CN113651792A - Improved synthesis method of doxepin hydrochloride - Google Patents
Improved synthesis method of doxepin hydrochloride Download PDFInfo
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- CN113651792A CN113651792A CN202110990016.1A CN202110990016A CN113651792A CN 113651792 A CN113651792 A CN 113651792A CN 202110990016 A CN202110990016 A CN 202110990016A CN 113651792 A CN113651792 A CN 113651792A
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- doxepin
- doxepin 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 40
- 229960002861 doxepin hydrochloride Drugs 0.000 title claims abstract description 39
- 238000001308 synthesis method Methods 0.000 title description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 89
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 31
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 27
- 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 abstract description 17
- -1 3-(dimethylamino)propyl Chemical group 0.000 claims abstract description 15
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 14
- 229960005426 doxepin Drugs 0.000 claims abstract description 12
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 claims abstract description 12
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000010189 synthetic method Methods 0.000 claims abstract 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 59
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 19
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 19
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 10
- 239000007795 chemical reaction product Substances 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
- 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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims 2
- NRUBUZBAZRTHHX-UHFFFAOYSA-N lithium;propan-2-ylazanide Chemical compound [Li+].CC(C)[NH-] NRUBUZBAZRTHHX-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 96
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- 239000000243 solution Substances 0.000 description 55
- 229940125898 compound 5 Drugs 0.000 description 46
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- 238000001035 drying Methods 0.000 description 29
- 238000001914 filtration Methods 0.000 description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 229940126214 compound 3 Drugs 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 18
- 238000001816 cooling Methods 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 239000012467 final product Substances 0.000 description 7
- 239000002585 base Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 150000004714 phosphonium salts Chemical class 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
- SSLURIRZNIDSSG-UHFFFAOYSA-M 3-(dimethylamino)propyl-triphenylphosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCN(C)C)C1=CC=CC=C1 SSLURIRZNIDSSG-UHFFFAOYSA-M 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000003839 salts Chemical class 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
- 239000003513 alkali Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000002207 metabolite Substances 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
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 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
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 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
- 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000011541 reaction mixture Substances 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
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种盐酸多塞平的改进合成方法。该方法包括以下合成步骤：(1)将三苯基膦与3‑氯‑1‑(N,N‑二甲基)丙胺进行反应，制得(3‑(二甲氨基)丙基)三苯基氯化膦；(2)将(3‑(二甲氨基)丙基)三苯基氯化膦与6,11‑二氢二苯并[b,e]噁庚英‑11‑酮在强碱条件下进行Wittig反应，制得多塞平；(3)将多塞平与盐酸进行成盐反应，制得盐酸多塞平。本发明于第二步反应中采用Wittig反应，使得反应更加简单，对溶剂及原料的水分、反应设备等条件要求更低，重复率更高。与现有的工艺相比，本发明具有工艺简单，生产成本低，工艺步骤少等优点。The present invention relates to an improved synthetic method of doxepin hydrochloride. The method comprises the following synthesis steps: (1) reacting triphenylphosphine with 3-chloro-1-(N,N-dimethyl)propylamine to obtain (3-(dimethylamino)propyl)triphenyl (2) (3-(dimethylamino)propyl)triphenylphosphine chloride and 6,11-dihydrodibenzo[b,e]oxepin-11-one in strong Doxepin is prepared by Wittig reaction under alkaline conditions; (3) Doxepin is prepared by salt-forming reaction with hydrochloric acid to prepare doxepin hydrochloride. In the present invention, the Wittig reaction is adopted in the second-step reaction, so that the reaction is simpler, the requirements for conditions such as solvent and raw material moisture, reaction equipment and the like are lower, and the repetition rate is higher. Compared with the prior art, the present invention 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 an improved 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 on doxepin hydrochloride, such as patent CN112079809A) and CN105085465A, 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 reactionThe reaction usually involves heating diethyl ether or tetrahydrofuran, and certain potential safety hazards exist in the production.
Disclosure of Invention
The invention aims to provide an improved synthesis method of doxepin hydrochloride, which aims to solve the problems of harsh synthesis conditions, complex process or high cost and the like in the prior art.
The purpose of the invention can be realized by the following technical scheme:
the invention provides an improved synthesis method of doxepin hydrochloride, which comprises the following steps:
(1) carrying out salt forming reaction on 3-chloro-1- (N, N-dimethyl) propylamine and triphenylphosphine to obtain (3- (dimethylamino) propyl) triphenylphosphine chloride;
(2) reacting the obtained (3- (dimethylamino) propyl) triphenyl phosphonium chloride with 6, 11-dihydrodibenzo [ b, e ] oxepin-11-ketone under the action of strong alkali to obtain a Wittig reaction product doxepin;
(3) and (3) taking the Wittig reaction product doxepin to react with HCl to obtain the target product.
