CN117886777A - Method for synthesizing 1-cyclopropyl piperazine - Google Patents
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- CN117886777A CN117886777A CN202410041797.3A CN202410041797A CN117886777A CN 117886777 A CN117886777 A CN 117886777A CN 202410041797 A CN202410041797 A CN 202410041797A CN 117886777 A CN117886777 A CN 117886777A
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- HNZJIWIXRPBFAN-UHFFFAOYSA-N 1-cyclopropylpiperazine Chemical compound C1CC1N1CCNCC1 HNZJIWIXRPBFAN-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 12
- -1 substituted alkyl formate Chemical compound 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 7
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims abstract description 5
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 3
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 3
- 238000006170 formylation reaction Methods 0.000 claims abstract description 3
- 239000007858 starting material Substances 0.000 claims abstract description 3
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- NKFAHRCLUXUXTJ-UHFFFAOYSA-N tert-butyl 4-formylpiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C=O)CC1 NKFAHRCLUXUXTJ-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- 238000004821 distillation Methods 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- ITNVWQNWHXEMNS-UHFFFAOYSA-N methanolate;titanium(4+) Chemical compound [Ti+4].[O-]C.[O-]C.[O-]C.[O-]C ITNVWQNWHXEMNS-UHFFFAOYSA-N 0.000 claims description 2
- HKJYVRJHDIPMQB-UHFFFAOYSA-N propan-1-olate;titanium(4+) Chemical compound CCCO[Ti](OCCC)(OCCC)OCCC HKJYVRJHDIPMQB-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 5
- 238000009776 industrial production Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- BZMMRNKDONDVIB-UHFFFAOYSA-N (1-ethoxycyclopropyl)oxy-trimethylsilane Chemical compound CCOC1(O[Si](C)(C)C)CC1 BZMMRNKDONDVIB-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- XGJOFCCBFCHEHK-UHFFFAOYSA-N 4-pyridin-4-ylsulfanylpyridine Chemical compound C=1C=NC=CC=1SC1=CC=NC=C1 XGJOFCCBFCHEHK-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- UNCLAXHNVIYBNX-UHFFFAOYSA-N tert-butyl 4-cyclopropylpiperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1CC1 UNCLAXHNVIYBNX-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing 1-cyclopropyl piperazine, which comprises the following steps: the preparation method comprises the steps of taking 1-tert-butoxycarbonyl piperazine shown in a formula 1 as a starting material, carrying out formylation reaction with excessive substituted alkyl formate HCOOR 1 to generate 4-formylpiperazine-1-tert-butyl carboxylate shown in a formula 2, then carrying out N-cyclopropylation reaction with ethyl magnesium bromide in a solvent under the catalysis of tetraalkyl titanate to generate an intermediate 3, and carrying out deprotection reaction of the intermediate 3 in the solvent under the action of acid to generate a target product 1-cyclopropylpiperazine shown in the formula 4, wherein the reaction route is as follows: Wherein, the substituent R 1 in the structure of the substituted alkyl formate HCOOR 1 is C1-C4 alkyl. The method has the advantages of low-cost and easily-obtained initial raw materials, short synthetic route, mild reaction conditions in each step, high overall yield and good industrialized prospect.
Description
Technical Field
The invention relates to a method for synthesizing 1-cyclopropyl piperazine.
Background
The 1-cyclopropyl piperazine is widely used for synthesizing various medicines and is an important medical intermediate. The synthesis of 1-cyclopropyl piperazine reported in the literature has three main routes. The first method is to take diethanolamine as a raw material, condense with trifluoroacetic anhydride to obtain an intermediate A2, carry out substitution reaction on the intermediate A2 and methanesulfonyl chloride to obtain an intermediate A3, cyclize the intermediate A3 with cyclopropylamine and then deprotect to obtain 1-cyclopropylpiperazine. The synthesis route is longer, the total yield is lower, the operation is complicated, and the industrial production is not facilitated. [ WO 2007-US86936,2007 ]
The second synthesis method is to take diethanolamine as raw material and carry out esterification with concentrated sulfuric acid to obtain an intermediate B2, and then heat and cyclize the obtained intermediate with cyclopropylamine at D 2 O to obtain the product 1-cyclopropyl piperazine. Although the reaction is short in step, the solvent is expensive, and the reaction is not suitable for industrial production. [ WO 2007-US86936,2007 ]
The other route is to take 1-tert-butoxycarbonyl piperazine as a raw material, take 1-ethoxy-1-trimethylsiloxy cyclopropane as an N-cyclopropylating reagent to obtain an intermediate C2, and then deprotect the intermediate C2 to obtain a final product, wherein the steps are short, but the catalyst is expensive, so that the method is not suitable for industrial production. [ ACS Med. Chem. Lett.,2015,6 (4): 450-454 ]
Disclosure of Invention
In view of the shortcomings of the prior art, the present invention aims to provide a new, cheaper and feasible method for synthesizing 1-cyclopropylpiperazine.
