A method for purifying crude orlistat

Abstract

The present invention relates to a method for purifying crude orlistat, and the process steps include water washing, ceramic membrane filtration, column chromatography, reduced pressure concentration, filtration and drying. The present invention adopts a new adsorbent to replace conventional materials, and only a single organic solvent is used in the extraction process. Compared with the current domestic conventional process, it has the characteristics of short chromatography cycle, small amount of adsorbent, high extraction yield, stable product quality, low production cost, etc., which is conducive to enhancing the foreign market competitiveness of the product.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a method for purifying crude orlistat. Background Art

[0002] Orlistat is a specific gastrointestinal lipase inhibitor that can reduce the risk factors associated with obesity and the incidence of other obesity-related diseases, including hypercholesterolemia, type II diabetes, impaired glucose tolerance, hyperinsulinemia, hypertension, and reduce the fat content in organs. It is suitable for long-term treatment of obese and overweight patients, including those who have already developed risk factors associated with obesity.

[0003] In recent years, with the continuous advancement of separation and purification technology, preparative liquid chromatography technology has been widely used. Domestic related patents and literature disclose a method for preparing orlistat, which uses silica gel or polymer resin as column filler, loads orlistat crude solution in batches and continuously, elutes with organic solvent, collects analytical solution in sections, and crystallizes and purifies the target orlistat.

[0004] At present, the problems of purifying crude orlistat by column chromatography are as follows:

[0005] 1. Using silica gel or resin as adsorbent, the chromatographic purification cycle is relatively long. Taking a chromatographic column with a height-to-diameter ratio of 10:1 as an example, if the adsorbent is silica gel or silica gel derivative, it takes about 240 hours to purify the crude orlistat; if the adsorbent is resin, it takes about 270 hours to purify the crude orlistat;

[0006] 2 The study found that the adsorption ratio of silica gel or silica gel derivatives or resins in the chromatographic column adsorbents disclosed in China is: W adsorbent: W orlistat = 1kg: 80-100g, and the adsorption ratio is relatively low;

[0007] 3 The public literature reports the purification method of crude orlistat, but there is no relevant information on whether the method is still effective when the effective content of crude orlistat is less than 60%. Summary of the invention

[0008] The purpose of the present invention is to overcome the defects in the above-mentioned prior art and provide a method with simple purification process steps, shortening column chromatography purification time and improving column chromatography efficiency.

[0009] The technical solutions adopted to achieve the above objectives are:

[0010] A method for purifying crude orlistat comprises the following steps:

[0011] (1) Washing

[0012] After the crude orlistat is dissolved, it is washed with water and separated;

[0013] (2) Ceramic membrane filtration

[0014] The orlistat solution was filtered through a ceramic membrane;

[0015] (3) Column chromatography

[0016] The orlistat organic solution is put into a chromatography column containing an adsorbent for chromatography to obtain a light white organic solution, wherein the adsorbent is made of the following components in parts by weight: 26-30 g of sodium alginate, 70-75 g of natural bleaching earth and 32-35 g of molecular sieve activation powder;

[0017] (4) Concentration under reduced pressure, filtration and drying

[0018] A saturated sodium chloride solution prepared with purified water is added to the orlistat organic solution, and the solution is concentrated under reduced pressure, filtered and dried to obtain pure orlistat.

[0019] Wherein, in step (1):

[0020] The weight percentage of orlistat in the crude orlistat is ≥40%, preferably ≥60%.

[0021] Dissolving means that the crude orlistat is dissolved in the isopropyl acetate solution to obtain the orlistat solution, and the compatibility ratio is W crude orlistat: L isopropyl acetate = 1kg: 2-4L.

[0022] Water washing means heating the saturated sodium chloride solution prepared with purified water to 40-60°C, adding the orlistat solution thereto, washing for 20-40 minutes, and the compatibility ratio is: V orlistat solution: V saturated sodium chloride solution prepared with purified water = 1L: 1-3L.

