CN104557778A - Preparation method and application of repaglinide - Google Patents
Preparation method and application of repaglinide Download PDFInfo
- Publication number
- CN104557778A CN104557778A CN201510011786.1A CN201510011786A CN104557778A CN 104557778 A CN104557778 A CN 104557778A CN 201510011786 A CN201510011786 A CN 201510011786A CN 104557778 A CN104557778 A CN 104557778A
- Authority
- CN
- China
- Prior art keywords
- repaglinide
- preparation
- add
- reaction
- described step
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method and application of repaglinide. The preparation method comprises the following steps of neutralizing repagamine.N-acetyl-L-glutamic acid and alkali to obtain repagamine, acylating repagamine, condensing acylated repagamine and ethoxy-4-ethoxycarbonyl phenyl acetic acid to obtain an intermediate and hydrolyzing the intermediate to obtain the repaglinide. The preparation method has the advantages of low cost, high yield, simple process and the like and is more suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, particularly a kind of preparation method of repaglinide and application thereof.
Background technology
Chemistry (S)-2-ethyoxyl-4-by name [2-[[methyl isophthalic acid-[2-(piperidino) phenyl] butyl] the is amino]-2-oxoethyl] benzoic acid of repaglinide, it is a kind of novel orally-taken blood sugar reducing medicine, insulin secretion can be promoted, have and absorb fast, that action time is short feature, physiological insulin secretion can be simulated in patients with NIDDM, effective control postprandial hyperglycemia, there is higher protein binding rate, can not accumulate in the tissue, safety is good.Repaglinide both can be used alone as a line antidiabetic medicine, and also can increase curative effect with other antidiabetic drug use in conjunction, the treatment for type Ⅱdiabetes mellitus provides a kind of new means.
About the preparation method of repaglinide, many sections of documents have report.
Synthetic route 1: describe in " Jilin University's journal " with 4-cresotic acid, 2-6-chlorophenyl nitrile for raw material, adopts LDA/DMPU catalytic carboxylation and Ph
3the reaction of P catalyzing and condensing is committed step synthesis repaglinide, and total recovery is 10.5%; The following synthetic route 1 of technological process:
The people such as Tang He report o fluorobenzaldehyde and obtain 1-(2-fluorophenyl)-3-methyl butanol through grignard reaction in " Chinese Journal of Pharmaceuticals ", through obtained 1-(2-the fluorophenyl)-3-espeleton of NaOCl oxidation, again through piperidines aminolysis, become oxime NaBH
4obtained 3-methyl isophthalic acid-[2-(piperidino) phenyl] butylamine of reduction, split through N-acetyl-Pidolidone, solve repaglinide with 3-Ethoxy-4-ethoxycarbonylphenylacetic acid condensation water in carbon tetrachloride, triphenyl phasphine, total recovery is 9.5%; The following synthetic route 2 of technological process:
Synthetic route 1 reactions steps is long, and reactions steps is long, adopts LDA/DMPU catalytic carboxylation, and reaction condition carries out under-75 DEG C and nitrogen protection.Severe reaction conditions, and yield is low, is unfavorable for that industry is large and produces; Synthetic route 2 applies grignard reaction, NaOCl oxidation, NaBH
4the reaction of condensation in reduction reaction, carbon tetrachloride, wherein carbon tetrachloride is a class toxic solvents, should not be used for industrialized great production.And reactions steps is many, the response time is long, and yield is not high yet.
Therefore, be necessary to provide that a kind of cost is low, yield is high and the preparation method of the simple repaglinide of technique.
Summary of the invention
In order to solve the problems of the technologies described above, the invention provides a kind of preparation method of repaglinide.
The invention provides a new process route preparing repaglinide; this preparation method by auspicious lattice amine N-acetyl-Pidolidone and alkali Zhong with get Rui Ge amine; auspicious lattice amine obtains intermediate with auspicious lattice acid condensation after acidylate; intermediate is hydrolyzed to repaglinide; there is efficient, low toxicity, low danger; simple operation and other advantages is a process route with fine industrial prospect.
First aspect, the invention provides a kind of preparation method of repaglinide, comprises the steps:
1) preparation is such as formula compound (S)-(+)-3-methyl isophthalic acid shown in B-(2-piperidinyl-phenyl) butylamine
Get and be added to the water such as formula the auspicious lattice amine of the compound shown in A-N-acetyl-Pidolidone, then add ammonia and be stirred to entirely molten, after reaction, extract organic layer, dry, filter, concentrating under reduced pressure, obtained such as formula the compd B shown in B;
2) preparation is such as formula compound (S)-2-ethyoxyl-4-[2-[3-methyl isophthalic acid-[2-(piperidino)-phenyl]-butane group]-amino]-2-carbonyl ethyl ethyl benzoate shown in D
Dissolve adding in toluene such as formula the auspicious lattice acid of the compound shown in C and triethylamine, be cooled to-10 ~ 0 DEG C, add the toluene solution being dissolved with pivaloyl chloride, obtain the first reactant liquor, after carrying out the first reaction at-10 ~ 0 DEG C, add and be dissolved with step 1) in the toluene solution of gained compd B, after room temperature reaction 9 ~ 12h, add water stirring, stratification, get organic layer, add saturated sodium bicarbonate solution, stir, stratification, get organic layer again and carry out drying, filter, after concentrating under reduced pressure, add normal hexane, cooling crystallization, obtained such as formula the Compound D shown in D;
3) preparation is such as formula compound (S)-2-ethyoxyl-4-[2-[[methyl isophthalic acid-[2-(piperidino) phenyl] butyl] the is amino]-2-oxoethyl] benzoic acid shown in E
Under alkali condition, add step 2 in ethanol) gained Compound D, 55 ~ 65 DEG C of Water Under solution reactions 3 ~ 10 hours, after reaction terminates, adjust ph is to acid, and cooling crystallization, obtains containing the repaglinide crude product such as formula compd E shown in E;
4) repaglinide is refining
Under stirring condition, by gained repaglinide dissolving crude product in the mixed solution of acetone and water, heating, backflow, filters, cooling crystallization, obtained repaglinide fine work.
