CN105837486A - Preparation method for L-hydroxyproline - Google Patents
Preparation method for L-hydroxyproline Download PDFInfo
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- 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
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Abstract
The invention provides a preparation method for L-hydroxyproline. The preparation method comprises the following steps: preparing pyroglutamic acid; preparing pyroglutamate; preparing pyroglutamic acid alcohol; preparing (3R,7aS)-3-phenyltetrahydropyrrolo[1,2]oxazole-5(3H)-one; and preparing L-hydroxyproline. Compared with the prior art, the invention has the following beneficial effects: the method overcomes the problems that a traditional manner of extraction of L-hydroxyproline from an animal donor has potential safety hazards and that production of L-hydroxyproline is limited as biological raw materials are utilized, and can synthesize L-hydroxyproline under the condition of shortage of biological raw materials; synthetic methods for L-hydroxyproline are enriched; the added value of L-hydroxyproline is increased; the application scope of L-hydroxyproline can be further broadened; prepared L-hydroxyproline is high in yield and purity, so the synthesis purity of atazanavir is indirectly improved; and common raw materials can be selected in preparation of L-hydroxyproline, so production cost is low.
Description
Technical field
The present invention relates to the preparation method of a kind of L-hydroxyproline, belong to Amino acid synthesis technical field.
Background technology
The important intermediate that L-hydroxyproline synthesizes as antiviral drugs atazanavir, has the highest using value.At present, the main source of L-hydroxyproline is to be hydrolyzed by the protein hydrochloric acid such as gelatin, osseocolla, casein, soybean cover, after extracting imidic acid with Nitrosation Process, carry out refining after resin chromatography separates, crystallize and form, it is all to obtain by the way of animal is extracted due to it, therefore there is potential TSE/BSE to pollute, i.e. Transmissible spongiform encephalopathy and Medulla Bovis seu Bubali spongiform disease, so when follow-up synthetically prepared medicine, its Drug safety also has certain risk, even can endanger the health of the mankind, seriously can causing death.
In view of this, the most existing research much prepared for L-hydroxyproline, as Chinese patent CN104894152 passes through genetic engineering means, utilize escherichia coli, by the proline-4-cis-4-'-hydroxylase gene after codon and mRNA secondary structure optimization is connected on the carrier containing suitable promoter, this hydroxylase of overexpression in host cell, thus the method that free L-PROLINE is converted into allohydroxyproline.The method avoids the band Viral risks proposing L-hydroxyproline from animal source raw material really, but, owing to it to build new biological bacterial strain, and need bacterial strain is screened, therefore, production cost is higher, and production efficiency is slower.
Summary of the invention
For defect of the prior art, it is an object of the invention to provide the preparation method of a kind of L-hydroxyproline.
The present invention is achieved by the following technical solutions:
The present invention provides the preparation method of a kind of L-hydroxyproline, and it comprises the steps:
S1: glutamic acid is added in retort, oil bath is heated to 220～290 DEG C, stirring dehydration, react 40～70 minutes under 130～180 DEG C of heat-retaining conditions, put in water and cool down, be filtrated to get pyroglutamic acid crude product, described pyroglutamic acid crude product is added water saturated at 40～70 DEG C, being cooled to 30～40 DEG C makes it crystallize, and isolates brilliant body detergent washing, dries and obtain pyroglutamic acid fine work；
S2: add dehydrated alcohol in flask, is cooled to less than-5 DEG C with cryosel bath, adds the pyroglutamic acid obtained in catalyst and step S1, and stirring slowly heats up and reacts 24～48 hours in 20～45 DEG C；Adjusting PH to 7～8 with neutralizing alkali, filtrate is collected by filtration, filtering residue detergent washs, and is concentrated to give crude product, by described crude product distillation purifying under the conditions of 130～150 DEG C/1～2mmHg, obtains pyroglutamic acid ester after being merged with filtrate by cleaning mixture；
