CN104447374A - Preparation method of sitagliptin and intermediate thereof - Google Patents
Preparation method of sitagliptin and intermediate thereof Download PDFInfo
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- CN104447374A CN104447374A CN201310425340.4A CN201310425340A CN104447374A CN 104447374 A CN104447374 A CN 104447374A CN 201310425340 A CN201310425340 A CN 201310425340A CN 104447374 A CN104447374 A CN 104447374A
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- 0 *OC(CC(Cc(c(F)c1)cc(F)c1F)=O)=O Chemical compound *OC(CC(Cc(c(F)c1)cc(F)c1F)=O)=O 0.000 description 8
- COUGIGFQGFTRPG-UHFFFAOYSA-N CC(C)(OC(C1=C(Cc(cc(c(F)c2)F)c2F)O)=O)OC1=O Chemical compound CC(C)(OC(C1=C(Cc(cc(c(F)c2)F)c2F)O)=O)OC1=O COUGIGFQGFTRPG-UHFFFAOYSA-N 0.000 description 1
- PMRULXSPRYTRIX-GFCCVEGCSA-N CCC[NH+](C(C[C@@H](Cc(cc(c(F)c1)F)c1F)NC(OC(C)(C)C)=O)=O)[O-] Chemical compound CCC[NH+](C(C[C@@H](Cc(cc(c(F)c1)F)c1F)NC(OC(C)(C)C)=O)=O)[O-] PMRULXSPRYTRIX-GFCCVEGCSA-N 0.000 description 1
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Abstract
The invention relates to the field of medicament synthesis and especially relates to a preparation method of sitagliptin and an intermediate thereof. The preparation method is as below: in the presence of a first organic solvent, a compound shown as formula I and a compound shown as formula II conduct reductive amination reaction under the action of sodium triacetoxyborohydride and lewis acid, so as to obtain a compound shown in formula III. The preparation method provided by the invention does not use precious metal as the catalyst, reduces the cost, simplifies the process, increases the yield, and improves the chemical purity and optical purity of sitagliptin. R1 represents C1-6 alkyl, C1-6 alkyl substituted alkyl or benzyl, R2 represents methyl or carbamoyl, and Ar represents phenyl, monosubstituted phenyl or polysubstituted phenyl.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, particularly the preparation method of a kind of sitagliptin and intermediate thereof.
Background technology
Due to factors such as the change of growth in the living standard, dietary structure, the rhythm of life be becoming tight day and few dynamic mode of life of sitting more, whole world onset diabetes rate rapid development, diabetes have become the chronic disease of the third-largest serious threat human health after tumour, cardiovascular pathological changes.Current global diabetic subject is more than 1.2 hundred million people, and Chinese patients people lives in groups the second in the world, and the onset diabetes rate of China is up to 9.6%, and in future 50 years, diabetes will be the serious public health problems of one, China.Based on type II diabetes in diabetes mellitus in China crowd, proportion reaches 93.7%, and therefore the medicine of prevention and therapy type II diabetes will have the market requirement widely.
The medicine for the treatment of diabetes mainly contains sulfonylureas, biguanides and two peptidyl peptide enzyme – IV (being called for short DPP-4) inhibitor class medicines.DPP-4 is the enzyme in a kind of body, and its main effect is the protein in decomposer, can decompose glucose-dependent insulinotropic peptide-1(and be called for short GLP-1).DPP-4 inhibitor class medicine can suppress the generation of DPP-4, increases GLP-1 level, thus reaches and stimulate Regular Insulin, the mode that suppresses glycemic element, suppress stomach emptying and allow islet cells live again to fall hypoglycemic object.Sitagliptin is a kind of DPP-4 inhibitor class medicine, it is the novel antidiabetic drug being used for the treatment of type II diabetes developed by Merck & Co., Inc., its structural formula is such as formula shown in IX, it can improve the ability that human body self reduces too high blood glucose level, its mechanism of action is: the level relatively improving natural generation incretin (comprising glucagon-like-peptide-1 and glucose-dependent-insulinotropic peptide) by suppressing DPP-4 active, trigger pancreas thus improve insulin production and make liver stop glucose production, reach the final clinical effectiveness reducing blood sugar concentration.
At present, existing preparation in the method for sitagliptin all needs to use expensive reagent (as rhodium, chiral ferrocene base diphosphine, platinum oxide etc.), and needs high-tension apparatus, and synthesis cost is high, is unsuitable for suitability for industrialized production.Therefore exploitation is simple, economical and to be suitable for the synthetic route of suitability for industrialized production very necessary.
Summary of the invention
In view of this, the invention provides the preparation method of a kind of sitagliptin and intermediate thereof.The method is by sodium triacetoxy borohydride and lewis acidic effect, make the generation of compound shown in formula I reductive amination process, obtain compound shown in formula III, obtain sitagliptin further again, the method, without the need to using noble metal as catalyzer, reduces cost, simplifies building-up process, improve yield, the chemical purity of sitagliptin and optical purity are all improved.
In order to realize foregoing invention object, the invention provides following technical scheme:
The invention provides the preparation method of compound shown in a kind of formula III, under the first organic solvent existent condition, compound shown in compound and formula II shown in modus ponens I, issues raw reductive amination process at sodium triacetoxy borohydride and lewis acidic effect, obtains compound shown in formula III;
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl; R
2for methyl or carbamyl; Ar is phenyl, monosubstituted phenyl or polysubstituted phenyl.
In embodiments more provided by the invention, R
1for methyl, ethyl or benzyl.
