CN102924424B - Method for synthesizing doxepin hydrochloride - Google Patents
Method for synthesizing doxepin hydrochloride Download PDFInfo
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- CN102924424B CN102924424B CN201210388828.XA CN201210388828A CN102924424B CN 102924424 B CN102924424 B CN 102924424B CN 201210388828 A CN201210388828 A CN 201210388828A CN 102924424 B CN102924424 B CN 102924424B
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Abstract
The invention provides a method for synthesizing doxepin hydrochloride. The method comprises the following steps of: 1, carrying out an addition reaction on 6,11-dihydrobenz [b,e] oxepin-11-one and 3-chloropropyl-methyl tert-butyl ether to obtain alcohol compounds; 2, removing hydroxyl from the alcohol compounds under the condition of concentrated hydrochloric acid to obtain olefin compounds; 3, reacting the olefin compounds with thionyl chloride in a reaction solvent to obtain chloride; 4, coupling the chloride with N,N-dimethyl methylamine to obtain doxepin; and 5, preparing the doxepin into hydrochloride of the doxepin to obtain the doxepin hydrochloride. An Ni(OAc)2/PPh3 system is creatively used in C-N coupling reaction in the step 4, thus the doxepin hydrochloride has the characteristics of good reaction selectivity, high yield and environmental friendliness; and the catalyst is can be recycled after being simply filtered, thus the production cost is greatly lowered. The whole method has the advantages of simpleness in operation, and easy obtaining and low cost of raw materials, accords with the requirement of industrial production, and is expected to be industrially applied.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to a kind of method of synthetic hydrochloric acid doxepin.
Background technology
Doxepin hydrochloride (Doxepin Hydrochloride) is the medicine that is used for the treatment of dysthymia disorders and anxiety neurosis, its role is to suppress the re-uptake of central nervous system to serotonin and norepinephrine, thereby make these two kinds of neurotransmitter Enrichments in synaptic cleft and bring into play antidepressant effect, also there is anxiety and sedative effect.Doxepin hydrochloride oral absorption is good, and bioavailability is 13-45%, and the transformation period (t1/2) is 8-12 hour, apparent volume of distribution (Vd) 9-33L/kg.Mainly, at liver metabolism, active metabolite is demethyl compound.Metabolite is from renal excretion, and metabolism and the discharge capacity of elderly patients to this product declines.Its chemistry N by name, N-dimethyl-3-dibenzo [b, e]-{ evil } English-11 in heptan (6H) subunit-1-propylamin hydrochloride cis-trans-isomer mixture, No. CAS: the structural formula of 1229-29-4. doxepin hydrochloride is as follows:
Up to now there are some to report (as patent US20100179215, US20100179214, US20100305326) about the complete synthesis of doxepin hydrochloride.Wherein relate to the reaction of the 4th carbon nitrogen coupling, great majority still use some harsh operational conditions or precious metal reagent, as Pd, Pt, Ru, Rh etc.Here not only relate to outside the shortcomings such as catalyzer cost is high, complex operation, also relate to recycling and the problem such as pollution to environment of catalyzer.And this step linked reaction is related to the synthetic of whole doxepin hydrochloride.Under this condition, develop environmental protection, low cost catalyzer nontoxic, that can be recycled just seems particularly important.It was gratifying that contriver surprisingly finds that reaction has peculiar effect to Ni catalyzer for this step, reaction yield is high, and by product is few, and crucial catalyzer is cheap and easy to get, can be recycled, and therefore, the present invention is by Ni (OAc)
2/ PPh
3catalyst system applied in synthesizing of doxepin hydrochloride.Meanwhile, reaction scheme is carried out to overall optimization and improvement, obtained a kind of method of desirable synthetic hydrochloric acid doxepin.
Summary of the invention
The object of the present invention is to provide a kind of can be simply, the method for environmental protection, synthetic hydrochloric acid doxepin that overall yield is high.
