A process for the preparation of a key intermediate of peginterferon alfa-2b

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a key intermediate of plerixafor. The preparation method of the plerixafor intermediate 1,4,8,11-tetraazacyclotetradecane provided by the application uses N,N'-di(2-hydroxyethyl)-1,3-propanediamine as a starting material, hydroxyl is first activated by sulfuric acid, then ring formation is carried out under alkaline conditions, and then 1,3-propanediamine is used for ring opening, ring expansion and ring closure to obtain 1,4,8,11-tetraazacyclotetradecane. The process effectively avoids the introduction and removal of Ts-protecting groups by changing the reaction conditions, is simple to operate, shortens the reaction steps, and reduces the production working hours. The whole synthesis method is simple to operate and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a key intermediate of plerixafor. BACKGROUND

[0002] Plerixafor, also known as English name plerixafor, is developed by Genezyme Corporation in the United States, and belongs to a small molecule monoclonal antibody targeted drug. In December 2008, plerixafor was first approved by FDA as a rare drug for marketing, and clinical studies show that plerixafor can greatly increase the number of white blood cells of patients and promote the flow of hematopoietic stem cells from bone marrow to blood, and has a synergistic effect with granulocyte colony-stimulating factor (G-CSF); it has been used for clinical treatment of stem cell transplantation for patients with multiple myeloma and non-Hodgkin's lymphoma, and its chemical structural formula is as follows:

[0003]

[0004] There are many disclosed methods for preparing plerixafor, most of which use 1,4,8,11-tetraazacyclotetradecane as a raw material, and then perform bridging with N1, N4, N8 tri-protection and 1,4-bis(halogenated methyl)benzene, and then perform deprotection to obtain the finished product, and the synthesis route is as follows:

[0005]

[0006] Therefore, 1,4,8,11-tetraazacyclotetradecane (cyclam) is used as a key intermediate for preparing plerixafor in various synthesis strategies, and cyclam can directly affect the production of the drug, and the current preparation methods of cyclam mainly include the following:

[0007] In patent US5811544A, 1,3-diaminopropane is used as a raw material, first reacts with 2 equiv of chloroacetyl chloride to generate an amide, then reacts with 1 equiv of 1,3-diaminopropane to cyclize, and then is reduced by 65% red aluminum toluene solution to obtain cyclam. Although the reaction steps in the literature are only three steps, the cyclization time of 1,3-diaminopropane and the amide generated in the first step at high temperature is relatively long, which needs 24 h, and the cyclization product is not pure, and generates more impurities as shown below, which needs column chromatography purification, thereby limiting industrial application. The synthesis route is as follows:

[0008]

[0009] WO9705123A1 uses di-(3-aminopropyl)ethylenediamine as raw material, first undergoes sulfonylation reaction with p-toluenesulfonyl chloride, then undergoes ring closure with 1,2-di(p-toluenesulfonyloxy)ethane, then removes the protection with 48% hydrobromic acid and glacial acetic acid, and finally alkalizes to obtain cyclam. The method has the advantages that the yield of the first step of substitution and the second step of ring closure is high, and the ring closure time of the second step is greatly shortened, but the 48% hydrobromic acid / glacial acetic acid system is used for Ts removal, and the yield is only 72.0%, which affects the overall yield. The synthetic route is as follows:

[0010]

[0011] In the document Tetrahedron Letters, 1992, 33(38): 5505-5508, di-(3-aminopropyl)ethylenediamine is used as raw material, first undergoes sulfonylation reaction with trifluoromethanesulfonic anhydride, then undergoes ring closure with 1,2-dibromoethane in the presence of potassium carbonate, and finally removes the protection group with sodium / liquid ammonia to obtain cyclam. The method has the following disadvantages: the yield of the first step using trifluoromethanesulfonic anhydride as the sulfonylation reagent is not high; the cyclization temperature of the second step is 110°C, which is relatively high and easy to cause side reactions; the third step of removing the trifluoromethanesulfonyl group uses sodium / liquid ammonia, and needs to be added dropwise at -33°C, which is complicated and not suitable for industrialization; the total yield of the second step and the third step is only 57.2%. The synthetic route is as follows:

