then dripping 100mL of ammonia water precooled to 0-10 ℃, naturally heating the system to room temperature, reacting for 12 hours, spinning off all solvents, separating out solids, performing suction filtration, leaching by using 50mL of water, and drying to obtain 7.2g of 2-difluoromethoxy-5-bromopyridine-3-formamide with the yield of 84.7%.
(5) Adding 7.2g of 2-difluoromethoxy-5-bromopyridine-3-formamide into 100mL of dichloromethane, then adding 21mL of triethylamine, cooling the reaction mixture to 0-5 ℃ by using an external ice water bath, dripping 14g of trifluoroacetic anhydride, naturally heating the reaction mixture to room temperature after dripping, reacting for 16 hours, pouring the mixture into 100mL of ice water mixture, separating liquid, extracting the aqueous phase once by using 50mL of dichloromethane, then washing the organic phase once by using 50mL of saturated salt, drying by using anhydrous sodium sulfate, carrying out suction filtration and spin drying to obtain 3.4g of 2-difluoromethoxy-3-cyano-5-bromopyridine, wherein the yield is 50.8%.
(6) Under the protection of nitrogen, 2.5g of 2-difluoromethoxy-3-cyano-5-bromopyridine (10mmol) is dissolved in 30mL of tetrahydrofuran, the reaction mixture is cooled to 0 ℃ by an external ice water bath, 40mL of borane tetrahydrofuran solution is dropwise added, the temperature is naturally raised to room temperature after the dropwise addition is finished, the reaction is kept for 1h while the temperature is kept for reaction, the reaction is kept for overnight, the temperature is lowered and the sample is taken out midway, the taken sample is slowly and dropwise added into methanol and water, after the HPLC-LCMS monitoring reaction is finished, the reaction mixture is cooled to 0 ℃, 70mL of methanol is slowly and dropwise added, after the dropwise addition is finished, the temperature is slowly raised to room temperature, the stirring is carried out for at least 1h, then the reflux is carried out for at least 1h, and the solvent is removed to obtain 2.39g of oily liquid 2-difluoromethoxy-5-bromopyridine-3-methylamine.
(7) 2.39g of 2-difluoromethoxy-5-bromopyridine-3-methylamine is dissolved in 30mL of methyl tert-butyl ether, the mixture is cooled to-10 ℃ by using an ice salt bath, 7N dioxane/HCl (2.5eq) is added dropwise, stirring reaction is carried out for at least 1h, and suction filtration is carried out to obtain 2.3g of 2-difluoromethoxy-5-bromopyridine-3-methylamine hydrochloride solid.
(8) 2.3g of 2-difluoromethoxy-5-bromopyridine-3-methylamine hydrochloride was well dispersed in 20mL of dichloromethane, 3.0g of triethylamine was added with low stirring, 3.3g of Boc anhydride (15mmol) was added in portions while maintaining the normal temperature, reaction was carried out for 3h, 10mL of water was added, 10mL of 3 dichloromethane was added for liquid separation, brine was washed, drying was carried out, the solvent was removed, column separation was carried out to obtain 950mg of Boc-protected 2-difluoromethoxy-5-bromopyridine-3-methylamine as a yellow oil, and the yield in the three steps (6) - (8) was 26.9%.
(9) 4.0g of Boc protected 2-difluoromethoxy-5-bromopyridine-3-methylamine (11.3mmol) was dissolved in 120mL of dioxane under stirring, 5.76g of bis (valeryl) diboron (22.6mmol, 2eq) and 3.33g of potassium acetate (33.9mmol, 3eq) were slowly added to the system at room temperature while maintaining stirring, the system was well dispersed while purging nitrogen three times, and 464mg of Pd (dppf) Cl was added to the system under nitrogen protection2-CH2Cl2(0.568mmol, 0.05eq), heating to 85 deg.C, refluxing, maintaining the temperature, reacting for at least 12h, monitoring by HPLC, cooling to room temperature, diluting with 360ml ethyl acetate, suction filtering, and spin-drying and stirringThe sample was purified by passing through a column packed with 200-fold silica gel 300 times in a ratio of 5: 1 (petroleum ether: ethyl acetate: 20: 1) to obtain 3g of a pure tert-butyl ((2-difluoromethoxy-5-pinacolato) pyridin-3-yl) methyl) carbamate (2.5 g) in a yield of 55.2% as a white solid, which was slurried with 30mL of petroleum ether for 30min and filtered under suction.
