CN108341792B - Preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine - Google Patents
Preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine Download PDFInfo
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- IVLIBVDZIYFXBZ-UHFFFAOYSA-N 1-(cyclopropylmethyl)piperazine Chemical compound C1CNCCN1CC1CC1 IVLIBVDZIYFXBZ-UHFFFAOYSA-N 0.000 title claims abstract description 30
- SXNJFOWDRLKDSF-STROYTFGSA-N volasertib Chemical compound C1CN([C@H]2CC[C@@H](CC2)NC(=O)C2=CC=C(C(=C2)OC)NC=2N=C3N(C(C)C)[C@@H](C(N(C)C3=CN=2)=O)CC)CCN1CC1CC1 SXNJFOWDRLKDSF-STROYTFGSA-N 0.000 title claims abstract description 21
- 229950003081 volasertib Drugs 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 15
- 239000007787 solid Substances 0.000 claims abstract description 14
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims abstract description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims abstract description 9
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 7
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012442 inert solvent Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 5
- 239000012074 organic phase Substances 0.000 claims abstract description 5
- 238000010791 quenching Methods 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000007864 aqueous solution Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 3
- 230000000171 quenching effect Effects 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- IREXWNMKXDFMFW-UHFFFAOYSA-N tert-butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1CC1 IREXWNMKXDFMFW-UHFFFAOYSA-N 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- WDDPLSXJAIFLJZ-UHFFFAOYSA-N tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1CC1CC1 WDDPLSXJAIFLJZ-UHFFFAOYSA-N 0.000 claims description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- 230000005311 nuclear magnetism Effects 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 3
- 238000010907 mechanical stirring Methods 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- ZVTQWXCKQTUVPY-UHFFFAOYSA-N chloromethylcyclopropane Chemical compound ClCC1CC1 ZVTQWXCKQTUVPY-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229940000673 orphan drug Drugs 0.000 description 2
- 239000002859 orphan drug Substances 0.000 description 2
- 108010056274 polo-like kinase 1 Proteins 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- -1 tert-butyloxycarbonyl (Boc) Chemical class 0.000 description 2
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- VEZNCHDBSQWUHQ-UHFFFAOYSA-N chlorocyclopropane Chemical compound ClC1CC1 VEZNCHDBSQWUHQ-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011368 intensive chemotherapy Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention provides a preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine, which comprises the following steps: s1, adding N-Boc-piperazine and triethylamine or pyridine into an inert solvent, dropwise adding cyclopropane carbonyl chloride, adding water to extract after the reaction is finished to obtain an organic phase, and concentrating to remove the organic solvent to obtain a solid; s2, adding the solid obtained in the S1 into an ether solvent, adding sodium borohydride, dropwise adding boron trifluoride-ethyl ether for reaction, quenching, extracting, concentrating and removing an organic solvent to obtain a solid; s3, adding an alcohol solvent into the solid obtained in the S2, dropwise adding concentrated hydrochloric acid to react, then alkalifying with a sodium hydroxide or potassium hydroxide aqueous solution, extracting and concentrating to obtain the compound 1-cyclopropyl methyl piperazine. The method has the advantages of easily available raw materials, low cost, simple operation, high safety, good product quality and high yield, and is convenient for large-scale production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine.
Background
1-cyclopropyl methyl piperazine (CAS number: 57184-25-5) is an intermediate raw material for synthesizing the orphan drug Volasertib. On day 17 of 4/2014, briringer-bergheim company (BI) announced that the united states Food and Drug Administration (FDA) qualifies the orphan drug of Volasertib with the european union committee for the treatment of Acute Myelogenous Leukemia (AML) patients. AML is an aggressive cancer of the bone marrow and blood, mostly a post-adult disease, with the average age of patients ranging from 65 to 70 years. The current recommended treatment criteria for this disease are intensive chemotherapy, limited treatment options, intolerance in most patients, and poor prognosis. Volasertib, by inhibiting Polo-like kinase 1(Plk1), the characteristic very high cell division of AML will be blocked, possibly preventing tumor growth, or causing a reduction in tumor cell division activity, thus prolonging the life of the patient.
