TW399057B - Asymmetric catalytic hydrogenation by ruthenium complexes - Google Patents

Abstract

The present invention provides a new type of Ru(diphosphine) catalyst with catalytic effect in asymmetric hydrogenation. Unlike the prior art complexes, the hydrogenation route is not only intermolecular reaction but also iintramecular reaction by the new Ru(diphosphine) catalyst.

Description

li ·· 二 89. 2. 2 ί 4i ¥ Year month β

COOH dehydronaproxen dehydronaproxen is supplemented in various organic bisphosphonate ligands (diPhOSphine ligand), p-2 2, bisdiphenyl-1.1'-bisnaphthalene (2,2, she oil _1.1) . _111. ) _1,1,: · binaphthyl (referred to as BINAP) has a wide range of researches on the asymmetric hydrogenation reaction, and the asymmetric catalyst formed by BINAP and many metals (such as ruthenium, osmium, silver) is useful for alkenyl or carbonyl The asymmetric hydrogenation reaction has very good stereoselectivity. The best example of industrialization is the asymmetric hydrogenation reaction of Naproxen, as shown in the following formula:

Naproxen Naproxen Noyori (Chemtedi 1992, Iune, 360) first proposed using Ru (S-BINAP) (OAc) 2 as a catalyst under high pressure hydrogenation to obtain a product with an optical purity of 97%. In 1992, ASC Chan's US Patent No. 5M4050 pointed out that Ru (S-BINAP) (acac) 2 was used as a catalyst and dehydronaproxen was first matured in methanol for three days and then hydrogenated. Speed up the reaction. However, dehydronaproxin is a weak acid containing double bonds, which will generate esters and dimers in methanol), which will cause problems in product purification. Moreover, the three-day ripening time will not only produce impurities but also take time. No, for industrial production. Therefore, how to manufacture high-efficiency catalysts without the loss of maturation time can be applied to the industrial production of high-purity optical products. The dimensions of this paper are in accordance with Chinese National Standard (CNS) A4 (2l0x297 mm) J. I n Loading n Stitching line f Please read the precautions on the back before filling out this page} Printed by the Central Consumers Bureau of the Ministry of Economic Affairs li ·· 二 89. 2. 2 ί 4i ¥ Year month β

COOH dehydronaproxen dehydronaproxen is supplemented in various organic bisphosphonate ligands (diPhOSphine ligand), p-2 2, bisdiphenyl-1.1'-bisnaphthalene (2,2, she oil _1.1) . _111. ) _1,1,: · binaphthyl (referred to as BINAP) has a wide range of researches on the asymmetric hydrogenation reaction, and the asymmetric catalyst formed by BINAP and many metals (such as ruthenium, osmium, silver) is useful for alkenyl or carbonyl groups The asymmetric hydrogenation reaction has very good stereoselectivity. The best example of industrialization is the asymmetric hydrogenation reaction of Naproxen, as shown in the following formula:

Naproxen Naproxen Noyori (Chemtedi 1992, Iune, 360) first proposed using Ru (S-BINAP) (OAc) 2 as a catalyst under high pressure hydrogenation to obtain a product with an optical purity of 97%. In 1992, ASC Chan's US Patent No. 5M4050 pointed out that Ru (S-BINAP) (acac) 2 was used as a catalyst and dehydronaproxen was first matured in methanol for three days and then hydrogenated. Speed up the reaction. However, dehydronaproxin is a weak acid containing double bonds, which will generate esters and dimers in methanol), which will cause problems in product purification. Moreover, the three-day ripening time will not only produce impurities but also take time. No, for industrial production. Therefore, how to manufacture high-efficiency catalysts without the loss of maturation time can be applied to the industrial production of high-purity optical products. The size of this paper is in accordance with Chinese National Standard (CNS) A4 (2l0x297mm) J. I n binding n binding line f Please read the notes on the back before filling out this page} Printed by the Consumers ’Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

Economic · Qiu Central Bureau of Standards Consumer Consumption 衽 Printing V. Invention Description (· 2) and Discussion on the Principles of Reaction Halpem, J.'s J. Am. Chem. Soc 1991, H3, 589; ASC Chan's and CC Chen Jnorg ·. Chim Acta 1995, 234, 95. It can be understood that in the hydrogenation process of traditional catalysts, the catalyst is mainly catalyzed by the intermolecular reaction between the catalyst and the cereal, as shown in the following formula: : Traditional hydrogenation diagram H ^ [H0CH3] OMe intermoleculer The present invention uses a 1,3-acetone dicarbonyl acid anion (1,3-acetonedicarboxylate anion for short) to synthesize the contact metal. Ru (S-BINAP) (acdca) 2 'its coordination type is to form a six-ring with ruthenium metal. Acdca not only plays the role of a ligand, but also an uncoordinated acid group, which can provide an acidic proton. This function is In the initial stage of the reaction, it is helpful to coordinate the binding of the antimony and the catalyst, so as to omit the ripening time before hydrogenation. During the reaction, the uncoordinated acid group can dissociate the bond of ruthenium metal and carbon bond, which makes the hydrogenation reaction from Intermolecular reaction modes between traditional catalysts and acidic protons Transfer reaction in the molecule, by shortening the distance intramolecular reaction to increase the reaction rate, shown in the following formula: hydrogenated illustrating the present invention, square

