CN102838603B - Preparation method of intermediate compound of sitagliptin - Google Patents
Preparation method of intermediate compound of sitagliptin Download PDFInfo
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Abstract
The invention discloses a preparation method of an intermediate compound of sitagliptin shown by a formula I. The preparation method comprises the following step of: performing reduction reaction of carbon-carbon double bond shown in the specification on a compound II in an organic solvent under the action of unsubstituted C1-C6 saturated fatty acid or halogen substituted C1-C6 saturated fatty acid and boron hydride, wherein R is a methyl group or a carbamyl group. The preparation method has the advantages of capability of avoiding use of heavy metal as a catalyst, low cost, simple post-treatment, high product yield, extremely high chemical purity and optical purity, de percentage of greater than 99.5 percent, capability of being smoothly used for synthesis of the sitagliptin and suitability for industrial production.
Description
Technical field
The present invention is specifically related to a kind of preparation method of midbody compound of sitagliptin.
Background technology
Sitagliptin (English name: Sitagliptin), chemistry is by name: 7-[1-oxo-3R-3-amino-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine, as shown in structural formula 1: be a kind of dipeptidyl peptidase-IV (DPP-IV) inhibitor that Merck company develops, be used for the treatment of type II diabetes clinically.
In sitagliptin preparation process, the main points being configured to synthetic route of chiral amino.At present, in sitagliptin preparation method, the method for main structure chiral amino is as follows:
Route one: (reference: WO2004/085378)
In this route, the structure of sitagliptin chiral amino is that the hydro-reduction reaction participated in by metal rhodium and chiral ferrocene base diphosphine is realized.The main shortcoming of the method has used metal rhodium and the very expensive reagent of chiral ferrocene ligands these two, and cost increases greatly, is difficult to applicable industrialized production.
Route two: (reference: WO2004/085661)
In this route, by introducing S-benzene G-NH2 as chiral auxiliary(reagent), platinum oxide catalytic hydrogenation induces required chiral amino, then obtains sitagliptin by debenzylation.The shortcoming of the method is because catalyst oxidation platinum is noble metal equally, improves the cost of route, is difficult to applicable industrialized production.
Route three: (reference: WO2009/085990)
This route chiral auxiliary(reagent) R-Alpha-Methyl benzylamine replaces S-benzene G-NH2, but makees catalyzer with expensive platinum oxide equally and carry out induction and obtain chiral amino.
Although prior art has reported several method preparing sitagliptin, they have one or more shortcomings, as used expensive reagent (platinum oxide, rhodium catalyst etc.), increase protection and deprotection steps etc.Therefore exploitation is simple, economical and can the synthetic route of industrialized production be very necessary.
Summary of the invention
Technical problem to be solved by this invention is in the method for key intermediate in order to overcome a kind of sitagliptin of existing preparation, expensive reagent need be used, cost is very high, be unsuitable for the defects such as industrialization, and provide preparation method that is a kind of and the key intermediate I of the diverse sitagliptin of prior art.Preparation method of the present invention avoids and uses noble metal to make catalyzer, and cost is low, and aftertreatment is simple, product yield is higher, and chemical purity and optical purity are all very high, and de% is greater than 99.5%, smoothly for the synthesis of sitagliptin, suitability for industrialized production can be suitable for.
Therefore, the present invention relates to the preparation method of the midbody compound I such as formula the sitagliptin shown in I, it comprises the following step: in organic solvent, at unsubstituted C
1~ C
6the C that saturated fatty acid or halogen (as F) replace
1~ C
6(as C
1~ C
3) saturated fatty acid, and under the effect of hydroborate, Compound II per is carried out the reduction reaction of carbon-carbon double bond as follows;
Wherein, R is methyl or carbamyl.
Wherein, described organic solvent can be the conventional solvent of this type of reduction reaction of this area, and one or more particularly preferably in tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether and acetonitrile of the present invention, better is tetrahydrofuran (THF).The consumption of organic solvent can be conventional chemical reaction consumption, and it compares preferably 5 ~ 10ml/g with the volume mass of Compound II per.
In the present invention, described hydroborate is hydroborating agents used in the reduction reaction commonly used of this area, and the present invention is sodium borohydride or POTASSIUM BOROHYDRIDE particularly preferably.The consumption of described hydroborate can be the conventional amount used in this type of reduction reaction of this area, and the present invention is following dosage scope particularly preferably: described hydroborate and the mol ratio of compound ii are preferably 1: 1 ~ 2: 1.
