CN111333528B - Synthesis method of multi-configuration O-phenyl-serine compound - Google Patents

Synthesis method of multi-configuration O-phenyl-serine compound Download PDF

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CN111333528B
CN111333528B CN202010277205.XA CN202010277205A CN111333528B CN 111333528 B CN111333528 B CN 111333528B CN 202010277205 A CN202010277205 A CN 202010277205A CN 111333528 B CN111333528 B CN 111333528B
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汪明中
朱明新
苏道
李金金
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Suzhou Amatek Biotechnology Co ltd
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Abstract

The invention relates to a synthetic method of a multi-configuration O-phenyl-serine compound, which comprises the following steps: (1) Under the protection of inert gas, reacting a compound shown as a formula I with a compound shown as a formula II in the presence of a solvent, alkali and a palladium catalyst to obtain an intermediate compound; (2) Carrying out deprotection reaction on the intermediate compound to obtain an O-phenyl-serine compound shown in a formula III; wherein the structural formula of the compound shown in the formula I is as follows:
Figure DDA0002445228030000011
the structural formula of the compound shown in the formula II is as follows:
Figure DDA0002445228030000012
the structural formula of the compound shown in the formula III is as follows:

Description

Synthesis method of multi-configuration O-phenyl-serine compound
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a synthesis method of a multi-configuration O-phenyl-serine compound.
Background
O-phenyl-serine compounds based on benzene ring monosubstitution are important medical intermediates and are widely applied in the field of medical chemistry. For example, as an intermediate for synthesizing drugs for treating tumors, such as chemotherapeutic agents.
In the methods for synthesizing these compounds, triphenylphosphine is usually used as a catalyst, and DIAD (diisopropyl azodicarboxylate) is involved in the reaction (for example, see Castelli R, tognolini M, vacond F, et al,. DELTA.5-cholesteryl-amino acids as selective and organic available amides of the Epheperephin system [ J ]. European Journal of Medicinal Chemistry 2015,103, 312-324), and not only the method is simple, the reaction is vigorous, and the method is carried out at a low temperature, and the effect is poor, and the yield is low. Triphenylphosphine has irritation to eyes, upper respiratory tract, mucosa and skin, has neurotoxic effect, and is required to be operated regularly, so that the operation is complicated, and the safety is low.
Disclosure of Invention
The invention aims to provide an improved synthesis method of a multi-configuration O-phenyl-serine compound, which has the advantages of simple process, mild reaction, safety, easy operation and high product yield.
In order to achieve the purpose, the invention adopts the technical scheme that:
a synthetic method of a multi-configuration O-phenyl-serine compound comprises the following steps:
(1) Under the protection of inert gas, reacting a compound shown as a formula I with a compound shown as a formula II in the presence of a solvent, alkali and a palladium catalyst to obtain an intermediate compound;
(2) Carrying out deprotection reaction on the intermediate compound under an acidic condition to obtain an O-phenyl-serine compound shown in a formula III;
wherein the structural formula of the compound shown in the formula I is as follows:
Figure BDA0002445228020000011
the structural formula of the compound shown in the formula II is as follows:
Figure BDA0002445228020000012
the structural formula of the compound shown in the formula III is as follows:
Figure BDA0002445228020000013
in the formulas I and III, the R can be substituted on the 2-position, the 3-position or the 4-position of a benzene ring, and the R is one of H, alkyl with 1-5 carbon atoms, alkoxy with 1-4 carbon atoms and halogen.
Further, R is H, methyl, methoxy or F.
Preferably, in the step (1), the palladium catalyst is one or more of bis (triphenylphosphine) palladium dichloride, tetratriphenylphosphine palladium, palladium chloride and palladium acetate.
According to a further embodiment of the present invention, the molar ratio of the compound of formula I to the compound of formula II is 1:1 to 2; the feeding molar ratio of the compound shown in the formula I to the palladium catalyst is 1.001-0.003.
According to a further embodiment of the present invention, in step (1), the base is one or more of potassium carbonate, sodium carbonate and cesium carbonate, the solvent is one or more of N, N-dimethylformamide, triethylamine, dimethyl sulfoxide, dimethylacetamide and methylpyrrolidone, and the inert gas is nitrogen.
