CN118045050A - Composition suitable for head and neck radiotherapy patient and capable of relieving xerostomia and preparation method thereof - Google Patents
Composition suitable for head and neck radiotherapy patient and capable of relieving xerostomia and preparation method thereof Download PDFInfo
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- 239000000203 mixture Substances 0.000 title claims abstract description 58
- 206010013781 dry mouth Diseases 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000001959 radiotherapy Methods 0.000 title claims abstract description 16
- 208000005946 Xerostomia Diseases 0.000 title claims abstract description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 54
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 36
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229930003268 Vitamin C Natural products 0.000 claims abstract description 18
- 235000019154 vitamin C Nutrition 0.000 claims abstract description 18
- 239000011718 vitamin C Substances 0.000 claims abstract description 18
- 239000000314 lubricant Substances 0.000 claims abstract description 17
- 239000000945 filler Substances 0.000 claims abstract description 16
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims abstract description 14
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940041616 menthol Drugs 0.000 claims abstract description 14
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims abstract description 13
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000811 xylitol Substances 0.000 claims abstract description 13
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims abstract description 13
- 229960002675 xylitol Drugs 0.000 claims abstract description 13
- 235000010447 xylitol Nutrition 0.000 claims abstract description 13
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a composition for relieving xerostomia, which is applicable to patients with head and neck radiotherapy, comprising: compound F, citric acid, menthol, vitamin C, xylitol, fillers, disintegrants, lubricants; wherein, the compound F is a brand new compound with M3 PAM activity, can greatly increase the secretion of saliva, and can effectively treat xerostomia; in addition, citric acid and vitamin C are added into the composition provided by the invention, so that not only can the secretion of saliva be promoted, but also the disintegration speed of the tablet can be increased, and nutrition can be provided for patients; the composition provided by the invention has few auxiliary materials, simple preparation process and good stability of the prepared tablet.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a composition suitable for head and neck radiotherapy patients and used for relieving xerostomia and a preparation method thereof.
Background
The malignant tumor (HEAD AND NECK CANCER) of the head and neck is the most common malignant tumor of the 6 th day worldwide, and refers to tumors of the parts of the ear, nose, throat, mouth, jaw face, neck and the like, including nasopharyngeal carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma, laryngeal carcinoma, oral cancer and the like. Radiation therapy (radiotherapy) is one of its main modes of treatment. Along with the improvement of radiotherapy technology, the accuracy of the radiotherapy of the head and neck tumor is also greatly improved: at the same time as higher doses are applied to the tumour tissue, the dose received by surrounding normal tissue can also be reduced. However, adverse reactions related to radiotherapy are still difficult to avoid, wherein dry mouth is one of the most common early complications and long-term sequelae.
Xerostomia (dry mouth) is defined as an abnormality caused by a decrease in oral saliva flow. The head and neck radiotherapy is easy to cause damage to salivary glands, so that salivary secretion is reduced, and the occurrence rate of dry mouth is almost 100%. The dry mouth can affect the speech of the patient, be unfavorable for eating, induce decayed teeth, cause discomfort such as burning sensation in the mouth, and seriously affect the life quality of the patient. At present, no medicine has been proved to repair the damage of saliva, and although some products for relieving oral symptoms exist on the market, the products belong to large bottled artificial saliva, oral wetting agents and the like, for example: patent CN105147818B, CN102085371B, CN110279710a cannot meet the needs of convenient use in the daily multi-scenario mode of the patient.
Sour taste can stimulate salivary glands to promote salivation, alleviate xerostomia, for example: the mature vinegar is added into the CN114504628A, so that the taste is sweet and sour, the salivary glands can be stimulated to secrete saliva, the dry mouth and thirst can be effectively improved, the mature vinegar has good antibacterial and bactericidal effects, the use effect of the oral spray can be improved by the citric acid and the vitamin C, and nutrition supplement can be effectively provided for patients.
