CN105367538A - Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material - Google Patents
Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material Download PDFInfo
- Publication number
- CN105367538A CN105367538A CN201510836795.4A CN201510836795A CN105367538A CN 105367538 A CN105367538 A CN 105367538A CN 201510836795 A CN201510836795 A CN 201510836795A CN 105367538 A CN105367538 A CN 105367538A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- compd
- ether
- consumption
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ODQWQRRAPPTVAG-BOPFTXTBSA-N CN(C)CC/C=C1\c(cccc2)c2OCc2c1cccc2 Chemical compound CN(C)CC/C=C1\c(cccc2)c2OCc2c1cccc2 ODQWQRRAPPTVAG-BOPFTXTBSA-N 0.000 description 2
- 0 *C1=CCCC=C1COc1ccccc1 Chemical compound *C1=CCCC=C1COc1ccccc1 0.000 description 1
- FQEMARONUOAYGT-UHFFFAOYSA-N OC1=CCCC=C1 Chemical compound OC1=CCCC=C1 FQEMARONUOAYGT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/12—[b,e]-condensed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as a raw material. In the method, o-halogen methyl methyl benzoate which is wide in source is used as a starting raw material, and sulfasalazine is obtained through substitution, hydrolysis, cyclization, nucleophilic addition, elimination reaction, nucleophilic substitution and neutralization reaction. The method comprises: during a nucleophilic substitution reaction obtained in the seventh step, using an organic lithium compound in an ether solution, so that the organic lithium compound and dimethylamine form an ammonium lithium salt (the formula is as shown in the description); then conducting an alkylation reaction on the ammonium lithium salt and a halide to improve the yield of tertiary amine, thereby ensuring the yield and purity of doxepin hydrochloride.
Description
Technical field
The present invention relates to the technical field of doxepin hydrochloride, particularly relate to a kind of with adjacent halogeno-toluene methyl-formiate for the method for doxepin hydrochloride prepared by raw material.
Background technology
Doxepin hydrochloride, chemical name is the mixture of the cis-trans-isomer of N, N-dimethyl-3-dibenzo (b, e)-Evil English in heptan-11 (6H) subunit-1-propylamine hydrochlorate.Its No. CAS is 1229-29-4, and structural formula is
Doxepin hydrochloride is the medicine being used for the treatment of dysthymia disorders and anxiety neurosis, its role is to the re-uptake suppressing central nervous system to serotonin and norepinephrine, thus make these two kinds of concentration of neurotransmitters in synaptic cleft increase and play antidepressant effect, also there is anxiety and sedative effect.Doxepin hydrochloride oral absorption is good, and bioavailability is 13-45%, transformation period (t
1/2) be 8-12 hour, apparent volume of distribution (Vd) 9-33L/kg.Main at liver metabolism, active metabolite is demethyl compound.Metabolite is from renal excretion, and elderly patients decline to the metabolism of this product and discharge capacity
Chinese patent CN102924486A discloses a kind of preparation method of doxepin hydrochloride.The method comprises C-N linked reaction, namely uses Ni (OAc)
2/ PPh
3amino-complex is received by system.Although the catalyst n i (OAc) of the reaction of this step
2comparatively cheap and easy to get, but the yield of this step reaction is lower, and the purity of product is lower.
Summary of the invention
In view of this, the invention provides a kind of preparation method of doxepin hydrochloride, purity and the yield of the refined product obtained through this preparation method are all higher.
A preparation method for doxepin hydrochloride, comprises the following steps:
(1) adjacent halogeno-toluene methyl-formiate and phenol are carried out substitution reaction in the alcoholic solvent of sodium methylate, obtain compound H, reaction formula is as follows,
(2) be hydrolyzed described compound H reaction, and obtain Compound I, reaction formula is as follows,
(3) described Compound I is carried out cyclization under the catalysis of trifluoroacetic anhydride in dichloroethane solvent, obtain 6,11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone (compd A), reaction formula is as follows,
(4) by 6,11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone (compd A) and 3-chloropropane base tertbutyl ether (compd B) are adding magnesium powder and are carrying out nucleophilic addition under the condition being solvent with THF and/or anhydrous diethyl ether, obtain hydroxy kind compound (Compound C), reaction formula is as follows
(5) heat in the alcoholic solvent of highly basic to described hydroxy kind compound and carry out eliminative reaction, obtain alkenes compounds (Compound D), reaction formula is as follows,
(6) described alkenes compounds is carried out nucleophilic substitution reaction under haloid acid, obtain halides (compd E), reaction formula is as follows,
Wherein, in compd E, X is-Cl ,-Br or-I;
(7) by described halides with dimethylamine add organolithium compound in the solvent of ether under carry out nucleophilic substitution reaction, obtain doxepin (compound F 17-hydroxy-corticosterone), reaction formula is as follows,
(8) described doxepin is carried out neutralization reaction with hydrochloric acid, obtain sulfasalazine (compound G), reaction formula is as follows,
Aforementioned, the said substitution reaction principle of step (4) is, the monochloromethyl of adjacent halogeno-toluene methyl-formiate and the phenolic hydroxyl group of phenol carry out de-a part haloid acid.This substitution reaction is S
nthe nucleophilic substitution course of 1 mechanism.Be specially, the benzyl halogen of the first step, adjacent halogeno-toluene methyl-formiate X negative ion of leaving away under the attack of highly basic sodium methylate generates comparatively stable benzyl carbenium ions; Sauerstoffatom on second step, phenol as nucleophilic reagent attack benzyl carbenium ions, and sloughs hydrogen ion simultaneously, obtains phenylbenzyl ether compound.