The technical scheme adopted by the invention is as follows:
A method for synthesizing 1-cyclopropyl piperazine, comprising the steps of:
1) Formylation reaction is carried out on 1-tert-butoxycarbonyl piperazine shown in a formula 1 serving as a starting material and excessive substituted alkyl formate HCOOR 1, and after the reaction is finished, the reaction liquid is subjected to aftertreatment to obtain 4-formylpiperazine-1-carboxylic acid tert-butyl ester shown in a formula 2;
2) Then taking 4-formylpiperazine-1-carboxylic acid tert-butyl ester shown in formula 2 as a raw material, carrying out N-cyclopropylating reaction with ethyl magnesium bromide in a solvent under the catalysis of tetraalkyl titanate, and carrying out aftertreatment on the reaction liquid after the reaction is finished to obtain an intermediate 3;
3) The intermediate 3 is subjected to deprotection reaction in a solvent under the action of acid, and after the reaction is finished, the reaction solution is subjected to aftertreatment to obtain a target product 1-cyclopropyl piperazine shown in a formula 4, wherein the reaction route is as follows:
Wherein, the substituent R 1 in the structure of the substituted alkyl formate HCOOR 1 is C1-C4 alkyl, and the substituted alkyl formate HCOOR 1 is methyl formate, ethyl formate, propyl formate or butyl formate.
Further, the reaction temperature in step 1) is 50 to 120 ℃, preferably the reflux temperature of the alkyl formate, and the reaction time is 2 to 5 hours.
Further, the post-treatment in step 1) comprises the following steps: after the reaction solution is cooled to room temperature, the pH value is adjusted to be alkaline by using saturated sodium bicarbonate aqueous solution, ethyl acetate is used for extracting and separating liquid, an organic layer is dried by using anhydrous sodium sulfate, filtration and concentration are carried out, and the product is subjected to recrystallization and purification by using ethyl acetate/petroleum ether, thus the treatment is completed.
Further, the tetraalkyl titanate in the step 2) is at least one of tetramethyl titanate, tetraethyl titanate, tetrapropyl titanate and tetraisopropyl titanate, preferably tetraisopropyl titanate.
Further, the molar ratio of the compound of formula 2 to ethyl magnesium bromide in step 2) is 3 to 4:1, preferably 3.5-3.6:1, a step of; the molar ratio of the compound of formula 2 to tetraisopropyl titanate is 1-2:1, preferably 1.1 to 1.25:1, a step of; the concentration of the compound of formula 2 in the solvent is 0.2 to 0.3mol/L. The reaction temperature in step 2) is room temperature and the reaction time is 3-6h.
Further, the post-treatment in step 2) comprises the following steps: the reaction solution was poured into a saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from methyl tert-butyl ether to complete the treatment.
Further, the solvent in the step 2) is tetrahydrofuran.
Further, the molar ratio of the acid to the intermediate 3 in the step 3) is 0.5-1.5:1, wherein the acid is an organic acid or an inorganic acid, the organic acid is at least one of trifluoroacetic acid, benzenesulfonic acid and p-toluenesulfonic acid, preferably trifluoroacetic acid, and the inorganic acid is at least one of hydrochloric acid, phosphoric acid and sulfuric acid, preferably hydrochloric acid.
Further, the solvent in the step 3) is at least one of dichloromethane, 1, 2-dichloroethane and chloroform; the reaction temperature in step 3) is room temperature and the reaction time is 0.5-2h. In the step (3), the reaction system is strictly anhydrous and oxygen-free.
Further, the post-treatment step in the step 3) is as follows: the reaction solution was alkalified with saturated aqueous sodium bicarbonate solution, the separated solution was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by distillation under reduced pressure to give the objective product.
Compared with the prior art, the synthetic route provided by the invention has the following advantages:
(1) The reagent is cheap and easy to obtain;
(2) The reaction conditions of each step are mild;
(3) The total yield is high, and the method has obvious advantages in production cost.
Detailed Description
The invention will be further illustrated with reference to specific examples, but the scope of the invention is not limited thereto.
Examples: the preparation of 1-cyclopropylpiperazine comprises the following steps:
50g of 1-t-butoxycarbonyl piperazine (0.268 mol) was added to the reaction flask, and 150mL of ethyl formate was added. Heating to reflux reaction for 3h. After the reaction was completed, the reaction solution was cooled to room temperature, then, the pH was adjusted to be alkaline with a saturated sodium bicarbonate solution, the separated solution was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and the product was purified by recrystallization from ethyl acetate/petroleum ether to obtain 52.1g of t-butyl 4-formylpiperazine-1-carboxylate as a white solid in a yield of 90.6%.
50G (0.233 mol) of tert-butyl 4-formylpiperazine-1-carboxylate were charged into a reaction flask, and 500mL of anhydrous tetrahydrofuran was added under nitrogen atmosphere. 85mL (0.287 mmol) of tetraisopropyl titanate is added. The reaction mixture was cooled to 0℃and 410mL (0.82 mol) of a tetrahydrofuran solution (2 mol/L) of ethyl magnesium bromide was added dropwise. After the completion of the dropping, the reaction was resumed at room temperature for 5 hours. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from methyl tert-butyl ether to give 47.2g of 1-cyclopropylpiperazine-4-carboxylic acid tert-butyl ester as a pale yellow solid, with a yield of 89.6%.
