CN103382154B - Synthetic method of methyl 4'-bromomethylbiphenyl-2-carboxylate - Google Patents
Synthetic method of methyl 4'-bromomethylbiphenyl-2-carboxylate Download PDFInfo
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- CN103382154B CN103382154B CN201310276892.3A CN201310276892A CN103382154B CN 103382154 B CN103382154 B CN 103382154B CN 201310276892 A CN201310276892 A CN 201310276892A CN 103382154 B CN103382154 B CN 103382154B
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Abstract
The invention belongs to the field of organic synthesis, and more specifically relates to a synthetic method of methyl 4'-bromomethylbiphenyl-2-carboxylate. The synthetic method comprises following steps: methyl 4'-bromomethylbiphenyl-2-carboxylate (II) is obtained by reacting 2-cyan-4'-bromomethylbiphenyl (I), methanol, water and a catalyst; and purified methyl 4'-bromomethylbiphenyl-2-carboxylate (II) is obtained after recrystallization. According to the synthetic method, technologies are simple; reaction steps are short; reaction conditions are easy to control; production cycle is short; raw materials are easily available; production cost is low; and environmental pollution is less.
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to a kind of synthetic method of 4'-bromomethyl biphenyl-2-methyl-formiate.
Background technology
Telmisartan is a kind of mechanism of action novelty, determined curative effect, the lasting and antihypertensive drug that side effect is little, belongs to a kind of novel Altace Ramipril.4'-bromomethyl biphenyl-2-methyl-formiate is the key intermediate of synthesis telmisartan.
Archiv der Pharmazie (Weinheim, Germany), 2001,344 (9), 617-626; Medicinal Chemistry Research, 2009,18 (8), 611-628; Organic Process Research & Development, 2007,11 (1), 81-85; Bioorganic & Medicinal Chemistry Letters, 2005,15 (9), 2385-2388; CN102557987, WO2006044754, US20040044041, US20040034064 report with 4-methyl diphenyl-2-methyl-formiate as raw material, the process recovery ratio obtaining 4'-bromomethyl biphenyl-2-methyl-formiate through a step bromo-reaction reaches 47% ~ 93%, but this technique Raw 4-methyl diphenyl-2-methyl-formiate price is higher, therefore products production cost is higher, does not have the market advantage.
Archiv der Pharmazie (Weinheim, Germany), 2011,344 (9), 617-626; US20040044041, US20040034064 report with 4-methyl diphenyl-2-formic acid as raw material, 4'-bromomethyl biphenyl-2-methyl-formiate is obtained through esterification and bromo-reaction, the methyl iodide used in its esterification or (TMS) diazomethane price all higher, therefore it is not suitable as industrialized route.
Archiv der Pharmazie (Weinheim, Germany), 2011,344 (9), 617-626 and Heilungkiang medical science, 2006(01): 40 to report with sartanbiphenyl be raw material, the operational path of 4'-bromomethyl biphenyl-2-methyl-formiate is obtained through highly basic hydrolysis reaction, esterification, bromo-reaction, in hydrolytic process, use a large amount of highly basic and strong acid, generate a large amount of inorganic salt, contaminate environment; And this operational path is longer, and total recovery is lower, and production cost is higher.
Medicinal Chemistry Research, 2009,18 (8), 611-628; Ger.Offen., 4006693,05Sep1991, EP412848 etc. report with adjacent halogenated benzoic acid methyl esters with to methylphenylboronic acid or operational path toluene halide being obtained to 4'-bromomethyl biphenyl-2-methyl-formiate through linked reaction, bromination reaction; In this technological process, expensive to methylphenylboronic acid, and in linked reaction, use plurality of heavy metal catalyzer, be difficult to recycle, contaminate environment; Therefore this route is not suitable for industrialization.Summary of the invention
The object of this invention is to provide a kind of synthetic method of 4'-bromomethyl biphenyl-2-methyl-formiate, raw material be easy to get, cost is low, reactions steps is short, reaction conditions be easy to control, environmental pollution is little.
