CN108409561B - Preparation method of 5-aminolevulinic acid hydrochloride and intermediate - Google Patents
Preparation method of 5-aminolevulinic acid hydrochloride and intermediate Download PDFInfo
- Publication number
- CN108409561B CN108409561B CN201710331157.6A CN201710331157A CN108409561B CN 108409561 B CN108409561 B CN 108409561B CN 201710331157 A CN201710331157 A CN 201710331157A CN 108409561 B CN108409561 B CN 108409561B
- Authority
- CN
- China
- Prior art keywords
- compound
- mol
- acid hydrochloride
- aminolevulinic acid
- ratio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
Abstract
The invention discloses a preparation method of 5-aminolevulinic acid hydrochloride and an intermediate thereof. A preparation method of a 5-aminolevulinic acid hydrochloride intermediate comprises the following steps: (1) reacting the compound 2 with isopropylidene malonate in an organic solvent under the action of organic base and a condensing agent to obtain a compound 3; (2) the compound 3 is in C1～C4Reacting in the alcohol solvent to obtain a compound 4; wherein R is1And R' are each independently C1～C4Alkyl group of (1). The invention also provides a method for preparing the 5-aminolevulinic acid hydrochloride by using the intermediate. In the method, the intermediate products are basically solid and are easy to crystallize and purify; high yield, low production cost, easy operation and contribution to industrial production.
Description
Technical Field
The invention relates to a preparation method of a photosensitizer 5-aminolevulinic acid hydrochloride and an intermediate thereof.
Background
Photodynamic therapy (PDT) was initiated in the seventies of the twentieth century and has gradually become one of the fundamental means for treating tumors in recent years due to the development and progress of photosensitizing substances and the like. The hydrochloride of 5-aminolevulinic acid is the hydrochloride of 5-aminolevulinic acid (5-ALA) which is a new generation photodynamic therapy medicament and is clinically used for treating Actinic Keratosis (AK).
Although the 5-aminolevulinic acid hydrochloride has a simple structure, the synthesis of the hydrochloride is difficult, and the synthesis process is particularly suitable for industrial production. The main synthesis method can be summarized as follows:
1. glycine is used as a raw material, and phthalic acid amidation, acyl chlorination, condensation, decarboxylation and hydrolysis (J.chem.Soc. (1954,1820)) are carried out:
2. using furan methylamine as raw material, performing phthalic amidation, photooxidation, reduction and hydrolysis (EP 607,952):
3. the method comprises the following steps of taking furan methylamine as a raw material, reducing, carrying out phthalic amidation, carrying out ruthenium catalytic oxidation, and hydrolyzing (EP 483,714):
4. using epichlorohydrin as a raw material, performing a Gerberry reaction, bromination, oxidation, condensation, hydrolysis, decarboxylation, and hydrolysis (J.org.chem. (1959,556)):
5. bromination, guerberi reaction, hydrolysis (can. j. of Chem. (1974,3257); ball. de soc. chimi. de France (1956,1750)) using levulinic acid as a starting material:
6. using succinic anhydride as a raw material, and performing mono-esterification, acyl chlorination, cyanidation, reduction and hydrolysis (tetra. Lett. (1984,2977)):
7. using levulinic acid as a raw material, and carrying out bromination, azide and hydrogenolysis (syn. Commun. (1994,2557)):
8. using succinic anhydride as a raw material, and performing mono-esterification, acyl chlorination, condensation, nitrosation, reduction and hydrolysis (syn) (1999,568)):
9. the method comprises the following steps of taking succinic anhydride as a raw material, and carrying out monoesterification, acyl chlorination, imidazolation, nitromethane substitution and hydrogenation reduction (syn) (1999,568)):
from the above synthetic route: or the synthesis route is too long, the yield is not high, and the equipment investment is large, so the cost is not too low even if the raw materials are cheap and easy to obtain (such as the routes 4 and 8); either the route is short but the reagents used are either highly contaminated (e.g., routes 4, 6), less safe (e.g., routes 6 and 7) or too expensive (e.g., routes 2, 3, and 9), or the conditions under which the procedure is performed are harsh (e.g., routes 1 and 2). The synthesis route with the most industrial prospect is 5, the reaction route is short, the raw materials are cheap, but the technical problem of the route in industrialization is that the bromination esterification of levulinic acid is carried out, the proportion of 3-position brominated products is high besides the desired 5-position brominated products, and the side reaction cannot be eliminated by controlling the reaction conditions and is mainly separated by purification. The prior art mainly separates by column chromatography or high vacuum rectification, which has high cost and large irritation of bromide, and can cause physical damage to operators. Recently, it has been reported (CN1490305A) that the product of bromination esterification of levulinic acid can be directly subjected to a Gerberil reaction without separation and then purified by recrystallization. However, the yield of this process is too low (7%), and the production cost is not low because a large amount of expensive potassium phthalimide salt is used.