S3: be dissolved in solvent by the pyroglutamic acid ester obtained in step S2, cools to be slowly added to reducing agent under 0～10 DEG C, stirring with cryosel bath, its proportioning is pyroglutamic acid ester: solvent: reducing agent=1mol: 100ml: (2～3) mol, stirring reaction 6～12 hours at this temperature, adds water after completion of the reaction, and adjusts PH to 6～6.5 with neutralizing acid, it is concentrated to give white flaky crystals, then solvent is added, this crystallization of solvent, filtering solution, filtrate is concentrated, obtains pale yellow oil；Add solvent acetone, dissolve this grease, solution is filtered, collect filtrate and concentrate, separate out white crystals after cooling, leach crystallization and wash this crystallization with cold acetone, being finally dried, obtain pyroglutamic acid alcohol；
The synthetic route of step S1～S3 is as follows:
S4: after the pyroglutamic acid alcohol obtained in step S3 is mixed with benzaldehyde, under the catalysis of acidic catalyst, carry out being condensed dehydration in 70～120 DEG C, obtain compound (3R, 7aS)-3-phenyl nafoxidine also [1,2] oxazole-5 (3H)-one；
S5: (the 3R that will obtain in step S4,7aS)-3-phenyl nafoxidine also [1,2] oxazole-5 (3H)-one is through β-Carbonyl group oxidation reaction, carbonyl reduction reaction, catalytic hydrogenation reaction and hydroxyl oxidize reaction, obtains L-hydroxyproline；
The synthetic route of step S4～S5 is as follows:
Wherein, the temperature of described β-Carbonyl group oxidation reaction is-40～-50 DEG C,
Preferably, the one in sulphuric acid, thionyl chloride, hydrochloric acid of the catalyst described in step S2.
Preferably, the one in sodium borohydride, lithium borohydride of the reducing agent described in step S3.
Preferably, the one in p-methyl benzenesulfonic acid, boron chloride ether, sulfosalicylic acid of the acidic catalyst described in step S4.
Preferably, the temperature of the condensation dehydration described in step S4 is 100 DEG C.
Preferably, the mass ratio of described pyroglutamic acid alcohol, benzaldehyde and acidic catalyst is 1: (0.15～1.3): (0.165～0.2).
Preferably, the mass ratio of described pyroglutamic acid alcohol, benzaldehyde and acidic catalyst is 1: 0.8: 0.18.
Preferably, the one in hydrofining, sodium hydride, the silica-based Lithamide. of hexamethyl of the dehydrogenation agent used by the β described in step S5-Carbonyl group oxidation reaction.
Preferably, described dehydrogenation agent is hydrofining.
Preferably, the oxidant in the β described in step S5-Carbonyl group oxidation reaction is selected from sodium hypochlorite, hydrogen peroxide, sodium chlorite, 2,2,6,6-tetramethyl piperidines.
Preferably, reducing agent used in the carbonyl reduction reaction described in step S5 is selected from Lithium Aluminium Hydride or sodium borohydride.
Preferably, the Stress control in the catalytic hydrogenation reaction described in step S5 is 1～1.5MPa, and catalyst is palladium charcoal.
Compared with prior art, the present invention has a following beneficial effect:
1, the problem that the mode of conventionally employed animal donor extraction can exist potential safety hazard has been abandoned, solve the employing biological raw material problem to the restriction of drug manufacture, also can synthesize in the case of lacking biological raw material and obtain target product, enrich the synthetic method of L-hydroxyproline, add the added value of L-hydroxyproline, it is possible to further expand the range of application of L-hydroxyproline；
2, the L-hydroxyproline productivity prepared and purity are the highest, indirectly improve the synthesis purity of atazanavir；
3, can select relatively conventional raw material in the preparation, therefore production cost is relatively low.
Accompanying drawing explanation
The detailed description with reference to the following drawings, non-limiting example made by reading, the other features, objects and advantages of the present invention will become more apparent upon:
Fig. 1 is the H-NMR collection of illustrative plates of L-hydroxyproline prepared by the present invention.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in detail.Following example will assist in those skilled in the art and are further appreciated by the present invention, but limit the present invention the most in any form.It should be pointed out that, to those skilled in the art, without departing from the inventive concept of the premise, it is also possible to make some deformation and improvement.These broadly fall into protection scope of the present invention.
