CN115626913A - Method for preparing key intermediate of remimazolam - Google Patents
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Abstract
The invention discloses a preparation method of a remazolam key intermediate (3S) -7-bromo-2, 3-dihydro-2-oxo-5- (2-pyridyl) -1H-1, 4-benzodiazepine-3-methyl propionate, and belongs to the technical field of medical intermediates. The method comprises the following steps of taking 2- (2-amino-5-bromo-benzoyl) pyridine A and N-Tr-glutamic acid-5-methyl ester as raw materials, carrying out condensation reaction under the action of a boron-containing reagent to obtain a compound B, carrying out deprotection to obtain a compound C, and finally carrying out ring closure under alkaline low-temperature conditions to obtain a compound D. The method has good process reproducibility, simple and stable operation, easy separation of products in each step, high yield, environmental protection and suitability for industrial scale production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a key intermediate of a labor pain anesthetic remimazolam.
Background
Remazolam (Remimazolam) is a ultrashort-acting intravenous benzodiazepine sedative/anesthetic acting on GABA- α receptors. In human body, remimazolam is rapidly metabolized into inactive metabolites by tissue esterase, is not metabolized by cytochrome dependent liver pathways, is an ultrashort-acting benzodiazepine drug, is used as a vein general anesthetic drug, and has the characteristics of quick response, short duration, quick awakening and good tolerance. The remazolam is used for anesthesia induction, anesthesia maintenance and daytime operation anesthesia, and has certain advantages compared with other products when being applied to patients with cardiovascular diseases, respiratory diseases, liver diseases and the elderly.
Remazolam besylate is officially approved to be marketed in 7 months in 2020, and is used for the fields of painless diagnosis and treatment sedation, general anesthesia, ICU sedation, local anesthesia tranquilization and the like. The remazolam besylate is a novel ultrashort-acting sedative anesthetic, and compared with other similar products, the remazolam besylate has the advantages of faster effect, rapid metabolism and low metabolite activity, and can reduce the interaction among the medicines. The presence of this drug may remodel the pattern of anesthetic administration.
WO0069836A1 and WO2013029431A1 disclose a method for preparing benzodiazepine derivatives and their tosilates, the specific method is as follows: according to the method, reactants used in the preparation of the compound 3 need to undergo coupling reaction under the action of a coupling agent, ring closure reaction is carried out under alkaline conditions, an acid deprotection group Fmoc needs to be added, the total yield is only 48.2%, and the yield is low. The reaction equation is as follows:
WO2011032692A1 discloses a preparation method of another benzodiazepine derivative, which comprises the following steps:
in the method, when a compound 4 is prepared, an initial reactant is N-Boc-Glu (OMe) -OH, the reaction is carried out under the action of a coupling agent DCC to obtain a compound 2, hydrochloric acid is added to remove Boc protecting group to obtain a compound 3, and sodium bicarbonate is added to carry out cyclization reaction to obtain a compound 4. The total yield of the three steps is 67 percent, and the chemical purity of the product is 98.35 percent. Compound 4 is a viscous oil, dissolved by heating in isopropanol, crystallized by cooling, and filtered to give yellow crystals. The obtained compounds 2 and 3 are crude products and are directly put into the next step, and a plurality of impurities are accumulated to the compound 4, so that the purity of the compound 4 is not high, and the product quality is influenced. The chemical purity of the remazolen obtained from the intermediate obtained by the process is 93.91%, and the product purity is lower.
WO2019/72944 discloses a preparation method when the protecting group is Cbz, the product purity in the literature is 99%, but no manual purity data, this experiment was repeated in inventive example 1, only 96.5% ee. However, due to the limited subsequent improvement means of the chiral purity of the product, for example, when recrystallization is adopted for improvement, the yield loss is large, and the yield can reach more than 99.8 percent by repeated recrystallization.
The remazolam is used as a medical product, has high requirement on the purity of the medicine, and the purity of a key intermediate is also important. Therefore, it is necessary to optimize the process and develop a method for preparing the high-purity remazolen intermediate.
