CN105541793A - Synthetic method of trelagliptin, trelagliptin synthesized through method and trelagliptin synthesis intermediate - Google Patents
Synthetic method of trelagliptin, trelagliptin synthesized through method and trelagliptin synthesis intermediate Download PDFInfo
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Abstract
The invention discloses a synthetic method of trelagliptin, trelagliptin synthesized through the method and a trelagliptin synthesis intermediate. The synthetic method of trelagliptin comprises the following steps: 1, taking 2-hydroxymethyl-4-fluorobenzonitrile as a starting raw material, and conducting a chlorination reaction, so that 2-chloromethyl-4-fluorobenzonitrile is obtained; 2, taking the 2-chloromethyl-4-fluorobenzonitrile as an intermediate, and conducting a condensation reaction, so that 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-4-fluorobenzonitrile is obtained; 3, taking the 2-[(6-chlorine-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidyl)methyl]-4-fluorobenzonitrile as an intermediate, and conducting an ammonolysis reaction, so that trelagliptin alkali is obtained. By means of the method, use of high-toxicity copper cyanide is avoided, safety of the synthesis process is improved, environment friendliness is achieved, the formed chloro intermediate is more stable, and no irritation is caused.
Description
Technical field
The present invention relates to a kind of synthetic method method of bent Ge Lieting, be specifically related to the synthetic method of a kind of bent Ge Lieting and the bent Ge Lieting synthesized by the method and bent Ge Lieting synthetic intermediate.
Background technology
Bent Ge Lieting is a kind of weekly DPP IV (DPP-4) inhibitor, suppresses DPP-4, control glucose level by selectivity, persistence.DPP-4 is a kind of enzyme, incretin (the inactivation of glucagon-like-peptide-1 (GLP-1) and diabetes dependency pancreotropic hormone polypeptide (GIP), and Regular Insulin falls in these two kinds of intestines plays an important role in blood glucose regulation can be caused.Suppress DPP-4, glucose level dependency insulin secretion can be increased, thus control glucose level.
Bent Ge Lieting is DPP-4 inhibitor, and its submission is based on the efficacy and saferry data of several III clinical trial phases carried out in Japanese 2 type ROMAN patients with NIDDMs.The curative effect that Qu Gelie orders all obtains confirmation in described test, has good security and tolerance simultaneously.Bent Ge Lieding Per-Hop behavior just effectively can control glucose level 1 time, is expected to the compliance improving patient.
World Health Organization's report of 2011 points out that the whole world has the moon 3.5 hundred million people to suffer from diabetes, it is reported, just there is the diabetic subject more than 100,000,000 in China, and as the inhibitor of a kind of DPP-4, bent Ge Lieting has been subject to paying close attention to of related researcher.
A kind of bent Ge Lieting (2-[[6-[(3R)-3-amino-piperidino]-3 is all referred in US Patent No. 2012197018A1 and US20090275750,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl]-4-fluorobenzonitrile succinate) and synthesis technique, its dominating process route is for raw material with the fluoro-2 bromo toluene of 5-, through cyaniding, bromo, condensation, ammonification, salify synthesizes bent Ge Lieting.For the synthesis technique of bent Ge Lieting involved in US2012197018A1, its synthesis route is as follows:
The concrete synthesis technique of the synthesis technique of above-mentioned bent Ge Lieting is as follows:
(1) synthesis of above-claimed cpd B (4-fluoro-2-methylbenzene formonitrile HCN)
The reflux 24h in DMF (100mL) by bromo-for 2-5-toluene fluoride (compd A) (3.5g, 18.5mmol) and CuCN (2g, 22mmol).Reaction solution dilute with water, normal hexane extraction, organic layer MgSO
4drying, steams and desolventizes to obtain product B (yield 60%).
1H-NMR(400MH
Z，CDCl
3)：δ7.60(dd，J＝5.6，8.8Hz，1H)，6.93-7.06(m，2H)，2.55(s，3H)。
(2) synthesis of above-claimed cpd C (2-brooethyl-4-fluorobenzonitrile)
By 4-fluoro-2-methylbenzene formonitrile HCN (compd B) (2g, 14.8mmol), N-bromosuccinimide (NBS) (2.64g, 15mmol), Diisopropyl azodicarboxylate (AIBN) (100mg) is dissolved in CCl
4in, under nitrogen protection, reflux 2h.Be chilled to room temperature, solids removed by filtration, concentrated obtain crude oil, be not purifiedly directly used in the next step.
1H-NMR(400MH
Z，CDCl
3)：δ7.68(dd，J＝5.2，8.4Hz，1H)，7.28(dd，J＝2.4，8.8Hz，1H)，7.12(m，1H),4.6(s，2H)。
(3) synthesis of above-claimed cpd E (2-[(chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (the 2H)-pyrimidyl of 6-) methyl]-4-fluorobenzonitrile)
By 3-methyl-6-chlorouracil (above-claimed cpd D) (0.6g, 3.8mmol), 2-brooethyl-4-fluorobenzonitrile (0.86g, 4mmol) and salt of wormwood (0.5g, 4mmol) be dissolved in DMSO (10mL), in 60 DEG C of heated and stirred 2h.Dilute with water, ethyl acetate is extracted.Organic layer MgSO
4drying, steaming desolventizes, and residue, through purification by column chromatography, obtains 0.66g product (yield 60%).
