CN104910002A - Dezocine key intermediate preparation method - Google Patents
Dezocine key intermediate preparation method Download PDFInfo
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- CN104910002A CN104910002A CN201510283102.3A CN201510283102A CN104910002A CN 104910002 A CN104910002 A CN 104910002A CN 201510283102 A CN201510283102 A CN 201510283102A CN 104910002 A CN104910002 A CN 104910002A
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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 present invention discloses a dezocine key intermediate preparation method, 7-methoxy-2-tetralone is used as a starting material for first benzyl-site methylation and then ortho alkylation of the carbonyl group, the dezocine key intermediate can be prepared by three strategies of stepwise synthesis, two-step and one-pot methods. The dezocine key intermediate preparation method has the advantages of simple synthetic route, less steps, high yield simple operation, great reduction of the synthesis cycle, mild reaction conditions, and improvement of the safety of the technology, the low raw material cost and easy industrialization. The preparation cost is greatly reduced by the simple synthesis method, the patient dosage cost is reduced, the national social security spending can be reduced to some extent, and some of the social and economic benefits are produced.
Description
Technical field
The invention belongs to technical field of medical chemistry, be specifically related to a kind of preparation method of Wy-16225 key intermediate.
Background technology
Wy-16225, formal name used at school (-)-[5R-(5 α, 11 α, 13S*)]-13-amino-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methylene benzo ring decene-3-phenol (No. CAS: 53648-55-8), belongs to a kind of typical opium alkaloids bases anodyne, is developed by AstraZeneca (Astrazeneca) company.Such medicine is played a role by exciting opiate receptor.Wy-16225 analgesic activity is better than pentazocine, is kappa receptor agonist, is also μ receptor antagonist.Wy-16225 is additive little, be applicable to treat Post operation medium to having an intense pain, the pain of internal organ angina and patient with advanced cancer.At present, Wy-16225 raw material and preparation obtained China National Drug food control office approval listing.Because Wy-16225 has good tolerance and security, market and medical institutions' degree of recognition constantly promote, and therefore its clinical demand also constantly increases, and are expected to the opium alkaloids bases anodyne becoming good market prospects.At present because the synthesis step of Wy-16225 is more, operate more loaded down with trivial details, synthesis cycle is longer, and partial reaction condition is harsh, and the security of indivedual reaction is not high, and thus the cost of raw material and preparation is all higher, thus causes the drug cost of patient higher.In order to reduce synthesis step, simplifying the operation, shortening synthesis cycle, improve the security of technique, reduce the raw materials cost of Wy-16225, for patient provides the product of super quality and competitive price.We further investigate its synthesis technique, have designed and found the high-efficiency synthesis method of a Wy-16225 key intermediate.
Summary of the invention
An object of the present invention is to provide that a kind of synthetic route is simple and direct, raw materials cost is low, reaction conditions is gentle, can the synthetic method of Wy-16225 key intermediate V of industrialization.
The invention provides a kind of preparation method of Wy-16225 key intermediate V, its synthetic route is as follows:
With 7-methoxy-2-tetralone for raw material, first methylate in benzyl position, then carry out alkylation at the ortho position of carbonyl, obtain Wy-16225 key intermediate V.
Further, take chemical compounds I as raw material, adopt stepwise synthesis, first methylate in benzyl position and obtain compound ii; Add activating reagent and alkylating reagent again by after described compound ii separation and purification, the monolateral alkylation carrying out carbonyl obtains compounds Ⅳ a and compounds Ⅳ b; By carrying out the alkylation of carbonyl the other side after described compounds Ⅳ a and compounds Ⅳ b and magazins' layout purifying again, finally obtain Wy-16225 key intermediate V.
Further, be raw material with chemical compounds I, adopt two step synthesis, first methylate in benzyl position and obtain compound ii; After described compound ii separation and purification, add activating reagent and alkylating reagent, do not need separation and purification to obtain monolateral alkylated compound IV a and the compounds Ⅳ b of carbonyl, directly compound ii is converted into all alkylating Wy-16225 key intermediate V in carbonyl both sides.
Further, be raw material with chemical compounds I, adopt two step synthesis, first methylate in benzyl position and obtain compound ii, do not carry out separation and purification, directly add activating reagent and alkylating reagent, obtain monolateral alkylated compound IV a and the compounds Ⅳ b of carbonyl; By carrying out the alkylation of carbonyl the other side after described compounds Ⅳ a and compounds Ⅳ b and magazins' layout purifying again, obtain Wy-16225 key intermediate V.