Embodiment
1
The present embodiment relates to the preparation method of a kind of L-hydroxyproline, specifically includes following steps:
In the electrical heating stainless steel reaction tank of 200L, add glutamic acid 60kg, carry out oil bath dehydration in 220～290 DEG C, at 140 DEG C after insulation reaction 55min, put in 10L water；
Stirring cooling, it is centrifuged to obtain pyroglutamic acid crude product, this pyroglutamic acid crude product is added water to saturated at 65 DEG C, centrifugal filtration, being cooled to 35 DEG C crystallize, by crystal centrifugation and wash, dry and obtain pyroglutamic acid fine work 28kg, yield 54% (feeds intake in terms of theoretical yield by glutamic acid), fusing point is 159～161 DEG C, [a]20=-11.6 (C=2, H2O)；
nullAccording to pyroglutamic acid、Dehydrated alcohol、The rate of charge of thionyl chloride is 1mol: 100ml: (0.06～1.2) mol carries out proportioning，Dehydrated alcohol 10L is added in dry there-necked flask，It is cooled to less than-5 DEG C with brine ice，Dropping thionyl chloride 300ml，Add pyroglutamic acid 1000g，Stirring is to slowly warm up at 35～40 DEG C，Reaction 24～36h，PH to 7～8 is regulated with the ethanol solution of potassium hydroxide，Filter and use absolute ethanol washing，Cleaning mixture merges with filtrate，It is concentrated to give the thick pyroglutamic acid ethyl ester of 1357g，After the distillation purifying under 155 DEG C/2mmHg，Obtain burnt glutaric acid ethyl ester fine work 1108g，Yield is 90% (in terms of pyroglutamic acid theoretical value)，Purity is not less than 99.0% (HPLC)，[a]20=4 (C=10, H2O)；
nullAccording to pyroglutamic acid ethyl ester、Absolute methanol、The rate of charge of sodium borohydride is 1mol: 100ml: (2～3) mol carries out proportioning，32g pyroglutamic acid ethyl ester is dissolved in 300ml absolute methanol，0～5 DEG C is cooled to by ice salt bath，15g sodium borohydride it is slowly added under stirring，After adding, stirring is reacted and monitors reaction process with TLC at this temperature，It is slowly added to 1ml water after completion of the reaction，Be neutralized with hydrochloric acid to PH be 6～6.5，Concentrating under reduced pressure obtains white flaky crystals，Add 300ml dehydrated alcohol，Stirring and dissolving filters，By filtrate reduced in volume，Obtain 22g yellow oil，Add 100ml acetone，Dissolving is deposited overnight，Filtering and concentrating is to dry，White crystals is obtained after the coldest，Filter and obtain white crystals with cold acetone washing，In low-temperature vacuum drying，Obtain product pyroglutamic acid alcohol 18g，Yield 78% (in terms of pyroglutamic acid ethyl ester feeds intake)，Purity is not less than 98.0% (HPLC)，[a]20=29 (C=2, EtOH)；
By pyroglutamic acid alcohol 100g, p-methyl benzenesulfonic acid monohydrate 16.5g, benzaldehyde 130g, toluene 350g is sequentially added in 2L reaction bulb, being heated to 70～120 DEG C of backflows 4～6h, decompression distillation and concentration evaporates solvent toluene and obtains grease, obtains 40.5g TSSA0200-A through column chromatography purification, HPLC:95%, yield 23%；
Taking TSSA0200-A 30g, add 900ml oxolane, 90g MoOPH is in 2L reaction bulb in addition, nitrogen protection borehole cooling to-40～-50 DEG C; dropping LiHMDS 240g, reacts 6～10h, and quencher is reacted; column chromatography obtains 9.7g TSSA0200-B, HPLC:94.2%, yield: 30%；
Being added in 100ml there-necked flask by TSSA0200-B 5g, nitrogen protection is lower adds 50ml oxolane, is cooled to-15～-20 DEG C; adding 0.8g Lithium Aluminium Hydride, be warming up to room temperature reaction 6～8h, quencher is reacted; column chromatography obtains 1.5g TSSA0200-C, HPLC:97%, yield: 31.7%；
TSSA0200-C 1.5g 30ml ethanol is dissolved, adds in autoclave, add 0.015g palladium charcoal, be passed through hydrogen to 1MPa, react 3h, be filtered to remove palladium charcoal, obtain 0.82g TSSA0200-D, yield: 96.5%；
TEMPO 0.082g is configured to the solution of 20wt%, TSSA0200-D 0.82g is configured to the solution of 10wt%, 5～10min are reacted in pump pumps into silicagel column, obtaining the solution of TSSA0200-D, concentrated crystallization obtains 0.6g L-hydroxyproline, yield 65.4%, confirm collection of illustrative plates as shown in Figure 1, wherein, the length of this silicagel column controls at 30cm, and diameter control is at 60cm.
