CN112358403B - Method for preparing pentazocine intermediate - Google Patents
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- CN112358403B CN112358403B CN202011573944.XA CN202011573944A CN112358403B CN 112358403 B CN112358403 B CN 112358403B CN 202011573944 A CN202011573944 A CN 202011573944A CN 112358403 B CN112358403 B CN 112358403B
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- C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
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- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
Abstract
The invention belongs to the technical field of chemical synthesis and provides a method for preparing a pentazocine intermediate, which takes methyl acetoacetate with low price as a raw material, and adopts a reducing agent to reduce after methylation, methoxy formylation and removal of one methoxy formyl group, and the reduction product reacts with alkyl sulfonyl chloride to generate a compound with dialkyl sulfonyl; reacting a compound with dialkyl sulfonyl with phthalimide potassium salt, removing alkyl sulfonyl and grafting phthalimide; the phthalimide product is subjected to dehydrogenation reaction under an alkaline condition to generate a vinyl compound, and the vinyl compound is reacted with hydrazine hydrate to obtain a pentazocine intermediate. The invention adopts cheap compounds as starting materials, avoids dangerous reaction at high pressure and high temperature in the whole route, and is beneficial to industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a pentazocine intermediate.
Background
Pentazocine was successfully marketed in 1967 by the wensber group of stirling, uk. Pentazocine is a derivative of benzomorphan, has mixed agonistic and antagonistic effects on opioid receptors, mainly excites opioid kappa receptors, can excite sigma receptors at a larger dose, and has partial agonistic or weak antagonistic effect on mu receptors. Pentazocine is suitable for relieving pain of moderate to severe pain, and has wide clinical application. For example, intraoperative adjuvant analgesia, postoperative analgesia, chronic pain therapy, cancer pain therapy, and the like can be applied. The pentazocine tablet for oral administration is the only opioid agonist antagonist analgesic that can be orally taken at present.
The existing preparation method of pentazocine comprises the following steps:
the method 1 comprises the steps of condensing 3, 4-dimethylpyridine serving as a raw material with methyl iodide and p-methoxybenzyl magnesium chloride, carrying out reduction and cyclization, carrying out protective acylation, demethylation and hydrolytic deprotection to obtain a key intermediate, and finally reacting with dimethyl bromopropylene.
The method 2 comprises the steps of taking cyanoacetic acid as a raw material, carrying out addition reaction on the cyanoacetic acid and butanone, and carrying out high-pressure hydrogenation reaction to obtain the 3-methyl-3-pentene-1-amine. 3-methyl-3-pentene-1-amine is condensed, then undergoes cyclization reaction under the acid condition to obtain a key intermediate, and finally reacts with 4-bromo-2-methyl-butene to obtain the pentazocine.
At present, the synthesis route of pentazocine uses conditions such as high pressure and the like, the yield is low, and the industrial production is difficult.
Disclosure of Invention
In order to solve the problems in the prior art and avoid the disadvantages of the prior synthetic route, the invention provides a method for preparing a pentazocine intermediate (3-methyl-3-penten-1-amine) suitable for industrial production, which comprises the following synthetic route:
R1selected from methyl, ethyl, n-propyl, isopropyl, benzyl;
R2and R3Each independently selected from the group consisting ofAlkyl, ethyl, n-propyl, isopropyl;
the method comprises the following steps:
step (1): methylating a compound I by using a methylating agent in an organic solvent 1 to obtain a compound II;
step (2): dissolving the compound II in an organic solvent 2, adding a hydrogen-removing reagent, and then adding chloroacetate for reaction to obtain a compound III;
and (3): dissolving the compound III in an organic solvent 3, adding water and halide salt, and reacting to obtain a compound IV;
the organic solvent 3 is at least one selected from N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-Dimethylacetamide (DMAC), N-methylpyrrolidone (NMP) and N, N-Diisopropylethylamine (DIPEA);
and (4): dissolving a compound IV in an organic solvent 4, dropwise adding a solution of a reducing agent dissolved in an organic solvent 4', and reducing the compound IV into a compound V;
and (5): dissolving the compound V in an organic solvent 5, adding an acid-binding agent, dropwise adding alkyl sulfonyl chloride, and reacting to obtain a compound VI;
and (6): dissolving the compound VI in an aprotic organic solvent 6, adding phthalimide potassium salt and tetrabutylammonium bromide, and reacting to obtain a compound VII;
and (7): dissolving a compound VII in an organic solvent 7, adding an alkaline reagent and a halide salt, and reacting at the temperature of below 100 ℃ to obtain a compound VIII;
and (8): dissolving a compound VIII in an organic solvent 8, dropwise adding hydrazine hydrate, and carrying out reflux reaction to obtain a compound TM; wherein the organic solvent 8 is selected from alcohol solvents.