1H-NMR(400MH
Z，CDCl
3)：δ7.73(dd，J＝7.2，8.4Hz，1H)，7.26(d，J＝4.0Hz，1H)，7.11-7.17(m，1H)，6.94(dd，J＝2.0，9.0Hz，1H)，6.034(s，2H)，3.39(s，3H)。MS (ES) [m+H] is according to C
13h
9clFN
3o
2calculated value, 293.68, measured value 293.68.
(4) synthesis of above-claimed cpd F (2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl]-4-fluorobenzonitrile)
2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl) methyl]-4-fluorobenzonitrile (compd E) (300mg, 1.0mmol), (R)-amino piperidine dihydrochloride (266mg, 1.5mmol), sodium bicarbonate (500mg, 5.4mmol), ethanol (3mL) in sealed tube 100 DEG C, stirs 2h.After HPLC purifying, with trifluoroacetic acid salify.
1H-NMR(400MH
Z，CD
3OD)：δ7.77-7.84(m，1H)，7.16-7.27(m，2H)，5.46(s，1H)，5.17-5.34(ABq，J＝35.2，15.6Hz，2H)，3.33-3.47(m，2H)，3.22(s，3H),2.98-3.08(m，1H)，2.67-2.92(m，2H)，2.07-2.17(m，1H)，1.82-1.92(m，1H)，1.51-1.79(m，2H)。MS (ES) [m+H] is according to C
18h
20fN
5o
2calculated value, 357.38, measured value 357.38.
(5) synthesis of Compound I (2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl]-4-fluorobenzonitrile succinate)
The 2-[[6-[(3R)-3-amino-piperidino]-3 that upper step is obtained, 4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl]-4-fluorobenzonitrile is dissolved in methylene dichloride, washs with saturated sodium carbonate solution.Dry organic layer, removal of solvent under reduced pressure.Cyanobenzene product (about 10mg) is dissolved in 1mL methyl alcohol, adds the THF solution of succsinic acid (1.05eq.), is exposed to by mixed solution in air and leaves standstill 3 days.If the precipitation of being formed, collecting by filtration.If do not form precipitation, concentrating under reduced pressure, obtains succinate except after desolventizing.
1H-NMR(400MH
Z，CD
3OD)：δ7.77-7.84(m，1H)，7.12-7.26(m，2H)，5.47(s，1H)，5.21-5.32(ABq，J＝32.0，16.0Hz，2H)，3.35-3.5(m，2H)，3.22(s，3H)，3.01-3.1(m，1H)，2.69-2.93(m，2H)，2.07-2.17(m，1H)，1.83-1.93(m，1H)，1.55-1.80(m，2H)。MS (ES) [m+H] is according to C
18h
20fN
5o
2calculated value, 357.38, measured value 357.38.
Existing this method can synthesize bent Ge Lieting (2-[[6-[(3R)-3-amino-piperidino]-3, 4-dihydro-3-methyl-2, 4-dioxo-1 (2H)-pyrimidyl] methyl]-4-fluorobenzonitrile), but, the existing this synthetic method that is raw material with the fluoro-2 bromo toluene of 5-, the cupric cyanide of high poison has all been used at cyanation step, like this and be unfavorable for safety in production and environment protection, and the benzyl bromine intermediate obtained in bromo step is unstable and cost is high, this intermediate pungency is strong in addition, easily cause the anaphylaxis of personnel aborning.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, the bent Ge Lieting providing the synthetic method of a kind of bent Ge Lieting and synthesized by the method and bent Ge Lieting synthetic intermediate, by with 2-methylol-4-fluorobenzonitrile for starting raw material synthesizes bent Ge Lieting, improve the security of building-up process, friendly environment.
For this reason, in one embodiment of the invention, provide the synthetic method of a kind of bent Ge Lieting, it is characterized in that, described synthetic method comprises the following steps: S1, with 2-methylol-4-fluorobenzonitrile for starting raw material, obtain 2-chloromethyl-4-fluorobenzonitrile through chlorination; S2, using described 2-chloromethyl-4-fluorobenzonitrile as intermediate, obtain 2-[(chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (the 2H)-pyrimidyl of 6-) methyl]-4-fluorobenzonitrile through condensation reaction; S3,2-[(chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (the 2H)-pyrimidyl of 6-) methyl]-4-fluorobenzonitrile, as intermediate, is obtained bent Ge Lieting alkali through aminating reaction.
With prior art mainly with 2-methyl-4-fluorobenzonitrile for raw material, through bromo condensation, the scheme that ammonification obtains bent Ge Lieting alkali is different.2-methylol-4-the fluorobenzonitrile that present invention employs price more cheap is starting raw material, obtains bent Ge Lieting alkali successively through chlorination, condensation reaction and aminating reaction.Simultaneously, the use that The method avoids the cupric cyanide of high poison provided by the present invention, not only increase the security of building-up process, friendly environment, and the chloro intermediate formed is also more stable than Bromo-intermediates of the prior art, and nonirritant, further avoid the infringement of the pungency existing for synthetic intermediate to operator ' s health.
