CN111620802A - Preparation method of cefditoren intermediate (R) -1-benzyl-3-aminopyrrolidine - Google Patents
Preparation method of cefditoren intermediate (R) -1-benzyl-3-aminopyrrolidine Download PDFInfo
- Publication number
- CN111620802A CN111620802A CN202010557257.2A CN202010557257A CN111620802A CN 111620802 A CN111620802 A CN 111620802A CN 202010557257 A CN202010557257 A CN 202010557257A CN 111620802 A CN111620802 A CN 111620802A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- temperature
- aminopyrrolidine
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a cefditoren intermediate (R) -1-benzyl-3-aminopyrrolidine, which comprises the following steps: using D-aspartic acid as a starting material, and obtaining the (R) -1-benzyl-3-aminopyrrolidine by amino protection, esterification, reduction, bromo-cyclization and 3-site amino protection removal. The invention solves the defects of expensive raw materials, high temperature and high pressure, noble metal catalysis and the like of the prior art for preparing the (R) -1-benzyl-3-aminopyrrolidine. The materials used in the invention are cheap and easily available, and the cost is low; the reaction can be carried out at normal temperature, the energy consumption is low, the industrial production is facilitated, and the pollution is low.
Description
Technical Field
The invention relates to a preparation method of a cefditoren intermediate, and particularly relates to a preparation method of a cefditoren intermediate (R) -1-benzyl-3-aminopyrrolidine.
Background
The 3-aminopyrrolidine and the derivatives thereof are used as important fine chemical intermediates, are widely applied to the fields of pesticides, medicines, fine chemical industry and the like, have good market prospects, and the 3-aminopyrrolidine and the derivatives thereof with optical activity are important intermediates of various quinolones and cephalosporins, wherein the (R) -1-benzyl-3-aminopyrrolidine is used as an important intermediate of a fifth generation cephalosporin antibiotic cefepime, and have good market prospects and economic benefits.
Currently, there are several synthetic routes for 3-aminopyrrolidine and its derivatives as follows:
(1) japanese laid-open patent publication No. JP61057579A reports that acrylic acid ester is used as a raw material, and is added with N-ethoxycarbonylglycine ethyl ester, and then Dieckmann cyclization is carried out, followed by selective hydrolysis and decarboxylation to obtain pyrrolidone, and then followed by oximation, reduction, acidic hydrolysis and decarboxylation to obtain 3-aminopyrrolidine.
The route has oximation reaction, is difficult to treat and has larger pollution. And dicarbonyl compound Dieckmann cyclization reaction is carried out under the strong alkali condition, and the yield is low.
(1) Japanese Kokai publication (CA 1978; 89; 43107V) reports that 1, 4-dichlorolimonene is used as a raw material, substituted and condensed with benzylamine, sequentially subjected to hydroboration oxidation, thionyl chloride chlorination and Gavriel method to obtain N-benzyl-3-aminopyrrolidine, and finally subjected to palladium-carbon hydrogenolysis to obtain 3-aminopyrrolidine.
The route relates to deprotection of N-benzyl, needs a method of catalytic hydrogenation of noble metal at high temperature and high pressure, has harsh adjustment and higher cost, and is not suitable for industrial production.
(2) Chinese patent application (CN1733720A) discloses a synthesis method of N-substituent-3-aminopyrrolidine and dihydrochloride thereof, which takes 1,2, 4-tribromobutanol as raw material, firstly halogenates the raw material, then aminolyzes the raw material and carries out condensation reaction with benzylamine, and finally uses palladium carbon for hydrogenolysis and deprotection to obtain the 3-aminopyrrolidine. The raw material 1,2, 4-tribromobutanol of the route is expensive, and simultaneously, deprotection of N-benzyl is also involved, so that the cost is too high, and the route is not suitable for industrial production.
(3) Shanghai application technology academy (Nature science edition) 1671-; the route also relates to the protection of removing N-CBZ by noble metal catalytic hydrogenation at high temperature and high pressure, and is high in cost and not suitable for industrial production.
(4) Chinese patent (200510060483.5) discloses a method for synthesizing N-substituent-3-aminopyrrolidine and dihydrochloride thereof, which takes 1,2, 4-butanetriol as a starting material and finally synthesizes the 3-aminopyrrolidine and the dihydrochloride thereof through halogenation and ammonolysis.