Preferably, described step 1) in ammonia can also change other alkali adopting and commonly use in this area into.
Preferably, described step 1) in, add ammonia be stirred to entirely molten after the reaction carried out be specially: stirring reaction 25 ~ 60 minutes.
Preferably, described step 1) in, so add ammonia be stirred to entirely molten after stir one hour again, make neutralization reaction complete.
Preferably, described step 1) in concentrating under reduced pressure temperature be 40 DEG C.
Preferably, described step 1) in, described extraction process stirs stratification after 30 minutes for adopting dichloromethane, gets organic layer, and wherein, described dichloromethane can also change into and adopt other organic solvents conventional in this area.
Preferably, described step 2) in, the response time of described first reaction is 50 ~ 60 minutes.
Preferably, described step 2) in, the temperature of described first reaction is-7 ~-10 DEG C.
Further preferably, described step 2) in, the reaction temperature of described first reaction is-7 DEG C.
Preferably, described step 2) in, described in be cooled to the mode of-10 ~ 0 DEG C for adopting the cooling of sub-cooled circulating slot.
Preferably, described step 2) in, the temperature of described room temperature reaction is 25 ~ 30 DEG C.
Preferably, described step 2) in, the temperature of described concentrating under reduced pressure is 58 ~ 62 DEG C.
Preferably, described step 3) in, the alkali that described alkali condition adopts is potassium hydroxide or sodium hydroxide, regulates pH to be 8 ~ 9.
Preferably, described step 3) in, the temperature of described hydrolysis is 53 ~ 57 DEG C.
Preferably, described step 3) in, the hydrolysis time of described hydrolysis is 5 ~ 10 hours.
Preferably, described step 3) in, described adjust ph, to acid, is tune pH to 4.5 ~ 5.5.
Further preferably, described step 3) in, adopt salt acid for adjusting pH value to acid, or adopt other acid conventional in this area.
Preferably, described step 4) in, in the mixed solution of described acetone and water, the volume ratio of acetone and water is 1:2 ~ 1.
Preferably, described step 4) in, the present invention preferably adopts the mixed solution of acetone and water to refine repaglinide crude product, described subtractive process, alternatively, also can adopt other regular refiner methods of this area.
Preferably, described step 2), 3) or 4) in, the temperature of cooling crystallization is-2 ~ 2 DEG C.
The preparation method of repaglinide provided by the invention, first adopts auspicious lattice amine N-acetyl-Pidolidone and alkali neutralization reaction get Rui Ge amine, and auspicious lattice amine obtains intermediate with auspicious lattice acid condensation after acidylate, and intermediate is hydrolyzed to repaglinide.Because auspicious lattice amine reactivity after acidylate increases, easier and auspicious lattice acid condensation, therefore the preparation method reaction condition of repaglinide provided by the invention is gentle, and productive rate is high.
Second aspect, the repaglinide obtained by preparation method of the preparation method or repaglinide as described in relation to the first aspect that the invention provides a kind of repaglinide is as described in relation to the first aspect preparing the application in hypoglycemic medicine.
The preparation method and the application thereof that the invention provides repaglinide have following beneficial effect:
(1) preparation method of repaglinide provided by the invention have efficiently, low toxicity, low danger, technique is simple, and cost is low, has fine industrial prospect;
(2) preparation method of repaglinide provided by the invention, adopt auspicious lattice amine N-acetyl-Pidolidone and alkali neutralization reaction get Rui Ge amine, auspicious lattice amine obtains intermediate with auspicious lattice acid condensation after acidylate, and intermediate is hydrolyzed to repaglinide, reaction condition is gentle, and productive rate is high;
(3) preparation method of repaglinide that also provides of the present invention or the repaglinide obtained by preparation method of described repaglinide are preparing the application in hypoglycemic medicine.
Accompanying drawing explanation
The schematic flow sheet of the preparation method of the repaglinide that Fig. 1 provides for the embodiment of the present invention.
Detailed description of the invention
The following stated is the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications are also considered as protection scope of the present invention.
If no special instructions, the purity (content) of repaglinide of the present invention, the assay method of related substance all adopt high performance liquid chromatography.
High performance liquid chromatograph (HITACHI 5410UV Detector, 5310Column oven, 5210Auto sampler, 5110Pump), methanol (chromatographically pure), purified water, Ammonium biphosphate (analytical pure), phosphoric acid (chromatographically pure).Repaglinide reference substance (Nat'l Pharmaceutical & Biological Products Control Institute), impurity A reference substance (USP standard substance, lot number: GOJ300), impurity B reference substance (USP standard substance, lot number: FOB269).
