CN118125995A - Synthesis method of 1- (2-methoxyphenyl) piperazine hydrochloride - Google Patents
Synthesis method of 1- (2-methoxyphenyl) piperazine hydrochloride Download PDFInfo
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- DDMVHGULHRJOEC-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazin-1-ium;chloride Chemical compound Cl.COC1=CC=CC=C1N1CCNCC1 DDMVHGULHRJOEC-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000001308 synthesis method Methods 0.000 title abstract description 10
- YMDZDFSUDFLGMX-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)ethanamine;hydron;chloride Chemical compound [Cl-].ClCC[NH2+]CCCl YMDZDFSUDFLGMX-UHFFFAOYSA-N 0.000 claims abstract description 42
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 claims abstract description 41
- TXFLGZOGNOOEFZ-UHFFFAOYSA-N bis(2-chloroethyl)amine Chemical compound ClCCNCCCl TXFLGZOGNOOEFZ-UHFFFAOYSA-N 0.000 claims abstract description 39
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 35
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims abstract description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 125000006239 protecting group Chemical group 0.000 claims abstract description 22
- -1 Boc group Chemical group 0.000 claims abstract description 15
- 238000006482 condensation reaction Methods 0.000 claims abstract description 14
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 81
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 44
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 28
- 238000010438 heat treatment Methods 0.000 claims description 26
- 238000010992 reflux Methods 0.000 claims description 25
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- 239000000047 product Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- 238000003786 synthesis reaction Methods 0.000 claims description 19
- 239000012043 crude product Substances 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000007363 ring formation reaction Methods 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 claims description 11
- 238000002390 rotary evaporation Methods 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 239000012535 impurity Substances 0.000 description 9
- 238000009833 condensation Methods 0.000 description 7
- 230000005494 condensation Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 229910000510 noble metal Inorganic materials 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229960001130 urapidil Drugs 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 229940127088 antihypertensive drug Drugs 0.000 description 2
- 150000008378 aryl ethers Chemical class 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- XCZCWGVXRBJCCD-UHFFFAOYSA-N 2-methoxyaniline;hydrochloride Chemical compound Cl.COC1=CC=CC=C1N XCZCWGVXRBJCCD-UHFFFAOYSA-N 0.000 description 1
- QVBKNQCTHMMDQP-UHFFFAOYSA-N 4-(3-hydroxypropylamino)-1,3-dimethyl-4h-pyrimidin-2-one Chemical compound CN1C=CC(NCCCO)N(C)C1=O QVBKNQCTHMMDQP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 102000017911 HTR1A Human genes 0.000 description 1
- 101150015707 HTR1A gene Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 102000030619 alpha-1 Adrenergic Receptor Human genes 0.000 description 1
- 108020004102 alpha-1 Adrenergic Receptor Proteins 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- MMCPOSDMTGQNKG-UHFFFAOYSA-N anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000005808 aromatic amination reaction Methods 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- DHNYUSXLKLFHTB-UHFFFAOYSA-N lithium;piperazine Chemical compound [Li].C1CNCCN1 DHNYUSXLKLFHTB-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- LOJAQAYKWFMKMR-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C LOJAQAYKWFMKMR-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ZGNPLWZYVAFUNZ-UHFFFAOYSA-N tert-butylphosphane Chemical compound CC(C)(C)P ZGNPLWZYVAFUNZ-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Abstract
The invention discloses a synthesis method of 1- (2-methoxyphenyl) piperazine hydrochloride, which comprises the following steps: (1) Taking diethanolamine as a basic raw material, and taking thionyl chloride as a chlorinating agent to carry out chlorination reaction to obtain bis (2-chloroethyl) amine hydrochloride; (2) And (3) performing Boc group protection on bis (2-chloroethyl) amine, performing ring-forming condensation reaction on the bis (2-chloroethyl) amine and o-methoxy aniline, removing the Boc protecting group to obtain 1- (2-methoxyphenyl) piperazine, and adding hydrochloric acid to form a salt to obtain 1- (2-methoxyphenyl) piperazine hydrochloride. The invention adopts diethanolamine as a basic raw material and thionyl chloride as a chlorinating agent, and firstly synthesizes bis (2-chloroethyl) amine hydrochloride, then carries out Boc group protection on the bis (2-chloroethyl) amine, then carries out ring-forming condensation reaction with o-methoxy aniline, then removes Boc protecting group, and finally salifies with HCl to obtain a target product. The route has the advantages of low cost and easy acquisition of raw materials, high yield, high product purity and the like, and is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a synthesis method of 1- (2-methoxyphenyl) piperazine hydrochloride.