The data detected is that the data is,1HNMR(400Hz，CDCl3):δppm 8.43(d，J＝1.6Hz，1H)，8.04(s，1H)，7.57(t，JH-F＝72.4Hz，1H)，4.97(brs，1H)，4.32(d，J＝5.2Hz，2H)，1.45(s，9H)，1.33(s，12H)。LCMS(retention time:3.277+4.589min):400.9([M+1]+)。
(10) 20.8g of NaBO3-4H2O (135mmol,3eq) dissolved in 40mL H2In O, the temperature is reduced to 0 ℃ by using an external ice water bath, 18g of tert-butyl ((2-difluoromethoxy-5-pinacolato) pyridin-3-yl) methyl) carbamate (45mmol) is dissolved in 360mL of tetrahydrofuran and then is dripped into the system, the temperature is raised to room temperature after the dripping is finished, after at least 2 hours of reaction, 400mL of saturated ammonium chloride and 400mL of ethyl acetate are added into the system, after liquid separation, the water phase is extracted again by 400mL of ethyl acetate, and the organic phase is extracted by 400mL of H2After O washing, drying and spin-drying, under the conditions of petroleum ether and ethyl acetate of 10:1, a sample of 200-fold stirring is 5-fold and silica gel is filtered through a column, and 10g of tert-butyl ((2- (difluoromethoxy) -5-hydroxypyridin-3-yl) methyl) carbamate is obtained as a light yellow solid with the yield of 76.6%.
The data detected is that the data is,1HNMR(400Hz,CDCl3):δppm 7.67(s,1H),7.35(t,JH-F＝73.6Hz,1H),7.23(d,J＝2.4Hz,1H),5.19(brs,1H),4.24(d,J＝6.0Hz,2H),1.45(s,9H)。LCMS(retention time:3.409min):290.9[M+0.7]。
the total yield is 2.26% by calculation, the same conditions are used, only a common vessel is used for extraction, other conditions are completely the same, the result yield is only 1.83%, the yield is obviously lower, and the time is about half longer.
Example 5
The extraction in the above (1) to (10) is carried out by using the ultrasonic extraction device, and the specific steps are as follows.
(A) The preparation method comprises the following steps: the extraction portion is cleaned and aired, the extraction portion is completely sleeved into the outer shell portion to be fixed, the outer shell portion is sleeved into the circular ring portion, so that the periphery (24) can be supported by the upper portion of the circular ring portion (42), the left side of the vibration head groove (27) is pushed into a concave pit on the main shell (22), and the vibration head groove is wound for multiple circles at high temperature by using electrical adhesive tapes and is fixed on the main shell (22). The degree of depth of this pit can be 5mm, and this pit can be hugged closely the adaptation with the groove left side of shaking, inserts and can tentatively fix, alleviates the fixed pressure of adhesive tape, should shake the groove left side can further have with the pit in specific convex part complex concave part to reinforcing fixed effect. Electrician's adhesive tape can be replaced by a belt of making things convenient for the dismouting, and the dismouting is easier, and fixed effect is better.
(B) Covering: the cover (13) is opened, the mixture to be extracted and the solvent are poured in, the demulsifying component is placed so that the ball part is outside the upper opening and the cone part is inward, and the cover is carefully closed. The upper cover can be additionally provided with an air vent which is provided with an air release valve, and the air release valve can allow air to pass through when being lifted to a certain degree and is used for adjusting the internal and external air pressure. The demulsification assembly can be provided with a plurality of cones with different heights.
(C) A vibration shaking step: and pushing the shell part to enable the shell part to swing back and forth 16 times, enabling the manual idle straight shell part to be approximately static, starting the ultrasonic device and enabling the vibration head to vibrate for 2min at the frequency of 30KHz, and standing for 2 min.
(D) Repeating the steps: repeat step C4 times. Substantially stable stratification can be confirmed via the observation tank before the start of each iteration.
(E) A receiving step: stopping extraction, opening the upper cover, taking out the demulsification component, respectively taking out the mixture of different phases below the liquid outlet by using different glassware, and pouring out the last phase of the extraction part from the upper opening.
Example 6
The specific steps of the extraction in the above (1) to (10) are as follows.
