CN112574245A - 4-10Preparation method of boric acid group-L-phenylalanine - Google Patents
4-10Preparation method of boric acid group-L-phenylalanine Download PDFInfo
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- CN112574245A CN112574245A CN202011639463.4A CN202011639463A CN112574245A CN 112574245 A CN112574245 A CN 112574245A CN 202011639463 A CN202011639463 A CN 202011639463A CN 112574245 A CN112574245 A CN 112574245A
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- 229960005190 phenylalanine Drugs 0.000 title claims abstract description 52
- 239000004327 boric acid Substances 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 23
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical group OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 title claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 39
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 238000003756 stirring Methods 0.000 claims abstract description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000010438 heat treatment Methods 0.000 claims abstract description 16
- 238000001914 filtration Methods 0.000 claims abstract description 12
- 239000007787 solid Substances 0.000 claims abstract description 12
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 11
- 238000005406 washing Methods 0.000 claims abstract description 11
- JZLZDBGQWRBTHN-NSHDSACASA-N (2s)-3-(4-iodophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(I)C=C1 JZLZDBGQWRBTHN-NSHDSACASA-N 0.000 claims abstract description 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical group OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000004537 pulping Methods 0.000 claims abstract description 6
- -1 boric acid ester Chemical class 0.000 claims abstract description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 206010028980 Neoplasm Diseases 0.000 claims description 19
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 claims description 19
- 238000002604 ultrasonography Methods 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 9
- 229910052796 boron Inorganic materials 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- JXHZRQHZVYDRGX-UHFFFAOYSA-M sodium;hydrogen sulfate;hydrate Chemical compound [OH-].[Na+].OS(O)(=O)=O JXHZRQHZVYDRGX-UHFFFAOYSA-M 0.000 claims description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical class NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 4
- ULNOXUAEIPUJMK-NSHDSACASA-N (2s)-3-(4-bromophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(Br)C=C1 ULNOXUAEIPUJMK-NSHDSACASA-N 0.000 claims description 3
- RBTMUWSFDUEZJT-QRPNPIFTSA-N B(O)(O)O.N[C@@H](CC1=CC=CC=C1)C(=O)O Chemical compound B(O)(O)O.N[C@@H](CC1=CC=CC=C1)C(=O)O RBTMUWSFDUEZJT-QRPNPIFTSA-N 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 208000025997 central nervous system neoplasm Diseases 0.000 claims description 3
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 230000005751 tumor progression Effects 0.000 claims description 3
- 229940000635 beta-alanine Drugs 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000007867 post-reaction treatment Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract 1
- 230000036632 reaction speed Effects 0.000 abstract 1
- 238000002156 mixing Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 201000007983 brain glioma Diseases 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000002994 phenylalanines Chemical class 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a 4-10A method for preparing boronic acid group-L-phenylalanine, comprising: using N-Boc-4-iodo-L-phenylalanine and10preparation of intermediate N-Boc-4-10borono-L-phenylalanine; N-Boc-4-ion is added into the reactor10Adding a hydrochloric acid solution into boric acid-L-phenylalanine and acetone, uniformly stirring at room temperature, heating for reaction, distilling to remove acetone, cooling the temperature of the residual reaction solution to below 10 ℃, adjusting the pH value to 5.5-6.5, separating out a white solid, filtering, pulping and washing by using dichloromethane, filtering out the residual solid, and drying in vacuum to obtain 4-valent alcohol10borono-L-phenylalanine. The method controls the reaction speed by changing the feeding sequence, so that the reaction has low temperature requirement, can be smoothly carried out under relatively mild low temperature conditions, reduces the using amount of n-butyllithium and boric acid ester, simplifies the post-reaction treatment, has high yield, greatly saves the production cost, and is suitable for industrialization of the productProviding the possibility.
Description
Technical Field
The invention relates to the technical field of medical intermediates, in particular to 4-10A method for preparing L-phenylalanine borate.
