CN104974060A - Method for preparing sodium, 8-(2-hydroxybenzamido)octanoate - Google Patents
Method for preparing sodium, 8-(2-hydroxybenzamido)octanoate Download PDFInfo
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- CN104974060A CN104974060A CN201510210475.8A CN201510210475A CN104974060A CN 104974060 A CN104974060 A CN 104974060A CN 201510210475 A CN201510210475 A CN 201510210475A CN 104974060 A CN104974060 A CN 104974060A
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Abstract
The invention discloses a method for preparing sodium, 8-(2-hydroxybenzamido)octanoate which is a drug intermediate. The method comprises the following steps of reacting salicylamide, which serves as a raw material, with ethyl chloroformate to produce an intermediate 2H-benzo[e][1,3]oxazine-2,4(3H)-dione, reacting the intermediate with 8-bromooctanoic acid ethyl ester, carrying out hydrolysis so as to obtain 8-(2-hydroxybenzamido)octanoic acid, and then, reacting 8-(2-hydroxybenzamido)octanoic acid with sodium hydroxide so as to obtain the final product, namely sodium, 8-(2-hydroxybenzamido)octanoate. According to the method, the raw material reacts with ethyl chloroformate to produce the intermediate 2H-benzo[e][1,3]oxazin-2,4(3H)-dione, so that the yield of the reaction is greatly increased, the selectivity of reaction is greatly improved, the production cost is reduced, the production of byproducts is lowered, industrial production is facilitated; and the method is environment-friendly.
Description
Technical field
The present invention relates to a kind of preparation method of technical field of pharmaceuticals, specifically pharmaceutical intermediate: the preparation method of 8-(2-Hydroxylbenzamide base) Sodium octoate.
Background technology
8-(2-Hydroxylbenzamide base) Sodium octoate, is called for short SNAC, is a kind of bisphosphonate absorption enhancer, is used for the treatment of gastrointestinal tract disease, be particularly useful for the intestines and stomach disease that bisphosphonate malabsorption causes.Confirm at present the intestines and stomach disease that oral 8-(2-Hydroxylbenzamide base) Sodium octoate (2.5 milligrams/every day) effectively can be treated bisphosphonate malabsorption and caused.8-(2-Hydroxylbenzamide base) Sodium octoate is as the renewal product for the treatment of stomach bisphosphonate malabsorption medicine, higher than medicine effect before safer, has considerable application prospect.
Through to existing literature search, take salicylic amide as raw material, obtain 8-(2-Hydroxylbenzamide base) Sodium octoate through polystep reaction.Name of document is WO2008028859A1.The main problem of this route be raw material salicylic amide directly and 8-bromine ethyl octylate react, reaction preference and productive rate are very low, by-product yields is higher, be separated very difficult, need to use solvent costly to carry out recrystallization or column chromatography, because be not suitable with large-scale commercial production, and recrystallization or column chromatography solvent can cause serious discharging of waste liquid problem.In a word, the subject matter that 8-(2-Hydroxylbenzamide base) Sodium octoate is produced how to improve salicylic amide directly and the productive rate that reacts of 8-bromine ethyl octylate and selectivity.
Summary of the invention
The object of the invention is to overcome above shortcomings in prior art, and a kind of reasonable in design is provided, the preparation method of 8-(2-Hydroxylbenzamide base) Sodium octoate.This preparation method can simplify the operation step, and improve selectivity of product and yield, convenient separation, production cost is low, is easy to industrialization.
The present invention's adopted technical scheme that solves the problem is:
A kind of preparation method of 8-(2-Hydroxylbenzamide base) Sodium octoate, it is characterized in that, comprise the following steps: step one: raw material salicylic amide is obtained by reacting reaction intermediate 2 hydrogen-benzo [e] [1 with Vinyl chloroformate in the first solvent, 3] oxazine-2,4 (3 hydrogen)-diketone; Step 2: the product 2 hydrogen-benzo [e] [1 in step one, 3] to obtain product 8-(2-Hydroxylbenzamide base) by hydrolysis reaction sad in the second solvent and after the reaction of 8-bromine ethyl octylate for oxazine-2,4 (3 hydrogen)-diketone; It is sad that the sad and sodium hydroxide of step 3: 8-(2-Hydroxylbenzamide base) obtains product 8-(2-Hydroxylbenzamide base) at the 3rd solvent reaction.