The synthesis route of the synthetic method of above-mentioned bent Ge Lieting is as follows:
Below with reference to the synthesis route of above-mentioned bent Ge Lieting, specifically the step of the synthetic method of above-mentioned bent Ge Lieting is described further, and the beneficial effect of the synthetic method of the bent Ge Lieting of further the present invention.
In the S1 of the synthetic method of above-mentioned bent Ge Lieting, focus on 2-methylol-4-fluorobenzonitrile as starting raw material carries out chlorination reaction to obtain intermediate-1 (2-chloromethyl-4-fluorobenzonitrile), not having particular requirement for the condition of chlorination reaction and the proportioning of raw material, can be the condition that can generate arbitrarily 2-chloromethyl-4-fluorobenzonitrile.In the S1 of the synthetic method of preferred above-mentioned bent Ge Lieting in the present invention, under chloridized condition, by 2-methylol-4-fluorobenzonitrile and chlorinating agent by weight 1:3.5-1:6 contact reacts, to obtain 2-chloromethyl-4-fluorobenzonitrile; Preferred described chlorinating agent is one or more in sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, trimethylchlorosilane, N-phenyl benzoyl imines chlorine, hexachloroacetone-triphenylphosphine, carbon tetrahalide-triphenyl phosphine, N-chlorosuccinimide-triphenylphosphine and methylsulfonyl chloride.More preferably, described chlorination reaction condition comprises: at 25-85 DEG C, under preferred 70-75 DEG C condition, and reaction 1-12h.
With prior art mainly with 2-methyl-4-fluorobenzonitrile for raw material, it is relatively high to add price, and the brominated reagent that used in amounts is excessive (NBS), and the step forming Bromo-intermediates-1 with bromo-reaction is different; For starting raw material forms chloro intermediate I by chlorination reaction in the present invention with 2-methylol-4-fluorobenzonitrile, chlorinating agent (preferred sulfur oxychloride) selected by the method is usually cheap, and excessive sulfur oxychloride can be applied mechanically by Distillation recovery, this just greatly reduces the synthesis cost of bent Ge Lieting.
In the S2 of the synthetic method of above-mentioned bent Ge Lieting, to focus on the intermediate-1 obtained in above-mentioned S1 step through condensation reaction to obtain intermediate-2 (2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl) methyl]-4-fluorobenzonitrile), for the solvent adopted in condensation reaction, and condensation reaction condition does not have particular requirement, can be to generate arbitrarily 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl) methyl] condition of-4-fluorobenzonitrile.
Preferred described S2 comprises the following steps in the present invention: be dissolved in the first organic solvent by 2-chloromethyl-4-fluorobenzonitrile, obtains 2-chloromethyl-4-fluorobenzonitrile solution; Chloro-for 6-3-6-Methyl Uracil is dissolved in the second organic solvent, obtains 6-chloro-3-6-Methyl Uracil solution; Under condensation reaction condition, by described 2-chloromethyl-4-fluorobenzonitrile solution and 6-chloro-3-6-Methyl Uracil solution contact reacts, obtain described 2-[(chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (the 2H)-pyrimidyl of 6-) methyl]-4-fluorobenzonitrile.
More preferably described condensation reaction condition comprises in the present invention: at 25-100 DEG C, under preferred 60-65 DEG C condition, described 2-chloromethyl-4-fluorobenzonitrile solution is dropped to described 6-chloro-3-6-Methyl Uracil solution, be added dropwise to complete rear continuation reaction 1-6h, preferred described 6-chloro-3-6-Methyl Uracil and 2-chloromethyl-4-fluorobenzonitrile in molar ratio 1:1 ~ 1:1.6 mix.
Operable described first organic solvent includes but not limited to one or more in toluene, DMF, benzene, chloroform and methyl tertiary butyl ether in the present invention; Operable described second organic solvent includes but not limited to N, N-diisopropylethylamine (DIPEA), N-Methyl pyrrolidone, N, dinethylformamide, N, one or more in N-N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF) and acetonitrile, more preferably described second organic solvent is the mixture of DIPEA (DIPEA) and N-Methyl pyrrolidone 3:7.
Preferred described S3 comprises the following steps in the present invention: by (R)-3-amino piperidine dihydrochloride and salt of wormwood and the 3rd solvent, obtain mixed reaction solution, by described 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl) methyl]-4-fluorobenzonitrile with (R)-3-amino piperidine dihydrochloride mol ratio is that 1:1 ~ 1.5 join in described mixed reaction solution according to it, carries out the bent Ge Lieting alkali crude product of reaction formation in described aminating reaction condition; Wherein operable 3rd solvent include but not limited to into Virahol, methyl alcohol, ethanol, n-propyl alcohol, propyl carbinol and tetrahydrofuran (THF) in one or more organic solvents and the mixing solutions of water, wherein the volume ratio of organic solvent and water is 22:1 ~ 17:1.Preferably described aminating reaction condition comprises in the present invention: temperature of reaction is 25 ~ 100 DEG C, preferred 65-70 DEG C, reaction time range 1 ~ 12h.
The present invention above-mentioned proposed by described 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl) methyl]-4-fluorobenzonitrile the step of synthesizing bent Ge Lieting alkali crude product carries out in the environment that is solvent with water and organic solvent mixed solution under salt of wormwood exists, although the method extends the reaction times, but the reaction eliminated in sealed tube, simplifies purification process.
