CN112851560A - Preparation method of cis-D-hydroxyproline - Google Patents
Preparation method of cis-D-hydroxyproline Download PDFInfo
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of cis-D-hydroxyproline, belonging to the technical field of chemical synthesis. The method comprises the following steps: racemizing trans-L-hydroxyproline, cooling for the first time, recrystallizing, and carrying out solid-liquid separation to obtain a first cis-D-hydroxyproline crude product and a first mother liquor; mixing the first mother liquor with new trans-L-hydroxyproline, racemizing, cooling for recrystallization for the second time, and carrying out solid-liquid separation to obtain a second cis-D-hydroxyproline crude product and a second mother liquor; mixing the second mother liquor with new trans-L-hydroxyproline for circulating to prepare a new cis-D-hydroxyproline crude product and a new mother liquor for at least 6 times; dissolving all the cis-D-hydroxyproline crude products in a mixed solution of methanol and ethyl acetate, and then cooling and recrystallizing to obtain the cis-D-hydroxyproline. The method can effectively prepare the cis-D-hydroxyproline with higher purity and yield, has simple steps and is beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of cis-D-hydroxyproline.
Background
The existing method for preparing cis-D-hydroxyproline has the disadvantages of expensive reaction raw materials, high cost, complex process, difficult operation and low yield of cis-D-hydroxyproline, and is not suitable for industrial production.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The present invention aims to provide a process for the preparation of cis-D-hydroxyproline which ameliorates the above technical problems.
The application can be realized as follows:
the application provides a preparation method of cis-D-hydroxyproline, which comprises the following steps:
racemizing the trans-L-hydroxyproline, cooling for recrystallization for the first time, and performing solid-liquid separation to obtain a first cis-D-hydroxyproline crude product and a first mother liquor.
Mixing the first mother liquor with new trans-L-hydroxyproline, racemizing, cooling for recrystallization for the second time, and carrying out solid-liquid separation to obtain a second cis-D-hydroxyproline crude product and a second mother liquor; mixing the second mother liquor with new trans-L-hydroxyproline and cyclically preparing the new crude cis-D-hydroxyproline and the new mother liquor at least 6 times in a manner to prepare the second crude cis-D-hydroxyproline and the second mother liquor.
And dissolving all prepared cis-D-hydroxyproline crude products in a mixed solution of methanol and ethyl acetate, and then cooling and recrystallizing to obtain the cis-D-hydroxyproline.
In an alternative embodiment, racemization is reacting trans-L-hydroxyproline with an organic acid and a racemizing agent.
In an alternative embodiment, the organic acid comprises at least one of acetic acid, propionic acid, and n-butyric acid, more preferably acetic acid.
In an alternative embodiment, the racemization agent comprises at least one of salicylaldehyde and n-butyraldehyde, more preferably n-butyraldehyde.
In an alternative embodiment, racemization is carried out at 85-90 ℃ for 8-15 h.
In an alternative embodiment, the organic acid and the racemizing agent used for the racemization reaction are acetic acid and n-butyraldehyde, respectively.
In an alternative embodiment, the mass ratio of trans-L-hydroxyproline to acetic acid is 1: 3-6, preferably 1: 4-5.
In an alternative embodiment, the mass ratio of trans-L-hydroxyproline to n-butyraldehyde is 1: 0.01 to 0.04, preferably 1: 0.02-0.03.
In an alternative embodiment, each recrystallization is carried out at 20-25 ℃.
In an alternative embodiment, all of the prepared crude cis-D-hydroxyproline is dissolved in a mixed solution of methanol and ethyl acetate at 80-85 ℃.
In an alternative embodiment, the mass ratio of the mixed solution of methanol and ethyl acetate to the crude cis-D-hydroxyproline is 0.45-0.55: 1, preferably 0.5: 1.
in an alternative embodiment, in the mixed solution of methanol and ethyl acetate, the mass ratio of methanol to ethyl acetate is 0.9-1.1: 0.9-1.1.
In an alternative embodiment, the number of cycles is 6-13, preferably 9-13.
