CN107311961A - A kind of reduction COMU synthesis technique - Google Patents
A kind of reduction COMU synthesis technique Download PDFInfo
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- CN107311961A CN107311961A CN201610266185.XA CN201610266185A CN107311961A CN 107311961 A CN107311961 A CN 107311961A CN 201610266185 A CN201610266185 A CN 201610266185A CN 107311961 A CN107311961 A CN 107311961A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
Abstract
The invention discloses a kind of reduction COMU synthesis technique.It is raw material with cyan-acetic ester and N, the formamide of N thebaines 4, is comprised the steps：(1) intermediate oximate is prepared using cyan-acetic ester；(2) N is applied, the formamide of N thebaines 4 prepares intermediate hexafluorophosphate；(3) the intermediate hexafluorophosphate that the intermediate oximate and step (2) that applying step (1) is obtained are obtained carries out the crude product that COMU is made in substitution reaction, then COMU crude product is carried out into the obtained sterling COMU of recrystallization.The beneficial effects of the invention are as follows technique is simple, strong operability, high income, the low advantage of cost, and also the product purity of synthesis is high.
Description
Technical field
The present invention relates to medicine and synthesis technology field, and in particular to the condensation examination of third generation polypeptide
Agent COMU synthesis technique.
Background technology
Reduction is mainly used in the synthesis of polypeptide drug molecule, in solid phase and liquid phase
It is widely used, relative to traditional first generation condensation reagent (carbodiimide class) using DCC as representative
And the second generation condensation reagent (salt) by representative of HATU, COMU have more preferable dissolubility,
It is stability, reactivity, low dangerous and to the hypoallergenic of human body；While by-product of its generation
Thing is soluble in water, can preferably remove, thus the synthesis of COMU polypeptide drug molecules, especially
Its advantage in synthesis in solid state is more obvious.
The existing pertinent literature report of COMU synthesis, but the operating process relatively low, the rear place that there is yield
Reason is complicated, and the reaction time is longer, is not suitable for large-scale industrial production.
The content of the invention
It is an object of the invention to provide a kind of reduction COMU synthesis technique, the technique
With technique is simple, strong operability, high income, the low advantage of cost, and also the product of synthesis is pure
Degree is high.
For achieving the above object, the technical solution adopted in the present invention is：
A kind of reduction COMU synthesis technique, it is with cyan-acetic ester and N, N- bis-
Methyl morpholine -4- formamides are raw material, are comprised the steps：
(1) intermediate oximate is prepared using cyan-acetic ester；
(2) N is applied, N- thebaine -4- formamides prepare intermediate hexafluorophosphate；
(3) intermediate that the intermediate oximate and step (2) that applying step (1) is obtained are obtained
Hexafluorophosphate carries out substitution reaction and COMU crude product is made, then COMU crude product is recrystallized
Sterling COMU is made.
Further, the method for intermediate oximate being prepared in the step (1) is：
A, cyan-acetic ester, nitrosification agent and water are added in reaction vessel, then stirred
Lower heating is mixed, when temperature rises to 30~40 DEG C, it is 2~4 to start that acid regulation pH value is added dropwise, and is added dropwise
After the completion of temperature is continually maintained in stir 25~35min at 30~40 DEG C；Then heating is stopped,
Continue to stir 1.8~2.5h, and reacting liquid temperature is cool below less than 15 DEG C, treat that temperature is low
Separate out and filtered after the completion of a large amount of solids, reaction when less than 15 DEG C, then by filter cake water and
Petroleum ether is washed successively；Obtained solid is finally obtained into oxime in 45 DEG C~50 DEG C drying；
B, by the oxime obtained in step a add reaction vessel in, while add solvent dissolving, temperature control
At -5 DEG C~5 DEG C, KOH ethanol solution or K is then added dropwise again2CO3Ethanol solution, be added drop-wise to
When separating out a large amount of solids, ethanol is added into system, continues temperature control and is added dropwise at -5 DEG C~5 DEG C,
0.8~1.2h is dripped off, and continues to react 25~35min after dripping off；Then toward stone is added dropwise in reaction vessel
Oily ether, continues temperature control and 1.5~2.5h is stirred at -5 DEG C~5 DEG C, finally filter, decompression drying is obtained
To intermediate oximate.
