CN109824755A - N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters production method - Google Patents
N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters production method Download PDFInfo
- Publication number
- CN109824755A CN109824755A CN201910280094.5A CN201910280094A CN109824755A CN 109824755 A CN109824755 A CN 109824755A CN 201910280094 A CN201910280094 A CN 201910280094A CN 109824755 A CN109824755 A CN 109824755A
- Authority
- CN
- China
- Prior art keywords
- microreactor
- tertbutyloxycarbonyl
- phenylalanine methyl
- leucyl
- leu
- 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.)
- Pending
Links
Abstract
The present invention relates to N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters (N-Boc-L-Leu-L-Phe-OMe) production methods, this method includes making 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphate (HATU) solution and N- tertbutyloxycarbonyl-L-Leu (N-Boc-L-Leu) solution synchronize be continuously pumped into online production Acibenzolar in the first microreactor, then the Acibenzolar of online production and L-phenylalanine methyl ester hydrochloride (L-Phe-OMe HCl) solution synchronize be continuously pumped into the second microreactor and carry out peptide formation.The present invention is for producing N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters, and completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield is greater than 99.5% to the conversion of raw material L-phenylalanine methyl ester hydrochloride under optimal conditions.The present invention has many advantages, such as that the reaction time is short, consumption of raw materials is few, high income, process are continuous.
Description
Technical field
The present invention relates to a kind of production methods of N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters, in particular to
N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters continuous producing method.
Background technique
N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters (abbreviation N-Boc-L-Leu-L-Phe-OMe, No. CAS:
5874-73-7), it has a wide range of applications in terms of the biological organics such as Peptide systhesis and synthetic proteins enzyme body inhibitor card is non-
Help the important intermediate of rice.At present primary synthetic methods be with N- tertbutyloxycarbonyl-L-Leu (abbreviation N-Boc-L-Leu,
No. CAS: 13139-15-6) and L-phenylalanine methyl ester hydrochloride (abbreviation L-Phe-OMe HCl, No. CAS: 7524-50-7)
Production peptide bond is reacted by amino acid condensation to be made.
The formation of peptide bond is nucleophilic substitution of the amino on carboxyl, is related to a tetrahedral intermediate, however, in room
Under temperature, the reaction product of carboxylic acid and ammonia or amine is ammonium salt rather than amide.Therefore, carboxyl group must live before peptide bond is formed
Change.In addition, peptide formation must be carried out in mild reaction condition.Currently, forming the most common method of peptide bond is carbodiimide
Method, mixed anhydride method, active ester method etc..
For carbodlimide method with N, N- dicyclohexylcarbodiimide (DCC) is representative.The reaction mechanism N- of DCC activated carboxyl
The amino acid of protection is reacted with DCC produces activated intermediate O- acylureas first, then activated intermediate O- acylureas and amino
Acid esters reaction then produces peptide ester, and releases the N of a molecule, N- dicyclohexylurea (DCU) (DCU).Currently, carbodlimide method is usually
It is carried out in tank reactor, intermittent operation, reaction needs strict control charging sequence, and the amino acid to guarantee N-protected is same
DCC reaction is completely converted into activated intermediate O- acylureas, which usually requires 30 min or more, and temperature is usually at 25 DEG C
Hereinafter, mode operation is added dropwise under nitrogen protection, need to use as early as possible after properly saving after the production of activated intermediate O- acylureas.
Mixed anhydride method is to grow up at the initial stage fifties.It is initially to be formed with acylamino acid with diphenylphosphoric acid
Mixed acid anhydride, followed by the mixed acid anhydride for forming mixed acid anhydride with same dibenzyl phosphoric acid and being formed with benzoic acid.Nitration mixture acid anhydride method
Raw material converts not exclusively sometimes, and by-product is more.Mixed anhydride method is very strict to the selection and control of reaction condition, such as
Reaction temperature usually requires control at 0 DEG C or less.Currently, mixed anhydride method is usually to carry out in tank reactor, it is intermittent
The step of operation, reaction needs strict control charging sequence, produces mixed acid anhydride, usually requires 30 min or more, under nitrogen protection
The operation of dropwise addition mode needs to use as early as possible after properly saving after mixed acid anhydride production.
Active ester method is developed in nineteen fifty-one Wei Lande (Wieland) and Xie Fei (Shoefr) and uses thio phenyl ester, is perhaps thorough
(Sehwyzer) nineteen fifty-five improves the activity of ester using cyanogen methyl esters, so as to the synthesis for peptide.Active ester method is usually in kettle
It is carried out in formula reactor, intermittent operation, reaction speed is usually relatively slow, and reaction needs strict control charging sequence, production activation
The step of ester, usually requires 30 min or more, and temperature is usually at 25 DEG C hereinafter, be added dropwise mode operation, Acibenzolar under nitrogen protection
It needs to use as early as possible after properly saving after production.
In summary, it currently, the production of N-Boc-L-Leu-L-Phe-OMe is usually to carry out in tank reactor, adopts
With batch process, strict control charging sequence is needed, the reaction time is longer, and reaction temperature is usually at 25 DEG C hereinafter, and need
Nitrogen protection is wanted, yield is lower, and intermediate product such as Acibenzolar saves inconvenience and need to use as early as possible.
Therefore, how to pass through the batch production technique for improving N-Boc-L-Leu-L-Phe-OMe, improve reaction yield,
The problem of in shortening reaction time, the storage of improvement intermediate active object and use pattern are urgent need to resolve.
Summary of the invention
Above-mentioned purpose is achieved through the following technical solutions:
(a) make 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphate (abbreviation HATU) solution and N-
Tertbutyloxycarbonyl-L-Leu (abbreviation N-Boc-L-Leu) solution, which synchronizes, is pumped into online production Acibenzolar in the first microreactor；
Wherein 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphate and N- tertbutyloxycarbonyl-L-Leu
Molar ratio be (1-1.2): 1, the first 30 DEG C -60 DEG C of microreactor temperature control；
(b) continue the Acibenzolar of online production same with L-phenylalanine methyl ester hydrochloride (abbreviation L-Phe-OMeHCl) solution
Step, which is pumped into the second microreactor, carries out peptide formation production N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters (referred to as
N-Boc-L-Leu-L-Phe-OMe)；Wherein N- tertbutyloxycarbonyl-L-Leu and L-phenylalanine methyl ester hydrochloride mole
Than for (1-1.2): 1, the second 30 DEG C -60 DEG C of microreactor temperature control.