For the synthesis of 1-cyclopropylmethylpiperazine, it is now common to react bromomethylcyclopropane or chlorocyclopropane with N-Boc-piperazine in N' N-dimethylformamide using potassium carbonate as a base, followed by removal of the tert-butoxycarbonyl group. Chloromethyl cyclopropane has poor activity, while bromomethyl cyclopropane has low molecular mole utilization rate, and the price of the chloromethyl cyclopropane and the bromomethyl cyclopropane is relatively expensive and has high cost. Another common method is the condensation of cyclopropaneacetic acid and piperazine, but the yield is very low
Therefore, a preparation method of 1-cyclopropyl methyl piperazine, which has the advantages of easily available raw materials, low cost, simple operation, high safety, good product quality, high yield and convenience for large-scale production, is urgently needed.
Disclosure of Invention
The invention aims to provide a preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine, which has the advantages of easily available raw materials, low cost, simple operation, high safety, good product quality, high yield and convenience for large-scale production.
The invention provides the following technical scheme:
a preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine comprises the following steps:
s1: sequentially adding N-Boc-piperazine and triethylamine or pyridine into an inert solvent, then dropwise adding cyclopropanecarbonyl chloride at 0-10 ℃ for reaction, adding water for extraction after the reaction is finished to obtain an organic phase, and concentrating to remove the organic solvent to obtain solid 4- (cyclopropanecarbonyl) piperazine-1-carboxylic acid tert-butyl ester;
s2: adding the solid 4- (cyclopropanecarbonyl) piperazine-1-carboxylic acid tert-butyl ester obtained in the step S1 into an ether solvent, adding sodium borohydride, dropwise adding boron trifluoride-diethyl ether at the temperature of 0-10 ℃ for reaction, quenching, extracting, concentrating and removing an organic solvent to obtain solid N-Boc-4- (cyclopropylmethyl) piperazine;
s3: adding the solid N-Boc-4- (cyclopropylmethyl) piperazine obtained in S2 into an alcohol solvent, dropwise adding concentrated hydrochloric acid at 40-60 ℃ for reaction, then alkalifying with a sodium hydroxide or potassium hydroxide aqueous solution, extracting and concentrating to obtain the compound 1-cyclopropylmethyl piperazine.
The reaction equation is:
preferably, the reaction temperature in the S1 is 0-20 ℃, and the reaction time is 2-4 hours.
Preferably, the molar weight ratio of cyclopropanecarbonyl chloride to N-Boc-piperazine in S1 is 1.1:1 to 1.3:1, and the molar weight ratio of triethylamine or pyridine to N-Boc-piperazine is 1.5:1 to 2.0: 1.
Preferably, the inert solvent in the S1 is dichloromethane or dichloroethane, and the mass ratio of the dichloromethane or dichloroethane to the N-Boc-piperazine is 3:1-5: 1.
Preferably, the reaction temperature in the S2 is 0-25 ℃, and the reaction time is 2-4 hours.
Preferably, the ether solvent in S2 is tetrahydrofuran or ethylene glycol dimethyl ether, and the mass ratio of tetrahydrofuran or ethylene glycol dimethyl ether to tert-butyl 4- (cyclopropanecarbonyl) piperazine-1-carboxylate is 2:1-3: 1.
Preferably, in the S2, the molar ratio of boron trifluoride-diethyl ether to tert-butyl 4- (cyclopropanecarbonyl) piperazine-1-carboxylate is 1.1:1-1.5:1, and the molar ratio of sodium borohydride to tert-butyl 4- (cyclopropanecarbonyl) piperazine-1-carboxylate is 1.5:1-2: 1.
