CN102336697A

CN102336697A - Synthetic method for (2S,4S)-4-hydroxyproline

Info

Publication number: CN102336697A
Application number: CN201110192951XA
Authority: CN
Inventors: 柴宗曦; 李建东; 田苗
Original assignee: LANZHOU CHENXI BIO-TECHNOLOGY CO LTD
Current assignee: LANZHOU CHENXI BIO-TECHNOLOGY CO LTD
Priority date: 2011-07-12
Filing date: 2011-07-12
Publication date: 2012-02-01

Abstract

The invention provides a synthetic method for (2S,4S)-4-hydroxyproline, which belongs to the technical field of organic synthesis. The method comprises the following steps: (1) with (2S,4S)-4-hydroxyproline I as a raw material, carrying out carboxyl esterification so as to obtain II; (2) reacting Cbz-ous [(N-benzyloxycarbonyloxy)succinimide] with II to obtain nitrogen-protected III; (3) carrying out carboxyl esterification on III so as to obtain IV; (4) hydrolyzing ester groups of IV to obtain V; (5) removing Cbz groups from V so as to obtain VI, that is, (2S,4S)-4-hydroxyproline. The (2S,4S)-4-hydroxyproline prepared by the synthetic method in the invention has high purity and high yield; cost for raw materials used in the method is low; a few organic reagents are used, and little pollution and environmental protection are obtained.

Description

A kind of (2S, 4S)-the 4-Hydroxyproline compound method

Technical field

The present invention relates to a kind of organic cpds compound method.

Background technology

(2S, 4S)-4-Hydroxyproline is the midbody of a kind of very important medicine, agricultural chemicals and other chemicaladditivess.At present; Domestic also do not have industriallization to generate (2S; 4S)-technology of 4-Hydroxyproline; All be in theoretical investigation and laboratory development through most companies of data base querying such as Baidu library, Google, Chongqing dimension are general, cause shortcomings such as the synthesis technique productive rate is underground, purity is low, power consumption is big, cost height, and can't continue amplification and carry out suitability for industrialized production.

Summary of the invention

The technical problem that the present invention will solve is the defective that overcomes existing compound method, provide that a kind of productive rate is high, purity is high (2S, 4S)-4-Hydroxyproline suitability for industrialized production synthetic route.

In order to solve the problems of the technologies described above, the invention provides following technical scheme:

A kind of (2S, 4S)-the 4-Hydroxyproline compound method, step is following,

(1) so that (2S 4R)-the 4-Hydroxyproline I is a raw material, carries out carboxyl esterification and gets II; (2) Cbz-ous (N-benzyl succinimdyl carbonate) and II react the III of nitrogen protection; (3) III is carried out hydroxy esterification and is got IV; (4) the IV ester hydrolysis gets V; (5) V is sloughed the basic VI that gets of Cbz.

Further, in the step (1), I and methanol solvate are at SOCl ₂Effect down, ice bath carries out carboxyl esterification, reaction finish the back concentrate II, SOCl ₂With the mol ratio of I be 1: (1～2).Preferably, SOCl ₂With the mol ratio of I be 1: (1.3～1.7).

In the step (2), II is at Et ₃Under N and methylene dichloride, trichloromethane or the Acetyl Chloride 98Min. solvency action, ice bath, with the Cbz-ous reaction, spissated III, the mol ratio of II and Cbz-ous are 1: (1.0～1.2).Preferably, the mol ratio of II and Cbz-ous is 1: (1.05～1.15).

In the step (3), III is in toluene or YLENE, diisopropyl azodiformate, at PPh ₃Under the effect, ice bath generates IV with acetic acidreaction, and concentrated, crystallization gets IV, III and diisopropyl azodiformate, PPh ₃Mol ratio be 1: (1.2～1.8).Preferably, III and diisopropyl azodiformate, PPh ₃Mol ratio be 1: (1.4～1.6).

In the step (4), IV is in low-alcohol solution, and under sodium hydroxide or potassium hydroxide solution effect, hydrolysis generates V, and concentrated, crystallization gets V, and the mol ratio of IV and sodium hydroxide is 1: (3～4).Said lower alcohol is methyl alcohol, ethanol, Virahol etc.

In the step (5), under Pd/C catalysis, hydro-reduction gets VI.

Raw materials cost of the present invention is lower, all is kind common on the market, and raw materials quality meets corresponding national standards and gets final product; No particular requirement uses organic reagent few simultaneously, pollutes little; Environmental protection through the laboratory lab scale, gets into the pilot scale scale-up stage; Research and development and optimization through to synthesis technique can significantly reduce production costs; Internal price is lacked part company again up to more than 20 ten thousand yuan of per kilograms mostly at 30,000 yuan/kilogram at present, and the present invention produced (2S, 4S)-the 4-Hydroxyproline price is 2.4 ten thousand yuan/kilogram.