Chromatographic condition: chromatographic column is ECOSIL C18 (250mm × 4.6mm, 5 μm), mobile phase is 0.2% Ammonium biphosphate (with phosphorus acid for adjusting pH to 2.5)-methanol (30:70), flow velocity is 1.0mL/min, determined wavelength is 210nm, column temperature is 40 DEG C, and sample size is 20 μ L, and solvent is 0.2% Ammonium biphosphate (with phosphorus acid for adjusting pH to 4.0)-methanol (30:70).
The miscellaneous equipment that the present invention adopts:
Embodiment 1
The schematic flow sheet of the preparation method of the repaglinide that Fig. 1 provides for the embodiment of the present invention, composition graphs 1, embodiments provides a kind of preparation method of repaglinide, and lab scale test comprises the steps:
Step 1: the preparation of compd B (HHRG-1)
250ml water is added in three mouthfuls of round-bottomed flasks of 1L, 22g compd A (auspicious lattice amine-N-acetyl-Pidolidone) is added under stirring condition, stir into suspension, add 20ml ammonia, be stirred to entirely molten, stir 1 hour again, add 300ml dichloromethane and stir 30 minutes, pour stratification in the separatory funnel of 1L into, water layer uses 200ml dichloromethane extraction again, merge organic layer, add anhydrous sodium sulfate drying, filter, filtrate 40 DEG C of concentrating under reduced pressure, obtain 12g pale yellowish oil liquid HHRG-I, yield is 96.4%, content is 98.2%, related substances content is 0.6%, reaction equation is as follows:
Step 2: the preparation of Compound D (HHRG-3)
Add toluene 190ml, triethylamine 9ml in three mouthfuls of round-bottomed flasks of 1L, under stirring condition, add the auspicious lattice acid (HHRG-2) of 14.75g.Mixture is stirred to dissolving, opens the cooling of sub-cooled circulating slot.The mixture dripping pivaloyl chloride 8ml and toluene 95ml is started when temperature is down to-7 DEG C.The mixture dripping auspicious lattice amine (HHRG-1 that step 1 is obtained, pale yellowish oil liquid) 12g and toluene 95ml after 1 hour is again reacted under-7 DEG C of conditions.Dropwise and close sub-cooled circulating slot, room temperature reaction spends the night (12 hours).Reaction terminates rear thin layer control (GF254), and developing solvent is toluene-acetone (10:1).Add 350ml water in the backward reaction system that reacts completely, stir 30 minutes.Pour in the separatory funnel of 1L, stratification, organic layer adds 350ml saturated sodium bicarbonate solution and stirs 30 minutes.Pour in the separatory funnel of 1L, stratification.Organic over anhydrous dried over sodium sulfate, filter, mother solution 60 DEG C of concentrating under reduced pressure, obtain off-white color solid.Slowly add normal hexane 200ml while hot, open sub-cooled circulating slot and cool to 0 DEG C of stirring and crystallizing, obtain 19g Compound D (HHRG-3), yield is 94%, and content is 98.6%, and its related substances is 0.4%, and reaction equation is as follows:
Step 3: the synthesis of repaglinide
| Composition | Consumption |
| HHRG-3 | 17g |
| 95% ethanol | 180ml |
| 1mol/L sodium hydroxide | 54ml |
95% ethanol 180ml is added in three mouthfuls of round-bottomed flasks of 1L, HHRG-317g is added under stirring condition, 1mol/L sodium hydroxide 54ml. opens heat cycles groove, be warming up to 55 DEG C, react 3 hours, HPLC method detection reaction terminal, is considered as reacting completely when the surplus of initiation material HHRG-3 is less than 1%.After reaction terminates, with glacial acetic acid adjust pH to 5.0 (with pH meter), open sub-cooled circulating slot and be cooled to 0 DEG C of stirring and crystallizing, obtain repaglinide crude product 14g, yield is 87%, and content is 98.3%, related substances content is 0.4%, and reaction equation is as follows:
Step 4: refining of repaglinide
| Composition | Consumption |
| Repaglinide crude product | 14g |
| Acetone | 336ml |
| Water | 280ml |
Add 336ml acetone and 280ml water in three mouthfuls of round-bottomed flasks of 1L, under stirring condition, add repaglinide crude product 14g.Open heat cycles groove, be warming up to 78 DEG C, backflow.Filtered while hot, filtrate adds in three mouthfuls of round-bottomed flasks of 1L, and open sub-cooled circulating slot and be cooled to 0 DEG C of stirring and crystallizing, obtain repaglinide 13g, content is 98.1%, and related substances content is 0.3%.
Embodiment 2
The schematic flow sheet of the preparation method of the repaglinide that Fig. 1 provides for the embodiment of the present invention, composition graphs 1, embodiments provide a kind of preparation method of repaglinide, pilot plant test comprises the steps:
The preparation of step 1:HHRG-1
2500ml water is added in the reactor of 10L, the auspicious lattice amine of 220g-N-acetyl-Pidolidone is added under stirring condition, stir into suspension, add 200ml ammonia, be stirred to entirely molten, stir 1 hour again, add 3000ml dichloromethane and stir 30 minutes, pour stratification in the separatory funnel of 10L into, water layer uses 2000ml dichloromethane extraction again, merge organic layer, add anhydrous sodium sulfate drying, filter, filtrate reduced in volume, concentrating under reduced pressure temperature is 40 DEG C, obtains HHRG-I (pale yellowish oil liquid) about 121g.Repeatedly the reaction yield scope of repeated trials is 92% ~ 97%.HHRG-I quality meets after its inner quality standard for the next step (related substances content is lower than 1%).