In an alternative embodiment, each additional supply of new trans-L-hydroxyproline is 42-46% of the mass of trans-L-hydroxyproline used in the initial preparation of crude cis-D-hydroxyproline.
The beneficial effect of this application includes:
the cis-D-hydroxyproline preparation method provided by the application takes low-price trans-L-hydroxyproline as a raw material, racemizes and recrystallizes the trans-L-hydroxyproline to obtain a cis-D-hydroxyproline crude product and a mother liquor, supplements new trans-L-hydroxyproline to the mother liquor to continuously prepare a new D-hydroxyproline crude product and obtain a new mother liquor, and circulates for at least 6 times in such a way, dissolves all cis-D-hydroxyproline crude products prepared in the above process in a mixed solution of methanol and ethyl acetate, and recrystallizes again to obtain the cis-D-hydroxyproline. The method is low in cost, environment-friendly, capable of obtaining cis-D-hydroxyproline with high purity and yield, simple in steps and beneficial to industrial production.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a flow diagram of a process for the preparation of cis-D-hydroxyproline according to the present application;
FIG. 2 is a high performance liquid chromatogram of a pure cis-D-hydroxyproline in example 1 of the present application.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The following is a specific description of the method for producing cis-D-hydroxyproline provided in the present application.
The inventor finds out through research that: the existing method for preparing cis-D-hydroxyproline has the disadvantages of expensive reaction raw materials, high cost, complex process, difficult operation and low yield of cis-D-hydroxyproline, and is not suitable for industrial production.
In the first of the three methods currently used, Boc-cis-D-hydroxyproline was dissolved in EtOH, and LiOH solution was added and stirred at room temperature. The resulting aqueous layer was then extracted once with ether, acidified with 10% citric acid, washed with saturated solution of sodium chloride, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting crystals were treated with 10 equivalents of hydrogen chloride at room temperature for 19 h. The solvent was then removed in vacuo to give the hydrochloride salt, treated with TEA in chilled EtOH, filtered to give the desired product and separated from H2Recrystallized cis-form of O-EtOH-D-hydroxyproline. The yield of the method is about 83 percent, but the method needs BOC-D-cis-hydroxyproline as a raw material, the BOC anhydride used by the compound is an expensive raw material, the cost is high, the reaction process needs to be extracted and concentrated for many times, and the steps are complicated.
The second was a solution of cis-D-hydroxyproline ethyl ester in ethanol at 50psi hydrogen pressure in 10% PD (OH)2Hydrogenation in the presence of hydrogen for 3 h. The catalyst was filtered and evaporated to dryness. Adding NaOH solution into the crude product, stirring for 2h, acidifying the reactant by acetic acid until the pH is 5, purifying by using resin, and eluting the product in 5% ammonia water. The yield of the method is about 80%, cis-D-hydroxyproline ethyl ester used in the process is also high in price, hydrogen is needed to be used for hydrogenation in the reaction process, the danger is high, the resin purification process is troublesome, and the method is not beneficial to industrial production.
The third is to dissolve trans-4-hydroxyproline in acetic acid and acetic anhydride and reflux for 24 hours. The reaction was then distilled to remove approximately 1L of solvent, and the remaining solvent was removed in vacuo. The compound was redissolved in 2M HCl and refluxed for another 24 hours, at which time the solvent was removed in vacuo using toluene as an azeotrope. The product was then dissolved in EtOH and TEA and heated to 70 ℃, after which water was added until a dark transparent solution was obtained. The solution was cooled to room temperature and then placed in a refrigerator at-20 ℃ overnight. The resulting crystals were collected by vacuum filtration and washed with cold EtOH to give cis-D-hydroxyproline. The yield of the method is about 74.7 percent, the trans-L-hydroxyproline is used as a raw material, the target product cis-D-hydroxyproline is obtained through catalysis of acetic acid and acetic anhydride and epimerization, the whole operation steps are simple, the whole period is long, and the yield is low.
In view of the above, the inventors have creatively proposed a novel method for preparing cis-D-hydroxyproline, i.e., a novel method for synthesizing cis-D-hydroxyproline by a dynamic method, wherein the flow chart is shown in FIG. 1.