(A) The preparation method comprises the following steps: the extraction portion is cleaned and aired, the extraction portion is completely sleeved into the outer shell portion to be fixed, the outer shell portion is sleeved into the circular ring portion, so that the periphery (24) can be supported by the upper portion of the circular ring portion (42), the left side of the vibration head groove (27) is pushed into a concave pit on the main shell (22), and the vibration head groove is wound for multiple circles at high temperature by using electrical adhesive tapes and is fixed on the main shell (22). The degree of depth of this pit can be 7mm, and this pit can be hugged closely the adaptation with the groove left side of shaking, inserts and can tentatively fix, alleviates the fixed pressure of adhesive tape, should shake the groove left side can further have with the pit in specific convex part complex concave part to reinforcing fixed effect. Electrician's adhesive tape can be replaced by a belt of making things convenient for the dismouting, and the dismouting is easier, and fixed effect is better.
(B) Covering: the cover (13) is opened, the mixture to be extracted and the solvent are poured in, the demulsifying component is placed so that the ball part is outside the upper opening and the cone part is inward, and the cover is carefully closed. The upper cover can be additionally provided with an air vent which is provided with an air release valve, and the air release valve can allow air to pass through when being lifted to a certain degree and is used for adjusting the internal and external air pressure. The demulsification assembly can be provided with a plurality of cones with different heights.
(C) A vibration shaking step: and pushing the shell part to enable the shell part to shake 20 times back and forth in a pendulum manner, enabling the manual idle straight shell part to be approximately static, starting the ultrasonic device and enabling the vibration head to vibrate for 2min at the frequency of 45KHz, and standing for 4 min.
(D) Repeating the steps: repeat step C5 times. Substantially stable stratification can be confirmed via the observation tank before the start of each iteration.
(E) A receiving step: stopping extraction, opening the upper cover, taking out the demulsification component, respectively taking out the mixture of different phases below the liquid outlet by using different glassware, and pouring out the last phase of the extraction part from the upper opening.
Preferably, all of the foregoing reagents are chemically pure or purer. The water is deionized water, preferably double distilled water. The dosage proportion selection is data prepared in an initial laboratory, in actual preparation, in order to achieve large dosage and good preparation, the dosage is generally calculated by at least multiplying 10 times, and at the moment, common extraction equipment is not used, special extraction equipment is needed, and large dosage extraction is dealt with.
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 (1)

1. A preparation method of poly-substituted fluorine-containing hexa-membered nitrogen heterocyclic methylamine with protection is characterized in that,
the ultrasonic extraction device comprises an extraction part (1), a shell part (2), an ultrasonic part (3), a cross rod part (4), a left support part (5), a right support part (6), a glass device (7) and a demulsification component (8);
the extraction part (1) comprises a cylindrical part (11), an upper opening (12), an upper cover (13), a conical part (14), a liquid stop plug group (15) and a liquid outlet (16); the main body part of the extraction part (1) is formed by splicing an upper opening (12), a cylindrical part (11) and a cone part (14) from top to bottom, the cylindrical part (11) is in a hollow cylinder shape, the upper opening (12) is large in size and small in size, the inner side face of the upper opening (12) is a frosted part (121), the outer edge of an upper cover (13) matched with the frosted part (121) is a frosted face, the center of the upper part of the upper cover (13) is provided with a handle part (131), the cone part (14) is in a hollow cone shape, a liquid stopping bolt group (15) is arranged between the cone part (14) and a liquid outlet (16), the liquid stopping bolt group (15) is provided with a liquid stopping cavity (153), a horizontal through hole vertical to a liquid passage is formed in the liquid stopping cavity (153), a liquid stopping bolt (151) is plugged in the liquid stopping cavity, and a liquid stopping bolt handle (152) is arranged on one side of the liquid stopping bolt;
