阅读说明：本技术 多取代含二氟甲氧基含氮杂环化合物的合成装置与方法 (Synthesis device and method of polysubstituted difluoromethoxy-containing nitrogen-containing heterocyclic compound ) 是由 苏德泳 蔡艳 张虎 林智杰 刘杰杰 于 2021-07-27 设计创作，主要内容包括：一种合成装置,包括反应釜(1)、外固定组(2)、漏斗部(3)；反应釜(1)包括主口(11)、主盖(111)、加料口(12)、密封套(121)、副加料口(13)、氮气入口(14)、氮气出口(15)；外固定组(2)包括法兰(22)、钢环(23)、左杆(241)、右杆(242)、左竖杆(251)、左固定件(252)、左底座(253)、右竖杆(254)、右固定件(255)、右底座(256)；漏斗部(3)包括下料管(31)、平坦部(32)、透明盖(33)、手套洞(34)等。还有一种2-氨基-5-氯-4-二氟甲氧基吡啶的合成方法,其利用前述合成装置以进行。(A synthesis device, which comprises a reaction kettle (1), an external fixed group (2) and a funnel part (3); the reaction kettle (1) comprises a main port (11), a main cover (111), a feed inlet (12), a seal sleeve (121), an auxiliary feed inlet (13), a nitrogen inlet (14) and a nitrogen outlet (15); the outer fixing group (2) comprises a flange (22), a steel ring (23), a left rod (241), a right rod (242), a left vertical rod (251), a left fixing piece (252), a left base (253), a right vertical rod (254), a right fixing piece (255) and a right base (256); the funnel part (3) comprises a blanking pipe (31), a flat part (32), a transparent cover (33), a glove hole (34) and the like. Also provided is a synthesis method of 2-amino-5-chloro-4-difluoromethoxypyridine, which is carried out by utilizing the synthesis device.)

1. A synthesis apparatus, characterized by:

comprises a reaction kettle (1), an external fixing group (2) and a funnel part (3);

the reaction kettle (1) comprises a main port (11), a main cover (111), a feed inlet (12), a seal sleeve (121), an auxiliary feed inlet (13), a nitrogen inlet (14) and a nitrogen outlet (15); the main port is positioned at the center of the upper surface of the reaction kettle, the main cover seals the main port, the charging port and the auxiliary charging port are respectively positioned at the right side and the left side of the main port, when the charging port is opened, the discharging pipe (31) is inserted into the main port, the discharging pipe and the inner side of the charging port are tightly sealed by an annular sealing sleeve (121), the side edge of the reaction kettle at the left side of the auxiliary charging port is provided with a nitrogen inlet, and the side edge of the reaction kettle at the right side of the charging port is provided with a nitrogen outlet;

the outer fixing group (2) comprises a flange (22), a steel ring (23), a left rod (241), a right rod (242), a left vertical rod (251), a left fixing part (252), a left base (253), a right vertical rod (254), a right fixing part (255) and a right base (256), wherein the flange (22) which is annularly and horizontally extended outwards is arranged on the outer side of the upper edge of the funnel part and is made of a stainless steel plate fixed on the outer side of the funnel part, the flange (22) is supported by the horizontal steel ring (23), the left side and the right side of the steel ring are respectively and integrally formed with the left rod (241) and the right rod (242), the left rod and the right rod are respectively and horizontally penetrated and fixed on the left fixing part and the right fixing part, the left fixing part and the right fixing part are respectively sleeved and fixed on the left vertical rod and the right vertical rod, and the left vertical rod and the right vertical rod are respectively and vertically fixed on the left base and the right base which are disc-shaped;

funnel portion (3) are including unloading pipe (31), flat portion (32), transparent cover (33), gloves hole (34), hole flange (341), gloves (342), POM packing ring (343), ribbon (344), mesopore (35), concave part (36), beaker (361), fixing base (362), the unloading pipe is big-end-up's hollow tube, the shape is inverted circular truncated cone, unloading pipe upper portion connects the mesopore, mesopore is horizontal flat portion all around, it has transparent cover to cover above the funnel portion, there is a circular shape gloves hole of hollowing in funnel portion rear side middle part, the gloves hole outwards has bellied round hole flange, the terminal cover of gloves is in the hole flange outside, the POM packing ring is sheatheed in again, it is fixed again by the ribbon, flat portion is located mesopore evenly distributed all around and has a plurality of concave part, the fixing base has been placed on the concave part, fixing base internal diameter and beaker adaptation.

2. A synthesis device according to claim 1, characterized in that:

the sealing sleeve is made of polyurethane or polytetrafluoroethylene, the charging hole and the auxiliary charging hole are provided with sealing covers, and the nitrogen inlet and the nitrogen outlet are provided with sealing plugs with nitrogen pipes;

the flange, the steel ring, the left rod, the right rod, the left vertical rod, the left fixing piece, the left base, the right vertical rod, the right fixing piece and the right base are all made of stainless steel materials, rubber gaskets are arranged in holes of the left fixing piece and the right fixing piece, the left fixing piece and the right fixing piece are square double-hole clamping seats, double holes are perpendicular to each other, and the left rod, the right rod, the left vertical rod and the right vertical rod are round rods with smooth surfaces; the flange and the funnel part are connected by welding or fixed by a plurality of rivets;

the transparent cover is made of corrosion-resistant glass or transparent resin, the gloves are rubber gloves made of corrosion-resistant materials, the binding belts are spirally fixed and fixed by screwdrivers, the beakers are made of corrosion-resistant glass or polytetrafluoroethylene materials, the sizes of the concave parts are fixed, the beakers and the fixing seats are two series with different sizes, and the beakers and the fixing seats are matched in pairs;

the reaction kettle is provided with a stirring device arranged from the lower part.

