CN111848430B - Synthetic method of 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compound - Google Patents
Synthetic method of 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compound Download PDFInfo
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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Abstract
The invention relates to 2- ([ 1,1' -biphenyl]Synthesis method of (E) -4-yl) -2-glycine compoundThe method comprises the steps of carrying out a suzuki reaction on a compound shown as a formula I and a compound shown as a formula II in the presence of alkali, a solvent and a catalyst under the protection of inert gas and the assistance of microwaves to prepare an intermediate compound, and then deprotecting the intermediate compound to prepare a compound shown as a formula III; wherein the structural formula of the compound shown in the formula I is as follows:
the structural formula of the compound shown in the formula II is as follows:
the structural formula of the compound shown in the formula III is as follows:
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a synthesis method of a 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compound.
Background
The 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compounds with monosubstituted or unsubstituted benzene rings in the amino acid derivatives are important medical intermediates and are widely applied in the field of medical chemistry, such as compounds for synthesizing protease inhibitors and intermediates of pharmaceutical compositions thereof.
However, at present, there is little research on the preparation method of the compound, and 4-biphenylcarboxaldehyde is generally used as a starting material in the synthesis method of the compound, such as the synthesis method disclosed in patent WO2003010130, and the route is as follows:
the synthesis steps are as follows: taking 4-biphenylcarboxaldehyde as a starting raw material, heating 4-biphenylcarboxaldehyde, ammonium formate and tert-butyl isocyanate in a methanol solution to 65 ℃, refluxing for 12h, cooling, decompressing to remove methanol, performing post-treatment to obtain an intermediate, dissolving the intermediate in concentrated hydrochloric acid, and reacting for 24h at 100 ℃ to obtain an amino acid product.
In the synthesis method, the raw material adopts the toxic and flammable substance, namely tert-butyl isocyanate, so that the safety is low. The second step reaction is carried out at high temperature, so that the intermediate reacts with concentrated hydrochloric acid, and the safety is further reduced. And the total reaction time is too long, and the yield is not high.
Disclosure of Invention
The invention aims to provide a synthetic method of a 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compound with low toxicity, safety, effectiveness and high yield.
In order to achieve the purpose, the invention adopts the technical scheme that:
a method of synthesizing 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compound, comprising the steps of:
(1) Under the protection of inert gas and the auxiliary condition of microwave, enabling a compound shown in a formula I and a compound shown in a formula II to perform a suzuki reaction in the presence of alkali, a solvent and a catalyst to prepare an intermediate compound with tert-butoxycarbonyl protection;
(2) Carrying out deprotection reaction on the intermediate compound in the presence of acid to obtain a 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compound shown as a formula III;
wherein the structural formula of the compound shown in the formula I is as follows:
the structural formula of the compound shown in the formula II is as follows:
the structural formula of the compound shown in the formula III is as follows:
in the formula I and the formula III, R is one of H, alkyl with 1-5 carbon atoms, alkoxy with 1-3 carbon atoms, halogen and trifluoromethyl.
According to some embodiments of the invention, R is H, methyl, methoxy, F, cl, br or trifluoromethyl.
In formula III, the substitution of R can be 2', 3', 4' positions of biphenyl.
In the invention, the synthesis method has the following route:
preferably, the compound of formula III is:
2- ([ 1,1' -biphenyl]-4-yl) -2-glycine having the formula
2-amino-2- (3 '-fluoro- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (2 '-fluoro- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (4 '-fluoro- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (3 '-bromo- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (2 '-bromo- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (4 '-bromo- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (3 '-chloro- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (2 '-chloro- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (4 '-chloro- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (3 '-methyl- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (2 '-methyl- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (4 '-methyl- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (3 '-methoxy- [1,1' -biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (2' -methoxy- [1,1)' -Biphenyl]-4-yl) acetic acid of the formula
2-amino-2- (4 '-methoxy- [1,1' -biphenyl]-4-yl) acetic acid of the formula
According to some embodiments of the invention, in step (1), the microwave-assisted time is 2 to 4min.
The power of the microwave assistance is 70-90W, preferably 80W.
According to some embodiment aspects of the present invention, in the step (1), after the feeding of the compound of formula I, the compound of formula II, the base, the solvent and the catalyst is completed under the protection of the inert gas, the mixture is microwave-assisted for 2-4 min, and then reacted at 80-100 ℃ for 6-10 h.
The microwave assistance is not particularly limited as to the temperature of the system, and may be performed at a temperature lower than the reaction temperature of the system (i.e., 80 to 100 ℃), or may be performed at a temperature up to the reaction temperature of the system.
