CN107540575B - Preparation method of sitagliptin intermediate - Google Patents
Preparation method of sitagliptin intermediate Download PDFInfo
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Abstract
The invention discloses a preparation method of a sitagliptin intermediate, belongs to the field of drug synthesis, and provides a preparation method of a compound 2, which avoids the use of an expensive catalyst resolving agent and harsh low-temperature conditions, prepares the compound 2, reduces the cost to a great extent, is short in process, high in purity and high in yield, and is suitable for quantitative production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of a Sitagliptin (Sitagliptin) intermediate for treating diabetes mellitus II.
Background
Sitagliptin phosphate is the first dipeptidyl enzyme-IV (DPP-4) inhibitor approved by FDA for marketing in 2006, the chemical name of sitagliptin: (3R) -3-amino-1- [3- (trifluoromethyl) -5, 6, 7, 8-tetrahydro-1, 2, 4-triazolo [4, 3-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) butan-1-one, the English name Sitagliptin, has the structure shown in formula 1:
the phosphate salt of the DPP-4 (DPP4) inhibitor is approved by the FDA of the United states as the first DPP4 inhibitor and is marketed for treating type II diabetes, and the phosphate salt becomes the only drug for treating type II diabetes dipeptidyl peptidase-4 (DPP4) inhibitor in the United states market to date. The preparation method of sitagliptin comprises the following steps: patent WO2004087650, publication date: 10/14/2004, applicant: merck Ltd
Among them, the group PG ═ Boc, Cbz, OBn, and other protecting groups, and compound 2 is an important intermediate for the preparation of sitagliptin.
Wherein, the synthesis method of the compound 2 mainly comprises the following steps,
the synthesis route of Merck company of original research works is mainly
Etc. as starting materials (Drugs of the Future 2005, 30 (4): 337-
To be provided with
The synthetic route of the starting material is shown in the reaction equation I, and the synthetic method is
The method is expensive, the reaction belongs to a linear reaction, the yield is low after seven steps of reactivity, in the synthetic route, a ruthenium catalyst is needed to carry out asymmetric catalytic hydrogenation on ketone in the key step, the price of the catalyst is expensive, in the later-stage industrialization, the amplification effect in the amplification process of the process is obvious, and the quality of the product is difficult to control.
To be provided with
The synthesis route for the starting material is shown as a reaction equation II, reagents used in the route are expensive, reaction conditions are relatively harsh, such as reaction conditions of-78 ℃ and-30 ℃ are required, some reactions require long time and are complicated to operate, and the intermediate product needs to be purified by column chromatography separation, so that the method is not suitable for industrial production conditions.
WO2005003135 discloses a third generation synthesis method developed by merck corporation to synthesize chiral amines using S-phenylglycinamide as a chiral auxiliary to induce catalytic hydrogenation. This synthetic route is relatively suitable, but there are also major problems in that two catalytic hydrogenations are required, a relatively expensive platinum catalyst is used, and a large amount of Pd (OH) is required for the last deprotection step2C, high cost
Other companies have also disclosed methods for the synthesis of compound 2, to
As a starting material
Patent US 2012/0016125A 1 discloses a method for preparing a medicine
The method is a synthetic method of raw materials, the route is shown in equation three, the yield is unstable, the cost is high, nitrine, sodium cyanide and the like which are highly toxic are needed in the experimental process, certain potential safety hazards exist in the experimental process, and the procedure for purchasing the highly toxic materials is complicated.
Patent WO 2010/122578A 2 discloses a method for preparing a composite material
The synthesis of the raw material is carried out by using osmium tetroxide as the active ingredient, and the process has safety hazard in experimental operation, and resolving agent is used in the fourth step, so the yield is low, and the process is not suitable for industrial production
The US patent 6699871 discloses a synthetic route for sitagliptin, which is a gram-scale synthetic method of research departments, and the synthetic route adopts a chiral source to induce out chiral α -amino acid, and then generates β -amino acid through diazotization operation to construct a required chiral center.
The invention content is as follows:
the invention aims to solve the problems of sitagliptin intermediates, most of the currently used compound 2 is prepared by the methods, the cost is high, the yield is low, the process is immature, and the method is not suitable for industrial production, so that an effective and economic synthetic route is found for preparing the compound 2, and the method is an urgent need of the global market.
In order to overcome the problems in the prior art, the invention provides a preparation method of the compound 2, which avoids using an expensive catalyst resolving agent and harsh low-temperature conditions, prepares the compound 2, greatly reduces the cost, has short process, high purity and high yield, and is suitable for quantitative production.