In the present invention preferably, described S3 also comprises the step of purification, more preferably the step of described purification comprises: add activated carbon after described bent Ge Lieting alkali crude product is added 95% ethanol heating for dissolving, reflux decolour 15-30min, heat filtering, stirring at room temperature crystallization 1-1.5h, suction filtration, drying, obtains bent Ge Lieting alkali crude product fine work.
The method adopting column chromatography to carry out purifying in former prior art is compared, and have employed recrystallization method in the present invention, and the requirement of the method to equipment is low, more easily synthesizes.And the present invention can obtain the higher bent Ge Lieting alkali crude product fine work of purity by adopting recrystallization method.
Meanwhile, additionally provide a kind of bent Ge Lieting in the present invention, this bent Ge Lieting is synthesized by the above-mentioned synthetic method of the present invention.
In addition, additionally provide a kind of bent Ge Lieting synthetic intermediate in the present invention, bent Ge Lieting synthetic intermediate is for having the 2-chloromethyl-4-fluorobenzonitrile of structure in formula (1).
Proposed by the invention is this using the 2-chloromethyl-4-fluorobenzonitrile with structure in formula (1) as bent Ge Lieting synthetic intermediate, not only can improve the stability of bent Ge Lieting synthetic intermediate, and then reduce the synthesis difficulty of bent Ge Lieting, and this 2-chloromethyl-4-fluorobenzonitrile itself is nontoxic, nonirritant, can avoid because the pungency existing for synthetic intermediate is to the infringement of operator ' s health.
The synthetic method of the above-mentioned a kind of bent Ge Lieting of the present invention and the bent Ge Lieting synthesized by the method and bent Ge Lieting synthetic intermediate, with prior art mainly with 2-methyl-4-fluorobenzonitrile for raw material, through bromo condensation, the scheme that ammonification obtains bent Ge Lieting alkali is different.2-methylol-4-the fluorobenzonitrile that present invention employs price more cheap is starting raw material, obtains bent Ge Lieting alkali successively through chlorination, condensation reaction and aminating reaction.Simultaneously, the use that The method avoids the cupric cyanide of high poison provided by the present invention, not only increase the security of building-up process, friendly environment, and the chloro intermediate formed is also more stable than Bromo-intermediates of the prior art, and nonirritant, further avoid the infringement of the pungency existing for synthetic intermediate to operator ' s health.
Embodiment:
Below in conjunction with in the embodiment of the present invention, technical scheme in embodiments of the invention is described in detail, but following embodiment is only understand the present invention, and can not limit the present invention, and the multitude of different ways that the present invention can be defined by the claims and cover is implemented.
Further illustrate the synthetic method of bent Ge Lieting and the beneficial effect of the bent Ge Lieting synthesized by the method and bent Ge Lieting synthetic intermediate below with reference to embodiment 1-3 and comparative example 1, wherein, the synthetic route of the synthetic method of bent Ge Lieting is as follows:
Embodiment 1
The synthetic method of bent Ge Lieting is as follows:
Step 1: the synthesis of intermediate-1 (2-chloromethyl-4-fluorobenzonitrile)
Room temperature, mixes 2-methylol-4-fluorobenzonitrile 21.2g (0.14mol) with sulfur oxychloride 80g under stirring, is warming up to 70 DEG C gradually, and stirring and refluxing is reacted, and reaction 2h, TLC detection reaction is complete.Reclaim excess thionyl chloride, be concentrated into dripless and obtain intermediate 1 (2-chloromethyl-4-fluorobenzonitrile), add the toluene of 2 times of quality volumes, for subsequent use.
Step 2: the synthesis of intermediate-2 (2-[(chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (the 2H)-pyrimidyl of 6-) methyl]-4-fluorobenzonitrile).
6-chloro-3-6-Methyl Uracil 22.5g (0.14mol) and DIPEA (DIPEA) 29mL add in N-Methyl pyrrolidone 70mL, stirring at room temperature 30min.By intermediate-1, (intermediate 1 reacts obtained by upper step, not purified, productive rate is by 100%) toluene solution of 23.8g (0.14mol) is slowly added drop-wise in reaction system, be warming up to 60 DEG C and stir 1h, be down to room temperature, add distilled water 110mL, cooling down to 5 DEG C stirring and crystallizing 1h.Suction filtration, filter cake is with washed with isopropyl alcohol (50mL × 3), and 45 DEG C of dry 4h, obtain intermediate-2 (33.7g, yield 82%, purity 97.8%).ESI-MS(m/z)294.04[M+H]
+，
1H-NMR(500MHz，CDCl
3)：δ7.73(dd，J＝8.5，3.5Hz，1H)，7.12-7.16(m，1H)，6.94(dd，J＝9.0，6.5Hz，1H)，5.50(s，2H)，6.041(s，1H)，3.39(s，3H)。
Step 3: the synthesis of bent Ge Lieting (2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl]-4-fluorobenzonitrile).
