CN112679442A - Preparation method of oxaagolide sodium - Google Patents
Preparation method of oxaagolide sodium Download PDFInfo
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Abstract
The invention provides a preparation method of oxaagolide sodium. The invention improves the synthesis route of the sodium oxagolide (Elagolix sodium), uses concentrated hydrochloric acid to remove Boc protecting group and then carries out salt-forming precipitation along the trend, greatly simplifies the operation and improves the yield. When the 4-ester butyl fragment is introduced, water is used as a reaction solvent, inorganic base is used as an acid-binding agent, the reaction condition is mild and controllable, and the ammonia nitrogen wastewater is little. The final product is obtained by using an isopropanol crystallization mode, the operation is simple, and the product purity is high. The route is simple and convenient to operate, low in cost, green and environment-friendly, and suitable for large-scale production.
Description
Technical Field
The invention relates to a preparation method of oxaagolide sodium, belonging to the technical field of drug synthesis.
Background
The oral GnRH antagonist developed by Eribvie (Abbvie) and the partner Neurocrine Biosciences together is the falagolide sodium (Elagolix sodium), and finally reduces the gonadal hormone level in blood circulation by inhibiting pituitary gonadotropin releasing hormone receptors. 23 Ri American Food and Drug Administration (FDA) approves the sodium falagolide to be sold on the market in 2018, 7 months and under the trade name of
Agolide sodium is the first FDA approved drug for the treatment of endometriosis by oral administration for over a decade. In addition, clinical three-phase studies of the compounds for controlling severe menstrual bleeding associated with uterine fibroids are also in progress. Prediction ofThe sale amount of the sodium falagolide reaches 11.52 to 13.58 billion dollars in 2022 years, so the development of the bulk drug of the sodium falagolide has better market prospect.
From the literature research situation, the molecular structure of the falagolide sodium consists of the following four fragments: a parent-nucleus bisamide fragment (fragment A), a 2-fluoro-3-methoxyphenyl fragment (fragment B), an alpha-aminophenylethyl fragment (fragment C) and a 4-esterbutyl fragment (fragment D). Wherein, the segment B is generally introduced by Suzuki coupling or Negishi coupling, the segment C is generally introduced by alkylation of nitrogen atom, and the segment D can be introduced by alkylation of nitrogen atom or reductive amination of aldehyde group.
The more complete synthetic route of the sodium oxagolide mainly comprises the following steps:
route one, the original route, is referred to patents US7056927, WO2005007165 and document j.med.chem.2008,51,7478-:
the route is a relatively typical synthetic route of the sodium oxaagolide. The subsequent patents reported about the synthetic route of the product are mostly based on the original research route. In the route, a reagent used for removing Boc is trifluoroacetic acid or methanesulfonic acid, the price is high, and methanesulfonic acid is easy to generate mesylate-based toxic impurities. The de-Boc product is oily or foamy and has low purity. In the introduction of fragment D, the reaction solvent is typically acetonitrile or DMF and the acid-binding agent is typically an organic base such as diisopropylethylamine. The final product is obtained by adjusting the pH value with citric acid and performing ion exchange, and the method is very complicated to operate, high in cost and not suitable for industrial production.
Route two, see patent US2020/0024239a 1:
abbvie improves the synthesis route in 2019, and the Boc removal product is prepared into salicylate which is precipitated in a solid form, so that the yield and the purity are improved. However, the operation is complicated because the methanesulfonic acid is firstly neutralized and then the salicylic acid is added to form the salt. In addition, salicylic acid is easily oxidized into quinone-based toxic impurities, increasing quality control cost. The final product is still complex in acquisition mode, the methyl isobutyl ketone solution of the product is washed by brine for four times, and then n-heptane is added for crystal forcing to obtain the product, and the high-salinity wastewater is more.
Route three, see patents CN110437159A, WO2018/198086a 1:
the route mainly changed the protecting group Boc to Cbz, and others did not have obvious innovation.