Further, take chemical compounds I as raw material, adopt one kettle way, first methylate in benzyl position and obtain compound ii, do not carry out separation and purification, add activating reagent and alkylating reagent directly carries out alkylation on the both sides of compound ii carbonyl, a step obtains Wy-16225 key intermediate V.
Further, described methylating reagent comprises one or more in methyl alcohol (MeOH), methyl iodide (MeI), monobromethane (MeBr), methyl-sulfate.
Further, described methylated activating reagent comprises imidazoles, pyrroles, pyridine, piperidines, morpholine, triethylamine, DIPEA (diisopropyl ethyl amine), Ag
2o, DMAP (DMAP), K
2cO
3, Cs
2cO
3, NaOH, KOH, LiOH, NaH, KH, NaOR, KO
tbu (potassium tert.-butoxide), NaO
tone or more in Bu (sodium tert-butoxide) and LDA (lithium diisopropylamine); In described NaOR, R is alkyl.
Further, each step reaction solvent used comprises water (H
2o), tetrahydrofuran (THF) (THF), methylene dichloride (CH
2cl
2), trichloromethane (CHCl
3), ethyl acetate (EtOAc), DMF (DMF), N,N-dimethylacetamide (DMA), pyridine, dioxane, 1,2-ethylene dichloride (ClCH
2cH
2cl), 1,1-ethylene dichloride (Cl
2cH
2cH
3), one or more in benzene, toluene, o-Xylol, m-xylene, p-Xylol, methyl-isobutyl ether, ether, acetone, methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol and the trimethyl carbinol.
Further, described alkylating reagent is the compound III containing five carbon atoms of end all containing leavings group, LG (leaving group, leavings group) comprises one in I, Br, Cl, benzene sulfonate, p-toluenesulfonic esters and methanesulfonates or two kinds.
Further, the temperature of described methylation reaction is-20 DEG C ~ 75 DEG C; The temperature of described alkylated reaction is-20 DEG C ~ 130 DEG C.
Further, described methylate is converted into the activating reagent that carbonyl monolateral alkylate IV a, IV b and carbonyl bilateral alkylate Wy-16225 intermediate V use and comprises imidazoles, pyrroles, pyridine, morpholine, piperidines, indoles, quinoline, ammoniacal liquor, triethylamine, DIPEA (diisopropyl ethyl amine), RNH
2, DMAP (DMAP), K
2cO
3, Na
2cO
3, Cs
2cO
3, NaH, KH, NaOH, KOH, LiOH, Ca (OH)
2, NaOR, KO
tbu (potassium tert.-butoxide), NaO
tbu (sodium tert-butoxide), BuLi (butyllithium),
tone or more in BuLi (tert-butyl lithium), KHMDS (hmds base potassium), LHMDS (hexamethyldisilazane lithium) and LDA (lithium diisopropylamine); Described RNH
2middle R is alkyl; In described NaOR, R is also alkyl.
Beneficial effect of the present invention is: the preparation method of Wy-16225 key intermediate of the present invention, and synthetic route is simple and direct, step is few, and productive rate is high, simple to operate, substantially reduces synthesis cycle; Reaction conditions is gentle, improves the security of technique; Raw materials cost is low; Be convenient to industrialization.Because the synthesis step of Wy-16225 is longer, and containing several chiral centre, the cost compare of raw material is high, and the cost sharing preparation is also relatively high.In addition, because the new drug monitoring phase spent by Wy-16225 preparation, You Duo company starts the imitated of Wy-16225, and future also can strengthen the demand of Wy-16225 raw material thereupon.This simple synthesis involved by invention reduces the cost of preparation to a great extent, and then reduces the consumption cost of patient, also can reduce the social security spending of country to a certain extent, produce certain Social and economic benef@.
Embodiment
Hereafter will describe the present invention in detail in conjunction with specific embodiments.It should be noted that the combination of technical characteristic or the technical characteristic described in following embodiment should not be considered to isolated, they can mutually be combined thus be reached better technique effect.
The preparation method of Wy-16225 key intermediate V of the present invention, its synthetic route is as follows:
With 7-methoxy-2-tetralone for raw material, first methylate in benzyl position, then carry out alkylation at the ortho position of carbonyl, obtain key intermediate V.