Embodiment
2
The present embodiment relates to the preparation method of a kind of L-hydroxyproline, specifically includes following steps:
In the electrical heating stainless steel reaction tank of 200L, add glutamic acid 80kg, carry out oil bath dehydration in 250～270 DEG C, at 160 DEG C after insulation reaction 50min, put in 10L water；
Stirring cooling, it is centrifuged to obtain pyroglutamic acid crude product, this pyroglutamic acid crude product is added water to saturated at 50 DEG C, centrifugal filtration, being cooled to 30 DEG C crystallize, by crystal centrifugation and wash, dry and obtain pyroglutamic acid fine work 37kg, yield 53.8% (feeds intake in terms of theoretical yield by glutamic acid), fusing point is 158.5～161 DEG C, [a]20=-11.5 (C=2, H2O)；
According to pyroglutamic acid, dehydrated alcohol, the rate of charge of concentrated sulphuric acid is 1mol: 100ml: (0.06～1.2) mol carries out proportioning, dehydrated alcohol 10L is added in dry there-necked flask, it is cooled to less than-5 DEG C with brine ice, dropping concentrated sulphuric acid 250ml, add pyroglutamic acid 1000g, stirring is to slowly warm up at 35～45 DEG C, reaction 36～48h, PH to 7～8 is regulated with the ethanol solution of potassium hydroxide, filter and use absolute ethanol washing, cleaning mixture merges with filtrate, it is concentrated to give the thick pyroglutamic acid ethyl ester of 1258g, after the distillation purifying under 150 DEG C/2mmHg, obtain burnt glutaric acid ethyl ester fine work 985g, yield is 88% (in terms of pyroglutamic acid theoretical value), purity is not less than 99.0% (HPLC), [a]20=9.8 (C=2, EtOH)；
nullAccording to pyroglutamic acid ethyl ester、Isopropanol、The rate of charge of sodium borohydride is 1mol: 100ml: (2～3) mol carries out proportioning，315g pyroglutamic acid ethyl ester is dissolved in 3000ml isopropanol，0～5 DEG C is cooled to by ice salt bath，160g sodium borohydride it is slowly added under stirring，After adding, stirring is reacted and monitors reaction process with TLC at this temperature，It is slowly added to 10ml water after completion of the reaction，Be neutralized with hydrochloric acid to PH be 6～6.5，Concentrating under reduced pressure obtains white flaky crystals，Add 3000ml dehydrated alcohol，Stirring and dissolving filters，By filtrate reduced in volume，Obtain 220g yellow oil，Add 1000ml acetone，Dissolving is deposited overnight，Filtering and concentrating is to dry，White crystals is obtained after the coldest，Filter and obtain white crystals with cold acetone washing，In low-temperature vacuum drying，Obtain product pyroglutamic acid alcohol 175g，Yield 76% (in terms of pyroglutamic acid ethyl ester feeds intake)，Purity is not less than 98.0% (HPLC)，[a]20=30 (C=2, EtOH)；
By pyroglutamic acid alcohol 100g, to boron trifluoride diethyl etherate 20g, benzaldehyde 15g, toluene 450g is sequentially added in 2L reaction bulb, being heated to 120 DEG C of backflows 4～6h, decompression distillation and concentration evaporates solvent toluene and obtains grease, obtains 37.6g TSSA0200-A through column chromatography purification, HPLC:94.2%, yield 30%；
Taking TSSA0200-A 30g, add 900ml oxolane, 120g MoOPH is in 2L reaction bulb in addition, and nitrogen protection borehole cooling is to-50 DEG C; dropping potassium cyanide 300g, reacts 6～10h, and quencher is reacted; column chromatography obtains 9.7g TSSA0200-B, HPLC:94.2%, yield: 30%；
Being added by TSSA0200-B 5g in 100ml there-necked flask, nitrogen protection is lower adds 50ml oxolane, is cooled to-15 DEG C; adding 1.2g Lithium Aluminium Hydride, be warming up to room temperature reaction 6～8h, quencher is reacted; column chromatography obtains 1.5g TSSA0200-C, HPLC:97%, yield: 31.7%；
TSSA0200-C 1.5g 30ml ethanol is dissolved, adds in autoclave, add 0.075g palladium charcoal, be passed through hydrogen to 1.2MPa, react 3h, be filtered to remove palladium charcoal, obtain 0.82g TSSA0200-D, yield: 96.5%；
TEMPO 0.1g is configured to the solution of 20wt%, TSSA0200-D 0.82g is configured to the solution of 10wt%, 10min is reacted in pump pumps into silicagel column, obtaining the solution of TSSA0200-D, concentrated crystallization obtains 0.6g L-hydroxyproline, yield 65.4%, confirm collection of illustrative plates as shown in Figure 1, wherein, the length of this silicagel column controls at 40cm, and diameter control is at 55cm.
