CN110368887A - Preparation method of novel amino-substituted spiro compound - Google Patents

Preparation method of novel amino-substituted spiro compound Download PDF

Info

Publication number
CN110368887A
CN110368887A CN201910702799.1A CN201910702799A CN110368887A CN 110368887 A CN110368887 A CN 110368887A CN 201910702799 A CN201910702799 A CN 201910702799A CN 110368887 A CN110368887 A CN 110368887A
Authority
CN
China
Prior art keywords
mixture
methyl
reaction
turns
kettle
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201910702799.1A
Other languages
Chinese (zh)
Other versions
CN110368887B (en
Inventor
江勇军
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Liuhe Ningyuan Pharmaceutical Technology Co ltd
Original Assignee
Beijing Liuhe Ningyuan Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Liuhe Ningyuan Technology Co ltd filed Critical Beijing Liuhe Ningyuan Technology Co ltd
Priority to CN201910702799.1A priority Critical patent/CN110368887B/en
Publication of CN110368887A publication Critical patent/CN110368887A/en
Application granted granted Critical
Publication of CN110368887B publication Critical patent/CN110368887B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • 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

A kind of amino replaces the preparation method of New-type spiro compound
Technical field
The present invention relates to medicine intermediate fields, and in particular to pharmaceutical intermediate ((4- (amino methyl) bicyclic [2.2.2] Decyl- 1- yl) methyl) carbonic acid benzyl ester synthetic method.
Background technique
Carbonic acid benzyl ester and its derivative are a kind of important compounds, have stronger bioactivity, are widely used in curing The fields such as medicine, pesticide, therefore the synthesis of carbonic acid benzyl derivatives has received widespread attention, the quilt especially among medicine intermediate It is widely applied.CN201410087799.2 gives a kind of carbon containing acid benzyl ester -2,3,8- trimethyl -6- hepta-fluoroiso-propyl -4- quinoline The bactericidal composition of quinoline ester, this is the example of carbonic acid benzyl derivatives application and synthesis, but the ((4- (amino that the application refers to Methyl) bicyclic [2.2.2] decyl- 1- yl) methyl) carbonic acid benzyl ester is rarely used as the application of medicine intermediate or preparation method to go out It is existing, either there are document or data to disclose out.
Due to the characteristic of the molecule, this method cannot be generalized in the synthesis of other similar structure.This is by trying many times What originality, higher yields and the non-reproduction of shorter reaction time for the preparation method tested determined, other routes Substantially can not there are higher yields or acceptable reaction time.
In addition, the prior art is there is also such problems, i.e., significant deficiency of the existing four-hole bottle as reaction vessel, General such laboratory preparation all uses four-hole bottle as reaction vessel, and it is with conspicuous characteristics that several points are insufficient: one, the deficiency of fixed performance, When mixture needs to stir in four-hole bottle, because four-hole bottle is typically all to clamp main bottleneck to realize high-speed stirred, but four Mouth bottom of bottle portion is uneven, so that stirring rod can not be goed deep into, and is difficult to realize high-speed stirred, is stirred with being inserted at the main mouth of existing four-hole bottle The mode of stick is mixed, at most stable mixing speed is too violent in 350-400 turns/min, then high device overall jitter later, has Whole bottle breakage risk, and due to the injustice of bottom of bottle, material effectively fully stir being many times also difficult to obtain, influence to react Sufficiently carry out；Two, the deficiency of existing nitrogen protection mode, existing nitrogen protection are all to be passed through nitrogen from a mouth of four-hole bottle Gas draws gas in bottle from another mouth, but such mode can be generated larger in bottle due to the limitation of four-hole bottle shape Dead volume or be not involved in the volume of convection current, detected according to infrared video, the appearance situation of this dead volume is maximum probability Event, and current simple logical nitrogen mode is difficult to overcome；Three, it removes reaction mixture and largely loses problem, four-hole bottle Multiple mouths and main mouth problem less than normal, so that reaction mixture is difficult to by appropriate removal when processing after each step, In practice it is a large amount of or it is most of lost, often each step will when removing due to operational issue reduce 1-2 at product Quantity not only affects the product amounts actually obtained, so that the calculation of yield of each step deviates from actual conditions, This can not be overcome using four-hole bottle system.
Summary of the invention
The present invention is to provide a kind of special reaction kettle first, and the reaction kettle is excellent with respect to four-hole bottle system significant performance, It is not only able to achieve stirring more stable under high speed, but also due to air flow structure, the effect of nitrogen protection is more preferable, and each step can be real Existing higher yield, and since structure is the wealthy mouth of cylinder and does not have side mouthful, reaction mixture can compare easily shifting completely Out, the loss that four-hole bottle reaction removes is avoided, in addition, contact area is big, bottom more than four-hole bottle since bottom is cylinder Portion is equipped with heating/refrigerating plant of adaptation, also can realize better heating/refrigerating effect than four-hole bottle system.
A kind of reaction kettle, the ontology with glass material, the ontology have kettle cover, lower flange, cylinder, and feature exists In: the reaction kettle further includes air inlet combination, outlet combination, fixed device, mixing part；There is interstitial hole at the center of kettle cover, Interstitial hole is the circular through hole that center is located at kettle cover center, and inner surface is in frosted shape, for the outer weekly form with outer tube Face paste is closed；Centered on the upper surface central point of kettle cover, two sides are symmetrically equipped with the air inlet of the identical cylindrical type through-hole of specification And venthole；The charging aperture of a circular through hole is additionally provided with beside the interstitial hole on kettle cover, which has frosted medial surface And matched charging plug, the charging, which is filled in, is greater than the piston part of charging aperture with sectional area and with frosted outer surface There is the frosted appearance of a circular ring type at body portion, the barrel outer surface middle part.
Air inlet combination includes air inlet pipe, air inlet hollow rubber plug and air through hole, and the air inlet pipe is that a cylindrical type is thin The height of wall hollow glass tube, the air inlet pipe is between 1-1.3 times of cylinder height, and the air inlet hollow rubber plug is by upper width Under narrow two parts rubber ring composition, and a cylindrical type up and down has been dug out at the center of this air inlet hollow rubber plug Air through hole, internal diameter make air inlet pipe be inserted and combine closely with air inlet hollow rubber plug.
Outlet combination includes escape pipe, outlet hollow rubber plug and exhaust through hole, and the escape pipe is that a cylindrical type is thin The height of wall hollow glass tube, the escape pipe is between 0.2-0.4 times of cylinder height, and the outlet hollow rubber plug is by upper Narrow two parts rubber ring composition under width, and a cylindrical type up and down has been dug out at the center of this outlet hollow rubber plug Exhaust through hole, internal diameter makes escape pipe be inserted and combine closely with outlet hollow rubber plug.
Fixed device has left fixed plate, right fixed plate, the first from left flange, the second from left flange, a right flange, right two flanges, preceding Bolt combination, rear bolt combination, left fixed station, right fixed station, fixed bottom plate, rubber back boxing.
Right side is intermediate in left fixed plate has left semicircle notch, has right semi-circle notch, institute among right fixed plate upper left side It states rubber back boxing to be made of semicircular left rubber back boxing and right rubber back boxing, left rubber back boxing and right rubber back boxing difference With being strongly adhesive in the notch of left semicircle notch and right semi-circle notch, so that left semicircle notch and right semi-circle notch merge shape At circumferential notch in, the frosted appearance of rubber back boxing and ontology is combined closely.
The first from left flange is located at the left fixed plate leading edge rightmost side, and the second from left flange is located at the left fixed plate back edge rightmost side, right One flange is located at the right fixed plate leading edge leftmost side, and right two flanges are located at the right fixed plate back edge leftmost side, when left fixed plate with When right fixed plate notch alignment split, the first from left flange and right flange alignment and through-hole thereon are also aligned, and use front bolt The front bolt and front nut that combination includes, which screw in, fixes, and the through-hole of the second from left flange with right two flanges alignment and thereon is also right Together, the rear bolt and back nut for including with rear bolt combination, which screw in, fixes；The first from left flange and the second from left flange and left fixation Plate be it is integrally formed, a right flange, right two flanges and right fixed plate are integrally formed.
The left fixed station has a left fixed base and left hoop of rectangular-shape, left hoop from the side in "Ji" type and Thickness between 2-5mm, lean on the first from left section and be fixed on left fixation with 2N symmetrical bolts by left fixed plate covered from above On pedestal, the right fixed station has the right fixed base and right hoop of rectangular-shape, and right hoop is in "Ji" type from the side And thickness, between 2-5mm, left fixed plate 41 covered from above leans on the first from left section and is fixed on a left side with 2N symmetrical bolts On fixed base.
Mixing part includes top cover, inner sleeve, outer tube, stirring rod, blade, and outer tube has upper outer tube and lower housing Pipe, top cover is inverted u-shaped, and lower edge has the first internal screw thread, which adapts to outside first of top side outside outer tube Screw thread, and after the first internal screw thread and the first external screw thread screw, inner sleeve upper surface is compressed among the lower part of the top cover, it is described Has the inner cavity there are three different inner diameters within upper outer tube from top to bottom, top first inner chamber internal diameter is maximum, intermediate second inner chamber Internal diameter is significantly less than first inner chamber, so that the annular step of a support inner sleeve lower part is formed at first inner chamber lower part, in third Intracavitary diameter is approximate with first inner chamber, and its side wall has the second internal screw thread, and inner sleeve is that solid and its outer diameter is slightly less than above-mentioned the One inner cavity is filled with vaseline between inner sleeve outside and the first cavity, and the lower outer tube generally annulus cover shape, centre have One is greater than the through-hole of stirring rod outside diameter, and there is a upward annulus protrusion in upside by outside, has on the outside of annulus protrusion and second Second external screw thread of internal screw thread adaptation, lower outer tube upside also higher second annulus protrusion on the inside of annulus protrusion, when After second internal screw thread and the second external screw thread screw completely, the top of the second annulus protrusion is with a distance from inner sleeve lower surface in 1cm Within.