3. A process for the preparation of 2-amino-5-chloro-4-difluoromethoxypyridine, carried out using a synthesis apparatus according to claim 2, characterized in that it comprises the following steps:

(1) putting 200ml of N, N-dimethylacetamide into the reaction kettle, sealing a main feeding port and an auxiliary feeding port of the reaction kettle, inserting and fixing a funnel part at the feeding ports, covering a transparent cover, fixing gloves outside a glove hole, introducing nitrogen at a speed of 1-3L/min from a nitrogen inlet, leading out the nitrogen at the same speed from a nitrogen outlet, keeping the nitrogen for more than 5min, separately containing 18-22g of 2-bromo-5-chloro-4-hydroxypyridine and 1.5eq of sodium hydroxide by using two beakers, matching a dosing spoon, opening the transparent cover, placing the beakers on a concave part under the condition that the beakers are matched with appropriate fixing seats, covering the transparent cover, continuously introducing nitrogen at the speed after pumping the nitrogen for a plurality of times, manually putting the gloves into the reaction kettle from the outer side, and sequentially adding all the 2-bromo-5-chloro-4-hydroxypyridine and the sodium hydroxide from a feeding pipe Putting the mixture into a reaction kettle, stirring and reacting for more than 3 hours, changing nitrogen into chlorine difluoromethane gas to be introduced for two hours at the speed of 1-3L/min, then changing the nitrogen to be introduced at the speed of 1-3L/min, and reacting for at least 12 hours at 35 ℃;

and (3) post-treatment: cooling the reaction mixture to room temperature, pouring all the reaction mixture into 600ml of water, continuously extracting the reaction mixture for three times by using 150ml of ethyl acetate, combining organic phases, washing the organic phases once by using 200ml of water, washing the organic phases twice by using 200ml of saturated sodium chloride, drying the organic phases by using 25g of anhydrous sodium sulfate, and concentrating the organic phases to obtain a crude product, wherein the petroleum ether is obtained by passing 200g of 100-mesh silica gel through a column under the condition that the ethyl acetate is 30:1 to 15:1 to obtain a product, namely 2-bromo-4-difluoromethoxy-5-chloropyridine;

(2) adding 10-12g of 2-bromo-4-difluoromethoxy-5-chloropyridine into 330ml of 1, 4-dioxane, placing the mixture into the reaction kettle, sealing a main port and an auxiliary feed port of the reaction kettle, inserting the feed port into a funnel part and fixing, covering a transparent cover, fixing gloves outside a glove hole, introducing nitrogen from a nitrogen inlet at a speed of 1-3L/min, leading out from a nitrogen outlet at the same speed, keeping for more than 5min, separately loading 1.0eq of tert-butyl carbamate equivalent to 2-bromo-4-difluoromethoxy-5-chloropyridine, 1.5eq of cesium carbonate, 0.05eq of palladium acetate and 0.1eq of X-phos in four beakers, preparing a dosing spoon, opening the transparent cover, placing the beakers on different concave parts under the condition that the beakers are adapted to appropriate fixing seats, covering a transparent cover, pumping nitrogen for a plurality of times, keeping the speed, continuously introducing the nitrogen, manually putting a glove into the reaction kettle from the outer side, sequentially adding tert-butyl carbamate, cesium carbonate, palladium acetate and X-phos into the reaction kettle from a feeding pipe, heating the system to 80 ℃ for reacting for at least 16 hours, detecting the complete reaction of the raw materials through LC-MS, cooling the reaction mixture, performing suction filtration, washing a filter cake with 100ml of ethyl acetate for a plurality of times, combining the filtrate, and performing reduced pressure concentration at 40 ℃ to obtain a crude product (5-chloro-4- (difluoromethoxy) pyridine-2-yl) tert-butyl carbonate; pulping for one hour at 40 ℃ by using 50ml of petroleum ether and ethyl acetate (25-15: 1), filtering, leaching and drying by using 20ml of petroleum ether to obtain a pure product (5-chloro-4- (difluoromethoxy) pyridine-2-yl) tert-butyl carbonate;

(3) 10-11g of tert-butyl (5-chloro-4- (difluoromethoxy) pyridin-2-yl) carbonate are added to 100mL of dichloromethane, cooling to 0-5 ℃, dripping 45-55g of trifluoroacetic acid, raising the temperature to 35 ℃ after dripping, reacting for at least 18h, after HPLC detection of the complete reaction of the raw materials, the trifluoroacetic acid is distilled off under reduced pressure at 45 ℃, then adding 100mL deionized water into the residue, extracting with 200mL dichloromethane for three times, washing the organic phase with 100mL 5% sodium bicarbonate once, drying with 10g anhydrous sodium sulfate for 15 minutes, filtering to remove the drying agent, combining the organic phases, concentrating to obtain a crude product, eluting with 100-200 mesh silica gel in petroleum ether: purification of ethyl acetate 3-1:1 gave 2-amino-4-difluoromethoxy-5-chloropyridine.