Embodiment
3
The present embodiment relates to the preparation method of a kind of L-hydroxyproline, specifically includes following steps:
In the electrical heating stainless steel reaction tank of 200L, add glutamic acid 60kg, carry out oil bath dehydration in 220～250 DEG C, at 140 DEG C after insulation reaction 55min, put in 10L water；
Stirring cooling, it is centrifuged to obtain pyroglutamic acid crude product, this pyroglutamic acid crude product is added water to saturated at 65 DEG C, centrifugal filtration, being cooled to 35 DEG C crystallize, by crystal centrifugation and wash, dry and obtain pyroglutamic acid fine work 28kg, yield 54% (feeds intake in terms of theoretical yield by glutamic acid), fusing point is 158.5～161 DEG C, [a]20=-11.5 (C=2, H2O)；
According to pyroglutamic acid, dehydrated alcohol, the rate of charge of hydrochloric acid is 1mol: 100ml: (0.06～1.2) mol carries out proportioning, dehydrated alcohol 1L is added in dry there-necked flask, it is cooled to less than-5 DEG C with brine ice, dropping hydrochloric acid 150g, add pyroglutamic acid 1000g, stirring is to slowly warm up at 35～45 DEG C, reaction 36～48h, PH to 7～8 is regulated with the ethanol solution of potassium hydroxide, filter and use absolute ethanol washing, cleaning mixture merges with filtrate, it is concentrated to give the thick pyroglutamic acid ethyl ester of 1100g, after the distillation purifying under 135 DEG C/2mmHg, obtain burnt glutaric acid ethyl ester fine work 1108g, yield is 90% (in terms of pyroglutamic acid theoretical value), purity is not less than 99.0% (HPLC), [a]20=3.5 (C=10, H2O)；
nullAccording to pyroglutamic acid methyl ester、Absolute methanol、The rate of charge of sodium borohydride is 1mol: 100ml: (2～3) mol carries out proportioning，290g pyroglutamic acid methyl ester is dissolved in 3000ml oxolane，0～5 DEG C is cooled to by ice salt bath，165g sodium borohydride it is slowly added under stirring，After adding, stirring is reacted and monitors reaction process with TLC at this temperature，It is slowly added to 10ml water after completion of the reaction，Be neutralized with hydrochloric acid to PH be 6～6.5，Concentrating under reduced pressure obtains white flaky crystals，Add 3000ml dehydrated alcohol，Stirring and dissolving filters，By filtrate reduced in volume，Obtain 230g yellow oil，Add 1000ml acetone，Dissolving is deposited overnight，Filtering and concentrating is to dry，White crystals is obtained after the coldest，Filter and obtain white crystals with cold acetone washing，In low-temperature vacuum drying，Obtain product pyroglutamic acid alcohol 180g，Yield 78% (in terms of pyroglutamic acid ethyl ester feeds intake)，Purity is not less than 98.0% (HPLC)，[a]20=31 (C=2, EtOH)；
By pyroglutamic acid alcohol 100g, p-methyl benzenesulfonic acid monohydrate 18g, benzaldehyde 80g, toluene 400g is sequentially added in 2L reaction bulb, being heated to 70 DEG C of backflows 4～6h, decompression distillation and concentration evaporates solvent toluene and obtains grease, obtains 39.5g TSSA0200-A through column chromatography purification, HPLC:95%, yield 22.4%；
Taking TSSA0200-A 30g, add 900ml oxolane, 90g MoOPH is in 2L reaction bulb in addition, and nitrogen protection borehole cooling is to-40 DEG C; dropping LiHMDS 240g, reacts 6～10h, and quencher is reacted; column chromatography obtains 9.7g TSSA0200-B, HPLC:94.2%, yield: 30%；
Being added in 100ml there-necked flask by TSSA0200-B 5g, nitrogen protection is lower adds 50ml oxolane, is cooled to-15～-20 DEG C; adding 0.8g Lithium Aluminium Hydride, be warming up to room temperature reaction 6～8h, quencher is reacted; column chromatography obtains 1.5g TSSA0200-C, HPLC:97%, yield: 31.7%；
TSSA0200-C 1.5g 30ml ethanol is dissolved, adds in autoclave, add 0.07g palladium charcoal, be passed through hydrogen to 1MPa, react 3h, be filtered to remove palladium charcoal, obtain 0.82g TSSA0200-D, yield: 96.5%；