[0023] Thereafter, in step (2):

[0024] Membrane filtration refers to ceramic membrane filtration. A ceramic membrane filtration device is used, the membrane material is silicon oxide, and a multi-channel configuration is adopted. The pore size of the ceramic membrane is 0.2um; during the membrane filtration process, the temperature is controlled at 30-40°C and the pressure difference is controlled at 0.3-0.4MPa; after the membrane filtration is completed, the orlistat solution is collected.

[0025] Wherein, in step (3):

[0026] Column chromatography means: the ratio of the height to the diameter of the chromatography column is 4-6:1; the adsorbent is loaded into the chromatography column, balanced with isopropyl acetate, the orlistat organic solution is put into the chromatography column, the sample amount is 25% to 30% of the column volume, isopropyl acetate is used for elution, the flow rate is controlled at 0.4 to 0.8 times the column volume / h, and the liquid in the light white area is collected.

[0027] The preparation method of the adsorbent refers to:

[0028] 1) Add sodium alginate to purified water and heat to 70-80°C. The sodium alginate addition ratio is 26-30g per 1L of water;

[0029] 2) Add natural bleaching earth and molecular sieve activation powder to the sodium alginate solution and stir for 140-160 minutes to obtain a suspension; the addition ratio of natural bleaching earth is 70-75g in 1L of sodium alginate solution; the addition ratio of molecular sieve activation powder is 32-35g in 1L of sodium alginate solution;

[0030] 3) preparing a saturated sodium chloride purified aqueous solution and cooling it to 0-3°C;

[0031] 4) Using the equipment for preparing gel balls, the suspension is sucked in to prepare gel balls, which are then dropped into a saturated sodium chloride purified aqueous solution and allowed to stand for 100-120 minutes. After filtration, gel balls with a pore size of 1-1.5 mm are obtained;

[0032] 5) The gel balls are washed with purified water and dried at 30-40°C;

[0033] 6) After drying, the gel spheres are added to PEG200 and allowed to stand for 100-120 minutes;

[0034] 7) After standing, washing and drying are performed to obtain an adsorbent;

[0035] 8) The ratio of adsorbent used: W adsorbent: W orlistat = 1 kg: 120-160 g.

[0036] Wherein, in step (4):

[0037] Concentration under reduced pressure means adding a saturated sodium chloride solution prepared with purified water to the orlistat organic solution obtained by chromatography, the addition ratio being: V saturated sodium chloride solution: V isopropyl acetate = 2-3L: 1L, heating to 85-90°C, and controlling the pressure at -0.05 to -0.1MPa. When the isopropyl acetate begins to be collected, a saturated sodium chloride solution prepared with purified water is added in a stream, and the amount added per hour is 1-3% of the initial volume;

[0038] After the isopropyl acetate is collected, keep warm and stir for 20-40 minutes, then slowly cool to 0-5°C, and the cooling rate is controlled at 4-6°C / h;

[0039] After cooling, continue stirring for 30-60 minutes and let stand for 100-120 minutes;

[0040] Filter and dry to obtain pure orlistat.

[0041] The technical advantages of this patent are reflected in the following aspects:

[0042] 1 This process is suitable for the purification of crude orlistat. As long as the effective content of the crude product is above 40%, it can be applied to this process, and the quality of the finished product can meet the USP quality standard.

[0043] 2 Sodium alginate is a natural polysaccharide compound extracted from kelp or seaweed. It is a polymer composed of two structural units, aL-guluronic acid (G segment) and β-D-mannuronic acid (M segment), connected by glycosidic bonds in four ways: GG, GM, MG, and MM (1-4). It has good biocompatibility, hydrophilicity, adhesion, and adsorption and is widely used; natural bleaching earth has a wide range of decolorization properties, great decolorization power, strong adsorption and purification power, and has a strong adsorption capacity for pigments and impurities; the main raw material of molecular sieve activation powder is aluminosilicate, which is made from molecular sieve raw powder by high-temperature roasting, so it has strong activity and can be used as an adsorbent with selective adsorption. It can adsorb impurities that affect product quality without changing the physical and chemical properties of the product itself. The above three materials are used to prepare adsorbents according to the process described in this patent, and its characteristics are:

[0044] 1) The new adsorbent has a higher adsorption ratio and reduces the amount of adsorbent used. The adsorption ratio of the adsorbent provided by this patent is: W adsorbent: W orlistat = 1kg: 140-150g, which has a higher adsorption ratio.