Find object for realizing, the present invention adopts following technical scheme:
A method for synthetic hydrochloric acid doxepin, comprises the following steps:
(1) 6,11-dihydro-dibenzo [b, e] Evil English-11-ketone in heptan and 3-chloropropyl-tertbutyl ether carry out addition reaction and obtain alcohol compound;
(2) described alcohol compound cancellation hydroxyl under concentrated hydrochloric acid condition obtains alkenes compounds;
(3) described alkenes compounds reacts with thionyl chloride and obtains chloro thing in reaction solvent;
(4) described chloro thing and N, the coupling of N-dimethyl methylamine obtains doxepin;
(5) doxepin is made to its hydrochloride, to be obtained final product.
Wherein, the present invention preferably described step 1 is: amount ratio is 1:1-1:1.5 6,11-dihydro-dibenzo [b, e] Evil English-11-ketone in heptan and 3-chloropropyl-tertbutyl ether carry out addition reaction under the effect of catalyzer in anhydrous diethyl ether, react the alcohol compound that refluxes to obtain, more preferably amount ratio is 1:1.2.
In specification sheets of the present invention, described 6,11-dihydro-dibenzo [b, e] Evil English-11-in heptan ketone (CAS:4504-87-4) i.e. cyclic ketones hereinafter described.
In addition,, in step 1, anhydrous diethyl ether drips as solvent, its volumetric usage is 6,11-dihydro-dibenzo [b, the 5.5-6.3 of e] Evil English-11-in heptan ketone weight is doubly, described catalyzer is magnesium powder, the injected volume of catalyzer is 6,11-dihydro-dibenzo [b, the 1.8-2.2 of e] Evil English-11-in heptan ketone times, reaction times is 2-5h, and temperature is 35-40 DEG C.
In this step, the 2%-6% per minute that the rate of addition of anhydrous diethyl ether is its consumption, under this rate of addition, [b, e] Evil English-11-ketone in heptan and 3-chloropropyl-tertbutyl ether can be realized more preferably addition reaction to 6,11-dihydro-dibenzo.
In step 2, alcohol compound keeps boiling under concentrated hydrochloric acid condition, and the 2-10 that the consumption of concentrated hydrochloric acid is reaction substrate doubly; Reaction times is 5-8h.
In step 3, reaction solvent is benzene or toluene, the amount ratio of alkenes compounds and thionyl chloride is 1:1-1:1.5,, reaction reflux 2-4h at 110-120 DEG C, the amount ratio of preferred alkenes compounds and thionyl chloride is 1:1.2, reaction reflux 3h at 115 DEG C.
Step 4 is with Ni (OAc)
2as catalysts, triphenylphosphine is as part.
Step 4 described in the present invention is preferably specially: under the effect of catalyzer, and chloro thing and N, N-dimethyl methylamine reacts 4-6h at DMF under 35-45 DEG C of condition, preferably under 40 DEG C of conditions, reacts 5h, and coupling obtains doxepin.
In this step 4, chloro thing and N, the amount ratio of N-dimethyl methylamine is 1:1-1:1.5, the injected volume of catalyzer is 2-8%, the amount ratio of part and chloro thing is 8:1-12:1, preferably chloro thing and N, and the amount ratio of N-dimethyl methylamine is 1:1.1, the injected volume of catalyzer is 5%, and the amount ratio of part and chloro thing is 10:1.
In addition, synthetic method step 1-4 of the present invention all also comprises each step products therefrom crude product is carried out to the operation of recrystallization, concrete recrystallization is grasped by those skilled in the art, the present invention preferably adopts sherwood oil to carry out recrystallization processing to step 1-4 gained intermediate product, and the productive rate of whole synthetic method and purity are further protected.
Step 5 described in the present invention is preferably: doxepin is in concentrated hydrochloric acid, obtain doxepin hydrochloride with 135-145 ° of C reaction 15-18h, the amount ratio of doxepin and concentrated hydrochloric acid is 1:4-1:6, preferably doxepin is in concentrated hydrochloric acid, obtain doxepin hydrochloride with 140 DEG C of reaction 16h, the amount ratio of doxepin and concentrated hydrochloric acid is 1:5.
Solvent of the present invention all passes through processing before using, and except concentrated hydrochloric acid can directly use, other solvents are all dried underpressure distillation again through hydrolith before using.
The present invention's hydrochloric acid used is that concentration of volume percent is 35-40%, preferably 37% concentrated hydrochloric acid.
