Preparation and purification method of oritavancin diphosphate

Abstract

The invention provides a purification method of oritavancin diphosphate. The method specifically comprises the following steps: step 1, decomplexing an oritavancin copper complex; step 2, preparation and purification; step 3, concentration; and 4, salifying and crystallizing. According to the preparation and purification method of the oritavancin diphosphate provided by the invention, the oritavancin with the purity of more than 99% can be obtained through silica gel C18 filler purification and only one-time chromatography, and the unknown impurity content is less than 0.1%; the method is simple to operate, low in cost, high in product quality and suitable for industrial production. By adopting the purification method disclosed by the invention, the yield of the purified crude product to the finished product can reach 68% or above, the purity can reach 99% or above, and the requirements of industrial production are met.

Description

Technical Field

[0001] The present invention belongs to the field of antibiotic separation and purification, and particularly relates to a method for preparing and purifying oritavancin diphosphate. Background Art

[0002] In August 2014, the FDA approved the antibiotic Orbactiv (oritavancin, IV) injection for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSIs) caused by susceptible Gram-positive bacteria (including methicillin-resistant Staphylococcus aureus, MRSA). Orbactiv is the first and only antibiotic with a single-dose treatment regimen approved by the FDA for the treatment of ABSSSIs. Patients only receive one infusion of Orbactiv, and the entire treatment regimen is completed. The approval of Orbactiv also represents a major advancement far beyond the current clinical standard in the treatment of bacterial skin and skin structure infections. Currently, patients often need multiple intravenous infusions of antibiotics, while the single-dose treatment regimen of Orbactiv will significantly reduce the dosing burden on patients.

[0003] Compound patent CN1119649A discloses a method for purifying oritavancin and its analogs. Through silica gel C18 reverse-phase preparation, elution is carried out at a fixed ratio with ammonium phosphate buffer and acetonitrile, and fractions are collected. After the qualified samples are desalted, oritavancin is obtained. This method involves relatively complex operations, and the yield of this method is only about 20 - 45%. Facing the increasing market demand and product quality requirements, the complex process and low yield will lead to an increase in production costs.

[0004] Process patent WO2016 / 011245A discloses a method for purifying oritavancin diphosphate. The crude oritavancin copper complex, after being decomplexed with phosphoric acid, is eluted through a polymer filler polystyrene - divinylbenzene resin with ammonium phosphate and acetonitrile solutions, fractions are collected, then ultrafiltration and concentration are carried out, and salt formation is carried out in an ethanol / water system to obtain oritavancin diphosphate. The purity of the product obtained by this method is about 95%. According to the drug safety requirements, the product purity requirement is > 98.0%, and the unknown single impurity is < 0.1%. The existing technology cannot meet the increasingly high product quality requirements.

[0005] Therefore, there is a continuing need in the art to find a purification method that can improve the quality of oritavancin products while reducing production costs and having simple operation steps, so as to overcome the defects existing in the prior art and meet the requirements of industrial production. Summary of the Invention

[0006] An object of the present invention is to provide a method for preparing and purifying oritavancin diphosphate.

[0007] The second object of the present invention is to provide a method for purifying oritavancin diphosphate.

[0008] To achieve the above object, the technical solution of the present invention is as follows:

[0009] The present invention provides a method for preparing and purifying oritavancin diphosphate in the first aspect, including the following steps: loading the decomplexed oritavancin filtrate into a preparation column and eluting with mobile phase B, where the mobile phase B is an aqueous solution of an acid or its salt - alcohol - acetonitrile,

[0010] wherein, the alcohol is methanol or ethanol.

[0011] Furthermore, the acid or its salt in the mobile phase B can be selected from any one or more of organic acids, inorganic acids, organic acid salts, and inorganic acid salts;

[0012] Preferably, the acid or its salt can be selected from any one or more of formic acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, phosphoric acid, sulfuric acid, ammonium phosphate salt, and ammonium acetate salt;

[0013] Preferably, the acid or its salt can be selected from any one or more of formic acid, acetic acid, phosphoric acid, trifluoroacetic acid, and ammonium phosphate salt.

[0014] Furthermore, the volume concentration of the aqueous solution of the acid or its salt in the mobile phase B is 0.1 - 1.0%;

[0015] Preferably, the volume concentration of the aqueous solution of the acid or its salt in the mobile phase B is 0.5%.

