- Integration of borylation of aryllithiums and Suzuki-Miyaura coupling using monolithic Pd catalyst
-
Integration of the preparation of arylboronic esters via aryllithiums and Suzuki-Miyaura coupling using monolithic Pd catalyst without an intentionally added base was achieved. A continuous operation has been done successfully for over 21 hours.
- Nagaki,Hirose,Moriwaki,Mitamura,Matsukawa,Ishizuka,Yoshida
-
-
Read Online
- Flow grams-per-hour production enabled by hierarchical bimodal porous silica gel supported palladium column reactor having low pressure drop
-
We describe a novel strategy to increase the unit-time-productivity of flow synthesis by using hierarchical bimodal porous silica gel (HBPSG) supported palladium column reactors. Because HBPSG has a significantly large surface area, the column reactors have low pressure drop, enabling high-volume production. We demonstrated flow synthesis of the precursor of adapalene, a pharmaceutical compound, at 5 g/h which is over 10-fold greater productivity than previous approaches.
- Ashikari, Yosuke,Bai, Hongzhi,Fujita, Chiemi,Maekawa, Kei,Matsuyama, Kiyoshi,Miyamoto, Riichi,Nagaki, Aiichiro,Takumi, Masahiro,Tomiyasu, Noriyuki
-
-
- Preparation method of adapalene
-
The invention discloses a preparation method of adapalene. According to the preparation method of adapalene, 2-methoxycarbonyl-6-naphthol p-toluenesulfonate and 4-methoxyphenylboronic acid which are low in price and easy to obtain are used as raw materials and bis (triphenylphosphine) nickel chloride is used as a catalyst, Suzuki coupling is performed to obtain 6-(4-methoxyphenyl)-2-methyl naphthoate, then alkylation reaction with 1-adamantanol is made to obtain 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-methyl naphthoate, and finally ester hydrolysis is performed to obtain the target product adapalene. The method is simple in process, raw materials are available, the yield is high and the cost is low, and the quality can reach a satisfactory level.
- -
-
-
- Room Temperature Deoxyfluorination of Benzaldehydes and α-Ketoesters with Sulfuryl Fluoride and Tetramethylammonium Fluoride
-
A method for the room temperature deoxyfluorination of benzaldehydes and α-ketoesters using sulfuryl fluoride and Me4NF is described. A large scope of aryl and heteroaryl substrates is demonstrated, and this method compares favorably to other common deoxyfluorination methods for many substrates.
- Melvin, Patrick R.,Ferguson, Devin M.,Schimler, Sydonie D.,Bland, Douglas C.,Sanford, Melanie S.
-
supporting information
p. 1350 - 1353
(2019/03/08)
-
- The Hiyama Cross-Coupling Reaction at Parts Per Million Levels of Pd: In Situ Formation of Highly Active Spirosilicates in Glycol Solvents
-
A palladium NNC-pincer complex at a 5 mol ppm loading efficiently catalyzed the Hiyama coupling reaction of aryl bromides with aryl(trialkoxy)silanes in propylene glycol to give the corresponding biaryls in excellent yields. This method was applied to the syntheses of adapalene and a biaryl-type liquid-crystalline compound, as well as to the derivatization of dextromethorphan and norfloxacin. ESI-MS and NMR analyses of the reaction mixture suggested the formation of pentacoordinate spirosilicate intermediates in situ. Preliminary theoretical studies revealed that the glycol-derived silicate intermediates formed in situ are quite reactive silicon reagents in the transmetalation step.
- Ichii, Shun,Hamasaka, Go,Uozumi, Yasuhiro
-
supporting information
p. 3850 - 3854
(2019/11/11)
-
- Influence of the adamantyl moiety on the activity of biphenylacrylohydroxamic acid-based HDAC inhibitors
-
To investigate the influence of the adamantyl group on the biological properties of known HDAC inhibitors with a 4-phenylcinnamic skeleton, a series of compounds having the adamantyl moiety in the cap structure were synthesized and compared to the corresponding hydroxamic acids lacking this group. An unexpected finding was the substantial reduction of inhibitory activity toward the tested enzymes, in particular HDAC6, following the introduction of the adamantyl group. In spite of the reduced ability to function as HDAC inhibitors, the compounds containing the adamantyl moiety still retained a good efficacy as antiproliferative and proapoptotic agents. A selected compound (2c; ST3056) of this series exhibited an appreciable antitumor activity against the colon carcinoma xenograft HCT116.