Furthermore, in the step (1), the molar ratio of triphenylphosphine to 3-chloro-1- (N, N-dimethyl) propylamine is 1 (1.1-1.3).
Further, in the step (1), the salt forming reaction temperature is 110-115 ℃, and the reaction time is 4-4.5 days.
Further, in the step (1), the solvent for salt forming reaction in the step (1) is toluene.
Further, in the step (2), the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the (3- (dimethylamino) propyl) triphenyl phosphine chloride is 1 (1.1-1.2).
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 lithium diisopropylamide. Specifically, the addition of a strong base to the Wittig reaction serves to convert the phosphonium salt to the corresponding Wittig nucleophile, which can react with the carbonyl compound and other polar groups, and the strength and choice of the base used depends primarily on the acidity of the hydrogen atom on the α -carbon of the phosphonium salt. In addition, the base is selected in consideration of the nature of the groups present in the phosphonium salt, e.g., when the phosphonium salt contains a carbonyl group, it is preferable to avoid the use of a metal alkyl compound and a metal hydride as the base.
Further, in the step (2), the molar ratio of the 6, 11-dihydrodibenzo [ b, e ] oxepin-11-one to the strong base is 1 (1.1-1.2).
Further, in the step (2), the reaction temperature is-78-0 ℃, and the reaction time is 16-18 h.
Further, in the step (2), the solvent for the reaction is tetrahydrofuran.
Furthermore, in the step (3), HCl reacted with the Wittig reaction product doxepin is added in the form of hydrochloric acid solution or hydrogen chloride gas, and the molar ratio of the Wittig reaction product doxepin to 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.
In the step (1), 3-chloro-1- (N, N-dimethyl) propylamine (compound 1) and triphenylphosphine (compound 2) are used as raw materials to prepare (3- (dimethylamino) propyl) triphenylphosphine chloride (compound 3), and excessive triphenylphosphine can ensure that the 3-chloro-1- (N, N-dimethyl) propylamine completely reacts; in the step (2), the (3- (dimethylamino) propyl) triphenyl phosphonium chloride and 6, 11-dihydrodibenzo [ b, e ] oxepin-11-ketone (compound 4) are subjected to Wittig reaction under a strong alkali condition to obtain an intermediate product doxepin (compound 5), and the excessive (3- (dimethylamino) propyl) triphenyl phosphonium chloride can improve the reaction yield; and then carrying out salifying reaction on the intermediate product doxepin 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:
the reaction process of the step (2) is as follows:
the reaction process of the step (3) is as follows:
compared with the prior art, the invention has the following advantages:
(1) the invention adopts Wittig reaction to synthesize doxepin hydrochloride, and has the advantages of simple process, few reaction steps, low cost and the like compared with the prior art.
(2) The invention adopts triphenylphosphine with lower price as raw material, thus greatly reducing cost. The Wittig 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 reaction solvent, water content of raw materials 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
3-chloro-1- (N, N-dimethyl) propylamine (45.9g,377.44mmol) was slowly added to a solution of triphenylphosphine (90g,343.13mmol) in toluene (400ml), heated to 110 deg.C, stirred for 4.5d and checked by TLC (UV254, ethyl acetate/petroleum ether ═ 1:3) to completion. The reaction liquid is naturally cooled and stirred for 8 hours of crystallizationThen, the reaction mixture was filtered off with suction and dried to obtain (3- (dimethylamino) propyl) triphenylphosphine chloride (Compound No. 3) in an amount of 117.8g and a yield of 89.43%.1H NMR(400MHz,CDCl3)δ1.74-1.87(m,2H),2.12(s,6H),2.53(t,J＝6.0Hz,2H),3.77-3.89(m,2H),7.69-7.89(m,15H)；13C NMR(125MHz,CDCl3)δ19.9(d,J＝52.2Hz),20.5(d,J＝3.3Hz),45.0(s),58.2(d,J＝16.0Hz),118.0(d,J＝86.2Hz),130.2(d,J＝12.6Hz),133.2(d,J＝9.9Hz),134.7(d,J＝2.8Hz).
Example 2
3-chloro-1- (N, N-dimethyl) propylamine (50.07g,411.76mmol) was slowly added to a solution of triphenylphosphine (90g,343.13mmol) in toluene (400ml), heated to 112 ℃ and stirred for 4.5d, with TLC detection (UV254, ethyl acetate/petroleum ether ═ 1:3) to completion. The reaction solution was naturally cooled, stirred and crystallized for 8 hours, suction-filtered and dried to obtain (3- (dimethylamino) propyl) triphenylphosphine chloride (compound 3) in an amount of 118.3g and in a yield of 89.81%.1H NMR(400MHz,CDCl3)δ1.74-1.87(m,2H),2.12(s,6H),2.53(t,J＝6.0Hz,2H),3.77-3.89(m,2H),7.69-7.89(m,15H)；13C NMR(125MHz,CDCl3)δ19.9(d,J＝52.2Hz),20.5(d,J＝3.3Hz),45.0(s),58.2(d,J＝16.0Hz),118.0(d,J＝86.2Hz),130.2(d,J＝12.6Hz),133.2(d,J＝9.9Hz),134.7(d,J＝2.8Hz).
