JP2020011948A - Method of synthesizing n-carboxyanhydride using flow reactor - Google Patents

Abstract

To provide a synthesis method that allows high-yield continuous production of a compound of interest in synthesis and production of N-carboxyanhydride (NCA) and the like using a flow reactor.SOLUTION: In a synthesis method using a flow reactor 100, a basic solution adjusted in advance to a pH of 7-14 becomes acidic with a pH of 0-7, or an acidic solution adjusted in advance to a pH of 0-7 becomes basic with a pH of 7-14, within 60 seconds after the start of mixture of at least two ingredient solutions.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a method for synthesizing a compound such as N-carboxy anhydride using a flow reactor.

  N-carboxy anhydride (NCA) is important as a building block for α-amino acids in the synthesis of oligopeptides and non-peptide compounds, and as a raw material for polypeptide synthesis. In particular, the latter use is of great importance, since NCA polymerization has become the first choice for polypeptide synthesis. The polymerization of various NCAs derived from protein-constituting amino acids and non-protein-constituting amino acids allows the properties of the resulting polypeptide to be freely changed, so that the polypeptide is a biocompatible material, a biodegradable polymer, a drug and It is used as a drug carrier. It is well known that, besides the side chain structure of the starting NCA, the purity of the NCA also greatly affects the properties of the polypeptide. Therefore, a technique for synthesizing high purity NCA from various amino acids is extremely important.

  The Fuchs-Farting method reported in 1922 (Non-Patent Documents 1 and 2) is still the only practical synthesis of NCA used industrially (see the following formula (A)). In this method, by reacting an amino acid with phosgene and a phosgene equivalent, the desired NCA (in the formula, described as “NCA (desired)”) can be synthesized in one step while producing hydrogen chloride. This method is characterized in that the number of steps is small, only carbon dioxide and hydrogen chloride are produced as by-products, and NCA is relatively stable under acidic conditions, so that it does not cause unwanted polymerization reactions and the like. On the other hand, under acidic conditions, the nucleophilicity of both amino and carboxyl groups of amino acids decreases, and a solution of solid amino acid and liquid phosgene and phosgene equivalent must be reacted. Relatively harsh reaction conditions are required, such as the need to heat for hours (eg, about 40-50 ° C., 2-5 hours, pH <1). For this reason, it is impossible to synthesize NCA having a functional group which is unstable under acidic conditions, and heating in the presence of hydrogen chloride often causes a ring-opening reaction of NCA, and undesired acid chlorides (by-products) are not allowed. Creatures) to reduce the purity of the target product.

  In the past, to solve these problems, a method using a scavenger of hydrogen chloride, a method using an urethane-protected amino acid, a method using diphenyl carbonate, a method involving nitrosation of N-carbamoylamino acid, Methods for removing hydrogen chloride using an airflow have been reported (Patent Documents 1 to 3 and the like). However, these methods have other disadvantages such as a decrease in purity, an increase in the number of steps, and a complicated process. Therefore, they have not yet replaced the Fuchs-Farting method.

  When the NCA synthesis represented by the following formula (B) is carried out under basic conditions, both the amino group and the carboxylate of the amino acid attack phosgene and phosgene equivalents quickly and in a short time even at a low temperature. However, under basic conditions, protons on the nitrogen atom of the NCA are rapidly extracted, and undesired polymerization reactions such as formation of polymer by-products are caused. In addition, free amino acids are usually only soluble in water in many cases, but it is assumed that NCA as a product is hydrolyzed when reacted under basic conditions in the presence of water. For these reasons, the reaction of NCA under basic conditions has not been reported.

  On the other hand, a synthesis method using a microflow reactor (microflow synthesis) is characterized in that a chemical reaction is caused in a space having a micrometer-order microchannel having an inner diameter of 1 mm or less, and a synthesis method using a flow reactor ( Flow synthesis), the reaction time and reaction temperature can be strictly controlled because the mixing time is shorter and the heat conduction space is higher than in the conventional batch synthesis method. Significant advantages have been reported in terms of ease of continuous production and safety of the reaction. In recent years, it has been reported that microflow synthesis is particularly suitable for synthesis of molecules having an unstable structure which is easily decomposed during the reaction under high temperature and high pressure, such as synthesis of proteins and heterocyclic compounds (Patent Document 4). However, in the synthesis of amino acid derivatives such as NCA, there are few examples in which the reduction of by-products is possible, and there are many problems at present.

JP-A-2002-145871 JP-A-2002-371070 Japanese Patent Publication No. 2008-518032 JP 2005-185972 A JP 2011-116731 A JP-A-2017-137244

F. Fuch, "Ber. Dtsch. Chem. Ges." (Germany), 1922, vol. 55, p. 2943. A. C. Furthing, "J. Chem. Soc." (UK), 1950, p. 3213-3217.

  The present invention has been made to solve the above-mentioned problem, and it is possible to continuously produce a target compound in high yield in the synthesis or production of N-carboxy anhydride (NCA) using a flow reactor. The purpose is to provide a synthesis method.

  In the synthesis of N-carboxy anhydride (NCA) or the like using a flow reactor such as a micro flow reactor, the present inventors use a reaction solution in a short time (instantaneously) after starting the synthesis (mixing of the raw material solutions). It has been found that by using a synthesis method for switching from acidic to acidic (or from acidic to basic), rapid progress of the reaction and suppression of polymerization of the product are compatible. In addition, by diluting the reaction solution by injecting a solvent such as an organic solvent using a flow reactor, the probability of contact between an acid such as hydrogen chloride and a product is reduced, and decomposition of a functional group that is unstable under acidic conditions is reduced. Can be avoided. That is, the present invention has the following contents.

1. A synthesis method using a flow reactor,
Within 60 seconds from the start of mixing of at least two kinds of raw material solutions,
It is characterized in that a basic solution previously adjusted to pH 7-14 changes to an acidity of pH 0 to 7, or an acidic solution previously adjusted to pH 0 to 7 changes to a basicity of pH 7-14. Synthesis method.

2. A synthesis method, characterized in that after starting the mixing of the raw material solution, the mixed solution is diluted 1.1 times or more by injecting a solvent.

3. The synthesis method, wherein the temperature range is -10 to 40C.

4. In the above synthesis method, the raw material solution may be pyridine, N-methylmorpholine, N-methylpiperidine, N, N-dimethylethylamine, N, N-diethylmethylamine, diethylamine, lithium hydroxide, sodium hydroxide, potassium hydroxide , A basic solution containing at least one base selected from calcium hydroxide, barium hydroxide, sodium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate and ammonia.

5. In the above synthesis method, the raw material solution is an acidic solution containing at least one acid selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, and formic acid.

6. The synthesis method, wherein the solvent of the raw material solution is an organic solvent.

7. In the above synthesis method, the solvent of the raw material solution is acetonitrile or tetrahydrofuran.

8. A synthesis method, wherein the solvent used for dilution after mixing the raw material solutions is an organic solvent or water.

9. A synthesis method wherein the solvent used for dilution after mixing the raw material solutions is ethyl acetate or dichloromethane.

10. In the synthesis method, the substance contained in the raw material solution may include:
A synthesis method which is a compound represented by the following general formulas (1-1) and (1-2).

[Wherein, R ^{1 to} R ³ each independently represent —H, —OH, —COOH, —COO ⁻ , —CN,
A thio group having 0 to 20 carbon atoms which may have a substituent,
A sulfo group having 0 to 20 carbon atoms which may have a substituent,
An amino group having 0 to 20 carbon atoms which may have a substituent,
A silyl group having 1 to 20 carbon atoms which may have a substituent,
A linear or branched alkyl group having 1 to 20 carbon atoms which may have a substituent,
A cycloalkyl group having 1 to 20 carbon atoms which may have a substituent,
A linear or branched alkenyl group having 2 to 20 carbon atoms which may have a substituent,
An alkynyl group having 2 to 20 carbon atoms which may have a substituent,
A linear or branched alkoxy group having 1 to 20 carbon atoms which may have a substituent,
A cycloalkoxy group having 5 to 20 carbon atoms which may have a substituent,
An acyl group having 1 to 20 carbon atoms which may have a substituent,
An aromatic hydrocarbon group having 6 to 20 carbon atoms which may have a substituent,
A heterocyclic group having 2 to 20 carbon atoms which may have a substituent, or an aryloxy group having 6 to 20 carbon atoms which may have a substituent;
R ^{1 to} R ³ may be bonded to each other by adjacent groups to form a ring.
m represents an integer of 1 to 6, and when m is 2 or more, a plurality of R ² and R ³ may be the same or different from each other.
M represents a hydrogen atom or an alkali metal atom. ]

Wherein X and Y are each independently —Cl, —OCCl ₃ ,
A thio group having 0 to 20 carbon atoms which may have a substituent,
A linear or branched alkenyl group having 2 to 20 carbon atoms which may have a substituent,
A linear or branched alkoxy group having 1 to 20 carbon atoms which may have a substituent,
It represents an optionally substituted heterocyclic group having 3 to 20 carbon atoms or an aryloxy group having 6 to 20 carbon atoms optionally having a substituent. ]

11. In the above general formula (1-1), a synthesis method wherein R ³ is —H, m is 1, and M is a sodium atom.

12. A synthesis method, wherein the flow reactor is a micro flow reactor.

  According to the synthesis method using the flow reactor of the present invention, a synthesis method capable of continuously producing a compound having an intended structure such as N-carboxy anhydride (NCA) in high yield can be provided. .

FIG. 2 is a schematic diagram illustrating a specific example of an apparatus used in the “synthesis method using a flow reactor” of the present invention. It is the schematic which represents the specific example of the apparatus which added the mechanism to dilute the solution after mixing to the apparatus used by the "synthesis method using a flow reactor" of this invention. FIG. 4 is a schematic diagram illustrating a specific example of synthesis using the “synthesis method using a flow reactor” of the present invention.

<Synthesis method using flow reactor (flow synthesis)>
This will be described in detail below using a schematic diagram of a specific example of the apparatus of FIG. 1 used in the synthesis method of the present invention. FIG. 1 schematically shows the minimum necessary equipment in the synthesis method of the present invention, and is not limited to the following examples. Omissions, substitutions, changes in numerical values and the like, exchange of preferred examples, and the like can be made without departing from the spirit of the present invention.

The “flow reactor” in the present invention has a mechanism shown by the flow reactor 100 in FIG. In the synthesis method using the flow reactor of the present invention, the raw material solution (1-1) containing the raw material before the chemical reaction (the symbol ○ in the figure) and the raw material solution (1 -2) (symbol in the figure) is mixed with a chemical reaction in the mixer 20 to obtain the product 2 (or the mixed solution 2 containing the product) (symbol in the figure). The synthesized product contains the product 2 in the mixed solution, and has a function of discharging the solution to the outside of the mixer 20.
The details of the "flow reactor" apparatus of the present invention will be described in detail. The flow reactor 100 has a raw material solution supply device 11 that can continuously supply the raw material solution (1-1). The raw material solution supply device 11 is connected to a liquid sending pipe 110, Tube 110 is connected to one inlet of mixer 20. Further, the flow reactor 100 has a raw material solution supply device 12 capable of continuously supplying the raw material solution (1-2), and the raw material solution supply device 12 is connected to a liquid sending pipe 120, The liquid feeding pipe 120 is connected to another inlet of the mixer 20. The mixer 20 has one outlet, which is connected to the reaction tube 21. The mixing of the raw material solution (1-1) and the raw material solution (1-2) starts in the space inside the mixer 20, a reaction takes place inside the mixer 20 and inside the reaction tube 21, and the solution containing the product 2 is formed. It moves and is discharged out of the flow reactor 100 through the reaction tube 21 to obtain the product 2. In the reaction tube 21, another mixer can be connected to the end opposite to the mixer 20 to perform the next chemical reaction or chemical treatment.

  The “flow reactor” in the present invention performs the reaction in a space of the mixer that is smaller than that of the batch-type reaction vessel, and thus has excellent heat conductivity and can perform the reaction with less deviation in the temperature distribution. Therefore, it is suitable for a reaction requiring a temperature (high temperature, low temperature) which is difficult for a batch type reaction vessel. In addition, since organic compounds unstable to strong acids and strong bases can be continuously handled in a small amount in a short time, they are also suitable for synthesis via unstable intermediates. Further, since the mixing can be performed instantaneously, there is an advantage that the reaction can be performed without passing through a non-uniform dispersion state in the solution. Further, pressurization can be easily performed, which is effective for increasing the reaction rate.

  The synthesis method of the present invention is a synthesis method using the above-mentioned flow reactor, wherein the basic pH is adjusted to pH 7-14 within 60 seconds from the start of mixing of at least two kinds of raw material solutions in the flow reactor. The synthesis method is characterized in that the solution is changed to an acidic solution of pH 0 to 7, or an acidic solution which has been adjusted to pH 0 to 7 is changed to a basic solution of pH 7-14. Here, the “raw material solution” means “a basic solution that has been previously adjusted to pH 7 to 14” or “an acidic solution that has been previously adjusted to pH 0 to 7”. Means the point at which a chemical reaction starts when any one of these raw material solutions is mixed with another “raw material solution”. That is, in FIG. 1, the raw material solution (1-1) in the raw material supply device 11 is introduced into the mixer 20 through the liquid supply pipe 11, and the raw material solution (1-2) in the raw material supply device 12 is supplied to the liquid supply pipe. It means the point in time when it is introduced into the mixer 20 through 12 and when the mixing of these substances starts.