According to some embodiments of the invention, in step (1), the catalyst is a palladium catalyst.
According to some example aspects of this invention, the palladium catalyst is Pd (PPh) 3 ) 4 、PdCl 2 、PdCl 2 (dppf)、Pd(OAc) 2 、Pd(PPh 3 ) 2 Cl 2 One or a combination of several of them. Preferably, the catalyst is Pd (PPh) 3 ) 4 。
According to some implementation aspects of the invention, in the step (1), the reaction temperature of the suzuki reaction is 80-100 ℃, and the reaction time is 6-10 h.
According to some embodiments of the invention, in the step (1), the base is one or a combination of potassium carbonate, cesium carbonate and sodium carbonate, and the solvent is an organic solvent.
Further, the alkali is added in the form of alkali aqueous solution, and the feeding concentration is 1-3M.
According to some embodiments of the invention, in the step (1), the solvent is one or more of Tetrahydrofuran (THF) and toluene. Preferably, the solvent is tetrahydrofuran.
According to some embodiments of the invention, in step (1), the molar ratio of the compound of formula I to the compound of formula II is 1 to 1.5:1, the feeding molar ratio of the catalyst to the compound shown in the formula II is 0.0001-0.0005: 1.
according to some embodiments of the invention, in the step (2), the acid is one or more of trifluoroacetic acid and HCl.
Further, the trifluoroacetic acid is dosed as a trifluoroacetic acid solution. Preferably, the trifluoroacetic acid solution is trifluoroacetic acid dichloromethane solution, and the volume concentration of the trifluoroacetic acid is 10-30%.
Further, the HCl is fed in the form of an HCl aqueous solution, and the feeding concentration of the HCl aqueous solution is 4-6M.
According to some embodiments of the present invention, in step (2), the reaction temperature of the deprotection reaction is 15 to 35 ℃, and preferably, the reaction temperature of the deprotection reaction is 22 to 26 ℃.
According to some example aspects of the invention, the synthesis method is embodied as: under the protection of inert gas, mixing a compound shown in a formula I, a compound shown in a formula II, an organic solvent and an aqueous solution of alkali, heating and stirring, then adding a palladium catalyst, using 70-90W of microwave for assisting for 2-4 min, then stirring and reacting at 80-100 ℃ for 10-14 h, after the reaction is finished, extracting ethyl acetate, drying anhydrous sodium sulfate, removing the solvent, carrying out chromatographic purification, eluting a mixed solution of petroleum ether and ethyl acetate to prepare an intermediate compound, then adding an acid solution, stirring and reacting at 15-35 ℃ for 0.5-2 h, after the reaction is finished, extracting aqueous phase ethyl acetate, combining organic phases, drying anhydrous sodium sulfate, removing the solvent, and recrystallizing to prepare a compound shown in a formula III.
Further, in the mixed solution of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate is 10 to 30.
The invention relates to application of 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compounds in the fields of synthesis and medicinal chemistry.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
according to the synthetic method, phenylboronic acid or mono-substituted phenylboronic acid is used as a starting material, a coupling reaction is carried out by adopting a SUZUKI method, then a protecting group is removed, and the product 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compound is prepared. The synthetic method has the advantages of low toxicity, high safety coefficient, simple and convenient operation, easy control, high reaction efficiency and high yield of more than 81 percent.
In the synthetic method, microwave assistance for a certain time is added in the suzuki reaction process, so that the reaction is promoted, the reaction efficiency is effectively improved, and the reaction time is shortened.
Detailed Description
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following examples are provided merely to further illustrate the invention and are not intended to limit the scope of the invention in any way.
The starting materials may be obtained from commercial sources or prepared by methods known in the art or according to the methods described herein.
The structure of the compound is determined by nuclear magnetic resonance 1 H-NMR)、( 13 C-NMR and/or Mass Spectrometry (MS). NMR was measured using a Bruker ACF-400 (400 MHz) nuclear magnetic resonance apparatus using deuterated chloroform (CDCl) as the solvent 3 ) Or deuterated dimethyl sulfoxide (DMSO-D) 6 ) TMS is an internal standard. The column chromatography adopts 200-300 mesh silica gel (produced by Qingdao ocean chemical plant).