[0012]

[0013] In the document Bulletin of the Academy of Sciences of the USSR Division of Chemical Science, 36(2): 372-376, ethylenediamine is used as raw material, undergoes substitution reaction with 1,3-dibromopropane to generate di(2-aminoethyl)propanediamine, then undergoes sulfonylation with p-toluenesulfonyl chloride in the presence of sodium ethoxide, then undergoes ring closure with 1,3-di(p-toluenesulfonyloxy)propane, and finally removes the protection with concentrated sulfuric acid to obtain cyclam by alkalization.

[0014] However, the method uses ethylenediamine as raw material, undergoes substitution reaction with 1,3-dibromopropane to generate di(2-aminoethyl)propanediamine, which is easy to generate a cyclopentane byproduct, and the yield of this step is not high, only 42.0%; the yield of the sulfonylation with p-toluenesulfonyl chloride in the presence of sodium ethoxide is only 52.1%; the ring closure yield with 1,3-di(p-toluenesulfonyloxy)propane is 65.3%; and the yield of the protection removal with concentrated sulfuric acid is 81.0%. As can be seen from the above, the overall yield of the method is not high. The synthetic route is as follows:

[0015]

[0016] Arkivoc, 2006(4):212-233 uses 1,3-propanediamine as raw material, and ethanedioic acid diethyl ester is cyclized into amide, and then reduced by borane, and finally obtained cyclam by acidification and then alkalization. In the process of cyclizing 1,3-propanediamine and ethanedioic acid diethyl ester into amide, ultrasonic is used in the process of reduction by borane, and the total yield is only 19.0%, which is not suitable for industrial expansion. The synthetic route is as follows:

[0017]

[0018] In view of the many deficiencies in the preparation of cyclam at present, therefore, it is still a problem to be solved at present to research and find a preparation process of cyclam suitable for industrial production, which is simple in operation, mild in reaction condition, safe and simple in operation process, high in product yield and purity. SUMMARY

[0019] In view of the many problems in the preparation of the key intermediate 1,4,8,11-tetraazacyclotetradecane of plerixafor at present, the present application provides a new preparation method of 1,4,8,11-tetraazacyclotetradecane. The method has mild reaction condition, safe and simple operation process, and the obtained target product has high purity and yield.

[0020] The specific technical scheme of the present application is as follows:

[0021] A preparation method of the key intermediate 1,4,8,11-tetraazacyclotetradecane of plerixafor, characterized by comprising the following steps:

[0022] Step 1: drop concentrated sulfuric acid into compound SM-1, control temperature T A After the reaction is completed, add toluene to reflux and remove water until no water is left, then reduce the reaction liquid to room temperature, add ethanol to pulp, and then vacuum dry the obtained solid to obtain compound I-1;

[0023] Step 2: add compound I-1 into an aqueous solution of base, control temperature and boil slightly, after the reaction is completed, add toluene to the reaction liquid, extract at 90-95 DEG C, combine the organic phases, wash with saturated brine, and then vacuum concentrate the organic phase to dryness to obtain compound I-2.

[0024] Step 3: add compound I-2 and 1,3-propanediamine into an alcohol-water mixed solvent, add a catalyst, control temperature T C After the reaction is completed, add a base to adjust the pH to weak alkaline, add toluene to the reaction liquid, extract at 70-75 DEG C, combine the organic phases, wash with saturated sodium carbonate solution, wash with saturated brine, and then vacuum concentrate the organic phase to dryness to obtain the target product I.

[0025] The synthetic route is as follows:

[0026]

[0027] Preferably, the molar ratio of the compound SM-1 to concentrated sulfuric acid in step 1 is 1:2.2-2.8, preferably 1:2.4.