Preferably, the reaction temperature in the S3 is 40-60 ℃, and the reaction time is 2-4 hours; the pH of the alkalinized solution of sodium hydroxide or potassium hydroxide is 10-11.
Preferably, the alcoholic solvent in S3 is isopropanol or methanol, and the mass ratio of the isopropanol or methanol to N-Boc-4- (cyclopropylmethyl) piperazine is 2:1-3: 1.
Preferably, the molar ratio of the concentrated hydrochloric acid in the S3 to the N-Boc-4- (cyclopropylmethyl) piperazine is 2.5:1 to 3: 1.
The invention has the beneficial effects that:
(1): the invention takes N-Boc-piperazine and cyclopropyl formyl chloride as raw materials, has low cost and easily obtained raw materials.
(2): the N-Boc-piperazine and cyclopropyl formyl chloride are used as raw materials to react, then reduction is carried out, and tert-butyloxycarbonyl (Boc) is removed to obtain the 1-cyclopropyl methyl piperazine.
(3): the 1-cyclopropyl methyl piperazine synthesized by the method has good product quality and high yield, and is convenient for large-scale production.
Detailed Description
Example 1
A preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine comprises the following steps:
s1: adding N-Boc-piperazine (1.82Kg, 9.77mol), triethylamine (1.48Kg, 14.66mol) and dichloromethane (5.46 Kg) into a 20L four-neck flask with mechanical stirring and thermometer, cooling to 0 ℃, slowly adding cyclopropyl formyl chloride (1.12Kg, 10.75mol) dropwise, controlling the temperature to be 0-10 ℃, and reacting for 3 hours at the temperature of 10-20 ℃ after dropwise adding. 5Kg of water was added, sodium carbonate was added to adjust the pH to 8-9, the organic phase was separated, 1.50Kg of the aqueous phase was added, dichloromethane was extracted once, the dichloromethane phases were combined, washed once with 2Kg of 0.05M dilute hydrochloric acid and once with 2Kg of water, and the dichloromethane was removed by concentration to obtain 2.43Kg of tert-butyl 4- (cyclopropanecarbonyl) piperazine-1-carboxylate, with a yield of 98%. The comparison of the nuclear magnetism is consistent with the standard map.
S2: A20L four-necked flask with a mechanical stirring and a thermometer is charged with tert-butyl 4- (cyclopropanecarbonyl) piperazine-1-carboxylate (2.40kg, 9.44mol), sodium borohydride (0.71kg, 18.88mol) and THF5.06Kg under the protection of nitrogen, cooled to 10 ℃ and slowly added with boron trifluoride diethyl etherate (2.02kg, 14.16mol) dropwise, and the temperature is controlled to be 0 ℃ to 10 ℃. After the dropwise addition, the reaction is carried out for 4 hours at the temperature of 10-25 ℃. The reaction solution was slowly poured into ice water of 5kg ice and 5kg water to quench, methyl tert-butyl ether was extracted (4kg x 2), the methyl tert-butyl ether phases were combined, washed once with 5kg saturated sodium chloride solution, and concentrated to remove methyl tert-butyl ether to give 2.13kg of N-Boc-4- (cyclopropylmethyl) piperazine as a pale yellow solid in 94% yield. The comparison of the nuclear magnetism is consistent with the standard map.
S3: A10L four-necked flask equipped with a mechanical stirrer and a thermometer was charged with N-Boc-4- (cyclopropylmethyl) piperazine (2.00kg, 8.32mol) and 5kg of isopropanol, heated to 40 ℃ and concentrated hydrochloric acid (2.04kg, 20.80mol) was slowly added dropwise thereto, the temperature being controlled at 40 ℃ to 50 ℃. After the dropwise addition, the reaction is carried out for 4 hours at the temperature of 40-50 ℃. The reaction was concentrated to remove most of the isopropanol, the residue was adjusted to pH 10-11 with 5mol/L aqueous sodium hydroxide solution, extracted with dichloromethane (5L × 3), the dichloromethane phases were combined, washed once with 5kg of saturated sodium chloride solution and concentrated to remove dichloromethane to give 1.11kg of 1-cyclopropylmethylpiperazine as a pale yellow liquid in 94% yield. The comparison of the nuclear magnetism is consistent with the standard map.
