Abstract:
This invention relates to an improved process for the preparation of substantially pure, stable anhydrous gabapentin. Thus, cyclohexane 1,1-diacetic acid monoamide is first treated with NaOH/NaClO to form 3,3-pentamethylenebutyrolactam, which is treated with aqueous HCl solution under reflux to provide gabapentin HCl salt, which is then neutralized with NaOH followed by a dehydration step to provide substantially pure, storage-stable, pharmaceutical grade gabapentin.

Description:
FIELD OF THE INVENTION 
       [0001]    This invention relates to a chemical process for the production of pharmaceutical grade gabapentin, a very useful therapeutic agent for cerebral disorders with extremely low toxicity in human. 
         [0002]    Benefit of priority to Chinese Applications 200610051909.5 and 200610051910.8, both filed Jun. 12, 2006, is claimed, and the contents of these applications are hereby incorporated by reference in their entirety. 
       BACKGROUND OF THE INVENTION 
       [0003]    Gabapentin, a generic name for 1-(aminomethyl)-1-cyclohexaneacetic acid (I), first disclosed in U.S. Pat. No. 4,024,175 by Warner-Lambert Co., is a very useful therapeutic agent for cerebral disorders with extremely low toxicity in human. 
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         [0000]    There are a number of patented processes for manufacturing this compound. Typical processes are exemplified by U.S. Pat. Nos. 4,024,175, 6,518,456, WO02/34709, WO2004046108, Indian patent 186285, U.S. Pat. Nos. 5,319,135, 5,091,567, and WO 9914184. 
         [0004]    U.S. Pat. Nos. 4,024,175 and 4,087,544 disclosed that gabapentin HCl salt (III) can be prepared by treating cyclohexane 1,1-diacetic acid monoamide (II) with NaOH/NaClO followed by HCl (Scheme 1). Gabapentin was obtained by passing the gabapentin HCl salt through an anion exchange column. However, no yield and purity was reported in these patents. Following similar procedures, except with a cation exchange resin for the last step, WO 02/34709 disclosed a method for the preparation of gabapentin with as much as 80% yield. However, the purity of the product again was not disclosed. These methods require a large amount of solvents for the ion exchange process. 
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         [0005]    A very useful improvement on the process of converting gabapentin HCl salt into gabapentin was disclosed in U.S. Pat. No. 6,518,456, in which gabapentin HCl salt was neutralized with a base, such as NaOH, to the isoelectric point of gabapentin, i.e., pH=7.1-7.2, thus allowing the precipitation and isolation monohydrate via filtration of crude gabapentin monohydrate (Ia) (Scheme 2). The crude gabapentin monohydrate can then be converted to gabapentin in alcohol/ether mixture. This process represents a major advancement for the isolation of gabapentin, avoiding the solvent-consuming ion exchange column chromatography method, although it needed very careful control of the amount and rate of the base added so that the pH of the solution would not fall out of the narrow range of 7.1-7.2. 
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         [0000]    In Indian patent 186,285, cyclohexane 1,1-diacetic acid monoamide (II) was converted into 3,3-pentamethylenebutyrolactam (IV) through the treatment with NaOH/Br 2 , although no yield or purity of the lactam was reported. Subsequently, the lactam IV was converted to gabapentin HCl salt (III), which was turned into gabapentin (I) by slowly neutralizing gabapentin HCl salt (III) with NaOH solution to pH between 7.4-7.8 (Scheme 3) for the isolation of gabapentin (I). The neutralization process needed to be very well controlled and took about 6 hours. WO 2004046108 disclosed an improved process for the first step, reaching a yield as high as 82%. These processes use bromine, a very corrosive chemical, which erodes manufacturing facilities and releases harmful fumes into the working environment, and thus not ideal for industrial scale application. 
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         [0000]    Other processes, exemplified by U.S. Pat. No. 5,091,567, WO 9914184 (Scheme 4), and U.S. Pat. No. 5,319,153 (Scheme 5), require catalytic hydrogenation of intermediates at elevated pressure and sometimes elevated temperatures. 
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       Thus, there remains a need for new and improved methods of manufacturing gabapentin (I) from, e.g., cyclohexane 1,1-diacetic acid monoamide (II), a mass produced feed stock that is mass produced. 
       [0006]    It has been shown that of 3,3-pentamethylenebutyrolactam (IV) can be formed during storage of gabapentin (I) for unknown reasons. The cytotoxicity of IV (LD 50 =300 mg/kg) is much higher than that of gabapentin (I) (LD 50 &gt;8000 mg/Kg) [U.S. Pat. No. 6,054,482]. Therefore, not only the initial content of IV must be controlled at less than 0.5%, but also the formation of IV from gabapentin (I) must be minimized for safety reason. Thus, another needed improvement is to manufacture stable gabapentin (I) under storage conditions. The formation of 3,3-pentamethylenebutyrolactam (IV) is a competing side reaction during the neutralization of gabapentin HCl salt (III) as well as during the dehydration process of gabapentin hydrate. Thus, yet another needed improvemetn is to recover as much 3,3-pentamethylenebutyrolactam (IV) as possible to reduce the loss of useful intermediates and increase the yield of the final product. 
       SUMMARY OF THE INVENTION 
       [0007]    This invention covers an improved process for the preparation of highly pure, stable, anhydrous gabapentin (I) from cyclohexane 1,1-diacetic acid monoamide (II). 
         [0008]    The first aspect of the invention is concerned with a high yielding process for the preparation of 3,3-pentamethylenebutyrolactam (IV) from cyclohexane 1,1-diacetic acid monoamide (II) and hypochlorite in water under basic conditions (step a). The product, IV, is produced in high yield after most of the base has been neutralized with an acid and can be easily separated in pure form from the impurities by either filtration or extracting the crude product with an organic solvent or combination of organic solvents. 
       Step A 
       [0009]    
       