Background
Boron Neutron Capture Therapy (BNCT) is a promising targeted chemoradiotherapy, the development of advanced Boron drugs has been the key of BNCT technology, and the continuous development of BNCT technology puts the following requirements on the research of Boron drugs: (1) the biological toxicity is low; (2) the tumor targeting specificity is high; (3) and (4) effectively enriching the boron source. Boric acid and its derivatives, and closed borane, as first generation boron drugs, are rapidly replaced by second generation boron drugs in the development of BNCT technology due to low absorption efficiency or short in-vivo retention time.
Currently, the second generation boronate, 4-boro-L-phenylalanine, has entered BNCT clinical trials. The 4-boron-L-phenylalanine is a derivative of phenylalanine, has higher tumor targeting property, and achieves the improvement of the ratio of tumor/blood (T/B) from 1.1 to 3.5 in the biodistribution of patients with brain glioma, melanoma and head and neck cancer, and the ratio of tumor/normal tissue (T/N) is 1.1-3.0. However, the existing 4-boron-L-phenylalanine process mainly comprises a Grignard reagent method and an n-butyllithium method, the reaction conditions are harsh, the reaction temperature is basically about-78 ℃, and the process is difficult to industrialize; both routes have poor yields and require large excesses of either grignard reagents or n-butyllithium, borate esters, which are commercially available10Boric acid esters are expensive, resulting in excessive product preparation costs.
Disclosure of Invention
An object of the present invention is to solve at least the above problems and/or disadvantages and to provide at least the advantages described hereinafter.
To achieve these objects and other advantages in accordance with the present invention, a 4-prime filter is provided10The preparation method of the borate-L-phenylalanine comprises the following steps:
step one, adding dry THF and N-Boc-4-iodine-L-phenylalanine into a low-temperature reactor keeping a nitrogen atmosphere, stirring for dissolving, cooling to-25-30 ℃, slowly dropping N-butyllithium solution, continuing to keep the temperature for 1-3 hours after dropping, gradually changing the color of the reaction solution into orange, heating to-20-15 ℃, and adding10Slowly dripping the tributyl borate, slowly heating to room temperature after dripping, stirring overnight, slowly pouring the obtained reaction liquid into a dilute hydrochloric acid solution, standing after completely acidifying to separate out an organic phase, extracting a water phase with ethyl acetate,combining organic phases, washing by saturated sodium chloride solution, drying by anhydrous sodium sulfate, and concentrating to obtain an intermediate N-Boc-4-10borono-L-phenylalanine;
step two, adding N-Boc-4-10Adding a hydrochloric acid solution into boric acid-L-phenylalanine and acetone, uniformly stirring at room temperature, heating to 40-60 ℃, reacting for 1-3 h, distilling to remove acetone, cooling the temperature of the residual reaction solution to below 10 ℃, adjusting the pH to 5.5-6.5 by using a sodium hydroxide solution, separating out a white solid, filtering, pulping and washing by using dichloromethane for 0.5-2 h, filtering out the residual solid, and drying in vacuum at the temperature below 50 ℃ to obtain 4-substituted beta-alanine10borono-L-phenylalanine.
Preferably, in the first step, the mass-to-volume ratio of the N-Boc-4-iodo-L-phenylalanine to the THF is 1g: 20-30 mL; the concentration of the n-butyllithium solution is 1.5-3.5 mol/L; the mass-volume ratio of the N-Boc-4-iodine-L-phenylalanine to the N-butyllithium solution is 1g: 1-2 mL; the N-Boc-4-iodo-L-phenylalanine is reacted with10The mass ratio of the tri-n-butyl borate is 1.2-1.6: 1; the concentration of the dilute hydrochloric acid solution is 0.5-1.5 mol/L; the mass-volume ratio of the N-Boc-4-iodine-L-phenylalanine to the dilute hydrochloric acid solution is 1g: 6-10 mL.
Preferably, in the first step, the speed of slowly dropping the n-butyllithium solution is 0.5-1.5 mL/min; the above-mentioned10The speed of slowly dropping the tri-n-butyl borate is 0.5-1 g/min; the speed of slowly pouring the reaction liquid into the dilute hydrochloric acid solution is 5-10 mL/min.
