CN106083684A - The preparation method of proline esters hydrochlorate - Google Patents

The preparation method of proline esters hydrochlorate Download PDF

Info

Publication number
CN106083684A
CN106083684A CN201610516980.XA CN201610516980A CN106083684A CN 106083684 A CN106083684 A CN 106083684A CN 201610516980 A CN201610516980 A CN 201610516980A CN 106083684 A CN106083684 A CN 106083684A
Authority
CN
China
Prior art keywords
proline
solvent
hydrochlorate
hydrogen chloride
chloride gas
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.)
Granted
Application number
CN201610516980.XA
Other languages
Chinese (zh)
Other versions
CN106083684B (en
Inventor
祁超
高锐
葛新
杨建平
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ma'anshan Angyang New Material Technology Co., Ltd.
Original Assignee
MAANSHAN DEHONG BIOTECHNOLOGY Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to CN201510456302 priority Critical
Priority to CN2015104563024 priority
Application filed by MAANSHAN DEHONG BIOTECHNOLOGY Co Ltd filed Critical MAANSHAN DEHONG BIOTECHNOLOGY Co Ltd
Publication of CN106083684A publication Critical patent/CN106083684A/en
Application granted granted Critical
Publication of CN106083684B publication Critical patent/CN106083684B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic 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
    • C07D207/04Heterocyclic 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
    • C07D207/10Heterocyclic 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 to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The invention discloses the preparation method of a kind of proline esters hydrochlorate, comprise the following steps successively: 1), primary response, follow the steps below successively: 1., proline, solvent, pyridines catalyst are put in container, being passed through hydrogen chloride gas again, under room temperature, reaction produces proline hydrochlorate;2., afterwards by alcohol putting in container, continue to be passed through hydrogen chloride gas, react at a reflux temperature, reactant liquor is steamed in rotation, and recrystallization cooling separates out solid, after washing with solvent, filters, filtration cakes torrefaction, obtains proline esters hydrochlorate;Filtrate rotation is steamed, as the mother solution of next one circulation;2), recycled: by step 1. in solvent account for the solvent of step 1. 0.5~0.7 volume times instead, with step 1) the mother solution alternative steps of gained 1. in pyridines catalyst, remaining same step 1), carries out the preparation of proline esters hydrochlorate, thus realizes recycled.

