CN101781272A - Method for preparing repaglinide amine and intermediate thereof - Google Patents
Method for preparing repaglinide amine and intermediate thereof Download PDFInfo
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- CN101781272A CN101781272A CN201010110353A CN201010110353A CN101781272A CN 101781272 A CN101781272 A CN 101781272A CN 201010110353 A CN201010110353 A CN 201010110353A CN 201010110353 A CN201010110353 A CN 201010110353A CN 101781272 A CN101781272 A CN 101781272A
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Abstract
The invention discloses a method for preparing repaglinide amine (a compound 1), which comprises the step of performing a reaction of removing a protective group (PG) of the amino-group on a compound 2, wherein the protective group (PG) is a conventional amino-protecting group, such as the carbonic ester protective group or the sulfonyl protective group. The invention also relates to an intermediate compound 2, 3, 4 or 5 for preparing the repaglinide amine (the compound 1). The preparation method of the invention has the advantages of lower cost, mild reaction conditions, easy operation and easy realization of the industrial production.
Description
Technical field
The present invention is specifically related to a kind of Preparation Method And Their Intermediate of repaglinide amine.
Background technology
Repaglinide is that the novel non-sulfonylurea Regular Insulin of U.S. FDA approval first in 1998 discharges promotor.This medicine convenient oral, dosage is little, and side effect is little, in the listing of a plurality of countries, can be used as the first-line treatment medicine of type ii diabetes.Repaglinide amine ((S)-sec.-propyl-(2-piperidines) phenyl-methylamine) is the key intermediate of synthetic repaglinide.
The chemistry of repaglinide is by name: (S)-2-oxyethyl group-4-[2-((3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl) amino-2-oxygen ethyl] phenylformic acid, structural formula is as follows:
Repaglinide (Repaglinide)
Several representational synthetic routes of repaglinide amine are at document J.Med.Chem.1998, detailed introduction are arranged in 5219.Concluding has the chirality of chirality prothetic group control synthetic basically, and catalysis asymmetric synthesis and chemistry fractionation wait several method.These methods all have the shortcoming that is difficult to overcome, and as the method for chirality prothetic group, the raw material costliness particularly will be used high-pressure hydrogenation, danger close during apo-; The asymmetry catalysis raw material sources are difficult for, severe reaction conditions; The kinetic resolution yield is not high.
People such as Wang Ensi are synthetic in 2000 (Jilin University's natural science journal 2000,4,83) report racemization repaglinide, and yield is not high also will to be split.
Chinese patent CN 1660826 has reported with the chirality boric acid ester to be the asymmetric synthesis repaglinide amine of raw material.This route has used the starting raw material of unstable costliness, and the result of chiral induction also has only the enantiomeric excess more than 80, also wants twice hydrogenation in the reaction.
Summary of the invention
Technical problem to be solved by this invention is that cost is higher among the preparation method who overcomes existing repaglinide amine, poor stability, and severe reaction conditions, defective such as yield is lower, and a kind of Preparation Method And Their Intermediate of repaglinide amine is provided.Preparation method of the present invention is different fully with the preparation method of existing repaglinide amine, and cost is lower, the reaction conditions gentleness, and aftertreatment is simple, and easy handling is easy to realize suitability for industrialized production.
The present invention relates to the preparation method of a kind of repaglinide amine (compound 1), the reaction that it comprises the following steps: compound 2 is carried out the protecting group (PG) of deaminize gets final product;
Wherein, protecting group PG is conventional amino protecting group, as carbonates protecting group or sulphonyl base class protecting group, and wherein said carbonates protecting group preferred tertiary butoxy carbonyl (Boc) or carbobenzoxy-(Cbz) (Cbz); The described preferred methylsulfonyl of sulphonyl base class protecting group (Ms), benzenesulfonyl (Bs) or p-toluenesulfonyl (Ts); Best, protecting group PG is tertbutyloxycarbonyl (Boc) or p-toluenesulfonyl (Ts).
Wherein, the method for the reaction of the protecting group of described deaminize (PG) and condition all can be the ordinary method and the condition of this type of reaction of this area.