  In the synthesis method of the present invention, one of the “at least two types of raw material solutions” (raw material solution (1-1)) is specifically prepared by converting a substance before a chemical reaction and a base or acid into water or It is a basic solution adjusted to pH 7 to 14 using a solvent such as an organic solvent, or an acidic solution adjusted to pH 0 to 7. One of the raw material solutions (raw material solution (1-1)) may be either a basic solution or an acidic solution, but is preferably a basic solution that has been adjusted to pH 7-14 in advance. The solvent of the basic solution is not limited as long as it dissolves the raw material contained in the raw material solution (1-1), and examples thereof include water, an aqueous solution, an organic solvent, or a mixture of water and an organic solvent. , Water or an aqueous solution.

  In the synthesis method of the present invention, of the at least two types of raw material solutions, another type (raw material solution (1-2)) is chemically reacted with the raw material in the raw material solution (1-1) in the mixer 20. Solution. The solvent of the raw material solution is not limited as long as it can dissolve the raw material contained in the raw material solution (1-2), and examples thereof include water, an aqueous solution, an organic solvent, or a mixture of water and an organic solvent. And an organic solvent.

  In the synthesis method of the present invention, the pH of a previously prepared basic or acidic solution changes due to a chemical reaction within a short time of 0 to 60 seconds after the start of mixing. The time (reaction time) of this chemical reaction is such that the mixed solution exits the outlet of the mixer, moves inside the reaction tube 21 and is discharged out of the tube from the time when the solution is introduced (injected) into the mixer and mixing is started. Or until it is introduced into the next mixer 30 (described below in FIG. 2). This time may be as short as 0 seconds after the start of the synthesis (for example, within 0.01 seconds to 0.1 seconds, or within 0.1 seconds to 1 second, etc.) and may be long. Is also preferably between 0 and 60 seconds. As described above, the present invention enables a short-time conversion (or instantaneous switch) from basic to acidic or from acidic to basic by performing efficient mixing using a flow reactor. ing.

  In the synthesis method of the present invention, FIG. 1 shows an example of the flow reactor 100 in a case where two kinds of substances of a raw material solution (1-1) and a raw material solution (1-2) react. The substance that reacts with 1-1) is not limited to only the raw material solution (1-2). For example, as in the case of the raw material solution (1-2), one or more of any one of the raw material solutions (1-3) to the raw material solution (1-9) other than the raw material solution (1-2) is supplied to the liquid supply pipe 130. , 140, 150, 160, 170, 180, and 190, piping may be performed such that they can be introduced into the mixer 20, thereby performing a desired chemical reaction. The number of substances that react with the raw material solution (1-1) is preferably one or two.

  In the synthesis method of the present invention, the solution after mixing (represented as product 2 in the figure) moved through the reaction tube 21 in FIG. 1 may be continuously introduced into the mixer 30. This case will be described with reference to a schematic diagram showing the flow reactor 100 of FIG. In the present invention, a solvent 22 (22 in the figure includes a solvent supply device) is passed through a liquid sending pipe 220 to an inlet of a mixer 30 different from the inlet of the solution 2 (product 2) after mixing. 30 is injected (or introduced). In the mixer 30, a state change occurs due to the mixing of the solution containing the product 2 and the solvent 22. In the present invention, this state change is caused by the injection of the solvent 22 after the mixing containing the product 2. Preferably, the step of diluting the solution is 1.1 times or more, that is, the solvent 22 is preferably a solvent capable of diluting the mixed solution containing the product 2. The solution mixed and diluted by the mixer 30 moves through the reaction tube 31 and can be obtained in the state of the solution containing the product 2 while maintaining the state of the target molecular structure and the like stably.

In the synthesis method of the present invention, the step of “diluting the mixed solution by 1.1 times or more by injecting a solvent” is a step in which the mixed solution containing the product 2 and the solvent 22 are first mixed in the mixer. It is that mixing is performed in a short time from the time when it is performed, and it is preferable that uniform mixing is performed and diluted within 0.1 to 60 seconds from the start of mixing, and until uniform mixing is performed. The shorter the time, the better.
Further, when the product 2 is diluted in the mixer 30, FIG. 2 shows an example in which a solution containing the product 2 and two kinds of substances of the solvent 22 are mixed. The solvent for diluting the contained solution is not limited to the solvent 22 alone. For example, any one or more of the solvents 23 to 29 other than the solvent 22 are all introduced into the mixer 30 through the corresponding liquid sending pipes 230, 240, 250, 260, 270, 280 and 290, similarly to the solvent 22. The desired dilution may be performed by piping so as to perform the dilution. Therefore, it is preferable that the number of types of the solvent to be used for diluting the solution (product 2) after mixing in the mixer 20 by injecting the solvent into the mixer 30 is one or two.

  In the synthesis method of the present invention, after the mixing of the raw material solution is started, it is preferable to dilute the mixed solution by injecting a solvent. The dilution ratio is preferably 1.1 times or more, and the higher the dilution ratio, the better.

  Each part of the flow reactor of the present invention will be described below in detail with reference to FIG. 1 or FIG. The raw material solution supply device represented by 11 is not particularly limited as long as it can continuously supply the raw material solution 2 containing a liquid raw material, and a commercially available one can be used. Specific examples include, but are not particularly limited to, a gas-tight syringe and a liquid feed pump using a syringe pump. The raw material solution supply device for supplying the raw material solution (1-2) represented by 12 or the solvent supply device 22 in FIG. The flow rate of the solution can be changed by appropriate equipment. Furthermore, regarding the amount (yield) of the finally recovered product, as long as the raw material solution is continuously supplied, the recovery time of the continuously discharged solution (reaction solution) after the reaction should be extended. As a result, more products can be recovered.

  In the flow reactor of the present invention, in FIG. 1 or FIG. 2, the liquid sending pipes 110 and 120 or the reaction pipes 21 and 31 are made of resin such as polytetrafluoroethylene (PTFE) resin and polyetheretherketone (PEEK) resin. Materials such as stainless steel and other metal materials are preferable, and those which do not deteriorate or corrode due to water, organic solvents, and temperature changes are preferable. A heating device (heater) and a cooling device can be attached to these liquid sending tubes and reaction tubes so that the temperature can be changed. Specifically, heating in a constant temperature bath such as an oil bath or a water bath or a hot air constant temperature bath, cooling in a constant temperature bath such as a cryostat containing a refrigerant such as alcohol, ethylene glycol, or liquid nitrogen, and supply of liquid and reaction tubes. Adjusting the reaction temperature and liquid transport temperature by changing the temperature around the liquid feed tube or reaction tube by a method such as energizing heating by winding a linear electric heater or ribbon heater around the periphery. be able to. It is preferable that the material of the liquid sending tube and the reaction tube be durable to a temperature change of −200 ° C. to 100 ° C. The shapes of the liquid sending tube and the reaction tube are not particularly limited, but preferably have the same inner diameter as the flow path inside the mixer described later. In the flow reactor of the present invention, the inside diameters of the liquid sending tube and the reaction tube can be of various sizes, several tens to several hundreds μm order, several mm order, several cm order, and even more. Can be used. Each inner diameter is preferably from 10 μm to 5 cm, more preferably from 0.1 mm to 1 cm, particularly preferably from 0.1 mm to 2 mm. Specifically, when a mixer (micromixer) having a flow path inner diameter of 1 mm or less is used, the inner diameter of the liquid sending tube and the reaction tube is preferably in the range of 0.15 mm to 1 mm. The lengths of the liquid sending tube and the reaction tube are not particularly limited, and may be any lengths that allow sufficient mixing and reaction in the reaction tube after mixing in the mixer. For example, a mixer having a channel inner diameter of 1 mm or less is used. In this case, the length is preferably from 100 mm to 1000 mm, and more preferably from 200 mm to 500 mm.

  In the synthesis method of the present invention, when the solvent contains water or an aqueous solution, the temperature range is preferably such that the solvent does not freeze, and the temperature range is preferably -10 to + 40 ° C.

In the “synthesis method using a flow reactor” of the present invention, a portion described as a mixer 20 or 30 in FIG. 1 or FIG. 2 generally includes a “microflow reactor” (or “microreactor”, “micromixer”). , "Micro heat exchangers", "flow micro reactors"), etc. These "micro flow reactors" are available on the order of micrometers up to 1 mm. Although it is an apparatus aimed at mixing a fluid such as a liquid substance or performing a chemical reaction in a space having a flow path with an inner diameter, the synthesis method using the “flow reactor” of the present invention requires a short time from the start of mixing of the raw material solution. Since it is a synthesis method characterized by converting the pH into, if the apparatus satisfies the conditions of this synthesis, Size of the space in the row reactor is not limited to the following flow path micrometer order ~ 1 mm. Accordingly, the flow path inside the mixer can be on the order of tens to hundreds of μm, on the order of several mm, on the order of several cm, and even more. In the present invention, the inner diameter of the flow path of the mixer is preferably 10 μm to 5 cm, more preferably 0.1 mm to 1 cm, particularly preferably 0.15 mm to 1 mm. The flow reactor is preferably a micro flow reactor.
Further, the “flow reactor” of the present invention can obtain different effects by having a unique channel shape structure according to the application. The mixer in FIG. 1 or FIG. 2 has two inlets and one outlet, and is not particularly limited as long as it has such a shape, and examples thereof include V-shaped and T-shaped ones. However, in the present invention, any shape can be used. When three or more raw material solutions are used, those having 3 to 9 inlets can be used. The material of the mixer is not particularly limited, and examples thereof include materials such as metal, glass, single-crystal silicon, and resin, and are made of stainless steel metal from the viewpoint of strength, heat conductivity of temperature, and corrosion resistance of a solvent. Is preferred.

In the synthesis method of the present invention, when the raw material solution is a basic solution, the base used for preparing the basic solution includes pyridine, methylpyridine, dimethylpyridine, N, N-dimethyl-4-aminopyridine, N-methylmorpholine (NMM), N, N-dimethylethylamine, N-methylpiperidine, N, N-diethylmethylamine, methylamine, dimethylamine, ethylamine, triethylamine, aniline, dimethylaniline, cyclohexylamine, N, N- Diisopropylethylamine, diazabicyclononene (DBN), diazabicycloundecene, piperazine, 1,4-ethylenepiperazine, imidazole, oxazole, 1,8-bis (dimethylamino) naphthalene, 1,4-diazabicyclo [2.2 .2] octane, Triethanolamine, tetramethylethylenediamine, organic bases such as hexamethylenediamine;
Lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), rubidium hydroxide (RbOH), cesium hydroxide (CsOH), beryllium hydroxide (Be (OH) ₂ ), magnesium hydroxide ( Mg (OH) ₂ ), calcium hydroxide (Ca (OH) ₂ ), strontium hydroxide (Sr (OH) ₂ ), barium hydroxide (Ba (OH) ₂ ), aluminum hydroxide (Al (OH) ₃ ) , Iron hydroxide (II, III) (Fe (OH) ₂ , Fe (OH) ₃ ), manganese hydroxide (Mn (OH) ₂ ), zinc hydroxide (Zn (OH) ₂ ), copper hydroxide (II ) (Cu (OH) ₂ ), lanthanum hydroxide (La (OH) ₃ ), sodium bicarbonate (NaHCO ₃ ), lithium carbonate (Li ₂ CO ₃ ), sodium carbonate (Na ₂ CO ₃ ), potassium carbonate (K ₂ CO ₃ ), rubidium carbonate (Rb ₂ CO ₃ ), cesium carbonate (Cs ₂ CO ₃ ), trisodium phosphate (Na ₃ PO ₄ ), tripotassium phosphate (K ₃ PO 3) ₄ ) inorganic bases such as disodium hydrogen phosphate (Na ₂ HPO ₄ ), dipotassium hydrogen phosphate (K ₂ HPO ₄ ), ammonia (NH ₃ ); or salts obtained by reacting with these bases can give. Among them, organic bases are preferable, and these bases may have a substituent. Among these, as the base when the raw material solution is adjusted to be basic in advance, those having an acid dissociation constant (pK _a ) of 5 to 12 in an aqueous solution at 25 ° C. are preferable.

In the synthesis method of the present invention, when the raw material solution is an acidic solution, the acid used for preparing the acidic solution includes hydrochloric acid (HCl), hypochlorous acid (HClO), chlorous acid (HClO ₂ ), Chloric acid (HClO ₃ ), perchloric acid (HClO ₄ ), hypoperchloric acid (HClO ₅ ), hydrobromic acid (HBr), hypobromous acid (HOBr), bromic acid (HBrO ₃ ), hydrogen fluoride Acid (HF), nitric acid (HNO ₃ ), sulfuric acid (H ₂ SO ₄ ), persulfuric acid (H ₂ SO ₅ ), phosphoric acid (H ₃ PO ₄ ), perphosphoric acid (H ₃ PO ₅ ), hexafluoro Loric acid (HPF ₆ ), potassium dihydrogen phosphate (KH ₂ PO ₄ ), sodium dihydrogen phosphate (NaH ₂ PO ₄ ), hexafluoroantimonic acid (HF ₆ Sb), iodic acid (HIO ₃ ), Iodic acid (HIO), Iodate iodide _{(HIO 4, H 5 IO 6} ), boric acid (B _{(OH) 3),} tetrafluoroboric acid _(HBF 4), carbonate _(H 2 _CO 3), percarbonate _{(H 2 CO 4, H 2} C ₂ O ₆ ), permanganic acid (HMnO ₄ ), chromic acid (H ₂ CrO ₄ ), acetic acid (CH ₃ COOH), peracetic acid (CH ₃ COO ₂ H), trifluoroacetic acid (CF ₃ COOH), chloroacetic acid (ClCH ₂ COOH), dichloroacetic acid (Cl ₂ COOH), trichloroacetic acid (Cl ₃ CCOOH), benzoic acid (C ₆ H ₅ COOH), perbenzoic acid (C ₆ H ₅ COO ₂ H), metachlorobenzoic acid (mClC) ₆ H ₄ COO ₂ H), methanesulfonic acid _(CH 3 _SO 3 H), ethanesulfonic acid _{(C 2 H 5 SO 3 H} ), benzenesulfonic acid, p- toluenesulfonic acid (CH ₃ C ₆ H ₄ SO ₃ H), trifluoromethanesulfonic acid (CF ₃ SO ₃ H), citric acid (C (OH) (CH ₂ COOH) ₂ COOH), formic acid (HCOOH), gluconic acid (HOCH ₂₎ CH (OH) CH (OH) CH (OH) CH (OH) COOH), lactic acid _{(CH 3 CH (OH) COOH} ), oxalic acid _{((COOH) 2),} tartaric acid _{((CH (OH) COOH)} 2) And inorganic acids such as thiocyanic acid (HSCN), organic acids or salts obtained by reacting with them.