Background
Phenylpiperazine is an important pharmaceutical structure, and is modified by introducing different substituents into the structure to produce various pharmacological activities such as antihypertensive, antitumor, analgesic, psychotic, antifungal and the like. 1- (2-methoxy phenyl) piperazine hydrochloride is used as phenyl piperazine compound and has wide application in the fields of pharmaceutical chemistry, organic chemistry, materials and the like. The 1- (2-methoxyphenyl) piperazine hydrochloride has a key effect in the process of synthesizing the antihypertensive drug urapidil, and the urapidil can be obtained by carrying out certain catalytic reaction on the 1- (2-methoxyphenyl) piperazine hydrochloride and the 6- (3-chloropropyl) amino-1, 3-dimethyluracil. Urapidil is used as a multi-target antihypertensive drug, can play a role in reducing blood pressure by selectively blocking alpha 1 adrenergic receptors and activating central 5-HT1A receptors, and is the first drug for clinically treating severe hypertension.
The molecular formula of the 1- (2-methoxyphenyl) piperazine hydrochloride is C11H16N2O & HCl, the molecular weight is 228.72, the melting point is 217-219 ℃, the boiling point is 379.9 ℃, and the CAS number is 5464-78-8. The product is white or white crystalline powder, and is soluble in DMSO and DMF, and water. The chemical structure of 1- (2-methoxyphenyl) piperazine hydrochloride is shown in the following formula I:
the main synthetic routes of 1- (2-methoxyphenyl) piperazine salts are mainly divided into the following classes:
(1) O-methoxyphenol or o-methoxyhalogenated benzene is condensed with piperazine under the catalysis of noble metal complexes (e.g., palladium/t-butylphosphine, etc.) (NISHIYAMA M et al ,Synthesis of N-arylpiperazines from aryl halides and piperazine under a palladium tri-tert-butylphosphine catalyst). but these noble metal complexes are not readily available and are expensive.
(2) The phenolic hydroxyl group of the o-methoxyphenol is modified to an easy leaving group and then condensed with piperazine (CN 114685399A). The technology can avoid the use of noble metal compound catalyst in theory, but has harsh reaction conditions in actual use, needs to use highly toxic methanesulfonyl chloride, and has low yield.
(3) The catalytic condensation cyclization of o-methoxyphenylamine hydrochloride and diethanolamine (Budai Z et al ,Process for producing phenylpiperazines by cyclocondensation of diethanolamine with aniline hydrochloride), but the reaction of the technology needs to be carried out under high temperature, and the corrosion of the reaction solution to equipment is large, which is a difficult problem in industrial production.
(4) 2-Methoxyaniline is condensed with bis (2-chloroethyl) amine salt to form a ring. The amine salt can be used for one-step reaction to obtain the required hydrochloride (Zhang Cuie and the like, and the synthesis research of 1- (2-methoxyphenyl) piperazine halogen acid salt), but the intermediate bis (2-chloroethyl) amine salt is not sold in the market and needs to be self-made.
(5) Wolter ten Hoeve, etc., uses lithium amide to directly replace aromatic ether (Direct substitution of aromatic ethers by lithium amides. A new aromatic amination reaction), but lithium piperazine which is required to be used for producing 1- (2-methoxyphenyl) piperazine hydrochloride has no industrial products, is difficult to manufacture, has high price, and is not suitable for industrial production.
(6) The chloroacetonitrile and the o-methoxy aniline are prepared by 5 steps of reactions such as condensation, hydrolysis, cyclization, salification and the like, and the method has complex process and low yield.
Among the above various synthetic methods, the synthetic scheme of (4) is generally economical and feasible and is suitable for industrial production, but the defects of high impurity content, low yield, low product purity and difficult purification are found in the production.
The present invention has been made in view of this.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects of the prior art and providing a synthesis method of 1- (2-methoxyphenyl) piperazine hydrochloride. The method comprises the steps of firstly synthesizing bis (2-chloroethyl) amine hydrochloride by taking diethanolamine as a basic raw material and thionyl chloride as a chlorinating agent, then protecting a Boc group of the bis (2-chloroethyl) amine, then carrying out a ring-forming condensation reaction with o-methoxy aniline, then removing the Boc protecting group, and finally salifying with HCl to obtain a target product. The route has the advantages of low cost and easy acquisition of raw materials, high yield, high product purity and the like, and is suitable for large-scale industrial production.
In order to solve the technical problems, the invention adopts the basic conception of the technical scheme that:
Zhang Cuie et al, in the "synthesis studies of 1- (2-methoxyphenyl) piperazine hydrohalate", the route of condensation of 2-methoxyaniline with bis (2-chloroethyl) amine salt to the ring is optimal in the various synthetic routes at present, but has the following drawbacks:
(1) The step of synthesizing the bis (2-chloroethyl) amine hydrochloride lacks a purification procedure, impurities including HCl and monochloro substituents are easily brought into the next reaction, and the quality of the product is seriously affected.
(2) The condensation cyclization reaction of the 2-methoxyaniline and the bis (2-chloroethyl) amine is nucleophilic substitution reaction, the amino lone pair electron of the 2-methoxyaniline attacks the carbon atom connected with chlorine on the bis (2-chloroethyl) amine to generate substitution reaction, and the chlorine atom becomes a leaving group. And the amino group of bis (2-chloroethyl) amine has a stronger nucleophilicity than that of 2-methoxyaniline, so that the bis (2-chloroethyl) amine is liable to undergo self-crosslinking reaction, a large amount of impurities are generated, the purification is very complicated and the yield is seriously affected.
