CN110368887B - Preparation method of amino substituted compound - Google Patents

Preparation method of amino substituted compound Download PDF

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CN110368887B
CN110368887B CN201910702799.1A CN201910702799A CN110368887B CN 110368887 B CN110368887 B CN 110368887B CN 201910702799 A CN201910702799 A CN 201910702799A CN 110368887 B CN110368887 B CN 110368887B
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CN110368887A (en
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江勇军
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Beijing Liuhe Ningyuan Pharmaceutical Technology Co ltd
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0006—Controlling or regulating processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/18—Stationary reactors having moving elements inside
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/44—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing eight carbon atoms

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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A preparation method of an amino-substituted novel spiro compound is characterized in that a special reaction kettle is utilized for preparation, the reaction kettle is provided with a glass body (1), the body is provided with a kettle cover (11), a lower flange (12) and a cylinder body (13), and the reaction kettle further comprises an air inlet assembly (2), an air outlet assembly (3), a fixing device (4) and a stirring part (5); benzyl ((4-cyanobicyclo [2.2.2] decan-1-yl) methyl) carbonate was prepared by dissolving 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] decane-1-carboxylic acid in THF, adding NEt3 and isobutyl chloroformate to give benzyl ((4-carbonamido-bicyclo [2.2.2] decan-1-yl) methyl) carbonate; adding anhydrous methanol, nickel chloride hexahydrate and anhydride at B ℃ to prepare benzyl ((4- ((((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] decan-1-yl) methyl) carbonate; adding the 1, 4-dioxane solution and the dioxane solution to MTBE to prepare benzyl ((4- (aminomethyl) bicyclo [2.2.2] decan-1-yl) methyl) carbonate.

Description

Preparation method of amino substituted compound
Technical Field
The invention relates to the field of medical intermediates, in particular to a synthetic method of a medical intermediate (4- (aminomethyl) bicyclo [2.2.2] octan-1-yl) methyl benzyl carbonate.
Background
Benzyl carbonate 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 benzyl carbonate derivatives is widely concerned, and particularly widely applied to medical intermediates. CN201410087799.2 shows a bactericidal composition containing benzyl carbonate-2, 3, 8-trimethyl-6-heptafluoroisopropyl-4-quinolinate, which is an example of the application and synthesis of benzyl carbonate derivatives, but the benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate mentioned in the application rarely appears as a medical intermediate or a preparation method, or documents or data are disclosed.
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 problems that the prior four-mouth bottle is obviously insufficient as a reaction vessel, and the laboratory preparation generally uses the four-mouth bottle as the reaction vessel, and the defects are prominent: firstly, the performance is not enough, when the mixture in the four-mouth bottle needs to be stirred, because the four-mouth bottle generally clamps the neck of the main bottle to realize high-speed stirring, but the bottom of the four-mouth bottle is uneven, the stirring rod cannot go deep and is difficult to realize high-speed stirring, the mode of inserting the stirring rod in the main mouth of the existing four-mouth bottle is adopted, the stirring speed is at most stable at 400 revolutions per minute, the whole device shakes too violently after the stirring rod is raised, the risk of breakage of the whole bottle is caused, and due to the uneven bottom of the bottle, the material is difficult to be effectively and fully stirred in many times, and the reaction is influenced to be fully carried out; secondly, the existing nitrogen protection mode is insufficient, nitrogen is introduced from one port of a four-port bottle in the existing nitrogen protection mode, and gas in the bottle is led out from the other port, but due to the limitation of the shape of the four-port bottle, a larger dead volume or a volume which does not participate in convection can be generated in the bottle in the existing nitrogen protection mode, according to infrared video detection, the occurrence condition of the dead volume is an approximate probability event, and the existing simple nitrogen introduction mode is difficult to overcome; thirdly, the problem of large loss of the reaction mixture during removal, the problem of small main opening and multiple openings of a four-opening bottle, so that the reaction mixture is difficult to be properly removed during treatment after each step, a large amount or most of the reaction mixture is lost in practice, the amount of products formed by 1-2 steps is reduced due to operation problems during removal of each step, the actual amount of the obtained products is influenced, the yield calculation of each step deviates from the actual condition, and the problem cannot be overcome by using a four-opening bottle system.
Disclosure of Invention
The invention firstly provides a special reaction kettle which has excellent performance compared with a four-mouth bottle system, can realize more stable stirring at high speed, has better nitrogen protection effect due to an airflow structure, can realize higher yield in each step, can easily and completely remove reaction mixture due to the structure of a cylindrical wide mouth without a side mouth, avoids the loss of reaction removal of the four-mouth bottle, and can realize better heating/refrigerating effect than the four-mouth bottle system due to the cylindrical bottom with a contact area far larger than that of the four-mouth bottle and the matched heating/refrigerating device arranged at the bottom.
The utility model provides a reaction kettle, its body that has the glass material, this body possesses kettle cover, lower flange, barrel, its characterized in that: the reaction kettle also comprises an air inlet combination, an air outlet combination, a fixing device and a stirring part; the center of the kettle cover is provided with a middle hole which is a circular through hole with the center positioned at the center of the kettle cover, and the inner side surface of the middle hole is frosted and is used for being attached to the peripheral surface of the outer sleeve; taking the central point of the upper surface of the kettle cover as a center, and symmetrically arranging an air inlet and an air outlet of cylindrical through holes with the same specification on two sides; the kettle cover beside the middle hole is also provided with a feeding hole with a circular through hole, the feeding hole is provided with a frosted inner side surface and a feeding plug matched with the frosted inner side surface, the feeding plug is provided with a plug part with a sectional area larger than that of the feeding hole and a body part with a frosted outer surface, and the middle part of the outer surface of the cylinder body is provided with a ring-shaped frosted outer surface.
The air inlet assembly comprises an air inlet pipe, an air inlet hollow rubber plug and an air inlet through hole, wherein the air inlet pipe is a cylindrical thin-wall hollow glass pipe, the height of the air inlet pipe is 1-1.3 times of the height of the cylinder body, the air inlet hollow rubber plug is composed of two rubber circular rings which are wide at the top and narrow at the bottom, the center of the air inlet hollow rubber plug is dug out of the cylindrical air inlet through hole which is communicated from top to bottom, and the air inlet pipe is inserted into the air inlet through hole and is tightly combined with the air inlet hollow rubber plug due to the inner diameter of the air inlet through hole.
The air outlet assembly comprises an air outlet pipe, an air outlet hollow rubber plug and an air outlet through hole, the air outlet pipe is a cylindrical thin-wall hollow glass pipe, the height of the air outlet pipe is 0.2-0.4 times of the height of the cylinder, the air outlet hollow rubber plug is composed of two rubber circular rings which are wide at the top and narrow at the bottom, a cylindrical air outlet through hole which is communicated from top to bottom is dug at the center of the air outlet hollow rubber plug, and the air outlet pipe is inserted into the air outlet through hole and is tightly combined with the air outlet hollow rubber plug due to the inner diameter of the air outlet through hole.
The fixing device is provided with a left fixing plate, a right fixing plate, a left first flange, a left second flange, a right first flange, a right second flange, a front bolt combination, a rear bolt combination, a left fixing table, a right fixing table, a fixing bottom plate and a rubber lining.
The middle of the right side of the left fixing plate is provided with a left semicircular notch, the middle of the left side of the right fixing plate is provided with a right semicircular notch, the rubber lining is composed of a semicircular left rubber lining and a semicircular right rubber lining, and the left rubber lining and the right rubber lining are respectively adhered in the notches of the left semicircular notch and the right semicircular notch by strong glue, so that the left semicircular notch and the right semicircular notch are combined to form a circular notch, and the rubber lining is tightly combined with the frosted appearance of the body.
When the gaps of the left fixing plate and the right fixing plate are aligned and spliced, the left flange and the right flange are aligned and the through holes on the left flange and the right flange are also aligned, a front bolt and a front nut included by a front bolt combination are screwed in and fixed, the left flange and the right flange are aligned and the through holes on the left flange and the right flange are also aligned, and a rear bolt and a rear nut included by a rear bolt combination are screwed in and fixed; the left first flange, the left second flange and the left fixing plate are integrally formed, and the right first flange, the right second flange and the right fixing plate are integrally formed.
The left fixing table is provided with a cuboid-shaped left fixing base and a left hoop, the left hoop is in a shape like a Chinese character 'ji' in side view and has a thickness of 2-5mm, the left section of the left fixing plate is covered on the left fixing base, the left hoop is fixed on the left fixing base through 2N symmetrical bolts, the right fixing table is provided with a cuboid-shaped right fixing base and a right hoop, the right hoop is in a shape like a Chinese character 'ji' in side view and has a thickness of 2-5mm, and the left section of the left fixing plate 41 is covered on the right fixing base through 2N symmetrical bolts.
