High-purity levosalbutamol hydrochloride intermediate and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a high-purity levosalbutamol hydrochloride intermediate III with the structure shown in the specification and a preparation method thereof. Wherein the levosalbutamol hydrochloride intermediate III is prepared by dissolving a crude product in an anhydrous organic solvent, heating, dissolving and clarifying, cooling to-5 to 30 DEG C, and crystallizing. The intermediate is high in purity, almost contains no isomer impurity I difficult to remove, the purity is greater than or equal to 99.9% and even 100.0%, the occurrence of a subsequent byproduct-dexsalbutamol is avoided, the yield is improved, the preparation process is simplified, the production cost is greatly reduced, the production period is greatly shortened, and the intermediate is very suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a high-purity intermediate of levalbuterol hydrochloride and a preparation method thereof. Background Art

[0002] Levalbuterol hydrochloride, with the chemical name of (R)-α - -[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride, and the CAS number is 34391-04-3. Its chemical structural formula is as follows:

[0003]

[0004] Levalbuterol hydrochloride is an adrenergic β2-receptor agonist, developed by Sepracor Inc. in the United States and launched in the United States in 1999 under the trade name Xopenex, and is clinically used for the treatment of bronchial asthma. In addition, clinical studies have shown that levalbuterol hydrochloride has a small dosage, a rapid onset, high efficacy and few adverse reactions. Moreover, in vitro studies have shown that the affinity of levalbuterol for the β2-receptor is 2 times that of the racemate and 100 times that of dextralbuterol; most of the physiological effects in the racemate are provided by levalbuterol, and the pharmacological effect of levalbuterol is 80 times that of dextralbuterol, with better efficacy; dextralbuterol can cause adverse reactions such as headache, dizziness, palpitation and finger tremor, and levalbuterol has fewer side effects than dextralbuterol.

[0005] Currently, in the prior art, the synthesis methods of levalbuterol hydrochloride mainly include asymmetric synthesis method and chemical resolution method. Intermediate III with the following structure is the key intermediate for the preparation of levalbuterol hydrochloride by chemical resolution method:

[0006]

[0007] This key intermediate III usually contains isomeric impurity I with the structure as shown above, and its content will directly affect the content of isomeric impurity dextralbuterol in levalbuterol, thereby affecting the quality and efficacy of levalbuterol. Therefore, it is necessary to remove isomeric impurity I in intermediate III as much as possible. If the method of directly removing isomeric impurity dextralbuterol in levalbuterol is adopted, it is necessary to carry out more than 3 times of purification to control the impurity content to below the limit of 0.2% specified in the United States Pharmacopeia. However, at the same time, a large amount of levalbuterol will be lost in this process, resulting in a significant decrease in the yield of the final chiral product. Therefore, the preparation of high-purity intermediate III of levalbuterol hydrochloride is a crucial and essential link in the whole preparation process.

[0008] At present, there is no report on the high-purity levalbuterol hydrochloride intermediate III and its preparation method in the existing technology. Therefore, in order to obtain a high-purity levalbuterol hydrochloride chiral product, reduce the number of purification steps, improve the yield, and reduce the cost, it is necessary to develop a new high-purity levalbuterol hydrochloride intermediate III and its preparation method to solve the above problems existing in the existing technology. Summary of the Invention

[0009] To solve the above technical problems, the present invention provides a high-purity levalbuterol hydrochloride intermediate III and its preparation method. The content of isomeric impurity I in the levalbuterol hydrochloride intermediate III is ≤0.1%. The preparation method can simply and efficiently reduce the content of isomeric impurity I in the levalbuterol intermediate III from ≥4% to ≤0.1%, and the intermediate purity is ≥99.9%, even 100.0%. Thus, the content of the subsequent by-product, salbutamol, in the finally obtained levalbuterol hydrochloride is greatly reduced, the step of further removing salbutamol is avoided, the yield is improved, the preparation process is simplified, the production cost and cycle are greatly reduced, and it is very suitable for industrial production.