Disclosure of Invention
The invention aims to overcome the defects of large pollution, poor safety, expensive raw materials or harsh operating conditions of the existing 5-aminolevulinic acid (5-ALA) hydrochloride preparation process, and provides a novel preparation method of 5-aminolevulinic acid hydrochloride and an intermediate, which is suitable for industrial production. In the method, the intermediate products are basically solid and are easy to crystallize and purify; high yield, low production cost, easy operation and contribution to industrial production.
The invention provides a preparation method of a 5-aminolevulinic acid hydrochloride intermediate, which comprises the following steps:
(1) reacting the compound 2 with isopropylidene malonate in an organic solvent under the action of organic base and a condensing agent to obtain a compound 3;
(2) the compound 3 is in C1～C4Reacting in the alcohol solvent to obtain a compound 4;
wherein R is1And R' are each independently C1～C4Alkyl group of (1).
Said R1Preferably methyl, ethyl or propyl.
R' is preferably methyl or ethyl.
In step (1), the organic solvent can be an organic solvent conventional in the reaction of the type in the art, and dichloromethane is particularly preferred in the present invention.
In step (1), the organic base may be an organic base conventional in this type of reaction in the art, for example, one or more of triethylamine, pyridine and 4-Dimethylaminopyridine (DMAP), with 4-dimethylaminopyridine being particularly preferred in the present invention.
In step (1), the condensing agent may be one conventional in the art for such reactions, and Dicyclohexylcarbodiimide (DCC) is particularly preferred in the present invention.
In the step (1), the amount of the organic solvent can be the amount conventionally used in the reaction in the field so as not to affect the reaction, and the volume molar ratio of the organic solvent to the compound 2 is particularly preferably 0.1L/mol to 5L/mol; more preferably 0.2L/mol to 0.5L/mol.
In the step (1), the molar ratio of the organic base to the isopropylidene malonate can be 1: 1-5: 1; preferably 1.5: 1.
In the step (1), the molar ratio of the condensing agent to the isopropylidene malonate can be 1: 1-2: 1; preferably 1.2: 1.
In the step (1), the molar ratio of the compound 2 to the isopropylidene malonate can be 1: 1-1: 2; preferably 1: 1.
In the step (1), the reaction temperature is a temperature conventional in the reaction in the field, and is particularly preferably 35-45 ℃ in the invention.
In the step (1), preferably, after the isopropylidene malonate, the organic base, the condensing agent and the organic solvent are mixed, the compound 2 is added dropwise to a mixed system of the isopropylidene malonate, the organic base, the condensing agent and the organic solvent; the mixing time of the mixed system is not particularly limited, but is generally 5 to 30 minutes, preferably 15 minutes.
After the reaction of step (1) is finished, preferably, after concentration and/or filtration treatment, a mixture containing the compound 3 is obtained and is directly subjected to step (2).
In the step (2), the step C1～C4The alcoholic solvent is preferably methanol and/or ethanol.
In the step (2), the volume mol ratio of the alcohol solvent to the compound 3 can be 0.1L/mol to 5L/mol; preferably 0.3L/mol.
In the step (2), the reaction temperature is a conventional temperature in the field, preferably 65 to 120 ℃, and preferably 80 to 100 ℃.
