CN104910002B - A kind of preparation method of dezocine key intermediate - Google Patents
A kind of preparation method of dezocine key intermediate Download PDFInfo
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- CN104910002B CN104910002B CN201510283102.3A CN201510283102A CN104910002B CN 104910002 B CN104910002 B CN 104910002B CN 201510283102 A CN201510283102 A CN 201510283102A CN 104910002 B CN104910002 B CN 104910002B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
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Abstract
The invention discloses a kind of preparation method of dezocine key intermediate, using the tetralone of 7 methoxyl group 2 as raw material, methylate, then be alkylated at the ortho position of carbonyl in benzyl position first, can be prepared by substep synthesis, three kinds of strategies of two-step method and one kettle way.The preparation method of the dezocine key intermediate of the present invention, synthetic route is simple and direct, step is few, and yield is high, simple to operate, substantially reduces synthesis cycle；Reaction condition is gentle, improves the security of technique；Cost of material is low；It is easy to industrialization.Simple synthesis involved in the present invention largely reduces the cost of preparation, and then reduces the consumption cost of patient, and the social security spending of country can be also reduced to a certain extent, certain social and economic benefit is produced.
Description
Technical field
The invention belongs to technical field of medical chemistry, and in particular to a kind of preparation method of dezocine key intermediate.
Background technology
Dezocine, scientific name (-)-[5R- (5 α, 11 α, 13S*)] -13- amino -5,6,7,8,9,10,11,12- octahydro -5-
Methyl -5,11- methylene benzo cyclodecene -3- phenol (No. CAS：53648-55-8), a kind of typical opium alkaloids bases town is belonged to
Pain medicine, is developed by AstraZeneca (Astrazeneca) company.Such medicine is played a role by exciting opiate receptor.Help on ground
Pungent analgesic activity is better than pentazocine, is kappa receptor activator, is also μ receptor antagonists.Dezocine is additive small, it is adaptable to control
Treat Post operation it is medium to having an intense pain, the pain of internal organ angina and patient with advanced cancer.At present, dezocine raw material and preparation be
Obtain the approval listing of China National Drug food control office.Because dezocine has good tolerance and security, city
Field and medical institutions' degree of recognition are constantly lifted, therefore its clinical demand also constantly increases, and are expected to as good market prospect
Opium alkaloids bases antalgesic.At present because the synthesis step of dezocine is more, operation is comparatively laborious, and synthesis cycle is longer, portion
Divide severe reaction conditions, the security reacted individually is not high, thus the cost of raw material and preparation is all higher, so as to cause patient's
Drug cost is higher.In order to reduce synthesis step, simplify operation, shorten synthesis cycle, improve the security of technique, reduction ground assistant
Pungent cost of material, the product of super quality and competitive price is provided for patient.We are furtherd investigate to its synthesis technique, are designed and are sent out
The high-efficiency synthesis method of a dezocine key intermediate is showed.
The content of the invention
An object of the present invention is to provide that a kind of synthetic route is simple and direct, cost of material is low, reaction condition is gentle, can be with
The synthetic method of the dezocine key intermediate V of industrialization.
The present invention provides a kind of preparation method of dezocine key intermediate V, and its synthetic route is as follows：
Using 7- methoxy-2-tetralones as raw material, methylate, then be alkylated at the ortho position of carbonyl in benzyl position first,
Obtain dezocine key intermediate V.
Further, using chemical compounds I as raw material, synthesized using substep, methylated in benzyl position obtains compound ii first；Will
The compound ii adds activating reagent and alkylating reagent after isolating and purifying, the unilateral alkylation for carrying out carbonyl obtains chemical combination
The a of thing IV and compounds Ⅳ b；Carbonyl another side is carried out again after the compounds Ⅳ a and compounds Ⅳ b and impurity are isolated and purified
Alkylation, finally gives dezocine key intermediate V.
