CN104250272A - Method for preparing Invokana medicine intermediate by using micro-reactor - Google Patents
Method for preparing Invokana medicine intermediate by using micro-reactor Download PDFInfo
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- CN104250272A CN104250272A CN201310264507.3A CN201310264507A CN104250272A CN 104250272 A CN104250272 A CN 104250272A CN 201310264507 A CN201310264507 A CN 201310264507A CN 104250272 A CN104250272 A CN 104250272A
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- 0 *Cc1cc([C@@](*)([C@]([C@]2O)O)O[C@](CO)[C@]2O)ccc1* Chemical compound *Cc1cc([C@@](*)([C@]([C@]2O)O)O[C@](CO)[C@]2O)ccc1* 0.000 description 2
- BWFISYIJSZXAOV-FVCCEPFGSA-N CC(OC[C@H]([C@H]([C@@H]([C@H]1OC(C)=O)OC(C)=O)OC(C)=O)OC1=O)=O Chemical compound CC(OC[C@H]([C@H]([C@@H]([C@H]1OC(C)=O)OC(C)=O)OC(C)=O)OC1=O)=O BWFISYIJSZXAOV-FVCCEPFGSA-N 0.000 description 1
- MGXZKAYHSITHMW-UHFFFAOYSA-N Cc(c(Cc1ccc(-c(cc2)ccc2F)[s]1)c1)ccc1I Chemical compound Cc(c(Cc1ccc(-c(cc2)ccc2F)[s]1)c1)ccc1I MGXZKAYHSITHMW-UHFFFAOYSA-N 0.000 description 1
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
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- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/04—Carbocyclic radicals
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00788—Three-dimensional assemblies, i.e. the reactor comprising a form other than a stack of plates
- B01J2219/00792—One or more tube-shaped elements
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00851—Additional features
- B01J2219/00867—Microreactors placed in series, on the same or on different supports
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- B01J2219/00873—Heat exchange
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00889—Mixing
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00891—Feeding or evacuation
- B01J2219/00894—More than two inlets
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/0095—Control aspects
- B01J2219/00952—Sensing operations
- B01J2219/00954—Measured properties
- B01J2219/00961—Temperature
Abstract
The invention discloses a method for preparing an Invokana medicine intermediate by using a micro-reactor, which is characterized in that a compound III dissolved in an organic solvent and an organometallic reagent respectively passes through a material channel and are mixed in a micro-reactor unit (L), and passes through (L) and flow to the micro-reactor unit (H); a compound II dissolved in the organic solvent passes through the material channel and then is mixed with the above mixed liquor in the micro-reactor unit (H) at preset temperature, then a mixture passes through the micro-reactor unit (H), flow out from an outlet after a reaction is completed, a reaction solution is subjected to post treatment to obtain the target compound-Invokana medicine intermediate I. According to the invention, the Invokana medicine intermediate (I) is synthesized by the micro-reactor, so that heat transfer problem of the reactions can be effectively solved, the reaction objects in the micro-reactor can be fully mixed, reaction time is shortened, reaction efficiency is increased, almost no amplification effect is generated on the micro-reactor, the method has high safety performance, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of microreactor that utilizes and prepare the method arranging clean class pharmaceutical intermediate, be specifically related to a kind of microreactor as shown in Figure 1 that utilizes and prepare anti-type ii diabetes new drug--the method for the clean class pharmaceutical intermediate I of row such as Da Gelie clean (Dapagliflozin), Kan Gelie clean (Canagliflozin) and (1S)-1,5-dehydration-1-C-[the chloro-3-of 4-[[4-[[(3S)-tetrahydrochysene-3-furyl] oxygen base] phenyl] methyl] phenyl]-D-Glucose alcohol (Empagliflozin).