The stirring part comprises a top cover, an inner sleeve, an outer sleeve, a stirring rod and blades, the outer sleeve is provided with an upper outer sleeve and a lower outer sleeve, the top cover is in an inverted U shape, a first internal thread is arranged on the lower edge of the top cover, the internal thread is adapted to a first external thread on the uppermost side of the outside of the upper outer sleeve, and after the first internal thread and the first external thread are screwed, the upper surface of the inner sleeve is compressed in the middle of the lower part of the top cover, inner cavities with three different inner diameters are arranged in the upper outer sleeve from top to bottom, the inner diameter of a first inner cavity above the upper outer sleeve is the largest, the inner diameter of a second inner cavity in the middle is obviously smaller than that of the first inner cavity, so that the lower part of the first inner cavity forms a circular step for supporting the lower part of the inner sleeve, the inner diameter of the third inner cavity is similar to that of the first inner cavity, the side wall of the inner sleeve is provided with a second internal thread, the outer sleeve is solid, the outer diameter of the inner sleeve is slightly smaller than the first inner cavity, vaseline is filled between the outside of the inner sleeve and the first cavity, and the lower outer sleeve is in a circular cover shape, the middle of the stirring rod is provided with a through hole larger than the outer diameter of the stirring rod, the upper side of the stirring rod is provided with an upward circular convex part close to the outer part, the outer side of the circular convex part is provided with a second external thread matched with the second internal thread, the upper side of the lower outer sleeve is also provided with a higher second circular convex part at the inner side of the circular convex part, and after the second internal thread and the second external thread are completely screwed, the distance from the top of the second circular convex part to the lower surface of the inner sleeve is within 1 cm.
Preferably, the device also comprises an ice-water bath kettle, a water bath kettle, an electric heating sleeve and a subzero cooling tank, wherein the inner tank is a hollow cylindrical tank and is larger than the lower part of the cylinder body; the inner diameter of the feeding hole is slightly larger than the dropper for sample feeding.
The present invention also provides a method for producing benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate, which is carried out in the aforementioned reaction vessel, comprising the following four steps.
1) Under the protection of nitrogen, taking the previous reaction kettle, cleaning and airing, fixing the body on a fixing device, opening a kettle cover, dissolving 4.8-5.2g of 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-formic acid in 20V THF, weighing the reactant A under the condition of 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-formic acid, adding 3eq NEt3 of the reactant A, closing the kettle cover, stirring the reaction mixture at a rotating speed of 100 plus 150 r/min, introducing nitrogen at 180ml/min of 100 plus, opening a charging plug, slowly dropwise adding 1.5eq isobutyl chloroformate of the reactant A from a charging hole, covering the charging plug after dropwise adding, increasing the stirring speed to 650 plus 750 r/min, and after 0.8-1.2h, stopping stirring, repeatedly taking a very small amount of reaction mixture from the feeding hole, performing HPLC tracking reaction until the raw materials disappear to generate an intermediate, sleeving the lower part of the cylinder body by a zero-temperature reduction tank, reducing the temperature of the reaction mixture to about-10 ℃ by using a mixture of ethanol and liquid nitrogen, starting a stirrer, at the rotating speed of 50-100 r/min, opening the charging plug and dropping a sufficient amount of saturated THF solution of NH3 into the system from the charging hole, after the dripping is finished, an ice water bath kettle filled with enough ice and water mixture is sleeved at the lower part of the cylinder body, keeping the temperature of 0 ℃ for reaction for at least 0.8 to 1.2 hours at the rotating speed of 50 to 100 r/min, if the intermediate does not disappear, continuing to stir at 50-100 rpm for reaction for 15min until the intermediate disappears and the reaction is complete as the reaction is found by tracking the reaction by HPLC from the feeding hole; then the kettle cover is opened, 135-150ml of deionized water is added into the reaction mixture, the mixture is completely removed, extracted 3-5 times by 50-70ml of EA, washed three times by 50-70ml of brine, dried and the organic phase is dried to obtain the product of the step 1, namely benzyl ((4-carbonamido bicyclo [2.2.2] octane-1-yl) methyl) carbonate, as a white solid.
2) Taking a clean and dry reaction kettle as described above, fixing the body on a fixing device, opening a kettle cover, dissolving 4.8-5.2g of the product in the step 1 in 15V pyridine to form a mixture, then placing the mixture in the reaction kettle, covering the kettle cover, stirring at the rotating speed of 600 plus 750 revolutions per minute for 10min, reducing the speed to 100 plus 180 revolutions per minute, introducing nitrogen at the speed of 100 plus 180ml per minute, sleeving an ice water bath kettle filled with sufficient ice water mixture at the lower part of a cylinder body, slowly dripping 5eq of POCl3 of the product in the step 1 from a feeding hole after the temperature is stably reduced to 0 ℃, sealing a feeding plug after the dripping is finished, keeping the temperature of 100 plus 180 revolutions per minute, reacting at the temperature of 0 ℃ for 1.5-2.5h under the condition of introducing nitrogen at the speed of 100 plus 180ml per minute, stopping stirring, repeatedly taking a very small amount of the reaction mixture from the feeding hole, tracking the reaction by HPLC, until the reaction was followed by HPLC to find disappearance of the starting material; removing the ice water bath kettle, adding 200ml of ice water mixture prepared by purified water into the reaction kettle, stirring for 10-15min at 180 revolutions/min of 100ml, extracting for 3-5 times by using 80ml of DCM, washing for 2-4 times by using 50ml of 2N hydrochloric acid, washing for 2-4 times by using 50ml of water, washing for 2-4 times by using 50ml of brine, drying and spin-drying to obtain a white solid crude product, dissolving the crude product in water, adjusting the pH value to 9 by using a 1N NaOH filtrate, standing for a period of time, extracting for 2-4 times by using 20ml of DCM, spin-drying to obtain a white solid crude product, pulping by using N-hexane 2V, and drying after suction filtration to obtain a product of the step 2, namely ((4-cyano bicyclo [2.2.2] octane-1-yl) methyl) benzyl carbonate.
3) Taking a reaction kettle which is cleaned and dried and is as described above, fixing a body on a fixing device, opening a kettle cover, adding 105 plus 115ml of anhydrous methanol into the reaction kettle, introducing nitrogen gas at the rate of 100 plus 180ml/min, rapidly adding 5.3-5.7g of the product of the step 2, 4.2-4.6g of nickel chloride hexahydrate and 20-20.2g of BOC anhydride, immediately covering the kettle cover tightly, sleeving an ice water bath kettle containing enough ice-water mixture on the lower part of a cylinder body, starting stirring at the rotating speed of 50-100 revolutions/min, opening a feeding plug after 4-6min, slowly adding 3.4-3.6g of sodium borohydride from a feeding hole, removing the ice water bath kettle after the addition is finished, stirring and reacting for 1.5-2.5h while slowly raising the reaction mixture to room temperature, sleeving a zero-temperature reduction tank on the lower part of the cylinder body, reducing the reaction mixture to about 10 ℃ by using a small amount of mixture of ethanol plus liquid nitrogen, slowly adding 40ml of water into a feeding hole, stirring at the rotation speed of 150-200 rpm for 10-20min, completely removing the reaction mixture from the reaction kettle, performing suction filtration by using a proper amount of diatomite, washing by using 90-110ml of DCM, extracting the mother liquor by using 90-110ml of DCM for 2-4 times, washing by using 70-90ml of brine for 2-4 times, drying and spin-drying to obtain a white solid crude product, performing sample mixing on the white solid product by using 1.5 times of 100-200 meshes of silica gel, sampling TLC plates respectively under the conditions of PE (EA) 2:1 and PE (EA) 25:1 to obtain an upper point, and flushing a lower point when PE (EA) 2:1 to obtain a product ((4- (((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-yl) methyl) benzyl carbonate in the step 3.
4) Taking a clean and dry reaction kettle as described above, fixing the body on a fixing device, opening a kettle cover, dissolving 2.4-2.6g of the product of the step 3 in 3V pyridine to form a mixture, adding 5eq of dioxane hydrochloride solution of the product of the step 3, tightly covering the kettle cover, reacting for 1-2h under the stirring of 150-250 r/min, then adding 20ml of MTBE from the charging hole, continuing stirring for 10min, stopping stirring, completely removing the reaction mixture, performing suction filtration to obtain a crude product, dissolving the crude product in a proper amount of deionized water, adjusting pH to 9 with 1N NaOH filtrate, standing for 10min, extracting with 18-22ml DCM for 3 times, spin-drying to obtain crude white solid, weighing, pulping the crude white solid with 3V N-hexane, and vacuum filtering to obtain final product, benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate.
The use of the obtained benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate as a pharmaceutical intermediate for the production of a medicament.
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: firstly, the improvement in the aspect of the device, the reaction kettle has excellent performance compared with a four-mouth bottle system, can realize more stable stirring at high speed, can easily realize more than 600-turn stable stirring, but a common four-mouth bottle system cannot or is extremely unstable at high speed and has the risk of falling, and because of an airflow structure, the nitrogen protection effect is better, higher yield can be realized in each step, the exact nitrogen protection effect is difficult to ensure by using a common four-mouth bottle, whether gas can be ejected out from the bottom of the middle part of the bottle or not has no control means and can only be used for listening to the weather, and because the structure is cylindrical and wide-mouth, a reaction mixture can be easily and completely moved out, the loss of reaction and movement of the common four-mouth bottle is avoided, the common four-mouth bottle has small mouth and multiple mouths, the complete and thorough movement of reactants is difficult, and because the bottom is cylindrical, the contact area is far larger than that of the four-mouth bottle, the bottom is provided with a heating/refrigerating device which is matched with the bottom, and the heating/refrigerating effect is better than that of a four-mouth bottle system, which is far from the time of using a common four-mouth bottle.