According to a further embodiment of the present invention, in the step (1), the reaction temperature of the reaction is 70 to 90 ℃. Preferably, the reaction temperature of the reaction is 75 to 85 ℃.
According to a further embodiment of the present invention, in the step (1), after the reaction is completed, the post-treatment of the reaction solution is specifically performed by: extracting reaction liquid, drying, removing a solvent, carrying out chromatography purification, and eluting to obtain the intermediate compound.
According to a further embodiment of the present invention, in step (2), the deprotection reaction is carried out in the presence of hydrochloric acid.
Preferably, in the step (2), the concentration of the hydrochloric acid is 5 to 7N.
According to a further embodiment of the present invention, in the step (2), after the reaction is completed, the post-treatment of the reaction solution is specifically performed by: and adjusting the pH value of the reaction solution to 6-7, removing water, and recrystallizing to obtain the compound shown in the formula III.
According to some embodiments of the invention, the method of synthesis is embodied as: dissolving a compound shown as a formula I and a compound shown as a formula II in a solvent under the protection of nitrogen, adding alkali and a palladium catalyst, stirring and reacting for 5-8h at 70-90 ℃, extracting with ethyl acetate after the reaction is finished, drying with anhydrous magnesium sulfate, removing the solvent, carrying out chromatographic purification, eluting with a mixed solution of dichloromethane and methanol to obtain an intermediate compound, then adding 5-7N HCl, stirring and reacting for 10-14h at 15-35 ℃, adjusting the pH of a reaction solution to 6-7 with alkali after the reaction is finished, removing water, and recrystallizing with petroleum ether to obtain the compound shown as a formula III.
Preferably, in the mixed solution of dichloromethane and methanol, the volume ratio of dichloromethane to methanol is 15 to 25.
Preferably, the compound of formula III is: O-phenyl-DL-serine, O-phenyl-D-serine, O-phenyl-L-serine, O- (2-tolyl) -DL-serine, O- (2-tolyl) -D-serine, O- (2-tolyl) -L-serine, O- (3-tolyl) -DL-serine, O- (3-tolyl) -D-serine, O- (3-tolyl) -L-serine, O- (4-tolyl) -DL-serine, O- (4-tolyl) -D-serine, O- (4-tolyl) -L-serine, O- (2-methoxyphenyl) -DL-serine, O- (2-methoxyphenyl) -D-serine, O- (2-methoxyphenyl) -L-serine, O- (3-methoxyphenyl) -DL-serine, O- (3-methoxyphenyl) -D-serine, O- (3-methoxyphenyl) -L-serine, O- (3-methoxyphenyl) -DL-serine, O- (3-methoxyphenyl) -L-serine, O- (4-methoxyphenyl) -DL-serine, O- (4-methoxyphenyl) -D-serine, O- (4-methoxyphenyl) -L-serine, O- (2-fluorophenyl) -DL-serine, O- (2-fluorophenyl) -D-serine, O- (2-fluorophenyl) -L-serine, O- (3-fluorophenyl) -DL-serine, O- (3-fluorophenyl) -D-serine, O- (3-fluorophenyl) -L-serine, O- (4-fluorophenyl) -DL-serine, O- (4-fluorophenyl) -D-serine or O- (4-fluorophenyl) -L-serine.
The multi-configuration O-phenyl-serine with mono-substituted benzene ring synthesized by the synthesis method is applied to 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:
the synthetic method takes monosubstituted iodobenzene and multi-configuration N-tert-butyloxycarbonyl-serine methyl ester as raw materials, adopts a palladium catalyst as a catalyst, enables the monosubstituted iodobenzene and the multi-configuration N-tert-butyloxycarbonyl-serine methyl ester to react in the presence of the palladium catalyst, alkali and a solvent, and then carries out deprotection to prepare a final product.
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 only to further illustrate the present invention and are not meant to limit the scope of the present 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 measurement was carried out by using ACF-400BRUK type nuclear magnetic resonance apparatus in which deuterated chloroform (CDCl) was used as a solvent 3 ) Or deuterated dimethyl sulfoxide (DMSO-D) 6 ) And TMS is an internal standard. The column chromatography adopts 200-300 mesh silica gel (produced by Qingdao ocean chemical plant).