  In the synthesis method of the present invention, examples of the solvent of the raw material solution include water, an aqueous solution, an organic solvent, a mixed solvent of water and an organic solvent, and a mixed solvent of a plurality of organic solvents (or an organic solution in which an organic compound is dissolved). And water or an organic solvent is preferred, and an organic solvent is more preferred. Specifically, acetonitrile (AN), acetone, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP); acetic acid, formic acid, ethyl acetate, butyl acetate and other esters; dichloromethane (DCM), chloroform; linear or branched alkanes such as pentane, hexane, cyclohexane, and octane; methanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol, 1-methoxy-2-propanol (propylene glycol 1 Alcohols and ethers such as propylene glycol 1-monomethyl ether 2-acetate and diethyl ether; keto such as acetone, 2-butanone, 2-pentanone and 3-pentanone. Aromatic hydrocarbons such as toluene, xylene, chlorobenzene, trichlorobenzene, aniline, phenol and diphenyl ether; pyridine, pyrrolidine, tetrahydrofuran (THF), tetrahydrothiophene, pyrrole, furan, thiophene, piperidine, tetrahydropyran, oxazole, thiazole, An organic solvent or a heterocyclic compound such as 1,3-dioxane, 1,4-dioxane, 1,3-dioxolane, ethylene oxide, morpholine, pyridazine, pyrazine, pyrimidine, indole, quinoline, isoquinoline, 1-benzofuran; Examples include organic compounds contained in the solvent.

  In the synthesis method of the present invention, the solvent used for dilution after mixing the raw material solutions is an organic solvent, water, an aqueous solution, a mixed solvent of an organic solvent and water, a plurality of organic solvents (or an organic solution in which an organic compound is dissolved). And the same solvents as those described above in "Solvent for Raw Material Solution" can be used. As a solvent used for dilution, an organic solvent or water is preferable, and an organic solvent is more preferable. When an organic solvent is used, the solvent is not particularly limited as long as it is an organic solvent having a relatively low acid or base solubility, and a solvent having low miscibility with water and suitable for liquid separation is preferable. Among the organic solvents, for example, ethyl acetate, dichloromethane, chloroform, diethyl ether, hexane, pentane, acetonitrile, tetrahydrofuran and the like can be mentioned, and ethyl acetate or dichloromethane is preferable.

  The substance obtained by the “synthesis method using a flow reactor” in the present invention may be any of an organic compound and an inorganic compound, and may be a complex thereof. Specific compounds include pigment compound materials such as pigments, dyes, food colors, organic electroluminescent materials and organic semiconductor materials; herbicides, insecticides, fertilizers and other agricultural chemicals; pharmaceutical intermediates; Related to biopolymers such as amino acids such as products (NCA); precursors of resin materials such as polyols and isocyanates; polymers such as thermoplastic resins such as epoxy resins, polycarbonate resins and urethane resins, and thermosetting and functional resins Compounds; compounds having an unstable group having a peroxide structure (—O—O—), such as hydrogen peroxide and peracetic acid; small-continuous synthesis of high-temperature reactions such as nitration, and toxic reactions such as phosgene or phosgene derivatives Compounds that require: a fullerene, carbon nanotube, graphene, or any of these compounds having a soluble substituent on the carbon material Compounds given the; can be applied to the synthesis of such.

As a preferred example in the synthesis method of the present invention, the substance contained in the raw material solution is a compound represented by the following general formulas (1-1) and (1-2). Specifically, a raw material solution containing a compound represented by the following general formula (1-1) and a raw material solution containing a compound represented by the following general formula (1-2) are used in a flow reactor. It is preferable to use a method of synthesizing a compound represented by the following general formula (2) by mixing and reacting by a synthesis method. In addition, the following general formula (1-1) represents a general structural formula of an amino acid. For example, when R ¹ = R ³ = H, m = 1, and M = H, it represents an α-amino acid. it can represent a variety of amino acids by replacing the R ^2. In this case, the following general formula (2) represents “α-amino acid-N-carboxy anhydride (commonly called NCA)”.

[Wherein, R ^{1 to} R ³ each independently represent —H, —OH, —COOH, —COO ⁻ , —CN,
A thiol group having 0 to 20 carbon atoms which may have a substituent,
A sulfo group having 0 to 20 carbon atoms which may have a substituent,
An amino group having 0 to 20 carbon atoms which may have a substituent,
A silyl group having 1 to 20 carbon atoms which may have a substituent,
A linear or branched alkyl group having 1 to 20 carbon atoms which may have a substituent,
A cycloalkyl group having 1 to 20 carbon atoms which may have a substituent,
A linear or branched alkenyl group having 2 to 20 carbon atoms which may have a substituent,
An alkynyl group having 2 to 20 carbon atoms which may have a substituent,
A linear or branched alkoxy group having 1 to 20 carbon atoms which may have a substituent,
A cycloalkoxy group having 5 to 20 carbon atoms which may have a substituent,
An acyl group having 1 to 20 carbon atoms which may have a substituent,
An aromatic hydrocarbon group having 6 to 20 carbon atoms which may have a substituent,
A heterocyclic group having 2 to 20 carbon atoms which may have a substituent, or an aryloxy group having 6 to 20 carbon atoms which may have a substituent;
R ^{1 to} R ³ may be bonded to each other by adjacent groups to form a ring.
m represents an integer of 1 to 6, and when m is 2 or more, a plurality of R ² and R ³ may be the same or different from each other.
M represents a hydrogen atom or an alkali metal atom. ]

Wherein X and Y are each independently —Cl, —OCCl ₃ ,
A thio group having 0 to 20 carbon atoms which may have a substituent,
A linear or branched alkenyl group having 2 to 20 carbon atoms which may have a substituent,
A linear or branched alkoxy group having 1 to 20 carbon atoms which may have a substituent,
A heterocyclic group having 2 to 20 carbon atoms which may have a substituent, or
And represents an aryloxy group having 6 to 20 carbon atoms which may have a substituent. ]

[Wherein, R ^{1 to} R ³ and m represent the same meaning as in the general formula (1-1). ]

  In the synthesis method of the present invention, the substance contained in the raw material solution is a compound represented by the general formulas (1-1) and (1-2), and a compound represented by the general formula (2). Is obtained as shown in the following formula (3) by omitting a part (such as M).

  Hereinafter, the above synthesis method will be described in detail. First, the general formula (1-1) will be described.

In the general formula (1-1), the “thio group” in the “optionally substituted thio group having 0 to 20 carbon atoms” represented by R ^{1 to} R ³ is represented by “—SH”. "Or a group having" -S- ", and the" substituent "in the" optionally substituted thio group having 0 to 20 carbon atoms "is bonded to one of" -S- " Means a substituent or a metal atom.

In the general formula (1-1), the “sulfo group” in the “optionally substituted sulfo group having 1 to 20 carbon atoms” represented by R ^{1 to} R ³ is represented by “—SO ₃ —H "or" -SO 3 _- means ",""substituent at sulfo group" good carbon atoms 0 to 20 which may have a substituent "," - SO 3 _- while binding to substitutions " Means a group or a metal atom.

In the general formula (1-1), “amino group having 0 to 20 carbon atoms” in “amino group having 0 to 20 carbon atoms which may have a substituent” represented by R ^{1 to} R ³ Specific examples include an unsubstituted amino group; a methylamino group, a dimethylamino group, a diethylamino group, an ethylmethylamino group, a methylpropylamino group, a di-t-butylamino group, a diphenylamino group, and the like.

In the general formula (1-1), “silyl group having 0 to 20 carbon atoms” in “silyl group having 0 to 20 carbon atoms which may have a substituent” represented by R ^{1 to} R ³ Specific examples include —SH ₃ , a trimethylsilyl group, a t-butyldimethylsilyl group, and the like.

In the general formula (1-1), “the number of carbon atoms” in the “optionally substituted linear or branched alkyl group having 1 to 20 carbon atoms” represented by R ^{1 to} R ³ Specific examples of the “1-20 linear or branched alkyl group” include a methyl group (—Me), an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, and a nonyl group. And linear alkyl groups such as decyl group; and branched alkyl groups such as isopropyl group, isobutyl group, s-butyl group, t-butyl group and isooctyl group.

In the general formula (1-1), “cycloalkyl having 3 to 20 carbon atoms” in “cycloalkyl group having 3 to 20 carbon atoms which may have a substituent” represented by R ^{1 to} R ³ Specific examples of the "group" include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group.

In the general formula (1-1), the “number of carbon atoms” in the “optionally substituted linear or branched alkenyl group having 2 to 20 carbon atoms” represented by R ^{1 to} R ³ Examples of the 2-20 linear or branched alkenyl groups "include vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, and isopropenyl. Group, an isobutenyl group, or a linear or branched alkenyl group in which a plurality of these alkenyl groups are bonded.

In the general formula (1-1), the “alkynyl group having 2 to 20 carbon atoms” in the “optionally substituted alkynyl group having 2 to 20 carbon atoms” represented by R ^{1 to} R ³ Examples thereof include an ethynyl group and a group having “—C≡C—”, and the “substituent” in the “optionally substituted alkynyl group having 2 to 20 carbon atoms” includes “—C "C-" means a substituent or metal atom bonded to one of the "C-".

In the general formula (1-1), “the number of carbon atoms” in the “optionally substituted linear or branched alkoxy group having 1 to 20 carbon atoms” represented by R ^{1 to} R ³ Examples of the “1-20 linear or branched alkoxy groups” include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, and nonyloxy. Linear alkoxy groups such as a group and decyloxy group; and branched alkoxy groups such as an isopropoxy group, an isobutoxy group, an s-butoxy group, a t-butoxy group and an isooctyloxy group.

In the general formula (1-1), “cycloalkoxy having 5 to 20 carbon atoms” in “cycloalkoxy group having 5 to 20 carbon atoms which may have a substituent” represented by R ^{1 to} R ³ Specific examples of the "group" include cycloalkyl groups such as cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, and cyclodecyl group; 1-adamantyl group, 2-adamantyl group, and the like.

In formula (1-1), “acyl group having 1 to 20 carbon atoms” in “acyl group having 1 to 20 carbon atoms which may have a substituent” represented by R ^{1 to} R ³ Specific examples include a formyl group, an acetyl group, a propionyl group, an acrylyl group, and a benzoyl group.

In the general formula (1-1), the “aromatic hydrocarbon group having 6 to 30 carbon atoms which may have a substituent” represented by “R ⁶ to C ³ ” represented by R ^{1 to} R ³ . Specific examples of the "aromatic hydrocarbon group" include aromatic hydrocarbon groups such as phenyl group, benzoyl group, naphthyl group, biphenyl group, anthryl group, phenanthryl group, pyrenyl group, triphenylenyl group, indenyl group, and fluorenyl group. The “aromatic hydrocarbon group” in the present invention includes an aryl group and a condensed polycyclic aromatic group.

In the general formula (1-1), the “heterocyclic group having 2 to 20 carbon atoms” in the “optionally substituted heterocyclic group having 2 to 20 carbon atoms” represented by R ^{1 to} R ³ Specific examples of the `` group '' include a pyridyl group, a pyrimidinyl group, a triazinyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a quinolyl group, an isoquinolyl group, a naphthyridinyl group, an indolyl group, a benzimidazolyl group, a carbazonyl group, and a carbolinyl group. , Acridinyl group, phenanthrolinyl group, furanyl group, benzofuranyl group, dibenzofuranyl group, thienyl group, benzothienyl group, dibenzothienyl group, oxazolyl group, benzooxazolyl group, thiazolyl group, benzothiazolyl group, etc. .

In the general formula (1-1), “aryloxy group having 6 to 20 carbon atoms” in “aryloxy group having 6 to 20 carbon atoms which may have a substituent” represented by R ^{1 to} R ³ Specific examples of the "group" include a phenyloxy group, a biphenylyloxy group, a naphthyloxy group, an anthracenyloxy group, and a phenanthrenyloxy group.

