CN105273057B - A method of preparing Carfilzomib - Google Patents
A method of preparing Carfilzomib Download PDFInfo
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- CN105273057B CN105273057B CN201410343409.3A CN201410343409A CN105273057B CN 105273057 B CN105273057 B CN 105273057B CN 201410343409 A CN201410343409 A CN 201410343409A CN 105273057 B CN105273057 B CN 105273057B
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Peptides Or Proteins (AREA)
Abstract
The present invention relates to a kind of methods for preparing Carfilzomib.Specific steps of the invention are as follows: A) in the presence of activator systems, it is coupled to obtain Fmoc-Phe- resin by resin solid phase carrier and Fmoc-Phe-OH；B) pass through solid-phase synthesis; it is successively coupled Fmoc-Leu-OH, Fmoc-Homophe-OH, Fmoc-Gly-OH, coupling finishes, and removes Fmoc protecting group; two (2- chloroethyl) ethers are added into resin under the conditions of triethylamine and synthesize morpholine ring, peptide resin cracks to obtain chemical compounds I；C) condensation reaction occurs for chemical compounds I and compound ii to get Carfilzomib.The technique effective component of synthetic modification directly on carrier avoids directly effective component of purchase or liquid phase synthesis valuableness, effectively improves yield, reduces production cost.
Description
Technical field
The present invention relates to a kind of preparation methods of polypeptide drug, and in particular to a kind of synthetic method of Carfilzomib.
Background technique
Carfilzomib, illustrious name are as follows: Carfilzomib is the tetrapeptide containing epoxy skeleton, and structural formula is as follows:
Huppert's disease is a kind of abnormal hyperplasia of thick liquid cell, causes a kind of malignant tumour for invading marrow.Pernicious bone
When myeloma generate, Osteoclasts activation can be caused, be destroyed along with the os osseum outside bone, cause the symptom of skeleton pain.
Currently, the drug of the most common treatment Huppert's disease mainly has Distaval or lenalidomide and dexamethasone cooperation to make
With and first generation protease inhibitors bortezomib.On July 20th, 2012, U.S. Food and Drug Administration (FDA) approval
The listing of ONYXPHARMSINC Products Carfilzomib (carfilzomib) freeze-dried powder injection.Ka Feizuo
Rice is a kind of tetrapeptide basic ring oxygen skelemin enzyme body inhibitor, the 20S for containing threonine by being irreversibly integrated to the end N-
Proteasome activity site plays anti-tumour cell proliferative and apoptotic effect.In animal, Carfilzomib protease inhibition body is living
In the blood and tissue of property and in multiple myeloma models, the tumor growth delay of blood and entity tumor.Carfilzomib
For second generation protease inhibitors, have the advantage that firstly, it is more lasting to the inhibiting effect of protease and irreversible,
Therefore a possibility that drug effect is more preferable, and patient develops drug resistance is lower；In addition, Carfilzomib and peripheral nerve mutation relationship it is smaller and
Inhibiting effect is more targeted, thus less side effects.
The existing synthetic method of Carfilzomib is straight line synthetic method, in patent US20050245435, Carfilzomib synthesis
Steps are as follows: N-Boc leucine and phenylalanine benzyl ester condensation reaction, then trifluoroacetic acid effect under deprotection obtain thirdly
Fluoroacetate, later n,N-diisopropylethylamine, 1- hydroxy benzo triazole catalysis under with amino acid condensation generate dipeptides
Amine reacts with chloracetyl chloride, sodium iodide, morpholine after the deprotection of two peptamine of gained, then is passed through hydrogen, restores under palladium carbon catalysis
To compound, gained compound and side chain are condensed up to Carfilzomib crude product.This method can finally synthesize Carfilzomib, but answer
There are still some problems when for being mass produced, if straight line synthetic method reaction yield is lower, sodium iodide chlorine substitution reaction used
Yield is not high, therefore consumes more starting material；And it is polluted larger in this synthetic method due to using chloracetyl chloride；This
Outside, reaction type is more in this synthetic method, and the complicated multiplicity of reaction condition, poor controllability is not suitable for large-scale industrial production.
