CN101863821B - Method for preparing chiral hydrazine by taking chiral proline ester as raw material - Google Patents

Abstract

The invention provides a method for preparing chiral hydrazine by using chiral proline ester as raw material. The method uses chiral proline ester or its hydrochloride as raw material, Boc protects the N on the tetrahydropyrrole ring in the chiral proline ester, and then uses Grignard reagent to attack the ester group to obtain the tertiary alcohol. The Boc on the N is removed at the same time, and the obtained salt is directly nitrated with a metal nitrite to obtain an N-nitroso compound, the tertiary alcohol is alkylated with an alkyl halide, and finally the N-nitroso is reduced by LiAlH4 to obtain the target chiral hydrazine. The method is simple in operation, mild in conditions, low in equipment requirements, can better meet the requirements of large-scale preparation, and the total yield is comparable to that reported in literature.

Description

A kind of method that takes chiral proline ester as raw material to prepare chiral hydrazine

technical field

The invention belongs to the technical field of chemical industry. In particular, it relates to a preparation method of chiral hydrazine. the

Background technique

The ortho-chirality of carbonyl groups is a key structural feature of many natural active substances, so the formation of carbon-carbon bonds or carbon-heteroatom bonds adjacent to carbonyl groups in a regio-enantioselective manner is one of the important processes in organic synthesis. The Enders research group obtained a class of widely used chiral auxiliaries by using chiral proline as raw material. SAMP and RAMP were first applied to the asymmetric synthesis of the carbonyl ortho-position, reacting with carbonyl compounds to obtain chiral hydrazones, deprotonated under the action of strong bases such as LDA, and electrophilic reagents attacked to obtain diastereomers, and then the chiral hydrazones It is cleaved and reduced to obtain the corresponding ortho-chiral carbonyl compound; in this process, the chiral hydrazine can be regenerated and recycled. If aldehyde is used as the starting material, cleavage under different conditions can give aldehyde, nitrile, amine, etc. Chiral hydrazone is easy to prepare and crack, which also makes chiral hydrazine a chiral resolution reagent for racemates containing carbonyl groups. the

SAMP and RAMP did not get satisfactory results in asymmetric synthesis as auxiliary agents. Considering the greater steric hindrance effect, SADP, SAEP, SAPP and RADP, RAEP, RAPP and other chiral hydrazines were designed to strengthen the asymmetric synthesis. Stereochemical control. the

The synthetic methods of chiral hydrazines such as SADP, SAEP, and SAPP come from Enders D. (see Bull.Soc.Chim.Belg., 1988, 97(8-9), 691-704.), and its route is:

Reagents and reaction conditions: (a) 1. MeOH, SOCl ₂ ; 2. O-benzyl-N, N′-dicyclohexylisourea, Et ₃ N. (b) RMgX, Et ₂ O. (c) NaH, CH ₃ I, THF. (d) 10% Pd/C, H ₂ , EtOH. (e) t-BuONO, THF. (f) LiAlH ₄ , THF.

In this route, using L-proline as raw material, the first step is to prepare L-proline methyl ester, and then react with O-benzyl-N, N'-dicyclohexylisourea to obtain (S)-1-benzyl Proline methyl ester, O-benzyl-N, N'-dicyclohexylisourea is prepared from dicyclohexylcarbodiimide (DCC) and benzyl alcohol, which adds a one-step reaction, and the product needs to be purified by vacuum distillation at the same time, and the yield is not high; The fourth step uses palladium-carbon catalytic hydrogenation to remove the benzyl group. It is difficult to complete the reaction under normal pressure for 48 hours. It needs to be separated and purified, and the yield cannot reach the literature value. The high-pressure hydrogenation device can increase the yield, but it has certain risks. ; The fifth step of nitrosation reaction uses isobutyl nitrite (t-BuONO), which has a low boiling point, is irritating and toxic, and has a higher cost. the

Contents of the invention

The purpose of the present invention is exactly to provide a kind of process simple, low-cost method for large-scale preparation of chiral hydrazine with chiral proline ester as raw material in view of the present situation of above-mentioned prior art. the

One, technical scheme of the present invention is made up of following steps successively:

1. Using chiral proline esters as raw materials, use Boc to protect the N on the tetrahydropyrrole ring in the chemical structure of chiral proline esters to obtain compound 1, namely:

2. Use Grignard reagent to attack the ester group in the chemical structure of compound 1 to obtain compound 2, namely:

3. Remove Boc on N in the chemical structure of compound 2 under acidic conditions to obtain compound 3, namely:

4. Directly use metal nitrite to nitrosate compound 3 to obtain compound 4, namely:

5. Alkylation of the tertiary alcohol in the chemical structure of compound 4 with alkyl halides gives compound 5, namely:

6. Use LiAlH ₄ to reduce the N-nitroso group in the structure of compound 5 to obtain chiral hydrazine, namely:

In practical application, the present invention can:

1. Reaction of chiral proline ester with (Boc) ₂ O under the action of excess Et ₃ N to obtain chiral 1-Boc-proline ester, namely compound 1;

2. Add the ether solution of compound 1 dropwise directly to the ether solution of slightly excess Grignard reagent R"MgX, and attack the ester group on the chemical structure of compound 1 from the R" in the chemical structure of the Grignard reagent to obtain a tertiary alcohol compound, namely compound 2;

3. Compound 2 is placed in an organic solution of hydrogen chloride (HCl), and the Boc on the N in the chemical structure is removed to obtain a salt of tetrahydropyrrole, that is, compound 3;

4. Put compound 3 into metal nitrite and make it nitrosate in acidic aqueous solution to obtain the N-nitroso compound, namely compound 4;

5. Put compound 4 under NaH, and make the hydroxyl group on the tertiary alcohol in its chemical structure be alkylated by R”’X to obtain compound 5;

6. Put compound 5 in THF and reduce the nitroso group in its chemical structure with LiAlH ₄ to obtain chiral hydrazine.

In the above steps: the chiral proline ester can be directly replaced by its hydrochloride; the ether solution of compound 1 can be directly replaced by its THF solution; the organic solution of hydrogen chloride (HCl) can be directly replaced by CF ₃ CO ₂ H and its solution; THF can be directly replaced by ether. R' = methyl, ethyl, etc.; R" = methyl, ethyl, propyl, phenyl, etc.; R"' = methyl, ethyl, benzyl, etc.; hydrogen chloride organic solution = ethyl acetate, ether , THF, methanol, ethanol, etc.

Two, the synthetic route of the present invention is:

That is, starting from a commercially available chiral proline ester or its hydrochloride, Boc protects the N on the tetrahydropyrrole ring in the proline ester to obtain compound 1, and then uses a Grignard reagent to attack the ester group to obtain a tertiary alcohol Compound 2, remove Boc on N under the action of acid to obtain salt 3, directly nitrate with metal nitrite to obtain N-nitroso compound 4, alkylate tertiary alcohol with haloalkane to obtain compound 5, and finally N-nitroso The target chiral hydrazine 6 was obtained by reduction with LiAlH ₄ . During the reaction, the chiral carbon does not change.

Three, the present invention has the following advantages:

Proline ester is liquid, and commercially available is basically proline ester hydrochloride, and the present invention both can use chiral proline ester, also can use its hydrochloride as raw material, and raw material is cheap and easy to get; Adopt Boc replaces benzyl to protect the N on tetrahydropyrrole, proline ester is slightly excess than (Boc) ₂ O, after the reaction is completed, wash with dilute acid to remove excess raw materials, and directly enter the next step without purification; use HCl The organic solution of CF ₃ CO ₂ H and its solution to remove Boc on N, compared with palladium carbon hydrogenation debenzylation, the operation is simple, the risk is small, the equipment requirements are low, and the reaction is complete; the salt after Boc removal is directly used Metal nitrite is nitrosated in acidic aqueous solution. Compared with isobutyl nitrite, which has a low boiling point, is irritating and toxic, it has low cost and simple operation. The total yield of the invention is about 50%, which is equivalent to that reported in the literature, but the raw materials are easy to obtain, the operation is simple, the dangerous raw materials and dangerous reactions are reduced, and it can be applied to large-scale industrial production.

Description of drawings

Accompanying drawing is the synthetic scheme diagram of the present invention. In the figure: 1-compound 1, 2-compound 2, 3-compound 3, 4-compound 4, 5-compound 5, 6-chiral hydrazine. the

Specific implementation method

Below with chiral L-proline methyl ester hydrochloride as raw material, the specific embodiment of preparing chiral hydrazine is further introduced as follows to the present invention:

1. Preparation of compound 1, i.e. (S)-1-Boc-proline methyl ester:

L-proline methyl ester hydrochloride (102.7g, 0.62mol) and (Boc) ₂ O (130.8g, 0.6mol) were added to CH ₂ Cl ₂ (500mL), cooled to 0°C in an ice-salt bath, and stirred vigorously _Et3N (251 mL, 2.4 mol) was added dropwise. After the addition was completed, it was raised to room temperature and stirred overnight. The solvent and excess Et ₃ N were distilled off, and the residue was added with EtOAc (500 mL) and H ₂ O (500 mL), stirred and separated. The EtOAc layer was washed with 0.5M HCl (100 mL×3), saturated NaHCO ₃ (100 mL×3) and brine (100 mL), dried over anhydrous Na ₂ SO ₄ , and evaporated to dryness under reduced pressure. After further drying, a colorless liquid, compound 1 (132.8 g, 93.4%) was obtained. R _f = 0.58 (EtOAc-petroleum ether, 1:3); [α] _D ²⁰ = -57.9° (c = 1.65, CH ₂ Cl ₂ ).

2. Preparation of compound 2, i.e. (S)-1-Boc-2-(1-hydroxyl-1-methylethyl)tetrahydropyrrole:

CH ₃ MgI (1.00 mol) was dissolved in dry Et ₂ O (400 mL), cooled to 0° C. in an ice-salt bath, and a solution of compound 1 (91.8 g, 0.40 mol) in dry Et ₂ O (200 mL) was added dropwise under vigorous stirring. After reacting at 0° C. for 1 h, the reaction solution was warmed to room temperature and stirred for 2 h. After the reaction solution was cooled to 0°C, it was quenched by dropping saturated NH ₄ Cl solution, the organic phase was separated, and the aqueous phase was extracted with Et ₂ O (300 mL×2). The combined organic phases were washed with saturated NaHCO ₃ (200 mL×3) and brine (200 mL), dried over anhydrous Na ₂ SO ₄ , and the solvent was evaporated to give a white solid, compound 2 (85.4 g, 93.1%). mp 72-73°C; _Rf = 0.51 (EtOAc-petroleumether, 1:3); [α] _D ²⁰ = -86.5° (c = 1.11, CH ₂ Cl ₂ ).

3. Preparation of compound 3, i.e. (S)-2-(1-hydroxyl-1-methylethyl)tetrahydropyrrole hydrochloride:

Compound 2 (84.0 g, 0.366 mol) was dissolved in EtOAc (300 mL), and HCl (0.55 mol/L) in EtOAc (200 mL) was added dropwise with stirring, and stirred overnight. Nitrogen was introduced to remove excess HCl, and evaporated to dryness under reduced pressure to obtain a white solid, compound 3 (yield nearly 100%). mp 146-147°C; [α] _D ²⁰ =-11.3° (c=2.02, MeOH).

4. Preparation of compound 4, i.e. (S)-1-nitroso-2-(1-hydroxyl-1-methylethyl)tetrahydropyrrole:

Compound 3 (0.366 mol) was dissolved in H ₂ O (400 mL), stirred, and a solution of NaNO ₂ (51.0 g, 0.732 mol) in H ₂ O (200 mL) was added dropwise at 70°C. During the dropwise addition, the reaction solution was acidified with 3M hydrochloric acid to keep the pH=4-5. After the addition was completed, the reaction was continued at 70°C for 3h. The reaction solution was cooled to 20 °C, saturated with NaCl, and extracted with EtOAc (400 mL×3). The combined EtOAc layers were washed with saturated NaHCO ₃ (200 mL) and brine (200 mL), dried over anhydrous Na ₂ SO ₄ , and the solvent was evaporated to give a yellow viscous liquid, compound 4 (47.8 g, 82.6%). R _f =0.43 (EtOAc-petroleum ether, 1:1), 0.22 (EtOAc-petroleum ether, 1:3); [α] _D ²⁰ =-290.9° (c=1.06, CH ₂ Cl ₂ ).

5. Preparation of compound 5, i.e. (S)-1-nitroso-2-(1-methoxy-1-methylethyl)tetrahydropyrrole:

Compound 4 (40 g, 0.252 mol) and iodomethane (23.6 mL, 0.380 mol) were dissolved in dry THF (400 mL), stirred, and NaH (55% suspended in mineral oil, 16.5 g, 0.380 mol) was added in portions. After stirring at room temperature for 1 h, it was heated to reflux for 3 h. After cooling to room temperature, the reaction was quenched by dropwise addition of saturated NH ₄ Cl solution. The organic phase was separated and the aqueous phase was extracted with EtOAc (100 mL x 2). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ , evaporated to dryness, and distilled under reduced pressure to obtain compound 5 (37.1 g, 85.5%) as a yellow liquid. R _f = 0.53 (EtOAc-petroleum ether, 1:3); [α] _D ²⁰ = -159.6° (c = 1.89, CH ₂ Cl ₂ ).