Route four, see patent CN 108586359:
the method develops a new way, introduces the fragment C and the fragment D by using a lactam ring-opening method, saves the use of a protecting group, but the lactam raw material is not easy to obtain, and the lactam ring-opening efficiency is a problem.
In conclusion, the method has important practical significance in developing a synthesis route of the oxagoline sodium, which is simple and convenient to operate, low in cost, controllable in quality and environment-friendly.
Disclosure of Invention
The invention aims to solve the technical problems of complex operation, low intermediate purity, more potential base toxic impurities, large amount of three wastes and the like in the existing synthesis route of the oxagolides sodium, provides a synthesis route which is simple to operate, low in cost, green and environment-friendly, and is suitable for large-scale production.
The preparation method of the agomelatine sodium comprises the following steps.
1) Adding a compound (5- (2-fluoro-3-methoxyphenyl) -1- (2-fluoro-6- (trifluoromethyl) phenyl) -6-methylpyrimidine-2, 4(1H,3H) -diketone) shown in a formula 1, a compound ((R) -2- ((tert-butoxycarbonyl) amino) -2-phenethyl-4-methylbenzenesulfonate) shown in a formula 2 and a base into an organic solvent, and heating and stirring until the reaction is finished;
2) concentrating the reaction solution to dryness, adding an organic solvent immiscible with water, washing with dilute acid, and layering; adding concentrated hydrochloric acid into the organic phase, and heating and stirring until the reaction is finished;
3) slowly cooling, stirring for crystallization, filtering, leaching a filter cake, and obtaining a compound ((R) -3- (2-amino-2-phenethyl-5- (2-fluoro-3-methoxyphenyl) -1- (2-fluoro-6- (trifluoromethyl) phenyl) -6-methylpyrimidine-2, 4(1H,3H) -diketone hydrochloride) shown in the formula 4;
4) adding inorganic base, a compound shown as a formula 4 and ethyl 4-bromobutyrate into water in sequence, heating and stirring until the reaction is finished, adding an organic solvent immiscible with water, layering, and concentrating an organic phase to be dry;
5) adding an alcohol solvent, water and strong base, and heating and stirring until the reaction is finished;
6) adding salt into the reaction solution, preserving heat for layering, taking an organic phase, and cooling and crystallizing the organic phase to obtain a compound shown in a formula 7, namely the oxagolite sodium;
as a preferable scheme:
compound 1 of the invention, i.e.: 5- (2-fluoro-3-methoxyphenyl) -1- (2-fluoro-6- (trifluoromethyl) phenyl) -6-methylpyrimidine-2, 4(1H,3H) -dione, which can be prepared by the method described in U.S. Pat. No. 2,2020, 0024239A 1.
The base in the step 1) can be one or more of triethylamine, tetramethylguanidine, 1, 8-diazabicycloundecen-7-ene, potassium carbonate and sodium carbonate, and is preferably tetramethylguanidine; the organic solvent can be one or more of acetonitrile, acetone and DMF, preferably DMF; the reaction temperature is 40-80 ℃, and preferably 50-60 ℃; the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 to the base is 1: (1.5-3): (2 to 4), preferably 1: (2-2.5): (2.5-3.5).
The organic solvent immiscible with water in the step 2) can be selected from toluene, methyl tert-ether, ethyl acetate, dichloromethane and the like, and toluene is preferred; the dilute acid can be dilute hydrochloric acid or dilute sulfuric acid; the mass fraction of the concentrated hydrochloric acid is about 36%, and the dosage of the concentrated hydrochloric acid is 2-4 times, preferably 3.5 times that of the compound shown in the formula 1; the reaction temperature is 80-110 ℃, and preferably 100 ℃.
The leaching solvent in the step 3) and the water-immiscible organic solvent in the step 2) are the same solvent.