The preparation of step 2:HHRG-3
| Composition | Consumption |
| HHRG-1 | 120g |
| HHRG-2 (auspicious lattice acid) | 147.5g |
| Triethylamine | 90ml |
| Pivaloyl chloride | 80ml |
| Toluene | 3800ml |
| Normal hexane | 2000ml |
| Saturated sodium bicarbonate solution | 3500ml |
| Water | 3500ml |
Add toluene 1900ml in the reactor of 10L, triethylamine 90ml, under stirring condition, add the auspicious lattice acid of 147.5g.Mixture is stirred to dissolving, opens the cooling of sub-cooled circulating slot.The mixture dripping pivaloyl chloride 80ml and toluene 950ml is started when temperature is down to-7 DEG C.Drip this thermotonus of rear maintenance 1 hour.React the mixture dripping auspicious lattice amine (HHRG-I, pale yellowish oil liquid) 120g and toluene 950ml after 1 hour again.Dropwise and close sub-cooled circulating slot, room temperature reaction spends the night (repeatedly the response time of repeated trials is 9 ~ 12 hours).Reaction terminates rear thin layer control (GF254), and developing solvent is toluene-acetone (10:1).Add 3500ml water in the backward reaction system that reacts completely, stir 30 minutes.Pour in the separatory funnel of 10L, stratification, organic layer adds 3500ml saturated sodium bicarbonate solution and stirs 30 minutes.Pour in the separatory funnel of 10L, stratification.Organic over anhydrous dried over sodium sulfate, filter, mother solution 60 DEG C of concentrating under reduced pressure, obtain off-white color solid.Slowly add normal hexane 2000ml while hot, open sub-cooled circulating slot and cool to 0 DEG C of stirring and crystallizing, obtain about 170gHHRG-3, repeatedly the reaction yield of repeated trials is 90% ~ 94%.HHRG-3 quality meets after its inner quality standard for the next step (related substances content is lower than 1%).
Step 3: the synthesis of repaglinide
| Composition | Consumption |
| HHRG-3 | 170g |
| 95% ethanol | 1800ml |
| 1mol/L sodium hydroxide | 540ml |
Add 95% ethanol 1800ml in the reactor of 10L, add 170g HHRG-3 under stirring condition, 1mol/L sodium hydroxide 540ml. opens heat cycles groove, be warming up to 55 DEG C, react 8 hours, HPLC method detection reaction terminal, is considered as reacting completely when the surplus of HHRG-3 is less than 1%.After reaction terminates, with glacial acetic acid adjust pH to 5.0 (with pH meter), open sub-cooled circulating slot and be cooled to 0 DEG C of stirring and crystallizing, obtain repaglinide crude product and be about 140g, repeatedly the reaction yield of repeated trials is 80% ~ 90%.Repaglinide crude product quality meets after its inner quality standard for the next step (related substances content is lower than 1%).
Step 4: refining of repaglinide
| Composition | Consumption |
| Repaglinide crude product | 140g |
| Acetone | 3360ml |
| Water | 2800ml |
Add 3360ml acetone and 2800ml water in the reactor of 10L, under stirring condition, add repaglinide crude product 140g.Open heat cycles groove, be warming up to 78 DEG C, backflow.Filtered while hot, filtrate adds in the reactor of 10L, opens sub-cooled circulating slot and is cooled to 0 DEG C of stirring and crystallizing, obtain repaglinide 121g.Repaglinide quality meets after its inner quality standard for the next step (related substances content is lower than 1%).
Embodiment 3
For further illustrating beneficial effect of the present invention, the embodiment of the present invention passes through different experimental condition research:
1) preparation condition of HHRG-1;
2) acylation reaction temperature is on the impact such as formula compound shown in D;
3) hydrolysis time is on the impact such as formula compound hydrolysis shown in D, comprises the steps;
One, following contrast test is first done:
The preparation of step 1:HHRG-1
Add 250ml water in three mouthfuls of round-bottomed flasks of 1L, add the auspicious lattice amine of 22g-N-acetyl-Pidolidone under stirring condition, stir into suspension, add 20ml ammonia, be stirred to entirely molten, add 300ml dichloromethane and stir 30 minutes, pour stratification in the separatory funnel of 1L into, water layer uses 200ml dichloromethane extraction again, merges organic layer, adds anhydrous sodium sulfate drying, filter, filtrate reduced in volume, concentrating under reduced pressure temperature is 40 DEG C, obtains HHRG-1 (pale yellowish oil liquid) 10g.Reaction yield is 80.3%.
