Process for the manufacture of a precursor of vitamin b1

Detailed description of the invention

0001The present invention is based on the hydrolysis of N- (4-amino-2-methyl-pyrimidine-5-yl-methyl) -alcanamide using an aqueous solution of alkali hydroxide or alkaline earth metal.<chemistry num="1"><img he="34" id="000002" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Glue-diamine (GDA; 5-aminomethyl-2-methyl-pyrimidine-4-yl-amine), according to a novel production method. More precisely, the present invention is such a hydrolysis of an N-substituted alcanamide, more preferably in the presence of an organic solvent, preferably in the presence of an organic solvent having a permittivity of 7-35. With respect to hydrolysis carried out in the presence of an organic solvent that is essentially insoluble in water under reaction conditions.

0002GDA is vitamin B₁It is an important precursor for the synthesis of. For example, G. Moine and HP. Hohmann, "Ullmann's Encyclopedia of Industrial Chemistry", VCH, A27, 1996, 515 ~ See page 517 and examples of citations.

0003The method described in the prior art (EP-A 1 138 675, DE-A 35 11 373), i.e., a severe reaction to hydrolyze N-acetyl GDA or N-formyl GDA. Conditions are needed. The method described in DE-A 35 11 373 has the disadvantages of low overall yield and the product must be further purified by sublimation.

0004Therefore, there is a need for a method for producing GDA that can obtain the product in high yield and high purity.

0005This need is met in the presence of organic solvents with alkali hydroxide or alkaline earth metal aqueous solutions according to formula II.<chemistry num="2"><img he="33" id="000003" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>(In the formula, R is hydrogen or straight chain or branched chain C_1~4It is achieved by a method for producing Grewe-diamine, which comprises the step of hydrolyzing the compound (which is alkyl) (step a).

0006About substituent R: Substituent R is hydrogen, methyl, ethyl, propyl or butyl. Preferably R is hydrogen, methyl, ethyl, n-propyl or n-butyl, more preferably R is hydrogen or methyl, and most preferably R is hydrogen.

0007The production of the compound of formula II is well known to those skilled in the art, for example, Japanese Patent Application Laid-Open No. 58-065279 (publication number. Application number is 56-162106), EP-A 0 172 515. , EP-A 0 001 760, US Pat. No. 4,226,799, and DE-A 35 11 273.

0008About organic solvents: Examples of suitable organic solvents are those with a dielectric constant (εr) in the range of 7-35 (C. Reichardt, C. Reichardt, "Solvents and Solvent Effects". in Organic Chemistry ), VCH, 1988, pp. 408-410). Examples of preferred solvents are aliphatic alcohols, especially aliphatic C._1~4-There are alcohols, ethers and mixtures thereof. Examples of more preferred solvents are organic solvents that are essentially insoluble in water under reaction conditions.

0009"Intrinsically insoluble in water under reaction conditions" means that a two-phase liquid system is produced. The two-phase liquid system is, for example, aliphatic C._3~4-Produced under reaction conditions with alcohols, ethers and mixtures thereof.

0010Aliphatic C_1~4-Examples of alcohols are methanol, ethanol, propane-1-ol, propane-2-ol, butane-1-ol, butane-2-ol, 2-methyl-propane-2-ol, and 2-methyl. -There is propan-1-ol.

0011Most preferred aliphatic C_3~4The alcohol is selected from the group consisting of propane-1-ol, propane-2-ol, butane-1-ol, butane-2-ol, and 2-methyl-propane-2-ol, more preferably propane. It is selected from the group consisting of -2-ol, butane-1-ol, and butane-2-ol. They are also the most preferred organic solvents used in the methods according to the invention.

0012The preferred ether is an ether in which GDA dissolves. The most preferred ethers are tetrahydrofuran and 1,2-dimethoxyethane.

0013About Alkali Hydroxide and Alkaline Earth Metals: Examples include sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide and magnesium hydroxide, with sodium hydroxide being preferred.

0014About alkaline hydroxide and alkaline earth metal solutions: Preferably, the concentration of the solution is in the range of 5-30% by weight, more preferably in the range of 15-28% by weight.

