Method for splitting ramipril intermediate

Abstract

The invention discloses a method for splitting a ramipril intermediate, and belongs to the field of pharmaceutical chemicals. According to the method, the ramipril intermediate is split by preparing the crystal of the compound shown in the formula (I), and the crystal is good in crystal morphology and easy to filter and separate, avoids the problems of pipeline blockage and the like, and has a good industrial use prospect. # imgabs0 #

Description

A method for splitting ramipril intermediates

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits to Chinese invention patent application No. 202211738868.2 filed with the State Intellectual Property Office of China on December 31, 2022, and all the contents disclosed in said application are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to the field of medical technology, in particular to a method for splitting a ramipril intermediate. Background Art

[0004] Ramipril is a long-acting, potent angiotensin-converting enzyme inhibitor (ACEI) and one of Aventis' global products. Developed by its predecessor, Hoechst, it is a first-line treatment for mild to moderate hypertension and malignant congestive heart failure. This product has the advantages of rapid onset of action, long duration of action, high tissue specificity, good tolerability, and low toxicity. Its chemical name is (S)-2-[N-(1-ethoxycarbonyl-3-phenyl-propyl)alanyl]-2-azabicyclo[3.3.0]octane-3-carboxylic acid, CAS number: 87333-19-5, and its structure is shown below:

[0005] Ramipril has five chiral centers, and resolving agents are required during synthesis to remove isomers and obtain optically pure compounds. Therefore, there is an urgent need to develop other methods for resolving ramipril intermediates.

[0006] SUMMARY OF THE INVENTION

[0007] The present invention provides a crystal of a compound of formula I and a preparation method thereof. The crystal has a crystal form with a significantly larger particle size and has a filtering advantage during the synthesis process.

[0008] In addition, the present invention also provides a crystal of an intermediate compound III and a preparation method thereof. The crystal is a needle-shaped crystal with a good crystalline morphology and has a filtering advantage during the synthesis process.

[0009] Furthermore, the present invention also provides a method for preparing ramipril, which is characterized by comprising a method for preparing the compound of formula III and / or the compound of formula I.

[0010] Detailed Description of the Invention

[0011] The present invention provides a compound of formula I in crystalline form, characterized by having an optical microscope image as shown in FIG1 .

[0012] The present invention also provides a crystalline composition comprising the aforementioned crystalline form of the compound of Formula I, wherein the weight of the crystalline form of the compound of Formula I accounts for greater than 85% by weight of the crystalline composition. In some embodiments of the present invention, the weight of the crystalline form of the compound of Formula I accounts for greater than 90% by weight of the crystalline composition; in some typical embodiments, the weight of the crystalline form of the compound of Formula I accounts for greater than 95% by weight of the crystalline composition; and in some more typical embodiments, the weight of the crystalline form of the compound of Formula I accounts for greater than 98% by weight of the crystalline composition.

[0013] The present invention also provides a method for crystallizing the compound of formula I, which is characterized in that the crude compound of formula I is heated and dissolved in an organic solvent, and then cooled to precipitate a solid.

[0014] In some embodiments of the present invention, the organic solvent is an optionally substituted 6-10 membered aromatic hydrocarbon; in some typical embodiments, the organic solvent is selected from benzene optionally substituted with one or more C1-C6 alkyl groups or halogens; in some typical embodiments, the organic solvent is selected from one or more mixed solvents of benzene, xylene, toluene, ethylbenzene, n-propylbenzene, trimethylbenzene, methylethylbenzene, n-propylbenzene, isopropylbenzene, diethylbenzene or isobutylbenzene; in some more typical embodiments, the organic solvent is selected from one or more mixed solvents of toluene, xylene, chlorobenzene and mesitylene; in some more typical embodiments, the organic solvent is a single solvent, and is one of benzene, one or more C1-C6 alkyl substituted benzene, one or more halogen substituted benzene; in some most typical embodiments, the organic solvent is one of toluene, xylene, chlorobenzene or mesitylene.

[0015] The present invention provides a method for preparing a compound of formula I, characterized in that:

[0016] In some embodiments, the present invention provides a method for preparing a crystalline compound of formula I, characterized in that: a compound of formula II or a salt thereof and a compound of formula III are reacted in an organic solvent to prepare a compound of formula I,

[0017] In some embodiments of the present invention, the compound of formula II or its salt exists in the form of a free base, hydrochloride, maleate, phosphate, fumarate, methanesulfonate, oxalate, hydrobromide or sulfate of the compound of formula II; in some typical embodiments, the compound of formula II or its salt exists in the form of a hydrochloride of the compound of formula II; in some more typical embodiments, the salt form of the compound of formula II is freed as a free base and then reacted with the compound of formula III; in some most typical embodiments, the present invention provides a method for preparing the compound of formula I, characterized in that it comprises the following steps:

[0018] a) reacting a compound of formula II-1 with a base in a mixed solution of an organic solvent and water;

[0019] b) After standing for separation, the aqueous layer was removed and the organic layer solution was retained;

[0020] c) adding the compound of formula III to the organic layer solution of step b), heating and reacting;

[0021] d) cooling and crystallizing to obtain the compound of formula I.