It preferably, further include inside groove for hollow cylinder slot and greater than ice water bath, water-bath, the electricity of the cylinder lower part Heating mantle, subzero cooling slot；The internal diameter of the charging aperture is slightly larger than sample-adding dropper.
It is also equipped with a kind of preparation method of ((bicyclic [2.2.2] the decyl- 1- yl of 4- (amino methyl)) methyl) carbonic acid benzyl ester, It is carried out using reaction kettle as previously described, preparation step is following four step.
1) it under nitrogen protection, taking just like preceding reaction kettle, cleaning is dried, and ontology is fixed on the securing means, open kettle 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclic [2.2.2] decane -1- formic acid of 4.8-5.2g, is dissolved in the THF of 20V by lid In, bicyclic [2.2.2] decane -1- formic acid of the 4- ((((benzyloxy) carbonyl) amino) methyl) calls reactant A in the following text, and reaction is added The NEt3 of the 3eq of object A, closes kettle cover, and the revolving speed for applying 100-150 turns/min to reaction mixture stirs, with 100-180ml/ Min is passed through nitrogen, opens charging plug, the isobutyl chlorocarbonate of the 1.5eq of reactant A is slowly added dropwise from charging aperture, drips Bi Hou covers charging and fills in, promotion mixing speed to 650-750 turns/min, after 0.8-1.2h, stops stirring, repeatedly from charging aperture Minute quantity reaction mixture HPLC tracking reaction is taken, disappears, generates until tracking reaction discovery raw material from charging aperture HPLC Intermediate is placed on cylinder lower part with subzero cooling slot at this time, and reaction mixture is cooled to -10 with ethyl alcohol+liquid nitrogen mixture DEG C or so, start blender, turn in 50-100/revolving speed of min under, open charging plug from charging aperture for the saturation of enough NH3 THF solution is added dropwise in system, after being added dropwise, uses instead and is loaded with the ice water bath of the mixture of ice and water of enough ice and is placed on cylinder Lower part keeps 0 DEG C of reaction at least 0.8-1.2h to continue 50- if intermediate does not disappear under the revolving speed of 50-100 turns/min 100 turns/min is stirred to react 15min, disappears until tracking reaction discovery intermediate from charging aperture HPLC, fully reacting；Then Kettle cover is opened, the deionized water of 135-150ml is added in the reactive mixture, mixture is all removed, is extracted with 50-70mlEA It takes 3-5 times, then is washed three times with the salt of 50-70ml, it is dry, it is spin-dried for organic phase, obtains step 1 product ((the 4- carbon of white solid Amido bicyclic [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester.
2) the foregoing reaction kettle for taking a clean dry, ontology is fixed on the securing means, kettle cover is opened, it will Step 1 product of 4.8-5.2g, which is dissolved in the pyridine of 15V, forms mixture, then mixture is placed in reaction kettle, covers kettle cover, 10min is stirred with the revolving speed of 600-750 turns/min, reduction of speed to 100-180 turns/min, is passed through nitrogen with 100-180ml/min, uses The ice water bath for being loaded with the mixture of ice and water of enough ice is placed on cylinder lower part, after stablizing and being cooled to 0 DEG C, delays from charging aperture P DEG C 3 of 1 product 5eq of slow a dropping step is added dropwise rear enclosed charging plug, keeps 100-180 turns/min and 100-180ml/ Min is passed through under condition of nitrogen gas, 0 DEG C of reaction 1.5-2.5h, stops stirring, and minute quantity reaction mixture is taken to use repeatedly from charging aperture HPLC tracking reaction disappears until tracking reaction discovery raw material with HPLC；Then ice water bath is removed, it will be made from pure water 200ml mixture of ice and water is added in reaction kettle, and 100-180 turns/min stirring 10-15min, is extracted 3-5 times, is used with the DCM of 80ml The 2N salt of 50ml pickling 2-4 times is washed 2-4 times with washing 2-4 times of 50ml with the salt of 50ml, and drying is simultaneously spin-dried for, and obtains white Solid crude product, crude product is soluble in water, with 1N NaOH filtrate tune PH=9, a period of time is stood, extracts 2-4 with the DCM of 20ml It is secondary, it is spin-dried for, obtains crude white solid, be beaten with n-hexane 2V, dried after filtering, obtain step 2 product ((4- cyano Bicyclic [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester.
3) the foregoing reaction kettle for taking a clean dry, ontology is fixed on the securing means, kettle cover is opened, it will The anhydrous methanol of 105-115ml is added in reaction kettle, is passed through nitrogen with 100-180ml/min, is rapidly added the step of 5.3-5.7g B DEG C of acid anhydrides of the six water nickel chlorides and 20-20.2g of rapid 2 product and 4.2-4.6g, covers tightly kettle cover at once, with being loaded with foot The ice water bath for measuring the mixture of ice and water of ice is placed on cylinder lower part, and starts to stir with the revolving speed of 50-100 turns/min, 4-6min Later, charging plug is opened, 3.4-3.6g sodium borohydride is slowly added to from charging aperture, removes ice water bath after adding, is being reacted Mixture is slowly increased to be stirred to react 1.5-2.5h while room temperature, is placed on cylinder lower part with subzero cooling slot, with a small amount of ethyl alcohol+ The mixture of liquid nitrogen cools down reaction mixture 10 DEG C or so, and 40ml water is slowly added to from charging aperture, turns/min with 150-200 Revolving speed stir 10-20min, reaction mixture is all removed from reaction kettle, with appropriate suction filtered through kieselguhr, uses 90-110ml DCM washing, the mother liquor DCM of 90-110ml is extracted 2-4 time, is washed 2-4 times with the salt of 70-90ml, is dried and be simultaneously spin-dried for, obtain To crude white solid, sample is mixed with 100~200 mesh silica gel, 1.5 times of quality and crosses column, under the conditions of PE:EA=2:1 and 25:1 respectively TLC plate is climbed in sampling, and when PE:EA=25:1 goes out a little, and when PE:EA=2:1 goes out lower point, obtains step 3 product ((4- ((((benzyloxy) carbonyl) amino) methyl) bicyclic [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester.
4) the foregoing reaction kettle for taking a clean dry, ontology is fixed on the securing means, kettle cover is opened, it will Step 3 product of 2.4-2.6g, which is dissolved in the pyridine of 3V, forms mixture, and the hydrochloric acid dioxane of step 3 product 5eq is added Solution covers tightly kettle cover, and to react 1-2h under the revolving speed stirring of 150-250 turns/min, it is total that MTBE then is added from charging aperture 20ml continues to stir 10min, stops stirring, reaction mixture is all removed, suction filtration obtains crude product, and crude product is dissolved in right amount In deionized water, with the NaOH filtrate tune pH value of 1N to 9,10min is stood, is extracted 3 times with the DCM of 18-22ml, is spin-dried for, obtains Crude white solid takes the n-hexane of 3V to be beaten the crude white solid after weighing, filter, obtain final product ((4- (ammonia Ylmethyl) bicyclic [2.2.2] decyl- 1- yl) methyl) carbonic acid benzyl ester.
A kind of application of medicine intermediate, with ((bicyclic [2.2.2] the decyl- 1- of 4- (amino methyl) of acquired preparation Base) methyl) carbonic acid benzyl ester be used as medicine intermediate to prepare drug.
Preferably, aforementioned all reagents are the pure above purity of chemistry, or are excellent pure grade.The water is deionization Water, it is therefore preferable to distilled water.
Compared with the prior art, the advantages of the present invention are as follows: one, it device in terms of improves, the reaction kettle is with respect to four-hole bottle System significant performance is excellent, is not only able to achieve stirring more stable under high speed, can easily realize that 600 turns or more of stabilization is stirred Mix, and common four-hole bottle system cannot or when high speed it is extremely unstable, have the risk fallen, and due to air flow structure, nitrogen The effect of gas shielded is more preferable, and each step can realize higher yield, with common four-hole bottle it is difficult to ensure that exact nitrogen protection Whether effect, bottle middle part bottom can eject gas without control means, can only leave it to chance, and since structure is cylinder-shaped wealthy Mouthful, reaction mixture can be more easily fully removed, and avoid the loss that common four-hole bottle reaction removes, common four-hole bottle It is mouthful small, more mouthfuls, it is desirable to it is extremely difficult to remove reactant for a full due, in addition, due to bottom be it is cylindrical, contact area more than Four-hole bottle be it is big, bottom is equipped with heating/refrigerating plant of adaptation, and better heating/refrigerating effect can be also realized than four-hole bottle system Fruit, this is also much too late with common four-hole bottle.
It is dissolved in THF, is added with 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclic [2.2.2] decane -1- formic acid NEt3, isobutyl chlorocarbonate obtain ((bicyclic [2.2.2] decane -1- base of 4- carbonamido) methyl) carbonic acid benzyl ester, thus prepare Obtain ((4- cyano-bicyclo [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；Add anhydrous methanol, six water nickel chlorides, B DEG C of acid ((4- ((((benzyloxy) carbonyl) amino) methyl) bicyclic [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester is made in acid anhydride；It is added In Isosorbide-5-Nitrae-dioxane solution, hydrochloric acid dioxane solution, MTBE is added, ((bicyclic [2.2.2] decyl- of 4- (amino methyl) is made 1- yl) methyl) carbonic acid benzyl ester, product report obtained is had no in currently available technology, compared with allied substances preparation method, The application method and step is finely investigated, and each step raw material availability is very high, has great value to realize industrial production, passes through this The method Fine design of invention, not only has effectively achieved synthesis, and yield is higher, the available 5g's of the raw material of first step 5g ((bicyclic [2.2.2] decane -1- base of 4- carbonamido) methyl) carbonic acid benzyl ester, the yield of second step is more than 56%, third step Yield is more than 62%, and the 4th step is more than 84%, and overall production rate is high, and economic value is larger, and the application passes through for filtration product It is operated under accurate operation and low temperature repeatedly, embodies extremely strong inventive concept and creativeness, achieve good preparation effect Fruit has no more similar public information in the prior art for using for reference, and the present invention program has originality.
Detailed description of the invention
Fig. 1 is the side sectional view of the application reaction kettle.
Fig. 2 is the cross-sectional view of the application air inlet combination and outlet combination from side.
Fig. 3 is the top view of the fixed device of the application.
Fig. 4 is the side sectional view of the application blender.
Fig. 5 is that ((bicyclic [2.2.2] the decyl- 1- yl of 4- (amino methyl)) methyl) carbonic acid benzyl ester is prepared in the present invention HNMR spectrogram.