0015Reaction conditions: Conveniently, the hydrolysis (step a) is carried out at a temperature in the range of 20 to 110 ° C, preferably in the temperature range of 30 ° C to 90 ° C, more preferably 40 ° C to 85 °. It is carried out at temperatures in the C range.

0016Conveniently, the reaction time is in the range of 30-240 minutes, preferably in the range of 30-120 minutes.

0017Conveniently, the reaction is carried out at normal pressure and may be carried out in an air atmosphere.

0018In certain embodiments of the invention, the method further comprises a plurality of steps. These steps depend on the organic solvent used (in step a).

0019If the hydrolysis (step a) is carried out, for example, in the presence of an organic solvent that is essentially insoluble in water under reaction conditions, the method will perform additional steps b1), c1), d1) and d2) (see below). ) Can be further included.

0020If the hydrolysis (step a) is carried out in the presence of methanol, the method may further comprise the additional step b2) (see below).

0021If the hydrolysis (step a) is carried out in the presence of ethanol, the method may further comprise additional steps b3), c3) and d3) (see below).

0022If the hydrolysis (step a) is carried out in the presence of an organic solvent that is essentially insoluble in water under reaction conditions, the method of the invention preferably comprises the following additional steps: b1) A step of phase-separating the reaction mixture after completion of the reaction in the aqueous phase and the organic phase. c1) In some cases, the process of extracting the aqueous phase with a solvent that is essentially insoluble in water and combining it with the organic phase.

0023Process b1): The aqueous phase, i.e. an aqueous solution of alkali hydroxide or alkaline earth metal, and a solvent that is essentially insoluble in water form a two-phase liquid system. After completion of the reaction, i.e., when the compound of formula II is hydrolyzed to GDA, the two phases separate from each other. The aqueous phase contains an alkali formic acid or alkaline earth metal salt produced during the reaction, and the organic phase contains a solvent and a product.

0024Preferably, the phase separation is carried out at a temperature in the range of 40 ° C to 80 ° C, more preferably in the temperature range of 50 ° C to 70 ° C.

0025In a preferred embodiment of the invention, steps a), b1) and c1) are performed sequentially in a predetermined order (which is the best embodiment of the invention).

0026According to other specific embodiments of the methods of the invention, isolation of the product GDA may be carried out for its treatment by either of the two alternatives d1) and d2).

0027Alternative 1 (step d1)): After performing steps a), b1) and c1), a solvent that is essentially insoluble in water is evaporated from the organic phase. This evaporation is preferably carried out at a temperature of 40 ° C to 80 ° C and / or a pressure of 5 to 30 mbar.

0028Alternative 2 (process d2)): After performing steps a), b1) and c1), GDA is crystallized from the separated organic phase. This can be achieved by cooling the organic phase, preferably to a temperature of 20 to -10 ° C, more preferably to a temperature of 5 to 0 ° C. Further GDA can be crystallized from the mother liquor. The GDA crystal is then separated from the liquid.

0029If the hydrolysis (step a) is carried out in the presence of methanol, this method is preferably preferred. b2) Crystallize Grewe-diamine from the reaction solution, Step b2) is further included.

0030This can be achieved by cooling the reaction solution, preferably to a temperature in the range of 20-10 ° C, more preferably to a temperature in the range of 5-0 ° C. Further GDA can be crystallized from the mother liquor. The GDA crystal is then separated from the liquid.

0031If the hydrolysis (step a) is carried out in the presence of ethanol, this method is preferably preferred. b3) Crystallizing by-product alkaline formic acid or alkaline earth salt from the reaction solution, c3) Separation of crystallized alkali formic acid or alkaline earth salt from the reaction solution, and d3) The process of evaporating water and ethanol from the remaining reaction solution, The steps b3), c3) and d3) are further included.

0032Step b3) can be accomplished by cooling the reaction solution, preferably to a temperature in the range of 20-10 ° C, more preferably to a temperature in the range of 5-0 ° C. Alkaline formate or alkaline earth metal salts can be further crystallized from the mother liquor.