In embodiments more provided by the invention, Ar is phenyl.
The present invention passes through sodium triacetoxy borohydride as reductive agent, compound shown in formula I obtains compound shown in formula III through reductive amination process, avoid noble metal as catalyzer on the one hand, the stereoselectivity of sitagliptin can be improved on the other hand, improve the optical purity of sitagliptin.
Lewis acid refers to electron acceptor, and also can regard the centrosome forming coordinate bond as, common Lewis acid has the fluoroform sulphonate of aluminum chloride, iron(ic) chloride, boron trifluoride, columbium pentachloride and lanthanon.In the present invention, Lewis acid can reduce the energy state of reductive amination process, improves the yield of compound shown in formula III, thus can improve the yield of sitagliptin.
In embodiments more provided by the invention, Lewis acid is three isopropoxy titanium chlorides.
In order to ensure that compound shown in formula I is reduced fully, as preferably, the mol ratio of compound shown in sodium triacetoxy borohydride and formula I is (1.2 ~ 3): 1.
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl.
In embodiments more provided by the invention, the mol ratio of compound shown in sodium triacetoxy borohydride and formula I is (1.4 ~ 2.0): 1.
As preferably, the mol ratio of compound shown in Lewis acid and formula I is (1.0 ~ 2.5): 1.
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl.
In embodiments more provided by the invention, the mol ratio of compound shown in Lewis acid and formula I is (1.5 ~ 2.2): 1.
As preferably, the mol ratio of compound shown in compound and formula II shown in formula I is 1:(1.0 ~ 4.0).
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl; R
2for methyl or carbamyl; Ar is phenyl, monosubstituted phenyl or polysubstituted phenyl.
Preferably, the mol ratio of compound shown in compound and formula II shown in formula I is 1:(1.2 ~ 1.6).
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl; R
2for methyl or carbamyl; Ar is phenyl, monosubstituted phenyl or polysubstituted phenyl.
In embodiments more provided by the invention, the first organic solvent is selected from a kind of or both the above mixed solutions in 1,2-ethylene dichloride, methylene dichloride, tetrahydrofuran (THF) or acetonitrile.
As preferably, in g/mL, the mass volume ratio of compound shown in formula I and the first organic solvent is 1:(5 ~ 15).
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl.
In order to compound shown in the formula III that obtained purity is higher, in the preparation method of compound shown in formula III, after obtaining compound shown in formula III, also comprise the step of purifying;
Formula III
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl; R
2for methyl or carbamyl; Ar is phenyl, monosubstituted phenyl or polysubstituted phenyl.
In embodiments more provided by the invention, purifying comprises the steps such as cancellation, extraction, washing, drying, concentrated or recrystallization.
In embodiments more provided by the invention, the preparation method of compound shown in formula I is: under the second organic solvent existent condition, 2,4, condensation reaction is there is in 5-trifluoro benzene acetic acid and isopropylidene malonate under the effect of activator and acid binding agent, obtain compound shown in formula IV, shown in described formula IV, compound and alcohol are through alcoholysis reaction, to obtain final product;
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl.
In embodiments more provided by the invention, the second organic solvent is acetonitrile.
In embodiments more provided by the invention, activator is pivaloyl chloride.
In embodiments more provided by the invention, acid binding agent is the mixture of DIPEA and DMAP.
In embodiments more provided by the invention, the alcohol adopted in the preparation method of compound shown in formula I is selected from methyl alcohol, ethanol or phenylcarbinol.
Present invention also offers a kind of preparation method of sitagliptin, comprise the steps:
Steps A, under the first solvent existent condition, compound shown in the formula III that shown in formula III provided by the invention, the preparation method of compound obtains, under the katalysis of palladium hydroxide carbon and formic acid, obtains compound shown in formula V through debenzylation;
Compound shown in formula V through Boc protection, esterification, condensation reaction, remove Boc protecting group, salt-forming reaction, obtain the sitagliptin shown in formula IX;
In the preparation method of sitagliptin, Boc protection is specially: under the second solvent existent condition, and compound shown in formula V, under the katalysis of lithium hydroxide, through Boc protection, obtains compound shown in formula VI;
In the preparation method of sitagliptin, esterification is specially: under the 3rd solvent existent condition, shown in modus ponens VI, compound mixes with HONb, under the katalysis of DCC, through esterification, obtains compound shown in formula VII;
In the preparation method of sitagliptin, condensation reaction is specially: under the 4th solvent existent condition, compound shown in formula VII and 3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine generation condensation reaction, obtains compound shown in formula VIII.
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl;
In above-mentioned sitagliptin preparation method, the preparation method of compound shown in formula III provided by the invention is: under the first organic solvent existent condition, compound shown in compound and formula II shown in modus ponens I, issue raw reductive amination process at sodium triacetoxy borohydride and lewis acidic effect, obtain compound shown in formula III; Lewis acid is three isopropoxy titanium chlorides; First organic solvent is selected from a kind of or both the above mixed solutions in 1,2-ethylene dichloride, methylene dichloride, tetrahydrofuran (THF) or acetonitrile; The step of purifying is also comprised after obtaining compound shown in formula III; Purifying comprises cancellation, extraction, washing, drying, concentrated or recrystallization; The preparation method of compound shown in formula I is: under the second organic solvent existent condition, 2,4, condensation reaction is there is in 5-trifluoro benzene acetic acid and isopropylidene malonate under the effect of activator and acid binding agent, obtain compound shown in formula IV, compound shown in formula IV and alcohol, through alcoholysis reaction, to obtain final product; The second organic solvent in the preparation method of compound shown in formula I is acetonitrile; Activator in the preparation method of compound shown in formula I is pivaloyl chloride; Acid binding agent is the mixture of DIPEA and DMAP.