Intramolecular (intramolecular), 0Me ----- ^ ------ batch coat ------ ΐτ ------ line (please read the precautions on the back before filling this page) This paper Applicable to China National Standard (CNS) A4 (210X297 mm)

Economic · Qiu Central Bureau of Standards Consumer Consumption 衽 Printing V. Invention Description (· 2) and Discussion on the Principles of Reaction Halpem, J.'s J. Am. Chem. Soc 1991, H3, 589; ASC Chan's and CC Chen Jnorg ·. Chim Acta 1995, 234, 95. It can be understood that in the hydrogenation process of traditional catalysts, the catalyst is mainly catalyzed by the intermolecular reaction between the catalyst and the cereal, as shown in the following formula: : Traditional hydrogenation diagram H ^ [H0CH3] OMe intermoleculer The present invention uses a 1,3-acetone dicarbonyl acid anion (1,3-acetonedicarboxylate anion for short) to synthesize the contact metal. Ru (S-BINAP) (acdca) 2 'its coordination type is to form a six-ring with ruthenium metal. Acdca not only plays the role of a ligand, but also an uncoordinated acid group, which can provide an acidic proton. This function is In the initial stage of the reaction, it is helpful to coordinate the binding of the antimony and the catalyst, so as to omit the ripening time before hydrogenation. During the reaction, the uncoordinated acid group can dissociate the bond of ruthenium metal and carbon bond, which makes the hydrogenation reaction from Intermolecular reaction modes between traditional catalysts and acidic protons Transfer reaction in the molecule, by shortening the distance intramolecular reaction to increase the reaction rate, shown in the following formula: hydrogenated illustrating the present invention, square

Intramolecular (intramolecular), 0Me ----- ^ ------ batch coat ------ ΐτ ------ line (please read the precautions on the back before filling this page) This paper The scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm ---- also- | B7_ V. Description of the invention (3) — This invention relates to a novel synthesis method of ruthenium metal compound and can be used in asymmetric hydrogenation reaction , As shown in formula ①:

Where 'and R2 may be cyclohexyl, phenyl ghenyi), alkynyl (cvg substituted phenyl, ether group (ς-g substituted phenyl, halogen substituted phenyl), Rs may be hydrogen, alkyl (-cj, nitro, primary amine, secondary amine, secondary amine, or halogen; η may be 0 to 5. Especially as shown by formula (IA) and its various isomers:

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, where Ri and R2 can be per-hexyl, phenyl, phenyl substituted with C ^ -Cg, or substituted with ether (ς-c) Phenyl, halogen-substituted phenyl. The representative compound (IA) of the present invention can be prepared by using ruthenium trichloride (RuClJI ^ O) as a starting material according to the following reaction formula; this paper size is applicable to China National Standards (CNS> (2 丨 〇χΜ? 公) (Epidemic) ---- also- | B7_ V. Description of the Invention (3) — The present invention relates to a novel method for synthesizing a ruthenium metal compound and can be used in asymmetric hydrogenation reactions, as shown in formula ①:

Where 'and R2 may be cyclohexyl, phenyl ghenyi), alkynyl (cvg substituted phenyl, ether group (ς-g substituted phenyl, halogen substituted phenyl), Rs may be hydrogen, alkyl (-cj, nitro, primary amine, secondary amine, secondary amine, or halogen; η may be 0 to 5. Especially as shown by formula (IA) and its various isomers:

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, where Ri and R2 can be per-hexyl, phenyl, phenyl substituted with C ^ -Cg, or substituted with ether (ς-c) Phenyl, halogen-substituted phenyl. The representative compound (IA) of the present invention can be prepared by using ruthenium trichloride (RuClJI ^ O) as a starting material according to the following reaction formula; this paper size is applicable to China National Standards (CNS> (2 丨 〇χΜ? 公) Epidemic

h2o Ru (〇H) 3 (2) Ru (OH) 3 + 3H (acdca)

V. Description of the invention (4)

(1) RuC13.3H20 + NH4〇H

(3) Ru (acdca) 3 + S-BINAP

Or prepared via Ru (S-B1NAP) (0Ac) 2;

----.------ Equipment ---- ^ --- Order (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs In addition to ΙΑ), a small amount of geometric isomers (ΙΒ) and (IQ " This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)

h2o Ru (〇H) 3 (2) Ru (OH) 3 + 3H (acdca)

V. Description of the invention (4)

(1) RuC13.3H20 + NH4〇H

(3) Ru (acdca) 3 + S-BINAP

Or prepared via Ru (S-B1NAP) (0Ac) 2;

----.------ Equipment ---- ^ --- Order (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs In addition to ΙΑ), a small amount of geometrical isomers (ΙΒ) and (IQ " are also produced. The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm).

Supplement I A7 B7

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

V. Description of Invention

COOH (1C) Compound (IA) In the hydrogenated perylene, the 1,3-acetone dicarbonyl acid anion (acdca) not only plays the role of a ligand, but the uncoordinated acid group provides an acidic proton during the hydrogenation. Function in the early stage of the reaction, which helps to coordinate the reaction between the reactant and the catalyst, so as to omit the maturation time before hydrogenation. During the reaction, the uncoordinated acid group can act as a bond that dissociates the ruthenium metal and hinders the bond. The reaction shifted from the traditional intermolecular reaction mode between catalyst and acid proton to an intramolecular reaction, which increases the reaction rate by shortening the molecular reaction distance. The diagram of nitriding reaction is as follows: Initial stage of reaction (IA-> H > IV) This paper size is applicable to China National Standard (CNS) person 4 specification (210X297 mm) --- ^ ------seed coat ---- i— n ------ line (please read the notes on the back before filling this page) 2.