(R)-3-amino piperidine dihydrochloride 17.3g (0.10mol), salt of wormwood 48.4g (0.35mol) and 7mL distilled water add in Virahol 150mL.Stirring at room temperature 30min, by intermediate-2 (2-[(chloro-3, the 4-dihydro-3-methyl-2 of 6-, 4-dioxo-1 (2H)-pyrimidyl) methyl]-4-fluorobenzonitrile) 29.3g (0.10mol) is added in reaction solution, be warming up to 65 DEG C, reaction 8h, TLC detect intermediate-2 and react complete, suction filtration while hot, filter cake hot Virahol (60 DEG C) washing (30mL × 3), merging filtrate, washing lotion, evaporated under reduced pressure, obtains red solid.Add 1g activated carbon, reflux decolour 20min, heat filtering after adding 95% ethanol 120mL heating for dissolving, stirring at room temperature crystallization 1h, suction filtration, 45 DEG C of dry 6h, obtain finished product, 25.73g, yield 72%, purity 99.6%.ESI-MS(m/z)358.14[M+H]
+，
1H-NMR(500MHz，CD
3OD)：δ7.80-7.82(m，1H)，7.21-7.23(t，J＝6.0，2.0Hz，1H)，7.09-7.11(m，1H)，5.41(s，1H)，5.27(s，2H)，3.30(s，3H)，3.18(d，1H)，3.03(d，1H)，2.84(t，J＝4.0Hz，1H)，2.64(s，1H)，2.,45(s，1H)，1.96(d，1H)，1.93(d，1H)，1.74-1.77(m，1H)，1.60(d，1H)，1.24(d，1H)，1.17(m，1H)。
Embodiment 2
The synthetic method of bent Ge Lieting is as follows:
Step 1: the synthesis of intermediate-1 (2-chloromethyl-4-fluorobenzonitrile)
Room temperature, mixes 2-methylol-4-fluorobenzonitrile 21.2g (0.14mol) with sulfur oxychloride 74.2g under stirring, is warming up to 75 DEG C gradually, and stirring and refluxing is reacted, and reaction 5h, TLC detection reaction is complete.Reclaim excess thionyl chloride, be concentrated into dripless and obtain intermediate 1 (2-chloromethyl-4-fluorobenzonitrile), add the toluene of 2 times of quality volumes, for subsequent use.
Step 2: the synthesis of intermediate 2 (2-[(chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (the 2H)-pyrimidyl of 6-) methyl]-4-fluorobenzonitrile).
6-chloro-3-6-Methyl Uracil 22.5g (0.14mol) and DIPEA (DIPEA) 29mL add in N-Methyl pyrrolidone 70mL, stirring at room temperature 30min.By intermediate 1, (intermediate 1 reacts obtained by upper step, not purified, productive rate is by 100%) toluene solution of 23.8g (0.14mol) is slowly added drop-wise in reaction system, be warming up to 25 DEG C and stir 6h, be down to room temperature, add distilled water 110mL, cooling down to 5 DEG C stirring and crystallizing 1h.Suction filtration, filter cake is with washed with isopropyl alcohol (50mL × 3), and 45 DEG C of dry 4h, obtain intermediate 2 (33.7g, yield 82%, purity 97.9%).ESI-MS(m/z)294.04[M+H]
+，
1H-NMR(500MHz，CDCl
3)：δ7.73(dd，J＝8.5，3.5Hz，1H)，7.12-7.16(m，1H)，6.94(dd，J＝9.0，6.5Hz，1H)，5.50(s，2H)，6.041(s，1H)，3.39(s，3H)。
Step 3: the synthesis of bent Ge Lieting (2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl]-4-fluorobenzonitrile).
(R)-3-amino piperidine dihydrochloride 17.3g (0.10mol), salt of wormwood 48.4g (0.35mol) and 7mL distilled water add in Virahol 150mL.Stirring at room temperature 30min, by intermediate-2 (2-[(chloro-3, the 4-dihydro-3-methyl-2 of 6-, 4-dioxo-1 (2H)-pyrimidyl) methyl]-4-fluorobenzonitrile) 29.3g (0.10mol) is added in reaction solution, be warming up to 25 DEG C, reaction 12h, TLC detect intermediate-2 and react complete, suction filtration while hot, filter cake hot Virahol (60 DEG C) washing (30mL × 3), merging filtrate, washing lotion, evaporated under reduced pressure, obtains red solid.Add 1g activated carbon, reflux decolour 20min, heat filtering after adding 95% ethanol 120mL heating for dissolving, stirring at room temperature crystallization 1h, suction filtration, 45 DEG C of dry 6h, obtain finished product, 25.73g, yield 72%, purity 99.5%.ESI-MS(m/z)358.14[M+H]
+，
1H-NMR(500MHz，CD
3OD)：δ7.80-7.82(m，1H)，7.21-7.23(t，J＝6.0，2.0Hz，1H)，7.09-7.11(m，1H)，5.41(s，1H)，5.27(s，2H)，3.30(s，3H)，3.18(d，1H)，3.03(d，1H)，2.84(t，J＝4.0Hz，1H)，2.64(s，1H)，2.,45(s，1H)，1.96(d，1H)，1.93(d，1H)，1.74-1.77(m，1H)，1.60(d，1H)，1.24(d，1H)，1.17(m，1H)。
Embodiment 3
The synthetic method of bent Ge Lieting is as follows:
Step 1: the synthesis of intermediate 1 (2-chloromethyl-4-fluorobenzonitrile)
Room temperature, mixes 2-methylol-4-fluorobenzonitrile 21.2g (0.14mol) with sulfur oxychloride 126g under stirring, is warming up to 70 DEG C gradually, and stirring and refluxing is reacted, and reaction 2h, TLC detection reaction is complete.Reclaim excess thionyl chloride, be concentrated into dripless and obtain intermediate 1 (2-chloromethyl-4-fluorobenzonitrile), add the toluene of 2 times of quality volumes, for subsequent use.