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl; R
2for methyl or carbamyl; Ar is phenyl, monosubstituted phenyl or polysubstituted phenyl.
In embodiments more provided by the invention, the first solvent is the mixed solution of tetrahydrofuran (THF) and methyl alcohol.
In embodiments more provided by the invention, the second solvent is water.
In embodiments more provided by the invention, the 3rd solvent is THF.
In embodiments more provided by the invention, the 4th solvent is the mixed solution of THF and water.
Sitagliptin is chiral drug, and the detection of chiral drug optical purity is crucial in chiral drug research and important step.Diastereomeric excess (diastereomeric excess, be abbreviated as de%), be commonly used to optical purity when characterizing two or more chiral centre, namely a kind of amount of diastereomer deducts the absolute value of the amount of another kind of diastereomer, then divided by sum of the two, its method of calculation are: the amount of the amount-diastereomer b of de%=(diastereomer a)/(amount of the amount+diastereomer b of diastereomer a).When HPLC measures, adopt achirality post, the peak area at diastereomer peak can be utilized directly to ask de% value; Enantiomeric excess (enantiomeric excess, be abbreviated as ee%), it is the percentage ratio that additional amount of another isomer of ratios of the isomers accounts for total amount in mixture of enantiomers, is also used for representing a kind of optical purity of chipal compounds, ee% is higher, and optical purity is also higher.When HPLC measures, adopt chiral column, the peak area at enantiomer peak can be utilized directly to ask ee% value.The present invention, by detecting de% value and ee% value, proves that the optical purity of the sitagliptin utilizing preparation method provided by the invention to obtain is higher.
The invention provides the preparation method of a kind of sitagliptin and intermediate thereof.The method is: under the first organic solvent existent condition, and compound shown in compound and formula II shown in modus ponens I issues raw reductive amination process at sodium triacetoxy borohydride and lewis acidic effect, obtains compound shown in formula III.The ee% of the sitagliptin utilizing the method to obtain can reach 99.2%, and by compound shown in formula I, yield reaches 57.5%.As can be seen here, preparation method provided by the invention, without the need to using noble metal as catalyzer, reduces cost, simplifies building-up process, improves yield, and the chemical purity of sitagliptin and optical purity are all improved.
Accompanying drawing explanation
Fig. 1 shows the mass spectrum of the sitagliptin that embodiment 8 provides;
Fig. 2 shows the chirality HPLC figure of the sitagliptin that embodiment 8 provides.
Embodiment
The invention discloses the preparation method of a kind of sitagliptin and intermediate thereof, those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope methods and applications as herein described are changed or suitably change with combination, realize and apply the technology of the present invention.
The abbreviation used in specification sheets and claims and English concrete meaning as follows:
In the preparation method of sitagliptin provided by the invention and intermediate thereof, raw materials used and reagent all can be buied by market.
Below in conjunction with embodiment, set forth the present invention further:
The preparation of compound shown in embodiment 1 formula I
25g2 is added in 500mL there-necked flask, 4,5-trifluoro benzene acetic acid, 21g isopropylidene malonate and 1.29g Dimethylamino pyridine (DMAP), add 75mL acetonitrile, under room temperature magnetic agitation, add diisopropylethylamine 49.2mL, be heated to 50 DEG C, slowly drip pivaloyl chloride 17.8mL, keep temperature not higher than 55 DEG C.Dropwise maintenance 50 ~ 55 DEG C reaction after 3 hours, reaction solution is cooled to 0 DEG C, slow dropping 260mL1mol/L hydrochloric acid, drip complete maintenance 0 ~ 5 DEG C and stir 1h, suction filtration, filter cake 20% acetonitrile wash four times, collect filter cake, after vacuum-drying 16h, obtain solid 39g, it is compound shown in formula IV after testing.
Above-mentioned solid (shown in formula IV compound) is added 300mL dehydrated alcohol, and under magnetic agitation after reflux 1h, thin-layer chromatography detects raw material and disappears.Decompression is revolved and is desolventized, residuum adds 200mL methyl tertiary butyl ether and dissolves, cross 20g100-200 order silica gel, silica gel is rinsed twice again with 50mL methyl tertiary butyl ether, merging filtrate, revolves after desolventizing and namely obtains 29.4g solid, and through mass spectrometric detection, it is compound shown in formula I, yield 85.5%, m/z:261.36 [M+H]
+.
Wherein, R
1for ethyl.
The preparation of compound shown in embodiment 2 formula I
25g2 is added in 500mL there-necked flask, 4,5-trifluoro benzene acetic acid, 21g isopropylidene malonate and 1.29g Dimethylamino pyridine (DMAP), add 75mL acetonitrile, under room temperature magnetic agitation, add diisopropylethylamine 49.2mL, be heated to 50 DEG C, slowly drip pivaloyl chloride 17.8mL, keep temperature not higher than 55 DEG C.Dropwise maintenance 50 ~ 55 DEG C reaction after 3 hours, reaction solution is cooled to 0 DEG C, slow dropping 260mL1mol/L hydrochloric acid, drip complete maintenance 0 ~ 5 DEG C and stir 1h, suction filtration, filter cake 20% acetonitrile wash four times, collect filter cake, after vacuum-drying 16h, obtain solid 39g, it is compound shown in formula IV after testing.