Preferably, in step (1), the methylating agent is selected from methyl iodide and dimethyl sulfate. The organic solvent 1 is an aprotic solvent. The optional aprotic solvent is selected from at least one of dichloromethane, acetone, acetonitrile.
Preferably, in step (1), the molar ratio of methyl iodide to compound of formula I is 1.0: 1. The molar ratio of methyl iodide to the compound of formula I is greater than 1: at 1, more bis-methyl substituted by-products are produced. Therefore, to reduce the production of by-products, a molar ratio of 1:1 is used.
Preferably, in step (1), a proper amount of water is further added. In practice, the inventors have surprisingly found that when the methylation reaction is carried out under anhydrous conditions, about 10% of the starting material (compound of formula I) remains methylated in step (1) and the conversion of the starting material is incomplete. After a proper amount of water is added, the compound in the formula I is almost completely converted into the compound in the formula II, and the yield is greatly improved. Preferably, the molar ratio of water added to compound I is from 1.5:1 to 2: 1.
Preferably, in the step (2), the hydrogen extracting reagent is at least one selected from sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium carbonate and sodium carbonate;
the molar ratio of the compound II to the hydrogen-withdrawing reagent is 1:1.
more preferably, the hydrogen abstraction agent is selected from sodium hydride and the reaction is continued at a temperature of 0 ℃ for 0.5 hours. Sodium hydride participates in the reaction, and the temperature of the system rises quickly, so that the reaction needs to be finished at low temperature. In addition, in the reaction involving sodium hydride, if the temperature is too high and the time is too long, impurities generated by the reaction are excessive, resulting in low purity and low yield of the reaction product.
In the case of the reaction of step (2), when a relatively strong hydrogen-withdrawing agent (e.g., sodium hydride) is used for the reaction, the reaction proceeds at a low temperature. More impurities are easily formed as the reaction temperature increases.
If a weaker hydrogen-withdrawing reagent (e.g., potassium carbonate, sodium carbonate, etc.) is used, the reaction requires a higher temperature to achieve the hydrogen-withdrawing effect, but the overall yield of the reaction is lower when the weaker hydrogen-withdrawing reagent is used than when sodium hydride is used.
Preferably, in the step (2), the organic solvent 2 is at least one selected from the group consisting of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N-Diisopropylethylamine (DIPEA); the chloroacetate is selected from at least one of methyl chloroacetate, ethyl chloroacetate, propyl chloroacetate and benzyl chloroacetate.
In step (3), the reaction is carried out in the presence of a halogen salt. The lithium halide is at least one selected from lithium chloride, lithium bromide, lithium iodide, sodium chloride, sodium bromide and sodium iodide
In the reaction of step (3), if the reaction temperature is lower than 80 ℃, the reaction hardly occurs. When the reaction temperature is 120 ℃ or higher, it is more advantageous for the reaction to be completed, but from the industrial viewpoint, when the temperature is raised to 120 ℃ or higher, the equipment requirements and costs are high. Therefore, the step (3) is carried out at a temperature of 90 ℃ to 120 ℃ in view of operability of industrial reaction and energy consumption.