The method mainly comprises the following steps: racemizing trans-L-hydroxyproline, cooling for the first time, recrystallizing, and performing solid-liquid separation to obtain a cis-D-hydroxyproline crude product and a mother solution; preparing a new cis-D-hydroxyproline crude product and a new mother liquor from the mother liquor and new trans-L-hydroxyproline according to the mode, and circulating at least 6 times; and dissolving all prepared cis-D-hydroxyproline crude products in a mixed solution of methanol and ethyl acetate, and then cooling and recrystallizing to obtain the cis-D-hydroxyproline.
The process can also be understood as racemizing trans-L-hydroxyproline, cooling and recrystallizing for the first time, and carrying out solid-liquid separation to obtain a first cis-D-hydroxyproline crude product and a first mother liquor. Mixing the first mother liquor with new trans-L-hydroxyproline, racemizing, cooling for recrystallization for the second time, and carrying out solid-liquid separation to obtain a second cis-D-hydroxyproline crude product and a second mother liquor; and mixing the second mother liquor with new trans-L-hydroxyproline, and circularly preparing the new cis-D-hydroxyproline crude product and the new mother liquor according to the mode of preparing the second cis-D-hydroxyproline crude product and the second mother liquor, wherein the circulation frequency is at least 6 times. And dissolving all prepared cis-D-hydroxyproline crude products in a mixed solution of methanol and ethyl acetate, and then cooling and recrystallizing to obtain the cis-D-hydroxyproline.
The route of the process can be summarized as:
wherein racemization is to react trans-L-hydroxyproline with organic acid and racemization agent. trans-L-hydroxyproline is isomerized by racemization to obtain cis-D-hydroxyproline, and part of unconverted raw material is also present in the process. The part of unconverted raw materials exist in the mother liquor, and new trans-L-hydroxyproline raw materials are continuously supplemented along with the mother liquor to carry out new racemization reaction according to the racemization conditions, and the racemization reaction is circularly applied for 7 to 18 times, so that the purity of the crude product after purification can reach more than 99.5 percent.
In alternative embodiments, the organic acid may be a commonly used organic acid, such as at least one of acetic acid, propionic acid, and n-butyric acid. In a preferred embodiment, the organic acid is acetic acid, which is a relatively inexpensive and readily available type of organic acid that is most suitable as a solvent for trans-L-hydroxyproline in the present application.
In alternative embodiments, the racemization agent may include at least one of salicylaldehyde and n-butyraldehyde. In a preferred embodiment, the racemization agent is n-butyraldehyde.
In a preferred embodiment, the organic acid and the racemizing agent used in the racemization reaction are acetic acid and n-butyraldehyde, respectively. Under the condition that the two substances exist simultaneously, the trans-L-hydroxyproline can be racemized effectively to obtain a cis-D-hydroxyproline crude product, the racemization degree is higher, and the two substances are low in price and are suitable for industrial application.
For reference, the mass ratio of trans-L-hydroxyproline to acetic acid may be 1: 3-6, such as 1: 3. 1: 4. 1: 5 or 1: 6, preferably 1: 4-5. The mass ratio of trans-L-hydroxyproline to n-butyraldehyde may be 1: 0.01-0.04, such as 1: 0.01, 1: 0.02, 1: 0.03 or 1: 0.04, etc., preferably 1: 0.02-0.03.
It is worth explaining that the usage amounts of acetic acid and n-butyraldehyde have obvious influences on the mother liquor application times and the crude product yield, when the usage amount of acetic acid reaches 4 times or more of trans-L-hydroxyproline and the usage amount of n-butyraldehyde reaches more than 2% of the trans-L-hydroxyproline, the mother liquor can be applied for more than 10 times basically, when the usage amount of acetic acid reaches more than 5 times of the trans-L-hydroxyproline and the n-butyraldehyde reaches 3% of the trans-L-hydroxyproline, the mother liquor can be applied for more times, but the crude product yield is not improved obviously, and the crude product degree is also reduced gradually along with the increase of the mother liquor application batches. Considering the problems of low purity of crude products and comprehensive cost, the dosage of acetic acid is preferably controlled to be 4-5 times of that of trans-L-hydroxyproline, the dosage of n-butyraldehyde is most suitably controlled to be 2-4% of that of the trans-L-hydroxyproline, the purity of the crude products can reach more than 95% under the condition, the yield can reach more than 88%, and the batch is mechanically used for 10-12 times.