[0016] Furthermore, the volume ratio of each component in the mobile phase B is: aqueous solution of acid or its salt : alcohol : acetonitrile = (80 - 90) : (5 - 10) : (5 - 10);

[0017] Preferably, aqueous solution of acid or its salt : alcohol : acetonitrile = 84 : 10 : 6;

[0018] wherein, the alcohol is methanol or ethanol.

[0019] Furthermore, the packing material of the preparation column is silica gel C18;

[0020] Preferably, the packing material can be selected from any one of 10C18 - 120AD, 10C18 - 100AA, and 10C18 - 100AB;

[0021] More preferably, the packing material is 10C18 - 120AD.

[0022] Furthermore, after eluting with mobile phase B for 80 - 120 min, collect the eluate with a purity > 99%;

[0023] Preferably, after eluting with mobile phase B for 100 min, the eluate with a purity > 99% is collected.

[0024] The second aspect of the present invention provides a method for purifying oritavancin diphosphate, comprising the following steps:

[0025] Step 1: Dissolve the crude oritavancin copper complex in an acidic aqueous solution for decoordination, and filter to obtain the filtered oritavancin solution after decoordination;

[0026] Step 2: Subject the filtered oritavancin solution after decoordination to silica gel C18 column chromatography, elute with mobile phase B, and collect the eluate with a purity > 99%; the mobile phase B is an aqueous solution of an acid or its salt - alcohol - acetonitrile;

[0027] Step 3: Nanofiltrate and concentrate the eluate to obtain a concentrated solution;

[0028] Step 4: After membrane - filtering the concentrated solution, form a salt with phosphoric acid to obtain oritavancin diphosphate.

[0029] Furthermore, in step 1, the acidic aqueous solution can be selected from any one of acetic acid aqueous solution, formic acid aqueous solution, and phosphoric acid aqueous solution.

[0030] Furthermore, in step 2, first pre - wash the column with elution phase A (5% acetonitrile (1.0% acetic acid)) for 50 min, and then elute with mobile phase B; after collecting the eluate in step 2, re - wash the column with elution phase C (85% acetonitrile (0.5% phosphoric acid)) for 25 min.

[0031] Furthermore, in step 2, the acid or its salt in mobile phase B can be selected from any one or more of formic acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, phosphoric acid, sulfuric acid, ammonium phosphate salt, and ammonium acetate salt;

[0032] Preferably, the acid or its salt can be selected from any one or more of formic acid, acetic acid, phosphoric acid, trifluoroacetic acid, and ammonium phosphate salt.

[0033] Furthermore, in step 2, the volume concentration of the aqueous solution of the acid or its salt is 0.1 - 1.0%;

[0034] Preferably, the volume concentration of the aqueous solution of the acid or its salt is 0.5%.

[0035] Furthermore, in step 2, the volume ratio of each component in mobile phase B is: aqueous solution of acid or its salt: alcohol: acetonitrile = (80 - 90):(5 - 10):(5 - 10);

[0036] Preferably, aqueous solution of acid or its salt: alcohol: acetonitrile = 84:10:6;

[0037] Wherein, the alcohol is methanol or ethanol.

[0038] Further, the silica gel C18 column chromatography packing prepared in step 2 can be selected from any one of 10C18-120AD, 10C18-100AA, and 10C18-100AB;

[0039] More preferably, the silica gel C18 column chromatography packing is 10C18-120AD.

[0040] Further, for the nanofiltration concentration in step 3, the conductivity of the concentrated filtrate < 500 μs / cm, and the concentration of the concentrated solution is not less than 60 g / L.

[0041] Further, in step 4, the phosphoric acid salt formation can be phosphoric acid, phosphate, or a mixed system of phosphoric acid and phosphate. The phosphate is preferably ammonium dihydrogen phosphate.

[0042] Further, after the concentrated solution is filtered through a filter membrane in step 4, an alcohol solution is added to the filtrate, the temperature is raised to 45-50 °C with stirring, an aqueous solution of ammonium dihydrogen phosphate is added, the pH is adjusted to 4-5 with phosphoric acid, and the temperature is lowered to 0-5 °C with stirring for crystallization to obtain olivanic acid diphosphate.

