CN103265473A - Method for producing saxagliptin - Google Patents
Method for producing saxagliptin Download PDFInfo
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- CN103265473A CN103265473A CN201310222269XA CN201310222269A CN103265473A CN 103265473 A CN103265473 A CN 103265473A CN 201310222269X A CN201310222269X A CN 201310222269XA CN 201310222269 A CN201310222269 A CN 201310222269A CN 103265473 A CN103265473 A CN 103265473A
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- FSMVRYKNHQASPI-INXMPTQFSA-N CC(C)(C)OC(N[C@@H](C(CC1C2)(CC1(C1)C2C2)CC12O)C(N1[C@](C2)(C3)[C@]23C[C@@H]1C(N)=O)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](C(CC1C2)(CC1(C1)C2C2)CC12O)C(N1[C@](C2)(C3)[C@]23C[C@@H]1C(N)=O)=O)=O FSMVRYKNHQASPI-INXMPTQFSA-N 0.000 description 1
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Abstract
The invention provides a method for producing saxagliptin. The method comprises the following steps of: 1, providing a compound d; and 2, reacting the compound d, isopropanol and concentrated hydrochloric acid at the temperature of between 50 and 80 DEG C, and collecting the product to obtain the saxagliptin. Compared with the prior art, the method has the advantages that the compound d is directly converted into the target product, so that the reaction rate is greatly improved, the reaction yield is improved, the post treatment method is simplified, and industrial wastewater is greatly reduced.
Description
Technical field
The present invention relates to a kind of synthetic method of compound, relate in particular to the method for a kind of Sha Gelieting of production.
Background technology
Sha Gelieting (saxagliptin) is novel dipeptidyl peptidase-IV (DPP-IV, the endogenous secretin) inhibitor that Shi Guibao company and Astrazeneca AB develop jointly.It suppresses DPP-4 by selectivity, and can raise endogenous glucagon-like-peptide-1 (GLP-1) and glucose dependency pancreotropic hormone discharge polypeptide (GIP) level, thereby regulates blood sugar.In March, 2010, drugs approved by FDA Sha Gelieting was used for the treatment of adult's diabetes B patient's hyperglycemia; And in May, 2011, obtain the SFDA official approval in China.But this medicine single therapy also can be in the not good basis associating N1,N1-Dimethylbiguanide treatment of N1,N1-Dimethylbiguanide control.Clinical study has confirmed that Sha Gelieting has advantages such as curative effect is outstanding, effect is lasting.
The Sha Gelieting chemical structure is as follows:
At present existing bibliographical information the synthetic method of Sha Gelieting, as patent documentation WO2011117393A, WO2010032129A, US20060035954, US2005090539, and document J.Med.Chem, 2005,48:5025-5037 and Org.Process.Res.Dev, 2009,13:1169-1176.The main synthetic route of prior art is as follows:
In this synthetic method, after obtaining compound d, slough protecting group-fluoroform acyl group on the hydroxyl and the Boc protecting group on the amino respectively, thereby obtain the hydrochloride of compound and the mixture f of water.By the adjusting of pH value, recrystallization obtains final Sha Gelieting hydrate g again.This reaction process, by the processing in three steps, total recovery decreases, and complex operation, produces a large amount of waste water simultaneously.
Summary of the invention
At the described problem that exists in the prior art, the applicant has carried out meticulous careful research to this Sha Gelieting is synthetic, proposes a novelty, effective synthetic route, has improved the yield of final product, and has reduced the generation of waste water in a large number.This environmentally friendly route makes that the big production of Sha Gelieting is more meaningful.
For this reason, the invention provides the method for a kind of Sha Gelieting of production.
The method of production Sha Gelieting of the present invention, step comprises:
Step 2 is reacted compound d, Virahol, concentrated hydrochloric acid at 50-80 ° of C, collect product and obtain Sha Gelieting.
Wherein, the compound d structural formula is as follows:
In the aforesaid method of the present invention, temperature of reaction is preferably 55-75 ° of C in the step 2, and 60-70 ° of C more preferably is as 65 ° of C.
In the aforesaid method of the present invention, the reaction terminating time can be judged by prior art by those skilled in the art in the step 2, as by means such as TLC tracking, infrared spectra tracking, in the present invention, reaction times is preferably 0.5-4h, more preferably 1-3h, more preferably 1.5-2h.