The progress of the reaction steps in the preparation of the 5-aminolevulinic acid hydrochloride intermediate can be monitored by means of conventional test methods in the art (e.g. TLC, HPLC or NMR), typically with the end point of the reaction being the disappearance or no longer reaction of the starting material.
The invention also provides a preparation method of the 5-aminolevulinic acid hydrochloride, which comprises the following steps:
(1) reacting the compound 2 with isopropylidene malonate in an organic solvent under the action of organic base and a condensing agent to obtain a compound 3;
(2) the compound 3 is in C1～C4To obtain a compound 4;
(3) reacting sodium nitrite with the compound 4 in acetic acid to obtain a compound 5;
(4) carrying out reduction reaction on the compound 5 in a zinc acetate powder reduction system or a hydrogenation reduction system to obtain a compound 6;
(5) reacting the compound 6 with aqueous solution of hydrogen chloride to obtain the compound 5-aminoketone valerate;
wherein R is1And R' are as defined above.
In the step (1) and the step (2), each preferable condition of the reaction is the same as described above.
In the step (3), the volume mol ratio of the acetic acid to the compound 4 can be 0.2L/mol to 5L/mol; preferably 0.5L/mol.
In the step (3), the molar ratio of the sodium nitrite to the compound 4 can be 1: 1-1.5: 1; preferably 1.1: 1.
In the step (3), the sodium nitrite can be conventional in the reaction of the type in the field, such as an aqueous solution, and the volume molar ratio of the water to the sodium nitrite is particularly preferably 0.1L/mol to 1L/mol; further preferably 0.2L/mol.
In the step (3), the reaction temperature is the temperature conventional in the reaction in the field, for example, 0-25 ℃; in the present invention, the temperature is particularly preferably 20 to 25 ℃.
In the step (4), the using amount of the zinc powder is the conventional using amount of the reaction in the field; in the invention, the molar ratio of the zinc powder to the compound 5 is particularly preferably 2: 1-10: 1; more preferably 4: 1.
In the step (4), the dosage of the acetic acid is the dosage which is conventional in the reaction in the field; in the invention, the volume mol ratio of the acetic acid to the compound 5 can be 0.2L/mol to 10L/mol; more preferably 0.5L/mol.
In step (4), the hydrogenation reduction system can be a hydrogenation reduction system conventional in the art for such reactions, and palladium on carbon and hydrogen are particularly preferred in the present invention.
In the step (4), the dosage of the palladium-carbon is the dosage which is conventional in the reaction in the field; in the present invention, it is particularly preferable that the mass molar ratio of the palladium on carbon to the compound 5 may be 1g/mol to 10 g/mol; preferably 2 g/mol.
In the step (5), the molar ratio of the hydrogen chloride to the compound 6 can be 2: 1-10: 1; preferably 5: 1.
In the step (5), the concentration of the aqueous hydrogen chloride solution is the concentration conventional in the reaction of the type in the field, for example, 1 to 12mol/L, and in the invention, 6mol/L is particularly preferred.
In the step (5), the reaction temperature is the temperature conventional in the reaction in the field, and is particularly preferably 80-120 ℃ in the invention.
The compound 5-aminolevulinic acid hydrochloride can be crystallized by using an organic solvent which is conventional in the reactions of the type in the field, and methanol and ethyl acetate are particularly preferred in the invention.
The volume mass ratio of the crystallized organic solvent to the 5-aminolevulinic acid hydrochloride can be the volume mass ratio which is conventional in the reactions in the field, and the volume mass ratio of the crystallized organic solvent to the 5-aminolevulinic acid hydrochloride is particularly preferably 1 mL/g-10 mL/g in the invention; preferably 2 to 3 mL/g.
The volume ratio of the methanol to the ethyl acetate can be 5: 1-1: 5; preferably 1: 1.
In the preparation of the 5-aminolevulinic acid hydrochloride salt, the progress of the reaction steps can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, or NMR), and the end point of the reaction is generally the disappearance or no longer reaction of the starting material.