Further, using chemical compounds I as raw material, synthesized using two steps, methylated in benzyl position obtains compound ii first；Will
After the compound ii is isolated and purified, activating reagent and alkylating reagent are added, is not required to isolate and purify the unilateral alkane for obtaining carbonyl
Compound ii, is directly converted into the middle of the dezocine key that carbonyl both sides are all alkylated by base compounds Ⅳ a and compounds Ⅳ b
Body V.
Further, using chemical compounds I as raw material, synthesized using two steps, methylated in benzyl position obtains compound ii first, no
Isolated and purified, be directly added into activating reagent and alkylating reagent, obtain a of unilateral alkylated compound IV and chemical combination of carbonyl
The b of thing IV；The alkylation of carbonyl another side is carried out after the compounds Ⅳ a and compounds Ⅳ b and impurity are isolated and purified again, is obtained
Dezocine key intermediate V.
Further, using chemical compounds I as raw material, using one kettle way, methylated in benzyl position obtain compound ii first, do not entered
Row is isolated and purified, and adds activating reagent and alkylating reagent is directly alkylated on the both sides of compound ii carbonyl, a step is obtained
To dezocine key intermediate V.
Further, the methylating reagent includes methanol (MeOH), iodomethane (MeI), bromomethane (MeBr), sulfuric acid two
One or more in methyl esters.
Further, the activating reagent methylated include imidazoles, pyrroles, pyridine, piperidines, morpholine, triethylamine,
DIPEA (diisopropyl ethyl amine), Ag2O, DMAP (DMAP), K2CO3、Cs2CO3、NaOH、KOH、LiOH、NaH、
KH、NaOR、KOtBu (potassium tert-butoxide), NaOtOne or more in Bu (sodium tert-butoxide) and LDA (lithium diisopropylamine)；Institute
It is alkyl to state R in NaOR.
Further, the solvent used in each step reaction includes water (H2O), tetrahydrofuran (THF), dichloromethane (CH2Cl2)、
Chloroform (CHCl3), ethyl acetate (EtOAc), N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA),
Pyridine, dioxane, 1,2- dichloroethanes (ClCH2CH2Cl), 1,1- dichloroethanes (Cl2CH2CH3), benzene, toluene, adjacent diformazan
It is benzene, meta-xylene, paraxylene, methyl-isobutyl ether, ether, acetone, methanol, ethanol, normal propyl alcohol, isopropanol, n-butanol, different
One or more in butanol and the tert-butyl alcohol.
Further, the alkylating reagent is compound containing five carbon atom of the end containing leaving group
III, LG (leaving group, leaving group) are included in I, Br, Cl, benzene sulfonate, p-methyl benzenesulfonic acid ester and methanesulfonates
One or two kinds of.
Further, the temperature of the methylation reaction is -20 DEG C~75 DEG C；The temperature of the alkylated reaction is -20
DEG C~130 DEG C.
Further, the methylate is converted into the unilateral a of alkylate IV of carbonyl, IV b and the bilateral alkane of carbonyl
Activating reagent used in base product dezocine intermediate V include imidazoles, pyrroles, pyridine, morpholine, piperidines, indoles, quinoline,
Ammoniacal liquor, triethylamine, DIPEA (diisopropyl ethyl amine), RNH2, DMAP (DMAP), K2CO3、Na2CO3、
Cs2CO3、NaH、KH、NaOH、KOH、LiOH、Ca(OH)2、NaOR、KOtBu (potassium tert-butoxide), NaOtBu (sodium tert-butoxide), BuLi
(butyl lithium),tBuLi (tert-butyl lithium), KHMDS (hmds base potassium), LHMDS (hexamethyldisilazane lithium) and LDA
One or more in (lithium diisopropylamine)；The RNH2Middle R is alkyl；R is also alkyl in the NaOR.