Because the phenolic hydroxyl group of phenol also can carry out transesterification reaction with the methyl-formiate of adjacent halogeno-toluene methyl-formiate, in order to make up the consumption that phenol causes because of this reaction, phenol is preferably excessive, and such as both ratios can be 1:1.05 ~ 1.15.Do not limit the temperature and time of substitution reaction in the present invention, such as temperature can be 50 ~ 60 DEG C, and the time of substitution reaction at this temperature can be 3 ~ 6h.The alcoholic solvent consumption of sodium methylate is 3 ~ 10 preferably, in the total mass of adjacent halogeno-toluene methyl-formiate and phenol for 1.The concrete composition of the alcoholic solvent of sodium methylate does not limit at this, and the yield etc. of its composition to reaction has no significant effect.
Aforementioned, adjacent halogeno-toluene methyl-formiate can be prepared by o-toluic acid.Be specially, first, adopt known temperature and time to obtain carboxylicesters in acid condition o-toluic acid and methyl alcohol; Then, carboxylicesters carries out (such as illumination, heating etc.) free radical at N-halosuccinimides (N-chlorosuccinimide, N-bromo-succinimide, N-N-iodosuccinimide) and replaces under known condition, obtain adjacent halogeno-toluene methyl-formiate (free radical substitution reaction can be carried out with reference to the report of periodical literature " progress of N-bromosuccinic acid imines in organic reaction; Wu is alert, Chemical Industry in Guangzhou 39 volumes the 9th phase in 2011 ").
Abovementioned steps (2), hydrolysis reaction is carboxyester hydrolysis and generates carboxylic acid.For providing reactive behavior, can carry out under the catalysis of alkali (such as sodium hydroxide, potassium hydroxide, lithium hydroxide).The temperature of hydrolysis reaction is preferably 30 ~ 40 DEG C, and the time of hydrolysis reaction is preferably 4 ~ 8h.
Aforementioned, in step (3), this cyclization is the electrophilic substitution on benzoyloxy and different phenyl ring generation phenyl ring.Preferably, the temperature of cyclization is 95 ~ 105 DEG C, and the time of cyclization is 6 ~ 12h.The consumption of trifluoroacetic anhydride can be 1.1 ~ 1.3, in the amount of Compound I for 1.The consumption of acid can be 1.5 ~ 5, in the volume of trifluoroacetic anhydride for 1.
The nucleophilic addition of step (4), first 3-chloropropane base tertbutyl ether is react with magnesium powder in solvent to generate Grignard reagent at THF and/or anhydrous diethyl ether, namely
carbanion and the employing S of the 3-propyl tertbutyl ether then in Grignard reagent
nto 6,11-dihydro-dibenzo, [carbonyl on b, e] Evil English in heptan-11-ketone carries out attack there is addition to 2 mechanism.
To above-mentioned 6,11-dihydro-dibenzos, [amount of b, e] Evil English in heptan-11-ketone, 3-chloropropane base tertbutyl ether is not made and being particularly limited in the present invention.In order to improve 6,11-dihydro-dibenzo, [transformation efficiency of b, e] Evil English in heptan-11-ketone, 3-chloropropane base tertbutyl ether can be made excessive a little, and both amounts can 1:1.1 ~ 1.5.The temperature of nucleophilic addition is advisable with 35 ~ 40 DEG C.Under the prerequisite of this temperature of reaction, the reaction times is preferably 2 ~ 5h.
In the reaction of aforementioned generation Grignard reagent, be 1 calculating with the quality of compd A, the add-on of magnesium powder can be 2 ~ 2.4, and the add-on of solvent can be 5 ~ 7.The composition form of solvent does not do special restriction, can be used alone THF, is used alone anhydrous diethyl ether, and any proportioning ground THF used in combination and anhydrous diethyl ether.
In step (5), aforesaid eliminative reaction is E2 mechanism, i.e. hydrogen on the ortho position carbon of hydroxy kind compound hydroxyl leave away and leaving away of hydroxyl is synchronously carried out.Temperature as this eliminative reaction is advisable with 65 ~ 80 DEG C, and the time of eliminative reaction is 2 ~ 4h.Be 1 calculating with the quality of reaction substrate hydroxy kind compound, the consumption of the alcoholic solvent of highly basic is preferably 1.5 ~ 5.The mass concentration of the alcoholic solvent of highly basic can be 10 ~ 70%.Here, mass concentration calculates under the prerequisite being solute with highly basic.Highly basic can adopt this area to commonly use, and such as potassium hydroxide, sodium hydroxide can also be sodium methylate, sodium ethylate etc.
In step (6), nucleophilic substitution reaction is the fracture of ehter bond.The mechanism of this reaction is S
n1, the O atom of the first step ehter bond forms melt salt under hydrionic effect; Second step, melt salt dissociates tertiary fourth carbonium ion, generates hydroxyl; 3rd step, this oxy-compound is combined with X negative ion, forms halides.The temperature of nucleophilic substitution reaction can be 50 ~ 60 DEG C, and the time of reaction can be 1.5 ~ 4h.The consumption of haloid acid is 1 ~ 2, in the amount of Compound D for 1.The percent mass concentration of haloid acid is 5 ~ 30%.For ensureing the reactive behavior of nucleophilic, haloid acid is preferably hydroiodic acid HI.
In step (7), organolithium compound and dimethylamine form ammonium lithium salts
then this ammonium lithium salts and halides carry out alkylated reaction.Adopt organolithium compound to improve the nucleophilicity of nitrogen-atoms in amine, carry out the yield that alkylated reaction can improve tertiary amine.