The preparation of step 2:HHRG-3
| Composition | Consumption |
| HHRG-1 | 10g |
| HHRG-2 | 14.75g |
| Triethylamine | 9ml |
| Pivaloyl chloride | 8ml |
| Toluene | 380ml |
| Normal hexane | 200ml |
| Saturated sodium bicarbonate solution | 350ml |
| Water | 350ml |
Add toluene 190ml, triethylamine 9ml in three mouthfuls of round-bottomed flasks of 1L, under stirring condition, add the auspicious lattice acid of 14.75g.Mixture is stirred to dissolving, opens the cooling of sub-cooled circulating slot.The mixture dripping pivaloyl chloride 8ml and toluene 95ml is started when temperature is down to 0 DEG C.React the mixture dripping auspicious lattice amine (HHRG-1, pale yellowish oil liquid) 10g and toluene 95ml after 1 hour again.Dropwise and close sub-cooled circulating slot, room temperature reaction spends the night.Reaction terminates rear thin layer control (GF254), and developing solvent is toluene-acetone (10:1).Add 350ml water in the backward reaction system that reacts completely, stir 30 minutes.Pour in the separatory funnel of 1L, stratification, organic layer adds 350ml saturated sodium bicarbonate solution and stirs 30 minutes.Pour in the separatory funnel of 1L, stratification.Organic over anhydrous dried over sodium sulfate, filter, mother solution 60 DEG C of concentrating under reduced pressure, obtain off-white color solid.Slowly add normal hexane 200ml while hot, open sub-cooled circulating slot and cool to 0 DEG C of stirring and crystallizing, obtain 17g HHRG-3, reaction yield is 70%.
Step 3: the synthesis of repaglinide
| Composition | Consumption |
| HHRG-3 | 17g |
| 95% ethanol | 180ml |
| 1mol/L sodium hydroxide | 54ml |
95% ethanol 180ml is added in three mouthfuls of round-bottomed flasks of 1L, 17g HHRG-3 is added under stirring condition, 1mol/L sodium hydroxide 54ml. opens heat cycles groove, be warming up to 55 DEG C, react 3 hours, HPLC method detection reaction terminal, is considered as reacting completely when the surplus of initiation material HHRG-3 is less than 1%.After reaction terminates, with glacial acetic acid adjust pH to 5.0 (with pH meter), open sub-cooled circulating slot and be cooled to 0 DEG C of stirring and crystallizing, obtain repaglinide crude product 14g.Crude product quality meets after its inner quality standard for the next step.
Step 4: refining of repaglinide
| Composition | Consumption |
| Repaglinide crude product | 14g |
| Acetone | 336ml |
| Water | 280ml |
Add 336ml acetone and 280ml water in three mouthfuls of round-bottomed flasks of 1L, under stirring condition, add 14g repaglinide crude product.Open heat cycles groove, be warming up to 78 DEG C, backflow.Filtered while hot, filtrate adds in three mouthfuls of round-bottomed flasks of 1L, opens sub-cooled circulating slot and is cooled to 0 DEG C of stirring and crystallizing, obtain repaglinide 12g.
Two, results and analysis:
| Composition | Related substance |
| HHRG-3 | 6％ |
| Repaglinide crude product | 2.6％ |
| Repaglinide highly finished product | 2.4％ |
Repaglinide highly finished product related substance is higher than standard as can be seen from the results, may be that step 1 reacts not exclusively impact reaction result below.Therefore process optimization is carried out to step 1.Be stirred to entirely molten after adding ammonia, may also not and auspicious lattice amine-N-acetyl-Pidolidone neutralization reaction complete, so be stirred to entirely molten after stir one hour again, make neutralization reaction complete, and carry out following lab scale synthesis technique:
Three, the improvement of process conditions:
The preparation of step 1:HHRG-1
Add 250ml water in three mouthfuls of round-bottomed flasks of 1L, add the auspicious lattice amine of 22g-N-acetyl-Pidolidone under stirring condition, stir into suspension, add 20ml ammonia, be stirred to entirely molten, then stir 1 hour, add 300ml dichloromethane and stir 30 minutes, pour stratification in the separatory funnel of 1L into, water layer uses 200ml dichloromethane extraction again, merges organic layer, add anhydrous sodium sulfate drying, filter, filtrate 40 DEG C of concentrating under reduced pressure, obtain HHRG-1 (pale yellowish oil liquid) 12g.Yield is 96.4%,
As can be seen from result, HHRG-1 yield improves 16 percentage points.
Synthesize three crowdes of HHRG-1 with this synthesis technique to be used for groping step 2.Three batches of HHRG-1 situations are:
| Lot number | Weight | Yield |
| 20110101 | 12g | 96.4％ |
| 20110102 | 12g | 96.4％ |
| 20110103 | 12g | 96.4％ |
Following experiment is done with above three batches:
In step 2, the temperature of acylation reaction is set as 0 DEG C ,-5 DEG C ,-7 DEG C ,-10 DEG C, synthesizes three crowdes of HHRG-3 by following synthesis technique.
