CN113582961A - Synthesis method of doxepin hydrochloride - Google Patents
Synthesis method of doxepin hydrochloride Download PDFInfo
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- CN113582961A CN113582961A CN202110988488.3A CN202110988488A CN113582961A CN 113582961 A CN113582961 A CN 113582961A CN 202110988488 A CN202110988488 A CN 202110988488A CN 113582961 A CN113582961 A CN 113582961A
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- dimethyl
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- propyl phosphate
- hydrochloride
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- MHNSPTUQQIYJOT-SJDTYFKWSA-N Doxepin Hydrochloride Chemical compound Cl.C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 MHNSPTUQQIYJOT-SJDTYFKWSA-N 0.000 title claims abstract description 39
- 229960002861 doxepin hydrochloride Drugs 0.000 title claims abstract description 38
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 93
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 71
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 64
- MHZDONKZSXBOGL-UHFFFAOYSA-N propyl dihydrogen phosphate Chemical compound CCCOP(O)(O)=O MHZDONKZSXBOGL-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 19
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 11
- 150000008301 phosphite esters Chemical class 0.000 claims abstract description 9
- SRLUQBBNWRQHNU-UHFFFAOYSA-N propyl dihydrogen phosphate;hydrochloride Chemical compound Cl.CCCOP(O)(O)=O SRLUQBBNWRQHNU-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 114
- YUSHFLBKQQILNV-UHFFFAOYSA-N 6h-benzo[c][1]benzoxepin-11-one Chemical compound C1OC2=CC=CC=C2C(=O)C2=CC=CC=C21 YUSHFLBKQQILNV-UHFFFAOYSA-N 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 23
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 17
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 13
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 8
- 239000007795 chemical reaction product Substances 0.000 claims description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical group COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 3
- KKFOMYPMTJLQGA-UHFFFAOYSA-N tribenzyl phosphite Chemical compound C=1C=CC=CC=1COP(OCC=1C=CC=CC=1)OCC1=CC=CC=C1 KKFOMYPMTJLQGA-UHFFFAOYSA-N 0.000 claims description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- -1 alkyl phosphate Chemical compound 0.000 abstract description 15
- 239000012467 final product Substances 0.000 abstract description 8
- 229910019142 PO4 Inorganic materials 0.000 abstract description 5
- 239000010452 phosphate Substances 0.000 abstract description 5
- 229960005426 doxepin Drugs 0.000 abstract description 4
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 88
- 150000001875 compounds Chemical class 0.000 description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- 238000001035 drying Methods 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- 238000001914 filtration Methods 0.000 description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 35
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 239000012074 organic phase Substances 0.000 description 27
- 239000012043 crude product Substances 0.000 description 26
- 238000001816 cooling Methods 0.000 description 19
- 238000010438 heat treatment Methods 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 16
- 229940126214 compound 3 Drugs 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000012295 chemical reaction liquid Substances 0.000 description 11
- 238000000605 extraction Methods 0.000 description 11
- 238000010791 quenching Methods 0.000 description 11
- 230000000171 quenching effect Effects 0.000 description 11
- 239000000203 mixture Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000003747 Grignard reaction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-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
Abstract
The invention relates to a synthesis method of doxepin hydrochloride. The method comprises the following synthetic steps: (1) carrying out an Ebazochralski reaction on phosphite ester and 3-chloro-1- (N, N-dimethyl) propylamine, and distilling and purifying to obtain 3- (N, N-dimethyl) propyl phosphate, or salifying and crystallizing the phosphate and hydrochloric acid to obtain 3- (N, N-dimethyl) propyl phosphate hydrochloride; (2) carrying out Wittig reaction on 3- (N, N-dimethyl) propyl phosphate or hydrochloride thereof and 6, 11-dihydrodibenzo [ b, e ] oxepin-11-ketone under a strong alkali condition to obtain doxepin; (3) and carrying out salifying reaction on doxepin and hydrochloric acid to prepare doxepin hydrochloride. In the first step of reaction, the yield of the alkyl phosphate prepared by the Ebefur reaction is high, so that the yield and the purity of the final product doxepin hydrochloride are ensured. Compared with the prior art, the method has the advantages of simple process, low production cost, few process steps and the like.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to a synthesis method of doxepin hydrochloride.