M cholinergic agonists, represented by pilocarpine, although able to ameliorate symptoms, require long-term administration, for example: patent CN114901283a discloses a dry mouth therapeutic agent with M3 PAM activity;
In summary, there is a need to provide a preparation with good effect, long action time and convenient use for treating dry mouth, so as to meet the needs of patients suffering from head and neck radiotherapy for relieving dry mouth in daily different scenes, and improve the quality of life and satisfaction of patients.
Disclosure of Invention
The invention aims to provide a composition for relieving xerostomia, which is suitable for patients with head and neck radiotherapy, and a preparation method thereof, so as to solve the technical problems of poor effect, short acting time and inconvenient use in the prior art.
In order to solve the technical problems, the invention provides the following technical scheme:
A composition for alleviating xerostomia suitable for use in patients with head and neck radiotherapy comprising: compound F, citric acid, menthol, vitamin C, xylitol, fillers, disintegrants, lubricants;
The compound F is selected from the following structures: The compound F accounts for 5-10% of the mass of the composition; preferably, compound F comprises 5%, 6%, 7%, 8%, 9% or 10% by mass of the composition;
The citric acid accounts for 1-3% of the composition by mass; preferably, the citric acid comprises 1%, 2% or 3% by mass of the composition;
The vitamin C accounts for 1-3% of the total mass of the composition; preferably, the vitamin C comprises 1%, 2% or 3% of the composition by mass;
The menthol accounts for 1-3% of the mass of the composition; preferably, the menthol comprises 1%, 2% or 3% by mass of the composition;
The xylitol accounts for 1-3% of the mass of the composition; preferably, the xylose comprises 1%, 2% or 3% by mass of the composition;
the filler is selected from: The filler accounts for 60-80% of the mass of the composition; preferably, the filler comprises 60%, 65%, 70%, 75% or 80% by mass of the composition;
The disintegrant is selected from: one or more of sodium carboxymethyl starch, croscarmellose sodium or cross-linked polyvinylpyrrolidone; the disintegrating agent accounts for 2-5% of the mass of the composition; preferably, the disintegrant is 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% by mass of the formulation;
The lubricant is selected from: one or more of polyethylene glycol 6000 or polyethylene glycol 4000; the mass percentage of the lubricant in the composition is 1-3%; preferably, the lubricant comprises 1%, 1.5%, 2%, 2.5% or 3% of the formulation by mass.
Further, the invention also provides a preparation method of the composition for relieving xerostomia, which is applicable to patients with head and neck radiotherapy, wherein the composition is prepared by adopting a powder direct compression method, and the preparation method comprises the following specific operation steps: 1) Weighing a compound F, citric acid, menthol, vitamin C, xylitol, a filler and a disintegrating agent according to the prescription amount, respectively sieving with a 80-mesh sieve, and adding into a three-dimensional mixer for uniform premixing; 2) Weighing the lubricant with the prescription amount, sieving with an 80-mesh sieve, adding into the premixed powder prepared in the step 1), continuously and uniformly mixing, and directly tabletting.
Further, the premixing time in the step 1) is 15-30min;
further, the mixing time in the step 2) is 5-10min;
further, the tablet weight of the tablet in the step 2) is 50mg, and the hardness of the tablet is 15-30N.
Further, the invention also provides a synthetic route of the compound F:
the method comprises the following steps:
1) Preparation of compound C: adding the compound A, the compound B and potassium carbonate into the DMSO solution, heating to 90-100 ℃, stirring for 2-6 hours, cooling to room temperature after the reaction is finished, diluting the reaction mixture with saturated ammonium chloride aqueous solution, and extracting with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purifying the residue by silica gel column chromatography to obtain compound C;
2) Preparation of Compound E: adding a compound C, a compound D and sodium dithionite into a DMF solution, heating to 110-120 ℃, stirring for 3-6 hours, cooling to room temperature, adding sodium dithionite, stirring for 3-6 hours at 100-110 ℃, cooling to room temperature after the reaction is finished, diluting with water and saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, washing an organic layer with water and saturated saline solution, drying with anhydrous magnesium sulfate, distilling off a solvent under reduced pressure, and purifying residues by silica gel column chromatography to obtain a compound E;
3) Stirring at room temperature, adding aqueous sodium hydroxide solution to ethanol solution of compound E, stirring at that temperature for 4-6 hours. The reaction mixture was diluted with water, neutralized with hydrochloric acid, the precipitated precipitate was filtered, washed with water, and dried to obtain compound F.