Represented by R ^{1 to} R ³ in the general formula (1-1),
"A thio group having 0 to 20 carbon atoms having a substituent",
"Substituted sulfo group having 0 to 20 carbon atoms",
"Substituted amino group having 0 to 20 carbon atoms",
"A silyl group having 0 to 20 carbon atoms having a substituent",
"A linear or branched alkyl group having 1 to 20 carbon atoms having a substituent",
"A cycloalkyl group having 3 to 20 carbon atoms having a substituent",
"A linear or branched alkenyl group having 2 to 20 carbon atoms having a substituent",
"Substituted alkynyl group having 2 to 20 carbon atoms",
"A linear or branched alkoxy group having 1 to 20 carbon atoms having a substituent",
"A cycloalkoxy group having 3 to 20 carbon atoms having a substituent",
"Substituted acyl group having 1 to 20 carbon atoms",
"Aromatic hydrocarbon group having 6 to 20 carbon atoms having a substituent",
As the “substituent” in the “heterocyclic group having 2 to 20 carbon atoms having a substituent” or the “aryloxy group having 6 to 20 carbon atoms having a substituent”,
Specifically, a hydroxyl group (—OH), a nitro group (—NO ₂ ), a nitroso group (—NO), a cyano group (—CN), a carboxyl group (—COOH), —COO ⁻ ,
—SO ₃ ⁻ , a thiol group (—SH), a thio group having a substituent (—S—), a sulfonamide group (—S (＝ O) ₂ —NH ₂ ), a mesyl group, a sulfonyl group such as a tosyl group ( A group having —S (＝ O) ₂ —);
Unsubstituted amino group; linear group having 1 to 20 carbon atoms such as methylamino group, dimethylamino group, diethylamino group, ethylmethylamino group, methylpropylamino group, di-t-butylamino group, diphenylamino group and the like. Or a monovalent or disubstituted amino group having a branched alkyl group or an aryl group having 6 to 20 carbon atoms;
A silyl group having 0 to 20 carbon atoms such as an unsubstituted silyl group, —SH ₃ , trimethylsilyl group, t-butyldimethylsilyl group;
Methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, pentyl, n-hexyl, isohexyl, heptyl, n-octyl, t- An octyl group, an isooctyl group, a nonyl group, a linear or branched alkyl group having 1 to 20 carbon atoms such as a decyl group;
A cycloalkyl group having 3 to 20 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, a cyclododecyl group;
Vinyl group, 1-propenyl group, allyl group, 1-butenyl group, 2-butenyl group, 1-pentenyl group, 1-hexenyl group, isopropenyl group, isobutenyl group, or the number of carbon atoms to which a plurality of these alkenyl groups are bonded 2 to 20 linear or branched alkenyl groups;
An ethynyl group or a group having 2 to 20 carbon atoms to which a plurality of “—C≡C—” are bonded;
A linear or branched alkoxy group having 1 to 20 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, a t-butoxy group, an n-pentyloxy group, an n-hexyloxy group;
A cycloalkoxy group having 3 to 20 carbon atoms such as a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group;
Formyl group, acetyl group, propionyl group, acrylyl group, acyl group having 1 to 20 carbon atoms such as benzoyl group, phenyl group, naphthyl group, anthryl group, phenanthryl group, pyrenyl group, triphenylenyl group, indenyl group, fluorenyl group and the like An aromatic hydrocarbon group having 6 to 20 carbon atoms;
Pyridyl, pyrimidinyl, triazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, quinolyl, isoquinolyl, naphthyridinyl, indolyl, benzimidazolyl, carbazonyl , Carbolinyl, acridinyl, phenanthrolinyl, phenanthridinyl, hydantoin, furanyl, benzofuranyl, dibenzofuranyl, pyranyl, coumarinyl, isobenzofuranyl, xanthenyl, oxanthrenyl , Pyranonyl group, thienyl group, thiopyranyl group, benzothienyl group, dibenzothienyl group, thioxanthenyl group, oxazolyl group, benzoxazolyl group, morpholinyl group, thiazolyl group, benzothia A heterocyclic group having 2 to 20 carbon atoms, such as Lil group;
3 to 3 carbon atoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, (1,3- or 1,4-) cyclohexadienyl, 1,5-cyclooctadienyl, etc. 20 cyclic olefin groups; and the like. Only one of these “substituents” may be included, or a plurality thereof may be included, and when a plurality is included, they may be the same or different from each other. Further, these "substituents" may have the substituents exemplified above, and further, these substituents are mutually bonded via a single bond, a substituted or unsubstituted methylene group, an oxygen atom or a sulfur atom. To form a ring.

In the general formula (1-1), R ¹ represents —H, a linear or branched alkyl group having 0 to 20 carbon atoms which may have a substituent, or a substituent. A linear or branched alkenyl group having 2 to 20 carbon atoms which may be preferable.

In the general formula (1-1), R ² and R ^{3 each} represent —H, a thio group having 0 to 20 carbon atoms which may have a substituent, or a carbon atom which may have a substituent. A linear or branched alkyl group having 0 to 20 or a linear or branched alkenyl group having 2 to 20 carbon atoms which may have a substituent is preferable.

In the general formula (1-1), R ^{1 to} R ³ may be bonded to each other by adjacent groups to form a ring, and when forming a ring, the group is a 5- or 6-membered ring Is preferred.

In the general formula (1-1), m represents a methylene group, the number of R ² and R ³ bonded to the methylene group, represents an integer of 1 to 6, preferably 1 or 2, and is preferably 1. Is more preferred.

  In the general formula (1-1), “M” represents a hydrogen atom or an alkali metal atom such as a lithium atom, a sodium atom, a potassium atom, a rubidium atom, and a cesium atom, and is preferably a sodium atom.

Next, the compound represented by Formula (1-2) will be described. In the general formula (1-2), represented by X and Y,
"Optionally substituted thio group having 0 to 20 carbon atoms",
"A linear or branched alkenyl group having 2 to 20 carbon atoms which may have a substituent",
"A linear or branched alkoxy group having 1 to 20 carbon atoms which may have a substituent",
The “optionally substituted heterocyclic group having 2 to 20 carbon atoms” or the “optionally substituted aryloxy group having 6 to 20 carbon atoms” is
In the general formula (1-1), it has the same meaning as each of the groups represented by R ^{1 to} R ³ .

  Specific examples of the compound represented by the general formula (1-2) include phosgene, diphosgene, bis (trichloromethyl) carbonate (or triphosgene), carbonyldiimidazole, 4-nitrophenyl chloroformate, and the like. It is not limited to these. Specific structures include, but are not limited to, compounds represented by the following formulas.

In the general formula (1-2), X and Y are preferably —OCCl ₃ . Further, the compound represented by the general formula (1-2) is preferably bis (trichloromethyl) carbonate or triphosgene.

  In the synthesis method using the flow reactor of the present invention, a synthesis method in which the substance contained in the raw material solution is a compound represented by the general formulas (1-1) and (1-2) will be described with reference to FIG. This will be described in detail below. FIG. 3 is a schematic diagram showing a synthesis example of a specific compound based on FIG. 1 or FIG. 2 illustrating the flow reactor 100 of the present invention.

  In FIG. 3, as a raw material solution (1-1), a compound (such as a sodium salt of an amino acid) (1 equivalent) and a base (1 equivalent or more) represented by the general formula (1-1) are mixed with a solvent 1 (for example, The raw material solution (1-1) dissolved in water) is referred to as a “basic solution that has been previously adjusted to pH 7-14”. This “basic solution” is injected at a flow rate suitable for the reaction using the raw material solution supply device 11. At the same time, as a raw material solution (1-2), a compound represented by the general formula (1-2) (for example, phosgene and a phosgene equivalent) (1 equivalent or more in terms of phosgene) is added to a solvent 2 (for example, an organic solvent). The raw material solution (1-2) dissolved in (1) is injected using the raw material solution supply device 12 at a flow rate suitable for the reaction. At this time, the flow rates of both raw material solutions are adjusted to flow rates that are stoichiometrically suitable for the reaction between the raw materials in the solutions. The flow rate of the raw material solution or the solvent to be diluted after the start of the mixing of the raw material solution in the present invention is different depending on the shape of the flow path of the flow reactor. The pressure may be between 0.1 and 50 mL / min, preferably 0.3 to 10 mL / min. Thus, when the raw material solution (1-1) and the raw material solution (1-2) are introduced into the mixer 20, the two kinds of solutions are mixed and the synthesis is started.

Subsequently, the reaction in the liquid feed pipe 21 through the outlet of the mixer 20 from the start of mixing in the mixer 20 is divided into three stages (steps 1 to 3 in FIG. 3). Hereinafter, for a simple explanation of each step, as shown in FIG. 3, in the general formula (1-1), R ¹ = R ³ = H and M = Na, and in the general formula (1-2), Describes an example of phosgene (or phosgene equivalent) where X = Y = Cl.
In step 1 (s1) immediately after mixing, the most nucleophilic carboxy group (—COO ⁻ ) attacks phosgene and phosgene equivalent first, followed by the amino group (—NH ₂ ) with phosgene and phosgene equivalent. To give the desired NCA and one equivalent of the hydrochloride salt of the base.
Next, in step 2 (s2), the phosgene and the phosgene equivalent added in excess will now react with water and decompose to produce hydrogen chloride. The remaining base reacts with hydrogen chloride and eventually all the base is consumed.
In the subsequent step 3 (s3), the generated hydrogen chloride remains free in the reaction solution, so that the reaction solution becomes acidic. This suppresses unwanted polymerization and hydrolysis of NCA under basic conditions. In this way, a compound represented by the general formula (2) such as NCA having the desired structure can be obtained.

  Also, the synthesized liquid containing NCA (the liquid after the above three steps is referred to as a reaction solution) contains water, an organic solvent, and hydrogen chloride, but if the organic solvent dissolves hydrogen chloride well. If the NCA has a functional group that is unstable under acidic conditions, this may be impaired. To prevent this, as shown in the flow reactor diagram of FIG. 2, the mixer 30 is connected to the end of the liquid feed pipe 21, and the reaction solution and the acid are supplied from the raw material supply source 22 through the liquid feed pipe 220 to the mixer 30. It is preferable to introduce a suitable solvent such as an organic solvent having low solubility and dilute it instantaneously in the mixer 30 to reduce the acid concentration in the organic layer. The compound represented by the general formula (2) can be obtained in higher yield.

  Specific examples of the compound represented by the general formula (2) obtained by the synthesis method of the present invention are shown below, but are not limited thereto. These include all possible structural isomers and stereoisomers, and some hydrogen atoms are omitted in the following structural formulas.

  Hereinafter, the present invention will be described specifically with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.

[Example 1]
<Assembly of micro flow reactor>
As an example of the flow reactor 100 as shown in FIG. 2, a micro flow reactor was assembled as follows. The gas tight syringe 11 as the raw material solution (1-1) supply device and the inlet of the mixer 20 were connected by a PTFE resin liquid supply pipe 110 and a stainless steel liquid supply pipe 110 (for controlling the temperature of the solution). Similarly, the gas tight syringe 12 as the supply source of the raw material solution (1-2) and the other inlet of the mixer 20 are connected to the PTFE resin liquid supply pipe 120 and the stainless steel liquid supply pipe 120 (temperature control of the solution). Connection). The outlet of the mixer 20 and the inlet of the mixer 30 were connected by a reaction tube 21 (made of PTFE resin), and the outlet of the mixer 30 and the back pressure valve were connected by a reaction tube 31. Each mixer and reaction tube were immersed in a water bath for temperature control.
Details of each part of the flow reactor are as follows.
Mixer: Micro mixer (Made by Sanko Seiki Co., Ltd., stainless steel, inner diameter: 0.25 mm)
Liquid sending tube or reaction tube: PTFE tube (manufactured by Senshu Chemical Co., Ltd. (inner diameter: 0.25 mm or 0.80 mm); PEEK union, stainless steel tube, stainless steel fitting, stainless steel union (inner diameter: 0.1 mm) 80 mm) and back pressure valve (40 psi (GL Science Co., Ltd.)
Raw material solution supply device (for solution introduction): syringe pump (manufactured by Harvard, PHD ULTRA and PHD2000), gas tight syringe (manufactured by SGE, 10 mL), gas tight syringe-PTFE tube connection connector (manufactured by Flon Industrial Co., Ltd.)

<Flow synthesis of NCA>
<Synthesis of L-phenylalanine-NCA (Formula (2a))>
As a raw material solution (1-1), an aqueous solution of a sodium salt of a free amino acid (L-phenylalanine) (0.50 M, 1.00 equivalent) and N-methylmorpholine (2.25 M, 4.50 equivalent) (flow rate: 2 .40 mL / min) and a triphosgene (0.25 M, 1.00 equivalent) solution (solvent: acetonitrile) (4.80 mL / min) as a raw material solution (1-2) in a water bath controlled at 20 ° C. Was introduced into the mixer 20 by a syringe pump and mixed. The mixed solution is passed through a reaction tube 21 (inner diameter: 0.25 mm, length: 244 mm, volume: 12.0 μL, reaction time: 0.10 sec) immersed in a water bath controlled at 20 ° C. react. The mixed solution and ethyl acetate (flow rate: 2.40 mL / min) are introduced by a syringe pump into a mixer 30 immersed in a water bath controlled at 20 ° C., and an ethyl acetate solvent is injected into the mixed solution. And diluted. The diluted solution was passed through a reaction tube 31 (inner diameter: 0.80 mm, length: 298 mm, volume: 150 μL, reaction time: 0.94 seconds) immersed in a water bath controlled at 20 ° C. And collected as a reaction solution in a flask containing 40 mL of ethyl acetate and cooled to 0 ° C. The reaction solution was collected 20 seconds after the start of the operation of the syringe pump and after the steady state was reached, and was collected for 100 seconds.
Only the organic layer of the obtained two-layer mixture was separated and collected, and the organic layer extracted from the aqueous layer with ethyl acetate was further mixed. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated at 10 ° C. to obtain a product, L-phenylalanine-NCA (formula (2a)).

In addition, the structural analysis and the purity evaluation of the product synthesized in the examples of the present invention were performed by the following measurements. Melting point measurement, nuclear magnetic resonance analysis ( ¹ H-NMR, ¹³ C-NMR, model number: AVANCE III HD 500 manufactured by Bruker), infrared spectroscopy (IR, model number: Fourier transform infrared spectrophotometer manufactured by JASCO Corporation) (FT-IR) FT / IR-4100, infrared-total reflection measurement (ATR, model number: ATR PRO ONE)), optical rotation analysis (model number: Polarimeter Autopol IV manufactured by Rudolf Research Analytical), mass spectrometry ( MS, model number: Bruker Co., Ltd. Electrospray ionization high-resolution mass spectrometry (HRMS) apparatus (ESI-TOF-MS), model number: micrOTOF II), high performance liquid chromatography analysis (HPLC, model number: Shimadzu Corporation LC-) 10AT VP, SPD-10A VP, CTO-20A, SCL-10A VP). When impurities other than the target substance were observed by NMR measurement, purification was performed by a recrystallization operation using an appropriate solvent.