Therefore, the technical scheme cannot obtain a high-quality 1- (2-methoxyphenyl) piperazine hydrochloride product.
The invention provides a synthesis method of 1- (2-methoxyphenyl) piperazine hydrochloride, which comprises the following steps:
(1) Taking diethanolamine as a basic raw material, and taking thionyl chloride as a chlorinating agent to carry out chlorination reaction to obtain bis (2-chloroethyl) amine hydrochloride;
(2) And (3) performing Boc group protection on bis (2-chloroethyl) amine, performing ring-forming condensation reaction on the bis (2-chloroethyl) amine and o-methoxy aniline, removing the Boc protecting group to obtain 1- (2-methoxyphenyl) piperazine, and adding hydrochloric acid to form a salt to obtain 1- (2-methoxyphenyl) piperazine hydrochloride.
The invention adopts diethanolamine as a basic raw material and thionyl chloride as a chlorinating agent, and firstly synthesizes bis (2-chloroethyl) amine hydrochloride, then carries out Boc group protection on the bis (2-chloroethyl) amine, then carries out ring-forming condensation reaction with o-methoxy aniline, then removes Boc protecting group, and finally salifies with HCl to obtain a target product. The route has the advantages of low cost and easy acquisition of raw materials, high yield, high product purity and the like, and is suitable for large-scale industrial production.
In the step (1), slowly dropwise adding a chloroform solution of diethanolamine into a chloroform solution of thionyl chloride under ice bath cooling, wherein the molar ratio of the diethanolamine to the thionyl chloride is 1:2.0-8.0, and the total chloroform dosage is 6.0-20.0 ml/g calculated by the diethanolamine; controlling the temperature of the reaction system to be less than 20-50 ℃; heating to room temperature for heat preservation after the dripping is completed, refluxing for 1-8 hours, cooling to room temperature after the reaction is completed, filtering, drying to obtain a crude product, and purifying.
Wherein the total chloroform is divided into two parts, and two reactants of diethanolamine and thionyl chloride are respectively dissolved. The total chloroform dosage refers to the total chloroform dosage in the two reactant solutions.
Further, the purifying comprises: after obtaining a crude product, adding absolute ethyl alcohol for recrystallization, and vacuum drying to obtain purified bis (2-chloroethyl) amine hydrochloride;
preferably, the amount of absolute ethanol is 5.0-20.0 ml/1g of crude product.
In a further scheme, the crude product is added into absolute ethyl alcohol (5 ml/1g of crude product), heated and refluxed to be completely dissolved, filtered while the crude product is hot, crystallized, pumped and filtered, and a filter cake is dried in vacuum to obtain bis (2-chloroethyl) amine hydrochloride.
According to the synthesis method, after the reaction of the bis (2-chloroethyl) amine hydrochloride is finished, a step of recrystallizing by using absolute ethyl alcohol is added to purify the bis (2-chloroethyl) amine hydrochloride intermediate. The solubility of the primary byproduct monochloro substituent of the reaction in absolute ethanol is relatively high and can be removed in the recrystallization process. The intermediate obtained by recrystallization is dried in vacuum to remove excess HCl, so that the intermediate is prevented from being carried into the next reaction.
In a further scheme, the intermediate bis (2-chloroethyl) amine hydrochloride prepared by the synthesis method has the yield of more than 80% and the purity of more than 98%.
In a further aspect, in step (2), the Boc group protection of the bis (2-chloroethyl) amine comprises:
Dissolving bis (2-chloroethyl) amine hydrochloride in water, adding potassium carbonate, stirring to dissolve, and then adding di-tert-butyl carbonate to react; the mol ratio of the bis (2-chloroethyl) amine hydrochloride to the potassium carbonate to the di-tert-butyl carbonate is 1:1.5-4.0:1.0-2.0, and the water dosage is 3-15 ml/1g of the bis (2-chloroethyl) amine hydrochloride.
Further, when the reaction is carried out, the stirring reaction is carried out for 30 to 180 minutes at the temperature of 20 to 80 ℃.
The di-tert-butyl carbonate is used for protecting the amino group on the bis (2-chloroethyl) amine, so that the self-crosslinking reaction of the bis (2-chloroethyl) amine is reduced, the generation of impurities is reduced, the subsequent purification is facilitated, and the yield is improved.
In a further scheme, in the step (2), the cyclic condensation reaction with o-methoxyaniline comprises the following steps:
Adding DMF to dissolve Boc-protected bis (2-chloroethyl) amine, then adding o-methoxyaniline, carrying out heating reflux reaction, and removing DMF by rotary evaporation after the reaction;
the mole ratio of the Boc protected bis (2-chloroethyl) amine to the o-methoxyaniline is 0.8-2.5:1, and the DMF dosage is 5-15 ml/1g o-methoxyaniline.