Chemical equation shown in step (a) are as follows:
Chemical equation shown in step (b) are as follows:
Total chemical equation are as follows:
In step (a) of the present invention, HATU and N-Boc-L-Leu are flowed into the first microreactor with the molar ratio of 1-1.2:1
It is reacted in reactor, and by the temperature of microreactor in 30-60 DEG C of control, the selection of reaction temperature is based on the company of step (a)
Continuous Chemical Kinetics investigates result, it is ensured that N-Boc-L-Leu is completely converted into active ester.HATU's and N-Boc-L-Leu
When molar ratio is less than 1, N-Boc-L-Leu conversion not exclusively, causes wastage of material；When N-Boc-L-Leu and HATU is greater than 1.2,
HATU is excessive, equally causes wastage of material.
In step (b) of the present invention, continue the Acibenzolar of step (a) online production and L-Phe-OMeHCl solution
It synchronizes to be pumped into the second microreactor and carries out peptide formation, Acibenzolar both produces and uses, avoid unstable activation without saving
Ester storing process generates side reaction.The molar ratio of N-Boc-L-Leu and L-Phe-OMeHCl is 1-1.2:1, second micro- reaction
30-60 DEG C of device temperature control, the continuous chemical kinetics that the selection of reaction temperature is based on step (b) investigate result, it is ensured that activation
Ester is completely converted into product N-Boc-L-Leu-L-Phe-OMe.
HATU solution of the present invention, the molar concentration of HATU are 0.5-4.3 mol/L, n,N-diisopropylethylamine (letter
Claim DIPEA) molar concentration it is identical as the molar concentration of HATU, solvent DMF；The molar concentration of HATU is based on N-Boc-L-
Leu molar concentration, HATU is excessive too small to be unsuitable for continuous production.The molar concentration phase of the molar concentration of DIPEA and HATU
Meanwhile activation effect of the HATU in continuous flow reaction is best, it being capable of concerted reaction progress.The molar concentration and HATU of DIPEA
Molar concentration difference it is larger when, reaction effect is poor.When solvent is DMF, the solute effect of HATU is good, is easy to participate in step
(a) flowing chemical reaction.
The molar concentration of N-Boc-L-Leu solution of the present invention, N-Boc-L-Leu is 0.5-3.6 mol/L, and solvent is
DMF；The molar concentration of N-Boc-L-Leu it is excessive it is too small be unsuitable for continuous production because concentration is less than 0.5 mol/L, then
Yield is not high, less economical；Concentration is greater than 3.6 mol/L, then liquid is more sticky, conveys more difficulty, and serialization
Reaction mixing is bad.The N-Boc-L-Leu solution of moderate concentration, that is, keep certain economy, and is conducive to the steady of reaction
It carries out.When the molar concentration of DIPEA and the identical molar concentration of N-Boc-L-Leu, reaction effect is best.DIPEA's is mole dense
When degree differs larger with the molar concentration of N-Boc-L-Leu, reaction effect is poor.When solvent is DMF, N-Boc-L-Leu's is molten
Solution effect is good, is easy to participate in the flowing chemical reaction of step (a).
In the L-Phe-OMeHCl solution, the molar concentration of L-Phe-OMeHCl is 0.5-3 mol/L, solvent
For DMF.The molar concentration of L-Phe-OMeHCl it is excessive it is too small be unsuitable for continuous production, because of L-Phe-OMeHCl
Molar concentration is less than 0.5 mol/L, then yield is not high, less economical；Molar concentration is greater than 3 mol/L, then liquid is more sticky,
Convey more difficulty, and continuous reaction mixing is bad.The L-Phe-OMeHCl solution of moderate concentration is kept certain
Economy, and be conducive to reaction mass conveying and effectively mixing.When solvent is DMF, the dissolution effect of L-Phe-OMeHCl
Fruit is good, is easy to participate in the flowing reactive of step (b).
The first microreactor residence time described in step (a) of the present invention is 0.5-5 min, step (b) institute
The the second microreactor residence time stated is 1-10 min.The selection of step (a) residence time is based on the continuous chemical of step (a)
The selection of kinetics investigation result and step (a) reaction temperature.By the way that 30 DEG C, 40 DEG C, 50 DEG C, 60 DEG C exist respectively
The residence-time conditions of 5s, 10s, 20s, 30s, 45s, 60s, 90s, 120s, 150s, 180s, 240s, 300s
Under each reactant and product measurement of concetration and calculating, establish step (a) flowing chemical reaction kinetics equation.We send out
Existing step (a), reaction temperature is higher, and reaction speed is faster, and the residence time for reacting required is shorter.Step (b) of the present invention
The second microreactor residence time is 1-10min, and the selection of step (b) residence time is based on the serialization of step (b)
Learn the selection that kinetics investigates result and step (b) reaction temperature.By the way that 30 DEG C, 40 DEG C, 50 DEG C, 60 DEG C exist respectively
The residence time of 10s, 20s, 30s, 45s, 60s, 90s, 120s, 180s, 240s, 300s, 360s, 480s, 600s
Under the conditions of each reactant and product measurement of concetration and calculating, establish step (b) flowing chemical reaction kinetics equation.I
Find step (b): reaction temperature is higher, and reaction speed is faster, and the residence time for reacting required is shorter.
The hydraulic diameter of microreactor of the present invention is 0.1-30mm, preferably 0.3-3mm；The waterpower of microreactor
Diameter matches with reaction-ure fluid flow velocity.Reaction-ure fluid flow velocity is faster, needs the hydraulic diameter of microreactor bigger, because
The too small resistance increase that will cause fluid flowing of hydraulic diameter shortens with the residence time.Microreactor internal fluid flow channel
Total volume is 0.2-100ml, preferably 0.2-20ml；The total volume of microreactor internal fluid flow channel is with yield phase
Match.Output demand is bigger, and the internal volume of microreactor is bigger；Output demand is smaller, and the internal volume of microreactor is smaller.It is micro-
The material of reactor is stainless steel, organic glass, Hastelloy and silicon carbide ceramics.It is preferred that Hastelloy and silicon carbide ceramics,
Good corrosion resistance, it is thermally conductive strong, to reaction system passivity.
The molar ratio of HATU and N-Boc-L-Leu is 1.05-1.1:1, first micro- reaction in step (a) of the present invention
30-50 DEG C of device temperature control；The molar ratio 1.05-1.1:1 of N-Boc-L-Leu and L-Phe-OMeHCl in step (b), second is micro- anti-
Answer 30-50 DEG C of device temperature control.The molar ratio of HATU and N-Boc-L-Leu in step (a) can advanced optimize 1.05-1.1:1,
Under the premise of guaranteeing that N-Boc-L-Leu is completely converted into active ester, 30-50 DEG C of moderate moisture is selected, HATU and N-Boc-
The molar ratio of L-Leu can minimize, to save material and reduce post-processing difficulty.N-Boc-L-Leu in step (b) with
The molar ratio of L-Phe-OMeHCl can advanced optimize 1.05-1.1:1, guarantee that L-Phe-OMeHCl is completely converted into
Under the premise of N-Boc-L-Leu-L-Phe-OMe, 30-50 DEG C of moderate moisture is selected, N-Boc-L-Leu and L-Phe-OMe
The molar ratio of HCl can minimize, to save material and reduce post-processing difficulty.