In the present application, racemization can be carried out for 8-15h (e.g., 8h, 10h, 12h or 15h, etc.) under the condition of 85-90 ℃ (e.g., 85 ℃, 86 ℃, 87 ℃, 88 ℃, 89 ℃ or 90 ℃, etc.).
In an alternative embodiment, each recrystallization may be performed at 20 to 25 ℃, and the solid phase obtained by recrystallization is cis-D-hydroxyproline.
After the first recrystallization, solid-liquid separation is carried out to obtain a first liquid phase and a first solid phase, wherein the first solid phase is mainly cis-D-hydroxyproline, and the first liquid phase is a first mother liquor containing part of unconverted raw materials (trans-L-hydroxyproline). The first mother liquor and a new raw material (trans-L-hydroxyproline) are subjected to a new racemization process according to the process, preferably under the same racemization conditions (including the types and the amounts of the solvent and the racemization agent, and the racemization temperature and time), and are recrystallized again and subjected to solid-liquid separation to obtain a second liquid phase and a second solid phase. Further, the second liquid phase and the new raw material trans-L-hydroxyproline are subjected to a new racemization process according to the same racemization conditions (including the types and the amounts of the solvent and the racemization agent, and the racemization temperature and time), and are recrystallized again and subjected to solid-liquid separation to obtain a third liquid phase and a third solid phase. Therefore, the mother liquor obtained by solid-liquid separation and new raw materials are racemized again, the mother liquor is recycled, a dynamic synthesis mode is formed, the cost is saved, the conversion rate of the raw materials can be improved, and the yield and the purity of the cis-D-hydroxyproline are effectively improved.
In an alternative embodiment, the second mother liquor is circulated at least 6 times, preferably 6 to 13 times, more preferably 9 to 13 times. The "number of cycles" of the second mother liquor refers to the number of cycles that the second mother liquor undergoes to the last mother liquor obtained. In other words, the total number of cycles of the entire preparation process is at least 7, preferably 7 to 14, more preferably 10 to 14. The cycle times in the whole preparation process refer to the cycle times from the first mother liquor to the mother liquor obtained at the last time, the first mother liquor is circulated once to obtain the second mother liquor, the first mother liquor is circulated twice to obtain the third mother liquor, and the like.
In an alternative embodiment, each additional supply of new trans-L-hydroxyproline is 42-46% of the mass of trans-L-hydroxyproline used in the initial preparation of crude cis-D-hydroxyproline. It is worth to be noted that, taking the amount of trans-L-hydroxyproline used in the initial preparation of crude cis-D-hydroxyproline as 524g as an example, when the amount of trans-L-hydroxyproline supplemented with raw material trans-L-hydroxyproline is below 55g, less substrate is caused, the converted product is reduced, the final yield is lower, when the amount of trans-L-hydroxyproline supplemented with raw material trans-L-hydroxyproline is above 60g, more substrate is caused, acetic acid and n-butyraldehyde are reduced relative to the substrate, so that the applied batch is reduced, and the yield is reduced, therefore, in the present application, the raw material supplemented each time is selected to be 55-60g, which is more suitable, namely 42-46 wt% of the initial raw material (trans-L-hydroxyproline used in the initial preparation of crude cis-D-hydroxyproline).
Further, after the mother liquor is recycled, all the obtained cis-D-hydroxyproline crude products are dissolved in a mixed solution of methanol and ethyl acetate, the temperature is raised to 80-85 ℃, after the crude products are stirred and completely dissolved, the temperature is reduced for recrystallization for the second time (the temperature is reduced to 20-25 ℃), and then the purification of cis-D-hydroxyproline can be realized, so that the cis-D-hydroxyproline pure product with high purity (more than 99.5%) is obtained.