0033Further advantages of the methods of the invention are the high yield (preferably 98%) and high purity (preferably 97%) of the product, as well as the resulting GDA being essentially aniline, 2- It is free of chloroaniline and / or any alkali formic acid or alkaline earth metal salts. In a preferred embodiment of the invention, the content of 2-chloroaniline is less than 250 ppm and / or the content of any alkali format or alkaline earth metal salt produced during hydrolysis is less than 2%.

0034The GDA thus obtained is, for example, carbon disulfide and 3-chloro-5-acetoxypentane-2-one, or 3-chloro-5-hydroxypentane-2-one, 3-mercapto-5-hydroxypentane. Further reaction with other chloroketone derivatives such as -2-one or 3-mercapto-5-acetoxypentane-2-one, formula III<chemistry num="3"><img he="39" id="000004" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>(In the formula, R¹Is C_1~4-Can produce compounds of alkanoyl, preferably acetyl (eg, by G. Moine and HP. Hohmann, "Ullmann's Encyclopedia of Industrial Chemistry (" Ullmann's Encyclopedia of Industrial Chemistry ")", VCH, Vol. A27, 1996, pp. 515-517 and examples thereof).

0035Therefore, methods for producing such compounds of formula III are also part of the present invention.

0036The compound of formula III then further reacts with the acid to produce the compound of formula IV.<chemistry num="4"><img he="38" id="000005" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>(For example, G. Moine and HP. Hohmann, "Ullmann's Encyclopedia of Industrial Chemistry", VCH, A27, 1996, 515. See page 517 and examples of citations).

0037Therefore, methods for producing such compounds of formula IV are also part of the present invention.

0038And the compound of formula IV is preferably H₂O₂Further oxidized in, vitamin B of formula V₁become.<chemistry num="5"><img he="40" id="000006" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>(For example, G. Moine and HP. Hohmann, "Ullmann's Encyclopedia of Industrial Chemistry", VCH, A27, 1996, 515. See page 517 and examples of citations).

0039Therefore, the present invention is based on vitamin B.₁Including the manufacturing method of, Equation II<chemistry num="6"><img he="38" id="000007" wi="149" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>(In the formula, R is hydrogen or straight chain or branched chain C_1~4The compound of) is alkyl<u style="single">,the above</u>The method of the present invention described in detail in<u style="single">Hydrolyzed according to</u>It becomes Glue-diamine and the resulting Glue-diamine is further reacted, preferably as described in more detail above, in Formula IV.<chemistry num="7"><img he="39" id="000008" wi="149" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>The resulting compound of formula IV is preferably H.₂O₂Further oxidize with B vitamins₁To get.

0040Finally, the present invention comprises using the GDA obtained by the method of the present invention as an intermediate product in the method for producing vitamin B1, as described above.

0041In the figure, the following abbreviations are used. "NFGDA" = N-Formyl GDA, "IT" = internal temperature, "w / w" = weight / weight, "eq." = Mole equivalent, "h" = time.

0042Figure 1 shows a method using methanol or ethanol as a solvent for hydrolyzing a compound of formula II (left side) and aliphatic C.₃-Or C₄-A brief schematic diagram of the method using alcohol as a solvent for hydrolyzing a compound of formula II (right side) is shown.

0043When methanol or ethanol is used as the solvent for hydrolyzing the compound of formula II, the reaction solution is a homogeneous reaction system, while aliphatic C₃-Or C₄-When alcohol is used as a solvent for the same purpose, the reaction solution is a heterogeneous reaction system.

0044When methanol is used as the solvent, GDA can be obtained by crystallization from the reaction solution.

0045When ethanol is used as the solvent, the by-product sodium formate is separated from the product GDA by crystallization. The GDA itself is then obtained by separating the crystalline sodium formate and then concentrating the solution (see Table 2 below).

0046Aliphatic C₃-Or C₄-When an alcohol or mixture thereof is used as a solvent, the aqueous phase and the organic phase are separated at the end of the reaction and either by concentration of the organic phase (see alternative 1 above) or by crystallization of GDA from the organic phase. (See alternative 2 above), GDA is obtained.

