CN110452258B - Preparation method of dipeptide valine boron proline salt - Google Patents
Preparation method of dipeptide valine boron proline salt Download PDFInfo
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
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- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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Abstract
The invention provides a preparation method of dipeptide valine boron proline salt, which adopts R1Group-protected pyrrolidinoboronic acids and R4The group-protected valine is used as an initial raw material, so that the problem of product loss caused by complex post-treatment during deprotection is avoided, the yield of a target product is greatly improved, and the mass production is facilitated; and the resolution method of the resolving agent is adopted, so that the problem of overlarge loss of a target configuration product caused by using resolution methods with different solubilities is solved, and the product yield of the target configuration is greatly improved.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and relates to a preparation method of dipeptide valine boron proline salt.
Background
Dipeptide valine boron proline salt is an important anticancer drug intermediate, the existing synthetic route starts from valine protected by tert-butyloxycarbonyl or trifluoroacetyl, so that a target product is very easy to dissolve in water during deprotection and is difficult to purify and separate from the water.
Gibson et al (Organic Process Research & Development 2002,6, 814-.
Therefore, it is desired in the art to find a method for preparing the boron proline salt of dipeptide valine with simple steps and high yield.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of dipeptide valine boron proline salt, which has the advantages of high yield of target configuration products, simple post-treatment and low loss.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of dipeptide valine boron proline salt, which comprises the following steps:
(1)R1reacting the group-protected pyrrolidine boronic acid with dihydric alcohol to obtain a compound shown as a formula I, wherein the reaction formula is as follows:
(2) a compound of formula I de R1Protecting groups, and then adding a resolving agent for resolution to obtain a compound shown as a formula II, wherein the reaction formula is as follows:
(3) a compound of formula II and R4Reacting the group-protected L-valine to obtain a compound shown in a formula III, wherein the reaction formula is as follows:
(4) reacting the compound shown in the formula III with acid to obtain a compound shown in a formula IV, wherein the reaction formula is as follows:
(5) de-R of a compound of formula IV4Group protection gives compounds of formula V, the reaction is as follows:
(6) reacting the compound shown in the formula V with acid HX to obtain dipeptide valine boron proline salt, wherein the reaction formula is as follows:
wherein R is1And R4The groups are independently selected from any one of alkoxycarbonyl, acyl or aryl; r2And R3Each group is independently selected from hydrogen, straight or branched chain alkyl; the anion X is independently selected from any one of alkyl sulfonate, halogen ion, sulfate ion or carboxylate ion.
The preparation method adopts R in the first step1Taking the pyrrolidine boric acid with the protected group as a raw material, reacting with dihydric alcohol, and protecting two hydroxyl groups of the boric acid and simultaneously carrying out chiral induction; in a second step, the compound shown as the formula I is subjected to R removal1Protecting groups, and then adding a resolving agent for resolution to obtain a compound shown in a formula II, wherein the yield of the obtained product with the target configuration is greatly improved by the method of resolving by using the resolving agent; the third step uses R4The valine protected by the group is used as a starting material, so that the product loss problem caused by complex post-treatment during deprotection is avoided, and the compound shown as the formula V can be directly salified with acid HX in the last step, so that the total yield of the dipeptide valine boron proline salt is improved, the post-treatment step of the reaction is simplified, and the loss of the final target product is reduced. The present invention provides a new technological synthesis method of dipeptide valine boroproline methane sulfonate (Talabostat methane sulfonate) as new anticancer medicine.
Preferably, R in step (1)1The molar mass ratio of the group-protected pyrrolidinoboric acid to the diol is (1-1.2):1 and may be, for example, 1:1, 1:1.02, 1:1.04, 1:1.06, 1:1.08, 1:1.09, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18, 1:1.19, 1:1.2, preferably 1:1.
Preferably, said R is1The group is selected from any one of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (cbz), benzyl (Bn), 2, 4-dimethoxybenzyl (Dmb) or trityl (Trt), and is preferably tert-butyloxycarbonyl (Boc).
Preferably, the diol is (1S,2S,3R,5S) -2, 3-pinanediol or pinacol.
Preferably, the reaction system in the step (1) further comprises a drying agent.
Preferably, the drying agent in the step (1) is anhydrous magnesium sulfate.
Preferably, the drying agent in step (1) is mixed with R1The molar mass ratio of the group-protected pyrrolidinoboric acid (1-3: 1) may be, for example, 1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3:1, preferably 2: 1.
Preferably, the reaction time in step (1) is 1-5h, for example, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5 h.
Preferably, the reaction temperature in step (1) is 10-30 deg.C, such as 10 deg.C, 12 deg.C, 14 deg.C, 16 deg.C, 18 deg.C, 19 deg.C, 20 deg.C, 22 deg.C, 24 deg.C, 26 deg.C, 28 deg.C, 30 deg.C.
Preferably, the solvent for the reaction of step (1) comprises any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran, preferably tetrahydrofuran.
Preferably, the R removal in the step (2)1The group protecting agent is an acid.
Preferably, the acid is hydrochloric acid and/or trifluoroacetic acid, preferably hydrochloric acid.
Preferably, the molar mass ratio of the acid in step (2) to the compound of formula I is (1-3):1, and may be, for example, 1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3: 1.
Preferably, the R removal in the step (2)1The reaction time for the group protection is 0.5 to 2 hours, and may be, for example, 0.5 hour, 0.6 hour, 0.7 hour, 0.8 hour, 0.9 hour, 1 hour, 1.2 hour, 1.4 hour, 1.6 hour, 1.8 hour, or 2 hours.
Preferably, the R removal in the step (2)1The reaction temperature for protecting the group is-10 to 5 ℃, and may be, for example, -10 ℃, -9 ℃, -8 ℃, -7 ℃, -6 ℃, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -10 ℃, 1 ℃,2 ℃,3 ℃,4 ℃,5 ℃.