As preferably, in described step one with Whitfield's ointment ethanamide for raw material, and intermediate 2 hydrogen-benzo [e] [1,3] oxazine-2,4 (3 hydrogen)-diketone are produced in Vinyl chloroformate reaction.
As preferably, described first reaction solvent adopts acetonitrile, pyridine or Vinyl chloroformate.
As preferably, in described step 2, use alkali to promote reaction, alkali adopts sodium carbonate or salt of wormwood.
As preferably, described second solvent adopts diethyl acetamide, N,N-DIMETHYLACETAMIDE or nitrogen methyl-2-pyrrolidone.
As preferably, 2 hydrogen-benzo [e] [1,3] oxazine-2,4 (3 hydrogen)-diketone with after the reaction of 8-bromine ethyl octylate without the need to being separated, directly add aqueous sodium hydroxide solution and be hydrolyzed.
As preferably, described 3rd solvent adopts water, acetone or alcohol.
Synthetic route of the present invention is as follows:
The present invention is with common raw material Vinyl chloroformate and salicylic amide reaction, obtain intermediate 2 hydrogen-benzo [e] [1,3] oxazines-2,4 (3 hydrogen)-diketone, this intermediate and the reaction of 8-bromine ethyl octylate have good selectivity and very high reaction yield, it is sad that product can obtain 8-(2-Hydroxylbenzamide base) without the need to separation and purification direct hydrolysis, can obtain final product 8-(2-Hydroxylbenzamide base) Sodium octoate through salt-forming reaction.Although the many step raw material salicylic amides of the method and Vinyl chloroformate produce the reaction of intermediate, but this middle physical efficiency greatly improves the low problem of poor selectivity and productive rate in former route, and the product generated without the need to be separated can direct hydrolysis to obtain 8-(2-Hydroxylbenzamide base) sad, greatly comparatively lower production cost, improves overall yield of reaction.
The present invention compared with prior art, has the following advantages and effect: 1) adopt the Vinyl chloroformate be cheaply easy to get to generate intermediate, greatly improve productive rate and the selectivity of reaction; 2) can direct hydrolysis without the need to separation and purification after the reaction of intermediate and 8-bromine ethyl octylate, reduce the separating difficulty 3 of former method) avoid using a large amount of solvent to carry out recrystallization or column chromatography, more friendly to environment.
Embodiment
Below by embodiment, the present invention is described in further detail, and following examples are explanation of the invention and the present invention is not limited to following examples.
The preparation method of the present embodiment 8-(2-Hydroxylbenzamide base) Sodium octoate, comprises the following steps:
Step one:
Salicylic amide 30 grams (1 equivalent) is dissolved in 64 milliliters of acetonitriles and 76 milliliters of pyridines, be cooled to 0-5 degree Celsius, slow dropping Vinyl chloroformate 26.1 grams (1.1 equivalent), slowly be warming up to 10 degrees Celsius, maintain 30 minutes, slowly be warming up to interior temperature and reach 90 degrees Celsius, by the water trap distillation most of solvent of removing (about 110 milliliters), until interior temperature rise to 124 degrees centigrade, reduce temperature to interior temperature at 90-124 degree Celsius, reaction is made to keep backflow but not steam solvent, keep 3 hours, room temperature is down in reaction, slowly pour in 200 ml waters, slowly add 16 milliliters of concentrated hydrochloric acids, collected by filtration thing, 200 ml waters wash 2 times, under 40 degrees Celsius, drying obtains 32 grams of white solids 1 for 8 hours.