Shown in whole reaction scheme is shown in down:
Adopt technique scheme, the present invention has following beneficial effect:
1, whole synthetic method is simply controlled, and response path is scientific and reasonable, and total recovery can reach 62%.
2, for the 4th step linked reaction in whole synthesizing, creatively use Ni/PPh
3catalyst system, makes reaction yield high, and by product is few, and selectivity is good, can reach more than 99%.
3, Ni is different from other noble metal catalysts, has reacted through simple filtration and just can continue to recycle, and the most important thing is cheap and easy to getly, has greatly saved production cost.
4, the five step caustics that the present invention relates to are little, environmentally friendly, meet the requirement of cleaner production, are conducive to suitability for industrialized production, meet the aim of the low-carbon (LC) of harmonious society.
Embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
(1)
In the reactor of 2 liters, add the anhydrous tetrahydro furan of 0.8 liter and the magnesium powder of 143g, the cyclic ketones raw material of 500g and 3-chloropropyl-tertbutyl ether of 895g, the anhydrous diethyl ether of 0.4 liter is divided and is added drop-wise to half an hour in reactor, maintenance system slight boiling condition, dropwise in system and pass into argon gas, continue backflow 2h.React complete and pour in saturated ammonium chloride solution after system is cooling, add ethyl acetate extraction three times, use anhydrous sodium sulfate drying 5h, the thick product sherwood oil recrystallization obtaining obtains product 698g, HPLC purity check >99%, yield 90%.Products molecule formula: C
21h
26o
3, molecular weight: 326.43.Fusing point: 124-126 ° C, LC-MS:326.46, ultimate analysis: C 77.27%, H 8.03%, O 14.70%.
(2)
The product 690g that adds step reaction to obtain in the withstand voltage still of 2 liters, then add concentrated hydrochloric acid 1500g, airtight withstand voltage still is heated to boiling, and hierarchy of control tensimeter is 3MPa, reaction 5h.React complete cooling, evaporate unnecessary solvent, the thick product sherwood oil recrystallization obtaining obtains product 619g, HPLC purity check >98%, yield 95%, products molecule formula: C
21h
24o
2, molecular weight: 308.41.Fusing point: 112-114 ° C, LC-MS:308.48, ultimate analysis: C 81.78%, H 7.84%, O 10.78%.
(3)
In the withstand voltage still of 2 liters, add product 615g that step reaction obtains and the benzene of 0.8 liter, the thionyl chloride of 283g is dissolved in to the benzene of 0.4 liter, divide at ambient temperature and be added drop-wise in withstand voltage still for one hour, dropwise airtight withstand voltage still being heated to refluxed, reaction 2h.React complete ethyl acetate extraction three times that add, use anhydrous sodium sulfate drying 5h, the thick product sherwood oil recrystallization obtaining obtains product 431g, HPLC purity check >99%, yield 80%, products molecule formula: C
17h
15clO, molecular weight: 270.75.Fusing point: 107-110 ° C, LC-MS:270.80, ultimate analysis: C 75.41%, H 5.58%, Cl 13.09%, O 5.91%.
(4)
In the reactor of 2 liters, add product 430g that step reaction obtains and the DMF of 1.2 liters to make solvent, then add 79g N, N-dimethyl methylamine, the salt of wormwood of two equivalents, then add respectively 5% Ni (OAc)
2with 10% PPh
3, under 40 ° of C conditions, react 5h.React complete ethyl acetate extraction three times that add, use anhydrous sodium sulfate drying 5h, the thick product sherwood oil recrystallization obtaining obtains product doxepin 435g, HPLC purity check >99%, yield 98%.Products molecule formula: C
19h
21nO, molecular weight: 279.38.Fusing point: 182-184 ° C, LC-MS:279.30, ultimate analysis: C 81.68%, H 7.58%, N 5.01%, O 5.73%.
(5)
The product 430g that adds step reaction to obtain in the withstand voltage still of 2 liters, then add concentrated hydrochloric acid 900g, airtight withstand voltage still is heated to 140 ° of C, and hierarchy of control tensimeter is 3MPa, reaction 1 5h.React complete be cooled to room temperature after filtration, the dry product 422g, HPLC purity check >98%, yield 87% of obtaining.Products molecule formula: C
19h
22clNO, molecular weight: 315.84.LC-MS:315.80, ultimate analysis: C 72.25%, H 7.02%, Cl 11.23%, N 4.43%, O 5.07%.