Disclosure of Invention
The invention provides an improved preparation method of a key intermediate D of rimazolen, which comprises the steps of taking 2- (2-amino-5-bromo-benzoyl) pyridine A and N-Tr-glutamic acid-5-methyl ester as raw materials, carrying out condensation reaction under the action of a boron-containing reagent to obtain a compound B, carrying out deprotection to obtain a compound C, and finally carrying out ring closure under the alkaline low-temperature condition to obtain the compound D. The method has good process reproducibility, simple and stable operation, easy separation of products in each step, high yield, environmental protection and suitability for industrial scale production.
The invention provides a preparation method of a key intermediate of rimazolam, which comprises the following steps: condensing 2- (2-amino-5-bromo-benzoyl) pyridine A with N-Tr-glutamic acid-5-methyl ester to obtain an intermediate B; then carrying out deprotection on the intermediate B to obtain an intermediate C; and carrying out ring closure reaction on the intermediate C to obtain a compound D. The synthetic route is as follows:
the technical method comprises the following steps:
the first step is as follows: synthesis of intermediate B
Condensing 2- (2-amino-5-bromo-benzoyl) pyridine A and N-Tr-glutamic acid-5-methyl ester E in an organic solvent in the presence of a catalyst to obtain an intermediate B;
further, the condensation reagent is selected from the group consisting of tris (trifluoroethanol) borate, 3, 5-dinitrophenylboronic acid and (C) 6 F 5 ) 3 B。
Further, the organic solvent is selected from one or more of tetrahydrofuran, dioxane, toluene, cyclohexane, n-hexane and sulfolane.
Further, the molar ratio of 2- (2-amino-5-bromo-benzoyl) pyridine a to N-Tr-glutamic acid-5-methyl ester E is 1:1-1.2.
The second step is that: synthesis of Compound D
Removing Tr protection from the intermediate B in an organic solvent under an acidic condition to obtain an intermediate C, and then closing the ring under an alkaline low-temperature condition to obtain a product D.
Further, the organic solvent is selected from one or more of tetrahydrofuran, dioxane, DMSO, DMF, 2-methyl tetrahydrofuran and sulfolane.
Further, the acid is selected from trifluoroacetic acid, hydrochloric acid, hydrogen chloride, and the like.
Further, the base is selected from organic bases such as DBU, morpholine, N-methylmorpholine, pyridine, triethylamine and the like. Among these, N-methylmorpholine and morpholine give the best selectivity for the reaction, and the reaction time can usually be completed within 2 hours.
Further, the low temperature condition is carried out at-10 ℃ to 0 ℃.
When common inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like are used, for example, when an experiment is repeated with reference to WO2011032692A1, the reaction enantioselectivity is reduced along with the reaction, the final enantioselectivity reaches 97-99%, and the reaction temperature cannot be adjusted to reach more than 99.5%. The reaction temperature is reduced to be below 0 ℃, the reaction speed is obviously slowed, more than 8 percent of raw materials are remained after 48 hours, and when the alkali equivalent is increased, the corresponding selectivity is obviously reduced.
The invention has the beneficial effects that
During the condensation reaction, tr is adopted to protect methyl glutamate and boron reagent for dehydration, compared with the traditional DCC condensation, the byproduct is easy to remove, and the enantioselectivity is not changed in the reflux dehydration process;
and secondly, deprotection and ring closing are carried out under the acidic condition of deprotection, ring closing is carried out under the organic base/low temperature condition (morpholine or N-methylmorpholine is adopted for reaction at 0-10 ℃), ring closing is carried out while dissociating the deprotected intermediate, and the phenomenon of racemization of a chiral center does not occur.