Further, in the b step KOH ethanol solution or K2CO3Ethanol solution in
KOH or K2CO3Quality be 0.5 times of cyan-acetic ester quality；The addition of solvent presses oxime
1g/2.5ml is added；The ethanol added is added by oxime 1g/1.25mL；The dripping quantity of petroleum ether presses oxime
1g/6.3mL is added.
Further, the method for intermediate hexafluorophosphate being prepared in the step (2) is：
C, by N, N- thebaine -4- formamides are added in reaction vessel, are then added and are acylated
Reagent, is heated to after 70~80 DEG C reacting 3~6h, then depressurizes reaction solution at 40~50 DEG C dense
After contracting is dry, anhydrous methylene chloride is continuously added, is concentrated under reduced pressure again at 40~50 DEG C, added again
Enter anhydrous methylene chloride, be concentrated under reduced pressure at 40~50 DEG C, obtain ammonium salt；
D, the obtained ammonium salts of step c are dissolved in solvent, add hexafluorophosphoric acid in batches at room temperature
Potassium, is warming up to 28~32 DEG C after adding, continue to react 1.8~2.5h, then by reacting liquid filtering,
Filter cake be washed once with dioxane, and residue adds acetonitrile dissolving after concentration is dry, and temperature control is no more than
20 DEG C are slowly added dropwise after isopropyl ether, completion of dropping 3.5~4.5h of crystallization in the case where temperature is 15-20 DEG C,
Filtering, filter cake is eluted once with isopropyl ether, and decompression drying obtains intermediate hexafluorophosphate.
Further, the addition of acylating reagent presses N, N- thebaines -4- in the step c
Formamide 1g/3~3.5mL is added；The addition of the anhydrous methylene chloride presses N, N- dimethyl
Quinoline -4- formamides 1g/1.5mL is added；
The addition of solvent presses N, N- thebaine -4- formamides 1g/7.5ml in the Step d
Add, the addition of the Potassium Hexafluorophosphate is N, N- thebaine -4- formamide quality
1.165 times, the addition of the dioxane presses N, N- thebaine -4- formamides 1g/1mL
Add；The addition of acetonitrile presses N, and N- thebaine -4- formamides 1g/2mL is added；Isopropyl ether
Dripping quantity press N, N- thebaine -4- formamides 1g/4mL add.
Further, the preparation method of the sterling COMU is：
The intermediate oximate obtained in step (1) is added in reaction vessel, while acetonitrile is added,
Then -5~5 DEG C are cooled to, the intermediate six obtained in step (2) is added portionwise after stirring
Fluorophosphate carries out substitution reaction；The intermediate hexafluorophosphate of addition and the quality of intermediate oximate
Than for 1.5~2：1, continue to react 25~35min after intermediate hexafluorophosphate is added, so
After be warming up to after 40~45 DEG C continue react 3~5h, be subsequently cooled to room temperature, filter, filter cake use
Acetonitrile washed once, and filtrate decompression is concentrated into 0.2~0.3 times of original volume, is slowly added to isopropyl
Ether, is -5~40 ° of lower 5.5~6.5h of crystallization in temperature, filters, filter cake is used is cooled to 0~5 DEG C in advance
The mixed solvent of acetonitrile and isopropyl ether washed once, and decompression drying obtains sterling COMU.
Further, the addition of acetonitrile presses intermediate oximate 1g/13~15ml in the step e
Add；The filter cake washs used acetonitrile with acetonitrile and washed by intermediate oximate 1g/1ml；
The addition of the isopropyl ether is added by intermediate oximate 1g/7ml；The acetonitrile and isopropyl ether
The volume ratio of in the mixed solvent acetonitrile and isopropyl ether is 1:2, the addition of mixed solvent presses intermediate
Oximate 1g/1.25ml is added.