Background technology
White 2 (SGLT2) of sodium glucose co-transporter 2 are the treating diabetes novel targets found recently.The utilization of SGLT2 inhibitor is conducive to the Regulation of blood glucose of 2-diabetes mellitus type, and provides a kind of new mechanism being improved diabetes and complication thereof by excretion excessive glucose.At present, global many pharmaceuticals and research and development institution continue to increase input, and active development SGLT2 inhibitor is as the novel drugs for the treatment of 2-patients with type Ⅰ DM.The Da Gelie clean (Dapagliflozin) that Bristol Myers Squibb and A Zilikang develop jointly, the Kan Gelie clean (Canagliflozin) of Johson & Johnson's exploitation and the Empagliflozin of Bo Lingeyinggehan company exploitation, the new drug of these treatment type ii diabetes all extensively had an optimistic view of by market.Their structural formula is as follows respectively:
Following intermediate compound I is experienced in the synthesis of this type of medicine mostly:
This intermediate compound I is carried out that addition reaction is prepared from usually under the existence of lithium reagent or grignard reagent by the D-Glucose lactone of hydroxyl protection and halogenated aryl hydrocarbon.But this type of exothermic heat of reaction is violent, and operation is restive, industrial amplification process cyrogenic equipment requires harsh.Owing to being subject to the impact of local heating, often industry amplification cannot obtain the productive rate identical with lab scale and quality product.
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-interchanger, microcontroller.Relative to traditional batch reaction process, microreactor has high-speed mixing, efficient heat transfer, narrow residence time destribution, reproducible, system response rapid, be convenient to Automated condtrol, almost without advantages such as scale effect and high safety performances.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of microreactor that utilizes to prepare the method arranging clean class pharmaceutical intermediate I, to overcome in existing preparation method the various defects existed.
Reaction formula of the present invention is as follows:
Wherein G is for protecting protecting group ethanoyl, or the silicon-based protecting group of C3-C9, as trimethyl silicon based, and benzyl etc.G ' is hydrogen, ethanoyl, benzyl etc., in same compound.X is halogen, and representative example is as bromine or iodine.Ar is aryl or the substituted aryl of C6-C15, as phenyl, to ethoxyl phenenyl, 5-to fluorophenyl-2-thienyl, 4-((S)-tetrahydrofuran (THF)-3-oxygen base) phenyl etc.R is substituting group, as chlorine, methyl or hydrogen.M is methyl or hydrogen.
Microreactor of the present invention, its structure as shown in Figure 1, comprises at least 3 material channels A, B, C and 2 micro-reaction member L, H, and an outlet D.Wherein, micro-reaction member L is together with H mounted on top, and micro-reaction member L is positioned at directly over H; Material channel A, B are located at the same side of micro-reaction member L respectively, and material channel C is located at the side of micro-reaction member H, and are relative position with material channel A, B; Outlet D is located at the opposite side of micro-reaction member H.
Also be respectively equipped with in described micro-reaction member L and H material channel (this material channel can be spination, linear pattern, spirrillum, or bending etc. all can), 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 the vertical material passage led in micro-reaction member H; Material channel one end in described micro-reaction member H is connected with from the vertical material passage of micro-reaction member L and material channel C, and the other end is connected with outlet D, thus makes whole microreactor form path.
The microreactor that utilizes of the present invention prepares the method arranging clean class pharmaceutical intermediate I, comprises the following steps:
(1) compound III being dissolved in organic solvent and organometallic reagent are flowed in microreactor unit L that preset temp is T1 respectively by material channel A, B mix, and flow to microreactor unit H through L;
(2) Compound II per being dissolved in organic solvent is mixed with above-mentioned mixed solution by material channel C in micro-reaction member H, and be micro-reaction member H of T2 by preset temp, flow out from outlet D after question response, aftertreatment is carried out to the reaction solution of this outflow, obtains target compound--arrange clean class pharmaceutical intermediate I.
In aforesaid method, the compound III strength of solution described in step (1) is 0.01g/mL ~ 2g/mL, and the flow velocity of compound III and organometallic reagent is respectively 0.1mL/min ~ 5.0mL/min.