the outer shell part (2) comprises a concave ring (21), a main shell (22), an observation groove (23), a peripheral edge (24), a bearing part (25) and a vibration head groove (27), the concave ring (21) is attached to the uppermost part of the cone part (14), the main shell (22) is attached to the cylindrical part (11), the observation groove (23) is a plurality of through grooves which are vertically formed in the main shell (22) and are rectangular through grooves with different heights and widths and variable positions, the peripheral edge (24) is a peripheral protruding edge of the lower part of the bearing part (25), and the inner side of the bearing part (25) bears the upper opening (12); the main shell (22) is provided with a concave pit matched with the left side of the vibration head groove (27), and the vibration head groove (27) is provided with a downward groove matched with the vibration head (31);
the ultrasonic part (3) comprises a vibration head (31), a transducer (32), a generator (33), a power supply (34) and a reinforced cable (35), the vibration head (31) is connected with the transducer (32) through the reinforced cable (35), a connecting line of the vibration head (31) and the transducer (32) is wrapped in the reinforced cable (35), the transducer (32) is connected with the generator (33), and the generator (33) is powered by the power supply (34); the vibration head (31) is inserted into the groove and is fixed by a groove screw (36);
the middle of the cross rod part (4) is provided with a circular ring part (42), the inner diameter of the circular ring part is matched with the outer diameter of the main shell (22), the periphery (24) is supported by the upper part of the circular ring part (42), and the left and the right of the circular ring part (42) are respectively connected with a left cylindrical cross rod (41) and a right cylindrical cross rod (43) integrally;
the left support part (5) comprises a left rod (51), a left base (52), a left upper ring (53), a left hinge part (54), a left lower ring (55), a left flange (56) and a left bearing (57), the left support part (5) is positioned on the left side of the extraction part (1), the left base (52) is a cylindrical base with a screw hole in the middle, the lower end of the left rod (51) is screwed into the screw hole for fixation, the upper end of the left rod (51) is welded with the left lower ring (55), the left lower ring (55) is buckled with the left upper ring (53) which is semi-annular in the upper part, the left sides of the left lower ring (55) and the left upper ring (53) are hinged through the left hinge part (54), and the right side is provided with a pair of matched left flanges (56), the left flange (56) is fixed by a bolt group, a left bearing (57) is fixed in the buckled left lower ring (55) and the left upper ring (53), and an inner hole of the left bearing (57) is inserted into the left cross rod (41);
the right support part (6) comprises a right rod (61), a right base (62), a right upper ring (63), a right hinge part (64), a right lower ring (65), a right flange (66) and a right bearing (67), the right support part (6) is positioned at the right side of the extraction part (1), the right base (62) is a cylindrical base with a screw hole in the middle, the lower end of the right rod (61) is screwed into the screw hole for fixation, the upper end of the right rod (61) is welded and connected with the right lower ring (65), the right lower ring (65) is buckled with the right upper ring (63) which is semi-annular at the upper part, the right lower ring (65) is hinged with the right upper ring (63) through the right hinge part (64), and the left side is provided with a pair of right flanges (66) which are matched, the right flange (56) is fixed by a bolt group, a right bearing (67) is fixed in the buckled right lower ring (65) and the right upper ring (63), and an inner hole of the right bearing (67) is inserted into the right cross rod (43);
the glass device (7) is positioned below the liquid outlet (16);
the demulsification assembly (8) comprises a ball part (81), a sheet part (82) and a cone part (83);
the extraction part is made of glass; vaseline is coated in the horizontal through hole;
the shell part is any one of nylon PA66 and polytetrafluoroethylene;
the head vibration groove (27) is wound and fixed on the main shell (22) by using electrical tape for multiple circles;
the working power of the vibration head is between 60 and 100W, the working frequency is between 15KHZ and 100KHZ, and the head part of the vibration head is in a horn shape and is provided with an extended straight column;
the cross rod part (4), the left support part (5) and the right support part (6) are made of stainless steel;
the left bearing and the right bearing are ball bearings; the left bearing and the right bearing are internally and externally provided with rubber gaskets;
the glass device (7) is a combination of a large-volume wide-mouth container or a large-caliber funnel and other glass vessels;
the demulsification component (8) is made of polytetrafluoroethylene;