[0022] In some embodiments, the organic solvent in step a) is an optionally substituted 6-10 membered aromatic hydrocarbon; in some typical embodiments, the organic solvent in step a) is selected from benzene optionally substituted with one or more C1-C6 alkyl groups or halogens; in some typical embodiments, the organic solvent in step a) is selected from one or a mixed solvent of two or more of benzene, xylene, toluene, ethylbenzene, n-propylbenzene, trimethylbenzene, methylethylbenzene, n-propylbenzene, isopropylbenzene, diethylbenzene or isobutylbenzene; in some more typical embodiments, the organic solvent in step a) is selected from one or a mixed solvent of two or more of toluene, xylene, chlorobenzene and mesitylene; in some more typical embodiments, the organic solvent in step a) is a single solvent, and is one of benzene, one or more C1-C6 alkyl substituted benzenes, or one or more halogen substituted benzenes; in some most typical embodiments, the organic solvent in step a) is one of toluene, xylene, chlorobenzene or mesitylene.

[0023] In some embodiments, the base in step a) is an organic base reagent, an inorganic base reagent, or a mixture of two thereof; in some embodiments, the base in step a) is selected from one or a mixture of two thereof selected from lithium carbonate, potassium carbonate, sodium carbonate, or cesium carbonate; in some preferred embodiments, the base in step a) is selected from sodium carbonate.

[0024] In some embodiments, the molar ratio of the II-1 compound to the base in step a) is 1:1-2; in some more typical embodiments, in step a1), the mass ratio of the II-1 compound to the base in step a) is 1:1.5-2; in some most typical embodiments, the mass ratio of the II-1 compound to the base in step a) is 1:1.6, 1:1.65, 1:1.70, 1:1.75, 1:1.80, 1:1.85 or 1:1.9 or any range therein.

[0025] In some embodiments, the feeding mass ratio of the compound of formula II-1 in step a) to the N-benzyloxycarbonyl-L-phenylalanine represented by formula III in step c) is 2:1 to 1:1; in some embodiments, the feeding mass ratio of the compound of formula II-1 in step a) to the N-benzyloxycarbonyl-L-phenylalanine represented by formula III in step c) is 1.9:1, 1.8:1, 1.7:1, 1:6:1, 1.5:1 or 1.4:1 or any range between these values.

[0026] In some embodiments, the reaction temperature in step c) is 0-100°C; in some typical embodiments, the reaction temperature in step c) is 30°C-90°C; in some more typical embodiments, the reaction temperature in step c) is 40°C-70°C; in some more typical embodiments, the reaction temperature in step c) is 50°C-60°C; in some more typical embodiments, the reaction temperature in step c) is 40°C, 55°C, 50°C, 60°C, 65°C, 70°C or any range therein.

[0027] In some embodiments, the crystallization temperature during the cooling and crystallization process in step d) is -20°C to 25°C; in some typical embodiments, the crystallization temperature during the cooling and crystallization process in step d) is -10°C to 10°C; in some more typical embodiments, the crystallization temperature during the cooling and crystallization process in step d) is -10°C to 0°C; in some most typical embodiments, the crystallization temperature during the cooling and crystallization process in step d) is -5°C to 0°C.

[0028] In some embodiments, the crystalline compound of Formula I obtained by the aforementioned preparation method has an optical microscope image as shown in FIG1 .

[0029] In some embodiments, the aforementioned preparation method optionally further comprises the aforementioned crystallization method of the compound of formula I.

[0030] In some embodiments, the aforementioned preparation method optionally further comprises reacting the compound of formula I in the presence of a solvent and a base to generate a compound of formula II-A,

[0031] In some embodiments, the solvent is a mixed solvent of an organic solvent and water, and the base is an inorganic base; in some typical embodiments, the solvent is a mixed solvent of water and dichloromethane, a mixed solvent of water and chloroform, or a mixed solvent of water, dichloromethane and chloroform, and the base is sodium hydroxide and / or potassium hydroxide; in some more typical embodiments, the solvent is a mixed solvent of water and dichloromethane, and the base is sodium hydroxide.

[0032] The present invention provides a compound of formula III in a crystalline form, characterized by having an optical microscope image as shown in FIG3 .

[0033] The present invention also provides a crystalline composition comprising the aforementioned crystalline form of the compound of Formula III, wherein the weight of the crystalline form of the compound of Formula III accounts for greater than 85% by weight of the crystalline composition. In some embodiments of the present invention, the weight of the crystalline form of the compound of Formula III accounts for greater than 90% by weight of the crystalline composition; in some typical embodiments, the weight of the crystalline form of the compound of Formula III accounts for greater than 95% by weight of the crystalline composition; and in some more typical embodiments, the weight of the crystalline form of the compound of Formula III accounts for greater than 98% by weight of the crystalline composition.