Therefore, a kind of high income, simple controllable, the synthesis side new suitable for the Carfilzomib of industrialized production of reaction are researched and developed
Method has great importance.
Summary of the invention
The existing synthetic method of the present inventor, prepares Carfilzomib, it is found that technical problem of the existing technology is: closing
Low at yield, reaction type is more, and the complicated multiplicity of reaction condition, poor controllability is not suitable for large-scale industrial production.For this purpose,
The present inventor studies the synthetic method of Carfilzomib, to obtain technical solution of the present invention.
The object of the present invention is to provide a kind of methods for preparing Carfilzomib.Synthetic route of the invention exists as shown in Figure 1:
In the presence of activator systems, it is coupled to obtain Fmoc-Phe- resin by resin solid phase carrier and Fmoc-Phe-OH；Pass through solid phase
Synthetic method is successively coupled Fmoc-Leu-OH, Fmoc-Homophe-OH, Fmoc-Gly-OH, Fmoc protecting group is removed, in three second
Two (2- chloroethyl) ethers are added under the conditions of amine into resin and synthesize morpholine ring, peptide resin cracks to obtain chemical compounds I；Chemical compounds I
Condensation reaction occurs to get Carfilzomib with compound ii.
Some common abbreviations have following meanings in the present invention；
Fmoc: fluorenylmethyloxycarbonyl
Fmoc-AA: the amino acid of fluorenylmethyloxycarbonyl protection
DIC: N, N '-Diisopropylcarbodiimide
EDCI.HCl: 1- [3- (dimethylamino) propyl] -3- ethyl-carbodiimide hydrochloride
PyBOP: hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus
HATU: 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester
HOBt: 1- hydroxy benzenes a pair of horses going side by side triazole
Gly: glycine
Phe: phenylalanine
Leu: leucine
Homophe: homophenylalanin
DMF: N, N '-dimethylformamide
MeOH: methanol
DCM: methylene chloride
NMP: N-Methyl pyrrolidone
DMSO: dimethyl sulfoxide
TFA: trifluoracetic acid
EDT: dithioglycol
Piperidine: hexahydropyridine
DMAP: 4-dimethylaminopyridine
DIEA: N, N '-diisopropylethylamine
TMP: 2,4,6- trimethylpyridine
NMM: N-methylmorpholine
The present invention provides a kind of synthetic method of Carfilzomib thus, and its step are as follows:
Step 1, it in the presence of activator systems, is coupled to obtain Fmoc- by resin solid phase carrier and Fmoc-Phe-OH
Phe- resin；
Step 2, by solid-phase synthesis, it is successively coupled Fmoc-Leu-OH, Fmoc-Homophe-OH, Fmoc-Gly-OH,
Coupling finishes, and removes Fmoc protecting group, and two (2- chloroethyl) ethers are added into resin under the conditions of triethylamine and synthesize morpholine ring,
Peptide resin cracks to obtain chemical compounds I；
Step 3, condensation reaction occurs for chemical compounds I and compound ii to get Carfilzomib.
Wherein, solid phase synthesis process described in step 1, the resin solid supports use 2-CTC resin, the activator
System is selected from DIEA, TMP or NMM, and the Fmoc-Phe- resin is the Fmoc-Phe-CTC of 0.10 ~ 0.90 mmol/g degree of substitution
Resin.
Wherein, solid phase synthesis process described in step 1, the resin solid supports use Wang Shuzhi, the activator system
System is made of DIC, HOBt and DMAP, and the Fmoc-Phe- Wang Shuzhi is the Fmoc-Phe- of 0.10 ~ 0.90 mmol/g degree of substitution
Wang Shuzhi.
In the present invention, the degree of substitution of the resin is used using the degree of substitution of the resin of Uv-spectrophotometric Determination
Volume ratio be 1:4 piperidines and DMF mixed solution by be coupled Fmoc protection type amino acid resin on Fmoc protecting group remove-insurance
Shield is got off, and with its concentration of Uv-spectrophotometric Determination, then uses the amino acid n-compound such as Fmoc- containing Fmoc
Leu-OH, with external standard method calibration resin on Fmoc mmol numerical value, divided by weight resin to get to resin degree of substitution or
Be substitution degree.