the preparation method of the poly-substituted fluorine-containing hexa-membered nitrogen-containing heterocyclic methylamine with the protection group comprises the following steps:
(1) dissolving 9-11g of 2-hydroxy-5-bromopyridine-3-formic acid in 105 ml of methanol, stirring until the system is colorless and transparent, heating to 65 ℃ for reflux, beginning to dropwise add 13-14g of thionyl chloride, finishing dropwise adding for 6-8min, gradually changing the system into yellow and transparent, keeping the temperature at 65 ℃ until the reaction is monitored by HPLC, cooling the reaction mixture to room temperature, carrying out spin-drying concentration on the reaction mixture, adding 50ml of ethyl acetate for dilution, then adding 20ml of water for washing, separating out solids, carrying out suction filtration on all the reaction mixture, pulping the solids by using 50ml of methyl tert-butyl ether, carrying out suction filtration, and drying to obtain 2-hydroxy-5-bromopyridine-3-methyl formate;
(2) dissolving 10-11g of 2-hydroxy-5-bromopyridine-3-methyl formate in 550ml of acetonitrile, cooling the system to 0 ℃ by using an external ice water bath, keeping the system stirred and kept in the external ice water bath, slowly adding 4.8-5.2g of 60% sodium hydride, dropwise adding 3.85-4.15g of 2-fluorosulfonyl difluoroacetic acid after the addition is finished, dropwise adding for at least 10min, removing the ice water bath, slowly raising the temperature to normal temperature, and continuously reacting until the reaction is finished by monitoring and reacting by using HPLC and LCMS20ml of saturated NH are added dropwise4Cl solution with 30ml H2Quenching sodium hydride by using O, gradually changing the solution into clear black brown liquid, separating out solids, completely filtering, adding 600ml of ethyl acetate into the mixed solution for extraction, separating an organic phase, washing the organic phase for 2 times by using 100ml of saturated sodium chloride solution each time, drying and spinning the organic phase, mixing the organic phase with 5 times of sample mixing mass, and mixing petroleum ether, ethyl acetate which is 7: 1, passing 200-300 silica gel through a column to obtain 2-difluoromethoxy-5-bromopyridine-3-methyl formate;
(3) dissolving 9.5-10.5g of 2-difluoromethoxy-5-bromopyridine-3-methyl formate in a mixed solution of 50ml of water and 50ml of tetrahydrofuran, cooling the system to about 10 ℃ by using an external ice water bath, slowly adding 4.25-4.75g of lithium hydroxide monohydrate into the system, finishing the addition for at least 2-4min, reacting for at least 2.5-3.5h, dropwise adding 12N HCl into the system until the pH is regulated to about 2 after the reaction is finished by monitoring HPLC and LCMS, then adding 100ml of dichloromethane each time to extract the mixture for 2 times, combining organic phases, drying and spin-drying to obtain 2-difluoromethoxy-5-bromopyridine-3-formic acid;
(4) adding 8-9g of 2-difluoromethoxy-5-bromopyridine-3-formic acid into 80mL of trichloromethane, cooling the system to 0-5 ℃ by using an external ice water bath, then dripping 15-17mL of thionyl chloride, heating the system to 50 ℃ after dripping, reacting for 30 minutes, completely spin-drying the reaction mixture, dissolving the residue in 50mL of tetrahydrofuran, then dripping 100mL of ammonia water precooled to 0-10 ℃, naturally heating the system to room temperature, reacting for 8-16 hours, spinning off all solvents, separating out solids, performing suction filtration, leaching by using 50mL of water, and drying to obtain 2-difluoromethoxy-5-bromopyridine-3-formamide;
(5) adding 7-7.5g of 2-difluoromethoxy-5-bromopyridine-3-formamide into 100mL of dichloromethane, then adding 20-22mL of triethylamine, cooling the reaction mixture to 0-5 ℃ by using an external ice water bath, dripping 13-15g of trifluoroacetic anhydride, naturally heating the reaction mixture to room temperature after dripping, reacting for 16 hours, pouring into 100mL of ice-water mixture, separating liquid, extracting the water phase once by using 50mL of dichloromethane, then washing the organic phase once by using 50mL of saturated salt, drying the anhydrous sodium sulfate, carrying out suction filtration, and carrying out spin drying to obtain 2-difluoromethoxy-3-cyano-5-bromopyridine;
(6) under the protection of nitrogen, 2.2 to 2.7g of 2-difluoromethoxy-3-cyano-5-bromopyridine is dissolved in 30mL of tetrahydrofuran, cooling the reaction mixture to 0 ℃ by using an external ice water bath, dropwise adding 40mL of borane tetrahydrofuran solution, naturally heating to room temperature after dropwise adding, carrying out heat preservation reaction for 1h, heating until reflux appears, keeping the reaction overnight, carrying out temperature reduction and sampling midway, slowly dropwise adding the taken sample into methanol and water, sending to HPLC-LCMS to monitor reaction, cooling the reaction mixture to 0 deg.C, slowly adding 70mL methanol dropwise, slowly heating to room temperature after dropwise addition, stirring for at least 1-2h, then refluxing for at least 1-2h, and removing the solvent to obtain oily liquid 2-difluoromethoxy-5-bromopyridine-3-methylamine;