0047Figure 2 shows the hydrolysis of aliphatic C₃-A diagram of an example of treatment and isolation of hydrolyzed GDA according to the present invention when carried out with alcohol or a mixture thereof is shown. As a starting material, NFGDA with a purity of 95% and a maximum 2-chloroaniline content of 4000 ppm is used. C containing 20% by weight NFGDA (relative to the total volume of reaction solution)₃-Hydrolyzed by reacting the alcohol solution with an aqueous NaOH solution containing 1.05 molar equivalents of NaOH (relative to the molar amount of NFGDA) at a temperature of 80-85 ° C for 2-5 hours. The organic and aqueous phases are then separated from each other at a temperature of 40-60 ° C.

0048Water phase C₃-Extract with alcohol and then evaporate to regain sodium formate in a yield of 80-90% of the amount of sodium formate produced during hydrolysis (= NFGDA usage) (Figure 2). See right side).

0049There are two options for treating the organic phase.

0050According to option 1 (left side), at a temperature of 50 ° C and a pressure of 10 mbar, the organic phase is concentrated, ie the solvent is evaporated. C separated in this way₃-In alcohol, it can be seen that the starting material contains 90-95% 2-chloroaniline. The GDA thus isolated is further dried at a temperature of 60 ° C. and a pressure of 20 mbar for 12 hours. The purity of GDA thus obtained was 90-94%, the content of 2-chloroaniline was less than 250 ppm, GDA contained 6-10% sodium formate, and the yield of isolated GDA was (NFGDA). It is 93 to 98% of the amount used.

0051According to option 2 (center), the organic phase is cooled to a temperature of 0 ° C for 12 hours, thereby crystallizing the GDA. The separated crystals are then dried at a temperature of 60 ° C. and a pressure of 20 mbar for 12 hours. The purity of GDA thus obtained was 94-96%, the content of 2-chloroaniline was less than 50 ppm, GDA contained 4-6% sodium formate, and the yield of isolated GDA was (NFGDA). 75-80% of the amount used.

0052Figure 3 shows the hydrolysis of aliphatic C₄-Shown is an example of treatment and isolation of hydrolyzed GDA according to the present invention, when performed in alcohol or a mixture thereof. As a starting material, NFGDA with a purity of 95% and a maximum 2-chloroaniline content of 4000 ppm is used. C containing 20% by weight NFGDA (relative to the total volume of reaction solution)₄-Hydrolyzed by reacting the alcohol solution with an aqueous NaOH solution containing 1.05 molar equivalents of NaOH (relative to the molar amount of NFGDA) at a temperature of 80-100 ° C for 1-4 hours. The organic and aqueous phases are then separated from each other at a temperature of 40-60 ° C.

0053Water phase C₄-Extract with alcohol and then evaporate to regain sodium formate in a yield of 80-90% of the amount of sodium formate produced during hydrolysis (= NFGDA usage) (right side of figure) See).

0054There are two options for treating the organic phase.

0055According to option 1 (left side), at a temperature of 60 ° C and a pressure of 20 mbar, the organic phase is concentrated, i.e. the solvent is evaporated. C separated in this way₄-In alcohol, it can be seen that the starting material contains 90-95% 2-chloroaniline. The GDA thus isolated is further dried at a temperature of 60 ° C. and a pressure of 20 mbar for 12 hours. The purity of GDA thus obtained was 93-95%, the content of 2-chloroaniline was less than 250 ppm, GDA contained 2-6% sodium formate, and the yield of isolated GDA was (NFGDA). 96-98% of the amount used.

0056According to option 2 (center), the organic phase is cooled to a temperature of 0 ° C for 12 hours, which causes the GDA to crystallize. The separated crystals are then dried at a temperature of 60 ° C. and a pressure of 20 mbar for 12 hours. The purity of GDA thus obtained was 94-97%, the content of 2-chloroaniline was less than 50 ppm, GDA contained 2-4% sodium formate, and the yield of isolated GDA was (NFGDA). It is 75 to 80% (relative to the amount used).

0057The present invention will be further described with reference to the following examples.

The hydrolysis conditions of Examples 1-33, the method of isolating GDA, and the method of isolating sodium formate are briefly described in Tables 1-9 below. Examples 3-8, 10, 11, 13, 15 and 17-33 will be briefly described only by this.

