CN116178185A - New crystalline forms of propranolol free base - Google Patents
New crystalline forms of propranolol free base Download PDFInfo
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- CN116178185A CN116178185A CN202211582857.XA CN202211582857A CN116178185A CN 116178185 A CN116178185 A CN 116178185A CN 202211582857 A CN202211582857 A CN 202211582857A CN 116178185 A CN116178185 A CN 116178185A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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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
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a crystal form of propranolol free base, which has a structure shown in a following figure and represented by a compound formula (I). The invention further relates to processes for preparing said crystalline forms, pharmaceutical compositions of said compounds containing the crystalline forms and therapeutic uses of said forms.
Description
The present application is filed application No. 201810364327.5, application date of 2018, 4 months and 20 days, and the invention name is "new crystal form of propranolol free base".
Technical Field
The invention relates to a form of a compound, in particular to a crystal form A of propranolol free alkali. The invention further relates to a process for preparing said crystalline form, to pharmaceutical compositions containing the crystalline form and to the use of said crystalline form.
Background
Propranolol hydrochloride is commonly called as 'propranolol', is a non-selective beta-receptor blocker, has antagonism on both myocardial beta 1 and beta 2 receptors, is suitable for treating sinus and supraventricular arrhythmias, atrial fibrillation, angina pectoris and pheochromocytoma preoperative treatment and hemangioma, and has a certain curative effect on treating hypertension. Propranolol was first prepared by English James W.Black in 1964. In 1976, WYETH's various specifications of tablets, commercially available under the trade name index, were approved for sale in the united states. In 1981, 25mg tablet of propranolol hydrochloride of Diao group is first marketed in China, and the main marketed dosage forms in China at present comprise the specifications of propranolol hydrochloride capsules, sustained release tablets, injection and the like. But no free base related crystalline forms and pharmaceutical compositions thereof are reported.
Disclosure of Invention
The present invention aims to provide a crystalline propranolol free base, i.e. a compound of the following scheme I:
the compound of formula (I) is present in a substantially crystalline form. The compounds of formula (I) are generally designated as 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol.
In one aspect of the invention, the crystalline form of the compound of formula (I) is form a, which is in a substantially anhydrous form.
Form a can be identified by its melting onset, powder X-ray diffraction pattern. The onset of melting of form a is in the range of 90-93 ℃.
When form a is in a substantially pure and substantially anhydrous form, it has an X-ray powder diffraction pattern with specific high intensity peaks at 7.5 (+ -0.1), 10.9 (+ -0.1), 14.3 (+ -0.1), 15.2 (+ -0.1), 16.6 (+ -0.1) 2θ. Still further, the X-ray powder diffraction pattern of form a has characteristic peaks at 7.5 (+ -0.1), 10.9 (+ -0.1), 14.3 (+ -0.1), 15.2 (+ -0.1), 16.6 (+ -0.1), 17.7 (+ -0.1), 18.5 (+ -0.1), 22.8 (+ -0.1), 25.0 (+ -0.1).
Thus, in one aspect of the present invention, there is provided crystalline form A of the compound of formula (I),
the compounds of formula (I) are generally designated as 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol.
According to another aspect of the present invention, there is provided crystalline form a of 1-isopropylamino-3- (naphthalen-1-oxy) propan-2-ol, characterized by an X-ray powder diffraction in terms of 2Θ having diffraction peaks at about 7.5 (+ -0.1), 10.9 (+ -0.1), 14.3 (+ -0.1), 15.2 (+ -0.1), 16.6 (+ -0.1).
According to another aspect of the present invention, there is provided crystalline form a of 1-isopropylamino-3- (naphthalen-1-oxy) propan-2-ol, characterized by X-ray powder diffraction expressed in terms of 2Θ having diffraction peaks at about 7.5 (+ -0.1), 10.9 (+ -0.1), 14.3 (+ -0.1), 15.2 (+ -0.1), 16.6 (+ -0.1), 17.7 (+ -0.1), 18.5 (+ -0.1), 22.8 (+ -0.1) and 25.0 (+ -0.1).