In the step (4), dissolving the compound IV in an organic solvent 4, and dropwise adding a solution of a reducing agent in an organic solvent 4', wherein the organic solvent 4 is at least one selected from Tetrahydrofuran (THF), N-Dimethylformamide (DMF) and Dichloromethane (DCM); the organic solvent 4' is at least one selected from methanol, ethanol, glycerol and isopropanol.
Preferably, the reducing agent is at least one selected from sodium borohydride, potassium borohydride and lithium aluminum hydride.
In some embodiments of the present invention, the acid-binding agent in step (5) is at least one of triethylamine, N-diisopropylethylamine, and pyridine; the organic solvent 5 is at least one selected from Dichloromethane (DCM) and Tetrahydrofuran (THF). The acid-binding agent is added to form an exothermic process, and the temperature is preferably controlled below 0 ℃.
Preferably, the alkyl sulfonyl chloride is selected from at least one of methyl sulfonyl chloride, ethyl sulfonyl chloride, isopropyl sulfonyl chloride and n-propyl sulfonyl chloride. The process of dripping the alkyl sulfonyl chloride is a heat release process, the temperature is controlled below 0 ℃, the generation of byproducts caused by overhigh temperature is avoided, and the safety of operation can be ensured.
Preferably, in the step (6), the aprotic organic solvent 6 is selected from at least one of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), N-Diisopropylethylamine (DIPEA); the molar ratio of the compound VI to the phthalimide potassium salt is in the range of 1:1.15-1.30, and the reaction time is 12 hours or more.
Preferably, in step (7), the organic solvent 7 is selected from at least one of DMF, DMAC, NMP, DIPEA; the halide salt is at least one selected from lithium bromide, lithium iodide and lithium chloride. In the step (7), the reaction is likely not to occur at a low reaction temperature, and the reaction is not complete at a temperature of 110 ℃ or lower. When the reaction temperature is 120 ℃ or higher, the reaction is more favorably completed.
Preferably, in the step (8), the alcohol solvent is at least one selected from methanol, ethanol, glycerol, and isopropanol.
The intermediate TM of pentazocine prepared by the method of the invention can be used for synthesizing the pentazocine. The method for synthesizing pentazocine from the pentazocine intermediate TM has a mature process and is not described herein again.
The invention has the advantages of
1. The starting material methyl acetoacetate used in the method has wide sources and low price, and other reaction reagents are common materials, so that the method is low in cost and very beneficial to environmental protection.
2. In each step of the method, the temperature is controlled below 120 ℃, high-temperature reaction is avoided, and the safety coefficient is high.
3. The method has the advantages of short synthetic route, short reaction steps, simple operation, common and easily-purchased reagents, low price, no need of high-temperature conditions and suitability for industrial production.
Drawings
FIG. 1 is a diagram of a compound II obtained by the process of the present invention1H NMR spectrum;
FIG. 2 is a mass spectrum of Compound II obtained by the method of the present invention;
FIG. 3 is a diagram of Compound III obtained by the method of the present invention1H NMR spectrum;
FIG. 4 is a drawing of Compound IV obtained by the method of the present invention1H NMR spectrum;
FIG. 5 is a diagram of Compound V obtained by the method of the present invention1H NMR spectrum;
FIG. 6 is a representation of the compound VIII obtained by the process of the invention1H NMR spectrum;
FIG. 7 is a diagram of the pentazocine intermediate TM obtained by the process of the invention1H NMR spectrum;
FIG. 8 is a gas chromatogram of the reaction products of the first step reaction of one embodiment of the method of the invention.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1
Synthesis of Compound II
In a 1L three-necked flask, Compound I (53 g, 1.0 eq), 500mL of acetone, and K were added2CO3(63 g, 1.0 eq), stirring at room temperature for 10-15min, and adding CH dropwise3I (64.8 g, 1.0 eq), no significant exotherm, complete addition of water (16.4 g, 2.0 eq) and reaction at room temperature overnight.