(5) World patent WO2004013097 discloses a preparation process of aminopyrrolidine derivatives, wherein hydroxylamine hydrochloride is used for ring closure, and Raney Ni and palladium carbon which are easy to catch fire are used in the process.
Disclosure of Invention
In order to overcome the defects of expensive raw materials, high temperature and high pressure, noble metal catalysis and the like of the (R) -1-benzyl-3-aminopyrrolidine preparation in the prior art, the invention provides a method for preparing (D-aspartic acid) by using D-aspartic acid as a starting raw material, which avoids resource waste caused by chiral resolution; in the preparation process, the reactions in each step can be carried out at normal temperature, so that the energy consumption is effectively reduced, and the environmental pollution is reduced.
The invention adopts the technical scheme that the invention aims to realize the purpose;
a preparation method of (R) -1-benzyl-3-aminopyrrolidine comprises the following steps:
A) using compound D-aspartic acid as starting material, and reacting with K2CO3Reacting with benzyl chloroformate to obtain a compound II;
B) reacting methyl chlorosulfonate generated by the reaction of thionyl chloride and methanol with the compound II obtained in the step A) to obtain a compound III dimethyl aspartate;
C) the compound III obtained in the step B) is subjected to LiAlH at low temperature4Reducing to compound IV;
D) substituting two hydroxyl groups of the compound IV obtained in the step C) into halogenated hydrocarbon to obtain a compound V;
E) the compound V obtained in the step D) is subjected to ring closing by benzylamine to obtain a compound VI;
F) removing the 3-amino protecting group CBZ from the compound VI obtained in the step E) to obtain a compound VII which is (R) -1-benzyl-3-aminopyrrolidine:
the reaction synthesis route is as follows:
further, in the step A), the D-aspartic acid and the K are2CO3The mol ratio of CBZ-Cl is 1: 1.5-3: 1-2, the stirring time is 8-12min, the temperature is increased to 20 ℃, the reaction time is 3-5h, and the lower reaction temperature ensures that the configuration of the chiral carbon atom cannot be changed.
Further, in the step B), the methanol was 34g, and the compound II was reacted with SOCl2The molar ratio of (1: 2) - (4), keeping the temperature at 0 ℃ for 25-35min, heating to 20 ℃, and reacting for 2-4 h.
Preferably, in said step B), the reaction time is comprised between 2.5 and 3 h.
Further, in the step C), the molar ratio of the compound III to LiAlH4 is 1: 1.2-2, the reaction time is 4-6h, and the THF is 112 g.
Further, in the step D), adding the compound IV into a reaction vessel, stirring and dissolving the compound IV in 90.0ml of dichloromethane, cooling to 0 ℃, dropwise adding a halogenated reagent, keeping the temperature of 0 ℃ for reaction for 4 hours, heating to 20 ℃, reacting for 1 hour, reacting at a speed of reaction, cooling the reactant to 0 ℃, slowly dropwise adding 20ml of water to quench the rest halogenated reagent, separating out an organic layer by liquid separation, extracting the water layer by dichloromethane for 3 times, combining organic phases, and using 10ml of 5.0% NaHCO3Carrying out backwashing once on the solution, separating out a water layer, and evaporating the solvent from an organic layer under reduced pressure to obtain a white solid compound V; the molar ratio of the compound IV to the halogenating reagent is 1:1 to 1.5.
Preferably, in said step D), X is Cl, Br, I halogen atom, and the halogenating agent used is SOCl2、HCl、HBr、PCl3、PBr3、PCl5。
Further, in the step E), the molar ratio of the compound V, pyridine and benzylamine is 1: 2-3: 1-1.5, the THF is 73g, the temperature is raised to 30 ℃, and the reaction time is 3-6 h.
Further, in said step F), said compound VI, 33% HBr in acetic acid, is in a molar ratio of 1: 4.5 to 8 ℃, the temperature is 20 to 25 ℃, and the reaction time is 3 to 4 hours.
Compared with other methods, the synthesis method of (R) -1-benzyl-3-aminopyrrolidine provided by the invention has the characteristics of cheap and easily available raw materials, mild reaction conditions, capability of well keeping the spatial configuration of chiral carbon, reduction of resource waste caused by resolution, easiness in industrial production and the like; the reaction of each step can be carried out at normal temperature, thereby effectively reducing energy consumption and environmental pollution. The (R) -1-benzyl-3-aminopyrrolidine prepared by the invention has high content, the content can reach more than 99 percent by HPLC detection, and the invention has positive effect on the subsequent synthesis.