The beneficial effects of the present invention are：The preparation method of the dezocine key intermediate of the present invention, synthetic route is simple and direct,
Step is few, and yield is high, simple to operate, substantially reduces synthesis cycle；Reaction condition is gentle, improves the security of technique；It is former
Expect that cost is low；It is easy to industrialization.Because the synthesis step of dezocine is longer, and contain several chiral centres, the cost ratio of raw material
Higher, the cost for sharing preparation is also relatively high.Further, since it's the new drug monitoring phase has past dezocine preparation, there is many
Company starts the imitated of dezocine, and the following demand to dezocine raw material can also be increased therewith.The involved letter of this invention
Prompt synthetic method largely reduces the cost of preparation, and then reduces the consumption cost of patient, also can be to a certain extent
The social security spending of country is reduced, certain social and economic benefit is produced.
Embodiment
The present invention is described in detail below in conjunction with specific embodiment.It should be noted that the skill described in following embodiments
The combination of art feature or technical characteristic be not construed as it is isolated, they can be mutually combined so as to reach preferably
Technique effect.
The preparation method of the dezocine key intermediate V of the present invention, its synthetic route is as follows：
Using 7- methoxy-2-tetralones as raw material, methylate, then be alkylated at the ortho position of carbonyl in benzyl position first,
Obtain key intermediate V.
Embodiment 1, prepare methylate II
7- methoxy-2-tetralones I (17.6g, 0.10mol) are dissolved in 30ml dichloromethane, reaction system is cooled down
To 0 DEG C, N is added portionwise into reaction system, N- diisopropyl ethyl amines (13.6ml, 0.1mol) are at this temperature, slowly past
Cooled iodomethane (6.22ml, 0.1mol) is added dropwise in the inside, and time for adding was more than 20 minutes.It is warming up to naturally after completion of dropping
Room temperature, reacts 4 hours, TLC point plates, raw material point disappears substantially at room temperature.Then in being with saturated ammonium chloride solution tune pH value
Property, three extractions are then carried out with EtOAc, 25ml is used every time.Organic phase after merging is washed with saturated sodium-chloride, and magnesium sulfate is done
Dry, concentration, column chromatography purifying obtains 16.2g methylates II, yield 85%.
Embodiment 2, prepare the carbonyl unilateral a of alkylate IV and IV b
Methylate II (15.2g, 80mmol) is dissolved in 35ml tetrahydrofurans (THF), reaction system is cooled to 0
DEG C, Et is slowly added into reaction system3N (22.2ml, 0.16mol), is stirred 30 minutes at this temperature.Then it is warming up to room
Temperature, adds dibromo pentane III (12.2ml, 88mmol), then be warming up to 40~45 DEG C, holding into reaction system at this temperature
This thermotonus 12 hours, TLC monitorings after the raw material that methylates disappears substantially, adjust pH value to be neutrality with 1mol/L hydrochloric acid solution,
Then extracted in three times with 90ml ethyl acetate.Organic phase after merging is washed with saturated sodium-chloride, and sodium sulphate is dried, decompression
Concentration, crosses post and obtains the carbonyl unilateral a of alkylate IV and IV b.Merged-quality is 22.4g, and it is 83% to merge yield.
Embodiment 3, prepare target compound-dezocine key intermediate V
The a of product IV of the unilateral alkylation of the carbonyl obtained in embodiment 2 and IV b (23.7g, 70mmol) are dissolved in into 30ml to do
In dry DMF, sodium hydride (3.36g, 70mmol, 50% purity) is added portionwise thereto under ice cooling, 4., will after adding
Temperature of reaction system is slowly warming up to 90~100 DEG C, stirring reaction 8 hours.It is concentrated under reduced pressure and boils off DMF and ooze to no liquid.It is cold
But to adjusting pH to be neutral with saturated ammonium chloride after room temperature, extracted in three times with 60ml ethyl acetate, saturation is used after merging organic phase
NaCl twice, dry, and is concentrated under reduced pressure, column chromatography obtains the 14.3g of brownish red grease V, yield is 79% by magnesium sulfate.