Embodiment 2
(1)
In the reactor of 4 liters, add the anhydrous tetrahydro furan of 2 liters and the magnesium powder of 280g, the cyclic ketones raw material of 1Kg and 3-chloropropyl-tertbutyl ether of 1.9Kg, the anhydrous diethyl ether of 1 liter is divided and is added drop-wise to half an hour in reactor, maintenance system slight boiling condition, dropwise in system and pass into argon gas, continue backflow 2h.Reacting complete pours in saturated ammonium chloride solution after system is cooling, add ethyl acetate extraction three times, use anhydrous sodium sulfate drying 5h, the thick product sherwood oil recrystallization obtaining obtains product 1.42Kg, HPLC purity check >99%, yield 88%.Products molecule formula: C
21h
26o
3, molecular weight: 326.43.Fusing point: 124-126 ° C, LC-MS:326.46, ultimate analysis: C 77.27%, H 8.03%, O 14.70%.
(2)
The product 1.4Kg that adds step reaction to obtain in the withstand voltage still of 4 liters, then add concentrated hydrochloric acid 3Kg, airtight withstand voltage still is heated to boiling, and hierarchy of control tensimeter is 3MPa, reaction 5h.React complete cooling, evaporate unnecessary solvent, the thick product sherwood oil recrystallization obtaining obtains product 1.21Kg, HPLC purity check >98%, yield 93%, products molecule formula: C
21h
24o
2, molecular weight: 308.41.Fusing point: 112-114 ° C, LC-MS:308.48, ultimate analysis: C 81.78%, H 7.84%, O 10.78%.
(3)
In the withstand voltage still of 4 liters, add product 1.2Kg that step reaction obtains and the benzene of 1.6 liters, the thionyl chloride of 0.56Kg is dissolved in to the benzene of 0.8 liter, divide at ambient temperature and be added drop-wise in withstand voltage still for one hour, dropwise airtight withstand voltage still being heated to refluxed, reaction 2h.React complete ethyl acetate extraction three times that add, use anhydrous sodium sulfate drying 5h, the thick product sherwood oil recrystallization obtaining obtains product 0.86Kg, HPLC purity check >99%, yield 79%, products molecule formula: C
17h
15clO, molecular weight: 270.75.Fusing point: 107-110 ° C, LC-MS:270.80, ultimate analysis: C 75.41%, H 5.58%, Cl 13.09%, O 5.91%.
(4)
In the reactor of 4 liters, add product 0.85Kg that step reaction obtains and the DMF of 2.5 liters to make solvent, then add 160g N, N-dimethyl methylamine, the salt of wormwood of two equivalents, then add respectively 5% Ni (OAc)
2with 10% PPh
3, under 40 ° of C conditions, react 5h.React complete ethyl acetate extraction three times that add, use anhydrous sodium sulfate drying 5h, the thick product sherwood oil recrystallization obtaining obtains product doxepin 0.85Kg, HPLC purity check >99%, yield 96%.Products molecule formula: C
19h
21nO, molecular weight: 279.38.Fusing point: 182-184 DEG C, LC-MS:279.30, ultimate analysis: C 81.68%, H 7.58%, N 5.01%, O 5.73%.
(5)
The product 0.85Kg that adds step reaction to obtain in the withstand voltage still of 4 liters, then add concentrated hydrochloric acid 1.8Kg, airtight withstand voltage still is heated to 140 DEG C, and hierarchy of control tensimeter is 3MPa, reaction 15h.React complete be cooled to room temperature after filtration, the dry product 0.84Kg, HPLC purity check >98%, yield 85% of obtaining.Products molecule formula: C
19h
22clNO, molecular weight: 315.84.LC-MS:315.80, ultimate analysis: C 72.25%, H 7.02%, Cl 11.23%, N 4.43%, O 5.07%.