[0034] The present invention also provides a method for crystallizing the compound of formula III, which is characterized by adding a crude product of the compound of formula III into an organic solvent, heating to dissolve it, cooling it, and precipitating a solid.

[0035] In some embodiments, the organic solvent is selected from C6-C8 alkanes, 6-10 aromatic hydrocarbons, C1-C6 halogenated hydrocarbons, (C1-C6 In some typical embodiments, the organic solvent is selected from one or more of hexane, heptane, cyclohexane, toluene, xylene, chlorobenzene, mesitylene, dichloromethane, 1,2-dichloroethane, ethylene glycol dimethyl ether, isopropyl ether, methyl tert-butyl ether, methyl isobutyl ketone, n-butanol or tert-butanol; in some more typical embodiments, the organic solvent is selected from one of hexane, heptane, cyclohexane, toluene, xylene, chlorobenzene, mesitylene, ethylene glycol dimethyl ether, isopropyl ether, methyl tert-butyl ether, n-butanol or tert-butanol; in some more typical embodiments, the organic solvent is selected from one of toluene, xylene, chlorobenzene or mesitylene.

[0036] The present invention also provides a method for preparing the compound of formula III, characterized in that:

[0037] a1) reacting L-phenylalanine represented by formula IV and a compound represented by formula V in water in the presence of a base;

[0038] b1) adding acid to adjust the pH to acidic;

[0039] c1) adding an organic solvent for extraction;

[0040] d1) cooling the organic solvent extract and crystallizing to obtain the compound represented by formula III,

[0041] Wherein, X is a halogen.

[0042] In some embodiments of the present invention, X is fluorine, chlorine, bromine, or iodine; in some typical embodiments, X is chlorine or bromine; in some more typical embodiments, X is chlorine.

[0043] In some embodiments of the present invention, in step a1), the molar ratio of L-phenylalanine represented by formula IV and the compound of formula V is 1:0.5-1.5; in some more typical embodiments, in step a1), the mass ratio of L-phenylalanine represented by formula IV and benzyl chloroformate represented by formula V is 1:0.8-1.5; in some most typical embodiments, in step a1), the mass ratio of L-phenylalanine represented by formula IV and benzyl chloroformate represented by formula V is 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3 or 1:1.4 or any range therein.

[0044] In some embodiments of the present invention, the base is sodium hydroxide; in some typical embodiments, the base is an aqueous sodium hydroxide solution; in some more typical embodiments, the base is an ion-exchange membrane liquid base.

[0045] In some embodiments, the reaction time in step a1) is 0.5 h to 5 h; in some more typical embodiments, the reaction time in step a1) is 0.5 h to 2 h; in some more typical embodiments, the reaction time in step a1) is 0.9 h to 1.2 h; in some more typical embodiments, the reaction time in step a1) is 1 h to 1.2 h; in some most typical embodiments, L-phenylalanine represented by formula IV, a portion of the base and water are first stirred for 25 min to 35 min, and then the compound of formula V and the remaining base are added dropwise. After the addition of the feed liquid is completed, stirring is continued for 25 min to 35 min.

[0046] In some embodiments of the present invention, the acid in step b1) is hydrochloric acid; in some typical embodiments, the acid in step b1) is purified hydrochloric acid.

[0047] In some embodiments of the present invention, step b1) adjusts the pH to 1-3; in some more typical embodiments, step b1) adjusts the pH to 1, 2, or 3, or any range therebetween; in some more typical embodiments, step b1) adjusts the pH to 1.

[0048] In some embodiments, the organic solvent for extraction in step c1) is selected from one of C6-C8 alkanes, 6-10 aromatic hydrocarbons, C1-C6 halogenated hydrocarbons, (C1-C6 alkyl)O(C1-C6 alkyl), (C1-C6 alkyl)CO(C1-C6 alkyl) and C1-C6 alkyl alcohols, or any mixture thereof; in some more typical embodiments, the organic solvent for extraction in step c1) is selected from hexane, heptane, cyclohexane, toluene, xylene, chlorobenzene, mesitylene, dichloromethane, 1,2-dichloroethane , ethylene glycol dimethyl ether, isopropyl ether, methyl tert-butyl ether, methyl isobutyl ketone, n-butanol or tert-butanol or a mixed solvent of two or more thereof; in some more typical embodiments, the step c1) extraction organic solvent is selected from one of hexane, heptane, cyclohexane, toluene, xylene, chlorobenzene, mesitylene, ethylene glycol dimethyl ether, isopropyl ether, methyl tert-butyl ether, n-butanol or tert-butanol; in some more typical embodiments, the step c1) extraction organic solvent is selected from one of toluene, chlorobenzene, xylene or mesitylene.