The synthetic method of 4'-bromomethyl biphenyl-2-methyl-formiate of the present invention obtains 4'-bromomethyl biphenyl-2-methyl-formiate (II) after 2-cyano group-4'-bromomethylbiphenyl (I), methyl alcohol, water and catalyst reaction, then after recrystallization, obtain 4'-bromomethyl biphenyl-2-methyl-formiate (II) sterling;
Reaction process is as follows:
Described catalyzer is the one in the industrial vitriol oil or industrial methylsulfonic acid.
Described 2-cyano group-4'-bromomethylbiphenyl (I) is 1:0.5 ~ 1.0 with the mass ratio of catalyzer.
Described 2-cyano group-4'-bromomethylbiphenyl (I) is 1:0.1 ~ 0.3 with the mass ratio of water.
Described 2-cyano group-4'-bromomethylbiphenyl (I) is 1:3.0 ~ 5.0 with the mass ratio of methyl alcohol.
Described reaction pressure is 1.0 ~ 2.5MPa.
Described temperature of reaction is 140 ~ 170 DEG C.
The described reaction times is 5 ~ 10 hours.
The concrete steps of the synthetic method of 4'-bromomethyl biphenyl-2-methyl-formiate of the present invention are as follows:
(1) 2-cyano group-4'-bromomethylbiphenyl (I) is put in autoclave, add first alcohol and water, under the condition stirred, add catalyzer, enclosed high pressure reactor, after nitrogen replacement 2 ~ 3 times, start to react and be incubated;
(2) after insulation, sampling, follows the tracks of reaction, when 2-cyano group-4'-bromomethylbiphenyl (I) HPLC purity is less than 1.0% in reaction solution with HPLC, stopped reaction, cool to 10 ~ 15 DEG C, regulate PH to 6.5 ~ 7.5, after underpressure distillation with 30% aqueous sodium hydroxide solution, extract with extraction agent, merge organic phase, underpressure distillation obtains 4'-bromomethyl biphenyl-2-methyl-formiate (II) crude product, obtains 4'-bromomethyl biphenyl-2-methyl-formiate (II) sterling after crude product recrystallization.
Described extraction agent is the one in methylene dichloride, chloroform or ethyl acetate, and extraction agent volume is 200 ~ 300ml.
Beneficial effect of the present invention is as follows:
Compared with prior art, present invention process is simple, and reactions steps is short and condition is easy to control, and with short production cycle, starting material are cheap and easy to get, and production cost is low, and environmental pollution is little.
Embodiment
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1
Get 27.2 g of compound (I), put in 250ml autoclave, add 108.8 grams of methyl alcohol and 5.4 grams of service waters, under the condition stirred, then drip 21.7 grams of industrial vitriol oils, enclosed high pressure reactor, after nitrogen replacement 3 times, be warmed up to 155 DEG C, pressure is elevated to 1.75MPa, starts insulation.
Be incubated after 6 hours, sampling, follows the tracks of reaction, when compound in reaction solution (I) HPLC purity is less than 1.0% with HPLC, stopped reaction, cool to 10 DEG C, regulate PH to 7.0, after solvent is fallen in underpressure distillation with 30% aqueous sodium hydroxide solution, with methylene dichloride 250ml lysate, after suction filtration falls inorganic salt, remove methylene dichloride under reduced pressure and obtain compound (II) crude product, after crude product recrystallization, obtain compound (II) sterling 27.97 grams.
Embodiment 2
Get 27.2 g of compound (I), put in 250ml autoclave, add 108.8 grams of methyl alcohol and 3.0 grams of service waters, under the condition stirred, then drip 21.7 grams of industrial vitriol oils, enclosed high pressure reactor, after nitrogen replacement 2 times, be warmed up to 140 DEG C, pressure is elevated to 1MPa, starts insulation.
Be incubated after 5 hours, sampling, follows the tracks of reaction, when compound in reaction solution (I) HPLC purity is less than 1.0% with HPLC, stopped reaction, cool to 12 DEG C, regulate PH to 6.5, after solvent is fallen in underpressure distillation with 30% aqueous sodium hydroxide solution, with chloroform 200ml lysate, cross after filtering inorganic salt, remove chloroform under reduced pressure and obtain compound (II) crude product, after crude product recrystallization, obtain compound (II) sterling 26.35 grams.