Drawings
FIG. 1 is a first-pass, controlled chiral HPLC spectrum of compound D of example 4;
FIG. 2 is a second-time, controlled chiral HPLC spectrum of Compound D of example 4;
FIG. 3 is a chiral HPLC chromatogram of example 4 after purification of Compound D;
Detailed Description
The invention will be further illustrated with reference to the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Example 1
The first step is as follows:
2- (2-amino-5-bromo-benzoyl) pyridine (38.6 g, 139mmol) and N-Cbz glutamic acid-5-methyl ester (45.2g, 153mmol) were added to dichloromethane (200 mL) at 15 ℃ and the solution was cooled to-10 ℃. A solution of N, N' -dicyclohexylcarbodiimide (32.2 g, 156mmol) in methylene chloride (65 mL) was slowly added to the above solution at-10 ℃ to stir the reaction at-10 ℃ for 48 hours, and the reaction mixture was filtered by warming to 15 ℃. The filtrate was distilled under reduced pressure at a temperature lower than 25 ℃ and then 250mL of methyl t-butyl ether was added, the solution was heated to 50 ℃ and then slowly cooled to 25 ℃, filtered and dried at 50 ℃ to obtain a pale yellow solid (72.3 g, yield: 93.6%).
The second step:
intermediate (35g, 63mmol) was added to glacial acetic acid (70 mL), a 33% hydrogen bromide/glacial acetic acid solution (45.7mL, 253mmol) was slowly added to the reaction at 10-12 deg.C, the temperature was raised to 20 deg.C, and the mixture was stirred at 15-20 deg.C for 2 hours. Water (120 mL) and dichloromethane (50 mL) were added, the aqueous phase was separated, the temperature was controlled at 25 ℃ and pH =3.8-4 was adjusted with sodium bicarbonate, extracted with dichloromethane, the organic phase was distilled under reduced pressure, 50mL isopropanol was added and heated to 82 ℃, 50mL n-heptane was added, slowly cooled to 20 ℃, filtered and dried to 22.4g, yield 88.2%, HPLC 99.83%,96.5% ee.
Example 2
The first step is as follows:
N-Tr-glutamic acid-5-methyl ester (1.46g, 3.61mmol), 2- (2-amino-5-bromo-benzoyl) pyridine A (1.0g, 3.61mmol) and dioxane (8 mL/cyclohexane (25 mL) were mixed and stirred uniformly. Followed by addition of B (OCH) 2 CF 3 ) 3 (0.22g, 0.72mmol) was heated, refluxed, and reacted for 8 hours, and the reaction was completed by TLC. Concentrating under reduced pressure, adding ethyl acetate and water to extract and react. Washing with saturated saline solution, rotary evaporating the organic layer to obtain a crude product, and recrystallizing with methanol/water to obtain an intermediate B2.22g with a yield of 93.0%.
The second step is that:
hydrogen chloride gas was introduced into tetrahydrofuran (15 ml) solution of B (1.46g, 2.2 mmol) for 15 minutes, TLC showed that the protection was removed, then cooled to-5 deg.C, morpholine (0.96g, 11mmol) was added dropwise, and the reaction was maintained at low temperature for 2 hours after the addition was completed. Extraction with dichloromethane, reduced pressure distillation of the organic phase, addition of 10mL of methyl tert-butyl ether, slow cooling to 20 ℃, filtration and drying to give 0.81g, yield 91.4%, HPLC:99.43%, EE:99.92 percent.
Example 3
The first step is as follows:
N-Tr-glutamic acid-5-methyl ester E (1.2kg, 2.99mol) and 2- (2-amino-5-bromo-benzoyl) pyridine A (0.69kg, 2.49mol) were added to tetrahydrofuran 5L/toluene 11L solvent, and stirred well. Followed by addition of B (C) 6 F 5 ) 3 (61.4g, 0.12mol), heating to reflux, carrying out water-splitting reaction for 6 hours, and detecting the reaction completion by TLC. Concentrating under reduced pressure, adding ethyl acetate and water to extract and react. The organic layer was washed with brine, dried and spin-dried to give a crude product, which was recrystallized from methanol/water to give intermediate B1.5kg, with a yield of 91.5%.
The second step:
adding the intermediate B (1.5kg, 2.26mol) and acetic acid (0.2kg, 3.39mol) into dioxane (8L), cooling to-10 ℃ after TLC shows that the protection is finished, then beginning to dropwise add triethylamine (1.14kg, 11.3mmol), and keeping the reaction at low temperature for 2 hours after dropwise adding. Extracting with dichloromethane, distilling the organic phase under reduced pressure, adding 10L methyl tert-butyl ether, slowly cooling to 20 deg.C, filtering and oven drying to obtain 0.84kg, yield 92.3%, HPLC 99.84%,99.42% ee.