Appended drawing reference indicates: ontology 1, kettle cover 11, lower flange 12, cylinder 13, air inlet combination 2, outlet combination 3, fixed dress Set 4, mixing part 5, interstitial hole 14, air inlet 15, venthole 16, charging aperture 18, charging plug 19, piston part 191, body portion 192, frosted Appearance 17, air inlet pipe 21, air inlet hollow rubber plug 22, air through hole 23, escape pipe 31, outlet hollow rubber plug 32, exhaust through hole 33, Left fixed plate 41, right fixed plate 42, the first from left flange 411, the second from left flange 412, a right flange 421, right two flanges 422, front bolt Combination 43, rear bolt combination 44, left fixed station 45, right fixed station 46, fixed bottom plate 47, rubber back boxing 48, left semicircle notch 410, right semi-circle notch 420, left rubber back boxing 481, right rubber back boxing 482, left semicircle notch 410, right semi-circle notch 420, a left side Fixed base 452, it is left hoop 451, right fixed base 462, it is right hoop 461, top cover 51, inner sleeve 52, outer tube 53, stirring rod 54, Blade 55, upper outer tube 531, lower outer tube 532.
Specific embodiment
The preferred embodiment of the present invention is described in detail with reference to the accompanying drawing, so that advantages and features of the invention energy It is easier to be readily appreciated by one skilled in the art, so as to make a clearer definition of the protection scope of the present invention.This hair It is bright to be embodied in many different forms, and should not be construed as limited to embodiment set forth herein.On the contrary, providing these Design of the invention so that this disclosure will be thorough and complete, and will be fully conveyed to art technology by embodiment Personnel, the present invention will only be defined by the appended claims.((bicyclic [2.2.2] the decyl- 1- yl of 4- (amino methyl)) provided by the invention Methyl) carbonic acid benzyl ester preparation method, process route is as follows:
Its synthetic method can be summarized as follows: be with 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclic [2.2.2] last of the ten Heavenly stems Alkane -1- formic acid is dissolved in THF, and NEt3 is added, and isobutyl chlorocarbonate obtains ((bicyclic [2.2.2] decane -1- of 4- carbonamido Base) methyl) ((4- cyano-bicyclo [2.2.2] decane -1- is prepared thus in the presence of P DEG C of l3 and pyridine in carbonic acid benzyl ester Base) methyl) carbonic acid benzyl ester；Anhydrous methanol, six water nickel chlorides, B DEG C of acid anhydrides are added, ((4- ((((benzyloxy) carbonyl) ammonia is made Base) methyl) bicyclic [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；It is added in pyridine, MTBE is added, ((4- (amino first is made Base) bicyclic [2.2.2] decyl- 1- yl) methyl) carbonic acid benzyl ester.
Embodiment 1
A kind of reaction kettle, the ontology 1 with glass material, the ontology have kettle cover 11, lower flange 12, cylinder 13, Be characterized in that: the reaction kettle further includes air inlet combination 2, outlet combination 3, fixed device 4, mixing part 5.The reaction kettle globality Ground improves the whole problem of current four-hole bottle system: not firm enough, base contact surface product is small, and heating refrigeration is slow, and stirring can not Speed is improved, nitrogen protection effect is bad, and charging must be opened wide thoroughly flatly, and removal reaction mixture is very troublesome and has been difficult Full problem.
There is interstitial hole 14 at the center of kettle cover 11, interstitial hole 14 is the circular through hole that center is located at 11 center of kettle cover, Its inner surface is in frosted shape, for being bonded with the peripheral surface of outer tube 53；Centered on the upper surface central point of kettle cover 11, Two sides are symmetrically equipped with the air inlet 15 and venthole 16 of the identical cylindrical type through-hole of specification；The 14 side kettle cover 11 of interstitial hole On be additionally provided with the charging aperture 18 of a circular through hole, which has frosted medial surface and matched charging plug 19, It is described charging plug 19 with sectional area greater than charging aperture 18 piston part 191 and with the body portion 192 of frosted outer surface, the cylinder There is the frosted appearance 17 of a circular ring type in the middle part of external surface.It is arranged so that the air-tightness of device entirety is guaranteed, and adds Material plug is easy to close unlatching, and bore is small, further air-tightness to be kept to provide guarantee.
Air inlet combination 2 includes air inlet pipe 21, air inlet hollow rubber plug 22 and air through hole 23, and the air inlet pipe 21 is one The height of cylindrical type thin-walled hollow glass tube, the air inlet pipe 21 is between 1-1.3 times of 13 height of cylinder, and the air inlet is hollow Rubber plug 22 is made of two parts rubber ring wide at the top and narrow at the bottom, and has been dug out on one at the center of this air inlet hollow rubber plug 22 The air through hole 23 of the cylindrical type of lower perforation, internal diameter make air inlet pipe 21 be inserted and closely tie with air inlet hollow rubber plug 22 It closes.Such to be arranged so that intake efficiency is guaranteed, nitrogen can be directly entered the position compared with bottom of bottle, and air inlet pipe can basis It needs to adjust insertion depth, can be raised when low whipping speed is higher.The connection nitrogen output device suitable for reading of air inlet pipe 21.
Outlet combination 3 includes escape pipe 31, outlet hollow rubber plug 32 and exhaust through hole 33, and the escape pipe 31 is one Cylindrical type thin-walled hollow glass tube, the height of the escape pipe 31 are between 0.2-0.4 times of 13 height of cylinder, and the outlet is empty Heart rubber plug 32 is made of two parts rubber ring wide at the top and narrow at the bottom, and one has been dug out at the center of this outlet hollow rubber plug 32 The exhaust through hole 33 of cylindrical type up and down, internal diameter are inserted escape pipe 31 and close with outlet hollow rubber plug 32 In conjunction with.Escape pipe 31 is suitable for reading to connect flow pump or spinner flowmeter with rubber tube or polyester transparent pipe.
Fixed device 4 has left fixed plate 41, right fixed plate 42, the first from left flange 411, the second from left flange 412, a right flange 421, right two flanges 422, front bolt combination 43, rear bolt combination 44, left fixed station 45, right fixed station 46, fixed bottom plate 47, rubber Glue back boxing 48.Such setting is able to maintain stabilization, if necessary so that ontology is effectively fixed high speed rotation Words, fixing below device 4 can select from the wooden cuboid cushion block with multiple height, pave ontology.In ordinary circumstance Under, the space below left fixed plate and right fixed plate holds ice water bath, water-bath, electric heating cover, subzero cooling slot enough.
Right side is intermediate in left fixed plate 41 has left semicircle notch 410, has right semi-circle among right 42 upper left side of fixed plate Notch 420, the rubber back boxing 48 is made of semicircular left rubber back boxing 481 and right rubber back boxing 482, in left rubber Lining 481 and right rubber back boxing 482 are adhesive in the notch of left semicircle notch 410 and right semi-circle notch 420 with strength respectively, so that It obtains left semicircle notch 410 and right semi-circle notch 420 merges in the circumferential notch formed, outside the frosted of rubber back boxing 48 and ontology 1 Table 17 is combined closely.The structure of two rubber back boxings ensure that the stability and toughness of combination, ontology are unlikely to be answered by big Power effect.In order to guarantee to observe performance and toughness, left fixed plate and right fixed plate, including flange, pa nurse plate material can be used.
The first from left flange 411 is located at the left 41 leading edge rightmost side of fixed plate, and the second from left flange 412 is located at left 41 back edge of fixed plate The rightmost side, a right flange 421 are located at the right 42 leading edge leftmost side of fixed plate, and right two flanges 422 are located at right 42 back edge of fixed plate The leftmost side, when left fixed plate 41 and the alignment split of 42 notch of right fixed plate, the first from left flange 411 and a right flange 422 are right Through-hole together and thereon is also aligned, and the front bolt and front nut for including with front bolt combination 43, which screw in, fixes, the second from left flange 412 with right two flanges 422 alignment and through-hole thereon is also aligned, and the rear bolt and back nut for including with rear bolt combination 44 screw in It is fixed；The first from left flange 411 and the second from left flange 412 and left fixed plate 41 be it is integrally formed, a right flange 421, Right two flanges 422 and right fixed plate 42 are integrally formed.
The left fixed station 45 has the left fixed base 452 and left hoop 451 of rectangular-shape, and left hoop 451 is from the side In "Ji" type and thickness is between 2-5mm, left fixed plate 41 covered from above by the first from left section and by with 2N symmetrical spiral shells Bolt is fixed on left fixed base 452, and the right fixed station 46 has the right fixed base 462 and right hoop of rectangular-shape 461, for right hoop 461 from the side in "Ji" type and thickness is between 2-5mm, left fixed plate 41 covered from above leans on the first from left section And it is fixed on left fixed base 452 with 2N symmetrical bolts.Seen from above, left hoop and right hoop respectively have at least The width of 30cm, to guarantee the validity of this fixation.
Mixing part 5 includes top cover 51, inner sleeve 52, outer tube 53, stirring rod 54, blade 55, and outer tube 53 has upper outer Casing 531 and lower outer tube 532, top cover 51 is inverted u-shaped, and lower edge has the first internal screw thread, which adapts to housing First external screw thread of 531 outside top side of pipe, and after the first internal screw thread and the first external screw thread screw, the lower part of the top cover 51 Centre compresses 52 upper surface of inner sleeve, has the inner cavity there are three different inner diameters, top within the upper outer tube 531 from top to bottom First inner chamber internal diameter is maximum, and intermediate second inner chamber internal diameter is significantly less than first inner chamber, so that a support is formed at first inner chamber lower part The annular step of 52 lower part of inner sleeve, third inner cavity internal diameter is approximate with first inner chamber, and its side wall has the second internal screw thread, interior Casing 52 is that solid and its outer diameter is slightly less than above-mentioned first inner chamber, is filled with all scholars between 52 outside of inner sleeve and the first cavity There are the through-hole for being greater than 54 outer diameter of stirring rod in woods, the lower outer tube 532 generally annulus cover shape, centre, and upside is by outside There is a upward annulus protrusion, there is the second external screw thread being adapted to the second internal screw thread on the outside of annulus protrusion, on lower outer tube 532 Side on the inside of annulus protrusion there are also a higher second annulus protrusion, after the second internal screw thread and the second external screw thread screw completely, The top of second annulus protrusion is with a distance from 52 lower surface of inner sleeve within 1cm.After being arranged in this way, in the side of inner sleeve 52 Vaseline is all smeared with lower part, both ensure that fixed effect in this way, and the combination of inner sleeve and stirring rod can also realize high speed Rotation can be fallen into the slot that lower outer tube 532 is formed if there is a small amount of vaseline is extruded, whole without flowing into reaction system Body provides effective guarantee for high-speed stirred.