Described organometallic reagent is selected from: the organolithium reagent of more than C4, as n-Butyl Lithium, s-butyl lithium or t-butyl lithium reagent; Or the chain alkane grignard reagent of C1-C4 and the mixing solutions of lithium chloride, as the mixing solutions of ethyl grignard reagent or sec.-propyl grignard reagent and lithium chloride, the mol ratio of the two is 1: 0.9 ~ 1: 1.2.
The preset temp T1 of micro-reaction member L is-90 ~ 20 DEG C, preferably-80 ~-5 DEG C.
In aforesaid method, the Compound II per strength of solution described in step (2) is 0.01g/mL ~ 2g/mL, and the flow velocity of Compound II per is 0.1mL/min ~ 5.0mL/min.
The preset temp T2 of micro-reaction member H is-90 ~ 20 DEG C, preferably-80 ~-15 DEG C.
In aforesaid method, described organic solvent is selected from: the ethers organic solution of C2-C7, as ether, methyl-phenoxide etc.; Or tetrahydrofuran (THF), 2-methyltetrahydrofuran; Or the arene solution of C6-C9, as benzene,toluene,xylene, a trimethylbenzene etc.
After completion of the reaction, the reaction solution flowed out from outlet D is collected in acidic aqueous solution (as formic acid, acetic acid, propionic acid etc.), or in the methanol solution being collected in containing methylsulfonic acid, through aftertreatments such as stirring, extract, wash, salt is washed, drying concentrates, obtain target compound--arrange clean class pharmaceutical intermediate I.
The present invention utilizes microreactor success Fast back-projection algorithm to go out target compound--arrange clean class pharmaceutical intermediate I, effectively can solve the heat transfer problem of this type of reaction, and due to the mixing of reactant in microreactor extremely abundant, thus shorten the reaction times, improve reaction efficiency, microreactor does not almost have scale effect, has higher safety performance simultaneously, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the structural representation of 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 T1, T2 are respectively the preset temp of microreactor unit L, H.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is described in further detail, but described embodiment does not limit the scope of the invention.Should be noted that, following examples are only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in right of the present invention.
The synthesis of the clean intermediate compound I a--of example 1 Da Gelie (3R, 4S, 5S, 6R)-2-(the chloro-3-of 4-(4-ethoxy benzyl) phenyl)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3,4,5-triol.
Method 1
The diethyl ether solution 163mL (163g, 0.5mol) of the chloro-2-of the bromo-1-of 4-(4-ethoxybenzyl) benzene of preparation 1g/mL, in material channel A, pass into above diethyl ether solution, coutroi velocity is 0.1mL/min.In material channel B, pass into the n-butyllithium solution 200mL altogether of 2.5M, coutroi velocity is 0.12mL/min, and wherein the preset temp T1 of micro-reaction member L is-80 ~-75 DEG C simultaneously.Subsequently to (the 3R passing into 0.5g/mL in material channel C, 4S, 5R, 6R)-3, the diethyl ether solution 514mL (257g, 0.55mol) of 4,5-tri-(trimethylsiloxy group)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyran-2-one, coutroi velocity is 0.3mL/min, and wherein the preset temp T2 of micro-reaction member H is-80 ~-70 DEG C.After question response, the reaction solution that outlet D flows out is passed in the methanol solution containing 0.6N methylsulfonic acid (1L), control temperature 15 ~ 25 DEG C, after system all passes into, stir 16h, system is through saturated sodium bicarbonate aqueous solution cancellation, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, concentrate to obtain target product, the i.e. clean intermediate compound I a--(3R of get Da Gelie, 4S, 5S, 6R)-2-(the chloro-3-of 4-(4-ethoxy benzyl) phenyl)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3, 4, 5-triol, 180g, productive rate 82%.