As, when PG is tertbutyloxycarbonyl, slough the method and the condition of the tertbutyloxycarbonyl protecting group of the method for reaction of tertbutyloxycarbonyl and the deaminize that condition all can be this area routine; Preferable methods and condition are as follows: in the organic solvent, compound 2 reacts under lewis acidic effect, gets final product.That wherein, described organic solvent is preferable is C
1-C
6Alkyl alcohol, ethyl acetate, tetrahydrofuran (THF) and toluene in one or more; That better is C
1-C
3Alkyl alcohol, ethyl acetate and tetrahydrofuran (THF) in one or more; The volume mass of organic solvent and compound 2 than preferable be 5～25ml/g; Described Lewis acid is preferable is in tosic acid, methanesulfonic, acetic acid, propionic acid, trifluoracetic acid, phenylformic acid, p-nitrobenzoic acid, formic acid, hydrochloric acid and the dilute sulphuric acid one or more, preferred tosic acid, methanesulfonic and trifluoracetic acid; Described lewis acidic consumption is preferable is 0.05～2 times of compound 2 molar weights, and better is 0.1～0.3 times; What the temperature of described reaction was preferable is 0～80 ℃, and better is 0～25 ℃; The time of described reaction preferable with detection reaction fully till, be generally 1～24 hour.
And for example, when PG is p-toluenesulfonyl, slough the method and the condition of the tosyl group protecting group of the method for reaction of tosyl group and the deaminize that condition all can be this area routine; Preferable methods and condition are as follows: in the organic solvent, compound 2 reacts under the effect of MAGNESIUM METAL, gets final product.That wherein, described organic solvent is preferable is C
1-C
6Alkyl alcohol, ethyl acetate, tetrahydrofuran (THF) and toluene in one or more, that better is C
1-C
3Alkyl alcohol; The volume mass of organic solvent and compound 2 than preferable be 5～25ml/g; The consumption of described MAGNESIUM METAL is preferable is 2～10 times of compound 2 molar weights, and better is 1～4 times; What the temperature of described reaction was preferable is 0～80 ℃, and better is 0～25 ℃; The time of described reaction preferable with detection reaction fully till, be generally 1～24 hour.
Among the present invention, described compound 2 can be made by following method: compound 3 and piperidines are carried out nucleophilic substitution reaction, get final product;
Wherein, the definition of protecting group PG is ditto described.
Wherein, the method for described nucleophilic substitution reaction and condition all can be the ordinary method and the condition of this type of reaction of this area.Preferred especially following method of the present invention and condition: in the solvent, under the effect of alkali, compound 3 and piperidines are carried out nucleophilic substitution reaction, get final product; Wherein, described preferred solvents be high boiling solvent, as methyl-sulphoxide, dimethylbenzene, N, in dinethylformamide and the methyl-phenoxide one or more, preferred methyl-sulphoxide and/or N, dinethylformamide, the volume mass of solvent and compound 3 than preferable be 5～25ml/g; That used alkali is preferable is salt of wormwood, yellow soda ash, triethylamine, pyridine and 4-N, one or more in the N-lutidine, preferred salt of wormwood and/or 4-N, N-lutidine; The consumption of alkali is preferable is 1～10 times of molar weight of compound 3, and better is 2～5 times; The consumption of piperidines is preferable is 1～10 times of molar weight of compound 3, and better is 1.5～5 times; The time of described reaction preferable with detection reaction fully till, be generally 12～24 hours; What the temperature of described reaction was preferable is 100～200 ℃, and better is 150～180 ℃.
Among the present invention, described compound 3 can be made by following method: compound 4 and sec.-propyl grignard reagent are carried out ring-opening reaction, get final product;
Wherein, the definition of protecting group PG is ditto described.
Wherein, the method of described ring-opening reaction and condition all can be the ordinary method and the condition of this type of reaction, preferred especially following method of the present invention and condition: in the solvent, under mantoquita catalysis, reaction with compound 4 and sec.-propyl Grignard reagent are opened the azepine triatomic ring gets final product; Wherein, described preferred solvents be tetrahydrofuran (THF), ether, methylene dichloride, 1,2-ethylene dichloride, acetonitrile, C
1-C
4Alkyl alcohol, toluene, ethyl acetate, dimethyl formamide, methyl-sulphoxide and dimethylbenzene in one or more, preferred tetrahydrofuran (THF) and/or ether, the volume mass of solvent and compound 4 than preferable be 5～25ml/g; Described sec.-propyl Grignard reagent is preferable is in isopropylmagnesium chloride, sec.-propyl bromination magnesium and the sec.-propyl iodate magnesium one or more, preferred isopropylmagnesium chloride; The consumption of sec.-propyl Grignard reagent is preferable is 1～10 times of molar weight of compound 4, and better is 2～5 times; What described mantoquita was preferable is cuprous salt, as in cuprous chloride, cuprous bromide, cuprous iodide and the cuprous cyanide one or more, and preferred cuprous iodide and/or cuprous cyanide; The consumption of mantoquita is preferable is 0.1～2 times of molar weight of compound 4, and better is 0.1～0.5 times; What the temperature of described reaction was preferable is 0～100 ℃, preferred 0～30 ℃; The time of described reaction preferable with detection reaction fully till, be generally 1～24 hour.