In reference, the mass ratio of the mixed solution of methanol and ethyl acetate to the crude cis-D-hydroxyproline is 0.45-0.55: 1, such as 0.45: 1. 0.5: 1 or 0.55: 1, preferably 0.5: 1. it is worth to be noted that, when the mass ratio of the mixed solvent to the cis-D-hydroxyproline crude product is below 0.45 times, the crude product cannot be completely dissolved, so that the recrystallization is incomplete, the purity is low, and when the mass ratio of the mixed solvent to the cis-D-hydroxyproline crude product is above 0.55 times, part of the product is dissolved in the solvent, and cannot be completely crystallized, so that the product loss is caused, and the yield is reduced. Therefore, the mass ratio of the crude product to the mixed solvent is set as 1: within the range of 0.45-0.55, the yield can be kept about 90%, and the purity can be purified to more than 99.5%.
In the mixed solution of methanol and ethyl acetate, the mass ratio of methanol to ethyl acetate is 0.9-1.1: 0.9-1.1, such as 0.9: 1.1, 0.9: 1. 1: 1. 1: 0.9, 1: 1.1, 1.1: 0.9 or 1.1: 1, preferably 1: 1. under the mass ratio, the product can be effectively dissolved, and the secondary cooling recrystallization is facilitated.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
Step 1: adding 131g of trans-L hydroxyproline into 524g of acetic acid, adding 2.6g of n-butyraldehyde, heating the reaction system to 90 ℃, gradually dissolving the materials in the heating process, keeping the temperature of 85-90 ℃ for reaction for 12 hours, cooling to 20-25 ℃ after the reaction is finished, filtering, standing the mother liquor, and drying the solid to obtain 61g of cis-D-hydroxyproline crude product with chiral purity of 96.3%.
Step 2: and continuously adding 60g of trans-L hydroxyproline into the mother liquor, heating the reaction system to 90 ℃, gradually dissolving the materials in the heating process, keeping the temperature of 85-90 ℃ for reaction for 12 hours, cooling to 20-25 ℃ after the reaction is finished, filtering, keeping the mother liquor for later use, and drying the solid to obtain 60.5g of crude product with chiral purity of 96.1%.
And (4) continuing to use the mother liquor circularly for 9 times according to the method in the step 2.
And step 3: 651.6g of cis-D-hydroxyproline crude product (crude product yield is 89.1%) is finally obtained and added into 325g of methanol/ethyl acetate mixed solution (mass ratio is 1: 1), the temperature is raised to 80 ℃, the mixture is stirred, after the mixture is completely dissolved, the temperature is reduced to 25 ℃, and the mixture is recrystallized to obtain 624.2g of cis-D-hydroxyproline, the chiral purity is 99.9% (a high performance liquid chromatogram and the specific information of each peak in the chromatogram are shown in figure 2), and the total yield is 85.4%.
Example 2
Step 1: adding 200g of trans-L hydroxyproline into 800g of acetic acid, adding 4g of n-butyl aldehyde, heating the reaction system to 88 ℃, gradually dissolving the materials in the heating process, keeping the temperature of 85-88 ℃ for reaction for 8 hours, cooling to 20-25 ℃ after the reaction is finished, filtering, standing mother liquor, and drying solids to obtain 92.8g of a cis-D-hydroxyproline crude product with chiral purity of 96.1%.
Step 2: and continuously adding 84g of trans-L hydroxyproline into the mother liquor, heating the reaction system to 88 ℃, gradually dissolving the materials in the heating process, keeping the temperature of 85-88 ℃ for reaction for 8 hours, cooling to 20-25 ℃ after the reaction is finished, filtering, keeping the mother liquor for later use, and drying the solid to obtain 92g of crude product with the chiral purity of 96.2%.
And (4) continuing to use the mother liquor circularly for 10 times according to the method in the step 2.
And step 3: 931.8g of cis-D-hydroxyproline crude product (crude product yield is 89.6%) is added into a methanol/ethyl acetate mixed solution (mass ratio is 0.9: 1) which is 0.45 time of the mass of the cis-D-hydroxyproline crude product, the temperature is raised to 82.5 ℃, the mixture is stirred, after the mixture is completely dissolved, the temperature is reduced to 25 ℃, recrystallization is carried out to obtain 892g of cis-D-hydroxyproline, the chiral purity is 99.8%, and the total yield is 85.8%.
