- Method for producing ester compound
-
The present invention relates to a method for producing an ester compound. The present invention addresses the problem of industrially advantageously producing 11-oxo-6, 11-dihydrodibenzo [b, e] oxepin-2-tert-butyl acetate which is an intermediate for the production of olopatadine. In the present invention, the 11-oxo-6, 11-dihydrodibenzo [b, e] oxepin-2-tert-butyl acetate can be produced by reacting 11-oxo-6, 11-dihydrodibenzo [b, e] oxepin-2-acetic acid, tert-butyl alcohol and di-tert-butyl dicarbonate in the presence of dimethylaminopyridine or N-methylimidazole and one or more bases selected from triethylamine, pyridine, diisopropylethylamine and dimethylaniline. Furthermore, the olopatadine can be produced by a reaction with 3dimethylaminopropyl magnesium chloride, a dehydration reaction, and a deesterification reaction.
- -
-
Paragraph 0058; 0059
(2021/01/11)
-
- Novel and Efficient Synthesis of Deuterium-Labeled Olopatadine-d6
-
A novel and highly efficient synthetic approach has been developed for the synthesis of deuterium-labeled olopatadine-d6 using inexpensive and commercially available dimethyl sulfate-d6 at the stage of alkylation of primary amine intermediate. The proposed synthetic path makes it possible to avoid the use of expensive labeled reagents such as dimethyl amine-d6 used as labeled precursor in the traditional synthetic route. The structure of the obtained olapatadine-d6 has been confirmed by 1H NMR and mass spectral data.
- Endoori,Gulipalli, K. Ch.,Bodige,Seelam
-
p. 1387 - 1393
(2019/11/03)
-
- A high active organic zinc reagent for the preparation of the new method of olopatadine hydrochloride
-
The invention discloses a novel method for preparing olopatadine hydrochloride. The method comprises the steps as follows: (1) high-activity zinc and 3-bromo-N,N-dimethylpropylamine form an organic zinc reagent (I); (2) the organic zinc reagent is eliminated after electrophilic substitution with isoxepac (II) to form olopatadine (III); (3) the olopatadine with higher purity is obtained through recrystalization of the olopatadine, wherein structural formulas of the organic zinc reagent (I), the isoxepac (II) and the olopatadine (III) are as follows.
- -
-
Paragraph 0027; 0036-0038; 0042-0051; 0054-0056
(2018/03/09)
-
- Preparation method of olopatadine
-
The invention provides an industrial preparation method of olopatadine. The method can accelerate the reaction speed and lower the environmental sensitivity, the process controllability is improved, the production cost is lowered, and safety is improved.
- -
-
Paragraph 0051; 0052; 0053
(2017/01/02)
-
- A process for the preparation of olopatadine hydrochloride
-
The invention relates to a method for preparing a compound, namely, olopatadine hydrochloride. The method specifically comprises the following steps: by taking 2-chloromethyl methyl benzoate and methyl 4-hydroxyphenylacetate as initial raw materials, performing etherification, hydrolysis and cyclization, further performing wittig reaction, and salifying, thereby synthesizing olopatadine hydrochloride. The process is gentle in process reaction condition, acetic anhydride is adopted to replace polyphosphoric acid, a hydrochloric acid organic solvent is adopted to effectively split Z/E type olopatadine so as to obtain olopatadine hydrochloride, conversion of Z/E configuration is effectively achieved after an E configuration byproduct is treated by using concentrated hydrochloric acid, the yield of olopatadine hydrochloride is increased, the product purity is good, and the feasibility of industrialization production is greatly improved.
- -
-
-
- PROCESS FOR PRODUCING DIBENZOXEPIN COMPOUND
-
A process for producing (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid or an acid addition salt thereof, which comprises subjecting 11-hydroxy-11- (3-dimethylaminopropyl)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid or a salt thereof to a heat treatment in a solvent and a water removal treatment in a reaction system in the presence of an acid selected from a group consisting of hydrogen chloride, sulfuric acid, methanesulfonic acid and p-toluenesulfonic acid, enables the production of (Z)-11-(3-dimethylamino-oropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid or an acid addition salt thereof, which is useful as a medicinal agent, in a high yield and in an industrially advantageous manner.