For compound 2, the company developed a route as follows:
PG＝Boc/OBn/cbz/
X＝Cl、Br、F、I
a preparation method of a compound shown as a formula 2 comprises the following steps:
(1) ring opening reaction: in a medium of tetrahydrofuran and toluene, at a temperature of between 20 ℃ below zero and 50 ℃ below zero, cuprous chloride is used as a catalyst, 2,4, 5-trifluorobromobenzene and a Grignard reagent RMgX are subjected to a Grignard reaction, wherein R is isopropyl and X is halogen, and the generated compound is subjected to a ring-opening reaction with a compound shown as a formula 3 to obtain a compound shown as a formula 4;
(2) substitution-hydrolysis reaction: reacting a compound shown as a formula 4, sodium acetate and tetrabutylammonium bromide in an N, N-dimethylformamide medium at the temperature of 70-80 ℃, adding sodium hydroxide for hydrolysis, and obtaining a compound shown as a formula 6
(3) And (3) oxidation reaction: the compound shown as the formula 6, 2,6, 6-tetramethyl piperidine oxide, sodium hypochlorite, sodium chlorite and buffering agents (disodium hydrogen phosphate and sodium dihydrogen phosphate) are subjected to oxidation reaction in an acetonitrile medium, quenched by using a reducing agent sodium sulfite, neutralized and extracted by ethyl acetate to obtain the compound shown as the formula 2.
In the step (1), the Grignard reagent RMgX is isopropyl magnesium chloride or isopropyl magnesium bromide.
2,4, 5-trifluorobromobenzene in the step (1): isopropyl magnesium chloride: the molar ratio of the compound shown as the formula 3 is 1: 1.5-2.5: 0.6-1.
In the step (2), the compound shown in the formula 4 is obtained: 2,2,6, 6-tetramethylpiperidine oxide: the molar ratio of sodium chlorite is 1: 0.05-0.1: 1.8-2.2.
The medium in step (1) may be tetrahydrofuran and toluene, tetrahydrofuran and methyl t-butyl ether, tetrahydrofuran and xylene, diethyl ether and toluene, diethyl ether and xylene, diethyl ether and methyl t-butyl ether, 2-methyltetrahydrofuran and toluene, 2-methyltetrahydrofuran and xylene, 2-methyltetrahydrofuran and methyl t-butyl ether.
The medium in the step (2) is one of DMF, DMAC, EA, DCM, THF and dioxane.
The medium in the step (3) is one of acetonitrile, tetrahydrofuran, methyl tert-butyl ether and organic solvent C1-C6 monohalogen or polyhalogen alkane.
A preparation method of a compound shown as a formula 3 comprises the following steps:
PG＝Boc/OBn/cbz/
X＝Cl、Br、F、I
(1) esterification reaction: adding thionyl chloride into a compound shown as a formula 7 in methanol as a medium at the temperature of 0-15 ℃, and reacting at the room temperature of 25 ℃ to obtain a compound shown as a formula 8
(2) Acylation reaction: adding triethylamine into a compound shown as a formula 8 in dichloromethane as a medium at a temperature of 0-15 ℃, adding a dichloromethane solution of a compound PG at a temperature of 15-25 ℃, reacting at a room temperature of 20-25 ℃ overnight, adjusting the pH value to 2.5-3 at a temperature of 0-10 ℃, extracting and concentrating to obtain the compound shown as a formula 9
(3) Reduction reaction: adding a reducing agent into the compound shown as the formula 9, controlling the temperature at 15 ℃, and reacting with methanol to obtain the compound shown as the formula 10
(4) And (3) substitution reaction: adding MsCl into a compound shown as a formula 10 in ethyl acetate and triethylamine as media to react to obtain a compound shown as a formula 11
(5) Ring closing reaction: adding a cyclization reagent into a compound shown as a formula 11 for reaction to obtain a compound shown as a formula 12
(6) And (3) substitution reaction: adding LiX into a solvent DMF of a compound shown as a formula 12 for reaction to obtain a compound shown as a formula 3
The mol ratio of the compound 7 to the thionyl chloride in the step (1) is 1.0: 2-3.
The mol ratio of the compound 4 to the triethylamine to the Boc acid anhydride in the step (2) is 1.0:2-4: 1-1.5.
The molar ratio of the compound 5 in the step (3) to the sodium borohydride is 1.0: 2.2-2.5.
The molar ratio of the compound 6 in the step (4) to the methylsulfonyl chloride is 1.0: 2.2-2.5.
The molar ratio of the compound 8 to the lithium chloride in the step (6) is 1.0: 1.2-15.
The medium in the step (2) can be one of dichloromethane, trichloromethane, carbon tetrachloride, ethyl acetate, toluene, methyl tert-butyl ether and tetrahydrofuran.
The medium in the step (4) can be one of triethylamine, diethylamine and diisopropylethylamine.