Organolithium compound and R-Li.Here R is alkoxyl group, such as straight or branched alkane, is preferably C
1~ C
4straight-chain paraffin base, using is n-Butyl Lithium comparatively widely; R can be aryl, such as phenyl.In order to ensure that organolithium compound does not lose reactive behavior, can now-making-now-using.The preparation method of organolithium compound can adopt method well known in the art, and such as n-Butyl Lithium can react obtained from chlorobutane and metallic lithium pentane or other liquid alkanes.Lithium methide, phenyl lithium etc. can be prepared from corresponding halohydrocarbon.The consumption of organolithium compound is 0.1 ~ 0.8, is 1 calculating with the quality of compd E.
Form for ether does not limit, and preferably, the carbochain in ether is not long, such as ether be selected from ether, methyl ethyl ether, propyl ether any one or two or more.The consumption of ether is 2 ~ 8, is 1 calculating with the quality of compd E.Based on the better effect of reaction, the temperature of nucleophilic substitution reaction is 40 ~ 50 DEG C, and the reaction times is 2 ~ 5h.
In step (8), the temperature of neutralization reaction is 130 ~ 150 DEG C, and the time of described reaction is 16 ~ 20h.Should be understood that, because this reaction system is aqueous phase, in order to reach the temperature of 130 ~ 150 DEG C, can carry out when pressurizeing.Concrete pressure is not limited, such as 3 ~ 4MPa.The mass concentration of hydrochloric acid is 30 ~ 38%, is the concentrated hydrochloric acid of about 37.7% preferably.In order to make doxepin thoroughly be neutralized, can ensure that hydrochloric acid is micro-excessive, the consumption of such as hydrochloric acid is 1.05 ~ 1.2, is 1 calculating with the amount of compound F 17-hydroxy-corticosterone.
The present invention for starting raw material, successively by replacement, hydrolysis, cyclisation, nucleophilic addition(Adn), eliminative reaction, nucleophilic substitution, nucleophilic substitution, neutralization reaction, obtains sulfasalazine with adjacent halogeno-toluene methyl-formiate widely of originating.Obtain in the nucleophilic substitution reaction step of the 7th step, adopt organolithium compound in the solvent of ether, make machine lithium compound and dimethylamine form ammonium lithium salts like this
then this ammonium lithium salts and halides carry out alkylated reaction, improve the yield of tertiary amine, ensure that yield and the purity of final doxepin hydrochloride thus.
Embodiment
Technical scheme of the present invention is further illustrated below in conjunction with embodiment.
Embodiment 1
In the reaction vessel of 20L, insert O-bromo methyl methyl benzoate, alcohol solvent (total mass of O-bromo methyl methyl benzoate and phenol is 1) that consumption is the sodium methylate of 3, the temperature regulating reaction solution is after 50 DEG C, start to instill the phenol (in the amount of O-bromo methyl methyl benzoate for 1) that amount is 1.05, time for adding is 1h.After dropwising, after isothermal reaction 5h, adopt known separation method, obtain adjacent methyl-formiate benzyl phenyl ether, by this called after compound H.
The aqueous solution of above-claimed cpd H and sodium hydroxide is inserted in reaction vessel, regulates temperature at 30 DEG C, stirring reaction 8h, adopt known separation means to be separated and obtain (adjacent formyloxy) benzyl phenyl ether, by called after Compound I.
Be the trifluoroacetic anhydride (in the amount of Compound I for 1) of 1.1 by above-claimed cpd I, consumption, consumption is that the ethylene dichloride (in the volume of trifluoroacetic anhydride for 1) of 5 volumes is inserted in reaction vessel, adjust the temperature to 95 DEG C.The time of question response is 12h.Known separation means is adopted to isolate 6,11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone.
6 are inserted in the reaction vessel of 20L, 11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone, 1.1 times of mole numbers are in 6, [the 3-chloropropane base tertbutyl ether of b, e] Evil English in heptan-11-ketone, 2 times of quality are in 6,11-dihydro-dibenzo [b for 11-dihydro-dibenzo, the magnesium powder of e] Evil English in heptan-11-ketone, get whole THF 2/5ths (5 times of quality are in 6,11-dihydro-dibenzo [THF of b, e] Evil English in heptan-11-ketone), and be heated to 35 DEG C make it reaction.Question response drips the THF of remaining 3/5 after starting.Wait to dropwise and pass into hydrogen in system, backflow.After total coreaction is 5h, stopped reaction.Pour in saturated ammonium chloride solution after system being cooled, add extraction into ethyl acetate secondary, use anhydrous sodium sulfate drying 5h, the thick product sherwood oil recrystallization obtained, obtains hydroxy kind compound again.
Above-mentioned hydroxy kind compound, 1.5 times of ethanolic solns to the sodium hydroxide of hydroxy kind compound quality (mass concentration 10wt%) are inserted in the reaction vessel of 20L, be heated to 65 DEG C, stopped reaction after eliminative reaction 2h, cooling, evaporate more than solvent, by obtained thick product sherwood oil crystallization, obtain alkenes compounds.
In the reaction vessel of 20L, insert above-mentioned alkenes compounds, 1 times of quality in the salt aqueous acid (mass concentration is 5wt%) added of alkenes compounds, be heated to 50 DEG C, make it nucleophilic substitution reaction.The time of question response is after 4h, stopped reaction, cooling, evaporate more than solvent, by obtained thick product sherwood oil crystallization, obtain halides.