The inorganic base in the step 4) can be one or more of lithium carbonate, sodium carbonate, potassium carbonate, disodium hydrogen phosphate and dipotassium hydrogen phosphate, and preferably sodium carbonate; the reaction temperature is 50-100 ℃, and preferably 60-80 ℃; the organic solvent immiscible with water can be selected from toluene, methyl tert-ether, ethyl acetate, dichloromethane, methyl isobutyl ketone and the like, and toluene and methyl tert-ether are preferred; the molar ratio of the inorganic base to the compound shown in the formula 4 to ethyl 4-bromobutyrate is (3-6): 1: (1.5-3), preferably (4-5): 1: (1.7-2.5).
The alcohol solvent in the step 5) can be one or more of ethanol, isopropanol and n-butanol, preferably isopropanol; the strong base can be one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide, and sodium hydroxide is preferred; the reaction temperature is 30-70 ℃, and preferably 40 ℃; the mass ratio of the alcohol solvent to the water to the compound represented by the formula 4 is (4-6): (1-1.5): 1, preferably (5-6): (1.2-1.5): 1; the molar ratio of the strong base to the compound shown in the formula 4 is 1.5-4: 1, preferably 2 to 3.5: 1.
step 6), the heat preservation layering temperature is 50-80 ℃, and preferably 60-70 ℃; the temperature for cooling and crystallizing is 0-30 ℃, and preferably 20-25 ℃; the amount of the common salt added is 0.3 to 1 time, preferably 0.4 to 0.6 time of the amount of the compound represented by the formula 4.
Compared with the prior art, the invention can overcome the technical problems of complex operation, low intermediate purity, more potential base toxic impurities, large amount of three wastes and the like in the existing synthesis route of the sodium oxadiargyl,
in the method, concentrated hydrochloric acid is used for removing Boc to replace trifluoroacetic acid or methanesulfonic acid. After the Boc is removed, the product is precipitated as a salt which is a homeotropic hydrochloride, so that the operation is greatly simplified, the yield and the quality are improved, and the generation of basic toxic impurities is reduced.
According to the method, when the fragment D is introduced, water is used for replacing an organic solvent as a reaction solvent, inorganic base is used for replacing organic base as an acid-binding agent, the reaction condition is mild and controllable, and the ammonia nitrogen wastewater is less.
The final product is obtained by cooling and crystallizing isopropanol, and the method is simple to operate, less in high-salinity wastewater and high in yield.
The method has the advantages of simple overall operation, lower cost and green and environment-friendly synthetic route, and is suitable for large-scale production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions.
EXAMPLE 1 preparation of Compound 4
110.28 g of compound, 218.26 g of compound, 9.73g of tetramethylguanidine, and 7.6g of DMF were added to the flask, and the temperature was raised to 50 to 60 ℃ to confirm completion of the reaction. The solvent was evaporated to dryness, cooled to room temperature, and 80g of toluene was added, washed with 50mL of 21 mol/L dilute hydrochloric acid. Layering, adding 35g of concentrated hydrochloric acid into the organic phase, stirring vigorously, reacting at 100 ℃ until the reaction is finished, and slowly cooling to room temperature. Stirring and crystallizing for 1h, leaching a filter cake by using 10g of precooled toluene, and drying at 50 ℃ to obtain a compound 4 with the yield of 95% and the purity of 99.3%.
1H NMR(CDCl3)δ2.08(s，3H),3.90(s，3H),4.12(m，1H),4.28(m，1H),4.40(dd，1H),5.50(s，2H),6.75-6.85(m，1H),6.95-6.99(dd，1H),7.12(m，1H),7.21-7.28(m，2H),7.33(t，2H),7.34-7.45(m，3H),7.55(d，1H)；MS(ESI)m/z:[M+H]+＝546.18.