In another aspect of the present invention, there is provided a process for the preparation of crystalline form a of a compound of formula (I) as defined above, by complete dissolution of the compound of formula (I) in a suitable solvent selected from the group consisting of: ethyl acetate, methanol, methyl tertiary butyl ether, acetonitrile, ethanol, tetrahydrofuran, more preferably the solvent is selected from the group consisting of: ethyl acetate, methanol, methyl tert-butyl ether or acetonitrile.
In a specific embodiment of the present invention, there is provided a crystallization method of the compound of formula (I), wherein the compound of formula (I) is completely dissolved in methyl tert-butyl ether, crystallized at room temperature, and then the solid is separated and dried to obtain the compound of formula (I) of crystalline form a.
In a specific embodiment of the invention, the dissolution is performed by heating.
In a specific embodiment of the present invention, there is provided another crystallization method of the compound of formula (I), in which the compound of formula (I) is completely dissolved in ethyl acetate, crystallized at room temperature, and then the solid is separated and dried to obtain the compound of formula (I) of crystalline form a.
In a specific embodiment of the present invention, there is provided another crystallization method of the compound of formula (I), wherein the compound of formula (I) is completely dissolved in methanol, crystallized at room temperature, and then the solid is separated and dried to obtain the compound of formula (I) of crystalline form a.
In another aspect of the present invention, there is provided another crystallization method of the compound of formula (I), wherein the compound of formula (I) is completely dissolved in acetonitrile, crystallized at room temperature, and then the solid crystalline form is separated, and dried to obtain the compound of formula (I) of form a. When the form a of the present invention is used as a pharmaceutical, the form a of the present invention is usually mixed with an appropriate excipient to prepare a preparation for use. However, this does not negate the use of form a of the present invention itself directly as a pharmaceutical. The pharmaceutical composition, wherein the propranolol free base can exist in the form of the crystal form A, and can also be prepared from the crystal form A and pharmaceutically acceptable excipients, such as various liquid preparations.
Examples of the excipient include fillers, binders, lubricants, disintegrants, colorants, flavoring agents, emulsifiers, surfactants, cosolvents, suspensions, isotonic agents, buffers, preservatives, antioxidants, stabilizers, absorption promoters and the like which are generally used in pharmaceuticals, and the above additives may be used in combination as appropriate as required.
Examples of the filler include lactose, white sugar, glucose, corn starch, mannitol, sorbitol, starch, dextrin, microcrystalline cellulose, silica, and calcium hydrogen phosphate.
Examples of the binder include polyvinyl alcohol, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and polyethylene glycol.
Examples of the lubricant include magnesium stearate, calcium stearate, sodium fumarstearate, talc, polyethylene glycol, and colloidal silica.
Examples of the disintegrating agent include microcrystalline cellulose, agar, gelatin, calcium carbonate, low-substituted hydroxypropylcellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch, and sodium carboxymethyl starch.
Examples of the coloring agent include coloring agents which are allowed to be added to pharmaceuticals such as ferric oxide, yellow ferric oxide, carmine, caramel, beta-carotene, titanium oxide, talc, and riboflavin sodium phosphate.
Examples of the taste-modifying agent include cocoa powder, menthol, peppermint oil, borneol, cinnamon powder, and the like.
Examples of the emulsifier or surfactant include octadecyl triethanolamine, sodium lauryl sulfate, dodecylaminopropionic acid, lecithin, glycerol monostearate, sucrose fatty acid ester, and glycerol fatty acid ester.
Examples of the cosolvent include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium citrate, tween 80, nicotinamide, cyclodextrin, and cyclodextrin derivatives, and organic and/or inorganic acids such as tartaric acid, acetic acid, citric acid, malic acid, sulfuric acid, and phosphoric acid.
Examples of the suspension include hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose, in addition to the surfactant.
Examples of the isotonic agent include glucose, sodium chloride, mannitol, and sorbitol.
Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate.
Examples of the preservative include methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
Examples of the antioxidant include sulfite, ascorbic acid, and α -tocopherol.
Examples of the preparation include tablets, powders, granules, capsules, syrups, troches, sublingual tablets, sublingual/buccal films, inhalants and the like; external preparations or injections such as suppositories, ointments, creams, gels, eye ointments, transdermal agents, eye drops, nasal drops, ear drops, cataplasm, and lotions.
The above oral preparation may be formulated by appropriately combining the above additives. The surface of the above-mentioned preparation may be coated as needed.
The external preparation may be formulated by appropriately combining the above additives, in particular, excipients, binders, flavoring agents, emulsifiers, surfactants, cosolvents, suspending agents, isotonic agents, preservatives, antioxidants, stabilizers, absorption promoters, film forming agents, and the like.
The above-mentioned injection can be formulated by appropriately combining the above-mentioned additives, in particular, an emulsifier, a surfactant, a cosolvent, a suspension, an isotonic agent, a buffer, a preservative, an antioxidant, a stabilizer, an absorption enhancer, and the like.
Regarding the type of composition in question, other ingredients conventional in the art may be included in addition to those specifically mentioned above.
Form a of the present invention may also be used to provide a controlled release composition comprising a carrier and an active ingredient of the present invention, wherein the release of the active ingredient may be controlled and regulated to allow for less frequent administration or to improve the pharmacokinetic or toxicity profile of the ingredient. The controlled release composition may be prepared according to conventional methods.
When the crystalline form a or the composition of the present invention is used as a pharmaceutical, the amount thereof varies depending on the symptoms, age and administration mode, and usually 5mg to 200mg is administered daily to an adult in 1 or several times. The dosage of children can be properly reduced.
When the crystal form a and the composition of the present invention are used as a pharmaceutical, they can be used for the following purposes: as a secondary prevention to reduce mortality from myocardial infarction; hypertension (alone or in combination with other antihypertensive agents); exertion type angina pectoris; the control of supraventricular tachyarrhythmias, ventricular arrhythmias, especially arrhythmias related to catecholamines or caused by digitalis, can be used for control of atrial flutter and atrial flutter ventricular rate with poor digitalis curative effect, can also be used for refractory extra-systole, and can improve symptoms of patients; reducing the pressure difference of outflow tracts of hypertrophic cardiomyopathy, and relieving the symptoms such as angina pectoris, palpitation, syncope and the like; matching with α Receptor blockers are used to control tachycardia in pheochromocytoma patients; the heart rate is too fast for controlling hyperthyroidism, and can also be used for treating thyroid crisis; for hemangiomas; for melanoma; portal high pressure esophageal fundus varices venous hemorrhage; migraine; cerebrovascular ischemic disease; essential tremor; schizophrenia; anxiety disorders; a method Le Shi tetrad (F4) hypoxic episode; epidemic hemorrhagic fever; aplastic anemia; contraception; restless legs syndrome; aortic dissection hematoma.
When the composition of the present invention is used as a pharmaceutical, it may contain another therapeutic agent depending on the disease, symptoms, age, etc., to obtain a further effect.
Drawings
Fig. 1: a compound of formula (I): DSC profile of crystalline form A of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol in methyl tert-butyl ether.
Fig. 2: a compound of formula (I): TGA profile of crystal a of 1-isopropylamino-3- (naphthalen-1-oxy) propan-2-ol crystallized in methyl tert-butyl ether.
Fig. 3: a compound of formula (I): XRPD spectrum of crystal a of 1-isopropylamino-3- (naphthalen-1-oxy) propan-2-ol crystallized in methyl tert-butyl ether.
Fig. 4: a compound of formula (I): DSC profile of crystalline form A of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol in ethyl acetate.
Fig. 5: a compound of formula (I): TGA profile of crystalline form a of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol in ethyl acetate.
Fig. 6: a compound of formula (I): XRPD spectrum of crystal a of 1-isopropylamino-3- (naphthalen-1-oxy) propan-2-ol crystallized in ethyl acetate.