4. A process for the preparation of 2-amino-5-chloro-4-difluoromethoxypyridine according to claim 3, characterized by comprising the following steps:

(1) putting 200ml of N, N-dimethylacetamide into the reaction kettle, sealing a main port and an auxiliary charging port of the reaction kettle, inserting and fixing the charging ports into a funnel part, covering a transparent cover, fixing gloves outside a glove hole, introducing nitrogen at a speed of 2-3L/min from a nitrogen inlet, leading out the nitrogen at the same speed from a nitrogen outlet, keeping the speed for more than 5min, separately containing 20g of 2-bromo-5-chloro-4-hydroxypyridine and 12.5g of sodium hydroxide by using two beakers, matching a dosing spoon, opening the transparent cover, placing the beakers on a concave part under the condition that a proper fixing seat is matched, covering the transparent cover, continuously introducing nitrogen at the speed after pumping the nitrogen for a plurality of times, manually putting the gloves on the outside, and sequentially adding the 2-bromo-5-chloro-4-hydroxypyridine and the sodium hydroxide into the reaction kettle from a discharging pipe Stirring for reaction for more than 3 hours, changing nitrogen into chlorine difluoromethane gas which is introduced at the speed of 1-3L/min for two hours, then changing the nitrogen into nitrogen which is introduced at the speed of 2-3L/min, and reacting for at least 12 hours at 35 ℃;

and (3) post-treatment: cooling the reaction mixture to room temperature, pouring all the reaction mixture into 600ml of water, continuously extracting the reaction mixture for three times by using 150ml of ethyl acetate, combining organic phases, washing the organic phases once by using 200ml of water, washing the organic phases twice by using 200ml of saturated sodium chloride, drying the organic phases by using 25g of anhydrous sodium sulfate, and concentrating the organic phases to obtain a crude product, wherein the crude product is obtained by passing 200g of 100-mesh silica gel through a column under the conditions that the petroleum ether and the ethyl acetate are 20:1 to 16:1 to obtain a product, namely 2-bromo-4-difluoromethoxy-5-chloropyridine;

(2) adding 11g of 2-bromo-4-difluoromethoxy-5-chloropyridine into 330ml of 1, 4-dioxane, putting the mixture into the reaction kettle, sealing a main feeding port and an auxiliary feeding port of the reaction kettle, inserting a funnel part into the feeding port and fixing the feeding port, covering a transparent cover, fixing gloves outside a glove hole, introducing nitrogen at a speed of 2-3L/min from a nitrogen inlet and leading out the nitrogen at the same speed from a nitrogen outlet, keeping the speed for more than 5min, separately loading 5g of tert-butyl carbamate, 21g of cesium carbonate, 0.5g of palladium acetate and 2.46g of X-phos by using four beakers, matching a dosing spoon, opening the transparent cover, placing the beakers on different concave parts under the condition that the beakers are matched with a proper fixing seat, covering the transparent cover, pumping nitrogen for a plurality of times, keeping the speed continuously introducing the nitrogen, manually putting a glove into the reaction kettle from the outside, sequentially adding tert-butyl carbamate, cesium carbonate, palladium acetate and X-phos into the reaction kettle from a feeding pipe, heating the system to 80 ℃ for reaction for at least 16h, detecting the reaction completion of raw materials through LC-MS, cooling the reaction mixture, performing suction filtration, washing a filter cake with 100ml of ethyl acetate for multiple times, combining filtrates, and performing reduced pressure concentration at 40 ℃ to obtain a crude product (5-chloro-4- (difluoromethoxy) pyridin-2-yl) tert-butyl carbonate; pulping for one hour at 40 ℃ by using 50ml of petroleum ether and ethyl acetate (20: 1), filtering, leaching and drying by using 20ml of petroleum ether to obtain a pure product of (5-chloro-4- (difluoromethoxy) pyridine-2-yl) tert-butyl carbonate;

(3) adding 10.2g of tert-butyl (5-chloro-4- (difluoromethoxy) pyridin-2-yl) carbonate into 100mL of dichloromethane, cooling to 0-5 ℃, dropwise adding 50g of trifluoroacetic acid, reacting for at least 18h after the dropwise addition is finished, distilling the trifluoroacetic acid at 45 ℃ under reduced pressure after HPLC detection of complete reaction of raw materials, adding 100mL of deionized water into the residue, extracting with 200mL of dichloromethane for three times, washing the organic phase once with 100mL of 5% sodium bicarbonate, drying for 15 min with 10g of anhydrous sodium sulfate, filtering to remove a drying agent, combining the organic phases, concentrating to obtain a crude product, and purifying with 100-mesh 200-mesh silica gel and an eluent petroleum ether ethyl acetate (ethyl acetate: 1) to obtain 2-amino-4-difluoromethoxy-5-chloropyridine.

5. The process for preparing 2-amino-5-chloro-4-difluoromethoxypyridine according to claim 4, wherein:

in the step (2), if the raw materials are not completely reacted through LC-MS detection, two additional beakers are used for containing 1g of tert-butyl carbamate and 0.55g of X-phos and are placed in a funnel part, after the nitrogen is pumped and filled for a plurality of times, the nitrogen is continuously introduced at the speed, a hand is manually inserted from the outside by wearing a glove, and 1g of tert-butyl carbamate and 0.55g of X-phos are sequentially and completely added into the reaction kettle from a feeding pipe.

Technical Field

The invention relates to the technical field of preparation of drug intermediates, in particular to a device and a method for synthesizing a polysubstituted difluoromethoxy-containing nitrogen-containing heterocyclic compound.

Background

2-amino-5-chloro-4-difluoromethoxypyridine and derivatives thereof are important compounds, have strong biological activity and can be applied to the field of medicines, but the methods mentioned in the application rarely appear as medical intermediates or are disclosed in 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.

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, no actual problems of nitrogen protection in the present application were noted, and no improvement in the apparatus was made in the same or similar manner as in the present application.