Background
Doxepin Hydrochloride (Doxepin Hydrochloride) is a mixture of cis and trans isomers of the subunit-1-alaninate, chemically known as N, N-dimethyl-3-dibenzo (b, e) -oxepin-11 (6H). The CAS number is 1229-29-4, and the chemical structural formula is as follows:
doxepin hydrochloride is a common tricyclic antidepressant and is used for treating depression and anxiety neurosis. Doxepin hydrochloride is a non-selective monoamine uptake inhibitor, and the action mechanism of the doxepin hydrochloride is that the doxepin hydrochloride can play an antidepressant role by inhibiting reuptake of Norepinephrine (NE) and 5-hydroxytryptamine (5-HT) to increase the concentration of synaptic cleft, and also has anxiolytic and sedative effects. The doxepin hydrochloride has good oral absorption, the bioavailability is 13-45%, the half-life (t1/2) is 8-12 hours, and the apparent distribution volume (Vd) is 9-33L/kg. Mainly metabolized in the liver, and the active metabolite is demethylated. Metabolites are excreted from the kidney, and the metabolic and excretory abilities of the product are reduced in elderly patients.
So far, there are many reports about the synthesis of doxepin hydrochloride, wherein most of the reaction conditions are harsh and involve the reaction of noble metals, so that the method has the disadvantages of high cost, environmental friendliness and the like, such as foreign reports about the synthesis of doxepin hydrochloride (such as patents US20100179214 and US 20100305326); however, domestic reports on doxepin hydrochloride exist, for example, patent CN102924424A discloses a preparation method of doxepin hydrochloride. The process involves a C-N coupling reaction, i.e. using Ni (OAc)2/PPh3The system is catalyzed. Although the catalyst is cheap and easy to obtain, the yield of the reaction in the step is low, and the purity of the product is low. Domestic patent reports about doxepin hydrochloride, such as patent CN112079809A) and CN105085465A, both relate to the Grignard reaction,the reaction has higher requirements on the moisture of a solvent and raw materials, the reaction environment and the like, and the Grignard reaction usually involves the heating of diethyl ether or tetrahydrofuran, so that certain potential safety hazards exist in the production.
Disclosure of Invention
The invention aims to provide a method for synthesizing doxepin hydrochloride, which solves the problems of harsh synthesis conditions, complex process and the like in the prior art.
The purpose of the invention can be realized by the following technical scheme:
the invention provides a method for synthesizing doxepin hydrochloride, which comprises the following steps:
(1) taking 3-chloro-1- (N, N-dimethyl) propylamine and phosphite ester to carry out an Ebazomib reaction to obtain 3- (N, N-dimethyl) propyl phosphate;
(2) reacting the obtained 3- (N, N-dimethyl) propyl phosphate or the hydrochloride of the 3- (N, N-dimethyl) propyl phosphate obtained by acidifying the 3- (N, N-dimethyl) propyl phosphate with 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one under the action of strong alkali to obtain a Wittig reaction product;
(3) and (3) reacting the Wittig reaction product with HCl to obtain the target product.
Further, in the step (1), the phosphite ester is trimethyl phosphite, triethyl phosphite, triisopropyl phosphite or tribenzyl phosphite, and may be triethyl phosphite.
Furthermore, in the step (1), the molar ratio of the 3-chloro-1- (N, N-dimethyl) propylamine to the phosphite ester is 1 (1.1-3).
Further, in the step (1), the temperature of the Ebefur reaction is 140-150 ℃, and the reaction time is 6-8 h.
Further, in the step (1) and the step (2), the process for preparing the 3- (N, N-dimethyl) propyl phosphate hydrochloride by acidifying the 3- (N, N-dimethyl) propyl phosphate specifically comprises the following steps:
dissolving 3- (N, N-dimethyl) propyl phosphate in ethyl acetate, introducing hydrogen chloride gas or adding hydrochloric acid, stirring and crystallizing to obtain 3- (N, N-dimethyl) propyl phosphate hydrochloride;
further, when hydrochloric acid was added, the pH of the ethyl acetate solution of 3- (N, N-dimethyl) propyl phosphate was adjusted to 1-2 by dropwise addition of hydrochloric acid.
Further, when hydrochloric acid was added, the concentration of hydrochloric acid was 12N.
Further, in the step (2), the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the 3- (N, N-dimethyl) propyl phosphate or the hydrochloride of the 3- (N, N-dimethyl) propyl phosphate is 1 (1.1-1.5).
