CN109336895A - A kind of synthetic method of pholcodine - Google Patents
A kind of synthetic method of pholcodine Download PDFInfo
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- CN109336895A CN109336895A CN201811325865.XA CN201811325865A CN109336895A CN 109336895 A CN109336895 A CN 109336895A CN 201811325865 A CN201811325865 A CN 201811325865A CN 109336895 A CN109336895 A CN 109336895A
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- pholcodine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention discloses a kind of synthetic methods of pholcodine, by being performed the derivatization in its phenolic hydroxyl group using morphine base as starting material, increase branch, then it is further reacted with the amido in morpholine in the intermediate and generates pholcodine crude product, then purify to obtain pholcodine by certain purification means.Reactions steps of this method is simple, and reagent is economical and easily available, avoids the application risk of a large amount of severe toxicity and inflammable and explosive solvent, substantially increases product yield and purity.
Description
Technical field
The present invention relates to combination drugs to synthesize field, and in particular to a kind of synthetic method of pholcodine.
Background technique
Pholcodine (Pholcodine), alias prodromine or actuss, belong to the semi-synthetic derivative of morphine.For in
Pivot antibechic depressant, and have calm and analgesic activity, it is similar to codeine, but oral antitussive effect is strong compared with codeine, and it is additive
Weaker, respiration inhibition effect is small compared with morphine.For treating severity dry cough and moderate pain, newborn and children are easy to be resistant to this
Medicine will not cause constipation and digestive disorders.Structural formula is as follows:
Few to the synthetic method of the existing report of pholcodine, reported synthetic method is usually to synthesize morpholine
Morpholine ethyl alcohol, then chlorination reaction is chlorination of hydrochloric acid dionin quinoline, generates pholcodine finally by being condensed with morphine base
(Aust.J.Chem, 1996,49,1235-1242) (Pharmazie, 1994,49,530-531).Or pass through 2- chloroethyl
Benzene sulfonic acid rouge reacted with morphine base obtain (Australian Journal of Chemistry, 1996,49,1235-
1242)。
Wherein chlorethanol used in addition process is poisonous reagent, and the ethylene oxide of generation is also toxic and is difficult to accurately
Control amount, the unstable of ethylene oxide cause to need to use in preparation in production, are passed into subsequent reactions in gaseous form
In, the amount of the ethylene oxide generated and the yield finally to product is all generated into huge shadow the case where contact with reaction solution
It rings.
This method uses more severe toxicity and strong corrosive reagent, and the repeatedly a large amount of of strong acid and strong base reagent use, and use has
Solvent is mostly inflammable and explosive solvent and aequum is relatively large, and condensation reaction condition is more demanding, is easy life
At product is eliminated, W-response step is more for generating operation increase difficulty and security risk being brought to reduce final products
Yield.
Summary of the invention
The technical solution of this patent passes through the introducing branch directly on morphine base and reacts synthesis pholcodine with morpholine again,
Synthetic route is optimized, synthesis step is reduced and improves the economy of atom, reduces the generation of by-product.
Wherein nano-CuI activates alkyl halide, while being catalyzed morpholine coupling and greatly improving reaction efficiency.Original is evaded
The poisonous reagent and a large amount of inflammable and explosive reagents arrived used in synthetic route, reduces the usage amount to strong acid-base, reacts item
Part is also comparatively safe gentle, improves safety and operability in production process.
The advantage compared with published synthetic method are as follows:
1. synthetic route is optimized, reducing synthesis step to improve whole yield reduces the life of by-product
It produces.
2. reaction step is answered with respect to letter, intermediate weight is more easier to control.To the control of ethylene oxide in former synthetic route
It makes more demanding, directly will affect the yield and quality of subsequent reactions.
3. selecting relatively more safe on synthetic agent, Conventional solvents have toluene and some strong acid-bases in former synthetic route
It is a large amount of to use.
4. in coupling reaction, using nano-CuI as catalyst, improving the reaction efficiency of morpholine coupling, entirely synthesizing
Journey time-consuming shortens.
If above formula is using morphine base as starting material, Bromofume is reacted with the phenolic hydroxyl group on morphine base, is increased branch and is formed
Intermediate 1, intermediate 1 are coupled under CuI catalytic action with morpholine, and pholcodine crude product can be obtained in two steps.