Further, the acid in the step a is in phosphoric acid, hydrochloric acid, sulfuric acid, acetic acid and nitric acid
Any one；Solvent in the step b is methanol, ethanol, in isopropanol and dichloromethane
Any one；Acylating reagent in the step c is in oxalyl chloride, phosgene and thionyl chloride
Any one；Solvent in the step d is dichloromethane, dioxane, tetrahydrofuran,
Any one in acetonitrile and water or two kinds.
Further, the acid in the step a is sulfuric acid；Solvent in the step b is ethanol；
Acylating reagent in the step c is thionyl chloride；Solvent in the step d is dioxane.
The building-up process of above-mentioned compound is：
The invention has the advantages that：
(1) synthetic intermediate oximate in the prior art, general yield only has 35%, and there is hydrolysis
Product is more, not easy purification, post-processes more difficult, the problems such as being difficult amplification；And present invention synthesis
In processing step (1), by changing the mode of operations, preferred acid, solvent and regulation and control reaction temperature,
The yield of intermediate oximate can reach 90%, and the reaction time is short, and accessory substance does not almost have, after
Processing is simple, is adapted to industrialized production；
(2) in synthesis technique step (2) of the present invention, acylating reagent and reaction dissolvent are changed,
Compared with prior art, cost of material is reduced, the reaction time has been saved, tediously long post processing is eliminated
Operation, reduces production cost, improves production efficiency；
(3) in synthesis technique step (3) of the present invention, change reaction temperature, make the reaction time by
7h of the prior art shorten to 3h, and crude product quality is identified and unaffected through nuclear-magnetism；Crude product is entered
Different recrystallisation solvents and solvent burden ratio, and crystallization temperature (such as second have been screened when row purification
Nitrile/isopropyl ether, acetonitrile/ether, acetonitrile/petroleum ether, dioxane/isopropyl ether, dioxane/first
Base tertbutyl ether, dichloromethane etc., solvent burden ratio between 1/1~1/4, crystallization temperature is -5~
40 DEG C) the sterling quality that finally gives is good, high income.
Embodiment
Embodiment one
A kind of reduction COMU synthesis technique, it is with cyan-acetic ester and N, N-
Thebaine -4- formamides are raw material, are comprised the steps：
(1) preparation of 2- oximes ethyl cyanoacetate sylvite
A, ethyl cyanoacetate (30g), water (90mL) and natrium nitrosum (19.2g) be added to
In 250mL there-necked flasks, after stirring, 62.5% aqueous sulfuric acid (22.9g) is added dropwise in 35 DEG C of temperature control,
Regulation pH value is to continue temperature control stirring reaction 30min at 35 DEG C after 3,30min is dripped off.TLC
Monitoring reaction is complete, then stops heating, continues to stir 2h, while it is low that reaction solution is cooled into temperature
In less than 15 DEG C, when the temperature of reaction solution are less than less than 15 DEG C, a large amount of solids are separated out, are filtered,
Filter cake water (washing twice, use water 10mL every time) and petroleum ether (wash twice, stone are used every time
Oily ether 15mL) wash successively, obtained solid obtains light yellow solid, i.e. oxime in 50 DEG C of drying
(36.8g, yield 98%).
B, the oxime obtained in step a is dissolved in ethanol (75mL), temperature control is no more than 5 DEG C, and KOH is added dropwise
Ethanol solution, when being added drop-wise to a large amount of solids of precipitation, add 38mL ethanol into system, continue control
Temperature is no more than at 5 DEG C and is added dropwise, and 1h is dripped off, and continues to react 30min after dripping off, then toward reaction bulb
Middle dropwise addition petroleum ether (190mL), continues temperature control and 2h is stirred at no more than 5 DEG C, filter, at 35 DEG C
Lower decompression drying obtains yellow solid, i.e. 2- oximes ethyl cyanoacetate sylvite (43g, yield 90%).