- -
-
Page/Page column 6
(2011/11/13)
-
- PROCESS FOR THE PREPARATION OF OLOPATADINE
-
The present invention relates to a novel process for the preparation of olopatadine hydrochloride starting from an advanced intermediate.
- -
-
Page/Page column 25-26
(2010/11/05)
-
- PROCESS FOR PREPARING OLOPATADINE AND/OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
-
The present invention relates to a process for the preparation of olopatadine and, more particularly, to an improved method of synthesizing olopatadine which comprises reacting a dibenz[b,e]oxepin-1 1-one derivative of formula (III) and a suitable reagent under Witting condition.
- -
-
Page/Page column 13-14
(2010/08/18)
-
- Polymorphic forms of olopatadine hydrochloride and methods for producing olopatadine and salts thereof
-
The present invention provides a novel polymorphic form of olopatadine hydrochloride ([(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride), a selective histamine H1-receptor antagonist that is used for the treatment of ocular symptoms of seasonal allergic conjunctivitis. The present invention also provides novel methods for producing olopatadine on a large scale, and in a manner that is cost effective, provides a low level of impurities and eliminates the need to use the costly and dangerous base, butyllithium, which is used in prior art reactions for making olopatadine. The present invention further provides novel processes for carrying out a large scale production of 3-dimethylaminopropyltriphenylphosphonium bromide and its corresponding hydrobromide salt, which are employed in the production of olopatadine, and pharmaceutically acceptable salts of olopatadine.
- -
-
Page/Page column 25; 26
(2008/06/13)
-
- PROCESS FOR THE PREPARATION OF 11-[(Z)-3-(DIMETHYLAMINO)PROPYLIDENE]-6,11-DIHYDRO-DIBENZ[B,E]OXEPIN-2-YL]-ACETIC ACID
-
Process for the preparation of olopatadine (I), which comprises reacting a compound of formula (V) in the presence of a palladium catalyst to provide a compound of formula (VI), wherein the acid protecting group is removed to provide the compound of formula (I) and if desired, transformation into its salts.
- -
-
Page/Page column title page; 7
(2008/06/13)
-
- Synthesis and Antiallergic Activity of 11-(Aminoalkylidene)-6,11-dihydrodibenzoxepin Derivatives
-
A new series of 11-substituted 6,11-dihydrodibenzoxepin-2-carboxylic acid derivatives was synthesized and demonstrated to be orally active antiallergic agents.These compounds are structurally related to 1 (KW-4994), which we had reported previously to be a new antiallergic agents.Most compounds synthesized exhibited potent inhibitory effects on 48-h homogolous passive cutaneous anaphylaxis (PCA) in rats and on IgG1-mediated bronchoconstriction in guinea pigs.Additionally, compounds possessing a terminal carboxyl group at the 2-position of the dibenzoxepin ring system exhibited inhibitory effects on specific pyrilamine binding to guinea pig cerebellum histamine H1 receptors, whereas these demonstrated negligible effects on specific QNB binding to rat striatum muscarinic acetylcholine M1 receptors.Structure-activity relationship studies revealed that the following key elements were required for enhanced antiallergic activities: (1) a 3-(dimethylamino)propylidene group as the side chain at the 11-position, (2) a terminal carboxyl moiety at the 2-position, and (3) a dibenzoxepin ring system.Among the compounds synthesized, (Z)-11--6,11-dihydrodibenzoxepin-2-acetic acid hydrochloride (16) was selected for further evaluation.It had an ED50 value of 0.049 mg/kg po in the PCA test in rats and an ID50 value of 0.030 mg/kg po in inhibiting anaphylactic bronchoconstriction in guinea pigs.Furthermore, it had a Ki value of 16 +/- 0.35 nM for the histamine H1 receptor, while it exhibited negligible CNS side effects up to a dose of 600 mg/kg po.Compound 16 is now under clinical evaluation as KW-4679.
- Ohshima, Etsuo,Otaki, Shizuo,Sato, Hideyuki,Kumazawa, Toshiaki,Obase, Hiroyuki,et al.
-
p. 2074 - 2084
(2007/10/02)
-