The preparation method of the compound 5-aminolevulinic acid hydrochloride can also comprise the following post-treatment steps: after the reaction in each step is finished, filtering and/or concentrating and separating to obtain the compound; preferably, after the reaction in each step is completed, the obtained compound is directly reacted in the next step without separation (i.e., without separation and purification of the compound or obtaining a mixture containing the compound; for example, the reaction solution is subjected to no post-treatment, or the reaction solution is subjected to simple post-treatment, such as filtration and concentration, etc.) to prepare the compound; for example, the reaction solution is filtered (may comprise washing the filter cake), and then the reaction in the next step is directly performed.
The term "room temperature" is used in the art to mean at 10-30 ℃.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: 1. in the method, the intermediate products are basically solid and are easy to crystallize and purify; 2. the method has the advantages of high yield, low production cost, easy operation and contribution to industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
1000ml of dichloromethane, 183g of DMAP, 250g of DCC and 144g of isopropylidene malonate are added into a 2000ml four-mouth bottle, after stirring for 15 minutes at room temperature, 132g of monomethyl succinate solution dissolved in 200ml of dichloromethane is added dropwise, heating reflux is carried out after the addition is finished, concentration is carried out after TLC detection reaction is finished, the obtained solid is washed by water, and the solid is directly used for the next step after vacuum drying.
And (3) dissolving the product of the previous step in 1000ml of absolute ethanol, heating and refluxing, and concentrating after TLC detection reaction is finished to obtain 170g of product which is directly used for the next step. (two-step yield>90% purity of>97％)1H NMR(300M，CDCl3)δ：1.26(t，3H)1.30(t，3H)，2.65(t，2H)，2.90(t，2H)，3.51(s，2H)，4.15(q，2H)，4.20(q，2H)。
Dissolving the product of the previous step in 1000ml of acetic acid, cooling to 0 ℃, dropwise adding a solution of sodium nitrite 69g in 200ml of water, controlling the dropping speed to ensure that the temperature does not exceed 5 ℃, slowly raising the temperature to react (20-25 ℃), precipitating a large amount of solid, and performing suction filtration and drying for the next step. 205g (yield > 90%, purity > 97%)
And (3) dissolving the product in the previous step in 1000ml of acetic acid, slowly adding 200g of zinc powder in batches, detecting by TLC, filtering after complete reaction, washing a filter cake by ethyl acetate, combining and concentrating, and directly using the obtained product in the next step.
The product obtained in the previous step and 500mL of 6N hydrochloric acid are heated and refluxed together for 6 hours, activated carbon is used for decolorization, water is concentrated, and the residue is recrystallized by using a mixed solvent of 2 times (mL/g) of methanol and ethyl acetate (1:1) to obtain 100g of a white solid product. mp: 148 ℃ and 149 ℃ (yield > 80%, purity > 99.5%).
1HNMR(300M，D2O)δ：2.50(2H,t,-CH2-),2.69(2H,t,-CH2-),3.92(2H,s,-CH2NH2)
Example 2
250 liters of dichloromethane is pumped into a 500 liter reaction kettle, 18.3kg of DMAP, 25kg of DCC and 14.4kg of isopropylidene malonate are added, after stirring for 15 minutes at room temperature, 14.6kg of solution of monoethyl succinate dissolved in 50 liters of dichloromethane is added dropwise, after the addition is finished, heating reflux is carried out, after TLC detection reaction is finished, concentration is carried out, the obtained solid is washed by water, and after vacuum drying, the solid is directly used for the next step.
And (3) dissolving the product of the previous step in 200L of anhydrous methanol, heating and refluxing, and concentrating after TLC detection reaction is finished to obtain 17kg of the product which is directly used for the next step. (two-step yield>90% purity of>97％)1H NMR(300M，CDCl3)δ：2.65(t，2H)，2.90(t，2H)，3.51(s，2H)，3.68(s，2H)，3.78(s，2H)。
Dissolving the product of the previous step in 100 liters of acetic acid, cooling to 0 ℃, dropwise adding 6.9kg of sodium nitrite solution in 20 liters of water, controlling the dropping speed to ensure that the temperature does not exceed 5 ℃, slowly raising the temperature to react (20-25 ℃) after the addition is finished, separating out a large amount of solid, performing suction filtration, and drying for the next step. 17.2kg (yield > 90%, purity > 97%).
