CN104193744A - Preparation method of sitagliptin intermediate - Google Patents

Preparation method of sitagliptin intermediate Download PDF

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Publication number
CN104193744A
CN104193744A CN201410334314.5A CN201410334314A CN104193744A CN 104193744 A CN104193744 A CN 104193744A CN 201410334314 A CN201410334314 A CN 201410334314A CN 104193744 A CN104193744 A CN 104193744A
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acid
organic solvent
preparation
pyrazine
triazole
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刘烽
潘仙华
王琨
于万盛
周艺军
张瑞敏
徐娜
徐璐
陈彦宇
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Shanghai Institute of Technology
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Shanghai Institute of Technology
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Abstract

The invention discloses a synthesis method of a sitagliptin intermediate. The sitagliptin intermediate is prepared by carrying out asymmetric reduction of carbon-carbon double bond on 7-[1-oxo-3-(1R-1-ethyl phenyl amino)-4-(2,4,5-trifluoro phenyl) butyl-2-alkenyl]-3-trifluoro methyl-5,6,7,8-tetrahydro-1,2,3-triazole [4,1-a] pyrazine. According to the preparation method, no precious metal is used as a catalyst so that the cost is low, the post-treatment is simple, the product yield is relatively high and both the chemical purity and the optical purity are high, so that the preparation method can be smoothly used for the synthesis of sitagliptin and is suitable for the industrial production.

Description

A kind of preparation method of sitagliptin intermediate
Technical field
The invention belongs to chemical field, relate in particular to a kind of preparation method of intermediate of sitagliptin.
 