Among the present invention, the preparation of described compound 4 can be with reference to existing method: Zhejiang Academy of Medical Sciences journal 2,007 63,3,26. and Molecules 2002,902; Synthetic route is as follows:
This synthetic route is a starting raw material with cheap o-chlorobenzene glycine, protection amino after the chiral separation, and the reduction carboxyl arrives alcohol, closes to encircle to obtain chirality Chloro-O-Phenyl azepine triatomic ring (compound 4).
Among the preparation method of the present invention, each optimum condition is arbitrary combination without prejudice to the field on the basis of common sense, promptly gets each preferred embodiments of the present invention.
The invention still further relates to the midbody compound 2,3,4 or 5 of preparation repaglinide amine (compound 1);
Wherein, the definition of protecting group PG is ditto described.
Except that specified otherwise, raw material that the present invention relates to and reagent are all commercially available to be got.
Positive progressive effect of the present invention is:
1, among the preparation method of the present invention, o-chlorobenzene glycine (compound 8) is cheap, and fractionation can suitability for industrialized production, technical maturity, and it is low to split cost, and its another enantiomer after splitting can be used as the raw material of chiral drug clopidogrel.
2, among the preparation method of the present invention, used reaction all is classical organic reaction, and intermediate substantially all is a solid, is easy to purifying, and is environmentally friendly.
3, among the preparation method of the present invention, the reaction conditions gentleness, aftertreatment is simple, and easy handling is beneficial to suitability for industrialized production.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Embodiment 1
In the 500ml exsiccant four-hole bottle; the Chloro-O-Phenyl azepine triatomic ring 15.4g (50mmol) that adds anhydrous tetrahydro furan 250ml and (R)-N-p-toluenesulfonyl protection; cuprous iodide 15g (79mmol); 25 degree drip the isopropylmagnesium chloride tetrahydrofuran solution 60ml of 1M down; finish; being stirred to the TLC demonstration reacts completely; pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 15g (43mmol), is directly used in next step reaction.15g (43mmol) open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g (109mmol), piperidinyl-1 5g (176mmol), heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and residuum is dissolved in the methyl alcohol, add 24g magnesium powder, reflux is stirred to the TLC demonstration and reacts completely, filter, concentrate, underpressure distillation gets the about 8g of product, three-step reaction total recovery: 65%.Product HPLC purity is greater than 99%.
Compound 1 spectroscopic data is as follows:
1H?NMR(500M，CDCl
3)δ：0.83(d，J＝6.4Hz，3H)，0.88(d，J＝6.4Hz，3H)，1.47-1.52(m，1H)，1.56-1.63(m，2H)，1.65-1.72(m，6H)，4.28-4.35(m，4H)，4.74-4.78(m，1H)，6.99-7.20(m，4H).
MS(M
++1)：247.3
Embodiment 2
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 15.4g (50mmol) of anhydrous diethyl ether 250ml and (R)-N-p-toluenesulfonyl protection, cuprous iodide 15g; 25 degree drip the isopropylmagnesium chloride diethyl ether solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 15g, is directly used in next step reaction.The 15g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and residuum is dissolved in the methyl alcohol, add 24g magnesium powder, reflux is stirred to the TLC demonstration and reacts completely, filter, concentrate, underpressure distillation gets the about 8g of product, three-step reaction total recovery: 65%.Product HPLC purity is greater than 99%.
Compound 1 spectroscopic data is with embodiment 1.