The preparation of step 2:HHRG-3:
| Composition | Consumption |
| HHRG-1 | 12g |
| HHRG-2 | 14.75g |
| Triethylamine | 9ml |
| Pivaloyl chloride | 8ml |
| Toluene | 380ml |
| Normal hexane | 200ml |
| Saturated sodium bicarbonate solution | 350ml |
| Water | 350ml |
Add toluene 190ml, triethylamine 9ml in three mouthfuls of round-bottomed flasks of 1L, under stirring condition, add the auspicious lattice acid of 14.75g.Mixture is stirred to dissolving, opens sub-cooled circulating slot cooling (being respectively 0 DEG C ,-5 DEG C ,-7 DEG C ,-10 DEG C); Then drip the mixture of pivaloyl chloride 8ml and toluene 95ml, under maintaining the constant condition of temperature control, (being namely respectively 0 DEG C ,-5 DEG C ,-7 DEG C ,-10 DEG C) reacts the mixture dripping auspicious lattice amine (pale yellowish oil liquid) 12g and toluene 95ml after 1 hour again.Dropwise and close sub-cooled circulating slot, room temperature reaction spends the night.Reaction terminates rear thin layer control (GF254), and developing solvent is toluene-acetone (10:1).Add 350ml water in the backward reaction system that reacts completely, stir 30 minutes.Pour in the separatory funnel of 1L, stratification, organic layer adds 350ml saturated sodium bicarbonate solution and stirs 30 minutes.Pour in the separatory funnel of 1L, stratification.Organic over anhydrous dried over sodium sulfate, filter, mother solution 60 DEG C of concentrating under reduced pressure, obtain grease.Slowly add normal hexane 200ml while hot, open sub-cooled circulating slot and cool to 0 DEG C of stirring and crystallizing, obtain HHRG-3:17g, 19g, 18g respectively.
Separately, comparative example is set, with step 2) unlike:
A) condition of " open sub-cooled circulating slot and be cooled to 0 DEG C ,-5 DEG C ,-7 DEG C or-10 DEG C " is adjusted to " cryosel bath cools to-5 ~ 0 DEG C ";
B) " will then drip the mixture of pivaloyl chloride 8ml and toluene 95ml; under maintaining the constant condition of temperature control, (being namely respectively 0 DEG C ,-5 DEG C ,-7 DEG C ,-10 DEG C) reacts 1 hour " to change into: " dripping the mixture of pivaloyl chloride 8ml and toluene 95ml; drip and finish; temperature control T=-5 ~ 5 DEG C, react 1 hour "
Result (the relevant parameter assay method of each batch is all identical):
| HHRG-3 (lot number) | Related substance | Content | Yield |
| 20110101 (comparative examples) | 1.2％ | 97.5％ | 55％ |
| 20110101(0℃) | 0.7％ | 98.1％ | 77％ |
| 20110101(-5℃) | 0.7％ | 98.0％ | 80％ |
| 20110102(-7℃) | 0.4％ | 98.6％ | 94％ |
| 20110103(-10℃) | 0.6％ | 98.3％ | 85％ |
Can find out that the reaction-7 DEG C time of acylation reaction temperature is the most complete by result, related substance is minimum, and content, yield are the highest.Therefore, selective response temperature is-7 DEG C, is undertaken, be hydrolyzed the surplus of a survey per hour initiation material HHRG-3 with HHRG-3 the 20110102nd crowd by following synthesis technique.
Step 3: the synthesis of repaglinide
| Composition | Consumption |
| HHRG-3 | 19g |
| 95% ethanol | 180ml |
| 1mol/L sodium hydroxide | 54ml |
Add 95% ethanol 180ml in three mouthfuls of round-bottomed flasks of 1L, add 19g HHRG-3 under stirring condition, 1mol/L sodium hydroxide 54ml. opens heat cycles groove, is warming up to 55 DEG C, and HPLC method detects intermediate II surplus.
Result is:
| Composition | 3h | 5h | 8h | 10h |
| Intermediate II | 1.14％ | 0.21％ | 0.17％ | 0.0077％ |
As can be seen from the results, hydrolysis 8h, 10h are all less than 1%, but hydrolysis 10h is much less than 8h, and almost completely, therefore we are to be hydrolyzed 10h for hydrolysis time in hydrolysis.With glacial acetic acid adjust pH to 5.0 (with pH meter), open sub-cooled circulating slot and be cooled to 0 DEG C of stirring and crystallizing, obtain repaglinide crude product 14g, yield is 87%.
Therefore, the step 3 after optimization: the synthesis technique of repaglinide is:
| Composition | Consumption |
| HHRG-3 | 19g |
| 95% ethanol | 180ml |
| 1mol/L sodium hydroxide | 54ml |
95% ethanol 180ml is added in three mouthfuls of round-bottomed flasks of 1L, add 19g HHRG-3 under stirring condition, 1mol/L sodium hydroxide 54ml. is warming up to 55 DEG C, reacts 10 hours, HPLC method detection reaction terminal, is considered as reacting completely when the surplus of initiation material HHRG-3 is less than 1%.After reaction terminates, with glacial acetic acid adjust pH to 5.0 (with pH meter), open sub-cooled circulating slot and be cooled to 0 DEG C of stirring and crystallizing, obtain repaglinide crude product 14g.
Step 4: refining of repaglinide
| Composition | Consumption |
| Repaglinide crude product | 14g |
| Acetone | 336ml |
| Water | 280ml |
Add 336ml acetone and 280ml water in three mouthfuls of round-bottomed flasks of 1L, under stirring condition, add repaglinide crude product 14g.Be warming up to 60 DEG C, backflow.Filtered while hot, filtrate adds in three mouthfuls of round-bottomed flasks of 1L, opens sub-cooled circulating slot and is cooled to 0 DEG C of stirring and crystallizing, obtain repaglinide 12g.
Embodiment 4
Further, the embodiment of the present invention is investigated:
The mode added of pivaloyl chloride, toluene and auspicious lattice amine is on the impact such as formula compound shown in D.