And (3) post-treatment: suction filtration, filtrate vacuum spin drying, adding 100mL of water, 200mL of methyl tert-butyl ether (MTBE), stirring, separating, aqueous phase extraction with 100mL of methyl tert-butyl ether (MTBE) 1 time, organic phase combination, water washing 1 time, saturated sodium chloride washing 1 time, anhydrous sodium sulfate drying, spin drying, get 53g of compound II crude product, reduced pressure distillation (oil pump), external temperature 50 ℃, top temperature 34-36 ℃, get 40.6g of compound II, yield 76%. Of compounds II1The H NMR spectrum is shown in figure 1, and the mass spectrum is shown in figure 2.
Synthesis of Compound III
Introducing nitrogen into a three-neck flask, adding sodium hydride (1 eq) and DMF (3V), dropwise adding compound II (44.5 g, 1 eq) dissolved in DMF (2V) at the temperature of about 0 ℃, keeping the temperature for reaction for 0.5h after dropwise adding, then dropwise adding methyl chloroacetate (1 eq) for 1h, and keeping the temperature for reaction for 1.5 h.
And (3) post-treatment: 200mL of water and 300mL of MTBE were added to the reaction mixture, and the mixture was stirred for 15min, separated, and the aqueous phase was added with 200mL of MTBE, stirred for 15min, separated, and the above operation was repeated once. The organic phases are combined, 100mL of water is added for stirring and washing for 15min, liquid is separated, and the operation is repeated once. The organic phase was washed with brine, dried and concentrated to obtain 62.64g of crude compound III. The major fraction was collected at an overhead temperature of 69-76 ℃ by using oil-pump distillation to give 47.66g of compound III in 68.93% yield. Process for preparing compounds III1The H NMR spectrum is shown in FIG. 3.
Synthesis of Compound IV
In a 250mL three-necked flask, Compound III (20.0 g, 1.0 eq), DMF100mL, LiBr (17.2 g, 2.0 eq), H were added at room temperature2O (3.6 g, 2.0 eq), heating to 120 deg.C and reacting overnight
And (3) post-treatment: 200mL of water and 300mL of MTBE300mL were added to the reaction system, followed by stirring, liquid separation, extraction of the aqueous phase with 200mL of TBE 1 time, combination of the organic phases, washing with water 2 times, washing with saturated sodium chloride 1 time, drying over anhydrous sodium sulfate, and spin-drying to obtain 10.5g of compound IV as a liquid with a yield of 74%. Sampling and sending to nuclear magnetic detection to obtain1The H NMR spectrum is shown in FIG. 4.
Synthesis of Compound V
In a 100mL three-necked flask, 160mL of Tetrahydrofuran (THF), NaBH4(10.6 g, 2.0 eq), heating to 45-50 deg.C, adding dropwise compound IV (20.0 g, 1.0 eq)/methanol (26.7 g, 6.0 eq) mixture, generating bubbles when adding about 1/3, releasing heat, heating to 50-60 deg.C, and finishing adding dropwiseAnd keeping the temperature for 6.0 h.
And (3) post-treatment: adjusting the pH value to 4-5 (about 60 mL) by using 4N hydrochloric acid in an ice water bath, performing suction filtration, washing a filter cake by using THF for 1 time, combining filter liquor, performing rotary drying on the THF and water, adding MTBE30mL, pulping, performing suction filtration, washing the filter cake by using MTBE for 1 time, adjusting the pH value of the combined filter liquor to 8-9 by using 15% sodium hydroxide, adding anhydrous magnesium sulfate, drying, performing suction filtration, washing the filter cake by using MTBE for 2 times, and performing rotary drying on the filter liquor to obtain 17g of yellow oily matter, and performing oil-pump distillation (external temperature 110 ℃, top temperature 82 ℃) to obtain the compound V11 g, wherein the yield is 67%.
Synthesis of Compound VI (isopropyl sulfonate)
V (5.0 g, 1.0 eq) and DCM50mL were added to a 250mL three-necked flask, the temperature was reduced to 0 deg.C, triethylamine TEA (12.86 g, 3.0 eq) was added without significant exotherm, isopropyl sulfonyl chloride (12.6 g, 2.1 eq) was added dropwise with exotherm, the temperature was maintained for 0.5h, and TLC monitoring indicated complete reaction of the starting materials.