Further, in the step (2), the strong base is potassium tert-butoxide, sodium hydride, sodium tert-butoxide, Lithium Diisopropylamide (LDA), lithium bis (trimethylsilyl) amide (LHMDS), potassium bis (trimethylsilyl) amide (KHMDS) or butyllithium, and may be potassium tert-butoxide or sodium hydride. Specifically, the strong base is added to convert 3- (N, N-dimethyl) propyl phosphate or hydrochloride thereof into carbanion intermediate, and the carbanion intermediate can resonate to generate the Wittig-Horner reagent. The strength and choice of base used depends primarily on the acidity of the hydrogen atom on the α -carbon of the phosphate ester.
Further, in the step (2), when the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one reacts with the 3- (N, N-dimethyl) propyl phosphate, the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the strong base is 1 (1.1-1.5).
Further, in the step (2), when the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one reacts with the 3- (N, N-dimethyl) propyl phosphate hydrochloride, the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the strong base is 1 (2.1-2.5).
Further, in the step (2), the solvent for the reaction is tetrahydrofuran.
Further, in the step (2), the reaction temperature is-78-25 ℃, and the reaction time is 10-12 hours.
Furthermore, in the step (3), HCl reacted with the Wittig reaction product is added in the form of hydrochloric acid or hydrogen chloride gas, and the molar ratio of the Wittig reaction product to the HCl is 1 (1.5-3).
Further, when hydrochloric acid was added, the concentration of hydrochloric acid was 12N.
Further, in the step (3), the reaction temperature is 135-150 ℃, and the reaction time is 18-22 h.
Further, in the step (3), the reaction solvent is ethyl acetate or ethanol.
According to the invention, 3-chloro-1- (N, N-dimethyl) propylamine (compound 1) and phosphite ester (compound 2) are used as raw materials in the step (1) to prepare 3- (N, N-dimethyl) propyl phosphate (compound 3) by an Ebazomib reaction, the added phosphite ester is not only used as a reactant, but also used as a reaction solvent, and excessive phosphite ester can ensure complete reaction of the 3-chloro-1- (N, N-dimethyl) propylamine; in the step (2), 3- (N, N-dimethyl) propyl phosphate or 3- (N, N-dimethyl) propyl phosphate hydrochloride (compound 4) obtained by acidifying 3- (N, N-dimethyl) propyl phosphate and 6, 11-dihydrodibenzo [ b, e ] oxepin-11-ketone (compound 5) are subjected to Wittig reaction under a strong alkali condition to obtain a doxepin intermediate product (compound 6), wherein the excessive 3- (N, N-dimethyl) propyl phosphate or 3- (N, N-dimethyl) propyl phosphate hydrochloride can improve the reaction yield in the reaction process; and then carrying out salification reaction on the doxepin intermediate product and hydrochloric acid to obtain the target product doxepin hydrochloride. The yield of the alkyl phosphate product prepared in the step (1) is higher, so that the yield and the purity of the final product doxepin hydrochloride are ensured.
The reaction process of the step (1) is as follows:
wherein R in the compound 2, the compound 3 and the compound 4 is-CH3、—CH2CH3、—CH(CH3)CH3or-CH2Ph。
The reaction process of the step (2) is as follows:
wherein, R in the compound 3 and the compound 4 is methyl, ethyl, isopropyl or benzyl.
The reaction process of the step (3) is as follows:
compared with the prior art, the invention has the following advantages:
(1) the doxepin hydrochloride can be synthesized through three steps of an Eberkoff reaction, a Wittig reaction and a salt forming reaction.
(2) The invention adopts triethyl phosphite with lower price as the raw material, thereby greatly reducing the cost. The wittig-horner reaction is used for replacing the Grignard reaction to construct the double bond, so that the reaction is simpler, the requirements on reaction conditions such as the moisture of a reaction solvent and raw materials, equipment and the like are lower, and the repetition rate is higher.
(3) The invention does not relate to the Grignard reaction, so the heating of the diethyl ether or the tetrahydrofuran is not related, and the production is safer.
Detailed Description
The present invention will be described in detail with reference to specific examples. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
In the following examples, the starting materials and treatment steps used are, unless otherwise specified, indicated by the conventional commercial products or conventional techniques.
Example 1
Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the mixture was distilled under reduced pressure to obtain diethyl 3- (N, N-dimethyl) propylphosphate (Compound No. 3) in an amount of 97.5g and a yield of 88.5%.