About the collected L-phenylalanine-NCA (the following formula (2a)), a purification method and an analysis result for identification are shown below. Table 1 shows the yield of L-phenylalanine-NCA obtained in Example 1.
Purification method: liquid separation operation; yield: 400 mg, 2.09 mmol, quant. , White solid;
Melting point: 88-89 ° C;
IR (ATR method): (cm ^-1 ) 3258, 1833, 1769, 1364, 1295, 1116, 917, 755.
[Α] ³¹ _D = -97.5 (c 1.05, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 7.34-7.27 (m, 3H), 7.17-7.16 (m, 2H), 6.62 (brs, 1H), 4 .52 (dd, J = 4.4, 7.5 Hz, 1H), 3.22 (dd, J = 4.4, 14.2 Hz, 1H), 3.01 (dd, J = 7.5, 14) .2Hz, 1H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 169.1, 152.4, 133.9, 129.4, 129.2, 128.0, 59.0, 37.7.

[Examples 2 and 3]
L-phenylalanine-NCA was synthesized in the same manner as in Example 1, except that the flow rate of the sodium salt of free amino acid / aqueous solution of N-methylmorpholine was changed to 1.8 mL / min and 1.2 mL / min. Table 1 also shows the yield.

[Example 4]
L-phenylalanine was prepared in the same manner as in Example 1 except that the solvent of the solution in which triphosgene was dissolved was changed from acetonitrile to tetrahydrofuran, and the flow rate of the sodium salt of free amino acid / aqueous N-methylmorpholine solution was set to 1.2 mL / min. -NCA was synthesized. Table 1 also shows the yield.

  As is clear from Table 1, the result using a solvent such as acetonitrile or tetrahydrofuran can synthesize L-phenylalanine-NCA in a high yield. In particular, in the case of an acetonitrile solvent, a higher yield is obtained. Was.

[Examples 5 to 10]
X was the equivalent of triphosgene, Y was the equivalent of the base, and a comparison was made of various bases having different acid dissociation constants (pK _a ) (water, 25 ° C.). Table 2 shows the results.

[Comparative Example 1]
<Synthesis of L-phenylalanine-NCA (formula (2a)) by a batch synthesis method>
An NCA represented by the following formula (2a) was synthesized by a batch-type synthesis method represented by the following formula (4). The method is described below. L-Phenylalanine sodium salt (the following formula (1a)) (0.50 M, 1.00 equivalent (eq.)) Under strong stirring (magnetic stirrer, 1000 rpm), N-methylmorpholine (NMM) (2.25 M, A solution of triphosgene (0.250 M, 1.0 eq.) In acetonitrile (MeCN) (2.00 mL) was added to an aqueous solution of .50 eq. (Eq.) (1.00 mL) under an argon atmosphere. C. at once. After stirring at 20 ° C. for 10 seconds (the reaction time is 0.1 second in the corresponding flow synthesis, but it is impossible to realize this operation in a batch-type reaction, so that it was set to 10 seconds). (0.00M, 10.0 equiv) in dichloromethane (DCM) (1.00 mL) at 20 ° C. Thereafter, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride were added, and after liquid separation, the aqueous layer was extracted twice with DCM. The obtained organic layer was dried over sodium sulfate and filtered to obtain a compound represented by the following formula (3a).

The identification analysis results of L-phenylalanine-NCA (formula (2a)) recovered by the above-mentioned batch-type synthesis method are shown below. The results of the yield are also shown in Table 2.
IR (neat): (cm < ^-1 >) 3299, 2972, 1651, 1524, 1455, 1366, 1173, 745, 702.
[Α] ³¹ _D = −48.9 (c 1.10, CH ₂ Cl ₂ ).
_{^{1 H NMR (500MHz, CDCl 3}} ): δ (ppm) 7.33-7.28 (m, 2H), 7.24-7.20 (m, 3H), 7.08 (brd, J = 7. 0 Hz, 1H), 4.08-4.01 (m, 1H), 3.54 (dd, J = 4.0, 9.0 Hz, 1H), 3.20 (dd, J = 4.0, 13 0.5 Hz, 1H), 2.71 (dd, J = 9.0, 13.5 Hz, 1H), 1.39 (brs, 2H), 1.11 (d, J = 6.5 Hz, 6H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 173.1, 137.8, 129.2, 128.4, 126.6, 56.2, 41.0, 40.6, 22.6, 22.6 22.5.
HRMS (ESI-TOF-MS): calcd. _{for [C 12 H 18 N 2} O + H] + 207.1492, found 207.1487.

From the results in Table 2, when the flow reactor of the present invention was used, reproducible yields of 60% or more were obtained with various bases. In particular, it was found that L-phenylalanine-NCA was obtained in high yield when triphosgene was 1.0 and N-methylmorpholine was 4.5 equivalents.
On the other hand, when the synthesis was performed by the batch synthesis method, when the synthesis was performed three times, the yield varied from 76 to 94%, and a highly reproducible result could not be obtained. This is because a slight difference in the mixing operation in the two-layer reaction also affects the reaction performance, and it is extremely difficult to carry out this reaction in a batch reaction with good reproducibility.

[Example 11]
<Synthesis of O-benzyl-L-serine-NCA (Formula (2b))>
A flow synthesis was performed in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to O-benzyl-L-serine, to obtain O-benzyl-L-serine-NCA represented by the following formula (2b). Obtained. The purification method and the results of the identification analysis are shown below.
Purification method: liquid separation operation and recrystallization yield: 370 mg (1.67 mmol), yield 84%, white solid; melting point 69-70 ° C.
IR (ATR method): (cm < ^-1 >) 3178, 2859, 1845, 1747, 1357, 1292, 1098, 921, 740.
[Α] ³² _D = -32.1 (c 1.11, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 7.39-7.28 (m, 5H), 5.89 (brs, 1H), 4.60-4.54 (m, 2H), 4 .44 (dd, J = 3.0, 5.5 Hz, 1H), 3.79-3.73 (m, 2H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 167.7, 152.6, 136.7, 128.8, 128.4, 128.0, 73.8, 67.9, 58.5.

[Example 12]
<Synthesis of O-benzyl-L-threonine-NCA (Formula (2c))>
A flow synthesis was carried out in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to O-benzyl-L-threonine, to obtain O-benzyl-L-threonine-NCA represented by the following formula (2c). Obtained. The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation yield: 473 mg, 2.01 mmol, quant. , White solid; mp 120-121 ° C.
IR (ATR method): (cm < ^-1 >) 3260,1852,1744,1252,1090,923,660.
[Α] ²⁶ _D = −68.5 (c 1.04, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 7.36-7.26 (m, 5H), 6.73 (brs, 1H), 4.61 (d, J = 11.5 Hz, 1H). , 4.43 (d, J = 11.5 Hz, 1H), 4.18 (d, J = 4.5 Hz, 1H), 3.94-3.89 (m, 1H), 1.33 (d, J = 6.0 Hz, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 167.8, 152.9, 137.0, 128.7, 128.3, 128.0, 73.2, 71.4, 63.0, 16.1.

Example 13
<Synthesis of S-benzyl-L-cysteine-NCA (Formula (2d))>
A flow synthesis was carried out in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to S-benzyl-L-cysteine, to give S-benzyl-L-cysteine-NCA represented by the following formula (2d). Obtained. The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation Yield: 491 mg, 2.07 mmol, quant. White solid; mp 100-101 ° C.
IR (ATR method): (cm < ^-1 >) 3299,1793,1291,1122,1077,928,753,713.
[Α] ²³ _D = -63.0 (c 1.28, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 7.36-7.26 (m, 5H), 6.42 (brs, 1H), 4.31 (dd, J = 3.6,7. 1 Hz, 1 H), 3.76 (s, 2 H), 2.95 (dd, J = 3.6, 14.5 Hz, 1 H), 2.77 (dd, J = 7.1, 14.5 Hz, 1 H ).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 168.2, 152.2, 137.2, 129.1, 129.0, 127.9, 57.8, 37.2, 32.8.

[Example 14]
<Synthesis of Sarcosine-NCA (Formula (2e))>
Flow synthesis was performed in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to sarcosine to obtain sarcosine-NCA represented by the following formula (2e). The purification method and the results of the identification analysis are shown below.
Purification method: separation operation and recrystallization yield: 186 mg, 1.62 mmol, yield 81%, white solid; melting point 95-96 ° C (decomposition).
IR (ATR method): (cm ^-1 ) 2968, 1847, 1557, 1444, 1401, 1274, 1218, 984, 902, 748.
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 4.13 (s, 2H), 3.06 (s, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 165.3, 152.4, 51.1, 30.5.

[Example 15]
<Synthesis of L-proline-NCA (Formula (2f))>
Flow synthesis was performed in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to L-proline, to obtain L-proline-NCA represented by the following formula (2f). The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation and recrystallization yield: 240 mg, 1.70 mmol, 85% yield, white solid; melting point 44-46 ° C.
IR (ATR method): (cm ^-1 ) 2912, 1822, 1765, 1363, 1326, 950, 919, 760.
[Α] ³³ _D = −100.9 (c 1.11, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 4.35 (dd, J = 7.8, 9.0 Hz, 1H), 3.82-3.76 (m, 1H), 3.36 − 3.31 (m, 1H), 2.36-2.30 (m, 1H), 2.26-2.19 (m, 1H), 2.18-2.09 (m, 1H), 2. 00-1.92 (m, 1H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 168.9, 155.0, 63.2, 46.7, 27.8, 27.0.

[Example 16]
<Synthesis of Glycine-NCA (Formula (2g))>
Glycine-NCA represented by the following formula (2g) was obtained in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to glycine. The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation and recrystallization yield: 132 mg, 1.31 mmol, yield 65%; yellow-white solid; melting point> 200 ° C.
IR (ATR method): (cm < ^-1 >) 3256, 1856, 1732, 1644, 1275, 1071, 930, 720, 637.
¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 8.83 (brs, 1H), 4.19 (s, 2H).
¹³ C NMR (125 MHz, DMSO-d ₆ ): δ (ppm) 169.4, 153.0, 46.3.

[Example 17]
<Synthesis of L-alanine-NCA (Formula (2h))>
Flow synthesis was performed in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to L-alanine, to obtain L-alanine-NCA represented by the following formula (2h). The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation Yield: 190 mg, 1.65 mmol, yield 83%, white solid; melting point 85-86 ° C.
IR (ATR method): (cm ^-1 ) 3324, 1832, 1763, 1359, 1281, 1142, 926, 742.
[Α] ²³ _D = +3.8 (c 1.05, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 9.00 (brs, 1H), 4.50-4.45 (m, 1H), 1.33 (d, J = 7.0 Hz, 3H).
¹³ C NMR (125 MHz, DMSO-d ₆ ): δ (ppm) 172.5, 151.8, 52.9, 16.8.

[Example 18]
<Synthesis of L-valine-NCA (Formula (2i))>
Flow synthesis was carried out in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to L-valine to obtain L-valine-NCA represented by the following formula (2i). The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation and recrystallization yield: 244 mg, 1.71 mmol, 86% yield, white solid; melting point 62-63 ° C (decomposition).
IR (ATR method): (cm < ^-1 >) 3288, 2974, 1838, 1748, 1368, 1255, 1112, 1084, 938, 753.
[Α] ³¹ _D = −45.5 (c 1.07, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 6.48 (brs, 1H), 4.22 to 4.21 (m, 1H), 2.29 to 2.21 (m, 1H), 1 0.09 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 168.8, 153.0, 63.2, 30.9, 18.4, 16.7.

[Example 19]
<Synthesis of L-leucine-NCA (Formula (2j))>
The flow synthesis was performed in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to L-leucine, and the reaction solution recovery time was changed to 1335 seconds. I got The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation and recrystallization yield: 3.81 g, 24.2 mmol, 91% yield, white solid; melting point 69-71 ° C.
IR (ATR method): (cm < ^-1 >) 3288, 2965, 1814, 1749, 1474, 1369, 1291, 935, 616.
[Α] ³³ _D = −45.6 (c 1.00, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 6.59 (brs, 1H), 4.34 (dd, J = 3.7, 8.8 Hz, 1H), 1.87-1.78 ( m, 2H), 1.72-1.65 (m, 1H), 1.01 (d, J = 6.4 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 170.0, 152.7, 56.3, 41.0, 25.2, 22.8, 21.7.

[Example 20]
<Synthesis of L-isoleucine-NCA (Formula (2k))>
Flow synthesis was performed in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to L-isoleucine, to obtain L-isoleucine-NCA represented by the following formula (2k). The results of the identification analysis are shown below.
Yield: 322 mg, 2.05 mmol, quant. , White solid; mp 67-68 ° C.
IR (ATR method): (cm < ^-1 >) 3276, 2969, 1847, 1761, 1355, 1311, 1230, 915, 759.
_{^{[Α] 23 D = -29.7 (}} c 1.15, CH 2 Cl 2).
¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 9.08 (s, 1H), 4.39 (d, J = 4.0 Hz, 1H), 1.82-1.78 (m, 1H), 1.39-1.31 (m, 1H), 1.26-1.17 (m, 1H), 0.92 (d, J = 6.9 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H).
¹³ C NMR (125 MHz, DMSO-d ₆ ): δ (ppm) 170.9, 152.2, 61.8, 36.5, 23.9, 14.8, 11.3.