Microreactor used in the present invention has both the function of mixing, reaction and heat transfer, and two fluids is by microreactor
Two entrances enter reactor, it is equal with microchannel hydraulic diameter, uniformly to form multiply through multiple bifurcated for every fluid streams
Fine branch fluid, branch fluid with bubble type or T-shape or Y-shaped hybrid mode at micropore in microchannel contact it is mixed
It closes, and completes to continues to mix and reaction process in the microchannel in micropore downstream.The temperature control method of microreactor can be used known
Electric heating, water-bath or steam heating, micro- heat exchanger channels can also be integrated in microreactor, by the fluid with certain temperature
Heat exchanger channels are imported to reactor temperature control.Since the hydraulic diameter of microchannel is small, concentration gradient, temperature gradient in microchannel,
Density gradient, velocity gradient etc. are very big, greatly enhance mass transfer, reaction and diabatic process, make reaction can be substantially in power
It learns and completes reaction in the desired time.
Micro-reacting tcchnology is used in the production method of N-Boc-L-Leu-L-Phe-OMe by the present invention, using microreactor
Two-step method continuous production N-Boc-L-Leu-L-Phe-OMe, first step step (a) is in the first microreactor online production high activity
Unstable earnest Acibenzolar, the Acibenzolar of second step step (b) online production and L-Phe-OMeHCl synchronize be input to second
N-Boc-L-Leu-L-Phe-OMe is produced in microreactor.L-Phe-OMeHCl conversion ratio is greater than 100% under optimum condition, produces
The selectivity of product N-Boc-L-Leu-L-Phe-OMe is greater than 99.5%.
It produces compared with existing batch process, the beneficial technical effect of the present invention lies in:
1, the reaction time shortens, and the reaction time more than a few hours is reduced to 3min from conventional batch technique, so as to shorten
Production cycle.
2, feed stock conversion, product yield are improved, and reduces post-processing difficulty.Not due to online production high activity
Resistate Acibenzolar is produced and is used, and avoids the problems such as Acibenzolar stores the degradation of process, conversion out of control；And microreactor system
With closure, avoids Acibenzolar and contact and react with oxygen, the moisture etc. in external environment, greatly reduce side reaction
Generation and Acibenzolar loss, so that last handling process is simpler.
3, the use of material is reduced, for the molar ratio of initial key material less than 1.2, material utilization is high.
4, using microreactor continuous process, convenient for quickly control molar ratio of material, residence time and reaction temperature, from
And realize the dynamics Controlling of Acibenzolar production, and it immediately engages in after so that activation ester concentration is reached maximum concentration and reacts in next step, it is living
Change ester, which both produces, to be used.
5, process units is simple, small in size, easy to install, disassembly and cleaning, easy to carry and mobile production.
Detailed description of the invention
Fig. 1 is microreactor system two-step method continuous production N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters
Device flow diagram.
Fig. 2 is inside micro scale channel structural schematic diagram (the Y type of microreactor 1 and microreactor 2 for use in the present invention
It is hybrid).
Description of symbols:
A in Fig. 11、A2、A3The respectively head tank of HATU solution, N-Boc-L-Leu solution, L-Phe-OMeHCl solution；B1,
B2, B3Respectively constant-flux pump；C1、C2Respectively microreactor 1, microreactor 2；D1、D2Respectively the first microreactor temperature control system
System, the second microreactor temperature-controlling system； E1、E2HATU entrance, the N-Boc-L-Leu entrance of respectively the first microreactor, E3、
E4Acibenzolar entrance, the L-Phe-OMeHCl entrance of respectively the second microreactor；F1 、F2Respectively microreactor 1 outlet,
Microreactor 2 exports；G is triple valve；H is product receiving flask.T-1, P-1 are the first thermometer, first pressure gauge；T-2, P-2
It is second temperature table, second pressure gauge；T-3, P-3 are third thermometer, third pressure gauge；T-4, P-4 are the 4th thermometers, the
Four pressure gauges.
A, B indicate the two strands of material streams flowed into from microreactor entrance in Fig. 2.1,1 ' is respectively A material stream and B material stream
Branched bottom, 2 be micron order reaction channel (parallel 16), and the tributary of material A and material B are in the micron-scale on reaction channel 2
Trip mixing, 3 be the thin chamber of product afflux for flowing out parallel micron order reaction channel, and 4 be the public outlet of microreactor product.
Specific embodiment
To facilitate the understanding of the present invention, below will to invention is more fully described, and give it is of the invention compared with
Good embodiment.But the invention can be realized in many different forms, however it is not limited to embodiment described herein.Phase
Instead, purpose of providing these embodiments is makes the disclosure of the present invention more thorough and comprehensive.
Unless otherwise defined, all technical and scientific terms used herein and belong to technical field of the invention
The normally understood meaning of technical staff is identical.Term as used herein in the specification of the present invention is intended merely to description tool
The purpose of the embodiment of body, it is not intended that in the limitation present invention.Term as used herein "and/or" includes one or more phases
Any and all combinations of the listed item of pass.
The present invention is explained below by way of non-limiting embodiment.
Use constant-flux pump B1、B2Control HATU solution A1With N-Boc-L-Leu solution A2Output, so that HATU solution and N-
Boc-L-Leu solution enters the first microreactor C by given pace respectively simultaneously1HATU entrance E1 and N-Boc-L-Leu enter
Mouth E2, pass through temperature-controlling system D1The temperature for controlling the first microreactor examines the dense of production Acibenzolar from bypass by triple valve G
Degree.First microreactor exports F1The Acibenzolar of outflow with pass through constant-flux pump B3Control the L-Phe-OMeHCl solution A of output3
Enter the second microreactor C simultaneously by given pace respectively2Entrance E3With entrance E4, pass through temperature-controlling system D2It is micro- to control second
The temperature of reactor.The outlet F of second microreactor2The product stream of outflow enters in product receiving flask H, then sampling analysis.
