CN114436836B - Method for preparing (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound - Google Patents
Method for preparing (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound Download PDFInfo
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- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
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Abstract
The invention discloses a method for preparing (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound, which utilizes the catalytic action of cheap copper catalyst and P, N-chiral ligand to synthesize the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound in one step, and has the advantages of easily obtained raw materials, simple preparation method and good yield and enantioselectivity; meanwhile, the catalyst consumption is small, and the cost can be greatly reduced. The method can be used for synthesizing key intermediates of tolterodine for treating overactive bladder.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compounds.
Background
2,3 diaryl substituted propionic acid esters are key intermediates of some important drugs, such as Tolterodine (Tolterodine), the dominant drug in the treatment of overactive bladder (OAB). OAB is of great interest and importance in the european and american countries, and the drug varieties for treatment of OAB mainly include solifenacin, tolterodine, fexodine and propiverine, which are sold in the amount of dollars 27.24 to about 25% of the total sales of all drugs for treatment of urinary system diseases, with tolterodine being dominant in the amount of dollars 16.90. The general synthetic scheme for tolterodine molecules and their enantiomers is shown in formula (1-1).
As shown in the formula (1-1), the tolterodine molecular structure contains 1 chiral center, the traditional synthetic route needs chiral resolution to obtain the optically pure tolterodine drug, and in industrialization, the theoretical yield of the chiral resolution synthetic drug is only 50%, and the actual production yield is far less than 50%. Therefore, the key intermediate is asymmetrically synthesized, and the realization of high yield and high stereoselectivity for controlling the synthesis of the medicine has very important scientific significance and practical value.
In recent years, rhodium catalyzed reports of asymmetric addition reactions of phenylboronic acid to alpha, beta-unsaturated ketone compounds can be used for synthesizing tolterodine key intermediate-2, 3 diaryl substituted ketone and propionate. However, expensive rhodium catalysts limit the application of this process. While inexpensive copper-catalyzed synthesis of 2,3 diaryl substituted propionic acid esters lacks relevant reports.
Disclosure of Invention
Aiming at the prior art, the invention provides a method for preparing (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound to solve the problems of expensive catalyst and difficult chiral resolution.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: a process for the preparation of methyl (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionate is provided. The preparation method comprises the following steps:
3- (2-methoxy-5-methyl) phenyl methyl acrylate and phenylboronic acid compound are dissolved in an organic solvent, and then a catalyst and a P, N-chiral ligand are added, and the mixture is uniformly mixed and reacted for 1 to 4 hours at the temperature of 40 to 100 ℃ to obtain the catalyst;
the structural formula of the phenylboronic acid compound is shown as a formula (I),
the structural formula of the P, N-type chiral ligand is shown as a formula (II),
wherein R is a chlorine atom, a fluorine atom, a cyano group, or a trifluoromethyl groupA group, an oxytrifluoromethyl group, an aryl group, a heteroaryl group or a saturated alkyl group having 1 to 12 carbon atoms; r is R 1 Is a saturated alkyl group, a substituted phenyl group, a chlorine atom, a fluorine atom or a heteroaryl group; r is R 2 Is phenyl or substituted phenyl; the structural formula of the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound is shown as a formula (III),
the reaction equation for preparing the compounds of the present invention is as follows:
on the basis of the technical scheme, the invention can be improved as follows.
Further, the organic solvent is tetrahydrofuran, chlorobenzene, toluene, xylene, mesitylene or ethyl acetate.
Further, the molar ratio of the 3- (2-methoxy-5-methyl) phenyl methyl acrylate to the phenylboronic acid compound is 1:1-1:3; the molar ratio of the catalyst to the 3- (2-methoxy-5-methyl) phenyl methyl acrylate is 0.005-0.1:1.
Further, the catalyst is a copper catalyst.
Further, the catalyst is cuprous chloride, cuprous bromide, cupric acetate or copper trifluoromethane sulfonate.
Further, aryl is phenyl or naphthyl; heteroaryl is furyl or thienyl.
The beneficial effects of the invention are as follows:
the method synthesizes the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenyl methyl propionate compound in the next step by using the catalysis of the cheap copper catalyst and the P, N-type chiral ligand, has the advantages of easily obtained raw materials, simple preparation method and good yield and enantioselectivity. Meanwhile, the catalyst consumption is small, and the cost can be greatly reduced. The method can be used for synthesizing a series of 2,3 diaryl substituted propionate compounds, and the synthesized product has biological activity.