It is of the invention the specific process is as follows: a kind of synthetic method of pholcodine, includes the following steps:
(1) under normal temperature condition, morphine base organic solvent is prepared；
(2) after alkali being added in the organic solvent containing condensation reagent, it is heated to 50-60 DEG C (preferably 60 under nitrogen protection
DEG C), morphine base organic solvent described in a dropping step (1) at such a temperature reacts 1-3h) morphine base is obtained after (preferably 2h)
Solution；
(3) distillation to dripless, crystallization adds water and stirs dissolution filter after fully reacting, collects insoluble matter, intermediately dry
Product；
(4) intermediate product described in morpholine and step (3) is dissolved in organic solvent, is mixed, nanometer is added
85-120 DEG C of reaction 6-12h (preferably 120 DEG C reaction 8h) is heated to after CuI catalyst and alkali；
(5) it filters, collects filtrate and distill to dripless, cool down crystallization after adding purified water heating to stir, and filters, collects filter cake
Obtain pholcodine crude product；
(6) pholcodine crude product and organic acid are obtained into pholcodine salt at salt；
(7) by pholcodine salinization of soil, crystallization is filtered, dry high-purity pholcodine.
Organic solvent described in the step (1) or (2) includes: N,N-dimethylformamide, tetrahydrofuran, two
Any one in first sulfoxide, acetonitrile；Organic solvent in step (4) includes N, N- dimethylformamide or dimethyl sulfoxide.
Alkali described in the step (2) includes: potassium carbonate, sodium carbonate, saleratus, any one in sodium bicarbonate
Kind；The additional amount of alkali and the molar ratio of morphine base are 1:0.5-2.
Condensation reagent described in the step (2) includes: Bromofume, ethylidene periodide or the iodo- ethane of the bromo- 2- of 1-.
Heating and insulation reaction temperature in the step (2) are 60 DEG C, and the reaction was continued, and the time is 2 hours.
It is 1:20 that nano-CuI additional amount in the step (4), which is with the molar ratio of morphine base,.
Alkali described in the step (4) includes: potassium carbonate or sodium carbonate；The additional amount of alkali and mole of morphine base
Than for 1:0.5-2.
The temperature that is heated to reflux in the step (4) is 120 DEG C, and the reaction time is 8 hours.
Organic acid in the step (6) is oxalic acid, citric acid or tartaric acid, i.e., pholcodine salt is corresponding includes:
Oxalates, citrate or tartrate.
Alkalizing agent in the step (7) includes: ammonium hydroxide, sodium hydroxide or potassium hydroxide.
Detailed description of the invention
Fig. 1 is 1 sample infrared light map of embodiment.
Two o'clock is control group on the left of Fig. 2, and 8 points of right side is schemed to detect after the sampling of embodiment 1.
Fig. 3 is 2 sample infrared light map of embodiment.
Two o'clock is control group on the right side of Fig. 4, and 3 points of left side is schemed to detect after the sampling of embodiment 2.
Fig. 5 is 3 sample infrared light map of embodiment.
The right side two o'clock of Fig. 6 is control group, and 5 points of left side is schemed to detect after the sampling of embodiment 3.
Fig. 7 is 4 sample infrared light map of embodiment.
Left side two o'clock shown in Fig. 8 is control group, and 8 points of right side is to apply detection figure after the sampling of example 4.
Fig. 9 is 5 sample infrared light map of embodiment.
Left side two o'clock shown in Fig. 10 be control group, right side be a little embodiment 5 sampling after detection figure.
Figure 11 is 6 sample infrared light map of embodiment.
Shown in Figure 12 left side two o'clock be control group, right side be a little embodiment 6 sampling after detection figure.
Specific embodiment
Deep elaboration is carried out to the present invention below in conjunction with specific embodiments, but it should be stated that the present embodiment is not
It can be considered limitation of the present invention.Purity check is according to second page 1496 of version of " Chinese Pharmacopoeia " 2015, embodiment purity
Testing result is in the accompanying drawings.
Embodiment 1
1) 285.3g morphine base is dissolved in the DMF solution of 2000ml.
2) 282g1,2- Bromofume is dissolved in the natrium carbonicum calcinatum that 110g in the DMF solution of 800ml and is added.Inflated with nitrogen
Protection, is warming up to 60 DEG C, and the DMF solution of prepared morphine base in 1) is slowly dripped to 1,2- Bromofume solution under stirring
In.It is added dropwise to complete subsequent continuous insulation reaction 2 hours.
3) fully reacting is evaporated under reduced pressure to dripless, and the stirring of 550ml purified water is added, dissolves inorganic salts.It is collected by filtration not
Molten object, it is dry.