Detailed Description
The present invention will be described in detail with reference to examples, but the scope of the invention to be claimed is not limited to the scope expressed by the examples.
Example 1
The specific preparation steps of the step A) are as follows:
a250 ml round bottom flask was charged with 7.8gK2CO3100.00g of water, stirring at room temperature to dissolve, adding 5.0g of D-aspartic acid, cooling to 0 ℃ after the aspartic acid is dissolved, and slowly dropwise adding 6.4g of CBZ-Cl at 0 ℃. After the stirring is finished for 10 minutes, the temperature is gradually raised to 20 ℃ for reaction for 3 hours, the reaction is finished by TLC detection, and the reaction is stopped. Extracting the reaction solution with petroleum ether for 3 times, collecting water layer, adjusting pH to about 1.0 with dilute hydrochloric acid, extracting with ethyl acetate for 3 times, mixing ethyl acetate, and adding anhydrous Na2SO4Drying and filtering to remove Na2SO4Ethyl acetate was recovered to give 9.72g of a colorless transparent oily compound II, content 96.37%, yield 93.28%.
The specific preparation steps of the step B) are as follows:
34.0g of anhydrous methanol was added to a 100ml round bottom flask and the temperature was lowered to 0 ℃ with stirring, and 7.57g of SOCl was slowly added dropwise2And keeping the temperature for 25 minutes at 0 ℃ after dripping. Adding 8.50g of compound II, gradually heating to 20 ℃, stirring for reacting for 2 hours, detecting the reaction completion by TLC, and stopping the reaction. Drying the solvent under reduced pressure to obtain colorless viscous substance, adding methyl tert-butyl ether, stirring and pulping, filtering after completely dispersing, leaching the filter cake with small amount of methyl tert-butyl ether, drying under reduced pressure to obtain white solid compound III 8.56g with content of 94.83%, and collectingThe rate was 89.52%.
The specific preparation steps of the step C) are as follows:
112g of THF and 8.0g of compound III are introduced into a 250ml round-bottom flask, dissolved with stirring and cooled to 0 ℃. 1.28g LiAlH4 was added slowly in portions, the reaction was maintained for 3 hours and the reaction was complete by TLC. Spin-drying solvent to obtain off-white solid, adding 20ml water, stirring for dissolving, adjusting pH to about 10 with dilute NaOH solution, extracting with ethyl acetate for 3 times, mixing ethyl acetate phases, and adding appropriate amount of anhydrous Na2SO4And (5) drying. Filtering off Na2SO4Ethyl acetate was evaporated under reduced pressure to give 6.14g of a white solid compound IV, content 96.32%, yield 91.23%.
The specific preparation steps of step D) are as follows:
6.0g of compound IV are dissolved in 90.0ml of dichloromethane in a 250ml round-bottom flask with stirring, the temperature is reduced to 0 ℃, and 7.86g of PBr are added dropwise3Then keeping the temperature at 0 ℃ for reaction for 3 hours, and then heating to 20 ℃ for reaction for 1 hour, wherein the reaction speed is fast. Cooling the reactant to 0 ℃, slowly dripping 20ml of water to quench the residual PBr3Then, the organic layer was separated, and the aqueous layer was extracted 3 times with dichloromethane. The organic phases were combined and washed with 10ml of 5.0% NaHCO3The solution was backwashed once to separate an aqueous layer, and an organic layer was evaporated under reduced pressure to remove the solvent, whereby 7.99g of a white solid compound V was obtained in an amount of 93.47% and a yield of 84.79%.
The specific preparation steps of step E) are as follows:
in a 250ml round bottom flask, 7.81g of Compound V was dissolved with stirring in a mixed solvent of 73g of THF and 3.44g of pyridine, 2.35g of benzylamine was added dropwise with stirring, and the reaction was stopped by raising the temperature to 30 ℃ and reacting for 5 hours. The solvent was distilled off under reduced pressure, 20ml of water was added, stirring was carried out uniformly, extraction was carried out 3 times with ethyl acetate, ethyl acetate was combined, and ethyl acetate was distilled off under reduced pressure to obtain 5.77g of a white solid compound VI, the content of which was 94.13%, and the yield was 87.47%.