Embodiment 1-10 is under the following conditions: in HATU solution, the concentration of HATU is 3.31 mol/L, the concentration of DIPEA
For 3.31 mol/L.In N-Boc-L-Leu solution, the concentration of N-Boc-L-Leu is 3.15 mol/L, and the concentration of DIPEA is
3.15 mol/L.In L-Phe-OMeHCl solution, the concentration of L-Phe-OMeHCl is 3 mol/L.It can be seen that initial anti-
HATU and N-Boc-L-Leu molar ratio are the molar ratio of 1.05:1, N-Boc-L-Leu and L-Phe-OMeHCl under the conditions of answering
For 1.05:1.Microreactor 1: NC super machining production;The quantity of micron order reaction channel 16；Adjacent two micron orders
Vertical interval 4.5mm between reaction channel;The wide 0.4mm in micron order hybrid channel, deep 0.4mm, long 200mm.Fluid flowing passage
Total volume 1ml, 0.4 mm of microchannel hydraulic diameter.Microreactor 2: NC super machining production, micron order reaction channel
Quantity 16, the vertical interval 4.5mm between adjacent two micron order reaction channels；The wide 0.8mm in micron order hybrid channel is deep
0.8mm, long 200mm；7.5 ml of total volume of fluid flowing passage, 0.6 mm of microchannel hydraulic diameter.Microreactor 1 and micro- anti-
The material for answering device 2 is -276 material of Hastelloy C alloys.
Embodiment 1
Use two Series II type constant-flux pump (Scientific Systems, Inc.) control HATU solution and N-Boc-L-
Leu solution output, so that HATU and N-Boc-L-Leu are pumped into microreactor 1, fluid in microreactor 1 simultaneously with 1ml/min
Residence time be 0.5min, HATU and N-Boc-L-Leu molar ratio be 1.05:1, with water bath with thermostatic control control microreactor 1
Temperature is 50 DEG C, and examining the concentration of production Acibenzolar from bypass by triple valve G is 1.575 mol/L.1 outlet stream of microreactor
Acibenzolar out exports flow velocity with by Series II type constant-flux pump (Scientific Systems, Inc.) control as 1ml/
The L-Phe-OMeHCl of min is simultaneously into being pumped into microreactor 2, and the residence time of fluid is 2.5min, N- in microreactor 2
The molar ratio of Boc-L-Leu and L-Phe-OMeHCl is 1.05:1, with the temperature of water bath with thermostatic control control microreactor 2 for 50
DEG C, the product stream of the outlet of microreactor 2 outflow enters in product receiving flask H.Sampling analysis in receiving flask H: L-Phe-OMe
HCl is converted completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 99.6%.
As can be seen that total reaction time of embodiment 1 is 3min (0.5min+2.5min).
Embodiment 2
First microreactor and the second microreactor reaction temperature are 60 DEG C, remaining condition is same as Example 1.Pass through threeway
It is 1.575 mol/L that valve G, which examines the concentration of production Acibenzolar from bypass,.Result of implementation: production is examined from bypass by triple valve G
The concentration of Acibenzolar is 1.575 mol/L.In receiving flask H: L-Phe-OMeHCl is converted completely, product N- tertbutyloxycarbonyl-
L- leucyl-L-phenylalanine methyl esters yield 99.2%.
Embodiment 3
First microreactor and the second microreactor reaction temperature are 40 DEG C, remaining condition is same as Example 1.Implement knot
Fruit: examining the concentration of production Acibenzolar from bypass by triple valve G is 1.55 mol/L.In receiving flask H: L-Phe-OMeHCl
Conversion completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 98.4%.
Embodiment 4
Use two Series II type constant-flux pump (Scientific Systems, Inc.) control HATU solution and N-Boc-L-
Leu solution output, so that HATU and N-Boc-L-Leu are pumped into microreactor 1 simultaneously with 0.75ml/min, in microreactor 1
The residence time of fluid is that 0.67min, HATU and N-Boc-L-Leu molar ratio are 1.05:1, controls micro- reaction with water bath with thermostatic control
The temperature of device 1 is 40 DEG C, and examining the concentration of production Acibenzolar from bypass by triple valve G is 1.57 mol/L.Microreactor 1 goes out
Mouthful outflow Acibenzolar with by Series II type constant-flux pump (Scientific Systems, Inc.) control output flow velocity be
The L-Phe-OMeHCl of 0.75ml/min is simultaneously into being pumped into microreactor 2, and the residence time of fluid is in microreactor 2
The molar ratio of 3.3min, N-Boc-L-Leu and L-Phe-OMeHCl are 1.05:1, with water bath with thermostatic control control microreactor 2
Temperature is 40 DEG C, and the product stream of the outlet of microreactor 2 outflow enters in product receiving flask H.Sampling analysis in receiving flask H: L-
Phe-OMeHCl is converted completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 99.3%.
Embodiment 5
Use two Series II type constant-flux pump (Scientific Systems, Inc.) control HATU solution and N-Boc-L-
Leu solution output, so that HATU and N-Boc-L-Leu are pumped into microreactor 1, stream in microreactor 1 simultaneously with 0.5ml/min
The residence time of body is that 1min, HATU and N-Boc-L-Leu molar ratio are 1.05:1, with water bath with thermostatic control control microreactor 1
Temperature is 40 DEG C, and examining the concentration of production Acibenzolar from bypass by triple valve G is 1.575 mol/L.1 outlet stream of microreactor
Acibenzolar out is with by Series II type constant-flux pump (Scientific Systems, Inc.) control output flow velocity
The L-Phe-OMeHCl of 0.5ml/min is simultaneously into being pumped into microreactor 2, and the residence time of fluid is in microreactor 2
The molar ratio of 5min, N-Boc-L-Leu and L-Phe-OMeHCl are 1.05:1, with the temperature of water bath with thermostatic control control microreactor 2
Degree is 40 DEG C, and the product stream of the outlet of microreactor 2 outflow enters in product receiving flask H.Sampling analysis in receiving flask H: L-Phe-
OMeHCl is converted completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 99.6%.
Embodiment 6
Use two Series II type constant-flux pump (Scientific Systems, Inc.) control HATU solution and N-Boc-L-
Leu solution output, so that HATU and N-Boc-L-Leu are pumped into microreactor 1, stream in microreactor 1 simultaneously with 0.4ml/min
The residence time of body is 1.25 min, and HATU and N-Boc-L-Leu molar ratio are 1.05:1, controls microreactor with water bath with thermostatic control
1 temperature is 30 DEG C, and examining the concentration of production Acibenzolar from bypass by triple valve G is 1.575 mol/L.Microreactor 1 goes out
Mouthful outflow Acibenzolar with by Series II type constant-flux pump (Scientific Systems, Inc.) control output flow velocity be
The L-Phe-OMeHCl of 0.4ml/min is simultaneously into being pumped into microreactor 2, and the residence time of fluid is in microreactor 2
The molar ratio of 6.25min, N-Boc-L-Leu and L-Phe-OMeHCl are 1.05:1, with water bath with thermostatic control control microreactor 2
Temperature is 30 DEG C, and the product stream of the outlet of microreactor 2 outflow enters in product receiving flask H.Sampling analysis in receiving flask H: L-
Phe-OMeHCl is converted completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 99.6%.