[0043] The alcohol in the above alcohol solution is selected from any one or more of methanol, ethanol, n-propanol, and isopropanol.

[0044] According to the technical solution provided by the present invention, the purity of the obtained olivanic acid diphosphate can reach more than 99%, the unknown single impurity < 0.1%, and the total yield can reach more than 68%. While ensuring the product purity, the total yield is increased, meeting the process production requirements, and the operation is simple and the cost is low, which is suitable for industrial production. Description of the Drawings

[0045] Figure 1 It is the chromatogram of the crude product in Example 1;

[0046] Figure 2 It is the chromatogram of the high-purity product obtained after preparation, purification, salt formation and crystallization in Example 1;

[0047] Figure 3 It is the chromatogram of the product obtained after purification, salt formation and crystallization in Comparative Example 1. Detailed Embodiments

[0048] The following describes the embodiments of the present invention, but the present invention is not limited thereto. The present invention is not limited to the following described components, and various changes can be made within the scope of the invention claimed. Embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and examples are also included in the technical scope of the present invention.

[0049] Unless otherwise defined, the technical and scientific terms used in the present invention have the same meanings as those commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0050] The raw materials used in the present invention can all be purchased commercially.

[0051] The crude product of oritavancin copper complex in the following examples of the present invention was prepared according to the method disclosed in Patent WO2016 / 011245A.

[0052] Example 1 The preparation and purification method of oritavancin diphosphate in this example includes the following steps:

[0053] Step 1: Dissociate the oritavancin copper complex: At room temperature, add 1 L of purified water to the crude product of oritavancin copper complex (containing 20 g of the product, the chromatogram is shown in the appendix Figure 1 , and the corresponding spectral data is shown in Table 1, the purity of the crude product is 74.1%), stir, add acetic acid to dissolve and adjust the pH to 2.5, add 50 ml of acetonitrile, mix well, filter through a 0.45 μm filter membrane, and collect the filtrate as the loading solution;

[0054] Step 2: Preparation and purification: Load the silica gel C18 reverse-phase packing material (10C18-120AD) into a 100DAC high-pressure preparation system, balance the column with mobile phase A, and then pump the loading solution into the preparation system;

[0055] Pre-wash, pre-wash with mobile phase A for 50 min;

[0056] Elute, elute with mobile phase B for about 100 min; Collect the product in fractions, detect by HPLC, and collect the eluate with a product purity > 99%;

[0057] Wash the column, wash the column with mobile phase C for 25 min; The specific preparation and ratio of the mobile phase are shown in Table 2;

[0058] Table 1 Figure 1 Corresponding spectral data

[0059]

[0060]

[0061] Table 2 Preparation and ratio of the mobile phase

[0062]

[0063] Step 3: Concentration: After combining the qualified eluates, dilute them with 1-fold purified water, then transfer them to a nanofiltration machine, nanofilter at a temperature below 20 °C until the concentration is not less than 60 g / L, and wash with purified water, and collect the nanofiltration concentrate;

[0064] Step 4, salt formation and crystallization: After the nanofiltration concentrate is filtered through a filter membrane, anhydrous ethanol is added to the filtrate, and the mixture is stirred and heated to 45 - 50 °C. Then, an aqueous solution of ammonium dihydrogen phosphate is added, and the pH is adjusted to 4 - 5 with phosphoric acid. The mixture is stirred and cooled to 0 - 5 °C and stirred for crystallization for 10 hours. Then, it is filtered, and the filter cake is rinsed with 60% aqueous ethanol solution and then filtered dry to obtain the wet product; The wet product is dried under reduced pressure at 20 - 30 °C to obtain 14.10 g of dry olivanic acid diphosphate product with a purity of 99.6% (the chromatogram is shown in the appendix Figure 2 , and the corresponding spectral data are shown in Table 3), and the yield is 70.5%.