In the reaction vessel of 20L, insert above-mentioned halides, 0.1 times of quality in the lithium methide of halides, 2 times of quality in the ether of halides, be heated to 40 DEG C, make it nucleophilic substitution reaction.The time of question response is after 5h, stopped reaction, reacts complete and adds extraction into ethyl acetate three times, use anhydrous sodium sulfate drying 5h, and namely the thick product sherwood oil recrystallization obtained obtains doxepin.
In the pressure-resistant reaction vessel of 20L, insert above-mentioned doxepin, 1.05 times of amounts in the hydrochloric acid (mass concentration is 30wt%) of doxepin, control pressure, in 3 ~ 4MPa, is heated to 130 DEG C, makes it neutralization reaction.The time of question response is after 20h, react complete be cooled to room temperature after filtration, drying obtains doxepin hydrochloride.In this example, total recovery is 45.6%, and recording its purity through HPLC is 99.2%.
Embodiment 2
In the reaction vessel of 20L, insert O-bromo methyl methyl benzoate, alcohol solvent (total mass of O-bromo methyl methyl benzoate and phenol is 1) that consumption is the sodium methylate of 10, the temperature regulating reaction solution is after 60 DEG C, start to instill the phenol (in the amount of O-bromo methyl methyl benzoate for 1) that amount is 1.15, time for adding is 1h.After dropwising, after isothermal reaction 5h, adopt known separation method, obtain adjacent methyl-formiate benzyl phenyl ether, by this called after compound H.
The aqueous solution of above-claimed cpd H and sodium hydroxide is inserted in reaction vessel, regulates temperature at 40 DEG C, stirring reaction 4h, adopt known separation means to be separated and obtain (adjacent formyloxy) benzyl phenyl ether, by called after Compound I.
Be the trifluoroacetic anhydride (in the amount of Compound I for 1) of 1.3 by above-claimed cpd I, consumption, consumption is that the ethylene dichloride (in the volume of trifluoroacetic anhydride for 1) of 1.5 volumes is inserted in reaction vessel, adjust the temperature to 105 DEG C.The time of question response is 6h.Known separation means is adopted to isolate 6,11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone.
6 are inserted in the reaction vessel of 20L, 11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone, 1.5 times of mole numbers are in 6, [the 3-chloropropane base tertbutyl ether of b, e] Evil English in heptan-11-ketone, 2.4 times of quality are in 6,11-dihydro-dibenzo [b for 11-dihydro-dibenzo, the magnesium powder of e] Evil English in heptan-11-ketone, get whole THF 2/5ths (5 ~ 7 times of quality are in 6,11-dihydro-dibenzo [THF of b, e] Evil English in heptan-11-ketone), and be heated to 40 DEG C make it reaction.Question response drips the THF of remaining 3/5 after starting.Wait to dropwise and pass into hydrogen in system, backflow.After total coreaction is 2h, stopped reaction.Pour in saturated ammonium chloride solution after system being cooled, add extraction into ethyl acetate secondary, use anhydrous sodium sulfate drying 5h, the thick product sherwood oil recrystallization obtained, obtains hydroxy kind compound again.
Above-mentioned hydroxy kind compound, 5 times of ethanolic solns to the sodium hydroxide of hydroxy kind compound quality (mass concentration 70wt%) are inserted in the reaction vessel of 20L, be heated to 80 DEG C, stopped reaction after eliminative reaction 1h, cooling, evaporate more than solvent, by obtained thick product sherwood oil crystallization, obtain alkenes compounds.
In the reaction vessel of 20L, insert above-mentioned alkenes compounds, 2 times of quality in the hydrobromic aqueous solution (mass concentration is 30wt%) added of alkenes compounds, be heated to 60 DEG C, make it nucleophilic substitution reaction.The time of question response is after 1.5h, stopped reaction, cooling, evaporate more than solvent, by obtained thick product sherwood oil crystallization, obtain halides.
In the reaction vessel of 20L, insert above-mentioned halides, 0.8 times of quality in the phenyl lithium of halides, 8 times of quality in the ether of halides, be heated to 50 DEG C, make it nucleophilic substitution reaction.The time of question response is after 2h, stopped reaction, reacts complete and adds extraction into ethyl acetate three times, use anhydrous sodium sulfate drying 5h, and namely the thick product sherwood oil recrystallization obtained obtains doxepin.
In the pressure-resistant reaction vessel of 20L, insert above-mentioned doxepin, 1.2 times of amounts in the hydrochloric acid (mass concentration is 38wt%) of doxepin, control pressure, in 3 ~ 4MPa, is heated to 150 DEG C, makes it neutralization reaction.The time of question response is after 16h, react complete be cooled to room temperature after filtration, drying obtains doxepin hydrochloride.In this example, total recovery is 46.7%, and recording its purity through HPLC is 99.4%.
Embodiment 3
In the reaction vessel of 20L, insert O-chioromethyl Methyl Benzoate, alcohol solvent (total mass of O-bromo methyl methyl benzoate and phenol is 1) that consumption is the sodium methylate of 6, the temperature regulating reaction solution is after 55 DEG C, start to instill the phenol (in the amount of O-bromo methyl methyl benzoate for 1) that amount is 1.10, time for adding is 1h.After dropwising, after isothermal reaction 3.5h, adopt known separation method, obtain adjacent methyl-formiate benzyl phenyl ether, by this called after compound H.