Use the following abbreviations. "NFGDA" means N-formylmethionide (Grewe-diamine) (Compound II, R = hydrogen), "ML" means mother liquor. "Rpm" means the number of revolutions per minute. "GC" means gas chromatography. "HPLC" means high performance / high pressure liquid chromatography. "Int." Means the inside. "Ext." Means the outside. "Overnight" means 12 hours.

<tables num="1"><img he="130" id="000009" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

<tables num="2"><img he="129" id="000010" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

<tables num="3"><img he="133" id="000011" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

<tables num="4"><img he="137" id="000012" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

<tables num="5"><img he="129" id="000013" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

<tables num="6"><img he="123" id="000014" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

<tables num="7"><img he="130" id="000015" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

<tables num="8"><img he="126" id="000016" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

<tables num="9"><img he="126" id="000017" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

Examples 1, 2, 9, 12, 14 and 16 will be described in more detail below.

Example 1: Preparation of GDA in methanol Under an Ar atmosphere, 9.36 g (53.5 mmol) of NFGDA was suspended in 16.6 g of methanol. The suspension was stirred at 400 rpm and heated to 340 K (internal temperature). 6.97 ml (56.2 mmol) of 25.17 wt% sodium hydroxide solution was added within 30 minutes (0.23 ml / min). The mixture was stirred at 349K for 4 hours. The mixture was cooled to 0 ° C. overnight in an ice bath and filtered. The crystals were dried at 333 K, 20 mbar overnight.

Purity: GDA 62.25% (analyzed by HPLC (internal standard)), 2-chloroaniline 20ppm, sodium formate 36.8% (analyzed by HPLC (external standard)), water 0.7% (analyzed by Karl Fischer titration), methanol 40ppm (Analyzed by headspace GC) gave 4.26 g of pale yellowish crystals. The isolated yield of 35.9% was based on NFGDA. The stock solution was evaporated under reduced pressure (10 mbar, 323 K) and dried at 333 K, 20 mbar overnight. 7.85g of yellowish residue is GDA 58.56% (analyzed by HPLC (internal standard)), sodium formate 27.0%, 2-chloroaniline 80ppm (analyzed by HPLC (external standard)), water 11.4% (curl) It contained 1 ppm of methanol (analyzed by Fischer titration) and 1 ppm of methanol (analyzed by headspace GC). The yield of 60.0% was based on NFGDA. The chemical yield of the reaction was 95.9% based on NFGDA. Sodium formate 56.3% was isolated in the mother liquor residue and 43.1% was detected in the pale yellowish crystals of the isolated GDA.

Example 2: Preparation of GDA in ethanol Under an Ar atmosphere, 18.72 g (107 mmol) of NFGDA was suspended in 47.8 g of ethanol. The suspension was stirred at 350 rpm and heated to 353 K (internal temperature). 18.64 g (112.3 mmol) of 24.1 wt% sodium hydroxide solution was added within 20 minutes. The mixture was stirred at 353 K for 3 hours and 40 minutes. Sodium formate was precipitated during this reaction. The mixture was cooled to room temperature and filtered. Sodium formate crystals were dried overnight at 323 K, 20 mbar. The purity was 94.04% sodium formate (analyzed by HPLC (external standard)) and GDA 0.88% (analyzed by HPLC (internal standard)) to obtain 4.86 g of white crystals. Sodium formate 62.8% was isolated based on NFGDA. The alcohol solution was evaporated under reduced pressure (10 mbar, 313 K).

Purity: GDA 68.28% (analyzed by HPLC (internal standard)), sodium formate 12.1%, 2-chloroaniline 610ppm (analyzed by HPLC (external standard)), water 13.5% (analyzed by Karl Fischer titration), ethanol 280ppm (Analyzed by headspace GC) gave 19.03 g of yellowish crystals. The isolated yield of 87.9% was based on NFGDA. The chemical yield of the reaction was 88.2% based on NFGDA. 31.6% sodium formate was detected in the pale yellowish crystals of the isolated GDA.