Embodiment 3
Compared with embodiment 1, the difference of the present embodiment is only:
Step 1 is: amount ratio is 1:1.2 6, and [b, e] Evil English-11-ketone in heptan and 3-chloropropyl-tertbutyl ether carry out addition reaction to 11-dihydro-dibenzo under the effect of catalyzer in anhydrous diethyl ether, the reaction alcohol compound that refluxes to obtain.Wherein, anhydrous diethyl ether drips as solvent, and its volumetric usage is 6,11-dihydro-dibenzo [b, 5.8 times of e] Evil English-11-in heptan ketone weight, its rate of addition is 5% per minute of its consumption, and described catalyzer is magnesium powder, and the injected volume of magnesium powder is 6,11-dihydro-dibenzo [b, 2 times of e] Evil English-11-in heptan ketone, the reaction times is 3h, temperature is 38 DEG C.
In step 2, alcohol compound keeps boiling under concentrated hydrochloric acid condition, the consumption of concentrated hydrochloric acid is reaction substrate 6 times; Reaction times is 6h.
In step 3, reaction solvent is benzene, and the amount ratio of alkenes compounds and thionyl chloride is 1:1.2, reaction reflux 3h at 115 DEG C.
Step 4 is specially: under the effect of catalyzer, and chloro thing and N, N-dimethyl methylamine reacts 5h at DMF under 40 ° of C conditions, and coupling obtains doxepin.Wherein, chloro thing and N, the amount ratio of N-dimethyl methylamine is 1:1.1, and the injected volume of catalyzer is 5%, and the amount ratio of part and chloro thing is 10:1.
Step 5 is: doxepin, in concentrated hydrochloric acid, obtains doxepin hydrochloride with 140 DEG C of reaction 16h, and the amount ratio of doxepin and concentrated hydrochloric acid is 1:5.
The purity of the present embodiment gained doxepin hydrochloride is 98%, and total recovery is 62%.
Embodiment 4
Compared with embodiment 1, the difference of the present embodiment is only: step 1 is: amount ratio is 1:1 6, [b, e] Evil English-11-ketone in heptan and 3-chloropropyl-tertbutyl ether carry out addition reaction to 11-dihydro-dibenzo under the effect of catalyzer in anhydrous diethyl ether, react the alcohol compound that refluxes to obtain.Wherein, its volumetric usage of anhydrous diethyl ether is 6,11-dihydro-dibenzo [b, 5.5 times of e] Evil English-11-in heptan ketone weight, 2% per minute that its rate of addition is its consumption.Described catalyzer is magnesium powder, and the injected volume of magnesium powder is that [reaction times is 2h to 6,11-dihydro-dibenzo for b, 1.8 times of e] Evil English-11-in heptan ketone, and temperature is 35 DEG C.
In step 2, alcohol compound keeps boiling under concentrated hydrochloric acid condition, the consumption of concentrated hydrochloric acid is reaction substrate 2 times; Reaction times is 5h.
In step 3, reaction solvent is toluene, and the amount ratio of alkenes compounds and thionyl chloride is 1:1, reaction reflux 2h at 110 DEG C.
Step 4 is specially: under the effect of catalyzer, and chloro thing and N, N-dimethyl methylamine reacts 4h at DMF under 35 DEG C of conditions, and coupling obtains doxepin.Wherein, chloro thing and N, the amount ratio of N-dimethyl methylamine is 1:1, and the injected volume of catalyzer is 2%, and the amount ratio of part and chloro thing is 8:1.
Step 5 is: doxepin, in concentrated hydrochloric acid, obtains doxepin hydrochloride with 135 DEG C of reaction 15h, and the amount ratio of doxepin and concentrated hydrochloric acid is 1:4.
The purity of the present embodiment gained doxepin hydrochloride is 99%, and total recovery is 60%.
Embodiment 5
Compared with embodiment 1, the difference of the present embodiment is only: step 1 is: amount ratio is 1:1.5 6, [b, e] Evil English-11-ketone in heptan and 3-chloropropyl-tertbutyl ether carry out addition reaction to 11-dihydro-dibenzo under the effect of catalyzer in anhydrous diethyl ether, react the alcohol compound that refluxes to obtain.Wherein, its volumetric usage of anhydrous diethyl ether is 6,11-dihydro-dibenzo [b, 6.3 times of e] Evil English-11-in heptan ketone weight, 6% per minute that its rate of addition is its consumption.Described catalyzer is magnesium powder, and the injected volume of magnesium powder is that [reaction times is 5h to 6,11-dihydro-dibenzo for b, 2.2 times of e] Evil English-11-in heptan ketone, and temperature is 40 DEG C.