Above-mentioned solid (shown in formula IV compound) is added 300mL methyl alcohol, and under magnetic agitation after reflux 1h, thin-layer chromatography detects raw material and disappears.Decompression is revolved and is desolventized, residuum adds 200mL methyl tertiary butyl ether and dissolves, cross 20g100-200 order silica gel, silica gel is rinsed twice again with 50mL methyl tertiary butyl ether, merging filtrate, revolves after desolventizing and namely obtains solid 28.9g, and through mass spectrometric detection, it is compound shown in formula I, yield 89.3%, m/z:246.28 [M+H]
+.
Wherein, R
1for methyl (Me).
The preparation of compound shown in embodiment 3 formula I
25g2 is added in 500mL there-necked flask, 4,5-trifluoro benzene acetic acid, 21g isopropylidene malonate and 1.29g Dimethylamino pyridine (DMAP), add 75mL acetonitrile, under room temperature magnetic agitation, add diisopropylethylamine 49.2mL, be heated to 50 DEG C, slowly drip pivaloyl chloride 17.8mL, keep temperature not higher than 55 DEG C.Dropwise maintenance 50 ~ 55 DEG C reaction after 3 hours, reaction solution is cooled to 0 DEG C, slow dropping 260mL1mol/L hydrochloric acid, drip complete maintenance 0 ~ 5 DEG C and stir 1h, suction filtration, filter cake 20% acetonitrile wash four times, collect filter cake, after vacuum-drying 16h, obtain solid 39g, it is compound shown in formula IV after testing.
Above-mentioned solid (shown in formula IV compound) is added 300mL phenylcarbinol, and under magnetic agitation after reflux 1h, thin-layer chromatography detects raw material and disappears.Decompression is revolved and is desolventized, residuum adds 200mL methyl tertiary butyl ether and dissolves, cross 20g100-200 order silica gel, silica gel is rinsed twice again with 50mL methyl tertiary butyl ether, merging filtrate, revolves after desolventizing and namely obtains solid 35.7g, and through mass spectrometric detection, it is compound shown in formula I, yield 84.2%, m/z:322.46 [M+H]
+.
Wherein, R
1for benzyl (Bzl).
The preparation of compound shown in embodiment 4 formula III
Compound shown in the formula I that 26.0g (0.10mol) embodiment 1 is provided; be dissolved in 130mL acetonitrile; 14.5g (0.12mol) (R)-α-phenylethylamine is dripped under magnetic agitation; dropwise, under nitrogen protection, add three isopropoxy titanium chloride 35.7mL (0.15mol).After magnetic agitation 10min, adding 29.7g (0.14mol) sodium triacetoxy borohydride and 1.2mL (0.02mol) acetic acid, after stirring at room temperature reacts 15 hours, TLC(thin-layer chromatography) monitoring reacts completely, stops stirring.Reaction solution extracts, wash twice with 120mL1mol/L hydrochloric acid successively, 120mL saturated sodium bicarbonate solution washes twice, and 120mL saturated aqueous common salt washes twice, after the organic addition anhydrous magnesium sulfate drying of gained, filtering magnesium sulfate, filtrate reduced in volume obtains solid 30.3g, and through mass spectrometric detection, it is compound shown in formula III, yield 83%, de%>99%, m/z:366.28 [M+H]
+.
Wherein, R
1for ethyl; R
2for methyl; Ar is phenyl.
The preparation of compound shown in embodiment 5 formula III
Compound shown in the formula I that 26.0g (0.10mol) embodiment 1 is provided; be dissolved in 250mL1; in 2-ethylene dichloride; 21.2g (0.14mol) (S)-alpha-amino group phenylacetamide is dripped under magnetic agitation; dropwise, under nitrogen protection, add three isopropoxy titanium chloride 42.9mL (0.18mol).After magnetic agitation 10min, add 36.0g (0.17mol) sodium triacetoxy borohydride and 1.2mL (0.02mol) acetic acid, after stirring at room temperature reacts 5 hours, TLC monitoring reacts completely, and stops stirring.Reaction solution extracts, and wash twice with 120mL1mol/L hydrochloric acid successively, 120mL saturated sodium bicarbonate solution washes twice, and 120mL saturated aqueous common salt washes twice.After the organic addition anhydrous magnesium sulfate drying of gained, filtering magnesium sulfate, filtrate reduced in volume obtains solid 31.6g, and through mass spectrometric detection, it is compound shown in formula III, yield 80%, de%>99%, m/z:395.31 [M+H]
+.
Wherein, R
1for ethyl; R
2for carbamyl; Ar is phenyl.
The preparation of compound shown in embodiment 6 formula III
By 24.6g(0.1mol) compound and 19.3g (0.16mol) (R)-α-phenylethylamine shown in the formula I that provides of embodiment 2; be dissolved in 370mL methylene dichloride, under nitrogen protection, add three isopropoxy titanium chloride 52.4mL (0.22mol).After magnetic agitation 10min, add 42.4g (0.20mol) sodium triacetoxy borohydride and 1.2mL (0.02mol) acetic acid, after stirring at room temperature reacts 12 hours, TLC monitoring reacts completely, and stops stirring.Reaction solution extracts, and wash twice with 120mL1mol/L hydrochloric acid successively, 120mL saturated sodium bicarbonate solution washes twice, and 120mL saturated aqueous common salt washes twice.After the organic addition anhydrous magnesium sulfate drying of gained, filtering magnesium sulfate, filtrate reduced in volume obtains solid 29.1g, and it is compound shown in formula III after testing, and yield 83%, de% is greater than 99%, m/z:352.23 [M+H]
+.