The specific preparation steps of step F) are as follows:
4.95g of compound VI and 34.65g of acetic acid are added to a 100ml round-bottom flask, stirred uniformly, and 16.1933% HBr acetic acid solution is added, after reaction for 3 hours at 20 ℃, the reaction is stopped. The solvent was distilled off under reduced pressure to give a pale yellow solid. 125ml of water is added and stirred to dissolve, and after dissolution and clarification, 125ml of methyl tert-butyl ether is used for extraction once. Collecting water layer, adjusting pH to about 8 with 5% NaOH solution, extracting with dichloromethane for 5 times, mixing dichloromethane, and adding anhydrous Na2SO4Drying, decompressing and distilling to remove the dichloromethane to obtain a white solid compound VII crude product, and crystallizing the crude product by using 95 percent ethanol to obtain 2.35g of the compound VII with the content of 99.02 percent and the yield of 87.88 percent.
Example 2
The specific preparation steps of the step A) are as follows:
a250 ml round bottom flask was charged with 10.40g K2CO3100.00g of water, stirring at room temperature to dissolve, adding 5.0g of aspartic acid, cooling to 0 ℃ after the aspartic acid is dissolved, and slowly dropwise adding 9.00g of CBZ-Cl at 0 ℃. After the stirring is finished for 10 minutes, the temperature is gradually raised to 20 ℃ for reaction for 4 hours, the TLC detects that the reaction is finished, and the reaction is stopped. Extracting the reaction solution with petroleum ether for 3 times, collecting water layer, adjusting pH to about 1.0 with dilute hydrochloric acid, extracting with ethyl acetate for 3 times, mixing ethyl acetate, and adding anhydrous Na2SO4Drying and filtering to remove Na2SO4Ethyl acetate was recovered to give 9.72g of a colorless transparent oily compound II, content 96.37%, yield 93.28%.
The specific preparation steps of the step B) are as follows:
34.0g of anhydrous methanol was added to a 100ml round bottom flask and the temperature was lowered to 0 ℃ with stirring, and 8.77g of SOCl was slowly added dropwise2And keeping the temperature for 30 minutes at 0 ℃ after dripping. Adding 8.50g of compound II, gradually heating to 20 ℃, stirring for reaction for 3 hours, detecting the reaction completion by TLC, and stopping the reaction. And (3) performing rotary drying on the solvent under reduced pressure to obtain a colorless sticky substance, adding methyl tert-butyl ether, stirring and pulping, filtering after complete dispersion, leaching a filter cake by using a small amount of methyl tert-butyl ether, and performing reduced pressure drying to obtain 8.56g of a white solid compound III with the content of 94.83 percent and the yield of 89.52 percent.
The specific preparation steps of the step C) are as follows:
112g of THF and 8.0g of compound III are introduced into a 250ml round-bottom flask, dissolved with stirring and cooled to 0 ℃. Slowly adding 1.54g LiAlH4 in portionsThe reaction was warmed for 5 hours and checked by TLC for completion. Spin-drying solvent to obtain off-white solid, adding 20ml water, stirring for dissolving, adjusting pH to about 10 with dilute NaOH solution, extracting with ethyl acetate for 3 times, mixing ethyl acetate phases, and adding appropriate amount of anhydrous Na2SO4And (5) drying. Filtering off Na2SO4Ethyl acetate was evaporated under reduced pressure to give 6.14g of a white solid compound IV, content 96.32%, yield 91.23%.
The specific preparation steps of step D) are as follows:
6.0g of compound IV is stirred and dissolved in 90.0ml of dichloromethane in a 250ml round-bottom flask, the temperature is reduced to 0 ℃, 1.06g of HCl is dripped, then the reaction is carried out for 4 hours under the condition of 0 ℃, the temperature is raised to 20 ℃ and the reaction is carried out for 1 hour, and the reaction speed is increased. After the temperature of the reaction product is reduced to 0 ℃, 20ml of water is slowly dropped to quench the residual HCl, then the organic layer is separated by liquid separation, and the water layer is extracted by dichloromethane for 3 times. The organic phases were combined and washed with 10ml of 5.0% NaHCO3The solution was back-washed once to separate an aqueous layer, and an organic layer was evaporated under reduced pressure to remove the solvent, whereby 7.99g of a white solid compound V was obtained in an amount of 93.47% and a yield of 84.79%.