The medium in the step (6) can be one of DMF, DMAC, THF, methyl tert-butyl ether and acetonitrile.
In the step (6), LiX is one of lithium chloride, lithium bromide, lithium fluoride and lithium iodide.
Has the advantages that:
1. the protecting group of the compound shown in formula 3 can be Boc, Cbz, OBn,
Compared with the prior art, the reaction effect is good without Boc functional groups, the intermediate 2 only receives Boc protecting groups in the current market, and other protecting groups have no market at all, so the synthesis route of the invention mainly uses the Boc protecting groups.
2. The chiral center of the compound shown as the formula 4 is directly brought from the raw material, and the compound is prepared without an additional expensive catalyst, so that the cost is saved.
3. The reaction in the step g belongs to a nonlinear reaction, 2,4, 5-trifluorobromobenzene is connected with a compound shown in a formula 3, and the 2,4, 5-trifluorobromobenzene is not needed to be adopted initially, so that the cost is saved to a certain extent, and the yield is greatly improved.
4. The reaction from the step a to the step d, the reaction from the step e to the step f, and the reaction from the step h to the step i can be continuously operated, so that the whole process has 5 steps of reaction, simple process, short route and 50 percent of total yield
5. The compound shown in the formula 3 is a compound newly developed by the company, and the original research company merck and other companies do not relate to the novel compound.
Drawings
FIG. 1 is an HPLC chart showing the purity of the compound represented by the formula 6 in example 2
FIG. 2 is a hydrogen spectrum of the compound represented by the formula 6 in example 2
FIG. 3 is an HPLC chart showing the purity of the compound represented by the formula 2 in example 2
FIG. 4 is an HPLC chart of chirality of the compound of formula 2 in example 2
FIG. 5 is a hydrogen spectrum of the compound represented by the formula 2 in example 2
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is described in detail below with reference to the drawings and specific examples.
Example 1 preparation of a Compound represented by the formula 3
A20L clean reaction kettle is provided with a hydrochloric acid tail gas absorption device, 6.8kg of methanol and a compound 7 (1.0kg) are added, the temperature is controlled to be 0-15 ℃, 2.58kg of thionyl chloride is dropwise added, the mixture is stirred and reacted at the temperature of 25-30 ℃ overnight, the methanol is distilled under reduced pressure at the temperature of 35-45 ℃ through TLC detection until no fraction is generated basically, 7.1kg of dichloromethane is added, the temperature is controlled to be 0-15 ℃, 2.28kg of triethylamine is dropwise added, the temperature is controlled to be 15-25 ℃, 1.64kg of Boc anhydride and 1.2kg of dichloromethane solution are dropwise added, the mixture is reacted at the temperature of 23-28 ℃ overnight, 1.5kg of water is added through a TLC point plate, the temperature is controlled to be 0-10 ℃, 4.5kg of 3N hydrochloric acid is added, the pH value is adjusted to be about 2.5-3, liquid separation is carried out, an organic phase is reserved. Distilling dichloromethane at 30-40 deg.C under reduced pressure until no fraction is obtained, adding 1.5kg tetrahydrofuran, dissolving, concentrating, adding 9kg tetrahydrofuran, and drying with molecular sieve for next reaction.
In a 20L drying reaction kettle, tail gas equipment is installed, a tetrahydrofuran solution of a compound 9 (about 0.98kg) is added, 0.313kg of sodium borohydride is added, nitrogen protection is carried out, the temperature is reduced to about 15 ℃, 1.5kg of methanol is divided into 8 equal parts, 1/8 methanol is taken and slowly dripped five times, about 37g of methanol is slowly dripped each time, the dripping reaction is carried out for 1 hour, the temperature is controlled to be 15-25 ℃, 2/8 methanol is dripped completely, 1/8 methanol is weighed each time for the rest, the dripping is slowly dripped, the dripping is completed each time, the reaction is carried out at intervals of 1 hour, the temperature is controlled to be 15-25 ℃, the dripping is completed, and a TLC point plate tracks the reaction condition until the. Cooling, dripping 1.3kg of 3N diluted hydrochloric acid for quenching, controlling the temperature to be less than 15 ℃, performing suction filtration, leaching a filter cake by using 1kg of tetrahydrofuran, merging mother liquor, adding 2.7kg of ethyl acetate, stirring, layering, collecting ethyl acetate, and concentrating under reduced pressure until no fraction is obtained.
8.5kg of ethyl acetate was added and the mixture was dried over a molecular sieve for the next reaction.