[0010] To achieve the above invention object, the technical solution of the present invention is as follows:

[0011] A levalbuterol hydrochloride intermediate III, wherein the content of isomeric impurity I in the levalbuterol hydrochloride intermediate III is ≤0.1%; wherein, the levalbuterol hydrochloride intermediate III is prepared by dissolving the crude product in an anhydrous organic solvent, heating to dissolve it clearly, and cooling to -5 - 30°C for crystallization. Preferably, the heating temperature is ≥50°C; preferably, the anhydrous organic solvent is selected from any one or a combination of anhydrous N,N-dimethylformamide, anhydrous methanol, anhydrous ethanol, and anhydrous isopropanol.

[0012] Preferably, the levalbuterol hydrochloride intermediate III does not contain isomeric impurity I.

[0013] A preparation method of a levalbuterol hydrochloride intermediate III, comprising the following steps: heating the crude product of the levalbuterol hydrochloride intermediate III to ≥50°C for reflux dissolution in an anhydrous organic solvent, cooling to -5 - 30°C for crystallization within ≥1 h, filtering, and drying to obtain.

[0014] Preferably, the volume ratio of the crude product of the levalbuterol hydrochloride intermediate III to the anhydrous organic solvent is 1:(9 - 60); further preferably, it is 1:(14 - 60).

[0015] Further, the anhydrous organic solvent is preferably any one or a combination of anhydrous N,N-dimethylformamide, anhydrous methanol, anhydrous ethanol, and anhydrous isopropanol; more preferably, the anhydrous organic solvent is a mixture of anhydrous methanol and anhydrous N,N-dimethylformamide or anhydrous methanol.

[0016] In some preferred embodiments, the volume ratio of the crude levosalbutamol hydrochloride intermediate III to the mixture of anhydrous methanol and anhydrous N,N-dimethylformamide is preferably 1:(9 - 30), more preferably 1:(14 - 20), and most preferably 1:(14 - 16). The volume ratio of the crude levosalbutamol hydrochloride intermediate III, anhydrous methanol, and anhydrous N,N-dimethylformamide is 1:(5 - 15):(4 - 15), more preferably 1:10:(4 - 10), still more preferably 1:10:(4 - 6), and most preferably 1:10:6.

[0017] In some preferred embodiments, the anhydrous organic solvent is anhydrous methanol; the volume ratio of the crude levosalbutamol hydrochloride intermediate III to anhydrous methanol is preferably 1:(50 - 60), more preferably 1:(55 - 60).

[0018] Further, according to the preparation method of the above intermediate III, the cooling rate is to cool down within ≥2 h, preferably within 2 - 8 h, and more preferably within 2 - 4 h.

[0019] Further, according to the preparation method of the above intermediate III, the reflux dissolution temperature is 50 - 80°C, preferably 50 - 70°C, and more preferably 50 - 60°C.

[0020] Further, according to the preparation method of the above intermediate III, the crystallization temperature is preferably -5 - 15°C, more preferably 0 - 15°C, still more preferably 0 - 10°C, and most preferably 0 - 5°C.

[0021] Further, according to the preparation method of the above intermediate III, the crystallization time is ≥1 h, preferably 1 - 8 h, and more preferably 3 - 5 h.

[0022] The crude product of the levosalbutamol hydrochloride intermediate III of the present invention can be prepared by subjecting salbutamol sulfate to a condensation reaction with 2,2-dimethylpropane under the catalysis of concentrated sulfuric acid and then further subjecting it to a resolution reaction under the action of a resolution reagent D-DBTA, and preferably can be prepared by the methods in Examples 1 - 5 of WO9942460A1.

[0023] The beneficial effects of the present invention are:

[0024] 1) The levalbuterol hydrochloride intermediate III of the present invention has high purity, contains almost no isomeric impurity I, with a purity of ≥ 99.9%, and even 100.0%. This avoids the appearance of the subsequent by-product, levalbuterol, and the removal steps of levalbuterol are complex and costly.

[0025] 2) The preparation method of the levalbuterol hydrochloride intermediate III of the present invention can simply and efficiently reduce the content of isomeric impurity I from ≥ 4% in the crude product to ≤ 0.1%, avoiding the subsequent step of further removing isomeric levalbuterol, simplifying the whole preparation process, reducing the purification times of the finished product, increasing the yield, greatly reducing the production cost and cycle, and being very suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. The drawings in the following description are only the embodiments of the present invention and do not constitute a limitation on the technical solutions of the present invention.