[0045] 2) The adsorbent is significantly better than a single adsorbent in adsorbing impurities.

[0046] 3) Use new adsorbents to shorten the purification cycle of column chromatography. Taking a chromatography column with a height-to-diameter ratio of 4-6:1 as an example, it takes 130-134 hours to purify crude orlistat. Compared with silica gel column chromatography or resin column chromatography, the purification cycle is shortened by more than 45%.

[0047] 3 The inventors have conducted a large number of experiments and optimized the best reaction conditions in each step, and finally obtained a stable orlistat purification production process. The process of the present invention is used to prepare orlistat, and the column chromatography yield is above 92%, the total yield is above 87%, the orlistat purity determined by HPLC is above 99.5%, and the single impurity is less than 0.1%, which is higher than the pharmaceutical standard. In addition, the equipment used in the process of the present invention is all ordinary chemical equipment, with low investment, and the solvents used can be recycled and reused, which can greatly reduce production costs and reduce environmental pollution, and achieve clean production. DETAILED DESCRIPTION

[0048] The present invention is described below with examples. It should be understood that the examples are used to illustrate the present invention rather than to limit the present invention. The scope and core content of the present invention are determined according to the claims.

[0049] The crude orlistat used in the present invention comes from:

[0050] At present, the domestic production of nipostatin adopts a fermentation model, that is, it uses Streptomyces toxicophilus and adopts a three-stage fermentation model. The nitrogen sources in the culture medium are mainly soybean powder, yeast powder, peptone and corn steep liquor, and the carbon source is mainly vegetable oil.

[0051] The nipostatin fermentation liquid is separated and purified through the steps of pretreatment, extraction, concentration, dissolution, filtration, column chromatography and crystallization, and the obtained nipostatin has a weight content of 70-85% and a purity of more than 90%.

[0052] Nipostatin is subjected to hydrogenation reaction to obtain crude orlistat.

[0053] Example 1

[0054] 100kg of crude orlistat, with an effective content of 42%.

[0055] (1) Washing

[0056] Add 200 L of isopropyl acetate to the crude orlistat, wash with water and separate.

[0057] (2) Ceramic membrane filtration

[0058] A ceramic membrane filtration device was used. The membrane material was silicon oxide and the multi-channel configuration was adopted. The pore size of the ceramic membrane was 0.2um. During the membrane filtration process, the temperature was controlled at 30-40°C and the pressure difference was controlled at 0.3-0.4MPa. After the membrane filtration was completed, 199.3L of orlistat solution was collected. The orlistat content was found to be 0.208kg / L after testing, and the yield was 98.7%.

[0059] (3) Column chromatography

[0060] The ratio of the column height to the diameter of the chromatography column is 4:1; 346 kg of adsorbent is loaded into the chromatography column, balanced with isopropyl acetate, and the orlistat solution is put into the chromatography column, the sample amount is 25% of the column volume, and the isopropyl acetate is eluted, and the flow rate is controlled at 0.4 times the column volume / h. The chromatography is completed in 132 hours. A total of 126 L of liquid in the white area is collected, the orlistat content is 0.303 kg / L, and the yield is 92.1%.

[0061] (4) Concentration under reduced pressure, filtration and drying

[0062] Add 252L of saturated sodium chloride solution prepared with purified water to 126L of orlistat solution. Raise the temperature to 85°C and control the pressure at -0.05 to -0.1MPa. When collecting isopropyl acetate, add saturated sodium chloride solution prepared with purified water at a rate of 1% of the initial volume per hour.