Further, the molar ratio of the compound A, the compound B and the potassium carbonate in the step 1) is as follows: 1:1-1.5:3-5; preferably, the molar ratio of the compound a, the compound B and the potassium carbonate in the step 1) is: 1:1.1-1.2:4-5; more preferably, the molar ratio of compound a, compound B and potassium carbonate in step 1) is: 1:1.1:5, a step of;
Further, the molar ratio of the compound C, the compound D and the sodium dithionite in the step 2) is as follows: 1:1-1.5:4-6; preferably, the molar ratio of compound C, compound D and sodium dithionite in step 2) is: 1:1:5, a step of;
further, the solubility of the sodium hydroxide aqueous solution in the step 3) is 2M; the concentration of hydrochloric acid in the step 3) is 2M;
The invention has the beneficial effects that:
1) The invention provides a composition suitable for head and neck radiotherapy patients for relieving xerostomia, wherein a compound F in the composition is a brand new compound which has M3 PAM activity, can greatly increase the secretion of saliva, and can effectively treat xerostomia;
2) The citric acid and the vitamin C are added into the composition provided by the invention, so that not only can the secretion of saliva be promoted, but also the disintegration speed of the tablet can be accelerated, and nutrition can be provided for patients;
3) The composition provided by the invention has few auxiliary materials, simple preparation process and good stability of the prepared tablet.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the following examplesIs composed of 70% of alpha-lactose monohydrate, 20% of microcrystalline cellulose (MCC) and 10% of corn starch, and each component meets Ph.Eur, USP-NF and JP pharmacopoeia requirements.
Example 1
Preparation of compound C:
14.25g of Compound A (0.1 mol), 20.49g of Compound B (0.11 mol) and 69.11g of potassium carbonate (0.5 mol) were weighed and dissolved in 500ml of an LDMSO solution, the temperature was raised to 90℃and stirred for 2 hours, after the reaction was completed, the reaction mixture was cooled to room temperature, diluted with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (300 mL. Times.3), the organic layers were combined, the organic layers were washed with water (300 mL. Times.1) and saturated brine (300 mL. Times.1), dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with an eluent of petroleum ether/ethyl acetate (volume ratio 10/1) to give 20.7g of Compound C in 71% yield.
Preparation of Compound E:
14.6g of Compound C (0.05 mol), 9.7g of Compound D (0.05 mol) and 21.8g of sodium dithionite (0.125 mol) are dissolved in a 200mL of a solution of LDMF, warmed to 110℃and stirred for 4 hours, cooled to room temperature, 21.8g of sodium dithionite (0.125 mol) is added, stirred for 3 hours at 100℃and cooled to room temperature, diluted with water (100 mL of 1), saturated aqueous sodium bicarbonate (200 mL of 1) and extracted with ethyl acetate (200 mL of 3), the organic layer is washed with water (200 mL of 1) and saturated brine (200 mL of 1), dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography with petroleum ether/ethyl acetate (volume ratio 10/1) to give 17.3g of Compound E in 74% yield.
Preparation of compound F:
11.67g of Compound E (0.025 mol) was taken in 60mL of ethanol solution, 2M aqueous sodium hydroxide solution (100 mL) was added with stirring at room temperature, the mixture was stirred at this temperature for 4 hours, the reaction mixture was diluted with water, neutralized with 2M hydrochloric acid, the precipitated precipitate was filtered, washed with water, and dried to give 10.5g of Compound F in yield 96％.MS-ESI：[M+H]+＝439.2,1H-NMR(400MHz,DMSO-d6):δ(ppm):13.08(s,1H),12.12(br,1H),8.01-8.53(m,3H),7.02(m,1H),3.60-3.74(m,14H),3.36-3.45(m,4H),2.38(m,2H).