Wherein, solid phase synthesis process described in step 2, the described method comprises the following steps:
1) Fmoc removed by volume ratio for the deprotection liquid that the piperidines of 1:4 and DMF are formed on Fmoc-Gly- resin is used
Protecting group obtains H-Gly- resin；
2) in the presence of coupling agent system, H-Phe- resin and Fmoc-Leu-OH are coupled to obtain Fmoc-Leu-Phe- tree
Rouge；
3) step 1), 2) is repeated, Fmoc-Homophe-OH, Fmoc-Gly-OH is successively coupled, obtains Fmoc-Gly-
Homophe-Leu-Phe- resin；
4) coupling finishes, and removes Fmoc protecting group, and two (2- chloroethyl) ethers are added into resin under the conditions of triethylamine and close
At morpholine ring, peptide resin cracks to obtain chemical compounds I.
Wherein, coupling agent system described in above-mentioned solid phase synthetic method step 2 includes condensing agent and reaction dissolvent, the contracting
Mixture is selected from DIC/HOBt, PyBOP/HOBt/DIEA or HATU/HOBt/DIEA；The reaction dissolvent be selected from DMF, DCM, NMP,
DMSO or any combination between them.
Wherein, above-mentioned solid phase synthetic method step 4) is added two (2- chloroethyl) ethers into resin under the conditions of triethylamine and closes
At in morpholine ring, the molar ratio of resin, two (2- chloroethyl) ethers and triethylamine is preferred are as follows: 1:1:3 ~ 1:1.2:3, reaction temperature
It is 15 ~ 35 DEG C, the reaction time is 3 ~ 5 hours；It is further preferred that resin, two (2- chloroethyls) and triethylamine ether molar ratio are preferred are as follows: 1:
1:3, reaction temperature are 15 DEG C, and the reaction time is 3 hours.
Method of the invention is obtained by screening, and screening process is as follows:
1) selection of molar ratio: the molar ratio of resin, two (2- chloroethyl) ethers and triethylamine is preferred are as follows: 1:1:3 and 1:
1.2:3；
2) selection of reaction temperature:
15 DEG C and 35 DEG C；
3) selection in reaction time:
3 hours and 5 hours.
8 kinds of experiment conditions are proposed thus:
Experiment condition 1: 20.07g H-Gly-Homophe-Leu-Phe- resin (10mmol), (the 2- chlorine of 14.30g bis- are taken
Ethyl) stirring and dissolving in 200mL DMF is added in ether (10 mmol) and 3.03g triethylamine (30mmol), and it is cooled to 0 DEG C, is added
In above-mentioned solution, reacting 3 hours at 15 DEG C, washed 3 times with DMF, DCM is washed 3 times, and MeOH is washed 3 times, and DCM is washed 3 times,
MeOH is washed 3 times, after dry, by TFA: methyl phenyl ethers anisole=95:5 volume ratio configures lysate 200mL, lysate is added above-mentioned
It in resin, reacts at room temperature 2 hours, filtering, resin 3 times after washing cracking with a small amount of TFA, merging filtrate, concentration, after concentration
Liquid be added in ice ether and precipitate 1 hour, be centrifuged, anhydrous ether centrifuge washing 6 times, vacuum drying obtains 4.42g chemical combination
Object I；Weigh 0.69g compound ii (4mmol) be added 10ml DMF in, under ice-water bath be added 2.27g chemical compounds I (4mmol),
0.51g DIC (4mmol) and 25 DEG C of 0.54g HOBt (4mmol) react 12 hours, be added in the reaction system ethyl acetate and
Water is extracted with ethyl acetate and is washed with saturated sodium bicarbonate, saturated ammonium chloride, saturated salt solution, and anhydrous sodium sulfate is dry, rotation
The thick peptide 2.24g of Carfilzomib is obtained after inspissation contracting；The above-mentioned thick peptide of 2.24g Carfilzomib is weighed, the acetic acid for the use of volume ratio being 1:4
Ethyl ester and petroleum ether mixed solvent cross column purification, and 2.00g white solid is obtained after concentration, recrystallize through ethyl acetate and petroleum ether
Obtain Carfilzomib fine peptide 1.06g, total recovery 37%, HPLC purity 99.75%.
