TWI453182B - Process for the preparation of (r)-β-amino-phenyl butyric acid derivatives - Google Patents

Description

Method for preparing R-β-aminophenylbutyric acid derivative

The present invention relates to a process for obtaining a single optical configuration of an R-β-aminophenylbutyric acid derivative (I) by a chemical synthesis method including a resolution method, and a compound of the formula (I) obtained by the process of the present invention can be used. For the synthesis of a variety of chiral drugs.

With the development of drug synthesis technology, more and more chiral atom-containing drugs tend to be made into a single optical configuration, and chiral β-aminophenylbutyric acid derivatives are important. Chiral drug intermediates, which are prepared by chiral catalytic reduction, are often reported; for example, JACS., 1987, 5856 describes the preparation of the above target using ethyl 2,4,5-trifluorophenylacetate as the starting material. Method for the reduction of Ru-(S)-BINAP by chiral reduction catalyst to obtain chiral β-hydroxy-2,4,5-trifluorophenylbutyric acid ethyl ester, followed by amination to obtain R-β-amino group 2,4,5-trifluorophenylbutyric acid ethyl ester; Reference: JACS., 1986, 7117 describes the screening of different ligands for chiral hydrogenation reduction to give chiral R-β-aminophenylbutyric acid derivatives The process of the article; PCT Patent Specification WO 2004085661 also describes in detail the synthetic route of the R-β-aminophenylbutyric acid derivative, which discloses a method for preparing the above chiral intermediate by chiral reduction, using S- Reaction of α-phenylglycine decylamine with 2,4,5-trifluorophenyridinium derivatives to form α,β-unsaturated with chiral ligands a β-amino-2,4,5-trifluorophenylbutyric acid derivative, which is then catalyzed by a platinum oxide to give a chiral β-amino-2,4,5-trifluorophenyl Acid derivatives; WO2005020920 describes the reduction of α,β-unsaturated β-amino-2,4,5-trifluorophenylbutyric acid derivatives with chlorinated cyclooctadiene ruthenium and a third butyl Josiphos catalyst A method of preparing the chiral intermediate represented by the above formula (I).

Although the literature on the preparation of chiral β-aminophenylbutyric acid derivatives by chiral reduction has been reported many times, the results obtained by chiral reduction methods are often unsatisfactory. First, the chiral reduction catalyst used in this method tends to be relatively expensive, thereby greatly increasing the manufacturing cost of the target compound. In practice, although homogeneous catalysis is likely to result in higher optical purity targets, homogeneously catalyzed catalyst recovery is difficult, which often leads to excessively high cost of synthesizing target compounds, making the synthetic route lose the value of industrial production. Secondly, the chiral reduction reaction conditions are harsh, the chiral reduction catalyst itself is not easy to prepare, and the process of chiral reduction is relatively cumbersome. Third, since the selectivity of the chiral reduction catalyst tends to be low, the optical purity of the product is therefore unsatisfactory, and the product often needs to undergo multiple recrystallization steps to meet the requirements, and it is difficult to achieve industrialized large-scale production. In comparison, the method of splitting a single optical configuration target with a resolving agent exhibits its advantages in all of the above aspects.

For the time being, the preparation of R-β-aminophenylbutyric acid derivatives by resolving agents has not been available for reference. In view of the medicinal value of the R-β-aminophenylbutyric acid derivative, an effective resolution method is sought, and the β-aminobenzene of the above R-configuration having high optical purity is obtained by high resolution and high yield by resolution. Butyric acid derivatives are very necessary.

In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a preparation method of a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative represented by formula (I). Wherein, in the formula (I), Ar is a substituted or unsubstituted phenyl group, and when Ar is a substituted phenyl group, the substituent is 1-5 selected from fluorine, methyl, trifluoromethyl or a group of a trifluoromethoxy group; R ₁ is hydrogen or a lower alkyl group having 1 to 6 carbon atoms; R ₂ is a hydrogen or an amine protecting group, including an alkoxycarbonyl group and a decyl group; The carbonyl group is selected from the group consisting of methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl; the sulfhydryl group is selected from the group consisting of methyl hydrazino, ethyl hydrazino, chloroethyl fluorenyl, trichloroethylene thiol, benzhydryl or phenyl A mercapto group, characterized in that the preparation method comprises the following steps: (1) using the substituted or unsubstituted phenylacetate acetate as a raw material, reacting with ammonium formate to form an imine, and then using a reducing agent Reduction of the corresponding β-aminophenylbutyrate racemate; (2) salt formation and crystallization in an alcohol solvent or an alcohol solution using a chiral resolving agent, and splitting the β-amino group obtained in the above step a benzobutyrate racemate to give a corresponding salt of a chiral β-aminophenylbutyrate and a resolving agent; (3) free hydrolysis of the chiral β-aminophenylbutyric acid obtained in the above step Ester and resolving agent The resulting salt, or amine-protected, gives the chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative as shown in formula (I).