The specific preparation steps of step E) are as follows:
in a 250ml round bottom flask, 7.81g of Compound V was dissolved with stirring in a mixed solvent of 73g of THF and 4.5g of pyridine, 2.57g of benzylamine was added dropwise with stirring, and then the reaction was stopped by raising the temperature to 30 ℃ for 5 hours. The solvent was distilled off under reduced pressure, 20ml of water was added, stirring was carried out uniformly, extraction was carried out 3 times with ethyl acetate, ethyl acetate was combined, and ethyl acetate was distilled off under reduced pressure to obtain 5.77g of a white solid compound VI, the content of which was 94.13%, and the yield was 87.47%.
The specific preparation steps of step F) are as follows:
4.95g of Compound VI and 34.65g of acetic acid were charged into a 100ml round-bottomed flask, and stirred uniformly, and then 24.75g of 33% HBr acetic acid solution was added thereto to react at 20 ℃ for 3.5 hours, and then the reaction was stopped. The solvent was distilled off under reduced pressure to give a pale yellow solid. 125ml of water is added and stirred to dissolve, and after dissolution and clarification, 125ml of methyl tert-butyl ether is used for extraction once. Collecting water layer, adjusting pH to about 8 with 5% NaOH solution, extracting with dichloromethane for 5 times, mixing dichloromethane, and adding anhydrous Na2SO4Drying, decompressing and distilling to remove the dichloromethane to obtain a white solid compound VII crude product, and crystallizing the crude product by using 95 percent ethanol to obtain 2.35g of the compound VII with the content of 99.02 percent and the yield of 87.88 percent.
Example 3
The specific preparation steps of the step A) are as follows:
a250 ml round bottom flask was charged with 15.6g K2CO3100.00g of water, stirring at room temperature to dissolve, adding 5.0g of D-aspartic acid, cooling to 0 ℃ after the aspartic acid is dissolved, and slowly dropwise adding 12.8g of CBZ-Cl at 0 ℃. After the stirring is finished, the temperature is gradually raised to 20 ℃ for reaction for 5 hours, the reaction is finished by TLC detection, and the reaction is stopped. Extracting the reaction solution with petroleum ether for 3 times, collecting water layer, adjusting pH to about 1.0 with dilute hydrochloric acid, extracting with ethyl acetate for 3 times, mixing ethyl acetate, and adding anhydrous Na2SO4Drying and filtering to remove Na2SO4Ethyl acetate was recovered to give 9.72g of a colorless transparent oily compound II, content 96.37%, yield 93.28%.
The specific preparation steps of the step B) are as follows:
34.0g of anhydrous methanol was added to a 100ml round bottom flask and the temperature was lowered to 0 ℃ with stirring, and 15.13g of SOCl was slowly added dropwise2And keeping the temperature for 30 minutes at 0 ℃ after dripping. Adding 8.50g of compound II, gradually heating to 20 ℃, stirring for reaction for 4 hours, detecting the reaction completion by TLC, and stopping the reaction. And (3) performing rotary drying on the solvent under reduced pressure to obtain a colorless sticky substance, adding methyl tert-butyl ether, stirring and pulping, filtering after complete dispersion, leaching a filter cake by using a small amount of methyl tert-butyl ether, and performing reduced pressure drying to obtain 8.56g of a white solid compound III with the content of 94.83 percent and the yield of 89.52 percent.
The specific preparation steps of the step C) are as follows:
112g of THF and 8.0g of compound III are introduced into a 250ml round-bottom flask, dissolved with stirring and cooled to 0 ℃. 2.16g of LiAlH4 was added slowly in portions, the reaction was kept for 6 hours and the reaction was complete by TLC. Spin-drying solvent to obtain off-white solid, adding 20ml water, stirring for dissolving, adjusting pH to about 10 with dilute NaOH solution, extracting with ethyl acetate for 3 times, mixing ethyl acetate phases, and adding appropriate amount of anhydrous Na2SO4And (5) drying. Filtering outNa2SO4Ethyl acetate was evaporated under reduced pressure to give 6.14g of a white solid compound IV, content 96.32%, yield 91.23%.
The specific preparation steps of step D) are as follows:
6.0g of Compound IV are dissolved in 90.0ml of dichloromethane in a 250ml round-bottom flask with stirring, the temperature is reduced to 0 ℃, and 11.79g of PBr are added dropwise3Then keeping the temperature at 0 ℃ for reaction for 6 hours, and then heating to 20 ℃ for reaction for 1 hour, wherein the reaction speed is fast. Cooling the reactant to 0 ℃, slowly dripping 20ml of water to quench the residual PBr3Then, the organic layer was separated, and the aqueous layer was extracted 3 times with dichloromethane. The organic phases were combined and washed with 10ml of 5.0% NaHCO3The solution was backwashed once to separate an aqueous layer, and an organic layer was evaporated under reduced pressure to remove the solvent, whereby 7.99g of a white solid compound V was obtained in an amount of 93.47% and a yield of 84.79%.