Example 1
Synthesis of 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine
Phenylboronic acid (1.33g, 11mmol), 2- (tert-butoxycarbonyl-amino) -2- (4-bromophenyl) acetic acid (3.30g, 10mmol), 2M K were added to a 100mL reaction flask under nitrogen protection 2 CO 3 (3 mL) and 20mL of THF were heated and stirred, and then Pd (PPh) was added 3 ) 4 (0.03g, 0.2 mmol), microwave-assisted with a microwave-assisted instrument (80W) for 3min, followed by stirring the reaction at 90 ℃ for 8h, extraction with ethyl acetate, drying over anhydrous sodium sulfate, removal of most of the solvent by rotation, purification by silica gel column chromatography, elution with petroleum ether/ethyl acetate (V/V = 20) to give tert-butoxycarbonyl protected 2- ([ 1,1' -biphenyl]-4-yl) -2-glycine, further 20% (V/V) TFA/CH 2 Cl 2 (30 mL), the reaction mixture was stirred at room temperature (25 ℃) for 1h, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the majority of the solvent was removed by swirling, and recrystallized from n-hexane to give 2- ([ 1,1' -biphenyl]-4-yl) -2-glycine (2.11 g) in 93% yield.
The results of nuclear magnetic structure testing of the product 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine are as follows:
1 H NMR(400MHz,DMSO)δ8.77(m,2H),7.59(m,2H),7.49(m,3H),7.43(m,3H),7.36(m,1H),5.15(m,1H).
13 C NMR(125MHz,DMSO)δ174.36(d),140.46(dd),139.64(t),137.53(dd),128.89(dt),128.45(t),127.99(m),127.30(t),59.72(dt).
example 2
Synthesis of 2-amino-2- (3 '-fluoro- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of the final product, 2-amino-2- (3 '-fluoro- [1,1' -biphenyl ] -4-yl) acetic acid, was the same as in example 1, using 3-fluorobenzeneboronic acid (11 mmol) instead of phenylboronic acid: 89 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ8.55(m,2H),7.46(m,6H),7.29(m,1H),7.07(m,1H),5.20(m,1H).
13 C NMR(125MHz,DMSO)δ174.35(d),138.58(m),130.24(m),128.29(m),115.59(m),59.72(dt).
example 3
Synthesis of 2-amino-2- (2 '-fluoro- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of 2-amino-2- (2 '-fluoro- [1,1' -biphenyl ] -4-yl) acetic acid as a final product was the same as in example 1, except that 2-fluorobenzeneboronic acid (11 mmol) was used instead of phenylboronic acid: 89 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ8.75(m,2H),7.62(m,1H),7.52(dq,2H),7.44(m,2H),7.38(m,2H),7.18(m,1H),5.20(m,1H).
13 C NMR(125MHz,DMSO)δ174.35(d),159.08(m),137.17(dd),134.87(t),130.13(p),129.44(m),128.61(m),124.56(dtd),115.57(dtd),59.72(dt).
example 4
Synthesis of 2-amino-2- (4 '-fluoro- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of 2-amino-2- (4 '-fluoro- [1,1' -biphenyl ] -4-yl) acetic acid as a final product was the same as in example 1, except that 4-fluorophenylboronic acid (11 mmol) was used instead of phenylboronic acid: 90 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ8.43(m,2H),7.56(m,2H),7.49(d,4H),7.18(m,2H),5.20(m,1H).
13 C NMR(125MHz,DMSO)δ174.35(d),163.59(d),161.57(d),139.86(t),137.53(dd),136.33(m),128.45(t),128.04(m),115.36(m),59.72(dt).
example 5
Synthesis of 2-amino-2- (3 '-bromo- [1,1' -biphenyl ] -4-yl) acetic acid
The yield of 2-amino-2- (3 '-bromo- [1,1' -biphenyl ] -4-yl) acetic acid as a final product in this example was the same as in example 1, using 3-bromobenzeneboronic acid (11 mmol) instead of phenylboronic acid: 83 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ12.43(m,1H),7.98(m,2H),7.58(ddt,2H),7.50(m,3H),7.45(m,2H),7.37(t,1H),5.15(m,1H).
13 C NMR(125MHz,DMSO)δ174.14(d),139.68(m),139.29(m),137.45(dd),132.15(td),130.53(q),130.16(dt),128.56(dt),128.02(q),122.71,59.47(dt).
example 6
Synthesis of 2-amino-2- (2 '-bromo- [1,1' -biphenyl ] -4-yl) acetic acid
The yield of 2-amino-2- (2 '-bromo- [1,1' -biphenyl ] -4-yl) acetic acid as a final product in this example was the same as in example 1, using 2-bromobenzeneboronic acid (11 mmol) instead of phenylboronic acid: 83 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ11.76(m,1H),8.18(m,2H),7.64(m,3H),7.57(dd,1H),7.48(m,2H),7.40(td,1H),7.32(td,1H),5.14(m,1H).