Experiment condition 2-8, for experimental implementation as shown in experiment condition 1, different experiment conditions and its experimental result are for example following
Table 1 shown in:
1 contrast and experiment of table
| Experiment condition | Molar ratio | Temperature | Time | Total recovery | Purity |
| Experiment condition 1 | 1:1:3 | 15℃ | 3 hours | 33% | 99.75% |
| Experiment condition 2 | 1:1:3 | 15℃ | 5 hours | 33% | 99.61% |
| Experiment condition 3 | 1:1:3 | 35℃ | 3 hours | 33% | 99.75% |
| Experiment condition 4 | 1:1:3 | 35℃ | 5 hours | 32% | 99.72% |
| Experiment condition 5 | 1:1.2:3 | 15℃ | 3 hours | 33% | 99.54% |
| Experiment condition 6 | 1:1.2:3 | 15℃ | 5 hours | 32% | 99.64% |
| Experiment condition 7 | 1:1.2:3 | 35℃ | 3 hours | 33% | 99.73% |
| Experiment condition 8 | 1:1.2:3 | 35℃ | 5 hours | 31% | 99.66% |
The above result shows that the result difference of experiment condition 1-8 is little, but 1 synthesis cost of experiment condition it is relatively low,
Reaction time is shorter, efficiency highest, so the synthesis result of experiment condition 1 is optimal.
Compared to the prior art method of the invention has apparent advantage, related comparative experiments is as shown in table 2 below:
2 contrast and experiment of table
| Patent | Total recovery/% | Purity/% |
| The technology of the present invention | 33 | 99.75 |
| CN201310703497.9 | 19 | 99.70 |
The beneficial effects of the present invention are: being successively coupled Fmoc-Phe-OH, Fmoc-Leu-OH, Fmoc- in resin
Homophe-OH, Fmoc-Gly-OH, two (2- chloroethyl) ethers synthesis morpholine ring is then added, is directly synthesized on peptide resin
Chemical compounds I avoids directly effective component of purchase or liquid phase synthesis valuableness, effectively improves yield, reduces and produce
Cost.
Detailed description of the invention
The synthetic route of Fig. 1 Carfilzomib of the present invention；
The HPLC spectrogram of Fig. 2 chemical compounds I；
The mass spectrogram of Fig. 3 chemical compounds I；
The HPLC spectrogram of the thick peptide of Fig. 4 Carfilzomib；
The HPLC spectrogram of Fig. 5 Carfilzomib fine peptide；
Fig. 6 Carfilzomib fine peptide mass spectrogram.
Specific embodiment
The present invention is further illustrated by the following examples.
Specifically, each commercially available amino acid and amino acid fragment and each commercially available tree involved in following example
Rouge, manufacturer and marque are as follows:
Fmoc protecting group amino acid starting material and Wang Shuzhi are that (producer: gill biochemistry (Shanghai) has for conventional commercial reagent
Limit company；Chemistry is pure)；Chemical compounds I is this patent description synthesis.
Organic solvent and other raw material sources are commercially available product (producer: Sinopharm Chemical Reagent Co., Ltd.；Chemistry
It is pure).
In addition, " concentrated by rotary evaporation " and " freeze-drying " mentioned in following example and measurement HPLC and mass spectrographic condition and
Device therefor model and manufacturer are described as follows:
Concentrated by rotary evaporation equipment: Rotary Evaporators R-200/205(Switzerland Buchi (cloth is odd) company)；
Concentrated by rotary evaporation condition: at 30 DEG C, concentrated by rotary evaporation under the conditions of vacuum (- 0.1Mpa), volume is total before revolving after concentration
Below volume 75%.