Supplement I A7 B7

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

V. Description of Invention

COOH (1C) Compound (IA) In the hydrogenated perylene, the 1,3-acetone dicarbonyl acid anion (acdca) not only plays the role of a ligand, but the uncoordinated acid group provides an acidic proton during the hydrogenation. Function in the early stage of the reaction, which helps to coordinate the reaction between the reactant and the catalyst, so as to omit the maturation time before hydrogenation. During the reaction, the uncoordinated acid group can act as a bond that dissociates the ruthenium metal and hinders the bond. The reaction shifted from the traditional intermolecular reaction mode between catalyst and acid proton to an intramolecular reaction, which increases the reaction rate by shortening the molecular reaction distance. The diagram of nitriding reaction is as follows: Initial stage of reaction (IA-> H > IV) This paper size is applicable to China National Standard (CNS) person 4 specification (210X297 mm) --- ^ ------seed coat ---- i-- n ------ line (Please read the precautions on the back before filling this page)

fsas. 22 · j; VI year and month V. Description of the invention (厶) Reaction process (IV-> V-> VI-> IV)

Dehydrona f Losing

(Please read the notes on the back before filling out this page. Binding Line Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

After the five-ring intermediate of carbon and ruthenium is formed, under high pressure hydrogen, it can react with the next hydrogen to form a hydrogenolysis reaction to dissociate the ruthenium metal and carbon bond, as shown in the following formula: This paper size applies to China National Standard (CNS) A4 specification (2 丨 0X297 mm)

fsas. 22 · j; VI year and month V. Description of the invention (厶) Reaction process (IV-> V-> VI-> IV)

Dehydrona f Losing

(Please read the notes on the back before filling out this page. Binding Line Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

After the five-ring intermediate of carbon and ruthenium is formed, under high pressure hydrogen, it can react with the next hydrogen to form a hydrogenolysis reaction to dissociate the ruthenium metal and carbon bond, as shown in the following formula: This paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) 〒. Is # 正 A7 B7 five & separation method to break the ruthenium metal and carbon bond as shown in the following formula: Bonding, such as

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Since two [] -acetone dicarbonyl acid anionic ligands do not need to coexist in the reaction process, it can be synthesized to contain only one 1 > 3 propionyl bis-iso-bis-chiric acid. An anionic ligand ruthenium metal compound to achieve the effect of transferring hydrogen from intermolecular to intramolecular, so equivalent strong acids can be used to obtain such a 1,3-acetone dicarbonyl acid anionic ligand ruthenium metal compound, The general formula is as follows: ~ Ru (BINAP) (acdca) 2 + HY -— ^ Ru (BINAP) (acdca) Y + Hacdca Y = Cl, Br, I, a〇4, BF4, this paper is suitable for each species Home Standard (CNS) A4 Specification (210 ^ 7 ^ * 7.-Binding-Thread--rf Please read the notes on the back before filling in this ¥ c 〒. 是 # 正 A7 B7 Five & way to break ruthenium The following formula for metal and carbon bonds is shown: Bonding, such as

Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Since two [] -acetone dicarbonyl acid anionic ligands do not need to coexist in the reaction process, it can be synthesized to contain only one 1 > 3 propionyl bis-iso-bis-chiric acid An anionic ligand ruthenium metal compound to achieve the effect of transferring hydrogen from intermolecular to intramolecular, so equivalent strong acids can be used to obtain such a 1,3-acetone dicarbonyl acid anionic ligand ruthenium metal compound, The general formula is as follows: ~ Ru (BINAP) (acdca) 2 + HY -— ^ Ru (BINAP) (acdca) Y + Hacdca Y = Cl, Br, I, a〇4, BF4, this paper is suitable for each species Home Standard (CNS) A4 Specification (210 ^ 7 ^ * 7.-Binding-Thread--rf Please read the notes on the back before filling in this ¥ c

V. Description of the invention (") When the equivalent acid is added, the ruthenium metal coordination number is changed from six to five. Such catalysts have very good reactivity for reducing keto groups to alcohols, such as the reaction of reducing acetamidine and acetone. : Ru (BINAP) (acdca) Q 〇h 〇ΟΛΛ η2

In addition, the effect of transferring hydrogen from intermolecular to intramolecular is not limited to the structure of 2,2'-bisdiphenylphosphine-1.1'-bisnaphthalene (BINNAρ). It is also suitable for the body, such as DIOP, DIPAMP, BPPFA, BPPM, CHIRAPHOS, NOPHOS, PROPHOS, CYCPHOS, SKEWPHOS, DEGPHOS, DuPHOS, PNNP. The structures are as follows: Phi (Please read the notes on the back before filling this page) Ministry of Economic Affairs Printed by the Central Consumers Bureau for Consumer Cooperation

DuPHOS -PPh2, PPh2 DEGPHOS

Fe PPh2 ^ -PPh2BPPFA

This paper size applies to China National Standard (CNS) Α4 specification (210X 297 mm)

, PPh2 C00-t ~ C4Hg BPPM

CYCPHOS, N., Isr • PPh2 / PPh2

. 6 latches 5 V PNNP, τ

V. Description of the invention (") When the equivalent acid is added, the ruthenium metal coordination number is changed from six to five. Such catalysts have very good reactivity for reducing keto groups to alcohols, such as the reaction of reducing acetamidine and acetone. : Ru (BINAP) (acdca) Q 〇h 〇ΟΛΛ η2

In addition, the effect of transferring hydrogen from intermolecular to intramolecular is not limited to the structure of 2,2'-bisdiphenylphosphine-1.1'-bisnaphthalene (BINNAρ). It is also suitable for the body, such as DIOP, DIPAMP, BPPFA, BPPM, CHIRAPHOS, NOPHOS, PROPHOS, CYCPHOS, SKEWPHOS, DEGPHOS, DuPHOS, PNNP. The structures are as follows: Phi (Please read the notes on the back before filling this page) Ministry of Economic Affairs Printed by the Central Consumers Bureau for Consumer Cooperation

DuPHOS -PPh2, PPh2 DEGPHOS

Fe PPh2 ^ -PPh2BPPFA

This paper size applies to China National Standard (CNS) Α4 specification (210X 297 mm)

, PPh2 C00-t ~ C4Hg BPPM

CYCPHOS, N., Isr • PPh2 / PPh2

. 6 latches 5 V PNNP, τ

Employees of the Central Bureau of Standards of the Ministry of Economic Affairs have cooperated with the printing of the company. V. Invention Description (γ) · And this nail metal compound is represented by the general formula Ru (diphosphine) (acdca) 2, or the synthesis contains only one 1,3 -Acetone dicarbonyl acid anionic ligand

Shu metal compounds, the general formula of which is Ru (diphosphirie) (acdca) (Y), where Y can be chlorine, bromine, iodine, hypochlorite (C104), boron tetrafluoride (BF4). In order to further explain the features and technical contents of the present invention, please refer to the following description of the embodiments of the present invention in detail. This is an example and is not intended to limit the present invention in any way. '' Example 1: Preparation of the compound Ru (acdca) 3 In a 50 mL single-necked flask, 5.20 g (20 mmol) of RuCipHp was added, and the solution was heated and dissolved in 10 mL of water, and the temperature was controlled at At 50 ° C, 10 ml of ammonia water was slowly added to react for four hours, cooled and filtered, and the precipitate was dried with a vacuum aspirator to obtain 2.5 g of Ru (OH) 3 as a black solid product.

Infrared spectrum of Ru (OH) 3: 3139 cmlOH); 1614 cm1; 1401 cm'1 (Ru-O) 0 Then 2.5 g of this (〇 印 3 and 8 g of ^ & acetone dicarbonyl acid in Heat to reflux in 40 ml methanol for eight hours, cool and filter, and dry the precipitate with a vacuum aspirator to obtain 3i2 g of solid product Ru (acdca) 3.

Infrared spectrum of Ru (acdca) 3: 3114 cm_1 (COOH); 1699 cm-1; 1619 cm'1; 1548 cm'1; 1391 cm'1 (Ru-O) This paper ^ Applicable_ 家 标 i ( CNS 71 ^^^ 97 公 楚)-Seed Thread (please read the precautions on the back before filling this page)

Employees of the Central Bureau of Standards of the Ministry of Economic Affairs have cooperated with the printing of the company. V. Invention Description (γ) · And this nail metal compound is represented by the general formula Ru (diphosphine) (acdca) 2, or the synthesis contains only one 1,3 -Acetone dicarbonyl acid anionic ligand

Shu metal compounds, the general formula of which is Ru (diphosphirie) (acdca) (Y), where Y can be chlorine, bromine, iodine, hypochlorite (C104), boron tetrafluoride (BF4). In order to further explain the features and technical contents of the present invention, please refer to the following description of the embodiments of the present invention in detail. This is an example and is not intended to limit the present invention in any way. '' Example 1: Preparation of the compound Ru (acdca) 3 In a 50 mL single-necked flask, 5.20 g (20 mmol) of RuCipHp was added, and the solution was heated and dissolved in 10 mL of water, and the temperature was controlled at At 50 ° C, 10 ml of ammonia water was slowly added to react for four hours, cooled and filtered, and the precipitate was dried with a vacuum aspirator to obtain 2.5 g of Ru (OH) 3 as a black solid product.

Infrared spectrum of Ru (OH) 3: 3139 cmlOH); 1614 cm1; 1401 cm'1 (Ru-O) 0 Then 2.5 g of this (〇 印 3 and 8 g of ^ & acetone dicarbonyl acid in Heat to reflux in 40 ml methanol for eight hours, cool and filter, and dry the precipitate with a vacuum aspirator to obtain 3i2 g of solid product Ru (acdca) 3.

Infrared spectrum of Ru (acdca) 3: 3114 cm_1 (COOH); 1699 cm-1; 1619 cm'1; 1548 cm'1; 1391 cm'1 (Ru-O) This paper ^ Applicable_ 家 标 i ( CNS 71 ^^^ 97 公 楚)-Seed sewing thread (please read the notes on the back first and then fill out this page) A7 A7 Preparation of printed compounds (IA) by Qu Ji, Shao Central Government Procurement Bureau employee consumer cooperative A 50 ml three-necked flask was charged with 1.072 g (2 mmol) of the example—the obtained compound Ru (acdca) s, 1.24 g (2 mmol) of S-BINAP and 4 g of powder, under nitrogen. Add 30 ml of previously deoxygenated ethanol, heat and reflux for eight hours, cool and filter off the powder, and then dry the yellow solution with a vacuum aspirator to obtain 1.62 g of a yellow solid product. The purity of the product is 31P NMR Measure it.

Phosphorus nuclear magnetic resonance spectrum of Ru (S-BINAP) (acdca) 2: P NMR (CDC13, 161 MHz, 25 ° C) d 57.53 (d, Jpp, == 42 Hz) 58-45 (d, Jpp,-42 Hz), 65.26 (d, Jpp, = 42 Hz), 68.02 (d, Jpp, ^ 42 Hz). Example 3: Preparation of Compound (IA)-A 100 ml three-necked flask was charged with 0.54 g of [ Ru (C〇D) Cl2] n, 1.244 g of S-BINAP, 2.5 g of NaOAc, in 50 mL of previously deoxygenated toluene and acetic acid mixed solution (volume ratio of 1: 1) Heat to reflux for eight days, cool to room temperature, then dry the solution with a vacuum aspirator, wash the sodium acetate with water that has been deoxidized beforehand, and then dry the water with a vacuum aspirator to obtain 16%. Gram of a yellow solid product Ru (S-BINAP) (OAc) 2 Ru (S-BINAP) (OAc) 2 Wall nuclear magnetic resonance spectrum 31P NMR (CDC13, 161 MHz, 25. 65 d. 100 ml double neck flask Add 0.84 g of Ru (S-BINAPX〇Ac) 2 and 0.29 g of 1,3-acetone dicarbonyl acid in 50 ml of deoxidized benzophenone. The paper size applies the Chinese National Standard (CNS) A4 specification ( 2! OX297 mm) 'In-In---.1 —-I!:!-F · ..... I--I-I. 一-, -I: 1------- ( (Please read the notes on the back before filling this page) A7 A7 Preparation of printed compounds (IA) printed by the employee consumer cooperative of Quji and Shao Central Bureau of quasi-branch The implementation of adding 1.072 g (2 mmol) to a 50 ml three-necked flask Example—The obtained compound Ru (acdca) s, 1.24 g (2 mmol) of S-BINAP and 4 g of powder, add 30 ml of deoxidized ethanol under nitrogen, and heat and reflux for eight hours. Filter off the powder, and then dry the yellow solution with a vacuum aspirator to obtain 1.62 g of a yellow solid product. The purity of the product can be measured with a 31P nuclear magnetic resonance instrument.

Phosphorus nuclear magnetic resonance spectrum of Ru (S-BINAP) (acdca) 2: P NMR (CDC13, 161 MHz, 25 ° C) d 57.53 (d, Jpp, == 42 Hz) 58-45 (d, Jpp,-42 Hz), 65.26 (d, Jpp, = 42 Hz), 68.02 (d, Jpp, ^ 42 Hz). Example 3: Preparation of Compound (IA)-A 100 ml three-necked flask was charged with 0.54 g of [ Ru (C〇D) Cl2] n, 1.244 g of S-BINAP, 2.5 g of NaOAc, in 50 mL of previously deoxygenated toluene and acetic acid mixed solution (volume ratio of 1: 1) Heat to reflux for eight days, cool to room temperature, then dry the solution with a vacuum aspirator, wash the sodium acetate with water that has been deoxidized beforehand, and then dry the water with a vacuum aspirator to obtain 16%. Gram of a yellow solid product Ru (S-BINAP) (OAc) 2 Ru (S-BINAP) (OAc) 2 Wall nuclear magnetic resonance spectrum 31P NMR (CDC13, 161 MHz, 25. 65 d. 100 ml double neck flask Add 0.84 g of Ru (S-BINAPX〇Ac) 2 and 0.29 g of 1,3-acetone dicarbonyl acid in 50 ml of deoxidized benzophenone. The paper size applies the Chinese National Standard (CNS) A4 specification ( 2! OX297 mm) 'In-In---.1 —-I!:!-F · ..... I--I-I. 一-, -I: 1------- ( Read the precautions on the back before filling this page.) 5. Description of the invention (丨 丨). Heat in a mixed solution with acetic acid to 50 X for four hours, and then dry the solution with a vacuum aspirator to obtain 1.0 g of solid. The product, the purity of the product was measured by a 31p nuclear magnetic resonance instrument, and confirmed, as described in Example 2. Example 4: Preparation of the compound Ru (S-BINAP) (acdca) Cl In a 50 ml three-necked flask, ijxq was added. (1_〇1) of the compound Ru (S_BINAp) (acdca) 2 obtained in Example 2 was added under nitrogen with 30 ml of previously deoxygenated ethanol and 0.05 N hydrochloric acid 0.02 mL. Stir for 30 minutes under temperature disturbance, and then dry the yellow solution with a vacuum aspirator to obtain 0.9 g of a yellow solid product. The purity of the product can be measured with a 31p nuclear magnetic resonance instrument. Ru (S-BINAP) (acdca) Cl Phosphorus Nuclear magnetic resonance spectrum: 31P NMR (CDC13, 81 MHz, 25 ° C) d 25.1 (d, Jpp ^ = 62 Hz) 41-4 (d, 6.3%, Jpp / = 62 Hz) Example 5: Central Standard of the Ministry of Economic Affairs Asymmetric hydrogenation of dehydronaproxine to dehydronaproxine by IAPC Consumer Cooperative (India) Compound (IA) It was dissolved in boml of methanol, placed in a 250ml autoclave, evacuated and aerated with nitrogen for three times, and then added 10 mg of compound gA), cooled to 0, and added 1000 psi of gas. For five hours, release hydrogen and dry the solution. The solid product was dissolved in 80 ml of acetone, and 30 liters of water was slowly added. The temperature was lowered to 0X, and the solid was slowly crystallized from the acetone aqueous solution. After repeated crystallization, 4.8 g was obtained. (S) -Naproxen 'optical purity is 99 6%, and optical rotation is {[α] +65.2. (c = l.〇CHCl》}. This paper (GNS) t ^ ~ ^ 21Qx 297 public-V. Description of the invention (丨 丨). Heat in a mixed solution with acetic acid to 50 X for four hours, cool and evacuate under vacuum The solution was drained by machine to obtain 1.0 g of solid product. The purity of the product was determined by a 31p nuclear magnetic resonance analyzer and confirmed as described in Example 2. Example 4: Compound Ru (S-BINAP) (acdca) Cl Preparation In a 50-ml three-necked flask, add ijxq g (1_〇1) of the compound Ru (S_BINAp) (acdca) 2 obtained in Example 2 and add 30 ml of previously deoxygenated ethanol and 0 under nitrogen. · 0.05 N of hydrochloric acid 0.02 mL, stir at room temperature for 30 minutes, and then dry the yellow solution with a vacuum aspirator to obtain 0.9 g of a yellow solid product. The purity of the product was measured by a 31p nuclear magnetic resonance instrument. Phosphorus nuclear magnetic resonance spectrum of Ru (S-BINAP) (acdca) Cl: 31P NMR (CDC13, 81 MHz, 25 ° C) d 25.1 (d, Jpp ^ = 62 Hz) 41-4 (d, 6.3%, Jpp / = 62 Hz) Example 5: Asymmetric hydrogenation of dehydronaproxin to dehydronaproxin by the Consumer Cooperative of the Consumer Standards Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, dehydrogenated 5.7 grams (2.5 moles) Proxim was dissolved in boml methanol, placed in a 250ml autoclave, evacuated and aerated with nitrogen for three times, and then added 10 mg of compound gA), cooled to 0, and added 1000 psi of gas. Stir for five hours, release hydrogen and dry the solution. The solid product is dissolved in 80 ml of acetone. Slowly add 30 liters of water, cool to 0X, and slowly crystallize the solid from the acetone aqueous solution. Repeat the crystallization once to obtain 4.8 g (S) -Naproxen 'The optical purity is 99 6%, and the optical rotation is {[α] +65.2. (c = l.〇CHCl》}. This paper (GNS) t ^ ~ ^ 21Qx 297 public-five '(to the first) A7 B7, description of the invention (/ 1) Table 1 is the compound (I) and other known Comparison of asymmetric hydrogenation reaction rates of ruthenium metal compounds for dehydronaproxin. Table 1 Comparison of hydrogenation reaction rates of various catalysts Catalyst reaction temperature (° c) Reaction time yield Ru (S-BINAP) (acdca) 2 24 mm 15 -Ji-100 RU (S-BINAP) (acac) 2 (called 24 15 3 Ru (S-BINAP) (OAc) 2 (Example 2) 24 15 25 [Ru (S-BINAP) C12] 2 -24 60 2 (NEg [Ru (S-BINAP) (p-Cymene)-24 60 13 C1] C1 RU (S-BINAP) (aCdca) 2 (Example 1) 0 180 100 Ru (S-BINAP) ( OAc) 2 (Example 2) 0 180 16 (Please read the notes on the back before filling out this page}--I -..... I-I- (Note 1) Reaction conditions: methanol as solvent; hydrogen The pressure is 1000 psig and the amount of dehydronaproxine and catalyst used is 4,000: 1 (Note 2) so that Ru (S-BINAP) (acac) 2 has not undergone the ripening step. Example 6. Compound ( IA) Asymmetric hydrogenation reaction of cis-2-amidinobut-2-enoic acid (tiglic acid) _ _,-& — Central Standard of the Ministry of Economics Printed by Bureau Staff Consumer Cooperative