13 C NMR(125MHz,DMSO)δ174.14(d),140.17(m),138.79(d),137.35(dd),131.93(m),130.03(q),129.44(tq),128.68(t),128.41(q),127.35(tt),122.83(m),59.47(dt).
example 7
Synthesis of 2-amino-2- (4 '-bromo- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of the final product, 2-amino-2- (4 '-bromo- [1,1' -biphenyl ] -4-yl) acetic acid, was the same as in example 1, using 4-bromobenzeneboronic acid (11 mmol) instead of phenylboronic acid: 81 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ12.06(m,1H),8.02(m,2H),7.67(m,2H),7.59(m,2H),7.50(m,2H),7.46(m,2H),5.15(m,1H).
13 C NMR(125MHz,DMSO)δ174.14(d),139.47(m),137.40(dd),131.81(m),128.40(m),122.39(d),59.47(dt).
example 8
Synthesis of 2-amino-2- (3 '-chloro- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of 2-amino-2- (3 '-chloro- [1,1' -biphenyl ] -4-yl) acetic acid as a final product was the same as in example 1, except that 3-chlorobenzeneboronic acid (11 mmol) was used instead of phenylboronic acid: 88 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ8.12(m,2H),7.59(t,1H),7.49(m,5H),7.39(t,1H),7.33(dt,1H),5.20(m,1H).
13 C NMR(125MHz,DMSO)δ174.04(d),139.79(d),138.68(m),137.57(dd),133.24,129.68(dt),129.22(td),128.72(t),128.33(m),127.87(m),59.72(dt).
example 9
Synthesis of 2-amino-2- (2 '-chloro- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of 2-amino-2- (2 '-chloro- [1,1' -biphenyl ] -4-yl) acetic acid as a final product was the same as in example 1, except that 2-chlorobenzeneboronic acid (11 mmol) was used instead of phenylboronic acid: 89 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ7.99(m,2H),7.58(m,3H),7.45(m,3H),7.38(td,1H),7.32(td,1H),5.20(m,1H).
13 C NMR(125MHz,DMSO)δ174.04(d),137.97(m),137.50(d),137.16(dd),132.90(m),129.99(m),129.31(q),128.50(m),126.70(tt),59.72(dt).
example 10
Synthesis of 2-amino-2- (4 '-chloro- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of 2-amino-2- (4 '-chloro- [1,1' -biphenyl ] -4-yl) acetic acid as a final product was the same as in example 1, except that 4-chlorobenzeneboronic acid (11 mmol) was used instead of phenylboronic acid: 88 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ8.19(m,2H),7.61(m,2H),7.48(m,6H),5.20(t,1H),4.94(dd,1H).
13 C NMR(125MHz,DMSO)δ174.04(d),139.72(t),138.68(m),137.53(dd),134.79(d),129.24(m),128.69(m),128.24(dd),127.89(q),59.72(dt).
example 11
Synthesis of 2-amino-2- (3 '-methyl- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of 2-amino-2- (3 '-methyl- [1,1' -biphenyl ] -4-yl) acetic acid as a final product was the same as in example 1 except that 3-methylphenylboronic acid (11 mmol) was used instead of phenylboronic acid: 95 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ8.56(m,2H),7.47(m,5H),7.36(t,1H),7.12(ddq,1H),6.94(m,1H),5.20(t,1H),2.37(m,3H).
13 C NMR(125MHz,DMSO)δ174.35(d),139.73(m),139.28(m),137.57(m),128.83(dtd),128.47(t),127.82(dq),126.19(q),59.72(dt),21.45(t).
example 12
Synthesis of 2-amino-2- (2 '-methyl- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of 2-amino-2- (2 '-methyl- [1,1' -biphenyl ] -4-yl) acetic acid as a final product was the same as in example 1, except that 2-methylphenylboronic acid (11 mmol) was used instead of phenylboronic acid: 96 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ8.56(m,2H),7.53(m,2H),7.44(dt,3H),7.32(m,1H),7.27(m,2H),5.20(m,1H),2.36(d,3H).