Example 2
A preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine comprises the following steps:
s1: A20L four-neck flask with a mechanical stirrer and a thermometer is added with N-Boc-piperazine (1.82Kg, 9.77mol), pyridine (1.16Kg, 14.66mol) and dichloromethane (5.46 Kg), cooled to 0 ℃, slowly added with cyclopropyl formyl chloride (1.12Kg, 10.75mol), controlled at 0-10 ℃, and reacted for 3h at 10-20 ℃ after the dropwise addition. 5Kg of water was added, sodium carbonate was added to adjust the pH to 8-9, the organic phase was separated, the aqueous phase was extracted once with 1.50Kg of dichloromethane, the dichloromethane phases were combined, washed once with 2Kg of 0.05M dilute hydrochloric acid and once with 2Kg of water, and the dichloromethane was removed by concentration to obtain 2.40Kg of tert-butyl 4- (cyclopropanecarbonyl) piperazine-1-carboxylate with a yield of 96.8%. The comparison of the nuclear magnetism is consistent with the standard map.
S2: A20L four-neck flask with a mechanical stirring and a thermometer is added with tert-butyl 4- (cyclopropanecarbonyl) piperazine-1-carboxylate (2.40Kg, 9.44mol), sodium borohydride (0.53Kg, 14.16mol) and ethylene glycol dimethyl ether (5.06 Kg) under the protection of nitrogen, cooled to 10 ℃, and boron trifluoride diethyl etherate (1.48Kg, 10.38mol) is slowly added dropwise and the temperature is controlled to be 0-10 ℃. After the dropwise addition, the reaction is carried out for 4 hours at the temperature of 10-25 ℃. The reaction solution was slowly poured into ice water of 5kg ice and 5kg water to quench, methyl tert-butyl ether was extracted (4kg x 2), the methyl tert-butyl ether phases were combined, washed once with 5kg saturated sodium chloride solution, and concentrated to remove methyl tert-butyl ether to give 2.02kg of N-Boc-4- (cyclopropylmethyl) piperazine as a pale yellow solid in 89% yield. The comparison of the nuclear magnetism is consistent with the standard map.
S3: A10L four-necked flask equipped with a mechanical stirrer and a thermometer was charged with N-Boc-4- (cyclopropylmethyl) piperazine (2.00kg, 8.32mol) and 5kg of methanol, heated to 50 deg.C, and concentrated hydrochloric acid (2.04kg, 20.80mol) was slowly added dropwise with controlling the temperature at 50 deg.C-60 deg.C. After the dropwise addition, the reaction is carried out for 4 hours at the temperature of 50-60 ℃. The reaction was concentrated to remove most of the methanol, the residue was adjusted to pH 10-11 with 5mol/L aqueous sodium hydroxide solution, extracted with dichloromethane (5L × 3), the dichloromethane phases were combined, washed once with 5kg of saturated sodium chloride solution, and concentrated to remove dichloromethane to give 1.08kg of 1-cyclopropylmethylpiperazine as a pale yellow liquid in 91% yield. The comparison of the nuclear magnetism is consistent with the standard map.