[Example 21]
<Synthesis of L-methionine-NCA (Formula (2l))>
Flow synthesis was carried out in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to L-methionine, to obtain L-methionine-NCA represented by the following formula (21). The results of the identification analysis are shown below.
Purification method: Separation operation Yield: 379 mg, 2.16 mmol, quant. , Yellow oil.
IR (neat): (cm < ^-1 >) 3319, 1853, 1781, 1271, 1099, 919, 758.
[Α] ²⁴ _D = -2.4 (c 0.83, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 7.12 (brs, 1H), 4.54-4.52 (m, 1H), 2.69 (t, J = 7.0 Hz, 2H). , 2.30-2.24 (m, 1H), 2.16-2.10 (m, 4H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 169.9, 152.9, 56.7, 30.2, 29.9, 15.2.

[Example 22]
<Synthesis of Ot-butyldimethylsilyl-L-serine-NCA (Formula (2o))>
Flow synthesis was carried out in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to Ot-butyldimethylsilyl-L-serine, and the reaction liquid recovery time was changed to 50 seconds. The indicated Ot-butyldimethylsilyl-L-serine-NCA was obtained. The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation Yield: 233 mg, 0.951 mmol, 95% yield, white solid; melting point 80-81 ° C.
IR (ATR method): (cm < ^-1 >) 3284, 2928, 2856, 1859, 1750, 1258, 1098, 895.
[Α] ²⁵ _D = -42.5 (c 1.13, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 6.42 (brs, 1H), 4.38 (t, J = 3.0 Hz, 1H), 4.01 (dd, J = 3.0, 11.0 Hz, 1H), 3.89 (dd, J = 3.0, 11.0 Hz, 1H), 0.88 (s, 9H), 0.08 (s, 6H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 168.1, 153.2, 61.9, 60.4, 25.7, 18.2, -5.4, -5.6.
HRMS (ESI-TOF-MS): calcd. for [C ₁₀ H ₁₉ NO ₄ Si + Na] ⁺ 268.0976, found 268.0994.

[Example 22]
<Synthesis of Ot-butyl-L-tyrosine-NCA (Formula (2p))>
Flow synthesis was carried out in the same manner as in Example 1 except that the free amino acid of Example 1 was changed to Ot-butyl-L-tyrosine, and Ot-butyl-L- represented by the following formula (2p) was obtained. Tyrosine-NCA was obtained. The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation Yield: 544 mg, 2.06 mmol, quant. , White solid; mp 110-111 ° C.
IR (ATR method): (cm < ^-1 >) 3272, 2975, 1853, 1742, 1506, 1366, 1159, 898, 753.
[Α] ²³ _D = -90.3 (c 1.21, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 9.05 (s, 1H), 7.08 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8. 5 Hz, 2H), 4.74 (t, J = 4.5 Hz, 1H), 2.98 (d, J = 4.5 Hz, 2H), 1.27 (s, 9H).
¹³ C NMR (125 MHz, DMSO-d ₆ ): δ (ppm) 170.9, 154.1, 151.6, 130.2, 129.3, 123.5, 77.8, 58.3, 35. 6,28.5.

[Example 23]
<Synthesis of L-aspartic acid-4-t-butyl ester-NCA (Formula (2q))>
A flow synthesis was carried out in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to L-aspartic acid-4-t-butyl ester, and L-aspartic acid-4 represented by the following formula (2q) was obtained. -T-Butyl ester-NCA was obtained. The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation Yield: 506 mg, 2.35 mmol, quant. , White solid; mp 137-139 ° C.
IR (ATR method): (cm ^-1 ) 3277,1750,1717,1368,1234,1157,1100,947,903,751.
_{^{[Α] 23 D = -59.7 (}} c 1.07, CH 2 Cl 2).
¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 8.98 (s, 1H), 4.61 (t, J = 4.0 Hz, 1H), 2.91 (dd, J = 4. 0, 17.5 Hz, 1H), 2.67 (dd, J = 4.0, 17.5 Hz, 1H), 1.38 (s, 9H).
¹³ C NMR (125 MHz, DMSO-d ₆ ): δ (ppm) 171.1, 168.2, 152.2, 81.5, 53.8, 35.9, 27.5.

[Example 24]
<Synthesis of L-glutamic acid-5-t-butyl ester-NCA (Formula (2r))>
Flow synthesis was carried out in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to L-glutamic acid-5-t-butyl ester, and the reaction liquid recovery time was set to 95 seconds. L-glutamic acid-5-t-butyl ester-NCA was obtained. The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation and recrystallization yield: 348 mg, 1.52 mmol, 80% yield, white solid; melting point 96-97 ° C.
IR (ATR method): (cm < ^-1 >) 3313, 2981, 1859, 1789, 1696, 1284, 1156, 1098, 924, 587.
[Α] ³¹ _D = −26.9 (c 1.04, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 6.38 (brs, 1H), 4.37-4.35 (m, 1H), 2.47 (t, J = 6.5 Hz, 2H). , 2.29-2.23 (m, 1H), 2.09-2.02 (m, 1H), 1.46 (s, 9H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 172.3, 169.7, 151.5, 82.2, 57.5, 31.5, 28.2, 27.2.

[Example 25]
<Synthesis of Nε- (t-butoxycarbonyl) -L-lysine-NCA (Formula (2u))>
The flow synthesis was carried out in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to Nε- (t-butoxycarbonyl) -L-lysine, and the reaction solution recovery time was changed to 80 seconds. Nε- (t-butoxycarbonyl) -L-lysine-NCA represented by the following formula: was obtained. The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation and recrystallization yield: 440 mg, 1.61 mmol, quant. , White solid; mp 135-136 ° C.
IR (ATR method): (cm < ^-1 >) 3374, 3284, 2949, 1815, 1760, 1687, 1523, 1245, 943, 747.
[Α] ³⁰ _D = −34.7 (c 1.17, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 6.85 (brs, 1H), 4.67 (brs, 1H), 4.32 (dd, J = 4.5, 6.5 Hz, 1H). , 3.18-3.10 (m, 2H), 2.05-2.00 (m, 1H), 1.88-1.81 (m, 1H), 1.57-1.45 (m, 2H) 13H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 170.1, 156.8, 152.2, 80.0, 57.6, 39.5, 30.8, 29.4, 28.6. 21.2.

[Example 26]
<Synthesis of 1-t-butoxycarbonyl-L-tryptophan-NCA (Formula (2v))>
Flow synthesis was carried out in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to 1-t-butoxycarbonyl-L-tryptophan, and the reaction solution recovery time was set to 23 seconds. 1-t-butoxycarbonyl-L-tryptophan-NCA was obtained. The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation yield: 159 mg, 0.482 mmol, quant. , White solid; mp 155-156 ° C.
IR (ATR method): (cm < ^-1 >) 3260, 1854, 1768, 1739, 1362, 1251, 1096, 913, 761.
[Α] ²⁶ _D = −52.2 (c 0.89, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 8.13 (brd, J = 7.5 Hz, 1H), 7.49-7.48 (m, 2H), 7.36-7.33 ( m, 1H), 7.27-7.24 (m, 1H), 6.24 (brs, 1H), 4.57 (dd, J = 3.5, 8.5 Hz, 1H), 3.39 ( dd, J = 3.5, 14.5 Hz, 1H), 3.06 (dd, J = 8.5, 14.5 Hz, 1H), 1.66 (s, 9H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 168.9, 152.0, 149.5, 135.7, 129.4, 125.2, 124.9, 123.1, 118.5. 115.8, 113.2, 84.5, 57.7, 28.3, 28.0.

[Example 27]
<Synthesis of L-allylglycine-NCA (Formula (2w))>
Flow synthesis was carried out in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to L-allylglycine, to obtain L-allylglycine-NCA represented by the following formula (2w). The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation Yield: 264 mg, 1.87 mmol, 94% yield, white solid; melting point 45-46 ° C.
IR (ATR method): (cm ^-1 ) 3288, 1826, 1761, 1363, 1292, 929, 742, 573.
[Α] ²³ _D = -57.9 (c 1.19, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 6.77 (brs, 1H), 5.80-5.71 (m, 1H), 5.30-5.25 (m, 2H), 4 .42 (dd, J = 4.5, 7.0 Hz, 1H), 2.74-2.69 (m, 1H), 2.57-2.51 (m, 1H);
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 169.1, 152.8, 129.9, 121.6, 57.3, 35.9.

[Example 28]
<Synthesis of DL-propargylglycine-NCA (Formula (2x))>
Flow synthesis was performed in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to DL-propargylglycine, to obtain DL-propargylglycine-NCA represented by the following formula (2x). The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation yield: 266 mg, 1.91 mmol, 96% yield, white solid; mp 113-115 ° C.
IR (ATR method): (cm ^-1 ) 3342,3289,1831,1749,1286,929,758.
¹ H NMR (500 MHz, acetone-d ₆ ): δ (ppm) 8.01 (brs, 1H), 4.75-4.73 (m, 1H), 2.84 (dd, J = 3.0, 4.5 Hz, 2H), 2.60 (t, J = 3.0 Hz, 1H).
¹³ C NMR (125 MHz, acetone-d ₆ ): δ (ppm) 170.5, 152.7, 78.2, 73.6, 57.3, 22.2.

[Example 29]
<Synthesis of L- (3,4-acetonide-dihydroxy) phenylalanine-NCA (Formula (2y))>
Flow synthesis was performed in the same manner as in Example 1 except that the free amino acid in Example 1 was changed to L- (3,4-acetonide-dihydroxy) phenylalanine, and the reaction solution recovery time was changed to 25 seconds. L- (3,4-acetonide-dihydroxy) phenylalanine-NCA represented by the following formula was obtained. The purification method and the results of the identification analysis are shown below.
Purification method: Separation operation and recrystallization yield: 106 mg, 0.402 mmol, 80% yield, white solid; melting point 130-132 ° C.
IR (ATR method): (cm < ^-1 >) 3358, 1850, 1766, 1493, 1259, 928, 758, 574.
[Α] ³¹ _D = -97.7 (c 0.894, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 6.69-6.57 (m, 3H), 6.02 (brs, 1H), 4.48-4.47 (m, 1H), 3 .20 (dd, J = 3.0, 14.0 Hz, 1H), 2.89 (dd, J = 9.0, 14.0 Hz, 1H), 1.67 (s, 6H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 168.8, 151.8, 148.3, 147.4, 126.9, 121.9, 118.7, 109.1, 108.8, 59.1, 37.8, 26.0.
HRMS (ESI-TOF-MS): calcd. for [C ₁₃ H ₁₃ NO ₅ + Na] ⁺ 286.0686, found 286.0689.

[Example 30]
<Synthesis of N-τ-trityl-L-histidine-NCA (Formula (2m))>
As a raw material solution (1-1), an aqueous solution of sodium salt of N-τ-trityl-L-histidine (0.20 M, 1.00 equivalent) and N-methylmorpholine (0.90 M, 4.50 equivalent) (flow rate) : 2.40 mL / min) and a solution of triphosgene (0.10 M, 1.00 equivalent) in acetonitrile (flow rate: 4.80 mL / min) as a raw material solution (1-2) in a water bath controlled at 40 ° C. It was introduced into the dipped mixer 20 with a syringe pump and mixed. The mixed solution reacts while passing through a reaction tube 21 (inner diameter: 0.25 mm, length: 244 mm, volume: 12.0 μL, reaction time: 0.10 sec) immersed in a water bath controlled at 40 ° C. I do. The mixed solution and ethyl acetate (flow rate: 2.40 mL / min) are introduced by a syringe pump into a mixer 30 immersed in a water bath controlled at 40 ° C., and an ethyl acetate solvent is injected into the mixed solution. And diluted. The diluted solution is passed through a reaction tube 31 (inner diameter: 0.80 mm, length: 298 mm, volume: 150 μL, reaction time: 0.94 seconds) immersed in a water bath controlled at 40 ° C. And collected as a reaction solution in a flask containing 40 mL of ethyl acetate and cooled to 0 ° C. The reaction solution was collected 20 seconds after the start of the operation of the syringe pump and after a steady state was reached, and then collected for 70 seconds.
N-methylmorpholine (44.0 μL, 0.400 mmol, 0.714 equivalent) was added to the recovered reaction solution at 0 ° C., and only an organic layer was obtained by liquid separation. The organic layer was washed with water and a saturated saline solution, dried over magnesium sulfate, and then concentrated at 10 ° C. to obtain a product N-τ-trityl-L-histidine-NCA (formula (2m)) (yield: 188 mg, 0.444 mmol, 79% yield) as a white solid.

The identification analysis results of the collected L-histidine-NCA (formula (2m) below) are shown below.
Melting point:> 200 ° C.
IR (ATR method): (cm ^-1 ) 3059, 1848, 1781, 1444, 1288, 923, 747, 699.
[Α] ²⁵ _D = −34.6 (c 1.04, CH ₂ Cl ₂ ).
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 7.59 (brs, 1H), 7.38-7.08 (m, 16H), 6.66 (s, 1H), 4.55 (dd) , J = 3.5, 8.0 Hz, 1H), 3.15 (dd, J = 3.5, 15.0 Hz, 1H), 2.97 (dd, J = 8.0, 15.0 Hz, 1H) ).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 170.1, 151.8, 142.2, 139.0, 134.8, 129.8, 128.4, 128.3, 119.8, 75.7, 58.1, 30.1.