In the embodiment of the present invention, the method further comprises reacting the chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative represented by the formula (I) obtained in the step (3) with hydrochloric acid to form a hydrochloride.

The preparation method of the chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative (I) to be disclosed in the present invention has the following reaction scheme:

Preferably, the first product (Ia): wherein Ar in the formula (I) is 2,4,5-trifluorophenyl, R ₁ and R ₂ are each a hydrogen atom; preferably, the second product ( Ib): wherein Ar in the formula (I) is 2,4,5-trifluorophenyl, R ₁ is ethyl and R ₂ is a hydrogen atom; preferably, the third product (Ic): wherein (I) Wherein Ar is 2,4,5-trifluorophenyl, R ₁ is a hydrogen atom, and R ₂ is a third butoxycarbonyl group.

In order to better understand the essence of the present invention, the preparation method of the preferred common chiral pharmaceutical intermediate R-β-amino-2,4,5-trifluorobenzenebutyric acid or a pharmaceutically acceptable salt thereof is taken as an example to the present invention. Explain it.

The preparation process of R-β-amino-2,4,5-trifluorobenzenebutyric acid comprises the following steps: firstly, using 2,4,5-trifluoroacetophenone acetate as a raw material, reacting with ammonium formate to form The imine is then reduced with sodium cyanoborohydride to obtain β-amino-2,4,5-trifluorophenylbutanoic acid ethyl ester; then the salt is crystallized in an alcohol solvent or an alcoholic aqueous solution using a chiral resolving agent. Separating the above-mentioned β-amino-2,4,5-trifluorophenylbutyric acid ethyl ester to obtain the corresponding chiral R-β-amino 2,4,5-trifluorophenylbutyric acid ethyl ester and disassembled a salt formed by the partitioning agent; a salt obtained by the free hydrolysis of the chiral R-β-amino-2,4,5-trifluorophenylbutyric acid ethyl ester and a resolving agent, or an amine group protection A chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative represented by formula (I) or a pharmaceutically acceptable salt thereof.

According to the technical solution of the present invention, the reducing agent used in the step (1) is sodium cyanoborohydride. The chiral resolving agent described in the step (2) is a bis-deuterated substituted chiral tartaric acid, and the chiral tartaric acid includes benzamidine-D-tartaric acid, benzamidine-L-tartaric acid, and di-p-toluene.醯-D-tartaric acid or di-p-toluidine-L-tartaric acid.

Preferably, the chiral resolving agent is selected from the group consisting of dip-toluidine-D-tartaric acid or di-p-tolylformamide-L-tartaric acid.

In the preparation method of the present invention, the di-p-tolylformin-L-tartaric acid or di-p-tolylformin-D-tartaric acid may be used alone; or the di-p-tolylformine-L- may be used in combination. Tartaric acid or di-p-toluidine-D-tartaric acid.

Further, in the method for producing a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative, the alcohol solvent described in the step (2) is a lower aliphatic alcohol having a carbon number of less than 3. The alcohol solvent is preferably methanol.

The aqueous alcohol solution described in the step (2) of the present invention is an aqueous solution of a lower aliphatic alcohol having a carbon number of less than 3.

Thus, it can be seen that the problem to be solved by the present invention is that the method of chemical synthesis involves the use of a resolving agent to resolve the mixed body of the β-aminophenylbutyric acid derivative, thereby obtaining the desired specific optical configuration. The target of formula (I) as defined above:

In the above reaction formula, the compound II (R ₁ is an alkyl group having 1 to 6 carbon atoms or a hydrogen atom) can be obtained by a method described in U.S. Patent No. 5,928,482. Using 2,4,5-trifluorobromobenzene as raw material, alkylation reaction with diethyl malonate, followed by hydrolysis and decarboxylation to obtain 2,4,5-trifluorophenylacetic acid, 2,4,5-trifluoro The phenylacetic acid is condensed with Meldrum's acid, then subjected to alcoholysis and then decarboxylated to obtain 2,4,5-trifluoroacetoacetic acid ethyl acetate; 2,4,5-trifluorophenylacetate ethyl acetate The above reaction formula is used as a raw material for preparing the target (I).