1H NMR(400MHz,D2O)δ3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).13C NMR(125MHz,D2O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.
Example 2
Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is decompressed, concentrated and dried to obtain a crude product.
Dissolving the crude product with ethyl acetate, introducing hydrogen chloride, stirring at room temperature for crystallization for 5 hours, filtering, and drying to obtain 3- (N, N-dimethyl) propyl diethyl phosphate hydrochloride (compound 4) with the amount of 110.8g and the yield of 86.47%.
1H NMR(400MHz,D2O)δ3.88(tt,J＝15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).13C NMR(125MHz,D2O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.
Example 3
Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is decompressed, concentrated and dried to obtain a crude product.
Dissolving the crude product with ethyl acetate, dropwise adding concentrated hydrochloric acid (12N) to adjust pH to 1-2, stirring at room temperature for 5 hours for crystallization, filtering, and drying to obtain 3- (N, N-dimethyl) propyl diethyl phosphate hydrochloride (compound 4) with an amount of 109.8g and a yield of 85.69%.
1H NMR(400MHz,D2O)δ3.88(tt,J＝15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).13C NMR(125MHz,D2O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.
Example 4
Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 90.4g of the compound 6 with the yield of 75.41%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 5
Sodium hydride (11.41g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at-40 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at-40 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain the compound 6 with the amount of 91.8g and the yield of 76.57%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 6
Lithium diisopropylamide (51.88g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen and the reaction stirred at-78 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at-78 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 87.86g of the compound 6 with the yield of 73.29 percent.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 7
Lithium bis (trimethylsilyl) amide (79.54g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at-78 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at-78 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 87.2g of the compound 6 with the yield of 72.74%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 8
Potassium bis (trimethylsilyl) amide (94.83g,475.37mmol) was added portionwise under nitrogen protection to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) and the reaction stirred at-78 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at-78 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 87g of the compound 6 with the yield of 72.57%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 9
After dissolving intermediate 6 (i.e., compound 6) (90g,324.43mmol) in ethyl acetate, hydrogen chloride was introduced, heated to 135 ℃, stirred for 22h, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooling to room temperature, suction filtering and drying to obtain the final product, namely, the doxepin hydrochloride white solid 91.5g, with the yield of 89.86%.
1H NMR(400MHz,CDCl3)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 10
Concentrated hydrochloric acid 54ml (12N) (containing 648mmol of HCl) was slowly added to a solution of intermediate 6 (i.e. compound 6) (90g,324.43mmol) in ethanol, heated to 140 ℃, stirred for 22h and run to completion by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooling to room temperature, suction filtering and drying to obtain the final product, namely doxepin hydrochloride white solid 92.1g, with the yield of 90.45%.
1H NMR(400MHz,CDCl3)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 11
Concentrated hydrochloric acid 81ml (12N) (containing 972mmol of HCl) was slowly added to a solution of intermediate 6 (i.e. compound 6) (90g,324.43mmol) in ethanol, heated to 150 ℃, stirred for 22h and run to completion by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooled to room temperature, filtered and dried to obtain the final product doxepin hydrochloride white solid 92.9g with the yield of 91.23%.
1H NMR(400MHz,CDCl3)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 12
Trimethyl phosphite (67.34g,542.73mmol) was slowly added to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the mixture was distilled under reduced pressure to obtain 3- (N, N-dimethyl) propyldimethyl phosphate (Compound No. 3) in an amount of 85.7g and a yield of 88.98%.
1H NMR(400MHz,D2O)δ3.69(s,3H),3.67(s,3H),2.49(t,J＝6.4Hz,2H),2.33(s,6H),2.04(dt,J＝12.0,6.0Hz,2H),1.73(p,J＝6.2Hz,2H).13C NMR(125MHz,D2O)δ57.74,57.66,52.47,52.42,44.78,26.34,25.58,24.20,24.15.
Example 13
Triisopropyl phosphite (113.02g,542.73mmol) was slowly added to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the mixture was distilled under reduced pressure to obtain diisopropyl 3- (N, N-dimethyl) propyl phosphate (Compound No. 3) in an amount of 109g in a yield of 87.91%.
1H NMR(400MHz,D2O)δ4.67(dhept,J＝8.2,6.2Hz,2H),2.54(t,J＝6.4Hz,2H),2.32(s,6H),2.03(dt,J＝12.0,6.0Hz,2H),1.74(p,J＝6.2Hz,2H),1.31(s,6H),1.30(s,6H).13C NMR(125MHz,D2O)δ71.01,70.96,57.67,57.59,44.73,27.63,26.87,24.14,24.08,23.64,23.59.