13 C NMR(125MHz,DMSO)δ174.35(d),138.87(m),138.18(m),137.25(dd),135.16(tt),129.47(m),128.99(m),128.09(t),127.29(q),126.21(tt),59.72(dt),20.18(d).
example 13
Synthesis of 2-amino-2- (4 '-methyl- [1,1' -biphenyl ] -4-yl) acetic acid
The yield of 2-amino-2- (4 '-methyl- [1,1' -biphenyl ] -4-yl) acetic acid as a final product in this example was the same as in example 1, using 4-methylbenzeneboronic acid (11 mmol) instead of phenylboronic acid: 95 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ8.76(m,2H),7.49(m,4H),7.39(m,2H),7.25(m,2H),5.20(t,1H),2.38(d,3H).
13 C NMR(125MHz,DMSO)δ174.35(d),139.26(t),137.92(td),137.53(dd),136.32(d),129.55(m),128.45(t),127.89(q),127.14(dd),59.72(dt),21.24(t).
example 14
Synthesis of 2-amino-2- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of the final product, 2-amino-2- (3 '-methoxy- [1,1' -biphenyl ] -4-yl) acetic acid, was the same as in example 1, using 3-methoxyphenylboronic acid (11 mmol) instead of phenylboronic acid: and 93 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ8.80(m,2H),7.48(m,2H),7.42(m,3H),7.36(t,1H),7.23(t,1H),6.92(dt,1H),5.20(m,1H),3.84(s,3H).
13 C NMR(125MHz,DMSO)δ174.04(d),159.57,139.72(dt),138.09(m),137.57(dd),129.80(m),128.61(m),128.12(q),122.12(dddd),113.81(td),110.59(q),59.72(dt),55.32.
example 15
Synthesis of 2-amino-2- (2 '-methoxy- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of the final product, 2-amino-2- (2 '-methoxy- [1,1' -biphenyl ] -4-yl) acetic acid, was the same as in example 1, using 2-methoxyphenylboronic acid (11 mmol) instead of phenylboronic acid: 94 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ8.66(m,2H),7.41(m,5H),7.27(td,1H),7.17(td,1H),6.97(dd,1H),5.20(t,1H),3.89(s,3H).
13 C NMR(125MHz,DMSO)δ174.04(d),157.67(m),138.25(dt),137.50(dd),131.73(m),130.16(tq),129.11(m),128.65(t),121.95(tt),114.00(td),59.72(dt),55.46.
example 16
Synthesis of 2-amino-2- (4 '-methoxy- [1,1' -biphenyl ] -4-yl) acetic acid
In this example, the yield of the final product, 2-amino-2- (4 '-methoxy- [1,1' -biphenyl ] -4-yl) acetic acid, was the same as in example 1, using 4-methoxyphenylboronic acid (11 mmol) instead of phenylboronic acid: 95 percent.
The results of the nuclear magnetic structure test of the product are as follows:
1 H NMR(400MHz,DMSO)δ8.73(m,2H),7.58(m,2H),7.49(m,4H),6.97(m,2H),5.20(t,1H),3.79(s,3H).
13 C NMR(125MHz,DMSO)δ174.04(d),160.06(d),139.51(t),137.52(dd),133.68(td),128.64(m),127.89(q),114.62(m),59.72(dt),55.35.
comparative example 1
Synthesis of 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine
Phenylboronic acid (1.33g, 11mmol), 2- (tert-butoxycarbonyl-amino) -2- (4-bromophenyl) acetic acid (3.30g, 10mmol), 2M K were added to a 100mL reaction flask under nitrogen protection 2 CO 3 (3 mL) and 20mL of THF, followed by stirring with heating, and addition of Pd (PPh) 3 ) 4 (0.03g, 0.2% mmol), reaction stirred at 90 ℃ for 12h, extracted with ethyl acetate, dried over anhydrous sodium sulfate, spun off most of the solvent, purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (V/V = 20) to give tert-butoxycarbonyl protected 2- ([ 1,1' -biphenyl]-4-yl) -2-glycine in combination with 20% (V/V) TFA-CH 2 Cl 2 (30 mL), the reaction mixture was stirred at room temperature (25 ℃ C.) for 1h, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the majority of the solvent was removed by rotary evaporation, and recrystallized from n-hexane to give 2- ([ 1,1' -biphenyl]-4-yl) -2-glycine (1.86 g) in 82% yield.