Embodiment 4, without middle purification procedures, target compound-dezocine is directly prepared by intermediate II crucial
Intermediate V
Such as the methylate II of the obtained purifying of the method for embodiment 1, methylate II (15.2g, 80mmol) is dissolved in
In 35ml tetrahydrofurans (THF), reaction system is cooled to 0 DEG C, Et is slowly added into reaction system3N (22.2ml,
0.16mol), stir 30 minutes at this temperature.Then room temperature is warming up to, dibromo penta is added into reaction system at this temperature
Alkane III (11.1ml, 80mmol), then it is warming up to 40~45 DEG C, keep this thermotonus 12 hours, process control monitoring methylates
After raw material disappears substantially, without isolating and purifying, temperature of reaction system is kept at room temperature, alkali is directly added into reaction system
The stronger sodium hydride (3.84g, 80mmol, 50% purity) of property, then temperature of reaction system is slowly warming up to 90~100 DEG C, stir
Mix reaction 10 hours.It is concentrated under reduced pressure and boils off tetrahydrofuran to no liquid and ooze.It is cooled to after room temperature and 20ml steamings is added into system
Distilled water, then adjust pH to be neutral with saturated ammonium chloride, extracted in three times with 75ml ethyl acetate, saturation chlorination is used after merging organic phase
Sodium is washed twice, and magnesium sulfate is dried, and is concentrated under reduced pressure, column chromatography obtains the 15.5g of brownish red grease V, yield is 75%.
Embodiment 5, by compound I (17.6g, 0.10mol) carry out benzyl position methylate after (such as method of embodiment 1), obtain
To intermediate II crude product (20.3g, 80%HPLC purity), directly the unilateral alkylation of carbonyl is carried out (strictly according to the facts without isolating and purifying
Apply the method for example 2), the carbonyl unilateral a of alkylated compound IV and IV b (20g, 70%) are obtained by isolating and purifying, then carry out carbonyl
The alkylation (such as embodiment 3) of another side, obtaining key intermediate V, (80%) 12.8g, yield is.
Embodiment 6, using one kettle way, without middle purification procedures, directly by raw material I prepare dezocine it is crucial in the middle of
Body V
7- methoxy-2-tetralones I (17.6g, 0.10mol) are dissolved in 30ml dichloromethane, reaction system is cooled down
To 0 DEG C, N is added portionwise into reaction system, N- diisopropyl ethyl amines (13.6ml, 0.1mol) are at this temperature, slowly past
It is added dropwise in reaction system through cooled iodomethane (6.22ml, 0.1mol), time for adding was more than 20 minutes.After completion of dropping certainly
So be warming up to room temperature, react 4 hours at room temperature, TLC point plates, after raw material point disappears substantially, by the solvent in reaction system and
Lower boiling activating substance concentration is dry, then adds in 20ml DMFs (DMF), will react into residue
System is cooled to 0 DEG C, and Et is slowly added into reaction system3N (26.2ml, 0.19mol), is stirred 45 minutes at this temperature.
Then room temperature is warming up to, dibromo pentane III (12.5ml, 80mmol) is added into reaction system at this temperature, then
40~45 DEG C are warming up to, this thermotonus is kept 12 hours, process control detection shows to methylate after raw material disappears substantially, without
Isolate and purify, keep temperature of reaction system at room temperature, added into reaction system the stronger sodium hydride of activation capacity (3.84g,
80mmol, 50% purity), then temperature of reaction system is slowly raised 90~100 DEG C, stirring reaction 12 hours.It is concentrated under reduced pressure
Boil off DMF and ooze to no liquid.It is cooled to after room temperature into system addition distilled water 20ml, then is adjusted with saturated ammonium chloride during pH is
Property, extracted, washed twice after merging organic phase with 50ml saturated sodium-chlorides in three times with 75ml ethyl acetate, magnesium sulfate is dried,
It is concentrated under reduced pressure, column chromatography obtains the 15.5g of brownish red grease V, yield is 75%.