[0063] After the collection of isopropyl acetate is completed, the mixture is kept warm and stirred for 20 minutes, and then slowly cooled to 0°C. The cooling rate is controlled at 4-6°C / h.

[0064] After cooling, continue stirring for 30 min and let stand for 100 min.

[0065] Filtration and drying were performed to obtain 36.9 kg of pure orlistat, with a total yield of 87.9%.

[0066] The purity of orlistat was 99.6% and the impurity was 0.08% by HPLC, which reached the pharmaceutical standard.

[0067] Example 2

[0068] 100kg of crude orlistat, with an effective content of 57%.

[0069] (1) Washing

[0070] 250 L of isopropyl acetate was added to the crude orlistat, and the mixture was washed with water and separated.

[0071] (2) Ceramic membrane filtration

[0072] A ceramic membrane filtration device was used. The membrane material was silicon oxide and the multi-channel configuration was adopted. The pore size of the ceramic membrane was 0.2um. During the membrane filtration process, the temperature was controlled at 30-40°C and the pressure difference was controlled at 0.3-0.4MPa. After the membrane filtration was completed, 249.2L of orlistat solution was collected. The orlistat content was found to be 0.226kg / L after testing, and the yield was 98.9%.

[0073] (3) Column chromatography

[0074] The ratio of the column height to the diameter of the chromatography column is 5:1; 434 kg of adsorbent is loaded into the chromatography column, balanced with isopropyl acetate, and the orlistat solution is put into the chromatography column, the sample amount is 27% of the column volume, and the isopropyl acetate is eluted, and the flow rate is controlled at 0.5 times the column volume / h. The chromatography is completed in 131 hours. A total of 159 L of liquid in the white area is collected, the orlistat content is 0.327 kg / L, and the yield is 92.4%.

[0075] (4) Concentration under reduced pressure, filtration and drying

[0076] Add 350L of saturated sodium chloride solution prepared with purified water to 159L of orlistat solution. Raise the temperature to 86°C and control the pressure at -0.05 to -0.1MPa. When collecting isopropyl acetate, add saturated sodium chloride solution prepared with purified water at a rate of 1.5% of the initial volume per hour.

[0077] After the collection of isopropyl acetate was completed, the mixture was kept warm and stirred for 25 min, and then slowly cooled to 1°C. The cooling rate was controlled at 4-6°C / h.

[0078] After cooling, continue stirring for 40 min and let stand for 105 min.

[0079] Filtration and drying were performed to obtain 50.3 kg of pure orlistat, with a total yield of 88.3%.

[0080] The purity of orlistat was 99.7% and the impurity was 0.06% by HPLC, which reached the pharmaceutical standard.

[0081] Example 3

[0082] 100kg of crude orlistat, with an effective content of 64%.

[0083] (1) Washing

[0084] 300 L of isopropyl acetate was added to the crude orlistat, and the mixture was washed with water and separated.

[0085] (2) Ceramic membrane filtration

[0086] A ceramic membrane filtration device was used. The membrane material was silicon oxide and the multi-channel configuration was adopted. The pore size of the ceramic membrane was 0.2um. During the membrane filtration process, the temperature was controlled at 30-40°C and the pressure difference was controlled at 0.3-0.4MPa. After the membrane filtration was completed, 299.3L of orlistat solution was collected. The orlistat content was found to be 0.212kg / L after testing, and the yield was 99.3%.

[0087] (3) Column chromatography

[0088] The ratio of column height to diameter of the chromatography column is 5:1; 454 kg of adsorbent is loaded into the chromatography column, balanced with isopropyl acetate, and the orlistat solution is put into the chromatography column, the sample amount is 28% of the column volume, and the isopropyl acetate is eluted, and the flow rate is controlled at 0.6 times the column volume / h. The chromatography is completed in 130 hours. A total of 184 L of liquid in the white area is collected, the orlistat content is 0.32 kg / L, and the yield is 92.9%.