- Cincinelli, Raffaella,Musso, Loana,Giannini, Giuseppe,Zuco, Valentina,De Cesare, Michelandrea,Zunino, Franco,Dallavalle, Sabrina
-
p. 251 - 259
(2014/05/06)
-
- COMBINATION COMPOSITION COMPRISING BENZOYL PEROXIDE AND ADAPALENE
-
An aqueous gel composition of the present invention comprising about 0.1 to 0.3 wt % adapalene and about 2.5 to 5.0 wt % benzoyl peroxide, as active ingredients, wherein both the active ingredients are stabilized in hydrophilic gelling matrix of pH dependent gelling agent comprising crosslinked, acrylic acid-based polymer(s).
- -
-
-
- New synthesis of 6[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid and evaluation of the influence of adamantyl group on the DNA binding of a naphthoic retinoid
-
6[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoic acid (Adapalene), a synthetic aromatic retinoid specific for RARβ and RARγ receptors, has been prepared utilizing a Pd/C-mediated Suzuki coupling between 6-bromo-2-naphthoic acid and 4-methoxyphenyl boronic acid, followed by introduction of an adamantyl group in the position 3 of the formed 6-(4-methoxyphenyl)-2-naphthoic acid. The interaction of 6-(4-methoxyphenyl)-2- naphthoic acid/ethyl ester and the 3-adamantyl analogs with DNA was studied in aqueous solution at physiological conditions by UV-vis spectroscopy. The calculated binding constants Kligand-DNA ranged between 1.1 × 104 M-1 and 1.1 × 105 M-1, the higher values corresponding to those of the adamantylated compounds. Molecular modeling studies have emphasized that the intercalative binding of adapalene and its derivatives to DNA is mainly stabilized by hydrophobic interactions related to the presence of the adamantyl group.
- Milanese, Alberto,Gorincioi, Elena,Rajabi, Mehdi,Vistoli, Giulio,Santaniello, Enzo
-
p. 151 - 158
(2011/11/07)
-
- ANHYDROUS PETROLEUM JELLY/ELASTOMER-FREE DEPIGMENTING COMPOSITIONS COMPRISING A SOLUBILIZED PHENOLIC COMPOUND AND A RETINOID
-
Novel dermatological depigmentation compositions, especially for topical application, contain as pharmaceutical active agents a dissolved phenolic compound and a retinoid, formulated as anhydrous compositions free of petroleum jelly and free of elastomer. The present invention relates to a novel depigmenting composition especially for topical application, comprising as pharmaceutical active agents a dissolved phenolic derivative and a retinoid, in the form of an anhydrous composition free of petroleum jelly and free of elastomer, to the process for preparing it and to its use in dermatology.
- -
-
-
- METHOD FOR PREPARATION OF 6-[3(1-ADAMANTYL) -4-METHOXYPHENYL]-2-NAPHTOIC ACID
-
A method for preparation of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid is disclosed based on “one pot” synthesis approach including a direct synthesis of boronic acid derivative from 2-(1-adamantyl)-4-bromoanisole and cycloboranes with a subsequent Suzuki-Miyaura coupling with 6-halonaphthenoates and basic hydrolysis of the reaction product in ethylene glycol or 1,2-propanediol.
- -
-
Page/Page column 4
(2010/04/23)
-
- PROCESS FOR PREPARATION OF 6-[3-(1-ADMANTYL)-4-METHOXYPHENYL]-2-NAPHTOIC ACID.
-
A process for preparation of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid from 2-(1-adamantyl)-4-bromanisolee is disclosed, based on transformation of 2-(1-adamantyl)-4-bromanisole into a Grignard's reagent by using metallic magnesium, anhydrous lithium chloride and dibromoethane followed by transmetallation with borates to 3-(adamantyl)-4-methoxyphenylboronic acid, which is converted into 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid esters by Suzuki-Miyaura cross-coupling reaction with alkyl-6-halonaftoates catalyzed by Pd [0] or Pd/phosphine ligands and followed by basic hydrolysis in ethylene glycol or 1,2-propanediol of ester thus obtained into 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid.
- -
-
Page/Page column 5-6
(2010/07/04)
-
- Process for the Preparation of Adapalene and Related Compounds
-
The invention provides an improved process for the preparation of a benzonaphthalene derivative including, in particular, the manufacture of high purity adapalene. The invention further includes a method for assessing the color of adapalene by means of a quantitative colorimetric measurement of the produced adapalene.
- -
-
Page/Page column 6
(2009/05/28)
-
- NOVEL PROCESS FOR PREPARATION OF ADAPALENE
-
Disclosed herein is a process for the preparation of the adamantyl derivative 6-[3-(l- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid known as adapalene employing a novel intermediate 3 - Adamantyl - 4 - methoxyphenyl potassium trifluoroborate.