Description of drawings

Accompanying drawing is used to provide further understanding of the present invention, and constitutes the part of specification sheets, is used to explain the present invention with embodiments of the invention, is not construed as limiting the invention.In the accompanying drawings:

Fig. 1 be production of the present invention (2S, 4S)-the 4-Hydroxyproline process flow sheet;

Fig. 2 be the present invention produce (2S, 4S)-the nucleus magnetic resonance figure of 4-Hydroxyproline;

Fig. 3 is the purity liquid chromatographic detection figure that the present invention produces (2S, 48)-4-Hydroxyproline.

Embodiment

Below in conjunction with accompanying drawing the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for explanation and explains the present invention, and be not used in qualification the present invention.

Used experiment supplementary material of this embodiment and reagent are commercially available, particularly:

Raw material:

(2S, 4R)-4-Hydroxyproline, purity 98.0% molecular formula: C ₅H ₉NO ₃, molecular weight 131.13, white plates crystallinity or crystalline powder are the unique sweet taste in the bitter taste, can improve the flavor matter of the local flavor of nectar, refreshment drink etc.Flavour is arranged, can make perfume material.274 ℃ of fusing points (decomposition), (25 ℃, 36.1%) soluble in water are slightly soluble in ethanol.

Auxiliary material:

SOCl ₂(THIONYL CHLORIDE 97), molecular weight: 118.97 proterties: colourless to pale yellow or light red fuming liquid, the smell of suffocating is arranged, high refractivity is arranged, can be miscible with benzene, chloroform and tetrachloro, fusing point-104.5 ℃, 76 ℃ of boiling points, refractive index 1.517.

Et ₃N (triethylamine), molecular formula: C ₆H ₁₅N relative molecular mass 101.19 colourless liquids can be miscible with ethanol, ether and the water below 18.7 ℃, is slightly soluble in the water more than 18.7 ℃, specific density 0.7255, fusing point-115 ℃.89～90 ℃ of boiling points, refractive index 1.4003, flash-point (closed-cup)-6 ℃, inflammable, medium poison is corrosive.

PPh ₃(triphenylphosphine), molecular formula: C ₁₈H ₁₅P, outward appearance and proterties: white or light yellow plate crystal, molecular weight: 262.30, flash-point: 180 ℃/open cup; Fusing point: 79～82 ℃, boiling point: 377 ℃, solvability: water insoluble; Be slightly soluble in ethanol, be dissolved in benzene, acetone, tetracol phenixin, density: specific density (water=1) 1.32; Specific density (air=1) 9.0 white crystals, purity 99%.

Cbz-ous (N-benzyl succinimdyl carbonate), molecular formula: C ₁₂H ₁₁NO ₅, molecular weight: 249.2226, white or off-white color crystalline powder, content:>=99%.

DIAD (diisopropyl azodiformate), molecular formula: C ₈H ₁₄N ₂O ₄, molecular weight: 202.21, density 1.02, fusing point 3-5 ℃, 75 ℃ of boiling points (0.2mmHg), specific refractory power 1.418-1.422,106 ℃ of flash-points.

Common agents: NaHCO ₃, Na ₂SO ₄, methyl alcohol, salt solution etc. (required) according to experiment.

Laboratory apparatus: 2L, 3L, 5L single port bottle, the 20L bottle of answering back, magnetic agitation, TM, ice bath and oil bath system, Rotary Evaporators, condensing crystal system, suction filtration system etc.

With the listed proportioning of table 1, by the present invention's step shown in Figure 1 synthetic (2S, 4S)-4-Hydroxyproline, the yield of each embodiment is as shown in the table:

Be example with embodiment 1 below, specify compound method of the present invention:

1, II is synthetic

Operation steps:

(1) in 3L single port bottle, adds I, 1.5L methyl alcohol, the ice bath cooling

(2) temperature begins to drip SOCl below 10 ℃ the time ₂, temperature control makes temperature be no more than 50 ℃

(3) wait to dropwise the back oil bath, temperature rising reflux, reaction is spent the night;

Aftertreatment: with system directly concentrate II, yield (promptly 100%) is disregarded in reaction.

2, III is synthetic

Operation steps:

In the 5L there-necked flask, add II, Et ₃N and 1.8L DCM (methylene dichloride) stir, frozen water dissolving cooling, and temperature control slowly adds Cbz-ous (N-benzyl succinimdyl carbonate) below 20 ℃, the reaction stirred overnight;

Aftertreatment: add 1L moisture liquid and handle, the back uses 2N salt acid elution to be acidity to water PH, adds saturated NaHCO ₃Wash salt washing, Na ₂SO ₄Drying, concentrate III, yield exceeds theoretical amount, in 100%.

3, IV is synthetic

Operation steps:

(1) in 3L single port bottle, adds III, 1L toluene, PPh ₃Ice bath is cooled to below 5 ℃

(2) begin to splash into toluene, DIAD in the time of below the temperature to 5 ℃

(3) dropwise, changing oil to bathe is warming up to about 40 ℃, and reaction is spent the night;

Aftertreatment: the suction filtration white solid is abandoned it, and mother liquor concentrates and steams toluene.Use EA: PE=1 then: 5 crystallizations, suction filtration again, mother liquor concentrates, IV, yield exceeds theoretical amount, by 100%.