Dissolving the product of the previous step in 200L of methanol and 5L of 6N hydrochloric acid, adding 1kg of 5% palladium carbon, hydrogenating under normal pressure, detecting by TLC, filtering after complete reaction, washing a filter cake with ethyl acetate, combining and concentrating, and directly using the obtained product for the next step.
The product obtained in the previous step was reacted with 200L of 6N hydrochloric acid under reflux with heating for 6 hours, decolorized with activated carbon, concentrated to remove water, and the residue was recrystallized from 3 times (mL/g) of methanol and ethyl acetate (1:1) to obtain 10kg of a white solid product (yield > 80%, purity > 99.5%).
mp：148-149℃。
The hydrogen spectra data are as above.
Example 3
1000ml of dichloromethane, 183g of DMAP, 250g of DCC and 144g of isopropylidene malonate are added into a 2000ml four-mouth bottle, stirred for 15 minutes at room temperature, 160g of monopropyl succinate solution dissolved in 200ml of dichloromethane is added dropwise, heating reflux is carried out after the addition is finished, concentration is carried out after TLC detection reaction is finished, the obtained solid is washed by water, and the solid is directly used for the next step after vacuum drying.
Dissolving the product of the previous step in 1000ml of absolute ethanol, heating and refluxing, detecting by TLC, concentrating after the reaction is finished, and directly using 200g of the obtained product for the next step (two-step yield)>90% purity of>97％)。1H NMR(300M，CDCl3)δ：1.26(t，3H)1.30(t，3H)，2.65(t，2H)，2.90(t，2H)，3.51(s，2H)，4.15(q，2H)，4.20(q，2H)。
Dissolving the product of the previous step in 1000ml of acetic acid, cooling to 0 ℃, dropwise adding a solution of sodium nitrite 69g in 200ml of water, controlling the dropping speed to ensure that the temperature does not exceed 5 ℃, slowly raising the temperature to react after the addition is finished, precipitating a large amount of solid, performing suction filtration, and drying to be used for the next step. 203g (yield > 90%, purity > 97%)
And (3) dissolving the product in the previous step in 1000ml of acetic acid, slowly adding 200g of zinc powder in batches, detecting by TLC, filtering after complete reaction, washing a filter cake by ethyl acetate, combining and concentrating, and directly using the obtained product in the next step.
The product obtained in the previous step was reacted with 500mL of 6N hydrochloric acid under reflux with heating for 6 hours, decolorized with activated carbon, concentrated to remove water, and the residue was recrystallized from 2-fold (mL/g) of methanol and ethyl acetate (1:1) to obtain 100g of a white solid product (yield > 80%, purity > 99.5%). mp: 148 ℃ and 149 ℃.
The hydrogen spectra data are as above.
Claims (15)
1. The preparation method of the 5-aminolevulinic acid hydrochloride is characterized by comprising the following steps:
(1) reacting the compound 2 with isopropylidene malonate in an organic solvent under the action of organic base and a condensing agent to obtain a compound 3;
(2) the compound 3 is in C1～C4To obtain a compound 4;
(3) reacting sodium nitrite with the compound 4 in acetic acid to obtain a compound 5;
(4) carrying out reduction reaction on the compound 5 in an acetic acid and zinc powder reduction system or a hydrogenation reduction system to obtain a compound 6;
(5) reacting the compound 6 with aqueous solution of hydrogen chloride to obtain the compound 5-aminoketone valerate;
wherein the content of the first and second substances,
R1when it is methyl or propyl, C1～C4The alcohol solvent is ethanol, and R' is ethyl; or R1Is ethyl, C1～C4The alcohol solvent is methanol, and R' is methyl.