Example 3
3-chloro-1- (N, N-dimethyl) propylamine (54.25g,446.07mmol) was slowly added to a solution of triphenylphosphine (90g,343.13mmol) in toluene (400ml), heated to 115 deg.C, stirred for 4.5d and checked by TLC (UV254, ethyl acetate/petroleum ether ═ 1:3) to completion. The reaction solution was naturally cooled, stirred and crystallized for 8 hours, suction-filtered and dried to obtain (3- (dimethylamino) propyl) triphenylphosphine chloride (compound 3) in an amount of 118.4g and in a yield of 89.88%.1H NMR(400MHz,CDCl3)δ1.74-1.87(m,2H),2.12(s,6H),2.53(t,J＝6.0Hz,2H),3.77-3.89(m,2H),7.69-7.89(m,15H)；13C NMR(125MHz,CDCl3)δ19.9(d,J＝52.2Hz),20.5(d,J＝3.3Hz),45.0(s),58.2(d,J＝16.0Hz),118.0(d,J＝86.2Hz),130.2(d,J＝12.6Hz),133.2(d,J＝9.9Hz),134.7(d,J＝2.8Hz).
Example 4
Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(182.49g,475.37mmol) 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 18 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 5.
And adding petroleum ether into the crude product of the compound 5, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 88.5g of the compound 5 with the yield of 73.99%.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 5
Sodium hydride (11.41g,475.37mmol) was added portionwise to a solution of compound 3(182.49g,475.37mmol) in tetrahydrofuran (300ml) under nitrogen and the reaction 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 18 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 5.
And adding petroleum ether into the crude product of the compound 5, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain the compound 5 with the amount of 85g and the yield of 70.9%.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(182.49g,475.37mmol) 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 18 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 5.
Adding petroleum ether into the crude product of the compound 5, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 85.87g of the compound 5 with yield of 71.80%.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(182.49g,475.37mmol) 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 18 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 5.
And adding petroleum ether into the crude product of the compound 5, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 84.98g of the compound 5 with the yield of 71.05%.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 to a solution of compound 3(182.49g,475.37mmol) 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 18 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 5.
And adding petroleum ether into the crude product of the compound 5, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 83.5g of the compound 5 with the yield of 69.81%.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 5 (i.e., compound 5) (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
54ml (12N) (containing 648mmol of HCl) of concentrated HCl in 2-fold molar amount to intermediate 5 (i.e. compound 5) was slowly added to an ethanol solution of intermediate 5(90g,324.43mmol), 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
A3-fold molar amount of concentrated HCl 81ml (12N) (containing 972mmol HCl) to intermediate 5 (i.e., Compound 5) was slowly added to a solution of intermediate 5(90g,324.43mmol) in ethanol, heated to 150 deg.C, and stirredThe reaction was 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
3-chloro-1- (N, N-dimethyl) propylamine (45.9g,377.44mmol) was slowly added to a solution of triphenylphosphine (90g,343.13mmol) in toluene (400ml), heated to 110 ℃ and stirred for 4d, with TLC detection (UV254, ethyl acetate/petroleum ether ═ 1:3) to completion. The reaction solution was naturally cooled, stirred and crystallized for 8 hours, suction-filtered and dried to obtain (3- (dimethylamino) propyl) triphenylphosphine chloride (compound 3) in an amount of 116.7g and in a yield of 88.59%.1H NMR(400MHz,CDCl3)δ1.74-1.87(m,2H),2.12(s,6H),2.53(t,J＝6.0Hz,2H),3.77-3.89(m,2H),7.69-7.89(m,15H)；13C NMR(125MHz,CDCl3)δ19.9(d,J＝52.2Hz),20.5(d,J＝3.3Hz),45.0(s),58.2(d,J＝16.0Hz),118.0(d,J＝86.2Hz),130.2(d,J＝12.6Hz),133.2(d,J＝9.9Hz),134.7(d,J＝2.8Hz).