4, V is synthetic

Operation steps:

, 20L adds IV in answering back bottle, methyl alcohol and 1N aqueous sodium hydroxide solution stirring reaction 3-4 hour;

Aftertreatment: system is concentrated, suction filtration, filter cake is abandoned it, and extracting impurities is to only containing small amount of impurities under alkaline condition, and acid adjustment is used the EA extraction product to there being a large amount of white solids to separate out (pH=1-2), the saturated common salt water washing, NaSO4 is dry, concentrates.Add EA: pH=1: 8 crystallization gained filter cakes are used EA: PE=1 again: 3 washings, dry to such an extent that white-yellowish solid V 160 restrains (yield is 56.5%).

5, VI is synthetic

Operation steps:

In 2L single port bottle, add V, Pd/C, ventilation add H ₂, about reaction 18h, (note: bleed once every separated half a hour);

Aftertreatment: elimination Pd/C, mother liquor concentrates, and the gained solid with EA washing 3 times, is washed 2 times with methyl alcohol again, gets finished product VI 92.1g (yield is 93.3%).

Embodiment 1 products therefrom is carried out magnetic resonance detection (deuterochloroform is a solvent), and spectrogram is as shown in Figure 2, wherein, NMR (CDCl3,400MHZ) δ: 2.13 (m, 1H), 2.35 (m, 1H), 3.37 (m, 2H), 4.05 (m, 1H), 4.44 (m, 1H); The liquid chromatogram explanation products obtained therefrom purity of Fig. 3 is greater than 94% (testing conditions, moving phase: methyl alcohol (100%), wavelength: 254nm, sample size: 10ul, flow: 1ml/min).

What should explain at last is: the above is merely the preferred embodiments of the present invention; Be not limited to the present invention; Although the present invention has been carried out detailed explanation with reference to previous embodiment; For a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.All within spirit of the present invention and principle, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.

Claims

1. one kind (2S, 4S)-the 4-Hydroxyproline compound method, it is characterized in that: step is following,

(1) so that (2S 4R)-the 4-Hydroxyproline I is a raw material, carries out carboxyl esterification and gets II; (2) N-benzyl succinimdyl carbonate and II react the III of nitrogen protection; (3) III is carried out hydroxy esterification and is got IV; (4) the IV ester hydrolysis gets V; (5) V is sloughed the basic VI that gets of Cbz.

It is 2. according to claim 1 that a kind of (2S, 4S)-the 4-Hydroxyproline compound method, it is characterized in that: in the said step (1), I and methanol solvate are at SOCl ₂Effect down, ice bath carries out carboxyl esterification, reaction finish the back concentrate II, SOCl ₂With the mol ratio of I be 1: (1～2).

3. according to claim 2 a kind of (2S 4S)-the 4-Hydroxyproline compound method, is characterized in that: in the said step (1), SOCl ₂With the mol ratio of I be 1: (1.3～1.7).

It is 4. according to claim 1 that a kind of (2S, 4S)-the 4-Hydroxyproline compound method, it is characterized in that: in the said step (2), II is at Et ₃Under N and methylene dichloride, trichloromethane or the Acetyl Chloride 98Min. solvency action, ice bath, with the reaction of N-benzyl succinimdyl carbonate, spissated III, the mol ratio of II and Cbz-ous N-benzyl succinimdyl carbonate is 1: (1.0～1.2).

It is 5. according to claim 4 that a kind of (2S, 4S)-the 4-Hydroxyproline compound method, it is characterized in that: in the said step (2), the mol ratio of II and Cbz-ous is 1: (1.05～1.15).

It is 6. according to claim 1 that a kind of (2S 4S)-the 4-Hydroxyproline compound method, is characterized in that: in the said step (3), III is in toluene or YLENE, diisopropyl azodiformate, at PPh ₃Under the effect, ice bath generates IV with acetic acidreaction, and concentrated, crystallization gets IV, III and diisopropyl azodiformate, PPh ₃Mol ratio be 1: (1.2～1.8).

7. according to claim 6 a kind of (2S 4S)-the 4-Hydroxyproline compound method, is characterized in that: in the said step (3), III and diisopropyl azodiformate, PPh ₃Mol ratio be 1: (1.4～1.6).

8. a kind of (2S according to claim 1; 4S)-and the 4-Hydroxyproline compound method, it is characterized in that: in the said step (4), IV is in low-alcohol solution; Under sodium hydroxide or potassium hydroxide solution effect; Hydrolysis generates V, and concentrated, crystallization gets V, and the mol ratio of IV and sodium hydroxide is 1: (3～4).

It is 9. according to claim 1 that a kind of (2S, 4S)-the 4-Hydroxyproline compound method, it is characterized in that: in the said step (5), under Pd/C catalysis, hydro-reduction gets VI.