Background technology
Sitagliptin phosphate (Sitagliptin phosphate) is first dipeptidyl peptidase-IV (DPP-4) inhibitor of FDA approval listing in 2006, be used for the treatment of type ii diabetes, it is alone or share obvious hypoglycemic activity with N1,N1-Dimethylbiguanide, pioglitazone, and take safety, better tolerance, untoward reaction is few.
The research and development of Sitagliptin phosphate Shi You Merck & Co., Inc., Augusts 8 in 2006, the Bei Mexico Ministry of Health ratified once-a-day medication treatment type ii diabetes, the commodity Januvia by name of listing.In the U.S., Sitagliptin phosphate was ratified by FDA on October 16th, 2006.In the whole world, 60 state approvals are used Sitagliptin phosphate, and within 2013, global marketing volume reaches 3,000,000,000 dollars, belongs to high " cookle " product of added value.
1) first-generation synthetic route of the sitagliptin that Kim etc. delivers, i.e. gram magnitude synthetic method of the research department of Merck & Co., Inc..This synthetic route adopts chiral source to induce the a-amino acid of chirality, and produces beta-amino acids by diazotization reaction, builds required chiral centre.The required raw materials cost of this synthetic route is relatively high, and the operation of reaction comparatively bothers, and in industrialization process, technological process and quality product are all difficult to control.Its synthetic route is as follows:
2) 2005, the Hansen of Merck & Co., Inc. etc. utilized chiral phosphorus ruthenium catalyst to carry out asymmetric catalytic hydrogenation to ketone, built chiral secondary alcohol, then chiral secondary alcohol was converted into the secondary amine of chirality to reach the object that builds Chiral Amine; In this synthetic route, need to use the asymmetric catalytic hydrogenation of rhodium catalysis in committed step, it is expensive that this step is reacted the price comparison of catalyzer not only, and when later stage industrialization, in the amplification process of technique, scale effect is obvious, and the difficult quality of product is controlled.Its synthetic route is as follows:
3) third generation synthetic method of Merck company exploitation is carried out inducing catalysis hydrogenation and synthesis of chiral amine with S-benzene G-NH2 as chiral auxiliary(reagent).This synthetic route is relatively suitable, but also has larger problem, needs exactly shortening twice, uses more expensive platinum catalyst, and in the end need to use a large amount of Pd (OH) 2/C during one-step removal protecting group, and cost is very high.Its synthetic route is as follows:
4) the latest generation synthetic method of Merck company has adopted chirality rhodium catalyst to build chiral centre to the asymmetric catalytic hydrogenation of enamine, this synthetic route brief introduction, step is shorter, but the method need to be used expensive catalyzer and chirality assistant agent, and the method also exists scale effect in industrialization process, cause the quality of product unstable.Its synthetic route is as follows:
Summary of the invention
For above-mentioned above-mentioned technical problem of the prior art, the invention provides a kind of sitagliptin intermediate 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] preparation method of pyrazine, described this preparation method will solve that preparation method's complex process of the prior art, cost are high, the unsettled technical problem of quality.
The preparation method of a kind of sitagliptin intermediate of the present invention, use Louis acid catalysis to 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] asymmetric reduction of pyrazine, obtain sitagliptin intermediate 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine, its reaction equation is as follows:
Further, first measure the first organic solvent, to adding quality in the first organic solvent, be 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2 of 1/2 ~ 1/50 of the first organic solvent quality, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine, in the first organic solvent, add Lewis acid successively again, reductive agent, described Lewis acid and 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] mol ratio of pyrazine is 0.1 ~ 5:1, described reductive agent and 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] mol ratio of pyrazine is 0.1 ~ 5:1,-78 ℃ ~ 25 ℃ reactions 0.25 ~ 2 hour, then add acid, described acid and 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] mol ratio of pyrazine is 0.1 ~ 5:1, insulation reaction 0.5 ~ 2 hour, after having reacted, water cancellation reaction, adopt the second organic solvent extraction, process dry solvent and steaming desolventize and obtain target product again.
Further, described organic solvent is methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, N, dinethylformamide, N, any one or more than one combination in the saturated fatty alcohol of N-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), tetramethylene sulfone, Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether, glycol dimethyl ether, C1 ~ C6 or acetonitrile.
Further, described Lewis acid is any one or more than one the combination in cobalt chloride, Manganous chloride tetrahydrate, nickelous chloride, zinc chloride, titanium chloride, calcium chloride, boron trifluoride, iron(ic) chloride, aluminum chloride or Cerium II Chloride.
Further, described reductive agent is any one or above-mentioned arbitrarily both mixing in lithium aluminum hydride, sodium borohydride or POTASSIUM BOROHYDRIDE.
Further, described acid is any one above-mentioned both mixing arbitrarily in hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, phenylformic acid, oxalic acid or trifluoroacetic acid, and its concentration range is between 0.5 ~ 3mol/L.
Further, described acid is dissolved in the first organic solvent, and the volume ratio of described acid and the first organic solvent is 1 ~ 3:5.
Further, the second described organic solvent is ethyl acetate.
Reaction principle of the present invention: be by 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] the pyrazine asymmetric reduction reaction that carries out carbon-carbon double bond transforms and to make, C1 ~ C6 saturated fatty acid in unsubstituted C1 ~ C6 saturated fatty acid or halogen replacement, under hydroborate and lewis acidic dual function, under a certain specified temp, by compound 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] the pyrazine asymmetric reduction reaction that carries out carbon-carbon double bond transforms and to make.
The present invention compares with prior art, and its technical progress is significant.Preparation method of the present invention has avoided use precious metal to make catalyzer, and cost is low, and aftertreatment is simple, and product yield is higher, and chemical purity and optical purity are all very high, can be smoothly synthetic for sitagliptin, be suitable for suitability for industrialized production.
 
Accompanying drawing explanation
Fig. 1 is 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1, the nucleus magnetic hydrogen spectrum spectrogram of 2,4-triazole [4,3-a] pyrazine.
 