Example 1
Synthesis of O-phenyl-DL-serine
Figure BDA0002445228020000031
Iodobenzene (2.0 g,10 mmol), N-tert-butoxycarbonyl-DL-serine methyl ester (2.2 g,10 mmol) were dissolved in DMF (50 mL) under nitrogen protection, and K was added 2 CO 3 (0.2g, 1.0 mmol), bis (triphenylphosphine) palladium dichloride (PdCl) 2 (P(C 6 H 5 ) 3 ) 2 ) (1.4mg, 2.0mmol%), heating and stirring at 80 ℃ for 6 hours, after completion of the reaction, extracting with ethyl acetate, drying over anhydrous magnesium sulfate, removing most of the solvent in the reaction solution, purifying by silica gel column chromatography, eluting with methylene chloride/methanol (V/V = 20/1) to obtain an intermediate, adding 6N HCl (80 mL), stirring at room temperature overnight for reaction, after completion of the reaction, adjusting pH =6.5 with — OH, and removing H 2 O, recrystallization from petroleum ether gave O-phenyl-DL-serine (1.6 g). Yield: 88 percent.
1 H NMR(400MHz,CDCl 3 )δ7.28(m,2H),6.97(tt,1H),6.91(m,2H),5.04(dd,1H),4.77(dd,1H),4.35(d,2H),3.92(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.63(dd),159.36(m),129.55(dt),121.10(tq),115.24(m),67.42(t),55.24(dd).
Example 2
Synthesis of O-phenyl-D-serine
Figure BDA0002445228020000041
The starting materials in this example were iodobenzene (10 mmol) and N-tert-butoxycarbonyl-D-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 86 percent.
1 H NMR(400MHz,CDCl 3 )δ7.28(m,2H),6.97(tt,1H),6.91(m,2H),5.04(dd,1H),4.77(dd,1H),4.35(d,2H),3.92(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.63(dd),159.36(m),129.56(dt),121.10(tq),115.23(dt),67.42(t),55.26(dd).
Example 3
Synthesis of O-phenyl-L-serine
Figure BDA0002445228020000042
The starting materials in this example were iodobenzene (10 mmol) and methyl N-tert-butoxycarbonyl-L-serine (10 mmol), otherwise as in example 1, product yield: 87 percent.
1 H NMR(400MHz,CDCl 3 )δ7.28(m,2H),6.97(tt,1H),6.91(m,2H),5.04(dd,1H),4.77(dd,1H),4.35(d,2H),3.92(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.63(dd),159.36(m),129.56(dt),121.10(tq),115.23(dt),67.42(t),55.26(dd).
Example 4
Synthesis of O- (2-tolyl) -DL-serine
Figure BDA0002445228020000043
The starting materials in this example were 1-iodo-2-methylbenzene (10 mmol) and N-tert-butoxycarbonyl-DL-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 83 percent.
1 H NMR(400MHz,CDCl 3 )δ7.16(td,1H),7.10(ddt,1H),6.92(td,1H),6.80(dd,1H),5.04(dd,1H),4.77(dd,1H),4.34(d,2H),3.90(tt,1H),2.20(d,3H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),157.73(m),130.55(tdt),128.08(tq),126.84(m),122.28(ddt),112.97(m),67.89(dd),55.28(dd),15.79(d).
Example 5
Synthesis of O- (2-tolyl) -D-serine
Figure BDA0002445228020000051
The starting materials in this example were 1-iodo-2-methylbenzene (10 mmol) and N-tert-butoxycarbonyl-D-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 82 percent.
1 H NMR(400MHz,CDCl 3 )δ7.16(td,1H),7.10(ddt,1H),6.92(td,1H),6.80(dd,1H),5.04(dd,1H),4.77(dd,1H),4.34(d,2H),3.90(tt,1H),2.20(d,3H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),157.73(m),130.56(tdt),128.08(tq),126.64(ddd),122.29(tq),112.99(tt),67.89(dd),55.12(dd),15.79(d).