The aqueous solution of above-claimed cpd H and sodium hydroxide is inserted in reaction vessel, regulates temperature at 35 DEG C, stirring reaction 6h, adopt known separation means to be separated and obtain (adjacent formyloxy) benzyl phenyl ether, by called after Compound I.
Be the trifluoroacetic anhydride (in the amount of Compound I for 1) of 1.2 by above-claimed cpd I, consumption, consumption is that the ethylene dichloride (in the volume of trifluoroacetic anhydride for 1) of 3.2 volumes is inserted in reaction vessel, adjust the temperature to 100 DEG C.The time of question response is 9h.Known separation means is adopted to isolate 6,11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone.
6 are inserted in the reaction vessel of 20L, 11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone, 1.3 times of mole numbers are in 6, [the 3-chloropropane base tertbutyl ether of b, e] Evil English in heptan-11-ketone, 2.2 times of quality are in 6,11-dihydro-dibenzo [b for 11-dihydro-dibenzo, the magnesium powder of e] Evil English in heptan-11-ketone, get whole THF 2/5ths (5 ~ 7 times of quality are in 6,11-dihydro-dibenzo [THF of b, e] Evil English in heptan-11-ketone), and be heated to 38 DEG C make it reaction.Question response drips the THF of remaining 3/5 after starting.Wait to dropwise and pass into hydrogen in system, backflow 2h.After total coreaction is 3.5h, stopped reaction.Pour in saturated ammonium chloride solution after system being cooled, add extraction into ethyl acetate secondary, use anhydrous sodium sulfate drying 5h, the thick product sherwood oil recrystallization obtained, obtains hydroxy kind compound again.
Above-mentioned hydroxy kind compound, 3 times of ethanolic solns to the sodium hydroxide of hydroxy kind compound quality (mass concentration 40wt%) are inserted in the reaction vessel of 20L, be heated to 75 DEG C, stopped reaction after eliminative reaction 1.5h, cooling, evaporate more than solvent, by obtained thick product sherwood oil crystallization, obtain alkenes compounds.
In the reaction vessel of 20L, insert above-mentioned alkenes compounds, 1.5 times of quality enter in the aqueous solution of the hydroiodic acid HI added of alkenes compounds (mass concentration is 18wt%), be heated to 55 DEG C, make it nucleophilic substitution reaction.The time of question response is after 2h, stopped reaction, cooling, evaporate more than solvent, by obtained thick product sherwood oil crystallization, obtain halides.
In the reaction vessel of 20L, insert above-mentioned halides, 0.4 times of quality in the n-Butyl Lithium of halides, 5 times of quality in the ether of halides, be heated to 45 DEG C, make it nucleophilic substitution reaction.The time of question response is after 3.5h, stopped reaction, reacts complete and adds extraction into ethyl acetate three times, use anhydrous sodium sulfate drying 5h, and namely the thick product sherwood oil recrystallization obtained obtains doxepin.
In the pressure-resistant reaction vessel of 20L, insert above-mentioned doxepin, 1.12 times of amounts in the hydrochloric acid (mass concentration is 34wt%) of doxepin, control pressure, in 3 ~ 4MPa, is heated to 140 DEG C, makes it neutralization reaction.The time of question response is after 18h, react complete be cooled to room temperature after filtration, drying obtains doxepin hydrochloride.In this example, total recovery is 50.3%, and recording its purity through HPLC is 99.5%.
Embodiment 4
In the reaction vessel of 20L, insert O-bromo methyl methyl benzoate, alcohol solvent (total mass of O-bromo methyl methyl benzoate and phenol is 1) that consumption is the sodium methylate of 5, the temperature regulating reaction solution is after 55 DEG C, start to instill the phenol (in the amount of O-bromo methyl methyl benzoate for 1) that amount is 1.15, time for adding is 1h.After dropwising, after isothermal reaction 5h, adopt known separation method, obtain adjacent methyl-formiate benzyl phenyl ether, by this called after compound H.
The aqueous solution of above-claimed cpd H and sodium hydroxide is inserted in reaction vessel, regulates temperature at 35 DEG C, stirring reaction 8h, adopt known separation means to be separated and obtain (adjacent formyloxy) benzyl phenyl ether, by called after Compound I.
Be the trifluoroacetic anhydride (in the amount of Compound I for 1) of 1.3 by above-claimed cpd I, consumption, consumption is that the ethylene dichloride (in the volume of trifluoroacetic anhydride for 1) of 3 volumes is inserted in reaction vessel, adjust the temperature to 100 DEG C.The time of question response is 12h.Known separation means is adopted to isolate 6,11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone.
6 are inserted in the reaction vessel of 20L, 11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone, 1.3 times of mole numbers are in 6, [the 3-chloropropane base tertbutyl ether of b, e] Evil English in heptan-11-ketone, 2.4 times of quality are in 6,11-dihydro-dibenzo [b for 11-dihydro-dibenzo, the magnesium powder of e] Evil English in heptan-11-ketone, get whole THF 2/5ths (5 ~ 7 times of quality are in 6,11-dihydro-dibenzo [THF of b, e] Evil English in heptan-11-ketone), and be heated to 40 DEG C make it reaction.Question response drips the THF of remaining 3/5 after starting.Wait to dropwise and pass into hydrogen in system, backflow.After total coreaction is 2h, stopped reaction.Pour in saturated ammonium chloride solution after system being cooled, add extraction into ethyl acetate secondary, use anhydrous sodium sulfate drying 5h, the thick product sherwood oil recrystallization obtained, obtains hydroxy kind compound again.