Benzyl ((4-cyanobicyclo [2.2.2] octan-1-yl) methyl) carbonate was prepared by dissolving 4- (((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-yl) formic acid in THF, adding NEt3 and isobutyl chloroformate to obtain benzyl ((4-carbonamido bicyclo [2.2.2] octan-1-yl) methyl) carbonate; adding anhydrous methanol, nickel chloride hexahydrate and BOC anhydride to prepare benzyl ((4- (((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-yl) methyl) carbonate; adding 1, 4-dioxane solution and dioxane solution, adding MTBE to prepare benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate, wherein no report on 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 of fine steps, high utilization rate of raw materials in each step, great value in industrial production, effective synthesis and high yield, 5g of benzyl ((4-carbonamido bicyclo [2.2.2] octane-1-yl) methyl) carbonate can be obtained from 5g of raw materials in the first step, the yield in the second step is over 56%, the yield in the third step is over 62%, the yield in the fourth step is over 84%, the overall yield is high, the economic value is high, and the method is implemented by repeated fine operation of filtering the product, and the operation at low temperature embodies extremely strong invention conception and creativity, obtains good preparation effect, does not have similar public information for reference in the prior art, and has originality.
Drawings
FIG. 1 is a side cross-sectional view of a reactor of the present application.
FIG. 2 is a side cross-sectional view of the inlet and outlet assemblies of the present application.
Fig. 3 is a top view of the fixation device of the present application.
FIG. 4 is a side cross-sectional view of the agitator of the present application.
FIG. 5 shows the HNMR spectrum of benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate prepared according to the invention.
The reference numerals denote: the device comprises a body 1, a kettle cover 11, a lower flange 12, a cylinder body 13, an air inlet combination 2, an air outlet combination 3, a fixing device 4, a stirring part 5, a middle hole 14, an air inlet hole 15, an air outlet hole 16, a charging hole 18, a charging plug 19, a plug part 191, a body part 192, a frosted appearance 17, an air inlet pipe 21, an air inlet hollow rubber plug 22, an air inlet through hole 23, an air outlet pipe 31, an air outlet hollow rubber plug 32, an air outlet through hole 33, a left fixing plate 41, a right fixing plate 42, a left flange 411, a left flange 412, a right flange 421, a right flange 422, a front bolt combination 43, a rear bolt combination 44, a left fixing platform 45, a right fixing platform 46, a fixing bottom plate 47, a rubber lining 48, a left semicircular notch 410, a right semicircular notch 420, a left rubber lining 481, a right rubber lining 482, a left semicircular notch 410, a right semicircular notch 420, a left fixing platform 452, a left hoop, a right fixing platform 462, a right hoop 461, a top cover 51, a top cover 451, a bottom cover, inner sleeve 52, outer sleeve 53, stirring rod 54, blade 55, upper outer sleeve 531 and lower outer sleeve 532.
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. This invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete and will fully convey the concept of the invention to those skilled in the art, and the present invention will only be defined by the appended claims. The invention provides a preparation method of ((4- (aminomethyl) bicyclo [2.2.2] octan-1-yl) methyl) benzyl carbonate, which comprises the following process route:
Figure GDA0003115566150000061
the synthesis method can be briefly described as follows: benzyl ((4-cyanobicyclo [2.2.2] octan-1-yl) methyl) carbonate was prepared by dissolving 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-yl) formic acid in THF, adding NEt3 and isobutyl chloroformate to obtain benzyl ((4-carbonamido bicyclo [2.2.2] octan-1-yl) methyl) carbonate in the presence of POCll3 and pyridine; adding anhydrous methanol, nickel chloride hexahydrate and BOC anhydride to prepare benzyl ((4- (((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-yl) methyl) carbonate; pyridine was added thereto, and MTBE was added to prepare benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate.
Example 1
A reaction kettle is provided with a glass body 1, which is provided with a kettle cover 11, a lower flange 12 and a cylinder 13, and is characterized in that: the reaction kettle further comprises an air inlet assembly 2, an air outlet assembly 3, a fixing device 4 and a stirring part 5. This reation kettle has improved the whole problem of present four mouthfuls of bottle systems wholely: not firm enough, bottom area of contact is little, and heating refrigeration is slow, stirs unable raising speed, and nitrogen protection effect is not good, and reinforced must thoroughly open a bite, and it is very troublesome and difficult complete problem to move out reaction mixture.
The center of the kettle cover 11 is provided with a middle hole 14, the middle hole 14 is a circular through hole with the center positioned at the center of the kettle cover 11, the inner side surface of the middle hole is frosted and is used for being attached to the outer peripheral surface of the outer sleeve 53; taking the central point of the upper surface of the kettle cover 11 as the center, and symmetrically arranging an air inlet 15 and an air outlet 16 with cylindrical through holes with the same specification at two sides; the kettle cover 11 beside the middle hole 14 is also provided with a feeding hole 18 with a circular through hole, the feeding hole 18 is provided with a frosted inner side surface and a feeding plug 19 matched with the frosted inner side surface, the feeding plug 19 is provided with a plug part 191 with a sectional area larger than that of the feeding hole 18 and a body part 192 with a frosted outer surface, and the middle part of the outer surface of the cylinder body is provided with a ring-shaped frosted outer surface 17. So set up and make the holistic gas tightness of device to guarantee, and the feeding stopper easily seals and opens, and the bore is little, provides the assurance for further keeping the gas tightness.
The air inlet assembly 2 comprises an air inlet pipe 21, an air inlet hollow rubber plug 22 and an air inlet through hole 23, wherein the air inlet pipe 21 is a cylindrical thin-wall hollow glass tube, the height of the air inlet pipe 21 is 1-1.3 times of the height of the barrel 13, the air inlet hollow rubber plug 22 is composed of two rubber circular rings which are wide at the top and narrow at the bottom, the center of the air inlet hollow rubber plug 22 is dug out of the cylindrical air inlet through hole 23 which is through up and down, and the air inlet pipe 21 is inserted into the air inlet through hole and tightly combined with the air inlet hollow rubber plug 22 through the inner diameter of the air inlet through hole. Such setting up makes the efficiency of admitting air can guarantee, and nitrogen gas can directly get into the position than the bottle bottom, and the intake pipe can adjust the depth of insertion as required, can go up the regulation when the stirring speed is higher. The upper opening of the air inlet pipe 21 is connected with a nitrogen output device.
The air outlet assembly 3 comprises an air outlet pipe 31, an air outlet hollow rubber plug 32 and air outlet through holes 33, the air outlet pipe 31 is a cylindrical thin-wall hollow glass pipe, the height of the air outlet pipe 31 is 0.2-0.4 times of the height of the cylinder body 13, the air outlet hollow rubber plug 32 is composed of two rubber circular rings which are wide at the top and narrow at the bottom, a cylindrical air outlet through hole 33 which is through up and down is dug at the center of the air outlet hollow rubber plug 32, and the inner diameter of the air outlet pipe 31 is enabled to be inserted into the air outlet hollow rubber plug and tightly combined with the air outlet hollow rubber plug 32. The upper opening of the air outlet pipe 31 is connected with a flow pump or a rotor flow meter by a rubber pipe or a polyester transparent pipe.
The fixing device 4 includes a left fixing plate 41, a right fixing plate 42, a left first flange 411, a left second flange 412, a right first flange 421, a right second flange 422, a front bolt assembly 43, a rear bolt assembly 44, a left fixing table 45, a right fixing table 46, a fixing base plate 47, and a rubber lining 48. Such an arrangement allows the body to be effectively secured and remain stable even at high speeds, and if desired, the underside of the fixture 4 can be selected from wooden cuboid blocks of various heights to lift the body. Under the common condition, the space below the left fixing plate and the right fixing plate is enough for accommodating the ice water bath kettle, the electric heating jacket and the subzero cooling tank.
The middle of the right side of the left fixing plate 41 is provided with a left semicircular notch 410, the middle of the left side of the right fixing plate 42 is provided with a right semicircular notch 420, the rubber lining 48 is composed of a semicircular left rubber lining 481 and a semicircular right rubber lining 482, and the left rubber lining 481 and the right rubber lining 482 are respectively adhered in the notches of the left semicircular notch 410 and the right semicircular notch 420 by strong glue, so that the rubber lining 48 is tightly combined with the frosted appearance 17 of the body 1 in the circular notch formed by combining the left semicircular notch 410 and the right semicircular notch 420. The structure of the two rubber linings ensures the stability and toughness of combination, and the body is not subjected to large stress. In order to ensure the observation performance and the toughness, the left fixing plate and the right fixing plate, including the flanges, can be made of a lamb plate material.