Preferably, in the second step, N-Boc-4-10The mass-volume ratio of the boric acid group-L-phenylalanine to the acetone is 1g: 6-10 mL; the preparation method of the hydrochloric acid solution comprises the following steps: is prepared by mixing hydrochloric acid and water in a volume ratio of 1: 1; said N-Boc-4-10The mass-volume ratio of the boric acid group-L-phenylalanine to the hydrochloric acid solution is 1g: 1-2 mL; the concentration of the sodium hydroxide solution is 3-5 mol/L.
Preferably, the10The preparation method of the tri-n-butyl borate comprises the following steps: will be provided with10Adding boric acid, n-butanol and sodium bisulfate monohydrate into a reactor with a water separator, and feeding at 100-120 DEG CCarrying out reflux reaction until no water is separated, distilling at normal pressure to remove excessive n-butanol, then distilling at reduced pressure, and collecting the product at 90-110 ℃/1.5KPa, namely10Tributyl borate.
Preferably, the10The mass-volume ratio of the boric acid to the n-butyl alcohol is 1g: 6-10 mL; the above-mentioned10The mass ratio of the boric acid to the sodium bisulfate monohydrate is 4-7: 1.
Preferably, in the second step, before distilling and removing the acetone, the reactant is subjected to pressure ultrasound for 30-60 min; the pressure of the pressurized ultrasound is 1.5-2.5 MPa, the frequency is 35-55 KHz, the pressurized ultrasound adopts intermittent ultrasound, namely ultrasound is carried out for 5min, and the ultrasound is stopped for 5 min.
Preferably, in the first step, the N-Boc-4-iodo-L-phenylalanine is replaced with N-Boc-4-bromo-L-phenylalanine.
The invention also provides 4-substituted benzene prepared by the preparation method10Application of L-phenylalanine borate in preparing medicine for treating tumor is disclosed.
Preferably, the treatment of the tumor comprises directly using the drug to treat the tumor or treating the tumor by using a boron neutron capture method; the tumor includes any one of a tumor of the central nervous system, a malignant tumor, or a metastatic tumor progression.
The invention at least comprises the following beneficial effects: the process of the invention is improved on the basis of the original n-butyllithium method, firstly, the reaction rate is controlled by changing the feeding sequence, so that the requirement of the reaction on the temperature is lowered, the reaction can be smoothly carried out under relatively mild low-temperature conditions, and secondly, the use amount of n-butyllithium and boric acid ester is reduced, so that the post-reaction treatment is simpler, the yield is higher, the production cost is greatly saved, and the possibility is provided for the industrialization of the product.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Description of the drawings:
FIG. 1 shows the 4-10Boric acidOf the group-L-phenylalanine1HNMR spectrogram;
FIG. 2 shows the 4-10HPLC profile of borono-L-phenylalanine;
FIG. 3 shows the 4-10Analysis result of HPLC chart of boronic acid group-L-phenylalanine.
The specific implementation mode is as follows:
the present invention is further described in detail below with reference to the attached drawings so that those skilled in the art can implement the invention by referring to the description text.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
Example 1:
4-10The preparation method of the borate-L-phenylalanine comprises the following steps:
step one, adding 250mL of dry THF and 25g N-Boc-4-iodine-L-phenylalanine into a 500mL low-temperature reaction bottle with a nitrogen atmosphere, stirring to dissolve, cooling to-30 ℃, dripping 30mL of 2.5mol/L n-butyllithium at a rate of 1mL/min, keeping the temperature for 2h after dripping, gradually changing the color of the reaction solution to orange, heating to-20 ℃, and adding 17g of n-butyllithium10Slowly dripping the tri-n-butyl borate (at 1g/min) from a constant-pressure dropping funnel, slowly heating to room temperature after dripping, and stirring overnight; slowly pouring the obtained reaction