The mixture 0.082g of sodium hypochlorite Yu TEMPO is configured to the solution of 20wt%, TSSA0200-D0.82g is configured to the solution of 10wt%, 5～10min are reacted in pump pumps into silicagel column, obtaining the solution of TSSA0200-D, concentrated crystallization obtains 0.63g L-hydroxyproline, yield 68.7%, confirm collection of illustrative plates as shown in Figure 1, wherein, the length of this silicagel column controls at 50cm, and diameter control is at 50cm.
Embodiment
4
The present embodiment relates to the preparation method of a kind of L-hydroxyproline, specifically includes following steps:
In the electrical heating stainless steel reaction tank of 200L, add glutamic acid 80kg, carry out oil bath dehydration in 220～290 DEG C, at 160 DEG C after insulation reaction 50min, put in 10L water；
Stirring cooling, it is centrifuged to obtain pyroglutamic acid crude product, this pyroglutamic acid crude product is added water to saturated at 50 DEG C, centrifugal filtration, being cooled to 35 DEG C crystallize, by crystal centrifugation and wash, dry and obtain pyroglutamic acid fine work 38kg, yield 55% (feeds intake in terms of theoretical yield by glutamic acid), fusing point is 159.5～161 DEG C, [a]20=-11.6 (C=2, H2O)；
According to pyroglutamic acid, absolute methanol, the rate of charge of ToSOH is 1mol: 100ml: (0.06～1.2) mol carries out proportioning, absolute methanol 1L is added in dry there-necked flask, it is cooled to less than-5 DEG C with brine ice, dropping ToSOH 860g, add pyroglutamic acid 1000g, stirring is to slowly warm up at 35～45 DEG C, reaction 36～48h, PH to 7～8 is regulated with solution of potassium carbonate, concentrate after filtration, the thick pyroglutamic acid ethyl ester of 995g is obtained through evaporation (135 DEG C/2mmHg), yield is 87.9% (in terms of pyroglutamic acid theoretical value), purity is not less than 99.0% (HPLC), [a]20=4 (C=2, EtOH)；
nullAccording to pyroglutamic acid methyl ester、Dehydrated alcohol、The rate of charge of sodium borohydride is 1mol: 100ml: (2～3) mol carries out proportioning，290g pyroglutamic acid ethyl ester is dissolved in 3000ml dehydrated alcohol，0～5 DEG C is cooled to by ice salt bath，165g sodium borohydride it is slowly added under stirring，After adding, stirring is reacted and monitors reaction process with TLC at this temperature，It is slowly added to 10ml water after completion of the reaction，Be neutralized with hydrochloric acid to PH be 6～6.5，Concentrating under reduced pressure obtains white flaky crystals，Add 3000ml dehydrated alcohol，Stirring and dissolving filters，By filtrate reduced in volume，Obtain 232g yellow oil，Add 1000ml acetone，Dissolving is deposited overnight，Filtering and concentrating is to dry，White crystals is obtained after the coldest，Filter and obtain white crystals with cold acetone washing，In low-temperature vacuum drying，Obtain product pyroglutamic acid alcohol 179g，Yield 78% (in terms of pyroglutamic acid ethyl ester feeds intake)，Purity is not less than 98.0% (HPLC)，[a]20=31 (C=2, EtOH)；
By pyroglutamic acid alcohol 100g, p-methyl benzenesulfonic acid monohydrate 16.5g, benzaldehyde 130g, toluene 350g is sequentially added in 2L reaction bulb, being heated to 70～120 DEG C of backflows 4～6h, decompression distillation and concentration evaporates solvent toluene and obtains grease, obtains 40.5g TSSA0200-A through column chromatography purification, HPLC:95%, yield 23%；
Taking TSSA0200-A 30g, add 900ml oxolane, 90g MoOPH is in 2L reaction bulb in addition, nitrogen protection borehole cooling to-40～-50 DEG C; dropping LiHMDS 240g, reacts 6～10h, and quencher is reacted; column chromatography obtains 9.7g TSSA0200-B, HPLC:94.2%, yield: 30%；