Preferably, the R removal in the step (2)1The group-protecting reaction solvent includes any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran, preferably diethyl ether.
Preferably, the resolving agent in the step (2) is any one of L-dibenzoyl tartaric acid monohydrate, L-dibenzoyl tartaric acid anhydride, L-mandelic acid, L-O-acetyl mandelic acid, L-di-p-methylbenzoyl tartaric acid monohydrate or L-di-p-methylbenzoyl tartaric acid anhydride, and is preferably L-dibenzoyl tartaric acid monohydrate.
Preferably, the molar mass ratio of the resolving agent to the compound of formula I in step (2) is (0.9-1):1, and may be, for example, 0.9:1, 0.91:1, 0.92:1, 0.93:1, 0.94:1, 0.95:1, 0.96:1, 0.97:1, 0.98:1, 0.99:1, 1:1, preferably 0.95: 1.
Preferably, the conditions for the resolution of step (2) are: the reaction is carried out for 0.5 to 2 hours (for example, 0.5 hour, 0.6 hour, 0.7 hour, 0.8 hour, 0.9 hour, 1 hour, 1.2 hour, 1.4 hour, 1.6 hour, 1.8 hour, 2 hour) at 50 to 60 ℃ (for example, 50 ℃, 52 ℃, 54 ℃, 56 ℃, 58 ℃, 60 ℃) and for 0.5 to 2 hours (for example, 0.5 hour, 0.6 hour, 0.7 hour, 0.8 hour, 0.9 hour, 1 hour, 1.2 hour, 1.4 hour, 1.6 hour, 1.8 hour, 2 hour) at-10 to 5 ℃ (for example, 10 ℃, -9 ℃, -7 ℃, -6 ℃, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -10 ℃, 1 ℃,2 ℃,3 ℃,4 ℃,5 ℃).
Preferably, the solvent for the resolution in step (2) comprises any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran, preferably ethyl acetate.
Preferably, the compound of formula II in step (3) is reacted with R4The molar mass ratio of the group-protected L-valine is (1-1.5):1, and may be, for example, 1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, and preferably 1:1.
Preferably, said R is4The group is selected from benzyloxycarbonyl (Cbz), fluorenyl-methoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), p-methoxybenzyl (Pmb) or benzyl (Bn)One, preferably benzyloxycarbonyl (Cbz);
preferably, the reaction system in the step (3) further comprises an organic base.
Preferably, the organic base in step (3) is diisopropylethylamine.
Preferably, the organic base of step (3) is reacted with R4The molar mass ratio of the group-protected L-valine is (1-1.5):1, and may be, for example, 1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5: 1.
Preferably, the reaction temperature in step (3) is-10 to 5 ℃, and may be, for example, -10 ℃, -9 ℃, -8 ℃, -7 ℃, -6 ℃, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -10 ℃, 1 ℃,2 ℃,3 ℃,4 ℃,5 ℃, preferably 0 ℃.
Preferably, the reaction time in step (3) is 6-10h, such as 6h, 7h, 8h, 9h, 10h, preferably 8 h.
Preferably, the reaction solvent of step (3) comprises any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran, preferably dichloromethane.
Preferably, the step (3) comprises the following specific steps: first, the activator is used to react R4Activating the group-protected L-valine, and then reacting with the compound shown in the formula II to obtain the compound shown in the formula III.
Preferably, the activating agent is isobutyl chloroformate.
Preferably, the activator is reacted with R4The molar mass ratio of the group-protected L-valine is (1-1.5):1, and may be, for example, 1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5: 1.
Preferably, the activation reaction system further comprises an organic base.
Preferably, the organic base is diisopropylethylamine.
Preferably, the organic base is reacted with R4The molar mass ratio of the group-protected L-valine is (1-1.5):1, and may be, for example, 1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5: 1.
Preferably, the activation reaction temperature is-10 to 5 ℃, for example, -10 ℃, -9 ℃, -8 ℃, -7 ℃, -6 ℃, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -10 ℃, 1 ℃,2 ℃,3 ℃,4 ℃,5 ℃, preferably 0 ℃.
Preferably, the activation reaction time is 0.5 to 2 hours, and may be, for example, 0.5 hour, 0.6 hour, 0.7 hour, 0.8 hour, 0.9 hour, 1 hour, 1.2 hour, 1.4 hour, 1.6 hour, 1.8 hour, 2 hours.
Preferably, the solvent for the activation reaction includes any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran, preferably dichloromethane.
Preferably, the molar mass ratio of the acid to the compound represented by the formula III in the step (4) is (10-15: 1), and may be, for example, 10:1, 11:1, 12:1, 13:1, 14:1, or 15: 1.
Preferably, the acids are phenylboronic acid and hydrochloric acid.
The molar mass ratio of the phenylboronic acid to the compound of the formula III is preferably (10-15):1, and may be, for example, 10:1, 11:1, 12:1, 13:1, 14:1, or 15: 1.
Preferably, the molar mass ratio of the hydrochloric acid to the compound represented by the formula III is (1-1.5):1, and may be, for example, 1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5: 1.
Preferably, the reaction time in step (4) is 10-20h, for example, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, preferably 12 h.
Preferably, the reaction temperature in step (4) is 10-30 deg.C, such as 10 deg.C, 12 deg.C, 14 deg.C, 16 deg.C, 18 deg.C, 19 deg.C, 20 deg.C, 22 deg.C, 24 deg.C, 26 deg.C, 28 deg.C, 30 deg.C.
Preferably, the reaction solvent of step (4) comprises any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methanol, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran, preferably methanol.
Preferably, the R removal in the step (5)4The group protection reaction is a catalytic hydrogenolysis reaction.
Preferably, the catalyst for the catalytic hydrogenolysis reaction is palladium on carbon.
The amount of the catalytic hydrogenolysis catalyst added is preferably 1 to 10% by mass of the compound represented by the formula iv, and may be, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, and preferably 5%.