[0028] Preferably, the reaction temperature T in step 1 is 40-80°C, preferably 45-50°C. A

[0029] Preferably, the base in step 2 is selected from one of sodium hydroxide, potassium hydroxide, preferably sodium hydroxide.

[0030] Preferably, the molar ratio of the compound I-1 to the base in step 2 is 1:6-14, preferably 1:9.

[0031] Preferably, the reaction solvent A in step 3 is selected from one of tert-butanol-water, isopropanol-water, ethanol-water, or a combination thereof, preferably isopropanol-water.

[0032] Preferably, the catalyst in step 3 is selected from one of formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid.

[0033] Preferably, the molar ratio of the compound I-2, 1,3-propanediamine, catalyst in step 3 is 1:1.3-2.0:0.8-1.2, preferably 1:1.5:1.0.

[0034] Preferably, the base in step 3 is selected from one or a combination of sodium hydroxide, potassium hydroxide, sodium carbonate solid or its aqueous solution.

[0035] Preferably, the reaction temperature T in step 3 is 70-80°C, preferably 75-80°C. C

[0036] Advantages of the present application:

[0037] 1. The present application provides a simple and efficient method for preparing the key intermediate of plerixafor, 1,4,8,11-tetraazacyclotetradecane. N,N'-di(2-hydroxyethyl)-1,3-propanediamine is used as the starting material, the hydroxyl group is first activated by sulfuric acid, then ring formation is carried out under basic conditions, and then the target product is prepared by ring opening and ring expansion of 1,3-propanediamine.

[0038] 2. The process effectively avoids the introduction and removal of Ts-protecting groups by changing the reaction conditions, is simple to operate, shortens the reaction steps, and reduces the production time.

[0039] 3. The target product prepared by the process has high yield and purity. DETAILED DESCRIPTION​​

[0040] The present application is further illustrated by the following examples, it should be understood that the examples of the present application are only used to illustrate the present application, but not limit the present application, so, the simple improvement of the present application under the method of the present application is within the scope of the present application.

[0041] The purity of 1,4,8,11-tetraazacyclotetradecane is determined by HPLC, and the chromatographic conditions are as follows:

[0042] Chromatographic column: Kromasil 100-5-C 18 4.6×250mm or a chromatographic column with equivalent performance and ghost trapping column (recommended Welch Ghost-Buster Column 4.6×50mm);

[0043] Chromatographic column: Supelco LC-ABE C 18 column (4.6mm×150mm, 5μm) or a chromatographic column with equivalent performance;

[0044] Mobile phase A: 0.1% phosphoric acid aqueous solution; mobile phase B: acetonitrile;

[0045] Acetonitrile: 25mmol / L ammonium dihydrogen phosphate (pH=5.0 adjusted by sodium hydroxide) (25:75);

[0046] Gradient elution:

[0047]

[0048] Column temperature: 30℃;

[0049] Detection wavelength: 200nm;

[0050] Flow rate: 1.2ml / min;

[0051] Injection volume: 10μl.

[0052] The structure confirmation data of the compound I-1 obtained by the present application are as follows:

[0053]

[0054] ESI-HRMS (m / z): 321.0378 [M-H] - ; 1H NMR (600 MHz, D2O) δ: 3.85~2.88 (m, 4H), 2.84~2.87 (m, 2H), 2.80~2.83 (m, 2H), 2.67 (t, J = 6.2 Hz, 2H), 2.60 (t, J = 6.2 Hz, 2H), 1.58~1.62 (m, 2H); 13 C NMR (125 MHz, D2O) δ: 69.35, 47.76, 47.18, 30.27.

[0055] The structural confirmation data of the compound I-2 obtained by the application are as follows:

[0056]

[0057] ESI-HRMS (m / z): 127.1228 [M+H] + ; 1 H NMR (600 MHz, CDCl3) δ: 2.22~2.30 (m, 4H), 1.67~1.72 (m, 4H), 1.03~1.12 (m, 6H); 13 C NMR (125 MHz, CDCl3) δ: 60.64, 30.73, 26.06.

