CN118994222A - Preparation method and application of intermediate of 4-boron-10 acid-L-phenylalanine - Google Patents
Preparation method and application of intermediate of 4-boron-10 acid-L-phenylalanine Download PDFInfo
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Abstract
The application provides a preparation method and application of an intermediate of 4-boron-10 acid-L-phenylalanine, wherein the structural formula of the intermediate is shown in a formula III, and the formula III compound is prepared by contacting and reacting a formula II compound with a formula I compound under the action of a Grignard reagent; the 4-boron-10 acid-L-phenylalanine is prepared by deprotection of a compound shown in a formula III, wherein R 1 is a linear or branched alkyl group with 1-10 carbon atoms, R 2 is any one selected from H or an alkyl protecting group, and R 3 and R 4 are each independently selected from any one of H, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, phthaloyl, p-toluenesulfonyl and trityl; the preparation method of the 4-boron-10 acid-L-phenylalanine has the advantages of low cost, short reaction time, high yield, simple and convenient operation, controllable risk, suitability for large-scale industrial production and the like.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a preparation method and application of a 4-boron-10 acid-L-phenylalanine intermediate.
Background
Boron neutron capture therapy (Boron Neutron Capture Therapy, BNCT) is a novel radiation therapy method, which utilizes the aggregation of boron-10 (10 B) isotopes in tumor cells, and then causes nuclear reaction through neutron irradiation to generate high-energy particles, and the particles release energy in the cells to destroy DNA of the tumor cells, thereby achieving the therapeutic purpose. BNCT has the advantages of accurate killing of tumor cells and protection of normal cells, because nuclear reaction mainly occurs in tumor cells containing boron, and the damage to surrounding normal tissues is small.
As a pharmaceutical agent for BNCT, a boron-containing compound having a boron atom or a boron group introduced into the basic skeleton is required. 4-boron-10 acid-L-phenylalanine (10 B-BPA) is a2 nd generation boron drug marketed in Japan in 2020, which has a relative biological effect coefficient much higher than that of mercaptododecane disodium salt (10 B-BSH), is easy to cross the blood brain barrier, and has fewer side effects. 10 B-BPA is taken up as a LAT1 as an amino acid transporter in the form of a mimetic of phenylalanine (mimic). Since LAT1 is highly expressed in cancer cells, 10 B-BPA is easily accumulated, and this property is used for the treatment of cancer.
The prior art is limited by the supply of boron-10 reagent, and most of the current 10 B-BPA main synthesis routes use boron-10 acid ester as raw material and use n-butyl lithium or Grignard reagent to access the mother nucleus. For example, the following synthetic route is reported in CN 110498810B:
The reported reaction temperature is-30 ℃, a large amount of Grignard reagent and tributyl borate are needed in the reaction process, and the production cost is relatively high. In addition, a plurality of patent documents report 10 B-BPA preparation methods at present, but the preparation methods have a series of problems of high cost, complex reaction operation and post-treatment process, more side reactions, long reaction time, severe reaction temperature, low yield and the like. Therefore, it is necessary to develop a preparation method of 4-boron-10 acid-L-phenylalanine which has low cost, mild reaction conditions, short reaction time, high yield, stable yield and is favorable for industrial production.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide a preparation method and application of an intermediate of 4-boron-10 acid-L-phenylalanine, which are used for solving a series of problems of complex preparation process, multiple side reactions, long reaction time, severe reaction temperature, low yield and the like of the 4-boron-10 acid-L-phenylalanine in the prior art.
To achieve the above and other related objects, the present invention is achieved by the following technical means.
The invention provides a pinacol boron-10 acid ester derivative, which has a structural formula shown in a formula I:
；
Wherein R 1 is a straight-chain or branched-chain alkyl group with 1-10 carbon atoms; preferably, R 1 is a linear or branched alkyl group having 1 to 6 carbon atoms.
Further preferably, R 1 is any one selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, and isobutyl.
In some specific embodiments, the R 1 is isopropyl.
The second aspect of the invention provides a method for preparing a pinacol boron-10 acid ester derivative, which is prepared by heating and refluxing boron-10 acid, pinacol and monoalcohol in the presence of a reaction solvent; the mono-alcohol is a straight-chain or branched-chain alkyl alcohol with 1-6 carbon atoms, and the reaction solvent is one or more selected from benzene series with 6-10 carbon atoms or alkane with 6-12 carbon atoms.
Preferably, the monoalcohol is any one of methanol, ethanol, isopropanol, propanol, n-butanol, 2-methyl-1-propanol and 2-butanol.