Wherein, R
1for methyl; R
2for methyl; Ar is phenyl.
The preparation of compound shown in embodiment 7 formula III
Compound shown in the formula I provide 32.2g embodiment 3, is dissolved in 300mL tetrahydrofuran (THF), drips 14.5g (R)-α-phenylethylamine under magnetic agitation.Dropwise, under nitrogen protection, add three isopropoxy titanium chloride 52.4mL (0.22mol).After magnetic agitation 10min, add 29.7g sodium triacetoxy borohydride and 1.2mL (0.02mol) acetic acid, after stirring at room temperature reacts 6 hours, TLC monitoring reacts completely, and stops stirring.Revolve except the tetrahydrofuran (THF) in reaction solution, residue adds 250mL methylene dichloride and dissolves, and extraction, wash twice with 120mL1mol/L hydrochloric acid successively, 120mL saturated sodium bicarbonate solution washes twice, and 120mL saturated aqueous common salt washes twice.After the organic addition anhydrous magnesium sulfate drying of gained, filtering magnesium sulfate, filtrate reduced in volume obtains solid 33.2g, and through mass spectrometric detection, it is compound shown in formula III, and yield 78%, de% is greater than 99%, m/z:428.39 [M+H]
+.
Wherein, R
1for benzyl; R
2for methyl; Ar is phenyl.
The preparation of embodiment 8 sitagliptin
By compound 200mL tetrahydrofuran (THF) and 200mL dissolve with methanol shown in formula III obtained for embodiment 4, add 6g20%Pd (OH)
2/ C and 30mL88% formic acid, after reflux 6h, TLC detection reaction is complete.Reacting liquid filtering removing palladium hydroxide carbon, washed with methanol filter cake, obtains the first filtrate for subsequent use, contains compound shown in formula V after testing in the first filtrate.
Adjust pH to be 9 above-mentioned first filtrate 5%NaOH solution, add 2.2g lithium hydroxide, room temperature magnetic agitation, react after 3 hours, TLC detection reaction is complete.24mL Boc is added in reaction solution
2o(tert-Butyl dicarbonate), room temperature reaction spends the night.Decompression is revolved except the organic solvent in reaction solution, and remaining liq adds 100mL water, 200mL n-hexane extraction, water layer sal enixum regulates pH to 3,150mL ethyl acetate (EA) extracting twice, merges EA layer, 10% potassium hydrogen sulfate solution extracts once, saturated aqueous common salt extracting twice.Gained EA solution, adds anhydrous sodium sulfate drying, concentrated to obtain white solid, uses EA:Hex=3:1 recrystallization, obtains solid 23.9g, after testing compound shown in its formula VI protected for Boc, yield 86.5%.
By compound 23.9g shown in above-mentioned formula VI and 14.1g HONb, be dissolved in 200mL THF, under nitrogen protection, add 17.9g DCC, stirring at room temperature 5 hours, filtering solid, obtains the second filtrate for subsequent use.
Get 18.1g3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and 13.2g sodium bicarbonate is dissolved in the mixed solution of 100mL THF and 200mL water; Get in above-mentioned second filtrate added drop-wise to above-mentioned mixed solution, dropwise, stirring at room temperature reacts 16 hours, and TLC detection reaction is complete.Decompression is revolved except the THF in reaction solution, and residual reaction liquid adds 400mL DCM and extracts, and DCM layer uses 10% potassium hydrogen sulfate solution and saturated common salt water washing successively, and gained DCM solution adds anhydrous sodium sulfate drying.After filtering sodium sulfate, filtrate adds 100mL TFA, and stirring at room temperature is reacted and removed Boc completely in 2 hours.Revolve and desolventize, gained sticky solid adds 140mL ethanol and 30mL water dissolution, is warming up to 50 DEG C, after once adding 85% phosphoric acid 8.3g, temperature rises to 74 DEG C, after 30min, be cooled to 65 DEG C again, add 0.1g sitagliptin phosphate crystal seed, after keeping 65 DEG C to stir 1h, slow cooling is to room temperature, add 560mL dehydrated alcohol, left at room temperature over night, filters, 80mL ice alcohol flushing filter cake.Collect filter cake, obtain solid 29.5g after vacuum-drying, it is sitagliptin after testing, by compound shown in formula III, and yield 67.9%, by formula I, yield 56.4%, m/z:408.33 [M+H]
+, as shown in Figure 1, ee%:99.19%, its collection of illustrative plates as shown in Figure 2 for its collection of illustrative plates.
Wherein, R
1for ethyl; R
2for methyl; Ar is phenyl.
The preparation of embodiment 9 sitagliptin
By compound 200mL tetrahydrofuran (THF) and 200mL dissolve with methanol shown in formula III obtained for embodiment 5, add 6g20%Pd (OH)
2/ C and 30mL88% formic acid, after reflux 6h, TLC detection reaction is complete.Reacting liquid filtering removing palladium hydroxide carbon, washed with methanol filter cake, obtains the first filtrate for subsequent use, contains compound shown in formula V after testing in the first filtrate.