                 
         
             
             
         
       
     
         [0010]    The second step of the invention is concerned with converting 3,3-pentamethylenebutyrolactam (IV) to a gabapentin salt (III) under acidic conditions in water (step b). The unreacted IV may be removed by extraction with an organic solvent or combination of organic solvents and recycled. 
       Step B 
       [0011]    
       
                 
         
             
             
         
       
     
         [0012]    The third step of the invention is concerned with treating gabapentin salt with a base to raise the pH to 8.0-8.5 in a water-C 1 -C 4  alcohol solution to allow the precipitation and isolation of gabapentin hydrate (Ia) (step c). The base used may be any of the inorganic bases such as NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , and KHCO 3 , or combinations thereof. 
       Step C 
       [0013]    
       
                 
         
             
             
         
       
     
         [0014]    The last step of the invention is concerned with converting gabapentin hydrate (Ia) to the corresponding pharmaceutical grade anhydrous form (I) (step d) by subjecting gabapentin hydrate (Ia) to an aqueous-alcoholic solution. 
       Step D 
       [0015]    
       
                 
         
             
             
         
       
     
     
     DETAILED DESCRIPTION OF THE INVENTION 
       [0016]    The instant invention is a high yielding for the preparation of highly pure, stable, anhydrous gabapentin (I) from cyclohexane 1,1-diacetic acid monoamide (II). 
         [0017]    In step (a), cyclohexane 1,1-diacetic acid monoamide (II) was treated with a base and a hypochlorite in aqueous solution at low temperature first, followed by at slightly elevated temperature to complete the Hofmann rearrangement. The excess amount of hypochlorite is then removed by a reducing agent, preferably NaHSO 3 . The pH of the reaction mixture is then lowered with an acid, preferably HCl, to 8-9, particularly 8.2-8.8. The mixture was refluxed for a few hours and then cooled. The pH again is adjusted with acid, preferably HCl, to 8.5±0.5, when necessary. The product is extracted with a non-water miscible organic solvent, preferably toluene or dichloromethane. The organic layer is then evaporated to dryness to provide 3,3-pentamethylenebutyrolactam (IV). The Hofmann rearrangement reaction performed under the conditions specified in the instant invention produces compound IV in very high purity with an over 95% yield, representing a significant improvement over Indian patent 186285 and WO 2004/046108A1, where NaOH/Br 2  were used to manufacture 3,3-pentamethylenebutyrolactam (IV), but only reached as high as 82% yield. 
         [0018]    In step (b), 3,3-pentamethylenebutyrolactam (IV) is treated with an aqueous acid, preferably HCl, at elevated temperature, preferably at reflux temperature, to provide the salt of gabapentin, preferably gabapentin HCl salt. Because of the poor solubility of gabapentin salt, the residual 3,3-pentamethylenebutyrolactam (IV) can be easily removed from the reaction mixture by extraction with a water immiscible organic solvent, preferably toluene and dichloromethane. The gabapentin salt can then be precipitated at low temperature, preferably at 0-5° C. The acidic mother liquor can be used to neutralize base in the previous step or its concentration can be raised by adding fresh, more concentrated acid and reused in this step. 
         [0019]    In step (c), gabapentin salt (III) is mixed with water and the pH of the solution is raised to 4.5-5.0 with a base to dissolve the solid, while the temperature is maintained at 20-30° C. Activated carbon was used to discolor the solution. After the activated carbon is removed by filtration, an alcohol is added to the filtrate and the temperature was lowered, preferably to 0-10° C. The pH is again raised, preferably to 8.0-8.5, with a base, preferably NaOH solution. The temperature is controlled at 0±2° C. to precipitate gabapentin. The solid product, gabapentin monohydrate, is separated via filtration and washed water and alcohol. 