[Example 31]
<Synthesis of N-ω-nitro-L-arginine-NCA (Formula (2n))>
As a raw material solution (1-1), an aqueous solution of sodium salt of N-ω-nitro-L-arginine (0.50 M, 1.00 equivalent) and N-methylmorpholine (2.25 M, 4.50 equivalent) (flow rate) : 2.40 mL / min) and a solution of triphosgene (0.25 M, 1.00 equivalent) in acetonitrile (flow rate: 4.80 mL / min) as a raw material solution (1-2) in a water bath controlled at 20 ° C. It was introduced into the dipped mixer 20 with a syringe pump and mixed. The mixed solution is passed through a reaction tube 21 (inner diameter: 0.25 mm, length: 244 mm, volume: 12.0 μL, reaction time: 0.10 sec) immersed in a water bath controlled at 20 ° C. react. The mixed solution and ethyl acetate (flow rate: 2.40 mL / min) are introduced by a syringe pump into a mixer 30 immersed in a water bath controlled at 20 ° C., and ethyl acetate is injected into the mixed solution. Dilution. The diluted solution was passed through a reaction tube 31 (inner diameter: 0.80 mm, length: 298 mm, volume: 150 μL, reaction time: 0.94 seconds) immersed in a water bath controlled at 20 ° C. And collected in a flask containing 40 mL of ethyl acetate and cooled to 0 ° C. The reaction solution was collected for 90 seconds, 20 seconds after the start of the operation of the syringe pump, and after the steady state was reached.
N-methylmorpholine (110 μL, 1.00 mmol, 0.556 equivalent) was added to the recovered solution at 0 ° C., and only an organic layer was obtained by liquid separation. The organic layer was washed with water and a saturated saline solution, dried over magnesium sulfate, and then concentrated at 10 ° C. to obtain N-ω-nitro-L-arginine-NCA (formula (2n)) (yield: 163 mg) , 0.665 mmol, 37% yield) as a white solid.

The identification analysis results of the recovered L-arginine-NCA (Formula (2n) below) are shown below.
Melting point:> 200 ° C.
IR (ATR method): (cm < ^-1 >) 3376, 3309, 3213, 1832, 1770, 1608, 1252, 1108, 926.
[[Alpha]] _D < ²⁵ > = -11.9 (c 0.60, DMF).
¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 9.12 (s, 1H), 8.56 (brs, 1H), 7.88 (brs, 2H), 4.45 (dd, J) = 5.0, 5.5 Hz, 1H), 3.18-3.17 (m, 2H), 1.81-1.58 (m, 4H).
¹³ C NMR (125 MHz, DMSO-d ₆ ): δ (ppm) 171.6, 159.3, 152.0, 63.4, 56.9, 52.5, 28.5.
HRMS (ESI-TOF-MS): calcd. for [C ₇ H ₁₁ N ₅ O ₅ + Na] ⁺ 268.0652, found 268.0660.

[Example 32]
<Synthesis of N-β-trityl-L-asparagine-NCA (Formula (2s))>
As a raw material solution (1-1), a sodium salt of a free amino acid (N-β-trityl-L-asparagine) (0.40 M, 1.00 equivalent) and N-methylmorpholine (1.80 M, 4.50 equivalent) And an acetonitrile solution (flow rate: 4.80 mL / min) of triphosgene (0.25 M, 1.00 equivalent) as a raw material solution (1-2) was controlled at 20 ° C. The mixture was introduced into the mixer 20 immersed in the immersed water bath with a syringe pump and mixed. The mixture reacts while passing through a reaction tube 21 (inner diameter: 0.25 mm, length: 244 mm, volume: 12.0 μL, reaction time: 0.10 sec) immersed in a water bath controlled at 20 ° C. The mixed solution and ethyl acetate (flow rate: 2.40 mL / min) are introduced by a syringe pump into a mixer 30 immersed in a water bath controlled at 20 ° C., and ethyl acetate is injected into the mixed solution. Dilution. The diluted mixture is passed through a reaction tube 31 (inner diameter: 0.80 mm, length: 298 mm, volume: 150 μL, reaction time: 0.94 seconds) immersed in a water bath controlled at 20 ° C. The mixture was passed through a pressure valve and collected as a reaction solution in a flask containing 40 mL of ethyl acetate and cooled to 0 ° C. The reaction solution was collected 20 seconds after the start of the operation of the syringe pump and after a steady state was reached, and then collected for 50 seconds.
Subsequently, only the organic layer was recovered by a liquid separation operation. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated at 10 ° C. to obtain a product N-β-trityl-L-asparagine-NCA (formula (2s)). .

The identification analysis result of the recovered N-β-trityl-L-asparagine-NCA (formula (2s) below) is shown below.
Yield: 310 mg, 0.774 mmol, 97%, white solid; mp> 200 ° C.
IR (ATR method): (cm ^-1 ) 3356, 1858, 1787, 1665, 1507, 1267, 907.
[[Alpha]] _D < ²⁵ > = -4.6 (c 0.62, DMF).
¹ H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) 8.99 (s, 1 H), 8.89 (s, 1 H), 7.28-7.14 (m, 15 H), 4.55 (T, J = 4.0 Hz, 1H), 3.06 (dd, J = 4.0, 16.5 Hz, 1H), 2.75 (dd, J = 4.0, 16.5 Hz, 1H).
¹³ C NMR (125 MHz, DMSO-d ₆ ): δ (ppm) 171.5, 167.8, 152.3, 144.4, 128.5, 127.6, 126.5, 69.6, 53. 9, 36.8.

[Example 33]
<Synthesis of N-ω-trityl-L-glutamine-NCA (Formula (2t))>
Flow synthesis was performed in the same manner as in Example 32, except that the free amino acid in Example 32 was changed to N-ω-trityl-L-glutamine, and the reaction liquid recovery time was changed to 80 seconds. To obtain N-ω-trityl-L-glutamine-NCA represented by the following formula (2t). The results of the identification analysis are shown below.
Yield: 434 mg, 1.05 mmol, 82% yield, white solid;
IR (ATR method): (cm ^-1 ) 3384, 3199, 1850, 1778, 1669, 1489, 915, 754, 700.
[Α] ²⁶ _D = −21.5 (c 1.01, CH ₂ Cl ₂ ).
_{^{1 H NMR (500MHz, DMSO-}} d 6): δ (ppm) 9.06 (s, 1H), 8.68 (s, 1H), 7.29-7.17 (m, 15H), 4.34 (T, J = 6.5 Hz, 1H), 2.48-2.34 (m, 2H), 1.94-1.83 (m, 2H).
¹³ C NMR (125 MHz, DMSO-d ₆ ): δ (ppm) 171.4, 170.6, 151.9, 144.8, 128.5, 127.5, 126.4, 69.4, 69.3, 56. 4,30.8,26.9.

[Example 34]
<Flow synthesis of β-NCA>
<Synthesis of β-phenylalanine-NCA (Formula (2-8i))>
As a raw material solution (1-1), an aqueous solution of sodium salt of free amino acid (β-phenylalanine) (0.25 M, 1.00 equivalent) and N-methylmorpholine (0.63 M, 2.52 equivalent) (flow rate: 2 .40 mL / min) and a triphosgene (0.084 M, 0.67 equivalent) solution (solvent: acetonitrile) (flow rate: 4.80 mL / min) as a raw material solution (1-2) were immersed in a water bath at 20 ° C. The mixture was introduced into the mixer 20 with a syringe pump and mixed. react. The mixed solution and ethyl acetate (flow rate: 2.40 mL / min) are introduced by a syringe pump into a mixer 30 immersed in a water bath controlled at 20 ° C., and an ethyl acetate solvent is injected into the mixed solution. And diluted. The diluted solution was passed through a reaction tube 31 (inner diameter: 0.80 mm, length: 298 mm, volume: 150 μL, reaction time: 0.94 sec) in a water bath at 20 ° C, and then passed through a back pressure valve. The reaction solution was collected in a flask cooled to 0 ° C. in 40 mL of ethyl acetate. The reaction solution was collected 20 seconds after the start of the operation of the syringe pump and after the steady state was reached, and was collected for 100 seconds.
The product β-phenylalanine represented by the following formula (2-8i) is obtained by washing the organic layer of the obtained two-layer mixture with water and saturated saline, drying over magnesium sulfate, and concentrating at 20 ° C. or lower. -NCA was obtained. The purification method and the results of the identification analysis are shown below.

Purification method: Separation operation yield: 127.5 mg, 0.74 mmol, yield 93%, white solid; melting point: 97-99 ° C.
IR (ATR method): (cm < ^-1 >) 3230,3148,1791,1734,1383,1332,1115,1023,977.
¹ H NMR (500 MHz, CD ₃ CN): δ (ppm) 7.42 to 7.39 (m, 2H), 7.37 to 7.33 (m, 3H), 6.94 (brs, 1H), 4.79-4.76 (m, 1H), 3.04 (dd, J = 5.5, 16.5 Hz, 1H), 2.88 (dd, J = 8.0, 16.5 Hz, 1H) .
¹³ C NMR (125 MHz, CD ₃ CN): δ (ppm) 163.9, 150.2, 137.6, 129.6, 129.4, 125.9, 51.0, 37.0.
HRMS (ESI-TOF-MS): calcd. for [C ₆ H ₉ NO ₃ + Na] ⁺ 214.0475, found 214.0476.

  Other β-amino acids in the following Examples were synthesized in the same manner as in Example 34, except that the free amino acids in Example 34 were changed to β-alanine derivatives having a corresponding substituent. The results are shown below together with the purification method and the results of the identification analysis.

[Example 35]
<Synthesis of β-alanine-NCA (Formula (2-8a))>
Purification method: Separation operation Yield: 65.9 mg, 0.57 mmol, yield 57%, white solid, 84-86 ° C decomp. ;
IR (ATR method): (cm < ^-1 >) 3254, 3150, 2929, 1798, 1705, 1344, 1060, 749.
¹ H NMR (500 MHz, CD ₃ CN): δ (ppm) 6.49 (brs, 1H), 3.33-3.30 (m, 2H), 2.71 (t, J = 7.0 Hz, 2H) ).
¹³ C NMR (125 MHz, CD ₃ CN): δ (ppm) 167.3, 150.8, 35.6, 29.1.
HRMS (ESI-TOF-MS): calcd. _{for [C 5 H 7 NO 3} + Na] + 138.0162, found 138.0161.

[Example 36]
<Synthesis of β-homoalanine-NCA ((2-8b))>
Purification method: Separation operation Yield: 56.4 mg, 0.44 mmol, 69% yield, white solid, 92-95 ° C deconp.
IR (ATR method): (cm ^-1 ) 3154, 2975, 1807, 1714, 1386, 1331, 1106, 995, 595.
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 6.95 (brs, 1H), 3.79-3.78 (m, 1H), 2.87 (dd, J = 4.0, 16. 0 Hz, 1H), 2.53 (dd, J = 9.5, 16.0 Hz, 1H), 1.35-1.34 (d, J = 6.5 Hz, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 164.5, 150.4, 42.9, 36.2, 20.7.

[Example 37]
<Synthesis of α-methyl-β-alanine-NCA (Formula (2-8c))>
Purification method: Separation operation Yield: 86.1 mg, 0.67 mmol, 67% yield, white solid; mp 112-114 ° C.
IR (ATR method): (cm < ^-1 >) 3280, 2338, 1792, 1734, 1642, 1354, 1077, 973, 598.
¹ H NMR (500 MHz, CD ₃ CN): δ (ppm) 6.58 (brs, 1H), 3.34-3.29 (m, 1H), 3.06 (t, J = 12.0 Hz, 1H). ), 2.87-2.79 (m, 1H), 1.16 (d, J = 4.3 Hz, 3H).
¹³ C NMR (125 MHz, CD ₃ CD): δ (ppm) 169.5, 150.0, 41.0, 33.6, 11.5.
HRMS (ESI-TOF-MS): calcd. _{for [C 5 H 7 NO 3} + Na] + 152.0318, found 152.0317.

[Example 38]
<Synthesis of N-methyl-β-alanine-NCA (Formula (2-8d))>
Purification method: Separation operation Yield: 62.5 mg, 0.48 mmol, 48% yield, colorless oil.
IR (neat): (cm < ^-1 >) 3500, 2935, 1796, 1731, 1356, 1152, 1097, 710.
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 3.47 (t, J = 6.5 Hz, 2H), 3.12 (s, 3H), 2.87 (t, J = 6.5 Hz, 2H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 164.9, 149.5, 42.9, 36.6, 29.4.
HRMS (ESI-TOF-MS): calcd. _{for [C 5 H 7 NO 3} + Na] + 152.0318, found 152.0318.

[Example 39]
<Synthesis of α-dimethyl-β-alanine-NCA (Formula (2-8e))>
Purification method: Separation operation yield: 106.2 mg, 0.74 mmol, 74% yield, white solid; melting point: 110-112 ° C.
IR (ATR method): (cm < ^-1 >) 3258, 3162, 2987, 1794, 1733, 1338, 1051, 961, 697.
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 7.06 (brs, 1H), 3.22 (d, J = 2.0 Hz, 2H), 1.36 (s, 6H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 170.5, 151.0, 47.7, 37.0, 22.6.
HRMS (ESI-TOF-MS): calcd. for [C ₆ H ₉ NO ₃ + Na] ⁺ 166.0475, found 166.0474.

[Example 40]
<Synthesis of β-homovaline-NCA (Formula (2-8f))>
Purification method: Separation operation yield: 86.2 mg, 0.67 mmol, 85% yield, white solid; melting point: 69-72 ° C.
IR (ATR method): (cm < ^-1 >) 3224, 2972, 2941, 1791, 1723, 1396, 1336, 1069, 966.
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 7.19 (brs, 1H), 3.45-3.41 (m, 1H), 2.82 (dd, J = 5.0, 16. 0 Hz, 1H), 2.64 (dd, J = 8.0, 16.0 Hz, 1H), 1.87-1.82 (m, 1H), 1.00 (t, J = 7.5 Hz, 6H) ).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 165.1, 150.9, 52.4, 32.1, 31.6, 17.9, 17.8.

