CN115626913B - Method for preparing key intermediate of Rayleigh Malun - Google Patents

Method for preparing key intermediate of Rayleigh Malun Download PDF

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CN115626913B
CN115626913B CN202211213190.6A CN202211213190A CN115626913B CN 115626913 B CN115626913 B CN 115626913B CN 202211213190 A CN202211213190 A CN 202211213190A CN 115626913 B CN115626913 B CN 115626913B
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malun
rayleigh
compound
key intermediate
bromo
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CN115626913A (en
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张欣
刘永榜
范涛
杨婷
熊锋
李涛
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Shanghai Zaiqi Bio Tech Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The invention discloses a preparation method of a key intermediate (3S) -7-bromo-2, 3-dihydro-2-oxo-5- (2-pyridyl) -1H-1, 4-benzodiazepine-3-methyl propionate of Rui Malun, and belongs to the technical field of medical intermediates. 2- (2-amino-5-bromo-benzoyl) pyridine A and N-Tr-glutamic acid-5-methyl ester are adopted as raw materials, condensation reaction is carried out under the action of a boron-containing reagent to obtain a compound B, deprotection is carried out to obtain a compound C, and finally ring closure is carried out under the alkaline low-temperature condition to obtain the compound D. The method has the advantages of good process reproducibility, simple and stable operation, easy separation of products in each step, high yield, environmental friendliness and suitability for industrial mass production.