Reaction kettle further include inside groove be hollow cylinder slot and be greater than the ice water bath of 13 lower part of cylinder, water-bath, Electric heating cover, subzero cooling slot；The internal diameter of the charging aperture 18 is slightly larger than sample-adding dropper.
Embodiment 2
The preparation method of ((bicyclic [2.2.2] the decyl- 1- yl of 4- (amino methyl)) methyl) carbonic acid benzyl ester, using such as preceding institute Reaction kettle progress is stated, preparation step is.
1) under nitrogen protection, a foregoing reaction kettle is taken, cleaning is dried, and ontology (1) is fixed on fixed device (4) On, it opens kettle cover (11), 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclic [2.2.2] decane -1- formic acid of 5.1g is molten In the THF of 20V, bicyclic [2.2.2] decane -1- formic acid of the 4- ((((benzyloxy) carbonyl) amino) methyl) calls reactant in the following text The NEt3 of the 3eq of reactant A is added in A, closes kettle cover (11), and the revolving speed for applying 150 turns/min to reaction mixture stirs, with 180ml/min is passed through nitrogen, opens charging plug (19), the chloro-carbonic acid of the 1.5eq of reactant A is slowly added dropwise from charging aperture (18) Isobutyl ester after being added dropwise, covers charging plug (19), promotes mixing speed to 750 turns/min, after 1.2h, stops stirring, from adding Material hole (18) takes minute quantity reaction mixture HPLC tracking reaction repeatedly, until tracking reaction hair from charging aperture (18) HPLC Existing raw material disappears, and generates intermediate, is placed on cylinder (13) lower part with subzero cooling slot at this time, will with ethyl alcohol+liquid nitrogen mixture Reaction mixture is cooled to -10 DEG C or so, starts blender, under the revolving speed of 100 turns/min, opens charging plug (19) from charging The saturation THF solution of enough NH3 is added dropwise in system in hole (18), after being added dropwise, uses the ice water for being loaded with enough ice instead The ice water bath of mixture is placed on cylinder (13) lower part, and 0 DEG C of reaction at least 1.2h is kept under the revolving speed of 100 turns/min, if Intermediate does not disappear, then continues 100 turns/min and be stirred to react 15min, until tracking reaction discovery from charging aperture (18) HPLC Intermediate disappears, fully reacting；Then kettle cover (11) are opened, the deionized water of 150ml is added in the reactive mixture, will mix Object all removes, and is extracted 3 times with 70mlEA, then is washed three times with the salt of 70ml, dry, is spin-dried for organic phase, obtains white solid Step 1 product ((bicyclic [2.2.2] decane -1- base of 4- carbonamido) methyl) carbonic acid benzyl ester；5.08g step 1 product is obtained, Its NMR data are as follows:
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) ontology (1) is fixed on fixed device (4) by the foregoing reaction kettle for taking a clean dry, opens kettle It covers (11), step 1 product of 5.2g is dissolved in the pyridine of 15V and forms mixture, then mixture is placed in reaction kettle, is covered Kettle cover (11) stirs 10min with the revolving speed of 750 turns/min, and reduction of speed to 180 turns/min is passed through nitrogen with 180ml/min, with Sheng The ice water bath of mixture of ice and water equipped with enough ice is placed on cylinder (13) lower part, after stablizing and being cooled to 0 DEG C, from charging aperture (18) P DEG C 3 of step 1 product 5eq is slowly added dropwise in, rear enclosed charging plug (19) is added dropwise, keeps 180 turns/min, and 180ml/min is passed through under condition of nitrogen gas, 0 DEG C of reaction 2h, is stopped stirring, is taken minute quantity reaction mixture repeatedly from charging aperture (18) It is tracked and is reacted with HPLC, disappeared until tracking reaction discovery raw material with HPLC；Then ice water bath is removed, it will be made from pure water 200ml mixture of ice and water is added in reaction kettle, and 180 turns/min stirs 15min, is extracted 5 times with the DCM of 80ml, with the 2N of 50ml It salt pickling 4 times, with washing 4 times of 50ml, is washed 4 times with the salt of 50ml, drying is simultaneously spin-dried for, and obtains crude white solid, will be thick Product are soluble in water, with 1N NaOH filtrate tune PH=9, stand a period of time, are extracted 4 times with the DCM of 20ml, are spin-dried for, obtain white Solid crude product is beaten after weighing with the n-hexane of 2V, is dried after filtering, is obtained step 2 product ((4- cyano-bicyclo [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；Step 2 product 2.75g, yield about 57%, NMR data are as follows:
1HNMR(400M,CDCl3): δ ppm7.36 (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) ontology (1) is fixed on fixed device (4) by the foregoing reaction kettle for taking a clean dry, opens kettle It covers (11), the anhydrous methanol of 115ml is added in reaction kettle, nitrogen is passed through with 150ml/min, is rapidly added the step 2 of 5.7g B DEG C of acid anhydrides of the six water nickel chlorides and 20.2g of product and 4.6g, covers tightly kettle cover (11) at once, with being loaded with enough ice The ice water bath of mixture of ice and water is placed on cylinder (13) lower part, and starts to stir with the revolving speed of 75 turns/min, after 6min, opens Charging plug (19), is slowly added to 3.6g sodium borohydride from charging aperture (18), removes ice water bath after adding, in reaction mixture It is slowly increased to be stirred to react 2.5h while room temperature, cylinder (13) lower part is placed on subzero cooling slot, with a small amount of ethyl alcohol+liquid nitrogen Mixture cools down reaction mixture 10 DEG C or so, 40ml water is slowly added to from charging aperture (18), with the revolving speed of 190 turns/min 20min is stirred, reaction mixture is all removed from reaction kettle, with appropriate suction filtered through kieselguhr, is washed with the DCM of 110ml, it will Mother liquor is extracted 4 times with the DCM of 110ml, is washed 4 times with the salt of 90ml, dry to be simultaneously spin-dried for, and obtains crude white solid, with 100~ 200 1.5 times of mesh silica gel quality mix sample and cross column, separately sampled under the conditions of PE:EA=2:1 and 25:1 to climb TLC plate, PE:EA=25: It is gone out when 1 a little, when PE:EA=2:1 goes out lower point, obtains step 3 product ((4- ((((benzyloxy) carbonyl) amino) methyl) Bicyclic [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；4.8g step 3 product, yield are about 63%, NMR data are as follows:
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) ontology (1) is fixed on fixed device (4) by the foregoing reaction kettle for taking a clean dry, opens kettle It covers (11), step 3 product of 2.5g is dissolved in the pyridine of 3V and forms mixture, the hydrochloric acid dioxy of step 3 product 5eq is added Six ring solution cover tightly kettle cover (11), to react 1.5h, then be added from charging aperture (18) under the revolving speed stirring of 200 turns/min The total 20ml of MTBE continues to stir 10min, stops stirring, reaction mixture is all removed, suction filtration obtains crude product, and crude product is molten In appropriate amount of deionized water, with the NaOH filtrate tune pH value of 1N to 9,10min is stood, is extracted 3 times with the DCM of 20ml, is spin-dried for, obtains To crude white solid, the n-hexane of 3V is taken to be beaten the crude white solid after weighing, filters, obtain final product ((4- (amino methyl) bicyclic [2.2.2] decyl- 1- yl) methyl) carbonic acid benzyl ester 1.6g, yield 84%.Its 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)+].It being calculated from numerical value above, overall production rate can be more than 23%, It is acceptable numerical value, is found in test, if yield is never greater than 15%, this Shen using traditional four-hole bottle system Please device using then minimum yield also in 21-22% or so, it is seen that use the unique advantage of the device of the application.
Embodiment 3
The preparation method of ((bicyclic [2.2.2] the decyl- 1- yl of 4- (amino methyl)) methyl) carbonic acid benzyl ester, using such as preceding institute Reaction kettle progress is stated, preparation step is.
1) under nitrogen protection, a foregoing reaction kettle is taken, cleaning is dried, and ontology (1) is fixed on fixed device (4) On, it opens kettle cover (11), 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclic [2.2.2] decane -1- formic acid of 5.1g is molten In the THF of 20V, bicyclic [2.2.2] decane -1- formic acid of the 4- ((((benzyloxy) carbonyl) amino) methyl) calls reactant in the following text The NEt3 of the 3eq of reactant A is added in A, closes kettle cover (11), and the revolving speed for applying 120-130 turns/min to reaction mixture stirs It mixes, nitrogen is passed through with 140-160ml/min, charging plug (19) is opened, reactant A is slowly added dropwise from charging aperture (18) The isobutyl chlorocarbonate of 1.5eq after being added dropwise, covers charging plug (19), and promotion mixing speed to 680-700 turns/min, 1h Afterwards, stop stirring, minute quantity reaction mixture HPLC tracking reaction is taken repeatedly from charging aperture (18), until from charging aperture (18) Reaction discovery raw material is tracked with HPLC to disappear, and is generated intermediate, is placed on cylinder (13) lower part with subzero cooling slot at this time, uses ethyl alcohol Reaction mixture is cooled to -10 DEG C or so by the mixture of+liquid nitrogen, starts blender, under the revolving speed of 65-75 turns/min, is beaten It opens charging plug (19) and the saturation THF solution of enough NH3 is added dropwise in system from charging aperture (18), after being added dropwise, use instead The ice water bath for being loaded with the mixture of ice and water of enough ice is placed on cylinder (13) lower part, keeps 0 under the revolving speed of 65-75 turns/min DEG C reaction at least 1h, if intermediate does not disappear, continue 65-75 turn/min is stirred to react 15min, until from charging aperture (18) It tracks reaction discovery intermediate with HPLC to disappear, fully reacting；Then kettle cover (11) are opened, be added in the reactive mixture Mixture is all removed, is extracted 4 times with 60mlEA, then washed three times with the salt of 60ml by the deionized water of 145ml, dry, rotation Dry organic phase, obtains step 1 product ((bicyclic [2.2.2] decane -1- base of 4- carbonamido) methyl) carbonic acid benzyl of white solid Ester；Obtain 5.12g step 1 product, NMR data are as follows:
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) ontology (1) is fixed on fixed device (4) by the foregoing reaction kettle for taking a clean dry, opens kettle It covers (11), step 1 product of 5g is dissolved in the pyridine of 15V and forms mixture, then mixture is placed in reaction kettle, covers kettle It covers (11), 10min is stirred with the revolving speed of 680-720 turns/min, reduction of speed to 140-160 is turned/min, is passed through with 140-160ml/min Nitrogen is placed on cylinder (13) lower part with the ice water bath for the mixture of ice and water for being loaded with enough ice, after stablizing and being cooled to 0 DEG C, P DEG C 3 of step 1 product 5eq is slowly added dropwise from charging aperture (18), rear enclosed charging plug (19) is added dropwise, keeps 140-160 Turn/min and 140-160ml/min be passed through under condition of nitrogen gas, 0 DEG C of reaction 2h stops stirring, takes pole repeatedly from charging aperture (18) A small amount of reaction mixture is tracked with HPLC to react, and disappears until tracking reaction discovery raw material with HPLC；Then ice water bath is removed, 200ml mixture of ice and water made from pure water is added in reaction kettle, 140-160 turns/min stirring 12min, with the DCM of 80ml Extraction 4 times, with washing 3 times of 50ml, is washed 3 times with the pickling of 2N salt 3 times of 50ml with the salt of 50ml, and drying is simultaneously spin-dried for, and is obtained Crude white solid, crude product is soluble in water, with 1N NaOH filtrate tune PH=9, a period of time is stood, is extracted with the DCM of 20ml It 3 times, is spin-dried for, obtains crude white solid, be beaten after weighing with the n-hexane of 2V, dried after filtering, obtain step 2 product ((4- cyano-bicyclo [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；Step 2 product 2.6g, yield about 56%, NMR number According to are as follows:
1HNMR(400M,CDCl3): δ ppm7.36 (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) ontology (1) is fixed on fixed device (4) by the foregoing reaction kettle for taking a clean dry, opens kettle It covers (11), the anhydrous methanol of 110ml is added in reaction kettle, nitrogen is passed through with 160-180ml/min, is rapidly added the step of 5.5g B DEG C of acid anhydrides of the six water nickel chlorides and 20.1g of rapid 2 product and 4.4g, covers tightly kettle cover (11) at once, enough with being loaded with The ice water bath of the mixture of ice and water of ice is placed on cylinder (13) lower part, and starts to stir with the revolving speed of 100 turns/min, 5min it Afterwards, charging plug (19) is opened, 3.5g sodium borohydride is slowly added to from charging aperture (18), removes ice water bath after adding, anti- Be stirred to react 2h while answering mixture to be slowly increased to room temperature, be placed on cylinder (13) lower part with subzero cooling slot, with a small amount of ethyl alcohol+ The mixture of liquid nitrogen cools down reaction mixture 10 DEG C or so, 40ml water is slowly added to from charging aperture (18), with 180 turns/min Revolving speed stir 15min, reaction mixture is all removed from reaction kettle, with appropriate suction filtered through kieselguhr, with the DCM of 100ml The mother liquor DCM of 100ml is extracted 3 times, is washed 3 times with the salt of 80ml by washing, and drying is simultaneously spin-dried for, and obtains crude white solid, Sample, which is mixed, with 100~200 mesh silica gel, 1.5 times of quality crosses column, separately sampled under the conditions of PE:EA=2:1 and 25:1 to climb TLC plate, PE: It is gone out when EA=25:1 a little, when PE:EA=2:1 goes out lower point, obtains step 3 product ((4- ((((benzyloxy) carbonyl) ammonia Base) methyl) bicyclic [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；4.5g step 3 product, yield are about 62%, NMR number According to are as follows:
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) ontology (1) is fixed on fixed device (4) by the foregoing reaction kettle for taking a clean dry, opens kettle It covers (11), step 3 product of 2.6g is dissolved in the pyridine of 3V and forms mixture, the hydrochloric acid dioxy of step 3 product 5eq is added Six ring solution cover tightly kettle cover (11), to react 2h, MTBE then is added from charging aperture (18) under the revolving speed stirring of 200 turns/min Total 20ml continues to stir 10min, stops stirring, reaction mixture is all removed, suction filtration obtains crude product, crude product is dissolved in suitable It measures in deionized water, with the NaOH filtrate tune pH value of 1N to 9, stands 10min, extracted 3 times with the DCM of 20ml, be spin-dried for, obtain white Color solid crude product takes the n-hexane of 3V to be beaten the crude white solid after weighing, filter, obtain final product ((4- (amino Methyl) bicyclic [2.2.2] decyl- 1- yl) methyl) carbonic acid benzyl ester 1.7g, yield 86%.Its 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)+]。
Embodiment 4
The preparation method of ((bicyclic [2.2.2] the decyl- 1- yl of 4- (amino methyl)) methyl) carbonic acid benzyl ester, using such as preceding institute Reaction kettle progress is stated, preparation step is.
1) under nitrogen protection, a foregoing reaction kettle is taken, cleaning is dried, and ontology (1) is fixed on fixed device (4) On, it opens kettle cover (11), 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclic [2.2.2] decane -1- formic acid of 5.2g is molten In the THF of 20V, bicyclic [2.2.2] decane -1- formic acid of the 4- ((((benzyloxy) carbonyl) amino) methyl) calls reactant in the following text The NEt3 of the 3eq of reactant A is added in A, closes kettle cover (11), and the revolving speed for applying 140 turns/min to reaction mixture stirs, with 170ml/min is passed through nitrogen, opens charging plug (19), the chloro-carbonic acid of the 1.5eq of reactant A is slowly added dropwise from charging aperture (18) Isobutyl ester after being added dropwise, covers charging plug (19), promotes mixing speed to 740 turns/min, after 1.1h, stops stirring, from adding Material hole (18) takes minute quantity reaction mixture HPLC tracking reaction repeatedly, until tracking reaction hair from charging aperture (18) HPLC Existing raw material disappears, and generates intermediate, is placed on cylinder (13) lower part with subzero cooling slot at this time, will with ethyl alcohol+liquid nitrogen mixture Reaction mixture is cooled to -10 DEG C or so, starts blender, under the revolving speed of 90 turns/min, opens charging plug (19) from charging The saturation THF solution of enough NH3 is added dropwise in system in hole (18), after being added dropwise, uses the ice water for being loaded with enough ice instead The ice water bath of mixture is placed on cylinder (13) lower part, and 0 DEG C of reaction at least 1.1h is kept under the revolving speed of 90 turns/min, if in Mesosome does not disappear, then continues 90 turns/min and be stirred to react 15min, until it is intermediate to track reaction discovery from charging aperture (18) HPLC Body disappears, fully reacting；Then kettle cover (11) are opened, the deionized water of 150ml is added in the reactive mixture, mixture is complete Portion removes, and is extracted 4 times with 65mlEA, then is washed three times with the salt of 65ml, dry, is spin-dried for organic phase, obtains the step of white solid Rapid 1 product ((bicyclic [2.2.2] decane -1- base of 4- carbonamido) methyl) carbonic acid benzyl ester；5.27g step 1 product is obtained, NMR data are as follows:
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) ontology (1) is fixed on fixed device (4) by the foregoing reaction kettle for taking a clean dry, opens kettle It covers (11), step 1 product of 5.1g is dissolved in the pyridine of 15V and forms mixture, then mixture is placed in reaction kettle, is covered Kettle cover (11) stirs 10min with the revolving speed of 740 turns/min, and reduction of speed to 170 turns/min is passed through nitrogen with 170ml/min, with Sheng The ice water bath of mixture of ice and water equipped with enough ice is placed on cylinder (13) lower part, after stablizing and being cooled to 0 DEG C, from charging aperture (18) P DEG C 3 of step 1 product 5eq is slowly added dropwise in, rear enclosed charging plug (19) is added dropwise, keeps 170 turns/min, and 170ml/min is passed through under condition of nitrogen gas, 0 DEG C of reaction 2.2h, stops stirring, takes few quantitative response to mix repeatedly from charging aperture (18) Object is tracked with HPLC to react, and disappears until tracking reaction discovery raw material with HPLC；Then ice water bath is removed, pure water is made 200ml mixture of ice and water be added in reaction kettle, 170 turns/min stirs 14min, is extracted 5 times with the DCM of 80ml, with 50ml's 2N salt pickling 4 times is washed 4 times with washing 4 times of 50ml with the salt of 50ml, and drying is simultaneously spin-dried for, and obtains crude white solid, will Crude product is soluble in water, with 1N NaOH filtrate tune PH=9, stands a period of time, is extracted 4 times with the DCM of 20ml, is spin-dried for, obtains white Color solid crude product is beaten after weighing with the n-hexane of 2V, is dried after filtering, is obtained step 2 product ((4- cyano-bicyclo [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；Step 2 product 2.72g, yield about 57.4%, NMR data are as follows:
1HNMR(400M,CDCl3): δ ppm7.36 (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) ontology (1) is fixed on fixed device (4) by the foregoing reaction kettle for taking a clean dry, opens kettle It covers (11), the anhydrous methanol of 112ml is added in reaction kettle, nitrogen is passed through with 170ml/min, is rapidly added the step 2 of 5.6g B DEG C of acid anhydrides of the six water nickel chlorides and 20.15g of product and 4.5g, covers tightly kettle cover (11) at once, with being loaded with enough ice The ice water bath of mixture of ice and water be placed on cylinder (13) lower part, and start to stir with the revolving speed of 100 turns/min, after 5min, Charging plug (19) is opened, 3.55g sodium borohydride is slowly added to from charging aperture (18), removes ice water bath after adding, reacting Mixture is slowly increased to be stirred to react 2.3h while room temperature, is placed on cylinder (13) lower part with subzero cooling slot, with a small amount of ethyl alcohol+ The mixture of liquid nitrogen cools down reaction mixture 10 DEG C or so, 40ml water is slowly added to from charging aperture (18), with 190 turns/min Revolving speed stir 18min, reaction mixture is all removed from reaction kettle, with appropriate suction filtered through kieselguhr, with the DCM of 105ml The mother liquor DCM of 105ml is extracted 4 times, is washed 4 times with the salt of 85ml by washing, and drying is simultaneously spin-dried for, and obtains crude white solid, Sample, which is mixed, with 100~200 mesh silica gel, 1.5 times of quality crosses column, separately sampled under the conditions of PE:EA=2:1 and 25:1 to climb TLC plate, PE: It is gone out when EA=25:1 a little, when PE:EA=2:1 goes out lower point, obtains step 3 product ((4- ((((benzyloxy) carbonyl) ammonia Base) methyl) bicyclic [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；4.73g step 3 product, yield are about 64%, NMR Data are as follows:
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) ontology (1) is fixed on fixed device (4) by the foregoing reaction kettle for taking a clean dry, opens kettle It covers (11), step 3 product of 2.55g is dissolved in the pyridine of 3V and forms mixture, the hydrochloric acid two of step 3 product 5eq is added Six ring solution of oxygen, covers tightly kettle cover (11), to react 1.8h, then be added from charging aperture (18) under the revolving speed stirring of 240 turns/min The total 20ml of MTBE continues to stir 10min, stops stirring, reaction mixture is all removed, suction filtration obtains crude product, and crude product is molten In appropriate amount of deionized water, with the NaOH filtrate tune pH value of 1N to 9,10min is stood, is extracted 4 times with the DCM of 22ml, is spin-dried for, obtains To crude white solid, the n-hexane of 3V is taken to be beaten the crude white solid after weighing, filters, obtain final product ((4- (amino methyl) bicyclic [2.2.2] decyl- 1- yl) methyl) carbonic acid benzyl ester 1.88g, yield 87%.Its 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)+]。
NMR spectra such as Fig. 5 of final product ((bicyclic [2.2.2] the decyl- 1- yl of 4- (amino methyl)) methyl) carbonic acid benzyl ester It is shown.
A kind of application of medicine intermediate, with prepare obtained by any one aforementioned method ((4- (amino methyl) is double Ring [2.2.2] decyl- 1- yl) methyl) carbonic acid benzyl ester be used as medicine intermediate to prepare drug.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any The change or replacement expected without creative work, should be covered by the protection scope of the present invention.Therefore, of the invention Protection scope should be determined by the scope of protection defined in the claims.