Example 4
The first step is as follows:
N-Ns-glutamic acid-5-methyl ester E (0.1kg, 0.29mol) and 2- (2-amino-5-bromo-benzoyl) pyridine A (0.088kg, 0.32mol) were added to tetrahydrofuran 0.3L/toluene 0.6L solvent and stirred uniformly. Followed by addition of B (C) 6 F 5 ) 3 (6.14g, 0.012mol), heating to reflux and reacting for 6 hours by water diversion, and detecting by TLC to finish the reaction. Concentrating under reduced pressure, adding ethyl acetate and water, and extracting. The organic layer was washed with brine, dried and spin dried to give crude product, which was recrystallized from methanol/water to give 0.15kg of intermediate in 85.71% yield.
The second step is that:
the intermediate (0.15kg, 0.25mol), triethylamine (76.28g, 0.75mol) and benzenethiol (33g, 0.3mol) were added to N, N-dimethylformamide (1.5L), stirred at 60 ℃ for 1 hour, and a sample was taken out with 98.92% ee (FIG. 1). Stirring was continued for 1 hour to complete the reaction. Adding water, extracting with dichloromethane, distilling the organic phase under reduced pressure, adding 1L methyl tert-butyl ether, slowly cooling to 20 deg.C, filtering and oven drying to obtain 91.84g, yield 91.60%, HPLC:99.82%,98.08% ee (FIG. 2). The crude product (50 g) was added to 50mL of isopropanol, slurried and stirred for 4 hours, filtered, and dried to give 16.21g of the objective compound in a yield of 32.42% and 99.08% ee (FIG. 3).
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (9)
1. A preparation method of a remazolam key intermediate is characterized by comprising the following steps:
condensing 2- (2-amino-5-bromo-benzoyl) pyridine A with N-Tr-glutamic acid-5-methyl ester to obtain an intermediate B; then carrying out deprotection on the intermediate B to obtain an intermediate C; and carrying out ring closure reaction on the intermediate C to obtain a compound D.
2. A process for the preparation of a remazolam key intermediate according to claim 1, characterized in that:
the first step is as follows: condensing 2- (2-amino-5-bromo-benzoyl) pyridine A and N-Tr-glutamic acid-5-methyl ester E in an organic solvent in the presence of a catalyst to obtain an intermediate B;
the second step is that: removing Tr protection from the intermediate B in an organic solvent under an acidic condition to obtain an intermediate C, and then closing the ring under an alkaline low-temperature condition to obtain a product D.
3. A process for the preparation of key remazolen intermediates according to claim 2, characterized in that: in the first step, the catalyst is selected from (C) 6 F 5 ) 3 B. Tris (trifluoroethanol) borate or 3, 5-dinitrophenylboronic acid.
4. A process for the preparation of a remazolam key intermediate according to claim 2, characterized in that: in the first step, the organic solvent is one or more selected from tetrahydrofuran, dioxane, toluene, cyclohexane, n-hexane and sulfolane.
5. A process for the preparation of a remazolam key intermediate according to claim 2, characterized in that: in the first step, the molar ratio of 2- (2-amino-5-bromo-benzoyl) pyridine a to N-Tr-glutamic acid-5-methyl ester E is 1:1-1.2.
6. A process for the preparation of a remazolam key intermediate according to claim 2, characterized in that: in the second step, the organic solvent is one or more selected from tetrahydrofuran, dioxane, DMSO, DMF, 2-methyltetrahydrofuran and sulfolane.
7. A process for the preparation of key remazolen intermediates according to claim 2, characterized in that: in the second step, the acid is selected from trifluoroacetic acid, hydrochloric acid or hydrogen chloride.
8. A process for the preparation of a remazolam key intermediate according to claim 2, characterized in that: in the second step, the base is an organic base selected from DBU, morpholine, N-methylmorpholine, pyridine or triethylamine.
9. A process for the preparation of a remazolam key intermediate according to claim 2, characterized in that: in the second step, the low temperature condition is carried out at-10 ℃ to 0 ℃.
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