[0027] Figure 1 It represents the HPLC chromatogram of the content of isomeric impurity I in the crude levalbuterol hydrochloride intermediate III used in the embodiments of the present application;

[0028] Figure 2 It represents the HPLC chromatogram of the content of isomeric impurity I in the high-purity levalbuterol hydrochloride intermediate III prepared in Example 1 of the present application;

[0029] Figure 3 It represents the HPLC chromatogram of the content of isomeric impurity I in the high-purity levalbuterol hydrochloride intermediate III prepared in Example 2 of the present application;

[0030] Figure 4 It represents the HPLC chromatogram of the content of isomeric impurity I in the high-purity levalbuterol hydrochloride intermediate III prepared in Example 3 of the present application. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0031] The following will combine the embodiments of the present application to clearly and completely describe the solutions in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all of the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the protection scope of the present application.

[0032] In the present invention, all volumes are in milliliters and all weights are in grams.

[0033] In the present invention, DMF refers to N,N-dimethylformamide, and THF refers to tetrahydrofuran.

[0034] In the present invention, the resolving agent D-DBTA in the chemical structure of levosalbutamol hydrochloride intermediate III, and the D-DBTA in the chemical structure of levosalbutamol hydrochloride isomer impurity I are both D-(+)-dibenzoyl tartaric acid, and its chemical structure is shown as follows:

[0035]

[0036] Other reagents and raw materials used in the present invention are all commercially available. The crude product of levosalbutamol hydrochloride intermediate III in the present invention can be prepared by the following reaction steps:

[0037]

[0038] Condensation reaction: Add salbutamol sulfate, concentrated sulfuric acid, and 2,2-dimethoxypropane into a reaction kettle for condensation to obtain levosalbutamol hydrochloride intermediate II;

[0039] Resolution reaction: Add levosalbutamol hydrochloride intermediate II and D-DBTA (resolving agent) into a reaction kettle for resolution to obtain the crude product of levosalbutamol hydrochloride intermediate III;

[0040] More specifically, the crude product of levosalbutamol hydrochloride intermediate III can be prepared by the method in Examples 1-5 of WO9942460A1.

[0041] Other reaction raw materials and reaction solvents used in the present invention except for the crude product of levosalbutamol hydrochloride intermediate III are all commercially available.

[0042] The detection method for the content of isomer impurity I in levosalbutamol hydrochloride intermediate III in the present invention is as follows:

[0043] Determined with reference to the high performance liquid chromatography method (General Principles 0512, Volume IV of Chinese Pharmacopoeia 2020 Edition);

[0044] Test solution: Weigh an appropriate amount of this product, dissolve and dilute it with the mobile phase to prepare a solution containing about 0.8 mg per 1 ml;

[0045] System suitability solution: Weigh appropriate amounts of the reference substance of levosalbutamol hydrochloride intermediate III and its enantiomer reference substance, dissolve and dilute them with the mobile phase to prepare a solution containing about 0.8 mg of levosalbutamol hydrochloride intermediate III and 0.008 mg of the enantiomer per 1 ml;

[0046] Chromatographic conditions: Using teicoplanin-bonded silica gel as the packing material (Astec Chirobiotic T, 4.6 mm × 250 mm, 5 μm or a chromatographic column with equivalent performance); the mobile phase is acetonitrile - methanol - acetic acid - triethylamine (50:50:0.3:0.1); the flow rate is 1.0 ml per minute; the detection wavelength is 225 nm; the column temperature is 30 °C; the injection volume is 20 μl.

[0047] After detection, the content of isomer impurity I in the crude product of levosalbutamol hydrochloride intermediate III prepared by the above method is 4.88% (see its HPLC chromatogram in Figure 1 ).

[0048] To enable those skilled in the art to better understand this application, the following is illustrated through multiple specific examples.