[0089] (4) Concentration under reduced pressure, filtration and drying

[0090] Add 460L of saturated sodium chloride solution prepared with purified water to 184L of orlistat solution. Raise the temperature to 87°C and control the pressure at -0.05 to -0.1MPa. When collecting isopropyl acetate, add saturated sodium chloride solution prepared with purified water at a rate of 2% of the initial volume per hour.

[0091] After the collection of isopropyl acetate is completed, the mixture is kept warm and stirred for 30 minutes, and then slowly cooled to 2°C. The cooling rate is controlled at 4-6°C / h.

[0092] After cooling, continue stirring for 45 minutes and let stand for 110 minutes.

[0093] Filtration and drying were performed to obtain 57.4 kg of pure orlistat, with a total yield of 89.7%.

[0094] The purity of orlistat was 99.8% and the impurity was 0.06% by HPLC, which reached the pharmaceutical standard.

[0095] Example 4

[0096] 100kg of crude orlistat, with an effective content of 71%.

[0097] (1) Washing

[0098] 350 L of isopropyl acetate was added to the crude orlistat, and the mixture was washed with water and separated.

[0099] (2) Ceramic membrane filtration

[0100] A ceramic membrane filtration device was used. The membrane material was silicon oxide and the multi-channel configuration was adopted. The pore size of the ceramic membrane was 0.2um. During the membrane filtration process, the temperature was controlled at 30-40°C and the pressure difference was controlled at 0.3-0.4MPa. After the membrane filtration was completed, 349.2L of orlistat solution was collected. The orlistat content was found to be 0.202kg / L after testing, and the yield was 99.3%.

[0101] (3) Column chromatography

[0102] The ratio of the column height to the diameter of the chromatography column is 6:1; 470 kg of adsorbent is loaded into the chromatography column, balanced with isopropyl acetate, and the orlistat solution is added to the chromatography column, the sample amount is 29% of the column volume, and the isopropyl acetate is eluted, and the flow rate is controlled at 0.7 times the column volume / h. The chromatography is completed in 131 hours. A total of 203 L of liquid in the white area is collected, the orlistat content is 0.32 kg / L, and the yield is 92.6%.

[0103] (4) Concentration under reduced pressure, filtration and drying

[0104] Add 550L of saturated sodium chloride solution prepared with purified water to 203L of orlistat solution. Raise the temperature to 88°C and control the pressure at -0.05 to -0.1MPa. When collecting isopropyl acetate, add saturated sodium chloride solution prepared with purified water at a rate of 2.5% of the initial volume per hour.

[0105] After the collection of isopropyl acetate was completed, the mixture was kept warm and stirred for 35 min, and then slowly cooled to 3°C. The cooling rate was controlled at 4-6°C / h.

[0106] After cooling, continue stirring for 50 min and let stand for 115 min.

[0107] Filtration and drying were performed to obtain 63.4 kg of pure orlistat, with a total yield of 89.4%.

[0108] The purity of orlistat was 99.7% and the impurity was 0.07% as determined by HPLC, reaching the pharmaceutical standard.

[0109] Example 5

[0110] 100kg of crude orlistat, with an effective content of 74%.

[0111] (1) Washing

[0112] 400 L of isopropyl acetate was added to the crude orlistat, and the mixture was washed with water and separated.

[0113] (2) Ceramic membrane filtration

[0114] A ceramic membrane filtration device was used. The membrane material was silicon oxide and the multi-channel configuration was adopted. The pore size of the ceramic membrane was 0.2um. During the membrane filtration process, the temperature was controlled at 30-40°C and the pressure difference was controlled at 0.3-0.4MPa. After the membrane filtration was completed, 399.1L of orlistat solution was collected. The orlistat content was found to be 0.183kg / L after testing, and the yield was 99.0%.