[0065] Table 3 Figure 2 The corresponding spectral data

[0066]

[0067]

[0068] Example 2 The preparation and purification method of olivanic acid diphosphate in this example includes the following steps:

[0069] Step 1, decoordination of the copper complex of olivanic acid: At room temperature, the crude copper complex of olivanic acid (containing 20 g of the product with a crude purity of 74.1%) is added to 1 L of purified water and stirred. Acetic acid is added to dissolve it and adjust the pH to 2.5. 50 ml of acetonitrile is added, and the mixture is mixed evenly and filtered through a 0.45 μm filter membrane. The filtrate is collected as the loading solution;

[0070] Step 2, preparation and purification: The silica gel C18 reverse-phase packing material (10C18 - 100AA) is loaded into a 100DAC high-pressure preparation system, and the column is equilibrated with mobile phase A. Subsequently, the loading solution is pumped into the preparation system;

[0071] Pre-washing, pre-washing with mobile phase A for 50 min;

[0072] Elution, eluting with mobile phase B for about 80 min; The product is collected in fractions and detected by HPLC. The eluate with a product purity > 99% is collected;

[0073] Column flushing, flushing the column with mobile phase C for 25 min; The specific preparation and ratio of the mobile phase are shown in Table 4;

[0074] Table 4 Preparation and ratio of the mobile phase

[0075]

[0076] Step 3, concentration: After the qualified eluates are combined, they are diluted 1-fold with purified water, and then transferred to a nanofiltration machine. Nanofiltration is carried out at a temperature below 20 °C until the concentration is not less than 60 g / L, and it is rinsed with purified water. The nanofiltration concentrate is collected;

[0077] Step 4, salt formation and crystallization: After the nanofiltration concentrate is filtered through a filter membrane, absolute ethanol is added to the filtrate, and the mixture is stirred and heated to 45 - 50 °C. Then, an aqueous solution of ammonium dihydrogen phosphate is added, and the pH is adjusted to 4 - 5 with phosphoric acid. The mixture is stirred and cooled to 0 - 5 °C and stirred for crystallization for 10 hours. Then, it is filtered, and the filter cake is rinsed with a 60% aqueous ethanol solution and then dried by filtration to obtain a wet product. The wet product is dried under reduced pressure at 20 - 30 °C to obtain 13.80 g of dry olivanic acid diphosphate product with a purity of 99.4% and a yield of 69.0%.

[0078] Example 3. The purification method of olivanic acid diphosphate in this example includes the following steps:

[0079] Step 1, decoordination of the copper complex of olivanic acid: At room temperature, the crude copper complex of olivanic acid (containing 20 g of the product) is added to 1 L of purified water and stirred. Acetic acid is added and stirred to dissolve, and the pH is adjusted to 2.5. 50 ml of acetonitrile is added, and the mixture is mixed evenly and filtered through a 0.45 μm filter membrane. The filtrate is collected as the loading solution.

[0080] Step 2, preparative purification: The silica gel C18 reversed-phase packing material (10C18 - 120AD) is loaded into a 100DAC high-pressure preparative system, and the column is equilibrated with mobile phase A. Subsequently, the loading solution is pumped into the preparative system for sample injection.

[0081] Pre-washing: Pre-wash with mobile phase A for 50 min.

[0082] Elution: Elute with mobile phase B for about 120 min. The product is collected in fractions and detected by HPLC. The eluate with a product purity > 99% is collected.

[0083] Column flushing: Flush the column with mobile phase C for 25 min. The specific preparation and ratio of the mobile phase are shown in Table 5.

[0084] Table 5 Preparation and ratio of the mobile phase

[0085]

[0086] Step 3, concentration: After the qualified eluates are combined, they are diluted 1-fold with purified water, and then transferred to a nanofiltration machine. Nanofiltration is carried out at a temperature below 20 °C until the concentration is not less than 60 g / L, and it is rinsed with purified water. The nanofiltration concentrate is collected.

[0087] Step 4, salt formation and crystallization: After the nanofiltration concentrate is filtered through a filter membrane, absolute ethanol is added to the filtrate, and the mixture is stirred and heated to 45 - 50 °C. Then, an aqueous solution of ammonium dihydrogen phosphate is added, and the pH is adjusted to 4 - 5 with phosphoric acid. The mixture is stirred and cooled to 0 - 5 °C and stirred for crystallization for 10 hours. Then, it is filtered, and the filter cake is rinsed with a 60% aqueous ethanol solution and then dried by filtration to obtain a wet product. The wet product is dried under reduced pressure at 20 - 30 °C to obtain 14.00 g of dry olivanic acid diphosphate product with a purity of 99.5% and a yield of 70.0%.