Comparative example 1
Preparation of Compound H:
Compound H was prepared by the method of patent CN112368282a and its structure was characterized using mass spectrometry data: MS-ESI: m+h + = 708.6.
Example 2
Tablet formulation 1:
Tabletting was carried out according to the amount of 20 tablets shown in Table 1, each tablet containing 5mg of compound F;
TABLE 1
1) Weighing compound F, citric acid, menthol, vitamin C, xylitol, filler and disintegrating agent according to the prescription amount, sieving with 80 mesh sieve respectively, and adding into a three-dimensional mixer for premixing for 15min; 2) Weighing lubricant with a prescription amount, sieving with a 80-mesh sieve, adding into the premixed powder prepared in the step 1), continuously mixing for 5min, directly tabletting the mixed powder by adopting a ZP-7A rotary tablet press after uniform mixing, and adjusting the tablet weight to 50mg and the tablet hardness to 15-30N.
Example 3
Tablet formulation 2:
tabletting was carried out according to the amount of 20 tablets shown in Table 2, each tablet containing 5mg of compound F;
TABLE 2
1) Weighing compound F, citric acid, menthol, vitamin C, xylitol, filler and disintegrating agent according to the prescription amount, sieving with 80 mesh sieve respectively, and adding into a three-dimensional mixer for premixing for 15min; 2) Weighing lubricant with a prescription amount, sieving with a 80-mesh sieve, adding into the premixed powder prepared in the step 1), continuously mixing for 5min, directly tabletting the mixed powder by adopting a ZP-7A rotary tablet press after uniform mixing, and adjusting the tablet weight to 50mg and the tablet hardness to 15-30N.
Comparative example 2
Tablet comparative formula 1:
tabletting was carried out according to the amount of 20 tablets shown in Table 3, each tablet containing 5mg of Compound H;
TABLE 3 Table 3
1) Weighing compound H, citric acid, menthol, vitamin C, xylitol, filler and disintegrating agent according to the prescription amount, sieving with 80 mesh sieve respectively, and adding into a three-dimensional mixer for premixing for 15min; 2) Weighing lubricant with a prescription amount, sieving with a 80-mesh sieve, adding into the premixed powder prepared in the step 1), continuously mixing for 5min, directly tabletting the mixed powder by adopting a ZP-7A rotary tablet press after uniform mixing, and adjusting the tablet weight to 50mg and the tablet hardness to 15-30N.
Comparative example 3
Tablet comparative prescription 2:
tabletting was carried out according to the amount of 20 tablets shown in Table 4, each tablet containing 5mg of Compound H;
TABLE 4 Table 4
1) Weighing compound H, menthol, xylitol, filler and disintegrating agent according to the prescription amount, sieving with 80 mesh sieve respectively, and adding into a three-dimensional mixer for premixing for 15min; 2) Weighing lubricant with a prescription amount, sieving with a 80-mesh sieve, adding into the premixed powder prepared in the step 1), continuously mixing for 5min, directly tabletting the mixed powder by adopting a ZP-7A rotary tablet press after uniform mixing, and adjusting the tablet weight to 50mg and the tablet hardness to 15-30N.
Example 4
Disintegration experiment:
About 2mL of purified water was added to a flat bottom test tube having a diameter of about 1.5cm, the water temperature was controlled at about 37℃and then 1 tablet prepared in examples 2-3 and comparative examples 2-3 was added, left to stand for 60S, and the time from the addition of the test tube to complete collapse of the tablet into powder was observed and recorded, and a total of 4 samples were tested, 6 tablets were measured in parallel for each sample, and the results are shown in Table 5.