Description

The preparation method of proline esters hydrochlorate
Technical field
The present invention relates to the preparation method of organic compound proline esters hydrochlorate.
Background technology
Proline methyl ester hydrochloride, molecular formula: C6H12ClNO2, sterling is white solid.Synthetic method currently mainly is Use thionyl chloride to make chlorinating agent, then become ester with alcohol.
Such as, in Wales, England patent 1072954, use proline and methanol, at SOCl2Effect under synthesize The method of proline methyl ester hydrochloride: under condition of ice bath, the proline of mol ratio 1:1 and SOCl2, methanol reacts 24h, Obtaining product again after vacuum takes off low-boiling-point substance, productivity is 98%.Although the method productivity is higher, but due to SOCl2Activity is high, instead Should be violent, palpus low-temperature operation, and SOCl2Toxicity is relatively big, releases the SO of mole2, the three wastes are big, and Atom economy is poor, environmental pollution Seriously.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of concise in technology, post processing is simple, yield is high, pollute few dried meat The preparation method of propylhomoserin esters hydrochlorate.
In order to solve above-mentioned technical problem, the present invention provides the preparation method of a kind of proline esters hydrochlorate, wraps successively Include following steps:
1), primary response, follow the steps below successively:
1., proline, solvent, pyridines catalyst are put in container (for example, there-necked flask), then be passed through hydrogen chloride Gas, under room temperature, reaction produces proline hydrochlorate (being used for protecting amino), and the response time is 0.5~1 hour;Hydrogen chloride gas It is 1:1 with the mol ratio of proline;
2., afterwards by alcohol put in container, continue to be passed through hydrogen chloride gas, react at a reflux temperature, in azeotropic Drip solvent (speed that dropping solvent rate=azeotropic band water process solvent is carried over) during band water, thus maintain in reaction The amount of solvent, after reacting 2~4 hours, rotation is steamed reactant liquor (reactant liquor be cooled to room temperature after vacuum rotary steam) thus is removed remaining Solvent and alcohol, recrystallization cools down and separates out solid, after washing with solvent, filters, and obtains filtrate and filter cake, filter cake drying respectively, obtains Proline esters hydrochlorate;
Remarks illustrate:
Above-mentioned filtrate is urged by the proline esters hydrochlorate as product, proline hydrochlorate, the pyridines as raw material Agent is dissolved in formed in solvent;
0.5~0.7 volume times (preferably 2/3 volume times) steaming the rotation of described filtrate to step 1. solvent, as next The mother solution of individual circulation;
The mixed liquor (this mixed liquor is made up of solvent and water) that above-mentioned azeotropic band water process steams through except water process after under One step uses (thus realizing recycling) as required solvent during dropping;
Proline is 1:1.1~1.5 (preferably 1:1.3) with the mol ratio of alcohol;
Proline and step 2. in the mol ratio of the hydrogen chloride gas continuing to be passed through be 1:0.16~1:0.6 (preferably 1:0.16~0.32);
Proline is 15:1~10:1 with the ratio of pyridines catalyst mole;
2), recycled:
By step 1. in solvent account for the molten of step 1. 0.5~0.7 volume times (preferably 1/2~2/3 volume times) instead Agent, with step 1) the mother solution alternative steps of gained 1. in pyridines catalyst, remaining same step 1), carry out proline esters hydrochloric acid The preparation of salt, thus realize recycled.
The improvement of preparation method as the proline esters hydrochlorate of the present invention: described pyridines catalyst is pyridine Or DMAP (DMAP) (Py).
The further of preparation method as the proline esters hydrochlorate of the present invention is improved:
Described solvent is dichloroethanes, dichloromethane, toluene, normal hexane or hexamethylene;
The volume of solvent and proline weight ratio are 1.2-2.6mL/g.
The further of preparation method as the proline esters hydrochlorate of the present invention is improved: described alcohol is methanol, ethanol Or propanol.
The further of preparation method as the proline esters hydrochlorate of the present invention is improved: step 2. middle band water backflow is anti- The temperature answered is 35~115 DEG C, and the response time is 2~4h.
The further improvement of preparation method as the proline esters hydrochlorate of the present invention: the number of times of recycled be to Few 5 times (that is, after single cycle, the mother solution obtained can be used for next recycled, and applying mechanically number of times is more than 5 times).
In the present invention, room temperature generally refers to 10~25 DEG C.
The synthetic method of the proline esters hydrochlorate of the present invention, with pyridines catalyst in suitable solvent, proline First generate proline hydrochlorate with hydrogen chloride, then, be esterified with alcohol at a reflux temperature, take generation water out of by azeotropic, promote Esterification, after having reacted, through last handling processes such as filtration, low pressure removing low-boiling-point substance, recrystallization, obtains target product dried meat ammonia Esters of gallic acid hydrochlorate.Recycling Mother Solution after recrystallization is applied mechanically, and cycle-index is more than 5 times.
The reaction equation of the proline esters hydrochlorate synthesis of the present invention is as follows:
The method of the present invention has that cost of material is relatively low, conversion ratio is higher, post processing is relatively simple, need not thionyl chloride etc. The advantages such as chlorinating agent, three waste discharge are less, it is adaptable to industrialized production.
Detailed description of the invention
Embodiment 1, the preparation method of a kind of proline esters hydrochlorate, with proline and methanol as raw material, carried out successively Following steps:
1), primary response, follow the steps below successively:
1., 11.5g (0.1mol) proline, 30ml dichloroethanes and 0.79g (0.01mol) Py (pyridine) are put into In 250ml there-necked flask, it is passed through hydrogen chloride gas with the speed of 1.25ml/s and (leads to this speed in the response time of 0.5h always Enter hydrogen chloride gas), react 0.5h under room temperature, consume HCl 0.1mol.