Example 3
Step 1: adding 200g of trans-L hydroxyproline into 1000g of acetic acid, adding 8g of n-butyl aldehyde, heating the reaction system to 85 ℃, gradually dissolving the materials in the heating process, keeping the temperature of 85 ℃ for reaction for 15 hours, cooling to 20-25 ℃ after the reaction is finished, filtering, standing mother liquor, and drying solids to obtain a cis-D-hydroxyproline crude product.
Step 2: and continuously adding 92g of trans-L hydroxyproline into the mother liquor, heating the reaction system to 85 ℃, gradually dissolving the materials in the heating process, keeping the temperature of 85 ℃ for reaction for 15 hours, cooling to 20-25 ℃ after the reaction is finished, filtering, standing the mother liquor, and drying the solid to obtain a crude product.
And (4) continuing to use the mother liquor circularly for 14 times according to the method in the step 2.
And step 3: and adding the cis-D-hydroxyproline crude product into a methanol/ethyl acetate mixed solution (the mass ratio is 1.1: 0.9) which is 0.55 times of the mass of the cis-D-hydroxyproline crude product, heating to 85 ℃, stirring, cooling to 25 ℃ after complete dissolution, and recrystallizing to obtain the cis-D-hydroxyproline.
Example 4
Step 1: adding 200g of trans-L hydroxyproline into 600g of acetic acid, adding 2g of n-butyl aldehyde, heating the reaction system to 87 ℃, gradually dissolving the materials in the heating process, keeping the temperature of 85-87 ℃ for reaction for 12 hours, cooling to 20-25 ℃ after the reaction is finished, filtering, standing mother liquor, and drying the solid to obtain a cis-D-hydroxyproline crude product.
Step 2: and continuously adding 90g of trans-L hydroxyproline into the mother liquor, heating the reaction system to 87 ℃, gradually dissolving the materials in the heating process, keeping the temperature of 85-87 ℃ for reaction for 12 hours, cooling to 20-25 ℃ after the reaction is finished, filtering, standing the mother liquor, and drying the solid to obtain a crude product.
And (4) continuing to use the mother liquor circularly for 12 times according to the method in the step 2.
And step 3: and adding the cis-D-hydroxyproline crude product into a methanol/ethyl acetate mixed solution (the mass ratio is 1.1: 0.9) which is 0.5 time of the mass of the cis-D-hydroxyproline crude product, heating to 87 ℃, stirring, cooling to 25 ℃ after complete dissolution, and recrystallizing to obtain the cis-D-hydroxyproline.
Example 5
Step 1: adding 200g of trans-L hydroxyproline into 1200g of acetic acid, adding 6g of n-butyl aldehyde, heating the reaction system to 90 ℃, gradually dissolving the materials in the heating process, keeping the temperature of 85-90 ℃ for reaction for 10 hours, cooling to 20-25 ℃ after the reaction is finished, filtering, standing mother liquor, and drying the solid to obtain 93g of cis-D-hydroxyproline crude product with the chiral purity of 96.0%.
Step 2: and (2) continuously adding 91g of trans-L hydroxyproline into the mother liquor, heating the reaction system to 90 ℃, gradually dissolving the materials in the heating process, keeping the temperature of 85-90 ℃ for reaction for 10 hours, cooling to 20-25 ℃ after the reaction is finished, filtering, keeping the mother liquor for later use, and drying the solid to obtain 92.7g of crude product with chiral purity of 96.1%.
And (4) continuing to use the mother liquor circularly for 12 times according to the method in the step 2.
And step 3: 1240.8g of cis-D-hydroxyproline crude product (crude product yield is 89.7%) is added into a methanol/ethyl acetate mixed solution (mass ratio is 1.1: 1) which is 0.5 time of the mass of the cis-D-hydroxyproline crude product, the temperature is raised to 90 ℃, the mixture is stirred, after the mixture is completely dissolved, the temperature is lowered to 25 ℃, recrystallization is carried out, 1182.5g of cis-D-hydroxyproline is obtained, the chiral purity is 99.8%, and the total yield is 85.5%.