         [0020]    In step (d), gabapentin monohydrate is stirred with a C1-C4 alcohol or alcohol-water mixture, preferably aqueous ethanol solution, most favorably 95% ethanol, at slightly elevated temperature, preferably 30-50° C., for a short period of time, preferably half an hour. Upon cooling, preferably to 0±2° C., and stirring at this temperature for 1 to 5 hours, preferably 1 to 3 hours, most favorably 1 to 2 hours, solid anhydrous gabapentin needles precipitates out and is collected by filtration. A small amount of 3,3-pentamethylenebutyrolactam (IV) formed during this dehydration process stays in the alcoholic mother liquor and can be recovered. 
       EXAMPLES 
       [0021]    The following examples describe the preferred embodiment of the invention and are not intended to limit the scope of the invention. The specification of these examples should only be considered exemplary, with the scope and spirit of the invention being indicated in the claims. 
       Example 1 
       [0022]    3,3-Pentamethylenebutyrolactam (IV). Water (380 mL), 324 g of NaOH solution (30%) were added to a 2000 mL reaction flask. The solution was cooled to 10-20° C. Cyclohexane 1,1-diacetic acid monoamide (II) (160 g) was added. The mixture was stirred until all solid dissolved, and the cooled to 0-15° C. NaClO solution (557 g, 11.3%) was added dropwise. The temperature was slowly raised to 40-50° C. and stirred at this temperature for 3 h. Sodium bisulfite was added to destroy remaining NaClO. The pH was adjusted to 11 to 12 with 31% aqueous HCl solution. The mixture was refluxed (100-105° C.) for 3 hours and then cooled to 50-60° C. The mixture was extracted with toluene. Toluene layer was evaporated to dryness to afford white crystalline 3,3-pentamethylenebutyrolactam (IV), 118 g, Yield: 95.9%; purity, 99.65% (HPLC). 
       Example 2 
       [0023]    3,3-Pentamethylenebutyrolactam (IV). Water (420 L) and 420 kg of NaOH solution (30%) were added to a 2000 L reaction vessel. The solution was cooled to 10-20° C. Cyclohexane 1,1-diacetic acid monoamide (II) (160 kg) was added. The mixture was stirred until all solid dissolved, and the cooled to 0-15° C. NaClO solution (630 kg, 11.3%) was added dropwise at 0-5° C. The temperature was slowly raised to 40-50° C. and stirred at this temperature for 3 h. Sodium bisulfite was added to destroy remaining NaClO and starch-KI paper was used to assure that the excess NaClO was all destroyed. The pH was adjusted to 11 to 12 with 30% aqueous HCl solution. The mixture was refluxed for 3 hours and then distilled and 300 to 400 L of water was distilled. The mixture was cooled to 0-5° C. and centrifuged. White crystalline product was obtained after toluene layer was evaporated the product was dried in vacuo, 115.5 kg, yield: 93.8%; purity, 99.7%, mp: 90-92° C. 
       Example 3 
       [0024]    Gabapentin HCl salt (III). 3,3-Pentamethylenebutyrolactam (IV) (250 g), concentrated HCl (1500 g) and water (300 g) was refluxed for 5 h and cooled to 80-90° C. The mixture was cooled to −5 to 5° C. to precipitate the crude product. The solid was filtered to provide wet gabapentin HCl salt (III), equivalent to 308 g of dry gabapentin HCl salt (the water content was measured with Karl-Fisher method and discounted); yield: 90.9%, purity, 98.5% (HPLC); 3,3-pentamethylenebutyrolactam (IV) content, 0.4%. The HCl concentration of filtrate is about 15-16%, which can be used to neutralize NaOH in the previous step or its HCl concentration can be raised to 22% by adding 36% HCl and reused in this step. 3,3-Pentamethylenebutyrolactam (IV) may also be recovered from this HCl solution (see Example 7). 