Example 6
Synthesis of O- (2-tolyl) -L-serine
Figure BDA0002445228020000052
The starting materials for this example were 1-iodo-2-methylbenzene (10 mmol) and N-tert-butoxycarbonyl-L-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 83 percent.
1 H NMR(400MHz,CDCl 3 )δ7.16(td,1H),7.10(ddt,1H),6.92(td,1H),6.80(dd,1H),5.04(dd,1H),4.77(dd,1H),4.34(d,2H),3.90(tt,1H),2.20(d,3H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),157.73(m),130.56(tdt),128.08(tq),126.64(ddd),122.29(tq),112.99(tt),67.89(dd),55.12(dd),15.79(d).
Example 7
Synthesis of O- (3-tolyl) -DL-serine
Figure BDA0002445228020000053
The starting materials for this example were 1-iodo-3-methylbenzene (10 mmol) and N-tert-butoxycarbonyl-DL-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 86 percent.
1 H NMR(400MHz,CDCl 3 )δ7.15(t,1H),6.90(dt,1H),6.80(dtt,1H),6.76(t,1H),5.04(dd,1H),4.77(dd,1H),4.37(d,2H),3.90(tt,1H),2.30(m,3H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),158.99(m),138.01,129.50(m),124.60(dtd),114.75(tdd),114.23(tt),67.53(dd),55.24(dd),20.76(t).
Example 8
Synthesis of O- (3-tolyl) -D-serine
Figure BDA0002445228020000061
The starting materials for this example were 1-iodo-3-methylbenzene (10 mmol) and N-tert-butoxycarbonyl-D-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 86 percent.
1 H NMR(400MHz,CDCl 3 )δ7.15(t,1H),6.90(dt,1H),6.80(dtt,1H),6.76(t,1H),5.04(dd,1H),4.77(dd,1H),4.37(d,2H),3.90(tt,1H),2.30(m,3H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),158.98(m),138.00,129.50(m),124.61(ddq),114.74(m),114.23(tt),67.53(dd),55.26(dd),20.76(t).
Example 9
Synthesis of O- (3-tolyl) -L-serine
Figure BDA0002445228020000062
The starting materials for this example were 1-iodo-3-methylbenzene (10 mmol) and N-tert-butoxycarbonyl-L-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 87 percent.
1 H NMR(400MHz,CDCl 3 )δ7.15(t,1H),6.90(dt,1H),6.80(dtt,1H),6.76(t,1H),5.04(dd,1H),4.77(dd,1H),4.37(d,2H),3.90(tt,1H),2.30(m,3H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),158.98(m),138.00,129.50(m),124.61(ddq),114.74(m),114.23(tt),67.53(dd),55.26(dd),20.76(t).
Example 10
Synthesis of O- (4-tolyl) -DL-serine
Figure BDA0002445228020000063
The starting materials for this example were 1-iodo-4-methylbenzene (10 mmol) and N-tert-butoxycarbonyl-DL-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 85 percent.
1 H NMR(400MHz,CDCl 3 )δ7.09(m,2H),6.80(m,2H),5.04(dd,1H),4.77(dd,1H),4.35(m,2H),3.90(tt,1H),2.29(d,3H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),157.30(td),132.27(d),130.46(ddd),115.01(d),67.55(t),55.24(dd),20.54(t).
Example 11
Synthesis of O- (4-tolyl) -D-serine
Figure BDA0002445228020000071
The starting materials for this example were 1-iodo-4-methylbenzene (10 mmol) and N-tert-butoxycarbonyl-D-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 83 percent.
1 H NMR(400MHz,CDCl 3 )δ7.09(m,2H),6.80(m,2H),5.04(dd,1H),4.77(dd,1H),4.35(m,2H),3.90(tt,1H),2.29(d,3H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),157.30(td),132.26(d),130.47(m),115.01(m),67.55(t),55.26(dd),20.54(t).
Example 12
Synthesis of O- (4-tolyl) -L-serine
Figure BDA0002445228020000072
The starting materials for this example were 1-iodo-4-methylbenzene (10 mmol) and N-tert-butoxycarbonyl-L-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 84 percent.