In step 2, alcohol compound keeps boiling under concentrated hydrochloric acid condition, the consumption of concentrated hydrochloric acid is reaction substrate 10 times; Reaction times is 8h.
In step 3, reaction solvent is toluene, and the amount ratio of alkenes compounds and thionyl chloride is 1:1.5, reaction reflux 4h at 120 DEG C.
Step 4 is specially: under the effect of catalyzer, and chloro thing and N, N-dimethyl methylamine reacts 6h at DMF under 45 DEG C of conditions, and coupling obtains doxepin.Wherein, chloro thing and N, the amount ratio of N-dimethyl methylamine is 1:1.5, and the injected volume of catalyzer is 8%, and the amount ratio of part and chloro thing is 12:1.
Step 5 is: doxepin, in concentrated hydrochloric acid, obtains doxepin hydrochloride with 145 DEG C of reaction 18h, and the amount ratio of doxepin and concentrated hydrochloric acid is 1:6.
The purity of the present embodiment gained doxepin hydrochloride is 98%, and total recovery is 62%.
Embodiment 6
Compared with embodiment 1, the difference of the present embodiment is only: step 1 is: amount ratio is 1:1.3 6, [b, e] Evil English-11-ketone in heptan and 3-chloropropyl-tertbutyl ether carry out addition reaction to 11-dihydro-dibenzo under the effect of catalyzer in anhydrous diethyl ether, react the alcohol compound that refluxes to obtain.Wherein, its volumetric usage of anhydrous diethyl ether is 6,11-dihydro-dibenzo [b, 5.9 times of e] Evil English-11-in heptan ketone weight, described catalyzer is magnesium powder, and the injected volume of magnesium powder is 6,11-dihydro-dibenzo [b, 1.9 times of e] Evil English-11-in heptan ketone, the reaction times is 2-5h, temperature is 35-40 DEG C.
In step 2, alcohol compound keeps boiling under concentrated hydrochloric acid condition, the consumption of concentrated hydrochloric acid is reaction substrate 5 times; Reaction times is 6h.
In step 3, reaction solvent is benzene, and the amount ratio of alkenes compounds and thionyl chloride is 1:1.3, reaction reflux 3h at 115 DEG C.
Step 4 is specially: under the effect of catalyzer, and chloro thing and N, N-dimethyl methylamine reacts 6h at DMF under 42 ° of C conditions, and coupling obtains doxepin.Wherein, chloro thing and N, the amount ratio of N-dimethyl methylamine is 1:1.3, and the injected volume of catalyzer is 5%, and the amount ratio of part and chloro thing is 8:1.
Step 5 is: doxepin, in concentrated hydrochloric acid, obtains doxepin hydrochloride with 142 DEG C of reaction 17h, and the amount ratio of doxepin and concentrated hydrochloric acid is 1:5.
The purity of the present embodiment gained doxepin hydrochloride is 99%, and total recovery is 62%.
Although, above use general explanation, embodiment and test, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (5)
1. a method for synthetic hydrochloric acid doxepin, is characterized in that: comprise the following steps:
By 6,11-dihydro-dibenzo [b, e] Evil English-11-ketone in heptan and 3-chloropropyl-tertbutyl ether carry out addition reaction and obtain alcohol compound;
Described alcohol compound cancellation hydroxyl under concentrated hydrochloric acid condition obtains alkenes compounds;
Described alkenes compounds reacts with thionyl chloride and obtains chloro thing in reaction solvent;
Described chloro thing and N, the coupling of N-dimethyl methylamine obtains doxepin;
Doxepin is made to its hydrochloride, to obtain final product;
Described step 1 is: amount ratio is 1:1.2 6, and 11-dihydro-dibenzo [b, e] Evil English-11-ketone in heptan and 3-chloropropyl-tertbutyl ether, under the effect of catalyzer, carry out addition reaction in anhydrous diethyl ether, the reaction alcohol compound that refluxes to obtain; Wherein, anhydrous diethyl ether drips as solvent, and its volumetric usage is 6,11-dihydro-dibenzo [b, the 5.5-6.3 of e] Evil English-11-in heptan ketone weight times, the 2%-6% per minute that its rate of addition is its consumption; Described catalyzer is magnesium powder, the injected volume of catalyzer be 6,11-dihydro-dibenzo [b, doubly, the reaction times is 2-5 h to the 1.8-2.2 of e] Evil English-11-in heptan ketone, temperature is 35-40 DEG C;
In described step 2, alcohol compound keeps boiling under concentrated hydrochloric acid condition, and the 2-10 that the consumption of concentrated hydrochloric acid is reaction substrate doubly; Reaction times is 5-8 h;
In described step 3, reaction solvent is benzene or toluene, and the amount ratio of alkenes compounds and thionyl chloride is 1:1.2, reaction reflux 2-4h at 110-120 DEG C;
Described step 4 is with Ni (OAc)
2as catalysts, triphenylphosphine is as part.