In the present invention, described unsubstituted C
1~ C
6saturated fatty acid is preferably formic acid, acetic acid, propionic acid, butyric acid or trimethylacetic acid, preferable formic acid.The C that described halogen (as F) replaces
1~ C
6saturated fatty acid is preferably trifluoroacetic acid.
Described unsubstituted C
1~ C
6the C that saturated fatty acid or halogen (as F) replace
1~ C
6(as C
1~ C
3) consumption of saturated fatty acid can be conventional amount used in this type of reduction reaction of this area, the present invention is following dosage particularly preferably: described unsubstituted C
1~ C
6the C that saturated fatty acid or halogen (as F) replace
1~ C
6(as C
1~ C
3) mol ratio of saturated fatty acid and hydroborate is preferably 3: 1 ~ 6: 1.
In the present invention, the temperature of described reduction reaction can be temperature conventional in this type of reduction reaction of this area, the present invention particularly preferably 0 DEG C to-40 DEG C, and best is-25 to-35 DEG C (as-30 DEG C).
In the present invention, till time of described reduction reaction completes by conventional sense means detection reaction, be generally 1 ~ 20 hour.
In the present invention, each condition of described reduction reaction, except above-mentioned special instruction, all can carry out according to the condition in this type of reduction reaction of this area.
After above-mentioned reduction reaction terminates, by simple aftertreatment, as extraction go out, extract, wash, drying, concentrate, recrystallization can obtain pure Compound I.
Midbody compound I of the present invention obtains sitagliptin by the method removing benzyl of routine, such as, with reference in the application's background technology, prepare the method for sitagliptin in the document that route 2 or 3 relates to, or document WO2004/085378 can prepare sitagliptin.
In the present invention, described compound ii, can refer to the method preparation of prior art.As, when R in Compound II per is carbamyl, can prepare by reference WO2004/085378, can prepare by reference WO2009/085990 when R in Compound II per is methyl.
In the present invention, de% refers to diastereomeric excess (diastereomer excess), and 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.It is generally defined as follows: de%=(amount of the amount-diastereomer b of diastereomer a)/(amount of the amount+diastereomer b of diastereomer a).
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Except specified otherwise, agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: preparation method of the present invention avoids and uses noble metal to make catalyzer, cost is low, and aftertreatment is simple, product yield is higher, chemical purity and optical purity are all very high, de% value is greater than 99.5%, smoothly for the synthesis of sitagliptin, can be suitable for suitability for industrialized production.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Embodiment 1:7-[1-oxo-3R-3-(1R-1-phenylethylcarbamate)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1, the preparation (in formula I, R is methyl) of 2,4-triazole [4,3-a] pyrazine
By sodium borohydride (0.448g, 11.8mmol) add in tetrahydrofuran (THF) (21mL), be cooled to 0-5 DEG C, keep less than 5 DEG C and drip formic acid (3.253g, 70.8mmol), after 10 DEG C of stirring 1h, be cooled to-30 DEG C, 7-[1-oxo-3-(1R-1-phenylethylcarbamate)-4-(2 is dripped at remaining on-30 DEG C, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (in general formula II, R is methyl) (3.000g, tetrahydrofuran (THF) (9mL) solution 5.9mmol),-25 ~-30 DEG C are reacted 18 hours, add saturated sodium carbonate solution (40mL) termination reaction, ethyl acetate 50mL extracts 3 times, merge organic phase, saturated common salt washes 3 times to neutral, anhydrous sodium sulfate drying, concentrated, solid 1.955g is obtained with Virahol (15mL) and sherwood oil (15mL) recrystallization, yield 65.0%, purity > 99.5%, de% > 99.5%.Fusing point: 132-134 DEG C.MS(ES+)：m/z 512(M+H)。