Adding an ethyl acetate solution of a compound 10 into a 20L drying reaction kettle, adding 1.2kg of triethylamine under the protection of nitrogen, controlling the temperature to be 5-5 ℃ below zero, slowly dropwise adding methylsulfonyl chloride (0.835kg of 7.31mol), after the dropwise adding is finished, tracking by TLC till the reaction is finished, distilling ethyl acetate at 40-45 ℃ under reduced pressure until no fraction is evaporated basically, controlling the temperature to be lower than 10 ℃, dropwise adding 25g of 3N diluted hydrochloric acid, adjusting the pH value to be 3-4, performing suction filtration, pulping a filter cake by using 3.5kg of water, performing suction filtration, and drying by using 60 ℃ air blasting to obtain the compound 11(2.4kg of 90%).
Adding 0.9kg of compound 11, 0.09kg of tetrabutylammonium bisulfate and 4kg of toluene into a dry 20L reaction kettle, stirring, cooling, weighing 0.5kg of sodium hydroxide, dissolving in 1kg of ice water, controlling the temperature to be 5-10 ℃, dropwise adding a sodium hydroxide aqueous solution, controlling the temperature to be 10-15 ℃ for reaction, tracking by HPLC and TLC until the reaction is finished, adding 1kg of water, stirring for layering, collecting a toluene layer, extracting the water layer with 1kg of toluene again, and combining toluene phases. Adding 1kg saturated sodium bicarbonate water solution to wash toluene phase, washing toluene phase with 1kg half saturated sodium chloride water solution, drying organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 50-55 deg.C until there is no fraction to obtain crude compound 12.
Adding 0.65kg of crude compound 12, 0.6kg of DMF and 0.25kg of tetrabutylammonium bromide into a 5L three-necked flask, stirring, cooling in an ice-water bath, adding 0.16kg of lithium chloride in five batches, controlling the temperature below 25 ℃, carrying out reaction at 20-25 ℃ at intervals of 0.5 hour per batch, tracking the reaction of raw materials to be complete by TLC and HPLC, transferring the reaction solution into a 30L reaction kettle, adding 5kg of ice water, stirring, adding 1.5kg of toluene for extraction and layering, collecting a toluene phase, re-extracting the water phase with 1.5kg of toluene, combining the organic phases, adding 0.09kg of tetrabutylammonium hydrogen sulfate, stirring, cooling, preparing 0.5kg of sodium hydroxide dissolved in 1kg of ice water, dropwise adding a sodium hydroxide aqueous solution, controlling the temperature to be lower than 10 ℃, finishing dropwise adding, carrying out reaction at 10-15 ℃, tracking the reaction by TLC until the reaction is finished, adding 1.7kg of water, stirring and layering, collecting the organic phases, extracting the water layer with 0.6kg of toluene again, the organic phases were combined, washed once with 0.6kg of saturated aqueous sodium bicarbonate solution and once with 0.6kg of half-saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and toluene concentrated at 50-55 ℃ under reduced pressure, and used directly in the next reaction to give compound 3(511g, 100% containing partial solvent) with a purity of 99.03%
Example 2 preparation of a Compound represented by formula 2
Adding 1.5kg of dry tetrahydrofuran and 40g of 2-chloropropane into a 5L dry reaction bottle, heating to a microflow (60 ℃), dropwise adding 5ml of isopropyl magnesium chloride for initiation, slowly dropwise adding 350g of the rest 2-chloropropane after the reaction is stable, controlling the temperature to keep micro reflux (68-72 ℃), dropwise adding reflux for 2 hours (till magnesium chips completely react, supplementing 2-chloropropane), cooling to room temperature after the reaction is finished, adding 1.3kg of dry tetrahydrofuran, 1.3kg of dry toluene and 682g of bromobenzene, reducing the protection of reaction liquid nitrogen to-25 ℃, controlling the temperature to be below 20 ℃ below zero, dropwise adding 2kg of isopropyl magnesium chloride, carrying out heat preservation reaction for 1 hour after the dropwise adding is finished, carrying out HPLC monitoring, adding 24g of cuprous chloride, carrying out heat preservation stirring for 30min, dropwise adding 0.5kg of a toluene solution of a compound 3(512g), reacting at-5 deg.C to-2 deg.C for 16 hr, monitoring by HPLC, slowly adding 1kg saturated ammonium chloride aqueous solution (quenching) dropwise at 5 deg.C or below, controlling the temperature below 10 deg.C, adding about 1.5kg 3N hydrochloric acid dropwise, and adjusting pH to about 4. The aqueous phase was extracted once with 0.5L of toluene, the organic phases were combined, washed once with dilute aqueous ammonia (100 g of concentrated aqueous ammonia with 0.5kg of water), then twice with half-saturated brine, the aqueous phases were combined and extracted once with 0.5kg of toluene, the toluene was distilled at 45-55 c under reduced pressure, 2kg of water was added when the reaction mixture became pasty, and concentration was continued until the distilled solvent was water. Adding 1kg of methanol, pulping overnight, filtering, washing a filter cake twice with water, and drying a product by air blast at 65 ℃ to obtain a compound 4(720g) as light yellow powder with the yield of 85%.