[0058] The structural confirmation data of the compound I obtained by the application are as follows:

[0059]

[0060] ESI-HRMS (m / z): 201.2035 [M+H] + ; 1 H NMR (600 MHz, CDCl3) δ: 2.77 (t, J = 6.4 Hz, 8H), 2.71 (s, 8H), 2.19 (s, 4H), 1.72~1.74 (m, 4H); 13 C NMR (125 MHz, CDCl3) δ: 50.05, 47.63, 30.14.

[0061] In each of the following examples, various processes and methods not described in detail are conventional methods known in the art.

[0062] Synthesis of I-1:

[0063] Example 1

[0064] Concentrated sulfuric acid (98%, 48.0 g, 0.48 mol) was added dropwise to compound SM-1 (32.45 g, 0.2 mol) at room temperature, and the reaction was continued at 45-50 °C for 1 h. Toluene was added, and the reaction was refluxed at 110 °C until water was removed. The reaction was cooled to room temperature, and ethanol was added to the slurry. The obtained solid was dried under reduced pressure to give compound I-1 in a yield of 98.3%.

[0065] Example 2

[0066] Concentrated sulfuric acid (98%, 44.0 g, 0.44 mol) was added dropwise to compound SM-1 (32.45 g, 0.2 mol) at room temperature, and the reaction was continued at 65-70 °C for 1 h. Toluene was added, and the reaction was refluxed at 110 °C until water was removed. The reaction was cooled to room temperature, and ethanol was added to the slurry. The obtained solid was dried under reduced pressure to give compound I-1 in a yield of 92.8%.

[0067] Example 3

[0068] Concentrated sulfuric acid (98%, 39.9 g, 0.4 mol) was added dropwise to compound SM-1 (32.45 g, 0.2 mol) at room temperature, and the reaction was continued at 75-80 °C for 1 h. Toluene was added, and the reaction was refluxed at 110 °C until water was removed. The reaction was cooled to room temperature, and ethanol was added to the slurry. The obtained solid was dried under reduced pressure to give compound I-1 in a yield of 86.0%.

[0069] Example 4

[0070] Concentrated sulfuric acid (98%, 56.0 g, 0.56 mol) was added dropwise to compound SM-1 (32.45 g, 0.2 mol) at room temperature, and the reaction was continued at 40-45 °C for 1 h. Toluene was added, and the reaction was refluxed at 110 °C until water was removed. The reaction was cooled to room temperature, and ethanol was added to the slurry. The obtained solid was dried under reduced pressure to give compound I-1 in a yield of 94.1%.

[0071] Example 5

[0072] Concentrated sulfuric acid (98%, 59.8 g, 0.6 mol) was added dropwise to compound SM-1 (32.45 g, 0.2 mol) at room temperature, and the reaction was continued at 40-45 °C for 1 h. Toluene was added, and the reaction was refluxed at 110 °C until water was removed. The reaction was cooled to room temperature, and ethanol was added to the slurry. The obtained solid was dried under reduced pressure to give compound I-1 in a yield of 87.5%.

[0073] Synthesis of compound I-2

[0074] Example 6

[0075] Compound I-1 (32.23 g, 0.10 mol) was added to a solution of sodium hydroxide (24.0 g, 0.6 mol) in water (60 ml) and the reaction was carried out under temperature control and boiling. After the reaction was completed, toluene (30 ml x 4) was added to the reaction solution, and extraction was carried out at 90-95°C. The organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to dryness to give compound I-2 in a yield of 92.4%.

[0076] Example 7

[0077] Compound I-1 (32.23 g, 0.10 mol) was added to a solution of sodium hydroxide (24.0 g, 0.6 mol) in water (60 ml) and the reaction was carried out under temperature control and boiling. After the reaction was completed, toluene (30 ml x 4) was added to the reaction solution, and extraction was carried out at 90-95°C. The organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to dryness to give compound I-2 in a yield of 92.4%.