2., afterwards by 4.16g (0.13mol) methanol putting in there-necked flask, (3h's is anti-to be passed through hydrogen chloride with 0.05ml/s It is passed through hydrogen chloride gas with this speed in Ying Shi always), to keep the hydrochlorate existence form of proline, at counterflow condition React under (about 84 DEG C), steam aqueous dichloroethanes (that is, the mixed liquor steamed for azeotropic band water process), and to reaction System drips anhydrous dichloroethanes with identical speed, thus maintains the amount of dichloroethanes in reaction to be basically unchanged, and reacts 3 hours Complete.Consume HCl 0.024mol, steam 120mL azeotropic mixture (that is, aqueous dichloroethanes) altogether.The reactant liquor of gained is cooled to After room temperature, vacuum rotary steam (pressure of 10mmHg, the temperature of 40 DEG C) removes remaining dichloroethanes (solvent) and methanol ,-10 At DEG C, recrystallization cooling separates out solid, after the 0 of 20ml DEG C of ice dichloroethanes washing, filters, obtains filtrate and filter cake, filter cake respectively Being dried 5h at 40 DEG C, obtain L-PROLINE methyl ester hydrochloride 12.15g (0.0734mol), yield is 73.4%.
Filtrate rotation steams (temperature of 40 DEG C) to 20ml, the mother solution (that is, putting into step 2 as raw material) circulated as the next one In).Containing proline esters hydrochlorate, the proline hydrochlorate as raw material, pyridines catalyst in this filtrate.
Mixed liquor (aqueous dichloroethanes) 120ml that above-mentioned band water process steams, through (using anhydrous sodium sulfate except water processes Except water) after obtain anhydrous dichloroethanes about 110mL, this anhydrous dichloroethanes can dropping anhydrous two in following recycled (thus realizing recycling) is used during ethyl chloride.
Above-mentioned steps 1) in the total consumption of HCl be 0.124mol.
2), apply mechanically first:
1., by 11.5g (0.1mol) proline, 15ml dichloroethanes and step 1) rotation of the mother solution (i.e. step 1) of gained Gained filtrate 20ml after steaming) put in 250ml there-necked flask, it is passed through hydrogen chloride gas with the speed of 1.25ml/s, anti-under room temperature Answer 0.5h, consume HCl 0.1mol.
2., afterwards by 4.16g (0.13mol) methanol put in there-necked flask, continue to be passed through hydrogen chloride gas (0.05ml/ S), under reflux conditions, steam aqueous dichloroethanes, and drip anhydrous dichloroethanes to response system with identical speed (can use step 1) is except the dichloroethanes of gained after water process), thus maintain the amount of dichloroethanes in reaction to be basically unchanged, instead After answering 3 hours, consume HCl 0.024mol, steam azeotropic mixture (aqueous dichloroethanes) 130ml altogether.The reactant liquor cooling of gained To room temperature, then vacuum rotary steam (pressure of 10mmHg, the temperature of 40 DEG C) reactant liquor remove remaining dichloroethanes (solvent) and Methanol, at-10 DEG C, recrystallization cooling separates out solid, after the 0 of 20ml DEG C of ice dichloroethanes washing, filters, obtains filtrate respectively And filter cake, it is dried 5h at filter cake 40 DEG C, obtaining proline methyl ester hydrochloride 14.3g (0.0866mol) yield is 86.6%.
Band water mixed liquid (aqueous dichloroethanes, i.e. azeotropic mixture) the about 130ml steamed, after processing except water, obtains nothing Water dichloroethanes about 120mL, this anhydrous dichloroethanes can be made when the anhydrous dichloroethanes of the dropping in following recycled With (thus realizing recycling).
Filtrate rotation steams (temperature of 40 DEG C) to 20ml, the mother solution (that is, putting into step 3 as raw material) circulated as the next one In).
Above-mentioned steps 2) in the total consumption of HCl be 0.124mol.
3), second time is applied mechanically:
1., by 11.5g (0.1mol) proline, 20ml dichloroethanes and step 2) mother liquid obtained (i.e. step 2) rotation steaming Rear filtrate 20ml) put in 250ml there-necked flask, it is passed through hydrogen chloride gas with the speed of 1.25ml/s, under room temperature, reacts 0.5h, Consume HCl0.1mol.
2., afterwards by 4.16g (0.13mol) methanol put in there-necked flask, continue to be passed through hydrogen chloride gas (0.05ml/ S) under reflux conditions, aqueous dichloroethanes is steamed, and (can with the identical speed anhydrous dichloroethanes of dropping to response system Use step 2) except the dichloroethanes of gained after water process), thus maintain the amount of dichloroethanes in reaction to be basically unchanged, react 3 After hour, consume HCl0.024mol, steam azeotropic mixture (aqueous dichloroethanes) about 140ml altogether.The reactant liquor of gained is cooled to After room temperature, then vacuum rotary steam (pressure of 10mmHg, the temperature of 40 DEG C) reactant liquor removes remaining dichloroethanes (solvent) and first Alcohol, at-10 DEG C, recrystallization cooling separates out solid, after the washing of the 0 of 20ml DEG C of ice dichloroethanes, filters, respectively filtrate and Filter cake, is dried 5h at filter cake 40 DEG C, obtaining proline methyl ester hydrochloride 16.5g (0.0996mol) yield is 99.6%.
The azeotropic mixture (aqueous dichloroethanes) steamed, after processing except water, obtains anhydrous dichloroethanes, this anhydrous dichloro Ethane can be used (thus realizing recycling) when the anhydrous dichloroethanes of the dropping in following recycled.
Filtrate rotation is steamed (temperature of 40 DEG C) and (that is, is put into follow-up step as raw material to 20ml, the mother solution as next one circulation In Zhou).
Above-mentioned steps 3) in the total consumption of HCl be 0.124mol.
(4), repeating above-mentioned applying mechanically, during to the 5th, proline methyl ester hydrochloride 16.5g (0.0996mol) yield is 99.6%.
Embodiment 2~embodiment 10,
Change the following reaction condition in embodiment 1: select solvent (being called for short s), alcohol (Acohol), catalyst (Cat), The total consumption of HCl (being called for short M), solvent load (V), response time (being called for short t), obtain embodiment 2~10, thus obtain corresponding dried meat The product quality (w) of propylhomoserin esters hydrochlorate, product yield are called for short (y).Particular content and data result are shown in Table 1.
Table 1
Remarks illustrate:
When alcohol is methanol, products therefrom is proline methyl ester hydrochloride;
When alcohol is ethanol, products therefrom is proline ethyl ester hydrochloride;
When alcohol is propanol, products therefrom is proline propyl ester hydrochloride.
Comparative example 1, made the solvent in embodiment 1 into " methanol " by " dichloroethanes ", " ice used during corresponding washing Dichloroethanes " also make " methanol " into;Remaining is equal to embodiment 1.
Table 2
This process can also circulate, but owing to esterification is a balancing response, present invention dichloroethanes is permissible Taking the water of reaction system out of, the forward of driving a reaction moves, and improves the yield of product.
Finally, in addition it is also necessary to be only several specific embodiments of the present invention it is noted that listed above.Obviously, this Bright it is not limited to above example, it is also possible to have many deformation.Those of ordinary skill in the art can be from present disclosure The all deformation directly derived or associate, are all considered as protection scope of the present invention.