Preferably, the reaction solvent is one or more of benzene, toluene, chlorobenzene, n-heptane and n-dodecane. More preferably, the reaction solvent is an azeotrope of water.
Further preferably, the reaction solvent is toluene.
In some specific embodiments of the application, toluene is selected as a reaction solvent, toluene is used as a water-splitting agent in the reaction process, and water generated in the reaction is carried out azeotropically by heating and refluxing, so that the water in the reaction is balanced, the reaction is promoted, and the yield of the product is improved.
Preferably, the molar ratio of boron-10 acid, pinacol and monoalcohol is 1: (0.9 to 1.5): (1-6).
Preferably, the adding amount of the reaction solvent is 1-50 mL based on the adding amount of 1g of boron-10 acid in the reaction.
Further preferably, the molar ratio of boron-10 acid, pinacol and monoalcohol is 1: (0.9 to 1.1): (3-6).
Further preferably, the addition amount of the reaction solvent is 4-6 mL based on the addition amount of 1g of boron-10 acid in the reaction.
Preferably, the reaction time is 2-24 hours.
In a third aspect, the invention provides a preparation method of an intermediate compound, wherein a compound in a formula II is contacted and reacted with the pinacol boron-10 acid ester derivative under the action of a Grignard reagent, the structure of the intermediate compound is shown as a formula III,
，；
The synthetic route of the compound of formula III is as follows:
The Grignard reagent is one or more selected from isopropyl magnesium chloride-lithium chloride, isopropyl magnesium bromide-lithium chloride, methyl magnesium chloride and methyl magnesium bromide.
Preferably, the grignard reagent is isopropyl magnesium chloride-lithium chloride.
And X is Br or I.
R 2 is any one of H or C1-C10 alkyl protecting groups.
R 3 and R 4 are each independently selected from any one of H, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, phthaloyl, p-toluenesulfonyl and trityl.
Preferably, R 2 is tert-butyl, and R 3 and R 4 are each independently selected from any one of H or tert-butoxycarbonyl.
The molar ratio of the compound of formula II, the boron-10 acid ester and the Grignard reagent is 1: (0.9-2): (1-3).
Preferably, the molar ratio of the compound of formula II, the boron-10 acid ester and the grignard reagent is 1: (0.9 to 1.05): (1-1.3).
The preparation method also comprises a reaction solvent, wherein the reaction solvent is any one selected from tetrahydrofuran, methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, methyl tertiary butyl ether, petroleum ether, benzene or toluene.
The preparation method also comprises an acid quenching step, wherein the acid is one or more selected from formic acid, acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, oxalic acid or tartaric acid.
Preferably, the acid used in the acid adding quenching step is glacial acetic acid, and the temperature of the acid adding quenching is 0-5 ℃.
Preferably, the acid is added in an amount of 3 to 6mol based on 1mol of the compound of formula III.
Preferably, the compound of formula II is prepared by protecting amino and carboxyl groups of L-phenylalanine and halogenating H at the 4-position of the L-phenylalanine.
Preferably, the preparation method adopts the following one-step process or two-step process:
1) The one-step process method comprises the following steps: firstly adding a compound of a formula II, a reaction solvent and the pinacol boron-10 acid ester derivative, adding a Grignard reagent at the temperature of a reaction system of-30-10 ℃, and reacting for 1-5 h at the temperature; finally adding acid for quenching; preferably, the temperature of the reaction system is 0-5 ℃, and the reaction time is 1-2 hours;
2) The two-step process method comprises the following steps: a) Firstly, adding a compound of a formula II and a reaction solvent, adding a Grignard reagent at the temperature of a reaction system of-30-10 ℃, and reacting for 0.5-2 hours at the temperature; b) Adding the pinacol boron-10 acid ester derivative at the temperature of a reaction system of-30-10 ℃ and reacting for 1-5 h at the temperature; finally adding acid for quenching; preferably, the reaction temperature of a) and b) is 0-5 ℃, the reaction time of a) is 0.5-1 h, and the reaction time of b) is 1-2 h.
Preferably, the preparation method further comprises a separation step of adding water and a first organic solvent to the solution after the reaction, and obtaining an oil-soluble substance through phase separation.
Further preferably, the first organic solvent is dichloromethane.
Preferably, the preparation method further comprises one or more of the steps of water washing, reduced pressure concentration, drying, suction filtration and distillation.
Further preferably, the washing with water is washing the organic phase with water and/or saturated saline.
In some specific embodiments, the washing with water is washing the organic phase with water.
Preferably, the water wash may be one or more times repeated.
Preferably, the preparation method further comprises a purification step of subjecting the separated and purified organic phase to column chromatography purification.