liquid into 200mL of 1mol/L diluted hydrochloric acid solution under the stirring state (10mL/min), standing and separating out an organic phase after complete acidification, extracting an aqueous phase for 2 times by using 100mL of ethyl acetate, combining the organic phases, washing once by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and concentrating to obtain an intermediate N-Boc-4-10borono-L-phenylalanine; the above-mentioned10The preparation method of the tri-n-butyl borate comprises the following steps: mixing 7g of the mixture10Adding boric acid, 56mL of n-butanol and 1.2g of sodium bisulfate monohydrate into a reactor with a water separator, carrying out reflux reaction at 110 ℃ until no water is separated, distilling at normal pressure to remove excessive n-butanol, then distilling at reduced pressure, and collecting 98-110 ℃/1.5KPa product, namely10Tributyl borate;
step two, adding 25g N-Boc-4-10Boric acid-L-phenylalanine and 200mL acetone, then adding 30mL hydrochloric acid solution (formed by mixing hydrochloric acid and water with the volume ratio of 1: 1), stirring uniformly at room temperature, heating to 50 ℃ for reaction for 2h, then distilling to remove acetone, cooling the residual reaction solution to below 10 ℃, adjusting the pH to 6 by using sodium hydroxide solution, separating out white solid, filtering, pulping and washing for 1h by using dichloromethane, filtering out the residual solid, and drying in vacuum at the temperature below 50 ℃ to obtain 4-10borono-L-phenylalanine, yield 55%; FIG. 1 shows 4-10Process for preparing boronic acid-L-phenylalanine1HNMR spectrogram; FIG. 2 shows 4-10HPLC chart of borono-L-phenylalanine, analysis of results is shown in FIG. 3; from the map and the result, the prepared 4-10The boric acid group-L-phenylalanine has higher purity.
Example 2:
4-10The preparation method of the borate-L-phenylalanine comprises the following steps:
step one, adding 250mL of dry THF and 25g N-Boc-4-bromo-L-phenylalanine into a 500mL low-temperature reaction bottle with a nitrogen atmosphere, stirring to dissolve, cooling to-30 ℃, dripping 30mL of 2.5mol/L n-butyllithium at a rate of 1mL/min, keeping the temperature for 2h after dripping, gradually changing the color of the reaction solution to orange, heating to-20 ℃, and adding 17g of n-butyllithium10Slowly dripping the tri-n-butyl borate (at 1g/min) from a constant-pressure dropping funnel, slowly heating to room temperature after dripping, and stirring overnight; slowly pouring the obtained reaction liquid into 200mL of 1mol/L diluted hydrochloric acid solution under the stirring state (10mL/min), standing and separating out an organic phase after complete acidification, extracting an aqueous phase for 2 times by using 100mL of ethyl acetate, combining the organic phases, washing once by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and concentrating to obtain an intermediate N-Boc-4-10borono-L-phenylalanine; the above-mentioned10The preparation method of the tri-n-butyl borate comprises the following steps: mixing 7g of the mixture10Adding boric acid, 56mL of n-butanol and 1.2g of sodium bisulfate monohydrate into a reactor with a water separator, carrying out reflux reaction at 110 ℃ until no water is separated, distilling at normal pressure to remove excessive n-butanol, then distilling under reduced pressure, collecting 98-110 ℃/1.5KPa productI.e. by10Tributyl borate;
step two, adding 25g N-Boc-4-10Boric acid-L-phenylalanine and 200mL acetone, then adding 30mL hydrochloric acid solution (formed by mixing hydrochloric acid and water with the volume ratio of 1: 1), stirring uniformly at room temperature, heating to 50 ℃ for reaction for 2h, then distilling to remove acetone, cooling the residual reaction solution to below 10 ℃, adjusting the pH to 6 by using sodium hydroxide solution, separating out white solid, filtering, pulping and washing for 1h by using dichloromethane, filtering out the residual solid, and drying in vacuum at the temperature below 50 ℃ to obtain 4-10borono-L-phenylalanine in 53% yield.