The left flange 411 is positioned at the rightmost side of the front edge of the left fixing plate 41, the left flange 412 is positioned at the rightmost side of the rear edge of the left fixing plate 41, the right flange 421 is positioned at the leftmost side of the front edge of the right fixing plate 42, the right flange 422 is positioned at the leftmost side of the rear edge of the right fixing plate 42, when the gaps of the left fixing plate 41 and the right fixing plate 42 are aligned and spliced, the left flange 411 and the right flange 422 are aligned and the through holes on the left flange are also aligned and fixed by screwing in through the front bolts and the front nuts included in the front bolt combination 43, the left flange 412 and the right flange 422 are aligned and the through holes on the left flange are also aligned and screwed in and fixed by the rear bolts and the rear nuts included in the rear bolt combination 44; the left first flange 411, the left second flange 412 and the left fixing plate 41 are integrally formed, and the right first flange 421, the right second flange 422 and the right fixing plate 42 are integrally formed.
The left fixing base 45 includes a rectangular parallelepiped left fixing base 452 and a left band 451, the left band 451 is formed in a shape of a little square in side view and has a thickness of 2 to 5mm, the left band is fixed to the left fixing base 452 by 2N symmetrical bolts while covering a left end portion of the left fixing plate 41 from above, the right fixing base 46 includes a rectangular parallelepiped right fixing base 462 and a right band 461, the right band 461 is formed in a shape of a little square in side view and has a thickness of 2 to 5mm, the left end portion of the left fixing plate 41 is covered from above and is fixed to the left fixing base 452 by 2N symmetrical bolts. The left and right cuffs each have a width, as viewed from above, of at least 30cm to ensure the effectiveness of this securement.
The stirring part 5 comprises a top cover 51, an inner sleeve 52, an outer sleeve 53, a stirring rod 54 and blades 55, wherein the outer sleeve 53 is provided with an upper outer sleeve 531 and a lower outer sleeve 532, the top cover 51 is in an inverted U shape, a first internal thread is arranged on the lower edge of the top cover 51, the internal thread is matched with a first external thread on the uppermost side outside the upper outer sleeve 531, after the first internal thread and the first external thread are screwed, the upper surface of the inner sleeve 52 is pressed in the middle of the lower part of the top cover 51, three inner cavities with different inner diameters are arranged in the upper outer sleeve 531 from top to bottom, the inner diameter of the first inner cavity is the largest, the inner diameter of the second inner cavity in the middle is obviously smaller than that of the first inner cavity, so that a circular step for supporting the lower part of the inner sleeve 52 is formed at the lower part of the first inner cavity, the inner diameter of the third inner cavity is similar to that of the first inner cavity, the side wall of the inner sleeve 52 is provided with a second internal thread, the outer diameter of the inner sleeve 52 is solid and slightly smaller than that the first inner cavity, vaseline is filled between the outer part of the inner sleeve 52 and the first inner cavity, the lower outer sleeve 532 is integrally in a circular cover shape, a through hole larger than the outer diameter of the stirring rod 54 is formed in the middle of the lower outer sleeve 532, an upward circular convex part is arranged on the upper side close to the outer part, a second external thread matched with the second internal thread is arranged on the outer side of the circular convex part, a higher second circular convex part is further arranged on the upper side of the lower outer sleeve 532 on the inner side of the circular convex part, and when the second internal thread and the second external thread are completely screwed, the distance between the top of the second circular convex part and the lower surface of the inner sleeve 52 is within 1 cm. After the arrangement, vaseline is coated on the side surface and the lower part of the inner sleeve 52, so that the fixing effect is ensured, the combination of the inner sleeve and the stirring rod can also realize high-speed rotation, if a small amount of vaseline is extruded, the vaseline can fall into a groove formed by the lower outer sleeve 532 and cannot flow into a reaction system, and the whole device provides effective guarantee for high-speed stirring.
The reaction kettle also comprises an ice water bath kettle, a water bath kettle, an electric heating sleeve and a subzero cooling tank, wherein the inner tank is a hollow cylindrical tank and is larger than the lower part of the barrel body 13; the inner diameter of the loading hole 18 is slightly larger than that of the dropper for loading.
Example 2
A process for the preparation of benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate, carried out using a reaction vessel as described above, which comprises the steps of preparation.
1) Taking a reaction kettle as described above under the protection of nitrogen, cleaning and airing, fixing the body (1) on a fixing device (4), opening a kettle cover (11), and adding 5.1g of 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2]Octane-1-carboxylic acid was dissolved in 20V THF, and the 4- (((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2]Weighing a reactant A under octane-1-formic acid, adding 3eq NEt3 of the reactant A, closing a kettle cover (11), stirring the reaction mixture at the rotation speed of 150 rpm, introducing nitrogen at 180ml/min, opening a charging plug (19), slowly dropwise adding 1.5eq isobutyl chloroformate of the reactant A from a charging hole (18), covering the charging plug (19) after dropwise adding, increasing the stirring speed to 750 rpm, stopping stirring after 1.2h, repeatedly taking a very small amount of the reaction mixture from the charging hole (18), tracking the reaction by HPLC until the raw materials disappear from the charging hole (18) by HPLC tracking reaction to generate an intermediate, sleeving the reaction mixture at the lower part of a barrel body (13) by a zero-temperature reduction tank, reducing the temperature of the reaction mixture to about-10 ℃ by a mixture of ethanol and liquid nitrogen, starting a stirrer, rotating at the rotation speed of 100 rpm, opening the charging plug (19) to drop enough NH3 saturated THF solution into the system from the charging hole (18), and after dropping, replacing the ice water bath containing enough ice and water mixtureSleeving the lower part of the cylinder body (13), keeping the temperature of 0 ℃ for reacting for at least 1.2h at the rotating speed of 100 revolutions per minute, and if the intermediate does not disappear, continuing stirring the mixture at 100 revolutions per minute for reacting for 15min until the intermediate disappears after the reaction is tracked by HPLC from the feeding hole (18) and the reaction is complete; the vessel lid (11) was then opened and 150ml of deionized water was added to the reaction mixture, the mixture was removed completely, extracted 3 times with 70ml of EA, washed three times with 70ml of brine, dried and the organic phase was dried to give the product of step 1 ((4-carbonamidobicyclo [ 2.2.2.2) white solid]Octane-1-yl) methyl) benzyl carbonate; 5.08g of the product of step 1 are obtained, the NMR data of which are:1HNMR(400M,CDCl3):δppm7.30-7.39(m,5H),5.49(s,1H),5.25(s,1H),5.09(s,2H),4.72(m,1H),2.98(d,J＝6.8Hz,2H),1.75-1.79(m,6H),1.43-1.47(m,6H)。
2) taking a clean and dry reaction kettle as described above, fixing the body (1) on a fixing device (4), opening a kettle cover (11), dissolving 5.2g of the product of the step 1 in 15V pyridine to form a mixture, then placing the mixture in the reaction kettle, covering the kettle cover (11), stirring at the rotating speed of 750 revolutions per minute for 10min, reducing the speed to 180 revolutions per minute, introducing nitrogen at 180ml per minute, sleeving an ice water bath kettle containing enough ice-water mixture on the lower part of a barrel body (13), slowly dripping 5eq of POCl3 of the product of the step 1 from a feeding hole (18) after the temperature is stably reduced to 0 ℃, closing a feeding plug (19) after the dripping is finished, keeping the rotation per minute at 180 revolutions per minute, reacting at 0 ℃ for 2h under the condition of introducing nitrogen at 180ml per minute, stopping stirring, repeatedly taking a very small amount of the reaction mixture from the feeding hole (18), tracking the reaction by HPLC, until the reaction was followed by HPLC to find disappearance of the starting material; removing the ice water bath kettle, adding 200ml of ice water mixture prepared by purified water into a reaction kettle, stirring for 15min at 180 revolutions/min, extracting for 5 times by using 80ml of DCM, washing for 4 times by using 50ml of 2N hydrochloric acid, washing for 4 times by using 50ml of water, washing for 4 times by using 50ml of brine, drying and spin-drying to obtain a white solid crude product, dissolving the crude product in water, adjusting the pH value of the crude product to 9 by using 1N NaOH filtrate, standing for a period of time, extracting for 4 times by using 20ml of DCM, spin-drying to obtain a white solid crude product, weighing, pulping by using 2V N-hexane, performing suction filtration and drying to obtain a product of benzyl ((4-cyanobicyclo [2.2.2] octane-1-yl) methyl) carbonate in the step 2; 2.75g of the product of step 2, in about 57% yield and NMR data:
1HNMR(400M,CDCl3):δppm7.36(m,5H),5.08(s,1H),4.70(m,1H),2.97(d,J＝6.9Hz,2H),1.89-1.95(m,6H),1.42-1.47(m,6H)。