Example 6
This example differs from example 1 in that: propionic acid was used instead of acetic acid, and salicylaldehyde was used instead of n-butyraldehyde.
Example 7
This example differs from example 1 in that: the mass ratio of the components is 1: 1A mixed solution of n-butyric acid and acetic acid was used in place of the acetic acid in example 1 in equal amounts.
Test example 1
Effect of the amounts of acetic acid and n-Butanal on the reaction
On the basis of example 1, the experimental conditions of step 1 were changed, and the final reaction results were verified under different experimental conditions.
The amounts of acetic acid and n-butyraldehyde were varied, and it was confirmed that the different amounts of acetic acid and n-butyraldehyde resulted in variations in the number of application of experiments and the final results, and the results are shown in table 1.
TABLE 1 results
As can be seen from Table 1, the usage amounts of acetic acid and n-butyraldehyde have obvious influence on the number of times of mother liquor application and yield, when the usage amount of acetic acid is more than 4 times of trans-L hydroxyproline, and the usage amount of n-butyraldehyde is more than 2 wt% of trans-L hydroxyproline, the mother liquor can be basically applied more than 10 times, but when the usage amount of acetic acid is more than 5 times of trans-L hydroxyproline, and the usage amount of n-butyraldehyde is more than 3 wt% of trans-L hydroxyproline, the mother liquor can be applied more times, but the yield of crude products is not obviously improved. And the purity of the crude product is gradually reduced along with the increase of the applied batch.
Therefore, when the consumption of acetic acid and n-butyl aldehyde is increased to 5 times and more than 3 wt% of trans-L hydroxyproline, the yield of the crude product is not obviously increased, the problems of low purity of the crude product and comprehensive cost are considered, the consumption of acetic acid is 4-5 times of that of the trans-L hydroxyproline, the consumption of n-butyl aldehyde is 2-3 wt% of that of the trans-L hydroxyproline is most suitable, the purity of the crude product can reach more than 95%, the yield can reach more than 88%, and the crude product is applied to 10-12 times in batch.
Test example 2
Effect of additional feed on the reaction
On the basis of example 1, the amount of the additional raw materials used in the batch was changed while keeping the other conditions unchanged, and the change caused by the difference in the amount of the additional raw materials was determined, and the results are shown in table 2.
TABLE 2 results
When the amount of the raw materials supplemented is less than 55g, the converted products are reduced along with the reduction of the amount of the substrates, and the final yield is low, when the amount of the raw materials supplemented is more than 60g, the amount of the substrates of acetic acid and n-butyraldehyde is reduced relative to the substrates, so that the applied batches are reduced, and the yield is reduced along with the reduction of the amount of the substrates, therefore, the raw materials supplemented each time are suitably selected to be 55-60g, which is 42-46 wt% of the initial raw materials.
Test example 3
Effect of methanol/Ethyl acetate Mixed solution on product purification
5 groups of crude products (purity 96.1%) from the same batch were taken and recrystallized according to the procedure of example 1 using different amounts of mixed solution, and the results are shown in Table 3.
TABLE 3 results
| Group of | Mass ratio of crude product to mixed solution | Yield (%) | Purity (%) |
| 1 | 1：0.4 | 92.5％ | 98.5 |
| 2 | 1：0.45 | 90.4 | 99.8 |
| 3 | 1:0.5 | 90.2 | 99.9 |
| 4 | 1:0.55 | 88.7 | 99.9 |
| 5 | 1:0.6 | 81.5 | 99.9 |
When the using amount of the mixed solution is less than 0.45 times of the mass of the crude product, the crude product cannot be completely dissolved, so that the recrystallization is incomplete, the purity is low, when the using amount of the mixed solution is more than 0.55 times of the mass of the crude product, part of products are dissolved in the solvent, the products cannot be completely crystallized, the product loss is caused, and the yield is reduced, so that the mass ratio of the crude product to the mixed solvent is selected to be 1: within the range of 0.45-0.55, the yield can be kept about 90%, and the purity can be purified to more than 99.5%.