Embodiment 7
Use two Series II type constant-flux pump (Scientific Systems, Inc.) control HATU solution and N-Boc-L-
Leu solution output, so that HATU and N-Boc-L-Leu are pumped into microreactor 1, stream in microreactor 1 simultaneously with 0.5ml/min
The residence time of body is 1 min, and HATU and N-Boc-L-Leu molar ratio are 1.05:1, with water bath with thermostatic control control microreactor 1
Temperature is 30 DEG C, and examining the concentration of production Acibenzolar from bypass by triple valve G is 1.57 mol/L.1 outlet stream of microreactor
Acibenzolar out is with by Series II type constant-flux pump (Scientific Systems, Inc.) control output flow velocity
The L-Phe-OMeHCl of 0.5ml/min is simultaneously into being pumped into microreactor 2, and the residence time of fluid is in microreactor 2
The molar ratio of 6.25min, N-Boc-L-Leu and L-Phe-OMeHCl are 1.05:1, with water bath with thermostatic control control microreactor 2
Temperature is 30 DEG C, and the product stream of the outlet of microreactor 2 outflow enters in product receiving flask H.Sampling analysis in receiving flask H: L-
Phe-OMeHCl is converted completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 99.3%.
Embodiment 8
Use two Series II type constant-flux pump (Scientific Systems, Inc.) control HATU solution and N-Boc-L-
Leu solution output, so that HATU and N-Boc-L-Leu are pumped into microreactor 1 simultaneously with 0.75ml/min, in microreactor 1
The residence time of fluid is 0.67 min, and HATU and N-Boc-L-Leu molar ratio are 1.05:1, controls micro- reaction with water bath with thermostatic control
The temperature of device 1 is 30 DEG C, and examining the concentration of production Acibenzolar from bypass by triple valve G is 1.56 mol/L.Microreactor 1 goes out
Mouthful outflow Acibenzolar with by Series II type constant-flux pump (Scientific Systems, Inc.) control output flow velocity be
The L-Phe-OMeHCl of 0.75ml/min is simultaneously into being pumped into microreactor 2, and the residence time of fluid is in microreactor 2
The molar ratio of 5min, N-Boc-L-Leu and L-Phe-OMeHCl are 1.05:1, with the temperature of water bath with thermostatic control control microreactor 2
Degree is 30 DEG C, and the product stream of the outlet of microreactor 2 outflow enters in product receiving flask H.Sampling analysis in receiving flask H: L-Phe-
OMeHCl is converted completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 98.6%.
Embodiment 9
First microreactor and the second microreactor reaction temperature are 30 DEG C, remaining condition is same as Example 1.Implement knot
Fruit: examining the concentration of production Acibenzolar from bypass by triple valve G is 1.55 mol/L.In receiving flask H: L-Phe-OMeHCl
Conversion completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 97.1%.
Embodiment 10
The material of microreactor 1 and microreactor 2 is silicon carbide ceramics.Remaining condition is same as Example 1, collects after reaction
Sampling analysis in bottle H: L-Phe-OMeHCl is converted completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine first
Ester yield 99.6%.
Embodiment 11
The material of microreactor 1 and microreactor 2 is 316L stainless steel.Remaining condition is same as Example 1, collects after reaction
Sampling analysis in bottle H: L-Phe-OMeHCl is converted completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine first
Ester yield 99.5%.
Embodiment 12
The material of microreactor 1 and microreactor 2 is glass.Remaining condition is same as Example 1, after reaction in receiving flask H
Sampling analysis: L-Phe-OMeHCl is converted completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield
99.4%。
Embodiment 13-21 is under the following conditions: in HATU solution, the concentration of HATU is 2.4 mol/L, the concentration of DIPEA
For 2.4 mol/L.In N-Boc-L-Leu solution, the concentration of N-Boc-L-Leu is 2.2mol/L, and the concentration of DIPEA is
2.2mol/L.In L-Phe-OMeHCl solution, the concentration of L-Phe-OMeHCl is 2 mol/L.It can be seen that initial reaction
Under the conditions of HATU and N-Boc-L-Leu molar ratio be that the molar ratio of 1.1:1, N-Boc-L-Leu and L-Phe-OMeHCl is
1.1:1.Microreactor 1: NC super machining production;The quantity of micron order reaction channel 16；Adjacent two micron order reactions
The vertical interval 4.5mm of interchannel;The wide 0.4mm in micron order hybrid channel, deep 0.4mm, long 200mm.Fluid flowing passage it is total
Volume 1ml, 0.4 mm of microchannel hydraulic diameter.Microreactor 2: NC super machining production, the quantity of micron order reaction channel
16, the vertical interval 4.5mm between adjacent two micron order reaction channels；The wide 0.8mm in micron order hybrid channel, deep 0.8mm, it is long
200mm；7.5 ml of total volume of fluid flowing passage, 0.6 mm of microchannel hydraulic diameter.Microreactor 1 and microreactor 2
Material is -276 material of Hastelloy C alloys.Respectively when the reaction temperature and material stop of change microreactor 1 and microreactor 2
Between.
The implementation condition and result of implementation of one embodiment 13-21 of table, result of implementation find raw material L-Phe-OMeHCl
Conversion, product yield are as follows completely:
| Embodiment number | Microreactor 1 controls temperature | 1 residence time of microreactor | Microreactor 2 controls temperature | 2 residence time of microreactor | Product yield |
| 13 | 50℃ | 0.5min | 50℃ | 2.5min | 99.6% |
| 14 | 60℃ | 0.5min | 60℃ | 2.5min | 99.3% |
| 15 | 40℃ | 0.5min | 40℃ | 2.5min | 98.6 % |
| 16 | 40℃ | 0.67min | 40℃ | 3.3min | 99.4% |
| 17 | 40℃ | 1min | 40℃ | 5min | 99.6 % |
| 18 | 30℃ | 1.25min | 30℃ | 6.25min | 99.6 % |
| 19 | 30℃ | 1min | 30℃ | 5min | 99.4 % |
| 20 | 30℃ | 0.67min | 30℃ | 3.3min | 98.7 % |
| 21 | 30℃ | 0.5min | 30℃ | 2.5min | 97.4% |
Embodiment 22
Initial reaction condition: in HATU solution, the concentration of HATU is 3 mol/L, and the concentration of DIPEA is 3mol/L.N-Boc-L-
In Leu solution, the concentration of N-Boc-L-Leu is 3mol/L, and the concentration of DIPEA is 3mol/L.L-Phe-OMeHCl solution
In, the concentration of L-Phe-OMeHCl is 3 mol/L.HATU and N-Boc-L-Leu molar ratio are 1:1 under the conditions of initial reaction,
The molar ratio of N-Boc-L-Leu and L-Phe-OMeHCl is 1:1.Remaining reaction condition is same as Example 1.Result of implementation:
L-Phe-OMeHCl conversion ratio 99.1%, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 98.2%.