And (3) post-treatment: 30mL of water was added, stirred, separated, the aqueous phase was extracted 1 time with DCM50mL, the organic phases were combined, washed 2 times with 5% sodium bisulfate (30 mL. times.2), washed 1 time with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin dried to give 11.9g of compound VI as a yellow liquid in 85% yield.
Synthesis of Compound VII
VI (2.0 g, 1.0 eq) and DMF (10 mL) are added into a 100mL three-neck flask, phthalimide potassium salt (1.35 g, 1.2 eq) is added at room temperature, no obvious heat is generated, after the addition is finished, tetrabutylammonium bromide (0.2 g, 10%) is added, the reaction is carried out overnight at the room temperature of 28-30 ℃, the temperature is kept for 2.0h, and a TLC point plate shows that a small amount of raw materials remain, so that the reaction can be judged to be finished.
And (3) post-treatment: 20mL of water and 30mL of methyl tert-butyl ether (MTBE) were added, followed by stirring, liquid separation, extraction of the aqueous phase with 20mL of TBE 1 time, combination of the organic phases, washing with water 2 times, washing with saturated sodium chloride 1 time, drying over anhydrous sodium sulfate, and spin-drying to obtain 1.8g of a liquid, Compound VII, in 85% yield.
Synthesis of Compound VIII
VII (210 g, 1.0 eq) and DMF (1000 ml, 5 vol) were added to a 2000ml reaction flask and dissolved and stirred, followed by addition of K2CO3(1.5 eq, 120.8 g) and LiBr (1.0 eq, 50.2 g), and the temperature is raised to 105 ℃ for reaction (the viscosity of the system is larger in the reaction process, and the stirring is not good). The reaction is carried out for about 3 hours, the detection shows that the intermediate state is generated, and the reaction is prolonged for 2 hours till the reaction is complete.
And (3) post-treatment: adding 1000ml of MTBE and 1000ml of water, stirring for 10min, separating liquid, extracting the aqueous phase once with the MTBE, combining the organic phases, washing once with water, washing twice with half-saturated NaCl solution, drying, and concentrating to obtain 120g of crude oil with the yield of about 88%. Sampling and sending to nuclear magnetic detection. Of compound VIII1The H NMR spectrum is shown in FIG. 6.
Synthesis of Compound TM
In a 1000ml three-necked flask, the compound VIII (57 g, 1.0 eq) and 95% ethanol (10 vol, 570 ml) were added and stirred uniformly, under nitrogen protection, hydrazine hydrate (80%, 15.6g, 1.0 eq) was added dropwise and heated to reflux, and the internal temperature was about 80 ℃ for reaction.
Post-treatment, cooling to about 0 ℃, adding 300ml of 20% NaOH solution, stirring for 15min, adding 300ml of MTBE, stirring for 10min, adding 300ml of water, separating, extracting the water phase with 100ml of MTBE once again, combining the organic phases, washing twice with saturated NaCl solution, drying the organic phase, dropwise adding 4mol/L HCl/EtOH 80ml (0.25 mol) to form salt, and spin-drying the reaction solution to obtain about 34g of salt-formed product, wherein the crude product yield is close to the theoretical amount. Process for the preparation of pentazocine intermediate TM1The H NMR spectrum is shown in FIG. 7.
Example 2
Synthesis of Compound II
Compound I (5 g, 1.0 eq), acetone 50mL, K2CO3 (6.37 g, 1.2 eq) were added to a 100mL three-necked flask, stirred at room temperature for 10min, dimethyl sulfate (5.33 g, 1.1 eq) was added dropwise without significant heat release, and after dropping, the temperature was raised to reflux for 2 h.
And (3) post-treatment: suction filtration, filtrate vacuum spin drying, adding water and MTBE, stirring, separating liquid, aqueous phase extraction with MTBE 1 time, organic phase combination, water washing 1 time, saturated sodium chloride washing 1 time, anhydrous sodium sulfate drying, spin drying, compound II crude product 2g, yield 36%.