Detailed Description
The following describes the present invention in detail with reference to examples.
Example 1
The preparation method of the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound specifically comprises the following steps:
in a dry 15mL pressure-resistant reaction tube, 103mg of methyl 3- (2-methoxy-5-methyl) phenylacrylate (CAS: 86761-35-5), 78mg of phenylboronic acid, 2.0mg of cuprous chloride, 7.8mg of P, N-type chiral ligand, 138mg of potassium carbonate and 2.5mL of tetrahydrofuran were added. The reaction was stirred for 2 hours at 50℃under nitrogen. After the reaction is finished, the mixture is cooled to room temperature and directly passes through a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 15:1), 108mg of a product is obtained, the yield is 76%, ee 89%, and the reaction process is shown as the following formula:
nuclear magnetic resonance and mass spectrometry were performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 ):δ＝7.40(t,J＝7.6Hz,2H),7.29(d,J＝7.6Hz,2H),7.27(d,J＝7.6Hz,1H),7.05(s,1H),6.94(d,J＝7.2Hz,1H),6.82(d,J＝7.2Hz,1H),4.69(dd,J＝3.2,1.2Hz,1H),3.83(s,3H),3.68(s,3H),3.00(dd,J＝3.2,1.2Hz,1H),2.75(dd,J＝3.2,1.2Hz,1H),2.34(s,3H).
13 C NMR(400MHz,CDCl 3 ):δ＝174.3,161.8,142.7,131.4,128.9,127.7,127.3,112.4,57.9,53.0,44.8,38.1,21.6.
HRMS: molecular formula C 18 H 21 O 3 Calculated as 285.1491 and detected as 285.1489.
Example 2
The preparation method of the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound specifically comprises the following steps:
to a dry 15mL pressure-resistant reaction tube, 103mg of methyl 3- (2-methoxy-5-methyl) phenylacrylate (CAS: 86761-35-5), 97mg of phenylboronic acid, 2.0mg of cuprous chloride, 7.8mg of P, N-type chiral ligand, 138mg of potassium carbonate and 2.5mL of tetrahydrofuran were added. The reaction was stirred for 2 hours at 50℃under nitrogen. After the reaction is finished, the mixture is cooled to room temperature and directly passes through a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 15:1), 114mg of a product is obtained, the yield is 73%, ee 91%, and the reaction process is shown in the following formula:
nuclear magnetic resonance and mass spectrometry were performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 ):δ＝7.38(t,J＝7.6Hz,2H),7.31(d,J＝7.6Hz,2H),7.23(d,J＝7.6Hz,1H),7.10(s,1H),6.77(d,J＝7.2Hz,1H),4.59(dd,J＝3.2,1.2Hz,1H),3.81(s,3H),3.66(s,3H),3.07(dd,J＝3.2,1.2Hz,1H),2.75(dd,J＝3.2,1.2Hz,1H),2.62(q,J＝7.6Hz,2H),2.34(s,3H),1.25(t,J＝7.6Hz,3H).
13 C NMR(400MHz,CDCl 3 ):δ＝175.1,161.7,141.9,132.2,128.5,127.3,127.1,112.1,58.2,53.1,44.5,38.2,28.2,21.6,14.5.
HRMS: molecular formula C 20 H 25 O 3 Calculated as 313.1804 and detected as 313.1806.
Example 3
The preparation method of the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound specifically comprises the following steps:
to a dry 15mL pressure-resistant reaction tube, 103mg of methyl 3- (2-methoxy-5-methyl) phenylacrylate (CAS: 86761-35-5), 93mg of 4-fluorophenylboric acid, 2.0mg of cuprous chloride, 7.8mg of P, N-type chiral ligand, 138mg of potassium carbonate and 2.5mL of tetrahydrofuran were added. The reaction was stirred for 2 hours at 50℃under nitrogen. After the reaction is finished, cooling to room temperature, and directly passing through a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 15:1) to obtain 106mg of a product, wherein the yield is 70%, ee 89%, and the reaction process is shown as the following formula:
nuclear magnetic resonance and mass spectrometry were performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 ):δ＝7.43(t,J＝7.6Hz,2H),7.37(d,J＝7.6Hz,2H),7.27(d,J＝7.6Hz,1H),7.14(s,1H),6.82(d,J＝7.2Hz,1H),4.63(dd,J＝3.2,1.2Hz,1H),3.85(s,3H),3.70(s,3H),3.09(dd,J＝3.2,1.2Hz,1H),2.75(dd,J＝3.2,1.2Hz,1H),2.38(s,3H).