Embodiment 1, prepare methylate II
By 7-methoxy-2-tetralone I (17.6g, 0.10mol) be dissolved in 30ml methylene dichloride, reaction system is cooled to 0 DEG C, add N, N-diisopropyl ethyl amine (13.6ml, 0.1mol) in reaction system in batches, at this temperature, slowly drip cooled methyl iodide (6.22ml, 0.1mol) inside, time for adding was more than 20 minutes.Dropwise and be naturally warmed up to room temperature afterwards, at room temperature react 4 hours, TLC point plate, raw material point disappears substantially.Then be neutral with saturated ammonium chloride solution adjust pH, then carry out three extractions with EtOAc, use 25ml at every turn.Organic phase saturated sodium-chloride after merging washs, dried over mgso, and concentrated, column chromatography purification obtains 16.2g methylate II, yield 85%.
Embodiment 2, prepare carbonyl monolateral alkylate IV a and IV b
Methylate II (15.2g, 80mmol) is dissolved in 35ml tetrahydrofuran (THF) (THF), reaction system is cooled to 0 DEG C, in reaction system, slowly add Et
3n (22.2ml, 0.16mol), stirs 30 minutes at this temperature.Then room temperature is warmed up to, dibromo pentane III (12.2ml is added at this temperature in reaction system, 88mmol), be warmed up to 40 ~ 45 DEG C again, keep this thermotonus 12 hours, TLC monitors, after the raw material that methylates disappears substantially, be neutral with the hydrochloric acid soln adjust pH of 1mol/L, then divide three extractions by the ethyl acetate of 90ml.Organic phase saturated sodium-chloride after merging washs, dried over sodium sulfate, concentrating under reduced pressure, crosses post and obtains carbonyl monolateral alkylate IV a and IV b.Merged-quality is 22.4g, and merging yield is 83%.
Embodiment 3, prepare target compound-Wy-16225 key intermediate V
Monolateral for the carbonyl obtained in embodiment 2 alkylating product IV a and IV b (23.7g, 70mmol) is dissolved in the DMF of 30ml drying, adds sodium hydride (3.36g, 70mmol, 50% purity) under ice cooling, 4 wherein in batches.After adding, temperature of reaction system is slowly warmed up to 90 ~ 100 DEG C, stirring reaction 8 hours.Concentrating under reduced pressure boils off DMF and oozes to absence of liquid.Adjust pH to be neutral with saturated ammonium chloride after being cooled to room temperature, divide three extractions by 60ml ethyl acetate, wash twice with saturated sodium-chloride after merging organic phase, dried over mgso, concentrating under reduced pressure, column chromatography obtains red-brown oily matter V 14.3g, and yield is 79%.
Embodiment 4, need not in the middle of purification procedures, directly prepare target compound-Wy-16225 key intermediate V by intermediate II
As embodiment 1 method obtains the methylate II of purifying, methylate II (15.2g, 80mmol) is dissolved in 35ml tetrahydrofuran (THF) (THF), reaction system is cooled to 0 DEG C, in reaction system, slowly add Et
3n (22.2ml, 0.16mol), stirs 30 minutes at this temperature.Then room temperature is warmed up to, dibromo pentane III (11.1ml is added at this temperature in reaction system, 80mmol), be warmed up to 40 ~ 45 DEG C again, keep this thermotonus 12 hours, process control is monitored, after the raw material that methylates disappears substantially, without separation and purification, temperature of reaction system is kept at room temperature, in reaction system, directly add the sodium hydride (3.84g that alkalescence is stronger, 80mmol, 50% purity), then temperature of reaction system is slowly warmed up to 90 ~ 100 DEG C, stirring reaction 10 hours.Concentrating under reduced pressure boils off tetrahydrofuran (THF) and oozes to absence of liquid.In system, add 20ml distilled water after being cooled to room temperature, then adjust pH to be neutral with saturated ammonium chloride, divide three extractions by 75ml ethyl acetate, wash twice with saturated sodium-chloride after merging organic phase, dried over mgso, concentrating under reduced pressure, column chromatography obtains red-brown oily matter V 15.5g, and yield is 75%.