Gradient elution is adopted in the column chromatography, the eluent is a mixed solution of n-heptane and ethyl acetate, and the volume ratio of the n-heptane in the eluent is sequentially reduced.
Further preferably, the volume ratio of the n-heptane to the ethyl acetate in the gradient elution is 50:1-10:1.
In a fourth aspect, the present invention provides a process for the preparation of 4-boron-10 acid-L-phenylalanine by further deprotection of a compound of formula III to produce 4-boron-10 acid-L-phenylalanine by acidification hydrolysis.
In some specific embodiments, the deprotection is performed for the compound of formula III without purification by removal of impurities and/or column chromatography.
In some specific embodiments, the deprotection is performed by deprotecting a compound of formula III after purification steps of the above-described purification steps of purification by column chromatography.
Preferably, the method comprises the steps of adding a second organic solvent, water and acid into the compound of the formula III, and reacting at 50-60 ℃ for 1-3 hours.
The second organic solvent is one or more selected from methanol, ethanol, isopropanol, acetone, butanone, methyl isobutyl ketone and acetonitrile, preferably acetone.
The acid is any one of concentrated hydrochloric acid and trifluoroacetic acid, preferably 36-38% of concentrated hydrochloric acid by mass.
The molar ratio of the compound of formula III to the acid added is 1: (5-12).
Further preferably, the molar ratio of the compound of formula III to the acid added is 1: (10-12).
Based on the amount of 1g of the compound shown in the formula III, the adding amount of the second organic solvent is 4-6 mL;
The volume ratio of the added water to the second organic solvent is 1: (5-10), preferably 1: (8-9).
Preferably, the method further comprises one or more steps of impurity removal such as reduced pressure concentration, water washing, organic solvent washing, suction filtration, drying and the like.
In some specific embodiments, the method comprises removing the second organic solvent in the reaction using reduced pressure distillation.
In some specific embodiments, the method comprises one or more washes with methylene chloride under acidic and basic conditions, respectively, to remove starting materials or byproducts.
In some specific embodiments, the method comprises neutralizing the reactant solution after washing with the second organic solvent, and performing suction filtration, and leaching the filter cake with water and ethanol.
In some specific embodiments, the method comprises drying the filter cake after rinsing to remove water and the second organic solvent.
Compared with the prior art, the invention has the following beneficial effects:
1. The preparation method of 4-boron-10 acid-L-phenylalanine can achieve higher yield by only needing a small amount of boron source and Grignard reagent, and has lower reaction cost.
2. The preparation method of 4-boron-10 acid-L-phenylalanine has short reaction time, does not need to lower the reaction temperature to be too low, and avoids the problem of high energy consumption of ultralow-temperature reaction.
3. The 4-boron-10 acid-L-phenylalanine prepared by the preparation method of the 4-boron-10 acid-L-phenylalanine has higher yield, high purity and stable quality, and is beneficial to quality control.
4. The preparation method of 4-boron-10 acid-L-phenylalanine has the advantages of simple operation, stable process, controllable risk, suitability for large-scale industrial production and the like.
Drawings
FIG. 1 is a hydrogen spectrum of tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- ((4-pinacolatoborate) phenyl) propionate prepared in example 5 of the present invention.
FIG. 2 is a hydrogen spectrum of t-butyl (S) -2- (t-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propanoate prepared in example 8 of the present invention.
FIG. 3 is a hydrogen spectrum of 4-boric acid-L-phenylalanine prepared in example 12 of the present invention.
FIG. 4 shows the result of X-ray powder diffraction of 4-boron-10 acid-L-phenylalanine prepared in example 13 of the present invention.
FIG. 5 shows the TGA test result of 4-boron-10 acid-L-phenylalanine prepared in example 13 of the present invention.
FIG. 6 is a chemical structural formula and an X-ray single crystal diffraction pattern of 4-boron-10 acid-L-phenylalanine hydrochloride dihydrate in example 13 of the present invention, wherein (A) is a chemical structural formula of 4-boron-10 acid-L-phenylalanine hydrochloride dihydrate and (B) is an X-ray single crystal diffraction pattern of 4-boron-10 acid-L-phenylalanine hydrochloride dihydrate.
Detailed Description
Further advantages and effects of the present invention will become apparent to those skilled in the art from the disclosure of the present invention, which is described by the following specific examples.
Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention. The test methods in the following examples, in which specific conditions are not noted, are generally conducted under conventional conditions or under conditions recommended by the respective manufacturers.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, materials used in the embodiments, any methods, devices, and materials of the prior art similar or equivalent to those described in the embodiments of the present invention may be used to practice the present invention according to the knowledge of one skilled in the art and the description of the present invention.