4) by 105g morpholine and 3) in insoluble matter be dissolved in 2000ml DMF, and 110g natrium carbonicum calcinatum and 10g is added
Nano-CuI powder.115 DEG C are warming up under nitrogen protection to react 6 hours.
5) it filters while hot, collects filtrate and distill to dripless, the stirring of 600ml purified water is added, cools down 5 DEG C of crystallizations 8 hours,
Filter to obtain pholcodine crude product.
6) 184g tartaric acid is added toward 650ml purified water, then addition pholcodine crude product is warming up to 70 DEG C and is completely dissolved,
Cool down 5 DEG C of crystallizations.Filter ethanol washing it is dry pholcodine tartrate.
7) pholcodine tartrate is dissolved in 700ml water, 35 DEG C of dropwise addition ammonium hydroxide adjust pH to 9, and cool down 6 DEG C of crystallizations 8
Hour, filter dry pholcodine.
8) pholcodine 195.9g, yield 47.0% are obtained after drying.It detects and sees attached drawing, purity 100.3%, residual content,
Moisture content etc. complies with standard, and TLC detects free from admixture spot.
The detection of pholcodine related substance and content assaying method: according to " Chinese Pharmacopoeia " 2015 version second 1496
Page, the identification of pholcodine, inspection, content assaying method are detected.
Being identified according to sample of the standard of " Chinese Pharmacopoeia " to embodiment 1, is checked, assay meets the requirements,
Inspection item such as following table
Fig. 1 is 1 sample infrared light map of embodiment
Solvent: chloroform；Adsorbent silica gel: G lamellae；Solvent: ethyl alcohol: toluene: acetone: liquor ammoniae fortis=70:
70:65:5；Point sample amount: 10ul；Duration of run: 120min；Developer: under the conditions of iodine vapor
Two o'clock is control group on the left of Fig. 2, and 8 points of right side shows free from admixture spot to detect after the sampling of embodiment 1.
Embodiment 2
1) 285.3g morphine base is dissolved in the DMF solution of 2000ml.
2) 423g1,2- ethylidene periodide is dissolved in the natrium carbonicum calcinatum that 110g in the DMF solution of 800ml and is added.Inflated with nitrogen
Protection, is warming up to 60 DEG C, and the DMF solution of prepared morphine base in 1) is slowly dripped to 1,2- ethylidene periodide solution under stirring
In.It is added dropwise to complete subsequent continuous insulation reaction 2 hours.
3) fully reacting is evaporated under reduced pressure to dripless, and the stirring of 550ml purified water is added, dissolves inorganic salts.It is collected by filtration not
Molten object, it is dry.
4) by 105g morpholine and 3) in insoluble matter be dissolved in 2000ml DMF, and 110g natrium carbonicum calcinatum and 10g is added
Nano-CuI powder.115 DEG C are warming up under nitrogen protection to react 8 hours.
5) it filters while hot, collects filtrate and distill to dripless, the stirring of 600ml purified water is added, cools down 3 DEG C of crystallizations 8 hours,
Filter to obtain pholcodine crude product.
6) 184g tartaric acid is added toward 650ml purified water, then addition pholcodine crude product is warming up to 70 DEG C and is completely dissolved,
Cool down 5 DEG C of crystallizations.Filter ethanol washing it is dry pholcodine tartrate.
7) pholcodine tartrate is dissolved in 700ml water, 35 DEG C of dropwise addition ammonium hydroxide adjust pH to 9, and cool down 5 DEG C of crystallizations 8
Hour, filter dry pholcodine.
8) pholcodine 187.0g, yield 44.9% are obtained after drying.It detects and sees attached drawing, purity 100.2%, residual content,
Moisture content etc. complies with standard, and TLC detects free from admixture spot.
Being identified according to sample of the standard of " Chinese Pharmacopoeia " to embodiment 2, is checked, assay meets the requirements,
Inspection item such as following table
Fig. 3 is 2 sample infrared light map of embodiment
In solvent: chloroform；Adsorbent silica gel: G lamellae；Solvent: ethyl alcohol: toluene: acetone: liquor ammoniae fortis=
70:70:65:5；Point sample amount: 10ul；Duration of run: 120min；Developer: under the conditions of iodine vapor,
Two o'clock is control group on the right side of Fig. 4, and 3 points of left side shows free from admixture spot to detect after the sampling of embodiment 2.