1 H NMR(400MHz,CDCl 3 )δ7.09(m,2H),6.80(m,2H),5.04(dd,1H),4.77(dd,1H),4.35(m,2H),3.90(tt,1H),2.29(d,3H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),157.30(td),132.26(d),130.47(m),115.01(m),67.55(t),55.26(dd),20.54(t).
Example 13
Synthesis of O- (2-methoxyphenyl) -DL-serine
Figure BDA0002445228020000073
The starting materials in this example were 1-iodo-2-methoxybenzene (10 mmol) and N-tert-butoxycarbonyl-DL-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 81 percent.
1 H NMR(400MHz,CDCl 3 )δ6.89(m,4H),5.03(dd,1H),4.82(dd,1H),4.39(d,2H),3.96(tt,1H),3.86(s,3H).
13 C NMR(125MHz,CDCl 3 )δ173.64(dd),149.38(m),121.57(dtd),114.90(tt),113.86(tt),67.66(dd),56.07,55.22(dd).
Example 14
Synthesis of O- (2-methoxyphenyl) -D-serine
Figure BDA0002445228020000081
The starting materials for this example were 1-iodo-2-methoxybenzene (10 mmol) and N-tert-butoxycarbonyl-D-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 81 percent.
1 H NMR(400MHz,CDCl 3 )δ6.95(td,1H),6.89(ddd,2H),6.85(m,1H),5.03(dd,1H),4.82(dd,1H),4.39(d,2H),3.96(tt,1H),3.86(s,3H).
13 C NMR(125MHz,CDCl 3 )δ173.64(dd),149.38(m),121.57(dtd),114.91(tq),113.86(tt),67.66(dd),56.07,55.07(dd).
Example 15
Synthesis of O- (2-methoxyphenyl) -L-serine
Figure BDA0002445228020000082
The starting materials in this example were 1-iodo-2-methoxybenzene (10 mmol) and N-tert-butoxycarbonyl-L-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 82 percent.
1 H NMR(400MHz,CDCl 3 )δ6.89(m,4H),5.03(dd,1H),4.82(dd,1H),4.39(d,2H),3.96(tt,1H),3.86(s,3H).
13 C NMR(125MHz,CDCl 3 )δ173.64(dd),149.38(m),121.57(dtd),114.91(tq),113.86(tt),67.66(dd),56.07,55.07(dd).
Example 16
Synthesis of O- (3-methoxyphenyl) -DL-serine
Figure BDA0002445228020000083
The starting materials for this example were 1-iodo-3-methoxybenzene (10 mmol) and N-tert-butoxycarbonyl-DL-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 82 percent.
1 H NMR(400MHz,CDCl 3 )δ7.15(t,1H),6.67(dt,1H),6.62(dt,1H),6.47(t,1H),5.03(dd,1H),4.82(dd,1H),4.37(d,2H),3.96(tt,1H),3.79(s,3H).
13 C NMR(125MHz,CDCl 3 )δ173.64(dd),160.46(m),130.11(dq),111.02(tt),108.56(ddd),101.57(td),67.37(dd),55.29(m).
Example 17
Synthesis of O- (3-methoxyphenyl) -D-serine
Figure BDA0002445228020000091
The starting materials for this example were 1-iodo-3-methoxybenzene (10 mmol) and N-tert-butoxycarbonyl-D-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 83 percent.
1 H NMR(400MHz,CDCl 3 )δ7.15(t,1H),6.67(dt,1H),6.62(dt,1H),6.47(t,1H),5.03(dd,1H),4.82(dd,1H),4.37(d,2H),3.96(tt,1H),3.79(s,3H).
13 C NMR(125MHz,CDCl 3 )δ173.64(dd),160.48(m),130.12(dq),111.02(tt),108.55(td),101.58(td),67.37(dd),55.31,55.08(dd).
Example 18
Synthesis of O- (3-methoxyphenyl) -L-serine
Figure BDA0002445228020000092
The starting materials in this example were 1-iodo-3-methoxybenzene (10 mmol) and N-tert-butoxycarbonyl-L-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 82 percent.
1 H NMR(400MHz,CDCl 3 )δ7.15(t,1H),6.67(dt,1H),6.62(dt,1H),6.47(t,1H),5.03(dd,1H),4.82(dd,1H),4.37(d,2H),3.96(tt,1H),3.79(s,3H).