Example 13
3-chloro-1- (N, N-dimethyl) propylamine (45.9g,377.44mmol) was slowly added to a solution of triphenylphosphine (90g,343.13mmol) in toluene (400ml), heated to 110 deg.C, stirred for 4.2d and checked by TLC (UV254, ethyl acetate/petroleum ether ═ 1:3) to completion. The reaction solution was naturally cooled, stirred and crystallized for 8 hours, suction filtered and dried to obtain (3- (dimethylamino) propyl) triphenylphosphine chloride (compound 3) in an amount of 116.9g with a yield of 88.74%.1H NMR(400MHz,CDCl3)δ1.74-1.87(m,2H),2.12(s,6H),2.53(t,J＝6.0Hz,2H),3.77-3.89(m,2H),7.69-7.89(m,15H)；13C NMR(125MHz,CDCl3)δ19.9(d,J＝52.2Hz),20.5(d,J＝3.3Hz),45.0(s),58.2(d,J＝16.0Hz),118.0(d,J＝86.2Hz),130.2(d,J＝12.6Hz),133.2(d,J＝9.9Hz),134.7(d,J＝2.8Hz).
Example 14
Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(190.78g,496.97mmol) 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 18 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 5.
Adding petroleum ether into the crude product of the compound 5, heating and refluxing to dissolve the crude product, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 88.61g of the compound 5 with the yield of 74.09%.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 15
Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(199.08g,518.58mmol) 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 18 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 5.
And adding petroleum ether into the crude product of the compound 5, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 88.63g of the compound 5 with the yield of 74.1%.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
Sodium tert-butoxide (45.68g,475.37mmol) was added portionwise to a solution of compound 3(182.49g,475.37mmol) 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 18 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 5.
And adding petroleum ether into the crude product of the compound 5, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 88.46g of the compound 5 with the yield of 73.96%.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
Butyllithium (30.45g, 475.37mmol) was added portionwise to a solution of compound 3(182.49g,475.37mmol) 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 18 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 5.
And adding petroleum ether into the crude product of the compound 5, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 86.1g of the compound 5 with the yield of 71.99%.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 18
Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(182.49g,475.37mmol) 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 16 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 5.
Adding petroleum ether into the crude product of the compound 5, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 86.52g of the compound 5 with yield of 72.34%.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 19
Potassium tert-butoxide (53.34g,475.37mmol) was added portionwise to a solution of compound 3(182.49g,475.37mmol) 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, the reaction was stirred at 0 ℃ for 17 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 5.
And adding petroleum ether into the crude product of the compound 5, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering, and drying to obtain 87.1g of the compound 5 with the yield of 72.82%.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 20
Slowly add 2 times the molar amount of concentrated HCl 40.5ml (12N) (containing 486mmol HCl) to intermediate 5 (i.e. compound 5) in ethanol solution of intermediate 5(90g,324.43mmol), heat to 140 ℃, stir for 22h, TLC check (UV254, methanol/dichloromethane ═ 1:8) to completion. Cooling to room temperature, suction filtering and drying to obtain the final product doxepin hydrochloride white solid 90.9g, with the yield of 89.34%.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 21
54ml (12N) (containing 648mmol of HCl) of concentrated HCl in 2-fold molar amount to intermediate 5 (i.e. compound 5) was slowly added to an ethanol solution of intermediate 5(90g,324.43mmol), 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 90.32g with the yield of 88.77%.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 22
54ml (12N) (containing 648mmol of HCl) of concentrated HCl in 2-fold molar amount to intermediate 5 (i.e. compound 5) was slowly added to an ethanol solution of intermediate 5(90g,324.43mmol), 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 91.32g with the yield of 89.75%.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 23
Potassium tert-butoxide (55.77g,496.97mmol) was added portionwise to a solution of compound 3(182.49g,475.37mmol) 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 18 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 5.
Adding petroleum ether into the crude product of the compound 5, heating and refluxing to be clear, naturally stirring, cooling and crystallizing, filtering and drying to obtain 89.10g of the compound 5 with the yield of 74.5%.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 (58.19g,518.58mmol) was added portionwise to a solution of compound 3(182.49g,475.37mmol) 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 18 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 5.
Adding petroleum ether into the crude product of the compound 5, and heating and refluxing the mixture until the mixture is clearNaturally stirring, cooling, crystallizing, filtering, and drying to obtain 89.13g of compound 5 with yield of 74.52%.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.
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.
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| CN104031020A (en) * | 2014-06-04 | 2014-09-10 | 北京嘉林药业股份有限公司 | Preparation method of o-hydroxyl Olopatadine |
| CN110343086A (en) * | 2019-08-07 | 2019-10-18 | 重庆西南制药二厂有限责任公司 | A kind of preparation method 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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| CN104031020A (en) * | 2014-06-04 | 2014-09-10 | 北京嘉林药业股份有限公司 | Preparation method of o-hydroxyl Olopatadine |
| CN110343086A (en) * | 2019-08-07 | 2019-10-18 | 重庆西南制药二厂有限责任公司 | A kind of preparation method 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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