HPLC:Dionex high performance liquid chromatograph；It is to fill out with (5 μm, 250 × 4.6mm) of octadecylsilane chemically bonded silica
Fill agent；Using 0.1%TFA solution as mobile phase A, using acetonitrile as Mobile phase B, gradient elution is carried out；Flow velocity is 1.0mL per minute；Inspection
Survey wavelength is 220nm；30 DEG C of column temperature.20 μ l of test solution is taken, liquid chromatograph is injected, records chromatogram.
Mass spectrum: MALDI-TOF-MS Matrix-Assisted Laser Desorption Ionization Time of Flight；Instrument model is AUTO
FLEX SPEED TOF-TOF。
Embodiment one: degree of substitution is the synthesis of the Fmoc-Phe-CTC resin of 0.10mmol/g
The 2-CTC resin 25g that degree of substitution is 0.40mmol/g is weighed, is added in solid phase reaction column, is washed 1 time with DMF,
After DMF swellable resins 30 minutes, takes 19.37g Fmoc-Phe-OH (50mmol) to be dissolved with DMF, 6.46g is added under ice-water bath
It after DIEA (50mmol) activation, is added in the above-mentioned reaction column equipped with resin, after reaction 2 hours, 200mL anhydrous methanol envelope is added
It closes 1 hour.It is washed 3 times with DMF, DCM is washed 3 times, is closed 30 minutes with anhydrous methanol, and methanol shrinks drying, obtains Fmoc-
Phe-CTC resin, detection substitution degree are 0.10mmol/g.
Embodiment two: degree of substitution is the synthesis of the Fmoc-Phe-CTC resin of 0.90mmol/g
The 2-CTC resin 20g that degree of substitution is 1.25mmol/g is weighed, is added in solid phase reaction column, is washed 1 time with DMF,
After DMF swellable resins 30 minutes, takes 48.43g Fmoc-Phe-OH (125mmol) to be dissolved with DMF, be added under ice-water bath
After 16.15g DIEA (125mmol) activation, be added in the above-mentioned reaction column equipped with resin, after reaction 2 hours, addition 200mL without
Water methanol is closed 1 hour.It is washed 3 times with DMF, DCM is washed 3 times, is closed 30 minutes with anhydrous methanol, and methanol shrinks drying, is obtained
To Fmoc-Phe-CTC resin, detection substitution degree is 0.90mmol/g.
Embodiment three: degree of substitution is the synthesis of the Fmoc-Phe- Wang Shuzhi of 0.10mmol/g
The Wang Shuzhi 25g that degree of substitution is 0.40mmol/g is weighed, is added in solid phase reaction column, is washed 1 time with DMF, is used
After DCM swellable resins 30 minutes, 19.37g Fmoc-Phe-OH (50mmol), 6.76g HOBt (50mmol) is taken to be dissolved with DMF,
After 6.31g DIC (50mmol) activation is added under ice-water bath, it is added in the above-mentioned reaction column equipped with resin, is added after five minutes
0.61g DMAP (5mmol) is washed 3 times after reaction 2 hours with DMF, and it is 1:1 acetic anhydride with volume ratio that DCM, which is washed 3 times,
Overnight, methanol shrinks drying to 100mL and pyridine 100mL reaction sealing end, obtains Fmoc-Phe- Wang Shuzhi, and detection substitution degree is
0.10mmol/g。
Example IV: degree of substitution is the synthesis of the Fmoc-Phe- Wang Shuzhi of 0.90mmol/g
The Wang Shuzhi 20g that degree of substitution is 1.25mmol/g is weighed, is added in solid phase reaction column, is washed 1 time with DMF, is used
After DCM swellable resins 30 minutes, take 48.43g Fmoc-Phe-OH (125mmol), 16.89g HOBt (125mmol) molten with DMF
Solution is added in the above-mentioned reaction column equipped with resin after 15.78g DIC (125mmol) activation is added under ice-water bath, after five minutes plus
Enter 1.53g DMAP (12.5mmol), after reaction 2 hours, is washed 3 times with DMF, DCM is washed 3 times, with 100mL acetic anhydride/pyridine
Overnight, methanol shrinks drying to sealing end, obtains Fmoc-Phe- Wang Shuzhi, and detection substitution degree is 0.90mmol/g.