Embodiment 3
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 15.4g (50mmol) of anhydrous tetrahydro furan 250ml and (R)-N-p-toluenesulfonyl protection, cuprous cyanide 15g (167mmol); 25 degree drip the isopropylmagnesium chloride tetrahydrofuran solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 15g, is directly used in next step reaction.The 15g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and residuum is dissolved in the methyl alcohol, add 24g magnesium powder, reflux is stirred to the TLC demonstration and reacts completely, filter, concentrate, underpressure distillation gets the about 8g of product, three-step reaction total recovery: 65%.Product HPLC purity is greater than 99%.
Compound 1 spectroscopic data is with embodiment 1.
Embodiment 4
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 15.4g (50mmol) of anhydrous tetrahydro furan 250ml and (R)-N-p-toluenesulfonyl protection, cuprous cyanide 15g; 25 degree drip the isopropylmagnesium chloride tetrahydrofuran solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 15g, is directly used in next step reaction.The 15g open-loop products is dissolved in the 250ml dimethyl formamide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and residuum is dissolved in the methyl alcohol, add 24g magnesium powder, reflux is stirred to the TLC demonstration and reacts completely, filter, concentrate, underpressure distillation gets the about 8g of product, three-step reaction total recovery: 65%.Product HPLC purity is greater than 99%.
Compound 1 spectroscopic data is with embodiment 1.
Embodiment 5
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 12.7g (50mmol) of anhydrous tetrahydro furan 250ml and (R)-N-tertbutyloxycarbonyl protection, cuprous iodide 15g; 25 degree drip the isopropylmagnesium chloride tetrahydrofuran solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 13.5g (45mmol), is directly used in next step reaction.The 13.5g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g (109mmol), piperidinyl-1 5g (176mmol), heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and residuum is dissolved in the methyl alcohol, add tosic acid 2g, be stirred to the TLC demonstration and react completely, filter, concentrate, underpressure distillation gets the about 8.5g of product, three-step reaction total recovery: 69%.Product HPLC purity is greater than 99%.
Compound 1 spectroscopic data is with embodiment 1.
Embodiment 6
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 12.7g (50mmol) of anhydrous tetrahydro furan 250ml and (R)-N-tertbutyloxycarbonyl protection, cuprous cyanide 15g; 25 degree drip the isopropylmagnesium chloride tetrahydrofuran solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 13.5g, is directly used in next step reaction.The 13.5g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and residuum is dissolved in the methyl alcohol, add trifluoracetic acid 2g, the 0-5 degree is stirred to the TLC demonstration and reacts completely, and filters, and concentrates, underpressure distillation gets the about 9g of product, three-step reaction total recovery: 73%.Product HPLC purity is greater than 99%.
Compound 1 spectroscopic data is with embodiment 1.
Embodiment 7
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 12.7g (50mmol) of anhydrous tetrahydro furan 250ml and (R)-N-tertbutyloxycarbonyl protection, cuprous cyanide 15g; 25 degree drip the isopropylmagnesium chloride tetrahydrofuran solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 13.5g, is directly used in next step reaction.The 13.5g open-loop products is dissolved in the 250ml dimethyl formamide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and residuum is dissolved in the methyl alcohol, add methanesulfonic 3g, be stirred to the TLC demonstration under the 20-25 degree and react completely, filter, concentrate, underpressure distillation gets the about 8g of product, three-step reaction total recovery: 65%.Product HPLC purity is greater than 99%.
Compound 1 spectroscopic data is with embodiment 1.
Embodiment 8
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 12.7g (50mmol) of anhydrous diethyl ether 250ml and (R)-N-tertbutyloxycarbonyl protection, cuprous iodide 15g; 25 degree drip the isopropylmagnesium chloride diethyl ether solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 13.5g, is directly used in next step reaction.The 13.5g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and residuum is dissolved in the methyl alcohol, add tosic acid 10g, be stirred to the TLC demonstration under the 20-25 degree and react completely, filter, concentrate, underpressure distillation gets the about 8.5g of product, three-step reaction total recovery: 69%.Product HPLC purity is greater than 99%.
Spectroscopic data is with embodiment 1.
Embodiment 9
The fractionation of o-chlorobenzene glycine can be according to document Zhejiang Academy of Medical Sciences journal 2,007 63,3,26..Be dissolved in 1 premium on currency and the acetone splitting good o-chlorobenzene glycine 185.6g, add solid sodium bicarbonate 500g, N, N-lutidine 10g, Tosyl chloride 230g, react under the room temperature to the raw material disappearance, filter, concentrate acetone, residuum transfers to pH＜3 with concentrated hydrochloric acid, ethyl acetate extraction, conventional aftertreatment obtains 330g compound 6a.The compound 6a that obtains is dissolved in the tetrahydrofuran (THF), and 10 degree are added drop-wise to the tetrahydrofuran solution usefulness that contains borine down, drip and finish, and room temperature reaction to raw material disappears, and conventional aftertreatment gets 260g compound 5a.The compound 5a that obtains is obtained compound 4a according to the method pass ring that document Molecules 2002,902. provides.