Example 3:
4-10The preparation method of the borate-L-phenylalanine comprises the following steps:
step one, adding 250mL of dry THF and 25g N-Boc-4-iodine-L-phenylalanine into a 500mL low-temperature reaction bottle with a nitrogen atmosphere, stirring to dissolve, cooling to-30 ℃, dripping 30mL of 2.5mol/L n-butyllithium at a rate of 1mL/min, keeping the temperature for 2h after dripping, gradually changing the color of the reaction solution to orange, heating to-20 ℃, and adding 17g of n-butyllithium10Slowly dripping the tri-n-butyl borate (at 1g/min) from a constant-pressure dropping funnel, slowly heating to room temperature after dripping, and stirring overnight; slowly pouring the obtained reaction liquid into 200mL of 1mol/L diluted hydrochloric acid solution under the stirring state (10mL/min), standing and separating out an organic phase after complete acidification, extracting an aqueous phase for 2 times by using 100mL of ethyl acetate, combining the organic phases, washing once by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and concentrating to obtain an intermediate N-Boc-4-10borono-L-phenylalanine; the above-mentioned10The preparation method of the tri-n-butyl borate comprises the following steps: mixing 7g of the mixture10Adding boric acid, 56mL of n-butanol and 1.2g of sodium bisulfate monohydrate into a reactor with a water separator, carrying out reflux reaction at 110 ℃ until no water is separated, distilling at normal pressure to remove excessive n-butanol, then distilling at reduced pressure, and collecting 98-110 ℃/1.5KPa product, namely10Tributyl borate;
step two, adding 25g N-Boc-4-10Boric acid group-L-phenylalanine and 200mL acetone, and then 30mL hydrochloric acid solution (volume ratio)Is 1: 1) and water), stirring uniformly at room temperature, heating to 50 ℃ for reaction for 2h, and pressurizing and ultrasonically treating the reactant for 60 min; the pressure of the pressurized ultrasound is 1.5MPa, the frequency is 35KHz, the pressurized ultrasound adopts intermittent ultrasound, namely ultrasound is carried out for 5min, and the ultrasound is stopped for 5 min; then distilling to remove acetone, cooling the temperature of the residual reaction solution to below 10 ℃, adjusting the pH value to 6 by using sodium hydroxide solution, separating out white solid, filtering, pulping and washing by using dichloromethane for 1h, filtering out the residual solid, and drying in vacuum at the temperature of below 50 ℃ to obtain 4-10borono-L-phenylalanine in 58% yield.
Example 4:
4-ion prepared in examples 1-310The boric acid group-L-phenylalanine is applied to preparing the medicine for treating the tumor; the treatment of the tumor comprises directly using the medicine to treat the tumor or treating the tumor by adopting a boron neutron capture method; the tumor includes any one of a tumor of the central nervous system, a malignant tumor, or a metastatic tumor progression.
While embodiments of the invention have been described above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable in various fields of endeavor to which the invention pertains, and further modifications may readily be made by those skilled in the art, it being understood that the invention is not limited to the details shown and described herein without departing from the general concept defined by the appended claims and their equivalents.
Claims (10)
1. 4-10The preparation method of the boric acid group-L-phenylalanine is characterized by comprising the following steps:
step one, adding dry THF and N-Boc-4-iodine-L-phenylalanine into a low-temperature reactor keeping a nitrogen atmosphere, stirring for dissolving, cooling to-25-30 ℃, slowly dropping N-butyllithium solution, continuing to keep the temperature for 1-3 hours after dropping, gradually changing the color of the reaction solution into orange, heating to-20-15 ℃, and adding10Slowly dripping the tributyl borate, slowly heating to room temperature after dripping, stirring overnight, slowly pouring the obtained reaction liquid into a dilute hydrochloric acid solution, standing after completely acidifying to separate an organic phase, and using ethyl acetate for an aqueous phaseExtracting, combining organic phases, washing by saturated sodium chloride solution, drying by anhydrous sodium sulfate, and concentrating to obtain an intermediate N-Boc-4-10borono-L-phenylalanine;
step two, adding N-Boc-4-10Adding a hydrochloric acid solution into boric acid-L-phenylalanine and acetone, uniformly stirring at room temperature, heating to 40-60 ℃, reacting for 1-3 h, distilling to remove acetone, cooling the temperature of the residual reaction solution to below 10 ℃, adjusting the pH to 5.5-6.5 by using a sodium hydroxide solution, separating out a white solid, filtering, pulping and washing by using dichloromethane for 0.5-2 h, filtering out the residual solid, and drying in vacuum at the temperature below 50 ℃ to obtain 4-substituted beta-alanine10borono-L-phenylalanine.