Example 1
The embodiment provides a preparation method of isopropanol pinacol borate, and the reaction synthesis route is as follows:
The specific operation steps are as follows: boric acid (100 g,1.0 eq), isopropyl alcohol (292 g,3.0 eq), pinacol (201 g,1.05 eq) and toluene (tolene) (500 mL) were added to the reaction flask. The water is separated by heating and refluxing, and isopropanol (about 200-300 g) is required to be added until the reaction is finished (about 5 hours). After toluene was removed by vacuum concentration, the mixture was distilled under reduced pressure to obtain 277.1g of a nearly colorless liquid, with a yield of 92.1%.
Comparative example 1
This comparative example 1 differs from example 1 only in that toluene was not added, and the remaining steps were the same as in example 1.
Specific: boric acid (100 g,1.0 eq), isopropyl alcohol (292 g,3.0 eq) and pinacol (201 g,1.05 eq) were added to the reaction flask. Heating to boil, continuously separating out fraction, and adding isopropanol until the reaction is balanced. After isopropanol is removed by vacuum concentration, vacuum rectification is carried out, and nearly colorless liquid 223.3 g is obtained, and the yield is 74.2%.
From the results of example 1 and comparative example 1, it can be seen that the addition of toluene as a solvent during the reaction greatly improves the yield of the product, because toluene acts as a water-distributing agent during the reaction, and water generated during the reaction is brought out azeotropically by heating and refluxing to balance the water in the reaction, promote the reaction, and improve the yield of the product.
Example 2
The embodiment provides a preparation method of isopropyl alcohol pinacol boron-10 acid ester, and the reaction synthesis route is as follows:
The specific operation steps are as follows: to the reaction flask were added boron-10 acid (100 g,1.0 eq), isopropyl alcohol (295 g,3.0 eq), pinacol (203 g,1.05 eq) and toluene (tolene) (500 mL). The water is separated by heating and refluxing, and isopropanol needs to be supplemented until the reaction is finished. After toluene is removed by vacuum concentration, vacuum rectification is carried out, thus obtaining approximately colorless liquid 274.4 g, and the yield is 90.4%.
Example 3
Example 3 on the basis of the above example 2, the influence of different monoalcohols on the yield of pinacol borate was examined, and the specific preparation method was the same as that of example 2, and the results were shown in the following table:
TABLE 1 influence of different monoalcohol species on yield of pinacol boronates
From the results of table 1, it can be seen that the yield of the produced pinacol borate was highest when isopropanol was used as a raw material.
Example 4
This example provides a method for preparing tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- ((4-pinacolatoborate) phenyl) propionate using a two-step procedure, the reaction synthesis route was as follows:
the specific operation steps are as follows:
1) Tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- (4-iodophenyl) propionate was prepared using a similar procedure to Synthesis (2019), 51 (3), 664-676.
2) To the reaction flask were added tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- (4-iodophenyl) propionate (10.00 g,1.0 eq) and tetrahydrofuran (50 mL). After nitrogen replacement, the temperature is reduced to 0 ℃, firstly, 1.3mol/L isopropyl magnesium chloride-lithium chloride tetrahydrofuran solution (18.3 mL,1.3 eq) is dropwise added at the temperature of 0-5 ℃ for reaction for 1 hour. And then isopropanol pinacol borate (3.57 g,1.05 eq) is added dropwise at the temperature of 0-5 ℃, and then the reaction is carried out for 2 hours at the temperature of 0-5 ℃. And finally, adding glacial acetic acid (5.48 g,5.0 eq) for quenching at the temperature of 0-5 ℃, then adding water (30 mL) and dichloromethane (50 mL), separating liquid, washing an organic phase with water (10 mL), and concentrating the organic phase under reduced pressure to be dry to obtain yellow oily matter. Column chromatography (n-heptane/ethyl acetate=50:1 to 10:1) gave 6.89g of a near colorless oil, yield 68.9%.
Example 5
This example provides a method for preparing tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- ((4-pinacolatoborate) phenyl) propionate using a one-step procedure, the reaction synthesis route was as follows:
The specific operation steps are as follows: to the reaction flask were charged tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- (4-iodophenyl) propionate (10.00 g,1.0 eq), pinacolato borate (3.57 g,1.05 eq) and tetrahydrofuran (50 mL) prepared in example 4 above. After nitrogen replacement, the temperature is reduced to 0 ℃,1.3 mol/L isopropyl magnesium chloride-lithium chloride tetrahydrofuran solution (18.3 mL,1.3 eq) is added dropwise at the temperature of 0-5 ℃, and then the reaction is carried out for 2 hours at the temperature of 0-5 ℃. Glacial acetic acid (5.48 g,5.0 eq) is added to quench at a temperature of 0-5 ℃, then water (30 mL) and dichloromethane (50 mL) are added, the solution is separated, the organic phase is washed with water (10 mL), and the organic phase is concentrated to dryness under reduced pressure to give a yellow oil. Column chromatography (n-heptane/ethyl acetate=50:1 to 10:1) gave a near colorless oil, 7.11 g, 71.1% yield.
