CN106279194A - A kind of method utilizing microreactor to prepare sodium-glucose co-transport enzyme inhibitor intermediate - Google Patents
A kind of method utilizing microreactor to prepare sodium-glucose co-transport enzyme inhibitor intermediate Download PDFInfo
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- CN106279194A CN106279194A CN201510261753.2A CN201510261753A CN106279194A CN 106279194 A CN106279194 A CN 106279194A CN 201510261753 A CN201510261753 A CN 201510261753A CN 106279194 A CN106279194 A CN 106279194A
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Abstract
The invention discloses a kind of method utilizing microreactor to prepare sodium-glucose co-transport enzyme inhibitor intermediate, the solution formed with organic solvent by compound III and organometallic reagent are mixed in microreactor unit (L) by material pipe respectively, and flow to microreactor unit (H) through (L)；The solution that compound II is formed with organic solvent is mixed with above-mentioned mixed liquor by material channel in microreactor unit (H) that preset temperature is (T2), and by this microreactor unit (H), flow out from outlet after question response, this outflow reactant liquor is carried out post processing, i.e. obtains target product sodium-glucose co-transport enzyme inhibitor intermediate compound I.The present invention utilizes microreactor to prepare intermediate compound I, can effectively solve the heat release problem of this type of reaction, not only increase the safety of reaction, also improve reaction yield, the most also shorten the response time, improve reaction efficiency.Microreactor there's almost no enlarge-effect, and therefore the method is suitable for industrialized production relative to traditional batch process.
Description
Technical field
The present invention relates to one utilizes microreactor to prepare novel sodium-glucose co-transport enzyme 2(SGLT2) method of inhibitor intermediate, it is specifically related to a kind of method that microreactor utilizing as shown in Figure 1 prepares the intermediate compound I of antidiabetic medicine Sotagliflozin.
Background technology
Sodium glucose co-transporter 2 is the treating diabetes novel targets found recently in vain.The Regulation of blood glucose using beneficially diabetes mellitus type of SGLT2 inhibitor, and provide a kind of new mechanism being improved diabetes and complication thereof by excretion excessive glucose.At present, the many pharmaceuticals in the whole world and research and development institution are continuing to increase input, and active development SGLT2 inhibitor is as the novel drugs for the treatment of diabetes, and the most existing multiple launch, such as canagliflozin, Da Gelie is clean and Yi Palie is clean.Lexicon drugmaker of the U.S. (Lexicon Pharmaceuticals, Inc) Sotagliflozin developed is unlike the SGLT2 inhibitor listed, this product is not only effective to type 2 diabetes mellitus, it may also be used for type 1 diabetes, therefore the more preferable market prospect of this product.
The synthetic route of this medicine experiences following intermediate compound I mostly:
This intermediate compound I is met and is often carried out what additive reaction was prepared from by the D-Glucose lactone of hydroxyl protection in the presence of lithium reagent or Grignard reagent with halogenated aryl hydrocarbon.But this type of exothermic heat of reaction is violent, and operation is difficult to control, industry amplification process cryogenic equipment requires harshness.Owing to being affected by local heating, often industry is amplified and cannot be obtained the productivity identical with lab scale and product quality;
The United States Patent (USP) US2009/30198 reported first synthetic method of intermediate compound I, reaction equation is as follows:
This reaction uses isopropylmagnesium chloride as organometallic reagent, and reaction temperature is 0～5 DEG C, and reaction yield is 76%.Owing to exothermic heat of reaction is relatively more violent, organomagnesium reagent is not the most the most stable, and therefore this reaction yield is the highest, and is difficult to amplify.This reaction is improved by United States Patent (USP) US2012/172320 for the problems referred to above, use isopropylmagnesium chloride lithium chloride complex as organometallic reagent, reaction temperature is reduced to subzero 20～subzero 25 DEG C, and yield can bring up to 81%, and reaction also can be amplified to the scale of 50 liters smoothly.But this technique also could not efficient solution be determined the problem of exothermic heat of reaction, therefore yield increase rate little.If effectively solving the heat release problem of this reaction, the space that reaction yield is also improved.
Microreactor (Micro-reactor) is also referred to as micro passage reaction (Micro-channel Reactor), is the common name of the microchannel chemical industry equipments such as microreactor, micro-mixer, micro-heat exchanger, microcontroller.Relative to traditional intermittent reaction technique, microreactor has mixed at high speed, efficient heat transfer, narrow residence time destribution, reproducible, system response is rapid, is easy to Automated condtrol, almost without advantages such as enlarge-effect and high security performances.Micro-reacting tcchnology is used for above-mentioned reaction, sees the problem that can effectively solve exothermic heat of reaction, be expected to improve further reaction yield.