Embodiment
Embodiment given below is to illustrate in greater detail the present invention, but scope of the present invention is not limited to these embodiment.
Embodiment 1
Under room temperature (25 ℃), to being furnished with reflux exchanger, thermometer, in 50 mL there-necked flasks of hollow plug, add successively 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (0.5 g, 0.93 mmol) and tetrahydrofuran (THF) 15 mL, be cooled to-65 ℃, add again zinc chloride (0.36 g, 2.65 mmol), sodium borohydride (0.05 g, 1.32 mmol), the system that is stirred to is molten clear, drip tetrahydrofuran solution (acetic acid 2 mL of acetic acid, tetrahydrofuran (THF) 5 mL), 3 h are stirred in insulation (65 ℃), react complete, by the 10 mL shrends system of going out, 10 mL*2 ethyl acetate extractions, dry organic phase is also steamed except ethyl acetate, obtain white product 0.49 g, molar yield 98 %, purity=99 % is de %=90 % wherein.
Adopt Avance 500MHz nuclear magnetic resonance spectrometer, Dionex MSOPlus mass spectrograph to measure the solid of above-mentioned gained, the nucleus magnetic hydrogen spectrum of gained, mass-spectrometric data result are as follows:
MS(ESI):m/z?541(M+H) +
1H?NMR?(500?MHz,?CDCl 3)?δ?7.57?(s,?1H),?7.38?(s,?1H),?7.20?(s,?5H),?7.00?–?6.89?(m,?1H),?6.84?(dd,?J?=?16.1,?9.4?Hz,?1H),?6.40?(s,?1H),?5.04?–?4.75?(m,?2H),?4.34?(s,?1H),?4.11?–?3.71?(m,?4H),?3.41?–?3.28?(m,?1H),?2.92?(ddd,?J?=?18.5,?13.4,?4.6?Hz,?1H),?2.72?–?2.59?(m,?1H),?2.52?(dt,?J?=?30.5,?12.1?Hz,?2H).
Further, its nucleus magnetic hydrogen spectrum spectrogram as shown in Figure 1;
From the nucleus magnetic hydrogen spectrum data of above-mentioned gained and mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, can draw, the white product of above-mentioned gained, its structural formula is as follows:
be 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine.
 
Embodiment 2
Under room temperature (25 ℃), to being furnished with reflux exchanger, thermometer, in 50 mL there-necked flasks of hollow plug, add successively 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (0.5 g, 0.93 mmol) and tetrahydrofuran (THF) 15 mL, be cooled to-65 ℃, add again cobalt chloride (0.34g, 2.65 mmol), sodium borohydride (0.05 g, 1.32 mmol), the system that is stirred to is molten clear, drip tetrahydrofuran solution (acetic acid 2 mL of acetic acid, tetrahydrofuran (THF) 5 mL), 3 h are stirred in insulation (65 ℃), react complete, by the 10 mL shrends system of going out, 10 mL*2 ethyl acetate extractions, dry organic phase is also steamed except ethyl acetate, obtain faint yellow oily matter 0.96 g, molar yield 93%, purity=99 %, de %=23 %.
The faint yellow oily matter of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, and result shows the faint yellow oily matter of above-mentioned gained, and its structural formula is as follows:
be 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine.
 
Embodiment 3
Under room temperature (25 ℃), to being furnished with reflux exchanger, thermometer, in 50 mL there-necked flasks of hollow plug, add successively 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (0.5 g, 0.93 mmol) and tetrahydrofuran (THF) 15 mL, be cooled to-35 ℃, add again zinc chloride (0.36 g, 2.65 mmol), sodium borohydride (0.05 g, 1.32 mmol), the system that is stirred to is molten clear, drip tetrahydrofuran solution (acetic acid 2 mL of acetic acid, tetrahydrofuran (THF) 5 mL), 3 h are stirred in insulation (65 ℃), react complete, by the 10 mL shrends system of going out, 10 mL*2 ethyl acetate extractions, dry organic phase is also steamed except ethyl acetate, obtain white product 0.41 g, molar yield 82 %, purity=99 %, de %=59 %.
The white product of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, and result shows the white product of above-mentioned gained, and its structural formula is as follows:
be 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine.
 