Description

Method for preparing key intermediate of Rayleigh Malun
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a key intermediate of an analgesic anesthetic Rate Malun.
Background
Rayleigh Malun (Remimazolam) is an ultra-short acting intravenous benzodiazepine sedative/anesthetic that acts on GABA-alpha receptors. In human body, remimazolam is rapidly metabolized by tissue esterase into inactive metabolites and is not metabolized by cytochrome dependent liver pathways, is an ultrashort-acting benzodiazepine drug, and has the characteristics of quick onset of action, short duration, quick recovery and good tolerance as a venous general anesthetic drug. The Rui Malun is used for anesthesia induction, anesthesia maintenance and daytime operation anesthesia, and has certain advantages when being applied to patients with cardiovascular diseases, respiratory diseases, liver diseases and the elderly compared with other products.
The remazolam besylate is formally obtained and sold in batches in 7 months in 2020, and is used in the fields of painless diagnosis and treatment sedation, general anesthesia, ICU sedation, local anesthesia sedation and the like. The benzenesulfonic acid rui Malun is a novel ultrashort-effect sedative anesthetic, and compared with other similar products, the benzenesulfonic acid rui mazolam has the advantages of quicker effect, rapid metabolism and low activity of metabolites, and can reduce interaction among medicines. The appearance of this drug may remodel the pattern of anesthetic administration.
WO0069836A1 and WO2013029431A1 disclose a process for the preparation of benzodiazepine derivatives and tosilates thereof, comprising the following steps: the method needs the coupling reaction of reactants under the action of coupling agent and ring-closure reaction under alkaline condition when preparing the compound 3, and needs to add Fmoc of acid deprotection group, the total yield is only 48.2%, and the yield is low. The reaction equation is as follows:
WO2011032692A1 discloses a further process for the preparation of benzodiazepine derivatives, in particular as follows:
in the method, when the compound 4 is prepared, an initial reactant is N-Boc-Glu (OMe) -OH, the initial reactant reacts under the action of a coupling agent DCC to obtain a compound 2, hydrochloric acid is added to remove a Boc protecting group to obtain a compound 3, and sodium bicarbonate is added to carry out cyclization reaction to obtain the 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 was a viscous oil, which was dissolved by heating with isopropanol, cooled for crystallization, and filtered to give yellow crystals. The obtained compounds 2 and 3 are crude products and are directly thrown into the next step, and a lot of impurities are accumulated to the step of the compound 4, so that the purity of the compound 4 is not high, and the product quality is affected. The intermediate obtained by the process has 93.91% of chemical purity of the Rayleigh Malun and lower purity of the product.
WO2019/72944 discloses a process for the preparation where the protecting group is Cbz, the product purity in the literature being 99%, but without chiral purity data, the experiment was repeated for example 1 of the present invention, with only 96.5% ee. However, the subsequent improvement means of the chiral purity of the product is limited, for example, when the product is improved by adopting recrystallization and the like, the yield loss is large, and more times of recrystallization are needed to reach more than 99.8 percent.
As a pharmaceutical product, the requisites Malun have high requirements on the purity of the medicines, and the purity of key intermediates is also important. Therefore, there is a need to optimize the process to develop a process for preparing high purity of the intermediate of r Malun.
Disclosure of Invention
The invention provides an improved preparation method of a key intermediate D of Rayleigh Malun, which adopts 2- (2-amino-5-bromo-benzoyl) pyridine A and N-Tr-glutamic acid-5-methyl ester as raw materials, and the compound B is obtained by condensation reaction under the action of a boron-containing reagent, then the compound C is obtained by deprotection, and finally the compound D is obtained by ring closure under the alkaline low-temperature condition. The method has the advantages of good process reproducibility, simple and stable operation, easy separation of products in each step, high yield, environmental friendliness and suitability for industrial mass production.
The invention provides a preparation method of a key intermediate of Rayleigh Malun, which comprises the following steps: starting from 2- (2-amino-5-bromo-benzoyl) pyridine a, condensing with N-Tr-glutamic acid-5-methyl ester to obtain intermediate B; then the intermediate B is deprotected to obtain an intermediate C; the intermediate C is subjected to a ring closure reaction to obtain a compound D. The synthetic route is as follows:
the technical method of the invention adopts the following specific steps:
the first step: synthesis of intermediate B
Starting from 2- (2-amino-5-bromo-benzoyl) pyridine A, carrying out condensation reaction with N-Tr-glutamic acid-5-methyl ester E in the presence of a catalyst in an organic solvent to obtain an intermediate B;
further, the condensing agent is selected from the group consisting of tris (trifluoroethanol) borate, 3, 5-dinitrophenylboronic acid or (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 the 2- (2-amino-5-bromo-benzoyl) pyridine A to the N-Tr-glutamic acid-5-methyl ester E is 1:1-1.2.
And a second step of: synthesis of Compound D
The intermediate B is subjected to Tr protection in an organic solvent under an acidic condition to obtain an intermediate C, and then the intermediate C is subjected to ring closure 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-methyltetrahydrofuran 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. Where N-methylmorpholine and morpholine are employed, the reaction times can generally be completed in 2 hours giving the best reaction response selectivity.
Further, the low temperature condition is-10 ℃ to 0 ℃.
When common inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate are adopted, for example, when experiments are repeated with reference to WO2011032692A1, the enantioselectivity of the reaction is reduced as the reaction proceeds, the final enantioselectivity reaches 97-99%, and the reaction temperature cannot be adjusted to be more than 99.5%. The reaction speed is obviously slowed by reducing the reaction temperature to below 0 ℃, more than 8% of raw materials remain after 48 hours, and the corresponding selectivity is obviously reduced when the alkali equivalent is increased.
The invention has the beneficial effects that
In the first and condensation reactions, 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 unchanged in the reflux dehydration process;
and secondly, deprotection and ring closure are carried out under the deprotection acidic condition, the ring closure is carried out under the organic base/low temperature condition (morpholine or N-methylmorpholine is adopted to react at 0 ℃ to-10 ℃), the ring closure is carried out while the intermediate after deprotection is released, and the racemization phenomenon of the chiral center is avoided.
Drawings
FIG. 1 is a chiral HPLC profile of a first time of compound D of example 4;
FIG. 2 is a chiral HPLC profile of a second time of control for compound D of example 4;
FIG. 3 is a chiral HPLC profile after purification of compound D of example 4;
Detailed Description
The invention will be further illustrated with reference to specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended claims.
Example 1
The first step:
2- (2-amino-5-bromo-benzoyl) pyridine (38.6 g,139 mmol) and N-Cbz glutamic acid-5-methyl ester (45.2 g,153 mmol) were added to dichloromethane (200 mL) at 15℃and the solution was cooled to-10 ℃. A solution of N, N' -dicyclohexylcarbodiimide (32.2 g,156 mmol) in methylene chloride (65 mL) was slowly added to the above solution at-10℃and the reaction was stirred at-10℃for 48 hours, and the reaction mixture was warmed to 15℃and filtered. The filtrate was distilled under reduced pressure below 25℃and then 250mL of methyl tert-butyl ether was added, the solution was heated to 50℃and then cooled slowly to 25℃and dried over filtration at 50℃to give a pale yellow solid (72.3 g, yield: 93.6%).
And a second step of:
intermediate (35 g,63 mmol) was added to glacial acetic acid (70 mL), a 33% hydrogen bromide/glacial acetic acid solution (45.7 mL, 255 mmol) was slowly added to the reaction at 10-12℃and the temperature was raised to 20℃after the addition and stirred at 15-20℃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 of isopropanol was added and heated to 82 ℃, 50mL of 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:
N-Tr-glutamic acid-5-methyl ester (1.46 g,3.61 mmol), 2- (2-amino-5-bromo-benzoyl) pyridine A (1.0 g,3.61 mmol) and dioxane 8 mL/cyclohexane 25mL were mixed and stirred well. Then B (OCH) is added 2 CF 3 ) 3 (0.22 g,0.72 mmol) was heated to reflux and the reaction was allowed to run for 8 hours, followed by TLC. Concentrating under reduced pressure, adding ethyl acetate and water for extraction reaction. The crude product is obtained by washing with saturated saline solution and rotary evaporation of the organic layer, and intermediate B2.22g is obtained by recrystallisation from methanol/water, and the yield is 93.0%.
And a second step of:
hydrogen chloride gas was introduced into a solution of B (1.46 g,2.2 mmol) in tetrahydrofuran (15 ml) for 15 minutes, after which TLC showed deprotection, the temperature was lowered to-5℃and then dropwise addition of morpholine (0.96 g,11 mmol) was started, and after completion of the dropwise addition the reaction was kept at low temperature for 2 hours. Extraction with dichloromethane, distillation of the organic phase under reduced pressure, addition of 10mL of methyl tert-butyl ether, slow cooling to 20 ℃, filtration and drying give 0.81g, yield 91.4%, HPLC:99.43%, EE:99.92%.
Example 3
The first step:
N-Tr-glutamic acid-5-methyl ester E (1.2 kg,2.99 mol) and 2- (2-amino-5-bromo-benzoyl) pyridine A (0.69 kg,2.49 mol) were added to tetrahydrofuran 5L/toluene 11L solvent and stirred well. Then B (C) 6 F 5 ) 3 (61.4 g,0.12 mol) was warmed to reflux and water-separated for 6 hours, and the reaction was completed by TLC. Concentrating under reduced pressure, adding ethyl acetate and water for extraction reaction. The organic layer was washed with brine, dried and spin-dried to give crude product, which was recrystallized from methanol/water to give intermediate b1.5kg, yield 91.5%.
And a second step of:
intermediate B (1.5 kg,2.26 mol) and acetic acid (0.2 kg,3.39 mol) were added to dioxane (8L), after TLC showed deprotection, the temperature was reduced to-10℃and then dropwise addition of triethylamine (1.14 kg,11.3 mmol) was started, and after dropwise addition, the reaction was maintained at low temperature for 2 hours. The mixture was extracted with dichloromethane, the organic phase was distilled under reduced pressure, 10L of methyl tert-butyl ether was added, the mixture was cooled slowly to 20℃and dried by filtration to give 0.84kg, 92.3% yield, 99.84% HPLC and 99.42% ee.
Example 4
The first step:
N-Ns-glutamic acid-5-methyl ester E (0.1 kg,0.29 mol) and 2- (2-amino-5-bromo-benzoyl) pyridine A (0.088 kg,0.32 mol) were added to a tetrahydrofuran 0.3L/toluene 0.6L solvent and stirred well. Then B (C) 6 F 5 ) 3 (6.14 g,0.012 mol) was warmed to reflux and water-separated for 6 hours, and TLC detection was completed. Concentrating under reduced pressure, adding ethyl acetate and water for extraction reaction. 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 with a yield of 85.71%.
And a second step of:
intermediate (0.15 kg,0.25 mol), triethylamine (76.28 g,0.75 mol) and benzenethiol (33 g,0.3 mol) were added to N, N-dimethylformamide (1.5L), stirred at 60℃for 1 hour, and sampled at 98.92% ee (FIG. 1). Stirring was continued for 1 hour and the reaction was completed. Water was added, extracted with dichloromethane, the organic phase was distilled under reduced pressure, 1L of methyl tert-butyl ether was added, slowly cooled to 20 ℃, filtered and dried to give 91.84g, yield 91.60%, HPLC:99.82%,98.08% ee (FIG. 2). The crude product (50 g) was added to 50mL of isopropyl alcohol, stirred for 4 hours with beating, filtered and dried to give 16.21g of the target compound in a yield of 32.42% and 99.08% ee (FIG. 3).
The foregoing embodiments illustrate the basic 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 above-described embodiments, and that the above-described embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the scope of the principles of the invention, which are defined in the appended claims.