3) taking a clean and dry reaction kettle as described above, fixing the body (1) on a fixing device (4), opening a kettle cover (11), adding 115ml of anhydrous methanol into the reaction kettle, introducing nitrogen at 150ml/min, rapidly adding 5.7g of the product in the step 2, 4.6g of nickel chloride hexahydrate and 20.2g of BOC anhydride, immediately covering the kettle cover (11), sleeving an ice water bath kettle containing enough ice water mixture on the lower part of a barrel body (13), starting stirring at the rotating speed of 75 revolutions/min, opening a charging plug (19) after 6min, slowly adding 3.6g of sodium borohydride from a charging hole (18), removing the ice water bath kettle after adding, stirring for reacting for 2.5h while slowly raising the reaction mixture to room temperature, sleeving a zero-temperature reduction tank on the lower part of the barrel body (13), reducing the reaction mixture to about 10 ℃ by using a small amount of a mixture of ethanol and liquid nitrogen, slowly adding 40ml of water into a feeding hole (18), stirring at the rotating speed of 190 rpm for 20min, completely removing the reaction mixture from the reaction kettle, performing suction filtration by using a proper amount of diatomite, washing by using 110ml of DCM, extracting the mother liquor by using 110ml of DCM for 4 times, washing by using 90ml of brine for 4 times, drying and spin-drying to obtain a white solid crude product, performing sample mixing and passing through a column by using 100-200 meshes of silica gel with the mass of 1.5 times, sampling and climbing TLC plates respectively under the conditions of PE (EA-2: 1 and PE-25: 1, flushing an upper point when the PE (EA-25: 1) is performed, and flushing a lower point when the PE (EA-2: 1) is performed to obtain a product of the step 3, namely benzyl ((4- ((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-yl) methyl) carbonate; 4.8g of the product of step 3, with a yield of about 63%, and NMR data:
1HNMR(400M,CDCl3) δ ppm7.31-7.36(m,5H),5.08(s,2H),4.69(m,1H),4.47(m,1H),2.93(d, J ═ 6.4Hz,2H),2.85(d, J ═ 6.4Hz,2H),1.43(s,9H),1.37(m, 12H). LCMS data 347.2[ (M + H-tBu)+]。
4) Taking a clean and dry reaction kettle as described above, fixing the body (1) on a fixing device (4), opening a kettle cover (11), dissolving 2.5g of the product of the step 3 in 3V pyridine to form a mixture, adding 5eq of hydrochloric acid dioxane solution of the product of the step 3, tightly covering the kettle cover (11), stirring at the rotating speed of 200 r/min, reacting for 1.5h, then adding 20ml of MTBE (methyl tert-butyl ether) from a feeding hole (18), continuing to stir for 10min, stopping stirring, completely removing the reaction mixture, performing suction filtration to obtain a crude product, dissolving the crude product in an appropriate amount of deionized water, adjusting the pH value to 9 by using 1N NaOH filtrate, standing for 10min, extracting for 3 times by using 20ml of DCM, performing rotary drying to obtain a white solid crude product, weighing, taking 3V N-hexane to pulp the white solid product, performing suction filtration to obtain 1.6g of final product (benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate, the yield thereof was found to be 84%. The NMR data are as follows:
1HNMR(400M,CDCl3):δppm7.33-7.35(m,5H),5.06(s,2H),2.85(s,2H),2.30(s,2H),1.38-1.40(m,12H)。LCMS:303.2[(M+H)+]. From the above values, the overall yield can exceed 23%, which is an acceptable value, and it was found in the experiment that if a conventional four-necked flask system is used, the yield never exceeds 15%, and the lowest yield is about 21-22% even when the apparatus of the present application is used, which is seen as a unique advantage of using the apparatus of the present application.
Example 3
A process for the preparation of benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate, carried out using a reaction vessel as described above, which comprises the steps of preparation.
1) Taking a reaction kettle as described above under the protection of nitrogen, cleaning and airing, fixing the body (1) on a fixing device (4), opening a kettle cover (11), and adding 5.1g of 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2]Octane-1-carboxylic acid was dissolved in 20V THF, and the 4- (((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2]Weighing a reactant A under octane-1-formic acid, adding 3eq NEt3 of the reactant A, closing a kettle cover (11), stirring the reaction mixture at the rotation speed of 120-,at the moment, a subzero cooling tank is sleeved at the lower part of a cylinder body (13), the reaction mixture is cooled to about minus 10 ℃ by a mixture of ethanol and liquid nitrogen, a stirrer is started, a feeding plug (19) is opened at the rotating speed of 65-75 r/min, a sufficient amount of saturated THF (tetrahydrofuran) solution of NH3 is dripped into the system from a feeding hole (18), after dripping is finished, an ice water bath kettle filled with a sufficient amount of ice-water mixture is sleeved at the lower part of the cylinder body (13), the reaction is kept at 0 ℃ for at least 1h at the rotating speed of 65-75 r/min, if the intermediate does not disappear, stirring at 65-75 r/min is continued for reaction for 15min until the intermediate disappears and is completely reacted after HPLC tracking the reaction from the feeding hole (18); the vessel lid (11) was then opened and 145ml of deionized water was added to the reaction mixture, the mixture was removed completely, extracted 4 times with 60ml of EA, washed three times with 60ml of brine, dried and the organic phase was dried to give the product of step 1 ((4-carbonamido bicyclo [ 2.2.2.2) as a white solid]Octane-1-yl) methyl) benzyl carbonate; 5.12g of the product of step 1 are obtained, the NMR data of which are:1HNMR(400M,CDCl3):δppm7.30-7.39(m,5H),5.49(s,1H),5.25(s,1H),5.09(s,2H),4.72(m,1H),2.98(d,J＝6.8Hz,2H),1.75-1.79(m,6H),1.43-1.47(m,6H)。
2) taking a clean and dry reaction kettle as described above, fixing the body (1) on a fixing device (4), opening a kettle cover (11), dissolving 5g of the product of the step 1 in 15V pyridine to form a mixture, then placing the mixture in the reaction kettle, covering the kettle cover (11), stirring at the rotating speed of 680-plus-720 r/min for 10min, reducing the speed to 140-plus-160 r/min, introducing nitrogen at 140-plus-160 ml/min, sleeving an ice water bath kettle containing enough ice-water mixture on the lower part of a barrel body (13), after stably cooling to 0 ℃, slowly adding 5eq POCl3 of the product of the step 1 from a feeding hole (18), closing a feeding plug (19) after adding dropwise, keeping 140-plus-160 r/min, reacting at 0 ℃ for 2h under the condition of introducing nitrogen at 140-plus-160 ml/min, stopping stirring, repeatedly taking a very small amount of the reaction mixture from the feeding hole (18) and tracking the reaction by HPLC, until the reaction was followed by HPLC to find disappearance of the starting material; removing the ice water bath kettle, adding 200ml of ice water mixture prepared by purified water into the reaction kettle, stirring for 12min at 160 rpm under 140 ℃, extracting for 4 times by using 80ml of DCM, washing for 3 times by using 50ml of 2N hydrochloric acid, washing for 3 times by using 50ml of water, washing for 3 times by using 50ml of brine, drying and spin-drying to obtain a white solid crude product, dissolving the crude product in water, adjusting the pH value to 9 by using 1N NaOH filtrate, standing for a period of time, extracting for 3 times by using 20ml of DCM, spin-drying to obtain a white solid crude product, weighing, pulping by using 2V N-hexane, and drying after suction filtration to obtain a product benzyl ((4-cyano bicyclo [2.2.2] octane-1-yl) methyl) carbonate in the step 2; 2.6g of the product of step 2, in a yield of about 56%, and having NMR data of:
1HNMR(400M,CDCl3):δppm7.36(m,5H),5.08(s,1H),4.70(m,1H),2.97(d,J＝6.9Hz,2H),1.89-1.95(m,6H),1.42-1.47(m,6H)。
3) taking a clean and dry reaction kettle as described above, fixing the body (1) on a fixing device (4), opening a kettle cover (11), adding 110ml of anhydrous methanol into the reaction kettle, introducing nitrogen gas at 180ml/min of 160-, slowly adding 40ml of water into a feeding hole (18), stirring at the rotating speed of 180 revolutions per minute for 15min, completely removing the reaction mixture from the reaction kettle, performing suction filtration by using a proper amount of diatomite, washing by using 100ml of DCM, extracting the mother liquor by using 100ml of DCM for 3 times, washing by using 80ml of brine for 3 times, drying and spin-drying to obtain a white solid crude product, mixing and passing through a column by using 100-200 meshes of silica gel with the mass of 1.5 times, sampling and climbing TLC plates respectively under the conditions of PE (EA ═ 2:1 and PE: 25:1, flushing an upper point when the PE: EA ═ 25:1 and a lower point when the PE: EA ═ 2:1 to obtain a product ((4- (((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-yl) methyl) benzyl carbonate in the step 3; 4.5g of the product of step 3, with a yield of about 62%, NMR data:
1HNMR(400M,CDCl3):δppm7.31-7.36(m,5H),5.08(s,2H),4.69(m,1H),4.47(m,1H),2.93(d,J＝6.4Hz,2H),2.85(d,J＝6.4Hz,2H),1.43(s,9H),1.37(m, 12H). LCMS data 347.2[ (M + H-tBu)+]。
4) Taking a clean and dry reaction kettle as described above, fixing a body (1) on a fixing device (4), opening a kettle cover (11), dissolving 2.6g of the product of the step 3 in 3V pyridine to form a mixture, adding 5eq hydrochloric acid dioxane solution of the product of the step 3, tightly covering the kettle cover (11), stirring at the rotating speed of 200 r/min for 2h, then adding 20ml of MTBE (methyl tert-butyl ether) from a feeding hole (18), continuously stirring for 10min, stopping stirring, completely removing the reaction mixture, performing suction filtration to obtain a crude product, dissolving the crude product in an appropriate amount of deionized water, adjusting the pH value to 9 with 1N NaOH filtrate, standing for 10min, extracting with 20ml of DCM for 3 times, performing rotary drying to obtain a white solid crude product, weighing, taking 3V N-hexane to pulp the white solid product, performing suction filtration to obtain 1.7g of final product (4- (aminomethyl) bicyclo [2.2.2] octyl-1-yl) methyl) benzyl carbonate, the yield thereof was found to be 86%. The NMR data are as follows:
1HNMR(400M,CDCl3):δppm7.33-7.35(m,5H),5.06(s,2H),2.85(s,2H),2.30(s,2H),1.38-1.40(m,12H)。LCMS:303.2[(M+H)+]。
example 4
A process for the preparation of benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate, carried out using a reaction vessel as described above, which comprises the steps of preparation.