Embodiment 3
1) 285.3g morphine base is dissolved in the DMSO solution of 2000ml.
2) 282g1,2- Bromofume is dissolved in the Anhydrous potassium carbonate that 140g in the DMSO solution of 800ml and is added.Nitrogen charging
Gas shielded is warming up to 60 DEG C, and the DMF solution of prepared morphine base in 1) is slowly dripped to 1,2- Bromofume solution under stirring
In.It is added dropwise to complete subsequent continuous insulation reaction 2 hours.
3) fully reacting is evaporated under reduced pressure to dripless, and the stirring of 550ml purified water is added, dissolves inorganic salts.It is collected by filtration not
Molten object, it is dry.
4) by 105g morpholine and 3) in insoluble matter be dissolved in 2000ml DMSO, and 140g Anhydrous potassium carbonate and 10g is added
Nano-CuI powder.120 DEG C are warming up under nitrogen protection to react 7 hours.
5) it filters while hot, collects filtrate and distill to dripless, the stirring of 600ml purified water is added, cools down 5 DEG C of crystallizations 8 hours,
Filter to obtain pholcodine crude product.
6) 184g tartaric acid is added toward 650ml purified water, then addition pholcodine crude product is warming up to 70 DEG C and is completely dissolved,
Cool down 0 DEG C of crystallization.Filter dry pholcodine tartrate.
7) pholcodine tartrate is dissolved in 700ml water, 35 DEG C of dropwise addition ammonium hydroxide adjust pH to 9, and cool down 0 DEG C of crystallization 8
Hour, filter dry pholcodine.
8) pholcodine 201.9g, yield 48.4% are obtained after drying.It detects and sees attached drawing, purity 100.3%, residual content,
Moisture content etc. complies with standard, and TLC detects free from admixture spot
Being identified according to sample of the standard of " Chinese Pharmacopoeia " to embodiment 3, is checked, assay meets the requirements,
Inspection item such as following table
Fig. 5 is 3 sample infrared light map of embodiment
In solvent: chloroform；Adsorbent silica gel: G lamellae；Solvent: ethyl alcohol: toluene: acetone: liquor ammoniae fortis=
70:70:65:5；Point sample amount: 10ul；Duration of run: 120min；Developer: under the conditions of iodine vapor
If the right side two o'clock of Fig. 6 is control group, 5 points of left side shows free from admixture spot to detect after the sampling of embodiment 3.
Embodiment 4
1) 285.3g morphine base is dissolved in the DMF solution of 2000ml.
2) bis- tolysulfonyl oxygroup ethane of 555g1,2- is dissolved in the DMF solution of 800ml and the anhydrous of 110g is added
Sodium carbonate.Nitrogen charging gas shielded is warming up to 60 DEG C, and the DMF solution of prepared morphine base in 1) is slowly dripped to 1,2- under stirring
In two tolysulfonyl oxygroup ethane solution.It is added dropwise to complete subsequent continuous insulation reaction 2 hours.
3) fully reacting is evaporated under reduced pressure to dripless, and the stirring of 550ml purified water is added, dissolves inorganic salts.It is collected by filtration not
Molten object, it is dry.
4) by 105g morpholine and 3) in insoluble matter be dissolved in 2000ml DMF, and 110g natrium carbonicum calcinatum and 10g is added
Nano-CuI powder.115 DEG C are warming up under nitrogen protection to react 7 hours.
5) it filters while hot, collects filtrate and distill to dripless, the stirring of 600ml purified water is added, cools down 5 DEG C of crystallizations 8 hours,
Filter to obtain pholcodine crude product.
6) 184g tartaric acid is added toward 650ml purified water, then addition pholcodine crude product is warming up to 70 DEG C and is completely dissolved,
Cool down 5 DEG C of crystallizations.Filter dry pholcodine tartrate.
7) pholcodine tartrate being dissolved in 700ml water, 30 DEG C of 10% sodium hydroxide solutions of dropwise addition adjust pH to 9,
Cool down 5 DEG C of crystallizations 8 hours, filters dry pholcodine.
8) pholcodine 180.0g, yield 43.2% are obtained after drying.It detects and sees attached drawing, purity 100.2%, residual content,
Moisture content etc. complies with standard, and TLC detects free from admixture spot
Being identified according to sample of the standard of " Chinese Pharmacopoeia " to embodiment 4, is checked, assay meets the requirements,
Inspection item such as following table
Fig. 7 is 4 sample infrared light map of embodiment
In solvent: chloroform；Adsorbent silica gel: G lamellae；Solvent: ethyl alcohol: toluene: acetone: liquor ammoniae fortis=
70:70:65:5；Point sample amount: 10ul；Duration of run: 120min；Developer: under the conditions of iodine vapor,
Left side two o'clock as shown in Figure 8 is control group, and 8 points of right side is to detect after applying the sampling of example 4, shows free from admixture spot
Point.