50G (0.22 mol) of tert-butyl 1-cyclopropylpiperazine-4-carboxylate, 200mL of methylene chloride and 20mL of trifluoroacetic acid were charged in the reaction flask, and after completion, the reaction was carried out at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was alkalified with a saturated aqueous sodium hydrogencarbonate solution, the separated solution was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by distillation under reduced pressure to give 25.8g of 1-cyclopropylpiperazine in 92.1% yield. 1H NMR(400MHz,CDCl3 ) Delta 3.15-3.10 (m,
4H),2.88–2.75(m,4H),1.80–1.70(m,1H),1.27–1.20(m,1H),0.56–0.36(m,4H)。
What has been described in this specification is merely an enumeration of possible forms of implementation for the inventive concept and may not be considered limiting of the scope of the present invention to the specific forms set forth in the examples.
Claims (10)
1. A method for synthesizing 1-cyclopropyl piperazine, which is characterized by comprising the following steps:
1) Formylation reaction is carried out on 1-tert-butoxycarbonyl piperazine shown in a formula 1 serving as a starting material and excessive substituted alkyl formate HCOOR 1, and after the reaction is finished, the reaction liquid is subjected to aftertreatment to obtain 4-formylpiperazine-1-carboxylic acid tert-butyl ester shown in a formula 2;
2) Then taking 4-formylpiperazine-1-carboxylic acid tert-butyl ester shown in formula 2 as a raw material, carrying out N-cyclopropylating reaction with ethyl magnesium bromide in a solvent under the catalysis of tetraalkyl titanate, and carrying out aftertreatment on the reaction liquid after the reaction is finished to obtain an intermediate 3;
3) The intermediate 3 is subjected to deprotection reaction in a solvent under the action of acid, and after the reaction is finished, the reaction solution is subjected to aftertreatment to obtain a target product 1-cyclopropyl piperazine shown in a formula 4, wherein the reaction route is as follows:
Wherein, the substituent R 1 in the structure of the substituted alkyl formate HCOOR 1 is C1-C4 alkyl.
2. A process for the synthesis of 1-cyclopropylpiperazine according to claim 1, characterized in that in step 1) the reaction temperature is 50-120 ℃, preferably the reflux temperature of the alkyl formate, and the reaction time is 2-5h.
3. A method for synthesizing 1-cyclopropylpiperazine according to claim 1, characterized in that the step of post-treatment in step 1) is: after the reaction solution is cooled to room temperature, the pH value is adjusted to be alkaline by using saturated sodium bicarbonate aqueous solution, ethyl acetate is used for extracting and separating liquid, an organic layer is dried by using anhydrous sodium sulfate, filtration and concentration are carried out, and the product is subjected to recrystallization and purification by using ethyl acetate/petroleum ether, thus the treatment is completed.
4. A method for synthesizing 1-cyclopropylpiperazine according to claim 1, characterized in that the tetraalkyl titanate in step 2) is at least one of tetramethyl titanate, tetraethyl titanate, tetrapropyl titanate, tetraisopropyl titanate, preferably tetraisopropyl titanate.
5. A process for the synthesis of 1-cyclopropylpiperazine, according to claim 1, characterized in that in step 2) the molar ratio of compound of formula 2 to ethylmagnesium bromide is 3 to 4:1, preferably 3.5-3.6:1, a step of; the molar ratio of the compound of formula 2 to tetraisopropyl titanate is 1-2:1, preferably 1.1 to 1.25:1, a step of; the reaction temperature in step 2) is room temperature and the reaction time is 3-6h.
6. A method for synthesizing 1-cyclopropylpiperazine according to claim 1, characterized in that the step of post-treatment in step 2) is: the reaction solution was poured into a saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from methyl tert-butyl ether to complete the treatment.
7. A process for the synthesis of 1-cyclopropylpiperazine according to claim 1, characterized in that in step 2) the solvent is tetrahydrofuran.
8. A process for the synthesis of 1-cyclopropylpiperazine, according to claim 1, characterized in that the molar ratio of acid to intermediate 3 in step 3) is 0.5-1.5:1, said acid being an organic acid or an inorganic acid, the organic acid being at least one of trifluoroacetic acid, benzenesulfonic acid and p-toluenesulfonic acid, preferably trifluoroacetic acid, the inorganic acid being at least one of hydrochloric acid, phosphoric acid and sulfuric acid, preferably hydrochloric acid.
9. A method for synthesizing 1-cyclopropylpiperazine according to claim 1, characterized in that the solvent in step 3) is at least one of dichloromethane, 1, 2-dichloroethane, chloroform; the reaction temperature in step 3) is room temperature and the reaction time is 0.5-2h.
10. A method for synthesizing 1-cyclopropylpiperazine according to claim 1, characterized in that the post-treatment step in step 3) is: the reaction solution was alkalified with saturated aqueous sodium bicarbonate solution, the separated solution was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by distillation under reduced pressure to give the objective product.
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