[0088] Example 4. The purification method of oritavancin diphosphate in this example includes the following steps:

[0089] Step 1. Dissociate the oritavancin copper complex: At room temperature, add 1 L of purified water to the crude oritavancin copper complex (containing 20 g of the product) and stir, add acetic acid and stir to dissolve, adjust the pH to 2.5, add 50 ml of acetonitrile, mix well, filter through a 0.45 μm filter membrane, and collect the filtrate as the loading solution for the column.

[0090] Step 2. Preparation and purification: Column packing, sample loading, and elution; Pack the silica C18 reverse-phase packing material (10C18-100AB) into a 100 DAC high-pressure preparation system, balance the column with mobile phase A, and then pump the loading solution into the preparation system.

[0091] Pre-washing: Pre-wash with mobile phase A for 50 min.

[0092] Elution: Elute with mobile phase B for about 100 min; Collect the product in fractions, detect by HPLC, and collect the eluate with a product purity > 99%.

[0093] Column flushing: Flush the column with mobile phase C for 25 min; The specific preparation and ratio of the mobile phase are shown in Table 6.

[0094] Table 6 Preparation and ratio of the mobile phase

[0095]

[0096] Step 3. Concentration: After combining the qualified eluates detected, dilute with purified water by 1 time, then transfer to a nanofiltration machine, perform nanofiltration at a temperature below 20 °C until the concentration is not less than 60 g / L, and wash with purified water, and collect the nanofiltration concentrate.

[0097] Step 4. Salt formation and crystallization: After filtering the nanofiltration concentrate through a filter membrane, add absolute ethanol to the filtrate, stir and heat to 45 - 50 °C, then add an aqueous solution of ammonium dihydrogen phosphate, adjust the pH to 4 - 5 with phosphoric acid, stir and cool to 0 - 5 °C and stir for crystallization for 10 hours, then filter, wash the filter cake with a 60% aqueous ethanol solution and filter dry to obtain the wet product; Dry the wet product under reduced pressure at 20 - 30 °C to obtain 13.60 g of dry oritavancin diphosphate product with a purity of 99.3% and a yield of 68.0%.

[0098] Comparative Example 1 Preparation and purification method of oritavancin diphosphate

[0099] Step 1. Dissociate the oritavancin copper complex: At room temperature, add 1 L of purified water to the crude oritavancin copper complex (containing 20 g of the product) and stir, add acetic acid and stir to dissolve, adjust the pH to 2.5, add 50 ml of acetonitrile, mix well, filter through a 0.45 μm filter membrane, and collect the filtrate as the loading solution for the column.

[0100] Step 2, Preparation and Purification: Load the polymer filler (UniPS30-300) into a 100DAC high-pressure preparation system, balance the column with mobile phase A, and then load the sample solution onto the column through a pump into the preparation system;

[0101] Pre-washing: Pre-wash with mobile phase A for 50 minutes;

[0102] Elution: Elute with mobile phase B for about 100 minutes; Collect the products in fractions and detect by HPLC. No product with a purity > 99% was found. Collect the eluate with a product purity > 95%;

[0103] Column Flushing: Flush the column with mobile phase C for 25 minutes; The specific preparation and ratio of the mobile phase are shown in Table 7;

[0104] Table 7 Preparation and Ratio of Mobile Phase

[0105]

[0106] Step 3, Concentration: After combining the eluates, dilute them with purified water by 1 time, then transfer them to a nanofiltration machine, and nanofilter at a temperature below 20°C until the concentration is not less than 60 g / L, and rinse with purified water. Collect the nanofiltered concentrate;

[0107] Step 4, Salt Formation and Crystallization: After filtering the nanofiltered concentrate through a filter membrane, add absolute ethanol to the filtrate, stir and heat up to 45 - 50°C, then add an aqueous solution of ammonium dihydrogen phosphate, adjust the pH = 4 - 5 with phosphoric acid, stir and cool down to 0 - 5°C and stir for crystallization for 10 hours, then filter. Wash the filter cake with a 60% aqueous ethanol solution and filter dry to obtain the wet product; Dry the wet product under reduced pressure at 20 - 30°C to obtain 8.60 g of dry olivanic acid diphosphate product with a purity of 96.5% (see the attached Figure 3 , and the corresponding spectral data are shown in Table 8), the maximum single impurity is 1.4%, and the yield is 43.0%.