Synthesis of Compound III
Potassium tert-butoxide (1 eq), DMF (3V), II (4 g, 1 eq) dissolved in DMF (2V) is added dropwise at about 0 deg.C, added dropwise for 0.5h, kept warm for 0.5h, added dropwise with ethyl chloroacetate (1 eq), added dropwise for 0.5h, kept warm and reacted for 1 h.
And (3) post-treatment: adding 20mL of water and 30mL of MTBE into the reaction solution, stirring for 15min, separating, adding 20mL of MTBE into the aqueous phase, stirring for 15min, separating, and repeating the operation once. The organic phases are combined, 10mL of water is added, stirred and washed for 15min, the liquid is separated, and the operation is repeated once. The organic phase was washed with saturated brine, dried and concentrated to give 5g of crude product.
Synthesis of Compound IV
In a 50mL three-necked flask, III (2.0 g, 1.0 eq) and DMAC (10 mL) were charged, and LiCl (0.78 g, 2.0 eq), H and water were added at room temperature2O (0.33 g, 2.0 eq), and the temperature was raised to 120 ℃ to react overnight.
And (3) post-treatment: 20mL of water and MTBE30mL were added, stirred, separated, the aqueous phase was extracted 1 time with 20 mM TBE, the organic phases were combined, washed 2 times with water, washed 1 time with saturated sodium chloride, dried over anhydrous sodium sulfate and spin dried to give 0.72g of liquid IV in 50% yield.
Synthesis of Compound V
Adding 16mL of DCM and lithium aluminum hydride (4.8 g, 2.0 eq) into a 100mL three-necked flask, cooling to about 0 ℃, dropwise adding IV (10 g, 1.0 eq)/ethanol mixed solution, generating bubbles when 1/3 is dropwise added, releasing heat in the reaction, controlling the reaction temperature to 0-5 ℃, and preserving the temperature for 1h after the dropwise adding is finished.
And (3) post-treatment: under the ice-water bath, adding water and 15wt% sodium hydroxide solution, stirring for 10min, adding DCM and anhydrous magnesium sulfate, stirring for 15-30min, performing suction filtration, and spin-drying the organic phase to obtain a product, namely a compound V3 g, with the yield of 37%.
Synthesis of Compound VI (mesylate)
Adding V (50 g, 1.0 eq) and dichloromethane (50 mL) into a 250mL three-neck flask, cooling to 0 ℃, adding pyridine (100 g, 3.0 eq) without obvious heat release, after the addition is finished, dropwise adding methylsulfonyl chloride (97 g, 2.1 eq), dropwise adding heat release, after the dropwise addition is finished, preserving the temperature for 0.5h, and completely reacting the TLC point plate raw materials.
And (3) post-treatment: adding 300mL of water, stirring, separating, extracting the aqueous phase with 500mL of dichloromethane for 1 time, combining the organic phases, washing with 5% sodium bisulfate (300 mL. times.2) for 2 times, washing with saturated sodium chloride for 1 time, drying with anhydrous sodium sulfate, and spin-drying to obtain 104g of yellow liquid, compound VI, with a yield of 95%
Synthesis of Compound VII
In a 100mL three-necked flask, compound VI (2 g, 1.0 eq) and DMF (100 mL) are added, phthalimide potassium salt (1.62 g, 1.2 eq) is added at room temperature, no obvious heat is generated, after the addition is finished, tetrabutylammonium bromide (0.2 g, 10%) is added, the reaction is carried out overnight at room temperature, the temperature is kept for 2.0h, and a detection means shows that not only the product, compound VII, but also byproducts exist. The by-product is a product in which both methanesulfonyl groups are substituted simultaneously.
Synthesis of Compound VIII
VII (16.7 g, 1.0 eq) and NMP (84 ml 5 v) were added to a 2000ml reaction flask, dissolved and stirred, and Na was added thereto2CO3(1.5 eq, 8.1 g) and LiCl (1.0 eq, 2.2 g) were reacted by heating to 100 ℃.