Example 14
Triisopropyl phosphite (191.24g,918.37mmol) was slowly added to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the resulting mixture was distilled under reduced pressure to obtain diisopropyl 3- (N, N-dimethyl) propyl phosphate (Compound No. 3) in an amount of 109.1g and a yield of 87.99%.
1H NMR(400MHz,D2O)δ4.67(dhept,J＝8.2,6.2Hz,2H),2.54(t,J＝6.4Hz,2H),2.32(s,6H),2.03(dt,J＝12.0,6.0Hz,2H),1.74(p,J＝6.2Hz,2H),1.31(s,6H),1.30(s,6H).13C NMR(125MHz,D2O)δ71.01,70.96,57.67,57.59,44.73,27.63,26.87,24.14,24.08,23.64,23.59.
Example 15
Sodium tert-butoxide (45.68g,475.31mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen and the reaction stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 90.29g of the compound 6 with yield of 75.31%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 16
Butyllithium (30.45g, 475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen and the reaction stirred at-78 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at-78 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
And adding petroleum ether into the crude product of the compound 6, heating and refluxing to dissolve and clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 87.5g of the compound 6 with the yield of 72.99%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 17
Triethyl phosphite (163.95g,986.76mmol) was slowly added to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 150 ℃ and stirred for 6 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the mixture was distilled under reduced pressure to obtain diethyl 3- (N, N-dimethyl) propylphosphate (Compound No. 3) in an amount of 98.2g and a yield of 89.15%.
1H NMR(400MHz,D2O)δ3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).13C NMR(125MHz,D2O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.
Example 18
Triethyl phosphite (245.93g,1480.14mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 145 ℃ and stirred for 7 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is concentrated under reduced pressure and dried. Then, the mixture was distilled under reduced pressure to obtain 98.6g of diethyl 3- (N, N-dimethyl) propylphosphate (Compound No. 3) in 88.61% yield.
1H NMR(400MHz,D2O)δ3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).13C NMR(125MHz,D2O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.
Example 19
Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is decompressed, concentrated and dried to obtain a crude product.
Dissolving the crude product with ethyl acetate, dropwise adding concentrated hydrochloric acid (12N) to adjust the pH value to 1, stirring at room temperature for crystallization for 5 hours, performing suction filtration and drying to obtain the 3- (N, N-dimethyl) propyl diethyl phosphate hydrochloride (compound 4) with the amount of 110.1g and the yield of 85.92%.
1H NMR(400MHz,D2O)δ3.88(tt,J＝15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).13C NMR(125MHz,D2O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.
Example 20
Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is decompressed, concentrated and dried to obtain a crude product.
Dissolving the crude product with ethyl acetate, dropwise adding concentrated hydrochloric acid (12N) to adjust the pH value to 2, stirring at room temperature for crystallization for 5 hours, performing suction filtration and drying to obtain the 3- (N, N-dimethyl) propyl diethyl phosphate hydrochloride (compound 4) with the amount of 109.6g and the yield of 85.53%.
1H NMR(400MHz,D2O)δ3.88(tt,J＝15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).13C NMR(125MHz,D2O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.
Example 21
Triethyl phosphite (90.18g,542.73mmol) was added slowly to 3-chloro-1- (N, N-dimethyl) propylamine (60g,493.38mmol), heated to 140 ℃ and stirred for 8 h. After the reaction liquid is cooled, water quenching is added, ethyl acetate is used for extraction for three times, and organic phase is decompressed, concentrated and dried to obtain a crude product.
Dissolving the crude product with ethyl acetate, dropwise adding concentrated hydrochloric acid (12N) to adjust pH to 1.5, stirring at room temperature for crystallization for 5 hours, filtering, and drying to obtain 3- (N, N-dimethyl) propyl diethyl phosphate hydrochloride (compound 4) with the amount of 109.78g and the yield of 85.67%.
1H NMR(400MHz,D2O)δ3.88(tt,J＝15.3,6.7Hz,1H),3.77–3.69(m,4H),3.01(q,J＝7.0,6.2Hz,2H),2.60(s,6H),1.93(dq,J＝12.0,6.4Hz,2H),1.66(dq,J＝12.0,6.4Hz,2H),0.99(t,J＝7.1Hz,6H).13C NMR(125MHz,D2O)δ61.30,61.25,57.74,57.66,44.73,26.05,25.29,24.13,24.07,16.23,16.18.
