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Synthesis method of DLin-MC3-DMA intermediate

A synthesis method and technology of dlin-mc3-dma, which is applied in the field of compound preparation, can solve the problems of harsh production equipment, poor reproducibility, and many by-products of the European Union, and achieve a high total yield, high reproducibility and easy operation. Effect

Inactive Publication Date: 2021-02-02
SUZHOU HIGHFINE BIOTECH
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  • Description
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  • Application Information

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Problems solved by technology

Since the Grignard reagent needs to be prepared under anhydrous and oxygen-free conditions, the production equipment required for this route is relatively harsh
And when preparing the Grignard reagent, the reproducibility of the reaction is often poor due to the large number of by-products of its own compound

Method used

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  • Synthesis method of DLin-MC3-DMA intermediate
  • Synthesis method of DLin-MC3-DMA intermediate
  • Synthesis method of DLin-MC3-DMA intermediate

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preparation example Construction

[0028] The synthesis method of (6Z,9Z,28Z,31Z)-heptadecane-6,9,28,31-tetraen-19 alcohol according to the embodiment of the present invention comprises the following steps:

[0029] Step S1, making (6Z,9Z)-18-bromooctadecane-6,9-diene undergo substitution reaction with nitromethane to obtain (6Z,9Z,28Z,31Z)-19-nitro-30 Hepta-6,9,28,31-tetraene.

[0030] Among them, (6Z,9Z)-18-bromooctadecane-6,9-diene, that is, compound I (the compound represented by I in the following reaction formula (1)), undergoes a substitution reaction with nitromethane to form (6Z, 9Z, 28Z, 31Z)-19-nitro-heptadecane-6,9,28,31-tetraene is compound II (the compound shown in II in the following reaction formula (1)), replacing The reaction formula of the reaction is shown in the following formula (1).

[0031]

[0032] Preferably, the substitution reaction occurs in the presence of an organic base comprising LDA, LHMDS, or a mixture thereof. Thus, LDA and LHMDS can well undergo a deprotonation reactio...

Embodiment 1

[0054] (a) Synthesis of compound Ⅱ, namely (6Z,9Z,28Z,31Z)-19-nitro-heptakadecane-6,9,28,31-tetraene

[0055] In a 150mL round bottom flask, 10g of compound I was dissolved in 80mL of tetrahydrofuran, cooled to -5°C, and 0.93g of nitromethane was added. 15.1 mL of 2M LDA was slowly added dropwise; after reacting at -5°C for 3 h, 50 mL of saline solution was added to quench the reaction.

[0056] The organic phase was washed with water, dried and evaporated to dryness; the crude product was purified by column chromatography to obtain 13.1 g of compound II with a yield of 77%.

[0057] (b) Synthesis of Compound Ⅲ (6Z, 9Z, 28Z, 31Z)-Heptadecane-6,9,28,31-tetraen-19-one

[0058] In a 150 mL round bottom flask, add 13 g of the above compound II into 40 mL of tetrahydrofuran and 10 mL of water, add 1.86 g of sodium hydroxide, and react at 50° C. for 4 h.

[0059] Tetrahydrofuran was distilled off, and 70 mL of dichloromethane was added for extraction. The organic phase was washed ...

Embodiment 2

[0063] (a) Synthesis of compound Ⅱ, namely (6Z,9Z,28Z,31Z)-19-nitro-heptakadecane-6,9,28,31-tetraene

[0064] In a 150mL round bottom flask, 10g of compound I was dissolved in 80mL of tetrahydrofuran, cooled to -5°C, and 0.93g of nitromethane was added. 15.1 mL of 2M LHMDS was slowly added dropwise; after reacting at -5°C for 6 h, 50 mL of saline solution was added to quench the reaction.

[0065] The organic phase was washed with water, dried and evaporated to dryness; the crude product was purified by column chromatography to obtain 13.1 g of compound II with a yield of 72%.

[0066] (b) Synthesis of Compound Ⅲ (6Z, 9Z, 28Z, 31Z)-Heptadecane-6,9,28,31-tetraen-19-one

[0067] In a 150mL round bottom flask, add 13g of compound II into 40mL of tetrahydrofuran and 10mL of water, add 2.61g of potassium hydroxide, and react at 60°C for 4h.

[0068] Tetrahydrofuran was distilled off, and 70 mL of dichloromethane was added for extraction. The organic phase was washed once more wit...

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Abstract

The invention provides a synthesis method of a DLin-MC3-DMA intermediate, the DLin-MC3-DMA intermediate is (6Z, 9Z, 28Z, 31Z)-triheptane-6, 9, 28, 31-tetraen-19-alcohol, and the synthesis method comprises the following steps: S1, carrying out substitution reaction on (6Z, 9Z)-18-bromooctadecane-6, 9-diene and nitromethane to obtain (6Z, 9Z, 28Z, 31Z), step S2, carrying out hydrolysis reaction on (6Z, 9Z, 28Z, 31Z)-19-nitrotriheptane-6, 9, 28, 31-tetraene to obtain (6Z, 9Z, 28Z, 31Z)-triheptane 6, 9, 28, 31-tetraen-19-ketone, and S3, the (6Z, 9Z, 28Z, 31Z)-triheptane-6, 9, 28, 31-tetraen-19-oneand a reducing agent are subjected to a reduction reaction, (6Z, 9Z, 28Z, 31Z)-triheptan-6, 9, 28, 31-tetraen-19-alcohol is obtained, and the reducing agent comprises sodium borohydride, potassium borohydride, lithium aluminum hydride or a mixture of sodium borohydride, potassium borohydride and lithium aluminum hydride. The synthesis method disclosed by the invention has the characteristics of simple process conditions, simplicity and convenience in operation, short route, high repeatability, higher total yield and contribution to industrial production.

Description

technical field [0001] The present invention relates to the technical field of compound preparation, in particular to a synthesis method of a DLin-MC3-DMA intermediate, more specifically to a (6Z, 9Z, 28Z, 31Z)-hexadecane-6,9,28, Synthetic method of 31-tetraen-19 alcohol. Background technique [0002] In RNA liposomes, the novel cationic lipid DLin-MC3-DMA plays an important role. In 2018, Onpattro, the world's first siRNA liposome product for the treatment of familial amyloid polyneuropathy, used DLin-MC3-DMA as the material for assembling cationic liposomes. Since then, the cationic lipid material DLin-MC3-DMA used in Onpattro has also attracted attention. The ionizable cationic liposome DLin-MC3-DMA is an efficient siRNA transport carrier, which can effectively encapsulate the corresponding siRNA and make it enter the cytoplasm, and then the two are separated, and the siRNA exerts its effect. [0003] The key intermediate for the preparation of DLin-MC3-DMA is (6Z,9Z,2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C29/143C07C33/02
CPCC07C201/06C07C45/00C07C29/143C07C205/03C07C49/203C07C33/02
Inventor 罗宇许鑫王子安
Owner SUZHOU HIGHFINE BIOTECH
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