       Example 4 
       [0025]    3,3-Pentamethylenebutyrolactam (IV). Water (380 mL), 324 g of NaOH solution (30%) were added to a 2000 mL reaction flask. The solution was cooled to 10-15° C. Cyclohexane 1,1-diacetic acid monoamide (II) (160 g) was added. The mixture was stirred until all solid dissolved, and the cooled to 0-5° C. NaClO solution (557 g, 11.3%) was added dropwise at 0-5° C. The mixture was further stirred for 1.5 h at 5-10° C. The temperature was slowly raised to 35-40° C. in an hour and stirred at this temperature for 2 h. Sodium bisulfite (2-5 g) was added to destroy remaining NaClO. The pH was adjusted to 8.5±0.3 with HCl solution recycled from the hydrolysis of 3,3-pentamethylenebutyrolactam (IV). The mixture was reflux (100-105° C.) for 3 hours and then cooled to 60-65° C. The pH again was adjusted with 31% HCl to 8.5±0.5. The mixture was extracted with toluene (400 mL×2). Toluene layer was evaporated to dryness, to obtain white crystalline 3,3-pentamethylenebutyrolactam (IV), 129 g, Yield: 104.8% (due to the use of recycled HCl, which contained some 3,3-pentamethylenebutyrolactam (IV), the yield is higher than 100%); purity, 99.9% (HPLC). 
       Example 5 
       [0026]    Gabapentin monohydrate (Ia). Purified water (750 mL), gabapentin HCl salt (III) (500 g) were mixed in a 2000 mL flask and stirred for 0.5 h. The pH was adjusted to 4.5-5.0 with 30% NaOH solution while the temperature was maintained at 20-30° C. After the solid all dissolved, the temperature was raised to 25-30° C. Activated carbon (2 g) and silicate (0.5 g) were added and stirred for 0.5 h. The suspension was filtered. Ethanol (95%, 300 mL) was added to the filtrate and the temperature was lowered to 0-5° C. The solid was filtered and washed with water to afford white solid, yield: 85%, purity, 99.5% (HPLC). The content of 3,3-pentamethylenebutyrolactam is less than 0.1%. 3,3-Pentamethylenebutyrolactam (IV) in the filtrate is recovered (see Example 7). 
       Example 6 
       [0027]    Anhydrous gabapentin. Ethanol (95%, 750 g) was heated to 45° C. while being stirred. Gabapentin (350 g) was added and stirred for 0.5 h at 35-40° C. The temperature was slowly lowered to 0±2° C. and stirred at this temperature for 2 h. The solid was filtered by centrifugation and washed with ice cold 95% ethanol. The wet product was dried. Yield: 95%; purity, 99.8%. 3,3-Pentamethylenebutyrolactam (IV) was not detected and the amount of Cl −  was 50 ppm. From the mother liquor, 3,3-pentamethylenebutyrolactam (IV) can be recovered after the alcohol has been distilled off (see Example 7). 
       Example 7 
       [0028]    Recovery of 3,3-pentamethylenebutyrolactam (IV). The pH of the mother liquor obtained from Example 3, 5, or 6 was adjusted with 30% aqueous NaOH solution to 10 to 14. The solution was refluxed for 2 hours. Part of the solvent was removed by distillation. The mixture was cooled to 0 to 5° C. The 3,3-pentamethylenebutyrolactam (IV) was filtered, washed with ice-water, and dried in vacuo. White crystalline product has a purity of 99.5% and can be used directly as starting material for the preparation of gabapentin salt. 
       Example 8 
       [0029]    Accelerated stability studies on gabapentin (I). Accelerated stability studies were carried out as per ICH guidelines at 40±2° C. and 75±5% relative humidity. Accelerated stability studies were carried out on three consecutive batches of final product, gabapentin (I). Six samples each of 10 g were drawn per batch, packed and sealed in double polyethylene bags, kept in cardboard drums, and stored under the following conditions. The analyses were performed at the preset time intervals for purity and impurities. 
       Conditions: 
       [0030]    a) Temperature: 40±2° C.
 