(7) dissolving all the 2-difluoromethoxy-5-bromopyridine-3-methylamine obtained in the step 6 in 30mL of methyl tert-butyl ether, cooling the mixture to-10 ℃ by using an ice salt bath, dropwise adding at least 2.5eq of 7N dioxane/HCl, stirring for reacting for at least 1-2h, and performing suction filtration to obtain 2-difluoromethoxy-5-bromopyridine-3-methylamine hydrochloride solid;
(8) fully dispersing the 2-difluoromethoxy-5-bromopyridine-3-methylamine hydrochloride obtained in the step 7 in 20mL of dichloromethane, adding 2.7-3.3g of triethylamine under low-speed stirring, adding 3-3.6g of Boc anhydride in batches at normal temperature, reacting for 3h, adding 10mL of water, separating by 10mLx3 dichloromethane, washing with brine, drying, removing the solvent, and carrying out column separation to obtain Boc protected 2-difluoromethoxy-5-bromopyridine-3-methylamine;
(9) under stirring, 3.8-4.2g of Boc protected 2-difluoromethoxy-5-bromopyridine-3-methylamine is dissolved in 120mL of dioxane, 5.5-6.1g of boron bis valeryl and 3-3.5g of potassium acetate are slowly added into the system at room temperature, the system is fully dispersed while stirring, after the system is pumped and flushed with nitrogen for three times, 450 mg of Pd (dppf) Cl under nitrogen protection is added into the system2-CH2Cl2Heating to 85 ℃, refluxing, keeping the temperature, reacting for at least 10-14h, cooling to room temperature after HPLC monitoring reaction, adding 360mL of ethyl acetate for dilution, performing suction filtration, then performing rotary drying and sample mixing, performing 5 times of sample mixing and 200 times of sample mixing and 300 silica gel column chromatography under the condition that the petroleum ether and the ethyl acetate are 20:1 to obtain a product, pulping for 30min by using 30mL of petroleum ether, and performing suction filtration to obtain the productTo pure tert-butyl ((2-difluoromethoxy-5-pinacolato) pyridin-3-yl) methyl) carbamate;
(10) 20-22g of NaBO3-4H2O in 40mL H2Cooling to 0 ℃ by using an external ice water bath, dissolving 18-20g of tert-butyl ((2-difluoromethoxy-5-pinacol ester group) pyridine-3-yl) methyl) carbamate in 360mL of tetrahydrofuran, dropwise adding the tetrahydrofuran into the system, heating to room temperature after dropwise adding, reacting for at least 2-4 hours, adding 400mL of saturated ammonium chloride and 400mL of ethyl acetate into the system, separating the liquid, extracting the water phase with 400mL of ethyl acetate again, and extracting the organic phase with 400mL of H2Washing with O, drying, spin-drying and stirring, and passing through a silica gel column of 200-fold stirring sample 300 under the conditions of petroleum ether and ethyl acetate of 10:1 to obtain a product, namely tert-butyl ((2- (difluoromethoxy) -5-hydroxypyridine-3-yl) methyl) carbamate;
the extraction in the steps (1) to (10) is implemented by using an ultrasonic extraction device, and the specific steps are as follows:
(A) the preparation method comprises the following steps: cleaning and airing the extraction part, completely sleeving the extraction part into the shell part for fixation, sleeving the shell part into the circular ring part so that the periphery (24) can be supported by the upper part of the circular ring part (42), pushing the left side of the vibration head groove (27) into a pit on the main shell (22), winding the vibration head groove for multiple circles at high temperature by using an electrical adhesive tape, and fixing the vibration head groove on the main shell (22);
(B) covering: opening the upper cover (13), pouring the mixture to be extracted and the solvent, placing the demulsification component to enable the ball part to be outside the upper opening and the cone part to be inward, and carefully covering the upper cover;
(C) a vibration shaking step: pushing the shell part to enable the shell part to shake forwards and backwards for 10-20 times in a pendulum manner, enabling the manual idle straight shell part to be approximately static, starting the ultrasonic part and enabling the vibration head to vibrate for 1-2min at a frequency of more than 20KHz, and standing for 2-4 min;
(D) repeating the steps: repeating the step C3-5 times;
(E) a receiving step: stopping extraction, opening the upper cover, taking out the demulsification component, respectively taking out the mixture of different phases below the liquid outlet by using different glassware, and pouring out the last phase of the extraction part from the upper opening.
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