Claims (5)

1. a kind of reaction kettle, the ontology (1) with glass material, the ontology have kettle cover (11), lower flange (12), cylinder (13), it is characterised in that:
The reaction kettle further includes air inlet combination (2), outlet combination (3), fixed device (4), mixing part (5)；
There are interstitial hole (14) at the center of kettle cover (11), interstitial hole (14) is that the circle that center is located at kettle cover (11) center is logical Hole, inner surface is in frosted shape, for being bonded with the peripheral surface of outer tube (53)；With the upper surface central point of kettle cover (11) Centered on, two sides are symmetrically equipped with the air inlet (15) and venthole (16) of the identical cylindrical type through-hole of specification；The interstitial hole (14) be additionally provided with the charging aperture (18) of a circular through hole on side kettle cover (11), the charging aperture (18) have frosted medial surface and Matched charging plug (19), piston part (191) and the tool that there is the charging plug (19) sectional area to be greater than charging aperture (18) There is the body portion (192) of frosted outer surface, there is the frosted appearance (17) of a circular ring type in the middle part of the barrel outer surface；
It includes air inlet pipe (21), air inlet hollow rubber plug (22) and air through hole (23), the air inlet pipe (21) that (2) are combined in air inlet It is a cylindrical type thin-walled hollow glass tube, the height of the air inlet pipe (21) is institute between 1-1.3 times of cylinder (13) height It states air inlet hollow rubber plug (22) to be made of two parts rubber ring wide at the top and narrow at the bottom, and the center of this air inlet hollow rubber plug (22) The air through hole (23) of a cylindrical type up and down has been dug out at place, internal diameter make air inlet pipe (21) be inserted and with into Gas hollow rubber plug (22) is combined closely；
It includes escape pipe (31), outlet hollow rubber plug (32) and exhaust through hole (33), the escape pipe (31) that outlet, which combines (3), It is a cylindrical type thin-walled hollow glass tube, the height of the escape pipe (31) is between 0.2-0.4 times of cylinder (13) height, The outlet hollow rubber plug (32) is made of two parts rubber ring wide at the top and narrow at the bottom, and in this outlet hollow rubber plug (32) Dug out the exhaust through hole (33) of a cylindrical type up and down at the heart, internal diameter make escape pipe (31) be inserted and with Outlet hollow rubber plug (32) is combined closely；
Fixed device (4) have left fixed plate (41), right fixed plate (42), the first from left flange (411), the second from left flange (412), the right side one Flange (421), right two flanges (422), front bolt combination (43), rear bolt combine (44), left fixed station (45), right fixed station (46), fixed bottom plate (47), rubber back boxing (48)；
Right side is intermediate on left fixed plate (41) has left semicircle notch (410), has right half among right fixed plate (42) upper left side Discount vibram outlet mouth (420), the rubber back boxing (48) are by semicircular left rubber back boxing (481) and right rubber back boxing (482) group Left semicircle notch (410) is adhesive in strength respectively at, left rubber back boxing (481) and right rubber back boxing (482) and right semi-circle is scarce In the notch of mouth (420), so that left semicircle notch (410) and right semi-circle notch (420) merge in the circumferential notch formed, rubber The frosted appearance (17) of glue back boxing (48) and ontology (1) is combined closely；
The first from left flange (411) is located at left fixed plate (41) leading edge rightmost side, after the second from left flange (412) is located at left fixed plate (41) The edge rightmost side, a right flange (421) are located at right fixed plate (42) leading edge leftmost side, and right two flanges (422) are located at right fixation Plate (42) back edge leftmost side, when left fixed plate (41) and the alignment split of right fixed plate (42) notch, the first from left flange (411) He Youyi flange (422) is aligned and through-hole thereon is also aligned, the front bolt for including with front bolt combination (43) and preceding spiral shell Mother, which screws in, to fix, and the second from left flange (412) and right two flanges (422) alignment and through-hole thereon are also aligned, with rear bolt group Close the rear bolt and back nut screw-in fixation that (44) include；The first from left flange (411) and the second from left flange (412) and left fixation Plate (41) be it is integrally formed, a right flange (421), right two flanges (422) and right fixed plate (42) are integrally formed；
The left fixed station (45) have rectangular-shape left fixed base (452) and left hoop (451), left hoop (451) is from side Face is seen in "Ji" type and thickness is between 2-5mm, and left fixed plate (41) covered from above leans on the first from left section and by a right with 2N The bolt of title is fixed on left fixed base (452), and the right fixed station (46) has the right fixed base of rectangular-shape (462) and right hoop (461), right hoop (461) is from the side in "Ji" type and thickness is between 2-5mm, a left side covered from above Fixed plate (41) is leaned on the first from left section and is fixed on left fixed base (452) with 2N symmetrical bolts；
Mixing part (5) includes top cover (51), inner sleeve (52), outer tube (53), stirring rod (54), blade (55), outer tube (53) have upper outer tube (531) and lower outer tube (532), top cover (51) is inverted u-shaped, and lower edge has the first internal screw thread, should Internal screw thread adapts to the first external screw thread of the external top side of outer tube (531), and revolves in the first internal screw thread and the first external screw thread Next, among the lower part of the top cover (51) compression inner sleeve (52) upper surface, within the upper outer tube (531) from top to bottom There are three the inner cavities of different inner diameters for tool, and top first inner chamber internal diameter is maximum, and intermediate second inner chamber internal diameter is significantly less than first inner chamber, So that the annular step of support inner sleeve (52) lower part is formed at first inner chamber lower part, third inner cavity internal diameter is close with first inner chamber Seemingly, and its side wall has the second internal screw thread, and inner sleeve (52) is that solid and its outer diameter is slightly less than above-mentioned first inner chamber, inner sleeve (52) it is filled with vaseline between external and the first cavity, lower outer tube (532) generally annulus cover shape, the centre has one Greater than the through-hole of stirring rod (54) outer diameter, there is a upward annulus protrusion in upside by outside, has on the outside of annulus protrusion and second Second external screw thread of internal screw thread adaptation, there are also higher second annulus is convex on the inside of annulus protrusion for lower outer tube (532) upside Portion, after the second internal screw thread and the second external screw thread screw completely, the top of the second annulus protrusion is from inner sleeve (52) lower surface Distance is within 1cm.
2. a kind of reaction kettle as described in claim 1, it is characterised in that:
Further include inside groove be hollow cylinder slot and be greater than the ice water bath of the cylinder (13) lower part, water-bath, electric heating cover, Subzero cooling slot；
The internal diameter of the charging aperture (18) is slightly larger than sample-adding dropper.
3. a kind of amino replaces the preparation method of New-type spiro compound, carried out using reaction kettle as claimed in claim 2, Preparation step is:
1) under nitrogen protection, a reaction kettle as claimed in claim 2 is taken, cleaning is dried, and ontology (1) is fixed on fixed device (4) On, it opens kettle cover (11), by 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclic [2.2.2] decane -1- first of 4.8-5.2g Acid is dissolved in the THF of 20V, and bicyclic [2.2.2] decane -1- formic acid of the 4- ((((benzyloxy) carbonyl) amino) methyl) is called in the following text instead Object A is answered, the NEt of the 3eq of reactant A is added3, kettle cover (11) are closed, apply the revolving speed of 100-150 turns/min to reaction mixture Stirring is passed through nitrogen with 100-180ml/min, opens charging plug (19), reactant A is slowly added dropwise from charging aperture (18) The isobutyl chlorocarbonate of 1.5eq after being added dropwise, covers charging plug (19), and promotion mixing speed to 650-750 turns/min, After 0.8-1.2h, stop stirring, minute quantity reaction mixture HPLC tracking reaction is taken repeatedly from charging aperture (18), until from adding Expect that hole (18) track reaction discovery raw material with HPLC and disappear, generates intermediate, be placed under cylinder (13) with subzero cooling slot at this time Reaction mixture is cooled to -10 DEG C or so with ethyl alcohol+liquid nitrogen mixture, starts blender, 50-100 turns/min's by portion Under revolving speed, charging plug (19) is opened from charging aperture (18) by enough NH3Saturation THF solution be added dropwise in system, drip Bi Hou is used instead and is loaded with the ice water bath of the mixture of ice and water of enough ice and is placed on cylinder (13) lower part, turn in 50-100/min 0 DEG C of reaction at least 0.8-1.2h is kept under revolving speed, if intermediate does not disappear, is continued 50-100 turns/min and is stirred to react 15min disappears until tracking reaction discovery intermediate from charging aperture (18) HPLC, fully reacting；Then kettle cover (11) are opened, The deionized water of 135-150ml is added in the reactive mixture, mixture is all removed, is extracted 3-5 times with 50-70mlEA, Again three times with the salt washing of 50-70ml, dry, it is spin-dried for organic phase, obtains step 1 product ((the 4- carbonamido pair of white solid Ring [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；
2) ontology (1) is fixed on fixed device (4) by the reaction kettle as claimed in claim 2 for taking a clean dry, is opened Step 1 product of 4.8-5.2g is dissolved in the pyridine of 15V and forms mixture, then mixture is placed in reaction kettle by kettle cover (11) In, kettle cover (11) are covered, 10min are stirred with the revolving speed of 600-750 turns/min, reduction of speed to 100-180 turns/min, with 100- 180ml/min is passed through nitrogen, cylinder (13) lower part is placed on the ice water bath for the mixture of ice and water for being loaded with enough ice, wait stablize After being cooled to 0 DEG C, P DEG C of step 1 product 5eq is slowly added dropwise from charging aperture (18)3, rear enclosed charging plug is added dropwise (19), 100-180 turns/min and 100-180ml/min is kept to be passed through under condition of nitrogen gas, 0℃1.5-2.5h is reacted, stirring is stopped, Minute quantity reaction mixture HPLC tracking reaction is taken repeatedly from charging aperture (18), is disappeared until tracking reaction discovery raw material with HPLC It loses；Then ice water bath is removed, 200ml mixture of ice and water made from pure water is added in reaction kettle, 100-180 turns/min is stirred 10-15min is mixed, is extracted 3-5 times with the DCM of 80ml, with 2N salt pickling 2-4 times of 50ml, with washing 2-4 times of 50ml, is used The salt of 50ml is washed 2-4 times, and drying is simultaneously spin-dried for, and obtains crude white solid, and crude product is soluble in water, with 1N NaOH filtrate tune PH=9 stands a period of time, is extracted 2-4 times with the DCM of 20ml, is spin-dried for, obtains crude white solid, is beaten with n-hexane 2V, It is dried after filtering, obtains step 2 product ((4- cyano-bicyclo [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；