In a further scheme, heating reflux reaction is carried out for 10 to 36 hours; and adding alkali in the middle, and controlling the PH of the system to be more than or equal to 10.
Preferably, the additional base is potassium hydroxide.
The invention uses DMF as solvent in the cyclization condensation reaction, which improves the reaction temperature and shortens the reaction time greatly. DMF is removed by rotary evaporation after the reaction, and the subsequent reaction is not affected.
Further, removing the Boc protecting group comprises:
after the cyclization condensation reaction, adding isopropanol dissolution product, adding p-toluenesulfonic acid, stirring for reaction, and removing Boc protecting group to obtain 1- (2-methoxyphenyl) piperazine;
The dosage of the p-toluenesulfonic acid is 0.8 to 2.0eq and the dosage of the isopropanol is 5 to 15ml/1g of the o-methoxy aniline based on the o-methoxy aniline.
In a further scheme, the temperature is controlled to be 20-80 ℃ and the reaction time is 30-180 minutes during stirring reaction.
The method uses the p-toluenesulfonic acid as the reagent for removing the Boc protecting group, and has mild reaction and good removal effect.
In a further scheme, in the step (2), adding hydrochloric acid to form a salt comprises:
After obtaining 1- (2-methoxyphenyl) piperazine, introducing dry HCL gas into a reaction system, precipitating white precipitate, carrying out suction filtration, washing (washing a filter cake with a small amount of isopropanol), and drying to obtain 1- (2-methoxyphenyl) piperazine hydrochloride.
In a further scheme, the 1- (2-methoxyphenyl) piperazine hydrochloride prepared by the synthesis method has the yield of more than 84 percent and the purity of more than 99 percent based on o-methoxy aniline.
As a specific embodiment, the synthesis method of the 1- (2-methoxyphenyl) piperazine hydrochloride comprises the following steps:
(1) Synthesis of bis (2-chloroethyl) amine hydrochloride
The sulfoxide chloride is dissolved in chloroform, and under the cooling of ice bath, the chloroform solution of diethanolamine is slowly added dropwise under vigorous stirring. Since this reaction is a strongly exothermic reaction, it is necessary to slowly drop-feed the mixed reaction raw materials and control the temperature of the reaction system to 30℃or lower. The mol ratio of the diethanolamine to the thionyl chloride is 1:6, and the dosage of the chloroform is 12ml/g calculated by the diethanolamine. After the dripping is completed, removing the ice bath, naturally heating to room temperature, then preserving heat for 30min, and continuously heating and refluxing for 3h. After the reaction was completed, it was cooled to room temperature. And (5) carrying out suction filtration and drying to obtain a crude product. Adding the crude product into absolute ethyl alcohol (5 ml/1g of crude product), heating and refluxing to completely dissolve the crude product, filtering while the crude product is hot, crystallizing the filtrate, filtering, and vacuum drying the filter cake to obtain bis (2-chloroethyl) amine hydrochloride.
(2) Synthesis of 1- (2-methoxyphenyl) piperazine hydrochloride
Bis (2-chloroethyl) amine hydrochloride is dissolved in distilled water, K 2CO3 is added, and the mixture is fully stirred until the bis (2-chloroethyl) amine hydrochloride is completely dissolved, and then di-tert-butyl carbonate is added, and the mixture is stirred and reacted for 60 minutes at 40 ℃. The molar ratio of the bis (2-chloroethyl) amine hydrochloride, the K 2CO3 and the di-tert-butyl carbonate is 1:3:1, distilled water was used in an amount of 7ml/1g of bis (2-chloroethyl) amine hydrochloride. And after the reaction is finished, removing the solvent by rotary evaporation to obtain Boc-protected bis (2-chloroethyl) amine.
Adding DMF into a flask to dissolve Boc-protected bis (2-chloroethyl) amine, then adding o-methoxyaniline, heating and refluxing for reaction for 8 hours, and then detecting the pH value of a reaction system, and adding potassium hydroxide according to requirements to ensure that the pH value is more than or equal to 10. Reflux was continued for 10 hours. The molar ratio of the bis (2-chloroethyl) amine to the o-methoxyaniline is 1:1, and the DMF dosage is 10ml/1g of o-methoxyaniline.
After the reaction was stopped, DMF was removed by rotary evaporation, and isopropanol was added to the product. Then adding p-toluenesulfonic acid at one time, heating to 40 ℃, stirring and reacting for 60 minutes to remove the Boc protecting group, and obtaining the 1- (2-methoxyphenyl) piperazine. The dosage of the p-toluenesulfonic acid is 1.05eq and the dosage of the isopropanol is 10ml/1g of the o-methoxyaniline calculated by the o-methoxyaniline.
Then, dry HCl gas is introduced into the reaction system, and white precipitate is separated out. The white solid filtered by suction is washed with a small amount of isopropanol and dried to obtain the 1- (2-methoxyphenyl) piperazine hydrochloride.
By adopting the technical scheme, compared with the prior art, the invention has the following beneficial effects.