Adjust pH to be 9 first filtrate 5%NaOH solution, add 2.1g lithium hydroxide, room temperature magnetic agitation, react after 3 hours, TLC detection reaction is complete.24mL Boc is added in reaction solution
2o(tert-Butyl dicarbonate), room temperature reaction spends the night.Decompression is revolved except the organic solvent in reaction solution, and remaining liq adds 100mL water, 200mL n-hexane extraction, water layer sal enixum regulates pH to 3,150mL ethyl acetate (EA) extracting twice, merges EA layer, 10% potassium hydrogen sulfate solution extracts once, saturated aqueous common salt extracting twice.Gained EA solution, adds anhydrous sodium sulfate drying, concentrated to obtain white solid, uses EA:Hex=3:1 recrystallization, obtains white solid 23.2g, after testing compound shown in its formula VI protected for Boc, yield 87.0%.
By compound 23.2g shown in above-mentioned formula VI and 14.0g HONb, be dissolved in 200mL THF, under nitrogen protection, add 17.8g DCC, stirring at room temperature 5 hours, filtering solid, obtains the second filtrate for subsequent use.
Get 18.0g3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and 13.2g sodium bicarbonate is dissolved in the mixed solution of 100mL THF and 200mL water; Get in above-mentioned second filtrate added drop-wise to above-mentioned mixed solution, dropwise, stirring at room temperature reacts 16 hours, and TLC detection reaction is complete.Decompression is revolved except the THF in reaction solution, and residual reaction liquid adds 400mL DCM and extracts, and DCM layer uses 10% potassium hydrogen sulfate solution and saturated common salt water washing successively, and gained DCM solution adds anhydrous sodium sulfate drying.After filtering sodium sulfate, filtrate adds 100mL TFA, and stirring at room temperature is reacted and removed Boc completely in 2 hours.Revolve and desolventize, gained sticky solid adds 140mL ethanol and 30mL water dissolution, is warming up to 50 DEG C, after once adding 85% phosphoric acid 8.0g, temperature rises to 74 DEG C, after 30min, be cooled to 65 DEG C again, add 0.1g sitagliptin phosphate crystal seed, after keeping 65 DEG C to stir 1h, slow cooling is to room temperature, add 560mL dehydrated alcohol, left at room temperature over night, filters, 80mL ice alcohol flushing filter cake.Collect filter cake, obtain solid 28.4g after vacuum-drying, it is sitagliptin after testing, by compound shown in formula III, and yield 67.8%, by formula I, yield 54.3%, m/z:408 [M+H]
+, ee%:99.12%.
Wherein, R
1for ethyl; R
2for carbamyl; Ar is phenyl.
The preparation of embodiment 10 sitagliptin
By compound 200mL tetrahydrofuran (THF) and 200mL dissolve with methanol shown in formula III obtained for embodiment 6, add 6g20%Pd (OH)
2/ C and 30mL88% formic acid, after reflux 6h, TLC detection reaction is complete.Reacting liquid filtering removing palladium hydroxide carbon, washed with methanol filter cake, obtains the first filtrate for subsequent use, contains compound shown in formula V after testing in the first filtrate.
Adjust pH to be 9 first filtrate 5%NaOH solution, add 2.2g lithium hydroxide, room temperature magnetic agitation, react after 3 hours, TLC detection reaction is complete.24mL Boc is added in reaction solution
2o(tert-Butyl dicarbonate), room temperature reaction spends the night.Decompression is revolved except the organic solvent in reaction solution, and remaining liq adds 100mL water, 200mL n-hexane extraction, water layer sal enixum regulates pH to 3,150mL ethyl acetate (EA) extracting twice, merges EA layer, 10% potassium hydrogen sulfate solution extracts once, saturated aqueous common salt extracting twice.Gained EA solution, adds anhydrous sodium sulfate drying, concentrated to obtain white solid, uses EA:Hex=3:1 recrystallization, obtains white solid 24.6g, after testing compound shown in its formula VI protected for sterling Boc, yield 89%.
By compound 24.6g shown in above-mentioned formula VI and 14.5g HONb, be dissolved in 200mL THF, under nitrogen protection, add 18.3g DCC, stirring at room temperature 5 hours, filtering solid, obtains the second filtrate for subsequent use.
Get 18.6g3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and g sodium bicarbonate is dissolved in the mixed solution of 100mL THF and 200mL water; Get in above-mentioned second filtrate added drop-wise to above-mentioned mixed solution, dropwise, stirring at room temperature reacts 16 hours, and TLC detection reaction is complete.Decompression is revolved except the THF in reaction solution, and residual reaction liquid adds 400mL DCM and extracts, and DCM layer uses 10% potassium hydrogen sulfate solution and saturated common salt water washing successively, and gained DCM solution adds anhydrous sodium sulfate drying.After filtering sodium sulfate, filtrate adds 100mL TFA, and stirring at room temperature is reacted and removed Boc completely in 2 hours.Revolve and desolventize, gained sticky solid adds 140mL ethanol and 30mL water dissolution, is warming up to 50 DEG C, after once adding 85% phosphoric acid 8.6g, temperature rises to 74 DEG C, after 30min, be cooled to 65 DEG C again, add 0.1g sitagliptin phosphate crystal seed, after keeping 65 DEG C to stir 1h, slow cooling is to room temperature, add 560mL dehydrated alcohol, left at room temperature over night, filters, 80mL ice alcohol flushing filter cake.Collect filter cake, obtain solid 30.1g after vacuum-drying, it is sitagliptin after testing, by compound shown in formula III, and yield 69.3%, by formula I, yield 57.5%, m/z:408 [M+H]
+, ee%:99.2%.
Wherein, R
1for methyl; R
2for methyl; Ar is phenyl.