The structure characterization of tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- ((4-pinacolatoborate) phenyl) propionate prepared in this example:
1H-NMR (DMSOd6, 500MHz): δ7.57(d, J=11.9Hz, 2H), 7.17(d, J=11.9Hz, 2H), 5.00(dd, J1=7.7Hz, J2=16.0Hz, 1H), 3.29(dd, J1=7.6Hz, J2=21.4Hz, 1H), 3.09(dd, J1=16.1Hz, J2=20.8Hz, 1H), 1.42(s, 9H), 1.34 (s, 18H), 1.28 (s, 12H)
The hydrogen spectrum of the t-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- ((4-pinacolatoborate) phenyl) propionate prepared above is shown in FIG. 1.
From the results of examples 4 and 5, it can be seen that the preparation method of tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- ((4-pinacolatoborate) phenyl) propionate using one-step procedure not only simplifies the operation procedure, but also saves time and allows the product to have higher yield.
Example 6
Based on the above example 5, the present example further examined the respective parameters of the reactant amount, the reaction temperature and the reaction time during the reaction and the corresponding yields, and the specific results are shown in the following table.
TABLE 2 influence of different parameters on the yield of tert-butyl (S) -2- (bis (tert-butoxycarbonyl) amino) -3- ((4-pinacolatoborate) phenyl) propionate
As can be seen from the results of Table 2, in the number 2-1, the yield can reach 71.1% when the amount of the pinacol borate in isopropanol is 1.05eq, the amount of the isopropyl magnesium chloride-lithium chloride is 1.3eq, the reaction temperature is 0-5 ℃ and the reaction time is 2 hours; the dosage of the isopropanol pinacol borate and the isopropyl magnesium chloride-lithium chloride is further increased, and the yield is only slightly improved; in addition, the reaction temperature is further reduced to-10-0 ℃, so that the yield can be improved by a small amount, and the yield is greatly reduced when the temperature is reduced to-30 to-20 ℃ or the temperature is increased to 10-15 ℃.
Therefore, the adoption of the conditions of each reaction parameter in the number 2-1 can save cost, simplify the operation steps and ensure higher yield.
Example 7
This example provides a method for preparing tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propanoate using a two-step procedure, the reaction synthesis route was as follows:
the specific operation steps are as follows:
1) Tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- (4-iodophenyl) propionate was prepared using a similar procedure as described in U.S. Pat. No. 5,125A 1.
2) To the reaction flask were added tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- (4-iodophenyl) propionate (10.00 g,1.0 eq) and tetrahydrofuran (50 mL). After nitrogen replacement, the temperature is reduced to-20 ℃, 1.3mol/L isopropyl magnesium chloride-lithium chloride tetrahydrofuran solution (36.1 mL,2.1 eq) is dropwise added at-20 to-10 ℃, then the reaction is carried out for 1 hour at-20 to-10 ℃, and isopropanol pinacol borate (4.35 g,1.05 eq) is dropwise added, and the reaction is carried out for 2 hours at-20 to-10 ℃. Glacial acetic acid (6.71 g,5.0 eq) is added for quenching at the temperature of-10-5 ℃, then water (30 mL) and dichloromethane (50 mL) are added for separating, the organic phase is washed with water (10 mL), and the organic phase is concentrated to dryness under reduced pressure to obtain yellow oily matter. Column chromatography (n-heptane/ethyl acetate=50:1 to 10:1) gave a near colorless oil, 7.15 g, 71.5% yield.
Example 8
This example provides a method for preparing tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propanoate using a one-step procedure, the reaction synthesis route was as follows:
The specific operation steps are as follows: to the reaction flask were charged tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- (4-iodophenyl) propionate (10.00 g,1.0 eq), pinacol borate (4.35 g,1.05 eq) and tetrahydrofuran (50 mL) prepared in example 7 above. After nitrogen replacement, the temperature is reduced to 0 ℃, 1.3mol/L isopropyl magnesium chloride-lithium chloride tetrahydrofuran solution (36.1 mL,2.1 eq) is dropwise added at the temperature of-20 to-10 ℃, and then the reaction is carried out for 2 hours at the temperature of-20 to-10 ℃. Glacial acetic acid (6.71 g,5.0 eq) was added at 0-5 ℃ to quench, then water (30 mL) and dichloromethane (50 mL) were added and the solution was separated, the organic phase was washed with water (10 mL) and the organic phase was concentrated to dryness under reduced pressure to give a yellow oil. Column chromatography (n-heptane/ethyl acetate=50:1 to 10:1) gave a near colorless oil, 7.33 g, 73.3% yield.