Preferably, the pressure at which hydrogen is passed through the catalytic hydrogenolysis reaction is 0.3 to 0.7MPa, and may be, for example, 0.3MPa, 0.4MPa, 0.5MPa, 0.6MPa, 0.7MPa, and preferably 0.5 MPa.
Preferably, the catalytic hydrogenolysis reaction time is 2 to 6h, for example, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, preferably 4 h.
Preferably, the catalytic hydrogenolysis reaction solvent comprises any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methanol, ethanol, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran, preferably methanol.
Preferably, the molar mass ratio of the compound of formula V to the acid HX in step (6) is (1-1.2):1, and may be, for example, 1:1, 1:1.02, 1:1.04, 1:1.06, 1:1.08, 1:1.09, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18, 1:1.19, 1: 1.2.
Preferably, the acid HX in step (6) is any one of methane sulfonic acid, ethane sulfonic acid, hydrochloric acid, sulfuric acid, acetic acid, formic acid or benzoic acid, preferably methane sulfonic acid.
Preferably, the reaction time in step (6) is 1-3h, for example, 1h, 1.5h, 2h, 2.5h, 3h, preferably 2 h.
Preferably, the reaction temperature in step (6) is 10 to 30 ℃, for example, 10 ℃, 12 ℃, 14 ℃, 16 ℃, 18 ℃, 19 ℃, 20 ℃, 22 ℃, 24 ℃, 26 ℃, 28 ℃, 30 ℃.
Preferably, the reaction solvent of step (6) comprises any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methanol, acetone, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran, preferably acetone.
Preferably, the preparation method specifically comprises the following steps:
(1) in the presence of a drying agent, R1Radical protectionReacting the pyrrolidine boronic acid with a dihydric alcohol to obtain a compound shown as a formula I, wherein R is1The molar mass ratio of the group-protected pyrrolidine boric acid to the dihydric alcohol is (1-1.2):1, the reaction time is 1-5h, and the reaction temperature is 10-30 ℃;
(2) the compound shown in the formula I reacts with acid to remove R1Protecting groups, wherein the molar mass ratio of the acid to the compound shown as the formula I is (1-3):1, and removing R1The reaction time of the group protection is 0.5 to 2 hours, and the R removal is carried out1The reaction temperature of the group protection is-10-5 ℃; and adding a resolving agent for resolution, wherein the molar mass ratio of the resolving agent to the compound shown in the formula I is (0.9-1):1, reacting at 50-60 ℃ for 0.5-2h, and reacting at-10-5 ℃ for 0.5-2h to obtain the compound shown in the formula II.
(3) Firstly, using an activating agent and an organic base to react R4Group-protected L-valine activation with R4The molar mass ratio of the group-protected L-valine is (1-1.5):1, and the organic base and R are4The molar mass ratio of the group-protected L-valine is (1-1.5):1, the activation reaction temperature is-10-5 ℃, and the activation reaction time is 0.5-2 h; re-activated R4Adding a compound of formula II to the group-protected L-valine for reaction with R4The molar mass ratio of the group-protected L-valine is (1-1.5):1, the reaction temperature is-10-5 ℃, the reaction time is 6-10h, and a compound shown in a formula III is obtained;
(4) reacting a compound shown as a formula III with acid to obtain a compound shown as a formula IV, wherein the molar mass ratio of the acid to the compound shown as the formula III is (10-15):1, the reaction time is 10-20h, and the reaction temperature is 10-30 ℃;
(5) carrying out catalytic hydrogenolysis reaction on the compound shown as the formula IV to remove R4Protecting groups to obtain a compound shown in a formula V, wherein the addition amount of the catalyst is 1-10% of the mass of the compound shown in the formula IV, the pressure of introducing hydrogen in the catalytic hydrogenolysis reaction is 0.3-0.7MPa, and the hydrogenation reaction time is 2-6 h;
(6) reacting a compound shown as a formula V with acid HX to obtain dipeptide valine boron proline salt, wherein the molar mass ratio of the compound shown as the formula V to the acid HX is (1-1.2):1, the reaction time is 1-3h, and the reaction temperature is 10-30 ℃.
Compared with the prior art, the invention has the following beneficial effects:
(1) the preparation method adopts R1Group-protected pyrrolidinoboronic acids and R4The protected valine is used as a starting material, so that the product loss problem caused by complex post-treatment during deprotection is avoided, the whole preparation process is simple, the total yield is high, the large-scale industrial production is facilitated, and the method has economic benefits and market values.
(2) According to the preparation method, the resolving agent is adopted for resolving in the second step, so that the problem of high product loss caused by the resolving method with different solubilities is solved, the product yield of the target configuration is greatly improved, and the yield can reach more than 33%.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1
This example prepares a mesylate salt of [ (2R) -1- [ (2S) -2-amino-3-methylbutyryl ] pyrrolidin-2-yl ] boronic acid
The synthetic route is
(1) N-Boc-2-pyrrolidineboronic acid (215g, 1mol) was dissolved in tetrahydrofuran (1.5L), anhydrous magnesium sulfate (240g, 2mol) was added with stirring, followed by addition of (1S,2S,3R,5S) -2, 3-pinanediol (170g, 1mol), reacted for two hours, filtered, washed, and the organic phase was concentrated to dryness, 331g affording intermediate A1.
(2) Intermediate A1(250g) was dissolved in 1000mL of diethyl ether and hydrogen chloride gas was bubbled through it at 0 ℃ for 30 min. The mixture was then slowly warmed to room temperature and stirred for an additional 3 h. Cooling to 0 ℃ and direct rotary evaporation gave 204g of white powder. The white powder was dissolved in water (1000mL), and a saturated aqueous sodium bicarbonate solution was added dropwise to a pH of 8.5. Then dichloromethane extraction, spin drying of the solvent, dissolution of the residue in ethyl acetate, addition of L-dibenzoyltartaric acid monohydrate (255g, 0.95eq), heating to 55 ℃ with stirring, stirring for 1h, then slowly cooling to 0 ℃, stirring for 1h at 0 ℃, filtration, washing of the filter cake with cold ether, drying to obtain 185g of white powder. The white powder was dissolved in 1000mL of water, aqueous sodium bicarbonate was added dropwise to pH 8.5, then extracted with dichloromethane, spin dried, dissolved in ether, charged with hydrogen chloride gas until the solution became acidic, stirred for 1h, then cooled to 0 ℃, filtered, washed with cold ether, and dried to give intermediate B1(82.7g, yield 33%).