[0049] Example 1 Preparation of high-purity levosalbutamol hydrochloride intermediate III

[0050] Add 10 g of the crude product of levosalbutamol hydrochloride intermediate III to a reaction flask, add anhydrous methanol (550 mL), heat to 50 - 70 °C and reflux until dissolved clearly, cool to 0 - 5 °C within 2 - 4 h, keep the temperature for crystallization for 4 h, filter, and dry to obtain 6.4 g of high-purity levosalbutamol hydrochloride intermediate III, with a yield of 64%, and no isomers detected (see its HPLC chromatogram in Figure 2 ).

[0051] Example 2 Preparation of high-purity levosalbutamol hydrochloride intermediate III

[0052] Add 10 g of the crude product of levosalbutamol hydrochloride intermediate III to a reaction flask, add anhydrous DMF (100 mL) and anhydrous methanol (60 mL), heat to 50 - 70 °C and reflux until dissolved clearly, cool to 10 - 15 °C within 2 - 4 h, keep the temperature for crystallization for 4 h, filter, and dry to obtain 6.9 g of high-purity levosalbutamol hydrochloride intermediate III, with a yield of 69%, and no isomers detected (see its HPLC chromatogram in Figure 3 ).

[0053] Example 3 Preparation of high-purity levosalbutamol hydrochloride intermediate III

[0054] Add 10 g of the crude product of levosalbutamol hydrochloride intermediate III to a reaction flask, add anhydrous DMF (100 mL) and anhydrous methanol (60 mL), heat to 50 - 70 °C and reflux until dissolved clearly, cool to 0 - 5 °C within 2 - 4 h, keep the temperature for crystallization for 4 h, filter, and dry to obtain 7.5 g of high-purity levosalbutamol hydrochloride intermediate III, with a yield of 75%, and no isomers detected (see its HPLC chromatogram in Figure 4 ).

[0055] Preparation of High-Purity Levosalbutamol Hydrochloride Intermediate III

[0056] Add 10 g of the crude product of levosalbutamol hydrochloride intermediate III to a reaction flask, add absolute ethanol (600 mL), heat up to 70 - 80 °C and reflux until dissolved clearly, cool down to 0 - 5 °C within 2 - 4 h, keep the temperature for crystallization for 4 h, filter, and dry to obtain 6.7 g of high-purity levosalbutamol hydrochloride intermediate III, with a yield of 67%, and the isomer detected: 0.05%.

[0057] Example 5 Preparation of High-Purity Levosalbutamol Hydrochloride Intermediate III

[0058] Add 10 g of the crude product of levosalbutamol hydrochloride intermediate III to a reaction flask, add absolute isopropanol (500 mL), heat up to 70 - 80 °C and reflux until dissolved clearly, cool down to 0 - 5 °C within 2 - 4 h, keep the temperature for crystallization for 4 h, filter, and dry to obtain 6.5 g of high-purity levosalbutamol hydrochloride intermediate III, with a yield of 65%, and the isomer detected: 0.09%.

[0059] Comparative Example 1 Preparation of High-Purity Levosalbutamol Hydrochloride Intermediate III

[0060] Add 10 g of the crude product of levosalbutamol hydrochloride intermediate III to a reaction flask, add absolute methanol (550 mL), heat up to 50 - 70 °C and reflux until dissolved clearly, then add water (100 mL), cool down to 0 - 5 °C within 2 - 4 h, keep the temperature for crystallization for 4 h, filter, and dry to obtain 8.5 g of high-purity levosalbutamol hydrochloride intermediate III, with a yield of 85%, and the isomer: 1.02%.

[0061] Comparative Example 2 Preparation of High-Purity Levosalbutamol Hydrochloride Intermediate III

[0062] Add 10 g of the crude product of levosalbutamol hydrochloride intermediate III to a reaction flask, add absolute acetonitrile (500 mL), heat up to 70 - 80 °C and reflux until dissolved clearly, cool down to 0 - 5 °C within 2 - 4 h, keep the temperature for crystallization for 4 h, filter, and dry to obtain 5.8 g of high-purity levosalbutamol hydrochloride intermediate III, with a yield of 58%, and the isomer detected: 0.28%.