A10L reaction flask was charged with 0.66kg of Compound 4, 0.51kg of sodium acetate, 0.13kg of tetrabutylammonium bromide, 1.9kg of DMAC (dimethylacetamide), reacted at 70-75 ℃ and followed by HPLC until the reaction was complete. Cooling the reaction solution to 0-5 ℃, weighing 0.16kg of sodium hydroxide, dissolving the sodium hydroxide in 0.6kg of ice water, controlling the temperature below 5 ℃, dropwise adding a sodium hydroxide aqueous solution, carrying out heat preservation reaction at 5-10 ℃, tracking the HPLC until the reaction is finished, controlling the temperature at 5-10 ℃, dropwise adding 0.15kg of acetic acid, slowly dropping 0.6kg of water into a bottle, stirring for one hour, dropping 0.6kg of water into the bottle, dropping 4kg of water into the bottle, stirring for 5-8 hours, carrying out suction filtration, pulping a filter cake with 2kg of water for half an hour, carrying out suction filtration, and drying the filter cake by air blowing at 70 ℃ to obtain a compound 6(580g) which is light yellow powder, wherein the yield is 93%, the purity is 96%, see the attached figures 1 and
A30L dry reactor was charged with 2.5kg of water, 86g of disodium hydrogenphosphate and 37.5g of sodium dihydrogenphosphate, stirred until the solid was completely dissolved, 1.8L of acetonitrile, 6(350g) of compound, and 12g of TEMPO were added, the temperature was raised to about 38 ℃, an aqueous solution of sodium chlorite (250 g of sodium chlorite and 1kg of water) and an aqueous solution of sodium hypochlorite (20ml) (75ml) were added in portions, and the portions were added in ten portions every 20 min. HPLC tracking till the reaction is complete, controlling the temperature below 10 ℃, dropwise adding saturated sodium sulfite aqueous solution, controlling the external temperature to be 50 ℃ and the internal temperature to be 40-45 ℃, distilling acetonitrile under reduced pressure, cooling the temperature of the reaction solution to be about 15 ℃, adding 350ml of ethyl acetate, 1.3kg of 3N hydrochloric acid to adjust the pH to be 3-4, adding 2.5L of water into the reaction solution, controlling the temperature to be 15-20 ℃, stirring for 30min, filtering, washing a filter cake twice with water, 1.5L each time, and drying the filter cake by air blowing at 65 ℃ to obtain a compound 2 (361g), white powder and yield of 98%, see attached figures 3, 4 and 5
Example 3 preparation of a Compound represented by the formula 3
A30L clean reaction kettle is provided with a hydrochloric acid tail gas absorption device, 13.43kg of methanol and a compound 7 (2.0kg) are added, the temperature is controlled to be 0-15 ℃, 5.15kg of thionyl chloride is dropwise added, the mixture is stirred and reacted at the temperature of 25-30 ℃ overnight, the methanol is distilled under reduced pressure at the temperature of 35-45 ℃ through TLC detection until no fraction is generated basically, 14.22kg (3.6V) of trichloromethane is added, the temperature is controlled to be 0-15 ℃, 4.56kg of triethylamine is dropwise added, the temperature is controlled to be 15-25 ℃ after the dropwise addition is finished, 3.279kg of Boc anhydride and 2.37kg of trichloromethane solution are dropwise added, the mixture is reacted at the temperature of 23-28 ℃ overnight, 2.97kg of water is added through a TLC point plate, the temperature is controlled to be 0-10 ℃, 8.91kg of 3N hydrochloric acid is added, the pH value is adjusted to be about 2.5-3, liquid is separated. Distilling dichloromethane at 30-40 deg.C under reduced pressure until no fraction is obtained, adding 3kg tetrahydrofuran, dissolving, concentrating, adding 17.84kg tetrahydrofuran, and drying with molecular sieve for next reaction.