[Example 41]
<Synthesis of β-homoleucine-NCA (Formula (2-8g))>
Purification method: Separation operation yield: 127.5 mg, 0.74 mmol, 98%, white solid; melting point: 63-65 ° C.
IR (ATR method): (cm ^-1 ) 3270, 2959, 1797, 1721, 1389, 1329, 1120, 1012, 977.
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 7.29 (s, 1 H), 3.69 (brs, 1 H), 2.88 (dd, J = 4.5, 16.0 Hz, 1 H). , 2.55 (dd, J = 8.0, 16.0 Hz, 1H), 1.78-1.70 (m, 1H), 1.57-1.52 (m, 1H), 1.39- 1.35 (m, 1H), 0.95 (d, J = 4.5 Hz, 6H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 164.8, 150.7, 45.7, 43.8, 34.7, 24.2, 22.5, 22.0.

[Example 42]
<Synthesis of β-homophenylalanine-NCA (Formula (2-8h))>
Purification method: Separation operation Yield: 208.6 mg, 1.02 mmol, quant. , White solid; melting point: 97-99 [deg.] C.
IR (ATR method): (cm ^-1 ) 3306, 1794, 1721, 1387, 1341, 1087, 982, 745, 695.
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 7.35-7.17 (m, 5H), 6.77 (brs, 1H), 3.86-3.83 (m, 1H), 2 .91-2.80 (m, 3H), 2.61 (dd, J = 8.0, 16.5 Hz, 1H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 164.4, 150.1, 134.8, 129.3, 129.2, 127.7, 48.1, 41.2, 33.7.

[Example 43]
<Synthesis of β-Torunylalanine-NCA (Formula (2-8j))>
Purification method: Separation operation Yield: 202.6 mg, 0.99 mmol, 99% yield, white solid; melting point: 119-120 ° C.
IR (ATR method): (cm < ^-1 >) 3253, 3165, 2933, 1792, 1741, 1340, 1079.
¹ H NMR (500 MHz, CD ₃ CN): δ (ppm) 7.21 (s, 4H), 6.92 (brs, 1H), 4.74-4.70 (m, 1H), 3.00 ( dd, J = 5.5, 16.5 Hz, 1H), 2.85 (dd, J = 8.5, 16.5 Hz, 1H), 2.31 (s, 3H).
¹³ C NMR (125 MHz, CD ₃ CN): δ (ppm) 166.3, 150.5, 139.4, 136.7, 130.5, 126.9, 50.8, 37.3, 21.0 .
HRMS (ESI-TOF-MS): calcd. for [C ₆ H ₉ NO ₃ + Na] ⁺ 228.0631, found 228.0632.

[Example 44]
<Synthesis of β- (4-methoxyphenyl) alanine-NCA (Formula (2-8k))>
Purification method: Separation operation Yield: 193.6 mg, 0.99 mmol, 88% yield, white solid; melting point: 117-119 ° C.
IR (ATR method): (cm < ^-1 >) 3221,3146,1799,1739,1614,1378,1174,823,598.
¹ H NMR (500 MHz, CD ₃ CN): δ (ppm) 7.26-7.23 (m, 2H), 6.94-6.91 (m, 2H), 6.87 (brs, 1H), 4.72-4.69 (m, 1H), 3.75 (s, 3H), 2.98 (dd, J = 5.0, 16.0 Hz, 1H), 2.86 (dd, J = 8) .5,16.0 Hz, 1H).
¹³ C NMR (125 MHz, CD ₃ CN): δ (ppm) 166.4, 160.7, 150.4, 131.5, 128.4, 115.1, 55.8, 50.6, 37.3 .
HRMS (ESI-TOF-MS): calcd. for [C ₁₁ H ₁₁ NO ₄ + Na] ⁺ 244.0580, found 244.0579.

[Example 45]
<Synthesis of β- (4-fluorophenyl) alanine-NCA (Formula (2-8l))>
Purification method: Separation operation Yield: 199.3 mg, 0.95 mmol, yield 95%, white solid; melting point: 85-87 ° C.
IR (ATR method): (cm ^-1 ) 3243,3155,1792,1737,1511,1323,1121,834,517.
¹ H NMR (500 MHz, CD ₃ CN): δ (ppm) 7.37-7.34 (m, 2H), 7.15-7.11 (m, 2H), 6.96 (brs, 1H), 4.79-4.76 (m, 1H), 3.05-3.00 (m, 1H), 2.87 (dd, J = 8.5, 16.5 Hz, 1H).
_{^{13 C NMR (125 MHz, CD}} 3 CN): δ (ppm) 165.3,163.583 (d, J C-F = 244.0Hz), 149.5,135.009 (d, J C-F _{= 2.7Hz), 128.409 (d,} J C-F = 8.5Hz), 115.800 (d, J C-F = 21.9Hz), 49.7,36.4.
¹⁹ F NMR (471 MHz, CD ₃ CN): δ (ppm) -115.0.
HRMS (ESI-TOF-MS): calcd. for [C ₁₀ H ₈ FNO ₃ + Na] ⁺ 232.0380, found 232.0382.

[Example 46]
<Synthesis of β- (4-chlorophenyl) alanine-NCA (Formula (2-8m))>
Purification method: Separation operation yield: 231.1 mg, 1.02 mmol, quant. , White solid; melting point: 117-120 ° C.
IR (ATR method): (cm < ^-1 >) 3240, 3150, 2258, 1793, 1739, 1371, 1326, 1119, 972.
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) 7.39 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 6.96 (brs, 1H), 4.79-4.76 (m, 1H), 3.04 (dd, J = 5.5, 16.5 Hz, 1H), 2.86 (dd, J = 8.5, 16.5 Hz) , 1H).
¹³ C NMR (125 MHz, CDCl ₃ ): δ (ppm) 165.9, 150.3, 138.6, 134.7, 129.9, 128.9, 50.5, 37.0.
HRMS (ESI-TOF-MS): calcd. for [C ₁₀ H ₈ ClNO ₃ + Na] ⁺ 248.0085, found 248.0087.

[Example 47]
<Synthesis of β- (4-nitrophenyl) alanine-NCA (Formula (2-8n))>
Purification method: Separation operation yield: 261.0 mg, 1.11 mmol, quant. , Yellow oil.
IR (neat): (cm < ^-1 >) 3300, 2264, 1801, 1748, 1520, 1350, 1079, 977.
¹ H NMR (500 MHz, CD ₃ CN): δ (ppm) 8.19 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.04 (brs) , 1H), 4.95-4.91 (m, 1H), 3.12 (dd, J = 5.5, 16.5 Hz, 1H), 2.91 (dd, J = 8.0, 16. 5Hz, 1H).
¹³ C NMR (125 MHz, CD ₃ CN): δ (ppm) 165.5, 150.1, 148.8, 146.9, 128.3, 124.9, 50.6, 36.6.
HRMS (ESI-TOF-MS): calcd. for [C ₁₁ H ₁₁ NO ₄ + Na] ⁺ 259.0325, found 259.0328.

[Example 48]
<Synthesis of Isatoic Anhydride (Formula (2-1))>
Purification method: Separation operation and recrystallization yield: 81.2 mg, 0.50 mmol, yield 50%, white solid; melting point: 235-238 ° C.
IR (ATR method): (cm < ^-1 >) 3069, 2937, 1760, 1722, 1615, 1362, 1008, 748.
¹ H NMR (500 MHz, DMSO): δ (ppm) 11.7 (brs, 1 H), 7.91 (dd, J = 2.5, 7.5 Hz, 1 H), 7.75-7.72 (m , 1H), 7.26-7.23 (m, 1H), 7.15 (d, J = 8.5 Hz, 1H).
¹³ C NMR (125 MHz, DMSO): δ (ppm) 159.9, 147.1, 141.4, 137.0, 129.0, 123.5, 115.4, 110.3.

[Example 49]
<Synthesis of α-Ot-butyl-β-aspartic acid-NCA (Formula (2-8p))>
Purification method: Separation operation Yield: 225.1 mg, 1.05 mmol, quant. , White solid; melting point: 84-86 ° C.
IR (ATR method): (cm ^-1 ) 3231, 3167, 2985, 1801, 1759, 1720, 1366, 1090.
[Α] ²⁹ _D = + 40.12 (c 1.00, CH ₃ CN)
¹ H NMR (500 MHz, CD ₃ CN): δ (ppm) 6.82 (brs, 1H), 4.10-4.07 (m, 1H), 3.02 (dd, J = 6.5, 16) 0.5Hz, 1H), 2.86 (dd, J = 4.5, 16.5Hz, 1H), 1.42 (s, 9H)
¹³ C NMR (125 MHz, CD ₃ CN): δ (ppm) 169.7, 165.4, 149.8, 84.2, 50.3, 31.8, 27.9.
HRMS (ESI-TOF-MS): calcd. for [C ₉ H ₁₃ NO ₅ + Na] ⁺ 238.0686, found 238.0683.

  According to the synthesis method of the present invention, even when a two-layer reaction raw material solution of an organic layer and an aqueous layer is used as in the above-described embodiment, highly efficient mixing is realized by using a mixer in a flow reactor. Therefore, it is possible to synthesize compounds such as NCA of various structures by conversion from basic to acidic or from acidic to basic in a short period of time, which is impossible in principle by batch synthesis. is there. In addition, it was found that the above synthesis can be performed more effectively by the synthesis method using the microflow reactor of the present invention.

  According to the synthesis method using the flow reactor of the present invention, it is possible to produce a compound having a target structure in high yield, that is, a mild pH conversion and dilution in a short time after mixing the raw material solution. A compound having an unstable functional group such as N-carboxy anhydride (NCA) can be continuously produced in a short time under a temperature condition.

REFERENCE SIGNS LIST 100 Flow reactor 1-1 and 1-2 Raw material solution 11 and 12 Raw material solution supply device 110, 120 and 220 Liquid feed tube 20 and 30 Mixer 21 and 31 Reaction tube 22 Solvent or solvent supply device 2 Solution after mixing)

Claims (12)

A synthesis method using a flow reactor,
Within 60 seconds from the start of mixing of at least two kinds of raw material solutions,
A basic solution which has been adjusted to pH 7-14 in advance is changed to an acidic solution of pH 0-7,
Alternatively, a synthesis method characterized in that an acidic solution previously adjusted to pH 0 to 7 is changed to basic pH 7 to 14.   The method according to claim 1, wherein after starting the mixing of the raw material solution, the mixed solution is diluted 1.1 times or more by injecting a solvent. In the above synthesis method, the temperature range is -10 to 40 ° C.
The method according to claim 1.   In the above synthesis method, the raw material solution may be pyridine, N-methylmorpholine, N-methylpiperidine, N, N-dimethylethylamine, N, N-diethylmethylamine, diethylamine, sodium hydroxide, potassium hydroxide, calcium hydroxide A basic solution containing at least one base selected from barium hydroxide, sodium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and ammonia. 4. The synthesis method according to any one of 3.   In the synthesis method, the raw material solution is an acidic solution containing at least one acid selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, and formic acid. The described synthesis method.   The synthesis method according to any one of claims 1 to 5, wherein in the synthesis method, a solvent of the raw material solution is an organic solvent.   The synthesis method according to claim 6, wherein in the synthesis method, the solvent of the raw material solution is acetonitrile or tetrahydrofuran.   The method according to any one of claims 1 to 7, wherein a solvent used for dilution after mixing the raw material solutions is an organic solvent or water.   The method according to claim 8, wherein the solvent used for dilution after mixing the raw material solutions is ethyl acetate or dichloromethane. In the synthesis method, the substance contained in the raw material solution may include:
The synthesis method according to any one of claims 1 to 9, which is a compound represented by the following general formulas (1-1) and (1-2).

[Wherein, R ^{1 to} R ³ each independently represent —H, —OH, —COOH, —COO ⁻ , —CN,
A thio group having 0 to 20 carbon atoms which may have a substituent,
A sulfo group having 0 to 20 carbon atoms which may have a substituent,
An amino group having 0 to 20 carbon atoms which may have a substituent,
A silyl group having 1 to 20 carbon atoms which may have a substituent,
A linear or branched alkyl group having 1 to 20 carbon atoms which may have a substituent,
A cycloalkyl group having 1 to 20 carbon atoms which may have a substituent,
A linear or branched alkenyl group having 2 to 20 carbon atoms which may have a substituent,
An alkynyl group having 2 to 20 carbon atoms which may have a substituent,
A linear or branched alkoxy group having 1 to 20 carbon atoms which may have a substituent,
A cycloalkoxy group having 5 to 20 carbon atoms which may have a substituent,
An acyl group having 1 to 20 carbon atoms which may have a substituent,
An aromatic hydrocarbon group having 6 to 20 carbon atoms which may have a substituent,
A heterocyclic group having 2 to 20 carbon atoms which may have a substituent, or an aryloxy group having 6 to 20 carbon atoms which may have a substituent;
R ^{1 to} R ³ may be bonded to each other by adjacent groups to form a ring.
m represents an integer of 1 to 6, and when m is 2 or more, a plurality of R ² and R ³ may be the same or different from each other.
M represents a hydrogen atom or an alkali metal atom. ]

Wherein X and Y are each independently —Cl, —OCCl ₃ ,
A thio group having 0 to 20 carbon atoms which may have a substituent,
A linear or branched alkenyl group having 2 to 20 carbon atoms which may have a substituent,
A linear or branched alkoxy group having 1 to 20 carbon atoms which may have a substituent,
It represents an optionally substituted heterocyclic group having 2 to 20 carbon atoms or an aryloxy group having 6 to 20 carbon atoms optionally having a substituent. ] 11. The method according to claim 10, wherein, in the general formula (1-1), R ³ is —H, m is 1, and M is a sodium atom.   The method according to any one of claims 1 to 11, wherein the flow reactor is a microflow reactor.

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