Table 5 results of disintegration experiments for tablet formulations
| Lot number | Disintegration time (S) |
| Example 2 | 34±2S |
| Example 3 | 26±2S |
| Comparative example 2 | 38±2S |
| Comparative example 3 | 66±2S |
As can be seen from the results of table 5, the tablet prepared by the present invention has a short disintegration time, completely meets the disintegration time requirement of orally disintegrating tablets, and has a remarkably prolonged disintegration time without adding citric acid and vitamin C, which indicates that citric acid and vitamin C can promote the disintegration of the tablet.
Example 5
Saliva secretion study:
Healthy male wistar rats (200+ -20 g), according to literature methods (Li Bixia, chen Qianyi, dai Zhenhui, she Jingyun, wang Wenjing, chen Shan, zhang Jiapeng, chen Peiyi. Radioactive xerostomia animal model establishment and biological effects of submaxillary gland radioactive tissue injury. Chinese tissue engineering study 2017,21 (32): 5164-5169) established a radioactive xerostomia animal model. 18 rats successfully molded were randomly divided into 3 groups, 6 rats/group. Respectively carrying out isovolumetric gastric administration: the control group was filled with 5 mg/dose of the aqueous suspension of the tablet of comparative example 2 (in terms of compound H, the same applies hereinafter), and the experimental group was filled with 5 mg/dose of the aqueous suspension of the tablets of examples 2 and 3 (in terms of compound F, the same applies hereinafter), respectively. Rats in each group were gavaged for 14 days, 1 time/day. 4 hours after the end of the administration, the dried cotton ball was taken, placed under the rat tongue, and saliva was sucked with the cotton ball. The weight difference of the cotton ball before and after sucking saliva was calculated as salivary quantity data (mg). The difference in salivation was compared between the groups of rats. The results are shown in Table 6:
TABLE 6 salivary secretion
| Group of | Salivary secretion (mg) |
| Control group (comparative example 2) | 230.46±28.46 |
| Experimental group (example 2) | 348.72±33.28 |
| Experimental group (example 3) | 373.84±40.14 |
As can be seen from the results of table 6, the tablet prepared by the present invention can effectively promote salivary secretion, and the effect is significantly better than that of the control group, which indicates that the compound F of the present invention has a good salivary secretion promoting effect.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (9)
1. A composition for alleviating xerostomia suitable for use in patients with head and neck radiotherapy comprising: compound F, citric acid, menthol, vitamin C, xylitol, fillers, disintegrants, lubricants;
The compound F is selected from the following structures: the compound F accounts for 5-10% of the mass of the composition;
the citric acid accounts for 1-3% of the composition by mass;
the vitamin C accounts for 1-3% of the total mass of the composition;
the menthol accounts for 1-3% of the mass of the composition;
The xylitol accounts for 1-3% of the mass of the composition;
the filler is selected from: the filler accounts for 60-80% of the mass of the composition;
The disintegrant is selected from: one or more of sodium carboxymethyl starch, croscarmellose sodium or cross-linked polyvinylpyrrolidone; the disintegrating agent accounts for 2-5% of the mass of the composition;
The lubricant is selected from: one or more of polyethylene glycol 6000 or polyethylene glycol 4000; the lubricant accounts for 1-3% of the mass of the composition.
2. The composition according to claim 1, wherein compound F comprises 5%, 6%, 7%, 8%, 9% or 10% by mass of the composition;
the citric acid accounts for 1%, 2% or 3% of the mass of the composition;
The vitamin C accounts for 1%, 2% or 3% of the total mass of the composition;
the menthol accounts for 1%, 2% or 3% of the mass of the composition;
the xylitol accounts for 1%, 2% or 3% of the mass of the composition;
The filler accounts for 60%, 65%, 70%, 75% or 80% of the mass of the composition;
the disintegrant accounts for 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% of the composition by mass;
The lubricant accounts for 1%, 1.5%, 2%, 2.5% or 3% of the mass of the preparation.