EXAMPLE 2 preparation of Compound 4
110.28 g of a compound, 218.26 g of a compound, 11.66g of potassium carbonate and 50g of acetone were added to the flask, and the temperature was raised to 50 to 60 ℃ to confirm completion of the reaction by spotting. The solvent was evaporated to dryness, cooled to room temperature, and 80g of toluene was added, washed with 50mL of 21 mol/L dilute hydrochloric acid. Layering, adding 35g of concentrated hydrochloric acid into the organic phase, stirring vigorously, reacting at 100 ℃ until the reaction is finished, and slowly cooling to room temperature. Stirring and crystallizing for 1h, leaching a filter cake by using 10g of precooled toluene, and drying at 50 ℃ to obtain the compound 4 with the yield of 90% and the purity of 98.1%.
EXAMPLE 3 preparation of Compound 4
110.28 g of compound, 218.26 g of compound, 9.73g of tetramethylguanidine and 50g of acetonitrile were added to a flask, and the temperature was raised to 50 to 60 ℃ to confirm completion of the reaction. The solvent was evaporated to dryness, cooled to room temperature, and 80g of toluene was added, washed with 50mL of 21 mol/L dilute hydrochloric acid. Layering, adding 35g of concentrated hydrochloric acid into the organic phase, stirring vigorously, reacting at 100 ℃ until the reaction is finished, and slowly cooling to room temperature. Stirring and crystallizing for 1h, leaching a filter cake by using 10g of precooled toluene, and drying at 50 ℃ to obtain the compound 4 with the yield of 92% and the purity of 99.1%.
EXAMPLE 4 preparation of Compound 7
10.6g of sodium carbonate, 70g of water, 411.6 g of compound and 9.8g of ethyl 4-bromobutyrate were added to the flask to conduct a reaction at 60 ℃ and completion of the reaction was confirmed on a dot plate.
The mixture was cooled to room temperature, and 70g of toluene was added thereto to separate layers. The organic layer was evaporated to dryness completely, 20g of isopropanol was added and evaporated, 64g of isopropanol, 14g of water and 2.5g of NaOH were added and reacted at 40 ℃ and the reaction was confirmed to be complete by spotting.
5g of salt is added into the reaction solution, the temperature is raised to 70 ℃, and the mixture is fully stirred and layered. The organic phase is cooled to 20 ℃, and white solid, namely the sodium oxagolide, is obtained by filtering, the yield is 86 percent, and the purity is 99.9 percent.
1H NMR(CD3OD)δ1.70(m，2H),2.10(s，3H),2.17(t，2H),2.52(t，2H),3.85(s，3H),4.25(m，3H),5.40(d，1H),5.45(d，1H),6.62-6.77(m，1H),7.12(m，2H),7.33(m，5H),7.41(m，1H),7.57(m，1H),7.62(d，1H)；MS(ESI)m/z:[M-Na]-＝630.20.
EXAMPLE 5 preparation of Compound 7
10.6g of sodium carbonate, 70g of water, 411.6 g of compound and 9.8g of ethyl 4-bromobutyrate were added to the flask to conduct a reaction at 60 ℃ and completion of the reaction was confirmed on a dot plate.
The mixture was cooled to room temperature, and 70g of toluene was added thereto to separate layers. The organic layer was evaporated to dryness completely, 20g of n-butanol was added and evaporated, 64g of n-butanol, 14g of water and 2.5g of NaOH were added and reacted at 40 ℃ and the reaction was confirmed to be completed by spotting.
5g of salt is added into the reaction solution, the temperature is raised to 70 ℃, and the mixture is fully stirred and layered. The organic phase is cooled to 20 ℃, and white solid, namely the sodium oxagolide, is obtained by filtering, the yield is 84 percent, and the purity is 99.7 percent.
EXAMPLE 6 preparation of Compound 7
10.6g of sodium carbonate, 70g of water, 411.6 g of compound and 9.8g of ethyl 4-bromobutyrate were added to the flask to conduct a reaction at 60 ℃ and completion of the reaction was confirmed on a dot plate.
The mixture was cooled to room temperature, and 70g of toluene was added thereto to separate layers. The organic layer was evaporated to dryness completely, 20g of n-butanol was added and evaporated, 64g of n-butanol, 14g of water and 2.5g of NaOH were added and reacted at 40 ℃ and the reaction was confirmed to be completed by spotting.