2. The process for the preparation of 5-aminolevulinic acid hydrochloride according to claim 1, wherein:
in the step (1), the organic solvent is dichloromethane;
or in the step (1), the organic base is one or more of triethylamine, pyridine and 4-dimethylaminopyridine;
or in the step (1), the condensing agent is dicyclohexylcarbodiimide;
or in the step (1), the volume mol ratio of the organic solvent to the compound 2 is 0.1L/mol to 5L/mol;
or in the step (1), the molar ratio of the organic base to the isopropylidene malonate is 1: 1-5: 1;
or in the step (1), the molar ratio of the condensing agent to the isopropylidene malonate is 1: 1-2: 1;
or in the step (1), the molar ratio of the compound 2 to the isopropylidene malonate is 1: 1-1: 2;
or in the step (2), the volume mol ratio of the alcohol solvent to the compound 3 is 0.1L/mol-5L/mol.
3. The process for the preparation of 5-aminolevulinic acid hydrochloride according to claim 2, wherein: in the step (1), the organic base is 4-dimethylaminopyridine;
or in the step (1), the volume mol ratio of the organic solvent to the compound 2 is 0.2L/mol to 0.5L/mol;
or in step (1), the molar ratio of the organic base to the isopropylidene malonate is 1.5: 1;
or in step (1), the molar ratio of the condensing agent to the isopropylidene malonate is 1.2: 1;
or in the step (1), the molar ratio of the compound 2 to the isopropylidene malonate is 1: 1;
or in the step (2), the volume mol ratio of the alcohol solvent to the compound 3 is 0.3L/mol.
4. A process for the preparation of 5-aminolevulinic acid hydrochloride according to any one of claims 1 to 3, wherein: in the step (1), the reaction temperature is 35-45 ℃;
or in the step (1), after the isopropylidene malonate, the organic base, the condensing agent and the organic solvent are mixed, the compound 2 is dripped into a mixed system of the isopropylidene malonate, the organic base, the condensing agent and the organic solvent; the mixing time of the mixed system is 5-30 minutes;
or after the reaction in the step (1) is finished, concentrating and/or filtering to obtain a mixture containing the compound 3, and directly performing the step (2);
or in the step (2), the reaction temperature is 65-120 ℃.
5. The process for preparing 5-aminolevulinic acid hydrochloride according to claim 4, wherein: in the step (1), the mixing time of the mixed system is 15 minutes;
or in the step (2), the reaction temperature is 80-100 ℃.
6. The process for the preparation of 5-aminolevulinic acid hydrochloride according to claim 1, wherein:
in the step (3), the volume mol ratio of the acetic acid to the compound 4 is 0.2L/mol to 5L/mol;
or in the step (3), the molar ratio of the sodium nitrite to the compound 4 is 1: 1-1.5: 1;
or in the step (3), the sodium nitrite is aqueous solution;
or in the step (4), the molar ratio of the zinc powder to the compound 5 is 2: 1-10: 1;
or in the step (4), the volume mol ratio of the acetic acid to the compound 5 is 0.2L/mol to 10L/mol;
or in the step (4), the hydrogenation reduction system is palladium carbon and hydrogen;
or in the step (5), the molar ratio of the hydrogen chloride to the compound 6 is 2: 1-10: 1;
or in the step (5), the concentration of the aqueous solution of hydrogen chloride is 1-12 mol/L.
7. The process for preparing 5-aminolevulinic acid hydrochloride according to claim 6, wherein:
in the step (3), the volume mol ratio of the acetic acid to the compound 4 is 0.5L/mol;
or in the step (3), the molar ratio of the sodium nitrite to the compound 4 is 1.1: 1;
or in the step (4), the molar ratio of the zinc powder to the compound 5 is 4: 1;
or in the step (4), the volume mol ratio of the acetic acid to the compound 5 is 0.5L/mol;
or in the step (5), the molar ratio of the hydrogen chloride to the compound 6 is 5: 1;
or in the step (5), the concentration of the aqueous hydrogen chloride solution is 6 mol/L.
8. The process for preparing 5-aminolevulinic acid hydrochloride according to claim 6, wherein:
in the step (3), the volume mol ratio of water in the sodium nitrite water solution to sodium nitrite is 0.1L/mol-1L/mol;
or in the step (4), the mass molar ratio of the palladium carbon to the compound 5 is 1g/mol to 10 g/mol.
