122334-01-4

Upstream product

• 122334-02-5 4-(3-methoxy-4-methylphenyl)butanoic acid 
• 67868-73-9 5-bromo-2-methylphenol methyl ether 
• 151073-69-7 (4-ethoxy-4-oxobutyl)zinc(II) bromide 
• 4685-50-1 3-methoxy-4-methylbenzyl alcohol 
• 4685-51-2 4-(chloromethyl)-2-methoxy-1-methylbenzene 
• 140-88-5 ethyl acrylate 
• 3556-83-0 methyl 4-methyl-3-methoxybenzoate 

Downstream Products

• 122334-02-5 4-(3-methoxy-4-methylphenyl)butanoic acid 

Relevant academic research and scientific papers

Total synthesis of (±)-Cephanolides B and C via a palladium-catalyzed cascade cyclization and late-stage sp3 C-H bond oxidation

Herein, we report the first total syntheses of complex cephalotaxus diterpenoids cephanolide B and C from commercially available 5-bromo-2-methylanisole. Key to the success of this synthetic route is a palladium-catalyzed cascade cyclization reaction, which allowed us to efficiently forge the 6-5-6 cis-fused tricyclic ring systems found in the entire family of cephalotaxus diterpenoids. Additionally, site-selective late-stage sp3 C-H bond oxidation served as a key strategic element in the chemical synthesis of cephanolide C.

Synthesis method of cephanolide B

The invention discloses a synthesis method of cephanolide B. The method comprises the steps of taking commercially available 5-bromine-2-methylanisole as a synthesis raw material, performing Ei-ichi Negishi reaction, methoxy contraposition halogenation, and lithium diisopropylamide formylation reaction to form a 1,3-dicarbonyl compound, allowing the compound and 3-pentene-2-ketone to give Robinsoncyclization reaction, performing Luche reduction, hydrolysis and esterification reaction to form a lactone compound, performing acid treatment after diisobutyl aluminum hydride reduction to form a Heck reaction precursor, performing palladium catalyzed carbonyl esterification coupling reaction and esterification to form cephalotaxus sinensis terpene skeleton compound, and performing carbonyl reduction and methoxy removal at last to achieve chemical synthesis of cephanolide B for the first time. The method has the advantages of concise and efficient synthesis route, easiness and simplicity inoperation, low cost and the like, is applicable to massive synthesis of cephanolide B and provides an important material basis for bioactivity evaluation of a natural product, namely cephanolide B.

A Cephalotaxus sinensis terpene skeleton synthetic method of the compound (by machine translation)

The invention discloses a Cephalotaxus sinensis terpene framework compound synthesis method, the method of the commercially available 5 - bromo - 2 - methyl anisole as a synthetic raw material, through the Negishi British reaction with the methoxy para-halogenated, re-read the second isopropyl [...] acylation reaction to obtain the 1, 3 - dicarbonyl compound, with 3 - pentene - 2 - one generating robin [...] reaction, through the Luche reduction, hydrolysis, esterification reaction to obtain compound [...], through the diisobutyl hydrogenated aluminum reduction after acid treatment to obtain Huckel reaction precursor, after palladium catalyzed [...] coupling reaction, then through esterification realizes Cephalotaxus sinensis terpene skeleton compounds of chemical synthesis. Synthetic route of this invention has the advantages of simplicity and high efficiency, simple operation, low cost and the like, and is suitable for a large number of Cephalotaxus sinensis terpene framework compound synthesis, is Cephalotaxus sinensis terpene natural product chemical synthesis provides an important basis for experiment. (by machine translation)

Synthesis method of cephanolide C

The invention discloses a synthesis method of cephanolide C. The method comprises the steps of taking commercially available 5-bromine-2-methylanisole as a synthesis raw material, performing Ei-ichi Negishi reaction, methoxy contraposition halogenation, and lithium diisopropylamide formylation reaction, allowing a product and 3-pentene-2-ketone to give Robinson cyclization reaction, performing Luche reduction, hydrolysis and esterification reaction to form a lactone compound, performing acid treatment after diisobutyl aluminum hydride reduction to form a Heck reaction precursor, performing palladium catalyzed carbonyl esterification coupling reaction, esterification and carbonyl reduction, then performing sequential oxidation, eemethylation and hydroxyl protection by trifluoromethylsulfonyl via 2,3-dichloro-5,6-dicyan para-quinone and pyridinium chlorochromate, and performing palladium catalyzed removal to achieve chemical synthesis of cephanolide C for the first time. The method has the advantages of concise and efficient synthesis route, easiness and simplicity in operation, low cost and the like, is applicable to massive synthesis of cephanolide C and provides an important material basis for bioactivity evaluation of a natural product, namely cephanolide C.

Discovery of a 1-Methyl-3,4-dihydronaphthalene-Based Sphingosine-1-Phosphate (S1P) Receptor Agonist Ceralifimod (ONO-4641). A S1P1 and S1P5 Selective Agonist for the Treatment of Autoimmune Diseases

The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing-remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure-activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/kg, 24 h after oral dosing).

Introduction of a putative dopaminergic prodrug moiety into a 6,7-substitution pattern characteristic of certain 2-aminotetralin dopaminergic agonists

On the basis of the premise that the dopaminergic agonist profile of 2-(di-n-propylamino)-5-hydroxy-6-methyltetralin (1a) is due to in vivo oxidation of the 6-methyl moiety and that 1a may represent a novel prodrug strategy, the vicinal methyl-hydroxyl substitution pattern was incorporated into the 6- and 7-positions of 2-(di-n-propylamino)tetralin to give the 6-methyl-7-hydroxy and 6-hydroxy-7-methyl isomers 8 and 9, respectively. A multistep synthetic approach was devised which permitted preparation of target molecules 8 and 9. Pharmacological data revealed that both target compounds exhibit modest dopamine-like effects in the cardioaccelerator nerve assay in the cat, but neither appeared to be metabolically activated as was the case with 1a. The effects of 9 (but not of 8) were antagonized by pretreatment with haloperidol. Thus, the 5-hydroxy-6-methyl substition pattern in the 2-aminotetralins remains unique as a dopaminergic agonist prodrug structure.