Summary of the invention
Description
The technical problem to be solved is to provide a kind of method utilizing microreactor to prepare sodium-glucose co-transport enzyme inhibitor intermediate compound I, to overcome various defects present in existing preparation method.
Microreactor of the present invention, its structure is as it is shown in figure 1, include at least 3 material temperature road A, B, C and 2 micro-reaction member L, H, and an outlet D.Wherein, together with micro-reaction member L and H mounted on top, micro-reaction member L is positioned at the surface of H；Material channel A, B are respectively arranged on the same side of micro-reaction member L, and material channel C is located at the side of micro-reaction member H, and is relative position with material channel A, B；Outlet D is located at the opposite side of micro-reaction member H.
Further respectively having material channel (this material channel can be zigzag, linear type, helical form, or bending etc. all can) in described micro-reaction member L and H, the two is connected by a vertical material.Wherein, the material channel one end in described micro-reaction member L is connected with material channel A, B, and the other end is connected with towards the vertical material passage in micro-reaction member H；Material channel one end in described micro-reaction member H is connected with vertical material passage and the material channel C from micro-reaction member L, and the other end is connected with outlet D, so that whole microreactor forms path.
The method utilizing microreactor to prepare sodium-glucose co-transport enzyme inhibitor intermediate compound I of the present invention, comprises the following steps:
(1) mix in the compound III being dissolved in organic solvent being flowed into, by material channel (A) and material channel (B), the microreactor unit (L) that preset temperature is (T1) respectively with organometallic reagent, and flow to microreactor unit (H) through (L)；
(2) the compound II being dissolved in organic solvent is mixed with the mixed liquor in step (1) by material channel (C) in microreactor unit (H) that preset temperature is (T2), and by this microreactor unit (H), flow out from outlet after question response, this outflow reactant liquor is carried out post processing, i.e. obtains target product sodium-glucose co-transport enzyme inhibitor intermediate compound I.
The reaction equation of the present invention is as follows:
Wherein: Z is leaving group, including halogen, alkoxyl, alkoxy carbonyl group and secondary amine；
Ar is aryl or substituted aryl；
X is bromine or iodine；
Y is hydrogen, the alkyl of C1-C8 and halogen；
P1, P2, P3 are hydroxy-protective group or M, and hydroxyl protecting group includes the alkyl of C1-C8, the acyl group of C1-C8, benzyl, substituted benzyl and trialkyl silyl, and M represents lithium, magnesium and zinc.P1, P2, P3 can be identical, it is also possible to different.
In said method, the compound III described in step (1) is 0.01 grams per milliliter ~ 2 grams per milliliter with the concentration of the solution that organic solvent is formed, and compound III is respectively 0.1 ml/min ~ 5.0 ml/min with the flow velocity of organometallic reagent.
Further, organometallic reagent described in step (1) is selected from: the alkyl lithium reagents of C1-C8 and the alkyl magnesium reagent of C1-C8, alkyl lithium reagents is preferably n-BuLi, s-butyl lithium, tert-butyl lithium, alkyl magnesium reagent is preferably isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, sec-butyl magnesium chloride and sec-butyl magnesium chloride lithium chloride complex, compound III is 1:0.9～1:1.2 with the mol ratio of organometallic reagent.
Also, the compound II solution concentration described in step (2) is 0.01 grams per milliliter ~ 2g grams per milliliter, the flow velocity of compound II is 0.1 ml/min～5.0 ml/min.
In said method, the preset temperature (T1) of described micro-reaction member (L) is subzero 90～20 DEG C, and the preset temperature (T2) of described micro-reaction member (H) is subzero 90～20 DEG C.
Further, described organic solvent is selected from: ether, methyl phenyl ethers anisole, oxolane, 2-methyltetrahydrofuran, benzene,toluene,xylene or a trimethylbenzene.
Further, will be collected in acidic aqueous solution from outlet (D) reactant liquor that flows out, or be collected in the methanol solution containing methanesulfonic acid, agitated, extract, wash, brine wash, be dried, concentrate, obtain target compound intermediate compound I.
The present invention utilizes microreactor success Fast back-projection algorithm to go out target compound one sodium-glucose co-transport enzyme inhibitor intermediate compound I, can effectively solve the heat transfer problem of this type of reaction, decrease the loss brought because reactive intermediate heat stability is the best, it is effectively increased reaction yield, no matter use aryl iodide or aromatic bromide, all reaction yield can be brought up to about 90% from the 80% of traditional handicraft.Compared with traditional intermittent reaction, owing in microreactor, the mixing of reactant is extremely abundant, thus shorten the response time, and the time that equipment cleans and prepares can be eliminated with continuous feed discharging, shorten the production time, improve reaction efficiency.Meanwhile, microreactor, almost without enlarge-effect, has higher security performance simultaneously, is more suitable for industrialized production.