The preparation of embodiment 11 sitagliptin
By compound 200mL tetrahydrofuran (THF) and 200mL dissolve with methanol shown in formula III obtained for embodiment 7, add 6g20%Pd (OH)
2/ C and 30mL88% formic acid, after reflux 6h, TLC detection reaction is complete.Reacting liquid filtering removing palladium hydroxide carbon, washed with methanol filter cake, obtains the first filtrate for subsequent use, contains compound shown in formula V after testing in the first filtrate.
Adjust pH to be 9 first filtrate 5%NaOH solution, add 2.1g lithium hydroxide, room temperature magnetic agitation, react after 3 hours, TLC detection reaction is complete.24mL Boc is added in reaction solution
2o(tert-Butyl dicarbonate), room temperature reaction spends the night.Decompression is revolved except the organic solvent in reaction solution, and remaining liq adds 100mL water, 200mL n-hexane extraction, water layer sal enixum regulates pH to 3,150mL ethyl acetate (EA) extracting twice, merges EA layer, 10% potassium hydrogen sulfate solution extracts once, saturated aqueous common salt extracting twice.Gained EA solution, adds anhydrous sodium sulfate drying, concentrated to obtain white solid, uses EA:Hex=3:1 recrystallization, obtains white solid 22.9g, after testing compound shown in its formula VI protected for sterling Boc, yield 88%.
By compound 22.9g shown in above-mentioned formula VI and 13.5g HONb, be dissolved in 200mL THF, under nitrogen protection, add 17.0g DCC, stirring at room temperature 5 hours, filtering solid, obtains the second filtrate for subsequent use.
Get 17.3g3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and 13.0g sodium bicarbonate is dissolved in the mixed solution of 100mL THF and 200mL water; Get in above-mentioned second filtrate added drop-wise to above-mentioned mixed solution, dropwise, stirring at room temperature reacts 16 hours, and TLC detection reaction is complete.Decompression is revolved except the THF in reaction solution, and residual reaction liquid adds 400mL DCM and extracts, and DCM layer uses 10% potassium hydrogen sulfate solution and saturated common salt water washing successively, and gained DCM solution adds anhydrous sodium sulfate drying.After filtering sodium sulfate, filtrate adds 100mL TFA, and stirring at room temperature is reacted and removed Boc completely in 2 hours.Revolve and desolventize, gained sticky solid adds 140mL ethanol and 30mL water dissolution, is warming up to 50 DEG C, after once adding 85% phosphoric acid 7.9g, temperature rises to 74 DEG C, after 30min, be cooled to 65 DEG C again, add 0.1g sitagliptin phosphate crystal seed, after keeping 65 DEG C to stir 1h, slow cooling is to room temperature, add 560mL dehydrated alcohol, left at room temperature over night, filters, 80mL ice alcohol flushing filter cake.Collect filter cake, obtain solid 27.8g after vacuum-drying, it is sitagliptin after testing, collects rate 68.2% by compound shown in formula III, by formula I, and yield 53.1%, m/z:408 [M+H]
+, ee%:99.2%.
Wherein, R
1for benzyl; R
2for methyl; Ar is phenyl.
The preparation of comparative example 1 sitagliptin
At room temperature, formula I 3.0g (12.0mmol) obtained for embodiment 2 is dissolved in 50mL methyl alcohol, add (R)-α-phenylethylamine 4.12g (24.0mmol) and acetic acid 0.8mL (12.0mmol) successively, in 40 DEG C of stirring reaction 18h.Decompression removing methyl alcohol, adds 50mL water and 50mL EA extracts, and water layer extracts 2 times with EA again, and merge EA layer, after saturated common salt water washing, after adding anhydrous sodium sulfate drying, concentrating under reduced pressure, flash column chromatography obtains colorless oil 4.28g.
Add in 30mL tetrahydrofuran (THF) by sodium cyanoborohydride 2.4g (37.2mmol), add 2.4mL acetic acid subsequently, under ice bath, add the above-mentioned oily matter of 4.28g, be slowly warming up to room temperature, stirring is spent the night.With saturated sodium carbonate solution adjust pH to 10, EA extracts, and saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, column chromatography for separation, obtains formula III compound 3.48g, and yield 76.4%, de% is 75.4%, m/z:352.23 [M+H]
+.
By compound 20mL tetrahydrofuran (THF) and 20mL dissolve with methanol shown in above-mentioned obtained formula III, add 0.6g20%Pd (OH)
2/ C and 3mL88% formic acid, after reflux 6h, TLC detection reaction is complete.Reacting liquid filtering removing palladium hydroxide carbon, washed with methanol filter cake, obtains the first filtrate for subsequent use, contains compound shown in formula V after testing in the first filtrate.
Adjust pH to be 9 first filtrate 5%NaOH solution, add 0.2g lithium hydroxide, room temperature magnetic agitation, react after 3 hours, TLC detection reaction is complete.2.5mL Boc is added in reaction solution
2o(tert-Butyl dicarbonate), room temperature reaction spends the night.Decompression is revolved except the organic solvent in reaction solution, and remaining liq adds 20mL water, 20mL n-hexane extraction, water layer sal enixum regulates pH to 3,50mL ethyl acetate (EA) extracting twice, merges EA layer, 10% potassium hydrogen sulfate solution extracts once, saturated aqueous common salt extracting twice.Gained EA solution, adds anhydrous sodium sulfate drying, concentrated to obtain white solid, uses EA:Hex=3:1 recrystallization, obtains white solid 2.81g, after testing compound shown in its formula VI protected for sterling Boc, yield 85%.