Embodiment 4
Under room temperature (25 ℃), to being furnished with reflux exchanger, thermometer, in 50 mL there-necked flasks of hollow plug, add successively 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (0.5 g, 0.93 mmol) and tetrahydrofuran (THF) 15 mL, be cooled to-15 ℃, add again zinc chloride (0.36 g, 2.65 mmol), sodium borohydride (0.05 g, 1.32 mmol), the system that is stirred to is molten clear, drip tetrahydrofuran solution (acetic acid 2 mL of acetic acid, tetrahydrofuran (THF) 5 mL), 3 h are stirred in insulation (65 ℃), react complete, by the 10 mL shrends system of going out, 10 mL*2 ethyl acetate extractions, dry organic phase is also steamed except ethyl acetate, obtain white product 0.30 g, molar yield 60 %, purity=99 %, de %=57%.
The white product of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, and result shows the white product of above-mentioned gained, and its structural formula is as follows:
be 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine.
 
Embodiment 5
Under room temperature (25 ℃), to being furnished with reflux exchanger, thermometer, in 50 mL there-necked flasks of hollow plug, add successively 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (0.5 g, 0.93 mmol) and tetrahydrofuran (THF) 15 mL, be cooled to-15 ℃, add again zinc chloride (0.36 g, 2.65 mmol), sodium borohydride (0.05 g, 1.32 mmol), the system that is stirred to is molten clear, drip tetrahydrofuran solution (trifluoroacetic acid 2 mL of trifluoroacetic acid, tetrahydrofuran (THF) 5 mL), 3 h are stirred in insulation (65 ℃), react complete, by the 10 mL shrends system of going out, 10 mL*2 ethyl acetate extractions, dry organic phase is also steamed except ethyl acetate, obtain white product 0.47 g, molar yield 97 %, purity=99 %, de %=38 %.
The white product of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, and result shows the white product of above-mentioned gained, and its structural formula is as follows:
be 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine.
 
Embodiment 6
Under room temperature (25 ℃), to being furnished with reflux exchanger, thermometer, in 50 mL there-necked flasks of hollow plug, add successively 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (0.5 g, 0.93 mmol) and tetrahydrofuran (THF) 15 mL, add again zinc chloride (0.36 g, 2.65 mmol), sodium borohydride (0.05 g, 1.32 mmol), the system that is stirred to is molten clear, be cooled to-78 ℃ of tetrahydrofuran solution (trifluoroacetic acid 2 mL that drip trifluoroacetic acid, tetrahydrofuran (THF) 5 mL), 3 h are stirred in insulation (78 ℃), react complete, by the 10 mL shrends system of going out, 10 mL*2 ethyl acetate extractions, dry organic phase is also steamed except ethyl acetate, obtain oily product 0.45 g, molar yield 90 %, purity=99 %, de %=62 %.
The oily product of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, and result shows the oily product of above-mentioned gained, and its structural formula is as follows:
be 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine.
 
Embodiment 7
Under room temperature (25 ℃), to being furnished with reflux exchanger, thermometer, in 50 mL there-necked flasks of hollow plug, add successively 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (0.5 g, 0.93 mmol) and methyl alcohol 15 mL, add again calcium chloride (0.29 g, 2.65 mmol), sodium borohydride (0.05 g, 1.32 mmol), the system that is stirred to is molten clear, drip methanol solution (propionic acid 2 mL of propionic acid, methyl alcohol 5 mL), room temperature (25 ℃) stirs 3 h, TLC detects a large amount of unreacteds of raw material, by the 10 mL shrends system of going out, 10 mL*2 ethyl acetate extractions, dry organic phase is also steamed except ethyl acetate, obtain oily product 0.47 g, molar yield 28 %, purity=30 %, de %=8 %.
The oily product of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, and result shows the oily product of above-mentioned gained, and its structural formula is as follows:
be 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine.
 