1H-NMR(CD
3CN)：δ1.13(m，3H)；2.45(m，1H)；2.61(m，3H)；2.95(m，1H)；3.78(m，2H)；3.96(m，2H，)；4.08(s，1H)；4.85(m，2H)；7.00(m，4H)；7.14(m，3H)。
Embodiment 2:7-[1-oxo-3R-3-(1R-1-phenylethylcarbamate)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1, the preparation (in formula I, R is methyl) of 2,4-triazole [4,3-a] pyrazine
By sodium borohydride (0.448g, 11.8mmol) add in glycol dimethyl ether (30mL), be cooled to 0-5 DEG C, keep less than 5 DEG C and drip trifluoroacetic acid (4.036g, 35.4mmol), after 10 DEG C of stirring 1h, be cooled to-40 DEG C, 7-[1-oxo-3-(1R-1-phenylethylcarbamate)-4-(2 is dripped at remaining on-30 DEG C, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (in general formula II, R is methyl) (3.000g, glycol dimethyl ether (9mL) solution 5.9mmol),-40 DEG C are reacted 1 hour, add saturated sodium carbonate solution (20mL) termination reaction, ethyl acetate 50mL extracts 3 times, merge organic phase, saturated common salt washes 3 times to neutral, anhydrous sodium sulfate drying, concentrated, solid 1.890g is obtained with Virahol (15mL) and sherwood oil (15mL) recrystallization, yield 62.8%, purity > 99.5%, de% > 99.5%.Fusing point: 132-134 DEG C.MS(ES+)：m/z 512(M+H)。
1H-NMR(CD
3CN)：δ1.13(m，3H)；2.45(m，1H)；2.61(m，3H)；2.95(m，1H)；3.78(m，2H)；3.96(m，2H，)；4.08(s，1H)；4.85(m，2H)；7.00(m，4H)；7.14(m，3H)。
Embodiment 3:7-[1-oxo-3R-3-(1R-1-phenylethylcarbamate)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1, the preparation (in formula I, R is methyl) of 2,4-triazole [4,3-a] pyrazine
By POTASSIUM BOROHYDRIDE (0.319g, 5.9mmol) add in acetonitrile (21mL), be cooled to 0-5 DEG C, keep less than 5 DEG C and drip trimethylacetic acid (3.611g, 35.4mmol), after 10 DEG C of stirring 1h, be cooled to-30 DEG C, 7-[1-oxo-3-(1R-1-phenylethylcarbamate)-4-(2 is dripped at remaining on-30 DEG C, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (in general formula II, R is methyl) (3.000g, acetonitrile (9mL) solution 5.9mmol),-30 DEG C are reacted 20 hours, add saturated sodium carbonate solution (20mL) termination reaction, ethyl acetate 50mL extracts 3 times, merge organic phase, saturated common salt washes 3 times to neutral, anhydrous sodium sulfate drying, concentrated, solid 1.850g is obtained with Virahol (15mL) and sherwood oil (15mL) recrystallization, yield 61.5%, purity > 99.5%, de% > 99.5%.Fusing point: 132-134 DEG C.MS(ES+)：m/z 512(M+H)。
1H-NMR(CD
3CN)：δ1.13(m，3H)；2.45(m，1H)；2.61(m，3H)；2.95(m，1H)；3.78(m，2H)；3.96(m，2H，)；4.08(s，1H)；4.85(m，2H)；7.00(m，4H)；7.14(m，3H)。
Embodiment 4:7-[1-oxo-3R-3-(1R-1-phenylethylcarbamate)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1, the preparation (in formula I, R is methyl) of 2,4-triazole [4,3-a] pyrazine
By POTASSIUM BOROHYDRIDE (0.637g, 11.8mmol) add in tetrahydrofuran (THF) (21mL), be cooled to 0-5 DEG C, keep less than 5 DEG C and drip acetic acid (4.248g, 70.8mmol), after 10 DEG C of stirring 1h, be cooled to 0 DEG C, 7-[1-oxo-3-(1R-1-phenylethylcarbamate)-4-(2 is dripped at remaining on-30 DEG C, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (in general formula II, R is methyl) (3.000g, tetrahydrofuran (THF) (9mL) solution 5.9mmol), 0 DEG C is reacted 16 hours, add saturated sodium carbonate solution (40mL) termination reaction, ethyl acetate 50mL extracts 3 times, merge organic phase, saturated common salt washes 3 times to neutral, anhydrous sodium sulfate drying, concentrated, solid 1.920g is obtained with Virahol (15mL) and sherwood oil (15mL) recrystallization, yield 63.8%, purity > 99.5%, de% > 99.5%.Fusing point: 132-134 DEG C.MS(ES+)：m/z 512(M+H)。