13 C NMR(125MHz,CDCl 3 )δ173.64(dd),160.48(m),130.12(dq),111.02(tt),108.55(td),101.58(td),67.37(dd),55.31,55.08(dd).
Example 19
Synthesis of O- (4-methoxyphenyl) -DL-serine
Figure BDA0002445228020000093
The starting materials for this example were 1-iodo-4-methoxybenzene (10 mmol) and N-tert-butoxycarbonyl-DL-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 85 percent.
1 H NMR(400MHz,CDCl 3 )δ6.85(s,4H),5.03(dd,1H),4.82(dd,1H),4.35(d,2H),3.96(tt,1H),3.78(s,3H).
13 C NMR(125MHz,CDCl 3 )δ173.64(dd),154.46(d),153.46(td),115.75(dd),114.63(ddd),67.39(dd),55.30(m).
Example 20
Synthesis of O- (4-methoxyphenyl) -D-serine
Figure BDA0002445228020000101
The starting materials in this example were 1-iodo-4-methoxybenzene (10 mmol) and N-tert-butoxycarbonyl-D-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 85 percent.
1 H NMR(400MHz,CDCl 3 )δ6.85(s,4H),5.03(dd,1H),4.82(dd,1H),4.35(d,2H),3.96(tt,1H),3.78(s,3H).
13 C NMR(125MHz,CDCl 3 )δ173.64(dd),154.47(d),153.46(td),115.75(dd),114.63(ddd),67.39(m),55.33,55.08(dd).
Example 21
Synthesis of O- (4-methoxyphenyl) -L-serine
Figure BDA0002445228020000102
The starting materials in this example were 1-iodo-4-methoxybenzene (10 mmol) and N-tert-butoxycarbonyl-L-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 86 percent.
1 H NMR(400MHz,CDCl 3 )δ6.85(s,4H),5.03(dd,1H),4.82(dd,1H),4.35(d,2H),3.96(tt,1H),3.78(s,3H).
13 C NMR(125MHz,CDCl 3 )δ173.64(dd),154.47(d),153.46(td),115.75(dd),114.63(ddd),67.39(m),55.33,55.08(dd).
Example 22
Synthesis of O- (2-fluorophenyl) -DL-serine
Figure BDA0002445228020000103
The starting materials in this example were 1-iodo-4-fluorobenzene (10 mmol) and N-tert-butoxycarbonyl-DL-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 89 percent.
1 H NMR(400MHz,CDCl 3 )δ7.12–7.04(m,2H),6.97–6.85(m,2H),5.03(dd,1H),4.82(dd,1H),4.39(d,2H),3.93(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),154.59(m),152.56(m),147.64(m),125.17(tdd),121.41(qq),116.56(m),67.76(q),55.22(dd).
Example 23
Synthesis of O- (2-fluorophenyl) -D-serine
Figure BDA0002445228020000111
The starting materials for this example were 1-iodo-4-fluorobenzene (10 mmol) and N-tert-butoxycarbonyl-D-serine methyl ester (10 mmol), otherwise as in example 1, product yield: and 90 percent.
1 H NMR(400MHz,CDCl 3 )δ7.08(m,2H),6.91(m,2H),5.03(dd,1H),4.82(dd,1H),4.39(d,2H),3.93(tt,1H).
13C NMR(125MHz,CDCl 3 )δ173.66(dd),154.93(m),152.92(m),147.62(m),125.18(tdt),121.41(qq),87.20(m).
Example 24
Synthesis of O- (2-fluorophenyl) -L-serine
Figure BDA0002445228020000112
The starting materials in this example were 1-iodo-4-fluorobenzene (10 mmol) and N-tert-butoxycarbonyl-L-serine methyl ester (10 mmol), otherwise as in example 1, yield of product: 88 percent.
1 H NMR(400MHz,CDCl 3 )δ7.08(m,2H),6.91(m,2H),5.03(dd,1H),4.82(dd,1H),4.39(d,2H),3.93(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),154.93(m),152.92(m),147.62(m),125.18(tdt),121.41(qq),87.20(m).