Compound 4a spectroscopic data is as follows:
1H?NMR(400M，CDCl
3)δ：7.89(2H，d，J＝8.0Hz)，7.34(2H，d，J＝8.0Hz)，7.35-7.30(1H，m)，7.21-7.16(3H，m)，4.04(1H，dd，J＝4.4，6.9Hz)，3.02(1H，d，J＝7.0Hz)，2.43(3H，s)，2.28(1H，d，J＝4.3Hz).
Embodiment 10
The fractionation of o-chlorobenzene glycine can be according to document Zhejiang Academy of Medical Sciences journal 2,007 63,3,26..Be dissolved in l premium on currency and the acetone splitting good o-chlorobenzene glycine 185.6g, add solid sodium bicarbonate 500g, Boc acid anhydrides 250g, react under the room temperature to the raw material disappearance, filter, concentrate acetone, residuum transfers to pH=3-5 with concentrated hydrochloric acid, ethyl acetate extraction, conventional aftertreatment obtains 270g compound 6b.The compound 6b that obtains is dissolved in the tetrahydrofuran (THF), and 10 degree are added drop-wise to the tetrahydrofuran solution usefulness that contains borine down, drip and finish, and room temperature reaction to raw material disappears, and conventional aftertreatment gets 230g compound 5b.The compound 5b that obtains is obtained compound 4b according to the method pass ring that document Molecules 2002,902. provides.
Embodiment 11
In the 500ml exsiccant four-hole bottle; add anhydrous 1; the Chloro-O-Phenyl azepine triatomic ring 15.4g (50mmol) of 2-ethylene dichloride 250ml and (R)-N-p-toluenesulfonyl protection; cuprous iodide 5mmol; 0 ℃ of sec.-propyl bromination magnesium tetrahydrofuran solution (50mmol) that drips 1M down; finish; being stirred to the TLC demonstration reacts completely; pour the reaction of going out of coming together in the frozen water into, separatory, water extraction; merge organic phase; the washing after drying concentrates, and the residuum recrystallization gets open-loop products 15g (43mmol), is directly used in next step reaction.15g (43mmol) open-loop products is dissolved in the 250ml methyl-sulphoxide, adds triethylamine (43mmol), piperidinyl-1 5g (43mmol), 100 ℃ are reacted to the disappearance of TLC demonstration raw material, pour in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and gets pure compound 2a, 2a (40mmol) is dissolved in the tetrahydrofuran (THF), adds magnesium powder (80mmol), 0 ℃ is stirred to the TLC demonstration and reacts completely, filter, concentrate, underpressure distillation gets product, three-step reaction total recovery: 64%.Product HPLC purity is greater than 99%.
Compound 1 spectroscopic data is with embodiment 1.
Embodiment 12
In the 500ml exsiccant four-hole bottle; the Chloro-O-Phenyl azepine triatomic ring 15.4g (50mmol) that adds dry toluene 250ml and (R)-N-p-toluenesulfonyl protection; cuprous iodide 100mmol; 25 ℃ of sec.-propyl iodate magnesium tetrahydrofuran solutions (500mmol) that drip 1M down; finish; being heated to 100 ℃ is stirred to TLC and shows and to react completely; pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 15g (43mmol), is directly used in next step reaction.15g (43mmol) open-loop products is dissolved in the 250ml methyl-sulphoxide, adds pyridine (430mmol), piperidines (430mmol), 100 ℃ are reacted to the disappearance of TLC demonstration raw material, pour in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and gets pure compound 2a, 2a (40mmol) is dissolved in the ethyl acetate, adds magnesium powder (400mmol), 80 ℃ are stirred to the TLC demonstration and react completely, filter, concentrate, underpressure distillation gets product, three-step reaction total recovery: 63%.Product HPLC purity is greater than 99%.
Compound 1 spectroscopic data is with embodiment 1.