Step 2: the synthesis of intermediate 2 (2-[(chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (the 2H)-pyrimidyl of 6-) methyl]-4-fluorobenzonitrile).
6-chloro-3-6-Methyl Uracil 22.5g (0.14mol) and DIPEA (DIPEA) 29mL add in N-Methyl pyrrolidone 70mL, stirring at room temperature 30min.By intermediate 1, (intermediate 1 reacts obtained by upper step, not purified, productive rate is by 100%) toluene solution of 38.02g (0.224mol) is slowly added drop-wise in reaction system, be warming up to 100 DEG C and stir 1h, be down to room temperature, add distilled water 110mL, cooling down to 5 DEG C stirring and crystallizing 1h.Suction filtration, filter cake is with washed with isopropyl alcohol (50mL × 3), and 45 DEG C of dry 4h, obtain intermediate 2 (34.5g, yield 84%, purity 97.8%).ESI-MS(m/z)294.04[M+H]
+，
1H-NMR(500MHz，CDCl
3)：δ7.73(dd，J＝8.5，3.5Hz，1H)，7.12-7.16(m，1H)，6.94(dd，J＝9.0，6.5Hz，1H)，5.50(s，2H)，6.041(s，1H)，3.39(s，3H)。
Step 3: the synthesis of bent Ge Lieting (2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl]-4-fluorobenzonitrile).
(R)-3-amino piperidine dihydrochloride 25.9g (0.15mol), salt of wormwood 48.4g (0.35mol) and 7mL distilled water add in Virahol 150mL.Stirring at room temperature 30min, by intermediate-2 (2-[(chloro-3, the 4-dihydro-3-methyl-2 of 6-, 4-dioxo-1 (2H)-pyrimidyl) methyl]-4-fluorobenzonitrile) 29.3g (0.10mol) is added in reaction solution, be warming up to 100 DEG C, reaction 2h, TLC detect intermediate-2 and react complete, suction filtration while hot, filter cake hot Virahol (60 DEG C) washing (30mL × 3), merging filtrate, washing lotion, evaporated under reduced pressure, obtains red solid.Add 1g activated carbon, reflux decolour 20min, heat filtering after adding 95% ethanol 120mL heating for dissolving, stirring at room temperature crystallization 1h, suction filtration, 45 DEG C of dry 6h, obtain finished product, 26.44g, yield 74%, purity 99.6%.ESI-MS(m/z)358.14[M+H]
+，
1H-NMR(500MHz，CD
3OD)：δ7.80-7.82(m，1H)，7.21-7.23(t，J＝6.0，2.0Hz，1H)，7.09-7.11(m，1H)，5.41(s，1H)，5.27(s，2H)，3.30(s，3H)，3.18(d，1H)，3.03(d，1H)，2.84(t，J＝4.0Hz，1H)，2.64(s，1H)，2.,45(s，1H)，1.96(d，1H)，1.93(d，1H)，1.74-1.77(m，1H)，1.60(d，1H)，1.24(d，1H)，1.17(m，1H)。
Comparative example 1
The synthesis technique of bent Ge Lieting involved in US Patent No. 2012197018A1, its synthesis route is as follows:
The concrete synthesis technique of the synthesis technique of above-mentioned bent Ge Lieting is as follows:
(1) synthesis of above-claimed cpd B-intermediate I (4-fluoro-2-methylbenzene formonitrile HCN)
The reflux 24h in DMF (100mL) by bromo-for 2-5-toluene fluoride (compd A) (3.5g, 18.5mmol) and CuCN (2g, 22mmol).Reaction solution dilute with water, normal hexane extraction, organic layer MgSO
4drying, steams and desolventizes to obtain product B (yield 60%).
1H-NMR(400MH
Z，CDCl
3)：δ7.60(dd，J＝5.6，8.8Hz，1H)，6.93-7.06(m，2H)，2.55(s，3H)。
(2) synthesis of above-claimed cpd C (2-brooethyl-4-fluorobenzonitrile)
By 4-fluoro-2-methylbenzene formonitrile HCN (compd B) (2g, 14.8mmol), N-bromosuccinimide (NBS) (2.64g, 15mmol), Diisopropyl azodicarboxylate (AIBN) (100mg) is dissolved in CCl
4in, under nitrogen protection, reflux 2h.Be chilled to room temperature, solids removed by filtration, concentrated obtain crude oil, be not purifiedly directly used in the next step.
1H-NMR(400MH
Z，CDCl
3)：δ7.68(dd，J＝5.2，8.4Hz，1H)，7.28(dd，J＝2.4，8.8Hz，1H)，7.12(m，1H),4.6(s，2H)。
(3) synthesis of above-claimed cpd E (2-[(chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (the 2H)-pyrimidyl of 6-) methyl]-4-fluorobenzonitrile)
By 3-methyl-6-chlorouracil (above-claimed cpd D) (0.6g, 3.8mmol), 2-brooethyl-4-fluorobenzonitrile (0.86g, 4mmol) and salt of wormwood (0.5g, 4mmol) be dissolved in DMSO (10mL), in 60 DEG C of heated and stirred 2h.Dilute with water, ethyl acetate is extracted.Organic layer MgSO
4drying, steaming desolventizes, and residue, through purification by column chromatography, obtains 0.66g product (yield 60%).