Example 25
Synthesis of O- (3-fluorophenyl) -DL-serine
Figure BDA0002445228020000113
The starting materials for this example were 1-iodo-4-fluorobenzene (10 mmol) and N-tert-butoxycarbonyl-DL-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 91 percent.
1 H NMR(400MHz,CDCl 3 )δ7.21(td,1H),6.88(tt,1H),6.78(dt,1H),6.71(dt,1H),5.03(dd,1H),4.82(dd,1H),4.37(dd,2H),3.90(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),163.86,161.84,159.64(ddd),129.80(tq),111.89(tq),110.09(dtd),103.64(m),67.54(t),55.24(dd).
Example 26
Synthesis of O- (3-fluorophenyl) -D-serine
Figure BDA0002445228020000121
The starting materials in this example were 1-iodo-4-fluorobenzene (10 mmol) and N-tert-butoxycarbonyl-D-serine methyl ester (10 mmol), otherwise as in example 1, yield of product: 90 percent.
1 H NMR(400MHz,CDCl 3 )δ7.21(td,1H),6.88(tt,1H),6.78(dt,1H),6.71(dt,1H),5.03(dd,1H),4.82(dd,1H),4.37(dd,2H),3.90(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),163.76,161.74,159.64(td),129.79(tt),111.90(tq),110.09(dtd),103.65(m),67.54(t),55.08(dd).
Example 27
Synthesis of O- (3-fluorophenyl) -L-serine
Figure BDA0002445228020000122
The starting materials for this example were 1-iodo-4-fluorobenzene (10 mmol) and N-tert-butoxycarbonyl-L-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 89 percent.
1 H NMR(400MHz,CDCl 3 )δ7.21(td,1H),6.88(tt,1H),6.78(dt,1H),6.71(dt,1H),5.03(dd,1H),4.82(dd,1H),4.37(dd,2H),3.90(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),163.76,161.74,159.64(td),129.79(tt),111.90(tq),110.09(dtd),103.65(m),67.54(t),55.08(dd).
Example 28
Synthesis of O- (4-fluorophenyl) -DL-serine
Figure BDA0002445228020000123
The starting materials in this example were 1-iodo-4-fluorobenzene (10 mmol) and N-tert-butoxycarbonyl-DL-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 89 percent.
1H NMR(500MHz,CDCl 3 )δ6.92(m,2H),6.87(m,2H),5.03(dd,1H),4.82(dd,1H),4.35(d,2H),3.91(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),159.03(d),157.01(d),156.25(tt),117.18(m),116.48(m),67.56(t),55.24(dd).
Example 29
Synthesis of O- (4-fluorophenyl) -D-serine
Figure BDA0002445228020000131
The starting materials for this example were 1-iodo-4-fluorobenzene (10 mmol) and N-tert-butoxycarbonyl-D-serine methyl ester (10 mmol), otherwise as in example 1, product yield: 90 percent.
1 H NMR(400MHz,CDCl 3 )δ6.92(m,2H),6.87(m,2H),5.03(dd,1H),4.82(dd,1H),4.35(d,2H),3.91(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),158.95(d),156.94(d),156.25(tt),117.16(m),116.49(m),67.56(t),55.08(dd).
Example 30
Synthesis of O- (4-fluorophenyl) -L-serine
Figure BDA0002445228020000132
The starting materials in this example were 1-iodo-4-fluorobenzene (10 mmol) and N-tert-butoxycarbonyl-L-serine methyl ester (10 mmol), otherwise as in example 1, yield of product: and 90 percent.
1 H NMR(400MHz,CDCl 3 )δ6.92(m,2H),6.87(m,2H),5.03(dd,1H),4.82(dd,1H),4.35(d,2H),3.91(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.66(dd),158.95(d),156.94(d),156.25(tt),117.16(m),116.49(m),67.56(t),55.08(dd).