In a 30L drying reaction kettle, tail gas equipment is installed, a tetrahydrofuran solution of a compound 9(1.96kg) is added, 0.626kg of sodium borohydride is added, nitrogen protection is carried out, the temperature is reduced to about 15 ℃, 3kg of methanol is divided into 8 equal parts, 1/8 methanol is taken and slowly dripped five times, 75g of methanol is slowly dripped every time, the dripping reaction is carried out for 1 hour, the temperature is controlled to be 15-25 ℃, 2/8 methanol is dripped, 1/8 methanol is weighed every time, the dripping is slowly dripped every time, the reaction is carried out for 1 hour at intervals, the temperature is controlled to be 15-25 ℃, the dripping is finished, and a TLC point plate tracks the reaction condition until the reaction is finished. Cooling, dripping 2.6kg of 3N diluted hydrochloric acid for quenching, controlling the temperature to be less than 15 ℃, carrying out suction filtration, leaching a filter cake by using 1.8kg of tetrahydrofuran, merging mother liquor, adding 5.4kg of ethyl acetate, stirring, layering, collecting ethyl acetate, and concentrating under reduced pressure until no fraction is obtained. Adding 16.8kg ethyl acetate, drying with molecular sieve for the next reaction to obtain compound 10
Adding a compound 10 in an ethyl acetate solution into a 30L drying reaction kettle, adding 2.27kg of diethylamine under the protection of nitrogen, controlling the temperature to be 5-5 ℃ below zero, slowly dropwise adding methylsulfonyl chloride (1.67kg of 14.62mol), after the dropwise addition is finished, tracking by TLC till the reaction is finished, distilling the ethyl acetate at 40-45 ℃ under reduced pressure until no fraction is evaporated out basically, controlling the temperature to be below 10 ℃, dropwise adding 50g of 3N diluted hydrochloric acid, adjusting the PH value to be 3-4, performing suction filtration, pulping a filter cake with 6.25kg of water, performing suction filtration, and performing blast drying at 60 ℃ to obtain a compound 11(4.87kg), wherein the yield is 90 percent
Adding 1.8kg of compound 11, 0.17kg of tetrabutylammonium bisulfate and 7.79kg of toluene into a reaction kettle of 30L, stirring, cooling, weighing 0.99kg of sodium hydroxide, dissolving in 2kg of ice water, controlling the temperature to be 5-10 ℃, dropwise adding an aqueous solution of sodium hydroxide, controlling the temperature to be 10-15 ℃ for reaction, tracking by HPLC and TLC until the reaction is finished, adding 1.8kg of water, stirring for layering, collecting a toluene layer, extracting the water layer with 1.6kg of toluene once again, and combining toluene phases. Adding 1.8kg saturated sodium bicarbonate water solution to wash toluene phase, washing toluene phase with 1.8kg half saturated sodium chloride water solution, drying organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 50-55 deg.C until there is no fraction to obtain crude compound 12
Adding crude product 1.32kg of compound 12, 1.25kg of DMAC and 0.48kg of tetrabutylammonium bromide into a 5L three-necked flask, stirring, cooling in an ice-water bath, adding 0.32kg of lithium chloride in five batches, controlling the temperature below 25 ℃, carrying out reaction at 20-25 ℃ at intervals of 0.5 hour in each batch, tracking the reaction through TLC and HPLC until the reaction of the raw materials is complete, transferring the reaction solution into a 30L reaction kettle, adding 10.5kg of ice water, stirring, adding 3.43kg of toluene, extracting and layering, collecting a toluene phase, re-extracting an aqueous phase with 2.4kg of toluene, combining organic phases, adding 0.17kg of tetrabutylammonium hydrogen sulfate, stirring, cooling, preparing 0.99kg of sodium hydroxide to be dissolved in 2.0kg of ice water, dropwise adding an aqueous solution of sodium hydroxide, controlling the temperature to be lower than 10 ℃, finishing the dropwise addition, carrying out reaction at 10-15 ℃, tracking the reaction by TLC until the end, adding 1.32kg of water, stirring and layering, collecting an organic phase, extracting an aqueous layer with 1.14kg of toluene again, the organic phases were combined, washed once with 1.32kg of saturated aqueous sodium bicarbonate solution and once with 1.32kg of half-saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and toluene was concentrated under reduced pressure at 50-55 ℃ and used directly in the next reaction to give compound 3(1.09kg) with 99% purity and 106% yield (containing a portion of solvent)
Example 4 preparation of a Compound represented by the formula 2