HPLC?ES/MS?m/z：461((M+Na)
+)
Method 2
The tetrahydrofuran solution 815mL (163g, 0.5mol) of the chloro-2-of the bromo-1-of 4-(4-ethoxybenzyl) benzene of preparation 0.2g/mL, passes into above tetrahydrofuran solution, coutroi velocity 1mL/min in material channel A.In material channel B, pass into n-butyllithium solution 200mL, the coutroi velocity 0.25mL/min altogether of 2.5M, wherein the preset temp T1 of micro-reaction member L is-80 ~-75 DEG C simultaneously.Subsequently to (the 3R passing into 0.4g/mL in material channel C, 4S, 5R, 6R)-3, the tetrahydrofuran solution 643mL (257g, 0.55mol) of 4,5-tri-(trimethylsiloxy group)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyran-2-one, coutroi velocity is 0.8mL/min, and wherein the preset temp T2 of micro-reaction member H is-80 ~-70 DEG C.After question response, the reaction solution that outlet D flows out is passed in the methanol solution containing 0.6N methylsulfonic acid (1L), control temperature 15-25 DEG C, after system all passes into, stir 16h, system is through saturated sodium bicarbonate aqueous solution cancellation, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, concentrate to obtain target product, the i.e. clean intermediate compound I a--(3R of Da Gelie, 4S, 5S, 6R)-2-(the chloro-3-of 4-(4-ethoxy benzyl) phenyl)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3, 4, 5-triol, 193g, productive rate 88%.
HPLC?ES/MS?m/z：461((M+Na)
+)
The clean intermediate compound I b--(3R of example 2 Kan Gelie, 4S, 5R, 6R)-6-(acetylmethyl)-2-(3-((5-(4-fluorophenyl) thiophene-2-base) methyl)-4-aminomethyl phenyl)-2-tetrahydrochysene-2H-pyrans-3, the synthesis of 4,5-triacetate.
The toluene solution 2040mL (204g, 0.5mol) of 2-(2-methyl-5-iodine benzyl)-5-(4-fluorophenyl) thiophene of preparation 0.1g/mL, passes into above toluene solution, coutroi velocity 2mL/min in material channel A.In material channel B, pass into the sec.-propyl grignard reagent of 2M and solution (grignard reagent and lithium chloride mol ratio are 1: the 1) 250mL altogether of lithium chloride simultaneously, coutroi velocity is 0.23mL/min, and wherein the preset temp T1 of micro-reaction member L is-10 ~ 0 DEG C.Subsequently to (the 2R passing into 0.2g/mL in material channel C, 3R, 4S, 5R)-2-(acetyl-o-methyl)-6-carbonyl tetrahydrochysene-2H-pyrans-3, the tetrahydrofuran solution 952mL (190g, 0.55mol) of 4,5-triacetate, coutroi velocity is 0.9mL/min, and wherein the preset temp T2 of micro-reaction member H is-35 ~-15 DEG C.After question response, the reaction solution of outlet D place outflow is passed in the mixed solution containing 38mL acetic acid and 425mL water, control temperature 15 ~ 25 DEG C, after system all passes into, stir 15min, system is through saturated sodium bicarbonate aqueous solution cancellation, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, obtain the clean intermediate compound I b--(3R of target compound Kan Gelie, 4S, 5R, 6R)-6-(acetylmethyl)-2-(3-((5-(4-fluorophenyl) thiophene-2-base) methyl)-4-aminomethyl phenyl)-2-tetrahydrochysene-2H-pyrans-3, 4, 5-triacetate, 260g, productive rate 83%.
HPLC?ES/MS?m/z：651((M+Na)
+)
The clean intermediate compound I c--(3R of example 3 Kan Gelie, 4S, 5R, 6R)-3, the synthesis of 4,5-tri-(benzyloxy)-6-(benzyloxymethyl)-2-(3-((5-(4-fluorophenyl) thiophene-2-base) methyl)-4-aminomethyl phenyl) tetrahydrochysene-2H-pyrans-2-oxygen alkane.