Embodiment five: the preparation of chemical compounds I
Weigh 16.67g(10mmol) Fmoc-Phe- Wang Shuzhi of the degree of substitution for 0.60mmol/g, addition solid phase reaction column
In, it is washed 1 time with DMF, is the mixing of 4:1 with DMF: pyridine volume ratio after being swollen Fmoc-Phe- Wang Shuzhi 30 minutes with DCM
Solution slough Fmoc protection, then washed 6 times with DMF, weigh 10.60g Fmoc-Leu-OH(30mmol), 4.05g HOBt
DCM the and DMF mixed solution that volume ratio is 1:1 is added in (30mmol), and 3.79g DIC(30mmol is added under ice-water bath) activation
Afterwards, it is added in the above-mentioned reaction column equipped with resin, after reacting 2 hours at room temperature, reaction end is judged with ninhydrin method detection, such as
Fruit tree rouge is colorless and transparent, then it represents that fully reacting；Resin colour developing, then it represents that reaction not exclusively, needs to react 1 hour again, this sentences
Disconnected standard judges reaction end suitable for subsequent amino-acid coupling with ninhydrin method detection.Repeat above-mentioned removing Fmoc protection and
The step of corresponding amino acid couplings are added is sequentially completed the coupling of Fmoc-Homophe-OH, Fmoc-Gly-OH.With DMF: pyridine
The mixed solution that volume ratio is 4:1 sloughs Fmoc protection, is then washed 6 times with DMF, takes 14.30g bis- (2- chloroethyl) ether (10
Mmol) and stirring and dissolving in 200mL DMF is added in 3.03g triethylamine (30mmol), is cooled to 0oC is added in above-mentioned solution,
15oC reacts 3 hours, is washed 3 times with DMF, and DCM is washed 3 times, and MeOH is washed 3 times, and DCM is washed 3 times, and MeOH is washed 3 times, does
20.70g resin is obtained after dry, is added in the three neck round bottom flask of 500mL, by TFA: the configuration of methyl phenyl ethers anisole=95:5 volume ratio
Lysate is added in above-mentioned resin lysate 200mL, reacts at room temperature 2 hours, filtering, the tree after washing cracking with a small amount of TFA
Rouge 3 times, the liquid after concentration is added in ice ether and precipitates 1 hour by merging filtrate, concentration, is centrifuged, and anhydrous ether centrifugation is washed
It washs 6 times, is dried in vacuo, obtains 4.42g chemical compounds I, HPLC spectrogram is as shown in Fig. 2, HPLC purity 92.30%(area normalization
Method), chemical compounds I yield 78%(yield calculates: 10mmol 5.66g, 4.42/5.66=78%).Its mass spectrum is as shown in figure 3, [M+
Na]+: 589.605, [M+K]+: 605.255, the theoretical accurate molecular weight of chemical compounds I are as follows: 566.31, sample mass spectral results and reason
It is consistent by molecular weight, structure is correct.
Embodiment six: the preparation of Carfilzomib
It weighs 1.35g compound ii (7.8mmol) to be added in 20ml DMF, 4.42g chemical compounds I is added under ice-water bath
(7.8mmol), 0.99g DIC (7.8mmol) and 25 DEG C of 1.05g HOBt (7.8mmol) react 12 hours, in the reaction system
Ethyl acetate and water is added, be extracted with ethyl acetate and is washed with saturated sodium bicarbonate, saturated ammonium chloride, saturated salt solution, nothing
Aqueous sodium persulfate is dry, obtains the thick peptide 4.37g of Carfilzomib after concentrated by rotary evaporation, HPLC spectrogram is as shown in figure 4, HPLC purity
83.98%, the thick peptide synthesis yield 78%(yield of Carfilzomib calculates: 7.8 mmol are 5.60g, 4.37/5.60=78%).Use body
Product obtains white solid than being that the mixed solvent of 1:4 ethyl acetate and petroleum ether crosses column purification after concentration, then through ethyl acetate and
Petroleum ether is recrystallized to give Carfilzomib fine peptide 2.40g, purifying yield: the 55%(Carfilzomib fine peptide/thick peptide of Carfilzomib=
2.40/4.37), total recovery is the calculating of 33%(yield: the thick peptide synthesis yield × purifying yield of chemical compounds I yield × Carfilzomib=
78% × 78% × 55%=33%), HPLC spectrogram is as shown in figure 5, HPLC purity 99.75%(area normalization method), mass spectrum is such as
Shown in Fig. 6, [M]+: 718.738, the theoretical accurate molecular weight of Carfilzomib are as follows: 718.43, sample mass spectral results and Theoretical molecular
Amount is consistent.