, 〇OH H2 catalyst

COOH tiglic acid 2 g (20 millimoles) of p-cis-2-fluorenylbut-2-enoic acid was dissolved in 50 ml of methanol and placed in a 250 ml autoclave. And three times aerating with nitrogen, then add 10 mg of compound (IA), and add 50 paper standards applicable to China Gardening Standards (CNS) A4 (2 丨 0X297 mm) five '(to one) A7 B7, DESCRIPTION OF THE INVENTION (/ 1) Table 1 shows the comparison of the asymmetric hydrogenation rate of compound (I) with other known ruthenium metal compounds for dehydronaproxin. Table 1 Comparison of hydrogenation reaction rates of various catalysts Catalyst reaction temperature (° c) Reaction time yield Ru (S-BINAP) (acdca) 2 24 mm 15 -Ji-100 RU (S-BINAP) (acac) 2 ( Call 24 15 3 Ru (S-BINAP) (OAc) 2 (Example 2) 24 15 25 [Ru (S-BINAP) C12] 2- 24 60 2 (NEg [Ru (S-BINAP) (p-Cymene) -24 60 13 C1] C1 RU (S-BINAP) (aCdca) 2 (Example 1) 0 180 100 Ru (S-BINAP) (OAc) 2 (Example 2) 0 180 16 (Please read the note on the back first Please fill in this page again for further information}--I -..... I-I- (Note 1) Reaction conditions: methanol as solvent; hydrogen pressure 1000 psig dehydronaproxine and catalyst usage molar ratio Is 4000: 1 (Note 2) so that Ru (S-BINAP) (acac) 2 is not subjected to the ripening step. Example 6. Compound (IA) p-cis-2-fluorenylbut-2-enoic acid (tiglic acid ) Asymmetric hydrogenation reaction Ding _ _,-& — printed by the staff of the Central Standards Bureau of the Ministry of Economic Affairs

, 〇OH H2 catalyst

COOH tiglic acid 2 g (20 millimoles) of p-cis-2-fluorenylbut-2-enoic acid was dissolved in 50 ml of methanol and placed in a 250 ml autoclave. Gas and aerated with nitrogen three times, then add 10 mg of compound (IA), and add 50 paper standards applicable to China Garden Standard (CNS) A4 (2 丨 0X297 mm)

I Α7 Β7 V. Description of the invention (3), Stir for 10 hours under 20 psi of hydrogen gas at psi, release hydrogen and drain the solution, and measure the optical purity by GC chiral column (CP-Chirasil-Dex CB) to 90.2 / ) 'Yield 100% hydrogenated product. Example 7: Asymmetric Gasification Reaction of Compound Ru (S-BINAP) (acdca) Cl on Ethyl Acetate 〇 0ΛΛ

Ru (BINAP) (acdca) Q 〇h h2

Dissolve 2 g (20 mmol) of acetamidine in 50 ml of methanol, place in a 250 ml high-pressure reactor, evacuate and aerate with nitrogen three times, and add 10 mg of the compound Ru (S-BINAP) (acdca) Cl, and add 50 atm of hydrogen at 60 ° C and stir for one hour, release the hydrogen and drain the solution. The optical purity was 99% measured by GC chiral column (CP-Chirasil-Dex CB), and the yield was 100. % Hydrogenated product. (Please read the precautions on the back before filling in this page.) Printed on 11th line Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs This paper is sized for China National Standard (CNS) A4 (2 丨 〇297mm)

I Α7 Β7 V. Description of the invention (3), Stir for 10 hours under 20 psi of hydrogen gas at psi, release hydrogen and drain the solution, and measure the optical purity by GC chiral column (CP-Chirasil-Dex CB) to 90.2 / ) 'Yield 100% hydrogenated product. Example 7: Asymmetric Gasification Reaction of Compound Ru (S-BINAP) (acdca) Cl on Ethyl Acetate 〇 0ΛΛ

Ru (BINAP) (acdca) Q 〇h h2

Dissolve 2 g (20 mmol) of acetamidine in 50 ml of methanol, place in a 250 ml high-pressure reactor, evacuate and aerate with nitrogen three times, and add 10 mg of the compound Ru (S-BINAP) (acdca) Cl, and add 50 atm of hydrogen at 60 ° C and stir for one hour, release the hydrogen and drain the solution. The optical purity was 99% measured by GC chiral column (CP-Chirasil-Dex CB), and the yield was 100. % Hydrogenated product. (Please read the precautions on the back before filling in this page.) Printed on 11th line Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs This paper is sized for China National Standard (CNS) A4 (2 丨 〇297mm)

Claims (1)