[0063] Comparative Example 3 Preparation of High-Purity Levosalbutamol Hydrochloride Intermediate III

[0064] Add 10 g of the crude product of levosalbutamol hydrochloride intermediate III to a reaction flask, add absolute THF (200 mL) and absolute methanol (100 mL), heat up to 50 - 70 °C and reflux until dissolved clearly, cool down to 0 - 5 °C within 2 - 4 h, keep the temperature for crystallization for 4 h, filter, and dry to obtain 7.6 g of high-purity levosalbutamol hydrochloride intermediate III, with a yield of 76%, and the isomer: 0.11%.

[0065] The yields, purities, and isomer impurities I of the highly pure levalbuterol hydrochloride intermediate III obtained from the above Examples 1-5 and Comparative Examples 1-3 were compared and the following results were obtained:

[0066] Table 1

[0067]

[0068]

[0069] According to the results in Table 1, when the preparation conditions of Examples 1-3 were adopted, the test results were the best and isomer impurity I was not detected; the whole preparation process was simple in operation, the solvents were easy to obtain, inexpensive, and the results were stable, which was very suitable for industrial production.

[0070] Screening test

[0071] Screening of the types of organic solvents in the preparation method of highly pure intermediate III in Screening Example 1

[0072] Among them, the following screening tests numbered 1-12 were the same as Example 1 above in other reaction steps and reaction conditions except for the types of organic solvents. The results are shown in the following table:

[0073] Serial number Type of organic solvent Yield Isomer content Phenomena and problems 1 Anhydrous methanol 64％ Not detected - 2 Anhydrous methanol and water 85％ 1.02％ Isomer content > 1% 3 Anhydrous DMF and anhydrous methanol 75％ Not detected - 4 Anhydrous THF and anhydrous methanol 76％ 0.11％ Isomer content > 0.1% 5 Anhydrous ethanol 67％ 0.05％ - 6 Anhydrous ethanol and water 79％ 1.58％ Isomer content > 1% 7 Anhydrous DMF and anhydrous ethanol 75％ 0.35％ Isomer content > 0.1% 8 Anhydrous isopropanol 65％ 0.09％ - 9 Anhydrous isopropanol and water 79％ 1.37％ Isomer content > 1% 10 Anhydrous DMF and anhydrous isopropanol 69％ 0.13％ Isomer content > 0.1% 11 Anhydrous acetonitrile 58％ 0.28％ Isomer content > 0.1% 12 Anhydrous DMF - - No crystal precipitation

[0074] Conclusion: The test results showed that when the preparation solvents were anhydrous methanol, anhydrous DMF, and anhydrous methanol, the preparation results were the best and isomer impurity I was not detected; when the preparation solvents were anhydrous ethanol and anhydrous isopropanol, the preparation results were acceptable and isomer impurity I was detected but the content ≤ 0.1%.

[0075] Screening of the purification methods in the preparation method of highly pure intermediate III in Screening Example 2

[0076] Among them, the following screening tests numbered 1-3 were the same as Example 1 above in other reaction steps and reaction conditions except for the purification methods; the following screening tests numbered 4-5 were the same as Example 3 above in other reaction steps and reaction conditions except for the purification methods;

[0077] The screening results are shown in the following table:

[0078]

[0079] Conclusion: The test results showed that when the crystallization method was to first heat to reflux until clear and then slowly cool to crystallize, the preparation results were the best and isomer impurity I was not detected.

[0080] Screening of the volume ratio of organic solvent to crude product in the preparation method of highly pure intermediate III in Screening Example 3

[0081] Among them, for the screening tests numbered 1-3 below, except for the different volume ratios of the organic solvent to the crude product, other reaction steps and reaction conditions are the same as those in Example 1 above; for the screening tests numbered 4-6 below, except for the different volume ratios of the organic solvent to the crude product, other reaction steps and reaction conditions are the same as those in Example 3 above;

[0082]

[0083]

[0084] Conclusion: The test results show that when the organic solvent is anhydrous methanol and the volume ratio of the crude product of Intermediate III to anhydrous methanol is 1:(50-60), the preparation result is acceptable, and isomeric impurity I is detected but the content ≤ 0.1%; when the volume ratio of the crude product of Intermediate III to anhydrous methanol is 1:(55-60), the preparation result is the best and isomeric impurity I is not detected. When the organic solvents are anhydrous DMF and anhydrous methanol and the volume ratio of the crude product of Intermediate III to anhydrous methanol and anhydrous DMF is 1:10:(4-10), the preparation result is acceptable, and isomeric impurity I is detected but the content ≤ 0.1%; when the volume ratio of the crude product of Intermediate III to anhydrous methanol and anhydrous DMF is 1:10:(4-6), the preparation result is the best and isomeric impurity I is not detected.