White solid 1 does nuclear magnetic resonance spectroscopy, and result is:
1HNMR(400MHZDMSO)б12.05(s,1H),7.94(dd,J＝7.7,1.3Hz,1H),7.84-7.75(m,1H),7.41(t,J＝8.3Hz,2H)
Step 2:
41.3 grams of 8-bromine ethyl octylates (1 equivalent) are added in 120 milliliters of N,N-DIMETHYLACETAMIDEs, 30 grams of (1.12 equivalent) products 1, with 39 grams of sodium carbonate, blast the air in nitrogen replacement system, water pump is evacuated to system pressure and is less than 0.02 MPa (actual is 0.07 MPa), is warming up to 70 degrees Celsius of stirrings and spends the night.170 ml waters and 29 milligrams of EDTA are added in reaction system, 20 degrees Celsius are stirred half an hour, drip 40 gram of 40% aqueous sodium hydroxide solution (4 equivalent), slowly be warming up to 100 degrees Celsius, stir 20 hours, be cooled to room temperature, reaction solution transferred in constant pressure funnel, slowly be added drop-wise in 45 milliliters of acetone and 36 milliliters of concentrated hydrochloric acids (adding ice bath), keep system temperature below 30 degrees Celsius.Dropwise, with the pH value of 20% sodium hydroxide regulation system to 4-5.Slowly be warming up to 60 degrees Celsius, keep one hour, be cooled to 20 degrees Celsius, keep 4 hours.Collected by filtration thing, 200 ml waters wash 2 times, and 40 degrees Celsius of dried overnight obtain 20.5 grams of off-white color solids 2.
Off-white color solid 2 does nuclear magnetic resonance spectroscopy, and result is:
1HNMR(400MHZDMSO)б12.74(s,1H),7.84(d,J＝7.3Hz,1H),7.39(s,1H),6.89(d,J＝7.8Hz,2H),3.28(dd,J＝6.7Hz,2H),3.28(dd,J＝6.7Hz,2H),2.19(t,J＝7.3Hz,2H),1.58-1.44(m,4H),1.29(s,6H)
Step 3:
20 grams of products 3 (1 equivalent) add in 77 milliliters of Virahols, be heated to 40 degrees Celsius, slow dropping 14.6 gram of 20% aqueous sodium hydroxide solution is (when dripping half left and right, reaction system becomes clarification), slowly be warming up to 50 degrees Celsius, keep half an hour, slowly cool to 35 degrees Celsius, keep one hour, continue to be cooled to 30 degrees Celsius, slow dropping 77 milliliters of Virahols, be cooled to room temperature, distillation removing 4/5 volume of solvent, remaining wet solid filtering is collected, wash 3 times with 50 milliliters of ethanol, 40 degrees Celsius of dryings obtain 20.5 grams of light yellow solids 3 for 20 hours.
Light yellow solid 3 does nucleus magnetic resonance, and result is:
1HNMR(400MHZDMSO)б7.53(dd,J＝7.8,1.2Hz,1H),7.31(dd,J＝11.3,4.3Hz,H),3.28(dd,J＝6.7Hz,2H),6.93-6.77(m,2H),3.21(t,J＝6.9Hz,2H),2.04(t,J＝7.5Hz,2H),1.53-1.32(m,4H),1.19(s,6H)
Above content described in this specification sheets is only made for the present invention illustrating.Those skilled in the art can make various amendment or supplement or adopt similar mode to substitute to described specific embodiment; only otherwise depart from the content of specification sheets of the present invention or surmount this scope as defined in the claims, protection scope of the present invention all should be belonged to.
Claims (7)
1. the preparation method of 8-(2-Hydroxylbenzamide base) Sodium octoate, it is characterized in that, comprise the following steps: step one: raw material salicylic amide is obtained by reacting reaction intermediate 2 hydrogen-benzo [e] [1 with Vinyl chloroformate in the first solvent, 3] oxazine-2,4 (3 hydrogen)-diketone; Step 2: the product 2 hydrogen-benzo [e] [1 in step one, 3] to obtain product 8-(2-Hydroxylbenzamide base) by hydrolysis reaction sad in the second solvent and after the reaction of 8-bromine ethyl octylate for oxazine-2,4 (3 hydrogen)-diketone; It is sad that the sad and sodium hydroxide of step 3: 8-(2-Hydroxylbenzamide base) obtains product 8-(2-Hydroxylbenzamide base) at the 3rd solvent reaction.
2. the preparation method of 8-according to claim 1 (2-Hydroxylbenzamide base) Sodium octoate, it is characterized in that: in described step one with Whitfield's ointment ethanamide for raw material, intermediate 2 hydrogen-benzo [e] [1 is produced with Vinyl chloroformate reaction, 3] oxazine-2,4 (3 hydrogen)-diketone.