13 C NMR(400MHz,CDCl 3 ):δ＝176.1,162.4,141.7,131.9,128.9,127.4,127.2,113.0,58.6,53.8,44.7,38.1,21.6.
HRMS: molecular formula C 18 H 20 FO 3 Calculated as 303.1396 and detected as 303.1395.
Example 4
The preparation method of the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound specifically comprises the following steps:
in a dry 15mL pressure-resistant reaction tube, 103mg of methyl 3- (2-methoxy-5-methyl) phenylacrylate (CAS: 86761-35-5), 97mg of 4-cyanobenzeneboronic acid, 2.0mg of cuprous chloride, 7.8mg of P, N-type chiral ligand, 38mg of potassium carbonate and 2.5mL of tetrahydrofuran were added. The reaction was stirred at 60℃for 2 hours under nitrogen. After the reaction is finished, cooling to room temperature, and directly passing through a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 10:1) to obtain 110mg of a product, wherein the yield is 71%, ee 90%, and the reaction process is shown as the following formula:
nuclear magnetic resonance and mass spectrometry were performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 ):δ＝7.45(t,J＝7.6Hz,2H),7.35(d,J＝7.6Hz,2H),7.29(d,J＝7.6Hz,1H),6.82(d,J＝7.2Hz,1H),7.15(s,1H),4.63(dd,J＝3.2,1.2Hz,1H),3.87(s,3H),3.71(s,3H),3.10(dd,J＝3.2,1.2Hz,1H),2.70(dd,J＝3.2,1.2Hz,1H),2.38(s,3H).
13 C NMR(400MHz,CDCl 3 ):δ＝176.3,162.3,156.4,141.4,131.8,127.9,127.1,126.2,114.1,58.8,53.8,44.9,38.2,21.6.
HRMS: molecular formula C 19 H 20 NO 3 Calculated as 310.1443 and detected as 310.1446.
Example 5
The preparation method of the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound specifically comprises the following steps:
to a dry 15mL pressure-resistant reaction tube, 103mg of methyl 3- (2-methoxy-5-methyl) phenylacrylate (CAS: 86761-35-5), 117mg of 4-phenylphenylboric acid, 2.0mg of cuprous chloride, 7.8mg of P, N-type chiral ligand, 138mg of potassium carbonate and 2.5mL of tetrahydrofuran were added. The reaction was stirred at 60℃for 3 hours under nitrogen. After the reaction is finished, the mixture is cooled to room temperature and directly passes through a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 10:1), 132mg of a product is obtained, the yield is 68%, ee 86%, and the reaction process is shown as the following formula:
nuclear magnetic resonance and mass spectrometry were performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 ):δ＝7.52(d,J＝7.6Hz,2H),7.50(t,J＝7.6Hz,2H),7.41(d,J＝7.6Hz,1H),7.40(d,J＝7.6Hz,2H),7.35(d,J＝7.6Hz,2H),7.05(s,1H),6.94(d,J＝7.2Hz,1H),6.82(d,J＝7.2Hz,1H),4.69(dd,J＝3.2,1.2Hz,1H),3.84(s,3H),3.70(s,3H),3.05(dd,J＝3.2,1.2Hz,1H),2.77(dd,J＝3.2,1.2Hz,1H),2.35(s,3H).
13 C NMR(400MHz,CDCl 3 ):δ＝173.3,160.6,141.9,140.8,138.3,131.4,131.2,131.1,129.2,128.7,128.4,127.9,127.6,127.5,112.2,56.1,51.9,38.6,21.6.
HRMS: molecular formula C 24 H 25 O 3 Calculated as 361.1804 and detected as 361.1803.