[0078] Example 8

[0079] Compound I-1 (32.23 g, 0.10 mol) was added to a solution of potassium hydroxide (30.86 g, 0.55 mol) in water (80 ml) and the reaction was carried out under temperature control and boiling. After the reaction was completed, toluene (30 ml x 4) was added to the reaction solution, and extraction was carried out at 90-95°C. The organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to dryness to give compound I-2 in a yield of 85.3%.

[0080] Example 9

[0081] Compound I-1 (32.23 g, 0.10 mol) was added to a solution of sodium hydroxide (56.0 g, 1.4 mol) in water (140 ml) and the reaction was carried out under temperature control and boiling. After the reaction was completed, toluene (30 ml x 4) was added to the reaction solution, and extraction was carried out at 90-95°C. The organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to dryness to give compound I-2 in a yield of 93.8%.

[0082] Example 10

[0083] Compound I-1 (32.23 g, 0.10 mol) was added to a solution of sodium hydroxide (60.0 g, 1.5 mol) in water (150 ml) and the reaction was carried out under temperature control and boiling. After the reaction was completed, toluene (30 ml x 4) was added to the reaction solution, and extraction was carried out at 90-95°C. The organic phases were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to dryness to give compound I-2 in a yield of 88.5%.

[0084] Synthesis of I

[0085] Synthesis of I

[0086] Example 11

[0087] Compound I-2 (6.31 g, 0.05 mol), 1,3-propanediamine (5.56 g, 0.075 mol) were added into a mixed solvent of isopropyl alcohol-water (V:V=8:1, 60 ml), anhydrous formic acid (2.30 g, 0.05 mol) was added, and the reaction was carried out at a temperature of 75-80°C. After the reaction was completed, sodium hydroxide was added to adjust the pH to alkaline, toluene (20 ml x 4) was added to the reaction solution, and extraction was carried out at 70-75°C. The organic phases were combined, washed with saturated sodium carbonate solution (20 ml), washed with saturated brine (20 ml), and concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 98.6% and an HPLC purity of 99.95%.

[0088] Example 12

[0089] Compound I-2 (6.31 g, 0.05 mol), 1,3-propanediamine (4.82 g, 0.065 mol) were added into a mixed solvent of isopropyl alcohol-water (V:V=8:1, 60 ml), trifluoroacetic acid (4.56 g, 0.04 mol) was added, and the reaction was carried out at a temperature of 75-80°C. After the reaction was completed, potassium hydroxide was added to adjust the pH to alkaline, toluene (20 ml x 4) was added to the reaction solution, and extraction was carried out at 70-75°C. The organic phases were combined, washed with saturated sodium carbonate solution (20 ml), washed with saturated brine (20 ml), and concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 92.8% and an HPLC purity of 99.62%.

[0090] Example 13

[0091] Compound I-2 (6.31 g, 0.05 mol), 1,3-propanediamine (3.71 g, 0.05 mol) were added into a mixed solvent of tert-butyl alcohol-water (V:V=7:1, 60 ml), anhydrous formic acid (1.38 g, 0.03 mol) was added, and the reaction was carried out at a temperature of 75-80°C. After the reaction was completed, sodium carbonate was added to adjust the pH to alkaline, toluene (20 ml x 4) was added to the reaction solution, and extraction was carried out at 70-75°C. The organic phases were combined, washed with saturated sodium carbonate solution (20 ml), washed with saturated brine (20 ml), and concentrated to dryness under reduced pressure to obtain the target product, with a yield of 84.2% and an HPLC purity of 98.88%.