b) Relative humidity: 75±5%
 
c) Interval for analysis: 0, 1, 2, 3, and 6 months
 
d) Total period: 6 months
 
         [0000]                                                                                                  TABLE 1                   Accelerated Stability Data                Impurities            Batch   Time       Water   Purity       Other unknown           Number   (month)   Appearance   content   (wt %)   Compound IV   impurities   Total impurities                    20041201   0   ✓ a     0.03%   100.96%   ND b     0.05%   0.05%           1   ✓   0.02%   100.01%   ND   0.06%   0.06%           2   ✓   0.02%   100.30%   ND   0.05%   0.05%           3   ✓   0.03%   100.41%   ND   0.05%   0.05%           6   ✓   0.03%   99.99%   ND   0.06%   0.06%       20041202   0   ✓   0.02%   101.36%   ND   0.04%   0.04%           1   ✓   0.03%   100.30%   ND   0.04%   0.04%           2   ✓   0.02%   100.28%   ND   0.04%   0.04%           3   ✓   0.02%   101.19%   ND   0.04%   0.04%           6   ✓   0.03%   100.01%   ND   0.05%   0.05%       20041203   0   ✓   0.02%   100.96%   ND   0.06%   0.06%           1   ✓   0.03%   100.30%   ND   0.06%   0.06%           2   ✓   0.03%   100.27%   ND   0.04%   0.04%           3   ✓   0.03%   100.43%   ND   0.05%   0.05%           6   ✓   0.02%   99.84%   ND   0.06%   0.06%               Note:         a The appearance of the sample stayed as white or off-white crystalline powder.         b ND = not detected.            
The test results showed that there are no apparent changes in the samples under the test conditions for up to six months. Therefore, it can be concluded that our product is stable under the accelerated stability test conditions.
 
       Example 9 
       [0031]    Long-term stability studies on gabapentin (I). Long term stability studies were carried out as per ICH guidelines at 25±2° C. and 60±5% relative humidity. The results shall be updated with the annual update. Long-term stability studies were carried out on three consecutive commercial batches. Twelve samples each of 10 g were drawn per batch, packed and sealed in double polyethylene bags, kept in cardboard drums, and stored under the following conditions. The analyses were performed at the preset time intervals for purity and impurities. 
       Conditions: 
       [0032]    a) Temperature: 25±2° C.
 
b) Relative humidity: 65±5%
 
c) Interval for analysis: 0, 3, 6, 9, 12, 18, 24, 36, and 48 months
 
d) Total period: 48 months
 
         [0000]                                                                                                  TABLE 2                   Long-term Stability Study Data                Impurity                Time       Water   Purity       Other unknown   Total       Batch Number   (month)   Appearance   content   (wt %)   Compound IV   impurities   impurities                    20041201   0   ✓ a     0.03%   100.96%   ND b     0.05%   0.05%           3   ✓   0.03%   99.75%   ND   0.06%   0.06%           6   ✓   0.02%   100.33%   ND   0.07%   0.07%           9   ✓   0.03%   100.30%   ND   0.06%   0.06%           12   ✓   0.03%   100.13%   ND   0.03%   0.03%       20041202   0   ✓   0.02%   101.36%   ND   0.04%   0.04%           3   ✓   0.03%   100.08%   ND   0.04%   0.04%           6   ✓   0.02%   100.64%   ND   0.05%   0.05%           9   ✓   0.02%   100.41%   ND   0.04%   0.04%           12   ✓   0.03%   100.00%   ND   0.02%   0.02%       20041203   0   ✓   0.02%   100.96%   ND   0.06%   0.06%           3   ✓   0.03%   99.82%   ND   0.06%   0.06%           6   ✓   0.03%   100.25%   ND   0.07%   0.07%           9   ✓   0.02%   100.12%   ND   0.07%   0.07%           12   ✓   0.02%   100.58%   ND   0.03%   0.03%               Note:         a The appearance of the sample stayed as white or off-white crystalline powder.         b ND = not detected.            
The test results showed that there are no apparent changes in the samples under the test conditions for up to 12 months. Therefore, it can be concluded that our product is stable under the long term stability test conditions for up to 12 months. The long term stability study is still on-going.
 
       REFERENCES 
       [0033]    The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference. 
         [0000]    U.S. Pat. No. 4,024,175
 
U.S. Pat. No. 4,087,544
 
U.S. Pat. No. 5,091,567
 
U.S. Pat. No. 5,319,135
 
U.S. Pat. No. 6,054,482
 
U.S. Pat. No. 6,518,456
 
PCT Appln. WO 02/34709
 
PCT Appln. WO 2004046108
 
PCT Appln. WO 9914184
 
Indian Appln. 186285