1H NMR(CDCl3,400MHz):10.20(brs,1H),8.65(brs,1H),4.44(dd,1H)，3.47-3.37(m,2H),3.30-3.20(m,1H)，2.37-2.20(m，3H)，2.10-1.90(m,6H),1.48(s,3H)，1.30(s,3H)，1.15(d,1H)，0.85(s,3H).
(3) Cbz protected valine (25.1g, 0.1mol) was dissolved in 500mL of dichloromethane, isobutyl chloroformate (15.7g, 0.11mol) was added under ice-bath, diisopropylethylamine (17.6g, 0.137mol) was added dropwise, and the reaction was carried out for one hour under ice-bath. Intermediate B1(28.5g, 0.1mol) was then added and diisopropylethylamine (17.6g, 0.137mol) was added dropwise. The mixture was reacted at 0 ℃ for 8 h. The reaction mixture was washed with citric acid, saturated sodium bicarbonate, water, dried, concentrated and flash column chromatographed to afford intermediate C1(43.4g, 90% yield) as a pale yellow gum-like viscous mass.
1H NMR(CDCl3,400MHz):7.38-7.30(m,5H),5.58(d s,1H),5.10(dd,2H)，4.34-4.25(m,2H),3.85-3.75(m,1H)，3.55-3.45(m,1H)，3.23-3.18(dd,1H),2.38-2.29(m，1H)，2.19-1.95(m，7H)，1.85-1.70(m，2H)，1.41(s，3H)，1.38(d，1H)，1.29(s,1H)，1.02(d，3H)，0.94(d，3H)，0.85(s，3H).
(4) Intermediate C1(35g, 0.072mol) was dissolved in 300mL of methanol and phenylboronic acid (111g, 0.908mol), 1N hydrochloric acid (100mL) was added. The reaction was stirred at room temperature for 12 h. The reaction was concentrated, then 300mL of water was added, extracted three times with 100mL of dichloromethane, the dichloromethane phases combined, the organic phase washed with sodium bicarbonate, dried and concentrated to give 30g of intermediate D1.
(5) Intermediate D1(30g, 0.086mol) was dissolved in 100mL of methanol, hydrogenated with 5% palladium on carbon (3g) under 5 atmospheres of hydrogen for 4h, filtered and concentrated to give 18g of intermediate E1.
(6) 18g of intermediate E1 was dissolved in 180mL of acetone and methanesulfonic acid (8.5g,0.087mol) was added dropwise, stirred at room temperature for 2h, filtered, washed with acetone, washed with diethyl ether and dried to give (2R) -1- [ (2S) -2-amino-3-methylbutyryl ] pyrrolidin-2-yl ] boronic acid methanesulfonate as a white powder (24g, yield 90%).
1H NMR(MeOH-d4,400MHz):4.03(d,1H),3.78-3.74(m,1H),3.49-3.42(m,1H),3.38-3.34(m,1H),3.34-3.19(m,1H),2.72(s,3H),2.25(ddd,1H)，2.16-2.05(m,2H)，2.04-1.92(m,1H)，1.80-1.67(m,1H)，1.13(s,3H)，1.08(s,3H).
Example 2
Steps (1), (2), (3), (4) and (5) are the same as those of example 1 except that the raw acid HX in step (6) is hydrochloric acid.
(6) 18g of intermediate E1 was dissolved in 180mL of acetone, hydrochloric acid (3.176g, 0.087mol) was added dropwise, stirred at room temperature for 2h, filtered, washed with acetone, washed with diethyl ether, and dried to give (2R) -1- [ (2S) -2-amino-3-methylbutyryl ] pyrrolidin-2-yl ] boronic acid hydrochloride as a white powder (19.4g, 92% yield).
1H NMR(MeOH-d4,400MHz):4.03(d,1H),3.78-3.74(m,1H),3.49-3.42(m,1H),3.38-3.34(m,1H),3.34-3.19(m,1H),2.25(ddd,1H)，2.16-2.05(m,2H)，2.04-1.92(m,1H)，1.80-1.67(m,1H)，1.13(s,3H)，1.08(s,3H).
Example 3
This example prepares a mesylate salt of [ (2R) -1- [ (2S) -2-amino-3-methylbutyryl ] pyrrolidin-2-yl ] boronic acid
The synthetic route is
(1) N-Boc-2-pyrrolidineboronic acid (215g, 1mol) was dissolved in tetrahydrofuran (1.5L), anhydrous magnesium sulfate (240g, 2mol) was added with stirring, followed by pinacol (118g, 1mol) and reaction for two hours, followed by filtration, washing, concentration and drying of the organic phase to give intermediate A2 (276 g).
(2) Intermediate A2(270g) was dissolved in 1000mL of diethyl ether and hydrogen chloride gas was bubbled through it at 0 ℃ for 30 min. The mixture was then slowly warmed to room temperature and stirred for an additional 3 h. Cooling to 0 ℃ and direct rotary evaporation gave 201g of white powder. The white powder was dissolved in water (1000mL), and a saturated aqueous sodium bicarbonate solution was added dropwise to a pH of 9. Then dichloromethane extraction is carried out, the solvent is dried by spinning, the residue is dissolved in ethyl acetate, L-di-p-methyl benzoyl tartaric acid monohydrate (332g, 1eq) is added, the temperature is raised to 55 ℃ under stirring, the stirring is carried out for 1h, then the temperature is slowly lowered to 0 ℃, the stirring is carried out for 1h at 0 ℃, the filtration is carried out, the filter cake is washed by cold ether, and the drying is carried out, thus obtaining 190g of white powder. The white powder was dissolved in 1000mL of water, aqueous sodium bicarbonate was added dropwise to pH 9, then extracted with dichloromethane, spin dried, dissolved in ether, charged with hydrogen chloride gas until the solution became acidic, stirred for 1h, then cooled to 0 ℃, filtered, washed with cold ether, and dried to give intermediate B2(76g, yield 38%).