2. the method for synthetic hydrochloric acid doxepin according to claim 1, is characterized in that: described step 4 is: under the effect of catalyzer, and chloro thing and N, N-dimethyl methylamine reacts 4-6h at DMF under 35-45 DEG C of condition, and coupling obtains doxepin.
3. the method for synthetic hydrochloric acid doxepin according to claim 2, it is characterized in that: chloro thing and N in described step 4, the amount ratio of N-dimethyl methylamine is 1:1-1:1.5, and the injected volume of catalyzer is 2-8%, and the amount ratio of part and chloro thing is 8:1-12:1.
4. according to the method for the synthetic hydrochloric acid doxepin described in claim 1, it is characterized in that: described step 5 is: doxepin, in concentrated hydrochloric acid, obtains doxepin hydrochloride with 135-145 DEG C of reaction 15-18 h, and the amount ratio of doxepin and concentrated hydrochloric acid is 1:4-1:6.
5. the method for synthetic hydrochloric acid doxepin according to claim 1, is characterized in that: the concentration of volume percent of described concentrated hydrochloric acid is 35-40%.
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| CN105061386A (en) * | 2015-08-17 | 2015-11-18 | 苏州黄河制药有限公司 | Method for synthesizing doxepin hydrochloride by utilizing phthalic anhydride as raw material |
| CN105085465A (en) * | 2015-08-17 | 2015-11-25 | 苏州黄河制药有限公司 | Method for synthesizing doxepin hydrochloride by taking halomethyl o-toluate as raw material |
| CN105111181A (en) * | 2015-08-17 | 2015-12-02 | 苏州黄河制药有限公司 | Synthetic method of doxepin hydrochloride using methylbenzoate as raw materials |
| CN105085464A (en) * | 2015-08-17 | 2015-11-25 | 苏州统华药品有限公司 | Synthesis method of doxepin hydrochloride |
| CN105330638A (en) * | 2015-11-26 | 2016-02-17 | 苏州黄河制药有限公司 | Method for synthesizing doxepin hydrochloride by utilizing o-toluic acid as raw material |
| CN105367538A (en) * | 2015-11-26 | 2016-03-02 | 苏州黄河制药有限公司 | Method for preparing doxepin hydrochloride using o-halogen methyl methyl benzoate as raw material |
| CN111790443B (en) * | 2020-07-17 | 2022-11-04 | 万华化学集团股份有限公司 | Supported catalyst and preparation method and application thereof |
| CN115124500B (en) * | 2022-08-08 | 2024-01-30 | 苏州弘森药业股份有限公司 | Method for refining doxepin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090042971A1 (en) * | 2006-05-19 | 2009-02-12 | Somaxon Pharmaceuticals, Inc. | Method of using low-dose doxepin for the improvement of sleep |
| US20100179215A1 (en) * | 2006-05-19 | 2010-07-15 | Somaxon Pharmaceuticals, Inc. | Doxepin isomers and isomeric mixtures and methods of using the same to treat sleep disorders |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090042971A1 (en) * | 2006-05-19 | 2009-02-12 | Somaxon Pharmaceuticals, Inc. | Method of using low-dose doxepin for the improvement of sleep |
| US20100179215A1 (en) * | 2006-05-19 | 2010-07-15 | Somaxon Pharmaceuticals, Inc. | Doxepin isomers and isomeric mixtures and methods of using the same to treat sleep disorders |
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