Accompanying drawing explanation
Fig. 1 is the structural representation of the microreactor of the present invention, and wherein A, B, C are respectively material channel, and L, H are respectively microreactor unit, and D is outlet, and Tl, T2 are respectively the preset temperature of microreactor unit L, H.
Detailed description of the invention
Below in conjunction with specific embodiment, technical scheme is described in further detail, but described embodiment is not intended to protection scope of the present invention.Should be noted that, following example are only in order to illustrate technical scheme and unrestricted, although the present invention being described in detail with reference to preferred embodiment, it will be understood by those within the art that, the technical scheme of invention can be modified or equivalent, without deviating from the spirit and scope of technical solution of the present invention, it all should be contained in scope of the presently claimed invention.
Embodiment 1:
Compound IV (150.3 grams, 0.55 mole) is dissolved in oxolane (150 milliliters), at room temperature drips the tert-butyl group magnesium chloride solution (44.6 milliliters) of 1.3 mol/L, stir 30 minutes, form the tetrahydrofuran solution of compound IIa.
Preparing the tetrahydrofuran solution 163 milliliters (162.8 grams, 0.5 mole) of the compound IIIa of l gram/mL, be passed through above tetrahydrofuran solution in material channel A, coutroi velocity is 0.1 ml/min.Being passed through the n-butyllithium solution totally 200 milliliters of 2. 5 mol/L in material channel B, coutroi velocity is 0.12 ml/min, and the preset temperature Tl of the most micro-reaction member L is subzero 80 ~ subzero 75 ° of C simultaneously.With being passed through the tetrahydrofuran solution of above-claimed cpd IIa in backward material channel C, coutroi velocity is 0.3 ml/min, and the preset temperature T2 of the most micro-reaction member H is subzero 80 ~ subzero 70 ° of C.After question response, the reactant liquor that outlet D flows out is passed through in saturated ammonium chloride solution (l liter), controls temperature 15～25 ° of C, after system is all passed through, stirring 1 hour, ethyl acetate extracts, and saturated aqueous common salt washs, anhydrous sodium sulfate is dried, it is concentrated to give the crude product of target product, through ethyl acetate normal heptane recrystallization, obtains solid 192.6 grams, obtain compound Ia, productivity 89 %.ESI/MS m/ z: 454 (M+Na+-1)
Embodiment 2:
The tetrahydrofuran solution 932 milliliters (186.3 grams, 0.5 mole) of the compound IIIb of 0.2 gram/mL of preparation, is passed through above tetrahydrofuran solution in material channel A, and coutroi velocity is 1 ml/min.Being passed through the isopropyl lithium chloride magnesium chloride solution totally 250 milliliters of 2 mol/L in material channel B, coutroi velocity is 0.25 ml/min, and the preset temperature Tl of the most micro-reaction member L is 0 ~ subzero 5 ° of C simultaneously.With the toluene solution 693 milliliters (277 grams, 0.55 mole) of 0.4 grams per milliliter being passed through above-claimed cpd IIb in backward material channel C, coutroi velocity is 0.4 ml/min, and the preset temperature T2 of the most micro-reaction member H is 0 ~ 5 ° of C.After question response, the reactant liquor that outlet D flows out is passed through in saturated ammonium chloride solution (l liter), controls temperature 15～25 ° of C, after system is all passed through, stir 1 hour, toluene extracts, and saturated aqueous common salt washs, and is concentrated to give the crude product of target product, through toluene normal heptane recrystallization, obtain solid 301.8 grams, obtain compound Ib, productivity 91 %.ESI/MS m/ z: 684 (M+Na+-1)
Embodiment 3:
Compound V (239.0 grams, 0.55 mole) is dissolved in toluene (1500 milliliters), at room temperature drips thionyl chloride (77.3 grams, 0.65 mole), stirring 2 hours under 60 ~ 65 ° of C, being evaporated to cumulative volume is 650 milliliters, forms the toluene solution of compound IIc.
