Preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate

A technology of methylpiperazine and diformate, applied in the field of organic compound synthesis, can solve the problems of low yield, high price of palladium carbon, unfavorable industrial production, etc., and achieves reduction of production cost, easy availability of raw materials, and mild reaction conditions. Effect

Pending Publication Date: 2021-02-05
SHANGHAI BALMXY PHARMA CO LTD
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Problems solved by technology

[0003] CN110183471A discloses a novel piperazine derivative and its preparation method and application. The compound is (R)-6-methyl-3-(4-(isopropylsulfonyl)phenyl)-6-chloro-1H -pyrrolo[2,3-b]pyridine)-4,5,6,7-tetrahydropyrazolo[1,5-a]piperazine, the technique is based on 1((R)-2-(benzyl Amino)propan-1-ol) and 2(3-formyl-4-bromopyrazole) as starting materials, the new piperazine derivatives prepared can effectively inhibit the proliferation of human breast cancer cells, and with Adriamycin The combined use of these factors has a good synergistic anti-human breast cancer cell effect, and the preparation process conditions of the compound are relatively mild, which overcomes the disadvantages of harsh synthesis conditions, low yield, and unsuitability for industrial production of piperazine compounds
[0009] The above preparation method needs to go through 8 reaction processes, and includes two processes of removing Cbz-protected amino groups. In the process of removing Cbz-protected amino groups, palladium carbon is used as a catalyst. Palladium carbon is expensive, which increases production costs and is not conducive to industrial production.

Method used

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  • Preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate
  • Preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate
  • Preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate

Examples

Experimental program
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Effect test

Embodiment 1

[0136] This example provides a method for preparing (3R,6R)-1-tert-butyl-3-methyl-6-methylpiperazine-1,3-dicarboxylate, which specifically includes the following steps:

[0137] (1)

[0138]Boc-D-alanine (183.5g, 0.97mol) was added to 2.5L of dichloromethane, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide was added dropwise under ice-cooling ( 205g, 1.07mol), stirred for 10min, then added dropwise L-serine methyl ester hydrochloride (158.7g, 1.02mol) and triethylamine (161mL, 1.16mol), naturally warmed to room temperature, and reacted for 10h; Add 3L of pure water, let it stand, and separate the liquids to obtain an organic phase and an aqueous phase. The aqueous phase is extracted once with 1L of dichloromethane, and the organic phases are combined, and successively passed through hydrochloric acid with a gram equivalent concentration of 1N, saturated sodium bicarbonate, pure Wash with water and saturated brine, dry over anhydrous sodium sulfate, and concentrate to obta...

Embodiment 2

[0158] This example provides a method for preparing (3R,6R)-1-tert-butyl-3-methyl-6-methylpiperazine-1,3-dicarboxylate, which specifically includes the following steps:

[0159] (1)

[0160] Add Boc-D-alanine (189g, 1mol) to 2.5L dichloroethane, add dicyclohexylcarbodiimide (206g, 1mol) dropwise under ice-cooling, stir for 5min, then add L-serine dropwise Methyl ester hydrochloride (176.8g, 1.14mol) and N-methylmorpholine (148mL, 1.7mol) were naturally warmed to room temperature and reacted for 9.5h; 3L of pure water was added to the reaction system, allowed to stand and separated, The organic phase and the aqueous phase were obtained, the aqueous phase was extracted once with 1L dichloroethane, the organic phases were combined and washed successively with 1N hydrochloric acid, saturated sodium bicarbonate, pure water, saturated brine, anhydrous sodium sulfate Dried and concentrated to give 258 g of product , the yield was 89%.

[0161] (2)

[0162] The product (255 g...

Embodiment 3

[0174] This example provides a method for preparing (3R,6R)-1-tert-butyl-3-methyl-6-methylpiperazine-1,3-dicarboxylate, which specifically includes the following steps:

[0175] (1)

[0176] Boc-D-alanine (200g, 1.06mol) was added to 2.5L chloroform, and 2-(7-azabenzotriazole)-N,N,N',N was added dropwise under ice-cooling '-Tetramethylurea hexafluorophosphate (334.6g, 0.88mol), stirred for 15min, then added dropwise L-serine methyl ester hydrochloride (206g, 1.33mol) and diisopropylethylamine (162.4mL, 1.17 mol), naturally warmed to room temperature, and reacted for 10.5h; 3L of pure water was added to the reaction system, left to stand and separated to obtain an organic phase and an aqueous phase, and the aqueous phase was extracted once with 1L of chloroform, and the organic phase was combined and sequentially Washed with 1N hydrochloric acid, saturated sodium bicarbonate, pure water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 280...

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Abstract

The invention provides a preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate, and particularly relates to a preparation method of (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate. The preparation method comprises the steps of taking Boc-D-alanine and L-serine methyl ester hydrochloride as initial raw materials, and preparing the chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate through condensation reaction, deamination protection, ring closing reaction, reduction reaction, amino protection, oxidation reaction, ring closing reactionand ring opening reaction. According to the preparation method provided by the invention, the Boc amino protective agent is used for protecting amino, so that the production cost is reduced, the rawmaterials are easy to obtain, the conditions are mild, the yield is relatively high, and the preparation method can be applied to large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic compound synthesis, and in particular relates to a preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1,3-dicarboxylate. Background technique [0002] Piperazine compounds are important nitrogen-containing heterocycles in heterocyclic compounds. Piperazine derivatives have been valued for their anti-depressant, anti-inflammatory, analgesic, and anti-tumor activities. In addition, the 1,4-position of the piperazine ring is a basic group. The group has good water solubility and alkalinity, so introducing it into the drug molecule can increase the water solubility of the drug, effectively regulate the acid-base balance of the drug, and thereby enhance the biological activity of the drug molecule in animals and plants. [0003] CN110183471A discloses a novel piperazine derivative and its preparation method and application. The compound is (R)-6-methyl-3-(4-(isopropylsulfonyl)phenyl)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/04
CPCC07D241/04
Inventor 吴天俊林增明覃俊
Owner SHANGHAI BALMXY PHARMA CO LTD
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