The specific preparation steps of step E) are as follows:
in a 250ml round bottom flask, 7.81g of Compound V was dissolved with stirring in a mixed solvent of 73g of THF and 4.37g of pyridine, 3.44g of benzylamine was added dropwise with stirring, and the reaction was stopped by raising the temperature to 30 ℃ and reacting for 6 hours. The solvent was distilled off under reduced pressure, 20ml of water was added, stirring was carried out uniformly, extraction was carried out 3 times with ethyl acetate, ethyl acetate was combined, and ethyl acetate was distilled off under reduced pressure to obtain 5.77g of a white solid compound VI, the content of which was 94.13%, and the yield was 87.47%.
The specific preparation steps of step F) are as follows:
4.95g of Compound VI and 34.65g of acetic acid were charged into a 100ml round-bottomed flask, stirred well, and 28.71g of 33% HBr in acetic acid was added to react at 20 ℃ for 4 hours, after which the reaction was stopped. The solvent was distilled off under reduced pressure to give a pale yellow solid. 125ml of water is added and stirred to dissolve, and after dissolution and clarification, 125ml of methyl tert-butyl ether is used for extraction once. Collecting water layer, adjusting pH to about 8 with 5% NaOH solution, extracting with dichloromethane for 5 times, mixing dichloromethane, and adding anhydrous Na2SO4Drying, decompressing and distilling to remove the dichloromethane to obtain a white solid compound VII crude product, and crystallizing the crude product by using 95 percent ethanol to obtain 2.35g of the compound VII with the content of 99.02 percent and the yield of 87.88 percent.
1H-NMR(CDCl3,250MHz):7.28(m,5H,H-ar),3.63 and 3.56(2xd, J ═ 12.5,2H, PhCH)2N)，2.69(m， 2H，NCH2CHNH2And NCH2CH2CHNH2)，2.44(m，1H，NCH2CH2CHNH2) 2.24(dd, J ═ 4.5 and 9.5,1H, NCH2CHNH2)，2.15(m，1H，NCH2CH2CHNH2)，1.45(bm，3H，NH2And NCH2CH2CHNH2) (ii) a Ir (film): (NH)3357(m), (NCH) 2789(s); MS (ion spray): 177.1(M + H)+)。
The reaction temperatures in step B) were compared and the results are shown in Table 1:
TABLE 1
| Comparative example | Reaction temperature | Time of day | Molar yield | Purity of |
| 1 | 0℃ | 10h | 87.7％ | 98.1％ |
| 2 | 10℃ | 7h | 88.2％ | 98.3％ |
| 3 | 20℃ | 3h | 88.3％ | 98.5％ |
| 4 | 25℃ | 3h | 88.1％ | 98.5％ |
| 5 | 40℃ | 2.5h | 88.5％ | 98.2％ |
| 6 | 65℃ | 2.5h | 88.3％ | 98.7％ |
The results show that: the reaction time is gradually shortened along with the increase of the temperature, but the reaction time is basically kept between 2.5 and 3 hours along with the increase of the temperature to be more than 20 ℃.
The amounts of lithium aluminum hydride used in step C) were compared and the results are shown in Table 2:
TABLE 2
| Comparative example | Compound III | Lithium aluminum hydride | Conversion rate |
| 1 | 1eq | 2eq | 54％ |
| 2 | 1eq | 3eq | 82％ |
| 3 | 1eq | 4eq | 93％ |
| 4 | 1eq | 5eq | 93％ |
The results show that: when the dosage of the lithium aluminum hydride is more than 4eq, the dimethyl ether at the 1, 4-position of the compound III can be reduced into the double alcohol to the maximum extent.