1H NMR(CDCl3,400MHz):10.20(brs,1H),8.65(brs,1H),4.44(dd,1H)，3.47-3.37(m,2H),3.30-3.20(m,1H)，2.37-2.20(m，3H)，2.10-1.90(m,6H),1.48(s,3H)，1.30(s,3H)，1.15(d,1H)，0.85(s,3H).
(3) Cbz protected valine (25.1g, 0.1mol) was dissolved in 500mL of dichloromethane, isobutyl chloroformate (15.7g, 0.11mol) was added under ice-bath, diisopropylethylamine (17.6g, 0.137mol) was added dropwise, and the reaction was carried out for one hour under ice-bath. Intermediate B2(23.5g, 0.1mol) was then added and diisopropylethylamine (17.6g, 0.137mol) was added dropwise. The mixture was reacted at 0 ℃ for 8 h. The reaction mixture was washed with citric acid, saturated sodium bicarbonate, water, dried, concentrated and flash column chromatographed to afford intermediate C1(39g, 90% yield) as a pale yellow gum-like viscous mass.
1H NMR(CDCl3,400MHz):7.38-7.30(m,5H),5.58(d s,1H),5.10(dd,2H)，4.34-4.25(m,2H),3.85-3.75(m,1H)，3.55-3.45(m,1H)，3.23-3.18(dd,1H),2.38-2.29(m，1H)，2.19-1.95(m，7H)，1.85-1.70(m，2H)，1.41(s，3H)，1.38(d，1H)，1.29(s,1H)，1.02(d，3H)，0.94(d，3H)，0.85(s，3H).
(4) Intermediate C1(35g, 0.081mol) was dissolved in 300mL of methanol, and phenylboronic acid (111g, 0.91mol), 1N hydrochloric acid (100mL) was added. The reaction was stirred at room temperature for 12 h. The reaction was concentrated, then 300mL of water was added, extracted three times with 100mL of dichloromethane, the dichloromethane phases combined, the organic phase washed with sodium bicarbonate, dried, and concentrated to give 18g of crude intermediate D1.
(5) Intermediate D1(30g, 0.086mol) was dissolved in 100mL of methanol, hydrogenated with 5% palladium on carbon (3g) under 5 atmospheres of hydrogen for 4h, filtered and concentrated to give 18g of intermediate E1.
(6) 18g of intermediate E1 was dissolved in 180mL of acetone and methanesulfonic acid (8.5g,0.087mol) was added dropwise, stirred at room temperature for 2h, filtered, washed with acetone, washed with diethyl ether and dried to give (2R) -1- [ (2S) -2-amino-3-methylbutyryl ] pyrrolidin-2-yl ] boronic acid methanesulfonate as a white powder (24g, yield 90%).
1H NMR(MeOH-d4,400MHz):4.03(d,1H),3.78-3.74(m,1H),3.49-3.42(m,1H),3.38-3.34(m,1H),3.34-3.19(m,1H),2.72(s,3H),2.25(ddd,1H)，2.16-2.05(m,2H)，2.04-1.92(m,1H)，1.80-1.67(m,1H)，1.13(s,3H)，1.08(s,3H).
Example 4
This example prepares a mesylate salt of [ (2R) -1- [ (2S) -2-amino-3-methylbutyryl ] pyrrolidin-2-yl ] boronic acid
The synthetic route is
(1) N-Trt-2-pyrrolidineboronic acid (357g, 1mol) was dissolved in tetrahydrofuran (1.5L), anhydrous magnesium sulfate (240g, 2mol) was added with stirring, followed by addition of (1S,2S,3R,5S) -2, 3-pinanediol (170g, 1mol), reacted for two hours, filtered, washed, and the organic phase was concentrated and dried to obtain 466g of intermediate A3.
(2) Intermediate A3(245.5g, 0.5mol) was dissolved in 1000mL of diethyl ether and hydrogen chloride gas was bubbled through it at 0 ℃ for 30 min. The mixture was then slowly warmed to room temperature and stirred for an additional 3 h. Cooling to 0 ℃ and direct rotary evaporation gave 150g of white powder. The white powder was dissolved in water (1000mL), and a saturated aqueous sodium bicarbonate solution was added dropwise to a pH of 8. Then extracting with dichloromethane, spin-drying the solvent, dissolving the residue in ethyl acetate, adding L-dibenzoyl tartaric acid monohydrate (192g, 0.475mol), heating to 55 deg.C under stirring, stirring for 1h, then slowly cooling to 0 deg.C, stirring for 1h at 0 deg.C, filtering, washing the filter cake with cold ether, and drying. The white powder was dissolved in 1000mL of water, aqueous sodium bicarbonate was added dropwise to pH 8, then extracted with dichloromethane, spin dried, dissolved in ether, charged with hydrogen chloride gas until the solution became acidic, stirred for 1h, then cooled to 0 ℃, filtered, washed with cold ether, and dried to give intermediate B1(50.76g, yield 35.5%).