1H-NMR(CD
3CN)：δ1.13(m，3H)；2.45(m，1H)；2.61(m，3H)；2.95(m，1H)；3.78(m，2H)；3.96(m，2H，)；4.08(s，1H)；4.85(m，2H)；7.00(m，4H)；7.14(m，3H)。
Embodiment 5:7-[1-oxo-3R-3-(1S-1-phenyl-1-carbamoyhnethyl is amino)-4-(2; 4; 5-trifluorophenyl) butyl]-3-trifluoromethyl-5; 6; 7,8-tetrahydrochysene-1,2; the preparation (in formula I, R is carbamyl) of 4-triazole [4,3-a] pyrazine
By sodium borohydride (0.562g, 14.8mmol) add in tetrahydrofuran (THF) (28mL), be cooled to 0-5 DEG C, keep less than 5 DEG C and drip formic acid (4.085g, 88.8mmol), after 10 DEG C of stirring 1h, be cooled to-30 DEG C, 7-[1-oxo-3-(1S-1-phenyl-1-carbamoyhnethyl is amino)-4-(2 is dripped at remaining on-30 DEG C, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (in general formula II, R is carbamyl) (4.000g, tetrahydrofuran (THF) (12mL) solution 7.4mmol),-30 DEG C are reacted 16 hours, add saturated sodium carbonate solution (40mL) termination reaction, ethyl acetate 50mL extracts 3 times, merge organic phase, saturated common salt washes 3 times to neutral, anhydrous sodium sulfate drying, concentrated, solid 2.610g is obtained with Virahol (20mL) and sherwood oil (20mL) recrystallization, yield 65.1%, purity > 99.5%, de% > 99.5%.Fusing point: 206-208 DEG C.MS(ES+)：m/z 541(M+H)。
1H-NMR(CD
3CN)：δ2.54(m，2H)；2.75(m，2H)；3.15(m，1H)；3.92(m，2H)；4.06(m，2H，)；4.30(d，1H)；4.87(m，2H)；7.10(m，4H)；7.21(m，3H)。
Embodiment 6:7-[1-oxo-3R-3-(1S-1-phenyl-1-carbamoyhnethyl is amino)-4-(2; 4; 5-trifluorophenyl) butyl]-3-trifluoromethyl-5; 6; 7,8-tetrahydrochysene-1,2; the preparation (in formula I, R is carbamyl) of 4-triazole [4,3-a] pyrazine
By POTASSIUM BOROHYDRIDE (0.799g, 14.8mmol) add in methyl tertiary butyl ether (28mL), be cooled to 0-5 DEG C, keep less than 5 DEG C and drip trifluoroacetic acid (5.061g, 44.4mmol), after 10 DEG C of stirring 1h, be cooled to-30 DEG C, 7-[1-oxo-3-(1S-1-phenyl-1-carbamoyhnethyl is amino)-4-(2 is dripped at remaining on-30 DEG C, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (in general formula II, R is carbamyl) (4.000g, methyl tertiary butyl ether 12mL 7.4mmol)) solution,-30 DEG C are reacted 1 hour, add saturated sodium carbonate solution (30mL) termination reaction, ethyl acetate 50mL extracts 3 times, merge organic phase, saturated common salt washes 3 times to neutral, anhydrous sodium sulfate drying, concentrated, solid 2.640g is obtained with Virahol (20mL) and sherwood oil (20mL) recrystallization, yield 65.8%, purity > 99.5%, de% > 99.5%.Fusing point: 206-208 DEG C.MS(ES+)：m/z 541(M+H)。
1H-NMR(CD
3CN)：δ2.54(m，2H)；2.75(m，2H)；3.15(m，1H)；3.92(m，2H)；4.06(m，2H，)；4.30(d，1H)；4.87(m，2H)；7.10(m，4H)；7.21(m，3H)。
Embodiment 7:7-[1-oxo-3R-3-(1S-1-phenyl-1-carbamoyhnethyl is amino)-4-(2; 4; 5-trifluorophenyl) butyl]-3-trifluoromethyl-5; 6; 7,8-tetrahydrochysene-1,2; the preparation (in formula I, R is carbamyl) of 4-triazole [4,3-a] pyrazine
By sodium borohydride (0.562g, 14.8mmol) add in acetonitrile (28mL), be cooled to 0-5 DEG C, keep less than 5 DEG C and drip propionic acid (3.286g, 44.4mmol), after 10 DEG C of stirring 1h, be cooled to-30 DEG C, 7-[1-oxo-3-(1S-1-phenyl-1-carbamoyhnethyl is amino)-4-(2 is dripped at remaining on-30 DEG C, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (in general formula II, R is carbamyl) (4.000g, acetonitrile (12mL) solution 7.4mmol),-30 DEG C are reacted 20 hours, add saturated sodium carbonate solution (40mL) termination reaction, ethyl acetate 50mL extracts 3 times, merge organic phase, saturated common salt washes 3 times to neutral, anhydrous sodium sulfate drying, concentrated, solid 2.580g is obtained with Virahol (20mL) and sherwood oil (20mL) recrystallization, yield 64.3%, purity > 99.5%, de% > 99.5%.Fusing point: 206-208 DEG C.MS(ES+)：m/z 541(M+H)。