- -
-
Page/Page column 10
(2008/12/08)
-
- A PROCESS FOR PREPARATION OF ADAPALENE
-
The present invention discloses a process for preparation of highly pure Adapalene, chemically designated as 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (I) comprising: a) reacting 1-adamantanol with 4-bromophenol (II) in presence of sulphonic acid with or without the use of organic solvent to give 2-(l-adamantyl)-4- bromophenol (III); b) alkylating compound of formula(III) with dimethylsulphate in presence of base in organic solvent to obtain 2-(l-adamantyl)-4-bromoanisole (IV); c) C-C coupling the compound of formula (IV) with methyl-6-bromo-2- naphthoate using magnesium, purified zinc chloride and NiCl2-DPPE in THF at a temperature of 40-60°C tO obtain methyl ester of 6-[3-(l- adamantyl)-4-methoxy phenyl] -2-naphthoic acid (V); d) purifying crude methyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2- naphthoic acid (V) using a mixture of organic solvent to obtain pure compound (V); e) hydrolyzing the compound (V) with a solution of alkali in organic solvent to obtain metal salt of 6-[3-(l-adamantyl)-4-methoxy phenyl] -2-naphthoic acid (VI); f) acidifying metal salt of adapalene (VI) using organic or inorganic acid to obtain crude adapalene (I) and g) recrystallizing the crude adapalene (I) using a mixture of organic solvents to obtain pure adapalene (I).
- -
-
-
- INTERMEDIATES AND PROCESS FOR THE PREPARATION OF AROMATIC DERIVATIVES OF 1-ADAMANTANE
-
Process for the preparation of aromatic derivatives of 1 -adamantane (tricyclo[3.3.1.1 (3,7)]decane), or an acceptable pharmaceutical salt thereof, based on a hydrolysis reaction of a precursor cyano compound. It also comprises different processes for obtaining the cyano compound. It is especially useful for obtaining Adapalene on an industrial scale in high yield and purity. It also comprises new intermediates useful in said preparation process.
- -
-
Page/Page column 27
(2010/11/27)
-
- PROCESS FOR THE PREPARATION OF AROMATIC DERIVATIVES OF 1-ADAMANTANE
-
Process for the obtaining of 1 -adamantane (tricycle[3.3.1.1 (3,7)]decane) derivatives, or of a pharmaceutically acceptable salt thereof, based on a carboxylation reaction, via metallation, of a precursor compound with an adequate leaving group. It also comprises the preparation of the precursor compound by means of a selective coupling of the corresponding boron, magnesium or zinc derivative with the corresponding disubstitute aromatic derivative. It is especially useful for the obtaining of Adapalene at industrial scale with good yield and high purity.
- -
-
Page/Page column 5; 15
(2008/06/13)
-
- BIPHENYL AND NAPHTHYL-PHENYL HYDROXAMIC ACID DERIVATIVES
-
Biphenyl and phenyl-naphthyl compounds bearing a hydroxamic group, which are endowed with antitumour, and anti-angiogenic activity These compounds are therefore particularly useful for the treatment of drug-resistant tumours.
- -
-
Page/Page column 19; 20
(2008/06/13)
-
- NEW METHOD FOR THE PREPARATION OF 6-(3-(1-ADAMANTYL)-4-METHOXPHENYL)-2-NAPHTHOIC ACID
-
The present invention relates to a novel method for preparing 6- [3- ( 1 - adamantyl ) -4-methoxyphenyl] -2- naphthoic acid.
- -
-
Page/Page column 11-12
(2008/06/13)
-
- A process for the preparation of adapalene
-
A process for the preparation of a compound of formula (I), or a salt thereof wherein R is H, C1-C8 alkyl, aryl or aryl-C1-C8 alkyl; comprising the reaction between a compound of formula (II) wherein R1 and R2 are independently hydrogen, C1-C8 alkyl, aryl, aryl-C1-C8 alkyl, or R1 and R2, taken together, form a -(CH2)m- V-(CH2)n-group, in which V is NR3 or C(R3)2 wherein R3 is hydrogen, C1-C8 alkyl, aryl or aryl-C1-C8 alkyl; and m and n, which can be the same or different, are 1 or 2; with a compound of formula (III) in which R4 and R5 are independently C1-C8 alkyl, aryl or aryl-C1-C8 alkyl; in the presence of a Ni (II) salt, an organic ligand and a basic agent, to obtain a compound of formula (I) wherein R is C1-C8 alkyl, aryl or aryl-C1-C8 alkyl and, if desired, its conversion to a compound of formula (I) wherein R is hydrogen or to a salt thereof.