In a kind of preferred embodiment of aforesaid method of the present invention, the method of described collection product is preferably: reaction solution is preferably 55-75 ° of C at 50-80 ° of C(, 60-70 ° of C more preferably, as 65 ° of C) concentrate after, add water and halohydrocarbon, regulate water layer pH value to 9-10, add sodium-chlor, stir; Collected organic layer; Remove halohydrocarbon; The solid that collection is separated out.
Wherein, in the described collection method, halohydrocarbon can be methylene dichloride, chloroform, and is preferably methylene dichloride.
Wherein, in the described collection method, regulating water layer pH value can be to implement by adding methods such as oxyhydroxide, ammoniacal liquor, carbonate, is preferably by adding salt of wormwood and implements.
Wherein, in the described collection method, the method for removing halohydrocarbon is preferably: earlier organic layer is concentrated, add ethyl acetate then, add water in batches, stir, halohydrocarbon is removed in distillation then.
Wherein, in the method for described removal halohydrocarbon, every 1000ml organic layer concentrated solution adds ethyl acetate 1500-3000ml(and is preferably 2000-2500ml), adding water cumulative volume is that 5-20ml(is preferably 6-15ml, more preferably 10-15ml).
Water can be branch at least twice adding, and the volume of each water that adds can be identical or different.
Wherein, in the method for described removal halohydrocarbon, churning time is preferably 10-60min after the adding ethyl acetate, more preferably 20-50min, more preferably 30-40min.
Wherein, in the method for described removal halohydrocarbon, churning time is preferably 10-60min after adding water at every turn, more preferably 20-50min, more preferably 30-40min.
In the aforesaid method of the present invention, the mass concentration of concentrated hydrochloric acid is preferably 36-38% in the step 2.
In the aforesaid method of the present invention, compound d can be to be obtained by prior art for preparing by those skilled in the art, as patent application WO2011117393A, WO2010032129A, US20060035954, US2005090539, and document J.Med.Chem, 2005,48:5025-5037 and Org.Process.Res.Dev, disclosed content among 2009, the 13:1169-1176.
In a preferred embodiment of the present invention, compound d is obtained by the compound c reaction, and method is: compound c and trifluoroacetic acid react under≤10 ° of C conditions.Wherein, the compound c structural formula is as follows:
In the aforesaid method of the present invention, compound c can be to be obtained by prior art for preparing by those skilled in the art, as patent application WO2011117393A, WO2010032129A, US20060035954, US2005090539, and document J.Med.Chem, 2005,48:5025-5037 and Org.Process.Res.Dev, disclosed content among 2009, the 13:1169-1176.
In a preferred embodiment of the present invention, compound c is obtained by compound a and compound b reaction, method is: compound a, compound b are at I-hydroxybenzotriazole (HOBT), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl), N, N-diisopropylethylamine (DIPEA) exists down, in 10-40 ° of C scope, (be preferably 15-35 ° of C, more preferably 20-30 ° of C as 25 ° of C, or reacts at ambient temperature) reaction.Wherein, compound a and b structural formula are as follows:
Wherein compound a can be obtained by compound a-1 reaction, reaction method is: compound a-1 and Virahol, methanesulfonic are preferably 55-75 ° of C at 50-80 ° of C(, and 60-70 ° of C more preferably is as 65 ° of C) reaction, be cooled to 0-5 ° of C then, collect the solid of separating out.Wherein, the structural formula of compd E is as follows:
The applicant is on the basis of a large amount of research work, realized compound d is converted into the method for Sha Gelieting smoothly, thereby improved the speed of reacting greatly, improved the productive rate of reaction, simplified post-treating method, reduced the generation of trade effluent in a large number.
Description of drawings
Fig. 1 is for producing the method reaction formula synoptic diagram of Sha Gelieting in a kind of preferred embodiment of the present invention;
Fig. 2 is for producing Sha Gelieting method synthetic route chart in the another kind of preferred embodiment of the present invention.
Embodiment
With reference to Fig. 1, the method for synthetic Sha Gelieting is as follows in the present embodiment:
Reference literature J.Med.Chem, the method for 2005,48:5025-5037, synthetic compound d.
Drop into compound d (384g), Virahol (384ml), water (384ml) and 36% hydrochloric acid (126ml) in the reaction flask, 65 ° of C of temperature stir 1.5h in being warming up to; TLC follows the tracks of and confirms to react completely.