(3) Pmb protected valine (23.7g, 0.1mol) was dissolved in 500mL of dichloromethane, isobutyl chloroformate (17.1g, 0.12mol) was added under ice-bath, diisopropylethylamine (17.6g, 0.137mol) was added dropwise, and the reaction was carried out for one hour under ice-bath. Intermediate B1(28.6g, 0.1mol) was then added and diisopropylethylamine (17.6g, 0.137mol) was added dropwise. The mixture was reacted at 0 ℃ for 8 h. The reaction mixture was washed with citric acid, saturated sodium bicarbonate, water, dried, concentrated and flash column chromatographed to afford intermediate C3(43.1g, 92% yield) as a pale yellow gum-like viscous mass.
(4) Intermediate C3(33.7g, 0.072mol) was dissolved in 300mL of methanol and phenylboronic acid (111g, 0.908mol), 1N hydrochloric acid (100mL) was added. The reaction was stirred at room temperature for 15 h. The reaction was concentrated, then 500mL of water was added, extracted three times with 200mL of dichloromethane, the dichloromethane phases combined, the organic phase washed with sodium bicarbonate, dried and concentrated to give 25g of intermediate D1.
(5) Intermediate D1(20g, 0.06mol) was dissolved in 100mL of methanol, hydrogenated with 10% palladium on carbon (1g) under 5 atmospheres of hydrogen for 5h, filtered and concentrated to give 13g of intermediate E1.
(6) 10g of intermediate E1 was dissolved in 180mL of acetone, methanesulfonic acid (6.1g, 0.062mol) was added dropwise, stirred at room temperature for 2h, filtered, washed with acetone, washed with diethyl ether, and dried to give (2R) -1- [ (2S) -2-amino-3-methylbutyryl ] pyrrolidin-2-yl ] boronic acid methanesulfonate as a white powder (13g, 91% yield).
1H NMR(MeOH-d4,400MHz):4.03(d,1H),3.78-3.74(m,1H),3.49-3.42(m,1H),3.38-3.34(m,1H),3.34-3.19(m,1H),2.72(s,3H),2.25(ddd,1H)，2.16-2.05(m,2H)，2.04-1.92(m,1H)，1.80-1.67(m,1H)，1.13(s,3H)，1.08(s,3H).
The applicant states that the present invention is illustrated by the above examples of a process for the preparation of the dipeptide valine boron prolinate of the invention, but the present invention is not limited to the above examples, i.e. it does not mean that the present invention must be practiced by relying on the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (77)
1. A preparation method of dipeptide valine boron proline salt is characterized by comprising the following steps:
（1）R1reacting the group-protected pyrrolidine boronic acid with dihydric alcohol to obtain a compound shown as a formula I, wherein the reaction formula is as follows:
(2) a compound of formula I de R1Protecting groups, and then adding a resolving agent for resolution to obtain a compound shown as a formula II, wherein the reaction formula is as follows:
(3) a compound of formula II and R4Radical-protectedL-Valine reaction to obtain a compound shown in a formula III, wherein the reaction formula is as follows:
(4) reacting the compound shown in the formula III with acid to obtain a compound shown in a formula IV, wherein the reaction formula is as follows:
(5) de-R of a compound of formula IV4Group protection gives compounds of formula V, the reaction is as follows:
(6) reacting the compound shown in the formula V with acid HX to obtain dipeptide valine boron proline salt, wherein the reaction formula is as follows:
wherein R is1And R4The groups are independently selected from any one of alkoxycarbonyl, acyl or aryl; r2And R3Each group is independently selected from hydrogen, straight or branched chain alkyl; the anion X is independently selected from any one of alkyl sulfonate, halogen ion, sulfate ion or carboxylate ion;
the resolving agent in the step (2) isL-Dibenzoyl tartaric acid monohydrate,LDibenzoyltartaric acid anhydride, dibenzoyltartaric acid anhydride,LDi-p-methylbenzoyl tartaric acid monohydrate orL-Any one of di-p-methylbenzoyl tartaric acid anhydride;
the molar mass ratio of the resolving agent to the compound shown in the formula I in the step (2) is (0.9-1) to 1;
the splitting condition in the step (2) is as follows: the reaction is carried out for 0.5 to 2 hours at 50 to 60 ℃ and then for 0.5 to 2 hours at-10 to 5 ℃.
2. The method according to claim 1, wherein R in the step (1)1The molar mass ratio of the group-protected pyrrolidineboronic acid to the diol is (1-1.2): 1.
3. The method according to claim 2, wherein R in the step (1)1The molar mass ratio of the group-protected pyrrolidineboronic acid to the diol is 1:1.
4. The method of claim 1, wherein R is1The group is selected from any one of tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, 2, 4-dimethoxybenzyl or trityl.
5. The method of claim 4, wherein R is1The group is tert-butyloxycarbonyl.
6. The method according to claim 1, wherein the diol of step (1) is (1S,2S,3R,5S) -2, 3-pinanediol or pinacol.
7. The method according to claim 1, wherein the reaction system of step (1) further comprises a drying agent.
8. The method according to claim 7, wherein the drying agent in step (1) is anhydrous magnesium sulfate.
9. The method according to claim 7, wherein the drying agent of step (1) is mixed with R1The molar mass ratio of the group-protected pyrrolidineboronic acid is (1-3): 1.
10. The method of claim 9, wherein step (1) comprises reacting said desiccant with R1The molar mass ratio of the group-protected pyrrolidineboronic acid was 2: 1.
11. The method according to claim 1, wherein the reaction time in step (1) is 1 to 5 hours.
12. The method according to claim 1, wherein the reaction temperature in the step (1) is 10 to 30 ℃.
13. The method according to claim 1, wherein the solvent for the reaction in step (1) is any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate, and tetrahydrofuran.
14. The method according to claim 13, wherein the solvent for the reaction in step (1) is tetrahydrofuran.
15. The method according to claim 1, wherein the R removal in the step (2)1The group protecting agent is an acid.
16. The method of claim 15, wherein the acid is hydrochloric acid and/or trifluoroacetic acid.
17. The method of claim 16, wherein the acid is hydrochloric acid.
18. The method according to claim 1, wherein the molar mass ratio of the acid in the step (2) to the compound represented by the formula I is (1-3): 1.