3. the preparation method of 8-according to claim 1 (2-Hydroxylbenzamide base) Sodium octoate, is characterized in that: described first reaction solvent adopts acetonitrile, pyridine or Vinyl chloroformate.
4. the preparation method of 8-according to claim 1 (2-Hydroxylbenzamide base) Sodium octoate, is characterized in that: in described step 2, and use alkali to promote reaction, alkali adopts sodium carbonate or salt of wormwood.
5. the preparation method of 8-according to claim 1 (2-Hydroxylbenzamide base) Sodium octoate, is characterized in that: described second solvent adopts diethyl acetamide, N,N-DIMETHYLACETAMIDE or nitrogen methyl-2-pyrrolidone.
6. the preparation method of 8-according to claim 1 (2-Hydroxylbenzamide base) Sodium octoate, it is characterized in that: 2 hydrogen-benzo [e] [1,3] oxazines-2, without the need to being separated after 4 (3 hydrogen)-diketone reacting with 8-bromine ethyl octylate, directly adding aqueous sodium hydroxide solution and being hydrolyzed.
7. the preparation method of 8-according to claim 1 (2-Hydroxylbenzamide base) Sodium octoate, is characterized in that: described 3rd solvent adopts water, acetone or alcohol.
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| CN108570012A (en) * | 2018-05-23 | 2018-09-25 | 中南大学 | 1,3- benzoxazines -2,4 (3H)-derovatives and its preparation method and use |
| CN108689876A (en) * | 2018-06-28 | 2018-10-23 | 苏州东南药业股份有限公司 | A kind of preparation method of 8- (2-Hydroxylbenzamide base) Sodium Caprylate |
| CN111269193A (en) * | 2020-04-02 | 2020-06-12 | 湖南海利常德农药化工有限公司 | Preparation method of benzo [ e ] [1,3] oxazine-2, 4-dione |
| CN111978193A (en) * | 2020-09-02 | 2020-11-24 | 无锡紫杉药业有限公司 | Sodium 8- (2-hydroxybenzamido) caprylate and preparation method thereof |
| CN112661662A (en) * | 2020-12-29 | 2021-04-16 | 苏州天马医药集团天吉生物制药有限公司 | Preparation method of sodium 8- (2-hydroxybenzamido) caprylate |
| CN112898220A (en) * | 2020-12-07 | 2021-06-04 | 旺山旺水(连云港)制药有限公司 | Preparation method of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate and intermediate thereof |
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- 2015-04-24 CN CN201510210475.8A patent/CN104974060A/en active Pending
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| CN108570012A (en) * | 2018-05-23 | 2018-09-25 | 中南大学 | 1,3- benzoxazines -2,4 (3H)-derovatives and its preparation method and use |
| CN108570012B (en) * | 2018-05-23 | 2021-11-12 | 中南大学 | 1, 3-benzoxazine-2, 4(3H) -diketone derivative and synthetic method and application thereof |
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| IT202000003251A1 (en) | 2020-02-18 | 2021-08-18 | Dipharma Francis Srl | PREPARATION OF A NON-STEROID ANALGESIC |
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| CN115108936A (en) * | 2022-07-29 | 2022-09-27 | 成都普康唯新生物科技有限公司 | Method for preparing anhydrous crystal form of sodium 8- (2-hydroxybenzamido) caprylate by anhydrous system |
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| CN115260116A (en) * | 2022-08-19 | 2022-11-01 | 株洲壹诺生物技术有限公司 | Preparation method of sodium 8- (2-hydroxybenzamido) caprylate, benzoxazine-2,4-diketone and 8-bromoethyl caprylate |
| CN115260116B (en) * | 2022-08-19 | 2024-04-12 | 株洲壹诺生物技术有限公司 | Preparation method of 8- (2-hydroxybenzoamido) sodium octoate and benzoxazine-2, 4-diketone and 8-bromooctoate |
| CN116041273A (en) * | 2022-12-28 | 2023-05-02 | 西宝生物科技（上海）股份有限公司 | Preparation method of benzo [ e ] [1,3] oxazine-2, 4-dione |
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Application publication date: 20151014 |