[0085] Screening of the crystallization temperature in the preparation method of high-purity Intermediate III in Screening Example 4

[0086] Among them, for the screening tests numbered 1-4 below, except for the different crystallization temperatures, other reaction steps and reaction conditions are the same as those in Example 1 above; for the screening tests numbered 5-8 below, except for the different crystallization temperatures, other reaction steps and reaction conditions are the same as those in Example 3 above;

[0087]

[0088]

[0089] Conclusion: The test results show that when the crystallization temperature is -5-15°C, the preparation result is acceptable, and isomeric impurity I is detected but the content ≤ 0.1%; when the crystallization temperature is 0-15°C, the preparation result is the best and isomeric impurity I is not detected.

[0090] The above is only the preferred implementation mode of the present invention. It should be noted that for those skilled in the art of this technology, without departing from the principle of the present invention, several improvements and refinements can still be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. Levosalbutamol Hydrochloride Intermediate III with the following structural formula, characterized in that the content of isomeric impurity I with the above structural formula in the Levosalbutamol Hydrochloride Intermediate III is ≤ 0.1%; wherein, the Levosalbutamol Hydrochloride Intermediate III is prepared by dissolving the crude product in an anhydrous organic solvent, heating to dissolve clearly, and cooling to -5 - 30 °C for crystallization.

2. The Levosalbutamol Hydrochloride Intermediate III according to claim 1, wherein The Levosalbutamol Hydrochloride Intermediate III does not contain isomeric impurity I.

3. A preparation method of levalbuterol hydrochloride intermediate III with the following structural formula, characterized in that, It includes the following steps: Heat the crude product of Levosalbutamol Hydrochloride Intermediate III to reflux and dissolve clearly at ≥ 50 °C in an anhydrous organic solvent, cool to -5 - 30 °C for crystallization within ≥ 1 h, filter, and dry to obtain; preferably, the volume ratio of the crude product of Levosalbutamol Hydrochloride Intermediate III to the anhydrous organic solvent is 1:(9 - 60).

4. The method for preparing intermediate III according to claim 3, wherein The anhydrous organic solvent is any one or a combination of anhydrous N,N - dimethylformamide, anhydrous methanol, anhydrous ethanol, and anhydrous isopropanol; preferably, the anhydrous organic solvent is a mixture of anhydrous methanol and anhydrous N,N - dimethylformamide or anhydrous methanol.

5. The method for preparing intermediate III according to claim 4, characterized in that, The volume ratio of the crude product of Levosalbutamol Hydrochloride Intermediate III to the mixture of anhydrous methanol and anhydrous N,N - dimethylformamide is 1:(9 - 30); or, the volume ratio of the crude product of Levosalbutamol Hydrochloride Intermediate III, anhydrous methanol, and anhydrous N,N - dimethylformamide is 1:(5 - 15):(4 - 15).

6. The preparation method of Intermediate III according to any one of claims 1-5, characterized in that, The anhydrous organic solvent is anhydrous methanol; preferably, the volume ratio of the crude product of Levosalbutamol Hydrochloride Intermediate III to anhydrous methanol is 1:(50 - 60).

7. The preparation method of Intermediate III according to any one of claims 1-6, characterized in that, The cooling rate is to cool within 2 - 4 h.

8. The method for preparing intermediate III according to any one of claims 1-6, characterized in that, The reflux and dissolution temperature rises to 50 - 70 °C.

9. The preparation method of intermediate III according to any one of claims 1-6, characterized in that, The crystallization temperature is -5 - 15 °C.

10. The method for preparing Intermediate III according to any one of claims 1-6, characterized in that, The crystallization time is 1 - 8 h.

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