Being added in 100ml there-necked flask by TSSA0200-B 5g, nitrogen protection is lower adds 50ml oxolane, is cooled to-15～-20 DEG C; adding 0.8g Lithium Aluminium Hydride, be warming up to room temperature reaction 6～8h, quencher is reacted; column chromatography obtains 1.5g TSSA0200-C, HPLC:97%, yield: 31.7%；
TSSA0200-C 1.5g 30ml ethanol is dissolved, adds in autoclave, add 0.015g palladium charcoal, be passed through hydrogen to 1MPa, react 3h, be filtered to remove palladium charcoal, obtain 0.82g TSSA0200-D, yield: 96.5%；
TEMPO 0.082g is configured to the solution of 20wt%, TSSA0200-D 0.82g is configured to the solution of 10wt%, 5～10min are reacted in pump pumps into silicagel column, obtaining the solution of TSSA0200-D, concentrated crystallization obtains 0.6g L-hydroxyproline, yield 65.4%, confirm collection of illustrative plates as shown in Figure 1, wherein, the length of this silicagel column controls at 30cm, and diameter control is at 60cm.
Above the specific embodiment of the present invention is described.It is to be appreciated that the invention is not limited in above-mentioned particular implementation, those skilled in the art can make various deformation or amendment within the scope of the claims, and this has no effect on the flesh and blood of the present invention.
Claims (10)
1. the preparation method of a L-hydroxyproline, it is characterised in that comprise the steps:
S1: added by glutamic acid in retort, oil bath is heated to 220～290 DEG C, and stirring dehydration, at 130～180 DEG C
React 40～70 minutes under heat-retaining condition, put in water and cool down, be filtrated to get pyroglutamic acid crude product, by described Jiao Gu
Propylhomoserin crude product adds water saturated at 40～70 DEG C, is cooled to 30～40 DEG C and makes it crystallize, and isolates brilliant body detergent
Washing, dries and obtains pyroglutamic acid fine work；
S2: add dehydrated alcohol in flask, is cooled to less than-5 DEG C with cryosel bath, adds catalyst and step S1
In the pyroglutamic acid that obtains, stirring slowly heats up and reacts 24～48 hours in 20～45 DEG C；PH is adjusted extremely with neutralizing alkali
7～8, filtrate is collected by filtration, filtering residue detergent washs, and is concentrated to give crude product with filtrate after being merged by cleaning mixture,
By described crude product distillation purifying under the conditions of 130～150 DEG C/1～2mmHg, obtain pyroglutamic acid ester；
S3: be dissolved in solvent by the pyroglutamic acid ester obtained in step S2, cools to 0～10 DEG C with cryosel bath, stirs
Mixing down and be slowly added to reducing agent, its proportioning is pyroglutamic acid ester: solvent: reducing agent=1mol: 100ml: (2～3)
Mol, at this temperature stirring reaction 6～12 hours, add water after completion of the reaction, and adjust PH to 6～6.5 with neutralizing acid,
It is concentrated to give white flaky crystals, then adds solvent, this crystallization of solvent, filtering solution, filtrate is concentrated,
Obtain pale yellow oil；Add solvent acetone, dissolve this grease, solution is filtered, collect filtrate and concentrate,
Separate out white crystals after cooling, leach crystallization and wash this crystallization with cold acetone, being finally dried, obtain pyroglutamic acid
Alcohol；
S4: after the pyroglutamic acid alcohol obtained in step S3 is mixed with benzaldehyde, under the catalysis of acidic catalyst,
Carry out being condensed dehydration in 70～120 DEG C, obtain compound (3R, 7aS)-3-phenyl nafoxidine also [1,2] oxazole
-5 (3H)-one；
S5: (3R, 7aS)-3-phenyl nafoxidine also [1,2] oxazole-5 (3H) the-one warp that will obtain in step S4
Cross β-Carbonyl group oxidation reaction, carbonyl reduction reaction, catalytic hydrogenation reaction and hydroxyl oxidize reaction, obtain L-hydroxyl
Base proline,
Wherein, the temperature of described β-Carbonyl group oxidation reaction is-40～-50 DEG C.