Fig. 7: a compound of formula (I): DSC profile of crystalline form A of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol crystallized in methanol.
Fig. 8: a compound of formula (I): TGA profile of crystalline a of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol in methanol.
Fig. 9: a compound of formula (I): XRPD spectrum of crystal a of 1-isopropylamino-3- (naphthalen-1-oxy) propan-2-ol crystallized in methanol.
Fig. 10: a compound of formula (I): DSC profile of crystalline form A of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol in acetonitrile.
Fig. 11: a compound of formula (I): TGA profile of crystal a of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol crystallized in acetonitrile.
Fig. 12: a compound of formula (I): XRPD spectrum of crystal a of 1-isopropylamino-3- (naphthalen-1-oxy) propan-2-ol crystallized in acetonitrile.
Detailed Description
For further explanation of the present invention, specific examples will be given below, but the following examples do not limit the scope of the present invention in any way.
Example 1: synthesis of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol.
10.00ml of purified water was added to a 100.00ml three-necked flask, 1.00g of propranolol hydrochloride (supplied by Adamas-beta reagent Co.) was added under stirring, 10.00ml of saturated sodium bicarbonate was added, stirring was performed, pH >7 was detected, 10.00ml of methylene chloride was added, stirring was performed to separate the liquid, the organic phase was collected, the aqueous phase was extracted once with 10.00ml of methylene chloride, the methylene chloride phases were combined, dried over anhydrous sodium sulfate and then methylene chloride was distilled off under reduced pressure to obtain 0.58g of an off-white solid, namely 1-isopropylamino-3- (naphthalene-1-oxy) propan-2-ol.
Example 2: preparation of crystalline form A of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol
0.58g of 1-isopropylamino-3- (naphthalen-1-oxy) propan-2-ol prepared in example 1 was added to 10.00ml of methyl tert-butyl ether, heated to 50 ℃, stirred for about 10 minutes to dissolve, then cooled to room temperature for crystallization, filtered, and the filter cake was air-dried at 40 ℃ to give 0.33g of a white solid, the melting onset temperature of which was 92.3 ℃ as determined by DSC (fig. 1), endothermic peak: the data of TGA (figure 2) and XRPD (figure 3) at 95.7 ℃ are shown in the drawings.
Example 3: preparation of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol crystals.
50.00mg of 1-isopropylamino-3- (naphthalene-1-oxy) propan-2-ol prepared in example 2 was weighed into 1.00ml of ethyl acetate, left open at room temperature, and after about 4 days the precipitated crystals were taken out and checked for feeding, and the onset of melting was determined by DSC (FIG. 4) to be 90.1 ℃ at the endothermic peak: the TGA (FIG. 5) at 95.0deg.C is shown in the accompanying figures. XRPD (fig. 6) is shown in detail in the accompanying drawings. The crystalline compound of formula (I) shows a DSC with almost the same melting point as crystal a.
Example 4: preparation of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol crystals.
50.00mg of 1-isopropylamino-3- (naphthalene-1-oxy) propan-2-ol prepared in example 2 was weighed into 1.00ml of methanol, and after about 4 days, the precipitated crystals were taken out and sampled for detection, and the melting start was determined to be 91.1℃by DSC (FIG. 7), the endothermic peak: the TGA (FIG. 8) at 94.9℃is shown in the accompanying figures. XRPD (fig. 9) is shown in detail in the accompanying drawings. The crystalline compound of formula (I) shows a DSC with almost the same melting point as crystal a.
Example 5: preparation of 1-isopropylamino-3- (naphthalen-1-yloxy) propan-2-ol crystals.
50.00mg of 1-isopropylamino-3- (naphthalene-1-oxy) propan-2-ol prepared in example 2 was weighed into 1.00ml of acetonitrile, and after about 4 days, the precipitated crystals were taken out and sampled for detection, and the melting start was determined to be 91.8℃by DSC (FIG. 10), the endothermic peak: the TGA (FIG. 11) at 95.5℃is shown in the accompanying figures. XRPD (fig. 12) is shown in detail in the accompanying drawings. The crystalline compound of formula (I) shows a DSC with almost the same melting point as crystal a.