The invention improves the condensation of 2-methoxyaniline and bis (2-chloroethyl) amine salt into a loop, adds a purification procedure in the step of synthesizing bis (2-chloroethyl) amine hydrochloride, adds a procedure of protecting amino of the bis (2-chloroethyl) amine by using a Boc group and adding a procedure of removing the Boc protecting group after the cyclization condensation reaction. The two processes related to the Boc protecting group can be performed in the same reaction kettle, and the production flow and the cost are not increased significantly. The improved scheme greatly improves the purity of the final product 1- (2-methoxyphenyl) piperazine hydrochloride, and realizes higher yield, and the specific scheme is as follows:
1. In the preparation method of the invention, after the reaction of the bis (2-chloroethyl) amine hydrochloride is finished, a step of using absolute ethyl alcohol for recrystallization is added to purify the bis (2-chloroethyl) amine hydrochloride intermediate. The solubility of the primary byproduct monochloro substituent of the reaction in absolute ethanol is relatively high and can be removed in the recrystallization process. The intermediate obtained by recrystallization is dried in vacuum to remove excess HCl, so that the intermediate is prevented from being carried into the next reaction.
2. The invention uses the di-tert-butyl carbonate to protect the amino group on the bis (2-chloroethyl) amine, reduces the self-crosslinking reaction of the bis (2-chloroethyl) amine, and reduces the generation of impurities.
3. The invention uses DMF as solvent in the cyclization condensation reaction, improves the reaction temperature, greatly shortens the reaction time, 4, uses p-toluenesulfonic acid as a reagent for removing Boc protecting group, has mild reaction and good removal effect,
5. The invention adopts a one-pot method to complete the procedures of introducing Boc protecting groups, forming ring condensation reaction, removing Boc protecting groups and the like, and does not obviously increase the production flow and the cost.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments will be clearly and completely described in conjunction with the embodiments of the present invention, and the following embodiments are used to illustrate the present invention, but are not intended to limit the scope of the present invention.
The detection method comprises the following steps:
HPLC method: octadecylsilane chemically bonded silica is used as a filler; mobile phase is 0.1% H 3PO4 water solution and acetonitrile; the wavelength was 254nm, the column temperature was 40℃and the flow rate was 1ml/min.
Yield: the theoretical yield of the product was calculated as o-methoxyaniline, and then the yield was calculated from the actual yield.
Purity: the content of the compound was determined by HPLC peak area normalization method.
Example 1
(1) Synthesis of bis (2-chloroethyl) amine hydrochloride
A100 mL three-neck flask is added with 20mL of chloroform solution of thionyl chloride (14.28 g,120.00 mmol), the solution is fully diluted, the solution is cooled in an ice bath, 6mL of chloroform solution of diethanolamine (2.10 g,20.00 mmol) is dropwise added under vigorous stirring, the reaction temperature is controlled to be not more than 30 ℃, the dropwise addition is slowly carried out (60 min dropwise addition time), and the generation of impurity morpholine is reduced. After the dripping is completed, removing the ice bath, naturally heating to room temperature, then preserving the heat for 30min, continuously heating and refluxing for 3h, and detecting the consumption condition of the diethanolamine by TLC. After the reaction was completed, the heating was stopped, and the reaction mixture was cooled to room temperature. Filtering, drying to obtain a slightly brown yellow solid, adding 10ml of absolute ethyl alcohol, heating and refluxing for 5 minutes, filtering while the solid is hot, crystallizing the filtrate at 5 ℃ for one hour, filtering, and vacuum drying the filter cake for 2 hours to obtain white crystalline powder bis (2-chloroethyl) amine hydrochloride which is used as a raw material for the next step of synthesis. Yield 87.49% and purity 98.77%.
(2) Synthesis of 1- (2-methoxyphenyl) piperazine hydrochloride
Bis (2-chloroethyl) amine hydrochloride (2.86 g,16.00 mmol) was dissolved in 20mL of distilled water in a 100mL three-necked flask, K 2CO3 (6.63 g,48.00 mmol) was added, and the mixture was stirred well to complete the dissolution, followed by addition of di-tert-butyl carbonate (3.49 g,16.00 mmol) and reaction was stirred at 40℃for 60 minutes. TLC detection was completed and then solvent was removed by rotary evaporation to give Boc-protected bis (2-chloroethyl) amine.
20Ml of DMF (dimethyl formamide) is added into a flask, the mixture is stirred fully to dissolve Boc-protected bis (2-chloroethyl) amine, then o-methoxyaniline (1.97 g,16.00 mmol) is added, after heating reflux reaction is carried out for 8 hours, the PH value of the reaction system is detected, and potassium hydroxide is added as required to ensure that the PH is more than or equal to 10. Reflux was continued for 10 hours. After the reaction was stopped, DMF was removed by rotary evaporation, and 20ml of isopropanol dissolved product was added to the product. Then p-toluenesulfonic acid (2.89 g,16.8 mmol) was added at a time, and the temperature was raised to 40℃and the reaction was stirred for 60 minutes to remove the Boc protecting group, thereby obtaining 1- (2-methoxyphenyl) piperazine. Then, dry HCl gas is introduced into the reaction system, and white precipitate is separated out. The white solid filtered by suction is washed with a small amount of isopropanol and dried to obtain the 1- (2-methoxyphenyl) piperazine hydrochloride. The yield is 85.82% and the purity is 99.58% based on o-methoxy aniline.