The structure of t-butyl (S) -2- (t-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propanoate prepared in this example was characterized:
1H-NMR (DMSOd6, 500MHz): δ7.59(d, J=6.5Hz, 2H), 7.25(d, J=6.5Hz, 2H), 7.16(d, J=6.7Hz, 1H), 4.01(td, J1=4.7Hz, J2=7.7Hz, J2=11.7Hz, 1H), 2.97(dd, J1=4.4Hz, J2=11.5Hz, 1H), 2.85(dd, J1=8.2Hz, J2=11.4Hz, 1H), 1.36(s, 9H), 1.34 (s, 9H), 1.29 (s, 12H)
LCMS（ESI）[M+H]=448.1；[M+Na]=470.1;[2M+H]=895.4；[M+HCOOH-H]=492.2
The hydrogen spectrum of t-butyl (S) -2- (t-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propanoate prepared above is shown in FIG. 2.
From the results of examples 7 and 8, it can be seen that the preparation method of tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propanoate using one-step procedure not only simplifies the operation procedure, saves time, but also allows the product to have higher yield.
Example 9
Based on the above example 8, the amount of reactants used in the reaction process, the reaction temperature, the reaction time, and the corresponding yields were further examined, and the specific results are shown in the following table.
TABLE 3 influence of different parameters on the yield of tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- ((4-pinacol boronate) phenyl) propanoate
As can be seen from the comparison of the results in table 3 and table 2, when the reactant is t-butyl (S) -2- (t-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propionate, the amount of grignard reagent needs to be increased to ensure the yield of the product, since the NHBoc site is not fully protected, compared to when the reactant is t-butyl (S) -2- (t-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propionate; in addition, the reaction temperature needs to be reduced below-10 ℃ to keep the yield of the product above 70%.
The results show that the complete protection of the amino and carboxyl groups of L-phenylalanine can achieve higher yields with minimal Grignard reagent usage and without having to reduce the reaction temperature to too low.
Example 10
The influence of the difference of borate esters during the reaction on the product yield was further examined based on the above example 8, and the specific results are shown in the following table.
TABLE 4 influence of different pinacol borate substitutions on the yield of tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propanoate
The results in Table 4 show that under the same reaction conditions, when isopropyl pinacol borate was used as the boron source, t-butyl (S) -2- (t-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propionate was produced with the highest yield.
Example 11
This example provides a method for preparing tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- ((4-pinacolato boron-10-carboxylate) phenyl) propionate using a one-step procedure, which further expands the amount of raw materials added as compared with example 5, and further evaluates the feasibility of subsequent industrial production using the method.
The specific operation steps are as follows: to the reaction flask were added tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- (4-iodophenyl) propionate (100.0 g,1.0 eq), pinacolato-10 acid isopropyl ester (35.7 g,1.05 eq) and tetrahydrofuran (500 mL). After nitrogen replacement, the temperature is reduced to 0 ℃,1.3 mol/L isopropyl magnesium chloride-lithium chloride tetrahydrofuran solution (183.0 mL,1.3 eq) is added dropwise at the temperature of 0-5 ℃ for reaction for 2 hours. Glacial acetic acid (54.8 g,5.0 eq) is added for quenching at the temperature of 0-5 ℃, then water (300 mL) and dichloromethane (500 mL) are added for separating, the organic phase is washed with water (100 mL), and the organic phase is concentrated to dryness under reduced pressure to obtain yellow oily matter 123.6 g.
Example 12
In this example, tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propionate prepared in example 8 above was used as a starting material to prepare 4-boric acid-L-phenylalanine by further deprotection, and the reaction synthesis route was as follows:
the specific operation steps are as follows: tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- ((4-pinacolatoborate) phenyl) propionate (7.0 g,1.0 eq), acetone (acetone) (35 mL) and water (4 mL). Concentrated hydrochloric acid (15.8 g,10.0 eq) is added after dissolution, and the temperature is raised to 55-60 ℃ for reflux reaction for 3 hours. The reaction solution is concentrated under reduced pressure to remove acetone, water (35 mL) is added for dissolution, dichloromethane (2X 35 mL) is used for washing, 50% potassium hydroxide solution is used for adjusting the pH value of the water phase to 12-13, dichloromethane (2X 35 mL) is used for washing, concentrated hydrochloric acid is used for adjusting the pH value of the water phase to 6-7, suction filtration is carried out, filter cakes are sequentially leached by a small amount of water and ethanol, and then blast drying is carried out at 60 ℃ until the weight is constant, so that white solid 3.02 g is obtained, and the yield is 92.3%.