Above-mentioned hydroxy kind compound, 5 times of ethanolic solns to the sodium hydroxide of hydroxy kind compound quality (mass concentration 70wt%) are inserted in the reaction vessel of 20L, be heated to 80 DEG C, stopped reaction after eliminative reaction 1h, cooling, evaporate more than solvent, by obtained thick product sherwood oil crystallization, obtain alkenes compounds.
In the reaction vessel of 20L, insert above-mentioned alkenes compounds, 1.5 times of quality enter in the aqueous solution of the hydroiodic acid HI added of alkenes compounds (mass concentration is 30wt%), be heated to 60 DEG C, make it nucleophilic substitution reaction.The time of question response is after 1.5h, stopped reaction, cooling, evaporate more than solvent, by obtained thick product sherwood oil crystallization, obtain halides.
In the reaction vessel of 20L, insert above-mentioned halides, 0.8 times of quality in the n-Butyl Lithium of halides, 8 times of quality in the ether of halides, be heated to 50 DEG C, make it nucleophilic substitution reaction.The time of question response is after 2h, stopped reaction, reacts complete and adds extraction into ethyl acetate three times, use anhydrous sodium sulfate drying 5h, and namely the thick product sherwood oil recrystallization obtained obtains doxepin.
In the pressure-resistant reaction vessel of 20L, insert above-mentioned doxepin, 1.2 times of amounts in the hydrochloric acid (mass concentration is 38wt%) of doxepin, control pressure, in 3 ~ 4MPa, is heated to 150 DEG C, makes it neutralization reaction.The time of question response is after 16h, react complete be cooled to room temperature after filtration, drying obtains doxepin hydrochloride.In this example, total recovery is 42.3%, and recording its purity through HPLC is 99.7%.
Embodiment 5
In the reaction vessel of 20L, insert O-bromo methyl methyl benzoate, alcohol solvent (total mass of O-bromo methyl methyl benzoate and phenol is 1) that consumption is the sodium methylate of 5, the temperature regulating reaction solution is after 55 DEG C, start to instill the phenol (in the amount of O-bromo methyl methyl benzoate for 1) that amount is 1.08, time for adding is 1h.After dropwising, after isothermal reaction 3h, adopt known separation method, obtain adjacent methyl-formiate benzyl phenyl ether, by this called after compound H.
The aqueous solution of above-claimed cpd H and sodium hydroxide is inserted in reaction vessel, regulates temperature at 35 DEG C, stirring reaction 6h, adopt known separation means to be separated and obtain (adjacent formyloxy) benzyl phenyl ether, by called after Compound I.
Be the trifluoroacetic anhydride (in the amount of Compound I for 1) of 1.15 by above-claimed cpd I, consumption, consumption is that the ethylene dichloride (in the volume of trifluoroacetic anhydride for 1) of 3 volumes is inserted in reaction vessel, adjust the temperature to 100 DEG C.The time of question response is 8h.Known separation means is adopted to isolate 6,11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone.
6 are inserted in the reaction vessel of 20L, 11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone, 1.2 times of mole numbers are in 6, [the 3-chloropropane base tertbutyl ether of b, e] Evil English in heptan-11-ketone, 2.2 times of quality are in 6,11-dihydro-dibenzo [b for 11-dihydro-dibenzo, the magnesium powder of e] Evil English in heptan-11-ketone, get whole THF 2/5ths (5 ~ 7 times of quality are in 6,11-dihydro-dibenzo [THF of b, e] Evil English in heptan-11-ketone), and be heated to 38 DEG C make it reaction.Question response drips the THF of remaining 3/5 after starting.Wait to dropwise and pass into hydrogen in system, backflow.After total coreaction is 2h, stopped reaction.Pour in saturated ammonium chloride solution after system being cooled, add extraction into ethyl acetate secondary, use anhydrous sodium sulfate drying 5h, the thick product sherwood oil recrystallization obtained, obtains hydroxy kind compound again.
Above-mentioned hydroxy kind compound, 2 times of ethanolic solns to the sodium hydroxide of hydroxy kind compound quality (mass concentration 40wt%) are inserted in the reaction vessel of 20L, be heated to 70 DEG C, stopped reaction after eliminative reaction 2h, cooling, evaporate more than solvent, by obtained thick product sherwood oil crystallization, obtain alkenes compounds.
In the reaction vessel of 20L, insert above-mentioned alkenes compounds, 1.5 times of quality enter in the aqueous solution of the hydroiodic acid HI added of alkenes compounds (mass concentration is 15wt%), be heated to 50 DEG C, make it nucleophilic substitution reaction.The time of question response is after 4h, stopped reaction, cooling, evaporate more than solvent, by obtained thick product sherwood oil crystallization, obtain halides.
In the reaction vessel of 20L, insert above-mentioned halides, 0.4 times of quality in the n-Butyl Lithium of halides, 2 ~ 8 times of quality in the ether of halides, be heated to 45 DEG C, make it nucleophilic substitution reaction.The time of question response is after 3h, stopped reaction, reacts complete and adds extraction into ethyl acetate three times, use anhydrous sodium sulfate drying 5h, and namely the thick product sherwood oil recrystallization obtained obtains doxepin.
In the pressure-resistant reaction vessel of 20L, insert above-mentioned doxepin, 1.12 times of amounts in the hydrochloric acid (mass concentration is 37.6wt%) of doxepin, control pressure, in 3 ~ 4MPa, is heated to 140 DEG C, makes it neutralization reaction.The time of question response is after 20h, react complete be cooled to room temperature after filtration, drying obtains doxepin hydrochloride.In this example, total recovery is 52.4%, and recording its purity through HPLC is 99.9%.