It should be noted that all documents mentioned in the present invention are incorporated by reference in the present application as if each were individually incorporated by reference. It will be appreciated that the foregoing describes specific embodiments of the invention and the technical principles applied thereto, and that those skilled in the art, after reading the disclosure of the present invention, may make various changes and modifications without departing from the spirit and scope of the invention, and these equivalent forms are also within the scope of the present invention.
Remarks: XRPD: x-ray powder diffraction
DSC: differential scanning calorimetry
TGA: thermogravimetric analysis.
Claims (10)
1. Form a of propranolol free base characterized in that the characteristic peaks 2 theta of the X-ray powder diffraction pattern are 7.5 (+ -0.1), 10.9 (+ -0.1), 14.3 (+ -0.1), 15.2 (+ -0.1) and 16.6 (+ -0.1), wherein the structural formula of the propranolol free base is shown as a formula (I),
2. form a of propranolol free base according to claim 1, characterized by an X-ray powder diffraction pattern having characteristic peaks 2Θ of 7.5 (±0.1), 10.9 (±0.1), 14.3 (±0.1), 15.2 (±0.1), 16.6 (±0.1), 17.7 (±0.1), 18.5 (±0.1), 22.8 (±0.1), 25.0 (±0.1).
3. A compound of formula (I) according to any one of claims 1 or 2, characterized in that its onset of melting of the differential scanning calorimetry curve is between 90 and 93 ℃.
4. A process for preparing crystalline form a of propranolol free base of claim 1 wherein the compound of formula (I) is fully dissolved in a solvent selected from the group consisting of: lower alkyl acetate, lower alkyl alcohol, dialkyl ether or acetonitrile, then crystallizing at room temperature, and drying to obtain a crystal form A.
5. The method according to claim 4, wherein the solvent is selected from the group consisting of: ethyl acetate, methanol, methyl tert-butyl ether or acetonitrile.
6. The process of claim 4, wherein the solvent is methyl tertiary butyl ether and the complete dissolution is by heating.
7. A pharmaceutical composition comprising crystalline form a of propranolol free base according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient.
8. The pharmaceutical composition of claim 7, further comprising an additional therapeutic agent.
9. The pharmaceutical composition of any one of claims 7-8, which is in the form of a tablet, powder, granule, capsule, syrup, lozenge, sublingual tablet, sublingual/buccal film, inhalant or the like; suppositories, ointments, creams, gels, eye ointments, transdermal agents, eye drops, nose drops, ear drops, cataplasms, lotions or injections.
10. Use of crystalline form a of propranolol free base according to any one of claims 1 to 3 or of the pharmaceutical composition according to any one of claims 7 to 9 for the preparation of a medicament for the treatment of sinus and supraventricular arrhythmias, atrial fibrillation, angina pectoris, preoperative treatment of pheochromocytoma, hypertension, hemangioma.
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| CN202211582857.XA CN116178185A (en) | 2018-04-20 | 2018-04-20 | New crystalline forms of propranolol free base |
| CN201810364327.5A CN110386879A (en) | 2018-04-20 | 2018-04-20 | The novel crystal forms of Propranolol free alkali |
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| US3534085A (en) * | 1968-10-16 | 1970-10-13 | Squibb & Sons Inc | 5,8-dihydronaphthloxy-aminopropanols and related compounds |
| HU167262B (en) * | 1972-12-22 | 1975-09-27 | ||
| US5290958A (en) * | 1993-03-18 | 1994-03-01 | Industrial Technology Research Institute | Phase transfer catalytic process for preparing intermediates of atenolol, propranolol, and their derivatives |
| CN103030567A (en) * | 2012-07-25 | 2013-04-10 | 浙江工业大学 | Propranolol medicine enantiomer resolution method |
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