The structural characterization of the 4-boric acid-L-phenylalanine prepared in this example was further performed:
1H-NMR (D2O+CF3COOH, 500MHz):δ7.55 (d, J=8.1Hz, 2H), 7.14 (d, J=7.6Hz, 2H), 4.18 (dd, J1=5.7Hz, J2=7.8Hz, 1H), 3.17 (dd, J1=5.7Hz, J2=14.6Hz, 1H), 3.03 (dd, J1=7.8Hz, J2=14.6Hz, 1H)
LCMS（ESI）[M+H]=210.1；[M-H]=209.1
The hydrogen spectrum of the 4-boric acid-L-phenylalanine prepared above is shown in FIG. 3.
Example 13
This example uses as a starting material tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- ((4-pinacolato-boron-10-carboxylate) phenyl) propionate prepared in example 11 above without purification by column chromatography to further deprotect and prepare 4-boron-10-acid-L-phenylalanine, the reaction synthesis route is as follows:
The specific operation steps are as follows: to the reaction flask were charged tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- ((4-pinacolato-boron-10-carboxylate) phenyl) propionate (theoretical 99.9 g,1.0 eq), acetone (acetone) (500 mL) and water (50 mL) prepared in example 11. Concentrated hydrochloric acid (211.0 g,11.4 eq) is added after dissolution, and the temperature is raised to 55-60 ℃ for reflux reaction for 3 hours. The reaction solution is concentrated under reduced pressure to remove acetone, water (500 mL) is added for dissolution, dichloromethane (2X 500 mL) is used for washing, 50% potassium hydroxide solution is used for adjusting pH to 12-13, dichloromethane (2X 500 mL) is used for washing, concentrated hydrochloric acid is used for adjusting pH to 6-7 for washing, suction filtration is carried out, filter cakes are sequentially leached by a small amount of water and ethanol, and then blast drying is carried out at 60 ℃ until constant weight is achieved, so that white solid 29.2 g is obtained, and the yield is 76.7%.
The structure of 4-boron-10 acid-L-phenylalanine prepared in this example was identified, and specific detection items and detection results are shown in the following table.
Table 5 4-boron-10 acid-L-phenylalanine identification and detection item and result
In the above test item, the X-ray powder diffraction result is shown in FIG. 4, and the TGA test result is shown in FIG. 5.
Further, the prepared 4-boron-10 acid-L-phenylalanine finished product is dissolved in hydrochloric acid solution, and is stood at room temperature for slow volatilization to separate out crystals, and the crystals are filtered and dried and then detected by an X-ray single crystal diffraction method to confirm that the absolute configuration is S-configuration. The X-ray single crystal diffraction pattern of the specific precipitated 4-boron-10 acid-L-phenylalanine hydrochloride dihydrate and the chemical structural formula thereof are shown in figure 6, wherein (A) is the chemical structural formula of the 4-boron-10 acid-L-phenylalanine hydrochloride dihydrate, and (B) is the X-ray single crystal diffraction pattern of the 4-boron-10 acid-L-phenylalanine hydrochloride dihydrate.
The results show that the total yield of the two steps is up to 76.7% even if the method is not used for preparing 4-boron-10 acid-L-phenylalanine by column chromatography purification, and the purity of the product is up to 97.8%; therefore, the method of the application greatly simplifies complex post-treatment steps in the reaction process while ensuring the yield and stability of the product, saves the cost and time, and can be suitable for large-scale industrial production.