(2) preparation of 2- chloros dimethylamino-morpholine-carbon hexafluorophosphate
C, by N, N- thebaine -4- formamides (40g) are added in reaction vessel, are then added
Thionyl chloride (120mL), is heated to after 70 DEG C reacting 5h, detection reaction is complete, then at 45 DEG C
Reaction solution is concentrated under reduced pressure after doing, adds anhydrous methylene chloride (65mL), subtract again at 45 DEG C
Pressure concentration, adds anhydrous methylene chloride (65mL), is concentrated under reduced pressure at 45 DEG C again, consolidate
Body, i.e. ammonium salt；
D, the solid ammonium salt for obtaining step c are directly dissolved with dioxane (300mL), room temperature
Under Potassium Hexafluorophosphate (46.6g) is added portionwise, be warming up to 30 DEG C after adding, continue to react 2h, so
Afterwards by reacting liquid filtering, filter cake washed once with dioxane (40mL), and residue adds after concentration is dry
Enter the dissolving of 80mL acetonitriles, then isopropyl ether (160mL) is slowly added dropwise no more than 20 DEG C in temperature control,
It in temperature is crystallization 4.5h at 15-20 DEG C, filtering, filter cake isopropyl to be in temperature after completion of dropping
Ether (20mL) is eluted once, and finally decompression drying obtains white solid, i.e. 2- chlorine at 40 DEG C
For dimethylamino-morpholine-carbon hexafluorophosphate (73g, yield 89.8%).
(3) (1- cyano group -2- ethyoxyl -2- oxo ethyleneiminos epoxide) dimethylamino-morpholine
The preparation of-carbon hexafluorophosphate
E, the 2- oxime ethyl cyanoacetate sylvite (40g) obtained in step (1) is dissolved in acetonitrile (560mL)
In, -5~5 DEG C are cooled to, the 2- chloros two obtained in step (2) are added portionwise after stirring
Methylamino-morpholine-carbon hexafluorophosphate (71.6g) carries out substitution reaction, continues anti-after adding
30min is answered, 40 DEG C is then heated to and continues to react 3h, detection reaction is complete.It is cooled to room temperature, mistake
Filter, filter cake washed once with acetonitrile (40mL), and filtrate decompression is concentrated into 140mL or so, slowly
Isopropyl ether (280mL) is added, room temperature crystallization 6h, filtering obtains filter cake, by filter cake with being cooled in advance
0~5 DEG C of acetonitrile and the mixed solvent (50mL) of isopropyl ether washed once, the acetonitrile and isopropyl
The in the mixed solvent acetonitrile of ether and the volume ratio of isopropyl ether are 1:2, the last decompression drying at 30 DEG C
Obtain white solid, i.e. sterling COMU (84g, yield 88.4%).
Embodiment two
A kind of reduction COMU synthesis technique, it is with cyan-acetic ester and N, N-
Thebaine -4- formamides are raw material, are comprised the steps：
(1) preparation of 2- oximes ethyl cyanoacetate sylvite
A, ethyl cyanoacetate (1Kg), water (3L) and natrium nitrosum (640g) be added to 10L
In there-necked flask, after stirring, 62.5% aqueous sulfuric acid (764g) is added dropwise in 30 DEG C of temperature control, adjusts
Section pH value is to continue temperature control stirring reaction 35min at 30 DEG C after 4,1h is dripped off.TLC monitorings are anti-
Should be complete, then stop heating, continue to stir 2h, while the temperature of reaction solution is cooled into temperature
Less than less than 15 DEG C, when the temperature of reaction solution is less than less than 15 DEG C, a large amount of solids, mistake are separated out
Filter, filter cake water (washing twice, use water 300mL every time) and petroleum ether (are washed twice, every time
With petroleum ether 500mL) wash successively, obtained solid obtains light yellow solid in 45 DEG C of drying,
That is oxime (1226.6g, yield 98%).
B, the oxime obtained in step a is dissolved in ethanol (2.5L), temperature control is no more than 5 DEG C, and KOH is added dropwise
Ethanol solution (500g KOH are dissolved in 2.5L ethanol), be added drop-wise to precipitation a large amount of solids when, it is past
1.27L ethanol is added in system, continues temperature control and is no more than dropwise addition at 5 DEG C, 2h is dripped off, after dripping off
Continue to react after 1h, petroleum ether (6.27L) is added dropwise into reaction bulb, continue temperature control no more than 5 DEG C
Lower stirring 2h, filtering, decompression drying obtains yellow solid, i.e. 2- oximes ethyl cyanoacetate at 40 DEG C
Sylvite (1.43Kg, yield 90%).
(2) preparation of 2- chloros dimethylamino-morpholine-carbon hexafluorophosphate
C, by N, N- thebaine -4- formamides (1Kg) are added in reaction vessel, are then added
Thionyl chloride (3L), is heated to after 75 DEG C reacting 3h, detection reaction is complete, then will at 50 DEG C
Reaction solution be concentrated under reduced pressure it is dry after, add anhydrous methylene chloride (1.5L), depressurized again at 50 DEG C
Concentration, adds anhydrous methylene chloride (1.5L), is concentrated under reduced pressure at 50 DEG C, obtains solid again,
That is ammonium salt；
D, the solid ammonium salt for obtaining step c are directly dissolved with dioxane (7.5L), room temperature
Under Potassium Hexafluorophosphate (1165g) is added portionwise, be warming up to after adding 32 DEG C continue react 2.5h,
Then by reacting liquid filtering, filter cake washed once with dioxane (1L), and residue adds after concentration is dry
Enter the dissolving of 2L acetonitriles, then isopropyl ether (4L) is slowly added dropwise no more than 20 DEG C in temperature control, drips
It in temperature is crystallization 4h at 15-20 DEG C to be in temperature after finishing, filtering, and filter cake is with isopropyl ether (0.5L)
Once, finally decompression drying obtains white solid, i.e. 2- chloros dimethylamino at 35 DEG C for elution
Base-morpholine-carbon hexafluorophosphate (1.83Kg, yield 89.8%).
(3) (1- cyano group -2- ethyoxyl -2- oxo ethyleneiminos epoxide) dimethylamino-morpholine
The preparation of-carbon hexafluorophosphate
E, the 2- oxime ethyl cyanoacetate sylvite (1kg) obtained in step (1) is dissolved in acetonitrile (14L)
In, -5~5 DEG C are cooled to, the 2- chloros two obtained in step (2) are added portionwise after stirring
Methylamino-morpholine-carbon hexafluorophosphate (1.79Kg) carries out substitution reaction, continues after adding
35min is reacted, 40 DEG C is then heated to and continues to react 5h, detection reaction is complete.It is cooled to room temperature,
Filtering, filter cake washed once with acetonitrile (1L), and filtrate decompression is concentrated into 3.5L or so, slow to add
Enter isopropyl ether (7L), room temperature crystallization 5.5h, filtering, filter cake with the acetonitrile for being cooled to 0~5 DEG C in advance and
The mixed solvent (1.25L) of isopropyl ether washed once, the mixed solvent of the acetonitrile and isopropyl ether
The volume ratio of middle acetonitrile and isopropyl ether is 1:2, it washed once, finally decompression drying is obtained at 40 DEG C
To white solid, i.e. sterling COMU (2.1Kg, yield 90%).
Embodiment 3
A kind of reduction COMU synthesis technique, it is with cyan-acetic ester and N, N-
Thebaine -4- formamides are raw material, are comprised the steps：
(1) preparation of 2- oximes ethyl cyanoacetate sylvite
A, by ethyl cyanoacetate (1000kg), water (3000L) and natrium nitrosum (640kg) plus
Enter into reaction vessel, after stirring, 62.5% aqueous acetic acid is added dropwise in 40 DEG C of temperature control
(22.9kg), regulation pH value is 3.5, continues temperature control stirring reaction 25min at 40 DEG C after dripping off.
TLC monitoring reactions are complete, then stop heating, continue to stir 2h, while reaction solution is cooled into temperature
Degree is less than less than 15 DEG C, when the temperature of reaction solution is less than less than 15 DEG C, separates out a large amount of solids,
Filtering, filter cake water (washing twice, use water 300L every time) and petroleum ether (are washed twice, every time
With petroleum ether 500L) wash successively, obtained solid obtains light yellow solid in 50 DEG C of drying,
That is oxime (1226.6kg, yield 98%)；
B, the oxime obtained in step a is dissolved in ethanol (92L), temperature control is no more than 5 DEG C, and KOH is added dropwise
Ethanol solution (500g KOH are dissolved in 2.5L ethanol), be added drop-wise to precipitation a large amount of solids when, it is past
46L ethanol is added in system, continues temperature control and is no more than dropwise addition at 5 DEG C, continue to react after dripping off
25min, then toward dropwise addition petroleum ether (231.84mL) in reaction bulb, continues temperature control no more than 5 DEG C
Lower stirring 1.5h, filtering, decompression drying obtains yellow solid, i.e. 2- oximes cyanoacetic acid second at 40 DEG C
Ester sylvite (1430Kg, yield 90%).
(2) preparation of 2- chloros dimethylamino-morpholine-carbon hexafluorophosphate
C, by N, N- thebaine -4- formamides (1000Kg) are added in reaction vessel, then
Oxalyl chloride (3500L) is added, is heated to after 70 DEG C reacting 3h, detection reaction is complete, then at 45 DEG C
It is lower by reaction solution be concentrated under reduced pressure it is dry after, anhydrous methylene chloride (1500L) is added, again at 40 DEG C
It is concentrated under reduced pressure, anhydrous methylene chloride (1500L) is added again, is concentrated under reduced pressure, obtains at 40 DEG C
Solid, i.e. ammonium salt；
D, the solid ammonium salt for obtaining step c are directly dissolved with acetonitrile (7500L), are divided at room temperature
Criticize and add Potassium Hexafluorophosphate (1165kg), 28 DEG C are warming up to after adding and continues to react 1.8h, then
By reacting liquid filtering, filter cake be washed once with acetonitrile (1000L), and residue is added after concentration is dry
2000L acetonitriles dissolve, and then isopropyl ether (4000L), completion of dropping are added dropwise no more than 20 DEG C for temperature control
It in temperature is crystallization 4h at 15-20 DEG C to be in temperature afterwards, filtering, and filter cake is with isopropyl ether (500L)
Once, finally decompression drying obtains white solid, i.e. 2- chloros dimethylamino at 35 DEG C for elution
Base-morpholine-carbon hexafluorophosphate (1830Kg, yield 89.8%).
(3) (1- cyano group -2- ethyoxyl -2- oxo ethyleneiminos epoxide) dimethylamino-morpholine
The preparation of-carbon hexafluorophosphate
E, the 2- oxime ethyl cyanoacetate sylvite (1000kg) obtained in step (1) is dissolved in acetonitrile
In (13000L), -5~5 DEG C are cooled to, is added portionwise in step (2) and obtains after stirring
2- chloros dimethylamino-morpholine-carbon hexafluorophosphate (1830Kg) carry out substitution reaction,
Continue to react 25min after adding, then heat to 45 DEG C and continue to react 4h, detection reaction is complete.It is cold
But to room temperature, filtering, filter cake washed once with acetonitrile (1000L), and filtrate decompression is concentrated into 3500L
Left and right, is slowly added to isopropyl ether (7000L), room temperature crystallization 6.5h, filtering, and filter cake with being cooled in advance
0~5 DEG C of acetonitrile and the mixed solvent (1250L) of isopropyl ether washed once, the acetonitrile and different
The in the mixed solvent acetonitrile of propyl ether and the volume ratio of isopropyl ether are 1:2, finally depressurize and dry at 40 DEG C
It is dry to obtain white solid, i.e. sterling COMU (2100Kg, yield 90%).
Claims (9)
1. a kind of reduction COMU synthesis technique, it is characterised in that：It is with cyano group second
Acetoacetic ester and N, N- thebaine -4- formamides are raw material, are comprised the steps：
(1) intermediate oximate is prepared using cyan-acetic ester；
(2) N is applied, N- thebaine -4- formamides prepare intermediate hexafluorophosphate；
(3) intermediate that the intermediate oximate and step (2) that applying step (1) is obtained are obtained
Hexafluorophosphate carries out substitution reaction and COMU crude product is made, then COMU crude product is recrystallized
Sterling COMU is made.
2. a kind of reduction COMU according to claim 1 synthesis technique, it is special
Levy and be：The method that intermediate oximate is prepared in the step (1) is：
A, cyan-acetic ester, nitrosification agent and water are added in reaction vessel, then stirred
Lower heating is mixed, when temperature rises to 30~40 DEG C, it is 2~4 to start that acid regulation pH value is added dropwise, and is added dropwise
After the completion of temperature is continually maintained in stir 25~35min at 30~40 DEG C；Then heating is stopped,
Continue to stir 1.8~2.5h, and reacting liquid temperature is cool below less than 15 DEG C, treat that temperature is low
Separate out and filtered after the completion of a large amount of solids, reaction when less than 15 DEG C, then by filter cake water and
Petroleum ether is washed successively；Obtained solid is finally obtained into oxime in 45 DEG C~50 DEG C drying；
B, by the oxime obtained in step a add reaction vessel in, while add solvent dissolving, temperature control
At -5 DEG C~5 DEG C, KOH ethanol solution or K is then added dropwise again2CO3Ethanol solution, be added drop-wise to
When separating out a large amount of solids, ethanol is added into system, continues temperature control and is added dropwise at -5 DEG C~5 DEG C,
0.8~1.2h is dripped off, and continues to react 25~35min after dripping off；Then toward stone is added dropwise in reaction vessel
Oily ether, continues temperature control and 1.5~2.5h is stirred at -5 DEG C~5 DEG C, finally filter, decompression drying is obtained
To intermediate oximate.
3. a kind of reduction COMU according to claim 1 or 2 synthesis technique,
It is characterized in that：The method that intermediate hexafluorophosphate is prepared in the step (2) is：
C, by N, N- thebaine -4- formamides are added in reaction vessel, are then added and are acylated
Reagent, is heated to after 70~80 DEG C reacting 3~6h, then depressurizes reaction solution at 40~50 DEG C dense
After contracting is dry, anhydrous methylene chloride is continuously added, is concentrated under reduced pressure again at 40~50 DEG C, added again
Enter anhydrous methylene chloride, be concentrated under reduced pressure at 40~50 DEG C, obtain ammonium salt；
D, the obtained ammonium salts of step c are dissolved in solvent, add hexafluorophosphoric acid in batches at room temperature
Potassium, is warming up to 28~32 DEG C after adding, continue to react 1.8~2.5h, then by reacting liquid filtering,
Filter cake be washed once with dioxane, and residue adds acetonitrile dissolving after concentration is dry, and temperature control is no more than
20 DEG C are slowly added dropwise after isopropyl ether, completion of dropping 3.5~4.5h of crystallization in the case where temperature is 15-20 DEG C,
Filtering, filter cake is eluted once with isopropyl ether, and decompression drying obtains intermediate hexafluorophosphate.
4. a kind of reduction COMU according to claim 3 synthesis technique, it is special
Levy and be：The preparation method of the sterling COMU is：
E, by the intermediate oximate obtained in step (1) add reaction vessel in, while add second
Nitrile, is then cooled to -5~5 DEG C, and the centre obtained in step (2) is added portionwise after stirring
Body hexafluorophosphate carries out substitution reaction；The intermediate hexafluorophosphate of addition and intermediate oximate
Mass ratio is 1.5~2：1, continue to react 25~35min after intermediate hexafluorophosphate is added,
Then heat to after 40~45 DEG C and continue to react 3~5h, be subsequently cooled to room temperature, filter, filter cake
It washed once with acetonitrile, filtrate decompression is concentrated into 0.2~0.3 times of original volume, is slowly added to different
Propyl ether, is -5~40 ° of lower 5.5~6.5h of crystallization in temperature, filtering, and filter cake with being cooled to 0~5 DEG C in advance
Acetonitrile and the mixed solvent of isopropyl ether washed once, decompression drying obtains sterling COMU.
5. a kind of reduction COMU according to claim 4 synthesis technique, it is special
Levy and be：KOH ethanol solution or K in the b step2CO3Ethanol solution in KOH or
K2CO3Quality be 0.5 times of cyan-acetic ester quality；The addition of solvent presses oxime
1g/2.5ml is added；The ethanol added is added by oxime 1g/1.25mL；The dripping quantity of petroleum ether presses oxime
1g/6.3mL is added.
6. a kind of reduction COMU according to claim 5 synthesis technique, it is special
Levy and be：The addition of acylating reagent presses N, N- thebaine -4- formamides in the step c
1g/3~3.5mL is added；The addition of the anhydrous methylene chloride presses N, N- thebaines -4-
Formamide 1g/1.5mL is added；
The addition of solvent presses N, N- thebaine -4- formamides 1g/7.5ml in the Step d
Add, the addition of the Potassium Hexafluorophosphate is N, N- thebaine -4- formamide quality
1.165 times, the addition of the dioxane presses N, N- thebaine -4- formamides 1g/1mL
Add；The addition of acetonitrile presses N, and N- thebaine -4- formamides 1g/2mL is added；Isopropyl ether
Dripping quantity press N, N- thebaine -4- formamides 1g/4mL add.
7. a kind of reduction COMU according to claim 6 synthesis technique, its
It is characterised by：The addition of acetonitrile is added by intermediate oximate 1g/13~15ml in the step e；
The filter cake washs used acetonitrile with acetonitrile and washed by intermediate oximate 1g/1ml；It is described different
The addition of propyl ether is added by intermediate oximate 1g/7ml；The mixing of the acetonitrile and isopropyl ether is molten
The volume ratio of acetonitrile and isopropyl ether is 1 in agent:2, the addition of mixed solvent presses intermediate oximate
1g/1.25ml is added.
8. a kind of reduction COMU according to claim 7 synthesis technique, its
It is characterised by：Acid in the step a is times in phosphoric acid, hydrochloric acid, sulfuric acid, acetic acid and nitric acid
Meaning is a kind of；Solvent in the step b is methanol, ethanol, appointing in isopropanol and dichloromethane
Meaning is a kind of；Acylating reagent in the step c is times in oxalyl chloride, phosgene and thionyl chloride
Meaning is a kind of；Solvent in the step d is dichloromethane, dioxane, tetrahydrofuran, acetonitrile
With any one in water or two kinds.
9. a kind of reduction COMU according to claim 5 synthesis technique, its
It is characterised by：Acid in the step a is sulfuric acid；Solvent in the step b is ethanol；Institute
It is thionyl chloride to state the acylating reagent in step c；Solvent in the step d is dioxane.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110563869A (en) * | 2019-09-05 | 2019-12-13 | 苏州昊帆生物股份有限公司 | Resin type polypeptide condensation reagent and preparation method and application thereof |
| CN115073322A (en) * | 2022-07-26 | 2022-09-20 | 苏州昊帆生物股份有限公司 | Preparation method of 2-oxime ethyl cyanoacetate potassium salt |
| CN115073322B (en) * | 2022-07-26 | 2024-04-26 | 苏州昊帆生物股份有限公司 | Preparation method of 2-oxime ethyl cyanoacetate potassium salt |
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| WO2009138985A2 (en) * | 2008-05-15 | 2009-11-19 | Luxembourg Bio Technologies Ltd. | Coupling agents for the synthesis of polypeptides and polynucleotides |
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|---|---|---|---|---|
| CN101784522A (en) * | 2007-05-16 | 2010-07-21 | 卢森堡生物科技有限公司 | proton acceptor iminium/carbocation-type coupling agents |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110563869A (en) * | 2019-09-05 | 2019-12-13 | 苏州昊帆生物股份有限公司 | Resin type polypeptide condensation reagent and preparation method and application thereof |
| CN110563869B (en) * | 2019-09-05 | 2021-05-11 | 苏州昊帆生物股份有限公司 | Resin type polypeptide condensation reagent and preparation method and application thereof |
| CN115073322A (en) * | 2022-07-26 | 2022-09-20 | 苏州昊帆生物股份有限公司 | Preparation method of 2-oxime ethyl cyanoacetate potassium salt |
| CN115073322B (en) * | 2022-07-26 | 2024-04-26 | 苏州昊帆生物股份有限公司 | Preparation method of 2-oxime ethyl cyanoacetate potassium salt |
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