With embodiment 3 prepare 20110102 batches such as formula compound shown in D, selective response temperature is-7 DEG C, carry out parallel laboratory test, when adding the mixture of the mixture of pivaloyl chloride and toluene and auspicious lattice amine and toluene, adopt respectively and drip and the disposable mode added, statistics productive rate, obtains following result:
Visible, when adding the mixture of the mixture of pivaloyl chloride and toluene and auspicious lattice amine and toluene, all adopting in temperature is that-7 DEG C of modes of carrying out dripping are reacted, and yield is the highest.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. a preparation method for repaglinide, is characterized in that, comprises the steps:
1) preparation is such as formula compound (S)-(+)-3-methyl isophthalic acid shown in B-(2-piperidinyl-phenyl) butylamine
Get and be added to the water such as formula the auspicious lattice amine of the compound shown in A-N-acetyl-Pidolidone, then add ammonia and be stirred to entirely molten, after reaction, extract organic layer, dry, filter, concentrating under reduced pressure, obtained such as formula the compd B shown in B;
2) preparation is such as formula compound (S)-2-ethyoxyl-4-[2-[3-methyl isophthalic acid-[2-(piperidino)-phenyl]-butane group]-amino]-2-carbonyl ethyl ethyl benzoate shown in D
Dissolve adding in toluene such as formula the auspicious lattice acid of the compound shown in C and triethylamine, be cooled to-10 ~ 0 DEG C, add the toluene solution being dissolved with pivaloyl chloride, obtain the first reactant liquor, after carrying out the first reaction at-10 ~ 0 DEG C, add and be dissolved with step 1) in the toluene solution of gained compd B, after room temperature reaction 9 ~ 12h, add water stirring, stratification, get organic layer, add saturated sodium bicarbonate solution, stir, stratification, get organic layer again and carry out drying, filter, after concentrating under reduced pressure, add normal hexane, cooling crystallization, obtained such as formula the Compound D shown in D;
3) preparation is such as formula compound (S)-2-ethyoxyl-4-[2-[[methyl isophthalic acid-[2-(piperidino) phenyl] butyl] the is amino]-2-oxoethyl] benzoic acid shown in E
Under alkali condition, add step 2 in ethanol) gained Compound D, 55 ~ 65 DEG C of Water Under solution reactions 3 ~ 10 hours, after reaction terminates, adjust ph is to acid, and cooling crystallization, obtains containing the repaglinide crude product such as formula compd E shown in E;
4) repaglinide is refining
Under stirring condition, by gained repaglinide dissolving crude product in the mixed solution of acetone and water, heating, backflow, filters, cooling crystallization, obtained repaglinide fine work.
2. the preparation method of repaglinide as claimed in claim 1, is characterized in that, described step 1) in, add ammonia be stirred to entirely molten after the reaction carried out be specially: stirring reaction 25 ~ 60 minutes.
3. the preparation method of repaglinide as claimed in claim 1, is characterized in that, described step 2) in, the response time of described first reaction is 50 ~ 60 minutes.
4. the preparation method of repaglinide as claimed in claim 1, is characterized in that, described step 2) in, the temperature of described first reaction is-7 ~-10 DEG C.
5. the preparation method of repaglinide as claimed in claim 1, it is characterized in that, described step 2) in, the mode adding the toluene solution being dissolved with pivaloyl chloride for dripping, described in add be dissolved with step 1) in the mode of toluene solution of gained compd B for dripping.
6. the preparation method of repaglinide as claimed in claim 1, is characterized in that, described step 2) in, described in be cooled to the mode of-10 ~ 0 DEG C for adopting the cooling of sub-cooled circulating slot.
7. the preparation method of repaglinide as claimed in claim 1, is characterized in that, described step 3) in, the hydrolysis time of described hydrolysis is 5 ~ 10 hours.
8. the preparation method of repaglinide as claimed in claim 1, is characterized in that, described step 3) in, described adjust ph, to acid, is tune pH to 4.5 ~ 5.5.
9. the preparation method of repaglinide as claimed in claim 1, is characterized in that, described step 2), 3) or 4) in, the temperature of cooling crystallization is-2 ~ 2 DEG C.