In addition, the prior art has the problem that the prior nitrogen protection is insufficient, the application needs the nitrogen protection in one or more steps, but the prior nitrogen protection mode is not complete, when the nitrogen is introduced and extracted from two ports in the case of glassware, and the raw material is added, a certain port is opened, and the influence of the generated air entering is not negligible for the quantity of glass bottles. For a reaction kettle, the problem is greater, if 3-5 relatively trivial raw materials are required to be added, the feeding port can be opened and closed for many times, the actual effect of nitrogen protection is greatly influenced, in reality, the nitrogen is pumped and filled for many times through one feeding, and the adverse effect of air entering cannot be completely avoided. In practice, the risk often occurs that a large amount of air enters due to carelessness, the yield is greatly reduced, even the reaction cannot be carried out, and the whole reaction mixture is wasted.

First, two steps of this application also must carry out long-time raw materials and add, even in reation kettle, remain throughout to lead to nitrogen gas, nevertheless at first for reaction effect, the raw materials will slowly add, rather than the addition of a brain, and this must lead to the charge door to be in the open mode for a long time, can not avoid the adverse effect of air admission completely. In practice, a large amount of air is often introduced carelessly, the yield is greatly reduced, the whole experiment is scrapped by one-time error, and the waste is dangerous.

Disclosure of Invention

The first purpose of the invention is to solve two specific problems in the prior art, namely, the problem of how to obtain 2-amino-5-chloro-4-difluoromethoxypyridine through few steps with high yield from 2-bromo-5-chloro-4-hydroxypyridine is perfectly solved by the scheme of the application, and the problem that the nitrogen environment cannot be stably ensured due to the fact that raw materials need to be slowly added in the steps I and II is solved by the scheme of the application.

The invention claims a synthesis device, which is characterized in that: comprises a reaction kettle, an external fixing group and a funnel part.

The reaction kettle comprises a main port, a main cover, a charging hole, a sealing sleeve, an auxiliary charging hole, a nitrogen inlet and a nitrogen outlet; the main entrance is located reation kettle center department above, and main lid seals the main entrance, and charge door and vice charge door are located the right side and the left side of main entrance respectively, and when the charge door was opened, the unloading pipe inserted wherein, and pastes tightly sealed by annular seal cover between unloading pipe and the charge door inboard, and the left reation kettle side department of vice charge door has the nitrogen gas entry, and the reation kettle side department on charge door right side has the nitrogen gas export.

The outer fixing group comprises a flange, a steel ring, a left rod, a right rod, a left vertical rod, a left fixing piece, a left base, a right vertical rod, a right fixing piece and a right base, wherein the flange extending outwards and horizontally is arranged on the outer side of the edge of the upper part of the funnel part in a circular ring shape;

the funnel portion includes the unloading pipe, the flat portion, transparent cover, the gloves hole, the hole flange, gloves, the POM packing ring, the ribbon, the mesopore, the concave part, the beaker, a fixed base, the unloading pipe is big-end-up's hollow tube, the shape is inverted circular truncated cone, unloading pipe upper portion connects the mesopore, mesopore is horizontally flat portion all around, it has transparent cover to cover above the funnel portion, there is a circular gloves hole of hollowing out at funnel portion rear side middle part, the gloves hole outwards has bellied round hole flange, the terminal cover of gloves is in the hole flange outside, sheathe in again the POM packing ring, it is fixed by the ribbon again, flat portion is located the evenly distributed all around of mesopore and has a plurality of concave part, the fixing base has been placed on the concave part, fixing base internal diameter and beaker adaptation.

Furthermore, the sealing sleeve is made of polyurethane or polytetrafluoroethylene, the charging hole and the auxiliary charging hole are provided with sealing covers, and the nitrogen inlet and the nitrogen outlet are provided with sealing plugs with nitrogen pipes;

the flange, the steel ring, the left rod, the right rod, the left vertical rod, the left fixing piece, the left base, the right vertical rod, the right fixing piece and the right base are all made of stainless steel materials, rubber gaskets are arranged in holes of the left fixing piece and the right fixing piece, the left fixing piece and the right fixing piece are square double-hole clamping seats, double holes are perpendicular to each other, and the left rod, the right rod, the left vertical rod and the right vertical rod are round rods with smooth surfaces; the flange and the funnel part are connected by welding or fixed by a plurality of rivets;

the transparent cover is made of corrosion-resistant glass or transparent resin, the gloves are rubber gloves made of corrosion-resistant materials, the binding belts are spirally fixed and fixed by screwdrivers, the beakers are made of corrosion-resistant glass or polytetrafluoroethylene materials, the sizes of the concave parts are fixed, the beakers and the fixing seats are two series with different sizes, and the beakers and the fixing seats are matched in pairs;

the reaction kettle is provided with a stirring device arranged from the lower part.

A process for the preparation of 2-amino-5-chloro-4-difluoromethoxypyridine, carried out using a synthesis apparatus as described above, characterized in that it comprises the following steps.

(1) Putting 200ml of N, N-dimethylacetamide into the reaction kettle, sealing a main feeding port and an auxiliary feeding port of the reaction kettle, inserting and fixing a funnel part at the feeding ports, covering a transparent cover, fixing gloves outside a glove hole, introducing nitrogen at a speed of 1-3L/min from a nitrogen inlet, leading out the nitrogen at the same speed from a nitrogen outlet, keeping the nitrogen for more than 5min, separately containing 18-22g of 2-bromo-5-chloro-4-hydroxypyridine and 1.5eq of sodium hydroxide by using two beakers, matching a dosing spoon, opening the transparent cover, placing the beakers on a concave part under the condition that the beakers are matched with appropriate fixing seats, covering the transparent cover, continuously introducing nitrogen at the speed after pumping the nitrogen for a plurality of times, manually putting the gloves into the reaction kettle from the outer side, and sequentially adding all the 2-bromo-5-chloro-4-hydroxypyridine and the sodium hydroxide from a feeding pipe Putting the mixture into a reaction kettle, stirring and reacting for more than 3 hours, changing nitrogen into chlorine difluoromethane gas to be introduced for two hours at the speed of 1-3L/min, then changing the nitrogen to be introduced at the speed of 1-3L/min, and reacting for at least 12 hours at 35 ℃;