Claims (9)
1. A preparation method of (R) -1-benzyl-3-aminopyrrolidine is characterized by comprising the following steps:
A) using compound D-aspartic acid as starting material, and reacting with K2CO3Reacting with benzyl chloroformate to obtain a compound II;
B) reacting methyl chlorosulfonate generated by the reaction of thionyl chloride and methanol with the compound II obtained in the step A) to obtain a compound III dimethyl aspartate;
C) the compound III obtained in the step B) is subjected to LiAlH at low temperature4Reducing to compound IV;
D) substituting two hydroxyl groups of the compound IV obtained in the step C) into halogenated hydrocarbon to obtain a compound V;
E) the compound V obtained in the step D) is subjected to ring closing by benzylamine to obtain a compound VI;
F) removing the 3-amino protecting group CBZ from the compound VI obtained in the step E) to obtain a compound VII which is (R) -1-benzyl-3-aminopyrrolidine:
the reaction synthesis route is as follows:
2. the method according to claim 1, wherein the D-aspartic acid and K are present in step A)2CO3The mol ratio of CBZ-Cl is 1: 1.5-3: 1-2, the stirring time is 8-12min, the temperature is raised to 20 ℃, and the reaction time is 3-5 h.
3. The process according to claim 1, wherein in step B), the methanol is 34g, and the compound II is reacted with SOCl2The molar ratio of (1: 2) - (4), keeping the temperature at 0 ℃ for 25-35min, heating to 20 ℃, and reacting for 2-4 h.
4. The method according to claim 3, wherein in step B), the reaction time is 2.5 to 3 hours.
5. The process according to claim 1, wherein in step C), the molar ratio of compound III to LiAlH4 is 1: 1.2-2, the reaction time is 4-6h, and the THF is 112 g.
6. The article of claim 1The preparation method is characterized in that in the step D), the compound IV is added into a reaction vessel and is stirred and dissolved in 90.0ml of dichloromethane, the temperature is reduced to 0 ℃, the halogenated reagent is dripped, the temperature is maintained at 0 ℃ for reaction for 3-5h, the temperature is raised to 20 ℃ for reaction for 1h, the reaction is finished, the reactant is cooled to 0 ℃, 20ml of water is slowly dripped to quench the residual halogenated reagent, then the liquid separation is carried out to separate an organic layer, the water layer is extracted for 3 times by dichloromethane, the organic layers are combined, and 10ml of 5.0 percent NaHCO is used for the organic layer3Carrying out backwashing once on the solution, separating out a water layer, and evaporating the solvent from an organic layer under reduced pressure to obtain a white solid compound V; the molar ratio of the compound IV to the halogenating reagent is 1:1 to 1.5.
7. The process according to any one of claims 1 to 6, wherein in step D), X is a Cl, Br, I halogen atom and the halogenating agent used is SOCl2、HCl、HBr、PCl3、PBr3、PCl5。
8. The preparation method according to claim 1, wherein in the step E), the molar ratio of the compound V, pyridine and benzylamine is 1: 2-3: 1-1.5, the THF is 73g, the temperature is raised to 30 ℃, and the reaction time is 3-6 h.
9. The process according to claim 1, wherein in step F), the molar ratio of compound VI, 33% HBr in acetic acid is 1: 4.5-8 ℃, the temperature is 20-25 ℃, and the reaction time is 3-4 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010557257.2A CN111620802A (en) | 2020-06-18 | 2020-06-18 | Preparation method of cefditoren intermediate (R) -1-benzyl-3-aminopyrrolidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010557257.2A CN111620802A (en) | 2020-06-18 | 2020-06-18 | Preparation method of cefditoren intermediate (R) -1-benzyl-3-aminopyrrolidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111620802A true CN111620802A (en) | 2020-09-04 |
Family
ID=72258467
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010557257.2A Withdrawn CN111620802A (en) | 2020-06-18 | 2020-06-18 | Preparation method of cefditoren intermediate (R) -1-benzyl-3-aminopyrrolidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111620802A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112920103A (en) * | 2021-03-02 | 2021-06-08 | 康化（上海）新药研发有限公司 | Method for mild preparation of 2-azaspiro [3.3] heptane hydrochloride |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5177217A (en) * | 1992-04-27 | 1993-01-05 | Warner-Lambert Company | Process for the manufacture of (S)-3-amino-1-substituted-pyrrolidines |