1H-NMR(400MH
Z，CDCl
3)：δ7.73(dd，J＝7.2，8.4Hz，1H)，7.26(d，J＝4.0Hz，1H)，7.11-7.17(m，1H)，6.94(dd，J＝2.0，9.0Hz，1H)，6.034(s，2H)，3.39(s，3H)。MS (ES) [m+H] is according to C
13h
9clFN
3o
2calculated value, 293.68, measured value 293.68.
(4) the above-claimed cpd F (synthesis of 2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl]-4-fluorobenzonitrile
2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl) methyl]-4-fluorobenzonitrile (compd E) (300mg, 1.0mmol), (R)-amino piperidine dihydrochloride (266mg, 1.5mmol), sodium bicarbonate (500mg, 5.4mmol), ethanol (3mL) in sealed tube 100 DEG C, stirs 2h.After HPLC purifying, with trifluoroacetic acid salify.
1H-NMR(400MH
Z，CD
3OD)：δ7.77-7.84(m，1H)，7.16-7.27(m，2H)，5.46(s，1H)，5.17-5.34(ABq，J＝35.2，15.6Hz，2H)，3.33-3.47(m，2H)，3.22(s，3H),2.98-3.08(m，1H)，2.67-2.92(m，2H)，2.07-2.17(m，1H)，1.82-1.92(m，1H)，1.51-1.79(m，2H)。MS (ES) [m+H] is according to C
18h
20fN
5o
2calculated value, 357.38, measured value 357.38.
In the synthetic method of the bent Ge Lieting that embodiment 1 to 3 and comparative example 1 provide, as stability and the pungency test of the 2-chloromethyl-4-fluorobenzonitrile of intermediate.
(1), stability test
Testing method: the intermediate 2-chloromethyl-4-fluorobenzonitrile produced in the intermediate 2-brooethyl-4-fluorobenzonitrile produced in comparative example 1 and embodiment 1-3 is dissolved in the toluene of 2 times of quality volumes preserve under room temperature condition respectively, respectively at the 2nd, 4,6,8, within 10,12 hours, carry out tlc (TLC) to detect.
Test result: namely 2-brooethyl-4-fluorobenzonitrile, in toluene solution, at room temperature in daylight started to occur obvious impure point in the 4th hour, and after the 12nd hour, impure point area accounts for 1/3rd of the area of principal spot.And 2-chloromethyl-4-fluorobenzonitrile is in toluene solution, at room temperature in daylight namely there is not obvious impure point yet in 12 hours, as can be seen here, be obviously better than by the stability of the intermediate 2-chloromethyl-4-fluorobenzonitrile produced in embodiment 1-3 the intermediate 2-brooethyl-4-fluorobenzonitrile that comparative example 1 produces.
(2), intermediate pungency test
Testing method: the somatic reaction of observation operator when synthesizing the intermediate 2-chloromethyl-4-fluorobenzonitrile produced in the intermediate 2-brooethyl-4-fluorobenzonitrile and embodiment 1-3 produced in comparative example 1.
Test result: operator, when synthesizing the intermediate 2-brooethyl-4-fluorobenzonitrile produced in comparative example 1, often occurs obviously shedding tears, the mucosa irritation symptoms such as runny nose, and with allergic skin symptom; And during the intermediate 2-chloromethyl-4-fluorobenzonitrile produced in synthetic example 1-3, do not find that untoward reaction appears in operator.
Known by forming 2-chloromethyl-4-fluorobenzonitrile as bent Ge Lieting synthetic intermediate by above-mentioned test, not only can improve the stability of bent Ge Lieting synthetic intermediate, and then reduce the synthesis difficulty of bent Ge Lieting, and this 2-chloromethyl-4-fluorobenzonitrile itself is nontoxic, nonirritant, can avoid because the pungency existing for synthetic intermediate is to the infringement of operator ' s health.
The synthetic method of the above-mentioned a kind of bent Ge Lieting of the present invention and the bent Ge Lieting synthesized by the method and bent Ge Lieting synthetic intermediate, with prior art mainly with 2-methyl-4-fluorobenzonitrile for raw material, through bromo condensation, the scheme that ammonification obtains bent Ge Lieting alkali is different.2-methylol-4-the fluorobenzonitrile that present invention employs price more cheap is starting raw material, obtains bent Ge Lieting alkali successively through chlorination, condensation reaction and aminating reaction.Simultaneously, the use that The method avoids the cupric cyanide of high poison provided by the present invention, not only increase the security of building-up process, friendly environment, and the chloro intermediate formed is also more stable than Bromo-intermediates of the prior art, and nonirritant, further avoid the infringement of the pungency existing for synthetic intermediate to operator ' s health.