Embodiment 5, by Compound I (17.6g, 0.10mol) carry out benzyl position methylate after (as embodiment 1 method), obtain intermediate II crude product (20.3g, 80%HPLC purity), the monolateral alkylation (as embodiment 2 method) of carbonyl is directly carried out without separation and purification, carbonyl monolateral alkylated compound IV a and IV b (20g is obtained by separation and purification, 70%), carry out the alkylation (as embodiment 3) of carbonyl the other side again, obtain key intermediate V (12.8g, yield is 80%).
Embodiment 6, adopt one kettle way, need not in the middle of purification procedures, directly prepare Wy-16225 key intermediate V by raw material I
By 7-methoxy-2-tetralone I (17.6g, 0.10mol) be dissolved in 30ml methylene dichloride, reaction system is cooled to 0 DEG C, add N, N-diisopropyl ethyl amine (13.6ml, 0.1mol) in reaction system in batches, at this temperature, slowly drip in reaction system through cooled methyl iodide (6.22ml, 0.1mol), time for adding was more than 20 minutes.Dropwise and be naturally warmed up to room temperature afterwards, at room temperature react 4 hours, TLC point plate, after raw material point disappears substantially, solvent in reaction system and lower boiling activating substance are concentrated dry, then adds in resistates in 20ml DMF (DMF), reaction system is cooled to 0 DEG C, in reaction system, slowly adds Et
3n (26.2ml, 0.19mol), stirs 45 minutes at this temperature.
Then room temperature is warmed up to, dibromo pentane III (12.5ml is added at this temperature in reaction system, 80mmol), be warmed up to 40 ~ 45 DEG C again, keep this thermotonus 12 hours, process control detects after the raw material that shows to methylate disappears substantially, without separation and purification, keep temperature of reaction system at room temperature, the stronger sodium hydride of activation capacity (3.84g, 80mmol, 50% purity) is added in reaction system, again temperature of reaction system is slowly elevated to 90 ~ 100 DEG C, stirring reaction 12 hours.Concentrating under reduced pressure boils off DMF and oozes to absence of liquid.In system, distilled water 20ml is added after being cooled to room temperature, pH is adjusted to be neutral with saturated ammonium chloride again, three extractions are divided by 75ml ethyl acetate, wash twice with 50ml saturated sodium-chloride after merging organic phase, dried over mgso, concentrating under reduced pressure, column chromatography obtains red-brown oily matter V 15.5g, and yield is 75%.
The preparation method of Wy-16225 key intermediate of the present invention, synthetic route is simple and direct, step is few, and productive rate is high, simple to operate, substantially reduces synthesis cycle; Reaction conditions is gentle, improves the security of technique; Raw materials cost is low; Be convenient to industrialization.Because the synthesis step of Wy-16225 is longer, and containing several chiral centre, the cost compare of raw material is high, and the cost sharing preparation is also relatively high.In addition, because the new drug monitoring phase spent by Wy-16225 preparation, You Duo company starts the imitated of Wy-16225, and future also can strengthen the demand of Wy-16225 raw material thereupon.This simple synthesis involved by invention reduces the cost of preparation to a great extent, and then reduces the consumption cost of patient, also can reduce the social security spending of country to a certain extent, produce certain Social and economic benef@.
Although give some embodiments of the present invention, it will be understood by those of skill in the art that without departing from the spirit of the invention herein, can change embodiment herein.Above-described embodiment is exemplary, should using embodiment herein as the restriction of interest field of the present invention.
Claims (10)
1. a preparation method for Wy-16225 key intermediate V, its synthetic route is as follows:
With 7-methoxy-2-tetralone for raw material, first methylate in benzyl position, then carry out alkylation at the ortho position of carbonyl, obtain Wy-16225 key intermediate V.
2. preparation method as claimed in claim 1, it is characterized in that, take chemical compounds I as raw material, adopts stepwise synthesis, first methylate in benzyl position and obtain compound ii; Add activating reagent and alkylating reagent again by after described compound ii separation and purification, the monolateral alkylation carrying out carbonyl obtains compounds Ⅳ a and compounds Ⅳ b; By carrying out the alkylation of carbonyl the other side after described compounds Ⅳ a and compounds Ⅳ b and magazins' layout purifying again, finally obtain Wy-16225 key intermediate V.
3. preparation method as claimed in claim 1, it is characterized in that, be raw material with chemical compounds I, adopts two step synthesis, first methylate in benzyl position and obtain compound ii; After described compound ii separation and purification, add activating reagent and alkylating reagent, do not need separation and purification to obtain monolateral alkylated compound IV a and the compounds Ⅳ b of carbonyl, directly compound ii is converted into all alkylating Wy-16225 key intermediate V in carbonyl both sides.