The toluene solution 2040mL (204g, 0.5mol) of 2-(2-methyl-5-iodine benzyl)-5-(4-fluorophenyl) thiophene of preparation 0.1g/mL, passes into above toluene solution, control speed 2mL/min in material channel A.In channel B, pass into ethyl grignard reagent and lithium chloride solution (grignard reagent and lithium chloride mol ratio are 1: 1.2) 250mL, the coutroi velocity 0.23mL/min altogether of 2M, wherein the preset temp T1 of micro-reaction member L is-10 ~ 0 DEG C simultaneously.Subsequently to (the 3R passing into 0.2g/mL in material channel C, 4S, 5R, 6R)-3, the tetrahydrofuran solution 1480mL (296g, 0.55mol) of 4,5-tri-(benzyloxy)-6-(benzyloxymethyl) tetrahydrochysene-2H-pyran-2-one, coutroi velocity is 1.4mL/min, and wherein the preset temp T2 of micro-reaction member H is-35 ~-15 DEG C.After question response, the reaction solution that outlet D flows out is passed in the mixed solution containing 38mL acetic acid and 425mL water, control temperature 15-25 DEG C, after system all passes into, stir 15min, system is through saturated sodium bicarbonate aqueous solution cancellation, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, obtain the clean intermediate compound I c--(3R of target compound Kan Gelie, 4S, 5R, 6R)-3, 4, 5-tri-(benzyloxy)-6-(benzyloxymethyl)-2-(3-((5-(4-fluorophenyl) thiophene-2-base) methyl)-4-aminomethyl phenyl) tetrahydrochysene-2H-pyrans-2-oxygen alkane, 324g, productive rate 79%.
HPLC?ES/MS?m/z：843((M+Na)
+)
Example 4Empagliflozin intermediate compound I d--(3R, 4S, 5S, 6R)-2-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3, the synthesis of 4,5-triol.
Tetrahydrofuran solution 414mL (the 207g of (S)-3-(4-(the 2-chloro-5-iodine benzyl) phenolic group) tetrahydrofuran (THF) of preparation 0.5g/mL, 0.5mol), in material channel A, pass into this tetrahydrofuran solution, coutroi velocity is 0.5mL/min.In material channel B, pass into the sec.-propyl grignard reagent of 2M and solution (grignard reagent and lithium chloride mol ratio are 1: the 0.9) 250mL altogether of lithium chloride simultaneously, coutroi velocity is 0.30mL/min, and wherein the preset temp T1 of micro-reaction member L is-15 ~-10 DEG C.Subsequently to (the 3R passing into 0.3g/mL in material channel C, 4S, 5R, 6R)-3, the tetrahydrofuran solution 857mL (257g, 0.55mol) of 4,5-tri-(trimethylsiloxy group)-6-((trimethylsiloxy group) methyl) tetrahydrochysene-2H-pyran-2-one, coutroi velocity is 1.0mL/min, and wherein the preset temp T2 of micro-reaction member H is-40 ~-20 DEG C.After question response, the reaction solution that outlet D place flows out is passed in the methanol solution containing 0.6N methylsulfonic acid (1L), control temperature 15 ~ 25 DEG C, after system all passes into, stir 16h, system is through saturated sodium bicarbonate aqueous solution cancellation, extraction into ethyl acetate, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, obtain target compound Empagliflozin intermediate compound I--(3R, 4S, 5S, 6R)-2-(the chloro-3-of 4-(4-((S)-tetrahydrofuran (THF)-3-oxygen base) benzyl) phenyl)-6-(methylol)-2-methoxyl group tetrahydrochysene-2H-pyrans-3, 4, 5-triol, 180g, productive rate 75%.