3) ontology (1) is fixed on fixed device (4) by the reaction kettle as claimed in claim 2 for taking a clean dry, is opened The anhydrous methanol of 105-115ml is added in reaction kettle, is passed through nitrogen with 100-180ml/min, is rapidly added by kettle cover (11) B DEG C of acid anhydrides of step 2 product of 5.3-5.7g and the six water nickel chlorides of 4.2-4.6g and 20-20.2g, covers tightly kettle at once It covers (11), is placed on cylinder (13) lower part with the ice water bath for the mixture of ice and water for being loaded with enough ice, and/min is turned with 50-100 Revolving speed start to stir, after 4-6min, open charging plug (19), 3.4-3.6g boron hydrogen is slowly added to from charging aperture (18) Change sodium, removes ice water bath after adding, 1.5-2.5h is stirred to react while reaction mixture is slowly increased to room temperature, use is subzero Cooling slot is placed on cylinder (13) lower part, reaction mixture is cooled down 10 DEG C or so with the mixture of a small amount of ethyl alcohol+liquid nitrogen, from charging Hole is slowly added to 40ml water in (18), is turned with 150-200/revolving speed of min stirs 10-20min, by reaction mixture from reaction kettle It is middle all to remove, it with appropriate suction filtered through kieselguhr, is washed with the DCM of 90-110ml, the mother liquor DCM of 90-110ml is extracted into 2-4 It is secondary, it is washed 2-4 times with the salt of 70-90ml, drying is simultaneously spin-dried for, and crude white solid is obtained, with 100~200 mesh silica gel, 1.5 times of matter Amount mixes sample and crosses column, separately sampled under the conditions of PE:EA=2:1 and 25:1 to climb TLC plate, and when PE:EA=25:1 goes out a little, PE: Lower point is gone out when EA=2:1, obtains step 3 product ((4- ((((benzyloxy) carbonyl) amino) methyl) bicyclic [2.2.2] decane- 1- yl) methyl) carbonic acid benzyl ester；
4) ontology (1) is fixed on fixed device (4) by the reaction kettle as claimed in claim 2 for taking a clean dry, is opened Step 3 product of 2.4-2.6g is dissolved in the pyridine of 3V and forms mixture by kettle cover (11), and the salt of step 3 product 5eq is added Sour dioxane solution covers tightly kettle cover (11), 1-2h is reacted, then from charging aperture under the revolving speed stirring of 150-250 turns/min (18) the total 20ml of MTBE is added, continues to stir 10min, stops stirring, reaction mixture is all removed, suction filtration obtains crude product, Crude product is dissolved in appropriate amount of deionized water, with the NaOH filtrate tune pH value of 1N to 9,10min is stood, is extracted with the DCM of 18-22ml It 3 times, is spin-dried for, obtains crude white solid, the n-hexane of 3V is taken to be beaten the crude white solid after weighing, filter, obtain most Final product ((bicyclic [2.2.2] the decyl- 1- yl of 4- (amino methyl)) methyl) carbonic acid benzyl ester.
4. a kind of preparation method as claimed in claim 3, it is characterised in that:
1) under nitrogen protection, a reaction kettle as claimed in claim 2 is taken, cleaning is dried, and ontology (1) is fixed on fixed device (4) On, it opens kettle cover (11), 4- ((((benzyloxy) carbonyl) amino) methyl) bicyclic [2.2.2] decane -1- formic acid of 5g is dissolved in In the THF of 20V, bicyclic [2.2.2] decane -1- formic acid of the 4- ((((benzyloxy) carbonyl) amino) methyl) calls reactant A in the following text, The NEt of the 3eq of reactant A is added3, kettle cover (11) are closed, the revolving speed for applying 120-130 turns/min to reaction mixture stirs, It is passed through nitrogen with 140-160ml/min, charging plug (19) is opened, is slowly added dropwise the 1.5eq's of reactant A from charging aperture (18) Isobutyl chlorocarbonate after being added dropwise, covers charging and fills in (19), promotion mixing speed to 680-700 turns/min, after 1h, stops Stirring takes minute quantity reaction mixture HPLC tracking reaction from charging aperture (18), until using HPLC from charging aperture (18) repeatedly Tracking reaction discovery raw material disappears, and generates intermediate, cylinder (13) lower part is placed on subzero cooling slot at this time, with ethyl alcohol+liquid nitrogen Mixture reaction mixture is cooled to -10 DEG C or so, start blender, turn in 65-75/revolving speed of min under, open charging (19) are filled in from charging aperture (18) by enough NH3Saturation THF solution be added dropwise in system, after being added dropwise, use instead and be loaded with The ice water bath of the mixture of ice and water of enough ice is placed on cylinder (13) lower part, and 0 DEG C of reaction is kept under the revolving speed of 65-75 turns/min At least 1h continues 65-75 turns/min and is stirred to react 15min if intermediate does not disappear, until using HPLC from charging aperture (18) Tracking reaction discovery intermediate disappears, fully reacting；Then kettle cover (11) are opened, going for 145ml is added in the reactive mixture Mixture is all removed, is extracted 4 times with 60mlEA, then washed three times with the salt of 60ml by ionized water, dry, is spin-dried for organic phase, Obtain step 1 product ((bicyclic [2.2.2] decane -1- base of 4- carbonamido) methyl) carbonic acid benzyl ester of white solid；
2) ontology (1) is fixed on fixed device (4) by the reaction kettle as claimed in claim 2 for taking a clean dry, is opened Step 1 product of 5g is dissolved in the pyridine of 15V and forms mixture, then mixture is placed in reaction kettle by kettle cover (11), covers Kettle cover (11) stirs 10min with the revolving speed of 680-720 turns/min, and reduction of speed to 140-160 turns/min, logical with 140-160ml/min Enter nitrogen, be placed on cylinder (13) lower part with the ice water bath for the mixture of ice and water for being loaded with enough ice, is cooled to 0 DEG C to stabilization Afterwards, P DEG C of step 1 product 5eq is slowly added dropwise from charging aperture (18)3, rear enclosed charging plug (19) is added dropwise, keeps 140- 160 turns/min and 140-160ml/min are passed through under condition of nitrogen gas, and 0℃2h is reacted, stops stirring, is taken repeatedly from charging aperture (18) Minute quantity reaction mixture is tracked with HPLC to react, and disappears until tracking reaction discovery raw material with HPLC；Then ice-water bath is removed 200ml mixture of ice and water made from pure water is added in reaction kettle pot, and 140-160 turns/min stirring 12min, with 80ml's DCM is extracted 4 times, with the pickling of 2N salt 3 times of 50ml, with washing 3 times of 50ml, is washed 3 times with the salt of 50ml, and drying is simultaneously spin-dried for, Crude white solid is obtained, crude product is soluble in water, with 1N NaOH filtrate tune PH=9, a period of time is stood, with the DCM of 20ml Extraction 3 times, is spin-dried for, obtains crude white solid, is beaten after weighing with the n-hexane of 2V, dries after filtering, obtains step 2 Product ((4- cyano-bicyclo [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；
3) ontology (1) is fixed on fixed device (4) by the reaction kettle as claimed in claim 2 for taking a clean dry, is opened The anhydrous methanol of 110ml is added in reaction kettle, is passed through nitrogen with 160-180ml/min, is rapidly added 5.5g's by kettle cover (11) B DEG C of acid anhydrides of the six water nickel chlorides and 20.1g of step 2 product and 4.4g, covers tightly kettle cover (11) at once, with being loaded with foot The ice water bath of mixture of ice and water for measuring ice is placed on cylinder (13) lower part, and starts to stir with the revolving speed of 100 turns/min, 5min it Afterwards, charging plug (19) is opened, 3.5g sodium borohydride is slowly added to from charging aperture (18), removes ice water bath after adding, anti- Be stirred to react 2h while answering mixture to be slowly increased to room temperature, be placed on cylinder (13) lower part with subzero cooling slot, with a small amount of ethyl alcohol+ The mixture of liquid nitrogen cools down reaction mixture 10 DEG C or so, 40ml water is slowly added to from charging aperture (18), with 180 turns/min Revolving speed stir 15min, reaction mixture is all removed from reaction kettle, with appropriate suction filtered through kieselguhr, with the DCM of 100ml The mother liquor DCM of 100ml is extracted 3 times, is washed 3 times with the salt of 80ml by washing, and drying is simultaneously spin-dried for, and obtains crude white solid, Sample, which is mixed, with 100~200 mesh silica gel, 1.5 times of quality crosses column, separately sampled under the conditions of PE:EA=2:1 and 25:1 to climb TLC plate, PE: It is gone out when EA=25:1 a little, when PE:EA=2:1 goes out lower point, obtains step 3 product ((4- ((((benzyloxy) carbonyl) ammonia Base) methyl) bicyclic [2.2.2] decane -1- base) methyl) carbonic acid benzyl ester；
4) ontology (1) is fixed on fixed device (4) by the reaction kettle as claimed in claim 2 for taking a clean dry, is opened Step 3 product of 2.5g is dissolved in the pyridine of 3V and forms mixture by kettle cover (11), and the hydrochloric acid two of step 3 product 5eq is added Six ring solution of oxygen, covers tightly kettle cover (11), to react 1.5h, then be added from charging aperture (18) under the revolving speed stirring of 200 turns/min The total 20ml of MTBE continues to stir 10min, stops stirring, reaction mixture is all removed, suction filtration obtains crude product, and crude product is molten In appropriate amount of deionized water, it is spin-dried for 9, standing 10min with DCM extraction 3 times of 20ml with the NaOH filtrate tune pH value of 1N, Crude white solid is obtained, the n-hexane of 3V is taken to be beaten the crude white solid after weighing, filters, obtains final product ((4- (amino methyl) bicyclic [2.2.2] decyl- 1- yl) methyl) carbonic acid benzyl ester.
5. a kind of application of medicine intermediate, ((4- (the amino first prepared obtained by any one method of claim 3-4 Base) bicyclic [2.2.2] decyl- 1- yl) methyl) carbonic acid benzyl ester is used as medicine intermediate to prepare drug.
CN201910702799.1A 2019-07-31 2019-07-31 Preparation method of amino substituted compound Active CN110368887B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910702799.1A CN110368887B (en) 2019-07-31 2019-07-31 Preparation method of amino substituted compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910702799.1A CN110368887B (en) 2019-07-31 2019-07-31 Preparation method of amino substituted compound

