Title of Invention

A PROCESS FOR PREPARING (1S)-1-ISOBUTOXYMETHYL-3-METHYLBUTYL-AMINE

Abstract

ABSTRACT 363/CHENP/2005 A process for preparing (IS)-l-isobutoxymethyl-3-methylbutyl-amine The present invention relates to a process for preparing (1S)-1-isobutoxymethyl-3-methylbuty[- amine having the following formula: which comprises the steps of: reacting L-leucinol and a compound having the following formula: in which X is a leaving group, in the presence of a base, to give a (lS)-l-(2-methyl-2-propenoxymethyI)-3-methyl- butylamine, and reducing the (1 S)-l -(2-methyl-2-propenoxymethyl)-3-methylbutylamine in a solvent not participating in the reducing reaction, at a hydrogen pressure of 1 to 100 atm., using a catalyst for catalytic reduction of a double bond.

Full Text

The present invention relates to a process for preparing( 1S)-1 -isobutoxymethyl-3 -methylbuty I-amine. [BACKGROUND OF THE INVENTION] The under-illustrated sodium (2S,3S)-3-([{lS)-1-iso-butaxymethyl-3-methylbutyl] carbamoyl] oxirane-2-carbox-ylate (hereinafter referred to as Compound A) shows a catheps in-inhibitory action and is useful as a remetty- for treating rheumatoid arthritis and osteoporosis (Patent reference 1: WO 99/11640 painphlet): Patent reference 1 describes a process for producing Conpound A accorditing to the following reaction scheme (see Example 48 of Patent reference 1) : There is a need to provide an industrially enplcy-able synthesis process for the production of Conpound A. [DISCLOSURE OF THE INVENTION] The present invention has an object to provide an amine derivative employable as an intermediate compound for the synthesis of Compound A. The amine derivative is (lS)-l-isobutoxytnethyl-3-methylbutylamine represented by the following formula: The invention also has an object to provide a pro¬cess for producing the amine derivative. The {lS)-l-isobatoxymethyl-3-inethylbutylamine can be obtained according to the following reaction scheme: Step 1: L-leucinol (2) - Conpound (3) The reaction, of L-leucinol (2) with the compound (4) can be performed in such a solvent not participating in. the reaction as THF or EMSO at a temperature between -30°C and the reflux temperature in the presence of a base. Exattples of the leaving groups represented by X in the conpound (4) include halogens such as chlorine, bro- , nine and iodine, p-toluenesulfonyloxy, and methanesulfon-loxy. Examples of the bases include alkali metal hydrides such as NaH, LiH and KH, alkaline earth metal hydrides such as CaH2, alkali metal alkoxides such as t-BuOK, inorganic bases such as NaCH and KCH, and organic bases such as triethylamine The starting compound, namely L-leucinol, can be obtained by reducing L-leucine {for example, united Stat¬es Patent 3,935,280) . Step 2: Compound f3) - Compound (1) The reaction can be performed in such a solvent not participating in the reaction as ethanol or acetic acid at a hydrogen pressure of 1 to 100 atm., using 0.1 to 20 % of such a catalyst employable for catalytic reduction of a double bond as Pd/C or Raney nickel. The (IS)-l-isobutoxymethyl-3-methibutylamine also can be produced according to the following reaction scheme: [in vAiich X has the same leaving group as above] . The aforementioned Conp^und A can be produced from the (IS)-l-isobut03qmethyl-3-methylbutylamine obtained above according to the following reaction scheme (see Exanples 48 and 18a of Patent reference 1) : The process of the invention can give the amine derivative, i.e., (IS) -l-isobutoxymethyl-3-methylbutyl-amine, in a high yield. The aforementioned Compound A can be obtained from this amine derivative in a high yield. The invention is further described by the following exanples. [Exanple 1] (IS) -1- (2-methyl-2-propenoxyethyl) -3-raethyl-butylamine To a solution of L-leucinol (20.0 g, 0.17 mol) in an anhydrous THF (200 mL) was portionwise added 60% NaH (7.92 g, 0.198 mol) , The resulting mixture was stirred for 30 min. at room temperature and further for 2 hours at 50°C. The mixture was then cooled to room temprature To the resulting suspension was dropwise added a solution of 3-chloro-2-methylpropene (15.45 g, 0.17 mol) in an anhydrous THF (50 mL) . The resulting mixture was stirred for 20 hours at room temperature. The THF was distilled off under reduced pressure. To the residue were succes¬sively added a mixture of ice and water and diethyl ether. The mixture was stirred for 5 min. at room tem¬perature, and the organic portion was separated. The aqueous portion was subjected to extraction with diethyl ether. The extract was combined with the organic por¬tion. The conmbined organic portion was washed with 1 mol/L aqueous hydrochloric acid (7 mL) and subjected to extraction with 1 mol/L aqueous hydrochloric acid (153 mL) . The resulting hydrochloric acid extract was made to approx. pH 10 by addition of potassium carbonate and subjected to extraction with diethyl ether. The organic portion was washed with water, dried over sodium sulfate, and placed under reduced pressure to distill the solvent off. There was obtained the titled compound (20.22 g, 69.2%) as an oily product. [Example 2] (1S)-l-Isobutoxymethyl-3-methylbutylamine A suspension of {1S)-1-(2-methyl-2-propenoxymethyl)-3-methylbutylamine (51.9 g, 0.3 mol) and 5%Pd/C (10.4 g) in ethanol (520 mL) was stirred for 18 hours at room tenperature in a hydrogen atmosphere (1 atm.) To the resulting reaction mixture was added 6 mol/L aqueous hydrochloric acid (52 mL) under cooling in ice bath. The aqueous mixture was subjected to filtration using celite for removing insolubles and then placed under reduced pressure for distilling the solvent off. The residue was dissolved in water, and the resulting aqueous solution was made to approx. pH 10 by addition of potassium car-bonate. The solution was subjected to extraction with diethyl ether The organic portion was dried over sodium sulfate and placed under reduced pressure for distilling off the solvent. There was obtained the titled compound {48.6 g, 92.6%) as an oily compound. bp: 66-67°C/5 mmHg WE CLAIM: 1. A process for preparing (lS)-l-isobutoxymethyl-3-methylbutyl- amine having the following formula: which comprises the steps of: reacting L-leucinoI and a compound having the following formula: in which X is a leaving group, in the presence of a base, to give a (lS)-l-(2-methyl-2-propenoxymethyI)-3-methyl- butylamine, and reducing the (1 S)-l -{2-methyl-2-propenoxymethyI)-3-methylbutylamine in a solvent not participating in the reducing reaction, at a hydrogen pressure of 1 to 100 atm., using a catalyst for catalytic reduction of a double bond. 2. (lS)-l-lsobutoxymethyl-3-methylbutylamine prepared by the process as claimed in claim 1.

Documents:

0363-chenp-2005 abstract-duplicate.pdf

0363-chenp-2005 abstract.pdf

0363-chenp-2005 claims-duplicate.pdf

0363-chenp-2005 claims.pdf

0363-chenp-2005 correspondence-others.pdf

0363-chenp-2005 correspondence-po.pdf

0363-chenp-2005 description (complete)-duplicate.pdf

0363-chenp-2005 description (complete).pdf

0363-chenp-2005 form-1.pdf

0363-chenp-2005 form-18.pdf

0363-chenp-2005 form-26.pdf

0363-chenp-2005 form-3.pdf

0363-chenp-2005 form-5.pdf

0363-chenp-2005 pct search report.pdf

0363-chenp-2005 pct.pdf

0363-chenp-2005 petition.pdf

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