[0049] In some embodiments of the present invention, the mass volume ratio of the compound of formula IV in step c1) to the extract is 50-500:1; in some typical embodiments, the mass volume ratio of the compound of formula IV in step c1) to the extract is 50-400:1; in some more typical embodiments, the mass volume ratio of the compound of formula IV in step c1) to the extract is 70-380:1; in some most typical embodiments, the mass volume ratio of the compound of formula IV in step c1) to the extract is The mass-to-volume ratio is 70:1, 75:1, 80:1, 85:1, 90:1, 93:1, 94:1, 95:1, 100:1, 102:1, 103:1, 110:1, 111:1, 112:1, 113:1, 120:1, 125:1, 150:1, 180:1, 185:1, 187:1, 188:1, 200:1, 225:1, 250:1, 300:1, 350:1, 375:1 or 380:1 or any range therein. The unit of mass-to-volume ratio is kg / m 3 .

[0050] In some embodiments of the present invention, the extraction temperature in step c1) is 25°C to 150°C; in some typical embodiments, the extraction temperature in step c1) is 30°C to 150°C; in some more typical embodiments, the extraction temperature in step c1) is 30°C to 150°C; in some most typical embodiments, the extraction temperature in step c1) is 25°C, 30°C, 45°C, 50°C, 65°C, 80°C, 100°C, 110°C, 120°C, 145°C, 150°C or any range therein.

[0051] In some embodiments of the present invention, step d1) further comprises partially distilling the extract before cooling.

[0052] In some embodiments of the present invention, the crystallization temperature during the cooling and crystallization process in step d1) is -20°C to 25°C; in some more typical embodiments, the crystallization temperature during the cooling and crystallization process in step d1) is -15°C to 10°C; in some more typical embodiments, the crystallization temperature during the cooling and crystallization process in step d1) is -5°C to 0°C; in some most typical embodiments, the crystallization temperature during the cooling and crystallization process in step d1) is -10°C, -5°C, 0°C, -5°C, -3°C, -1°C, 0°C, 2°C, 5°C or any range therein.

[0053] In some embodiments, the method for preparing the compound of formula III optionally further comprises the aforementioned method for crystallizing the compound of formula III.

[0054] The present invention also provides a method for preparing ramipril, which is characterized by comprising the method for preparing the compound of formula I.

[0055] The present invention also provides a method for preparing ramipril, which is characterized by comprising the method for preparing the compound of formula III.

[0056] The present invention also provides a method for preparing ramipril, characterized by sequentially comprising the method for preparing the compound of Formula III, the method for preparing the compound of Formula I, and the method for preparing the compound of Formula II-A. In the present invention, the optical microscope images were obtained using an Olympus optical microscope; the optical microscope images in Figures 1 and 2 were magnified 400x.

[0057] In the present invention, the isomer is a compound of formula II-B and / or an acid addition salt thereof: that is, the isomer is one or a mixture of two or more of the compound of formula II-B, the compound of formula II-B1 and / or the compound of formula II-B2;

[0058] In the present invention, the content of the compound of formula I and its isomers, and the purity of the compound of formula III are all measured by HPLC. The chromatographic conditions used are conventional technical conditions in the art. An exemplary detection method is as follows:

[0059] (1) The compound of formula I and the compound of formula II-B2 can be detected using the following HPLC detection conditions:

[0060] Instrument: Agilent liquid chromatography detector equipped with UV detector and autosampler;

[0061] Chromatographic column: CHIRALPAK AD-H, 4.6×250 mm, 5 μm;

[0062] Column temperature: 35°C;

[0063] Wavelength: 220nm;

[0064] Mobile phase: isopropanol:n-hexane:diethylamine = 10:90:0.1 (volume percentage);

[0065] Injection volume: 20 μl;

[0066] Run time: 30 minutes

[0067] Flow rate: 0.7 mL / min;

[0068] Diluent: isopropyl alcohol;

[0069] Blank solution: isopropanol.

[0070] (2) The compound of formula III can be detected using the following HPLC detection conditions:

[0071] Instrument: High performance liquid chromatography equipped with ultraviolet detector (UV);

[0072] Column: NUCLEOSIL 100-3 C18 250×4.0mm, 3μm

[0073] Column temperature: 65°C;

[0074] Wavelength: 210nm;

[0075] Buffer configuration:

[0076] Buffer A: Dissolve 2.3 g of sodium perchlorate monohydrate in 800 ml of water, add 0.5 ml of triethylamine, and adjust the pH to 3.6 with concentrated H3PO4;

[0077] Buffer B: Dissolve 2.3 g of sodium perchlorate monohydrate in 300 ml of water, add 0.5 ml of triethylamine, and adjust the pH to 2.6 with concentrated H3PO4;

[0078] Mobile phase configuration:

[0079] Mobile phase A: buffer A: acetonitrile = 800:200 (volume ratio);

[0080] Mobile phase B: buffer B: acetonitrile = 300:700 (volume ratio);

[0081] Injection volume: 10 μl;

[0082] Flow rate: 1.0 mL / min;

[0083] Gradient table:

[0084] Table 1

[0085] Blank solution: mobile phase A.