Claims (6)

1. the preparation method of proline esters hydrochlorate, is characterized in that comprising the following steps successively:
1), primary response, follow the steps below successively:
1., proline, solvent, pyridines catalyst being put in container, then be passed through hydrogen chloride gas, under room temperature, reaction produces dried meat Propylhomoserin hydrochlorate, the response time is 0.5~1 hour;Hydrogen chloride gas is 1:1 with the mol ratio of proline;
2., afterwards by alcohol put in container, continue to be passed through hydrogen chloride gas, react at a reflux temperature, in azeotropic band water During drip solvent, thus maintain the amount of solvent in reaction, after react 2~4 hours, reactant liquor is steamed in rotation, and recrystallization cooling is analysed Go out solid, after washing with solvent, filter, obtain filtrate and filter cake, filter cake drying respectively, obtain amino-acid benzyl ester hydrochloride;
0.5~0.7 volume times to step 1. solvent is steamed in the rotation of described filtrate, as the mother solution of next one circulation;
The mixed liquor that above-mentioned azeotropic band water process steams through except water process after in the next step as dropping time required solvent Use;
Proline is 1:1.1~1.5 with the mol ratio of alcohol;
Proline and step 2. in the mol ratio of the hydrogen chloride gas continuing to be passed through be 1:0.16~1:0.6;
Proline is 15:1~10:1 with the ratio of pyridines catalyst mole;
2), recycled:
By step 1. in solvent account for the solvent of step 1. 0.5~0.7 volume times, with step 1 instead) mother solution of gained substitutes step Rapid 1. middle pyridines catalyst, remaining same step 1), carry out the preparation of proline esters hydrochlorate, thus realize recycled.
The preparation method of proline esters hydrochlorate the most according to claim 1, is characterized in that: described pyridines catalyst For pyridine or DMAP.
The preparation method of proline esters hydrochlorate the most according to claim 2, is characterized in that:
Described solvent is dichloroethanes, dichloromethane, toluene, normal hexane or hexamethylene;
The volume of solvent and proline weight ratio are 1.2-2.6mL/g.
4., according to the preparation method of the proline esters hydrochlorate described in Claims 2 or 3, it is characterized in that: described alcohol be methanol, Ethanol or propanol.
The preparation method of proline esters hydrochlorate the most according to claim 4, is characterized in that: step 2. middle band water backflow The temperature of reaction is 35~115 DEG C, and the response time is 2~4h.
6., according to the preparation method of the arbitrary described proline esters hydrochlorate of Claims 1 to 5, it is characterized in that: recycled Number of times be at least 5 times.
CN201610516980.XA 2015-07-27 2016-07-01 The preparation method of proline esters hydrochloride Active CN106083684B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201510456302 2015-07-27
CN2015104563024 2015-07-27