Embodiment 13
In the 500ml exsiccant four-hole bottle; the Chloro-O-Phenyl azepine triatomic ring 15.4g (50mmol) that adds anhydrous dimethyl sulfoxide 250ml and (R)-N-p-toluenesulfonyl protection; cuprous iodide 100mmol; 25 ℃ of isopropylmagnesium chloride tetrahydrofuran solutions (250mmol) that drip 1M down; finish; being heated to 100 ℃ is stirred to TLC and shows and to react completely; pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 15g (43mmol), is directly used in next step reaction.15g (43mmol) open-loop products is dissolved in the 250ml methyl-sulphoxide, adds 4-N, N-lutidine (430mmol), piperidines (430mmol), 100 ℃ are reacted to the disappearance of TLC demonstration raw material, pour in the frozen water after the cooling, extraction merges organic phase, and the washing after drying concentrates, get pure compound 2a, 2a (40mmol) is dissolved in the toluene, add magnesium powder (240mmol), 40 ℃ are stirred to TLC and show and to react completely, and filter, and concentrate, underpressure distillation gets product, three-step reaction total recovery: 63%.Product HPLC purity is greater than 99%.
Compound 1 spectroscopic data is with embodiment 1.
Embodiment 14
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 12.7g (50mmol) of anhydrous diethyl ether 250ml and (R)-N-tertbutyloxycarbonyl protection, cuprous iodide 15g; 25 degree drip the isopropylmagnesium chloride diethyl ether solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 13.5g (45.3mmol), is directly used in next step reaction.The 13.5g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and gets pure compound 2b, 2b (40mmol) is dissolved in the ethyl acetate, adds p-nitrobenzoic acid (2mmol), 0 ℃ is stirred to the TLC demonstration and reacts completely, filter, concentrate, underpressure distillation gets product, three-step reaction total recovery: 68%.Product HPLC purity is greater than 99%.
The spectroscopic data of compound 1 is with embodiment 1.
Embodiment 15
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 12.7g (50mmol) of anhydrous diethyl ether 250ml and (R)-N-tertbutyloxycarbonyl protection, cuprous iodide 15g; 25 degree drip the isopropylmagnesium chloride diethyl ether solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 13.5g (45.3mmol), is directly used in next step reaction.The 13.5g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and gets pure compound 2b, 2b (40mmol) is dissolved in the toluene, adds acetic acid (80mmol), 80 ℃ are stirred to the TLC demonstration and react completely, filter, concentrate, underpressure distillation gets product, three-step reaction total recovery: 68%.Product HPLC purity is greater than 99%.
The spectroscopic data of compound 1 is with embodiment 1.
Embodiment 16
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 12.7g (50mmol) of anhydrous diethyl ether 250ml and (R)-N-tertbutyloxycarbonyl protection, cuprous iodide 15g; 25 degree drip the isopropylmagnesium chloride diethyl ether solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 13.5g (45.3mmol), is directly used in next step reaction.The 13.5g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and gets pure compound 2b, 2b (40mmol) is dissolved in the tetrahydrofuran (THF), adds propionic acid (40mmol), 40 ℃ are stirred to the TLC demonstration and react completely, filter, concentrate, underpressure distillation gets product, three-step reaction total recovery: 67%.Product HPLC purity is greater than 99%.
The spectroscopic data of compound 1 is with embodiment 1.
Embodiment 17
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 12.7g (50mmol) of anhydrous diethyl ether 250ml and (R)-N-tertbutyloxycarbonyl protection, cuprous iodide 15g; 25 degree drip the isopropylmagnesium chloride diethyl ether solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 13.5g (45.3mmol), is directly used in next step reaction.The 13.5g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and gets pure compound 2b, 2b (40mmol) is dissolved in the methyl alcohol, adds hydrochloric acid (40mmol), 40 ℃ are stirred to the TLC demonstration and react completely, filter, concentrate, underpressure distillation gets product, three-step reaction total recovery: 67%.Product HPLC purity is greater than 99%.
The spectroscopic data of compound 1 is with embodiment 1.
Embodiment 18
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 12.7g (50mmol) of anhydrous diethyl ether 250ml and (R)-N-tertbutyloxycarbonyl protection, cuprous iodide 15g; 25 degree drip the isopropylmagnesium chloride diethyl ether solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 13.5g (45.3mmol), is directly used in next step reaction.The 13.5g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and gets pure compound 2b, 2b (40mmol) is dissolved in the methyl alcohol, adds phenylformic acid (40mmol), 40 ℃ are stirred to the TLC demonstration and react completely, filter, concentrate, underpressure distillation gets product, three-step reaction total recovery: 67%.Product HPLC purity is greater than 99%.