[0086] (3) The compounds of formula II-B and II-B1 can be detected using the following HPLC conditions:

[0087] Instrument: High performance liquid chromatography equipped with UV detector

[0088] Chromatographic column: Agilent SB-C8, 150 × 4.6 mm, 3.5 μm

[0089] Column temperature: 25°C;

[0090] Wavelength: 210nm;

[0091] Buffer configuration:

[0092] Dissolve 1.36 g of potassium dihydrogen phosphate in 1000 mL of water, add 2.0 mL of triethylamine, and adjust the pH to 3.0 with phosphoric acid;

[0093] Mobile phase configuration: buffer: acetonitrile = 70:30 (volume ratio)

[0094] Injection volume: 20 μl;

[0095] Injection sample requirements: The injection solution needs to be injected at 5°C;

[0096] Run time: 30 minutes

[0097] Flow rate: 1.0 mL / min;

[0098] Diluent: mobile phase;

[0099] Blank solution: mobile phase.

[0100] It is readily understood by those skilled in the art that the error ranges of the parameters listed in the present invention also fall within the scope of protection of the present invention, and the error ranges include but are not limited to the degree of expected experimental error, technical error, and instrument error of a given technology for measuring the value.

[0101] It is easy for those skilled in the art to understand that the determination of the reaction endpoint can be achieved based on the experience, experimental phenomena, technical means monitoring, etc. of those skilled in the art; the "technical means monitoring" includes but is not limited to thin layer chromatography, high performance liquid chromatography, ultraviolet spectrophotometer, etc.; the "at the reaction endpoint" only represents a program node, and does not mean that it must be continuous in time. For example, "at the reaction endpoint, adjust the pH value" only means that a procedure for adjusting the pH value needs to be performed after the reaction endpoint, and does not mean that the reaction endpoint and the adjustment of the pH value must be continuous in time. The two can be performed continuously or there can be a time interval.

[0102] Reaction time refers to the time from the addition of the first material to the end of the reaction.

[0103] In the present invention, the yield of the compound of formula I is calculated by "the amount of the compound of formula I / the amount of the compound of formula II*100%".

[0104] In the present invention, unless otherwise specified, the following terms have the following meanings:

[0105] "h" means hour; "min" means minute;

[0106] "g" means gram; "kg" means kilogram;

[0107] “L” refers to liters;

[0108] “HPLC” means high performance liquid chromatography;

[0109] "pH" refers to the degree of acidity or alkalinity of a solution;

[0110] "Ionic membrane liquid alkali" refers to a sodium hydroxide solution with a mass fraction of 30%;

[0111] "Refined hydrochloric acid" refers to Aqueous hydrochloric acid solution, i.e. aqueous hydrogen chloride solution;

[0112] "Bn" refers to benzyl, also known as phenylmethyl;

[0113] “Mesitylene” means 1,3,5-trimethylbenzene;

[0114] "Xylene" refers to one or a mixed solvent of o-xylene, m-xylene, and p-xylene; the xylene used in the examples is a conventional commercially available mixture of isomers of xylene;

[0115] "Methylethylbenzene" refers to one or a mixed solvent of two or more of o-methylethylbenzene, m-methylethylbenzene and p-methylethylbenzene;

[0116] "Diethylbenzene" refers to one or a mixed solvent of two or more of o-diethylbenzene, m-diethylbenzene and p-diethylbenzene;

[0117] "1N" means 1Mol / L;

[0118] An appropriate amount refers to an amount that can achieve normal reaction according to common understanding in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0119] Figure 1 Optical microscope image of the crystal form of the compound of formula I in Example 19

[0120] Figure 2 Optical microscope imaging of the crystal form of the compound of Formula I in Comparative Example 2

[0121] Figure 3 Optical microscope image of the crystal form of compound of formula III in Example 1

[0122] Figure 4 Optical microscope imaging of the crystal form of the compound of formula III in Comparative Example 1 DETAILED DESCRIPTION

[0123] For the sake of clarity, the present invention is further described below with reference to examples. However, it should be understood that these examples do not limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. The benzyl ester hydrochloride of Formula II-1 used in Examples 19, 20, 21, 22, 23, and Comparative Example 1 below has an initial optical purity of 50%.