Example two
(1) Synthesis of bis (2-chloroethyl) amine hydrochloride
6ML of chloroform solution of thionyl chloride (4.76 g,40.00 mmol) is added into a 100mL three-neck flask, the mixture is fully diluted, the ice bath is cooled, 6mL of chloroform solution of diethanolamine (2.10 g,20.00 mmol) is dropwise added under vigorous stirring, the reaction temperature is controlled to be not more than 20 ℃, and the dropwise addition is slowly carried out (30 min dropwise addition time) to reduce the generation of impurity morpholine. After the dripping is completed, removing the ice bath, naturally heating to room temperature, then preserving the heat for 30min, continuously heating and refluxing for 1h, and detecting the consumption condition of the diethanolamine by TLC. After the reaction was completed, the heating was stopped, and the reaction mixture was cooled to room temperature. Filtering, drying to obtain a slightly brown yellow solid, adding 5ml of absolute ethyl alcohol, heating and refluxing for 5 minutes, filtering while the solid is hot, crystallizing the filtrate at 5 ℃ for one hour, filtering, and vacuum drying the filter cake for 2 hours to obtain white crystalline powder bis (2-chloroethyl) amine hydrochloride which is used as a raw material for the next step of synthesis. Yield 81.41%, purity 98.12%.
(2) Synthesis of 1- (2-methoxyphenyl) piperazine hydrochloride
Bis (2-chloroethyl) amine hydrochloride (2.86 g,16.00 mmol) was dissolved in 20mL of distilled water in a 100mL three-necked flask, K 2CO3 (3.32 g,24.00 mmol) was added, and the mixture was stirred well to dissolve completely, followed by addition of di-tert-butyl carbonate (5.24 g,24.00 mmol) and reaction was stirred at 20℃for 180 minutes. TLC detection was completed and then solvent was removed by rotary evaporation to give Boc-protected bis (2-chloroethyl) amine.
10Ml of DMF (dimethyl formamide) is added into a flask, the mixture is stirred fully to dissolve Boc-protected bis (2-chloroethyl) amine, then o-methoxyaniline (2.46 g,20.00 mmol) is added, after heating reflux reaction is carried out for 12 hours, the PH value of the reaction system is detected, and potassium hydroxide is added as required to ensure that the PH is more than or equal to 10. Reflux was continued for 12 hours. After the reaction was stopped, DMF was removed by rotary evaporation, and 15ml of isopropanol solution was added to the product. Then p-toluenesulfonic acid (2.75 g,16.0 mmol) was added at a time, and the temperature was raised to 20℃and the reaction was stirred for 180 minutes to remove the Boc protecting group, thereby obtaining 1- (2-methoxyphenyl) piperazine. Then, dry HCl gas is introduced into the reaction system, and white precipitate is separated out. The white solid filtered by suction is washed with a small amount of isopropanol and dried to obtain the 1- (2-methoxyphenyl) piperazine hydrochloride. The yield is 86.74% and the purity is 99.21% based on o-methoxyaniline.
Example III
(1) Synthesis of bis (2-chloroethyl) amine hydrochloride
30ML of chloroform solution of thionyl chloride (19.04 g,160.00 mmol) is added into a 100mL three-neck flask, the mixture is sufficiently diluted, cooled in an ice bath, 10mL of chloroform solution of diethanolamine (2.10 g,20.00 mmol) is dropwise added under vigorous stirring, the reaction temperature is controlled to be not more than 50 ℃, and the dropwise addition is slowly carried out (60 min dropwise addition time) to reduce the generation of impurity morpholine. After the dripping is completed, removing the ice bath, naturally heating to room temperature, then preserving the heat for 60min, continuously heating and refluxing for 8h, and detecting the consumption condition of the diethanolamine by TLC. After the reaction was completed, the heating was stopped, and the reaction mixture was cooled to room temperature. Filtering, drying to obtain a slightly brownish yellow solid, adding 20ml of absolute ethyl alcohol, heating and refluxing for 5 minutes, filtering while the solid is hot, crystallizing the filtrate at 5 ℃ for one hour, filtering, and vacuum drying the filter cake for 2 hours to obtain white crystalline powder bis (2-chloroethyl) amine hydrochloride which is used as a raw material for the next step of synthesis. The yield was 89.05% and the purity was 99.17%.
(2) Synthesis of 1- (2-methoxyphenyl) piperazine hydrochloride
Bis (2-chloroethyl) amine hydrochloride (2.86 g,16.00 mmol) was dissolved in 35mL of distilled water in a 100mL three-necked flask, K 2CO3 (8.84 g,64.00 mmol) was added, and the mixture was stirred well to complete the dissolution, followed by addition of di-t-butyl carbonate (6.98 g,32.00 mmol) and the reaction was stirred at 80℃for 30 minutes. TLC detection was completed and then solvent was removed by rotary evaporation to give Boc-protected bis (2-chloroethyl) amine.