4. preparation method as claimed in claim 1, it is characterized in that, take chemical compounds I as raw material, adopt two step synthesis, first methylate in benzyl position and obtain compound ii, do not carry out separation and purification, directly add activating reagent and alkylating reagent, obtain monolateral alkylated compound IV a and the compounds Ⅳ b of carbonyl; By carrying out the alkylation of carbonyl the other side after described compounds Ⅳ a and compounds Ⅳ b and magazins' layout purifying again, obtain Wy-16225 key intermediate V.
5. preparation method as claimed in claim 1, it is characterized in that, take chemical compounds I as raw material, adopt one kettle way, first methylate in benzyl position and obtain compound ii, do not carry out separation and purification, add activating reagent and alkylating reagent directly carries out alkylation on the both sides of compound ii carbonyl, a step obtains Wy-16225 key intermediate V.
6. preparation method as described in any one of claim 1-5, is characterized in that, described methylating reagent comprise in methyl alcohol, methyl iodide, monobromethane, methyl-sulfate one or more;
Described methylated activating reagent comprises imidazoles, pyrroles, pyridine, piperidines, morpholine, triethylamine, diisopropyl ethyl amine, Ag
2o, DMAP, K
2cO
3, Cs
2cO
3, NaOH, KOH, LiOH, NaH, KH, NaOR, potassium tert.-butoxide, one or more in sodium tert-butoxide and lithium diisopropylamine; In described NaOR, R is alkyl.
7. preparation method as claimed in claim 6, it is characterized in that, the solvent that each step is reacted used comprises water, tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethyl acetate, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, pyridine, dioxane, 1, one or more in 2-ethylene dichloride, 1,1-ethylene dichloride, benzene, toluene, o-Xylol, m-xylene, p-Xylol, methyl-isobutyl ether, ether, acetone, methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol and the trimethyl carbinol.
8. the preparation method as described in claim 1-5 or 7 any one, it is characterized in that, described alkylating reagent be end all containing leavings group containing the compound III of five carbon atoms, LG comprises one in I, Br, Cl, benzene sulfonate, p-toluenesulfonic esters and methanesulfonates or two kinds.
9. preparation method as claimed in claim 8, it is characterized in that, it is characterized in that, the temperature of described methylation reaction is-20 DEG C ~ 75 DEG C; The temperature of described alkylated reaction is-20 DEG C ~ 130 DEG C.
10. the preparation method as described in claim 1-5,7 or 9 any one, is converted into the activating reagent that carbonyl monolateral alkylate IV a, IV b and carbonyl bilateral alkylate Wy-16225 intermediate V use and comprises imidazoles, pyrroles, pyridine, morpholine, piperidines, indoles, quinoline, ammoniacal liquor, triethylamine, diisopropyl ethyl amine, RNH by described methylate
2, DMAP, K
2cO
3, Na
2cO
3, Cs
2cO
3, NaH, KH, NaOH, KOH, LiOH, Ca (OH)
2, NaOR, potassium tert.-butoxide, sodium tert-butoxide, butyllithium, tert-butyl lithium, hmds base potassium, one or more in hexamethyldisilazane lithium and lithium diisopropylamine.
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| CN108299173A (en) * | 2018-01-26 | 2018-07-20 | 扬子江药业集团有限公司 | A kind of method of asymmetric synthesis of dezocine key intermediate |
| CN109206385A (en) * | 2017-07-03 | 2019-01-15 | 扬子江药业集团有限公司 | A kind of preparation method of dezocine impurity A and its homologue |
| CN113896621A (en) * | 2021-10-09 | 2022-01-07 | 宁波赜军医药科技有限公司 | 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 |
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| CN109206385A (en) * | 2017-07-03 | 2019-01-15 | 扬子江药业集团有限公司 | A kind of preparation method of dezocine impurity A and its homologue |
| 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 |
| CN108299173A (en) * | 2018-01-26 | 2018-07-20 | 扬子江药业集团有限公司 | A kind of method of asymmetric synthesis of dezocine key intermediate |
| 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 |
| CN113896621A (en) * | 2021-10-09 | 2022-01-07 | 宁波赜军医药科技有限公司 | Asymmetric synthesis method of dezocine key intermediate |
| 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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