[0124] Example 1 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0125] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to the reactor and stir for 30 ± 5 minutes until dissolved. Then, add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 500 L of toluene, raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the toluene solution to -5°C–0°C and stir to allow crystallization for 60 ± 10 minutes. Filter and rinse the filter cake with a small amount of toluene. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.6%; yield: 90%). Observe the product under an optical microscope at 400x magnification, as shown in Figure 3. Figure 3 shows that the product is a needle-shaped solid with good crystalline morphology, which is easy to separate by filtration after crystallization.

[0126] Example 2 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0127] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to the reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 1000 L of toluene, raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Maintain the vacuum in the reactor at 0.08–0.10 MPa and ≤60°C, then remove 600 L of toluene under reduced pressure. Upon completion of the distillation, slowly cool the solution to -5°C–0°C and stir to allow crystallization for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of toluene. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.2%; yield: 94%).

[0128] Example 3 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0129] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 1200 L of hexane, raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the hexane solution to -15°C–10°C and stir to allow crystallization for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of hexane. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.4%; yield: 82%).

[0130] Example 4 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0131] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 1500 L of cyclohexane, raise the temperature to 45°C to 50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the cyclohexane solution to -5°C to 0°C and stir to allow crystallization for 60 ± 10 minutes. Filter and rinse the filter cake with a small amount of cyclohexane. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.1%; yield: 80%).

[0132] Example 5 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0133] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 1500 L of heptane, raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the heptane solution to -5°C–0°C and stir to allow crystallization for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of toluene. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.5%; yield: 82%).

[0134] Example 6 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0135] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 with purified hydrochloric acid. Add 500 L of chlorobenzene, raise the temperature to 100°C–110°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the chlorobenzene solution to -5°C–0°C and stir to crystallize for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of chlorobenzene. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.4%; yield: 91%).

[0136] Example 7 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0137] Add 650 L of drinking water, 75 L of ion-exchange membrane solution, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane solution dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 500 L of xylene, raise the temperature to 120°C to 125°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the xylene solution to -5°C to 0°C and stir to crystallize for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of xylene. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.8%; yield: 94%).

[0138] Example 8 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0139] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 500 L of mesitylene and raise the temperature to 145°C–150°C. Stir and dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the mesitylene solution to -5°C–0°C and stir to allow crystallization for 60 ± 10 minutes. Filter and rinse the filter cake with a small amount of mesitylene. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.7%; yield: 95%).

[0140] Example 9 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0141] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 300 L of dichloromethane, raise the temperature to 25°C to 30°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the dichloromethane solution to -5°C to 0°C and stir to allow crystallization for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of dichloromethane. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.6%; yield: 70%).

[0142] Example 10 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0143] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 500 L of 1,2-dichloroethane, raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the 1,2-dichloroethane solution to -5°C–0°C and stir for 60 ± 10 minutes to allow crystallization. Filter the solution, and rinse the filter cake with a small amount of 1,2-dichloroethane. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.2%; yield: 79%).

[0144] Example 11 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0145] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 with purified hydrochloric acid. Add 500 L of ethylene glycol dimethyl ether (EGDE), raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the EGDE solution to -5°C–0°C and stir to crystallize for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of EGDE. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 98.9%; yield: 85%).

[0146] Example 12 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0147] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 900 L of isopropyl ether, raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the isopropyl ether solution to -5°C–0°C and stir to allow crystallization for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of isopropyl ether. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.3%; yield: 86%).

[0148] Example 13 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0149] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 with purified hydrochloric acid. Add 1200 L of methyl tert-butyl ether (MTBE), raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Discard the solution. Slowly cool the MTBE solution to -5°C–0°C and stir to crystallize for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of MTBE. Dry the filter cake to yield N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.3%; yield: 84%).

[0150] Example 14 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0151] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 with purified hydrochloric acid. Add 600 L of methyl isobutyl ketone (MIBK), raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the MIBK solution to -5°C–0°C and stir to crystallize for 60 ± 10 minutes. Filter the solution, and rinse the filter cake with a small amount of MIBK. Dry the filter cake to yield N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.9%; yield: 72%).

[0152] Example 15 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0153] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 1000 L of n-butanol, raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the n-butanol solution to -5°C–0°C and stir to allow crystallization for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of n-butanol. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.9%; yield: 88%).

[0154] Example 16 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0155] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 1 by adding purified hydrochloric acid. Add 1100 L of tert-butyl alcohol, raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the tert-butyl alcohol solution to -5°C–0°C and stir to crystallize for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of tert-butyl alcohol. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.7%; yield: 84%).

[0156] Example 17 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0157] Add 650 L of drinking water, 75 L of ion-exchange membrane caustic soda, and 112.5 kg of L-phenylalanine to a reactor and stir for 30 ± 5 minutes until dissolved. Add 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30 ± 5 minutes. After the reaction is complete, adjust the pH of the solution to 4 by adding purified hydrochloric acid. Add 500 L of toluene, raise the temperature to 45°C–50°C, and stir to dissolve for 30 ± 5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the toluene solution to -5°C–0°C and stir to allow crystallization for 60 ± 10 minutes. Filter, and rinse the filter cake with a small amount of toluene. Dry the filter cake to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 99.6%; yield: 60%).