The spectroscopic data of compound 1 is with embodiment 1.
Embodiment 19
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 12.7g (50mmol) of anhydrous diethyl ether 250ml and (R)-N-tertbutyloxycarbonyl protection, cuprous iodide 15g; 25 degree drip the isopropylmagnesium chloride diethyl ether solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 13.5g (45.3mmol), is directly used in next step reaction.The 13.5g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and gets pure compound 2b, 2b (40mmol) is dissolved in the propyl alcohol, adds formic acid (40mmol), 40 ℃ are stirred to the TLC demonstration and react completely, filter, concentrate, underpressure distillation gets product, three-step reaction total recovery: 67%.Product HPLC purity is greater than 99%.
The spectroscopic data of compound 1 is with embodiment 1.
Embodiment 20
In the 500ml exsiccant four-hole bottle, add the Chloro-O-Phenyl azepine triatomic ring 12.7g (50mmol) of anhydrous diethyl ether 250ml and (R)-N-tertbutyloxycarbonyl protection, cuprous iodide 15g; 25 degree drip the isopropylmagnesium chloride diethyl ether solution 60ml of 1M down; finish, be stirred to the TLC demonstration and react completely, pour the reaction of going out of coming together in the frozen water into; separatory; the water extraction merges organic phase, and the washing after drying concentrates; the residuum recrystallization gets open-loop products 13.5g (45.3mmol), is directly used in next step reaction.The 13.5g open-loop products is dissolved in the 250ml methyl-sulphoxide, adds salt of wormwood 15g, piperidinyl-1 5g, heating reflux reaction shows that to TLC raw material disappears, and pours in the frozen water extraction after the cooling into, merge organic phase, the washing after drying concentrates, and gets pure compound 2b, 2b (40mmol) is dissolved in the methyl alcohol, adds the dilute sulphuric acid (40mmol) of massfraction 30%, 40 ℃ are stirred to the TLC demonstration and react completely, filter, concentrate, underpressure distillation gets product, three-step reaction total recovery: 67%.Product HPLC purity is greater than 99%.
The spectroscopic data of compound 1 is with embodiment 1.
Claims (10)
1. the preparation method of a repaglinide amine as shown in Equation 1 is characterized in that comprising the following steps: compound 2 is carried out the reaction of the protecting group PG of deaminize, gets final product;
Wherein, protecting group PG is conventional amino protecting group.
2. preparation method as claimed in claim 1 is characterized in that: described protecting group PG is carbonates protecting group or sulphonyl base class protecting group.
3. preparation method as claimed in claim 2 is characterized in that: described carbonates protecting group is tertbutyloxycarbonyl or carbobenzoxy-(Cbz); Described sulphonyl base class protecting group is methylsulfonyl, benzenesulfonyl or p-toluenesulfonyl.
4. preparation method as claimed in claim 1 is characterized in that: when PG was tertbutyloxycarbonyl, the method for the reaction of the protecting group PG of described deaminize was as follows: in the organic solvent, compound 2 reacts under lewis acidic effect, gets final product; Wherein, described organic solvent is C
1-C
6Alkyl alcohol, ethyl acetate, tetrahydrofuran (THF) and toluene in one or more; Described Lewis acid is one or more in tosic acid, methanesulfonic, acetic acid, propionic acid, trifluoracetic acid, phenylformic acid, p-nitrobenzoic acid, formic acid, hydrochloric acid and the dilute sulphuric acid; Described lewis acidic consumption is 0.05～2 times of compound 2 molar weights; The temperature of described reaction is 0～80 ℃; The time of described reaction with detection reaction fully till.
5. preparation method as claimed in claim 1 is characterized in that: when PG was p-toluenesulfonyl, the method for the reaction of the protecting group PG of described deaminize was as follows: in the organic solvent, compound 2 reacts under the effect of MAGNESIUM METAL, gets final product; Wherein, described organic solvent is C
1-C
6Alkyl alcohol, ethyl acetate, tetrahydrofuran (THF) and toluene in one or more; The consumption of described MAGNESIUM METAL is 2～10 times of compound 2 molar weights; The temperature of described reaction is 0～80 ℃; The time of described reaction with detection reaction fully till.