Comparative example 2
This comparative example 2 was a comparative example of the above examples 4 and 12, in which the boron source was replaced with tributyl borate, the reaction temperature was further lowered, the reaction time was prolonged, and trifluoroacetic acid was used in deprotection of amino groups and carboxyl groups, and the influence on the product yield was examined, and the reaction synthesis route was as follows:
The specific operation steps are as follows: to the reaction flask were added tert-butyl (S) -2- (bis (t-butoxycarbonyl) amino) -3- (4-iodophenyl) propionate (10.00 g,1.0 eq) and tetrahydrofuran (40 mL). After nitrogen replacement, the temperature is reduced to-20 ℃,1.3 mol/L isopropyl magnesium chloride-lithium chloride tetrahydrofuran solution (17.1 mL,1.2 eq) is dropwise added at-20 ℃ to-15 ℃, and then the temperature is controlled to-20 ℃ to-15 ℃ for reaction for 0.5 hour. Tributyl borate (5.52 g,1.3 eq) is added dropwise at the temperature of-20 to-15 ℃ and then reacted for 16 hours at the temperature of-20 to-15 ℃.3% (w/w) hydrochloric acid solution (33.0 g,1.5 eq) is added to adjust the pH to 4-5 at the temperature of-20-10 ℃, and then the temperature is kept at 0-20 ℃ for reaction for 0.5 hours. Ethyl acetate was added to the reaction solution to extract (2×450 mL), the combined organic phases were washed 1 time with saturated brine (300 mL), dried over anhydrous sodium sulfate (50 g), filtered, the filter cake was rinsed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure until no more liquid was discharged, to give a yellow oil 12.24: 12.24 g. Column chromatography (n-heptane/ethyl acetate=50:1 to 10:1) gave 4.43g of a near colorless oil, yield 52.1%.
Trifluoroacetic acid (27.5 g,30.0 eq) was added to 4.40g (1.0 eq) of the oil, the mixture was reacted at 20-30℃for 24 hours, concentrated to dryness under reduced pressure, toluene (3X 90 mL) was added, concentrated under reduced pressure for 3 times, the obtained viscous material was slurried with dichloromethane (45 mL) and washed, suction filtered, and the filter cake was air-dried at 60℃to constant weight to obtain an off-white solid 1.44 g in 85.5% yield.
Comparative example 3
This comparative example 3 was a comparative example of the above examples 11 and 13, in which the boron source was replaced with tributyl borate, the reaction temperature was further lowered, the reaction time was prolonged, and tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- ((4-pinacol borate) phenyl) propionate, which was not purified by column chromatography, was examined for the effect on the total yield of the two steps, and the reaction synthesis route was as follows:
The specific operation steps are as follows: to the reaction flask were added tert-butyl (S) -2- (tert-butoxycarbonylamino) -3- (4-iodophenyl) propionate (10.00 g,1.0 eq), toluene (tolue) (56 mL) and tetrahydrofuran (56 mL). After nitrogen replacement, the temperature is reduced to-20 ℃, 1.3mol/L isopropyl magnesium chloride-lithium chloride tetrahydrofuran solution (36.6 mL,2.1 eq) is dropwise added at-20 ℃ to-15 ℃, and then the temperature is controlled to-20 ℃ to-15 ℃ for reaction for 5 hours. Tributyl borate (5.66 g,1.1 eq) is added dropwise at-20 to-15 ℃ and then reacted for 16 hours at-20 to-15 ℃. 3% (w/w) hydrochloric acid solution (136.0 g,5.0 eq) is added to adjust the pH to about 1 at the temperature of-20-10 ℃, and then the temperature is kept at 0-20 ℃ for reaction for 0.5h. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, extracted with ethyl acetate (2X 75 mL), the combined organic phases were washed 1 time with saturated brine (45 mL), the organic phases were dried over anhydrous sodium sulfate (10 g), filtered, the filter cake was rinsed with ethyl acetate (50 mL), and the filtrate was concentrated under reduced pressure until no more liquid was removed, affording 9.63 g as a yellow oil, 8.17g of theory.
Isopropanol (8 mL), water (32 mL) and concentrated hydrochloric acid (22.6 g,10.0 eq) are added to the oily matter 9.62 g (theoretical amount 8.17g,1.0 eq), the mixture is heated to 55-60 ℃ for reaction for 5h, cooled to 20-30 ℃, water (70 mL) is added, then ethyl acetate (70 mL) is used for washing, the pH of the aqueous phase is regulated to 6-7 by 20% sodium hydroxide solution, suction filtration is carried out, a filter cake is leached by water and acetone in sequence, and then the mixture is dried to constant weight by blowing at 60 ℃ to obtain yellow solid 2.06g, and the total yield of two steps is 44.1%.
From the results of comparative examples 2 and 3 described above, it can be seen that when the boron source is replaced with tributyl borate, even if the reaction temperature is lowered and the reaction time is greatly prolonged, the yield of the product is greatly lowered. This is because tributyl borate has relatively low reactivity as a boration reagent, which results in high reaction difficulty, and a large amount of boration reagent and grignard reagent are often required at this time, and a low reaction temperature and a long reaction time are required to achieve a high product yield.
In summary, the application provides a novel preparation method of 4-boron-10 acid-L-phenylalanine, which further shortens the reaction time under the condition of less boron source and Grignard reagent, can obtain a product with higher yield without reducing the temperature to be too low, has the purity of more than 97%, ensures the yield and purity of the product while reducing the cost, and is suitable for industrial mass production.
The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.
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