Adding 3kg of dried ether and 80g of 2-chloropropane into a 5L dry reaction bottle, heating to micro reflux (60 ℃), adding 10ml of isopropyl magnesium chloride dropwise for initiation, slowly adding 700g of the remaining 2-chloropropane dropwise after the reaction is stable, controlling the temperature to keep micro reflux (68-72 ℃), adding dropwise reflux for 2 hours (until magnesium chips completely react, adding 2-chloropropane), cooling to room temperature after the reaction is finished, adding 2.67kg of dried ether, 2.61kg of dried xylene and 1.327kg of trifluorobromobenzene into a 30L reaction kettle, reducing the protection of reaction liquid nitrogen to-25 ℃, controlling the temperature to be below minus 20 ℃, adding 3.9kg of isopropyl magnesium chloride dropwise, keeping the temperature for 1 hour after the reaction is finished, monitoring by HPLC, adding 47.7g of cuprous chloride, keeping the temperature and stirring for 30min, adding 1kg of xylene solution of compound 3(1023g), reacting at-5 deg.C to-2 deg.C for 16 hr, monitoring by HPLC, slowly adding 2kg saturated ammonium chloride aqueous solution (quenching) dropwise at 5 deg.C or below, controlling the temperature below 10 deg.C, adding about 2.8kg 3N hydrochloric acid dropwise, and adjusting pH to about 4. The aqueous phase was extracted once with 1L of toluene, the organic phases were combined, washed once with dilute aqueous ammonia (200 g of concentrated aqueous ammonia with 1kg of water), then twice with 1kg of half-saturated brine, the aqueous phases were combined and extracted once with 1kg of toluene, the toluene was distilled at 45-55 ℃ under reduced pressure, 4kg of water was added when the reaction mixture became pasty, and concentration was continued until the distilled solvent was water. Adding methanol 2kg, pulping overnight, filtering, washing the filter cake twice with water, and air drying at 65 deg.C to obtain compound 4(1278g) as light yellow powder with purity of 96% and yield of 87%
A10L reaction flask was charged with 1.315kg of Compound 4, 1.01kg of sodium acetate, 0.25kg of tetrabutylammonium bromide, and 3.73kg of DMAC, reacted at 70-75 ℃ and followed by HPLC until the reaction was complete. Cooling the reaction liquid to 0-5 ℃, weighing 0.31kg of sodium hydroxide, dissolving the sodium hydroxide in 1.31kg of ice water, controlling the temperature below 5 ℃, dropwise adding a sodium hydroxide aqueous solution, carrying out heat preservation reaction at 5-10 ℃, tracking the HPLC until the reaction is finished, controlling the temperature at 5-10 ℃, dropwise adding 0.26kg of acetic acid, slowly dropping 1.31kg of water into a bottle, stirring for one hour, dropping 1.31kg of water into the bottle, dropping 7.89kg of water into the bottle, stirring for 5-8 hours, carrying out suction filtration, pulping a filter cake with 3.94kg of water, carrying out suction filtration, carrying out forced air drying on the filter cake at 70 ℃ to obtain a compound 6(1070g), pale yellow powder, wherein the yield is 86%
A30L dry reactor was charged with 4.9kg of water, 172.2g of disodium hydrogenphosphate and 74.8g of sodium dihydrogenphosphate, stirred until the solid was completely dissolved, 3.5L of methyl t-butyl ether, compound 6(700g), TEMPO (24g), warmed to about 38 ℃ and added with an aqueous solution of sodium chlorite (495 g of sodium chlorite, 2kg of water) and an aqueous solution of sodium hypochlorite (40ml) (150ml) in portions, ten times, and added at intervals of 20 min. HPLC (high performance liquid chromatography) is carried out until the reaction is complete, the temperature is controlled to be below 10 ℃, a saturated sodium sulfite aqueous solution is dropwise added, the external temperature is 50 ℃, the internal temperature is 40-45 ℃, methyl tert-butyl ether is distilled under reduced pressure, the temperature of a reaction solution is reduced to about 15 ℃, 700ml of ethyl acetate is added, 2.5kg of 3N hydrochloric acid is added to adjust the pH to 3-4, 5L of water is added into the reaction solution, the temperature is controlled to be 15-20 ℃, stirring is carried out for 30min, filtering is carried out, a filter cake is washed twice by 3L of water each time, and the filter cake is dried by air blowing at 65 ℃ to obtain a.
Claims (10)
1. A preparation method of a compound shown as a formula 2 comprises the following steps:
(1) ring opening reaction: at the temperature of-20 ℃ to-50 ℃, cuprous chloride is used as a catalyst, 2,4, 5-trifluorobromobenzene and a Grignard reagent RMgX are subjected to a Grignard reaction by taking cuprous chloride as a catalyst, wherein R is isopropyl and X is halogen, and the generated compound is subjected to a ring-opening reaction with a compound shown as a formula 3 to obtain a compound shown as a formula 4;
(2) substitution-hydrolysis reaction: reacting the compound shown in the formula 4, sodium acetate and tetrabutylammonium bromide at the temperature of 70-80 ℃ to obtain a compound shown in a formula 6;
(3) and (3) oxidation reaction: the compound shown in the formula 6 is subjected to oxidation reaction with 2,2,6, 6-tetramethylpiperidine oxide, sodium hypochlorite, sodium chlorite and a buffering agent to obtain the compound shown in the formula 2, wherein the buffering agent is disodium hydrogen phosphate or sodium dihydrogen phosphate.