3. Composition according to claim 1 or 2, characterized in that compound F represents 10% by mass of the composition;
The citric acid accounts for 1% of the composition by mass;
The vitamin C accounts for 1 mass percent of the composition;
the menthol accounts for 1 mass percent of the composition;
The xylitol accounts for 2 mass percent of the composition;
the filler accounts for 80 percent of the mass of the composition;
The disintegrating agent accounts for 3 mass percent of the composition;
The lubricant accounts for 2% of the preparation by mass.
4. A composition according to any one of claims 1 or 2, wherein the disintegrant is selected from the group consisting of: croscarmellose sodium;
the lubricant is selected from: polyethylene glycol 4000.
5. A process for the preparation of a composition as claimed in any one of claims 1 to 4, comprising the steps of:
1) Weighing a compound F, citric acid, menthol, vitamin C, xylitol, a filler and a disintegrating agent according to the prescription amount, respectively sieving with a 80-mesh sieve, and adding into a three-dimensional mixer for uniform premixing;
2) Weighing the lubricant with the prescription amount, sieving with an 80-mesh sieve, adding into the premixed powder prepared in the step 1), continuously and uniformly mixing, and directly tabletting.
6. The method according to claim 5, wherein the premixing time in step 1) is 15 to 30min; the mixing time in the step 2) is 5-10min; the tablet weight of the tablet in the step 2) is 50mg, and the hardness of the tablet is 15-30N.
7. The process for the preparation of compound F according to any one of claims 1 to 6, characterized in that the synthetic route is: the specific synthesis steps are as follows:
1) Preparation of compound C: adding the compound A, the compound B and potassium carbonate into the DMSO solution, heating to 90-100 ℃, stirring for 2-6 hours, cooling to room temperature after the reaction is finished, diluting the reaction mixture with saturated ammonium chloride aqueous solution, and extracting with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purifying the residue by silica gel column chromatography to obtain compound C;
2) Preparation of Compound E: adding a compound C, a compound D and sodium dithionite into a DMF solution, heating to 110-120 ℃, stirring for 3-6 hours, cooling to room temperature, adding sodium dithionite, stirring for 3-6 hours at 100-110 ℃, cooling to room temperature after the reaction is finished, diluting with water and saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate, washing an organic layer with water and saturated saline solution, drying with anhydrous magnesium sulfate, distilling off a solvent under reduced pressure, and purifying residues by silica gel column chromatography to obtain a compound E;
3) Stirring at room temperature, adding aqueous sodium hydroxide solution to ethanol solution of compound E, stirring at that temperature for 4-6 hours. The reaction mixture was diluted with water, neutralized with hydrochloric acid, the precipitated precipitate was filtered, washed with water, and dried to obtain compound F.
8. The method of manufacturing according to claim 7, wherein: the molar ratio of the compound A to the compound B to the potassium carbonate in the step 1) is as follows: 1:1-1.5:3-5; the molar ratio of the compound C, the compound D and the sodium dithionite in the step 2) is as follows: 1:1-1.5:4-6; the solubility of the sodium hydroxide aqueous solution in the step 3) is 2M; the concentration of hydrochloric acid in the step 3) is 2M.
9. The method of manufacturing according to claim 8, wherein: the molar ratio of the compound A to the compound B to the potassium carbonate in the step 1) is as follows: 1:1.1:5, a step of; the molar ratio of the compound C, the compound D and the sodium dithionite in the step 2) is as follows: 1:1-1:5.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311525417.5A CN118045050A (en) | 2023-11-16 | 2023-11-16 | Composition suitable for head and neck radiotherapy patient and capable of relieving xerostomia and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311525417.5A CN118045050A (en) | 2023-11-16 | 2023-11-16 | Composition suitable for head and neck radiotherapy patient and capable of relieving xerostomia and preparation method thereof |
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| CN118045050A true CN118045050A (en) | 2024-05-17 |
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| CN (1) | CN118045050A (en) |
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