And (3) post-treatment: adding 100ml of MTBE and 100ml of water, stirring for 10min, separating liquid, extracting the aqueous phase once with MTBE, combining the organic phases, washing once with water, washing twice with half-saturated NaCl solution, drying the organic phase, and concentrating to obtain 10g of crude product, namely the compound VIII, of oily matter with the yield of 85%.
Synthesis of Compound TM
In a 100ml three-neck flask, raw materials VIII (5 g, 1.0 eq) and isopropanol (10 vol, 50 ml) are stirred uniformly, hydrazine hydrate (the content of hydrazine hydrate is 80wt%, 1.4g, 1.0 eq) is added dropwise under the protection of nitrogen, and the mixture is heated to reflux and reacted at the internal temperature of about 80 ℃.
And (3) post-treatment: cooling to about 0 ℃, adding 30ml of 20% NaOH solution, stirring for 15min, adding 30ml of MTBE, stirring for 10min, adding 30ml of water, separating, extracting the water phase with 10ml of MTBE once again, combining the organic phases, washing twice with saturated NaCl solution, drying the organic phase, dropwise adding 4mol/L HCl/EtOH for salification, and spin-drying the reaction solution to obtain about 3g of salified product.
Example 3
A5L three-necked flask was charged with Compound I (200 g, 1.72 mol, 1.0 eq), 1500mL of acetone, and K2CO3(238 g, 1.72 mol, 1.0 eq), stirring at room temperature for 10-15min, and dropwise adding CH3I (244.5 g, 1.72 mol, 1.0 eq), CH is added dropwise3No heat is generated during the process I, and the reaction is carried out at room temperature overnight after the dripping is finished. By gas chromatography detection, 19% of the starting compound I remained and the starting material conversion was incomplete. The temperature was raised to 35-40 ℃ and the reaction was continued for 3 hours, and by gas chromatography it was found that 15% of the starting compound I remained. Supplemented with 25g of CH3The reaction was continued for 3 hours and the starting compound I was found to remain at about 15% by gas chromatography. Supplement 36g K2CO3And 400mL of acetone, and the reaction was continued overnight. The next morning, 15% of the starting compound I was still found to be remaining by gas chromatography. 62.0g (3.44 mol, 2.0 eq) of water was added, the reaction was continued for 3 hours, and by gas chromatography, 0.35% of the starting compound I was found to remain, and the reaction was terminated.
From this example, it can be seen that the addition of water has a significant effect on the progress of the reaction. The addition of water increases the conversion of the starting materials and greatly shortens the course of the reaction.
The work-up procedure of the reaction of this step and the subsequent preparation of pentazocine can be referred to example 1.
Example 4
In a 100mL three-necked flask, Compound I (5.0 g, 38.4 mmol, 1.0 eq), 50mL of acetone, and K were added2CO3(6.37 g, 46.1mmol, 1.2 eq), stirring at room temperature for 10-15min, and adding CH dropwise3I (6.54 g, 46.1mmol, 1.2 eq), no significant exotherm, after which 1.4g (76.8 mmol, 2.0 eq) of water was added dropwise. The temperature is increased to reflux, and the reflux reaction is carried out for 5 hours. As a result of Gas Chromatography (GC) detection (see fig. 8), 0.32% of the starting compound I remained, the main peak content of the main product (compound II) was 80%, and the content of the bis-methyl-substituted by-product was 18%.
The working up and subsequent preparation steps can be referred to example 1.
The method takes methyl acetoacetate with wide source and low price as a starting material to prepare the pentazocine intermediate, has mild reaction in each step, avoids high-temperature reaction at temperature, has high safety coefficient, and is suitable for industrial production.