1) Taking a reaction kettle as described above under the protection of nitrogen, cleaning and airing, fixing the body (1) on a fixing device (4), opening a kettle cover (11), dissolving 5.2g of 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-formic acid in 20V THF, weighing a reactant A under the condition of the 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-formic acid, adding 3eq NEt3 of the reactant A, closing the kettle cover (11), stirring the reaction mixture at a rotating speed of 140 revolutions per minute, introducing nitrogen at 170ml/min, opening a charging plug (19), slowly dropwise adding 1.5eq isobutyl chloroformate of the reactant A from a charging hole (18), covering the charging plug (19) after dropwise adding, and increasing the stirring speed to 740 revolutions per minute, after 1.1h, stopping stirring, repeatedly taking a very small amount of reaction mixture from a feeding hole (18), tracking the reaction by HPLC until the raw materials disappear by HPLC tracking the reaction from the feeding hole (18), generating an intermediate, sleeving a zero-temperature cooling tank on the lower part of a cylinder (13), cooling the reaction mixture to about-10 ℃ by using a mixture of ethanol and liquid nitrogen, starting a stirrer, opening a feeding plug (19) at the rotating speed of 90 r/min, dropwise adding a sufficient amount of saturated THF solution of NH3 into the system from the feeding hole (18), after the dropwise addition, sleeving an ice water bath pot filled with a sufficient amount of ice water mixture on the lower part of the cylinder (13), keeping the reaction at 0 ℃ at the rotating speed of 90 r/min for at least 1.1h, if the intermediate does not disappear, continuing stirring the reaction for 15min at 90 r/min until the intermediate disappears by HPLC tracking the reaction from the feeding hole (18), the reaction is complete; then opening the kettle cover (11), adding 150ml of deionized water into the reaction mixture, removing the mixture completely, extracting with 65ml of EA for 4 times, washing with 65ml of brine for three times, drying, and spin-drying the organic phase to obtain a white solid, namely benzyl ((4-carbonamido bicyclo [2.2.2] octane-1-yl) methyl) carbonate of the product in the step 1; 5.27g of the product of step 1 are obtained, the NMR data of which are:
1HNMR(400M,CDCl3):δppm7.30-7.39(m,5H),5.49(s,1H),5.25(s,1H),5.09(s,2H),4.72(m,1H),2.98(d,J＝6.8Hz,2H),1.75-1.79(m,6H),1.43-1.47(m,6H)。
2) taking a clean and dry reaction kettle as described above, fixing the body (1) on a fixing device (4), opening a kettle cover (11), dissolving 5.1g of the product of the step 1 in 15V pyridine to form a mixture, then placing the mixture in the reaction kettle, covering the kettle cover (11), stirring at 740 r/min for 10min, reducing the speed to 170 r/min, introducing nitrogen at 170ml/min, sleeving an ice water bath kettle containing enough ice and water mixture on the lower part of a barrel body (13), slowly dripping 5eq of POCl3 of the product of the step 1 from a feeding hole (18) after the temperature is stably reduced to 0 ℃, closing a feeding plug (19) after the dripping is finished, keeping 170 r/min, reacting at 0 ℃ for 2.2h under the condition of introducing nitrogen at 170ml/min, stopping stirring, repeatedly taking a very small amount of reaction mixture from the feeding hole (18), tracking the reaction by HPLC, until the reaction was followed by HPLC to find disappearance of the starting material; removing the ice water bath kettle, adding 200ml of ice water mixture prepared by purified water into a reaction kettle, stirring for 14min at 170 rpm, extracting for 5 times by using 80ml of DCM, washing for 4 times by using 50ml of 2N hydrochloric acid, washing for 4 times by using 50ml of water, washing for 4 times by using 50ml of brine, drying and spin-drying to obtain a white solid crude product, dissolving the crude product in water, adjusting the pH value of the crude product to 9 by using 1N NaOH filtrate, standing for a period of time, extracting for 4 times by using 20ml of DCM, spin-drying to obtain a white solid crude product, weighing, pulping by using 2V N-hexane, performing suction filtration and drying to obtain a product of benzyl ((4-cyanobicyclo [2.2.2] octane-1-yl) methyl) carbonate in the step 2; 2.72g of step 2 product (5), about 57.4% yield, NMR:
1HNMR(400M,CDCl3):δppm7.36(m,5H),5.08(s,1H),4.70(m,1H),2.97(d,J＝6.9Hz,2H),1.89-1.95(m,6H),1.42-1.47(m,6H)。
3) taking a clean and dry reaction kettle as described above, fixing the body (1) on a fixing device (4), opening a kettle cover (11), adding 112ml of anhydrous methanol into the reaction kettle, introducing nitrogen at 170ml/min, rapidly adding 5.6g of the product in the step 2, 4.5g of nickel chloride hexahydrate and 20.15g of BOC anhydride, immediately covering the kettle cover (11), sleeving an ice water bath kettle containing enough ice water mixture on the lower part of a cylinder body (13), starting stirring at the rotating speed of 100 revolutions/min, opening a charging plug (19) after 5min, slowly adding 3.55g of sodium borohydride from a charging hole (18), removing the ice water bath kettle after adding, stirring for reaction for 2.3h while slowly raising the reaction mixture to room temperature, sleeving a zero-temperature reduction tank on the lower part of the cylinder body (13), reducing the reaction mixture to about 10 ℃ by using a small amount of a mixture of ethanol and liquid nitrogen, slowly adding 40ml of water into a feeding hole (18), stirring at the rotating speed of 190 rpm for 18min, completely removing the reaction mixture from the reaction kettle, performing suction filtration by using a proper amount of diatomite, washing by using 105ml of DCM, extracting mother liquor by using 105ml of DCM for 4 times, washing by using 85ml of brine for 4 times, drying and spin-drying to obtain a white solid crude product, performing sample mixing and passing through a column by using 100-200 meshes of silica gel with the mass of 1.5 times, sampling and climbing TLC plates respectively under the conditions of PE (EA ═ 2:1 and PE: 25:1, flushing an upper point when the PE: EA ═ 25:1 and a lower point when the PE: EA ═ 2:1 to obtain a product ((4- (((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-yl) methyl) benzyl carbonate in the step 3; 4.73g of the product of step 3, in about 64% yield and NMR data:
1HNMR(400M,CDCl3) δ ppm7.31-7.36(m,5H),5.08(s,2H),4.69(m,1H),4.47(m,1H),2.93(d, J ═ 6.4Hz,2H),2.85(d, J ═ 6.4Hz,2H),1.43(s,9H),1.37(m, 12H). LCMS data 347.2[ (M + H-tBu)+]。
4) Taking a clean and dry reaction kettle as described above, fixing the body (1) on a fixing device (4), opening a kettle cover (11), dissolving 2.55g of the product of the step 3 in 3V pyridine to form a mixture, adding 5eq of hydrochloric acid dioxane solution of the product of the step 3, tightly covering the kettle cover (11), stirring at the rotating speed of 240 r/min, reacting for 1.8h, then adding 20ml of MTBE into a feeding hole (18), continuously stirring for 10min, stopping stirring, completely removing the reaction mixture, performing suction filtration to obtain a crude product, dissolving the crude product in an appropriate amount of deionized water, adjusting the pH value to 9 by using 1N NaOH filtrate, standing for 10min, extracting for 4 times by using 22ml of DCM, performing rotary drying to obtain a white solid crude product, weighing, taking 3V N-hexane to pulp the white solid product, performing suction filtration to obtain 1.88g of final product (benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate, the yield thereof was found to be 87%. The NMR data are as follows:
1HNMR(400M,CDCl3):δppm7.33-7.35(m,5H),5.06(s,2H),2.85(s,2H),2.30(s,2H),1.38-1.40(m,12H)。LCMS:303.2[(M+H)+]。
the NMR spectrum of benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate of the final product is shown in FIG. 5.
Use of benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate prepared by any one of the aforementioned methods as a pharmaceutical intermediate for the preparation of a medicament.