Example 6
The preparation method of the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound specifically comprises the following steps:
in a dry 15mL pressure-resistant reaction tube, 103mg of methyl 3- (2-methoxy-5-methyl) phenylacrylate (CAS: 86761-35-5), 97mg of 4-cyanobenzeneboronic acid, 2.0mg of cuprous chloride, 7.8mg of P, N-type chiral ligand, 138mg of potassium carbonate and 2.5mL of tetrahydrofuran were added. The reaction was stirred for 2 hours at 50℃under nitrogen. After the reaction is finished, cooling to room temperature, and directly passing through a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 10:1) to obtain 110mg of a product, wherein the yield is 71%, ee 90%, and the reaction process is shown as the following formula:
nuclear magnetic resonance and mass spectrometry were performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 ):δ＝7.86(d,J＝7.6Hz,1H),7.74(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),7.07(d,J＝7.6Hz,1H),7.05(s,1H),6.94(d,J＝7.6Hz,1H),6.82(d,J＝7.6Hz,1H),6.68(dd,J＝7.6Hz,1H),4.69(dd,J＝3.2,1.2Hz,1H),3.83(s,3H),3.68(s,3H),3.02(dd,J＝3.2,1.2Hz,1H),2.75(dd,J＝3.2,1.2Hz,1H),2.34(s,3H).
13 C NMR(400MHz,CDCl 3 ):δ＝173.1,160.6,154.0,143.0,142.9,131.8,131.2,131.1,128.7,127.8,127.5,125.5,112.2,122.0,112.1,56.8,51.8,38.9,21.6.
HRMS: molecular formula C 22 H 23 O 4 Calculated as 351.1596 and detected as 351.1596.
Example 7
The preparation method of the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound specifically comprises the following steps:
in a dry 15mL pressure-resistant reaction tube, 103mg of methyl 3- (2-methoxy-5-methyl) phenylacrylate (CAS: 86761-35-5), 78mg of phenylboronic acid, 2.0mg of cuprous chloride, 8.9mg of P, N-type chiral ligand, 138mg of potassium carbonate and 2.5mL of tetrahydrofuran were added. The reaction was stirred for 2 hours at 50℃under nitrogen. After the reaction is finished, cooling to room temperature, and directly passing through a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 15:1) to obtain 114mg of a product, wherein the yield is 73%, ee 88%, and the reaction process is shown as the following formula:
nuclear magnetic resonance and mass spectrometry were performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 ):δ＝7.40(t,J＝7.6Hz,2H),7.29(d,J＝7.6Hz,2H),7.27(d,J＝7.6Hz,1H),6.94(d,J＝7.2Hz,1H),6.82(d,J＝7.2Hz,1H),7.05(s,1H),4.69(dd,J＝3.2,1.2Hz,1H),3.83(s,3H),3.68(s,3H),3.00(dd,J＝3.2,1.2Hz,1H),2.75(dd,J＝3.2,1.2Hz,1H),2.34(s,3H).
13 C NMR(400MHz,CDCl 3 ):δ＝174.3,161.8,142.7,131.4,128.9,127.7,127.3,112.4,57.9,53.0,44.8,38.1,21.6.
HRMS: molecular formula C 18 H 21 O 3 Calculated as 285.1491 and detected as 285.1489.
Example 8
The preparation method of the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound specifically comprises the following steps:
in a dry 15mL pressure-resistant reaction tube, 103mg of methyl 3- (2-methoxy-5-methyl) phenylacrylate (CAS: 86761-35-5), 78mg of phenylboronic acid, 2.0mg of cuprous chloride, 10.4mg of P, N-type chiral ligand, 138mg of potassium carbonate and 2.5mL of tetrahydrofuran were added. The reaction was stirred for 2 hours at 50℃under nitrogen. After the reaction is finished, the mixture is cooled to room temperature and directly passes through a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 15:1), 117mg of a product is obtained, the yield is 75%, ee 86%, and the reaction process is shown as the following formula:
nuclear magnetic resonance and mass spectrometry were performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 ):δ＝7.40(t,J＝7.6Hz,2H),7.29(d,J＝7.6Hz,2H),7.27(d,J＝7.6Hz,1H),6.94(d,J＝7.2Hz,1H),6.82(d,J＝7.2Hz,1H),7.05(s,1H),4.69(dd,J＝3.2,1.2Hz,1H),3.83(s,3H),3.68(s,3H),3.00(dd,J＝3.2,1.2Hz,1H),2.75(dd,J＝3.2,1.2Hz,1H),2.34(s,3H).