Embodiment 5
1) 285.3g morphine base is dissolved in the DMSO solution of 2000ml.
2) 282g1,2- Bromofume is dissolved in the natrium carbonicum calcinatum that 110g in the DMSO solution of 800ml and is added.Nitrogen charging
Gas shielded is warming up to 60 DEG C, and the DMF solution of prepared morphine base in 1) is slowly dripped to 1,2- Bromofume solution under stirring
In.It is added dropwise to complete subsequent continuous insulation reaction 2 hours.
3) fully reacting is evaporated under reduced pressure to dripless, and the stirring of 550ml purified water is added, dissolves inorganic salts.It is collected by filtration not
Molten object, it is dry.
4) by 105g morpholine and 3) in insoluble matter be dissolved in 2000ml DMSO, and 110g natrium carbonicum calcinatum and 10g is added
Nano-CuI powder.120 DEG C are warming up under nitrogen protection to react 6 hours.
5) it filters while hot, collects filtrate and distill to dripless, the stirring of 600ml purified water is added, cools down 4 DEG C of crystallizations 8 hours,
Filter to obtain pholcodine crude product.
6) 205g citric acid is added toward 650ml purified water, then addition pholcodine crude product is warming up to 70 DEG C and is completely dissolved,
Cool down 5 DEG C of crystallizations.Filter dry pholcodine citrate.
7) pholcodine tartrate is dissolved in 700ml water, 30 DEG C of dropwise addition ammonium hydroxide adjust pH to 9, and cool down 4 DEG C of crystallizations 8
Hour, filter dry pholcodine.
8) pholcodine 190.3g, yield 45.7% are obtained after drying.Attached drawing, purity 99.2%, residual content, water are shown in detection
Point content etc. complies with standard, and TLC detects free from admixture spot
Being identified according to sample of the standard of " Chinese Pharmacopoeia " to embodiment 5, is checked, assay meets the requirements,
Inspection item such as following table
Fig. 9 is 5 sample infrared light map of embodiment
In solvent: chloroform；Adsorbent silica gel: G lamellae；Solvent: ethyl alcohol: toluene: acetone: liquor ammoniae fortis=
70:70:65:5；Point sample amount: 10ul；Duration of run: 120min；Developer: under the conditions of iodine vapor
Left side two o'clock as shown in Figure 10 be control group, right side be a little embodiment 5 sampling after detect, show free from admixture
Spot.
Embodiment 6
1) 285.3g morphine base is dissolved in the DMSO solution of 2000ml.
2) 423g1,2- ethylidene periodide is dissolved in the Anhydrous potassium carbonate that 140g in the DMSO solution of 800ml and is added.Nitrogen charging
Gas shielded is warming up to 60 DEG C, and the DMF solution of prepared morphine base in 1) is slowly dripped to 1,2- ethylidene periodide solution under stirring
In.It is added dropwise to complete subsequent continuous insulation reaction 2 hours.
3) fully reacting is evaporated under reduced pressure to dripless, and the stirring of 550ml purified water is added, dissolves inorganic salts.It is collected by filtration not
Molten object, it is dry.
4) by 105g morpholine and 3) in insoluble matter be dissolved in 2000ml DMSO, and 140g Anhydrous potassium carbonate and 10g is added
Nano-CuI powder.120 DEG C are warming up under nitrogen protection to react 6.5 hours.
5) it filters while hot, collects filtrate and distill to dripless, the stirring of 600ml purified water is added, cools down 5 DEG C of crystallizations 8 hours,
Filter to obtain pholcodine crude product.
6) 184g tartaric acid is added toward 650ml purified water, then addition pholcodine crude product is warming up to 70 DEG C and is completely dissolved,
Cool down 5 DEG C of crystallizations.Filter dry pholcodine tartrate.
7) pholcodine tartrate is dissolved in 700ml water, 35 DEG C of dropwise addition ammonium hydroxide adjust pH to 9, and cool down 2 DEG C of crystallizations 8
Hour, filter dry pholcodine.