Reaction solution is concentrated in 65 ° of C water-baths; Add water (500ml) in the enriched material, methylene dichloride (3.0L), stirring down, 20% solution of potassium carbonate adjusting upper strata pH value adds sodium-chlor (480g) to 9-10, stirring 30min; Leave standstill, the upper strata extracts with methylene dichloride (3.0L), and TLC does not abandon after having product; Merge lower floor, water (3.0L) is washed, and removes by filter wherein mechanical impurity.
Be concentrated into about 500ml, add ethyl acetate (1.2L), slowly stir; 0.5h after, add water 3ml, stir 0.5h, add water 3ml again, stirring at room 0.5h; Residual methylene dichloride in the system is removed in 45 ℃ of distillations; Stirring at room 15h; Filter, the washing of solid ethyl acetate, 55 ℃ of dry 18h get white or off-white color solid 89g, and purity is more than 99%.
Embodiment 2
Compound d is provided.
Drop into compound d (350g), Virahol (385ml), water (385ml) and 36% hydrochloric acid (125ml) in the reaction flask, 65 ° of C of temperature stir 1.5h in being warming up to; TLC follows the tracks of and confirms to react completely.
Reaction solution is concentrated in 65 ° of C water-baths; Add water (500ml) in the enriched material, methylene dichloride (3.0L), stirring down, 20% solution of potassium carbonate adjusting upper strata pH value adds sodium-chlor (480g) to 9-10, stirring 30min; The upper strata dichloromethane extraction; Merge lower floor, water (3.0L) is washed, and removes by filter wherein mechanical impurity.
Be concentrated into about 500ml, add ethyl acetate (1.2L), slowly stir; 0.5h after, add water 3ml, stir 0.5h, add water 3ml again, stirring at room 0.5h; Remove residual methylene dichloride in the system; Stirring at room 15h; Filter, the washing of solid ethyl acetate, drying gets white or off-white color solid 88g, and purity is more than 99%.
Embodiment 3
With reference to Fig. 2, the method for synthetic Sha Gelieting is as follows in the present embodiment:
The preparation of compound a
In the four-hole boiling flask, compound a-1(150g, 0.667mol, (1S, 3S, 5S)-3-(aminocarboxyl)-2-azabicyclo [3.1.0], CAS:361440-67-7), Virahol Virahol (1.5L), methanesulfonic (83.2g, 0.866mol), 65 ° of C of temperature in being warming up under stirring, insulated and stirred 3h, reaction solution are cooled to 0-5 ° of C, insulated and stirred 1h, a large amount of solids are separated out, and filter, solid 200ml washed with isopropyl alcohol, 55 ° of dry 8h of C obtain off-white color solid a(142.5g).
The preparation of compound c
Under the room temperature, in reaction flask, drop into a(142.5g), b(204.5g, N-tertbutyloxycarbonyl-3-hydroxyl-1-adamantyl-D-glycine, CAS:361442-00-4), HOBT(86.6g, CAS:80029-43-2), EDCHCl(131.3g, CAS:25952-53-8), DIPEA(170.5g, CAS:7087-68-5) with acetonitrile (520ml), stirring at room 3h is dropped in ethyl acetate (500ml) dissolving back.In reaction solution, add ethyl acetate (2.0L), 1N hydrochloric acid (650ml), saturated aqueous common salt (650ml) stirs 30min, leaves standstill; Lower floor abandons, and the upper strata adds saturated sodium bicarbonate solution (650ml), stirs 30min, leaves standstill; Lower floor abandons, and previous action 2 times are repeated on the upper strata; The upper strata adds saturated aqueous common salt (1.0L) then, stirs 15min, leaves standstill; Lower floor abandons, and the upper strata is concentrated into spumescence, does not have obvious dissolvent residual and gets final product.
The preparation of compound d
Drop into D(320g in the reaction flask), tetrahydrofuran (THF) (3.2L), pyridine (292g) is cooled to 0-5 ° of C; In reaction solution, drip trifluoroacetic anhydride (544g), in the dropping process, keep temperature to be no more than 10 ° of C; Dropwise insulated and stirred 1h; TLC follows the tracks of the affirmation reaction and finishes (if unreacted is complete, can add trifluoroacetic anhydride (0.1eq) to reacting completely); Reaction solution is concentrated into no cut and steams, 55 ° of C of bath temperature; Add ethyl acetate (1.5L), water (350ml) stirs 30min, leaves standstill; Lower floor abandons, and the upper strata adds saturated aqueous common salt (350ml), stirs 30min, leaves standstill, and lower floor abandons, and 55 ° of C underpressure distillation of upper water bath temperature get yellow oil 384g.