2. The method of claim 1, wherein the step of (A) is carried out in the presence of a catalyst10The preparation method of the borate-L-phenylalanine is characterized in that in the first step, the mass-volume ratio of the N-Boc-4-iodine-L-phenylalanine to the THF is 1g: 20-30 mL; the concentration of the n-butyllithium solution is 1.5-3.5 mol/L; the mass-volume ratio of the N-Boc-4-iodine-L-phenylalanine to the N-butyllithium solution is 1g: 1-2 mL; the N-Boc-4-iodo-L-phenylalanine is reacted with10The mass ratio of the tri-n-butyl borate is 1.2-1.6: 1; the concentration of the dilute hydrochloric acid solution is 0.5-1.5 mol/L; the mass-volume ratio of the N-Boc-4-iodine-L-phenylalanine to the dilute hydrochloric acid solution is 1g: 6-10 mL.
3. The method of claim 1, wherein the step of (A) is carried out in the presence of a catalyst10The preparation method of the borate-L-phenylalanine is characterized in that in the first step, the speed of slowly dropping the n-butyllithium solution is 0.5-1.5 mL/min; the above-mentioned10The speed of slowly dropping the tri-n-butyl borate is 0.5-1 g/min; the speed of slowly pouring the reaction liquid into the dilute hydrochloric acid solution is 5-10 mL/min.
4. The method of claim 1, wherein the step of (A) is carried out in the presence of a catalyst10The preparation method of the borate-L-phenylalanine is characterized in that in the second step, N-Boc-4-10The mass-volume ratio of the boric acid group-L-phenylalanine to the acetone is 1g: 6-10 mL; the preparation method of the hydrochloric acid solution comprises the following steps: by volumeMixing hydrochloric acid and water in a ratio of 1: 1; said N-Boc-4-10The mass-volume ratio of the boric acid group-L-phenylalanine to the hydrochloric acid solution is 1g: 1-2 mL; the concentration of the sodium hydroxide solution is 3-5 mol/L.
5. The method of claim 1, wherein the step of (A) is carried out in the presence of a catalyst10A process for producing L-phenylalanine at a boronic acid level, characterized in that10The preparation method of the tri-n-butyl borate comprises the following steps: will be provided with10Adding boric acid, n-butanol and sodium bisulfate monohydrate into a reactor with a water separator, performing reflux reaction at 100-120 ℃ until no water is separated, distilling at normal pressure to remove excessive n-butanol, then distilling under reduced pressure, and collecting a product at 90-110 ℃/1.5KPa, namely10Tributyl borate.
6. The method of claim 1, wherein the step of (A) is carried out in the presence of a catalyst10A process for producing L-phenylalanine at a boronic acid level, characterized in that10The mass-volume ratio of the boric acid to the n-butyl alcohol is 1g: 6-10 mL; the above-mentioned10The mass ratio of the boric acid to the sodium bisulfate monohydrate is 4-7: 1.
7. The method of claim 1, wherein the step of (A) is carried out in the presence of a catalyst10The preparation method of the boric acid group-L-phenylalanine is characterized in that in the second step, before the acetone is distilled and removed, the reactant is subjected to pressure ultrasound for 30-60 min; the pressure of the pressurized ultrasound is 1.5-2.5 MPa, the frequency is 35-55 KHz, the pressurized ultrasound adopts intermittent ultrasound, namely ultrasound is carried out for 5min, and the ultrasound is stopped for 5 min.
8. The method of claim 1, wherein the step of (A) is carried out in the presence of a catalyst10The method for preparing the boronic acid group-L-phenylalanine is characterized in that in the first step, the N-Boc-4-iodo-L-phenylalanine is replaced by N-Boc-4-bromo-L-phenylalanine.
9. 4-substituted benzene prepared by the preparation method as claimed in any one of claims 1 to 810Application of L-phenylalanine borate in preparing medicine for treating tumor is disclosed.
10. The use of claim 9, wherein treating the tumor comprises using the medicament directly to treat the tumor or treating the tumor with boron neutron capture; the tumor includes any one of a tumor of the central nervous system, a malignant tumor, or a metastatic tumor progression.
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