Example 22
Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(125.43g,561.80mmol) prepared in example 1 in tetrahydrofuran (320ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 90.46g of the compound 6 with the yield of 75.46%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 23
Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(144.72g,648.23mmol) prepared in example 1 in tetrahydrofuran (340ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain the compound 6 with the amount of 90.1g and the yield of 75.16%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 24
Potassium tert-butoxide (101.83g,907.52mmol) was added portionwise to a solution of compound 4(123.46g,475.37mmol) prepared in example 2 in tetrahydrofuran (320ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 90.31g of the compound 6 with yield of 75.33%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 25
Potassium tert-butoxide (111.53g,993.95mmol) was added portionwise to a solution of compound 4(145.91g,561.80mmol) prepared in example 2 in tetrahydrofuran (340ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 90.6g of the compound 6 with the yield of 75.57%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 26
Potassium tert-butoxide (121.23g,1080.38mmol) was added portionwise to a solution of compound 4(168.36g,648.23mmol) prepared in example 2 in tetrahydrofuran (360ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 90.62g of the compound 6 with the yield of 75.59 percent.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 27
Potassium tert-butoxide (63.04g,561.80mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 90.45g of the compound 6 with the yield of 75.45%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 28
Potassium tert-butoxide (72.74g,648.23mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition was completed, the reaction was stirred at 0 ℃ for 12 hours, and the reaction was completed by TLC (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 90.44g of the compound 6 with yield of 75.44%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 29
Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at 25 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition, the reaction was stirred at 25 ℃ for 10 hours and was completed by TLC detection (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
And adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 85.7g of the compound 6 with the yield of 71.49%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 30
Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(106.13g,475.37mmol) prepared in example 1 in tetrahydrofuran (300ml) under nitrogen, and the reaction was stirred at 0 ℃ for 30 min. Then, a solution of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one (90g,432.15mmol) in tetrahydrofuran (400ml) was added dropwise slowly, and after the addition, the reaction was stirred at 0 ℃ for 11 hours and was completed by TLC detection (UV254, methanol/dichloromethane ═ 1: 6). Pouring the reaction solution into water, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated sodium chloride aqueous solution respectively, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain a crude compound 6.
Adding petroleum ether into the crude product of the compound 6, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 90.38g of the compound 6 with the yield of 75.39%.
1H NMR(400MHz,CDCl3)δ7.39–7.29(m,3H),7.25(d,J＝6.5Hz,1H),7.22(d,J＝7.4Hz,1H),7.10(td,J＝7.8,1.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.75(dd,J＝8.2,1.4Hz,1H),6.02(t,J＝6.9Hz,1H),5.75–5.43(m,1H),4.81(s,1H),2.36(dq,J＝12.6,6.4Hz,4H),2.16(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 31
Concentrated hydrochloric acid 40.5ml (12N) (containing 486mmol of HCl) was slowly added to a solution of intermediate 6 (i.e. compound 6) (90g,324.43mmol) in ethanol, heated to 140 ℃, stirred for 22h and run to completion by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooling to room temperature, suction filtering and drying to obtain the final product, namely, the doxepin hydrochloride white solid 91.6g with the yield of 89.96 percent.
1H NMR(400MHz,CDCl3)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 32
Concentrated hydrochloric acid 54ml (12N) (containing 648mmol of HCl) was slowly added to a solution of intermediate 6 (i.e. compound 6) (90g,324.43mmol) in ethanol, heated to 140 ℃, stirred for 18h and run to completion by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooled to room temperature, filtered and dried to obtain the final product doxepin hydrochloride white solid 91.18g with the yield of 89.54%.
1H NMR(400MHz,CDCl3)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
Example 33
Concentrated hydrochloric acid 54ml (12N) (containing 648mmol of HCl) was slowly added to a solution of intermediate 6 (i.e. compound 6) (90g,324.43mmol) in ethanol, heated to 140 ℃, stirred for 20h and run to completion by TLC (UV254, methanol/dichloromethane ═ 1: 8). Cooled to room temperature, filtered and dried to obtain the final product doxepin hydrochloride white solid 91.2g with the yield of 89.56%.