Claims (10)
1. A process for the preparation of pentazocine intermediates, comprising the following synthetic route:
R1selected from methyl, ethyl, n-propyl, isopropyl, benzyl;
R2and R3Each independently selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl;
the method comprises the following steps:
step (1): methylating a compound I by using a methylating agent in an organic solvent 1 to obtain a compound II; the methylating agent is selected from methyl iodide and dimethyl sulfate; the organic solvent 1 is at least one selected from dichloromethane, acetone and acetonitrile;
step (2): dissolving the compound II in an organic solvent 2, adding a hydrogen-removing reagent, and then adding chloroacetate for reaction to obtain a compound III;
and (3): dissolving the compound III in an aprotic organic solvent 3, adding water and halide salt, and reacting to obtain a compound IV;
and (4): dissolving a compound IV in an organic solvent 4, dropwise adding a solution of a reducing agent dissolved in an organic solvent 4', and reducing the compound IV into a compound V;
and (5): dissolving the compound V in an organic solvent 5, adding an acid-binding agent, dropwise adding alkyl sulfonyl chloride, and reacting to obtain a compound VI;
and (6): dissolving a compound VI in an aprotic organic solvent 6, adding phthalimide potassium salt and tetrabutylammonium bromide, and reacting to obtain a compound VII;
and (7): dissolving a compound VII in an organic solvent 7, adding an alkaline reagent and a halide salt, and reacting at a temperature of more than 100 ℃ to obtain a compound VIII;
and (8): dissolving a compound VIII in an organic solvent 8, dropwise adding hydrazine hydrate, and heating and refluxing to react after dropwise adding to obtain a compound TM; wherein the organic solvent 8 is an alcohol solvent.
2. The process of claim 1, wherein in step (1), the methylating agent is methyl iodide and the molar ratio of methyl iodide to compound I is 1:1.
3. The method of claim 2, wherein in step (1), further comprising adding water, the molar ratio of water added to compound I is 1.0:1 to 2: 1.
4. The method according to claim 1, wherein in the step (2), the organic solvent 2 is at least one selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and N, N-diisopropylethylamine;
the hydrogen extraction reagent is selected from at least one of sodium hydride, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium carbonate and sodium carbonate;
the chloroacetate is selected from at least one of methyl chloroacetate, ethyl chloroacetate, propyl chloroacetate and benzyl chloroacetate.
5. The method of claim 4, wherein the molar ratio of compound II to the hydrogen abstraction reagent is 1: 1; and the hydrogen drawing reagent is sodium hydride, and the reaction is carried out at the temperature of below 0 ℃.
6. The method according to claim 1, wherein in the step (3), the aprotic organic solvent 3 is selected from at least one of N, N-dimethylformamide, dimethyl sulfoxide, N-dimethylacetamide, N-methylpyrrolidone, and N, N-diisopropylethylamine, and the halide salt is selected from at least one of lithium chloride, lithium bromide, lithium iodide, sodium chloride, sodium bromide, and sodium iodide; the step (3) is carried out at the temperature of 90-120 ℃.
7. The method according to claim 1, wherein in the step (4), the reducing agent is at least one selected from sodium borohydride, potassium borohydride and lithium aluminum hydride;
the organic solvent 4 is at least one selected from tetrahydrofuran, N-dimethylformamide and dichloromethane; the organic solvent 4' is at least one selected from methanol, ethanol, glycerol and isopropanol.
8. The method of claim 1, wherein in step (5), the acid scavenger is at least one of triethylamine, N-diisopropylethylamine, and pyridine;
the organic solvent 5 is at least one selected from dichloromethane and tetrahydrofuran;
the alkyl sulfonyl chloride is at least one selected from methyl sulfonyl chloride, ethyl sulfonyl chloride, isopropyl sulfonyl chloride and n-propyl sulfonyl chloride.
9. The method according to claim 1, wherein in the step (6), the aprotic organic solvent 6 is selected from at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, N-diisopropylethylamine; the molar ratio of the compound VI to the phthalimide potassium salt is 1: 1.15-1.30.
10. The method according to claim 1, wherein in the step (7), the organic solvent 7 is selected from at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, N-diisopropylethylamine;
the alkaline reagent is selected from at least one of sodium carbonate and potassium carbonate;
the halide salt is selected from at least one of lithium chloride, lithium bromide, lithium iodide, sodium chloride, sodium bromide and sodium iodide.
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