and (3) post-treatment: cooling the reaction mixture to room temperature, pouring all the reaction mixture into 600ml of water, continuously extracting the reaction mixture for three times by using 150ml of ethyl acetate, combining organic phases, washing the organic phases once by using 200ml of water, washing the organic phases twice by using 200ml of saturated sodium chloride, drying the organic phases by using 25g of anhydrous sodium sulfate, and concentrating the organic phases to obtain a crude product, wherein the petroleum ether is obtained by passing 200g of 100-mesh silica gel through a column under the condition that the ethyl acetate is 30:1 to 15:1 to obtain a product, namely 2-bromo-4-difluoromethoxy-5-chloropyridine;

(2) adding 10-12g of 2-bromo-4-difluoromethoxy-5-chloropyridine into 330ml of 1, 4-dioxane, placing the mixture into the reaction kettle, sealing a main port and an auxiliary feed port of the reaction kettle, inserting the feed port into a funnel part and fixing, covering a transparent cover, fixing gloves outside a glove hole, introducing nitrogen from a nitrogen inlet at a speed of 1-3L/min, leading out from a nitrogen outlet at the same speed, keeping for more than 5min, separately loading 1.0eq of tert-butyl carbamate equivalent to 2-bromo-4-difluoromethoxy-5-chloropyridine, 1.5eq of cesium carbonate, 0.05eq of palladium acetate and 0.1eq of X-phos in four beakers, preparing a dosing spoon, opening the transparent cover, placing the beakers on different concave parts under the condition that the beakers are adapted to appropriate fixing seats, covering a transparent cover, pumping nitrogen for a plurality of times, keeping the speed, continuously introducing the nitrogen, manually putting a glove into the reaction kettle from the outer side, sequentially adding tert-butyl carbamate, cesium carbonate, palladium acetate and X-phos into the reaction kettle from a feeding pipe, heating the system to 80 ℃ for reacting for at least 16 hours, detecting the complete reaction of the raw materials through LC-MS, cooling the reaction mixture, performing suction filtration, washing a filter cake with 100ml of ethyl acetate for a plurality of times, combining the filtrate, and performing reduced pressure concentration at 40 ℃ to obtain a crude product (5-chloro-4- (difluoromethoxy) pyridine-2-yl) tert-butyl carbonate; pulping for one hour at 40 ℃ by using 50ml of petroleum ether and ethyl acetate (25-15: 1), filtering, leaching and drying by using 20ml of petroleum ether to obtain a pure product (5-chloro-4- (difluoromethoxy) pyridine-2-yl) tert-butyl carbonate;

(3) 10-11g of tert-butyl (5-chloro-4- (difluoromethoxy) pyridin-2-yl) carbonate are added to 100mL of dichloromethane, cooling to 0-5 ℃, dripping 45-55g of trifluoroacetic acid, raising the temperature to 35 ℃ after dripping, reacting for at least 18h, after HPLC detection of the complete reaction of the raw materials, the trifluoroacetic acid is distilled off under reduced pressure at 45 ℃, then adding 100mL deionized water into the residue, extracting with 200mL dichloromethane for three times, washing the organic phase with 100mL 5% sodium bicarbonate once, drying with 10g anhydrous sodium sulfate for 15 minutes, filtering to remove the drying agent, combining the organic phases, concentrating to obtain a crude product, eluting with 100-200 mesh silica gel in petroleum ether: purification of ethyl acetate 3-1:1 gave 2-amino-4-difluoromethoxy-5-chloropyridine.

Preferably, all of the foregoing reagents are chemically pure or purer. The water is deionized water, preferably double distilled water. The seal cover can increase the outward-extending part for fixing effect, and is contacted with the upper surface of the reaction kettle, so as to enhance the supporting effect.

Compared with the prior art, the invention has the advantages that: the improvement on the device is that the device perfectly solves the problem that the slow addition of raw materials and the nitrogen protection conflict in the first step and the second step; through tests, whether the first step and the second step strictly maintain nitrogen protection is significant, under the condition of the current relatively leisurely adding, the yield of the first step and the second step can easily reach 79 percent and about 78 percent, if a synthesis device of the application is not used, for example, raw materials are rapidly added, the conditions that the reaction is incomplete because of one-shot addition, the reaction yield is insufficient often occur, the yield of the first step and the second step in the conditions is 65 percent and 67 percent and the like, if the raw materials are slowly added, the influence of the addition of reactants is removed, but the nitrogen protection is not strict, the yield is insufficient, even a meaningful amount of products cannot be obtained at all, the reaction cannot be carried out due to the entry of a large amount of air, a large amount of byproducts are generated, and an effective amount of the desired products cannot be obtained effectively.

Moreover, the ultrasonic device of the application has unique combination mode, and the special design of the funnel part makes it possible to add various reagents without urgency under the protection of nitrogen. The sealing mode of the glove hole is also considered, so that the glove hole is firmer and can play a role. The transparent cover solves the observation problem, and the required reagent can be clearly and effectively added through proper operation of personnel. The structure of the external fixed group results in an effective support of the funnel part.