Embodiment 23
Initial reaction condition: in HATU solution, the concentration of HATU is 4.3 mol/L, and the concentration of DIPEA is 4.3 mol/L.N-
In Boc-L-Leu solution, the concentration of N-Boc-L-Leu is 3.6mol/L, and the concentration of DIPEA is 3.6mol/L.L-Phe-
In OMeHCl solution, the concentration of L-Phe-OMeHCl is 3 mol/L.HATU and N-Boc-L-Leu under the conditions of initial reaction
Molar ratio is that the molar ratio of 1.2:1, N-Boc-L-Leu and L-Phe-OMeHCl are 1.2:1.Remaining reaction condition and implementation
Example 1 is identical.Result of implementation: L-Phe-OMeHCl conversion is complete, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine
Methyl esters yield 99.5%.
Comparative example 1:
DCC method batch process: stirred tank with nitrogen displaced air three times after, by 2. 5kg N-Boc-L-Leu (10 mol,
1 eq) it is added in stirred autoclave, starting agitating device after addition 5L DMF dissolves N-Boc-L-Leu.Add under ice bath
Enter 2.16kg I-hydroxybenzotriazole (abbreviation HOBt prevents racemization, 1.6 eq), 3.9kg n,N-diisopropylethylamine is added
(abbreviation DIPEA, 3 eq), it is 6mol/L DCC solution (30 mol, 3 eq) that 5L concentration, which is then added dropwise, and the speed of dropwise addition cannot
It is too fast, maintain feed liquid temperature no more than 5 DEG C.DCC solution is added dropwise in 6h.Then the L- that 5L concentration is 1.6mol/L is added dropwise
Phe-OMeHCl solution (8 mol, 0.8 eq).The speed of dropwise addition cannot be too fast, maintains feed liquid temperature no more than 25 DEG C.
L-Phe-OMeHCl solution is added dropwise in 18h.After L-Phe-OMeHCl solution is added dropwise, 25 DEG C the reaction was continued for 24 hours
Stop reaction afterwards.Sampling analysis: L-Phe-OMeHCl conversion is complete, product N- tertbutyloxycarbonyl-L- leucyl-L- phenylpropyl alcohol ammonia
Sour methyl esters yield 92.1%.Can be seen that comparative example 1 total dropwise addition material time and reaction time is 48h, N-Boc-L-Leu
Initial molar ratio with L-Phe-OMeHCl is 1.25:1.
From embodiment 1 and comparative example 1 as can be seen that using microreactor continuous reaction process, by N-Boc-L-Leu with
The initial molar ratio of L-Phe-OMeHCl is reduced to 1.05:1 from 1.25:1, and reaction process has shortened to 3min, product from 48h
N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield is increased to 99.6% from 92.1%, reduces material consumption, shortens
Production cycle improves product yield.
Comparative example 2:
Mixed anhydride method batch process: stirred tank with nitrogen displaced air three times after, by 2.5kg N-Boc-L-Leu (10
Mol, 1 eq) it is added in stirred autoclave, starting agitating device after addition 5L DMF dissolves N-Boc-L-Leu.-30
1.22 kg N-methylmorpholines (12mol, 1.2 eq) are added at DEG C, it is that 2mol/L ethyl chloroformate is molten that 6L concentration, which is then added dropwise,
The speed of liquid (12 mol, 1.2 eq), dropwise addition cannot be too fast, maintains feed liquid temperature no more than -20 DEG C.Ethyl chloroformate is molten
Liquor is added dropwise in 6h.Then be added dropwise 5L concentration be 1.6mol/L L-Phe-OMeHCl solution (8 mol, 0.8
Eq).The speed of dropwise addition cannot be too fast, maintains feed liquid temperature no more than 25 DEG C.L-Phe-OMeHCl solution is dripped in 18h
Finish.After L-Phe-OMeHCl solution is added dropwise, 25 DEG C the reaction was continued for 24 hours afterwards stop reaction.Sampling analysis: L-Phe-
OMeHCl conversion is complete, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 75.1%.As can be seen that
The total dropwise addition material time of comparative example 2 and reaction time are initially rubbing for 48h, N-Boc-L-Leu and L-Phe-OMeHCl
You are than being 1.25:1.
From embodiment 1 and comparative example 2 as can be seen that using microreactor continuous reaction process, by N-Boc-L-Leu with
The initial molar ratio of L-Phe-OMeHCl is reduced to 1.05:1 from 1.25:1, and reaction process has shortened to 3min, product from 48h
N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield is increased to 99.6% from 75.1%, reduces material consumption, shortens
Production cycle improves product yield.
Comparative example 3:
Active ester method batch process: stirred tank with nitrogen displaced air three times after, by 2. 5kg N-Boc-L-Leu (10
Mol, 1 eq) it is added in stirred autoclave, starting agitating device after addition 5L DMF dissolves N-Boc-L-Leu.Ice bath
3.3kg n,N-diisopropylethylamine (abbreviation DIPEA, 2.5 eq) is added in lower addition, and it is 3mol/L that 4L concentration, which is then added dropwise,
The speed of HATU solution (12 mol, 1.2 eq), dropwise addition cannot be too fast, maintains feed liquid temperature no more than 5 DEG C.HATU solution
It is added dropwise in 6h.Then the L-Phe-OMeHCl solution (8 mol, 0.8 eq) that 5L concentration is 1.6mol/L is added dropwise.It is added dropwise
Speed cannot be too fast, maintain feed liquid temperature no more than 25 DEG C.L-Phe-OMeHCl solution is added dropwise in 18h.L-
After Phe-OMeHCl solution is added dropwise, 25 DEG C the reaction was continued for 24 hours afterwards stop reaction.Sampling analysis: L-Phe-OMeHCl
Conversion is complete, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 95.5%.As can be seen that comparative example 3 is total
The dropwise addition material time and the reaction time be 48h, N-Boc-L-Leu and L-Phe-OMeHCl initial molar ratio be
1.25:1。
From embodiment 1 and comparative example 3 as can be seen that using microreactor continuous reaction process, by N-Boc-L-Leu with
The initial molar ratio of L-Phe-OMeHCl is reduced to 1.05:1 from 1.25:1, and reaction process has shortened to 3min, product from 48h
N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield is increased to 99.6% from 75.1%, reduces material consumption, shortens
Production cycle improves product yield.