Ethyl 2,4,5-trifluorophenylacetate (II, R ₁ =Et) is converted to the imine with ammonium formate and then reduced with sodium cyanoborohydride to give compound III (R ₁ =Et); Fractional resolution gives compound IV (R ₁ =Et), IV is freely hydrolyzed or subjected to amine group protection to obtain target (I). When R ₁ and R ₂ in formula (I) have different expressions, the target substance (I) represents specific compounds of different stages, such as Ia, Ib and Ic shown in the above reaction formula.

After extensive and in-depth research, the inventors found that in the above-mentioned disintegration process, the commonly used acidic resolving agent, besides R-camphorsulfonic acid, has certain selectivity for the resolution of the mixed formula of the formula (III), The various resolving agents are basically ineffective for the resolution of the mixed formula of formula (III); some resolving agents cannot effectively form crystal precipitation with the mixed formula of formula (III) in various solvents, although some resolving agents can And the mixed formula of formula (III) forms a crystalline precipitate in a solvent, but has no resolution selectivity, and the precipitate is still a mixed-rotator; the inventors have confirmed by experiments that a resolving agent which does not produce an ideal disintegration effect has L - tartaric acid, R-mandelic acid, N-acetamidine-L-glutamic acid, L-leucine, and the like.

Further, the inventors have unexpectedly found that among the large number of commonly used acidic resolving agents tested, only chiral tartaric acid such as benzophenone-L protected by benzamidine or substituted benzamidine bismuth. - tartaric acid (L-DBTA), benzotriene-D-tartaric acid (D-DBTA), di-p-toluidine-L-tartaric acid (L-DTTA) or di-p-toluidine-D-tartaric acid (D-DTTA) The β-amino phenylbutyric acid derivative of the R-configuration and the S-configuration can be effectively separated.

Broadly speaking, the present invention relates to a process for the preparation of a pharmaceutical intermediate R-β-aminophenylbutyric acid derivative (I), which comprises both the chemical preparation process of the mixed formula of formula (III) and the use of resolution a step of salting and crystallizing a mixture of the agent and the compound of formula (III) in an alcohol solvent or an aqueous alcohol solution, the resolving agent being benzophenone-L-tartaric acid (L-DBTA), diphenyl醯-D-tartaric acid (D-DBTA), di-p-toluidine-L-tartaric acid (L-DTTA) or di-p-toluidine-D-tartaric acid (D-DTTA), preferably di-p-toluidine -L-tartaric acid or di-p-tolylformin-D-tartaric acid, wherein the target product structure obtained is an R-β-aminophenylbutyric acid derivative represented by the formula (I) or a corresponding S-β-amine A phenylbutyric acid derivative.

To obtain a single optical configuration of a compound of formula (I), such as Ib in the R configuration, using 1 mole (mol) of D-DTTA with 2 moles of a compound of formula III (R ₁ =Et) in methanol The salt is precipitated and purified to obtain a salt of D-DTTA (IV, R ₁ =Et) of the R configuration compound, which is freed to obtain a single R configuration compound Ib. Conversely, if a compound of the S configuration is required, it can be resolved by L-DTTA to obtain the corresponding S configuration compound.

Further, the resolution method of the present invention includes a recrystallization process after salt formation and crystallization. The resolving agent used in the method of the present invention, di-p-tolylformine-L-tartaric acid (L-DTTA) and di-p-tolylformin-D-tartaric acid (D-DTTA) may be used singly or in combination. In particular, the present invention relates to a process for the resolution of the intermediate β-aminophenylbutyric acid derivative of the formula (I). The problem solved by the present invention is to obtain a pharmaceutically acceptable optical purity of the above-mentioned R-configuration of the compound of the formula (I) in an excellent yield by resolution using di-p-tolylformamide-L-tartaric acid. The method is characterized in that the mixed body of the formula (III) is combined with a chiral resolving agent to form a corresponding salt in a specific solvent, and the desired chiral intermediate β-aminophenylbutyric acid is selectively precipitated. Crystallization of the salt of the substance.