Publications (2)

Publication Number Publication Date
CN110368887A true CN110368887A (en) 2019-10-25
CN110368887B CN110368887B (en) 2021-07-30

Family

ID=68257447

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910702799.1A Active CN110368887B (en) 2019-07-31 2019-07-31 Preparation method of amino substituted compound

Country Status (1)

Country Link
CN (1) CN110368887B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110270295A (en) * 2019-07-31 2019-09-24 北京六合宁远科技有限公司 Preparation method of amino-substituted phenylpropylpyridine nitrogen-containing heterocycle
CN114452912A (en) * 2022-02-16 2022-05-10 上海罕道医药科技有限公司 Preparation method of polysubstituted nitrogen-containing heterocyclic methylamine compound
CN114471412A (en) * 2022-02-16 2022-05-13 上海罕道医药科技有限公司 Preparation method of substituted pyridopyrrole compound

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090125392A (en) * 2008-06-02 2009-12-07 플러스이엔지 주식회사 Drum clamping structure of shaker
CN205667835U (en) * 2016-05-30 2016-11-02 黑龙江科技大学 A kind of visualization stirring-type gas hydration reaction experimental provision
CN106831575A (en) * 2017-02-13 2017-06-13 北京六合宁远科技有限公司 A kind of preparation method of the methyl alcohol of 1 aminoisoquinoline 6
CN208091115U (en) * 2018-01-26 2018-11-13 江苏天力干燥工程有限公司 A kind of bipyramid dry mixed machine
CN208865617U (en) * 2018-07-13 2019-05-17 上海经天新材料科技有限公司 Reaction kettle
CN208959905U (en) * 2018-10-12 2019-06-11 光山县博正树脂有限公司 A kind of glue double-layer glass reaction kettle

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090125392A (en) * 2008-06-02 2009-12-07 플러스이엔지 주식회사 Drum clamping structure of shaker
CN205667835U (en) * 2016-05-30 2016-11-02 黑龙江科技大学 A kind of visualization stirring-type gas hydration reaction experimental provision
CN106831575A (en) * 2017-02-13 2017-06-13 北京六合宁远科技有限公司 A kind of preparation method of the methyl alcohol of 1 aminoisoquinoline 6
CN208091115U (en) * 2018-01-26 2018-11-13 江苏天力干燥工程有限公司 A kind of bipyramid dry mixed machine
CN208865617U (en) * 2018-07-13 2019-05-17 上海经天新材料科技有限公司 Reaction kettle
CN208959905U (en) * 2018-10-12 2019-06-11 光山县博正树脂有限公司 A kind of glue double-layer glass reaction kettle

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110270295A (en) * 2019-07-31 2019-09-24 北京六合宁远科技有限公司 Preparation method of amino-substituted phenylpropylpyridine nitrogen-containing heterocycle
CN114452912A (en) * 2022-02-16 2022-05-10 上海罕道医药科技有限公司 Preparation method of polysubstituted nitrogen-containing heterocyclic methylamine compound
CN114471412A (en) * 2022-02-16 2022-05-13 上海罕道医药科技有限公司 Preparation method of substituted pyridopyrrole compound
CN114452912B (en) * 2022-02-16 2023-09-12 上海罕道医药科技有限公司 Preparation method of polysubstituted nitrogen-containing heterocyclic methylamine compound
CN114471412B (en) * 2022-02-16 2023-09-26 上海罕道医药科技有限公司 Preparation method of substituted pyridopyrrole compound

Also Published As

Publication number Publication date
CN110368887B (en) 2021-07-30

Similar Documents

Publication Publication Date Title
CN110368887A (en) Preparation method of novel amino-substituted spiro compound
CN110385096A (en) Preparation method of difluoromethoxy polysubstituted nitrogen-containing heterocyclic compound
Friščić et al. Exploring cocrystal–cocrystal reactivity via liquid-assisted grinding: the assembling of racemic and dismantling of enantiomeric cocrystals
CN105272982B (en) Li Gelieting novel crystal forms and preparation method thereof
CN106279340A (en) A kind of method synthesizing momestasone furoate or its monohydrate
CN104447782B (en) Bromo norcantharidin mono-acid benzyl ester and synthetic method thereof and application
CN106065006A (en) A kind of neutral endopeptidase inhibitor salt crystal formation and preparation method thereof
CN105503627B (en) A kind of new gossypol Shiff base derivative and preparation method and application
CN110302733A (en) Preparation method of double-halogen nitrogen-containing heterocyclic compound
CN106632574A (en) Compound as well as preparation method and application thereof
CN110404497A (en) Preparation method of polysubstituted bromofluorine substituted benzimidazole compound
CN108276260A (en) A kind of preparation method and products thereof of novel fluoro cyclopentenone
CN107629051A (en) A kind of method that rutaecarpin is synthesized using carbonylation three-step approach
CN105348186A (en) Deuterated bisarylurea compound and preparation method thereof, and application of compound in preparation of antitumor drug
CN103965231A (en) Amide borate for detecting bortezomib intermediate purity, preparation method and application thereof
CN110270295A (en) Preparation method of amino-substituted phenylpropylpyridine nitrogen-containing heterocycle
CN106866770B (en) Cholic acid derivative, preparation method and medical usage
Guha et al. Construction of helical nanofibers from self‐assembling pseudopeptide building blocks: modulating the handedness and breaking the helicity
Le Gac et al. Calix [6] arene tris-carboxylic acid derivatives: X-ray and NMR characterization of their remarkable host-guest properties toward ammonium ions
CN212813644U (en) A novel air pump for aquaculture
CN102846561A (en) Ozagrel sodium drug combination for injection
CN109824553A (en) 2-((tert-butoxycarbonyl) amino) ethyl-1- sulfonic acid and preparation method thereof
CN105641713B (en) A kind of preparation method of Allopurinol-cucurbit(7)uril inclusion compound
CN101104609B (en) Solanesyl polyamine derivative, preparation and application thereof
CN101058581B (en) Method of preparing eszopiclone intermediate 6-(5-chloro-2-pyridyl)-5,7-dioxy-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazine

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CP01 Change in the name or title of a patent holder
CP01 Change in the name or title of a patent holder

Address after: 101300 east area, building 10, Maohua workshop, 1 CAIDA 3rd Street, Nancai Town, Shunyi District, Beijing

Patentee after: Beijing Liuhe Ningyuan Pharmaceutical Technology Co.,Ltd.

Address before: 101300 east area, building 10, Maohua workshop, 1 CAIDA 3rd Street, Nancai Town, Shunyi District, Beijing

Patentee before: BELLEN CHEMISTRY Co.,Ltd.

CP02 Change in the address of a patent holder
CP02 Change in the address of a patent holder

Address after: 101300 Building 9, courtyard 10, Linhe street, Shunyi District, Beijing

Patentee after: Beijing Liuhe Ningyuan Pharmaceutical Technology Co.,Ltd.

Address before: 101300 east area, building 10, Maohua workshop, 1 CAIDA 3rd Street, Nancai Town, Shunyi District, Beijing

Patentee before: Beijing Liuhe Ningyuan Pharmaceutical Technology Co.,Ltd.