Embodiment 8
Under room temperature (25 ℃), to being furnished with reflux exchanger, thermometer, in 50 mL there-necked flasks of hollow plug, add successively 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine (0.5 g, 0.93 mmol) and dehydrated alcohol 15 mL, add again calcium chloride (0.29 g, 2.65 mmol), sodium borohydride (0.05 g, 1.32 mmol), the system that is stirred to is molten clear, drip ethanol solution (propionic acid 2 mL of propionic acid, dehydrated alcohol 5 mL), room temperature (25 ℃) stirs 3 h, TLC detects a large amount of unreacteds of raw material, by the 10 mL shrends system of going out, 10 mL*2 ethyl acetate extractions, dry organic phase is also steamed except ethyl acetate, obtain oily product 0.40 g, molar yield 23 %, purity=29 %, de %=7 %.
The oily product of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, and result shows the oily product of above-mentioned gained, and its structural formula is as follows:
be 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine.

Claims (8)

1. the preparation method of a sitagliptin intermediate, it is characterized in that: use Louis acid catalysis to 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] asymmetric reduction of pyrazine, obtain sitagliptin intermediate 7-[1-oxo-3R-3-(1R-1-phenylethyl is amino)-4-(2,4,5-trifluorophenyl) butyl]-3-trifluoromethyl-5,6,7,8-tetrahydrochysene-1,2,4-triazole [4,3-a] pyrazine.
2. the preparation method of a kind of sitagliptin intermediate as claimed in claim 1, it is characterized in that: first measure the first organic solvent, to adding quality in the first organic solvent, be 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2 of 1/2 ~ 1/50 of the first organic solvent quality, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] pyrazine, in the first organic solvent, add Lewis acid successively again, reductive agent, described Lewis acid and 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] mol ratio of pyrazine is 0.1 ~ 5:1, described reductive agent and 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] mol ratio of pyrazine is 0.1 ~ 5:1,-78 ℃ ~ 25 ℃ reactions 0.25 ~ 2 hour, then add acid, described acid and 7-[1-oxo-3-(1R-1-phenylethyl is amino)-4-(2, 4, 5-trifluorophenyl) but-2-ene base]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrochysene-1, 2, 4-triazole [4, 3-a] mol ratio of pyrazine is 0.1 ~ 5:1, insulation reaction 0.5 ~ 2 hour, after having reacted, water cancellation reaction, adopt the second organic solvent extraction, process dry solvent and steaming desolventize and obtain target product again.
3. the preparation method of a kind of sitagliptin intermediate as claimed in claim 2, it is characterized in that: the first described organic solvent and the second organic solvent are methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, N, dinethylformamide, N, any one or more than one combination in the saturated fatty alcohol of N-N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), tetramethylene sulfone, Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether, glycol dimethyl ether, C1 ~ C6 or acetonitrile.
4. the preparation method of a kind of sitagliptin intermediate as claimed in claim 2, is characterized in that: described Lewis acid is any one or more than one the combination in cobalt chloride, Manganous chloride tetrahydrate, nickelous chloride, zinc chloride, titanium chloride, calcium chloride, boron trifluoride, iron(ic) chloride, aluminum chloride or Cerium II Chloride.
5. the preparation method of a kind of sitagliptin intermediate as claimed in claim 2, is characterized in that: described reductive agent is any one or above-mentioned both mixing arbitrarily in lithium aluminum hydride, sodium borohydride, POTASSIUM BOROHYDRIDE.
6. the preparation method of a kind of sitagliptin intermediate as claimed in claim 2, is characterized in that: described acid is any one or above-mentioned both mixing arbitrarily in hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, phenylformic acid, oxalic acid, trifluoroacetic acid.
7. the preparation method of a kind of sitagliptin intermediate as claimed in claim 2, is characterized in that: described acid is dissolved in the first organic solvent, and the volume ratio of described acid and the first organic solvent is 1 ~ 3:5.
8. the preparation method of a kind of sitagliptin intermediate as claimed in claim 2, is characterized in that: the second described organic solvent is ethyl acetate.
CN201410334314.5A 2014-07-15 2014-07-15 Preparation method of sitagliptin intermediate Pending CN104193744A (en)

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