30Ml of DMF (dimethyl formamide) is added into a flask, the mixture is stirred fully to dissolve Boc-protected bis (2-chloroethyl) amine, then o-methoxyaniline (0.99 g,8.00 mmol) is added, after heating reflux reaction is carried out for 18 hours, the PH value of the reaction system is detected, potassium hydroxide is added as required, and the PH is ensured to be more than or equal to 10. Reflux was continued for 18 hours. After the reaction was stopped, DMF was removed by rotary evaporation, and 15ml of isopropanol solution was added to the product. Then p-toluenesulfonic acid (2.75 g,16.0 mmol) was added at a time, and the temperature was raised to 80℃and the reaction was stirred for 30 minutes to remove the Boc protecting group, thereby obtaining 1- (2-methoxyphenyl) piperazine. Then, dry HCl gas is introduced into the reaction system, and white precipitate is separated out. The white solid filtered by suction is washed with a small amount of isopropanol and dried to obtain the 1- (2-methoxyphenyl) piperazine hydrochloride. The yield is 84.26 percent and the purity is 99.45 percent based on the o-methoxy aniline.
Comparative example 1 scheme before improvement
(1) Synthesis of bis (2-chloroethyl) amine hydrochloride
Diethanolamine (2.10 g,20.00 mmol) and thionyl chloride (9.57 g,80 mmol) were dissolved in chloroform (3 ml and 11ml respectively), and a chloroform solution of diethanolamine was slowly added dropwise to a chloroform solution of thionyl chloride, the temperature of the reaction system was kept at 25℃to 30℃for 2.5 hours. After the completion of the dropwise addition, the mixture was kept for 1 hour, and then heated to reflux and held for 30 minutes. After the reaction is finished, cooling, filtering, and leaching and drying by chloroform. The product was white crystals. Yield 85.41%, purity 91.26%.
(2) Synthesis of 1- (2-methoxy) phenylpiperazine hydrochloride
Bis (2-chloroethyl) amine hydrochloride (2.86 g,16 mmol) and o-methoxyaniline (1.79 g,14.5 mmol) were dissolved in 18ml of n-butanol and the condensation cyclisation was carried out under the catalysis of 1.98g potassium carbonate, the catalyst amount being added in two portions. The reflux reaction was maintained for 12 hours, and then the reaction system was concentrated before the second addition of the catalyst in order to accelerate the cyclization reaction, and 3ml of n-butanol was distilled off to increase the concentration of the reactant and promote the progress of cyclization. The reflux reaction was continued for 13 hours. Cooling, rotary evaporating to remove n-butanol, and recrystallizing the obtained crude product with absolute ethanol to obtain light brown powder. Yield 67.54% and purity 63.82%.
Comparative example 2
This comparative example differs from example one in that after the pale yellowish solid (crude bis (2-chloroethyl) amine hydrochloride) obtained in step (1), no subsequent purification steps are carried out.
Comparative example 3
This comparative example differs from example one in that potassium carbonate was replaced with potassium hydroxide when the Boc group protection was performed on bis (2-chloroethyl) amine in step (2).
Comparative example 4
The difference between this comparative example and example one is that DMF is replaced with DMSO in the ring-forming condensation reaction carried out in step (2).
Comparative example 5
This comparative example differs from example one in that p-toluene sulfonic acid was replaced with dilute hydrochloric acid when the Boc protecting group was removed in step (2).
The results obtained for comparative examples 2 to 5 are shown in Table 1 below:
TABLE 1
| Example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | |
| Product yield (%) | 85.82 | 68.07 | 81.64 | 43.27 | 83.29 |
| Purity of product (%) | 99.58 | 95.34 | 97.28 | 65.36 | 99.03 |
Analysis of results:
In comparative example 2, the pale yellowish solid obtained in step (1) was not purified, but the crude bis (2-chloroethyl) amine hydrochloride obtained in the first step was mixed with a monochlorosubstituted impurity, which reacted with o-methoxyaniline to affect the yield and caused difficulties in purifying the final product, resulting in a substantial decrease in the yield and purity of the final product.
Comparative example 3 uses a strong base for Boc group protection of bis (2-chloroethyl) amine, and the yield and purity of the final product are reduced compared to example 1. The base used in the Boc group protection of bis (2-chloroethyl) amine hydrochloride must not be too strong, which has a certain effect on the yield and purity of the final product.
The use of DMSO as a solvent in the condensation cyclization reaction in comparative example 4 had a catastrophic effect on the reaction, because DMSO is a weak oxidant that oxidizes o-methoxyaniline at high temperatures, causing the reaction to fail.
In comparative example 5, dilute hydrochloric acid was used in removing the Boc protecting group, which was not as safe as p-toluenesulfonic acid, and had a slight effect on yield and purity.