[0158] Example 18 Preparation of Formula III Compound N-Benzyloxycarbonyl-L-phenylalanine

[0159] Add 650L of drinking water, 75L of ion-exchange membrane caustic soda, and 112.5kg of L-phenylalanine to the reactor and stir for 30±5 minutes until dissolved. Add 118kg of benzyl chloroformate and 75L of ion-exchange membrane caustic soda dropwise to the reactor. After the addition of the solution, continue stirring for 30±5 minutes. After the reaction is complete, add refined hydrochloric acid to adjust the pH to 1. Add 500L of ethyl acetate, raise the temperature to 45°C-50°C, and stir to dissolve for 30±5 minutes. Separate the layers and discard the aqueous layer. Slowly cool the ethyl acetate solution to -10°C and stir to crystallize for 60±10 minutes. No solid precipitation should occur.

[0160] Example 19 Preparation of the compound of formula I

[0161] Add 1200L of drinking water and 210kg of sodium carbonate to the reactor and stir until dissolved. Add 300kg of benzyl ester hydrochloride shown in formula II-1 to the reactor and add an appropriate amount of toluene. Stir for 60±5 minutes, let stand for 30±5 minutes, separate the layers, and retain the toluene layer. Add 165kg of N-benzyloxycarbonyl-L-phenylalanine, the compound of formula III in Example 1, to the toluene liquid. Control the liquid temperature at 50℃~60℃ and stir the reaction for 30±5 minutes. Cool to -5℃~0℃, filter, and dry to obtain the compound of formula I (isomer content: 0.5%; yield 43%). The crystal structure is shown in Figure 1. The crystal has a clear crystal morphology and a large particle size, which is easy to filter.

[0162] Example 20 Preparation of the compound of formula I

[0163] Add 1200L of drinking water and 210kg of sodium carbonate to the reactor and stir until dissolved. Add 300kg of benzyl ester hydrochloride represented by formula II-1 to the reactor and add an appropriate amount of chlorobenzene. Stir for 60±5 minutes, let stand for 30±5 minutes, separate the layers, and retain the chlorobenzene layer. Add 165kg of N-benzyloxycarbonyl-L-phenylalanine, the compound of formula III in Example 6, to the chlorobenzene liquid. Control the liquid temperature at 50℃~60℃ and stir the reaction for 30±5 minutes. Cool to -5℃~0℃, filter, and dry to obtain the resolved intermediate (i.e., compound of formula I) (isomer content: 0.8%; yield: 44%).

[0164] Example 21 Preparation of the compound of formula I

[0165] Add 1200L of drinking water and 210kg of sodium carbonate to the reactor and stir until dissolved. Add 300kg of benzyl ester hydrochloride represented by formula II-1 to the reactor and add an appropriate amount of xylene. Stir for 60±5 minutes, let stand for 30±5 minutes, separate into layers, and retain the xylene layer. Add 165kg of N-benzyloxycarbonyl-L-phenylalanine, the compound of formula III in Example 7, to the xylene liquid. Control the liquid temperature at 50-60°C and stir the reaction for 30±5 minutes. Cool to -5-0°C, filter, and dry to obtain the resolved intermediate (i.e., compound of formula I) (isomer content: 0.2%; yield: 41%).

[0166] Example 22 Preparation of the compound of formula I

[0167] Add 1200L of drinking water and 210kg of sodium carbonate to the reactor and stir until dissolved. Add 300kg of benzyl ester hydrochloride represented by formula II-1 to the reactor and add an appropriate amount of mesitylene. Stir for 60±5 minutes, let stand for 30±5 minutes, separate the layers, and retain the mesitylene layer. Add 165kg of N-benzyloxycarbonyl-L-phenylalanine, the compound of formula III in Example 8, to the mesitylene liquid. Control the liquid temperature at 50℃~60℃ and stir the reaction for 30±5 minutes. Cool to -5℃~0℃, filter, and dry to obtain the resolved intermediate (i.e., compound of formula I) (isomer content: 0.4%; yield: 42%).