2. the preparation method of L-hydroxyproline as claimed in claim 1, it is characterised in that institute in step S2
The catalyst stated one in sulphuric acid, thionyl chloride, hydrochloric acid.
3. the preparation method of L-hydroxyproline as claimed in claim 1, it is characterised in that institute in step S3
The reducing agent stated one in sodium borohydride, lithium borohydride.
4. the preparation method of L-hydroxyproline as claimed in claim 1, it is characterised in that institute in step S4
The acidic catalyst stated one in p-methyl benzenesulfonic acid, boron chloride ether, sulfosalicylic acid.
5. the preparation method of L-hydroxyproline as claimed in claim 1, it is characterised in that institute in step S4
The temperature of the condensation dehydration stated is 100 DEG C.
6. the preparation method of L-hydroxyproline as claimed in claim 1, it is characterised in that in step S4,
The mass ratio of described pyroglutamic acid alcohol, benzaldehyde and acidic catalyst is 1: (0.15～1.3): (0.165～0.2).
7. the preparation method of L-hydroxyproline as claimed in claim 6, it is characterised in that described burnt paddy ammonia
The mass ratio of acid alcohol, benzaldehyde and acidic catalyst is 1: 0.8: 0.18.
8. the preparation method of L-hydroxyproline as claimed in claim 1, it is characterised in that institute in step S5
Dehydrogenation agent used by the β stated-Carbonyl group oxidation reaction is selected from hydrofining, sodium hydride, the silica-based Lithamide. of hexamethyl
Kind.
9. the preparation method of L-hydroxyproline as claimed in claim 8, it is characterised in that described dehydrogenation agent
For hydrofining.
10. the preparation method of L-hydroxyproline as claimed in claim 1, it is characterised in that described in step S5
Carbonyl reduction reaction in used reducing agent selected from Lithium Aluminium Hydride or sodium borohydride.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349237A (en) * | 2016-08-15 | 2017-01-25 | 南通普悦生物医药有限公司 | Method for preparing hydrobromic acid teneligliptin |
| CN107245048A (en) * | 2017-06-29 | 2017-10-13 | 河北科技大学 | A kind of preparation method of L hydroxyprolines monocrystalline |
| CN110105258A (en) * | 2019-05-17 | 2019-08-09 | 南通普悦生物医药有限公司 | A kind of method of efficient production L-PROLINE |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294532A (en) * | 2015-12-07 | 2016-02-03 | 四川同晟氨基酸有限公司 | Preparation method of L-hydroxyproline |
-
2016
- 2016-03-10 CN CN201610133099.1A patent/CN105837486A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294532A (en) * | 2015-12-07 | 2016-02-03 | 四川同晟氨基酸有限公司 | Preparation method of L-hydroxyproline |
Non-Patent Citations (2)
| Title |
|---|
| ABDULLAH SALEH ET AL.: ""Synthesis of 3-Guaninyl- and 3-Adeninyl-5-hydroxymethyl-2-pyrrolidinone Nucleosides"", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| YASUMASA HAMADA ET AL.: ""Efficient total synthesis of AI-77-B, a gastroprotective substance from Bacillus pumilus AI-77"", 《TETRAHEDRON》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349237A (en) * | 2016-08-15 | 2017-01-25 | 南通普悦生物医药有限公司 | Method for preparing hydrobromic acid teneligliptin |
| CN107245048A (en) * | 2017-06-29 | 2017-10-13 | 河北科技大学 | A kind of preparation method of L hydroxyprolines monocrystalline |
| CN107245048B (en) * | 2017-06-29 | 2019-10-29 | 河北科技大学 | A kind of preparation method of L- hydroxyproline monocrystalline |
| CN110105258A (en) * | 2019-05-17 | 2019-08-09 | 南通普悦生物医药有限公司 | A kind of method of efficient production L-PROLINE |
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