7g of common salt is added into the reaction solution, the temperature is raised to 70 ℃, and the mixture is fully stirred and layered. The organic phase is cooled to 20 ℃, and white solid, namely the sodium oxagolide, is obtained by filtering, the yield is 91 percent, and the purity is 98.1 percent.
Claims (10)
1. A preparation method of the sodium oxaagolide is characterized by comprising the following steps:
1) adding a compound shown in a formula 1, a compound shown in a formula 2 and alkali into an organic solvent, and heating and stirring until the reaction is finished;
2) concentrating the reaction solution to dryness, adding an organic solvent immiscible with water, washing with dilute acid, and layering; adding concentrated hydrochloric acid into the organic phase, and heating and stirring until the reaction is finished;
3) cooling, crystallizing, filtering, leaching a filter cake to obtain a compound shown in a formula 4;
4) adding inorganic base, a compound shown as a formula 4 and ethyl 4-bromobutyrate into water in sequence, heating and stirring until the reaction is finished, adding an organic solvent immiscible with water, layering, and concentrating an organic phase to be dry;
5) adding an alcohol solvent, water and strong base, and heating and stirring until the reaction is finished;
6) adding salt into the reaction solution, preserving heat for layering, taking an organic phase, and cooling and crystallizing the organic phase to obtain a compound shown in a formula 7, namely the oxagolite sodium;
the synthetic route is as follows:
2. the method according to claim 1, wherein the base in step 1) is one or more selected from triethylamine, tetramethylguanidine, 1, 8-diazabicycloundecen-7-ene, potassium carbonate and sodium carbonate; the organic solvent in the step 1) is one or more of acetonitrile, acetone or DMF; the reaction temperature in the step 1) is 40-80 ℃.
3. The method of claim 1, wherein the water-immiscible organic solvent in step 2) is one or more selected from toluene, methyl tert-ether, ethyl acetate and dichloromethane; step 2) selecting dilute hydrochloric acid or dilute sulfuric acid as the dilute acid; the dosage of the concentrated hydrochloric acid in the step 2) is 2-4 times of that of the compound shown in the formula 1; and 2) controlling the reaction temperature to be 80-110 ℃.
4. The method of claim 1, wherein the inorganic base in step 4) is one or more of lithium carbonate, sodium carbonate, potassium carbonate, disodium hydrogen phosphate or dipotassium hydrogen phosphate; step 4), the reaction temperature is 50-100 ℃; and 4) selecting one or more of toluene, methyl tert-ether, ethyl acetate, dichloromethane or methyl isobutyl ketone as the water-immiscible organic solvent in the step 4).
5. The method according to claim 1, wherein the alcohol solvent in step 5) is one or more selected from ethanol, isopropanol and n-butanol; step 5), selecting one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide as the strong base; and step 5), the reaction temperature is 30-70 ℃.
6. The method according to claim 1, wherein the temperature of the heat preservation and delamination in the step 6) is 50-80 ℃; cooling and crystallizing at the temperature of 0-30 ℃; the addition amount of the common salt is 0.3 to 1 time of the amount of the compound shown in the formula 4.
7. The method of claim 1, wherein the rinsing solvent of step 3) and the water-immiscible organic solvent of step 2) are the same solvent.
8. The method according to claim 1, wherein the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 in step 1) to the base is 1: (1.5-3): (2-4).
9. The method according to claim 1, wherein the molar ratio of the inorganic base in the step 4), the compound represented by the formula 4 and the ethyl 4-bromobutyrate is (3-6): 1: (1.5 to 3).
10. The method according to claim 1, wherein the mass ratio of the alcohol solvent, the water and the compound represented by the formula 4 in the step 5) is (4-6): (1-1.5): 1, the molar ratio of the strong base to the compound shown in the formula 4 is 1.5-4: 1.
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