The preparation method of the dezocine key intermediate of the present invention, synthetic route is simple and direct, step is few, and yield is high, operation letter
It is single, substantially reduce synthesis cycle；Reaction condition is gentle, improves the security of technique；Cost of material is low；It is easy to industrialization.
Because the synthesis step of dezocine is longer, and containing several chiral centres, the cost of raw material is higher, shares the cost of preparation
Also it is relatively high.Further, since it's the new drug monitoring phase has past dezocine preparation, You Duo companies start the imitative of dezocine
System, the following demand to dezocine raw material can also be increased therewith.The involved simple synthesis of this invention is largely
The cost of upper reduction preparation, and then the consumption cost of patient is reduced, the social security spending of country, production can be also reduced to a certain extent
Raw certain social and economic benefit.
Although having been presented for some embodiments of the present invention herein, it will be appreciated by those of skill in the art that
Without departing from the spirit of the invention, the embodiments herein can be changed.Above-described embodiment be it is exemplary, no
The restriction of interest field of the present invention should be used as using the embodiments herein.
Claims (1)
1. a kind of preparation method of dezocine key intermediate V, its synthetic route is as follows：
Using 7- methoxy-2-tetralones as raw material, methylate, then be alkylated at the ortho position of carbonyl in benzyl position first, obtained
Dezocine key intermediate V；
The methylating reagent is iodomethane, and the activating reagent methylated is diisopropyl ethyl amine, is methylated used
Solvent is dichloromethane；
The preparation method, using one kettle way, methylates in benzyl position obtain compound ii first using chemical compounds I as raw material, without
Isolate and purify, add activating reagent and alkylating reagent is directly alkylated on the both sides of compound ii carbonyl, a step is obtained
Dezocine key intermediate V；
Alkylation solvent used is tetrahydrofuran；
The alkylating reagent is compound III containing five carbon atom of the end containing leaving group, and LG is Br；
The temperature of the methylation reaction is -20 DEG C~75 DEG C；The temperature of the alkylated reaction is -20 DEG C~130 DEG C；
The methylate is converted into activating reagent used in the unilateral a of alkylate IV of carbonyl, IV b for triethylamine；
The unilateral a of alkylate IV of the carbonyl, IV b are converted into the bilateral alkylate dezocine intermediate V of carbonyl is made
Activating reagent is NaH.
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| CN109206385B (en) * | 2017-07-03 | 2022-04-22 | 扬子江药业集团有限公司 | Preparation method of dezocine impurity A and homologues thereof |
| CN108299173B (en) * | 2018-01-26 | 2021-01-12 | 扬子江药业集团有限公司 | Asymmetric synthesis method of dezocine key intermediate |
| CN114524717A (en) * | 2020-11-23 | 2022-05-24 | 江西博腾药业有限公司 | 1,2,3, 4-tetrahydronaphthalene derivative and preparation method and application thereof |
| CN113896621B (en) * | 2021-10-09 | 2024-04-16 | 宁波赜军医药科技有限公司 | Asymmetric synthesis method of dezocine key intermediate |
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| US3891657A (en) * | 1972-10-26 | 1975-06-24 | Bristol Myers Co | 9Beta-hydroxy-5-methyl-6,7-benzomorphans |
| US3956336A (en) * | 1974-04-18 | 1976-05-11 | Bristol-Myers Company | 9-Alkoxy-5-methyl-6,7-benzomorphans |
| US4150032A (en) * | 1978-01-18 | 1979-04-17 | Bristol-Myers Company | 9-Oxobenzomorphan process and intermediates |
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| CN101671269B (en) * | 2009-10-26 | 2015-04-22 | 扬子江药业集团有限公司 | Preparation method of substituted methylene benzocyclodecene ketoxime |
| CN102503840B (en) * | 2011-12-15 | 2013-06-19 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of dezocine |
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