The results of nuclear magnetic structure testing of the product 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine are as follows:
1H NMR(400MHz,DMSO)δ8.77(m,2H),7.59(m,2H),7.49(m,3H),7.43(m,3H),7.36(m,1H),5.15(m,1H).
comparative example 2
Synthesis of 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine
Phenylboronic acid (1.33g, 11mmol), 2- (tert-butoxycarbonyl-amino) -2- (4-bromophenyl) acetic acid (3.30g, 10mmol), 2M K were added to a 100mL reaction flask under nitrogen protection 2 CO 3 (3 mL) and 20mL of THF were heated and stirred, and then Pd (PPh) was added 3 ) 4 (0.03g, 0.2% mmol), 10min using a microwave-assisted instrument (80W), then stirring the reaction at 90 ℃ for 8h, extracting with ethyl acetate, drying over anhydrous sodium sulfate, spinning off most of the solvent, purifying by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (V/V = 20) to give a tert-butoxycarbonyl protected 2- ([ 1,1' -biphenyl]-4-yl) -2-glycine, further 20% (V/V) TFA/CH 2 Cl 2 (30 mL), the reaction mixture was stirred at room temperature (25 ℃ C.) for 1h, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the majority of the solvent was removed by rotary evaporation, and recrystallized from n-hexane to give 2- ([ 1,1' -biphenyl]-4-yl) -2-glycine (1.95 g) in 86% yield.
The results of nuclear magnetic structure testing of the product 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine are as follows:
1H NMR(400MHz,DMSO)δ8.77(m,2H),7.59(m,2H),7.49(m,3H),7.43(m,3H),7.36(m,1H),5.15(m,1H).
the above examples show that the synthesis method adopted by the invention has mild reaction, relatively shorter reaction time compared with the existing method, simple and easy operation and control, and high yield, and in the suzuki reaction process in the step (1), the microwave assistance with a certain time is adopted, which is beneficial to promoting the reaction, effectively improving the reaction efficiency, shortening the reaction time and improving the product yield, and if the time is too long, the reaction is unfavorable, and the final product yield is reduced.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered in the protection scope of the present invention.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
Claims (5)
1. A method for synthesizing 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compounds, comprising the steps of:
(1) Under the protection of inert gas and the assistance of microwave, carrying out a suzuki reaction on a compound shown in a formula I and a compound shown in a formula II in the presence of alkali, an organic solvent and a palladium catalyst to prepare an intermediate compound with tert-butoxycarbonyl protection; under the protection of inert gas, after the feeding of the compound shown in the formula I, the compound shown in the formula II, alkali, an organic solvent and a palladium catalyst is finished, performing microwave assistance for 2-4 min, and then reacting for 6-10 h at 80-100 ℃; the alkali is one or more of potassium carbonate, sodium carbonate and cesium carbonate; the feeding molar ratio of the compound shown in the formula I to the compound shown in the formula II is 1-1.5: 1, the feeding molar ratio of the catalyst to the compound shown in the formula II is 0.0001-0.0005: 1;
(2) Carrying out deprotection reaction on the intermediate compound in the presence of acid to obtain a 2- ([ 1,1' -biphenyl ] -4-yl) -2-glycine compound shown as a formula III;
wherein the structural formula of the compound shown in the formula I is as follows:
the structural formula of the compound shown in the formula II is as follows:
the structural formula of the compound shown in the formula III is as follows:
in the formulas I and III, R is one of H, alkyl with 1-5 carbon atoms, alkoxy with 1-3 carbon atoms, halogen and trifluoromethyl.
2. The method of synthesis according to claim 1, characterized in that: and R is H, methyl, methoxyl, F, cl, br or trifluoromethyl.
3. The method of synthesis according to claim 1, characterized in that: the base is added in the form of an aqueous base solution.
4. The method of synthesis according to claim 1, characterized in that: in the step (2), the acid is one or more of trifluoroacetic acid and HCl.
5. The synthesis process according to any one of claims 1 to 4, characterized in that: the synthesis method is specifically implemented as follows: under the protection of inert gas, mixing a compound shown as a formula I, a compound shown as a formula II, an organic solvent and an aqueous solution of alkali, heating and stirring, then adding a palladium catalyst, assisting for 2-4 min by using microwave, then stirring and reacting for 6-10 h at 80-100 ℃, after the reaction is finished, extracting ethyl acetate, drying anhydrous sodium sulfate, removing the solvent, carrying out chromatographic purification, eluting a mixed solution of petroleum ether and ethyl acetate to prepare an intermediate compound, then adding an acid solution, stirring and reacting for 0.5-2 h at 15-35 ℃, after the reaction is finished, extracting aqueous phase ethyl acetate, combining organic phases, drying anhydrous sodium sulfate, removing the solvent and recrystallizing to prepare a compound shown as a formula III.
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