These are only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. a synthetic method of bent Ge Lieting, is characterized in that, described synthetic method comprises the following steps:
S1, with 2-methylol-4-fluorobenzonitrile for starting raw material, obtain 2-chloromethyl-4-fluorobenzonitrile through chlorination;
S2, using described 2-chloromethyl-4-fluorobenzonitrile as intermediate, obtain 2-[(chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (the 2H)-pyrimidyl of 6-) methyl]-4-fluorobenzonitrile through condensation reaction;
S3,2-[(chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (the 2H)-pyrimidyl of 6-) methyl]-4-fluorobenzonitrile, as intermediate, is obtained bent Ge Lieting alkali through aminating reaction.
2. synthetic method according to claim 1, is characterized in that, described S1 comprises the following steps:
Under chloridized condition, by 2-methylol-4-fluorobenzonitrile and chlorinating agent 1:3.5-1:6 contact reacts by weight, to obtain 2-chloromethyl-4-fluorobenzonitrile; Preferred described chlorinating agent is one or more in sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, trimethylchlorosilane, N-phenyl benzoyl imines chlorine, hexachloroacetone-triphenylphosphine, carbon tetrahalide-triphenyl phosphine, N-chlorosuccinimide-triphenylphosphine and methylsulfonyl chloride.
3. synthetic method according to claim 2, is characterized in that, described chlorination reaction condition comprises: at 25-85 DEG C, under preferred 70-75 DEG C condition, and reaction 1-12h.
4. synthetic method according to claim 1, is characterized in that, described S2 comprises the following steps:
Be dissolved in the first organic solvent by 2-chloromethyl-4-fluorobenzonitrile, obtain 2-chloromethyl-4-fluorobenzonitrile solution, preferably described first organic solvent is one or more in toluene, DMF, benzene, chloroform and methyl tertiary butyl ether;
Chloro-for 6-3-6-Methyl Uracil is dissolved in the second organic solvent, obtain 6-chloro-3-6-Methyl Uracil solution, preferably described second organic solvent is N, N-diisopropylethylamine, N-Methyl pyrrolidone, N, dinethylformamide, N, one or more in N-N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF) and acetonitrile, more preferably described second organic solvent is the mixture of DIPEA and N-Methyl pyrrolidone 3:7;
Under condensation reaction condition, by described 2-chloromethyl-4-fluorobenzonitrile solution and 6-chloro-3-6-Methyl Uracil solution contact reacts, obtain described 2-[(chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (the 2H)-pyrimidyl of 6-) methyl]-4-fluorobenzonitrile.
5. synthetic method according to claim 4, it is characterized in that, described condensation reaction condition comprises: at 25-100 DEG C, under preferred 60-65 DEG C condition, described 2-chloromethyl-4-fluorobenzonitrile solution is dropped to described 6-chloro-3-6-Methyl Uracil solution, be added dropwise to complete rear continuation reaction 1-6h, preferred described 6-chloro-3-6-Methyl Uracil and 2-chloromethyl-4-fluorobenzonitrile in molar ratio 1:1 ~ 1:1.6 mix.
6. synthetic method according to claim 1, is characterized in that, described S3 comprises the following steps:
By (R)-3-amino piperidine dihydrochloride and salt of wormwood and the 3rd solvent, obtain mixed reaction solution, one or more organic solvents in Virahol, methyl alcohol, ethanol, n-propyl alcohol, propyl carbinol and tetrahydrofuran (THF) that described 3rd solvent is and the mixing solutions of water, and the volume ratio of organic solvent and water is 22:1 ~ 17:1;
By described 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl) methyl]-4-fluorobenzonitrile is that 1:1 ~ 1.5 join in described mixed reaction solution according to its mol ratio with (R)-3-amino piperidine dihydrochloride, carries out the described bent Ge Lieting alkali crude product of reaction formation under described aminating reaction condition.
7. synthetic method according to claim 6, is characterized in that, described S3 is further comprising the steps of:
Activated carbon is added, reflux decolour 15-30min, heat filtering, stirring at room temperature crystallization 1-1.5h, suction filtration after described bent Ge Lieting alkali crude product is added 95% ethanol heating for dissolving, dry, obtain bent Ge Lieting alkali crude product fine work.
8. the synthetic method according to claim 6 or 7, is characterized in that, described aminating reaction condition comprises: temperature of reaction is 25 ~ 100 DEG C, preferred 65-70 DEG C, reaction 1 ~ 12h.
9. a bent Ge Lieting, is characterized in that, described bent Ge Lieting is synthesized by the synthetic method in claim 1 to 8 described in any one.
10. a bent Ge Lieting synthetic intermediate, is characterized in that, described bent Ge Lieting synthetic intermediate for having the 2-chloromethyl-4-fluorobenzonitrile of structure in formula (1),
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| CN109503551A (en) * | 2018-11-21 | 2019-03-22 | 安阳师范学院 | The preparation method of one koji Ge Lieting |
| CN109705089A (en) * | 2019-02-27 | 2019-05-03 | 浙江华贝药业有限责任公司 | The purification process of compound |
| CN111349075A (en) * | 2018-12-21 | 2020-06-30 | 浙江万晟药业有限公司 | Preparation method of trelagliptin succinate |
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| CN109503551A (en) * | 2018-11-21 | 2019-03-22 | 安阳师范学院 | The preparation method of one koji Ge Lieting |
| CN111349075A (en) * | 2018-12-21 | 2020-06-30 | 浙江万晟药业有限公司 | Preparation method of trelagliptin succinate |
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