1H-NMR(CD
3CN)：δ2.54(m，2H)；2.75(m，2H)；3.15(m，1H)；3.92(m，2H)；4.06(m，2H，)；4.30(d，1H)；4.87(m，2H)；7.10(m，4H)；7.21(m，3H)。
Embodiment 8:7-[1-oxo-3R-3-(1S-1-phenyl-1-carbamoyhnethyl is amino)-4-(2; 4; 5-trifluorophenyl) butyl]-3-trifluoromethyl-5; 6; 7,8-tetrahydrochysene-1,2; the preparation (in formula I, R is carbamyl) of 4-triazole [4,3-a] pyrazine
By sodium borohydride (0.562g, 14.8mmol) add in acetonitrile (28mL), be cooled to 0-5 DEG C, keep less than 5 DEG C and drip butyric acid (3.907g, 44.4mmol), after 10 DEG C of stirring 1h, be cooled to-10 DEG C, 7-[1-oxo-3-(1S-1-phenyl-1-carbamoyhnethyl is amino)-4-(2 is dripped at remaining on-10 DEG C, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (in general formula II, R is carbamyl) (4.000g, acetonitrile (12mL) solution 7.4mmol),-10 DEG C are reacted 10 hours, add saturated sodium carbonate solution (40mL) termination reaction, ethyl acetate 50mL extracts 3 times, merge organic phase, saturated common salt washes 3 times to neutral, anhydrous sodium sulfate drying, concentrated, solid 2.340g is obtained with Virahol (20mL) and sherwood oil (20mL) recrystallization, yield 58.3%, purity > 99.5%, de% > 99.5%.Fusing point: 206-208 DEG C.MS(ES+)：m/z 541(M+H)。
1H-NMR(CD
3CN)：δ2.54(m，2H)；2.75(m，2H)；3.15(m，1H)；3.92(m，2H)；4.06(m，2H，)；4.30(d，1H)；4.87(m，2H)；7.10(m，4H)；7.21(m，3H)。
The preparation of embodiment 9:7-[1-oxo-3R-3-amino-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine (sitagliptin)
By 7-[1-oxo-3R-3-(1R-1-phenylethylcarbamate)-4-(2, 4, 5-trifluorophenyl) butyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (in formula I, R is methyl) (3.000g, 5.87mmol) be dissolved in methyl alcohol 30mL and water 3mL, add acetic acid (0.88g, 14.68mmol) He 20% palladium hydroxide charcoal (0.9g, 30%wt), hydrogenation to pressure is 1.0MPa, 50 DEG C are reacted 14 hours, suction filtration removing catalyzer, concentrate and obtain solid 1.94g, yield 81.2%, purity > 99.5%, ee% > 99.5%.Fusing point: 118-120 DEG C.MS(ES+)：m/z 408(M+H)。
1H-NMR(CDCl
3)：δ2.48(m，2H)；2.73(m，2H)；3.56(m，1H)；4.08(m，4H)；4.94(m，2H)；6.90(m，1H)；7.07(m，1H)。
Claims (5)
1. the preparation method such as formula the midbody compound I of the sitagliptin shown in I, it is characterized in that comprising the following step: in organic solvent, at formic acid or trifluoroacetic acid, and under the effect of hydroborate, Compound II per is carried out the reduction reaction of carbon-carbon double bond as follows;
Wherein, R is methyl or carbamyl, and the temperature of described reduction reaction is-25 to-35 DEG C.
2. preparation method as claimed in claim 1, is characterized in that: described organic solvent is one or more in tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether and acetonitrile.
3. preparation method as claimed in claim 1, is characterized in that: described hydroborate is sodium borohydride or POTASSIUM BOROHYDRIDE.
4. preparation method as claimed in claim 1, is characterized in that: described hydroborate and the mol ratio of compound ii are 1:1 ~ 2:1.
5. preparation method as claimed in claim 1, is characterized in that: the mol ratio of described formic acid or trifluoroacetic acid and hydroborate is 3:1 ~ 6:1.
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