1H NMR(400MHz,CDCl3)δ12.50(s,1H),7.36(dtt,J＝14.3,7.7,1.9Hz,3H),7.24(dd,J＝7.7,1.6Hz,1H),7.20(dd,J＝6.9,1.7Hz,1H),7.15(td,J＝7.7,1.7Hz,1H),6.93–6.86(m,1H),6.76(dd,J＝8.2,1.2Hz,1H),5.92(t,J＝7.3Hz,1H),5.65–5.44(m,1H),4.81(s,1H),3.28–2.91(m,3H),2.72(s,6H).13C NMR(125MHz,CDCl3)δ157.11,136.84,134.63,133.00,129.61,129.49,129.08,128.81,127.53,127.50,127.33,125.15,122.55,117.86,71.40,58.15,44.96,27.15.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. A synthetic method of doxepin hydrochloride is characterized by comprising the following steps:
(1): taking 3-chloro-1- (N, N-dimethyl) propylamine and phosphite ester to carry out an Ebazomib reaction to obtain 3- (N, N-dimethyl) propyl phosphate;
(2): reacting the obtained 3- (N, N-dimethyl) propyl phosphate or the hydrochloride of the 3- (N, N-dimethyl) propyl phosphate obtained by acidifying the 3- (N, N-dimethyl) propyl phosphate with 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one under the action of strong alkali to obtain a Wittig reaction product;
(3): and (3) reacting the Wittig reaction product with HCl to obtain the target product.
2. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (1), the phosphite is trimethyl phosphite, triethyl phosphite, triisopropyl phosphite or tribenzyl phosphite.
3. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (1), the molar ratio of 3-chloro-1- (N, N-dimethyl) propylamine to phosphite ester is 1 (1.1-3).
4. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (1), the temperature of the Ebezomib reaction is 140-150 ℃, and the reaction time is 6-8 h.
5. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (2), the process for preparing the hydrochloride of 3- (N, N-dimethyl) propyl phosphate by acidifying 3- (N, N-dimethyl) propyl phosphate specifically comprises the following steps:
dissolving 3- (N, N-dimethyl) propyl phosphate in ethyl acetate, introducing hydrogen chloride gas or adding hydrochloric acid, stirring and crystallizing to obtain 3- (N, N-dimethyl) propyl phosphate hydrochloride;
when hydrochloric acid was added, the pH of the ethyl acetate solution of 3- (N, N-dimethyl) propyl phosphate was adjusted to 1-2 by dropwise addition of hydrochloric acid.
6. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (2), the molar ratio of 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to 3- (N, N-dimethyl) propyl phosphate or 3- (N, N-dimethyl) propyl phosphate hydrochloride is 1 (1.1-1.5).
7. The method according to claim 1, wherein in the step (2), the strong base is potassium tert-butoxide, sodium hydride, sodium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, or butyllithium.
8. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (2), when the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one reacts with 3- (N, N-dimethyl) propyl phosphate, the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the strong base is 1 (1.1-1.5);
when the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one reacts with 3- (N, N-dimethyl) propyl phosphate hydrochloride, the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the strong base is 1 (2.1-2.5).
9. The method for synthesizing doxepin hydrochloride according to claim 1, wherein in the step (2), the reaction temperature is-78-25 ℃ and the reaction time is 10-12 h.
10. The method for synthesizing doxepin hydrochloride according to claim 1, wherein HCl reacted with the Wittig reaction product is added in the form of hydrochloric acid or hydrogen chloride gas in the step (3), and the molar ratio of the Wittig reaction product to HCl is 1 (1.5-3);
in the step (3), the reaction temperature is 135-150 ℃, and the reaction time is 18-22 h.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693685A (en) * | 2016-02-01 | 2016-06-22 | 山东罗欣药业集团股份有限公司 | Preparation technique of olopatadine hydrochloride |
| CN112079809A (en) * | 2020-10-19 | 2020-12-15 | 武汉爱民制药股份有限公司 | Synthesis method of doxepin hydrochloride |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105693685A (en) * | 2016-02-01 | 2016-06-22 | 山东罗欣药业集团股份有限公司 | Preparation technique of olopatadine hydrochloride |
| CN112079809A (en) * | 2020-10-19 | 2020-12-15 | 武汉爱民制药股份有限公司 | Synthesis method of doxepin hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| MITSUAKI WATANABE ET AL.: "Reaction of Lithiated Senecioamide and Related Compounds with Benzynes: Efficient Syntheses of Naphthols and Naphthoquinones", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
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