19. The method according to claim 1, wherein the R removal in the step (2)1The reaction time of the group protection is 0.5-2 h.
20. The method according to claim 1, wherein the R removal in the step (2)1The reaction temperature of the group protection is-10-5 ℃.
21. The method according to claim 1, wherein the R removal in the step (2)1The group-protecting reaction solvent is any one or combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran.
22. The method of claim 21, wherein the de-R in step (2)1The group-protected reaction solvent is diethyl ether.
23. The process according to claim 1, wherein the resolving agent in step (2) isL-Dibenzoyltartaric acid monohydrate.
24. The preparation method according to claim 1, wherein the molar mass ratio of the resolving agent to the compound represented by the formula I in the step (2) is 0.95: 1.
25. The preparation method according to claim 1, wherein the solvent for the resolution in step (2) is any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran.
26. The process of claim 25, wherein the solvent for the resolution in step (2) is ethyl acetate.
27. According toThe process according to claim 1, wherein the compound of formula II in the step (3) is reacted with R4Radical-protectedL-The molar mass ratio of valine is (1-1.5) to 1.
28. The method according to claim 27, wherein the compound of formula II and R in step (3)4Radical-protectedL-The molar mass ratio of valine is 1:1.
29. The method according to claim 1, wherein R in the step (3)4The group is selected from any one of benzyloxycarbonyl, fluorenyl methoxycarbonyl, allyloxycarbonyl, p-methoxybenzyl or benzyl.
30. The method of claim 1, wherein R is4The radical is benzyloxycarbonyl.
31. The method according to claim 1, wherein the reaction system in the step (3) further comprises an organic base.
32. The method according to claim 31, wherein the organic base in step (3) is diisopropylethylamine.
33. The method according to claim 31, wherein the organic base of step (3) is reacted with R4Radical-protectedL-The molar mass ratio of valine is (1-1.5) to 1.
34. The method according to claim 1, wherein the reaction temperature in the step (3) is-10 to 5 ℃.
35. The method according to claim 34, wherein the reaction temperature in the step (3) is 0 ℃.
36. The method according to claim 1, wherein the reaction time in the step (3) is 6 to 10 hours.
37. The method according to claim 36, wherein the reaction time in the step (3) is 8 hours.
38. The method according to claim 1, wherein the reaction solvent in step (3) is any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate, or tetrahydrofuran.
39. The method according to claim 38, wherein the reaction solvent in the step (3) is dichloromethane.
40. The preparation method according to claim 1, wherein the step (3) comprises the following specific steps: first, the activator is used to react R4Radical-protectedL-Valine activation and reaction with the compound shown in the formula II to obtain the compound shown in the formula III.
41. The method of claim 40, wherein the activator is isobutyl chloroformate.
42. The method of claim 40, wherein the activator is reacted with R4Radical-protectedL-The molar mass ratio of valine is (1-1.5) to 1.
43. The method of claim 40, wherein the activation reaction system further comprises an organic base.
44. The method of claim 43, wherein the organic base is diisopropylethylamine.
45. The method of claim 43, wherein the organic base is reacted with R4Radical-protectedL-The molar mass ratio of valine is (1-1.5) to 1.
46. The method according to claim 40, wherein the activation reaction temperature is-10 to 5 ℃.
47. The method of claim 40, wherein the activation reaction time is 0.5 to 2 hours.
48. The method according to claim 40, wherein the solvent for the activation reaction is any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methyl tert-butyl ether, ethyl acetate, or tetrahydrofuran.
49. The method of claim 40, wherein the solvent for the activation reaction is dichloromethane.
50. The preparation method according to claim 1, wherein the molar mass ratio of the acid in the step (4) to the compound represented by the formula III is (10-15): 1.
51. The method according to claim 1, wherein the acid in the step (4) is phenylboronic acid and hydrochloric acid.
52. The method according to claim 51, wherein the molar mass ratio of the phenylboronic acid to the compound represented by the formula III is (10-15): 1.
53. The method according to claim 51, wherein the molar mass ratio of the hydrochloric acid to the compound represented by the formula III is (1-1.5): 1.
54. The method according to claim 1, wherein the reaction time in the step (4) is 10 to 20 hours.
55. The method as claimed in claim 54, wherein the reaction time in step (4) is 12 h.
56. The method according to claim 1, wherein the reaction temperature in the step (4) is 10 to 30 ℃.
57. The method according to claim 1, wherein the reaction solvent in step (4) is any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methanol, methyl tert-butyl ether, ethyl acetate, or tetrahydrofuran.
58. The method according to claim 57, wherein the reaction solvent in the step (4) is methanol.
59. The method according to claim 1, wherein the R removal in the step (5)4The group protection reaction is a catalytic hydrogenolysis reaction.
60. The method of claim 59, wherein the catalyst for the catalytic hydrogenolysis reaction is palladium on carbon.
61. The method of claim 59, wherein the catalytic hydrogenolysis catalyst is added in an amount of 1-10% by weight based on the amount of the compound of formula IV.
62. The method of claim 61, wherein the catalytic hydrogenolysis catalyst is added in an amount of 5% by weight based on the amount of the compound of formula IV.
63. The method of claim 59, wherein the catalytic hydrogenolysis reaction is conducted under a hydrogen gas pressure of 0.3-0.7 MPa.
64. The method of claim 63, wherein the catalytic hydrogenolysis reaction is conducted under a hydrogen gas pressure of 0.5 MPa.
65. The method of claim 59, wherein the catalytic hydrogenolysis reaction time is 2-6 hours.
66. The method of claim 65, wherein the catalytic hydrogenolysis reaction time is 4 hours.
67. The method of claim 59, wherein the catalytic hydrogenolysis solvent is any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methanol, ethanol, methyl tert-butyl ether, ethyl acetate or tetrahydrofuran.