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 fine and exquisite, 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 fine in design, the synthesis is effectively realized, the yield is higher, the average rate is more than 54%, such as 54.84%, and the like, the method has a certain industrial production value and a great economic value, the method disclosed by the invention embodies extremely strong invention conception and creativity through the fine design of a feeding link under the protection of nitrogen, a good preparation effect is obtained, no similar public information can be used for reference in the prior art, and the scheme disclosed by the invention has originality. In contrast, the conventional method for carrying out such reaction inevitably has one of two defects that the reaction material is added too fast and is not completely dissolved, or the reaction material is opened for too long time and lacks the nitrogen protection. These two problems are difficult to solve with the general method, and then the productivity is seriously influenced, and the applicant is carried out with the traditional apparatus, compared with the method of the present application, the productivity is reduced by at least 15%, and the method has considerable risks that the first step and the second step can not be carried out correctly.

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 structural diagram of main components of the reaction kettle.

Fig. 3 is a schematic view of the front structure of the outer fixed group and the funnel part.

Figure 4 is a schematic view of the main components of the funnel.

Figure 5 is a schematic view of a top part of the funnel.

FIG. 6 is a schematic view of the exterior of a glove aperture and a side view of a recess fitting.

FIG. 7 is a schematic diagram of the main synthetic route of the final product.

FIG. 8 is a nuclear magnetic map of the final product.

Reference numerals: reaction kettle 1, main port 11, main cover 111, charging port 12, sealing sleeve 121, auxiliary charging port 13, nitrogen inlet 14, nitrogen outlet 15, external fixing group 2, flange 22, steel ring 23, left rod 241, right rod 242, left vertical rod 251, left fixing piece 252, left base 253, right vertical rod 254, right fixing piece 255, right base 256, funnel part 3, blanking pipe 31, flat part 32, transparent cover 33, glove hole 34, hole flange 341, gloves 342, POM gasket 343, bandage 344, middle hole 35, concave part 36, beaker 361 and fixing seat 362.

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 apparatus, characterized by: comprises a reaction kettle 1, an external fixing group 2 and a funnel part 3.

The reaction kettle 1 comprises a main port 11, a main cover 111, a feed inlet 12, a seal sleeve 121, an auxiliary feed inlet 13, a nitrogen inlet 14 and a nitrogen outlet 15; the main entrance is located reation kettle center department above, and main lid seals the main entrance, and charge door and vice charge door are located the right side and the left side of main entrance respectively, and when the charge door was opened, unloading pipe 31 inserted wherein, and pastes tight seal by annular seal cover 121 between unloading pipe and the charge door inboard, and the left reation kettle side department of vice charge door has the nitrogen gas entry, and the reation kettle side department on charge door right side has the nitrogen gas export. Where the inlet and outlet are placed at the edge for ease of routing and handling, nitrogen gas lines are for example commercially available. Fitted with a sealed rubber stopper, or other more corrosion resistant stopper, to exclude air. 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. In order to prevent mutual influence, the reaction kettle is selected to extend into the reaction kettle from the lower part, or a stirrer extending into the reaction kettle from a main port is selected, wherein the main port needs to be sealed and vented.

The outer fixing group 2 comprises a flange 22, a steel ring 23, a left rod 241, a right rod 242, a left vertical rod 251, a left fixing part 252, a left base 253, a right vertical rod 254, a right fixing part 255 and a right base 256, the outer side of the upper edge of the funnel part is provided with a circular flange which extends outwards in a flat mode, the flange is made of a stainless steel plate fixed on the outer side of the funnel part and is supported by the horizontal steel ring, the left side and the right side of the steel ring are respectively and integrally formed with the left rod 241 and the right rod 242, the left rod and the right rod are respectively and horizontally penetrated and fixed on the left fixing part and the right fixing part, the left fixing part and the right fixing part are respectively sleeved on the left vertical rod and the right vertical rod and are fixed on the left base and the right base which are disc-shaped, an inward annular inner flange is arranged at the joint of the outer sleeve and the inverted circular ring shape, and is in contact with a flat part 32 and supports the funnel part 3. The thickness of the casing is not less than 3mm, preferably 5mm or more, for example 8 mm. The width of the flange side extension is not less than 8cm, and the upper surface of the steel ring can be horizontal.

The funnel part 3 comprises a blanking pipe 31, a flat part 32, a transparent cover 33, a glove hole 34, a hole flange 341, gloves 342, a POM gasket 343, a binding belt 344, a middle hole 35, a concave part 36, a beaker 361 and a fixing seat 362, wherein the blanking pipe is a hollow pipe with a large upper part and a small lower part and is in an inverted circular truncated cone shape, the upper part of the blanking pipe is connected with the middle hole, the periphery of the middle hole is a horizontal flat part, the upper surface of the funnel part is covered with the transparent cover, the middle part of the rear side of the funnel part is provided with a hollowed circular glove hole, the glove hole is outwards provided with a convex circle of hole flange, the tail end of each glove is sleeved on the outer side of the hole flange, the POM gasket is sleeved on the hole flange and is fixed by the binding belt, the plurality of concave parts are uniformly distributed around the flat part, the fixing seats are placed on the concave parts, and the inner diameter of the fixing seats is matched with the beaker. The gloves can be sleeved on the hole flanges reversely, so that the gloves are turned inwards in work and are just in a correct wearing mode. The size of the recess may be fixed or may be of various sizes corresponding to different sizes of beakers. E.g., 8cm, 12cm, 16cm, 20cm, 25cm diameter. The funnel part 3 has enough space inside for the gloves to take and move, and the diameter of the funnel part is not less than 45 cm.

Furthermore, the sealing sleeve is made of polyurethane or polytetrafluoroethylene, the charging hole and the auxiliary charging hole are provided with sealing covers, and the nitrogen inlet and the nitrogen outlet are provided with sealing plugs with nitrogen pipes; the flange, the steel ring, the left pole, the right pole, the left montant, the left mounting, the left base, the right montant, the right mounting, the right base are all stainless steel, there is the rubber packing ring in the downthehole of left mounting and right mounting, left mounting and right mounting are the diplopore holder of square shape, diplopore mutually perpendicular, and left pole, right pole, left montant, right montant all are the smooth round bar in outward appearance.