Publications (2)

Publication Number Publication Date
CN106083684A true CN106083684A (en) 2016-11-09
CN106083684B CN106083684B (en) 2018-08-14

Family

ID=57211915

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610516980.XA Active CN106083684B (en) 2015-07-27 2016-07-01 The preparation method of proline esters hydrochloride

Country Status (1)

Country Link
CN (1) CN106083684B (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001163842A (en) * 1999-12-06 2001-06-19 Tokuyama Corp Method for producing amino acid ester hydrochloride
CN1616411A (en) * 2004-10-11 2005-05-18 温州师范学院 Novel chiral amino acid derivative and its synthetic method and use
CN104447759A (en) * 2014-11-24 2015-03-25 吉林农业大学 Production method for cyclic dipeptide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001163842A (en) * 1999-12-06 2001-06-19 Tokuyama Corp Method for producing amino acid ester hydrochloride
CN1616411A (en) * 2004-10-11 2005-05-18 温州师范学院 Novel chiral amino acid derivative and its synthetic method and use
CN104447759A (en) * 2014-11-24 2015-03-25 吉林农业大学 Production method for cyclic dipeptide

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TORATANE MUNEGUMI等: "Diastereoselective Catalytic Hydrogenation of Schiff Bases of N-Pyruvoyl-(S)-Proline Esters", 《INTERNATIONAL JOURNAL OF ORGANIC CHEMISTRY》 *
殷霞等: "具有手性吡咯烷侧环的噁唑烷酮类化合物的合成及抗菌活性研究", 《中国药物化学杂志》 *

Also Published As

Publication number Publication date
CN106083684B (en) 2018-08-14

Similar Documents

Publication Publication Date Title
CN101774923B (en) Method of preparing fluoroethylene carbonate
CN104311448B (en) A kind of preparation method of dinitolmide
CN100591649C (en) Method of preparing R-(+)-3-chlorophenylpropanol
CN111285884A (en) Preparation method of pentaerythritol sulfate
CN103204801A (en) Synthesis method for N-Boc-3-piperidone
CN110183367A (en) A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization
CN102924289B (en) Synthetic process of hydrochloric acid trientine
CN108033903B (en) Synthesis process for water-borne esterification of DL-p-methylsulfonylphenylserine ethyl ester
CN106083684A (en) The preparation method of proline esters hydrochlorate
CN105061283A (en) Preparation method for amino acid benzyl ester hydrochloride
CN101973909B (en) Preparation method of mildronate
CN104086475B (en) A kind of preparation method of N-benzyloxycarbonyl group-L-prolineamide
CN106317024A (en) Crizotinib intermediate, preparation method and crizotinib preparation method
CN105384654B (en) A kind of crystallization purifications of hydroxyalkyl amide
CN110615753A (en) Synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid
CN106349125B (en) Utilize the method for manganese salt selectivity synthesis (E) vinyl sulfone compound
CN104788431B (en) Synthetic method for chiral marine natural product with high optical activity
CN106432227B (en) A kind of method for preparing pirenzepine hydrochloride key intermediate
CN104311471A (en) Improved mitiglinide calcium industrialized preparation method
CN105001096B (en) A kind of method for preparing 4 amino N alkylbenzylamines
CN109320498A (en) The bromo- 1-(3- chloro-2-pyridyl of 3-) -1H- pyrazoles -5- formic acid alkyl ester preparation method
CN109422719A (en) The preparation method of cyclic sulfates
CN102807516A (en) Intermediate in amisulpride and method for preparing amisulpride by using intermediate
CN106866453A (en) A kind of method that microreactor prepares scheme for lacosamide
CN105111134A (en) Method for preparing (R)-or(S)-3-aminopiperidine dihydrochloride

Legal Events

Date Code Title Description
PB01 Publication
C06 Publication
SE01 Entry into force of request for substantive examination
C10 Entry into substantive examination
GR01 Patent grant
GR01 Patent grant
CP03 Change of name, title or address

Address after: 243000 Prince Road, Cihu Economic Development Zone, Ma'anshan City, Anhui Province

Patentee after: Ma'anshan Angyang New Material Technology Co., Ltd.

Address before: 243000 Prince Avenue 1057, Cihu National High-tech Development Zone, Ma'anshan City, Anhui Province

Patentee before: Maanshan Dehong Biotechnology Co., Ltd.

CP03 Change of name, title or address