68. The method of claim 67, wherein the catalytic hydrogenolysis reaction solvent is methanol.
69. The method according to claim 1, wherein the molar mass ratio of the compound of formula V to the acid HX in step (6) is (1-1.2): 1.
70. The method according to claim 1, wherein the acid HX in step (6) is any one of methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, acetic acid, formic acid, and benzoic acid.
71. The method according to claim 70, wherein the acid HX in step (6) is methanesulfonic acid.
72. The method according to claim 1, wherein the reaction time in the step (6) is 1 to 3 hours.
73. The method according to claim 72, wherein the reaction time in step (6) is 2 hours.
74. The method according to claim 1, wherein the reaction temperature in the step (6) is 10 to 30 ℃.
75. The method according to claim 1, wherein the reaction solvent in step (6) is any one or a combination of at least two of dichloromethane, chloroform, n-hexane, acetonitrile, diethyl ether, methanol, acetone, methyl tert-butyl ether, ethyl acetate, and tetrahydrofuran.
76. The method according to claim 75, wherein the reaction solvent in the step (6) is acetone.
77. The preparation method according to claim 1, comprising in particular the steps of:
(1) in the presence of a drying agent, R1Reacting the group-protected pyrrolidine boronic acid with dihydric alcohol to obtain a compound shown as a formula I, wherein R is1The molar mass ratio of the group-protected pyrrolidine boric acid to the dihydric alcohol is (1-1.2):1, the reaction time is 1-5h, and the reaction temperature is 10-30 ℃;
(2) the compound shown in the formula I reacts with acid to remove R1Protecting groups, wherein the molar mass ratio of the acid to the compound shown as the formula I is (1-3):1, and removing R1The reaction time of the group protection is 0.5 to 2 hours, and the R removal is carried out1The reaction temperature of the group protection is-10-5 ℃; adding a resolving agent for resolution, wherein the molar mass ratio of the resolving agent to the compound shown in the formula I is (0.9-1):1, reacting at 50-60 ℃ for 0.5-2h, and reacting at-10-5 ℃ for 0.5-2h to obtain a compound shown in the formula II;
(3) firstly, using an activating agent and an organic base to react R4Radical-protectedL-Valine activation, said activation reagent with R4Radical-protectedL-The molar mass ratio of valine (1-1.5) to 1, the organic base and R4Radical-protectedL-The molar mass ratio of valine is (1-1.5) to 1, the activation reaction temperature is-10-5 ℃, and the activation reaction time is 0.5-2 h; re-activated R4Radical-protectedL-Adding a compound shown as a formula II into valine to react, wherein the compound shown as the formula II is reacted with R4Radical-protectedL-The molar mass ratio of valine is (1-1.5) to 1, the reaction temperature is-10-5 ℃, the reaction time is 6-10h, and a compound shown in a formula III is obtained;
(4) reacting a compound shown as a formula III with acid to obtain a compound shown as a formula IV, wherein the molar mass ratio of the acid to the compound shown as the formula III is (10-15):1, the reaction time is 10-20h, and the reaction temperature is 10-30 ℃;
(5) carrying out catalytic hydrogenolysis reaction on the compound shown as the formula IV to remove R4Protecting groups to obtain a compound shown in a formula V, wherein the addition amount of the catalyst is 1-10% of the mass of the compound shown in the formula IV, the pressure of introducing hydrogen in the catalytic hydrogenolysis reaction is 0.3-0.7MPa, and the hydrogenation reaction time is 2-6 h;
(6) reacting a compound shown as a formula V with acid HX to obtain dipeptide valine boron proline salt, wherein the molar mass ratio of the compound shown as the formula V to the acid HX is (1-1.2):1, the reaction time is 1-3h, and the reaction temperature is 10-30 ℃.
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| CN1073946A (en) * | 1991-11-22 | 1993-07-07 | 博灵格英格海母制药公司 | The method for preparing borate proline |
| TW575574B (en) * | 1998-06-05 | 2004-02-11 | Point Therapeutics Inc | Cyclic boroproline compounds |
| CN102286011A (en) * | 2010-03-16 | 2011-12-21 | 广州市迈德医药技术有限公司 | Pyrrolidine botonate ester dipeptidyl peptidase inhibitor and its pharmaceutical composition |
| CN108047257A (en) * | 2017-12-17 | 2018-05-18 | 沧州普瑞东方科技有限公司 | A kind of preparation process of chirality N-BOC- pyrrolidines -2- boric acid |
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| WO1991016339A1 (en) * | 1990-04-14 | 1991-10-31 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type iv |
| WO2008066729A2 (en) * | 2006-11-22 | 2008-06-05 | Dara Biosciences, Inc. | Boronic acid containing compositions |
| WO2018187698A2 (en) * | 2017-04-07 | 2018-10-11 | Trustees Of Tufts College | Combination therapies using caspase-1 dependent anticancer agents and pge2 antagonists |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1073946A (en) * | 1991-11-22 | 1993-07-07 | 博灵格英格海母制药公司 | The method for preparing borate proline |
| TW575574B (en) * | 1998-06-05 | 2004-02-11 | Point Therapeutics Inc | Cyclic boroproline compounds |
| CN102286011A (en) * | 2010-03-16 | 2011-12-21 | 广州市迈德医药技术有限公司 | Pyrrolidine botonate ester dipeptidyl peptidase inhibitor and its pharmaceutical composition |
| CN108047257A (en) * | 2017-12-17 | 2018-05-18 | 沧州普瑞东方科技有限公司 | A kind of preparation process of chirality N-BOC- pyrrolidines -2- boric acid |
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Denomination of invention: A preparation method of dipeptide valine boron proline salt Effective date of registration: 20211123 Granted publication date: 20210101 Pledgee: The Bank of Shanghai branch Caohejing Limited by Share Ltd. Pledgor: SHANGHAI BALMXY PHARMACEUTICAL Co.,Ltd. Registration number: Y2021310000107 |