The foregoing description is only illustrative of the preferred embodiment of the present invention, and is not to be construed as limiting the invention, but is to be construed as limiting the invention to any simple modification, equivalent variation and variation of the above embodiments according to the technical matter of the present invention without departing from the scope of the invention.
Claims (10)
1. A method for synthesizing 1- (2-methoxyphenyl) piperazine hydrochloride, which is characterized by comprising the following steps:
(1) Taking diethanolamine as a basic raw material, and taking thionyl chloride as a chlorinating agent to carry out chlorination reaction to obtain bis (2-chloroethyl) amine hydrochloride;
(2) And (3) performing Boc group protection on bis (2-chloroethyl) amine, performing ring-forming condensation reaction on the bis (2-chloroethyl) amine and o-methoxy aniline, removing the Boc protecting group to obtain 1- (2-methoxyphenyl) piperazine, and adding hydrochloric acid to form a salt to obtain 1- (2-methoxyphenyl) piperazine hydrochloride.
2. The method for synthesizing 1- (2-methoxyphenyl) piperazine hydrochloride according to claim 1, wherein in the step (2), the Boc group protection of bis (2-chloroethyl) amine comprises:
Dissolving bis (2-chloroethyl) amine hydrochloride in water, adding potassium carbonate, stirring to dissolve, and then adding di-tert-butyl carbonate to react; the mol ratio of the bis (2-chloroethyl) amine hydrochloride to the potassium carbonate to the di-tert-butyl carbonate is 1:1.5-4.0:1.0-2.0, and the water dosage is 3-15 ml/1g of the bis (2-chloroethyl) amine hydrochloride.
3. The method for synthesizing 1- (2-methoxyphenyl) piperazine hydrochloride according to claim 2, wherein the reaction is carried out at 20 to 80 ℃ with stirring for 30 to 180 minutes.
4. A method for the synthesis of 1- (2-methoxyphenyl) piperazine hydrochloride according to any one of claims 1 to 3, wherein in step (2), the cyclic condensation reaction with o-methoxyaniline comprises:
Adding DMF to dissolve Boc-protected bis (2-chloroethyl) amine, then adding o-methoxyaniline, carrying out heating reflux reaction, and removing DMF by rotary evaporation after the reaction;
the mole ratio of the Boc protected bis (2-chloroethyl) amine to the o-methoxyaniline is 0.8-2.5:1, and the DMF dosage is 5-15 ml/1g o-methoxyaniline.
5. The method for synthesizing 1- (2-methoxyphenyl) piperazine hydrochloride according to claim 4, wherein the heating reflux reaction is performed for 10 to 36 hours; and adding alkali in the middle, and controlling the PH of the system to be more than or equal to 10.
6. The method for synthesizing 1- (2-methoxyphenyl) piperazine hydrochloride according to any one of claims 1 to 5, wherein removing the Boc protecting group comprises:
after the cyclization condensation reaction, adding isopropanol dissolution product, adding p-toluenesulfonic acid, stirring for reaction, and removing Boc protecting group to obtain 1- (2-methoxyphenyl) piperazine;
The dosage of the p-toluenesulfonic acid is 0.8 to 2.0eq and the dosage of the isopropanol is 5 to 15ml/1g of the o-methoxy aniline based on the o-methoxy aniline.
7. The method for synthesizing 1- (2-methoxyphenyl) piperazine hydrochloride according to claim 6, wherein the temperature is controlled to be 20-80 ℃ and the reaction time is 30-180 minutes during the stirring reaction.
8. The method for synthesizing 1- (2-methoxyphenyl) piperazine hydrochloride according to any one of claims 1 to 7, wherein in the step (2), adding hydrochloride to form a salt comprises:
After obtaining 1- (2-methoxyphenyl) piperazine, introducing HCl gas into the reaction system, precipitating white precipitate, filtering, washing and drying to obtain 1- (2-methoxyphenyl) piperazine hydrochloride.
9. The process for the synthesis of 1- (2-methoxyphenyl) piperazine hydrochloride according to any one of claims 1 to 8, wherein in step (1), a chloroform solution of diethanolamine is slowly added dropwise to a chloroform solution of thionyl chloride under ice bath cooling, the molar ratio of diethanolamine to thionyl chloride is 1:2.0 to 8.0, and the total amount of chloroform is 6.0 to 20.0ml/g calculated as diethanolamine; controlling the temperature of the reaction system to be less than 20-50 ℃; heating to room temperature for heat preservation after the dripping is completed, refluxing for 1-8 hours, cooling to room temperature after the reaction is completed, filtering, drying to obtain a crude product, and purifying.
10. The method for synthesizing 1- (2-methoxyphenyl) piperazine hydrochloride according to claim 9, wherein the purifying comprises: after obtaining a crude product, adding absolute ethyl alcohol for recrystallization, and drying to obtain purified bis (2-chloroethyl) amine hydrochloride;
preferably, the amount of absolute ethanol is 5.0-20.0 ml/1g of crude product.
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