Comparative example 1
Synthesis of O-phenyl-DL-serine
Figure BDA0002445228020000133
Phenol (2.0g, 10mmol) and N-tert-butoxycarbonyl-DL-serine methyl ester (2.2g, 10mmol) were dissolved in THF (50 mL) under nitrogen protection, triphenylphosphine (3.9g, 15mmol) was added, stirring was performed at 0 ℃ for 20min, then diisopropyl DIAD azodicarboxylate (3.0g, 15mmol) was added dropwise after completion of the reaction, ethyl acetate extraction was performed, anhydrous magnesium sulfate was dried, most of the solvent in the reaction solution was removed, purification was performed by silica gel column chromatography, dichloromethane/methanol (V/V = 20/1) was eluted to obtain an intermediate, 6N HCl (80 mL) was added, stirring was performed overnight at room temperature, after completion of the reaction, pH =6.5 was adjusted with-OH, and H was removed 2 O, recrystallization from petroleum ether gave O-phenyl-DL-serine (1.1 g). Yield: and 63 percent.
1 H NMR(400MHz,CDCl 3 )δ7.29(m,2H),6.97(tt,1H),6.92(m,2H),5.04(dd,1H),4.77(dd,1H),4.35(d,2H),3.91(tt,1H).
13 C NMR(125MHz,CDCl 3 )δ173.65(dd),159.36(m),129.55(dt),121.10(tq),115.25(m),67.42(t),55.22(dd).
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 within the protection scope of the present invention.

Claims (6)

1. A synthetic method of a multi-configuration O-phenyl-serine compound is characterized by comprising the following steps:
(1) Under the protection of inert gas, enabling a compound shown as a formula I and a compound shown as a formula II to react at 80 ℃ in the presence of DMF, potassium carbonate and bis (triphenylphosphine) palladium dichloride to prepare an intermediate compound; the feeding molar ratio of the compound shown in the formula I to the compound shown in the formula II is 1:1-2, wherein the feeding molar ratio of the compound shown in the formula I to bis (triphenylphosphine) palladium dichloride is 1:0.001-0.003;
(2) Carrying out deprotection reaction on the intermediate compound under an acidic condition to obtain an O-phenyl-serine compound shown in a formula III;
wherein the structural formula of the compound shown in the formula I is as follows:
Figure FDA0003841379830000011
the structural formula of the compound shown in the formula II is as follows:
Figure FDA0003841379830000012
the compound shown in the formula III has the structural formula:
Figure FDA0003841379830000013
in the formula I and the formula III, R is one of H, C1-5 alkyl, C1-4 alkoxy and halogen.
2. The method of synthesis according to claim 1, characterized in that: and R is H, methyl, methoxy or F.
3. The method of synthesis according to claim 1, characterized in that: in the step (1), after the reaction is finished, post-treating the reaction solution, wherein the post-treating is specifically implemented as follows: and extracting the reaction solution with ethyl acetate, drying, removing the solvent, carrying out chromatographic purification, and eluting to obtain the intermediate compound.
4. The method of synthesis according to claim 1, characterized in that: in the step (2), the deprotection reaction is carried out in the presence of hydrochloric acid.
5. The method of synthesis according to claim 4, characterized in that: the concentration of the hydrochloric acid is 5-7N.
6. The method of synthesis according to any one of claims 1 to 5, wherein: dissolving a compound shown in a formula I and a compound shown in a formula II in DMF (dimethyl formamide), adding potassium carbonate and bis (triphenylphosphine) palladium dichloride, stirring and reacting for 5-8h at 80 ℃, extracting with ethyl acetate after the reaction is finished, drying with anhydrous magnesium sulfate, removing a solvent, performing chromatographic purification, eluting with a mixed solution of dichloromethane and methanol to obtain an intermediate compound, then adding 5-7N HCl, stirring and reacting for 10-14h at 15-35 ℃, adjusting the pH of a reaction solution to 6-7 with alkali after the reaction is finished, removing water, and recrystallizing with petroleum ether to obtain the compound shown in the formula III.
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A Single Phosphine Ligand Allows Palladium-Catalyzed Intermolecular C-O Bond Formation with Secondary and Primary Alcohols;Wu Xiaoxing等;《Angewandte Chemie International Edition》;20111010;第50卷(第42期);9943–9947 *
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Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases;Harris Philip A.等;《Journal of Medicinal Chemistry》;20170202;第60卷;1247-1261 *
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