The above content is combine specifically repair select embodiment further detailed description of the invention, and it cannot be said that
Specific implementation of the invention is only limited to these instructions.For those of ordinary skill in the art to which the present invention belongs, exist
Under the premise of not departing from present inventive concept, a number of simple deductions or replacements can also be made, all shall be regarded as belonging to of the invention
Protection scope.
Claims (6)
1. a kind of method for preparing Carfilzomib, which is characterized in that shown method the following steps are included:
Step 1, it in the presence of activator systems, is coupled to obtain Fmoc-Phe- tree by resin solid phase carrier and Fmoc-Phe-OH
Rouge；
Step 2, by solid-phase synthesis, Fmoc-Leu-OH, Fmoc-Homophe-OH, Fmoc-Gly-OH, coupling are successively coupled
It finishes, removes Fmoc protecting group, two (2- chloroethyl) ethers are added into resin under the conditions of triethylamine and synthesize morpholine ring, peptide tree
Rouge cracks to obtain compound I:
Step 3, compound I and compound II:Condensation reaction occurs to get Carfilzomib is arrived, wherein
The molar ratio of resin, two (2- chloroethyl) ethers and triethylamine in the step 2 are as follows: 1:1:3-1:1.2:3, reaction temperature 15-
35 DEG C, the reaction time is 3-5 hours.
2. according to the method described in claim 1, it is characterized in that:
Wherein, resin solid supports described in step 1 use 2-CTC resin, the activator systems be selected from DIEA, TMP or
NMM, the Fmoc-Phe- resin are the Fmoc-Phe-CTC resin of 0.10-0.90mmol/g degree of substitution.
3. according to the method described in claim 1, it is characterized in that:
Wherein, resin solid supports described in step 1 use Wang Shuzhi, and the activator systems are by DIC, HOBt and DMAP group
At the Fmoc-Phe- resin is the Fmoc-Phe- resin of 0.10-0.90/g degree of substitution.
4. according to the method described in claim 1, it is characterized in that:
Wherein, solid phase synthesis process described in step 2, the described method comprises the following steps:
1) the Fmoc protection removed by volume ratio for the deprotection liquid that the piperidines of 1:4 and DMF are formed on Fmoc-Phe- resin is used
Base obtains H-Phe- resin；
2) in the presence of coupling agent system, H-Phe- resin and Fmoc-Leu-OH are coupled to obtain Fmoc-Leu-Phe- resin；
3) step 1), 2) is repeated, Fmoc-Homophe-OH, Fmoc-Gly-OH is successively coupled, obtains Fmoc-Gly-Homophe-
Leu-Phe- resin；
4) coupling finishes, and removes Fmoc protecting group, and the synthesis of two (2- chloroethyl) ethers is added into resin under the conditions of triethylamine
Coffee quinoline ring；
5) peptide resin cracks to obtain compound I.
5. according to the method described in claim 4, it is characterized in that:
Resin, two (2- chloroethyl) ethers and triethylamine molar ratio are as follows: 1:1:3, reaction temperature are 15 DEG C, and the reaction time is 3 hours.
6. according to the method described in claim 4, it is characterized in that:
The activator systems are made of DIC, HOBt and DMAP；The coupling agent system includes condensing agent and reaction dissolvent, institute
It states condensing agent and is selected from DIC/HOBt, PyBOP/HOBt/DIEA or HATU/HOBt/DIEA；The reaction dissolvent be selected from DMF, DCM,
NMP, DMSO or the combination between them.
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| 吗啉的生产路线和国内生产概况;李正西;《石油化工动态》;19960331;第4卷(第3期);39-40、46 |
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