The transparent cover is made of corrosion-resistant glass or transparent resin, the gloves are rubber gloves made of corrosion-resistant materials, the binding belts are spirally fixed and fixed by screwdrivers, the beakers are made of corrosion-resistant glass or polytetrafluoroethylene materials, the sizes of the concave parts are fixed, the beakers and the fixing seats are two series with different sizes, the beakers and the fixing seats are matched in pairs, for example, 50ml of beakers are matched with the largest fixing seat, 500ml of beakers are matched with the smallest/thinnest fixing seat, and 250ml of fixing seats are matched with each other, and the beakers can be firmly fixed in the concave parts by the fixing seats, so that reagents can be conveniently placed. The reaction vessel is, for example, a vessel having a stirring device disposed from the lower part.

Example 2

A preparation method of 2-amino-5-chloro-4-difluoromethoxypyridine is characterized by comprising the following steps.

(1) Putting 200ml of N, N-dimethylacetamide into the reaction kettle, sealing a main port and an auxiliary charging port of the reaction kettle, inserting and fixing the charging ports into a funnel part, covering a transparent cover, fixing gloves outside a glove hole, introducing nitrogen at a speed of 2-3L/min from a nitrogen inlet, leading out the nitrogen at the same speed from a nitrogen outlet, keeping the speed for more than 5min, separately containing 20g of 2-bromo-5-chloro-4-hydroxypyridine and 12.5g of sodium hydroxide by using two beakers, matching a dosing spoon, opening the transparent cover, placing the beakers on a concave part under the condition that a proper fixing seat is matched, covering the transparent cover, continuously introducing nitrogen at the speed after pumping the nitrogen for a plurality of times, manually putting the gloves on the outside, and sequentially adding the 2-bromo-5-chloro-4-hydroxypyridine and the sodium hydroxide into the reaction kettle from a discharging pipe Stirring for reaction for more than 3 hours, changing nitrogen into chlorine difluoromethane gas which is introduced at the speed of 1-3L/min for two hours, then changing the nitrogen into nitrogen which is introduced at the speed of 2-3L/min, and reacting for at least 12 hours at 35 ℃;

and (3) post-treatment: the reaction mixture was cooled to room temperature, poured into 600ml of water in its entirety, extracted three times with 150ml of ethyl acetate successively, the organic phases were combined, washed once with 200ml of water, washed twice with 200ml of saturated brine, dried over 25g of anhydrous sodium sulfate and concentrated to give the crude product, which was passed through a column using 200g of 100-mesh 200-mesh silica gel under the conditions of ethyl acetate: 20:1 to 16:1 as petroleum ether, to give 19.7g of 2-bromo-4-difluoromethoxy-5-chloropyridine, yield 79.5%.

(2) Adding 11g of 2-bromo-4-difluoromethoxy-5-chloropyridine into 330ml of 1, 4-dioxane, putting the mixture into the reaction kettle, sealing a main feeding port and an auxiliary feeding port of the reaction kettle, inserting a funnel part into the feeding port and fixing the feeding port, covering a transparent cover, fixing gloves outside a glove hole, introducing nitrogen at a speed of 2-3L/min from a nitrogen inlet and leading out the nitrogen at the same speed from a nitrogen outlet, keeping the speed for more than 5min, separately loading 5g of tert-butyl carbamate, 21g of cesium carbonate, 0.5g of palladium acetate and 2.46g of X-phos by using four beakers, matching a dosing spoon, opening the transparent cover, placing the beakers on different concave parts under the condition that the beakers are matched with a proper fixing seat, covering the transparent cover, pumping nitrogen for a plurality of times, keeping the speed continuously introducing the nitrogen, manually putting a glove into the reaction kettle from the outside, sequentially adding tert-butyl carbamate, cesium carbonate, palladium acetate and X-phos into the reaction kettle from a feeding pipe, heating the system to 80 ℃ for reaction for at least 16h, detecting the reaction completion of raw materials through LC-MS, cooling the reaction mixture, performing suction filtration, washing a filter cake with 100ml of ethyl acetate for multiple times, combining filtrates, and performing reduced pressure concentration at 40 ℃ to obtain a crude product (5-chloro-4- (difluoromethoxy) pyridin-2-yl) tert-butyl carbonate; pulping 50ml of petroleum ether and ethyl acetate 20:1 at 40 ℃ for one hour, filtering, leaching and drying by using 20ml of petroleum ether to obtain 9.8g of pure tert-butyl (5-chloro-4- (difluoromethoxy) pyridin-2-yl) carbonate with the yield of 78.4%.

(3) 10.2g of tert-butyl (5-chloro-4- (difluoromethoxy) pyridin-2-yl) carbonate are added to 100mL of dichloromethane, cooling to 0-5 ℃, dripping 50g of trifluoroacetic acid, raising the temperature to 35 ℃ after dripping, reacting for at least 18h, after HPLC detection of the complete reaction of the raw materials, the trifluoroacetic acid is distilled off under reduced pressure at 45 ℃, then adding 100mL deionized water into the residue, extracting with 200mL dichloromethane for three times, washing the organic phase with 100mL 5% sodium bicarbonate once, drying with 10g anhydrous sodium sulfate for 15 minutes, filtering to remove the drying agent, combining the organic phases, concentrating to obtain a crude product, eluting with 100-200 mesh silica gel in petroleum ether: purification of ethyl acetate 1:1 gave 5.8g of 2-amino-4-difluoromethoxy-5-chloropyridine in 89% yield.