[0115] (3) Column chromatography

[0116] The ratio of the column height to the diameter of the chromatography column is 5:1; 458 kg of adsorbent is loaded into the chromatography column, balanced with isopropyl acetate, and the orlistat solution is put into the chromatography column, the sample amount is 30% of the column volume, and the isopropyl acetate is eluted, and the flow rate is controlled at 0.8 times the column volume / h. The chromatography is completed in 130 hours. A total of 284 L of liquid in the white area is collected, the orlistat content is 0.24 kg / L, and the yield is 92.3%.

[0117] (4) Concentration under reduced pressure, filtration and drying

[0118] Add 1150L of saturated sodium chloride solution prepared with purified water to 384L of orlistat solution. Raise the temperature to 90°C and control the pressure at -0.05 to -0.1MPa. When collecting isopropyl acetate, add saturated sodium chloride solution prepared with purified water at a rate of 3% of the initial volume per hour.

[0119] After the collection of isopropyl acetate was completed, the mixture was kept warm and stirred for 35 min, and then slowly cooled to 5°C. The cooling rate was controlled at 4-6°C / h.

[0120] After cooling, continue stirring for 60 min and let stand for 120 min.

[0121] Filtration and drying were performed to obtain 65.8 kg of pure orlistat, with a total yield of 88.9%.

[0122] The purity of orlistat was 99.6% and the impurity was 0.06% by HPLC, which reached the pharmaceutical standard.

[0123] Comparative Example 1

[0124] 100kg of crude orlistat, with an effective content of 70%.

[0125] (1) Washing

[0126] 300 L of isopropyl acetate was added to the crude orlistat, and the mixture was washed with water and separated.

[0127] (2) Ceramic membrane filtration

[0128] A ceramic membrane filtration device was used. The membrane material was silicon oxide and the multi-channel configuration was adopted. The pore size of the ceramic membrane was 0.2um. During the membrane filtration process, the temperature was controlled at 30-40°C and the pressure difference was controlled at 0.3-0.4MPa. After the membrane filtration was completed, 299.2L of orlistat solution was collected. The orlistat content was found to be 0.232kg / L after testing, and the yield was 99.2%.

[0129] (3) Column chromatography

[0130] The ratio of the column height to the diameter of the chromatography column is 6:1; 695 kg of adsorbent silica gel is loaded into the chromatography column, balanced with isopropyl acetate, and the orlistat solution is put into the chromatography column, the sample amount is 25% of the column volume, and the isopropyl acetate is eluted, and the flow rate is controlled at 0.5 times the column volume / h. The chromatography is completed in 274 hours. A total of 273 L of liquid in the white area is collected, the orlistat content is 0.21 kg / L, and the yield is 82.6%.

[0131] (4) Concentration under reduced pressure, filtration and drying

[0132] Add 550L of saturated sodium chloride solution prepared with purified water to 273L of orlistat solution. Raise the temperature to 88°C and control the pressure at -0.05 to -0.1MPa. When collecting isopropyl acetate, add saturated sodium chloride solution prepared with purified water at a rate of 2% of the initial volume per hour.

[0133] After the collection of isopropyl acetate is completed, the mixture is kept warm and stirred for 30 minutes, and then slowly cooled to 2°C. The cooling rate is controlled at 4-6°C / h.

[0134] After cooling, continue stirring for 45 minutes and let stand for 110 minutes.

[0135] Filtration and drying were performed to obtain 52.2 kg of pure orlistat, with a total yield of 74.6%.

[0136] The purity of orlistat was 99.5% and the impurity was 0.09% by HPLC.

[0137] Comparative Example 2

[0138] 100kg of crude orlistat, with an effective content of 68%.

[0139] (1) Washing

[0140] 300 L of isopropyl acetate was added to the crude orlistat, and the mixture was washed with water and separated.

[0141] (2) Ceramic membrane filtration

[0142] A ceramic membrane filtration device was used. The membrane material was silicon oxide and the multi-channel configuration was adopted. The pore size of the ceramic membrane was 0.2um. During the membrane filtration process, the temperature was controlled at 30-40°C and the pressure difference was controlled at 0.3-0.4MPa. After the membrane filtration was completed, 299.3L of orlistat solution was collected. The orlistat content was found to be 0.229kg / L after testing, and the yield was 99.3%.

