TW201002668A - Preparing method of repaglinide - Google Patents

Abstract

The present invention relates to a method of preparing Repaglinide for the treatment of Diabetes Mellitus. The preparation method comprises: the amidation is carried out by reacting a S configuration compound of formula (II) with a compound of formula (III) in the presence of a condensation agent to form a S configuration compound of formula (IV); the S configuration compound of formula (IV) takes off R2 group in the presence of a base, then takes off R1 group in the presence of a acid. The S configuration compounds of formulas (II), (III), (IV) and R1, R2 groups have definition as they are given in the description. In the present preparation method, reaction time is shorten and yield is increased because of introducing R1 group and improved step of deprotection. The method is safer and more suitable for industrial production.

Description

201002668 IX. INSTRUCTIONS: [Technical Field] The present invention relates to the field of pharmaceutical organic synthesis, and in particular to a method for preparing a drug for treating diabetes, Repaglinide. [Prior Art] The chemical name of repaglinide is s(+)_2_ethoxy_4_[n_{1_(2, •V 丄, hydrogen σ pyridine group) stupyl)-3-methylbutyl }aminocarbonylcarbonyl]benzoic acid, the structural formula is

COOH - This is known from the U.S. patent (Patent No.: Kakawa). Research::: Repaglinide is an enantiomer 'Xiao R(-)·2-ethoxyl 4-(N^(hexahydropurine))-steryl]-butylamine Base: What?] The formic acid has a long-term biological activity in the human body. The pancreatic fistula = I: is a new type of hypoglycemic drug that can promote the fruit knife of the island. With fast absorption and short duration of action, it can simulate physiological insulin secretion in η t diabetic patients, effective blood sugar, and high protein binding rate. The food is good. repaglinide can be used in: And the weaving of the animal, the safety of the Ang-line anti-diabetes drug alone used 94340 6 201002668, can also be combined with other hypoglycemic agents to increase the efficacy, is a new drug for the treatment of π-type diabetes. A variety of literature reported Regal The synthesis of linnaphine is mainly carried out by condensing a compound of the formula (ii) with a compound of the formula (VI) to obtain a compound (VII), which is then hydrolyzed to obtain a product (I). The process is as follows:

Wherein R represents a carboxy protecting group such as a methyl group, an ethyl group or a benzyl group. In various literature reports (e.g., patent document US Pat. No. 5,312,924 or CN1 571 769), the researchers have mainly studied the condensation processes of formula (ii) and formula (VI) to improve the yield and reduce the cost. However, it is undeniable that among these condensation reactions, the condensing agents used are mostly DCC, triphenylphosphine + CC14, etc., and have disadvantages such as long reaction time and high toxicity, which are disadvantageous for industrial production. Therefore, it is of great significance and value to develop a process path that can solve the above problems. The invention provides a new process route for preparing repaglinide, which has the advantages of short reaction time, high yield, low toxicity, low risk, and simple operation, and is a process with good industrialization prospects. path. Disclosure of the Invention An object of the present invention is to provide a process for producing repaglinide which has a short reaction time, a high yield, and is suitable for industrial applications. The invention discloses a preparation method for preparing repaglinide of the formula (I).

• COOH OEt (I) The method comprises: a compound represented by the formula (n) and a compound represented by the formula (m) are subjected to a guanidation reaction in the presence of a condensing agent to form a formula (IV). Compound of type (s), ie

(Π) (m) (i\r) where, 8 94340 201002668

Ri is preferably selected from the group consisting of benzyl, preferably p-R2, selected from methyloxy, p-nitrobenzyl, p-nonylbenzyl, p-nonyloctyl, oxybenzyl; ethyl, second The butyl, benzyl, p-nitrobenzyl or palladium is preferably ethyl. Further, the (S) type compound represented by the formula (IV) is subjected to R2 and R, and the repaglinide product represented by the formula (I). The compound (II) is 3_mercapto-1-(2_(丄 A, 1 ^ U, pyridinium-1-1, poor)

Ri is obtained by dissociating the pen A H a* A from the oxime, and the specific path is as follows:

Soil)··butanone is a starting material, which is commercially available as a dehydration, reduction, and decomposing compound, wherein R 2 is an ethyl group; and step (2) in the specific example is further optimized, and the type (8) is shown. The hydrazine is removed in the presence of a base, and the R] group is removed in the presence of an acid after removal of the compound. - group, then 94340 9 201002668 • Ri 'N* -c〇or2 OEt (IV) The base in the above preferred embodiment is selected from an organic or inorganic test, wherein the organic base is selected from the group consisting of sodium methoxide, sodium ethoxide or the third Potassium butoxide; the inorganic base is selected from the group consisting of sodium carbonate, carbonic acid, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide or hydrogen hydroxide. The acid in the above preferred embodiment is selected from the group consisting of mixed acids of trifluoroacetic acid and methanesulfonic acid. In this specific example, the preferred structural formula of the (S) type compound represented by the formula (Π) is

In the present embodiment, the "condensing agent" means a dehydrating agent or an acid activator used for the acid or activating ester to react with an amine group, and is selected from the group consisting of Dcc,

HoBt+EDC, Ph3P+DIAD, Ph3P+DEAD, CDI, etc., preferably CDI. In the preparation method, due to the introduction of the R] group, not only the side reaction at the amine group is avoided, but also the nucleophilicity of the amine group is increased, so that the (S) type compound represented by the formula (π) and the formula The condensation reaction carried out by the compound shown in (dish) is easier, the reaction time is shortened, and the purity of the product is improved. Meanwhile, in the present invention, the (S) type compound represented by the formula (IV) is first present in the presence of a base. The R2 group is removed and then the R group is removed in the presence of an acid, and the reaction is more complete, higher yield, and more suitable for industrial production than the conventional deprotection reaction. [Embodiment] In order to explain the present invention in more detail, the following preparation examples are provided. However, the scope of the invention is not limited thereto. Example 1 Preparation of (S)-N-(4-methoxybenzyl)-3-methyl-l-[2-(l-hexahydroacridinyl)phenyl]butyl-1-amine 3-mercapto-1-(2-(hexahydropyridin-1-yl)phenyl)-1-butanone (3.3 Kg, 13.4 mol), toluene (30 L), p-sulfonic acid ( 330 g), 4-methoxy sulfhydramine (4.5 Kg, 32.5 mol) was placed in the reaction crucible, and the water was refluxed for five hours. The reaction was continued overnight by adding anhydrous sodium sulphate (1.6 Kg). The next day, the reaction solution was cooled to room temperature, poured into a saturated aqueous solution of sodium bicarbonate (20 L), and the aqueous layer was extracted with ethyl acetate (I0 L). Matter: 8.0 Kg. II 94340 201002668 TLC : petroleum ether / ethyl acetate 20 / l, Rf raw material = 〇. 7, Rf product = 0.3

The upper step oil (8.0 Kg), decyl alcohol (30 L), and nickel chloride hexahydrate (7 Kg) were placed in the reaction dad and cooled to 〇°c. Rotary sodium hydride (4.5 Kg) was added in portions below Yu Yiyi. The color of the reaction solution turned black, and a large amount of bubbles were generated, and the exothermic heat was apparent. After the addition, the temperature was naturally raised for five hours. The reaction solution was adjusted to pH=1 to 2 with concentrated hydrochloric acid, then the solution of the carbonic acid was adjusted to pH=9 to 10, and the ethyl acetate was extracted (20 L x 3) to extract the organic layer, dried over anhydrous magnesium sulfate, concentrated to dryness, and the column layer was dried. An oily product: 3.6 Kg. Developing solvent: petroleum ether / ethyl acetate = 3 / l, Rf raw material = 〇.9, Rf product = 〇.6 The oil of the above step (3.6 Kg, 9.7 mol), L-mandelic acid (1.5 Kg '9.4 Mol), isopropanol / water (〗: 〗) mixed solvent (17 L) was put into the reaction vessel, heated to reflux, dissolved and clarified, naturally placed in the crystal, filtered, dried to obtain a crude product: 3.2 Kg; The solid was poured into a reaction vessel, and a mixed solvent of decyl alcohol/water (1: hydrazine) (26 L) was added thereto to heat to reflux, and the mixture was allowed to crystallize by cooling, filtered, and dried to give a solid: 1.53 Kg. Sodium hydroxide (120 g ' 3. 〇 mol) and purified water (11 L) were placed in a 2 L reactor, toluene (6.8 L) and the resulting solid (1.53 Kg, 2.95 mo) were added and stirred at room temperature. Reaction for 45 minutes. The layers were separated, and the organic layer was washed with water (li. After filtration, the target compound filtrate was directly used in the next step of the reaction. Example 2(S)-4-(2-((4.methoxyl group)) (3-methyl hexachloropurine) phenyl) butyl)amino)-2-ethoxy) · Preparation of 2_ethoxybenzoic acid ethyl ester 94340 201002668 (S)_N_(4_曱oxybenzyl)_3_methyl-丨-^7·hexahydropyridinyl) benzene in the above step ] 丁基 丨 曱 曱 曱 曱 曱 之 之 之 无水 、 、 、 、 、 、 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水The reaction mixture was stirred with EtOAc (4 mL). Drying over anhydrous magnesium sulfate. Filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane; /methanol-100:1). ^ TLC: petroleum ether: ethyl acetate = 3: starting material = 〇 6, Rf product cdi: n, n-carbonyl diimidazole. Example 3 () 2 ethoxy _4_{2-[(3-methyl Preparation of 1-(2-(1-hexahydropyridinyl)phenyl)butyl)3⁄4:yl]-2-ethoxy}benzoic acid (repaglinide) 1) Solution The intermediate 3 (1·34 Kg), decyl alcohol (8 L), sodium hydroxide water, and solution (sodium oxide/water = 560 g/2.2 L) were put into a 2 〇L reactor and heated. The reaction was refluxed for 2 hours. The methanol was concentrated under reduced pressure, and the residue was adjusted to 4 to 5 with 2% hydrochloric acid. The material was taken (2.8 Lx2), and the organic layers were combined and dried over magnesium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the obtained mixture was taken to the next step starting material. TLC: petroleum ether / acetic acid ethyl acetate = 3 / 1, Rf product = 〇 3, Rf raw material 2) acid hydrolysis ^ Add the trifluoroacetic acid (5.4 L) to the intermediate step, stir for 2 minutes, add 曱The sulfonic acid (〇.92L) was stirred at room temperature for 15 hours. Add ^ 94340 13 201002668 Water (8.5 L) 'Use 40% hydrogen negative ^ Bu, 々, - two. ^ _ Potassium solution ΡΉ ΡΉ = 6, stir for 2 〇 minutes, 酉夂 B S 曰 (5 L) Stroke, skin®, 5〇/ή_, u with acetic acid B (four) called stripping, combined with organic layer) / 〇 虱 虱 卸 ( ( (5 Γ ^ .. 欣 (5 L) extraction, organic layer Then extract it with 5% of hydrazine hydroxide solution (2.5 Lx2), and then extract the water layer with hydrochloric acid, adjust pH=5 with hydrochloric acid, and extract the combined organic layer with ethyl acetate (6Lx2). Brine (5Lx2) washed with sodium, dried with magnesium sulfate dihydrate. Filtration, concentration of the filtrate under reduced pressure to a volume of about 2.0 L, cooling and crystallization, filtration, and drying to obtain repaglinide: 61 〇g. [Simple description] Main component symbol description no 94340 14

Claims (1)

201002668 X. Patent application scope: 1. A method for preparing repaglinide of formula (I), The method comprises the following steps: (1) The compound of the formula (II) represented by the formula (II) and the compound of the formula (III) are subjected to a guanidation reaction in the presence of a condensing agent to form (S) represented by the formula (IV). Type compound, ie K is selected from the group consisting of benzyl, p-nitrobenzyl, p-methoxybenzyl, p-nonylbenzyl; R2 is selected from decyl, ethyl, tert-butyl, benzyl, p-nitrobenzyl or p-quinone (2) The compound of the (S) type represented by the formula (IV) is subjected to the deprotection of the 112 and R groups to obtain the repaglinide product of the formula (I): 15 94340 201002668 4 . 2. The method of claim 1, wherein the condensing agent is selected from the group consisting of DCC, DIC, a combination of HoBt and EDC, a combination of Ph3P and DIAD, a combination of Ph3P and DEAD, or CDI. 3. The method of claim 2, wherein the condensing agent used is CDI. 4. The method of claim 1, wherein & is p-methoxybenzyl. 5. The method of claim 1, wherein R2 is ethyl. 6. The method of claim 1, wherein the (S)-type compound represented by formula (IV) (IV) The R2 group is first removed in the presence of a base, and then the R1 group is removed in the presence of an acid. 7. The process according to claim 6, wherein the base is selected from the group consisting of sodium decoxide, sodium ethoxide, tert-butanol _, sodium carbonate, potassium carbonate, sodium hydroxide 16 94340 201002668 ψ or potassium hydroxide. 8. The preparation method of claim 7, wherein the base is sodium hydroxide or potassium hydroxide. 9. The preparation method of claim 6, wherein the acid is a mixed acid of trifluoroacetic acid and sulfonic acid. 17 94340 201002668 VII. Designated representative map: There is no schema in this case (1) The representative representative figure of this case is: (). (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 5 94340 201002668 Winter "B Correction Women's Cooling Patent Specification (This manual's format, order and bold type, please do not change it at all, please do not fill in the ※ part) ※Application number: p 7 , y Upload ※Application Date: f? λ f ^IPC : CoTP Jl/^>m〇6.〇h I. Invention name: (Chinese/English) A method for preparing repaglinide. Preparing method of repaglinide I. Applicant: 1 person) Name or Name (Chinese/English) JIANGSU HANSEN PHARMACEUTICAL CO., LTD. Representative: (Chinese / English) Zheng Daozhong / CHENG, TO CHONG Residence or business address: (Chinese / English) Lianyungang Economic and Technological Development Zone, Jiangsu Province, China Post Code: 222〇47 ECONOMIC & TECHNICAL DEVELOPMENT ZONE, LIANYUNGANG CITY, JIANGSU, CHINA PC : 222047 Nationality: (Chinese/English) China/CHINA II. Inventor: (4 persons in total) Name: (Chinese/English) 1. Lv Aifeng / LV, AI FENG 2. Kong Shuanghua / KONG, SHUANG HUA 3. Xiao Jun / XIAO, JUN 4. Chen Gangsheng / CHE N, GANG SHENG Nationality: (Chinese/English) 1. to 4. Mainland China/CHINA 1 94340 201002668 6. The present invention relates to a method of preparing Repaglinide for the treatment of Diabetes Mellitus. The amidation is carried out by reacting a S configuration compound of formula (II) with a compound of formula (III) in the presence of a condensation agent to form a S configuration compound of fonnula (IV); the S configuration compound of formula (TV) takes off R2 group in the presence of a base, then takes off Rj group in the presence of a acid. The S configuration compounds of formulas (II), (III), (IV) and Rb R2 groups have definition as In the present preparation method, reaction time is shorten and yield is increased because of introducing R] group and improved step of deprotection. The method is safer and more suitable for industrial production. 0