[0092] Example 14

[0093] Compound I-2 (6.31 g, 0.05 mol), 1,3-propanediamine (7.41 g, 0.1 mol) were added into a mixed solvent of ethanol-water (V:V = 9:1, 60 ml), and acetic acid (3.60 g, 0.06 mol) was added to control the temperature at 70-75 °C for reaction. After the reaction was detected to be completed, sodium hydroxide was added to adjust the pH to alkaline. Toluene (20 ml x 4) was added to the reaction liquid for extraction at 70-75 °C. The organic phases were combined and washed with saturated sodium carbonate solution (20 ml) and saturated brine (20 ml). The organic phase was concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 93.8% and an HPLC purity of 99.42%.

[0094] Example 15

[0095] Compound I-2 (6.31 g, 0.05 mol), 1,3-propanediamine (7.78 g, 0.105 mol) were added into a mixed solvent of isopropyl alcohol-water (V:V = 8:1, 60 ml), and benzenesulfonic acid (11.07 g, 0.07 mol) was added to control the temperature at 70-75 °C for reaction. After the reaction was detected to be completed, sodium hydroxide was added to adjust the pH to alkaline. Toluene (20 ml x 4) was added to the reaction liquid for extraction at 70-75 °C. The organic phases were combined and washed with saturated sodium carbonate solution (20 ml) and saturated brine (20 ml). The organic phase was concentrated to dryness under reduced pressure to obtain the target product I, with a yield of 86.3% and an HPLC purity of 97.23%.

Claims

1. A process for the preparation of a key intermediate of pegaspargase, characterized in that, The preparation method comprises the following steps: Step 1: Concentrated sulfuric acid was added dropwise to compound SM-1, temperature T A After the reaction was completed, toluene was added to reflux and water was removed by distillation until no water was present. The reaction solution was cooled to room temperature, ethanol was added to pulp, and the resulting solid was dried under reduced pressure and vacuum to obtain compound I-1. Step 2: Compound I-1 is added into an aqueous solution of a base, and the reaction is carried out under temperature control and micro boiling; after the reaction is completed, toluene is added into the reaction solution, extraction is carried out at 90-95 DEG C, the organic phases are combined, and the combined organic phases are washed with saturated brine; after the organic phases are concentrated to dryness under reduced pressure, compound I-2 is obtained; Step 3: Compound I-2, 1,3-propanediamine is added into an alcohol-water mixed solvent, a catalyst is added, and the temperature is controlled at T C After the reaction is detected to be completed, a base is added to adjust the pH to weak alkaline, toluene is added into the reaction solution, extraction is performed at 70-75°C, the organic phases are combined, saturated sodium carbonate solution is used for washing, saturated brine is used for washing, and the organic phase is concentrated to dryness under reduced pressure to obtain the target product I. The catalyst in step 3 is selected from one of formic acid, acetic acid, trifluoroacetic acid and benzenesulfonic acid; The synthetic route is as follows: 。 2. The production method according to claim 1, characterized by, The molar ratio of the compound SM-1 to concentrated sulfuric acid in step 1 is 1:2.2-2.

8.

3. The method of claim 1, wherein, The reaction temperature T described in Step 1 A is 40 to 80°C.

4. The method of claim 1, wherein, The base in step 2 is selected from one of sodium hydroxide and potassium hydroxide.

5. The preparation method according to claim 1, characterized in that, The molar ratio of the compound I-1 to the base in step 2 is 1:6-14.

6. The method of claim 1, wherein, The alcohol-water mixed solvent in step 3 is selected from one of t-butyl alcohol-water, isopropyl alcohol-water and ethanol-water or a combination thereof.

7. The preparation method according to claim 1, characterized in that, The molar ratio of the compound I-2, 1,3-propanediamine and the catalyst in step 3 is 1:1.3-2.0:0.8-1.

2.

8. The method of claim 1, wherein, The base in step 3 is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate solid or an aqueous solution thereof or a combination thereof.

9. The method of claim 1, wherein, The reaction temperature T described in Step 3 is 70 to 80°C. C is 70 to 80°C.

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