6. Prepare chiral hydrazine 6, i.e. SADP:

LiAlH ₄ (15.2g, 0.400mol) was dissolved in anhydrous THF (100mL), cooled to 0°C in an ice-salt bath, protected by Ar, and a THF (100mL) solution of compound 5 (35.0g, 0.203mol) was carefully added dropwise under vigorous stirring, After the addition, the temperature was raised to reflux until the reaction was complete (TLC detection). Excess _LiAlH4 was decomposed by adding 20% KOH aqueous solution at 0 °C. After hydrolysis, the reaction liquid was refluxed for 15 minutes, and suction filtered while it was hot. The precipitate was extracted with THF (100mL×2) under reflux and stirring conditions, and the extract was filtered while hot. The filtrates were combined, dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure. Distillation under reduced pressure gave a colorless liquid, chiral hydrazine 6 (26.0 g, 80.9%). [α] _D ²⁰ = -13.5° (c = 1.04, CH ₂ Cl ₂ ).

Claims (3)

1. one kind is the method for feedstock production chiral hydrazine with the chiral proline ester, it is characterized in that being made up of following steps in sequence:

1) with the chiral proline ester is raw material; With the N on the Pyrrolidine ring in the proline ester chemical structure of Boc protection chirality; Obtain compound 1, that is:

2) obtain compound 2 with the ester group in Grignard reagent attack compound 1 chemical structure, that is:

3) under acidic conditions, slough the Boc on the N in compound 2 chemical structures; Obtain compound 3, that is:

4) directly use metal nitrite nitrosification compound 3; Obtain compound 4, that is:

5) with the tertiary alcohol in haloalkane alkylated compound 4 chemical structures; Obtain compound 5, that is:

6) use LiAlH ₄N-nitroso-group in reducing compound 5 structures obtains chiral hydrazine, that is:

In the above-claimed cpd: R '=methyl, ethyl; R ' '=methyl, ethyl, propyl group, phenyl; R ' ' '=methyl, ethyl, benzyl.

2. according to claim 1 a kind of be the method for feedstock production chiral hydrazine with the chiral proline ester, it is characterized in that:

1) described compound 1 is at excessive Et by chiral proline ester ₃Under the N effect, with (Boc) ₂The O reaction obtains the 1-Boc-proline ester of chirality;

2) described compound 2 is that ethereal solution by compound 1 directly is added drop-wise to excessive slightly Grignard reagent R " in the ethereal solution of MgX, by the R in the Grignard reagent chemical structure " tertiary alcohol compound that obtains of ester group in attack compound 1 chemical structure;

3) described compound 3 is a salt of under the organic solution effect of hydrogenchloride (HCl), being sloughed the Pyrrolidine that the Boc on the N obtains in its chemical structure by compound 2;

4) described compound 4 is directly with the metal nitrite N-nitroso compound that nitrosification obtains in acidic aqueous solution with compound 3;

5) described compound 5 is under NaH, to use R " ' hydroxyl in X alkylated compound 4 chemical structures on the tertiary alcohol obtains;

6) described hand hydrazine 6 be compound 5 in THF through LiAlH ₄The nitroso-group in its chemical structure of reducing obtains.

3. according to claim 1 a kind of be the method for feedstock production chiral hydrazine with the chiral proline ester, it is characterized in that:

1) described compound 1 is at excessive Et by the chiral proline ester hydrochloride ₃Under the N effect, with (Boc) ₂The O reaction obtains the 1-Boc-proline ester of chirality;

2) described compound 2 is that THF solution by compound 1 directly is added drop-wise to excessive slightly Grignard reagent R " in the THF solution of MgX, by the R in the Grignard reagent chemical structure " tertiary alcohol compound that obtains of ester group on attack compound 1 chemical structure;

3) described compound 3 is at CF by compound 2 ₃CO ₂Slough the salt of the Pyrrolidine that the Boc on the N obtains in its chemical structure under H and the solution effects thereof;

4) described compound 4 is directly with the metal nitrite N-nitroso compound that nitrosification obtains in acidic aqueous solution with compound 3;

5) described compound 5 is under NaH, to use R " ' hydroxyl in X alkylated compound 4 chemical structures on the tertiary alcohol obtains;

6) described hand hydrazine 6 be compound 5 in ether through LiAlH ₄The nitroso-group in its chemical structure of reducing obtains.

Images