Embodiment 3
Get 27.2 g of compound (I), put in 250ml autoclave, add 81.6 grams of methyl alcohol and 5.4 grams of service waters, under the condition stirred, then drip 21.7 grams of industrial methylsulfonic acids, enclosed high pressure reactor, after nitrogen replacement 3 times, be warmed up to 170 DEG C, pressure is elevated to 1.2MPa, starts insulation.
Be incubated after 7 hours, sampling, follows the tracks of reaction, when compound in reaction solution (I) HPLC purity is less than 1.0% with HPLC, stopped reaction, cool to 15 DEG C, regulate PH to 7.5, after solvent is fallen in underpressure distillation with 30% aqueous sodium hydroxide solution, with methylene dichloride 300ml lysate, cross after filtering inorganic salt, remove methylene dichloride under reduced pressure and obtain compound (II) crude product, after crude product recrystallization, obtain compound (II) sterling 22.93 grams.
Embodiment 4
Get 27.2 g of compound (I), put in 250ml autoclave, add 108.8 grams of methyl alcohol and 6.8 grams of service waters, under the condition stirred, then drip 21.7 grams of industrial vitriol oils, enclosed high pressure reactor, after nitrogen replacement 2 times, be warmed up to 165 DEG C, pressure is elevated to 2.25MPa, starts insulation.
Be incubated after 8 hours, sampling, follows the tracks of reaction, when compound in reaction solution (I) HPLC purity is less than 1.0% with HPLC, stopped reaction, cool to 13 DEG C, regulate PH to 6.5, after solvent is fallen in underpressure distillation with 30% aqueous sodium hydroxide solution, with ethyl acetate 300ml lysate, cross after filtering inorganic salt, remove ethyl acetate under reduced pressure and obtain compound (II) crude product, after crude product recrystallization, obtain compound (II) sterling 26.82 grams.
Embodiment 5
Get 27.2 g of compound (I), put in 250ml autoclave, add 136.0 grams of methyl alcohol and 8.1 grams of service waters, under the condition stirred, then drip 24.5 grams of industrial vitriol oils, enclosed high pressure reactor, after nitrogen replacement 3 times, be warmed up to 145 DEG C, pressure is elevated to 1.25MPa, starts insulation.
Be incubated after 9 hours, sampling, follows the tracks of reaction, when compound in reaction solution (I) HPLC purity is less than 1.0% with HPLC, stopped reaction, cool to 11 DEG C, regulate PH to 7.5, after solvent is fallen in underpressure distillation with 30% aqueous sodium hydroxide solution, with methylene dichloride 250ml lysate, cross after filtering inorganic salt, remove methylene dichloride under reduced pressure and obtain compound (II) crude product, after crude product recrystallization, obtain compound (II) sterling 26.34 grams.
Embodiment 6
Get 27.2 g of compound (I), put in 250ml autoclave, add 107.5 grams of methyl alcohol and 5.4 grams of service waters, under the condition stirred, then drip 13.6 grams of industrial vitriol oils, enclosed high pressure reactor, after nitrogen replacement 2 times, be warmed up to 150 DEG C, pressure is elevated to 2.5MPa, starts insulation.
Be incubated after 10 hours, sampling, follows the tracks of reaction, when compound in reaction solution (I) HPLC purity is less than 1.0% with HPLC, stopped reaction, cool to 14 DEG C, regulate PH to 7.0, after solvent is fallen in underpressure distillation with 30% aqueous sodium hydroxide solution, with chloroform 300ml lysate, cross after filtering inorganic salt, remove chloroform under reduced pressure and obtain compound (II) crude product, after crude product recrystallization, obtain compound (II) sterling 24.58 grams.
Embodiment 7
Get 27.2 g of compound (I), put in 250ml autoclave, add 108.8 grams of methyl alcohol and 2.8 grams of service waters, under the condition stirred, then drip 16.3 grams of industrial vitriol oils, enclosed high pressure reactor, after nitrogen replacement 3 times, be warmed up to 160 DEG C, pressure is elevated to 2.3MPa, starts insulation.