9. The process for the preparation of 5-aminolevulinic acid hydrochloride according to claim 8, wherein:
in the step (3), the volume mol ratio of water in the sodium nitrite aqueous solution to sodium nitrite is 0.2L/mol;
or in the step (4), the mass molar ratio of the palladium carbon to the compound 5 is 2 g/mol.
10. The method for producing 5-aminolevulinic acid hydrochloride according to any one of claims 1 to 3 or 6 to 9, wherein: in the step (3), the reaction temperature is 0-25 ℃;
or in the step (5), the reaction temperature is 80-120 ℃.
11. The process for the preparation of 5-aminolevulinic acid hydrochloride according to claim 10, wherein: in the step (3), the reaction temperature is 20-25 ℃.
12. The method for producing 5-aminolevulinic acid hydrochloride according to any one of claims 1 to 3 or 6 to 9, further comprising the steps of: the compound 5-aminolevulinic acid hydrochloride is crystallized by an organic solvent.
13. A process for the preparation of 5-aminolevulinic acid hydrochloride according to claim 12, wherein: the volume-mass ratio of the crystallized organic solvent to the 5-aminolevulinic acid hydrochloride is 1 mL/g-10 mL/g;
or the organic solvent for crystallization is methanol and ethyl acetate.
14. A process for the preparation of 5-aminolevulinic acid hydrochloride according to claim 13, wherein: the volume-mass ratio of the crystallized organic solvent to the 5-aminolevulinic acid hydrochloride is 2 mL/g-3 mL/g;
or the volume ratio of the methanol to the ethyl acetate is 5: 1-1: 5.
15. A process for the preparation of 5-aminolevulinic acid hydrochloride according to claim 14, wherein: the volume ratio of the methanol to the ethyl acetate is 1: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710331157.6A CN108409561B (en) | 2017-05-11 | 2017-05-11 | Preparation method of 5-aminolevulinic acid hydrochloride and intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710331157.6A CN108409561B (en) | 2017-05-11 | 2017-05-11 | Preparation method of 5-aminolevulinic acid hydrochloride and intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108409561A CN108409561A (en) | 2018-08-17 |
| CN108409561B true CN108409561B (en) | 2022-03-29 |
Family
ID=63125412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710331157.6A Active CN108409561B (en) | 2017-05-11 | 2017-05-11 | Preparation method of 5-aminolevulinic acid hydrochloride and intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108409561B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114085161A (en) * | 2021-08-09 | 2022-02-25 | 湖南复瑞生物医药技术有限责任公司 | Intermediate for preparing 5-ALA & HCl and preparation method of 5-ALA & HCl |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012082947A1 (en) * | 2010-12-16 | 2012-06-21 | Irm Llc | Compounds and compositions as tgr5 agonists |
| WO2013025939A2 (en) * | 2011-08-16 | 2013-02-21 | Indiana University Research And Technology Corporation | Compounds and methods for treating cancer by inhibiting the urokinase receptor |
| CN104496834A (en) * | 2014-11-27 | 2015-04-08 | 爱斯特（成都）生物制药有限公司 | Preparation method of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101462974B (en) * | 2007-12-18 | 2012-01-11 | 福建南方制药股份有限公司 | Process for synthesizing 5-aminovaleric acid hydrochloride |
| CN101538261B (en) * | 2009-04-28 | 2012-11-07 | 中国医药集团总公司四川抗菌素工业研究所 | Method for preparing (3R, 5S)-3, 5-O-isopropylidene-3, 5, 6-trihydroxy caproic acid hexylic acid derivative |
| CN101891639A (en) * | 2009-05-20 | 2010-11-24 | 上海先导化学有限公司 | Method for preparing 5-aminolevulinic acid hydrochloride |
| CN102627573B (en) * | 2012-03-30 | 2013-09-25 | 山东大学 | Synthesis method for 5-aminolevulinic acid hydrochloride |