The resolution process of the intermediate amine of the formula (III) by the present inventors refers to salt crystallization, recrystallization refining and free extraction from the intermediate amine of the formula (III) and a chiral resolving agent to obtain an intermediate amine. The entire process of Ib, further including the process of hydrolyzing Ib to obtain Ia or protecting the amine to obtain Ic, these useful chiral pharmaceutical intermediates can be used for the synthesis of various active pharmaceutical compounds.

Regarding the amount of the resolving agent, theoretically, according to the correspondence of the acid base salt forming reaction, the molar ratio of the intermediate amine and the resolving agent may be 2:1; if only the corresponding desired configuration is considered, The molar ratio is 4:1; if the molar salt is considered to obtain the acid salt, the molar ratio can also be 1:1; and the inventors have found that a higher ratio of the resolving agent is beneficial to A more desirable yield results in a resolution product of high optical purity. In general, the molar ratio of the intermediate amine to the resolving agent may range from 4:1 to 1:1, with a preferred ratio of from 2:1 to 1:1, and an excess of the resolving agent. There is no greater help.

The process of dissolving the mixed formula of the formula (III) is carried out in a conventional solvent, preferably in an organic solvent, and the organic solvent is more preferably an alcohol solvent, and the alcohol solvent may be used alone or in combination with other solvents. The organic solvent is used in combination. The alcohol solvent used in the method of the present invention includes an alcohol solvent used alone and a mixed solvent mainly composed of an alcohol, and the alcohol solvent is a lower aliphatic alcohol having 3 or less carbon atoms, more preferably methanol. The alcohol solution described is an aqueous solution of the above lower aliphatic alcohol.

In order to increase the optical purity of the intermediate amine of the formula (I) obtained by the resolution, a step of recrystallizing the resolving agent salt obtained by the resolution is sometimes necessary. The process of the separation can generally be carried out at normal temperature, if necessary under heating conditions, and the recrystallization step can generally be carried out under heating, first heating to dissolve the resolved salt in a specific solvent. Then, the process of recrystallization is slowly completed at room temperature. In general, the optical purity is often satisfactory after secondary recrystallization of the product, and its ee value is generally above 99%.

The process of the free intermediate is conventional, and the base used for the free is preferably sodium hydrogencarbonate; the solvent used for the extraction is generally selected from hydrophobic organic solvents conventionally used for extraction, such as ethyl acetate, dichloromethane and chloroform, etc., preferably. It was ethyl acetate and chloroform. The process of hydrolysis of the compound of formula (I) is also conventional, and the base used is preferably sodium hydroxide. The acid used for salt formation is preferably hydrochloric acid, and the method of salt formation is conventional, and it is relatively easy for a professionally trained person to do this.

The ester or acid of the compound of formula (I) obtained according to the process of the invention has an optical purity of up to 99% or more, and is particularly suitable for use as a pharmaceutical intermediate for the synthesis of chiral drugs.

The invention is explained in more detail below with reference to the embodiments, which are intended to illustrate the technical solutions of the invention and not to limit the nature of the invention.

Preparation Example 1

114 g (g) (0.60 mol) of 2,4,5-trifluorophenylacetic acid, 600 ml (ml) of THF was added, and 0.7 g (0.66 mol) of N,N-carbonyldiimidazole was slowly added thereto with stirring ( After adding a part, a large amount of solid appeared, and then it was dissolved with further addition. After the addition, the temperature was raised to 50 ° C, and 95.1 g (0.66 mol) of Myric acid was added, and the reaction was kept for 3 hours. Concentrated to remove THF, 600 ml of water and 800 ml of dichloromethane were added, the pH of the aqueous layer was adjusted to 2, the organic phase was separated, washed with 0.1N HCl, washed with 600 ml of water, and dried to give a solid condensate of 182 g of 2,2-dimethyl- 5-[2-(2,4,5-trifluorophenyl)-ethinyl]-[1,3]dioxolane-4,6-dione (ethyl acetate can be recrystallized to give a white solid powder ), melting point: 101.5 to 103.5 ° C, yield 96%.

Example 1

60 g (0.190 mol) of the condensate of Preparation Example 1 was added to 600 ml of ethanol, and the mixture was stirred and heated to 70 ° C for 3 hours, at which time 2,4,5-trifluorophenylacetate ethyl acetate (II) was obtained. To the reaction solution, 70 g (1.11 mol) of ammonium formate was added, and the mixture was refluxed for 3 hours, and then slightly cooled to about 40 ° C, and 15 g (0.239 mol) of sodium cyanoborohydride was gradually added thereto, followed by reflux for 2 hours. After cooling, it is concentrated to remove ethanol, then water is added, the pH is adjusted to 9, the mixture is extracted with dichloromethane, washed with a small amount of water, and dried to give a brown oily compound of <RTI ID=0.0> 45 g, yield 90.5%.

Example 2

Β-amino-2,4,5-trifluorophenylbutanoic acid ethyl ester racemate 5.18g (20mmol), dissolved in methanol 60ml, added D-DTTA3.86g (10mmol) with stirring, quickly precipitated a large amount of white The solid was heated to reflux for 1 to 2 hours (the solid was not completely dissolved), and then cooled to below 10 ° C. The precipitated solid was filtered, washed with a small amount of methanol, and then re-crystallized twice with methanol to give a white solid powder 3.37 g, melting point: 187.0 to 188.0 ° C, [a] _D ²⁵ = +96.7 ° (C1, 0.1 M NaOH), 3.0 g of white solid was obtained to obtain R-β-amino-2,4,5-trifluoro with an optical purity of 99.7% or more. Ethyl phenylbutyrate (Ib) 1.20 g. The yield of one resolution was 52.2%.

The mother liquor obtained in the above splitting and two crystallization processes was combined, concentrated to dryness, and then freed with a saturated solution of sodium hydrogencarbonate, and extracted with chloroform to obtain 4.7 g of a mixture of S-forms, HPLC analysis The configuration accounted for 71.3%, dissolved in 60 ml of methanol, and then added to L-DTTA 3.86 g (10 mmol) for reverse resolution, heated to clarify, allowed to cool, precipitated solid, filtered, and dried. HPLC analysis of the S configuration accounted for 95.6%. The obtained crude solid of the S configuration was added to 60 ml of methanol, refluxed to clarify, and allowed to cool, and the solid was precipitated, filtered, and dried to give 3.44 g of the L-DTTA salt of the S configuration, melting point: 182.0 to 183.5 ° C, [a] _D ²⁵ =-90.3° (Cl, 0.1 M NaOH). The yield of the S-form split obtained by the reverse splitting was 53.3%. HPLC analysis of the S configuration accounted for 98.4%.

The mother liquor obtained by the above splitting and recrystallization was combined, concentrated to dryness, and then freed with a saturated solution of sodium hydrogencarbonate, and extracted with chloroform to obtain 1.9 g of a mixed form mainly in the R configuration, HPLC analysis The configuration accounted for 67.4%, dissolved in 20 ml of methanol, and then added with 1.5 g of D-DTTA, heated to clarify, allowed to cool, precipitated solid, filtered, and the obtained crude solid was added to ethanol 20 ml, refluxed to clarify, allowed to cool, and solid was precipitated. It was filtered and dried to give 0.92 g. HPLC analysis of the R configuration accounted for 99.30%. The obtained solid was dissolved in a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform to give 0.5 g of the intermediate amine (Ib) of the R configuration. The yield was 19.5%, and the R configuration was 99.3% by HPLC analysis. The total resolution was 71.4%.

Example 3

Β-amino-2,4,5-trifluorophenylbutyric acid ethyl ester racemate 5.18g (20mmol), dissolved in methanol 60ml, added 3.86g (10mmol) L-DTTA solids under stirring, quickly precipitated a large amount White solid, heated under reflux for 1 to 2 hours (solids can not be completely dissolved), then cooled to below 10 ° C, the precipitated solid was filtered, washed with a small amount of methanol, the mother liquid was concentrated to dryness, 70 ml of water was added, saturated sodium carbonate was adjusted to pH 8 Extracted with dichloromethane, washed with water and concentrated to give an oil.

Further, 60 ml of methanol was added to the oil, and 3.86 g (10 mmol) of D-DTTA was added thereto with stirring, and a large amount of white solid was quickly precipitated, and the mixture was heated under reflux for 1 to 2 hours, and then cooled to 10 ° C or less. The precipitated solid was filtered and washed with a small amount of methanol. The solid was re-crystallized from methanol to give a white solid powder (4.17 g, m.p.: 185.0 to 186.5 ° C, [a] _D ²⁵ = +95.8 (C1, 0.1 M NaOH), and 4.0 g of free was obtained to obtain an optical purity of 99.7% or more. -β-Amino-2,4,5-trifluorophenylbutyric acid ethyl ester (Ib) 1.61 g. The resolution was 64.8%.

Example 4

Β-amino-2,4,5-trifluorophenylbutyric acid ethyl ester racemate 5.18g (20mmol), dissolved in 120ml of ethanol, then added D-DTTA 3.86g (10mmol), heated to reflux clarification, put Cold, precipitated solid, filtered and dried. HPLC analysis of the R configuration accounted for 89.4%.

The crude product solid was recrystallized twice from ethanol (120 ml) to give white solid (yield: 2.82 g, m.p.: 186.0 to 187.0 ° C, [a] _D ²⁵ = +96.4 (C1, 0.1 M NaOH), and the R configuration of HPLC analysis was 99.1%. . Add 20 ml of water to the solid, adjust the pH to 8 to 9 with anhydrous sodium carbonate, extract twice with dichloromethane (10 ml×2), wash the organic phase once with water, concentrate to remove dichloromethane and concentrate to dryness to give R-β- Amino-2,4,5-trifluorophenylbutanoic acid ethyl ester (Ib) 1.13 g, [a] _D ²⁵ = -2.6 ° (c = 0.8, methanol), yield: 43.6%.

Example 5

Β-amino-2,4,5-trifluorophenylbutyric acid ethyl ester racemate 5.18g (20mmol), dissolved in 100ml of ethanol, then added D-DBTA 3.58g (10mmol), heated to reflux clarification, put Cold, precipitated solid, filtered and dried. HPLC analysis of the R configuration accounted for 83.37%.

The crude solid was recrystallized twice from ethanol (100 ml) to give white solid (yield: 2.59 g). Add 18 ml of water to the solid, adjust the pH to 8 to 9 with anhydrous sodium carbonate, extract twice with dichloromethane (10 ml × 2), wash the organic phase with water once, concentrate to remove dichloromethane, and concentrate to dryness to give R-β-amine Ethyl 2-,4,5-trifluorophenylbutanoate (Ib) 1.03 g, [a] _D ²⁵ = -2.7 (c = 0.8, methanol), yield: 39.8%.

Example 6

1 g (3.84 mmol) of the resolved product (Ib) was added to a mixture of 10 ml of a sodium carbonate solution of pH 10 and 10 ml of methanol, and then 1.0 g of (BOC) ₂ O acid was added thereto, and reacted at 30 ° C for 3 hours to complete the reaction. After adding 8 ml of 4M NaOH, hydrolysis was carried out at 40-45 ° C, and the reaction was carried out for 2 hours and then detected by TLC. Evaporate dry methanol, adjust the pH to 3, slowly adjust not to exceed, extract with ethyl acetate, wash with acid water, dry, concentrate, crystallize to give the product R-β-t-butoxycarbonylamino-2,4 5-trifluorophenylbutyric acid (Ic) 1.14 g. Melting point: 127-128 ° C, [a] _D ²⁵ = 14.2 ° (c = 1, methanol), yield: 89.1%.

Example 7

R-β-t-butoxycarbonylamino-2,4,5-trifluorobenzenebutyric acid (Ic) 1.0 g (3.0 mmol), adding 2M HCl-ethyl acetate 20 ml, stirring at room temperature for 4 hours, concentrated at low temperature To the remaining half volume, a solid was precipitated, filtered, and dried to give 0.67 g of R-β-amino-2,4,5-trifluorobenzenebutyrate (Ia). Melting point: 204.5 to 207.5 ° C, [a] _D ²⁵ = -6.8 ° (c = 0.8, methanol), yield 82.8%.

Example 8

1 g (3.84 mmol) of the isolated product (Ib) was added to 10 ml of methanol, and 6 ml of 4M NaOH was added thereto, and the mixture was hydrolyzed at 40 ° C, and reacted for 2 hours and detected by TLC. Adjust the pH to 3, evaporate the methanol and water, and dissolve the residue with chloroform/methanol (4:1). The insoluble material is filtered off. The filtrate is applied to a short gel column, and the positive component is concentrated to dryness. 16 ml of the ester was stirred at room temperature for 2 hours, filtered and dried to give 0.90 g of R-β-amino-2,4,5-trifluorobenzenebutyrate (Ia). Melting point: 203.0 to 206.0 ° C, [a] _D ²⁵ = -6.4 ° (c = 0.8, methanol), yield: 87.1%.