8) pholcodine 184.1g, yield 44.2% are obtained after drying.It detects and sees attached drawing, purity 100.1%, residual content,
Moisture content etc. complies with standard, and TLC detects free from admixture spot.
Being identified according to sample of the standard of " Chinese Pharmacopoeia " to embodiment 6, is checked, assay meets the requirements,
Inspection item such as following table
Figure 11 is 6 sample infrared light map of embodiment
In solvent: chloroform；Adsorbent silica gel: G lamellae；Solvent: ethyl alcohol: toluene: acetone: liquor ammoniae fortis=
70:70:65:5；Point sample amount: 10ul；Duration of run: 120min；Developer: under the conditions of iodine vapor, left side two as shown in figure 12
Point be control group, right side be a little embodiment 6 sampling after detect, show free from admixture spot.
Claims (10)
1. a kind of synthetic method of pholcodine, which comprises the steps of:
(1) under normal temperature condition, morphine base organic solvent is prepared；
(2) after alkali being added in the organic solvent containing condensation reagent, it is heated to 50-60 DEG C under nitrogen protection, drips at such a temperature
Add morphine base organic solvent described in step (1), obtains morphine aqueous slkali after reacting 1-3h；
(3) distillation to dripless, crystallization adds water and stirs dissolution filter after fully reacting, collects insoluble matter, dry that is produced from centre
Object；
(4) intermediate product described in morpholine and step (3) is dissolved in organic solvent, is mixed, nano-CuI is added and urges
85-120 DEG C of reaction 6-12h is heated to after agent and alkali；
(5) it filters, collects filtrate and distill to dripless, cool down crystallization after adding purified water heating to stir, and filters, and collects filter cake and obtains good fortune
You can determine crude product；
(6) pholcodine crude product and organic acid are obtained into pholcodine salt at salt；
(7) by pholcodine salinization of soil, crystallization is filtered, dry high-purity pholcodine.
2. the synthetic method of pholcodine according to claim 1, it is characterised in that: described in step (1) or (2)
Organic solvent includes: N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, any one in acetonitrile；In step (4)
Organic solvent includes N, N- dimethylformamide or dimethyl sulfoxide.
3. the synthetic method of pholcodine according to claim 1, it is characterised in that: alkali described in step (2) includes:
Potassium carbonate, sodium carbonate, saleratus, any one in sodium bicarbonate；The additional amount of alkali and the molar ratio of morphine base are 1:
0.5-2。
4. the synthetic method of pholcodine according to claim 1, it is characterised in that: the examination of condensation described in step (2)
Agent includes: Bromofume, ethylidene periodide or the iodo- ethane of the bromo- 2- of 1-.
5. the synthetic method of pholcodine according to claim 1, it is characterised in that: heating and heat preservation in step (2)
Reaction temperature is 60 DEG C, and the reaction was continued, and the time is 2 hours.
6. the synthetic method of pholcodine according to claim 1, it is characterised in that: the nano-CuI in step (4) is added
Amount is 1:15-25 for the molar ratio with morphine base.
7. the synthetic method of pholcodine according to claim 1, it is characterised in that: alkali described in step (4) includes:
Potassium carbonate or sodium carbonate；The additional amount of alkali and the molar ratio of morphine base are 1:0.5-2.
8. the synthetic method of pholcodine according to claim 1, it is characterised in that: be heated to reflux temperature in step (4)
Degree is 120 DEG C, and the reaction time is 8 hours.
9. the synthetic method of pholcodine according to claim 1, it is characterised in that: the organic acid in step (6) is grass
Acid, citric acid or tartaric acid, i.e., it includes: oxalates, citrate or tartrate that pholcodine salt is corresponding.
10. the synthetic method of pholcodine according to claim 1, it is characterised in that: the alkalizing agent packet in step (7)
It includes: ammonium hydroxide, sodium hydroxide or potassium hydroxide.
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| CN201811325865.XA CN109336895B (en) | 2018-11-08 | 2018-11-08 | Synthesis method of pholcodine |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB680952A (en) * | 1949-08-30 | 1952-10-15 | Lab Dausse | Improvements in new morphine derivatives and production thereof |
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2018
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB680952A (en) * | 1949-08-30 | 1952-10-15 | Lab Dausse | Improvements in new morphine derivatives and production thereof |
Non-Patent Citations (1)
| Title |
|---|
| VAN-HAI HOANG, 等: "Discovery of Potent Human Glutaminyl Cyclase Inhibitors as Anti-Alzheimer’s Agents Based on Rational Design", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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