Comparative example 4(active ester method microreactor continuous processing):
The first microreactor and the second microreactor reaction temperature are 25 DEG C under primary condition, remaining condition and 1 phase of embodiment
Together.Result of implementation: it is 1.4 mol/L that triple valve G, which examines the concentration of production Acibenzolar from bypass,.Sampling analysis in receiving flask H: L-
Phe-OMeHCl is converted completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 98.5%.
From embodiment 1 and comparative example 4 as can be seen that after 4 reaction temperature of comparative example is reduced to 25 DEG C, product N- tertiary butyloxycarbonyl
Base-L- leucyl-L-phenylalanine methyl esters yield is reduced to 98.5%.
Comparative example 5(active ester method microreactor continuous processing):
98.5% the first microreactors and the second microreactor reaction temperature are 65 DEG C, remaining condition is same as Example 1.It is real
Apply result: it is 1.575 mol/L that triple valve G, which examines the concentration of production Acibenzolar from bypass,.Sampling analysis in receiving flask H: L-
Phe-OMeHCl is converted completely, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters yield 98.9%.
From embodiment 1 and comparative example 5 as can be seen that 5 reaction temperature of comparative example is improved to after 65 DEG C, product N- tertiary butyloxycarbonyl
Base-L- leucyl-L-phenylalanine methyl esters yield is reduced to 98.9%.
Comparative example 6(active ester method microreactor continuous processing):
Initial reactant concentration: in HATU solution, the concentration of HATU is 3.31 mol/L, and the concentration of DIPEA is 1.65 mol/L.
In N-Boc-L-Leu solution, the concentration of N-Boc-L-Leu is 3.15 mol/L, and the concentration of DIPEA is 1.58 mol/L.L-
In Phe-OMeHCl solution, the concentration of L-Phe-OMeHCl is 3 mol/L.Remaining condition is same as Example 1.It is initial anti-
It answers under object concentration conditions: in HATU solution, the molar concentration rate 2:1 of HATU and DIPEA.In N-Boc-L-Leu solution, N-Boc-
The molar concentration rate of L-Leu and DIPEA is 2:1.Result of implementation: triple valve G from bypass examine production Acibenzolar concentration be
1.25 mol/L.Sampling analysis in receiving flask H: L-Phe-OMeHCl conversion ratio 78.5%, product N- tertbutyloxycarbonyl-L- are bright
Aminoacyl-L-phenylalanine methyl esters yield 78.4%.
From embodiment 1 and comparative example 6 as can be seen that molar concentration rate, the N-Boc-L- of the HATU and DIPEA of comparative example 6
After the molar concentration rate of Leu and DIPEA doubles, product N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters is received
Rate is reduced to 78.4%.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention
Protect range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (8)
1. a kind of production method of N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters, steps are as follows:
(a) make 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid salting liquid and N- tertbutyloxycarbonyl-
L-Leu solution, which synchronizes, is pumped into online production Acibenzolar in the first microreactor；Wherein 2- (7- aoxidizes benzotriazole)-N,
N, N', N'- tetramethylurea hexafluorophosphate and N- tertbutyloxycarbonyl-L-Leu molar ratio are (1-1.2): 1, first is micro- anti-
Answer 30 DEG C -60 DEG C of device temperature control；
(b) make online production Acibenzolar continue with L-phenylalanine methyl ester hydrochloride solution synchronize be pumped into the second microreactor
It carries out peptide formation and produces N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters；The wherein bright ammonia of N- tertbutyloxycarbonyl-L-
The molar ratio of acid and L-phenylalanine methyl ester hydrochloride is (1-1.2): 1, the second 30 DEG C -60 DEG C of microreactor temperature control.
2. the production method of N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters as described in claim 1, the 2-
(7- aoxidize benzotriazole)-N, N, N', in N'- tetramethylurea hexafluorophosphoric acid salting liquid, 2- (7- aoxidizes benzotriazole)-N,
The molar concentration of N, N', N'- tetramethylurea hexafluorophosphate is 0.5mol/L-4.3 mol/L, and n,N-diisopropylethylamine is rubbed
That concentration and 2- (7- aoxidizes benzotriazole)-N, N, N', the molar concentration of N'- tetramethylurea hexafluorophosphate is identical, solvent
For DMF；In the N- tertbutyloxycarbonyl-L- leucyl solution, the molar concentration of N- tertbutyloxycarbonyl-L- leucyl is
0.5mol/L-3.6 mol/L, the molar concentration of n,N-diisopropylethylamine and N- tertbutyloxycarbonyl-L- leucyl it is mole dense
Spend identical, solvent DMF；In the L-phenylalanine methyl ester hydrochloride solution, mole of L-phenylalanine methyl ester hydrochloride
Concentration is 0.5mol/L-3 mol/L, solvent DMF.
3. the production method of N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters as described in claim 1, step (a)
Described in the first microreactor fluid retention time be 0.5min-5 min, the second microreactor stream described in step (b)
The body residence time is 1min-10 min.
4. such as the production of claim 1 or N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters as claimed in claim 3
Method, which is characterized in that the hydraulic diameter of first microreactor and second microreactor is 0.1mm-30mm；Institute
The total volume for stating the internal fluid flow channel of the first microreactor and second microreactor is 0.2ml-100ml.
5. the production method of N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters as claimed in claim 4, feature
It is, the hydraulic diameter of first microreactor and second microreactor is 0.3mm-3mm.
6. the production method of N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters as claimed in claim 4, feature
It is, the total volume of first microreactor and the second microreactor internal fluid flow channel is 0.2ml-
20ml。
7. such as the production of claim 1 or N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters as claimed in claim 3
Method, which is characterized in that the material of first microreactor and the second microreactor is stainless steel, organic glass, Kazakhstan conjunction
Gold or silicon carbide ceramics.