6. preparation method as claimed in claim 1 is characterized in that: described compound 2 is made by following method: compound 3 and piperidines are carried out nucleophilic substitution reaction, get final product;
Wherein, the definition of protecting group PG such as claim 1 to 3 are described in each.
7. preparation method as claimed in claim 6 is characterized in that: described compound 2 is made by following method: in the solvent, under the effect of alkali, compound 3 and piperidines are carried out nucleophilic substitution reaction, get final product; Wherein, described solvent is a high boiling solvent; Described alkali is salt of wormwood, yellow soda ash, triethylamine, pyridine and 4-N, one or more in the N-lutidine; The consumption of alkali is 1～10 times of molar weight of compound 3; The consumption of piperidines is 1～10 times of molar weight of compound 3; The time of described reaction with detection reaction fully till; The temperature of described reaction is 100～200 ℃.
8. preparation method as claimed in claim 6 is characterized in that: described compound 3 is made by following method: compound 4 and sec.-propyl grignard reagent are carried out ring-opening reaction, get final product;
Wherein, the definition of protecting group PG such as claim 1 to 3 are described in each.
9. preparation method as claimed in claim 8 is characterized in that: described compound 3 is made by following method: in the solvent, under mantoquita catalysis, the reaction with compound 4 and sec.-propyl Grignard reagent are opened the azepine triatomic ring gets final product; Wherein, described solvent is tetrahydrofuran (THF), ether, methylene dichloride, 1,2-ethylene dichloride, acetonitrile, C
1～C
4Alkyl alcohol, toluene, ethyl acetate, dimethyl formamide, methyl-sulphoxide and dimethylbenzene in one or more; Described sec.-propyl Grignard reagent is one or more in isopropylmagnesium chloride, sec.-propyl bromination magnesium and the sec.-propyl iodate magnesium; The consumption of sec.-propyl Grignard reagent is 1～10 times of molar weight of compound 4; Described mantoquita is a cuprous salt; The consumption of mantoquita is 0.1～2 times of molar weight of compound 4; The temperature of described reaction is 0～100 ℃; The time of described reaction with detection reaction fully till.
10. the midbody compound 2,3,4 or 5 for preparing repaglinide amine;
Wherein, the definition of protecting group PG such as claim 1～3 are described in each.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659646A (en) * | 2012-04-26 | 2012-09-12 | 广东石油化工学院 | Method for preparing beta-amino-carbonyl compounds |
| CN102746312A (en) * | 2011-04-21 | 2012-10-24 | 上海药明康德新药开发有限公司 | Preparation method of oxalate and acetate of 2-oxa-6-aza-spiro[3, 3]heptane |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1305863C (en) * | 2004-12-27 | 2007-03-21 | 浙江大学 | Method for synthesizing (S)-isopropyl-(2-piperidine) phenyl-methylhistamine |
| US20070123564A1 (en) * | 2003-05-14 | 2007-05-31 | Rainer Heck | Method for preparing phenyl acetic acid derivatives |
| CN101481363A (en) * | 2008-01-10 | 2009-07-15 | 江苏豪森药业股份有限公司 | Method for preparing repaglinide |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070123564A1 (en) * | 2003-05-14 | 2007-05-31 | Rainer Heck | Method for preparing phenyl acetic acid derivatives |
| CN1305863C (en) * | 2004-12-27 | 2007-03-21 | 浙江大学 | Method for synthesizing (S)-isopropyl-(2-piperidine) phenyl-methylhistamine |
| CN101481363A (en) * | 2008-01-10 | 2009-07-15 | 江苏豪森药业股份有限公司 | Method for preparing repaglinide |
Non-Patent Citations (1)
| Title |
|---|
| 《Journal of Medicinal Chemistry》 19981203 Wolfgang Grell et al. Repaglinide and Related Hypoglycemic Benzoic Acid Derivatives 第5219-5246页 1-7 第41卷, 第26期 2 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746312A (en) * | 2011-04-21 | 2012-10-24 | 上海药明康德新药开发有限公司 | Preparation method of oxalate and acetate of 2-oxa-6-aza-spiro[3, 3]heptane |
| CN102659646A (en) * | 2012-04-26 | 2012-09-12 | 广东石油化工学院 | Method for preparing beta-amino-carbonyl compounds |
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