The preparation method of 1-cyclopropyl methyl piperazine provided by the invention solves the problems of expensive raw materials, low yield and the like in the prior art, and has the advantages of easily available raw materials, low cost, simple operation, high safety, good product quality, high yield and convenience for large-scale production.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine is characterized by comprising the following steps:
s1: sequentially adding N-Boc-piperazine and triethylamine or pyridine into an inert solvent, then dropwise adding cyclopropanecarbonyl chloride at 0-10 ℃ for reaction, adding water for extraction after the reaction is finished to obtain an organic phase, and concentrating to remove the organic solvent to obtain solid 4- (cyclopropanecarbonyl) piperazine-1-carboxylic acid tert-butyl ester;
s2: adding the solid 4- (cyclopropanecarbonyl) piperazine-1-carboxylic acid tert-butyl ester obtained in the step S1 into an ether solvent, adding sodium borohydride, dropwise adding boron trifluoride-diethyl ether at the temperature of 0-10 ℃ for reaction, quenching, extracting, concentrating and removing an organic solvent to obtain solid N-Boc-4- (cyclopropylmethyl) piperazine;
s3: adding solid N-Boc-4- (cyclopropylmethyl) piperazine obtained in S2 into an alcohol solvent, dropwise adding concentrated hydrochloric acid at 40-60 ℃ for reaction, then alkalifying with a sodium hydroxide or potassium hydroxide aqueous solution, extracting and concentrating to obtain a compound 1-cyclopropylmethyl piperazine,
the reaction equation is:
2. the preparation method of Volasertib intermediate 1-cyclopropylmethylpiperazine according to claim 1, characterized in that the reaction temperature in S1 is 0-20 ℃ and the reaction time is 2-4 hours.
3. The method for preparing Volasertib intermediate 1-cyclopropylmethylpiperazine according to claim 1, characterized in that the molar weight ratio of cyclopropanecarbonyl chloride to N-Boc-piperazine in S1 is 1.1:1-1.3:1, and the molar weight ratio of triethylamine or pyridine to N-Boc-piperazine is 1.5:1-2.0: 1.
4. The preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine according to claim 1, wherein the inert solvent in S1 is dichloromethane or dichloroethane, and the mass ratio of dichloromethane or dichloroethane to N-Boc-piperazine is 3:1-5: 1.
5. The preparation method of Volasertib intermediate 1-cyclopropylmethylpiperazine according to claim 1, characterized in that the reaction temperature in S2 is 0-25 ℃ and the reaction time is 2-4 hours.
6. The method for preparing Volasertib intermediate 1-cyclopropylmethylpiperazine according to claim 1, wherein the ether solvent in S2 is tetrahydrofuran or ethylene glycol dimethyl ether, and the mass ratio of the tetrahydrofuran or ethylene glycol dimethyl ether to the 4- (cyclopropanecarbonyl) piperazine-1-carboxylic acid tert-butyl ester is 2:1-3: 1.
7. The preparation method of Volasertib intermediate 1-cyclopropylmethylpiperazine according to claim 1, wherein the molar ratio of boron trifluoride-diethyl ether to tert-butyl 4- (cyclopropanecarbonyl) piperazine-1-carboxylate in S2 is 1.1:1-1.5:1, and the molar ratio of sodium borohydride to tert-butyl 4- (cyclopropanecarbonyl) piperazine-1-carboxylate is 1.5:1-2: 1.
8. The preparation method of Volasertib intermediate 1-cyclopropylmethylpiperazine according to claim 1, characterized in that the reaction temperature in S3 is 40-60 ℃ and the reaction time is 2-4 hours; the pH of the alkalinized solution of sodium hydroxide or potassium hydroxide is 10-11.
9. The preparation method of Volasertib intermediate 1-cyclopropylmethylpiperazine according to claim 1, wherein the alcoholic solvent of S3 is isopropanol or methanol, and the mass ratio of the isopropanol or methanol to N-Boc-4- (cyclopropylmethyl) piperazine is 2:1-3: 1.
10. The preparation method of Volasertib intermediate 1-cyclopropylmethylpiperazine according to claim 1, characterized in that the molar ratio of concentrated hydrochloric acid in S3 to N-Boc-4- (cyclopropylmethyl) piperazine is 2.5:1-3: 1.
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