[0168] Example 23 Organic solvent screening

[0169] Referring to the experimental method of Example 19, the organic solvent was replaced with the organic solvent in Table 1. The corresponding product yield, target product, and isomer results are shown in Table 1:

[0170] Table 1

[0171] Comparative Example 1

[0172] 650 L of drinking water, 75 L of ion-exchange membrane solution, and 112.5 kg of L-phenylalanine were added to a reactor and stirred for 30 ± 5 minutes until dissolved. 118 kg of benzyl chloroformate and 75 L of ion-exchange membrane solution were added dropwise to the reactor. After the addition of the solution, stirring was continued for 30 ± 5 minutes. After the reaction, the solution was adjusted to pH 1 by adding purified hydrochloric acid, and then extracted with 1100 L of ethyl acetate. The ethyl acetate extract was washed with saturated brine, and the ethyl acetate solution was crystallized by adding 1000 L of n-hexane. The filter cake was dried to obtain N-benzyloxycarbonyl-L-phenylalanine (HPLC purity: 91.7%; yield: 90%). Observation under a 400x optical microscope (Figure 4) shows that the product has no distinct crystal morphology and exhibits severe agglomeration. After crystallization, the material easily agglomerates, clogging the pipes and making separation difficult.

[0173] Comparative Example 2

[0174] 166.0 g (0.589 mol) of the benzyl ester hydrochloride represented by Formula II-1 was suspended in 500 ml of dichloromethane. 250 ml of a sodium hydroxide solution containing 25 g (0.625 mol) was added. The dichloromethane layer was separated and washed once with 100 ml of 0.1N sodium hydroxide solution and twice with 50 ml of water. The aqueous layers were combined and extracted twice with 100 ml of dichloromethane each time. The combined dichloromethane layers were dried over sodium sulfate and distilled under reduced pressure. The substrate was immediately dissolved in 100 ml of ethyl acetate, and 200 ml of an ethyl acetate solution containing 117.6 g (0.39 mol) of the compound of Formula III was added to the solution. The reaction mixture was rinsed with 100 ml of ethyl acetate and 1600 ml of cyclohexane, stirred, and a clear solution was obtained at room temperature. Scraping the solvent wall caused crystals to begin to precipitate, which was then allowed to stand overnight at a relatively cool room temperature. The crystals were filtered and washed with 250 ml of ethyl acetate / cyclohexane (1+4). Drying afforded the resolved intermediate (i.e., compound of Formula I) (isomer content: 1.8%; yield: 42%). The crystal structure is shown in Figure 2. The crystals exhibit irregular morphology and small particle size, resulting in agglomeration and difficulty in filtration.

[0175] The above-described embodiments merely illustrate several implementations of the present invention. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, and all such variations and improvements fall within the scope of protection of the present invention.

Claims

1. A compound of formula I in crystalline form, Features With an optical microscope image as shown in FIG1, 2. A crystallization process for preparing the compound of formula I in the crystalline form as claimed in claim 1, It is characterized in that The crude product of the compound of formula I is heated in an organic solvent to dissolve, and then cooled to precipitate a solid.

3. A method for preparing the compound of formula I in crystalline form as claimed in claim 1, It is characterized in that The following steps are involved: a) reacting a compound of formula II-1 with a base in a mixed solution of an organic solvent and water; b) After standing for stratification, the aqueous layer is removed and the organic layer solution is retained; c) adding the compound of formula III to the organic layer solution of step b), heating and reacting; d) cooling and crystallizing to obtain the compound of formula I.

4. The method according to any one of claims 2 to 3, It is characterized in that The organic solvent is selected from one or a mixed solvent of benzene, xylene, toluene, ethylbenzene, n-propylbenzene, trimethylbenzene, methylethylbenzene, n-propylbenzene, isopropylbenzene, diethylbenzene or isobutylbenzene. Preferably, the organic solvent is selected from one or a mixed solvent of toluene, xylene, chlorobenzene or trimethylbenzene.

5. The method according to any one of claims 2 to 4, It is characterized in that The crystallization temperature during the cooling and crystallization process in step d) is -10°C to 10°C. Preferably, the crystallization temperature during the cooling and crystallization process in step d) is -5°C to 0°C.

6. A compound of formula III in crystalline form, It is characterized in that With an optical microscope image as shown in FIG3, 7. A method for preparing the compound of formula III in the crystalline form as claimed in claim 6, It is characterized in that a1) reacting L-phenylalanine represented by formula IV and a compound represented by formula V in water in the presence of a base; b1) adding acid to adjust the pH to acidic; c1) adding an organic solvent for extraction; d1) cooling the organic solvent extract and crystallizing to obtain the compound represented by formula III, Wherein, X is a halogen.

8. A method for preparing the compound of formula I in crystalline form according to claim 3, It is characterized in that The following steps are also included: a1) reacting L-phenylalanine represented by formula IV and a compound represented by formula V in water in the presence of a base; b1) adding acid to adjust the pH to acidic; c1) adding an organic solvent for extraction; d1) cooling the organic solvent extract and crystallizing to obtain the compound represented by formula III, Wherein, X is a halogen.

9. A method for preparing a compound of formula II-A, It is characterized in that The method for preparing the compound of formula I according to claim 3 further comprises the step of preparing the compound of formula II-A from the compound of formula I in the presence of a solvent and a base, 10. A method for preparing ramipril, It is characterized in that The method comprises the preparation method described in any one of claims 3, 8 and 9.

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