Test example 4
Effect of different mixed solutions on product purification
2 groups of crude products from the same batch (purity 96.1%) were taken, and the crude products were recrystallized using the same amount of mixed solution formed by mixing different reagents, wherein the mixed solution in group 1 was methanol and ethyl acetate 1 in example 1: 1, the mixed solution in the group 2 is ethanol and ethyl acetate 1: 1, and the results are shown in table 4.
TABLE 4 results
The mixed solution of methanol and ethyl acetate is adopted to carry out purification smoothly, the yield and the purity are normal, and ethanol and ethyl acetate are adopted to carry out recrystallization, so that although the purity is improved to some extent, the product is seriously dissolved, and the yield of the final pure product is low.
In conclusion, compared with the prior art, the process provided by the application adopts trans-L-hydroxyproline as a raw material, cis-D-hydroxyproline is obtained through racemization and isomerization, the raw material of the unconverted part is continuously supplemented with the mother liquor to continuously react, the mother liquor is recycled and reused for many times, the mother liquor is reused for many times (particularly for more than 10 times), the total yield can reach more than 85%, the purity of the crude product after purification can reach more than 99.5%, the operation is simple, and the cost is low.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of cis-D-hydroxyproline is characterized by comprising the following steps:
racemizing trans-L-hydroxyproline, cooling for the first time, recrystallizing, and carrying out solid-liquid separation to obtain a first cis-D-hydroxyproline crude product and a first mother liquor;
mixing the first mother liquor with new trans-L-hydroxyproline, racemizing, cooling for recrystallization for the second time, and carrying out solid-liquid separation to obtain a second cis-D-hydroxyproline crude product and a second mother liquor; mixing the second mother liquor with new trans-L-hydroxyproline and circularly preparing the new crude cis-D-hydroxyproline and the new mother liquor for at least 6 times according to the mode of preparing the second crude cis-D-hydroxyproline and the second mother liquor;
and dissolving all prepared cis-D-hydroxyproline crude products in a mixed solution of methanol and ethyl acetate, and then cooling and recrystallizing to obtain the cis-D-hydroxyproline.
2. The method according to claim 1, wherein racemization is carried out by reacting the trans-L-hydroxyproline with an organic acid and a racemizing agent;
preferably, the organic acid comprises at least one of acetic acid, propionic acid and n-butyric acid, more preferably acetic acid;
preferably, the racemization agent comprises at least one of salicylaldehyde and n-butyraldehyde, and more preferably n-butyraldehyde.
3. The method of claim 2, wherein racemization is carried out at 85-90 ℃ for 8-15 h.
4. The production process according to claim 2 or 3, wherein the organic acid and the racemizing agent used in the racemization reaction are acetic acid and n-butyraldehyde, respectively;
preferably, the mass ratio of the trans-L-hydroxyproline to the acetic acid is 1: 3-6, preferably 1: 4-5;
preferably, the mass ratio of the trans-L-hydroxyproline to the n-butyraldehyde is 1: 0.01 to 0.04, preferably 1: 0.02-0.03.
5. The method according to claim 1, wherein the recrystallization is carried out at 20 to 25 ℃.
6. The method according to claim 1, wherein all of the crude cis-D-hydroxyproline produced is dissolved in a mixed solution of methanol and ethyl acetate at 80-85 ℃.
7. The preparation method according to claim 6, wherein the mass ratio of the mixed solution of methanol and ethyl acetate to the crude cis-D-hydroxyproline is 0.45-0.55: 1, preferably 0.5: 1.
8. the preparation method according to claim 7, wherein in the mixed solution of methanol and ethyl acetate, the mass ratio of methanol to ethyl acetate is 0.9-1.1: 0.9-1.1.
9. The method of claim 1, wherein the number of cycles is 6 to 13, preferably 9 to 13.
10. The method according to claim 1, wherein the amount of the trans-L-hydroxyproline newly added at each time is 42 to 46% by mass based on the amount of the trans-L-hydroxyproline used in the initial preparation of the crude cis-D-hydroxyproline.
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| CN113979909A (en) * | 2021-10-21 | 2022-01-28 | 上海吉奉生物科技有限公司 | Synthesis method of (3S,5R) -5- (hydroxymethyl) pyrrolidine-3-alkoxide |
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