8. the production method of N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters as described in claim 1, feature
It is, 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphate and N- tertiary butyloxycarbonyl in step (a)
Base-L-Leu molar ratio is (1.05-1.1): 1, described 30 DEG C -50 DEG C of first microreactor temperature control；Uncle N- in step (b)
The molar ratio (1.05-1.1) of butoxy carbonyl-L-Leu and L-phenylalanine methyl ester hydrochloride: 1, second microreactor
30 DEG C -50 DEG C of temperature control.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910280094.5A CN109824755A (en) | 2019-04-09 | 2019-04-09 | N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters production method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910280094.5A CN109824755A (en) | 2019-04-09 | 2019-04-09 | N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters production method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109824755A true CN109824755A (en) | 2019-05-31 |
Family
ID=66874368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910280094.5A Pending CN109824755A (en) | 2019-04-09 | 2019-04-09 | N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters production method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109824755A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021238964A1 (en) * | 2020-05-28 | 2021-12-02 | 杭州中美华东制药有限公司 | Method for preparing glp-1 receptor agonist free base |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006169165A (en) * | 2004-12-15 | 2006-06-29 | Itoham Foods Inc | Peptide-synthesizing method using microchip pileup type chemical reactor |
| CN101462962A (en) * | 2007-12-19 | 2009-06-24 | 中国科学院大连化学物理研究所 | Method for synthesizing isooctyl nitrate and microchannel reactor |
| CN104447759A (en) * | 2014-11-24 | 2015-03-25 | 吉林农业大学 | Production method for cyclic dipeptide |
| CN105017118A (en) * | 2015-07-17 | 2015-11-04 | 上海化学试剂研究所有限公司 | Method for preparing 2-methylaziridine by using microchannel reactor |
| CN106946981A (en) * | 2017-03-08 | 2017-07-14 | 南京师范大学 | A kind of tetrapeptide propylene oxide derivatives and its production and use |
| CN107445851A (en) * | 2017-06-21 | 2017-12-08 | 南京工业大学 | A kind of method that quaternary ammonium salt is continuously synthesized using micro-reaction device |
| US20180298056A1 (en) * | 2015-04-22 | 2018-10-18 | Srinivasan Thirumalai Rajan | Process for the preparation of (2s)-n-((s)-1-((s)-4-methyl-1-((r)-2-methyl oxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((s)-2-(2-morpholino acetamido)-4-phenylbutanamido)-4-methylpentanamide |
| CN109400593A (en) * | 2018-12-03 | 2019-03-01 | 河南湾流生物科技有限公司 | A kind of sulfur-containing amino acid feed addictive and preparation method thereof |
-
2019
- 2019-04-09 CN CN201910280094.5A patent/CN109824755A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006169165A (en) * | 2004-12-15 | 2006-06-29 | Itoham Foods Inc | Peptide-synthesizing method using microchip pileup type chemical reactor |
| CN101462962A (en) * | 2007-12-19 | 2009-06-24 | 中国科学院大连化学物理研究所 | Method for synthesizing isooctyl nitrate and microchannel reactor |
| CN104447759A (en) * | 2014-11-24 | 2015-03-25 | 吉林农业大学 | Production method for cyclic dipeptide |
| US20180298056A1 (en) * | 2015-04-22 | 2018-10-18 | Srinivasan Thirumalai Rajan | Process for the preparation of (2s)-n-((s)-1-((s)-4-methyl-1-((r)-2-methyl oxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((s)-2-(2-morpholino acetamido)-4-phenylbutanamido)-4-methylpentanamide |
| CN105017118A (en) * | 2015-07-17 | 2015-11-04 | 上海化学试剂研究所有限公司 | Method for preparing 2-methylaziridine by using microchannel reactor |
| CN106946981A (en) * | 2017-03-08 | 2017-07-14 | 南京师范大学 | A kind of tetrapeptide propylene oxide derivatives and its production and use |
| CN107445851A (en) * | 2017-06-21 | 2017-12-08 | 南京工业大学 | A kind of method that quaternary ammonium salt is continuously synthesized using micro-reaction device |
| CN109400593A (en) * | 2018-12-03 | 2019-03-01 | 河南湾流生物科技有限公司 | A kind of sulfur-containing amino acid feed addictive and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| ANURADHA M V, RAVINDRANATH B: "《Ultrasound in peptide synthesis. 4: Rapid cleavage of polymer-bound protected peptides by alkali and alkanolamines》", 《TETRAHEDRON》 * |
| 张勇等: "《含有甘氨酸和L-脯氨酸多肽的转角结构研究》", 《河北科技大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021238964A1 (en) * | 2020-05-28 | 2021-12-02 | 杭州中美华东制药有限公司 | Method for preparing glp-1 receptor agonist free base |
| CN115667268A (en) * | 2020-05-28 | 2023-01-31 | 杭州中美华东制药有限公司 | Preparation method of GLP-1 receptor agonist free base |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106536745A (en) | Method for producing compound and compound production system used in said production method | |
| CN105601542B (en) | A kind of method that nitration mixture crystallizes N carbamylglutamic acids | |
| CN109824755A (en) | N- tertbutyloxycarbonyl-L- leucyl-L-phenylalanine methyl esters production method | |
| CN106086126A (en) | A kind of method of Enzyme catalyzed synthesis glutathion | |
| CN113292470B (en) | Continuous flow synthesis process of peroxy-2-ethylhexyl tert-butyl carbonate without amplification effect | |
| CN111115658B (en) | Ammonia production method and system based on chemical chain reaction | |
| CN109180502B (en) | Tubular reactor and method for producing choline chloride by using chlormequat chloride production tail gas | |
| CN102659650B (en) | Device and method for preparing DL-methionine salt | |
| CN108610293B (en) | Method for preparing dorvitinib intermediate by adopting microchannel reaction device | |
| CN109400484A (en) | A kind of the ethamine production system and technique of saline solution extraction-hydrolysis | |
| CN109810024A (en) | A kind of spray circuits reactor being used to prepare penta diisocyanate and its application method | |
| CN106345387B (en) | A kind of continuous reaction apparatus and method of amino acid surfactant | |
| US6416981B1 (en) | Production of gluconate salts | |
| CN105541673B (en) | A kind of method of duct type continuous production CLT acid itrated compound | |
| CN109796411A (en) | The method that 4,5- Nitroimidazole is prepared using micro passage reaction | |
| CN207941488U (en) | Dropping feeder during 3,5 dichlorophenyl isocyanate cold light | |
| JPS59175890A (en) | Method for performing biochemical or chemical reaction | |
| CN113813895B (en) | Continuous reaction device and continuous preparation method of 5-nitropyridine-3-formic acid | |
| CN213699808U (en) | P-chlorophenylhydrazine hydrochloride continuous flow reaction system | |
| CN101148425B (en) | Synthesizing method for urea | |
| CN105585465B (en) | A kind of 3,3 dimethyl butyraldehyde preparation technologies and preparation facilities | |
| US20230002312A1 (en) | A continuous flow process for the synthesis of hydroxamic acid | |
| CN108033914A (en) | A kind of preparation method of Ai Qu pools pa | |
| CN213416716U (en) | Production device for reducing biuret in urea | |
| CN209352804U (en) | A kind of ethamine production system of saline solution extraction-hydrolysis |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190531 |
|
| WD01 | Invention patent application deemed withdrawn after publication |