HPLC?ES/MS?m/z：503((M+Na)
+)
Claims (10)
1. a microreactor, is characterized in that,
Comprise at least 3 material channels (A, B, C) and 2 micro-reaction members (L) and (H), and an outlet (D);
Wherein, together, micro-reaction member (L) is positioned at directly over (H) for micro-reaction member (L) and (H) mounted on top; Material channel (A, B) is located at the same side of micro-reaction member (L) respectively, and material channel (C) is located at the side of micro-reaction member H, and with material channel (A, B) in relative position; The opposite side of micro-reaction member (H) is located in outlet (D).
2. microreactor according to claim 1, is characterized in that, be also respectively equipped with material channel in described micro-reaction member (L) and (H), the two is connected by a vertical material passage.
3. microreactor according to claim 1 and 2, it is characterized in that, material channel one end in described micro-reaction member (L) is connected with material channel (A, B), and the other end is connected with the vertical material passage led in micro-reaction member (H); Material channel one end in described micro-reaction member (H) is connected with from the vertical material passage of micro-reaction member (L) and material channel (C), the other end is connected with outlet (D), thus makes whole microreactor form path.
4. utilize microreactor to prepare the method arranging clean class pharmaceutical intermediate I, it is characterized in that, comprise the following steps:
(1) compound III being dissolved in organic solvent and organometallic reagent are flowed in microreactor unit (L) that preset temp is (T1) respectively by material channel (A, B) mix, and warp (L) flows to microreactor unit (H);
(2) Compound II per being dissolved in organic solvent is mixed with above-mentioned mixed solution by material channel (C) in micro-reaction member (H) that preset temp is (T2), and by this micro-reaction member (H), flow out from outlet (D) after question response, aftertreatment is carried out to the reaction solution of this outflow, obtains target compound--arrange clean class pharmaceutical intermediate I;
Reaction formula is as follows:
Wherein G is protecting group ethanoyl, trimethyl silicon based, or benzyl; G ' is hydrogen, ethanoyl, or benzyl; X is bromine or iodine; Ar is phenyl, to ethoxyl phenenyl, 5-to fluorophenyl-2-thienyl, or 4-((S)-tetrahydrofuran (THF)-3-oxygen base) phenyl; R is chlorine, methyl or hydrogen; M is methyl or hydrogen.
5. method according to claim 4, is characterized in that, the compound III strength of solution described in step (1) is 0.01g/mL ~ 2g/mL, and the flow velocity of compound III and organometallic reagent is respectively 0.1mL/min ~ 5.0mL/min.
6. method according to claim 4, is characterized in that, the organometallic reagent described in step (1) is selected from: n-Butyl Lithium, tert-butyl lithium; And the mixing solutions of ethyl grignard reagent or sec.-propyl grignard reagent and lithium chloride, the mol ratio of the two is 1: 0.9 ~ 1: 1.2.
7. method according to claim 4, is characterized in that, the Compound II per strength of solution described in step (2) is 0.01g/mL ~ 2g/mL, and the flow velocity of Compound II per is 0.1mL/min ~ 5.0mL/min.
8. method according to claim 4, it is characterized in that, the preset temp (T1) of described micro-reaction member (L) is-90 ~ 20 DEG C, and the preset temp (T2) of described micro-reaction member (H) is-90 ~ 20 DEG C.
9. method according to claim 4, is characterized in that, described organic solvent is selected from: ether, methyl-phenoxide, tetrahydrofuran (THF), 2-methyltetrahydrofuran, benzene,toluene,xylene, or a trimethylbenzene.
10. method according to claim 4, it is characterized in that, the reaction solution flowed out from outlet (D) is collected in acidic aqueous solution, or in the methanol solution being collected in containing methylsulfonic acid, through stirring, extraction, washing, salt washes, dry, concentrated, obtain target compound--arrange clean class pharmaceutical intermediate I.
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| CN105254610A (en) * | 2015-11-06 | 2016-01-20 | 西安近代化学研究所 | Method for preparing difluoro piperonal by utilizing continuous flow microchannel reactor |
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| WO2014206299A1 (en) | 2014-12-31 |
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