Because the numerical range of each processing parameter involved in the present invention can not all embody in the above-described embodiments, as long as but those skilled in the art can imagine any numerical value fallen in this numerical range above-mentioned completely all can implement the present invention, certainly also comprise the arbitrary combination of occurrence in some numerical ranges.Herein, for the consideration of length, eliminate the embodiment providing occurrence in certain one or more numerical range, this should not be considered as the insufficient disclosure of technical scheme of the present invention.
Applicant states, the present invention illustrates detailed process equipment and process flow process of the present invention by above-described embodiment, but the present invention is not limited to above-mentioned detailed process equipment and process flow process, namely do not mean that the present invention must rely on above-mentioned detailed process equipment and process flow process and could implement.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of ancillary component, the concrete way choice etc. of each raw material of product of the present invention, all drops within protection scope of the present invention and open scope.
Claims (9)
1. with adjacent halogeno-toluene methyl-formiate for the method for doxepin hydrochloride prepared by raw material, it is characterized in that, comprise the following steps:
(1) adjacent halogeno-toluene methyl-formiate and phenol are carried out substitution reaction in the alcoholic solvent of sodium methylate, obtain compound H, reaction formula is as follows,
(2) be hydrolyzed described compound H reaction, and obtain Compound I, reaction formula is as follows,
(3) described Compound I is carried out cyclization under the catalysis of trifluoroacetic anhydride in dichloroethane solvent, obtain 6,11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone (compd A), reaction formula is as follows,
(4) by 6,11-dihydro-dibenzo [b, e] Evil English in heptan-11-ketone (compd A) and 3-chloropropane base tertbutyl ether (compd B) are adding magnesium powder and are carrying out nucleophilic addition under the condition being solvent with THF and/or anhydrous diethyl ether, obtain hydroxy kind compound (Compound C), reaction formula is as follows
(5) heat in the alcoholic solvent of highly basic to described hydroxy kind compound and carry out eliminative reaction, obtain alkenes compounds (Compound D), reaction formula is as follows,
(6) described alkenes compounds is carried out nucleophilic substitution reaction under haloid acid, obtain halides (compd E), reaction formula is as follows,
Wherein, in compd E, X is-Cl ,-Br or-I;
(7) by described halides with dimethylamine add organolithium compound in the solvent of ether under carry out nucleophilic substitution reaction, obtain doxepin (compound F 17-hydroxy-corticosterone), reaction formula is as follows,
(8) described doxepin is carried out neutralization reaction with hydrochloric acid, obtain sulfasalazine (compound G), reaction formula is as follows,
2. preparation method according to claim 1, is characterized in that, in step (1):
Adjacent halogeno-toluene methyl-formiate is 1:1.05 ~ 1.15 with the ratio of the amount of phenol;
Preferably, the temperature of described substitution reaction is 50 ~ 60 DEG C, and the time of described substitution reaction is 3 ~ 6h;
Preferably, the alcoholic solvent consumption of described sodium methylate is 3 ~ 10, in the total mass of adjacent halogeno-toluene methyl-formiate and phenol for 1.
3. preparation method according to claim 1, is characterized in that, in step (2):
The temperature of described hydrolysis reaction is 30 ~ 40 DEG C, and the time of described hydrolysis reaction is 4 ~ 8h;
Preferably, described hydrolysis reaction take alkali as catalyzer;
Preferably, described alkali be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide any one or two or more.
4. preparation method according to claim 1, is characterized in that, in step (3):
The consumption of described trifluoroacetic anhydride is 1.1 ~ 1.3, in the amount of Compound I for 1;
Preferably, the consumption of described ethylene dichloride is 1.5 ~ 5, in the volume of trifluoroacetic anhydride for 1;
Preferably, the temperature of described cyclization is 95 ~ 105 DEG C, and the time of described cyclization is 6 ~ 12h.
5. preparation method according to claim 1, is characterized in that, in step (4):
Described compd A is 1:1.1 ~ 1.5 with the ratio of the amount of compd B;
Preferably, the temperature of described nucleophilic addition is 35 ~ 40 DEG C, and the reaction times is 2 ~ 5h;
Preferably, the add-on of described magnesium powder is 2 ~ 2.4, is 1 calculating with compd A quality;
Preferably, the add-on of described solvent is 5 ~ 7, is 1 calculating with compd A quality.
6. preparation method according to claim 1, is characterized in that, in step (5):
The temperature of described eliminative reaction is 65 ~ 80 DEG C;
Preferably, the mass concentration of the alcoholic solvent of described highly basic is 10 ~ 70%;
Preferably, the consumption of the alcoholic solvent of described highly basic is 1.5 ~ 5, is 1 calculating with the quality of Compound C.
7. preparation method according to claim 1, is characterized in that, in step (6):
The temperature of described nucleophilic substitution reaction is 50 ~ 60 DEG C, and the time of reaction is 1.5 ~ 4h;
Preferably, the consumption of described haloid acid is 1 ~ 2, with the amount of Compound D for 1;
Preferably, the mass concentration of described haloid acid is 5 ~ 30%.
8. preparation method according to claim 1, is characterized in that, in step (7):
Described organolithium compound is C
1~ C
4straight-chain paraffin base lithium;
Preferably, the consumption of described organolithium compound is 0.1 ~ 0.8, is 1 calculating with the quality of compd E;
Preferably, described ether be selected from ether, methyl ethyl ether, propyl ether any one or two or more;
Preferably, the consumption of described ether is 2 ~ 8, is 1 calculating with the quality of compd E;
Preferably, the temperature of described nucleophilic substitution reaction is 40 ~ 50 DEG C, and the reaction times is 2 ~ 5h.