Scope of patent application 399057 1. A compound is shown by the following formula ①: R3 ho (I), wherein Min and Chi 2 can be cyclohexyl, phenyl 0henyl), phenyl substituted with a carbyl group ^-^, oxygen-seeking surface. G take shape Phenyl, self-substituted phenyl; R3 can be hydrogen, alkyl (ς-Q, nitro, mono (ς_ς alkyl) amino, bis (Cr iridyl) amino, tri (Ci_C6 alkyl) ) Amine group or functin; n may be 0 to 5. 1 2. A kind of bisphosphorus ruthenium metal compound containing one; L, 3-acetone dicarbonyl acid anionic ligand, and its chemical formula is Ru (BINAPXaedcaXY) The compound structure is shown in Putian: Side (BFJ, Min and & may be phosphyl, phenyl, and alkynyl (c ^ c ^. · Substituted phenyl, alkoxy (CrQ substituted phenyl, halogen substituted phenyl · '& may be oxygen, radix (g-g, alkynyl), mono (Ci-c6 ^ yl) amino, bis (radio) amine, tris (Crc6) amine or oxine Η can be from 0 to 5. --------- install ------ order. _, ----- line (please read the precautions on the back before filling this page) Central of the Ministry of Economy Printed by the Standards Bureau Employee Consumer Cooperative Scope of patent application 399057 1. A compound is shown by the following formula ①: R3 ho (I), wherein Min and Chi 2 can be cyclohexyl, phenyl 0henyl), phenyl substituted with a carbyl group ^-^, oxygen-seeking surface. G take shape Phenyl, self-substituted phenyl; R3 can be hydrogen, alkyl (ς-Q, nitro, mono (ς_ς alkyl) amino, bis (Cr iridyl) amino, tri (Ci_C6 alkyl) ) Amine group or functin; n may be 0 to 5. 1 2. A kind of bisphosphorus ruthenium metal compound containing one; L, 3-acetone dicarbonyl acid anionic ligand, and its chemical formula is Ru (BINAPXaedcaXY) The compound structure is shown in Putian: Side (BFJ, Min and & may be phosphyl, phenyl, and alkynyl (c ^ c ^. · Substituted phenyl, alkoxy (CrQ substituted phenyl, halogen substituted phenyl · '& may be oxygen, radix (g-g, alkynyl), mono (Ci-c6 ^ yl) amino, bis (radio) amine, tris (Crc6) amine or oxine Η can be from 0 to 5. --------- install ------ order. _, ----- line (please read the precautions on the back before filling this page) Central of the Ministry of Economy Printed by the Standards Bureau Employee Consumer Cooperative A8 B8 C8 3. A compound is represented by the following formula (vni): CH2) n HO VIII COOH compounds are represented by the general formula Ru (diphosphine) (acdca) 2, where the diphosphine can be DIOP, DIPAMP, BPPFA 'BPPM' CHIRAPHOS 'PROPHOS' NORPHOS 'CYCPHO S, SKEWPHOS, DEGPHOS, DuPHOS, PNNP; R1 and R2 may be cyclohexyl, phenyl, phenyl substituted with alkoxy (ς-C), phenyl substituted with ether (ς-c), Halogen-substituted phenyl; n may be 0 to 5. 4. A compound is represented by the following formula: 0 ×): The general formula of the compound can be represented by Ru (diphospliine) (acdca) ⑺, where Y can be chlorine, bromine, iodine, hypochlorite (C10J, boron tetrafluoride-OF), and bisphosphine Can be DIOP, DIPAMP, BPPFA, BPPM, CHIRAPHOS, PROPHOS, NORPHOS, CYCPHOS, SKEWPHOS, DEGPHOS, DuPHOS, PNNP; Min and & Can be cyclohexyl, phenyl (phenyl), alkyl (ς-Q substituted Stupid ^ paper wave ruler is applicable; national and national standards (CNS) Α4 wash grid (210X297) 嫠 ~ ----- A8 B8 C8 3. A compound is represented by the following formula (vni): CH2) n HO VIII COOH compounds are represented by the general formula Ru (diphosphine) (acdca) 2, where the diphosphine can be DIOP, DIPAMP, BPPFA 'BPPM' CHIRAPHOS 'PROPHOS' NORPHOS 'CYCPHO S, SKEWPHOS, DEGPHOS, DuPHOS, PNNP; R1 and R2 may be cyclohexyl, phenyl, phenyl substituted with alkoxy (ς-C), phenyl substituted with ether (ς-c), Halogen-substituted phenyl; n may be 0 to 5. 4. A compound is represented by the following formula: 0 ×): The general formula of the compound can be represented by Ru (diphospliine) (acdca) ⑺, where Y can be chlorine, bromine, iodine, hypochlorite (C10J, boron tetrafluoride-OF), and bisphosphine Can be DIOP, DIPAMP, BPPFA, BPPM, CHIRAPHOS, PROPHOS, NORPHOS, CYCPHOS, SKEWPHOS, DEGPHOS, DuPHOS, PNNP; Min and & Can be cyclohexyl, phenyl (phenyl), alkyl (ς-Q substituted Stupid ^ paper wave ruler is applicable; China National Standard (CNS) Α4 wash grid (210X297)-~ ----- Ί 39905? 8 8 8 8 ABCD 6. Application scope _ base, alkoxy ( ς-g substituted phenyl, dentin-substituted phenyl; η may be 0 to 5. 5.-A catalyst composition used in asymmetric hydrogenation reaction, which is based on the scope of patent applications 1, 2, 3 Or the numerator contained in item 4 is the main component. (Please read the precautions on the back before filling out this page.) Packing. — Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperatives. II! 11 ...... I —11 I---I -1 I »---------1 This paper size applies to China National Standard (CNS) Α4 size (210 × 297 mm) Ί 39905? 8 8 8 8 ABCD VI. Patent application scope _ group, alkoxy (ς-g substituted phenyl, dentin-substituted phenyl; η can be 0 to 5. 5. A kind of asymmetric hydrogenation reaction The catalyst composition is mainly composed of the molecules contained in the scope of patent application No. 1, 2, 3 or 4. (Please read the precautions on the back before filling this page) Installation. —Central Standard of the Ministry of Economics Printed by the Bureau ’s Consumer Cooperatives. II! 11 ...... I —11 I---I -1 I »---------1 This paper size applies to the Chinese National Standard (CNS) Α4 Specifications (210 × 297 mm)