[0143] (3) Column chromatography

[0144] The ratio of the column height to the diameter of the chromatography column is 5:1; 675 kg of adsorbent macroporous resin is loaded into the chromatography column, balanced with isopropyl acetate, and the orlistat solution is put into the chromatography column, the sample amount is 25% of the column volume, and the isopropyl acetate is eluted, and the flow rate is controlled at 0.6 times the column volume / h. The chromatography is completed in 281 hours. A total of 294 L of liquid in the white area is collected, the orlistat content is 0.18 kg / L, and the yield is 79.8%.

[0145] (4) Concentration under reduced pressure, filtration and drying

[0146] Add 600L of saturated sodium chloride solution prepared with purified water to 294L of orlistat solution. Raise the temperature to 90°C and control the pressure at -0.05 to -0.1MPa. When collecting isopropyl acetate, add saturated sodium chloride solution prepared with purified water at a rate of 1% of the initial volume per hour.

[0147] After the collection of isopropyl acetate is completed, the mixture is kept warm and stirred for 30 minutes, and then slowly cooled to 0°C. The cooling rate is controlled at 4-6°C / h.

[0148] After cooling, continue stirring for 45 minutes and let stand for 120 minutes.

[0149] Filtration and drying were performed to obtain 48.7 kg of pure orlistat, with a total yield of 71.6%.

[0150] The purity of orlistat was 99.6% and the impurity was 0.08% by HPLC.

[0151] Comparative Example 3

[0152] 100 kg of crude orlistat, with an effective content of 60%, was dissolved in 200 L of heptane.

[0153] 700 kg of 80-100 mesh silica gel was activated and wet loaded into the column, with a column height-to-diameter ratio of 10:1. After the column was balanced with heptane, the column loading began. The loading speed was controlled to be 3.5 liters / hour. After the loading was completed, the mobile phase of heptane: ethyl acetate = 4:1 was used for elution. The components containing orlistat were collected until no orlistat was detected. After the end, 148 liters of elution phase were obtained, and the time was 281 hours. The orlistat content was 0.33 kg / L, and the yield was 81.5%.

[0154] The orlistat solution was concentrated, crystallized and dried to obtain 43.9 kg of off-white substance with a total yield of 73.2%.

[0155] The purity of orlistat was 99.7% and the impurity was 0.07% as determined by HPLC.

[0156] Comparative Example 4

[0157] 100 kg of crude orlistat, with an effective content of 52%, was dissolved in 200 L of heptane.

[0158] 700 kg of 80-100 mesh silica gel was activated and wet loaded into the column, with a column height-to-diameter ratio of 10:1. After the column was balanced with heptane, loading began. The loading speed was controlled to be 3.5 liters / hour. After the loading was completed, heptane: ethyl acetate = 4:1 mobile phase was used for elution. The components containing orlistat were collected until no orlistat was detected. After the end, 150 liters of elution phase were obtained, and the time was 282 hours. The orlistat content was 0.184 kg / L, and the yield was 76.2%.

[0159] The orlistat solution was concentrated, crystallized and dried to obtain 33.44 kg of off-white substance with a total yield of 64.3%.

[0160] The purity of orlistat was 96.5% and the impurity was 0.09% by HPLC.