10. the preparation method of a repaglinide as claimed in claim 1 or the repaglinide obtained by preparation method of repaglinide as claimed in claim 1 are preparing the application in hypoglycemic medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510011786.1A CN104557778A (en) | 2015-01-09 | 2015-01-09 | Preparation method and application of repaglinide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510011786.1A CN104557778A (en) | 2015-01-09 | 2015-01-09 | Preparation method and application of repaglinide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104557778A true CN104557778A (en) | 2015-04-29 |
Family
ID=53074952
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510011786.1A Pending CN104557778A (en) | 2015-01-09 | 2015-01-09 | Preparation method and application of repaglinide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104557778A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111635379A (en) * | 2020-07-21 | 2020-09-08 | 江西博雅欣和制药有限公司 | Synthesis process of blood sugar reducing medicine repaglinide |
| CN111808047A (en) * | 2020-07-21 | 2020-10-23 | 江西博雅欣和制药有限公司 | Novel method for preparing repaglinide intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003027072A1 (en) * | 2001-09-25 | 2003-04-03 | Ranbaxy Laboratories Limited | Process for the preparation of repaglinide |
| CN1865253A (en) * | 2006-06-21 | 2006-11-22 | 浙江大学 | Repaglinide synthesis process |
| CN102633750A (en) * | 2012-03-26 | 2012-08-15 | 浙江昂利康制药有限公司 | One-pot method for synthesizing repaglinide for treating diabetes |
| CN102731436A (en) * | 2012-04-09 | 2012-10-17 | 海南中化联合制药工业股份有限公司 | Preparation and refining method of repaglinide |
| CN102766112A (en) * | 2012-08-10 | 2012-11-07 | 河北富格药业有限公司 | Synthetic method of repaglinide |
-
2015
- 2015-01-09 CN CN201510011786.1A patent/CN104557778A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003027072A1 (en) * | 2001-09-25 | 2003-04-03 | Ranbaxy Laboratories Limited | Process for the preparation of repaglinide |
| CN1571769A (en) * | 2001-09-25 | 2005-01-26 | 兰贝克赛实验室有限公司 | Process for the preparation of repaglinide |
| CN1865253A (en) * | 2006-06-21 | 2006-11-22 | 浙江大学 | Repaglinide synthesis process |
| CN102633750A (en) * | 2012-03-26 | 2012-08-15 | 浙江昂利康制药有限公司 | One-pot method for synthesizing repaglinide for treating diabetes |
| CN102731436A (en) * | 2012-04-09 | 2012-10-17 | 海南中化联合制药工业股份有限公司 | Preparation and refining method of repaglinide |
| CN102766112A (en) * | 2012-08-10 | 2012-11-07 | 河北富格药业有限公司 | Synthetic method of repaglinide |
Non-Patent Citations (5)
| Title |
|---|
| 何勇等: "瑞格列奈的合成", 《中国医药工业杂志》, vol. 43, no. 2, 10 February 2012 (2012-02-10), pages 84 - 86 * |
| 彭勇等: "瑞格列奈及其中间体合成的研究进展", 《河北师范大学学报（自然科学版）》, vol. 34, no. 1, 31 January 2010 (2010-01-31), pages 89 - 92 * |
| 赵伟等: "瑞格列奈的合成", 《煤炭与化工》, vol. 37, no. 7, 31 July 2014 (2014-07-31), pages 77 - 80 * |
| 赵爽等: "抗糖尿病药物瑞格列奈的合成", 《吉林大学学报（理学版）》, vol. 46, no. 3, 31 May 2008 (2008-05-31), pages 556 - 559 * |
| 陈浩等: "新型口服降糖药瑞格列奈的合成", 《山东化工》, vol. 41, no. 12, 31 December 2012 (2012-12-31) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111635379A (en) * | 2020-07-21 | 2020-09-08 | 江西博雅欣和制药有限公司 | Synthesis process of blood sugar reducing medicine repaglinide |
| CN111808047A (en) * | 2020-07-21 | 2020-10-23 | 江西博雅欣和制药有限公司 | Novel method for preparing repaglinide intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105461772A (en) | Trifluridine intermediate and preparation method of trifluridine | |
| CN104788332B (en) | A kind of preparation and purification method of oleic monoethanolamide | |
| CN114436924B (en) | Synthesis method of hydroxy pinacolone retinoic acid ester | |
| CN104557778A (en) | Preparation method and application of repaglinide | |
| CN105367455B (en) | A kind of preparation method of his isomers of Baily department | |
| CN101838212B (en) | Method for synthesizing L-carnitine by using (R)-(-)-3-chlorine-1,2-propylene glycol as chiral initiative raw material | |
| CN107253914B (en) | The method for preparing 2- Amino-4-nitrophenol using Disperse Blue 2BLN byproduct | |
| CN104829515A (en) | Pregabalin impurity preparation method | |
| CN109456221A (en) | A kind of synthetic method of acetanilide derivative | |
| CN102827229B (en) | A kind of method of purifying halometasone carboxylicesters | |
| CN104151170A (en) | 4-nitrophenethylamine hydrochloride and preparation method thereof | |
| CN102617418B (en) | Method for recovering amino acid ester from amino acid esterification mother liquor | |
| CN106279194A (en) | A kind of method utilizing microreactor to prepare sodium-glucose co-transport enzyme inhibitor intermediate | |
| CN114105858B (en) | 3-azido indoline compound and method for electrochemically synthesizing 3-azido indoline compound | |
| CN112110879A (en) | Preparation method of sulcardine free alkali | |
| CN106518729A (en) | Lurasidone hydrochloride intermediate preparation method | |
| CN106749038A (en) | A kind of preparation method of flibanserin | |
| CN105523957A (en) | Method for preparing Lacosamide by one-pot method | |
| CN110229087B (en) | Purification method of (1R,2R) -1- [ (4-methylsulfonyl) phenyl ] -2-amino-1, 3-propanediol | |
| CN105153023A (en) | Synthetic method of 2-amino-4-bromopyridine | |
| CN110028457A (en) | A kind of sulfabromomethazine and its synthetic method of stable isotope labeling | |
| CN104876856A (en) | Method for preparing (R)-(+)-3-piperidinamine dihydrochloride by using resolution method | |
| CN103304405B (en) | A kind of method of selective chlorination | |
| CN114746399A (en) | Preparation method of carbocisteine | |
| CN104447776A (en) | Novel heterocyclic organic compound and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150429 |