2. The method of claim 1, wherein: in the step (1), a Grignard reagent RMgX is isopropyl magnesium chloride or isopropyl magnesium bromide, and in the step (1), one of tetrahydrofuran and toluene, tetrahydrofuran and methyl tert-butyl ether, tetrahydrofuran and xylene, diethyl ether and toluene, diethyl ether and xylene, diethyl ether and methyl tert-butyl ether, 2-methyl tetrahydrofuran and toluene, 2-methyl tetrahydrofuran and xylene, and 2-methyl tetrahydrofuran and methyl tert-butyl ether is used as a medium; 2,4, 5-trifluorobromobenzene: isopropyl magnesium chloride: the molar ratio of the compound represented by formula 3 is 1: 1.5-2.5: 0.6-1.
3. The method of claim 1, wherein: and (2) adopting one of DMF, DMAC, EA, DCM, THF and dioxane as a medium.
4. The method of claim 1, wherein: the medium in the step (3) is one of acetonitrile, tetrahydrofuran, methyl tert-butyl ether, C1-C6 monohalogen or polyhalogen alkane.
5. The method of claim 1, wherein: the preparation method of the compound shown as the formula 3 comprises the following steps
(a) Esterification reaction: adding thionyl chloride into a compound shown as a formula 7 in methanol as a medium at the temperature of 0-15 ℃, and reacting at the room temperature of 25 ℃ to obtain a compound shown as a formula 8;
(b) acylation reaction: in the compound shown as the formula 8, triethylamine is added into one of dichloromethane, chloroform and toluene as media at the temperature of 0-15 ℃, dichloromethane solution of a compound containing a protective group PG is added at the temperature of 15-25 ℃, and the compound shown as the formula 9 is obtained by reaction at the room temperature of 20-25 ℃;
(c) reduction reaction: adding a reducing agent into the compound shown as the formula 9, controlling the temperature at 15 ℃, and reacting with methanol to obtain a compound shown as a formula 10;
(d) and (3) substitution reaction: adding MsCl into triethylamine serving as a medium to react to obtain a compound shown as a formula 10, and obtaining a compound shown as a formula 11;
(e) ring closing reaction: adding a cyclization reagent into the compound shown as the formula 11 to react to obtain a compound shown as a formula 12;
(f) and (3) substitution reaction: adding lithium chloride into a solvent DMF of the compound shown as the formula 12 for reaction to obtain the compound shown as the formula 3.
6. The method of claim 5, wherein: the molar ratio of the compound 7 to the thionyl chloride in the step (a) is 1.0: 2-3.
7. The method of claim 5, wherein: the compound containing the protecting group PG is Boc anhydride, and the compound 8 in the step (b): triethylamine: the mole ratio of Boc anhydride was 1.0:2-4: 1-1.5.
8. The method of claim 5, wherein: the reducing agent in the step (c) is sodium borohydride, and the compound of formula 9: the molar ratio of the sodium borohydride is 1.0: 2.2-2.5.
9. The method of claim 5, wherein: the compound of step (d) 10: mole ratio of methanesulfonyl chloride 1.0: 2.2-2.5.
10. The method of claim 5, wherein: compound 12 in step (f): the molar ratio of lithium chloride was 1.0: 1.2-1.5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102485718A (en) * | 2010-12-03 | 2012-06-06 | 浙江海翔药业股份有限公司 | Sitagliptin intermediate and its preparation method |
| CN105017081A (en) * | 2015-07-08 | 2015-11-04 | 和鼎（南京）医药技术有限公司 | Preparation method for sitagliptin intermediate |
| CN105061434A (en) * | 2015-07-30 | 2015-11-18 | 新发药业有限公司 | Low-cost preparation method of sitagliptin phosphate |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102485718A (en) * | 2010-12-03 | 2012-06-06 | 浙江海翔药业股份有限公司 | Sitagliptin intermediate and its preparation method |
| CN105017081A (en) * | 2015-07-08 | 2015-11-04 | 和鼎（南京）医药技术有限公司 | Preparation method for sitagliptin intermediate |
| CN105061434A (en) * | 2015-07-30 | 2015-11-18 | 新发药业有限公司 | Low-cost preparation method of sitagliptin phosphate |
Non-Patent Citations (3)
| Title |
|---|
| "Efficient Synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric Acid";Pan Xianhua等;《Synthetic Communications》;20150415;第45卷(第12期);第1-6页 * |
| "Efficient synthesis of sitagliptin phosphate, a novel DPP-IV inhibitor, via a chiral aziridine intermediate";Pan Xianhua等;《Tetrahedron Letters》;20131003;第54卷;第6807-6809页 * |
| "Enantiospecific Synthesis of ( R )-3-Amino-4-(2,4,5-trifluorophenyl)butanoic Acid Using (S )-Serine as a Chiral Pool";Aytekin K.等;《Helvetica Chimica Acta》;20150210;第98卷;第260-266页 * |
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