In the step (2), if the raw materials are not completely reacted through LC-MS detection, two additional beakers are used for containing 1g of tert-butyl carbamate and 0.55g of X-phos and are placed in a funnel part, after the nitrogen is pumped and filled for a plurality of times, the nitrogen is continuously introduced at the speed, a hand is manually inserted from the outside by wearing a glove, and 1g of tert-butyl carbamate and 0.55g of X-phos are sequentially and completely added into the reaction kettle from a feeding pipe.

Example 3

A preparation method of 2-amino-5-chloro-4-difluoromethoxypyridine is characterized by comprising the following steps.

(1) Putting 200ml of N, N-dimethylacetamide into the reaction kettle, sealing a main port and an auxiliary charging port of the reaction kettle, inserting and fixing the charging ports into a funnel part, covering a transparent cover, fixing gloves outside a glove hole, introducing nitrogen at a speed of 2-3L/min from a nitrogen inlet, leading out the nitrogen at the same speed from a nitrogen outlet, keeping the speed for more than 5min, separately containing 21g of 2-bromo-5-chloro-4-hydroxypyridine and 13.125g of sodium hydroxide by using two beakers, matching a dosing spoon, opening the transparent cover, placing the beakers on a concave part under the condition that a proper fixing seat is matched, covering the transparent cover, continuously introducing nitrogen at the speed after pumping the nitrogen for a plurality of times, manually putting the gloves on the outside, and sequentially adding the 2-bromo-5-chloro-4-hydroxypyridine and the sodium hydroxide into the reaction kettle from a discharging pipe Stirring for reaction for more than 3 hours, introducing chlorodifluoromethane gas at the speed of 1-3L/min for two hours by using nitrogen, introducing nitrogen at the speed of 2-3L/min, and reacting for at least 12 hours at the temperature of 35 ℃.

And (3) post-treatment: the reaction mixture was cooled to room temperature, poured into 600ml of water in its entirety, extracted three times with 150ml of ethyl acetate successively, the organic phases were combined, washed once with 200ml of water, washed twice with 200ml of saturated brine, dried with 25g of anhydrous sodium sulfate, and the organic phase was concentrated to give a crude product, which was passed through a column using 200g of 100-mesh silica gel 100-.

(2) Adding 11g of 2-bromo-4-difluoromethoxy-5-chloropyridine into 330ml of 1, 4-dioxane, putting the mixture into the reaction kettle, sealing a main feeding port and an auxiliary feeding port of the reaction kettle, inserting a funnel part into the feeding port and fixing the feeding port, covering a transparent cover, fixing gloves outside a glove hole, introducing nitrogen at a speed of 2-3L/min from a nitrogen inlet and leading out the nitrogen at the same speed from a nitrogen outlet, keeping the speed for more than 5min, separately loading 5g of tert-butyl carbamate, 21g of cesium carbonate, 0.5g of palladium acetate and 2.46g of X-phos by using four beakers, matching a dosing spoon, opening the transparent cover, placing the beakers on different concave parts under the condition that the beakers are matched with a proper fixing seat, covering the transparent cover, pumping nitrogen for a plurality of times, keeping the speed continuously introducing the nitrogen, manually putting a glove into the reaction kettle from the outside, sequentially adding tert-butyl carbamate, cesium carbonate, palladium acetate and X-phos into the reaction kettle from a feeding pipe, heating the system to 80 ℃ for reaction for at least 16h, detecting the reaction completion of raw materials through LC-MS, cooling the reaction mixture, performing suction filtration, washing a filter cake with 100ml of ethyl acetate for multiple times, combining filtrates, and performing reduced pressure concentration at 40 ℃ to obtain a crude product (5-chloro-4- (difluoromethoxy) pyridin-2-yl) tert-butyl carbonate; pulping 50ml of petroleum ether and ethyl acetate 20:1 at 40 ℃ for one hour, filtering, leaching and drying by using 20ml of petroleum ether to obtain 10.1g of pure tert-butyl (5-chloro-4- (difluoromethoxy) pyridin-2-yl) carbonate with the yield of 80%;

(3) 11g of tert-butyl (5-chloro-4- (difluoromethoxy) pyridin-2-yl) carbonate were added to 100mL of dichloromethane, cooling to 0-5 ℃, dripping 54g of trifluoroacetic acid, raising the temperature to 35 ℃ after dripping, reacting for at least 18h, after HPLC detection of the complete reaction of the raw materials, the trifluoroacetic acid is distilled off under reduced pressure at 45 ℃, then adding 100mL deionized water into the residue, extracting with 200mL dichloromethane for three times, washing the organic phase with 100mL 5% sodium bicarbonate once, drying with 10g anhydrous sodium sulfate for 15 minutes, filtering to remove the drying agent, combining the organic phases, concentrating to obtain a crude product, eluting with 100-200 mesh silica gel in petroleum ether: purification of ethyl acetate 1:1 gave 6.32g of 2-amino-4-difluoromethoxy-5-chloropyridine in 90.0% yield. The overall yield is significantly higher than in example 2.

Preferably, all of the foregoing reagents are chemically pure or purer. The water is deionized water, preferably double distilled water. The selection of above-mentioned dosage ratio all is the data that laboratory made originally, and funnel portion is enough big to in the operation of gloves inside, but also not too big, too big funnel portion does not have practical meaning, still increases the device solvent, increases and rocks the risk, generally can hold 4 500ml beakers and can also have abundant space to operate can, in order to prevent that the ladle from taking by mistake, reinforced in turn when not allowing the operation, different ladle fixing bases can correspond the different colours. In order to place the dropper stably, a plastic piece is sleeved on the dropper and used for being clamped on the edge of the beaker.

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.