| CN1733720A (en) * | 2005-08-25 | 2006-02-15 | 浙江大学 | Synthesis method of N-substituted-3-amidopyrrolidine and its bihydrochlorate |
| WO2007056143A2 (en) * | 2005-11-02 | 2007-05-18 | Cytokinetics, Inc. | Certain chemical entities, compositions, and methods |
| CN101323583A (en) * | 2007-06-12 | 2008-12-17 | 沈阳感光化工研究院 | Synthetic method of 3-substituted-pyrrolidine derivates |
| CN101955457A (en) * | 2010-09-21 | 2011-01-26 | 海门慧聚药业有限公司 | General preparation method of optical-activity 3-aminopyrrolidine, 3-alkyl amino piperidine and derivatives thereof |
| CN103570601A (en) * | 2012-07-20 | 2014-02-12 | 重庆博腾制药科技股份有限公司 | Preparation method of optical active medicine intermediate |
| WO2016202232A1 (en) * | 2015-06-19 | 2016-12-22 | 重庆博腾制药科技股份有限公司 | Synthesis method for (4s)-n-boc-4-methoxy methyl-l-proline amine salt |
-
2020
- 2020-06-18 CN CN202010557257.2A patent/CN111620802A/en not_active Withdrawn
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5177217A (en) * | 1992-04-27 | 1993-01-05 | Warner-Lambert Company | Process for the manufacture of (S)-3-amino-1-substituted-pyrrolidines |
| CN1733720A (en) * | 2005-08-25 | 2006-02-15 | 浙江大学 | Synthesis method of N-substituted-3-amidopyrrolidine and its bihydrochlorate |
| WO2007056143A2 (en) * | 2005-11-02 | 2007-05-18 | Cytokinetics, Inc. | Certain chemical entities, compositions, and methods |
| CN101323583A (en) * | 2007-06-12 | 2008-12-17 | 沈阳感光化工研究院 | Synthetic method of 3-substituted-pyrrolidine derivates |
| CN101955457A (en) * | 2010-09-21 | 2011-01-26 | 海门慧聚药业有限公司 | General preparation method of optical-activity 3-aminopyrrolidine, 3-alkyl amino piperidine and derivatives thereof |
| CN103570601A (en) * | 2012-07-20 | 2014-02-12 | 重庆博腾制药科技股份有限公司 | Preparation method of optical active medicine intermediate |
| WO2016202232A1 (en) * | 2015-06-19 | 2016-12-22 | 重庆博腾制药科技股份有限公司 | Synthesis method for (4s)-n-boc-4-methoxy methyl-l-proline amine salt |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112920103A (en) * | 2021-03-02 | 2021-06-08 | 康化（上海）新药研发有限公司 | Method for mild preparation of 2-azaspiro [3.3] heptane hydrochloride |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107778223B (en) | Preparation method of betrixaban maleate | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN108430999A (en) | The preparation method of Yi Zhong oxazolidone intermediates | |
| CN112062767B (en) | Preparation method and intermediate of rumepilone | |
| CN107337676A (en) | A kind of support method replaces the preparation method of cloth initiation material | |
| US8809581B2 (en) | Method of making 6-aminocaproic acid as active pharmaceutical ingredient | |
| NZ506312A (en) | Process for preparing a protected 4-aminomethyl-pyrrolidin-3-one | |
| WO2005044805A1 (en) | A novel process for preparing donepezil and its derivatives | |
| CN111620802A (en) | Preparation method of cefditoren intermediate (R) -1-benzyl-3-aminopyrrolidine | |
| US8735585B2 (en) | Indenopyridine derivatives | |
| WO2009139002A2 (en) | An improved process for the preparation of solifenacin and its pharmaceutically acceptable salts thereof | |
| CN111689869A (en) | Preparation method of L-phenylephrine hydrochloride | |
| CN115850286B (en) | Vitamin Bei Gelong intermediate and preparation method thereof | |
| CN114181117A (en) | Preparation method of peramivir intermediate | |
| CN112939849B (en) | (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and preparation method and application thereof | |
| CN105330590B (en) | The preparation method of sitafloxacin five-membered ring side chain intermediate | |
| CN111646991B (en) | Preparation method of avibactam sodium intermediate | |
| CN109651234B (en) | Synthesis method of donepezil hydrochloride | |
| CN109776505B (en) | Preparation method of avanafil | |
| CN109824516B (en) | Preparation method of trans-4-hydroxycyclohexanecarboxylic acid tert-butyl ester | |
| CN111100062A (en) | Synthesis method of donepezil hydrochloride | |
| CN112250615A (en) | Preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride | |
| CN101088999A (en) | Process of synthesizing 3-amino quinine dihydrochloride | |
| CN101412678B (en) | Method for synthesizing memantine hydrochloride | |
| CN114853619B (en) | Preparation method of N-methyltyramine hydrochloride suitable for industrial production |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20200904 |
|
| WW01 | Invention patent application withdrawn after publication |