The preparation of Sha Gelieting (I)
Drop into compound d (363g), Virahol (380ml), water (380ml) and 36% hydrochloric acid (125ml) in the reaction flask, 65 ° of C of temperature stir 1.5h in being warming up to; TLC follows the tracks of and confirms to react completely.
Reaction solution is concentrated in 65 ° of C water-baths; Add water (500ml) in the enriched material, methylene dichloride (3.0L), stirring down, 20% solution of potassium carbonate adjusting upper strata pH value adds sodium-chlor (480g) to 9-10, stirring 30min; Leave standstill, the upper strata extracts with methylene dichloride (3.0L), and TLC does not abandon after having product; Merge lower floor, water (3.0L) is washed, and removes by filter wherein mechanical impurity.
Be concentrated into about 500ml, add ethyl acetate (1.2L), slowly stir; 0.5h after, add water 3ml, stir 0.5h, add water 3ml again, stirring at room 0.5h; Residual methylene dichloride in the system is removed in 45 ℃ of distillations; Stirring at room 15h; Filter, the washing of solid ethyl acetate, 55 ℃ of dry 18h get white or off-white color solid 89g, and purity is more than 99%.
More than specific embodiments of the invention are described in detail, but it does not limit the scope of the invention.Any equivalent modifications that the present invention is carried out and substituting also all among category of the present invention.Therefore, not breaking away from impartial conversion and the modification of doing under the spirit and scope of the present invention, all should contain within the scope of the invention.
Claims (10)
1. method of producing Sha Gelieting is characterized in that step comprises:
Step 1 provides compound d; Wherein, the compound d structural formula is as follows:
Step 2 is reacted compound d, Virahol, concentrated hydrochloric acid at 50-80 ° of C, collect product and obtain Sha Gelieting.
2. method according to claim 1 is characterized in that, temperature of reaction is 55-75 ° of C in the step 2.
3. method according to claim 1 is characterized in that, the reaction times is 0.5-4h in the step 2.
4. method according to claim 1 is characterized in that, the method for collecting product described in the step 2 is: reaction solution after 50-80 ° of C concentrates, is added water and halohydrocarbon, regulate water layer pH value to 9-10, add sodium-chlor, stir; Collected organic layer; Remove halohydrocarbon; The solid that collection is separated out.
5. method according to claim 4 is characterized in that, in the described collection method, the method for removing halohydrocarbon is: earlier organic layer is concentrated, add ethyl acetate then, add water in batches, stir, halohydrocarbon is removed in distillation then.
6. method according to claim 1 is characterized in that, the mass concentration of concentrated hydrochloric acid is preferably 36-38% in the step 2.
7. method according to claim 1 is characterized in that, compound d is reacted under≤10 ° of C conditions by compound c and trifluoroacetic acid and obtained, and wherein, the compound c structural formula is as follows:
8. method according to claim 7, it is characterized in that, compound c by compound a and compound b at I-hydroxybenzotriazole (HOBT), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl), N, N-diisopropylethylamine (DIPEA) exists down, obtains at 10-40 ° of C scope internal reaction; Wherein, compound a and b structural formula are as follows:
9. method according to claim 8 is characterized in that, compound a is obtained 50-80 ° of C reaction by compound a-1 and Virahol, methanesulfonic.
10. method according to claim 9 is characterized in that, compound a-1 is cooled to 0-5 ° of C with Virahol, methanesulfonic reaction solution, collects the solid of separating out, and obtains compound a.
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| CN201310222269XA CN103265473A (en) | 2013-06-04 | 2013-06-04 | Method for producing saxagliptin |
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| CN201310222269XA CN103265473A (en) | 2013-06-04 | 2013-06-04 | Method for producing saxagliptin |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910669A (en) * | 2014-04-04 | 2014-07-09 | 苏州景泓生物技术有限公司 | Process for preparing a saxagliptin critical intermediate |
| CN105037245A (en) * | 2015-08-03 | 2015-11-11 | 沧州那瑞化学科技有限公司 | Saxagliptin midbody preparing method |
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| CN105037245A (en) * | 2015-08-03 | 2015-11-11 | 沧州那瑞化学科技有限公司 | Saxagliptin midbody preparing method |
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Application publication date: 20130828 |