- -
-
Page/Page column 4
(2010/11/23)
-
- A high yield and pilot-scale process for the preparation of adapalene
-
Strategies that were adopted during the process development of adapalene to achieve a cost-effective commercial-scale synthesis are described herein. These included (1) the use of AcOH/H2SO4 to afford 2-(1-adamantyl)-4-bromophenol in quantitative yield; (2) the dimethyl sulfate methylation to enhance the yield of methylation to 95%; (3) direct conversion of the Grignard reagent into methyl 6-(3-(1-adamantyl)-4-methoxyphenyl)-2- naphthoate by the catalysis of both PdCl2-(PPh3) 2 and ZnCl2 in high yield; (4) the use of EDTA-disodium salt dihydrate to ensure the heavy metal's content within acceptable limits; (5) the use of toluene to simplify the original Chromatographic purification to recrystallization. The pilot-scale synthesis of adapalene is described in detail in the Experimental Section.
- Liu, Zhichang,Xiang, Jiannan
-
p. 285 - 288
(2012/12/22)
-
- Phenolic/naphtholic retinoids for promoting skin/exoskeleton pigmentation
-
Pigmentation of the skin, hair and/or nails of individuals is promoted by administering thereto, advantageously topically and advantageously in combination with enzymes exhibiting tyrosinase activity, effective pigmentation-promoting amounts of at least one retinoid compound which comprises a phenolic or naphtholic functional group.
- -
-
-
- Retinoid inhibition of expression of VEGF
-
The retinoids, in particular the anti-AP-1 retinoids, effectively inhibit the expression of VEGF, and thus are useful for the therapeutic treatment of disease states manifesting an overexpression of VEGF.
- -
-
-
- Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes
-
The retinoic acid receptors (RARs) transduce retinoid dependant gene regulation, and many biological effects of retinoids are mediated through binding and activation of three closely related receptor subtypes (RARα, RARβ, and RARγ). In order to investigate the role of receptor subtypes, we have carried out a chemical synthesis program to seek selective retinoids for these receptors. We measured receptor binding affinity using recombinant RARα, -β, and -γ proteins and assessed cellular differentiating activity in F9 murine teratocarcinoma cells (F9 cells). This research has identified the 4-substituted-3-(1-adamantyl)phenyl moiety as a new pharmacophore which can replace the β-cyclogeranylidene ring of the naturally ocurring all- trans-retinoic acid. Two chemical series derived from the general structures 6-(3-tertioalkyl-phenyl)-2-naphthoic acid (series I) and 4-[(E)-2-(3- tertioalkylphenyl)propenyl]benzoic acid (series II) were developed. In particular, we have obtained the RARγ selective derivatives 6-[3-(1- adamantyl)-4-hydroxyphenyl]-2-naphthoic acid (7) [K(i)(RARα) = 6500 nM, Ki(RARβ) = 2480 nM, K(i)(RARγ) = 77 nM] and 4-[(E)-2-[3-(1-adamantyl)-4- hydroxyphenyl]propenyl]benzoic acid (19) [K(i)(RARα) = 1 144 nM, K(i)(RARβ) = 1245 nM, K(i)(RARγ) = 53 nM]. In series I, the presence of a phenol group, irrespective of the nature of tertioalkyl group, imparted at least partial RARγ selectivity, whereas in series II, the presence of both adamantyl and phenol groups is needed to confer RARγ selectivity. The RARγ selective ligands induce differentiation in F9 cells (7, AC50 = 33 nM; 19, AC50 = 66 nM). From series I, a mixed RARβ-γ agonist with potent cellular differentiating activity was selected for development as a topical antiacne agent, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid (5, CD 271) [K(i)(RARα) = 1100 nM, K(i)-(RARβ) = 34 nM, K(i)(RARγ) = 130 nM, AC50(F9) = 37 nM]. Finally, from series II, we have obtained a weak antagonist in the F9 cellular differentiation assay, 4-[(E)-2-(3-tert-butyl- 4-hydroxyphenyl)propenyl]benzoic acid (15, IC50 = 700 nM).
- Charpentier,Bernardon,Eustache,Millois,Martin,Michel,Shroot
-
p. 4993 - 5006
(2007/10/03)
-
- Compound marked with tritium, its preparation and its use in the location of nuclear receptors of retinoids
-
6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid marked with tritium; its preparation; and its use as a radioactive marker, in the titration of nuclear receptors of retinoids in the presence of contaminating CRABP, or in the measurement of the affinity of retinoids for these nuclear receptors.
- -
-
-