| CN102617540A (en) * | 2012-04-19 | 2012-08-01 | 江苏施美康药业有限公司 | Method for preparing (S)-3,6-dioxo-5,6-isopropylidene-5,6-dyhydroxyl hexanoic acid tert-butyl ester |
| CN103467326A (en) * | 2013-08-02 | 2013-12-25 | 苏州摩尔医药有限公司 | Synthetic method for 5-aminolevulinic acid hydrochloride |
| CN106187844B (en) * | 2015-05-04 | 2018-02-27 | 复旦大学 | A kind of preparation method of the mercaptopentanoic acid of (S) 4 amino 5 |
-
2017
- 2017-05-11 CN CN201710331157.6A patent/CN108409561B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012082947A1 (en) * | 2010-12-16 | 2012-06-21 | Irm Llc | Compounds and compositions as tgr5 agonists |
| WO2013025939A2 (en) * | 2011-08-16 | 2013-02-21 | Indiana University Research And Technology Corporation | Compounds and methods for treating cancer by inhibiting the urokinase receptor |
| CN104496834A (en) * | 2014-11-27 | 2015-04-08 | 爱斯特（成都）生物制药有限公司 | Preparation method of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid |
Non-Patent Citations (1)
| Title |
|---|
| "Hantzsch-Type Three-Component Approach to a New Family of Carbon-Linked Glycosyl Amino Acids. Synthesis of C-Glycosylmethyl Pyridylalanines";Alessandro Dondoni, et al.,;《J. Org. Chem.》;20070906;第72卷(第20期);第7677-7687页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108409561A (en) | 2018-08-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2839344B2 (en) | Method for producing cyclic amino acid and intermediate thereof | |
| CN110330500B (en) | Stereoselective synthesis method of 6 beta-hydroxy-7, 8-dihydro-morphine derivative | |
| CN112851646B (en) | Preparation method of tergolian prazan | |
| CN113121416A (en) | Preparation method of lefenacin | |
| CN116640088A (en) | Preparation method of high-purity Lei Fen narasin | |
| JP2005507900A (en) | Citalopram manufacturing method | |
| CN108409561B (en) | Preparation method of 5-aminolevulinic acid hydrochloride and intermediate | |
| JP4729039B2 (en) | Method for preparing gabapentin | |
| JPH0250908B2 (en) | ||
| CN113480480B (en) | Synthesis method of (R) -5' -methoxy laudan | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN114478290A (en) | Synthetic method of oseltamivir intermediate | |
| CN110903211B (en) | Preparation method of L-theanine | |
| CN111004255A (en) | Preparation method of cefcapene lactone compound or hydrochloride thereof | |
| JP2020070296A (en) | Method for producing linagliptin | |
| CN111100110A (en) | Process for preparing 7-piperazinylbenzothiophenes or salts thereof | |
| CN114195684B (en) | Synthesis method of amino protecting group N-substituted chiral amino acid | |
| CN109535025B (en) | Preparation method of Evonib intermediate 3, 3-difluorocyclobutylamine hydrochloride | |
| CN109796353B (en) | Synthetic method of 5-aminolevulinic acid hydrochloride | |
| JP2018016569A (en) | Production method of (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile oxalate | |
| FI86714C (en) | FRAME STEERING FOR AMINOMALONSYRADINITRILSALTER | |
| CN116947616A (en) | Vitamin K1 purification method | |
| CN114736157A (en) | Preparation method of rosxastat, and pharmaceutical composition and application thereof | |
| CN110885315A (en) | Preparation method of important intermediate of levosimendan | |
| CN114085161A (en) | Intermediate for preparing 5-ALA & HCl and preparation method of 5-ALA & HCl |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20181207 Address after: 361027 B7 Building, Xiamen Biomedical Industrial Park, 2062 Wengjiao West Road, Haicang District, Xiamen City, Fujian Province Applicant after: Xiamen Ben Su Pharmaceutical Co., Ltd. Address before: 201612 Six Floors of 20 Building 201 Minyi Road, Songjiang District, Shanghai Applicant before: Shanghai Medicine Technology Co., Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |