WO2009114987A1 - Process for preparing repaglinide intermediate - Google Patents

Abstract

A process for the preparation of repaglinde intermediate (I), wherein repaglinde is a therapy drug for diabetes. The preparation process has high yield and better security, thus it is more suitable for industrial production.

Description

 Method for preparing repaglinide intermediates

 The invention relates to the field of organic medicine synthesis, in particular to a preparation method of a drug repaglinide intermediate for treating diabetes. Background technique

 The chemical name of repaglinide is S (+) -2-ethoxy-4-[N- {1- (2-piperidinylphenyl)-3-methyl-1-butyl}aminocarbonyl Benzoic acid, the structural formula is

 It is known from the U.S. Patent (Patent No.: US5312924). Studies have shown that repaglinide is a potent enantiomer with R(-)-2-ethoxy-4-[N-{1-(2-piperidinylphenyl)-3-methyl-1 Compared with -butyl}aminocarbonylmethyl]benzoic acid, it has long-term biological activity in human body and is eliminated more rapidly. It is a new type of oral hypoglycemic agent that promotes insulin secretion and has fast absorption. The short duration of action can simulate physiological insulin secretion in patients with type 2 diabetes, effectively control postprandial hyperglycemia, have a high protein binding rate, do not accumulate in tissues, and have good safety. Repaglinide can be used alone as a first-line antidiabetic drug, or it can be combined with other hypoglycemic agents to increase the efficacy and provide a new means for the treatment of type II diabetes.

The ritiglinide can be prepared by condensing and hydrolyzing the compound of the formula (I) with the compound of the formula (VIII), and compared with the methods reported in various literatures (for example, US5312924 or CN1571769), It has the advantages of short reaction time, low toxicity, environmental protection, etc. Therefore, the compound of formula (I) is a key intermediate for the development of repaglinide.

 (1) (VIII) It is therefore of great significance and value to develop a new preparation method for the compound of formula (I). The invention provides a new preparation method, which has the advantages of short reaction time, high yield, low toxicity, low risk, simple operation, etc., and is a process route with good industrialization prospects. Summary of the invention

 It is an object of the present invention to provide a process for the preparation of repaglinide intermediates which are high in yield and suitable for industrial applications.

 The invention discloses a preparation method for preparing the repaglinide intermediate represented by the formula (I).

 (I)

The method includes:

(1) o-chlorobenzaldehyde and a Grignard reagent of the formula (II) are reacted in the presence of a metal salt to form a compound of the formula (III),

 (III)

 (2) A compound of formula (III) is reacted in the presence of an oxidizing agent to form a compound of formula (IV)

 (III) (IV)

 (3) The compound of formula (IV) is condensed with piperidine under closed, high temperature conditions to form a compound of formula (V).

(IV)

 The compound of the formula (V) is reacted with 4-methoxybenzylamine in the presence of an acid catalyst to form a compound of the formula (VI) which is subjected to a reduction reaction in the presence of a reducing agent to form a compound of the formula (VII).

(5) The compound of formula (VII) is resolved with an acid resolving agent to form a compound of formula (I).

Wherein, the steps in the present scheme are further optimized. In the preparation of the compound of the formula (III), the metal salt used is selected from the group consisting of cuprous halides such as cuprous chloride, cuprous bromide or cuprous iodide. Copper bromide is preferred.

 Further optimizing the steps in this scheme, in the preparation of the compound of the formula σν), the oxidizing agent used is chromium trioxide.

 Further optimizing the steps in the present scheme, in the preparation of the compound of the formula (V), the reaction is carried out in a closed autoclave, and the temperature of the reaction is controlled at 100 ° C to 180 ° C, preferably 150 ° C to 180 ° C.

 Further optimizing the steps in the present scheme, in the preparation of the compound of the formula (VII), the acid catalyst used in the reaction is p-toluenesulfonic acid, and the reducing agent is selected from lithium borohydride, sodium borohydride, potassium borohydride or lithium aluminum hydride. Sodium borohydride is preferred.

 In the present embodiment, the "acid dissolving agent" is an optically pure and acidic resolving agent such as L-tartaric acid, L-mandelic acid, N-acetyl-L-glutamic acid, etc., preferably L-mandelic acid . detailed description

 In order to explain the present invention in more detail, the following preparation examples are given. However, the scope of the invention is not limited thereto. Embodiment 1

 Preparation of 1-(2-chlorophenyl)-3-methylbutanol

 Method A

Magnesium turnings (12 Kg), THF (300 L) and isobutyl bromide (7.3 L, 1.26 g/ml) were added to a 500 L reactor, and the reaction was initiated by heating, and the remaining isobutyl bromide (80 L) was added dropwise. After the addition is completed, the reaction is continued for 40 minutes, cooled, and the reaction solution is transferred to a freezer, and the temperature is lowered to below 10 ° C, and hexamethylphosphoramide (33 L) and cuprous bromide (1.25 Kg) are added and stirred. A mixture of o-chlorobenzaldehyde (40 Kg) and THF (40 L) was added dropwise, and the reaction was kept for 2 hours. Diluted hydrochloric acid was added to the reaction mixture to adjust the pH = 1 to 2, and extracted with ethyl acetate. Washed, dried, and concentrated in oil: 56 Kg ₀ ESI-MS (m/z): 198.5 ([M+H])

Method B

The same preparation method as Method A was employed except that isobutyl bromide was changed to isobutyl chloride. Embodiment 2

 Preparation of 1-(2-chlorophenyl)-3-methyl-1-butanone

 Add chromium trioxide (84 Kg) and glacial acetic acid (250 L) to a 500 L reactor, cool to about 0 ° C, add the first intermediate (56 Kg), and add 10% hydrochloric acid (20 L) after the dropwise addition. Stirring was continued overnight, water was added to the reaction mixture, and the mixture was adjusted to pH = 9 with potassium carbonate, extracted with petroleum ether, combined, washed with water, dried and concentrated to give an oil: 28 Kg. ESI-MS (m/z): 196.5 ([M+H])

Embodiment 3

 Preparation of 3-methyl-1-[2-(1-piperidyl)phenyl]-1-butanone

 The intermediates (28 Kg), hexahydropyridine (70 L) and potassium carbonate (42 Kg) were placed in an autoclave, and the temperature was raised to an internal temperature of 180 ° C. The reaction was stirred for 5 hours, cooled to room temperature, and petroleum ether was used. Extraction, the aqueous phase was back-purified with petroleum ether, combined organic layers, washed with water, dried and concentrated to dry oil: 33 Kg. ESI-MS (m/z): 246.0 ([M+H])

Example 4

 Preparation of (4-methoxyphenyl)-N-(3-methyl-1-(2-(1-piperidinyl)phenyl)butylene)methylamine

 The third intermediate (33 Kg), toluene (300 L), p-toluenesulfonic acid (3.3 Kg), 4-methoxybenzylamine (44.6 Kg) was placed in a reaction kettle, and refluxed for five hours. Anhydrous sodium sulfate (16 Kg) was added and the reaction was continued overnight. On the next day, the reaction solution was cooled to room temperature, washed with EtOAc EtOAc (EtOAc) : 80.8 Kg.

 TLC: petroleum ether / ethyl acetate = 20 / l, Rf intermediate = 0.7, Rf product = 0.3 Example 5

Preparation of N-(4-methoxybenzyl)-3-methyl-1-[2-(1-piperidinyl)phenyl]-1-butylamine Example 4 Intermediate (80.8 Kg), Methanol (300 L), nickel chloride hexahydrate (70 Kg) input In the reaction vessel, it was cooled to 0 °C. Sodium borohydride (45.7 Kg) was added in portions below 0 Torr. The color of the reaction solution turned black, and a large amount of air bubbles were generated, and the heat release was remarkable. After the addition, the temperature was naturally raised for five hours. The reaction mixture was adjusted to pH=1~2 with concentrated hydrochloric acid, then EtOAc (EtOAc (EtOAc) (EtOAc) : 35.5 Kgo ESI-MS (m/z): 367.0 ([M+H]) Developer: petroleum ether / ethyl acetate = 3 / l, Rf intermediate = 0.9, Rf product = 0.6 Example 6

 (S)-N-(4-Methoxybenzyl)-3-methyl- 1-[2-(1-piperidinyl)phenyl]-1-butanamine Preparation

 A mixed solvent (170 L) of the intermediate of Example 5 (35.5 Kg), L-mandelic acid (14.8 Kg), and isopropanol/water (1:1) was placed in the reaction vessel, heated to reflux, and dissolved, naturally. Place the crystallization, filter, and dry to obtain a crude product: 31.9 Kg;

 The upper solid is put into the reaction vessel, and a mixed solvent of methanol/water (1:1) is added (260

L) Heating to reflux, crystallization, natural crystallization, filtration, and drying to give a solid: 15.3 Kg.

 Sodium hydroxide (1.2 Kg) and purified water (10 L) were placed in a 200 L reaction vessel, toluene (80 L) and solid (15.Kg) were added, and the reaction was stirred at room temperature for 45 minutes.

 The layers were separated, and the organic layer was washed with water (li. After filtration, the filtrate was concentrated to dryness to give the title compound. According to the prior art identification method, it is understood that the compound of the formula (I) obtained in the examples of the present invention is the target compound.

Claims

Claims: 1. A method of preparing a repaglinide intermediate of the formula (I),

Including the following steps:  (1) o-chlorobenzaldehyde and a Grignard reagent of the formula (Π) are reacted in the presence of a metal salt to form a compound of the formula (III), '

 (III)  (2) a compound of formula (III) is reacted in the presence of an oxidizing agent to form a compound of formula (IV),

 (III) (IV)  (3) a compound of formula (IV) is condensed with piperidine under closed, high temperature conditions to form a compound of formula (V),

(IV) (4) a compound of the formula (V) and a 4-methoxybenzylamine are condensed in the presence of an acid catalyst to form a compound of the formula (VI), which is reduced in the presence of a reducing agent to form a compound of the formula (VII).

 (5) The compound of the formula (VII) is resolved with an acid resolving agent to obtain a compound of the formula (I), wherein  X is a halogen atom;  The metal salt is selected from the group consisting of cuprous chloride, cuprous bromide or cuprous iodide;  The oxidizing agent is selected from potassium permanganate or chromium trioxide;  The reducing agent is selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride or lithium aluminum hydride. The process according to claim 1, wherein X is a chlorine atom or a bromine atom. 3. A process according to claim 2, characterized in that X is a bromine atom. The process according to claim 1, wherein in the preparation of the compound of the formula, the metal salt is cuprous bromide. The process according to claim 1, wherein in the preparation of the compound of the formula (W), the oxidizing agent is chromium trioxide. The process according to claim 1, wherein in the preparation of the compound of the formula (V), the reaction temperature is controlled to be from 100 ° C to 180 ° C. 7. The production method according to claim 6, wherein the reaction temperature is from 150 ° C to 180 ° C. 8. The preparation method according to claim 1, wherein in the preparation of the formula (VII) In the case of the compound, the acid catalyst used is p-toluenesulfonic acid; and the reducing agent is sodium borohydride.  The process according to claim 1, characterized in that in the preparation of the compound of the formula (I), the acid resolving agent used is selected from the group consisting of L-tartaric acid or L-mandelic acid.  10. The preparation method according to claim 9, wherein the acid resolving agent is L-