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 (5)

1. A reaction kettle is provided with a glass body (1), which is provided with a kettle cover (11), a lower flange (12) and a cylinder body (13), and is characterized in that:
the reaction kettle also comprises an air inlet assembly (2), an air outlet assembly (3), a fixing device (4) and a stirring part (5);
the center of the kettle cover (11) is provided with a middle hole (14), the middle hole (14) is a circular through hole with the center positioned at the center of the kettle cover (11), the inner side surface of the middle hole is frosted and is used for being attached to the outer peripheral surface of the outer sleeve (53); an air inlet (15) and an air outlet (16) of cylindrical through holes with the same specification are symmetrically arranged on two sides by taking the central point of the upper surface of the kettle cover (11) as the center; a charging hole (18) with a circular through hole is further formed in the kettle cover (11) beside the middle hole (14), the charging hole (18) is provided with a frosted inner side surface and a charging plug (19) matched with the frosted inner side surface, the charging plug (19) is provided with a plug part (191) with a sectional area larger than that of the charging hole (18) and a body part with a frosted outer surface, and the middle part of the outer surface of the cylinder body is provided with a ring-shaped frosted outer surface;
the air inlet assembly (2) comprises an air inlet pipe (21), an air inlet hollow rubber plug (22) and an air inlet through hole (23), wherein the air inlet pipe (21) is a cylindrical thin-wall hollow glass tube, the height of the air inlet pipe (21) is 1-1.3 times of the height of the barrel body (13), the air inlet hollow rubber plug (22) is composed of two rubber circular rings which are wide at the top and narrow at the bottom, a cylindrical air inlet through hole (23) which is communicated with the top and the bottom is dug in the center of the air inlet hollow rubber plug (22), and the air inlet pipe (21) is inserted into the air inlet hollow rubber plug and is tightly combined with the air inlet hollow rubber plug (22) through the inner diameter of the cylindrical air inlet through hole;
the air outlet assembly (3) comprises an air outlet pipe (31), an air outlet hollow rubber plug (32) and air outlet through holes (33), wherein the air outlet pipe (31) is a cylindrical thin-wall hollow glass pipe, the height of the air outlet pipe (31) is 0.2-0.4 times of the height of the cylinder body (13), the air outlet hollow rubber plug (32) is composed of two rubber circular rings which are wide at the top and narrow at the bottom, a cylindrical air outlet through hole (33) which is communicated with the upper part and the lower part is dug out at the center of the air outlet hollow rubber plug (32), and the inner diameter of the air outlet hollow rubber plug enables the air outlet pipe (31) to be inserted into the air outlet hollow rubber plug and tightly combined with the air outlet hollow rubber plug (32);
the fixing device (4) is provided with a left fixing plate (41), a right fixing plate (42), a left flange (411), a left flange (412), a right flange (421), a right flange (422), a front bolt combination (43), a rear bolt combination (44), a left fixing table (45), a right fixing table (46), a fixing bottom plate (47) and a rubber lining (48);
the middle of the right side of the left fixing plate (41) is provided with a left semicircular notch, the middle of the left side of the right fixing plate (42) is provided with a right semicircular notch, the rubber lining (48) consists of a semicircular left rubber lining (481) and a semicircular right rubber lining (482), and the left rubber lining (481) and the right rubber lining (482) are respectively glued in the notches of the left semicircular notch and the right semicircular notch by strong glue, so that the circular notch formed by combining the left semicircular notch and the right semicircular notch is tightly combined with the frosted appearance of the rubber lining (48) and the body (1);
the left first flange (411) is positioned at the rightmost side of the front edge of the left fixing plate (41), the left second flange (412) is positioned at the rightmost side of the rear edge of the left fixing plate (41), the right first flange (421) is positioned at the leftmost side of the front edge of the right fixing plate (42), the right second flange (422) is positioned at the leftmost side of the rear edge of the right fixing plate (42), when gaps of the left fixing plate (41) and the right fixing plate (42) are aligned and spliced, the left first flange (411) and the right first flange (421) are aligned and through holes in the left first flange are aligned, a front bolt and a front nut included in a front bolt combination (43) are used for screwing and fixing, the left second flange (412) and the right second flange (422) are aligned and through holes in the right flange are aligned, and a rear bolt and a rear nut included in a; the left first flange (411), the left second flange (412) and the left fixing plate (41) are integrally formed, and the right first flange (421), the right second flange (422) and the right fixing plate (42) are integrally formed;
the left fixing table (45) is provided with a cuboid-shaped left fixing base (452) and a left hoop (451), the left hoop (451) is in a shape like a Chinese character 'ji' in side view and has a thickness of 2-5mm, the left hoop covers the left section of the left fixing plate (41) from the top and is fixed on the left fixing base (452) by 2N symmetrical bolts, the right fixing table (46) is provided with a cuboid-shaped right fixing base (462) and a right hoop (461), the right hoop (461) is in a shape like a Chinese character 'ji' in side view and has a thickness of 2-5mm, the left section of the left fixing plate (41) covers the left section of the left fixing plate (41) from the top and is fixed on the left fixing base (452) by 2N symmetrical bolts;
the stirring part (5) comprises a top cover (51), an inner sleeve (52), an outer sleeve (53), a stirring rod (54) and blades (55), the outer sleeve (53) is provided with an upper outer sleeve (531) and a lower outer sleeve (532), the top cover (51) is in an inverted U shape, a first internal thread is arranged on the lower edge of the top cover, the internal thread is adapted to a first external thread on the uppermost side outside the upper outer sleeve (531), after the first internal thread and the first external thread are screwed, the upper surface of the inner sleeve (52) is pressed in the middle of the lower part of the top cover (51), three inner cavities with different inner diameters are arranged in the upper outer sleeve (531) from top to bottom, the inner diameter of the first inner cavity above is the largest, the inner diameter of the middle second inner cavity is obviously smaller than that of the first inner cavity, so that a circular step for bearing the lower part of the inner sleeve (52) is formed on the lower part of the first inner cavity, the inner diameter of the third inner cavity is approximate to the first inner cavity, and the side wall of the third inner cavity is provided with a second internal thread, the inner sleeve (52) is solid, the outer diameter of the inner sleeve is slightly smaller than the first inner cavity, vaseline is filled between the outer portion of the inner sleeve (52) and the first cavity, the lower outer sleeve (532) is in a circular cover shape as a whole, a through hole larger than the outer diameter of the stirring rod (54) is formed in the middle of the lower outer sleeve, an upward circular convex portion is arranged on the upper side of the lower outer sleeve close to the outer portion, second external threads matched with the second internal threads are arranged on the outer side of the circular convex portion, a second higher circular convex portion is further arranged on the inner side of the circular convex portion on the upper side of the lower outer sleeve (532), and after the second internal threads and the second external threads are completely screwed, the distance from the top of the second circular convex portion to the lower surface of the inner sleeve (52) is within 1 cm.
2. The reactor of claim 1, wherein:
the inner grooves are hollow cylindrical grooves and are larger than the ice water bath kettle, the electric heating sleeve and the subzero cooling groove at the lower part of the barrel body (13);
the inner diameter of the feeding hole (18) is slightly larger than that of the dropper for sample feeding.