By compound 2.81g shown in above-mentioned formula VI and 1.66g HONb, be dissolved in 30mL THF, under nitrogen protection, add 1.98g DCC, stirring at room temperature 5 hours, filtering solid, obtains the second filtrate for subsequent use.
Get 2.01g3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-[1,2,4] triazolo [4,3-a] pyrazine hydrochloride and 2.5g sodium bicarbonate is dissolved in the mixed solution of 20mL THF and 20mL water; Get in above-mentioned second filtrate added drop-wise to above-mentioned mixed solution, dropwise, stirring at room temperature reacts 16 hours, and TLC detection reaction is complete.Decompression is revolved except the THF in reaction solution, and residual reaction liquid adds 40mL DCM and extracts, and DCM layer uses 10% potassium hydrogen sulfate solution and saturated common salt water washing successively, and gained DCM solution adds anhydrous sodium sulfate drying.After filtering sodium sulfate, filtrate adds 10mL TFA, and stirring at room temperature is reacted and removed Boc completely in 2 hours.Revolve and desolventize, gained sticky solid adds 15mL ethanol and 3mL water dissolution, is warming up to 50 DEG C, after once adding 85% phosphoric acid 0.97g, temperature rises to 74 DEG C, after 30min, be cooled to 65 DEG C again, add 0.05g sitagliptin phosphate crystal seed, after keeping 65 DEG C to stir 1h, slow cooling is to room temperature, add 56mL dehydrated alcohol, left at room temperature over night, filters, 10mL ice alcohol flushing filter cake.Collect filter cake, obtain solid 3.38g after vacuum-drying, it is sitagliptin after testing, by compound shown in formula III, and yield 65.2%, by formula I, yield 49.8%, m/z:408 [M+H]
+, ee%:75.2%.
Wherein, R
1for methyl; R
2for methyl; Ar is phenyl.
From above-mentioned test-results, compound yield shown in the formula III utilizing preparation method provided by the invention to obtain can reach 83%, de% and be greater than 99%; And compound yield shown in the formula III that the preparation method utilizing comparative example to provide obtains 76.4%, de% is only 75.4%, as can be seen here, utilizes the preparation method of compound shown in formula III provided by the invention can improve yield and the optical purity of compound shown in formula III; By formula I, the sitagliptin yield utilizing preparation method provided by the invention to obtain can reach 57.5%, ee% and reach 99.2%; And the sitagliptin yield that the preparation method utilizing comparative example to provide obtains 49.8%, ee% is only 75.2%, as can be seen here, utilizes the preparation method of sitagliptin provided by the invention can improve yield and the optical purity of sitagliptin.
The above is only 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 also should be considered as protection scope of the present invention.
Claims (10)
1. the preparation method of compound shown in a formula III, it is characterized in that, under the first organic solvent existent condition, compound shown in compound and formula II shown in modus ponens I, issue raw reductive amination process at sodium triacetoxy borohydride and lewis acidic effect, obtain compound shown in formula III;
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl; R
2for methyl or carbamyl; Ar is phenyl, monosubstituted phenyl or polysubstituted phenyl.
2. preparation method according to claim 1, is characterized in that, described Lewis acid is three isopropoxy titanium chlorides.
3. preparation method according to claim 1, is characterized in that, described first organic solvent is selected from a kind of or both the above mixed solutions in 1,2-ethylene dichloride, methylene dichloride, tetrahydrofuran (THF) or acetonitrile.
4. preparation method according to claim 1, is characterized in that, described in obtain compound shown in formula III after also comprise the step of purifying;
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl; R
2for methyl or carbamyl; Ar is phenyl, monosubstituted phenyl or polysubstituted phenyl.
5. preparation method according to claim 4, is characterized in that, described purifying comprises cancellation, extraction, washing, drying, concentrated or recrystallization.
6. preparation method according to claim 1, it is characterized in that, the preparation method of compound shown in described formula I is: under the second organic solvent existent condition, 2, there is condensation reaction in 4,5-trifluoro benzene acetic acid and isopropylidene malonate, obtain compound shown in formula IV under the effect of activator and acid binding agent, shown in described formula IV, compound and alcohol are through alcoholysis reaction, to obtain final product;
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl; R
2for methyl or carbamyl; Ar is phenyl, monosubstituted phenyl or polysubstituted phenyl.
7. preparation method according to claim 6, is characterized in that, described second organic solvent is acetonitrile.
8. preparation method according to claim 6, is characterized in that, described activator is pivaloyl chloride.
9. preparation method according to claim 6, is characterized in that, described acid binding agent is the mixture of DIPEA and DMAP.
10. a preparation method for sitagliptin, is characterized in that, comprises the steps:
Under the first solvent existent condition, compound shown in the formula III that preparation method obtains as described in claim 1 to 9, under the katalysis of palladium hydroxide carbon and formic acid, obtains compound shown in formula V through debenzylation;
Compound shown in described formula V through Boc protection, esterification, condensation reaction, remove Boc protecting group, salt-forming reaction, to obtain final product;
Wherein, R
1for C
1-6alkyl, C
1-6substituted alkyl or benzyl; R
2for methyl or carbamyl; Ar is phenyl, monosubstituted phenyl or polysubstituted phenyl.
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| CN103172539A (en) * | 2011-12-23 | 2013-06-26 | 上海阳帆医药科技有限公司 | Preparation method of new diabetes drug sitagliptin intermediate aminobenzene butyric acid derivative |
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