9. preparation method according to claim 1, is characterized in that, in step (8):
The temperature of described neutralization reaction is 130 ~ 150 DEG C, and the time of described reaction is 16 ~ 20h;
Preferably, the mass concentration of described hydrochloric acid is 30 ~ 38%;
Preferably, the consumption of described hydrochloric acid is 1.05 ~ 1.2, is 1 calculating with the amount of compound F 17-hydroxy-corticosterone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510836795.4A CN105367538A (en) | 2015-11-26 | 2015-11-26 | Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510836795.4A CN105367538A (en) | 2015-11-26 | 2015-11-26 | Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105367538A true CN105367538A (en) | 2016-03-02 |
Family
ID=55370226
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510836795.4A Pending CN105367538A (en) | 2015-11-26 | 2015-11-26 | Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105367538A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574073A (en) * | 2020-12-14 | 2021-03-30 | 河北允升精细化工有限公司 | Process for recycling o-methyl formate benzyl sulfonamide production wastewater |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005102335A2 (en) * | 2004-04-23 | 2005-11-03 | Hypnion, Inc. | Methods of treating sleep disorders |
| CN101878042A (en) * | 2007-11-28 | 2010-11-03 | 尼克塔治疗公司 | Oligomer-tricyclic conjugates |
| WO2011091050A1 (en) * | 2010-01-19 | 2011-07-28 | Nektar Therapeutics | Oligomer-tricyclic conjugates |
| CN102924424A (en) * | 2012-09-04 | 2013-02-13 | 苏州弘森药业有限公司 | Method for synthesizing doxepin hydrochloride |
| CN104262318A (en) * | 2014-09-03 | 2015-01-07 | 石家庄创建医药科技有限公司 | Method for preparing olopatadine hydrochloride |
-
2015
- 2015-11-26 CN CN201510836795.4A patent/CN105367538A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005102335A2 (en) * | 2004-04-23 | 2005-11-03 | Hypnion, Inc. | Methods of treating sleep disorders |
| CN101878042A (en) * | 2007-11-28 | 2010-11-03 | 尼克塔治疗公司 | Oligomer-tricyclic conjugates |
| WO2011091050A1 (en) * | 2010-01-19 | 2011-07-28 | Nektar Therapeutics | Oligomer-tricyclic conjugates |
| CN102924424A (en) * | 2012-09-04 | 2013-02-13 | 苏州弘森药业有限公司 | Method for synthesizing doxepin hydrochloride |
| CN104262318A (en) * | 2014-09-03 | 2015-01-07 | 石家庄创建医药科技有限公司 | Method for preparing olopatadine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| JALANDER. LARS等: "Synthesis of dothiepin and doxepin by Grignard reactions in toluene", 《SYNTHETIC COMMUNICATIONS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574073A (en) * | 2020-12-14 | 2021-03-30 | 河北允升精细化工有限公司 | Process for recycling o-methyl formate benzyl sulfonamide production wastewater |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1312151C (en) | (imidazol-1-yl-methyl)-pyridazine as NMDA receptor blocker | |
| CN102046576B (en) | Process of preparing derivatives of 1-(2-halobiphenyl-4-yl)-cyclopropanecarboxylic acid | |
| CN106279074A (en) | A kind of compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| CN101910235B (en) | Epoxy compound and manufacturing method thereof | |
| CN103168025B (en) | Process for the preparation of substituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds | |
| CN101228109B (en) | Resolution of stereoisomeric n,n-dialkylamino-2-alkyl-3-phenyl alkanes | |
| CN104557572A (en) | Levalbuterol intermediate and levalbuterol hydrochloride synthesis method | |
| CN106432030A (en) | Preparation method of brivaracetam | |
| CN105085465A (en) | Method for synthesizing doxepin hydrochloride by taking halomethyl o-toluate as raw material | |
| CN105367538A (en) | Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material | |
| CN105061386A (en) | Method for synthesizing doxepin hydrochloride by utilizing phthalic anhydride as raw material | |
| CN105111181A (en) | Synthetic method of doxepin hydrochloride using methylbenzoate as raw materials | |
| CN105418577A (en) | Method for synthesizing doxepin hydrochloride from o-phthalaldehyde | |
| CN102320984B (en) | Preparation method of (R)-3-(3-methoxy phenyl)-N,N,2-trimethylpent-3-ene-1-amine | |
| CN104844654B (en) | A kind of quaternary salt compounds and preparation method thereof | |
| CN102002034B (en) | Method for separating flupentixol hydrochloride isomers | |
| CN103342664B (en) | Method for preparing tartrate | |
| CN105330638A (en) | Method for synthesizing doxepin hydrochloride by utilizing o-toluic acid as raw material | |
| CN105859589B (en) | A method of preparing bambuterol impurity C | |
| CN105330639A (en) | Synthetic method of doxepin hydrochloride adopting o-halogen methyl benzoate as raw material | |
| CN103664577B (en) | Preparation method of cinacalcet intermediate | |
| CN105085464A (en) | Synthesis method of doxepin hydrochloride | |
| CN102796022B (en) | Method for preparing 2-amino-2-[2-(4-alkyl phenyl) ethyl]-1,3-propanediol hydrochloride | |
| CN104803861B (en) | Method for synthesizing tapentadol hydrochloride | |
| CN102516236B (en) | Preparation method of antipsychotic drug iloperidone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160302 |