Claims (13)

A method for preparing a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative represented by formula (I), Wherein in the formula (I), Ar is a substituted or unsubstituted phenyl group, and when Ar is a substituted phenyl group, the substituent is selected from a fluorine, a methyl group, a trifluoromethyl group or a trifluoromethoxy group. 1-5 groups; R ₁ is hydrogen or a lower alkyl group having 1 to 6 carbon atoms; R ₂ is a hydrogen or an amine protecting group, including an alkoxycarbonyl group and a decyl group; the alkoxycarbonyl group Is selected from the group consisting of methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl; the oxime group is selected from the group consisting of methyl ketone, ethyl hydrazino, chloroethyl fluorenyl, trichloro ethane, benzyl hydrazino or benzene An acetamyl group, characterized in that the preparation method comprises the following steps: (1) using the substituted or unsubstituted phenylacetate acetate as a raw material, reacting with ammonium formate to form an imine, and then using a reducing agent Reduction of the corresponding β-aminophenylbutyrate racemate; (2) salt formation and crystallization in an alcohol solvent or an alcohol solution using a chiral resolving agent to resolve the above β-amino phenyl butyl a racemate of the acid ester to give a salt of the corresponding chiral β-aminophenylbutyrate and a resolving agent; (3) free hydrolysis of the chiral β-aminophenylbutyrate obtained in the above step And the salt formed by the resolving agent Or performing amine group protection to give a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative as shown in formula (I). A process for the preparation of a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative according to the first aspect of the patent application, characterized in that Ar in the formula (I) is 2,4,5-trifluorophenyl, R ₁ and R ₂ are each a hydrogen atom. A process for the preparation of a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative according to the first aspect of the patent application, characterized in that Ar in the formula (I) is 2,4,5-trifluorophenyl, R ₁ is an ethyl group and R ₂ is a hydrogen atom. A process for the preparation of a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative according to the first aspect of the patent application, characterized in that Ar in the formula (I) is 2,4,5-trifluorophenyl, R ₁ is a hydrogen atom and R ₂ is a third butoxycarbonyl group. A method for producing a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative according to claim 1, which is characterized in that the chiral pharmaceutical intermediate R represented by the formula (I) obtained in the step (3) The ?-amino phenylbutyric acid derivative is reacted with hydrochloric acid to form a hydrochloride. A process for the preparation of a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative according to any one of claims 1 to 4, characterized in that the reducing agent used in the step (I) is a cyanoborohydride sodium. A method for producing a chiral pharmaceutical intermediate R-β-amino substituted phenylbutyric acid derivative according to any one of claims 1 to 4, characterized in that the chiral separation described in the step (2) The agent is a bis-deuterated substituted chiral tartaric acid, and the chiral tartaric acid includes benzamidine-D-tartaric acid, benzamidine-L-tartaric acid, di-p-tolylformin-D-tartaric acid or di-p-tolylformine- L-tartaric acid. A method for preparing a chiral pharmaceutical intermediate R-β-amino substituted phenylbutyric acid derivative according to claim 7 of the patent application, characterized in that the chiral resolving agent is selected from the group consisting of dip-toluidine-D-tartaric acid Or two pairs of toluene formazan-L-wine Stone acid. A method for preparing a chiral pharmaceutical intermediate R-β-amino-substituted phenylbutyric acid derivative according to claim 7 of the patent application, characterized in that the di-p-tolyl-L-tartaric acid or di-p-tolylformine is used alone. -D-tartaric acid. A method for preparing a chiral pharmaceutical intermediate R-β-amino-substituted phenylbutyric acid derivative according to claim 7 of the patent application, characterized in that the di-p-tolyl-L-tartaric acid or di-p-tolylformine is used in combination. -D-tartaric acid. The method for preparing a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative according to any one of claims 1 to 4, wherein the alcohol solvent in the step (2) is a carbon atom Lower aliphatic alcohols less than 3. A method for producing a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative according to claim 11 of the patent application, characterized in that the alcohol solvent is methanol. The method for preparing a chiral pharmaceutical intermediate R-β-aminophenylbutyric acid derivative according to any one of claims 1 to 4, wherein the aqueous alcohol solution in the step (2) is a carbon number. An aqueous solution of a lower aliphatic alcohol of less than 3.