Be incubated after 6 hours, sampling, follows the tracks of reaction, when compound in reaction solution (I) HPLC purity is less than 1.0% with HPLC, stopped reaction, cool to 10 DEG C, regulate PH to 6.5, after solvent is fallen in underpressure distillation with 30% aqueous sodium hydroxide solution, with ethyl acetate 200ml lysate, cross and filter inorganic salt, remove ethyl acetate under reduced pressure and obtain compound (II) crude product, after crude product recrystallization, obtain compound (II) sterling 26.18 grams.
Embodiment 8
Get 27.2 g of compound (I), put in 250ml autoclave, add 108.8 grams of methyl alcohol and 5.4 grams of service waters, under the condition stirred, then drip 27.2 grams of industrial vitriol oils, enclosed high pressure reactor, after nitrogen replacement 2 times, be warmed up to 155 DEG C, pressure is elevated to 1.5MPa, starts insulation.
Be incubated after 8 hours, sampling, follows the tracks of reaction, when compound in reaction solution (I) HPLC purity is less than 1.0% with HPLC, stopped reaction, cool to 15 DEG C, regulate PH to 7.0, after solvent is fallen in underpressure distillation with 30% aqueous sodium hydroxide solution, with methylene dichloride 250ml lysate, cross after filtering inorganic salt, remove methylene dichloride under reduced pressure and obtain compound (II) crude product, after crude product recrystallization, obtain compound (II) sterling 27.16 grams.
Claims (6)
1. the synthetic method of a 4'-bromomethyl biphenyl-2-methyl-formiate, obtain 4'-bromomethyl biphenyl-2-methyl-formiate (II) after it is characterized in that 2-cyano group-4'-bromomethylbiphenyl (I), methyl alcohol, water and catalyst reaction, then after recrystallization, obtain 4'-bromomethyl biphenyl-2-methyl-formiate (II) sterling;
Reaction process is as follows:
Described catalyzer is the one in the industrial vitriol oil or industrial methylsulfonic acid;
Described reaction pressure is 1.0 ~ 2.5MPa;
Described temperature of reaction is 140 ~ 170 DEG C.
2. the synthetic method of 4'-bromomethyl biphenyl-2-methyl-formiate according to claim 1, is characterized in that described 2-cyano group-4'-bromomethylbiphenyl (I) is 1:0.5 ~ 1.0 with the mass ratio of catalyzer.
3. the synthetic method of 4'-bromomethyl biphenyl-2-methyl-formiate according to claim 1, is characterized in that described 2-cyano group-4'-bromomethylbiphenyl (I) is 1:0.1 ~ 0.3 with the mass ratio of water.
4. the synthetic method of 4'-bromomethyl biphenyl-2-methyl-formiate according to claim 1, is characterized in that described 2-cyano group-4'-bromomethylbiphenyl (I) is 1:3.0 ~ 5.0 with the mass ratio of methyl alcohol.
5. the synthetic method of 4'-bromomethyl biphenyl-2-methyl-formiate according to claim 1, is characterized in that the described reaction times is 5 ~ 10 hours.
6. the synthetic method of 4'-bromomethyl biphenyl-2-methyl-formiate according to claim 1, is characterized in that concrete steps are as follows:
(1) 2-cyano group-4'-bromomethylbiphenyl (I) is put in autoclave, add first alcohol and water, under the condition stirred, add catalyzer and start to react and be incubated;
(2) when after insulation, in detection reaction liquid, 2-cyano group-4'-bromomethylbiphenyl (I) HPLC purity is less than 1.0%, stopped reaction, cool to 10 ~ 15 DEG C, regulate pH to 6.5 ~ 7.5, after underpressure distillation, add extraction agent extraction, underpressure distillation obtains 4'-bromomethyl biphenyl-2-methyl-formiate (II) crude product, obtains 4'-bromomethyl biphenyl-2-methyl-formiate (II) sterling after crude product recrystallization.
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Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: SHANDONG JINCHENG PHARMACEUTICAL GROUP CO.,LTD. Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL CO.,LTD. Address after: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee after: SHANDONG JINCHENG PHARMACEUTICAL CO.,LTD. Address before: 255129 Zichuan District Economic Development Zone, Zibo, Shandong Patentee before: SHANDONG JINCHENG PHARMACEUTICAL & CHEMICAL Co.,Ltd. |