0.2 gram/mL of preparation
The tetrahydrofuran solution 932 milliliters (186.3 grams, 0.5 mole) of compound IIIc, in material channel A, be passed through above tetrahydrofuran solution, coutroi velocity is 1 ml/min.Being passed through the isopropyl lithium chloride magnesium chloride solution totally 250 milliliters of 2 mol/L in material channel B, coutroi velocity is 0.25 ml/min, and the preset temperature Tl of the most micro-reaction member L is 0 ~ subzero 5 ° of C simultaneously.With the toluene solution 693 milliliters (277 grams, 0.55 mole) of 0.4 grams per milliliter being passed through above-claimed cpd IIb in backward material channel C, coutroi velocity is 0.4 ml/min, and the preset temperature T2 of the most micro-reaction member H is 0 ~ 5 ° of C.After question response, the reactant liquor that outlet D flows out is passed through in saturated ammonium chloride solution (l liter), controls temperature 15～25 ° of C, after system is all passed through, stir 1 hour, toluene extracts, and saturated aqueous common salt washs, and is concentrated to give the crude product of target product, through toluene normal heptane recrystallization, obtain solid 398.4 grams, obtain compound Ic, productivity 90 %.ESI/MS m/ z: 684 (M+Na+-1)。
Claims (7)
1. one kind utilizes the method that microreactor prepares sodium-glucose co-transport enzyme inhibitor intermediate, it is characterised in that comprise the following steps:
(1) mix in the compound III being dissolved in organic solvent being flowed into, by material channel (A) and material channel (B), the microreactor unit (L) that preset temperature is (T1) respectively with organometallic reagent, and flow to microreactor unit (H) through (L)；
(2) the compound II being dissolved in organic solvent is mixed with the mixed liquor in step (1) by material channel (C) in microreactor unit (H) that preset temperature is (T2), and by this microreactor unit (H), flow out from outlet after question response, this outflow reactant liquor is carried out post processing, i.e. obtains target product sodium-glucose co-transport enzyme inhibitor intermediate compound I；
Reaction equation is as follows:
Wherein: Z is leaving group, including halogen, alkoxyl, alkoxy carbonyl group and secondary amine；
Ar is aryl or substituted aryl；
X is bromine or iodine；
Y is hydrogen, the alkyl of C1-C8 and halogen；
P1, P2, P3 are hydroxy-protective group or M, and hydroxyl protecting group includes the alkyl of C1-C8, the acyl group of C1-C8, benzyl, substituted benzyl and trialkyl silyl, and M represents lithium, magnesium and zinc；P1, P2, P3 can be identical, it is also possible to different.
Method the most according to claim 1, it is characterized in that, compound III described in step (1) is 0.01 grams per milliliter ~ 2 grams per milliliter with the concentration of the solution that organic solvent is formed, and compound III is respectively 0.1 ml/min ~ 5.0 ml/min with the flow velocity of organometallic reagent.
Method the most according to claim 1, it is characterized in that, organometallic reagent described in step (1) is selected from: the alkyl lithium reagents of C1-C8 and the alkyl magnesium reagent of C1-C8, alkyl lithium reagents is preferably n-BuLi, s-butyl lithium, tert-butyl lithium, alkyl magnesium reagent is preferably isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, sec-butyl magnesium chloride and sec-butyl magnesium chloride lithium chloride complex, compound III is 1:0.9～1:1.2 with the mol ratio of organometallic reagent.
Method the most according to claim 1, it is characterised in that the compound II solution concentration described in step (2) is 0.01 grams per milliliter ~ 2g grams per milliliter, the flow velocity of compound II is 0.1 ml/min～5.0 ml/min.
Method the most according to claim 1, it is characterised in that the preset temperature (T1) of described micro-reaction member (L)
For subzero 90～20 DEG C, the preset temperature (T2) of described micro-reaction member (H) is subzero 90～20 DEG C.
6. according to the method described in claim 1, it is characterised in that described organic solvent is selected from: ether, methyl phenyl ethers anisole, oxolane, 2-methyltetrahydrofuran, benzene,toluene,xylene or a trimethylbenzene.
Method the most according to claim 1, it is characterized in that, the reactant liquor flowed out from outlet (D) is collected in acidic aqueous solution, or is collected in the methanol solution containing methanesulfonic acid, agitated, extract, wash, brine wash, be dried, concentrate, obtain target compound intermediate compound I.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540685A (en) * | 2017-09-04 | 2018-01-05 | 杭州科巢生物科技有限公司 | A kind of Sotagliflozin Preparation Method And Their Intermediate |
| CN109400561A (en) * | 2018-12-21 | 2019-03-01 | 山东豪迈化工技术有限公司 | The synthetic method of Dapagliflozin |
| CN114570303A (en) * | 2022-03-02 | 2022-06-03 | 南京市计量监督检测院 | Microchannel reactor and method for preparing dapagliflozin intermediate based on reactor |
-
2015
- 2015-05-21 CN CN201510261753.2A patent/CN106279194A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107540685A (en) * | 2017-09-04 | 2018-01-05 | 杭州科巢生物科技有限公司 | A kind of Sotagliflozin Preparation Method And Their Intermediate |
| CN109400561A (en) * | 2018-12-21 | 2019-03-01 | 山东豪迈化工技术有限公司 | The synthetic method of Dapagliflozin |
| CN114570303A (en) * | 2022-03-02 | 2022-06-03 | 南京市计量监督检测院 | Microchannel reactor and method for preparing dapagliflozin intermediate based on reactor |
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