[0108] Table 8 Figure 3 Corresponding Spectral Data

[0109]

[0110] It can be found from the comparison of Examples 1 - 4 and Comparative Example 1 above that the purity of the high-purity olivanic acid diphosphate obtained in Comparative Example 1 is less than 98%, the maximum unknown single impurity is 1.4%, which does not meet the drug safety requirements, and the total yield is only about 40%. While according to the technical solution provided by the present invention, the purity of the obtained olivanic acid diphosphate can reach more than 99%, the unknown single impurity < 0.1%, the total yield can reach more than 68%, meeting the process production requirements, and the total yield is significantly improved. The total yield is increased while ensuring the product purity, and the operation is simple and the cost is low, which is suitable for industrial production.

[0111] Those skilled in the art can make various corresponding changes and deformations according to the technical solutions and concepts described above, and all such changes and deformations should fall within the protection scope of the claims of the present invention.

Claims

1. A method for the preparation and purification of oritavancin diphosphate, characterized in that, Load the filtrate of oritavancin after decoordination into a preparation column and elute with mobile phase B, where mobile phase B is an aqueous solution of an acid or its salt - alcohol - acetonitrile; Among them, the alcohol is methanol or ethanol.

2. The purification method according to claim 1, wherein The acid or its salt in mobile phase B can be selected from any one or more of organic acids, inorganic acids, organic acid salts, and inorganic acid salts; Preferably, the acid or its salt can be selected from any one or more of formic acid, acetic acid, propionic acid, methanesulfonic acid, trifluoroacetic acid, phosphoric acid, sulfuric acid, hydrochloric acid, ammonium phosphate salt, ammonium acetate salt, and ammonium formate salt.

3. The purification method according to claim 1, characterized in that, The volume concentration of the aqueous solution of the acid or its salt in mobile phase B is 0.1 - 1.0%.

4. The purification method according to claim 1, characterized in that, The volume ratio of each component in mobile phase B is: aqueous solution of acid or its salt: alcohol: acetonitrile = (80 - 90):(5 - 10):(5 - 10); among them, the alcohol is methanol or ethanol.

5. The purification method according to claim 1, characterized in that The packing material of the preparation column is silica gel C18; Preferably, the packing material can be selected from any one of 10C18 - 120AD, 10C18 - 100AA, and 10C18 - 100AB; More preferably, the packing material is 10C18 - 120AD.

6. A method for purifying oritavancin diphosphate, characterized in that, It includes the following steps: Step 1: Dissolve the crude oritavancin copper complex in an acidic aqueous solution for decoordination, filter to obtain the filtrate of oritavancin after decoordination; Step 2: Subject the filtrate of oritavancin after decoordination to silica gel C18 column chromatography, elute with mobile phase B, and collect the eluate with a purity > 99%; mobile phase B is an aqueous solution of an acid or its salt - alcohol - acetonitrile; Step 3: Nanofiltrate and concentrate the eluate to obtain a concentrated solution; Step 4: After membrane - filtering the concentrated solution, obtain oritavancin diphosphate by salting with phosphoric acid.

7. The purification method according to claim 6, wherein The acidic aqueous solution in Step 1 can be selected from any one of acetic acid aqueous solution, formic acid aqueous solution, and phosphoric acid aqueous solution.

8. The purification method according to claim 6, characterized in that, For the nanofiltration concentration in Step 3, the conductivity of the concentrated filtrate is < 500 μs / cm, and the concentration of the concentrated solution is not less than 60 g / L.

9. The purification method according to claim 6, wherein Specifically, in Step 4, after passing the concentrated solution through a filter membrane, add an alcohol solution to the filtrate, stir and heat to 45 - 50 °C, then add an aqueous solution of ammonium dihydrogen phosphate, adjust the pH = 4 - 5 with phosphoric acid, stir and cool to 0 - 5 °C and stir for crystallization to obtain oritavancin diphosphate.

10. The purification method according to claim 9, characterized in that, The alcohol in the alcohol solution in Step 4 is selected from any one or more of methanol, ethanol, n - propanol, and isopropanol.

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