Example 9: Preparation of GDA in Propan-2-ol (Isolation of GDA by enrichment of organic (alcohol) phase) Under an Ar atmosphere, 52.5 g (300 mmol) of NFGDA was suspended in 175 g of propane-2-ol. The suspension was stirred at 400 rpm and heated to 355 K (internal temperature). 38.95 ml (315 mmol) of 25.35 wt% sodium hydroxide solution was added within 30 minutes (1.3 ml / min). The mixture was stirred at 356 K for 5 hours. Liquid-liquid phase separation was performed at 353 K. To avoid crystallization of sodium formate, 10 ml of distilled water was added to the aqueous phase. The aqueous phase was extracted with 3 x 15 ml propane-2-ol at room temperature. An aqueous phase of 60.81 g containing 28.92% sodium formate (analyzed by HPLC (external standard)) was obtained. GDA and 2-chloroaniline were not detected (analyzed by HPLC (internal / external standard)). The combined organic phases were evaporated under reduced pressure (10 mbar, 323 K) and dried overnight at 333 K, 20 mbar. 2-Chloroaniline 1430ppm was detected in distilled propane-2-ol.

Purity: GDA 87.09% (analyzed by HPLC (internal standard)), 2-chloroaniline 390ppm, sodium formate 4.5% (analyzed by HPLC (external standard)), water 8.3% (analyzed by Karl Fischer titration), methanol 420ppm (Analyzed by headspace GC) gave 45.84 g of pale yellowish crystals. The isolated yield of 96.3% was based on NFGDA. Sodium formate 86.2% was isolated in the aqueous phase and 10.1% was detected in the pale yellowish crystals of the isolated GDA.

Example 12: Preparation of GDA in Propan-2-ol (Isolation of GDA by crystallization from organic (alcohol) phase) Under an Ar atmosphere, 52.5 g (300 mmol) of NFGDA was suspended in 72.1 g of propane-2-ol. The suspension was stirred at 500 rpm and heated to 356 K (internal temperature). 39.1 ml (315 mmol) of 25.17 wt% sodium hydroxide solution was added within 30 minutes (1.3 ml / min). The mixture was stirred at 357K for 3.5 hours. Liquid-liquid phase separation was performed at 343K. To avoid crystallization of sodium formate, 10 ml of distilled water was added to the aqueous phase. The aqueous phase was extracted with 3 x 15 ml propane-2-ol at room temperature. An aqueous phase of 53.97 g containing 33.24% sodium formate, trace amounts of 2-chloroaniline (analyzed by HPLC (external standard)) and less than 0.1% GDA (analyzed by HPLC (internal standard)) was obtained. The combined organic phases were cooled to 0 ° C. overnight in an ice bath and filtered. The crystals were dried at 333 K, 20 mbar overnight.

Purity: GDA 95.60% (analyzed by HPLC (internal standard)), 2-chloroaniline 130ppm, sodium formate 4.4% (analyzed by HPLC (external standard)), water 1.0% (analyzed by Karl Fischer titration), trace amount Propane-2-ol (analyzed by headspace GC) gave 33.20 g of white crystals. The isolated yield of 76.60% was based on NFGDA. The stock solution was evaporated under reduced pressure (10 mbar, 323 K) and dried at 333 K, 20 mbar overnight.

8.75g of yellowish residue is GDA 79.60% (analyzed by HPLC (internal standard)), sodium formate 6.1%, 2-chloroaniline 1250ppm (analyzed by HPLC (external standard)), water 8.1% (Karl Fischer) Analyzed by titration) and contained 110 ppm of propane-2-ol (analyzed by headspace GC). The yield of 16.8% was based on NFGDA. The chemical yield of the reaction was 93.4% based on NFGDA. Sodium formate 87.8% was isolated in the aqueous phase and 7.2% was detected in the isolated white crystals of GDA.