Claims (5)

1. The preparation method of the key intermediate of the Rayleigh Malun is characterized by comprising the following steps of:
the first step: from 2- (2-Starting from amino-5-bromo-benzoyl) pyridine A, carrying out condensation reaction with N-Tr-glutamic acid-5-methyl ester E in the presence of a catalyst in an organic solvent to obtain an intermediate B; the catalyst is selected from (C) 6 F 5 ) 3 B. Tri (trifluoroethanol) borate or 3, 5-dinitrophenylboronic acid;
and a second step of: removing Tr protection of 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; the base is an organic base selected from DBU, morpholine, N-methylmorpholine, pyridine or triethylamine; the low temperature condition is-10 ℃ to 0 ℃.
2. The method for preparing the key intermediate of the Rayleigh Malun, according to claim 1, which is characterized in that: in the first step, the organic solvent is selected from one or more of tetrahydrofuran, dioxane, toluene, cyclohexane, n-hexane and sulfolane.
3. The method for preparing the key intermediate of the Rayleigh Malun, according to claim 1, which is characterized in that: in the first step, the molar ratio of the 2- (2-amino-5-bromo-benzoyl) pyridine A to the N-Tr-glutamic acid-5-methyl ester E is 1:1-1.2.
4. The method for preparing the key intermediate of the Rayleigh Malun, according to claim 1, which is characterized in that: in the second step, the organic solvent is selected from one or more of tetrahydrofuran, dioxane, DMSO, DMF, 2-methyltetrahydrofuran and sulfolane.
5. The method for preparing the key intermediate of the Rayleigh Malun, according to claim 1, which is characterized in that: in the second step, the acid is selected from trifluoroacetic acid, hydrochloric acid or hydrogen chloride.
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