13 C NMR(400MHz,CDCl 3 ):δ＝174.3,161.8,142.7,131.4,128.9,127.7,127.3,112.4,57.9,53.0,44.8,38.1,21.6.
HRMS: molecular formula C 18 H 21 O 3 Calculated as 285.1491 and detected as 285.1489.
Example 9
The preparation method of the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound specifically comprises the following steps:
in a dry 15mL pressure-resistant reaction tube, 103mg of methyl 3- (2-methoxy-5-methyl) phenylacrylate (CAS: 86761-35-5), 78mg of phenylboronic acid, 2.0mg of cuprous chloride, 8.3mg of P, N-type chiral ligand, 138mg of potassium carbonate and 2.5mL of tetrahydrofuran were added. The reaction was stirred for 2 hours at 50℃under nitrogen. After the reaction is finished, cooling to room temperature, and directly passing through a silica gel column (the volume ratio of petroleum ether to ethyl acetate is 15:1) to obtain 109mg of a product, wherein the yield is 70%, ee 87%, and the reaction process is shown as the following formula:
nuclear magnetic resonance and mass spectrometry were performed on the product prepared in this example:
1 H NMR(400MHz,CDCl 3 ):δ＝7.40(t,J＝7.6Hz,2H),7.29(d,J＝7.6Hz,2H),7.27(d,J＝7.6Hz,1H),6.94(d,J＝7.2Hz,1H),6.82(d,J＝7.2Hz,1H),7.05(s,1H),4.69(dd,J＝3.2,1.2Hz,1H),3.83(s,3H),3.68(s,3H),3.00(dd,J＝3.2,1.2Hz,1H),2.75(dd,J＝3.2,1.2Hz,1H),2.34(s,3H).
13 C NMR(400MHz,CDCl 3 ):δ＝174.3,161.8,142.7,131.4,128.9,127.7,127.3,112.4,57.9,53.0,44.8,38.1,21.6.
HRMS: molecular formula C 18 H 21 O 3 Calculated as 285.1491 and detected as 285.1489.
While specific embodiments of the invention have been described in detail in connection with the examples, it should not be construed as limiting the scope of protection of the patent. Various modifications and variations which may be made by those skilled in the art without the creative effort are within the scope of the patent described in the claims.
Claims (3)
1. A process for the preparation of (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound comprising the steps of:
3- (2-methoxy-5-methyl) phenyl methyl acrylate and phenylboronic acid compound are dissolved in an organic solvent, cuprous chloride, P, N-chiral ligand and potassium carbonate are added, and the mixture is uniformly mixed and then reacted for 1 to 4 hours at the temperature of 40 to 100 ℃ to obtain the catalyst;
the structural formula of the phenylboronic acid compound is shown as a formula (I),
the P, N-type chiral ligand is selected from,
wherein R is fluorine atom, cyano or phenyl;
the structural formula of the (R) -3- (2-methoxy-5-methyl) phenyl-3-phenylpropionic acid methyl ester compound is shown as a formula (III),
2. the method of manufacturing according to claim 1, characterized in that: the organic solvent is tetrahydrofuran, chlorobenzene, toluene, xylene, mesitylene or ethyl acetate.
3. The method of manufacturing according to claim 1, characterized in that: the molar ratio of the 3- (2-methoxy-5-methyl) phenyl methyl acrylate to the phenylboronic acid compound is 1:1-1:3; the molar ratio of the cuprous chloride to the 3- (2-methoxy-5-methyl) phenyl methyl acrylate is 0.005-0.1:1.
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| Title |
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| Bin Li,et al.Cu-Catalyzed Enantioselective Ring Opening of Cyclic Diaryliodoniums toward the Synthesis of Chiral Diarylmethanes.《J. Am. Chem. Soc.》.2018,第140卷第9400−9403页. * |
| Gaurav Dahiya, et al.Configuration Sampling With Five-Membered Atropisomeric P,NLigands.《Angew. Chem. Int. Ed.》.2021,第60卷第19604-19608页. * |
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