Example 14: Preparation of GDA in butane-1-ol (Isolation of GDA by crystallization from organic (alcohol) phase) Under an Ar atmosphere, 35.0 g (200 mmol) of NFGDA was suspended in 149 g of butane-1-ol. The suspension was stirred at 400 rpm and heated to 373 K (internal temperature). 26.1 ml (210 mmol) of 25.17 wt% sodium hydroxide solution was added within 30 minutes (0.87 ml / min). The mixture was stirred at 353 K for 1 hour. Liquid-liquid phase separation was performed at 297K. To avoid crystallization of sodium formate, 10 ml of distilled water was added to the aqueous phase. The aqueous phase was extracted with 3 x 10 ml butane-1-ol at room temperature. An aqueous phase (47.8 g) containing 24.6% sodium formate and 0.3% GDA (analyzed by HPLC (internal standard)) was obtained. The combined organic phases were cooled to 0 ° C. overnight in an ice bath and filtered. The crystals were dried at 333 K, 20 mbar overnight.

Purity: GDA 94.50% (analyzed by HPLC (internal standard)), 2-chloroaniline 95 ppm, sodium formate 3.9% (analyzed by HPLC (external standard)), water 1.0% (analyzed by Karl Fischer titration), butane- 24.2 g of white crystals were obtained with 1-all 400 ppm (analyzed by headspace GC). The isolated yield of 82.7% was based on NFGDA. The mother liquor was evaporated under reduced pressure (15 mbar, 333 K) and dried at 333 K, 20 mbar overnight.

3.1 g of yellowish residue is GDA 91.60% (analyzed by HPLC (internal standard)), sodium formate 0.8%, 2-chloroaniline 650 ppm (analyzed by HPLC (external standard)), water 5.1% (Karl Fischer) Analyzed by titration), butane-1-ol 500 ppm (analyzed by headspace GC) was contained. The yield of 10.2% was based on NFGDA. The chemical yield of the reaction was 92.9% based on NFGDA. Sodium formate 86.2% was isolated from the aqueous phase and 6.9% was detected in the isolated white crystals of GDA.

Example 16: Preparation of GDA in butane-1-ol (Isolation of GDA by enrichment of organic (alcohol) phase) Under an atmosphere of argon, 810 g of butane-1-ol was added to 186.9 g (1000 mmol) of NFGDA. The suspension was stirred at 400 rpm and heated to 373 K (internal temperature). 129.8 ml (1050 mmol) of 25.35 wt% sodium hydroxide solution was added within 30 minutes (4.33 ml / min). The reaction solution was stirred at 373 K for 3.5 hours. At the end of the reaction, the internal temperature was cooled to 313K. Liquid-liquid phase separation was performed at 313K. To avoid crystallization of sodium formate, 50 ml of distilled water was added to the aqueous phase. The aqueous phase was extracted with 3 x 50 ml butane-1-ol at room temperature. An aqueous phase of 186.6 g containing 33.1% sodium formate (analyzed by HPLC (external standard)) and less than 0.1% GDA (analyzed by HPLC (internal standard)) was obtained. 2-Chloroaniline was not detected (analyzed by HPLC (external standard)). The combined organic phases were evaporated under reduced pressure (20 mbar, 333 K) and dried overnight at 333 K, 20 mbar. 2-Chloroaniline 565ppm was detected in distilled butane-1-ol.

Purity: GDA 95.20% (analyzed by HPLC (internal standard)), 2-chloroaniline 200ppm, sodium formate 3.6% (analyzed by HPLC (external standard)), water 0.9% (analyzed by Karl Fischer titration), butane- At 1-all 650 ppm (analyzed by headspace GC), 139.70 g of pale yellowish crystals were obtained. The isolated yield of 96.2% was based on NFGDA. Sodium formate 90.9% was isolated from the aqueous phase and 7.4% was detected in the pale yellowish crystals of the isolated GDA.

The results regarding the yield and purity of Examples 1-33 are summarized in Table 10 below.

<tables num="10"><img he="227" id="000018" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

<tables num="11"><img he="227" id="000019" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

<tables num="12"><img he="227" id="000020" wi="147" file="JP5191237B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

<figref num="1">Outline of isolation method.</figref><figref num="2">C₃-NFGDA (= N-formylglue-diamine) hydrolysis and waste separation in alcohol.</figref><figref num="3">C₄-NFGDA (= N-formylglue-diamine) hydrolysis and waste separation in alcohol.</figref>