3. A method for producing an amino-substituted compound, which is carried out using the reaction vessel according to claim 2, comprising the steps of:
1) taking a reaction kettle as in claim 2 under the protection of nitrogen, cleaning and airing, fixing the body (1) on a fixing device (4), opening a kettle cover (11), and adding 4.8-5.2g of 4- (((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2]Octane-1-carboxylic acid was dissolved in 20V THF,the 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2]Octane-1-carboxylic acid reactant A was weighed out and 3eq NEt of reactant A was added3Closing the kettle cover (11), stirring the reaction mixture at the rotating speed of 100-, introducing nitrogen at the flow rate of 100 and 180ml/min, opening the charging plug (19), slowly dripping 1.5eq of isobutyl chloroformate of the reactant A from the charging hole (18), after finishing dripping, covering the charging plug (19), increasing the stirring speed to 650-750 revolutions/min, after 0.8-1.2h, stopping stirring, repeatedly taking a very small amount of reaction mixture from the feeding hole (18), tracking the reaction by HPLC until the raw materials disappear and generating an intermediate by tracking the reaction by HPLC from the feeding hole (18), sleeving the lower part of the cylinder body (13) by a subzero cooling tank, cooling the reaction mixture to about-10 ℃ by a mixture of ethanol and liquid nitrogen, starting a stirrer, at a speed of 50-100 rpm, the filler plug (19) is opened to supply sufficient NH from the orifice (18).3After the saturated THF solution is dripped into the system, an ice water bath kettle filled with enough ice and water mixture is sleeved at the lower part of the cylinder body (13), the reaction is kept at 0 ℃ for at least 0.8-1.2h at the rotating speed of 50-100 r/min, if the intermediate is not disappeared, the stirring reaction is continued for 15min at 50-100 r/min until the intermediate disappears after the HPLC tracking reaction from the charging hole (18), and the reaction is completed; then the kettle cover (11) is opened, 135-150ml of deionized water is added into the reaction mixture, the mixture is completely removed, extracted by 50-70ml of EA for 3-5 times, washed by 50-70ml of salt for three times, dried and the organic phase is dried to obtain the product of the step 1 ((4-carbonamido bicyclo [2.2.2] white solid)]Octane-1-yl) methyl) benzyl carbonate;
2) taking a clean and dry reaction kettle as claimed in claim 2, fixing the body (1) on a fixing device (4), opening a kettle cover (11), dissolving 4.8-5.2g of the product of the step 1 in 15V pyridine to form a mixture, then placing the mixture in the reaction kettle, covering the kettle cover (11), stirring at the rotation speed of 600-3After the dripping is finished, the charging plug (19) is closed,keeping the reaction temperature at 100-; removing the ice water bath kettle, adding 200ml of ice water mixture prepared by purified water into the reaction kettle, stirring for 10-15min at 180 revolutions/min under 100ml of ice water, extracting for 3-5 times by using 80ml of DCM, washing for 2-4 times by using 50ml of 2N hydrochloric acid, washing for 2-4 times by using 50ml of water, washing for 2-4 times by using 50ml of brine, drying and spin-drying to obtain a white solid crude product, dissolving the crude product in water, adjusting the PH value to 9 by using a 1N NaOH filtrate, standing for a period of time, extracting for 2-4 times by using 20ml of DCM, spin-drying to obtain a white solid crude product, pulping by using N-hexane 2V, performing suction filtration and drying to obtain a product ((4-cyano bicyclo [ 2.2.2.2) in the step 2]Octane-1-yl) methyl) benzyl carbonate;
3) taking a clean and dry reaction kettle as claimed in claim 2, fixing the body (1) on a fixing device (4), opening a kettle cover (11), adding 105-115ml of anhydrous methanol into the reaction kettle, introducing nitrogen at 100-180ml/min, rapidly adding 5.3-5.7g of the product of the step 2, 4.2-4.6g of nickel chloride hexahydrate and 20-20.2g of BOC anhydride, immediately covering the kettle cover (11), sleeving a water bath ice pot containing sufficient ice and water mixture on the lower part of a barrel body (13), starting stirring at the rotating speed of 50-100 r/min, opening a plug (19) after 4-6min, slowly adding 3.4-3.6g of sodium borohydride from a feeding hole (18), removing the ice and water bath after the addition is finished, and stirring and reacting for 1.5-2.5h while slowly raising the reaction mixture to room temperature, sleeving a barrel body (13) at the lower part by using a subzero cooling tank, cooling the reaction mixture by using a small amount of mixture of ethanol and liquid nitrogen to about 10 ℃, slowly adding 40ml of water into a feeding hole (18), stirring at the rotating speed of 150- (ii) a
4) Taking a clean and dry reaction kettle as claimed in claim 2, fixing the body (1) on a fixing device (4), opening a kettle cover (11), dissolving 2.4-2.6g of the product of the step 3 in 3V pyridine to form a mixture, adding 5eq hydrochloric acid dioxane solution of the product of the step 3, covering the kettle cover (11), reacting for 1-2h under stirring at the rotating speed of 150 revolutions per minute (250 revolutions per minute), then adding 20ml MTBE into a feeding hole (18), continuing stirring for 10min, stopping stirring, completely removing the reaction mixture, performing suction filtration to obtain a crude product, dissolving the crude product in an appropriate amount of deionized water, adjusting the pH value to 9 by using 1N NaOH filtrate, standing for 10min, extracting for 3 times by using 18-22ml DCM, performing rotary drying to obtain a white crude product, weighing, taking 3V N-hexane, pulping the white solid crude product, and weighing to obtain a final product ((4- (aminomethyl) bicyclo [2.2 ] oct-1-yl) Methyl) benzyl carbonate.
4. A method of making according to claim 3, wherein:
1) taking a reaction kettle according to claim 2 under the protection of nitrogen, cleaning and airing, fixing the body (1) on a fixing device (4), opening a kettle cover (11), and adding 5g of 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2]Octane-1-carboxylic acid was dissolved in 20V THF, and the 4- (((((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2]Octane-1-carboxylic acid reactant A was weighed out and 3eq NEt of reactant A was added3Closing the kettle cover (11), stirring the reaction mixture at the rotating speed of 120-, introducing nitrogen at 140-, covering the charging plug (19), increasing the stirring speed to 680-700 r/min, after 1h, stopping stirring, repeatedly taking a very small amount of reaction mixture from the feeding hole (18), tracking the reaction by HPLC until the raw materials disappear and generating an intermediate by tracking the reaction by HPLC from the feeding hole (18), sleeving the lower part of the cylinder body (13) by a subzero cooling tank, cooling the reaction mixture to about-10 ℃ by a mixture of ethanol and liquid nitrogen, starting a stirrer, at a speed of 65-75 rpm, the filler plug (19) is opened to supply a sufficient amount of NH from the orifice (18).3After the saturated THF solution is dripped into the system, an ice water bath kettle filled with enough ice and water mixture is sleeved at the lower part of the cylinder body (13), the reaction is kept at 0 ℃ for at least 1h at the rotating speed of 65-75 r/min, if the intermediate does not disappear, the stirring reaction is continued for 15min at 65-75 r/min until the intermediate disappears after the reaction is tracked by HPLC from the feeding hole (18), and the reaction is complete; the vessel lid (11) was then opened and 145ml of deionized water was added to the reaction mixture, the mixture was removed completely, extracted 4 times with 60ml of EA, washed three times with 60ml of brine, dried and the organic phase was dried to give the product of step 1 ((4-carbonamido bicyclo [ 2.2.2.2) as a white solid]Octane-1-yl) methyl) benzyl carbonate;
2) taking a clean and dry reaction kettle as claimed in claim 2, fixing the body (1) on a fixing device (4), opening a kettle cover (11), dissolving 5g of the product of the step 1 in 15V pyridine to form a mixture, then placing the mixture in the reaction kettle, covering the kettle cover (11), stirring at the rotating speed of 680-720 rpm for 10min, reducing the speed to 140-160 rpm, introducing nitrogen at 140-160ml/min, sleeving an ice-water bath pot containing enough ice-water mixture on the lower part of the barrel body (13), and slowly dropping 5eq of POCl of the product of the step 1 from a charging hole (18) after the temperature is stably reduced to 0 DEG C3After the dropwise addition, the charging plug (19) is closed, the reaction is carried out for 2h at the temperature of 0 ℃ under the conditions that the nitrogen is introduced for 160 r/min at the temperature of 140-; removing the ice water bath kettle, adding 200ml of ice water mixture prepared by purified water into the reaction kettle, stirring for 12min at 140 revolutions/min, extracting for 4 times by using 80ml of DCM, washing for 3 times by using 50ml of 2N hydrochloric acid, washing for 3 times by using 50ml of water, washing for 3 times by using 50ml of brine, drying and spin-drying to obtain a white solid crude product, dissolving the crude product in water, adjusting the pH value to 9 by using 1N NaOH filtrate, standing for a period of time, extracting for 3 times by using 20ml of DCM, spin-drying to obtain a white solid crude product, weighing, pulping by using 2V N-hexane, and drying after suction filtration to obtain a product in the step 2 ((4-cyano bicyclo [ 2.2.2)]Octane-1-yl) methyl) benzyl carbonate;
3) taking a clean and dry reaction kettle as claimed in claim 2, fixing the body (1) on a fixing device (4), opening a kettle cover (11), adding 110ml of anhydrous methanol into the reaction kettle, introducing nitrogen gas at 180ml/min of 160-, slowly adding 40ml of water into a feeding hole (18), stirring at the rotating speed of 180 revolutions per minute for 15min, completely removing the reaction mixture from the reaction kettle, performing suction filtration by using a proper amount of diatomite, washing by using 100ml of DCM, extracting the mother liquor by using 100ml of DCM for 3 times, washing by using 80ml of brine for 3 times, drying and spin-drying to obtain a white solid crude product, mixing and passing through a column by using 100-200 meshes of silica gel with the mass of 1.5 times, sampling and climbing TLC plates respectively under the conditions of PE (EA ═ 2:1 and PE: 25:1, flushing an upper point when the PE: EA ═ 25:1 and a lower point when the PE: EA ═ 2:1 to obtain a product ((4- (((benzyloxy) carbonyl) amino) methyl) bicyclo [2.2.2] octane-1-yl) methyl) benzyl carbonate in the step 3;
4) a clean and dry reaction kettle as claimed in claim 2, fixing the body (1) on the fixing device (4), opening the kettle cover (11), dissolving 2.5g of the product of step 3 in 3V pyridine to form a mixture, adding 5eq of dioxane hydrochloride solution of the product of step 3, tightly covering the kettle cover (11), stirring at 200 r/min, reacting for 1.5h, then adding 20ml of MTBE from a charging hole (18), continuing stirring for 10min, stopping stirring, completely removing the reaction mixture, performing suction filtration to obtain a crude product, dissolving the crude product in a proper amount of deionized water, adjusting the pH value to 9 with 1N NaOH filtrate, standing for 10min, extracting for 3 times with 20ml DCM, spin-drying to obtain a crude white solid, weighing, taking 3V N-hexane to pulp the crude white solid, and performing suction filtration to obtain the final product, namely benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate.
5. Use of benzyl ((4- (aminomethyl) bicyclo [2.2.2] oct-1-yl) methyl) carbonate prepared by the method according to any one of claims 3 to 4 as a pharmaceutical intermediate for the production of a medicament.
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