Claims

1. A method for purifying crude orlistat, comprising the following steps: (1) Washing After the crude orlistat is dissolved, it is washed with water and separated; (2) Ceramic membrane filtration The orlistat organic solution was filtered through a ceramic membrane; (3) Column chromatography The orlistat organic solution is put into a chromatography column containing an adsorbent for chromatography to obtain a light white organic solution, wherein the adsorbent is made of the following components in parts by weight: 26-30 g of sodium alginate, 70-75 g of natural bleaching earth and 32-35 g of molecular sieve activation powder; (4) Concentration under reduced pressure, filtration and drying A saturated sodium chloride solution prepared with purified water is added to the orlistat organic solution, and the solution is concentrated under reduced pressure, filtered and dried to obtain pure orlistat. in, The preparation method of the adsorbent in step (3) refers to: 1) Add sodium alginate to purified water and heat to 70-80°C. The addition ratio of sodium alginate is 26-30g per 1L of water. 2) adding natural bleaching earth and molecular sieve activation powder to the sodium alginate solution and stirring for 140-160 minutes to obtain a suspension, wherein the addition ratio of natural bleaching earth is 70-75 g per 1 L sodium alginate solution, and the addition ratio of molecular sieve activation powder is 32-35 g per 1 L sodium alginate solution; 3) preparing a saturated sodium chloride purified aqueous solution and cooling it to 0-3°C; 4) Using a device for preparing gel balls, the suspension is sucked in to prepare gel balls, which are then dropped into a saturated sodium chloride purified aqueous solution, allowed to stand for 100-120 minutes, and filtered to obtain gel balls with a pore size of 1-1.5 mm; 5) The gel balls are washed with purified water and dried at 30-40°C; 6) After drying, the gel spheres are added to PEG200 and allowed to stand for 100-120 minutes; 7) After standing, washing and drying are performed to obtain an adsorbent; 8) The ratio of adsorbent used: W adsorbent: W orlistat = 1 kg: 120-160 g.

2. The method for purifying crude orlistat according to claim 1, characterized in that In step (1), the weight percentage of orlistat in the crude orlistat is ≥40%.

3. The method for purifying crude orlistat according to claim 1, characterized in that In step (1), the dissolving refers to dissolving the crude orlistat in an isopropyl acetate solution to obtain an orlistat organic solution, and the compatibility ratio is W crude orlistat: V isopropyl acetate = 1 kg: 2-4 L.

4. The method for purifying crude orlistat according to claim 1, characterized in that In step (1), the water washing refers to heating the saturated sodium chloride solution prepared with purified water to 40-60°C, adding the orlistat organic solution thereto, and washing for 20-40 minutes. The compatibility ratio is: V orlistat organic solution: V saturated sodium chloride solution prepared with purified water = 1L: 1-3L.

5. The method for purifying crude orlistat according to claim 1, characterized in that In step (2), the ceramic membrane filtration uses a ceramic membrane filtration device, the membrane material is silicon oxide, a multi-channel configuration is adopted, and the pore size of the ceramic membrane is 0.2um; during the membrane filtration process, the temperature is controlled at 30-40°C, and the pressure difference is controlled at 0.3-0.4MPa; after the membrane filtration is completed, the orlistat organic solution is collected.

6. The method for purifying crude orlistat according to claim 1, characterized in that In step (3), the column chromatography refers to: the ratio of the height to the diameter of the chromatography column is 4-6:1; the adsorbent is loaded into the chromatography column, balanced with isopropyl acetate, the orlistat organic solution is added to the chromatography column, the sample amount is 25% to 30% of the column volume, isopropyl acetate is eluted, the flow rate is controlled at 0.4 to 0.8 times the column volume / h, and the liquid in the light white area is collected.

7. The method for purifying crude orlistat according to claim 3, characterized in that In step (4), the reduced pressure concentration refers to adding a saturated sodium chloride solution prepared with purified water to the orlistat organic solution obtained by chromatography, the addition ratio is: V saturated sodium chloride solution: V isopropyl acetate = 2-3L: 1L, heating to 85-90°C, and controlling the pressure at -0.05 to -0.1Mpa; when collecting isopropyl acetate, adding a saturated sodium chloride solution prepared with purified water, the amount added per hour is 1-3% of the initial volume; after the collection of isopropyl acetate is completed, keeping warm and stirring for 20-40 minutes, and then slowly cooling to 0-5°C, the cooling rate is controlled at 4-6°C / h; after cooling, continue stirring for 30-60 minutes, and let stand for 100-120 minutes; filtering and drying to obtain pure orlistat.